Sarcoidosis is a multisystem inflammatory disease of unclear etiology that primarily affects the lungs. It can occur at any age but usually develops before the age of 50 years, with an initial peak incidence at 20 to 29 years and a second peak incidence after 50 years of age, especially among women in Scandinavia and Japan.¹ Sarcoidosis affects men and women of all racial and ethnic groups throughout the world, but differences based on race, sex, and geography are noted.¹

The highest rates are reported in northern European and African-American individuals, particularly in women.^1,2 The adjusted annual incidence of sarcoidosis among African Americans is approximately 3 times that among White Americans³ and is more likely to be chronic and fatal in African Americans.³ The disease can be familial with a possible recessive inheritance mode with incomplete penetrance.⁴ Risk of sarcoidosis in monozygotic twins appears to be 80 times greater than that in the general population, which supports genetic factors accounting for two-thirds of disease susceptibility.⁵

Likely factors in the development of sarcoidosis

The exact cause of sarcoidosis is unknown, but we have insights into its pathogenesis and potential triggers.^1,6-9 Genes involved are being identified: class I and II human leukocyte antigen (HLA) molecules are most consistently associated with risk of sarcoidosis. Environmental exposures can activate the innate immune system and precondition a susceptible individual to react to potential causative antigens in a highly polarized, antigen-specific Th1 immune response. The epithelioid granulomatous response involves local proinflammatory cytokine production and enhanced T-cell immunity at sites of inflammation.¹⁰ Granulomas generally form to confine pathogens, restrict inflammation, and protect surrounding tissue.^11-13

Sarcoidosis is a diagnosis of exclusion; one must rule out infections, occupational or environmental exposures, malignancies, and other disorders that cause granulomatous inflammation.

ACCESS (A Case Control Etiologic Study of Sarcoidosis) identified several environmental exposures such as chemicals used in the agriculture industry, mold or mildew, and musty odors at work.¹⁴ Tobacco use was not associated with sarcoidosis.¹⁴ Recent studies have shown positive associations with service in the US Navy,¹⁵ metal working,¹⁶ firefighting,¹⁷ the handling of building supplies,¹⁸ and onsite exposure while assisting in rescue efforts at the World Trade Center disaster.¹⁹ Other data support the likelihood that specific environmental exposures associated with microbe-rich environments modestly increase the risk of sarcoidosis.¹⁴ Mycobacterial and propionibacterial DNA and RNA are potentially associated with sarcoidosis.²⁰

Clinical manifestations are nonspecific

The diagnosis of sarcoidosis can be difficult and delayed due to diverse organ involvement and nonspecific presentations. TABLE 1^21-31 shows the diverse manifestations in a patient with suspected sarcoidosis. Around 50% of the patients are asymptomatic.^23,24 Sarcoidosis is a diagnosis of exclusion, starting with a detailed history to rule out infections, occupational or environmental exposures, malignancies, and other possible disorders (TABLE 2).²²

Diagnostic work-up

The primary objective of a diagnostic evaluation in most suspected cases of sarcoidosis is to corroborate the clinical and radiologic features with pathologic evidence of non-necrotizing granulomas and to exclude other causes of granulomatous inflammation.²²

Radiologic studies

Chest x-ray (CXR) provides diagnostic and prognostic information in the evaluation of sarcoidosis using the Scadding classification system (FIGURE 1).^21,25,32,33 Interobserver variability, especially between stages II and III and III and IV is the major limitation of this system.³² At presentation, radiographs are abnormal in approximately 90% of patients.³⁴ Lymphadenopathy is the most common radiographic abnormality, occurring in more than two-thirds of cases, and pulmonary opacities (nodules and reticulation) with a middle to upper lobe predilection are present in 20% to 50% of patients.^1,31,35 The nodules vary in size and can coalesce and cause alveolar collapse, thus producing consolidation.³⁶ Linear opacities radiating laterally from the hilum into the middle and upper zones are characteristic in fibrotic disease.

Continue to: High-resoluton computed tomography

High-resolution computed tomography (HRCT). Micronodules in a perilymphatic distribution with upper lobe predominance combined with subcarinal and symmetrical hilar lymph node enlargement is practically diagnostic of sarcoidosis in the right clinical context. TABLE 3^21,23,25,32 and FIGURE 2^21,23,25,32 summarize the common CT chest findings of sarcoidosis.

Advanced imaging such as (18)F-fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) are used in specialized settings for advanced pulmonary, cardiac, or neurosarcoidosis.

Tissue biopsy

Skin lesions (other than erythema nodosum), eye lesions, and peripheral lymph nodes are considered the safest extrapulmonary locations for biopsy.^21,25 If pulmonary infiltrates or lymphadenopathy are present, or if extrapulmonary biopsy sites are not available, then flexible bronchoscopy with biopsy is the mainstay for tissue sampling.²⁵

Bronchoalveolar lavage (BAL), transbronchial biopsy (TBB), endobronchial biopsy (EBB), and endobronchial ultrasound (EBUS) are invaluable modalities that have reduced the need for open lung biopsy. BAL in sarcoidosis can show lymphocytosis > 15% (nonspecific) and a CD4:CD8 lymphocyte ratio > 3.5 (specificity > 90%).^21,22 TBB is more sensitive than EBB; however, sensitivity overall is heightened when both of them are combined. The advent of EBUS has increased the safety and efficiency of needle aspiration of mediastinal lymph nodes. Diagnostic yield of EBUS (~80%) is superior to that with TBB and EBB (~50%), especially in stage I and II sarcoidosis.³⁷ The combination of EBUS with TBB improves the diagnostic yield to ~90%.³⁷

The decision to obtain biopsy samples hinges on the nature of clinical and radiologic findings (FIGURE 3).^22,25,26

Continue to: Laboratory studies

Multiple abnormalities may be seen in sarcoidosis, and specific lab tests may help support a diagnosis of sarcoidosis or detect organ-specific disease activity (TABLE 4).^22,23,25,38 However, no consistently accurate biomarkers exist for use in clinical practice. An angiotensin-converting enzyme (ACE) level greater than 2 times the upper limit of normal may be helpful; however, sensitivity remains low, and genetic polymorphisms can influence the ACE level.²⁵ Biomarkers sometimes used to assess disease activity are serum interleukin-2 receptor, neopterin, chitotriosidase, lysozyme, KL-6 glycoprotein, and amyloid A.²¹

Additional tests to assess specific features or organ involvement

Pulmonary function testing (PFT) is reviewed in detail below under “pulmonary sarcoidosis.”

Electrocardiogram (EKG)/transthoracic echocardiogram (TTE). EKG abnormalities—conduction disturbances, arrhythmias, or nonspecific ST segment and T-wave changes—are the most common nonspecific findings.³⁰ TTE findings are also nonspecific but have value in assessing cardiac chamber size and function and myocardial involvement. TTE is indeed the most common screening modality for sarcoidosis-associated pulmonary hypertension (SAPH), which is definitively diagnosed by right heart catheterization (RHC). Further evaluation for cardiac sarcoidosis can be done with cardiac MRI or fluorodeoxyglucose PET in specialized settings.

Lumbar puncture (LP) may reveal lymphocytic infiltration in suspected neurosarcoidosis, but the finding is nonspecific and can reflect infection or malignancy. Oligoclonal bands may also be seen in about one-third of neurosarcoidosis cases, and it is imperative to rule out multiple sclerosis.²⁸

Pulmonary sarcoidosis

Pulmonary sarcoidosis accounts for most of the morbidity, mortality, and health care use associated with sarcoidosis.^39,40

Continue to: Pathology of early and advanced pulmonary sarcoidosis

Pathology of early and advanced pulmonary sarcoidosis

Sarcoidosis is characterized by coalescing, tightly clustered, nonnecrotizing granulomas in the lung (FIGURE 4), most often located along the lymphatic routes of the pleura, interlobular septa, and bronchovascular bundles.⁴¹ Granulomas contain epithelioid cells or multinucleated giant cells surrounded by a chronic lymphocytic infiltrate. Typically, intracytoplasmic inclusions, such as Schaumann bodies, asteroid bodies, and blue bodies of calcium oxalates are noted within giant cells.

In chronic disease, lymphocytic infiltrate vanishes and granulomas tend to become increasingly fibrotic and enlarge to form hyalinized nodules rich with densely eosinophilic collagen. In 10% to 30% of cases, the lungs undergo progressive fibrosis.⁴⁰ Nonresolving inflammation appears to be the major cause of fibrosis and the peribronchovascular localization leading to marked bronchial distortion.

Clinical features, monitoring, and outcomes

Pulmonary involvement occurs in most patients with sarcoidosis, and subclinical pulmonary disease is generally present, even when extrathoracic manifestations predominate.²³ Dry cough, dyspnea, and chest discomfort are the most common symptoms. Chest auscultation is usually unremarkable. Wheezing is more common in those with fibrosis and is attributed to airway-centric fibrosis.⁴² There is often a substantial delay between the onset of symptoms and the diagnosis of pulmonary sarcoidosis, as symptoms are nonspecific and might be mistaken for more common pulmonary diseases, such as asthma or chronic bronchitis.⁴³

Since sarcoidosis can affect pulmonary parenchyma, interstitium, large and small airways, pulmonary vasculature, and respiratory muscles, the pattern of lung function impairment on PFT varies from normal to obstruction, restriction, isolated diffusion defect, or a combination of these. The typical physiologic abnormality is a restrictive ventilatory defect with a decreased diffusing capacity of the lung for carbon monoxide (DLCO). Extent of disease seen on HRCT correlates with level of restriction.⁴⁴ Airway obstruction can be multifactorial and due to airway distortion (more likely to occur in fibrotic lung disease) and luminal disease.^45-48 The 6-minute walk test and DLCO can also aid in the diagnosis of SAPH and advanced parenchymal lung disease.

While monitoring is done clinically and with testing (PFT and imaging) as needed, the optimal approach is unclear. Nevertheless, longitudinal monitoring with testing may provide useful management and prognostic information.⁴⁰ Pulmonary function can remain stable in fibrotic sarcoidosis over extended periods and actually can improve in some patients.⁴⁹ Serial spirometry, particularly forced vital capacity, is the most reliable tool for monitoring; when a decline in measurement occurs, chest radiography can elucidate the mechanism.^50,51

Continue to: Because sarcoidosis is a multisystem disease...

Because sarcoidosis is a multisystem disease, caution needs to be exercised when evaluating a patient’s new or worsening respiratory symptoms to accurately determine the cause of symptoms and direct therapy accordingly. In addition to refractory inflammatory pulmonary disease, airway disease, infection, fibrosis, and SAPH, one needs to consider extrapulmonary involvement or complications such as cardiac or neurologic disease, musculoskeletal disease, depression, or fatigue. Adverse medication effects, deconditioning, or unrelated (or possibly related) disorders (eg pulmonary embolism) may be to blame.

Determining prognosis

Prognosis of sarcoidosis varies and depends on epidemiologic factors, clinical presentation, and course, as well as specific organ involvement. Patients may develop life-threatening pulmonary, cardiac, or neurologic complications. End-stage disease may require organ transplantation for eligible patients.

Most patients with pulmonary sarcoidosis experience clinical remission with minimal residual organ impairment and a favorable long-term outcome. Advanced pulmonary disease (known as APS) occurs in a small proportion of patients with sarcoidosis but accounts for most of the poor outcomes in sarcoidosis.⁴⁰ APS is variably defined, but it generally includes pulmonary fibrosis, SAPH, and respiratory infection.

One percent to 5% of patients with sarcoidosis die from complications, and mortality is higher in women and African Americans.⁵² Mortality and morbidity may be increasing.⁵³ The reasons behind these trends are unclear but could include true increases in disease incidence, better detection rates, greater severity of disease, or an aging population. Increased hospitalizations and health care use might be due to organ damage from granulomatous inflammation (and resultant fibrosis), complications associated with treatment, and psychosocial effects of the disease/treatment.

Management

Management consists primarily of anti-­inflammatory or immunosuppressive therapies but can also include measures to address specific complications (such as fatigue) and organ transplant, as well as efforts to counter adverse medication effects. Other supportive and preventive measures may include, on a case-by-case basis, oxygen supplementation, vaccinations, or pulmonary rehabilitation. Details of these are found in other, more in-depth reviews on treatment; we will briefly review anti-inflammatory therapy, which forms the cornerstone of treatment in most patients with sarcoidosis.

Continue to: General approach to treatment decisions

General approach to treatment decisions. Anti-inflammatory therapy is used to reduce granulomatous inflammation, thereby preserving organ function and reducing symptoms. A decision to begin treatment is one shared with the patient and is based on symptoms and potential danger of organ system failure.⁵⁴ Patients who are symptomatic or have progressive disease or physiologic impairment are generally candidates for treatment. Monitoring usually suffices for those who have minimal symptoms, stable disease, and preserved organ function.

Patients with pulmonary sarcoidosis at CXR stage 0 should not receive treatment, given that large, randomized trials have shown no meaningful benefit and that these patients have a high likelihood of spontaneous remission and excellent long-term prognosis.^55-58 However, a subgroup of patients classified as stage 0/I on CXR may show parenchymal disease on HRCT,⁵⁹ and, if more symptomatic, could be considered for treatment. For patients with stage II to IV pulmonary sarcoidosis with symptoms, there is good evidence that treatment may improve lung function and reduce dyspnea and fatigue.^57,60-62

Corticosteroids are first-line treatment for most patients. Based on expert opinion, treatment of pulmonary sarcoidosis is generally started with oral prednisone (or an equivalent corticosteroid). A starting dose of 20 to 40 mg/d generally is sufficient for most patients. If the patient responds to initial treatment, prednisone dose is tapered over a period of months. If symptoms worsen during tapering, the minimum effective dose is maintained without further attempts at tapering. Treatment is continued for at least 3 to 6 months but it might be needed for longer durations; unfortunately, evidence-based guidelines are lacking.⁶³ Once the patient goes into remission, close monitoring is done for possible relapses. Inhaled corticosteroids alone have not reduced symptoms or improved lung function in patients with pulmonary sarcoidosis.^64-66

Steroid-sparing agents are added for many patients. For patients receiving chronic prednisone therapy (≥ 10 mg for > 6 months), steroid-sparing agents are considered to minimize the adverse effects of steroids or to better control the inflammatory activity of sarcoidosis. These agents must be carefully selected, and clinical and laboratory monitoring need to be done throughout therapy. TABLE 5^58,64,67-81shows the major anti-inflammatory treatment agents used for sarcoidosis.

The management might be complicated for extrapulmonary, multi-organ, and advanced sarcoidosis (advanced pulmonary sarcoidosis, cardiac disease, neurosarcoidosis, lupus pernio, etc) when specialized testing, as well as a combination of corticosteroids and steroid-sparing agents (with higher doses or prolonged courses), might be needed. This should be performed at an expert sarcoidosis center, ideally in a multidisciplinary setting involving pulmonologists and/or rheumatologists, chest radiologists, and specialists as indicated, based on specific organ involvement.

Continue to: Research and future directions

Research and future directions

Key goals for research are identifying more accurate biomarkers of disease, improving diagnosis of multi-organ disease, determining validated endpoints of clinical trials in sarcoidosis, and developing treatments for refractory cases.

There is optimism and opportunity in the field of sarcoidosis overall. An example of an advancement is in the area of APS, as the severity and importance of this phenotype has been better understood. Worldwide registries and trials of pulmonary vasodilator therapy (bosentan, sildenafil, epoprostenol, and inhaled iloprost) in patients with SAPH without left ventricular dysfunction are promising.^82-85 However, no benefit in survival has been shown.

RioSAPH is a double-blind, placebo-controlled trial of Riociguat (a stimulator of soluble guanylate cyclase) for SAPH (NCT02625558) that is closed to enrollment and undergoing data review. Similarly, results of the phase IV study of pirfenidone, an antifibrotic agent that was shown to decrease disease progression and deaths in idiopathic pulmonary fibrosis,⁸⁶ are awaited in the near future.

Other potential directions being explored are multicenter patient registries and randomized controlled trials, analyses of existing databases, use of biobanking, and patient-centered outcome measures. Hopefully, the care of patients with sarcoidosis will become more evidence based with ongoing and upcoming research in this field.

CORRESPONDENCE
Rohit Gupta, MBBS, FCCP, 3401 North Broad Street, 7 Parkinson Pavilion, Philadelphia, PA 19140; [email protected]

Sarcoidosis is a multisystem inflammatory disease of unclear etiology that primarily affects the lungs. It can occur at any age but usually develops before the age of 50 years, with an initial peak incidence at 20 to 29 years and a second peak incidence after 50 years of age, especially among women in Scandinavia and Japan.¹ Sarcoidosis affects men and women of all racial and ethnic groups throughout the world, but differences based on race, sex, and geography are noted.¹

The highest rates are reported in northern European and African-American individuals, particularly in women.^1,2 The adjusted annual incidence of sarcoidosis among African Americans is approximately 3 times that among White Americans³ and is more likely to be chronic and fatal in African Americans.³ The disease can be familial with a possible recessive inheritance mode with incomplete penetrance.⁴ Risk of sarcoidosis in monozygotic twins appears to be 80 times greater than that in the general population, which supports genetic factors accounting for two-thirds of disease susceptibility.⁵

Likely factors in the development of sarcoidosis

The exact cause of sarcoidosis is unknown, but we have insights into its pathogenesis and potential triggers.^1,6-9 Genes involved are being identified: class I and II human leukocyte antigen (HLA) molecules are most consistently associated with risk of sarcoidosis. Environmental exposures can activate the innate immune system and precondition a susceptible individual to react to potential causative antigens in a highly polarized, antigen-specific Th1 immune response. The epithelioid granulomatous response involves local proinflammatory cytokine production and enhanced T-cell immunity at sites of inflammation.¹⁰ Granulomas generally form to confine pathogens, restrict inflammation, and protect surrounding tissue.^11-13

Sarcoidosis is a diagnosis of exclusion; one must rule out infections, occupational or environmental exposures, malignancies, and other disorders that cause granulomatous inflammation.

ACCESS (A Case Control Etiologic Study of Sarcoidosis) identified several environmental exposures such as chemicals used in the agriculture industry, mold or mildew, and musty odors at work.¹⁴ Tobacco use was not associated with sarcoidosis.¹⁴ Recent studies have shown positive associations with service in the US Navy,¹⁵ metal working,¹⁶ firefighting,¹⁷ the handling of building supplies,¹⁸ and onsite exposure while assisting in rescue efforts at the World Trade Center disaster.¹⁹ Other data support the likelihood that specific environmental exposures associated with microbe-rich environments modestly increase the risk of sarcoidosis.¹⁴ Mycobacterial and propionibacterial DNA and RNA are potentially associated with sarcoidosis.²⁰

Clinical manifestations are nonspecific

The diagnosis of sarcoidosis can be difficult and delayed due to diverse organ involvement and nonspecific presentations. TABLE 1^21-31 shows the diverse manifestations in a patient with suspected sarcoidosis. Around 50% of the patients are asymptomatic.^23,24 Sarcoidosis is a diagnosis of exclusion, starting with a detailed history to rule out infections, occupational or environmental exposures, malignancies, and other possible disorders (TABLE 2).²²

Diagnostic work-up

The primary objective of a diagnostic evaluation in most suspected cases of sarcoidosis is to corroborate the clinical and radiologic features with pathologic evidence of non-necrotizing granulomas and to exclude other causes of granulomatous inflammation.²²

Radiologic studies

Chest x-ray (CXR) provides diagnostic and prognostic information in the evaluation of sarcoidosis using the Scadding classification system (FIGURE 1).^21,25,32,33 Interobserver variability, especially between stages II and III and III and IV is the major limitation of this system.³² At presentation, radiographs are abnormal in approximately 90% of patients.³⁴ Lymphadenopathy is the most common radiographic abnormality, occurring in more than two-thirds of cases, and pulmonary opacities (nodules and reticulation) with a middle to upper lobe predilection are present in 20% to 50% of patients.^1,31,35 The nodules vary in size and can coalesce and cause alveolar collapse, thus producing consolidation.³⁶ Linear opacities radiating laterally from the hilum into the middle and upper zones are characteristic in fibrotic disease.

Continue to: High-resoluton computed tomography

High-resolution computed tomography (HRCT). Micronodules in a perilymphatic distribution with upper lobe predominance combined with subcarinal and symmetrical hilar lymph node enlargement is practically diagnostic of sarcoidosis in the right clinical context. TABLE 3^21,23,25,32 and FIGURE 2^21,23,25,32 summarize the common CT chest findings of sarcoidosis.

Advanced imaging such as (18)F-fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) are used in specialized settings for advanced pulmonary, cardiac, or neurosarcoidosis.

Tissue biopsy

Skin lesions (other than erythema nodosum), eye lesions, and peripheral lymph nodes are considered the safest extrapulmonary locations for biopsy.^21,25 If pulmonary infiltrates or lymphadenopathy are present, or if extrapulmonary biopsy sites are not available, then flexible bronchoscopy with biopsy is the mainstay for tissue sampling.²⁵

Bronchoalveolar lavage (BAL), transbronchial biopsy (TBB), endobronchial biopsy (EBB), and endobronchial ultrasound (EBUS) are invaluable modalities that have reduced the need for open lung biopsy. BAL in sarcoidosis can show lymphocytosis > 15% (nonspecific) and a CD4:CD8 lymphocyte ratio > 3.5 (specificity > 90%).^21,22 TBB is more sensitive than EBB; however, sensitivity overall is heightened when both of them are combined. The advent of EBUS has increased the safety and efficiency of needle aspiration of mediastinal lymph nodes. Diagnostic yield of EBUS (~80%) is superior to that with TBB and EBB (~50%), especially in stage I and II sarcoidosis.³⁷ The combination of EBUS with TBB improves the diagnostic yield to ~90%.³⁷

The decision to obtain biopsy samples hinges on the nature of clinical and radiologic findings (FIGURE 3).^22,25,26

Continue to: Laboratory studies

Multiple abnormalities may be seen in sarcoidosis, and specific lab tests may help support a diagnosis of sarcoidosis or detect organ-specific disease activity (TABLE 4).^22,23,25,38 However, no consistently accurate biomarkers exist for use in clinical practice. An angiotensin-converting enzyme (ACE) level greater than 2 times the upper limit of normal may be helpful; however, sensitivity remains low, and genetic polymorphisms can influence the ACE level.²⁵ Biomarkers sometimes used to assess disease activity are serum interleukin-2 receptor, neopterin, chitotriosidase, lysozyme, KL-6 glycoprotein, and amyloid A.²¹

Additional tests to assess specific features or organ involvement

Pulmonary function testing (PFT) is reviewed in detail below under “pulmonary sarcoidosis.”

Electrocardiogram (EKG)/transthoracic echocardiogram (TTE). EKG abnormalities—conduction disturbances, arrhythmias, or nonspecific ST segment and T-wave changes—are the most common nonspecific findings.³⁰ TTE findings are also nonspecific but have value in assessing cardiac chamber size and function and myocardial involvement. TTE is indeed the most common screening modality for sarcoidosis-associated pulmonary hypertension (SAPH), which is definitively diagnosed by right heart catheterization (RHC). Further evaluation for cardiac sarcoidosis can be done with cardiac MRI or fluorodeoxyglucose PET in specialized settings.

Lumbar puncture (LP) may reveal lymphocytic infiltration in suspected neurosarcoidosis, but the finding is nonspecific and can reflect infection or malignancy. Oligoclonal bands may also be seen in about one-third of neurosarcoidosis cases, and it is imperative to rule out multiple sclerosis.²⁸

Pulmonary sarcoidosis

Pulmonary sarcoidosis accounts for most of the morbidity, mortality, and health care use associated with sarcoidosis.^39,40

Continue to: Pathology of early and advanced pulmonary sarcoidosis

Pathology of early and advanced pulmonary sarcoidosis

Sarcoidosis is characterized by coalescing, tightly clustered, nonnecrotizing granulomas in the lung (FIGURE 4), most often located along the lymphatic routes of the pleura, interlobular septa, and bronchovascular bundles.⁴¹ Granulomas contain epithelioid cells or multinucleated giant cells surrounded by a chronic lymphocytic infiltrate. Typically, intracytoplasmic inclusions, such as Schaumann bodies, asteroid bodies, and blue bodies of calcium oxalates are noted within giant cells.

In chronic disease, lymphocytic infiltrate vanishes and granulomas tend to become increasingly fibrotic and enlarge to form hyalinized nodules rich with densely eosinophilic collagen. In 10% to 30% of cases, the lungs undergo progressive fibrosis.⁴⁰ Nonresolving inflammation appears to be the major cause of fibrosis and the peribronchovascular localization leading to marked bronchial distortion.

Clinical features, monitoring, and outcomes

Pulmonary involvement occurs in most patients with sarcoidosis, and subclinical pulmonary disease is generally present, even when extrathoracic manifestations predominate.²³ Dry cough, dyspnea, and chest discomfort are the most common symptoms. Chest auscultation is usually unremarkable. Wheezing is more common in those with fibrosis and is attributed to airway-centric fibrosis.⁴² There is often a substantial delay between the onset of symptoms and the diagnosis of pulmonary sarcoidosis, as symptoms are nonspecific and might be mistaken for more common pulmonary diseases, such as asthma or chronic bronchitis.⁴³

Since sarcoidosis can affect pulmonary parenchyma, interstitium, large and small airways, pulmonary vasculature, and respiratory muscles, the pattern of lung function impairment on PFT varies from normal to obstruction, restriction, isolated diffusion defect, or a combination of these. The typical physiologic abnormality is a restrictive ventilatory defect with a decreased diffusing capacity of the lung for carbon monoxide (DLCO). Extent of disease seen on HRCT correlates with level of restriction.⁴⁴ Airway obstruction can be multifactorial and due to airway distortion (more likely to occur in fibrotic lung disease) and luminal disease.^45-48 The 6-minute walk test and DLCO can also aid in the diagnosis of SAPH and advanced parenchymal lung disease.

While monitoring is done clinically and with testing (PFT and imaging) as needed, the optimal approach is unclear. Nevertheless, longitudinal monitoring with testing may provide useful management and prognostic information.⁴⁰ Pulmonary function can remain stable in fibrotic sarcoidosis over extended periods and actually can improve in some patients.⁴⁹ Serial spirometry, particularly forced vital capacity, is the most reliable tool for monitoring; when a decline in measurement occurs, chest radiography can elucidate the mechanism.^50,51

Continue to: Because sarcoidosis is a multisystem disease...

Because sarcoidosis is a multisystem disease, caution needs to be exercised when evaluating a patient’s new or worsening respiratory symptoms to accurately determine the cause of symptoms and direct therapy accordingly. In addition to refractory inflammatory pulmonary disease, airway disease, infection, fibrosis, and SAPH, one needs to consider extrapulmonary involvement or complications such as cardiac or neurologic disease, musculoskeletal disease, depression, or fatigue. Adverse medication effects, deconditioning, or unrelated (or possibly related) disorders (eg pulmonary embolism) may be to blame.

Determining prognosis

Prognosis of sarcoidosis varies and depends on epidemiologic factors, clinical presentation, and course, as well as specific organ involvement. Patients may develop life-threatening pulmonary, cardiac, or neurologic complications. End-stage disease may require organ transplantation for eligible patients.

Most patients with pulmonary sarcoidosis experience clinical remission with minimal residual organ impairment and a favorable long-term outcome. Advanced pulmonary disease (known as APS) occurs in a small proportion of patients with sarcoidosis but accounts for most of the poor outcomes in sarcoidosis.⁴⁰ APS is variably defined, but it generally includes pulmonary fibrosis, SAPH, and respiratory infection.

One percent to 5% of patients with sarcoidosis die from complications, and mortality is higher in women and African Americans.⁵² Mortality and morbidity may be increasing.⁵³ The reasons behind these trends are unclear but could include true increases in disease incidence, better detection rates, greater severity of disease, or an aging population. Increased hospitalizations and health care use might be due to organ damage from granulomatous inflammation (and resultant fibrosis), complications associated with treatment, and psychosocial effects of the disease/treatment.

Management

Management consists primarily of anti-­inflammatory or immunosuppressive therapies but can also include measures to address specific complications (such as fatigue) and organ transplant, as well as efforts to counter adverse medication effects. Other supportive and preventive measures may include, on a case-by-case basis, oxygen supplementation, vaccinations, or pulmonary rehabilitation. Details of these are found in other, more in-depth reviews on treatment; we will briefly review anti-inflammatory therapy, which forms the cornerstone of treatment in most patients with sarcoidosis.

Continue to: General approach to treatment decisions

General approach to treatment decisions. Anti-inflammatory therapy is used to reduce granulomatous inflammation, thereby preserving organ function and reducing symptoms. A decision to begin treatment is one shared with the patient and is based on symptoms and potential danger of organ system failure.⁵⁴ Patients who are symptomatic or have progressive disease or physiologic impairment are generally candidates for treatment. Monitoring usually suffices for those who have minimal symptoms, stable disease, and preserved organ function.

Patients with pulmonary sarcoidosis at CXR stage 0 should not receive treatment, given that large, randomized trials have shown no meaningful benefit and that these patients have a high likelihood of spontaneous remission and excellent long-term prognosis.^55-58 However, a subgroup of patients classified as stage 0/I on CXR may show parenchymal disease on HRCT,⁵⁹ and, if more symptomatic, could be considered for treatment. For patients with stage II to IV pulmonary sarcoidosis with symptoms, there is good evidence that treatment may improve lung function and reduce dyspnea and fatigue.^57,60-62

Corticosteroids are first-line treatment for most patients. Based on expert opinion, treatment of pulmonary sarcoidosis is generally started with oral prednisone (or an equivalent corticosteroid). A starting dose of 20 to 40 mg/d generally is sufficient for most patients. If the patient responds to initial treatment, prednisone dose is tapered over a period of months. If symptoms worsen during tapering, the minimum effective dose is maintained without further attempts at tapering. Treatment is continued for at least 3 to 6 months but it might be needed for longer durations; unfortunately, evidence-based guidelines are lacking.⁶³ Once the patient goes into remission, close monitoring is done for possible relapses. Inhaled corticosteroids alone have not reduced symptoms or improved lung function in patients with pulmonary sarcoidosis.^64-66

Steroid-sparing agents are added for many patients. For patients receiving chronic prednisone therapy (≥ 10 mg for > 6 months), steroid-sparing agents are considered to minimize the adverse effects of steroids or to better control the inflammatory activity of sarcoidosis. These agents must be carefully selected, and clinical and laboratory monitoring need to be done throughout therapy. TABLE 5^58,64,67-81shows the major anti-inflammatory treatment agents used for sarcoidosis.

The management might be complicated for extrapulmonary, multi-organ, and advanced sarcoidosis (advanced pulmonary sarcoidosis, cardiac disease, neurosarcoidosis, lupus pernio, etc) when specialized testing, as well as a combination of corticosteroids and steroid-sparing agents (with higher doses or prolonged courses), might be needed. This should be performed at an expert sarcoidosis center, ideally in a multidisciplinary setting involving pulmonologists and/or rheumatologists, chest radiologists, and specialists as indicated, based on specific organ involvement.

Continue to: Research and future directions

Research and future directions

Key goals for research are identifying more accurate biomarkers of disease, improving diagnosis of multi-organ disease, determining validated endpoints of clinical trials in sarcoidosis, and developing treatments for refractory cases.

There is optimism and opportunity in the field of sarcoidosis overall. An example of an advancement is in the area of APS, as the severity and importance of this phenotype has been better understood. Worldwide registries and trials of pulmonary vasodilator therapy (bosentan, sildenafil, epoprostenol, and inhaled iloprost) in patients with SAPH without left ventricular dysfunction are promising.^82-85 However, no benefit in survival has been shown.

RioSAPH is a double-blind, placebo-controlled trial of Riociguat (a stimulator of soluble guanylate cyclase) for SAPH (NCT02625558) that is closed to enrollment and undergoing data review. Similarly, results of the phase IV study of pirfenidone, an antifibrotic agent that was shown to decrease disease progression and deaths in idiopathic pulmonary fibrosis,⁸⁶ are awaited in the near future.

Other potential directions being explored are multicenter patient registries and randomized controlled trials, analyses of existing databases, use of biobanking, and patient-centered outcome measures. Hopefully, the care of patients with sarcoidosis will become more evidence based with ongoing and upcoming research in this field.

CORRESPONDENCE
Rohit Gupta, MBBS, FCCP, 3401 North Broad Street, 7 Parkinson Pavilion, Philadelphia, PA 19140; [email protected]

Sarcoidosis is a multisystem inflammatory disease of unclear etiology that primarily affects the lungs. It can occur at any age but usually develops before the age of 50 years, with an initial peak incidence at 20 to 29 years and a second peak incidence after 50 years of age, especially among women in Scandinavia and Japan.¹ Sarcoidosis affects men and women of all racial and ethnic groups throughout the world, but differences based on race, sex, and geography are noted.¹

The highest rates are reported in northern European and African-American individuals, particularly in women.^1,2 The adjusted annual incidence of sarcoidosis among African Americans is approximately 3 times that among White Americans³ and is more likely to be chronic and fatal in African Americans.³ The disease can be familial with a possible recessive inheritance mode with incomplete penetrance.⁴ Risk of sarcoidosis in monozygotic twins appears to be 80 times greater than that in the general population, which supports genetic factors accounting for two-thirds of disease susceptibility.⁵

Likely factors in the development of sarcoidosis

The exact cause of sarcoidosis is unknown, but we have insights into its pathogenesis and potential triggers.^1,6-9 Genes involved are being identified: class I and II human leukocyte antigen (HLA) molecules are most consistently associated with risk of sarcoidosis. Environmental exposures can activate the innate immune system and precondition a susceptible individual to react to potential causative antigens in a highly polarized, antigen-specific Th1 immune response. The epithelioid granulomatous response involves local proinflammatory cytokine production and enhanced T-cell immunity at sites of inflammation.¹⁰ Granulomas generally form to confine pathogens, restrict inflammation, and protect surrounding tissue.^11-13

Sarcoidosis is a diagnosis of exclusion; one must rule out infections, occupational or environmental exposures, malignancies, and other disorders that cause granulomatous inflammation.

ACCESS (A Case Control Etiologic Study of Sarcoidosis) identified several environmental exposures such as chemicals used in the agriculture industry, mold or mildew, and musty odors at work.¹⁴ Tobacco use was not associated with sarcoidosis.¹⁴ Recent studies have shown positive associations with service in the US Navy,¹⁵ metal working,¹⁶ firefighting,¹⁷ the handling of building supplies,¹⁸ and onsite exposure while assisting in rescue efforts at the World Trade Center disaster.¹⁹ Other data support the likelihood that specific environmental exposures associated with microbe-rich environments modestly increase the risk of sarcoidosis.¹⁴ Mycobacterial and propionibacterial DNA and RNA are potentially associated with sarcoidosis.²⁰

Clinical manifestations are nonspecific

The diagnosis of sarcoidosis can be difficult and delayed due to diverse organ involvement and nonspecific presentations. TABLE 1^21-31 shows the diverse manifestations in a patient with suspected sarcoidosis. Around 50% of the patients are asymptomatic.^23,24 Sarcoidosis is a diagnosis of exclusion, starting with a detailed history to rule out infections, occupational or environmental exposures, malignancies, and other possible disorders (TABLE 2).²²

Diagnostic work-up

The primary objective of a diagnostic evaluation in most suspected cases of sarcoidosis is to corroborate the clinical and radiologic features with pathologic evidence of non-necrotizing granulomas and to exclude other causes of granulomatous inflammation.²²

Radiologic studies

Chest x-ray (CXR) provides diagnostic and prognostic information in the evaluation of sarcoidosis using the Scadding classification system (FIGURE 1).^21,25,32,33 Interobserver variability, especially between stages II and III and III and IV is the major limitation of this system.³² At presentation, radiographs are abnormal in approximately 90% of patients.³⁴ Lymphadenopathy is the most common radiographic abnormality, occurring in more than two-thirds of cases, and pulmonary opacities (nodules and reticulation) with a middle to upper lobe predilection are present in 20% to 50% of patients.^1,31,35 The nodules vary in size and can coalesce and cause alveolar collapse, thus producing consolidation.³⁶ Linear opacities radiating laterally from the hilum into the middle and upper zones are characteristic in fibrotic disease.

Continue to: High-resoluton computed tomography

High-resolution computed tomography (HRCT). Micronodules in a perilymphatic distribution with upper lobe predominance combined with subcarinal and symmetrical hilar lymph node enlargement is practically diagnostic of sarcoidosis in the right clinical context. TABLE 3^21,23,25,32 and FIGURE 2^21,23,25,32 summarize the common CT chest findings of sarcoidosis.

Advanced imaging such as (18)F-fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) are used in specialized settings for advanced pulmonary, cardiac, or neurosarcoidosis.

Tissue biopsy

Skin lesions (other than erythema nodosum), eye lesions, and peripheral lymph nodes are considered the safest extrapulmonary locations for biopsy.^21,25 If pulmonary infiltrates or lymphadenopathy are present, or if extrapulmonary biopsy sites are not available, then flexible bronchoscopy with biopsy is the mainstay for tissue sampling.²⁵

Bronchoalveolar lavage (BAL), transbronchial biopsy (TBB), endobronchial biopsy (EBB), and endobronchial ultrasound (EBUS) are invaluable modalities that have reduced the need for open lung biopsy. BAL in sarcoidosis can show lymphocytosis > 15% (nonspecific) and a CD4:CD8 lymphocyte ratio > 3.5 (specificity > 90%).^21,22 TBB is more sensitive than EBB; however, sensitivity overall is heightened when both of them are combined. The advent of EBUS has increased the safety and efficiency of needle aspiration of mediastinal lymph nodes. Diagnostic yield of EBUS (~80%) is superior to that with TBB and EBB (~50%), especially in stage I and II sarcoidosis.³⁷ The combination of EBUS with TBB improves the diagnostic yield to ~90%.³⁷

The decision to obtain biopsy samples hinges on the nature of clinical and radiologic findings (FIGURE 3).^22,25,26

Continue to: Laboratory studies

Multiple abnormalities may be seen in sarcoidosis, and specific lab tests may help support a diagnosis of sarcoidosis or detect organ-specific disease activity (TABLE 4).^22,23,25,38 However, no consistently accurate biomarkers exist for use in clinical practice. An angiotensin-converting enzyme (ACE) level greater than 2 times the upper limit of normal may be helpful; however, sensitivity remains low, and genetic polymorphisms can influence the ACE level.²⁵ Biomarkers sometimes used to assess disease activity are serum interleukin-2 receptor, neopterin, chitotriosidase, lysozyme, KL-6 glycoprotein, and amyloid A.²¹

Additional tests to assess specific features or organ involvement

Pulmonary function testing (PFT) is reviewed in detail below under “pulmonary sarcoidosis.”

Electrocardiogram (EKG)/transthoracic echocardiogram (TTE). EKG abnormalities—conduction disturbances, arrhythmias, or nonspecific ST segment and T-wave changes—are the most common nonspecific findings.³⁰ TTE findings are also nonspecific but have value in assessing cardiac chamber size and function and myocardial involvement. TTE is indeed the most common screening modality for sarcoidosis-associated pulmonary hypertension (SAPH), which is definitively diagnosed by right heart catheterization (RHC). Further evaluation for cardiac sarcoidosis can be done with cardiac MRI or fluorodeoxyglucose PET in specialized settings.

Lumbar puncture (LP) may reveal lymphocytic infiltration in suspected neurosarcoidosis, but the finding is nonspecific and can reflect infection or malignancy. Oligoclonal bands may also be seen in about one-third of neurosarcoidosis cases, and it is imperative to rule out multiple sclerosis.²⁸

Pulmonary sarcoidosis

Pulmonary sarcoidosis accounts for most of the morbidity, mortality, and health care use associated with sarcoidosis.^39,40

Continue to: Pathology of early and advanced pulmonary sarcoidosis

Pathology of early and advanced pulmonary sarcoidosis

Sarcoidosis is characterized by coalescing, tightly clustered, nonnecrotizing granulomas in the lung (FIGURE 4), most often located along the lymphatic routes of the pleura, interlobular septa, and bronchovascular bundles.⁴¹ Granulomas contain epithelioid cells or multinucleated giant cells surrounded by a chronic lymphocytic infiltrate. Typically, intracytoplasmic inclusions, such as Schaumann bodies, asteroid bodies, and blue bodies of calcium oxalates are noted within giant cells.

In chronic disease, lymphocytic infiltrate vanishes and granulomas tend to become increasingly fibrotic and enlarge to form hyalinized nodules rich with densely eosinophilic collagen. In 10% to 30% of cases, the lungs undergo progressive fibrosis.⁴⁰ Nonresolving inflammation appears to be the major cause of fibrosis and the peribronchovascular localization leading to marked bronchial distortion.

Clinical features, monitoring, and outcomes

Pulmonary involvement occurs in most patients with sarcoidosis, and subclinical pulmonary disease is generally present, even when extrathoracic manifestations predominate.²³ Dry cough, dyspnea, and chest discomfort are the most common symptoms. Chest auscultation is usually unremarkable. Wheezing is more common in those with fibrosis and is attributed to airway-centric fibrosis.⁴² There is often a substantial delay between the onset of symptoms and the diagnosis of pulmonary sarcoidosis, as symptoms are nonspecific and might be mistaken for more common pulmonary diseases, such as asthma or chronic bronchitis.⁴³

Since sarcoidosis can affect pulmonary parenchyma, interstitium, large and small airways, pulmonary vasculature, and respiratory muscles, the pattern of lung function impairment on PFT varies from normal to obstruction, restriction, isolated diffusion defect, or a combination of these. The typical physiologic abnormality is a restrictive ventilatory defect with a decreased diffusing capacity of the lung for carbon monoxide (DLCO). Extent of disease seen on HRCT correlates with level of restriction.⁴⁴ Airway obstruction can be multifactorial and due to airway distortion (more likely to occur in fibrotic lung disease) and luminal disease.^45-48 The 6-minute walk test and DLCO can also aid in the diagnosis of SAPH and advanced parenchymal lung disease.

While monitoring is done clinically and with testing (PFT and imaging) as needed, the optimal approach is unclear. Nevertheless, longitudinal monitoring with testing may provide useful management and prognostic information.⁴⁰ Pulmonary function can remain stable in fibrotic sarcoidosis over extended periods and actually can improve in some patients.⁴⁹ Serial spirometry, particularly forced vital capacity, is the most reliable tool for monitoring; when a decline in measurement occurs, chest radiography can elucidate the mechanism.^50,51

Continue to: Because sarcoidosis is a multisystem disease...

Because sarcoidosis is a multisystem disease, caution needs to be exercised when evaluating a patient’s new or worsening respiratory symptoms to accurately determine the cause of symptoms and direct therapy accordingly. In addition to refractory inflammatory pulmonary disease, airway disease, infection, fibrosis, and SAPH, one needs to consider extrapulmonary involvement or complications such as cardiac or neurologic disease, musculoskeletal disease, depression, or fatigue. Adverse medication effects, deconditioning, or unrelated (or possibly related) disorders (eg pulmonary embolism) may be to blame.

Determining prognosis

Prognosis of sarcoidosis varies and depends on epidemiologic factors, clinical presentation, and course, as well as specific organ involvement. Patients may develop life-threatening pulmonary, cardiac, or neurologic complications. End-stage disease may require organ transplantation for eligible patients.

Most patients with pulmonary sarcoidosis experience clinical remission with minimal residual organ impairment and a favorable long-term outcome. Advanced pulmonary disease (known as APS) occurs in a small proportion of patients with sarcoidosis but accounts for most of the poor outcomes in sarcoidosis.⁴⁰ APS is variably defined, but it generally includes pulmonary fibrosis, SAPH, and respiratory infection.

One percent to 5% of patients with sarcoidosis die from complications, and mortality is higher in women and African Americans.⁵² Mortality and morbidity may be increasing.⁵³ The reasons behind these trends are unclear but could include true increases in disease incidence, better detection rates, greater severity of disease, or an aging population. Increased hospitalizations and health care use might be due to organ damage from granulomatous inflammation (and resultant fibrosis), complications associated with treatment, and psychosocial effects of the disease/treatment.

Management

Management consists primarily of anti-­inflammatory or immunosuppressive therapies but can also include measures to address specific complications (such as fatigue) and organ transplant, as well as efforts to counter adverse medication effects. Other supportive and preventive measures may include, on a case-by-case basis, oxygen supplementation, vaccinations, or pulmonary rehabilitation. Details of these are found in other, more in-depth reviews on treatment; we will briefly review anti-inflammatory therapy, which forms the cornerstone of treatment in most patients with sarcoidosis.

Continue to: General approach to treatment decisions

General approach to treatment decisions. Anti-inflammatory therapy is used to reduce granulomatous inflammation, thereby preserving organ function and reducing symptoms. A decision to begin treatment is one shared with the patient and is based on symptoms and potential danger of organ system failure.⁵⁴ Patients who are symptomatic or have progressive disease or physiologic impairment are generally candidates for treatment. Monitoring usually suffices for those who have minimal symptoms, stable disease, and preserved organ function.

Patients with pulmonary sarcoidosis at CXR stage 0 should not receive treatment, given that large, randomized trials have shown no meaningful benefit and that these patients have a high likelihood of spontaneous remission and excellent long-term prognosis.^55-58 However, a subgroup of patients classified as stage 0/I on CXR may show parenchymal disease on HRCT,⁵⁹ and, if more symptomatic, could be considered for treatment. For patients with stage II to IV pulmonary sarcoidosis with symptoms, there is good evidence that treatment may improve lung function and reduce dyspnea and fatigue.^57,60-62

Corticosteroids are first-line treatment for most patients. Based on expert opinion, treatment of pulmonary sarcoidosis is generally started with oral prednisone (or an equivalent corticosteroid). A starting dose of 20 to 40 mg/d generally is sufficient for most patients. If the patient responds to initial treatment, prednisone dose is tapered over a period of months. If symptoms worsen during tapering, the minimum effective dose is maintained without further attempts at tapering. Treatment is continued for at least 3 to 6 months but it might be needed for longer durations; unfortunately, evidence-based guidelines are lacking.⁶³ Once the patient goes into remission, close monitoring is done for possible relapses. Inhaled corticosteroids alone have not reduced symptoms or improved lung function in patients with pulmonary sarcoidosis.^64-66

Steroid-sparing agents are added for many patients. For patients receiving chronic prednisone therapy (≥ 10 mg for > 6 months), steroid-sparing agents are considered to minimize the adverse effects of steroids or to better control the inflammatory activity of sarcoidosis. These agents must be carefully selected, and clinical and laboratory monitoring need to be done throughout therapy. TABLE 5^58,64,67-81shows the major anti-inflammatory treatment agents used for sarcoidosis.

The management might be complicated for extrapulmonary, multi-organ, and advanced sarcoidosis (advanced pulmonary sarcoidosis, cardiac disease, neurosarcoidosis, lupus pernio, etc) when specialized testing, as well as a combination of corticosteroids and steroid-sparing agents (with higher doses or prolonged courses), might be needed. This should be performed at an expert sarcoidosis center, ideally in a multidisciplinary setting involving pulmonologists and/or rheumatologists, chest radiologists, and specialists as indicated, based on specific organ involvement.

Continue to: Research and future directions

Research and future directions

Key goals for research are identifying more accurate biomarkers of disease, improving diagnosis of multi-organ disease, determining validated endpoints of clinical trials in sarcoidosis, and developing treatments for refractory cases.

There is optimism and opportunity in the field of sarcoidosis overall. An example of an advancement is in the area of APS, as the severity and importance of this phenotype has been better understood. Worldwide registries and trials of pulmonary vasodilator therapy (bosentan, sildenafil, epoprostenol, and inhaled iloprost) in patients with SAPH without left ventricular dysfunction are promising.^82-85 However, no benefit in survival has been shown.

RioSAPH is a double-blind, placebo-controlled trial of Riociguat (a stimulator of soluble guanylate cyclase) for SAPH (NCT02625558) that is closed to enrollment and undergoing data review. Similarly, results of the phase IV study of pirfenidone, an antifibrotic agent that was shown to decrease disease progression and deaths in idiopathic pulmonary fibrosis,⁸⁶ are awaited in the near future.

Other potential directions being explored are multicenter patient registries and randomized controlled trials, analyses of existing databases, use of biobanking, and patient-centered outcome measures. Hopefully, the care of patients with sarcoidosis will become more evidence based with ongoing and upcoming research in this field.

CORRESPONDENCE
Rohit Gupta, MBBS, FCCP, 3401 North Broad Street, 7 Parkinson Pavilion, Philadelphia, PA 19140; [email protected]

The combination of copanlisib plus rituximab led to a 48% reduction in the risk of disease progression or death, when compared with rituximab plus placebo in a phase 3 trial of patients with relapsed, indolent non-Hodgkin lymphoma (NHL).

The trial, dubbed CHRONOS-3, is the first to report “a broad benefit” across histologic subtypes of relapsed, indolent NHL, and the results are “essentially a long-awaited proof of concept” for combining a PI3K inhibitor with rituximab, according to investigator Matthew Matasar, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Matasar presented results from CHRONOS-3 at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT001). The findings were simultaneously published in The Lancet Oncology.

Charles Swanton, MBPhD, of the Francis Crick Institute and UCL Cancer Institute in London, called the results “strongly positive” and said the copanlisib-rituximab combination is “a potential new treatment option” for indolent NHL in patients with a long remission after first-line therapy or those who are unfit for chemotherapy.

Dr. Swanton noted, however, that “one should also bear in mind” the serious adverse events (AEs) seen with copanlisib, particularly hypertension and hyperglycemia. When asked about these AEs, Dr. Matasar said he thinks the combination would be appropriate for patients who meet the study criteria as long as they don’t have severe baseline diabetes or uncontrolled hypertension.
 

Patient and treatment details

The study included 458 patients with CD20-positive, relapsed, indolent, B-cell NHL. Subtypes included follicular lymphoma (n = 275), marginal zone lymphoma (n = 95), small lymphocytic lymphoma (n = 50), and lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia (n = 38).

All patients were progression free and treatment free before their relapse for at least 12 months after their last rituximab-containing regimen, or at least 6 months before relapse if they were unwilling or unable to undergo chemotherapy.

The patients’ median age was 63 years, and just over half of them were men (52%). About 37% of patients had a history of hypertension at baseline, and about 15% had a history of diabetes.

Patients were randomized to receive copanlisib plus rituximab (n = 307) or rituximab plus placebo (n = 151). Copanlisib was given at 60 mg IV on days 1, 8, and 15 of a 28-day cycle. In both arms, rituximab was given at 375 mg/m² on days 1, 8, 15, and 22 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9.
 

Progression-free survival benefit

At a median follow-up of 19.2 months, the median progression-free survival (PFS) was 21.5 months in the copanlisib-rituximab arm and 13.8 months in the placebo-rituximab arm (hazard ratio, 0.52; P < .0001).

The PFS advantage with copanlisib was seen across subtypes:

• Follicular lymphoma – 22.2 months vs. 18.7 months (P = .001)
• Small lymphocytic lymphoma – 14.2 months vs. 5.7 months (P < .0001)
• Marginal zone lymphoma – 22.1 months vs. 11.5 months (P = .012)
• Lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia – 33.4 months vs. 16.6 months (P = .054)

The PFS difference among patients with lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia was likely not statistically significant because of the small sample size, Dr. Matasar said.

He reported that the overall response rate was 81% with copanlisib-rituximab, including a 34% complete response rate. In the placebo arm, the overall response rate was 48%, and 15% of patients had a complete response.

The median overall survival was not estimable in either treatment arm. At a median follow-up of 30.1 months, 14% of patients in the copanlisib arm and 13.2% of patients in the placebo arm had died.
 

More than double the rate of serious AEs

The rate of serious treatment-emergent AEs was 47.2% in the combination arm and 18.5% in the placebo arm.

There were six grade 5 treatment-emergent AEs in the combination arm. One of these – pneumonitis – was deemed treatment related. There was one treatment-emergent death in the placebo arm.

Hyperglycemia and hypertension were the most common grade 3/4 treatment-emergent AEs with the combination. Diarrhea, nausea, neutropenia, and pyrexia were also more frequent with the combination than with rituximab-placebo.

More than half of patients in the combination arm (56.3%) developed grade 3/4 hyperglycemia. In the placebo arm, the incidence of grade 3 hyperglycemia was 8.2%, and there was no grade 4 hyperglycemia.

Rates of grade 3 hypertension were 39.7% in the combination arm and 8.9% in the placebo arm. There was no grade 4 hypertension.

In the combination arm, 2.6% of patients stopped treatment because of hyperglycemia and 0.7% stopped because of hypertension.

Any-grade pneumonitis occurred in 6.8% of patients in the combination arm and 1.4% of those in the placebo arm. The rate of grade 3/4 pneumonitis was 2.7% in the copanlisib arm, and the rate of grade 3 pneumonitis was 0.7% in the placebo arm.

The study was funded by Bayer, the company developing copanlisib. Dr. Matasar disclosed relationships with Bayer, its subsidiaries, and Roche/Genentech. Dr. Swanton disclosed relationships with numerous companies, including Pfizer, Novartis, and GlaxoSmithKline.

[email protected]

The combination of copanlisib plus rituximab led to a 48% reduction in the risk of disease progression or death, when compared with rituximab plus placebo in a phase 3 trial of patients with relapsed, indolent non-Hodgkin lymphoma (NHL).

The trial, dubbed CHRONOS-3, is the first to report “a broad benefit” across histologic subtypes of relapsed, indolent NHL, and the results are “essentially a long-awaited proof of concept” for combining a PI3K inhibitor with rituximab, according to investigator Matthew Matasar, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Matasar presented results from CHRONOS-3 at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT001). The findings were simultaneously published in The Lancet Oncology.

Charles Swanton, MBPhD, of the Francis Crick Institute and UCL Cancer Institute in London, called the results “strongly positive” and said the copanlisib-rituximab combination is “a potential new treatment option” for indolent NHL in patients with a long remission after first-line therapy or those who are unfit for chemotherapy.

Dr. Swanton noted, however, that “one should also bear in mind” the serious adverse events (AEs) seen with copanlisib, particularly hypertension and hyperglycemia. When asked about these AEs, Dr. Matasar said he thinks the combination would be appropriate for patients who meet the study criteria as long as they don’t have severe baseline diabetes or uncontrolled hypertension.
 

Patient and treatment details

The study included 458 patients with CD20-positive, relapsed, indolent, B-cell NHL. Subtypes included follicular lymphoma (n = 275), marginal zone lymphoma (n = 95), small lymphocytic lymphoma (n = 50), and lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia (n = 38).

All patients were progression free and treatment free before their relapse for at least 12 months after their last rituximab-containing regimen, or at least 6 months before relapse if they were unwilling or unable to undergo chemotherapy.

The patients’ median age was 63 years, and just over half of them were men (52%). About 37% of patients had a history of hypertension at baseline, and about 15% had a history of diabetes.

Patients were randomized to receive copanlisib plus rituximab (n = 307) or rituximab plus placebo (n = 151). Copanlisib was given at 60 mg IV on days 1, 8, and 15 of a 28-day cycle. In both arms, rituximab was given at 375 mg/m² on days 1, 8, 15, and 22 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9.
 

Progression-free survival benefit

At a median follow-up of 19.2 months, the median progression-free survival (PFS) was 21.5 months in the copanlisib-rituximab arm and 13.8 months in the placebo-rituximab arm (hazard ratio, 0.52; P < .0001).

The PFS advantage with copanlisib was seen across subtypes:

• Follicular lymphoma – 22.2 months vs. 18.7 months (P = .001)
• Small lymphocytic lymphoma – 14.2 months vs. 5.7 months (P < .0001)
• Marginal zone lymphoma – 22.1 months vs. 11.5 months (P = .012)
• Lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia – 33.4 months vs. 16.6 months (P = .054)

The PFS difference among patients with lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia was likely not statistically significant because of the small sample size, Dr. Matasar said.

He reported that the overall response rate was 81% with copanlisib-rituximab, including a 34% complete response rate. In the placebo arm, the overall response rate was 48%, and 15% of patients had a complete response.

The median overall survival was not estimable in either treatment arm. At a median follow-up of 30.1 months, 14% of patients in the copanlisib arm and 13.2% of patients in the placebo arm had died.
 

More than double the rate of serious AEs

The rate of serious treatment-emergent AEs was 47.2% in the combination arm and 18.5% in the placebo arm.

There were six grade 5 treatment-emergent AEs in the combination arm. One of these – pneumonitis – was deemed treatment related. There was one treatment-emergent death in the placebo arm.

Hyperglycemia and hypertension were the most common grade 3/4 treatment-emergent AEs with the combination. Diarrhea, nausea, neutropenia, and pyrexia were also more frequent with the combination than with rituximab-placebo.

More than half of patients in the combination arm (56.3%) developed grade 3/4 hyperglycemia. In the placebo arm, the incidence of grade 3 hyperglycemia was 8.2%, and there was no grade 4 hyperglycemia.

Rates of grade 3 hypertension were 39.7% in the combination arm and 8.9% in the placebo arm. There was no grade 4 hypertension.

In the combination arm, 2.6% of patients stopped treatment because of hyperglycemia and 0.7% stopped because of hypertension.

Any-grade pneumonitis occurred in 6.8% of patients in the combination arm and 1.4% of those in the placebo arm. The rate of grade 3/4 pneumonitis was 2.7% in the copanlisib arm, and the rate of grade 3 pneumonitis was 0.7% in the placebo arm.

The study was funded by Bayer, the company developing copanlisib. Dr. Matasar disclosed relationships with Bayer, its subsidiaries, and Roche/Genentech. Dr. Swanton disclosed relationships with numerous companies, including Pfizer, Novartis, and GlaxoSmithKline.

[email protected]

The combination of copanlisib plus rituximab led to a 48% reduction in the risk of disease progression or death, when compared with rituximab plus placebo in a phase 3 trial of patients with relapsed, indolent non-Hodgkin lymphoma (NHL).

The trial, dubbed CHRONOS-3, is the first to report “a broad benefit” across histologic subtypes of relapsed, indolent NHL, and the results are “essentially a long-awaited proof of concept” for combining a PI3K inhibitor with rituximab, according to investigator Matthew Matasar, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Matasar presented results from CHRONOS-3 at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT001). The findings were simultaneously published in The Lancet Oncology.

Charles Swanton, MBPhD, of the Francis Crick Institute and UCL Cancer Institute in London, called the results “strongly positive” and said the copanlisib-rituximab combination is “a potential new treatment option” for indolent NHL in patients with a long remission after first-line therapy or those who are unfit for chemotherapy.

Dr. Swanton noted, however, that “one should also bear in mind” the serious adverse events (AEs) seen with copanlisib, particularly hypertension and hyperglycemia. When asked about these AEs, Dr. Matasar said he thinks the combination would be appropriate for patients who meet the study criteria as long as they don’t have severe baseline diabetes or uncontrolled hypertension.
 

Patient and treatment details

The study included 458 patients with CD20-positive, relapsed, indolent, B-cell NHL. Subtypes included follicular lymphoma (n = 275), marginal zone lymphoma (n = 95), small lymphocytic lymphoma (n = 50), and lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia (n = 38).

All patients were progression free and treatment free before their relapse for at least 12 months after their last rituximab-containing regimen, or at least 6 months before relapse if they were unwilling or unable to undergo chemotherapy.

The patients’ median age was 63 years, and just over half of them were men (52%). About 37% of patients had a history of hypertension at baseline, and about 15% had a history of diabetes.

Patients were randomized to receive copanlisib plus rituximab (n = 307) or rituximab plus placebo (n = 151). Copanlisib was given at 60 mg IV on days 1, 8, and 15 of a 28-day cycle. In both arms, rituximab was given at 375 mg/m² on days 1, 8, 15, and 22 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9.
 

Progression-free survival benefit

At a median follow-up of 19.2 months, the median progression-free survival (PFS) was 21.5 months in the copanlisib-rituximab arm and 13.8 months in the placebo-rituximab arm (hazard ratio, 0.52; P < .0001).

The PFS advantage with copanlisib was seen across subtypes:

• Follicular lymphoma – 22.2 months vs. 18.7 months (P = .001)
• Small lymphocytic lymphoma – 14.2 months vs. 5.7 months (P < .0001)
• Marginal zone lymphoma – 22.1 months vs. 11.5 months (P = .012)
• Lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia – 33.4 months vs. 16.6 months (P = .054)

The PFS difference among patients with lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia was likely not statistically significant because of the small sample size, Dr. Matasar said.

He reported that the overall response rate was 81% with copanlisib-rituximab, including a 34% complete response rate. In the placebo arm, the overall response rate was 48%, and 15% of patients had a complete response.

The median overall survival was not estimable in either treatment arm. At a median follow-up of 30.1 months, 14% of patients in the copanlisib arm and 13.2% of patients in the placebo arm had died.
 

More than double the rate of serious AEs

The rate of serious treatment-emergent AEs was 47.2% in the combination arm and 18.5% in the placebo arm.

There were six grade 5 treatment-emergent AEs in the combination arm. One of these – pneumonitis – was deemed treatment related. There was one treatment-emergent death in the placebo arm.

Hyperglycemia and hypertension were the most common grade 3/4 treatment-emergent AEs with the combination. Diarrhea, nausea, neutropenia, and pyrexia were also more frequent with the combination than with rituximab-placebo.

More than half of patients in the combination arm (56.3%) developed grade 3/4 hyperglycemia. In the placebo arm, the incidence of grade 3 hyperglycemia was 8.2%, and there was no grade 4 hyperglycemia.

Rates of grade 3 hypertension were 39.7% in the combination arm and 8.9% in the placebo arm. There was no grade 4 hypertension.

In the combination arm, 2.6% of patients stopped treatment because of hyperglycemia and 0.7% stopped because of hypertension.

Any-grade pneumonitis occurred in 6.8% of patients in the combination arm and 1.4% of those in the placebo arm. The rate of grade 3/4 pneumonitis was 2.7% in the copanlisib arm, and the rate of grade 3 pneumonitis was 0.7% in the placebo arm.

The study was funded by Bayer, the company developing copanlisib. Dr. Matasar disclosed relationships with Bayer, its subsidiaries, and Roche/Genentech. Dr. Swanton disclosed relationships with numerous companies, including Pfizer, Novartis, and GlaxoSmithKline.

[email protected]

Adults with knee osteoarthritis (OA) who participated in a self-directed, web-based exercise program with automated text-message reminders and encouragement for 6 months showed significant improvement in overall knee pain and physical function, compared with patients who received web-based OA information alone, in a randomized trial of 180 individuals.

copyright Nandyphotos/Thinkstock

The results support a role for web-based exercise intervention to improve knee OA patients’ access to recommended exercises and to assist clinicians in managing patients on a population level, according to the first author of the study, Rachel Kate Nelligan, of the University of Melbourne, and colleagues. Their report is in JAMA Internal Medicine.

“Our free-to-access, unsupervised program could serve as an entry-level intervention, with participants who do not experience clinical benefits progressing to subsequent steps for more intensive, personalized management,” they said. “Such an approach has the potential to better distribute limited health care resources and reduce demand for contact with health professionals, thus improving access for those requiring it.”

Only two other randomized, clinical trials have evaluated web-based interventions for OA without contact from health professionals, according to the authors. While one of those did not find any differences in outcomes at 4 months when comparing a self-directed progressive lower-limb strength, flexibility, and walking program to being on a wait list, a separate trial evaluating a 9-module physical activity program in adults with knee and/or hip OA vs. a wait-list control group found evidence for efficacy for physical function at 3 months, but not quality of life or function in sport and recreation.

For the current study, researchers recruited 206 adults in Australia with clinically diagnosed knee OA via online advertisements and a volunteer database. Participants were aged 45 years or older, and reported activity-related knee pain and morning knee stiffness lasting at least 30 minutes; knee pain on most days for at least 3 months; and average knee pain severity of 4 or higher on an 11-point numeric rating scale in the previous week. In addition, participants were required to own a cell phone with text messaging, have Internet access, and be able to complete assessments.

Patients randomized to the intervention of the My Knee Exercise website received web-based information about OA and the value of exercise, with a 24-week self-directed program of strengthening exercises plus automated text messages to motivate behavior changes and encourage adherence to the exercise program. Controls received access to web-based information about OA and the value of exercise, but without the prescribed exercises or texts. Patients in the intervention group received an average of 60 text messages during the study period, and the average reply rate was 73%.

The primary study outcomes were changes in overall knee pain based on a numeric 0-10 rating scale and changes in physical function based on the Western Ontario and McMaster Universities Osteoarthritis Index 0-68 scale. A total of 180 participants completed both primary outcome measures at 24 weeks. The average age of the participants was 60 years, and 61% were women.

After 24 weeks, the intervention group averaged significantly greater improvement of 1.6 units for overall knee pain (P < .001) and 5.2 units for physical function (P = .002), compared with controls.

In addition, the proportion of patients who exceeded the minimal clinically important difference in pain improvement of at least 1.8 units was significantly higher in the intervention group, compared with controls (72.1% vs. 42.0%; P < .001). Similarly, more intervention-group patients achieved the minimal clinically important difference in WOMAC physical function of improvement of at least 6 units (68.0% vs. 40.8%; P < .001).

Secondary outcomes included additional measures of knee pain, knee function for sport and recreation, quality of life, physical activity, self-efficacy, overall improvement, and treatment satisfaction. Between-group differences favored the intervention on most measures, including Knee Injury and Osteoarthritis Outcome Score subscales for pain, sports/recreation, and quality of life; health-related quality of life; Arthritis Self-Efficacy Scale (ASES) pain subscale, individual change since baseline, and overall patient satisfaction. “Changes in PASE [Physical Activity Scale for the Elderly], ASES function, and SEE [Self Efficacy Exercise] were similar in both groups,” the researchers said.

No serious adverse events were reported by any study participants. Eight patients in the intervention group reported knee pain during the study, compared with one of the controls, and use of pain medications was similar between the groups, except that more control participants used massage, heat or cold, and topical anti-inflammatories.

The results suggest that a majority of participants in the intervention group improved pain and function without the need for in-person contact with a health professional, the researchers noted. However, more intensive management may be needed to support the 30% who did not benefit from the unsupervised approach, they said.

The study findings were limited by several factors, including the potential bias of a volunteer study population, possible lack of generalizability to individuals with lower levels of education or self-efficacy, and lack of direct comparison between web-based intervention and clinician-delivered intervention, the researchers noted.

The study was funded by the National Health and Medical Research Council, whose fellowships supported two of the authors. Lead author Ms. Nelligan disclosed a PhD scholarship from the Australian Government Research Training Program and personal fees from the University of Melbourne unrelated to the current study.

Adults with knee osteoarthritis (OA) who participated in a self-directed, web-based exercise program with automated text-message reminders and encouragement for 6 months showed significant improvement in overall knee pain and physical function, compared with patients who received web-based OA information alone, in a randomized trial of 180 individuals.

copyright Nandyphotos/Thinkstock

The results support a role for web-based exercise intervention to improve knee OA patients’ access to recommended exercises and to assist clinicians in managing patients on a population level, according to the first author of the study, Rachel Kate Nelligan, of the University of Melbourne, and colleagues. Their report is in JAMA Internal Medicine.

“Our free-to-access, unsupervised program could serve as an entry-level intervention, with participants who do not experience clinical benefits progressing to subsequent steps for more intensive, personalized management,” they said. “Such an approach has the potential to better distribute limited health care resources and reduce demand for contact with health professionals, thus improving access for those requiring it.”

Only two other randomized, clinical trials have evaluated web-based interventions for OA without contact from health professionals, according to the authors. While one of those did not find any differences in outcomes at 4 months when comparing a self-directed progressive lower-limb strength, flexibility, and walking program to being on a wait list, a separate trial evaluating a 9-module physical activity program in adults with knee and/or hip OA vs. a wait-list control group found evidence for efficacy for physical function at 3 months, but not quality of life or function in sport and recreation.

For the current study, researchers recruited 206 adults in Australia with clinically diagnosed knee OA via online advertisements and a volunteer database. Participants were aged 45 years or older, and reported activity-related knee pain and morning knee stiffness lasting at least 30 minutes; knee pain on most days for at least 3 months; and average knee pain severity of 4 or higher on an 11-point numeric rating scale in the previous week. In addition, participants were required to own a cell phone with text messaging, have Internet access, and be able to complete assessments.

Patients randomized to the intervention of the My Knee Exercise website received web-based information about OA and the value of exercise, with a 24-week self-directed program of strengthening exercises plus automated text messages to motivate behavior changes and encourage adherence to the exercise program. Controls received access to web-based information about OA and the value of exercise, but without the prescribed exercises or texts. Patients in the intervention group received an average of 60 text messages during the study period, and the average reply rate was 73%.

The primary study outcomes were changes in overall knee pain based on a numeric 0-10 rating scale and changes in physical function based on the Western Ontario and McMaster Universities Osteoarthritis Index 0-68 scale. A total of 180 participants completed both primary outcome measures at 24 weeks. The average age of the participants was 60 years, and 61% were women.

After 24 weeks, the intervention group averaged significantly greater improvement of 1.6 units for overall knee pain (P < .001) and 5.2 units for physical function (P = .002), compared with controls.

In addition, the proportion of patients who exceeded the minimal clinically important difference in pain improvement of at least 1.8 units was significantly higher in the intervention group, compared with controls (72.1% vs. 42.0%; P < .001). Similarly, more intervention-group patients achieved the minimal clinically important difference in WOMAC physical function of improvement of at least 6 units (68.0% vs. 40.8%; P < .001).

Secondary outcomes included additional measures of knee pain, knee function for sport and recreation, quality of life, physical activity, self-efficacy, overall improvement, and treatment satisfaction. Between-group differences favored the intervention on most measures, including Knee Injury and Osteoarthritis Outcome Score subscales for pain, sports/recreation, and quality of life; health-related quality of life; Arthritis Self-Efficacy Scale (ASES) pain subscale, individual change since baseline, and overall patient satisfaction. “Changes in PASE [Physical Activity Scale for the Elderly], ASES function, and SEE [Self Efficacy Exercise] were similar in both groups,” the researchers said.

No serious adverse events were reported by any study participants. Eight patients in the intervention group reported knee pain during the study, compared with one of the controls, and use of pain medications was similar between the groups, except that more control participants used massage, heat or cold, and topical anti-inflammatories.

The results suggest that a majority of participants in the intervention group improved pain and function without the need for in-person contact with a health professional, the researchers noted. However, more intensive management may be needed to support the 30% who did not benefit from the unsupervised approach, they said.

The study findings were limited by several factors, including the potential bias of a volunteer study population, possible lack of generalizability to individuals with lower levels of education or self-efficacy, and lack of direct comparison between web-based intervention and clinician-delivered intervention, the researchers noted.

The study was funded by the National Health and Medical Research Council, whose fellowships supported two of the authors. Lead author Ms. Nelligan disclosed a PhD scholarship from the Australian Government Research Training Program and personal fees from the University of Melbourne unrelated to the current study.

Adults with knee osteoarthritis (OA) who participated in a self-directed, web-based exercise program with automated text-message reminders and encouragement for 6 months showed significant improvement in overall knee pain and physical function, compared with patients who received web-based OA information alone, in a randomized trial of 180 individuals.

copyright Nandyphotos/Thinkstock

The results support a role for web-based exercise intervention to improve knee OA patients’ access to recommended exercises and to assist clinicians in managing patients on a population level, according to the first author of the study, Rachel Kate Nelligan, of the University of Melbourne, and colleagues. Their report is in JAMA Internal Medicine.

“Our free-to-access, unsupervised program could serve as an entry-level intervention, with participants who do not experience clinical benefits progressing to subsequent steps for more intensive, personalized management,” they said. “Such an approach has the potential to better distribute limited health care resources and reduce demand for contact with health professionals, thus improving access for those requiring it.”

Only two other randomized, clinical trials have evaluated web-based interventions for OA without contact from health professionals, according to the authors. While one of those did not find any differences in outcomes at 4 months when comparing a self-directed progressive lower-limb strength, flexibility, and walking program to being on a wait list, a separate trial evaluating a 9-module physical activity program in adults with knee and/or hip OA vs. a wait-list control group found evidence for efficacy for physical function at 3 months, but not quality of life or function in sport and recreation.

For the current study, researchers recruited 206 adults in Australia with clinically diagnosed knee OA via online advertisements and a volunteer database. Participants were aged 45 years or older, and reported activity-related knee pain and morning knee stiffness lasting at least 30 minutes; knee pain on most days for at least 3 months; and average knee pain severity of 4 or higher on an 11-point numeric rating scale in the previous week. In addition, participants were required to own a cell phone with text messaging, have Internet access, and be able to complete assessments.

Patients randomized to the intervention of the My Knee Exercise website received web-based information about OA and the value of exercise, with a 24-week self-directed program of strengthening exercises plus automated text messages to motivate behavior changes and encourage adherence to the exercise program. Controls received access to web-based information about OA and the value of exercise, but without the prescribed exercises or texts. Patients in the intervention group received an average of 60 text messages during the study period, and the average reply rate was 73%.

The primary study outcomes were changes in overall knee pain based on a numeric 0-10 rating scale and changes in physical function based on the Western Ontario and McMaster Universities Osteoarthritis Index 0-68 scale. A total of 180 participants completed both primary outcome measures at 24 weeks. The average age of the participants was 60 years, and 61% were women.

After 24 weeks, the intervention group averaged significantly greater improvement of 1.6 units for overall knee pain (P < .001) and 5.2 units for physical function (P = .002), compared with controls.

In addition, the proportion of patients who exceeded the minimal clinically important difference in pain improvement of at least 1.8 units was significantly higher in the intervention group, compared with controls (72.1% vs. 42.0%; P < .001). Similarly, more intervention-group patients achieved the minimal clinically important difference in WOMAC physical function of improvement of at least 6 units (68.0% vs. 40.8%; P < .001).

Secondary outcomes included additional measures of knee pain, knee function for sport and recreation, quality of life, physical activity, self-efficacy, overall improvement, and treatment satisfaction. Between-group differences favored the intervention on most measures, including Knee Injury and Osteoarthritis Outcome Score subscales for pain, sports/recreation, and quality of life; health-related quality of life; Arthritis Self-Efficacy Scale (ASES) pain subscale, individual change since baseline, and overall patient satisfaction. “Changes in PASE [Physical Activity Scale for the Elderly], ASES function, and SEE [Self Efficacy Exercise] were similar in both groups,” the researchers said.

No serious adverse events were reported by any study participants. Eight patients in the intervention group reported knee pain during the study, compared with one of the controls, and use of pain medications was similar between the groups, except that more control participants used massage, heat or cold, and topical anti-inflammatories.

The results suggest that a majority of participants in the intervention group improved pain and function without the need for in-person contact with a health professional, the researchers noted. However, more intensive management may be needed to support the 30% who did not benefit from the unsupervised approach, they said.

The study findings were limited by several factors, including the potential bias of a volunteer study population, possible lack of generalizability to individuals with lower levels of education or self-efficacy, and lack of direct comparison between web-based intervention and clinician-delivered intervention, the researchers noted.

The study was funded by the National Health and Medical Research Council, whose fellowships supported two of the authors. Lead author Ms. Nelligan disclosed a PhD scholarship from the Australian Government Research Training Program and personal fees from the University of Melbourne unrelated to the current study.

Patients with resectable non–small cell lung cancer (NSCLC) often receive treatment before they undergo surgery. For such patients who achieve a pathologic complete response (pCR), the chances of survival are improved.

However, only a small percentage of patients achieve a pCR with neoadjuvant chemotherapy alone.

Adding the immune checkpoint inhibitor nivolumab to platinum-doublet chemotherapy in the neoadjuvant setting boosts the success rate.

Results from the CheckMate 816 trial show that pCR rates improved from 2.2% with chemotherapy alone to 24% when nivolumab was added.

This difference translated into an odds ratio for achieving a pCR with nivolumab plus chemotherapy of 13.94 (P < .0001), reported Patrick M. Forde, MBBCh, from the Johns Hopkins Kimmel Cancer Center, Baltimore.

This primary endpoint, pCR, was defined as complete regression in both the primary tumor and lymph nodes.

“The magnitude of pCR with nivo plus chemo was similar in stage 1B, II, and stage IIIA disease, as well as in both squamous and nonsquamous histologies,” he added.

Dr. Forde presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT003).

The higher pCR rates were seen regardless of PD-L1 expression or tumor mutational burden, Dr. Forde said.

The benefit was also seen when the researchers considered only those patients who subsequently underwent resection (pCR rate of 30.5% with the combination versus 3.2% with chemotherapy alone) and when only the primary tumor was considered (pCR rate of 25.7% vs. 2.8%, respectively).
 

Change in trial design

Invited discussant Jhanelle Gray, MD, from the Moffitt Cancer Center, Tampa, pointed out that the CheckMate 816 trial originally included an experimental arm with double immunotherapy – ipilimumab plus nivolumab – added onto chemotherapy.

However, this third arm was closed after other trials reported promising results from adding a single immunotherapy onto chemotherapy. For example, results of the single-arm NADIM phase 2 study showed a 77.1% progression-free survival rate at 24 months with the combination of nivolumab, paclitaxel, and carboplatin, and the phase 2 KEYNOTE-021 trial showed that adding pembrolizumab to a standard platinum-doublet chemotherapy regimen nearly doubled response rates among patients with previously untreated advanced nonsquamous NSCLC (although there was no advantage in overall survival).

“Even with the change in trial design, patient characteristics were well balanced between the two arms, and the study met its primary endpoint in the intent-to-treat population,” she said.

Dr. Gray also commented that the choice of pCR as a primary endpoint is “intriguing, and the question remains if it represents a valid surrogate endpoint for survival.”

She noted that a meta-analysis of 32 neoadjuvant chemotherapy-based studies in NSCLC, presented at the 2020 European Society of Medical Oncology annual meeting, showed clear associations of pCR and major pathologic response to both overall survival and event-free survival.

“As these findings were established in a backdrop of chemotherapy, work is needed to confirm these findings in the setting of immunotherapy in particular, as at times, radiographic findings do not correlate with histological findings,” Dr. Gray said.
 

CheckMate 816 particulars

CheckMate 816 was conducted in 358 patients with newly diagnosed NSCLC with resectable stage IB tumors of at least 4 cm up to stage IIIA tumors, good performance status, and no known EGFR mutations or ALK alterations.

Patients were randomly assigned on an equal basis to receive either nivolumab at 360 mg plus chemotherapy every 3 weeks for three cycles or chemotherapy alone.

Surgery was planned within 6 week after neoadjuvant therapy. Patients could receive (at the investigator’s discretion) adjuvant chemotherapy with or without radiotherapy but no further immunotherapy during follow-up.

In this analysis, patients who did not undergo surgery or for whom evaluable tissue samples were not available were counted among those whose conditions did not respond to therapy.

Major pathologic response rate (≤10% residual viable tumor cells in the primary lung tumor and sampled lymph nodes), which was a secondary endpoint, was also significantly better, at 36.9% versus 8.9%, translating into an OR of 5.70 (95% confidence interval, 3.16-10.26).

In a subset of patients, the investigators assessed clearance of circulating tumor DNA (ctDNA) from day 1 of the first cycle to day 1 of the third cycle using a highly sensitive tumor-informed approach. They found that ctDNA was notably higher with the combination than with chemotherapy alone and that ctDNA clearance correlated with pCR.
 

Safety similar

“Remarkably, safety was quite similar across the two treatment arms,” Dr. Forde said.

The addition of nivolumab to chemotherapy did not appear to increase either treatment-related adverse events or adverse events of any cause. Grade 3-4 adverse events occurred in 41% of patients in the combination arm versus 44% in the chemotherapy-alone arm.

Treatment-related adverse events leading to discontinuation occurred in 10% of patients in each arm.

Two patients in the nivolumab-chemotherapy arm died from surgically related adverse events (one pulmonary embolism and one aortic rupture). These events were deemed to be unrelated to the study drug.

The investigators are continuing to assess event-free survival and overall survival.

CheckMate 816 is funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Forde has received grants/research support and advisory fees from Bristol-Myers Squibb and others. Dr. Gray has consulted for and has received grant/research support from Bristol-Myers Squibb and others.

A version of this article first appeared on Medscape.com.

Patients with resectable non–small cell lung cancer (NSCLC) often receive treatment before they undergo surgery. For such patients who achieve a pathologic complete response (pCR), the chances of survival are improved.

However, only a small percentage of patients achieve a pCR with neoadjuvant chemotherapy alone.

Adding the immune checkpoint inhibitor nivolumab to platinum-doublet chemotherapy in the neoadjuvant setting boosts the success rate.

Results from the CheckMate 816 trial show that pCR rates improved from 2.2% with chemotherapy alone to 24% when nivolumab was added.

This difference translated into an odds ratio for achieving a pCR with nivolumab plus chemotherapy of 13.94 (P < .0001), reported Patrick M. Forde, MBBCh, from the Johns Hopkins Kimmel Cancer Center, Baltimore.

This primary endpoint, pCR, was defined as complete regression in both the primary tumor and lymph nodes.

“The magnitude of pCR with nivo plus chemo was similar in stage 1B, II, and stage IIIA disease, as well as in both squamous and nonsquamous histologies,” he added.

Dr. Forde presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT003).

The higher pCR rates were seen regardless of PD-L1 expression or tumor mutational burden, Dr. Forde said.

The benefit was also seen when the researchers considered only those patients who subsequently underwent resection (pCR rate of 30.5% with the combination versus 3.2% with chemotherapy alone) and when only the primary tumor was considered (pCR rate of 25.7% vs. 2.8%, respectively).
 

Change in trial design

Invited discussant Jhanelle Gray, MD, from the Moffitt Cancer Center, Tampa, pointed out that the CheckMate 816 trial originally included an experimental arm with double immunotherapy – ipilimumab plus nivolumab – added onto chemotherapy.

However, this third arm was closed after other trials reported promising results from adding a single immunotherapy onto chemotherapy. For example, results of the single-arm NADIM phase 2 study showed a 77.1% progression-free survival rate at 24 months with the combination of nivolumab, paclitaxel, and carboplatin, and the phase 2 KEYNOTE-021 trial showed that adding pembrolizumab to a standard platinum-doublet chemotherapy regimen nearly doubled response rates among patients with previously untreated advanced nonsquamous NSCLC (although there was no advantage in overall survival).

“Even with the change in trial design, patient characteristics were well balanced between the two arms, and the study met its primary endpoint in the intent-to-treat population,” she said.

Dr. Gray also commented that the choice of pCR as a primary endpoint is “intriguing, and the question remains if it represents a valid surrogate endpoint for survival.”

She noted that a meta-analysis of 32 neoadjuvant chemotherapy-based studies in NSCLC, presented at the 2020 European Society of Medical Oncology annual meeting, showed clear associations of pCR and major pathologic response to both overall survival and event-free survival.

“As these findings were established in a backdrop of chemotherapy, work is needed to confirm these findings in the setting of immunotherapy in particular, as at times, radiographic findings do not correlate with histological findings,” Dr. Gray said.
 

CheckMate 816 particulars

CheckMate 816 was conducted in 358 patients with newly diagnosed NSCLC with resectable stage IB tumors of at least 4 cm up to stage IIIA tumors, good performance status, and no known EGFR mutations or ALK alterations.

Patients were randomly assigned on an equal basis to receive either nivolumab at 360 mg plus chemotherapy every 3 weeks for three cycles or chemotherapy alone.

Surgery was planned within 6 week after neoadjuvant therapy. Patients could receive (at the investigator’s discretion) adjuvant chemotherapy with or without radiotherapy but no further immunotherapy during follow-up.

In this analysis, patients who did not undergo surgery or for whom evaluable tissue samples were not available were counted among those whose conditions did not respond to therapy.

Major pathologic response rate (≤10% residual viable tumor cells in the primary lung tumor and sampled lymph nodes), which was a secondary endpoint, was also significantly better, at 36.9% versus 8.9%, translating into an OR of 5.70 (95% confidence interval, 3.16-10.26).

In a subset of patients, the investigators assessed clearance of circulating tumor DNA (ctDNA) from day 1 of the first cycle to day 1 of the third cycle using a highly sensitive tumor-informed approach. They found that ctDNA was notably higher with the combination than with chemotherapy alone and that ctDNA clearance correlated with pCR.
 

Safety similar

“Remarkably, safety was quite similar across the two treatment arms,” Dr. Forde said.

The addition of nivolumab to chemotherapy did not appear to increase either treatment-related adverse events or adverse events of any cause. Grade 3-4 adverse events occurred in 41% of patients in the combination arm versus 44% in the chemotherapy-alone arm.

Treatment-related adverse events leading to discontinuation occurred in 10% of patients in each arm.

Two patients in the nivolumab-chemotherapy arm died from surgically related adverse events (one pulmonary embolism and one aortic rupture). These events were deemed to be unrelated to the study drug.

The investigators are continuing to assess event-free survival and overall survival.

CheckMate 816 is funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Forde has received grants/research support and advisory fees from Bristol-Myers Squibb and others. Dr. Gray has consulted for and has received grant/research support from Bristol-Myers Squibb and others.

A version of this article first appeared on Medscape.com.

Patients with resectable non–small cell lung cancer (NSCLC) often receive treatment before they undergo surgery. For such patients who achieve a pathologic complete response (pCR), the chances of survival are improved.

However, only a small percentage of patients achieve a pCR with neoadjuvant chemotherapy alone.

Adding the immune checkpoint inhibitor nivolumab to platinum-doublet chemotherapy in the neoadjuvant setting boosts the success rate.

Results from the CheckMate 816 trial show that pCR rates improved from 2.2% with chemotherapy alone to 24% when nivolumab was added.

This difference translated into an odds ratio for achieving a pCR with nivolumab plus chemotherapy of 13.94 (P < .0001), reported Patrick M. Forde, MBBCh, from the Johns Hopkins Kimmel Cancer Center, Baltimore.

This primary endpoint, pCR, was defined as complete regression in both the primary tumor and lymph nodes.

“The magnitude of pCR with nivo plus chemo was similar in stage 1B, II, and stage IIIA disease, as well as in both squamous and nonsquamous histologies,” he added.

Dr. Forde presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT003).

The higher pCR rates were seen regardless of PD-L1 expression or tumor mutational burden, Dr. Forde said.

The benefit was also seen when the researchers considered only those patients who subsequently underwent resection (pCR rate of 30.5% with the combination versus 3.2% with chemotherapy alone) and when only the primary tumor was considered (pCR rate of 25.7% vs. 2.8%, respectively).
 

Change in trial design

Invited discussant Jhanelle Gray, MD, from the Moffitt Cancer Center, Tampa, pointed out that the CheckMate 816 trial originally included an experimental arm with double immunotherapy – ipilimumab plus nivolumab – added onto chemotherapy.

However, this third arm was closed after other trials reported promising results from adding a single immunotherapy onto chemotherapy. For example, results of the single-arm NADIM phase 2 study showed a 77.1% progression-free survival rate at 24 months with the combination of nivolumab, paclitaxel, and carboplatin, and the phase 2 KEYNOTE-021 trial showed that adding pembrolizumab to a standard platinum-doublet chemotherapy regimen nearly doubled response rates among patients with previously untreated advanced nonsquamous NSCLC (although there was no advantage in overall survival).

“Even with the change in trial design, patient characteristics were well balanced between the two arms, and the study met its primary endpoint in the intent-to-treat population,” she said.

Dr. Gray also commented that the choice of pCR as a primary endpoint is “intriguing, and the question remains if it represents a valid surrogate endpoint for survival.”

She noted that a meta-analysis of 32 neoadjuvant chemotherapy-based studies in NSCLC, presented at the 2020 European Society of Medical Oncology annual meeting, showed clear associations of pCR and major pathologic response to both overall survival and event-free survival.

“As these findings were established in a backdrop of chemotherapy, work is needed to confirm these findings in the setting of immunotherapy in particular, as at times, radiographic findings do not correlate with histological findings,” Dr. Gray said.
 

CheckMate 816 particulars

CheckMate 816 was conducted in 358 patients with newly diagnosed NSCLC with resectable stage IB tumors of at least 4 cm up to stage IIIA tumors, good performance status, and no known EGFR mutations or ALK alterations.

Patients were randomly assigned on an equal basis to receive either nivolumab at 360 mg plus chemotherapy every 3 weeks for three cycles or chemotherapy alone.

Surgery was planned within 6 week after neoadjuvant therapy. Patients could receive (at the investigator’s discretion) adjuvant chemotherapy with or without radiotherapy but no further immunotherapy during follow-up.

In this analysis, patients who did not undergo surgery or for whom evaluable tissue samples were not available were counted among those whose conditions did not respond to therapy.

Major pathologic response rate (≤10% residual viable tumor cells in the primary lung tumor and sampled lymph nodes), which was a secondary endpoint, was also significantly better, at 36.9% versus 8.9%, translating into an OR of 5.70 (95% confidence interval, 3.16-10.26).

In a subset of patients, the investigators assessed clearance of circulating tumor DNA (ctDNA) from day 1 of the first cycle to day 1 of the third cycle using a highly sensitive tumor-informed approach. They found that ctDNA was notably higher with the combination than with chemotherapy alone and that ctDNA clearance correlated with pCR.
 

Safety similar

“Remarkably, safety was quite similar across the two treatment arms,” Dr. Forde said.

The addition of nivolumab to chemotherapy did not appear to increase either treatment-related adverse events or adverse events of any cause. Grade 3-4 adverse events occurred in 41% of patients in the combination arm versus 44% in the chemotherapy-alone arm.

Treatment-related adverse events leading to discontinuation occurred in 10% of patients in each arm.

Two patients in the nivolumab-chemotherapy arm died from surgically related adverse events (one pulmonary embolism and one aortic rupture). These events were deemed to be unrelated to the study drug.

The investigators are continuing to assess event-free survival and overall survival.

CheckMate 816 is funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Forde has received grants/research support and advisory fees from Bristol-Myers Squibb and others. Dr. Gray has consulted for and has received grant/research support from Bristol-Myers Squibb and others.

A version of this article first appeared on Medscape.com.

Prenatal diagnosis has expanded from identification of aneuploidy to include copy number variants detected on microarray (such as 22q11 deletion syndrome) and now single-gene disorders identified by targeted or exome and genome sequencing. How and when different sequencing tests should be used clinically are questions faced by every provider engaged in modern prenatal diagnosis.

In this Update, we highlight new clinical insights into prenatal sequencing and explore how information gained from sequencing may help us understand some of the unanswered questions in obstetrics.

What is the yield of a RASopathy gene panel with specific prenatal findings?

Scott A, Di Giosaffatte N, Pinna V, et al. When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort. Genet Med. Published online February 10, 2021. doi:10.1038/s41436-020-01093-7.

RASopathies, a group of genetic conditions caused by mutations in the RAS/mitogen-activated protein kinase (RAS-MAPK) pathway, are common, occurring in 1:1,000 to 1:2,500 live births. RASopathies are much more common than 22q11 deletion syndrome, or DiGeorge syndrome, which occurs in 1.4:10,000 live births.¹

RASopathy disorders include Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, and Noonan-like syndrome with loose anagen hair. These are autosomal dominant disorders caused by a pathogenic variant (or mutation) in 1 of more than 20 genes in the RAS-MAPK signaling pathway in the body. Clinical features include congenital anomalies of the kidney and urinary tract, lymphatic anomalies, congenital heart disease (CHD), hypertrophic cardiomyopathy (HCM), postnatal growth disorders, neurodevelopmental disorders, and more rarely hematologic malignancies. Prenatal clues include an increased nuchal translucency (NT), CHD, cystic hygroma, lymphatic anomalies, anomalies of the kidney and urinary tract, hydrops, and HCM.

Cohort of pregnancies that received a RASopathy panel

Scott and colleagues sought to clarify the utility of testing for RASopathies with a prenatal gene panel. They conducted a multicenter retrospective cohort study with cases from 2 hospitals in Italy and Canada; data were collected between 2012 and 2019.

Eligible fetuses were those referred to the prenatal genetics clinic because of an increased NT, increased nuchal fold (NF), hydrops, ascites, thoracic effusions, chylothorax, other lymphatic anomalies, CHD, or HCM with a nondiagnostic (negative) microarray or karyotype. All eligible cases had RASopathy molecular testing in the prenatal or neonatal period.

Among the 352 referrals to clinic, 50 cases of a RASopathy disorder were diagnosed. Additionally, to complement this cohort over the same time period, 25 postnatal diagnoses were made after retrospective review performed to ascertain additional prenatal findings. The size of the testing panel ranged from 9 to 20 genes, which were sent to clinical laboratories that performed sequencing based on standard protocols.

Study outcomes

Overall, 14% of fetuses with an indication for testing had a pathogenic or likely pathogenic variant (diagnostic) on panel testing among 11 genes (notably, all presented results are after excluding copy number variants and aneuploidy). Fetuses with only 1 ultrasonography finding were much less likely to have a positive result than those with more than 1 ultrasonography finding, 3% versus 18%. The highest diagnostic yields were for HCM at 69%; thoracic effusions and ascites, 41%; persistent hydrops, 39%; cystic hygroma combined with another suggestive ultrasonography finding, 28%; CHD, 23%; and persistent cystic hygroma, 21%. Five fetuses were affected with CHD and HCM, and 44% had an intrauterine fetal demise.

Importance of NT size. An isolated increased NT had a diagnostic yield of 1% overall (1/90); however, the size of the NT mattered. Seventeen fetuses had an NT between 3 and 3.5 mm and none of these had diagnostic sequencing, whereas 26% with an NT greater than 6 mm had a diagnostic result (11/43). An increased NF had a diagnostic yield of 25%.

Other findings. Of fetuses with a cystic hygroma, 16% had a pathogenic or likely pathogenic variant, and when these persisted into the second trimester or were associated with other anomalies, the percentages increased to 21% and 28%, respectively. Of prenatal patients, 20.6% had variants of uncertain significance, and 12% of the pathogenic and likely pathogenic variants were inherited, which is less than previously reported series. Additionally, 48% of the postnatal RASopathy diagnosis group did not have an ultrasonography finding on record review.

Continue to: Study strengths and limitations...

Study strengths and limitations

This study presents a large cohort of prenatal and neonatal patients tested for RASopathies at 2 international centers with very granular and clinically useful data about ultrasonography findings and yield of panel testing. Prenatal care providers, geneticists, and computational biologists may find this study of great interest and take away useful information and ideas due to the authors’ presentation and details.

The number of genes tested changed over the inclusion time period, but this is an inescapable reality of retrospective clinical research in an advancing field. The authors presented the prenatal and postnatal diagnoses ultrasonography findings separately and together. Given the different nature of cohort ascertainment, we prefer to consider these groups separately and have presented the data for the prenatal group.

Sequencing provides insights into twin pregnancies

Jonsson H, Magnusdottir E, Eggertsson HP, et al. Differences between germline genomes of monozygotic twins. Nat Genet. 2021;53:27-34. doi:10.1038/s41588 -020-00755-1.

You have a monozygotic twin pair with an anomaly and intend to do diagnostic testing for prenatal diagnosis. The question always arises: Do you sample both twins or just one? Surely, they are genetically identical? A wise mentor once instilled a valuable lesson: Monozygotic twins are more likely to have an anomaly. Their existence is already out of the realm of normal. Finally, we now have an engaging and interesting answer to this and other fascinating embryology questions through the work of Jonsson and colleagues.

Study eligibility criteria and treatment protocol

The authors enrolled 381 twin pairs and 2 monozygotic triplets and compared genome sequencing of different tissues (cheek cells and blood). They went further to assess what other tissues might share the genetic change. To do this, they sequenced the children and the partners of 181 of the pairs. Presumably, if a twin and their offspring shared a genetic change that was not present in the spouse or twin, this genetic change must be present in the oocytes or sperm of the parent twin. The goal of sequencing multiple tissue sources in each twin was to help determine when the genetic change occurred in embryonic development.

Study outcomes

The authors found that 15% of twins had mutations that were absent in the other twin. Because of the extent of tissues that had the genetic change, the authors asserted that these changes must have occurred very early in embryonic development (even from one cell after twinning) for the changes to be near-constitutional (among sampled tissues).

An average of 14 genetic differences were found between twin pairs that developed after twinning. However, the number of differences varied. For example, 39 pairs of twins differed by more than 100 changes, and 38 did not differ at all. Differences between twins were more likely in blood samples than in cheek swabs, suggesting that some differences were due to acquired genetic changes in hematologic cell lines, or clonal hematopoiesis.

The authors also looked at what percentage of sequenced DNA contained the variants (or mutations) and found that many of these DNA differences were present at high amounts in sequencing reads. This suggests that the DNA changes happened very early after twinning in about one-third of pairs. Additionally, if one twin had a near-constitutional change, in 42% of pairs the other twin had a different near-constitutional change. Among the triplets, 2 of a triplet pair shared more genetic similarity and were likely descendent from a single split cell and the third likely was formed from a different set of cells.

By examining the offspring of twins, Jonsson and colleagues found that there were 2.6 early embryonic mutations, and this did not differ when blood or buccal DNA was compared. The rate of transmission of a variant to offspring was proportional to the variant allele frequency (proportion of alternate alleles) in the blood or buccal cells. This is an important counseling point when considering patients with mosaic genetic disorders and counseling about the likelihood of inheritance or transmission to future offspring. If the rate of mosaicism was higher in blood or buccal cells, the likelihood of transmission was higher. Additionally, the mutations did not differ by sex, and there was no relationship to whether the chromosome was maternally or paternally inherited.

Continue to: Study strengths and limitations...

Study strengths and limitations

The authors did not have access to information about chorionicity of the monozygotic twin pairs. Consequently, they were unable to correlate chorionicity with the degree of noted genetic difference between the monozygotic twin pairs. Additionally, although the authors were thoughtful in their utilization of offspring and spouses to infer germline genomic content, the study had a limited number of tissues sampled, which could reduce the applicability. However, the sample size, clinically accessible tissue sampling, and thoughtful analysis used in this study make it an interesting and relevant contribution to reproductive medicine and evolutionary biology.

The genetic landscape of the placenta

Coorens TH, Oliver TR, Sanghvi R, et al. Inherent mosaicism and extensive mutation of human placentas. Nature. Published online March 10, 2021. doi:10.1038/ s41586-021-03345-1.

Confined placental mosaicism (CPM) is a phenomenon in which the genetics of the placenta are different from those of the fetus. Historically, this phenomenon has been described in 1% to 2% of pregnancies based on karyotype data obtained from chorionic villus sampling. Some studies have demonstrated adverse pregnancy outcomes in the setting of CPM, thought to be secondary to aneuploid cells in the placenta leading to insufficiency or dysfunction.

Although our sophistication and level of detail in prenatal genetic testing has rapidly expanded to include information about copy number variants and singlenucleotide changes, their contribution to CPM has been understudied. Coorens and colleagues recently published a landmark study that describes a surprisingly high rate of mosaicism for these smaller genetic changes.

A cohort study of placentas

The authors performed whole genome sequencing on placental samples obtained from 37 term pregnancies. Umbilical cord tissue and maternal blood also were collected and served as controls for fetal and maternal genetic profiles, respectively.

In a subgroup of 5 placentas, lasercapture microscopy was used to separate placental cells of different origins, including trophoblastic cells, mesenchymal core cells, and cells originating from the inner cell mass. To investigate variation within different geographic regions of a single placenta, these cell lines were derived multiple times from each quadrant of the 5 placentas.

Placental biopsies revealed “bottlenecks” of genetic differentiation

Genome sequencing was used uniquely in this study to help delineate the phylogeny of placental cells by tracking somatic mutations both in different geographic locations of each placenta and between different cells of origin within 1 placenta.

The authors concluded that bottlenecks of differentiation in placental development led to unique genetic signatures in every bulk placental sample studied. Their findings led them to describe the placenta as a “patchwork” of independent genetic units resulting from clonal expansion at different stages of embryonic development.

Early insights into human placental cells

This study provides fascinating insight into the surprisingly high rates of copy number variants and single-gene changes that exist, in mosaic form, within human placentas. The authors distinguish the placenta from other human organs (such as the colon, endometrium, liver, and skin) in which many fewer genetic changes exist. In fact, they suggest parallels between the “mutational signature” of the placenta with rapidly dividing neoplastic cells.

As one of the first investigations into the variation and complexity of genetic changes within the placenta, this study was not designed to draw conclusions regarding the clinical impact of the numerous genetic changes described. Further studies will elucidate the potential contribution of genetically mosaic placentas to common adverse obstetric outcomes. ●

Prenatal diagnosis has expanded from identification of aneuploidy to include copy number variants detected on microarray (such as 22q11 deletion syndrome) and now single-gene disorders identified by targeted or exome and genome sequencing. How and when different sequencing tests should be used clinically are questions faced by every provider engaged in modern prenatal diagnosis.

In this Update, we highlight new clinical insights into prenatal sequencing and explore how information gained from sequencing may help us understand some of the unanswered questions in obstetrics.

What is the yield of a RASopathy gene panel with specific prenatal findings?

Scott A, Di Giosaffatte N, Pinna V, et al. When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort. Genet Med. Published online February 10, 2021. doi:10.1038/s41436-020-01093-7.

RASopathies, a group of genetic conditions caused by mutations in the RAS/mitogen-activated protein kinase (RAS-MAPK) pathway, are common, occurring in 1:1,000 to 1:2,500 live births. RASopathies are much more common than 22q11 deletion syndrome, or DiGeorge syndrome, which occurs in 1.4:10,000 live births.¹

RASopathy disorders include Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, and Noonan-like syndrome with loose anagen hair. These are autosomal dominant disorders caused by a pathogenic variant (or mutation) in 1 of more than 20 genes in the RAS-MAPK signaling pathway in the body. Clinical features include congenital anomalies of the kidney and urinary tract, lymphatic anomalies, congenital heart disease (CHD), hypertrophic cardiomyopathy (HCM), postnatal growth disorders, neurodevelopmental disorders, and more rarely hematologic malignancies. Prenatal clues include an increased nuchal translucency (NT), CHD, cystic hygroma, lymphatic anomalies, anomalies of the kidney and urinary tract, hydrops, and HCM.

Cohort of pregnancies that received a RASopathy panel

Scott and colleagues sought to clarify the utility of testing for RASopathies with a prenatal gene panel. They conducted a multicenter retrospective cohort study with cases from 2 hospitals in Italy and Canada; data were collected between 2012 and 2019.

Eligible fetuses were those referred to the prenatal genetics clinic because of an increased NT, increased nuchal fold (NF), hydrops, ascites, thoracic effusions, chylothorax, other lymphatic anomalies, CHD, or HCM with a nondiagnostic (negative) microarray or karyotype. All eligible cases had RASopathy molecular testing in the prenatal or neonatal period.

Among the 352 referrals to clinic, 50 cases of a RASopathy disorder were diagnosed. Additionally, to complement this cohort over the same time period, 25 postnatal diagnoses were made after retrospective review performed to ascertain additional prenatal findings. The size of the testing panel ranged from 9 to 20 genes, which were sent to clinical laboratories that performed sequencing based on standard protocols.

Study outcomes

Overall, 14% of fetuses with an indication for testing had a pathogenic or likely pathogenic variant (diagnostic) on panel testing among 11 genes (notably, all presented results are after excluding copy number variants and aneuploidy). Fetuses with only 1 ultrasonography finding were much less likely to have a positive result than those with more than 1 ultrasonography finding, 3% versus 18%. The highest diagnostic yields were for HCM at 69%; thoracic effusions and ascites, 41%; persistent hydrops, 39%; cystic hygroma combined with another suggestive ultrasonography finding, 28%; CHD, 23%; and persistent cystic hygroma, 21%. Five fetuses were affected with CHD and HCM, and 44% had an intrauterine fetal demise.

Importance of NT size. An isolated increased NT had a diagnostic yield of 1% overall (1/90); however, the size of the NT mattered. Seventeen fetuses had an NT between 3 and 3.5 mm and none of these had diagnostic sequencing, whereas 26% with an NT greater than 6 mm had a diagnostic result (11/43). An increased NF had a diagnostic yield of 25%.

Other findings. Of fetuses with a cystic hygroma, 16% had a pathogenic or likely pathogenic variant, and when these persisted into the second trimester or were associated with other anomalies, the percentages increased to 21% and 28%, respectively. Of prenatal patients, 20.6% had variants of uncertain significance, and 12% of the pathogenic and likely pathogenic variants were inherited, which is less than previously reported series. Additionally, 48% of the postnatal RASopathy diagnosis group did not have an ultrasonography finding on record review.

Continue to: Study strengths and limitations...

Study strengths and limitations

This study presents a large cohort of prenatal and neonatal patients tested for RASopathies at 2 international centers with very granular and clinically useful data about ultrasonography findings and yield of panel testing. Prenatal care providers, geneticists, and computational biologists may find this study of great interest and take away useful information and ideas due to the authors’ presentation and details.

The number of genes tested changed over the inclusion time period, but this is an inescapable reality of retrospective clinical research in an advancing field. The authors presented the prenatal and postnatal diagnoses ultrasonography findings separately and together. Given the different nature of cohort ascertainment, we prefer to consider these groups separately and have presented the data for the prenatal group.

Sequencing provides insights into twin pregnancies

Jonsson H, Magnusdottir E, Eggertsson HP, et al. Differences between germline genomes of monozygotic twins. Nat Genet. 2021;53:27-34. doi:10.1038/s41588 -020-00755-1.

You have a monozygotic twin pair with an anomaly and intend to do diagnostic testing for prenatal diagnosis. The question always arises: Do you sample both twins or just one? Surely, they are genetically identical? A wise mentor once instilled a valuable lesson: Monozygotic twins are more likely to have an anomaly. Their existence is already out of the realm of normal. Finally, we now have an engaging and interesting answer to this and other fascinating embryology questions through the work of Jonsson and colleagues.

Study eligibility criteria and treatment protocol

The authors enrolled 381 twin pairs and 2 monozygotic triplets and compared genome sequencing of different tissues (cheek cells and blood). They went further to assess what other tissues might share the genetic change. To do this, they sequenced the children and the partners of 181 of the pairs. Presumably, if a twin and their offspring shared a genetic change that was not present in the spouse or twin, this genetic change must be present in the oocytes or sperm of the parent twin. The goal of sequencing multiple tissue sources in each twin was to help determine when the genetic change occurred in embryonic development.

Study outcomes

The authors found that 15% of twins had mutations that were absent in the other twin. Because of the extent of tissues that had the genetic change, the authors asserted that these changes must have occurred very early in embryonic development (even from one cell after twinning) for the changes to be near-constitutional (among sampled tissues).

An average of 14 genetic differences were found between twin pairs that developed after twinning. However, the number of differences varied. For example, 39 pairs of twins differed by more than 100 changes, and 38 did not differ at all. Differences between twins were more likely in blood samples than in cheek swabs, suggesting that some differences were due to acquired genetic changes in hematologic cell lines, or clonal hematopoiesis.

The authors also looked at what percentage of sequenced DNA contained the variants (or mutations) and found that many of these DNA differences were present at high amounts in sequencing reads. This suggests that the DNA changes happened very early after twinning in about one-third of pairs. Additionally, if one twin had a near-constitutional change, in 42% of pairs the other twin had a different near-constitutional change. Among the triplets, 2 of a triplet pair shared more genetic similarity and were likely descendent from a single split cell and the third likely was formed from a different set of cells.

By examining the offspring of twins, Jonsson and colleagues found that there were 2.6 early embryonic mutations, and this did not differ when blood or buccal DNA was compared. The rate of transmission of a variant to offspring was proportional to the variant allele frequency (proportion of alternate alleles) in the blood or buccal cells. This is an important counseling point when considering patients with mosaic genetic disorders and counseling about the likelihood of inheritance or transmission to future offspring. If the rate of mosaicism was higher in blood or buccal cells, the likelihood of transmission was higher. Additionally, the mutations did not differ by sex, and there was no relationship to whether the chromosome was maternally or paternally inherited.

Continue to: Study strengths and limitations...

Study strengths and limitations

The authors did not have access to information about chorionicity of the monozygotic twin pairs. Consequently, they were unable to correlate chorionicity with the degree of noted genetic difference between the monozygotic twin pairs. Additionally, although the authors were thoughtful in their utilization of offspring and spouses to infer germline genomic content, the study had a limited number of tissues sampled, which could reduce the applicability. However, the sample size, clinically accessible tissue sampling, and thoughtful analysis used in this study make it an interesting and relevant contribution to reproductive medicine and evolutionary biology.

The genetic landscape of the placenta

Coorens TH, Oliver TR, Sanghvi R, et al. Inherent mosaicism and extensive mutation of human placentas. Nature. Published online March 10, 2021. doi:10.1038/ s41586-021-03345-1.

Confined placental mosaicism (CPM) is a phenomenon in which the genetics of the placenta are different from those of the fetus. Historically, this phenomenon has been described in 1% to 2% of pregnancies based on karyotype data obtained from chorionic villus sampling. Some studies have demonstrated adverse pregnancy outcomes in the setting of CPM, thought to be secondary to aneuploid cells in the placenta leading to insufficiency or dysfunction.

Although our sophistication and level of detail in prenatal genetic testing has rapidly expanded to include information about copy number variants and singlenucleotide changes, their contribution to CPM has been understudied. Coorens and colleagues recently published a landmark study that describes a surprisingly high rate of mosaicism for these smaller genetic changes.

A cohort study of placentas

The authors performed whole genome sequencing on placental samples obtained from 37 term pregnancies. Umbilical cord tissue and maternal blood also were collected and served as controls for fetal and maternal genetic profiles, respectively.

In a subgroup of 5 placentas, lasercapture microscopy was used to separate placental cells of different origins, including trophoblastic cells, mesenchymal core cells, and cells originating from the inner cell mass. To investigate variation within different geographic regions of a single placenta, these cell lines were derived multiple times from each quadrant of the 5 placentas.

Placental biopsies revealed “bottlenecks” of genetic differentiation

Genome sequencing was used uniquely in this study to help delineate the phylogeny of placental cells by tracking somatic mutations both in different geographic locations of each placenta and between different cells of origin within 1 placenta.

The authors concluded that bottlenecks of differentiation in placental development led to unique genetic signatures in every bulk placental sample studied. Their findings led them to describe the placenta as a “patchwork” of independent genetic units resulting from clonal expansion at different stages of embryonic development.

Early insights into human placental cells

This study provides fascinating insight into the surprisingly high rates of copy number variants and single-gene changes that exist, in mosaic form, within human placentas. The authors distinguish the placenta from other human organs (such as the colon, endometrium, liver, and skin) in which many fewer genetic changes exist. In fact, they suggest parallels between the “mutational signature” of the placenta with rapidly dividing neoplastic cells.

As one of the first investigations into the variation and complexity of genetic changes within the placenta, this study was not designed to draw conclusions regarding the clinical impact of the numerous genetic changes described. Further studies will elucidate the potential contribution of genetically mosaic placentas to common adverse obstetric outcomes. ●

Prenatal diagnosis has expanded from identification of aneuploidy to include copy number variants detected on microarray (such as 22q11 deletion syndrome) and now single-gene disorders identified by targeted or exome and genome sequencing. How and when different sequencing tests should be used clinically are questions faced by every provider engaged in modern prenatal diagnosis.

In this Update, we highlight new clinical insights into prenatal sequencing and explore how information gained from sequencing may help us understand some of the unanswered questions in obstetrics.

What is the yield of a RASopathy gene panel with specific prenatal findings?

Scott A, Di Giosaffatte N, Pinna V, et al. When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort. Genet Med. Published online February 10, 2021. doi:10.1038/s41436-020-01093-7.

RASopathies, a group of genetic conditions caused by mutations in the RAS/mitogen-activated protein kinase (RAS-MAPK) pathway, are common, occurring in 1:1,000 to 1:2,500 live births. RASopathies are much more common than 22q11 deletion syndrome, or DiGeorge syndrome, which occurs in 1.4:10,000 live births.¹

RASopathy disorders include Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, and Noonan-like syndrome with loose anagen hair. These are autosomal dominant disorders caused by a pathogenic variant (or mutation) in 1 of more than 20 genes in the RAS-MAPK signaling pathway in the body. Clinical features include congenital anomalies of the kidney and urinary tract, lymphatic anomalies, congenital heart disease (CHD), hypertrophic cardiomyopathy (HCM), postnatal growth disorders, neurodevelopmental disorders, and more rarely hematologic malignancies. Prenatal clues include an increased nuchal translucency (NT), CHD, cystic hygroma, lymphatic anomalies, anomalies of the kidney and urinary tract, hydrops, and HCM.

Cohort of pregnancies that received a RASopathy panel

Scott and colleagues sought to clarify the utility of testing for RASopathies with a prenatal gene panel. They conducted a multicenter retrospective cohort study with cases from 2 hospitals in Italy and Canada; data were collected between 2012 and 2019.

Eligible fetuses were those referred to the prenatal genetics clinic because of an increased NT, increased nuchal fold (NF), hydrops, ascites, thoracic effusions, chylothorax, other lymphatic anomalies, CHD, or HCM with a nondiagnostic (negative) microarray or karyotype. All eligible cases had RASopathy molecular testing in the prenatal or neonatal period.

Among the 352 referrals to clinic, 50 cases of a RASopathy disorder were diagnosed. Additionally, to complement this cohort over the same time period, 25 postnatal diagnoses were made after retrospective review performed to ascertain additional prenatal findings. The size of the testing panel ranged from 9 to 20 genes, which were sent to clinical laboratories that performed sequencing based on standard protocols.

Study outcomes

Overall, 14% of fetuses with an indication for testing had a pathogenic or likely pathogenic variant (diagnostic) on panel testing among 11 genes (notably, all presented results are after excluding copy number variants and aneuploidy). Fetuses with only 1 ultrasonography finding were much less likely to have a positive result than those with more than 1 ultrasonography finding, 3% versus 18%. The highest diagnostic yields were for HCM at 69%; thoracic effusions and ascites, 41%; persistent hydrops, 39%; cystic hygroma combined with another suggestive ultrasonography finding, 28%; CHD, 23%; and persistent cystic hygroma, 21%. Five fetuses were affected with CHD and HCM, and 44% had an intrauterine fetal demise.

Importance of NT size. An isolated increased NT had a diagnostic yield of 1% overall (1/90); however, the size of the NT mattered. Seventeen fetuses had an NT between 3 and 3.5 mm and none of these had diagnostic sequencing, whereas 26% with an NT greater than 6 mm had a diagnostic result (11/43). An increased NF had a diagnostic yield of 25%.

Other findings. Of fetuses with a cystic hygroma, 16% had a pathogenic or likely pathogenic variant, and when these persisted into the second trimester or were associated with other anomalies, the percentages increased to 21% and 28%, respectively. Of prenatal patients, 20.6% had variants of uncertain significance, and 12% of the pathogenic and likely pathogenic variants were inherited, which is less than previously reported series. Additionally, 48% of the postnatal RASopathy diagnosis group did not have an ultrasonography finding on record review.

Continue to: Study strengths and limitations...

Study strengths and limitations

This study presents a large cohort of prenatal and neonatal patients tested for RASopathies at 2 international centers with very granular and clinically useful data about ultrasonography findings and yield of panel testing. Prenatal care providers, geneticists, and computational biologists may find this study of great interest and take away useful information and ideas due to the authors’ presentation and details.

The number of genes tested changed over the inclusion time period, but this is an inescapable reality of retrospective clinical research in an advancing field. The authors presented the prenatal and postnatal diagnoses ultrasonography findings separately and together. Given the different nature of cohort ascertainment, we prefer to consider these groups separately and have presented the data for the prenatal group.

Sequencing provides insights into twin pregnancies

Jonsson H, Magnusdottir E, Eggertsson HP, et al. Differences between germline genomes of monozygotic twins. Nat Genet. 2021;53:27-34. doi:10.1038/s41588 -020-00755-1.

You have a monozygotic twin pair with an anomaly and intend to do diagnostic testing for prenatal diagnosis. The question always arises: Do you sample both twins or just one? Surely, they are genetically identical? A wise mentor once instilled a valuable lesson: Monozygotic twins are more likely to have an anomaly. Their existence is already out of the realm of normal. Finally, we now have an engaging and interesting answer to this and other fascinating embryology questions through the work of Jonsson and colleagues.

Study eligibility criteria and treatment protocol

The authors enrolled 381 twin pairs and 2 monozygotic triplets and compared genome sequencing of different tissues (cheek cells and blood). They went further to assess what other tissues might share the genetic change. To do this, they sequenced the children and the partners of 181 of the pairs. Presumably, if a twin and their offspring shared a genetic change that was not present in the spouse or twin, this genetic change must be present in the oocytes or sperm of the parent twin. The goal of sequencing multiple tissue sources in each twin was to help determine when the genetic change occurred in embryonic development.

Study outcomes

The authors found that 15% of twins had mutations that were absent in the other twin. Because of the extent of tissues that had the genetic change, the authors asserted that these changes must have occurred very early in embryonic development (even from one cell after twinning) for the changes to be near-constitutional (among sampled tissues).

An average of 14 genetic differences were found between twin pairs that developed after twinning. However, the number of differences varied. For example, 39 pairs of twins differed by more than 100 changes, and 38 did not differ at all. Differences between twins were more likely in blood samples than in cheek swabs, suggesting that some differences were due to acquired genetic changes in hematologic cell lines, or clonal hematopoiesis.

The authors also looked at what percentage of sequenced DNA contained the variants (or mutations) and found that many of these DNA differences were present at high amounts in sequencing reads. This suggests that the DNA changes happened very early after twinning in about one-third of pairs. Additionally, if one twin had a near-constitutional change, in 42% of pairs the other twin had a different near-constitutional change. Among the triplets, 2 of a triplet pair shared more genetic similarity and were likely descendent from a single split cell and the third likely was formed from a different set of cells.

By examining the offspring of twins, Jonsson and colleagues found that there were 2.6 early embryonic mutations, and this did not differ when blood or buccal DNA was compared. The rate of transmission of a variant to offspring was proportional to the variant allele frequency (proportion of alternate alleles) in the blood or buccal cells. This is an important counseling point when considering patients with mosaic genetic disorders and counseling about the likelihood of inheritance or transmission to future offspring. If the rate of mosaicism was higher in blood or buccal cells, the likelihood of transmission was higher. Additionally, the mutations did not differ by sex, and there was no relationship to whether the chromosome was maternally or paternally inherited.

Continue to: Study strengths and limitations...

Study strengths and limitations

The authors did not have access to information about chorionicity of the monozygotic twin pairs. Consequently, they were unable to correlate chorionicity with the degree of noted genetic difference between the monozygotic twin pairs. Additionally, although the authors were thoughtful in their utilization of offspring and spouses to infer germline genomic content, the study had a limited number of tissues sampled, which could reduce the applicability. However, the sample size, clinically accessible tissue sampling, and thoughtful analysis used in this study make it an interesting and relevant contribution to reproductive medicine and evolutionary biology.

The genetic landscape of the placenta

Coorens TH, Oliver TR, Sanghvi R, et al. Inherent mosaicism and extensive mutation of human placentas. Nature. Published online March 10, 2021. doi:10.1038/ s41586-021-03345-1.

Confined placental mosaicism (CPM) is a phenomenon in which the genetics of the placenta are different from those of the fetus. Historically, this phenomenon has been described in 1% to 2% of pregnancies based on karyotype data obtained from chorionic villus sampling. Some studies have demonstrated adverse pregnancy outcomes in the setting of CPM, thought to be secondary to aneuploid cells in the placenta leading to insufficiency or dysfunction.

Although our sophistication and level of detail in prenatal genetic testing has rapidly expanded to include information about copy number variants and singlenucleotide changes, their contribution to CPM has been understudied. Coorens and colleagues recently published a landmark study that describes a surprisingly high rate of mosaicism for these smaller genetic changes.

A cohort study of placentas

The authors performed whole genome sequencing on placental samples obtained from 37 term pregnancies. Umbilical cord tissue and maternal blood also were collected and served as controls for fetal and maternal genetic profiles, respectively.

In a subgroup of 5 placentas, lasercapture microscopy was used to separate placental cells of different origins, including trophoblastic cells, mesenchymal core cells, and cells originating from the inner cell mass. To investigate variation within different geographic regions of a single placenta, these cell lines were derived multiple times from each quadrant of the 5 placentas.

Placental biopsies revealed “bottlenecks” of genetic differentiation

Genome sequencing was used uniquely in this study to help delineate the phylogeny of placental cells by tracking somatic mutations both in different geographic locations of each placenta and between different cells of origin within 1 placenta.

The authors concluded that bottlenecks of differentiation in placental development led to unique genetic signatures in every bulk placental sample studied. Their findings led them to describe the placenta as a “patchwork” of independent genetic units resulting from clonal expansion at different stages of embryonic development.

Early insights into human placental cells

This study provides fascinating insight into the surprisingly high rates of copy number variants and single-gene changes that exist, in mosaic form, within human placentas. The authors distinguish the placenta from other human organs (such as the colon, endometrium, liver, and skin) in which many fewer genetic changes exist. In fact, they suggest parallels between the “mutational signature” of the placenta with rapidly dividing neoplastic cells.

As one of the first investigations into the variation and complexity of genetic changes within the placenta, this study was not designed to draw conclusions regarding the clinical impact of the numerous genetic changes described. Further studies will elucidate the potential contribution of genetically mosaic placentas to common adverse obstetric outcomes. ●

Retail Health Clinics (RHCs) are health care facilities located in high-traffic retail outlets with adjacent pharmacies that are intended to provide convenient and affordable care without sacrificing quality. The clinics add an option that complements services to individuals and families who otherwise would need to wait for an appointment with a traditional primary care physician or provider.¹ Appointments are not necessary for episodic health needs. Usually open 7 days a week, RHCs offer extended hours on weekdays.²

The clinics are staffed by licensed, qualified advance practice providers, such as nurse practitioners and physician assistants, who are supervised by family physicians where required by state law. These clinicians have advanced education to diagnose, treat, and prescribe for nonemergent ailments such as colds and flu, rashes and skin irritation, and muscle strains or sprains.³ They are supported by an electronic health record that contains established evidence-based protocols.^2,4

Evolution of retail health clinics

The first RHC, operated by QuickMedx, opened its doors in 2000 in Minneapolis– St. Paul.^1,5 Only patients with a very limited number of illnesses were seen, and payment was cash. In 2005, this clinic was acquired by a major pharmacy retailer, which led to several acquisitions by other retailers and health care systems. In addition to accepting cash for a visit, the clinics formed contracts with health insurance companies. The average cost of a visit to an RHC in 2016 was estimated to be $70, considerably less than the cost at urgent care clinics ($124) and emergency rooms ($356).⁶

Today, more than 20 companies provide health care services at RHCs (TABLE 1). CVS (MinuteClinic) has the most retail clinics, followed by Walgreens, Kroger, Rite Aid, and Zoom+Care.^1,2 There are now about 3,300 clinics in the United States, Canada, and Mexico (nearly all are located in the United States).² Currently, RHCs are present in 44 states and the District of Columbia. Alabama, Alaska, Idaho, North Dakota, Vermont, and Wyoming are the only states without an RHC, while large-population states (California, Florida, Ohio, Pennsylvania, and Texas) have experienced an explosion in clinic openings.²

RHCs are found in high foot traffic locations, such as large retailers and grocery stores, and in prioritizing services such as drug stores. By analyzing 2019 clinic openings and population centers, the Convenient Care Association determined that more than half of the US population now lives within a 10-minute drive of an RHC.² New locations are established on a regular basis, resulting in some flux in the total number of clinics.

Continue to: Services that RHCs provide...

As RHC locations expand, so do their services. Most RHCs pursue 1 of 2 models: health hubs or virtual care. Health hubs offer an expansion of services, which has resulted in retail health looking and operating more like the primary care providers in their communities.^1,2 While most chains intend for patient visits to be brief, the growing health hub model intends to expand the period for patient visits. The major companies, CVS, Kroger, and Walmart, are offering an increase in their services and granting their providers a greater capacity to screen and treat patients for a wider range of conditions. By contrast, other clinic operators, such as Rite Aid RediClinics, are pursuing a more episodic and convenient care model with a greater adoption and expansion of telehealth and telemedicine.

Services at RHCs involve primarily acute care as well as some basic chronic disease management. About 90% of visits are for the following conditions: influenza, immunizations, upper respiratory infections, sinusitis, bronchitis, sore throat, inner ear infection, conjunctivitis, urinary tract infections, and blood tests.^1-3 Other services available at most RHC locations involve screening and monitoring, wellness and physicals, travel health, treatment of minor injuries, and vaccinations and injections.

Women constitute half of all customers, and all RHCs offer women’s health services.⁷ Along with addressing acute care needs, women’s health services include contraception care and options, human papillomavirus (HPV) screening, pregnancy testing and initial prenatal evaluation, and evaluation for and treatment of urinary tract, bladder, and yeast infections.^2,6

All RHCs provide counseling on sexual health concerns. Nearly all retail clinics in the United States provide screening and treatment for patients and their partners with sexually transmitted infections. RHC providers are required to follow up with patients regarding any blood work or culture results. When positive test results are confirmed for serious infections, such as hepatitis B and C, syphilis, and HIV, patients customarily are referred for treatment.²

The RHC patient base

RHCs serve an expanding base of patients who cite convenience as their primary motivation for utilizing these clinics. This consumer-driven market now encompasses, by some measures, nearly 50 million visits annually.² These numbers have risen every year alongside a consistent increase in the number and spread of clinics across the country. During the COVID-19 pandemic, visits declined, consistent with other health care touchpoints, due to concerns about spreading the coronavirus.

The RHC industry has continued to adapt to a changing health care climate by embracing new telehealth solutions, enabling remote care, and expanding services by consumer demand.^1,7 While convenience is a primary motivation for visiting an RHC, about two-thirds of RHC patients do not have a primary care provider.¹ To support a broader continuum of care, RHCs regularly refer patients who do not have a primary care provider to other health care touchpoints when necessary.

Young and middle-aged adults (18–44 years) comprise the largest group of RHC patients. When patients were asked why they chose an RHC over “traditional doctors’ clinics,” many cited difficulties in accessing care, the appeal of lower costs, and proximity. The proportion of female RHC users was 50.9% and 56.8% for RHC nonusers.^1-3

How RHCs compare with other episodic care clinics

The consumer has more choices to seek episodic care other than at physicians’ clinics or emergency rooms. An RHC, urgent care clinic, or freestanding emergency clinic increase access points for consumers. Along with the expanding number of RHCs, there are nearly 9,000 US urgent care centers, according to the Urgent Care Association, and more than 550 freestanding emergency rooms.⁸

The main differences between these episodic care clinics are shown in TABLE 2. Hours of operation, types of conditions, available providers, location of the facility, and estimated costs are compared. All provide expanded business hours. Retail clinics address some chronic disease management along with acute care, engage only advanced practitioners, use retail stores, and are less costly to consumers.^3,4,9

An RHC, urgent care clinic, or emergency department increases access points for consumers. Many emergency department visits can be handled in ambulatory settings such as RHCs and urgent care clinics.^9,10 This can be helpful, especially in rural areas with a shortage of physicians. Most people want a relationship with a physician who will manage their care rather than seeing a different provider at every visit. While ObGyns deliver comprehensive care to women, however, in some underserved areas non-ObGyn clinics can fill the void. For example, RHCs can sometimes provide needed immunizations and health care information required in underserved areas.¹¹

Many physicians are frustrated when they see patients who do not have a complete copy of their medical record and must piecemeal how to treat a patient. RHCs have adopted electronic medical records, and they regularly encourage patients to contact their physician (or find one, which can be difficult). Another limitation can be a referral from an RHC to a subspecialist rather than a primary care physician who could equally handle the condition.

Continue to: What ObGyns can do...

What ObGyns can do

Consumers have become accustomed to obtaining services where and when they want them, and they expect the same from their health care providers. While ObGyn practices are less affected by RHCs than family physicians or general internists, health care delivery in traditional clinics must be user friendly—that is, better, cheaper, and faster—for the patient-consumer to be more satisfied. Looking ahead, a nearby women’s health care group needs to have someone on call 24 hours a day, 7 days a week. That way, you can tell your patients that they can call you first if they need help. In the case of an ObGyn recommending that a patient go to an RHC or urgent care center, you will be aware of the visit and can follow up with your patient afterward.

Traditional clinics need to create ways for patients with acute illnesses to be seen that same day. Offering extended hours or technology options, such as online support, can help. Text message reminders, same-day access for appointments, and price transparency are necessary. It is important to encourage your women’s health patients to become more responsible for their own health and care, while taking into consideration their social determinants of health. While ObGyns should discuss with their patients when to visit an RHC (especially when their clinic is closed), emphasize that your own clinic is the patient’s medical home and encourage the importance of communicating what occurred during the RHC visit.

Working as a team by communicating well can create a community of health. It would be appropriate for you to represent your group by meeting practitioners at the nearby RHC. Being accessible and helpful would create a friendly and open professional relationship. Conversely, providers at retail clinics need to continually appreciate that women’s health clinics offer more comprehensive care. Select referrals from RHCs would help the most important person, the patient herself. ●

Retail Health Clinics (RHCs) are health care facilities located in high-traffic retail outlets with adjacent pharmacies that are intended to provide convenient and affordable care without sacrificing quality. The clinics add an option that complements services to individuals and families who otherwise would need to wait for an appointment with a traditional primary care physician or provider.¹ Appointments are not necessary for episodic health needs. Usually open 7 days a week, RHCs offer extended hours on weekdays.²

The clinics are staffed by licensed, qualified advance practice providers, such as nurse practitioners and physician assistants, who are supervised by family physicians where required by state law. These clinicians have advanced education to diagnose, treat, and prescribe for nonemergent ailments such as colds and flu, rashes and skin irritation, and muscle strains or sprains.³ They are supported by an electronic health record that contains established evidence-based protocols.^2,4

Evolution of retail health clinics

The first RHC, operated by QuickMedx, opened its doors in 2000 in Minneapolis– St. Paul.^1,5 Only patients with a very limited number of illnesses were seen, and payment was cash. In 2005, this clinic was acquired by a major pharmacy retailer, which led to several acquisitions by other retailers and health care systems. In addition to accepting cash for a visit, the clinics formed contracts with health insurance companies. The average cost of a visit to an RHC in 2016 was estimated to be $70, considerably less than the cost at urgent care clinics ($124) and emergency rooms ($356).⁶

Today, more than 20 companies provide health care services at RHCs (TABLE 1). CVS (MinuteClinic) has the most retail clinics, followed by Walgreens, Kroger, Rite Aid, and Zoom+Care.^1,2 There are now about 3,300 clinics in the United States, Canada, and Mexico (nearly all are located in the United States).² Currently, RHCs are present in 44 states and the District of Columbia. Alabama, Alaska, Idaho, North Dakota, Vermont, and Wyoming are the only states without an RHC, while large-population states (California, Florida, Ohio, Pennsylvania, and Texas) have experienced an explosion in clinic openings.²

RHCs are found in high foot traffic locations, such as large retailers and grocery stores, and in prioritizing services such as drug stores. By analyzing 2019 clinic openings and population centers, the Convenient Care Association determined that more than half of the US population now lives within a 10-minute drive of an RHC.² New locations are established on a regular basis, resulting in some flux in the total number of clinics.

Continue to: Services that RHCs provide...

As RHC locations expand, so do their services. Most RHCs pursue 1 of 2 models: health hubs or virtual care. Health hubs offer an expansion of services, which has resulted in retail health looking and operating more like the primary care providers in their communities.^1,2 While most chains intend for patient visits to be brief, the growing health hub model intends to expand the period for patient visits. The major companies, CVS, Kroger, and Walmart, are offering an increase in their services and granting their providers a greater capacity to screen and treat patients for a wider range of conditions. By contrast, other clinic operators, such as Rite Aid RediClinics, are pursuing a more episodic and convenient care model with a greater adoption and expansion of telehealth and telemedicine.

Services at RHCs involve primarily acute care as well as some basic chronic disease management. About 90% of visits are for the following conditions: influenza, immunizations, upper respiratory infections, sinusitis, bronchitis, sore throat, inner ear infection, conjunctivitis, urinary tract infections, and blood tests.^1-3 Other services available at most RHC locations involve screening and monitoring, wellness and physicals, travel health, treatment of minor injuries, and vaccinations and injections.

Women constitute half of all customers, and all RHCs offer women’s health services.⁷ Along with addressing acute care needs, women’s health services include contraception care and options, human papillomavirus (HPV) screening, pregnancy testing and initial prenatal evaluation, and evaluation for and treatment of urinary tract, bladder, and yeast infections.^2,6

All RHCs provide counseling on sexual health concerns. Nearly all retail clinics in the United States provide screening and treatment for patients and their partners with sexually transmitted infections. RHC providers are required to follow up with patients regarding any blood work or culture results. When positive test results are confirmed for serious infections, such as hepatitis B and C, syphilis, and HIV, patients customarily are referred for treatment.²

The RHC patient base

RHCs serve an expanding base of patients who cite convenience as their primary motivation for utilizing these clinics. This consumer-driven market now encompasses, by some measures, nearly 50 million visits annually.² These numbers have risen every year alongside a consistent increase in the number and spread of clinics across the country. During the COVID-19 pandemic, visits declined, consistent with other health care touchpoints, due to concerns about spreading the coronavirus.

The RHC industry has continued to adapt to a changing health care climate by embracing new telehealth solutions, enabling remote care, and expanding services by consumer demand.^1,7 While convenience is a primary motivation for visiting an RHC, about two-thirds of RHC patients do not have a primary care provider.¹ To support a broader continuum of care, RHCs regularly refer patients who do not have a primary care provider to other health care touchpoints when necessary.

Young and middle-aged adults (18–44 years) comprise the largest group of RHC patients. When patients were asked why they chose an RHC over “traditional doctors’ clinics,” many cited difficulties in accessing care, the appeal of lower costs, and proximity. The proportion of female RHC users was 50.9% and 56.8% for RHC nonusers.^1-3

How RHCs compare with other episodic care clinics

The consumer has more choices to seek episodic care other than at physicians’ clinics or emergency rooms. An RHC, urgent care clinic, or freestanding emergency clinic increase access points for consumers. Along with the expanding number of RHCs, there are nearly 9,000 US urgent care centers, according to the Urgent Care Association, and more than 550 freestanding emergency rooms.⁸

The main differences between these episodic care clinics are shown in TABLE 2. Hours of operation, types of conditions, available providers, location of the facility, and estimated costs are compared. All provide expanded business hours. Retail clinics address some chronic disease management along with acute care, engage only advanced practitioners, use retail stores, and are less costly to consumers.^3,4,9

An RHC, urgent care clinic, or emergency department increases access points for consumers. Many emergency department visits can be handled in ambulatory settings such as RHCs and urgent care clinics.^9,10 This can be helpful, especially in rural areas with a shortage of physicians. Most people want a relationship with a physician who will manage their care rather than seeing a different provider at every visit. While ObGyns deliver comprehensive care to women, however, in some underserved areas non-ObGyn clinics can fill the void. For example, RHCs can sometimes provide needed immunizations and health care information required in underserved areas.¹¹

Many physicians are frustrated when they see patients who do not have a complete copy of their medical record and must piecemeal how to treat a patient. RHCs have adopted electronic medical records, and they regularly encourage patients to contact their physician (or find one, which can be difficult). Another limitation can be a referral from an RHC to a subspecialist rather than a primary care physician who could equally handle the condition.

Continue to: What ObGyns can do...

What ObGyns can do

Consumers have become accustomed to obtaining services where and when they want them, and they expect the same from their health care providers. While ObGyn practices are less affected by RHCs than family physicians or general internists, health care delivery in traditional clinics must be user friendly—that is, better, cheaper, and faster—for the patient-consumer to be more satisfied. Looking ahead, a nearby women’s health care group needs to have someone on call 24 hours a day, 7 days a week. That way, you can tell your patients that they can call you first if they need help. In the case of an ObGyn recommending that a patient go to an RHC or urgent care center, you will be aware of the visit and can follow up with your patient afterward.

Traditional clinics need to create ways for patients with acute illnesses to be seen that same day. Offering extended hours or technology options, such as online support, can help. Text message reminders, same-day access for appointments, and price transparency are necessary. It is important to encourage your women’s health patients to become more responsible for their own health and care, while taking into consideration their social determinants of health. While ObGyns should discuss with their patients when to visit an RHC (especially when their clinic is closed), emphasize that your own clinic is the patient’s medical home and encourage the importance of communicating what occurred during the RHC visit.

Working as a team by communicating well can create a community of health. It would be appropriate for you to represent your group by meeting practitioners at the nearby RHC. Being accessible and helpful would create a friendly and open professional relationship. Conversely, providers at retail clinics need to continually appreciate that women’s health clinics offer more comprehensive care. Select referrals from RHCs would help the most important person, the patient herself. ●

Retail Health Clinics (RHCs) are health care facilities located in high-traffic retail outlets with adjacent pharmacies that are intended to provide convenient and affordable care without sacrificing quality. The clinics add an option that complements services to individuals and families who otherwise would need to wait for an appointment with a traditional primary care physician or provider.¹ Appointments are not necessary for episodic health needs. Usually open 7 days a week, RHCs offer extended hours on weekdays.²

The clinics are staffed by licensed, qualified advance practice providers, such as nurse practitioners and physician assistants, who are supervised by family physicians where required by state law. These clinicians have advanced education to diagnose, treat, and prescribe for nonemergent ailments such as colds and flu, rashes and skin irritation, and muscle strains or sprains.³ They are supported by an electronic health record that contains established evidence-based protocols.^2,4

Evolution of retail health clinics

The first RHC, operated by QuickMedx, opened its doors in 2000 in Minneapolis– St. Paul.^1,5 Only patients with a very limited number of illnesses were seen, and payment was cash. In 2005, this clinic was acquired by a major pharmacy retailer, which led to several acquisitions by other retailers and health care systems. In addition to accepting cash for a visit, the clinics formed contracts with health insurance companies. The average cost of a visit to an RHC in 2016 was estimated to be $70, considerably less than the cost at urgent care clinics ($124) and emergency rooms ($356).⁶

Today, more than 20 companies provide health care services at RHCs (TABLE 1). CVS (MinuteClinic) has the most retail clinics, followed by Walgreens, Kroger, Rite Aid, and Zoom+Care.^1,2 There are now about 3,300 clinics in the United States, Canada, and Mexico (nearly all are located in the United States).² Currently, RHCs are present in 44 states and the District of Columbia. Alabama, Alaska, Idaho, North Dakota, Vermont, and Wyoming are the only states without an RHC, while large-population states (California, Florida, Ohio, Pennsylvania, and Texas) have experienced an explosion in clinic openings.²

RHCs are found in high foot traffic locations, such as large retailers and grocery stores, and in prioritizing services such as drug stores. By analyzing 2019 clinic openings and population centers, the Convenient Care Association determined that more than half of the US population now lives within a 10-minute drive of an RHC.² New locations are established on a regular basis, resulting in some flux in the total number of clinics.

Continue to: Services that RHCs provide...

As RHC locations expand, so do their services. Most RHCs pursue 1 of 2 models: health hubs or virtual care. Health hubs offer an expansion of services, which has resulted in retail health looking and operating more like the primary care providers in their communities.^1,2 While most chains intend for patient visits to be brief, the growing health hub model intends to expand the period for patient visits. The major companies, CVS, Kroger, and Walmart, are offering an increase in their services and granting their providers a greater capacity to screen and treat patients for a wider range of conditions. By contrast, other clinic operators, such as Rite Aid RediClinics, are pursuing a more episodic and convenient care model with a greater adoption and expansion of telehealth and telemedicine.

Services at RHCs involve primarily acute care as well as some basic chronic disease management. About 90% of visits are for the following conditions: influenza, immunizations, upper respiratory infections, sinusitis, bronchitis, sore throat, inner ear infection, conjunctivitis, urinary tract infections, and blood tests.^1-3 Other services available at most RHC locations involve screening and monitoring, wellness and physicals, travel health, treatment of minor injuries, and vaccinations and injections.

Women constitute half of all customers, and all RHCs offer women’s health services.⁷ Along with addressing acute care needs, women’s health services include contraception care and options, human papillomavirus (HPV) screening, pregnancy testing and initial prenatal evaluation, and evaluation for and treatment of urinary tract, bladder, and yeast infections.^2,6

All RHCs provide counseling on sexual health concerns. Nearly all retail clinics in the United States provide screening and treatment for patients and their partners with sexually transmitted infections. RHC providers are required to follow up with patients regarding any blood work or culture results. When positive test results are confirmed for serious infections, such as hepatitis B and C, syphilis, and HIV, patients customarily are referred for treatment.²

The RHC patient base

RHCs serve an expanding base of patients who cite convenience as their primary motivation for utilizing these clinics. This consumer-driven market now encompasses, by some measures, nearly 50 million visits annually.² These numbers have risen every year alongside a consistent increase in the number and spread of clinics across the country. During the COVID-19 pandemic, visits declined, consistent with other health care touchpoints, due to concerns about spreading the coronavirus.

The RHC industry has continued to adapt to a changing health care climate by embracing new telehealth solutions, enabling remote care, and expanding services by consumer demand.^1,7 While convenience is a primary motivation for visiting an RHC, about two-thirds of RHC patients do not have a primary care provider.¹ To support a broader continuum of care, RHCs regularly refer patients who do not have a primary care provider to other health care touchpoints when necessary.

Young and middle-aged adults (18–44 years) comprise the largest group of RHC patients. When patients were asked why they chose an RHC over “traditional doctors’ clinics,” many cited difficulties in accessing care, the appeal of lower costs, and proximity. The proportion of female RHC users was 50.9% and 56.8% for RHC nonusers.^1-3

How RHCs compare with other episodic care clinics

The consumer has more choices to seek episodic care other than at physicians’ clinics or emergency rooms. An RHC, urgent care clinic, or freestanding emergency clinic increase access points for consumers. Along with the expanding number of RHCs, there are nearly 9,000 US urgent care centers, according to the Urgent Care Association, and more than 550 freestanding emergency rooms.⁸

The main differences between these episodic care clinics are shown in TABLE 2. Hours of operation, types of conditions, available providers, location of the facility, and estimated costs are compared. All provide expanded business hours. Retail clinics address some chronic disease management along with acute care, engage only advanced practitioners, use retail stores, and are less costly to consumers.^3,4,9

An RHC, urgent care clinic, or emergency department increases access points for consumers. Many emergency department visits can be handled in ambulatory settings such as RHCs and urgent care clinics.^9,10 This can be helpful, especially in rural areas with a shortage of physicians. Most people want a relationship with a physician who will manage their care rather than seeing a different provider at every visit. While ObGyns deliver comprehensive care to women, however, in some underserved areas non-ObGyn clinics can fill the void. For example, RHCs can sometimes provide needed immunizations and health care information required in underserved areas.¹¹

Many physicians are frustrated when they see patients who do not have a complete copy of their medical record and must piecemeal how to treat a patient. RHCs have adopted electronic medical records, and they regularly encourage patients to contact their physician (or find one, which can be difficult). Another limitation can be a referral from an RHC to a subspecialist rather than a primary care physician who could equally handle the condition.

Continue to: What ObGyns can do...

What ObGyns can do

Consumers have become accustomed to obtaining services where and when they want them, and they expect the same from their health care providers. While ObGyn practices are less affected by RHCs than family physicians or general internists, health care delivery in traditional clinics must be user friendly—that is, better, cheaper, and faster—for the patient-consumer to be more satisfied. Looking ahead, a nearby women’s health care group needs to have someone on call 24 hours a day, 7 days a week. That way, you can tell your patients that they can call you first if they need help. In the case of an ObGyn recommending that a patient go to an RHC or urgent care center, you will be aware of the visit and can follow up with your patient afterward.

Traditional clinics need to create ways for patients with acute illnesses to be seen that same day. Offering extended hours or technology options, such as online support, can help. Text message reminders, same-day access for appointments, and price transparency are necessary. It is important to encourage your women’s health patients to become more responsible for their own health and care, while taking into consideration their social determinants of health. While ObGyns should discuss with their patients when to visit an RHC (especially when their clinic is closed), emphasize that your own clinic is the patient’s medical home and encourage the importance of communicating what occurred during the RHC visit.

Working as a team by communicating well can create a community of health. It would be appropriate for you to represent your group by meeting practitioners at the nearby RHC. Being accessible and helpful would create a friendly and open professional relationship. Conversely, providers at retail clinics need to continually appreciate that women’s health clinics offer more comprehensive care. Select referrals from RHCs would help the most important person, the patient herself. ●

CASE Pregnant woman with herpes simplex virus

A 26-year-old primigravid woman at 12 weeks of gestation indicates that she had an initial episode of herpes simplex virus (HSV) 6 years prior to presentation. Subsequently, she has had 1 to 2 recurrent episodes each year. She asks about the implications of HSV infection in pregnancy, particularly if anything can be done to prevent a recurrent outbreak near her due date and reduce the need for a cesarean delivery.

How would you counsel this patient?

Meet our perpetrator

Herpes simplex virus (HSV), the most prevalent sexually transmitted infection, is a DNA virus that has 2 major strains: HSV-1 and HSV-2. HSV-1 frequently is acquired in early childhood through nonsexual contact and typically causes orolabial and, less commonly, genital outbreaks. HSV-2 is almost always acquired through sexual contact and causes mainly genital outbreaks.¹

There are 3 classifications of HSV infection: primary, initial-nonprimary, and recurrent (TABLE).

Primary infection refers to infection in a person without antibodies to either type of HSV.

Initial-nonprimary infection refers to acquisition of HSV-2 in a patient with preexisting antibodies to HSV-1 or vice versa. Patients tend to have more severe symptoms with primary as opposed to initial-nonprimary infection because, with the latter condition, preexisting antibodies provide partial protection against the opposing HSV type.¹ According to the Centers for Disease Control and Prevention, the seroprevalence of HSV-1 has decreased by approximately 23% in adolescents aged 14 to 19 years, with a resultant increase in the number of primary HSV-1 genital infections through oral-sexual contact in adulthood.²

Recurrent infection refers to reactivation of the same HSV type corresponding to the serum antibodies.

Clinical presentation

After an incubation period of 4 to 7 days, symptomatic patients with primary and initial-nonprimary genital HSV infections typically present with multiple, bilateral genital lesions at various stages of development. These lesions begin as small erythematous macules and then progress to papules, vesicles, pustules, ulcers, and crusted scabs over a period of 3 to 6 weeks¹ (FIGURE). Patients also may present with fever, headache, fatigue, dysuria, and painful inguinal lymphadenopathy. Patients with recurrent infections usually experience prodromal itching or tingling for 2 to 5 days prior to the appearance of unilateral lesions, which persist for only 5 to 10 days. Systemic symptoms rarely are present. HSV-1 genital infection has a symptomatic recurrence rate of 20% to 50% within the first year, while HSV-2 has a recurrence rate of 70% to 90%.¹

The majority of primary and initial-nonprimary infections are subclinical. One study showed that 74% of HSV-1 and 63% of HSV-2 initial genital herpes infections were asymptomatic.³ The relevance of this observation is that patients may not pre­sent for evaluation unless they experience a symptomatic recurrent infection. Meanwhile, they are asymptomatically shedding the virus and unknowingly transmitting HSV to their sexual partners. Asymptomatic viral shedding is more common with HSV-2 and is the most common source of transmission.⁴ The rate of asymptomatic shedding is unpredictable and has been shown to occur on 10% to 20% of days.¹

Diagnosis and treatment

The gold standard for diagnosing HSV infection is viral culture; however, polymerase chain reaction (PCR) assays are faster to result and more sensitive.^4,5 Both culture and PCR studies can distinguish the HSV type, allowing physicians to counsel patients regarding the expected clinical course, rate of recurrence, and implications for future pregnancies. After an initial infection, it may take up to 12 weeks for patients to develop detectable antibodies. Therefore, serology can be quite useful in determining the timing and classification of the infection. For example, a patient with HSV-2 isolated on viral culture or PCR and HSV-1 antibodies identified on serology is classified as having an initial-nonprimary infection.⁴

HSV treatment is dependent on the classification of infection. Treatment of primary and initial-nonprimary infection includes:

• acyclovir 400 mg orally 3 times daily
• valacyclovir 1,000 mg orally twice daily, or
• famciclovir 250 mg orally 3 times daily for 7 to 10 days.

Ideally, treatment should be initiated within 72 hours of symptom onset.

Recurrent infections may be treated with:

• acyclovir 400 mg orally three times daily for 5 days
• valacyclovir 1,000 mg orally once daily for 5 days, or
• famciclovir 1,000 mg orally every 12 hours for 2 doses.

Ideally, treatment should begin within 24 hours of symptom onset.^4,6

Patients with immunocompromising conditions, severe/frequent outbreaks (>6 per year), or who desire to reduce the risk of transmission to HSV-uninfected partners are candidates for chronic suppressive therapy. Suppressive options include acyclovir 400 mg orally twice daily, valacyclovir 500 mg orally once daily, and famciclovir 250 mg orally twice daily. Of note, there are many regimens available for acyclovir, valacyclovir, and famciclovir; all have similar efficacy in decreasing symptom severity, time to lesion healing, and duration of viral shedding.⁶ Acyclovir generally is the least expensive option.⁴

Continue to: Pregnancy and prevention...

During pregnancy, 2% of women will acquire HSV, and 70% of these women will be asymptomatic.^4,7 Approximately one-third to one-half of neonatal infections are caused by HSV-1.⁸ The most devastating complication of HSV infection in pregnancy is transmission to the newborn. Neonatal herpes is defined as the diagnosis of an HSV infection in a neonate within the first 28 days of life. The disease spectrum varies widely, and early recognition and treatment can substantially reduce the degree of morbidity and mortality associated with systemic infections.

HSV infection limited to the skin, eyes, and mucosal surfaces accounts for 45% of neonatal infections. When this condition is promptly recognized, neonates typically respond well to intravenous acyclovir, with prevention of systemic progression and overall good clinical outcomes. Infections of the central nervous system account for 30% of infections and are more difficult to diagnose due to the nonspecific symptomatology, including lethargy, poor feeding, seizures, and possible absence of lesions. The risk for death decreases from 50% to 6% with treatment; however, most neonates will still require close long-term surveillance for achievement of neurodevelopmental milestones and frequent ophthalmologic and hearing assessments.^8,9 Disseminated HSV accounts for 25% of infections and can cause multiorgan failure, with a 31% risk for death despite treatment.⁵ Therefore, the cornerstone of managing HSV infection in pregnancy is focusing clinical efforts on prevention of transmission to the neonate.

More than 90% of neonatal herpes infections are acquired intrapartum,⁴ with 60% to 80% of cases occurring in women who developed HSV in the third trimester near the time of delivery.⁵ Neonates delivered vaginally to these women have a 30% to 50% risk of infection, compared to a <1% risk in neonates born to women with recurrent HSV.^1,5,10 The discrepancy in infection risk is thought to be secondary to higher HSV viral loads after an initial infection as opposed to a recurrent infection. Furthermore, acquisition of HSV near term does not allow for the 6 to 12 weeks necessary to develop antibodies that can cross the placenta and provide neonatal protection. The risk of vertical transmission is approximately 25% with an initial-nonprimary episode, reflecting the partial protection afforded by antibody against the other viral serotype.¹¹

Prophylactic therapy has been shown to reduce the rate of asymptomatic viral shedding and recurrent infections near term.⁷ To reduce the risk of intrapartum transmission, women with a history of HSV prior to or during pregnancy should be treated with acyclovir 400 mg orally 3 times daily starting at 36 weeks of gestation. When patients present with rupture of membranes or labor, they should be asked about prodromal symptoms and thoroughly examined. If prodromal symptoms are present or genital lesions identified, patients should undergo cesarean delivery.¹² Some experts also recommend cesarean delivery for women who acquire primary or initial-nonprimary HSV infection in the third trimester due to higher viral loads and potential lack of antibodies at the time of delivery.^8,12 However, this recommendation has not been validated by a rigorous prospective randomized clinical trial. When clinically feasible, avoidance of invasive fetal monitoring during labor also has been shown to decrease the risk of HSV transmission by approximately 84% in women with asymptomatic viral shedding.¹² This concept may be extrapolated to include assisted delivery with vacuum or forceps.

Universal screening for HSV infection in pregnancy is controversial and widely debated. Most HSV seropositive patients are asymptomatic and will not report a history of HSV infection at the initial prenatal visit. Universal screening, therefore, may increase the rate of unnecessary cesarean deliveries and medical interventions. HSV serology may be beneficial, however, in identifying seronegative pregnant women who have seropositive partners. Two recent studies have shown that 15% to 25% of couples have discordant HSV serologies and consequently are at risk of acquiring primary or initial-nonprimary HSV near term.^4,5 These couples should be counseled concerning the use of condoms in the first and second trimester (50% reduction in HSV transmission) and abstinence in the third trimester.⁵ The seropositive partner also can be offered suppressive therapy, which provides a 48% reduction in the risk of HSV transmission.⁴ Ultimately, the difficulty lies in balancing the clinical benefits and cost of asymptomatic screening.¹¹

CASE Resolved

The patient should be counseled that HSV infection rarely affects the fetus in utero, and transmission almost always occurs during the delivery process. This patient should receive prophylactic treatment with acyclovir beginning at 36 weeks of gestation to reduce the risk of an outbreak near the time of delivery. ●

CASE Pregnant woman with herpes simplex virus

A 26-year-old primigravid woman at 12 weeks of gestation indicates that she had an initial episode of herpes simplex virus (HSV) 6 years prior to presentation. Subsequently, she has had 1 to 2 recurrent episodes each year. She asks about the implications of HSV infection in pregnancy, particularly if anything can be done to prevent a recurrent outbreak near her due date and reduce the need for a cesarean delivery.

How would you counsel this patient?

Meet our perpetrator

Herpes simplex virus (HSV), the most prevalent sexually transmitted infection, is a DNA virus that has 2 major strains: HSV-1 and HSV-2. HSV-1 frequently is acquired in early childhood through nonsexual contact and typically causes orolabial and, less commonly, genital outbreaks. HSV-2 is almost always acquired through sexual contact and causes mainly genital outbreaks.¹

There are 3 classifications of HSV infection: primary, initial-nonprimary, and recurrent (TABLE).

Primary infection refers to infection in a person without antibodies to either type of HSV.

Initial-nonprimary infection refers to acquisition of HSV-2 in a patient with preexisting antibodies to HSV-1 or vice versa. Patients tend to have more severe symptoms with primary as opposed to initial-nonprimary infection because, with the latter condition, preexisting antibodies provide partial protection against the opposing HSV type.¹ According to the Centers for Disease Control and Prevention, the seroprevalence of HSV-1 has decreased by approximately 23% in adolescents aged 14 to 19 years, with a resultant increase in the number of primary HSV-1 genital infections through oral-sexual contact in adulthood.²

Recurrent infection refers to reactivation of the same HSV type corresponding to the serum antibodies.

Clinical presentation

After an incubation period of 4 to 7 days, symptomatic patients with primary and initial-nonprimary genital HSV infections typically present with multiple, bilateral genital lesions at various stages of development. These lesions begin as small erythematous macules and then progress to papules, vesicles, pustules, ulcers, and crusted scabs over a period of 3 to 6 weeks¹ (FIGURE). Patients also may present with fever, headache, fatigue, dysuria, and painful inguinal lymphadenopathy. Patients with recurrent infections usually experience prodromal itching or tingling for 2 to 5 days prior to the appearance of unilateral lesions, which persist for only 5 to 10 days. Systemic symptoms rarely are present. HSV-1 genital infection has a symptomatic recurrence rate of 20% to 50% within the first year, while HSV-2 has a recurrence rate of 70% to 90%.¹

The majority of primary and initial-nonprimary infections are subclinical. One study showed that 74% of HSV-1 and 63% of HSV-2 initial genital herpes infections were asymptomatic.³ The relevance of this observation is that patients may not pre­sent for evaluation unless they experience a symptomatic recurrent infection. Meanwhile, they are asymptomatically shedding the virus and unknowingly transmitting HSV to their sexual partners. Asymptomatic viral shedding is more common with HSV-2 and is the most common source of transmission.⁴ The rate of asymptomatic shedding is unpredictable and has been shown to occur on 10% to 20% of days.¹

Diagnosis and treatment

The gold standard for diagnosing HSV infection is viral culture; however, polymerase chain reaction (PCR) assays are faster to result and more sensitive.^4,5 Both culture and PCR studies can distinguish the HSV type, allowing physicians to counsel patients regarding the expected clinical course, rate of recurrence, and implications for future pregnancies. After an initial infection, it may take up to 12 weeks for patients to develop detectable antibodies. Therefore, serology can be quite useful in determining the timing and classification of the infection. For example, a patient with HSV-2 isolated on viral culture or PCR and HSV-1 antibodies identified on serology is classified as having an initial-nonprimary infection.⁴

HSV treatment is dependent on the classification of infection. Treatment of primary and initial-nonprimary infection includes:

• acyclovir 400 mg orally 3 times daily
• valacyclovir 1,000 mg orally twice daily, or
• famciclovir 250 mg orally 3 times daily for 7 to 10 days.

Ideally, treatment should be initiated within 72 hours of symptom onset.

Recurrent infections may be treated with:

• acyclovir 400 mg orally three times daily for 5 days
• valacyclovir 1,000 mg orally once daily for 5 days, or
• famciclovir 1,000 mg orally every 12 hours for 2 doses.

Ideally, treatment should begin within 24 hours of symptom onset.^4,6

Patients with immunocompromising conditions, severe/frequent outbreaks (>6 per year), or who desire to reduce the risk of transmission to HSV-uninfected partners are candidates for chronic suppressive therapy. Suppressive options include acyclovir 400 mg orally twice daily, valacyclovir 500 mg orally once daily, and famciclovir 250 mg orally twice daily. Of note, there are many regimens available for acyclovir, valacyclovir, and famciclovir; all have similar efficacy in decreasing symptom severity, time to lesion healing, and duration of viral shedding.⁶ Acyclovir generally is the least expensive option.⁴

Continue to: Pregnancy and prevention...

During pregnancy, 2% of women will acquire HSV, and 70% of these women will be asymptomatic.^4,7 Approximately one-third to one-half of neonatal infections are caused by HSV-1.⁸ The most devastating complication of HSV infection in pregnancy is transmission to the newborn. Neonatal herpes is defined as the diagnosis of an HSV infection in a neonate within the first 28 days of life. The disease spectrum varies widely, and early recognition and treatment can substantially reduce the degree of morbidity and mortality associated with systemic infections.

HSV infection limited to the skin, eyes, and mucosal surfaces accounts for 45% of neonatal infections. When this condition is promptly recognized, neonates typically respond well to intravenous acyclovir, with prevention of systemic progression and overall good clinical outcomes. Infections of the central nervous system account for 30% of infections and are more difficult to diagnose due to the nonspecific symptomatology, including lethargy, poor feeding, seizures, and possible absence of lesions. The risk for death decreases from 50% to 6% with treatment; however, most neonates will still require close long-term surveillance for achievement of neurodevelopmental milestones and frequent ophthalmologic and hearing assessments.^8,9 Disseminated HSV accounts for 25% of infections and can cause multiorgan failure, with a 31% risk for death despite treatment.⁵ Therefore, the cornerstone of managing HSV infection in pregnancy is focusing clinical efforts on prevention of transmission to the neonate.

More than 90% of neonatal herpes infections are acquired intrapartum,⁴ with 60% to 80% of cases occurring in women who developed HSV in the third trimester near the time of delivery.⁵ Neonates delivered vaginally to these women have a 30% to 50% risk of infection, compared to a <1% risk in neonates born to women with recurrent HSV.^1,5,10 The discrepancy in infection risk is thought to be secondary to higher HSV viral loads after an initial infection as opposed to a recurrent infection. Furthermore, acquisition of HSV near term does not allow for the 6 to 12 weeks necessary to develop antibodies that can cross the placenta and provide neonatal protection. The risk of vertical transmission is approximately 25% with an initial-nonprimary episode, reflecting the partial protection afforded by antibody against the other viral serotype.¹¹

Prophylactic therapy has been shown to reduce the rate of asymptomatic viral shedding and recurrent infections near term.⁷ To reduce the risk of intrapartum transmission, women with a history of HSV prior to or during pregnancy should be treated with acyclovir 400 mg orally 3 times daily starting at 36 weeks of gestation. When patients present with rupture of membranes or labor, they should be asked about prodromal symptoms and thoroughly examined. If prodromal symptoms are present or genital lesions identified, patients should undergo cesarean delivery.¹² Some experts also recommend cesarean delivery for women who acquire primary or initial-nonprimary HSV infection in the third trimester due to higher viral loads and potential lack of antibodies at the time of delivery.^8,12 However, this recommendation has not been validated by a rigorous prospective randomized clinical trial. When clinically feasible, avoidance of invasive fetal monitoring during labor also has been shown to decrease the risk of HSV transmission by approximately 84% in women with asymptomatic viral shedding.¹² This concept may be extrapolated to include assisted delivery with vacuum or forceps.

Universal screening for HSV infection in pregnancy is controversial and widely debated. Most HSV seropositive patients are asymptomatic and will not report a history of HSV infection at the initial prenatal visit. Universal screening, therefore, may increase the rate of unnecessary cesarean deliveries and medical interventions. HSV serology may be beneficial, however, in identifying seronegative pregnant women who have seropositive partners. Two recent studies have shown that 15% to 25% of couples have discordant HSV serologies and consequently are at risk of acquiring primary or initial-nonprimary HSV near term.^4,5 These couples should be counseled concerning the use of condoms in the first and second trimester (50% reduction in HSV transmission) and abstinence in the third trimester.⁵ The seropositive partner also can be offered suppressive therapy, which provides a 48% reduction in the risk of HSV transmission.⁴ Ultimately, the difficulty lies in balancing the clinical benefits and cost of asymptomatic screening.¹¹

CASE Resolved

The patient should be counseled that HSV infection rarely affects the fetus in utero, and transmission almost always occurs during the delivery process. This patient should receive prophylactic treatment with acyclovir beginning at 36 weeks of gestation to reduce the risk of an outbreak near the time of delivery. ●

CASE Pregnant woman with herpes simplex virus

A 26-year-old primigravid woman at 12 weeks of gestation indicates that she had an initial episode of herpes simplex virus (HSV) 6 years prior to presentation. Subsequently, she has had 1 to 2 recurrent episodes each year. She asks about the implications of HSV infection in pregnancy, particularly if anything can be done to prevent a recurrent outbreak near her due date and reduce the need for a cesarean delivery.

How would you counsel this patient?

Meet our perpetrator

Herpes simplex virus (HSV), the most prevalent sexually transmitted infection, is a DNA virus that has 2 major strains: HSV-1 and HSV-2. HSV-1 frequently is acquired in early childhood through nonsexual contact and typically causes orolabial and, less commonly, genital outbreaks. HSV-2 is almost always acquired through sexual contact and causes mainly genital outbreaks.¹

There are 3 classifications of HSV infection: primary, initial-nonprimary, and recurrent (TABLE).

Primary infection refers to infection in a person without antibodies to either type of HSV.

Initial-nonprimary infection refers to acquisition of HSV-2 in a patient with preexisting antibodies to HSV-1 or vice versa. Patients tend to have more severe symptoms with primary as opposed to initial-nonprimary infection because, with the latter condition, preexisting antibodies provide partial protection against the opposing HSV type.¹ According to the Centers for Disease Control and Prevention, the seroprevalence of HSV-1 has decreased by approximately 23% in adolescents aged 14 to 19 years, with a resultant increase in the number of primary HSV-1 genital infections through oral-sexual contact in adulthood.²

Recurrent infection refers to reactivation of the same HSV type corresponding to the serum antibodies.

Clinical presentation

After an incubation period of 4 to 7 days, symptomatic patients with primary and initial-nonprimary genital HSV infections typically present with multiple, bilateral genital lesions at various stages of development. These lesions begin as small erythematous macules and then progress to papules, vesicles, pustules, ulcers, and crusted scabs over a period of 3 to 6 weeks¹ (FIGURE). Patients also may present with fever, headache, fatigue, dysuria, and painful inguinal lymphadenopathy. Patients with recurrent infections usually experience prodromal itching or tingling for 2 to 5 days prior to the appearance of unilateral lesions, which persist for only 5 to 10 days. Systemic symptoms rarely are present. HSV-1 genital infection has a symptomatic recurrence rate of 20% to 50% within the first year, while HSV-2 has a recurrence rate of 70% to 90%.¹

The majority of primary and initial-nonprimary infections are subclinical. One study showed that 74% of HSV-1 and 63% of HSV-2 initial genital herpes infections were asymptomatic.³ The relevance of this observation is that patients may not pre­sent for evaluation unless they experience a symptomatic recurrent infection. Meanwhile, they are asymptomatically shedding the virus and unknowingly transmitting HSV to their sexual partners. Asymptomatic viral shedding is more common with HSV-2 and is the most common source of transmission.⁴ The rate of asymptomatic shedding is unpredictable and has been shown to occur on 10% to 20% of days.¹

Diagnosis and treatment

The gold standard for diagnosing HSV infection is viral culture; however, polymerase chain reaction (PCR) assays are faster to result and more sensitive.^4,5 Both culture and PCR studies can distinguish the HSV type, allowing physicians to counsel patients regarding the expected clinical course, rate of recurrence, and implications for future pregnancies. After an initial infection, it may take up to 12 weeks for patients to develop detectable antibodies. Therefore, serology can be quite useful in determining the timing and classification of the infection. For example, a patient with HSV-2 isolated on viral culture or PCR and HSV-1 antibodies identified on serology is classified as having an initial-nonprimary infection.⁴

HSV treatment is dependent on the classification of infection. Treatment of primary and initial-nonprimary infection includes:

• acyclovir 400 mg orally 3 times daily
• valacyclovir 1,000 mg orally twice daily, or
• famciclovir 250 mg orally 3 times daily for 7 to 10 days.

Ideally, treatment should be initiated within 72 hours of symptom onset.

Recurrent infections may be treated with:

• acyclovir 400 mg orally three times daily for 5 days
• valacyclovir 1,000 mg orally once daily for 5 days, or
• famciclovir 1,000 mg orally every 12 hours for 2 doses.

Ideally, treatment should begin within 24 hours of symptom onset.^4,6

Patients with immunocompromising conditions, severe/frequent outbreaks (>6 per year), or who desire to reduce the risk of transmission to HSV-uninfected partners are candidates for chronic suppressive therapy. Suppressive options include acyclovir 400 mg orally twice daily, valacyclovir 500 mg orally once daily, and famciclovir 250 mg orally twice daily. Of note, there are many regimens available for acyclovir, valacyclovir, and famciclovir; all have similar efficacy in decreasing symptom severity, time to lesion healing, and duration of viral shedding.⁶ Acyclovir generally is the least expensive option.⁴

Continue to: Pregnancy and prevention...

During pregnancy, 2% of women will acquire HSV, and 70% of these women will be asymptomatic.^4,7 Approximately one-third to one-half of neonatal infections are caused by HSV-1.⁸ The most devastating complication of HSV infection in pregnancy is transmission to the newborn. Neonatal herpes is defined as the diagnosis of an HSV infection in a neonate within the first 28 days of life. The disease spectrum varies widely, and early recognition and treatment can substantially reduce the degree of morbidity and mortality associated with systemic infections.

HSV infection limited to the skin, eyes, and mucosal surfaces accounts for 45% of neonatal infections. When this condition is promptly recognized, neonates typically respond well to intravenous acyclovir, with prevention of systemic progression and overall good clinical outcomes. Infections of the central nervous system account for 30% of infections and are more difficult to diagnose due to the nonspecific symptomatology, including lethargy, poor feeding, seizures, and possible absence of lesions. The risk for death decreases from 50% to 6% with treatment; however, most neonates will still require close long-term surveillance for achievement of neurodevelopmental milestones and frequent ophthalmologic and hearing assessments.^8,9 Disseminated HSV accounts for 25% of infections and can cause multiorgan failure, with a 31% risk for death despite treatment.⁵ Therefore, the cornerstone of managing HSV infection in pregnancy is focusing clinical efforts on prevention of transmission to the neonate.

More than 90% of neonatal herpes infections are acquired intrapartum,⁴ with 60% to 80% of cases occurring in women who developed HSV in the third trimester near the time of delivery.⁵ Neonates delivered vaginally to these women have a 30% to 50% risk of infection, compared to a <1% risk in neonates born to women with recurrent HSV.^1,5,10 The discrepancy in infection risk is thought to be secondary to higher HSV viral loads after an initial infection as opposed to a recurrent infection. Furthermore, acquisition of HSV near term does not allow for the 6 to 12 weeks necessary to develop antibodies that can cross the placenta and provide neonatal protection. The risk of vertical transmission is approximately 25% with an initial-nonprimary episode, reflecting the partial protection afforded by antibody against the other viral serotype.¹¹

Prophylactic therapy has been shown to reduce the rate of asymptomatic viral shedding and recurrent infections near term.⁷ To reduce the risk of intrapartum transmission, women with a history of HSV prior to or during pregnancy should be treated with acyclovir 400 mg orally 3 times daily starting at 36 weeks of gestation. When patients present with rupture of membranes or labor, they should be asked about prodromal symptoms and thoroughly examined. If prodromal symptoms are present or genital lesions identified, patients should undergo cesarean delivery.¹² Some experts also recommend cesarean delivery for women who acquire primary or initial-nonprimary HSV infection in the third trimester due to higher viral loads and potential lack of antibodies at the time of delivery.^8,12 However, this recommendation has not been validated by a rigorous prospective randomized clinical trial. When clinically feasible, avoidance of invasive fetal monitoring during labor also has been shown to decrease the risk of HSV transmission by approximately 84% in women with asymptomatic viral shedding.¹² This concept may be extrapolated to include assisted delivery with vacuum or forceps.

Universal screening for HSV infection in pregnancy is controversial and widely debated. Most HSV seropositive patients are asymptomatic and will not report a history of HSV infection at the initial prenatal visit. Universal screening, therefore, may increase the rate of unnecessary cesarean deliveries and medical interventions. HSV serology may be beneficial, however, in identifying seronegative pregnant women who have seropositive partners. Two recent studies have shown that 15% to 25% of couples have discordant HSV serologies and consequently are at risk of acquiring primary or initial-nonprimary HSV near term.^4,5 These couples should be counseled concerning the use of condoms in the first and second trimester (50% reduction in HSV transmission) and abstinence in the third trimester.⁵ The seropositive partner also can be offered suppressive therapy, which provides a 48% reduction in the risk of HSV transmission.⁴ Ultimately, the difficulty lies in balancing the clinical benefits and cost of asymptomatic screening.¹¹

CASE Resolved

The patient should be counseled that HSV infection rarely affects the fetus in utero, and transmission almost always occurs during the delivery process. This patient should receive prophylactic treatment with acyclovir beginning at 36 weeks of gestation to reduce the risk of an outbreak near the time of delivery. ●

CASE Patient-centered counseling for contraception

A 19-year-old woman (G0) with moderately well-controlled seizure disorder while taking levetiracetam, who reports migraines, and has a BMI of 32 kg/m² presents to your office seeking contraception. She is currently sexually active with her second lifetime partner and uses condoms inconsistently. She is otherwise healthy and has no problems to report. Her last menstrual period (LMP) was 1 week ago, and a pregnancy test today is negative. How do you approach counseling for this patient?

The modern contraceptive patient

Our patients are becoming increasingly medically and socially complicated. Meeting the contraceptive needs of patients with multiple comorbidities can be a daunting task. Doing so in a patient-centered way that also recognizes the social contexts and intimacy inherent to contraceptive care can feel overwhelming. However, by employing a systematic approach to each patient, we can provide safe, effective, individualized care to our medically complex patients. Having a few “go-to tools” can streamline the process.

Medically complex patients are often told that they need to avoid pregnancy or optimize their health conditions prior to becoming pregnant, but they may not receive medically-appropriate contraception.^1-3 Additionally, obesity rates in women of reproductive age in the United States are increasing, along with related medical complexities.⁴ Disparities in contraceptive access and use of particular methods exist by socioeconomic status, body mass index (BMI), age, and geography. ^5,6 Evidence-based, shared decision making can improve contraceptive satisfaction.⁷

Clinicians need to stay attuned to all options. Staying current on available contraceptive methods can broaden clinicians’ thinking and allow patients more choices that are compatible with their medical needs. In the last 2 years alone, a 1-year combined estrogen-progestin vaginal ring, a drospirinone-only pill, and a nonhormonal spermicide have become available for prescription.^8-10 Both 52 mg levonorgestrel-containing intrauterine devices (IUDs) are now US Food and Drug Administration (FDA)-approved for 6 years, and there is excellent data for off-label use to 7 years.¹¹

Tools are available for use. To ensure patient safety, we must evaluate the relative risks of each method given their specific medical history. The Centers for Disease Control and Prevention (CDC) Medical Eligibility Criteria (MEC) provides a comprehensive reference for using each contraceptive method category with preexisting medical conditions on a scale from 1 (no restrictions) to 4 (unacceptable health risk) (TABLE 1).¹² It is important to remember that pregnancy often poses a larger risk even than category 4 methods. With proper counseling and documentation, a category 3 method may be appropriate in some circumstances. The CDC MEC can serve as an excellent counseling tool and is available as a free smartphone app. The app can be downloaded via https://www.cdc.gov/reproductivehealth/contraception/mmwr/mec/summary.html (TABLE 2).

In a shared decision-making model, we contribute our medical knowledge, and the patient provides expertise on her own values and social context.¹³ By starting the contraceptive conversation with open-ended questions, we invite the patient to lead the discussion. We partner with them in finding a safe, effective method that is compatible with both the medical history and stated preferences. Bedsider.org has an interactive tool that allows patients to explore different contraceptive methods and compare their various characteristics. While tiered efficacy models may help us to organize our thinking as clinicians, it is important to recognize that patients may consider side effect profiles, nonreliance on clinicians for discontinuation, or other priorities above effectiveness.

Continue to: How to craft your approach...

How to craft your approach

Developing a systematic approach to the medically complex patient seeking contraception can help to change an initially daunting task into a fulfilling experience (FIGURE 1). Begin by eliciting patient priorities. Then frame the discussion around them, rather than around efficacy. Although anecdotal reasoning can initially be frustrating (“My best friend’s IUD was really painful and I don’t want anything like that inside me!”), learning about these experiences prior to counseling can be incredibly informative. Ask detailed questions about medical comorbidities, as these subtleties may change the relative safety of each method. Finally, engage the patient in a frank discussion of the relative merits, safety, and use of all medically appropriate contraceptive methods. The right method is the method that the patient will use.

CASE Continued: Applying our counseling method

Upon open-ended questioning, the patient tells you that she absolutely cannot be on a contraceptive method that will make her gain weight. She has several friends who told her that they gained weight on “the shot” and “the implant.” She wants to avoid these at all costs and thinks she might want to take “the pill.” She also tells you that she is in college and that her daily routine varies significantly between weekdays and weekends. She definitely does not want to get pregnant until she has completed her education, which will be at least 3 years from now.

To best counsel this patient and arrive at the most appropriate contraceptive option for her, clarify her medical history and employ shared decision-making for her chosen method.

Probe her seizure history

She tells you that she has had seizures since she was a child, and the last one occurred 4 months ago when she ran out of her anticonvulsant medication. Her seizures have never been associated with her menses. This is an important piece of information. The frequency of catamenial seizures can be decreased with use of any method that suppresses ovulation, such as depot-medroxyprogesterone (DMPA) injections, continuous combined hormonal contraceptive (CHC) pills or ring, or the implant. Noncatamenial seizures also can be suppressed by DMPA, which increases the seizure threshold.¹⁴ Many anticonvulsants are metabolized through cytochrome P450 in the liver and, therefore, interact with all oral contraceptive formulations. However, levetiracetam is not among them and may be safely taken with progestin-only pills. At this point, all contraceptive methods remain CDC MEC category 1 (FIGURE 2).¹²

Ask migraine specifics

It is important to clarify whether or not the patient experiences aura with her migraines. She says that she always knows when a migraine is coming on because she sees floaters in her vision for about 30 minutes prior to the onset of excruciating headache. One tool that may aid in the diagnosis of aura is the Visual Aura Rating Scale (VARS).¹⁵ The presence of aura renders all CHCs category 4 by the CDC MEC.¹² (See FIGURE 2.)

Discuss contraceptive pros and cons

Have a frank discussion about the relative risks and benefits of each method. For instance, although DMPA may improve the patient’s seizures, she has expressed a desire to avoid weight gain, and DMPA is the only method consistently shown in studies to do so.¹⁶ Her seizures are not associated with menses, so menstrual suppression is neither beneficial nor deleterious. Although her current medication levetiracetam does not influence the metabolism of contraceptive methods, many anticonvulsants do. Offer anticipatory guidance around seeking gynecologic consultation with any future seizure medication changes.

Allow for shared decision-making on a final choice

The patient indicated that she had been considering “the pill” when she made this appointment, but you have explained that CHCs are contraindicated for her. She is concerned that she will not be able to stick to the strict dosing schedule of a progestin-only pill. Although you inform her that the drospirinone-only pill has a more forgiving window, the patient decides that she wants a “set it and forget it” method and opts for an IUD. 

CASE Resolved

Following recommendations from the American College of Obstetricians and Gynecologists (ACOG), you provide for same-day insertion of a 52-mg levonorgestrel IUD.¹⁷ You use a paracervical block in addition to ibuprofen for pain control.¹⁸ The patient undergoes same-day testing for gonorrhea and chlamydia, and she understands that if a test is found to be positive, she can be treated without removing the IUD. You provide instruction on the importance of dual contraceptive use with barrier methods for the prevention of STIs. The patient is instructed on self-string checks, and she acknowledges that she will call if she has any concerns; no routine follow-up is required. She leaves her visit satisfied with her preferred, safe, effective contraceptive method in situ. ●

CASE Patient-centered counseling for contraception

A 19-year-old woman (G0) with moderately well-controlled seizure disorder while taking levetiracetam, who reports migraines, and has a BMI of 32 kg/m² presents to your office seeking contraception. She is currently sexually active with her second lifetime partner and uses condoms inconsistently. She is otherwise healthy and has no problems to report. Her last menstrual period (LMP) was 1 week ago, and a pregnancy test today is negative. How do you approach counseling for this patient?

The modern contraceptive patient

Our patients are becoming increasingly medically and socially complicated. Meeting the contraceptive needs of patients with multiple comorbidities can be a daunting task. Doing so in a patient-centered way that also recognizes the social contexts and intimacy inherent to contraceptive care can feel overwhelming. However, by employing a systematic approach to each patient, we can provide safe, effective, individualized care to our medically complex patients. Having a few “go-to tools” can streamline the process.

Medically complex patients are often told that they need to avoid pregnancy or optimize their health conditions prior to becoming pregnant, but they may not receive medically-appropriate contraception.^1-3 Additionally, obesity rates in women of reproductive age in the United States are increasing, along with related medical complexities.⁴ Disparities in contraceptive access and use of particular methods exist by socioeconomic status, body mass index (BMI), age, and geography. ^5,6 Evidence-based, shared decision making can improve contraceptive satisfaction.⁷

Clinicians need to stay attuned to all options. Staying current on available contraceptive methods can broaden clinicians’ thinking and allow patients more choices that are compatible with their medical needs. In the last 2 years alone, a 1-year combined estrogen-progestin vaginal ring, a drospirinone-only pill, and a nonhormonal spermicide have become available for prescription.^8-10 Both 52 mg levonorgestrel-containing intrauterine devices (IUDs) are now US Food and Drug Administration (FDA)-approved for 6 years, and there is excellent data for off-label use to 7 years.¹¹

Tools are available for use. To ensure patient safety, we must evaluate the relative risks of each method given their specific medical history. The Centers for Disease Control and Prevention (CDC) Medical Eligibility Criteria (MEC) provides a comprehensive reference for using each contraceptive method category with preexisting medical conditions on a scale from 1 (no restrictions) to 4 (unacceptable health risk) (TABLE 1).¹² It is important to remember that pregnancy often poses a larger risk even than category 4 methods. With proper counseling and documentation, a category 3 method may be appropriate in some circumstances. The CDC MEC can serve as an excellent counseling tool and is available as a free smartphone app. The app can be downloaded via https://www.cdc.gov/reproductivehealth/contraception/mmwr/mec/summary.html (TABLE 2).

In a shared decision-making model, we contribute our medical knowledge, and the patient provides expertise on her own values and social context.¹³ By starting the contraceptive conversation with open-ended questions, we invite the patient to lead the discussion. We partner with them in finding a safe, effective method that is compatible with both the medical history and stated preferences. Bedsider.org has an interactive tool that allows patients to explore different contraceptive methods and compare their various characteristics. While tiered efficacy models may help us to organize our thinking as clinicians, it is important to recognize that patients may consider side effect profiles, nonreliance on clinicians for discontinuation, or other priorities above effectiveness.

Continue to: How to craft your approach...

How to craft your approach

Developing a systematic approach to the medically complex patient seeking contraception can help to change an initially daunting task into a fulfilling experience (FIGURE 1). Begin by eliciting patient priorities. Then frame the discussion around them, rather than around efficacy. Although anecdotal reasoning can initially be frustrating (“My best friend’s IUD was really painful and I don’t want anything like that inside me!”), learning about these experiences prior to counseling can be incredibly informative. Ask detailed questions about medical comorbidities, as these subtleties may change the relative safety of each method. Finally, engage the patient in a frank discussion of the relative merits, safety, and use of all medically appropriate contraceptive methods. The right method is the method that the patient will use.

CASE Continued: Applying our counseling method

Upon open-ended questioning, the patient tells you that she absolutely cannot be on a contraceptive method that will make her gain weight. She has several friends who told her that they gained weight on “the shot” and “the implant.” She wants to avoid these at all costs and thinks she might want to take “the pill.” She also tells you that she is in college and that her daily routine varies significantly between weekdays and weekends. She definitely does not want to get pregnant until she has completed her education, which will be at least 3 years from now.

To best counsel this patient and arrive at the most appropriate contraceptive option for her, clarify her medical history and employ shared decision-making for her chosen method.

Probe her seizure history

She tells you that she has had seizures since she was a child, and the last one occurred 4 months ago when she ran out of her anticonvulsant medication. Her seizures have never been associated with her menses. This is an important piece of information. The frequency of catamenial seizures can be decreased with use of any method that suppresses ovulation, such as depot-medroxyprogesterone (DMPA) injections, continuous combined hormonal contraceptive (CHC) pills or ring, or the implant. Noncatamenial seizures also can be suppressed by DMPA, which increases the seizure threshold.¹⁴ Many anticonvulsants are metabolized through cytochrome P450 in the liver and, therefore, interact with all oral contraceptive formulations. However, levetiracetam is not among them and may be safely taken with progestin-only pills. At this point, all contraceptive methods remain CDC MEC category 1 (FIGURE 2).¹²

Ask migraine specifics

It is important to clarify whether or not the patient experiences aura with her migraines. She says that she always knows when a migraine is coming on because she sees floaters in her vision for about 30 minutes prior to the onset of excruciating headache. One tool that may aid in the diagnosis of aura is the Visual Aura Rating Scale (VARS).¹⁵ The presence of aura renders all CHCs category 4 by the CDC MEC.¹² (See FIGURE 2.)

Discuss contraceptive pros and cons

Have a frank discussion about the relative risks and benefits of each method. For instance, although DMPA may improve the patient’s seizures, she has expressed a desire to avoid weight gain, and DMPA is the only method consistently shown in studies to do so.¹⁶ Her seizures are not associated with menses, so menstrual suppression is neither beneficial nor deleterious. Although her current medication levetiracetam does not influence the metabolism of contraceptive methods, many anticonvulsants do. Offer anticipatory guidance around seeking gynecologic consultation with any future seizure medication changes.

Allow for shared decision-making on a final choice

The patient indicated that she had been considering “the pill” when she made this appointment, but you have explained that CHCs are contraindicated for her. She is concerned that she will not be able to stick to the strict dosing schedule of a progestin-only pill. Although you inform her that the drospirinone-only pill has a more forgiving window, the patient decides that she wants a “set it and forget it” method and opts for an IUD. 

CASE Resolved

Following recommendations from the American College of Obstetricians and Gynecologists (ACOG), you provide for same-day insertion of a 52-mg levonorgestrel IUD.¹⁷ You use a paracervical block in addition to ibuprofen for pain control.¹⁸ The patient undergoes same-day testing for gonorrhea and chlamydia, and she understands that if a test is found to be positive, she can be treated without removing the IUD. You provide instruction on the importance of dual contraceptive use with barrier methods for the prevention of STIs. The patient is instructed on self-string checks, and she acknowledges that she will call if she has any concerns; no routine follow-up is required. She leaves her visit satisfied with her preferred, safe, effective contraceptive method in situ. ●

CASE Patient-centered counseling for contraception

A 19-year-old woman (G0) with moderately well-controlled seizure disorder while taking levetiracetam, who reports migraines, and has a BMI of 32 kg/m² presents to your office seeking contraception. She is currently sexually active with her second lifetime partner and uses condoms inconsistently. She is otherwise healthy and has no problems to report. Her last menstrual period (LMP) was 1 week ago, and a pregnancy test today is negative. How do you approach counseling for this patient?

The modern contraceptive patient

Our patients are becoming increasingly medically and socially complicated. Meeting the contraceptive needs of patients with multiple comorbidities can be a daunting task. Doing so in a patient-centered way that also recognizes the social contexts and intimacy inherent to contraceptive care can feel overwhelming. However, by employing a systematic approach to each patient, we can provide safe, effective, individualized care to our medically complex patients. Having a few “go-to tools” can streamline the process.

Medically complex patients are often told that they need to avoid pregnancy or optimize their health conditions prior to becoming pregnant, but they may not receive medically-appropriate contraception.^1-3 Additionally, obesity rates in women of reproductive age in the United States are increasing, along with related medical complexities.⁴ Disparities in contraceptive access and use of particular methods exist by socioeconomic status, body mass index (BMI), age, and geography. ^5,6 Evidence-based, shared decision making can improve contraceptive satisfaction.⁷

Clinicians need to stay attuned to all options. Staying current on available contraceptive methods can broaden clinicians’ thinking and allow patients more choices that are compatible with their medical needs. In the last 2 years alone, a 1-year combined estrogen-progestin vaginal ring, a drospirinone-only pill, and a nonhormonal spermicide have become available for prescription.^8-10 Both 52 mg levonorgestrel-containing intrauterine devices (IUDs) are now US Food and Drug Administration (FDA)-approved for 6 years, and there is excellent data for off-label use to 7 years.¹¹

Tools are available for use. To ensure patient safety, we must evaluate the relative risks of each method given their specific medical history. The Centers for Disease Control and Prevention (CDC) Medical Eligibility Criteria (MEC) provides a comprehensive reference for using each contraceptive method category with preexisting medical conditions on a scale from 1 (no restrictions) to 4 (unacceptable health risk) (TABLE 1).¹² It is important to remember that pregnancy often poses a larger risk even than category 4 methods. With proper counseling and documentation, a category 3 method may be appropriate in some circumstances. The CDC MEC can serve as an excellent counseling tool and is available as a free smartphone app. The app can be downloaded via https://www.cdc.gov/reproductivehealth/contraception/mmwr/mec/summary.html (TABLE 2).

In a shared decision-making model, we contribute our medical knowledge, and the patient provides expertise on her own values and social context.¹³ By starting the contraceptive conversation with open-ended questions, we invite the patient to lead the discussion. We partner with them in finding a safe, effective method that is compatible with both the medical history and stated preferences. Bedsider.org has an interactive tool that allows patients to explore different contraceptive methods and compare their various characteristics. While tiered efficacy models may help us to organize our thinking as clinicians, it is important to recognize that patients may consider side effect profiles, nonreliance on clinicians for discontinuation, or other priorities above effectiveness.

Continue to: How to craft your approach...

How to craft your approach

Developing a systematic approach to the medically complex patient seeking contraception can help to change an initially daunting task into a fulfilling experience (FIGURE 1). Begin by eliciting patient priorities. Then frame the discussion around them, rather than around efficacy. Although anecdotal reasoning can initially be frustrating (“My best friend’s IUD was really painful and I don’t want anything like that inside me!”), learning about these experiences prior to counseling can be incredibly informative. Ask detailed questions about medical comorbidities, as these subtleties may change the relative safety of each method. Finally, engage the patient in a frank discussion of the relative merits, safety, and use of all medically appropriate contraceptive methods. The right method is the method that the patient will use.

CASE Continued: Applying our counseling method

Upon open-ended questioning, the patient tells you that she absolutely cannot be on a contraceptive method that will make her gain weight. She has several friends who told her that they gained weight on “the shot” and “the implant.” She wants to avoid these at all costs and thinks she might want to take “the pill.” She also tells you that she is in college and that her daily routine varies significantly between weekdays and weekends. She definitely does not want to get pregnant until she has completed her education, which will be at least 3 years from now.

To best counsel this patient and arrive at the most appropriate contraceptive option for her, clarify her medical history and employ shared decision-making for her chosen method.

Probe her seizure history

She tells you that she has had seizures since she was a child, and the last one occurred 4 months ago when she ran out of her anticonvulsant medication. Her seizures have never been associated with her menses. This is an important piece of information. The frequency of catamenial seizures can be decreased with use of any method that suppresses ovulation, such as depot-medroxyprogesterone (DMPA) injections, continuous combined hormonal contraceptive (CHC) pills or ring, or the implant. Noncatamenial seizures also can be suppressed by DMPA, which increases the seizure threshold.¹⁴ Many anticonvulsants are metabolized through cytochrome P450 in the liver and, therefore, interact with all oral contraceptive formulations. However, levetiracetam is not among them and may be safely taken with progestin-only pills. At this point, all contraceptive methods remain CDC MEC category 1 (FIGURE 2).¹²

Ask migraine specifics

It is important to clarify whether or not the patient experiences aura with her migraines. She says that she always knows when a migraine is coming on because she sees floaters in her vision for about 30 minutes prior to the onset of excruciating headache. One tool that may aid in the diagnosis of aura is the Visual Aura Rating Scale (VARS).¹⁵ The presence of aura renders all CHCs category 4 by the CDC MEC.¹² (See FIGURE 2.)

Discuss contraceptive pros and cons

Have a frank discussion about the relative risks and benefits of each method. For instance, although DMPA may improve the patient’s seizures, she has expressed a desire to avoid weight gain, and DMPA is the only method consistently shown in studies to do so.¹⁶ Her seizures are not associated with menses, so menstrual suppression is neither beneficial nor deleterious. Although her current medication levetiracetam does not influence the metabolism of contraceptive methods, many anticonvulsants do. Offer anticipatory guidance around seeking gynecologic consultation with any future seizure medication changes.

Allow for shared decision-making on a final choice

The patient indicated that she had been considering “the pill” when she made this appointment, but you have explained that CHCs are contraindicated for her. She is concerned that she will not be able to stick to the strict dosing schedule of a progestin-only pill. Although you inform her that the drospirinone-only pill has a more forgiving window, the patient decides that she wants a “set it and forget it” method and opts for an IUD. 

CASE Resolved

Following recommendations from the American College of Obstetricians and Gynecologists (ACOG), you provide for same-day insertion of a 52-mg levonorgestrel IUD.¹⁷ You use a paracervical block in addition to ibuprofen for pain control.¹⁸ The patient undergoes same-day testing for gonorrhea and chlamydia, and she understands that if a test is found to be positive, she can be treated without removing the IUD. You provide instruction on the importance of dual contraceptive use with barrier methods for the prevention of STIs. The patient is instructed on self-string checks, and she acknowledges that she will call if she has any concerns; no routine follow-up is required. She leaves her visit satisfied with her preferred, safe, effective contraceptive method in situ. ●

Al-Hendy A, Lukes AS, Poindexter AN 3rd, et al. Treatment of uterine fibroid symptoms with relugolix combination therapy. N Engl J Med. 2021;384:630-642. doi: 10.1056/NEJMoa2008283

Expert Commentary

By age 50, approximately 70% of White women and 80% of Black women will have uterine fibroids.¹ Of these, about 25% will have symptoms—most often including heavy menstrual bleeding,² and associated pain the second most common symptom.³ First-line treatment has traditionally been hormonal contraceptives. Injectable gonadotropin-releasing hormone (GnRH) antagonist like leuprolide acetate have been commonly employed, although their actual approved indication is “for concomitant use with iron therapy for preoperative hematologic improvement of patients with anemia caused by uterine leiomyomata (fibroids).”⁴ Recently, an oral GnRH antagonist, elagolix, combined with estrogen and progestogen, was approved for treatment of uterine fibroids for up to 24 months. However, it is dosed twice per day because of its short half-life and results in a loss of bone mineral density at 1 year.^5,6

Details of the studies

Al-Hendy and colleagues report on two double-blind 24-week phase 3 trials involving women with heavy menstrual bleeding associated with fibroids. There were just under 400 women in each trial. There was a 1:1:1 randomization to: placebo, once-daily oral relugolix 40 mg with 1 mg estradiol and 0.5 mg norethindrone acetate, or oral relugolix by itself for 12 weeks followed by the combination for 12 weeks (referred to as the “delayed relugolix combination therapy” arm).

Results. The primary end point was the percentage of patients who had a volume of menstrual blood loss less than 80 mL and a ≥50% reduction in blood loss volume as measured by the alkaline hematin method. The baseline blood loss in these studies ranged from approximately 210–250 mL. Secondary end points included amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, uterine volume, and the largest fibroid volume.

In trials one and two, 73% and 71% of patients in the relugolix combination groups, respectively, achieved the primary endpoint, compared with 19% and 15% in the placebo groups (P <.001). In addition, all secondary endpoints except largest fibroid volume were significantly improved versus placebo. Adverse events, including any change in bone mineral density, were no different between the combination and placebo groups. The delayed combination groups did have more hot flashes and diminished bone density compared with both the placebo and combination groups.

Strengths and weaknesses

The studies appropriately enrolled women with a mean age of 41–42 years and a mean BMI >30 kg/m², and more than 50% were African American. Thus, the samples are adequately representative of the type of population most likely to have fibroids and associated symptoms. The results showed the advantages of built-in “add back therapy” with estrogen plus progestogen, as the vasomotor symptoms and bone loss that treatment with a GnRH antagonist alone produces were reduced.

Although the trials were only conducted for 24 weeks, efficacy was seen as early as 4 weeks, and was clearly maintained throughout the full trials—and there is no scientific reason to assume it would not be maintained indefinitely. However, one cannot make a similar assumption about long-term safety. As another GnRH antagonist, with a shorter half-life requiring twice-daily-dosing with add back therapy, has been approved for use for 2 years, it is likely that the once-daily formulation of combination relugolix will be approved for this timeframe as well. Still, with patients’ mean age of 41–42 years, what will clinicians do after 2-year treatment? Clearly, study of long-term safety would be valuable. ●

Al-Hendy A, Lukes AS, Poindexter AN 3rd, et al. Treatment of uterine fibroid symptoms with relugolix combination therapy. N Engl J Med. 2021;384:630-642. doi: 10.1056/NEJMoa2008283

Expert Commentary

By age 50, approximately 70% of White women and 80% of Black women will have uterine fibroids.¹ Of these, about 25% will have symptoms—most often including heavy menstrual bleeding,² and associated pain the second most common symptom.³ First-line treatment has traditionally been hormonal contraceptives. Injectable gonadotropin-releasing hormone (GnRH) antagonist like leuprolide acetate have been commonly employed, although their actual approved indication is “for concomitant use with iron therapy for preoperative hematologic improvement of patients with anemia caused by uterine leiomyomata (fibroids).”⁴ Recently, an oral GnRH antagonist, elagolix, combined with estrogen and progestogen, was approved for treatment of uterine fibroids for up to 24 months. However, it is dosed twice per day because of its short half-life and results in a loss of bone mineral density at 1 year.^5,6

Details of the studies

Al-Hendy and colleagues report on two double-blind 24-week phase 3 trials involving women with heavy menstrual bleeding associated with fibroids. There were just under 400 women in each trial. There was a 1:1:1 randomization to: placebo, once-daily oral relugolix 40 mg with 1 mg estradiol and 0.5 mg norethindrone acetate, or oral relugolix by itself for 12 weeks followed by the combination for 12 weeks (referred to as the “delayed relugolix combination therapy” arm).

Results. The primary end point was the percentage of patients who had a volume of menstrual blood loss less than 80 mL and a ≥50% reduction in blood loss volume as measured by the alkaline hematin method. The baseline blood loss in these studies ranged from approximately 210–250 mL. Secondary end points included amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, uterine volume, and the largest fibroid volume.

In trials one and two, 73% and 71% of patients in the relugolix combination groups, respectively, achieved the primary endpoint, compared with 19% and 15% in the placebo groups (P <.001). In addition, all secondary endpoints except largest fibroid volume were significantly improved versus placebo. Adverse events, including any change in bone mineral density, were no different between the combination and placebo groups. The delayed combination groups did have more hot flashes and diminished bone density compared with both the placebo and combination groups.

Strengths and weaknesses

The studies appropriately enrolled women with a mean age of 41–42 years and a mean BMI >30 kg/m², and more than 50% were African American. Thus, the samples are adequately representative of the type of population most likely to have fibroids and associated symptoms. The results showed the advantages of built-in “add back therapy” with estrogen plus progestogen, as the vasomotor symptoms and bone loss that treatment with a GnRH antagonist alone produces were reduced.

Although the trials were only conducted for 24 weeks, efficacy was seen as early as 4 weeks, and was clearly maintained throughout the full trials—and there is no scientific reason to assume it would not be maintained indefinitely. However, one cannot make a similar assumption about long-term safety. As another GnRH antagonist, with a shorter half-life requiring twice-daily-dosing with add back therapy, has been approved for use for 2 years, it is likely that the once-daily formulation of combination relugolix will be approved for this timeframe as well. Still, with patients’ mean age of 41–42 years, what will clinicians do after 2-year treatment? Clearly, study of long-term safety would be valuable. ●

Al-Hendy A, Lukes AS, Poindexter AN 3rd, et al. Treatment of uterine fibroid symptoms with relugolix combination therapy. N Engl J Med. 2021;384:630-642. doi: 10.1056/NEJMoa2008283

Expert Commentary

By age 50, approximately 70% of White women and 80% of Black women will have uterine fibroids.¹ Of these, about 25% will have symptoms—most often including heavy menstrual bleeding,² and associated pain the second most common symptom.³ First-line treatment has traditionally been hormonal contraceptives. Injectable gonadotropin-releasing hormone (GnRH) antagonist like leuprolide acetate have been commonly employed, although their actual approved indication is “for concomitant use with iron therapy for preoperative hematologic improvement of patients with anemia caused by uterine leiomyomata (fibroids).”⁴ Recently, an oral GnRH antagonist, elagolix, combined with estrogen and progestogen, was approved for treatment of uterine fibroids for up to 24 months. However, it is dosed twice per day because of its short half-life and results in a loss of bone mineral density at 1 year.^5,6

Details of the studies

Al-Hendy and colleagues report on two double-blind 24-week phase 3 trials involving women with heavy menstrual bleeding associated with fibroids. There were just under 400 women in each trial. There was a 1:1:1 randomization to: placebo, once-daily oral relugolix 40 mg with 1 mg estradiol and 0.5 mg norethindrone acetate, or oral relugolix by itself for 12 weeks followed by the combination for 12 weeks (referred to as the “delayed relugolix combination therapy” arm).

Results. The primary end point was the percentage of patients who had a volume of menstrual blood loss less than 80 mL and a ≥50% reduction in blood loss volume as measured by the alkaline hematin method. The baseline blood loss in these studies ranged from approximately 210–250 mL. Secondary end points included amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, uterine volume, and the largest fibroid volume.

In trials one and two, 73% and 71% of patients in the relugolix combination groups, respectively, achieved the primary endpoint, compared with 19% and 15% in the placebo groups (P <.001). In addition, all secondary endpoints except largest fibroid volume were significantly improved versus placebo. Adverse events, including any change in bone mineral density, were no different between the combination and placebo groups. The delayed combination groups did have more hot flashes and diminished bone density compared with both the placebo and combination groups.

Strengths and weaknesses

The studies appropriately enrolled women with a mean age of 41–42 years and a mean BMI >30 kg/m², and more than 50% were African American. Thus, the samples are adequately representative of the type of population most likely to have fibroids and associated symptoms. The results showed the advantages of built-in “add back therapy” with estrogen plus progestogen, as the vasomotor symptoms and bone loss that treatment with a GnRH antagonist alone produces were reduced.

Although the trials were only conducted for 24 weeks, efficacy was seen as early as 4 weeks, and was clearly maintained throughout the full trials—and there is no scientific reason to assume it would not be maintained indefinitely. However, one cannot make a similar assumption about long-term safety. As another GnRH antagonist, with a shorter half-life requiring twice-daily-dosing with add back therapy, has been approved for use for 2 years, it is likely that the once-daily formulation of combination relugolix will be approved for this timeframe as well. Still, with patients’ mean age of 41–42 years, what will clinicians do after 2-year treatment? Clearly, study of long-term safety would be valuable. ●

A shorter period between eating and going to sleep increased the risk of GERD during pregnancy by approximately 12%, according to data from 400 women.

Antonio_Diaz/iStock/via Getty Images

Gastroesophageal reflux disease (GERD) is a common condition in pregnancy because of changes in gastrointestinal motility caused by hormonal changes, and a short meal-to-bed time (MTBT) also has been associated with increased GERD symptoms, but data on the impact of MTBT on GERD in pregnant women in particular are lacking, wrote Duc T. Quach, MD, of the University of Medicine and Pharmacy in Ho Chi Minh City, Vietnam, and colleagues.

In a cross-sectional study published in the Journal of Clinical Gastroenterology, the researchers identified 400 pregnant women aged 18 years and older in various stages of pregnancy who were seen at a single hospital in Vietnam. A short MTBT was defined as going to bed 2 hours or less after eating. Primary outcomes were GERD, defined as troublesome heartburn and/or regurgitation at least once a week, and reflux-related insomnia, defined as trouble initiating or maintaining nighttime sleep. Participants also reported the number of days of troublesome reflux symptoms and frequency of reflux-related insomnia over the last 7 days.

A total of 154 participants had a diagnosis of GERD, for an overall prevalence of 38.5%, similar to that seen in GERD studies of GERD and pregnancy, the researchers noted, and of those with GERD, 20 participants (13.0%) reported reflux-related insomnia.

The overall prevalence of heartburn, regurgitation, nausea with or without vomiting, and epigastric pain were 11.8%, 35.8%, 30.0%, and 5.5%, respectively. A total of 139 women reported reflux symptoms on at least 2 of the past 7 days, and 40 women reported both daytime and nighttime reflux symptoms.
 

Short meal-to-bed time shows strongest association

A short MTBT was the strongest predictor of GERD in multivariate analysis (odds ratio, 12.73; 95% confidence interval, 2.92-55.45; P = .001); previous history of reflux symptoms (OR, 9.05; 95% CI, 5.29-15.50; P < 001) and being in the third trimester versus first or second of pregnancy (OR, 1.66, 95% CI, 1.03-2.69; P = .039) also remained significant predictors in a multivariate analysis. In addition, nighttime short MTBT (but not daytime short MTBT) was the strongest risk factor for reflux-related insomnia (OR, 4.60), although alcohol consumption and a history of reflux-related symptoms also remained significant in multivariate analysis.

“Interestingly, the number of days during which reflux symptoms were experienced during the last 7 days sequentially increased across subgroups of participants with no short MTBT, either daytime or nighttime short MTBT, and with both daytime and nighttime MTBT,” the researchers wrote. At 4-7 days, none of the patients with no short MTBT reported reflux symptoms, compared with 7.5% of those with either daytime or nighttime MTBT and 20.9% of those with both daytime and nighttime MTBT.

The study findings were limited by several factors, including the inability to accurately record participants’ diets and the potential for overestimating the odds ratio of risk factors in patients with reflux-related insomnia because of the small numbers. However, the results support findings from previous studies and suggest that dietary modifications could provide a nonpharmacological treatment target for managing GERD in pregnant women, they concluded.
 

Behavioral intervention may benefit pregnant women

The study is important because heartburn and regurgitation are common challenges during pregnancy, Ziad F. Gellad, MD, of Duke University, Durham, N.C., said in an interview. “Understanding risk factors for these conditions can be helpful in designing behavioral and pharmaceutical therapeutic interventions.”

The link between short MTBT and increased risk for GERD is well-known, said Dr. Gellad. “Lengthening the time to laying supine after a meal is a common recommendation given to patients with GERD and is included in published GERD guidelines.” Although pregnant woman may have been excluded from trials on which the guidelines and recommendations are based, “it is reasonable to expect that findings would translate to this population that is generally higher risk for reflux,” he noted.

Dr. Gellad was interested to see the dose response between MTBT and reflux, with those patients having both daytime and nighttime short MTBT experiencing reflux more often than those with short MTBT in only one of those time periods (4-7 days vs. 1-3 days).

The key message for clinicians is that, for all individuals, pregnant or not, “avoiding late night meals and short meal-to-bed time is an appropriate behavioral intervention to recommend for patients with troublesome heartburn or regurgitation,” Dr. Gellad emphasized. However, more research is needed in some areas, “implementation studies would be helpful to understand how best to educate patients on behavioral modifications known to decrease reflux symptoms.”

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Gellad had no relevant financial disclosures, but serves as a member of the GI & Hepatology News board of editors.

A shorter period between eating and going to sleep increased the risk of GERD during pregnancy by approximately 12%, according to data from 400 women.

Antonio_Diaz/iStock/via Getty Images

Gastroesophageal reflux disease (GERD) is a common condition in pregnancy because of changes in gastrointestinal motility caused by hormonal changes, and a short meal-to-bed time (MTBT) also has been associated with increased GERD symptoms, but data on the impact of MTBT on GERD in pregnant women in particular are lacking, wrote Duc T. Quach, MD, of the University of Medicine and Pharmacy in Ho Chi Minh City, Vietnam, and colleagues.

In a cross-sectional study published in the Journal of Clinical Gastroenterology, the researchers identified 400 pregnant women aged 18 years and older in various stages of pregnancy who were seen at a single hospital in Vietnam. A short MTBT was defined as going to bed 2 hours or less after eating. Primary outcomes were GERD, defined as troublesome heartburn and/or regurgitation at least once a week, and reflux-related insomnia, defined as trouble initiating or maintaining nighttime sleep. Participants also reported the number of days of troublesome reflux symptoms and frequency of reflux-related insomnia over the last 7 days.

A total of 154 participants had a diagnosis of GERD, for an overall prevalence of 38.5%, similar to that seen in GERD studies of GERD and pregnancy, the researchers noted, and of those with GERD, 20 participants (13.0%) reported reflux-related insomnia.

The overall prevalence of heartburn, regurgitation, nausea with or without vomiting, and epigastric pain were 11.8%, 35.8%, 30.0%, and 5.5%, respectively. A total of 139 women reported reflux symptoms on at least 2 of the past 7 days, and 40 women reported both daytime and nighttime reflux symptoms.
 

Short meal-to-bed time shows strongest association

A short MTBT was the strongest predictor of GERD in multivariate analysis (odds ratio, 12.73; 95% confidence interval, 2.92-55.45; P = .001); previous history of reflux symptoms (OR, 9.05; 95% CI, 5.29-15.50; P < 001) and being in the third trimester versus first or second of pregnancy (OR, 1.66, 95% CI, 1.03-2.69; P = .039) also remained significant predictors in a multivariate analysis. In addition, nighttime short MTBT (but not daytime short MTBT) was the strongest risk factor for reflux-related insomnia (OR, 4.60), although alcohol consumption and a history of reflux-related symptoms also remained significant in multivariate analysis.

“Interestingly, the number of days during which reflux symptoms were experienced during the last 7 days sequentially increased across subgroups of participants with no short MTBT, either daytime or nighttime short MTBT, and with both daytime and nighttime MTBT,” the researchers wrote. At 4-7 days, none of the patients with no short MTBT reported reflux symptoms, compared with 7.5% of those with either daytime or nighttime MTBT and 20.9% of those with both daytime and nighttime MTBT.

The study findings were limited by several factors, including the inability to accurately record participants’ diets and the potential for overestimating the odds ratio of risk factors in patients with reflux-related insomnia because of the small numbers. However, the results support findings from previous studies and suggest that dietary modifications could provide a nonpharmacological treatment target for managing GERD in pregnant women, they concluded.
 

Behavioral intervention may benefit pregnant women

The study is important because heartburn and regurgitation are common challenges during pregnancy, Ziad F. Gellad, MD, of Duke University, Durham, N.C., said in an interview. “Understanding risk factors for these conditions can be helpful in designing behavioral and pharmaceutical therapeutic interventions.”

The link between short MTBT and increased risk for GERD is well-known, said Dr. Gellad. “Lengthening the time to laying supine after a meal is a common recommendation given to patients with GERD and is included in published GERD guidelines.” Although pregnant woman may have been excluded from trials on which the guidelines and recommendations are based, “it is reasonable to expect that findings would translate to this population that is generally higher risk for reflux,” he noted.

Dr. Gellad was interested to see the dose response between MTBT and reflux, with those patients having both daytime and nighttime short MTBT experiencing reflux more often than those with short MTBT in only one of those time periods (4-7 days vs. 1-3 days).

The key message for clinicians is that, for all individuals, pregnant or not, “avoiding late night meals and short meal-to-bed time is an appropriate behavioral intervention to recommend for patients with troublesome heartburn or regurgitation,” Dr. Gellad emphasized. However, more research is needed in some areas, “implementation studies would be helpful to understand how best to educate patients on behavioral modifications known to decrease reflux symptoms.”

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Gellad had no relevant financial disclosures, but serves as a member of the GI & Hepatology News board of editors.

A shorter period between eating and going to sleep increased the risk of GERD during pregnancy by approximately 12%, according to data from 400 women.

Antonio_Diaz/iStock/via Getty Images

Gastroesophageal reflux disease (GERD) is a common condition in pregnancy because of changes in gastrointestinal motility caused by hormonal changes, and a short meal-to-bed time (MTBT) also has been associated with increased GERD symptoms, but data on the impact of MTBT on GERD in pregnant women in particular are lacking, wrote Duc T. Quach, MD, of the University of Medicine and Pharmacy in Ho Chi Minh City, Vietnam, and colleagues.

In a cross-sectional study published in the Journal of Clinical Gastroenterology, the researchers identified 400 pregnant women aged 18 years and older in various stages of pregnancy who were seen at a single hospital in Vietnam. A short MTBT was defined as going to bed 2 hours or less after eating. Primary outcomes were GERD, defined as troublesome heartburn and/or regurgitation at least once a week, and reflux-related insomnia, defined as trouble initiating or maintaining nighttime sleep. Participants also reported the number of days of troublesome reflux symptoms and frequency of reflux-related insomnia over the last 7 days.

A total of 154 participants had a diagnosis of GERD, for an overall prevalence of 38.5%, similar to that seen in GERD studies of GERD and pregnancy, the researchers noted, and of those with GERD, 20 participants (13.0%) reported reflux-related insomnia.

The overall prevalence of heartburn, regurgitation, nausea with or without vomiting, and epigastric pain were 11.8%, 35.8%, 30.0%, and 5.5%, respectively. A total of 139 women reported reflux symptoms on at least 2 of the past 7 days, and 40 women reported both daytime and nighttime reflux symptoms.
 

Short meal-to-bed time shows strongest association

A short MTBT was the strongest predictor of GERD in multivariate analysis (odds ratio, 12.73; 95% confidence interval, 2.92-55.45; P = .001); previous history of reflux symptoms (OR, 9.05; 95% CI, 5.29-15.50; P < 001) and being in the third trimester versus first or second of pregnancy (OR, 1.66, 95% CI, 1.03-2.69; P = .039) also remained significant predictors in a multivariate analysis. In addition, nighttime short MTBT (but not daytime short MTBT) was the strongest risk factor for reflux-related insomnia (OR, 4.60), although alcohol consumption and a history of reflux-related symptoms also remained significant in multivariate analysis.

“Interestingly, the number of days during which reflux symptoms were experienced during the last 7 days sequentially increased across subgroups of participants with no short MTBT, either daytime or nighttime short MTBT, and with both daytime and nighttime MTBT,” the researchers wrote. At 4-7 days, none of the patients with no short MTBT reported reflux symptoms, compared with 7.5% of those with either daytime or nighttime MTBT and 20.9% of those with both daytime and nighttime MTBT.

The study findings were limited by several factors, including the inability to accurately record participants’ diets and the potential for overestimating the odds ratio of risk factors in patients with reflux-related insomnia because of the small numbers. However, the results support findings from previous studies and suggest that dietary modifications could provide a nonpharmacological treatment target for managing GERD in pregnant women, they concluded.
 

Behavioral intervention may benefit pregnant women

The study is important because heartburn and regurgitation are common challenges during pregnancy, Ziad F. Gellad, MD, of Duke University, Durham, N.C., said in an interview. “Understanding risk factors for these conditions can be helpful in designing behavioral and pharmaceutical therapeutic interventions.”

The link between short MTBT and increased risk for GERD is well-known, said Dr. Gellad. “Lengthening the time to laying supine after a meal is a common recommendation given to patients with GERD and is included in published GERD guidelines.” Although pregnant woman may have been excluded from trials on which the guidelines and recommendations are based, “it is reasonable to expect that findings would translate to this population that is generally higher risk for reflux,” he noted.

Dr. Gellad was interested to see the dose response between MTBT and reflux, with those patients having both daytime and nighttime short MTBT experiencing reflux more often than those with short MTBT in only one of those time periods (4-7 days vs. 1-3 days).

The key message for clinicians is that, for all individuals, pregnant or not, “avoiding late night meals and short meal-to-bed time is an appropriate behavioral intervention to recommend for patients with troublesome heartburn or regurgitation,” Dr. Gellad emphasized. However, more research is needed in some areas, “implementation studies would be helpful to understand how best to educate patients on behavioral modifications known to decrease reflux symptoms.”

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Gellad had no relevant financial disclosures, but serves as a member of the GI & Hepatology News board of editors.