In this supplement to Family Practice, Heather M. Territo, MD, and Gale R. Burstein, MD, MPH discuss how primary care physicians play an essential role in screening for STIs in young patients. 

Read More 

In this supplement to Family Practice, Heather M. Territo, MD, and Gale R. Burstein, MD, MPH discuss how primary care physicians play an essential role in screening for STIs in young patients. 

Read More 

In this supplement to Family Practice, Heather M. Territo, MD, and Gale R. Burstein, MD, MPH discuss how primary care physicians play an essential role in screening for STIs in young patients. 

Read More 

To the Editor:

Subcutaneous panniculitic T-cell lymphoma (SPTCL) is a rare cutaneous T-cell lymphoma that was first described in 1991¹ and comprises less than 1% of all non-Hodgkin lymphomas (NHLs). It most commonly occurs in young adults, with a median patient age of 36 years and a slight female predominance.² Patients typically present with skin nodules or deep-seated plaques involving the legs, arms, and/or trunk. Presentation on the face is less common.^2,3 Paraneoplastic edema has been reported in several cases of SPTCL with facial and periorbital swelling.^4-9

Diagnosis of SPTCL is achieved via analysis of a deep tissue skin biopsy and close clinicopathologic correlation. Histopathology demonstrates lobular panniculitis with an atypical lymphoid infiltrate in the subcutaneous tissue with predominantly CD8⁺ T cells without overlying epidermotropism or interface dermatitis.³ The degree of cellular atypia, fat necrosis, karyorrhexis, cytophagia, and lack of angioinvasion can help to distinguish SPTCL from other panniculitides.^2,3

The prognosis of SPTCL is good, with a 5-year survival rate of 82%, and many patients are able to achieve remission.² However, SPTCL can progress to a fatal hemophagocytic syndrome, which has been reported in 17% of cases, making early diagnosis and treatment of this malignancy imperative.^1,2 Treatment varies depending on the progression and extent of disease and can include the use of steroids, multidrug chemotherapy regimens, radiotherapy, and stem cell transplant in refractory cases.^2-4,10,11

Subcutaneous panniculitic T-cell lymphoma with edema has been reported in a 2-year-old child.¹² We present a case of SPTCL in an adult patient with known stage IV chronic lymphocytic leukemia (CLL) who also had full-body edema.

A 60-year-old woman with a 7-year history of stage IV CLL presented with anasarca of 3 months’ duration. At the time of presentation to dermatology, physical examination revealed erythematous tender nodules on the arms and legs. She had no other medical conditions and was undergoing treatment with ibrutinib for the CLL. The patient reported profound fatigue but no fever, chills, night sweats, cough, or dyspnea. The swelling had begun initially in the legs and progressively worsened to involve the arms, face, and body. She was hospitalized and treated with intravenous steroids and antihistamines, which led to minor improvement in the swelling. The patient’s preliminary diagnosis of erythema nodosum was thought to be related to the CLL or ibrutinib; therefore, treatment subsequently was discontinued and she was discharged from the hospital.

The swelling continued to worsen over the following 3 months, and the patient gained approximately 25 pounds. She presented to our office again with severe periorbital, facial, and lip edema as well as diffuse edema of the torso, arms, and legs (Figure 1). Erythematous tender subcutaneous nodules were noted on the right proximal thigh, left lateral calf, and forearms. She was again hospitalized, and extensive evaluation was performed to exclude other causes of anasarca, including a complete blood cell count; comprehensive metabolic profile; hepatitis panels; HIV test; C3 and C4, complement CH50, C1 esterase inhibitor, IgE, and angiotensin-converting enzyme levels; urine protein to creatinine ratio; computed tomography of the chest, abdomen, and pelvis; and allergy evaluation. The analyses failed to reveal the cause of the anasarca.

During hospitalization, the patient underwent a lymph node biopsy, bone marrow biopsy, and a 6-mm punch biopsy of the right thigh nodule. The lymph node and bone marrow biopsy results were consistent with the known diagnosis of CLL, and the patient was started on intravenous chemotherapy with bendamustine. The skin biopsy demonstrated a predominant T-cell infiltrate consistent with a lobular panniculitis with variable amounts of adipocytes rimmed by lymphocytes, nuclear debris, and karyorrhexis (Figure 2). CD3⁺, CD8⁺, and CD4⁻ T cells were positive for T-cell receptor (TCR) βF1 and negative for TCR-γ with strong expression of cytotoxic markers including granzyme B, perforin, and T-cell intracytoplasmic antigen 1. Rare CD56⁺ cells also were noted. The biopsy did not demonstrate any notable interface dermatitis, epidermotropism, or angioinvasion. T-cell receptor gene rearrangement studies did not show clonality for γ- or β-chain probes. Subcutaneous panniculitic T-cell lymphoma was diagnosed, making this case unique with the presentation of anasarca. This case also is noteworthy due to the rare diagnosis of the secondary malignancy of SPTCL in a patient with known CLL. The patient opted to pursue hospice and comfort measures due to the effects of persistent pancytopenia and the progression of CLL. She died 2 months later.

Clinical courses of SPTCL vary based on the TCR phenotype and immunophenotypic characteristics of the tumor cells. The TCR-αβ phenotype, as described in this case, typically is CD4⁻, CD8⁺, and CD56^– and leads to a more indolent disease course. Lymphomas with the TCR-γδ phenotype typically are CD4⁻, CD8⁻, and CD56⁺; they often are associated with hemophagocytic syndrome and thus a worse prognosis. In 2009, the World Health Organization–European Organization for Research and Treatment of Cancer classification of primary cutaneous lymphomas restricted the category of SPTCL to the TCR-αβ phenotype due to the stark differences between the 2 types. The TCR-γδ phenotype was given its own diagnostic category—primary cutaneous γδ T-cell lymphoma.³

Patients with SPTCL commonly present with nodular skin lesions or deep-seated plaques on the legs, arms, and/or trunk; presentation on the face is rare.^2,3 Fever, chills, night sweats, and/or weight loss were present in approximately 50% of recorded cases. Underlying autoimmune disease was present in 12 of 63 (19%) patients in a 2008 study.² Facial and periorbital swelling with SPTCL has been reported.^4-9 The presentation of anasarca, as seen in our adult patient, has been reported in a 2-year-old child.¹² Anasarca as a presenting symptom of NHL is a rare phenomenon proposed to be induced by malignant cells secreting a cytokine that causes a vascular leak syndrome.¹³ Specifically, tumor necrosis factor α was found to be elevated in at least 2 patients with NHL presenting with anasarca in a prior study. Tumor necrosis factor α is known to cause increased capillary permeability, vascular leakage, and development of edema.¹³ In retrospect, obtaining cytokine levels in our patient would have been useful to support or refute tumor necrosis factor α as a possible cause of anasarca in the setting of NHL. This case continues to highlight that a diagnosis of SPTCL and analysis of a skin biopsy should be considered in cases of sudden unremitting facial and/or body swelling that cannot be explained by other more common causes.

Subcutaneous panniculitic T-cell lymphoma can be diagnosed and distinguished from other panniculitides via analysis of a deep tissue skin biopsy. Multiple biopsies may be required to ensure an adequate sample is obtained.⁴ Histopathology displays an atypical lymphoid infiltrate with a predominant presence of T cells. Neoplastic cells show CD3⁺, CD8⁺, and CD4⁻ T cells, which strongly express cytotoxic proteins such as granzyme B, T-cell intracellular antigen 1, and perforin.³ The degree of cellular atypia, fat necrosis, karyorrhexis, and cytophagia, as well as the lack of angioinvasion, interface dermatitis, and epidermotropism help to distinguish SPTCL from other panniculitides.^2,3 According to a previous study, clonal TCR gene rearrangement was identified in 50% to 80% of cases, but the absence of this clonal rearrangement does not exclude the diagnosis.¹⁴

This case also highlights the occurrence of secondary malignancies in patients with CLL, an NHL that is classified as a low-grade lymphoproliferative malignancy with clonal expansion of B cells.¹⁵ Secondary CTCLs in patients with CLL are rare, but they have been previously described. In 2017, Chang et al¹⁶ identified 12 patients with CLL who subsequently developed CTCL between 1992 and 2008. Of the 12 patients, 7 developed mycosis fungoides, 3 had CTCL not otherwise specified, 1 had mature T-cell lymphoma not otherwise specified, and 1 had primary cutaneous CD30⁺ T-cell lymphoma.¹⁶ The proliferation of 2 separate lymphocytic lineages is rare, but this study demonstrated an increased risk for CTCL to develop in patients with CLL. One possible explanation is that malignant cells come from a common stem cell progenitor or from genetic events. They occur secondary to carcinogens, viruses, or cytokines from T-cell or B-cell clones; they evolve due to treatment of the preexisting lymphoproliferative disease; or they occur simply by coincidence. The behavior of the CTCL may be more aggressive in patients with CLL due to immunosuppression, which may have contributed to the extreme presentation in our patient.¹⁶ Subcutaneous panniculitic T-cell lymphoma also has been reported in a patient with CLL that was thought to be associated with prior rituximab treatment.¹⁷

Treatment of SPTCL depends on the severity and course of the disease. In patients with more indolent disease, systemic steroids have been the most frequently used initial treatment.^2,3,10 However, the disease often will progress after steroid tapering and require further intervention. Localized lesions may be treated with radiation alone or in combination with other systemic therapies.^3,10 In refractory, aggressive, or relapsing cases, polychemotherapeutic regimens have proven to produce long-term remission in 30% of patients, with an overall response rate of 50%.¹⁰ These regimens most commonly have included cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like treatment (EPOCH regimen [etoposide, prednisone, oncovin, cyclophosphamide, and doxorubicin hydrochloride]).^3,10 A stem cell transplant can be considered in patients with recurrent and refractory disease, and it also has been shown to induce remission.^4,17 In patients with a good response to therapy, the disease often can be controlled for long periods of time, with an estimated 5-year survival rate of 80%.¹⁵

This case highlights the diagnostic challenges and variable presentations of SPTCL. Dermatologists, oncologists, and dermatopathologists should be aware of this condition and consider it in the differential diagnosis of a patient with a hematologic malignancy and unremitting facial and/or body swelling without any other cause. The possibility of a secondary hematologic cancer in a patient with CLL also must be taken into consideration. Early diagnosis and treatment can minimize morbidity and induce remission in most patients.

To the Editor:

Subcutaneous panniculitic T-cell lymphoma (SPTCL) is a rare cutaneous T-cell lymphoma that was first described in 1991¹ and comprises less than 1% of all non-Hodgkin lymphomas (NHLs). It most commonly occurs in young adults, with a median patient age of 36 years and a slight female predominance.² Patients typically present with skin nodules or deep-seated plaques involving the legs, arms, and/or trunk. Presentation on the face is less common.^2,3 Paraneoplastic edema has been reported in several cases of SPTCL with facial and periorbital swelling.^4-9

Diagnosis of SPTCL is achieved via analysis of a deep tissue skin biopsy and close clinicopathologic correlation. Histopathology demonstrates lobular panniculitis with an atypical lymphoid infiltrate in the subcutaneous tissue with predominantly CD8⁺ T cells without overlying epidermotropism or interface dermatitis.³ The degree of cellular atypia, fat necrosis, karyorrhexis, cytophagia, and lack of angioinvasion can help to distinguish SPTCL from other panniculitides.^2,3

The prognosis of SPTCL is good, with a 5-year survival rate of 82%, and many patients are able to achieve remission.² However, SPTCL can progress to a fatal hemophagocytic syndrome, which has been reported in 17% of cases, making early diagnosis and treatment of this malignancy imperative.^1,2 Treatment varies depending on the progression and extent of disease and can include the use of steroids, multidrug chemotherapy regimens, radiotherapy, and stem cell transplant in refractory cases.^2-4,10,11

Subcutaneous panniculitic T-cell lymphoma with edema has been reported in a 2-year-old child.¹² We present a case of SPTCL in an adult patient with known stage IV chronic lymphocytic leukemia (CLL) who also had full-body edema.

A 60-year-old woman with a 7-year history of stage IV CLL presented with anasarca of 3 months’ duration. At the time of presentation to dermatology, physical examination revealed erythematous tender nodules on the arms and legs. She had no other medical conditions and was undergoing treatment with ibrutinib for the CLL. The patient reported profound fatigue but no fever, chills, night sweats, cough, or dyspnea. The swelling had begun initially in the legs and progressively worsened to involve the arms, face, and body. She was hospitalized and treated with intravenous steroids and antihistamines, which led to minor improvement in the swelling. The patient’s preliminary diagnosis of erythema nodosum was thought to be related to the CLL or ibrutinib; therefore, treatment subsequently was discontinued and she was discharged from the hospital.

The swelling continued to worsen over the following 3 months, and the patient gained approximately 25 pounds. She presented to our office again with severe periorbital, facial, and lip edema as well as diffuse edema of the torso, arms, and legs (Figure 1). Erythematous tender subcutaneous nodules were noted on the right proximal thigh, left lateral calf, and forearms. She was again hospitalized, and extensive evaluation was performed to exclude other causes of anasarca, including a complete blood cell count; comprehensive metabolic profile; hepatitis panels; HIV test; C3 and C4, complement CH50, C1 esterase inhibitor, IgE, and angiotensin-converting enzyme levels; urine protein to creatinine ratio; computed tomography of the chest, abdomen, and pelvis; and allergy evaluation. The analyses failed to reveal the cause of the anasarca.

During hospitalization, the patient underwent a lymph node biopsy, bone marrow biopsy, and a 6-mm punch biopsy of the right thigh nodule. The lymph node and bone marrow biopsy results were consistent with the known diagnosis of CLL, and the patient was started on intravenous chemotherapy with bendamustine. The skin biopsy demonstrated a predominant T-cell infiltrate consistent with a lobular panniculitis with variable amounts of adipocytes rimmed by lymphocytes, nuclear debris, and karyorrhexis (Figure 2). CD3⁺, CD8⁺, and CD4⁻ T cells were positive for T-cell receptor (TCR) βF1 and negative for TCR-γ with strong expression of cytotoxic markers including granzyme B, perforin, and T-cell intracytoplasmic antigen 1. Rare CD56⁺ cells also were noted. The biopsy did not demonstrate any notable interface dermatitis, epidermotropism, or angioinvasion. T-cell receptor gene rearrangement studies did not show clonality for γ- or β-chain probes. Subcutaneous panniculitic T-cell lymphoma was diagnosed, making this case unique with the presentation of anasarca. This case also is noteworthy due to the rare diagnosis of the secondary malignancy of SPTCL in a patient with known CLL. The patient opted to pursue hospice and comfort measures due to the effects of persistent pancytopenia and the progression of CLL. She died 2 months later.

Clinical courses of SPTCL vary based on the TCR phenotype and immunophenotypic characteristics of the tumor cells. The TCR-αβ phenotype, as described in this case, typically is CD4⁻, CD8⁺, and CD56^– and leads to a more indolent disease course. Lymphomas with the TCR-γδ phenotype typically are CD4⁻, CD8⁻, and CD56⁺; they often are associated with hemophagocytic syndrome and thus a worse prognosis. In 2009, the World Health Organization–European Organization for Research and Treatment of Cancer classification of primary cutaneous lymphomas restricted the category of SPTCL to the TCR-αβ phenotype due to the stark differences between the 2 types. The TCR-γδ phenotype was given its own diagnostic category—primary cutaneous γδ T-cell lymphoma.³

Patients with SPTCL commonly present with nodular skin lesions or deep-seated plaques on the legs, arms, and/or trunk; presentation on the face is rare.^2,3 Fever, chills, night sweats, and/or weight loss were present in approximately 50% of recorded cases. Underlying autoimmune disease was present in 12 of 63 (19%) patients in a 2008 study.² Facial and periorbital swelling with SPTCL has been reported.^4-9 The presentation of anasarca, as seen in our adult patient, has been reported in a 2-year-old child.¹² Anasarca as a presenting symptom of NHL is a rare phenomenon proposed to be induced by malignant cells secreting a cytokine that causes a vascular leak syndrome.¹³ Specifically, tumor necrosis factor α was found to be elevated in at least 2 patients with NHL presenting with anasarca in a prior study. Tumor necrosis factor α is known to cause increased capillary permeability, vascular leakage, and development of edema.¹³ In retrospect, obtaining cytokine levels in our patient would have been useful to support or refute tumor necrosis factor α as a possible cause of anasarca in the setting of NHL. This case continues to highlight that a diagnosis of SPTCL and analysis of a skin biopsy should be considered in cases of sudden unremitting facial and/or body swelling that cannot be explained by other more common causes.

Subcutaneous panniculitic T-cell lymphoma can be diagnosed and distinguished from other panniculitides via analysis of a deep tissue skin biopsy. Multiple biopsies may be required to ensure an adequate sample is obtained.⁴ Histopathology displays an atypical lymphoid infiltrate with a predominant presence of T cells. Neoplastic cells show CD3⁺, CD8⁺, and CD4⁻ T cells, which strongly express cytotoxic proteins such as granzyme B, T-cell intracellular antigen 1, and perforin.³ The degree of cellular atypia, fat necrosis, karyorrhexis, and cytophagia, as well as the lack of angioinvasion, interface dermatitis, and epidermotropism help to distinguish SPTCL from other panniculitides.^2,3 According to a previous study, clonal TCR gene rearrangement was identified in 50% to 80% of cases, but the absence of this clonal rearrangement does not exclude the diagnosis.¹⁴

This case also highlights the occurrence of secondary malignancies in patients with CLL, an NHL that is classified as a low-grade lymphoproliferative malignancy with clonal expansion of B cells.¹⁵ Secondary CTCLs in patients with CLL are rare, but they have been previously described. In 2017, Chang et al¹⁶ identified 12 patients with CLL who subsequently developed CTCL between 1992 and 2008. Of the 12 patients, 7 developed mycosis fungoides, 3 had CTCL not otherwise specified, 1 had mature T-cell lymphoma not otherwise specified, and 1 had primary cutaneous CD30⁺ T-cell lymphoma.¹⁶ The proliferation of 2 separate lymphocytic lineages is rare, but this study demonstrated an increased risk for CTCL to develop in patients with CLL. One possible explanation is that malignant cells come from a common stem cell progenitor or from genetic events. They occur secondary to carcinogens, viruses, or cytokines from T-cell or B-cell clones; they evolve due to treatment of the preexisting lymphoproliferative disease; or they occur simply by coincidence. The behavior of the CTCL may be more aggressive in patients with CLL due to immunosuppression, which may have contributed to the extreme presentation in our patient.¹⁶ Subcutaneous panniculitic T-cell lymphoma also has been reported in a patient with CLL that was thought to be associated with prior rituximab treatment.¹⁷

Treatment of SPTCL depends on the severity and course of the disease. In patients with more indolent disease, systemic steroids have been the most frequently used initial treatment.^2,3,10 However, the disease often will progress after steroid tapering and require further intervention. Localized lesions may be treated with radiation alone or in combination with other systemic therapies.^3,10 In refractory, aggressive, or relapsing cases, polychemotherapeutic regimens have proven to produce long-term remission in 30% of patients, with an overall response rate of 50%.¹⁰ These regimens most commonly have included cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like treatment (EPOCH regimen [etoposide, prednisone, oncovin, cyclophosphamide, and doxorubicin hydrochloride]).^3,10 A stem cell transplant can be considered in patients with recurrent and refractory disease, and it also has been shown to induce remission.^4,17 In patients with a good response to therapy, the disease often can be controlled for long periods of time, with an estimated 5-year survival rate of 80%.¹⁵

This case highlights the diagnostic challenges and variable presentations of SPTCL. Dermatologists, oncologists, and dermatopathologists should be aware of this condition and consider it in the differential diagnosis of a patient with a hematologic malignancy and unremitting facial and/or body swelling without any other cause. The possibility of a secondary hematologic cancer in a patient with CLL also must be taken into consideration. Early diagnosis and treatment can minimize morbidity and induce remission in most patients.

To the Editor:

Subcutaneous panniculitic T-cell lymphoma (SPTCL) is a rare cutaneous T-cell lymphoma that was first described in 1991¹ and comprises less than 1% of all non-Hodgkin lymphomas (NHLs). It most commonly occurs in young adults, with a median patient age of 36 years and a slight female predominance.² Patients typically present with skin nodules or deep-seated plaques involving the legs, arms, and/or trunk. Presentation on the face is less common.^2,3 Paraneoplastic edema has been reported in several cases of SPTCL with facial and periorbital swelling.^4-9

Diagnosis of SPTCL is achieved via analysis of a deep tissue skin biopsy and close clinicopathologic correlation. Histopathology demonstrates lobular panniculitis with an atypical lymphoid infiltrate in the subcutaneous tissue with predominantly CD8⁺ T cells without overlying epidermotropism or interface dermatitis.³ The degree of cellular atypia, fat necrosis, karyorrhexis, cytophagia, and lack of angioinvasion can help to distinguish SPTCL from other panniculitides.^2,3

The prognosis of SPTCL is good, with a 5-year survival rate of 82%, and many patients are able to achieve remission.² However, SPTCL can progress to a fatal hemophagocytic syndrome, which has been reported in 17% of cases, making early diagnosis and treatment of this malignancy imperative.^1,2 Treatment varies depending on the progression and extent of disease and can include the use of steroids, multidrug chemotherapy regimens, radiotherapy, and stem cell transplant in refractory cases.^2-4,10,11

Subcutaneous panniculitic T-cell lymphoma with edema has been reported in a 2-year-old child.¹² We present a case of SPTCL in an adult patient with known stage IV chronic lymphocytic leukemia (CLL) who also had full-body edema.

A 60-year-old woman with a 7-year history of stage IV CLL presented with anasarca of 3 months’ duration. At the time of presentation to dermatology, physical examination revealed erythematous tender nodules on the arms and legs. She had no other medical conditions and was undergoing treatment with ibrutinib for the CLL. The patient reported profound fatigue but no fever, chills, night sweats, cough, or dyspnea. The swelling had begun initially in the legs and progressively worsened to involve the arms, face, and body. She was hospitalized and treated with intravenous steroids and antihistamines, which led to minor improvement in the swelling. The patient’s preliminary diagnosis of erythema nodosum was thought to be related to the CLL or ibrutinib; therefore, treatment subsequently was discontinued and she was discharged from the hospital.

The swelling continued to worsen over the following 3 months, and the patient gained approximately 25 pounds. She presented to our office again with severe periorbital, facial, and lip edema as well as diffuse edema of the torso, arms, and legs (Figure 1). Erythematous tender subcutaneous nodules were noted on the right proximal thigh, left lateral calf, and forearms. She was again hospitalized, and extensive evaluation was performed to exclude other causes of anasarca, including a complete blood cell count; comprehensive metabolic profile; hepatitis panels; HIV test; C3 and C4, complement CH50, C1 esterase inhibitor, IgE, and angiotensin-converting enzyme levels; urine protein to creatinine ratio; computed tomography of the chest, abdomen, and pelvis; and allergy evaluation. The analyses failed to reveal the cause of the anasarca.

During hospitalization, the patient underwent a lymph node biopsy, bone marrow biopsy, and a 6-mm punch biopsy of the right thigh nodule. The lymph node and bone marrow biopsy results were consistent with the known diagnosis of CLL, and the patient was started on intravenous chemotherapy with bendamustine. The skin biopsy demonstrated a predominant T-cell infiltrate consistent with a lobular panniculitis with variable amounts of adipocytes rimmed by lymphocytes, nuclear debris, and karyorrhexis (Figure 2). CD3⁺, CD8⁺, and CD4⁻ T cells were positive for T-cell receptor (TCR) βF1 and negative for TCR-γ with strong expression of cytotoxic markers including granzyme B, perforin, and T-cell intracytoplasmic antigen 1. Rare CD56⁺ cells also were noted. The biopsy did not demonstrate any notable interface dermatitis, epidermotropism, or angioinvasion. T-cell receptor gene rearrangement studies did not show clonality for γ- or β-chain probes. Subcutaneous panniculitic T-cell lymphoma was diagnosed, making this case unique with the presentation of anasarca. This case also is noteworthy due to the rare diagnosis of the secondary malignancy of SPTCL in a patient with known CLL. The patient opted to pursue hospice and comfort measures due to the effects of persistent pancytopenia and the progression of CLL. She died 2 months later.

Clinical courses of SPTCL vary based on the TCR phenotype and immunophenotypic characteristics of the tumor cells. The TCR-αβ phenotype, as described in this case, typically is CD4⁻, CD8⁺, and CD56^– and leads to a more indolent disease course. Lymphomas with the TCR-γδ phenotype typically are CD4⁻, CD8⁻, and CD56⁺; they often are associated with hemophagocytic syndrome and thus a worse prognosis. In 2009, the World Health Organization–European Organization for Research and Treatment of Cancer classification of primary cutaneous lymphomas restricted the category of SPTCL to the TCR-αβ phenotype due to the stark differences between the 2 types. The TCR-γδ phenotype was given its own diagnostic category—primary cutaneous γδ T-cell lymphoma.³

Patients with SPTCL commonly present with nodular skin lesions or deep-seated plaques on the legs, arms, and/or trunk; presentation on the face is rare.^2,3 Fever, chills, night sweats, and/or weight loss were present in approximately 50% of recorded cases. Underlying autoimmune disease was present in 12 of 63 (19%) patients in a 2008 study.² Facial and periorbital swelling with SPTCL has been reported.^4-9 The presentation of anasarca, as seen in our adult patient, has been reported in a 2-year-old child.¹² Anasarca as a presenting symptom of NHL is a rare phenomenon proposed to be induced by malignant cells secreting a cytokine that causes a vascular leak syndrome.¹³ Specifically, tumor necrosis factor α was found to be elevated in at least 2 patients with NHL presenting with anasarca in a prior study. Tumor necrosis factor α is known to cause increased capillary permeability, vascular leakage, and development of edema.¹³ In retrospect, obtaining cytokine levels in our patient would have been useful to support or refute tumor necrosis factor α as a possible cause of anasarca in the setting of NHL. This case continues to highlight that a diagnosis of SPTCL and analysis of a skin biopsy should be considered in cases of sudden unremitting facial and/or body swelling that cannot be explained by other more common causes.

Subcutaneous panniculitic T-cell lymphoma can be diagnosed and distinguished from other panniculitides via analysis of a deep tissue skin biopsy. Multiple biopsies may be required to ensure an adequate sample is obtained.⁴ Histopathology displays an atypical lymphoid infiltrate with a predominant presence of T cells. Neoplastic cells show CD3⁺, CD8⁺, and CD4⁻ T cells, which strongly express cytotoxic proteins such as granzyme B, T-cell intracellular antigen 1, and perforin.³ The degree of cellular atypia, fat necrosis, karyorrhexis, and cytophagia, as well as the lack of angioinvasion, interface dermatitis, and epidermotropism help to distinguish SPTCL from other panniculitides.^2,3 According to a previous study, clonal TCR gene rearrangement was identified in 50% to 80% of cases, but the absence of this clonal rearrangement does not exclude the diagnosis.¹⁴

This case also highlights the occurrence of secondary malignancies in patients with CLL, an NHL that is classified as a low-grade lymphoproliferative malignancy with clonal expansion of B cells.¹⁵ Secondary CTCLs in patients with CLL are rare, but they have been previously described. In 2017, Chang et al¹⁶ identified 12 patients with CLL who subsequently developed CTCL between 1992 and 2008. Of the 12 patients, 7 developed mycosis fungoides, 3 had CTCL not otherwise specified, 1 had mature T-cell lymphoma not otherwise specified, and 1 had primary cutaneous CD30⁺ T-cell lymphoma.¹⁶ The proliferation of 2 separate lymphocytic lineages is rare, but this study demonstrated an increased risk for CTCL to develop in patients with CLL. One possible explanation is that malignant cells come from a common stem cell progenitor or from genetic events. They occur secondary to carcinogens, viruses, or cytokines from T-cell or B-cell clones; they evolve due to treatment of the preexisting lymphoproliferative disease; or they occur simply by coincidence. The behavior of the CTCL may be more aggressive in patients with CLL due to immunosuppression, which may have contributed to the extreme presentation in our patient.¹⁶ Subcutaneous panniculitic T-cell lymphoma also has been reported in a patient with CLL that was thought to be associated with prior rituximab treatment.¹⁷

Treatment of SPTCL depends on the severity and course of the disease. In patients with more indolent disease, systemic steroids have been the most frequently used initial treatment.^2,3,10 However, the disease often will progress after steroid tapering and require further intervention. Localized lesions may be treated with radiation alone or in combination with other systemic therapies.^3,10 In refractory, aggressive, or relapsing cases, polychemotherapeutic regimens have proven to produce long-term remission in 30% of patients, with an overall response rate of 50%.¹⁰ These regimens most commonly have included cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like treatment (EPOCH regimen [etoposide, prednisone, oncovin, cyclophosphamide, and doxorubicin hydrochloride]).^3,10 A stem cell transplant can be considered in patients with recurrent and refractory disease, and it also has been shown to induce remission.^4,17 In patients with a good response to therapy, the disease often can be controlled for long periods of time, with an estimated 5-year survival rate of 80%.¹⁵

This case highlights the diagnostic challenges and variable presentations of SPTCL. Dermatologists, oncologists, and dermatopathologists should be aware of this condition and consider it in the differential diagnosis of a patient with a hematologic malignancy and unremitting facial and/or body swelling without any other cause. The possibility of a secondary hematologic cancer in a patient with CLL also must be taken into consideration. Early diagnosis and treatment can minimize morbidity and induce remission in most patients.

An intervention tailored for Black first-time mothers helped increase their infants’ sleep time, researchers have found, a notable result as many studies have shown Black infants get less sleep on average than White infants.

Less sleep has historically put Black children at higher risk for negative outcomes including obesity and poorer social-emotional functioning and cognitive development. These disparities persist into adulthood, the researchers note, as previous studies have shown.

Justin A. Lavner, PhD, with the department of psychology at the University of Georgia in Athens, led this post hoc secondary analysis of the Sleep SAAF (Strong African American Families) study, a randomized clinical trial of 234 participants comparing a responsive parenting (RP) intervention with a safety control group over the first 16 weeks post partum. The original analysis studied the effects of the intervention on rapid weight gain.

In the original analysis, the authors write that “From birth to 2, the prevalence of high weight for length (above the 95th percentile) is 25% higher among African American children compared to White children. From age 2 to 19, the rate of obesity is more than 50% higher among African American children compared to White children. Similar disparities persist into adulthood: rates of obesity are approximately 25% higher among African American adults compared to White adults.”

The differences in early rapid weight gain may be driving the disparities, the authors write.

Elements of the intervention

The intervention in the current analysis included materials delivered at the 3- and 8-week home visits focused on soothing and crying, feeding, and interactive play in the babies’ first months. Families were recruited from Augusta University Medical Center in Augusta, Ga., and had home visits at 1, 3, 8, and 16 weeks post partum.

Mothers got a packet of handouts and facilitators walked through the information with them. The measures involved hands-on activities, discussion, and videos, all tailored for Black families, the authors state.

Mothers were taught about responding appropriately at night when their baby cries, including giving the baby a couple of minutes to fall back to sleep independently and by using calming messages, such as shushing or white noise, before picking the baby up.
 

Babies learn to fall asleep on their own

They also learned to put infants to bed early (ideally by 8 p.m.) so the babies would be calm but awake and could learn to fall asleep on their own.

The control group’s guidance was matched for intensity and session length but focused on sleep and home safety, such as reducing the risk of sudden infant death syndrome (SIDS), keeping the baby’s sleep area close to, but away from, the mother’s bed, and preventing shaken baby syndrome.

In both groups, the 3-week visit session lasted about 90-120 minutes and the 8-week visit lasted about 45-60 minutes.
 

Longer sleep with the intervention

A total of 212 Black mothers, average age 22.7, were randomized – 108 to the RP group and 104 to the control group. Answers on questionnaires were analyzed and at 16 weeks post partum, infants in the RP group (relative to controls) had:

• Longer reported nighttime sleep (mean difference, 40 minutes [95% confidence interval, 3-77]).
• Longer total sleep duration (mean difference, 73 minutes [95% CI, 14-131]).
• Fewer nighttime wakings (mean difference, −0.4 wakings [95% CI, −0.6 to −0.1]).
• Greater likelihood of meeting guidelines of at least 12 hours of sleep per day (risk ratio, 1.4 [95% CI, 1.1 to 1.8]) than controls.

Findings were published in JAMA Network Open.

Additionally, mothers in the RP group more frequently reported they engaged in practices such as letting babies have a few minutes to fall back to sleep on their own (RR, 1.6 [95% CI, 1.0-2.6]) and being less likely to feed their infant just before the baby’s bedtime (RR, 0.5 [95% CI, 0.3-0.8]).

In an accompanying invited commentary, Sarah M. Honaker, PhD, department of pediatrics, Indiana University, Indianapolis, and Alicia Chung, EdD, Center for Early Childhood Health and Development at New York University, write that though the added average sleep duration is one of the most significant findings, there is a possibility of desirability bias because it was reported by the mothers after specific guidance by the facilitators.

“Nonetheless,” the editorialists write, “even if the true effect were half as small, this additional sleep duration could yield notable benefits in infant development if the effect persisted over time. The difference in night wakings between the intervention and control groups (1.8 vs 1.5 per night) at 16 weeks postpartum was statistically significant, though it is unclear whether this difference is clinically meaningful to families.”

They note that it is unclear from the study how the intervention was culturally adapted and how the adaptation might have affected outcomes.

Sleep intervention trials have focused on White families

The editorialists write that much is known about the benefits of behavioral sleep intervention in controlled trials and general population settings, and no adverse effects on infant attachment or cortisol levels have been linked to the interventions.

However, they add, “Unfortunately, this substantial progress in our understanding of infant BSI [behavioral sleep intervention] comes with a caveat, in that most previous studies have been performed with White families from mid-to-high socioeconomic backgrounds.”

Dr. Honaker and Dr. Chung write, “[I]t is important to note that much work remains to examine the acceptability, feasibility, and efficacy of infant BSI in other groups that have been historically marginalized.”

Dr. Lavner and colleagues point out that before their study, there had been little emphasis on interventions to encourage better sleep in general for Black infants, “as most early sleep interventions for this population have focused on SIDS prevention.”

The study by Dr. Lavner et al. was funded by the National Institutes of Health, a Harrington Faculty Fellowship from the University of Texas, and an award from the Penn State Clinical and Translational Sciences Institute supported by the National Center for Advancing Translational Sciences. Editorialist Dr. Honaker reported receiving grants from Nationwide Children’s Hospital (parent grant, Centers for Disease Control and Prevention) to evaluate the acceptability of infant behavioral sleep intervention in Black families.

An intervention tailored for Black first-time mothers helped increase their infants’ sleep time, researchers have found, a notable result as many studies have shown Black infants get less sleep on average than White infants.

Less sleep has historically put Black children at higher risk for negative outcomes including obesity and poorer social-emotional functioning and cognitive development. These disparities persist into adulthood, the researchers note, as previous studies have shown.

Justin A. Lavner, PhD, with the department of psychology at the University of Georgia in Athens, led this post hoc secondary analysis of the Sleep SAAF (Strong African American Families) study, a randomized clinical trial of 234 participants comparing a responsive parenting (RP) intervention with a safety control group over the first 16 weeks post partum. The original analysis studied the effects of the intervention on rapid weight gain.

In the original analysis, the authors write that “From birth to 2, the prevalence of high weight for length (above the 95th percentile) is 25% higher among African American children compared to White children. From age 2 to 19, the rate of obesity is more than 50% higher among African American children compared to White children. Similar disparities persist into adulthood: rates of obesity are approximately 25% higher among African American adults compared to White adults.”

The differences in early rapid weight gain may be driving the disparities, the authors write.

Elements of the intervention

The intervention in the current analysis included materials delivered at the 3- and 8-week home visits focused on soothing and crying, feeding, and interactive play in the babies’ first months. Families were recruited from Augusta University Medical Center in Augusta, Ga., and had home visits at 1, 3, 8, and 16 weeks post partum.

Mothers got a packet of handouts and facilitators walked through the information with them. The measures involved hands-on activities, discussion, and videos, all tailored for Black families, the authors state.

Mothers were taught about responding appropriately at night when their baby cries, including giving the baby a couple of minutes to fall back to sleep independently and by using calming messages, such as shushing or white noise, before picking the baby up.
 

Babies learn to fall asleep on their own

They also learned to put infants to bed early (ideally by 8 p.m.) so the babies would be calm but awake and could learn to fall asleep on their own.

The control group’s guidance was matched for intensity and session length but focused on sleep and home safety, such as reducing the risk of sudden infant death syndrome (SIDS), keeping the baby’s sleep area close to, but away from, the mother’s bed, and preventing shaken baby syndrome.

In both groups, the 3-week visit session lasted about 90-120 minutes and the 8-week visit lasted about 45-60 minutes.
 

Longer sleep with the intervention

A total of 212 Black mothers, average age 22.7, were randomized – 108 to the RP group and 104 to the control group. Answers on questionnaires were analyzed and at 16 weeks post partum, infants in the RP group (relative to controls) had:

• Longer reported nighttime sleep (mean difference, 40 minutes [95% confidence interval, 3-77]).
• Longer total sleep duration (mean difference, 73 minutes [95% CI, 14-131]).
• Fewer nighttime wakings (mean difference, −0.4 wakings [95% CI, −0.6 to −0.1]).
• Greater likelihood of meeting guidelines of at least 12 hours of sleep per day (risk ratio, 1.4 [95% CI, 1.1 to 1.8]) than controls.

Findings were published in JAMA Network Open.

Additionally, mothers in the RP group more frequently reported they engaged in practices such as letting babies have a few minutes to fall back to sleep on their own (RR, 1.6 [95% CI, 1.0-2.6]) and being less likely to feed their infant just before the baby’s bedtime (RR, 0.5 [95% CI, 0.3-0.8]).

In an accompanying invited commentary, Sarah M. Honaker, PhD, department of pediatrics, Indiana University, Indianapolis, and Alicia Chung, EdD, Center for Early Childhood Health and Development at New York University, write that though the added average sleep duration is one of the most significant findings, there is a possibility of desirability bias because it was reported by the mothers after specific guidance by the facilitators.

“Nonetheless,” the editorialists write, “even if the true effect were half as small, this additional sleep duration could yield notable benefits in infant development if the effect persisted over time. The difference in night wakings between the intervention and control groups (1.8 vs 1.5 per night) at 16 weeks postpartum was statistically significant, though it is unclear whether this difference is clinically meaningful to families.”

They note that it is unclear from the study how the intervention was culturally adapted and how the adaptation might have affected outcomes.

Sleep intervention trials have focused on White families

The editorialists write that much is known about the benefits of behavioral sleep intervention in controlled trials and general population settings, and no adverse effects on infant attachment or cortisol levels have been linked to the interventions.

However, they add, “Unfortunately, this substantial progress in our understanding of infant BSI [behavioral sleep intervention] comes with a caveat, in that most previous studies have been performed with White families from mid-to-high socioeconomic backgrounds.”

Dr. Honaker and Dr. Chung write, “[I]t is important to note that much work remains to examine the acceptability, feasibility, and efficacy of infant BSI in other groups that have been historically marginalized.”

Dr. Lavner and colleagues point out that before their study, there had been little emphasis on interventions to encourage better sleep in general for Black infants, “as most early sleep interventions for this population have focused on SIDS prevention.”

The study by Dr. Lavner et al. was funded by the National Institutes of Health, a Harrington Faculty Fellowship from the University of Texas, and an award from the Penn State Clinical and Translational Sciences Institute supported by the National Center for Advancing Translational Sciences. Editorialist Dr. Honaker reported receiving grants from Nationwide Children’s Hospital (parent grant, Centers for Disease Control and Prevention) to evaluate the acceptability of infant behavioral sleep intervention in Black families.

An intervention tailored for Black first-time mothers helped increase their infants’ sleep time, researchers have found, a notable result as many studies have shown Black infants get less sleep on average than White infants.

Less sleep has historically put Black children at higher risk for negative outcomes including obesity and poorer social-emotional functioning and cognitive development. These disparities persist into adulthood, the researchers note, as previous studies have shown.

Justin A. Lavner, PhD, with the department of psychology at the University of Georgia in Athens, led this post hoc secondary analysis of the Sleep SAAF (Strong African American Families) study, a randomized clinical trial of 234 participants comparing a responsive parenting (RP) intervention with a safety control group over the first 16 weeks post partum. The original analysis studied the effects of the intervention on rapid weight gain.

In the original analysis, the authors write that “From birth to 2, the prevalence of high weight for length (above the 95th percentile) is 25% higher among African American children compared to White children. From age 2 to 19, the rate of obesity is more than 50% higher among African American children compared to White children. Similar disparities persist into adulthood: rates of obesity are approximately 25% higher among African American adults compared to White adults.”

The differences in early rapid weight gain may be driving the disparities, the authors write.

Elements of the intervention

The intervention in the current analysis included materials delivered at the 3- and 8-week home visits focused on soothing and crying, feeding, and interactive play in the babies’ first months. Families were recruited from Augusta University Medical Center in Augusta, Ga., and had home visits at 1, 3, 8, and 16 weeks post partum.

Mothers got a packet of handouts and facilitators walked through the information with them. The measures involved hands-on activities, discussion, and videos, all tailored for Black families, the authors state.

Mothers were taught about responding appropriately at night when their baby cries, including giving the baby a couple of minutes to fall back to sleep independently and by using calming messages, such as shushing or white noise, before picking the baby up.
 

Babies learn to fall asleep on their own

They also learned to put infants to bed early (ideally by 8 p.m.) so the babies would be calm but awake and could learn to fall asleep on their own.

The control group’s guidance was matched for intensity and session length but focused on sleep and home safety, such as reducing the risk of sudden infant death syndrome (SIDS), keeping the baby’s sleep area close to, but away from, the mother’s bed, and preventing shaken baby syndrome.

In both groups, the 3-week visit session lasted about 90-120 minutes and the 8-week visit lasted about 45-60 minutes.
 

Longer sleep with the intervention

A total of 212 Black mothers, average age 22.7, were randomized – 108 to the RP group and 104 to the control group. Answers on questionnaires were analyzed and at 16 weeks post partum, infants in the RP group (relative to controls) had:

• Longer reported nighttime sleep (mean difference, 40 minutes [95% confidence interval, 3-77]).
• Longer total sleep duration (mean difference, 73 minutes [95% CI, 14-131]).
• Fewer nighttime wakings (mean difference, −0.4 wakings [95% CI, −0.6 to −0.1]).
• Greater likelihood of meeting guidelines of at least 12 hours of sleep per day (risk ratio, 1.4 [95% CI, 1.1 to 1.8]) than controls.

Findings were published in JAMA Network Open.

Additionally, mothers in the RP group more frequently reported they engaged in practices such as letting babies have a few minutes to fall back to sleep on their own (RR, 1.6 [95% CI, 1.0-2.6]) and being less likely to feed their infant just before the baby’s bedtime (RR, 0.5 [95% CI, 0.3-0.8]).

In an accompanying invited commentary, Sarah M. Honaker, PhD, department of pediatrics, Indiana University, Indianapolis, and Alicia Chung, EdD, Center for Early Childhood Health and Development at New York University, write that though the added average sleep duration is one of the most significant findings, there is a possibility of desirability bias because it was reported by the mothers after specific guidance by the facilitators.

“Nonetheless,” the editorialists write, “even if the true effect were half as small, this additional sleep duration could yield notable benefits in infant development if the effect persisted over time. The difference in night wakings between the intervention and control groups (1.8 vs 1.5 per night) at 16 weeks postpartum was statistically significant, though it is unclear whether this difference is clinically meaningful to families.”

They note that it is unclear from the study how the intervention was culturally adapted and how the adaptation might have affected outcomes.

Sleep intervention trials have focused on White families

The editorialists write that much is known about the benefits of behavioral sleep intervention in controlled trials and general population settings, and no adverse effects on infant attachment or cortisol levels have been linked to the interventions.

However, they add, “Unfortunately, this substantial progress in our understanding of infant BSI [behavioral sleep intervention] comes with a caveat, in that most previous studies have been performed with White families from mid-to-high socioeconomic backgrounds.”

Dr. Honaker and Dr. Chung write, “[I]t is important to note that much work remains to examine the acceptability, feasibility, and efficacy of infant BSI in other groups that have been historically marginalized.”

Dr. Lavner and colleagues point out that before their study, there had been little emphasis on interventions to encourage better sleep in general for Black infants, “as most early sleep interventions for this population have focused on SIDS prevention.”

The study by Dr. Lavner et al. was funded by the National Institutes of Health, a Harrington Faculty Fellowship from the University of Texas, and an award from the Penn State Clinical and Translational Sciences Institute supported by the National Center for Advancing Translational Sciences. Editorialist Dr. Honaker reported receiving grants from Nationwide Children’s Hospital (parent grant, Centers for Disease Control and Prevention) to evaluate the acceptability of infant behavioral sleep intervention in Black families.

To the Editor:

The organisms of the genus Nocardia are gram-positive, ubiquitous, aerobic actinomycetes found worldwide in soil, decaying organic material, and water.¹ The genus Nocardia includes more than 50 species; some species, such as Nocardia asteroides, Nocardia farcinica, Nocardia nova, and Nocardia brasiliensis, are the cause of nocardiosis in humans and animals.^2,3 Nocardiosis is a rare and opportunistic infection that predominantly affects immunocompromised individuals; however, up to 30% of infections can occur in immunocompetent hosts.⁴ Nocardiosis can manifest in 3 disease forms: cutaneous, pulmonary, or disseminated. Cutaneous nocardiosis commonly develops in immunocompetent individuals who have experienced a predisposing traumatic injury to the skin,⁵ and it can exhibit a diverse variety of clinical manifestations, making diagnosis difficult. We describe a case of serious progressive primary cutaneous nocardiosis with an unusual presentation in an immunocompetent patient.

A 26-year-old immunocompetent man presented with pain, swelling, nodules, abscesses, ulcers, and sinus drainage of the left arm. The left elbow lesion initially developed at the site of a trauma 6 years prior that was painless but was contaminated with mossy soil. The condition slowly progressed over the next 2 years, and the patient experienced increased swelling and eventually developed multiple draining sinus tracts. Over the next 4 years, the lesions multiplied, spreading to the forearm and upper arm; associated severe pain and swelling at the elbow and wrist joint developed. The patient sought medical care at a local hospital and subsequently was diagnosed with suspected cutaneous tuberculosis. The patient was empirically treated with a 6-month course of isoniazid, rifampicin, pyrazinamide, and ethambutol; however, the lesions continued to progress and worsen. The patient had to stop antibiotic treatment because of substantially elevated alanine aminotransferase and aspartate aminotransferase levels.

He subsequently was evaluated at our hospital. He had no notable medical history and was afebrile. Physical examination revealed multiple erythematous nodules, abscesses, and ulcers on the left arm. There were several nodules with open sinus tracts and seropurulent crusts along with numerous atrophic, ovoid, stellate scars. Other nodules and ulcers with purulent drainage were located along the lymphatic nodes extending up the patient’s left forearm (Figure 1A). The yellowish-white pus discharge from several active sinuses contained no apparent granules. The lesions were densely distributed along the elbow, wrist, and shoulder, which resulted in associated skin swelling and restricted joint movement. The left axillary lymph nodes were enlarged.

Laboratory analyses revealed a hemoglobin level of 9.6 g/dL (reference range, 13–17.5 g/dL), platelet count of 621×10⁹/L (reference range, 125–350×10⁹/L), and leukocyte count of 14.3×10⁹/L (reference range, 3.5–9.5 ×10⁹/L). C-reactive protein level was 88.4 mg/L (reference range, 0–10 mg/L). Blood, renal, and liver tests, as well as tumor marker, peripheral blood lymphocyte subset, immunoglobulin, and complement results were within reference ranges. Results for Treponema pallidum and HIV antibody tests were negative. Hepatitis B virus markers were positive for hepatitis B surface antigen, hepatitis B e antigen, and hepatitis B core antibody, and the serum concentration of hepatitis B virus DNA was 3.12×10⁷ IU/mL (reference range, <5×10² IU/mL). Computed tomography of the chest and cranium were unremarkable. Ultrasonography of the left arm revealed multiple vertical sinus tracts and several horizontal communicating branches that were accompanied by worm-eaten bone destruction (Figure 2).

Additional testing included histopathologic staining of a skin tissue specimen—hematoxylin and eosin, periodic acid–Schiff, and acid-fast staining—showed nonspecific, diffuse, inflammatory cell infiltration suggestive of chronic suppurative granuloma (Figure 3) but failed to reveal any special strains or organisms. Gram stain examination of the purulent fluid collected from the subcutaneous tissue showed no apparent positive bacillus or filamentous granules. The specimen was then inoculated on Sabouraud dextrose agar and Lowenstein-Jensen medium for fungus and mycobacteria culture, respectively. After 5 days, chalky, yellow, adherent colonies were observed on the Löwenstein-Jensen medium, and after 26 days, yellow crinkled colonies were observed on Sabouraud dextrose agar. The colonies were then inoculated on Columbia blood agar and incubated for 1 week to aid in the identification of organisms. Growth of yellow colonies that were adherent to the agar, moist, and smooth with a velvety surface, as well as a characteristic moldy odor resulted. Gram staining revealed gram-positive, thin, and beaded branching filaments (Figure 4). Based on colony characteristics, physiological properties, and biochemical tests, the isolate was identified as Nocardia. Results of further investigations employing polymerase chain reaction analysis of the skin specimen and bacterial colonies using a Nocardia genus 596-bp fragment of 16S ribosomal RNA primer (forward primer NG1: 5’-ACCGACCACAAGGGG-3’, reverse primer NG2: 5’-GGTTGTAACCTCTTCGA-3’)⁶ were completely consistent with the reference for identification of N brasiliensis. Evaluation of these results led to a diagnosis of cutaneous nocardiosis after traumatic inoculation.

Because there was a high suspicion of actinophytosis or nocardiosis at admission, the patient received a combination antibiotic treatment with intravenous aqueous penicillin (4 million U every 4 hours) and oral trimethoprim-sulfamethoxazole (160/800 mg twice daily). Subsequently, treatment was changed to a combination of oral trimethoprim-sulfamethoxazole (160/800 mg twice daily) and moxifloxacin (400 mg once daily) based on pathogen identification and antibiotic sensitivity testing. After 1 month of treatment, the cutaneous lesions and left limb swelling dramatically improved and purulent drainage ceased, though some scarring occurred during the healing process. In addition, the mobility of the affected shoulder, elbow, and wrist joints slightly improved. Notable improvement in the mobility and swelling of the joints was observed at 6-month follow-up (Figure 1B). The patient continues to be monitored on an outpatient basis.

Cutaneous nocardiosis is a disfiguring granulomatous infection involving cutaneous and subcutaneous tissue that can progress to cause injury to viscera and bone.⁷ It has been called one of the great imitators because cutaneous nocardiosis can present in multiple forms,^8,9 including mycetoma, sporotrichoid infection, superficial skin infection, and disseminated infection with cutaneous involvement. The differential diagnoses of cutaneous nocardiosis are broad and include tuberculosis; actinomycosis; deep fungal infections such as sporotrichosis, blastomycosis, phaeohyphomycosis, histoplasmosis, and coccidioidomycosis; other bacterial causes of cellulitis, abscess, or ecthyma; and malignancies.¹⁰ The principle method of diagnosis is the identification of Nocardia from the infection site.

Our patient ultimately was diagnosed with primary cutaneous nocardiosis resulting from a traumatic injury to the skin that was contaminated with soil. The clinical manifestation pattern was a compound type, including both mycetoma and sporotrichoid infections. Initially, Nocardia mycetoma occurred with subcutaneous infection by direct extension^10,11 and appeared as dense, predominantly painless, swollen lesions. After 4 years, the skin lesions continued to spread linearly to the patient’s upper arm and forearm and manifested as the sporotrichoid infection type with painful swollen lesions at the site of inoculation and painful enlargement of the ipsilateral axillary lymph node.

Although nocardiosis is found worldwide, it is endemic to tropical and subtropical regions such as India, Africa, Southeast Asia, and Latin America.¹² Nocardiosis most often is observed in individuals aged 20 to 40 years. It affects men more than women, and it commonly occurs in field laborers and cultivators whose occupations involve direct contact with the soil.¹³ Most lesions are found on the lower extremities, though localized nocardiosis infections can occur in other areas such as the neck, breasts, back, buttocks, and elbows.

Our patient initially was misdiagnosed, and treatment was delayed for several reasons. First, nocardiosis is not common in China, and most clinicians are unfamiliar with the disease. Second, the related lesions do not have specific features, and our patient had a complex clinical presentation that included mycetoma and sporotrichoid infection. Third, the characteristic grain of Nocardia species is small but that of N brasiliensis is even smaller (approximately 0.1–0.2 mm in diameter), which makes visualization difficult in both histopathologic and microbiologic examinations.¹⁴ The histopathologic examination results of our patient in the local hospital were nonspecific. Fourth, our patient did not initially go to the hospital but instead purchased some over-the-counter antibiotic ointments for external application because the lesions were painless. Moreover, microbiologic smear and culture examinations were not conducted in the local hospital before administering antituberculosis treatment to the patient. Instead, a polymerase chain reaction examination of skin lesion tissue for tubercle bacilli and atypical mycobacteria was negative. These findings imply that the traditional microbial smear and culture evaluations cannot be omitted. Furthermore, culture examinations should be conducted on multiple skin tissue and purulent fluid specimens to increase the likelihood of detection. These cultures should be monitored for at least 2 to 4 weeks because Nocardia is a slow-growing organism.¹⁰

The optimal antimicrobial treatment regimens for nocardiosis have not been firmly established.¹⁵ Trimethoprim-sulfamethoxazole is regarded as the first-line antimicrobial agent for treatment of nocardial infections. The optimal duration of antimicrobial therapy for nocardiosis also has not been determined, and the treatment regimen depends on the severity and extent of the infection as well as on the presence of infection-related complications. The main complication is bone involvement. Notable bony changes include periosteal thickening, osteoporosis, and osteolysis.

We considered the severity of skin lesions and bone marrow invasion in our patient and planned to treat him continually with oral trimethoprim-sulfamethoxazole according to the in vitro drug susceptibility test. The patient showed clinical improvement after 1 month of treatment, and he continued to improve after 6 months of treatment. To prevent recurrence, we found it necessary to treat the patient with a long-term antibiotic course over 6 to 12 months.¹⁶

Cutaneous nocardiosis remains a diagnostic challenge because of its nonspecific and diverse clinical and histopathological presentations. Diagnosis is further complicated by the inherent difficulty of cultivating and identifying the clinical isolate in the laboratory. A high degree of clinical suspicion followed by successful identification of the organism by a laboratory technologist will aid in the early diagnosis and treatment of the infection, ultimately reducing the risk for complications and morbidity.

To the Editor:

The organisms of the genus Nocardia are gram-positive, ubiquitous, aerobic actinomycetes found worldwide in soil, decaying organic material, and water.¹ The genus Nocardia includes more than 50 species; some species, such as Nocardia asteroides, Nocardia farcinica, Nocardia nova, and Nocardia brasiliensis, are the cause of nocardiosis in humans and animals.^2,3 Nocardiosis is a rare and opportunistic infection that predominantly affects immunocompromised individuals; however, up to 30% of infections can occur in immunocompetent hosts.⁴ Nocardiosis can manifest in 3 disease forms: cutaneous, pulmonary, or disseminated. Cutaneous nocardiosis commonly develops in immunocompetent individuals who have experienced a predisposing traumatic injury to the skin,⁵ and it can exhibit a diverse variety of clinical manifestations, making diagnosis difficult. We describe a case of serious progressive primary cutaneous nocardiosis with an unusual presentation in an immunocompetent patient.

A 26-year-old immunocompetent man presented with pain, swelling, nodules, abscesses, ulcers, and sinus drainage of the left arm. The left elbow lesion initially developed at the site of a trauma 6 years prior that was painless but was contaminated with mossy soil. The condition slowly progressed over the next 2 years, and the patient experienced increased swelling and eventually developed multiple draining sinus tracts. Over the next 4 years, the lesions multiplied, spreading to the forearm and upper arm; associated severe pain and swelling at the elbow and wrist joint developed. The patient sought medical care at a local hospital and subsequently was diagnosed with suspected cutaneous tuberculosis. The patient was empirically treated with a 6-month course of isoniazid, rifampicin, pyrazinamide, and ethambutol; however, the lesions continued to progress and worsen. The patient had to stop antibiotic treatment because of substantially elevated alanine aminotransferase and aspartate aminotransferase levels.

He subsequently was evaluated at our hospital. He had no notable medical history and was afebrile. Physical examination revealed multiple erythematous nodules, abscesses, and ulcers on the left arm. There were several nodules with open sinus tracts and seropurulent crusts along with numerous atrophic, ovoid, stellate scars. Other nodules and ulcers with purulent drainage were located along the lymphatic nodes extending up the patient’s left forearm (Figure 1A). The yellowish-white pus discharge from several active sinuses contained no apparent granules. The lesions were densely distributed along the elbow, wrist, and shoulder, which resulted in associated skin swelling and restricted joint movement. The left axillary lymph nodes were enlarged.

Laboratory analyses revealed a hemoglobin level of 9.6 g/dL (reference range, 13–17.5 g/dL), platelet count of 621×10⁹/L (reference range, 125–350×10⁹/L), and leukocyte count of 14.3×10⁹/L (reference range, 3.5–9.5 ×10⁹/L). C-reactive protein level was 88.4 mg/L (reference range, 0–10 mg/L). Blood, renal, and liver tests, as well as tumor marker, peripheral blood lymphocyte subset, immunoglobulin, and complement results were within reference ranges. Results for Treponema pallidum and HIV antibody tests were negative. Hepatitis B virus markers were positive for hepatitis B surface antigen, hepatitis B e antigen, and hepatitis B core antibody, and the serum concentration of hepatitis B virus DNA was 3.12×10⁷ IU/mL (reference range, <5×10² IU/mL). Computed tomography of the chest and cranium were unremarkable. Ultrasonography of the left arm revealed multiple vertical sinus tracts and several horizontal communicating branches that were accompanied by worm-eaten bone destruction (Figure 2).

Additional testing included histopathologic staining of a skin tissue specimen—hematoxylin and eosin, periodic acid–Schiff, and acid-fast staining—showed nonspecific, diffuse, inflammatory cell infiltration suggestive of chronic suppurative granuloma (Figure 3) but failed to reveal any special strains or organisms. Gram stain examination of the purulent fluid collected from the subcutaneous tissue showed no apparent positive bacillus or filamentous granules. The specimen was then inoculated on Sabouraud dextrose agar and Lowenstein-Jensen medium for fungus and mycobacteria culture, respectively. After 5 days, chalky, yellow, adherent colonies were observed on the Löwenstein-Jensen medium, and after 26 days, yellow crinkled colonies were observed on Sabouraud dextrose agar. The colonies were then inoculated on Columbia blood agar and incubated for 1 week to aid in the identification of organisms. Growth of yellow colonies that were adherent to the agar, moist, and smooth with a velvety surface, as well as a characteristic moldy odor resulted. Gram staining revealed gram-positive, thin, and beaded branching filaments (Figure 4). Based on colony characteristics, physiological properties, and biochemical tests, the isolate was identified as Nocardia. Results of further investigations employing polymerase chain reaction analysis of the skin specimen and bacterial colonies using a Nocardia genus 596-bp fragment of 16S ribosomal RNA primer (forward primer NG1: 5’-ACCGACCACAAGGGG-3’, reverse primer NG2: 5’-GGTTGTAACCTCTTCGA-3’)⁶ were completely consistent with the reference for identification of N brasiliensis. Evaluation of these results led to a diagnosis of cutaneous nocardiosis after traumatic inoculation.

Because there was a high suspicion of actinophytosis or nocardiosis at admission, the patient received a combination antibiotic treatment with intravenous aqueous penicillin (4 million U every 4 hours) and oral trimethoprim-sulfamethoxazole (160/800 mg twice daily). Subsequently, treatment was changed to a combination of oral trimethoprim-sulfamethoxazole (160/800 mg twice daily) and moxifloxacin (400 mg once daily) based on pathogen identification and antibiotic sensitivity testing. After 1 month of treatment, the cutaneous lesions and left limb swelling dramatically improved and purulent drainage ceased, though some scarring occurred during the healing process. In addition, the mobility of the affected shoulder, elbow, and wrist joints slightly improved. Notable improvement in the mobility and swelling of the joints was observed at 6-month follow-up (Figure 1B). The patient continues to be monitored on an outpatient basis.

Cutaneous nocardiosis is a disfiguring granulomatous infection involving cutaneous and subcutaneous tissue that can progress to cause injury to viscera and bone.⁷ It has been called one of the great imitators because cutaneous nocardiosis can present in multiple forms,^8,9 including mycetoma, sporotrichoid infection, superficial skin infection, and disseminated infection with cutaneous involvement. The differential diagnoses of cutaneous nocardiosis are broad and include tuberculosis; actinomycosis; deep fungal infections such as sporotrichosis, blastomycosis, phaeohyphomycosis, histoplasmosis, and coccidioidomycosis; other bacterial causes of cellulitis, abscess, or ecthyma; and malignancies.¹⁰ The principle method of diagnosis is the identification of Nocardia from the infection site.

Our patient ultimately was diagnosed with primary cutaneous nocardiosis resulting from a traumatic injury to the skin that was contaminated with soil. The clinical manifestation pattern was a compound type, including both mycetoma and sporotrichoid infections. Initially, Nocardia mycetoma occurred with subcutaneous infection by direct extension^10,11 and appeared as dense, predominantly painless, swollen lesions. After 4 years, the skin lesions continued to spread linearly to the patient’s upper arm and forearm and manifested as the sporotrichoid infection type with painful swollen lesions at the site of inoculation and painful enlargement of the ipsilateral axillary lymph node.

Although nocardiosis is found worldwide, it is endemic to tropical and subtropical regions such as India, Africa, Southeast Asia, and Latin America.¹² Nocardiosis most often is observed in individuals aged 20 to 40 years. It affects men more than women, and it commonly occurs in field laborers and cultivators whose occupations involve direct contact with the soil.¹³ Most lesions are found on the lower extremities, though localized nocardiosis infections can occur in other areas such as the neck, breasts, back, buttocks, and elbows.

Our patient initially was misdiagnosed, and treatment was delayed for several reasons. First, nocardiosis is not common in China, and most clinicians are unfamiliar with the disease. Second, the related lesions do not have specific features, and our patient had a complex clinical presentation that included mycetoma and sporotrichoid infection. Third, the characteristic grain of Nocardia species is small but that of N brasiliensis is even smaller (approximately 0.1–0.2 mm in diameter), which makes visualization difficult in both histopathologic and microbiologic examinations.¹⁴ The histopathologic examination results of our patient in the local hospital were nonspecific. Fourth, our patient did not initially go to the hospital but instead purchased some over-the-counter antibiotic ointments for external application because the lesions were painless. Moreover, microbiologic smear and culture examinations were not conducted in the local hospital before administering antituberculosis treatment to the patient. Instead, a polymerase chain reaction examination of skin lesion tissue for tubercle bacilli and atypical mycobacteria was negative. These findings imply that the traditional microbial smear and culture evaluations cannot be omitted. Furthermore, culture examinations should be conducted on multiple skin tissue and purulent fluid specimens to increase the likelihood of detection. These cultures should be monitored for at least 2 to 4 weeks because Nocardia is a slow-growing organism.¹⁰

The optimal antimicrobial treatment regimens for nocardiosis have not been firmly established.¹⁵ Trimethoprim-sulfamethoxazole is regarded as the first-line antimicrobial agent for treatment of nocardial infections. The optimal duration of antimicrobial therapy for nocardiosis also has not been determined, and the treatment regimen depends on the severity and extent of the infection as well as on the presence of infection-related complications. The main complication is bone involvement. Notable bony changes include periosteal thickening, osteoporosis, and osteolysis.

We considered the severity of skin lesions and bone marrow invasion in our patient and planned to treat him continually with oral trimethoprim-sulfamethoxazole according to the in vitro drug susceptibility test. The patient showed clinical improvement after 1 month of treatment, and he continued to improve after 6 months of treatment. To prevent recurrence, we found it necessary to treat the patient with a long-term antibiotic course over 6 to 12 months.¹⁶

Cutaneous nocardiosis remains a diagnostic challenge because of its nonspecific and diverse clinical and histopathological presentations. Diagnosis is further complicated by the inherent difficulty of cultivating and identifying the clinical isolate in the laboratory. A high degree of clinical suspicion followed by successful identification of the organism by a laboratory technologist will aid in the early diagnosis and treatment of the infection, ultimately reducing the risk for complications and morbidity.

To the Editor:

The organisms of the genus Nocardia are gram-positive, ubiquitous, aerobic actinomycetes found worldwide in soil, decaying organic material, and water.¹ The genus Nocardia includes more than 50 species; some species, such as Nocardia asteroides, Nocardia farcinica, Nocardia nova, and Nocardia brasiliensis, are the cause of nocardiosis in humans and animals.^2,3 Nocardiosis is a rare and opportunistic infection that predominantly affects immunocompromised individuals; however, up to 30% of infections can occur in immunocompetent hosts.⁴ Nocardiosis can manifest in 3 disease forms: cutaneous, pulmonary, or disseminated. Cutaneous nocardiosis commonly develops in immunocompetent individuals who have experienced a predisposing traumatic injury to the skin,⁵ and it can exhibit a diverse variety of clinical manifestations, making diagnosis difficult. We describe a case of serious progressive primary cutaneous nocardiosis with an unusual presentation in an immunocompetent patient.

A 26-year-old immunocompetent man presented with pain, swelling, nodules, abscesses, ulcers, and sinus drainage of the left arm. The left elbow lesion initially developed at the site of a trauma 6 years prior that was painless but was contaminated with mossy soil. The condition slowly progressed over the next 2 years, and the patient experienced increased swelling and eventually developed multiple draining sinus tracts. Over the next 4 years, the lesions multiplied, spreading to the forearm and upper arm; associated severe pain and swelling at the elbow and wrist joint developed. The patient sought medical care at a local hospital and subsequently was diagnosed with suspected cutaneous tuberculosis. The patient was empirically treated with a 6-month course of isoniazid, rifampicin, pyrazinamide, and ethambutol; however, the lesions continued to progress and worsen. The patient had to stop antibiotic treatment because of substantially elevated alanine aminotransferase and aspartate aminotransferase levels.

He subsequently was evaluated at our hospital. He had no notable medical history and was afebrile. Physical examination revealed multiple erythematous nodules, abscesses, and ulcers on the left arm. There were several nodules with open sinus tracts and seropurulent crusts along with numerous atrophic, ovoid, stellate scars. Other nodules and ulcers with purulent drainage were located along the lymphatic nodes extending up the patient’s left forearm (Figure 1A). The yellowish-white pus discharge from several active sinuses contained no apparent granules. The lesions were densely distributed along the elbow, wrist, and shoulder, which resulted in associated skin swelling and restricted joint movement. The left axillary lymph nodes were enlarged.

Laboratory analyses revealed a hemoglobin level of 9.6 g/dL (reference range, 13–17.5 g/dL), platelet count of 621×10⁹/L (reference range, 125–350×10⁹/L), and leukocyte count of 14.3×10⁹/L (reference range, 3.5–9.5 ×10⁹/L). C-reactive protein level was 88.4 mg/L (reference range, 0–10 mg/L). Blood, renal, and liver tests, as well as tumor marker, peripheral blood lymphocyte subset, immunoglobulin, and complement results were within reference ranges. Results for Treponema pallidum and HIV antibody tests were negative. Hepatitis B virus markers were positive for hepatitis B surface antigen, hepatitis B e antigen, and hepatitis B core antibody, and the serum concentration of hepatitis B virus DNA was 3.12×10⁷ IU/mL (reference range, <5×10² IU/mL). Computed tomography of the chest and cranium were unremarkable. Ultrasonography of the left arm revealed multiple vertical sinus tracts and several horizontal communicating branches that were accompanied by worm-eaten bone destruction (Figure 2).

Additional testing included histopathologic staining of a skin tissue specimen—hematoxylin and eosin, periodic acid–Schiff, and acid-fast staining—showed nonspecific, diffuse, inflammatory cell infiltration suggestive of chronic suppurative granuloma (Figure 3) but failed to reveal any special strains or organisms. Gram stain examination of the purulent fluid collected from the subcutaneous tissue showed no apparent positive bacillus or filamentous granules. The specimen was then inoculated on Sabouraud dextrose agar and Lowenstein-Jensen medium for fungus and mycobacteria culture, respectively. After 5 days, chalky, yellow, adherent colonies were observed on the Löwenstein-Jensen medium, and after 26 days, yellow crinkled colonies were observed on Sabouraud dextrose agar. The colonies were then inoculated on Columbia blood agar and incubated for 1 week to aid in the identification of organisms. Growth of yellow colonies that were adherent to the agar, moist, and smooth with a velvety surface, as well as a characteristic moldy odor resulted. Gram staining revealed gram-positive, thin, and beaded branching filaments (Figure 4). Based on colony characteristics, physiological properties, and biochemical tests, the isolate was identified as Nocardia. Results of further investigations employing polymerase chain reaction analysis of the skin specimen and bacterial colonies using a Nocardia genus 596-bp fragment of 16S ribosomal RNA primer (forward primer NG1: 5’-ACCGACCACAAGGGG-3’, reverse primer NG2: 5’-GGTTGTAACCTCTTCGA-3’)⁶ were completely consistent with the reference for identification of N brasiliensis. Evaluation of these results led to a diagnosis of cutaneous nocardiosis after traumatic inoculation.

Because there was a high suspicion of actinophytosis or nocardiosis at admission, the patient received a combination antibiotic treatment with intravenous aqueous penicillin (4 million U every 4 hours) and oral trimethoprim-sulfamethoxazole (160/800 mg twice daily). Subsequently, treatment was changed to a combination of oral trimethoprim-sulfamethoxazole (160/800 mg twice daily) and moxifloxacin (400 mg once daily) based on pathogen identification and antibiotic sensitivity testing. After 1 month of treatment, the cutaneous lesions and left limb swelling dramatically improved and purulent drainage ceased, though some scarring occurred during the healing process. In addition, the mobility of the affected shoulder, elbow, and wrist joints slightly improved. Notable improvement in the mobility and swelling of the joints was observed at 6-month follow-up (Figure 1B). The patient continues to be monitored on an outpatient basis.

Cutaneous nocardiosis is a disfiguring granulomatous infection involving cutaneous and subcutaneous tissue that can progress to cause injury to viscera and bone.⁷ It has been called one of the great imitators because cutaneous nocardiosis can present in multiple forms,^8,9 including mycetoma, sporotrichoid infection, superficial skin infection, and disseminated infection with cutaneous involvement. The differential diagnoses of cutaneous nocardiosis are broad and include tuberculosis; actinomycosis; deep fungal infections such as sporotrichosis, blastomycosis, phaeohyphomycosis, histoplasmosis, and coccidioidomycosis; other bacterial causes of cellulitis, abscess, or ecthyma; and malignancies.¹⁰ The principle method of diagnosis is the identification of Nocardia from the infection site.

Our patient ultimately was diagnosed with primary cutaneous nocardiosis resulting from a traumatic injury to the skin that was contaminated with soil. The clinical manifestation pattern was a compound type, including both mycetoma and sporotrichoid infections. Initially, Nocardia mycetoma occurred with subcutaneous infection by direct extension^10,11 and appeared as dense, predominantly painless, swollen lesions. After 4 years, the skin lesions continued to spread linearly to the patient’s upper arm and forearm and manifested as the sporotrichoid infection type with painful swollen lesions at the site of inoculation and painful enlargement of the ipsilateral axillary lymph node.

Although nocardiosis is found worldwide, it is endemic to tropical and subtropical regions such as India, Africa, Southeast Asia, and Latin America.¹² Nocardiosis most often is observed in individuals aged 20 to 40 years. It affects men more than women, and it commonly occurs in field laborers and cultivators whose occupations involve direct contact with the soil.¹³ Most lesions are found on the lower extremities, though localized nocardiosis infections can occur in other areas such as the neck, breasts, back, buttocks, and elbows.

Our patient initially was misdiagnosed, and treatment was delayed for several reasons. First, nocardiosis is not common in China, and most clinicians are unfamiliar with the disease. Second, the related lesions do not have specific features, and our patient had a complex clinical presentation that included mycetoma and sporotrichoid infection. Third, the characteristic grain of Nocardia species is small but that of N brasiliensis is even smaller (approximately 0.1–0.2 mm in diameter), which makes visualization difficult in both histopathologic and microbiologic examinations.¹⁴ The histopathologic examination results of our patient in the local hospital were nonspecific. Fourth, our patient did not initially go to the hospital but instead purchased some over-the-counter antibiotic ointments for external application because the lesions were painless. Moreover, microbiologic smear and culture examinations were not conducted in the local hospital before administering antituberculosis treatment to the patient. Instead, a polymerase chain reaction examination of skin lesion tissue for tubercle bacilli and atypical mycobacteria was negative. These findings imply that the traditional microbial smear and culture evaluations cannot be omitted. Furthermore, culture examinations should be conducted on multiple skin tissue and purulent fluid specimens to increase the likelihood of detection. These cultures should be monitored for at least 2 to 4 weeks because Nocardia is a slow-growing organism.¹⁰

The optimal antimicrobial treatment regimens for nocardiosis have not been firmly established.¹⁵ Trimethoprim-sulfamethoxazole is regarded as the first-line antimicrobial agent for treatment of nocardial infections. The optimal duration of antimicrobial therapy for nocardiosis also has not been determined, and the treatment regimen depends on the severity and extent of the infection as well as on the presence of infection-related complications. The main complication is bone involvement. Notable bony changes include periosteal thickening, osteoporosis, and osteolysis.

We considered the severity of skin lesions and bone marrow invasion in our patient and planned to treat him continually with oral trimethoprim-sulfamethoxazole according to the in vitro drug susceptibility test. The patient showed clinical improvement after 1 month of treatment, and he continued to improve after 6 months of treatment. To prevent recurrence, we found it necessary to treat the patient with a long-term antibiotic course over 6 to 12 months.¹⁶

Cutaneous nocardiosis remains a diagnostic challenge because of its nonspecific and diverse clinical and histopathological presentations. Diagnosis is further complicated by the inherent difficulty of cultivating and identifying the clinical isolate in the laboratory. A high degree of clinical suspicion followed by successful identification of the organism by a laboratory technologist will aid in the early diagnosis and treatment of the infection, ultimately reducing the risk for complications and morbidity.

Patients with active PsA require early effective therapy to improve long-term outcomes. The choice of therapy should balance effectiveness and potential toxicity. Janus kinase (JAK) inhibitors are a relatively new class of drugs that have been shown to be efficacious in treating PsA, but there are concerns about safety. To evaluate the efficacy and safety of JAK inhibitors in patients with psoriatic disease, Yang and colleagues conducted a systematic review and meta-analysis of 17 phase 2/3 randomized controlled trials including 6802 patients with PsA or moderate to severe plaque psoriasis who received at least one JAK inhibitor. They demonstrated that, compared with placebo, JAK inhibitors were associated with a significantly higher American College of Rheumatology 20 response rate (relative risk [RR] 2.09; P < .00001), with the response being the highest for filgotinib (RR 2.40; P < .00001), followed by upadacitinib, tofacitinib, and deucravacitinib. However, the overall incidence of adverse events was higher with JAK inhibitors vs placebo (RR 1.17; P < .00001) and significantly higher with 10-mg vs 5-mg tofacitinib (P = .03). Thus, JAK inhibitors are efficacious in the treatment of PsA but are associated with adverse effects, particularly at higher doses.

Safety is best assessed in real-world observational studies. Clinical trials have raised concerns about a higher cancer risk in rheumatoid arthritis (RA) patients treated with JAK inhibitors compared with patients treated with tumor necrosis factor (TNF) inhibitors. To evaluate this further, Huss and colleagues conducted an observational cohort study that evaluated prospectively collected data from national Swedish data sources on 4443 patients with PsA and 10,447 patients with RA, all without previous cancer, who received JAK inhibitors, TNF inhibitors, or other non–TNF inhibitor biologic disease-modifying antirheumatic drugs. Overall, use of JAK inhibitors vs TNF inhibitors was not significantly associated with a higher risk for cancer other than nonmelanoma skin cancer, especially in RA. In patients with PsA, there was a trend toward higher risk for nonmelanoma skin cancer, but it was not statistically significant. The study provides reassurance that JAK inhibitors are generally as safe, as are TNF inhibitors in PsA, but continued vigilance is required.

There are limited data on the effect of disease activity on pregnancy outcomes in individuals with PsA. Using data from the Medical Birth Registry of Norway linked to data from a Norwegian nationwide observational register recruiting women with inflammatory rheumatic diseases, Skorpen and colleagues evaluated the association of active disease and cesarean section (CS) rates in singleton births in women with PsA (n = 121), axial spondyloarthritis (n = 312), and controls (n = 575,798). Compared with control individuals, women with PsA had a higher risk for CS (risk difference [RD] 15.0%; P < .001) and for emergency CS (RD 10.6%; P < .001), with active disease in the third trimester further amplifying both risks (CS: RD 17.7%; P = .028; emergency CS: RD 15.9%; P = .015). Thus, although in many patients disease activity decreases during pregnancy, this study highlights the importance of pregestational counseling and disease control along with regular monitoring of PsA during pregnancy such that disease activity remains well controlled.

Patients with active PsA require early effective therapy to improve long-term outcomes. The choice of therapy should balance effectiveness and potential toxicity. Janus kinase (JAK) inhibitors are a relatively new class of drugs that have been shown to be efficacious in treating PsA, but there are concerns about safety. To evaluate the efficacy and safety of JAK inhibitors in patients with psoriatic disease, Yang and colleagues conducted a systematic review and meta-analysis of 17 phase 2/3 randomized controlled trials including 6802 patients with PsA or moderate to severe plaque psoriasis who received at least one JAK inhibitor. They demonstrated that, compared with placebo, JAK inhibitors were associated with a significantly higher American College of Rheumatology 20 response rate (relative risk [RR] 2.09; P < .00001), with the response being the highest for filgotinib (RR 2.40; P < .00001), followed by upadacitinib, tofacitinib, and deucravacitinib. However, the overall incidence of adverse events was higher with JAK inhibitors vs placebo (RR 1.17; P < .00001) and significantly higher with 10-mg vs 5-mg tofacitinib (P = .03). Thus, JAK inhibitors are efficacious in the treatment of PsA but are associated with adverse effects, particularly at higher doses.

Safety is best assessed in real-world observational studies. Clinical trials have raised concerns about a higher cancer risk in rheumatoid arthritis (RA) patients treated with JAK inhibitors compared with patients treated with tumor necrosis factor (TNF) inhibitors. To evaluate this further, Huss and colleagues conducted an observational cohort study that evaluated prospectively collected data from national Swedish data sources on 4443 patients with PsA and 10,447 patients with RA, all without previous cancer, who received JAK inhibitors, TNF inhibitors, or other non–TNF inhibitor biologic disease-modifying antirheumatic drugs. Overall, use of JAK inhibitors vs TNF inhibitors was not significantly associated with a higher risk for cancer other than nonmelanoma skin cancer, especially in RA. In patients with PsA, there was a trend toward higher risk for nonmelanoma skin cancer, but it was not statistically significant. The study provides reassurance that JAK inhibitors are generally as safe, as are TNF inhibitors in PsA, but continued vigilance is required.

There are limited data on the effect of disease activity on pregnancy outcomes in individuals with PsA. Using data from the Medical Birth Registry of Norway linked to data from a Norwegian nationwide observational register recruiting women with inflammatory rheumatic diseases, Skorpen and colleagues evaluated the association of active disease and cesarean section (CS) rates in singleton births in women with PsA (n = 121), axial spondyloarthritis (n = 312), and controls (n = 575,798). Compared with control individuals, women with PsA had a higher risk for CS (risk difference [RD] 15.0%; P < .001) and for emergency CS (RD 10.6%; P < .001), with active disease in the third trimester further amplifying both risks (CS: RD 17.7%; P = .028; emergency CS: RD 15.9%; P = .015). Thus, although in many patients disease activity decreases during pregnancy, this study highlights the importance of pregestational counseling and disease control along with regular monitoring of PsA during pregnancy such that disease activity remains well controlled.

Patients with active PsA require early effective therapy to improve long-term outcomes. The choice of therapy should balance effectiveness and potential toxicity. Janus kinase (JAK) inhibitors are a relatively new class of drugs that have been shown to be efficacious in treating PsA, but there are concerns about safety. To evaluate the efficacy and safety of JAK inhibitors in patients with psoriatic disease, Yang and colleagues conducted a systematic review and meta-analysis of 17 phase 2/3 randomized controlled trials including 6802 patients with PsA or moderate to severe plaque psoriasis who received at least one JAK inhibitor. They demonstrated that, compared with placebo, JAK inhibitors were associated with a significantly higher American College of Rheumatology 20 response rate (relative risk [RR] 2.09; P < .00001), with the response being the highest for filgotinib (RR 2.40; P < .00001), followed by upadacitinib, tofacitinib, and deucravacitinib. However, the overall incidence of adverse events was higher with JAK inhibitors vs placebo (RR 1.17; P < .00001) and significantly higher with 10-mg vs 5-mg tofacitinib (P = .03). Thus, JAK inhibitors are efficacious in the treatment of PsA but are associated with adverse effects, particularly at higher doses.

Safety is best assessed in real-world observational studies. Clinical trials have raised concerns about a higher cancer risk in rheumatoid arthritis (RA) patients treated with JAK inhibitors compared with patients treated with tumor necrosis factor (TNF) inhibitors. To evaluate this further, Huss and colleagues conducted an observational cohort study that evaluated prospectively collected data from national Swedish data sources on 4443 patients with PsA and 10,447 patients with RA, all without previous cancer, who received JAK inhibitors, TNF inhibitors, or other non–TNF inhibitor biologic disease-modifying antirheumatic drugs. Overall, use of JAK inhibitors vs TNF inhibitors was not significantly associated with a higher risk for cancer other than nonmelanoma skin cancer, especially in RA. In patients with PsA, there was a trend toward higher risk for nonmelanoma skin cancer, but it was not statistically significant. The study provides reassurance that JAK inhibitors are generally as safe, as are TNF inhibitors in PsA, but continued vigilance is required.

There are limited data on the effect of disease activity on pregnancy outcomes in individuals with PsA. Using data from the Medical Birth Registry of Norway linked to data from a Norwegian nationwide observational register recruiting women with inflammatory rheumatic diseases, Skorpen and colleagues evaluated the association of active disease and cesarean section (CS) rates in singleton births in women with PsA (n = 121), axial spondyloarthritis (n = 312), and controls (n = 575,798). Compared with control individuals, women with PsA had a higher risk for CS (risk difference [RD] 15.0%; P < .001) and for emergency CS (RD 10.6%; P < .001), with active disease in the third trimester further amplifying both risks (CS: RD 17.7%; P = .028; emergency CS: RD 15.9%; P = .015). Thus, although in many patients disease activity decreases during pregnancy, this study highlights the importance of pregestational counseling and disease control along with regular monitoring of PsA during pregnancy such that disease activity remains well controlled.

Patients with active PsA require early effective therapy to improve long-term outcomes. The choice of therapy should balance effectiveness and potential toxicity. Janus kinase (JAK) inhibitors are a relatively new class of drugs that have been shown to be efficacious in treating PsA, but there are concerns about safety. To evaluate the efficacy and safety of JAK inhibitors in patients with psoriatic disease, Yang and colleagues conducted a systematic review and meta-analysis of 17 phase 2/3 randomized controlled trials including 6802 patients with PsA or moderate to severe plaque psoriasis who received at least one JAK inhibitor. They demonstrated that, compared with placebo, JAK inhibitors were associated with a significantly higher American College of Rheumatology 20 response rate (relative risk [RR] 2.09; P < .00001), with the response being the highest for filgotinib (RR 2.40; P < .00001), followed by upadacitinib, tofacitinib, and deucravacitinib. However, the overall incidence of adverse events was higher with JAK inhibitors vs placebo (RR 1.17; P < .00001) and significantly higher with 10-mg vs 5-mg tofacitinib (P = .03). Thus, JAK inhibitors are efficacious in the treatment of PsA but are associated with adverse effects, particularly at higher doses.

Safety is best assessed in real-world observational studies. Clinical trials have raised concerns about a higher cancer risk in rheumatoid arthritis (RA) patients treated with JAK inhibitors compared with patients treated with tumor necrosis factor (TNF) inhibitors. To evaluate this further, Huss and colleagues conducted an observational cohort study that evaluated prospectively collected data from national Swedish data sources on 4443 patients with PsA and 10,447 patients with RA, all without previous cancer, who received JAK inhibitors, TNF inhibitors, or other non–TNF inhibitor biologic disease-modifying antirheumatic drugs. Overall, use of JAK inhibitors vs TNF inhibitors was not significantly associated with a higher risk for cancer other than nonmelanoma skin cancer, especially in RA. In patients with PsA, there was a trend toward higher risk for nonmelanoma skin cancer, but it was not statistically significant. The study provides reassurance that JAK inhibitors are generally as safe, as are TNF inhibitors in PsA, but continued vigilance is required.

There are limited data on the effect of disease activity on pregnancy outcomes in individuals with PsA. Using data from the Medical Birth Registry of Norway linked to data from a Norwegian nationwide observational register recruiting women with inflammatory rheumatic diseases, Skorpen and colleagues evaluated the association of active disease and cesarean section (CS) rates in singleton births in women with PsA (n = 121), axial spondyloarthritis (n = 312), and controls (n = 575,798). Compared with control individuals, women with PsA had a higher risk for CS (risk difference [RD] 15.0%; P < .001) and for emergency CS (RD 10.6%; P < .001), with active disease in the third trimester further amplifying both risks (CS: RD 17.7%; P = .028; emergency CS: RD 15.9%; P = .015). Thus, although in many patients disease activity decreases during pregnancy, this study highlights the importance of pregestational counseling and disease control along with regular monitoring of PsA during pregnancy such that disease activity remains well controlled.

Patients with active PsA require early effective therapy to improve long-term outcomes. The choice of therapy should balance effectiveness and potential toxicity. Janus kinase (JAK) inhibitors are a relatively new class of drugs that have been shown to be efficacious in treating PsA, but there are concerns about safety. To evaluate the efficacy and safety of JAK inhibitors in patients with psoriatic disease, Yang and colleagues conducted a systematic review and meta-analysis of 17 phase 2/3 randomized controlled trials including 6802 patients with PsA or moderate to severe plaque psoriasis who received at least one JAK inhibitor. They demonstrated that, compared with placebo, JAK inhibitors were associated with a significantly higher American College of Rheumatology 20 response rate (relative risk [RR] 2.09; P < .00001), with the response being the highest for filgotinib (RR 2.40; P < .00001), followed by upadacitinib, tofacitinib, and deucravacitinib. However, the overall incidence of adverse events was higher with JAK inhibitors vs placebo (RR 1.17; P < .00001) and significantly higher with 10-mg vs 5-mg tofacitinib (P = .03). Thus, JAK inhibitors are efficacious in the treatment of PsA but are associated with adverse effects, particularly at higher doses.

Safety is best assessed in real-world observational studies. Clinical trials have raised concerns about a higher cancer risk in rheumatoid arthritis (RA) patients treated with JAK inhibitors compared with patients treated with tumor necrosis factor (TNF) inhibitors. To evaluate this further, Huss and colleagues conducted an observational cohort study that evaluated prospectively collected data from national Swedish data sources on 4443 patients with PsA and 10,447 patients with RA, all without previous cancer, who received JAK inhibitors, TNF inhibitors, or other non–TNF inhibitor biologic disease-modifying antirheumatic drugs. Overall, use of JAK inhibitors vs TNF inhibitors was not significantly associated with a higher risk for cancer other than nonmelanoma skin cancer, especially in RA. In patients with PsA, there was a trend toward higher risk for nonmelanoma skin cancer, but it was not statistically significant. The study provides reassurance that JAK inhibitors are generally as safe, as are TNF inhibitors in PsA, but continued vigilance is required.

There are limited data on the effect of disease activity on pregnancy outcomes in individuals with PsA. Using data from the Medical Birth Registry of Norway linked to data from a Norwegian nationwide observational register recruiting women with inflammatory rheumatic diseases, Skorpen and colleagues evaluated the association of active disease and cesarean section (CS) rates in singleton births in women with PsA (n = 121), axial spondyloarthritis (n = 312), and controls (n = 575,798). Compared with control individuals, women with PsA had a higher risk for CS (risk difference [RD] 15.0%; P < .001) and for emergency CS (RD 10.6%; P < .001), with active disease in the third trimester further amplifying both risks (CS: RD 17.7%; P = .028; emergency CS: RD 15.9%; P = .015). Thus, although in many patients disease activity decreases during pregnancy, this study highlights the importance of pregestational counseling and disease control along with regular monitoring of PsA during pregnancy such that disease activity remains well controlled.

Patients with active PsA require early effective therapy to improve long-term outcomes. The choice of therapy should balance effectiveness and potential toxicity. Janus kinase (JAK) inhibitors are a relatively new class of drugs that have been shown to be efficacious in treating PsA, but there are concerns about safety. To evaluate the efficacy and safety of JAK inhibitors in patients with psoriatic disease, Yang and colleagues conducted a systematic review and meta-analysis of 17 phase 2/3 randomized controlled trials including 6802 patients with PsA or moderate to severe plaque psoriasis who received at least one JAK inhibitor. They demonstrated that, compared with placebo, JAK inhibitors were associated with a significantly higher American College of Rheumatology 20 response rate (relative risk [RR] 2.09; P < .00001), with the response being the highest for filgotinib (RR 2.40; P < .00001), followed by upadacitinib, tofacitinib, and deucravacitinib. However, the overall incidence of adverse events was higher with JAK inhibitors vs placebo (RR 1.17; P < .00001) and significantly higher with 10-mg vs 5-mg tofacitinib (P = .03). Thus, JAK inhibitors are efficacious in the treatment of PsA but are associated with adverse effects, particularly at higher doses.

Safety is best assessed in real-world observational studies. Clinical trials have raised concerns about a higher cancer risk in rheumatoid arthritis (RA) patients treated with JAK inhibitors compared with patients treated with tumor necrosis factor (TNF) inhibitors. To evaluate this further, Huss and colleagues conducted an observational cohort study that evaluated prospectively collected data from national Swedish data sources on 4443 patients with PsA and 10,447 patients with RA, all without previous cancer, who received JAK inhibitors, TNF inhibitors, or other non–TNF inhibitor biologic disease-modifying antirheumatic drugs. Overall, use of JAK inhibitors vs TNF inhibitors was not significantly associated with a higher risk for cancer other than nonmelanoma skin cancer, especially in RA. In patients with PsA, there was a trend toward higher risk for nonmelanoma skin cancer, but it was not statistically significant. The study provides reassurance that JAK inhibitors are generally as safe, as are TNF inhibitors in PsA, but continued vigilance is required.

There are limited data on the effect of disease activity on pregnancy outcomes in individuals with PsA. Using data from the Medical Birth Registry of Norway linked to data from a Norwegian nationwide observational register recruiting women with inflammatory rheumatic diseases, Skorpen and colleagues evaluated the association of active disease and cesarean section (CS) rates in singleton births in women with PsA (n = 121), axial spondyloarthritis (n = 312), and controls (n = 575,798). Compared with control individuals, women with PsA had a higher risk for CS (risk difference [RD] 15.0%; P < .001) and for emergency CS (RD 10.6%; P < .001), with active disease in the third trimester further amplifying both risks (CS: RD 17.7%; P = .028; emergency CS: RD 15.9%; P = .015). Thus, although in many patients disease activity decreases during pregnancy, this study highlights the importance of pregestational counseling and disease control along with regular monitoring of PsA during pregnancy such that disease activity remains well controlled.

This transcript has been edited for clarity.

“Excess deaths.” You’ve heard the phrase countless times by now. It is one of the myriad of previously esoteric epidemiology terms that the pandemic brought squarely into the zeitgeist.

As a sort of standard candle of the performance of a state or a region or a country in terms of health care, it has a lot of utility – if for nothing more than Monday-morning quarterbacking. But this week, I want to dig in on the concept a bit because, according to a new study, the excess death gap between the United States and Western Europe has never been higher.

What do we mean when we say “excess mortality?” The central connotation of the idea is that there are simply some deaths that should not have occurred. You might imagine that the best way to figure this out is for some group of intelligent people to review each death and decide, somehow, whether it was expected or not. But aside from being impractical, this would end up being somewhat subjective. That older person who died from pneumonia – was that an expected death? Could it have been avoided?

Rather, the calculation of excess mortality relies on large numbers and statistical inference to compare an expected number of deaths with those that are observed.

The difference is excess mortality, even if you can never be sure whether any particular death was expected or not.

As always, however, the devil is in the details. What data do you use to define the expected number of deaths?

There are options here. Probably the most straightforward analysis uses past data from the country of interest. You look at annual deaths over some historical period of time and compare those numbers with the rates today. Two issues need to be accounted for here: population growth – a larger population will have more deaths, so you need to adjust the historical population with current levels, and demographic shifts – an older or more male population will have more deaths, so you need to adjust for that as well.

But provided you take care of those factors, you can estimate fairly well how many deaths you can expect to see in any given period of time.

Still, you should see right away that excess mortality is a relative concept. If you think that, just perhaps, the United States has some systematic failure to deliver care that has been stable and persistent over time, you wouldn’t capture that failing in an excess mortality calculation that uses U.S. historical data as the baseline.

The best way to get around that is to use data from other countries, and that’s just what this article – a rare single-author piece by Patrick Heuveline – does, calculating excess deaths in the United States by standardizing our mortality rates to the five largest Western European countries: the United Kingdom, France, Germany, Italy, and Spain.

Controlling for the differences in the demographics of that European population, here is the expected number of deaths in the United States over the past 5 years.

US observed mortality and US expected mortalty (2017-2021)

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale University’s Clinical and Translational Research Accelerator in New Haven,Conn. He reported no relevant conflicts of interest.
 

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

This transcript has been edited for clarity.

“Excess deaths.” You’ve heard the phrase countless times by now. It is one of the myriad of previously esoteric epidemiology terms that the pandemic brought squarely into the zeitgeist.

As a sort of standard candle of the performance of a state or a region or a country in terms of health care, it has a lot of utility – if for nothing more than Monday-morning quarterbacking. But this week, I want to dig in on the concept a bit because, according to a new study, the excess death gap between the United States and Western Europe has never been higher.

What do we mean when we say “excess mortality?” The central connotation of the idea is that there are simply some deaths that should not have occurred. You might imagine that the best way to figure this out is for some group of intelligent people to review each death and decide, somehow, whether it was expected or not. But aside from being impractical, this would end up being somewhat subjective. That older person who died from pneumonia – was that an expected death? Could it have been avoided?

Rather, the calculation of excess mortality relies on large numbers and statistical inference to compare an expected number of deaths with those that are observed.

The difference is excess mortality, even if you can never be sure whether any particular death was expected or not.

As always, however, the devil is in the details. What data do you use to define the expected number of deaths?

There are options here. Probably the most straightforward analysis uses past data from the country of interest. You look at annual deaths over some historical period of time and compare those numbers with the rates today. Two issues need to be accounted for here: population growth – a larger population will have more deaths, so you need to adjust the historical population with current levels, and demographic shifts – an older or more male population will have more deaths, so you need to adjust for that as well.

But provided you take care of those factors, you can estimate fairly well how many deaths you can expect to see in any given period of time.

Still, you should see right away that excess mortality is a relative concept. If you think that, just perhaps, the United States has some systematic failure to deliver care that has been stable and persistent over time, you wouldn’t capture that failing in an excess mortality calculation that uses U.S. historical data as the baseline.

The best way to get around that is to use data from other countries, and that’s just what this article – a rare single-author piece by Patrick Heuveline – does, calculating excess deaths in the United States by standardizing our mortality rates to the five largest Western European countries: the United Kingdom, France, Germany, Italy, and Spain.

Controlling for the differences in the demographics of that European population, here is the expected number of deaths in the United States over the past 5 years.

US observed mortality and US expected mortalty (2017-2021)

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale University’s Clinical and Translational Research Accelerator in New Haven,Conn. He reported no relevant conflicts of interest.
 

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

This transcript has been edited for clarity.

“Excess deaths.” You’ve heard the phrase countless times by now. It is one of the myriad of previously esoteric epidemiology terms that the pandemic brought squarely into the zeitgeist.

As a sort of standard candle of the performance of a state or a region or a country in terms of health care, it has a lot of utility – if for nothing more than Monday-morning quarterbacking. But this week, I want to dig in on the concept a bit because, according to a new study, the excess death gap between the United States and Western Europe has never been higher.

What do we mean when we say “excess mortality?” The central connotation of the idea is that there are simply some deaths that should not have occurred. You might imagine that the best way to figure this out is for some group of intelligent people to review each death and decide, somehow, whether it was expected or not. But aside from being impractical, this would end up being somewhat subjective. That older person who died from pneumonia – was that an expected death? Could it have been avoided?

Rather, the calculation of excess mortality relies on large numbers and statistical inference to compare an expected number of deaths with those that are observed.

The difference is excess mortality, even if you can never be sure whether any particular death was expected or not.

As always, however, the devil is in the details. What data do you use to define the expected number of deaths?

There are options here. Probably the most straightforward analysis uses past data from the country of interest. You look at annual deaths over some historical period of time and compare those numbers with the rates today. Two issues need to be accounted for here: population growth – a larger population will have more deaths, so you need to adjust the historical population with current levels, and demographic shifts – an older or more male population will have more deaths, so you need to adjust for that as well.

But provided you take care of those factors, you can estimate fairly well how many deaths you can expect to see in any given period of time.

Still, you should see right away that excess mortality is a relative concept. If you think that, just perhaps, the United States has some systematic failure to deliver care that has been stable and persistent over time, you wouldn’t capture that failing in an excess mortality calculation that uses U.S. historical data as the baseline.

The best way to get around that is to use data from other countries, and that’s just what this article – a rare single-author piece by Patrick Heuveline – does, calculating excess deaths in the United States by standardizing our mortality rates to the five largest Western European countries: the United Kingdom, France, Germany, Italy, and Spain.

Controlling for the differences in the demographics of that European population, here is the expected number of deaths in the United States over the past 5 years.

US observed mortality and US expected mortalty (2017-2021)

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale University’s Clinical and Translational Research Accelerator in New Haven,Conn. He reported no relevant conflicts of interest.
 

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

Recent trial evidence has failed to show a cardiovascular benefit to treating high triglycerides. The publication of the PROMINENT trial, where pemafibrate successfully lowered high levels but was not associated with a lower risk for cardiovascular events, reinforced the point. Is it time to stop measuring and treating high triglycerides?

There may be noncardiovascular reasons to treat hypertriglyceridemia. Pancreatitis is the most cited one, given that the risk for pancreatitis increases with increasing triglyceride levels, especially in patients with a prior episode.

There may also be practical reasons to lower trigs. Because most cholesterol panels use the Friedewald equation to calculate low-density lipoprotein cholesterol (LDL-C) rather than measuring it directly, very high triglyceride levels can invalidate the calculation and return error messages on lab reports.

But we now have alternatives to measuring LDL-C, including non–high-density lipoprotein cholesterol (HDL-C) and apolipoprotein B (apoB), that better predict risk and are usable even in the setting of nonfasting samples when triglycerides are elevated.
 

Independent cardiovascular risk factor?

If we are going to measure and treat high triglycerides for cardiovascular reasons, the relevant question is, are high triglycerides an independent risk factor for cardiovascular disease?

Proponents have a broad swath of supportive literature to point at. Multiple studies have shown an association between triglyceride levels and cardiovascular risk. The evidence even extends beyond traditional epidemiologic analyses, to genetic studies that should be free from some of the problems seen in observational cohorts.

But it is difficult to be certain whether these associations are causal or merely confounding. An unhealthy diet will increase triglycerides, as will alcohol. Patients with diabetes or metabolic syndrome have high triglycerides. So do patients with nephrotic syndrome or hypothyroidism, or hypertensive patients taking thiazide diuretics. Adjusting for these baseline factors is possible but imperfect, and residual confounding is always an issue. An analysis of the Reykjavik and the EPIC-Norfolk studies found an association between triglyceride levels and cardiovascular risk. That risk was attenuated, but not eliminated, when adjusted for traditional risk factors such as age, smoking, blood pressure, diabetes, and cholesterol.

Randomized trials of triglyceride-lowering therapies would help resolve the question of whether hypertriglyceridemia contributes to coronary disease or simply identifies high-risk patients. Early trials seemed to support the idea of a causal link. The Helsinki Heart Study randomized patients to gemfibrozil or placebo and found a 34% relative risk reduction in coronary artery disease with the fibrate. But gemfibrozil didn’t only reduce triglycerides. It also increased HDL-C and lowered LDL-C relative to placebo, which may explain the observed benefit.

Gemfibrozil is rarely used today because we can achieve much greater LDL-C reductions with statins, as well as ezetimibe and PCSK9 inhibitors. The success of these drugs may not leave any room for triglyceride-lowering medications.
 

The pre- vs. post-statin era

In the 2005 FIELD study, participants were randomized to receive fenofibrate or placebo. Although patients weren’t taking statin at study entry, 17% of the placebo group started taking one during the trial. Fenofibrate wasn’t associated with a reduction in the primary endpoint, a combination of coronary heart disease death or nonfatal myocardial infarction (MI). Among the many secondary endpoints, nonfatal MI was lower but cardiovascular mortality was not in the fibrate-treated patients. In the same vein, the 2010 ACCORD study randomized patients to receive simvastatin plus fenofibrate or simvastatin alone. The composite primary outcome of MI, stroke, and cardiovascular mortality was not lowered nor were any secondary outcomes with the combination therapy. In the statin era, triglyceride-lowering therapies have not shown much benefit.

The final nail in the coffin may very well be the aforementioned PROMINENT trial. The new agent, pemafibrate, fared no better than its predecessor fenofibrate. Pemafibrate had no impact on the study’s primary composite outcome of nonfatal MI, stroke, coronary revascularization, or cardiovascular death despite being very effective at lowering triglycerides (by more than 25%). Patients treated with pemafibrate had increased LDL-C and apoB compared with the placebo group. When you realize that, the results of the study are not very surprising.

Some point to the results of REDUCE-IT as proof that triglycerides are still a valid target for pharmacotherapy. The debate on whether REDUCE-IT tested a good drug or a bad placebo is one for another day. The salient point for today is that the benefits of eicosapentaenoic acid (EPA) were seen regardless of either baseline or final triglyceride level. EPA may lower cardiac risk, but there is no widespread consensus that it does so by lowering triglycerides. There may be other mechanisms at work.

You could still argue that high triglycerides have value as a risk prediction tool even if their role as a target for drug therapy is questionable. There was a time when medications to lower triglycerides had a benefit. But this is the post-statin era, and that time has passed.

If you see patients with high triglycerides, treating them with triglyceride-lowering medication probably isn’t going to reduce their cardiovascular risk. Dietary interventions, encouraging exercise, and reducing alcohol consumption are better options. Not only will they lead to lower cholesterol levels, but they’ll lower cardiovascular risk, too.

Dr. Labos is a cardiologist at Hôpital Notre-Dame, Montreal, with a degree in epidemiology. He has disclosed no relevant financial relationships. He spends most of his time doing things that he doesn’t get paid for, like research, teaching, and podcasting. Occasionally he finds time to practice cardiology to pay the rent. He realizes that half of his research findings will be disproved in 5 years; he just doesn’t know which half. He is a regular contributor to the Montreal Gazette, CJAD radio, and CTV television in Montreal and is host of the award-winning podcast The Body of Evidence. The Body of Evidence.

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

Recent trial evidence has failed to show a cardiovascular benefit to treating high triglycerides. The publication of the PROMINENT trial, where pemafibrate successfully lowered high levels but was not associated with a lower risk for cardiovascular events, reinforced the point. Is it time to stop measuring and treating high triglycerides?

There may be noncardiovascular reasons to treat hypertriglyceridemia. Pancreatitis is the most cited one, given that the risk for pancreatitis increases with increasing triglyceride levels, especially in patients with a prior episode.

There may also be practical reasons to lower trigs. Because most cholesterol panels use the Friedewald equation to calculate low-density lipoprotein cholesterol (LDL-C) rather than measuring it directly, very high triglyceride levels can invalidate the calculation and return error messages on lab reports.

But we now have alternatives to measuring LDL-C, including non–high-density lipoprotein cholesterol (HDL-C) and apolipoprotein B (apoB), that better predict risk and are usable even in the setting of nonfasting samples when triglycerides are elevated.
 

Independent cardiovascular risk factor?

If we are going to measure and treat high triglycerides for cardiovascular reasons, the relevant question is, are high triglycerides an independent risk factor for cardiovascular disease?

Proponents have a broad swath of supportive literature to point at. Multiple studies have shown an association between triglyceride levels and cardiovascular risk. The evidence even extends beyond traditional epidemiologic analyses, to genetic studies that should be free from some of the problems seen in observational cohorts.

But it is difficult to be certain whether these associations are causal or merely confounding. An unhealthy diet will increase triglycerides, as will alcohol. Patients with diabetes or metabolic syndrome have high triglycerides. So do patients with nephrotic syndrome or hypothyroidism, or hypertensive patients taking thiazide diuretics. Adjusting for these baseline factors is possible but imperfect, and residual confounding is always an issue. An analysis of the Reykjavik and the EPIC-Norfolk studies found an association between triglyceride levels and cardiovascular risk. That risk was attenuated, but not eliminated, when adjusted for traditional risk factors such as age, smoking, blood pressure, diabetes, and cholesterol.

Randomized trials of triglyceride-lowering therapies would help resolve the question of whether hypertriglyceridemia contributes to coronary disease or simply identifies high-risk patients. Early trials seemed to support the idea of a causal link. The Helsinki Heart Study randomized patients to gemfibrozil or placebo and found a 34% relative risk reduction in coronary artery disease with the fibrate. But gemfibrozil didn’t only reduce triglycerides. It also increased HDL-C and lowered LDL-C relative to placebo, which may explain the observed benefit.

Gemfibrozil is rarely used today because we can achieve much greater LDL-C reductions with statins, as well as ezetimibe and PCSK9 inhibitors. The success of these drugs may not leave any room for triglyceride-lowering medications.
 

The pre- vs. post-statin era

In the 2005 FIELD study, participants were randomized to receive fenofibrate or placebo. Although patients weren’t taking statin at study entry, 17% of the placebo group started taking one during the trial. Fenofibrate wasn’t associated with a reduction in the primary endpoint, a combination of coronary heart disease death or nonfatal myocardial infarction (MI). Among the many secondary endpoints, nonfatal MI was lower but cardiovascular mortality was not in the fibrate-treated patients. In the same vein, the 2010 ACCORD study randomized patients to receive simvastatin plus fenofibrate or simvastatin alone. The composite primary outcome of MI, stroke, and cardiovascular mortality was not lowered nor were any secondary outcomes with the combination therapy. In the statin era, triglyceride-lowering therapies have not shown much benefit.

The final nail in the coffin may very well be the aforementioned PROMINENT trial. The new agent, pemafibrate, fared no better than its predecessor fenofibrate. Pemafibrate had no impact on the study’s primary composite outcome of nonfatal MI, stroke, coronary revascularization, or cardiovascular death despite being very effective at lowering triglycerides (by more than 25%). Patients treated with pemafibrate had increased LDL-C and apoB compared with the placebo group. When you realize that, the results of the study are not very surprising.

Some point to the results of REDUCE-IT as proof that triglycerides are still a valid target for pharmacotherapy. The debate on whether REDUCE-IT tested a good drug or a bad placebo is one for another day. The salient point for today is that the benefits of eicosapentaenoic acid (EPA) were seen regardless of either baseline or final triglyceride level. EPA may lower cardiac risk, but there is no widespread consensus that it does so by lowering triglycerides. There may be other mechanisms at work.

You could still argue that high triglycerides have value as a risk prediction tool even if their role as a target for drug therapy is questionable. There was a time when medications to lower triglycerides had a benefit. But this is the post-statin era, and that time has passed.

If you see patients with high triglycerides, treating them with triglyceride-lowering medication probably isn’t going to reduce their cardiovascular risk. Dietary interventions, encouraging exercise, and reducing alcohol consumption are better options. Not only will they lead to lower cholesterol levels, but they’ll lower cardiovascular risk, too.

Dr. Labos is a cardiologist at Hôpital Notre-Dame, Montreal, with a degree in epidemiology. He has disclosed no relevant financial relationships. He spends most of his time doing things that he doesn’t get paid for, like research, teaching, and podcasting. Occasionally he finds time to practice cardiology to pay the rent. He realizes that half of his research findings will be disproved in 5 years; he just doesn’t know which half. He is a regular contributor to the Montreal Gazette, CJAD radio, and CTV television in Montreal and is host of the award-winning podcast The Body of Evidence. The Body of Evidence.

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

Recent trial evidence has failed to show a cardiovascular benefit to treating high triglycerides. The publication of the PROMINENT trial, where pemafibrate successfully lowered high levels but was not associated with a lower risk for cardiovascular events, reinforced the point. Is it time to stop measuring and treating high triglycerides?

There may be noncardiovascular reasons to treat hypertriglyceridemia. Pancreatitis is the most cited one, given that the risk for pancreatitis increases with increasing triglyceride levels, especially in patients with a prior episode.

There may also be practical reasons to lower trigs. Because most cholesterol panels use the Friedewald equation to calculate low-density lipoprotein cholesterol (LDL-C) rather than measuring it directly, very high triglyceride levels can invalidate the calculation and return error messages on lab reports.

But we now have alternatives to measuring LDL-C, including non–high-density lipoprotein cholesterol (HDL-C) and apolipoprotein B (apoB), that better predict risk and are usable even in the setting of nonfasting samples when triglycerides are elevated.
 

Independent cardiovascular risk factor?

If we are going to measure and treat high triglycerides for cardiovascular reasons, the relevant question is, are high triglycerides an independent risk factor for cardiovascular disease?

Proponents have a broad swath of supportive literature to point at. Multiple studies have shown an association between triglyceride levels and cardiovascular risk. The evidence even extends beyond traditional epidemiologic analyses, to genetic studies that should be free from some of the problems seen in observational cohorts.

But it is difficult to be certain whether these associations are causal or merely confounding. An unhealthy diet will increase triglycerides, as will alcohol. Patients with diabetes or metabolic syndrome have high triglycerides. So do patients with nephrotic syndrome or hypothyroidism, or hypertensive patients taking thiazide diuretics. Adjusting for these baseline factors is possible but imperfect, and residual confounding is always an issue. An analysis of the Reykjavik and the EPIC-Norfolk studies found an association between triglyceride levels and cardiovascular risk. That risk was attenuated, but not eliminated, when adjusted for traditional risk factors such as age, smoking, blood pressure, diabetes, and cholesterol.

Randomized trials of triglyceride-lowering therapies would help resolve the question of whether hypertriglyceridemia contributes to coronary disease or simply identifies high-risk patients. Early trials seemed to support the idea of a causal link. The Helsinki Heart Study randomized patients to gemfibrozil or placebo and found a 34% relative risk reduction in coronary artery disease with the fibrate. But gemfibrozil didn’t only reduce triglycerides. It also increased HDL-C and lowered LDL-C relative to placebo, which may explain the observed benefit.

Gemfibrozil is rarely used today because we can achieve much greater LDL-C reductions with statins, as well as ezetimibe and PCSK9 inhibitors. The success of these drugs may not leave any room for triglyceride-lowering medications.
 

The pre- vs. post-statin era

In the 2005 FIELD study, participants were randomized to receive fenofibrate or placebo. Although patients weren’t taking statin at study entry, 17% of the placebo group started taking one during the trial. Fenofibrate wasn’t associated with a reduction in the primary endpoint, a combination of coronary heart disease death or nonfatal myocardial infarction (MI). Among the many secondary endpoints, nonfatal MI was lower but cardiovascular mortality was not in the fibrate-treated patients. In the same vein, the 2010 ACCORD study randomized patients to receive simvastatin plus fenofibrate or simvastatin alone. The composite primary outcome of MI, stroke, and cardiovascular mortality was not lowered nor were any secondary outcomes with the combination therapy. In the statin era, triglyceride-lowering therapies have not shown much benefit.

The final nail in the coffin may very well be the aforementioned PROMINENT trial. The new agent, pemafibrate, fared no better than its predecessor fenofibrate. Pemafibrate had no impact on the study’s primary composite outcome of nonfatal MI, stroke, coronary revascularization, or cardiovascular death despite being very effective at lowering triglycerides (by more than 25%). Patients treated with pemafibrate had increased LDL-C and apoB compared with the placebo group. When you realize that, the results of the study are not very surprising.

Some point to the results of REDUCE-IT as proof that triglycerides are still a valid target for pharmacotherapy. The debate on whether REDUCE-IT tested a good drug or a bad placebo is one for another day. The salient point for today is that the benefits of eicosapentaenoic acid (EPA) were seen regardless of either baseline or final triglyceride level. EPA may lower cardiac risk, but there is no widespread consensus that it does so by lowering triglycerides. There may be other mechanisms at work.

You could still argue that high triglycerides have value as a risk prediction tool even if their role as a target for drug therapy is questionable. There was a time when medications to lower triglycerides had a benefit. But this is the post-statin era, and that time has passed.

If you see patients with high triglycerides, treating them with triglyceride-lowering medication probably isn’t going to reduce their cardiovascular risk. Dietary interventions, encouraging exercise, and reducing alcohol consumption are better options. Not only will they lead to lower cholesterol levels, but they’ll lower cardiovascular risk, too.

Dr. Labos is a cardiologist at Hôpital Notre-Dame, Montreal, with a degree in epidemiology. He has disclosed no relevant financial relationships. He spends most of his time doing things that he doesn’t get paid for, like research, teaching, and podcasting. Occasionally he finds time to practice cardiology to pay the rent. He realizes that half of his research findings will be disproved in 5 years; he just doesn’t know which half. He is a regular contributor to the Montreal Gazette, CJAD radio, and CTV television in Montreal and is host of the award-winning podcast The Body of Evidence. The Body of Evidence.

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

It’s possible to flag suicide risk by automatically extracting clinical notes on social determinants of health (SDOH) from a patient’s electronic health record using natural language processing (NLP), a form of artificial intelligence, new research shows.

Researchers found SDOH are risk factors for suicide among U.S. veterans and NLP can be leveraged to extract SDOH information from unstructured data in the EHR.

“Since SDOH is overwhelmingly described in EHR notes, the importance of NLP-extracted SDOH can be very significant, meaning that NLP can be used as an effective method for epidemiological and public health study,” senior investigator Hong Yu, PhD, from Miner School of Information and Computer Sciences, University of Massachusetts Lowell, told this news organization.

Although the study was conducted among U.S. veterans, the results likely hold for the general population as well.

“The NLP methods are generalizable. The SDOH categories are generalizable. There may be some variations in terms of the strength of associations in NLP-extracted SDOH and suicide death, but the overall findings are generalizable,” Dr. Yu said.

The study was published online JAMA Network Open.
 

Improved risk assessment

SDOH, which include factors such as socioeconomic status, access to healthy food, education, housing, and physical environment, are strong predictors of suicidal behaviors.

Several studies have identified a range of common risk factors for suicide using International Classification of Diseases (ICD) codes and other “structured” data from the EHR.  However, the use of unstructured EHR data from clinician notes has received little attention in investigating potential associations between suicide and SDOH.

Using the large Veterans Health Administration EHR system, the researchers determined associations between veterans’ death by suicide and recent SDOH, identified using both structured data (ICD-10 codes and Veterans Health Administration stop codes) and unstructured data (NLP-processed clinical notes).

Participants included 8,821 veterans who committed suicide and 35,284 matched controls. The cohort was mostly male (96%) and White (79%). The mean age was 58 years.

The NLP-extracted SDOH were social isolation, job or financial insecurity, housing instability, legal problems, violence, barriers to care, transition of care, and food insecurity.

All of these unstructured clinical notes on SDOH were significantly associated with increased risk for death by suicide.

Legal problems had the largest estimated effect size, more than twice the risk of those with no exposure (adjusted odds ratio 2.62; 95% confidence interval, 2.38-2.89), followed by violence (aOR, 2.34; 95% CI, 2.17-2.52) and social isolation (aOR, 1.94; 95% CI, 1.83-2.06).

Similarly, all of the structured SDOH – social or family problems, employment or financial problems, housing instability, legal problems, violence, and nonspecific psychosocial needs – also showed significant associations with increased risk for suicide death, once again, with legal problems linked to the highest risk (aOR, 2.63; 95% CI, 2.37-2.91).

When combining the structured and NLP-extracted unstructured data, the top three risk factors for death by suicide were legal problems (aOR, 2.66; 95% CI 2.46-2.89), violence (aOR, 2.12; 95% CI, 1.98-2.27), and nonspecific psychosocial needs (aOR, 2.07; 95% CI, 1.92-2.23).

“To our knowledge, this the first large-scale study to implement and use an NLP system to extract SDOH information from unstructured EHR data,” the researchers write.

“We strongly believe that analyzing all available SDOH information, including those contained in clinical notes, can help develop a better system for risk assessment and suicide prevention. However, more studies are required to investigate ways of seamlessly incorporating SDOHs into existing health care systems,” they conclude.

Dr. Yu said it’s also important to note that their NLP system is built upon “the most advanced deep-learning technologies and therefore is more generalizable than most existing work that mainly used rule-based approaches or traditional machine learning for identifying social determinants of health.”

In an accompanying editorial, Ishanu Chattopadhyay, PhD, of the University of Chicago, said this suggests that unstructured clinical notes “may efficiently identify at-risk individuals even when structured data on the relevant variables are missing or incomplete.”

This work may provide “the foundation for addressing the key hurdles in enacting efficient universal assessment for suicide risk among the veterans and perhaps in the general population,” Dr. Chattopadhyay added.

This research was funded by a grant from the National Institute of Mental Health. The study authors and editorialist report no relevant financial relationships.

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

It’s possible to flag suicide risk by automatically extracting clinical notes on social determinants of health (SDOH) from a patient’s electronic health record using natural language processing (NLP), a form of artificial intelligence, new research shows.

Researchers found SDOH are risk factors for suicide among U.S. veterans and NLP can be leveraged to extract SDOH information from unstructured data in the EHR.

“Since SDOH is overwhelmingly described in EHR notes, the importance of NLP-extracted SDOH can be very significant, meaning that NLP can be used as an effective method for epidemiological and public health study,” senior investigator Hong Yu, PhD, from Miner School of Information and Computer Sciences, University of Massachusetts Lowell, told this news organization.

Although the study was conducted among U.S. veterans, the results likely hold for the general population as well.

“The NLP methods are generalizable. The SDOH categories are generalizable. There may be some variations in terms of the strength of associations in NLP-extracted SDOH and suicide death, but the overall findings are generalizable,” Dr. Yu said.

The study was published online JAMA Network Open.
 

Improved risk assessment

SDOH, which include factors such as socioeconomic status, access to healthy food, education, housing, and physical environment, are strong predictors of suicidal behaviors.

Several studies have identified a range of common risk factors for suicide using International Classification of Diseases (ICD) codes and other “structured” data from the EHR.  However, the use of unstructured EHR data from clinician notes has received little attention in investigating potential associations between suicide and SDOH.

Using the large Veterans Health Administration EHR system, the researchers determined associations between veterans’ death by suicide and recent SDOH, identified using both structured data (ICD-10 codes and Veterans Health Administration stop codes) and unstructured data (NLP-processed clinical notes).

Participants included 8,821 veterans who committed suicide and 35,284 matched controls. The cohort was mostly male (96%) and White (79%). The mean age was 58 years.

The NLP-extracted SDOH were social isolation, job or financial insecurity, housing instability, legal problems, violence, barriers to care, transition of care, and food insecurity.

All of these unstructured clinical notes on SDOH were significantly associated with increased risk for death by suicide.

Legal problems had the largest estimated effect size, more than twice the risk of those with no exposure (adjusted odds ratio 2.62; 95% confidence interval, 2.38-2.89), followed by violence (aOR, 2.34; 95% CI, 2.17-2.52) and social isolation (aOR, 1.94; 95% CI, 1.83-2.06).

Similarly, all of the structured SDOH – social or family problems, employment or financial problems, housing instability, legal problems, violence, and nonspecific psychosocial needs – also showed significant associations with increased risk for suicide death, once again, with legal problems linked to the highest risk (aOR, 2.63; 95% CI, 2.37-2.91).

When combining the structured and NLP-extracted unstructured data, the top three risk factors for death by suicide were legal problems (aOR, 2.66; 95% CI 2.46-2.89), violence (aOR, 2.12; 95% CI, 1.98-2.27), and nonspecific psychosocial needs (aOR, 2.07; 95% CI, 1.92-2.23).

“To our knowledge, this the first large-scale study to implement and use an NLP system to extract SDOH information from unstructured EHR data,” the researchers write.

“We strongly believe that analyzing all available SDOH information, including those contained in clinical notes, can help develop a better system for risk assessment and suicide prevention. However, more studies are required to investigate ways of seamlessly incorporating SDOHs into existing health care systems,” they conclude.

Dr. Yu said it’s also important to note that their NLP system is built upon “the most advanced deep-learning technologies and therefore is more generalizable than most existing work that mainly used rule-based approaches or traditional machine learning for identifying social determinants of health.”

In an accompanying editorial, Ishanu Chattopadhyay, PhD, of the University of Chicago, said this suggests that unstructured clinical notes “may efficiently identify at-risk individuals even when structured data on the relevant variables are missing or incomplete.”

This work may provide “the foundation for addressing the key hurdles in enacting efficient universal assessment for suicide risk among the veterans and perhaps in the general population,” Dr. Chattopadhyay added.

This research was funded by a grant from the National Institute of Mental Health. The study authors and editorialist report no relevant financial relationships.

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

It’s possible to flag suicide risk by automatically extracting clinical notes on social determinants of health (SDOH) from a patient’s electronic health record using natural language processing (NLP), a form of artificial intelligence, new research shows.

Researchers found SDOH are risk factors for suicide among U.S. veterans and NLP can be leveraged to extract SDOH information from unstructured data in the EHR.

“Since SDOH is overwhelmingly described in EHR notes, the importance of NLP-extracted SDOH can be very significant, meaning that NLP can be used as an effective method for epidemiological and public health study,” senior investigator Hong Yu, PhD, from Miner School of Information and Computer Sciences, University of Massachusetts Lowell, told this news organization.

Although the study was conducted among U.S. veterans, the results likely hold for the general population as well.

“The NLP methods are generalizable. The SDOH categories are generalizable. There may be some variations in terms of the strength of associations in NLP-extracted SDOH and suicide death, but the overall findings are generalizable,” Dr. Yu said.

The study was published online JAMA Network Open.
 

Improved risk assessment

SDOH, which include factors such as socioeconomic status, access to healthy food, education, housing, and physical environment, are strong predictors of suicidal behaviors.

Several studies have identified a range of common risk factors for suicide using International Classification of Diseases (ICD) codes and other “structured” data from the EHR.  However, the use of unstructured EHR data from clinician notes has received little attention in investigating potential associations between suicide and SDOH.

Using the large Veterans Health Administration EHR system, the researchers determined associations between veterans’ death by suicide and recent SDOH, identified using both structured data (ICD-10 codes and Veterans Health Administration stop codes) and unstructured data (NLP-processed clinical notes).

Participants included 8,821 veterans who committed suicide and 35,284 matched controls. The cohort was mostly male (96%) and White (79%). The mean age was 58 years.

The NLP-extracted SDOH were social isolation, job or financial insecurity, housing instability, legal problems, violence, barriers to care, transition of care, and food insecurity.

All of these unstructured clinical notes on SDOH were significantly associated with increased risk for death by suicide.

Legal problems had the largest estimated effect size, more than twice the risk of those with no exposure (adjusted odds ratio 2.62; 95% confidence interval, 2.38-2.89), followed by violence (aOR, 2.34; 95% CI, 2.17-2.52) and social isolation (aOR, 1.94; 95% CI, 1.83-2.06).

Similarly, all of the structured SDOH – social or family problems, employment or financial problems, housing instability, legal problems, violence, and nonspecific psychosocial needs – also showed significant associations with increased risk for suicide death, once again, with legal problems linked to the highest risk (aOR, 2.63; 95% CI, 2.37-2.91).

When combining the structured and NLP-extracted unstructured data, the top three risk factors for death by suicide were legal problems (aOR, 2.66; 95% CI 2.46-2.89), violence (aOR, 2.12; 95% CI, 1.98-2.27), and nonspecific psychosocial needs (aOR, 2.07; 95% CI, 1.92-2.23).

“To our knowledge, this the first large-scale study to implement and use an NLP system to extract SDOH information from unstructured EHR data,” the researchers write.

“We strongly believe that analyzing all available SDOH information, including those contained in clinical notes, can help develop a better system for risk assessment and suicide prevention. However, more studies are required to investigate ways of seamlessly incorporating SDOHs into existing health care systems,” they conclude.

Dr. Yu said it’s also important to note that their NLP system is built upon “the most advanced deep-learning technologies and therefore is more generalizable than most existing work that mainly used rule-based approaches or traditional machine learning for identifying social determinants of health.”

In an accompanying editorial, Ishanu Chattopadhyay, PhD, of the University of Chicago, said this suggests that unstructured clinical notes “may efficiently identify at-risk individuals even when structured data on the relevant variables are missing or incomplete.”

This work may provide “the foundation for addressing the key hurdles in enacting efficient universal assessment for suicide risk among the veterans and perhaps in the general population,” Dr. Chattopadhyay added.

This research was funded by a grant from the National Institute of Mental Health. The study authors and editorialist report no relevant financial relationships.

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

Imaging tests may miss early signs of multiple sclerosis (MS) in children who have no symptoms of the disease, according to a recent study that points to the need for a change in diagnostic criteria for the neuromuscular condition.

The findings suggest that children, unlike adults, may not need to meet the current clinical standard criteria to be considered at risk for MS.

“This is an important study confirming that some children who have no symptoms of demyelinating disease may nonetheless have MRI findings suggestive of demyelination detected on brain imaging,” said Naila Makhani, MD, associate professor of pediatrics and of neurology at Yale University and director of the Yale Pediatric Neuroimmunology Program, New Haven, Conn. Dr. Makhani was not affiliated with the study.

Researchers reviewed the MRI scans of 38 children aged 7-17 years who had radiologically isolated syndrome (RIS), a possible precursor to MS.

Like MS, RIS is characterized by destruction of the myelin. However, RIS is generally asymptomatic.

While RIS has been linked to MS, a diagnosis of RIS does not mean someone will be diagnosed with MS. Previous studies have shown that at least 3% of MS cases begin before age 16.

The children in the study likely received an MRI because of complaints of headaches or after having been diagnosed with a concussion, according to the researchers. The participants also did not show physical symptoms for MS, nor did they meet the McDonald or Barkohf criteria, which are clinical standards used to diagnose the condition in adults and children.

Within an average of 3 years following the imaging and RIS diagnosis, almost 36% of the children experienced a clinical attack, which led to an MS diagnosis. Almost three-fourths of the children developed additional brain and spinal cord lesions in the myelin that were evident on MRI.

MS often is diagnosed after a patient has had a clinical attack, such as vision impairment, loss of balance, inflammation, or severe fatigue. Identifying the potential for the disease earlier may allow clinicians to treat sooner, according to Leslie Benson, MD, assistant director of pediatric neuroimmunology at Massachusetts General Hospital, Boston, and one of the study authors.

“The field is leaning toward [the question of], ‘Should we treat presymptomatic MS?’ ” said Dr. Benson. “If we have the opportunity to prevent disability and improve long-term outcomes with safe medications, then we would like to do so.”

The findings were published in the journal Multiple Sclerosis and Related Disorders.

According to Dr. Benson and her colleagues, adjustments to the McDonald or Barkohf criteria for children may help in the detection of RIS and may allow earlier identification of MS.

“We don’t really know when MS first starts,” Dr. Benson said. “Unless you happen to have an MRI or symptoms, there’s no way to know how long the lesions have been evolving and how long the disease progression that led to those lesions has been there.”

MRI images showing lesions in the brain stem and spinal cord of children appeared to be different from those typically seen in adults, according to Tanuja Chitnis, MD, director of the Mass General Brigham Pediatric MS Center in Boston, who is one of the study’s coauthors.

“The concern of many practitioners is whether we should be treating at the first sign of MS,” Dr. Chitnis said. “We need to understand it better in children, and in teenagers especially, when these probably start biologically.”

Dr. Benson said current criteria for diagnosing MS in children require meeting a high threshold, which may limit diagnoses to those whose condition has progressed.

“This may miss patients at risk for MS,” Dr. Benson said. “That idea of who do you diagnose RIS and what criteria work to accurately diagnose RIS is really important.”

For now, the challenge remains of investigating characteristics of patients with RIS who will later have a clinical attack.

“We need a better understanding of what criteria do need to be met and how we can best risk-stratify our patients,” Dr. Benson said. “If it is recommended to treat presymptomatic cases, that we can best stratify those at risk and not overtreat those not at risk.”

Dr. Makhani receives funding from the National Institutes of Health, the Charles H. Hood Foundation, and the Multiple Sclerosis Society.

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

Imaging tests may miss early signs of multiple sclerosis (MS) in children who have no symptoms of the disease, according to a recent study that points to the need for a change in diagnostic criteria for the neuromuscular condition.

The findings suggest that children, unlike adults, may not need to meet the current clinical standard criteria to be considered at risk for MS.

“This is an important study confirming that some children who have no symptoms of demyelinating disease may nonetheless have MRI findings suggestive of demyelination detected on brain imaging,” said Naila Makhani, MD, associate professor of pediatrics and of neurology at Yale University and director of the Yale Pediatric Neuroimmunology Program, New Haven, Conn. Dr. Makhani was not affiliated with the study.

Researchers reviewed the MRI scans of 38 children aged 7-17 years who had radiologically isolated syndrome (RIS), a possible precursor to MS.

Like MS, RIS is characterized by destruction of the myelin. However, RIS is generally asymptomatic.

While RIS has been linked to MS, a diagnosis of RIS does not mean someone will be diagnosed with MS. Previous studies have shown that at least 3% of MS cases begin before age 16.

The children in the study likely received an MRI because of complaints of headaches or after having been diagnosed with a concussion, according to the researchers. The participants also did not show physical symptoms for MS, nor did they meet the McDonald or Barkohf criteria, which are clinical standards used to diagnose the condition in adults and children.

Within an average of 3 years following the imaging and RIS diagnosis, almost 36% of the children experienced a clinical attack, which led to an MS diagnosis. Almost three-fourths of the children developed additional brain and spinal cord lesions in the myelin that were evident on MRI.

MS often is diagnosed after a patient has had a clinical attack, such as vision impairment, loss of balance, inflammation, or severe fatigue. Identifying the potential for the disease earlier may allow clinicians to treat sooner, according to Leslie Benson, MD, assistant director of pediatric neuroimmunology at Massachusetts General Hospital, Boston, and one of the study authors.

“The field is leaning toward [the question of], ‘Should we treat presymptomatic MS?’ ” said Dr. Benson. “If we have the opportunity to prevent disability and improve long-term outcomes with safe medications, then we would like to do so.”

The findings were published in the journal Multiple Sclerosis and Related Disorders.

According to Dr. Benson and her colleagues, adjustments to the McDonald or Barkohf criteria for children may help in the detection of RIS and may allow earlier identification of MS.

“We don’t really know when MS first starts,” Dr. Benson said. “Unless you happen to have an MRI or symptoms, there’s no way to know how long the lesions have been evolving and how long the disease progression that led to those lesions has been there.”

MRI images showing lesions in the brain stem and spinal cord of children appeared to be different from those typically seen in adults, according to Tanuja Chitnis, MD, director of the Mass General Brigham Pediatric MS Center in Boston, who is one of the study’s coauthors.

“The concern of many practitioners is whether we should be treating at the first sign of MS,” Dr. Chitnis said. “We need to understand it better in children, and in teenagers especially, when these probably start biologically.”

Dr. Benson said current criteria for diagnosing MS in children require meeting a high threshold, which may limit diagnoses to those whose condition has progressed.

“This may miss patients at risk for MS,” Dr. Benson said. “That idea of who do you diagnose RIS and what criteria work to accurately diagnose RIS is really important.”

For now, the challenge remains of investigating characteristics of patients with RIS who will later have a clinical attack.

“We need a better understanding of what criteria do need to be met and how we can best risk-stratify our patients,” Dr. Benson said. “If it is recommended to treat presymptomatic cases, that we can best stratify those at risk and not overtreat those not at risk.”

Dr. Makhani receives funding from the National Institutes of Health, the Charles H. Hood Foundation, and the Multiple Sclerosis Society.

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

Imaging tests may miss early signs of multiple sclerosis (MS) in children who have no symptoms of the disease, according to a recent study that points to the need for a change in diagnostic criteria for the neuromuscular condition.

The findings suggest that children, unlike adults, may not need to meet the current clinical standard criteria to be considered at risk for MS.

“This is an important study confirming that some children who have no symptoms of demyelinating disease may nonetheless have MRI findings suggestive of demyelination detected on brain imaging,” said Naila Makhani, MD, associate professor of pediatrics and of neurology at Yale University and director of the Yale Pediatric Neuroimmunology Program, New Haven, Conn. Dr. Makhani was not affiliated with the study.

Researchers reviewed the MRI scans of 38 children aged 7-17 years who had radiologically isolated syndrome (RIS), a possible precursor to MS.

Like MS, RIS is characterized by destruction of the myelin. However, RIS is generally asymptomatic.

While RIS has been linked to MS, a diagnosis of RIS does not mean someone will be diagnosed with MS. Previous studies have shown that at least 3% of MS cases begin before age 16.

The children in the study likely received an MRI because of complaints of headaches or after having been diagnosed with a concussion, according to the researchers. The participants also did not show physical symptoms for MS, nor did they meet the McDonald or Barkohf criteria, which are clinical standards used to diagnose the condition in adults and children.

Within an average of 3 years following the imaging and RIS diagnosis, almost 36% of the children experienced a clinical attack, which led to an MS diagnosis. Almost three-fourths of the children developed additional brain and spinal cord lesions in the myelin that were evident on MRI.

MS often is diagnosed after a patient has had a clinical attack, such as vision impairment, loss of balance, inflammation, or severe fatigue. Identifying the potential for the disease earlier may allow clinicians to treat sooner, according to Leslie Benson, MD, assistant director of pediatric neuroimmunology at Massachusetts General Hospital, Boston, and one of the study authors.

“The field is leaning toward [the question of], ‘Should we treat presymptomatic MS?’ ” said Dr. Benson. “If we have the opportunity to prevent disability and improve long-term outcomes with safe medications, then we would like to do so.”

The findings were published in the journal Multiple Sclerosis and Related Disorders.

According to Dr. Benson and her colleagues, adjustments to the McDonald or Barkohf criteria for children may help in the detection of RIS and may allow earlier identification of MS.

“We don’t really know when MS first starts,” Dr. Benson said. “Unless you happen to have an MRI or symptoms, there’s no way to know how long the lesions have been evolving and how long the disease progression that led to those lesions has been there.”

MRI images showing lesions in the brain stem and spinal cord of children appeared to be different from those typically seen in adults, according to Tanuja Chitnis, MD, director of the Mass General Brigham Pediatric MS Center in Boston, who is one of the study’s coauthors.

“The concern of many practitioners is whether we should be treating at the first sign of MS,” Dr. Chitnis said. “We need to understand it better in children, and in teenagers especially, when these probably start biologically.”

Dr. Benson said current criteria for diagnosing MS in children require meeting a high threshold, which may limit diagnoses to those whose condition has progressed.

“This may miss patients at risk for MS,” Dr. Benson said. “That idea of who do you diagnose RIS and what criteria work to accurately diagnose RIS is really important.”

For now, the challenge remains of investigating characteristics of patients with RIS who will later have a clinical attack.

“We need a better understanding of what criteria do need to be met and how we can best risk-stratify our patients,” Dr. Benson said. “If it is recommended to treat presymptomatic cases, that we can best stratify those at risk and not overtreat those not at risk.”

Dr. Makhani receives funding from the National Institutes of Health, the Charles H. Hood Foundation, and the Multiple Sclerosis Society.

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