Article

Schizophrenia is characterized by psychotic symptoms that typically follow a prodromal period of premonitory signs and symptoms that appear before the manifestation of the full-blown syndrome. Signs and symptoms during the prodromal phase are subsyndromal, which implies a lower degree of intensity, duration, or frequency than observed when the patient meets the full criteria for the syndrome. Early detection of prodromal symptoms can improve prognosis, but these subtle symptoms may go unrecognized.

In schizophrenia, a patient may exhibit prodromal signs and symptoms before the appearance of pathognomonic symptoms, such as delusions, hallucinations, and disorganization. The schizophrenia prodrome can be conceptualized as a period of prepsychotic disturbances depicting an alteration in the individual’s behavior and perception. Prodromal symptoms can last from weeks to years before the psychotic illness clinically manifests.¹ The prodromal symptom cluster typically becomes evident during adolescence and young adulthood.²

In the mid-1990s, investigators tried to identify a “putative prodrome” for psychosis. The term “at-risk mental state” (ARMS) for psychosis is based on retrospective reports of prodromal symptoms in first-episode psychosis. Over the next 2 decades, scales such as the Comprehensive Assessment of ARMS (CAARMS)³ and the Structured Interview for Prodromal Syndrome⁴ were designed to enhance the objectivity and diagnostic accuracy of the ARMS. These scales have reasonable interrater reliability.⁵

Researchers also have attempted to stage the severity of ARMS.⁶ Key symptom group predictors were studied to determine which individual symptoms or cluster of symptoms are most associated with poor outcomes and progression to psychosis. Raballo et al⁷ found the severity of the CAARMS disorganization dimension was the strongest predictor of transition to frank psychosis. Other research suggests that approximately one-third of ARMS patients transition to psychosis within 3 years, another one-third have persistent attenuated psychotic symptoms, and the remaining one-third experience symptom remission.^8,9

Despite multiple studies and meta-analyses, current scales and clinical predictors continue to be imperfect.⁸ Efforts to identify specific biological markers and predictors of transition to clinical psychosis have not been successful for ARMS.^10,11 The Table^8,9,12,13 summarizes diagnostic criteria that have been developed to more clearly identify which ARMS patients face the highest imminent risk for transition to psychosis; these have been referred to as ultra high-risk (UHR) criteria.¹⁴ These UHR criteria depict 3 categories of clinical presentation believed to confer risk of transition to psychosis: attenuated psychotic symptoms, transient psychotic symptoms, and genetic predisposition. Subsequent research found that certain additional symptom variables, as well as combinations of specific symptom clusters, conferred increased risk and improved the positive predictive sensitivity to as high as 83%.¹⁵ In addition to the UHR criteria, the Table^8,9,12,13 also lists these additional variables shown to confer a high positive predictive value (PPV) of transition, alone or in combination with the UHR criterion. Thompson et al¹⁶ provide more detailed information on these later variables and their relative PPV.

What about treatment?

While discussion of the optimal treatment options for patients with prodromal symptoms of schizophrenia is beyond the scope of this article, early interventions can focus on preventing the biological, psychological, and social disruption that results from such symptoms. Establishing a therapeutic alliance with the patient while they retain insight and engaging supportive family members is a key starting point. Case management, cognitive-behavioral or supportive therapy, and treatment of comorbid mood, anxiety, or substance use disorders are helpful. There is no clear consensus on the utility of pharmacotherapy in the prodromal stage of psychosis. While scales and structured interviews can guide assessment, clinical judgment is the key driver of the appropriateness of initiating pharmacologic treatment to address symptoms. Because up to two-thirds of patients who satisfy UHR criteria do not go on to develop schizophrenia,¹⁶ clinicians should be thoughtful about the risks and benefits of antipsychotics.

Schizophrenia is characterized by psychotic symptoms that typically follow a prodromal period of premonitory signs and symptoms that appear before the manifestation of the full-blown syndrome. Signs and symptoms during the prodromal phase are subsyndromal, which implies a lower degree of intensity, duration, or frequency than observed when the patient meets the full criteria for the syndrome. Early detection of prodromal symptoms can improve prognosis, but these subtle symptoms may go unrecognized.

In schizophrenia, a patient may exhibit prodromal signs and symptoms before the appearance of pathognomonic symptoms, such as delusions, hallucinations, and disorganization. The schizophrenia prodrome can be conceptualized as a period of prepsychotic disturbances depicting an alteration in the individual’s behavior and perception. Prodromal symptoms can last from weeks to years before the psychotic illness clinically manifests.¹ The prodromal symptom cluster typically becomes evident during adolescence and young adulthood.²

In the mid-1990s, investigators tried to identify a “putative prodrome” for psychosis. The term “at-risk mental state” (ARMS) for psychosis is based on retrospective reports of prodromal symptoms in first-episode psychosis. Over the next 2 decades, scales such as the Comprehensive Assessment of ARMS (CAARMS)³ and the Structured Interview for Prodromal Syndrome⁴ were designed to enhance the objectivity and diagnostic accuracy of the ARMS. These scales have reasonable interrater reliability.⁵

Researchers also have attempted to stage the severity of ARMS.⁶ Key symptom group predictors were studied to determine which individual symptoms or cluster of symptoms are most associated with poor outcomes and progression to psychosis. Raballo et al⁷ found the severity of the CAARMS disorganization dimension was the strongest predictor of transition to frank psychosis. Other research suggests that approximately one-third of ARMS patients transition to psychosis within 3 years, another one-third have persistent attenuated psychotic symptoms, and the remaining one-third experience symptom remission.^8,9

Despite multiple studies and meta-analyses, current scales and clinical predictors continue to be imperfect.⁸ Efforts to identify specific biological markers and predictors of transition to clinical psychosis have not been successful for ARMS.^10,11 The Table^8,9,12,13 summarizes diagnostic criteria that have been developed to more clearly identify which ARMS patients face the highest imminent risk for transition to psychosis; these have been referred to as ultra high-risk (UHR) criteria.¹⁴ These UHR criteria depict 3 categories of clinical presentation believed to confer risk of transition to psychosis: attenuated psychotic symptoms, transient psychotic symptoms, and genetic predisposition. Subsequent research found that certain additional symptom variables, as well as combinations of specific symptom clusters, conferred increased risk and improved the positive predictive sensitivity to as high as 83%.¹⁵ In addition to the UHR criteria, the Table^8,9,12,13 also lists these additional variables shown to confer a high positive predictive value (PPV) of transition, alone or in combination with the UHR criterion. Thompson et al¹⁶ provide more detailed information on these later variables and their relative PPV.

What about treatment?

While discussion of the optimal treatment options for patients with prodromal symptoms of schizophrenia is beyond the scope of this article, early interventions can focus on preventing the biological, psychological, and social disruption that results from such symptoms. Establishing a therapeutic alliance with the patient while they retain insight and engaging supportive family members is a key starting point. Case management, cognitive-behavioral or supportive therapy, and treatment of comorbid mood, anxiety, or substance use disorders are helpful. There is no clear consensus on the utility of pharmacotherapy in the prodromal stage of psychosis. While scales and structured interviews can guide assessment, clinical judgment is the key driver of the appropriateness of initiating pharmacologic treatment to address symptoms. Because up to two-thirds of patients who satisfy UHR criteria do not go on to develop schizophrenia,¹⁶ clinicians should be thoughtful about the risks and benefits of antipsychotics.

Schizophrenia is characterized by psychotic symptoms that typically follow a prodromal period of premonitory signs and symptoms that appear before the manifestation of the full-blown syndrome. Signs and symptoms during the prodromal phase are subsyndromal, which implies a lower degree of intensity, duration, or frequency than observed when the patient meets the full criteria for the syndrome. Early detection of prodromal symptoms can improve prognosis, but these subtle symptoms may go unrecognized.

In schizophrenia, a patient may exhibit prodromal signs and symptoms before the appearance of pathognomonic symptoms, such as delusions, hallucinations, and disorganization. The schizophrenia prodrome can be conceptualized as a period of prepsychotic disturbances depicting an alteration in the individual’s behavior and perception. Prodromal symptoms can last from weeks to years before the psychotic illness clinically manifests.¹ The prodromal symptom cluster typically becomes evident during adolescence and young adulthood.²

In the mid-1990s, investigators tried to identify a “putative prodrome” for psychosis. The term “at-risk mental state” (ARMS) for psychosis is based on retrospective reports of prodromal symptoms in first-episode psychosis. Over the next 2 decades, scales such as the Comprehensive Assessment of ARMS (CAARMS)³ and the Structured Interview for Prodromal Syndrome⁴ were designed to enhance the objectivity and diagnostic accuracy of the ARMS. These scales have reasonable interrater reliability.⁵

Researchers also have attempted to stage the severity of ARMS.⁶ Key symptom group predictors were studied to determine which individual symptoms or cluster of symptoms are most associated with poor outcomes and progression to psychosis. Raballo et al⁷ found the severity of the CAARMS disorganization dimension was the strongest predictor of transition to frank psychosis. Other research suggests that approximately one-third of ARMS patients transition to psychosis within 3 years, another one-third have persistent attenuated psychotic symptoms, and the remaining one-third experience symptom remission.^8,9

Despite multiple studies and meta-analyses, current scales and clinical predictors continue to be imperfect.⁸ Efforts to identify specific biological markers and predictors of transition to clinical psychosis have not been successful for ARMS.^10,11 The Table^8,9,12,13 summarizes diagnostic criteria that have been developed to more clearly identify which ARMS patients face the highest imminent risk for transition to psychosis; these have been referred to as ultra high-risk (UHR) criteria.¹⁴ These UHR criteria depict 3 categories of clinical presentation believed to confer risk of transition to psychosis: attenuated psychotic symptoms, transient psychotic symptoms, and genetic predisposition. Subsequent research found that certain additional symptom variables, as well as combinations of specific symptom clusters, conferred increased risk and improved the positive predictive sensitivity to as high as 83%.¹⁵ In addition to the UHR criteria, the Table^8,9,12,13 also lists these additional variables shown to confer a high positive predictive value (PPV) of transition, alone or in combination with the UHR criterion. Thompson et al¹⁶ provide more detailed information on these later variables and their relative PPV.

What about treatment?

While discussion of the optimal treatment options for patients with prodromal symptoms of schizophrenia is beyond the scope of this article, early interventions can focus on preventing the biological, psychological, and social disruption that results from such symptoms. Establishing a therapeutic alliance with the patient while they retain insight and engaging supportive family members is a key starting point. Case management, cognitive-behavioral or supportive therapy, and treatment of comorbid mood, anxiety, or substance use disorders are helpful. There is no clear consensus on the utility of pharmacotherapy in the prodromal stage of psychosis. While scales and structured interviews can guide assessment, clinical judgment is the key driver of the appropriateness of initiating pharmacologic treatment to address symptoms. Because up to two-thirds of patients who satisfy UHR criteria do not go on to develop schizophrenia,¹⁶ clinicians should be thoughtful about the risks and benefits of antipsychotics.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact letters@currentpsychiatry.com.

I (MZP) just completed my first semester of medical school. An important lesson imparted in my coursework so far has been to remain a staunch advocate for patients. Yet compared to the rigors of medical school, over the past year it has been far more difficult to help patients locate generic Adderall. Physicians were already overburdened with administrative responsibilities stretching into burnout territory well before the shortage, and now this! Unlike paper prescriptions of old, which patients could take to any pharmacy, e-prescribing apps require selection of a specific pharmacy, and controlled substances such as stimulants require 2-factor authentication. But if the designated pharmacy does not have the medication in stock, the entire process must be repeated with an alternative pharmacy, long after the visit has concluded.

To add insult to injury, the generic stimulant shortage has grown even worse. As of February 2023, generic Adderall remained hard to find and generic Concerta was also in short supply. How did this happen? In 1985, Bulow et al¹ coined the game theory concept of “strategic substitutes,” where (for example) as beef becomes less readily accessible, consumers may switch to eating chicken as their protein. Unable to locate generic Adderall, many patients have turned to generic Concerta as a substitute psychostimulant to continue management of their attention-deficit/hyperactivity disorder.

In addition to the increase in demand, compounding the shortage is that one of the manufacturers of generic Concerta has discontinued production.² Branded methylphenidates and amphetamines, which are much more expensive than their generic counterparts, have remained in ample supply, but many insurers require trials of generics before considering coverage for more expensive brands.

Our approach to this situation

Each morning we call our local and chain pharmacies to take a census of their supply of generic stimulants. Some pharmacies refuse to release this information. Despite these census reports, we have found cases where patients have been turned away from pharmacies when they are not “regular customers,” while patients whom the pharmacies know retain access as “members.” Hence, a patient is unlikely to obtain these medications if their regular pharmacy is out of stock.

We want to share a workaround that has been effective. After unsuccessfully searching for generic stimulants at the patient’s regular pharmacy, I (RLP) write “dispense as written” for the closest branded version and file a prior authorization with the patient’s insurance company, noting “patient unable to trial any generic amphetamines or methylphenidates due to current nationwide shortage.” Even with the most difficult insurers, the response has been “a temporary 3-month authorization has been granted,” which is at least a small victory for our desperate patients and busy prescribers who are both struggling to negotiate a fragmented health care system.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact letters@currentpsychiatry.com.

I (MZP) just completed my first semester of medical school. An important lesson imparted in my coursework so far has been to remain a staunch advocate for patients. Yet compared to the rigors of medical school, over the past year it has been far more difficult to help patients locate generic Adderall. Physicians were already overburdened with administrative responsibilities stretching into burnout territory well before the shortage, and now this! Unlike paper prescriptions of old, which patients could take to any pharmacy, e-prescribing apps require selection of a specific pharmacy, and controlled substances such as stimulants require 2-factor authentication. But if the designated pharmacy does not have the medication in stock, the entire process must be repeated with an alternative pharmacy, long after the visit has concluded.

To add insult to injury, the generic stimulant shortage has grown even worse. As of February 2023, generic Adderall remained hard to find and generic Concerta was also in short supply. How did this happen? In 1985, Bulow et al¹ coined the game theory concept of “strategic substitutes,” where (for example) as beef becomes less readily accessible, consumers may switch to eating chicken as their protein. Unable to locate generic Adderall, many patients have turned to generic Concerta as a substitute psychostimulant to continue management of their attention-deficit/hyperactivity disorder.

In addition to the increase in demand, compounding the shortage is that one of the manufacturers of generic Concerta has discontinued production.² Branded methylphenidates and amphetamines, which are much more expensive than their generic counterparts, have remained in ample supply, but many insurers require trials of generics before considering coverage for more expensive brands.

Our approach to this situation

Each morning we call our local and chain pharmacies to take a census of their supply of generic stimulants. Some pharmacies refuse to release this information. Despite these census reports, we have found cases where patients have been turned away from pharmacies when they are not “regular customers,” while patients whom the pharmacies know retain access as “members.” Hence, a patient is unlikely to obtain these medications if their regular pharmacy is out of stock.

We want to share a workaround that has been effective. After unsuccessfully searching for generic stimulants at the patient’s regular pharmacy, I (RLP) write “dispense as written” for the closest branded version and file a prior authorization with the patient’s insurance company, noting “patient unable to trial any generic amphetamines or methylphenidates due to current nationwide shortage.” Even with the most difficult insurers, the response has been “a temporary 3-month authorization has been granted,” which is at least a small victory for our desperate patients and busy prescribers who are both struggling to negotiate a fragmented health care system.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact letters@currentpsychiatry.com.

I (MZP) just completed my first semester of medical school. An important lesson imparted in my coursework so far has been to remain a staunch advocate for patients. Yet compared to the rigors of medical school, over the past year it has been far more difficult to help patients locate generic Adderall. Physicians were already overburdened with administrative responsibilities stretching into burnout territory well before the shortage, and now this! Unlike paper prescriptions of old, which patients could take to any pharmacy, e-prescribing apps require selection of a specific pharmacy, and controlled substances such as stimulants require 2-factor authentication. But if the designated pharmacy does not have the medication in stock, the entire process must be repeated with an alternative pharmacy, long after the visit has concluded.

To add insult to injury, the generic stimulant shortage has grown even worse. As of February 2023, generic Adderall remained hard to find and generic Concerta was also in short supply. How did this happen? In 1985, Bulow et al¹ coined the game theory concept of “strategic substitutes,” where (for example) as beef becomes less readily accessible, consumers may switch to eating chicken as their protein. Unable to locate generic Adderall, many patients have turned to generic Concerta as a substitute psychostimulant to continue management of their attention-deficit/hyperactivity disorder.

In addition to the increase in demand, compounding the shortage is that one of the manufacturers of generic Concerta has discontinued production.² Branded methylphenidates and amphetamines, which are much more expensive than their generic counterparts, have remained in ample supply, but many insurers require trials of generics before considering coverage for more expensive brands.

Our approach to this situation

Each morning we call our local and chain pharmacies to take a census of their supply of generic stimulants. Some pharmacies refuse to release this information. Despite these census reports, we have found cases where patients have been turned away from pharmacies when they are not “regular customers,” while patients whom the pharmacies know retain access as “members.” Hence, a patient is unlikely to obtain these medications if their regular pharmacy is out of stock.

We want to share a workaround that has been effective. After unsuccessfully searching for generic stimulants at the patient’s regular pharmacy, I (RLP) write “dispense as written” for the closest branded version and file a prior authorization with the patient’s insurance company, noting “patient unable to trial any generic amphetamines or methylphenidates due to current nationwide shortage.” Even with the most difficult insurers, the response has been “a temporary 3-month authorization has been granted,” which is at least a small victory for our desperate patients and busy prescribers who are both struggling to negotiate a fragmented health care system.

Mantle cell lymphoma (MCL) has served as a paradigm of progress among the non-Hodgkin lymphomas over the past 30 years. It was originally defined within the Kiel classification as centrocytic lymphoma, then renamed MCL once the characteristic translocation and resulting cyclin D1 overexpression were identified. These diagnostic markers allowed for the characterization of MCL subtypes as well as the initiation of MCL-focused clinical trials which, in turn, led to regulatory approval of more effective regimens, new therapeutic agents, and an improvement in overall survival (OS) from around 3 years to more than 10 years for many patients.

Despite this progress, virtually all patients relapse, and a cure remains elusive for most. In younger (< 65 to 70 years), medically-fit patients who are transplant-eligible and have symptomatic MCL, a standard of care has been induction chemoimmunotherapy containing high-dose cytarabine followed by ASCT consolidation. For example, a clinical trial of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) alternating with R-DHAP (rituximab, dexamethasone, high-dose cytarabine, cisplatin; 3 cycles each) showed a significant benefit over R-CHOP x 6 cycles; at a median follow-up of 10.6 years, the time-to-treatment failure was 8.4 v 3.9 years. In another trial, all patients received induction R-DHAP (with cisplatin or an alternative platinum agent) x 4 cycles followed by ASCT. Those patients randomized to post-ASCT maintenance rituximab for 3 years had significantly improved, 4-year progression-free survival (PFS) as compared with observation only (83% vs 64%, p < 0.001); maintenance also significantly improved OS. 

Although ASCT consolidation followed by maintenance became widely adopted on the basis of these and other clinical trials, important questions remain:

• First, MCL is biologically and clinically quite heterogeneous. Several prognostic tools such as the MCL International Prognostic Index (MIPI) scoring system and biomarkers are available to define lower- versus higher-risk subtypes, but none is routinely used for treatment planning. About 15% of MCL patients present with a highly-aggressive blastoid or pleomorphic variant that usually carries a TP53 mutation or deletion. Given the short survival and limited benefit from dose-intensive chemotherapy and ASCT in TP53-mutated MCL, should transplant be avoided in these patients?    

• Second, if deep remission is achieved following front-line therapy, defined as positron emission tomography (PET) negative and measurable residual disease (MRD) negative, will high-dose chemotherapy and ASCT provide additional benefits or only toxicity?  This question is being addressed by the ongoing ECOG 4151 study, a risk-adapted trial in which post-induction MRD-negative patients are randomized to standard ASCT consolidation plus maintenance rituximab vs maintenance only. 

Bruton tyrosine kinase inhibitors (BTKi) are now among the most used agents for relapsed MCL. Recent clinical trials testing the integration of a BTKi into first- or second-line therapy have shown increased response rates and variable clinical outcomes and toxicities for the combinations, depending upon the chemotherapy- and non-chemotherapy backbones utilized, as well as the BTKi. Combinations with the BCL2 inhibitor venetoclax plus chemotherapy or BTKi are also showing promise.

The activity of BTKi in MCL led the European MCL Network (EMCL) to design the 3-arm TRIANGLE study to analyze the potential of ibrutinib to improve outcomes when given in conjunction with standard ASCT consolidation, and the ability to replace the need for ASCT. The TRIANGLE results were presented by Dr. Martin Dreyling in the Plenary Session at the December 2022 American Society of Hematology (ASH) Annual Meeting. Transplant-eligible MCL patients < 65 years of age were randomized to the EMCL’s established front-line therapy of alternating R-CHOP/R-DHAP plus ASCT; the same regimen plus oral ibrutinib given with the R-CHOP induction cycles and then post-ASCT ibrutinib maintenance therapy for 2 years (Arm A+I); or the A+I regimen minus ASCT (Arm I). Maintenance rituximab was allowed in each arm, on the basis of the treating centers’ institutional guidelines. Overall, 54%-58% of patients in each study arm received rituximab maintenance, with no differential benefit in efficacy noted for those so treated. 

The results showed that 94%-98% of patients responded by the end of induction (defined as R-chemo and ASCT), with complete remissions in 36%-45% (from computerized tomography imaging, not PET scan). With a median follow-up of 31 months, failure-free survival (FFS; the primary study endpoint) was significantly improved for A+I vs A (3 year FFS of 88% vs 72%, respectively; p = 0.0008). In a subgroup analysis, FFS was notably improved for A+I in patients with high-level TP53 overexpression by immunohistochemistry. Toxicity did not differ during the induction and ASCT periods among the 3 arms regarding cytopenia, gastrointestinal disorders, and infections. However, neutropenia and infections were increased in the ibrutinib-containing arms during maintenance therapy—especially for Arm A+I. 

The authors concluded that ASCT plus ibrutinib (Arm A+I) is superior to ASCT only (Arm A), and that Arm A is not superior to ibrutinib without ASCT (Arm I). No decision can yet be made regarding A+I versus I for which FFS to date remains very similar; however, the authors favor ibrutinib without ASCT due to lower toxicity. OS is trending to favor the ibrutinib arms, but longer follow-up will be needed to fully assess.

Should ASCT consolidation now be replaced by ibrutinib-containing induction R-CHOP/R-DHAP and maintenance ibrutinib, with or without maintenance rituximab? A definitive answer will require the fully-published TRIANGLE results, as well as ongoing analysis with longer follow-up. However, it seems very likely that ASCT indeed will be replaced by the new approach. TP53-mutated MCL should be treated with ibrutinib plus R-CHOP/R-DHAP and ibrutinib maintenance as validated in this trial. 

Many centers have begun using a second-generation BTKi, acalabrutinib or zanubrutinib, rather than ibrutinib due to equivalent response rates with more favorable side effect profiles and fewer treatment discontinuations. Caution is warranted regarding simply adding a BTKi to one’s favored MCL induction regimen and foregoing ASCT—pending additional studies and the safety of such alternative approaches. 

These are indeed exciting times of therapeutic progress, as they have been improving outcomes and providing longer survival outcomes for MCL patients. Targeted agents facilitate this shift to less intensive and chemotherapy-free regimens that provide enhanced response and mitigate short- and longer-term toxicities. More results will be forthcoming for MRD as a treatment endpoint, guiding maintenance therapy, and for risk-adapted treatment of newly-diagnosed and relapsing patients (based upon MCL subtype and biomarker profiles). Enrolling patients into clinical trials is strongly encouraged as the best mechanism to help answer emerging questions in the field and open the pathway to continued progress.

Mantle cell lymphoma (MCL) has served as a paradigm of progress among the non-Hodgkin lymphomas over the past 30 years. It was originally defined within the Kiel classification as centrocytic lymphoma, then renamed MCL once the characteristic translocation and resulting cyclin D1 overexpression were identified. These diagnostic markers allowed for the characterization of MCL subtypes as well as the initiation of MCL-focused clinical trials which, in turn, led to regulatory approval of more effective regimens, new therapeutic agents, and an improvement in overall survival (OS) from around 3 years to more than 10 years for many patients.

Despite this progress, virtually all patients relapse, and a cure remains elusive for most. In younger (< 65 to 70 years), medically-fit patients who are transplant-eligible and have symptomatic MCL, a standard of care has been induction chemoimmunotherapy containing high-dose cytarabine followed by ASCT consolidation. For example, a clinical trial of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) alternating with R-DHAP (rituximab, dexamethasone, high-dose cytarabine, cisplatin; 3 cycles each) showed a significant benefit over R-CHOP x 6 cycles; at a median follow-up of 10.6 years, the time-to-treatment failure was 8.4 v 3.9 years. In another trial, all patients received induction R-DHAP (with cisplatin or an alternative platinum agent) x 4 cycles followed by ASCT. Those patients randomized to post-ASCT maintenance rituximab for 3 years had significantly improved, 4-year progression-free survival (PFS) as compared with observation only (83% vs 64%, p < 0.001); maintenance also significantly improved OS. 

Although ASCT consolidation followed by maintenance became widely adopted on the basis of these and other clinical trials, important questions remain:

• First, MCL is biologically and clinically quite heterogeneous. Several prognostic tools such as the MCL International Prognostic Index (MIPI) scoring system and biomarkers are available to define lower- versus higher-risk subtypes, but none is routinely used for treatment planning. About 15% of MCL patients present with a highly-aggressive blastoid or pleomorphic variant that usually carries a TP53 mutation or deletion. Given the short survival and limited benefit from dose-intensive chemotherapy and ASCT in TP53-mutated MCL, should transplant be avoided in these patients?    

• Second, if deep remission is achieved following front-line therapy, defined as positron emission tomography (PET) negative and measurable residual disease (MRD) negative, will high-dose chemotherapy and ASCT provide additional benefits or only toxicity?  This question is being addressed by the ongoing ECOG 4151 study, a risk-adapted trial in which post-induction MRD-negative patients are randomized to standard ASCT consolidation plus maintenance rituximab vs maintenance only. 

Bruton tyrosine kinase inhibitors (BTKi) are now among the most used agents for relapsed MCL. Recent clinical trials testing the integration of a BTKi into first- or second-line therapy have shown increased response rates and variable clinical outcomes and toxicities for the combinations, depending upon the chemotherapy- and non-chemotherapy backbones utilized, as well as the BTKi. Combinations with the BCL2 inhibitor venetoclax plus chemotherapy or BTKi are also showing promise.

The activity of BTKi in MCL led the European MCL Network (EMCL) to design the 3-arm TRIANGLE study to analyze the potential of ibrutinib to improve outcomes when given in conjunction with standard ASCT consolidation, and the ability to replace the need for ASCT. The TRIANGLE results were presented by Dr. Martin Dreyling in the Plenary Session at the December 2022 American Society of Hematology (ASH) Annual Meeting. Transplant-eligible MCL patients < 65 years of age were randomized to the EMCL’s established front-line therapy of alternating R-CHOP/R-DHAP plus ASCT; the same regimen plus oral ibrutinib given with the R-CHOP induction cycles and then post-ASCT ibrutinib maintenance therapy for 2 years (Arm A+I); or the A+I regimen minus ASCT (Arm I). Maintenance rituximab was allowed in each arm, on the basis of the treating centers’ institutional guidelines. Overall, 54%-58% of patients in each study arm received rituximab maintenance, with no differential benefit in efficacy noted for those so treated. 

The results showed that 94%-98% of patients responded by the end of induction (defined as R-chemo and ASCT), with complete remissions in 36%-45% (from computerized tomography imaging, not PET scan). With a median follow-up of 31 months, failure-free survival (FFS; the primary study endpoint) was significantly improved for A+I vs A (3 year FFS of 88% vs 72%, respectively; p = 0.0008). In a subgroup analysis, FFS was notably improved for A+I in patients with high-level TP53 overexpression by immunohistochemistry. Toxicity did not differ during the induction and ASCT periods among the 3 arms regarding cytopenia, gastrointestinal disorders, and infections. However, neutropenia and infections were increased in the ibrutinib-containing arms during maintenance therapy—especially for Arm A+I. 

The authors concluded that ASCT plus ibrutinib (Arm A+I) is superior to ASCT only (Arm A), and that Arm A is not superior to ibrutinib without ASCT (Arm I). No decision can yet be made regarding A+I versus I for which FFS to date remains very similar; however, the authors favor ibrutinib without ASCT due to lower toxicity. OS is trending to favor the ibrutinib arms, but longer follow-up will be needed to fully assess.

Should ASCT consolidation now be replaced by ibrutinib-containing induction R-CHOP/R-DHAP and maintenance ibrutinib, with or without maintenance rituximab? A definitive answer will require the fully-published TRIANGLE results, as well as ongoing analysis with longer follow-up. However, it seems very likely that ASCT indeed will be replaced by the new approach. TP53-mutated MCL should be treated with ibrutinib plus R-CHOP/R-DHAP and ibrutinib maintenance as validated in this trial. 

Many centers have begun using a second-generation BTKi, acalabrutinib or zanubrutinib, rather than ibrutinib due to equivalent response rates with more favorable side effect profiles and fewer treatment discontinuations. Caution is warranted regarding simply adding a BTKi to one’s favored MCL induction regimen and foregoing ASCT—pending additional studies and the safety of such alternative approaches. 

These are indeed exciting times of therapeutic progress, as they have been improving outcomes and providing longer survival outcomes for MCL patients. Targeted agents facilitate this shift to less intensive and chemotherapy-free regimens that provide enhanced response and mitigate short- and longer-term toxicities. More results will be forthcoming for MRD as a treatment endpoint, guiding maintenance therapy, and for risk-adapted treatment of newly-diagnosed and relapsing patients (based upon MCL subtype and biomarker profiles). Enrolling patients into clinical trials is strongly encouraged as the best mechanism to help answer emerging questions in the field and open the pathway to continued progress.

Mantle cell lymphoma (MCL) has served as a paradigm of progress among the non-Hodgkin lymphomas over the past 30 years. It was originally defined within the Kiel classification as centrocytic lymphoma, then renamed MCL once the characteristic translocation and resulting cyclin D1 overexpression were identified. These diagnostic markers allowed for the characterization of MCL subtypes as well as the initiation of MCL-focused clinical trials which, in turn, led to regulatory approval of more effective regimens, new therapeutic agents, and an improvement in overall survival (OS) from around 3 years to more than 10 years for many patients.

Despite this progress, virtually all patients relapse, and a cure remains elusive for most. In younger (< 65 to 70 years), medically-fit patients who are transplant-eligible and have symptomatic MCL, a standard of care has been induction chemoimmunotherapy containing high-dose cytarabine followed by ASCT consolidation. For example, a clinical trial of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) alternating with R-DHAP (rituximab, dexamethasone, high-dose cytarabine, cisplatin; 3 cycles each) showed a significant benefit over R-CHOP x 6 cycles; at a median follow-up of 10.6 years, the time-to-treatment failure was 8.4 v 3.9 years. In another trial, all patients received induction R-DHAP (with cisplatin or an alternative platinum agent) x 4 cycles followed by ASCT. Those patients randomized to post-ASCT maintenance rituximab for 3 years had significantly improved, 4-year progression-free survival (PFS) as compared with observation only (83% vs 64%, p < 0.001); maintenance also significantly improved OS. 

Although ASCT consolidation followed by maintenance became widely adopted on the basis of these and other clinical trials, important questions remain:

• First, MCL is biologically and clinically quite heterogeneous. Several prognostic tools such as the MCL International Prognostic Index (MIPI) scoring system and biomarkers are available to define lower- versus higher-risk subtypes, but none is routinely used for treatment planning. About 15% of MCL patients present with a highly-aggressive blastoid or pleomorphic variant that usually carries a TP53 mutation or deletion. Given the short survival and limited benefit from dose-intensive chemotherapy and ASCT in TP53-mutated MCL, should transplant be avoided in these patients?    

• Second, if deep remission is achieved following front-line therapy, defined as positron emission tomography (PET) negative and measurable residual disease (MRD) negative, will high-dose chemotherapy and ASCT provide additional benefits or only toxicity?  This question is being addressed by the ongoing ECOG 4151 study, a risk-adapted trial in which post-induction MRD-negative patients are randomized to standard ASCT consolidation plus maintenance rituximab vs maintenance only. 

Bruton tyrosine kinase inhibitors (BTKi) are now among the most used agents for relapsed MCL. Recent clinical trials testing the integration of a BTKi into first- or second-line therapy have shown increased response rates and variable clinical outcomes and toxicities for the combinations, depending upon the chemotherapy- and non-chemotherapy backbones utilized, as well as the BTKi. Combinations with the BCL2 inhibitor venetoclax plus chemotherapy or BTKi are also showing promise.

The activity of BTKi in MCL led the European MCL Network (EMCL) to design the 3-arm TRIANGLE study to analyze the potential of ibrutinib to improve outcomes when given in conjunction with standard ASCT consolidation, and the ability to replace the need for ASCT. The TRIANGLE results were presented by Dr. Martin Dreyling in the Plenary Session at the December 2022 American Society of Hematology (ASH) Annual Meeting. Transplant-eligible MCL patients < 65 years of age were randomized to the EMCL’s established front-line therapy of alternating R-CHOP/R-DHAP plus ASCT; the same regimen plus oral ibrutinib given with the R-CHOP induction cycles and then post-ASCT ibrutinib maintenance therapy for 2 years (Arm A+I); or the A+I regimen minus ASCT (Arm I). Maintenance rituximab was allowed in each arm, on the basis of the treating centers’ institutional guidelines. Overall, 54%-58% of patients in each study arm received rituximab maintenance, with no differential benefit in efficacy noted for those so treated. 

The results showed that 94%-98% of patients responded by the end of induction (defined as R-chemo and ASCT), with complete remissions in 36%-45% (from computerized tomography imaging, not PET scan). With a median follow-up of 31 months, failure-free survival (FFS; the primary study endpoint) was significantly improved for A+I vs A (3 year FFS of 88% vs 72%, respectively; p = 0.0008). In a subgroup analysis, FFS was notably improved for A+I in patients with high-level TP53 overexpression by immunohistochemistry. Toxicity did not differ during the induction and ASCT periods among the 3 arms regarding cytopenia, gastrointestinal disorders, and infections. However, neutropenia and infections were increased in the ibrutinib-containing arms during maintenance therapy—especially for Arm A+I. 

The authors concluded that ASCT plus ibrutinib (Arm A+I) is superior to ASCT only (Arm A), and that Arm A is not superior to ibrutinib without ASCT (Arm I). No decision can yet be made regarding A+I versus I for which FFS to date remains very similar; however, the authors favor ibrutinib without ASCT due to lower toxicity. OS is trending to favor the ibrutinib arms, but longer follow-up will be needed to fully assess.

Should ASCT consolidation now be replaced by ibrutinib-containing induction R-CHOP/R-DHAP and maintenance ibrutinib, with or without maintenance rituximab? A definitive answer will require the fully-published TRIANGLE results, as well as ongoing analysis with longer follow-up. However, it seems very likely that ASCT indeed will be replaced by the new approach. TP53-mutated MCL should be treated with ibrutinib plus R-CHOP/R-DHAP and ibrutinib maintenance as validated in this trial. 

Many centers have begun using a second-generation BTKi, acalabrutinib or zanubrutinib, rather than ibrutinib due to equivalent response rates with more favorable side effect profiles and fewer treatment discontinuations. Caution is warranted regarding simply adding a BTKi to one’s favored MCL induction regimen and foregoing ASCT—pending additional studies and the safety of such alternative approaches. 

These are indeed exciting times of therapeutic progress, as they have been improving outcomes and providing longer survival outcomes for MCL patients. Targeted agents facilitate this shift to less intensive and chemotherapy-free regimens that provide enhanced response and mitigate short- and longer-term toxicities. More results will be forthcoming for MRD as a treatment endpoint, guiding maintenance therapy, and for risk-adapted treatment of newly-diagnosed and relapsing patients (based upon MCL subtype and biomarker profiles). Enrolling patients into clinical trials is strongly encouraged as the best mechanism to help answer emerging questions in the field and open the pathway to continued progress.

Psoriatic arthritis (PsA) is a heterogenous inflammatory disease that may involve several different domains, including peripheral joints, entheses, nails, axial skeleton, and skin. A recent increased awareness of PsA has accompanied a large increase in available therapeutic options. In addition to traditional disease-modifying antirheumatic drugs (DMARDs), new biologics and targeted small molecules have now been shown to be effective in PsA. These agents include those targeting pathways involving tumor necrosis factor (TNF), cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), interleukins (IL) 12, 17, 23, janus kinase (JAK), and phosphodiesterase 4 (PDE4). These agents have demonstrated efficacy in outcome measures developed for peripheral arthritis, such as the American College of Rheumatology 20 (ACR20) response. However, an ongoing question is whether these agents are equally effective in axial disease. Based on our experience and the existing literature, we believe that some of these agents, including PDE4 and IL-23 inhibitors, are not effective for axial disease. 

Moll and Wright’s original description of PsA estimated that 5% of patients with PsA had axial disease¹; however, they were describing patients in whom axial arthritis was the predominant, or the only, manifestation. There are many patients for whom axial symptoms are just one of several domains of disease activity. With this in mind, and depending on the cohort studied, the estimated overall prevalence of axial disease ranges from 7% to 32% in patients with PsA.² This is in contrast to peripheral arthritis, a domain that occurs in most patients with PsA and is the most common manifestation of PsA.² We believe there are differences in axial and peripheral response among some of the drugs used to treat PsA; therefore it is critical to consider both the presence and magnitude of axial involvement.  

An absence of axial PsA–specific clinical trials complicates navigating this treatment domain. Most considerations regarding treatment options for axial disease in PsA are extrapolated from ankylosing spondylitis (AS) trials and experience, as is the case for the TNF and JAK inhibitors. To our knowledge, only one high-quality randomized trial, MAXIMISE, looked specifically at the treatment of axial PsA, in this case with the IL-17 inhibitor secukinumab.³ This trial demonstrated efficacy of secukinumab in reducing symptoms and acute phase reactants in patients with PsA who were categorized as having active axial disease using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Other than conclusions drawn from AS trials and from this single axial PsA randomized controlled trial, data on the treatment of axial PsA are drawn entirely from observational and post-hoc analyses. As there are no consensus criteria for axial PsA, the cohorts included in these data may vary. This heterogeneity showcases the diversity in patients with PsA with axial disease but complicates the generalizability of the findings to individual patients. 

Another challenge in understanding axial response to medication is the lack of specific, validated outcome measures for axial PsA. The BASDAI and, more recently, the Assessment in Ankylosing Spondylitis (ASAS) and the Ankylosing Spondylitis Disease Activity Score (ASDAS), all developed specifically for AS, are often used to measure treatment response. The BASDAI incorporates patient-reported symptoms which include fatigue, peripheral joint pain/swelling, tenderness, and morning stiffness not specifically localized to the back. The ASDAS also includes a C-reactive protein measurement.

When used to assess response in PsA, however, these patient-reported outcomes may not be precise enough to separate the impact of axial disease or symptoms from that of peripheral disease. Only question 2 on the BASDAI specifically addresses axial complaints: “How would you describe the overall level of AS-related pain you have had in your neck, back, or hips?” Even this question is vulnerable to confounding from noninflammatory causes of back pain. Although these issues exist with patient-reported outcomes, objective spinal mobility measures used in evaluation of AS, including the modified Schober test, lumbar side flexion, and cervical rotation, have been demonstrated also to perform well in axial PsA.⁴ 

This was corroborated in the INSPIRE study, which showed adequate interobserver reliability in primary AS that was equally reproducible in axial PsA, with most measures, including occiput to wall, modified Schober test, cervical rotation, lateral bending, and hip mobility, performing in a “good to excellent” manner.⁵ Therefore, the inclusion of these objective measures in future therapeutic studies may enhance the external validation of available data. 

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) has established therapeutic guidelines for psoriatic disease based on currently available literature and data. Similar to previous iterations of guidelines, GRAPPA continues to recommend agents with TNF inhibition or IL-17 inhibition for patients with PsA with axial disease who have failed conservative therapy with nonsteroidal anti-inflammatory drugs (NSAIDs), physical therapy, and/or glucocorticoid injections. Newly recommended in the latest iteration of the GRAPPA guidelines, based on the efficacy of these agents in AS, is the use of JAK inhibitors for axial PsA.⁶ 

Although TNF, IL-17, and JAK targeted therapies have demonstrated more likely benefit, albeit subject to the trial limitations previously discussed, the question remains whether agents targeting PDE4 and IL-23 are an effective option for axial PsA. Studies of both PDE4 and IL-23 inhibitors in AS have not demonstrated adequate benefit, which, importantly, contrasts with the previously mentioned and recommended therapies. Additionally, there are no primary randomized control trials that have directly evaluated the efficacy of IL-23 therapy in axial PsA. 

Existing data about potential benefit come from post-hoc analyses of the PSUMMIT 1 and 2 trials^7-10 with ustekinumab (which inhibits IL-12 and IL-23) and the DISCOVER trials^11-13 with guselkumab (a pure IL-23 inhibitor). However, these analyses relied on a physician-reported diagnosis of axial disease and not on prespecified entry criteria. This lack of uniform diagnostic criteria may introduce bias into the interpretation of the results and limit external validation. All patients in these trials had a significant burden of peripheral arthritis; therefore it is hard to know whether, even in patients with physician-reported axial disease, improvement in general outcome measures were due to true amelioration of axial disease or were confounded by improvement in peripheral and skin domains. The analysis of these trials did look specifically at patient answers to BASDAI question 2 regarding level of neck, back, or hip pain. However, it remains difficult to be certain that the results are truly a reflection of axial symptoms and are not driven by patient-perceived improvement in other disease domains and an overall positive trajectory in well-being. 

In our years of practice, when we turned to biologic agents, the IL-23 inhibitors and the IL-12/23 inhibitor have not been as effective in patients with PsA who have axial-predominant symptoms. The lack of efficacy of these agents in AS, in contrast to their benefit in psoriatic skin and peripheral joint disease, raises questions about the pathophysiologic role of IL-23 in axial disease, which is yet to be fully understood. For patients with a significant burden of axial pain, in concordance with the consensus from GRAPPA,⁶ our strategy is to start with TNF, IL-17, or JAK targeted therapies, with the choice based on patient-specific factors, including patient comorbidities, patient administration preference, and insurance coverage. We do believe it is reasonable to try IL-23–targeted therapies in patients who have mild axial symptoms when their predominant symptoms are in other domains, such as the peripheral joints or skin. In our opinion, more convincing data supporting IL-23 inhibition are required to move this into the forefront of axial-predominant PsA therapy. Clearly the investigation of axial disease in PsA lags behind that of peripheral and skin domains. Specific classification criteria for axial PsA, as are being currently developed by GRAPPA, should facilitate more focused therapeutic trials that can better inform optimal treatment of patients with this subset of disease. 

Psoriatic arthritis (PsA) is a heterogenous inflammatory disease that may involve several different domains, including peripheral joints, entheses, nails, axial skeleton, and skin. A recent increased awareness of PsA has accompanied a large increase in available therapeutic options. In addition to traditional disease-modifying antirheumatic drugs (DMARDs), new biologics and targeted small molecules have now been shown to be effective in PsA. These agents include those targeting pathways involving tumor necrosis factor (TNF), cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), interleukins (IL) 12, 17, 23, janus kinase (JAK), and phosphodiesterase 4 (PDE4). These agents have demonstrated efficacy in outcome measures developed for peripheral arthritis, such as the American College of Rheumatology 20 (ACR20) response. However, an ongoing question is whether these agents are equally effective in axial disease. Based on our experience and the existing literature, we believe that some of these agents, including PDE4 and IL-23 inhibitors, are not effective for axial disease. 

Moll and Wright’s original description of PsA estimated that 5% of patients with PsA had axial disease¹; however, they were describing patients in whom axial arthritis was the predominant, or the only, manifestation. There are many patients for whom axial symptoms are just one of several domains of disease activity. With this in mind, and depending on the cohort studied, the estimated overall prevalence of axial disease ranges from 7% to 32% in patients with PsA.² This is in contrast to peripheral arthritis, a domain that occurs in most patients with PsA and is the most common manifestation of PsA.² We believe there are differences in axial and peripheral response among some of the drugs used to treat PsA; therefore it is critical to consider both the presence and magnitude of axial involvement.  

An absence of axial PsA–specific clinical trials complicates navigating this treatment domain. Most considerations regarding treatment options for axial disease in PsA are extrapolated from ankylosing spondylitis (AS) trials and experience, as is the case for the TNF and JAK inhibitors. To our knowledge, only one high-quality randomized trial, MAXIMISE, looked specifically at the treatment of axial PsA, in this case with the IL-17 inhibitor secukinumab.³ This trial demonstrated efficacy of secukinumab in reducing symptoms and acute phase reactants in patients with PsA who were categorized as having active axial disease using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Other than conclusions drawn from AS trials and from this single axial PsA randomized controlled trial, data on the treatment of axial PsA are drawn entirely from observational and post-hoc analyses. As there are no consensus criteria for axial PsA, the cohorts included in these data may vary. This heterogeneity showcases the diversity in patients with PsA with axial disease but complicates the generalizability of the findings to individual patients. 

Another challenge in understanding axial response to medication is the lack of specific, validated outcome measures for axial PsA. The BASDAI and, more recently, the Assessment in Ankylosing Spondylitis (ASAS) and the Ankylosing Spondylitis Disease Activity Score (ASDAS), all developed specifically for AS, are often used to measure treatment response. The BASDAI incorporates patient-reported symptoms which include fatigue, peripheral joint pain/swelling, tenderness, and morning stiffness not specifically localized to the back. The ASDAS also includes a C-reactive protein measurement.

When used to assess response in PsA, however, these patient-reported outcomes may not be precise enough to separate the impact of axial disease or symptoms from that of peripheral disease. Only question 2 on the BASDAI specifically addresses axial complaints: “How would you describe the overall level of AS-related pain you have had in your neck, back, or hips?” Even this question is vulnerable to confounding from noninflammatory causes of back pain. Although these issues exist with patient-reported outcomes, objective spinal mobility measures used in evaluation of AS, including the modified Schober test, lumbar side flexion, and cervical rotation, have been demonstrated also to perform well in axial PsA.⁴ 

This was corroborated in the INSPIRE study, which showed adequate interobserver reliability in primary AS that was equally reproducible in axial PsA, with most measures, including occiput to wall, modified Schober test, cervical rotation, lateral bending, and hip mobility, performing in a “good to excellent” manner.⁵ Therefore, the inclusion of these objective measures in future therapeutic studies may enhance the external validation of available data. 

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) has established therapeutic guidelines for psoriatic disease based on currently available literature and data. Similar to previous iterations of guidelines, GRAPPA continues to recommend agents with TNF inhibition or IL-17 inhibition for patients with PsA with axial disease who have failed conservative therapy with nonsteroidal anti-inflammatory drugs (NSAIDs), physical therapy, and/or glucocorticoid injections. Newly recommended in the latest iteration of the GRAPPA guidelines, based on the efficacy of these agents in AS, is the use of JAK inhibitors for axial PsA.⁶ 

Although TNF, IL-17, and JAK targeted therapies have demonstrated more likely benefit, albeit subject to the trial limitations previously discussed, the question remains whether agents targeting PDE4 and IL-23 are an effective option for axial PsA. Studies of both PDE4 and IL-23 inhibitors in AS have not demonstrated adequate benefit, which, importantly, contrasts with the previously mentioned and recommended therapies. Additionally, there are no primary randomized control trials that have directly evaluated the efficacy of IL-23 therapy in axial PsA. 

Existing data about potential benefit come from post-hoc analyses of the PSUMMIT 1 and 2 trials^7-10 with ustekinumab (which inhibits IL-12 and IL-23) and the DISCOVER trials^11-13 with guselkumab (a pure IL-23 inhibitor). However, these analyses relied on a physician-reported diagnosis of axial disease and not on prespecified entry criteria. This lack of uniform diagnostic criteria may introduce bias into the interpretation of the results and limit external validation. All patients in these trials had a significant burden of peripheral arthritis; therefore it is hard to know whether, even in patients with physician-reported axial disease, improvement in general outcome measures were due to true amelioration of axial disease or were confounded by improvement in peripheral and skin domains. The analysis of these trials did look specifically at patient answers to BASDAI question 2 regarding level of neck, back, or hip pain. However, it remains difficult to be certain that the results are truly a reflection of axial symptoms and are not driven by patient-perceived improvement in other disease domains and an overall positive trajectory in well-being. 

In our years of practice, when we turned to biologic agents, the IL-23 inhibitors and the IL-12/23 inhibitor have not been as effective in patients with PsA who have axial-predominant symptoms. The lack of efficacy of these agents in AS, in contrast to their benefit in psoriatic skin and peripheral joint disease, raises questions about the pathophysiologic role of IL-23 in axial disease, which is yet to be fully understood. For patients with a significant burden of axial pain, in concordance with the consensus from GRAPPA,⁶ our strategy is to start with TNF, IL-17, or JAK targeted therapies, with the choice based on patient-specific factors, including patient comorbidities, patient administration preference, and insurance coverage. We do believe it is reasonable to try IL-23–targeted therapies in patients who have mild axial symptoms when their predominant symptoms are in other domains, such as the peripheral joints or skin. In our opinion, more convincing data supporting IL-23 inhibition are required to move this into the forefront of axial-predominant PsA therapy. Clearly the investigation of axial disease in PsA lags behind that of peripheral and skin domains. Specific classification criteria for axial PsA, as are being currently developed by GRAPPA, should facilitate more focused therapeutic trials that can better inform optimal treatment of patients with this subset of disease. 

Psoriatic arthritis (PsA) is a heterogenous inflammatory disease that may involve several different domains, including peripheral joints, entheses, nails, axial skeleton, and skin. A recent increased awareness of PsA has accompanied a large increase in available therapeutic options. In addition to traditional disease-modifying antirheumatic drugs (DMARDs), new biologics and targeted small molecules have now been shown to be effective in PsA. These agents include those targeting pathways involving tumor necrosis factor (TNF), cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), interleukins (IL) 12, 17, 23, janus kinase (JAK), and phosphodiesterase 4 (PDE4). These agents have demonstrated efficacy in outcome measures developed for peripheral arthritis, such as the American College of Rheumatology 20 (ACR20) response. However, an ongoing question is whether these agents are equally effective in axial disease. Based on our experience and the existing literature, we believe that some of these agents, including PDE4 and IL-23 inhibitors, are not effective for axial disease. 

Moll and Wright’s original description of PsA estimated that 5% of patients with PsA had axial disease¹; however, they were describing patients in whom axial arthritis was the predominant, or the only, manifestation. There are many patients for whom axial symptoms are just one of several domains of disease activity. With this in mind, and depending on the cohort studied, the estimated overall prevalence of axial disease ranges from 7% to 32% in patients with PsA.² This is in contrast to peripheral arthritis, a domain that occurs in most patients with PsA and is the most common manifestation of PsA.² We believe there are differences in axial and peripheral response among some of the drugs used to treat PsA; therefore it is critical to consider both the presence and magnitude of axial involvement.  

An absence of axial PsA–specific clinical trials complicates navigating this treatment domain. Most considerations regarding treatment options for axial disease in PsA are extrapolated from ankylosing spondylitis (AS) trials and experience, as is the case for the TNF and JAK inhibitors. To our knowledge, only one high-quality randomized trial, MAXIMISE, looked specifically at the treatment of axial PsA, in this case with the IL-17 inhibitor secukinumab.³ This trial demonstrated efficacy of secukinumab in reducing symptoms and acute phase reactants in patients with PsA who were categorized as having active axial disease using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Other than conclusions drawn from AS trials and from this single axial PsA randomized controlled trial, data on the treatment of axial PsA are drawn entirely from observational and post-hoc analyses. As there are no consensus criteria for axial PsA, the cohorts included in these data may vary. This heterogeneity showcases the diversity in patients with PsA with axial disease but complicates the generalizability of the findings to individual patients. 

Another challenge in understanding axial response to medication is the lack of specific, validated outcome measures for axial PsA. The BASDAI and, more recently, the Assessment in Ankylosing Spondylitis (ASAS) and the Ankylosing Spondylitis Disease Activity Score (ASDAS), all developed specifically for AS, are often used to measure treatment response. The BASDAI incorporates patient-reported symptoms which include fatigue, peripheral joint pain/swelling, tenderness, and morning stiffness not specifically localized to the back. The ASDAS also includes a C-reactive protein measurement.

When used to assess response in PsA, however, these patient-reported outcomes may not be precise enough to separate the impact of axial disease or symptoms from that of peripheral disease. Only question 2 on the BASDAI specifically addresses axial complaints: “How would you describe the overall level of AS-related pain you have had in your neck, back, or hips?” Even this question is vulnerable to confounding from noninflammatory causes of back pain. Although these issues exist with patient-reported outcomes, objective spinal mobility measures used in evaluation of AS, including the modified Schober test, lumbar side flexion, and cervical rotation, have been demonstrated also to perform well in axial PsA.⁴ 

This was corroborated in the INSPIRE study, which showed adequate interobserver reliability in primary AS that was equally reproducible in axial PsA, with most measures, including occiput to wall, modified Schober test, cervical rotation, lateral bending, and hip mobility, performing in a “good to excellent” manner.⁵ Therefore, the inclusion of these objective measures in future therapeutic studies may enhance the external validation of available data. 

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) has established therapeutic guidelines for psoriatic disease based on currently available literature and data. Similar to previous iterations of guidelines, GRAPPA continues to recommend agents with TNF inhibition or IL-17 inhibition for patients with PsA with axial disease who have failed conservative therapy with nonsteroidal anti-inflammatory drugs (NSAIDs), physical therapy, and/or glucocorticoid injections. Newly recommended in the latest iteration of the GRAPPA guidelines, based on the efficacy of these agents in AS, is the use of JAK inhibitors for axial PsA.⁶ 

Although TNF, IL-17, and JAK targeted therapies have demonstrated more likely benefit, albeit subject to the trial limitations previously discussed, the question remains whether agents targeting PDE4 and IL-23 are an effective option for axial PsA. Studies of both PDE4 and IL-23 inhibitors in AS have not demonstrated adequate benefit, which, importantly, contrasts with the previously mentioned and recommended therapies. Additionally, there are no primary randomized control trials that have directly evaluated the efficacy of IL-23 therapy in axial PsA. 

Existing data about potential benefit come from post-hoc analyses of the PSUMMIT 1 and 2 trials^7-10 with ustekinumab (which inhibits IL-12 and IL-23) and the DISCOVER trials^11-13 with guselkumab (a pure IL-23 inhibitor). However, these analyses relied on a physician-reported diagnosis of axial disease and not on prespecified entry criteria. This lack of uniform diagnostic criteria may introduce bias into the interpretation of the results and limit external validation. All patients in these trials had a significant burden of peripheral arthritis; therefore it is hard to know whether, even in patients with physician-reported axial disease, improvement in general outcome measures were due to true amelioration of axial disease or were confounded by improvement in peripheral and skin domains. The analysis of these trials did look specifically at patient answers to BASDAI question 2 regarding level of neck, back, or hip pain. However, it remains difficult to be certain that the results are truly a reflection of axial symptoms and are not driven by patient-perceived improvement in other disease domains and an overall positive trajectory in well-being. 

In our years of practice, when we turned to biologic agents, the IL-23 inhibitors and the IL-12/23 inhibitor have not been as effective in patients with PsA who have axial-predominant symptoms. The lack of efficacy of these agents in AS, in contrast to their benefit in psoriatic skin and peripheral joint disease, raises questions about the pathophysiologic role of IL-23 in axial disease, which is yet to be fully understood. For patients with a significant burden of axial pain, in concordance with the consensus from GRAPPA,⁶ our strategy is to start with TNF, IL-17, or JAK targeted therapies, with the choice based on patient-specific factors, including patient comorbidities, patient administration preference, and insurance coverage. We do believe it is reasonable to try IL-23–targeted therapies in patients who have mild axial symptoms when their predominant symptoms are in other domains, such as the peripheral joints or skin. In our opinion, more convincing data supporting IL-23 inhibition are required to move this into the forefront of axial-predominant PsA therapy. Clearly the investigation of axial disease in PsA lags behind that of peripheral and skin domains. Specific classification criteria for axial PsA, as are being currently developed by GRAPPA, should facilitate more focused therapeutic trials that can better inform optimal treatment of patients with this subset of disease. 

Spinal muscular atrophy (SMA) is a hereditary neuromuscular disease that typically begins in infancy or childhood but can manifest at any age. 

It is characterized by the irreversible and progressive degeneration of motor neurons in the spinal cord and brainstem. This results in a wide range of symptoms, in addition to which there is substantial variation in the rate of progression and disease prognosis. 

Although early diagnosis and timely therapy can slow or prevent disease progression, disease-modifying therapies since 2016 have significantly advanced the management of SMA. 

In a clinically focused program, Dr Perry Shieh, a neuromuscular neurologist from the University of California, Los Angeles, discusses the three medications currently approved by the US Food and Drug Administration: nusinersen, risdiplam, and onasemnogene abeparvovec. 

He weighs the clinical benefits and key considerations for the use of each drug and emphasizes the need for shared decision-making with the patient. 

--

Professor, Departments of Neurology and Pediatrics, University of California, Los Angeles; Neuromuscular Neurologist, Ronald Reagan UCLA Medical Center, Los Angeles, California 

Perry Shieh, MD, PhD, has disclosed the following relevant financial relationships: 

Serve(d) as a speaker or a member of a speakers bureau for: Grifolis; Biogen; Genentech; CSL Behring; Alexion; Argenx; Catalyst 

Received income in an amount equal to or greater than $250 from: Sarepta; Novartis; Biogen; Genentech; Alexion; Argenx; Catalyst; UCB 

Spinal muscular atrophy (SMA) is a hereditary neuromuscular disease that typically begins in infancy or childhood but can manifest at any age. 

It is characterized by the irreversible and progressive degeneration of motor neurons in the spinal cord and brainstem. This results in a wide range of symptoms, in addition to which there is substantial variation in the rate of progression and disease prognosis. 

Although early diagnosis and timely therapy can slow or prevent disease progression, disease-modifying therapies since 2016 have significantly advanced the management of SMA. 

In a clinically focused program, Dr Perry Shieh, a neuromuscular neurologist from the University of California, Los Angeles, discusses the three medications currently approved by the US Food and Drug Administration: nusinersen, risdiplam, and onasemnogene abeparvovec. 

He weighs the clinical benefits and key considerations for the use of each drug and emphasizes the need for shared decision-making with the patient. 

--

Professor, Departments of Neurology and Pediatrics, University of California, Los Angeles; Neuromuscular Neurologist, Ronald Reagan UCLA Medical Center, Los Angeles, California 

Perry Shieh, MD, PhD, has disclosed the following relevant financial relationships: 

Serve(d) as a speaker or a member of a speakers bureau for: Grifolis; Biogen; Genentech; CSL Behring; Alexion; Argenx; Catalyst 

Received income in an amount equal to or greater than $250 from: Sarepta; Novartis; Biogen; Genentech; Alexion; Argenx; Catalyst; UCB 

Spinal muscular atrophy (SMA) is a hereditary neuromuscular disease that typically begins in infancy or childhood but can manifest at any age. 

It is characterized by the irreversible and progressive degeneration of motor neurons in the spinal cord and brainstem. This results in a wide range of symptoms, in addition to which there is substantial variation in the rate of progression and disease prognosis. 

Although early diagnosis and timely therapy can slow or prevent disease progression, disease-modifying therapies since 2016 have significantly advanced the management of SMA. 

In a clinically focused program, Dr Perry Shieh, a neuromuscular neurologist from the University of California, Los Angeles, discusses the three medications currently approved by the US Food and Drug Administration: nusinersen, risdiplam, and onasemnogene abeparvovec. 

He weighs the clinical benefits and key considerations for the use of each drug and emphasizes the need for shared decision-making with the patient. 

--

Professor, Departments of Neurology and Pediatrics, University of California, Los Angeles; Neuromuscular Neurologist, Ronald Reagan UCLA Medical Center, Los Angeles, California 

Perry Shieh, MD, PhD, has disclosed the following relevant financial relationships: 

Serve(d) as a speaker or a member of a speakers bureau for: Grifolis; Biogen; Genentech; CSL Behring; Alexion; Argenx; Catalyst 

Received income in an amount equal to or greater than $250 from: Sarepta; Novartis; Biogen; Genentech; Alexion; Argenx; Catalyst; UCB 

Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma characterized by the proliferation of CD5-positive B cells within the mantle zone that surrounds normal germinal center follicles. MCL is a rare disease that most commonly presents in adult men (male to female ratio > 2:1) in the fifth and sixth decades of life. Individuals diagnosed with MCL typically present with constitutional symptoms, such as weight loss, night sweats, persistent fever, and fatigue. Approximately 25% of cases present with extranodal involvement with the bone marrow; peripheral blood and gastrointestinal tract are most often involved. In patients with extensive node involvement in the gastrointestinal tract, additional symptoms at presentation often include abdominal pain, abdominal fullness, and bloating. Skin involvement in MCL is rare and usually indicates widespread disease. 

According to the guidelines of the World Health Organization–European Organization for Research and Treatment of Cancer, a diagnosis of MCL is established on the basis of the morphologic examination findings and immunophenotyping. 

Immunohistochemically, expression of cyclin D1 in normal lymphoid cells is very low and often undetectable; only hairy cell leukemia shows moderate expression of cyclin D1. Therefore, positive immunohistochemistry for cyclin D1 is pathognomonic for MCL. Increased expression of cyclin D1 protein leads to dysregulation of the cell cycle and stimulates uncontrolled cell proliferation. It is also indirect evidence of the chromosomal translocation (11;14)(q13;q32) on the CCND1 gene, which is detected in 95% of cases of MCL. In addition, negative expression of antigens may also help to differentiate MCL from other lymphomas. MCL does not usually express the antigens that are associated with germinal centers, such as CD10, CD23, and BCL6. Thus, these antigens can be used to distinguish MCL from B-cell lymphomas of germinal center origin, including follicular lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma.

The National Comprehensive Cancer Network recommends chemotherapy followed by radiation for stage I or II disease. In general, patients with advanced-stage disease benefit from systemic chemotherapy. Because MCL is clinically heterogeneous, treatment may require adjustment on the basis of the patient's age, underlying comorbidities, and underlying MCL biology such as TP53 mutations. During induction therapy, prophylaxis and monitoring for tumor lysis syndrome is strongly recommended to be considered. Before treatment, hepatitis B virus testing is recommended because of an increased risk for viral reactivation with use of immunotherapy regimens for treatment.

Timothy J. Voorhees, MD, MSCR, Assistant Professor of Internal Medicine - Clinical, Division of Hematology, The Ohio State University James Comprehensive Cancer Center, Columbus, OH.

Timothy J. Voorhees, MD, MSCR, has disclosed the following relevant financial relationships:
Received research grant from: AstraZeneca; Morphosys; Incyte; Recordati.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma characterized by the proliferation of CD5-positive B cells within the mantle zone that surrounds normal germinal center follicles. MCL is a rare disease that most commonly presents in adult men (male to female ratio > 2:1) in the fifth and sixth decades of life. Individuals diagnosed with MCL typically present with constitutional symptoms, such as weight loss, night sweats, persistent fever, and fatigue. Approximately 25% of cases present with extranodal involvement with the bone marrow; peripheral blood and gastrointestinal tract are most often involved. In patients with extensive node involvement in the gastrointestinal tract, additional symptoms at presentation often include abdominal pain, abdominal fullness, and bloating. Skin involvement in MCL is rare and usually indicates widespread disease. 

According to the guidelines of the World Health Organization–European Organization for Research and Treatment of Cancer, a diagnosis of MCL is established on the basis of the morphologic examination findings and immunophenotyping. 

Immunohistochemically, expression of cyclin D1 in normal lymphoid cells is very low and often undetectable; only hairy cell leukemia shows moderate expression of cyclin D1. Therefore, positive immunohistochemistry for cyclin D1 is pathognomonic for MCL. Increased expression of cyclin D1 protein leads to dysregulation of the cell cycle and stimulates uncontrolled cell proliferation. It is also indirect evidence of the chromosomal translocation (11;14)(q13;q32) on the CCND1 gene, which is detected in 95% of cases of MCL. In addition, negative expression of antigens may also help to differentiate MCL from other lymphomas. MCL does not usually express the antigens that are associated with germinal centers, such as CD10, CD23, and BCL6. Thus, these antigens can be used to distinguish MCL from B-cell lymphomas of germinal center origin, including follicular lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma.

The National Comprehensive Cancer Network recommends chemotherapy followed by radiation for stage I or II disease. In general, patients with advanced-stage disease benefit from systemic chemotherapy. Because MCL is clinically heterogeneous, treatment may require adjustment on the basis of the patient's age, underlying comorbidities, and underlying MCL biology such as TP53 mutations. During induction therapy, prophylaxis and monitoring for tumor lysis syndrome is strongly recommended to be considered. Before treatment, hepatitis B virus testing is recommended because of an increased risk for viral reactivation with use of immunotherapy regimens for treatment.

Timothy J. Voorhees, MD, MSCR, Assistant Professor of Internal Medicine - Clinical, Division of Hematology, The Ohio State University James Comprehensive Cancer Center, Columbus, OH.

Timothy J. Voorhees, MD, MSCR, has disclosed the following relevant financial relationships:
Received research grant from: AstraZeneca; Morphosys; Incyte; Recordati.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma characterized by the proliferation of CD5-positive B cells within the mantle zone that surrounds normal germinal center follicles. MCL is a rare disease that most commonly presents in adult men (male to female ratio > 2:1) in the fifth and sixth decades of life. Individuals diagnosed with MCL typically present with constitutional symptoms, such as weight loss, night sweats, persistent fever, and fatigue. Approximately 25% of cases present with extranodal involvement with the bone marrow; peripheral blood and gastrointestinal tract are most often involved. In patients with extensive node involvement in the gastrointestinal tract, additional symptoms at presentation often include abdominal pain, abdominal fullness, and bloating. Skin involvement in MCL is rare and usually indicates widespread disease. 

According to the guidelines of the World Health Organization–European Organization for Research and Treatment of Cancer, a diagnosis of MCL is established on the basis of the morphologic examination findings and immunophenotyping. 

Immunohistochemically, expression of cyclin D1 in normal lymphoid cells is very low and often undetectable; only hairy cell leukemia shows moderate expression of cyclin D1. Therefore, positive immunohistochemistry for cyclin D1 is pathognomonic for MCL. Increased expression of cyclin D1 protein leads to dysregulation of the cell cycle and stimulates uncontrolled cell proliferation. It is also indirect evidence of the chromosomal translocation (11;14)(q13;q32) on the CCND1 gene, which is detected in 95% of cases of MCL. In addition, negative expression of antigens may also help to differentiate MCL from other lymphomas. MCL does not usually express the antigens that are associated with germinal centers, such as CD10, CD23, and BCL6. Thus, these antigens can be used to distinguish MCL from B-cell lymphomas of germinal center origin, including follicular lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma.

The National Comprehensive Cancer Network recommends chemotherapy followed by radiation for stage I or II disease. In general, patients with advanced-stage disease benefit from systemic chemotherapy. Because MCL is clinically heterogeneous, treatment may require adjustment on the basis of the patient's age, underlying comorbidities, and underlying MCL biology such as TP53 mutations. During induction therapy, prophylaxis and monitoring for tumor lysis syndrome is strongly recommended to be considered. Before treatment, hepatitis B virus testing is recommended because of an increased risk for viral reactivation with use of immunotherapy regimens for treatment.

Timothy J. Voorhees, MD, MSCR, Assistant Professor of Internal Medicine - Clinical, Division of Hematology, The Ohio State University James Comprehensive Cancer Center, Columbus, OH.

Timothy J. Voorhees, MD, MSCR, has disclosed the following relevant financial relationships:
Received research grant from: AstraZeneca; Morphosys; Incyte; Recordati.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

A scoop shave biopsy was performed, including at least a 1-mm margin of normal-looking skin. Pathology was consistent with melanoma in situ.

Melanoma in situ, also called Stage 0 melanoma, is defined by atypical melanocytes that have not begun to invade the dermis and, therefore, have a Breslow thickness of 0 mm. While invasive melanoma is responsible for the largest number of skin cancer deaths in the United States (estimated to be 7990 in 2023), melanoma in situ maintains a very high cure rate when treated appropriately.¹

Dermoscopy can help differentiate melanoma from benign nevi or other benign skin lesions. In this case, dermoscopy revealed a fine pigment network at the periphery that indicated this lesion was made up of melanocytes. There were also atypical vascular markings (the milky red color) in the center. Taken together, these findings were strongly indicative of melanoma.

Standard of care for melanoma in situ is a wide local excision with a margin of 5 to 10 mm. Melanoma in situ does not require sentinel lymph node biopsy. However, a lymph node biopsy would have been necessary if the melanoma had been ≥ 1 mm in thickness or if it had been ≥ 0.8 mm in thickness with higher-risk features, such as an increased number of mitoses per high-power field on pathology. Mohs micrographic surgery (MMS) is emerging as an alternative method to wide local excision to treat melanoma in situ. However, it can only be done in specialized centers that can do rapid immunohistochemical staining on frozen sections. MMS is especially useful in cosmetically sensitive areas of the body and in areas where the true size of the melanoma in situ is unclear.

This patient subsequently underwent a wide local excision in the office with a margin of 6 mm. A sentinel lymph node biopsy was not performed. The patient will continue with skin surveillance consisting of full skin exams 3 to 4 times in the first year of diagnosis, then twice annually for Years 2 to 5. He will then come in for annual skin exams after that.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

A scoop shave biopsy was performed, including at least a 1-mm margin of normal-looking skin. Pathology was consistent with melanoma in situ.

Melanoma in situ, also called Stage 0 melanoma, is defined by atypical melanocytes that have not begun to invade the dermis and, therefore, have a Breslow thickness of 0 mm. While invasive melanoma is responsible for the largest number of skin cancer deaths in the United States (estimated to be 7990 in 2023), melanoma in situ maintains a very high cure rate when treated appropriately.¹

Dermoscopy can help differentiate melanoma from benign nevi or other benign skin lesions. In this case, dermoscopy revealed a fine pigment network at the periphery that indicated this lesion was made up of melanocytes. There were also atypical vascular markings (the milky red color) in the center. Taken together, these findings were strongly indicative of melanoma.

Standard of care for melanoma in situ is a wide local excision with a margin of 5 to 10 mm. Melanoma in situ does not require sentinel lymph node biopsy. However, a lymph node biopsy would have been necessary if the melanoma had been ≥ 1 mm in thickness or if it had been ≥ 0.8 mm in thickness with higher-risk features, such as an increased number of mitoses per high-power field on pathology. Mohs micrographic surgery (MMS) is emerging as an alternative method to wide local excision to treat melanoma in situ. However, it can only be done in specialized centers that can do rapid immunohistochemical staining on frozen sections. MMS is especially useful in cosmetically sensitive areas of the body and in areas where the true size of the melanoma in situ is unclear.

This patient subsequently underwent a wide local excision in the office with a margin of 6 mm. A sentinel lymph node biopsy was not performed. The patient will continue with skin surveillance consisting of full skin exams 3 to 4 times in the first year of diagnosis, then twice annually for Years 2 to 5. He will then come in for annual skin exams after that.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

A scoop shave biopsy was performed, including at least a 1-mm margin of normal-looking skin. Pathology was consistent with melanoma in situ.

Melanoma in situ, also called Stage 0 melanoma, is defined by atypical melanocytes that have not begun to invade the dermis and, therefore, have a Breslow thickness of 0 mm. While invasive melanoma is responsible for the largest number of skin cancer deaths in the United States (estimated to be 7990 in 2023), melanoma in situ maintains a very high cure rate when treated appropriately.¹

Dermoscopy can help differentiate melanoma from benign nevi or other benign skin lesions. In this case, dermoscopy revealed a fine pigment network at the periphery that indicated this lesion was made up of melanocytes. There were also atypical vascular markings (the milky red color) in the center. Taken together, these findings were strongly indicative of melanoma.

Standard of care for melanoma in situ is a wide local excision with a margin of 5 to 10 mm. Melanoma in situ does not require sentinel lymph node biopsy. However, a lymph node biopsy would have been necessary if the melanoma had been ≥ 1 mm in thickness or if it had been ≥ 0.8 mm in thickness with higher-risk features, such as an increased number of mitoses per high-power field on pathology. Mohs micrographic surgery (MMS) is emerging as an alternative method to wide local excision to treat melanoma in situ. However, it can only be done in specialized centers that can do rapid immunohistochemical staining on frozen sections. MMS is especially useful in cosmetically sensitive areas of the body and in areas where the true size of the melanoma in situ is unclear.

This patient subsequently underwent a wide local excision in the office with a margin of 6 mm. A sentinel lymph node biopsy was not performed. The patient will continue with skin surveillance consisting of full skin exams 3 to 4 times in the first year of diagnosis, then twice annually for Years 2 to 5. He will then come in for annual skin exams after that.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

The patient is sent for lymphoscintigraphy, which showed impaired lymphatic drainage of both lower extremities consistent with obesity-induced lymphedema. 

Lymphedema is a chronic condition caused by the abnormal development of the lymphatic system (primary lymphedema) or injury to lymphatic vasculature (secondary lymphedema). Chronic interstitial fluid accumulation may lead to fibrosis, persistent inflammation, and adipose deposition, which often results in massive hypertrophy. Obesity, which affects approximately 40% of the US population, is a rising cause of secondary lymphedema. Obesity-induced lymphedema (OIL) is a result of external compression of the lymphatic system by adipose tissue and increased production of lymph, which results in direct injury to the lymphatic endothelium. As BMI increases, lymphedema worsens and ambulation becomes more difficult, placing patients in an unfavorable cycle of weight gain and lymphatic injury. 

The diagnosis of OIL is made by history and physical and is confirmed with diagnostic imaging. The classic presentation of lymphedema is edema of the lower extremities and a positive Stemmer sign. The Stemmer sign is positive if the examiner is unable to grab the dorsal skin between the thumb and index finger. The gold standard for lymphatic imaging is radionuclide lymphoscintigraphy. It involves injecting a tracer protein into the distal extremity, which should be taken up by the lymphatic vasculature and visualized in patients with normal lymphatic function. Lymphoscintigraphy has a high sensitivity (96%) and specificity (100%) for the diagnosis of lymphedema. 

The risk for lymphatic dysfunction increases with elevated BMI. A BMI threshold appears to exist between 53 and 59, at which point lower-extremity lymphatic dysfunction begins to occur and is almost universal when BMI exceeds 60. Sixty percent of patients with OIL will develop massive localized lymphedema; the higher the BMI, the greater the risk for massive localized lymphedema. Typical areas of localized lymphedema include the lower extremities, genitals, and abdominal wall. In addition, patients with OIL are at increased risk for infections, such as cellulitis. Other complications of OIL include functional disabilities, psychosocial morbidity, and malignant transformation. 

Patients at risk for OIL should be counseled and educated about weight management interventions, such as intensive treatment programs, lifestyle changes, and medications before their BMI reaches 50, a threshold where irreversible lower-extremity lymphedema may occur. Although weight loss may reduce symptoms of OIL, irreversible lymphatic dysfunction also may occur. Individuals at risk for OIL are often referred to a bariatric surgical weight management center. 

Lymphedema management consists of compression regimens, physiotherapy, and manual lymphatic drainage. Adipose deposition in the late stages of lymphedema may decrease the response to such manual treatments. Operative procedures are typically used when these treatment options have been inadequate. Patients with chronic advanced lymphedema, in whom lymphatic impairment is accompanied by deposition of fibroadipose tissue, may also require debulking surgery. 

Courtney Whittle, MD, MSW, Diplomate of ABOM, Pediatric Lead, Obesity Champion, TSPMG, Weight A Minute Clinic, Atlanta, Georgia.

Courtney Whittle, MD, MSW, Diplomate of ABOM, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The patient is sent for lymphoscintigraphy, which showed impaired lymphatic drainage of both lower extremities consistent with obesity-induced lymphedema. 

Lymphedema is a chronic condition caused by the abnormal development of the lymphatic system (primary lymphedema) or injury to lymphatic vasculature (secondary lymphedema). Chronic interstitial fluid accumulation may lead to fibrosis, persistent inflammation, and adipose deposition, which often results in massive hypertrophy. Obesity, which affects approximately 40% of the US population, is a rising cause of secondary lymphedema. Obesity-induced lymphedema (OIL) is a result of external compression of the lymphatic system by adipose tissue and increased production of lymph, which results in direct injury to the lymphatic endothelium. As BMI increases, lymphedema worsens and ambulation becomes more difficult, placing patients in an unfavorable cycle of weight gain and lymphatic injury. 

The diagnosis of OIL is made by history and physical and is confirmed with diagnostic imaging. The classic presentation of lymphedema is edema of the lower extremities and a positive Stemmer sign. The Stemmer sign is positive if the examiner is unable to grab the dorsal skin between the thumb and index finger. The gold standard for lymphatic imaging is radionuclide lymphoscintigraphy. It involves injecting a tracer protein into the distal extremity, which should be taken up by the lymphatic vasculature and visualized in patients with normal lymphatic function. Lymphoscintigraphy has a high sensitivity (96%) and specificity (100%) for the diagnosis of lymphedema. 

The risk for lymphatic dysfunction increases with elevated BMI. A BMI threshold appears to exist between 53 and 59, at which point lower-extremity lymphatic dysfunction begins to occur and is almost universal when BMI exceeds 60. Sixty percent of patients with OIL will develop massive localized lymphedema; the higher the BMI, the greater the risk for massive localized lymphedema. Typical areas of localized lymphedema include the lower extremities, genitals, and abdominal wall. In addition, patients with OIL are at increased risk for infections, such as cellulitis. Other complications of OIL include functional disabilities, psychosocial morbidity, and malignant transformation. 

Patients at risk for OIL should be counseled and educated about weight management interventions, such as intensive treatment programs, lifestyle changes, and medications before their BMI reaches 50, a threshold where irreversible lower-extremity lymphedema may occur. Although weight loss may reduce symptoms of OIL, irreversible lymphatic dysfunction also may occur. Individuals at risk for OIL are often referred to a bariatric surgical weight management center. 

Lymphedema management consists of compression regimens, physiotherapy, and manual lymphatic drainage. Adipose deposition in the late stages of lymphedema may decrease the response to such manual treatments. Operative procedures are typically used when these treatment options have been inadequate. Patients with chronic advanced lymphedema, in whom lymphatic impairment is accompanied by deposition of fibroadipose tissue, may also require debulking surgery. 

Courtney Whittle, MD, MSW, Diplomate of ABOM, Pediatric Lead, Obesity Champion, TSPMG, Weight A Minute Clinic, Atlanta, Georgia.

Courtney Whittle, MD, MSW, Diplomate of ABOM, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The patient is sent for lymphoscintigraphy, which showed impaired lymphatic drainage of both lower extremities consistent with obesity-induced lymphedema. 

Lymphedema is a chronic condition caused by the abnormal development of the lymphatic system (primary lymphedema) or injury to lymphatic vasculature (secondary lymphedema). Chronic interstitial fluid accumulation may lead to fibrosis, persistent inflammation, and adipose deposition, which often results in massive hypertrophy. Obesity, which affects approximately 40% of the US population, is a rising cause of secondary lymphedema. Obesity-induced lymphedema (OIL) is a result of external compression of the lymphatic system by adipose tissue and increased production of lymph, which results in direct injury to the lymphatic endothelium. As BMI increases, lymphedema worsens and ambulation becomes more difficult, placing patients in an unfavorable cycle of weight gain and lymphatic injury. 

The diagnosis of OIL is made by history and physical and is confirmed with diagnostic imaging. The classic presentation of lymphedema is edema of the lower extremities and a positive Stemmer sign. The Stemmer sign is positive if the examiner is unable to grab the dorsal skin between the thumb and index finger. The gold standard for lymphatic imaging is radionuclide lymphoscintigraphy. It involves injecting a tracer protein into the distal extremity, which should be taken up by the lymphatic vasculature and visualized in patients with normal lymphatic function. Lymphoscintigraphy has a high sensitivity (96%) and specificity (100%) for the diagnosis of lymphedema. 

The risk for lymphatic dysfunction increases with elevated BMI. A BMI threshold appears to exist between 53 and 59, at which point lower-extremity lymphatic dysfunction begins to occur and is almost universal when BMI exceeds 60. Sixty percent of patients with OIL will develop massive localized lymphedema; the higher the BMI, the greater the risk for massive localized lymphedema. Typical areas of localized lymphedema include the lower extremities, genitals, and abdominal wall. In addition, patients with OIL are at increased risk for infections, such as cellulitis. Other complications of OIL include functional disabilities, psychosocial morbidity, and malignant transformation. 

Patients at risk for OIL should be counseled and educated about weight management interventions, such as intensive treatment programs, lifestyle changes, and medications before their BMI reaches 50, a threshold where irreversible lower-extremity lymphedema may occur. Although weight loss may reduce symptoms of OIL, irreversible lymphatic dysfunction also may occur. Individuals at risk for OIL are often referred to a bariatric surgical weight management center. 

Lymphedema management consists of compression regimens, physiotherapy, and manual lymphatic drainage. Adipose deposition in the late stages of lymphedema may decrease the response to such manual treatments. Operative procedures are typically used when these treatment options have been inadequate. Patients with chronic advanced lymphedema, in whom lymphatic impairment is accompanied by deposition of fibroadipose tissue, may also require debulking surgery. 

Courtney Whittle, MD, MSW, Diplomate of ABOM, Pediatric Lead, Obesity Champion, TSPMG, Weight A Minute Clinic, Atlanta, Georgia.

Courtney Whittle, MD, MSW, Diplomate of ABOM, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

How does endometriosis affect the whole body, and how often is it misunderstood for another condition?

Dr. Taylor: Far too often, we think about endometriosis as just a cause of bad menstrual cramps. So many times, we miss the signs and falsely attribute symptoms to other diseases. I cannot tell you the number of people who have seen multiple practitioners for other conditions, when the underlying problem was actually endometriosis.

Endometriosis affects the whole body. It can affect the intestines, the bladder, and body weight, and the brain and mood. Endometriosis causes fatigue and inflammation, and in the long run it can lead to an increased risk for cardiovascular disease. When we as physicians do surgery or laparoscopy, we find these little blue and brown lesions in the pelvis, and they certainly do cause pain, but that is not the whole disease.

Endometriosis heightens pain and nerve sensitivity for patients, and we should not dismiss the debilitating effect of these symptoms. Things actually do hurt more. In fact, the pain can spread from beyond the time of the menstrual period and spread to other areas besides the uterus.

We cannot ignore the totality of the effects of the disease and only focus on one part of the problem. More importantly, we cannot be distracted and discount endometriosis or mistake it for another condition. I have seen many patients who went to a gastroenterologist first and may even have had a colonoscopy because of some bowel symptoms, but then we come to find out it was endometriosis irritating the bowels at the time of their period and not another primary disease.

Another example is that the patient may see a urologist and have a cystoscopy to assess bladder pain, especially if the pain comes on around the time of menses. However, that pain is probably due to endometriosis irritating the bladder, not a primary bladder problem.

I have even had patients who were sent to a psychiatrist first because of anxiety that was actually being caused by the endometriosis. It is important to understand that treating the primary problem—endometriosis—should be our focus.

Which effects of this chronic disease can have the most long-term impact?

Dr. Taylor: It is important to understand that endometriosis has long-term effects on the entire body. For example, it affects the brain, increasing anxiety and depression. It causes pain sensitization, fatigue, and body inflammation. Endometriosis can also damage blood vessels or cause atherosclerosis.

A quick diagnosis is crucial because often this disease affects women at the most critical points in their life—either when they are in school, or in the early part of their career, when they need to be able to focus. It is important to get their endometriosis under control early and prevent long-term complications. Unfortunately, the long-term impacts are an aspect we do not focus on enough.

Infertility is another common long-term consequence of endometriosis. The sooner we can diagnose endometriosis, the sooner we can begin treatment and the more likely we can preserve someone's fertility. Our goal is to catch endometriosis early enough, preserve the patient’s fertility, and prevent any damage, so they hopefully will not have trouble getting pregnant or need medical intervention to get pregnant.

What methods do you use to diagnose endometriosis as quickly as possible?

Dr. Taylor: The sooner we can pinpoint the correct diagnosis and begin treatment, the more we can not only relieve patients of pain, but also stop that inflammation and all of these other manifestations of endometriosis so that they are not saddled with this for life.

We used to say you needed a laparoscopy to accurately diagnose endometriosis, and that statement is still true. You cannot see the most common types of endometriosis on an ultrasound or MRI. The endometriosis has to be pretty bad before you see it on an MRI or an ultrasound, and at that point it is often a big cyst in the ovary or a big nodule that is invasive.

However, you can diagnose endometriosis just by listening to your patients. If they have extremely painful menstrual cycles, dysmenorrhea, or painful menstrual cramps that get worse over the years, the problem is most likely endometriosis. You can rule out a few other things, and you can make that empiric clinical diagnosis of endometriosis. You can know with confidence that somebody likely has endometriosis. The treatments are benign. The first-line therapy would be to try a birth control pill. If we had to perform a laparoscopy before beginning endometriosis treatment, I think we would be doing our patients a huge disservice.

In addition to birth control pills, what are the most common therapeutic treatments you use in day-to-day practice?

Dr. Taylor: Birth control pills are still the first-line therapy. We use birth control pills because they are easy, well-tolerated, and inexpensive, but about a third of women will be resistant. Birth control pills are a great option when they work, but they do not always work 100% of the time.

We have a couple of other hormonal treatment options. Rarely, but occasionally, we use something called danazol, which is a mild male hormone. Side effects can be acne or hair growth, but it works well and is inexpensive. We used to give injectable agents, like leuprolide. Leuprolide is a harsh medication with once-a-month injections, and it puts someone in a temporary menopausal state with hot flashes and the possibility of decreased bone mineral density.

Today, we have the new class of GnRH antagonists that are a milder, gentler version of those injectable medications. They are oral, and you do not have to fully suppress estrogen levels all the way down to menopause. Patients can take the GnRH antagonists, stop treatment, and try to get pregnant at their next cycle.

Occasionally, we find that someone does not respond to any medical therapies, so surgery still has an important role. The usual reason for surgery is that you may suppress the active disease with medications, but the old damage is still there causing some pain, which can only be removed with surgery. Surgery is a good way to relieve that pain and it helps improve pregnancy rates for people with endometriosis wishing to conceive.

What does the future look like for endometriosis-related infertility, particularly related to in vitro fertilization (IVF)?

Dr. Taylor: We currently have an IVF trial in the works, in which we are using a hormone-suppressing GnRH (gonadotropin-releasing hormone) antagonist, elagolix, which suppresses endometriosis. The medication is administered before IVF. The goal is to determine if this approach leads to a better pregnancy rate in IVF cycles.

We are also working on nonhormonal medications in the laboratory, but these strategies are not yet ready for human clinical trials. These laboratory trials are investigating the basic biology of endometriosis, with the goal of learning what makes endometrial tissue grow in the wrong place, what makes it grow aggressively, and how it signals to other organs to cause damage.

We are looking at some additional nonhormonal medications that may possibly be used in someone trying to conceive, so that we can increase their chances of becoming pregnant. We are testing these medications in mice, but eventually we hope they progress to human clinical trials. The future for endometriosis therapy is nonhormonal treatments that can be used in somebody trying to conceive. That is what we have on the horizon.

Unfortunately for people with endometriosis wishing to conceive, all the classic first-line medications used to treat the condition are reproductive hormones that interfere with the ability to become pregnant. When we stop these medications, many women with endometriosis get pregnant spontaneously always suggest patients with endometriosis wishing to conceive try this approach, unless we know the endometriosis is very extensive. However, IVF is a good way to correct even the worst cases of endometriosis. As long as somebody has not waited until they are in their 40s and they have run out of eggs, IVF will usually correct endometriosis-related infertility.

Overall, how we treat endometriosis has been revolutionized and we have much better options than we had just 5 years ago. In my day-to-day practice, I recognize the importance of talking more openly about endometriosis, understanding the different symptoms, and not dismissing those connections. We should be able to talk about this important medical problem and all of its manifestations. I published a paper in The Lancet at the end of 2021 about the concept of endometriosis as a systemic whole-body disease and its effects. I think open conversations with patients about endometriosis is making a world of difference for the women with this disease.

How does endometriosis affect the whole body, and how often is it misunderstood for another condition?

Dr. Taylor: Far too often, we think about endometriosis as just a cause of bad menstrual cramps. So many times, we miss the signs and falsely attribute symptoms to other diseases. I cannot tell you the number of people who have seen multiple practitioners for other conditions, when the underlying problem was actually endometriosis.

Endometriosis affects the whole body. It can affect the intestines, the bladder, and body weight, and the brain and mood. Endometriosis causes fatigue and inflammation, and in the long run it can lead to an increased risk for cardiovascular disease. When we as physicians do surgery or laparoscopy, we find these little blue and brown lesions in the pelvis, and they certainly do cause pain, but that is not the whole disease.

Endometriosis heightens pain and nerve sensitivity for patients, and we should not dismiss the debilitating effect of these symptoms. Things actually do hurt more. In fact, the pain can spread from beyond the time of the menstrual period and spread to other areas besides the uterus.

We cannot ignore the totality of the effects of the disease and only focus on one part of the problem. More importantly, we cannot be distracted and discount endometriosis or mistake it for another condition. I have seen many patients who went to a gastroenterologist first and may even have had a colonoscopy because of some bowel symptoms, but then we come to find out it was endometriosis irritating the bowels at the time of their period and not another primary disease.

Another example is that the patient may see a urologist and have a cystoscopy to assess bladder pain, especially if the pain comes on around the time of menses. However, that pain is probably due to endometriosis irritating the bladder, not a primary bladder problem.

I have even had patients who were sent to a psychiatrist first because of anxiety that was actually being caused by the endometriosis. It is important to understand that treating the primary problem—endometriosis—should be our focus.

Which effects of this chronic disease can have the most long-term impact?

Dr. Taylor: It is important to understand that endometriosis has long-term effects on the entire body. For example, it affects the brain, increasing anxiety and depression. It causes pain sensitization, fatigue, and body inflammation. Endometriosis can also damage blood vessels or cause atherosclerosis.

A quick diagnosis is crucial because often this disease affects women at the most critical points in their life—either when they are in school, or in the early part of their career, when they need to be able to focus. It is important to get their endometriosis under control early and prevent long-term complications. Unfortunately, the long-term impacts are an aspect we do not focus on enough.

Infertility is another common long-term consequence of endometriosis. The sooner we can diagnose endometriosis, the sooner we can begin treatment and the more likely we can preserve someone's fertility. Our goal is to catch endometriosis early enough, preserve the patient’s fertility, and prevent any damage, so they hopefully will not have trouble getting pregnant or need medical intervention to get pregnant.

What methods do you use to diagnose endometriosis as quickly as possible?

Dr. Taylor: The sooner we can pinpoint the correct diagnosis and begin treatment, the more we can not only relieve patients of pain, but also stop that inflammation and all of these other manifestations of endometriosis so that they are not saddled with this for life.

We used to say you needed a laparoscopy to accurately diagnose endometriosis, and that statement is still true. You cannot see the most common types of endometriosis on an ultrasound or MRI. The endometriosis has to be pretty bad before you see it on an MRI or an ultrasound, and at that point it is often a big cyst in the ovary or a big nodule that is invasive.

However, you can diagnose endometriosis just by listening to your patients. If they have extremely painful menstrual cycles, dysmenorrhea, or painful menstrual cramps that get worse over the years, the problem is most likely endometriosis. You can rule out a few other things, and you can make that empiric clinical diagnosis of endometriosis. You can know with confidence that somebody likely has endometriosis. The treatments are benign. The first-line therapy would be to try a birth control pill. If we had to perform a laparoscopy before beginning endometriosis treatment, I think we would be doing our patients a huge disservice.

In addition to birth control pills, what are the most common therapeutic treatments you use in day-to-day practice?

Dr. Taylor: Birth control pills are still the first-line therapy. We use birth control pills because they are easy, well-tolerated, and inexpensive, but about a third of women will be resistant. Birth control pills are a great option when they work, but they do not always work 100% of the time.

We have a couple of other hormonal treatment options. Rarely, but occasionally, we use something called danazol, which is a mild male hormone. Side effects can be acne or hair growth, but it works well and is inexpensive. We used to give injectable agents, like leuprolide. Leuprolide is a harsh medication with once-a-month injections, and it puts someone in a temporary menopausal state with hot flashes and the possibility of decreased bone mineral density.

Today, we have the new class of GnRH antagonists that are a milder, gentler version of those injectable medications. They are oral, and you do not have to fully suppress estrogen levels all the way down to menopause. Patients can take the GnRH antagonists, stop treatment, and try to get pregnant at their next cycle.

Occasionally, we find that someone does not respond to any medical therapies, so surgery still has an important role. The usual reason for surgery is that you may suppress the active disease with medications, but the old damage is still there causing some pain, which can only be removed with surgery. Surgery is a good way to relieve that pain and it helps improve pregnancy rates for people with endometriosis wishing to conceive.

What does the future look like for endometriosis-related infertility, particularly related to in vitro fertilization (IVF)?

Dr. Taylor: We currently have an IVF trial in the works, in which we are using a hormone-suppressing GnRH (gonadotropin-releasing hormone) antagonist, elagolix, which suppresses endometriosis. The medication is administered before IVF. The goal is to determine if this approach leads to a better pregnancy rate in IVF cycles.

We are also working on nonhormonal medications in the laboratory, but these strategies are not yet ready for human clinical trials. These laboratory trials are investigating the basic biology of endometriosis, with the goal of learning what makes endometrial tissue grow in the wrong place, what makes it grow aggressively, and how it signals to other organs to cause damage.

We are looking at some additional nonhormonal medications that may possibly be used in someone trying to conceive, so that we can increase their chances of becoming pregnant. We are testing these medications in mice, but eventually we hope they progress to human clinical trials. The future for endometriosis therapy is nonhormonal treatments that can be used in somebody trying to conceive. That is what we have on the horizon.

Unfortunately for people with endometriosis wishing to conceive, all the classic first-line medications used to treat the condition are reproductive hormones that interfere with the ability to become pregnant. When we stop these medications, many women with endometriosis get pregnant spontaneously always suggest patients with endometriosis wishing to conceive try this approach, unless we know the endometriosis is very extensive. However, IVF is a good way to correct even the worst cases of endometriosis. As long as somebody has not waited until they are in their 40s and they have run out of eggs, IVF will usually correct endometriosis-related infertility.

Overall, how we treat endometriosis has been revolutionized and we have much better options than we had just 5 years ago. In my day-to-day practice, I recognize the importance of talking more openly about endometriosis, understanding the different symptoms, and not dismissing those connections. We should be able to talk about this important medical problem and all of its manifestations. I published a paper in The Lancet at the end of 2021 about the concept of endometriosis as a systemic whole-body disease and its effects. I think open conversations with patients about endometriosis is making a world of difference for the women with this disease.

How does endometriosis affect the whole body, and how often is it misunderstood for another condition?

Dr. Taylor: Far too often, we think about endometriosis as just a cause of bad menstrual cramps. So many times, we miss the signs and falsely attribute symptoms to other diseases. I cannot tell you the number of people who have seen multiple practitioners for other conditions, when the underlying problem was actually endometriosis.

Endometriosis affects the whole body. It can affect the intestines, the bladder, and body weight, and the brain and mood. Endometriosis causes fatigue and inflammation, and in the long run it can lead to an increased risk for cardiovascular disease. When we as physicians do surgery or laparoscopy, we find these little blue and brown lesions in the pelvis, and they certainly do cause pain, but that is not the whole disease.

Endometriosis heightens pain and nerve sensitivity for patients, and we should not dismiss the debilitating effect of these symptoms. Things actually do hurt more. In fact, the pain can spread from beyond the time of the menstrual period and spread to other areas besides the uterus.

We cannot ignore the totality of the effects of the disease and only focus on one part of the problem. More importantly, we cannot be distracted and discount endometriosis or mistake it for another condition. I have seen many patients who went to a gastroenterologist first and may even have had a colonoscopy because of some bowel symptoms, but then we come to find out it was endometriosis irritating the bowels at the time of their period and not another primary disease.

Another example is that the patient may see a urologist and have a cystoscopy to assess bladder pain, especially if the pain comes on around the time of menses. However, that pain is probably due to endometriosis irritating the bladder, not a primary bladder problem.

I have even had patients who were sent to a psychiatrist first because of anxiety that was actually being caused by the endometriosis. It is important to understand that treating the primary problem—endometriosis—should be our focus.

Which effects of this chronic disease can have the most long-term impact?

Dr. Taylor: It is important to understand that endometriosis has long-term effects on the entire body. For example, it affects the brain, increasing anxiety and depression. It causes pain sensitization, fatigue, and body inflammation. Endometriosis can also damage blood vessels or cause atherosclerosis.

A quick diagnosis is crucial because often this disease affects women at the most critical points in their life—either when they are in school, or in the early part of their career, when they need to be able to focus. It is important to get their endometriosis under control early and prevent long-term complications. Unfortunately, the long-term impacts are an aspect we do not focus on enough.

Infertility is another common long-term consequence of endometriosis. The sooner we can diagnose endometriosis, the sooner we can begin treatment and the more likely we can preserve someone's fertility. Our goal is to catch endometriosis early enough, preserve the patient’s fertility, and prevent any damage, so they hopefully will not have trouble getting pregnant or need medical intervention to get pregnant.

What methods do you use to diagnose endometriosis as quickly as possible?

Dr. Taylor: The sooner we can pinpoint the correct diagnosis and begin treatment, the more we can not only relieve patients of pain, but also stop that inflammation and all of these other manifestations of endometriosis so that they are not saddled with this for life.

We used to say you needed a laparoscopy to accurately diagnose endometriosis, and that statement is still true. You cannot see the most common types of endometriosis on an ultrasound or MRI. The endometriosis has to be pretty bad before you see it on an MRI or an ultrasound, and at that point it is often a big cyst in the ovary or a big nodule that is invasive.

However, you can diagnose endometriosis just by listening to your patients. If they have extremely painful menstrual cycles, dysmenorrhea, or painful menstrual cramps that get worse over the years, the problem is most likely endometriosis. You can rule out a few other things, and you can make that empiric clinical diagnosis of endometriosis. You can know with confidence that somebody likely has endometriosis. The treatments are benign. The first-line therapy would be to try a birth control pill. If we had to perform a laparoscopy before beginning endometriosis treatment, I think we would be doing our patients a huge disservice.

In addition to birth control pills, what are the most common therapeutic treatments you use in day-to-day practice?

Dr. Taylor: Birth control pills are still the first-line therapy. We use birth control pills because they are easy, well-tolerated, and inexpensive, but about a third of women will be resistant. Birth control pills are a great option when they work, but they do not always work 100% of the time.

We have a couple of other hormonal treatment options. Rarely, but occasionally, we use something called danazol, which is a mild male hormone. Side effects can be acne or hair growth, but it works well and is inexpensive. We used to give injectable agents, like leuprolide. Leuprolide is a harsh medication with once-a-month injections, and it puts someone in a temporary menopausal state with hot flashes and the possibility of decreased bone mineral density.

Today, we have the new class of GnRH antagonists that are a milder, gentler version of those injectable medications. They are oral, and you do not have to fully suppress estrogen levels all the way down to menopause. Patients can take the GnRH antagonists, stop treatment, and try to get pregnant at their next cycle.

Occasionally, we find that someone does not respond to any medical therapies, so surgery still has an important role. The usual reason for surgery is that you may suppress the active disease with medications, but the old damage is still there causing some pain, which can only be removed with surgery. Surgery is a good way to relieve that pain and it helps improve pregnancy rates for people with endometriosis wishing to conceive.

What does the future look like for endometriosis-related infertility, particularly related to in vitro fertilization (IVF)?

Dr. Taylor: We currently have an IVF trial in the works, in which we are using a hormone-suppressing GnRH (gonadotropin-releasing hormone) antagonist, elagolix, which suppresses endometriosis. The medication is administered before IVF. The goal is to determine if this approach leads to a better pregnancy rate in IVF cycles.

We are also working on nonhormonal medications in the laboratory, but these strategies are not yet ready for human clinical trials. These laboratory trials are investigating the basic biology of endometriosis, with the goal of learning what makes endometrial tissue grow in the wrong place, what makes it grow aggressively, and how it signals to other organs to cause damage.

We are looking at some additional nonhormonal medications that may possibly be used in someone trying to conceive, so that we can increase their chances of becoming pregnant. We are testing these medications in mice, but eventually we hope they progress to human clinical trials. The future for endometriosis therapy is nonhormonal treatments that can be used in somebody trying to conceive. That is what we have on the horizon.

Unfortunately for people with endometriosis wishing to conceive, all the classic first-line medications used to treat the condition are reproductive hormones that interfere with the ability to become pregnant. When we stop these medications, many women with endometriosis get pregnant spontaneously always suggest patients with endometriosis wishing to conceive try this approach, unless we know the endometriosis is very extensive. However, IVF is a good way to correct even the worst cases of endometriosis. As long as somebody has not waited until they are in their 40s and they have run out of eggs, IVF will usually correct endometriosis-related infertility.

Overall, how we treat endometriosis has been revolutionized and we have much better options than we had just 5 years ago. In my day-to-day practice, I recognize the importance of talking more openly about endometriosis, understanding the different symptoms, and not dismissing those connections. We should be able to talk about this important medical problem and all of its manifestations. I published a paper in The Lancet at the end of 2021 about the concept of endometriosis as a systemic whole-body disease and its effects. I think open conversations with patients about endometriosis is making a world of difference for the women with this disease.