Article

Federal Practitioner, in collaboration with the Association of VA Hematology/Oncology (AVAHO), present the 2022 edition of Cancer Data Trends (click to view the digital edition). This special issue provides updates on some of the top cancers and related concerns affecting veterans through original infographics and visual storytelling.

In this issue:

• Exposure-Related Cancers
• Cancer in Women
• Genitourinary Cancers
• Gastrointestinal Cancers
• Telehealth in Oncology
•  Precision Oncology
•  Palliative and Hospice Care
•  Alcohol and Cancer
•  Lung Cancer
•  Oropharyngeal Cancer
• Hematologic Cancers

Federal Practitioner and AVAHO would like to thank the following experts for their contributions to this issue:

Anita Aggarwal, DO, PhD; Sara Ahmed, PhD; Katherine Faricy-Anderson, MD; Apar Kishor Ganti, MD, MS; Solomon A Graf, MD; Kate Hendricks Thomas, PhD; Michael Kelley, MD; Mark Klein, MD, Gina McWhirter, MSN, MBA, RN; Bruce Montgomery, MD; Vida Almario Passero, MD, MBA; Thomas D Rodgers, MD; Vlad C Sandulache, MD, PhD; David H Wang, MD, PhD.

Federal Practitioner, in collaboration with the Association of VA Hematology/Oncology (AVAHO), present the 2022 edition of Cancer Data Trends (click to view the digital edition). This special issue provides updates on some of the top cancers and related concerns affecting veterans through original infographics and visual storytelling.

In this issue:

• Exposure-Related Cancers
• Cancer in Women
• Genitourinary Cancers
• Gastrointestinal Cancers
• Telehealth in Oncology
•  Precision Oncology
•  Palliative and Hospice Care
•  Alcohol and Cancer
•  Lung Cancer
•  Oropharyngeal Cancer
• Hematologic Cancers

Federal Practitioner and AVAHO would like to thank the following experts for their contributions to this issue:

Anita Aggarwal, DO, PhD; Sara Ahmed, PhD; Katherine Faricy-Anderson, MD; Apar Kishor Ganti, MD, MS; Solomon A Graf, MD; Kate Hendricks Thomas, PhD; Michael Kelley, MD; Mark Klein, MD, Gina McWhirter, MSN, MBA, RN; Bruce Montgomery, MD; Vida Almario Passero, MD, MBA; Thomas D Rodgers, MD; Vlad C Sandulache, MD, PhD; David H Wang, MD, PhD.

Federal Practitioner, in collaboration with the Association of VA Hematology/Oncology (AVAHO), present the 2022 edition of Cancer Data Trends (click to view the digital edition). This special issue provides updates on some of the top cancers and related concerns affecting veterans through original infographics and visual storytelling.

In this issue:

• Exposure-Related Cancers
• Cancer in Women
• Genitourinary Cancers
• Gastrointestinal Cancers
• Telehealth in Oncology
•  Precision Oncology
•  Palliative and Hospice Care
•  Alcohol and Cancer
•  Lung Cancer
•  Oropharyngeal Cancer
• Hematologic Cancers

Federal Practitioner and AVAHO would like to thank the following experts for their contributions to this issue:

Anita Aggarwal, DO, PhD; Sara Ahmed, PhD; Katherine Faricy-Anderson, MD; Apar Kishor Ganti, MD, MS; Solomon A Graf, MD; Kate Hendricks Thomas, PhD; Michael Kelley, MD; Mark Klein, MD, Gina McWhirter, MSN, MBA, RN; Bruce Montgomery, MD; Vida Almario Passero, MD, MBA; Thomas D Rodgers, MD; Vlad C Sandulache, MD, PhD; David H Wang, MD, PhD.

Moderate-quality evidence demonstrates a decrease in obstetric anal sphincter injury (OASIS) with the use of intrapartum warm compresses to the perineum and perineal massage, reported Editor in Chief Robert L. Barbieri, MD, in his editorial, “Obstetric anal sphincter injury: Prevention and repair” (May 2021). He also said that warm compresses may enhance the positive sensory experience of women laboring in natural childbirth. A poll for readers asked, “Do you use intrapartum or warm compresses to the perineum or perineal massage in your practice?”

Moderate-quality evidence demonstrates a decrease in obstetric anal sphincter injury (OASIS) with the use of intrapartum warm compresses to the perineum and perineal massage, reported Editor in Chief Robert L. Barbieri, MD, in his editorial, “Obstetric anal sphincter injury: Prevention and repair” (May 2021). He also said that warm compresses may enhance the positive sensory experience of women laboring in natural childbirth. A poll for readers asked, “Do you use intrapartum or warm compresses to the perineum or perineal massage in your practice?”

Moderate-quality evidence demonstrates a decrease in obstetric anal sphincter injury (OASIS) with the use of intrapartum warm compresses to the perineum and perineal massage, reported Editor in Chief Robert L. Barbieri, MD, in his editorial, “Obstetric anal sphincter injury: Prevention and repair” (May 2021). He also said that warm compresses may enhance the positive sensory experience of women laboring in natural childbirth. A poll for readers asked, “Do you use intrapartum or warm compresses to the perineum or perineal massage in your practice?”

Neuromodulation is an up-and-coming subtype of treatments for migraine. These treatments vary significantly from transcutaneous electrical nerve stimulation (TENS)–like devices to transcranial magnetic stimulation to remote electrical stimulation of nociceptors in the arm or the vagus nerve. Some of these devices are primarily preventive in nature, whereas others are primarily for the acute treatment of migraine. Transcranial direct-current stimulation (TDCS) has recently been investigated in a number of other neurologic conditions, including multiple sclerosis and stroke, specifically for its ability to reverse manifestations of specific pathologic changes. With migraine, the question remains of whether central sensitization can similarly be reversed.

Prior studies looking at TDCS in the context of episodic migraine were mostly inconclusive. These were looking primarily at acute treatment rather than prevention. In a recent study, Hodai and colleagues took a small group of patients with treatment-refractory chronic migraine and randomly assigned them to TDCS or sham stimulation over a course of 2 months. The stimulations that the patients received were similar to protocols that have been investigated in multiple sclerosis and stroke, specifically anodal TDCS, which is thought to reverse gamma-aminobutyric acid (GABA)-ergic and glutamatergic dysregulations when the right or left cortex was stimulated.

The primary outcome of this study was decrease in baseline migraine attack frequency per month; secondary endpoints were improvement in the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) scores, the Short-Form Survey (SF-12) quality of life assessment, the Hospital Anxiety and Depression Scale (HADS) assessment, and a Clinical Global Impression (CGI) scale.

A total of 36 patients were randomly assigned to a sham or TDCS intervention. A larger reduction of migraine days per month was seen by the intervention group. The interventions were also well tolerated, and no serious adverse events were reported. None of the secondary outcomes, however, showed significance. Further analysis of responder rates showed a 50% responder rate of 36% in the intervention group vs. 14% in the sham group.

This is the first sham-controlled study investigating the use of this neuromodulation therapy for the prevention of migraine. TDCS appears to show promise even when selected for some of the most refractory situations. The question will become how this can be more practical for patient use in the future.

Prognosticating treatment effects in chronic migraine is extremely difficult to do. Most specialists have an extensive discussion with their patients that includes the likelihood of improvement in addition to the risks and benefits of the medications they are considering starting. There has been background discussion in the headache community over whether improvement with one calcitonin gene–related peptide (CGRP) antagonist medication is predictive of benefit with other medications in the class or with long-term improvement in migraine. Buse and colleagues present findings from a post hoc analysis of the PROMISE-2 study of eptinezumab for the prevention of chronic migraine.

Eptinezumab is an intravenously administered CGRP monoclonal antibody, given at either 100 mg or 300 mg every 3 months. PROMISE-2 was a randomized controlled trial that led to US Food and Drug Administration approval of eptinezumab for the prevention of chronic migraine. The authors here reviewed the data between the two intervention groups and the placebo group and then regrouped these patients according to response at month 1, defined by whether the patient was in a response group of 25%, 50%, or 75% response after 1 month of treatment. This was then compared with the patient global impact of change (PGIC) score at month 6.

This post hoc analysis did not include patients that had no response at all to either intervention or placebo at month 6. A total of 1072 patients were included in this analysis; the 100-mg, 300-mg, and placebo groups had approximately one third of patients in each.

The majority of patients in the 75% responder group continued to improve; more than half of those patients maintained the 75% response rate at month 6. More than two thirds of the 50% responders remained at a 50% response at 6 months as well. Those who responded at < 25% at month 1 were much less likely to achieve 50% response at month 6; however, the patients in the active groups were more likely to achieve a response compared with those in the placebo group.

The PGIC scores also showed significant improvement when comparing among the groups. Those who were "very much improved" at month 1 were significantly more likely to remain that way at the conclusion of the study.

Although prognosticating among different subtypes of CGRP antagonists is not yet possible, the authors here do show the ability to better inform and educate our patients when considering eptinezumab therapy for chronic migraine.

There is an age-old debate among headache specialists about overused medications: to wean or not to wean. The overuse of acute medications has long been shown to contribute to a higher frequency of migraine attacks over time, initially being called "transformed migraine" and subsequently being understood either as a subtype of chronic migraine or a separate headache disorder completely. Medication overuse headache (MOH) is something screened for by all headache providers when evaluating patients for worsening headaches. The addition of a preventive medication is the mainstay of treatment of any instance of higher frequency migraine; when MOH is a contributing factor, many practitioners will recommend complete discontinuation of the overused medications, whereas others will recommend waiting for the preventive medication to offer benefit first. As yet, there have not been any head-to-head trials investigating discontinuation vs. non-discontinuation of overused medications in this population.

Schwedt and colleagues designed a multisite trial prospectively enrolling patients with an International Classification of Headache Disorders (ICHD-3) diagnosis of both chronic migraine and MOH. Participants were told not to change their preventive medications for 4 weeks prior to enrollment. A total of 720 participants were enrolled through 14 clinics. Any patients already on preventive therapy were optimized to the best dose of that therapy or switched to other medications on the basis of the clinical investigator's judgement; all participants were randomly assigned to either discontinuation of the overused medication and given a novel acute therapy or were told to remain on their current acute therapy. No bridging therapies were recommended when switching or discontinuing acute therapies.

Of the 720 participants enrolled, 42% were already on preventive medicine. The overused medications ranged from simple analgesics for 64% of the study population to triptans, combination analgesics, and even opiates in 4% of the population. Butalbital use was included in the combination analgesic group. The primary outcome was reduction in moderate to severe migraine days, and secondary outcomes were scores for disability, depression, and quality of life (based on questionnaires).

There appeared to be no significant difference between the discontinuation and non-discontinuation groups. The authors describe this as noninferiority between the groups. To answer the age-old question of to wean or not to wean — there probably is not an answer that fits every patient. Patient adherence determines the effectiveness of anything we recommend. When evaluating patients with MOH, we have to consider whether discontinuing a medication that the patient has been depending on for months or longer will make it more or less likely for them to adhere to the other recommendations that we are making. Some patients will be very agreeable to try another acute option and stop overusing altogether. Others will be very apprehensive, and a slower, steadier approach that includes using the overused medication may be necessary. We aim always to individualize our recommendations for patients, and this should be no different.

Neuromodulation is an up-and-coming subtype of treatments for migraine. These treatments vary significantly from transcutaneous electrical nerve stimulation (TENS)–like devices to transcranial magnetic stimulation to remote electrical stimulation of nociceptors in the arm or the vagus nerve. Some of these devices are primarily preventive in nature, whereas others are primarily for the acute treatment of migraine. Transcranial direct-current stimulation (TDCS) has recently been investigated in a number of other neurologic conditions, including multiple sclerosis and stroke, specifically for its ability to reverse manifestations of specific pathologic changes. With migraine, the question remains of whether central sensitization can similarly be reversed.

Prior studies looking at TDCS in the context of episodic migraine were mostly inconclusive. These were looking primarily at acute treatment rather than prevention. In a recent study, Hodai and colleagues took a small group of patients with treatment-refractory chronic migraine and randomly assigned them to TDCS or sham stimulation over a course of 2 months. The stimulations that the patients received were similar to protocols that have been investigated in multiple sclerosis and stroke, specifically anodal TDCS, which is thought to reverse gamma-aminobutyric acid (GABA)-ergic and glutamatergic dysregulations when the right or left cortex was stimulated.

The primary outcome of this study was decrease in baseline migraine attack frequency per month; secondary endpoints were improvement in the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) scores, the Short-Form Survey (SF-12) quality of life assessment, the Hospital Anxiety and Depression Scale (HADS) assessment, and a Clinical Global Impression (CGI) scale.

A total of 36 patients were randomly assigned to a sham or TDCS intervention. A larger reduction of migraine days per month was seen by the intervention group. The interventions were also well tolerated, and no serious adverse events were reported. None of the secondary outcomes, however, showed significance. Further analysis of responder rates showed a 50% responder rate of 36% in the intervention group vs. 14% in the sham group.

This is the first sham-controlled study investigating the use of this neuromodulation therapy for the prevention of migraine. TDCS appears to show promise even when selected for some of the most refractory situations. The question will become how this can be more practical for patient use in the future.

Prognosticating treatment effects in chronic migraine is extremely difficult to do. Most specialists have an extensive discussion with their patients that includes the likelihood of improvement in addition to the risks and benefits of the medications they are considering starting. There has been background discussion in the headache community over whether improvement with one calcitonin gene–related peptide (CGRP) antagonist medication is predictive of benefit with other medications in the class or with long-term improvement in migraine. Buse and colleagues present findings from a post hoc analysis of the PROMISE-2 study of eptinezumab for the prevention of chronic migraine.

Eptinezumab is an intravenously administered CGRP monoclonal antibody, given at either 100 mg or 300 mg every 3 months. PROMISE-2 was a randomized controlled trial that led to US Food and Drug Administration approval of eptinezumab for the prevention of chronic migraine. The authors here reviewed the data between the two intervention groups and the placebo group and then regrouped these patients according to response at month 1, defined by whether the patient was in a response group of 25%, 50%, or 75% response after 1 month of treatment. This was then compared with the patient global impact of change (PGIC) score at month 6.

This post hoc analysis did not include patients that had no response at all to either intervention or placebo at month 6. A total of 1072 patients were included in this analysis; the 100-mg, 300-mg, and placebo groups had approximately one third of patients in each.

The majority of patients in the 75% responder group continued to improve; more than half of those patients maintained the 75% response rate at month 6. More than two thirds of the 50% responders remained at a 50% response at 6 months as well. Those who responded at < 25% at month 1 were much less likely to achieve 50% response at month 6; however, the patients in the active groups were more likely to achieve a response compared with those in the placebo group.

The PGIC scores also showed significant improvement when comparing among the groups. Those who were "very much improved" at month 1 were significantly more likely to remain that way at the conclusion of the study.

Although prognosticating among different subtypes of CGRP antagonists is not yet possible, the authors here do show the ability to better inform and educate our patients when considering eptinezumab therapy for chronic migraine.

There is an age-old debate among headache specialists about overused medications: to wean or not to wean. The overuse of acute medications has long been shown to contribute to a higher frequency of migraine attacks over time, initially being called "transformed migraine" and subsequently being understood either as a subtype of chronic migraine or a separate headache disorder completely. Medication overuse headache (MOH) is something screened for by all headache providers when evaluating patients for worsening headaches. The addition of a preventive medication is the mainstay of treatment of any instance of higher frequency migraine; when MOH is a contributing factor, many practitioners will recommend complete discontinuation of the overused medications, whereas others will recommend waiting for the preventive medication to offer benefit first. As yet, there have not been any head-to-head trials investigating discontinuation vs. non-discontinuation of overused medications in this population.

Schwedt and colleagues designed a multisite trial prospectively enrolling patients with an International Classification of Headache Disorders (ICHD-3) diagnosis of both chronic migraine and MOH. Participants were told not to change their preventive medications for 4 weeks prior to enrollment. A total of 720 participants were enrolled through 14 clinics. Any patients already on preventive therapy were optimized to the best dose of that therapy or switched to other medications on the basis of the clinical investigator's judgement; all participants were randomly assigned to either discontinuation of the overused medication and given a novel acute therapy or were told to remain on their current acute therapy. No bridging therapies were recommended when switching or discontinuing acute therapies.

Of the 720 participants enrolled, 42% were already on preventive medicine. The overused medications ranged from simple analgesics for 64% of the study population to triptans, combination analgesics, and even opiates in 4% of the population. Butalbital use was included in the combination analgesic group. The primary outcome was reduction in moderate to severe migraine days, and secondary outcomes were scores for disability, depression, and quality of life (based on questionnaires).

There appeared to be no significant difference between the discontinuation and non-discontinuation groups. The authors describe this as noninferiority between the groups. To answer the age-old question of to wean or not to wean — there probably is not an answer that fits every patient. Patient adherence determines the effectiveness of anything we recommend. When evaluating patients with MOH, we have to consider whether discontinuing a medication that the patient has been depending on for months or longer will make it more or less likely for them to adhere to the other recommendations that we are making. Some patients will be very agreeable to try another acute option and stop overusing altogether. Others will be very apprehensive, and a slower, steadier approach that includes using the overused medication may be necessary. We aim always to individualize our recommendations for patients, and this should be no different.

Neuromodulation is an up-and-coming subtype of treatments for migraine. These treatments vary significantly from transcutaneous electrical nerve stimulation (TENS)–like devices to transcranial magnetic stimulation to remote electrical stimulation of nociceptors in the arm or the vagus nerve. Some of these devices are primarily preventive in nature, whereas others are primarily for the acute treatment of migraine. Transcranial direct-current stimulation (TDCS) has recently been investigated in a number of other neurologic conditions, including multiple sclerosis and stroke, specifically for its ability to reverse manifestations of specific pathologic changes. With migraine, the question remains of whether central sensitization can similarly be reversed.

Prior studies looking at TDCS in the context of episodic migraine were mostly inconclusive. These were looking primarily at acute treatment rather than prevention. In a recent study, Hodai and colleagues took a small group of patients with treatment-refractory chronic migraine and randomly assigned them to TDCS or sham stimulation over a course of 2 months. The stimulations that the patients received were similar to protocols that have been investigated in multiple sclerosis and stroke, specifically anodal TDCS, which is thought to reverse gamma-aminobutyric acid (GABA)-ergic and glutamatergic dysregulations when the right or left cortex was stimulated.

The primary outcome of this study was decrease in baseline migraine attack frequency per month; secondary endpoints were improvement in the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) scores, the Short-Form Survey (SF-12) quality of life assessment, the Hospital Anxiety and Depression Scale (HADS) assessment, and a Clinical Global Impression (CGI) scale.

A total of 36 patients were randomly assigned to a sham or TDCS intervention. A larger reduction of migraine days per month was seen by the intervention group. The interventions were also well tolerated, and no serious adverse events were reported. None of the secondary outcomes, however, showed significance. Further analysis of responder rates showed a 50% responder rate of 36% in the intervention group vs. 14% in the sham group.

This is the first sham-controlled study investigating the use of this neuromodulation therapy for the prevention of migraine. TDCS appears to show promise even when selected for some of the most refractory situations. The question will become how this can be more practical for patient use in the future.

Prognosticating treatment effects in chronic migraine is extremely difficult to do. Most specialists have an extensive discussion with their patients that includes the likelihood of improvement in addition to the risks and benefits of the medications they are considering starting. There has been background discussion in the headache community over whether improvement with one calcitonin gene–related peptide (CGRP) antagonist medication is predictive of benefit with other medications in the class or with long-term improvement in migraine. Buse and colleagues present findings from a post hoc analysis of the PROMISE-2 study of eptinezumab for the prevention of chronic migraine.

Eptinezumab is an intravenously administered CGRP monoclonal antibody, given at either 100 mg or 300 mg every 3 months. PROMISE-2 was a randomized controlled trial that led to US Food and Drug Administration approval of eptinezumab for the prevention of chronic migraine. The authors here reviewed the data between the two intervention groups and the placebo group and then regrouped these patients according to response at month 1, defined by whether the patient was in a response group of 25%, 50%, or 75% response after 1 month of treatment. This was then compared with the patient global impact of change (PGIC) score at month 6.

This post hoc analysis did not include patients that had no response at all to either intervention or placebo at month 6. A total of 1072 patients were included in this analysis; the 100-mg, 300-mg, and placebo groups had approximately one third of patients in each.

The majority of patients in the 75% responder group continued to improve; more than half of those patients maintained the 75% response rate at month 6. More than two thirds of the 50% responders remained at a 50% response at 6 months as well. Those who responded at < 25% at month 1 were much less likely to achieve 50% response at month 6; however, the patients in the active groups were more likely to achieve a response compared with those in the placebo group.

The PGIC scores also showed significant improvement when comparing among the groups. Those who were "very much improved" at month 1 were significantly more likely to remain that way at the conclusion of the study.

Although prognosticating among different subtypes of CGRP antagonists is not yet possible, the authors here do show the ability to better inform and educate our patients when considering eptinezumab therapy for chronic migraine.

There is an age-old debate among headache specialists about overused medications: to wean or not to wean. The overuse of acute medications has long been shown to contribute to a higher frequency of migraine attacks over time, initially being called "transformed migraine" and subsequently being understood either as a subtype of chronic migraine or a separate headache disorder completely. Medication overuse headache (MOH) is something screened for by all headache providers when evaluating patients for worsening headaches. The addition of a preventive medication is the mainstay of treatment of any instance of higher frequency migraine; when MOH is a contributing factor, many practitioners will recommend complete discontinuation of the overused medications, whereas others will recommend waiting for the preventive medication to offer benefit first. As yet, there have not been any head-to-head trials investigating discontinuation vs. non-discontinuation of overused medications in this population.

Schwedt and colleagues designed a multisite trial prospectively enrolling patients with an International Classification of Headache Disorders (ICHD-3) diagnosis of both chronic migraine and MOH. Participants were told not to change their preventive medications for 4 weeks prior to enrollment. A total of 720 participants were enrolled through 14 clinics. Any patients already on preventive therapy were optimized to the best dose of that therapy or switched to other medications on the basis of the clinical investigator's judgement; all participants were randomly assigned to either discontinuation of the overused medication and given a novel acute therapy or were told to remain on their current acute therapy. No bridging therapies were recommended when switching or discontinuing acute therapies.

Of the 720 participants enrolled, 42% were already on preventive medicine. The overused medications ranged from simple analgesics for 64% of the study population to triptans, combination analgesics, and even opiates in 4% of the population. Butalbital use was included in the combination analgesic group. The primary outcome was reduction in moderate to severe migraine days, and secondary outcomes were scores for disability, depression, and quality of life (based on questionnaires).

There appeared to be no significant difference between the discontinuation and non-discontinuation groups. The authors describe this as noninferiority between the groups. To answer the age-old question of to wean or not to wean — there probably is not an answer that fits every patient. Patient adherence determines the effectiveness of anything we recommend. When evaluating patients with MOH, we have to consider whether discontinuing a medication that the patient has been depending on for months or longer will make it more or less likely for them to adhere to the other recommendations that we are making. Some patients will be very agreeable to try another acute option and stop overusing altogether. Others will be very apprehensive, and a slower, steadier approach that includes using the overused medication may be necessary. We aim always to individualize our recommendations for patients, and this should be no different.

Treatment of psoriatic arthritis (PsA) was the focus of clinical research papers published this month. Despite the advances made in treating PsA with targeted therapies, in most parts of the world, conventional disease-modifying antirheumatic drugs (DMARDs) are the first line of treatment. Methotrexate (MTX) and leflunomide (LEF) are commonly used, but there are limited data on the effectiveness of combination therapy. To address this issue, Mulder and colleagues enrolled 78 patients with active PsA who have two or more swollen joints and randomly allocated them to either 25 mg oral MTX weekly after 4 weeks of 15 mg weekly plus 20 mg LEF daily (n = 39) or MTX plus placebo (monotherapy; n = 39). At week 16, PsA disease activity score was improved significantly in the MTX + LEF vs. MTX monotherapy group (3.1 vs. 3.7; P = .025). Incidence of mild adverse events, such as nausea/vomiting (44% vs. 28%) and altered bowel habits (26% vs. 8%), was higher with MTX + LEF vs. MTX + placebo. So although less well tolerated, MTX + LEF therapy was superior to MTX monotherapy at improving disease activity in patients with PsA.

Biologics targeting tumor necrosis factor (TNF), interleukin (IL) -12/23, -23, and -17A are efficacious for the management of PsA, but questions remain about comparative effectiveness. Gossec and colleagues reported the results from their prospective observational PsABio study that evaluated real-world treatment persistence and effectiveness at 1 year after initiation of first-line to third-line IL-12/23 inhibitor ustekinumab or a TNF inhibitor (TNFi). Their study followed 893 patients. After 1 year of treatment, ustekinumab and the TNFi showed similar persistence (hazard ratio [HR] for stopping/switching treatment 0.82; 95% CI 0.60-1.13) and a similar proportion of patients achieving (on the Disease Activity Index for PsA) clinical low disease activity (odds ratio [OR] 0.80; 95% CI 0.57-1.10) and remission (OR 0.73; 95% CI 0.49-1.07), along with similar safety profiles. Thus in real-world studies, TNFi and ustekinumab seem to have similar effectiveness and safety.

Drug persistence between patients with psoriasis alone vs. those with PsA is also of interest. In a real-life study including 62 patients with psoriasis and 90 patients with PsA who initiated treatment with secukinumab and were followed up for 24 months or until discontinuation, Ortolan and colleagues demonstrated that the retention rate of secukinumab was higher in psoriasis vs. PsA at 12 (85% vs. 68%) and 24 (61% vs. 57%) months, with the risk for secukinumab discontinuation being higher among patients with PsA in the overall cohort (HR 2.43; P = .035) and in patients with obesity in the PsA cohort (P = .021). Thus, the presence of PsA and obesity lower the secukinumab retention rate.

1. Despite the advent of many targeted therapies for PsA, there remain many unmet needs. Deucravacitinib is a novel oral selective inhibitor of tyrosine kinase 2 (TYK2) acting via binding to the TYK2 regulatory domain. In a phase 2 study including 203 patients with active PsA that was intolerant to at least one therapy who were randomly assigned to receive 6 mg deucravacitinib once daily, 12 mg deucravacitinib once daily, or placebo for 16 weeks, Mease and colleagues demonstrated that at week 16, American College of Rheumatology 20 (ACR20) response was significantly higher with 6 mg once-daily deucravacitinib (52.9%, adjusted OR [aOR] 2.4; P = .0134) and 12 mg (62.7%, aOR 3.6; P = .0004) vs. placebo (31.8%), with 12 mg deucravacitinib improving ACR20 response as early as at 8 weeks (P < .05). No serious adverse events were reported. Thus, TYK2 inhibition shows promise in the treatment of PsA and the results from phase 3 trials are awaited.

Treatment of psoriatic arthritis (PsA) was the focus of clinical research papers published this month. Despite the advances made in treating PsA with targeted therapies, in most parts of the world, conventional disease-modifying antirheumatic drugs (DMARDs) are the first line of treatment. Methotrexate (MTX) and leflunomide (LEF) are commonly used, but there are limited data on the effectiveness of combination therapy. To address this issue, Mulder and colleagues enrolled 78 patients with active PsA who have two or more swollen joints and randomly allocated them to either 25 mg oral MTX weekly after 4 weeks of 15 mg weekly plus 20 mg LEF daily (n = 39) or MTX plus placebo (monotherapy; n = 39). At week 16, PsA disease activity score was improved significantly in the MTX + LEF vs. MTX monotherapy group (3.1 vs. 3.7; P = .025). Incidence of mild adverse events, such as nausea/vomiting (44% vs. 28%) and altered bowel habits (26% vs. 8%), was higher with MTX + LEF vs. MTX + placebo. So although less well tolerated, MTX + LEF therapy was superior to MTX monotherapy at improving disease activity in patients with PsA.

Biologics targeting tumor necrosis factor (TNF), interleukin (IL) -12/23, -23, and -17A are efficacious for the management of PsA, but questions remain about comparative effectiveness. Gossec and colleagues reported the results from their prospective observational PsABio study that evaluated real-world treatment persistence and effectiveness at 1 year after initiation of first-line to third-line IL-12/23 inhibitor ustekinumab or a TNF inhibitor (TNFi). Their study followed 893 patients. After 1 year of treatment, ustekinumab and the TNFi showed similar persistence (hazard ratio [HR] for stopping/switching treatment 0.82; 95% CI 0.60-1.13) and a similar proportion of patients achieving (on the Disease Activity Index for PsA) clinical low disease activity (odds ratio [OR] 0.80; 95% CI 0.57-1.10) and remission (OR 0.73; 95% CI 0.49-1.07), along with similar safety profiles. Thus in real-world studies, TNFi and ustekinumab seem to have similar effectiveness and safety.

Drug persistence between patients with psoriasis alone vs. those with PsA is also of interest. In a real-life study including 62 patients with psoriasis and 90 patients with PsA who initiated treatment with secukinumab and were followed up for 24 months or until discontinuation, Ortolan and colleagues demonstrated that the retention rate of secukinumab was higher in psoriasis vs. PsA at 12 (85% vs. 68%) and 24 (61% vs. 57%) months, with the risk for secukinumab discontinuation being higher among patients with PsA in the overall cohort (HR 2.43; P = .035) and in patients with obesity in the PsA cohort (P = .021). Thus, the presence of PsA and obesity lower the secukinumab retention rate.

1. Despite the advent of many targeted therapies for PsA, there remain many unmet needs. Deucravacitinib is a novel oral selective inhibitor of tyrosine kinase 2 (TYK2) acting via binding to the TYK2 regulatory domain. In a phase 2 study including 203 patients with active PsA that was intolerant to at least one therapy who were randomly assigned to receive 6 mg deucravacitinib once daily, 12 mg deucravacitinib once daily, or placebo for 16 weeks, Mease and colleagues demonstrated that at week 16, American College of Rheumatology 20 (ACR20) response was significantly higher with 6 mg once-daily deucravacitinib (52.9%, adjusted OR [aOR] 2.4; P = .0134) and 12 mg (62.7%, aOR 3.6; P = .0004) vs. placebo (31.8%), with 12 mg deucravacitinib improving ACR20 response as early as at 8 weeks (P < .05). No serious adverse events were reported. Thus, TYK2 inhibition shows promise in the treatment of PsA and the results from phase 3 trials are awaited.

Treatment of psoriatic arthritis (PsA) was the focus of clinical research papers published this month. Despite the advances made in treating PsA with targeted therapies, in most parts of the world, conventional disease-modifying antirheumatic drugs (DMARDs) are the first line of treatment. Methotrexate (MTX) and leflunomide (LEF) are commonly used, but there are limited data on the effectiveness of combination therapy. To address this issue, Mulder and colleagues enrolled 78 patients with active PsA who have two or more swollen joints and randomly allocated them to either 25 mg oral MTX weekly after 4 weeks of 15 mg weekly plus 20 mg LEF daily (n = 39) or MTX plus placebo (monotherapy; n = 39). At week 16, PsA disease activity score was improved significantly in the MTX + LEF vs. MTX monotherapy group (3.1 vs. 3.7; P = .025). Incidence of mild adverse events, such as nausea/vomiting (44% vs. 28%) and altered bowel habits (26% vs. 8%), was higher with MTX + LEF vs. MTX + placebo. So although less well tolerated, MTX + LEF therapy was superior to MTX monotherapy at improving disease activity in patients with PsA.

Biologics targeting tumor necrosis factor (TNF), interleukin (IL) -12/23, -23, and -17A are efficacious for the management of PsA, but questions remain about comparative effectiveness. Gossec and colleagues reported the results from their prospective observational PsABio study that evaluated real-world treatment persistence and effectiveness at 1 year after initiation of first-line to third-line IL-12/23 inhibitor ustekinumab or a TNF inhibitor (TNFi). Their study followed 893 patients. After 1 year of treatment, ustekinumab and the TNFi showed similar persistence (hazard ratio [HR] for stopping/switching treatment 0.82; 95% CI 0.60-1.13) and a similar proportion of patients achieving (on the Disease Activity Index for PsA) clinical low disease activity (odds ratio [OR] 0.80; 95% CI 0.57-1.10) and remission (OR 0.73; 95% CI 0.49-1.07), along with similar safety profiles. Thus in real-world studies, TNFi and ustekinumab seem to have similar effectiveness and safety.

Drug persistence between patients with psoriasis alone vs. those with PsA is also of interest. In a real-life study including 62 patients with psoriasis and 90 patients with PsA who initiated treatment with secukinumab and were followed up for 24 months or until discontinuation, Ortolan and colleagues demonstrated that the retention rate of secukinumab was higher in psoriasis vs. PsA at 12 (85% vs. 68%) and 24 (61% vs. 57%) months, with the risk for secukinumab discontinuation being higher among patients with PsA in the overall cohort (HR 2.43; P = .035) and in patients with obesity in the PsA cohort (P = .021). Thus, the presence of PsA and obesity lower the secukinumab retention rate.

1. Despite the advent of many targeted therapies for PsA, there remain many unmet needs. Deucravacitinib is a novel oral selective inhibitor of tyrosine kinase 2 (TYK2) acting via binding to the TYK2 regulatory domain. In a phase 2 study including 203 patients with active PsA that was intolerant to at least one therapy who were randomly assigned to receive 6 mg deucravacitinib once daily, 12 mg deucravacitinib once daily, or placebo for 16 weeks, Mease and colleagues demonstrated that at week 16, American College of Rheumatology 20 (ACR20) response was significantly higher with 6 mg once-daily deucravacitinib (52.9%, adjusted OR [aOR] 2.4; P = .0134) and 12 mg (62.7%, aOR 3.6; P = .0004) vs. placebo (31.8%), with 12 mg deucravacitinib improving ACR20 response as early as at 8 weeks (P < .05). No serious adverse events were reported. Thus, TYK2 inhibition shows promise in the treatment of PsA and the results from phase 3 trials are awaited.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare and aggressive lymphoma arising from follicular T-helper cells that predominantly affects older adults and carries a 5-year overall survival rate of 32%.¹ Notably, as many as 50% of AITL patients present with a skin rash in addition to the more common but nonspecific acute-onset generalized lymphadenopathy, hepatosplenomegaly, and anemia.² At presentation, most AITL patients are already at an advanced (III/IV) stage of disease.

Formerly known as angioimmunoblastic lymphadenopathy with dysproteinemia, AITL was once considered a benign entity that carried a risk for malignant transformation. As more cases have been identified and explored, this entity has been recategorized as a frank lymphoma.³ Therefore, it is critical that AITL be diagnosed and treated as early as possible.

We present the case of a 65-year-old man with clinical features that resembled drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). After extensive workup, he was found to have AITL. This atypical case highlights the importance of maintaining a flexible differential diagnosis in patients with a persistent rash that does not improve with appropriate drug withdrawal and therapy.

Case Report

A 65-year-old Filipino man whose medical history was notable for hepatitis B that had been treated with entecavir for years without issue was admitted to the internal medicine service with fever of unknown origin and malaise of approximately 6 weeks’ duration. Six days prior to admission and 5 days after completing courses of the antiviral oseltamivir phosphate and amoxicillin for an upper respiratory tract infection and sinusitis, he developed worsening of an intermittently pruritic rash of approximately 1 month's duration. The dermatology department was consulted the day of hospital admission for evaluation of the rash. Chronic home medications included entecavir, lisinopril/hydrochlorothiazide, amlodipine, atorvastatin, metformin, salsalate, and over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) as needed.

Physical examination was notable for mild erythema and scale distributed across the entire face; mild facial edema; and a blanchable, nonconfluent, macular erythema distributed across the trunk and upper and proximal lower extremities (Figure). In addition, the patient displayed conjunctival injection, pitting edema of the hands, and bilateral cervical and inguinal lymphadenopathy.

Photographs courtesy of James Contestable, MD (Camp Lejeune, North Carolina).

Laboratory tests revealed mild leukocytosis (11.6×10⁹/L, [reference range, 4.0–10.5×10⁹/L]), anemia (hemoglobin, 125 g/L (reference range, 138–170 g/L); hematocrit, 36.9%, [reference range, 40.0%–50.0%)], eosinophilia (1.07×10⁹/L [reference range, 0.00–0.70×10⁹/L)], hyponatremia, hypokalemia, and a mildly elevated creatinine level. Computed tomography and full-body positron-emission tomography (PET) scans during admission demonstrated diffuse lymphadenopathy. A skin biopsy from the left chest and a left inguinal lymph node biopsy also were performed.

Despite the lack of a clear medication trigger within the usual timeline for severe cutaneous drug-induced hypersensitivity reactions, DRESS syndrome was high on the differential diagnosis at the time of the initial presentation given the diffuse morbilliform eruption with pruritus, facial edema, eosinophilia, and lymphadenopathy.

Home medications were discontinued except for amlodipine, atorvastatin, and entecavir. The patient was treated symptomatically with topical steroids because it was believed that, if the clinical presentation represented DRESS syndrome, it was a mild variant that could be treated topically.⁴ His case was considered mild because of a lack of confirmed organ dysfunction and a mild protracted course.

After discharge following a 3-day inpatient stay, the patient was followed in the clinic weekly for 3 weeks without considerable change in the skin or laboratory findings. Discontinuation of entecavir was discussed and approved by his hepatologist.

Posthospitalization analysis of the punch biopsy specimen from the chest performed during the patient’s hospital stay revealed a superficial and deep dermal lymphoid infiltrate comprising CD3-, CD5-, and programmed cell death protein 1–positive cells with cytologic atypia in a perivascular distribution. Analysis of the lymph node biopsy specimen performed during the hospitalization showed effacement of the nodal architecture, a polymorphous lymphoid cell population with irregular nuclear contour, and abundant clear cytoplasm associated with high endothelial venules (HEVs). Cells of interest were positive for CD3, CD4, CD2, CD5, and CD7, with a subset staining positive for programmed cell death protein 1, inducible costimulator, CD10, and chemokine (C-X-C motif) ligand (CXCL) 13. CD21 demonstrated an expanded follicular dendritic cell meshwork in association with HEVs. Polymerase chain reaction revealed a clonal T-cell population. These findings of the skin and lymph node biopsies were consistent with AITL. Subsequent bone marrow biopsy with flow cytometry showed a normal CD4:CD8 ratio in T cells and no increase in natural killer cells.

Cyclophosphamide–hydroxydaunorubicin–Oncovin–prednisone (CHOP) chemotherapy was initiated; the patient completed a total of 6 cycles. He has had near resolution of the skin findings and is considered in remission based on a PET scan performed approximately 7 months after the initial presentation.

Comment

Angioimmunoblastic T-cell lymphoma is a rare peripheral T-cell lymphoma, part of a group of aggressive neoplasms that constitute approximately 15% of peripheral T-cell lymphomas and approximately 2% of non-Hodgkin lymphomas in adults worldwide.⁵ Cutaneous involvement occurs in approximately half of AITL cases and can be the first manifestation of disease.² Skin findings are largely nonspecific, ranging from simple morbilliform rashes to erythroderma, at times manifesting with purpura.

Given this variability in the presentation of AITL, early diagnosis is challenging in the absence of more specific signs and symptoms.² It can conceivably be mistaken for common entities such as viral exanthems or drug eruptions, depending on the history and context. DRESS syndrome, a T cell-mediated, delayed type-IV hypersensitivity drug reaction can present in a manner highly similar to that of AITL, with cutaneous involvement (diffuse morbilliform rash, fever, facial edema, and generalized lymphadenopathy) and variable systemic involvement. Laboratory findings of eosinophilia, atypical lymphocytes, and thrombocytopenia also might be seen in both entities.⁶ Furthermore, the AITL in our patient was accompanied by electrolyte disturbances that were concerning for syndrome of inappropriate antidiuretic hormone secretion, a rare complication of patients with DRESS syndrome complicated by encephalitis.^7,8

Our patient met 4 RegiSCAR criteria for DRESS syndrome, warranting high clinical suspicion for an offending drug.⁹ DRESS syndrome can be caused by numerous medications—most commonly anticonvulsants, sulfonamides, antibiotics, allopurinol, and NSAIDs. A review of our patient’s medication list identified NSAIDs (including salsalate), entecavir, and amoxicillin, as possible culpable medications. Notably, the only new addition to the patient’s regimen was amoxicillin, which did not fit the typical 2- to 8-week timeline for a DRESS syndrome nidus.¹⁰ Our patient’s fever began well before the antibiotic was initiated, and skin findings appeared within 1 week after the course of amoxicillin was completed. Although there is documented variability in the latency of onset of DRESS syndrome following administration of a culprit medication,¹¹ it is critical to maintain a broad differential diagnosis to allow for further diagnostic information to be obtained, especially when the medication timeline does not align with the clinical presentation.

DRESS syndrome is far more common than AITL. Similarities in their clinical presentation pose a substantial challenge and often cause a delay in the diagnosis of AITL, which is made by excisional tissue biopsy, most commonly of a lymph node, with assessment of morphology and immunophenotyping. Histologic assessment of tissue reveals a polymorphous infiltrate of variably sized atypical lymphocytes with prominent arborizing HEVs as well as expanded populations of follicular dendritic cells that can be detected by CD21 staining. Cells express CD3 and CD4, variably express BCL6 (B-cell lymphoma 6 antigen) and CD10, and also may have partial or complete loss of expression of a subset of pan T-cell antigens (CD2, CD3, CD5, and CD7).^12-18

The treatment approach to AITL mirrors that of other nodal peripheral T-cell lymphomas, including chemotherapy and consideration of autologous stem-cell transplantation. Recent prospective trials of CHOP and CHOP-like chemotherapy have reported 3-year event-free survival and overall survival rates of 50% and 68%, respectively.¹⁹ Novel chemotherapeutic targets and gene-expression profiling are being investigated as potential therapeutic avenues.²⁰

Conclusion

DRESS syndrome and AITL can have near-identical presentations. Clinicians should maintain a high index of suspicion for AITL in patients with presumed DRESS syndrome whose rash does not improve with appropriate drug withdrawal and steroid therapy or who lack a strong offending medication history. In such cases, skin and lymph node biopsies should be performed as early as possible to evaluate for AITL and so that appropriate therapy can be initiated.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare and aggressive lymphoma arising from follicular T-helper cells that predominantly affects older adults and carries a 5-year overall survival rate of 32%.¹ Notably, as many as 50% of AITL patients present with a skin rash in addition to the more common but nonspecific acute-onset generalized lymphadenopathy, hepatosplenomegaly, and anemia.² At presentation, most AITL patients are already at an advanced (III/IV) stage of disease.

Formerly known as angioimmunoblastic lymphadenopathy with dysproteinemia, AITL was once considered a benign entity that carried a risk for malignant transformation. As more cases have been identified and explored, this entity has been recategorized as a frank lymphoma.³ Therefore, it is critical that AITL be diagnosed and treated as early as possible.

We present the case of a 65-year-old man with clinical features that resembled drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). After extensive workup, he was found to have AITL. This atypical case highlights the importance of maintaining a flexible differential diagnosis in patients with a persistent rash that does not improve with appropriate drug withdrawal and therapy.

Case Report

A 65-year-old Filipino man whose medical history was notable for hepatitis B that had been treated with entecavir for years without issue was admitted to the internal medicine service with fever of unknown origin and malaise of approximately 6 weeks’ duration. Six days prior to admission and 5 days after completing courses of the antiviral oseltamivir phosphate and amoxicillin for an upper respiratory tract infection and sinusitis, he developed worsening of an intermittently pruritic rash of approximately 1 month's duration. The dermatology department was consulted the day of hospital admission for evaluation of the rash. Chronic home medications included entecavir, lisinopril/hydrochlorothiazide, amlodipine, atorvastatin, metformin, salsalate, and over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) as needed.

Physical examination was notable for mild erythema and scale distributed across the entire face; mild facial edema; and a blanchable, nonconfluent, macular erythema distributed across the trunk and upper and proximal lower extremities (Figure). In addition, the patient displayed conjunctival injection, pitting edema of the hands, and bilateral cervical and inguinal lymphadenopathy.

Photographs courtesy of James Contestable, MD (Camp Lejeune, North Carolina).

Laboratory tests revealed mild leukocytosis (11.6×10⁹/L, [reference range, 4.0–10.5×10⁹/L]), anemia (hemoglobin, 125 g/L (reference range, 138–170 g/L); hematocrit, 36.9%, [reference range, 40.0%–50.0%)], eosinophilia (1.07×10⁹/L [reference range, 0.00–0.70×10⁹/L)], hyponatremia, hypokalemia, and a mildly elevated creatinine level. Computed tomography and full-body positron-emission tomography (PET) scans during admission demonstrated diffuse lymphadenopathy. A skin biopsy from the left chest and a left inguinal lymph node biopsy also were performed.

Despite the lack of a clear medication trigger within the usual timeline for severe cutaneous drug-induced hypersensitivity reactions, DRESS syndrome was high on the differential diagnosis at the time of the initial presentation given the diffuse morbilliform eruption with pruritus, facial edema, eosinophilia, and lymphadenopathy.

Home medications were discontinued except for amlodipine, atorvastatin, and entecavir. The patient was treated symptomatically with topical steroids because it was believed that, if the clinical presentation represented DRESS syndrome, it was a mild variant that could be treated topically.⁴ His case was considered mild because of a lack of confirmed organ dysfunction and a mild protracted course.

After discharge following a 3-day inpatient stay, the patient was followed in the clinic weekly for 3 weeks without considerable change in the skin or laboratory findings. Discontinuation of entecavir was discussed and approved by his hepatologist.

Posthospitalization analysis of the punch biopsy specimen from the chest performed during the patient’s hospital stay revealed a superficial and deep dermal lymphoid infiltrate comprising CD3-, CD5-, and programmed cell death protein 1–positive cells with cytologic atypia in a perivascular distribution. Analysis of the lymph node biopsy specimen performed during the hospitalization showed effacement of the nodal architecture, a polymorphous lymphoid cell population with irregular nuclear contour, and abundant clear cytoplasm associated with high endothelial venules (HEVs). Cells of interest were positive for CD3, CD4, CD2, CD5, and CD7, with a subset staining positive for programmed cell death protein 1, inducible costimulator, CD10, and chemokine (C-X-C motif) ligand (CXCL) 13. CD21 demonstrated an expanded follicular dendritic cell meshwork in association with HEVs. Polymerase chain reaction revealed a clonal T-cell population. These findings of the skin and lymph node biopsies were consistent with AITL. Subsequent bone marrow biopsy with flow cytometry showed a normal CD4:CD8 ratio in T cells and no increase in natural killer cells.

Cyclophosphamide–hydroxydaunorubicin–Oncovin–prednisone (CHOP) chemotherapy was initiated; the patient completed a total of 6 cycles. He has had near resolution of the skin findings and is considered in remission based on a PET scan performed approximately 7 months after the initial presentation.

Comment

Angioimmunoblastic T-cell lymphoma is a rare peripheral T-cell lymphoma, part of a group of aggressive neoplasms that constitute approximately 15% of peripheral T-cell lymphomas and approximately 2% of non-Hodgkin lymphomas in adults worldwide.⁵ Cutaneous involvement occurs in approximately half of AITL cases and can be the first manifestation of disease.² Skin findings are largely nonspecific, ranging from simple morbilliform rashes to erythroderma, at times manifesting with purpura.

Given this variability in the presentation of AITL, early diagnosis is challenging in the absence of more specific signs and symptoms.² It can conceivably be mistaken for common entities such as viral exanthems or drug eruptions, depending on the history and context. DRESS syndrome, a T cell-mediated, delayed type-IV hypersensitivity drug reaction can present in a manner highly similar to that of AITL, with cutaneous involvement (diffuse morbilliform rash, fever, facial edema, and generalized lymphadenopathy) and variable systemic involvement. Laboratory findings of eosinophilia, atypical lymphocytes, and thrombocytopenia also might be seen in both entities.⁶ Furthermore, the AITL in our patient was accompanied by electrolyte disturbances that were concerning for syndrome of inappropriate antidiuretic hormone secretion, a rare complication of patients with DRESS syndrome complicated by encephalitis.^7,8

Our patient met 4 RegiSCAR criteria for DRESS syndrome, warranting high clinical suspicion for an offending drug.⁹ DRESS syndrome can be caused by numerous medications—most commonly anticonvulsants, sulfonamides, antibiotics, allopurinol, and NSAIDs. A review of our patient’s medication list identified NSAIDs (including salsalate), entecavir, and amoxicillin, as possible culpable medications. Notably, the only new addition to the patient’s regimen was amoxicillin, which did not fit the typical 2- to 8-week timeline for a DRESS syndrome nidus.¹⁰ Our patient’s fever began well before the antibiotic was initiated, and skin findings appeared within 1 week after the course of amoxicillin was completed. Although there is documented variability in the latency of onset of DRESS syndrome following administration of a culprit medication,¹¹ it is critical to maintain a broad differential diagnosis to allow for further diagnostic information to be obtained, especially when the medication timeline does not align with the clinical presentation.

DRESS syndrome is far more common than AITL. Similarities in their clinical presentation pose a substantial challenge and often cause a delay in the diagnosis of AITL, which is made by excisional tissue biopsy, most commonly of a lymph node, with assessment of morphology and immunophenotyping. Histologic assessment of tissue reveals a polymorphous infiltrate of variably sized atypical lymphocytes with prominent arborizing HEVs as well as expanded populations of follicular dendritic cells that can be detected by CD21 staining. Cells express CD3 and CD4, variably express BCL6 (B-cell lymphoma 6 antigen) and CD10, and also may have partial or complete loss of expression of a subset of pan T-cell antigens (CD2, CD3, CD5, and CD7).^12-18

The treatment approach to AITL mirrors that of other nodal peripheral T-cell lymphomas, including chemotherapy and consideration of autologous stem-cell transplantation. Recent prospective trials of CHOP and CHOP-like chemotherapy have reported 3-year event-free survival and overall survival rates of 50% and 68%, respectively.¹⁹ Novel chemotherapeutic targets and gene-expression profiling are being investigated as potential therapeutic avenues.²⁰

Conclusion

DRESS syndrome and AITL can have near-identical presentations. Clinicians should maintain a high index of suspicion for AITL in patients with presumed DRESS syndrome whose rash does not improve with appropriate drug withdrawal and steroid therapy or who lack a strong offending medication history. In such cases, skin and lymph node biopsies should be performed as early as possible to evaluate for AITL and so that appropriate therapy can be initiated.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare and aggressive lymphoma arising from follicular T-helper cells that predominantly affects older adults and carries a 5-year overall survival rate of 32%.¹ Notably, as many as 50% of AITL patients present with a skin rash in addition to the more common but nonspecific acute-onset generalized lymphadenopathy, hepatosplenomegaly, and anemia.² At presentation, most AITL patients are already at an advanced (III/IV) stage of disease.

Formerly known as angioimmunoblastic lymphadenopathy with dysproteinemia, AITL was once considered a benign entity that carried a risk for malignant transformation. As more cases have been identified and explored, this entity has been recategorized as a frank lymphoma.³ Therefore, it is critical that AITL be diagnosed and treated as early as possible.

We present the case of a 65-year-old man with clinical features that resembled drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). After extensive workup, he was found to have AITL. This atypical case highlights the importance of maintaining a flexible differential diagnosis in patients with a persistent rash that does not improve with appropriate drug withdrawal and therapy.

Case Report

A 65-year-old Filipino man whose medical history was notable for hepatitis B that had been treated with entecavir for years without issue was admitted to the internal medicine service with fever of unknown origin and malaise of approximately 6 weeks’ duration. Six days prior to admission and 5 days after completing courses of the antiviral oseltamivir phosphate and amoxicillin for an upper respiratory tract infection and sinusitis, he developed worsening of an intermittently pruritic rash of approximately 1 month's duration. The dermatology department was consulted the day of hospital admission for evaluation of the rash. Chronic home medications included entecavir, lisinopril/hydrochlorothiazide, amlodipine, atorvastatin, metformin, salsalate, and over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) as needed.

Physical examination was notable for mild erythema and scale distributed across the entire face; mild facial edema; and a blanchable, nonconfluent, macular erythema distributed across the trunk and upper and proximal lower extremities (Figure). In addition, the patient displayed conjunctival injection, pitting edema of the hands, and bilateral cervical and inguinal lymphadenopathy.

Photographs courtesy of James Contestable, MD (Camp Lejeune, North Carolina).

Laboratory tests revealed mild leukocytosis (11.6×10⁹/L, [reference range, 4.0–10.5×10⁹/L]), anemia (hemoglobin, 125 g/L (reference range, 138–170 g/L); hematocrit, 36.9%, [reference range, 40.0%–50.0%)], eosinophilia (1.07×10⁹/L [reference range, 0.00–0.70×10⁹/L)], hyponatremia, hypokalemia, and a mildly elevated creatinine level. Computed tomography and full-body positron-emission tomography (PET) scans during admission demonstrated diffuse lymphadenopathy. A skin biopsy from the left chest and a left inguinal lymph node biopsy also were performed.

Despite the lack of a clear medication trigger within the usual timeline for severe cutaneous drug-induced hypersensitivity reactions, DRESS syndrome was high on the differential diagnosis at the time of the initial presentation given the diffuse morbilliform eruption with pruritus, facial edema, eosinophilia, and lymphadenopathy.

Home medications were discontinued except for amlodipine, atorvastatin, and entecavir. The patient was treated symptomatically with topical steroids because it was believed that, if the clinical presentation represented DRESS syndrome, it was a mild variant that could be treated topically.⁴ His case was considered mild because of a lack of confirmed organ dysfunction and a mild protracted course.

After discharge following a 3-day inpatient stay, the patient was followed in the clinic weekly for 3 weeks without considerable change in the skin or laboratory findings. Discontinuation of entecavir was discussed and approved by his hepatologist.

Posthospitalization analysis of the punch biopsy specimen from the chest performed during the patient’s hospital stay revealed a superficial and deep dermal lymphoid infiltrate comprising CD3-, CD5-, and programmed cell death protein 1–positive cells with cytologic atypia in a perivascular distribution. Analysis of the lymph node biopsy specimen performed during the hospitalization showed effacement of the nodal architecture, a polymorphous lymphoid cell population with irregular nuclear contour, and abundant clear cytoplasm associated with high endothelial venules (HEVs). Cells of interest were positive for CD3, CD4, CD2, CD5, and CD7, with a subset staining positive for programmed cell death protein 1, inducible costimulator, CD10, and chemokine (C-X-C motif) ligand (CXCL) 13. CD21 demonstrated an expanded follicular dendritic cell meshwork in association with HEVs. Polymerase chain reaction revealed a clonal T-cell population. These findings of the skin and lymph node biopsies were consistent with AITL. Subsequent bone marrow biopsy with flow cytometry showed a normal CD4:CD8 ratio in T cells and no increase in natural killer cells.

Cyclophosphamide–hydroxydaunorubicin–Oncovin–prednisone (CHOP) chemotherapy was initiated; the patient completed a total of 6 cycles. He has had near resolution of the skin findings and is considered in remission based on a PET scan performed approximately 7 months after the initial presentation.

Comment

Angioimmunoblastic T-cell lymphoma is a rare peripheral T-cell lymphoma, part of a group of aggressive neoplasms that constitute approximately 15% of peripheral T-cell lymphomas and approximately 2% of non-Hodgkin lymphomas in adults worldwide.⁵ Cutaneous involvement occurs in approximately half of AITL cases and can be the first manifestation of disease.² Skin findings are largely nonspecific, ranging from simple morbilliform rashes to erythroderma, at times manifesting with purpura.

Given this variability in the presentation of AITL, early diagnosis is challenging in the absence of more specific signs and symptoms.² It can conceivably be mistaken for common entities such as viral exanthems or drug eruptions, depending on the history and context. DRESS syndrome, a T cell-mediated, delayed type-IV hypersensitivity drug reaction can present in a manner highly similar to that of AITL, with cutaneous involvement (diffuse morbilliform rash, fever, facial edema, and generalized lymphadenopathy) and variable systemic involvement. Laboratory findings of eosinophilia, atypical lymphocytes, and thrombocytopenia also might be seen in both entities.⁶ Furthermore, the AITL in our patient was accompanied by electrolyte disturbances that were concerning for syndrome of inappropriate antidiuretic hormone secretion, a rare complication of patients with DRESS syndrome complicated by encephalitis.^7,8

Our patient met 4 RegiSCAR criteria for DRESS syndrome, warranting high clinical suspicion for an offending drug.⁹ DRESS syndrome can be caused by numerous medications—most commonly anticonvulsants, sulfonamides, antibiotics, allopurinol, and NSAIDs. A review of our patient’s medication list identified NSAIDs (including salsalate), entecavir, and amoxicillin, as possible culpable medications. Notably, the only new addition to the patient’s regimen was amoxicillin, which did not fit the typical 2- to 8-week timeline for a DRESS syndrome nidus.¹⁰ Our patient’s fever began well before the antibiotic was initiated, and skin findings appeared within 1 week after the course of amoxicillin was completed. Although there is documented variability in the latency of onset of DRESS syndrome following administration of a culprit medication,¹¹ it is critical to maintain a broad differential diagnosis to allow for further diagnostic information to be obtained, especially when the medication timeline does not align with the clinical presentation.

DRESS syndrome is far more common than AITL. Similarities in their clinical presentation pose a substantial challenge and often cause a delay in the diagnosis of AITL, which is made by excisional tissue biopsy, most commonly of a lymph node, with assessment of morphology and immunophenotyping. Histologic assessment of tissue reveals a polymorphous infiltrate of variably sized atypical lymphocytes with prominent arborizing HEVs as well as expanded populations of follicular dendritic cells that can be detected by CD21 staining. Cells express CD3 and CD4, variably express BCL6 (B-cell lymphoma 6 antigen) and CD10, and also may have partial or complete loss of expression of a subset of pan T-cell antigens (CD2, CD3, CD5, and CD7).^12-18

The treatment approach to AITL mirrors that of other nodal peripheral T-cell lymphomas, including chemotherapy and consideration of autologous stem-cell transplantation. Recent prospective trials of CHOP and CHOP-like chemotherapy have reported 3-year event-free survival and overall survival rates of 50% and 68%, respectively.¹⁹ Novel chemotherapeutic targets and gene-expression profiling are being investigated as potential therapeutic avenues.²⁰

Conclusion

DRESS syndrome and AITL can have near-identical presentations. Clinicians should maintain a high index of suspicion for AITL in patients with presumed DRESS syndrome whose rash does not improve with appropriate drug withdrawal and steroid therapy or who lack a strong offending medication history. In such cases, skin and lymph node biopsies should be performed as early as possible to evaluate for AITL and so that appropriate therapy can be initiated.

Dr James de Lemos, professor of internal medicine at the University of Texas Southwestern Medical Center, presents a framework to address the most common questions that patients have about the reported muscular, cognitive, and hepatotoxic side effects of statin therapy.

To start, he presents clinical data to address areas of patient concern. Next, he discusses ways to develop — from the first visit — a partnership with patients and encourage their informed decision-making by guiding them to reliable medical sources.

Finally, Dr de Lemos presents strategies that clinicians can use to improve adherence to statin therapy to reach LDL-C treatment goals

--

James de Lemos, MD, PhD
Professor, Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, Texas

James de Lemos, MD, PhD, has disclosed the following relevant financial relationships:

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Amgen; Regeneron; AstraZeneca

Dr James de Lemos, professor of internal medicine at the University of Texas Southwestern Medical Center, presents a framework to address the most common questions that patients have about the reported muscular, cognitive, and hepatotoxic side effects of statin therapy.

To start, he presents clinical data to address areas of patient concern. Next, he discusses ways to develop — from the first visit — a partnership with patients and encourage their informed decision-making by guiding them to reliable medical sources.

Finally, Dr de Lemos presents strategies that clinicians can use to improve adherence to statin therapy to reach LDL-C treatment goals

--

James de Lemos, MD, PhD
Professor, Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, Texas

James de Lemos, MD, PhD, has disclosed the following relevant financial relationships:

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Amgen; Regeneron; AstraZeneca

Dr James de Lemos, professor of internal medicine at the University of Texas Southwestern Medical Center, presents a framework to address the most common questions that patients have about the reported muscular, cognitive, and hepatotoxic side effects of statin therapy.

To start, he presents clinical data to address areas of patient concern. Next, he discusses ways to develop — from the first visit — a partnership with patients and encourage their informed decision-making by guiding them to reliable medical sources.

Finally, Dr de Lemos presents strategies that clinicians can use to improve adherence to statin therapy to reach LDL-C treatment goals

--

James de Lemos, MD, PhD
Professor, Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, Texas

James de Lemos, MD, PhD, has disclosed the following relevant financial relationships:

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Amgen; Regeneron; AstraZeneca