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Enthesitis, arthritis, tenosynovitis linked to dupilumab use for atopic dermatitis
Around 5% of patients treated with dupilumab (Dupixent) for moderate-to-severe atopic dermatitis experience musculoskeletal (MSK) symptoms, according to the results of a descriptive study.
The main MSK symptom seen in the observational cohort was enthesitis, but some patients also experienced arthritis and tenosynovitis a median of 17 weeks after starting dupilumab treatment. Together these symptoms represent a new MSK syndrome, say researchers from the United Kingdom.
“The pattern of MSK symptoms and signs is characteristic of psoriatic arthritis/peripheral spondyloarthritis,” Bruce Kirkham, MD, and collaborators report in Arthritis & Rheumatology.
“We started a few years ago and have been following the patients for quite a long time,” Dr. Kirkham, a consultant rheumatologist at Guy’s and St. Thomas’ NHS Foundation Trust, London, told this news organization.
“We’re still seeing patients with the same type of syndrome presenting occasionally. It’s not a very common adverse event, but we think it continues,” he observed.
“Most of them don’t have very severe problems, and a lot of them can be treated with quite simple drugs or, alternatively, reducing the frequency of the injection,” Dr. Kirkham added.
Characterizing the MSK symptoms
Of 470 patients with atopic dermatitis who started treatment with dupilumab at Guy’s and St. Thomas’ NHS Foundation Trust between October 2018 and February 2021, 36 (7.65%) developed rheumatic symptoms and were referred to the rheumatology department. These individuals had their family history assessed and thorough MSK evaluations, which included antibody and inflammatory markers, ultrasound of the peripheral small joints, and MRI of the large joints and spine.
A total of 26 (5.5%) patients – 14 of whom were male – had inflammatory enthesitis, arthritis, and/or tenosynovitis. Of the others, seven had osteoarthritis and three had degenerative spine disease.
Enthesitis was the most common finding in those with rheumatic symptoms, occurring on its own in 11 patients, with arthritis in three patients, and tenosynovitis in two patients.
These symptoms appeared 2-48 weeks after starting dupilumab treatment and were categorized as mild in 16 (61%) cases, moderate in six cases, and severe in four cases.
No specific predictors of the MSK symptoms seen were noted. Patient age, sex, duration of their atopic dermatitis, or how their skin condition had been previously treated did not help identify those who might develop rheumatic problems.
Conservative management approach
All patients had “outstanding” responses to treatment, Dr. Kirkham noted: The mean Eczema Area and Severity Index score before dupilumab treatment was 21, falling to 4.2 with treatment, indicating a mean 80% improvement.
Co-author Joseph Nathan, MBChB, of London North West Healthcare NHS Trust, who collaborated on the research while working within Dr. Kirkham’s group, said separately: “The concern that patients have is that when they start a medication and develop a side effect is that the medication is going to be stopped.”
Clinicians treating the patients took a conservative approach, prescribing NSAIDs such as cyclooxygenase-2 inhibitors or altering the frequency with which dupilumab was given.
With this approach, MSK symptoms resolved in 15 patients who remained on treatment and in seven who had to stop dupilumab. There were four patients, however, who had unresolved symptoms even once dupilumab treatment had been stopped.
Altering the local cytokine balance
Dupilumab is a monoclonal antibody that binds to the alpha subunit of the interleukin-4 receptor. This results in blocking the function of not only IL-4 but also IL-13.
Dr. Kirkham and colleagues think this might not only alter the balance of cytokines in the skin but also in the joints and entheses with IL-17, IL-23, or even tumor necrosis factor playing a possible role. Another thought is that many circulating T-cells in the skin move to the joints and entheses to trigger symptoms.
IL-13 inhibition does seem to be important, as another British research team, from the Centre for Epidemiology Versus Arthritis at the University of Manchester (England), has found.
At the recent annual meeting of the British Society for Rheumatology, Sizheng Steven Zhao, MBChB, PhD, and colleagues reported that among people who carried a genetic variant predisposing them to having low IL-13 function, there was a higher risk for inflammatory diseases such as psoriatic arthritis and other spondyloarthropathy-related diseases.
Indeed, when the single nucleotide polymorphism rs20541 was present, the odds for having psoriatic arthritis and psoriasis were higher than when it was not.
The findings are consistent with the idea that IL-4 and IL-13 may be acting as a restraint towards MSK diseases in some patients, Dr. Zhao and co-authors suggest.
“The genetic data supports what [Dr. Kirkham and team] have said from a mechanistic point of view,” Dr. Zhao said in an interview. “What you’re observing has a genetic basis.”
Dermatology perspective
Approved by the U.S. Food and Drug Administration in 2017, dupilumab has since been hailed as a “breakthrough” in atopic dermatitis treatment. Given as a subcutaneous injection every 2 weeks, it provides a much-needed option for people who have moderate-to-severe disease and have tried other available treatments, including corticosteroids.
Dupilumab has since also been approved for asthma, chronic sinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis and is used off-label for other skin conditions such as contact dermatitis, chronic spontaneous urticaria, and alopecia areata.
“Dupilumab, like a lot of medications for atopic dermatitis, is a relatively new drug, and we are still learning about its safety,” Joel M. Gelfand, MD, MSCE, of the University of Pennsylvania Perelman School of Medicine, Philadelphia, told this news organization.
“Inflammatory arthritis has been reported in patients treated with dupilumab, and this new study provides some useful estimates,” added Dr. Gelfand, who is a professor of dermatology and epidemiology and directs the Psoriasis and Phototherapy Treatment Center, Philadelphia.
“There was no control group,” Dr. Gelfand said, so “a causal relationship cannot be well established based on these data alone. The mechanism is not known but may result from a shifting of the immune system.”
Dr. Zhao observed: “We don’t know what the natural history of these adverse events is. We don’t know if stopping the drug early will prevent long-term adverse events. So, we don’t know if people will ultimately develop permanent psoriatic arthritis if we don’t intervene quick enough when we observe an adverse event.”
Being aware of the possibility of rheumatic side effects occurring with dupilumab and similar agents is key, Dr. Gelfand and Dr. Kirkham both said independently.
“I have personally seen this entity in my practice,” Dr. Gelfand said. “It is important to clinicians prescribing dupilumab to alert patients about this potential side effect and ask about joint symptoms in follow-up.”
Dr. Kirkham said: “Prescribers need to be aware of it, because up until now it’s been just very vaguely discussed as sort of aches and pains, arthralgias, and it’s a much more specific of a kind of syndrome of enthesitis, arthritis, tenosynovitis – a little like psoriatic arthritis.”
Not everyone has come across these side effects, however, as Steven Daveluy, MD, associate professor and dermatology program director at Wayne State University, Detroit, said in an interview.
“This article and the other case series both noted the musculoskeletal symptoms occurred in about 5% of patients, which surprised me since I haven’t seen it in my practice and have enough patients being treated with dupilumab that I would expect to see a case at that rate,” Dr. Daveluy said.
“The majority of cases are mild and respond to treatment with anti-inflammatories like naproxen, which is available over the counter. It’s likely that patients with a mild case could simply treat their pain with naproxen that’s already in their medicine cabinet until it resolves, never bringing it to the doctor’s attention,” he suggested.
“Dupilumab is still a safe and effective medication that can change the lives of patients suffering from atopic dermatitis,” he said.
“Awareness of this potential side effect can help dermatologists recognize it early and work together with patients to determine the best course of action.”
All research mentioned in this article was independently supported. Dr. Kirkham, Mr. Nathan, Dr. Zhao, and Dr. Daveluy report no relevant financial relationships. Dr. Gelfand has served as a consultant for numerous pharmaceutical companies and receives research grants from Amgen, Boehringer Ingelheim, and Pfizer. He is a co-patent holder of resiquimod for treatment of cutaneous T-cell lymphoma.
A version of this article first appeared on Medscape.com.
Around 5% of patients treated with dupilumab (Dupixent) for moderate-to-severe atopic dermatitis experience musculoskeletal (MSK) symptoms, according to the results of a descriptive study.
The main MSK symptom seen in the observational cohort was enthesitis, but some patients also experienced arthritis and tenosynovitis a median of 17 weeks after starting dupilumab treatment. Together these symptoms represent a new MSK syndrome, say researchers from the United Kingdom.
“The pattern of MSK symptoms and signs is characteristic of psoriatic arthritis/peripheral spondyloarthritis,” Bruce Kirkham, MD, and collaborators report in Arthritis & Rheumatology.
“We started a few years ago and have been following the patients for quite a long time,” Dr. Kirkham, a consultant rheumatologist at Guy’s and St. Thomas’ NHS Foundation Trust, London, told this news organization.
“We’re still seeing patients with the same type of syndrome presenting occasionally. It’s not a very common adverse event, but we think it continues,” he observed.
“Most of them don’t have very severe problems, and a lot of them can be treated with quite simple drugs or, alternatively, reducing the frequency of the injection,” Dr. Kirkham added.
Characterizing the MSK symptoms
Of 470 patients with atopic dermatitis who started treatment with dupilumab at Guy’s and St. Thomas’ NHS Foundation Trust between October 2018 and February 2021, 36 (7.65%) developed rheumatic symptoms and were referred to the rheumatology department. These individuals had their family history assessed and thorough MSK evaluations, which included antibody and inflammatory markers, ultrasound of the peripheral small joints, and MRI of the large joints and spine.
A total of 26 (5.5%) patients – 14 of whom were male – had inflammatory enthesitis, arthritis, and/or tenosynovitis. Of the others, seven had osteoarthritis and three had degenerative spine disease.
Enthesitis was the most common finding in those with rheumatic symptoms, occurring on its own in 11 patients, with arthritis in three patients, and tenosynovitis in two patients.
These symptoms appeared 2-48 weeks after starting dupilumab treatment and were categorized as mild in 16 (61%) cases, moderate in six cases, and severe in four cases.
No specific predictors of the MSK symptoms seen were noted. Patient age, sex, duration of their atopic dermatitis, or how their skin condition had been previously treated did not help identify those who might develop rheumatic problems.
Conservative management approach
All patients had “outstanding” responses to treatment, Dr. Kirkham noted: The mean Eczema Area and Severity Index score before dupilumab treatment was 21, falling to 4.2 with treatment, indicating a mean 80% improvement.
Co-author Joseph Nathan, MBChB, of London North West Healthcare NHS Trust, who collaborated on the research while working within Dr. Kirkham’s group, said separately: “The concern that patients have is that when they start a medication and develop a side effect is that the medication is going to be stopped.”
Clinicians treating the patients took a conservative approach, prescribing NSAIDs such as cyclooxygenase-2 inhibitors or altering the frequency with which dupilumab was given.
With this approach, MSK symptoms resolved in 15 patients who remained on treatment and in seven who had to stop dupilumab. There were four patients, however, who had unresolved symptoms even once dupilumab treatment had been stopped.
Altering the local cytokine balance
Dupilumab is a monoclonal antibody that binds to the alpha subunit of the interleukin-4 receptor. This results in blocking the function of not only IL-4 but also IL-13.
Dr. Kirkham and colleagues think this might not only alter the balance of cytokines in the skin but also in the joints and entheses with IL-17, IL-23, or even tumor necrosis factor playing a possible role. Another thought is that many circulating T-cells in the skin move to the joints and entheses to trigger symptoms.
IL-13 inhibition does seem to be important, as another British research team, from the Centre for Epidemiology Versus Arthritis at the University of Manchester (England), has found.
At the recent annual meeting of the British Society for Rheumatology, Sizheng Steven Zhao, MBChB, PhD, and colleagues reported that among people who carried a genetic variant predisposing them to having low IL-13 function, there was a higher risk for inflammatory diseases such as psoriatic arthritis and other spondyloarthropathy-related diseases.
Indeed, when the single nucleotide polymorphism rs20541 was present, the odds for having psoriatic arthritis and psoriasis were higher than when it was not.
The findings are consistent with the idea that IL-4 and IL-13 may be acting as a restraint towards MSK diseases in some patients, Dr. Zhao and co-authors suggest.
“The genetic data supports what [Dr. Kirkham and team] have said from a mechanistic point of view,” Dr. Zhao said in an interview. “What you’re observing has a genetic basis.”
Dermatology perspective
Approved by the U.S. Food and Drug Administration in 2017, dupilumab has since been hailed as a “breakthrough” in atopic dermatitis treatment. Given as a subcutaneous injection every 2 weeks, it provides a much-needed option for people who have moderate-to-severe disease and have tried other available treatments, including corticosteroids.
Dupilumab has since also been approved for asthma, chronic sinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis and is used off-label for other skin conditions such as contact dermatitis, chronic spontaneous urticaria, and alopecia areata.
“Dupilumab, like a lot of medications for atopic dermatitis, is a relatively new drug, and we are still learning about its safety,” Joel M. Gelfand, MD, MSCE, of the University of Pennsylvania Perelman School of Medicine, Philadelphia, told this news organization.
“Inflammatory arthritis has been reported in patients treated with dupilumab, and this new study provides some useful estimates,” added Dr. Gelfand, who is a professor of dermatology and epidemiology and directs the Psoriasis and Phototherapy Treatment Center, Philadelphia.
“There was no control group,” Dr. Gelfand said, so “a causal relationship cannot be well established based on these data alone. The mechanism is not known but may result from a shifting of the immune system.”
Dr. Zhao observed: “We don’t know what the natural history of these adverse events is. We don’t know if stopping the drug early will prevent long-term adverse events. So, we don’t know if people will ultimately develop permanent psoriatic arthritis if we don’t intervene quick enough when we observe an adverse event.”
Being aware of the possibility of rheumatic side effects occurring with dupilumab and similar agents is key, Dr. Gelfand and Dr. Kirkham both said independently.
“I have personally seen this entity in my practice,” Dr. Gelfand said. “It is important to clinicians prescribing dupilumab to alert patients about this potential side effect and ask about joint symptoms in follow-up.”
Dr. Kirkham said: “Prescribers need to be aware of it, because up until now it’s been just very vaguely discussed as sort of aches and pains, arthralgias, and it’s a much more specific of a kind of syndrome of enthesitis, arthritis, tenosynovitis – a little like psoriatic arthritis.”
Not everyone has come across these side effects, however, as Steven Daveluy, MD, associate professor and dermatology program director at Wayne State University, Detroit, said in an interview.
“This article and the other case series both noted the musculoskeletal symptoms occurred in about 5% of patients, which surprised me since I haven’t seen it in my practice and have enough patients being treated with dupilumab that I would expect to see a case at that rate,” Dr. Daveluy said.
“The majority of cases are mild and respond to treatment with anti-inflammatories like naproxen, which is available over the counter. It’s likely that patients with a mild case could simply treat their pain with naproxen that’s already in their medicine cabinet until it resolves, never bringing it to the doctor’s attention,” he suggested.
“Dupilumab is still a safe and effective medication that can change the lives of patients suffering from atopic dermatitis,” he said.
“Awareness of this potential side effect can help dermatologists recognize it early and work together with patients to determine the best course of action.”
All research mentioned in this article was independently supported. Dr. Kirkham, Mr. Nathan, Dr. Zhao, and Dr. Daveluy report no relevant financial relationships. Dr. Gelfand has served as a consultant for numerous pharmaceutical companies and receives research grants from Amgen, Boehringer Ingelheim, and Pfizer. He is a co-patent holder of resiquimod for treatment of cutaneous T-cell lymphoma.
A version of this article first appeared on Medscape.com.
Around 5% of patients treated with dupilumab (Dupixent) for moderate-to-severe atopic dermatitis experience musculoskeletal (MSK) symptoms, according to the results of a descriptive study.
The main MSK symptom seen in the observational cohort was enthesitis, but some patients also experienced arthritis and tenosynovitis a median of 17 weeks after starting dupilumab treatment. Together these symptoms represent a new MSK syndrome, say researchers from the United Kingdom.
“The pattern of MSK symptoms and signs is characteristic of psoriatic arthritis/peripheral spondyloarthritis,” Bruce Kirkham, MD, and collaborators report in Arthritis & Rheumatology.
“We started a few years ago and have been following the patients for quite a long time,” Dr. Kirkham, a consultant rheumatologist at Guy’s and St. Thomas’ NHS Foundation Trust, London, told this news organization.
“We’re still seeing patients with the same type of syndrome presenting occasionally. It’s not a very common adverse event, but we think it continues,” he observed.
“Most of them don’t have very severe problems, and a lot of them can be treated with quite simple drugs or, alternatively, reducing the frequency of the injection,” Dr. Kirkham added.
Characterizing the MSK symptoms
Of 470 patients with atopic dermatitis who started treatment with dupilumab at Guy’s and St. Thomas’ NHS Foundation Trust between October 2018 and February 2021, 36 (7.65%) developed rheumatic symptoms and were referred to the rheumatology department. These individuals had their family history assessed and thorough MSK evaluations, which included antibody and inflammatory markers, ultrasound of the peripheral small joints, and MRI of the large joints and spine.
A total of 26 (5.5%) patients – 14 of whom were male – had inflammatory enthesitis, arthritis, and/or tenosynovitis. Of the others, seven had osteoarthritis and three had degenerative spine disease.
Enthesitis was the most common finding in those with rheumatic symptoms, occurring on its own in 11 patients, with arthritis in three patients, and tenosynovitis in two patients.
These symptoms appeared 2-48 weeks after starting dupilumab treatment and were categorized as mild in 16 (61%) cases, moderate in six cases, and severe in four cases.
No specific predictors of the MSK symptoms seen were noted. Patient age, sex, duration of their atopic dermatitis, or how their skin condition had been previously treated did not help identify those who might develop rheumatic problems.
Conservative management approach
All patients had “outstanding” responses to treatment, Dr. Kirkham noted: The mean Eczema Area and Severity Index score before dupilumab treatment was 21, falling to 4.2 with treatment, indicating a mean 80% improvement.
Co-author Joseph Nathan, MBChB, of London North West Healthcare NHS Trust, who collaborated on the research while working within Dr. Kirkham’s group, said separately: “The concern that patients have is that when they start a medication and develop a side effect is that the medication is going to be stopped.”
Clinicians treating the patients took a conservative approach, prescribing NSAIDs such as cyclooxygenase-2 inhibitors or altering the frequency with which dupilumab was given.
With this approach, MSK symptoms resolved in 15 patients who remained on treatment and in seven who had to stop dupilumab. There were four patients, however, who had unresolved symptoms even once dupilumab treatment had been stopped.
Altering the local cytokine balance
Dupilumab is a monoclonal antibody that binds to the alpha subunit of the interleukin-4 receptor. This results in blocking the function of not only IL-4 but also IL-13.
Dr. Kirkham and colleagues think this might not only alter the balance of cytokines in the skin but also in the joints and entheses with IL-17, IL-23, or even tumor necrosis factor playing a possible role. Another thought is that many circulating T-cells in the skin move to the joints and entheses to trigger symptoms.
IL-13 inhibition does seem to be important, as another British research team, from the Centre for Epidemiology Versus Arthritis at the University of Manchester (England), has found.
At the recent annual meeting of the British Society for Rheumatology, Sizheng Steven Zhao, MBChB, PhD, and colleagues reported that among people who carried a genetic variant predisposing them to having low IL-13 function, there was a higher risk for inflammatory diseases such as psoriatic arthritis and other spondyloarthropathy-related diseases.
Indeed, when the single nucleotide polymorphism rs20541 was present, the odds for having psoriatic arthritis and psoriasis were higher than when it was not.
The findings are consistent with the idea that IL-4 and IL-13 may be acting as a restraint towards MSK diseases in some patients, Dr. Zhao and co-authors suggest.
“The genetic data supports what [Dr. Kirkham and team] have said from a mechanistic point of view,” Dr. Zhao said in an interview. “What you’re observing has a genetic basis.”
Dermatology perspective
Approved by the U.S. Food and Drug Administration in 2017, dupilumab has since been hailed as a “breakthrough” in atopic dermatitis treatment. Given as a subcutaneous injection every 2 weeks, it provides a much-needed option for people who have moderate-to-severe disease and have tried other available treatments, including corticosteroids.
Dupilumab has since also been approved for asthma, chronic sinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis and is used off-label for other skin conditions such as contact dermatitis, chronic spontaneous urticaria, and alopecia areata.
“Dupilumab, like a lot of medications for atopic dermatitis, is a relatively new drug, and we are still learning about its safety,” Joel M. Gelfand, MD, MSCE, of the University of Pennsylvania Perelman School of Medicine, Philadelphia, told this news organization.
“Inflammatory arthritis has been reported in patients treated with dupilumab, and this new study provides some useful estimates,” added Dr. Gelfand, who is a professor of dermatology and epidemiology and directs the Psoriasis and Phototherapy Treatment Center, Philadelphia.
“There was no control group,” Dr. Gelfand said, so “a causal relationship cannot be well established based on these data alone. The mechanism is not known but may result from a shifting of the immune system.”
Dr. Zhao observed: “We don’t know what the natural history of these adverse events is. We don’t know if stopping the drug early will prevent long-term adverse events. So, we don’t know if people will ultimately develop permanent psoriatic arthritis if we don’t intervene quick enough when we observe an adverse event.”
Being aware of the possibility of rheumatic side effects occurring with dupilumab and similar agents is key, Dr. Gelfand and Dr. Kirkham both said independently.
“I have personally seen this entity in my practice,” Dr. Gelfand said. “It is important to clinicians prescribing dupilumab to alert patients about this potential side effect and ask about joint symptoms in follow-up.”
Dr. Kirkham said: “Prescribers need to be aware of it, because up until now it’s been just very vaguely discussed as sort of aches and pains, arthralgias, and it’s a much more specific of a kind of syndrome of enthesitis, arthritis, tenosynovitis – a little like psoriatic arthritis.”
Not everyone has come across these side effects, however, as Steven Daveluy, MD, associate professor and dermatology program director at Wayne State University, Detroit, said in an interview.
“This article and the other case series both noted the musculoskeletal symptoms occurred in about 5% of patients, which surprised me since I haven’t seen it in my practice and have enough patients being treated with dupilumab that I would expect to see a case at that rate,” Dr. Daveluy said.
“The majority of cases are mild and respond to treatment with anti-inflammatories like naproxen, which is available over the counter. It’s likely that patients with a mild case could simply treat their pain with naproxen that’s already in their medicine cabinet until it resolves, never bringing it to the doctor’s attention,” he suggested.
“Dupilumab is still a safe and effective medication that can change the lives of patients suffering from atopic dermatitis,” he said.
“Awareness of this potential side effect can help dermatologists recognize it early and work together with patients to determine the best course of action.”
All research mentioned in this article was independently supported. Dr. Kirkham, Mr. Nathan, Dr. Zhao, and Dr. Daveluy report no relevant financial relationships. Dr. Gelfand has served as a consultant for numerous pharmaceutical companies and receives research grants from Amgen, Boehringer Ingelheim, and Pfizer. He is a co-patent holder of resiquimod for treatment of cutaneous T-cell lymphoma.
A version of this article first appeared on Medscape.com.
FROM ARTHRITIS & RHEUMATOLOGY
Two biologics show no difference in axial spondyloarthritis radiographic progression over 2 years
MILAN – Secukinumab (Cosentyx) and biosimilar adalimumab-adaz (Hyrimoz) injection proved to have similar efficacy for limiting spinal radiographic progression over a 2-year period in patients with radiographic axial spondyloarthritis (r-axSpA) in the SURPASS study, a phase 3b, randomized controlled trial.
The study, presented at the annual European Congress of Rheumatology, represents the first head-to-head trial comparing the effects of two biologic disease-modifying antirheumatic drugs (bDMARDs) in axSpA. Notably, secukinumab and adalimumab-adaz target different pathways as an interleukin-17A inhibitor and a tumor necrosis factor (TNF) inhibitor, respectively.
Both TNF and IL-17A have been implicated in the pathogenesis of axSpA. Anti-TNF agents and the IL-17A inhibitor secukinumab have demonstrated effectiveness in improving symptoms, signs, and physical function in patients with axSpA and are approved therapies for the disease. However, limited data exist regarding the effect of bDMARDs in slowing radiographic progression, which is a key therapeutic goal in axSpA to prevent irreversible structural damage.
The SURPASS trial, funded by Novartis, enrolled 859 biologic-naive adult patients with moderate to severe r-axSpA. Participants were randomly assigned (1:1:1) to receive secukinumab 150 mg (n = 287), secukinumab 300 mg (n = 286), or adalimumab-adaz 40 mg (n = 286). The primary endpoint was the proportion of patients with no radiographic progression at the 2-year mark (week 104). Radiographic progression was defined as a change from baseline in modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; range, 0-72) of 0.5 or less. The radiographic assessments were conducted by three independent evaluators who were blinded to treatment and the chronology of images.
Baseline characteristics indicated that the study population (78.5% male; mean age, 42.1 years) had a high risk of radiographic progression. The proportion of patients with no radiographic progression at week 104 was 66.1% in the secukinumab 150-mg arm, 66.9% in the secukinumab 300-mg arm, and 65.6% in the adalimumab-adaz arm. The mean change from baseline in mSASSS was 0.54, 0.55, and 0.72, respectively.
Notably, more than half of the patients (56.9%, 53.8%, and 53.3%, respectively) with at least one syndesmophyte at baseline did not develop new syndesmophytes over the 2-year period. The observed reductions in sacroiliac joint and spinal edema were comparable across all treatment groups. The safety profile of secukinumab and adalimumab-adaz was consistent with their well-established profiles.
No significant differences were observed between the treatment groups in terms of the primary and secondary endpoints. Study presenter and lead author Xenofon Baraliakos, MD, PhD, medical director of the Rheumatism Centre and professor of internal medicine and rheumatology at Ruhr University Bochum (Germany), stated: “Anti-TNF therapy has been considered the gold-standard treatment for axial spondyloarthritis in terms of slowing or halting radiographic progression. Our aim was to investigate whether other modes of action, such as IL-17 inhibition, achieve the same results. The primary hypothesis was that IL-17 inhibition could be even more effective than TNF blockade. However, our data indicate that secukinumab is at least as good as TNF blockers.
“Several risk factors, including high C-reactive protein [CRP] levels, male gender, high disease activity, and baseline radiographic damage (e.g., presence of syndesmophytes), are associated with structural progression,” Dr. Baraliakos explained. “We performed subgroup analyses and found no differences. This is a positive outcome as it suggests that there is no need to select patients based on either secukinumab or anti-TNF agents.”
When making treatment decisions, other factors must be taken into consideration. “Our study specifically examined radiographic progression. The clinical outcomes, indications, and contraindications for anti-TNF agents and secukinumab differ,” Dr. Baraliakos explained. “For instance, secukinumab may be preferred for patients with psoriasis, while adalimumab is more suitable for those with inflammatory bowel disease. Although these bDMARDs are not interchangeable, they have the same positive effect on radiographic progression.”
Not a definitive answer about structural progression
An open question remains. Alexandre Sepriano, MD, PhD, a rheumatologist at Hospital Egas Moniz and researcher at NOVA Medical School, both in Lisbon, commented: “The study was designed to maximize the chances of detecting a difference, if any, in spinal radiographic progression between secukinumab 150 mg and 300 mg and adalimumab. The included patients had a high risk of progression at baseline; in addition to back pain, they either had elevated CRP or at least one syndesmophyte on spine radiographs. Consequently, baseline structural damage was high [mean mSASSS, 17].”
“After 2 years, no difference was observed in the percentage of patients with no progression across the study arms. This finding does not definitively answer whether bDMARDs can modify structural progression or if secukinumab and adalimumab are equally effective in this regard,” explained Dr. Sepriano, who was not involved in the study. “However, there is good news for patients. Both secukinumab and adalimumab are potent anti-inflammatory drugs that effectively alleviate axial inflammation caused by the disease. This was demonstrated by the reduction in inflammatory scores on MRI in the SURPASS study. It aligns with robust evidence that both IL-17 inhibitors and TNF inhibitors are effective in improving symptoms in individuals with axSpA.
“Researchers continue to make significant efforts to understand how axial inflammation contributes to pathological new bone formation in axSpA,” Dr. Sepriano continued. “Understanding these mechanisms can guide future research aimed at interfering with disease progression. Furthermore, the use of new methods to quantify structural progression in axSpA, such as low-dose CT, which has shown greater sensitivity to change than traditional methods, can pave the way for new studies with fewer patients and shorter follow-up periods, thereby increasing the likelihood of detecting treatment effects.”
Dr. Baraliakos has received speaking and consulting fees and grant/research support from AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, and UCB. Dr. Sepriano has received speaking and/or consulting fees from AbbVie, Novartis, UCB, and Lilly. The trial was sponsored by Novartis.
A version of this article first appeared on Medscape.com.
MILAN – Secukinumab (Cosentyx) and biosimilar adalimumab-adaz (Hyrimoz) injection proved to have similar efficacy for limiting spinal radiographic progression over a 2-year period in patients with radiographic axial spondyloarthritis (r-axSpA) in the SURPASS study, a phase 3b, randomized controlled trial.
The study, presented at the annual European Congress of Rheumatology, represents the first head-to-head trial comparing the effects of two biologic disease-modifying antirheumatic drugs (bDMARDs) in axSpA. Notably, secukinumab and adalimumab-adaz target different pathways as an interleukin-17A inhibitor and a tumor necrosis factor (TNF) inhibitor, respectively.
Both TNF and IL-17A have been implicated in the pathogenesis of axSpA. Anti-TNF agents and the IL-17A inhibitor secukinumab have demonstrated effectiveness in improving symptoms, signs, and physical function in patients with axSpA and are approved therapies for the disease. However, limited data exist regarding the effect of bDMARDs in slowing radiographic progression, which is a key therapeutic goal in axSpA to prevent irreversible structural damage.
The SURPASS trial, funded by Novartis, enrolled 859 biologic-naive adult patients with moderate to severe r-axSpA. Participants were randomly assigned (1:1:1) to receive secukinumab 150 mg (n = 287), secukinumab 300 mg (n = 286), or adalimumab-adaz 40 mg (n = 286). The primary endpoint was the proportion of patients with no radiographic progression at the 2-year mark (week 104). Radiographic progression was defined as a change from baseline in modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; range, 0-72) of 0.5 or less. The radiographic assessments were conducted by three independent evaluators who were blinded to treatment and the chronology of images.
Baseline characteristics indicated that the study population (78.5% male; mean age, 42.1 years) had a high risk of radiographic progression. The proportion of patients with no radiographic progression at week 104 was 66.1% in the secukinumab 150-mg arm, 66.9% in the secukinumab 300-mg arm, and 65.6% in the adalimumab-adaz arm. The mean change from baseline in mSASSS was 0.54, 0.55, and 0.72, respectively.
Notably, more than half of the patients (56.9%, 53.8%, and 53.3%, respectively) with at least one syndesmophyte at baseline did not develop new syndesmophytes over the 2-year period. The observed reductions in sacroiliac joint and spinal edema were comparable across all treatment groups. The safety profile of secukinumab and adalimumab-adaz was consistent with their well-established profiles.
No significant differences were observed between the treatment groups in terms of the primary and secondary endpoints. Study presenter and lead author Xenofon Baraliakos, MD, PhD, medical director of the Rheumatism Centre and professor of internal medicine and rheumatology at Ruhr University Bochum (Germany), stated: “Anti-TNF therapy has been considered the gold-standard treatment for axial spondyloarthritis in terms of slowing or halting radiographic progression. Our aim was to investigate whether other modes of action, such as IL-17 inhibition, achieve the same results. The primary hypothesis was that IL-17 inhibition could be even more effective than TNF blockade. However, our data indicate that secukinumab is at least as good as TNF blockers.
“Several risk factors, including high C-reactive protein [CRP] levels, male gender, high disease activity, and baseline radiographic damage (e.g., presence of syndesmophytes), are associated with structural progression,” Dr. Baraliakos explained. “We performed subgroup analyses and found no differences. This is a positive outcome as it suggests that there is no need to select patients based on either secukinumab or anti-TNF agents.”
When making treatment decisions, other factors must be taken into consideration. “Our study specifically examined radiographic progression. The clinical outcomes, indications, and contraindications for anti-TNF agents and secukinumab differ,” Dr. Baraliakos explained. “For instance, secukinumab may be preferred for patients with psoriasis, while adalimumab is more suitable for those with inflammatory bowel disease. Although these bDMARDs are not interchangeable, they have the same positive effect on radiographic progression.”
Not a definitive answer about structural progression
An open question remains. Alexandre Sepriano, MD, PhD, a rheumatologist at Hospital Egas Moniz and researcher at NOVA Medical School, both in Lisbon, commented: “The study was designed to maximize the chances of detecting a difference, if any, in spinal radiographic progression between secukinumab 150 mg and 300 mg and adalimumab. The included patients had a high risk of progression at baseline; in addition to back pain, they either had elevated CRP or at least one syndesmophyte on spine radiographs. Consequently, baseline structural damage was high [mean mSASSS, 17].”
“After 2 years, no difference was observed in the percentage of patients with no progression across the study arms. This finding does not definitively answer whether bDMARDs can modify structural progression or if secukinumab and adalimumab are equally effective in this regard,” explained Dr. Sepriano, who was not involved in the study. “However, there is good news for patients. Both secukinumab and adalimumab are potent anti-inflammatory drugs that effectively alleviate axial inflammation caused by the disease. This was demonstrated by the reduction in inflammatory scores on MRI in the SURPASS study. It aligns with robust evidence that both IL-17 inhibitors and TNF inhibitors are effective in improving symptoms in individuals with axSpA.
“Researchers continue to make significant efforts to understand how axial inflammation contributes to pathological new bone formation in axSpA,” Dr. Sepriano continued. “Understanding these mechanisms can guide future research aimed at interfering with disease progression. Furthermore, the use of new methods to quantify structural progression in axSpA, such as low-dose CT, which has shown greater sensitivity to change than traditional methods, can pave the way for new studies with fewer patients and shorter follow-up periods, thereby increasing the likelihood of detecting treatment effects.”
Dr. Baraliakos has received speaking and consulting fees and grant/research support from AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, and UCB. Dr. Sepriano has received speaking and/or consulting fees from AbbVie, Novartis, UCB, and Lilly. The trial was sponsored by Novartis.
A version of this article first appeared on Medscape.com.
MILAN – Secukinumab (Cosentyx) and biosimilar adalimumab-adaz (Hyrimoz) injection proved to have similar efficacy for limiting spinal radiographic progression over a 2-year period in patients with radiographic axial spondyloarthritis (r-axSpA) in the SURPASS study, a phase 3b, randomized controlled trial.
The study, presented at the annual European Congress of Rheumatology, represents the first head-to-head trial comparing the effects of two biologic disease-modifying antirheumatic drugs (bDMARDs) in axSpA. Notably, secukinumab and adalimumab-adaz target different pathways as an interleukin-17A inhibitor and a tumor necrosis factor (TNF) inhibitor, respectively.
Both TNF and IL-17A have been implicated in the pathogenesis of axSpA. Anti-TNF agents and the IL-17A inhibitor secukinumab have demonstrated effectiveness in improving symptoms, signs, and physical function in patients with axSpA and are approved therapies for the disease. However, limited data exist regarding the effect of bDMARDs in slowing radiographic progression, which is a key therapeutic goal in axSpA to prevent irreversible structural damage.
The SURPASS trial, funded by Novartis, enrolled 859 biologic-naive adult patients with moderate to severe r-axSpA. Participants were randomly assigned (1:1:1) to receive secukinumab 150 mg (n = 287), secukinumab 300 mg (n = 286), or adalimumab-adaz 40 mg (n = 286). The primary endpoint was the proportion of patients with no radiographic progression at the 2-year mark (week 104). Radiographic progression was defined as a change from baseline in modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; range, 0-72) of 0.5 or less. The radiographic assessments were conducted by three independent evaluators who were blinded to treatment and the chronology of images.
Baseline characteristics indicated that the study population (78.5% male; mean age, 42.1 years) had a high risk of radiographic progression. The proportion of patients with no radiographic progression at week 104 was 66.1% in the secukinumab 150-mg arm, 66.9% in the secukinumab 300-mg arm, and 65.6% in the adalimumab-adaz arm. The mean change from baseline in mSASSS was 0.54, 0.55, and 0.72, respectively.
Notably, more than half of the patients (56.9%, 53.8%, and 53.3%, respectively) with at least one syndesmophyte at baseline did not develop new syndesmophytes over the 2-year period. The observed reductions in sacroiliac joint and spinal edema were comparable across all treatment groups. The safety profile of secukinumab and adalimumab-adaz was consistent with their well-established profiles.
No significant differences were observed between the treatment groups in terms of the primary and secondary endpoints. Study presenter and lead author Xenofon Baraliakos, MD, PhD, medical director of the Rheumatism Centre and professor of internal medicine and rheumatology at Ruhr University Bochum (Germany), stated: “Anti-TNF therapy has been considered the gold-standard treatment for axial spondyloarthritis in terms of slowing or halting radiographic progression. Our aim was to investigate whether other modes of action, such as IL-17 inhibition, achieve the same results. The primary hypothesis was that IL-17 inhibition could be even more effective than TNF blockade. However, our data indicate that secukinumab is at least as good as TNF blockers.
“Several risk factors, including high C-reactive protein [CRP] levels, male gender, high disease activity, and baseline radiographic damage (e.g., presence of syndesmophytes), are associated with structural progression,” Dr. Baraliakos explained. “We performed subgroup analyses and found no differences. This is a positive outcome as it suggests that there is no need to select patients based on either secukinumab or anti-TNF agents.”
When making treatment decisions, other factors must be taken into consideration. “Our study specifically examined radiographic progression. The clinical outcomes, indications, and contraindications for anti-TNF agents and secukinumab differ,” Dr. Baraliakos explained. “For instance, secukinumab may be preferred for patients with psoriasis, while adalimumab is more suitable for those with inflammatory bowel disease. Although these bDMARDs are not interchangeable, they have the same positive effect on radiographic progression.”
Not a definitive answer about structural progression
An open question remains. Alexandre Sepriano, MD, PhD, a rheumatologist at Hospital Egas Moniz and researcher at NOVA Medical School, both in Lisbon, commented: “The study was designed to maximize the chances of detecting a difference, if any, in spinal radiographic progression between secukinumab 150 mg and 300 mg and adalimumab. The included patients had a high risk of progression at baseline; in addition to back pain, they either had elevated CRP or at least one syndesmophyte on spine radiographs. Consequently, baseline structural damage was high [mean mSASSS, 17].”
“After 2 years, no difference was observed in the percentage of patients with no progression across the study arms. This finding does not definitively answer whether bDMARDs can modify structural progression or if secukinumab and adalimumab are equally effective in this regard,” explained Dr. Sepriano, who was not involved in the study. “However, there is good news for patients. Both secukinumab and adalimumab are potent anti-inflammatory drugs that effectively alleviate axial inflammation caused by the disease. This was demonstrated by the reduction in inflammatory scores on MRI in the SURPASS study. It aligns with robust evidence that both IL-17 inhibitors and TNF inhibitors are effective in improving symptoms in individuals with axSpA.
“Researchers continue to make significant efforts to understand how axial inflammation contributes to pathological new bone formation in axSpA,” Dr. Sepriano continued. “Understanding these mechanisms can guide future research aimed at interfering with disease progression. Furthermore, the use of new methods to quantify structural progression in axSpA, such as low-dose CT, which has shown greater sensitivity to change than traditional methods, can pave the way for new studies with fewer patients and shorter follow-up periods, thereby increasing the likelihood of detecting treatment effects.”
Dr. Baraliakos has received speaking and consulting fees and grant/research support from AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, and UCB. Dr. Sepriano has received speaking and/or consulting fees from AbbVie, Novartis, UCB, and Lilly. The trial was sponsored by Novartis.
A version of this article first appeared on Medscape.com.
AT EULAR 2023
Lupus nephritis: Hopes, questions arise for baricitinib
MILAN – The oral Janus kinase (JAK) 1/2 inhibitor baricitinib (Olumiant) demonstrated significantly better efficacy than cyclophosphamide infusions in the treatment of lupus nephritis in a small, independently funded, phase 3, double-blind clinical trial, Manal Hassanien, MD, reported at the annual European Congress of Rheumatology.
Baricitinib, licensed by Eli Lilly, has been recognized as a potential therapeutic option in systemic lupus, and is approved in the United States to treat RA, alopecia areata, and COVID-19 in certain hospitalized adults. It is also approved to treat atopic dermatitis in Europe. However, it previously yielded disappointing results in phase 3 clinical trials SLE-BRAVE-I and SLE-BRAVE-II for systemic lupus erythematosus. The trial results presented at EULAR suggest that baricitinib could be beneficial in the treatment of lupus nephritis, further establishing the role of JAK inhibitors in autoimmune disease therapy.
“Lupus nephritis typically develops within 5 years of initial lupus symptoms,” said Dr. Hassanien, of the rheumatology research and advanced therapeutics department at Assiut (Egypt) University. “Research has shown that up to 60% of lupus patients will eventually develop lupus nephritis. The management of proliferative lupus nephritis usually involves an initial phase focused on preventing the development of irreversible damage, followed by a maintenance phase to control lupus activity. Despite significant progress, lupus nephritis still carries an increased risk of end-stage renal disease and mortality.”
The study’s primary endpoint of 24-hour proteinuria response rate (≥ 50% reduction from baseline) at week 12 was significantly greater with baricitinib 4 mg daily, compared with monthly cyclophosphamide infusions at 0.7 mg/m2 (70% vs. 43%; P < .0001). At week 24, 76.6% of the baricitinib group met the primary endpoint, compared with 50% in the cyclophosphamide group. Two multiplicity-controlled secondary endpoints, C3 serum level and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), also showed statistical significance at 12 weeks (P < .01).
The 6-month trial included 60 adult patients (age 18 years and older) with a clinical diagnosis of lupus nephritis fulfilling classification criteria for LN grade III and IV. Patients needed to demonstrate objective signs of active nephritis consistent with persistent proteinuria greater than 0.5 g/day and/or cellular casts at screening to be included. Additional inclusion criteria were SLEDAI-2K greater than 4 and assessment of anti–double-stranded DNA and C3 serum levels at study entry. The patients were randomly assigned to two equal-sized groups, with one group receiving baricitinib 4 mg daily and a monthly placebo saline infusion, and the other group receiving monthly cyclophosphamide infusions and oral placebo tablets.
The incidence of adverse events was comparable between the two treatment groups, with 48% of patients in the baricitinib group and 46% in the cyclophosphamide group experiencing adverse events. Only three serious adverse events, specifically serious infection or herpes zoster, were recorded, leading to treatment discontinuation.
Two patients (6.6%) in the baricitinib group and one patient (3.3%) in the cyclophosphamide group were affected. The researchers recorded no major adverse cardiovascular or venous thromboembolic events, which are known to occur at higher rates among some users of baricitinib and other JAK inhibitors. The safety profile of baricitinib was consistent with observations made in other inflammatory musculoskeletal diseases, and no new risks were identified.
However, there were some concerns expressed by audience members during the presentation.
“The primary endpoint is limited at proteinuria, while biopsy is considered the gold standard for measuring efficacy,” said Eric F. Morand, MD, head of the Monash Health rheumatology unit, Melbourne. This was not the only critical comment regarding the study that emerged during the discussion. The use of a 4-mg dosage regimen throughout the entire study duration (despite official recommendations suggesting a 2-mg dosage in the long run) and the positive outcomes observed in the control group treated with cyclophosphamide were also mentioned.
Dr. Hassanien acknowledged that this is a small and relatively short study and disclosed plans to extend the follow-up period to 1 year and conduct a renal biopsy.
Dr. Hassanien reported no relevant financial relationships. Assiut University funded the trial.
A version of this article first appeared on Medscape.com.
MILAN – The oral Janus kinase (JAK) 1/2 inhibitor baricitinib (Olumiant) demonstrated significantly better efficacy than cyclophosphamide infusions in the treatment of lupus nephritis in a small, independently funded, phase 3, double-blind clinical trial, Manal Hassanien, MD, reported at the annual European Congress of Rheumatology.
Baricitinib, licensed by Eli Lilly, has been recognized as a potential therapeutic option in systemic lupus, and is approved in the United States to treat RA, alopecia areata, and COVID-19 in certain hospitalized adults. It is also approved to treat atopic dermatitis in Europe. However, it previously yielded disappointing results in phase 3 clinical trials SLE-BRAVE-I and SLE-BRAVE-II for systemic lupus erythematosus. The trial results presented at EULAR suggest that baricitinib could be beneficial in the treatment of lupus nephritis, further establishing the role of JAK inhibitors in autoimmune disease therapy.
“Lupus nephritis typically develops within 5 years of initial lupus symptoms,” said Dr. Hassanien, of the rheumatology research and advanced therapeutics department at Assiut (Egypt) University. “Research has shown that up to 60% of lupus patients will eventually develop lupus nephritis. The management of proliferative lupus nephritis usually involves an initial phase focused on preventing the development of irreversible damage, followed by a maintenance phase to control lupus activity. Despite significant progress, lupus nephritis still carries an increased risk of end-stage renal disease and mortality.”
The study’s primary endpoint of 24-hour proteinuria response rate (≥ 50% reduction from baseline) at week 12 was significantly greater with baricitinib 4 mg daily, compared with monthly cyclophosphamide infusions at 0.7 mg/m2 (70% vs. 43%; P < .0001). At week 24, 76.6% of the baricitinib group met the primary endpoint, compared with 50% in the cyclophosphamide group. Two multiplicity-controlled secondary endpoints, C3 serum level and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), also showed statistical significance at 12 weeks (P < .01).
The 6-month trial included 60 adult patients (age 18 years and older) with a clinical diagnosis of lupus nephritis fulfilling classification criteria for LN grade III and IV. Patients needed to demonstrate objective signs of active nephritis consistent with persistent proteinuria greater than 0.5 g/day and/or cellular casts at screening to be included. Additional inclusion criteria were SLEDAI-2K greater than 4 and assessment of anti–double-stranded DNA and C3 serum levels at study entry. The patients were randomly assigned to two equal-sized groups, with one group receiving baricitinib 4 mg daily and a monthly placebo saline infusion, and the other group receiving monthly cyclophosphamide infusions and oral placebo tablets.
The incidence of adverse events was comparable between the two treatment groups, with 48% of patients in the baricitinib group and 46% in the cyclophosphamide group experiencing adverse events. Only three serious adverse events, specifically serious infection or herpes zoster, were recorded, leading to treatment discontinuation.
Two patients (6.6%) in the baricitinib group and one patient (3.3%) in the cyclophosphamide group were affected. The researchers recorded no major adverse cardiovascular or venous thromboembolic events, which are known to occur at higher rates among some users of baricitinib and other JAK inhibitors. The safety profile of baricitinib was consistent with observations made in other inflammatory musculoskeletal diseases, and no new risks were identified.
However, there were some concerns expressed by audience members during the presentation.
“The primary endpoint is limited at proteinuria, while biopsy is considered the gold standard for measuring efficacy,” said Eric F. Morand, MD, head of the Monash Health rheumatology unit, Melbourne. This was not the only critical comment regarding the study that emerged during the discussion. The use of a 4-mg dosage regimen throughout the entire study duration (despite official recommendations suggesting a 2-mg dosage in the long run) and the positive outcomes observed in the control group treated with cyclophosphamide were also mentioned.
Dr. Hassanien acknowledged that this is a small and relatively short study and disclosed plans to extend the follow-up period to 1 year and conduct a renal biopsy.
Dr. Hassanien reported no relevant financial relationships. Assiut University funded the trial.
A version of this article first appeared on Medscape.com.
MILAN – The oral Janus kinase (JAK) 1/2 inhibitor baricitinib (Olumiant) demonstrated significantly better efficacy than cyclophosphamide infusions in the treatment of lupus nephritis in a small, independently funded, phase 3, double-blind clinical trial, Manal Hassanien, MD, reported at the annual European Congress of Rheumatology.
Baricitinib, licensed by Eli Lilly, has been recognized as a potential therapeutic option in systemic lupus, and is approved in the United States to treat RA, alopecia areata, and COVID-19 in certain hospitalized adults. It is also approved to treat atopic dermatitis in Europe. However, it previously yielded disappointing results in phase 3 clinical trials SLE-BRAVE-I and SLE-BRAVE-II for systemic lupus erythematosus. The trial results presented at EULAR suggest that baricitinib could be beneficial in the treatment of lupus nephritis, further establishing the role of JAK inhibitors in autoimmune disease therapy.
“Lupus nephritis typically develops within 5 years of initial lupus symptoms,” said Dr. Hassanien, of the rheumatology research and advanced therapeutics department at Assiut (Egypt) University. “Research has shown that up to 60% of lupus patients will eventually develop lupus nephritis. The management of proliferative lupus nephritis usually involves an initial phase focused on preventing the development of irreversible damage, followed by a maintenance phase to control lupus activity. Despite significant progress, lupus nephritis still carries an increased risk of end-stage renal disease and mortality.”
The study’s primary endpoint of 24-hour proteinuria response rate (≥ 50% reduction from baseline) at week 12 was significantly greater with baricitinib 4 mg daily, compared with monthly cyclophosphamide infusions at 0.7 mg/m2 (70% vs. 43%; P < .0001). At week 24, 76.6% of the baricitinib group met the primary endpoint, compared with 50% in the cyclophosphamide group. Two multiplicity-controlled secondary endpoints, C3 serum level and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), also showed statistical significance at 12 weeks (P < .01).
The 6-month trial included 60 adult patients (age 18 years and older) with a clinical diagnosis of lupus nephritis fulfilling classification criteria for LN grade III and IV. Patients needed to demonstrate objective signs of active nephritis consistent with persistent proteinuria greater than 0.5 g/day and/or cellular casts at screening to be included. Additional inclusion criteria were SLEDAI-2K greater than 4 and assessment of anti–double-stranded DNA and C3 serum levels at study entry. The patients were randomly assigned to two equal-sized groups, with one group receiving baricitinib 4 mg daily and a monthly placebo saline infusion, and the other group receiving monthly cyclophosphamide infusions and oral placebo tablets.
The incidence of adverse events was comparable between the two treatment groups, with 48% of patients in the baricitinib group and 46% in the cyclophosphamide group experiencing adverse events. Only three serious adverse events, specifically serious infection or herpes zoster, were recorded, leading to treatment discontinuation.
Two patients (6.6%) in the baricitinib group and one patient (3.3%) in the cyclophosphamide group were affected. The researchers recorded no major adverse cardiovascular or venous thromboembolic events, which are known to occur at higher rates among some users of baricitinib and other JAK inhibitors. The safety profile of baricitinib was consistent with observations made in other inflammatory musculoskeletal diseases, and no new risks were identified.
However, there were some concerns expressed by audience members during the presentation.
“The primary endpoint is limited at proteinuria, while biopsy is considered the gold standard for measuring efficacy,” said Eric F. Morand, MD, head of the Monash Health rheumatology unit, Melbourne. This was not the only critical comment regarding the study that emerged during the discussion. The use of a 4-mg dosage regimen throughout the entire study duration (despite official recommendations suggesting a 2-mg dosage in the long run) and the positive outcomes observed in the control group treated with cyclophosphamide were also mentioned.
Dr. Hassanien acknowledged that this is a small and relatively short study and disclosed plans to extend the follow-up period to 1 year and conduct a renal biopsy.
Dr. Hassanien reported no relevant financial relationships. Assiut University funded the trial.
A version of this article first appeared on Medscape.com.
AT EULAR 2023
Buprenorphine update: Looser rules and a helpful injectable
SAN FRANCISCO – As the opioid epidemic continues to grow and evolve, the federal government is trying to make it easier for clinicians to treat abusers with the drug buprenorphine, psychiatrists told colleagues at the annual meeting of the American Psychiatric Association. And an injectable version of the drug is making a big difference.
John A. Renner Jr., MD, of Boston University, said in a presentation at the APA meeting.
As Dr. Renner explained, the United States is now in the fourth wave of nearly a quarter-century of opioid overdose-related deaths. The outbreak began in 1999 as prescription opioids spurred deaths, and heroin overdoses began to rise in 2010. The third wave brought rises in deaths from synthetic opioids such as fentanyl in 2013. In 2015, the fourth wave – driven by deaths from combinations of synthetic opioids and psychostimulants like methamphetamines – started in 2015.
COVID-19 seems to have played a role too: In 2020, opioid overdose deaths spiked during the early months of the pandemic. In 2021, drug-related overdose deaths overall hit a high of 106,889, including 80,411 linked to opioids. In contrast, fewer than 20,000 drug-related overdose deaths were reported in 1999.
On the other hand, deaths from prescription drug overdoses are falling, Dr. Renner said, suggesting “improvement in terms of how clinicians are handling medications and our prescribing practices. But that’s being masked by what’s happened with fentanyl and methamphetamine.”
Buprenorphine (Subutex), used to treat opioid use withdrawal, is itself an opioid and can cause addiction and death in some cases. However, Dr. Renner highlighted a 2023 study that determined that efforts to increase its use from 2019 to 2021 didn’t appear to boost buprenorphine-related overdose deaths in the United States.
New federal regulations aim to make it easier to prescribe buprenorphine. Thanks to Congressional legislation, the Drug Enforcement Administration in January 2023 eliminated regulations requiring clinicians to undergo special training to get an “X-waiver” to be able to prescribe buprenorphine. But they’re not off the hook entirely: As of June 27, 2023, providers must have undergone training in order to apply for – or renew – a DEA license to prescribe certain controlled substances like buprenorphine.
“I’m afraid that people will be able to meet that requirement easily, and they’re not going to get good coordinated teaching,” Dr. Renner said. “I’m not sure that’s really going to improve the quality of care that we’re delivering.”
In regard to treatment, psychiatrist Dong Chan Park, MD, of Boston University, touted a long-acting injectable form of buprenorphine known by the brand name Sublocade. The FDA approved Sublocade in 2017 for patients who’ve been taking sublingual buprenorphine for at least 7 days, although Dr. Park said research suggests the 7-day period may not be necessary.
“We’ve utilized this about 2.5-plus years in my hospital, and it’s really been a game changer for some of our sickest, most challenging patients,” he said at the APA presentation. As he explained, one benefit is that patients can’t repeatedly avoid doses depending on how they feel, as they may do with the sublingual version. “On the first day of injection, you can actually stop the sublingual buprenorphine.”
Dr. Renner emphasized the importance of getting users on buprenorphine as fast as possible. If the treatment begins in the ED, he said, “they need to have a system that is going to be able to pick them up and continue the care.”
Otherwise, the risk is high. “We’re in a very dangerous era,” he said, “where the patient walks out the door, and then they die.”
Dr. Park had no disclosures, and Dr. Renner disclosed royalties from the APA.
SAN FRANCISCO – As the opioid epidemic continues to grow and evolve, the federal government is trying to make it easier for clinicians to treat abusers with the drug buprenorphine, psychiatrists told colleagues at the annual meeting of the American Psychiatric Association. And an injectable version of the drug is making a big difference.
John A. Renner Jr., MD, of Boston University, said in a presentation at the APA meeting.
As Dr. Renner explained, the United States is now in the fourth wave of nearly a quarter-century of opioid overdose-related deaths. The outbreak began in 1999 as prescription opioids spurred deaths, and heroin overdoses began to rise in 2010. The third wave brought rises in deaths from synthetic opioids such as fentanyl in 2013. In 2015, the fourth wave – driven by deaths from combinations of synthetic opioids and psychostimulants like methamphetamines – started in 2015.
COVID-19 seems to have played a role too: In 2020, opioid overdose deaths spiked during the early months of the pandemic. In 2021, drug-related overdose deaths overall hit a high of 106,889, including 80,411 linked to opioids. In contrast, fewer than 20,000 drug-related overdose deaths were reported in 1999.
On the other hand, deaths from prescription drug overdoses are falling, Dr. Renner said, suggesting “improvement in terms of how clinicians are handling medications and our prescribing practices. But that’s being masked by what’s happened with fentanyl and methamphetamine.”
Buprenorphine (Subutex), used to treat opioid use withdrawal, is itself an opioid and can cause addiction and death in some cases. However, Dr. Renner highlighted a 2023 study that determined that efforts to increase its use from 2019 to 2021 didn’t appear to boost buprenorphine-related overdose deaths in the United States.
New federal regulations aim to make it easier to prescribe buprenorphine. Thanks to Congressional legislation, the Drug Enforcement Administration in January 2023 eliminated regulations requiring clinicians to undergo special training to get an “X-waiver” to be able to prescribe buprenorphine. But they’re not off the hook entirely: As of June 27, 2023, providers must have undergone training in order to apply for – or renew – a DEA license to prescribe certain controlled substances like buprenorphine.
“I’m afraid that people will be able to meet that requirement easily, and they’re not going to get good coordinated teaching,” Dr. Renner said. “I’m not sure that’s really going to improve the quality of care that we’re delivering.”
In regard to treatment, psychiatrist Dong Chan Park, MD, of Boston University, touted a long-acting injectable form of buprenorphine known by the brand name Sublocade. The FDA approved Sublocade in 2017 for patients who’ve been taking sublingual buprenorphine for at least 7 days, although Dr. Park said research suggests the 7-day period may not be necessary.
“We’ve utilized this about 2.5-plus years in my hospital, and it’s really been a game changer for some of our sickest, most challenging patients,” he said at the APA presentation. As he explained, one benefit is that patients can’t repeatedly avoid doses depending on how they feel, as they may do with the sublingual version. “On the first day of injection, you can actually stop the sublingual buprenorphine.”
Dr. Renner emphasized the importance of getting users on buprenorphine as fast as possible. If the treatment begins in the ED, he said, “they need to have a system that is going to be able to pick them up and continue the care.”
Otherwise, the risk is high. “We’re in a very dangerous era,” he said, “where the patient walks out the door, and then they die.”
Dr. Park had no disclosures, and Dr. Renner disclosed royalties from the APA.
SAN FRANCISCO – As the opioid epidemic continues to grow and evolve, the federal government is trying to make it easier for clinicians to treat abusers with the drug buprenorphine, psychiatrists told colleagues at the annual meeting of the American Psychiatric Association. And an injectable version of the drug is making a big difference.
John A. Renner Jr., MD, of Boston University, said in a presentation at the APA meeting.
As Dr. Renner explained, the United States is now in the fourth wave of nearly a quarter-century of opioid overdose-related deaths. The outbreak began in 1999 as prescription opioids spurred deaths, and heroin overdoses began to rise in 2010. The third wave brought rises in deaths from synthetic opioids such as fentanyl in 2013. In 2015, the fourth wave – driven by deaths from combinations of synthetic opioids and psychostimulants like methamphetamines – started in 2015.
COVID-19 seems to have played a role too: In 2020, opioid overdose deaths spiked during the early months of the pandemic. In 2021, drug-related overdose deaths overall hit a high of 106,889, including 80,411 linked to opioids. In contrast, fewer than 20,000 drug-related overdose deaths were reported in 1999.
On the other hand, deaths from prescription drug overdoses are falling, Dr. Renner said, suggesting “improvement in terms of how clinicians are handling medications and our prescribing practices. But that’s being masked by what’s happened with fentanyl and methamphetamine.”
Buprenorphine (Subutex), used to treat opioid use withdrawal, is itself an opioid and can cause addiction and death in some cases. However, Dr. Renner highlighted a 2023 study that determined that efforts to increase its use from 2019 to 2021 didn’t appear to boost buprenorphine-related overdose deaths in the United States.
New federal regulations aim to make it easier to prescribe buprenorphine. Thanks to Congressional legislation, the Drug Enforcement Administration in January 2023 eliminated regulations requiring clinicians to undergo special training to get an “X-waiver” to be able to prescribe buprenorphine. But they’re not off the hook entirely: As of June 27, 2023, providers must have undergone training in order to apply for – or renew – a DEA license to prescribe certain controlled substances like buprenorphine.
“I’m afraid that people will be able to meet that requirement easily, and they’re not going to get good coordinated teaching,” Dr. Renner said. “I’m not sure that’s really going to improve the quality of care that we’re delivering.”
In regard to treatment, psychiatrist Dong Chan Park, MD, of Boston University, touted a long-acting injectable form of buprenorphine known by the brand name Sublocade. The FDA approved Sublocade in 2017 for patients who’ve been taking sublingual buprenorphine for at least 7 days, although Dr. Park said research suggests the 7-day period may not be necessary.
“We’ve utilized this about 2.5-plus years in my hospital, and it’s really been a game changer for some of our sickest, most challenging patients,” he said at the APA presentation. As he explained, one benefit is that patients can’t repeatedly avoid doses depending on how they feel, as they may do with the sublingual version. “On the first day of injection, you can actually stop the sublingual buprenorphine.”
Dr. Renner emphasized the importance of getting users on buprenorphine as fast as possible. If the treatment begins in the ED, he said, “they need to have a system that is going to be able to pick them up and continue the care.”
Otherwise, the risk is high. “We’re in a very dangerous era,” he said, “where the patient walks out the door, and then they die.”
Dr. Park had no disclosures, and Dr. Renner disclosed royalties from the APA.
AT APA 2023
Crusted Scabies Presenting as Erythroderma in a Patient With Iatrogenic Immunosuppression for Treatment of Granulomatosis With Polyangiitis
Scabies is caused by cutaneous ectoparasitic infection by the mite Sarcoptes scabiei var hominis. The infection is highly contagious via direct skin-to-skin contact or indirectly through infested bedding, clothing or fomites.1,2 Scabies occurs at all ages, in all ethnic groups, and at all socioeconomic levels.1 Analysis by the Global Burden of Disease estimates that 200 million individuals have been infected with scabies worldwide. The World Health Organization has declared scabies a neglected tropical disease.3
Crusted scabies is a severe and rare form of scabies, with hyperinfestation of thousands to millions of mites, and more commonly is associated with immunosuppressed states, including HIV and hematologic malignancies.1,2,4 Crusted scabies has a high mortality rate due to sepsis when left untreated.3,5
Occasionally, iatrogenic immunosuppression contributes to the development of crusted scabies.1,2 Iatrogenic immunosuppression leading to crusted scabies most commonly occurs secondary to immunosuppression after bone marrow or solid organ transplantation.6 Less often, crusted scabies is caused by iatrogenic immunosuppression from other clinical scenarios.1,2
We describe a patient with iatrogenic immunosuppression due to azathioprine-induced myelosuppression for the treatment of granulomatosis with polyangiitis (GPA) who developed crusted scabies that clinically presented as erythroderma. Crusted scabies should be included in the differential diagnosis of erythroderma, especially in the setting of iatrogenic immunosuppression, for timely and appropriate management.
Case Report
An 84-year-old man presented with worsening pruritus, erythema, and thick yellow scale that progressed to erythroderma over the last 2 weeks. He was diagnosed with GPA 6 months prior to presentation and was treated with azathioprine 150 mg/d, prednisone 10 mg/d, and sulfamethoxazole 800 mg plus trimethoprim 160 mg twice weekly for prophylaxis against Pneumocystis jirovecii pneumonia.
Three weeks prior to presentation, the patient was hospitalized for pancytopenia attributed to azathioprine-induced myelosuppression (hemoglobin, 6.1 g/dL [reference range, 13.5–18.0 g/dL]; hematocrit, 17.5% [reference range, 42%–52%]; white blood cell count, 1.66×103/μL [reference range, 4.0–10.5×103/μL]; platelet count, 146×103/μL [reference range, 150–450×103/μL]; absolute neutrophil count, 1.29×103/μL [reference range, 1.4–6.5×103/μL]). He was transferred to a skilled nursing facility after discharge and referred to dermatology for evaluation of the worsening pruritic rash.
At the current presentation, the patient denied close contact with anyone who had a similar rash at home or at the skilled nursing facility. Physical examination revealed diffuse erythroderma with yellow scale on the scalp, trunk, arms, and legs (Figure 1). The palms showed scattered 2- to 3-mm pustules. The mucosal surfaces did not have lesions. A punch biopsy of a pustule from the right arm revealed focal spongiosis, parakeratosis, and acanthosis, as well as a perivascular and interstitial mixed inflammatory infiltrate with lymphocytes and eosinophils. Organisms morphologically compatible with scabies were found in the stratum corneum (Figure 2). Another punch biopsy of a pustule from the right arm was performed for direct immunofluorescence (DIF) and was negative for immunoglobulin deposition. Mineral oil preparation from pustules on the palm was positive for mites.
The patient was treated with permethrin cream 5% and oral ivermectin 200 μg/kg on day 1 and day 10. The prednisone dosage was increased from 10 mg/d to 50 mg/d and tapered over 2 weeks to treat the symptomatic rash and GPA. He remains on maintenance rituximab for GPA, without recurrence of scabies.
Comment
Pathogenesis—As an obligate parasite, S scabiei spends its entire life cycle within the host. Impregnated female mites burrow into the epidermis after mating and lay eggs daily for 1 to 2 months. Eggs hatch 2 or 3 days later. Larvae then migrate to the skin surface; burrow into the stratum corneum, where they mature into adults; and then mate on the skin surface.1,4
Clinical Presentation and Sequelae—Typically, scabies presents 2 to 6 weeks after initial exposure with generalized and intense itching and inflammatory pruritic papules on the finger webs, wrists, elbows, axillae, buttocks, umbilicus, genitalia, and areolae.1 Burrows are specific for scabies but may not always be present. Often, there are nonspecific secondary lesions, including excoriations, dermatitis, and impetiginization.
Complications of scabies can be severe, with initial colonization and infection of the skin resulting in impetigo and cellulitis. Systematic sequelae from local skin infection include post-streptococcal glomerulonephritis, rheumatic fever, and sepsis. Mortality from sepsis in scabies can be high.3,5
Classic Crusted Scabies and Other Variants—Crusted scabies presents with psoriasiform hyperkeratotic plaques involving the hands and feet with potential nail involvement that can become more generalized.1 Alterations in CD4+ T-cell function have been implicated in the development of crusted scabies, in which an excessive helper T cell (TH2) response is elicited against the ectoparasite, which may help explain the intense pruritus of scabies.6 Occasionally, iatrogenic immunosuppression contributes to development of crusted scabies,1 as was the case with our patient. However, it is rare for crusted scabies to present with erythroderma.7
Other atypical presentations of scabies include a seborrheic dermatitis–like presentation in infants, nodular lesions in the groin and axillae in more chronic scabies, and vesicles or bullous lesions.1
Diagnosis—Identification of mites, eggs, or feces is necessary for definitive diagnosis of scabies.8 These materials can be obtained through skin scrapings with mineral oil and observed under light microscopy or direct dermoscopy. Multiple scrapings on many lesions should be performed because failure to identify mites can be common and does not rule out scabies. Dermoscopic examination of active lesions under low power also can be helpful, given that identification of dark brown triangular structures can correspond to visualization of the pigmented anterior section of the mite.9-11 A skin biopsy can help identify mites, but histopathology often shows a nonspecific hypersensitivity reaction.12 Therefore, empiric treatment often is necessary.
Differential Diagnosis—The differential diagnosis of erythroderma is broad and includes a drug eruption; Sézary syndrome; and pre-existing skin diseases, including psoriasis, atopic dermatitis, pityriasis rubra pilaris, pemphigus foliaceus, and bullous pemphigoid. Histopathology is critical to differentiate these diagnoses. Bullous pemphigoid and pemphigus foliaceus are immunobullous diseases that typically are positive for immunoglobulin deposition on DIF. In rare cases, scabies also can present with bullae and positive DIF test results.13
Treatment—First-line treatment of crusted scabies in the United States is permethrin cream 5%, followed by oral ivermectin 200 μg/kg.4,5,14,15 Other scabicides include topicals such as benzyl benzoate 10% to 25%; precipitated sulfur 2% to 10%; crotamiton 10%; malathion 0.5%; and lindane 1%.5 The association of neurotoxicity with lindane has considerably reduced the drug’s use.1
During treatment of scabies, it is important to isolate patients to mitigate the possibility of spread.4 Pruritus can persist for a few weeks after completion of therapy.5 Patients should be closely monitored to ensure that this symptom is secondary to skin inflammation and not incomplete treatment.
Treatment of crusted scabies may require repeated treatments to decrease the notable mite burden as well as the associated crusting and scale. Adding a keratolytic such as 5% to 10% salicylic acid in petrolatum to the treatment regimen may be useful for breaking up thick scale.5
Immunosuppression—With numerous immunomodulatory drugs for treating autoimmunity comes an increased risk for iatrogenic immunosuppression that may contribute to the development of crusted scabies.16 In a number of autoimmune diseases such as rheumatoid arthritis,17-19 psoriasis,20,21 pemphigus vulgaris,22 systemic lupus erythematosus,23 systemic sclerosis,22,24 bullous pemphigoid,25,26 and dermatomyositis,27 patients have developed crusted scabies secondary to treatment-related immunosuppression. These immunosuppressive therapies include systemic steroids,22-24,26-31 methotrexate,23 infliximab,18 adalimumab,21 toclizumab,19 and etanercept.20 In a case of drug-induced Stevens-Johnson syndrome, the patient developed crusted scabies during long-term use of oral steroids.22
Patients with a malignancy who are being treated with chemotherapy also can develop crusted scabies.28 Crusted scabies has even been associated with long-term topical steroid32-34 and topical calcineurin inhibitor use.16
Iatrogenic immunosuppression in our patient resulted from treatment of GPA with azathioprine, an immunosuppressive drug that acts as an antagonist of the breakdown of purines, leading to inhibition of DNA, RNA, and protein synthesis.35 On occasion, azathioprine can induce immunosuppression in the form of myelosuppression and resulting pancytopenia, as was the case with our patient.
Conclusion
Although scabies is designated as a neglected tropical disease by the World Health Organization, it still causes a notable burden worldwide, regardless of the economics. Our case highlights an unusual presentation of scabies as erythroderma in the setting of iatrogenic immunosuppression from azathioprine use. Dermatologists should consider crusted scabies in the differential diagnosis of erythroderma, especially in immunocompromised patients, to avoid delays in diagnosis and treatment. Immunosuppressive therapy is an important mainstay in the treatment of many conditions, but it is important to consider that these medications can place patients at an increased risk for rare opportunistic infections. Therefore, patients receiving such treatment should be closely monitored.
- Chosidow O. Clinical practices. Scabies. N Engl J Med. 2006;354:1718-1727. doi:10.1056/NEJMcp052784
- Salgado F, Elston DM. What’s eating you? scabies in the developing world. Cutis. 2017;100:287-289.
- Karimkhani C, Colombara DV, Drucker AM, et al. The global burden of scabies: a cross-sectional analysis from the Global Burden of Disease Study 2015. Lancet Infect Dis. 2017;17:1247-1254. doi:10.1016/S1473-3099(17)30483-8
- Currie BJ, McCarthy JS. Permethrin and ivermectin for scabies. N Engl J Med. 2010;362:717-725. doi:10.1056/NEJMct0910329
- Thomas C, Coates SJ, Engelman D, et al. Ectoparasites: scabies. J Am Acad Dermatol. 2020;82:533-548. doi:10.1016/j.jaad.2019.05.109
- Roberts LJ, Huffam SE, Walton SF, et al. Crusted scabies: clinical and immunological findings in seventy-eight patients and a review of the literature. J Infect. 2005;50:375-381. doi:10.1016/j.jinf.2004.08.033
- Wang X-D, Shen H, Liu Z-H. Contagious erythroderma. J Emerg Med. 2016;51:180-181. doi:10.1016/j.jemermed.2016.05.027
- Johnston G, Sladden M. Scabies: diagnosis and treatment. BMJ. 2005;331:619-622. doi:10.1136/bmj.331.7517.619
- Micali G, Lacarrubba F, Massimino D, et al. Dermatoscopy: alternative uses in daily clinical practice. J Am Acad Dermatol. 2011;64:1135-1146. doi:10.1016/j.jaad.2010.03.010
- Bollea Garlatti LA, Torre AC, Bollea Garlatti ML, et al.. Dermoscopy aids the diagnosis of crusted scabies in an erythrodermic patient. J Am Acad Dermatol. 2015;73:E93-E95. doi:10.1016/j.jaad.2015.04.061
- Tang J, You Z, Ran Y. Simple methods to enhance the diagnosis of scabies. J Am Acad Dermatol. 2019;80:E99-E100. doi:10.1016/j.jaad.2017.07.038
- Falk ES, Eide TJ. Histologic and clinical findings in human scabies. Int J Dermatol. 1981;20:600-605. doi:10.1111/j.1365-4362.1981.tb00844.x
- Shahab RKA, Loo DS. Bullous scabies. J Am Acad Dermatol. 2003;49:346-350. doi:10.1067/s0190-9622(03)00876-4
- Strong M, Johnstone P. Interventions for treating scabies. Cochrane Database Syst Rev. 2007:CD000320. doi:10.1002/14651858.CD000320.pub2
- Rosumeck S, Nast A, Dressler C. Evaluation of ivermectin vs permethrin for treating scabies—summary of a Cochrane Review. JAMA Dermatol. 2019;155:730-732. doi:10.1001/jamadermatol.2019.0279
- Ruiz-Maldonado R. Pimecrolimus related crusted scabies in an infant. Pediatr Dermatol. 2006;23:299-300. doi:10.1111/j.1525-1470.2006.00241.x
- Bu X, Fan J, Hu X, et al. Norwegian scabies in a patient treated with Tripterygium glycoside for rheumatoid arthritis. An Bras Dermatol. 2017;92:556-558. doi:10.1590/abd1806-4841.20174946
- Pipitone MA, Adams B, Sheth A, et al. Crusted scabies in a patient being treated with infliximab for juvenile rheumatoid arthritis. J Am Acad Dermatol. 2005;52:719-720. doi:10.1016/j.jaad.2004.12.039
- Baccouche K, Sellam J, Guegan S, et al. Crusted Norwegian scabies, an opportunistic infection, with tocilizumab in rheumatoid arthritis. Joint Bone Spine. 2011;78:402-404. doi:10.1016/j.jbspin.2011.02.008
- Saillard C, Darrieux L, Safa G. Crusted scabies complicates etanercept therapy in a patient with severe psoriasis. J Am Acad Dermatol. 2013;68:E138-E139. doi:10.1016/j.jaad.2012.09.049
- Belvisi V, Orsi GB, Del Borgo C, et al. Large nosocomial outbreakassociated with a Norwegian scabies index case undergoing TNF-α inhibitor treatment: management and control. Infect Control Hosp Epidemiol. 2015;36:1358-1360. doi:10.1017/ice.2015.188
- Nofal A. Variable response of crusted scabies to oral ivermectin: report on eight Egyptian patients. J Eur Acad Dermatol Venereol. 2009;23:793-797. doi:10.1111/j.1468-3083.2009.03177.x
- Yee BE, Carlos CA, Hata T. Crusted scabies of the scalp in a patient with systemic lupus erythematosus. Dermatol Online J. 2014;20:13030/qt9dm891gd.
- Bumb RA, Mehta RD. Crusted scabies in a patient of systemic sclerosis. Indian J Dermatol Venereol Leprol. 2000;66:143-144.
- Hylwa SA, Loss L, Grassi M. Crusted scabies and tinea corporis after treatment of presumed bullous pemphigoid. Cutis. 2013;92:193-198.
- Svecova D, Chmurova N, Pallova A, et al. Norwegian scabies in immunosuppressed patient misdiagnosed as an adverse drug reaction. Epidemiol Mikrobiol Imunol. 2009;58:121-123.
- Dourmishev AL, Serafimova DK, Dourmishev LA, et al. Crusted scabies of the scalp in dermatomyositis patients: three cases treated with oral ivermectin. Int J Dermatol. 1998;37:231-234. doi:10.1046/j.1365-4362.1998.00330.x
- Mortazavi H, Abedini R, Sadri F, et al. Crusted scabies in a patient with brain astrocytoma: report of a case. Int J Infect Dis. 2010;14:E526-E527. doi:10.1016/j.ijid.2009.06.011
- Lima FCDR, Cerqueira AMM, MBS, et al. Crusted scabies due to indiscriminate use of glucocorticoid therapy in infant. An Bras Dermatol. 2017;92:383-385. doi:10.1590/abd1806-4841.20174433
- Binic´ I, Jankovic´ A, Jovanovic´ D, et al. Crusted (Norwegian) scabies following systemic and topical corticosteroid therapy. J Korean Med Sci. 2010;25:188-191. doi:10.3346/jkms.2010.25.1.188
- Ohtaki N, Taniguchi H, Ohtomo H. Oral ivermectin treatment in two cases of scabies: effective in crusted scabies induced by corticosteroid but ineffective in nail scabies. J Dermatol. 2003;30:411-416. doi:10.1111/j.1346-8138.2003.tb00408.x
- Bilan P, Colin-Gorski AM, Chapelon E, et al. Crusted scabies induced by topical corticosteroids: a case report [in French]. Arch Pediatr. 2015;22:1292-1294. doi:10.1016/j.arcped.2015.09.004
- Marlière V, Roul S, C, et al. Crusted (Norwegian) scabies induced by use of topical corticosteroids and treated successfully with ivermectin. J Pediatr. 1999;135:122-124. doi:10.1016/s0022-3476(99)70342-2
- Jaramillo-Ayerbe F, J. Ivermectin for crusted Norwegian scabies induced by use of topical steroids. Arch Dermatol. 1998;134:143-145. doi:10.1001/archderm.134.2.143
- Elion GB. The purine path to chemotherapy. Science. 1989;244:41-47. doi:10.1126/science.2649979
Scabies is caused by cutaneous ectoparasitic infection by the mite Sarcoptes scabiei var hominis. The infection is highly contagious via direct skin-to-skin contact or indirectly through infested bedding, clothing or fomites.1,2 Scabies occurs at all ages, in all ethnic groups, and at all socioeconomic levels.1 Analysis by the Global Burden of Disease estimates that 200 million individuals have been infected with scabies worldwide. The World Health Organization has declared scabies a neglected tropical disease.3
Crusted scabies is a severe and rare form of scabies, with hyperinfestation of thousands to millions of mites, and more commonly is associated with immunosuppressed states, including HIV and hematologic malignancies.1,2,4 Crusted scabies has a high mortality rate due to sepsis when left untreated.3,5
Occasionally, iatrogenic immunosuppression contributes to the development of crusted scabies.1,2 Iatrogenic immunosuppression leading to crusted scabies most commonly occurs secondary to immunosuppression after bone marrow or solid organ transplantation.6 Less often, crusted scabies is caused by iatrogenic immunosuppression from other clinical scenarios.1,2
We describe a patient with iatrogenic immunosuppression due to azathioprine-induced myelosuppression for the treatment of granulomatosis with polyangiitis (GPA) who developed crusted scabies that clinically presented as erythroderma. Crusted scabies should be included in the differential diagnosis of erythroderma, especially in the setting of iatrogenic immunosuppression, for timely and appropriate management.
Case Report
An 84-year-old man presented with worsening pruritus, erythema, and thick yellow scale that progressed to erythroderma over the last 2 weeks. He was diagnosed with GPA 6 months prior to presentation and was treated with azathioprine 150 mg/d, prednisone 10 mg/d, and sulfamethoxazole 800 mg plus trimethoprim 160 mg twice weekly for prophylaxis against Pneumocystis jirovecii pneumonia.
Three weeks prior to presentation, the patient was hospitalized for pancytopenia attributed to azathioprine-induced myelosuppression (hemoglobin, 6.1 g/dL [reference range, 13.5–18.0 g/dL]; hematocrit, 17.5% [reference range, 42%–52%]; white blood cell count, 1.66×103/μL [reference range, 4.0–10.5×103/μL]; platelet count, 146×103/μL [reference range, 150–450×103/μL]; absolute neutrophil count, 1.29×103/μL [reference range, 1.4–6.5×103/μL]). He was transferred to a skilled nursing facility after discharge and referred to dermatology for evaluation of the worsening pruritic rash.
At the current presentation, the patient denied close contact with anyone who had a similar rash at home or at the skilled nursing facility. Physical examination revealed diffuse erythroderma with yellow scale on the scalp, trunk, arms, and legs (Figure 1). The palms showed scattered 2- to 3-mm pustules. The mucosal surfaces did not have lesions. A punch biopsy of a pustule from the right arm revealed focal spongiosis, parakeratosis, and acanthosis, as well as a perivascular and interstitial mixed inflammatory infiltrate with lymphocytes and eosinophils. Organisms morphologically compatible with scabies were found in the stratum corneum (Figure 2). Another punch biopsy of a pustule from the right arm was performed for direct immunofluorescence (DIF) and was negative for immunoglobulin deposition. Mineral oil preparation from pustules on the palm was positive for mites.
The patient was treated with permethrin cream 5% and oral ivermectin 200 μg/kg on day 1 and day 10. The prednisone dosage was increased from 10 mg/d to 50 mg/d and tapered over 2 weeks to treat the symptomatic rash and GPA. He remains on maintenance rituximab for GPA, without recurrence of scabies.
Comment
Pathogenesis—As an obligate parasite, S scabiei spends its entire life cycle within the host. Impregnated female mites burrow into the epidermis after mating and lay eggs daily for 1 to 2 months. Eggs hatch 2 or 3 days later. Larvae then migrate to the skin surface; burrow into the stratum corneum, where they mature into adults; and then mate on the skin surface.1,4
Clinical Presentation and Sequelae—Typically, scabies presents 2 to 6 weeks after initial exposure with generalized and intense itching and inflammatory pruritic papules on the finger webs, wrists, elbows, axillae, buttocks, umbilicus, genitalia, and areolae.1 Burrows are specific for scabies but may not always be present. Often, there are nonspecific secondary lesions, including excoriations, dermatitis, and impetiginization.
Complications of scabies can be severe, with initial colonization and infection of the skin resulting in impetigo and cellulitis. Systematic sequelae from local skin infection include post-streptococcal glomerulonephritis, rheumatic fever, and sepsis. Mortality from sepsis in scabies can be high.3,5
Classic Crusted Scabies and Other Variants—Crusted scabies presents with psoriasiform hyperkeratotic plaques involving the hands and feet with potential nail involvement that can become more generalized.1 Alterations in CD4+ T-cell function have been implicated in the development of crusted scabies, in which an excessive helper T cell (TH2) response is elicited against the ectoparasite, which may help explain the intense pruritus of scabies.6 Occasionally, iatrogenic immunosuppression contributes to development of crusted scabies,1 as was the case with our patient. However, it is rare for crusted scabies to present with erythroderma.7
Other atypical presentations of scabies include a seborrheic dermatitis–like presentation in infants, nodular lesions in the groin and axillae in more chronic scabies, and vesicles or bullous lesions.1
Diagnosis—Identification of mites, eggs, or feces is necessary for definitive diagnosis of scabies.8 These materials can be obtained through skin scrapings with mineral oil and observed under light microscopy or direct dermoscopy. Multiple scrapings on many lesions should be performed because failure to identify mites can be common and does not rule out scabies. Dermoscopic examination of active lesions under low power also can be helpful, given that identification of dark brown triangular structures can correspond to visualization of the pigmented anterior section of the mite.9-11 A skin biopsy can help identify mites, but histopathology often shows a nonspecific hypersensitivity reaction.12 Therefore, empiric treatment often is necessary.
Differential Diagnosis—The differential diagnosis of erythroderma is broad and includes a drug eruption; Sézary syndrome; and pre-existing skin diseases, including psoriasis, atopic dermatitis, pityriasis rubra pilaris, pemphigus foliaceus, and bullous pemphigoid. Histopathology is critical to differentiate these diagnoses. Bullous pemphigoid and pemphigus foliaceus are immunobullous diseases that typically are positive for immunoglobulin deposition on DIF. In rare cases, scabies also can present with bullae and positive DIF test results.13
Treatment—First-line treatment of crusted scabies in the United States is permethrin cream 5%, followed by oral ivermectin 200 μg/kg.4,5,14,15 Other scabicides include topicals such as benzyl benzoate 10% to 25%; precipitated sulfur 2% to 10%; crotamiton 10%; malathion 0.5%; and lindane 1%.5 The association of neurotoxicity with lindane has considerably reduced the drug’s use.1
During treatment of scabies, it is important to isolate patients to mitigate the possibility of spread.4 Pruritus can persist for a few weeks after completion of therapy.5 Patients should be closely monitored to ensure that this symptom is secondary to skin inflammation and not incomplete treatment.
Treatment of crusted scabies may require repeated treatments to decrease the notable mite burden as well as the associated crusting and scale. Adding a keratolytic such as 5% to 10% salicylic acid in petrolatum to the treatment regimen may be useful for breaking up thick scale.5
Immunosuppression—With numerous immunomodulatory drugs for treating autoimmunity comes an increased risk for iatrogenic immunosuppression that may contribute to the development of crusted scabies.16 In a number of autoimmune diseases such as rheumatoid arthritis,17-19 psoriasis,20,21 pemphigus vulgaris,22 systemic lupus erythematosus,23 systemic sclerosis,22,24 bullous pemphigoid,25,26 and dermatomyositis,27 patients have developed crusted scabies secondary to treatment-related immunosuppression. These immunosuppressive therapies include systemic steroids,22-24,26-31 methotrexate,23 infliximab,18 adalimumab,21 toclizumab,19 and etanercept.20 In a case of drug-induced Stevens-Johnson syndrome, the patient developed crusted scabies during long-term use of oral steroids.22
Patients with a malignancy who are being treated with chemotherapy also can develop crusted scabies.28 Crusted scabies has even been associated with long-term topical steroid32-34 and topical calcineurin inhibitor use.16
Iatrogenic immunosuppression in our patient resulted from treatment of GPA with azathioprine, an immunosuppressive drug that acts as an antagonist of the breakdown of purines, leading to inhibition of DNA, RNA, and protein synthesis.35 On occasion, azathioprine can induce immunosuppression in the form of myelosuppression and resulting pancytopenia, as was the case with our patient.
Conclusion
Although scabies is designated as a neglected tropical disease by the World Health Organization, it still causes a notable burden worldwide, regardless of the economics. Our case highlights an unusual presentation of scabies as erythroderma in the setting of iatrogenic immunosuppression from azathioprine use. Dermatologists should consider crusted scabies in the differential diagnosis of erythroderma, especially in immunocompromised patients, to avoid delays in diagnosis and treatment. Immunosuppressive therapy is an important mainstay in the treatment of many conditions, but it is important to consider that these medications can place patients at an increased risk for rare opportunistic infections. Therefore, patients receiving such treatment should be closely monitored.
Scabies is caused by cutaneous ectoparasitic infection by the mite Sarcoptes scabiei var hominis. The infection is highly contagious via direct skin-to-skin contact or indirectly through infested bedding, clothing or fomites.1,2 Scabies occurs at all ages, in all ethnic groups, and at all socioeconomic levels.1 Analysis by the Global Burden of Disease estimates that 200 million individuals have been infected with scabies worldwide. The World Health Organization has declared scabies a neglected tropical disease.3
Crusted scabies is a severe and rare form of scabies, with hyperinfestation of thousands to millions of mites, and more commonly is associated with immunosuppressed states, including HIV and hematologic malignancies.1,2,4 Crusted scabies has a high mortality rate due to sepsis when left untreated.3,5
Occasionally, iatrogenic immunosuppression contributes to the development of crusted scabies.1,2 Iatrogenic immunosuppression leading to crusted scabies most commonly occurs secondary to immunosuppression after bone marrow or solid organ transplantation.6 Less often, crusted scabies is caused by iatrogenic immunosuppression from other clinical scenarios.1,2
We describe a patient with iatrogenic immunosuppression due to azathioprine-induced myelosuppression for the treatment of granulomatosis with polyangiitis (GPA) who developed crusted scabies that clinically presented as erythroderma. Crusted scabies should be included in the differential diagnosis of erythroderma, especially in the setting of iatrogenic immunosuppression, for timely and appropriate management.
Case Report
An 84-year-old man presented with worsening pruritus, erythema, and thick yellow scale that progressed to erythroderma over the last 2 weeks. He was diagnosed with GPA 6 months prior to presentation and was treated with azathioprine 150 mg/d, prednisone 10 mg/d, and sulfamethoxazole 800 mg plus trimethoprim 160 mg twice weekly for prophylaxis against Pneumocystis jirovecii pneumonia.
Three weeks prior to presentation, the patient was hospitalized for pancytopenia attributed to azathioprine-induced myelosuppression (hemoglobin, 6.1 g/dL [reference range, 13.5–18.0 g/dL]; hematocrit, 17.5% [reference range, 42%–52%]; white blood cell count, 1.66×103/μL [reference range, 4.0–10.5×103/μL]; platelet count, 146×103/μL [reference range, 150–450×103/μL]; absolute neutrophil count, 1.29×103/μL [reference range, 1.4–6.5×103/μL]). He was transferred to a skilled nursing facility after discharge and referred to dermatology for evaluation of the worsening pruritic rash.
At the current presentation, the patient denied close contact with anyone who had a similar rash at home or at the skilled nursing facility. Physical examination revealed diffuse erythroderma with yellow scale on the scalp, trunk, arms, and legs (Figure 1). The palms showed scattered 2- to 3-mm pustules. The mucosal surfaces did not have lesions. A punch biopsy of a pustule from the right arm revealed focal spongiosis, parakeratosis, and acanthosis, as well as a perivascular and interstitial mixed inflammatory infiltrate with lymphocytes and eosinophils. Organisms morphologically compatible with scabies were found in the stratum corneum (Figure 2). Another punch biopsy of a pustule from the right arm was performed for direct immunofluorescence (DIF) and was negative for immunoglobulin deposition. Mineral oil preparation from pustules on the palm was positive for mites.
The patient was treated with permethrin cream 5% and oral ivermectin 200 μg/kg on day 1 and day 10. The prednisone dosage was increased from 10 mg/d to 50 mg/d and tapered over 2 weeks to treat the symptomatic rash and GPA. He remains on maintenance rituximab for GPA, without recurrence of scabies.
Comment
Pathogenesis—As an obligate parasite, S scabiei spends its entire life cycle within the host. Impregnated female mites burrow into the epidermis after mating and lay eggs daily for 1 to 2 months. Eggs hatch 2 or 3 days later. Larvae then migrate to the skin surface; burrow into the stratum corneum, where they mature into adults; and then mate on the skin surface.1,4
Clinical Presentation and Sequelae—Typically, scabies presents 2 to 6 weeks after initial exposure with generalized and intense itching and inflammatory pruritic papules on the finger webs, wrists, elbows, axillae, buttocks, umbilicus, genitalia, and areolae.1 Burrows are specific for scabies but may not always be present. Often, there are nonspecific secondary lesions, including excoriations, dermatitis, and impetiginization.
Complications of scabies can be severe, with initial colonization and infection of the skin resulting in impetigo and cellulitis. Systematic sequelae from local skin infection include post-streptococcal glomerulonephritis, rheumatic fever, and sepsis. Mortality from sepsis in scabies can be high.3,5
Classic Crusted Scabies and Other Variants—Crusted scabies presents with psoriasiform hyperkeratotic plaques involving the hands and feet with potential nail involvement that can become more generalized.1 Alterations in CD4+ T-cell function have been implicated in the development of crusted scabies, in which an excessive helper T cell (TH2) response is elicited against the ectoparasite, which may help explain the intense pruritus of scabies.6 Occasionally, iatrogenic immunosuppression contributes to development of crusted scabies,1 as was the case with our patient. However, it is rare for crusted scabies to present with erythroderma.7
Other atypical presentations of scabies include a seborrheic dermatitis–like presentation in infants, nodular lesions in the groin and axillae in more chronic scabies, and vesicles or bullous lesions.1
Diagnosis—Identification of mites, eggs, or feces is necessary for definitive diagnosis of scabies.8 These materials can be obtained through skin scrapings with mineral oil and observed under light microscopy or direct dermoscopy. Multiple scrapings on many lesions should be performed because failure to identify mites can be common and does not rule out scabies. Dermoscopic examination of active lesions under low power also can be helpful, given that identification of dark brown triangular structures can correspond to visualization of the pigmented anterior section of the mite.9-11 A skin biopsy can help identify mites, but histopathology often shows a nonspecific hypersensitivity reaction.12 Therefore, empiric treatment often is necessary.
Differential Diagnosis—The differential diagnosis of erythroderma is broad and includes a drug eruption; Sézary syndrome; and pre-existing skin diseases, including psoriasis, atopic dermatitis, pityriasis rubra pilaris, pemphigus foliaceus, and bullous pemphigoid. Histopathology is critical to differentiate these diagnoses. Bullous pemphigoid and pemphigus foliaceus are immunobullous diseases that typically are positive for immunoglobulin deposition on DIF. In rare cases, scabies also can present with bullae and positive DIF test results.13
Treatment—First-line treatment of crusted scabies in the United States is permethrin cream 5%, followed by oral ivermectin 200 μg/kg.4,5,14,15 Other scabicides include topicals such as benzyl benzoate 10% to 25%; precipitated sulfur 2% to 10%; crotamiton 10%; malathion 0.5%; and lindane 1%.5 The association of neurotoxicity with lindane has considerably reduced the drug’s use.1
During treatment of scabies, it is important to isolate patients to mitigate the possibility of spread.4 Pruritus can persist for a few weeks after completion of therapy.5 Patients should be closely monitored to ensure that this symptom is secondary to skin inflammation and not incomplete treatment.
Treatment of crusted scabies may require repeated treatments to decrease the notable mite burden as well as the associated crusting and scale. Adding a keratolytic such as 5% to 10% salicylic acid in petrolatum to the treatment regimen may be useful for breaking up thick scale.5
Immunosuppression—With numerous immunomodulatory drugs for treating autoimmunity comes an increased risk for iatrogenic immunosuppression that may contribute to the development of crusted scabies.16 In a number of autoimmune diseases such as rheumatoid arthritis,17-19 psoriasis,20,21 pemphigus vulgaris,22 systemic lupus erythematosus,23 systemic sclerosis,22,24 bullous pemphigoid,25,26 and dermatomyositis,27 patients have developed crusted scabies secondary to treatment-related immunosuppression. These immunosuppressive therapies include systemic steroids,22-24,26-31 methotrexate,23 infliximab,18 adalimumab,21 toclizumab,19 and etanercept.20 In a case of drug-induced Stevens-Johnson syndrome, the patient developed crusted scabies during long-term use of oral steroids.22
Patients with a malignancy who are being treated with chemotherapy also can develop crusted scabies.28 Crusted scabies has even been associated with long-term topical steroid32-34 and topical calcineurin inhibitor use.16
Iatrogenic immunosuppression in our patient resulted from treatment of GPA with azathioprine, an immunosuppressive drug that acts as an antagonist of the breakdown of purines, leading to inhibition of DNA, RNA, and protein synthesis.35 On occasion, azathioprine can induce immunosuppression in the form of myelosuppression and resulting pancytopenia, as was the case with our patient.
Conclusion
Although scabies is designated as a neglected tropical disease by the World Health Organization, it still causes a notable burden worldwide, regardless of the economics. Our case highlights an unusual presentation of scabies as erythroderma in the setting of iatrogenic immunosuppression from azathioprine use. Dermatologists should consider crusted scabies in the differential diagnosis of erythroderma, especially in immunocompromised patients, to avoid delays in diagnosis and treatment. Immunosuppressive therapy is an important mainstay in the treatment of many conditions, but it is important to consider that these medications can place patients at an increased risk for rare opportunistic infections. Therefore, patients receiving such treatment should be closely monitored.
- Chosidow O. Clinical practices. Scabies. N Engl J Med. 2006;354:1718-1727. doi:10.1056/NEJMcp052784
- Salgado F, Elston DM. What’s eating you? scabies in the developing world. Cutis. 2017;100:287-289.
- Karimkhani C, Colombara DV, Drucker AM, et al. The global burden of scabies: a cross-sectional analysis from the Global Burden of Disease Study 2015. Lancet Infect Dis. 2017;17:1247-1254. doi:10.1016/S1473-3099(17)30483-8
- Currie BJ, McCarthy JS. Permethrin and ivermectin for scabies. N Engl J Med. 2010;362:717-725. doi:10.1056/NEJMct0910329
- Thomas C, Coates SJ, Engelman D, et al. Ectoparasites: scabies. J Am Acad Dermatol. 2020;82:533-548. doi:10.1016/j.jaad.2019.05.109
- Roberts LJ, Huffam SE, Walton SF, et al. Crusted scabies: clinical and immunological findings in seventy-eight patients and a review of the literature. J Infect. 2005;50:375-381. doi:10.1016/j.jinf.2004.08.033
- Wang X-D, Shen H, Liu Z-H. Contagious erythroderma. J Emerg Med. 2016;51:180-181. doi:10.1016/j.jemermed.2016.05.027
- Johnston G, Sladden M. Scabies: diagnosis and treatment. BMJ. 2005;331:619-622. doi:10.1136/bmj.331.7517.619
- Micali G, Lacarrubba F, Massimino D, et al. Dermatoscopy: alternative uses in daily clinical practice. J Am Acad Dermatol. 2011;64:1135-1146. doi:10.1016/j.jaad.2010.03.010
- Bollea Garlatti LA, Torre AC, Bollea Garlatti ML, et al.. Dermoscopy aids the diagnosis of crusted scabies in an erythrodermic patient. J Am Acad Dermatol. 2015;73:E93-E95. doi:10.1016/j.jaad.2015.04.061
- Tang J, You Z, Ran Y. Simple methods to enhance the diagnosis of scabies. J Am Acad Dermatol. 2019;80:E99-E100. doi:10.1016/j.jaad.2017.07.038
- Falk ES, Eide TJ. Histologic and clinical findings in human scabies. Int J Dermatol. 1981;20:600-605. doi:10.1111/j.1365-4362.1981.tb00844.x
- Shahab RKA, Loo DS. Bullous scabies. J Am Acad Dermatol. 2003;49:346-350. doi:10.1067/s0190-9622(03)00876-4
- Strong M, Johnstone P. Interventions for treating scabies. Cochrane Database Syst Rev. 2007:CD000320. doi:10.1002/14651858.CD000320.pub2
- Rosumeck S, Nast A, Dressler C. Evaluation of ivermectin vs permethrin for treating scabies—summary of a Cochrane Review. JAMA Dermatol. 2019;155:730-732. doi:10.1001/jamadermatol.2019.0279
- Ruiz-Maldonado R. Pimecrolimus related crusted scabies in an infant. Pediatr Dermatol. 2006;23:299-300. doi:10.1111/j.1525-1470.2006.00241.x
- Bu X, Fan J, Hu X, et al. Norwegian scabies in a patient treated with Tripterygium glycoside for rheumatoid arthritis. An Bras Dermatol. 2017;92:556-558. doi:10.1590/abd1806-4841.20174946
- Pipitone MA, Adams B, Sheth A, et al. Crusted scabies in a patient being treated with infliximab for juvenile rheumatoid arthritis. J Am Acad Dermatol. 2005;52:719-720. doi:10.1016/j.jaad.2004.12.039
- Baccouche K, Sellam J, Guegan S, et al. Crusted Norwegian scabies, an opportunistic infection, with tocilizumab in rheumatoid arthritis. Joint Bone Spine. 2011;78:402-404. doi:10.1016/j.jbspin.2011.02.008
- Saillard C, Darrieux L, Safa G. Crusted scabies complicates etanercept therapy in a patient with severe psoriasis. J Am Acad Dermatol. 2013;68:E138-E139. doi:10.1016/j.jaad.2012.09.049
- Belvisi V, Orsi GB, Del Borgo C, et al. Large nosocomial outbreakassociated with a Norwegian scabies index case undergoing TNF-α inhibitor treatment: management and control. Infect Control Hosp Epidemiol. 2015;36:1358-1360. doi:10.1017/ice.2015.188
- Nofal A. Variable response of crusted scabies to oral ivermectin: report on eight Egyptian patients. J Eur Acad Dermatol Venereol. 2009;23:793-797. doi:10.1111/j.1468-3083.2009.03177.x
- Yee BE, Carlos CA, Hata T. Crusted scabies of the scalp in a patient with systemic lupus erythematosus. Dermatol Online J. 2014;20:13030/qt9dm891gd.
- Bumb RA, Mehta RD. Crusted scabies in a patient of systemic sclerosis. Indian J Dermatol Venereol Leprol. 2000;66:143-144.
- Hylwa SA, Loss L, Grassi M. Crusted scabies and tinea corporis after treatment of presumed bullous pemphigoid. Cutis. 2013;92:193-198.
- Svecova D, Chmurova N, Pallova A, et al. Norwegian scabies in immunosuppressed patient misdiagnosed as an adverse drug reaction. Epidemiol Mikrobiol Imunol. 2009;58:121-123.
- Dourmishev AL, Serafimova DK, Dourmishev LA, et al. Crusted scabies of the scalp in dermatomyositis patients: three cases treated with oral ivermectin. Int J Dermatol. 1998;37:231-234. doi:10.1046/j.1365-4362.1998.00330.x
- Mortazavi H, Abedini R, Sadri F, et al. Crusted scabies in a patient with brain astrocytoma: report of a case. Int J Infect Dis. 2010;14:E526-E527. doi:10.1016/j.ijid.2009.06.011
- Lima FCDR, Cerqueira AMM, MBS, et al. Crusted scabies due to indiscriminate use of glucocorticoid therapy in infant. An Bras Dermatol. 2017;92:383-385. doi:10.1590/abd1806-4841.20174433
- Binic´ I, Jankovic´ A, Jovanovic´ D, et al. Crusted (Norwegian) scabies following systemic and topical corticosteroid therapy. J Korean Med Sci. 2010;25:188-191. doi:10.3346/jkms.2010.25.1.188
- Ohtaki N, Taniguchi H, Ohtomo H. Oral ivermectin treatment in two cases of scabies: effective in crusted scabies induced by corticosteroid but ineffective in nail scabies. J Dermatol. 2003;30:411-416. doi:10.1111/j.1346-8138.2003.tb00408.x
- Bilan P, Colin-Gorski AM, Chapelon E, et al. Crusted scabies induced by topical corticosteroids: a case report [in French]. Arch Pediatr. 2015;22:1292-1294. doi:10.1016/j.arcped.2015.09.004
- Marlière V, Roul S, C, et al. Crusted (Norwegian) scabies induced by use of topical corticosteroids and treated successfully with ivermectin. J Pediatr. 1999;135:122-124. doi:10.1016/s0022-3476(99)70342-2
- Jaramillo-Ayerbe F, J. Ivermectin for crusted Norwegian scabies induced by use of topical steroids. Arch Dermatol. 1998;134:143-145. doi:10.1001/archderm.134.2.143
- Elion GB. The purine path to chemotherapy. Science. 1989;244:41-47. doi:10.1126/science.2649979
- Chosidow O. Clinical practices. Scabies. N Engl J Med. 2006;354:1718-1727. doi:10.1056/NEJMcp052784
- Salgado F, Elston DM. What’s eating you? scabies in the developing world. Cutis. 2017;100:287-289.
- Karimkhani C, Colombara DV, Drucker AM, et al. The global burden of scabies: a cross-sectional analysis from the Global Burden of Disease Study 2015. Lancet Infect Dis. 2017;17:1247-1254. doi:10.1016/S1473-3099(17)30483-8
- Currie BJ, McCarthy JS. Permethrin and ivermectin for scabies. N Engl J Med. 2010;362:717-725. doi:10.1056/NEJMct0910329
- Thomas C, Coates SJ, Engelman D, et al. Ectoparasites: scabies. J Am Acad Dermatol. 2020;82:533-548. doi:10.1016/j.jaad.2019.05.109
- Roberts LJ, Huffam SE, Walton SF, et al. Crusted scabies: clinical and immunological findings in seventy-eight patients and a review of the literature. J Infect. 2005;50:375-381. doi:10.1016/j.jinf.2004.08.033
- Wang X-D, Shen H, Liu Z-H. Contagious erythroderma. J Emerg Med. 2016;51:180-181. doi:10.1016/j.jemermed.2016.05.027
- Johnston G, Sladden M. Scabies: diagnosis and treatment. BMJ. 2005;331:619-622. doi:10.1136/bmj.331.7517.619
- Micali G, Lacarrubba F, Massimino D, et al. Dermatoscopy: alternative uses in daily clinical practice. J Am Acad Dermatol. 2011;64:1135-1146. doi:10.1016/j.jaad.2010.03.010
- Bollea Garlatti LA, Torre AC, Bollea Garlatti ML, et al.. Dermoscopy aids the diagnosis of crusted scabies in an erythrodermic patient. J Am Acad Dermatol. 2015;73:E93-E95. doi:10.1016/j.jaad.2015.04.061
- Tang J, You Z, Ran Y. Simple methods to enhance the diagnosis of scabies. J Am Acad Dermatol. 2019;80:E99-E100. doi:10.1016/j.jaad.2017.07.038
- Falk ES, Eide TJ. Histologic and clinical findings in human scabies. Int J Dermatol. 1981;20:600-605. doi:10.1111/j.1365-4362.1981.tb00844.x
- Shahab RKA, Loo DS. Bullous scabies. J Am Acad Dermatol. 2003;49:346-350. doi:10.1067/s0190-9622(03)00876-4
- Strong M, Johnstone P. Interventions for treating scabies. Cochrane Database Syst Rev. 2007:CD000320. doi:10.1002/14651858.CD000320.pub2
- Rosumeck S, Nast A, Dressler C. Evaluation of ivermectin vs permethrin for treating scabies—summary of a Cochrane Review. JAMA Dermatol. 2019;155:730-732. doi:10.1001/jamadermatol.2019.0279
- Ruiz-Maldonado R. Pimecrolimus related crusted scabies in an infant. Pediatr Dermatol. 2006;23:299-300. doi:10.1111/j.1525-1470.2006.00241.x
- Bu X, Fan J, Hu X, et al. Norwegian scabies in a patient treated with Tripterygium glycoside for rheumatoid arthritis. An Bras Dermatol. 2017;92:556-558. doi:10.1590/abd1806-4841.20174946
- Pipitone MA, Adams B, Sheth A, et al. Crusted scabies in a patient being treated with infliximab for juvenile rheumatoid arthritis. J Am Acad Dermatol. 2005;52:719-720. doi:10.1016/j.jaad.2004.12.039
- Baccouche K, Sellam J, Guegan S, et al. Crusted Norwegian scabies, an opportunistic infection, with tocilizumab in rheumatoid arthritis. Joint Bone Spine. 2011;78:402-404. doi:10.1016/j.jbspin.2011.02.008
- Saillard C, Darrieux L, Safa G. Crusted scabies complicates etanercept therapy in a patient with severe psoriasis. J Am Acad Dermatol. 2013;68:E138-E139. doi:10.1016/j.jaad.2012.09.049
- Belvisi V, Orsi GB, Del Borgo C, et al. Large nosocomial outbreakassociated with a Norwegian scabies index case undergoing TNF-α inhibitor treatment: management and control. Infect Control Hosp Epidemiol. 2015;36:1358-1360. doi:10.1017/ice.2015.188
- Nofal A. Variable response of crusted scabies to oral ivermectin: report on eight Egyptian patients. J Eur Acad Dermatol Venereol. 2009;23:793-797. doi:10.1111/j.1468-3083.2009.03177.x
- Yee BE, Carlos CA, Hata T. Crusted scabies of the scalp in a patient with systemic lupus erythematosus. Dermatol Online J. 2014;20:13030/qt9dm891gd.
- Bumb RA, Mehta RD. Crusted scabies in a patient of systemic sclerosis. Indian J Dermatol Venereol Leprol. 2000;66:143-144.
- Hylwa SA, Loss L, Grassi M. Crusted scabies and tinea corporis after treatment of presumed bullous pemphigoid. Cutis. 2013;92:193-198.
- Svecova D, Chmurova N, Pallova A, et al. Norwegian scabies in immunosuppressed patient misdiagnosed as an adverse drug reaction. Epidemiol Mikrobiol Imunol. 2009;58:121-123.
- Dourmishev AL, Serafimova DK, Dourmishev LA, et al. Crusted scabies of the scalp in dermatomyositis patients: three cases treated with oral ivermectin. Int J Dermatol. 1998;37:231-234. doi:10.1046/j.1365-4362.1998.00330.x
- Mortazavi H, Abedini R, Sadri F, et al. Crusted scabies in a patient with brain astrocytoma: report of a case. Int J Infect Dis. 2010;14:E526-E527. doi:10.1016/j.ijid.2009.06.011
- Lima FCDR, Cerqueira AMM, MBS, et al. Crusted scabies due to indiscriminate use of glucocorticoid therapy in infant. An Bras Dermatol. 2017;92:383-385. doi:10.1590/abd1806-4841.20174433
- Binic´ I, Jankovic´ A, Jovanovic´ D, et al. Crusted (Norwegian) scabies following systemic and topical corticosteroid therapy. J Korean Med Sci. 2010;25:188-191. doi:10.3346/jkms.2010.25.1.188
- Ohtaki N, Taniguchi H, Ohtomo H. Oral ivermectin treatment in two cases of scabies: effective in crusted scabies induced by corticosteroid but ineffective in nail scabies. J Dermatol. 2003;30:411-416. doi:10.1111/j.1346-8138.2003.tb00408.x
- Bilan P, Colin-Gorski AM, Chapelon E, et al. Crusted scabies induced by topical corticosteroids: a case report [in French]. Arch Pediatr. 2015;22:1292-1294. doi:10.1016/j.arcped.2015.09.004
- Marlière V, Roul S, C, et al. Crusted (Norwegian) scabies induced by use of topical corticosteroids and treated successfully with ivermectin. J Pediatr. 1999;135:122-124. doi:10.1016/s0022-3476(99)70342-2
- Jaramillo-Ayerbe F, J. Ivermectin for crusted Norwegian scabies induced by use of topical steroids. Arch Dermatol. 1998;134:143-145. doi:10.1001/archderm.134.2.143
- Elion GB. The purine path to chemotherapy. Science. 1989;244:41-47. doi:10.1126/science.2649979
Practice Points
- Crusted scabies is a highly contagious, severe cutaneous ectoparasitic infection that can present atypically in the form of erythroderma.
- Immunomodulatory drugs for the treatment of autoimmune disease can predispose patients to infection, including ectoparasitic infection.
- Dermatologists should be familiar with the full scope of the clinical presentations of scabies and should especially consider this condition in the differential diagnosis of patients who present in an immunosuppressed state.
Primary Effusion Lymphoma: An Infiltrative Plaque in a Patient With HIV
To the Editor:
A 47-year-old man presented to the dermatology service with an asymptomatic plaque on the right thigh of 2 months’ duration. He had a medical history of HIV and Kaposi sarcoma as well as a recently relapsed primary effusion lymphoma (PEL) subsequent to an allogeneic bone marrow transplant. He initially was diagnosed with PEL 3 years prior to the current presentation during a workup for fever and weight loss. Imaging at the time demonstrated a bladder mass, which was biopsied and demonstrated PEL. Further imaging demonstrated both sinus and bone marrow involvement. Prior to dermatologic consultation, he had been treated with 6 cycles of etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (EPOCH); 6 cycles of brentuximab; 4 cycles of rituximab with gemcitabine and oxaliplatin; and 2 cycles of ifosfamide, carboplatin, and etoposide. Despite these therapies, he had 3 relapses, and oncology determined the need for a matched unrelated donor allogeneic stem cell transplant for his PEL.
At the time of dermatology consultation, the patient was being managed on daratumumab and bortezomib. Physical examination revealed an infiltrative plaque on the right inferomedial thigh measuring approximately 6.0 cm (largest dimension) with a small amount of peripheral scale (Figure 1). An ultrasound revealed notable subcutaneous tissue edema and increased vascularity without a discrete mass or fluid collection. A 4-mm punch biopsy demonstrated a dense infiltrate comprised of collections of histiocytes admixed with scattered plasma cells and mature lymphoid aggregates. Additionally, rare enlarged plasmablastic cells with scant basophilic cytoplasm and slightly irregular nuclear contours were visualized (Figure 2A). Immunohistochemistry was positive for CD3 with a normal CD4:CD8 ratio, CD68-highlighted histiocytes within the lymphoid aggregates, and human herpesvirus 8 (HHV-8)(or Kaposi sarcoma–associated herpesvirus) demonstrated stippled nuclear staining within the scattered large cells (Figure 2B). Epstein-Barr virus–encoded RNA staining was negative, though the area of interest was lost on deeper sectioning of the tissue block. The histopathologic findings were consistent with cutaneous extracavitary PEL. Shortly after this diagnosis, he died from disease complications.
Primary effusion lymphoma is an aggressive non-Hodgkin B-cell lymphoma that was first described by Knowles et al1 in 1989. Primary effusion lymphoma occurs exclusively in the setting of HHV-8 infection and typically is associated with chronic immunosuppression related to HIV/AIDS. Cases that are negative for HIV-1 are rare but have been reported in organ transplant recipients and elderly men from areas with a high prevalence of HHV-8 infections. Most HIV-associated cases show concurrent Epstein-Barr virus infection, though the pathogenic meaning of this co-infection remains unclear.2,3
Primary effusion lymphoma classically presents as an isolated effusion of malignant lymphoid cells within body cavities in the absence of solid tumor masses. The pleural, peritoneal, and pericardial spaces most commonly are involved. Extracavitary PEL, a rare variant, may present as a solid mass without effusion. In general, extracavitary tumors may occur in the setting of de novo malignancy or recurrent PEL.4 Cutaneous manifestations associated with extracavitary PEL are rare; 4 cases have been described in which skin lesions were the heralding sign of the disease.3 Interestingly, despite obligatory underlying HHV-8 infection, a review by Pielasinski et al3 noted only 2 patients with cutaneous PEL who had prior or concurrent Kaposi sarcoma. This heterogeneity in HHV-8–related phenotypes may be related to differences in microRNA expression, but further study is needed.5
The diagnosis of PEL relies on histologic, immunophenotypic, and molecular analysis of the affected tissue. The malignant cells typically are large with round to irregular nuclei. These cells may demonstrate a variety of appearances, including anaplastic, plasmablastic, and immunoblastic morphologies.6,7 The immunophenotype displays CD45 positivity and markers of lymphocyte activation (CD30, CD38, CD71), while typical B-cell (CD19, CD20, CD79a) and T-cell (CD3, CD4, CD8) markers often are absent.6-8 Human herpesvirus 8 detection by polymerase chain reaction testing of the peripheral blood or by immunohistochemistry staining of the affected tissue is required for diagnosis.6,7 Epstein-Barr virus infection may be detected via in situ hybridization, though it is not required for diagnosis.
The overall prognosis for PEL is poor; Brimo et al6 reported a median survival of less than 6 months, and Guillet et al9 reported 5-year overall survival (OS) for PEL vs extracavitary PEL to be 43% vs 39%. Another review noted variation in survival contingent on the number of body cavities involved; patients with a single body cavity involved experienced a median OS of 18 months, whereas patients with multiple involved cavities experienced a median OS of 4 months,7 possibly due to the limited study of treatment regimens or disease aggressiveness. Even in cases of successful initial treatment, relapse within 6 to 8 months is common. Extracavitary PEL may have improved disease-free survival relative to classic PEL, though the data were less clear for OS.9 Limitations of the Guillet et al9 study included a small sample size, the impossibility to randomize to disease type, and loss of power on the log-rank test for OS in the setting of possible nonproportional hazards (crossing survival curves). Overall, prognostic differences between the groups may be challenging to ascertain until further data are obtained.
As with many HIV-associated neoplasms, antiretroviral treatment (ART) for HIV-positive patients affords a better prognosis when used in addition to therapy directed at malignancy.7 The general approach is for concurrent ART with systemic therapies such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for the rare CD20+ cases, and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or dose-adjusted EPOCH therapy in the more common CD20− PEL cases. Narkhede et al7 suggested avoidance of methotrexate in patients with effusions because of increased toxicity, but it is unclear if this recommendation is applicable in extracavitary PEL patients without an effusion. Additionally, second-line treatment modalities include radiation for solid PEL masses, HHV-8–targeted antivirals, and stem cell transplantation, though evidence is limited. Of note, there is a phase I-II trial (ClinicalTrials.gov identifier NCT02911142) ongoing for treatment-naïve PEL patients involving the experimental treatment DA-EPOCH-R plus lenalidomide, but the trial is ongoing.10
We report a case of cutaneous PEL in a patient with a history of Kaposi sarcoma. The patient’s deterioration and ultimate death despite initial treatment with EPOCH and bone marrow transplantation followed by final management with daratumumab and bortezomib confirm other reports that PEL has a poor prognosis and that optimal treatments are not well delineated for these patients. In general, the current approach is to utilize ART for HIV-positive patients and to then implement chemotherapy such as CHOP. Without continued research and careful planning of treatments, data will remain limited on how best to serve patients with PEL.
- Knowles DM, Inghirami G, Ubriaco A, et al. Molecular genetic analysis of three AIDS-associated neoplasms of uncertain lineage demonstrates their B-cell derivation and the possible pathogenetic role of the Epstein-Barr virus. Blood. 1989;73:792-799.
- Kugasia IAR, Kumar A, Khatri A, et al. Primary effusion lymphoma of the pleural space: report of a rare complication of cardiac transplant with review of the literature. Transpl Infect Dis. 2019;21:E13005.
- Pielasinski U, Santonja C, Rodriguez-Pinilla SM, et al. Extracavitary primary effusion lymphoma presenting as a cutaneous tumor: a case report and literature review. J Cutan Pathol. 2014;41:745-753.
- Boulanger E, Meignin V, Afonso PV, et al. Extracavitary tumor after primary effusion lymphoma: relapse or second distinct lymphoma? Haematologica. 2007;92:1275-1276.
- Goncalves PH, Uldrick TS, Yarchoan R. HIV-associated Kaposi sarcoma and related diseases. AIDS. 2017;31:1903-1916.
- Brimo F, Michel RP, Khetani K, et al. Primary effusion lymphoma: a series of 4 cases and review of the literature with emphasis on cytomorphologic and immunocytochemical differential diagnosis. Cancer. 2007;111:224-233.
- Narkhede M, Arora S, Ujjani C. Primary effusion lymphoma: current perspectives. Onco Targets Ther. 2018;11:3747-3754.
- Chen YB, Rahemtullah A, Hochberg E. Primary effusion lymphoma. Oncologist. 2007;12:569-576.
- Guillet S, Gerard L, Meignin V, et al. Classic and extracavitary primary effusion lymphoma in 51 HIV-infected patients from a single institution. Am J Hematol. 2016;91:233-237.
To the Editor:
A 47-year-old man presented to the dermatology service with an asymptomatic plaque on the right thigh of 2 months’ duration. He had a medical history of HIV and Kaposi sarcoma as well as a recently relapsed primary effusion lymphoma (PEL) subsequent to an allogeneic bone marrow transplant. He initially was diagnosed with PEL 3 years prior to the current presentation during a workup for fever and weight loss. Imaging at the time demonstrated a bladder mass, which was biopsied and demonstrated PEL. Further imaging demonstrated both sinus and bone marrow involvement. Prior to dermatologic consultation, he had been treated with 6 cycles of etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (EPOCH); 6 cycles of brentuximab; 4 cycles of rituximab with gemcitabine and oxaliplatin; and 2 cycles of ifosfamide, carboplatin, and etoposide. Despite these therapies, he had 3 relapses, and oncology determined the need for a matched unrelated donor allogeneic stem cell transplant for his PEL.
At the time of dermatology consultation, the patient was being managed on daratumumab and bortezomib. Physical examination revealed an infiltrative plaque on the right inferomedial thigh measuring approximately 6.0 cm (largest dimension) with a small amount of peripheral scale (Figure 1). An ultrasound revealed notable subcutaneous tissue edema and increased vascularity without a discrete mass or fluid collection. A 4-mm punch biopsy demonstrated a dense infiltrate comprised of collections of histiocytes admixed with scattered plasma cells and mature lymphoid aggregates. Additionally, rare enlarged plasmablastic cells with scant basophilic cytoplasm and slightly irregular nuclear contours were visualized (Figure 2A). Immunohistochemistry was positive for CD3 with a normal CD4:CD8 ratio, CD68-highlighted histiocytes within the lymphoid aggregates, and human herpesvirus 8 (HHV-8)(or Kaposi sarcoma–associated herpesvirus) demonstrated stippled nuclear staining within the scattered large cells (Figure 2B). Epstein-Barr virus–encoded RNA staining was negative, though the area of interest was lost on deeper sectioning of the tissue block. The histopathologic findings were consistent with cutaneous extracavitary PEL. Shortly after this diagnosis, he died from disease complications.
Primary effusion lymphoma is an aggressive non-Hodgkin B-cell lymphoma that was first described by Knowles et al1 in 1989. Primary effusion lymphoma occurs exclusively in the setting of HHV-8 infection and typically is associated with chronic immunosuppression related to HIV/AIDS. Cases that are negative for HIV-1 are rare but have been reported in organ transplant recipients and elderly men from areas with a high prevalence of HHV-8 infections. Most HIV-associated cases show concurrent Epstein-Barr virus infection, though the pathogenic meaning of this co-infection remains unclear.2,3
Primary effusion lymphoma classically presents as an isolated effusion of malignant lymphoid cells within body cavities in the absence of solid tumor masses. The pleural, peritoneal, and pericardial spaces most commonly are involved. Extracavitary PEL, a rare variant, may present as a solid mass without effusion. In general, extracavitary tumors may occur in the setting of de novo malignancy or recurrent PEL.4 Cutaneous manifestations associated with extracavitary PEL are rare; 4 cases have been described in which skin lesions were the heralding sign of the disease.3 Interestingly, despite obligatory underlying HHV-8 infection, a review by Pielasinski et al3 noted only 2 patients with cutaneous PEL who had prior or concurrent Kaposi sarcoma. This heterogeneity in HHV-8–related phenotypes may be related to differences in microRNA expression, but further study is needed.5
The diagnosis of PEL relies on histologic, immunophenotypic, and molecular analysis of the affected tissue. The malignant cells typically are large with round to irregular nuclei. These cells may demonstrate a variety of appearances, including anaplastic, plasmablastic, and immunoblastic morphologies.6,7 The immunophenotype displays CD45 positivity and markers of lymphocyte activation (CD30, CD38, CD71), while typical B-cell (CD19, CD20, CD79a) and T-cell (CD3, CD4, CD8) markers often are absent.6-8 Human herpesvirus 8 detection by polymerase chain reaction testing of the peripheral blood or by immunohistochemistry staining of the affected tissue is required for diagnosis.6,7 Epstein-Barr virus infection may be detected via in situ hybridization, though it is not required for diagnosis.
The overall prognosis for PEL is poor; Brimo et al6 reported a median survival of less than 6 months, and Guillet et al9 reported 5-year overall survival (OS) for PEL vs extracavitary PEL to be 43% vs 39%. Another review noted variation in survival contingent on the number of body cavities involved; patients with a single body cavity involved experienced a median OS of 18 months, whereas patients with multiple involved cavities experienced a median OS of 4 months,7 possibly due to the limited study of treatment regimens or disease aggressiveness. Even in cases of successful initial treatment, relapse within 6 to 8 months is common. Extracavitary PEL may have improved disease-free survival relative to classic PEL, though the data were less clear for OS.9 Limitations of the Guillet et al9 study included a small sample size, the impossibility to randomize to disease type, and loss of power on the log-rank test for OS in the setting of possible nonproportional hazards (crossing survival curves). Overall, prognostic differences between the groups may be challenging to ascertain until further data are obtained.
As with many HIV-associated neoplasms, antiretroviral treatment (ART) for HIV-positive patients affords a better prognosis when used in addition to therapy directed at malignancy.7 The general approach is for concurrent ART with systemic therapies such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for the rare CD20+ cases, and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or dose-adjusted EPOCH therapy in the more common CD20− PEL cases. Narkhede et al7 suggested avoidance of methotrexate in patients with effusions because of increased toxicity, but it is unclear if this recommendation is applicable in extracavitary PEL patients without an effusion. Additionally, second-line treatment modalities include radiation for solid PEL masses, HHV-8–targeted antivirals, and stem cell transplantation, though evidence is limited. Of note, there is a phase I-II trial (ClinicalTrials.gov identifier NCT02911142) ongoing for treatment-naïve PEL patients involving the experimental treatment DA-EPOCH-R plus lenalidomide, but the trial is ongoing.10
We report a case of cutaneous PEL in a patient with a history of Kaposi sarcoma. The patient’s deterioration and ultimate death despite initial treatment with EPOCH and bone marrow transplantation followed by final management with daratumumab and bortezomib confirm other reports that PEL has a poor prognosis and that optimal treatments are not well delineated for these patients. In general, the current approach is to utilize ART for HIV-positive patients and to then implement chemotherapy such as CHOP. Without continued research and careful planning of treatments, data will remain limited on how best to serve patients with PEL.
To the Editor:
A 47-year-old man presented to the dermatology service with an asymptomatic plaque on the right thigh of 2 months’ duration. He had a medical history of HIV and Kaposi sarcoma as well as a recently relapsed primary effusion lymphoma (PEL) subsequent to an allogeneic bone marrow transplant. He initially was diagnosed with PEL 3 years prior to the current presentation during a workup for fever and weight loss. Imaging at the time demonstrated a bladder mass, which was biopsied and demonstrated PEL. Further imaging demonstrated both sinus and bone marrow involvement. Prior to dermatologic consultation, he had been treated with 6 cycles of etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (EPOCH); 6 cycles of brentuximab; 4 cycles of rituximab with gemcitabine and oxaliplatin; and 2 cycles of ifosfamide, carboplatin, and etoposide. Despite these therapies, he had 3 relapses, and oncology determined the need for a matched unrelated donor allogeneic stem cell transplant for his PEL.
At the time of dermatology consultation, the patient was being managed on daratumumab and bortezomib. Physical examination revealed an infiltrative plaque on the right inferomedial thigh measuring approximately 6.0 cm (largest dimension) with a small amount of peripheral scale (Figure 1). An ultrasound revealed notable subcutaneous tissue edema and increased vascularity without a discrete mass or fluid collection. A 4-mm punch biopsy demonstrated a dense infiltrate comprised of collections of histiocytes admixed with scattered plasma cells and mature lymphoid aggregates. Additionally, rare enlarged plasmablastic cells with scant basophilic cytoplasm and slightly irregular nuclear contours were visualized (Figure 2A). Immunohistochemistry was positive for CD3 with a normal CD4:CD8 ratio, CD68-highlighted histiocytes within the lymphoid aggregates, and human herpesvirus 8 (HHV-8)(or Kaposi sarcoma–associated herpesvirus) demonstrated stippled nuclear staining within the scattered large cells (Figure 2B). Epstein-Barr virus–encoded RNA staining was negative, though the area of interest was lost on deeper sectioning of the tissue block. The histopathologic findings were consistent with cutaneous extracavitary PEL. Shortly after this diagnosis, he died from disease complications.
Primary effusion lymphoma is an aggressive non-Hodgkin B-cell lymphoma that was first described by Knowles et al1 in 1989. Primary effusion lymphoma occurs exclusively in the setting of HHV-8 infection and typically is associated with chronic immunosuppression related to HIV/AIDS. Cases that are negative for HIV-1 are rare but have been reported in organ transplant recipients and elderly men from areas with a high prevalence of HHV-8 infections. Most HIV-associated cases show concurrent Epstein-Barr virus infection, though the pathogenic meaning of this co-infection remains unclear.2,3
Primary effusion lymphoma classically presents as an isolated effusion of malignant lymphoid cells within body cavities in the absence of solid tumor masses. The pleural, peritoneal, and pericardial spaces most commonly are involved. Extracavitary PEL, a rare variant, may present as a solid mass without effusion. In general, extracavitary tumors may occur in the setting of de novo malignancy or recurrent PEL.4 Cutaneous manifestations associated with extracavitary PEL are rare; 4 cases have been described in which skin lesions were the heralding sign of the disease.3 Interestingly, despite obligatory underlying HHV-8 infection, a review by Pielasinski et al3 noted only 2 patients with cutaneous PEL who had prior or concurrent Kaposi sarcoma. This heterogeneity in HHV-8–related phenotypes may be related to differences in microRNA expression, but further study is needed.5
The diagnosis of PEL relies on histologic, immunophenotypic, and molecular analysis of the affected tissue. The malignant cells typically are large with round to irregular nuclei. These cells may demonstrate a variety of appearances, including anaplastic, plasmablastic, and immunoblastic morphologies.6,7 The immunophenotype displays CD45 positivity and markers of lymphocyte activation (CD30, CD38, CD71), while typical B-cell (CD19, CD20, CD79a) and T-cell (CD3, CD4, CD8) markers often are absent.6-8 Human herpesvirus 8 detection by polymerase chain reaction testing of the peripheral blood or by immunohistochemistry staining of the affected tissue is required for diagnosis.6,7 Epstein-Barr virus infection may be detected via in situ hybridization, though it is not required for diagnosis.
The overall prognosis for PEL is poor; Brimo et al6 reported a median survival of less than 6 months, and Guillet et al9 reported 5-year overall survival (OS) for PEL vs extracavitary PEL to be 43% vs 39%. Another review noted variation in survival contingent on the number of body cavities involved; patients with a single body cavity involved experienced a median OS of 18 months, whereas patients with multiple involved cavities experienced a median OS of 4 months,7 possibly due to the limited study of treatment regimens or disease aggressiveness. Even in cases of successful initial treatment, relapse within 6 to 8 months is common. Extracavitary PEL may have improved disease-free survival relative to classic PEL, though the data were less clear for OS.9 Limitations of the Guillet et al9 study included a small sample size, the impossibility to randomize to disease type, and loss of power on the log-rank test for OS in the setting of possible nonproportional hazards (crossing survival curves). Overall, prognostic differences between the groups may be challenging to ascertain until further data are obtained.
As with many HIV-associated neoplasms, antiretroviral treatment (ART) for HIV-positive patients affords a better prognosis when used in addition to therapy directed at malignancy.7 The general approach is for concurrent ART with systemic therapies such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for the rare CD20+ cases, and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or dose-adjusted EPOCH therapy in the more common CD20− PEL cases. Narkhede et al7 suggested avoidance of methotrexate in patients with effusions because of increased toxicity, but it is unclear if this recommendation is applicable in extracavitary PEL patients without an effusion. Additionally, second-line treatment modalities include radiation for solid PEL masses, HHV-8–targeted antivirals, and stem cell transplantation, though evidence is limited. Of note, there is a phase I-II trial (ClinicalTrials.gov identifier NCT02911142) ongoing for treatment-naïve PEL patients involving the experimental treatment DA-EPOCH-R plus lenalidomide, but the trial is ongoing.10
We report a case of cutaneous PEL in a patient with a history of Kaposi sarcoma. The patient’s deterioration and ultimate death despite initial treatment with EPOCH and bone marrow transplantation followed by final management with daratumumab and bortezomib confirm other reports that PEL has a poor prognosis and that optimal treatments are not well delineated for these patients. In general, the current approach is to utilize ART for HIV-positive patients and to then implement chemotherapy such as CHOP. Without continued research and careful planning of treatments, data will remain limited on how best to serve patients with PEL.
- Knowles DM, Inghirami G, Ubriaco A, et al. Molecular genetic analysis of three AIDS-associated neoplasms of uncertain lineage demonstrates their B-cell derivation and the possible pathogenetic role of the Epstein-Barr virus. Blood. 1989;73:792-799.
- Kugasia IAR, Kumar A, Khatri A, et al. Primary effusion lymphoma of the pleural space: report of a rare complication of cardiac transplant with review of the literature. Transpl Infect Dis. 2019;21:E13005.
- Pielasinski U, Santonja C, Rodriguez-Pinilla SM, et al. Extracavitary primary effusion lymphoma presenting as a cutaneous tumor: a case report and literature review. J Cutan Pathol. 2014;41:745-753.
- Boulanger E, Meignin V, Afonso PV, et al. Extracavitary tumor after primary effusion lymphoma: relapse or second distinct lymphoma? Haematologica. 2007;92:1275-1276.
- Goncalves PH, Uldrick TS, Yarchoan R. HIV-associated Kaposi sarcoma and related diseases. AIDS. 2017;31:1903-1916.
- Brimo F, Michel RP, Khetani K, et al. Primary effusion lymphoma: a series of 4 cases and review of the literature with emphasis on cytomorphologic and immunocytochemical differential diagnosis. Cancer. 2007;111:224-233.
- Narkhede M, Arora S, Ujjani C. Primary effusion lymphoma: current perspectives. Onco Targets Ther. 2018;11:3747-3754.
- Chen YB, Rahemtullah A, Hochberg E. Primary effusion lymphoma. Oncologist. 2007;12:569-576.
- Guillet S, Gerard L, Meignin V, et al. Classic and extracavitary primary effusion lymphoma in 51 HIV-infected patients from a single institution. Am J Hematol. 2016;91:233-237.
- Knowles DM, Inghirami G, Ubriaco A, et al. Molecular genetic analysis of three AIDS-associated neoplasms of uncertain lineage demonstrates their B-cell derivation and the possible pathogenetic role of the Epstein-Barr virus. Blood. 1989;73:792-799.
- Kugasia IAR, Kumar A, Khatri A, et al. Primary effusion lymphoma of the pleural space: report of a rare complication of cardiac transplant with review of the literature. Transpl Infect Dis. 2019;21:E13005.
- Pielasinski U, Santonja C, Rodriguez-Pinilla SM, et al. Extracavitary primary effusion lymphoma presenting as a cutaneous tumor: a case report and literature review. J Cutan Pathol. 2014;41:745-753.
- Boulanger E, Meignin V, Afonso PV, et al. Extracavitary tumor after primary effusion lymphoma: relapse or second distinct lymphoma? Haematologica. 2007;92:1275-1276.
- Goncalves PH, Uldrick TS, Yarchoan R. HIV-associated Kaposi sarcoma and related diseases. AIDS. 2017;31:1903-1916.
- Brimo F, Michel RP, Khetani K, et al. Primary effusion lymphoma: a series of 4 cases and review of the literature with emphasis on cytomorphologic and immunocytochemical differential diagnosis. Cancer. 2007;111:224-233.
- Narkhede M, Arora S, Ujjani C. Primary effusion lymphoma: current perspectives. Onco Targets Ther. 2018;11:3747-3754.
- Chen YB, Rahemtullah A, Hochberg E. Primary effusion lymphoma. Oncologist. 2007;12:569-576.
- Guillet S, Gerard L, Meignin V, et al. Classic and extracavitary primary effusion lymphoma in 51 HIV-infected patients from a single institution. Am J Hematol. 2016;91:233-237.
Practice Points
- Extracavitary primary effusion lymphoma is an aggressive non-Hodgkin B-cell lymphoma that occurs solely in the presence of human herpesvirus 8 infection and typically is associated with HIV/AIDS.
- Diagnosis necessitates a thorough workup and correlation of histologic, molecular, and immunophenotypic analysis.
- Antiretroviral therapy in HIV-positive patients and intensive chemotherapy regimens are the current recommended treatments. Despite newer targeted agents, the prognosis remains poor.
ILD risk elevated in RA, PsA after starting biologic or targeted synthetic DMARDs
MILAN – Patients with psoriatic arthritis (PsA) who are using biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) have fivefold higher risk for interstitial lung disease (ILD) than does the general population, according to the first study to explore risk of ILD in this particular patient group.
The study also found 10-fold higher risk of ILD in patients with RA who were starting a b/tsDMARD, compared with the general population, while the addition of methotrexate did not appear to be associated with increased risk for ILD in either RA nor PsA.
Sella Aarrestad Provan, MD, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital, Oslo, presented the results at the annual European Congress of Rheumatology.
Explaining the motivation for the study, Dr. Aarrestad Provan said that, in RA, methotrexate’s role in ILD development remained unclear, while some small studies linked b/tsDMARDs with risk for ILD. “In PsA, very few studies have explored the risk of ILD, and no systematic studies have looked at ILD risk factors in this disease.”
The researchers analyzed patient data from hospital and death registries across five Nordic countries (Denmark, Norway, Finland, Iceland, and Sweden) and compared them with general population controls. They calculated risk ratios for people who developed ILD within 5 years of starting a b/tsDMARD (with or without methotrexate).
A total of 37,010 patients with RA, 12,341 with PsA, and 569,451 members of the general population were included in the analysis, with respective disease durations of 10 and 8.9 years. Methotrexate was used along with b/tsDMARDs in 49% of patients with RA and 41% with PsA, and most patients were already on methotrexate when b/tsDMARDs were started. The tumor necrosis factor inhibitor etanercept (Enbrel) was the most commonly used b/tsDMARD in both RA and PsA, followed by infliximab (Remicade and biosimilars) and adalimumab (Humira and biosimilars).
The incidence of ILD within 5 years of starting a b/tsDMARD was 0.8% in patients with RA, 0.2% with PsA, and 0.1% in the general population, and these findings generated hazard ratios of 10.1 (95% confidence interval, 8.6-11.9) for RA and 5.0 (95% CI, 3.4-7.4) for PsA, compared with the general population as reference.
When the risk for ILD was explored according to methotrexate use in RA patients, “there was no signal of increased risk across patients using methotrexate,” Dr. Aarrestad Provan reported. When risk of ILD was explored according to b/tsDMARD use in RA patients, a signal of increased risk was observed with rituximab, she noted, “but upon adjusting for age, sex, and comorbidities, this association was no longer significant, but was still numerically increased.”
Iain McInnes, MD, PhD, vice principal, professor of rheumatology, and head of the College of Medical, Veterinary and Life Sciences at the University of Glasgow, remarked that he “loves results that are unexpected” and thanked the researcher for such an “important study.”
“For years, we’ve been interested in the potential for DMARDs to impact interstitial lung disease, with potential that drugs could make it worse, or better,” he said. “This study is wonderful and novel because first of all, there hasn’t, until now, been a direct comparison between RA and PsA in quite this way, and secondly, we haven’t really assessed whether there is a drug-related risk in PsA. Note that drug related does not necessarily imply causality.”
Regarding mechanisms, Dr. McInnes added that “epidemiologic studies suggest that PsA often coexists with the presence of cardiometabolic syndrome and obesity, which has a higher prevalence in PsA than in RA. Obesity is also related to ILD. As such, it begs the question of whether cardiometabolic, diabetes, or obesity-related features may give us a clue as to what is going on in these PsA patients.”
The research was supported by NordForsk and FOREUM. Dr. Aarrestad Provan reported serving as a consultant to Boehringer Ingelheim and Novartis and receiving grant/research support from Boehringer Ingelheim. Dr. McInnes declared no disclosures relevant to this study.
MILAN – Patients with psoriatic arthritis (PsA) who are using biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) have fivefold higher risk for interstitial lung disease (ILD) than does the general population, according to the first study to explore risk of ILD in this particular patient group.
The study also found 10-fold higher risk of ILD in patients with RA who were starting a b/tsDMARD, compared with the general population, while the addition of methotrexate did not appear to be associated with increased risk for ILD in either RA nor PsA.
Sella Aarrestad Provan, MD, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital, Oslo, presented the results at the annual European Congress of Rheumatology.
Explaining the motivation for the study, Dr. Aarrestad Provan said that, in RA, methotrexate’s role in ILD development remained unclear, while some small studies linked b/tsDMARDs with risk for ILD. “In PsA, very few studies have explored the risk of ILD, and no systematic studies have looked at ILD risk factors in this disease.”
The researchers analyzed patient data from hospital and death registries across five Nordic countries (Denmark, Norway, Finland, Iceland, and Sweden) and compared them with general population controls. They calculated risk ratios for people who developed ILD within 5 years of starting a b/tsDMARD (with or without methotrexate).
A total of 37,010 patients with RA, 12,341 with PsA, and 569,451 members of the general population were included in the analysis, with respective disease durations of 10 and 8.9 years. Methotrexate was used along with b/tsDMARDs in 49% of patients with RA and 41% with PsA, and most patients were already on methotrexate when b/tsDMARDs were started. The tumor necrosis factor inhibitor etanercept (Enbrel) was the most commonly used b/tsDMARD in both RA and PsA, followed by infliximab (Remicade and biosimilars) and adalimumab (Humira and biosimilars).
The incidence of ILD within 5 years of starting a b/tsDMARD was 0.8% in patients with RA, 0.2% with PsA, and 0.1% in the general population, and these findings generated hazard ratios of 10.1 (95% confidence interval, 8.6-11.9) for RA and 5.0 (95% CI, 3.4-7.4) for PsA, compared with the general population as reference.
When the risk for ILD was explored according to methotrexate use in RA patients, “there was no signal of increased risk across patients using methotrexate,” Dr. Aarrestad Provan reported. When risk of ILD was explored according to b/tsDMARD use in RA patients, a signal of increased risk was observed with rituximab, she noted, “but upon adjusting for age, sex, and comorbidities, this association was no longer significant, but was still numerically increased.”
Iain McInnes, MD, PhD, vice principal, professor of rheumatology, and head of the College of Medical, Veterinary and Life Sciences at the University of Glasgow, remarked that he “loves results that are unexpected” and thanked the researcher for such an “important study.”
“For years, we’ve been interested in the potential for DMARDs to impact interstitial lung disease, with potential that drugs could make it worse, or better,” he said. “This study is wonderful and novel because first of all, there hasn’t, until now, been a direct comparison between RA and PsA in quite this way, and secondly, we haven’t really assessed whether there is a drug-related risk in PsA. Note that drug related does not necessarily imply causality.”
Regarding mechanisms, Dr. McInnes added that “epidemiologic studies suggest that PsA often coexists with the presence of cardiometabolic syndrome and obesity, which has a higher prevalence in PsA than in RA. Obesity is also related to ILD. As such, it begs the question of whether cardiometabolic, diabetes, or obesity-related features may give us a clue as to what is going on in these PsA patients.”
The research was supported by NordForsk and FOREUM. Dr. Aarrestad Provan reported serving as a consultant to Boehringer Ingelheim and Novartis and receiving grant/research support from Boehringer Ingelheim. Dr. McInnes declared no disclosures relevant to this study.
MILAN – Patients with psoriatic arthritis (PsA) who are using biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) have fivefold higher risk for interstitial lung disease (ILD) than does the general population, according to the first study to explore risk of ILD in this particular patient group.
The study also found 10-fold higher risk of ILD in patients with RA who were starting a b/tsDMARD, compared with the general population, while the addition of methotrexate did not appear to be associated with increased risk for ILD in either RA nor PsA.
Sella Aarrestad Provan, MD, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital, Oslo, presented the results at the annual European Congress of Rheumatology.
Explaining the motivation for the study, Dr. Aarrestad Provan said that, in RA, methotrexate’s role in ILD development remained unclear, while some small studies linked b/tsDMARDs with risk for ILD. “In PsA, very few studies have explored the risk of ILD, and no systematic studies have looked at ILD risk factors in this disease.”
The researchers analyzed patient data from hospital and death registries across five Nordic countries (Denmark, Norway, Finland, Iceland, and Sweden) and compared them with general population controls. They calculated risk ratios for people who developed ILD within 5 years of starting a b/tsDMARD (with or without methotrexate).
A total of 37,010 patients with RA, 12,341 with PsA, and 569,451 members of the general population were included in the analysis, with respective disease durations of 10 and 8.9 years. Methotrexate was used along with b/tsDMARDs in 49% of patients with RA and 41% with PsA, and most patients were already on methotrexate when b/tsDMARDs were started. The tumor necrosis factor inhibitor etanercept (Enbrel) was the most commonly used b/tsDMARD in both RA and PsA, followed by infliximab (Remicade and biosimilars) and adalimumab (Humira and biosimilars).
The incidence of ILD within 5 years of starting a b/tsDMARD was 0.8% in patients with RA, 0.2% with PsA, and 0.1% in the general population, and these findings generated hazard ratios of 10.1 (95% confidence interval, 8.6-11.9) for RA and 5.0 (95% CI, 3.4-7.4) for PsA, compared with the general population as reference.
When the risk for ILD was explored according to methotrexate use in RA patients, “there was no signal of increased risk across patients using methotrexate,” Dr. Aarrestad Provan reported. When risk of ILD was explored according to b/tsDMARD use in RA patients, a signal of increased risk was observed with rituximab, she noted, “but upon adjusting for age, sex, and comorbidities, this association was no longer significant, but was still numerically increased.”
Iain McInnes, MD, PhD, vice principal, professor of rheumatology, and head of the College of Medical, Veterinary and Life Sciences at the University of Glasgow, remarked that he “loves results that are unexpected” and thanked the researcher for such an “important study.”
“For years, we’ve been interested in the potential for DMARDs to impact interstitial lung disease, with potential that drugs could make it worse, or better,” he said. “This study is wonderful and novel because first of all, there hasn’t, until now, been a direct comparison between RA and PsA in quite this way, and secondly, we haven’t really assessed whether there is a drug-related risk in PsA. Note that drug related does not necessarily imply causality.”
Regarding mechanisms, Dr. McInnes added that “epidemiologic studies suggest that PsA often coexists with the presence of cardiometabolic syndrome and obesity, which has a higher prevalence in PsA than in RA. Obesity is also related to ILD. As such, it begs the question of whether cardiometabolic, diabetes, or obesity-related features may give us a clue as to what is going on in these PsA patients.”
The research was supported by NordForsk and FOREUM. Dr. Aarrestad Provan reported serving as a consultant to Boehringer Ingelheim and Novartis and receiving grant/research support from Boehringer Ingelheim. Dr. McInnes declared no disclosures relevant to this study.
AT EULAR 2023
Minimally invasive vs. open surgery in pancreatic cancer
, suggest results from the international DIPLOMA study.
In the trial, around 260 patients were randomly assigned to undergo either open surgery or minimally invasive laparoscopic or robot-assisted surgery. Rates of complete tumor removal were comparable between the groups.
In addition, the disease-free and overall survival rates at 3 years were nearly identical.
“For pancreatic cancer, we have proven for the first time that minimally invasive distal pancreatectomy is as good as open surgery,” commented principal investigator Mohammad Abu Hilal, MD, PhD, surgical director at the Instituto Ospedaliero Fondazione Poliambulanza in Brescia, Italy.
“Our research provides reassurance for surgeons and can help patients by giving them the information they need to have a conversation with their doctor about how they want to be treated,” he added.
Dr. Hilal was speaking at a press briefing ahead of the annual meeting of the American Society of Clinical Oncology, where the study will be presented (abstract 4163) on June 5.
The study was not able to show that there was a benefit in terms of shorter hospital stays or greater functional recovery with the minimally invasive approach, Dr. Hilal noted, but he suggested that this could be because of differences in postoperative procedures between the participating centers.
He said in an interview that minimally invasive surgery is becoming “very common all over the world,” particularly in the United States, and that randomized controlled trials are “always the last step” in convincing people to use the technique.
He also emphasized that the “best results are obtained in high-volume centers where surgeons do more than at least 50 pancreatic resections a year,” because the minimally invasive approach is “quite complex and difficult,” more so than open surgery.
“This confirmatory study proves that minimally invasive surgical techniques are a safe and effective option for resectable pancreatic cancer,” commented ASCO expert Jennifer F. Tseng, MD, chair of surgery at Boston University and surgeon-in-chief at the Boston Medical Center. It may also “provide benefits like faster recovery time and less infection risk, without increasing cancer risk.”
The results from this trial “will help both surgeons and patients feel comfortable that minimally invasive surgery, in expert hands, is not inferior to open surgery,” she commented in a statement.
Minimally invasive surgery
Only around 12% of patients with pancreatic cancer are diagnosed when the disease is at an early enough stage for surgical resection to be a possibility, Dr. Hilal noted. Minimally invasive pancreatectomy, particularly the distal procedure, was introduced around 25 years ago, but it was initially used only for benign tumors or borderline malignancies.
It took another 10 years before it was considered in cases of confirmed malignancies, “and the main reason for this delay was concerns about the oncological efficiency” of MIDP in terms of its ability to achieve radical resection and an adequate lymph node yield. At the same time, some concerns about minimally invasive surgery for cancer were raised because of results from randomized trials in other cancer types, such as hysterectomy for cervical cancer. Some studies showed worse survival after minimally invasive surgery than after open surgery.
In recent years, use of minimally invasive techniques for pancreatic cancer has become an increasingly “hot topic in many surgical forums,” Dr. Hilal said.
So his team set out to investigate the approach in a phase 3 noninferiority trial. The investigators focused on patients who had an indication for elective distal pancreatectomy plus splenectomy because of proven or highly suspected pancreatic ductal adenocarcinoma in the pancreatic body or tail.
Patients from 35 centers in 12 countries were recruited between May 2018 and May 2021 and were randomly assigned to undergo either MIDP or open distal pancreatectomy.
Patients, nurses, and pathologists were blinded to the surgical procedure by covering of the abdominal wall.
None of the patients underwent adjuvant or neoadjuvant chemotherapy.
Following the procedure, the patients were followed up at 2 weeks and at 1, 3, 6, and 12 months, and a CT scan was performed at 12 months. A range of assessments was performed at each visit, including quality of life measures.
From 1,146 patients initially screened, 261 patients were included.
A few patients withdrew; 131 patients underwent MIDP, and 127 underwent open surgery and were included in the intention-to-treat analysis. Of those, 129 and 125, respectively, were included in the follow-up analysis.
The results confirmed the noninferiority of MIDP, compared with open surgery, with a rate of R0 radical resection (defined as ≥ 1 mm distance between the tumor and the surgical margin) of 73% vs. 69% (P = .039).
In addition, the lymph node yield was comparable between the two approaches, at an average of 22 nodes for MIDP vs. 23 for open surgery (P = .89), and the time to functional recovery was identical, at 5 days for both (P = .22).
The rate of intraperitoneal recurrence was found to be 41% with MIDP, compared with 38% for patients who underwent open surgery.
Dr. Hilal also showed that the rate of serious adverse events, such as bleeding or organ damage, was similar between the two procedures, at 18% with minimally invasive surgery vs. 22% for the open procedure.
Turning to the survival curves, he noted that it is “very clear” that the two procedures achieved near-identical results, at a hazard ratio of 0.99 (P = .94) for overall survival and 0.97 (P = .88) for disease-free survival when comparing MIDP with open surgery.
The researchers will continue to follow up the patients for 3-5 years and will analyze the lymph nodes retrieved to determine whether removal of the spleen is necessary.
The study was funded by Medtronic and Ethicon. Dr. Hilal has relationships with Ethicon and Medtronic. Dr. Tseng has relationships with Aegerion, Amgen, AstraZeneca, Bristol-Myers Squibb, Cubist, Curadel Surgical Innovations, Daiichi Sankyo/Lilly, GlaxoSmithKline, Intarcia Therapeutics, Merck, MyoKardia, PanTher Therapeutics, Pfizer, Quest Diagnostics, Sanofi, Vertex, and Zeus.
A version of this article first appeared on Medscape.com.
, suggest results from the international DIPLOMA study.
In the trial, around 260 patients were randomly assigned to undergo either open surgery or minimally invasive laparoscopic or robot-assisted surgery. Rates of complete tumor removal were comparable between the groups.
In addition, the disease-free and overall survival rates at 3 years were nearly identical.
“For pancreatic cancer, we have proven for the first time that minimally invasive distal pancreatectomy is as good as open surgery,” commented principal investigator Mohammad Abu Hilal, MD, PhD, surgical director at the Instituto Ospedaliero Fondazione Poliambulanza in Brescia, Italy.
“Our research provides reassurance for surgeons and can help patients by giving them the information they need to have a conversation with their doctor about how they want to be treated,” he added.
Dr. Hilal was speaking at a press briefing ahead of the annual meeting of the American Society of Clinical Oncology, where the study will be presented (abstract 4163) on June 5.
The study was not able to show that there was a benefit in terms of shorter hospital stays or greater functional recovery with the minimally invasive approach, Dr. Hilal noted, but he suggested that this could be because of differences in postoperative procedures between the participating centers.
He said in an interview that minimally invasive surgery is becoming “very common all over the world,” particularly in the United States, and that randomized controlled trials are “always the last step” in convincing people to use the technique.
He also emphasized that the “best results are obtained in high-volume centers where surgeons do more than at least 50 pancreatic resections a year,” because the minimally invasive approach is “quite complex and difficult,” more so than open surgery.
“This confirmatory study proves that minimally invasive surgical techniques are a safe and effective option for resectable pancreatic cancer,” commented ASCO expert Jennifer F. Tseng, MD, chair of surgery at Boston University and surgeon-in-chief at the Boston Medical Center. It may also “provide benefits like faster recovery time and less infection risk, without increasing cancer risk.”
The results from this trial “will help both surgeons and patients feel comfortable that minimally invasive surgery, in expert hands, is not inferior to open surgery,” she commented in a statement.
Minimally invasive surgery
Only around 12% of patients with pancreatic cancer are diagnosed when the disease is at an early enough stage for surgical resection to be a possibility, Dr. Hilal noted. Minimally invasive pancreatectomy, particularly the distal procedure, was introduced around 25 years ago, but it was initially used only for benign tumors or borderline malignancies.
It took another 10 years before it was considered in cases of confirmed malignancies, “and the main reason for this delay was concerns about the oncological efficiency” of MIDP in terms of its ability to achieve radical resection and an adequate lymph node yield. At the same time, some concerns about minimally invasive surgery for cancer were raised because of results from randomized trials in other cancer types, such as hysterectomy for cervical cancer. Some studies showed worse survival after minimally invasive surgery than after open surgery.
In recent years, use of minimally invasive techniques for pancreatic cancer has become an increasingly “hot topic in many surgical forums,” Dr. Hilal said.
So his team set out to investigate the approach in a phase 3 noninferiority trial. The investigators focused on patients who had an indication for elective distal pancreatectomy plus splenectomy because of proven or highly suspected pancreatic ductal adenocarcinoma in the pancreatic body or tail.
Patients from 35 centers in 12 countries were recruited between May 2018 and May 2021 and were randomly assigned to undergo either MIDP or open distal pancreatectomy.
Patients, nurses, and pathologists were blinded to the surgical procedure by covering of the abdominal wall.
None of the patients underwent adjuvant or neoadjuvant chemotherapy.
Following the procedure, the patients were followed up at 2 weeks and at 1, 3, 6, and 12 months, and a CT scan was performed at 12 months. A range of assessments was performed at each visit, including quality of life measures.
From 1,146 patients initially screened, 261 patients were included.
A few patients withdrew; 131 patients underwent MIDP, and 127 underwent open surgery and were included in the intention-to-treat analysis. Of those, 129 and 125, respectively, were included in the follow-up analysis.
The results confirmed the noninferiority of MIDP, compared with open surgery, with a rate of R0 radical resection (defined as ≥ 1 mm distance between the tumor and the surgical margin) of 73% vs. 69% (P = .039).
In addition, the lymph node yield was comparable between the two approaches, at an average of 22 nodes for MIDP vs. 23 for open surgery (P = .89), and the time to functional recovery was identical, at 5 days for both (P = .22).
The rate of intraperitoneal recurrence was found to be 41% with MIDP, compared with 38% for patients who underwent open surgery.
Dr. Hilal also showed that the rate of serious adverse events, such as bleeding or organ damage, was similar between the two procedures, at 18% with minimally invasive surgery vs. 22% for the open procedure.
Turning to the survival curves, he noted that it is “very clear” that the two procedures achieved near-identical results, at a hazard ratio of 0.99 (P = .94) for overall survival and 0.97 (P = .88) for disease-free survival when comparing MIDP with open surgery.
The researchers will continue to follow up the patients for 3-5 years and will analyze the lymph nodes retrieved to determine whether removal of the spleen is necessary.
The study was funded by Medtronic and Ethicon. Dr. Hilal has relationships with Ethicon and Medtronic. Dr. Tseng has relationships with Aegerion, Amgen, AstraZeneca, Bristol-Myers Squibb, Cubist, Curadel Surgical Innovations, Daiichi Sankyo/Lilly, GlaxoSmithKline, Intarcia Therapeutics, Merck, MyoKardia, PanTher Therapeutics, Pfizer, Quest Diagnostics, Sanofi, Vertex, and Zeus.
A version of this article first appeared on Medscape.com.
, suggest results from the international DIPLOMA study.
In the trial, around 260 patients were randomly assigned to undergo either open surgery or minimally invasive laparoscopic or robot-assisted surgery. Rates of complete tumor removal were comparable between the groups.
In addition, the disease-free and overall survival rates at 3 years were nearly identical.
“For pancreatic cancer, we have proven for the first time that minimally invasive distal pancreatectomy is as good as open surgery,” commented principal investigator Mohammad Abu Hilal, MD, PhD, surgical director at the Instituto Ospedaliero Fondazione Poliambulanza in Brescia, Italy.
“Our research provides reassurance for surgeons and can help patients by giving them the information they need to have a conversation with their doctor about how they want to be treated,” he added.
Dr. Hilal was speaking at a press briefing ahead of the annual meeting of the American Society of Clinical Oncology, where the study will be presented (abstract 4163) on June 5.
The study was not able to show that there was a benefit in terms of shorter hospital stays or greater functional recovery with the minimally invasive approach, Dr. Hilal noted, but he suggested that this could be because of differences in postoperative procedures between the participating centers.
He said in an interview that minimally invasive surgery is becoming “very common all over the world,” particularly in the United States, and that randomized controlled trials are “always the last step” in convincing people to use the technique.
He also emphasized that the “best results are obtained in high-volume centers where surgeons do more than at least 50 pancreatic resections a year,” because the minimally invasive approach is “quite complex and difficult,” more so than open surgery.
“This confirmatory study proves that minimally invasive surgical techniques are a safe and effective option for resectable pancreatic cancer,” commented ASCO expert Jennifer F. Tseng, MD, chair of surgery at Boston University and surgeon-in-chief at the Boston Medical Center. It may also “provide benefits like faster recovery time and less infection risk, without increasing cancer risk.”
The results from this trial “will help both surgeons and patients feel comfortable that minimally invasive surgery, in expert hands, is not inferior to open surgery,” she commented in a statement.
Minimally invasive surgery
Only around 12% of patients with pancreatic cancer are diagnosed when the disease is at an early enough stage for surgical resection to be a possibility, Dr. Hilal noted. Minimally invasive pancreatectomy, particularly the distal procedure, was introduced around 25 years ago, but it was initially used only for benign tumors or borderline malignancies.
It took another 10 years before it was considered in cases of confirmed malignancies, “and the main reason for this delay was concerns about the oncological efficiency” of MIDP in terms of its ability to achieve radical resection and an adequate lymph node yield. At the same time, some concerns about minimally invasive surgery for cancer were raised because of results from randomized trials in other cancer types, such as hysterectomy for cervical cancer. Some studies showed worse survival after minimally invasive surgery than after open surgery.
In recent years, use of minimally invasive techniques for pancreatic cancer has become an increasingly “hot topic in many surgical forums,” Dr. Hilal said.
So his team set out to investigate the approach in a phase 3 noninferiority trial. The investigators focused on patients who had an indication for elective distal pancreatectomy plus splenectomy because of proven or highly suspected pancreatic ductal adenocarcinoma in the pancreatic body or tail.
Patients from 35 centers in 12 countries were recruited between May 2018 and May 2021 and were randomly assigned to undergo either MIDP or open distal pancreatectomy.
Patients, nurses, and pathologists were blinded to the surgical procedure by covering of the abdominal wall.
None of the patients underwent adjuvant or neoadjuvant chemotherapy.
Following the procedure, the patients were followed up at 2 weeks and at 1, 3, 6, and 12 months, and a CT scan was performed at 12 months. A range of assessments was performed at each visit, including quality of life measures.
From 1,146 patients initially screened, 261 patients were included.
A few patients withdrew; 131 patients underwent MIDP, and 127 underwent open surgery and were included in the intention-to-treat analysis. Of those, 129 and 125, respectively, were included in the follow-up analysis.
The results confirmed the noninferiority of MIDP, compared with open surgery, with a rate of R0 radical resection (defined as ≥ 1 mm distance between the tumor and the surgical margin) of 73% vs. 69% (P = .039).
In addition, the lymph node yield was comparable between the two approaches, at an average of 22 nodes for MIDP vs. 23 for open surgery (P = .89), and the time to functional recovery was identical, at 5 days for both (P = .22).
The rate of intraperitoneal recurrence was found to be 41% with MIDP, compared with 38% for patients who underwent open surgery.
Dr. Hilal also showed that the rate of serious adverse events, such as bleeding or organ damage, was similar between the two procedures, at 18% with minimally invasive surgery vs. 22% for the open procedure.
Turning to the survival curves, he noted that it is “very clear” that the two procedures achieved near-identical results, at a hazard ratio of 0.99 (P = .94) for overall survival and 0.97 (P = .88) for disease-free survival when comparing MIDP with open surgery.
The researchers will continue to follow up the patients for 3-5 years and will analyze the lymph nodes retrieved to determine whether removal of the spleen is necessary.
The study was funded by Medtronic and Ethicon. Dr. Hilal has relationships with Ethicon and Medtronic. Dr. Tseng has relationships with Aegerion, Amgen, AstraZeneca, Bristol-Myers Squibb, Cubist, Curadel Surgical Innovations, Daiichi Sankyo/Lilly, GlaxoSmithKline, Intarcia Therapeutics, Merck, MyoKardia, PanTher Therapeutics, Pfizer, Quest Diagnostics, Sanofi, Vertex, and Zeus.
A version of this article first appeared on Medscape.com.
FROM ASCO 2023
Warning on use of sotorasib after ICI in lung cancer
because of the risk of increased toxicity.
Sotorasib is indicated for adults with locally advanced or metastatic NSCLC who carry a KRASG12C mutation, which occurs in about 13% of cases.
Since its approval in 2021, sotorasib has emerged as “a new standard of care” for such patients after chemotherapy and anti–PD-L1 failure, the investigators say.
The new warning comes after the team compared 48 patients who received an anti–PD-L1 – most often pembrolizumab alone or in combination with platinum-based chemotherapy – before sotorasib with a control group of 54 patients who either didn’t receive an anti–PD-L1 before sotorasib or had at least one other treatment in between.
The team found that sequential anti–PD-L1 and sotorasib therapy significantly increased the risk of severe sotorasib-related hepatotoxicity and also the risk of non-liver adverse events, typically in patients who received sotorasib within 30 days of an anti–PD-L1.
“We suggest avoiding starting sotorasib within 30 days from the last anti–PD-(L)1 infusion,” say senior author Michaël Duruisseaux, MD, PhD, Louis Pradel Hospital, Bron, France, and collegues.
The findings should also “prompt a close monitoring for the development of hepatotoxicity and non-liver AEs [in] patients who receive sotorasib after anti–PD-(L)1,” they add.
The study was published in the Journal of Thoracic Oncology.
Actionable findings
“I consider the results to be highly credible and informative to my own practice,” said Jack West, MD, a thoracic medical oncologist at the City of Hope outside of Los Angeles, said in an interview.
The findings “may lead me to favor a trial of docetaxel as an intervening therapy for patients who have very recently discontinued immunotherapy, deferring sotorasib at least a few weeks and ideally several months,” Dr. West commented. “I think this is a particularly reasonable approach when we remember that sotorasib conferred no improvement in overall survival at all over docetaxel in the CodeBreaK 200 trial in KRASG12C-mutated NSCLC.”
Overall, the study “corroborates what we’ve seen in the limited first-line experience of sotorasib combined with immunotherapy and also echoes our experience of other targeted therapies, such as osimertinib administered in the weeks just after patients received immunotherapy, which is known to be associated with life-threatening pneumonitis,” he said.
Jared Weiss, MD, a thoracic medical oncologist at the University of North Carolina, Chapel Hill, said that given the long half-life of immune checkpoint inhibitors, “it is quite understandable that the toxicity challenges we previously saw with concurrent administration of immunotherapy and certain targeted therapies would be recapitulated in patients who had a relatively short interval between prior checkpoint inhibitor therapy and sotorasib.”
Even so, because of the aggressiveness of NSCLC, long treatment delays between immunotherapy and sotorasib therapy are “not a favored option.”
Like Dr. West, Dr. Weiss said docetaxel (with or without ramucirumab) is a sound intervening alternative.
Another option is to use adagrasib in the second line instead of sotorasib, Dr. Weiss suggested. It’s also a KRASG12C inhibitor but hasn’t so far been associated with severe hepatotoxicity, he said.
Hossein Borghaei, DO, a thoracic medical oncologist at Fox Chase Cancer Center, Philadelphia, agrees with his colleagues and thinks that what the French team found “is real.”
As the investigators suggest, “it might be that sotorasib leads to an inflammatory microenvironment that causes hepatotoxicity in the presence of a checkpoint inhibitor. In that case,” a lower dose of sotorasib might help reduce toxicity while remaining effective, Dr. Broghaei suggested.
Study details
The French team was prompted to investigate the issue by a report of life-threatening hepatitis in a patient with NSCLC for whom sotorasib therapy was initiated 14 weeks after treatment with pembrolizumab, as well as by “the long story of adverse events ... observed with sequential use of [immune checkpoint inhibitors] and targeted therapy.”
Like Dr. Weiss, they note that severe hepatotoxicity after anti–PD-L1 therapy has not, to date, been reported for other KRASG12C inhibitors.
Patients in the study were treated outside of clinical trials at 16 medical centers in France.
Half of the patients (24/48) who were treated immediately with an anti–PD-L1 after sotorasib therapy developed grade 3 or higher sotorasib-related adverse events, including 16 (33%) with severe sotorasib-related hepatotoxicity. Severe diarrhea and fatigue were also more frequent with sequential therapy.
Severe events typically occurred within 30 days of the last anti–PD-L1 infusion and to a lesser extent within 31-60 days.
In the control arm, the rate of severe sotorasib-related adverse events was 13% (7/54). Six patients (11%) experienced severe hepatotoxicity. There was one sotorasib-related death in the sequential therapy arm, which was due to toxic epidermal necrosis. No deaths occurred in the control group.
The two groups were balanced with respect to history of daily alcohol consumption and the presence of liver metastasis. More patients in the control arm had a history of hepatobiliary disease.
The study received no outside funding. Many of the authors report ties with pharmaceutical companies, including to Amgen, the maker of sotorasib, and Mirati Therapeutics, the maker of adagrasib. Dr. Weiss was an adagrasib investigator for Mirati. Dr. West is a regular contribiutor to Medscape and is an adviser for Amgen and Mirati as well as a speaker for Amgen. Dr. Borghaei reported extensive company ties. He has received research support, travel funding, and consulting fees from Amgen as well as consulting fees from Mirati.
A version of this article first appeared on Medscape.com.
because of the risk of increased toxicity.
Sotorasib is indicated for adults with locally advanced or metastatic NSCLC who carry a KRASG12C mutation, which occurs in about 13% of cases.
Since its approval in 2021, sotorasib has emerged as “a new standard of care” for such patients after chemotherapy and anti–PD-L1 failure, the investigators say.
The new warning comes after the team compared 48 patients who received an anti–PD-L1 – most often pembrolizumab alone or in combination with platinum-based chemotherapy – before sotorasib with a control group of 54 patients who either didn’t receive an anti–PD-L1 before sotorasib or had at least one other treatment in between.
The team found that sequential anti–PD-L1 and sotorasib therapy significantly increased the risk of severe sotorasib-related hepatotoxicity and also the risk of non-liver adverse events, typically in patients who received sotorasib within 30 days of an anti–PD-L1.
“We suggest avoiding starting sotorasib within 30 days from the last anti–PD-(L)1 infusion,” say senior author Michaël Duruisseaux, MD, PhD, Louis Pradel Hospital, Bron, France, and collegues.
The findings should also “prompt a close monitoring for the development of hepatotoxicity and non-liver AEs [in] patients who receive sotorasib after anti–PD-(L)1,” they add.
The study was published in the Journal of Thoracic Oncology.
Actionable findings
“I consider the results to be highly credible and informative to my own practice,” said Jack West, MD, a thoracic medical oncologist at the City of Hope outside of Los Angeles, said in an interview.
The findings “may lead me to favor a trial of docetaxel as an intervening therapy for patients who have very recently discontinued immunotherapy, deferring sotorasib at least a few weeks and ideally several months,” Dr. West commented. “I think this is a particularly reasonable approach when we remember that sotorasib conferred no improvement in overall survival at all over docetaxel in the CodeBreaK 200 trial in KRASG12C-mutated NSCLC.”
Overall, the study “corroborates what we’ve seen in the limited first-line experience of sotorasib combined with immunotherapy and also echoes our experience of other targeted therapies, such as osimertinib administered in the weeks just after patients received immunotherapy, which is known to be associated with life-threatening pneumonitis,” he said.
Jared Weiss, MD, a thoracic medical oncologist at the University of North Carolina, Chapel Hill, said that given the long half-life of immune checkpoint inhibitors, “it is quite understandable that the toxicity challenges we previously saw with concurrent administration of immunotherapy and certain targeted therapies would be recapitulated in patients who had a relatively short interval between prior checkpoint inhibitor therapy and sotorasib.”
Even so, because of the aggressiveness of NSCLC, long treatment delays between immunotherapy and sotorasib therapy are “not a favored option.”
Like Dr. West, Dr. Weiss said docetaxel (with or without ramucirumab) is a sound intervening alternative.
Another option is to use adagrasib in the second line instead of sotorasib, Dr. Weiss suggested. It’s also a KRASG12C inhibitor but hasn’t so far been associated with severe hepatotoxicity, he said.
Hossein Borghaei, DO, a thoracic medical oncologist at Fox Chase Cancer Center, Philadelphia, agrees with his colleagues and thinks that what the French team found “is real.”
As the investigators suggest, “it might be that sotorasib leads to an inflammatory microenvironment that causes hepatotoxicity in the presence of a checkpoint inhibitor. In that case,” a lower dose of sotorasib might help reduce toxicity while remaining effective, Dr. Broghaei suggested.
Study details
The French team was prompted to investigate the issue by a report of life-threatening hepatitis in a patient with NSCLC for whom sotorasib therapy was initiated 14 weeks after treatment with pembrolizumab, as well as by “the long story of adverse events ... observed with sequential use of [immune checkpoint inhibitors] and targeted therapy.”
Like Dr. Weiss, they note that severe hepatotoxicity after anti–PD-L1 therapy has not, to date, been reported for other KRASG12C inhibitors.
Patients in the study were treated outside of clinical trials at 16 medical centers in France.
Half of the patients (24/48) who were treated immediately with an anti–PD-L1 after sotorasib therapy developed grade 3 or higher sotorasib-related adverse events, including 16 (33%) with severe sotorasib-related hepatotoxicity. Severe diarrhea and fatigue were also more frequent with sequential therapy.
Severe events typically occurred within 30 days of the last anti–PD-L1 infusion and to a lesser extent within 31-60 days.
In the control arm, the rate of severe sotorasib-related adverse events was 13% (7/54). Six patients (11%) experienced severe hepatotoxicity. There was one sotorasib-related death in the sequential therapy arm, which was due to toxic epidermal necrosis. No deaths occurred in the control group.
The two groups were balanced with respect to history of daily alcohol consumption and the presence of liver metastasis. More patients in the control arm had a history of hepatobiliary disease.
The study received no outside funding. Many of the authors report ties with pharmaceutical companies, including to Amgen, the maker of sotorasib, and Mirati Therapeutics, the maker of adagrasib. Dr. Weiss was an adagrasib investigator for Mirati. Dr. West is a regular contribiutor to Medscape and is an adviser for Amgen and Mirati as well as a speaker for Amgen. Dr. Borghaei reported extensive company ties. He has received research support, travel funding, and consulting fees from Amgen as well as consulting fees from Mirati.
A version of this article first appeared on Medscape.com.
because of the risk of increased toxicity.
Sotorasib is indicated for adults with locally advanced or metastatic NSCLC who carry a KRASG12C mutation, which occurs in about 13% of cases.
Since its approval in 2021, sotorasib has emerged as “a new standard of care” for such patients after chemotherapy and anti–PD-L1 failure, the investigators say.
The new warning comes after the team compared 48 patients who received an anti–PD-L1 – most often pembrolizumab alone or in combination with platinum-based chemotherapy – before sotorasib with a control group of 54 patients who either didn’t receive an anti–PD-L1 before sotorasib or had at least one other treatment in between.
The team found that sequential anti–PD-L1 and sotorasib therapy significantly increased the risk of severe sotorasib-related hepatotoxicity and also the risk of non-liver adverse events, typically in patients who received sotorasib within 30 days of an anti–PD-L1.
“We suggest avoiding starting sotorasib within 30 days from the last anti–PD-(L)1 infusion,” say senior author Michaël Duruisseaux, MD, PhD, Louis Pradel Hospital, Bron, France, and collegues.
The findings should also “prompt a close monitoring for the development of hepatotoxicity and non-liver AEs [in] patients who receive sotorasib after anti–PD-(L)1,” they add.
The study was published in the Journal of Thoracic Oncology.
Actionable findings
“I consider the results to be highly credible and informative to my own practice,” said Jack West, MD, a thoracic medical oncologist at the City of Hope outside of Los Angeles, said in an interview.
The findings “may lead me to favor a trial of docetaxel as an intervening therapy for patients who have very recently discontinued immunotherapy, deferring sotorasib at least a few weeks and ideally several months,” Dr. West commented. “I think this is a particularly reasonable approach when we remember that sotorasib conferred no improvement in overall survival at all over docetaxel in the CodeBreaK 200 trial in KRASG12C-mutated NSCLC.”
Overall, the study “corroborates what we’ve seen in the limited first-line experience of sotorasib combined with immunotherapy and also echoes our experience of other targeted therapies, such as osimertinib administered in the weeks just after patients received immunotherapy, which is known to be associated with life-threatening pneumonitis,” he said.
Jared Weiss, MD, a thoracic medical oncologist at the University of North Carolina, Chapel Hill, said that given the long half-life of immune checkpoint inhibitors, “it is quite understandable that the toxicity challenges we previously saw with concurrent administration of immunotherapy and certain targeted therapies would be recapitulated in patients who had a relatively short interval between prior checkpoint inhibitor therapy and sotorasib.”
Even so, because of the aggressiveness of NSCLC, long treatment delays between immunotherapy and sotorasib therapy are “not a favored option.”
Like Dr. West, Dr. Weiss said docetaxel (with or without ramucirumab) is a sound intervening alternative.
Another option is to use adagrasib in the second line instead of sotorasib, Dr. Weiss suggested. It’s also a KRASG12C inhibitor but hasn’t so far been associated with severe hepatotoxicity, he said.
Hossein Borghaei, DO, a thoracic medical oncologist at Fox Chase Cancer Center, Philadelphia, agrees with his colleagues and thinks that what the French team found “is real.”
As the investigators suggest, “it might be that sotorasib leads to an inflammatory microenvironment that causes hepatotoxicity in the presence of a checkpoint inhibitor. In that case,” a lower dose of sotorasib might help reduce toxicity while remaining effective, Dr. Broghaei suggested.
Study details
The French team was prompted to investigate the issue by a report of life-threatening hepatitis in a patient with NSCLC for whom sotorasib therapy was initiated 14 weeks after treatment with pembrolizumab, as well as by “the long story of adverse events ... observed with sequential use of [immune checkpoint inhibitors] and targeted therapy.”
Like Dr. Weiss, they note that severe hepatotoxicity after anti–PD-L1 therapy has not, to date, been reported for other KRASG12C inhibitors.
Patients in the study were treated outside of clinical trials at 16 medical centers in France.
Half of the patients (24/48) who were treated immediately with an anti–PD-L1 after sotorasib therapy developed grade 3 or higher sotorasib-related adverse events, including 16 (33%) with severe sotorasib-related hepatotoxicity. Severe diarrhea and fatigue were also more frequent with sequential therapy.
Severe events typically occurred within 30 days of the last anti–PD-L1 infusion and to a lesser extent within 31-60 days.
In the control arm, the rate of severe sotorasib-related adverse events was 13% (7/54). Six patients (11%) experienced severe hepatotoxicity. There was one sotorasib-related death in the sequential therapy arm, which was due to toxic epidermal necrosis. No deaths occurred in the control group.
The two groups were balanced with respect to history of daily alcohol consumption and the presence of liver metastasis. More patients in the control arm had a history of hepatobiliary disease.
The study received no outside funding. Many of the authors report ties with pharmaceutical companies, including to Amgen, the maker of sotorasib, and Mirati Therapeutics, the maker of adagrasib. Dr. Weiss was an adagrasib investigator for Mirati. Dr. West is a regular contribiutor to Medscape and is an adviser for Amgen and Mirati as well as a speaker for Amgen. Dr. Borghaei reported extensive company ties. He has received research support, travel funding, and consulting fees from Amgen as well as consulting fees from Mirati.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF THORACIC ONCOLOGY
Posluma approved for PET imaging in prostate cancer
The product is approved for use in men with suspected metastasis who are candidates for definitive therapy and for men with suspected recurrence, as evidenced by elevations in serum prostate-specific antigen (PSA) level, according to a press release from marketer Blue Earth Diagnostics.
Posluma binds prostate-specific membrane antigen (PSMA), which is usually overexpressed on prostate cancer cells, and tags the cells with fluorine-18 (F18), a positron emitter. Because of the radiolabeling, PET imaging can be used to gauge the extent of disease.
Posluma will be available in the United States in June 2023 from Blue Earth’s U.S. manufacturer and distributor, PETNET Solutions.
Blue Earth says that its new agent, which was known as 18F-rhPSMA-7.3 PET during trials, “is the first and only FDA-approved, PSMA-targeted imaging agent developed with proprietary radiohybrid technology.”
However, a similar product is currently on the U.S. market – the PSMA PET imaging radiopharmaceutical gallium-68 gozetotide (Illuccix, Locometz), which has the same two indications. Gozetotide is also indicated for metastatic prostate cancer amenable to lutetium Lu 177 vipivotide tetraxetan PSMA-directed therapy.
Approval based on two single-arm trials
Posluma’s approval was based on two single-arm trials from Blue Earth.
In the LIGHTHOUSE trial, 296 men underwent Posluma PET imaging before radical prostatectomy with pelvic lymph node dissection. About a quarter turned out to have positive nodes on pathology.
Posluma’s sensitivity for predicting positive nodes was low, ranging from 23% to 30% among three readers who were blinded to clinical information, but its specificity was high, ranging from 93% to 97%, according to the product labeling.
“The study showed that Posluma PET provided clinically valuable information prior to surgery that would likely result in management changes for these patients,” said investigator Brian Chapin, MD, a urologist at the University of Texas MD Anderson Cancer Center, Houston, in the company press release.
The second trial, SPOTLIGHT, included 389 men suspected of experiencing recurrence on the basis of elevations in PSA.
Posluma PET’s ability to detect true recurrence was compared with use of histology or other imaging techniques, including CT, MRI, technetium-99m bone scan, and fluciclovine F18 PET. In regions deemed positive for recurrence on Posluma PET by three readers, 46%-60% were positive by the other techniques, the labeling says.
Overall, the “results demonstrated high detection rates ... even at low PSA levels,” Blue Earth said.
Adverse events were minimal in the trials. The most frequent were diarrhea (0.7%), increases in blood pressure (0.5%), and injection-site pain (0.4%).
The product labeling warns that Posluma PET contributes to patients’ overall long-term cumulative radiation exposure and that interpretation with respect to recurrence may differ among readers.
The labeling also cautions that “a negative image does not rule out the presence of prostate cancer and a positive image does not confirm the presence of prostate cancer. ... Uptake is not specific for prostate cancer and may occur in other types of cancer, in nonmalignant processes, and in normal tissues.”
In addition, it notes that androgen deprivation therapy “and other therapies targeting the androgen pathway, such as androgen receptor antagonists, may result in changes in uptake of flotufolastat F18 in prostate cancer.”
The labeling for gozetotide carries the same warnings and precautions.
A version of this article first appeared on Medscape.com.
The product is approved for use in men with suspected metastasis who are candidates for definitive therapy and for men with suspected recurrence, as evidenced by elevations in serum prostate-specific antigen (PSA) level, according to a press release from marketer Blue Earth Diagnostics.
Posluma binds prostate-specific membrane antigen (PSMA), which is usually overexpressed on prostate cancer cells, and tags the cells with fluorine-18 (F18), a positron emitter. Because of the radiolabeling, PET imaging can be used to gauge the extent of disease.
Posluma will be available in the United States in June 2023 from Blue Earth’s U.S. manufacturer and distributor, PETNET Solutions.
Blue Earth says that its new agent, which was known as 18F-rhPSMA-7.3 PET during trials, “is the first and only FDA-approved, PSMA-targeted imaging agent developed with proprietary radiohybrid technology.”
However, a similar product is currently on the U.S. market – the PSMA PET imaging radiopharmaceutical gallium-68 gozetotide (Illuccix, Locometz), which has the same two indications. Gozetotide is also indicated for metastatic prostate cancer amenable to lutetium Lu 177 vipivotide tetraxetan PSMA-directed therapy.
Approval based on two single-arm trials
Posluma’s approval was based on two single-arm trials from Blue Earth.
In the LIGHTHOUSE trial, 296 men underwent Posluma PET imaging before radical prostatectomy with pelvic lymph node dissection. About a quarter turned out to have positive nodes on pathology.
Posluma’s sensitivity for predicting positive nodes was low, ranging from 23% to 30% among three readers who were blinded to clinical information, but its specificity was high, ranging from 93% to 97%, according to the product labeling.
“The study showed that Posluma PET provided clinically valuable information prior to surgery that would likely result in management changes for these patients,” said investigator Brian Chapin, MD, a urologist at the University of Texas MD Anderson Cancer Center, Houston, in the company press release.
The second trial, SPOTLIGHT, included 389 men suspected of experiencing recurrence on the basis of elevations in PSA.
Posluma PET’s ability to detect true recurrence was compared with use of histology or other imaging techniques, including CT, MRI, technetium-99m bone scan, and fluciclovine F18 PET. In regions deemed positive for recurrence on Posluma PET by three readers, 46%-60% were positive by the other techniques, the labeling says.
Overall, the “results demonstrated high detection rates ... even at low PSA levels,” Blue Earth said.
Adverse events were minimal in the trials. The most frequent were diarrhea (0.7%), increases in blood pressure (0.5%), and injection-site pain (0.4%).
The product labeling warns that Posluma PET contributes to patients’ overall long-term cumulative radiation exposure and that interpretation with respect to recurrence may differ among readers.
The labeling also cautions that “a negative image does not rule out the presence of prostate cancer and a positive image does not confirm the presence of prostate cancer. ... Uptake is not specific for prostate cancer and may occur in other types of cancer, in nonmalignant processes, and in normal tissues.”
In addition, it notes that androgen deprivation therapy “and other therapies targeting the androgen pathway, such as androgen receptor antagonists, may result in changes in uptake of flotufolastat F18 in prostate cancer.”
The labeling for gozetotide carries the same warnings and precautions.
A version of this article first appeared on Medscape.com.
The product is approved for use in men with suspected metastasis who are candidates for definitive therapy and for men with suspected recurrence, as evidenced by elevations in serum prostate-specific antigen (PSA) level, according to a press release from marketer Blue Earth Diagnostics.
Posluma binds prostate-specific membrane antigen (PSMA), which is usually overexpressed on prostate cancer cells, and tags the cells with fluorine-18 (F18), a positron emitter. Because of the radiolabeling, PET imaging can be used to gauge the extent of disease.
Posluma will be available in the United States in June 2023 from Blue Earth’s U.S. manufacturer and distributor, PETNET Solutions.
Blue Earth says that its new agent, which was known as 18F-rhPSMA-7.3 PET during trials, “is the first and only FDA-approved, PSMA-targeted imaging agent developed with proprietary radiohybrid technology.”
However, a similar product is currently on the U.S. market – the PSMA PET imaging radiopharmaceutical gallium-68 gozetotide (Illuccix, Locometz), which has the same two indications. Gozetotide is also indicated for metastatic prostate cancer amenable to lutetium Lu 177 vipivotide tetraxetan PSMA-directed therapy.
Approval based on two single-arm trials
Posluma’s approval was based on two single-arm trials from Blue Earth.
In the LIGHTHOUSE trial, 296 men underwent Posluma PET imaging before radical prostatectomy with pelvic lymph node dissection. About a quarter turned out to have positive nodes on pathology.
Posluma’s sensitivity for predicting positive nodes was low, ranging from 23% to 30% among three readers who were blinded to clinical information, but its specificity was high, ranging from 93% to 97%, according to the product labeling.
“The study showed that Posluma PET provided clinically valuable information prior to surgery that would likely result in management changes for these patients,” said investigator Brian Chapin, MD, a urologist at the University of Texas MD Anderson Cancer Center, Houston, in the company press release.
The second trial, SPOTLIGHT, included 389 men suspected of experiencing recurrence on the basis of elevations in PSA.
Posluma PET’s ability to detect true recurrence was compared with use of histology or other imaging techniques, including CT, MRI, technetium-99m bone scan, and fluciclovine F18 PET. In regions deemed positive for recurrence on Posluma PET by three readers, 46%-60% were positive by the other techniques, the labeling says.
Overall, the “results demonstrated high detection rates ... even at low PSA levels,” Blue Earth said.
Adverse events were minimal in the trials. The most frequent were diarrhea (0.7%), increases in blood pressure (0.5%), and injection-site pain (0.4%).
The product labeling warns that Posluma PET contributes to patients’ overall long-term cumulative radiation exposure and that interpretation with respect to recurrence may differ among readers.
The labeling also cautions that “a negative image does not rule out the presence of prostate cancer and a positive image does not confirm the presence of prostate cancer. ... Uptake is not specific for prostate cancer and may occur in other types of cancer, in nonmalignant processes, and in normal tissues.”
In addition, it notes that androgen deprivation therapy “and other therapies targeting the androgen pathway, such as androgen receptor antagonists, may result in changes in uptake of flotufolastat F18 in prostate cancer.”
The labeling for gozetotide carries the same warnings and precautions.
A version of this article first appeared on Medscape.com.