Most checkpoint inhibitor–induced rheumatic complications in cancer patients can be treated successfully with corticosteroids, albeit often at considerably higher doses than rheumatologists typically use in managing rheumatoid arthritis, Eric M. Ruderman, MD, observed at the 2021 Rheumatology Winter Clinical Symposium.
Dr. Eric M. Ruderman
“In RA, we’re all used to the idea that 5 or 10 mg of corticosteroids per day can make a tremendous difference. That’s not always the case here. Patients who develop rheumatic immunotherapy-related adverse events often require 20-30 mg/day to get symptoms under control,” according to Dr. Ruderman, professor of medicine (rheumatology) at Northwestern University, Chicago.
This may be in part because oncologists typically don’t refer affected patients to rheumatologists early on. Guidelines from the National Comprehensive Cancer Network and other oncology groups suggest referral only once a patient develops grade 3 immunotherapy-related rheumatic adverse events, meaning the symptoms significantly impair daily activities, he explained.
Checkpoint inhibitors, which induce T-cell activation to fight the patient’s malignancy, can produce a plethora of off-target effects. These adverse events may involve the skin, heart, lungs, kidneys, eyes, blood, GI tract, and endocrine organs. The drugs also can cause rheumatic or neurologic complications. The most common of these adverse events are colitis and rash. Next most common are arthritis and arthralgia. Rheumatic side effects are most common as a consequence of immunotherapy using a CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, but can also occur in association with programmed cell death protein 1 (PD-1) inhibitors and PD-ligand 1 inhibitors. Arthritis and other rheumatic adverse events are more common in patients undergoing combination therapy.
Some form of frank inflammatory arthritis occurs in 5%-10% of cancer patients undergoing checkpoint inhibitor therapy. This can manifest as an RA-like polyarthritis, spondyloarthritis, polymyalgia rheumatica, necrotizing myositis, or vasculitis. Arthralgia occurs in up to 40% of treated patients.
This immunotherapy-related arthritis is typically more inflammatory than RA. It also has a much more abrupt onset. It is usually seronegative and has no gender predisposition, and the limited available evidence to date suggests there is no increased risk of this complication in checkpoint inhibitor–treated patients with a history of prior rheumatic disease, according to Dr. Ruderman.
Delayed onset and resolution of rheumatologic immune-related adverse events
“Onset and resolution of rheumatologic adverse events with immunotherapy may be delayed. This is an important point: While skin rash and colitis often show up pretty early in the course of immunotherapy, some of the arthritic events can happen later. They can actually continue after the immunotherapy is stopped,” the rheumatologist said.
Indeed, a retrospective nationwide Canadian study of 117 patients at nine academic centers who developed 136 rheumatic immune-related adverse events in conjunction with cancer immunotherapy found that the mean time to the first such event was 6.8 months into checkpoint inhibitor therapy. The most common rheumatic complication was symmetric polyarthritis, affecting 45 patients. Other rheumatologic immune-related complications included polymyalgia rheumatica in 17 patients, noninflammatory musculoskeletal symptoms in 18, and myositis in 9.
Seventy-six patients were treated with prednisone for a mean of 8.4 months at a maximum dose of 60 mg/day. Forty-two moved up the treatment ladder to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to manage their symptoms. Only two patients required escalation to biologic therapy. A reassuring finding in this relatively small study was that treatment of the patients’ rheumatic complications didn’t appear to worsen the tumor response to immunotherapy: Twenty-three patients experienced tumor progression prior to treatment of their rheumatic disorder, and 14 did so following treatment.
Flares of preexisting rheumatic diseases
These tend to occur much earlier in the course of immune checkpoint inhibitor therapy for cancer than de novo immunotherapy-related rheumatic adverse events. In a retrospective Australian study of 12 cancer patients with preexisting rheumatic disease before going on a PD-1 inhibitor and 24 others with no such history, all of whom developed rheumatic adverse events while on the checkpoint inhibitor, the mean time to a flare of preexisting rheumatic disease was 6.2 weeks, compared to 21.5 weeks in patients who experienced a de novo rheumatic adverse event.
Dr. Ruderman supports recommendations from the European Alliance of Associations for Rheumatology (EULAR) for the management of rheumatic immune-related adverse events due to cancer immunotherapy, even though the underlying level of evidence is fairly weak. The recommendations call for the use of csDMARDs when corticosteroids don’t adequately control symptoms. And when the response to csDMARDs is insufficient, the next step is a biologic, preferably a tumor necrosis factor inhibitor or interleukin-6 inhibitor.
“At our institution, the oncologists are a little bit nervous about using biologics in cancer patients, but I think more and more they’re going to have to accept it. And so far there isn’t a ton of evidence that suggests the addition of biologics interferes with the efficacy of the immunotherapy,” the rheumatologist said.
He underscored the critical importance of one of the overarching principles of the EULAR guidelines: the need for interdisciplinary coordination between rheumatologists and oncologists regarding the problem of rheumatologic immune-related adverse events.
“Oncologists aren’t good at managing inflammatory arthritis. I think they really need us,” he said.
Dr. Ruderman reported serving as a consultant to and/or receiving a research grant from nine pharmaceutical companies.
Most checkpoint inhibitor–induced rheumatic complications in cancer patients can be treated successfully with corticosteroids, albeit often at considerably higher doses than rheumatologists typically use in managing rheumatoid arthritis, Eric M. Ruderman, MD, observed at the 2021 Rheumatology Winter Clinical Symposium.
Dr. Eric M. Ruderman
“In RA, we’re all used to the idea that 5 or 10 mg of corticosteroids per day can make a tremendous difference. That’s not always the case here. Patients who develop rheumatic immunotherapy-related adverse events often require 20-30 mg/day to get symptoms under control,” according to Dr. Ruderman, professor of medicine (rheumatology) at Northwestern University, Chicago.
This may be in part because oncologists typically don’t refer affected patients to rheumatologists early on. Guidelines from the National Comprehensive Cancer Network and other oncology groups suggest referral only once a patient develops grade 3 immunotherapy-related rheumatic adverse events, meaning the symptoms significantly impair daily activities, he explained.
Checkpoint inhibitors, which induce T-cell activation to fight the patient’s malignancy, can produce a plethora of off-target effects. These adverse events may involve the skin, heart, lungs, kidneys, eyes, blood, GI tract, and endocrine organs. The drugs also can cause rheumatic or neurologic complications. The most common of these adverse events are colitis and rash. Next most common are arthritis and arthralgia. Rheumatic side effects are most common as a consequence of immunotherapy using a CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, but can also occur in association with programmed cell death protein 1 (PD-1) inhibitors and PD-ligand 1 inhibitors. Arthritis and other rheumatic adverse events are more common in patients undergoing combination therapy.
Some form of frank inflammatory arthritis occurs in 5%-10% of cancer patients undergoing checkpoint inhibitor therapy. This can manifest as an RA-like polyarthritis, spondyloarthritis, polymyalgia rheumatica, necrotizing myositis, or vasculitis. Arthralgia occurs in up to 40% of treated patients.
This immunotherapy-related arthritis is typically more inflammatory than RA. It also has a much more abrupt onset. It is usually seronegative and has no gender predisposition, and the limited available evidence to date suggests there is no increased risk of this complication in checkpoint inhibitor–treated patients with a history of prior rheumatic disease, according to Dr. Ruderman.
Delayed onset and resolution of rheumatologic immune-related adverse events
“Onset and resolution of rheumatologic adverse events with immunotherapy may be delayed. This is an important point: While skin rash and colitis often show up pretty early in the course of immunotherapy, some of the arthritic events can happen later. They can actually continue after the immunotherapy is stopped,” the rheumatologist said.
Indeed, a retrospective nationwide Canadian study of 117 patients at nine academic centers who developed 136 rheumatic immune-related adverse events in conjunction with cancer immunotherapy found that the mean time to the first such event was 6.8 months into checkpoint inhibitor therapy. The most common rheumatic complication was symmetric polyarthritis, affecting 45 patients. Other rheumatologic immune-related complications included polymyalgia rheumatica in 17 patients, noninflammatory musculoskeletal symptoms in 18, and myositis in 9.
Seventy-six patients were treated with prednisone for a mean of 8.4 months at a maximum dose of 60 mg/day. Forty-two moved up the treatment ladder to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to manage their symptoms. Only two patients required escalation to biologic therapy. A reassuring finding in this relatively small study was that treatment of the patients’ rheumatic complications didn’t appear to worsen the tumor response to immunotherapy: Twenty-three patients experienced tumor progression prior to treatment of their rheumatic disorder, and 14 did so following treatment.
Flares of preexisting rheumatic diseases
These tend to occur much earlier in the course of immune checkpoint inhibitor therapy for cancer than de novo immunotherapy-related rheumatic adverse events. In a retrospective Australian study of 12 cancer patients with preexisting rheumatic disease before going on a PD-1 inhibitor and 24 others with no such history, all of whom developed rheumatic adverse events while on the checkpoint inhibitor, the mean time to a flare of preexisting rheumatic disease was 6.2 weeks, compared to 21.5 weeks in patients who experienced a de novo rheumatic adverse event.
Dr. Ruderman supports recommendations from the European Alliance of Associations for Rheumatology (EULAR) for the management of rheumatic immune-related adverse events due to cancer immunotherapy, even though the underlying level of evidence is fairly weak. The recommendations call for the use of csDMARDs when corticosteroids don’t adequately control symptoms. And when the response to csDMARDs is insufficient, the next step is a biologic, preferably a tumor necrosis factor inhibitor or interleukin-6 inhibitor.
“At our institution, the oncologists are a little bit nervous about using biologics in cancer patients, but I think more and more they’re going to have to accept it. And so far there isn’t a ton of evidence that suggests the addition of biologics interferes with the efficacy of the immunotherapy,” the rheumatologist said.
He underscored the critical importance of one of the overarching principles of the EULAR guidelines: the need for interdisciplinary coordination between rheumatologists and oncologists regarding the problem of rheumatologic immune-related adverse events.
“Oncologists aren’t good at managing inflammatory arthritis. I think they really need us,” he said.
Dr. Ruderman reported serving as a consultant to and/or receiving a research grant from nine pharmaceutical companies.
Most checkpoint inhibitor–induced rheumatic complications in cancer patients can be treated successfully with corticosteroids, albeit often at considerably higher doses than rheumatologists typically use in managing rheumatoid arthritis, Eric M. Ruderman, MD, observed at the 2021 Rheumatology Winter Clinical Symposium.
Dr. Eric M. Ruderman
“In RA, we’re all used to the idea that 5 or 10 mg of corticosteroids per day can make a tremendous difference. That’s not always the case here. Patients who develop rheumatic immunotherapy-related adverse events often require 20-30 mg/day to get symptoms under control,” according to Dr. Ruderman, professor of medicine (rheumatology) at Northwestern University, Chicago.
This may be in part because oncologists typically don’t refer affected patients to rheumatologists early on. Guidelines from the National Comprehensive Cancer Network and other oncology groups suggest referral only once a patient develops grade 3 immunotherapy-related rheumatic adverse events, meaning the symptoms significantly impair daily activities, he explained.
Checkpoint inhibitors, which induce T-cell activation to fight the patient’s malignancy, can produce a plethora of off-target effects. These adverse events may involve the skin, heart, lungs, kidneys, eyes, blood, GI tract, and endocrine organs. The drugs also can cause rheumatic or neurologic complications. The most common of these adverse events are colitis and rash. Next most common are arthritis and arthralgia. Rheumatic side effects are most common as a consequence of immunotherapy using a CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, but can also occur in association with programmed cell death protein 1 (PD-1) inhibitors and PD-ligand 1 inhibitors. Arthritis and other rheumatic adverse events are more common in patients undergoing combination therapy.
Some form of frank inflammatory arthritis occurs in 5%-10% of cancer patients undergoing checkpoint inhibitor therapy. This can manifest as an RA-like polyarthritis, spondyloarthritis, polymyalgia rheumatica, necrotizing myositis, or vasculitis. Arthralgia occurs in up to 40% of treated patients.
This immunotherapy-related arthritis is typically more inflammatory than RA. It also has a much more abrupt onset. It is usually seronegative and has no gender predisposition, and the limited available evidence to date suggests there is no increased risk of this complication in checkpoint inhibitor–treated patients with a history of prior rheumatic disease, according to Dr. Ruderman.
Delayed onset and resolution of rheumatologic immune-related adverse events
“Onset and resolution of rheumatologic adverse events with immunotherapy may be delayed. This is an important point: While skin rash and colitis often show up pretty early in the course of immunotherapy, some of the arthritic events can happen later. They can actually continue after the immunotherapy is stopped,” the rheumatologist said.
Indeed, a retrospective nationwide Canadian study of 117 patients at nine academic centers who developed 136 rheumatic immune-related adverse events in conjunction with cancer immunotherapy found that the mean time to the first such event was 6.8 months into checkpoint inhibitor therapy. The most common rheumatic complication was symmetric polyarthritis, affecting 45 patients. Other rheumatologic immune-related complications included polymyalgia rheumatica in 17 patients, noninflammatory musculoskeletal symptoms in 18, and myositis in 9.
Seventy-six patients were treated with prednisone for a mean of 8.4 months at a maximum dose of 60 mg/day. Forty-two moved up the treatment ladder to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to manage their symptoms. Only two patients required escalation to biologic therapy. A reassuring finding in this relatively small study was that treatment of the patients’ rheumatic complications didn’t appear to worsen the tumor response to immunotherapy: Twenty-three patients experienced tumor progression prior to treatment of their rheumatic disorder, and 14 did so following treatment.
Flares of preexisting rheumatic diseases
These tend to occur much earlier in the course of immune checkpoint inhibitor therapy for cancer than de novo immunotherapy-related rheumatic adverse events. In a retrospective Australian study of 12 cancer patients with preexisting rheumatic disease before going on a PD-1 inhibitor and 24 others with no such history, all of whom developed rheumatic adverse events while on the checkpoint inhibitor, the mean time to a flare of preexisting rheumatic disease was 6.2 weeks, compared to 21.5 weeks in patients who experienced a de novo rheumatic adverse event.
Dr. Ruderman supports recommendations from the European Alliance of Associations for Rheumatology (EULAR) for the management of rheumatic immune-related adverse events due to cancer immunotherapy, even though the underlying level of evidence is fairly weak. The recommendations call for the use of csDMARDs when corticosteroids don’t adequately control symptoms. And when the response to csDMARDs is insufficient, the next step is a biologic, preferably a tumor necrosis factor inhibitor or interleukin-6 inhibitor.
“At our institution, the oncologists are a little bit nervous about using biologics in cancer patients, but I think more and more they’re going to have to accept it. And so far there isn’t a ton of evidence that suggests the addition of biologics interferes with the efficacy of the immunotherapy,” the rheumatologist said.
He underscored the critical importance of one of the overarching principles of the EULAR guidelines: the need for interdisciplinary coordination between rheumatologists and oncologists regarding the problem of rheumatologic immune-related adverse events.
“Oncologists aren’t good at managing inflammatory arthritis. I think they really need us,” he said.
Dr. Ruderman reported serving as a consultant to and/or receiving a research grant from nine pharmaceutical companies.
People with systemic lupus erythematosus (SLE) experienced significantly higher rates of first severe infections, a higher number of severe infections overall, and greater infection-related mortality, compared with controls, based on data from a population-based cohort study of more than 30,000 individuals.
Infections remain a leading cause of morbidity and early mortality in patients with SLE, wrote Kai Zhao, MSc, of Arthritis Research Canada, Richmond, and colleagues. However, “limitations from existing studies including selected samples, small sizes, and prevalent cohorts can negatively affect the accuracy of both the absolute and relative risk estimates of infections in SLE at the population level,” they said.
In a study published in Rheumatology, the researchers identified 5,169 people newly diagnosed with SLE between Jan. 1, 1997, and March 31, 2015, and matched them with 25,845 non-SLE controls using an administrative health database of all health care services funded in British Columbia during the time period. The investigators said the study is the first “to evaluate the risk of severe infections in a large population-based and incident SLE cohort.”
The average age of the patients was 46.9 at the time of their index SLE diagnosis, and 86% were women. The average follow-up period was approximately 10 years.
The primary outcome was the first severe infection after the onset of SLE that required hospitalization or occurred in the hospital setting. A total of 955 (18.5%) first severe infections occurred in the SLE group, compared with 1,988 (7.7%) in the controls, for incidence rates of 19.7 events per 1,000 person-years and 7.6 events per 1,000 person-years, respectively, yielding an 82% increased risk of severe infection for SLE patients after adjustment for confounding baseline factors.
Secondary outcomes of the total number of severe infections and infection-related mortality both showed significant increases in SLE patients, compared with controls. The total number of severe infections in the SLE and control groups was 1,898 and 3,114, respectively, with an adjusted risk ratio of 2.07.
As for mortality, a total of 539 deaths occurred in SLE patients during the study period, and 114 (21%) were related to severe infection. A total of 1,495 deaths occurred in the control group, including 269 (18%) related to severe infection. The adjusted hazard ratio was 1.61 after adjustment for confounding baseline variables.
The risks for first severe infection, total number of severe infections, and infection-related mortality were “independent of traditional risk factors for infection and the results remain robust in the presence of an unmeasured confounder (smoking) and competing risk of death,” the researchers said. Reasons for the increased risk are uncertain, but likely result from intrinsic factors such as immune system dysfunction and extrinsic factors such as the impact of immunosuppressive medications. “Future research can focus on quantifying the relative contributions of these intrinsic and extrinsic factors on the increased infection risk in SLE patients,” they added.
The study findings were limited by several factors linked to the observational design, including possible misdiagnosis of SLE and inaccurate measure of SLE onset, the researchers noted. In addition, no data were available for certain confounders such as smoking and nonhospitalized infections, they said.
However, the results were strengthened by the large size and general population and the use of sensitivity analyses, they noted. For SLE patients, “increased awareness of the risk of infections can identify their early signs and potentially prevent hospitalizations,” and clinicians can promote infection prevention strategies, including vaccinations when appropriate, they added.
Based on their findings, “we recommend a closer surveillance for severe infections in SLE patients and risk assessment for severe infections for SLE patients after diagnosis,” the researchers emphasized. “Further studies are warranted to further identify risk factors for infections in SLE patients to develop personalized treatment regimens and to select treatment in practice by synthesizing patient information,” they concluded.
The study was supported by the Canadian Institutes for Health Research. The researchers had no financial conflicts to disclose.
People with systemic lupus erythematosus (SLE) experienced significantly higher rates of first severe infections, a higher number of severe infections overall, and greater infection-related mortality, compared with controls, based on data from a population-based cohort study of more than 30,000 individuals.
Infections remain a leading cause of morbidity and early mortality in patients with SLE, wrote Kai Zhao, MSc, of Arthritis Research Canada, Richmond, and colleagues. However, “limitations from existing studies including selected samples, small sizes, and prevalent cohorts can negatively affect the accuracy of both the absolute and relative risk estimates of infections in SLE at the population level,” they said.
In a study published in Rheumatology, the researchers identified 5,169 people newly diagnosed with SLE between Jan. 1, 1997, and March 31, 2015, and matched them with 25,845 non-SLE controls using an administrative health database of all health care services funded in British Columbia during the time period. The investigators said the study is the first “to evaluate the risk of severe infections in a large population-based and incident SLE cohort.”
The average age of the patients was 46.9 at the time of their index SLE diagnosis, and 86% were women. The average follow-up period was approximately 10 years.
The primary outcome was the first severe infection after the onset of SLE that required hospitalization or occurred in the hospital setting. A total of 955 (18.5%) first severe infections occurred in the SLE group, compared with 1,988 (7.7%) in the controls, for incidence rates of 19.7 events per 1,000 person-years and 7.6 events per 1,000 person-years, respectively, yielding an 82% increased risk of severe infection for SLE patients after adjustment for confounding baseline factors.
Secondary outcomes of the total number of severe infections and infection-related mortality both showed significant increases in SLE patients, compared with controls. The total number of severe infections in the SLE and control groups was 1,898 and 3,114, respectively, with an adjusted risk ratio of 2.07.
As for mortality, a total of 539 deaths occurred in SLE patients during the study period, and 114 (21%) were related to severe infection. A total of 1,495 deaths occurred in the control group, including 269 (18%) related to severe infection. The adjusted hazard ratio was 1.61 after adjustment for confounding baseline variables.
The risks for first severe infection, total number of severe infections, and infection-related mortality were “independent of traditional risk factors for infection and the results remain robust in the presence of an unmeasured confounder (smoking) and competing risk of death,” the researchers said. Reasons for the increased risk are uncertain, but likely result from intrinsic factors such as immune system dysfunction and extrinsic factors such as the impact of immunosuppressive medications. “Future research can focus on quantifying the relative contributions of these intrinsic and extrinsic factors on the increased infection risk in SLE patients,” they added.
The study findings were limited by several factors linked to the observational design, including possible misdiagnosis of SLE and inaccurate measure of SLE onset, the researchers noted. In addition, no data were available for certain confounders such as smoking and nonhospitalized infections, they said.
However, the results were strengthened by the large size and general population and the use of sensitivity analyses, they noted. For SLE patients, “increased awareness of the risk of infections can identify their early signs and potentially prevent hospitalizations,” and clinicians can promote infection prevention strategies, including vaccinations when appropriate, they added.
Based on their findings, “we recommend a closer surveillance for severe infections in SLE patients and risk assessment for severe infections for SLE patients after diagnosis,” the researchers emphasized. “Further studies are warranted to further identify risk factors for infections in SLE patients to develop personalized treatment regimens and to select treatment in practice by synthesizing patient information,” they concluded.
The study was supported by the Canadian Institutes for Health Research. The researchers had no financial conflicts to disclose.
People with systemic lupus erythematosus (SLE) experienced significantly higher rates of first severe infections, a higher number of severe infections overall, and greater infection-related mortality, compared with controls, based on data from a population-based cohort study of more than 30,000 individuals.
Infections remain a leading cause of morbidity and early mortality in patients with SLE, wrote Kai Zhao, MSc, of Arthritis Research Canada, Richmond, and colleagues. However, “limitations from existing studies including selected samples, small sizes, and prevalent cohorts can negatively affect the accuracy of both the absolute and relative risk estimates of infections in SLE at the population level,” they said.
In a study published in Rheumatology, the researchers identified 5,169 people newly diagnosed with SLE between Jan. 1, 1997, and March 31, 2015, and matched them with 25,845 non-SLE controls using an administrative health database of all health care services funded in British Columbia during the time period. The investigators said the study is the first “to evaluate the risk of severe infections in a large population-based and incident SLE cohort.”
The average age of the patients was 46.9 at the time of their index SLE diagnosis, and 86% were women. The average follow-up period was approximately 10 years.
The primary outcome was the first severe infection after the onset of SLE that required hospitalization or occurred in the hospital setting. A total of 955 (18.5%) first severe infections occurred in the SLE group, compared with 1,988 (7.7%) in the controls, for incidence rates of 19.7 events per 1,000 person-years and 7.6 events per 1,000 person-years, respectively, yielding an 82% increased risk of severe infection for SLE patients after adjustment for confounding baseline factors.
Secondary outcomes of the total number of severe infections and infection-related mortality both showed significant increases in SLE patients, compared with controls. The total number of severe infections in the SLE and control groups was 1,898 and 3,114, respectively, with an adjusted risk ratio of 2.07.
As for mortality, a total of 539 deaths occurred in SLE patients during the study period, and 114 (21%) were related to severe infection. A total of 1,495 deaths occurred in the control group, including 269 (18%) related to severe infection. The adjusted hazard ratio was 1.61 after adjustment for confounding baseline variables.
The risks for first severe infection, total number of severe infections, and infection-related mortality were “independent of traditional risk factors for infection and the results remain robust in the presence of an unmeasured confounder (smoking) and competing risk of death,” the researchers said. Reasons for the increased risk are uncertain, but likely result from intrinsic factors such as immune system dysfunction and extrinsic factors such as the impact of immunosuppressive medications. “Future research can focus on quantifying the relative contributions of these intrinsic and extrinsic factors on the increased infection risk in SLE patients,” they added.
The study findings were limited by several factors linked to the observational design, including possible misdiagnosis of SLE and inaccurate measure of SLE onset, the researchers noted. In addition, no data were available for certain confounders such as smoking and nonhospitalized infections, they said.
However, the results were strengthened by the large size and general population and the use of sensitivity analyses, they noted. For SLE patients, “increased awareness of the risk of infections can identify their early signs and potentially prevent hospitalizations,” and clinicians can promote infection prevention strategies, including vaccinations when appropriate, they added.
Based on their findings, “we recommend a closer surveillance for severe infections in SLE patients and risk assessment for severe infections for SLE patients after diagnosis,” the researchers emphasized. “Further studies are warranted to further identify risk factors for infections in SLE patients to develop personalized treatment regimens and to select treatment in practice by synthesizing patient information,” they concluded.
The study was supported by the Canadian Institutes for Health Research. The researchers had no financial conflicts to disclose.
Hydroxychloroquine can be used safely and effectively with attention to dosing, risk factors, and screening, but communication among physicians, patients, and eye care specialists is key to optimizing outcomes and preventing complications, according to a joint statement from four medical societies.
Dr. James T. Rosenbaum
The American College of Rheumatology, American Academy of Dermatology, Rheumatologic Dermatology Society, and the American Academy of Ophthalmology have produced a statement, published in Arthritis & Rheumatology, “to emphasize points of agreement that should be recognized by practitioners in all specialties,” lead author James T. Rosenbaum, MD, of Oregon Health & Science University, Portland, and colleagues wrote.
The statement was developed by a working group that included rheumatologists, ophthalmologists, and dermatologists with records of published studies on the use of hydroxychloroquine (HCQ) and its toxicity. The statement updated elements of the 2016 American Academy of Ophthalmology guidelines for monitoring patients for retinal toxicity when using HCQ.
“The need for collaborative management has triggered this joint statement, which applies only to managing the risk of HCQ retinopathy and does not include consideration of cardiac, muscle, dermatologic, or other toxicities,” the authors noted.
The authors emphasized that HCQ plays a valuable role in controlling many rheumatic diseases, and should not be abandoned out of fear of retinopathy. However, proper dosing, recognition of risk factors, and screening strategies are essential.
Dosing data
Data on HCQ dosing and retinopathy are limited, but the authors cited a study of 2,361 rheumatic disease patients with an average HCQ dosing regimen of 5.0 mg/kg per day or less in which the toxicity risk was less than 2% for up to 10 years of use. Although data show some increase in risk with duration of use, “for a patient with a normal screening exam in a given year, the risk of developing retinopathy in the ensuing year is low (e.g., less than 5%), even after 20 years of use,” the authors said.
Risk factor recognition
“High daily [HCQ] dosage relative to body weight and cumulative dose are the primary risk factors for retinopathy,” the authors noted. Reduced renal function is an additional risk factor, and patients with renal insufficiency should be monitored and may need lower doses.
In addition, patients with a phenotype of initial parafoveal toxicity may be at increased risk for advanced disease evidenced by damage to the foveal center. “The phenotype of initial parafoveal toxicity is not universal, and in many patients (East Asians particularly) the retinal changes may appear initially along the pericentral vascular arcades,” so these patients should be screened with additional tests beyond the central macula, they emphasized.
Screening strategies
Patients should receive a baseline retinal exam within a few months of starting HCQ to rule out underlying retinal disease, according to the statement. The goal of screening is “to detect early retinopathy before a bullseye becomes visible on ophthalmoscopy, since at that severe stage the damage tends to progress even after discontinuing the medication and may eventually threaten central vision,” the authors said.
Marc Bruxelle/Getty Images
In the absence of risk factors, patients can defer screening for 5 years, but should be screened annually from 5 years and forward, they said. Examples of underlying retinal disease include “significant macular degeneration, severe diabetic retinopathy, or hereditary disorders of retinal function, but these are judgments best made by the ophthalmologist since mild and stable abnormalities that do not interfere with interpretation of critical diagnostic tests may not be a contraindication” to use of HCQ.
The consensus opinion statement has limitations, notably the shortage of data on optimum HCQ dosage and the lack of prospective studies of toxicity, including the need for studies of the impact of blood levels on toxicity and studies of pharmacogenomics to stratify risk, the authors noted.
“It is important that the drug is not stopped prematurely, but also that it is not continued in the face of definitive evidence of retinal toxicity except in some situations with unusual medical need,” they said.
“Suggestive or uncertain findings should be discussed with the patient and prescribing physician to justify further examinations, but the drug need not be stopped until evidence for retinopathy is definitive, in particular for patients with active rheumatic or cutaneous disease,” and the overall risk of retinopathy remains low if the principles described in the statement are followed, they concluded.
First author Dr. Rosenbaum disclosed financial relationships with AbbVie, UCB, Gilead, Novartis, Horizon, Roche, Eyevensys, Santen, Corvus, Affibody, Kyverna, Pfizer, Horizon, and UpToDate. Another 5 of the study’s 11 authors also disclosed relationships with multiple companies.
Hydroxychloroquine can be used safely and effectively with attention to dosing, risk factors, and screening, but communication among physicians, patients, and eye care specialists is key to optimizing outcomes and preventing complications, according to a joint statement from four medical societies.
Dr. James T. Rosenbaum
The American College of Rheumatology, American Academy of Dermatology, Rheumatologic Dermatology Society, and the American Academy of Ophthalmology have produced a statement, published in Arthritis & Rheumatology, “to emphasize points of agreement that should be recognized by practitioners in all specialties,” lead author James T. Rosenbaum, MD, of Oregon Health & Science University, Portland, and colleagues wrote.
The statement was developed by a working group that included rheumatologists, ophthalmologists, and dermatologists with records of published studies on the use of hydroxychloroquine (HCQ) and its toxicity. The statement updated elements of the 2016 American Academy of Ophthalmology guidelines for monitoring patients for retinal toxicity when using HCQ.
“The need for collaborative management has triggered this joint statement, which applies only to managing the risk of HCQ retinopathy and does not include consideration of cardiac, muscle, dermatologic, or other toxicities,” the authors noted.
The authors emphasized that HCQ plays a valuable role in controlling many rheumatic diseases, and should not be abandoned out of fear of retinopathy. However, proper dosing, recognition of risk factors, and screening strategies are essential.
Dosing data
Data on HCQ dosing and retinopathy are limited, but the authors cited a study of 2,361 rheumatic disease patients with an average HCQ dosing regimen of 5.0 mg/kg per day or less in which the toxicity risk was less than 2% for up to 10 years of use. Although data show some increase in risk with duration of use, “for a patient with a normal screening exam in a given year, the risk of developing retinopathy in the ensuing year is low (e.g., less than 5%), even after 20 years of use,” the authors said.
Risk factor recognition
“High daily [HCQ] dosage relative to body weight and cumulative dose are the primary risk factors for retinopathy,” the authors noted. Reduced renal function is an additional risk factor, and patients with renal insufficiency should be monitored and may need lower doses.
In addition, patients with a phenotype of initial parafoveal toxicity may be at increased risk for advanced disease evidenced by damage to the foveal center. “The phenotype of initial parafoveal toxicity is not universal, and in many patients (East Asians particularly) the retinal changes may appear initially along the pericentral vascular arcades,” so these patients should be screened with additional tests beyond the central macula, they emphasized.
Screening strategies
Patients should receive a baseline retinal exam within a few months of starting HCQ to rule out underlying retinal disease, according to the statement. The goal of screening is “to detect early retinopathy before a bullseye becomes visible on ophthalmoscopy, since at that severe stage the damage tends to progress even after discontinuing the medication and may eventually threaten central vision,” the authors said.
Marc Bruxelle/Getty Images
In the absence of risk factors, patients can defer screening for 5 years, but should be screened annually from 5 years and forward, they said. Examples of underlying retinal disease include “significant macular degeneration, severe diabetic retinopathy, or hereditary disorders of retinal function, but these are judgments best made by the ophthalmologist since mild and stable abnormalities that do not interfere with interpretation of critical diagnostic tests may not be a contraindication” to use of HCQ.
The consensus opinion statement has limitations, notably the shortage of data on optimum HCQ dosage and the lack of prospective studies of toxicity, including the need for studies of the impact of blood levels on toxicity and studies of pharmacogenomics to stratify risk, the authors noted.
“It is important that the drug is not stopped prematurely, but also that it is not continued in the face of definitive evidence of retinal toxicity except in some situations with unusual medical need,” they said.
“Suggestive or uncertain findings should be discussed with the patient and prescribing physician to justify further examinations, but the drug need not be stopped until evidence for retinopathy is definitive, in particular for patients with active rheumatic or cutaneous disease,” and the overall risk of retinopathy remains low if the principles described in the statement are followed, they concluded.
First author Dr. Rosenbaum disclosed financial relationships with AbbVie, UCB, Gilead, Novartis, Horizon, Roche, Eyevensys, Santen, Corvus, Affibody, Kyverna, Pfizer, Horizon, and UpToDate. Another 5 of the study’s 11 authors also disclosed relationships with multiple companies.
Hydroxychloroquine can be used safely and effectively with attention to dosing, risk factors, and screening, but communication among physicians, patients, and eye care specialists is key to optimizing outcomes and preventing complications, according to a joint statement from four medical societies.
Dr. James T. Rosenbaum
The American College of Rheumatology, American Academy of Dermatology, Rheumatologic Dermatology Society, and the American Academy of Ophthalmology have produced a statement, published in Arthritis & Rheumatology, “to emphasize points of agreement that should be recognized by practitioners in all specialties,” lead author James T. Rosenbaum, MD, of Oregon Health & Science University, Portland, and colleagues wrote.
The statement was developed by a working group that included rheumatologists, ophthalmologists, and dermatologists with records of published studies on the use of hydroxychloroquine (HCQ) and its toxicity. The statement updated elements of the 2016 American Academy of Ophthalmology guidelines for monitoring patients for retinal toxicity when using HCQ.
“The need for collaborative management has triggered this joint statement, which applies only to managing the risk of HCQ retinopathy and does not include consideration of cardiac, muscle, dermatologic, or other toxicities,” the authors noted.
The authors emphasized that HCQ plays a valuable role in controlling many rheumatic diseases, and should not be abandoned out of fear of retinopathy. However, proper dosing, recognition of risk factors, and screening strategies are essential.
Dosing data
Data on HCQ dosing and retinopathy are limited, but the authors cited a study of 2,361 rheumatic disease patients with an average HCQ dosing regimen of 5.0 mg/kg per day or less in which the toxicity risk was less than 2% for up to 10 years of use. Although data show some increase in risk with duration of use, “for a patient with a normal screening exam in a given year, the risk of developing retinopathy in the ensuing year is low (e.g., less than 5%), even after 20 years of use,” the authors said.
Risk factor recognition
“High daily [HCQ] dosage relative to body weight and cumulative dose are the primary risk factors for retinopathy,” the authors noted. Reduced renal function is an additional risk factor, and patients with renal insufficiency should be monitored and may need lower doses.
In addition, patients with a phenotype of initial parafoveal toxicity may be at increased risk for advanced disease evidenced by damage to the foveal center. “The phenotype of initial parafoveal toxicity is not universal, and in many patients (East Asians particularly) the retinal changes may appear initially along the pericentral vascular arcades,” so these patients should be screened with additional tests beyond the central macula, they emphasized.
Screening strategies
Patients should receive a baseline retinal exam within a few months of starting HCQ to rule out underlying retinal disease, according to the statement. The goal of screening is “to detect early retinopathy before a bullseye becomes visible on ophthalmoscopy, since at that severe stage the damage tends to progress even after discontinuing the medication and may eventually threaten central vision,” the authors said.
Marc Bruxelle/Getty Images
In the absence of risk factors, patients can defer screening for 5 years, but should be screened annually from 5 years and forward, they said. Examples of underlying retinal disease include “significant macular degeneration, severe diabetic retinopathy, or hereditary disorders of retinal function, but these are judgments best made by the ophthalmologist since mild and stable abnormalities that do not interfere with interpretation of critical diagnostic tests may not be a contraindication” to use of HCQ.
The consensus opinion statement has limitations, notably the shortage of data on optimum HCQ dosage and the lack of prospective studies of toxicity, including the need for studies of the impact of blood levels on toxicity and studies of pharmacogenomics to stratify risk, the authors noted.
“It is important that the drug is not stopped prematurely, but also that it is not continued in the face of definitive evidence of retinal toxicity except in some situations with unusual medical need,” they said.
“Suggestive or uncertain findings should be discussed with the patient and prescribing physician to justify further examinations, but the drug need not be stopped until evidence for retinopathy is definitive, in particular for patients with active rheumatic or cutaneous disease,” and the overall risk of retinopathy remains low if the principles described in the statement are followed, they concluded.
First author Dr. Rosenbaum disclosed financial relationships with AbbVie, UCB, Gilead, Novartis, Horizon, Roche, Eyevensys, Santen, Corvus, Affibody, Kyverna, Pfizer, Horizon, and UpToDate. Another 5 of the study’s 11 authors also disclosed relationships with multiple companies.
Home-based subcutaneous immune globulin therapy is a promising alternative to intravenous immune globulin therapy for patients with refractory dermatomyositis or polymyositis, Anna Postolova, MD, MPH, declared at the 2021 Rheumatology Winter Clinical Symposium.
Dr. Anna Postolova
“This is really exciting. I think in the years to come we may see a change to having our patients be able to do immune globulin therapy at home,” said Dr. Postolova, a rheumatologist and allergist/immunologist at Stanford (Calif.) Health Care.
“The technology is there. I think our patients might feel more comfortable getting immune globulin at home,” she said. “I would love to switch more patients from IVIg to SCIg [subcutaneous immune globulin] in my practice.”
A few caveats: SCIg remains off label for treatment of dermatomyositis (DM) or polymyositis (PM). Its approved indication is as replacement therapy in patients with primary or secondary immunodeficiency diseases. IVIg is approved for this indication, but is also approved for DM/PM refractory to high-dose corticosteroids and immunosuppressants. Yet SCIg is clearly effective for these autoimmune inflammatory diseases, albeit to date the supporting evidence comes chiefly from observational studies and anecdotal experience.
“I don’t know if insurers will cover it, but they should because it’s obviously a lot cheaper to do it at home,” she noted.
SCIg advantages
SCIg offers compelling advantages over IVIg in addition to its substantially lower cost. These include far fewer systemic side effects, shorter infusion time, greater bioavailability, and better quality of life. Patients self-administer SCIg at home, avoiding the inconvenience of IVIg therapy, which entails travel time for once-monthly hospitalization or long hours spent in an infusion center, she explained.
French investigators recently documented a previously unappreciated further advantage of home-based SCIg. They convened a focus group of patients with DM or PM experienced with both IVIg and home SCIg and determined that participants uniformly preferred home SCIg. The patients cited a new and welcome feeling of autonomy and control.
“All patients with experience of IVIg and SCIg expressed a clear preference for SCIg, which was described to be easy, less disruptive for daily life, well tolerated, and less time-consuming. Preference was mainly related to a restoration of autonomy. Home-based self-administration reinforced the feeling of independence,” according to the investigators.
Available products
Six preparations of SCIg are commercially available. Most are in 10% concentration, as are all IVIg products. However, a 20% formulation of SCIg known as Hizentra allows for a smaller infusion volume and quicker completion of a treatment session. And one SCIg product, HyQvia, uses recombinant human hyaluronidase-facilitated 10% immune globulin, allowing home infusion of large volumes of sustained-release immune globulin on a once-monthly basis.
The relatively recent introduction of home SCIg for treatment of autoimmune inflammatory diseases, including DM, PM, and chronic inflammatory demyelinating polyneuropathy, has been pioneered mainly by European investigators. The treatment is often given by programmable mechanical pump once weekly. Italian investigators have reported efficacy in DM using 0.2 g/kg per week, which is about half the monthly total dose of IVIg employed. The infusion rate is 10-40 mL/hour, with a volume of around 35 mL per injection site.
Alternatively, SCIg can be delivered by rapid push infusions of smaller volumes with a syringe two or three times per week; that’s the regimen that was used at 2 g/kg over the course of a month by patients in the French focus group study, who didn’t mind the more frequent dosing.
“As they have had severe long-lasting symptoms, SCIg was perceived as a curative rather than a preventive therapy,” according to the French investigators.
More than 40% of patients experience adverse reactions to IVIg. These often involve headaches, nausea, back or abdominal pain, arthralgias, and/or difficulty breathing. Thromboembolic events and acute renal failure occur occasionally. For this reason, many physicians give a prophylactic dose of corticosteroids an hour before a patient’s first dose of IVIg. These systemic side effects are so rare with SCIg that Dr. Postolova has never pretreated with steroids, even though the main reason she resorts to the home therapy is a patient’s track record of poor tolerance of IVIg. The lower abdomen and thigh are the most commonly used subcutaneous infusion sites. Mild local infusion site reactions are fairly common.
Formulating IVIg and SCIg is a complex process that entails plasma procurement and pooling, fractionation, and purification. It takes 10,000-60,000 plasma donations to make one lot of IVIg. Donations are accepted only from repeated donors. Samples are held for 6 months and tested for infectious agents. However, efforts are underway to develop bioengineered recombinant immune globulin products that don’t require donated plasma. These products are being designed to capture and enhance the most important mechanisms of benefit of plasma-derived immunoglobulins using Fc fragments that target key receptors, rather than relying on full-length immune globulin. The goal is enhanced efficacy at much lower doses than with IVIg or SCIg.
Dr. Postolova reported having no financial conflicts regarding her presentation.
Home-based subcutaneous immune globulin therapy is a promising alternative to intravenous immune globulin therapy for patients with refractory dermatomyositis or polymyositis, Anna Postolova, MD, MPH, declared at the 2021 Rheumatology Winter Clinical Symposium.
Dr. Anna Postolova
“This is really exciting. I think in the years to come we may see a change to having our patients be able to do immune globulin therapy at home,” said Dr. Postolova, a rheumatologist and allergist/immunologist at Stanford (Calif.) Health Care.
“The technology is there. I think our patients might feel more comfortable getting immune globulin at home,” she said. “I would love to switch more patients from IVIg to SCIg [subcutaneous immune globulin] in my practice.”
A few caveats: SCIg remains off label for treatment of dermatomyositis (DM) or polymyositis (PM). Its approved indication is as replacement therapy in patients with primary or secondary immunodeficiency diseases. IVIg is approved for this indication, but is also approved for DM/PM refractory to high-dose corticosteroids and immunosuppressants. Yet SCIg is clearly effective for these autoimmune inflammatory diseases, albeit to date the supporting evidence comes chiefly from observational studies and anecdotal experience.
“I don’t know if insurers will cover it, but they should because it’s obviously a lot cheaper to do it at home,” she noted.
SCIg advantages
SCIg offers compelling advantages over IVIg in addition to its substantially lower cost. These include far fewer systemic side effects, shorter infusion time, greater bioavailability, and better quality of life. Patients self-administer SCIg at home, avoiding the inconvenience of IVIg therapy, which entails travel time for once-monthly hospitalization or long hours spent in an infusion center, she explained.
French investigators recently documented a previously unappreciated further advantage of home-based SCIg. They convened a focus group of patients with DM or PM experienced with both IVIg and home SCIg and determined that participants uniformly preferred home SCIg. The patients cited a new and welcome feeling of autonomy and control.
“All patients with experience of IVIg and SCIg expressed a clear preference for SCIg, which was described to be easy, less disruptive for daily life, well tolerated, and less time-consuming. Preference was mainly related to a restoration of autonomy. Home-based self-administration reinforced the feeling of independence,” according to the investigators.
Available products
Six preparations of SCIg are commercially available. Most are in 10% concentration, as are all IVIg products. However, a 20% formulation of SCIg known as Hizentra allows for a smaller infusion volume and quicker completion of a treatment session. And one SCIg product, HyQvia, uses recombinant human hyaluronidase-facilitated 10% immune globulin, allowing home infusion of large volumes of sustained-release immune globulin on a once-monthly basis.
The relatively recent introduction of home SCIg for treatment of autoimmune inflammatory diseases, including DM, PM, and chronic inflammatory demyelinating polyneuropathy, has been pioneered mainly by European investigators. The treatment is often given by programmable mechanical pump once weekly. Italian investigators have reported efficacy in DM using 0.2 g/kg per week, which is about half the monthly total dose of IVIg employed. The infusion rate is 10-40 mL/hour, with a volume of around 35 mL per injection site.
Alternatively, SCIg can be delivered by rapid push infusions of smaller volumes with a syringe two or three times per week; that’s the regimen that was used at 2 g/kg over the course of a month by patients in the French focus group study, who didn’t mind the more frequent dosing.
“As they have had severe long-lasting symptoms, SCIg was perceived as a curative rather than a preventive therapy,” according to the French investigators.
More than 40% of patients experience adverse reactions to IVIg. These often involve headaches, nausea, back or abdominal pain, arthralgias, and/or difficulty breathing. Thromboembolic events and acute renal failure occur occasionally. For this reason, many physicians give a prophylactic dose of corticosteroids an hour before a patient’s first dose of IVIg. These systemic side effects are so rare with SCIg that Dr. Postolova has never pretreated with steroids, even though the main reason she resorts to the home therapy is a patient’s track record of poor tolerance of IVIg. The lower abdomen and thigh are the most commonly used subcutaneous infusion sites. Mild local infusion site reactions are fairly common.
Formulating IVIg and SCIg is a complex process that entails plasma procurement and pooling, fractionation, and purification. It takes 10,000-60,000 plasma donations to make one lot of IVIg. Donations are accepted only from repeated donors. Samples are held for 6 months and tested for infectious agents. However, efforts are underway to develop bioengineered recombinant immune globulin products that don’t require donated plasma. These products are being designed to capture and enhance the most important mechanisms of benefit of plasma-derived immunoglobulins using Fc fragments that target key receptors, rather than relying on full-length immune globulin. The goal is enhanced efficacy at much lower doses than with IVIg or SCIg.
Dr. Postolova reported having no financial conflicts regarding her presentation.
Home-based subcutaneous immune globulin therapy is a promising alternative to intravenous immune globulin therapy for patients with refractory dermatomyositis or polymyositis, Anna Postolova, MD, MPH, declared at the 2021 Rheumatology Winter Clinical Symposium.
Dr. Anna Postolova
“This is really exciting. I think in the years to come we may see a change to having our patients be able to do immune globulin therapy at home,” said Dr. Postolova, a rheumatologist and allergist/immunologist at Stanford (Calif.) Health Care.
“The technology is there. I think our patients might feel more comfortable getting immune globulin at home,” she said. “I would love to switch more patients from IVIg to SCIg [subcutaneous immune globulin] in my practice.”
A few caveats: SCIg remains off label for treatment of dermatomyositis (DM) or polymyositis (PM). Its approved indication is as replacement therapy in patients with primary or secondary immunodeficiency diseases. IVIg is approved for this indication, but is also approved for DM/PM refractory to high-dose corticosteroids and immunosuppressants. Yet SCIg is clearly effective for these autoimmune inflammatory diseases, albeit to date the supporting evidence comes chiefly from observational studies and anecdotal experience.
“I don’t know if insurers will cover it, but they should because it’s obviously a lot cheaper to do it at home,” she noted.
SCIg advantages
SCIg offers compelling advantages over IVIg in addition to its substantially lower cost. These include far fewer systemic side effects, shorter infusion time, greater bioavailability, and better quality of life. Patients self-administer SCIg at home, avoiding the inconvenience of IVIg therapy, which entails travel time for once-monthly hospitalization or long hours spent in an infusion center, she explained.
French investigators recently documented a previously unappreciated further advantage of home-based SCIg. They convened a focus group of patients with DM or PM experienced with both IVIg and home SCIg and determined that participants uniformly preferred home SCIg. The patients cited a new and welcome feeling of autonomy and control.
“All patients with experience of IVIg and SCIg expressed a clear preference for SCIg, which was described to be easy, less disruptive for daily life, well tolerated, and less time-consuming. Preference was mainly related to a restoration of autonomy. Home-based self-administration reinforced the feeling of independence,” according to the investigators.
Available products
Six preparations of SCIg are commercially available. Most are in 10% concentration, as are all IVIg products. However, a 20% formulation of SCIg known as Hizentra allows for a smaller infusion volume and quicker completion of a treatment session. And one SCIg product, HyQvia, uses recombinant human hyaluronidase-facilitated 10% immune globulin, allowing home infusion of large volumes of sustained-release immune globulin on a once-monthly basis.
The relatively recent introduction of home SCIg for treatment of autoimmune inflammatory diseases, including DM, PM, and chronic inflammatory demyelinating polyneuropathy, has been pioneered mainly by European investigators. The treatment is often given by programmable mechanical pump once weekly. Italian investigators have reported efficacy in DM using 0.2 g/kg per week, which is about half the monthly total dose of IVIg employed. The infusion rate is 10-40 mL/hour, with a volume of around 35 mL per injection site.
Alternatively, SCIg can be delivered by rapid push infusions of smaller volumes with a syringe two or three times per week; that’s the regimen that was used at 2 g/kg over the course of a month by patients in the French focus group study, who didn’t mind the more frequent dosing.
“As they have had severe long-lasting symptoms, SCIg was perceived as a curative rather than a preventive therapy,” according to the French investigators.
More than 40% of patients experience adverse reactions to IVIg. These often involve headaches, nausea, back or abdominal pain, arthralgias, and/or difficulty breathing. Thromboembolic events and acute renal failure occur occasionally. For this reason, many physicians give a prophylactic dose of corticosteroids an hour before a patient’s first dose of IVIg. These systemic side effects are so rare with SCIg that Dr. Postolova has never pretreated with steroids, even though the main reason she resorts to the home therapy is a patient’s track record of poor tolerance of IVIg. The lower abdomen and thigh are the most commonly used subcutaneous infusion sites. Mild local infusion site reactions are fairly common.
Formulating IVIg and SCIg is a complex process that entails plasma procurement and pooling, fractionation, and purification. It takes 10,000-60,000 plasma donations to make one lot of IVIg. Donations are accepted only from repeated donors. Samples are held for 6 months and tested for infectious agents. However, efforts are underway to develop bioengineered recombinant immune globulin products that don’t require donated plasma. These products are being designed to capture and enhance the most important mechanisms of benefit of plasma-derived immunoglobulins using Fc fragments that target key receptors, rather than relying on full-length immune globulin. The goal is enhanced efficacy at much lower doses than with IVIg or SCIg.
Dr. Postolova reported having no financial conflicts regarding her presentation.
In support of previously published case reports, a study using cross-linked national population data in Denmark has now associated cumulative exposure to high-potency topical steroids with osteoporotic fractures in a dose-response relationship.
In a stepwise manner, the hazard ratios for major osteoporotic fracture (MOF) were found to start climbing incrementally for those with a cumulative topical steroid dose equivalent of more than 500 g of mometasone furoate when compared with exposure of 200-499 g, according to the team of investigators from the University of Copenhagen.
“Use of these drugs is very common, and we found an estimated population-attributable risk of as much as 4.3%,” the investigators reported in the study, published in JAMA Dermatology.
The retrospective cohort study drew data from the Danish National Patient Registry, which covers 99% of the country’s population. It was linked to the Danish National Prescription Registry, which captures data on pharmacy-dispensed medications. Data collected from the beginning of 2003 to the end of 2017 were evaluated.
Exposures to potent or very potent topical corticosteroids were converted into a single standard with potency equivalent to 1 mg/g of mometasone furoate. Four strata of exposure were compared to a reference exposure of 200-499 g. These were 500-999 g, 1,000-1,999 g, 2,000-9,999 g, and 10,000 g or greater.
For the first strata, the small increased risk for MOF did not reach significance (HR, 1.01; 95% confidence interval, 0.99-1.03), but each of the others did. These climbed from a 5% greater risk (HR 1.05 95% CI 1.02-1.08) for a cumulative exposure of 1,000 to 1,999 g, to a 10% greater risk (HR, 1.10; 95% CI, 1.07-1.13) for a cumulative exposure of 2,000-9,999 g, and finally to a 27% greater risk (HR, 1.27; 95% CI, 1.19-1.35) for a cumulative exposure of 10,000 g or higher.
The study included more than 700,000 individuals exposed to topical mometasone at a potency equivalent of 200 g or more over the study period. The reference group (200-499 g) was the largest (317,907 individuals). The first strata (500-999 g) included 186,359 patients; the second (1,000-1,999 g), 111,203 patients; the third (2,000-9,999 g), 94,334 patients; and the fifth (10,000 g or more), 13,448 patients.
“A 3% increase in the relative risk of osteoporosis and MOF was observed per doubling of the TCS dose,” according to the investigators.
Patients exposed to doses of high-potency topical steroids that put them at risk of MOF is limited but substantial, according to the senior author, Alexander Egeberg, MD, PhD, of the department of dermatology and allergy at Herlev and Gentofte Hospital, Copenhagen.
“It is true that the risk is modest for the average user of topical steroids,” Dr. Egeberg said in an interview. However, despite the fact that topical steroids are intended for short-term use, “2% of all our users had been exposed to the equivalent of 10,000 g of mometasone, which mean 100 tubes of 100 g.”
If the other two strata at significantly increased risk of MOF (greater than 1,000 g) are included, an additional 28% of all users are facing the potential for clinically significant osteoporosis, according to the Danish data.
The adverse effect of steroids on bone metabolism has been established previously, and several studies have linked systemic corticosteroid exposure, including inhaled corticosteroids, with increased risk of osteoporotic fracture. For example, one study showed that patients with chronic obstructive pulmonary disease on daily inhaled doses of the equivalent of fluticasone at or above 1,000 mcg for more than 4 years had about a 10% increased risk of MOF relative to those not exposed.
The data associate topical steroids with increased risk of osteoporotic fracture, but Dr. Egeberg said osteoporosis is not the only reason to use topical steroids prudently.
“It is important to keep in mind that osteoporosis and fractures are at the extreme end of the side-effect profile and that other side effects, such as striae formation, skin thinning, and dysregulated diabetes, can occur with much lower quantities of topical steroids,” Dr. Egeberg said
For avoiding this risk, “there are no specific cutoffs” recommended for topical steroids in current guidelines, but dermatologists should be aware that many of the indications for topical steroids, such as psoriasis and atopic dermatitis, involve skin with an impaired barrier function, exposing patients to an increased likelihood of absorption, according to Dr. Egeberg.
“A general rule of thumb that we use is that, if a patient with persistent disease activity requires a new prescription of the equivalent of 100 g mometasone every 1-2 months, it might be worth considering if there is a suitable alternative,” Dr. Egeberg said.
In an accompanying editorial, Rebecca D. Jackson, MD, of the division of endocrinology, diabetes, and metabolism in the department of internal medicine at Ohio State University, Columbus, agreed that no guidelines specific to avoiding the risks of topical corticosteroids are currently available, but she advised clinicians to be considering these risks nonetheless. In general, she suggested that topical steroids, like oral steroids, should be used at “the lowest dose for the shortest duration necessary to manage the underlying medical condition.”
The correlation between topical corticosteroids and increased risk of osteoporotic fracture, although not established previously in a large study, is not surprising, according to Victoria Werth, MD, chief of dermatology at the Philadelphia Veterans Affairs Hospital and professor of dermatology at the University of Pennsylvania, also in Philadelphia.
“Systemic absorption of potent topical steroids has previously been demonstrated with a rapid decrease in serum cortisol levels,” Dr. Werth said in an interview. She indicated that concern about the risk of osteoporosis imposed by use of potent steroids over large body surface areas is appropriate.
To minimize this risk, “it is reasonable to use the lowest dose of steroid possible and to try to substitute other medications when possible,” she said.
Dr. Egeberg reported financial relationships with Abbvie, Almirall, Bristol-Myers Squibb, Dermavant Sciences, Galderma, Janssen Pharmaceuticals, Eli Lilly, Novartis, Pfizer, Samsung, Bioepis, and UCB. Five authors had disclosures related to some of those pharmaceutical companies and/or others. Dr. Jackson had no disclosures.
In support of previously published case reports, a study using cross-linked national population data in Denmark has now associated cumulative exposure to high-potency topical steroids with osteoporotic fractures in a dose-response relationship.
In a stepwise manner, the hazard ratios for major osteoporotic fracture (MOF) were found to start climbing incrementally for those with a cumulative topical steroid dose equivalent of more than 500 g of mometasone furoate when compared with exposure of 200-499 g, according to the team of investigators from the University of Copenhagen.
“Use of these drugs is very common, and we found an estimated population-attributable risk of as much as 4.3%,” the investigators reported in the study, published in JAMA Dermatology.
The retrospective cohort study drew data from the Danish National Patient Registry, which covers 99% of the country’s population. It was linked to the Danish National Prescription Registry, which captures data on pharmacy-dispensed medications. Data collected from the beginning of 2003 to the end of 2017 were evaluated.
Exposures to potent or very potent topical corticosteroids were converted into a single standard with potency equivalent to 1 mg/g of mometasone furoate. Four strata of exposure were compared to a reference exposure of 200-499 g. These were 500-999 g, 1,000-1,999 g, 2,000-9,999 g, and 10,000 g or greater.
For the first strata, the small increased risk for MOF did not reach significance (HR, 1.01; 95% confidence interval, 0.99-1.03), but each of the others did. These climbed from a 5% greater risk (HR 1.05 95% CI 1.02-1.08) for a cumulative exposure of 1,000 to 1,999 g, to a 10% greater risk (HR, 1.10; 95% CI, 1.07-1.13) for a cumulative exposure of 2,000-9,999 g, and finally to a 27% greater risk (HR, 1.27; 95% CI, 1.19-1.35) for a cumulative exposure of 10,000 g or higher.
The study included more than 700,000 individuals exposed to topical mometasone at a potency equivalent of 200 g or more over the study period. The reference group (200-499 g) was the largest (317,907 individuals). The first strata (500-999 g) included 186,359 patients; the second (1,000-1,999 g), 111,203 patients; the third (2,000-9,999 g), 94,334 patients; and the fifth (10,000 g or more), 13,448 patients.
“A 3% increase in the relative risk of osteoporosis and MOF was observed per doubling of the TCS dose,” according to the investigators.
Patients exposed to doses of high-potency topical steroids that put them at risk of MOF is limited but substantial, according to the senior author, Alexander Egeberg, MD, PhD, of the department of dermatology and allergy at Herlev and Gentofte Hospital, Copenhagen.
“It is true that the risk is modest for the average user of topical steroids,” Dr. Egeberg said in an interview. However, despite the fact that topical steroids are intended for short-term use, “2% of all our users had been exposed to the equivalent of 10,000 g of mometasone, which mean 100 tubes of 100 g.”
If the other two strata at significantly increased risk of MOF (greater than 1,000 g) are included, an additional 28% of all users are facing the potential for clinically significant osteoporosis, according to the Danish data.
The adverse effect of steroids on bone metabolism has been established previously, and several studies have linked systemic corticosteroid exposure, including inhaled corticosteroids, with increased risk of osteoporotic fracture. For example, one study showed that patients with chronic obstructive pulmonary disease on daily inhaled doses of the equivalent of fluticasone at or above 1,000 mcg for more than 4 years had about a 10% increased risk of MOF relative to those not exposed.
The data associate topical steroids with increased risk of osteoporotic fracture, but Dr. Egeberg said osteoporosis is not the only reason to use topical steroids prudently.
“It is important to keep in mind that osteoporosis and fractures are at the extreme end of the side-effect profile and that other side effects, such as striae formation, skin thinning, and dysregulated diabetes, can occur with much lower quantities of topical steroids,” Dr. Egeberg said
For avoiding this risk, “there are no specific cutoffs” recommended for topical steroids in current guidelines, but dermatologists should be aware that many of the indications for topical steroids, such as psoriasis and atopic dermatitis, involve skin with an impaired barrier function, exposing patients to an increased likelihood of absorption, according to Dr. Egeberg.
“A general rule of thumb that we use is that, if a patient with persistent disease activity requires a new prescription of the equivalent of 100 g mometasone every 1-2 months, it might be worth considering if there is a suitable alternative,” Dr. Egeberg said.
In an accompanying editorial, Rebecca D. Jackson, MD, of the division of endocrinology, diabetes, and metabolism in the department of internal medicine at Ohio State University, Columbus, agreed that no guidelines specific to avoiding the risks of topical corticosteroids are currently available, but she advised clinicians to be considering these risks nonetheless. In general, she suggested that topical steroids, like oral steroids, should be used at “the lowest dose for the shortest duration necessary to manage the underlying medical condition.”
The correlation between topical corticosteroids and increased risk of osteoporotic fracture, although not established previously in a large study, is not surprising, according to Victoria Werth, MD, chief of dermatology at the Philadelphia Veterans Affairs Hospital and professor of dermatology at the University of Pennsylvania, also in Philadelphia.
“Systemic absorption of potent topical steroids has previously been demonstrated with a rapid decrease in serum cortisol levels,” Dr. Werth said in an interview. She indicated that concern about the risk of osteoporosis imposed by use of potent steroids over large body surface areas is appropriate.
To minimize this risk, “it is reasonable to use the lowest dose of steroid possible and to try to substitute other medications when possible,” she said.
Dr. Egeberg reported financial relationships with Abbvie, Almirall, Bristol-Myers Squibb, Dermavant Sciences, Galderma, Janssen Pharmaceuticals, Eli Lilly, Novartis, Pfizer, Samsung, Bioepis, and UCB. Five authors had disclosures related to some of those pharmaceutical companies and/or others. Dr. Jackson had no disclosures.
In support of previously published case reports, a study using cross-linked national population data in Denmark has now associated cumulative exposure to high-potency topical steroids with osteoporotic fractures in a dose-response relationship.
In a stepwise manner, the hazard ratios for major osteoporotic fracture (MOF) were found to start climbing incrementally for those with a cumulative topical steroid dose equivalent of more than 500 g of mometasone furoate when compared with exposure of 200-499 g, according to the team of investigators from the University of Copenhagen.
“Use of these drugs is very common, and we found an estimated population-attributable risk of as much as 4.3%,” the investigators reported in the study, published in JAMA Dermatology.
The retrospective cohort study drew data from the Danish National Patient Registry, which covers 99% of the country’s population. It was linked to the Danish National Prescription Registry, which captures data on pharmacy-dispensed medications. Data collected from the beginning of 2003 to the end of 2017 were evaluated.
Exposures to potent or very potent topical corticosteroids were converted into a single standard with potency equivalent to 1 mg/g of mometasone furoate. Four strata of exposure were compared to a reference exposure of 200-499 g. These were 500-999 g, 1,000-1,999 g, 2,000-9,999 g, and 10,000 g or greater.
For the first strata, the small increased risk for MOF did not reach significance (HR, 1.01; 95% confidence interval, 0.99-1.03), but each of the others did. These climbed from a 5% greater risk (HR 1.05 95% CI 1.02-1.08) for a cumulative exposure of 1,000 to 1,999 g, to a 10% greater risk (HR, 1.10; 95% CI, 1.07-1.13) for a cumulative exposure of 2,000-9,999 g, and finally to a 27% greater risk (HR, 1.27; 95% CI, 1.19-1.35) for a cumulative exposure of 10,000 g or higher.
The study included more than 700,000 individuals exposed to topical mometasone at a potency equivalent of 200 g or more over the study period. The reference group (200-499 g) was the largest (317,907 individuals). The first strata (500-999 g) included 186,359 patients; the second (1,000-1,999 g), 111,203 patients; the third (2,000-9,999 g), 94,334 patients; and the fifth (10,000 g or more), 13,448 patients.
“A 3% increase in the relative risk of osteoporosis and MOF was observed per doubling of the TCS dose,” according to the investigators.
Patients exposed to doses of high-potency topical steroids that put them at risk of MOF is limited but substantial, according to the senior author, Alexander Egeberg, MD, PhD, of the department of dermatology and allergy at Herlev and Gentofte Hospital, Copenhagen.
“It is true that the risk is modest for the average user of topical steroids,” Dr. Egeberg said in an interview. However, despite the fact that topical steroids are intended for short-term use, “2% of all our users had been exposed to the equivalent of 10,000 g of mometasone, which mean 100 tubes of 100 g.”
If the other two strata at significantly increased risk of MOF (greater than 1,000 g) are included, an additional 28% of all users are facing the potential for clinically significant osteoporosis, according to the Danish data.
The adverse effect of steroids on bone metabolism has been established previously, and several studies have linked systemic corticosteroid exposure, including inhaled corticosteroids, with increased risk of osteoporotic fracture. For example, one study showed that patients with chronic obstructive pulmonary disease on daily inhaled doses of the equivalent of fluticasone at or above 1,000 mcg for more than 4 years had about a 10% increased risk of MOF relative to those not exposed.
The data associate topical steroids with increased risk of osteoporotic fracture, but Dr. Egeberg said osteoporosis is not the only reason to use topical steroids prudently.
“It is important to keep in mind that osteoporosis and fractures are at the extreme end of the side-effect profile and that other side effects, such as striae formation, skin thinning, and dysregulated diabetes, can occur with much lower quantities of topical steroids,” Dr. Egeberg said
For avoiding this risk, “there are no specific cutoffs” recommended for topical steroids in current guidelines, but dermatologists should be aware that many of the indications for topical steroids, such as psoriasis and atopic dermatitis, involve skin with an impaired barrier function, exposing patients to an increased likelihood of absorption, according to Dr. Egeberg.
“A general rule of thumb that we use is that, if a patient with persistent disease activity requires a new prescription of the equivalent of 100 g mometasone every 1-2 months, it might be worth considering if there is a suitable alternative,” Dr. Egeberg said.
In an accompanying editorial, Rebecca D. Jackson, MD, of the division of endocrinology, diabetes, and metabolism in the department of internal medicine at Ohio State University, Columbus, agreed that no guidelines specific to avoiding the risks of topical corticosteroids are currently available, but she advised clinicians to be considering these risks nonetheless. In general, she suggested that topical steroids, like oral steroids, should be used at “the lowest dose for the shortest duration necessary to manage the underlying medical condition.”
The correlation between topical corticosteroids and increased risk of osteoporotic fracture, although not established previously in a large study, is not surprising, according to Victoria Werth, MD, chief of dermatology at the Philadelphia Veterans Affairs Hospital and professor of dermatology at the University of Pennsylvania, also in Philadelphia.
“Systemic absorption of potent topical steroids has previously been demonstrated with a rapid decrease in serum cortisol levels,” Dr. Werth said in an interview. She indicated that concern about the risk of osteoporosis imposed by use of potent steroids over large body surface areas is appropriate.
To minimize this risk, “it is reasonable to use the lowest dose of steroid possible and to try to substitute other medications when possible,” she said.
Dr. Egeberg reported financial relationships with Abbvie, Almirall, Bristol-Myers Squibb, Dermavant Sciences, Galderma, Janssen Pharmaceuticals, Eli Lilly, Novartis, Pfizer, Samsung, Bioepis, and UCB. Five authors had disclosures related to some of those pharmaceutical companies and/or others. Dr. Jackson had no disclosures.
Tuberous sclerosis (TS), also known as Bourneville’s syndrome or epiloia (epi: epilepsy, loi: low intelligence, a: adenoma sebaceum), is a genetic disease inherited in an autosomal dominant pattern, although up to 75% of cases may be caused by a spontaneous mutation. It is caused by mutations in the TSC1 gene on chromosome 9q34–encoding hamartin or the TSC2 gene on chromosome I6pl3–encoding tuberin. Patients present at birth and males and females are affected equally.
There are multiple skin findings in TS that may herald the diagnosis. The earliest findings are hypopigmented macules, found in 85% of patients. They may be in an ash-leaf shape or confetti pattern. Adenoma sebaceum, or angiofibromas, are present on the forehead, nose, and cheeks, and often present in childhood. Periungual angiofibromas called Koenen tumors tend to occur at puberty. Connective-tissue nevi called Shagreen plaques, or collagenomas, may be present, which is what our patient exhibits on his back. The lumbosacral region is the most common area for these to appear in the first decade of life.
TS can affect other organ systems in the body. Seizures, neuropsychiatric diseases, and mental deficiency are common. Cortical tumors, gliomas, and astrocytomas may develop in the brain. Congenital retinal hamartomas (phakomas) occur. Renal cysts and angiomyolipomas may occur in the kidneys. In the lungs, patients may develop lymphangiomyomatosis. Rhabdomyomas can occur in the heart in infancy and may regress spontaneously over time. Bony changes such as cysts and sclerosis may occur.
Treatment and monitoring of TS requires a multidisciplinary approach with neurology, pulmonology, cardiology, ophthalmology, orthopedics, and dermatology. Cosmetic treatment for angiofibromas includes CO2 laser, shaving, and dermabrasion. Topical rapamycin use has been described in the literature to improve the appearance of angiofibromas. Our patient has been using rapamycin 1% cream for more than 5 years and has had a substantial reduction in the size and number of angiofibromas.
Dr. Donna Bilu Martin
This case and photo were submitted by Dr. Bilu Martin.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].
References:
Spitz J. Genodermatoses. A Clinical Guide to Genetic Skin Disorders. Philadelphia: Lippincott Williams & Wilkins, 2005.
James W et al. Andrews’ Diseases of the Skin. Philadelphia: Saunders, 2006.
Bolognia JL et al. Dermatology. London: Mosby Elsevier, 2008.
Tuberous sclerosis (TS), also known as Bourneville’s syndrome or epiloia (epi: epilepsy, loi: low intelligence, a: adenoma sebaceum), is a genetic disease inherited in an autosomal dominant pattern, although up to 75% of cases may be caused by a spontaneous mutation. It is caused by mutations in the TSC1 gene on chromosome 9q34–encoding hamartin or the TSC2 gene on chromosome I6pl3–encoding tuberin. Patients present at birth and males and females are affected equally.
There are multiple skin findings in TS that may herald the diagnosis. The earliest findings are hypopigmented macules, found in 85% of patients. They may be in an ash-leaf shape or confetti pattern. Adenoma sebaceum, or angiofibromas, are present on the forehead, nose, and cheeks, and often present in childhood. Periungual angiofibromas called Koenen tumors tend to occur at puberty. Connective-tissue nevi called Shagreen plaques, or collagenomas, may be present, which is what our patient exhibits on his back. The lumbosacral region is the most common area for these to appear in the first decade of life.
TS can affect other organ systems in the body. Seizures, neuropsychiatric diseases, and mental deficiency are common. Cortical tumors, gliomas, and astrocytomas may develop in the brain. Congenital retinal hamartomas (phakomas) occur. Renal cysts and angiomyolipomas may occur in the kidneys. In the lungs, patients may develop lymphangiomyomatosis. Rhabdomyomas can occur in the heart in infancy and may regress spontaneously over time. Bony changes such as cysts and sclerosis may occur.
Treatment and monitoring of TS requires a multidisciplinary approach with neurology, pulmonology, cardiology, ophthalmology, orthopedics, and dermatology. Cosmetic treatment for angiofibromas includes CO2 laser, shaving, and dermabrasion. Topical rapamycin use has been described in the literature to improve the appearance of angiofibromas. Our patient has been using rapamycin 1% cream for more than 5 years and has had a substantial reduction in the size and number of angiofibromas.
Dr. Donna Bilu Martin
This case and photo were submitted by Dr. Bilu Martin.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].
References:
Spitz J. Genodermatoses. A Clinical Guide to Genetic Skin Disorders. Philadelphia: Lippincott Williams & Wilkins, 2005.
James W et al. Andrews’ Diseases of the Skin. Philadelphia: Saunders, 2006.
Bolognia JL et al. Dermatology. London: Mosby Elsevier, 2008.
Tuberous sclerosis (TS), also known as Bourneville’s syndrome or epiloia (epi: epilepsy, loi: low intelligence, a: adenoma sebaceum), is a genetic disease inherited in an autosomal dominant pattern, although up to 75% of cases may be caused by a spontaneous mutation. It is caused by mutations in the TSC1 gene on chromosome 9q34–encoding hamartin or the TSC2 gene on chromosome I6pl3–encoding tuberin. Patients present at birth and males and females are affected equally.
There are multiple skin findings in TS that may herald the diagnosis. The earliest findings are hypopigmented macules, found in 85% of patients. They may be in an ash-leaf shape or confetti pattern. Adenoma sebaceum, or angiofibromas, are present on the forehead, nose, and cheeks, and often present in childhood. Periungual angiofibromas called Koenen tumors tend to occur at puberty. Connective-tissue nevi called Shagreen plaques, or collagenomas, may be present, which is what our patient exhibits on his back. The lumbosacral region is the most common area for these to appear in the first decade of life.
TS can affect other organ systems in the body. Seizures, neuropsychiatric diseases, and mental deficiency are common. Cortical tumors, gliomas, and astrocytomas may develop in the brain. Congenital retinal hamartomas (phakomas) occur. Renal cysts and angiomyolipomas may occur in the kidneys. In the lungs, patients may develop lymphangiomyomatosis. Rhabdomyomas can occur in the heart in infancy and may regress spontaneously over time. Bony changes such as cysts and sclerosis may occur.
Treatment and monitoring of TS requires a multidisciplinary approach with neurology, pulmonology, cardiology, ophthalmology, orthopedics, and dermatology. Cosmetic treatment for angiofibromas includes CO2 laser, shaving, and dermabrasion. Topical rapamycin use has been described in the literature to improve the appearance of angiofibromas. Our patient has been using rapamycin 1% cream for more than 5 years and has had a substantial reduction in the size and number of angiofibromas.
Dr. Donna Bilu Martin
This case and photo were submitted by Dr. Bilu Martin.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].
References:
Spitz J. Genodermatoses. A Clinical Guide to Genetic Skin Disorders. Philadelphia: Lippincott Williams & Wilkins, 2005.
James W et al. Andrews’ Diseases of the Skin. Philadelphia: Saunders, 2006.
Bolognia JL et al. Dermatology. London: Mosby Elsevier, 2008.
A 35-year-old male presented for follow-up with asymptomatic lesions on his nose and cheeks present since childhood. He also has a skin-colored plaque on his mid-back present since birth. The patient takes antiseizure medication.
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From time to time, Joslyn Kirby, MD, asks other physicians about their experience with certain medications used in dermatology, especially when something new hits the market.
“Sometimes I get an answer like, ‘The last time I used that medicine, my patient needed a liver transplant,’ ” Dr. Kirby, associate professor of dermatology, Penn State University, Hershey, said during the Orlando Dermatology Aesthetic and Clinical Conference. “It’s typically a story of something rare, uncommon, and awful. The challenge with an anecdote is that for all its power, it has a lower level of evidence. But it sticks with us and influences us more than a better level of evidence because it’s a situation and a story that we might relate to.”
Dr. Joslyn Kirby
Dr. Kirby said that when she thinks about managing side effects from drugs used in dermatology, it usually relates to something common and low-risk such as sore, dry skin with isotretinoin use. In contrast, if there is an uncommon but serious side effect, then mitigation rather than management is key. “I want to mitigate the risk – meaning warn my patient about it or be careful about how I select my patients when it is a serious side effect that happens infrequently,” she said. “The worst combination is a frequent and severe side effect. That is something we should avoid, for sure.”
Isotretinoin
But another aspect of prescribing a new drug for patients can be less clear-cut, Dr. Kirby continued, such as the rationale for routine lab monitoring. She began by discussing one of her male patients with moderate to severe acne. After he failed oral antibiotics and topical retinoids, she recommended isotretinoin, which carries a risk of hypertriglyceridemia-associated pancreatitis. “Early in my career, I was getting a lot of monthly labs in patients on this drug that were totally normal and not influencing my practice,” Dr. Kirby recalled. “We’ve seen studies coming out on isotretinoin lab monitoring, showing us that we can keep our patients safe and that we really don’t need to be checking labs as often, because lab changes are infrequent.”
In one of those studies, researchers evaluated 1,863 patients treated with isotretinoin for acne between Jan. 1, 2008, and June 30, 2017 (J Am Acad Dermatol. 2020 Jan;82[1]:72-9).Over time, fewer than 1% of patients screened developed grade 3 or greater triglyceride testing abnormalities, while fewer than 0.5% developed liver function testing (LFT) abnormalities. Authors of a separate systematic review concluded that for patients on isotretinoin therapy without elevated baseline triglycerides, or risk thereof, monitoring triglycerides is of little value (Br J Dermatol. 2017 Oct;177[4]:960-6). Of the 25 patients in the analysis who developed pancreatitis on isotretinoin, only 3 had elevated triglycerides at baseline.
“I was taught that I need to check triglycerides frequently due to the risk of pancreatitis developing with isotretinoin use,” Dr. Kirby said. “Lipid changes on therapy are expected, but they tend to peak early, meaning the first 3 months of treatment when we’re ramping up from a starting dose to a maintenance dose. It’s rare for somebody to be a late bloomer, meaning that they have totally normal labs in the first 3 months and then suddenly develop an abnormality. People are either going to demonstrate an abnormality early or not have one at all.”
When Dr. Kirby starts patients on isotretinoin, she orders baseline LFTs and a lipid panel and repeats them 60 days later. “If everything is fine or only mildly high, we don’t do more testing, only a review of systems,” she said. “This is valuable to our patients because fear of needles and fainting peak during adolescence.”
Spironolactone
The clinical use of regularly monitoring potassium levels in young women taking spironolactone for acne has also been questioned. The drug has been linked to an increased risk for hyperkalemia, but the prevalence is unclear. “I got a lot of normal potassium levels in these patients [when] I was in training and I really questioned, ‘Why am I doing this? What is the rationale?’ ” Dr. Kirby said.
In a study that informed her own practice, researchers reviewed the rate of hyperkalemia in 974 healthy young women taking spironolactone for acne or for an endocrine disorder with associated acne between Dec. 1, 2000, and March 31, 2014 (JAMA Dermatol. 2015 Sep;151[9]:941-4). Of the total of 1,802 serum potassium measurements taken during treatment, 13 (0.72%) were mildly elevated levels and none of the patients had a potassium level above 5.5 mEq/L. Retesting within 1 to 3 weeks in 6 of 13 patients with elevated levels found that potassium levels were normal. “The recommendation for spironolactone in healthy women is not to check the potassium level,” Dr. Kirby said, adding that she does counsel patients about the risk of breast tenderness (which can occur 5% to 40% of the time) and spotting (which can occur in 10% to 20% of patients). Gynecomastia can occur in 10% to 30% of men, which is one of the reasons she does not use spironolactone in male patients.
TB testing and biologics
Whether or not to test for TB in patients with psoriasis taking biologic therapies represents another conundrum, she continued. Patients taking biologics are at risk of reactivation of latent TB infection, but in her experience, package inserts contain language like “perform TB testing at baseline, then periodically,” or “use at baseline, then with active TB symptoms,” and “after treatment is discontinued.”
“What the inserts didn’t recommend was to perform TB testing every year, which is what my routine had been,” Dr. Kirby said. “In the United States, thankfully we don’t have a lot of TB.” In a study that informed her own practice, researchers at a single academic medical center retrospectively reviewed the TB seroconversion rate among 316 patients treated with second-generation biologics (J Am Acad Dermatol. 2020 Oct 1;S0190-9622[20]32676-1. doi: 10.1016/j.jaad.2020.09.075). It found that only six patients (2%) converted and had a positive TB test later during treatment with the biologic. “Of these six people, all had grown up outside the U.S., had traveled outside of the U.S., or were in a group living situation,” said Dr. Kirby, who was not affiliated with the study.
“This informs our rationale for how we can do this testing. If insurance requires it every year, fine. But if they don’t, I ask patients about travel, about their living situation, and how they’re feeling. If everything’s going great, I don’t order TB testing. I do favor the interferon-gamma release assays because they’re a lot more effective than PPDs [purified protein derivative skin tests]. Also, PPDs are difficult for patients who have a low rate of returning to have that test read.”
Terbinafine for onychomycosis
Dr. Kirby also discussed the rationale for ordering regular LFTs in patients taking terbinafine for onychomycosis. “There is a risk of drug-induced liver injury from taking terbinafine, but it’s rare,” she said. “Can we be thoughtful about which patients we expose?”
Evidence suggests that patients with hyperkeratosis greater than 2 mm, with nail matrix involvement, with 50% or more of the nail involved, or having concomitant peripheral vascular disease and diabetes are recalcitrant to treatment with terbinafine
(J Am Acad Dermatol. 2019 Apr;80[4]:853-67). “If we can frame this risk, then we can frame it for our patients,” she said. “We’re more likely to cause liver injury with an antibiotic. When it comes to an oral antifungal, itraconazole is more likely than terbinafine to cause liver injury. The rate of liver injury with terbinafine is only about 2 out of 100,000. It’s five times more likely with itraconazole and 21 times more likely with Augmentin.”
She recommends obtaining a baseline LFT in patients starting terbinafine therapy “to make sure their liver is normal from the start.” In addition, she advised, “let them know that there is a TB seroconversion risk of about 1 in 50,000 people, and that if it happens there would be symptomatic changes. They would maybe notice pruritus and have a darkening in their urine, and they’d have some flu-like symptoms, which would mean stop the drug and get some care.”
Dr. Kirby emphasized that a patient’s propensity for developing drug-induced liver injury from terbinafine use is not predictable from LFT monitoring. “What you’re more likely to find is an asymptomatic LFT rise in about 1% of people,” she said.
She disclosed that she has received honoraria from AbbVie, ChemoCentryx, Incyte, Janssen, Novartis, and UCB Pharma.
From time to time, Joslyn Kirby, MD, asks other physicians about their experience with certain medications used in dermatology, especially when something new hits the market.
“Sometimes I get an answer like, ‘The last time I used that medicine, my patient needed a liver transplant,’ ” Dr. Kirby, associate professor of dermatology, Penn State University, Hershey, said during the Orlando Dermatology Aesthetic and Clinical Conference. “It’s typically a story of something rare, uncommon, and awful. The challenge with an anecdote is that for all its power, it has a lower level of evidence. But it sticks with us and influences us more than a better level of evidence because it’s a situation and a story that we might relate to.”
Dr. Joslyn Kirby
Dr. Kirby said that when she thinks about managing side effects from drugs used in dermatology, it usually relates to something common and low-risk such as sore, dry skin with isotretinoin use. In contrast, if there is an uncommon but serious side effect, then mitigation rather than management is key. “I want to mitigate the risk – meaning warn my patient about it or be careful about how I select my patients when it is a serious side effect that happens infrequently,” she said. “The worst combination is a frequent and severe side effect. That is something we should avoid, for sure.”
Isotretinoin
But another aspect of prescribing a new drug for patients can be less clear-cut, Dr. Kirby continued, such as the rationale for routine lab monitoring. She began by discussing one of her male patients with moderate to severe acne. After he failed oral antibiotics and topical retinoids, she recommended isotretinoin, which carries a risk of hypertriglyceridemia-associated pancreatitis. “Early in my career, I was getting a lot of monthly labs in patients on this drug that were totally normal and not influencing my practice,” Dr. Kirby recalled. “We’ve seen studies coming out on isotretinoin lab monitoring, showing us that we can keep our patients safe and that we really don’t need to be checking labs as often, because lab changes are infrequent.”
In one of those studies, researchers evaluated 1,863 patients treated with isotretinoin for acne between Jan. 1, 2008, and June 30, 2017 (J Am Acad Dermatol. 2020 Jan;82[1]:72-9).Over time, fewer than 1% of patients screened developed grade 3 or greater triglyceride testing abnormalities, while fewer than 0.5% developed liver function testing (LFT) abnormalities. Authors of a separate systematic review concluded that for patients on isotretinoin therapy without elevated baseline triglycerides, or risk thereof, monitoring triglycerides is of little value (Br J Dermatol. 2017 Oct;177[4]:960-6). Of the 25 patients in the analysis who developed pancreatitis on isotretinoin, only 3 had elevated triglycerides at baseline.
“I was taught that I need to check triglycerides frequently due to the risk of pancreatitis developing with isotretinoin use,” Dr. Kirby said. “Lipid changes on therapy are expected, but they tend to peak early, meaning the first 3 months of treatment when we’re ramping up from a starting dose to a maintenance dose. It’s rare for somebody to be a late bloomer, meaning that they have totally normal labs in the first 3 months and then suddenly develop an abnormality. People are either going to demonstrate an abnormality early or not have one at all.”
When Dr. Kirby starts patients on isotretinoin, she orders baseline LFTs and a lipid panel and repeats them 60 days later. “If everything is fine or only mildly high, we don’t do more testing, only a review of systems,” she said. “This is valuable to our patients because fear of needles and fainting peak during adolescence.”
Spironolactone
The clinical use of regularly monitoring potassium levels in young women taking spironolactone for acne has also been questioned. The drug has been linked to an increased risk for hyperkalemia, but the prevalence is unclear. “I got a lot of normal potassium levels in these patients [when] I was in training and I really questioned, ‘Why am I doing this? What is the rationale?’ ” Dr. Kirby said.
In a study that informed her own practice, researchers reviewed the rate of hyperkalemia in 974 healthy young women taking spironolactone for acne or for an endocrine disorder with associated acne between Dec. 1, 2000, and March 31, 2014 (JAMA Dermatol. 2015 Sep;151[9]:941-4). Of the total of 1,802 serum potassium measurements taken during treatment, 13 (0.72%) were mildly elevated levels and none of the patients had a potassium level above 5.5 mEq/L. Retesting within 1 to 3 weeks in 6 of 13 patients with elevated levels found that potassium levels were normal. “The recommendation for spironolactone in healthy women is not to check the potassium level,” Dr. Kirby said, adding that she does counsel patients about the risk of breast tenderness (which can occur 5% to 40% of the time) and spotting (which can occur in 10% to 20% of patients). Gynecomastia can occur in 10% to 30% of men, which is one of the reasons she does not use spironolactone in male patients.
TB testing and biologics
Whether or not to test for TB in patients with psoriasis taking biologic therapies represents another conundrum, she continued. Patients taking biologics are at risk of reactivation of latent TB infection, but in her experience, package inserts contain language like “perform TB testing at baseline, then periodically,” or “use at baseline, then with active TB symptoms,” and “after treatment is discontinued.”
“What the inserts didn’t recommend was to perform TB testing every year, which is what my routine had been,” Dr. Kirby said. “In the United States, thankfully we don’t have a lot of TB.” In a study that informed her own practice, researchers at a single academic medical center retrospectively reviewed the TB seroconversion rate among 316 patients treated with second-generation biologics (J Am Acad Dermatol. 2020 Oct 1;S0190-9622[20]32676-1. doi: 10.1016/j.jaad.2020.09.075). It found that only six patients (2%) converted and had a positive TB test later during treatment with the biologic. “Of these six people, all had grown up outside the U.S., had traveled outside of the U.S., or were in a group living situation,” said Dr. Kirby, who was not affiliated with the study.
“This informs our rationale for how we can do this testing. If insurance requires it every year, fine. But if they don’t, I ask patients about travel, about their living situation, and how they’re feeling. If everything’s going great, I don’t order TB testing. I do favor the interferon-gamma release assays because they’re a lot more effective than PPDs [purified protein derivative skin tests]. Also, PPDs are difficult for patients who have a low rate of returning to have that test read.”
Terbinafine for onychomycosis
Dr. Kirby also discussed the rationale for ordering regular LFTs in patients taking terbinafine for onychomycosis. “There is a risk of drug-induced liver injury from taking terbinafine, but it’s rare,” she said. “Can we be thoughtful about which patients we expose?”
Evidence suggests that patients with hyperkeratosis greater than 2 mm, with nail matrix involvement, with 50% or more of the nail involved, or having concomitant peripheral vascular disease and diabetes are recalcitrant to treatment with terbinafine
(J Am Acad Dermatol. 2019 Apr;80[4]:853-67). “If we can frame this risk, then we can frame it for our patients,” she said. “We’re more likely to cause liver injury with an antibiotic. When it comes to an oral antifungal, itraconazole is more likely than terbinafine to cause liver injury. The rate of liver injury with terbinafine is only about 2 out of 100,000. It’s five times more likely with itraconazole and 21 times more likely with Augmentin.”
She recommends obtaining a baseline LFT in patients starting terbinafine therapy “to make sure their liver is normal from the start.” In addition, she advised, “let them know that there is a TB seroconversion risk of about 1 in 50,000 people, and that if it happens there would be symptomatic changes. They would maybe notice pruritus and have a darkening in their urine, and they’d have some flu-like symptoms, which would mean stop the drug and get some care.”
Dr. Kirby emphasized that a patient’s propensity for developing drug-induced liver injury from terbinafine use is not predictable from LFT monitoring. “What you’re more likely to find is an asymptomatic LFT rise in about 1% of people,” she said.
She disclosed that she has received honoraria from AbbVie, ChemoCentryx, Incyte, Janssen, Novartis, and UCB Pharma.
From time to time, Joslyn Kirby, MD, asks other physicians about their experience with certain medications used in dermatology, especially when something new hits the market.
“Sometimes I get an answer like, ‘The last time I used that medicine, my patient needed a liver transplant,’ ” Dr. Kirby, associate professor of dermatology, Penn State University, Hershey, said during the Orlando Dermatology Aesthetic and Clinical Conference. “It’s typically a story of something rare, uncommon, and awful. The challenge with an anecdote is that for all its power, it has a lower level of evidence. But it sticks with us and influences us more than a better level of evidence because it’s a situation and a story that we might relate to.”
Dr. Joslyn Kirby
Dr. Kirby said that when she thinks about managing side effects from drugs used in dermatology, it usually relates to something common and low-risk such as sore, dry skin with isotretinoin use. In contrast, if there is an uncommon but serious side effect, then mitigation rather than management is key. “I want to mitigate the risk – meaning warn my patient about it or be careful about how I select my patients when it is a serious side effect that happens infrequently,” she said. “The worst combination is a frequent and severe side effect. That is something we should avoid, for sure.”
Isotretinoin
But another aspect of prescribing a new drug for patients can be less clear-cut, Dr. Kirby continued, such as the rationale for routine lab monitoring. She began by discussing one of her male patients with moderate to severe acne. After he failed oral antibiotics and topical retinoids, she recommended isotretinoin, which carries a risk of hypertriglyceridemia-associated pancreatitis. “Early in my career, I was getting a lot of monthly labs in patients on this drug that were totally normal and not influencing my practice,” Dr. Kirby recalled. “We’ve seen studies coming out on isotretinoin lab monitoring, showing us that we can keep our patients safe and that we really don’t need to be checking labs as often, because lab changes are infrequent.”
In one of those studies, researchers evaluated 1,863 patients treated with isotretinoin for acne between Jan. 1, 2008, and June 30, 2017 (J Am Acad Dermatol. 2020 Jan;82[1]:72-9).Over time, fewer than 1% of patients screened developed grade 3 or greater triglyceride testing abnormalities, while fewer than 0.5% developed liver function testing (LFT) abnormalities. Authors of a separate systematic review concluded that for patients on isotretinoin therapy without elevated baseline triglycerides, or risk thereof, monitoring triglycerides is of little value (Br J Dermatol. 2017 Oct;177[4]:960-6). Of the 25 patients in the analysis who developed pancreatitis on isotretinoin, only 3 had elevated triglycerides at baseline.
“I was taught that I need to check triglycerides frequently due to the risk of pancreatitis developing with isotretinoin use,” Dr. Kirby said. “Lipid changes on therapy are expected, but they tend to peak early, meaning the first 3 months of treatment when we’re ramping up from a starting dose to a maintenance dose. It’s rare for somebody to be a late bloomer, meaning that they have totally normal labs in the first 3 months and then suddenly develop an abnormality. People are either going to demonstrate an abnormality early or not have one at all.”
When Dr. Kirby starts patients on isotretinoin, she orders baseline LFTs and a lipid panel and repeats them 60 days later. “If everything is fine or only mildly high, we don’t do more testing, only a review of systems,” she said. “This is valuable to our patients because fear of needles and fainting peak during adolescence.”
Spironolactone
The clinical use of regularly monitoring potassium levels in young women taking spironolactone for acne has also been questioned. The drug has been linked to an increased risk for hyperkalemia, but the prevalence is unclear. “I got a lot of normal potassium levels in these patients [when] I was in training and I really questioned, ‘Why am I doing this? What is the rationale?’ ” Dr. Kirby said.
In a study that informed her own practice, researchers reviewed the rate of hyperkalemia in 974 healthy young women taking spironolactone for acne or for an endocrine disorder with associated acne between Dec. 1, 2000, and March 31, 2014 (JAMA Dermatol. 2015 Sep;151[9]:941-4). Of the total of 1,802 serum potassium measurements taken during treatment, 13 (0.72%) were mildly elevated levels and none of the patients had a potassium level above 5.5 mEq/L. Retesting within 1 to 3 weeks in 6 of 13 patients with elevated levels found that potassium levels were normal. “The recommendation for spironolactone in healthy women is not to check the potassium level,” Dr. Kirby said, adding that she does counsel patients about the risk of breast tenderness (which can occur 5% to 40% of the time) and spotting (which can occur in 10% to 20% of patients). Gynecomastia can occur in 10% to 30% of men, which is one of the reasons she does not use spironolactone in male patients.
TB testing and biologics
Whether or not to test for TB in patients with psoriasis taking biologic therapies represents another conundrum, she continued. Patients taking biologics are at risk of reactivation of latent TB infection, but in her experience, package inserts contain language like “perform TB testing at baseline, then periodically,” or “use at baseline, then with active TB symptoms,” and “after treatment is discontinued.”
“What the inserts didn’t recommend was to perform TB testing every year, which is what my routine had been,” Dr. Kirby said. “In the United States, thankfully we don’t have a lot of TB.” In a study that informed her own practice, researchers at a single academic medical center retrospectively reviewed the TB seroconversion rate among 316 patients treated with second-generation biologics (J Am Acad Dermatol. 2020 Oct 1;S0190-9622[20]32676-1. doi: 10.1016/j.jaad.2020.09.075). It found that only six patients (2%) converted and had a positive TB test later during treatment with the biologic. “Of these six people, all had grown up outside the U.S., had traveled outside of the U.S., or were in a group living situation,” said Dr. Kirby, who was not affiliated with the study.
“This informs our rationale for how we can do this testing. If insurance requires it every year, fine. But if they don’t, I ask patients about travel, about their living situation, and how they’re feeling. If everything’s going great, I don’t order TB testing. I do favor the interferon-gamma release assays because they’re a lot more effective than PPDs [purified protein derivative skin tests]. Also, PPDs are difficult for patients who have a low rate of returning to have that test read.”
Terbinafine for onychomycosis
Dr. Kirby also discussed the rationale for ordering regular LFTs in patients taking terbinafine for onychomycosis. “There is a risk of drug-induced liver injury from taking terbinafine, but it’s rare,” she said. “Can we be thoughtful about which patients we expose?”
Evidence suggests that patients with hyperkeratosis greater than 2 mm, with nail matrix involvement, with 50% or more of the nail involved, or having concomitant peripheral vascular disease and diabetes are recalcitrant to treatment with terbinafine
(J Am Acad Dermatol. 2019 Apr;80[4]:853-67). “If we can frame this risk, then we can frame it for our patients,” she said. “We’re more likely to cause liver injury with an antibiotic. When it comes to an oral antifungal, itraconazole is more likely than terbinafine to cause liver injury. The rate of liver injury with terbinafine is only about 2 out of 100,000. It’s five times more likely with itraconazole and 21 times more likely with Augmentin.”
She recommends obtaining a baseline LFT in patients starting terbinafine therapy “to make sure their liver is normal from the start.” In addition, she advised, “let them know that there is a TB seroconversion risk of about 1 in 50,000 people, and that if it happens there would be symptomatic changes. They would maybe notice pruritus and have a darkening in their urine, and they’d have some flu-like symptoms, which would mean stop the drug and get some care.”
Dr. Kirby emphasized that a patient’s propensity for developing drug-induced liver injury from terbinafine use is not predictable from LFT monitoring. “What you’re more likely to find is an asymptomatic LFT rise in about 1% of people,” she said.
She disclosed that she has received honoraria from AbbVie, ChemoCentryx, Incyte, Janssen, Novartis, and UCB Pharma.
Sixteen dysregulated genes strongly characterize hidradenitis suppurativa (HS), Andre da Costa, PhD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.
He presented highlights of a multicenter translational study, which utilized whole transcriptome analysis of lesional and nonlesional skin from patients with HS and normal controls along with quantitative real-time PCR and immunohistochemistry. The purpose was to further define the molecular taxonomy of this inflammatory disease. And while this objective was achieved, the results also underscored a truism regarding the painful and scarring disease: “HS is characterized by an ever-growing complexity, which translates into multiple potential mechanistic drivers,” observed Dr. da Costa, head of immunology precision medicine at AstraZeneca in Gothenburg, Sweden.
Indeed, the study identified a panel of immune-related drivers in HS that influence innate immunity and cell differentiation in follicular and epidermal keratinocytes. The research by Dr. da Costa and coinvestigators identified a broad array of promising novel therapeutic targets in HS.
“Our findings provide evidence of an inflammatory process coupled with impaired barrier function, altered epidermal cell differentiation, and possibly abnormal microbiome activity which can be seen at the follicular and epidermal keratinocytes and also to a minor degree at the level of the skin glands,” Dr. da Costa said.
There is a huge unmet need for new therapies for HS, since at present adalimumab (Humira) is the only approved medication for this debilitating inflammatory disease. Some good news that emerged from this translational study is that some of the novel molecular mediators implicated in HS are targeted by multiple Food and Drug Administration–approved therapies that have other indications. From a drug development standpoint, repurposing a commercially available drug for a novel indication is a much more efficient and less costly endeavor than is necessary to establish the safety and efficacy of an unproven new agent.
The translational work demonstrated that the proteins calgranulin-A and -B and serpin-B4 were strongly expressed in the hair root sheaths of patients with HS. Connexin-32 and koebnerisin were present in stratum granulosum, matrix metallopeptidase-9 was strongly expressed in resident monocytes, small prolin-rich protein 3 in apocrine sweat glands and ducts as well as in sebaceous glands and ducts, and transcobalamin-1 was prominent in stratum spinosum.
Of the 19 key molecular mediators of HS identified in the study, FDA-approved agents are already available that target 12 of them. For example, apremilast (Otezla) targets interferon-gamma and tumor necrosis factor–alpha. Gentamicin targets growth arrest-specific 6 (GAS6) and interleukin-17 (IL-17). Secukinumab (Cosentyx) and ixekizumab (Taltz) target IL-17A, and brodalumab (Siliq) more broadly targets IL-17A as well as all the other IL-17 receptors. Thalidomide targets hepatocyte growth factor (HGF) and TNF-alpha. Spironolactone targets androgen receptor (AR) and TNF-alpha. Colchicine targets tubulin. Anakinra (Kineret) homes in on the IL-1 receptor. And prednisone targets NFxB.
Other key molecular mediators of HS, which are targeted by commercially available drugs, include epidermal growth factor (EGF), macrophage colony-stimulating factor (MCSF), epiregulin (EREG), fibroblast growth factor 1 (FGF1), FGF2, insulin-like growth factor 2 (IGF2), and IL-6, according to Dr. da Costa.
In addition, clinical trials are underway in HS involving totally investigational agents, including several Janus kinase inhibitors and tyrosine kinase 2 inhibitors.
The work described by Dr. da Costa had multiple funding sources, including the European Hidradenitis Suppurativa Foundation, the University of Copenhagen, the Icahn School of Medicine at Mount Sinai, AstraZeneca, and the German Federal Ministry of Education and Research. Dr. da Costa is an employee of AstraZeneca, Gothenburg, Sweden.
Sixteen dysregulated genes strongly characterize hidradenitis suppurativa (HS), Andre da Costa, PhD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.
He presented highlights of a multicenter translational study, which utilized whole transcriptome analysis of lesional and nonlesional skin from patients with HS and normal controls along with quantitative real-time PCR and immunohistochemistry. The purpose was to further define the molecular taxonomy of this inflammatory disease. And while this objective was achieved, the results also underscored a truism regarding the painful and scarring disease: “HS is characterized by an ever-growing complexity, which translates into multiple potential mechanistic drivers,” observed Dr. da Costa, head of immunology precision medicine at AstraZeneca in Gothenburg, Sweden.
Indeed, the study identified a panel of immune-related drivers in HS that influence innate immunity and cell differentiation in follicular and epidermal keratinocytes. The research by Dr. da Costa and coinvestigators identified a broad array of promising novel therapeutic targets in HS.
“Our findings provide evidence of an inflammatory process coupled with impaired barrier function, altered epidermal cell differentiation, and possibly abnormal microbiome activity which can be seen at the follicular and epidermal keratinocytes and also to a minor degree at the level of the skin glands,” Dr. da Costa said.
There is a huge unmet need for new therapies for HS, since at present adalimumab (Humira) is the only approved medication for this debilitating inflammatory disease. Some good news that emerged from this translational study is that some of the novel molecular mediators implicated in HS are targeted by multiple Food and Drug Administration–approved therapies that have other indications. From a drug development standpoint, repurposing a commercially available drug for a novel indication is a much more efficient and less costly endeavor than is necessary to establish the safety and efficacy of an unproven new agent.
The translational work demonstrated that the proteins calgranulin-A and -B and serpin-B4 were strongly expressed in the hair root sheaths of patients with HS. Connexin-32 and koebnerisin were present in stratum granulosum, matrix metallopeptidase-9 was strongly expressed in resident monocytes, small prolin-rich protein 3 in apocrine sweat glands and ducts as well as in sebaceous glands and ducts, and transcobalamin-1 was prominent in stratum spinosum.
Of the 19 key molecular mediators of HS identified in the study, FDA-approved agents are already available that target 12 of them. For example, apremilast (Otezla) targets interferon-gamma and tumor necrosis factor–alpha. Gentamicin targets growth arrest-specific 6 (GAS6) and interleukin-17 (IL-17). Secukinumab (Cosentyx) and ixekizumab (Taltz) target IL-17A, and brodalumab (Siliq) more broadly targets IL-17A as well as all the other IL-17 receptors. Thalidomide targets hepatocyte growth factor (HGF) and TNF-alpha. Spironolactone targets androgen receptor (AR) and TNF-alpha. Colchicine targets tubulin. Anakinra (Kineret) homes in on the IL-1 receptor. And prednisone targets NFxB.
Other key molecular mediators of HS, which are targeted by commercially available drugs, include epidermal growth factor (EGF), macrophage colony-stimulating factor (MCSF), epiregulin (EREG), fibroblast growth factor 1 (FGF1), FGF2, insulin-like growth factor 2 (IGF2), and IL-6, according to Dr. da Costa.
In addition, clinical trials are underway in HS involving totally investigational agents, including several Janus kinase inhibitors and tyrosine kinase 2 inhibitors.
The work described by Dr. da Costa had multiple funding sources, including the European Hidradenitis Suppurativa Foundation, the University of Copenhagen, the Icahn School of Medicine at Mount Sinai, AstraZeneca, and the German Federal Ministry of Education and Research. Dr. da Costa is an employee of AstraZeneca, Gothenburg, Sweden.
Sixteen dysregulated genes strongly characterize hidradenitis suppurativa (HS), Andre da Costa, PhD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.
He presented highlights of a multicenter translational study, which utilized whole transcriptome analysis of lesional and nonlesional skin from patients with HS and normal controls along with quantitative real-time PCR and immunohistochemistry. The purpose was to further define the molecular taxonomy of this inflammatory disease. And while this objective was achieved, the results also underscored a truism regarding the painful and scarring disease: “HS is characterized by an ever-growing complexity, which translates into multiple potential mechanistic drivers,” observed Dr. da Costa, head of immunology precision medicine at AstraZeneca in Gothenburg, Sweden.
Indeed, the study identified a panel of immune-related drivers in HS that influence innate immunity and cell differentiation in follicular and epidermal keratinocytes. The research by Dr. da Costa and coinvestigators identified a broad array of promising novel therapeutic targets in HS.
“Our findings provide evidence of an inflammatory process coupled with impaired barrier function, altered epidermal cell differentiation, and possibly abnormal microbiome activity which can be seen at the follicular and epidermal keratinocytes and also to a minor degree at the level of the skin glands,” Dr. da Costa said.
There is a huge unmet need for new therapies for HS, since at present adalimumab (Humira) is the only approved medication for this debilitating inflammatory disease. Some good news that emerged from this translational study is that some of the novel molecular mediators implicated in HS are targeted by multiple Food and Drug Administration–approved therapies that have other indications. From a drug development standpoint, repurposing a commercially available drug for a novel indication is a much more efficient and less costly endeavor than is necessary to establish the safety and efficacy of an unproven new agent.
The translational work demonstrated that the proteins calgranulin-A and -B and serpin-B4 were strongly expressed in the hair root sheaths of patients with HS. Connexin-32 and koebnerisin were present in stratum granulosum, matrix metallopeptidase-9 was strongly expressed in resident monocytes, small prolin-rich protein 3 in apocrine sweat glands and ducts as well as in sebaceous glands and ducts, and transcobalamin-1 was prominent in stratum spinosum.
Of the 19 key molecular mediators of HS identified in the study, FDA-approved agents are already available that target 12 of them. For example, apremilast (Otezla) targets interferon-gamma and tumor necrosis factor–alpha. Gentamicin targets growth arrest-specific 6 (GAS6) and interleukin-17 (IL-17). Secukinumab (Cosentyx) and ixekizumab (Taltz) target IL-17A, and brodalumab (Siliq) more broadly targets IL-17A as well as all the other IL-17 receptors. Thalidomide targets hepatocyte growth factor (HGF) and TNF-alpha. Spironolactone targets androgen receptor (AR) and TNF-alpha. Colchicine targets tubulin. Anakinra (Kineret) homes in on the IL-1 receptor. And prednisone targets NFxB.
Other key molecular mediators of HS, which are targeted by commercially available drugs, include epidermal growth factor (EGF), macrophage colony-stimulating factor (MCSF), epiregulin (EREG), fibroblast growth factor 1 (FGF1), FGF2, insulin-like growth factor 2 (IGF2), and IL-6, according to Dr. da Costa.
In addition, clinical trials are underway in HS involving totally investigational agents, including several Janus kinase inhibitors and tyrosine kinase 2 inhibitors.
The work described by Dr. da Costa had multiple funding sources, including the European Hidradenitis Suppurativa Foundation, the University of Copenhagen, the Icahn School of Medicine at Mount Sinai, AstraZeneca, and the German Federal Ministry of Education and Research. Dr. da Costa is an employee of AstraZeneca, Gothenburg, Sweden.
Many women with hidradenitis suppurativa have pregnancy-related concerns that go unaddressed by their doctors, according to a study that surveyed 59 women with HS.
Previous studies have shown the potential for adverse pregnancy outcomes associated with inflammatory conditions such as systemic vasculitis and lupus, but such data on HS and pregnancy are limited, which makes patient counseling a challenge, Ademide A. Adelekun, MD, of the University of Pennsylvania, Philadelphia, and colleagues wrote.
In a research letter published in JAMA Dermatology, they reported their findings from an email survey of female patients at two academic dermatology departments. A total of 59 women responded to the survey; their average age was 32 years, the majority (76%) had Hurley stage II disease, and 29 (49%) reported having ever been pregnant.
Two of the 29 women (7%) were pregnant at the time of the study survey; 20 of the other 27 pregnant women (74%) said they had full-term births, 4 (15%) reported miscarriages, and 3 (11%) had undergone an abortion.
A total of five patients (9%) reported difficulty getting pregnant after 1 year, and seven (12%) reported undergoing fertility treatments.
Nearly three-quarters of the women (73%) reported that HS had a negative impact on their sexual health, and 54% said they wished their doctors provided more counseling on HS and pregnancy.
A total of 14 patients (24%) said they believed HS affected their ability to become pregnant because of either decreased sexual activity or decreased fertility caused by HS medications, and nearly half (49%) said they believed that discontinuing all HS medications during pregnancy was necessary for safety reasons.
Patients also expressed concern about the possible heritability of HS: 80% said that physicians had not counseled them about HS heritability and 68% expressed concern that their child would have HS.
In addition, 83% said they had not received information about the potential impact of HS on pregnancy, and 22%, or 13 women, were concerned that childbirth would be more difficult; 11 of these 13 women (85%) had HS that affected the vulva and groin, and 4 of the 8 women who reported concerns about difficulty breastfeeding had HS that involved the breast.
Of the 59 patients surveyed, 12 (20%) said they believed HS poses risks to the child, including through transmission of HS in 8 (67%) or through an infection during a vaginal delivery in 7 women (58%).
The prevalence of HS patients’ concerns about pregnancy “may have unfavorable implications for family planning and mental health and may play a role in the inadequate treatment of HS in patients who are pregnant or planning to become pregnant,” the authors noted. “Family planning and prenatal counseling are particularly critical for those with HS given that clinicians weigh the risks of medication use against the benefits of disease control, which is associated with improved pregnancy outcomes for those with inflammatory conditions.”
The study findings were limited by several factors including “recall bias, low response rate, use of a nonvalidated survey, and generalizability to nonacademic settings,” the researchers noted. However, the results emphasize the often-underrecognized concerns of women with HS and the need for improvements in pregnancy-related counseling and systematic evaluation of outcomes.
The researchers had no financial conflicts to disclose. This study was funded by a FOCUS Medical Student Fellowship in Women’s Health grant.
Many women with hidradenitis suppurativa have pregnancy-related concerns that go unaddressed by their doctors, according to a study that surveyed 59 women with HS.
Previous studies have shown the potential for adverse pregnancy outcomes associated with inflammatory conditions such as systemic vasculitis and lupus, but such data on HS and pregnancy are limited, which makes patient counseling a challenge, Ademide A. Adelekun, MD, of the University of Pennsylvania, Philadelphia, and colleagues wrote.
In a research letter published in JAMA Dermatology, they reported their findings from an email survey of female patients at two academic dermatology departments. A total of 59 women responded to the survey; their average age was 32 years, the majority (76%) had Hurley stage II disease, and 29 (49%) reported having ever been pregnant.
Two of the 29 women (7%) were pregnant at the time of the study survey; 20 of the other 27 pregnant women (74%) said they had full-term births, 4 (15%) reported miscarriages, and 3 (11%) had undergone an abortion.
A total of five patients (9%) reported difficulty getting pregnant after 1 year, and seven (12%) reported undergoing fertility treatments.
Nearly three-quarters of the women (73%) reported that HS had a negative impact on their sexual health, and 54% said they wished their doctors provided more counseling on HS and pregnancy.
A total of 14 patients (24%) said they believed HS affected their ability to become pregnant because of either decreased sexual activity or decreased fertility caused by HS medications, and nearly half (49%) said they believed that discontinuing all HS medications during pregnancy was necessary for safety reasons.
Patients also expressed concern about the possible heritability of HS: 80% said that physicians had not counseled them about HS heritability and 68% expressed concern that their child would have HS.
In addition, 83% said they had not received information about the potential impact of HS on pregnancy, and 22%, or 13 women, were concerned that childbirth would be more difficult; 11 of these 13 women (85%) had HS that affected the vulva and groin, and 4 of the 8 women who reported concerns about difficulty breastfeeding had HS that involved the breast.
Of the 59 patients surveyed, 12 (20%) said they believed HS poses risks to the child, including through transmission of HS in 8 (67%) or through an infection during a vaginal delivery in 7 women (58%).
The prevalence of HS patients’ concerns about pregnancy “may have unfavorable implications for family planning and mental health and may play a role in the inadequate treatment of HS in patients who are pregnant or planning to become pregnant,” the authors noted. “Family planning and prenatal counseling are particularly critical for those with HS given that clinicians weigh the risks of medication use against the benefits of disease control, which is associated with improved pregnancy outcomes for those with inflammatory conditions.”
The study findings were limited by several factors including “recall bias, low response rate, use of a nonvalidated survey, and generalizability to nonacademic settings,” the researchers noted. However, the results emphasize the often-underrecognized concerns of women with HS and the need for improvements in pregnancy-related counseling and systematic evaluation of outcomes.
The researchers had no financial conflicts to disclose. This study was funded by a FOCUS Medical Student Fellowship in Women’s Health grant.
Many women with hidradenitis suppurativa have pregnancy-related concerns that go unaddressed by their doctors, according to a study that surveyed 59 women with HS.
Previous studies have shown the potential for adverse pregnancy outcomes associated with inflammatory conditions such as systemic vasculitis and lupus, but such data on HS and pregnancy are limited, which makes patient counseling a challenge, Ademide A. Adelekun, MD, of the University of Pennsylvania, Philadelphia, and colleagues wrote.
In a research letter published in JAMA Dermatology, they reported their findings from an email survey of female patients at two academic dermatology departments. A total of 59 women responded to the survey; their average age was 32 years, the majority (76%) had Hurley stage II disease, and 29 (49%) reported having ever been pregnant.
Two of the 29 women (7%) were pregnant at the time of the study survey; 20 of the other 27 pregnant women (74%) said they had full-term births, 4 (15%) reported miscarriages, and 3 (11%) had undergone an abortion.
A total of five patients (9%) reported difficulty getting pregnant after 1 year, and seven (12%) reported undergoing fertility treatments.
Nearly three-quarters of the women (73%) reported that HS had a negative impact on their sexual health, and 54% said they wished their doctors provided more counseling on HS and pregnancy.
A total of 14 patients (24%) said they believed HS affected their ability to become pregnant because of either decreased sexual activity or decreased fertility caused by HS medications, and nearly half (49%) said they believed that discontinuing all HS medications during pregnancy was necessary for safety reasons.
Patients also expressed concern about the possible heritability of HS: 80% said that physicians had not counseled them about HS heritability and 68% expressed concern that their child would have HS.
In addition, 83% said they had not received information about the potential impact of HS on pregnancy, and 22%, or 13 women, were concerned that childbirth would be more difficult; 11 of these 13 women (85%) had HS that affected the vulva and groin, and 4 of the 8 women who reported concerns about difficulty breastfeeding had HS that involved the breast.
Of the 59 patients surveyed, 12 (20%) said they believed HS poses risks to the child, including through transmission of HS in 8 (67%) or through an infection during a vaginal delivery in 7 women (58%).
The prevalence of HS patients’ concerns about pregnancy “may have unfavorable implications for family planning and mental health and may play a role in the inadequate treatment of HS in patients who are pregnant or planning to become pregnant,” the authors noted. “Family planning and prenatal counseling are particularly critical for those with HS given that clinicians weigh the risks of medication use against the benefits of disease control, which is associated with improved pregnancy outcomes for those with inflammatory conditions.”
The study findings were limited by several factors including “recall bias, low response rate, use of a nonvalidated survey, and generalizability to nonacademic settings,” the researchers noted. However, the results emphasize the often-underrecognized concerns of women with HS and the need for improvements in pregnancy-related counseling and systematic evaluation of outcomes.
The researchers had no financial conflicts to disclose. This study was funded by a FOCUS Medical Student Fellowship in Women’s Health grant.
Psychiatrists with expertise in delusional infestation have some advice for dermatologists, infectious disease specialists, and primary care physicians who encounter affected patients: If you want to try to help them, initiate treatment yourself.
Dr. Peter Lepping
“If you see it, try and treat it. These patients are unlikely to agree to see a psychiatrist,” Peter Lepping, MD, said at the Entomology 2020 annual meeting.
Indeed, one of the hallmarks of delusional infestation (DI) is a refusal to even consider referral to a mental health professional, noted Dr. Lepping, a consultation-liaison psychiatrist at Bangor (Wales) University who, together with an infectious disease specialist, codirects one of the world’s few DI multispecialty referral clinics, located at the University of Liverpool School of Tropical Medicine.
That being said, he offered another piece of advice: “Accept that it is not easy to help these patients.”
Dr. Lepping was among a group of distinguished psychiatrists, dermatologists, entomologists, and a neurologist at the annual meeting who participated in a comprehensive session devoted to DI. The experts shared tips on making the diagnosis, establishing the rapport necessary to persuade affected patients to try taking a very-low-dose antipsychotic agent for their delusion, and how to achieve a high rate of therapeutic success. They also highlighted recent research advances in the field, including brain MRI evidence suggesting that impaired somatosensory neural networks mediate symptoms in DI, but not in nonsomatic delusional disorders.
COVID-19 pandemic triggers surge in DI
Entomologist Gail E. Ridge, PhD, has taken notes on all of her thousands of consultations with individuals with suspected DI since the late 1990s. A sharp jump in such contacts occurred during the Great Recession of 2008 in conjunction with the widespread social distress of job loss and threatened economic ruin. Now the same thing is happening as the catastrophic COVID-19 pandemic stretches on. Indeed, during the first 8 months of the pandemic she documented 500 interactions involving people with suspected DI. She’s learned to identify the clues, including a chattering mind, defensiveness, physician avoidance, and rigid body tension.
Courtesy Dr. Gale E. Ridge
Dr. Gale E. Ridge
“They’re fearful of judgment and suggestions of madness. And they’ll pounce on any perceived negativity. I never debunk beliefs; that can immediately backfire. If the medical profession was educated about DI, then many cases could be caught early. I, as the entomologist, and the mental health professionals are often last in line to be seen,” said Dr. Ridge, director of the Insect Information Office at the Connecticut Agricultural Experiment Station in New Haven.
She has noticed a recurring theme in her interactions with these patients: DI often starts with a real underlying medical condition, such as, for example, a cutaneous drug reaction, which over time, progresses to gain a psychiatric component. And she has found that a tipping point often occurs after roughly 6 months of unrelieved symptoms and sensations. Prior to that, affected individuals are concerned about their condition and will seek medical help in a genuine effort to understand what’s going on. They can be redirected. After about 6 months, however, Dr. Ridge has observed “they slide into the rabbit hole of fanaticism and despair.”
Arriving at the diagnosis
In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), DI is classified as a “delusional disorder, somatic type 297.1 F22.” The diagnosis requires that the delusion be present for at least 1 month, criteria for schizophrenia are not met, and the condition cannot be attributed to other medical or neuropsychiatric conditions.
“Many of these people are very high-functioning. I have corporate CEOs who fly in to see me in their private jets. At work, they’re king of their domain. At home, their family is falling apart because of their delusion,” said Dirk M. Elston, MD, professor and chair of the department of dermatology and dermatologic surgery at the Medical University of South Carolina, Charleston.
Dr. Dirk M. Elston
“These people suffer, and the people around them suffer,” he emphasized.
Dozens of medical conditions can cause intractable itching or biting sensations. Far and away at the top of the medical differential diagnosis is thyroid disease, given its high incidence and frequent presentation with anxiety and itch. Other possibilities that can readily be ruled out via lab tests include substance use – especially involving amphetamine/methamphetamine, cocaine, or opioids – liver or kidney disease, diabetes and other sources of peripheral neuropathy, polycythemia, dermatitis herpetiformis, and pemphigus, Dr. Elston said.
Scott A. Norton, MD, MPH, MSc, a dermatologist and preventive medicine specialist at the Uniformed Services University of the Health Sciences in Bethesda, Md., noted that a diagnosis of DI requires three elements: The presence of abnormal sensations in the skin, a patient’s tenacious conviction that the sensations are caused by an infestation, and a lack of supporting evidence for that conviction.
Dr. Scott A. Norton
Taking an accurate medical history can be a challenge in these patients because they are often so guarded. They won’t disclose that they’ve already seen other health care providers, or that they’ve been self-treating with OTC veterinary medicine products, such as high-dose topical or oral ivermectin. They’ll often even deny repeated scratching despite clear evidence to the contrary from the skin exam.
As a dermatologist, Dr. Norton considers his first task to be a search for evidence of an infestation. Scabies is usually the first diagnosis proposed to account for the uncomfortable skin sensations. The presentation can be subtle. While the classic teaching is that the telltale signs of infestation by Sarcoptes scabiei are burrows in the skin and a rash in the web spaces between the fingers, he finds these features are often absent or equivocal.
“I think there are two more reliable presentations of scabies: Check to see if there’s symmetric involvement of the volar or palm side of the wrists; if there isn’t, I’m skeptical of the diagnosis. And every male older than 1 year of age with scabies will have scabies nodules on their genitalia. If the penis, the glans, or the scrotum aren’t involved with the nodules, I discard scabies as a possible diagnosis and look for evidence of other skin conditions that can plausibly explain the sensations and skin lesions, like eczema, contact dermatitis, scalp folliculitis, or dry skin,” he said.
If he can’t find evidence of infestation, he next systematically looks for another dermatologic cause of the patient’s sensations. When that proves fruitless, he tries to determine if there might be a biomedical or neuropsychiatric cause, such as depression, anxiety, schizophrenia, or dementia.
Taking a personal hygiene history is helpful. Patients who believe they have an infestation may bathe or shower three to five times daily with harsh soaps, causing dry, inflamed, itchy and uncomfortable skin.
“Many patients are thrilled to hear the good news that the history, physical examination, and lab tests do not show an infestation and that we have another explanation to account for their unwanted sensations. However, there are some patients who vehemently reject that idea and immediately return to their unwavering, unalterable belief that they are in fact infested. At this point, the possible diagnosis of DI looms large,” the dermatologist said.
Clues suggestive of DI include a patient’s obsessive focus on collecting “specimens” of the offending pathogen in Ziplock bags for assessment during the office visit – “usually a mix of unhelpful household debris and environmental detritus” – and eager presentation of a lengthy and detailed infestation diary, Dr. Norton said.
“Among the most distinctive signs that the patient is detached from reality are the biologically implausible descriptions and explanations of the supposed attacking organism. It’s a fanciful amalgamation of mutable features, behaviors, and life cycles composed of a composite of taxonomically unrelated organisms – for example, fungal hyphae with wings – that shapeshift at will to evade detection,” he said.
Dr. Elston observed that DI skin lesions are typically excoriated, sometimes because of a patient’s systematic use of a sharp object in an effort to dig out the infestation.
“One of the clues is the angularity of the lesion,” the dermatologist noted. “We always say round-to-oval lesions suggest an inside job; angulated lesions suggest an outside job, like fingernail work. There’s often a row of good healing border showing there’s really nothing wrong with wound healing, but a fibrinoid base where the excoriations have occurred. And the lesions are often in various stages of healing.”
Don’t forget neuropathic itch in nondelusional individuals as a potential cause of sensations of infestation and self-injury due to relentless scratching, urged Anne Louise Oaklander, MD, PhD, associate professor of neurology, Harvard Medical School, Boston, who is director of the nerve unit and the neurodiagnostic skin biopsy lab at Massachusetts General Hospital, Boston.
Dr. Anne Louise Oaklander
“There’s no one cause of patients’ impressions that they may have insects. Let’s be sympathetic: It is a normal assumption that insects may be present if the skin itches. One problem is that when patients don’t get good medical diagnoses they make up their own explanations, and sometimes these include persistent ideas of infestation. Many of them don’t realize that their scratching is a cause, not a result, of their skin lesions,” said Dr. Oaklander, who has conducted pioneering research on unintentional self-injury due to neuropathic itch accompanied by loss of pain signaling.
“Rapport first, medication later”
“The office visits are typically difficult to conclude, but skills can be learned and make it much easier to help these people,” Dr. Elston said.
John Koo, MD, emphasized that establishing rapport is “by far” the most important part of managing patients with DI.
Dr. John Koo
“Rapport first, medication later. This may require multiple visits,” said Dr. Koo, professor of dermatology at the University of California, San Francisco, who is a board-certified psychiatrist.
He makes sure he walks into the examination room all smiles and positivity. Patients with DI are eager to expound on their ailment; he lets them talk for a while, then when the timing is right, he actively encourages them to shift their focus away from etiology to treatment.
Dr. Koo and coworkers have described a spectrum of mental fixation in DI ranging from having only crawling and biting sensations, progressing to holding an overvalued idea as to their cause, then on to DSM-5 somatic preoccupation, followed by becoming truly delusional, and finally terminal delusion, where the patient doesn’t care about getting better, but only wants the physician to agree there is an infestation (J Clin Exp Dermatol Res. 2014 Oct. 3. doi: 10.4172/2155-9554.1000241).
“You cannot argue with people with delusions. How you talk to them as a clinician depends on whether they are entirely delusional or not,” he advised. “I cannot agree with their ideation, but I can agree with their misery – and that’s how I make a connection.”
Declining a DI patient’s request for a skin biopsy when it’s obvious there is no infestation can lead to a counterproductive power struggle. Instead, Dr. Koo turns the patient request into an opportunity to form a verbal contract: “I ask, ‘If the result comes back negative, can you be open-minded about the possibility of other etiologies besides parasites?’ ”
As for Dr. Norton, when his schedule shows a patient is coming in for a first visit for a supposed skin infestation, he tells his staff to expect a lengthy session as he works at establishing a good relationship.
“When my patients arrive with bags of specimens, I ask them to select two or three that they’re most confident will have a creature in them. Then I bring a two-headed microscope into the exam room and ask the patient to join me in examining the material. It helps with rapport by showing that I genuinely want to determine if there’s an infestation,” he explained.
He then sends the specimens to a laboratory, which provides a full report of the findings.
In performing a skin biopsy in a patient with suspected DI, Dr. Norton routinely biopsies two sites so the patient can’t claim sampling error when the pathology report comes back with no pathogens or parasites found. Also, he asks the patient to choose biopsy sites with intact skin where he or she believes the infestation exists. There is no point in biopsying excoriated lesions because they often contain snagged textile fibers.
Another rapport-building strategy: “I try to design a treatment regimen that will palliate the uncomfortable sensations and help relieve the patient’s misery while we continue working towards treating those delusions,” Dr. Norton said.
This might entail cutting back to one lukewarm shower per day with gentle or no soap, coupled with moisturizing, oral antihistamines or doxepin for itch, topical corticosteroids for the associated inflammation, and oral or topical antibiotics for any secondary bacterial skin infection.
What he doesn’t recommend as a rapport-building strategy or simply in order to get the patient out of the office is offering a therapeutic trial of an antiparasitic agent. That’s counterproductive. It may reinforce the false belief of infestation, and when the medication doesn’t bring lasting belief, the patient may conclude the infestation is resistant to conventional treatment.
Dr. Koo tells affected patients that he suspects they have Morgellons syndrome. He doesn’t call it DI in their presence.
“These people would not like their condition to be called delusional,” he explained. “Morgellons is a more neutral term. I tell them it’s a mysterious condition, and that what I’m really interested in is in trying to get them out of their misery.”
Treatment tips
Dr. Koo’s first-line medication for DI is pimozide (Orap), which in the United States has the advantage of being approved only for Tourette syndrome; it’s an antipsychotic without the perceived stigma of a psychiatric indication.
“Many of these patients will not consider taking any medication that has any psychiatric indication,” he noted.
Low-dose pimozide is highly effective, according to Dr. Koo, who recommends starting at 0.5 mg to 1 mg/day, increasing by 0.5 mg/day every 2-4 weeks. The drug is usually effective at a dose of 3 mg/day or less. Once a patient’s symptoms become clear or almost clear, the patient is maintained on that dose for another 3-4 months, then tapered by 0.5 mg/day every 2-4 weeks.
“In 35 years of seeing a new patient on average every week or two, I’ve had only five patients with one recurrence and one patient with two recurrences. All six responded to repeat therapy,” Dr. Koo said.
Side effects at these low doses are “very rare,” he added. Diphenhydramine (Benadryl) at 25 mg up to four times daily is effective for complaints of stiffness or restlessness. Prolongation of the QT interval is a potential concern, but Dr. Koo has never encountered it despite routinely ordering ECGs for patients on pimozide with known heart disease or who are over age 50.
When a patient can’t tolerate pimozide, Dr. Koo’s second-line antipsychotic for DI is low-dose risperidone (Risperdal), which is also highly effective.
Dr. Lepping noted that the European situation is different. There, unlike in the United States, pimozide has regulatory approval as an antipsychotic, so it loses the advantage of being an under-the-radar neuroleptic. His go-to medication is the first-generation antipsychotic sulpiride (Dogmatil), which he finds has a more favorable side effect profile than pimozide, particularly in the elderly. (Sulpiride is not approved in the United States.)
In treating DI, he prefers more dopaminergic-focused antipsychotics over those covering a broader spectrum of receptors. His alternatives to sulpiride include risperidone and olanzapine, atypical antipsychotics. He explains to patients that just as aspirin is used in low doses for its antiplatelet effect and in higher doses for pain relief, these medications can help them feel better at much lower doses than for schizophrenia.
“Once we get some rapport and a trusting relationship going, we normally try to persuade people to basically try something against their better judgment. We know that they don’t believe in it, but you try to get them to at least try something because everything else has failed,” Dr. Lepping explained. “We tell them it’s a condition we have seen before, and we have seen these medications to be useful because they are good for their distress, they help with making them calmer, and they might help with their symptoms. We say, ‘What do you have to lose if you trust us?’
“About 60% of our patients take the medication and almost invariably they all get better,” the psychiatrist said. “The others we either lose to follow-up or they just refuse to take the medication.”
A patient’s first visit to the Liverpool multispecialty DI referral clinic is 1 hour long. “They know that in advance, and we very much stick to that hour. We say to people up front, ‘We have an hour – that’s a lot, but we don’t have more,’ ” he said.
The initial visit is typically followed by two to four 30-minute follow-up visits. Dr. Lepping recommends that when possible, patients with DI should be seen jointly by a psychiatrist and a nonpsychiatrist physician. He finds this approach leads to substantially better clinical outcomes than with a single health care provider.
“If you have two people in the clinic with the patient, when you get really annoyed and your amygdala really starts going, that’s the time when you can then turn to your colleague and say, ‘Oh yes, and Professor Squire, what do you have to say to that?’ So as you see the red mist rising in yourself because you’re getting so exasperated, you have the other person there to take over so you can calm down. And then the other person does the same. That can be really important to deescalate a heated situation,” Dr. Lepping explained.
Roughly 10% of patients with DI have what is termed folie à deux, where the delusion of infestation is shared by another person.
“Anecdotally, I would say those are much more difficult to treat,” said Jason S. Reichenberg, MD, MBA, professor of medicine (dermatology) at the University of Texas at Austin and president of the Ascension Medical Group Texas.
Dr. Jason S. Reichenberg
“It’s like getting somebody to quit smoking when everybody else in the house is still smoking. It’s very hard to convince a single family member that they’re wrong when everybody else in their family keeps telling them they’re right,” he said.
Recent advances in DI research
Dr. Lepping and coinvestigators at multispecialist DI clinics in London, Italy, and Moscow reported in an unusually large observational study of 236 affected patients that longer duration of untreated psychosis was associated with significantly worse clinical outcome. It’s a finding consistent with Dr. Koo’s construct of progressive stages of delusionality, and it underscores the need for early treatment.
“Having said that, improvement is still possible, even if people have had quite a long time of untreated psychosis,” Dr. Lepping said. The same study also showed that older age at illness onset was inversely associated with good outcome.
In another study, Dr. Lepping and colleagues reported that substance use involving amphetamines, cocaine, opioids, and other drugs that can cause itch was roughly twice as common in a group of patients with DI compared to the general population. “I highly recommend, if at all possible, a drug screen in suspected DI,” he said.
In a large survey of U.S. and Canadian veterinarians, Dr. Lepping and coinvestigators found that these practitioners not infrequently encountered delusional infestation among pet owners who claimed their dog or cat is infested when it’s not. This is called “delusion by proxy,” and it often leads to unwarranted animal euthanasia. Some of these pet owners claim they, too, are infested, which the investigators termed “double delusional infestation.”
MRI studies
Recent structural brain MRI studies support the concept that impaired somatosensory neural networks mediate the delusional symptoms of DI, but not in delusional disorders without somatic content. This was demonstrated in an MRI study by Dr. Lepping and others conducted in 18 patients with DI, 19 others with nonsomatic delusional disorders centered on themes of persecution or jealousy, and 20 healthy volunteers. The DI group had lower gray matter volume in prefrontal, thalamic, striatal, and insular regions of the brain compared to the other two groups.
Of note, mapping of the insula and dorsal striatum indicates they are part of the peripersonal space network, which integrates tactile and visual perceptions involving the area near the body surface. The insula also mediates feelings of pain and disgust.
Some of the same investigators have also recently reported brain MRI evidence specifically of cerebellar dysfunction in patients with DI, who displayed decreased gray matter volume in left lobule VIIa of the cerebellum and increased gray matter volume in bilateral lobule VIIa/crus II compared to patients with non-somatic delusions. This points to a role for impaired cerebellar neural networks related to somatosensory perception in patients with DI but not in those with non-somatic delusions.
Delusional infestation: What’s in a name?
Ekbom syndrome. Delusional parasitosis. Morgellons syndrome. These and other terms are increasingly giving way to ‘delusional infestation’ as the preferred moniker for the disorder. That’s in part because the delusional focus in patients with this condition has shifted over time. In the 19th century, for example, affected patients often attributed their infestation to typhus.
In contemporary practice, roughly one-quarter of affected patients think they are infested by small inanimate objects, most commonly fibers or threads emerging from the skin, rather than by parasites, insects, or worms. In a study of 148 consecutive European patients with suspected DI, Dr. Lepping and coinvestigators reported only 35% believed they were infested by parasites.
“The name ‘delusional infestation’ emphasizes the constantly changing pathogens and covers all present and future variations of the theme that are bound to occur,” Dr. Lepping observed.
All speakers reported having no conflicts of interest.
Psychiatrists with expertise in delusional infestation have some advice for dermatologists, infectious disease specialists, and primary care physicians who encounter affected patients: If you want to try to help them, initiate treatment yourself.
Dr. Peter Lepping
“If you see it, try and treat it. These patients are unlikely to agree to see a psychiatrist,” Peter Lepping, MD, said at the Entomology 2020 annual meeting.
Indeed, one of the hallmarks of delusional infestation (DI) is a refusal to even consider referral to a mental health professional, noted Dr. Lepping, a consultation-liaison psychiatrist at Bangor (Wales) University who, together with an infectious disease specialist, codirects one of the world’s few DI multispecialty referral clinics, located at the University of Liverpool School of Tropical Medicine.
That being said, he offered another piece of advice: “Accept that it is not easy to help these patients.”
Dr. Lepping was among a group of distinguished psychiatrists, dermatologists, entomologists, and a neurologist at the annual meeting who participated in a comprehensive session devoted to DI. The experts shared tips on making the diagnosis, establishing the rapport necessary to persuade affected patients to try taking a very-low-dose antipsychotic agent for their delusion, and how to achieve a high rate of therapeutic success. They also highlighted recent research advances in the field, including brain MRI evidence suggesting that impaired somatosensory neural networks mediate symptoms in DI, but not in nonsomatic delusional disorders.
COVID-19 pandemic triggers surge in DI
Entomologist Gail E. Ridge, PhD, has taken notes on all of her thousands of consultations with individuals with suspected DI since the late 1990s. A sharp jump in such contacts occurred during the Great Recession of 2008 in conjunction with the widespread social distress of job loss and threatened economic ruin. Now the same thing is happening as the catastrophic COVID-19 pandemic stretches on. Indeed, during the first 8 months of the pandemic she documented 500 interactions involving people with suspected DI. She’s learned to identify the clues, including a chattering mind, defensiveness, physician avoidance, and rigid body tension.
Courtesy Dr. Gale E. Ridge
Dr. Gale E. Ridge
“They’re fearful of judgment and suggestions of madness. And they’ll pounce on any perceived negativity. I never debunk beliefs; that can immediately backfire. If the medical profession was educated about DI, then many cases could be caught early. I, as the entomologist, and the mental health professionals are often last in line to be seen,” said Dr. Ridge, director of the Insect Information Office at the Connecticut Agricultural Experiment Station in New Haven.
She has noticed a recurring theme in her interactions with these patients: DI often starts with a real underlying medical condition, such as, for example, a cutaneous drug reaction, which over time, progresses to gain a psychiatric component. And she has found that a tipping point often occurs after roughly 6 months of unrelieved symptoms and sensations. Prior to that, affected individuals are concerned about their condition and will seek medical help in a genuine effort to understand what’s going on. They can be redirected. After about 6 months, however, Dr. Ridge has observed “they slide into the rabbit hole of fanaticism and despair.”
Arriving at the diagnosis
In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), DI is classified as a “delusional disorder, somatic type 297.1 F22.” The diagnosis requires that the delusion be present for at least 1 month, criteria for schizophrenia are not met, and the condition cannot be attributed to other medical or neuropsychiatric conditions.
“Many of these people are very high-functioning. I have corporate CEOs who fly in to see me in their private jets. At work, they’re king of their domain. At home, their family is falling apart because of their delusion,” said Dirk M. Elston, MD, professor and chair of the department of dermatology and dermatologic surgery at the Medical University of South Carolina, Charleston.
Dr. Dirk M. Elston
“These people suffer, and the people around them suffer,” he emphasized.
Dozens of medical conditions can cause intractable itching or biting sensations. Far and away at the top of the medical differential diagnosis is thyroid disease, given its high incidence and frequent presentation with anxiety and itch. Other possibilities that can readily be ruled out via lab tests include substance use – especially involving amphetamine/methamphetamine, cocaine, or opioids – liver or kidney disease, diabetes and other sources of peripheral neuropathy, polycythemia, dermatitis herpetiformis, and pemphigus, Dr. Elston said.
Scott A. Norton, MD, MPH, MSc, a dermatologist and preventive medicine specialist at the Uniformed Services University of the Health Sciences in Bethesda, Md., noted that a diagnosis of DI requires three elements: The presence of abnormal sensations in the skin, a patient’s tenacious conviction that the sensations are caused by an infestation, and a lack of supporting evidence for that conviction.
Dr. Scott A. Norton
Taking an accurate medical history can be a challenge in these patients because they are often so guarded. They won’t disclose that they’ve already seen other health care providers, or that they’ve been self-treating with OTC veterinary medicine products, such as high-dose topical or oral ivermectin. They’ll often even deny repeated scratching despite clear evidence to the contrary from the skin exam.
As a dermatologist, Dr. Norton considers his first task to be a search for evidence of an infestation. Scabies is usually the first diagnosis proposed to account for the uncomfortable skin sensations. The presentation can be subtle. While the classic teaching is that the telltale signs of infestation by Sarcoptes scabiei are burrows in the skin and a rash in the web spaces between the fingers, he finds these features are often absent or equivocal.
“I think there are two more reliable presentations of scabies: Check to see if there’s symmetric involvement of the volar or palm side of the wrists; if there isn’t, I’m skeptical of the diagnosis. And every male older than 1 year of age with scabies will have scabies nodules on their genitalia. If the penis, the glans, or the scrotum aren’t involved with the nodules, I discard scabies as a possible diagnosis and look for evidence of other skin conditions that can plausibly explain the sensations and skin lesions, like eczema, contact dermatitis, scalp folliculitis, or dry skin,” he said.
If he can’t find evidence of infestation, he next systematically looks for another dermatologic cause of the patient’s sensations. When that proves fruitless, he tries to determine if there might be a biomedical or neuropsychiatric cause, such as depression, anxiety, schizophrenia, or dementia.
Taking a personal hygiene history is helpful. Patients who believe they have an infestation may bathe or shower three to five times daily with harsh soaps, causing dry, inflamed, itchy and uncomfortable skin.
“Many patients are thrilled to hear the good news that the history, physical examination, and lab tests do not show an infestation and that we have another explanation to account for their unwanted sensations. However, there are some patients who vehemently reject that idea and immediately return to their unwavering, unalterable belief that they are in fact infested. At this point, the possible diagnosis of DI looms large,” the dermatologist said.
Clues suggestive of DI include a patient’s obsessive focus on collecting “specimens” of the offending pathogen in Ziplock bags for assessment during the office visit – “usually a mix of unhelpful household debris and environmental detritus” – and eager presentation of a lengthy and detailed infestation diary, Dr. Norton said.
“Among the most distinctive signs that the patient is detached from reality are the biologically implausible descriptions and explanations of the supposed attacking organism. It’s a fanciful amalgamation of mutable features, behaviors, and life cycles composed of a composite of taxonomically unrelated organisms – for example, fungal hyphae with wings – that shapeshift at will to evade detection,” he said.
Dr. Elston observed that DI skin lesions are typically excoriated, sometimes because of a patient’s systematic use of a sharp object in an effort to dig out the infestation.
“One of the clues is the angularity of the lesion,” the dermatologist noted. “We always say round-to-oval lesions suggest an inside job; angulated lesions suggest an outside job, like fingernail work. There’s often a row of good healing border showing there’s really nothing wrong with wound healing, but a fibrinoid base where the excoriations have occurred. And the lesions are often in various stages of healing.”
Don’t forget neuropathic itch in nondelusional individuals as a potential cause of sensations of infestation and self-injury due to relentless scratching, urged Anne Louise Oaklander, MD, PhD, associate professor of neurology, Harvard Medical School, Boston, who is director of the nerve unit and the neurodiagnostic skin biopsy lab at Massachusetts General Hospital, Boston.
Dr. Anne Louise Oaklander
“There’s no one cause of patients’ impressions that they may have insects. Let’s be sympathetic: It is a normal assumption that insects may be present if the skin itches. One problem is that when patients don’t get good medical diagnoses they make up their own explanations, and sometimes these include persistent ideas of infestation. Many of them don’t realize that their scratching is a cause, not a result, of their skin lesions,” said Dr. Oaklander, who has conducted pioneering research on unintentional self-injury due to neuropathic itch accompanied by loss of pain signaling.
“Rapport first, medication later”
“The office visits are typically difficult to conclude, but skills can be learned and make it much easier to help these people,” Dr. Elston said.
John Koo, MD, emphasized that establishing rapport is “by far” the most important part of managing patients with DI.
Dr. John Koo
“Rapport first, medication later. This may require multiple visits,” said Dr. Koo, professor of dermatology at the University of California, San Francisco, who is a board-certified psychiatrist.
He makes sure he walks into the examination room all smiles and positivity. Patients with DI are eager to expound on their ailment; he lets them talk for a while, then when the timing is right, he actively encourages them to shift their focus away from etiology to treatment.
Dr. Koo and coworkers have described a spectrum of mental fixation in DI ranging from having only crawling and biting sensations, progressing to holding an overvalued idea as to their cause, then on to DSM-5 somatic preoccupation, followed by becoming truly delusional, and finally terminal delusion, where the patient doesn’t care about getting better, but only wants the physician to agree there is an infestation (J Clin Exp Dermatol Res. 2014 Oct. 3. doi: 10.4172/2155-9554.1000241).
“You cannot argue with people with delusions. How you talk to them as a clinician depends on whether they are entirely delusional or not,” he advised. “I cannot agree with their ideation, but I can agree with their misery – and that’s how I make a connection.”
Declining a DI patient’s request for a skin biopsy when it’s obvious there is no infestation can lead to a counterproductive power struggle. Instead, Dr. Koo turns the patient request into an opportunity to form a verbal contract: “I ask, ‘If the result comes back negative, can you be open-minded about the possibility of other etiologies besides parasites?’ ”
As for Dr. Norton, when his schedule shows a patient is coming in for a first visit for a supposed skin infestation, he tells his staff to expect a lengthy session as he works at establishing a good relationship.
“When my patients arrive with bags of specimens, I ask them to select two or three that they’re most confident will have a creature in them. Then I bring a two-headed microscope into the exam room and ask the patient to join me in examining the material. It helps with rapport by showing that I genuinely want to determine if there’s an infestation,” he explained.
He then sends the specimens to a laboratory, which provides a full report of the findings.
In performing a skin biopsy in a patient with suspected DI, Dr. Norton routinely biopsies two sites so the patient can’t claim sampling error when the pathology report comes back with no pathogens or parasites found. Also, he asks the patient to choose biopsy sites with intact skin where he or she believes the infestation exists. There is no point in biopsying excoriated lesions because they often contain snagged textile fibers.
Another rapport-building strategy: “I try to design a treatment regimen that will palliate the uncomfortable sensations and help relieve the patient’s misery while we continue working towards treating those delusions,” Dr. Norton said.
This might entail cutting back to one lukewarm shower per day with gentle or no soap, coupled with moisturizing, oral antihistamines or doxepin for itch, topical corticosteroids for the associated inflammation, and oral or topical antibiotics for any secondary bacterial skin infection.
What he doesn’t recommend as a rapport-building strategy or simply in order to get the patient out of the office is offering a therapeutic trial of an antiparasitic agent. That’s counterproductive. It may reinforce the false belief of infestation, and when the medication doesn’t bring lasting belief, the patient may conclude the infestation is resistant to conventional treatment.
Dr. Koo tells affected patients that he suspects they have Morgellons syndrome. He doesn’t call it DI in their presence.
“These people would not like their condition to be called delusional,” he explained. “Morgellons is a more neutral term. I tell them it’s a mysterious condition, and that what I’m really interested in is in trying to get them out of their misery.”
Treatment tips
Dr. Koo’s first-line medication for DI is pimozide (Orap), which in the United States has the advantage of being approved only for Tourette syndrome; it’s an antipsychotic without the perceived stigma of a psychiatric indication.
“Many of these patients will not consider taking any medication that has any psychiatric indication,” he noted.
Low-dose pimozide is highly effective, according to Dr. Koo, who recommends starting at 0.5 mg to 1 mg/day, increasing by 0.5 mg/day every 2-4 weeks. The drug is usually effective at a dose of 3 mg/day or less. Once a patient’s symptoms become clear or almost clear, the patient is maintained on that dose for another 3-4 months, then tapered by 0.5 mg/day every 2-4 weeks.
“In 35 years of seeing a new patient on average every week or two, I’ve had only five patients with one recurrence and one patient with two recurrences. All six responded to repeat therapy,” Dr. Koo said.
Side effects at these low doses are “very rare,” he added. Diphenhydramine (Benadryl) at 25 mg up to four times daily is effective for complaints of stiffness or restlessness. Prolongation of the QT interval is a potential concern, but Dr. Koo has never encountered it despite routinely ordering ECGs for patients on pimozide with known heart disease or who are over age 50.
When a patient can’t tolerate pimozide, Dr. Koo’s second-line antipsychotic for DI is low-dose risperidone (Risperdal), which is also highly effective.
Dr. Lepping noted that the European situation is different. There, unlike in the United States, pimozide has regulatory approval as an antipsychotic, so it loses the advantage of being an under-the-radar neuroleptic. His go-to medication is the first-generation antipsychotic sulpiride (Dogmatil), which he finds has a more favorable side effect profile than pimozide, particularly in the elderly. (Sulpiride is not approved in the United States.)
In treating DI, he prefers more dopaminergic-focused antipsychotics over those covering a broader spectrum of receptors. His alternatives to sulpiride include risperidone and olanzapine, atypical antipsychotics. He explains to patients that just as aspirin is used in low doses for its antiplatelet effect and in higher doses for pain relief, these medications can help them feel better at much lower doses than for schizophrenia.
“Once we get some rapport and a trusting relationship going, we normally try to persuade people to basically try something against their better judgment. We know that they don’t believe in it, but you try to get them to at least try something because everything else has failed,” Dr. Lepping explained. “We tell them it’s a condition we have seen before, and we have seen these medications to be useful because they are good for their distress, they help with making them calmer, and they might help with their symptoms. We say, ‘What do you have to lose if you trust us?’
“About 60% of our patients take the medication and almost invariably they all get better,” the psychiatrist said. “The others we either lose to follow-up or they just refuse to take the medication.”
A patient’s first visit to the Liverpool multispecialty DI referral clinic is 1 hour long. “They know that in advance, and we very much stick to that hour. We say to people up front, ‘We have an hour – that’s a lot, but we don’t have more,’ ” he said.
The initial visit is typically followed by two to four 30-minute follow-up visits. Dr. Lepping recommends that when possible, patients with DI should be seen jointly by a psychiatrist and a nonpsychiatrist physician. He finds this approach leads to substantially better clinical outcomes than with a single health care provider.
“If you have two people in the clinic with the patient, when you get really annoyed and your amygdala really starts going, that’s the time when you can then turn to your colleague and say, ‘Oh yes, and Professor Squire, what do you have to say to that?’ So as you see the red mist rising in yourself because you’re getting so exasperated, you have the other person there to take over so you can calm down. And then the other person does the same. That can be really important to deescalate a heated situation,” Dr. Lepping explained.
Roughly 10% of patients with DI have what is termed folie à deux, where the delusion of infestation is shared by another person.
“Anecdotally, I would say those are much more difficult to treat,” said Jason S. Reichenberg, MD, MBA, professor of medicine (dermatology) at the University of Texas at Austin and president of the Ascension Medical Group Texas.
Dr. Jason S. Reichenberg
“It’s like getting somebody to quit smoking when everybody else in the house is still smoking. It’s very hard to convince a single family member that they’re wrong when everybody else in their family keeps telling them they’re right,” he said.
Recent advances in DI research
Dr. Lepping and coinvestigators at multispecialist DI clinics in London, Italy, and Moscow reported in an unusually large observational study of 236 affected patients that longer duration of untreated psychosis was associated with significantly worse clinical outcome. It’s a finding consistent with Dr. Koo’s construct of progressive stages of delusionality, and it underscores the need for early treatment.
“Having said that, improvement is still possible, even if people have had quite a long time of untreated psychosis,” Dr. Lepping said. The same study also showed that older age at illness onset was inversely associated with good outcome.
In another study, Dr. Lepping and colleagues reported that substance use involving amphetamines, cocaine, opioids, and other drugs that can cause itch was roughly twice as common in a group of patients with DI compared to the general population. “I highly recommend, if at all possible, a drug screen in suspected DI,” he said.
In a large survey of U.S. and Canadian veterinarians, Dr. Lepping and coinvestigators found that these practitioners not infrequently encountered delusional infestation among pet owners who claimed their dog or cat is infested when it’s not. This is called “delusion by proxy,” and it often leads to unwarranted animal euthanasia. Some of these pet owners claim they, too, are infested, which the investigators termed “double delusional infestation.”
MRI studies
Recent structural brain MRI studies support the concept that impaired somatosensory neural networks mediate the delusional symptoms of DI, but not in delusional disorders without somatic content. This was demonstrated in an MRI study by Dr. Lepping and others conducted in 18 patients with DI, 19 others with nonsomatic delusional disorders centered on themes of persecution or jealousy, and 20 healthy volunteers. The DI group had lower gray matter volume in prefrontal, thalamic, striatal, and insular regions of the brain compared to the other two groups.
Of note, mapping of the insula and dorsal striatum indicates they are part of the peripersonal space network, which integrates tactile and visual perceptions involving the area near the body surface. The insula also mediates feelings of pain and disgust.
Some of the same investigators have also recently reported brain MRI evidence specifically of cerebellar dysfunction in patients with DI, who displayed decreased gray matter volume in left lobule VIIa of the cerebellum and increased gray matter volume in bilateral lobule VIIa/crus II compared to patients with non-somatic delusions. This points to a role for impaired cerebellar neural networks related to somatosensory perception in patients with DI but not in those with non-somatic delusions.
Delusional infestation: What’s in a name?
Ekbom syndrome. Delusional parasitosis. Morgellons syndrome. These and other terms are increasingly giving way to ‘delusional infestation’ as the preferred moniker for the disorder. That’s in part because the delusional focus in patients with this condition has shifted over time. In the 19th century, for example, affected patients often attributed their infestation to typhus.
In contemporary practice, roughly one-quarter of affected patients think they are infested by small inanimate objects, most commonly fibers or threads emerging from the skin, rather than by parasites, insects, or worms. In a study of 148 consecutive European patients with suspected DI, Dr. Lepping and coinvestigators reported only 35% believed they were infested by parasites.
“The name ‘delusional infestation’ emphasizes the constantly changing pathogens and covers all present and future variations of the theme that are bound to occur,” Dr. Lepping observed.
All speakers reported having no conflicts of interest.
Psychiatrists with expertise in delusional infestation have some advice for dermatologists, infectious disease specialists, and primary care physicians who encounter affected patients: If you want to try to help them, initiate treatment yourself.
Dr. Peter Lepping
“If you see it, try and treat it. These patients are unlikely to agree to see a psychiatrist,” Peter Lepping, MD, said at the Entomology 2020 annual meeting.
Indeed, one of the hallmarks of delusional infestation (DI) is a refusal to even consider referral to a mental health professional, noted Dr. Lepping, a consultation-liaison psychiatrist at Bangor (Wales) University who, together with an infectious disease specialist, codirects one of the world’s few DI multispecialty referral clinics, located at the University of Liverpool School of Tropical Medicine.
That being said, he offered another piece of advice: “Accept that it is not easy to help these patients.”
Dr. Lepping was among a group of distinguished psychiatrists, dermatologists, entomologists, and a neurologist at the annual meeting who participated in a comprehensive session devoted to DI. The experts shared tips on making the diagnosis, establishing the rapport necessary to persuade affected patients to try taking a very-low-dose antipsychotic agent for their delusion, and how to achieve a high rate of therapeutic success. They also highlighted recent research advances in the field, including brain MRI evidence suggesting that impaired somatosensory neural networks mediate symptoms in DI, but not in nonsomatic delusional disorders.
COVID-19 pandemic triggers surge in DI
Entomologist Gail E. Ridge, PhD, has taken notes on all of her thousands of consultations with individuals with suspected DI since the late 1990s. A sharp jump in such contacts occurred during the Great Recession of 2008 in conjunction with the widespread social distress of job loss and threatened economic ruin. Now the same thing is happening as the catastrophic COVID-19 pandemic stretches on. Indeed, during the first 8 months of the pandemic she documented 500 interactions involving people with suspected DI. She’s learned to identify the clues, including a chattering mind, defensiveness, physician avoidance, and rigid body tension.
Courtesy Dr. Gale E. Ridge
Dr. Gale E. Ridge
“They’re fearful of judgment and suggestions of madness. And they’ll pounce on any perceived negativity. I never debunk beliefs; that can immediately backfire. If the medical profession was educated about DI, then many cases could be caught early. I, as the entomologist, and the mental health professionals are often last in line to be seen,” said Dr. Ridge, director of the Insect Information Office at the Connecticut Agricultural Experiment Station in New Haven.
She has noticed a recurring theme in her interactions with these patients: DI often starts with a real underlying medical condition, such as, for example, a cutaneous drug reaction, which over time, progresses to gain a psychiatric component. And she has found that a tipping point often occurs after roughly 6 months of unrelieved symptoms and sensations. Prior to that, affected individuals are concerned about their condition and will seek medical help in a genuine effort to understand what’s going on. They can be redirected. After about 6 months, however, Dr. Ridge has observed “they slide into the rabbit hole of fanaticism and despair.”
Arriving at the diagnosis
In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), DI is classified as a “delusional disorder, somatic type 297.1 F22.” The diagnosis requires that the delusion be present for at least 1 month, criteria for schizophrenia are not met, and the condition cannot be attributed to other medical or neuropsychiatric conditions.
“Many of these people are very high-functioning. I have corporate CEOs who fly in to see me in their private jets. At work, they’re king of their domain. At home, their family is falling apart because of their delusion,” said Dirk M. Elston, MD, professor and chair of the department of dermatology and dermatologic surgery at the Medical University of South Carolina, Charleston.
Dr. Dirk M. Elston
“These people suffer, and the people around them suffer,” he emphasized.
Dozens of medical conditions can cause intractable itching or biting sensations. Far and away at the top of the medical differential diagnosis is thyroid disease, given its high incidence and frequent presentation with anxiety and itch. Other possibilities that can readily be ruled out via lab tests include substance use – especially involving amphetamine/methamphetamine, cocaine, or opioids – liver or kidney disease, diabetes and other sources of peripheral neuropathy, polycythemia, dermatitis herpetiformis, and pemphigus, Dr. Elston said.
Scott A. Norton, MD, MPH, MSc, a dermatologist and preventive medicine specialist at the Uniformed Services University of the Health Sciences in Bethesda, Md., noted that a diagnosis of DI requires three elements: The presence of abnormal sensations in the skin, a patient’s tenacious conviction that the sensations are caused by an infestation, and a lack of supporting evidence for that conviction.
Dr. Scott A. Norton
Taking an accurate medical history can be a challenge in these patients because they are often so guarded. They won’t disclose that they’ve already seen other health care providers, or that they’ve been self-treating with OTC veterinary medicine products, such as high-dose topical or oral ivermectin. They’ll often even deny repeated scratching despite clear evidence to the contrary from the skin exam.
As a dermatologist, Dr. Norton considers his first task to be a search for evidence of an infestation. Scabies is usually the first diagnosis proposed to account for the uncomfortable skin sensations. The presentation can be subtle. While the classic teaching is that the telltale signs of infestation by Sarcoptes scabiei are burrows in the skin and a rash in the web spaces between the fingers, he finds these features are often absent or equivocal.
“I think there are two more reliable presentations of scabies: Check to see if there’s symmetric involvement of the volar or palm side of the wrists; if there isn’t, I’m skeptical of the diagnosis. And every male older than 1 year of age with scabies will have scabies nodules on their genitalia. If the penis, the glans, or the scrotum aren’t involved with the nodules, I discard scabies as a possible diagnosis and look for evidence of other skin conditions that can plausibly explain the sensations and skin lesions, like eczema, contact dermatitis, scalp folliculitis, or dry skin,” he said.
If he can’t find evidence of infestation, he next systematically looks for another dermatologic cause of the patient’s sensations. When that proves fruitless, he tries to determine if there might be a biomedical or neuropsychiatric cause, such as depression, anxiety, schizophrenia, or dementia.
Taking a personal hygiene history is helpful. Patients who believe they have an infestation may bathe or shower three to five times daily with harsh soaps, causing dry, inflamed, itchy and uncomfortable skin.
“Many patients are thrilled to hear the good news that the history, physical examination, and lab tests do not show an infestation and that we have another explanation to account for their unwanted sensations. However, there are some patients who vehemently reject that idea and immediately return to their unwavering, unalterable belief that they are in fact infested. At this point, the possible diagnosis of DI looms large,” the dermatologist said.
Clues suggestive of DI include a patient’s obsessive focus on collecting “specimens” of the offending pathogen in Ziplock bags for assessment during the office visit – “usually a mix of unhelpful household debris and environmental detritus” – and eager presentation of a lengthy and detailed infestation diary, Dr. Norton said.
“Among the most distinctive signs that the patient is detached from reality are the biologically implausible descriptions and explanations of the supposed attacking organism. It’s a fanciful amalgamation of mutable features, behaviors, and life cycles composed of a composite of taxonomically unrelated organisms – for example, fungal hyphae with wings – that shapeshift at will to evade detection,” he said.
Dr. Elston observed that DI skin lesions are typically excoriated, sometimes because of a patient’s systematic use of a sharp object in an effort to dig out the infestation.
“One of the clues is the angularity of the lesion,” the dermatologist noted. “We always say round-to-oval lesions suggest an inside job; angulated lesions suggest an outside job, like fingernail work. There’s often a row of good healing border showing there’s really nothing wrong with wound healing, but a fibrinoid base where the excoriations have occurred. And the lesions are often in various stages of healing.”
Don’t forget neuropathic itch in nondelusional individuals as a potential cause of sensations of infestation and self-injury due to relentless scratching, urged Anne Louise Oaklander, MD, PhD, associate professor of neurology, Harvard Medical School, Boston, who is director of the nerve unit and the neurodiagnostic skin biopsy lab at Massachusetts General Hospital, Boston.
Dr. Anne Louise Oaklander
“There’s no one cause of patients’ impressions that they may have insects. Let’s be sympathetic: It is a normal assumption that insects may be present if the skin itches. One problem is that when patients don’t get good medical diagnoses they make up their own explanations, and sometimes these include persistent ideas of infestation. Many of them don’t realize that their scratching is a cause, not a result, of their skin lesions,” said Dr. Oaklander, who has conducted pioneering research on unintentional self-injury due to neuropathic itch accompanied by loss of pain signaling.
“Rapport first, medication later”
“The office visits are typically difficult to conclude, but skills can be learned and make it much easier to help these people,” Dr. Elston said.
John Koo, MD, emphasized that establishing rapport is “by far” the most important part of managing patients with DI.
Dr. John Koo
“Rapport first, medication later. This may require multiple visits,” said Dr. Koo, professor of dermatology at the University of California, San Francisco, who is a board-certified psychiatrist.
He makes sure he walks into the examination room all smiles and positivity. Patients with DI are eager to expound on their ailment; he lets them talk for a while, then when the timing is right, he actively encourages them to shift their focus away from etiology to treatment.
Dr. Koo and coworkers have described a spectrum of mental fixation in DI ranging from having only crawling and biting sensations, progressing to holding an overvalued idea as to their cause, then on to DSM-5 somatic preoccupation, followed by becoming truly delusional, and finally terminal delusion, where the patient doesn’t care about getting better, but only wants the physician to agree there is an infestation (J Clin Exp Dermatol Res. 2014 Oct. 3. doi: 10.4172/2155-9554.1000241).
“You cannot argue with people with delusions. How you talk to them as a clinician depends on whether they are entirely delusional or not,” he advised. “I cannot agree with their ideation, but I can agree with their misery – and that’s how I make a connection.”
Declining a DI patient’s request for a skin biopsy when it’s obvious there is no infestation can lead to a counterproductive power struggle. Instead, Dr. Koo turns the patient request into an opportunity to form a verbal contract: “I ask, ‘If the result comes back negative, can you be open-minded about the possibility of other etiologies besides parasites?’ ”
As for Dr. Norton, when his schedule shows a patient is coming in for a first visit for a supposed skin infestation, he tells his staff to expect a lengthy session as he works at establishing a good relationship.
“When my patients arrive with bags of specimens, I ask them to select two or three that they’re most confident will have a creature in them. Then I bring a two-headed microscope into the exam room and ask the patient to join me in examining the material. It helps with rapport by showing that I genuinely want to determine if there’s an infestation,” he explained.
He then sends the specimens to a laboratory, which provides a full report of the findings.
In performing a skin biopsy in a patient with suspected DI, Dr. Norton routinely biopsies two sites so the patient can’t claim sampling error when the pathology report comes back with no pathogens or parasites found. Also, he asks the patient to choose biopsy sites with intact skin where he or she believes the infestation exists. There is no point in biopsying excoriated lesions because they often contain snagged textile fibers.
Another rapport-building strategy: “I try to design a treatment regimen that will palliate the uncomfortable sensations and help relieve the patient’s misery while we continue working towards treating those delusions,” Dr. Norton said.
This might entail cutting back to one lukewarm shower per day with gentle or no soap, coupled with moisturizing, oral antihistamines or doxepin for itch, topical corticosteroids for the associated inflammation, and oral or topical antibiotics for any secondary bacterial skin infection.
What he doesn’t recommend as a rapport-building strategy or simply in order to get the patient out of the office is offering a therapeutic trial of an antiparasitic agent. That’s counterproductive. It may reinforce the false belief of infestation, and when the medication doesn’t bring lasting belief, the patient may conclude the infestation is resistant to conventional treatment.
Dr. Koo tells affected patients that he suspects they have Morgellons syndrome. He doesn’t call it DI in their presence.
“These people would not like their condition to be called delusional,” he explained. “Morgellons is a more neutral term. I tell them it’s a mysterious condition, and that what I’m really interested in is in trying to get them out of their misery.”
Treatment tips
Dr. Koo’s first-line medication for DI is pimozide (Orap), which in the United States has the advantage of being approved only for Tourette syndrome; it’s an antipsychotic without the perceived stigma of a psychiatric indication.
“Many of these patients will not consider taking any medication that has any psychiatric indication,” he noted.
Low-dose pimozide is highly effective, according to Dr. Koo, who recommends starting at 0.5 mg to 1 mg/day, increasing by 0.5 mg/day every 2-4 weeks. The drug is usually effective at a dose of 3 mg/day or less. Once a patient’s symptoms become clear or almost clear, the patient is maintained on that dose for another 3-4 months, then tapered by 0.5 mg/day every 2-4 weeks.
“In 35 years of seeing a new patient on average every week or two, I’ve had only five patients with one recurrence and one patient with two recurrences. All six responded to repeat therapy,” Dr. Koo said.
Side effects at these low doses are “very rare,” he added. Diphenhydramine (Benadryl) at 25 mg up to four times daily is effective for complaints of stiffness or restlessness. Prolongation of the QT interval is a potential concern, but Dr. Koo has never encountered it despite routinely ordering ECGs for patients on pimozide with known heart disease or who are over age 50.
When a patient can’t tolerate pimozide, Dr. Koo’s second-line antipsychotic for DI is low-dose risperidone (Risperdal), which is also highly effective.
Dr. Lepping noted that the European situation is different. There, unlike in the United States, pimozide has regulatory approval as an antipsychotic, so it loses the advantage of being an under-the-radar neuroleptic. His go-to medication is the first-generation antipsychotic sulpiride (Dogmatil), which he finds has a more favorable side effect profile than pimozide, particularly in the elderly. (Sulpiride is not approved in the United States.)
In treating DI, he prefers more dopaminergic-focused antipsychotics over those covering a broader spectrum of receptors. His alternatives to sulpiride include risperidone and olanzapine, atypical antipsychotics. He explains to patients that just as aspirin is used in low doses for its antiplatelet effect and in higher doses for pain relief, these medications can help them feel better at much lower doses than for schizophrenia.
“Once we get some rapport and a trusting relationship going, we normally try to persuade people to basically try something against their better judgment. We know that they don’t believe in it, but you try to get them to at least try something because everything else has failed,” Dr. Lepping explained. “We tell them it’s a condition we have seen before, and we have seen these medications to be useful because they are good for their distress, they help with making them calmer, and they might help with their symptoms. We say, ‘What do you have to lose if you trust us?’
“About 60% of our patients take the medication and almost invariably they all get better,” the psychiatrist said. “The others we either lose to follow-up or they just refuse to take the medication.”
A patient’s first visit to the Liverpool multispecialty DI referral clinic is 1 hour long. “They know that in advance, and we very much stick to that hour. We say to people up front, ‘We have an hour – that’s a lot, but we don’t have more,’ ” he said.
The initial visit is typically followed by two to four 30-minute follow-up visits. Dr. Lepping recommends that when possible, patients with DI should be seen jointly by a psychiatrist and a nonpsychiatrist physician. He finds this approach leads to substantially better clinical outcomes than with a single health care provider.
“If you have two people in the clinic with the patient, when you get really annoyed and your amygdala really starts going, that’s the time when you can then turn to your colleague and say, ‘Oh yes, and Professor Squire, what do you have to say to that?’ So as you see the red mist rising in yourself because you’re getting so exasperated, you have the other person there to take over so you can calm down. And then the other person does the same. That can be really important to deescalate a heated situation,” Dr. Lepping explained.
Roughly 10% of patients with DI have what is termed folie à deux, where the delusion of infestation is shared by another person.
“Anecdotally, I would say those are much more difficult to treat,” said Jason S. Reichenberg, MD, MBA, professor of medicine (dermatology) at the University of Texas at Austin and president of the Ascension Medical Group Texas.
Dr. Jason S. Reichenberg
“It’s like getting somebody to quit smoking when everybody else in the house is still smoking. It’s very hard to convince a single family member that they’re wrong when everybody else in their family keeps telling them they’re right,” he said.
Recent advances in DI research
Dr. Lepping and coinvestigators at multispecialist DI clinics in London, Italy, and Moscow reported in an unusually large observational study of 236 affected patients that longer duration of untreated psychosis was associated with significantly worse clinical outcome. It’s a finding consistent with Dr. Koo’s construct of progressive stages of delusionality, and it underscores the need for early treatment.
“Having said that, improvement is still possible, even if people have had quite a long time of untreated psychosis,” Dr. Lepping said. The same study also showed that older age at illness onset was inversely associated with good outcome.
In another study, Dr. Lepping and colleagues reported that substance use involving amphetamines, cocaine, opioids, and other drugs that can cause itch was roughly twice as common in a group of patients with DI compared to the general population. “I highly recommend, if at all possible, a drug screen in suspected DI,” he said.
In a large survey of U.S. and Canadian veterinarians, Dr. Lepping and coinvestigators found that these practitioners not infrequently encountered delusional infestation among pet owners who claimed their dog or cat is infested when it’s not. This is called “delusion by proxy,” and it often leads to unwarranted animal euthanasia. Some of these pet owners claim they, too, are infested, which the investigators termed “double delusional infestation.”
MRI studies
Recent structural brain MRI studies support the concept that impaired somatosensory neural networks mediate the delusional symptoms of DI, but not in delusional disorders without somatic content. This was demonstrated in an MRI study by Dr. Lepping and others conducted in 18 patients with DI, 19 others with nonsomatic delusional disorders centered on themes of persecution or jealousy, and 20 healthy volunteers. The DI group had lower gray matter volume in prefrontal, thalamic, striatal, and insular regions of the brain compared to the other two groups.
Of note, mapping of the insula and dorsal striatum indicates they are part of the peripersonal space network, which integrates tactile and visual perceptions involving the area near the body surface. The insula also mediates feelings of pain and disgust.
Some of the same investigators have also recently reported brain MRI evidence specifically of cerebellar dysfunction in patients with DI, who displayed decreased gray matter volume in left lobule VIIa of the cerebellum and increased gray matter volume in bilateral lobule VIIa/crus II compared to patients with non-somatic delusions. This points to a role for impaired cerebellar neural networks related to somatosensory perception in patients with DI but not in those with non-somatic delusions.
Delusional infestation: What’s in a name?
Ekbom syndrome. Delusional parasitosis. Morgellons syndrome. These and other terms are increasingly giving way to ‘delusional infestation’ as the preferred moniker for the disorder. That’s in part because the delusional focus in patients with this condition has shifted over time. In the 19th century, for example, affected patients often attributed their infestation to typhus.
In contemporary practice, roughly one-quarter of affected patients think they are infested by small inanimate objects, most commonly fibers or threads emerging from the skin, rather than by parasites, insects, or worms. In a study of 148 consecutive European patients with suspected DI, Dr. Lepping and coinvestigators reported only 35% believed they were infested by parasites.
“The name ‘delusional infestation’ emphasizes the constantly changing pathogens and covers all present and future variations of the theme that are bound to occur,” Dr. Lepping observed.
All speakers reported having no conflicts of interest.
