Autoimmune Diseases

To the Editor:

Alopecia areata (AA), an autoimmune disease characterized by inflammatory and nonscarring hair loss, can have a considerable impact on quality of life.¹ Baricitinib is a Janus kinase inhibitor that recently was approved by the US Food and Drug Administration for treatment of severe AA in adult patients, becoming the only on-label treatment available.² So far, the most common adverse effects reported in phase 3 trials have been acne, upper respiratory tract infections, headaches, urinary tract infections, and elevated creatine kinase levels.³

At our trichology unit in the dermatology department of a Spanish tertiary-care hospital in Seville, we have successfully used baricitinib to treat 18 patients with severe, therapy-resistant AA. Herein, we present a case of trichilemmal cyst reactivation in one of our patients following successful treatment with baricitinib.

A 53-year-old woman with a history of trichilemmal cysts presented to the dermatology department with total body hair loss of 5 years' duration that was diagnosed as AA universalis (Figure, A). The patient reported that the trichilemmal cysts had shrunk drastically 1 month after complete loss of body hair (Severity of Alopecia Tool [SALT] score, 100)(Figure, B). The largest cyst was surgically removed, and the diagnosis was histologically confirmed by a pathologist. Her mother and sister also had a history of multiple trichilemmal cysts.

The patient previously had failed treatment with oral prednisone 50 mg/d, oral cyclosporine 4 mg/kg/d, oral dexamethasone 4 mg twice weekly, and oral azathioprine 300 mg/wk. Due to the new indication of baricitinib for AA, we opted to start the patient on oral baricitinib 4 mg/d. By week 8 of treatment, she had achieved total hair regrowth (SALT score, 0). This rapid response might indicate a quick-responder phenotype, referring to a subset of patients who exhibit a fast and robust response to treatment (SALT90), generally before week 16, although more evidence is needed.

Notably, we observed the reactivation of 4 trichilemmal cysts on the scalp 6 weeks after starting baricitinib. To our knowledge, this side effect has not previously been reported. We hypothesize that reactivation of the cysts may have been due to the inhibition of the Janus kinase/signal transducer and activator of transcription pathway, which reduces the effects of cytokines and leads to reactivation of hair follicles that were inactive because of inflammation.⁴ As a result, the outer root sheath of the hair follicle can once again be filled with keratin, thereby reactivating the trichilemmal cysts. Based on our experience with this case, it may be relevant to consider personal and family history of trichilemmal cysts before starting treatment with baricitinib for AA and advise the patient about the possibility of this adverse effect.

To the Editor:

Alopecia areata (AA), an autoimmune disease characterized by inflammatory and nonscarring hair loss, can have a considerable impact on quality of life.¹ Baricitinib is a Janus kinase inhibitor that recently was approved by the US Food and Drug Administration for treatment of severe AA in adult patients, becoming the only on-label treatment available.² So far, the most common adverse effects reported in phase 3 trials have been acne, upper respiratory tract infections, headaches, urinary tract infections, and elevated creatine kinase levels.³

At our trichology unit in the dermatology department of a Spanish tertiary-care hospital in Seville, we have successfully used baricitinib to treat 18 patients with severe, therapy-resistant AA. Herein, we present a case of trichilemmal cyst reactivation in one of our patients following successful treatment with baricitinib.

A 53-year-old woman with a history of trichilemmal cysts presented to the dermatology department with total body hair loss of 5 years' duration that was diagnosed as AA universalis (Figure, A). The patient reported that the trichilemmal cysts had shrunk drastically 1 month after complete loss of body hair (Severity of Alopecia Tool [SALT] score, 100)(Figure, B). The largest cyst was surgically removed, and the diagnosis was histologically confirmed by a pathologist. Her mother and sister also had a history of multiple trichilemmal cysts.

The patient previously had failed treatment with oral prednisone 50 mg/d, oral cyclosporine 4 mg/kg/d, oral dexamethasone 4 mg twice weekly, and oral azathioprine 300 mg/wk. Due to the new indication of baricitinib for AA, we opted to start the patient on oral baricitinib 4 mg/d. By week 8 of treatment, she had achieved total hair regrowth (SALT score, 0). This rapid response might indicate a quick-responder phenotype, referring to a subset of patients who exhibit a fast and robust response to treatment (SALT90), generally before week 16, although more evidence is needed.

Notably, we observed the reactivation of 4 trichilemmal cysts on the scalp 6 weeks after starting baricitinib. To our knowledge, this side effect has not previously been reported. We hypothesize that reactivation of the cysts may have been due to the inhibition of the Janus kinase/signal transducer and activator of transcription pathway, which reduces the effects of cytokines and leads to reactivation of hair follicles that were inactive because of inflammation.⁴ As a result, the outer root sheath of the hair follicle can once again be filled with keratin, thereby reactivating the trichilemmal cysts. Based on our experience with this case, it may be relevant to consider personal and family history of trichilemmal cysts before starting treatment with baricitinib for AA and advise the patient about the possibility of this adverse effect.

To the Editor:

Alopecia areata (AA), an autoimmune disease characterized by inflammatory and nonscarring hair loss, can have a considerable impact on quality of life.¹ Baricitinib is a Janus kinase inhibitor that recently was approved by the US Food and Drug Administration for treatment of severe AA in adult patients, becoming the only on-label treatment available.² So far, the most common adverse effects reported in phase 3 trials have been acne, upper respiratory tract infections, headaches, urinary tract infections, and elevated creatine kinase levels.³

At our trichology unit in the dermatology department of a Spanish tertiary-care hospital in Seville, we have successfully used baricitinib to treat 18 patients with severe, therapy-resistant AA. Herein, we present a case of trichilemmal cyst reactivation in one of our patients following successful treatment with baricitinib.

A 53-year-old woman with a history of trichilemmal cysts presented to the dermatology department with total body hair loss of 5 years' duration that was diagnosed as AA universalis (Figure, A). The patient reported that the trichilemmal cysts had shrunk drastically 1 month after complete loss of body hair (Severity of Alopecia Tool [SALT] score, 100)(Figure, B). The largest cyst was surgically removed, and the diagnosis was histologically confirmed by a pathologist. Her mother and sister also had a history of multiple trichilemmal cysts.

The patient previously had failed treatment with oral prednisone 50 mg/d, oral cyclosporine 4 mg/kg/d, oral dexamethasone 4 mg twice weekly, and oral azathioprine 300 mg/wk. Due to the new indication of baricitinib for AA, we opted to start the patient on oral baricitinib 4 mg/d. By week 8 of treatment, she had achieved total hair regrowth (SALT score, 0). This rapid response might indicate a quick-responder phenotype, referring to a subset of patients who exhibit a fast and robust response to treatment (SALT90), generally before week 16, although more evidence is needed.

Notably, we observed the reactivation of 4 trichilemmal cysts on the scalp 6 weeks after starting baricitinib. To our knowledge, this side effect has not previously been reported. We hypothesize that reactivation of the cysts may have been due to the inhibition of the Janus kinase/signal transducer and activator of transcription pathway, which reduces the effects of cytokines and leads to reactivation of hair follicles that were inactive because of inflammation.⁴ As a result, the outer root sheath of the hair follicle can once again be filled with keratin, thereby reactivating the trichilemmal cysts. Based on our experience with this case, it may be relevant to consider personal and family history of trichilemmal cysts before starting treatment with baricitinib for AA and advise the patient about the possibility of this adverse effect.

Muscle-related complaints occur in 7% to 25% of patients taking statin medications.¹ In most instances, these adverse effects are quickly resolved when the medication is discontinued, but in rare occurrences, the statin can trigger an autoimmune response that progresses even after stopping use. This uncommon condition is typically accompanied by symmetrical proximal muscle weakness and an elevated CPK leading to a necrotizing myopathy requiring treatment with immunosuppressive therapy. Although less common, some patients may also present with dysphagia, myalgia, weight loss, and/or skin rash.¹

Statin medications have been the cornerstone of lipid-lowering therapy due to their mechanism of inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), which is the rate-limiting step within the cholesterol synthesis pathway to produce mevalonic acid. There is a proven genetic association with human leukocyte antigen (HLA)-DRB1*11:01 in adults and anti-HMGCR–associated myopathy.¹ The incidence of statin-induced necrotizing autoimmune myopathy (SINAM) in relation to each specific statin agent remains unknown; however, a systematic review of case reports found higher correlations for atorvastatin and simvastatin.²

There are 2 ways to confirm a SINAM diagnosis. The first and simplest includes checking for the presence of antibodies against HMGCR. The anti-HMGCR antibody test is typically used as a definitive diagnosis because it has a high specificity for SINAM.³ The second and more invasive diagnosis method involves a muscle biopsy, which is identified as positive if the biopsy shows the presence of necrotic muscle fibers.^1,3

The anti-HMGCR antibody test can serve as a marker for disease activity because the antibodies are strongly correlated with CPK levels.¹ CPK levels indicate the severity of muscle injury and is often used in addition to either of the confirmatory tests because it is faster and less expensive. Anti-HMGCR titers may remain positive while CPK returns to baseline when SINAM is dormant. In addition, clinicians may use an electromyography (EMG) test to measure the muscle response in association to nerve stimulation. ¹ This test can show potential features of myopathic lesions such as positive sharp waves, spontaneous fibrillations, or myotonic repetitive potentials.

Typical treatment includes glucocorticoids as first-line agents, but SINAM can be difficult to treat due to its complicated pathophysiology processes.³ Escalation of therapy is sometimes required beyond a single agent; in these complex scenarios, methotrexate and/or intravenous (IV) immunoglobulin (IVIG) therapy are frequently added to the steroid therapy. There have been concerns with steroid use in specific patient populations due to the undesired adverse effect (AE) profile, and as a result IVIG has been used as monotherapy at a dose of 2 g/kg per month.³ Studies looking at IVIG monotherapy showed a reduction in CPK levels and improvement in strength after just 2 to 3 rounds of monthly treatment.³ Some patients receiving IVIG monotherapy even achieved baseline strength and no longer reported muscle-related symptoms, although the total treatment duration varied. A systematic review of 39 articles where glucocorticoids, IVIG, methotrexate and/or a combination were used to treat SINAM found an average time to remission of 8.6 months. Additionally, this systematic review observed more patients returned to baseline or experienced improvement in symptoms when being treated with a combination of glucocorticoid plus IVIG plus methotrexate.² Suggested dosing recommendations are available in Table 1.

Patients diagnosed with HMGCR antibody myopathy are contraindicated for future statin therapy.¹ Rechallenge of statins in this patient population has led to worsening of disease and therefore these patients should have a severe statin allergy listed in their medical documentation record.

CASE PRESENTATION

A 59-year-old male patient with a medical history including atrial fibrillation, peripheral vascular disease, type 2 diabetes mellitus (T2DM), hypertension, and peripheral neuropathy was referred by his primary care clinical pharmacist practitioner for an outpatient neurology consult. The patient reported a 4-month history of fatigue, lower extremity paresthesia, and progressive proximal muscle weakness which began in his legs, mostly noticeable when walking upstairs but quickly developed into bilateral arm weakness. The patient reported significant impact on his quality of life: he could no longer lift his arms above his head and had difficulty with daily activities such as brushing his hair or getting up from a chair. He reported multiple falls at home, and began to use a cane for assistance with ambulation. He confirmed adherence to atorvastatin over the past year. Laboratory testing on the day of the visit revealed an elevated CPK level at 9729 mcg/L (reference range for men, 30-300 mcg/L).

The patient was urged to go to the emergency department where his CPK level had increased to 12,990 mcg/L (Figure 1). The workup began to find the source of rhabdomyolysis and elevated liver enzymes differentiating autoimmune vs medication-induced myopathy. Upon admission atorvastatin was discontinued, anti-HMGCR antibody level was ordered, and IV fluids were started.

After 8 days of hospital admission with minimal improvement, Rheumatology and Neurology services were consulted in the setting of persistent CPK elevation and the potential neuropathic component of muscle weakness. Both consulting services agreed to consider muscle biopsy and EMG if the patient did not begin to show signs of improvement. The patient’s CPK levels remained elevated with minimal change in muscle weakness. The next step was a right quadricep muscle biopsy performed on Day 14 of admission. Sixteen days after admission, the anti-HMGCR antibody test (originally obtained upon admission) was positive and elevated at 249 CU/mL (reference range, < 20 CU/mL negative; reference range, ≥ 60 CU/mL strong positive), which confirmed the SINAM diagnosis (Table 2).

On Day 17 of hospitalization, the Neurology service initiated IVIG monotherapy to avoid the undesired glycemic AEs associated with glucocorticoids. The patient had a history of T2DM that was difficult to manage and his hemoglobin A_1c level was the best it had ever been (6.2%) relative to a peak A_1c of 11.0% 9 months prior. The patient was treated with a total IVIG dose of 2 g/kg divided into 3 daily doses while still obtaining CPK levels with daily laboratory tests to assist with trending the extent of disease severity improvement (Figures 2-4). After a 20-day hospital stay, the patient was discharged home with rehabilitation services and a scheduled outpatient EMG the following week.

The patient continued to report generalized body weakness, pain, and deconditioning upon discharge and was unable to attend the EMG neurology appointment. The patient did eventually attend a follow-up appointment about 6 weeks after hospital discharge and reported continued weakness. The Neurology service prescribed a 2-day IVIG regimen (total dose = 2 g/kg) monthly for the next 2 months. The patient returned to the neurology clinic 8 weeks later following 2 rounds of IVIG posthospitalization and reported that his muscle strength was returning, and he was able to slowly reintroduce exercise into his daily routine. During a follow-up appointment about 11 months after the initial hospitalization, the patient’s primary care clinical pharmacist provided education of effective management of cholesterol without statins, including use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors as recommended by the Neurology service. At this time, the patient’s calculated low-density lipoprotein (LDL) was 110 mg/dL (reference range, 0-99 mg/dL). The patient preferred to work on a healthy diet and positive lifestyle choices before trialing any lipid lowering therapies.

The patient appeared to tolerate this treatment regimen following 7 rounds of IVIG. He noted fatigue for about 24 hours after his infusion sessions but otherwise reported no additional AEs. He has continued to attend weekly physical therapy sessions and is able to walk without the assistance of a cane. He can now walk a mile before he begins to feel fatigued or experience bilateral lower leg pain. The pain appears neuropathic in nature, as the patient reports ongoing “pins and needles” sensation in his legs and feet. The patient has noticed a major improvement in his overall function, strength, and exercise tolerance since starting IVIG treatments and although he is not yet back to his baseline, he is motivated to continue his recovery. Neurology is considering ongoing treatment with IVIG monthly infusions given his continued clinical improvement.

DISCUSSION

There is limited evidence on the use of IVIG monotherapy for SINAM, although it may be a viable option for patients deemed poor candidates for glucocorticoid or methotrexate therapy. This particularly applies to patients with DM for which there may be concerns for managing blood glucose levels with steroid use. The Johns Hopkins Myositis Center evaluated 3 patients with SINAM who declined glucocorticoid therapy and had documented DM and weakness in the proximal arms and legs. Following 2 to 3 monthly rounds of IVIG 2 g/kg monotherapy, these patients had reduced CPK levels and had improvement in both arm and hip-flexion strength. Two patients reported no muscle-related symptoms after completing IVIG monotherapy treatment for 9 and 19 months.³

The optimal treatment duration for IVIG monotherapy for SINAM is still uncertain given the limited available data. The patient in this case report showed clinically significant muscle-related improvement following 7 monthly rounds of 2 g/kg IVIG treatments. The mechanism of action for IVIG in this setting is still unknown, although the medication may allow muscle regeneration to surpass muscle destruction, thus leading to resolution of the muscle-related symptoms.³

There are numerous concerns with IVIG use to consider prior to initiating treatment, including expense, AEs, patient response, and comorbidities. IVIG is considerably more expensive than glucocorticoid and methotrexate alternatives. Systemic reactions have been shown to occur in 5% to 15% of patients receiving IVIG infusion.⁴ The majority of these infusion reactions occur early during infusion or within a few hours after administration is complete.⁵ Early AEs to monitor for include injection site reactions, flu-like symptoms, dermatologic reactions, anaphylaxis, transfusion-related acute lung injury, and transfusion-associated circulatory overload. Additional AEs may be delayed, including thromboembolic events, acute kidney injury, aseptic meningitis, hemolysis, neutropenia, and blood-borne infection.⁶ IVIG has a boxed warning for thrombosis, renal dysfunction, and acute renal failure risk.⁷ There are multiple strategies documented to reduce the risk of IVIG reactions including slowing the infusion rate, ensuring adequate hydration, and/or giving analgesics, antihistamines, or steroids prior to infusion.⁶ The patient in this case had monthly IVIG infusions without the need of any pretreatment medications and only reported fatigue for about 24 hours following the infusion.

An essential question is how to provide safe cholesterol management for patients with SINAM. Some evidence has suggested that other lipid-lowering medications that avoid the mevalonate pathway, such as fenofibrate or ezetimibe, may be used cautiously initially at lower doses.¹ Due to the severity of SINAM, it is crucial to closely monitor and ensure tolerability as new lipid-lowering agents are introduced. More evidence suggests that PCSK9 inhibitors are a safer option.⁸ PCSK9 inhibitors avoid the mevalonate pathway and block PCSK9 from binding to LDL receptors, allowing LDL to be removed from circulation.

Tiniakou et al followed 8 individuals for a mean 1.5 years who had anti-HMGCR immune-mediated myopathy at high cardiovascular risk. Muscle strength, CPK levels, and serum anti-HMGCR antibody titers were assessed at baseline and again after initiation of PCSK9 inhibitor. None of the patients experienced a decline in their muscle strength. CPK, anti-HMGCR antibody levels, and LDL trended down in all participants and 2 patients were able to reduce their immunosuppression treatment while still achieving clinical improvement. Tiniakou et al suggest that PCSK9 inhibitors are a safe and effective option to lower cholesterol in patients with SINAM.⁸

Alirocumab is the preferred PCSK9 inhibitor for patients at the US Department of Veterans Affairs (VA). The VA Pharmacy Benefits Management (PBM) Service guidance recommends alirocumab for patients with a history of atherosclerotic cardiovascular disease (ASCVD) or severe hypercholesterolemia.⁹ PBM guidance suggests alirocumab use for patients with a contraindication, intolerance, or insufficient LDL reduction with a maximally tolerated dose of statin and ezetimibe with a desire to reduce ASCVD risk by lowering LDL. Per the PBM Criteria for Use guidance, patients should follow the stepwise approach and trial ezetimibe prior to being considered for PCSK9 inhibitor therapy. Given the patient’s contraindication to future statin use and severity of myopathy, in this case the Neurology Service felt that the safest option to reach goal LDL reduction would be a PCSK9 inhibitor. Consideration can be made for alirocumab use when considering an alternative lipid lowering therapy.

CONCLUSIONS

This report demonstrates a case of SINAM caused by atorvastatin therapy. Patients presenting with proximal muscle weakness and elevated CPK even after statin discontinuation should be considered for a full workup to determine whether SINAM may be involved. This uncommon form of myopathy can be diagnosed based on the detection of anti-HMGCR antibodies and/or presence of necrosis on muscle biopsy. A combination of glucocorticoid, methotrexate, and IVIG is recommended for a patient’s best chance of muscle symptom improvement. IVIG monotherapy should be considered for patients with glycemic control concerns.

Muscle-related complaints occur in 7% to 25% of patients taking statin medications.¹ In most instances, these adverse effects are quickly resolved when the medication is discontinued, but in rare occurrences, the statin can trigger an autoimmune response that progresses even after stopping use. This uncommon condition is typically accompanied by symmetrical proximal muscle weakness and an elevated CPK leading to a necrotizing myopathy requiring treatment with immunosuppressive therapy. Although less common, some patients may also present with dysphagia, myalgia, weight loss, and/or skin rash.¹

Statin medications have been the cornerstone of lipid-lowering therapy due to their mechanism of inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), which is the rate-limiting step within the cholesterol synthesis pathway to produce mevalonic acid. There is a proven genetic association with human leukocyte antigen (HLA)-DRB1*11:01 in adults and anti-HMGCR–associated myopathy.¹ The incidence of statin-induced necrotizing autoimmune myopathy (SINAM) in relation to each specific statin agent remains unknown; however, a systematic review of case reports found higher correlations for atorvastatin and simvastatin.²

There are 2 ways to confirm a SINAM diagnosis. The first and simplest includes checking for the presence of antibodies against HMGCR. The anti-HMGCR antibody test is typically used as a definitive diagnosis because it has a high specificity for SINAM.³ The second and more invasive diagnosis method involves a muscle biopsy, which is identified as positive if the biopsy shows the presence of necrotic muscle fibers.^1,3

The anti-HMGCR antibody test can serve as a marker for disease activity because the antibodies are strongly correlated with CPK levels.¹ CPK levels indicate the severity of muscle injury and is often used in addition to either of the confirmatory tests because it is faster and less expensive. Anti-HMGCR titers may remain positive while CPK returns to baseline when SINAM is dormant. In addition, clinicians may use an electromyography (EMG) test to measure the muscle response in association to nerve stimulation. ¹ This test can show potential features of myopathic lesions such as positive sharp waves, spontaneous fibrillations, or myotonic repetitive potentials.

Typical treatment includes glucocorticoids as first-line agents, but SINAM can be difficult to treat due to its complicated pathophysiology processes.³ Escalation of therapy is sometimes required beyond a single agent; in these complex scenarios, methotrexate and/or intravenous (IV) immunoglobulin (IVIG) therapy are frequently added to the steroid therapy. There have been concerns with steroid use in specific patient populations due to the undesired adverse effect (AE) profile, and as a result IVIG has been used as monotherapy at a dose of 2 g/kg per month.³ Studies looking at IVIG monotherapy showed a reduction in CPK levels and improvement in strength after just 2 to 3 rounds of monthly treatment.³ Some patients receiving IVIG monotherapy even achieved baseline strength and no longer reported muscle-related symptoms, although the total treatment duration varied. A systematic review of 39 articles where glucocorticoids, IVIG, methotrexate and/or a combination were used to treat SINAM found an average time to remission of 8.6 months. Additionally, this systematic review observed more patients returned to baseline or experienced improvement in symptoms when being treated with a combination of glucocorticoid plus IVIG plus methotrexate.² Suggested dosing recommendations are available in Table 1.

Patients diagnosed with HMGCR antibody myopathy are contraindicated for future statin therapy.¹ Rechallenge of statins in this patient population has led to worsening of disease and therefore these patients should have a severe statin allergy listed in their medical documentation record.

CASE PRESENTATION

A 59-year-old male patient with a medical history including atrial fibrillation, peripheral vascular disease, type 2 diabetes mellitus (T2DM), hypertension, and peripheral neuropathy was referred by his primary care clinical pharmacist practitioner for an outpatient neurology consult. The patient reported a 4-month history of fatigue, lower extremity paresthesia, and progressive proximal muscle weakness which began in his legs, mostly noticeable when walking upstairs but quickly developed into bilateral arm weakness. The patient reported significant impact on his quality of life: he could no longer lift his arms above his head and had difficulty with daily activities such as brushing his hair or getting up from a chair. He reported multiple falls at home, and began to use a cane for assistance with ambulation. He confirmed adherence to atorvastatin over the past year. Laboratory testing on the day of the visit revealed an elevated CPK level at 9729 mcg/L (reference range for men, 30-300 mcg/L).

The patient was urged to go to the emergency department where his CPK level had increased to 12,990 mcg/L (Figure 1). The workup began to find the source of rhabdomyolysis and elevated liver enzymes differentiating autoimmune vs medication-induced myopathy. Upon admission atorvastatin was discontinued, anti-HMGCR antibody level was ordered, and IV fluids were started.

After 8 days of hospital admission with minimal improvement, Rheumatology and Neurology services were consulted in the setting of persistent CPK elevation and the potential neuropathic component of muscle weakness. Both consulting services agreed to consider muscle biopsy and EMG if the patient did not begin to show signs of improvement. The patient’s CPK levels remained elevated with minimal change in muscle weakness. The next step was a right quadricep muscle biopsy performed on Day 14 of admission. Sixteen days after admission, the anti-HMGCR antibody test (originally obtained upon admission) was positive and elevated at 249 CU/mL (reference range, < 20 CU/mL negative; reference range, ≥ 60 CU/mL strong positive), which confirmed the SINAM diagnosis (Table 2).

On Day 17 of hospitalization, the Neurology service initiated IVIG monotherapy to avoid the undesired glycemic AEs associated with glucocorticoids. The patient had a history of T2DM that was difficult to manage and his hemoglobin A_1c level was the best it had ever been (6.2%) relative to a peak A_1c of 11.0% 9 months prior. The patient was treated with a total IVIG dose of 2 g/kg divided into 3 daily doses while still obtaining CPK levels with daily laboratory tests to assist with trending the extent of disease severity improvement (Figures 2-4). After a 20-day hospital stay, the patient was discharged home with rehabilitation services and a scheduled outpatient EMG the following week.

The patient continued to report generalized body weakness, pain, and deconditioning upon discharge and was unable to attend the EMG neurology appointment. The patient did eventually attend a follow-up appointment about 6 weeks after hospital discharge and reported continued weakness. The Neurology service prescribed a 2-day IVIG regimen (total dose = 2 g/kg) monthly for the next 2 months. The patient returned to the neurology clinic 8 weeks later following 2 rounds of IVIG posthospitalization and reported that his muscle strength was returning, and he was able to slowly reintroduce exercise into his daily routine. During a follow-up appointment about 11 months after the initial hospitalization, the patient’s primary care clinical pharmacist provided education of effective management of cholesterol without statins, including use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors as recommended by the Neurology service. At this time, the patient’s calculated low-density lipoprotein (LDL) was 110 mg/dL (reference range, 0-99 mg/dL). The patient preferred to work on a healthy diet and positive lifestyle choices before trialing any lipid lowering therapies.

The patient appeared to tolerate this treatment regimen following 7 rounds of IVIG. He noted fatigue for about 24 hours after his infusion sessions but otherwise reported no additional AEs. He has continued to attend weekly physical therapy sessions and is able to walk without the assistance of a cane. He can now walk a mile before he begins to feel fatigued or experience bilateral lower leg pain. The pain appears neuropathic in nature, as the patient reports ongoing “pins and needles” sensation in his legs and feet. The patient has noticed a major improvement in his overall function, strength, and exercise tolerance since starting IVIG treatments and although he is not yet back to his baseline, he is motivated to continue his recovery. Neurology is considering ongoing treatment with IVIG monthly infusions given his continued clinical improvement.

DISCUSSION

There is limited evidence on the use of IVIG monotherapy for SINAM, although it may be a viable option for patients deemed poor candidates for glucocorticoid or methotrexate therapy. This particularly applies to patients with DM for which there may be concerns for managing blood glucose levels with steroid use. The Johns Hopkins Myositis Center evaluated 3 patients with SINAM who declined glucocorticoid therapy and had documented DM and weakness in the proximal arms and legs. Following 2 to 3 monthly rounds of IVIG 2 g/kg monotherapy, these patients had reduced CPK levels and had improvement in both arm and hip-flexion strength. Two patients reported no muscle-related symptoms after completing IVIG monotherapy treatment for 9 and 19 months.³

The optimal treatment duration for IVIG monotherapy for SINAM is still uncertain given the limited available data. The patient in this case report showed clinically significant muscle-related improvement following 7 monthly rounds of 2 g/kg IVIG treatments. The mechanism of action for IVIG in this setting is still unknown, although the medication may allow muscle regeneration to surpass muscle destruction, thus leading to resolution of the muscle-related symptoms.³

There are numerous concerns with IVIG use to consider prior to initiating treatment, including expense, AEs, patient response, and comorbidities. IVIG is considerably more expensive than glucocorticoid and methotrexate alternatives. Systemic reactions have been shown to occur in 5% to 15% of patients receiving IVIG infusion.⁴ The majority of these infusion reactions occur early during infusion or within a few hours after administration is complete.⁵ Early AEs to monitor for include injection site reactions, flu-like symptoms, dermatologic reactions, anaphylaxis, transfusion-related acute lung injury, and transfusion-associated circulatory overload. Additional AEs may be delayed, including thromboembolic events, acute kidney injury, aseptic meningitis, hemolysis, neutropenia, and blood-borne infection.⁶ IVIG has a boxed warning for thrombosis, renal dysfunction, and acute renal failure risk.⁷ There are multiple strategies documented to reduce the risk of IVIG reactions including slowing the infusion rate, ensuring adequate hydration, and/or giving analgesics, antihistamines, or steroids prior to infusion.⁶ The patient in this case had monthly IVIG infusions without the need of any pretreatment medications and only reported fatigue for about 24 hours following the infusion.

An essential question is how to provide safe cholesterol management for patients with SINAM. Some evidence has suggested that other lipid-lowering medications that avoid the mevalonate pathway, such as fenofibrate or ezetimibe, may be used cautiously initially at lower doses.¹ Due to the severity of SINAM, it is crucial to closely monitor and ensure tolerability as new lipid-lowering agents are introduced. More evidence suggests that PCSK9 inhibitors are a safer option.⁸ PCSK9 inhibitors avoid the mevalonate pathway and block PCSK9 from binding to LDL receptors, allowing LDL to be removed from circulation.

Tiniakou et al followed 8 individuals for a mean 1.5 years who had anti-HMGCR immune-mediated myopathy at high cardiovascular risk. Muscle strength, CPK levels, and serum anti-HMGCR antibody titers were assessed at baseline and again after initiation of PCSK9 inhibitor. None of the patients experienced a decline in their muscle strength. CPK, anti-HMGCR antibody levels, and LDL trended down in all participants and 2 patients were able to reduce their immunosuppression treatment while still achieving clinical improvement. Tiniakou et al suggest that PCSK9 inhibitors are a safe and effective option to lower cholesterol in patients with SINAM.⁸

Alirocumab is the preferred PCSK9 inhibitor for patients at the US Department of Veterans Affairs (VA). The VA Pharmacy Benefits Management (PBM) Service guidance recommends alirocumab for patients with a history of atherosclerotic cardiovascular disease (ASCVD) or severe hypercholesterolemia.⁹ PBM guidance suggests alirocumab use for patients with a contraindication, intolerance, or insufficient LDL reduction with a maximally tolerated dose of statin and ezetimibe with a desire to reduce ASCVD risk by lowering LDL. Per the PBM Criteria for Use guidance, patients should follow the stepwise approach and trial ezetimibe prior to being considered for PCSK9 inhibitor therapy. Given the patient’s contraindication to future statin use and severity of myopathy, in this case the Neurology Service felt that the safest option to reach goal LDL reduction would be a PCSK9 inhibitor. Consideration can be made for alirocumab use when considering an alternative lipid lowering therapy.

CONCLUSIONS

This report demonstrates a case of SINAM caused by atorvastatin therapy. Patients presenting with proximal muscle weakness and elevated CPK even after statin discontinuation should be considered for a full workup to determine whether SINAM may be involved. This uncommon form of myopathy can be diagnosed based on the detection of anti-HMGCR antibodies and/or presence of necrosis on muscle biopsy. A combination of glucocorticoid, methotrexate, and IVIG is recommended for a patient’s best chance of muscle symptom improvement. IVIG monotherapy should be considered for patients with glycemic control concerns.

Muscle-related complaints occur in 7% to 25% of patients taking statin medications.¹ In most instances, these adverse effects are quickly resolved when the medication is discontinued, but in rare occurrences, the statin can trigger an autoimmune response that progresses even after stopping use. This uncommon condition is typically accompanied by symmetrical proximal muscle weakness and an elevated CPK leading to a necrotizing myopathy requiring treatment with immunosuppressive therapy. Although less common, some patients may also present with dysphagia, myalgia, weight loss, and/or skin rash.¹

Statin medications have been the cornerstone of lipid-lowering therapy due to their mechanism of inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), which is the rate-limiting step within the cholesterol synthesis pathway to produce mevalonic acid. There is a proven genetic association with human leukocyte antigen (HLA)-DRB1*11:01 in adults and anti-HMGCR–associated myopathy.¹ The incidence of statin-induced necrotizing autoimmune myopathy (SINAM) in relation to each specific statin agent remains unknown; however, a systematic review of case reports found higher correlations for atorvastatin and simvastatin.²

There are 2 ways to confirm a SINAM diagnosis. The first and simplest includes checking for the presence of antibodies against HMGCR. The anti-HMGCR antibody test is typically used as a definitive diagnosis because it has a high specificity for SINAM.³ The second and more invasive diagnosis method involves a muscle biopsy, which is identified as positive if the biopsy shows the presence of necrotic muscle fibers.^1,3

The anti-HMGCR antibody test can serve as a marker for disease activity because the antibodies are strongly correlated with CPK levels.¹ CPK levels indicate the severity of muscle injury and is often used in addition to either of the confirmatory tests because it is faster and less expensive. Anti-HMGCR titers may remain positive while CPK returns to baseline when SINAM is dormant. In addition, clinicians may use an electromyography (EMG) test to measure the muscle response in association to nerve stimulation. ¹ This test can show potential features of myopathic lesions such as positive sharp waves, spontaneous fibrillations, or myotonic repetitive potentials.

Typical treatment includes glucocorticoids as first-line agents, but SINAM can be difficult to treat due to its complicated pathophysiology processes.³ Escalation of therapy is sometimes required beyond a single agent; in these complex scenarios, methotrexate and/or intravenous (IV) immunoglobulin (IVIG) therapy are frequently added to the steroid therapy. There have been concerns with steroid use in specific patient populations due to the undesired adverse effect (AE) profile, and as a result IVIG has been used as monotherapy at a dose of 2 g/kg per month.³ Studies looking at IVIG monotherapy showed a reduction in CPK levels and improvement in strength after just 2 to 3 rounds of monthly treatment.³ Some patients receiving IVIG monotherapy even achieved baseline strength and no longer reported muscle-related symptoms, although the total treatment duration varied. A systematic review of 39 articles where glucocorticoids, IVIG, methotrexate and/or a combination were used to treat SINAM found an average time to remission of 8.6 months. Additionally, this systematic review observed more patients returned to baseline or experienced improvement in symptoms when being treated with a combination of glucocorticoid plus IVIG plus methotrexate.² Suggested dosing recommendations are available in Table 1.

Patients diagnosed with HMGCR antibody myopathy are contraindicated for future statin therapy.¹ Rechallenge of statins in this patient population has led to worsening of disease and therefore these patients should have a severe statin allergy listed in their medical documentation record.

CASE PRESENTATION

A 59-year-old male patient with a medical history including atrial fibrillation, peripheral vascular disease, type 2 diabetes mellitus (T2DM), hypertension, and peripheral neuropathy was referred by his primary care clinical pharmacist practitioner for an outpatient neurology consult. The patient reported a 4-month history of fatigue, lower extremity paresthesia, and progressive proximal muscle weakness which began in his legs, mostly noticeable when walking upstairs but quickly developed into bilateral arm weakness. The patient reported significant impact on his quality of life: he could no longer lift his arms above his head and had difficulty with daily activities such as brushing his hair or getting up from a chair. He reported multiple falls at home, and began to use a cane for assistance with ambulation. He confirmed adherence to atorvastatin over the past year. Laboratory testing on the day of the visit revealed an elevated CPK level at 9729 mcg/L (reference range for men, 30-300 mcg/L).

The patient was urged to go to the emergency department where his CPK level had increased to 12,990 mcg/L (Figure 1). The workup began to find the source of rhabdomyolysis and elevated liver enzymes differentiating autoimmune vs medication-induced myopathy. Upon admission atorvastatin was discontinued, anti-HMGCR antibody level was ordered, and IV fluids were started.

After 8 days of hospital admission with minimal improvement, Rheumatology and Neurology services were consulted in the setting of persistent CPK elevation and the potential neuropathic component of muscle weakness. Both consulting services agreed to consider muscle biopsy and EMG if the patient did not begin to show signs of improvement. The patient’s CPK levels remained elevated with minimal change in muscle weakness. The next step was a right quadricep muscle biopsy performed on Day 14 of admission. Sixteen days after admission, the anti-HMGCR antibody test (originally obtained upon admission) was positive and elevated at 249 CU/mL (reference range, < 20 CU/mL negative; reference range, ≥ 60 CU/mL strong positive), which confirmed the SINAM diagnosis (Table 2).

On Day 17 of hospitalization, the Neurology service initiated IVIG monotherapy to avoid the undesired glycemic AEs associated with glucocorticoids. The patient had a history of T2DM that was difficult to manage and his hemoglobin A_1c level was the best it had ever been (6.2%) relative to a peak A_1c of 11.0% 9 months prior. The patient was treated with a total IVIG dose of 2 g/kg divided into 3 daily doses while still obtaining CPK levels with daily laboratory tests to assist with trending the extent of disease severity improvement (Figures 2-4). After a 20-day hospital stay, the patient was discharged home with rehabilitation services and a scheduled outpatient EMG the following week.

The patient continued to report generalized body weakness, pain, and deconditioning upon discharge and was unable to attend the EMG neurology appointment. The patient did eventually attend a follow-up appointment about 6 weeks after hospital discharge and reported continued weakness. The Neurology service prescribed a 2-day IVIG regimen (total dose = 2 g/kg) monthly for the next 2 months. The patient returned to the neurology clinic 8 weeks later following 2 rounds of IVIG posthospitalization and reported that his muscle strength was returning, and he was able to slowly reintroduce exercise into his daily routine. During a follow-up appointment about 11 months after the initial hospitalization, the patient’s primary care clinical pharmacist provided education of effective management of cholesterol without statins, including use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors as recommended by the Neurology service. At this time, the patient’s calculated low-density lipoprotein (LDL) was 110 mg/dL (reference range, 0-99 mg/dL). The patient preferred to work on a healthy diet and positive lifestyle choices before trialing any lipid lowering therapies.

The patient appeared to tolerate this treatment regimen following 7 rounds of IVIG. He noted fatigue for about 24 hours after his infusion sessions but otherwise reported no additional AEs. He has continued to attend weekly physical therapy sessions and is able to walk without the assistance of a cane. He can now walk a mile before he begins to feel fatigued or experience bilateral lower leg pain. The pain appears neuropathic in nature, as the patient reports ongoing “pins and needles” sensation in his legs and feet. The patient has noticed a major improvement in his overall function, strength, and exercise tolerance since starting IVIG treatments and although he is not yet back to his baseline, he is motivated to continue his recovery. Neurology is considering ongoing treatment with IVIG monthly infusions given his continued clinical improvement.

DISCUSSION

There is limited evidence on the use of IVIG monotherapy for SINAM, although it may be a viable option for patients deemed poor candidates for glucocorticoid or methotrexate therapy. This particularly applies to patients with DM for which there may be concerns for managing blood glucose levels with steroid use. The Johns Hopkins Myositis Center evaluated 3 patients with SINAM who declined glucocorticoid therapy and had documented DM and weakness in the proximal arms and legs. Following 2 to 3 monthly rounds of IVIG 2 g/kg monotherapy, these patients had reduced CPK levels and had improvement in both arm and hip-flexion strength. Two patients reported no muscle-related symptoms after completing IVIG monotherapy treatment for 9 and 19 months.³

The optimal treatment duration for IVIG monotherapy for SINAM is still uncertain given the limited available data. The patient in this case report showed clinically significant muscle-related improvement following 7 monthly rounds of 2 g/kg IVIG treatments. The mechanism of action for IVIG in this setting is still unknown, although the medication may allow muscle regeneration to surpass muscle destruction, thus leading to resolution of the muscle-related symptoms.³

There are numerous concerns with IVIG use to consider prior to initiating treatment, including expense, AEs, patient response, and comorbidities. IVIG is considerably more expensive than glucocorticoid and methotrexate alternatives. Systemic reactions have been shown to occur in 5% to 15% of patients receiving IVIG infusion.⁴ The majority of these infusion reactions occur early during infusion or within a few hours after administration is complete.⁵ Early AEs to monitor for include injection site reactions, flu-like symptoms, dermatologic reactions, anaphylaxis, transfusion-related acute lung injury, and transfusion-associated circulatory overload. Additional AEs may be delayed, including thromboembolic events, acute kidney injury, aseptic meningitis, hemolysis, neutropenia, and blood-borne infection.⁶ IVIG has a boxed warning for thrombosis, renal dysfunction, and acute renal failure risk.⁷ There are multiple strategies documented to reduce the risk of IVIG reactions including slowing the infusion rate, ensuring adequate hydration, and/or giving analgesics, antihistamines, or steroids prior to infusion.⁶ The patient in this case had monthly IVIG infusions without the need of any pretreatment medications and only reported fatigue for about 24 hours following the infusion.

An essential question is how to provide safe cholesterol management for patients with SINAM. Some evidence has suggested that other lipid-lowering medications that avoid the mevalonate pathway, such as fenofibrate or ezetimibe, may be used cautiously initially at lower doses.¹ Due to the severity of SINAM, it is crucial to closely monitor and ensure tolerability as new lipid-lowering agents are introduced. More evidence suggests that PCSK9 inhibitors are a safer option.⁸ PCSK9 inhibitors avoid the mevalonate pathway and block PCSK9 from binding to LDL receptors, allowing LDL to be removed from circulation.

Tiniakou et al followed 8 individuals for a mean 1.5 years who had anti-HMGCR immune-mediated myopathy at high cardiovascular risk. Muscle strength, CPK levels, and serum anti-HMGCR antibody titers were assessed at baseline and again after initiation of PCSK9 inhibitor. None of the patients experienced a decline in their muscle strength. CPK, anti-HMGCR antibody levels, and LDL trended down in all participants and 2 patients were able to reduce their immunosuppression treatment while still achieving clinical improvement. Tiniakou et al suggest that PCSK9 inhibitors are a safe and effective option to lower cholesterol in patients with SINAM.⁸

Alirocumab is the preferred PCSK9 inhibitor for patients at the US Department of Veterans Affairs (VA). The VA Pharmacy Benefits Management (PBM) Service guidance recommends alirocumab for patients with a history of atherosclerotic cardiovascular disease (ASCVD) or severe hypercholesterolemia.⁹ PBM guidance suggests alirocumab use for patients with a contraindication, intolerance, or insufficient LDL reduction with a maximally tolerated dose of statin and ezetimibe with a desire to reduce ASCVD risk by lowering LDL. Per the PBM Criteria for Use guidance, patients should follow the stepwise approach and trial ezetimibe prior to being considered for PCSK9 inhibitor therapy. Given the patient’s contraindication to future statin use and severity of myopathy, in this case the Neurology Service felt that the safest option to reach goal LDL reduction would be a PCSK9 inhibitor. Consideration can be made for alirocumab use when considering an alternative lipid lowering therapy.

CONCLUSIONS

This report demonstrates a case of SINAM caused by atorvastatin therapy. Patients presenting with proximal muscle weakness and elevated CPK even after statin discontinuation should be considered for a full workup to determine whether SINAM may be involved. This uncommon form of myopathy can be diagnosed based on the detection of anti-HMGCR antibodies and/or presence of necrosis on muscle biopsy. A combination of glucocorticoid, methotrexate, and IVIG is recommended for a patient’s best chance of muscle symptom improvement. IVIG monotherapy should be considered for patients with glycemic control concerns.

Pemphigoid gestationis (PG), which manifests in the second or third trimester of pregnancy, is thought to result from an excessive type 2 inflammatory response that leads to the formation of antibodies primarily targeting BP180 antigens with resultant damage to the skin basement membrane.¹ Maternal antibodies can be transferred to the fetus, resulting in neonatal pemphigoid with the development of widespread vesicles and bullae.² Maternal morbidity from placental insufficiency, intrauterine growth restriction, and premature labor are common comorbidities of PG, underscoring the critical need for safe and effective treatments for this condition.³

Systemic corticosteroids currently are the first-line treatment for moderate to severe PG but carry considerable risks to both the mother and fetus, including preterm labor and intrauterine growth restriction.^4,5 Dupilumab is approved by the US Food and Drug Administration for moderate to severe atopic dermatitis in children aged 6 months and older. Dupilumab inhibits downstream signaling of IL-4Rα, reducing IL-4 and IL-13. Use of dupilumab to target the type 2 inflammatory response has shown significant promise in the treatment of BP, where it met primary and secondary endpoints in adults with moderate to severe disease, but studies in PG are limited.^6-8 There are multiple reports in the literature demonstrating the safety of dupilumab in pregnancy and postpartum,^9-27 including a pharmacovigilance report that found no adverse drug reactions from dupilumab reported during pregnancy.⁹ There also are 4 reports of pregnant patients who were diagnosed with PG and treated with dupilumab, all of whom were initially started on prednisone prior to treatment initiation.^9-12 In this article, we report 2 additional cases of dupilumab treatment in patients with PG.

Case Reports

Patient 1—A 39-year-old G5P1 woman presented to the dermatology department at 27.5 weeks’ gestation with a widespread eruption of erythematous, annular, urticarial, edematous papules and plaques on the abdomen of 4 weeks’ duration (Figure 1A). Direct immunofluorescence was positive, indirect immunofluorescence confirmed an IgG-positive epidermal pattern, and serum BP180 levels were elevated, supporting a diagnosis of PG. The patient was prescribed prednisone (60 mg/d) but developed type 1 diabetes mellitus after 1 week of treatment. Following insurance approval, dupilumab therapy was initiated 3 weeks later at a dose of 300 mg subcutaneously every 2 weeks. Rapid and complete resolution of papules and plaques as well as symptomatic relief from pruritus was noted within 2 weeks of treatment (Figure 1B). The prednisone dose was tapered to 2.5 mg every other day at 6 weeks prior to induction of labor; the diabetes resolved 7 weeks after initiation of dupilumab.

At the recommendation of the patient’s high-risk maternal-fetal medicine team, 100 mg of stress-dose hydrocortisone was administered intravenously just prior to delivery to prevent flaring of PG. She delivered a healthy infant at 37 weeks and 3 days’ gestation without bullous disease and was discharged from the hospital the day after delivery on a prednisone dose of 2.5 mg every other day.

The patient subsequently developed localized pruritic papules on the hands and feet at 2 weeks postpartum. Based on shared decision-making and the patient’s concern for the severity of the previous pruritic eruption, prednisone was increased to 10 mg daily for 5 days and then was tapered over 2 weeks without flaring. Dupilumab was continued until 12 weeks postpartum with complete resolution of PG and no further sequelae.

Patient 2—A 30-year-old G1P0 woman presented to the dermatology department at 25 weeks’ gestation with a widespread eruption of 1 week’s duration on the abdomen, hands, thighs, legs, buttocks, and feet that was clinically consistent with PG (Figure 2A). Direct immunofluorescence was positive, indirect immunofluorescence showed an IgG-positive epidermal pattern, and an enzyme-linked immunosorbent assay for BP180 was elevated, confirming a diagnosis of PG. The patient was started on 40 mg of prednisone and topical steroids daily, with improvement of the pruritus but persistence of the eruption after 3 to 4 days. Five days after the initial presentation following expedited insurance approval, dupilumab 300 mg was initiated subcutaneously every 2 weeks along with a slow taper of prednisone to 5 mg, with complete clearance of the eruption within 4 weeks (Figure 2B). She delivered a healthy infant at 38 weeks’ gestation without bullous disease.

In contrast to patient 1, this patient did not receive corticosteroids at the time of delivery and did not experience flaring of her disease. The patient remained on dupilumab 5 weeks postpartum without subsequent recurrence after treatment discontinuation.

Comment

Although a myriad of effective treatments exist for bullous pemphigoid, there are very few options for PG due to the need for treatment during pregnancy. Systemic corticosteroids—the treatment of choice in severe PG disease—are not without risk in pregnancy and complicate assessment of morbidity, as both PG and chronic steroid exposure are associated with preterm labor and intrauterine growth restriction.³

Dupilumab currently is undergoing phase III trials (Clinicaltrials.gov identifiers NCT02277743 and NCT02277769) for the treatment of bullous pemphigoid, with interim reports suggesting efficacy across all primary and key secondary endpoints in moderate to severe disease, including notable steroid-sparing effects.⁸ In our patients, treatment with dupilumab resulted in resolution of cutaneous disease and was well tolerated, facilitating the tapering of corticosteroids and resolution of type 1 diabetes in patient 1. Although the response to dupilumab in both cases may have been confounded by concomitant steroid administration, which was started due to the severity of symptoms and uncertainty regarding insurance approval, the dose was tapered in both patients after initiation of dupilumab. Patient 1 was given a stress dose of hydrocortisone during delivery and developed a mild flare following delivery, consistent with previous literature.^{28, 29} Because the flare was localized to the hands and feet, she might have responded to clobetasol in addition to dupilumab, but given the severity of disease at presentation and her concern that it might worsen, low-dose prednisone was added with resolution of the flare within 2 weeks.

Dupilumab dosing regimens have not been studied in a controlled prospective manner for PG. We acknowledge that dupilumab (at least using the conventional atopic dermatitis dosing regimen) may be insufficient as monotherapy to control PG, as both patients received steroids prior to initiation of dupilumab, in part due to concern that the insurance might delay or deny approval. Previous World Health Organization vigilance reporting has suggested that dupilumab appears safe during pregnancy although it lacks pregnancy categorization in the United States due to limited studies in this population.^9-28 This observation supports the conclusion that, like bullous pemphigoid, PG also is driven by Th2–mediated inflammation. Treatment with dupilumab may be safe and effective in pregnancy, reducing maternal complications from long-term corticosteroids. Additional studies are needed to confirm these hypotheses.

Pemphigoid gestationis (PG), which manifests in the second or third trimester of pregnancy, is thought to result from an excessive type 2 inflammatory response that leads to the formation of antibodies primarily targeting BP180 antigens with resultant damage to the skin basement membrane.¹ Maternal antibodies can be transferred to the fetus, resulting in neonatal pemphigoid with the development of widespread vesicles and bullae.² Maternal morbidity from placental insufficiency, intrauterine growth restriction, and premature labor are common comorbidities of PG, underscoring the critical need for safe and effective treatments for this condition.³

Systemic corticosteroids currently are the first-line treatment for moderate to severe PG but carry considerable risks to both the mother and fetus, including preterm labor and intrauterine growth restriction.^4,5 Dupilumab is approved by the US Food and Drug Administration for moderate to severe atopic dermatitis in children aged 6 months and older. Dupilumab inhibits downstream signaling of IL-4Rα, reducing IL-4 and IL-13. Use of dupilumab to target the type 2 inflammatory response has shown significant promise in the treatment of BP, where it met primary and secondary endpoints in adults with moderate to severe disease, but studies in PG are limited.^6-8 There are multiple reports in the literature demonstrating the safety of dupilumab in pregnancy and postpartum,^9-27 including a pharmacovigilance report that found no adverse drug reactions from dupilumab reported during pregnancy.⁹ There also are 4 reports of pregnant patients who were diagnosed with PG and treated with dupilumab, all of whom were initially started on prednisone prior to treatment initiation.^9-12 In this article, we report 2 additional cases of dupilumab treatment in patients with PG.

Case Reports

Patient 1—A 39-year-old G5P1 woman presented to the dermatology department at 27.5 weeks’ gestation with a widespread eruption of erythematous, annular, urticarial, edematous papules and plaques on the abdomen of 4 weeks’ duration (Figure 1A). Direct immunofluorescence was positive, indirect immunofluorescence confirmed an IgG-positive epidermal pattern, and serum BP180 levels were elevated, supporting a diagnosis of PG. The patient was prescribed prednisone (60 mg/d) but developed type 1 diabetes mellitus after 1 week of treatment. Following insurance approval, dupilumab therapy was initiated 3 weeks later at a dose of 300 mg subcutaneously every 2 weeks. Rapid and complete resolution of papules and plaques as well as symptomatic relief from pruritus was noted within 2 weeks of treatment (Figure 1B). The prednisone dose was tapered to 2.5 mg every other day at 6 weeks prior to induction of labor; the diabetes resolved 7 weeks after initiation of dupilumab.

At the recommendation of the patient’s high-risk maternal-fetal medicine team, 100 mg of stress-dose hydrocortisone was administered intravenously just prior to delivery to prevent flaring of PG. She delivered a healthy infant at 37 weeks and 3 days’ gestation without bullous disease and was discharged from the hospital the day after delivery on a prednisone dose of 2.5 mg every other day.

The patient subsequently developed localized pruritic papules on the hands and feet at 2 weeks postpartum. Based on shared decision-making and the patient’s concern for the severity of the previous pruritic eruption, prednisone was increased to 10 mg daily for 5 days and then was tapered over 2 weeks without flaring. Dupilumab was continued until 12 weeks postpartum with complete resolution of PG and no further sequelae.

Patient 2—A 30-year-old G1P0 woman presented to the dermatology department at 25 weeks’ gestation with a widespread eruption of 1 week’s duration on the abdomen, hands, thighs, legs, buttocks, and feet that was clinically consistent with PG (Figure 2A). Direct immunofluorescence was positive, indirect immunofluorescence showed an IgG-positive epidermal pattern, and an enzyme-linked immunosorbent assay for BP180 was elevated, confirming a diagnosis of PG. The patient was started on 40 mg of prednisone and topical steroids daily, with improvement of the pruritus but persistence of the eruption after 3 to 4 days. Five days after the initial presentation following expedited insurance approval, dupilumab 300 mg was initiated subcutaneously every 2 weeks along with a slow taper of prednisone to 5 mg, with complete clearance of the eruption within 4 weeks (Figure 2B). She delivered a healthy infant at 38 weeks’ gestation without bullous disease.

In contrast to patient 1, this patient did not receive corticosteroids at the time of delivery and did not experience flaring of her disease. The patient remained on dupilumab 5 weeks postpartum without subsequent recurrence after treatment discontinuation.

Comment

Although a myriad of effective treatments exist for bullous pemphigoid, there are very few options for PG due to the need for treatment during pregnancy. Systemic corticosteroids—the treatment of choice in severe PG disease—are not without risk in pregnancy and complicate assessment of morbidity, as both PG and chronic steroid exposure are associated with preterm labor and intrauterine growth restriction.³

Dupilumab currently is undergoing phase III trials (Clinicaltrials.gov identifiers NCT02277743 and NCT02277769) for the treatment of bullous pemphigoid, with interim reports suggesting efficacy across all primary and key secondary endpoints in moderate to severe disease, including notable steroid-sparing effects.⁸ In our patients, treatment with dupilumab resulted in resolution of cutaneous disease and was well tolerated, facilitating the tapering of corticosteroids and resolution of type 1 diabetes in patient 1. Although the response to dupilumab in both cases may have been confounded by concomitant steroid administration, which was started due to the severity of symptoms and uncertainty regarding insurance approval, the dose was tapered in both patients after initiation of dupilumab. Patient 1 was given a stress dose of hydrocortisone during delivery and developed a mild flare following delivery, consistent with previous literature.^{28, 29} Because the flare was localized to the hands and feet, she might have responded to clobetasol in addition to dupilumab, but given the severity of disease at presentation and her concern that it might worsen, low-dose prednisone was added with resolution of the flare within 2 weeks.

Dupilumab dosing regimens have not been studied in a controlled prospective manner for PG. We acknowledge that dupilumab (at least using the conventional atopic dermatitis dosing regimen) may be insufficient as monotherapy to control PG, as both patients received steroids prior to initiation of dupilumab, in part due to concern that the insurance might delay or deny approval. Previous World Health Organization vigilance reporting has suggested that dupilumab appears safe during pregnancy although it lacks pregnancy categorization in the United States due to limited studies in this population.^9-28 This observation supports the conclusion that, like bullous pemphigoid, PG also is driven by Th2–mediated inflammation. Treatment with dupilumab may be safe and effective in pregnancy, reducing maternal complications from long-term corticosteroids. Additional studies are needed to confirm these hypotheses.

Pemphigoid gestationis (PG), which manifests in the second or third trimester of pregnancy, is thought to result from an excessive type 2 inflammatory response that leads to the formation of antibodies primarily targeting BP180 antigens with resultant damage to the skin basement membrane.¹ Maternal antibodies can be transferred to the fetus, resulting in neonatal pemphigoid with the development of widespread vesicles and bullae.² Maternal morbidity from placental insufficiency, intrauterine growth restriction, and premature labor are common comorbidities of PG, underscoring the critical need for safe and effective treatments for this condition.³

Systemic corticosteroids currently are the first-line treatment for moderate to severe PG but carry considerable risks to both the mother and fetus, including preterm labor and intrauterine growth restriction.^4,5 Dupilumab is approved by the US Food and Drug Administration for moderate to severe atopic dermatitis in children aged 6 months and older. Dupilumab inhibits downstream signaling of IL-4Rα, reducing IL-4 and IL-13. Use of dupilumab to target the type 2 inflammatory response has shown significant promise in the treatment of BP, where it met primary and secondary endpoints in adults with moderate to severe disease, but studies in PG are limited.^6-8 There are multiple reports in the literature demonstrating the safety of dupilumab in pregnancy and postpartum,^9-27 including a pharmacovigilance report that found no adverse drug reactions from dupilumab reported during pregnancy.⁹ There also are 4 reports of pregnant patients who were diagnosed with PG and treated with dupilumab, all of whom were initially started on prednisone prior to treatment initiation.^9-12 In this article, we report 2 additional cases of dupilumab treatment in patients with PG.

Case Reports

Patient 1—A 39-year-old G5P1 woman presented to the dermatology department at 27.5 weeks’ gestation with a widespread eruption of erythematous, annular, urticarial, edematous papules and plaques on the abdomen of 4 weeks’ duration (Figure 1A). Direct immunofluorescence was positive, indirect immunofluorescence confirmed an IgG-positive epidermal pattern, and serum BP180 levels were elevated, supporting a diagnosis of PG. The patient was prescribed prednisone (60 mg/d) but developed type 1 diabetes mellitus after 1 week of treatment. Following insurance approval, dupilumab therapy was initiated 3 weeks later at a dose of 300 mg subcutaneously every 2 weeks. Rapid and complete resolution of papules and plaques as well as symptomatic relief from pruritus was noted within 2 weeks of treatment (Figure 1B). The prednisone dose was tapered to 2.5 mg every other day at 6 weeks prior to induction of labor; the diabetes resolved 7 weeks after initiation of dupilumab.

At the recommendation of the patient’s high-risk maternal-fetal medicine team, 100 mg of stress-dose hydrocortisone was administered intravenously just prior to delivery to prevent flaring of PG. She delivered a healthy infant at 37 weeks and 3 days’ gestation without bullous disease and was discharged from the hospital the day after delivery on a prednisone dose of 2.5 mg every other day.

The patient subsequently developed localized pruritic papules on the hands and feet at 2 weeks postpartum. Based on shared decision-making and the patient’s concern for the severity of the previous pruritic eruption, prednisone was increased to 10 mg daily for 5 days and then was tapered over 2 weeks without flaring. Dupilumab was continued until 12 weeks postpartum with complete resolution of PG and no further sequelae.

Patient 2—A 30-year-old G1P0 woman presented to the dermatology department at 25 weeks’ gestation with a widespread eruption of 1 week’s duration on the abdomen, hands, thighs, legs, buttocks, and feet that was clinically consistent with PG (Figure 2A). Direct immunofluorescence was positive, indirect immunofluorescence showed an IgG-positive epidermal pattern, and an enzyme-linked immunosorbent assay for BP180 was elevated, confirming a diagnosis of PG. The patient was started on 40 mg of prednisone and topical steroids daily, with improvement of the pruritus but persistence of the eruption after 3 to 4 days. Five days after the initial presentation following expedited insurance approval, dupilumab 300 mg was initiated subcutaneously every 2 weeks along with a slow taper of prednisone to 5 mg, with complete clearance of the eruption within 4 weeks (Figure 2B). She delivered a healthy infant at 38 weeks’ gestation without bullous disease.

In contrast to patient 1, this patient did not receive corticosteroids at the time of delivery and did not experience flaring of her disease. The patient remained on dupilumab 5 weeks postpartum without subsequent recurrence after treatment discontinuation.

Comment

Although a myriad of effective treatments exist for bullous pemphigoid, there are very few options for PG due to the need for treatment during pregnancy. Systemic corticosteroids—the treatment of choice in severe PG disease—are not without risk in pregnancy and complicate assessment of morbidity, as both PG and chronic steroid exposure are associated with preterm labor and intrauterine growth restriction.³

Dupilumab currently is undergoing phase III trials (Clinicaltrials.gov identifiers NCT02277743 and NCT02277769) for the treatment of bullous pemphigoid, with interim reports suggesting efficacy across all primary and key secondary endpoints in moderate to severe disease, including notable steroid-sparing effects.⁸ In our patients, treatment with dupilumab resulted in resolution of cutaneous disease and was well tolerated, facilitating the tapering of corticosteroids and resolution of type 1 diabetes in patient 1. Although the response to dupilumab in both cases may have been confounded by concomitant steroid administration, which was started due to the severity of symptoms and uncertainty regarding insurance approval, the dose was tapered in both patients after initiation of dupilumab. Patient 1 was given a stress dose of hydrocortisone during delivery and developed a mild flare following delivery, consistent with previous literature.^{28, 29} Because the flare was localized to the hands and feet, she might have responded to clobetasol in addition to dupilumab, but given the severity of disease at presentation and her concern that it might worsen, low-dose prednisone was added with resolution of the flare within 2 weeks.

Dupilumab dosing regimens have not been studied in a controlled prospective manner for PG. We acknowledge that dupilumab (at least using the conventional atopic dermatitis dosing regimen) may be insufficient as monotherapy to control PG, as both patients received steroids prior to initiation of dupilumab, in part due to concern that the insurance might delay or deny approval. Previous World Health Organization vigilance reporting has suggested that dupilumab appears safe during pregnancy although it lacks pregnancy categorization in the United States due to limited studies in this population.^9-28 This observation supports the conclusion that, like bullous pemphigoid, PG also is driven by Th2–mediated inflammation. Treatment with dupilumab may be safe and effective in pregnancy, reducing maternal complications from long-term corticosteroids. Additional studies are needed to confirm these hypotheses.

THE DIAGNOSIS: Hypertrophic Lupus Erythematosus

The biopsy of the face collected at the initial appointment revealed interface dermatitis with epidermal hyperplasia with no parakeratosis or eosinophils (Figure 1). Microscopic findings were suggestive of hypertrophic lupus erythematosus (HLE) or hypertrophic lichen planus. The rapid plasma reagin and HIV labs collected at the initial appointment were negative, and a review of systems was negative for systemic symptoms. Considering these results and the clinical distribution of the lesions primarily affecting sun-exposed areas of the upper body, a final diagnosis of HLE was made. The patient was counseled on the importance of photoprotection and was started on hydroxychloroquine.

Hypertrophic lupus erythematosus, a rare variant of chronic cutaneous lupus erythematosus (CCLE), typically manifests as verrucous plaques or nodules commonly found on sun-exposed areas of the body, as was observed in our patient on the face, scalp (Figures 2 and 3), chest, and upper extremities.¹ Lesions can have a variable appearance, from hyperkeratotic ulcers to depigmented plaques and keratoacanthomalike lesions.² On histopathology, HLE falls into the category of lichenoid interface dermatitis and commonly demonstrates hyperkeratosis, acanthosis, follicular plugging, superficial and deep infiltrate, and increased mucin deposition in the dermis.³

Although rare, it is critical to remain vigilant for the development of squamous cell carcinoma in patients with chronic untreated CCLE. Hypertrophic lupus erythematosus, specifically, is the most likely variant to give rise to invasive squamous cell carcinoma and can be more aggressive as a result of this malignant transformation.^3,4 Ruling out squamous cell carcinoma in the setting of HLE can be achieved by staining for CD123, as HLE commonly is associated with many CD123+ plasmacytoid dendritic cells adjacent to the epithelium, unlike squamous cell carcinoma.³ Fortunately no evidence of invasive squamous cell carcinoma, including cellular atypia or increased mitotic figures, was seen on histology in our patient.

A thorough history and physical examination are essential for screening for HLE, as positive antinuclear antibodies are observed only in half of the patients diagnosed with CCLE.⁵ Furthermore, antinuclear antibodies sometimes can be negative in patients with HLE who have end-stage organ involvement.

Hypertrophic lupus erythematosus can be challenging to treat. First-line therapies include antimalarials, topical steroids, and sun-protective measures. Intralesional triamcinolone injection also can be used as an adjunctive therapy to expedite the treatment response.⁶ Evidence supports good response following treatment with acitretin or a combination of isotretinoin and hydroxychloroquine.² Another therapeutic strategy is implementing immunosuppressants such as methotrexate, mycophenolate mofetil, and azathioprine for persistent disease. Immunomodulators such as thalidomide historically have been shown to treat severe recalcitrant cases of HLE but typically are reserved for extreme cases due to adverse effects. Biologic agents such as intravenous immunoglobulins and rituximab have been shown to treat CCLE successfully, but routine use is limited due to high cost and lack of strong clinical trials.⁷

There have been reports of experimental therapies such as monoclonal antibodies (eg, anifrolumab and tocilizumab therapy) providing remission for patients with refractory CCLE, but information on their efficacy—specifically in patients with HLE—is lacking.⁸ Chronic cutaneous lupus erythematosus and its variants require further investigation regarding which treatment options provide the greatest benefit while minimizing adverse effects.

It is important to distinguish HLE from other potential diagnoses. Features of HLE can mimic hypertrophic lichen planus; however, the latter typically appears on the legs while HLE appears more commonly on the upper extremities and face in a photodistributed pattern.⁹ Since HLE has a lichenoid appearance histologically, it may appear clinically similar to hypertrophic lichen planus. Although not performed in our patient due to cost, direct immunofluorescence can aid in distinguishing HLE from hypertrophic lichen planus. Chronic cutaneous lupus erythematosus shows a granular pattern of deposition of IgM (primarily), IgG, IgA, and C3. In contrast, hypertrophic lichen planus exhibits cytoid bodies that stain positive for IgM as well as linear deposition of fibrinogen along the basement membrane.^3,10

Blastomycosis also can lead to development of verrucous plaques in sun-exposed areas, but the lesions typically originate as pustules that ulcerate over time. Lesions also can manifest with central scarring and a heaped edge.³ Unlike HLE, pseudoepitheliomatous hyperplasia with mixed infiltrate and intradermal pustules are seen in blastomycosis.³ Fungal organisms often are seen on pathology and are relatively large and uniform in size and shape, are found within giant cells, and have a thick refractile asymmetrical wall.¹¹ In rupioid psoriasis, skin lesions mostly are widespread and are not limited to sun-exposed areas. Additionally, biopsies from active rupioid lesions typically show psoriasiform epidermal hyperplasia with parakeratosis with no interface inflammation—a key differentiator.¹² In secondary syphilis, chancres often are missed and are not reported by patients. Clinically, secondary syphilis often manifests as scaly patches and plaques with palmar involvement and positive rapid plasma reagin, which was negative in our patient.¹³ Histologically, secondary syphilis can exhibit a vacuolar or lichenoid interface dermatitis; however, it typically exhibits slender acanthosis with long rete ridges and neutrophils in the stratum corneum.³ Furthermore, plasma cells are present in about two-thirds of cases in the United States, with obliteration of the lumen of small vessels and perivascular histiocytes and lymphocytes with apparent cytoplasm commonly seen on pathology. Silver staining or immunostaining for Treponema pallidum may reveal the spirochetes that cause this condition.³

THE DIAGNOSIS: Hypertrophic Lupus Erythematosus

The biopsy of the face collected at the initial appointment revealed interface dermatitis with epidermal hyperplasia with no parakeratosis or eosinophils (Figure 1). Microscopic findings were suggestive of hypertrophic lupus erythematosus (HLE) or hypertrophic lichen planus. The rapid plasma reagin and HIV labs collected at the initial appointment were negative, and a review of systems was negative for systemic symptoms. Considering these results and the clinical distribution of the lesions primarily affecting sun-exposed areas of the upper body, a final diagnosis of HLE was made. The patient was counseled on the importance of photoprotection and was started on hydroxychloroquine.

Hypertrophic lupus erythematosus, a rare variant of chronic cutaneous lupus erythematosus (CCLE), typically manifests as verrucous plaques or nodules commonly found on sun-exposed areas of the body, as was observed in our patient on the face, scalp (Figures 2 and 3), chest, and upper extremities.¹ Lesions can have a variable appearance, from hyperkeratotic ulcers to depigmented plaques and keratoacanthomalike lesions.² On histopathology, HLE falls into the category of lichenoid interface dermatitis and commonly demonstrates hyperkeratosis, acanthosis, follicular plugging, superficial and deep infiltrate, and increased mucin deposition in the dermis.³

Although rare, it is critical to remain vigilant for the development of squamous cell carcinoma in patients with chronic untreated CCLE. Hypertrophic lupus erythematosus, specifically, is the most likely variant to give rise to invasive squamous cell carcinoma and can be more aggressive as a result of this malignant transformation.^3,4 Ruling out squamous cell carcinoma in the setting of HLE can be achieved by staining for CD123, as HLE commonly is associated with many CD123+ plasmacytoid dendritic cells adjacent to the epithelium, unlike squamous cell carcinoma.³ Fortunately no evidence of invasive squamous cell carcinoma, including cellular atypia or increased mitotic figures, was seen on histology in our patient.

A thorough history and physical examination are essential for screening for HLE, as positive antinuclear antibodies are observed only in half of the patients diagnosed with CCLE.⁵ Furthermore, antinuclear antibodies sometimes can be negative in patients with HLE who have end-stage organ involvement.

Hypertrophic lupus erythematosus can be challenging to treat. First-line therapies include antimalarials, topical steroids, and sun-protective measures. Intralesional triamcinolone injection also can be used as an adjunctive therapy to expedite the treatment response.⁶ Evidence supports good response following treatment with acitretin or a combination of isotretinoin and hydroxychloroquine.² Another therapeutic strategy is implementing immunosuppressants such as methotrexate, mycophenolate mofetil, and azathioprine for persistent disease. Immunomodulators such as thalidomide historically have been shown to treat severe recalcitrant cases of HLE but typically are reserved for extreme cases due to adverse effects. Biologic agents such as intravenous immunoglobulins and rituximab have been shown to treat CCLE successfully, but routine use is limited due to high cost and lack of strong clinical trials.⁷

There have been reports of experimental therapies such as monoclonal antibodies (eg, anifrolumab and tocilizumab therapy) providing remission for patients with refractory CCLE, but information on their efficacy—specifically in patients with HLE—is lacking.⁸ Chronic cutaneous lupus erythematosus and its variants require further investigation regarding which treatment options provide the greatest benefit while minimizing adverse effects.

It is important to distinguish HLE from other potential diagnoses. Features of HLE can mimic hypertrophic lichen planus; however, the latter typically appears on the legs while HLE appears more commonly on the upper extremities and face in a photodistributed pattern.⁹ Since HLE has a lichenoid appearance histologically, it may appear clinically similar to hypertrophic lichen planus. Although not performed in our patient due to cost, direct immunofluorescence can aid in distinguishing HLE from hypertrophic lichen planus. Chronic cutaneous lupus erythematosus shows a granular pattern of deposition of IgM (primarily), IgG, IgA, and C3. In contrast, hypertrophic lichen planus exhibits cytoid bodies that stain positive for IgM as well as linear deposition of fibrinogen along the basement membrane.^3,10

Blastomycosis also can lead to development of verrucous plaques in sun-exposed areas, but the lesions typically originate as pustules that ulcerate over time. Lesions also can manifest with central scarring and a heaped edge.³ Unlike HLE, pseudoepitheliomatous hyperplasia with mixed infiltrate and intradermal pustules are seen in blastomycosis.³ Fungal organisms often are seen on pathology and are relatively large and uniform in size and shape, are found within giant cells, and have a thick refractile asymmetrical wall.¹¹ In rupioid psoriasis, skin lesions mostly are widespread and are not limited to sun-exposed areas. Additionally, biopsies from active rupioid lesions typically show psoriasiform epidermal hyperplasia with parakeratosis with no interface inflammation—a key differentiator.¹² In secondary syphilis, chancres often are missed and are not reported by patients. Clinically, secondary syphilis often manifests as scaly patches and plaques with palmar involvement and positive rapid plasma reagin, which was negative in our patient.¹³ Histologically, secondary syphilis can exhibit a vacuolar or lichenoid interface dermatitis; however, it typically exhibits slender acanthosis with long rete ridges and neutrophils in the stratum corneum.³ Furthermore, plasma cells are present in about two-thirds of cases in the United States, with obliteration of the lumen of small vessels and perivascular histiocytes and lymphocytes with apparent cytoplasm commonly seen on pathology. Silver staining or immunostaining for Treponema pallidum may reveal the spirochetes that cause this condition.³

THE DIAGNOSIS: Hypertrophic Lupus Erythematosus

The biopsy of the face collected at the initial appointment revealed interface dermatitis with epidermal hyperplasia with no parakeratosis or eosinophils (Figure 1). Microscopic findings were suggestive of hypertrophic lupus erythematosus (HLE) or hypertrophic lichen planus. The rapid plasma reagin and HIV labs collected at the initial appointment were negative, and a review of systems was negative for systemic symptoms. Considering these results and the clinical distribution of the lesions primarily affecting sun-exposed areas of the upper body, a final diagnosis of HLE was made. The patient was counseled on the importance of photoprotection and was started on hydroxychloroquine.

Hypertrophic lupus erythematosus, a rare variant of chronic cutaneous lupus erythematosus (CCLE), typically manifests as verrucous plaques or nodules commonly found on sun-exposed areas of the body, as was observed in our patient on the face, scalp (Figures 2 and 3), chest, and upper extremities.¹ Lesions can have a variable appearance, from hyperkeratotic ulcers to depigmented plaques and keratoacanthomalike lesions.² On histopathology, HLE falls into the category of lichenoid interface dermatitis and commonly demonstrates hyperkeratosis, acanthosis, follicular plugging, superficial and deep infiltrate, and increased mucin deposition in the dermis.³

Although rare, it is critical to remain vigilant for the development of squamous cell carcinoma in patients with chronic untreated CCLE. Hypertrophic lupus erythematosus, specifically, is the most likely variant to give rise to invasive squamous cell carcinoma and can be more aggressive as a result of this malignant transformation.^3,4 Ruling out squamous cell carcinoma in the setting of HLE can be achieved by staining for CD123, as HLE commonly is associated with many CD123+ plasmacytoid dendritic cells adjacent to the epithelium, unlike squamous cell carcinoma.³ Fortunately no evidence of invasive squamous cell carcinoma, including cellular atypia or increased mitotic figures, was seen on histology in our patient.

A thorough history and physical examination are essential for screening for HLE, as positive antinuclear antibodies are observed only in half of the patients diagnosed with CCLE.⁵ Furthermore, antinuclear antibodies sometimes can be negative in patients with HLE who have end-stage organ involvement.

Hypertrophic lupus erythematosus can be challenging to treat. First-line therapies include antimalarials, topical steroids, and sun-protective measures. Intralesional triamcinolone injection also can be used as an adjunctive therapy to expedite the treatment response.⁶ Evidence supports good response following treatment with acitretin or a combination of isotretinoin and hydroxychloroquine.² Another therapeutic strategy is implementing immunosuppressants such as methotrexate, mycophenolate mofetil, and azathioprine for persistent disease. Immunomodulators such as thalidomide historically have been shown to treat severe recalcitrant cases of HLE but typically are reserved for extreme cases due to adverse effects. Biologic agents such as intravenous immunoglobulins and rituximab have been shown to treat CCLE successfully, but routine use is limited due to high cost and lack of strong clinical trials.⁷

There have been reports of experimental therapies such as monoclonal antibodies (eg, anifrolumab and tocilizumab therapy) providing remission for patients with refractory CCLE, but information on their efficacy—specifically in patients with HLE—is lacking.⁸ Chronic cutaneous lupus erythematosus and its variants require further investigation regarding which treatment options provide the greatest benefit while minimizing adverse effects.

It is important to distinguish HLE from other potential diagnoses. Features of HLE can mimic hypertrophic lichen planus; however, the latter typically appears on the legs while HLE appears more commonly on the upper extremities and face in a photodistributed pattern.⁹ Since HLE has a lichenoid appearance histologically, it may appear clinically similar to hypertrophic lichen planus. Although not performed in our patient due to cost, direct immunofluorescence can aid in distinguishing HLE from hypertrophic lichen planus. Chronic cutaneous lupus erythematosus shows a granular pattern of deposition of IgM (primarily), IgG, IgA, and C3. In contrast, hypertrophic lichen planus exhibits cytoid bodies that stain positive for IgM as well as linear deposition of fibrinogen along the basement membrane.^3,10

Blastomycosis also can lead to development of verrucous plaques in sun-exposed areas, but the lesions typically originate as pustules that ulcerate over time. Lesions also can manifest with central scarring and a heaped edge.³ Unlike HLE, pseudoepitheliomatous hyperplasia with mixed infiltrate and intradermal pustules are seen in blastomycosis.³ Fungal organisms often are seen on pathology and are relatively large and uniform in size and shape, are found within giant cells, and have a thick refractile asymmetrical wall.¹¹ In rupioid psoriasis, skin lesions mostly are widespread and are not limited to sun-exposed areas. Additionally, biopsies from active rupioid lesions typically show psoriasiform epidermal hyperplasia with parakeratosis with no interface inflammation—a key differentiator.¹² In secondary syphilis, chancres often are missed and are not reported by patients. Clinically, secondary syphilis often manifests as scaly patches and plaques with palmar involvement and positive rapid plasma reagin, which was negative in our patient.¹³ Histologically, secondary syphilis can exhibit a vacuolar or lichenoid interface dermatitis; however, it typically exhibits slender acanthosis with long rete ridges and neutrophils in the stratum corneum.³ Furthermore, plasma cells are present in about two-thirds of cases in the United States, with obliteration of the lumen of small vessels and perivascular histiocytes and lymphocytes with apparent cytoplasm commonly seen on pathology. Silver staining or immunostaining for Treponema pallidum may reveal the spirochetes that cause this condition.³

TOPLINE:

Changes in Krebs von den Lungen 6 (KL-6) levels after 12 months of treatment with mycophenolate mofetil (MMF) or cyclophosphamide (CYC) are associated with the development of progressive pulmonary fibrosis (PPF) in patients with systemic sclerosis–associated interstitial lung disease (SSc-ILD) in the following year.

METHODOLOGY:

• Despite available treatments, about 25% of patients with SSc-ILD develop PPF, highlighting the need for reliable early treatment response indicators, such as blood biomarkers, which may help predict the risk for PPF.
• Researchers conducted post hoc analyses of a randomized control trial that compared treatment responses to MMF with those to CYC in patients with SSc-ILD. Patients received either oral CYC for 12 months followed by placebo for 12 months or MMF for 24 months.
• A total of 92 patients with complete biomarker measurements at baseline and 12 months were included in the analysis (mean age, 52.2 years; 73.9% women; 68.5% White).
• The analysis included measurement of multiple blood biomarker levels, including C-reactive protein (CRP), interleukin-6, chemokine ligand 4 (CXCL4), CXCL18, and KL-6. Changes in these levels were evaluated from baseline to 12 months.
• The primary outcome was the development of PPF between 12 and 24 months, defined by meeting at least two of these following conditions: Worsening respiratory symptoms, a decline in forced vital capacity ≥ 5% and/or a decline in diffusing capacity for carbon monoxide ≥ 10%, or radiological disease progression.

TAKEAWAY:

• Among 92 patients, 19 developed PPF between 12 and 24 months, with 10 patients in the MMF arm and 9 patients in the CYC arm.
• KL-6 levels increased from baseline to 12 months in patients who developed PPF and decreased in those who did not (mean change, 365.68 vs –207.45 u/mL; P < .001).
• A 0.10-unit increase in KL-6 levels was associated with a 40% increase in the odds of developing PPF in an adjusted analysis (P = .0002).
• In the MMF group, levels of KL-6, CRP, and CXCL4 differed significantly between patients who developed PPF and those who did not (P = .004, P = .04, and P = .038, respectively).

IN PRACTICE:

“Reliable response biomarkers detectable early in the course of SSc-ILD treatment could minimize exposure to toxic therapies that are not conferring benefit and maximize exposure to alternative therapies that do confer benefit,” the authors wrote.

SOURCE:

The study was led by Elizabeth R. Volkmann, MD, MS, University of California, Los Angeles David Geffen School of Medicine. It was published online in Arthritis Care & Research.

LIMITATIONS:

The study population consisted of patients who were treatment-naive to MMF and CYC and had a relatively early disease course, potentially limiting generalizability to patients at later disease stages or with different treatment histories. Additionally, biomarker measurements were conducted at 12 months, when treatment response may be detectable through currently available methods, rather than at earlier timepoints.

DISCLOSURES:

The study was funded by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute and the Department of Defense. MMF was supplied by Hoffmann–La Roche. Some authors reported having financial relationships with pharmaceutical companies, including Hoffmann–La Roche.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Changes in Krebs von den Lungen 6 (KL-6) levels after 12 months of treatment with mycophenolate mofetil (MMF) or cyclophosphamide (CYC) are associated with the development of progressive pulmonary fibrosis (PPF) in patients with systemic sclerosis–associated interstitial lung disease (SSc-ILD) in the following year.

METHODOLOGY:

• Despite available treatments, about 25% of patients with SSc-ILD develop PPF, highlighting the need for reliable early treatment response indicators, such as blood biomarkers, which may help predict the risk for PPF.
• Researchers conducted post hoc analyses of a randomized control trial that compared treatment responses to MMF with those to CYC in patients with SSc-ILD. Patients received either oral CYC for 12 months followed by placebo for 12 months or MMF for 24 months.
• A total of 92 patients with complete biomarker measurements at baseline and 12 months were included in the analysis (mean age, 52.2 years; 73.9% women; 68.5% White).
• The analysis included measurement of multiple blood biomarker levels, including C-reactive protein (CRP), interleukin-6, chemokine ligand 4 (CXCL4), CXCL18, and KL-6. Changes in these levels were evaluated from baseline to 12 months.
• The primary outcome was the development of PPF between 12 and 24 months, defined by meeting at least two of these following conditions: Worsening respiratory symptoms, a decline in forced vital capacity ≥ 5% and/or a decline in diffusing capacity for carbon monoxide ≥ 10%, or radiological disease progression.

TAKEAWAY:

• Among 92 patients, 19 developed PPF between 12 and 24 months, with 10 patients in the MMF arm and 9 patients in the CYC arm.
• KL-6 levels increased from baseline to 12 months in patients who developed PPF and decreased in those who did not (mean change, 365.68 vs –207.45 u/mL; P < .001).
• A 0.10-unit increase in KL-6 levels was associated with a 40% increase in the odds of developing PPF in an adjusted analysis (P = .0002).
• In the MMF group, levels of KL-6, CRP, and CXCL4 differed significantly between patients who developed PPF and those who did not (P = .004, P = .04, and P = .038, respectively).

IN PRACTICE:

“Reliable response biomarkers detectable early in the course of SSc-ILD treatment could minimize exposure to toxic therapies that are not conferring benefit and maximize exposure to alternative therapies that do confer benefit,” the authors wrote.

SOURCE:

The study was led by Elizabeth R. Volkmann, MD, MS, University of California, Los Angeles David Geffen School of Medicine. It was published online in Arthritis Care & Research.

LIMITATIONS:

The study population consisted of patients who were treatment-naive to MMF and CYC and had a relatively early disease course, potentially limiting generalizability to patients at later disease stages or with different treatment histories. Additionally, biomarker measurements were conducted at 12 months, when treatment response may be detectable through currently available methods, rather than at earlier timepoints.

DISCLOSURES:

The study was funded by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute and the Department of Defense. MMF was supplied by Hoffmann–La Roche. Some authors reported having financial relationships with pharmaceutical companies, including Hoffmann–La Roche.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Changes in Krebs von den Lungen 6 (KL-6) levels after 12 months of treatment with mycophenolate mofetil (MMF) or cyclophosphamide (CYC) are associated with the development of progressive pulmonary fibrosis (PPF) in patients with systemic sclerosis–associated interstitial lung disease (SSc-ILD) in the following year.

METHODOLOGY:

• Despite available treatments, about 25% of patients with SSc-ILD develop PPF, highlighting the need for reliable early treatment response indicators, such as blood biomarkers, which may help predict the risk for PPF.
• Researchers conducted post hoc analyses of a randomized control trial that compared treatment responses to MMF with those to CYC in patients with SSc-ILD. Patients received either oral CYC for 12 months followed by placebo for 12 months or MMF for 24 months.
• A total of 92 patients with complete biomarker measurements at baseline and 12 months were included in the analysis (mean age, 52.2 years; 73.9% women; 68.5% White).
• The analysis included measurement of multiple blood biomarker levels, including C-reactive protein (CRP), interleukin-6, chemokine ligand 4 (CXCL4), CXCL18, and KL-6. Changes in these levels were evaluated from baseline to 12 months.
• The primary outcome was the development of PPF between 12 and 24 months, defined by meeting at least two of these following conditions: Worsening respiratory symptoms, a decline in forced vital capacity ≥ 5% and/or a decline in diffusing capacity for carbon monoxide ≥ 10%, or radiological disease progression.

TAKEAWAY:

• Among 92 patients, 19 developed PPF between 12 and 24 months, with 10 patients in the MMF arm and 9 patients in the CYC arm.
• KL-6 levels increased from baseline to 12 months in patients who developed PPF and decreased in those who did not (mean change, 365.68 vs –207.45 u/mL; P < .001).
• A 0.10-unit increase in KL-6 levels was associated with a 40% increase in the odds of developing PPF in an adjusted analysis (P = .0002).
• In the MMF group, levels of KL-6, CRP, and CXCL4 differed significantly between patients who developed PPF and those who did not (P = .004, P = .04, and P = .038, respectively).

IN PRACTICE:

“Reliable response biomarkers detectable early in the course of SSc-ILD treatment could minimize exposure to toxic therapies that are not conferring benefit and maximize exposure to alternative therapies that do confer benefit,” the authors wrote.

SOURCE:

The study was led by Elizabeth R. Volkmann, MD, MS, University of California, Los Angeles David Geffen School of Medicine. It was published online in Arthritis Care & Research.

LIMITATIONS:

The study population consisted of patients who were treatment-naive to MMF and CYC and had a relatively early disease course, potentially limiting generalizability to patients at later disease stages or with different treatment histories. Additionally, biomarker measurements were conducted at 12 months, when treatment response may be detectable through currently available methods, rather than at earlier timepoints.

DISCLOSURES:

The study was funded by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute and the Department of Defense. MMF was supplied by Hoffmann–La Roche. Some authors reported having financial relationships with pharmaceutical companies, including Hoffmann–La Roche.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

In 2022, autoimmune diseases affected over 15 million individuals in the United States, with women nearly twice as likely to be affected as men and more than one third of affected individuals having more than one autoimmune condition.

METHODOLOGY:

• Researchers used electronic health record (EHR) data from six healthcare systems in the United States between 2011 and 2022 to estimate the prevalence of autoimmune diseases according to sex and age.
• They selected 105 autoimmune diseases from the textbook The Autoimmune Diseases and estimated their prevalence in more than 10 million individuals from these healthcare systems; these statistics were subsequently extrapolated to an estimated US population of 333.3 million.
• An individual was considered to have a diagnosis of an autoimmune disease if they had at least two diagnosis codes for the condition, with the codes being at least 30 days apart.
• A software program was developed to compute the prevalence of autoimmune diseases alone and in aggregate, enabling other researchers to replicate or modify the analysis over time.

TAKEAWAY:

• More than 15 million people, accounting for 4.6% of the US population, were diagnosed with at least one autoimmune disease from January 2011 to June 2022; 34% were diagnosed with more than one autoimmune disease.
• Sex-stratified analysis revealed that 63% of patients diagnosed with autoimmune disease were women, and only 37% were men, establishing a female-to-male ratio of 1.7:1; age-stratified analysis revealed increasing prevalence of autoimmune conditions with age, peaking in individuals aged ≥ 65 years.
• Among individuals with autoimmune diseases, 65% of patients had one condition, whereas 24% had two, 8% had three, and 2% had four or more autoimmune diseases (does not add to 100% due to rounding).
• Rheumatoid arthritis emerged as the most prevalent autoimmune disease, followed by psoriasis, type 1 diabetes, Grave’s disease, and autoimmune thyroiditis; 19 of the top 20 most prevalent autoimmune diseases occurred more frequently in women.

IN PRACTICE:

“Accurate data on the prevalence of autoimmune diseases as a category of disease and for individual autoimmune diseases are needed to further clinical and basic research to improve diagnosis, biomarkers, and therapies for these diseases, which significantly impact the US population,” the authors wrote.

SOURCE:

The study was led by Aaron H. Abend, Autoimmune Registry, Guilford, Connecticut, and was published online in The Journal of Clinical Investigation.

LIMITATIONS:

The use of EHR data presented several challenges, including potential inaccuracies in diagnosis codes and the possibility of missing patients with single diagnosis codes because of the two-code requirement. Certain autoimmune diseases evolve over time and involve nonspecific clinical signs and symptoms that can mimic other diseases, potentially resulting in underdiagnosis. Moreover, rare diseases lacking specific diagnosis codes may have been underrepresented.

DISCLOSURES:

The study received support from Autoimmune Registry; the National Institutes of Health National Center for Advancing Translational Sciences; the National Heart, Lung, and Blood Institute; and other sources. Information on potential conflicts of interest was not disclosed.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

In 2022, autoimmune diseases affected over 15 million individuals in the United States, with women nearly twice as likely to be affected as men and more than one third of affected individuals having more than one autoimmune condition.

METHODOLOGY:

• Researchers used electronic health record (EHR) data from six healthcare systems in the United States between 2011 and 2022 to estimate the prevalence of autoimmune diseases according to sex and age.
• They selected 105 autoimmune diseases from the textbook The Autoimmune Diseases and estimated their prevalence in more than 10 million individuals from these healthcare systems; these statistics were subsequently extrapolated to an estimated US population of 333.3 million.
• An individual was considered to have a diagnosis of an autoimmune disease if they had at least two diagnosis codes for the condition, with the codes being at least 30 days apart.
• A software program was developed to compute the prevalence of autoimmune diseases alone and in aggregate, enabling other researchers to replicate or modify the analysis over time.

TAKEAWAY:

• More than 15 million people, accounting for 4.6% of the US population, were diagnosed with at least one autoimmune disease from January 2011 to June 2022; 34% were diagnosed with more than one autoimmune disease.
• Sex-stratified analysis revealed that 63% of patients diagnosed with autoimmune disease were women, and only 37% were men, establishing a female-to-male ratio of 1.7:1; age-stratified analysis revealed increasing prevalence of autoimmune conditions with age, peaking in individuals aged ≥ 65 years.
• Among individuals with autoimmune diseases, 65% of patients had one condition, whereas 24% had two, 8% had three, and 2% had four or more autoimmune diseases (does not add to 100% due to rounding).
• Rheumatoid arthritis emerged as the most prevalent autoimmune disease, followed by psoriasis, type 1 diabetes, Grave’s disease, and autoimmune thyroiditis; 19 of the top 20 most prevalent autoimmune diseases occurred more frequently in women.

IN PRACTICE:

“Accurate data on the prevalence of autoimmune diseases as a category of disease and for individual autoimmune diseases are needed to further clinical and basic research to improve diagnosis, biomarkers, and therapies for these diseases, which significantly impact the US population,” the authors wrote.

SOURCE:

The study was led by Aaron H. Abend, Autoimmune Registry, Guilford, Connecticut, and was published online in The Journal of Clinical Investigation.

LIMITATIONS:

The use of EHR data presented several challenges, including potential inaccuracies in diagnosis codes and the possibility of missing patients with single diagnosis codes because of the two-code requirement. Certain autoimmune diseases evolve over time and involve nonspecific clinical signs and symptoms that can mimic other diseases, potentially resulting in underdiagnosis. Moreover, rare diseases lacking specific diagnosis codes may have been underrepresented.

DISCLOSURES:

The study received support from Autoimmune Registry; the National Institutes of Health National Center for Advancing Translational Sciences; the National Heart, Lung, and Blood Institute; and other sources. Information on potential conflicts of interest was not disclosed.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

In 2022, autoimmune diseases affected over 15 million individuals in the United States, with women nearly twice as likely to be affected as men and more than one third of affected individuals having more than one autoimmune condition.

METHODOLOGY:

• Researchers used electronic health record (EHR) data from six healthcare systems in the United States between 2011 and 2022 to estimate the prevalence of autoimmune diseases according to sex and age.
• They selected 105 autoimmune diseases from the textbook The Autoimmune Diseases and estimated their prevalence in more than 10 million individuals from these healthcare systems; these statistics were subsequently extrapolated to an estimated US population of 333.3 million.
• An individual was considered to have a diagnosis of an autoimmune disease if they had at least two diagnosis codes for the condition, with the codes being at least 30 days apart.
• A software program was developed to compute the prevalence of autoimmune diseases alone and in aggregate, enabling other researchers to replicate or modify the analysis over time.

TAKEAWAY:

• More than 15 million people, accounting for 4.6% of the US population, were diagnosed with at least one autoimmune disease from January 2011 to June 2022; 34% were diagnosed with more than one autoimmune disease.
• Sex-stratified analysis revealed that 63% of patients diagnosed with autoimmune disease were women, and only 37% were men, establishing a female-to-male ratio of 1.7:1; age-stratified analysis revealed increasing prevalence of autoimmune conditions with age, peaking in individuals aged ≥ 65 years.
• Among individuals with autoimmune diseases, 65% of patients had one condition, whereas 24% had two, 8% had three, and 2% had four or more autoimmune diseases (does not add to 100% due to rounding).
• Rheumatoid arthritis emerged as the most prevalent autoimmune disease, followed by psoriasis, type 1 diabetes, Grave’s disease, and autoimmune thyroiditis; 19 of the top 20 most prevalent autoimmune diseases occurred more frequently in women.

IN PRACTICE:

“Accurate data on the prevalence of autoimmune diseases as a category of disease and for individual autoimmune diseases are needed to further clinical and basic research to improve diagnosis, biomarkers, and therapies for these diseases, which significantly impact the US population,” the authors wrote.

SOURCE:

The study was led by Aaron H. Abend, Autoimmune Registry, Guilford, Connecticut, and was published online in The Journal of Clinical Investigation.

LIMITATIONS:

The use of EHR data presented several challenges, including potential inaccuracies in diagnosis codes and the possibility of missing patients with single diagnosis codes because of the two-code requirement. Certain autoimmune diseases evolve over time and involve nonspecific clinical signs and symptoms that can mimic other diseases, potentially resulting in underdiagnosis. Moreover, rare diseases lacking specific diagnosis codes may have been underrepresented.

DISCLOSURES:

The study received support from Autoimmune Registry; the National Institutes of Health National Center for Advancing Translational Sciences; the National Heart, Lung, and Blood Institute; and other sources. Information on potential conflicts of interest was not disclosed.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The use of valaciclovir as prophylaxis prevents herpes zoster (HZ) in patients with systemic lupus erythematosus (SLE) receiving anifrolumab treatment, with no cases of zoster reported during the follow-up period in patients receiving valaciclovir.

METHODOLOGY:

• Anifrolumab, a human monoclonal antibody binding to type I interferon receptor subunit 1, increases the risk for HZ in patients with SLE; however, specific recommendations to prevent HZ are currently nonexistent for patients with SLE receiving anifrolumab.
• Researchers conducted a multicenter observational study in France from November 2021 to July 2024 to evaluate the prophylactic benefits of valaciclovir in 132 patients with SLE (mean age, 42 years; 92% women) treated with anifrolumab for ≥ 3 months.
• Among these patients, 87 received either 500 mg/d valaciclovir (n = 69) or 1000 mg/d valaciclovir (n = 18) as prophylaxis, whereas 45 did not receive valaciclovir.
• The patients were followed up for a median duration of 234 days under anifrolumab treatment, with monitoring for the development of herpes zoster.

TAKEAWAY:

• The risk for HZ was significantly lower in patients who received valaciclovir than in those who did not (hazard ratio, 0.08; P = .01).
• None of the patients treated with valaciclovir developed HZ during the survey period.
• The frequency of HZ in patients who did not receive valaciclovir increased progressively from 2.2% at 3 months to 6.2% at 6 months, reaching 23% at 12 months.
• None of the reported cases of HZ required hospitalization or led to anifrolumab discontinuation, although one patient developed neuralgia.

IN PRACTICE:

“Prophylactic treatment with valaciclovir is effective for preventing HZ [herpes zoster] infection in SLE patients treated with anifrolumab,” the authors wrote. “This finding is particularly relevant for SLE patients who cannot receive the recombinant HZ vaccine or for whom it is unavailable,” they added.

SOURCE:

The study was led by Ludovic Trefond, MD, PhD, Centre Hospitalier Universitaire de Clermont-Ferrand in France. It was published online on January 4, 2025, in RMD Open.

LIMITATIONS:

The observational design of the study and the low number of herpes zoster events during the follow-up period may have affected the robustness of the findings.

DISCLOSURES:

The authors did not receive any specific grants. Some authors reported having financial relationships with various pharmaceutical companies.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The use of valaciclovir as prophylaxis prevents herpes zoster (HZ) in patients with systemic lupus erythematosus (SLE) receiving anifrolumab treatment, with no cases of zoster reported during the follow-up period in patients receiving valaciclovir.

METHODOLOGY:

• Anifrolumab, a human monoclonal antibody binding to type I interferon receptor subunit 1, increases the risk for HZ in patients with SLE; however, specific recommendations to prevent HZ are currently nonexistent for patients with SLE receiving anifrolumab.
• Researchers conducted a multicenter observational study in France from November 2021 to July 2024 to evaluate the prophylactic benefits of valaciclovir in 132 patients with SLE (mean age, 42 years; 92% women) treated with anifrolumab for ≥ 3 months.
• Among these patients, 87 received either 500 mg/d valaciclovir (n = 69) or 1000 mg/d valaciclovir (n = 18) as prophylaxis, whereas 45 did not receive valaciclovir.
• The patients were followed up for a median duration of 234 days under anifrolumab treatment, with monitoring for the development of herpes zoster.

TAKEAWAY:

• The risk for HZ was significantly lower in patients who received valaciclovir than in those who did not (hazard ratio, 0.08; P = .01).
• None of the patients treated with valaciclovir developed HZ during the survey period.
• The frequency of HZ in patients who did not receive valaciclovir increased progressively from 2.2% at 3 months to 6.2% at 6 months, reaching 23% at 12 months.
• None of the reported cases of HZ required hospitalization or led to anifrolumab discontinuation, although one patient developed neuralgia.

IN PRACTICE:

“Prophylactic treatment with valaciclovir is effective for preventing HZ [herpes zoster] infection in SLE patients treated with anifrolumab,” the authors wrote. “This finding is particularly relevant for SLE patients who cannot receive the recombinant HZ vaccine or for whom it is unavailable,” they added.

SOURCE:

The study was led by Ludovic Trefond, MD, PhD, Centre Hospitalier Universitaire de Clermont-Ferrand in France. It was published online on January 4, 2025, in RMD Open.

LIMITATIONS:

The observational design of the study and the low number of herpes zoster events during the follow-up period may have affected the robustness of the findings.

DISCLOSURES:

The authors did not receive any specific grants. Some authors reported having financial relationships with various pharmaceutical companies.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The use of valaciclovir as prophylaxis prevents herpes zoster (HZ) in patients with systemic lupus erythematosus (SLE) receiving anifrolumab treatment, with no cases of zoster reported during the follow-up period in patients receiving valaciclovir.

METHODOLOGY:

• Anifrolumab, a human monoclonal antibody binding to type I interferon receptor subunit 1, increases the risk for HZ in patients with SLE; however, specific recommendations to prevent HZ are currently nonexistent for patients with SLE receiving anifrolumab.
• Researchers conducted a multicenter observational study in France from November 2021 to July 2024 to evaluate the prophylactic benefits of valaciclovir in 132 patients with SLE (mean age, 42 years; 92% women) treated with anifrolumab for ≥ 3 months.
• Among these patients, 87 received either 500 mg/d valaciclovir (n = 69) or 1000 mg/d valaciclovir (n = 18) as prophylaxis, whereas 45 did not receive valaciclovir.
• The patients were followed up for a median duration of 234 days under anifrolumab treatment, with monitoring for the development of herpes zoster.

TAKEAWAY:

• The risk for HZ was significantly lower in patients who received valaciclovir than in those who did not (hazard ratio, 0.08; P = .01).
• None of the patients treated with valaciclovir developed HZ during the survey period.
• The frequency of HZ in patients who did not receive valaciclovir increased progressively from 2.2% at 3 months to 6.2% at 6 months, reaching 23% at 12 months.
• None of the reported cases of HZ required hospitalization or led to anifrolumab discontinuation, although one patient developed neuralgia.

IN PRACTICE:

“Prophylactic treatment with valaciclovir is effective for preventing HZ [herpes zoster] infection in SLE patients treated with anifrolumab,” the authors wrote. “This finding is particularly relevant for SLE patients who cannot receive the recombinant HZ vaccine or for whom it is unavailable,” they added.

SOURCE:

The study was led by Ludovic Trefond, MD, PhD, Centre Hospitalier Universitaire de Clermont-Ferrand in France. It was published online on January 4, 2025, in RMD Open.

LIMITATIONS:

The observational design of the study and the low number of herpes zoster events during the follow-up period may have affected the robustness of the findings.

DISCLOSURES:

The authors did not receive any specific grants. Some authors reported having financial relationships with various pharmaceutical companies.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

CD19-targeting chimeric antigen receptor (CAR) T-cell therapy shows potential to intercept fibrotic organ manifestations and improve disease measures in patients with diffuse cutaneous systemic sclerosis (SSc) who had disease progression despite multiple previous treatments.

METHODOLOGY:

• Researchers conducted a case series to examine the effect of CD19-targeting CAR T-cell therapy on fibrotic and vascular organ manifestations in six patients with diffuse cutaneous SSc (median age, 42 years; four men and two women) who had an insufficient response to at least two previous treatments.
• Participants received CD19-targeting CAR T-cell treatment at a dose of 1 × 106 CAR T cells per kilogram of body weight after lymphodepletion with fludarabine and cyclophosphamide.
• The primary outcome was event-free time or treatment intensification after study entry, with events defined as the progression of interstitial lung disease, onset of congestive heart or renal failure or arterial hypertension, or initiation of new therapy.
• The secondary outcomes included changes in the modified Rodnan skin score (mRSS), imaging and laboratory assessments, patient-reported outcomes, and the modified American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS), assessed at baseline and 3, 6, 9, and 12 months after treatment.

TAKEAWAY:

• No progression of organ manifestations or new lung, cardiac, or renal events occurred within the median follow-up period of 487 days.
• The probability of improvement in the ACR-CRISS score increased to a median value of 100% within 6 and 12 months of CAR T-cell treatment compared with baseline.
• Skin involvement improved in all the patients after CAR T-cell treatment, with a median mRSS decrease of 8 points within 100 days; the improvements were maintained throughout the 1-year follow-up period.
• This treatment also led to a depletion of antinuclear antibodies and SSc-specific autoantibodies.

IN PRACTICE:

“This case series highlights the potential of CAR T-cell therapy to address a crucial unmet need in refractory systemic sclerosis treatment. The study’s most significant contribution is the demonstration that CD19-targeting CAR T-cell therapy can halt or reverse aspects of fibrosis in systemic sclerosis,” Jérôme Avouac, Service de Rhumatologie, Hôpital Cochin, AP-HP Centre-Université Paris Cité, Paris, France, wrote in an accompanying editorial.

SOURCE:

The study was led by Janina Auth, MD, Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen in Germany, and was published online on November 11, 2024, in The Lancet Rheumatology.

LIMITATIONS:

The study lacked a control group, which limited the ability to draw definitive conclusions about the efficacy of CD19-targeting CAR T-cell therapy compared with standard treatments. The unpredictable nature of SSc, in which periods of stability can occur spontaneously, makes it difficult to attribute the improvements merely to the intervention. Moreover, the effect of CAR T-cell therapy on other disease manifestations, such as pulmonary hypertension, myocardial involvement, and scleroderma renal crisis, remains unclear.

DISCLOSURES:

The study was funded by Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, ELAN Foundation Erlangen, Interdisziplinäres Zentrum für Klinische Forschung Erlangen, Bundesministerium für Bildung und Forschung, and the European Union. Some authors reported receiving research grants, consulting fees, speaker fees, honoraria, or travel grants from Boehringer Ingelheim, Novartis, Almirall, and other pharmaceutical companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

CD19-targeting chimeric antigen receptor (CAR) T-cell therapy shows potential to intercept fibrotic organ manifestations and improve disease measures in patients with diffuse cutaneous systemic sclerosis (SSc) who had disease progression despite multiple previous treatments.

METHODOLOGY:

• Researchers conducted a case series to examine the effect of CD19-targeting CAR T-cell therapy on fibrotic and vascular organ manifestations in six patients with diffuse cutaneous SSc (median age, 42 years; four men and two women) who had an insufficient response to at least two previous treatments.
• Participants received CD19-targeting CAR T-cell treatment at a dose of 1 × 106 CAR T cells per kilogram of body weight after lymphodepletion with fludarabine and cyclophosphamide.
• The primary outcome was event-free time or treatment intensification after study entry, with events defined as the progression of interstitial lung disease, onset of congestive heart or renal failure or arterial hypertension, or initiation of new therapy.
• The secondary outcomes included changes in the modified Rodnan skin score (mRSS), imaging and laboratory assessments, patient-reported outcomes, and the modified American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS), assessed at baseline and 3, 6, 9, and 12 months after treatment.

TAKEAWAY:

• No progression of organ manifestations or new lung, cardiac, or renal events occurred within the median follow-up period of 487 days.
• The probability of improvement in the ACR-CRISS score increased to a median value of 100% within 6 and 12 months of CAR T-cell treatment compared with baseline.
• Skin involvement improved in all the patients after CAR T-cell treatment, with a median mRSS decrease of 8 points within 100 days; the improvements were maintained throughout the 1-year follow-up period.
• This treatment also led to a depletion of antinuclear antibodies and SSc-specific autoantibodies.

IN PRACTICE:

“This case series highlights the potential of CAR T-cell therapy to address a crucial unmet need in refractory systemic sclerosis treatment. The study’s most significant contribution is the demonstration that CD19-targeting CAR T-cell therapy can halt or reverse aspects of fibrosis in systemic sclerosis,” Jérôme Avouac, Service de Rhumatologie, Hôpital Cochin, AP-HP Centre-Université Paris Cité, Paris, France, wrote in an accompanying editorial.

SOURCE:

The study was led by Janina Auth, MD, Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen in Germany, and was published online on November 11, 2024, in The Lancet Rheumatology.

LIMITATIONS:

The study lacked a control group, which limited the ability to draw definitive conclusions about the efficacy of CD19-targeting CAR T-cell therapy compared with standard treatments. The unpredictable nature of SSc, in which periods of stability can occur spontaneously, makes it difficult to attribute the improvements merely to the intervention. Moreover, the effect of CAR T-cell therapy on other disease manifestations, such as pulmonary hypertension, myocardial involvement, and scleroderma renal crisis, remains unclear.

DISCLOSURES:

The study was funded by Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, ELAN Foundation Erlangen, Interdisziplinäres Zentrum für Klinische Forschung Erlangen, Bundesministerium für Bildung und Forschung, and the European Union. Some authors reported receiving research grants, consulting fees, speaker fees, honoraria, or travel grants from Boehringer Ingelheim, Novartis, Almirall, and other pharmaceutical companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

CD19-targeting chimeric antigen receptor (CAR) T-cell therapy shows potential to intercept fibrotic organ manifestations and improve disease measures in patients with diffuse cutaneous systemic sclerosis (SSc) who had disease progression despite multiple previous treatments.

METHODOLOGY:

• Researchers conducted a case series to examine the effect of CD19-targeting CAR T-cell therapy on fibrotic and vascular organ manifestations in six patients with diffuse cutaneous SSc (median age, 42 years; four men and two women) who had an insufficient response to at least two previous treatments.
• Participants received CD19-targeting CAR T-cell treatment at a dose of 1 × 106 CAR T cells per kilogram of body weight after lymphodepletion with fludarabine and cyclophosphamide.
• The primary outcome was event-free time or treatment intensification after study entry, with events defined as the progression of interstitial lung disease, onset of congestive heart or renal failure or arterial hypertension, or initiation of new therapy.
• The secondary outcomes included changes in the modified Rodnan skin score (mRSS), imaging and laboratory assessments, patient-reported outcomes, and the modified American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS), assessed at baseline and 3, 6, 9, and 12 months after treatment.

TAKEAWAY:

• No progression of organ manifestations or new lung, cardiac, or renal events occurred within the median follow-up period of 487 days.
• The probability of improvement in the ACR-CRISS score increased to a median value of 100% within 6 and 12 months of CAR T-cell treatment compared with baseline.
• Skin involvement improved in all the patients after CAR T-cell treatment, with a median mRSS decrease of 8 points within 100 days; the improvements were maintained throughout the 1-year follow-up period.
• This treatment also led to a depletion of antinuclear antibodies and SSc-specific autoantibodies.

IN PRACTICE:

“This case series highlights the potential of CAR T-cell therapy to address a crucial unmet need in refractory systemic sclerosis treatment. The study’s most significant contribution is the demonstration that CD19-targeting CAR T-cell therapy can halt or reverse aspects of fibrosis in systemic sclerosis,” Jérôme Avouac, Service de Rhumatologie, Hôpital Cochin, AP-HP Centre-Université Paris Cité, Paris, France, wrote in an accompanying editorial.

SOURCE:

The study was led by Janina Auth, MD, Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen in Germany, and was published online on November 11, 2024, in The Lancet Rheumatology.

LIMITATIONS:

The study lacked a control group, which limited the ability to draw definitive conclusions about the efficacy of CD19-targeting CAR T-cell therapy compared with standard treatments. The unpredictable nature of SSc, in which periods of stability can occur spontaneously, makes it difficult to attribute the improvements merely to the intervention. Moreover, the effect of CAR T-cell therapy on other disease manifestations, such as pulmonary hypertension, myocardial involvement, and scleroderma renal crisis, remains unclear.

DISCLOSURES:

The study was funded by Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, ELAN Foundation Erlangen, Interdisziplinäres Zentrum für Klinische Forschung Erlangen, Bundesministerium für Bildung und Forschung, and the European Union. Some authors reported receiving research grants, consulting fees, speaker fees, honoraria, or travel grants from Boehringer Ingelheim, Novartis, Almirall, and other pharmaceutical companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

THE DIAGNOSIS: Pemphigus Vegetans

Histopathologic examination of the biopsies from the scalp and left anterior thigh revealed suprabasal clefting with acantholytic cells extending into the follicular infundibulum with eosinophilic pustules within the epidermis. The dermis contained perivascular lymphohistiocytic and eosinophilic inflammatory infiltrates without viral cytopathic effects (Figure 1). Direct immunofluorescence revealed strong IgG and moderate IgA pericellular deposition around keratinocyte cytoplasms (Figure 2). Serologic evaluation demonstrated anti–desmoglein 3 antibodies. Based on the clinical presentation and histopathologic correlation, a diagnosis of pemphigus vegetans was made.

Pemphigus vegetans is a vesiculobullous autoimmune disease that is similar to pemphigus vulgaris but is characterized by the formation of vegetative plaques along the intertriginous areas and on the oral mucosa.¹ It is the rarest variant of all pemphigus subtypes and was first described by Neumann in 1876.² There are 2 subtypes of this variant: Hallopeau and Neumann, each with unique characteristics and physical manifestations. The Hallopeau type initially manifests with pustular lesions that rupture and evolve into erosions that commonly become infected. Gradually they merge and multiply to become more painful and vegetative.³ It has a more indolent course and typically responds well to treatment, and prolonged remission can be reached.⁴ The Neumann type is more severe and manifests with large vesiculobullous and erosive lesions that rupture and ulcerate, forming verrucous crusted vegetative plaques over the erosions.⁵ The erosions along the edge of the lesions induce new vegetation, becoming dry, hyperkeratotic, and fissured.³ The Neumann type often requires higher-dose steroids and typically is resistant to treatment.⁴ Patients can present with oral stomatitis and occasionally can develop a fissured or cerebriform appearance of the tongue, as seen in our patient (Figure 3).^1,2 Nail changes include onychorrhexis, onychomadesis, subungual pustules, and ultimately nail atrophy.⁵

Pemphigus diseases are characterized by IgG autoantibodies against desmoglein 3 and/or desmoglein 1. These are components of desmosomes that are responsible for keratinocyte adhesion, disruption of which results in the blister formation seen in pemphigus subtypes. The unique physical manifestation of pemphigus vegetans is thought to be due not only to autoantibodies against desmogleins 1 and 3 but also to autoantibodies against desmocollin 1 and 2.¹

Histopathologic examination reveals hyperkeratosis and pseudoepitheliomatous hyperplasia with acantholysis that creates a suprabasal cleft. Basal cells remain intact to the basement membrane by hemidesmosomes, resulting in a tombstone appearance. The Hallopeau type typically manifests with a large eosinophilic inflammatory response, leading to eosinophilic spongiosis and intraepidermal microabscesses. The Neumann type manifests with more of a neutrophilic and lymphocytic infiltrate, accompanied by the eosinophilic response.¹ For evaluation, obtain histopathology as well as direct immunofluorescence or enzyme-linked immunosorbent assay to look for intracellular deposition of desmoglein autoantibodies.

First-line treatment for pemphigus vulgaris and its variants is rituximab, an anti-CD20 monoclonal antibody. It has also been shown to have therapeutic benefit with combination of corticosteroids and rituximab. Corticosteroids should be given at a dose of 1 mg/kg daily for 2 to 4 weeks. Other immunosuppressive agents (steroid sparing) include azathioprine, dapsone, mycophenolate mofetil, methotrexate, cyclophosphamide, cyclosporine, and intravenous immunoglobulin. Pulse therapy with intermittent intravenous corticosteroids and immunosuppressants is another second-line therapeutic option. Topical therapeutic options include steroids, tacrolimus, and nicotinamide with oral tetracycline at onset and relapse. The goal of therapy is to maintain remission for 1 year then slowly taper treatment over another year.¹

Our patient initially was treated with prednisone, and subsequent courses of azathioprine and mycophenolate mofetil failed. He then was treated with 2 infusions of rituximab that were given 2 weeks apart. He was able to taper off the prednisone 1 month after the last infusion with complete remission of disease. He has been disease free for more than 9 months postinfusion.

Differential diagnoses for pemphigus vegetans can include bullous pemphigoid, bullous systemic lupus erythematosus, dermatitis herpetiformis, and pemphigus vulgaris. Lesion characteristics are key to differentiating pemphigus vegetans from other autoimmune blistering disorders. Bullous pemphigoid will manifest with tense blisters where pemphigus vulgaris will be flaccid; this is due to the difference in autoantibody targets between the conditions. Diagnosis depends on clinical presentation and histopathologic findings.

THE DIAGNOSIS: Pemphigus Vegetans

Histopathologic examination of the biopsies from the scalp and left anterior thigh revealed suprabasal clefting with acantholytic cells extending into the follicular infundibulum with eosinophilic pustules within the epidermis. The dermis contained perivascular lymphohistiocytic and eosinophilic inflammatory infiltrates without viral cytopathic effects (Figure 1). Direct immunofluorescence revealed strong IgG and moderate IgA pericellular deposition around keratinocyte cytoplasms (Figure 2). Serologic evaluation demonstrated anti–desmoglein 3 antibodies. Based on the clinical presentation and histopathologic correlation, a diagnosis of pemphigus vegetans was made.

Pemphigus vegetans is a vesiculobullous autoimmune disease that is similar to pemphigus vulgaris but is characterized by the formation of vegetative plaques along the intertriginous areas and on the oral mucosa.¹ It is the rarest variant of all pemphigus subtypes and was first described by Neumann in 1876.² There are 2 subtypes of this variant: Hallopeau and Neumann, each with unique characteristics and physical manifestations. The Hallopeau type initially manifests with pustular lesions that rupture and evolve into erosions that commonly become infected. Gradually they merge and multiply to become more painful and vegetative.³ It has a more indolent course and typically responds well to treatment, and prolonged remission can be reached.⁴ The Neumann type is more severe and manifests with large vesiculobullous and erosive lesions that rupture and ulcerate, forming verrucous crusted vegetative plaques over the erosions.⁵ The erosions along the edge of the lesions induce new vegetation, becoming dry, hyperkeratotic, and fissured.³ The Neumann type often requires higher-dose steroids and typically is resistant to treatment.⁴ Patients can present with oral stomatitis and occasionally can develop a fissured or cerebriform appearance of the tongue, as seen in our patient (Figure 3).^1,2 Nail changes include onychorrhexis, onychomadesis, subungual pustules, and ultimately nail atrophy.⁵

Pemphigus diseases are characterized by IgG autoantibodies against desmoglein 3 and/or desmoglein 1. These are components of desmosomes that are responsible for keratinocyte adhesion, disruption of which results in the blister formation seen in pemphigus subtypes. The unique physical manifestation of pemphigus vegetans is thought to be due not only to autoantibodies against desmogleins 1 and 3 but also to autoantibodies against desmocollin 1 and 2.¹

Histopathologic examination reveals hyperkeratosis and pseudoepitheliomatous hyperplasia with acantholysis that creates a suprabasal cleft. Basal cells remain intact to the basement membrane by hemidesmosomes, resulting in a tombstone appearance. The Hallopeau type typically manifests with a large eosinophilic inflammatory response, leading to eosinophilic spongiosis and intraepidermal microabscesses. The Neumann type manifests with more of a neutrophilic and lymphocytic infiltrate, accompanied by the eosinophilic response.¹ For evaluation, obtain histopathology as well as direct immunofluorescence or enzyme-linked immunosorbent assay to look for intracellular deposition of desmoglein autoantibodies.

First-line treatment for pemphigus vulgaris and its variants is rituximab, an anti-CD20 monoclonal antibody. It has also been shown to have therapeutic benefit with combination of corticosteroids and rituximab. Corticosteroids should be given at a dose of 1 mg/kg daily for 2 to 4 weeks. Other immunosuppressive agents (steroid sparing) include azathioprine, dapsone, mycophenolate mofetil, methotrexate, cyclophosphamide, cyclosporine, and intravenous immunoglobulin. Pulse therapy with intermittent intravenous corticosteroids and immunosuppressants is another second-line therapeutic option. Topical therapeutic options include steroids, tacrolimus, and nicotinamide with oral tetracycline at onset and relapse. The goal of therapy is to maintain remission for 1 year then slowly taper treatment over another year.¹

Our patient initially was treated with prednisone, and subsequent courses of azathioprine and mycophenolate mofetil failed. He then was treated with 2 infusions of rituximab that were given 2 weeks apart. He was able to taper off the prednisone 1 month after the last infusion with complete remission of disease. He has been disease free for more than 9 months postinfusion.

Differential diagnoses for pemphigus vegetans can include bullous pemphigoid, bullous systemic lupus erythematosus, dermatitis herpetiformis, and pemphigus vulgaris. Lesion characteristics are key to differentiating pemphigus vegetans from other autoimmune blistering disorders. Bullous pemphigoid will manifest with tense blisters where pemphigus vulgaris will be flaccid; this is due to the difference in autoantibody targets between the conditions. Diagnosis depends on clinical presentation and histopathologic findings.

THE DIAGNOSIS: Pemphigus Vegetans

Histopathologic examination of the biopsies from the scalp and left anterior thigh revealed suprabasal clefting with acantholytic cells extending into the follicular infundibulum with eosinophilic pustules within the epidermis. The dermis contained perivascular lymphohistiocytic and eosinophilic inflammatory infiltrates without viral cytopathic effects (Figure 1). Direct immunofluorescence revealed strong IgG and moderate IgA pericellular deposition around keratinocyte cytoplasms (Figure 2). Serologic evaluation demonstrated anti–desmoglein 3 antibodies. Based on the clinical presentation and histopathologic correlation, a diagnosis of pemphigus vegetans was made.

Pemphigus vegetans is a vesiculobullous autoimmune disease that is similar to pemphigus vulgaris but is characterized by the formation of vegetative plaques along the intertriginous areas and on the oral mucosa.¹ It is the rarest variant of all pemphigus subtypes and was first described by Neumann in 1876.² There are 2 subtypes of this variant: Hallopeau and Neumann, each with unique characteristics and physical manifestations. The Hallopeau type initially manifests with pustular lesions that rupture and evolve into erosions that commonly become infected. Gradually they merge and multiply to become more painful and vegetative.³ It has a more indolent course and typically responds well to treatment, and prolonged remission can be reached.⁴ The Neumann type is more severe and manifests with large vesiculobullous and erosive lesions that rupture and ulcerate, forming verrucous crusted vegetative plaques over the erosions.⁵ The erosions along the edge of the lesions induce new vegetation, becoming dry, hyperkeratotic, and fissured.³ The Neumann type often requires higher-dose steroids and typically is resistant to treatment.⁴ Patients can present with oral stomatitis and occasionally can develop a fissured or cerebriform appearance of the tongue, as seen in our patient (Figure 3).^1,2 Nail changes include onychorrhexis, onychomadesis, subungual pustules, and ultimately nail atrophy.⁵

Pemphigus diseases are characterized by IgG autoantibodies against desmoglein 3 and/or desmoglein 1. These are components of desmosomes that are responsible for keratinocyte adhesion, disruption of which results in the blister formation seen in pemphigus subtypes. The unique physical manifestation of pemphigus vegetans is thought to be due not only to autoantibodies against desmogleins 1 and 3 but also to autoantibodies against desmocollin 1 and 2.¹

Histopathologic examination reveals hyperkeratosis and pseudoepitheliomatous hyperplasia with acantholysis that creates a suprabasal cleft. Basal cells remain intact to the basement membrane by hemidesmosomes, resulting in a tombstone appearance. The Hallopeau type typically manifests with a large eosinophilic inflammatory response, leading to eosinophilic spongiosis and intraepidermal microabscesses. The Neumann type manifests with more of a neutrophilic and lymphocytic infiltrate, accompanied by the eosinophilic response.¹ For evaluation, obtain histopathology as well as direct immunofluorescence or enzyme-linked immunosorbent assay to look for intracellular deposition of desmoglein autoantibodies.

First-line treatment for pemphigus vulgaris and its variants is rituximab, an anti-CD20 monoclonal antibody. It has also been shown to have therapeutic benefit with combination of corticosteroids and rituximab. Corticosteroids should be given at a dose of 1 mg/kg daily for 2 to 4 weeks. Other immunosuppressive agents (steroid sparing) include azathioprine, dapsone, mycophenolate mofetil, methotrexate, cyclophosphamide, cyclosporine, and intravenous immunoglobulin. Pulse therapy with intermittent intravenous corticosteroids and immunosuppressants is another second-line therapeutic option. Topical therapeutic options include steroids, tacrolimus, and nicotinamide with oral tetracycline at onset and relapse. The goal of therapy is to maintain remission for 1 year then slowly taper treatment over another year.¹

Our patient initially was treated with prednisone, and subsequent courses of azathioprine and mycophenolate mofetil failed. He then was treated with 2 infusions of rituximab that were given 2 weeks apart. He was able to taper off the prednisone 1 month after the last infusion with complete remission of disease. He has been disease free for more than 9 months postinfusion.

Differential diagnoses for pemphigus vegetans can include bullous pemphigoid, bullous systemic lupus erythematosus, dermatitis herpetiformis, and pemphigus vulgaris. Lesion characteristics are key to differentiating pemphigus vegetans from other autoimmune blistering disorders. Bullous pemphigoid will manifest with tense blisters where pemphigus vulgaris will be flaccid; this is due to the difference in autoantibody targets between the conditions. Diagnosis depends on clinical presentation and histopathologic findings.

TOPLINE:

Atherosclerotic cardiovascular disease (ASCVD) risk is higher with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) than with psoriasis.

METHODOLOGY:

• A retrospective matched longitudinal study compared the incidence and prevalence of ASCVD of 8138 individuals with CLE; 24,675 with SLE; 192,577 with psoriasis; and 81,380 control individuals.
• The disease-free control population was matched in a 10:1 ratio to the CLE population on the basis of age, sex, insurance type, and enrollment duration.
• Prevalent ASCVD was defined as coronary artery disease, prior myocardial infarction, or cerebrovascular accident, with ASCVD incidence assessed by number of hospitalizations over 3 years.

TAKEAWAY:

• Persons with CLE had higher ASCVD risk than control individuals (odds ratio [OR], 1.72; P < .001), similar to those with SLE (OR, 2.41; P < .001) but unlike those with psoriasis (OR, 1.03; P = .48).
• ASCVD incidence at 3 years was 24.8 per 1000 person-years for SLE, 15.2 per 1000 person-years for CLE, 14.0 per 1000 person-years for psoriasis, and 10.3 per 1000 person-years for controls.
• Multivariable Cox proportional regression modeling showed ASCVD risk was highest in those with SLE (hazard ratio [HR], 2.23; P < .001) vs CLE (HR, 1.32; P < .001) and psoriasis (HR, 1.06; P = .09).
• ASCVD prevalence was higher in individuals with CLE receiving systemic therapy (2.7%) than in those receiving no therapy (1.6%), suggesting a potential link between disease severity and CVD risk.

IN PRACTICE:

“Persons with CLE are at higher risk for ASCVD, and guidelines for the evaluation and management of ASCVD may improve their quality of care,” the authors wrote.

SOURCE:

The study was led by Henry W. Chen, MD, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas. It was published online on December 4, 2024, in JAMA Dermatology.

LIMITATIONS: 

The study was limited by its relatively young population (median age, 49 years) and the exclusion of adults aged > 65 years on Medicare insurance plans. The database lacked race and ethnicity data, and the analysis was restricted to a shorter 3-year period. The study could not fully evaluate detailed risk factors such as blood pressure levels, cholesterol measurements, or glycemic control, nor could it accurately assess smoking status.

DISCLOSURES:

The research was supported by the Department of Dermatology at the University of Texas Southwestern Medical Center and a grant from the National Institutes of Health. Several authors reported receiving grants or personal fees from various pharmaceutical companies. One author reported being a deputy editor for diversity, equity, and inclusion at JAMA Cardiology. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Atherosclerotic cardiovascular disease (ASCVD) risk is higher with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) than with psoriasis.

METHODOLOGY:

• A retrospective matched longitudinal study compared the incidence and prevalence of ASCVD of 8138 individuals with CLE; 24,675 with SLE; 192,577 with psoriasis; and 81,380 control individuals.
• The disease-free control population was matched in a 10:1 ratio to the CLE population on the basis of age, sex, insurance type, and enrollment duration.
• Prevalent ASCVD was defined as coronary artery disease, prior myocardial infarction, or cerebrovascular accident, with ASCVD incidence assessed by number of hospitalizations over 3 years.

TAKEAWAY:

• Persons with CLE had higher ASCVD risk than control individuals (odds ratio [OR], 1.72; P < .001), similar to those with SLE (OR, 2.41; P < .001) but unlike those with psoriasis (OR, 1.03; P = .48).
• ASCVD incidence at 3 years was 24.8 per 1000 person-years for SLE, 15.2 per 1000 person-years for CLE, 14.0 per 1000 person-years for psoriasis, and 10.3 per 1000 person-years for controls.
• Multivariable Cox proportional regression modeling showed ASCVD risk was highest in those with SLE (hazard ratio [HR], 2.23; P < .001) vs CLE (HR, 1.32; P < .001) and psoriasis (HR, 1.06; P = .09).
• ASCVD prevalence was higher in individuals with CLE receiving systemic therapy (2.7%) than in those receiving no therapy (1.6%), suggesting a potential link between disease severity and CVD risk.

IN PRACTICE:

“Persons with CLE are at higher risk for ASCVD, and guidelines for the evaluation and management of ASCVD may improve their quality of care,” the authors wrote.

SOURCE:

The study was led by Henry W. Chen, MD, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas. It was published online on December 4, 2024, in JAMA Dermatology.

LIMITATIONS: 

The study was limited by its relatively young population (median age, 49 years) and the exclusion of adults aged > 65 years on Medicare insurance plans. The database lacked race and ethnicity data, and the analysis was restricted to a shorter 3-year period. The study could not fully evaluate detailed risk factors such as blood pressure levels, cholesterol measurements, or glycemic control, nor could it accurately assess smoking status.

DISCLOSURES:

The research was supported by the Department of Dermatology at the University of Texas Southwestern Medical Center and a grant from the National Institutes of Health. Several authors reported receiving grants or personal fees from various pharmaceutical companies. One author reported being a deputy editor for diversity, equity, and inclusion at JAMA Cardiology. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Atherosclerotic cardiovascular disease (ASCVD) risk is higher with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) than with psoriasis.

METHODOLOGY:

• A retrospective matched longitudinal study compared the incidence and prevalence of ASCVD of 8138 individuals with CLE; 24,675 with SLE; 192,577 with psoriasis; and 81,380 control individuals.
• The disease-free control population was matched in a 10:1 ratio to the CLE population on the basis of age, sex, insurance type, and enrollment duration.
• Prevalent ASCVD was defined as coronary artery disease, prior myocardial infarction, or cerebrovascular accident, with ASCVD incidence assessed by number of hospitalizations over 3 years.

TAKEAWAY:

• Persons with CLE had higher ASCVD risk than control individuals (odds ratio [OR], 1.72; P < .001), similar to those with SLE (OR, 2.41; P < .001) but unlike those with psoriasis (OR, 1.03; P = .48).
• ASCVD incidence at 3 years was 24.8 per 1000 person-years for SLE, 15.2 per 1000 person-years for CLE, 14.0 per 1000 person-years for psoriasis, and 10.3 per 1000 person-years for controls.
• Multivariable Cox proportional regression modeling showed ASCVD risk was highest in those with SLE (hazard ratio [HR], 2.23; P < .001) vs CLE (HR, 1.32; P < .001) and psoriasis (HR, 1.06; P = .09).
• ASCVD prevalence was higher in individuals with CLE receiving systemic therapy (2.7%) than in those receiving no therapy (1.6%), suggesting a potential link between disease severity and CVD risk.

IN PRACTICE:

“Persons with CLE are at higher risk for ASCVD, and guidelines for the evaluation and management of ASCVD may improve their quality of care,” the authors wrote.

SOURCE:

The study was led by Henry W. Chen, MD, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas. It was published online on December 4, 2024, in JAMA Dermatology.

LIMITATIONS: 

The study was limited by its relatively young population (median age, 49 years) and the exclusion of adults aged > 65 years on Medicare insurance plans. The database lacked race and ethnicity data, and the analysis was restricted to a shorter 3-year period. The study could not fully evaluate detailed risk factors such as blood pressure levels, cholesterol measurements, or glycemic control, nor could it accurately assess smoking status.

DISCLOSURES:

The research was supported by the Department of Dermatology at the University of Texas Southwestern Medical Center and a grant from the National Institutes of Health. Several authors reported receiving grants or personal fees from various pharmaceutical companies. One author reported being a deputy editor for diversity, equity, and inclusion at JAMA Cardiology. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.