Article

Key clinical point: The risk for infections in patients with psoriatic arthritis (PsA) did not increase with most biologic and small-molecule therapies, except bimekizumab, apremilast, and 30 mg upadacitinib.

Major finding: In patients with PsA, bimekizumab (relative risk [RR] 14.23; 95% CI 1.97-102.60), apremilast (RR 1.41; 95% CI 1.08-1.83) and 30 mg upadacitinib (RR 1.37; 95% CI 1.05-1.80) led to a significantly higher risk of infections compared to placebo, with 30 mg upadacitinib vs placebo also increasing the risk for serious infections (RR 3.66; 95% CI 1.43-9.38).

Study details: Findings are from a network meta-analysis of 94 randomized controlled trials including 54,369 patients with PsA or psoriasis who were treated with 14 biologics, five small molecules, or placebo.

Disclosures: This study was partly funded by grants from the National Taiwan University Hospital and Chang Gung Memorial Hospital. HY Chiu and YH Huang declared receiving speaking fees or honoraria from, serving as principal investigator for, or having other ties with various sources.

Source: Chiu HY et al. Comparative short-term risks of infection and serious infection in patients receiving biologic and small-molecule therapies for psoriasis and psoriatic arthritis: A systemic review and network meta-analysis of randomized controlled trials. Ther Adv Chronic Dis. 2023;14:20406223231206225. (Oct 27). doi: 10.1177/20406223231206225

Key clinical point: The risk for infections in patients with psoriatic arthritis (PsA) did not increase with most biologic and small-molecule therapies, except bimekizumab, apremilast, and 30 mg upadacitinib.

Major finding: In patients with PsA, bimekizumab (relative risk [RR] 14.23; 95% CI 1.97-102.60), apremilast (RR 1.41; 95% CI 1.08-1.83) and 30 mg upadacitinib (RR 1.37; 95% CI 1.05-1.80) led to a significantly higher risk of infections compared to placebo, with 30 mg upadacitinib vs placebo also increasing the risk for serious infections (RR 3.66; 95% CI 1.43-9.38).

Study details: Findings are from a network meta-analysis of 94 randomized controlled trials including 54,369 patients with PsA or psoriasis who were treated with 14 biologics, five small molecules, or placebo.

Disclosures: This study was partly funded by grants from the National Taiwan University Hospital and Chang Gung Memorial Hospital. HY Chiu and YH Huang declared receiving speaking fees or honoraria from, serving as principal investigator for, or having other ties with various sources.

Source: Chiu HY et al. Comparative short-term risks of infection and serious infection in patients receiving biologic and small-molecule therapies for psoriasis and psoriatic arthritis: A systemic review and network meta-analysis of randomized controlled trials. Ther Adv Chronic Dis. 2023;14:20406223231206225. (Oct 27). doi: 10.1177/20406223231206225

Key clinical point: The risk for infections in patients with psoriatic arthritis (PsA) did not increase with most biologic and small-molecule therapies, except bimekizumab, apremilast, and 30 mg upadacitinib.

Major finding: In patients with PsA, bimekizumab (relative risk [RR] 14.23; 95% CI 1.97-102.60), apremilast (RR 1.41; 95% CI 1.08-1.83) and 30 mg upadacitinib (RR 1.37; 95% CI 1.05-1.80) led to a significantly higher risk of infections compared to placebo, with 30 mg upadacitinib vs placebo also increasing the risk for serious infections (RR 3.66; 95% CI 1.43-9.38).

Study details: Findings are from a network meta-analysis of 94 randomized controlled trials including 54,369 patients with PsA or psoriasis who were treated with 14 biologics, five small molecules, or placebo.

Disclosures: This study was partly funded by grants from the National Taiwan University Hospital and Chang Gung Memorial Hospital. HY Chiu and YH Huang declared receiving speaking fees or honoraria from, serving as principal investigator for, or having other ties with various sources.

Source: Chiu HY et al. Comparative short-term risks of infection and serious infection in patients receiving biologic and small-molecule therapies for psoriasis and psoriatic arthritis: A systemic review and network meta-analysis of randomized controlled trials. Ther Adv Chronic Dis. 2023;14:20406223231206225. (Oct 27). doi: 10.1177/20406223231206225

Key clinical point: A diagnosis of psoriatic arthritis (PsA) significantly increased the odds of functional impairment and the prevalence of depressive symptoms in patients with psoriatic disease.

Major finding: A diagnosis of PsA was associated with increased odds of functional impairment in everyday life (odds ratio [OR] 9.56, P = .005) and the presence of moderate-to-severe depressive symptoms (OR 2.69, P = .046).

Study details: Findings are from a cross-sectional study including 300 patients with psoriatic disease, of whom 189 patients had PsA.

Disclosures: This study was partly sponsored by Novartis Pharma GmbH, Germany. Some authors declared receiving speaker honoraria, travel grants, or research funding from or having other ties with various sources, including Novartis. The other authors declared no conflicts of interest.

Source: Frede N et al. Psoriasis and psoriatic arthritis have a major impact on quality of life and depressive symptoms: A cross-sectional study of 300 patients. Rheumatol Ther. 2023 (Oct 15). doi: 10.1007/s40744-023-00602-9

Key clinical point: A diagnosis of psoriatic arthritis (PsA) significantly increased the odds of functional impairment and the prevalence of depressive symptoms in patients with psoriatic disease.

Major finding: A diagnosis of PsA was associated with increased odds of functional impairment in everyday life (odds ratio [OR] 9.56, P = .005) and the presence of moderate-to-severe depressive symptoms (OR 2.69, P = .046).

Study details: Findings are from a cross-sectional study including 300 patients with psoriatic disease, of whom 189 patients had PsA.

Disclosures: This study was partly sponsored by Novartis Pharma GmbH, Germany. Some authors declared receiving speaker honoraria, travel grants, or research funding from or having other ties with various sources, including Novartis. The other authors declared no conflicts of interest.

Source: Frede N et al. Psoriasis and psoriatic arthritis have a major impact on quality of life and depressive symptoms: A cross-sectional study of 300 patients. Rheumatol Ther. 2023 (Oct 15). doi: 10.1007/s40744-023-00602-9

Key clinical point: A diagnosis of psoriatic arthritis (PsA) significantly increased the odds of functional impairment and the prevalence of depressive symptoms in patients with psoriatic disease.

Major finding: A diagnosis of PsA was associated with increased odds of functional impairment in everyday life (odds ratio [OR] 9.56, P = .005) and the presence of moderate-to-severe depressive symptoms (OR 2.69, P = .046).

Study details: Findings are from a cross-sectional study including 300 patients with psoriatic disease, of whom 189 patients had PsA.

Disclosures: This study was partly sponsored by Novartis Pharma GmbH, Germany. Some authors declared receiving speaker honoraria, travel grants, or research funding from or having other ties with various sources, including Novartis. The other authors declared no conflicts of interest.

Source: Frede N et al. Psoriasis and psoriatic arthritis have a major impact on quality of life and depressive symptoms: A cross-sectional study of 300 patients. Rheumatol Ther. 2023 (Oct 15). doi: 10.1007/s40744-023-00602-9

Key clinical point: Patients with psoriatic arthritis (PsA) had higher levels of cathepsins G and K in the serum and synovial fluid than patients with gonarthrosis or control individuals having no physical findings related to their internal organs, skin, or joints.

Major finding: Cathepsin G and cathepsin K levels in the serum (P < .01) and synovial fluid (P < .02) were significantly higher in the PsA group than in the gonarthrosis or control group. Serum cathepsin G levels > 6 ng/mL and serum cathepsin K levels > 0.86 ng/mL showed 100% diagnostic accuracy in distinguishing patients with PsA from control individuals and patients with gonarthrosis, respectively, whereas synovial fluid cathepsin G levels > 2 ng/mL showed 100% accuracy in distinguishing PsA from gonarthrosis.

Study details: This retrospective case-control study included 156 patients having PsA with synovial effusion, 50 patients with gonarthrosis, and 30 control individuals.

Disclosures: This study did not receive any external funding. The authors declared no conflicts of interest.

Source: Popova-Belova SD et al. Serum and synovial levels of cathepsin G and cathepsin K in patients with psoriatic arthritis and their correlation with disease activity indices. Diagnostics (Basel). 2023;13(20):3250 (Oct 19). doi: 10.3390/diagnostics13203250

Key clinical point: Patients with psoriatic arthritis (PsA) had higher levels of cathepsins G and K in the serum and synovial fluid than patients with gonarthrosis or control individuals having no physical findings related to their internal organs, skin, or joints.

Major finding: Cathepsin G and cathepsin K levels in the serum (P < .01) and synovial fluid (P < .02) were significantly higher in the PsA group than in the gonarthrosis or control group. Serum cathepsin G levels > 6 ng/mL and serum cathepsin K levels > 0.86 ng/mL showed 100% diagnostic accuracy in distinguishing patients with PsA from control individuals and patients with gonarthrosis, respectively, whereas synovial fluid cathepsin G levels > 2 ng/mL showed 100% accuracy in distinguishing PsA from gonarthrosis.

Study details: This retrospective case-control study included 156 patients having PsA with synovial effusion, 50 patients with gonarthrosis, and 30 control individuals.

Disclosures: This study did not receive any external funding. The authors declared no conflicts of interest.

Source: Popova-Belova SD et al. Serum and synovial levels of cathepsin G and cathepsin K in patients with psoriatic arthritis and their correlation with disease activity indices. Diagnostics (Basel). 2023;13(20):3250 (Oct 19). doi: 10.3390/diagnostics13203250

Key clinical point: Patients with psoriatic arthritis (PsA) had higher levels of cathepsins G and K in the serum and synovial fluid than patients with gonarthrosis or control individuals having no physical findings related to their internal organs, skin, or joints.

Major finding: Cathepsin G and cathepsin K levels in the serum (P < .01) and synovial fluid (P < .02) were significantly higher in the PsA group than in the gonarthrosis or control group. Serum cathepsin G levels > 6 ng/mL and serum cathepsin K levels > 0.86 ng/mL showed 100% diagnostic accuracy in distinguishing patients with PsA from control individuals and patients with gonarthrosis, respectively, whereas synovial fluid cathepsin G levels > 2 ng/mL showed 100% accuracy in distinguishing PsA from gonarthrosis.

Study details: This retrospective case-control study included 156 patients having PsA with synovial effusion, 50 patients with gonarthrosis, and 30 control individuals.

Disclosures: This study did not receive any external funding. The authors declared no conflicts of interest.

Source: Popova-Belova SD et al. Serum and synovial levels of cathepsin G and cathepsin K in patients with psoriatic arthritis and their correlation with disease activity indices. Diagnostics (Basel). 2023;13(20):3250 (Oct 19). doi: 10.3390/diagnostics13203250

Key clinical point: Tildrakizumab was able to reduce the occurrence of psoriatic arthritis (PsA) in patients with psoriasis by improving nailfold bleeding (NFB) and capillary enlargement, which are well-known risk factors for the development of PsA.

Major finding: NFB (hazard ratio [HR] 2.92; P = .003) and capillary enlargement (HR 4.61; P < .0001) were recognized as risk factors for PsA development; however, both conditions improved significantly after 1 month of tildrakizumab initiation, with the improvements being sustained up to 13 months (all P < .01). Therefore, tildrakizumab treatment significantly reduced the risk for PsA (HR 0.06; P = .007) in patients with psoriasis.

Study details: Findings are from a prospective cohort study which included 246 patients with psoriasis vulgaris having no prior exposure to systemic treatments and topical treatments for distal interphalangeal joints and nails who received either tildrakizumab (n = 20) or topical agents (n = 226).

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Fukasawa T et al. The optimal use of tildrakizumab in the elderly via improvement of Treg function and its preventive effect of psoriatic arthritis. Front Immunol. 2023;14:1286251. (Oct 19) doi: 10.3389/fimmu.2023.1286251

Key clinical point: Tildrakizumab was able to reduce the occurrence of psoriatic arthritis (PsA) in patients with psoriasis by improving nailfold bleeding (NFB) and capillary enlargement, which are well-known risk factors for the development of PsA.

Major finding: NFB (hazard ratio [HR] 2.92; P = .003) and capillary enlargement (HR 4.61; P < .0001) were recognized as risk factors for PsA development; however, both conditions improved significantly after 1 month of tildrakizumab initiation, with the improvements being sustained up to 13 months (all P < .01). Therefore, tildrakizumab treatment significantly reduced the risk for PsA (HR 0.06; P = .007) in patients with psoriasis.

Study details: Findings are from a prospective cohort study which included 246 patients with psoriasis vulgaris having no prior exposure to systemic treatments and topical treatments for distal interphalangeal joints and nails who received either tildrakizumab (n = 20) or topical agents (n = 226).

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Fukasawa T et al. The optimal use of tildrakizumab in the elderly via improvement of Treg function and its preventive effect of psoriatic arthritis. Front Immunol. 2023;14:1286251. (Oct 19) doi: 10.3389/fimmu.2023.1286251

Key clinical point: Tildrakizumab was able to reduce the occurrence of psoriatic arthritis (PsA) in patients with psoriasis by improving nailfold bleeding (NFB) and capillary enlargement, which are well-known risk factors for the development of PsA.

Major finding: NFB (hazard ratio [HR] 2.92; P = .003) and capillary enlargement (HR 4.61; P < .0001) were recognized as risk factors for PsA development; however, both conditions improved significantly after 1 month of tildrakizumab initiation, with the improvements being sustained up to 13 months (all P < .01). Therefore, tildrakizumab treatment significantly reduced the risk for PsA (HR 0.06; P = .007) in patients with psoriasis.

Study details: Findings are from a prospective cohort study which included 246 patients with psoriasis vulgaris having no prior exposure to systemic treatments and topical treatments for distal interphalangeal joints and nails who received either tildrakizumab (n = 20) or topical agents (n = 226).

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Fukasawa T et al. The optimal use of tildrakizumab in the elderly via improvement of Treg function and its preventive effect of psoriatic arthritis. Front Immunol. 2023;14:1286251. (Oct 19) doi: 10.3389/fimmu.2023.1286251

Key clinical point: Treatment with ixekizumab for 24 weeks improved disease activity outcomes without causing any new adverse events (AE) in patients with severe peripheral psoriatic arthritis (PsA).

Major finding: At week 24, a significantly higher proportion of patients with severe PsA receiving ixekizumab every 4 weeks and ixekizumab every 2 weeks vs placebo achieved ≥20% improvement in the American College of Rheumatology scores (63.3% and 60.4% vs 24.5%, P ≤ .001). No new AE were reported.

Study details: Findings are from a post hoc analysis of the SPIRIT-P1 trial including 204 patients with severe peripheral PsA who received ixekizumab, adalimumab, or placebo for 24 weeks.

Disclosures: This study was funded by Eli Lilly and Company. Four authors declared being employees or stockholders of Eli Lilly Japan KK, Lilly Deutschland GmbH, or Eli Lilly and Company. The other authors declared ties with various sources, including Eli Lilly.

Source: Kameda H et al. Ixekizumab efficacy in patients with severe peripheral psoriatic arthritis: A post hoc analysis of a phase 3, randomized, double-blind, placebo-controlled study (SPIRIT-P1). Rheumatol Ther. 2023 (Oct 19). doi: 10.1007/s40744-023-00605-6

Key clinical point: Treatment with ixekizumab for 24 weeks improved disease activity outcomes without causing any new adverse events (AE) in patients with severe peripheral psoriatic arthritis (PsA).

Major finding: At week 24, a significantly higher proportion of patients with severe PsA receiving ixekizumab every 4 weeks and ixekizumab every 2 weeks vs placebo achieved ≥20% improvement in the American College of Rheumatology scores (63.3% and 60.4% vs 24.5%, P ≤ .001). No new AE were reported.

Study details: Findings are from a post hoc analysis of the SPIRIT-P1 trial including 204 patients with severe peripheral PsA who received ixekizumab, adalimumab, or placebo for 24 weeks.

Disclosures: This study was funded by Eli Lilly and Company. Four authors declared being employees or stockholders of Eli Lilly Japan KK, Lilly Deutschland GmbH, or Eli Lilly and Company. The other authors declared ties with various sources, including Eli Lilly.

Source: Kameda H et al. Ixekizumab efficacy in patients with severe peripheral psoriatic arthritis: A post hoc analysis of a phase 3, randomized, double-blind, placebo-controlled study (SPIRIT-P1). Rheumatol Ther. 2023 (Oct 19). doi: 10.1007/s40744-023-00605-6

Key clinical point: Treatment with ixekizumab for 24 weeks improved disease activity outcomes without causing any new adverse events (AE) in patients with severe peripheral psoriatic arthritis (PsA).

Major finding: At week 24, a significantly higher proportion of patients with severe PsA receiving ixekizumab every 4 weeks and ixekizumab every 2 weeks vs placebo achieved ≥20% improvement in the American College of Rheumatology scores (63.3% and 60.4% vs 24.5%, P ≤ .001). No new AE were reported.

Study details: Findings are from a post hoc analysis of the SPIRIT-P1 trial including 204 patients with severe peripheral PsA who received ixekizumab, adalimumab, or placebo for 24 weeks.

Disclosures: This study was funded by Eli Lilly and Company. Four authors declared being employees or stockholders of Eli Lilly Japan KK, Lilly Deutschland GmbH, or Eli Lilly and Company. The other authors declared ties with various sources, including Eli Lilly.

Source: Kameda H et al. Ixekizumab efficacy in patients with severe peripheral psoriatic arthritis: A post hoc analysis of a phase 3, randomized, double-blind, placebo-controlled study (SPIRIT-P1). Rheumatol Ther. 2023 (Oct 19). doi: 10.1007/s40744-023-00605-6

Key clinical point: Dual targeted therapy (DTT) combining two biological disease-modifying antirheumatic drugs (bDMARD) or targeted synthetic (ts) DMARD led to satisfactory clinical improvements and no serious adverse events in patients with difficult-to-treat refractory psoriatic arthritis (PsA).

Major finding: At a median exposure of 14.86 months, the DTT retention rate in patients with PsA was 42.8%, with 40.0% and 53.3% of patients achieving remission or low activity and major clinical improvements, respectively. Treatment discontinuation due to adverse events was reported in one patient with PsA and multiple comorbidities.

Study details: Findings are from an observational, retrospective, cross-sectional study including patients with refractory PsA (n = 14) or spondyloarthritis (n = 22) who simultaneously received two bDMARD or tsDMARD with different therapeutic targets.

Disclosures: This study did not receive any funding. R García-Vicuña declared receiving educational grants, research grants, consultancies, speaking fees, or support for attending meetings from various sources.

Source: Valero-Martinez C et al. Dual targeted therapy in patients with psoriatic arthritis and spondyloarthritis: A real-world multicenter experience from Spain. Front Immunol. 2023;14:1283251 (Oct 23). doi: 10.3389/fimmu.2023.1283251

Key clinical point: Dual targeted therapy (DTT) combining two biological disease-modifying antirheumatic drugs (bDMARD) or targeted synthetic (ts) DMARD led to satisfactory clinical improvements and no serious adverse events in patients with difficult-to-treat refractory psoriatic arthritis (PsA).

Major finding: At a median exposure of 14.86 months, the DTT retention rate in patients with PsA was 42.8%, with 40.0% and 53.3% of patients achieving remission or low activity and major clinical improvements, respectively. Treatment discontinuation due to adverse events was reported in one patient with PsA and multiple comorbidities.

Study details: Findings are from an observational, retrospective, cross-sectional study including patients with refractory PsA (n = 14) or spondyloarthritis (n = 22) who simultaneously received two bDMARD or tsDMARD with different therapeutic targets.

Disclosures: This study did not receive any funding. R García-Vicuña declared receiving educational grants, research grants, consultancies, speaking fees, or support for attending meetings from various sources.

Source: Valero-Martinez C et al. Dual targeted therapy in patients with psoriatic arthritis and spondyloarthritis: A real-world multicenter experience from Spain. Front Immunol. 2023;14:1283251 (Oct 23). doi: 10.3389/fimmu.2023.1283251

Key clinical point: Dual targeted therapy (DTT) combining two biological disease-modifying antirheumatic drugs (bDMARD) or targeted synthetic (ts) DMARD led to satisfactory clinical improvements and no serious adverse events in patients with difficult-to-treat refractory psoriatic arthritis (PsA).

Major finding: At a median exposure of 14.86 months, the DTT retention rate in patients with PsA was 42.8%, with 40.0% and 53.3% of patients achieving remission or low activity and major clinical improvements, respectively. Treatment discontinuation due to adverse events was reported in one patient with PsA and multiple comorbidities.

Study details: Findings are from an observational, retrospective, cross-sectional study including patients with refractory PsA (n = 14) or spondyloarthritis (n = 22) who simultaneously received two bDMARD or tsDMARD with different therapeutic targets.

Disclosures: This study did not receive any funding. R García-Vicuña declared receiving educational grants, research grants, consultancies, speaking fees, or support for attending meetings from various sources.

Source: Valero-Martinez C et al. Dual targeted therapy in patients with psoriatic arthritis and spondyloarthritis: A real-world multicenter experience from Spain. Front Immunol. 2023;14:1283251 (Oct 23). doi: 10.3389/fimmu.2023.1283251

Key clinical point: This real-world study validated the efficacy of upadacitinib and elucidated the variables influencing the attainment of minimal disease activity (MDA) in response to upadacitinib therapy in patients with psoriatic arthritis (PsA).

Major finding: At week 24, nearly half (47%) of the patients treated with upadacitinib achieved MDA, with males (odds ratio [OR] 2.54; P = .043), patients naive to biologic disease-modifying antirheumatic drugs (OR 4.13; P = .013), and patients with high baseline C-reactive protein levels (OR 2.49; P = .046) having higher odds of achieving MDA.

Study details: Findings are from the preliminary results of the ongoing UPREAL-PsA study including 126 patients with peripheral or axial PsA who received 15 mg upadacitinib once daily.

Disclosures: This study did not receive any specific funding. The authors declared no conflicts of interest.

Source: Luchetti Gentiloni MM et al. Upadacitinib effectiveness and factors associated with minimal disease activity achievement in patients with psoriatic arthritis: Preliminary data of a real-life multicenter study. Arthritis Res Ther. 2023;25:196. (Oct 11). doi: 10.1186/s13075-023-03182-9

Key clinical point: This real-world study validated the efficacy of upadacitinib and elucidated the variables influencing the attainment of minimal disease activity (MDA) in response to upadacitinib therapy in patients with psoriatic arthritis (PsA).

Major finding: At week 24, nearly half (47%) of the patients treated with upadacitinib achieved MDA, with males (odds ratio [OR] 2.54; P = .043), patients naive to biologic disease-modifying antirheumatic drugs (OR 4.13; P = .013), and patients with high baseline C-reactive protein levels (OR 2.49; P = .046) having higher odds of achieving MDA.

Study details: Findings are from the preliminary results of the ongoing UPREAL-PsA study including 126 patients with peripheral or axial PsA who received 15 mg upadacitinib once daily.

Disclosures: This study did not receive any specific funding. The authors declared no conflicts of interest.

Source: Luchetti Gentiloni MM et al. Upadacitinib effectiveness and factors associated with minimal disease activity achievement in patients with psoriatic arthritis: Preliminary data of a real-life multicenter study. Arthritis Res Ther. 2023;25:196. (Oct 11). doi: 10.1186/s13075-023-03182-9

Key clinical point: This real-world study validated the efficacy of upadacitinib and elucidated the variables influencing the attainment of minimal disease activity (MDA) in response to upadacitinib therapy in patients with psoriatic arthritis (PsA).

Major finding: At week 24, nearly half (47%) of the patients treated with upadacitinib achieved MDA, with males (odds ratio [OR] 2.54; P = .043), patients naive to biologic disease-modifying antirheumatic drugs (OR 4.13; P = .013), and patients with high baseline C-reactive protein levels (OR 2.49; P = .046) having higher odds of achieving MDA.

Study details: Findings are from the preliminary results of the ongoing UPREAL-PsA study including 126 patients with peripheral or axial PsA who received 15 mg upadacitinib once daily.

Disclosures: This study did not receive any specific funding. The authors declared no conflicts of interest.

Source: Luchetti Gentiloni MM et al. Upadacitinib effectiveness and factors associated with minimal disease activity achievement in patients with psoriatic arthritis: Preliminary data of a real-life multicenter study. Arthritis Res Ther. 2023;25:196. (Oct 11). doi: 10.1186/s13075-023-03182-9

To the Editor:

Biologic medications are increasingly utilized in adults with moderate to severe atopic dermatitis (AD) that is inadequately controlled with topical medication. By targeting the IL-4 receptor alpha subunit, dupilumab inhibits the biologic effects of IL-4 and IL-13, resulting in remarkable improvement in disease and quality of life for many patients with refractory AD.¹

In 2017, the US Food and Drug Administration approved dupilumab for use in AD, asthma, and chronic rhinosinusitis. However, there is evidence of the drug’s off-label efficacy in conditions such as eosinophilic annular erythema.² We present a patient with dyshidrotic eczema treated with dupilumab who experienced contemporaneous secondary improvement in chronic eosinophilic pneumonia (CEP) and interstitial lung disease (ILD).

A 45-year-old man was referred to our dermatology clinic for chronic hand dermatitis refractory to increasing strengths of topical corticosteroids. He had a history of progressive shortness of breath of unknown cause, which began 2 years prior, and he was being followed at our institution’s ILD clinic. Earlier pulmonary function testing revealed a restrictive pattern with interstitial infiltrates seen on chest computed tomography. A lung biopsy demonstrated features of fibrotic nonspecific interstitial pneumonitis with superimposed eosinophilic pneumonia. His pulmonary symptoms had progressively worsened; over a period of several months, the supplemental oxygen requirement had increased to 6 L at rest and 12 L upon exertion. Prednisone therapy was initiated, which alleviated respiratory symptoms; however, the patient was unable to tolerate a gradual wean of the medication, which rendered him steroid dependent at 30 mg/d.

Along with respiratory symptoms, the patient reported symptoms consistent with an autoimmune process, including dry eyes. Muscle weakness and tenderness also were noted. Ultimately, a diagnosis of anti–PL-7 (anti-threonyl-transfer RNA synthetase) antisynthetase syndrome was rendered by identification of anti–PL-7 antibodies and an elevated level of creatinine kinase.

Physical examination at our clinic revealed subtle palmar scaling on the hands and multiple small clear vesicles on the lateral aspects of the digits (Figure, A), consistent with dyshidrotic eczema. He initially was treated with clobetasol propionate ointment 0.05%. Despite adherence to this high-potency topical corticosteroid, he experienced only minimal improvement over a period of 3 months. Dupilumab was started at standard dosing—600 mg at initiation, followed by 300 mg every 2 weeks. The patient reported rapid improvement in dyshidrotic eczema over several months with near-complete resolution (Figure, B).

Concurrent with initiation and continued use of dupilumab, without other changes in his medication regimen, the patient noted gradual improvement in respiratory symptoms. At 6-month follow-up he reported notable improvement in respiratory function and quality of life. He then tolerated a gradual wean of prednisone to 10 mg/d, with a similar reduction in supplemental oxygen.

Off-label use of dupilumab for various eosinophilic conditions has shown promising efficacy. Our patient experienced improvement in CEP shortly after initiation of dupilumab, enabling weaning of prednisone, which has a well established adverse effect profile associated with long term use.^3,4 In comparison, dupilumab generally is well tolerated, with rare ophthalmologic complications and injection-site reactions.⁵

One case report suggested that CEP may represent a potential rare adverse effect of dupilumab initiation.⁶ However, prior to initiation of dupilumab, that patient had poorly controlled asthma requiring frequent oral corticosteroid therapy. It is possible that CEP was subclinical prior to initiation of dupilumab and became more noticeable once the patient was weaned from corticosteroids, which had served as an indirect treatment.⁶ Nonetheless, more research is needed to definitively establish the efficacy of dupilumab in CEP prior to more widespread use.

Irrespective of the potential efficacy of dupilumab for the treatment of CEP, our case highlights the growing body of evidence that dupilumab should be considered in the treatment of dyshidrotic eczema, particularly in cases refractory to topical treatment.⁷ When a systemic medication is preferred, dupilumab likely represents an option with a relatively well-tolerated adverse effect profile compared to traditional systemic treatments for dyshidrotic eczema.

To the Editor:

Biologic medications are increasingly utilized in adults with moderate to severe atopic dermatitis (AD) that is inadequately controlled with topical medication. By targeting the IL-4 receptor alpha subunit, dupilumab inhibits the biologic effects of IL-4 and IL-13, resulting in remarkable improvement in disease and quality of life for many patients with refractory AD.¹

In 2017, the US Food and Drug Administration approved dupilumab for use in AD, asthma, and chronic rhinosinusitis. However, there is evidence of the drug’s off-label efficacy in conditions such as eosinophilic annular erythema.² We present a patient with dyshidrotic eczema treated with dupilumab who experienced contemporaneous secondary improvement in chronic eosinophilic pneumonia (CEP) and interstitial lung disease (ILD).

A 45-year-old man was referred to our dermatology clinic for chronic hand dermatitis refractory to increasing strengths of topical corticosteroids. He had a history of progressive shortness of breath of unknown cause, which began 2 years prior, and he was being followed at our institution’s ILD clinic. Earlier pulmonary function testing revealed a restrictive pattern with interstitial infiltrates seen on chest computed tomography. A lung biopsy demonstrated features of fibrotic nonspecific interstitial pneumonitis with superimposed eosinophilic pneumonia. His pulmonary symptoms had progressively worsened; over a period of several months, the supplemental oxygen requirement had increased to 6 L at rest and 12 L upon exertion. Prednisone therapy was initiated, which alleviated respiratory symptoms; however, the patient was unable to tolerate a gradual wean of the medication, which rendered him steroid dependent at 30 mg/d.

Along with respiratory symptoms, the patient reported symptoms consistent with an autoimmune process, including dry eyes. Muscle weakness and tenderness also were noted. Ultimately, a diagnosis of anti–PL-7 (anti-threonyl-transfer RNA synthetase) antisynthetase syndrome was rendered by identification of anti–PL-7 antibodies and an elevated level of creatinine kinase.

Physical examination at our clinic revealed subtle palmar scaling on the hands and multiple small clear vesicles on the lateral aspects of the digits (Figure, A), consistent with dyshidrotic eczema. He initially was treated with clobetasol propionate ointment 0.05%. Despite adherence to this high-potency topical corticosteroid, he experienced only minimal improvement over a period of 3 months. Dupilumab was started at standard dosing—600 mg at initiation, followed by 300 mg every 2 weeks. The patient reported rapid improvement in dyshidrotic eczema over several months with near-complete resolution (Figure, B).

Concurrent with initiation and continued use of dupilumab, without other changes in his medication regimen, the patient noted gradual improvement in respiratory symptoms. At 6-month follow-up he reported notable improvement in respiratory function and quality of life. He then tolerated a gradual wean of prednisone to 10 mg/d, with a similar reduction in supplemental oxygen.

Off-label use of dupilumab for various eosinophilic conditions has shown promising efficacy. Our patient experienced improvement in CEP shortly after initiation of dupilumab, enabling weaning of prednisone, which has a well established adverse effect profile associated with long term use.^3,4 In comparison, dupilumab generally is well tolerated, with rare ophthalmologic complications and injection-site reactions.⁵

One case report suggested that CEP may represent a potential rare adverse effect of dupilumab initiation.⁶ However, prior to initiation of dupilumab, that patient had poorly controlled asthma requiring frequent oral corticosteroid therapy. It is possible that CEP was subclinical prior to initiation of dupilumab and became more noticeable once the patient was weaned from corticosteroids, which had served as an indirect treatment.⁶ Nonetheless, more research is needed to definitively establish the efficacy of dupilumab in CEP prior to more widespread use.

Irrespective of the potential efficacy of dupilumab for the treatment of CEP, our case highlights the growing body of evidence that dupilumab should be considered in the treatment of dyshidrotic eczema, particularly in cases refractory to topical treatment.⁷ When a systemic medication is preferred, dupilumab likely represents an option with a relatively well-tolerated adverse effect profile compared to traditional systemic treatments for dyshidrotic eczema.

To the Editor:

Biologic medications are increasingly utilized in adults with moderate to severe atopic dermatitis (AD) that is inadequately controlled with topical medication. By targeting the IL-4 receptor alpha subunit, dupilumab inhibits the biologic effects of IL-4 and IL-13, resulting in remarkable improvement in disease and quality of life for many patients with refractory AD.¹

In 2017, the US Food and Drug Administration approved dupilumab for use in AD, asthma, and chronic rhinosinusitis. However, there is evidence of the drug’s off-label efficacy in conditions such as eosinophilic annular erythema.² We present a patient with dyshidrotic eczema treated with dupilumab who experienced contemporaneous secondary improvement in chronic eosinophilic pneumonia (CEP) and interstitial lung disease (ILD).

A 45-year-old man was referred to our dermatology clinic for chronic hand dermatitis refractory to increasing strengths of topical corticosteroids. He had a history of progressive shortness of breath of unknown cause, which began 2 years prior, and he was being followed at our institution’s ILD clinic. Earlier pulmonary function testing revealed a restrictive pattern with interstitial infiltrates seen on chest computed tomography. A lung biopsy demonstrated features of fibrotic nonspecific interstitial pneumonitis with superimposed eosinophilic pneumonia. His pulmonary symptoms had progressively worsened; over a period of several months, the supplemental oxygen requirement had increased to 6 L at rest and 12 L upon exertion. Prednisone therapy was initiated, which alleviated respiratory symptoms; however, the patient was unable to tolerate a gradual wean of the medication, which rendered him steroid dependent at 30 mg/d.

Along with respiratory symptoms, the patient reported symptoms consistent with an autoimmune process, including dry eyes. Muscle weakness and tenderness also were noted. Ultimately, a diagnosis of anti–PL-7 (anti-threonyl-transfer RNA synthetase) antisynthetase syndrome was rendered by identification of anti–PL-7 antibodies and an elevated level of creatinine kinase.

Physical examination at our clinic revealed subtle palmar scaling on the hands and multiple small clear vesicles on the lateral aspects of the digits (Figure, A), consistent with dyshidrotic eczema. He initially was treated with clobetasol propionate ointment 0.05%. Despite adherence to this high-potency topical corticosteroid, he experienced only minimal improvement over a period of 3 months. Dupilumab was started at standard dosing—600 mg at initiation, followed by 300 mg every 2 weeks. The patient reported rapid improvement in dyshidrotic eczema over several months with near-complete resolution (Figure, B).

Concurrent with initiation and continued use of dupilumab, without other changes in his medication regimen, the patient noted gradual improvement in respiratory symptoms. At 6-month follow-up he reported notable improvement in respiratory function and quality of life. He then tolerated a gradual wean of prednisone to 10 mg/d, with a similar reduction in supplemental oxygen.

Off-label use of dupilumab for various eosinophilic conditions has shown promising efficacy. Our patient experienced improvement in CEP shortly after initiation of dupilumab, enabling weaning of prednisone, which has a well established adverse effect profile associated with long term use.^3,4 In comparison, dupilumab generally is well tolerated, with rare ophthalmologic complications and injection-site reactions.⁵

One case report suggested that CEP may represent a potential rare adverse effect of dupilumab initiation.⁶ However, prior to initiation of dupilumab, that patient had poorly controlled asthma requiring frequent oral corticosteroid therapy. It is possible that CEP was subclinical prior to initiation of dupilumab and became more noticeable once the patient was weaned from corticosteroids, which had served as an indirect treatment.⁶ Nonetheless, more research is needed to definitively establish the efficacy of dupilumab in CEP prior to more widespread use.

Irrespective of the potential efficacy of dupilumab for the treatment of CEP, our case highlights the growing body of evidence that dupilumab should be considered in the treatment of dyshidrotic eczema, particularly in cases refractory to topical treatment.⁷ When a systemic medication is preferred, dupilumab likely represents an option with a relatively well-tolerated adverse effect profile compared to traditional systemic treatments for dyshidrotic eczema.

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory condition of the pilosebaceous unit that occurs in concert with elevations of various cytokines, including tumor necrosis factor α (TNF-α), IL-1β, IL-10, and IL-17.^1,2 Adalimumab is a TNF-α inhibitor approved by the US Food and Drug Administration for the treatment of HS. Although TNF-α inhibitors are effective for many immune-mediated inflammatory disorders, paradoxical drug reactions have been reported following treatment with these agents.^3-6 True paradoxical drug reactions likely are immune mediated and directly lead to new onset of a pathologic condition that would otherwise respond to that drug. For example, there are reports of rheumatoid arthritis patients who were treated with a TNF-α inhibitor and developed psoriatic skin lesions.^3,6 Paradoxical drug reactions also have been reported with acute-onset inflammatory bowel disease and HS or less commonly pyoderma gangrenosum (PG), uveitis, granulomatous reactions, and vasculitis.^4,5 We present the case of a patient with HS who was treated with a TNF-α inhibitor and developed 2 distinct paradoxical drug reactions. We also provide an overview of paradoxical drug reactions associated with TNF-α inhibitors.

A 38-year-old woman developed a painful “boil” on the right leg that was previously treated in the emergency department with incision and drainage as well as oral clindamycin for 7 days, but the lesion spread and continued to worsen. She had a history of HS in the axillae and groin region that had been present since 12 years of age. The condition was poorly controlled despite multiple courses of oral antibiotics and surgical resections. An oral contraceptive also was attempted, but the patient discontinued treatment when liver enzyme levels became elevated. The patient had no other notable medical history, including skin disease. There was a family history of HS in her father and a sibling. Seeking more effective treatment, the patient was offered adalimumab approximately 4 months prior to clinical presentation and agreed to start a course of the drug. She received a loading dose of 160 mg on day 1 and 80 mg on day 15 followed by a maintenance dosage of 40 mg weekly. She experienced improvement in HS symptoms after 3 months on adalimumab; however, she developed scaly pruritic patches on the scalp, arms, and legs that were consistent with psoriasis. Because of the absence of a personal or family history of psoriasis, the patient was informed of the probability of paradoxical psoriasis resulting from adalimumab. She elected to continue adalimumab because of the improvement in HS symptoms, and the psoriatic lesions were mild and adequately controlled with a topical steroid.

At the current presentation 1 month later, physical examination revealed a large indurated and ulcerated area with jagged edges at the incision and drainage site (Figure 1). Pyoderma gangrenosum was clinically suspected; a biopsy was performed, and the patient was started on oral prednisone. At 2-week follow-up, the ulcer was found to be rapidly resolving with prednisone and healing with cribriform scarring (Figure 2). Histopathology revealed an undermining neutrophilic inflammatory process that was consistent with PG. A diagnosis of PG was made based on previously published criteria⁷ and the following major/minor criteria in the patient: pathology; absence of infection on histologic analysis; history of pathergy related to worsening ulceration at the site of incision and drainage of the initial boil; clinical findings of an ulcer with peripheral violaceous erythema; undermined borders and tenderness at the site; and rapid resolution of the ulcer with prednisone.

Cessation of adalimumab gradually led to clearance of both psoriasiform lesions and PG; however, HS lesions persisted. At 2-month follow-up, the patient remained clear of new psoriatic and PG lesions. Alternative treatment options for HS, including isotretinoin and other biologic agents, were discussed with the patient. She was subsequently lost to follow-up.

Although the precise pathogenesis of HS is unclear, both genetic abnormalities of the pilosebaceous unit and a dysregulated immune reaction appear to lead to the clinical characteristics of chronic inflammation and scarring seen in HS. A key effector appears to be helper T-cell (T_H17) lymphocyte activation, with increased secretion of TNF-α, IL-1β, and IL-17.^1,2 In turn, IL-17 induces higher expression of TNF-α, leading to a persistent cycle of inflammation. Peripheral recruitment of IL-17–producing neutrophils also may contribute to chronic inflammation.⁸

Adalimumab is the only US Food and Drug Administration–approved biologic indicated for the treatment of HS. Our patient initially responded to adalimumab with improvement of HS; however, treatment had to be discontinued because of the unusual occurrence of 2 distinct paradoxical reactions in a short span of time. Psoriasis and PG are both considered true paradoxical reactions because primary occurrences of both diseases usually are responsive to treatment with adalimumab.

Tumor necrosis factor α inhibitor–induced psoriasis arises de novo and is estimated to occur in approximately 5% of patients with rheumatoid arthritis.^3,6 Palmoplantar pustular psoriasiform reactions are the most common form of paradoxical psoriasis. Topical medications can be used to treat skin lesions, but systemic treatment is required in many cases. Switching to an alternate class of a biologic, such as an IL-17, IL-12/23, or IL-23 inhibitor, can improve the skin reaction; however, such treatment is inconsistently successful, and paradoxical drug reactions also have been seen with these other classes of biologics.^4,9

Recent studies support distinct immune causes for classical and paradoxical psoriasis. In classical psoriasis, plasmacytoid dendritic cells (pDCs) produce IFN-α, which stimulates conventional dendritic cells to produce TNF-α. However, TNF-α matures both pDCs and conventional dendritic cells; upon maturation, both types of dendritic cells lose the ability to produce IFN-α, thus allowing TNF-α to become dominant.¹⁰ The blockade of TNF-α prevents pDC maturation, leading to uninhibited IFN-α, which appears to drive inflammation in paradoxical psoriasis. In classical psoriasis, oligoclonal dermal CD4⁺ T cells and epidermal CD8⁺ T cells remain, even in resolved skin lesions, and can cause disease recurrence through reactivation of skin-resident memory T cells.¹¹ No relapse of paradoxical psoriasis occurs with discontinuation of anti-TNF-α therapy, which supports the notion of an absence of memory T cells.

The incidence of paradoxical psoriasis in patients receiving a TNF-α inhibitor for HS is unclear.¹² There are case series in which patients who had concurrent psoriasis and HS were successfully treated with a TNF-α inhibitor.¹³ A recently recognized condition—PASH syndrome—encompasses the clinical triad of PG, acne, and HS.¹⁰

Our patient had no history of acne or PG, only a long-standing history of HS. New-onset PG occurred only after a TNF-α inhibitor was initiated. Notably, PASH syndrome has been successfully treated with TNF-α inhibitors, highlighting the shared inflammatory etiology of HS and PG.¹⁴ In patients with concurrent PG and HS, TNF-α inhibitors were more effective for treating PG than for HS.

Pyoderma gangrenosum is an inflammatory disorder that often occurs concomitantly with other conditions, such as inflammatory bowel disease. The exact underlying cause of PG is unclear, but there appears to be both neutrophil and T-cell dysfunction in PG, with excess inflammatory cytokine production (eg, IL-1β, TNF-α, IL-17).¹⁵

The mainstay of treatment of PG is systemic corticosteroids and immunosuppressives, such as cyclosporine. Tumor necrosis factor α inhibitors as well as other interleukin inhibitors are increasingly utilized as potential therapeutic alternatives for PG.^16,17

Unlike paradoxical psoriasis, the underlying cause of paradoxical PG is unclear.^18,19 A similar mechanism may be postulated whereby inhibition of TNF-α leads to excessive activation of alternative inflammatory pathways that result in paradoxical PG. In one study, the prevalence of PG among 68,232 patients with HS was 0.18% compared with 0.01% among those without HS; therefore, patients with HS appear to be more predisposed to PG.²⁰

This case illustrates the complex, often conflicting effects of cytokine inhibition in the paradoxical elicitation of alternative inflammatory disorders as an unintended consequence of the initial cytokine blockade. It is likely that genetic predisposition allows for paradoxical reactions in some patients when there is predominant inhibition of one cytokine in the inflammatory pathway. In rare cases, multiple paradoxical reactions are possible.

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory condition of the pilosebaceous unit that occurs in concert with elevations of various cytokines, including tumor necrosis factor α (TNF-α), IL-1β, IL-10, and IL-17.^1,2 Adalimumab is a TNF-α inhibitor approved by the US Food and Drug Administration for the treatment of HS. Although TNF-α inhibitors are effective for many immune-mediated inflammatory disorders, paradoxical drug reactions have been reported following treatment with these agents.^3-6 True paradoxical drug reactions likely are immune mediated and directly lead to new onset of a pathologic condition that would otherwise respond to that drug. For example, there are reports of rheumatoid arthritis patients who were treated with a TNF-α inhibitor and developed psoriatic skin lesions.^3,6 Paradoxical drug reactions also have been reported with acute-onset inflammatory bowel disease and HS or less commonly pyoderma gangrenosum (PG), uveitis, granulomatous reactions, and vasculitis.^4,5 We present the case of a patient with HS who was treated with a TNF-α inhibitor and developed 2 distinct paradoxical drug reactions. We also provide an overview of paradoxical drug reactions associated with TNF-α inhibitors.

A 38-year-old woman developed a painful “boil” on the right leg that was previously treated in the emergency department with incision and drainage as well as oral clindamycin for 7 days, but the lesion spread and continued to worsen. She had a history of HS in the axillae and groin region that had been present since 12 years of age. The condition was poorly controlled despite multiple courses of oral antibiotics and surgical resections. An oral contraceptive also was attempted, but the patient discontinued treatment when liver enzyme levels became elevated. The patient had no other notable medical history, including skin disease. There was a family history of HS in her father and a sibling. Seeking more effective treatment, the patient was offered adalimumab approximately 4 months prior to clinical presentation and agreed to start a course of the drug. She received a loading dose of 160 mg on day 1 and 80 mg on day 15 followed by a maintenance dosage of 40 mg weekly. She experienced improvement in HS symptoms after 3 months on adalimumab; however, she developed scaly pruritic patches on the scalp, arms, and legs that were consistent with psoriasis. Because of the absence of a personal or family history of psoriasis, the patient was informed of the probability of paradoxical psoriasis resulting from adalimumab. She elected to continue adalimumab because of the improvement in HS symptoms, and the psoriatic lesions were mild and adequately controlled with a topical steroid.

At the current presentation 1 month later, physical examination revealed a large indurated and ulcerated area with jagged edges at the incision and drainage site (Figure 1). Pyoderma gangrenosum was clinically suspected; a biopsy was performed, and the patient was started on oral prednisone. At 2-week follow-up, the ulcer was found to be rapidly resolving with prednisone and healing with cribriform scarring (Figure 2). Histopathology revealed an undermining neutrophilic inflammatory process that was consistent with PG. A diagnosis of PG was made based on previously published criteria⁷ and the following major/minor criteria in the patient: pathology; absence of infection on histologic analysis; history of pathergy related to worsening ulceration at the site of incision and drainage of the initial boil; clinical findings of an ulcer with peripheral violaceous erythema; undermined borders and tenderness at the site; and rapid resolution of the ulcer with prednisone.

Cessation of adalimumab gradually led to clearance of both psoriasiform lesions and PG; however, HS lesions persisted. At 2-month follow-up, the patient remained clear of new psoriatic and PG lesions. Alternative treatment options for HS, including isotretinoin and other biologic agents, were discussed with the patient. She was subsequently lost to follow-up.

Although the precise pathogenesis of HS is unclear, both genetic abnormalities of the pilosebaceous unit and a dysregulated immune reaction appear to lead to the clinical characteristics of chronic inflammation and scarring seen in HS. A key effector appears to be helper T-cell (T_H17) lymphocyte activation, with increased secretion of TNF-α, IL-1β, and IL-17.^1,2 In turn, IL-17 induces higher expression of TNF-α, leading to a persistent cycle of inflammation. Peripheral recruitment of IL-17–producing neutrophils also may contribute to chronic inflammation.⁸

Adalimumab is the only US Food and Drug Administration–approved biologic indicated for the treatment of HS. Our patient initially responded to adalimumab with improvement of HS; however, treatment had to be discontinued because of the unusual occurrence of 2 distinct paradoxical reactions in a short span of time. Psoriasis and PG are both considered true paradoxical reactions because primary occurrences of both diseases usually are responsive to treatment with adalimumab.

Tumor necrosis factor α inhibitor–induced psoriasis arises de novo and is estimated to occur in approximately 5% of patients with rheumatoid arthritis.^3,6 Palmoplantar pustular psoriasiform reactions are the most common form of paradoxical psoriasis. Topical medications can be used to treat skin lesions, but systemic treatment is required in many cases. Switching to an alternate class of a biologic, such as an IL-17, IL-12/23, or IL-23 inhibitor, can improve the skin reaction; however, such treatment is inconsistently successful, and paradoxical drug reactions also have been seen with these other classes of biologics.^4,9

Recent studies support distinct immune causes for classical and paradoxical psoriasis. In classical psoriasis, plasmacytoid dendritic cells (pDCs) produce IFN-α, which stimulates conventional dendritic cells to produce TNF-α. However, TNF-α matures both pDCs and conventional dendritic cells; upon maturation, both types of dendritic cells lose the ability to produce IFN-α, thus allowing TNF-α to become dominant.¹⁰ The blockade of TNF-α prevents pDC maturation, leading to uninhibited IFN-α, which appears to drive inflammation in paradoxical psoriasis. In classical psoriasis, oligoclonal dermal CD4⁺ T cells and epidermal CD8⁺ T cells remain, even in resolved skin lesions, and can cause disease recurrence through reactivation of skin-resident memory T cells.¹¹ No relapse of paradoxical psoriasis occurs with discontinuation of anti-TNF-α therapy, which supports the notion of an absence of memory T cells.

The incidence of paradoxical psoriasis in patients receiving a TNF-α inhibitor for HS is unclear.¹² There are case series in which patients who had concurrent psoriasis and HS were successfully treated with a TNF-α inhibitor.¹³ A recently recognized condition—PASH syndrome—encompasses the clinical triad of PG, acne, and HS.¹⁰

Our patient had no history of acne or PG, only a long-standing history of HS. New-onset PG occurred only after a TNF-α inhibitor was initiated. Notably, PASH syndrome has been successfully treated with TNF-α inhibitors, highlighting the shared inflammatory etiology of HS and PG.¹⁴ In patients with concurrent PG and HS, TNF-α inhibitors were more effective for treating PG than for HS.

Pyoderma gangrenosum is an inflammatory disorder that often occurs concomitantly with other conditions, such as inflammatory bowel disease. The exact underlying cause of PG is unclear, but there appears to be both neutrophil and T-cell dysfunction in PG, with excess inflammatory cytokine production (eg, IL-1β, TNF-α, IL-17).¹⁵

The mainstay of treatment of PG is systemic corticosteroids and immunosuppressives, such as cyclosporine. Tumor necrosis factor α inhibitors as well as other interleukin inhibitors are increasingly utilized as potential therapeutic alternatives for PG.^16,17

Unlike paradoxical psoriasis, the underlying cause of paradoxical PG is unclear.^18,19 A similar mechanism may be postulated whereby inhibition of TNF-α leads to excessive activation of alternative inflammatory pathways that result in paradoxical PG. In one study, the prevalence of PG among 68,232 patients with HS was 0.18% compared with 0.01% among those without HS; therefore, patients with HS appear to be more predisposed to PG.²⁰

This case illustrates the complex, often conflicting effects of cytokine inhibition in the paradoxical elicitation of alternative inflammatory disorders as an unintended consequence of the initial cytokine blockade. It is likely that genetic predisposition allows for paradoxical reactions in some patients when there is predominant inhibition of one cytokine in the inflammatory pathway. In rare cases, multiple paradoxical reactions are possible.

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory condition of the pilosebaceous unit that occurs in concert with elevations of various cytokines, including tumor necrosis factor α (TNF-α), IL-1β, IL-10, and IL-17.^1,2 Adalimumab is a TNF-α inhibitor approved by the US Food and Drug Administration for the treatment of HS. Although TNF-α inhibitors are effective for many immune-mediated inflammatory disorders, paradoxical drug reactions have been reported following treatment with these agents.^3-6 True paradoxical drug reactions likely are immune mediated and directly lead to new onset of a pathologic condition that would otherwise respond to that drug. For example, there are reports of rheumatoid arthritis patients who were treated with a TNF-α inhibitor and developed psoriatic skin lesions.^3,6 Paradoxical drug reactions also have been reported with acute-onset inflammatory bowel disease and HS or less commonly pyoderma gangrenosum (PG), uveitis, granulomatous reactions, and vasculitis.^4,5 We present the case of a patient with HS who was treated with a TNF-α inhibitor and developed 2 distinct paradoxical drug reactions. We also provide an overview of paradoxical drug reactions associated with TNF-α inhibitors.

A 38-year-old woman developed a painful “boil” on the right leg that was previously treated in the emergency department with incision and drainage as well as oral clindamycin for 7 days, but the lesion spread and continued to worsen. She had a history of HS in the axillae and groin region that had been present since 12 years of age. The condition was poorly controlled despite multiple courses of oral antibiotics and surgical resections. An oral contraceptive also was attempted, but the patient discontinued treatment when liver enzyme levels became elevated. The patient had no other notable medical history, including skin disease. There was a family history of HS in her father and a sibling. Seeking more effective treatment, the patient was offered adalimumab approximately 4 months prior to clinical presentation and agreed to start a course of the drug. She received a loading dose of 160 mg on day 1 and 80 mg on day 15 followed by a maintenance dosage of 40 mg weekly. She experienced improvement in HS symptoms after 3 months on adalimumab; however, she developed scaly pruritic patches on the scalp, arms, and legs that were consistent with psoriasis. Because of the absence of a personal or family history of psoriasis, the patient was informed of the probability of paradoxical psoriasis resulting from adalimumab. She elected to continue adalimumab because of the improvement in HS symptoms, and the psoriatic lesions were mild and adequately controlled with a topical steroid.

At the current presentation 1 month later, physical examination revealed a large indurated and ulcerated area with jagged edges at the incision and drainage site (Figure 1). Pyoderma gangrenosum was clinically suspected; a biopsy was performed, and the patient was started on oral prednisone. At 2-week follow-up, the ulcer was found to be rapidly resolving with prednisone and healing with cribriform scarring (Figure 2). Histopathology revealed an undermining neutrophilic inflammatory process that was consistent with PG. A diagnosis of PG was made based on previously published criteria⁷ and the following major/minor criteria in the patient: pathology; absence of infection on histologic analysis; history of pathergy related to worsening ulceration at the site of incision and drainage of the initial boil; clinical findings of an ulcer with peripheral violaceous erythema; undermined borders and tenderness at the site; and rapid resolution of the ulcer with prednisone.

Cessation of adalimumab gradually led to clearance of both psoriasiform lesions and PG; however, HS lesions persisted. At 2-month follow-up, the patient remained clear of new psoriatic and PG lesions. Alternative treatment options for HS, including isotretinoin and other biologic agents, were discussed with the patient. She was subsequently lost to follow-up.

Although the precise pathogenesis of HS is unclear, both genetic abnormalities of the pilosebaceous unit and a dysregulated immune reaction appear to lead to the clinical characteristics of chronic inflammation and scarring seen in HS. A key effector appears to be helper T-cell (T_H17) lymphocyte activation, with increased secretion of TNF-α, IL-1β, and IL-17.^1,2 In turn, IL-17 induces higher expression of TNF-α, leading to a persistent cycle of inflammation. Peripheral recruitment of IL-17–producing neutrophils also may contribute to chronic inflammation.⁸

Adalimumab is the only US Food and Drug Administration–approved biologic indicated for the treatment of HS. Our patient initially responded to adalimumab with improvement of HS; however, treatment had to be discontinued because of the unusual occurrence of 2 distinct paradoxical reactions in a short span of time. Psoriasis and PG are both considered true paradoxical reactions because primary occurrences of both diseases usually are responsive to treatment with adalimumab.

Tumor necrosis factor α inhibitor–induced psoriasis arises de novo and is estimated to occur in approximately 5% of patients with rheumatoid arthritis.^3,6 Palmoplantar pustular psoriasiform reactions are the most common form of paradoxical psoriasis. Topical medications can be used to treat skin lesions, but systemic treatment is required in many cases. Switching to an alternate class of a biologic, such as an IL-17, IL-12/23, or IL-23 inhibitor, can improve the skin reaction; however, such treatment is inconsistently successful, and paradoxical drug reactions also have been seen with these other classes of biologics.^4,9

Recent studies support distinct immune causes for classical and paradoxical psoriasis. In classical psoriasis, plasmacytoid dendritic cells (pDCs) produce IFN-α, which stimulates conventional dendritic cells to produce TNF-α. However, TNF-α matures both pDCs and conventional dendritic cells; upon maturation, both types of dendritic cells lose the ability to produce IFN-α, thus allowing TNF-α to become dominant.¹⁰ The blockade of TNF-α prevents pDC maturation, leading to uninhibited IFN-α, which appears to drive inflammation in paradoxical psoriasis. In classical psoriasis, oligoclonal dermal CD4⁺ T cells and epidermal CD8⁺ T cells remain, even in resolved skin lesions, and can cause disease recurrence through reactivation of skin-resident memory T cells.¹¹ No relapse of paradoxical psoriasis occurs with discontinuation of anti-TNF-α therapy, which supports the notion of an absence of memory T cells.

The incidence of paradoxical psoriasis in patients receiving a TNF-α inhibitor for HS is unclear.¹² There are case series in which patients who had concurrent psoriasis and HS were successfully treated with a TNF-α inhibitor.¹³ A recently recognized condition—PASH syndrome—encompasses the clinical triad of PG, acne, and HS.¹⁰

Our patient had no history of acne or PG, only a long-standing history of HS. New-onset PG occurred only after a TNF-α inhibitor was initiated. Notably, PASH syndrome has been successfully treated with TNF-α inhibitors, highlighting the shared inflammatory etiology of HS and PG.¹⁴ In patients with concurrent PG and HS, TNF-α inhibitors were more effective for treating PG than for HS.

Pyoderma gangrenosum is an inflammatory disorder that often occurs concomitantly with other conditions, such as inflammatory bowel disease. The exact underlying cause of PG is unclear, but there appears to be both neutrophil and T-cell dysfunction in PG, with excess inflammatory cytokine production (eg, IL-1β, TNF-α, IL-17).¹⁵

The mainstay of treatment of PG is systemic corticosteroids and immunosuppressives, such as cyclosporine. Tumor necrosis factor α inhibitors as well as other interleukin inhibitors are increasingly utilized as potential therapeutic alternatives for PG.^16,17

Unlike paradoxical psoriasis, the underlying cause of paradoxical PG is unclear.^18,19 A similar mechanism may be postulated whereby inhibition of TNF-α leads to excessive activation of alternative inflammatory pathways that result in paradoxical PG. In one study, the prevalence of PG among 68,232 patients with HS was 0.18% compared with 0.01% among those without HS; therefore, patients with HS appear to be more predisposed to PG.²⁰

This case illustrates the complex, often conflicting effects of cytokine inhibition in the paradoxical elicitation of alternative inflammatory disorders as an unintended consequence of the initial cytokine blockade. It is likely that genetic predisposition allows for paradoxical reactions in some patients when there is predominant inhibition of one cytokine in the inflammatory pathway. In rare cases, multiple paradoxical reactions are possible.

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