Risk of Paradoxical Eczema in Patients Receiving Biologics for Psoriasis.

Importance: Biologics used for plaque psoriasis have been reported to be associated with an atopic dermatitis (AD) phenotype, or paradoxical eczema, in some patients. The risk factors for this are unknown. Objective: To explore risk of paradoxical eczema by biologic class and identify factors associated with paradoxical eczema. Design, Setting, and Participants: This prospective cohort study used data from the British Association of Dermatologists Biologics and Immunomodulators Register for adults treated with biologics for plaque psoriasis who were seen at multicenter dermatology clinics in the UK and Ireland. Included participants were registered and had 1 or more follow-up visits between September 2007 and December 2022. Exposures: Duration of exposure to tumor necrosis factor (TNF) inhibitors, interleukin (IL) 17 inhibitors, IL-12/23 inhibitors, or IL-23 inhibitors until paradoxical eczema onset, treatment discontinuation, last follow-up, or death. Main Outcomes and Measures: Incidence rates of paradoxical eczema, paradoxical eczema risk by biologic class, and the association of demographic and clinical variables with risk of paradoxical eczema were assessed using propensity score-weighted Cox proportional hazards regression models. Results: Of 56 553 drug exposures considered, 24 997 from 13 699 participants were included. The 24 997 included exposures (median age, 46 years [IQR, 36-55 years]; 57% male) accrued a total exposure time of 81 441 patient-years. A total of 273 exposures (1%) were associated with paradoxical eczema. The adjusted incidence rates were 1.22 per 100 000 person-years for IL-17 inhibitors, 0.94 per 100 000 person-years for TNF inhibitors, 0.80 per 100 000 person-years for IL-12/23 inhibitors, and 0.56 per 100 000 person-years for IL-23 inhibitors. Compared with TNF inhibitors, IL-23 inhibitors were associated with a lower risk of paradoxical eczema (hazard ratio [HR], 0.39; 95% CI, 0.19-0.81), and there was no association of IL-17 inhibitors (HR, 1.03; 95% CI, 0.74-1.42) or IL-12/23 inhibitors (HR, 0.87; 95% CI, 0.66-1.16) with risk of paradoxical eczema. Increasing age (HR, 1.02 per year; 95% CI, 1.01-1.03) and history of AD (HR, 12.40; 95% CI, 6.97-22.06) or hay fever (HR, 3.78; 95% CI, 1.49-9.53) were associated with higher risk of paradoxical eczema. There was a lower risk in males (HR, 0.60; 95% CI, 0.45-0.78). Conclusions and Relevance: In this study, in biologic-treated patients with psoriasis, paradoxical eczema risk was lowest in patients receiving IL-23 inhibitors. Increasing age, female sex, and history of AD or hay fever were associated with higher risk of paradoxical eczema. The overall incidence of paradoxical eczema was low. Further study is needed to replicate these findings.

Integrated proteomics and genomics analysis of paradoxical eczema in psoriasis patients treated with biologics.

BACKGROUND: Few studies have explored the immunology and genetic risk of paradoxical eczema occurring as an adverse event of biologic therapy in patients with psoriasis. OBJECTIVES: We sought to describe the systemic inflammatory signature of paradoxical eczema using proteomics and explore whether this is genetically mediated. METHODS: This study used the Olink Target 96 Inflammation panel on 256 serum samples from 71 patients with psoriasis and paradoxical eczema, and 75 controls with psoriasis to identify differentially expressed proteins and enriched gene sets. Case samples from 1 or more time points (T1 prebiologic, T2 postbiologic, and T3 postparadoxical eczema) were matched 1:1 with control samples. Genes contributing to enriched gene sets were selected, and functional single nucleotide polymorphisms used to create polygenic risk scores in a genotyped cohort of 88 paradoxical eczema cases and 3124 psoriasis controls. RESULTS: STAMBP expression was lower in cases at T1 than in controls (log-fold change: -0.44; adjusted P = .022); no other proteins reached statistical significance at equivalent time points. Eleven gene sets including cytokine and chemokine pathways were enriched in cases at T2 and 10 at T3. Of the 39 proteins contributing to enriched gene sets, the majority are associated with the atopic dermatitis serum proteome. A polygenic risk score including 38 functional single nucleotide polymorphisms linked to enriched gene sets was associated with paradoxical eczema (adjusted P = .046). CONCLUSIONS: The paradoxical eczema systemic inflammatory proteome trends toward atopic dermatitis at a gene-set level and is detectable before onset of the phenotype. This signature could be genetically determined.

Atopic Polygenic Risk Score Is Associated with Paradoxical Eczema Developing in Patients with Psoriasis Treated with Biologics.

Biologic therapies for psoriasis can cause paradoxical eczema. The role of genetic factors in its pathogenesis is unknown. To identify risk variants, we conducted a GWAS of 3,212 patients with psoriasis, of whom 88 developed paradoxical eczema. Two lead SNPs reached genome-wide significance (P ≤ 5 × 10-8) for association with paradoxical eczema: rs192705221 (near UNC5B, P = 9.52 × 10-10) and rs72925168 (within SLC1A2, P = 1.66 × 10-9). Genome-wide significant SNPs from published GWAS were used to generate polygenic risk scores (PRSs) for atopic eczema, general atopic disease, or a combination, which were tested for association with paradoxical eczema. Improvement over a clinical risk model was assessed by the area under the curve. All three atopy polygenic risk scores were associated with paradoxical eczema (P < 0.05); polygenic risk score for a combination of atopic eczema and general atopic disease had the strongest association (OR = 1.83, 95% CI = 1.17-2.84, P = 0.0078). Including atopic polygenic risk scores in the multivariable model, which included age, sex, atopic background, and psoriatic arthritis history, increased the area under the curve from 0.671 to 0.681-0.686. Atopic genetic burden is associated with paradoxical eczema occurring in biologic-treated patients with psoriasis, indicating shared underlying mechanisms. Incorporating genetic risk may improve treatment outcome prediction models for psoriasis.

The effect of immunomodulators on seroconversion after BNT162b2 and AZD1222 vaccines in patients with immune-mediated inflammatory diseases: a prospective cohort study.

BACKGROUND: Biologic and nonbiologic immunomodulators, used to treat immune-mediated inflammatory diseases (IMIDs), could impair the immune response to COVID-19 vaccines and thus vaccine effectiveness. OBJECTIVES: Our objective was to investigate the association between biologic and nonbiologic immunomodulators and seroconversion following the first and second dose of COVID-19 vaccines in patients with IMIDs. METHODS: Serum samples were collected following the first or second dose of the BNT162b2 or AZD1222 vaccines from patients receiving biologic and/or nonbiologic immunomodulators for one or more of psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease or systemic lupus erythematosus. Seroconversion was defined as a positive Roche Elecsys® Anti-SARS-CoV-2 S (spike protein subunit S1/receptor binding domain) immunoassay (≥ 0.8 U mL-1). Association between immunomodulator exposure and seroconversion was assessed using logistic regression, adjusting for age and sex. RESULTS: After excluding those with prior COVID-19, post-first vaccine dose samples from 193 participants and post-second dose samples from 312 participants were included in the analysis. Following the first vaccine dose, 17.6% (n = 34) of participants did not seroconvert. Seroconversion was reduced for those on nonbiologic [adjusted odds ratio (OR) 0.29, 95% confidence interval (CI) 0.12-0.69] or combined nonbiologic and biologic treatment (adjusted OR 0.14, 95% CI 0.045-0.45) compared with those on biologic monotherapy. Subgroup analysis demonstrated reduced odds of seroconversion in those on methotrexate (adjusted OR 0.097, 95% CI 0.19-0.49) or prednisolone treatment (adjusted OR 0.044, 95% CI 0.002-1.00) relative to tumour necrosis factor-α inhibitor monotherapy. No participants receiving rituximab (n < 5) seroconverted after the first vaccine dose. Following the second vaccine dose, 1.6% of all participants did not seroconvert. Non-seroconversion was associated with receiving rituximab (n = 3 of 4) compared with those receiving other therapies (n = 2 of 308, P < 0.001). Post hoc analyses demonstrated that non-seroconversion was associated with age [adjusted OR 0.18, 95% CI 0.037-0.93 for those aged 60 years and over (reference category age 18-39 years)], but not sex, ethnicity or vaccine type. CONCLUSIONS: Treatment with nonbiologics, particularly methotrexate, is associated with impaired seroconversion following two BNT162b2 or AZD1222 vaccine doses, in patients with IMIDs. These findings are consistent with those of other published studies. While this could indicate reduced protection against COVID-19, the immunological parameters that correlate most closely with vaccine effectiveness need to be defined to reach this conclusion.

International eDelphi Study to Reach Consensus on the Methotrexate Dosing Regimen in Patients With Psoriasis.

Importance: A clear dosing regimen for methotrexate in psoriasis is lacking, and this might lead to a suboptimal treatment. Because methotrexate is affordable and globally available, a uniform dosing regimen could potentially optimize the treatment of patients with psoriasis worldwide. Objective: To reach international consensus among psoriasis experts on a uniform dosing regimen for treatment with methotrexate in adult and pediatric patients with psoriasis and identify potential future research topics. Design, Setting, and Participants: Between September 2020 and March 2021, a survey study with a modified eDelphi procedure that was developed and distributed by the Amsterdam University Medical Center and completed by 180 participants worldwide (55 [30.6%] resided in non-Western countries) was conducted in 3 rounds. The proposals on which no consensus was reached were discussed in a conference meeting (June 2021). Participants voted on 21 proposals with a 9-point scale (1-3 disagree, 4-6 neither agree nor disagree, 7-9 agree) and were recruited through the Skin Inflammation and Psoriasis International Network and European Academy of Dermatology and Venereology in June 2020. Apart from being a dermatologist/dermatology resident, there were no specific criteria for participation in the survey. The participants worked mainly at a university hospital (97 [53.9%]) and were experienced in treating patients with psoriasis with methotrexate (163 [91.6%] had more than 10 years of experience). Main Outcomes and Measures: In a survey with eDelphi procedure, we tried to reach consensus on 21 proposals. Consensus was defined as less than 15% voting disagree (1-3). For the consensus meeting, consensus was defined as less than 30% voting disagree. Results: Of 251 participants, 180 (71.7%) completed all 3 survey rounds, and 58 participants (23.1%) joined the conference meeting. Consensus was achieved on 11 proposals in round 1, 3 proposals in round 2, and 2 proposals in round 3. In the consensus meeting, consensus was achieved on 4 proposals. More research is needed, especially for the proposals on folic acid and the dosing of methotrexate for treating subpopulations such as children and vulnerable patients. Conclusions and Relevance: In this eDelphi consensus study, consensus was reached on 20 of 21 proposals involving methotrexate dosing in patients with psoriasis. This consensus may potentially be used to harmonize the treatment with methotrexate in patients with psoriasis.

Paradoxical eczema in patients with psoriasis receiving biologics: a case series.

Atopic eczema and psoriasis are chronic, inflammatory dermatoses that can significantly affect the quality of life of those affected. Although both diseases are common, they rarely occur together. Severe psoriasis can be treated with biologic therapies targeting specific cytokine pathways involved in disease pathogenesis. There are reports of paradoxical eczema developing in biologic-treated patients with psoriasis, sometimes necessitating treatment discontinuation and thus leading to poor disease control. This retrospective case series identified 36 such events occurring in 23 patients. All currently available biologic classes were implicated. Eosinophilia (n = 19) and elevated serum IgE (n = 3) were identified in some cases. Treatment strategies included no treatment, topical corticosteroids, broad-acting systemic agents, and discontinuation or switch of biologic therapy. Two patients had persistent eczema and psoriasis despite discontinuation of all biologic therapies.

Maintaining Clinical Freedom Whilst Achieving Value in Biologics Prescribing: An Integrated Cross-Specialty Consensus of UK Dermatologists, Rheumatologists and Gastroenterologists.

BACKGROUND: Biologics are now key drugs in the management of immune-mediated inflammatory diseases. However, the increasingly complex biologics environment and growing cost pressures in the UK have led to variability in drug commissioning and inequity of patient access across regions. OBJECTIVES: Our objectives were to provide consensus recommendations for enhancing the current situation in biologic prescribing in the UK by balancing clinical freedom with equitable distribution of biologics given the limited availability of resources. METHODS: A modified Delphi approach was used to reach integrated, cross-specialty consensus among dermatologists, rheumatologists and gastroenterologists practising within the English National Health Service (NHS). RESULTS: We describe the concepts of clinical freedom and clinical judgement and demonstrate how, together with patient choice, they can be exercised in the context of biologic prescribing in the NHS. We highlight that in England, local variations occur that are at odds with National Institute for Health and Care Excellence (NICE) guidance; these variably limit the degree to which clinicians can exercise clinical freedom and impact on equity of patient access to treatments. We define factors encompassing a drug's value and identify challenges to the measurement and interpretation of this concept, which can raise barriers to the freedom of clinical choice and appropriate prescribing decisions allowing practices of holistic and personalised medicine. Cross-specialty consensus recommendations on ensuring equitable access to biologics in the NHS while protecting appropriate and individualised drug selection for patients are provided. We have also provided strategies for improving physician-commissioner communication to harmonise equity of patient access to biologics across England and improve patient outcomes. Commentary from patient advisory groups indicates that they welcome our exploration that value does not equal cost and agree that there should be an emphasis on shared decision making, which requires the clinician to practice clinical freedom by aligning the patient's needs and preferences with available treatment choices. CONCLUSIONS: This consensus highlights the need to strike a balance between clinical freedom and short-term cost restrictions to support equitable resource distribution within the English NHS. Consideration of these recommendations may help to harmonise local, regional and national services and balance equity of patient access to biologic treatments with excellence in the NHS.

Treatment of psoriatic arthritis with biologic and targeted synthetic DMARDs: British Society for Rheumatology guideline scope.

The aim of this guideline is to provide an update on evidence-based recommendations for treatment of adult patients with PsA. The previous BSR guidelines for PsA were published in 2012 and since that time, there have been many new advanced therapies licensed for PsA. This update will provide practical guidance for clinicians on the optimal selection of advanced therapies taking into account different domains of PsA (arthritis, enthesitis, dactylitis, axial disease and psoriasis) and key associated comorbidities. It will also update guidance on treatment strategy including the use of a treat-to-target approach. The guideline will be developed using the methods and processes outlined in Creating Clinical Guidelines: Our Protocol. (1) This development process to produce guidance, advice and recommendations for practice has National Institute for Health and Care Excellence (NICE) accreditation.

Brodalumab in psoriasis: evidence to date and clinical potential.

Brodalumab is a recombinant, fully human monoclonal antibody (IgG2) which binds with high affinity to the interleukin (IL) 17 receptor A (IL17R). Brodalumab is now licensed and approved for the treatment of moderate-to-severe chronic plaque psoriasis in North America and Europe. As the third to market in the class of agents targeting IL-17, we review its place in the expanding armamentarium of cytokine-directed therapies for patients with severe psoriasis. Brodalumab is a highly efficacious therapy for psoriasis, whose mechanism of action is separate from other treatments targeting IL-17. Its use is associated with rapid control of the disease. We suggest that brodalumab is likely to be considered in those patients requiring rapid control of disease, where there is no known history of depression or suicidal ideation.

A Framework for Multi-Omic Prediction of Treatment Response to Biologic Therapy for Psoriasis.

Biologic therapies have shown high efficacy in psoriasis, but individual response varies and is poorly understood. To inform biomarker discovery in the Psoriasis Stratification to Optimise Relevant Therapy (i.e., PSORT) study, we evaluated a comprehensive array of omics platforms across three time points and multiple tissues in a pilot investigation of 10 patients with severe psoriasis, treated with the tumor necrosis factor (TNF) inhibitor, etanercept. We used RNA sequencing to analyze mRNA and small RNA transcriptome in blood, lesional and nonlesional skin, and the SOMAscan platform to investigate the serum proteome. Using an integrative systems biology approach, we identified signals of treatment response in genes and pathways associated with TNF signaling, psoriasis pathology, and the major histocompatibility complex region. We found association between clinical response and TNF-regulated genes in blood and skin. Using a combination of differential expression testing, upstream regulator analysis, clustering techniques, and predictive modeling, we show that baseline samples are indicative of patient response to biologic therapies, including signals in blood, which have traditionally been considered unreliable for inference in dermatology. In conclusion, our pilot study provides both an analytical framework and empirical basis to estimate power for larger studies, specifically the ongoing PSORT study, which we show as powered for biomarker discovery and patient stratification.

Research Techniques Made Simple: Bioinformatics for Genome-Scale Biology.

High-throughput biology presents unique opportunities and challenges for dermatological research. Drawing on a small handful of exemplary studies, we review some of the major lessons of these new technologies. We caution against several common errors and introduce helpful statistical concepts that may be unfamiliar to researchers without experience in bioinformatics. We recommend specific software tools that can aid dermatologists at varying levels of computational literacy, including platforms with command line and graphical user interfaces. The future of dermatology lies in integrative research, in which clinicians, laboratory scientists, and data analysts come together to plan, execute, and publish their work in open forums that promote critical discussion and reproducibility. In this article, we offer guidelines that we hope will steer researchers toward best practices for this new and dynamic era of data intensive dermatology.

Pharmacogenomics and the resulting impact on psoriasis therapies.

Psoriasis is a model disease for the development of pharmacogenomic markers of treatment response, with ready access to diseased tissue and objective validated outcome measures. With the application of state-of-the-art technologies and investment in careful experimental design, the goal of stratified medicine in psoriasis may be possible. Current pharmacogenomic studies in psoriasis show excellence in many areas, including the investigation of a broad range of psoriasis therapies. To facilitate the advent of stratified medicine in psoriasis, uniformity of study design is required, with high quality, consistent phenotyping strategies for participants; definitions of outcome; and the publication of reproducible methodologies.

Methotrexate toxicity during treatment of chronic plaque psoriasis: a case report and review of the literature.

Methotrexate continues to be one of the most widely used systemic immunosuppressive agents in dermatology. In addition to the important, well-characterized adverse effects such as hepatotoxicity and myelosuppression, methotrexate may induce a number of rare cutaneous adverse events including methotrexate-induced ulceration. We present a case of methotrexate-induced cutaneous ulceration in a patient with chronic plaque psoriasis occurring during long-standing methotrexate therapy. Withdrawal of the drug and appropriate skin care led to rapid healing of the ulceration and the agent was later safely reintroduced for the ongoing management of the patient's chronic plaque psoriasis. Review of the literature demonstrates cases of this important rare adverse event, primarily occurring in patients with chronic plaque psoriasis, induced by triggers such as accidental overdose or introduction of an interacting agent. Cutaneous ulceration typically precedes other markers of toxicity. Active treatment with folinic acid (calcium leucovorin) may be required. Early recognition, prompt cessation of methotrexate, and appropriate treatment minimizes morbidity. Dermatologists need to be alert to the possibility of cutaneous adverse events associated with methotrexate therapy, aware of potential drug interactions, and confident in the management of methotrexate toxicity.

Unmasking of axial spondyloarthritis and oligoarthritis following discontinuation of tumour necrosis factor inhibitor therapy for psoriasis.

Psoriatic arthritis remains a common cause of morbidity in patients with psoriasis. Little is known about the natural history of the disease and dermatologists do not consistently screen for its presence. We describe a patient with severe psoriasis where long-term biologic therapy with a tumour necrosis factor inhibitor was interrupted for clinical reasons, leading to a rapidly evolving axial spondyloarthritis and oligoarthritis. This unusual presentation of psoriatic arthritis may reflect masking of the disease by long-term treatment with a tumour necrosis factor inhibitor. We advocate the use of screening for psoriatic arthritis, including before and during treatment with biologic therapies.

Patients' narratives.

Patients who suffer from inflammatory skin disease are at risk of stigmatisation and physical and psychological co-morbidities. To an extent these issues can be offset by effective coping strategies. The cumulative balance of these interactions will often lead to impairment, especially in those whose coping mechanisms are maladaptive or do not exist. When this situation arises, the detrimental effect of these various morbidities is termed 'cumulative life course impairment' (CLCI). We present 2 typical cases, one of a patient suffering from severe psoriasis and another of a patient suffering severe atopic eczema, as examples of how patients with inflammatory skin disease may be affected by CLCI. Their experiences demonstrate that the presence of inflammatory skin disease changes key life choices with resultant effect on career and relationships, amongst others. Although longitudinal evidence to support this CLCI is lacking, these patient narratives add support to the concept of CLCI.