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Funding The study received support from the American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR). OBJECTIVES: To investigate factors associated with severe COVID-19 in people with psoriasis (PsO), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). METHODS: Demographic data, clinical characteristics and COVID-19 outcome severity of adults with PsO, PsA and axSpA were obtained from two international physician-reported registries. A three-point ordinal COVID-19 severity scale was defined: no hospitalisation, hospitalisation (and no death) and death. ORs were estimated using multivariable ordinal logistic regression. RESULTS: Of 5045 cases, 18.3% had PsO, 45.5% PsA and 36.3% axSpA. Most (83.6%) were not hospitalised, 14.6% were hospitalised and 1.8% died. Older age was non-linearly associated with COVID-19 severity. Male sex (OR 1.54, 95% CI 1.30 to 1.83), cardiovascular, respiratory, renal, metabolic and cancer comorbidities (ORs 1.25-2.89), moderate/high disease activity and/or glucocorticoid use (ORs 1.39-2.23, vs remission/low disease activity and no glucocorticoids) were associated with increased odds of severe COVID-19. Later pandemic time periods (ORs 0.42-0.52, vs until 15 June 2020), PsO (OR 0.49, 95% CI 0.37 to 0.65, vs PsA) and baseline exposure to TNFi, IL17i and IL-23i/IL-12+23i (OR 0.57, 95% CI 0.44 to 0.73; OR 0.62, 95% CI 0.45 to 0.87; OR 0.67, 95% CI 0.45 to 0.98; respectively; vs no disease-modifying antirheumatic drug) were associated with reduced odds of severe COVID-19. CONCLUSION: Older age, male sex, comorbidity burden, higher disease activity and glucocorticoid intake were associated with more severe COVID-19. Later pandemic time periods, PsO and exposure to TNFi, IL17i and IL-23i/IL-12+23i were associated with less severe COVID-19. These findings will enable risk stratification and inform management decisions for patients with PsO, PsA and axSpA during COVID-19 waves or similar future respiratory pandemics. publishersversion published

Background Responses to the systemic treatments commonly used to treat psoriasis vary. Biomarkers that accurately predict effectiveness and safety would enable targeted treatment selection, improved patient outcomes and more cost-effective healthcare. Objectives To perform a scoping review to identify and catalogue candidate biomarkers of systemic treatment response in psoriasis for the translational research community. Methods A systematic search of CENTRAL, Embase, LILACS and MEDLINE was performed for relevant articles published between 1990 and December 2021. Eligibility criteria were studies involving patients with psoriasis (any age, n ≥ 50) reporting biomarkers associated with systemic treatment response. The main outcomes were any measure of systemic treatment efficacy or safety. Data were extracted by one reviewer and checked by a second; studies meeting minimal quality criteria (use of methods to control for confounding) were formally assessed for bias. Candidate biomarkers were identified by an expert multistakeholder group using a majority voting consensus exercise and mapped to relevant cellular and molecular pathways. Results Of 71 included studies (67 studying effectiveness outcomes and eight safety outcomes; four studied both), most reported genomic or proteomic biomarkers associated with response to biologics (48 studies). Methodological or reporting limitations frequently compromised the interpretation of findings, including inadequate control for key covariates, lack of adjustment for multiple testing, and selective outcome reporting. We identified candidate biomarkers of efficacy to tumour necrosis factor inhibitors [variation in CARD14, CDKAL1, IL1B, IL12B and IL17RA loci, and lipopolysaccharide-induced phosphorylation of nuclear factor (NF)-κB in type 2 dendritic cells] and ustekinumab (HLA-C*06:02 and variation in an IL1B locus). None were supported by sufficient evidence for clinical use without further validation studies. Candidate biomarkers were found to be involved in the immune cellular crosstalk implicated in psoriasis pathogenesis, most notably antigen presentation, T helper (Th)17 cell differentiation, positive regulation of NF-κB, and Th17 cell activation. Conclusions This comprehensive catalogue provides a key resource for researchers and reveals a diverse range of biomarker types and outcomes in the included studies. The candidate biomarkers identified require further evaluation in methodologically robust studies to establish potential clinical utility. Future studies should aim to address the common methodological limitations highlighted in this review to expedite discovery and validation of biomarkers for clinical use. What is already known about this topic? Responses to the systemic treatments commonly used to treat psoriasis vary.Biomarkers that accurately predict effectiveness and safety would enable targeted treatment selection, improved patient outcomes and more cost-effective healthcare. What does this study add? This review provides a comprehensive catalogue of investigated biomarkers of systemic treatment response in psoriasis.A diverse range of biomarker types and outcomes was found in the included studies, serving as a key resource for the translational research community.

Contains fulltext : 251813.pdf (Publisher’s version ) (Closed access) 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.

Background COVID-19 vaccination is efficacious at protecting against severe COVID-19 outcomes in the general population. However, vaccine hesitancy (unwillingness for vaccination despite available vaccination services) threatens public health. Individuals taking immunosuppression for psoriasis have been prioritised for COVID-19 vaccination, however there is a paucity of information on vaccine hesitancy in this population, including contributing factors. While global healthcare has been severely disrupted in the pandemic, the impact on access to psoriasis care and whether this may negatively influence vaccine uptake, is underexplored.Objectives To explore organisational and individual factors associated with COVID-19 vaccine hesitancy in individuals with psoriasis.Methods Individuals with psoriasis, identified through global patient organisations and social media, completed a cross-sectional self-reported online survey. The primary outcome was COVID-19 vaccine hesitancy. Logistic regression was used to examine the association between predictor variables (organisational and individual factors) and outcome.Results Self-reported data from 802 individuals with psoriasis across 89 countries were available (65.6% female, median age 51 years [IQR 37-61], 43.7% taking systemic immunosuppression). Eight percent (n=63) reported vaccine hesitancy. Those reporting vaccine hesitancy were younger, more likely to be of non-white ethnicity, non-UK resident, have a lower BMI, not taking systemic immunosuppression and with shorter disease duration compared to those not reporting vaccine hesitancy. The commonest reasons for vaccine hesitancy were concerns regarding vaccine side-effects, that the vaccine is too new or that psoriasis may worsen post-vaccination. Forty percent (n=322) reported that their psoriasis care had been disrupted by the pandemic. These individuals were younger, of non-white ethnicity, with shorter duration and more severe psoriasis. Disruption to psoriasis care was associated with vaccine hesitancy (unadjusted OR 2.97 (95%CI 1.23-7.13), p=0.015), although not statistically significant in the adjusted model.Conclusion A minority of individuals with psoriasis from our study reported COVID-19 vaccine hesitancy. Similar to general population trends, vaccine hesitancy in our psoriasis sample is most common in younger age and ethnic minority groups. Our data highlight patient concerns regarding COVID-19 vaccination, which are important to address during patient-clinician interactions to help optimise vaccine uptake and mitigate risks from the ongoing pandemic in individuals with psoriasis.What’s already known about this topic?The COVID-19 vaccine is highly efficacious at protecting against severe COVID-19 outcomes in the general population. Vaccine hesitancy (unwillingness to receive vaccination despite available vaccination services) poses a major threat to global public health and is more common in women, younger age and ethnic minority groups in the general population.Individuals with psoriasis taking systemic immunosuppression were considered at high risk of severe COVID-19 outcomes and prioritised for vaccination, however there is a paucity of information on vaccine hesitancy in this group, including contributing factors.While global healthcare has been severely disrupted by the COVID-19 pandemic, access to psoriasis care and its potential impact on vaccine hesitancy is underexplored.What does this study add?A substantial proportion (40%) of individuals with psoriasis reported disrupted access to psoriasis care during the COVID-19 pandemic. Disrupted care was most commonly reported in younger age and ethnic minority groups.COVID-19 vaccine hesitancy was reported by a minority (8%) of individuals with psoriasis. Those reporting vaccine hesitancy were younger and more likely to be of non-white ethnicity, in keeping with trends in the general population.The commonest reasons for vaccine hesitancy were concerns regarding vaccine side effects, that the vaccine is too new or that psoriasis may worsen post-vaccination. These concerns are important to address during patient-clinician interactions to help mitigate risks from the ongoing pandemic in individuals with psoriasis.Competing Interest StatementNothing to disclose: Dr Bechman, Ms Cook, Dr Dand, Prof. Langan, Dr. Norton, Dr. Tsakok, Dr. Yiu, Dr De La Cruz, Dr. Contreras, Ms. Vesty, Ms. Vincent, Mr. Bola Coker, Ms. Meynell, Dr. Lambert, Prof. Brown, Prof. Naldi. Prof. Barker reports grants and personal fees from Abbvie, grants and personal fees from Novartis, grants and personal fees from Lilly, grants and personal fees from J&J, from null, during the conduct of the study. Prof. Griffiths reports grants and personal fees from AbbVie, grants from Amgen, grants from BMS, grants and personal fees from Janssen, grants from LEO, grants and personal fees from Novartis, grants from Pfizer, grants from Almirall, grants and personal fees from Lilly, grants and personal fees from UCB Pharma, outside the submitted work. Prof. Jullien reports personal fees and non-financial support from Abbvie, personal fees and non-financial support from Novartis, personal fees and non-financial support from Janssen-Cilag, personal fees and non-financial support from Lilly, personal fees and non-financial support from Leo-Pharma, personal fees and non-financial support from MEDAC, personal fees and non-financial support from Celgene, personal fees from Amgen, outside the submitted work. Dr. Capon reports consultancy fees from AnaptysBio, grants from Boheringer-Ingelheim, outside the submitted work. Prof. Bachelez reports personal fees from Abbvie, personal fees from Janssen, personal fees from LEO Pharma, personal fees from Novartis, personal fees from UCB, personal fees from Almirall, personal fees from Biocad, personal fees from Boehringer-Ingelheim, personal fees from Kyowa Kirin, personal fees from Pfizer, outside the submitted work. Prof. Gisondi reports personal fees from Abbvie, Amgen, Eli Lilly, Janssen, Novartis, Pierre Fabre, Sandoz, UCB, outside the submitted work. Dr. Galloway reports personal fees from Abbvie, personal fees from Sanofi, personal fees from Novartis, personal fees from Pfizer, grants from Eli Lilly, personal fees from Janssen, personal fees from UCB, outside the submitted work. Prof. Weinmann has presented talks for Abbvie, Abbott, Bayer, Chiesi, Boehringer Ingelheim, Roche and Merck. Dr. Mason reports personal fees from LEO Pharma and Novartis, outside the submitted work. Ms. Moorhead reports personal fees from Abbvie, personal fees from Celgene, personal fees from Janssen, personal fees from LEO Pharma, personal fees from Novartis, personal fees from UCB, outside the submitted work. Dr. Puig reports grants and personal fees from AbbVie, grants and personal fees from Almirall, grants and personal fees from Amgen, grants and personal fees from Boehringer Ingelheim, personal fees from Bristol Myers Squibb, personal fees from Fresenius-Kabi, grants and personal fees from Janssen, grants and personal fees from Lilly, personal fees from Mylan, grants and personal fees from Novartis, personal fees from Pfizer, personal fees from Sandoz, personal fees from Sanofi, personal fees from Samsung-Bioepis, grants and personal fees from UCB, outside the submitted work. Dr. Mahil reports departmental income from Abbvie, Almirall, Eli Lilly, Janssen-Cilag, Novartis, Sanofi, UCB, outside the submitted work. Dr. Di Meglio reports grants and personal fees from UCB, personal fees from Novartis, personal fees from Janssen, outside the submitted work. Prof. Warren reports grants and personal fees from Abbvie, grants and personal fees from Celgene, grants and personal fees from Eli Lilly, grants and personal fees from Novartis, personal fees from Sanofi, grants and personal fees from UCB|, grants and personal fees from Almirall, grants and personal fees from Amgen, grants and personal fees from Janssen, grants and personal fees from Leo, grants and personal fees from Pfizer, personal fees from Arena, personal fees from Avillion, personal fees from Bristol Myers Squibb, personal fees from Boehringer Ingelheim, outside the submitted work. Prof. Smith reports grants from Abbvie, Sanofi, Novartis, and Pfizer and through consortia with multiple academic partners (psort.org.uk, BIOMAP-IMI.eu), outside the submitted work. Dr. Torres reports grants and personal fees from AbbVie, Almirall, Amgen, Arena Pharmaceuticals, Biogen, Biocad, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, LEO Pharma, MSD, Novartis, Pfizer, Samsung-Bioepis, Sandoz, during the conduct of the study. Dr. Waweru is on the Board of the International Federation of Psoriasis Associations who have received grants from Abbvie, Almirall, Amgen, Bristol Meyers Squibb, Boehringer Ingelheim, Celgene, Janssen, Leo Pharma, Eli Lilly, Novartis, Sun Pharma, Pfizer, and UCB, outside the submitted work. Mr. Urmston reports grants from Almirall, grants from Abbvie, grants from Amgen, grants from Celgene, grants from Dermal Laboratories, grants from Eli Lilly, grants from Janssen, grants from LEO Pharma, grants from T and R Derma, grants from UCB, outside the submitted work. Ms. McAteer reports grants from Abbvie, grants from Almirall, grants from Amgen, grants from Celgene, grants from Dermal Laboratories, grants from Eli Lilly, grants from Janssen, grants from LEO Pharma, grants from UCB, grants from T and R Derma, outside the submitted work. Prof. Spuls has done consultancies in the past for Sanofi 111017 and AbbVie 041217 (unpaid), received a departmental independent research grant for TREAT NL registry LeoPharma December 2019; is involved in performing clinical trials with many pharmaceutical industries that manufacture drugs used for the treatment of diseases such as psoriasis and atopic dermatitis, for which financial compensation is paid to the department/hospital; and is chief investigator of the

The identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused our attention on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole-exome sequencing of 19 unrelated affected individuals, we identified a subject harboring a homozygous splice-site mutation (c.2031−2A>C) in MPO. This encodes myeloperoxidase, an essential component of neutrophil azurophil granules. MPO screening in conditions phenotypically related to GPP uncovered further disease alleles in one subject with acral pustular psoriasis (c.2031−2A>C;c.2031−2A>C) and in two individuals with acute generalized exanthematous pustulosis (c.1705C>T;c.2031−2A>C and c.1552_1565del;c.1552_1565del). A subsequent analysis of UK Biobank data demonstrated that the c.2031−2A>C and c.1705C>T (p.Arg569Trp) disease alleles were also associated with increased neutrophil abundance in the general population (p = 5.1 × 10−6 and p = 3.6 × 10−5, respectively). The same applied to three further deleterious variants that had been genotyped in the cohort, with two alleles (c.995C>T [p.Ala332Val] and c.752T>C [p.Met251Thr]) yielding p values < 10−10. Finally, treatment of healthy neutrophils with an MPO inhibitor (4-Aminobenzoic acid hydrazide) increased cell viability and delayed apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers. These findings identify MPO as a genetic determinant of pustular skin disease and neutrophil abundance. Given the recent interest in the development of MPO antagonists for the treatment of neurodegenerative disease, our results also suggest that the pro-inflammatory effects of these agents should be closely monitored.