Full length interleukin 33 aggravates radiation-induced skin reaction

The interleukin (IL)-1 family member IL-33 has been described as intracellular alarmin with broad roles in wound healing, skin inflammation but also autoimmunity. Its dichotomy between full length (fl) IL-33 and the mature (m) form of IL-33 and its release by necrosis is still not fully understood. Here, we compare functional consequences of both forms in the skin in vivo, and therefore generated two lines of transgenic mice which selectively overexpress mmIL-33 and flmIL-33 in basal keratinocytes. Transgene mRNA was expressed at high level in skin of both lines but not in organs due to the specific K14 promoter. We could demonstrate that transgenic overexpression of mmIL-33 in murine keratinocytes leads to a spontaneous skin inflammation as opposed to flmIL-33. K14-mmIL-33 mice synthesize and secrete high amounts of mmIL-33 along with massive cutaneous manifestations, like increased epidermis and dermis thickness, infiltration of mast cells in the epidermis and dermis layers and marked hyperkeratosis. Using skin inflammation models such as IL-23 administration, imiquimod treatment, or mechanical irritation did not lead to exacerbated inflammation in the K14-flmIL-33 strain. As radiation induces a strong dermatitis due to apoptosis and necrosis, we determined the effect of fractionated radiation (12 Gy, 4 times). In comparison to wild-type mice, an increase in ear thickness in flmIL-33 transgenic mice was observed 25 days after irradiation. Macroscopic examination showed more severe skin symptoms in irradiated ears compared to controls. In summary, secreted mmIL-33 itself has a potent capacity in skin inflammation whereas fl IL-33 is limited due to its intracellular retention. During tissue damage, fl IL-33 exacerbated radiation-induced skin reaction

Disease interception with interleukin-17 inhibition in high-risk psoriasis patients with subclinical joint inflammation—data from the prospective IVEPSA study

Background A specific subset of psoriasis patients is characterized by subclinical inflammatory changes. These patients frequently present with arthralgia and have a higher risk to develop psoriatic arthritis (PsA). We hypothesized that IL-17A inhibition in this subset of patients can intercept the link between skin and joint disease and resolves pain and inflammatory changes. Methods Psoriasis, but no PsA, patients were included in the open prospective exploratory Interception in very early PsA (IVEPSA) study. Patients had to have nail or scalp involvement or a high psoriasis area severity index (PASI) (> 6) as well as inflammatory or erosive changes in MRI or CT. Patients received treatment with the anti-interleukin (IL)-17A antibody secukinumab over 24 weeks. Clinical assessments of skin and joint disease were done at baseline and after 12 and 24 weeks, MRI and CT at baseline and after 24 weeks. Results Twenty patients were included, 85% of them reporting arthralgia and 40% had tender joints at the examination. Eighty-three percent had at least one inflammatory lesion in the MRI, most of them synovitis/enthesitis. Skin disease (PASI: p < 0.002; BSA: p < 0.003) and arthralgia (VAS pain: p < 0.003) significantly improved after 24 weeks. Total PsAMRIS (p = 0.005) and synovitis subscore (p = 0.008) also significantly improved. Erosions and enthesiophytes did not progress, while bone mass in the distal radius significantly (p = 0.020) increased after 24 weeks. Conclusions These data suggest that very early disease interception in PsA is possible leading to a comprehensive decline in skin symptoms, pain, and subclinical inflammation. IVEPSA therefore provides rationale for future early interventions with the concept to prevent the onset of PsA in high-risk individuals. Trial registration Trial registry name PSARTROS; trial registry number: NCT02483234; June 26, 2015

Effect of disease-modifying anti-rheumatic drugs on bone structure and strength in psoriatic arthritis patients

Objectives To address whether the use of methotrexate (MTX) and biological disease-modifying anti-rheumatic drugs (bDMARDs) impacts bone structure and biomechanical properties in patients with psoriatic arthritis (PsA). Methods This is a cross-sectional study in PsA patients receiving no DMARDs, MTX, or bDMARDs. Volumetric bone mineral densities (vBMDs), microstructural parameters, and biomechanical properties (stiffness/failure load) were determined by high-resolution peripheral quantitative CT and micro-finite element analysis in the respective groups. Bone parameters were compared between PsA patients with no DMARDs and those receiving any DMARDs, MTX, or bDMARDs, respectively. Results One hundred sixty-five PsA patients were analyzed, 79 received no DMARDs, 86 received DMARDs, of them 52 bDMARDs (TNF, IL-17- or IL-12/23 inhibitors) and 34 MTX. Groups were balanced for age, sex, comorbidities, functional index, and bone-active therapy, while disease duration was longest in the bDMARD group (7.8 ± 7.4 years), followed by the MTX group (4.6 ± 7.4) and the no-DMARD group (2.9 ± 5.2). No difference in bone parameters was found between the no-DMARD group and the MTX group. In contrast, the bDMARD group revealed significantly higher total (p = 0.001) and trabecular vBMD (p = 0.005) as well as failure load (p = 0.012) and stiffness (p = 0.012). In regression models, age and bDMARDs influenced total vBMD, while age, sex, and bDMARDs influenced failure load and stiffness. Conclusion Despite longer disease duration, bDMARD-treated PsA patients benefit from higher bone mass and better bone strength than PsA patients receiving MTX or no DMARDs. These data support the concept of better control of PsA-related bone disease by bDMARDs

Structural insights into heme binding to IL-36α proinflammatory cytokine

Cytokines of the interleukin (IL)-1 family regulate immune and inflammatory responses. The recently discovered IL-36 family members are involved in psoriasis, rheumatoid arthritis, and pulmonary diseases. Here, we show that IL-36α interacts with heme thereby contributing to its regulation. Based on in-depth spectroscopic analyses, we describe two heme-binding sites in IL-36α that associate with heme in a pentacoordinated fashion. Solution NMR analysis reveals structural features of IL-36α and its complex with heme. Structural investigation of a truncated IL-36α supports the notion that the N-terminus is necessary for association with its cognate receptor. Consistent with our structural studies, IL-36-mediated signal transduction was negatively regulated by heme in synovial fibroblast-like synoviocytes from rheumatoid arthritis patients. Taken together, our results provide a structural framework for heme-binding proteins and add IL-1 cytokines to the group of potentially heme-regulated proteins

Polymorphisms in the Hsp70 gene locus are genetically associated with systemic lupus erythematosus

Background Heat shock proteins (Hsps) play a role in the delivery and presentation of antigenic peptides and are thought to be involved in the pathogenesis of multifactorial diseases. Objective To investigate genes encoding cytosolic Hsp70 proteins for associations of allelic variants with systemic lupus erythematosus (SLE). Methods Case-control studies of two independent Caucasian SLE cohorts were performed. In a haplotype-tagging single-nucleotide polymorphism approach, common variants of HspA1L, HspA1A and HspA1B were genotyped and principal component analyses were performed for the cohort from the Oklahoma Medical Research Foundation (OMRF). Relative quantification of mRNA was carried out for each Hsp70 gene in healthy controls. Conditional regression analysis was performed to determine if allelic variants in Hsp70 act independently of HLA-DR3. Results On analysis of common genetic variants of HspA1L, HspA1A and HspA1B, a haplotype significantly associated with SLE in the Erlangen-SLE cohort was identified, which was confirmed in the OMRF cohort. Depending on the cohorts, OR ranging from 1.43 to 1.88 and 2.64 to 3.16 was observed for individuals heterozygous and homozygous for the associated haplotype, respectively. Patients carrying the risk haplotype or the risk allele more often displayed autoantibodies to Ro and La in both cohorts. In healthy controls bearing this haplotype, the amount of HspA1A mRNA was significantly increased, whereas total Hsp70 protein concentration was not altered. Conclusions Allelic variants of the Hsp70 genes are significantly associated with SLE in Caucasians, independently of HLA-DR3, and correlate with the presence of autoantibodies to Ro and La. Hence, the Hsp70 gene locus appears to be involved in SLE pathogenesis

Machine learning-based improvement of an online rheumatology referral and triage system

IntroductionRheport is an online rheumatology referral system allowing automatic appointment triaging of new rheumatology patient referrals according to the respective probability of an inflammatory rheumatic disease (IRD). Previous research reported that Rheport was well accepted among IRD patients. Its accuracy was, however, limited, currently being based on an expert-based weighted sum score. This study aimed to evaluate whether machine learning (ML) models could improve this limited accuracy.Materials and methodsData from a national rheumatology registry (RHADAR) was used to train and test nine different ML models to correctly classify IRD patients. Diagnostic performance was compared of ML models and the current algorithm was compared using the area under the receiver operating curve (AUROC). Feature importance was investigated using shapley additive explanation (SHAP).ResultsA complete data set of 2265 patients was used to train and test ML models. 30.5% of patients were diagnosed with an IRD, 69.3% were female. The diagnostic accuracy of the current Rheport algorithm (AUROC of 0.534) could be improved with all ML models, (AUROC ranging between 0.630 and 0.737). Targeting a sensitivity of 90%, the logistic regression model could double current specificity (17% vs. 33%). Finger joint pain, inflammatory marker levels, psoriasis, symptom duration and female sex were the five most important features of the best performing logistic regression model for IRD classification.ConclusionIn summary, ML could improve the accuracy of a currently used rheumatology online referral system. Including further laboratory parameters and enabling individual feature importance adaption could increase accuracy and lead to broader usage

An international multicentre analysis of current prescribing practices and shared decision-making in psoriatic arthritis

Objectives Shared decision-making (SDM) is advocated to improve patient outcomes in PsA. We analysed current prescribing practices and the extent of SDM in PsA across Europe. Methods The ASSIST study was a cross-sectional observational study of PsA patients ≥18 years of age attending face-to-face appointments between July 2021 and March 2022. Patient demographics, current treatment and treatment decisions were recorded. SDM was measured by the clinician’s effort to collaborate (CollaboRATE questionnaire) and patient communication confidence (PEPPI-5 tool). Results A total of 503 patients were included from 24 centres across the UK, France, Germany, Italy and Spain. Physician- and patient-reported measures of disease activity were highest in the UK. Conventional synthetic DMARDs constituted a higher percentage of current PsA treatment in the UK than continental Europe (66.4% vs 44.9%), which differed from biologic DMARDs (36.4% vs 64.4%). Implementing treatment escalation was most common in the UK. CollaboRATE and PEPPI-5 scores were high across centres. Of 31 patients with low CollaboRATE scores (<4.5), no patients with low PsAID-12 scores (<5) had treatment escalation. However, of 465 patients with CollaboRATE scores ≥4.5, 59 patients with low PsAID-12 scores received treatment escalation. Conclusions Higher rates of treatment escalation seen in the UK may be explained by higher disease activity and a younger cohort. High levels of collaboration in face-to-face PsA consultations suggests effective implementation of the SDM approach. Our data indicate that in patients with mild disease activity, only those with higher perceived collaboration underwent treatment escalation. Prospective studies should examine the impact of SDM on PsA patient outcomes

Edgeworthentwicklungen fuer die Dichten von differenzierbaren gefilterten Poissonprozessen

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