The role of the cytokines IL-17A and IL-33 in inflammatory arthritis and psoriasis

The inflammatory autoimmune diseases rheumatoid arthritis, psoriatic arthritis and psoriasis have seen a break through in therapy by targeting cytokines in the last decade. Interleukin-17A, a potential new target, is considered as a crucial player in rheumatoid arthritis, and has been suggested to be produced by CD4+ T cells (Th17 cells). I explored the cellular sources of IL-17A in human established RA synovium. Surprisingly, only a small proportion of IL-17 positive cells were T cells without expression of a Th17 marker CCR6. Unexpectedly, the majority of IL-17A expression colocalized within mast cells. These data do not contradict a crucial role for IL-17A in RA pathogenesis, however, suggest that in addition to Th17 cells, cells of the innate immune system, particularly mast cells, may be an important component of the effector IL-17A response. Psoriasis is a common chronic autoimmune disease of the skin characterized by hyperplasia of epidermal keratinocytes with associated inflammation. IL-33 is a new member of the IL-1 superfamily that signals through the ST2 receptor and was originally defined as an inducer of T helper 2 (Th2) cytokines. Recently broader immune potential has been discovered for IL-33 particularly via mast cell activation. With its expression at body barrier surfaces it is assumed to act as an alarmin. In this thesis I demonstrate that IL-33 expression is up-regulated in the epidermis of psoriatic lesions, compared to healthy skin, thus indicating that IL-33 may be a mediator regulating crosstalk between keratinocytes and infiltrating immune cells in psoriatic plaques. In a phorbol ester-induced model of skin inflammation ST2-/- mice exhibited reduced cutaneous inflammatory responses compared to WT mice. Furthermore, consecutive injections of IL-33 into the ears of mice induced a psoriasis-like inflammatory lesion. This was partially mast cell dependent and cellular analysis demonstrated recruitment of neutrophils to the ear. This concludes that IL-33, via activation of mast cells and recruitment of neutrophils, may play a role in psoriasis plaque inflammation. In the last part of the thesis I tested if nanoparticles can be utilized to image cytokine driven inflammation. Bio-linkages with protein-nanoparticles have been established and in vivo detection of nanoparticles performed. This final interdisciplinary outlook demonstrates a still to be established/finalized method with great potential

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

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

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

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

Rheumatology training experience across Europe : Analysis of core competences

Publisher Copyright: © 2016 The Author(s). Copyright: Copyright 2019 Elsevier B.V., All rights reserved.Background: The aim of this project was to analyze and compare the educational experience in rheumatology specialty training programs across European countries, with a focus on self-reported ability. Method: An electronic survey was designed to assess the training experience in terms of self-reported ability, existence of formal education, number of patients managed and assessments performed during rheumatology training in 21 core competences including managing specific diseases, generic competences and procedures. The target population consisted of rheumatology trainees and recently certified rheumatologists across Europe. The relationship between the country of training and the self-reported ability or training methods for each competence was analyzed through linear or logistic regression, as appropriate. Results: In total 1079 questionnaires from 41 countries were gathered. Self-reported ability was high for most competences, range 7.5-9.4 (0-10 scale) for clinical competences, 5.8-9.0 for technical procedures and 7.8-8.9 for generic competences. Competences with lower self-reported ability included managing patients with vasculitis, identifying crystals and performing an ultrasound. Between 53 and 91 % of the trainees received formal education and between 7 and 61 % of the trainees reported limited practical experience (managing ≤10 patients) in each competence. Evaluation of each competence was reported by 29-60 % of the respondents. In adjusted multivariable analysis, the country of training was associated with significant differences in self-reported ability for all individual competences. Conclusion: Even though self-reported ability is generally high, there are significant differences amongst European countries, including differences in the learning structure and assessment of competences. This suggests that educational outcomes may also differ. Efforts to promote European harmonization in rheumatology training should be encouraged and supported.publishersversionPeer reviewe

Educational needs and preferences of young European clinicians and physician researchers working in the field of rheumatology

Funding Information: CB: Grant BE 5191/1-1 of the Deutsche Forschungsgemeinschaft.Objectives: To understand the educational needs and preferences of young clinicians and physician researchers in the field of rheumatology in Europe. Methods: An international online survey was performed as a joint venture of ESCET and EMEUNET. The survey assessed the acceptance of and the access to the current European League Against Rheumatism (EULAR) educational portfolio, as well as the unmet educational needs and learning preferences among individuals below the age of 40 years working in rheumatology in Europe. Results: Among 568 European clinicians and physician researchers, 65% indicated that the existing EULAR educational portfolio adequately covers their educational needs. Within the EULAR portfolio, the online course on rheumatic diseases and the postgraduate course were the most appreciated. Participants were very much in favour of new educational courses on imaging techniques, and 63% of participants indicated a particular interest in musculoskeletal ultrasound. A strong interest in refresher (60%) and general review (55%) courses was observed. Lack of funding was considered the major obstacle to participating in existing EULAR programmes. Finally, participants showed diverse preferences regarding learning modalities with common interests in live courses and conferences. Conclusions: EULAR's training opportunities are well appreciated among young clinicians and physician researchers in rheumatology. The results from this survey will help to develop EULAR's future educational portfolio.publishersversionPeer reviewe

How do patient-reported outcome measures affect treatment intensification and patient satisfaction in the management of psoriatic arthritis? A cross sectional study of 503 patients

Objectives The AsseSSing Impact in pSoriatic Treatment (ASSIST) study investigated prescribing in routine PsA care and whether the patient-reported outcome—PsA Impact of Disease questionnaire (PsAID-12)—impacted treatment. This study also assessed a range of patient and clinician factors and their relationship to PsAID-12 scoring and treatment modification. Methods Patients with PsA were selected across the UK and Europe between July 2021 and March 2022. Patients completed the PsAID questionnaire and the results were shared with their physician. Patient characteristics, disease activity, current treatment methods, treatment strategies, medication changes and patient satisfaction scores were recorded. Results A total of 503 patients were recruited. Some 36.2% had changes made to treatment, and 88.8% of these had treatment escalation. Overall, the mean PsAID-12 score was higher for patients with treatment escalation; increase in PSAID-12 score is associated with increased odds of treatment escalation (odds ratio 1.58; P < 0.0001). However, most clinicians reported that PsAID-12 did not impact their decision to escalate treatment, instead supporting treatment reduction decisions. Physician’s assessment of disease activity had the most statistically significant effect on likelihood of treatment escalation (odds ratio 2.68, per 1-point score increase). Escalation was more likely in patients not treated with biologic therapies. Additional factors associated with treatment escalation included: patient characteristics, physician characteristics, disease activity and disease impact. Conclusion This study highlights multiple factors impacting treatment decision-making for individuals with PsA. PsAID-12 scoring correlates with multiple measures of disease severity and odds of treatment escalation. However, most clinicians reported that the PsAID-12 did not influence treatment escalation decisions. Psoriatic Arthritis Impact of Disease (PsAID) scoring could be used to increase confidence in treatment de-escalation

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