[Position paper of the commission on digital rheumatology of the German Society of Rheumatology: tasks, targets and perspectives for a modern rheumatology]. / Positionspapier der Kommission Digitale Rheumatologie der Deutschen Gesellschaft für Rheumatologie e. V.: Aufgaben, Ziele und Perspektiven für eine moderne Rheumatologie.

Digitalization in the healthcare system is a great challenge for rheumatology as for other medical disciplines. The German Society for Rheumatology (DGRh) wants to actively participate in this process and benefit from it. By founding the commission on digital rheumatology, the DGRh has created a committee that deals with the associated tasks, advises the DGRh on questions and positions associated with digital health. For the DGRh, this affects the most diverse areas of digitalization in medicine and rheumatology. This position paper presents the topics and developments currently handled by the commission and the tasks identified.

The ageing joint-standard age- and sex-related values of bone erosions and osteophytes in the hand joints of healthy individuals.

OBJECTIVE: To analyze the age-related changes of the physiological hand joint architecture. METHOD: To address this concept, healthy individuals (each 10 women and 10 men in six different age decades spanning from 21 to 80 years) were recruited through a field campaign, investigated for the absence of rheumatic diseases and other comorbidities and received high-resolution quantitative computed tomography (HR-pQCT) examination of the hand joints. Number and extent of erosions and osteophytes were quantified across the ages and different sexes. RESULTS: Bone erosions [median (Q1-Q3), 1 (0-2)] and osteophytes [2 (1-4)] were found in healthy women and men with no significant sex differences. Structural changes however accumulated with age: the overall incidence rate ratio (IRR) for the number of erosions and osteophytes per age were 1.04 (95% CI: erosions 1.03-1.06; osteophytes: 1.03-1.05). This means a 4% increase in the number of erosions and osteophytes per year. Using third decade as reference, healthy individuals in the age decades from 50 years had higher IRR for erosion numbers (sixth, seventh, eigth decade: 4.87 (2.20-11.75), 6.81 (3.08-16.46) and 6.92 (3.11-16.79)) compared to younger subjects (fourth, fifth decade: 1.80 (0.69-4.87), 1.53 (0.59-4.10)). The IRRs of osteophytes also indicate a gradual increase after the fifth decade, with IRRs of 2.32 (1.32-4.17), 4.17 (2.38-7.49) and 6.86 (3.97-12.20) for the sixth, seventh and eigth decades, respectively. CONCLUSIONS: Structural changes in the hand joints of healthy individuals are age dependent. While being rare under 50 years of age, erosions and osteophytes accumulate above the age of 50, suggesting that the threshold between "normal" and "pathological" is shifted with the increase of age.

ALIGNed on adherence: subanalysis of adherence in immune-mediated inflammatory diseases in the DACH region of the global ALIGN study.

BACKGROUND: Non-adherence to medication is a challenging problem in daily clinical practice. OBJECTIVE: To assess reasons for non-adherence in patients with chronic immune-mediated inflammatory diseases (IMIDs) in a direct comparison including evaluation of treatment necessity and concerns. METHODS: ALIGN was a non-interventional, multicountry, multicentre, self-administered, cross-sectional, epidemiologic survey study. Here, we investigate the German, Austrian and Swiss (DACH) cohort. Six hundred thirty-one patients with different IMIDs (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn's disease and ulcerative colitis) under systemic therapies were evaluated concerning adherence, beliefs of necessity and concerns towards treatment in patients with IMIDs. RESULTS: The DACH cohort had significantly different levels of adherence depending on the IMID (P < 0.05) and the type of therapy (P < 0.05). Based on the significant influence of concerns on treatment adherence (P < 0.05) and the high belief of treatment necessity, patients could be classified in four attitudinal segments, which were unequally distributed throughout various IMIDs. High concerns had a significant influence on non-adherence, whereas necessity did not. Older age, female sex, TNFi mono-, conventional combination and TNFi combination therapy are positively associated with adherence. CONCLUSIONS: In the DACH region, patients are less concerned about medication and believe in the necessity of treatment. Therefore, we suggest adapting the communication in the various patient groups.

[Depression as comorbidity of rheumatoid arthritis]. / Depression als Komorbidität bei rheumatoider Arthritis.

Depressive disorders are among the most common comorbidities in patients not only with rheumatoid arthritis (RA) but also with other forms of inflammatory rheumatic diseases. The prevalence of a depressive disorder in RA is estimated to be between 9.5% and 41.5% depending on the study and with women being more affected. After adjusting for sex, age and other parameters the risk of depression in RA was significantly elevated with an odds ratio of 1.63 (95% CI, 1.43-1.87) compared to the general population. In RA the risk of developing a depressive disorder is highest in the first 5 years and depression is a better predictor of work disability than disease activity and response to treatment. Depression in RA is associated with more pain, fatigue and impaired quality of life, whereby the association between depression and RA is bidirectional. Therefore, the risk to develop a depression is increased with impaired function as measured by the health assessment questionnaire (HAQ) and there is evidence that increased disease activity increases the risk for depression in RA. In addition, a depressive disorder also affects the subjective severity of patient-reported outcomes (PRO), such as tender joints and the global patient assessment with respect to disease activity and thus exhibiting a direct influence on the DAS28. Finally, it could be shown that depression unfavorably influences the response to therapy, the rate of remission is lower and the mortality is increased in RA patients. Taken together, this indicates that it is necessary to detect a depression in patients with RA as early as possible in order to initiate appropriate treatment of depression in such cases.

[Use of medical apps and online platforms among German rheumatologists : Results of the 2016 and 2018 DGRh conference surveys and research conducted by rheumadocs]. / Nutzung von Medizin-Apps und Online-Plattformen unter deutschen Rheumatologen : Ergebnisse der rheumadocs-Recherche und DGRh-Kongress-Umfragen von 2016 und 2018.

BACKGROUND: Apps and online platforms play an ever increasing role in the daily work routine of physicians. The aim of this study was to investigate which medical apps and online platforms are used by German rheumatologists for certain tasks and to identify usage trends. METHODS: Data were collected via a SurveyMonkey survey conducted by members of rheumadocs (Young German Rheumatology Association) at the 2016 and 2018 German Society for Rheumatology (DGRh) conferences. RESULTS: In 2016 and 2018 the survey was completed by 75 and 84 assistant and specialist rheumatologists, respectively. In 2016, 37% of rheumatologists were using medical apps in routine care which changed to 49% in 2018. In 2016, 47% compared to 68% in 2018, planned to integrate medical apps into routine care. In total, 20 different medical apps were recommended for colleagues to use; however only 2 of these apps were specific for rheumatology. In contrast to 52 app recommendations for colleagues, only 8 app recommendations for patients were recorded. Most recommendations to physicians received the app "Arznei aktuell" (21%). "Embryotox" was the app, most recommended to patients (38%). In 2016 the online database PubMed was most popular and 97% of participants were familiar with it. Use of other online platforms showed great age dependency in 2016: Amboss (a digital learning platform) was used by 31% of the age group 21-30 years and was not used at all by the age group 51-60 years. DISCUSSION: Use of medical apps and planned integration of medical apps into routine care is increasing among German rheumatologists. On the other hand, recommendable rheumatological apps for rheumatologists and especially for patients are currently largely unknown to rheumatologists.

Evidence for genetic overlap between adult onset Still's disease and hereditary periodic fever syndromes.

OBJECTIVE: Adult onset Still's disease (AOSD) is a severe, autoimmune disease that can be challenging to treat with conventional therapeutics and biologicals in a considerable number of cases. Therefore, there is a high need to understand its pathogenesis better. As major clinical symptoms overlap between AOSD and hereditary periodic fever syndromes (HPFS), we analysed four known HPFS genes in AOSD. METHODS: We performed Sanger sequencing and quantitative analysis of all coding regions of MEFV, TNFRSF1A, MVK and NLRP3 in 40 AOSD patients. All rare coding variants (n = 6) were evaluated for several aspects to classify them as benign to pathogenic variants. Statistical analysis was performed to analyse whether variants classified as (likely) pathogenic were associated with AOSD. RESULTS: We identified three rare variants in MEFV, one previously not described. Association to the three likely pathogenic MEFV variants was significant (p c = 2.34E- 03), and two of the three carriers had a severe course of disease. We observed strong evidence for significant association to mutations in TNFRSF1A (p c = 2.40E- 04), as 5% of patients (2/40) carried a (likely) pathogenic variant in this gene. Both of them received a biological for treatment. CONCLUSION: Our results indicate TNFRSF1A as a relevant gene in AOSD, especially in patients with a more challenging course of disease, while causal variants remain to be identified in the majority of patients.

[Novel molecular mechanisms in the pathophysiology of psoriatic arthritis]. / Neue molekulare Mechanismen in der Pathophysiologie der Psoriasisarthritis.

The complex pathogenesis of psoriatic arthritis (PsA) is still only partially understood; however, recently a greatly improved understanding of this disease has been achieved, especially with respect to the inflammatory processes of the entheses. Thus, the clinical aspects of enthesitis increasingly differentiate PsA from other autoimmune diseases and sharpen the unique pathological clinical picture of PsA. Better pathophysiological understanding and the development of different biomarker approaches will bolster early detection of PsA. Therefore, the successful early recognition of PsA and more reliable identification of psoriasis patients at risk might be possible in the near future.

[New aspects on the pathogenesis of psoriatic arthritis]. / Neues zur Pathogenese der Psoriasisarthritis.

Psoriasis and psoriatic arthritis (PsA) are immune-mediated inflammatory diseases with a high burden of disability and increased mortality. The pathogenesis of the disease comprises a dysregulated interaction between stromal and immune cells and a dysfunctional cytokine network supporting chronic inflammation of the skin, entheses and joints. In addition to recent advances in the understanding of TNF blockade, more targets have been discovered delivering insights into the pathogenesis of PsA. This article gives a translational approach by utilizing current clinical development programs providing an insight into the IL-12/IL-23 and the IL-17 axes and also focuses on tissue damage and new small molecules.

Interleukin-33: a novel mediator with a role in distinct disease pathologies.

Interleukin-33 (IL-33) is a novel member of IL-1 cytokine family. It can act both as a nuclear factor and as a soluble mediator; however, the precise role of IL-33 within the nucleus is still not clear. As a cytokine, IL-33 is suggested to function as an alarmin that is released upon endothelial or epithelial cell damage. As such, IL-33 targets multiple cell types thereby alerting the immune system to endogenous trauma such as physical stress or infection. However, a dysregulated release of IL-33 has a potential to drive distinct pathologies. In this review, we discuss the contribution of IL-33 to the pathophysiology of asthma, arthritis, obesity and atherosclerosis as well as the potential of IL-33 for therapeutic intervention.

CD95: more than just a death factor?

The CD95 protein delivers crucial signals for lymphocyte death, and may also negatively regulate T-lymphocyte activation by preventing the influx of calcium ions from the cell's exterior. The block in calcium-ion influx occurs through the activation of acidic sphingomyelinase and the release of ceramide, a metabolite that can also induce cell death.

Prediction of response to Certolizumab-Pegol in rheumatoid arthritis (PreCePRA) by functional MRI of the brain - Study protocol for a randomized double-blind controlled study.

BACKGROUND: Tumor necrosis factor inhibitors (TNFi) signify a major advance in the treatment of rheumatoid arthritis (RA). However, treatment success initially remains uncertain as approximately half of the patients do not respond adequately to TNFi. Thus, an unmet need exists to better predict therapeutic outcome of biologicals. OBJECTIVES: We investigated whether brain activity associated with arthritis measured by functional magnetic resonance imaging (fMRI) of the brain can serve as a predictor of response to TNFi in RA patients. METHODS: PreCePRA is a multi-center, randomized, double-blind, placebo-controlled fMRI trial on patients with RA [1] [2]. Active RA patients failing csDMARDs therapy with a DAS28 > 3.2 and at least three tender and/or swollen joints underwent a brain BOLD (blood-oxygen-level dependent) fMRI scan upon joint compression at screening. Patients were then randomized into a 12-week double-blinded treatment phase with 200 mg Certolizumab Pegol (CZP) every two weeks (arm 1: fMRI BOLD signal activated volume > 2000 voxel, i.e. 2 cm3; arm 2: fMRI BOLD signal activated volume <2000 voxel) or placebo (arm 3). DAS28 low disease activity at 12 weeks was assigned as primary endpoint. A 12-week follow-up phase in which patients were switched from the placebo to the treatment arm followed the blinded phase. fMRI was carried out at screening as well as after 12 and 24 weeks of receiving CZP or placebo. CONCLUSION: We hypothesize that high-level central nervous representation of pain in patients with rheumatoid arthritis predicts response to the TNFi CZP which we further investigate in the PreCePRA trial.

Thy-1 triggers mouse thymocyte apoptosis through a bcl-2-resistant mechanism.

Programmed cell death plays an important role during thymocyte development, since a vast majority (97%) of mouse cortical thymocytes die in thymus, whereas only 3% of these cells are rescued from cell death and positively selected. Although it seems well established that thymocyte fate depends upon appropriate surface-expressed T cell receptor, little is known about the molecular mechanism(s) responsible for the massive thymocyte elimination that occurs in the thymus. We report here that Thy-1 is capable of triggering mouse thymocyte death in vitro through a bcl-2-resistant mechanism. We have previously shown that Thy-1 is involved in mouse thymocyte adhesion to thymic stroma through interaction with an epithelial cell ligand. To examine the Thy-1 signaling function in thymocytes, we have mimicked its interaction with stromal cells by culturing mouse thymocytes onto tissue culture plates coated with monoclonal antibodies (mAb) directed at distinct Thy-1 epitope regions. mAb recognizing determinants in a defined Thy-1 structural domain, but not others, were found to induce marked thymocyte apoptosis as evidenced by morphological and biochemical data. Use of a quantitative DNA dot blot assay indicated that Thy-1-mediated thymocyte apoptosis was not blocked by RNA or protein synthesis inhibitors, EGTA, or by cyclosporin A, and differed, therefore, from "activation-driven cell death". Moreover, Thy-1(+)-transfected, but not wild-type AKR1 (Thy-1-d) thymoma cells underwent apoptosis after ligation with apoptosis-inducing, Thy-1-specific mAb. In contrast to thymocytes, the latter event was inhibitable by RNA and protein synthesis inhibitors, an indication that thymocytes, but not thymoma cells, contain the molecular components necessary for Thy-1-driven apoptosis. We further showed that Thy-1-triggered thymocyte death is a developmentally regulated process operative in fetal thymocytes from day 17 of gestation, but not in peripheral T cells. Indeed, the target of apoptosis by anti-Thy-1 was found to reside mainly within the CD4+8+3- and CD4+8+3lo double positive immature thymocyte subsets. Finally, it is of major interest that Thy-1-mediated apoptosis, which was found to be readily detectable in thymocytes from bcl-2-transgenic mice, represents a thus far unique experimental system for studying bcl-2-resistant thymocyte death mechanism(s).

Regulating Vav1 phosphorylation by the SHP-1 tyrosine phosphatase is a fine-tuning mechanism for the negative regulation of DISC formation and Fas-mediated cell death signaling.

The actin cytoskeleton association is required for caspase 8-independent Fas/CD95 receptor internalization, a critical step for an optimal death-inducing signaling complex formation along the endocytic pathway, leading to efficient activation of the caspase cascade and, ultimately, cell death. However, the way in which this initiation phase of Fas receptor signaling is regulated is still unknown. We report herein that, in B cells, upon Fas engagement, the tyrosine phosphatase SHP-1-regulated Vav dephosphorylation, by downmodulating the Fas-ezrin-actin linkage is a fine-tune switch-off mechanism that the cell uses as a way to terminate the receptor internalization, controlling therefore the time and extent of the DISC formation and cell death.

Photopheresis with UV-A light and 8-methoxypsoralen leads to cell death and to release of blebs with anti-inflammatory phenotype in activated and non-activated lymphocytes.

BACKGROUND: Extracorporeal photopheresis is a therapy for treatment of autoimmune diseases, cutaneous T-cell lymphoma, organ graft rejection as well as graft-versus-host diseases. The exact mechanism how the combination of 8-methoxypsoralen plus UV-A irradiation (PUVA) acts is still unclear. We investigated the cell death of activated and non-activated lymphocytes after PUVA treatment as well as the rate of released blebs and their antigen composition. RESULTS: In presence of 8-MOP, UV-A light highly significantly increased the cell death of activated lymphocytes. The same was observed to a lesser extent in non-activated cells. Blebs derived from activated lymphocytes after PUVA treatment showed the highest surface exposition of phosphatidylserine. These blebs also displayed a high exposure of the antigens CD5 and CD8 as well as a low exposure of CD28 and CD86. CONCLUSION: PUVA treatment exerts anti-inflammatory effects by inducing apoptosis and apoptotic cell-derived blebs with immune suppressive surface composition.

Adaptation and cross-cultural validation of the rheumatoid arthritis work instability scale (RA-WIS).

BACKGROUND: Despite recent advances, work disability in rheumatoid arthritis (RA) remains common. Work disability is frequently preceded by a period of work instability characterised by a mismatch between an individual's functional abilities and job demands. This could raise the risk of work disability if not resolved. A work instability scale for RA (RA-WIS) has previously been developed to screen for this risk. The objective of this study was the adaptation of this scale into French, Dutch and German. METHOD: Different language versions of the RA-WIS were produced through a process of forward and back translations. The new scales were tested for face validity. English data from the original developmental study was pooled with data generated through postal surveys in each country. The internal construct and cross-cultural validity of the new scales were assessed using Rasch analysis, including differential item functioning (DIF) by culture. RESULTS: The pooled data showed good fit to the Rasch model and demonstrated strict unidimensionality. DIF was found to be present for six items, but these appeared both to cancel out at the test level and have only a marginal effect on the test score itself. CONCLUSIONS: The RA-WIS was shown to be robust to adaptation into different languages. Data fitted Rasch model expectations and strict tests of unidimensionality. This project and the continuing work on further cross-cultural adaptations have the potential to help ensure clinicians across Europe are able to support RA patients to achieve their potential in work through early identification of those most at risk.

Requirement for the CD95 receptor-ligand pathway in c-Myc-induced apoptosis.

Induction of apoptosis by oncogenes like c-myc may be important in restraining the emergence of neoplasia. However, the mechanism by which c-myc induces apoptosis is unknown. CD95 (also termed Fas or APO-1) is a cell surface transmembrane receptor of the tumor necrosis factor receptor family that activates an intrinsic apoptotic suicide program in cells upon binding either its ligand CD95L or antibody. c-myc-induced apoptosis was shown to require interaction on the cell surface between CD95 and its ligand. c-Myc acts downstream of the CD95 receptor by sensitizing cells to the CD95 death signal. Moreover, IGF-I signaling and Bcl-2 suppress c-myc-induced apoptosis by also acting downstream of CD95. These findings link two apoptotic pathways previously thought to be independent and establish the dependency of Myc on CD95 signaling for its killing activity.

The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells.

Fas ligand (FasL) is a type II transmembrane protein belonging to the tumor necrosis factor family. Its binding to the cognate Fas receptor triggers the apoptosis that plays a pivotal role in the maintenance of immune system homeostasis. The cell death-inducing property of FasL has been associated with its extracellular domain, which can be cleaved off by metalloprotease activity to produce soluble FasL. The fate of the remaining membrane-anchored N-terminal part of the FasL molecule has not been determined. Here we show that post-translational processing of overexpressed and endogenous FasL in T-cells by the disintegrin and metalloprotease ADAM10 generates a 17-kDa N-terminal fragment, which lacks the receptor-binding extracellular domain. This FasL remnant is membrane anchored and further processed by SPPL2a, a member of the signal peptide peptidase-like family of intramembrane-cleaving proteases. SPPL2a cleavage liberates a smaller and highly unstable fragment mainly containing the intracellular FasL domain (FasL ICD). We show that this fragment translocates to the nucleus and is capable of inhibiting gene transcription. With ADAM10 and SPPL2a we have identified two proteases implicated in FasL processing and release of the FasL ICD, which has been shown to be important for retrograde FasL signaling.

Requirement for Daxx in mature T-cell proliferation and activation.

The protein Daxx promotes Fas-mediated cell death through activation of apoptosis signal-regulating kinase 1, leading to the activation of the MAPKs JNK and p38. Owing to the in utero lethality of daxx-deficient mice, the in vivo role of Daxx has been so far difficult to analyze. We have generated transgenic mice expressing a dominant-negative form of Daxx (Daxx-DN) in the T-cell lineage. We show that Daxx is recruited to the Fas receptor upon FasL engagement and that Daxx-DN expression protects activated T cells from Fas-induced cell death, by preventing the death-inducing signal complex to be properly formed. Normal lymphocyte development and homeostasis are nevertheless observed. Interestingly, we report that both in vitro and in vivo stimulation of Daxx-DN T-lymphocytes leads to increased proliferative T-cell responses. This increased proliferation is associated with a marked increase in tyrosine phosphorylation of LAT and ZAP70 as Daxx-DN favor their recruitment to the T-cell receptor (TCR) complex. These findings identify Daxx as a critical regulator of T-lymphocyte homeostasis by decreasing TCR-induced cell proliferation and by promoting Fas-mediated cell death.