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Hintergrund: Chronische Entzündungserkrankungen (engl. «immune-mediated inflammatory diseases» [IMID]) sind mit einer erheblichen Krankheitslast verbunden. Diese ist umso ausgeprägter, sofern diese gleichzeitig bei Patienten auftreten oder z. B. weitere Komorbiditäten bestehen. Die Versorgung der IMID ist komplex und involviert diverse medizinische Fachdisziplinen. Ziel der Arbeit: Die Beschreibung der Krankheitslast und der aktuellen Arzneimittelversorgung der Patienten mit IMID. Material und Methoden: Die retrospektive Querschnittanalyse erfolgte unter Nutzung von Abrechnungsdaten der gesetzlichen Krankenversicherung der InGef-Datenbank. Unter 3.988.695 Versicherten wurden im Jahr 2018 anhand dokumentierter Diagnosen (ICD-10-GM) prävalente Patienten mit Psoriasis (Pso), Psoriasisarthritis (PsA), Spondyloarthritiden (SpA), rheumatoider Arthritis (RA), Morbus Crohn (MC), Colitis ulcerosa (CU) oder Kollagenosen identifiziert. Das gemeinsame Auftreten verschiedener IMID sowie weiterer Begleiterkrankungen wurde im Vergleich zur Referenzpopulation untersucht. Die medikamentöse Versorgung wurde basierend auf vordefinierten Therapieformen beschrieben. Ergebnisse: Im Jahr 2018 wurden 188.440 Patienten mit IMID (4,7%) identifiziert. Im Vergleich zur Referenzpopulation war die Prävalenz von depressiven Episoden und kardiovaskulären Risikoerkrankungen bei Patienten mit IMID höher. Bei MC, CU, RA, und PsA wurden DMARDs (engl. «disease-modifying antirheumatic drugs») und klassische systemische Therapien am häufigsten eingesetzt. Bei Pso, SpA und Kollagenosen waren NSAR (nichtsteroidale Antirheumatika) die häufigsten Therapieformen oft in Kombination mit anderen Wirkstoffen. Diskussion: Ein beträchtlicher Anteil der Patienten mit IMIDs (16,9–27,5%) leidet an unterschiedlichen Erkrankungen des IMID-Formenkreises. Sie sind häufig von Begleiterkrankungen betroffen und bedürfen einer interdisziplinären medizinischen Versorgung.

Background: Rheumatoid arthritis is the most common autoimmune disease worldwide and requires long-term treatment to suppress inflammation. Currently, treatment is started when arthritis is clinically apparent. We aimed to evaluate whether earlier intervention, in the preceding phase of arthralgia and subclinical joint inflammation, could prevent the development of clinical arthritis or reduce the disease burden. Methods: We conducted a randomised, double-blind, placebo-controlled, proof-of-concept-trial at the Leiden University Medical Centre, Leiden, Netherlands. Adults aged 18 years or older with arthralgia clinically suspected of progressing to rheumatoid arthritis and MRI-detected subclinical joint inflammation were eligible for enrolment across 13 rheumatology outpatient clinics in the southwest region of the Netherlands and randomly assigned (1:1) to a single intramuscular glucocorticoid injection (120 mg) and a 1-year course of oral methotrexate (up to 25 mg/week), or placebo (single injection and tablets for 1 year). Participants and investigators were masked to group assignment. Follow-up continued for 1 year after the end of the 1-year treatment period. The primary endpoint was development of clinical arthritis (fulfilling the 2010 rheumatoid arthritis classification criteria or involving two or more joints) that persisted for at least 2 weeks. Patient-reported physical functioning, symptoms, and work productivity were secondary endpoints, which were measured every 4 months. Additionally, the course of MRI-detected inflammation was studied. All participants entered the intention-to-treat analy­sis. This trial is registered with EudraCT, 2014-004472-35, and the Netherlands Trial Register, NTR4853-trial-NL4599. Findings: Between April 16, 2015, and Sept 11, 2019, 901 patients were assessed for eligibility and 236 were enrolled and randomly assigned to active treatment (n = 119) or placebo (n = 117). At 2 years, the frequency of the primary endpoint was similar between the groups (23 [19%] of 119 participants in the treatment group vs 21 [18%] of 117 in the placebo group; hazard ratio 0.81, 95% CI 0.45 to 1.48). Physical functioning improved more in the treatment group during the first 4 months and remained better than in the placebo group (mean between-group difference in Health Assessment Questionnaire disability index over 2 years: –0.09, 95% CI –0.16 to –0.03; p = 0.0042). Similarly, pain (on scale 0–100, mean between-group difference: –8, 95% CI –12 to –4; p < 0.0001), morning stiffness of joints (–12, –16 to –8; p < 0.0001), presenteeism (–8%, –13 to –3; p = 0.0007), and MRI-detected joint inflammation (–1.4 points, –2.0 to –0.9; p < 0.0001) showed sustained improvement in the treatment group compared with the placebo group. The number of serious adverse events was equal in both groups; adverse events were consistent with the known safety profile for methotrexate. Interpretation: Methotrexate, the cornerstone treatment of rheumatoid arthritis, initiated at the pre-arthritis stage of symptoms and subclinical inflammation, did not prevent the development of clinical arthritis, but modified the disease course as shown by sustained improvement in MRI-detected inflammation, related symptoms, and impairments compared with placebo.

In dieser retrospektiven multizentrischen Studie wurden Daten von 1199 Patienten mit chronischer spontaner Urtikaria (CSU) analysiert, um die Assoziation zu autoimmunen Komorbiditäten und das therapeutische Ansprechen auf Omalizumab zu untersuchen. Die Diagnose Typ IIb autoimmune CSU (aiCSU) wurde gestellt, wenn folgende 3 Tests positiv ausfielen: autologer Serum-Haut-Test, Basophilen-Histamin-Freisetzungs- und/oder Basophilenaktivierungstest und IgG-Autoantikörpertest gegen spezifische IgE-Rezeptoren. 28% der CSU-Patienten hatten mindestens eine Autoimmunerkrankung, 2% der Patienten zwei oder mehr. Außerdem zeigte sich, dass Patienten, bei denen Marker für Autoimmunerkrankungen, antinukleäre Antikörper und/oder IgG für Anti-TPO-Antikörper vorlagen, gehäuft nicht auf die Therapie mit Omalizumab ansprachen.

Background: Due to the absence of curative treatments for inborn errors of immunity (IEI), children born with IEI require long-term follow-up for disease manifestations and related complications that occur over the lifespan. Effective transition from pediatric to adult services is known to significantly improve adherence to treatment and long-term outcomes. It is currently not known what transition services are available for young people with IEI in Europe. Objective: To understand the prevalence and practice of transition services in Europe for young people with IEI, encompassing both primary immunodeficiencies (PID) and systemic autoinflammatory disorders (AID). Methods: A survey was generated by the European Reference Network on immunodeficiency, autoinflammatory, and autoimmune diseases Transition Working Group and electronically circulated, through professional networks, to pediatric centers across Europe looking after children with IEI. Results: Seventy-six responses were received from 52 centers, in 45 cities across 17 different countries. All services transitioned patients to adult services, mainly to specialist PID or AID centers, typically transferring up to ten patients to adult care each year. The transition process started at a median age of 16–18 years with transfer to the adult center occurring at a median age of 18–20 years. 75% of PID and 68% of AID centers held at least one joint appointment with pediatric and adult services prior to the transfer of care. Approximately 75% of PID and AID services reported having a defined transition process, but few centers reported national disease-specific transition guidelines to refer to. Conclusions: Transition services for children with IEI in Europe are available in many countries but lack standardized guidelines to promote best practice.

Objectives: The main purpose of this retrospective cohort study was to provide an evaluation of Ankylosing spondylitis (AS) patients’ fibromyalgia risk in different age and sex subgroups by analyzing large study samples. Methods: Datasets from the National Taiwan Insurance Research Database (NHIRD) were retrieved in this retrospective cohort study. This study was approved by the Institutional Review Board of Chung Shan Medical University (IRB permit number CS15134). Within the Longitudinal Health Insurance Database (LHID), and the subset of NHIRD, we identified AS patients to explore the risk of further fibromyalgia. The exposure cohort included patients with newly-diagnosed AS (ICD-9-CM:720.0) during 2000–2013. After 1:4 age-sex matching and 1:2 propensity score matching, and adjusting potential confounders, individuals without AS were identified as a comparison cohort. The adjusted hazard ratio of subsequent development of fibromyalgia in people with AS was evaluated. Further stratification analyses of different ages and genders were then undertaken to validate the results. Results: In total, 17 088 individuals were included in the present study, including 5,696 patients with AS and 11,392 individuals without AS. Respective incidence rates (per 1,000 person-months) of fibromyalgia was 0.52 (95% CI, 0.46–0.59) in the AS cohort and 0.39 (95% CI, 0.35–0.44) in the non-AS cohort. Compared with the non-AS cohort, aHR of developing fibromyalgia was 1.32 (95% CI, 1.12–1.55) in people with AS. This association was consistent in both statistical models of 1:4 age-sex matching and 1:2 propensity score matching. Conclusion: Patients with AS were associated with a higher risk of fibromyalgia, especially those over 65 years old. In managing patients with AS, clinicians should be aware of this association, which could impact diagnosis, disease activity evaluation, and treatment.

Die Riesenzellarteriitis als häufigste Manifestation einer Großgefäßvaskulitis im Alter über 50 Jahren wird nach wie vor mit einer großen Zeitverzögerung diagnostiziert. Klinische Zeichen und entsprechende Symptomatik werden hier noch einmal kurz dargestellt und sollen bei der möglichst raschen Diagnosefindung helfen. Selbst nach Diagnosestellung herrscht oft Unsicherheit darüber, wer eine spezialisierte Betreuung wann vornehmen sollte und wie eine optimale Therapiestrategie aussehen sollte. Die aktuellen Empfehlungen zum Management der Riesenzellarteriitis tragen dem Rechnung und stellen eine klar strukturierte Vorgehensweise dar. Hierzu gehört auch die möglichst rasche Zuweisung an ein spezialisiertes Zentrum.

Nailfold videocapillaroscopy (NVC) is an easy tool used for the assessment of patients with Raynaud’s phenomenon (RP) as possibly associated with systemic sclerosis (SSc). Recent insights have also highlighted its role in the diagnostic assessment of idiopathic inflammatory myopathies (IIMs). The aim of this study is to describe the diagnostic role of NVC in a series of 361 consecutive patients with interstitial lung disease (ILD). All the patients were assessed by clinical pulmonary and rheumatic examinations, blood exams, high-resolution computed tomography and NVC. NVC was considered positive only in the presence of avascular areas or giant capillaries, but also, the presence of bushy capillaries (BCs) was recorded. NVC was positive in 17.7% of ILD patients and in 78.1% of ILD patients associated with a diagnosis of connective tissue disease (CTD). In 25% of SSc-ILD patients, NVC proved necessary for a correct diagnosis. The presence of BCs and/or NVC positivity in ILD patients with normal levels of creatine phosphokinase is associated with amyopathic IIM, regardless the presence of RP. In conclusion, NVC is useful for the diagnostic assessment of incomplete forms of CTD and in amyopathic IIMs. NVC should be considered in the diagnostic assessment of ILD patients regardless of the presence of RP.

Objectives: Ultrasound of temporal and axillary arteries may reveal vessel wall inflammation in patients with giant cell arteritis (GCA). We developed a ultrasound scoring system to quantify the extent of vascular inflammation and investigated its diagnostic accuracy and association with clinical factors in GCA. Methods: This is a prospective study including 89 patients suspected of having GCA, of whom 58 had a confirmed clinical diagnosis of GCA after 6 months follow-up. All patients underwent bilateral ultrasound examination of the three temporal artery (TA) segments and axillary arteries, prior to TA biopsy. The extent of vascular inflammation was quantified by (1) counting the number of TA segments and axillary arteries with a halo and (2) calculating a composite Halo Score that also incorporated the thickness of each halo. Results: Halo counts and Halo Scores showed moderate diagnostic accuracy for a clinical diagnosis of GCA. They correlated positively with systemic inflammation. When compared with the halo count, the Halo Score correlated better with C-reactive protein (CRP) levels and allowed to firmly establish the diagnosis of GCA in more patients. Higher halo counts and Halo Scores were associated with a higher risk of ocular ischaemia. They allowed to identify subgroups of patients with low risk (≤5%) and high risk of ocular ischaemia (>30%). Conclusion: Ultrasound halo scoring allows to quantify the extent of vascular inflammation in GCA. Extensive vascular inflammation on ultrasound may provide strong diagnostic confirmation and associates with ocular ischaemia in GCA.

The pathogeneses of recurrent fever are quite complicated when excluding repeated infections. Recurrent fever is a common symptom for autoinflammatory diseases, relapse of Systemic-onset juvenile idiopathic arthritis (SoJIA) and recurrent Kawasaki disease (KD). There are no specific diagnostic laboratory tests for the diseases. Some studies showed that KD was the precursor of hemophagocytic lymphohistiocytosis (HLH). Macrophage activation syndrome (MAS) is another form of HLH in SoJIA. Cytokine disturbances are considered to be involved in the pathogenesis of the diseases. We describe a Chinese female toddler that developed three separate fever episodes with eventual diagnose of SoJIA within about 10 months. The first episode was diagnosed as IKD, immunoglobulin nonresponsive KD, and HLH. The second and third episodes were diagnosed as IKD and SoJIA, respectively. The fever was hard to be relieved by antipyretics, and the peak axillary temperature was above 40°C. For every fever episode, infections were excluded. For the first episode, trends over time of hemoglobin, platelets, fibrinogen, and triglycerides indicated HLH, which was finally diagnosed and treated according to the HLH-2004 protocol. For the second episode 6 months later, after excluding an HLH relapse and infections, IKD was finally diagnosed. Oral aspirin was administered, and the HLH treatment was ceased. The third episode occurred 3 months later, and SoJIA was finally diagnosed. For each episode, except for relative tests, we only tested for cytokines interleukin-1β, interleukin-6, and interferon-γ, due to limited laboratory test availability. These cytokines were elevated during remission and rose much higher in the fever phases. The case showed the difficulty to differentiating the recurrent fever in clinical practice. Surveillance of routine laboratory parameters over time might reveal a trend that indicates possible disease, even when parameter values do not meet diagnostic criteria. Changes in cytokine profiles are promising markers for differentiating recurrent fever diseases in future. An unknown immunological defect for the case may contribute to the recurrent immunological insults, and we are following up the recurrence of fever episode.

Background Vasculitides comprise a group of rare diseases which affect less than 5 in 10.000 individuals. Most types of vasculitis can become organ- and life-threatening and are characterized by chronicity, high morbidity and relapses, altogether resulting in significant morbidity and mortality. Previous studies have been either monocentric or mainly retrospective – studies with a prospective design mostly consisted of rather small cohorts of 100 to 200 patients. The aim of the Joint Vasculitis Registry in German-speaking countries (GeVas) is to record all patients who have been recently diagnosed with vasculitis or who have changed their treatment due to a relapse (inception cohort). In GeVas, data are collected prospectively in a multicenter design in Germany, Austria and Switzerland. By this approach, courses of vasculitis and their outcomes can be monitored over an extended period. Methods GeVas is a prospective, web-based, multicenter, clinician-driven registry for the documentation of organ manifestations, damage, long-term progress and other outcomes of various types of vasculitis. The registry started recruiting in June 2019. As of October 2020, 14 centers have been initiated and started recruiting patients in Germany. Involvement of sites in Austria and the German-speaking counties of Switzerland is scheduled in the near future. Discussion In June 2019, we successfully established a prospective multicenter vasculitis registry being the first of its kind in German-speaking countries. The participating centers are currently recruiting, and systematic analysis of long-term vasculitis outcomes is expected in the ensuing period. Trial registration German Clinical Trials Register (Deutsches Register Klinischer Studien): DRKS00011866. Registered 10 May 2019.

BackgroundPatients with diffuse cutaneous systemic sclerosis (dcSSc) have a poor prognosis. The importance of monitoring subjective measures of functioning and disability, such as the Health Assessment Questionnaire-Disability Index (HAQ-DI), is important as dcSSc is rated by patients as worse than diabetes or hemodialysis for quality of life impairment. This European Scleroderma Trials and Research (EUSTAR) database analysis was undertaken to examine the importance of impaired functionality in dcSSc prognosis. The primary objectives were to identify predictors of death and HAQ-DI score progression over 1 year. HAQ-DI score, major advanced organ involvement, and death rate were also used to develop a comprehensive model to predict lifetime dcSSc progression.MethodsThis was an observational, longitudinal study in patients with dcSSc registered in EUSTAR. Death and HAQ-DI scores were, respectively, analyzed by Cox regression and linear regression analyses in relation to baseline covariates. A microsimulation Markov model was developed to estimate/predict natural progression of dcSSc over a patient’s lifetime.ResultsThe analysis included dcSSc patients with (N = 690) and without (N = 4132) HAQ-DI score assessments from the EUSTAR database. Baseline HAQ-DI score, corticosteroid treatment, and major advanced organ involvement were predictive of death on multivariable analysis; a 1-point increase in baseline HAQ-DI score multiplied the risk of death by 2.7 (p p p ConclusionsHAQ-DI score and major advanced organ involvement were comparable predictors of mortality risk in dcSSc. Baseline mRSS and baseline HAQ-DI score were predictive of HAQ-DI score progression at 1 year, indicating a correlation between these endpoints in monitoring disease progression. It is hoped that this EUSTAR analysis may change physician perception about the importance of the HAQ-DI score in dcSSc.

Gastrointestinal (GI) involvement is almost universal in patients with systemic sclerosis (SSc) and is associated with significant disease-related morbidity and mortality.1 The entire GI tract can be involved and other disease features (eg, low mood, terminal organ failure and functional hand impairment) can result in significant nutritional impairment. Severe GI involvement has been reported to occur in ~10% of patients with SSc and often occurs early in the course of the disease.2 However, identification of patients at high risk of clinically significant weight loss is extremely challenging, including from the high prevalence of GI symptoms in patients with SSc. Therefore, there is a need to understand high-risk patients including potentially modifiable risk factors, with a view to early intervention strategies. Against this background, the aim of this study was to examine potential clinical risk factors of significant weight loss in patients with SSc. We performed an analysis of patients with SSc enrolled in the multinational, longitudinal European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) database. In our study, we defined significant weight loss as 4.5 kg and/or least 5% of their body weight at 5 months onwards.3 Patients with a recorded second visit after 3 months and before 12 months were included in the analysis. We adopted a pragmatic approach (relevant to clinical practice) in …

Type 1 diabetes (T1D) is mainly precipitated by the destruction of insulin-producing β-cells in the pancreatic islets of Langerhans by autoaggressive T cells. The etiology of the disease is still not clear, but besides genetic predisposition the exposure to environmental triggers seems to play a major role. Virus infection of islets has been demonstrated in biopsies of T1D patients, but there is still no firm proof that such an infection indeed results in islet-specific autoimmunity. However, virus infection results in a local inflammation with expression of inflammatory factors, such as cytokines and chemokines that attract and activate immune cells, including potential autoreactive T cells. Many chemokines have been found to be elevated in the serum and expressed by islet cells of T1D patients. In mouse models, it has been demonstrated that β-cells express chemokines involved in the initial recruitment of immune cells to the islets. The bulk load of chemokines is however released by the infiltrating immune cells that also express multiple chemokine receptors. The result is a mutual attraction of antigen-presenting cells and effector immune cells in the local islet microenvironment. Although there is a considerable redundancy within the chemokine ligand-receptor network, a few chemokines, such as CXCL10, seem to play a key role in the T1D pathogenesis. Studies with neutralizing antibodies and investigations in chemokine-deficient mice demonstrated that interfering with certain chemokine ligand-receptor axes might also ameliorate human T1D. However, one important aspect of such a treatment is the time of administration. Blockade of the recruitment of immune cells to the site of autoimmune destruction might not be effective when the disease process is already ongoing. By that time, autoaggressive cells have already arrived in the islet microenvironment and a blockade of migration might even hold them in place leading to accelerated destruction. Thus, an anti-chemokine therapy makes most sense in situations where the cells have not yet migrated to the islets. Such situations include treatment of patients at risk already carrying islet-antigen autoantibodies but are not yet diabetic, islet transplantation recipients, and patients that have undergone a T cell reset as occurring after anti-CD3 antibody treatment.

In dieser retrospektiven multizentrischen Studie wurden Daten von 1199 Patienten mit chronischer spontaner Urtikaria (CSU) analysiert, um die Assoziation zu autoimmunen Komorbiditäten und das therapeutische Ansprechen auf Omalizumab zu untersuchen. Die Diagnose Typ IIb autoimmune CSU (aiCSU) wurde gestellt, wenn folgende 3 Tests positiv ausfielen: autologer Serum-Haut-Test, Basophilen-Histamin-Freisetzungs- und/oder Basophilenaktivierungstest und IgG-Autoantikörpertest gegen spezifische IgE-Rezeptoren. 28% der CSU-Patienten hatten mindestens eine Autoimmunerkrankung, 2% der Patienten zwei oder mehr. Außerdem zeigte sich, dass Patienten, bei denen Marker für Autoimmunerkrankungen, antinukleäre Antikörper und/oder IgG für Anti-TPO-Antikörper vorlagen, gehäuft nicht auf die Therapie mit Omalizumab ansprachen.

Date Presented Accepted for AOTA INSPIRE 2021 but unable to be presented due to online event limitations. This qualitative action research study explored the potential partnership of OT and social movements that work to end structural poverty. Limited research in OT provides neither an accurate analysis nor an effective intervention strategy for addressing and dismantling the structural causes of poverty in the United States. This research centers the narratives and expertise of social movements to provide an alternate analysis and path to ending structural poverty in the United States. Primary Author and Speaker: Sabine Adler Contributing Authors: Melinda Cozzolino, Alicia Swords

Objective Behcet's syndrome is a rare systemic autoimmune/autoinflammatory disease affecting mucocutaneous tissues, the skin and the eyes, as well as the joints, the central nervous system, the gastrointestinal tract and blood vessels. Because of the lack of clinical data in Switzerland, the aims of this cohort study were to calculate the disease prevalence and to analyse the disease manifestations and the immune-suppressive medication. Methods Data were extracted from 52 patient charts. Thereafter, all patients were interviewed with a questionnaire and 46 had an additional physical examination and laboratory analyses. For calculation of prevalence, data of the national statistical bureau were used. Results A disease prevalence of 4.03/100,000 inhabitants was calculated. The mean delay between first disease manifestation and diagnosis was 8 years. It was 2 years longer for Swiss than for non-Swiss individuals (p = 0.45). The time intervals between diagnosis and occurrence of different organ manifestations ranged from +8 to -11 years. There was no difference in organ involvement between different ethnicities. Colchicine was prescribed for 52% of patients only, whereas tumour necrosis factor (TNF) inhibitors and glucocorticoids were most frequently prescribed (80 and 64%, respectively). In almost half of the patients, TNF blockers could be stopped and replaced by conventional immunosuppressive drugs. Conclusion The data from this cohort of Behcet's syndrome patients, the largest in Switzerland, documents a prevalence higher than anticipated. The diagnostic delay underlines an urgent need to improve awareness of the disease and allow timely treatment.

Background Primary Sjögren’s syndrome is the second most common rheumatological disorder after rheumatoid arthritis. It typically presents as xerophthalmia and xerostomia in postmenopausal women. Involvement of the central nervous system has been recognized, although its pathogenesis and characteristics are poorly understood. Central nervous system complications are a diagnostic challenge and emphasize the need for systematic screening of patients with new peripheral and central neurological symptoms. Case report We report a case of a 58-year-old Swiss woman presenting with rapidly progressive sensorimotor distal polyneuropathy together with new-onset generalized seizures. Initial magnetic resonance imaging (MRI) of the brain performed after the first seizure showed multiple, bihemispheric, confluent white matter hyperintensities with contrast enhancement. Follow-up imaging 3 days after the initial magnetic resonance imaging demonstrated a fulminant disease progression associated with the serious clinical deterioration of the patient. In light of the results of a minor salivary gland biopsy, autoantibody testing, nerve conduction studies, and cranial magnetic resonance imaging, primary Sjögren’s syndrome with cryoglobulinemia type II was diagnosed. Response to plasmapheresis and subsequent administration of cyclophosphamide was favorable. Conclusion Even though exocrinopathy is the hallmark of Sjögren’s syndrome, systemic symptoms are observed in one-third of patients. There is an urgent need to better characterize the mechanisms underlying different disease phenotypes and to perform randomized controlled trials in order to provide tailored and evidence-based treatment for primary Sjögren’s syndrome.

Objective It is currently unknown how long GCA should be treated with tocilizumab. In the first randomized controlled trial, the biologic agent was stopped after 52 weeks. We therefore studied what proportion of patients relapsed, when relapses occurred and whether factors might predict relapse after tocilizumab treatment discontinuation. Methods All patients in the tocilizumab arm who had received a 52-week treatment were evaluated. In case of lasting remission, magnetic resonance angiography (MRA) was performed and sera were taken to search for biomarkers associated with subclinical disease activity. Results Seventeen of 20 patients randomized to the tocilizumab treatment arm were in lasting remission without any co-medication at week 52. Mean follow-up after study end was 28.1 months (range 17–44). Eight patients relapsed after a mean of 6.3 months (range 2–14) (six within the first 5 months, two patients at months 13 and 14, respectively). Relapsing patients were younger and showed more signs of mural enhancement in MRA compared with non-relapsing patients. MRA documented low-intensity vessel wall signals in all subjects. No morphological changes such as formation of aneurysm of aorta occurred. Biomarkers in sera did not indicate subclinical disease activity: levels of IL-6, MMP-3, soluble TNF receptor 2, soluble CD163, soluble intercellular adhesion molecule-1 and Pentraxin-3 did not differ from matched healthy controls. Conclusion The data show that a 52-week treatment with tocilizumab induces a lasting remission that persists in half of the patients after treatment stop. None of the clinical, serological or MRA findings qualify to predict relapse. Remarkably, MRA revealed a persisting wall enhancement of the descending aorta.

Objectives We aimed to assess the safety and immunogenicity of a diphtheria/tetanus vaccine booster dose in three different patient groups with rheumatic diseases on a variety of immunosuppressive/immunomodulatory medications compared with healthy controls (HCs). Methods We conducted a multi-centre prospective cohort study in Switzerland. We enrolled patients with RA, axial SpA/PsA, vasculitis (Behçet’s disease, ANCA-associated vasculitis) and HCs. Diphtheria/tetanus vaccination was administered according to the Swiss vaccination recommendations. Blood samples were drawn before vaccination, and 1 month and 3 months afterwards. Antibody concentrations against vaccine antigens were measured by ELISA. Immunogenicity was compared between patient and medication groups. A mixed model was applied for multivariate analysis. Missing data were dealt with using multiple imputation. Results Between January 2014 and December 2015, we enrolled 284 patients with rheumatic diseases (131 RA, 114 SpA/PsA, 39 vasculitis) and 253 HCs. Of the patients, 89% were on immunosuppressive/immunomodulatory medication. Three months post-vaccination 100% of HCs vs 98% of patients were protected against tetanus and 84% vs 73% against diphtheria. HCs and SpA/PsA patients had significantly higher responses than RA and vasculitis patients. Assessing underlying diseases and medications in a multivariate model, rituximab was the only factor negatively influencing tetanus immunogenicity, whereas only MTX treatment had a negative influence on diphtheria antibody responses. No vaccine-related serious adverse events were recorded. Conclusion Diphtheria/tetanus booster vaccination was safe. Tetanus vaccination was immunogenic; the diphtheria component was less immunogenic. Vaccine responses were blunted by rituximab and MTX. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, Identifier: NCT01947465.

Objective Tocilizumab is effective in inducing and maintaining remission of GCA. Despite clinical and serological control of disease, magnetic resonance angiography may show persistence of inflammatory signals of unknown significance in arterial walls. Thus, there is an unmet need for tools to detect subclinical disease activity. Methods Immune-inflammatory markers were measured in prospectively collected sera of the first randomized, double-blind, placebo-controlled trial investigating the use of tocilizumab in GCA. As a comparison, immune-inflammatory markers were also measured in sera from age- and sex-matched healthy volunteers. The biomarkers were quantified using luminex technology. Results Of all the parameters determined, only MMP-3, pentraxin-3 and sTNFR2 were significantly elevated, while ICAM-1 and CD163 were significantly decreased during the early stages of the study, at time points of full clinical remission under treatment with tocilizumab plus glucocorticoids. In contrast, tocilizumab monotherapy towards the end of the study resulted in an almost complete normalization of immune-inflammatory molecules, as defined by the healthy controls. MMP-3 levels showed a weak association with magnetic resonance signal intensity; none of the biomarkers predicted relapse occurring within 6 months after study end. Conclusion The data documented a subclinical disease activity in GCA that was more pronounced during the early stages of treatment and almost disappeared towards the study end. They indicated that tocilizumab treatment of at least 52 weeks is necessary in order to reset a broad range of immune-inflammatory pathways. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT01450137.

Between childhood and adulthood, there often exists a difficult period of coming of age. This phase frequently represents a significant challenge for adolescents and young adults at the physical, psychological, and social level. Having trouble with adolescence itself it puts an extra weight on young people with chronic rheumatic diseases. Thus, medical and interpersonal support can be multifaceted. In light of this, support from an interprofessional team in the form of a specialist transition clinic has proven to be of great value. In the outpatient clinic established at the Inselspital Bern (Bern University Hospital), specialists in pediatric and adult rheumatology work together with a team of nurses, physiotherapists, occupational therapists, social workers, and psychologists, who are called in on an individual-requirement basis. All personnel involved in the care of these young patients should understand that a rheumatic disease developing in childhood normally progresses differently than it does if first developed during adulthood.

Die Zuweisung der 58-jahrigen Patientin erfolgte durch eine niedergelassene Neurologin zur weiteren atiologischen Zuordnung einer Polyneuropathie.

Background Since the time when Paul Ehrlich conceived the term “horror autotoxicus”, autoantibodies have been associated with the development of autoimmune diseases. However, several works have recently shown the presence of autoantibodies in sera from healthy subjects (n=489), who do not develop autoimmune diseases. Objectives Here, we report a network of immunoglobulin G (IgG) autoantibodies targeting G protein-coupled receptors (GPCRs), growth factors and growth factor-related molecules in sera from healthy subjects. Methods Autoantibody levels in sera were assessed using ELISA. Autoantibody network was analysed by exploratory factor analysis (EFA), dandelion plot method, hierarchical clustering, and multi-study factor analysis (MFA). We also reverse engineered autoantibody functions through in silico evaluation of autoantibody target interactions using STRING and gene ontology (GO). To test the autoantibodies functionality we assessed the in vitro production of IL-8 by PBMCs and neutrophil migration in response to IgG from healthy subjects as well as ETAR-immunised and control mice. Leukocyte cellularity to secondary immune organs was analysed comparing ETAR-immunised with control mice. Results Gender, age and the presence of pathological conditions (systemic sclerosis n=84, Alzheimer’s disease n=91 and ovarian cancer n=207) changed correlations between the autoantibodies and their hierarchical clustering distribution. Notably, subjects at age below and above 65 years or with pathological conditions exhibited particular autoantibody hierarchical clustering signatures. In addition, females at age above 65 years, representing the group of subjects with higher risk to develop SSc, displayed the closest link to SSc in terms of autoantibody hierarchical clustering. Finally, autoantibody directed against the endothelin receptor type A (ETAR) showed an essential role in the autoantibody network by orchestrating neutrophil trafficking in vitro and in ETAR-immunised mice. Conclusions Our data provide a framework for the existence of a physiological network of autoantibodies and reveal a new paradigmatic view on these physiological molecules. Disclosure of Interest None declared

Background Scleroderma renal crisis (SRC) represents a rare but life-threatening manifestation in systemic sclerosis (SSc). Survival remains poor despite therapeutic use of ACE inhibitors (ACEi). Factors influencing the risk of SRC are not well characterised. In particular, ACEi are discussed as promoting but also as protecting SRC. Objectives To investigate the effect of ACEi on SRC incidence in prospectively collected data of a cohort of SSc patients. Methods EUSTAR database analysis with focus on arterial hypertension, antihypertensive medication and glucocorticoids. Subgroup analysis of a dataset with defined documentation of medication from January 2009 until November 2017. Results Out of 14’524 patients in the database we identified 7’648 patients with at least one follow-up after 2009. 102 patients developed SRC in 27’450 person-years (py), representing an incidence of 3.72 (3.06–4.51) per 1’000 py. In a multivariable time-to-event analysis adjusted for age, sex, disease severity and onset, arterial hypertension, tendon friction rubs, SCL70 and ACA positivity, 78 of 6083 patients developed SRC. Herein, use of ACEi displayed an increased risk for the development of SRC with a hazard ratio (HR) of 2.07 (95% confidence interval (CI):1.28–3.36). Calcium channel blockers (CCB), angiotensin receptor blockers, endothelin receptor antagonists and glucocorticoids did not influence SRC incidence. Medication strategies were not altered after renal crisis. Cumulative mortality 5 years after renal crisis was 18.6% (95% CI: 13.0%–26.3%). Conclusions This EUSTAR analysis supports the notion that ACEi should be avoided in arterial hypertension in SSc patients. Alternative antihypertensive drugs as CCB might be preferred. References [1] Hudson M, Baron M, Tatibouet S, Furst DE, Khanna D, International Scleroderma Renal Crisis Study I. Exposure to ACE inhibitors prior to the onset of scleroderma renal crisis-results from the International Scleroderma Renal Crisis Survey. Seminars in arthritis and rheumatism2014;43(5):666–72. [2] Guillevin L, Berezne A, Seror R, Teixeira L, Pourrat J, Mahr A, et al. Scleroderma renal crisis: a retrospective multicentre study on 91 patients and 427 controls. Rheumatology (Oxford)2012;51(3):460–7. [3] Mouthon L, Bussone G, Berezne A, Noel LH, Guillevin L. Scleroderma renal crisis. The Journal of rheumatology. 2014;41(6):1040–8. [4] Shanmugam VK, Steen VD. Renal disease in scleroderma: an update on evaluation, risk stratification, pathogenesis and management. Current opinion in rheumatology2012;24(6):669–76. Acknowledgements We acknowledge the work of all participating EUSTAR centres for contributing to this work. Disclosure of Interest None declared

Autoantibodies have been associated with autoimmune diseases. However, studies have identified autoantibodies in healthy donors (HD) who do not develop autoimmune disorders. Here we provide evidence of a network of immunoglobulin G (IgG) autoantibodies targeting G protein-coupled receptors (GPCR) in HD compared to patients with systemic sclerosis, Alzheimer’s disease, and ovarian cancer. Sex, age and pathological conditions affect autoantibody correlation and hierarchical clustering signatures, yet many of the correlations are shared across all groups, indicating alterations to homeostasis. Furthermore, we identify relationships between autoantibodies targeting structurally and functionally related molecules, such as vascular, neuronal or chemokine receptors. Finally, autoantibodies targeting the endothelin receptor type A (EDNRA) exhibit chemotactic activity, as demonstrated by neutrophil migration toward HD-IgG in an EDNRA-dependent manner and in the direction of IgG from EDNRA-immunized mice. Our data characterizing the in vivo signatures of anti-GPCR autoantibodies thus suggest that they are a physiological part of the immune system., Autoantibodies are implicated in autoimmunity, but may also be present in healthy individuals. Here the authors find that the autoantibody specificity signatures against various G protein-coupled receptors are associated with multiple parameters, including disease states, to imply a physiological function in maintaining immune homeostasis.

Objective. To analyse magnetic resonance angiographic (MRA) vessel wall signals from a randomized controlled trial of tocilizumab (TCZ) to treat GCA. Methods. Participants were assigned in a 2:1 ratio to receive either TCZ + glucocorticoids (GCs) or placebo +GC infusions at 4-week intervals for 52 weeks. GCs were started at 1 mg/kg/day, then tapered to 0.1 mg/kg/day at week 12 and thereafter down to zero. Patients with initial positive MRA findings underwent control MRA at weeks 12 and 52. Vessel wall signals were scored from 0 (normal) to 3 (intense late enhancement). Outcomes were the number of patients with complete MRA remission at weeks 12 and 52, and changes in vasculitis score, vessel anatomy and atherosclerosis. Results. Of the 30 randomized participants, nine TCZ and two placebo patients had no vessel wall enhancement on initial MRA. At week 12, MRAs were performed in nine TCZ and four placebo patients (nine and three in clinical remission, respectively). Three (33%) TCZ patients showed normalization of vessel wall signals compared with one (25%) placebo patient. At week 52, there was additional MRA improvement in some TCZ patients, but one-third showed persistent or increased late vessel wall enhancement. There was no formation of aneurysms or stenosis and no increase in atherosclerosis. Conclusions. Although TCZ resulted in complete clinical and laboratory remission of GCA over 52 weeks, MRA signals in vessel walls normalized in only one-third of patients. Whether these signals are of prognostic importance remains to be determined.

Given the hypothesis of an initial exogenous agent attacking/infecting ocular and oral glands in Sjogren’s syndrome, we propose a primarily T cell-guided reaction with ensuing recruitment of B cells and finally resulting in auto-antibody production. From an immunological standpoint, the first clinical signs do represent established disease. Nevertheless, targeted therapy should start as early as possible, and they may target B as well as T cells. A primarily local therapy by CsA eye-drops is worthwhile applying in case of strictly ocular involvement only. Otherwise, a short cycle of leflunomide might prove efficient. If not, based on the most possibly underlying pathophysiology of T and B cell interaction and our own experience, a 6-month treatment with abatacept during the early phase of disease can reach the target cells and lead to clinical improvement. In the later stages, especially in case of cryoglobulinemic vasculitis or pulmonary involvement, a B cell depletional therapy may be highly effective. Based on the available data, it would be interesting to initiate a study targeting both cellular arms of the adaptive immune system, i.e., B cell depletion with, e.g., rituximab and T cell inhibition using abatacept. Trials with alefacept have shown T cell-targeted, positive effects on exocrine gland function in a primary SS (pSS)-associated non-obese diabetic (NOD) mouse model. Whether this molecular intervention is beneficial in human disease will have to be shown.

Multicentric carpotarsal osteolysis (MCTO) is an autosomal dominant disease of the skeleton characterised by progressive destruction of carpal and tarsal bones. Recently, it has been demonstrated that this disease is caused by heterozygous mutations in the gene for the transcriptional repressor MAFB. We analysed genomic DNA and RNA from leucocytes of a female patient diagnosed with MCTO. We identified the mutation c.161C>T in the genomic sequence and in the expressed messenger RNA for MAFB. This is the second report of the c.161C>T mutation in a MCTO patient. Since the parents do not possess this mutation, the daughter must have acquired a de novo mutation. At the level of the gene, this mutation is found at a CpG dinucleotide sequence, suggesting that DNA methylation was involved in the occurrence of the DNA aberration. At the level of the protein, the mutation exchanges a serine with a leucine residue at a position on MAFB that can become phosphorylated in the wild-type protein. MAFB negatively regulates the RANKL-dependent differentiation of monocytes into osteoclasts. It is likely that the mutation will affect the phosphorylation status of the protein and its biological activity. When the activity of the transcriptional repressor is reduced, osteoclastogenesis will be increased, which might explain the carpotarsal bone destruction observed in the patient.

Background Interstitial lung disease in systemic sclerosis (SSc-ILD) is a major cause of SSc-related death. Imunosuppressive treatment (IS) is used in patients with SSc for various organ manifestations mainly to ameliorate progression of SSc-ILD. Data on everyday IS prescription patterns and clinical courses of lung function during and after therapy are scarce. Methods We analysed patients fulfilling American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) 2013 criteria for SSc-ILD and at least one report of IS. Types of IS, pulmonary function tests (PFT) and PFT courses during IS treatment were evaluated. Results EUSTAR contains 3778/11,496 patients with SSc-ILD (33%), with IS in 2681/3,778 (71%). Glucocorticoid (GC) monotherapy was prescribed in 30.6% patients with GC combinations plus cyclophosphamide (CYC) (11.9%), azathioprine (AZA) (9.2%), methotrexate (MTX) (8.7%), or mycophenolate mofetil (MMF) (7.3%). Intensive IS (MMF + GC, CYC or CYC + GC) was started in patients with the worst PFTs and ground glass opacifications on imaging. Patients without IS showed slightly less worsening in forced vital capacity (FVC) when starting with FVC 50–75% or >75%. GC showed negative trends when starting with FVC