Search

The SARS-CoV-2 pandemic not only resulted in millions of acute infections worldwide, but also caused innumerable cases of post-infectious syndromes, colloquially referred to as “long COVID”. Due to the heterogeneous nature of symptoms and scarcity of available tissue samples, little is known about the underlying mechanisms. We present an in-depth analysis of skeletal muscle biopsies obtained from eleven patients suffering from enduring fatigue and post-exertional malaise after an infection with SARS-CoV-2. Compared to two independent historical control cohorts, patients with post-COVID exertion intolerance had fewer capillaries, thicker capillary basement membranes and increased numbers of CD169+macrophages. SARS-CoV-2 RNA could not be detected in the muscle tissues, but transcriptomic analysis revealed distinct gene signatures compared to the two control cohorts, indicating immune dysregulations and altered metabolic pathways. We hypothesize that the initial viral infection may have caused immune-mediated structural changes of the microvasculature, potentially explaining the exercise-dependent fatigue and muscle pain.

Background: The purpose of this trial was to evaluate the effectiveness and safety of the IL-6 receptor antibody Tocilizumab (TCZ) in the treatment of Familial Mediterranean Fever (FMF). Methods: This was a randomized, double-blinded, placebo-controlled phase II trial in adult patients with active FMF and an inadequate response or intolerance to colchicine (crFMF). The physician’s global assessment of disease activity (PGA), based on a five-point scale for six symptoms, was used as a clinical score, which had to be >2 at screening, together with elevated c-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) and serum amyloid A (SAA) levels, to be eligible for inclusion. Patients were randomized 1:1 to either receive monthly TCZ or a placebo over a period of 24 weeks. The primary endpoint was the number of patients achieving an adequate response to treatment at week 16, defined as a PGA of ≤2 and normalized ESR or CRP and normalized SAA. Results: We randomized 25 patients with a median age of 31 years. At week 16, an adequate treatment response was achieved by two patients in the TCZ and none of the patients in the placebo arm (p = 0.089). SAA levels normalized with TCZ, but not with the placebo (p = 0.015). Conclusion: In this first randomized, placebo-controlled study in patients with active crFMF, more patients in the TCZ arm experienced a response to treatment in comparison to those receiving the placebo. As the prevention of amyloidosis is a major treatment goal in FMF, the normalization of SAA in TCZ-treated patients is essential. These findings have to be confirmed in a larger trial.

A subset of patients has long-lasting symptoms after mild to moderate Coronavirus disease 2019 (COVID-19). In a prospective observational cohort study, we analyze clinical and laboratory parameters in 42 post-COVID-19 syndrome patients (29 female/13 male, median age 36.5 years) with persistent moderate to severe fatigue and exertion intolerance six months following COVID-19. Further we evaluate an age- and sex-matched postinfectious non-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome cohort comparatively. Most post-COVID-19 syndrome patients are moderately to severely impaired in daily live. 19 post-COVID-19 syndrome patients fulfill the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome. Disease severity and symptom burden is similar in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome and non-COVID-19/myalgic encephalomyelitis/chronic fatigue syndrome patients. Hand grip strength is diminished in most patients compared to normal values in healthy. Association of hand grip strength with hemoglobin, interleukin 8 and C-reactive protein in post-COVID-19 syndrome/non-myalgic encephalomyelitis/chronic fatigue syndrome and with hemoglobin, N-terminal prohormone of brain natriuretic peptide, bilirubin, and ferritin in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome may indicate low level inflammation and hypoperfusion as potential pathomechanisms.

BackgroundInhibition of interleukin (IL)-1 represents a promising treatment option in adult-onset Still's disease (AOSD).ObjectiveTo investigate the efficacy and safety of canakinumab in patients with AOSD and active joint involvement by means of a multicentre, double-blind, randomised, placebo-controlled trial.MethodsPatients with AOSD and active joint involvement (tender and swollen joint counts of ≥4 each) were treated with canakinumab (4 mg/kg, maximum 300 mg subcutaneous every 4 weeks) or placebo. The primary endpoint was the proportion of patients with a clinically relevant reduction in disease activity at week 12 as determined by the change in disease activity score (ΔDAS28>1.2).ResultsAt enrolment, patients had high active disease with a mean DAS28(ESR) of 5.4 in the canakinumab and 5.3 in the placebo group, respectively. In the intention-to-treat analysis, 12 patients (67%) in the canakinumab group and 7 patients (41%) in the placebo group fulfilled the primary outcome criterion (p=0.18). In the per-protocol analysis, significantly higher American College of Rheumatology (ACR) 30% (61% vs 20%, p=0.033), ACR 50% (50% vs 6.7%, p=0.009) and ACR 70% (28% vs 0%, p=0.049) response rates were observed in the canakinumab group compared with the placebo group. Two patients in the canakinumab group experienced a serious adverse event.ConclusionAlthough the study was terminated prematurely and the primary endpoint was not achieved, treatment with canakinumab led to an improvement of several outcome measures in AOSD. The overall safety findings were consistent with the known profile of canakinumab. Thus, our data support indication for IL-1 inhibition with canakinumab in AOSD.

Background: The current subclassification of systemic sclerosis into cutaneous subtypes does not fully capture the heterogeneity of the disease. We aimed to compare the performances of stratification into LeRoy's cutaneous subtypes versus stratification by autoantibody status in systemic sclerosis. Methods: For this cohort study, we assessed people with systemic sclerosis in the multicentre international European Scleroderma Trials and Research (EUSTAR) database. Individuals positive for systemic-sclerosis autoantibodies of two specificities were excluded, and remaining individuals were classified by cutaneous subtype, according to their systemic sclerosis-specific autoantibodies, or both. We assessed the performance of each model to predict overall survival, progression-free survival, disease progression, and different organ involvement. The three models were compared by use of the area under the curve (AUC) of the receiver operating characteristic and the net reclassification improvement (NRI). Missing data were imputed. Findings: We assessed the database on July 26, 2019. Of 16 939 patients assessed for eligibility, 10 711 patients were included: 1647 (15·4%) of 10 709 were male, 9062 (84·6%) were female, mean age was 54·4 (SD 13·8) years, and mean disease duration was 7·9 (SD 8·2) years. Information regarding cutaneous subtype was available for 10 176 participants and antibody data were available for 9643 participants. In the prognostic analysis, there was no difference in AUC for overall survival (0·82, 95% CI 0·81–0·84 for cutaneous only vs 0·84, 0·82–0·85 for antibody only vs 0·84, 0·83–0·86 for combined) or for progression-free survival (0·70, 0·69–0·71 vs 0·71, 0·70–0·72 vs 0·71, 0·70–0·72). However, at 4 years the NRI showed substantial improvement for the antibody-only model compared with the cutaneous-only model in prediction of overall survival (0·57, 0·46–0·71 for antibody only vs 0·29, 0·19–0·39 for cutaneous only) and disease progression (0·36, 0·29–0·46 vs 0·21, 0·14–0·28). The antibody-only model did better than the cutaneous-only model in predicting renal crisis (AUC 0·72, 0·70–0·74 for antibody only vs 0·66, 0·64–0·69 for cutaneous only) and lung fibrosis leading to restrictive lung function (AUC 0·76, 0·75–0·77 vs 0·71, 0·70–0·72). The combined model improved the prediction of digital ulcers and elevated systolic pulmonary artery pressure, but did poorly for cardiac involvement. Interpretation: The autoantibody-only model outperforms cutaneous-only subsetting for risk stratifying people with systemic sclerosis in the EUSTAR cohort. Physicians should be aware of these findings at the time of decision making for patient management. Funding: World Scleroderma Foundation.

Adult-onset Still���s disease (AOSD) is a systemic auto-inflammatory disease characterized by the presence of immunologically mediated inflammation and deficient resolution of inflammation. Canakinumab is an approved IL-1�� inhibitor in the treatment of AOSD with a balanced efficacy and safety profile. Since inflammatory cytokines play a major role in the pathogenesis of AOSD, we investigated the effects of canakinumab on the cytokine profile of AOSD patients from a randomized controlled trial. Multiplex analysis and ELISA were used to test the concentrations of several cytokines at three time points���week 0 (baseline), week 1 and week 4���in two patient groups���placebo and canakinumab. Two-way repeated-measures analysis of variance revealed a significant temporal effect on the concentrations of MRP 8/14, S100A12, IL-6 and IL-18 with a significant decrease at week 4 in the canakinumab group exclusively. Comparing responders with non-responders to canakinumab showed a significant decrease in MRP 8/14, IL-1RA, IL-18 and IL-6 in responders at week 4, while S100A12 levels decreased significantly in responders and non-responders. In summary, canakinumab showed a striking effect on the cytokine profile in patients with AOSD, exhibiting a clear association with clinical response.

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an acquired complex disease with patients suffering from the cardinal symptoms of fatigue, post-exertional malaise (PEM), cognitive impairment, pain and autonomous dysfunction. ME/CFS is triggered by an infection in the majority of patients. Initial evidence for a potential role of natural regulatory autoantibodies (AAB) to beta-adrenergic (AdR) and muscarinic acetylcholine receptors (M-AChR) in ME/CFS patients comes from a few studies. Methods: Here, we analyzed the correlations of symptom severity with levels of AAB to vasoregulative AdR, AChR and Endothelin-1 type A and B (ETA/B) and Angiotensin II type 1 (AT1) receptor in a Berlin cohort of ME/CFS patients (n = 116) by ELISA. The severity of disease, symptoms and autonomic dysfunction were assessed by questionnaires. Results: We found levels of most AABs significantly correlated with key symptoms of fatigue and muscle pain in patients with infection-triggered onset. The severity of cognitive impairment correlated with AT1-R- and ETA-R-AAB and severity of gastrointestinal symptoms with alpha1/2-AdR-AAB. In contrast, the patients with non-infection-triggered ME/CFS showed fewer and other correlations. Conclusion: Correlations of specific AAB against G-protein-coupled receptors (GPCR) with symptoms provide evidence for a role of these AAB or respective receptor pathways in disease pathomechanism.

Introduction: The past decade has seen increasingly rapid advances in understanding the pathogenic nature of adult-onset Still’s disease (AOSD) and its shared symptoms with the systemic juvenile idiopathic arthritis (sJIA). Interleukin-1 (IL-1) blocking agents are key elements in the treatment. In this updated systematic review, we focus on studies on efficacy and safety of IL-1 blockers published in the past 5 years and review on latest available therapies. Methods: We conducted searches using Medline, Biosis, Embase, and Cochrane databases between 2016 and 2021 using the terms AOSD, IL1, IL-18, canakinumab, anakinra, tadekinig, and rilonacept and if applicable their trade names. Duplicates, case reports, and manuscripts with incomplete data were excluded. Results: Of the 1013 screened publications, 17 were eligible after careful selection. We only found two published randomized controlled studies in the past 5 years. Review manuscripts of rare diseases, like our work, usually rely on retrospective studies and case series. Anakinra and canakinumab can be successfully used as first- or further-line treatment in patients with AOSD refractory to steroids. A homogeneous outcome is not established yet. Thus, a combination of clinical and laboratory tests can support the experienced clinician in the decision-making process. Conclusion: The approval of IL-1 inhibitors for AOSD brought us into a new era in the treatment of AOSD. The overall efficacy-safety profile of the IL-1 inhibitors is favorable reflecting a targeted approach as standard of care. We can expect that the successful treatment of AOSD with IL-1 inhibition will facilitate further clinical and basic research with impact on other auto-inflammatory and hyper-inflammatory conditions.

A subset of patients has long-lasting symptoms after mild to moderate COVID-19. In a prospective observational cohort study we analysed clinical and laboratory parameters in 42 patients (29 female/13 male, median age 36.5 years) with persistent moderate to severe fatigue and exertion intolerance six months following COVID-19 referred to as Chronic COVID-19 Syndrome (CCS). Most patients were moderately to severely impaired in daily live. 19 patients fulfilled the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome referred to as CFS/CCS. Hand grip strength (HGS) was diminished in most patients. Association of several biomarker with key symptoms of physical and mental fatigue and post exertional malaise indicate low level inflammation and hypoperfusion as potential pathomechanisms.

ObjectiveCharacterization of the clinical features of patients with persistent symptoms after mild to moderate COVID-19 infection and exploration of factors associated with the development of Chronic COVID-19 Syndrome (CCS).MethodsSetting: Charité Fatigue Center with clinical immunologists and rheumatologist, neurologists and cardiologists at Charité University hospital.Participants: 42 patients who presented with persistent moderate to severe fatigue six months following a mostly mild SARS-CoV-2 infection at the Charité Fatigue Center from July to November 2020.Main outcome measures: The primary outcomes were clinical and paraclinical data and meeting diagnostic criteria for Chronic Fatigue Syndrome (ME/CFS). Relevant neurological and cardiopulmonary morbidity was excluded.ResultsThe median age was 36.5, range 22–62, 29 patients were female and 13 male. At six months post acute COVID-19 all patients had fatigue (Chalder Fatigue Score median 25 of 33, range 14–32), the most frequent other symptoms were post exertional malaise (n=41), cognitive symptoms (n=40), headache (n=38), and muscle pain (n=35). Most patients were moderately to severely impaired in daily live with a median Bell disability score of 50 (range 15–90) of 100 (healthy) and Short Form 36 (SF-36) physical function score of 63 (range 15-80) of 100. 19 of 42 patients fulfilled the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These patients reported more fatigue in the Chalder Fatigue Score (p=0.006), more stress intolerance (p=0.042) and more frequent and longer post exertional malaise (PEM) (p=0.003), and hypersensitivity to noise (p=0.029), light (p=0.0143) and temperature (p=0.024) compared to patients not meeting ME/CFS criteria. Handgrip force was diminished in most patients compared to healthy control values, and lower in CCS/CFS compared to non-CFS CCS (Fmax1 p=0.085, Fmax2, p=0.050, Fmean1 p=0.043, Fmean2 p=0.034, mean of 10 repeat handgrips, 29 female patients). Mannose-binding lectin (MBL) deficiency was observed frequently (22% of all patients) and elevated IL-8 levels were found in 43% of patients.ConclusionsChronic COVID-19 Syndrome at months 6 is a multisymptomatic frequently debilitating disease fulfilling diagnostic criteria of ME/CFS in about half of the patients in our study. Research in mechanisms and clinical trials are urgently needed.

ObjectivesHand osteoarthritis (OA) is a condition characterised by cartilage degradation and frequently erosive changes. Analgesics and non-steroidal anti-inflammatory drugs are used for symptomatic relief but are often poorly tolerated or contraindicated. Previous publications suggest hydroxychloroquine (HCQ) as a possible treatment for hand OA. The OA-TREAT study aimed to investigate the efficacy and safety of HCQ in patients with inflammatory and erosive hand OA (EOA).MethodsOA-TREAT was an investigator-initiated, multicentre, randomised, double-blind, placebo (PBO)-controlled trial. Patients with inflammatory and EOA, according to the ACR criteria, with radiographically erosive disease were randomised 1:1 to HCQ 200–400 mg/day or PBO for 52 weeks (W52). Both groups received stable standard therapy. The primary endpoint was Australian Canadian Hand Osteoarthritis Index (AUSCAN) for pain and hand disability at W52.Results75 patients were randomised to HCQ and 78 to PBO. At W52, mean AUSCAN pain was 26.7 in HCQ and 26.5 in PBO patients (p=0.92). Hand disability measured by AUSCAN function (mean) was 48.1 in HCQ and 51.3 in PBO patients (p=0.36). Changes in radiographic scores did not differ significantly (p>0.05) between treatment groups. There were 7 serious adverse events in the HCQ and 15 in the PBO group.ConclusionsOA-TREAT is the first large randomised PBO controlled trial focusing on EOA. HCQ was no more effective than PBO for changes in pain, function and radiographic scores in the 52-week period. Overall safety findings were consistent with the known profile of HCQ.

Der adulte Morbus Still (Englisch: adult-onset Still’s disease – AOSD) ist eine seltene auto-inflammatorische Erkrankung bisher unbekannter Atiologie und Pathogenese. Dabei kann von einem Krankheitskontinuum der systemischen juvenilen idiopathischen Arthritis (sJIA) ausgegangen werden. Die Diagnose wird nach Ausschluss infektioser, hamatologischer und autoimmuner Erkrankungen gestellt. Hier mussen insbesondere Sepsis, Endokarditis, Neoplasien und Kollagenosen ausgeschlossen werden. Zu den Hauptsymptomen des AOSD zahlen u. a. Fieber, Gelenkbeteiligung, Halsschmerzen sowie lachsfarbenes Exanthem. Aufgrund des Fiebers gehort das AOSD zu den Differenzialdiagnosen bei Patienten mit Fieber unklarer Genese und wird in bis zu 3–20% der Falle diagnostiziert. Zur Klassifikation liegen unterschiedliche Kriterien vor, wobei am haufigsten die nach Yamaguchi (1992) oder Faultrel (2002) eingesetzt werden. Neue Erkenntnisse zur Pathogenese deuten auf eine wichtige Rolle der IL-1 und IL-6 Signalwege hin. Die diagnostische Wertigkeit von neuen Biomarkern wie S100 Proteine und IL-18 mus beim AOSD noch evaluiert werden. Die aktuellen Therapieempfehlungen basieren uberwiegend auf Erfahrungswerten, wobei initial NSAR und Glukokortikoide eingesetzt werden. Zu konventionellen und biologischen Basismedikamenten sind bisher keine kontrollierten Studien bei AOSD publiziert. Aus der klinischen Erfahrung und Behandlungsergebnissen des sJIA konnen verschiedene Therapieansatze fur den AOSD extrapoliert werden, dabei zeigen insbesondere eine IL-1 oder IL-6 Blockade gute Effekte. Auf Grundlage des Krankheitskontinuums und neuer molekularbiologischer Daten wurde aktuell eine Erweiterung der Zulassung fur den IL-1 Inhibitor Canakinumab von der sJIA auf das AOSD durch die EMA ausgesprochen.

Background:Hand osteoarthritis (OA) is a very common condition with cartilage degradation and frequently erosive bone changes. It may be very painful and can greatly affect everyday activities. Common analgesics and NSAIDs are used for symptomatic relief but are often poorly tolerated or contraindicated especially in elderly patients. There is no effective and proven disease modifying therapy available. Previous publications and anecdotal reports suggest hydroxychloroquine (HCQ) as a possible treatment, and some physicians use HCQ off-label for the treatment of OAObjectives:To investigate the efficacy and safety of HCQ in patients with inflammatoryanderosive hand OA in a randomized, double-blind, placebo controlled, multi-centre, investigator-initiated trialMethods:Patients with inflammatory and erosive hand OA, according to the ACR criteria, with radiographically proven erosive disease were randomized 1:1 to HCQ 200-400mg per day or matching placebo (PBO) for 52 weeks. Both groups received standard therapy (stable NSAIDs). The primary endpoint was AUSCAN for pain and hand disability at week 52 (W52). A secondary endpoint was radiographic progression from baseline (BL) to W52. A multiple endpoint test and analysis of covariance was used to compare changes between groups. All analyses were conducted on an intention-to-treat baseResults:Of 156 patients 3 were excluded and 75 were randomized to HCQ and 78 to PBO. Mean age was 52.4 (SD 8.1) in the HCQ and 50.2 (SD 6.6) years in the PBO group. 68 (90.7%) of the patients were female in the HCQ and 60 (76.9%) in the PBO group. Disease duration was 9.5 (SD 7.5) in HCQ and 10.8 (SD 8.8) years in PBO group. CRP and ESR were normal in both groups. BL pain (AUSCAN) was 31.1 (SD 8.2) and 30.7 (SD 8.9), BL function (AUSCAN) was 58.5 (SD 15.5) in HCQ and 57.8 (SD 17.1) in PBO patients. Table 1 shows clinical and functional parameters at W52. Only morning stiffness was significantly reduced in the HCQ group (p=0.001). Changes in radiographic scores did not differ significantly (p>0.05) between treatment groups. There were 7 SAE in the HCQ and 15 in the PBO group. No new safety issues were detectedTable 1.Results of the covariance analysis (ANCOVA)-adjusted mean values and 95%-confidence intervals for primary and secondary outcomes at W52, as well as a p-value for group comparisonOutcomeAdj. Mean HCQ95%-CI HCQAdj. Mean PBO95%-CI PBOP-value HCQ x PBOAUSCAN Function48.14353.351.346.6560.36AUSCAN Pain26.723.929.426.523.929.10.92tender joint6.44.87.97.15.48.70.49swollen joint21.32.72.11.42.70.93ESR (mm/h)8.26.99.611.710.113.5HAQ0.90.810.80.70.90.46Phys. Global3.22.83.63.533.90.39Pat. Global4.53.95.15.24.65.80.14SF36 mental48.846.65150.848.752.80.22SF36 physical39.83841.639.938.241.60.95Morning Stiffness (min)30.22436.316.310.322.30.001Modif. Kallmann Score53.652.155.152.851.454.20.24The associated BL value or, if available, a mean value from BL and screening was included in the ANCOVA model as a covariate.Conclusion:The OATREAT trial examined the clinical and radiological efficacy and safety of HCQ as a treatment option for inflammatory and erosive OA over 52 weeks. OATREAT is the first large randomized PBO controlled trial focusing on erosive hand OA. HCQ was no more effective than PBO for changes in pain, function and radiographic scores in the 52-week period. Overall safety findings were consistent with the known profile of HCQ. Thus, our data failed to show that HCQ is effective in patients with inflammatory, erosive hand OADisclosure of Interests:Claudia Kedor Consultant of: Advisory Board for Novartis Pharma GmbH, Jacqueline Detert: None declared, Rolf Rau: None declared, Siegfried Wassenberg: None declared, Joachim Listing: None declared, Pascal Klaus Employee of: Pfizer Pharma GmbH, Tanja Braun: None declared, Walter Hermann: None declared, Stefan Weiner: None declared, Martin Bohl-Bühler: None declared, Frank Buttgereit Grant/research support from: Amgen, BMS, Celgene, Generic Assays, GSK, Hexal, Horizon, Lilly, medac, Mundipharma, Novartis, Pfizer, Roche, and Sanofi., Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma

Background Inhibition of interleukin-1 (IL-1) represents a promising treatment option in adult-onset Still’s disease (AOSD). Canakinumab (CAN) is approved for treatment of systemic juvenile idiopathic arthritis (sJIA) since 2013 and recently for AOSD in Europe. In sJIA, CAN has a proven marked impact on systemic and articular disease activity, but for AOSD RCT data is limited. Objectives Investigation of efficacy and safety of CAN in AOSD patients with joint involvement by means of a multi-centre, double-blinded, randomized, placebo controlled trial. Methods AOSD patients with joint involvement (tender and swollen joint count ≥4 each) were stratified by pre-treatment status with biologics and randomized in a ratio of 1:1 to CAN (4 mg/kg up to a maximum of 300 mg) or placebo (PBO) s.c. every 4wks. The primary endpoint was defined as the proportion of patients with a clinical-relevant reduction (≥1.2) in disease activity as measured by change in disease activity score (DAS28) at week 12. There were two major protocol violations: two PBO patients received blinded CAN at week 4. Therefore, a per-protocol (PP) analysis, which excluded data of these two patients, was performed. Results The study was prematurely stopped with 35 out of 68 planned patients enrolled due to approval of CAN for AOSD by EMA. At enrollment, mean DAS28 represented high disease activity for both: 5.4 in CAN (n=18) and 5.3 in PBO (n=17). In the intention-to-treat analysis, 12 (67%) CAN and 7 (41%) PBO patients met the primary endpoint. The 25.5% [95%CI: -10.3%; 55.9%] difference in the response rate did not achieve statistical significance (p=0.18). Using the PP analysis, the treatment difference for primary endpoint was 33.4% [95%CI: -10.3%; 55.9%, p=0.08]. We observed higher ACR50 (50% CAN vs. 6.7% PBO, p= 0.009), ACR70 (28% CAN vs. 0% PBO, p=0.049) response rates, (PP analysis). Higher mean improvements in the CAN vs PBO group for DAS28(ESR and CRP), ESR, CRP, 66 swollen and 68 tender joint counts at week 12 were observed (PP analysis). There were 47 and 21 non-serious adverse events (AE) reported in CAN and PBO groups, respectively. Two CAN patients experienced an SAE (hepatotoxicity and patellofemoral pain syndrome). Conclusion Although the study was terminated prematurely and the primary endpoint did not achieve statistical significance, treatment of patients with active AOSD with CAN led to improvement of several outcome measures. In addition, safety profile was similar to that reported in sJIA and no unexpected safety issues were observed. This data support the treatment of AOSD patients with CAN. References [1] Ruperto. NEJM (2012): 2396-2406 Disclosure of Interests Claudia Kedor Grant/research support from: Sobi, Consultant for: Novartis, Speakers bureau: Novartis, Roche, Joachim Listing: None declared, Jan Zernicke: None declared, Anja Weis: None declared, Frank Behrens Grant/research support from: AbbVie, Pfizer, Roche, Chugai, Prophylix, Bioline, Novartis, Consultant for: AbbVie, Pfizer, Roche, Chugai, UCB, Bristol-Myers Squibb, Celgene, MSD, Novartis, Biotest, Janssen, Genzyme, Eli Lilly, Speakers bureau: Ad board: AbbVie, Pfizer, Roche, Chugai, UCB, Bristol-Myers Squibb, Celgene, Novartis, Biotest, Janssen, Genzyme, Eli Lilly, Norbert Blank Grant/research support from: SOBI and Novartis, Speakers bureau: Novartis and SOBI, Jorg Henes: None declared, Jorn Kekow: None declared, Andrea Rubbert-Roth Consultant for: Chugai, Eli Lilly, Roche, and Sanofi , Speakers bureau: AbbVie, Bristol-Myers Squibb, Chugai, Hexal/Novartis, Janssen, Eli Lilly, Merck Sharp & Dohme, Pfizer, Roche, and Sanofi , Hendrik Schulze-Koops Grant/research support from: Novartis, Pfizer, Roche, Consultant for: Abbvie, Actelion, Amgen, AstraZeneca, Biogen International, BMS, Celgene, Chugai, GSK, Hospira, Janssen-Cilag, Leo Pharmaceuticals, Lilly, MSD, Medac, Merck, Novartis, Pfizer, Hexal Sandoz, Sanofi, Roche, UCB, Paid instructor for: Abbvie, Actelion, Amgen, AstraZeneca, Biogen International, BMS, Celgene, Chugai, GSK, Hospira, Janssen-Cilag, Leo Pharmaceuticals, Lilly, MSD, Medac, Merck, Novartis, Pfizer, Hexal Sandoz, Sanofi, Roche, UCB, Speakers bureau: Abbvie, Actelion, Amgen, AstraZeneca, Biogen International, BMS, Celgene, Chugai, GSK, Hospira, Janssen-Cilag, Leo Pharmaceuticals, Lilly, MSD, Medac, Merck, Novartis, Pfizer, Hexal Sandoz, Sanofi, Roche, UCB, Eva Seipelt: None declared, Christof Specker: None declared, Eugen Feist Grant/research support from: Pfizer, Roche, Novartis, BMS, Sanofi, Lilly, Consultant for: Pfizer, Roche, Novartis, BMS, Abbvie, Celgene, Sanofi, MSD, Lilly, Speakers bureau: Pfizer, Roche, Novartis, BMS, Abbvie, Celgene, Sanofi, Lilly

Background: Inhibition of interleukin-1 (IL-1) represents a promising treatment option in adult-onset Still's disease (AOSD). Canakinumab is approved for treatment of systemic juvenile idiopathic arthritis and has a marked impact on systemic as well as articular activity of the disease. Objective: To investigate the efficacy and safety of canakinumab in patients with AOSD and active joint involvement by means of a multi-centre, double-blinded, randomized, placebo controlled trial. Methods: Patients with AOSD and active joint involvement (tender and swollen joint count ≥4 each) were stratified by pre-treatment status with biologic DMARDs to canakinumab (4 mg/kg, maximum 300 mg s.c. q4w) or placebo. After approval of canakinumab for AOSD by the European Medicines Agency, recruitment was stopped prematurely with enrollment of 35 out of 68 planned patients. The primary endpoint was the proportion of patients with a clinically-relevant reduction in disease activity at week 12 as determined by the change in disease activity score (ΔDAS28 >1·2). Results: At enrollment, patients had high active disease with a mean DAS28(ESR) of 5·4 in the canakinumab group (n=18, [CI 43·1 ; 85·2]) and 5·3 in the placebo group (n=17, [CI 20·1 ; 65·0]). In the intention-to-treat analysis, 12 (67%) canakinumab and 7 (41%) placebo patients fulfilled the primary outcome criterion (p=0.18). In the per-protocol analysis, significantly higher ACR30 (61% vs. 33% p=0.033), ACR50 (50% vs. 6·7% p= 0.009) and ACR70 (28% vs. 0% p=0·049) response rates were observed in the canakinumab group compared with placebo. Two patients in the canakinumab group experienced an SAE. Conclusion: Although the study was terminated prematurely and the primary endpoint was not achieved, treatment with canakinumab led to an improvement of several outcome measures in AOSD. The overall safety findings were consistent with the known profile of canakinumab. Thus, our data support indication for IL-1 inhibition with canakinumab in AOSD. Trial Registration: EudraCT No. 2011-001027-20. Funding Statement: Novartis Pharma GmbH Deutschland for financial support and study drug provision. Declaration of Interests: CK has received personal advisory board and congress fees from Novartis, Pfizer, Roche, and Sobi. FB has received grants from Abbvie, Pfizer, Roche, Chugai, Janssen and consultant, speaker, or advisory board fees from Abbvie, Pfizer, Roche, Chugai, UCB, BMS, Celgene, MSD, Novartis, Biotest, Janssen, Genzyme, Lilly; Boehringer; and Sandoz. NB has received grants from Novartis and Sobi, and personal fees from Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, and Roche. JH has received grants from Novartis, Roche, Celgene, and advisory board and speaker fees from Novartis, Roche, Pfizer, Abbvie, Sanofi, Boehringer-Ingelheim, and Celgene. ARR has received speaker fees from UCB, and advisory board and speaker fees from Novartis, Roche, Lilly, Pfizer, Abbvie, BMS, Janssen, Sanofi, and Celgene. CS has received personal fess from Abbvie, BoehringerIngelheim, Chugai, Lilly, Novartis, Sobi, UCB, Celgene, Janssen-Cilag, MSD, Pfizer, Roche, UCB, and Toshiba. EF has received advisory board and speaker fees from Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, and Sanofi. The remaining authors declare no competing interests. Ethics Approval Statement: The study was conducted according to the ethical principles of the Declaration of Helsinki. The study protocol and all amendments were reviewed by the Independent Ethics Commission of the State of Berlin (Ethik-Kommission des Landes Berlin) and Independent Ethics Committees for each center (EudraCT No. 2011-001027-20, Protocol No.: CACZ885GDE01T, ethic No 11/0561 – ZS EK 11). All patients provided written informed consent before any assessment was performed.

Muraviov and Muraviova are asking for further1 elucidation of the chosen endpoints and a more detailed characterisation of the included patients in our study of canakinumab for the treatment of patients with adult-onset Still’s disease (AOSD) with articular involvement.2 As mentioned in our previous communication, at the time of Canakinumab for treatment of adult ONset StIll’s Disease to achiEve Reduction of arthritic manifestation (CONSIDER) trial conception in 2012, there were no approved drugs and no validated scores available for AOSD. On the other hand, accumulating evidence suggested that inhibition of Interleukin-1 (IL1) could be beneficial for the patients.2–5 Thus, our aim was to investigate the effects of canakinumab in a controlled setting to provide convincing data, which could even be useful for regulatory …

We would like to thank Ruscitti et al 1 for their interest in our recent publication, in which we presented the results of the Canakinumab for treatment of adult onset Still‘s disease to achieve reduction ofarthritic manifestation (CONSIDER) trial. In this study, we investigated the efficacy of canakinumab for the treatment of patients with adult-onset Still’s disease (AOSD) with articular involvement (tender and swollen joint counts≥4 each) by means of a multicentre, double-blind, randomised, placebo-controlled trial.2 Patients were randomised to receive either canakinumab 4 mg/kg body weight (maximum 300 mg) every 4 weeks or placebo. According to the study goal, the primary endpoint was defined as the proportion of patients with a clinically relevant reduction in Disease Activity Score (DAS 28 >1.2) at week 12. Since no controlled studies existed in this indication at that time of the study initiation, we were not able to base our statistical considerations on known facts of response rates to placebo or any immunosuppressive regimen. After careful consideration, our sample size calculation indicated that it requires a total of n=68 randomised patients to show a significant difference between the groups. …

Background:Inhibition of interleukin-1 (IL-1) represents a promising treatment option in adult-onset Still’s disease (AOSD). Canakinumab is approved for treatment of systemic juvenile idiopathic arthritis and has a marked impact on systemic as well as articular activity of the disease.Objectives:To investigate the efficacy and safety of canakinumab in patients with AOSD and active joint involvement by means of a multi-centre, double-blinded, randomized, placebo controlled trial over a period of 24 weeks with the option of a long-term extension.Methods:Patients with AOSD and active joint involvement (tender and swollen joint count ≥4 each) were stratified by pre-treatment status with biologic DMARDs to canakinumab (4 mg/kg, maximum 300 mg s.c. q4w) or placebo. After approval of canakinumab for AOSD by the European Medicines Agency, recruitment was stopped prematurely with enrollment of 35 out of 68 planned patients. The primary endpoint was the proportion of patients with a clinically-relevant reduction in disease activity at week 12 as determined by the change in disease activity score (ΔDAS28 >1.2).Results:At enrollment, patients had high active disease with a mean DAS28(ESR) of 5.4 in the canakinumab group (n=18, [CI 43.1; 85.2]) and 5·3 in the placebo group (n=17, [CI 20.1; 65.0]). In the intention-to-treat analysis, 12 (67%) canakinumab and 7 (41%) placebo patients fulfilled the primary outcome criterion (p=0.18). Figure 2 shows the DAS28-ESR disease activity by treatment groups and visits with imputation. In the per-protocol analysis, significantly higher ACR30 (61% vs. 33% p=0.033), ACR50 (50% vs. 6.7% p= 0.009) and ACR70 (28% vs. 0% p=0.049) response rates were observed in the canakinumab group compared with placebo (Figure 1). Two patients in the canakinumab group experienced an SAE.Figure 1.Response rates (PP)Figure 2.DAS28-ESR disease activity by treatment groups and visits with imputationConclusion:Although the study was terminated prematurely and the primary endpoint was not achieved, treatment with canakinumab led to an improvement of several outcome measures in AOSD. The overall safety findings were consistent with the known profile of canakinumab. Thus, our data support indication for IL-1 inhibition with canakinumab in AOSD.References:[1]Nirmala N et al. Gene-expression analysis of AOSD and SJIA is consistent with a continuum of a single disease entity. Pediatr Rheumatol Online J. 2015P-values are shown above each pair of bars; P-values in red are significant ACR, American College of Rheumatology; CRP, C-reactive protein; DAS, disease activity score; EULAR, European League Against Rheumatism; PP, per-protocolDisclosure of Interests:Claudia Kedor Consultant of: Advisory Board for Novartis Pharma GmbH, Joachim Listing: None declared, Jan Zernicke: None declared, Anja Weiß: None declared, Frank Behrens Grant/research support from: Abbvie, Pfizer, Roche, Chugai, Janssen, Consultant of: Abbvie, Pfizer, Roche, Chugai, UCB, BMS, Celgene, MSD, Novartis, Biotest, Janssen, Genzyme, Lilly; Boehringer; Sandoz, Speakers bureau: Abbvie, Pfizer, Roche, Chugai, UCB, BMS, Celgene, MSD, Novartis, Biotest, Janssen, Genzyme, Lilly; Boehringer; Sandoz, Norbert Blank Grant/research support from: Novartis, Sobi, Consultant of: Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, Roche, Jörg Henes Grant/research support from: Novartis, Roche-Chugai, Consultant of: Novartis, Roche, Celgene, Pfizer, Abbvie, Sanofi, Boehringer-Ingelheim,, Jörn Kekow Speakers bureau: BMS, MSD, Pfizer, Roche, Andrea Rubbert-Roth Consultant of: Abbvie, BMS, Chugai, Pfizer, Roche, Janssen, Lilly, Sanofi, Amgen, Novartis, Hendrik Schulze-Koops Grant/research support from: Pfizer Inc, Eva Seipelt: None declared, Christof Specker Consultant of: Abbvie, Boehringer Ingelheim, Chugai, Lilly, Novartis, Sobi, UCB, Celgene, Janssen-Cilag, MSD, Pfizer, Roche, UCB, Toshiba, Eugen Feist Consultant of: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, Speakers bureau: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi

Background:Abatacept (CTLA4-Ig) is a biological DMARD (bDMARD) for treatment of rheumatoid arthritis (RA) and selectively modulates the co-stimulatory signal by CD28: CD80/CD86 interaction required for T cell activation. CD28 mediated signaling regulates many T cell functions including cytokine production. The role of proteasome was approved in many autoimmune diseases, and the effect of Abatacept on modifying cytokines including interferon-γ that alters proteasome proteolytic activities was shown in RA.Objectives:To characterize the effect of Abatacept on the expression and proteolytic activity of the immunoproteasome.Methods:Effects of Abatacept on the proteasome system were investigated in 39 patients with rheumatoid arthritis over a period of 24 weeks. Using real time PCR, transcript expression levels of constitutive and corresponding immunoproteasome catalytic subunits were investigated at baseline (T0), week 16 (T16) and week 24 (T24) in sorted blood cells. Proteasomal activity and induction of apoptosis after proteasome inhibition were also evaluated in cellular subsets.Results:Upon treatment with Abatacept, remission or low disease activity according to DAS28 was achieved in 55 % of patients at T16 and in 70 % at T24. By Two- (time and type of response) way ANOVA, a significant reduction of proteasome immunosubunit β1i expression was shown only in CD4+ and CD8+ T cells of prolonged responders at both T16 and T24 (P= 0.0390 andP= 0.0198, respectively). One-way ANOVA analysis for each response group separately confirmed the results and showed significant reduction at T24;P= 0.0396 difference between T0 and T24,P= 0.0260 between T16 and T24 in CD4+ T cells of the same group. Abatacept did not influence chymotrypsin like activity of proteasome, which is carried out by the subunit β5i and had no effect on induction of apoptosis under exposure to a proteasome inhibitor in-vitro.Conclusion:Treatment with Abatacept showed a clear effect on the expression of the proteasome immunosubunit β1i. This phenomenon was only seen in CD4+ and CD8+ T cells of prolonged responding patients with RA suggesting an association between persistent induction of β1i and failure to the T cell directed therapy with Abatacept.References:[1]Keating, G.M., Abatacept: A Review of its Use in the Management of Rheumatoid Arthritis. Drugs, 2013. 73(10): p. 1095-1119.[2]Ferrington, D.A. and D.S. Gregerson, Immunoproteasomes: Structure, Function, and Antigen Presentation. Progress in molecular biology and translational science, 2012. 109: p. 75-112.[3]Marti, L., et al., Alterations in Cytokine Profile and Dendritic Cells Subsets in Peripheral Blood of Rheumatoid Arthritis Patients before and after Biologic Therapy. Annals of the New York Academy of Sciences, 2009. 1173: p. 334-42.Disclosure of Interests:Khetam Ghannam: None declared, Lorena Martinez Gamboa: None declared, Claudia Kedor Consultant of: Advisory Board for Novartis Pharma GmbH, Lydia Spengler: None declared, Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Eugen Feist Consultant of: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, Speakers bureau: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi

Background Physical exercises and physiotherapy are of great importance for maintenance of joint function in patients with rheumatoid arthritis (RA). However, many RA patients complain about problems to receive prescriptions or have a lack of access to physiotherapy. Recent reports have shown positive effects of the Wii game console on physical and psychosocial conditions of patients with other underlying diseases. The primary objectives of this prospective controlled pilot study were to investigate feasibility and patients’ assessment using an animated home-based exercise program. Method This pilot study was conducted as a single-center, cross-over trial with two treatment arms over 24 weeks. Eligibility criteria included patients with RA reaching low disease activity under therapy with a biological disease modifying anti-rheumatic drug (bDMARD). After detailed instruction, 15 patients started with a conventional home-based physical exercise program and 15 patients began with a predefined animated exercise program by using the Wii game console for 12 weeks. Afterwards, patients were crossed-over to the other treatment arm for another period of 12 weeks. Multi-methodical assessments were performed by qualitative analysis of the interview-data as well as statistical analysis of functional tests and patient reported outcomes (PRO’s). Results Evaluation of the interviews indicated feasibility and usefulness of the chosen animated home-based exercise program. Forefoot disabilities were identified as a main limiting factor for performing some of the animated exercises. After 12 weeks, both treatment arms showed improvement of functional tests without significant differences between groups: Overall muscle strength improved for a mean value of 10 Newton (+12 %) and the mean 6-min walk test (6-MWT) distance increased for 28 meters (+5 %). Conclusion This study showed that an animated home-based exercise program by using a Wii game console was feasible and beneficial for RA patients. Compared to standard physical home exercises, similar effects were observed indicating that such an animated program might be an alternative supportive option for RA patients. Trial registration ClinicalTrials.gov ID: NCT02658370 (19-Jan-2016). Electronic supplementary material The online version of this article (doi:10.1186/s12891-016-1208-3) contains supplementary material, which is available to authorized users.

This study aims to investigate the efficacy and safety of low-dose cyclosporine A (CyA) in patients with primary Sjogren’s syndrome (pSS) and articular involvement. This phase II open-label clinical study included 30 patients meeting the American-European Consensus group criteria for pSS with active joint involvement under stable symptomatic therapy. Treatment consisted of approximately 2 mg kg−1 body weight of CyA day−1 over a period of 16 weeks. The primary endpoint was defined as a reduction in the number of painful and/or swollen joints at end of treatment (EOT). Secondary endpoints included the changes in general health, sicca symptoms, European League Against Rheumatism (EULAR) Sjogren’s Syndrome Disease Activity Index (ESSDAI), arthrosonography, and safety profile. At baseline (BL), the mean number of tender joints (68 count) was 16.2 (±13.2) and at EOT 10.4 (±11.9; p = 0.002). The mean number of swollen joints (66 counts) was reduced from 3.2 (±3.3) at BL to 1.3 (±3.2) at EOT (p

Objective.Regulatory T cells are characterized by expression of the transcription factor FoxP3 and are thought to be involved in the pathogenesis of autoimmune diseases. We determined the frequency and phenotypic characteristics of CD4+FoxP3+ T cells in the blood and synovial fluid (SF) of patients with inflammatory joint diseases.Methods.SF from 10 patients with ankylosing spondylitis (AS), 20 patients with other spondyloarthritides or with peripheral arthritis (pSpA), and 12 patients with rheumatoid arthritis (RA), and peripheral blood (PB) from 22 patients with AS, 19 with pSpA, 15 with RA, and 12 healthy controls were stained for CD4, FoxP3, CD25, and CD127 and different effector cytokines and then analyzed by flow cytometry. Methylation pattern of the Treg-specific demethylated region (TSDR) was determined after bisulfite treatment by quantitative polymerase chain reaction.Results.In all groups of patients we observed higher frequencies of Foxp3+ cells/CD4+ T cells within SF compared to PB. The frequency of synovial Foxp3+ cells/CD4+ T cells was significantly higher in patients with pSpA (18.79% ± 6.41%) compared to patients with AS (9.69% ± 4.11%) and patients with RA (5.95% ± 2.21%). CD4+FoxP3+ T cells were CD25+ and CD127− and lacked effector cytokine production in any of the different patient groups. The majority of the CD4+CD25+CD127− T cells showed demethylation of the TSDR within the Foxp3 locus, confirming its regulatory phenotype.Conclusion.Our data show accumulation of Foxp3+ T cells within inflamed joints. These Foxp3+ T cells are mainly of stable T regulatory phenotype. The high frequency of Foxp3+ T cells in pSpA might contribute to the spontaneous resolution and remitting course of arthritis in pSpA as compared to the more persistent joint inflammation in RA.

Background Physical exercises and physiotherapy are of high importance for maintenance of joint function in patients with rheumatoid arthritis (RA). However, many RA patients complain about problems to receive prescriptions for or lack of access to physical therapy. Recent reports have shown positive effects of the Wii™ game console (Nintendo®) on physical and psychosocial conditions of patients with other underlying diseases. In fact, a home-based animated physical exercise program could be cost-effective, freely available and adjustable to the individual situation. Objectives To investigate practicability and effects of an animated home-based exercise program for RA patients treated with biologic DMARDs. Methods This study was conducted as an investigator initiated, not manufacturer supported, single-center, cross-over trial with two treatment arms over 24 weeks. Eligibility criteria included patients with RA with low disease activity according to DAS28 under biological DMARD therapy. After detailed instruction, 10 patients started with a conventional home-based physical exercise program and 10 patients with the animated exercise program by using the Wii™ game console for 12 weeks. Afterwards, patients were crossed over to the other treatment arm for another period of 12 weeks. A multi-methodical approach was used for this study: A qualitative analysis of the interview-data was performed by interpretation and inter-individual comparison of given answers. Measurements for muscle strength (isometric measurement) and 6-minute walk test (6-MWT) were compared from Baseline to week 12 and week 24. Statistical computing was performed with SPSS using the 9Analysis of Covariance9 (ANCOVA), adjusted for baseline status. Results We evaluated data from 20 patients (17 females) with a mean age of 55,5 (±9) years. More than 14 hours of interview data were transcribed and analyzed. By using a special software for coding patients response, categories were identified indicating practicability and easy accessibility. Of note, mainly fore foot disabilities were described as limiting factors for performing some exercises of the program. Many patients stated a positive influence by the game console on their perseverance to doing exercises. Over the observation period, both groups showed a clear benefit from the exercise programs and the analysis of test results showed no significant differences between both treatment arms after 12 weeks: Muscle strength improved by mean of 11 N (increase of 13% from baseline) with a non-significant difference of 3 N between both groups (p=0,64). The mean 6-MWT distance was increased by 50 meters (increase of 9% from baseline) without a relevant difference between both groups (p=0,73). Results from week 24 suggested that beginning with the home based physical exercise program followed by a subsequent Wii™ game console program was the most effective program. Conclusions This study showed that an animated home-based exercise program by using a Wii™ game console was beneficial for RA-Patients. Compared to standard physical home exercises, similar effects in both treatment groups were observed indicating that such an animated and well received program might be an alternative or additional option for RA-patients depending on their own preferences. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2305