Abatacept inhibits inflammation and onset of rheumatoid arthritis in individuals at high risk (ARIAA): a randomised, international, multicentre, double-blind, placebo-controlled trial.

BACKGROUND: Individuals with anti-citrullinated protein antibodies (ACPAs) and subclinical inflammatory changes in joints are at high risk of developing rheumatoid arthritis. Treatment strategies to intercept this pre-stage clinical disease remain to be developed. We aimed to assess whether 6-month treatment with abatacept improves inflammation in preclinical rheumatoid arthritis. METHODS: The abatacept reversing subclinical inflammation as measured by MRI in ACPA positive arthralgia (ARIAA) study is a randomised, international, multicentre, double-blind, placebo-controlled trial done in 14 hospitals and community centres across Europe (11 in Germany, two in Spain, and one in the Czech Republic). Adults (aged ≥18 years) with ACPA positivity, joint pain (but no swelling), and signs of osteitis, synovitis, or tenosynovitis in hand MRI were randomly assigned (1:1) to weekly subcutaneous abatacept 125 mg or placebo for 6 months followed by a double-blind, drug-free, observation phase for 12 months. The primary outcome was the proportion of participants with any reduction in inflammatory MRI lesions at 6 months. The primary efficacy analysis was done in the modified intention-to-treat population, which included participants who were randomly assigned and received study medication. Safety analyses were conducted in participants who received the study medication and had at least one post-baseline observation. The study was registered with the EUDRA-CT (2014-000555-93). FINDINGS: Between Nov 6, 2014, and June 15, 2021, 139 participants were screened. Of 100 participants, 50 were randomly assigned to abatacept 125 mg and 50 to placebo. Two participants (one from each group) were excluded due to administration failure or refusing treatment; thus, 98 were included in the modified intention-to-treat population. 70 (71%) of 98 participants were female and 28 (29%) of 98 were male. At 6 months, 28 (57%) of 49 participants in the abatacept group and 15 (31%) of 49 participants in the placebo group showed improvement in MRI subclinical inflammation (absolute difference 26·5%, 95% CI 5·9-45·6; p=0·014). Four (8%) of 49 participants in the abatacept group and 17 (35%) of 49 participants in the placebo group developed rheumatoid arthritis (hazard ratio [HR] 0·14 [0·04-0·47]; p=0·0016). Improvement of MRI inflammation (25 [51%] of 49 participants in the abatacept group, 12 [24%] of 49 in the placebo group; p=0·012) and progression to rheumatoid arthritis (17 [35%] of 49, 28 [57%] of 49; HR 0·14 [0·04-0·47]; p=0·018) remained significantly different between the two groups after 18 months, 12 months after the end of the intervention. There were 12 serious adverse events in 11 participants (four [8%] of 48 in the abatacept group and 7 [14%] of 49 in the placebo group). No deaths occurred during the study. INTERPRETATION: 6-month treatment with abatacept decreases MRI inflammation, clinical symptoms, and risk of rheumatoid arthritis development in participants at high risk. The effects of the intervention persist through a 1-year drug-free observation phase. FUNDING: Innovative Medicine Initiative.

Olokizumab versus Placebo or Adalimumab in Rheumatoid Arthritis.

BACKGROUND: The cytokine interleukin-6 is involved in the pathogenesis of rheumatoid arthritis. Olokizumab, a humanized monoclonal antibody targeting the interleukin-6 cytokine directly, is being tested for the treatment of rheumatoid arthritis. METHODS: In a 24-week, phase 3, multicenter, placebo- and active-controlled trial, we randomly assigned (in a 2:2:2:1 ratio) patients with rheumatoid arthritis and an inadequate response to methotrexate to receive subcutaneous olokizumab at a dose of 64 mg every 2 or 4 weeks, adalimumab (40 mg every 2 weeks), or placebo; all patients continued methotrexate therapy. The primary end point was an American College of Rheumatology 20 (ACR20) response (≥20% fewer tender and swollen joints and ≥20% improvement in three of five other domains) at week 12, with each olokizumab dose tested for superiority to placebo. We also tested the noninferiority of each olokizumab dose to adalimumab with respect to the percentage of patients with an ACR20 response (noninferiority margin, -12 percentage points in the lower boundary of the 97.5% confidence interval for the difference between groups). RESULTS: A total of 464 patients were assigned to receive olokizumab every 2 weeks, 479 to receive olokizumab every 4 weeks, 462 to receive adalimumab, and 243 to receive placebo. An ACR20 response at week 12 occurred in 44.4% of the patients receiving placebo, in 70.3% receiving olokizumab every 2 weeks (difference vs. placebo, 25.9 percentage points; 97.5% confidence interval [CI], 17.1 to 34.1), in 71.4% receiving olokizumab every 4 weeks (difference vs. placebo, 27.0 percentage points; 97.5% CI, 18.3 to 35.2), and in 66.9% receiving adalimumab (difference vs. placebo, 22.5 percentage points; 95% CI, 14.8 to 29.8) (P<0.001 for the superiority of each olokizumab dose to placebo). Both olokizumab doses were noninferior to adalimumab with respect to the percentage of patients with an ACR20 response at week 12 (difference, 3.4 percentage points [97.5% CI, -3.5 to 10.2] with olokizumab every 2 weeks and 4.5 percentage points [97.5% CI, -2.2 to 11.2] with olokizumab every 4 weeks). Adverse events, most commonly infections, occurred in approximately 70% of the patients who received olokizumab. Antibodies against olokizumab were detected in 3.8% of the patients receiving the drug every 2 weeks and in 5.1% of those receiving it every 4 weeks. CONCLUSIONS: In patients with rheumatoid arthritis who were receiving maintenance methotrexate, olokizumab was superior to placebo and noninferior to adalimumab in producing an ACR20 response at 12 weeks. Larger and longer trials are required to determine the efficacy and safety of olokizumab in patients with rheumatoid arthritis. (Supported by R-Pharm; CREDO2 ClinicalTrials.gov number, NCT02760407.).

Olokizumab plus methotrexate: safety and efficacy over 106 weeks of treatment.

OBJECTIVE: To report long-term safety and tolerability of olokizumab (OKZ) in combination with methotrexate (MTX) in subjects with active rheumatoid arthritis (RA), using pooled data from three randomised clinical trials (RCT) followed by open-label extension (OLE) study. METHODS: Cumulative data from three phase 3 core trials and their OLE were analysed. Safety variables assessed included treatment-emergent adverse events (AEs), serious AEs (SAEs), AEs of special interest and laboratory results. Efficacy assessments included ACR20/50/70 responses, Disease Activity Score 28 (C-reactive protein) <3.2, CDAI remission and low disease activity (LDA), SDAI remission and LDA, HAQ-DI decrease of 0.22 unit and Boolean 2.0 remission. RESULTS: A total of 2304 patients received OKZ in combination with MTX either once every 2 weeks or once every 4 weeks. Event rates per 100 patient-years in OKZ every 2 weeks and OKZ every 4 weeks, respectively, were 9.57 and 9.13 for SAEs; 2.95 and 2.34 for serious infections; 0.09 and 0.05 for gastrointestinal perforations; 0.58 and 0.83 for major adverse cardiovascular events; and 0.45 and 0.50 for malignancies. No increase in the rate of any AE was observed over 106 weeks of treatment. The evaluation of laboratory variables demonstrated the expected changes, like neutropenia, elevation of liver enzymes and blood lipids. Clinical response rates remained stable during the OLE. CONCLUSION: The long-term safety and tolerability of OKZ in combination with MTX remained stable. The efficacy of OKZ was maintained through week 106. These findings support OKZ as a treatment option for patients with active RA.

Systematic Review and Metaanalysis of Pharmacological Interventions in Adult-Onset Still Disease and the Role of Biologic Disease-Modifying Antirheumatic Drugs.

OBJECTIVE: To conduct a systematic review of the effectiveness and safety of pharmacological treatments for adult-onset Still disease (AOSD). METHODS: Six databases, 2 trial registries, and conference abstracts were searched from January 2012 to February 2023 for studies of pharmacological interventions in people with AOSD. Outcomes were rates of remission and response, discontinuation of concurrent treatments, complications of AOSD, and treatment-related adverse events. Risk of bias was assessed with the Cochrane risk of bias tool and the Joanna Briggs Institute tool for case series. RESULTS: Forty-four studies evaluated treatments, including nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids (CS), conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and biologic DMARDs (bDMARDs). For bDMARDs, tocilizumab (TCZ), anakinra (ANK), and canakinumab (CNK) had the most available data. Although 3 randomized controlled trials did not show statistically significant benefits of bDMARDs, metaanalyses showed high rates of complete remission and CS discontinuation. Complete remission was 80% (95% CI 59-92%, I 2 36%), 73% (95% CI 58-84%, I 2 66%), and 77% (95% CI 29-97%, I 2 82%) and CS discontinuation was 57% (95% CI 29-81%, I 2 66%), 47% (95% CI 18-78%, I 2 79%), and 34% (95% CI 6-81%, I 2 59%), respectively, for TCZ, ANK, and CNK. Studies with a higher proportion of patients previously treated with bDMARDs showed a trend toward lower rates of CS discontinuation (P = 0.05). The analyses had high clinical heterogeneity, largely because treatments were prescribed as different lines of therapy. CONCLUSION: Evidence supports TCZ, ANK, and CNK therapy for AOSD. However, the magnitude of effect and comparative effectiveness of treatments is uncertain.

[Adult-onset Still's disease : Diagnosis and treatment according to the new S2e guidelines of the German Society of Rheumatology (DGRh)]. / Adultes Still-Syndrom : Diagnostik und Therapie unter Berücksichtigung der neuen DGRh(Deutsche Gesellschaft für Rheumatologie)-S2e-Leitlinie.

Adult-onset Still's disease (AOSD) is a rare autoinflammatory disease characterized by intermittent fever and a combination of symptoms, such as an evanescent rash synchronous with fever, arthralgia/arthritis, lymphadenopathy and hepatosplenomegaly. The diagnosis is based on a characteristic constellation of symptoms and the exclusion of infections, hemato-oncological diseases, infectious diseases and alternative rheumatological causes. The systemic inflammatory reaction is reflected by high levels of ferritin and C­reactive protein (CRP). The pharmacological treatment concept includes glucocorticoids often in combination with methotrexate (MTX) and ciclosporine (CSA) for reduction of steroids. The interleukin 1 (IL-1) receptor antagonist anakinra, the IL-1beta antibody canakinumab or an IL­6 receptor blockage with tocilizumab (off label for AOSD) are used where there is no response to MTX or CSA. Anakinra or canakinumab can be used as a primary option in AOSD in cases of moderate and severe disease activity.

[General knowledge of frequently applied test procedures in rheumatological and immunological diagnostics and research]. / Allgemeine Kenntnisse zu häufig angewandten Testverfahren in der rheumatologisch-immunologischen Diagnostik und Forschung.

Knowledge of test procedures is essential for an optimal approach in rheumatological and immunological diagnostics as well as for a correct interpretation of the findings. In practice, they are a basis for the independent provision of diagnostic laboratory services. For scientific questions they have become indispensable tools in many areas. This article gives an overview on the most frequently used and important test methods in a comprehensive form. The advantages and performance of the different methods are addressed and the limitations and possible sources or error are discussed. Quality control increasingly plays a decisive role in the diagnostic and scientific practice, with the legal regulations applying to all test procedures in laboratory diagnostics. For the discipline of rheumatology, the rheumatological and immunological diagnostics are of particular importance as the majority of the known disease-specific markers are detectable by means of these procedures. At the same time, immunological laboratory diagnostics are a highly interesting field of activity which are expected to have a strong impact on the future developments in rheumatology.

[Autoinflammatory syndromes]. / Autoinflammatorische Syndrome.

The concept of autoinflammation includes a heterogeneous group of monogenic and polygenic diseases. These are characterized by excessive activation of the innate immune system without antigen-specific T cells or autoantibodies. The diseases are characterized by periodic episodes of fever and increased inflammation parameters. Monogenic diseases include familial Mediterranean fever (FMF) and the newly described VEXAS (vacuoles, E1 enzyme, X­linked, autoinflammatory, somatic) syndrome. Heterogeneous diseases include adult-onset Still's disease and Schnitzler syndrome. Treatment is aimed at preventing the excessive inflammatory reaction in order to avoid long-term damage, such as amyloid A (AA) amyloidosis.

Olokizumab, a monoclonal antibody against interleukin-6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by tumour necrosis factor inhibitor therapy: efficacy and safety results of a randomised controlled phase III study.

OBJECTIVES: To assess the efficacy and safety of olokizumab (OKZ), a monoclonal antibody against the interleukin-6 (IL-6) cytokine, versus placebo (PBO) in patients with prior inadequate response to tumour necrosis factor inhibitors (TNFi-IRs). METHODS: In this 24-week multicentre, placebo-controlled, double-blind study, the patients were randomised in a 2:2:1 ratio to receive subcutaneously administered OKZ 64 mg once every 2 weeks (q2w), OKZ 64 mg once every 4 weeks (q4w) or PBO plus methotrexate. At week 16, the patients on PBO were randomised to receive either OKZ regime. The primary endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at week 12. Disease Activity Score 28-joint count C-reactive protein (DAS28 (CRP))<3.2 at week 12 was the major secondary efficacy endpoint. Safety and immunogenicity were assessed. RESULTS: In 368 patients randomised, ACR20 response rates were 60.9% in OKZ q2w, 59.6% in OKZ q4w and 40.6% in PBO (p<0.01 for both comparisons). Achievement of DAS28 (CRP) <3.2 was significantly different, favouring the OKZ arms. Improvements in efficacy and patient-reported outcomes were maintained throughout 24 weeks and were noted after week 16 in patients who switched from PBO.Dose-related treatment-emergent serious adverse events were 7% in OKZ q2w, 3.2% in OKZ q4w and none in the PBO group. CONCLUSIONS: Direct inhibition of IL-6 with OKZ resulted in significant improvements in the signs and symptoms of rheumatoid arthritis compared with PBO in TNF-IR patients with a similar safety profile as observed for monoclonal antibodies to the IL-6 receptor. TRIAL REGISTRATION NUMBER: NCT02760433.

Olokizumab, a monoclonal antibody against interleukin 6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by methotrexate: efficacy and safety results of a randomised controlled phase III study.

OBJECTIVE: To evaluate the efficacy and safety of olokizumab (OKZ) in patients with active rheumatoid arthritis despite treatment with methotrexate (MTX). METHODS: In this 24-week multicentre, placebo-controlled, double-blind study, patients were randomised 1:1:1 to receive subcutaneously administered OKZ 64 mg once every 2 weeks, OKZ 64 mg once every 4 weeks, or placebo plus MTX. The primary efficacy endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at week 12. The secondary efficacy endpoints included percentage of subjects achieving Disease Activity Score 28-joint count based on C reactive protein <3.2, Health Assessment Questionnaire Disability Index at week 12, ACR50 response and Clinical Disease Activity Index ≤2.8 at week 24. Safety and immunogenicity were assessed throughout the study. RESULTS: A total of 428 patients were randomised. ACR20 responses were more frequent with OKZ every 2 weeks (63.6%) and OKZ every 4 weeks (70.4%) than placebo (25.9%) (p<0.0001 for both comparisons). There were significant differences in all secondary efficacy endpoints between OKZ-treated arms and placebo. Treatment-emergent serious adverse events (TESAEs) were reported by more patients in the OKZ groups compared with placebo. Infections were the most common TESAEs. No subjects developed neutralising antidrug antibodies. CONCLUSIONS: Treatment with OKZ was associated with significant improvement in signs, symptoms and physical function of rheumatoid arthritis without discernible differences between the two regimens. Safety was as expected for this class of agents. Low immunogenicity was observed. Trial registration number NCT02760368.

Skeletal muscle provides the immunological micro-milieu for specific plasma cells in anti-synthetase syndrome-associated myositis.

Anti-synthetase syndrome (ASyS)-associated myositis is a major subgroup of the idiopathic inflammatory myopathies (IIM) and is characterized by disease chronicity with musculoskeletal, dermatological and pulmonary manifestations. One of eight autoantibodies against the aminoacyl-transferase RNA synthetases (ARS) is detectable in the serum of affected patients. However, disease-specific therapeutic approaches have not yet been established.To obtain a deeper understanding of the underlying pathogenesis and to identify putative therapeutic targets, we comparatively investigated the most common forms of ASyS associated with anti-PL-7, anti-PL-12 and anti-Jo-1. Our cohort consisted of 80 ASyS patients as well as healthy controls (n = 40), diseased controls (n = 40) and non-diseased controls (n = 20). We detected a reduced extent of necrosis and regeneration in muscle biopsies from PL-12+ patients compared to Jo-1+ patients, while PL-7+ patients had higher capillary dropout in biopsies of skeletal muscle. Aside from these subtle alterations, no significant differences between ASyS subgroups were observed. Interestingly, a tissue-specific subpopulation of CD138+ plasma cells and CXCL12+/CXCL13+CD20+ B cells common to ASyS myositis were identified. These cells were localized in the endomysium associated with alkaline phosphatase+ activated mesenchymal fibroblasts and CD68+MHC-II+CD169+ macrophages. An MHC-I+ and MHC-II+ MxA negative type II interferon-driven milieu of myofiber activation, topographically restricted to the perifascicular area and the adjacent perimysium, as well as perimysial clusters of T follicular helper cells defined an extra-medullary immunological niche for plasma cells and activated B cells. Consistent with this, proteomic analyses of muscle tissues from ASyS patients demonstrated alterations in antigen processing and presentation. In-depth immunological analyses of peripheral blood supported a B-cell/plasma-cell-driven pathology with a shift towards immature B cells, an increase of B-cell-related cytokines and chemokines, and activation of the complement system. We hypothesize that a B-cell-driven pathology with the presence and persistence of a specific subtype of plasma cells in the skeletal muscle is crucially involved in the self-perpetuating chronicity of ASyS myositis. This work provides the conceptual framework for the application of plasma-cell-targeting therapies in ASyS myositis.

A retrospective analysis of colchicine in combination with NSAIDs therapy in patients with systemic form of adult-onset Still's disease with serositis.

OBJECTIVES: Adult-onset Still's disease (AOSD) is increasingly viewed as autoinflammatory disease associated with the so-called inflammasomopathy. Proinflammatory cytokines, such as IL-18 and IL-1ß, processed through the inflammasome machinery, play an important role in the pathogenesis of AOSD. AOSD is heterogenous, therefore there are two subtypes of the disease, systemic and articular, which probably imply different approaches for the treatment. Over 20% of patients with systemic AOSD have serositis. Recently, colchicine in combination with non-steroidal anti-inflammatory drugs (NSAIDs) has become the "gold standard" for recurrent pericarditis treatment. However, data on this combination therapy in AOSD are scarce. METHODS: In this retrospective case series study, we assessed the medical history of 20 patients with a systemic form of AOSD. All patients had pericarditis and received а combination of NSAIDs (in most cases ibuprofen 600-800 mg x3 daily) and colchicine (1 mg daily) for treatment. RESULTS: 13/20 (65%) of patients responded to this combination of anti-inflammatory drugs. Of note, not only pericarditis, but also other manifestations were improved such as arthritis, rash, hepatomegaly, acute phase reactants, and abnormal liver tests. CONCLUSIONS: The low cost, safety and wide availability of such therapy make this option relevant and determine the need for further study.

[Myositis]. / Myositis.

The S2e guidelines on myositis were completely updated and revised under the leadership of the German Society for Neurology and the participation of many other specialist societies. Immune-mediated necrotizing myopathy and antisynthetase syndrome are now regarded as independent entities in the classification of myositis. With respect to the diagnostics, the guidelines provide concrete recommendations on dysphagia screening, especially for inclusion body myositis and for cancer diagnostics in certain forms of myositis. Following the positive ProDERM study, the use of intravenous immunoglobulins (Octagam®) is available for treatment as an approved substance. Based on the INBUILD study, antifibrotic treatment with nintedanib is available for progressive fibrosing pulmonary involvement. For rheumatologists, the updated guidelines represent a document relevant for daily practice with many recommendations for the treatment of patients with myositis.

[Polyarticular juvenile idiopathic arthritis and rheumatoid arthritis : Common features and differences]. / Polyartikuläre juvenile idiopathische Arthritis und rheumatoide Arthritis : Gemeinsamkeiten und Unterschiede.

The spectrum of polyarthritic diseases in childhood as well as in adulthood is wide. In the differential diagnostics different age-related diseases must be taken into consideration. Although, a clear similarity is obvious in all age groups for the classical diseases of polyarticular juvenile idiopathic arthritis and rheumatoid arthritis with respect to the pathogenesis, clinical manifestation and treatment options, this review points to specific differences. The prognosis of polyarthritis in children mainly depends on the joint manifestation, whereas extra-articular comorbidities play a predominant role in the older adult population.

Unique autoantibody prevalence in long-term recovered SARS-CoV-2-infected individuals.

The variability in resolution of SARS-CoV-2-infections between individuals neither is comprehended, nor are the long-term immunological consequences. To assess the long-term impact of a SARS-CoV-2-infection on the immune system, we conducted a prospective study of 80 acute and former SARS-CoV-2 infected individuals and 39 unexposed donors to evaluate autoantibody responses and immune composition. Autoantibody levels against cyclic citrullinated peptide (CCP), a specific predictor for rheumatoid arthritis (RA), were significantly (p = 0.035) elevated in convalescents only, whereas both acute COVID-19 patients and long-term convalescents showed critically increased levels of anti-tissue transglutaminase (TG), a specific predictor of celiac disease (CD) (p = 0.002). Both, anti-CCP and anti-TG antibody levels were still detectable after 4-8 months post infection. Anti-TG antibodies occurred predominantly in aged patients in a context of a post-SARS-CoV-2-specific immune composition (R2 = 0.31; p = 0.044). This study shows that increased anti-CCP and anti-TG autoantibody levels can remain long-term after recovering even from mildly experienced COVID-19. The inter-relationship of the lung as viral entry side and RA- and CD-associated autoimmunity indicates that a SARS-CoV-2-infection could be a relevant environmental factor in their pathogenesis.

Early phase studies of JAK1 selective inhibitors in rheumatoid arthritis.

The first approved Janus kinase (JAK) inhibitors for treatment of RA targeted more than one JAK molecule. Although this brings an advantage of simultaneous blocking of more cytokines involved in RA, it may also carry an increased risk of toxicity. Subsequently, more selective JAK inhibitors were developed with the aim of improving the safety-efficacy profile and to further increase drug maintenance. With this proposal, early phase trials of selective JAK1 inhibitors, namely upadacitinib, filgotinib and itacitinib, were initiated in recent years to identify the efficacy and adverse effects of these agents and to define their potential role in treatment of inflammatory and autoimmune diseases. Early phase (Phase I-II) studies of upadacitinib and filgotinib provided evidence for efficacy and safety of the selective JAK1 inhibitors in refractory populations of RA patients and allowed informed selection of the appropriate dose by balancing the optimal benefit-risk profile for further evaluation in the later successfully performed Phase III trials. Although itacitinib also demonstrated a good efficacy and safety in a Phase II trial in RA patients, it is mainly in development for haematologic and oncologic conditions.

Peripheral blood mononuclear cells are hypomethylated in active rheumatoid arthritis and methylation correlates with disease activity.

OBJECTIVE: Epigenetic modifications are dynamic and influence cellular disease activity. The aim of this study was to investigate global DNA methylation in peripheral blood mononuclear cells (PBMCs) of RA patients to clarify whether global DNA methylation pattern testing might be useful in monitoring disease activity as well as the response to therapeutics. METHODS: Flow cytometric measurement of 5-methyl-cytosine (5'-mC) was established using the cell line U937. In the subsequent prospective study, 62 blood samples were investigated, including 17 healthy donors and 45 RA patients at baseline and after 3 months of treatment with methotrexate, the IL-6 receptor inhibitor sarilumab, and Janus kinase inhibitors. Methylation status was assessed with an anti-5'-mC antibody and analysed in PBMCs and CD4+, CD8+, CD14+ and CD19+ subsets. Signal intensities of 5'-mC were correlated with 28-joint DASs with ESR and CRP (DAS28-ESR and DAS28-CRP). RESULTS: Compared with healthy individuals, PBMCs of RA patients showed a significant global DNA hypomethylation. Signal intensities of 5'-mC correlated with transcription levels of DNMT1, DNMT3B and MTR genes involved in methylation processes. Using flow cytometry, significant good correlations and linear regression values were achieved in RA patients between global methylation levels and DAS28-ESR values for PBMCs (r = -0.55, P = 0.002), lymphocytes (r = -0.57, P = 0.001), CD4+ (r = -0.57, P = 0.001), CD8+ (r = -0.54, P = 0.001), CD14+ (r = -0.49, P = 0.008) and CD19+ (r = -0.52, P = 0.004) cells. CONCLUSIONS: The degree of global DNA methylation was found to be associated with disease activity. Based on this novel approach, the degree of global methylation is a promising biomarker for therapy monitoring and the prediction of therapy outcome in inflammatory diseases.

Rituximab plus leflunomide in rheumatoid arthritis: a randomized, placebo-controlled, investigator-initiated clinical trial (AMARA study).

OBJECTIVE: To investigate the efficacy and safety of rituximab + LEF in patients with RA. METHODS: In this investigator-initiated, randomized, double-blind, placebo-controlled phase 3 trial, patients with an inadequate response to LEF who had failed one or more DMARD were randomly assigned 2:1 to i.v. rituximab 1000 mg or placebo on day 1 and 15 plus ongoing oral LEF. The primary efficacy outcome was the difference between ≥50% improvement in ACR criteria (ACR50 response) rates at week 24 (P ≤ 0.025). Secondary endpoints included ACR20/70 responses, ACR50 responses at earlier timepoints and adverse event (AE) rates. The planned sample size was not achieved due to events beyond the investigators' control. RESULTS: Between 13 August 2010 and 28 January 2015, 140 patients received rituximab (n = 93) or placebo (n = 47) plus ongoing LEF. Rituximab + LEF resulted in an increase in the ACR50 response rate that was significant at week 16 (32 vs 15%; P = 0.020), but not week 24 (27 vs 15%; P = 0.081), the primary endpoint. Significant differences favouring the rituximab + LEF arm were observed in some secondary endpoints, including ACR20 rates from weeks 12 to 24. The rituximab and placebo arms had similar AE rates (71 vs 70%), but the rituximab arm had a higher rate of serious AEs (SAEs 20 vs 2%), primarily infections and musculoskeletal disorders. CONCLUSION: The primary endpoint was not reached, but rituximab + LEF demonstrated clinical benefits vs LEF in secondary endpoints. Although generally well tolerated, the combination was associated with additional SAEs and requires monitoring. TRIAL REGISTRATION: EudraCT: 2009-015950-39; ClinicalTrials.gov: NCT01244958.

Tocilizumab-associated posterior reversible encephalopathy syndrome in giant-cell arteritis - case report.

BACKROUND: We describe one of the first cases of a Posterior reversible encephalopathy syndrome (PRES) under tocilizumab as treatment of Giant cell arteritis (GCA). CASE PRESENTATION: A 65-year-old female with known GCA and treatment with Tocilizumab (TCZ) developed a convulsive epileptic seizure for the first time. MRI was suggestive of PRES and an associated left sided occipital hemorrhage. Extensive high blood pressure values were not detected. The patient recovered within a week and no further seizures occurred under anticonvulsive medication. CONCLUSION: PRES during the treatment with Tocilizumab hasn't been described in GCA so far. There are single reports of an association between TCZ and PRES in other entities. Thus, a link between interleukin-6 and the integrity of the vasculature could be considered. The clinical consequence should be a stringent blood pressure monitoring in the ambulant setting of patients receiving TCZ.

[Care atlas rheumatology : Approaches and concepts for improving care in outpatient rheumatology]. / Versorgungsatlas Rheumatologie : Ansätze und Konzepte zur Verbesserung der Versorgung in der ambulanten Rheumatologie.

Inflammatory rheumatic diseases affect 1.5 million adults and an estimated 20,000 children and adolescents throughout Germany. The successful treatment of these patients is largely based on the availability of high-quality medical care. To be able to provide sufficient care and prevent long waiting times even though the number of rheumatologists is below demand, efficient practice structures and approaches that go beyond standard care play an important role. The present study takes a look at the current state of rheumatological outpatient care as well as innovative care initiatives to support the service provision structures and to improve the care situation in rheumatology and points out: to ensure guideline-based care despite scarce resources, selective contracts, integrated outpatient specialist care (ASV), early or emergency consultation hours, disease management programs (DMP) and appropriate delegation of medical services play an important role. New care concepts increasingly focus on interdisciplinary cooperation (DMP and ASV), strengthened self-management through structured patient training (DMP) and targeted patient management through screening tools. To ensure an up to date and high-quality treatment in the long term, an increase in further training in rheumatology is necessary. This should be achieved by attracting more students and, if necessary, adjusting the training system.

[What is confirmed in the treatment of autoinflammatory fever diseases?] / Was ist gesichert in der Therapie von autoinflammatorischen Fiebererkrankungen?

In the last 20 years the clarification of monogenic periodic febrile diseases has led to the independent concept of autoinflammation. In this heterogeneous group polygenic complex diseases are also now included. The spectrum of symptoms is continuously growing. The main difference to autoimmunity is an excessive activation of the innate immune system without formation of autoantibodies or antigen-specific T­cells. The cardinal symptom is recurrent fever episodes accompanied by signs of inflammation, which in the periodic manifestations alternate with intervals of general well-being. The classical monogenic diseases are also known as hereditary recurrent fever (HRF). Examples are familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor receptor 1­associated periodic syndrome (TRAPS), adenosine deaminase 2 (ADA2) deficiency and mevalonate kinase deficiency (MKD, hyper-IgD syndrome). The polygenic diseases are also known as nonhereditary fever syndromes. These include adult-onset Still's disease (AoSD), Adamantiades-Behçet disease, the PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) and gouty arthritis. All autoinflammatory fever syndromes are accompanied by a long-term risk of development of amyloid A amyloidosis, depending on the individual severity and treatment success. In some diseases severe complications can sometimes occur.