Publications by authors named "Gerd R Burmester"

242 Publications

Long-term safety and efficacy of sarilumab over 5 years in patients with rheumatoid arthritis refractory to TNF inhibitors.

Rheumatology (Oxford) 2021 Apr 19. Epub 2021 Apr 19.

Department of Rheumatology and Clinical Immunology, Charité - University Medicine Berlin, Berlin, Germany.

Objective: To evaluate long-term safety and efficacy of sarilumab over 5 years in patients with RA refractory to TNF inhibitors (TNFi).

Methods: Patients in the 24-week randomized controlled trial (RCT) TARGET (NCT01709578) whoreceived double-blind placebo or sarilumab 150 or 200 mg every 2 weeks (q2w), plus conventionalsynthetic DMARDs (csDMARDs), were eligible to receive open-label sarilumab 200 mg q2w pluscsDMARDs in the open-label extension (OLE), EXTEND (NCT01146652). OLE dose reduction to 150 mg q2w was permitted per investigators' judgement or protocol-mandated safety concerns. Safety and efficacy were assessed through treatment-emergent adverse events (AEs), laboratoryabnormalities and clinical disease activity scores. All statistics are descriptive.

Results: Of 546 patients, 454 (83%) were treated with sarilumab in the OLE. Cumulative observation period was 1654.8 patient-years (PY; n = 521); 268 patients (51%) had ≥4 years' exposure. Incidencerates per 100 PY of AEs, AEs leading to discontinuation, infection and serious infection were 160.4, 8.1, 57.8 and 3.9, respectively. Neutropenia was the most common AE (15.3 per 100 PY). Absoluteneutrophil count <1000 cells/mm3 (Grade 3/4 neutropenia) was observed in 74 patients (14.2%) and normalized on treatment in 48. Clinical efficacy was sustained through 5 years' follow-up. Efficacy was similar for patients with 1 and >1 TNFi failure, and between patients who either remained on 200mg or reduced to 150 mg.

Conclusion: In patients with RA refractory to TNFi, sarilumab's long-term term safety profile was consistent with previous clinical studies and post-marketing reports. Efficacy was sustained over 5years.
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http://dx.doi.org/10.1093/rheumatology/keab355DOI Listing
April 2021

Systemic sclerosis-associated myositis features minimal inflammation and characteristic capillary pathology.

Acta Neuropathol 2021 Jun 17;141(6):917-927. Epub 2021 Apr 17.

Department of Neuropathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Charitéplatz 1, 10117, Berlin, Germany.

Systemic sclerosis represents a chronic connective tissue disease featuring fibrosis, vasculopathy and autoimmunity, affecting skin, multiple internal organs, and skeletal muscles. The vasculopathy is considered obliterative, but its pathogenesis is still poorly understood. This may partially be due to limitations of conventional transmission electron microscopy previously being conducted only in single patients. The aim of our study was therefore to precisely characterize immune inflammatory features and capillary morphology of systemic sclerosis patients suffering from muscle weakness. In this study, we identified 18 individuals who underwent muscle biopsy because of muscle weakness and myalgia in a cohort of 367 systemic sclerosis patients. We performed detailed conventional and immunohistochemical analysis and large-scale electron microscopy by digitizing entire sections for in-depth ultrastructural analysis. Muscle biopsies of 12 of these 18 patients (67%) presented minimal features of myositis but clear capillary alteration, which we termed minimal myositis with capillary pathology (MMCP). Our study provides novel findings in systemic sclerosis-associated myositis. First, we identified a characteristic and specific morphological pattern termed MMCP in 67% of the cases, while the other 33% feature alterations characteristic of other overlap syndromes. This is also reflected by a relatively homogeneous clinical picture among MMCP patients. They have milder disease with little muscle weakness and a low prevalence of interstitial lung disease (20%) and diffuse skin involvement (10%) and no cases of either pulmonary arterial hypertension or renal crisis. Second, large-scale electron microscopy, introducing a new level of precision in ultrastructural analysis, revealed a characteristic capillary morphology with basement membrane thickening and reduplications, endothelial activation and pericyte proliferation. We provide open-access pan-and-zoom analysis to our datasets, enabling critical discussion and data mining. We clearly highlight characteristic capillary pathology in skeletal muscles of systemic sclerosis patients.
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http://dx.doi.org/10.1007/s00401-021-02305-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113184PMC
June 2021

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

Rheumatology (Oxford) 2021 Mar 19. Epub 2021 Mar 19.

Division of Rheumatology, University Hospital Frankfurt, Goethe University.

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.
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http://dx.doi.org/10.1093/rheumatology/keab153DOI Listing
March 2021

EULAR points to consider on pathophysiology and use of immunomodulatory therapies in COVID-19.

Ann Rheum Dis 2021 Feb 5. Epub 2021 Feb 5.

Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, INSERM UMR1184, Department of Rheumatology, Université Paris-Saclay, Le Kremlin Bicêtre, France

Objectives: Severe systemic inflammation associated with some stages of COVID-19 and in fatal cases led therapeutic agents developed or used frequently in Rheumatology being at the vanguard of experimental therapeutics strategies. The aim of this project was to elaborate EULAR Points to consider (PtCs) on COVID-19 pathophysiology and immunomodulatory therapies.

Methods: PtCs were developed in accordance with EULAR standard operating procedures for endorsed recommendations, led by an international multidisciplinary Task Force, including rheumatologists, translational immunologists, haematologists, paediatricians, patients and health professionals, based on a systemic literature review up to 15 December 2020. Overarching principles (OPs) and PtCs were formulated and consolidated by formal voting.

Results: Two OPs and fourteen PtCs were developed. OPs highlight the heterogeneous clinical spectrum of SARS-CoV-2 infection and the need of a multifaceted approach to target the different pathophysiological mechanisms. PtCs 1-6 encompass the pathophysiology of SARS-CoV-2 including immune response, endothelial dysfunction and biomarkers. PtCs 7-14 focus on the management of SARS-CoV-2 infection with immunomodulators. There was evidence supporting the use of glucocorticoids, especially dexamethasone, in COVID-19 cases requiring oxygen therapy. No other immunomodulator demonstrated efficacy on mortality to date, with however inconsistent results for tocilizumab. Immunomodulatory therapy was not associated with higher infection rates.

Conclusions: Multifactorial pathophysiological mechanisms, including immune abnormalities, play a key role in COVID-19. The efficacy of glucocorticoids in cases requiring oxygen therapy suggests that immunomodulatory treatment might be effective in COVID-19 subsets. Involvement of rheumatologists, as systemic inflammatory diseases experts, should continue in ongoing clinical trials delineating optimal immunomodulatory therapy utilisation in COVID-19.
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http://dx.doi.org/10.1136/annrheumdis-2020-219724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871226PMC
February 2021

Filgotinib in combination with methotrexate or as monotherapy versus methotrexate monotherapy in patients with active rheumatoid arthritis and limited or no prior exposure to methotrexate: the phase 3, randomised controlled FINCH 3 trial.

Ann Rheum Dis 2021 Jan 15. Epub 2021 Jan 15.

Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany.

Objectives: To investigate efficacy and safety of the Janus kinase-1 inhibitor filgotinib in patients with active rheumatoid arthritis (RA) with limited or no prior methotrexate (MTX) exposure.

Methods: This 52-week, phase 3, multicentre, double-blind clinical trial (NCT02886728) evaluated once-daily oral filgotinib in 1252 patients with RA randomised 2:1:1:2 to filgotinib 200 mg with MTX (FIL200 +MTX), filgotinib 100 mg with MTX (FIL100 +MTX), filgotinib 200 mg monotherapy (FIL200), or MTX. The primary endpoint was proportion achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 24.

Results: The primary endpoint was achieved by 81% of patients receiving FIL200+ MTX versus 71% receiving MTX (p<0.001). A significantly greater proportion treated with FIL100+ MTX compared with MTX achieved an ACR20 response (80%, p=0.017) at week 24. Significant improvement in Health Assessment Questionnaire-Disability Index was seen at week 24; least-squares mean change from baseline was -1.0 and -0.94 with FIL200+MTX and FIL100+MTX, respectively, versus -0.81 with MTX (p<0.001, p=0.008, respectively). Significantly higher proportions receiving FIL200+MTX (54%) and FIL100+MTX (43%) achieved DAS28(CRP) <2.6 versus MTX (29%) (p<0.001 for both) at week 24. Hierarchical testing stopped for comparison of ACR20 for FIL200 monotherapy (78%) versus MTX (71%) at week 24 (p=0.058). Adverse event rates through week 52 were comparable between all treatments.

Conclusions: FIL200+MTX and FIL100+MTX both significantly improved signs and symptoms and physical function in patients with active RA and limited or no prior MTX exposure; FIL200 monotherapy did not have a superior ACR20 response rate versus MTX. Filgotinib was well tolerated, with acceptable safety compared with MTX.
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http://dx.doi.org/10.1136/annrheumdis-2020-219213DOI Listing
January 2021

The impact of COVID-19 on rare and complex connective tissue diseases: the experience of ERN ReCONNET.

Nat Rev Rheumatol 2021 03 6;17(3):177-184. Epub 2021 Jan 6.

Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

During the COVID-19 pandemic, the need to provide high-level care for a large number of patients with COVID-19 has affected resourcing for, and limited the routine care of, all other conditions. The impact of this health emergency is particularly relevant in the rare connective tissue diseases (rCTDs) communities, as discussed in this Perspective article by the multi-stakeholder European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ERN ReCONNET). The clinical, organizational and health economic challenges faced by health-care providers, institutions, patients and their families during the SARS-CoV-2 outbreak have demonstrated the importance of ensuring continuity of care in the management of rCTDs, including adequate diagnostics and monitoring protocols, and highlighted the need for a structured emergency strategy. The vulnerability of patients with rCTDs needs to be taken into account when planning future health policies, in preparation for not only the post-COVID era, but also any possible new health emergencies.
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http://dx.doi.org/10.1038/s41584-020-00565-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786339PMC
March 2021

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

Rheumatology (Oxford) 2021 Apr;60(4):1984-1995

Division of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Institute of Health, Freie Universität and Humboldt-Universität, Berlin, Germany.

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.
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http://dx.doi.org/10.1093/rheumatology/keaa649DOI Listing
April 2021

Publishing in 2@84.

Ann Rheum Dis 2021 01 11;80(1):11-13. Epub 2020 Nov 11.

Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany.

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http://dx.doi.org/10.1136/annrheumdis-2020-219135DOI Listing
January 2021

Johann Lucas Schoenlein (1793-1864): impact without publications.

Ann Rheum Dis 2021 02 2;80(2):140-142. Epub 2020 Nov 2.

Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany.

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http://dx.doi.org/10.1136/annrheumdis-2020-219205DOI Listing
February 2021

Safety profile of upadacitinib in rheumatoid arthritis: integrated analysis from the SELECT phase III clinical programme.

Ann Rheum Dis 2020 Oct 28. Epub 2020 Oct 28.

Charité Universitätsmedizin Berlin, Berlin, Germany.

Objectives: This integrated analysis presents the safety profile of upadacitinib, a Janus kinase inhibitor, at 15 mg and 30 mg once daily in patients with moderately to severely active rheumatoid arthritis (RA).

Methods: Treatment-emergent adverse events (TEAEs) and laboratory data from five randomised, placebo- or active-controlled phase III trials of upadacitinib for patients with RA were analysed and summarised. Exposure-adjusted event rates are shown for placebo (three trials; 12/14 weeks), methotrexate (two trials; mean exposure: 36 weeks), adalimumab (one trial; mean exposure: 42 weeks), upadacitinib 15 mg (five trials; mean exposure: 53 weeks) and upadacitinib 30 mg (four trials; mean exposure: 59 weeks).

Results: 3834 patients received one or more doses of upadacitinib 15 mg (n=2630) or 30 mg (n=1204), for a total of 4020.1 patient-years of exposure. Upper respiratory tract infection, nasopharyngitis and urinary tract infection were the most commonly reported TEAEs with upadacitinib. Rates of serious infection were similar between upadacitinib 15 mg and adalimumab but higher compared with methotrexate. Rates of herpes zoster and creatine phosphokinase (CPK) elevations were higher in both upadacitinib groups versus methotrexate and adalimumab, and rates of gastrointestinal perforations were higher with upadacitinib 30 mg. Rates of deaths, malignancies, adjudicated major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs) were similar across treatment groups.

Conclusion: In the phase III clinical programme for RA, patients receiving upadacitinib had an increased risk of herpes zoster and CPK elevation versus adalimumab. Rates of malignancies, MACEs and VTEs were similar among patients receiving upadacitinib, methotrexate or adalimumab.

Trial Registration Numbers: SELECT-EARLY: NCT02706873; SELECT-NEXT: NCT02675426; SELECT-COMPARE: NCT02629159; SELECT-MONOTHERAPY: NCT02706951; SELECT-BEYOND: NCT02706847.
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http://dx.doi.org/10.1136/annrheumdis-2020-218510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892382PMC
October 2020

Trajectories of COVID-19 information in the Annals of the Rheumatic Diseases: the first months of the pandemic.

Ann Rheum Dis 2021 01 14;80(1):26-30. Epub 2020 Oct 14.

Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Freie Universitität und Humboldt-University Berlin, Berlin, Germany.

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http://dx.doi.org/10.1136/annrheumdis-2020-219217DOI Listing
January 2021

PRIME Cells Predicting Rheumatoid Arthritis Flares.

N Engl J Med 2020 10;383(16):1595

Charité-Universitätsmedizin Berlin, Berlin, Germany

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http://dx.doi.org/10.1056/NEJMc2027492DOI Listing
October 2020

Interleukin-6 receptor blockade or TNFα inhibition for reducing glycaemia in patients with RA and diabetes: post hoc analyses of three randomised, controlled trials.

Arthritis Res Ther 2020 09 9;22(1):206. Epub 2020 Sep 9.

Metroplex Clinical Research Center and University of Texas Southwestern Medical Center, Dallas, TX, USA.

Background: Diabetes is common in patients with rheumatoid arthritis (RA). Interleukin (IL)-6 is implicated in both the pathogenesis of RA and in glucose homeostasis; this post hoc analysis investigated the effects of IL-6 receptor vs. tumour necrosis factor inhibition on glycosylated haemoglobin (HbA1c) in patients with RA with or without diabetes.

Methods: Data were from two placebo-controlled phase III studies of subcutaneous sarilumab 150/200 mg q2w + methotrexate or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and a phase III monotherapy study of sarilumab 200 mg q2w vs. adalimumab 40 mg q2w. Patients with diabetes were identified by medical history or use of antidiabetic medication (patients with HbA1c ≥ 9% were excluded from all three studies). HbA1c was measured at baseline and weeks 12/24. Safety and efficacy were assessed in RA patients with or without diabetes.

Results: Patients with diabetes (n = 184) were older, weighed more and exhibited higher RA disease activity than patients without diabetes (n = 1928). Regardless of diabetes status, in patients on background csDMARDs, least squares (LS) mean difference (95% CI) in change from baseline in HbA1c for sarilumab 150 mg/200 mg vs. placebo at week 24 was - 0.28 (- 0.40, - 0.16; nominal p <  0.0001) and - 0.42 (- 0.54, - 0.31; nominal p <  0.0001), respectively. Without csDMARDs, LS mean difference for sarilumab 200 mg vs. adalimumab 40 mg at week 24 was - 0.13 (- 0.22, - 0.04; nominal p = 0.0043). Greater reduction in HbA1c than placebo or adalimumab was observed at week 24 with sarilumab in patients with diabetes and/or baseline HbA1c ≥ 7%. There was no correlation between baseline/change from baseline in HbA1c and baseline/change from baseline in C-reactive protein, 28-joint Disease Activity Score, or haemoglobin, nor between HbA1c change from baseline and baseline glucocorticoid use. Medical history of diabetes or use of diabetes treatments had limited impact on safety and efficacy of sarilumab and was consistent with overall phase III findings in patients with RA.

Conclusions: In post hoc analyses, sarilumab was associated with a greater reduction in HbA1c than csDMARDs or adalimumab, independent of sarilumab anti-inflammatory effects. Prospective studies are required to further assess these preliminary findings.

Trial Registration: ClinTrials.gov NCT01061736: date of registration February 03, 2010; ClinTrials.gov NCT01709578: date of registration October 18, 2012; ClinTrials.gov NCT02332590: date of registration January 07, 2015.
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http://dx.doi.org/10.1186/s13075-020-02229-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488252PMC
September 2020

Continuing versus tapering glucocorticoids after achievement of low disease activity or remission in rheumatoid arthritis (SEMIRA): a double-blind, multicentre, randomised controlled trial.

Lancet 2020 07;396(10246):267-276

Pharmaceuticals Division, F Hoffmann-La Roche, Basel, Switzerland.

Background: Patients with inflammatory diseases, such as rheumatoid arthritis, often receive glucocorticoids, but long-term use can produce adverse effects. Evidence from randomised controlled trials to guide tapering of oral glucocorticoids is scarce. We investigated a scheme for tapering oral glucocorticoids compared with continuing low-dose oral glucocorticoids in patients with rheumatoid arthritis.

Methods: The Steroid EliMination In Rheumatoid Arthritis (SEMIRA) trial was a double-blind, multicentre, two parallel-arm, randomised controlled trial done at 39 centres from six countries (France, Germany, Italy, Russia, Serbia, and Tunisia). Adult patients with rheumatoid arthritis receiving tocilizumab and glucocorticoids 5-15 mg per day for 24 weeks or more were eligible for inclusion if they had received prednisone 5 mg per day for 4 weeks or more and had stable low disease activaity, confirmed by a Disease Activity Score for 28 joints-erythrocyte sedimentation rate (DAS28-ESR) of 3·2 or less 4-6 weeks before and on the day of randomisation. Patients were randomly assigned 1:1 to either continue masked prednisone 5 mg per day for 24 weeks or to taper masked prednisone reaching 0 mg per day at week 16. All patients received tocilizumab (162 mg subcutaneously every week or 8 mg/kg intravenously every 4 weeks) with or without csDMARDs maintained at stable doses during the entire 24-week study. The primary outcome was the difference in mean DAS28-ESR change from baseline to week 24, with a difference of more than 0·6 defined as clinically relevant between the continued-prednisone group and the tapered-prednisone group. The trial is registered with ClinicalTrials.gov, NCT02573012.

Findings: Between Oct 21, 2015, and June 9, 2017, 421 patients were screened and 259 (200 [77%] women and 59 [23%] men) were recruited onto the trial. In all 128 patients assigned to the continued-prednisone regimen, disease activity control was superior to that in all 131 patients assigned to the tapered-prednisone regimen; the estimated mean change in DAS28-ESR from baseline to week 24 was 0·54 (95% CI 0·35-0·73) with tapered prednisone and -0·08 (-0·27 to 0·12) with continued prednisone (difference 0·61 [0·35-0·88]; p<0·0001), favouring continuing prednisone 5 mg per day for 24 weeks. Treatment was regarded as successful (defined as low disease activity at week 24, plus absence of rheumatoid arthritis flare for 24 weeks and no confirmed adrenal insufficiency) in 99 (77%) patients in the continued-prednisone group versus 85 (65%) patients in the tapered-prednisone group (relative risk 0·83; 95% CI 0·71-0·97). Serious adverse events occurred in seven (5%) patients in the tapered-prednisone group and four (3%) patients in the continued-prednisone group; no patients had symptomatic adrenal insufficiency.

Interpretation: In patients who achieved low disease activity with tocilizumab and at least 24 weeks of glucocorticoid treatment, continuing glucocorticoids at 5 mg per day for 24 weeks provided safe and better disease control than tapering glucocorticoids, although two-thirds of patients were able to safely taper their glucocorticoid dose.

Funding: F Hoffmann-La Roche.
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http://dx.doi.org/10.1016/S0140-6736(20)30636-XDOI Listing
July 2020

Role for antimalarials in the management of COVID-19.

Curr Opin Rheumatol 2020 09;32(5):449-457

Department of Medicine/Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin.

Purpose Of Review: The current review highlights recent insights into direct antiviral effects by antimalarials against severe acute respiratory syndrome (SARS)-CoV-2 and other viruses and their potential indirect effects on the host by avoiding exaggerated immune responses (reduced cytokine release, Toll-like receptor response, antigen presentation related to lysosomal processing).

Recent Findings: Currently, there is a large debate on the use of antimalarials for prophylaxis and treatment of SARS-CoV-2-induced disease based on preclinical in-vitro data, small case series and extrapolation from earlier studies of their effect on intracellular pathogens, including many viruses. Hydroxychloroquine (HCQ) or chloroquine have not demonstrated robust efficacy in prior randomized controlled studies against several other viruses. In-vitro data indicate a reduced viral replication of SARS-CoV-2. Especially immunomodulatory effects of antimalarials might also contribute to a clinical efficacy. For SARS-CoV-2 various large studies will provide answers as to whether antimalarials have a place in prophylaxis or treatment of the acute virus infection with SARS-CoV-2 but compelling data are missing so far.

Summary: In-vitro data provide a theoretical framework for an efficacy of antimalarials in SARS-CoV-2-induced disease but clinical proof is currently missing.
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http://dx.doi.org/10.1097/BOR.0000000000000731DOI Listing
September 2020

Methotrexate: what are the true risks of treatment?

Ann Rheum Dis 2020 10 1;79(10):1267-1268. Epub 2020 Jul 1.

Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany.

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http://dx.doi.org/10.1136/annrheumdis-2020-217207DOI Listing
October 2020

Bacterial citrullinated epitopes generated by infection-a missing link for ACPA production.

Ann Rheum Dis 2020 09 12;79(9):1194-1202. Epub 2020 Jun 12.

Department of Rheumatology and Clinical Immunology, Charité University Medicine Berlin, Corporate Member of Free University Berlin, Humboldt University Berlin and Berlin Institute of Health, Berlin, Germany

Objectives: (.) is discussed to be involved in triggering self-reactive immune responses. The aim of this study was to investigate the autocitrullinated prokaryotic peptidylarginine deiminase (PPAD) from . CH2007 (RA-PPAD) from a rheumatoid arthritis (RA) patient and a synthetic citrullinated PPAD peptide (CPP) containing the main autocitrullination site as potential targets for antibody reactivity in RA and to analyse the possibility of citrullinating native human proteins by PPAD in the context of RA.

Methods: Recombinant RA-PPAD was cloned and expressed in . Purified RA-PPAD and its enzymatic activity was analysed using two-dimensional electrophoresis, mass spectrometry, immunoblot and ELISA. Autoantibody response to different modified proteins and peptides was recorded and bioinformatically evaluated.

Results: RA-PPAD was capable to citrullinate major RA autoantigens, such as fibrinogen, vimentin, hnRNP-A2/B1, histone H1 and multiple peptides, which identify a common RG/RGG consensus motif. 33% of RA patients (n=30) revealed increased reactivity for α-cit-RA-PPAD before RA onset. 77% of RA patients (n=99) presented α-cit-specific signals to CPP amino acids 57-71 which were positively correlated to α-CCP2 antibody levels. Interestingly, 48% of the α-CPP-positives were rheumatoidfactor IgM/anti-citrullinated peptide/protein antibodies (ACPA)-negative. Anti-CPP and α-RA-PPAD antibody levels increase with age. Protein macroarrays that were citrullinated by RA-PPAD and screened with RA patient sera (n=6) and controls (n=4) uncovered 16 RA-PPAD citrullinated RA autoantigens and 9 autoantigens associated with lung diseases. We showed that the α-CPP response could be an important determinant in parenchymal changes in the lung at the time of RA diagnosis (n=106; p=0.018).

Conclusions: RA-PPAD induced internal citrullination of major RA autoantigens. Anti-RA-PPAD correlates with ACPA levels and interstitial lung disease autoantigen reactivity, supporting an infection-based concept for induction of ACPAs via enzymatic mimicry.
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http://dx.doi.org/10.1136/annrheumdis-2019-216919DOI Listing
September 2020

Smart battles: immunosuppression versus immunomodulation in the inflammatory RMDs.

Ann Rheum Dis 2020 08 11;79(8):991-993. Epub 2020 Jun 11.

Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany.

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http://dx.doi.org/10.1136/annrheumdis-2020-218019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392482PMC
August 2020

Digital crowdsourcing: unleashing its power in rheumatology.

Ann Rheum Dis 2020 09 11;79(9):1139-1140. Epub 2020 Jun 11.

Department of Internal Medicine 3, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany.

The COVID-19 pandemic forces the whole rheumatic and musculoskeletal diseases community to reassemble established treatment and research standards. Digital crowdsourcing is a key tool in this pandemic to create and distil desperately needed clinical evidence and exchange of knowledge for patients and physicians alike. This viewpoint explains the concept of digital crowdsourcing and discusses examples and opportunities in rheumatology. First experiences of digital crowdsourcing in rheumatology show transparent, accessible, accelerated research results empowering patients and rheumatologists.
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http://dx.doi.org/10.1136/annrheumdis-2020-217697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456558PMC
September 2020

Efficacy and safety of sarilumab in combination with csDMARDs or as monotherapy in subpopulations of patients with moderately to severely active rheumatoid arthritis in three phase III randomized, controlled studies.

Arthritis Res Ther 2020 06 10;22(1):139. Epub 2020 Jun 10.

Charité-University Medicine Berlin, Free University and Humboldt University Berlin, Berlin, Germany.

Background: The interleukin-6 receptor inhibitor sarilumab demonstrated efficacy in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or as monotherapy in patients with moderately to severely active rheumatoid arthritis (RA) with an inadequate response (IR) or intolerant (INT) to methotrexate (MTX) or tumour necrosis factor (TNF)-α inhibitors. This analysis investigated the efficacy and safety of sarilumab in patient subgroups.

Methods: Data were included from phase III studies: two placebo-controlled studies of subcutaneous sarilumab 150/200 mg every 2 weeks (q2w) either + MTX in MTX-IR patients (52 weeks) or + csDMARDs in TNF-IR/INT patients (24 weeks), and a monotherapy study of sarilumab 200 mg q2w vs. adalimumab 40 mg q2w in MTX-IR/INT patients (24 weeks). Prespecified and post hoc subgroups included patient demographics, disease characteristics, and prior treatments. Prespecified and post hoc endpoints included clinical, radiographic, and physical function measures, and p values are considered nominal. Safety was assessed during double-blind treatment.

Results: The superiority of sarilumab (either as monotherapy vs. adalimumab or in combination with csDMARDs vs. placebo + csDMARDs) across clinical endpoints was generally consistent across subgroups defined by patient demographics, disease characteristics, and prior treatments, demonstrating the benefit of sarilumab treatment for a wide range of patient types. Interaction p values of < 0.05 were consistently observed across studies only for baseline anti-cyclic citrullinated peptide antibody (ACPA) status for American College of Rheumatology 20% response, but not American College of Rheumatology 50% or 70% response. Adverse events and worsening laboratory parameters occurred more frequently in sarilumab-treated vs. placebo-treated patients and were more frequent in the small number of patients ≥ 65 years (n = 289) vs. patients < 65 years (n = 1819). Serious infections occurred in six patients aged ≥ 65 years receiving sarilumab, although the incidence of serious infections was generally higher in patients aged ≥ 65 years regardless of treatment.

Conclusions: Apart from ACPA status, there were no consistent signals indicating differential effects of sarilumab in any of the subpopulations assessed. Sarilumab demonstrated consistent efficacy and safety across a wide range of patients with RA.

Trial Registration: ClinicalTrials.gov NCT01061736, registered on February 03, 2010; ClinicalTrials.gov NCT01709578, registered on October 18, 2012; ClinicalTrials.gov NCT02332590, registered on January 07, 2015.
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http://dx.doi.org/10.1186/s13075-020-02194-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288435PMC
June 2020

EULAR provisional recommendations for the management of rheumatic and musculoskeletal diseases in the context of SARS-CoV-2.

Ann Rheum Dis 2020 07 5;79(7):851-858. Epub 2020 Jun 5.

Division of Rheumatology and Clinical Immunology, Department of Medicine IV, Ludwig Maximilian University of Munich, Munich, Germany.

The provisional EULAR recommendations address several aspects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus, and the disease caused by SARS-CoV-2, COVID-19 and are meant for patients with rheumatic and musculoskeletal diseases (RMD) and their caregivers. A task force of 20 members was convened by EULAR that met several times by videoconferencing in April 2020. The task force finally agreed on five overarching principles and 13 recommendations covering four generic themes: (1) General measures and prevention of SARS-CoV-2 infection. (2) The management of RMD when local measures of social distancing are in effect. (3) The management of COVID-19 in the context of RMD. (4) The prevention of infections other than SARS-CoV-2. EULAR considers this set of recommendations as a 'living document' and a starting point, which will be updated as soon as promising new developments with potential impact on the care of patients with RMD become available.
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http://dx.doi.org/10.1136/annrheumdis-2020-217877DOI Listing
July 2020

EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2019 update.

Ann Rheum Dis 2020 06;79(6):700-712

Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Wien, Austria.

Objective: To update the European League Against Rheumatism (EULAR) recommendations for the pharmacological treatment of psoriatic arthritis (PsA).

Methods: According to the EULAR standardised operating procedures, a systematic literature review was followed by a consensus meeting to develop this update involving 28 international taskforce members in May 2019. Levels of evidence and strengths of recommendations were determined.

Results: The updated recommendations comprise 6 overarching principles and 12 recommendations. The overarching principles address the nature of PsA and diversity of both musculoskeletal and non-musculoskeletal manifestations; the need for collaborative management and shared decision-making is highlighted. The recommendations provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs and local glucocorticoid injections are proposed as initial therapy; for patients with arthritis and poor prognostic factors, such as polyarthritis or monoarthritis/oligoarthritis accompanied by factors such as dactylitis or joint damage, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drugs (bDMARDs) targeting tumour necrosis factor (TNF), interleukin (IL)-17A or IL-12/23 should be initiated, taking into account skin involvement if relevant. If axial disease predominates, a TNF inhibitor or IL-17A inhibitor should be started as first-line disease-modifying antirheumatic drug. Use of Janus kinase inhibitors is addressed primarily after bDMARD failure. Phosphodiesterase-4 inhibition is proposed for patients in whom these other drugs are inappropriate, generally in the context of mild disease. Drug switches and tapering in sustained remission are addressed.

Conclusion: These recommendations provide stakeholders with an updated consensus on the pharmacological management of PsA, based on a combination of evidence and expert opinion.
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http://dx.doi.org/10.1136/annrheumdis-2020-217159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286048PMC
June 2020

Synovial tissue transcriptomes of long-standing rheumatoid arthritis are dominated by activated macrophages that reflect microbial stimulation.

Sci Rep 2020 05 13;10(1):7907. Epub 2020 May 13.

Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin, Berlin, Germany.

Advances in microbiome research suggest involvement in chronic inflammatory diseases such as rheumatoid arthritis (RA). Searching for initial trigger(s) in RA, we compared transcriptome profiles of highly inflamed RA synovial tissue (RA-ST) and osteoarthritis (OA)-ST with 182 selected reference transcriptomes of defined cell types and their activation by exogenous (microbial) and endogenous inflammatory stimuli. Screening for dominant changes in RA-ST demonstrated activation of monocytes/macrophages with gene-patterns induced by bacterial and fungal triggers. Gene-patterns of activated B- or T-cells in RA-ST reflected a response to activated monocytes/macrophages rather than inducing their activation. In contrast, OA-ST was dominated by gene-patterns of non-activated macrophages and fibroblasts. The difference between RA and OA was more prominent in transcripts of secreted proteins and was confirmed by protein quantification in synovial fluid (SF) and serum. In total, 24 proteins of activated cells were confirmed in RA-SF compared to OA-SF and some like CXCL13, CCL18, S100A8/A9, sCD14, LBP reflected this increase even in RA serum. Consequently, pathogen-like response patterns in RA suggest that direct microbial influences exist. This challenges the current concept of autoimmunity and immunosuppressive treatment and advocates new diagnostic and therapeutic strategies that consider microbial persistence as important trigger(s) in the etiopathogenesis of RA.
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http://dx.doi.org/10.1038/s41598-020-64431-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220941PMC
May 2020

Adalimumab dose tapering in patients with rheumatoid arthritis who are in long-standing clinical remission: results of the phase IV PREDICTRA study.

Ann Rheum Dis 2020 08 13;79(8):1023-1030. Epub 2020 May 13.

Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.

Objective: To investigate the association between baseline disease activity and the occurrence of flares after adalimumab tapering or withdrawal in patients with rheumatoid arthritis (RA) in sustained remission.

Methods: The PREDICTRA phase IV, randomised, double-blind (DB) study (Imact of esidual Inflammation Detected via Imaging Tchniques, rug Levels, and Patient Characteristics on the Outcome of Dose Taperng of Adalimumab in linical Remission Rheumatoid Arhritis () Patients) enrolled patients with RA receiving adalimumab 40 mg every other week who were in sustained remission ≥6 months. After a 4-week, open-label lead-in (OL-LI) period, patients were randomised 5:1 to DB adalimumab taper (every 3 weeks) or withdrawal (placebo) for 36 weeks. The primary endpoint was the association between DB baseline hand and wrist MRI-detected inflammation with flare occurrence.

Results: Of 146 patients treated during the OL-LI period, 122 were randomised to taper (n=102) or withdrawal (n=20) arms. Patients had a mean 12.9 years of active disease and had received adalimumab for a mean of 5.4 years (mean 2.2 years in sustained remission). Overall, 37 (36%) and 9 (45%) patients experienced a flare in the taper and withdrawal arms, respectively (time to flare, 18.0 and 13.3 weeks). None of the DB baseline disease characteristics or adalimumab concentration was associated with flare occurrence after adalimumab tapering. Approximately half of the patients who flared regained clinical remission after 16 weeks of open-label rescue adalimumab. The safety profile was consistent with previous studies.

Conclusions: Approximately one-third of patients who tapered adalimumab versus half who withdrew adalimumab experienced a flare within 36 weeks. Time to flare was numerically longer in the taper versus withdrawal arm. Baseline MRI inflammation was not associated with flare occurrence.

Trial Registration Number: NCT02198651, EudraCT 2014-001114-26.
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http://dx.doi.org/10.1136/annrheumdis-2020-217246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392484PMC
August 2020

Association of High Serum Interleukin-6 Levels With Severe Progression of Rheumatoid Arthritis and Increased Treatment Response Differentiating Sarilumab From Adalimumab or Methotrexate in a Post Hoc Analysis.

Arthritis Rheumatol 2020 09 25;72(9):1456-1466. Epub 2020 Aug 25.

Regeneron Pharmaceuticals, Tarrytown, New York.

Objective: The development of biomarkers to guide treatment decisions is a major research focus in rheumatoid arthritis (RA). Patients with RA have elevated interleukin-6 (IL-6) levels; however, the utility of IL-6 as a predictor of treatment response is unclear. This study was undertaken to investigate, by post hoc analysis, whether baseline IL-6 levels are predictive of sarilumab treatment responses in 2 phase III studies.

Methods: Serum IL-6 concentrations were measured in patients with RA prior to receiving sarilumab 200 mg (n = 148) or adalimumab 40 mg (n = 152) every 2 weeks (in the MONARCH trial; ClinicalTrials.gov identifier: NCT02332590) or sarilumab 150 mg, sarilumab 200 mg, or placebo every 2 weeks plus methotrexate (MTX) (n = 401, n = 396, and n = 397, respectively) (in the MOBILITY trial; ClinicalTrials.gov identifier: NCT01061736). Efficacy and patient-reported outcomes were compared between and within groups according to IL-6 tertile using linear and logistic regression.

Results: In MONARCH, patients with high baseline IL-6 levels (all ≥3 times the upper limit of normal; n = 100) had higher disease activity at baseline than those with low IL-6 levels (n = 100). The magnitude of clinical improvement over 24 weeks with sarilumab versus adalimumab was greater in patients with high compared to those with low baseline IL-6 levels. In MOBILITY, compared to patients with low IL-6 levels (n = 397), patients with high IL-6 levels (n = 398) had higher disease activity and joint damage at baseline, were more likely to have joint progression, and had less clinical improvement over 52 weeks' treatment with placebo plus MTX compared to sarilumab 150 mg or 200 mg plus MTX. Baseline IL-6 and C-reactive protein levels were both predictive of outcomes. Safety profiles were similar between defined IL-6 tertiles.

Conclusion: IL-6 may be a prognostic marker of disease progression and severity, and patients with high IL-6 levels may be likely to benefit from sarilumab compared to adalimumab or MTX. Prospective validation is warranted to confirm the results of these post hoc analyses.
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http://dx.doi.org/10.1002/art.41299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496495PMC
September 2020

Sarilumab and adalimumab differential effects on bone remodelling and cardiovascular risk biomarkers, and predictions of treatment outcomes.

Arthritis Res Ther 2020 04 7;22(1):70. Epub 2020 Apr 7.

Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA.

Background: Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a key role in the pathogenesis of rheumatoid arthritis. Sarilumab is a human monoclonal antibody that binds membrane-bound and soluble IL-6 receptor-α to inhibit IL-6 signalling. The aim of this study was to compare the effects of sarilumab and adalimumab (a tumour necrosis factor alpha inhibitor) monotherapy on levels of circulating biomarkers associated with the acute-phase response, bone remodelling, atherothrombosis, anaemia of chronic disease and markers purported to reflect synovial lymphoid and myeloid cell infiltrates, as well as the potential of these biomarkers to differentially predict clinical and patient-reported outcomes with sarilumab vs. adalimumab.

Methods: In this post hoc analysis, serum samples were analysed at baseline and prespecified post-treatment timepoints up to week 24 in adults with moderate-to-severe active rheumatoid arthritis intolerant of or inadequate responders to methotrexate from the MONARCH trial (NCT02332590).

Results: Greater reductions in C-reactive protein (CRP; - 94.0% vs. -24.0%), serum amyloid A (SAA; - 83.2% vs. -17.4%), total receptor activator of nuclear factor-κB ligand (RANKL; - 18.3% vs. 10.5%) and lipoprotein (a) (- 41.0% vs. -2.8%) were observed at week 24 with sarilumab vs. adalimumab, respectively (adjusted p < 0.0001). Greater increases in procollagen type 1 N-terminal propeptide (P1NP) were observed with sarilumab vs. adalimumab at week 24 (22.8% vs. 6.2%, p = 0.027). Patients with high baseline SAA, CRP and matrix metalloproteinase-3 (MMP-3) were more likely to achieve clinical efficacy, including American College of Rheumatology 20% improvement criteria and Disease Activity Score (28 joints)-CRP < 3.2, and report improvements in patient-reported outcomes, including Health Assessment Questionnaire-Disability Index and pain visual analogue scale, with sarilumab than adalimumab.

Conclusion: Sarilumab was associated with greater positive effects on bone remodelling and decreases in biomarkers of the acute-phase response, synovial inflammation and cardiovascular risk vs. adalimumab. High baseline concentrations of SAA, CRP and MMP-3 are predictive of clinical and patient-reported outcome responses to sarilumab treatment and prospective validation is warranted to confirm these results.

Trial Registration: ClinicalTrials.gov, NCT02332590. Registered on 5 January 2015.
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http://dx.doi.org/10.1186/s13075-020-02163-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137491PMC
April 2020

Safety of synthetic and biological DMARDs: a systematic literature review informing the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis.

Ann Rheum Dis 2020 06 7;79(6):760-770. Epub 2020 Feb 7.

Amsterdam University Medical Center (ARC), Amsterdam, The Netherlands.

Objectives: To perform a systematic literature review (SLR) concerning the safety of synthetic (s) and biological (b) disease-modifying anti rheumatic dugs (DMARDs) to inform the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis (RA).

Methods: An SLR of observational studies comparing safety outcomes of any DMARD with another intervention for the management of RA. A comparator group was required for inclusion. For treatments still without registry data (eg, sarilumab and the Janus kinase (JAK) inhibitors baricitinib, upadacitinib), randomised controlled trials (RCTs) and long-term extensions (LTEs) were used. Risk of bias (RoB) was assessed according to standard procedures.

Results: Forty-two observational studies fulfilled the inclusion criteria, addressing safety outcomes with bDMARDs and sDMARDs. Nine studies showed no difference in the risk of serious infections across bDMARDs and two studies (high RoB) showed an increased risk with bDMARDs compared with conventional synthetic (cs) DMARDs (adjusted incidence rate ratio 3.1-3.9). The risk of Herpes zoster infection was similar across bDMARDs, but one study showed an increased risk with tofacitinib compared with abatacept (adjusted HR (aHR) 2.0). Five studies showed no increased risk of cancer for bDMARDs compared with csDMARDs. An increased risk of lower intestinal perforation was found for tocilizumab compared with csDMARDs (aHR 4.5) and tumour necrosis factor inhibitor (TNFi) (aHR 2.6-4.0). Sixty manuscripts reported safety data from RCTs/LTEs. Overall, no unexpected safety outcomes were found, except for the possibly increased risk of venous thromboembolism (VTE) with JAK inhibitors.

Conclusion: Data obtained by this SLR confirm the known safety profile of bDMARDs. The risk of VTE in RA, especially in patients on JAK inhibitors, needs further evaluation.
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http://dx.doi.org/10.1136/annrheumdis-2019-216653DOI Listing
June 2020

Efficacy of pharmacological treatment in rheumatoid arthritis: a systematic literature research informing the 2019 update of the EULAR recommendations for management of rheumatoid arthritis.

Ann Rheum Dis 2020 06 7;79(6):744-759. Epub 2020 Feb 7.

Amsterdam Rheumatology Center, Amsterdam, The Netherlands.

Objectives: To inform the 2019 update of the European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA).

Methods: A systematic literature research (SLR) to investigate the efficacy of any disease-modifying antirheumatic drug (DMARD) (conventional synthetic (cs)DMARD, biological (b) and biosimilar DMARD, targeted synthetic (ts)DMARD) or glucocorticoid (GC) therapy in patients with RA was done by searching MEDLINE, Embase and the Cochrane Library for articles published between 2016 and 8 March 2019.

Results: 234 abstracts were selected for detailed assessment, with 136 finally included. They comprised the efficacy of bDMARDs versus placebo or other bDMARDs, efficacy of Janus kinase (JAK) inhibitors (JAKi) across different patient populations and head-to-head of different bDMARDs versus JAKi or other bDMARDs. Switching of bDMARDs to other bDMARDs or tsDMARDs, strategic trials and tapering studies of bDMARDs, csDMARDs and JAKi were assessed. The drugs evaluated included abatacept, adalimumab, ABT-122, baricitinib, certolizumab pegol, SBI-087, CNTO6785, decernotinib, etanercept, filgotinib, golimumab, GCs, GS-9876, guselkumab, hydroxychloroquine, infliximab, leflunomide, mavrilimumab, methotrexate, olokizumab, otilimab, peficitinib, rituximab, sarilumab, salazopyrine, secukinumab, sirukumab, tacrolimus, tocilizumab, tofacitinib, tregalizumab, upadacitinib, ustekinumab and vobarilizumab. The efficacy of many bDMARDs and tsDMARDs was shown. Switching to another tumour necrosis factor inhibitor (TNFi) or non-TNFi bDMARDs after TNFi treatment failure is efficacious. Tapering of DMARDs is possible in patients achieving long-standing stringent clinical remission; in patients with residual disease activity (including patients in LDA) the risk of flares is increased during the tapering. Biosimilars are non-inferior to their reference products.

Conclusion: This SLR informed the task force regarding the evidence base of various therapeutic regimen for the development of the update of EULAR's RA management recommendation.
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http://dx.doi.org/10.1136/annrheumdis-2019-216656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286044PMC
June 2020

An Integrated Analysis of the Safety of Tofacitinib in Psoriatic Arthritis across Phase III and Long-Term Extension Studies with Comparison to Real-World Observational Data.

Drug Saf 2020 04;43(4):379-392

Pfizer Inc, 445 Eastern Point Rd (MS 8260-2578), Groton, CT, 06340, USA.

Introduction: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA).

Objective: Our objective was to compare the incidence rates (IRs) of adverse events in tofacitinib clinical trials and real-world observational data for alternative treatments.

Methods: The tofacitinib "dose-comparison cohort" included months 0-12 of two phase III studies (tofacitinib 5 [n = 238] and 10 [n = 236] mg twice daily [BID]); the "all-tofacitinib comparison cohort" (n = 783) included two phase III and one ongoing long-term extension study (data cutoff May 2016). An "observational comparison cohort" (n = 5799) comprised patients initiating a conventional synthetic disease-modifying antirheumatic drug (DMARD), biologic DMARD, or apremilast in the US Truven MarketScan database from 2010 to 2015. IRs for serious infections (SIEs; requiring hospitalization), herpes zoster (HZ), malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC, and major adverse cardiovascular events (MACE) across cohorts were qualitatively compared.

Results: IRs (patients with events/100 patient-years) for SIEs were similar between the tofacitinib dose-comparison cohort (5 mg BID: 1.3; 10 mg BID: 2.0) and the observational comparison cohort (1.1-7.9; treatment dependent). The tofacitinib dose-comparison cohort had a higher rate of HZ (5 mg BID: 2.0; 10 mg BID: 2.7) than did the observational comparison cohort (0.8-2.0). IRs for NMSC were generally lower in the all-tofacitinib comparison cohort (0.5) than in the observational comparison cohort (0.4-6.0). IRs for MACE, malignancies excluding NMSC, and NMSC were similar between cohorts.

Conclusion: In patients with PsA, tofacitinib had a safety profile similar to that of other systemic therapies in real-world settings, except for the risk of HZ, a known risk of tofacitinib.

Trial Registration: ClinicalTrials.gov: NCT01877668; NCT01882439; NCT01976364.
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http://dx.doi.org/10.1007/s40264-020-00904-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105422PMC
April 2020

The etiology of rheumatoid arthritis.

J Autoimmun 2020 06 22;110:102400. Epub 2020 Jan 22.

Department of Rheumatology and Clinical Immunology, Charité-University Medicine Berlin, Berlin, Germany.

Rheumatoid arthritis is a heterogeneous disease, which can be, based on data combining genetic risk factors and autoantibodies, sub-classified into ACPA-positive and -negative RA. Presence of ACPA and RF as well as rising CRP-levels in some patients years before onset of clinical symptoms indicate that relevant immune responses for RA development are initiated very early. ACPA are highly specific for RA, whereas RF can also be found among healthy (elderly) individuals and patients with other autoimmune diseases or infection. The most important genetic risk factor for RA development, the shared epitope alleles, resides in the MHC class II region. Shared epitope alleles, however, only predispose to the development of ACPA-positive RA. Smoking is thus far the most important environmental risk factor associated with the development of RA. Studies on synovitis have shown the importance not only of adaptive but also of innate immune responses. In summary of the various results from immunological changes in blood and synovial tissue, the extension of the immune response from a diffuse myeloid to a lympho-myeloid inflammation appears to be associated with a more successful therapeutic response to biologics. With respect to advances in synovitis research, new targets for treatment against pathological subsets of immune cells or fibroblasts are already on the horizon. However, alternative strategies involving the microbiome may play an important role as well and research in this field is growing rapidly.
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http://dx.doi.org/10.1016/j.jaut.2019.102400DOI Listing
June 2020