Changes in macrophage transcriptome associate with systemic sclerosis and mediate GSDMA contribution to disease risk Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-13 Aida Moreno-Moral, Marta Bagnati, Surya Koturan, Jeong-Hun Ko, Carmen Fonseca, Nathan Harmston, Laurence Game, Javier Martin, Voon Ong, David J Abraham, Christopher P Denton, Jacques Behmoaras, Enrico Petretto
Objectives Several common and rare risk variants have been reported for systemic sclerosis (SSc), but the effector cell(s) mediating the function of these genetic variants remains to be elucidated. While innate immune cells have been proposed as the critical targets to interfere with the disease process underlying SSc, no studies have comprehensively established their effector role. Here we investigated the contribution of monocyte-derived macrophages (MDMs) in mediating genetic susceptibility to SSc. Methods We carried out RNA sequencing and genome-wide genotyping in MDMs from 57 patients with SSc and 15 controls. Our differential expression and expression quantitative trait locus (eQTL) analysis in SSc was further integrated with epigenetic, expression and eQTL data from skin, monocytes, neutrophils and lymphocytes. Results We identified 602 genes upregulated and downregulated in SSc macrophages that were significantly enriched for genes previously implicated in SSc susceptibility (P=5×10−4), and 270 cis -regulated genes in MDMs. Among these, GSDMA was reported to carry an SSc risk variant (rs3894194) regulating expression of neighbouring genes in blood. We show that GSDMA is upregulated in SSc MDMs (P=8.4×10−4) but not in the skin, and is a significant eQTL in SSc macrophages and lipopolysaccharide/interferon gamma (IFNγ)-stimulated monocytes. Furthermore, we identify an SSc macrophage transcriptome signature characterised by upregulation of glycolysis, hypoxia and mTOR signalling and a downregulation of IFNγ response pathways. Conclusions Our data further establish the link between macrophages and SSc, and suggest that the contribution of the rs3894194 risk variant to SSc susceptibility can be mediated by GSDMA expression in macrophages.
Effect of rituximab on a salivary gland ultrasound score in primary Sjögren’s syndrome: results of the TRACTISS randomised double-blind multicentre substudy Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-17 Benjamin A Fisher, Colin C Everett, John Rout, John L O’Dwyer, Paul Emery, Costantino Pitzalis, Wan-Fai Ng, Andrew Carr, Colin T Pease, Elizabeth J Price, Nurhan Sutcliffe, Jimmy Makdissi, Anwar R Tappuni, Nagui S T Gendi, Frances C Hall, Sharon P Ruddock, Catherine Fernandez, Claire T Hulme, Kevin A Davies, Christopher John Edwards, Peter C Lanyon, Robert J Moots, Euthalia Roussou, Andrea Richards, Linda D Sharples, Michele Bombardieri, Simon J Bowman
Objectives To compare the effects of rituximab versus placebo on salivary gland ultrasound (SGUS) in primary Sjögren’s syndrome (PSS) in a multicentre, multiobserver phase III trial substudy. Methods Subjects consenting to SGUS were randomised to rituximab or placebo given at weeks 0, 2, 24 and 26, and scanned at baseline and weeks 16 and 48. Sonographers completed a 0–11 total ultrasound score (TUS) comprising domains of echogenicity, homogeneity, glandular definition, glands involved and hypoechoic foci size. Baseline-adjusted TUS values were analysed over time, modelling change from baseline at each time point. For each TUS domain, we fitted a repeated-measures logistic regression model to model the odds of a response in the rituximab arm (≥1-point improvement) as a function of the baseline score, age category, disease duration and time point. Results 52 patients (n=26 rituximab and n=26 placebo) from nine centres completed baseline and one or more follow-up visits. Estimated between-group differences (rituximab-placebo) in baseline-adjusted TUS were −1.2 (95% CI −2.1 to −0.3; P=0.0099) and −1.2 (95% CI −2.0 to −0.5; P=0.0023) at weeks 16 and 48. Glandular definition improved in the rituximab arm with an OR of 6.8 (95% CI 1.1 to 43.0; P=0.043) at week 16 and 10.3 (95% CI 1.0 to 105.9; P=0.050) at week 48. Conclusions We demonstrated statistically significant improvement in TUS after rituximab compared with placebo. This encourages further research into both B cell depletion therapies in PSS and SGUS as an imaging biomarker. Trial registration number 65360827, 2010-021430-64; Results.
Limited radiographic progression and sustained reductions in MRI inflammation in patients with axial spondyloarthritis: 4-year imaging outcomes from the RAPID-axSpA phase III randomised trial Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-17 Désirée van der Heijde, Xenofon Baraliakos, Kay-Geert A Hermann, Robert B M Landewé, Pedro M Machado, Walter P Maksymowych, Owen R Davies, Natasha de Peyrecave, Bengt Hoepken, Lars Bauer, Tommi Nurminen, Juergen Braun
Objectives To report 4-year imaging outcomes in the RAPID-axSpA ([NCT01087762]) study of patients with ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA), treated with certolizumab pegol (CZP). Methods This phase III, randomised trial was placebo-controlled and double-blind to week 24, dose-blind to week 48 and open-label to week 204. Patients fulfilling the Assessment of Spondyloarthritis International Society (ASAS) axSpA criteria with active disease were stratified (AS/nr-axSpA) according to the modified New York (mNY) criteria at randomisation. Spinal radiographs were assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). MRI inflammation used the Spondyloarthritis Research Consortium of Canada (SPARCC) score for sacroiliac joints (SIJ) and the Berlin spinal score (remission defined as SPARCC <2 and Berlin ≤2, respectively). Results MRI improvements from baseline (BL) to week 12 were maintained to week 204 (SPARCC BL: AS=8.5, nr-axSpA=7.5; SPARCC week 204: AS=1.3, nr-axSpA=2.4; Berlin BL: AS=7.4, nr-axSpA=4.4; Berlin week 204: AS=2.6, nr-axSpA=1.9). 66.7% of patients with AS and 69.6% of patients with nr-axSpA with BL SPARCC scores ≥2, and 65.4% of patients with AS and 57.3% of patients with nr-axSpA with BL Berlin score >2, achieved remission at week 204. Mean mSASSS change in AS from BL to week 204 was 0.98 (95% CI 0.34, 1.63); 0.67 (95% CI 0.21,1.13) from BL to week 96; and 0.31 (95% CI 0.02,0.60) from week 96 to week 204. Corresponding nr-axSpA changes were 0.06 (95% CI −0.17,0.28), –0.01 (95% CI −0.19,0.17) and 0.07 (95% CI −0.07,0.20). 4.5% of patients with nr-axSpA fulfilled the mNY criteria at week 204, while 4.3% of patients with AS no longer did so. Conclusions In patients with CZP-treated axSpA, rapid decreases in spinal and SIJ MRI inflammation were maintained to week 204. Overall, 4-year spinal progression was low, with less progression during years 2–4 than 0–2. Radiographic SIJ grading changes demonstrated limited progression. Trial registration number [NCT01087762]; Post-results. : /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01087762&atom=%2Fannrheumdis%2Fearly%2F2018%2F01%2F17%2Fannrheumdis-2017-212377.atom
Response to: ‘Remission or low disease activity as a target in systemic lupus erythematosus’ by Ugarte-Gil et al Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-17 Margherita Zen, Andrea Doria
We appreciated the comments by Ugarte-Gil and co-authors1 on our report dealing with lupus low disease activity state (LLDAS) in Caucasian patients.2 We agree that Caucasian patients with systemic lupus erythematosus (SLE) have a better prognosis compared with non-Caucasian ones, but, in our opinion, race does not fully elucidate the different results in terms of prevalence of low disease activity and remission obtained in the studies by Zen et al 2 and Ugarte-Gil et al .3 The different design of the studies is more relevant than race in explaining the divergent results. Indeed, the Grupo Latino Americano De Estudio del Lupus (GLADEL) study3 analysed an inception cohort of patients shortly after the disease onset (median disease duration 0.3 years), and the authors assessed remission and low disease activity status (LDAS) during the first years of follow-up. …
Early and sustained efficacy with apremilast monotherapy in biological-naïve patients with psoriatic arthritis: a phase IIIB, randomised controlled trial (ACTIVE) Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-17 Peter Nash, Kamal Ohson, Jessica Walsh, Nikolay Delev, Dianne Nguyen, Lichen Teng, Juan J Gómez-Reino, Jacob A Aelion
Objective Evaluate apremilast efficacy across various psoriatic arthritis (PsA) manifestations beginning at week 2 in biological-naïve patients with PsA. Methods Patients were randomised (1:1) to apremilast 30 mg twice daily or placebo. At week 16, patients whose swollen and tender joint counts had not improved by ≥10% were eligible for early escape. At week 24, all patients received apremilast through week 52. Results Among 219 randomised patients (apremilast: n=110; placebo: n=109), a significantly greater American College of Rheumatology 20 response at week 16 (primary outcome) was observed with apremilast versus placebo (38.2% (42/110) vs 20.2% (22/109); P=0.004); response rates at week 2 (first assessment) were 16.4% (18/110) versus 6.4% (7/109) (P=0.025). Improvements in other efficacy outcomes, including 28-joint count Disease Activity Score (DAS-28) using C reactive protein (CRP), swollen joint count, Health Assessment Questionnaire-Disability Index (HAQ-DI), enthesitis and morning stiffness severity, were observed with apremilast at week 2. At week 16, apremilast significantly reduced PsA disease activity versus placebo, with changes in DAS-28 (CRP) (P<0.0001), HAQ-DI (P=0.023) and Gladman Enthesitis Index (P=0.001). Improvements were maintained with continued treatment through week 52. Over 52 weeks, apremilast’s safety profile was consistent with prior phase 3 studies in psoriasis and PsA. During weeks 0–24, the incidence of protocol-defined diarrhoea was 11.0% (apremilast) and 8.3% (placebo); serious adverse event rates were 2.8% (apremilast) and 4.6% (placebo). Conclusions In biological-naïve patients with PsA, onset of effect with apremilast was observed at week 2 and continued through week 52. The safety profile was consistent with previous reports. Trial registration number [NCT01925768; Results]. : /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01925768&atom=%2Fannrheumdis%2Fearly%2F2018%2F01%2F17%2Fannrheumdis-2017-211568.atom
Circular RNA VMA21 protects against intervertebral disc degeneration through targeting miR-200c and X linked inhibitor-of-apoptosis protein Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-17 Xiaofei Cheng, Liang Zhang, Kai Zhang, Guoying Zhang, Ying Hu, Xiaojiang Sun, Changqing Zhao, Hua Li, Yan Michael Li, Jie Zhao
Objectives Circular RNAs (circRNAs) have been proven to function as competing endogenous RNAs to interact with microRNAs (miRNAs) and influence the expression of miRNA target mRNAs. In this study, we investigated whether circRNAs could act as competing endogenous RNAs to regulate the pathological process of intervertebral disc degeneration (IVDD). Methods The role and mechanism of a circRNA, circVMA21, in IVDD were explored in nucleus pulposus (NP) cells and degenerative NP tissues from patients and rat models. The interaction between circVMA21 and miR-200c as well as the target mRNA, X linked inhibitor-of-apoptosis protein (XIAP), was examined. Results The decreased expression of XIAP in the inflammatory cytokines-treated NP cells and the degenerative NP tissues was directly associated with excessive apoptosis and imbalance between anabolic and catabolic factors of extracellular matrix. miR-200c regulated NP cell viability and functions through inhibiting XIAP. circVMA21 acted as a sponge of miR-200c and functioned in NP cells through targeting miR-200c and XIAP. Intradiscal injection of circVMA21 alleviated IVDD in the rat model. Conclusions CircVMA21 could alleviate inflammatory cytokines-induced NP cell apoptosis and imbalance between anabolism and catabolism of extracellular matrix through miR-200c-XIAP pathway. It provides a potentially effective therapeutic strategy for IVDD.
Response to: ‘Neuropsychiatric lupus or not? Cerebral hypoperfusion by perfusion-weighted MRI in normal-appearing white matter in primary neuropsychiatric lupus erythematosus’ by Papadaki et al Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-17 Daniel J Wallace
I read with interest the article by Papadaki et al 1 relating to the role of cerebral hypoperfusion in neuropsychiatric lupus. While I applaud the quality of work and the intricate interpretation of enhanced MR imaging, the authors came to the wrong conclusions. First of all, the definitions (of which I was a co-author) for evaluating a diverse group of patients as having central nervous system systemic …
Efficacy and safety of tregalizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase IIb, randomised, placebo-controlled trial Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-17 Ronald F van Vollenhoven, Edward Clark Keystone, Vibeke Strand, Cesar Pacheco-Tena, Jiří Vencovský, Frank Behrens, Arthur Racewicz, Daniela Zipp, Faiza Rharbaoui, Ralf Wolter, Luise Knierim, Rainer Schmeidl, Xuefei Zhou, Silke Aigner, Benjamin Dälken, Andrea Wartenberg-Demand
Objective To evaluate the efficacy, biological activity and safety of tregalizumab in patients with active rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). Methods 321 patients were randomised (1:1:1:1) to placebo or tregalizumab 25, 100 or 200 mg once-weekly subcutaneously in addition to MTX treatment. Responders at week 12 continued the same treatment, and non-responders at week 12 were escalated to the next higher tregalizumab dose level or re-randomised from placebo to active treatment. After 24 weeks, patients could continue treatment with tregalizumab for 24 weeks (extension phase). The primary endpoint was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. Safety and biological activity were monitored through week 48. Results At week 12, ACR20 response rates were not statistically significantly different between placebo and any of the tregalizumab doses. Tregalizumab injections were well tolerated; most adverse events were mild to moderate and comparable among treatment and placebo groups. Biological activity was shown by dose-dependent CD4 downmodulation. Conclusion Treatment with tregalizumab did not show significant clinical efficacy in patients with active RA compared with placebo but resulted in the expected biological effect on CD4 modulation. Tregalizumab was generally well tolerated, and no new safety findings were identified. Trial registration number [NCT01999192; Results]. : /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01999192&atom=%2Fannrheumdis%2Fearly%2F2018%2F01%2F17%2Fannrheumdis-2017-212478.atom
Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-13 Yuta Kochi, Yoichiro Kamatani, Yuya Kondo, Akari Suzuki, Eiryo Kawakami, Ryosuke Hiwa, Yukihide Momozawa, Manabu Fujimoto, Masatoshi Jinnin, Yoshiya Tanaka, Takashi Kanda, Robert G Cooper, Hector Chinoy, Simon Rothwell, Janine A Lamb, Jiří Vencovský, Heřman Mann, Koichiro Ohmura, Keiko Myouzen, Kazuyoshi Ishigaki, Ran Nakashima, Yuji Hosono, Hiroto Tsuboi, Hidenaga Kawasumi, Yukiko Iwasaki, Hiroshi Kajiyama, Tetsuya Horita, Mariko Ogawa-Momohara, Akito Takamura, Shinichiro Tsunoda, Jun Shimizu, Keishi Fujio, Hirofumi Amano, Akio Mimori, Atsushi Kawakami, Hisanori Umehara, Tsutomu Takeuchi, Hajime Sano, Yoshinao Muro, Tatsuya Atsumi, Toshihide Mimura, Yasushi Kawaguchi, Tsuneyo Mimori, Atsushi Takahashi, Michiaki Kubo, Hitoshi Kohsaka, Takayuki Sumida, Kazuhiko Yamamoto
Objectives Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases in which both genetic and environmental factors play important roles. To identify genetic factors of IIM including polymyositis, dermatomyositis (DM) and clinically amyopathic DM (CADM), we performed the first genome-wide association study for IIM in an Asian population. Methods We genotyped and tested 496 819 single nucleotide polymorphism for association using 576 patients with IIM and 6270 control subjects. We also examined the causal mechanism of disease-associated variants by in silico analyses using publicly available data sets as well as by in in vitro analyses using reporter assays and apoptosis assays. Results We identified a variant in WDFY4 that was significantly associated with CADM (rs7919656; OR=3.87; P=1.5×10−8). This variant had a cis-splicing quantitative trait locus (QTL) effect for a truncated WDFY4 isoform (tr- WDFY4 ), with higher expression in the risk allele. Transexpression QTL analysis of this variant showed a positive correlation with the expression of NF-κB associated genes. Furthermore, we demonstrated that both WDFY4 and tr-WDFY4 interacted with pattern recognition receptors such as TLR3, TLR4, TLR9 and MDA5 and augmented the NF-κB activation by these receptors. WDFY4 isoforms also enhanced MDA5-induced apoptosis to a greater extent in the tr-WDFY4-transfected cells. Conclusions As CADM is characterised by the appearance of anti-MDA5 autoantibodies and severe lung inflammation, the WDFY4 variant may play a critical role in the pathogenesis of CADM.
Impact of broad regulatory regions on Gdf5 expression and function in knee development and susceptibility to osteoarthritis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-13 Steven K Pregizer, Ata M Kiapour, Mariel Young, Hao Chen, Michael Schoor, Zun Liu, Jiaxue Cao, Vicki Rosen, Terence D Capellini
Objectives Given the role of growth and differentiation factor 5 ( GDF5 ) in knee development and osteoarthritis risk, we sought to characterise knee defects resulting from Gdf5 loss of function and how its regulatory regions control knee formation and morphology. Methods The brachypodism ( bp ) mouse line, which harbours an inactivating mutation in Gdf5 , was used to survey how Gdf5 loss of function impacts knee morphology, while two transgenic Gdf5 reporter bacterial artificial chromosome mouse lines were used to assess the spatiotemporal activity and function of Gdf5 regulatory sequences in the context of clinically relevant knee anatomical features. Results Knees from homozygous bp mice ( bp/bp ) exhibit underdeveloped femoral condyles and tibial plateaus, no cruciate ligaments, and poorly developed menisci. Secondary ossification is also delayed in the distal femur and proximal tibia. bp/bp mice have significantly narrower femoral condyles, femoral notches and tibial plateaus, and curvier medial femoral condyles, shallower trochlea, steeper lateral tibial slopes and smaller tibial spines. Regulatory sequences upstream from Gdf5 were weakly active in the prenatal knee, while downstream regulatory sequences were active throughout life. Importantly, downstream but not upstream Gdf5 regulatory sequences fully restored all the key morphological features disrupted in the bp/bp mice. Conclusions Knee morphology is profoundly affected by Gdf5 absence, and downstream regulatory sequences mediate its effects by controlling Gdf5 expression in knee tissues. This downstream region contains numerous enhancers harbouring human variants that span the osteoarthritis association interval. We posit that subtle alterations to morphology driven by changes in downstream regulatory sequence underlie this locus’ role in osteoarthritis risk.
Response to: ’Standard dose of ustekinumab for childhood-onset deficiency of interleukin-36 receptor antagonist’ by Cherqaoui et al Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-13 Nadia Bonekamp, Roberta Caorsi, Joost Frenkel, Marco Gattorno
The case reported by Cherqaoui et al 1 on ustekinumab in the treatment of deficiency of interleukin-36 receptor antagonist (DITRA) is interesting in several aspects. The authors describe intrathecal elevation of proinflammatory cytokines, which is a novel and intriguing finding. The mutation in their case is identical to that of the Dutch/Moroccan patient we described. The total absence …
Bout of the corner men and not the boxers? Contextual effects flex their muscles Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Martin Englund
Increased use of MRI in the quest to explain symptoms, and patients’ hope for a ‘quick-fix’, often challenge healthcare professionals in their choice of treatment for the painful ageing knee. In the USA, there are about one million knee arthroscopies per year and the majority involve removal of torn meniscal tissue in middle-aged patients. The absolute number of arthroscopic partial meniscectomies (APMs) in Europe is unknown but may be even greater due to the larger European population. The popularity of this procedure is understandable — multiple case series and randomised controlled trials (RCTs), not to mention doctors’ personal observations of patients, show sustained improvement after APM. However, the last few years, the efficacy of the actual therapeutic element , resection of meniscal tissue, has been called into question. A hallmark RCT is the exquisitely designed, randomised, double-blinded, sham-surgery-controlled Finnish Degenerative Meniscal Lesion Study (FIDELITY).1 The main findings of the trial so far are summarised in these short film clips: In the provocative New Engl J Med article from 2013, Sihvonen et al reported that outcomes in the middle-aged patients, where resection of meniscus was only simulated during the diagnostic arthroscopy, were very similar to those of actual APM. Patients in both the APM arm and the sham-surgery arm improved substantially and sustainably, indicating that the improvement observed after APM is attributable to what are collectively referred to as contextual effects. Thus, it was not the actual therapeutic element of the surgery, which is resection of torn meniscal tissue. Now, in the present 2-year follow-up of the FIDELITY patients,2 Sihvonen et al strengthen their original …
The evolving role of the rheumatologist in the management of immune-related adverse events (irAEs) caused by cancer immunotherapy Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Leonard Calabrese, Xavier Mariette
The rapid introduction of immunotherapies for cancer-targeting immunological checkpoints has led to a new class of toxicities that appear to be of autoimmune and or autoinflammatory origin. These disorders are now referred to as immune-related adverse events (irAEs) and pose considerable challenges to patient care in terms of how to optimally manage these formidable toxicities while allowing effective antitumoural therapy to continue. While rheumatologists will naturally be called on to manage those irAEs of rheumatic origin, we believe there is a need and an opportunity for rheumatologists to participate as central figures in this evolving field, in large part because of our familiarity with multiorgan autoimmune disease and our expertise in crafting and utilising both traditional and biological immune-based therapies. Rheumatologists urgently need education in this evolving field to be best positioned as contributors to care of such patients and investigators of the underlying mechanisms of these complications.
Consensus-based recommendations for the use of biosimilars to treat rheumatological diseases Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Jonathan Kay, Monika M Schoels, Thomas Dörner, Paul Emery, Tore K Kvien, Josef S Smolen, Ferdinand C Breedveld
The study aimed to develop evidence-based recommendations regarding the evaluation and use of biosimilars to treat rheumatological diseases. The task force comprised an expert group of specialists in rheumatology, dermatology and gastroenterology, and pharmacologists, patients and a regulator from ten countries. Four key topics regarding biosimilars were identified through a process of discussion and consensus. Using a Delphi process, specific questions were then formulated to guide a systematic literature review. Relevant English-language publications through November 2016 were searched systematically for each topic using Medline; selected papers and pertinent reviews were examined for additional relevant references; and abstracts presented at the 2015 and 2016 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) annual scientific meetings were searched for those about biosimilars. The experts used evidence obtained from these studies to develop a set of overarching principles and consensus recommendations. The level of evidence and grade of recommendation were determined for each. By the search strategy, 490 references were identified. Of these, 29 full-text papers were included in the systematic review. Additionally, 20 abstracts were retrieved from the ACR and EULAR conference abstract databases. Five overarching principles and eight consensus recommendations were generated, encompassing considerations regarding clinical trials, immunogenicity, extrapolation of indications, switching between bio-originators and biosimilars and among biosimilars, and cost. The level of evidence and grade of recommendation for each varied according to available published evidence. Five overarching principles and eight consensus recommendations regarding the evaluation and use of biosimilars to treat rheumatological diseases were developed using research-based evidence and expert opinion.
Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis? Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Kenneth F Baker, John D Isaacs
The past three decades have witnessed remarkable advances in our ability to target specific elements of the immune and inflammatory response, fuelled by advances in both biotechnology and disease knowledge. As well as providing superior treatments for immune-mediated inflammatory diseases (IMIDs), such therapies also offer unrivalled opportunities to study the underlying immunopathological basis of these conditions. In this review, we explore recent approaches to the treatment of IMIDs and the insights to pathobiology that they provide. We review novel biologic agents targeting the T-helper 17 axis, including therapies directed towards interleukin (IL)-17 (secukinumab, ixekizumab, bimekizumab), IL-17R (brodalumab), IL-12/23p40 (ustekinumab, briakinumab) and IL-23p19 (guselkumab, tildrakizumab, brazikumab, risankizumab, mirikizumab). We also present an overview of biologics active against type I and II interferons, including sifalumumab, rontalizumab, anifrolumab and fontolizumab. Emerging strategies to interfere with cellular adhesion processes involved in lymphocyte recruitment are discussed, including both integrin blockade (natalizumab, vedolizumab, etrolizumab) and sphingosine-1-phosphate receptor inhibition (fingolimod, ozanimod). We summarise the development and recent application of Janus kinase (JAK) inhibitors in the treatment of IMIDs, including first-generation pan-JAK inhibitors (tofacitinib, baricitinib, ruxolitinib, peficitinib) and second-generation selective JAK inhibitors (decernotinib, filgotinib, upadacitinib). New biologics targeting B-cells (including ocrelizumab, veltuzumab, tabalumab and atacicept) and the development of novel strategies for regulatory T-cell modulation (including low-dose IL-2 therapy and Tregitopes) are also discussed. Finally, we explore recent biotechnological advances such as the development of bispecific antibodies (ABT-122, COVA322), and their application to the treatment of IMIDs.
Arthroscopic partial meniscectomy versus placebo surgery for a degenerative meniscus tear: a 2-year follow-up of the randomised controlled trial Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Raine Sihvonen, Mika Paavola, Antti Malmivaara, Ari Itälä, Antti Joukainen, Heikki Nurmi, Juha Kalske, Anna Ikonen, Timo Järvelä, Tero A H Järvinen, Kari Kanto, Janne Karhunen, Jani Knifsund, Heikki Kröger, Tommi Kääriäinen, Janne Lehtinen, Jukka Nyrhinen, Juha Paloneva, Outi Päiväniemi, Marko Raivio, Janne Sahlman, Roope Sarvilinna, Sikri Tukiainen, Ville-Valtteri Välimäki, Ville Äärimaa, Pirjo Toivonen, Teppo L N Järvinen
Objective To assess if arthroscopic partial meniscectomy (APM) is superior to placebo surgery in the treatment of patients with degenerative tear of the medial meniscus. Methods In this multicentre, randomised, participant-blinded and outcome assessor-blinded, placebo-surgery controlled trial, 146 adults, aged 35–65 years, with knee symptoms consistent with degenerative medial meniscus tear and no knee osteoarthritis were randomised to APM or placebo surgery. The primary outcome was the between-group difference in the change from baseline in the Western Ontario Meniscal Evaluation Tool (WOMET) and Lysholm knee scores and knee pain after exercise at 24 months after surgery. Secondary outcomes included the frequency of unblinding of the treatment-group allocation, participants' satisfaction, impression of change, return to normal activities, the incidence of serious adverse events and the presence of meniscal symptoms in clinical examination. Two subgroup analyses, assessing the outcome on those with mechanical symptoms and those with unstable meniscus tears, were also carried out. Results In the intention-to-treat analysis, there were no significant between-group differences in the mean changes from baseline to 24 months in WOMET score: 27.3 in the APM group as compared with 31.6 in the placebo-surgery group (between-group difference, −4.3; 95% CI, −11.3 to 2.6); Lysholm knee score: 23.1 and 26.3, respectively (−3.2; −8.9 to 2.4) or knee pain after exercise, 3.5 and 3.9, respectively (−0.4; −1.3 to 0.5). There were no statistically significant differences between the two groups in any of the secondary outcomes or within the analysed subgroups. Conclusions In this 2-year follow-up of patients without knee osteoarthritis but with symptoms of a degenerative medial meniscus tear, the outcomes after APM were no better than those after placebo surgery. No evidence could be found to support the prevailing ideas that patients with presence of mechanical symptoms or certain meniscus tear characteristics or those who have failed initial conservative treatment are more likely to benefit from APM.
Cigarette smoking and the risk of systemic lupus erythematosus, overall and by anti-double stranded DNA antibody subtype, in the Nurses’ Health Study cohorts Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Medha Barbhaiya, Sara K Tedeschi, Bing Lu, Susan Malspeis, David Kreps, Jeffrey A Sparks, Elizabeth W Karlson, Karen H Costenbader
Objectives Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease, subtyped according to clinical manifestations and autoantibodies. Evidence concerning cigarette smoking and SLE risk has been conflicting. We investigated smoking and SLE risk, overall and by anti-double stranded DNA (dsDNA) presence, in two prospective cohort studies. Methods The Nurses’ Health Study (NHS) enrolled 121 701 US female nurses in 1976; Nurses’ Health Study II (NHSII) enrolled 116 430 in 1989. Lifestyle, environmental and medical data were collected through biennial questionnaires. Incident SLE was confirmed by medical record review. Cox regression models estimated HRs of SLE, overall and by dsDNA subtype, in association with time-varying smoking status and cumulative smoking pack-years through the 2-year cycle prior to diagnosis, controlling for potential confounders. Results Among 286 SLE cases identified (159 in NHS (1978–2012) and 127 in NHSII (1991–2013)), mean age was 49.2 (10.3) years and 42% were dsDNA+ at SLE diagnosis. At baseline, 45% of women had ever smoked, 51% of whom currently smoked. Compared with never smokers, current smokers had increased dsDNA+ SLE risk (HR 1.86 (1.14–3.04)), whereas past smokers did not (HR 1.31 (0.85–2.00)). Women who smoked >10 pack-years (vs never) had an elevated dsDNA+ SLE risk (HR 1.60(95% CI 1.04 to 2.45)) compared with never smokers. No associations were observed between smoking status or pack-years and overall SLE or dsDNA− SLE. Conclusion Strong and specific associations of current smoking and >10 pack-years of smoking with dsDNA+ SLE were observed. This novel finding suggests smoking is involved in dsDNA+ SLE pathogenesis.
Anticitrullinated protein/peptide antibody multiplexing defines an extended group of ACPA-positive rheumatoid arthritis patients with distinct genetic and environmental determinants Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Johan Rönnelid, Monika Hansson, Linda Mathsson-Alm, Martin Cornillet, Evan Reed, Per-Johan Jakobsson, Lars Alfredsson, Rikard Holmdahl, Karl Skriner, Guy Serre, Karin Lundberg, Lars Klareskog
Introduction The second generation anticycliccitrullinated peptide (anti-CCP2) assay detects the majority but not all anticitrullinated protein/peptide antibodies (ACPA). Anti-CCP2-positive rheumatoid arthritis (RA) is associated with HLA-DRB1* shared epitope (SE) alleles and smoking. Using a multiplex assay to detect multiple specific ACPA, we have investigated the fine specificity of individual ACPA responses and the biological impact of additional ACPA reactivity among anti-CCP2-negative patients. Methods We investigated 2825 patients with RA and 551 healthy controls with full data on anti-CCP2, HLA-DRB1* alleles and smoking history concerning reactivity against 16 citrullinated peptides and arginine control peptides with a multiplex array. Results The prevalence of the 16 ACPA specificities ranged from 9% to 58%. When reactivity to arginine peptides was subtracted, the mean diagnostic sensitivity increased by 3.2% with maintained 98% specificity. Of the anti-CCP2-negative patients, 16% were found to be ACPA positive. All ACPA specificities associated with SE, and all but one with smoking. Correction for arginine reactivity also conveyed a stronger association with SE for 13/16 peptides. Importantly, when all ACPA specificities were analysed together, SE and smoking associated with RA in synergy among ACPA positive, but not among ACPA-negative subjects also in the anti-CCP2-negative subset. Conclusions Multiplexing detects an enlarged group of ACPA-positive but anti-CCP2-negative patients with genetic and environmental attributes previously assigned to anti-CCP2-positive patients. The individual correction for arginine peptide reactivity confers both higher diagnostic sensitivity and stronger association to SE than gross ACPA measurement.
Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate) Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Dinesh Khanna, Christopher P Denton, Celia J F Lin, Jacob M van Laar, Tracy M Frech, Marina E Anderson, Murray Baron, Lorinda Chung, Gerhard Fierlbeck, Santhanam Lakshminarayanan, Yannick Allanore, Janet E Pope, Gabriela Riemekasten, Virginia Steen, Ulf Müller-Ladner, Helen Spotswood, Laura Burke, Jeffrey Siegel, Angelika Jahreis, Daniel E Furst
Objectives Assess the efficacy and safety of tocilizumab in patients with systemic sclerosis (SSc) in a phase II study. Methods Patients with SSc were treated for 48 weeks in an open-label extension phase of the faSScinate study with weekly 162 mg subcutaneous tocilizumab. Exploratory end points included modified Rodnan Skin Score (mRSS) and per cent predicted forced vital capacity (%pFVC) through week 96. Results Overall, 24/44 (55%) placebo-tocilizumab and 27/43 (63%) continuous-tocilizumab patients completed week 96. Observed mean (SD (95% CI)) change from baseline in mRSS was –3.1 (6.3 (–5.4 to –0.9)) for placebo and –5.6 (9.1 (–8.9 to–2.4)) for tocilizumab at week 48 and –9.4 (5.6 (–8.9 to –2.4)) for placebo-tocilizumab and –9.1 (8.7 (–12.5 to –5.6)) for continuous-tocilizumab at week 96. Of patients who completed week 96, any decline in %pFVC was observed for 10/24 (42% (95% CI 22% to 63%)) placebo-tocilizumab and 12/26 (46% (95% CI 27% to 67%)) continuous-tocilizumab patients in the open-label period; no patients had >10% absolute decline in %pFVC. Serious infection rates/100 patient-years (95% CI) were 10.9 (3.0 to 27.9) with placebo and 34.8 (18.0 to 60.8) with tocilizumab during the double-blind period by week 48 and 19.6 (7.2 to 42.7) with placebo-tocilizumab and 0.0 (0.0 to 12.2) with continuous-tocilizumab during the open-label period. Conclusions Skin score improvement and FVC stabilisation in the double-blind period were observed in placebo-treated patients who transitioned to tocilizumab and were maintained in the open-label period. Safety data indicated increased serious infections in patients with SSc but no new safety signals with tocilizumab. Trial registration number NCT01532869; Results.
Evaluation of the change in structural radiographic sacroiliac joint damage after 2 years of etanercept therapy (EMBARK trial) in comparison to a contemporary control cohort (DESIR cohort) in recent onset axial spondyloarthritis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Maxime Dougados, Walter P Maksymowych, Robert B M Landewé, Anna Moltó, Pascal Claudepierre, Manouk de Hooge, Robert G Lambert, Randi Bonin, Jack F Bukowski, Heather E Jones, Isabelle Logeart, Ron Pedersen, Annette Szumski, Bonnie Vlahos, Désirée van der Heijde
Objective To compare 2 years of radiographic sacroiliac joint (SIJ) changes in patients with recent onset axial spondyloarthritis (axSpA) receiving etanercept in a clinical trial (EMBARK) to similar patients not receiving biologics in a cohort study (DESIR). Methods Endpoints were changes at week 104 per the modified New York (mNY) grading system in total SIJ score (primary endpoint) and net percentage of patients with progression defined three ways. Treatment effect was analysed with and without adjustment for baseline covariates. Results At 104 weeks, total SIJ score improved in the etanercept group (n=154, adjusted least-squares mean change: –0.14) and worsened in the control group (n=182, change: 0.08). The adjusted difference between groups (etanercept minus control) was –0.22 (95% CI –0.38 to –0.06), p=0.008. The net percentage of patients with progression was significantly lower in the etanercept versus the control group for two of three binary endpoints: –1.9% versus 1.6% (adjusted difference for etanercept minus control: –4.7%,95% CI –9.9 to 0.5, p=0.07) for change in mNY criteria; –1.9% versus 7.8% (adjusted difference: –18.2%,95% CI –30.9 to –5.6, p=0.005) for change ≥1 grade in ≥1 SIJ; and –0.6% versus 6.7% (adjusted difference: –16.4%,95% CI –27.9 to –5.0, p=0.005) for change ≥1 grade in ≥1 SIJ, with shift from 0 to 1 or 1 to 0 considered no change. Conclusion Despite the slow radiographic SIJ progression rate over 2 years in axSpA, this study suggests a lower rate of progression in the SIJ with etanercept than without anti-tumour necrosis factor therapy. Trial registration numbers [NCT01258738], [NCT01648907]; Post-results. : /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01258738&atom=%2Fannrheumdis%2F77%2F2%2F221.atom : /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01648907&atom=%2Fannrheumdis%2F77%2F2%2F221.atom
Lack of placental transfer of certolizumab pegol during pregnancy: results from CRIB, a prospective, postmarketing, pharmacokinetic study Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Xavier Mariette, Frauke Förger, Bincy Abraham, Ann D Flynn, Anna Moltó, René-Marc Flipo, Astrid van Tubergen, Laura Shaughnessy, Jeff Simpson, Marie Teil, Eric Helmer, Maggie Wang, Eliza F Chakravarty
Objectives There is a need for effective and safe treatment during pregnancy in women with chronic inflammatory diseases. This study evaluated placental transfer of certolizumab pegol (CZP), an Fc-free anti-tumour necrosis factor drug, from CZP-treated pregnant women to their infants. Methods CRIB was a pharmacokinetic (PK) study of women ≥30 weeks pregnant receiving commercial CZP for a locally approved indication (last dose ≤35 days prior to delivery). Blood samples were collected from mothers, umbilical cords and infants at delivery, and infants again at weeks 4 and 8 post-delivery. CZP plasma concentrations were measured with a highly sensitive and CZP-specific electrochemiluminescence immunoassay (lower limit of quantification 0.032 μg/mL). Results Sixteen women entered and completed the study. Maternal CZP plasma levels at delivery were within the expected therapeutic range (median [range] 24.4 [5.0–49.4] μg/mL). Of the 16 infants, 2 were excluded from the per-protocol set: 1 due to missing data at birth and 1 due to implausible PK data. Of the remaining 14 infants, 13 had no quantifiable CZP levels at birth (<0.032 μg/mL), and 1 had a minimal CZP level of 0.042 μg/mL (infant/mother plasma ratio 0.0009); no infants had quantifiable CZP levels at weeks 4 and 8. Of 16 umbilical cord samples, 1 was excluded due to missing data; 3/15 had quantifiable CZP levels (maximum 0.048 μg/mL). Conclusions There was no to minimal placental transfer of CZP from mothers to infants, suggesting lack of in utero foetal exposure during the third trimester. These results support continuation of CZP treatment during pregnancy, when considered necessary. Trial registration number [NCT02019602]; Results. : /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02019602&atom=%2Fannrheumdis%2F77%2F2%2F228.atom
Safety, immunogenicity and efficacy after switching from reference infliximab to biosimilar SB2 compared with continuing reference infliximab and SB2 in patients with rheumatoid arthritis: results of a randomised, double-blind, phase III transition study Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Josef S Smolen, Jung-Yoon Choe, Nenad Prodanovic, Jaroslaw Niebrzydowski, Ivan Staykov, Eva Dokoupilova, Asta Baranauskaite, Roman Yatsyshyn, Mevludin Mekic, Wieslawa Porawska, Hana Ciferska, Krystyna Jedrychowicz-Rosiak, Agnieszka Zielinska, Younju Lee, Young Hee Rho
Objectives Efficacy, safety and immunogenicity results from the phase III study of SB2, a biosimilar of reference infliximab (INF), were previously reported through 54 weeks. This transition period compared results in patients with rheumatoid arthritis (RA) who switched from INF to SB2 with those in patients who maintained treatment with INF or SB2. Methods Patients with moderate to severe RA despite methotrexate treatment were randomised (1:1) to receive SB2 or INF at weeks 0, 2 and 6 and every 8 weeks thereafter until week 46. At week 54, patients previously receiving INF were rerandomised (1:1) to switch to SB2 (INF/SB2 (n=94)) or to continue on INF (INF/INF (n=101)) up to week 70. Patients previously receiving SB2 continued on SB2 (SB2/SB2 (n=201)) up to week 70. Efficacy, safety and immunogenicity were assessed up to week 78. Results Efficacy was sustained and comparable across treatment groups. American College of Rheumatology (ACR) 20 responses between weeks 54 and 78 ranged from 63.5% to 72.3% with INF/SB2, 66.3%%–69.4% with INF/INF and 65.6%–68.3% with SB2/SB2. Treatment-emergent adverse events during this time occurred in 36.2%, 35.6% and 40.3%, respectively, and infusion-related reactions in 3.2%, 2.0% and 3.5%. Among patients who were negative for antidrug antibodies (ADA) up to week 54, newly developed ADAs were reported in 14.6%, 14.9% and 14.1% of the INF/SB2, INF/INF and SB2/SB2 groups, respectively. Conclusions The efficacy, safety and immunogenicity profiles remained comparable among the INF/SB2, INF/INF and SB2/SB2 groups up to week 78, with no treatment-emergent issues or clinically relevant immunogenicity after switching from INF to SB2. Trial registration number NCT01936181; EudraCT number: 2012-005733-37.
Development of a consensus core dataset in juvenile dermatomyositis for clinical use to inform research Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Liza J McCann, Clarissa A Pilkington, Adam M Huber, Angelo Ravelli, Duncan Appelbe, Jamie J Kirkham, Paula R Williamson, Amita Aggarwal, Lisa Christopher-Stine, Tamas Constantin, Brian M Feldman, Ingrid Lundberg, Sue Maillard, Pernille Mathiesen, Ruth Murphy, Lauren M Pachman, Ann M Reed, Lisa G Rider, Annet van Royen-Kerkof, Ricardo Russo, Stefan Spinty, Lucy R Wedderburn, Michael W Beresford
Objectives This study aimed to develop consensus on an internationally agreed dataset for juvenile dermatomyositis (JDM), designed for clinical use, to enhance collaborative research and allow integration of data between centres. Methods A prototype dataset was developed through a formal process that included analysing items within existing databases of patients with idiopathic inflammatory myopathies. This template was used to aid a structured multistage consensus process. Exploiting Delphi methodology, two web-based questionnaires were distributed to healthcare professionals caring for patients with JDM identified through email distribution lists of international paediatric rheumatology and myositis research groups. A separate questionnaire was sent to parents of children with JDM and patients with JDM, identified through established research networks and patient support groups. The results of these parallel processes informed a face-to-face nominal group consensus meeting of international myositis experts, tasked with defining the content of the dataset. This developed dataset was tested in routine clinical practice before review and finalisation. Results A dataset containing 123 items was formulated with an accompanying glossary. Demographic and diagnostic data are contained within form A collected at baseline visit only, disease activity measures are included within form B collected at every visit and disease damage items within form C collected at baseline and annual visits thereafter. Conclusions Through a robust international process, a consensus dataset for JDM has been formulated that can capture disease activity and damage over time. This dataset can be incorporated into national and international collaborative efforts, including existing clinical research databases.
Ideal target for psoriatic arthritis? Comparison of remission and low disease activity states in a real-life cohort Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Leonieke J J van Mens, Marleen G H van de Sande, Arno W R van Kuijk, Dominique Baeten, Laura C Coates
Background Psoriatic arthritis (PsA) recommendations state that the target of treatment should be remission or low disease activity (LDA). We used a real-life dataset to compare different potential targets. Methods 250 patients with PsA considered in an acceptable disease state according to their rheumatologist were included. Targets for remission were the Disease Activity Index for Psoriatic Arthritis (DAPSA) and clinical DAPSA (cDAPSA) remission (≤4), very low disease activity (VLDA) and Psoriatic Arthritis Disease Activity Score ≤1.9. LDA targets analysed were the DAPSA ≤14, cDAPSA ≤13, minimal disease activity (MDA) and adjusted MDA targets: MDAjoints with both tender joint count (TJC) and swollen joint count (SJC) mandated, MDAskin (psoriasis area and severity index (PASI) mandated) and MDAjoints&skin with TJC, SJC and PASI mandated. Results Comparison of the several candidate targets demonstrates that VLDA is achieved by the lowest proportion of patients and includes patients with the lowest residual disease activity compared with the other remission targets. The modified MDA measures are the most stringent targets for LDA in terms of residual disease on joints, psoriasis and enthesitis within patients achieving the target. In both remission and LDA, the inclusion of C reactive protein did not show an added value. The exclusion of a skin domain, as in the DAPSA measures, resulted in negligence of skin disease and a negative impact on the quality of life in some patients. Conclusions The different remission and LDA targets show us significant overlap between measures, but these measures targeting the same definition do differ in terms of allowance of residual disease. Inclusion of laboratory markers seems unnecessary, although exclusion of a skin domain may result in psoriasis not being assessed resulting in residual impactful skin disease.
Development and psychometric validation of a patient-reported outcome measure to assess fears in rheumatoid arthritis and axial spondyloarthritis: the Fear Assessment in Inflammatory Rheumatic diseases (FAIR) questionnaire Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Laure Gossec, Pierre Chauvin, Alain Saraux, Christophe Hudry, Gabrielle Cukierman, Thibault de Chalus, Caroline Dreuillet, Vincent Saulot, Sabine Tong, Françoise Russo-Marie, Jean-Michel Joubert, Francis Berenbaum
Objectives To develop and validate an outcome measure for assessing fears in patients with rheumatoid arthritis (RA) and axial spondyloarthritis (axSpA). Methods Fears were identified in a qualitative study, and reformulated as assertions with which participants could rate their agreement (on a 0–10 numeric rating scale). A cross-sectional validation study was performed including patients diagnosed with RA or axSpA. Redundant items (correlation >0.65) were excluded. Internal consistency (Cronbach’s α) and factorial structure (principal component analysis) were assessed. Patients were classified into fear levels (cluster analysis). Associations between patient variables and fear levels were evaluated using multiple logistic regression. Results 672 patients were included in the validation study (432 RA, 240 axSpA); most had moderate disease activity and were prescribed biologics. The final questionnaire included 10 questions with high internal consistency (α: 0.89) and a single dimension. Mean scores (±SD) were 51.2 (±25.4) in RA and 60.5 (±22.9) in axSpA. Groups of patients with high (17.2%), moderate (41.1%) and low (41.7%) fear scores were identified. High fear scores were associated with high Arthritis Helplessness Index scores (OR 6.85, 95% CI (3.95 to 11.87)); high Hospital Anxiety and Depression Scale anxiety (OR 5.80, 95% CI (1.19 to 4.22)) and depression (OR 2.37, 95% CI (1.29 to 4.37)) scores; low education level (OR 3.48, 95% CI (1.37 to 8.83)); and high perceived disease activity (OR 2.36, 95% CI (1.10 to 5.04)). Conclusions Overall, 17.2% of patients had high fear scores, although disease was often well controlled. High fear scores were associated with psychological distress. This questionnaire could be useful both in routine practice and clinical trials.
Influence of disease activity and medications on offspring birth weight, pre-eclampsia and preterm birth in systemic lupus erythematosus: a population-based study Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Carina Götestam Skorpen, Stian Lydersen, Inge-Margrethe Gilboe, Johan Fredrik Skomsvoll, Kjell Å Salvesen, Øyvind Palm, Hege Suorza Svean Koksvik, Bente Jakobsen, Marianne Wallenius
Objectives Exploring the associations between disease activity and medications with offspring birth weight, pre-eclampsia and preterm birth in systemic lupus erythematosus (SLE). Methods Data from the Medical Birth Registry of Norway (MBRN) were linked with data from RevNatus, a nationwide observational register recruiting women with inflammatory rheumatic diseases. Singleton births in women with SLE included in RevNatus 2006–2015 were cases (n=180). All other singleton births registered in MBRN during this time (n=498 849) served as population controls. Z-score for birth weight adjusted for gestational age and gender was calculated. Disease activity was assessed using Lupus Activity Index in Pregnancy. We compared z-scores for birth weight, pre-eclampsia and preterm birth in cases with inactive disease, cases with active disease and population controls. Results Z-scores for birth weight in offspring were lower in inactive (−0.64) and active (−0.53) diseases than population controls (−0.11). Inactive disease did not predict pre-eclampsia while active disease yielded OR 5.33 and OR 3.38 compared with population controls and inactive disease, respectively. Preterm birth occurred more often in inactive (OR 2.57) and active (OR 8.66) diseases compared with population controls, and in active compared with inactive disease (OR 3.36). Conclusions SLE has an increased odds for low birth weight and preterm birth, amplified by active disease. The odds for pre-eclampsia is elevated in active, but not inactive disease. This calls for tight follow-up targeting inactive disease before and throughout pregnancy.
Stepwise dose increase of febuxostat is comparable with colchicine prophylaxis for the prevention of gout flares during the initial phase of urate-lowering therapy: results from FORTUNE-1, a prospective, multicentre randomised study Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Hisashi Yamanaka, Shigenori Tamaki, Yumiko Ide, Hyeteko Kim, Kouichi Inoue, Masayuki Sugimoto, Yuji Hidaka, Atsuo Taniguchi, Shin Fujimori, Tetsuya Yamamoto
Objectives To determine whether febuxostat with stepwise dose increase is as useful as colchicine prophylaxis in reducing gout flares during the initial introduction of urate-lowering therapy in patients with gout in comparison with febuxostat with no dose titration. Methods In this prospective, multicentre, randomised open-label comparative study, patients were randomised to group A (stepwise dose increase of febuxostat from 10 to 40 mg/day), group B (fixed-dose febuxostat 40 mg/day plus colchicine 0.5 mg/day) or group C (fixed-dose febuxostat 40 mg/day) and observed for 12 weeks. Gout flare was defined as non-steroidal anti-inflammatory drug use for gout symptoms. Results A total of 255 patients were randomised, and 241 patients were treated. Among the treated patients, gout flares were experienced by 20/96 (20.8%) in group A, 18/95 (18.9%) in group B and 18/50 (36.0%) in group C. The incidence of flare was significantly lower in groups A and B than that in group C (P=0.047 and P=0.024, respectively), although the differences were not significant after correction for multiple comparisons. No significant difference was noted between the incidence of gout flare in groups A and B. Conclusions Our data suggested that stepwise dose increase of febuxostat and low-dose colchicine prophylaxis effectively reduced gout flares in comparison with fixed-dose febuxostat alone. Stepwise dose increase of febuxostat may be an effective alternative to low-dose colchicine prophylaxis during the introduction of urate-lowering therapy. Trial registration number UMIN 000008414 .
Risk of uveitis and inflammatory bowel disease in people with psoriatic arthritis: a population-based cohort study Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Rachel Charlton, Amelia Green, Gavin Shaddick, Julia Snowball, Alison Nightingale, William Tillett, Catherine H Smith, Neil McHugh
Objectives To determine the risk of uveitis and inflammatory bowel disease (IBD) in patients with psoriatic arthritis (PsA) compared with the general population and patients with psoriasis. Methods A cohort study using data from the UK Clinical Practice Research Datalink between 1998 and 2014. Patients with incident PsA aged 18–89 years were identified and matched to a cohort of patients with psoriasis and a general population cohort. The incidence of uveitis, all IBD, Crohn’s disease and ulcerative colitis was calculated for each study cohort and adjusted relative risks (RRadj) were calculated using conditional Poisson regression. Results 6783 incident cases of PsA were identified with a median age of 49 years. The risk of uveitis was significantly higher in the PsA cohort than in the general population and psoriasis cohorts (RRadj 3.55, 95% CI 2.21 to 5.70 and RRadj 2.13, 95% CI 1.40 to 3.24, respectively). A significant increase was observed for Crohn’s disease (RRadj 2.96, 95% CI 1.46 to 6.00 and RRadj3.60, 95% CI 1.83 to 7.10) but not for ulcerative colitis (RRadj1.30, 95% CI 0.66 to 2.56 and RRadj0.98, 95% CI 0.50 to 1.92). Conclusions In a primary care-based incidence cohort of patients with PsA, there were substantial risks of developing uveitis and/or Crohn’s disease, but not ulcerative colitis, when compared with the general population and psoriasis controls.
Predictors of revision, prosthetic joint infection and mortality following total hip or total knee arthroplasty in patients with rheumatoid arthritis: a nationwide cohort study using Danish healthcare registers Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Rene Lindholm Cordtz, Kristian Zobbe, Pil Højgaard, Lars Erik Kristensen, Søren Overgaard, Anders Odgaard, Hanne Lindegaard, Lene Dreyer
Objectives To investigate predictors of 10-year risk of revision and 1-year risk of prosthetic joint infection (PJI) and death following total hip/total knee arthroplasty (THA/TKA) in (1) patients with rheumatoid arthritis (RA) compared with patients with osteoarthritis (OA); and (2) patients with RA treated with biological disease-modifying antirheumatic drugs (bDMARD) within 90 days preceding surgery compared with non-treated. Methods Register-based cohort study using the Danish National Patient Register, the DANBIO rheumatology register (RA-specific confounders and treatment episodes) and the Danish Hip and Knee Arthroplasty Registers. Survival analyses were used to calculate confounder-adjusted sub-HRs (SHR) and HRs. Results In total, 3913 patients with RA with THA/TKA were compared with 120 499 patients with OA. Patients with RA had decreased risk of revision (SHR 0.71 (0.57–0.89)), but increased risk of PJI (SHR=1.46 (1.13–1.88)) and death (HR=1.25 (1.01–1.55)). In DANBIO, 345 of 1946 patients with RA with THA/TKA had received bDMARD treatment within 90 days preceding surgery. bDMARD-treated patients did not have a statistically significant increased risk of revision (SHR=1.49 (0.65–3.40)), PJI (SHR=1.61 (0.70–3.69)) nor death (HR=0.75 (0.24–2.33)) compared with non-treated. Glucocorticoid exposure (HR=2.87 (1.12–7.34)) and increasing DAS28 (HR=1.49 (1.01–2.20)) were risk factors for mortality. Conclusion Patients with RA had a decreased 10-year risk of revision while the risk of death and PJI was increased compared with patients with OA following THA/TKA. bDMARD exposure was not associated with statistically significant increased risk of neither PJI nor death in this study. Glucocorticoid exposure and increased disease activity were associated with an increased risk of death.
Testing treat-to-target outcomes with initial methotrexate monotherapy compared with initial tumour necrosis factor inhibitor (adalimumab) plus methotrexate in early rheumatoid arthritis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Arthur Kavanaugh, Ronald F van Vollenhoven, Roy Fleischmann, Paul Emery, Iain Sainsbury, Stefan Florentinus, Su Chen, Benoît Guérette, Hartmut Kupper, Josef S Smolen
Objectives To compare responses in patients with early rheumatoid arthritis (RA) initially treated with the tumour necrosis factor inhibitor (TNFi) adalimumab+methotrexate (MTX) versus MTX monotherapy who may have continued receiving MTX or switched to adalimumab rescue therapy after inadequate response to MTX. Methods OPTIMA enrolled MTX-naive patients with active RA for <1 year. This post hoc analysis determined the proportion of patients, stratified by initial treatment, who achieved 28-joint modified Disease Activity Score based on C reactive protein <3.2, normal function and/or no radiographic progression at weeks 26, 52 and 78. Results Significantly greater proportions of patients initially treated with adalimumab+MTX (n=466) compared with MTX monotherapy (n=460) achieved good clinical (53% vs 30%), functional (45% vs 33%) and radiographic (87% vs 72%) outcomes at week 26. From weeks 26 to 78, adalimumab rescue patients achieved similar clinical and functional outcomes versus patients initially treated with adalimumab+MTX. However, significantly more patients initially treated with adalimumab+MTX had no radiographic progression at weeks 52 and 78 versus patients initially treated with MTX (both timepoints: 86% vs 72%). Conclusions In early RA, starting with MTX monotherapy and adding TNFi after 26 weeks yields similar longer term clinical results as starting with TNFi+MTX combination therapy but allows a small but significant accrual of radiographic damage.
Low-dose CT detects more progression of bone formation in comparison to conventional radiography in patients with ankylosing spondylitis: results from the SIAS cohort Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Anoek de Koning, Freek de Bruin, Rosaline van den Berg, Sofia Ramiro, Xenofon Baraliakos, Juergen Braun, Floris A van Gaalen, Monique Reijnierse, Désirée van der Heijde
Objectives To compare the CT Syndesmophyte Score (CTSS) for low-dose CT (ldCT) with the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) for conventional radiographs (CR) in patients with ankylosing spondylitis (AS). Methods Patients with AS in the Sensitive Imaging in Ankylosing Spondylitis cohort had lateral cervical and lumbar spine CR and whole spine ldCT at baseline and 2 years. CR and ldCT images were scored by two readers, paired by patient, blinded to time order, per imaging modality. For the total score analysis, we used average scores of readers per corner on CR or quadrant on ldCT. For the syndesmophyte analysis we used individual reader and consensus scores, regarding new or growing syndesmophyte at the same corner/quadrant. Results 50 patients were included in the syndesmophyte analysis and 37 in the total score analysis. Mean (SD) status scores for mSASSS (range 0–72) and CTSS (range 0–552) at baseline were 17.9 (13.8) and 161.6 (126.6), and mean progression was 2.4 (3.8) and 17.9 (22.1). Three times as many patients showed new or growing syndesmophytes at ≥3 quadrants on ldCT compared with ≥3 corners on CR for individual readers; for consensus this increased to five times. In 50 patients, 36 new or growing syndesmophytes are seen on CR compared with 151 on ldCT, most being found in the thoracic spine. Conclusions ldCT, covering the whole spine, detects more progression in the form of new and growing syndesmophytes in patients with AS compared with CR, which is limited to the cervical and lumbar spine. Most progression occurred in the thoracic spine.
Monocyte alterations in rheumatoid arthritis are dominated by preterm release from bone marrow and prominent triggering in the joint Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Biljana Smiljanovic, Anna Radzikowska, Ewa Kuca-Warnawin, Weronika Kurowska, Joachim R Grün, Bruno Stuhlmüller, Marc Bonin, Ursula Schulte-Wrede, Till Sörensen, Chieko Kyogoku, Anne Bruns, Sandra Hermann, Sarah Ohrndorf, Karlfried Aupperle, Marina Backhaus, Gerd R Burmester, Andreas Radbruch, Andreas Grützkau, Wlodzimierz Maslinski, Thomas Häupl
Objective Rheumatoid arthritis (RA) accompanies infiltration and activation of monocytes in inflamed joints. We investigated dominant alterations of RA monocytes in bone marrow (BM), blood and inflamed joints. Methods CD14+ cells from BM and peripheral blood (PB) of patients with RA and osteoarthritis (OA) were profiled with GeneChip microarrays. Detailed functional analysis was performed with reference transcriptomes of BM precursors, monocyte blood subsets, monocyte activation and mobilisation. Cytometric profiling determined monocyte subsets of CD14++CD16−, CD14++CD16+ and CD14+CD16+ cells in BM, PB and synovial fluid (SF) and ELISAs quantified the release of activation markers into SF and serum. Results Investigation of genes differentially expressed between RA and OA monocytes with reference transcriptomes revealed gene patterns of early myeloid precursors in RA-BM and late myeloid precursors along with reduced terminal differentiation to CD14+CD16+monocytes in RA-PB. Patterns associated with tumor necrosis factor/lipopolysaccharide (TNF/LPS) stimulation were weak and more pronounced in RA-PB than RA-BM. Cytometric phenotyping of cells in BM, blood and SF disclosed differences related to monocyte subsets and confirmed the reduced frequency of terminally differentiated CD14+CD16+monocytes in RA-PB. Monocyte activation in SF was characterised by the predominance of CD14++CD16++CD163+HLA-DR+ cells and elevated concentrations of sCD14, sCD163 and S100P. Conclusion Patterns of less mature and less differentiated RA-BM and RA-PB monocytes suggest increased turnover with accelerated monocytopoiesis, BM egress and migration into inflamed joints. Predominant activation in the joint indicates the action of local and primary stimuli, which may also promote adaptive immune triggering through monocytes, potentially leading to new diagnostic and therapeutic strategies.
Immunoscintigraphic detection of tumour necrosis factor by radiolabelled certolizumab pegol in patients with erosive hand osteoarthritis: a proof-of-concept study Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Ruth Wittoek, Philippe Carron, Bieke Lambert, Paulien Meersseman, Gust Verbruggen, Filip Van den Bosch, Dirk Elewaut
Erosive hand osteoarthritis (OA) of the interphalangeal (IP) joints is characterised by a more pronounced inflammatory burden of disease.1 Whether it is a subset of hand OA or just a radiographic phase remains a matter of debate. The pathogenesis of erosive OA is not yet understood, but articular cartilage degeneration and subchondral bone resorption are some of the major characteristics. In general, several cytokine-driven pathways such as receptor activator of nuclear factor κB, interleukin-1 and tumour necrosis factor (TNF) alpha are involved at the level of the subchondral bone-inducing dynamic morphological changes.2–4 In post hoc analyses in two recent placebo-controlled pilot studies in erosive OA, it was shown that adalimumab and etanercept were able to diminish structural progression after 1 year of treatment in a subgroup of patients who showed soft tissue swelling at baseline.5 ,6 We hypothesised …
The EULAR points to consider for health professionals undertaking musculoskeletal ultrasound for rheumatic and musculoskeletal diseases Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Heidi J Siddle, Peter Mandl, Daniel Aletaha, Thea P Vliet Vlieland, Marina Backhaus, Patricia Cornell, Maria-Antonietta D'Agostino, Karen Ellegaard, Annamaria Iagnocco, Bente Jakobsen, Tiina Jasinski, Nina H Kildal, Michaela Lehner, Ingrid Möller, Gabriela M Supp, Philip O'Connor, Anthony C Redmond, Esperanza Naredo, Richard J Wakefield
Musculoskeletal ultrasound has evolved into an important clinical decision-making tool by assisting in the diagnosis of inflammatory arthritis, monitoring disease activity and therapeutic response, and guiding interventions.1–7 The role of the non-medical health professional has advanced, with many undertaking training and using musculoskeletal ultrasound to improve patient care and in doing so, increasing their scope of practice. Health professionals with clinical expertise and experience using ultrasound are also providing training for colleagues and medical clinicians. As previously described among rheumatologists,8 ,9 the use of musculoskeletal ultrasound and training undertaken varies significantly between different professional groups and across Europe. Guidelines to support training for rheumatologists have been formulated10 but currently there are no recommendations to support the education and training needs of non-medical health professionals using musculoskeletal ultrasound. A European League Against Rheumatism (EULAR) task force was established to reach a consensus on the role of, and education and training needs of health professionals undertaking musculoskeletal ultrasound for the management of people with …
Plasma oxypurinol as a measure of adherence in clinical trials Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Lisa K Stamp, Tony Merriman, Christopher Frampton, Mei Zhang, Mary Wallace, Jeffrey N Miner, Nicola Dalbeth
Adherence to urate-lowering therapy (ULT) in people with gout is often poor. A recent systematic review revealed 10%–46% of people with gout adhere to treatment.1 Among chronic diseases, gout has particularly low adherence rates.2 Adherence in clinical trials of ULT is a particularly important issue, as the primary efficacy endpoint for most studies (including phase III studies that form the basis of regulatory approval) is the ability of the agent to reduce serum urate (SU). Pill count-based adherence ≥80% is frequently regarded as an appropriate cut-off for good adherence; however, this is an indirect measure. Measurement of drug concentration may be an improved measure of the adherence.3 The aim of this study was to establish the relationship between two different measures of adherence and SU endpoints in a clinical trial of allopurinol in gout. Data, including demographics, SU, estimated glomerular filtration rate (eGFR), and plasma oxypurinol and allopurinol concentrations were available from a single study visit, and cumulative pill counts from the entire study period were available for 395 …
Eplerenone treatment alleviates the development of joint lesions in a new rat model of spontaneous metabolic-associated osteoarthritis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Chaohua Deng, Arnaud Bianchi, Nathalie Presle, David Moulin, Meriem Koufany, Cécile Guillaume, Hervé Kempf, Anne Pizard
Increasing epidemiological and clinical studies suggest that metabolic syndrome (MetS) plays a role in the incidence and progression of osteoarthritis (OA).1 2 However, in absence of an appropriate MetS-associated OA experimental model,3 the MetS contribution to the joint phenotype in OA remains difficult to investigate and the evaluation of potential disease-modifying OA drugs (DMOADs) is complicated. Noteworthy, in contrast to their lean SHHF+/+(spontaneously hypertensive heart failure) controls, obese SHHFcp/cp rats, a well-characterised model of MetS,4 develop drastic metabolic, cardiovascular and renal alterations that are substantially improved through an early chronic mineralocorticoid receptor antagonism (MRA) treatment.5 Thus, by comparing young (1.5 months) and aged (12.5 months) lean SHHF+/+ and obese SHHFcp/cp rats, we sought to evaluate for the first time the potential (1) contribution of MetS to joint alterations and (2) therapeutic benefits derived from chronic MRA treatment by eplerenone (figure 1A). Figure 1 Preventive 11-month treatment with mineralocorticoid receptor antagonist eplerenone alleviated the metabolic syndrome (MetS)-associated joint lesions in SHHF model. (A) Experimental design of the study. Lean spontaneously hypertensive heart failure (SHHF+/+) and obese SHHFcp/cp rats were divided randomly into treatment groups. Untreated groups (n=4 for SHHF+/+ and n=4 for SHHFcp/cp) were given …
Ustekinumab inhibits Th1 and Th17 polarisation in a patient with giant cell arteritis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Maxime Samson, Thibault Ghesquière, Sabine Berthier, Bernard Bonnotte
Although glucocorticoids (GC) remain the corner stone of giant cell arteritis (GCA) treatment, GC-sparing strategies are needed because GC are responsible for side effects.1 Recent advances in the pathophysiology of GCA showed that CD4+ T cells are recruited in the arterial wall and polarised into Th1 and Th17 cells,2 3 the latter being sensitive to GC-mediated suppression, whereas Th1 response persists in GC-treated patients,2 which triggers the recruitment of macrophages4 and could be implicated in the occurrence of relapses when GC are tapered. Interleukin (IL)-12 and IL-23 are two cytokines involved in Th1 and Th17 polarisations, respectively.5 These two cytokines share a common subunit (p40), which allows ustekinumab, a humanised anti-p40 monoclonal antibody, to target both IL-12 and IL-23 pathways, thus disrupting in theory Th1 and Th17 immune responses.6 Recently, an open-label study reported on the efficacy and safety of …
Response to: ustekinumab inhibits Th1 and Th17 polarisation in a giant-cell arteritis patient by Samson et al Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Richard Conway, Ursula Fearon, Eamonn S Molloy
We thank Samson et al for their interest in our article on ustekinumab in giant-cell arteritis (GCA) and for their comments on our study.1 2 Our initial pilot study reported promising results with the use of ustekinumab in refractory GCA.1 GCA is associated with considerable disease-related and treatment-related morbidity.3 4 While glucocorticoids remain the cornerstone of treatment, the associated increased rates of adverse events such as fractures, sepsis, hypertension and diabetes mellitus are significant concerns to both physicians and patients.4 There is a critical unmet need for new treatment options in GCA to minimise the cumulative glucocorticoid burden …
ANCA-associated vasculitis: mission incomplete Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Sergey V Moiseev, Pavel I Novikov, Ilya Smitienko
Over the last decades, introduction of high-dose corticosteroids and immunosuppressive agents and later rituximab into the current algorithms for remission induction and maintenance treatment resulted in a tremendous improvement in the survival of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). However, in the recent meta-analysis of observational studies, Tan et al showed a 2.7-fold increased risk of death in patients with AAV when compared with the general population.1 Notably, there was a trend towards lower mortality in the most recent compared with the earlier cohorts. In our own study in 242 patients with granulomatosis with polyangiitis, we also found a significant decrease in mortality in the recent years (2004–2012 vs 1970–2003; p=0.04) and a shift towards a higher percentage of cardiovascular events and complications of immunosuppression as the causes of death.2 The results of Tan et al ’s meta-analysis are not surprising and suggest that AAV, particularly if not promptly diagnosed and treated, remains a life-threatening disease and requires proper management. The pitfalls of the current treatment for AAV are well known and include relatively frequent relapses, especially in proteinase-3 (PR3) ANCA-positive patients (up to 50% within 5 years), delayed diagnosis and late initiation of treatment in a proportion of patients, high rate of end-stage renal disease (ESRD), which did not change significantly in the current era, unknown optimal duration of maintenance therapy, burden of immunosuppression (eg, infections and malignancy), and increased risk of cardiovascular and thromboembolic events, which may be related …
Response to: ‘Mortality in ANCA-associated vasculitis: mission incomplete’ by Moiseev et al Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Juan Antonio Avina-Zubieta, Natasha Dehghan, Ju Ann Tan
We thank Professor Moiseev and colleagues for their comments on our article.1 We acknowledge the limitations of including observational studies in our meta-analysis. We also agree that observational studies often suffer from confounding and selection biases, limiting the comparability between studies.2 This was also reflected by the …
Comment on CONCEPT by Reginster et al: are the authors’ interpretations supported by the data analysis? Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Sinan Kardeş
I read with great interest the ChONdroitin versus CElecoxib versus Placebo Trial (CONCEPT) by Reginster et al. 1 I would like to raise some worthwhile issues that need to be clarified. The authors concluded that 800 mg/day pharmaceutical-grade chondroitin sulfate (CS) is similar to celecoxib in improving pain and function after 6 months in patients with symptomatic knee osteoarthritis (OA).1 However, the interpretation of similarity between these two active treatments was not based on the analysis of the data. Because, the authors did not assess whether these treatments are similar by equivalence analysis. Rather, the authors assessed the superiority between these two active treatments by aiming to detect a difference in intention-to-treat (ITT) populations—although the study might not be powered to be able to detect differences between these two active treatments (type 2 error), since sample size is calculated to show superiority of CS over placebo; and they failed to show a difference between CS and celecoxib. According to the Consolidated Standards of Reporting Trials 2010 statement on reporting of non-inferiority and equivalence randomised trials, ’Failure to show a difference does not mean they are equivalent. By contrast, …
CONCEPT provides robust evidence that chondroitin sulfate is superior to placebo and similar to celecoxib in the symptomatic management of osteoarthritis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-01 Jean-Yves L Reginster
We are very grateful to our distinguished colleague for his constructive comments.1 However it seems that some keypoints of our study were grossly misunderstood.2 As clearly stated, the objective of the CONCEPT study was to confirm that chondroitin sulfate (CS) is superior to placebo (PLB) in the symptomatic treatment of osteoarthritis, with the addition of a Celebrex (CLB) arm, as requested by the European Medicines Agency, to provide an external validation and to better assess the relevance of the difference in pain relief observed between the CS and PLB arms. There was no intent to demonstrate a non-inferiority of CS versus Celebrex. In such a case, a non-inferiority margin for the comparison would be mentioned in the protocol, and the power calculation would be substantially different. The use of the word similar in describing Visual Analogue Scale (VAS) and Lequesne scoring …
Response to: ‘Calprotectin is not independent from baseline erosion in predicting radiological progression in early rheumatoid arthritis’ by Chevreau et al Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-10 Maria Karolina Jonsson, Nina Paulshus Sundlisæter, Hilde Haugedal Nordal, Hilde Berner Hammer, Anna-Birgitte Aga, Désirée van der Heijde, Tore Kristian Kvien, Bjørg-Tilde Svanes Fevang, Siri Lillegraven, Espen Andre Haavardsholm
We appreciate the additional data regarding calprotectin and radiographic progression provided by Chevreau et al 1 as an eLetter addressing our published research paper.2 It is important to explore new biomarkers in different cohorts of patients with early and established rheumatoid arthritis (RA). Calprotectin levels have previously been shown to be associated with joint damage in established RA.3 4 Hammer et al 5 have shown that calprotectin was an independent predictor of radiographic joint damage after 10 years of follow-up. Chevreau et al present data on baseline calprotectin as a predictor of rapid radiographic progression (defined as an increase of ≥5 van der Heijde Sharp score units/year) in a large cohort of patients with early RA, and did not find calprotectin to be associated with structural damage when baseline erosions were …
Calprotectin is not independent from baseline erosion in predicting radiological progression in early rheumatoid arthritis. Comment on ‘Calprotectin as a marker of inflammation in patients with early rheumatoid arthritis’ by Jonsson et al Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-10 Maxime Chevreau, Marie-Hélène Paclet, Xavier Romand, Jean-Louis Quesada, Olivier Vittecoq, Philippe Dieudé, Bertrand Toussaint, Philippe Gaudin, Athan Baillet
We have read with great interest the article by Jonsson et al that was recently published online in ARD ,1 which suggested that calprotectin, also known as S100A8/S100A9 heterodimer, was associated with radiographic progression in early rheumatoid arthritis (RA). Calprotectin correlates significantly with inflammatory markers and disease activity score.2 Besides correlations between baseline calprotectin levels, Clinical Disease Activity Index and ultrasonography power Doppler, the authors showed that baseline calprotectin levels correlated with van der Heijde modified Sharp score (SHS) progression (defined as an increase ≥1 unit/year from 0 to 24 months), independently of age, gender, Clinical Disease Activity Index, erythrocyte sedimentation rate (ESR), C reactive protein (CRP) levels and rheumatoid factor positivity.1We analysed the initial serum calprotectin among patients with early RA fulfilling American College of Rheumatology/European League Against Rheumatism 2010 of the French observational cohort Etude et Suivi des POlyarthrites Indifférenciées Récentes (ESPOIR). Calprotectin serum concentrations were assessed according to manufacturer method (Hycult, Frontstraat, Netherlands; …
A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-09 Florence A Aeschlimann, Ezgi D Batu, Scott W Canna, Ellen Go, Ahmet Gül, Patrycja Hoffmann, Helen L Leavis, Seza Ozen, Daniella M Schwartz, Deborah L Stone, Annet van Royen-Kerkof, Daniel L Kastner, Ivona Aksentijevich, Ronald M Laxer
Objectives The association between mutations in TNFAIP3 , encoding the NF-kB regulatory protein A20, and a new autoinflammatory disease has recently been recognised. This study aims at describing the clinical phenotypes and disease course of patients with A20 haploinsufficiency (HA20). Methods Data for all cases from the initial publication, and additional cases identified through collaborations since, were collected using standardised data collection forms. Results A total of 16 patients (13 female) from seven families with a genetic diagnosis of HA20 were included. The disease commonly manifested in early childhood (range: first week of life to 29 years of age). The main clinical symptoms were recurrent oral, genital and/or gastrointestinal ulcers (16/16), musculoskeletal (9/16) and gastrointestinal complaints (9/16), cutaneous lesions (8/16), episodic fever (7/16), and recurrent infections (7/16). Clinical phenotypes varied considerably, even within families. Relapsing-remitting disease course was most common, and one patient died. Laboratory abnormalities included elevated acute-phase reactants and fluctuating presence of various autoantibodies such as antinuclear antibodies (4/10 patients tested) and anti-dsDNA (2/5). Tissue biopsy of different sites revealed non-specific chronic inflammation (6/12 patients tested), findings consistent with class V lupus nephritis in one patient, and pustules and normal results in two patients each. All patients were treated: 4/16 received colchicine and 12/16 various immunosuppressive agents. Cytokine inhibitors effectively suppressed systemic inflammation in 7/9 patients. Conclusions Early-onset recurrent oral, genital and/or gastrointestinal ulcers are the hallmark feature of HA20. Frequency and intensity of other clinical manifestations varied highly. Treatment regimens should be based on disease severity, and cytokine inhibitors are often required to control relapses.
Response to: ‘Performance of the 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies in clinical practice’ by Hočevar et al Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-09 Ingrid E Lundberg, Matteo Bottai, Anna Tjärnlund
We read with interest the letter titled ‘Performance of the 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies in clinical practice’ by Hočevar et al published in the Annals of the Rheumatic Diseases .1 In the letter the authors report the sensitivity and specificity of the recently published ‘ 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups ’2 observed in a retrospective cohort of 95 patients with idiopathic inflammatory myopathies (IIM) collected between 2010 and 2017 in a Slovenian rheumatology centre. As comparators, they used 72 subjects who had had a work-up for …
Inequity in biological DMARD prescription for spondyloarthritis across the globe: results from the ASAS-COMOSPA study Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-12-08 Elena Nikiphorou, Désirée van der Heijde, Sam Norton, Robert BM Landewé, Anna Molto, Maxime Dougados, Filip E Van den Bosch, Sofia Ramiro
Objectives The value of biological disease-modifying antirheumatic drugs (bDMARDs) in spondyloarthritis (SpA) is well recognised, but global access to these treatments can be limited due to high costs and other factors. This study explores country variation in the use of bDMARDs in SpA in relation to country-level socioeconomic factors. Methods Patients fulfilling the Assessment in SpondyloArthritis International Society (ASAS) SpA criteria in the multinational, cross-sectional ASAS Comorbidities in Spondyloarthritis study were studied. Current use of bDMARDs or conventional synthetic DMARDs (csDMARDs) was investigated in separate models, with multilevel logistic regression analysis, taking the country level into account. Contribution of socioeconomic factors, including country health expenditures, gross domestic product and human development index as independent country-level factors, was explored individually, in models adjusted for sociodemographic as well as clinical variables. Results In total, 3370 patients from 22 countries were included (mean (SD) age 43 (14) years; 66% male; 88% axial disease). Across countries, 1275 (38%) patients were bDMARD users. Crude mean bDMARD use varied between 5% (China) to 74% (Belgium). After adjustment for relevant sociodemographic and clinical variables, important variation in bDMARD use across countries remained (P<0.001). Country-level socioeconomic factors, specifically higher health expenditures, were related to higher bDMARD uptake, though not meeting statistical significance (OR 1.96; 95% CI 0.94 to 4.10). csDMARD uptake was significantly lower in countries with higher health expenditures (OR 0.32; 95% CI 0.15 to 0.65). Similar trends were seen with the other socioeconomic variables. Conclusions There remains important residual variation across countries in bDMARD uptake of patients with SpA followed in specialised SpA centres. This is independent of well-known factors for bDMARD use such as clinical and country-level socioeconomic factors.
Protein kinases G are essential downstream mediators of the antifibrotic effects of sGC stimulators Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-08 Alexandru-Emil Matei, Christian Beyer, Andrea-Hermina Györfi, Alina Soare, Chih-Wei Chen, Clara Dees, Christina Bergmann, Andreas Ramming, Andreas Friebe, Franz Hofmann, Oliver Distler, Georg Schett, Jörg H W Distler
Objectives Stimulators of soluble guanylate cyclase (sGC) are currently investigated in clinical trials for the treatment of fibrosis in systemic sclerosis (SSc). In this study, we aim to investigate the role of protein kinases G (PKG) as downstream mediators of sGC–cyclic guanosine monophosphate (cGMP) in SSc.Methods Mice with combined knockout of PKG1 and 2 were challenged with bleomycin and treated with the sGC stimulator BAY 41-2272. Fibroblasts were treated with BAY 41-2272 and with the PKG inhibitor KT 5823.Results PKG1 and 2 are upregulated in SSc in a transforming growth factor-β1 (TGFβ1)-dependent manner, as an attempt to compensate for the decreased signalling through the sGC–cGMP–PKG pathway. Inhibition or knockout of PKG1 and 2 abrogates the inhibitory effects of sGC stimulation on fibroblast activation in a SMAD-independent, but extracellular signal-regulated kinase (ERK)-dependent manner. In vivo, sGC stimulation fails to prevent bleomycin-induced fibrosis in PKG1 and 2 knockout mice.Conclusions Our data provide evidence that PKGs are essential mediators of the antifibrotic effects of sGC stimulators through interfering with non-canonical TGFβ signalling. TGFβ1 promotes its profibrotic effects through inhibition of sGC–cGMP–PKG signalling, sGC stimulation exerts its antifibrotic effects by inhibition of TGFβ1-induced ERK phosphorylation.
Depression and anxiety associate with less remission after 1 year in rheumatoid arthritis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-08 Aleid C Boer, Tom W J Huizinga, Annette H M van der Helm-van Mil
Depression and anxiety have been considered to influence disease activity, and with great interest we read the recently published report by Michelsen et al .1 In this large, prospective, multicentre observational study, depression and anxiety reduced the likelihood of joint remission based on composite scores, in rheumatoid arthritis (RA) after 3 and 6 months. Differences were predominantly caused by subjective markers of disease activity rather than by C reactive protein or erythrocyte sedimentation rate. The study cannot prove causality; however, their findings imply that baseline depression/anxiety can impair the fulfilment of remission criteria during follow-up, influencing important treatment decisions.As replication is a keystone in research, we aimed to validate their findings in an independent cohort, the Leiden Early Arthritis Clinic (EAC), to assess generalisability of the results. The EAC is a population-based inception cohort of patients with newly diagnosed arthritis that started in 1993; from 2010 onwards patients completed the Short Form-36 (SF-36) at …
Remission or low disease activity as a target in systemic lupus erythematosus Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-08 Manuel Francisco Ugarte-Gil, Daniel Wojdyla, Guillermo J Pons-Estel, Bernardo A Pons-Estel, Graciela S Alarcón
We read the report by Zen et al 1 on the impact of lupus low disease activity state (LLDAS) on damage accrual with great interest and would like to congratulate the authors on their work. In this single-centre Caucasian cohort, followed for 7 years, only 38 of their 293 patients (11.3%) failed to achieve LLDAS for at least 1 year; moreover, of the 255 patients who achieved LLDAS for at least 1 year, 246 (96.5%) also satisfied the definition of remission for the same length of time. And, in 214 (83.9%) patients, the duration of remission was the same as that of LLDAS. Being in LLDAS for at least 2 years was associated with a reduced risk of damage; …
Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-06 Ariane L Herrick, Sebastien Peytrignet, Mark Lunt, Xiaoyan Pan, Roger Hesselstrand, Luc Mouthon, Alan J Silman, Graham Dinsdale, Edith Brown, László Czirják, Jörg H W Distler, Oliver Distler, Kim Fligelstone, William J Gregory, Rachel Ochiel, Madelon C Vonk, Codrina Ancuţa, Voon H Ong, Dominique Farge, Marie Hudson, Marco Matucci-Cerinic, Alexandra Balbir-Gurman, Øyvind Midtvedt, Paresh Jobanputra, Alison C Jordan, Wendy Stevens, Pia Moinzadeh, Frances C Hall, Christian Agard, Marina E Anderson, Elisabeth Diot, Rajan Madhok, Mohammed Akil, Maya H Buch, Lorinda Chung, Nemanja S Damjanov, Harsha Gunawardena, Peter Lanyon, Yasmeen Ahmad, Kuntal Chakravarty, Søren Jacobsen, Alexander J MacGregor, Neil McHugh, Ulf Müller-Ladner, Gabriela Riemekasten, Michael Becker, Janet Roddy, Patricia E Carreira, Anne Laure Fauchais, Eric Hachulla, Jennifer Hamilton, Murat İnanç, John S McLaren, Jacob M van Laar, Sanjay Pathare, Susanna M Proudman, Anna Rudin, Joanne Sahhar, Brigitte Coppere, Christine Serratrice, Tom Sheeran, Douglas J Veale, Claire Grange, Georges-Selim Trad, Christopher P Denton
Objectives Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). Methods The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. ‘Progressors’ were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). Results 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. Conclusions Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. Trial registration number NCT02339441.
Adalimumab concentration-based tapering strategy: as good as the recommended dosage Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-06 Denis Mulleman, Alejandro Balsa
Drug monitoring consists of observing, recording or detecting the effects of a substance administered to an individual. Therapeutic drug monitoring (TDM) aims at improving patient care based on drug concentration measurement in order to adjust the dose or time interval individually.1 TDM is based on the assumption of a definable relation between dose and plasma/blood drug concentration and between concentration and therapeutic effects. In ARD , l’Ami et al conducted an open-label randomised trial comparing an increasing dosing interval of adalimumab from 2 to 3 weeks with a standard-dose conservative strategy in patients with rheumatoid arthritis (RA) with an adalimumab trough concentration >8 mg/L.2 The authors concluded that the dose tapering strategy was not inferior to the conservative strategy over 26 weeks. This important contribution is a step towards implementation of TDM in clinical practice. Prior to this work, the same group found that a drug concentration between 5 and 8 mg/L was associated with a good clinical response and strongly suggested that no additional improvement could be expected by increasing the dose (ie, by reducing the time interval) in patients with trough concentration >8 mg/L.3 A similar range has been described for adalimumab in psoriatic arthritis, which validates these findings.4 In the economic context, this tapering strategy can be seen as an opportunity to alleviate the burden for society. However, in the l’Ami et al ’s study, the target sample size was not reached, which somehow minimises the strength of the conclusion and raises the question of acceptability by patients to participate in the study. Indeed, some patients could have feared a flare or, more probably, because they wanted to taper the dose, did not want to be allocated to the conservative arm. Whatever this limitation, tapering adalimumab seems to perform as good as the recommended dose in patients with RA with …
2017 EULAR recommendations for a core data set to support observational research and clinical care in rheumatoid arthritis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-04 Helga Radner, Katerina Chatzidionysiou, Elena Nikiphorou, Laure Gossec, Kimme L Hyrich, Condruta Zabalan, Yvonne van Eijk-Hustings, Paula R Williamson, Andra Balanescu, Gerd R Burmester, Loreto Carmona, Maxime Dougados, Axel Finckh, Glenn Haugeberg, Merete Lund Hetland, Susan Oliver, Duncan Porter, Karim Raza, Patrick Ryan, Maria Jose Santos, Annette van der Helm-van Mil, Piet van Riel, Gabrielle von Krause, Jakub Zavada, William G Dixon, Johan Askling
Personalised medicine, new discoveries and studies on rare exposures or outcomes require large samples that are increasingly difficult for any single investigator to obtain. Collaborative work is limited by heterogeneities, both what is being collected and how it is defined. To develop a core set for data collection in rheumatoid arthritis (RA) research which (1) allows harmonisation of data collection in future observational studies, (2) acts as a common data model against which existing databases can be mapped and (3) serves as a template for standardised data collection in routine clinical practice to support generation of research-quality data. A multistep, international multistakeholder consensus process was carried out involving voting via online surveys and two face-to-face meetings. A core set of 21 items (‘what to collect’) and their instruments (‘how to collect’) was agreed: age, gender, disease duration, diagnosis of RA, body mass index, smoking, swollen/tender joints, patient/evaluator global, pain, quality of life, function, composite scores, acute phase reactants, serology, structural damage, treatment and comorbidities. The core set should facilitate collaborative research, allow for comparisons across studies and harmonise future data from clinical practice via electronic medical record systems.
Inconsistency between Danish incidence and prevalence data about psoriatic arthritis (PsA) Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-02 Philipp Sewerin, Annika Hoyer, Matthias Schneider, Benedikt Ostendorf, Ralph Brinks
We are grateful to Egeberg and Kristensen for presenting the detailed data about the prevalence and incidence of psoriatic arthritis (PsA).1 Based on these detailed information, we tried to estimate the excess mortality of people with diagnosed PsA by uising a mathematical relation between incidence, prevalence and mortality.2 3 During analysis of the incidence and prevalence data, we have made the following observation: if we assume that — on population average — people with PsA do not have a better survival than those without PsA, we can compute a lower …
A pivotal phase III, randomised, placebo-controlled study of belimumab in patients with systemic lupus erythematosus located in China, Japan and South Korea Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-01-02 Fengchun Zhang, Sang-Cheol Bae, Damon Bass, Myron Chu, Sally Egginton, David Gordon, David A Roth, Jie Zheng, Yoshiya Tanaka
Background Intravenous belimumab plus standard of care (SoC) is approved in the USA and Europe for treatment of active, autoantibody-positive systemic lupus erythematosus (SLE). Methods This phase III, multicentre, randomised, double-blind, placebo-controlled study (BEL113750; [NCT01345253]) was conducted in 49 centres across China, Japan and South Korea (May 2011 – September 2015). Patients with SLE were randomised 2:1 to intravenous belimumab 10 mg/kg or placebo, plus SoC, every 4 weeks until Week 48. The primary endpoint was the SLE Responder Index (SRI) 4 response rate at Week 52. Secondary endpoints were the percentage of patients with ≥4 point reduction in Safety of Oestrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI), SRI7, time to first severe flare and number of days prednisone (or equivalent) dose ≤7.5 mg/day and/or reduced by 50% from baseline. Safety was assessed. Results The modified intent-to-treat population included 677 patients (belimumab n=451, placebo n=226). At Week 52, the SRI4 response rate was higher with belimumab versus placebo (53.8% vs 40.1%; OR: 1.99 (95% CI: 1.40, 2.82; P=0.0001)). The percentages of patients with a ≥4 point reduction in SELENA-SLEDAI and an SRI7 response were significantly greater for belimumab versus placebo. Patients in the belimumab group had a 50% lower risk of experiencing a severe flare than those receiving placebo (P=0.0004). In patients with baseline prednisone dose >7.5 mg/day, there was a significant reduction in steroid use favouring belimumab (P=0.0228). The incidence of adverse events was similar between groups. Conclusions In patients with SLE from North East Asia, belimumab significantly improved disease activity, while reducing prednisone use, with no new safety issues. : /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01345253&atom=%2Fannrheumdis%2Fearly%2F2018%2F01%2F02%2Fannrheumdis-2017-211631.atom
Switching from the bio-originators to biosimilar: is it premature to recommend this procedure? Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-12-29 Fabrizio Cantini, Maurizio Benucci
We read with interest the recently published recommendations for the use of biosimilars in rheumatology practice.1 However, we have some concerns regarding recommendation 6 on the efficacy and safety of switching from the originator biologic to the respective biosimilar. Considering the strong impact of the European League Against Rheumatism recommendations on real-life clinical decisions, such recommendation seems not sufficiently supported by the evidence because available data do not allow to draw definitive conclusion on the switching strategy. To date, the efficacy and safety of infliximab and etanercept biosimilars in substitution of the bio-originators have been assessed in four long-term extension reports following the blinded phase …
Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-12-29 Young Ho Lee, Gwan Gyu Song
We have read with interest the article by Nakaoka and colleagues1 on the efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis. The authors have presented a randomised controlled trial in which they suggest a preference for tocilizumab over placebo for time to relapse of Takayasu arteritis, without any new safety concerns. We would like to draw attention to a few points in this regard. First, Takayasu arteritis and giant cell arteritis share some similarities in terms of …
Simultaneous inhibition of α4/β7 integrin and tumour necrosis factor-α in concomitant spondyloarthritis and inflammatory bowel disease Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-12-29 Nicolas Richard, Elizabeth M Hazel, Nigil Haroon, Robert D Inman
We read with interest the article by Varkas et al 1 suggesting a temporal association between the initiation of vedolizumab (VDZ) for inflammatory bowel disease (IBD) and induction or worsening of spondyloarthritis (SpA). This suggests that in patients with IBD, there may be limited efficacy of α4/β7 integrin blockade for management of extraintestinal manifestations, particularly for arthritis and sacroiliitis.2 3 Treatment of SpA in subjects on VDZ for associated IBD is highly challenging for the treating physician. We describe below two patients who were treated with a combination treatment of VDZ and certolizumab pegol …
ADJUVITE: a double-blind, randomised, placebo-controlled trial of adalimumab in early onset, chronic, juvenile idiopathic arthritis-associated anterior uveitis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-12-23 Pierre Quartier, Amandine Baptiste, Véronique Despert, Emma Allain-Launay, Isabelle Koné-Paut, Alexandre Belot, Laurent Kodjikian, Dominique Monnet, Michel Weber, Caroline Elie, Bahram Bodaghi
Objectives To assess the efficacy and safety of adalimumab on uveitis in patients with early onset, chronic, juvenile idiopathic arthritis (JIA)-associated or idiopathic anterior uveitis and an inadequate response to topical steroids and methotrexate (MTX). Methods Patients aged 4 years or more with ocular inflammation quantified by laser flare photometry (LFP) ≥30 photon units/ms were double-blindly randomised (1:1) to 2 groups, one treated with placebo and one with adalimumab subcutaneously at a dose of 24 mg/m2 in patients aged <13 years, 40 mg in the others, every other week. The primary outcome was response at month 2 (M2) defined as a 30% reduction of inflammation on LFP in the assessable eye with more severe baseline inflammation and no worsening on slit lamp examination. From M2 to M12, all patients received adalimumab. Results At M2, among 31 patients included in intention-to-treat analysis, there were 9/16 responders on adalimumab and 3/15 on placebo (P=0.038, Χ2 test; relative risk=2.81, 95% CI 0.94 to 8.45; risk difference: 36.3%, 95% CI 2.1 to 60.6); there was no significant difference using the Standardised Uveitis Nomenclature classification criteria of improvement. Thirty patients continued the trial after M2 and received adalimumab (open-label phase), 29 reached M12. There were seven serious adverse events none related to study treatment. Conclusions This trial is in favour of using adalimumab in patients with early onset, chronic anterior uveitis, which is in most cases associated with JIA, in case of inadequate response to topical therapy and MTX. LFP could be a valuable tool to assess early treatment efficacy. Trial registration number NCT01385826.
Dual IL-17A and IL-17F neutralisation by bimekizumab in psoriatic arthritis: evidence from preclinical experiments and a randomised placebo-controlled clinical trial that IL-17F contributes to human chronic tissue inflammation Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-12-23 Sophie Glatt, Dominique Baeten, Terry Baker, Meryn Griffiths, Lucian Ionescu, Alastair D G Lawson, Ash Maroof, Ruth Oliver, Serghei Popa, Foteini Strimenopoulou, Pavan Vajjah, Mark I L Watling, Nataliya Yeremenko, Pierre Miossec, Stevan Shaw
Objective Interleukin (IL)-17A has emerged as pivotal in driving tissue pathology in immune-mediated inflammatory diseases. The role of IL-17F, sharing 50% sequence homology and overlapping biological function, remains less clear. We hypothesised that IL-17F, together with IL-17A, contributes to chronic tissue inflammation, and that dual neutralisation may lead to more profound suppression of inflammation than inhibition of IL-17A alone. Methods Preclinical experiments assessed the role of IL-17A and IL-17F in tissue inflammation using disease-relevant human cells. A placebo-controlled proof-of-concept (PoC) clinical trial randomised patients with psoriatic arthritis (PsA) to bimekizumab (n=39) or placebo (n=14). Safety, pharmacokinetics and clinical efficacy of multiple doses (weeks 0, 3, 6 (240 mg/160 mg/160 mg; 80 mg/40 mg/40 mg; 160 mg/80 mg/80 mg and 560 mg/320 mg/320 mg)) of bimekizumab, a humanised monoclonal IgG1 antibody neutralising both IL-17A and IL-17F, were investigated. Results IL-17F induced qualitatively similar inflammatory responses to IL-17A in skin and joint cells. Neutralisation of IL-17A and IL-17F with bimekizumab more effectively suppressed in vitro cytokine responses and neutrophil chemotaxis than inhibition of IL-17A or IL-17F alone. The PoC trial met both prespecified efficacy success criteria and showed rapid, profound responses in both joint and skin (pooled top three doses vs placebo at week 8: American College of Rheumatology 20% response criteria 80.0% vs 16.7% (posterior probability >99%); Psoriasis Area and Severity Index 100% response criteria 86.7% vs 0%), sustained to week 20, without unexpected safety signals. Conclusions These data support IL-17F as a key driver of human chronic tissue inflammation and the rationale for dual neutralisation of IL-17A and IL-17F in PsA and related conditions. Trial registration number NCT02141763; Results.
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