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The implications of COVID-19 are wide-ranging for specialties such as rheumatology in which immunomodulatory therapies are prescribed. There has been much trepidation among many healthcare professionals regarding the best course of management during this time.

Summary The mechanisms underlying the exaggerated inflammatory response in Behçet's syndrome (BS) remain poorly understood. We investigated the response of CD14+ blood monocytes to interferon (IFN)-γ, focusing on the chemokine CXCL10. Chemokine synthesis and release were analysed at a protein and mRNA level following stimulation with IFN-γ. Findings in BS patients were compared with 25 healthy controls (HC), 15 rheumatoid arthritis (RA) and 15 systemic lupus erythematosus (SLE) disease control patients. BS monocytes produced significantly more CXCL10 protein than HC monocytes from 2 h following IFN-γ stimulation, despite equivalent quantities of mRNA, suggesting more efficient translation. This was significantly more pronounced in BS with high disease activity and in those with ocular and neurological clinical manifestations. The imbalance between CXCL10 protein and mRNA expression was not observed in either RA or SLE patients, and was not seen with other chemokines studied (CXCL9, CXCL11 and CCL2). Furthermore, BS monocytes treated with an alternative stimulant (LPS) did not show abnormal tumour necrosis factor (TNF)-α release. Sucrose density gradients to segregate monocyte CXCL10 mRNA into free RNA or polysome-associated RNA showed equal proportions in BS and HC samples, suggesting that the difference between BS and HC may be due to reduced negative control of CXCL10 translation in BS at a post-initiation level. We conclude that BS monocytes have dysfunctional post-transcriptional regulation of CXCL10 mRNA, resulting in over-expression of CXCL10 protein upon IFN-γ stimulation. As CXCL10 is a chemokine that recruits mononuclear cells, this abnormality may contribute to the exaggerated inflammatory responses that characterizes BS.

The seronegative spondyloarthropathies, including psoriatic arthritis (PsA) and ankylosing spondylitis (AS), are characterized by varied clinical symptoms, severity, and disease course [1], [2]. Diagnosis and monitoring can be challenging because there is no definitive laboratory biomarker for reliably measuring inflammation or other disease processes associated with spondyloarthropathies. Over time, many patients with PsA and AS eventually experience significant disability and impaired quality of life [1], [2]. This may be partially accounted for by delays in diagnosis and subsequent treatment [3], as well as the presence of comorbidities. In recent years, research efforts aimed at identifying risk factors for PsA, including clinical, imaging, genetic, and laboratory assessments, have yielded major advances. The Platform for the Exchange of Expertise and Research (PEER) was formed to facilitate the exchange of research insights, sharing of expertise, and discussion of unmet needs in rheumatology research. The objective of the current report is to provide an overview of the 2017 PEER meeting, which was held on May 19–20, 2017, in London, UK, and highlighted the most up-to-date research findings regarding PsA and AS pathophysiology, early detection, comorbidities, and treatment.

Psoriatic arthritis (PsA) causes inflammation in and around the joints and usually affects people who already have psoriasis. However, some patients develop the joint problems before the psoriasis. Currently, there are five anti-TNF-α agents licensed for use in patients with PsA: adalimumab, certolizumab pegol, etanercept, golimumab and infliximab. Golimumab, a human monoclonal antibody, has been approved by the US FDA for the treatment of PsA and is targeted against the pro-inflammatory molecule TNF-α. The Phase III GO-REVEAL study confirmed this drug was well tolerated and showed significant improvement in disease activity compared with placebo.

Background There is a lack of validated outcome measures in non-psoriatic peripheral spondyloarthritis (pSpA). Therefore, a modified version of the minimal disease activity (mMDA) 1 was developed and validated. Identification of factors that predict long-term mMDA response in pSpA patients (pts) can facilitate decisions regarding treatment initiation and maintenance. Objectives The purpose of this analysis was to determine predictors of long-term mMDA response following adalimumab (ADA) treatment in pSpA pts from the ABILITY-2 study. Methods ABILITY-2 2 was a phase 3 randomized, double-blind trial evaluating the efficacy and safety of 40 mg ADA every other week versus placebo (PBO) over 12 weeks (wks) followed by open-label (OL) ADA for 144 wks in pts with pSpA. This post-hoc analysis included pts who received at least one dose of ADA during the PBO-controlled period or OL extension. The mMDA for pSpA was defined as achieving at least 5 out of the following 6 criteria: 1) TJC78 ≤1; 2) SJC76 ≤1; 3) pt pain visual analog scale (VAS) ≤15 of 100 mm; 4) pt global activity (PtGA) VAS ≤20 of 100 mm; 5) HAQ-DI ≤0.5; and 6) tender entheseal points ≤1 (Leeds Enthesitis Index [LEI] or Spondyloarthritis Research Consortium of Canada [SPARCC] Enthesitis Index). In this post hoc analysis, multiple logistic regression with stepwise variable selection was used to determine predictors of long-term (yrs 1–3) and sustained (defined as mMDA for at least 24 consecutive wks) mMDA responses. Variable selection of baseline (BL) pt demographics and disease characteristics were performed with and without mMDA response at wk 16 (mMDA16) as a candidate. In pts achieving mMDA at wk 16, ADA exposure ranged between 4 and 16 wks. Results In pSpA pts treated with ADA, mMDA (5/6 LEI or SPARCC) was achieved by almost 41%, 49%, and 50% of pts at yrs 1, 2, and 3, respectively and sustained mMDA response was achieved by 42% of pts. Regardless of mMDA definition, achieving mMDA response at wk 16 (up to 16 wks of ADA) was a robust positive predictor of attaining both long-term mMDA at yrs 1–3 and sustained mMDA (Figure). In the model examining the BL predictors (model without mMDA16), age, BL enthesitis and BL BASDAI scores were most commonly selected as negative predictors for achieving long-term and sustained mMDA. Other selected predictors included BL dactylitis, physician9s global assessment, hsCRP, and male sex; however, these predictors were not consistently selected for all time points or sustained mMDA. Conclusions Early mMDA response is a stronger and more consistent predictor of long-term mMDA, whether at 1, 2, or 3 yrs or sustained over time, than BL characteristics. The 5/6 versions of mMDA could be an appropriate treatment target in pSpA pts. References Coates LC, et al., Ann Rheum Dis, 2016; 75:334. Mease PJ, et al., Arthritis Rheumatol, 2015; 67(4): p.914–23. Acknowledgements AbbVie funded the study (NCT01064856), contributed to its design, and participated in data collection, analysis and interpretation of the data, and in writing, review, and approval of the publication. Medical writing support was provided by Deepa Venkitaramani, PhD, of AbbVie. Disclosure of Interest L. Coates Grant/research support from: AbbVie, Boehringer-Ingelheim, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Sun Pharma, and UCB, Consultant for: AbbVie, Boehringer-Ingelheim, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Sun Pharma, and UCB, Speakers bureau: AbbVie, Boehringer-Ingelheim, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Sun Pharma, and UCB, S. Abraham Grant/research support from: AbbVie, Celgene, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Celgene, Novartis, Pfizer, and UCB, Speakers bureau: AbbVie, Celgene, Novartis, Pfizer, and UCB, W. Tillett Grant/research support from: AbbVie, Celgene, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Celgene, Novartis, Pfizer, and UCB, Speakers bureau: AbbVie, Celgene, Novartis, Pfizer, and UCB, P. Mease Grant/research support from: AbbVie, Amgen, Bristol Myers, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, Sun Pharma, and UCB, Consultant for: AbbVie, Amgen, Bristol Myers, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, Sun Pharma, and UCB, Speakers bureau: AbbVie, Amgen, Bristol Myers, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, Sun Pharma, and UCB, S. Ramiro: None declared, T. Wu Shareholder of: AbbVie, Employee of: AbbVie, X. Wang Shareholder of: AbbVie, Employee of: AbbVie, A. Pangan Shareholder of: AbbVie, Employee of: AbbVie, I.-H. Song Shareholder of: AbbVie, Employee of: AbbVie

Objective.To assess the evolution of preexisting extraarticular manifestations of rheumatoid arthritis (EA-RA) in patients treated with anti-tumor necrosis factor-α (TNF-α), as well as the development of new EA-RA.Methods.We assessed EA-RA in 152 patients receiving anti-TNF-α treatment.Results.In 22 cases, a new EA-RA developed. In 5 cases, there was evidence of progression of preexisting EA-RA. Regression was found in 4 cases. Some patients were in disease remission when they developed EA-RA, whereas some patients had moderate/high disease activity.Conclusion.EA-RA are still present in patients treated with anti-TNF-α. Development of new severe EA-RA is rare in patients receiving anti-TNF therapy.

To the Editor: Psoriatic arthritis (PsA) is a chronic inflammatory disease involving the skin and joints. It requires detection in primary care, subsequent referral, and initiation of management in secondary care and ongoing joint management. PsA has been associated with greater cardiovascular (CV) disease mortality, morbidity, and atherosclerosis1. The increased CV mortality risk has been shown to be comparable with that of rheumatoid arthritis (RA) and diabetes (risk ratio 1.74, 95% CI 1.32–2.30)2. In addition, risk factors for CV disease, such as hypercholesterolemia, impaired glucose tolerance, and obesity, have all been associated with PsA1,2,3. We sought to establish the current knowledgebase and lifestyle choices of patients with PsA managed in secondary care. This data could then guide changes to services to assist patients in reducing their risk of CV morbidity and mortality. A hundred patients diagnosed with PsA sequentially attending a rheumatology outpatient clinic completed an anonymous electronic questionnaire. Patients were asked to … Address correspondence to Dr. Anna Timmis, Imperial GP Specialty Training, Department of Primary Care and Public Health, Imperial College London, Charing Cross Campus, Reynolds Building, London W6 8RP, UK. E-mail: anna.timmis{at}doctors.org.uk

Objectives To establish if changes in Th1/Th17 cell populations previously reported in experimental arthritis occur in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor α (TNFα) agents, and whether the therapeutic response to anti-TNFα is compromised in patients and mice because of elevated Th17/IL-17 levels. Finally, to assess the efficacy of combined blockade of anti-TNFα and anti-IL-17 in experimental arthritis. Methods A longitudinal study of two independent cohorts (cohort 1, n=24; cohort 2, n=19) of patients with RA treated with anti-TNFα biological agents was carried out to assess their Th17/IL-17 levels before and after the start of anti-TNFα therapy. IL-12/23p40 production was assessed in plasma Peripheral blood lymphocytes (PBLs) and monocytes. Mice with collagen-induced arthritis (CIA) were treated with anti-TNFα alone, anti-IL17 alone or a combination of the two. Efficacy of treatment and response was assessed from changes in Disease Activity Score 28–erythrocyte sedimentation rate scores in patients, and in clinical scores and histological analysis in CIA. Results Significant increases in circulating Th17 cells were observed in patients after anti-TNFα therapy and this was accompanied by increased production of IL-12/23p40. There was an inverse relationship between baseline Th17 levels and the subsequent response of patients with RA to anti-TNFα therapy. In addition, PBLs from non-responder patients showed evidence of increased IL-17 production. Similarly, in anti-TNFα-treated mice, there was a strong correlation between IL-17 production and clinical score. Finally combined blockade of TNFα and IL-17 in CIA was more effective than monotherapy, particularly with respect to the duration of the therapeutic effect. Conclusions These findings, which need to be confirmed in a larger cohort, suggest that a Th17-targeted therapeutic approach may be useful for anti-TNFα non-responder patients or as an adjunct to anti-TNFα therapy, provided that safety concerns can be addressed.

Objective Bone formation and destruction are usually tightly linked; however, in disorders such as rheumatoid arthritis, periodontal disease, and osteoporosis, elevated osteoclast activity leads to bone destruction. Osteoclast formation and activation are controlled by many signaling pathways, including p38 MAPK. Dual-specificity phosphatase 1 (DUSP-1) is a factor involved in the negative regulation of p38 MAPK. The purpose of this study was to examine the effect of Dusp1 deficiency on bone destruction. Methods Penetrance, onset, and severity of collagen-induced arthritis were recorded in DUSP-1+/+ and DUSP-1−/− mice. Bone destruction was assessed by histologic and micro–computed tomographic examination of the joints. The in vitro formation and activation of osteoclasts from DUSP-1+/+ and DUSP-1−/− precursors were assessed in the absence or presence of tumor necrosis factor (TNF). Results The formation and activation of osteoclasts in vitro in the presence of TNF were enhanced by Dusp1 gene disruption. DUSP-1−/− mice exhibited higher penetrance, earlier onset, and increased severity of experimental arthritis, accompanied by greater numbers of osteoclasts in inflamed joints and more extensive loss of bone. A DUSP-1−/− mouse colony of mixed genetic background also demonstrated striking spontaneous osteolytic destruction of distal phalanges. Conclusion DUSP-1 is a critical regulator of osteoclast activity and limits bone destruction in an experimental model of rheumatoid arthritis. Defects in the expression or activity of DUSP1 in humans may correlate with a propensity to develop osteolytic lesions in arthritis.

Secretory phospholipase A2 group IIA (sPLA2-IIA) was examined as a point of care marker for determining disease activity in rheumatoid (RA) and psoriatic (PsA) arthritis. Serum concentration and activity of sPLA2-IIA were measured using in-house antibodies and a novel point of care lateral flow device assay in patients diagnosed with varying severities of RA (n = 30) and PsA (n = 25) and found to correlate strongly with C-reactive protein (CRP). Levels of all markers were elevated in patients with active RA over those with inactive RA as well as both active and inactive PsA, indicating that sPLA2-IIA can be used as an analogue to CRP for RA diagnosis at point of care.

The human body consists of millions of commensal bacteria (the microbiome), with the intestinal tract being the most prevalent site of colonization. This colonization process begins at birth, and despite numerous factors such as ageing, diet and drug use affecting the microbiome make-up, by adulthood the composition of the gut bacteria is relatively consistent across local populations. The recent advent of new scientific techniques has enabled us to explore how the microbiome affects health and, in particular, has shed light on the involvement of the microbiome in the pathogenesis of inflammatory disease. In this review we highlight the current evidence for microbiome manipulation in inflammatory arthritis in animal and human models and discuss potential therapeutics targeting the microbiome as treatment for these diseases.

Summary We investigated changes in circulating T helper type 17 (Th17) cells following anti-tumour necrosis factor (TNF) in rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) patients. Peripheral blood mononuclear cells (PBMC) were isolated from 25 RA, 15 AS and eight PsA patients at baseline 4 and 12 weeks after treatment, and Th17 cell frequencies were analysed using interleukin (IL)-17 enzyme-linked immunospot (ELISPOT) and flow cytometry. A significant increase in IL-17-producing cells was observed by ELISPOT in RA and AS patients at 12 weeks. Flow cytometry confirmed significant increases in CD4+IL-17+ cells at 12 weeks in RA and AS and 4 weeks in PsA patients. Anti-TNF treatment increases circulating Th17 cells in three different diseases.

Glucocorticoids (GCs), which are used in the treatment of immune-mediated inflammatory diseases, inhibit the expression of many inflammatory mediators. They can also induce the expression of dual specificity phosphatase 1 (DUSP1; otherwise known as mitogen-activated protein kinase [MAPK] phosphatase 1), which dephosphorylates and inactivates MAPKs. We investigated the role of DUSP1 in the antiinflammatory action of the GC dexamethasone (Dex). Dex-mediated inhibition of c-Jun N-terminal kinase and p38 MAPK was abrogated in DUSP1−/− mouse macrophages. Dex-mediated suppression of several proinflammatory genes (including tumor necrosis factor, cyclooxygenase 2, and interleukin 1α and 1β) was impaired in DUSP1−/− mouse macrophages, whereas other proinflammatory genes were inhibited by Dex in a DUSP1-independent manner. In vivo antiinflammatory effects of Dex on zymosan-induced inflammation were impaired in DUSP1−/− mice. Therefore, the expression of DUSP1 is required for the inhibition of proinflammatory signaling pathways by Dex in mouse macrophages. Furthermore, DUSP1 contributes to the antiinflammatory effects of Dex in vitro and in vivo.

Background Due to lack of validated outcome measures in non-psoriatic peripheral spondyloarthritis (pSpA), recent studies in this patient (pt) population have used varying endpoints [1]. Thus, developing new pSpA-specific indices may be worthwhile. Minimal Disease Activity (MDA) has been validated in psoriatic arthritis but not in pSpA. Objectives To evaluate the performance of a modification of the MDA criteria (excluding psoriasis) in pSpA patients (pts) from the ABILITY-2 study [2]. Methods This post-hoc analysis evaluated the validity of a modified MDA (mMDA) in pSpA. ABILITY-2 was a 12-week trial comparing adalimumab (ADA) with placebo (PBO) in pSpA followed by a 144 week extension. The mMDA for pSpA was defined as achieving at least 4 or 5 out of the following 6 criteria: (1) tender joint count (TJC, 78 joints) ≤1; (2) swollen joint count (SJC, 76 joints) ≤1; (3) pt pain visual analog scale (VAS) ≤15 of 100 mm; (4) pt global activity (PtGA) VAS ≤20 of 100 mm; (5) health assessment questionnaire–disability index (HAQ-DI)≤0.5; and (6) tender entheseal points ≤1. Enthesitis was assessed by the Leeds Enthesitis Index (LEI) or the Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index for this analysis. The proportion of pts achieving the 4 different versions of mMDA were evaluated (either 4 or 5 of 6 using LEI and either 4 or 5 of 6 using SPARCC). The correlations between mMDA and the novel pSpA response criteria [PSpARC] remission from ABILITY-2 and Ankylosing Spondylitis Disease Activity Score Inactive Disease [ASDAS ID] were evaluated by tetrachoric correlation ( r tet ). Results Of the 163 pts (82 ADA, 81 PBO) who completed wk 12, significantly greater proportion of pts receiving ADA achieved mMDA (regardless of the definition) compared with PBO (P r tet >0.9) than ASDAS ID ( r tet >0.75) at wk 12, and yrs 1–3. Among pts who fulfilled the 4/6 criteria (LEI or SPARCC), approximately 20–30% of pts did not meet TJC and SJC criterion (Table 1b). However, the 5/6 criteria (LEI or SPARCC) were more stringent with approximately 5% and 13% not meeting the TJC and SJC criterion, respectively. Conclusions All 4 versions of mMDA discriminated between ADA and PBO treatment groups; both entheseal indices performed similarly. The mMDA (particularly the 5/6 versions which closely represents the concept of MDA) could be an appropriate treatment target in pSpA pts. References Turina, M.C., et al., Ann Rheum Dis, 2015. (doi: 10.1136/annrheumdis-2014-207235). Mease, P., et al., Arthritis Rheumatol, 2015. 67(4): p. 914–23. Acknowledgement AbbVie funded the study (NCT01064856), contributed to its design and participated in data collection, analysis and interpretation of the data, and in writing, review, and approval of the publication. Statistical support was provided by Nupun Varothai, former employee of AbbVie. Medical writing was provided by Deepa Venkitaramani, PhD, of AbbVie. Disclosure of Interest L. Coates Grant/research support from: AbbVie, Celgene, Janssen, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Celgene, Janssen, Novartis, Pfizer, and UCB, Speakers bureau: AbbVie, Celgene, Janssen, Novartis, Pfizer, and UCB, S. Abraham Grant/research support from: AbbVie, Celgene, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Celgene, Novartis, Pfizer, and UCB, Speakers bureau: AbbVie, Celgene, Novartis, Pfizer, and UCB, W. Tillett Grant/research support from: AbbVie, Celgene, Pfizer, and UCB, Consultant for: AbbVie, Celgene, Pfizer, and UCB, Speakers bureau: AbbVie, Celgene, Pfizer, and UCB, P. Mease Grant/research support from: AbbVie, Amgen, Bristol Myers, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, and UCB., Consultant for: AbbVie, Amgen, Bristol Myers, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, and UCB., Speakers bureau: AbbVie, Amgen, Bristol Myers, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, and UCB., S. Ramiro: None declared, Y. Xia Employee of: Former AbbVie contract employee, X. Wang Shareholder of: AbbVie, Employee of: AbbVie, A. Pangan Shareholder of: AbbVie, Employee of: AbbVie, I.-H. Song Shareholder of: AbbVie, Employee of: AbbVie

Mycobaterium tuberculosis (MTB) accounts for significant morbidity and mortality worldwide. Non-tuberculous mycobacteria (NTM) species, usually considered benign contaminants, are increasingly recognized to be associated with pulmonary disease in immuno-compromised hosts. The tuberculin skin test (TST) is of limited benefit in immuno-supressed individuals who often fail to mount a delayed type hypersensitivity reaction. In such patients, the ELISpot assay is considered a more robust method of diagnosing tuberculosis. We present a case which illustrates that ELISpot can be negative in mycobacterial disease. A 51 year old Jamaican housekeeper, living in the UK for the past 45 years, presented with a 5-month history of a productive cough, shortness of breath and fatigue. She had a 10 year history of sero-positive rheumatoid arthritis which was well controlled with methotrexate and etanercept, an anti-tumour necrosis factor (TNF) biologic. She had …

To the Editor: We thank Bachmeyer, et al 1 for their interest in our article “Extraarticular Manifestations of Rheumatoid Arthritis Develop in Patients Receiving Anti-tumor Necrosis Factor-α Treatment: A Retrospective Chart Review from a UK Center”2. Our study assessed the development of extraarticular manifestations of rheumatoid arthritis (RA) — lung disease, renal disease, nodules, and vasculitis — in patients receiving anti-tumor necrosis factor-α (TNF-α) treatment. There were 152 patients (86.7% women) with an established diagnosis of RA being followed up in the rheumatology department at the time of the study, and who had received anti-TNF-α therapy [infliximab, etanercept (ETN), adalimumab (ADA)] initiated between 2000 and 2011. We acknowledge that a wide range of lung … Address correspondence to Dr. A. Negoescu, Rheumatology Research Unit, Addenbrooke’s Hospital, Rheumatology, Box 194, Hills Road, Cambridge, Cambridgeshire CB2 0QQ, UK. E-mail: andra_negoesc08{at}yahoo.com

A 65 year old white woman presented with a 5 year history of pain and intermittent swelling of the left ankle. There had been no preceding trauma to the ankle and the symptoms were initially gradual in onset with aching and stiffness but then evolved into a continuous pain, particularly nocturnally. Her previous medical history included a right total hip replacement aged 53, menopause aged 53, and essential hypertension. There was no family history of rheumatological illness and her mother died of a myocardial infarction aged 56 years. Examination disclosed evidence of osteoarthritis in her hands and an unusual symmetrical bony swelling of her 1st and 2nd metacarpophalangeal joints. Her left ankle was swollen and warm to the touch (fig 1). Figure 1 Left ankle demonstrating a palpable bony swelling. Investigations disclosed …

Background Anti-TNFα agents have revolutionised treatment of rheumatoid arthritis (RA), although a significant proportion of patients respond inadequately. Studies in murine and human arthritis have paradoxically shown that anti-TNF treatment can increase circulating Th17 cells but the relationship of these changes to treatment responses remains unclear. Objectives To investigate immune correlates of anti-TNF treatment response or failure in RA patients we conducted a longitudinal study using serial clinical, ultrasound and T cells immunological assessments. Methods 25 RA patients naive to biological therapy were followed at 4 predetermined protocol visits during the first 12 weeks of anti-TNF treatment (etanercept or adalimumab). Improvement in Disease Activity Score of 28 joints (DAS28) defined treatment responders (n=16) and non-responders (n=9). Changes in synovial thickening and vascularity of 10 metacarpophalangeal joints were quantitatively assessed by 2D high frequency grey scale and power Doppler ultrasound (PDUS) using a digitalised pixel counter. Changes in the frequency of circulating Th17 cells during treatment were evaluated by IL17 ELISpot assay and Flow Cytometry (FACS) of PBMCs. Results ELISpot analysis demonstrated a significant increase in circulating IL17-producing cells 12 weeks after anti-TNFα initiation (baseline mean ± SD 466±277 vs 12 weeks mean ± SD 759±510 spSFC/10 6 , p=0.003). FACS analysis confirmed a significant increase in CD4+IL17+ cells at treatment week 12 (baseline mean ± SD 0.7±0.5% vs 12 weeks mean ± SD 1.1±0.5%; p=0.01). This increase in circulating Th17 cells during anti-TNFα treatment was observed in patients treated with different types of anti-TNFα agents, suggesting this may be a class effect. The increase in circulating Th17 cells during treatment correlated significantly with reduction in synovial vascularity (Spearman rank r= -0.68, p=0.007) and synovial thickening (Spearman rank r= -0.39; p=0.04) as determined by PDUS. Higher numbers of circulating Th17 cells at baseline were associated with poorer anti-TNFα treatment response as defined by ultrasonographic measures. Conclusions This is the first study to link changes in circulating Th17 cells evaluated by cellular assays with resolution of ultrasonographic features of synovitis during anti-TNF treatment. The findings may reflect redistribution of Th17 cells from inflamed joints during treatment or that TNFa may play a role in the regulation of Th17 cell production, but these two hypotheses are not mutually exclusive. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.1030

Background Anti-tumour necrosis factor (TNF) agents have revolutionised the treatment of rheumatoid arthritis, although a substantial proportion of patients respond inadequately. Studies in murine and human arthritis have paradoxically shown that anti-TNF treatment can increase circulating interleukin-17-producing T helper (Th17) cells but the association of these changes with treatment responses remains unclear. To investigate immune correlates of anti-TNF treatment response in patients with rheumatoid arthritis we did a longitudinal study using serial clinical, ultrasonographic, and T-cell immunological assessments. Methods 25 patients with rheumatoid arthritis naive to biological therapy were followed at four predetermined protocol visits during the first 12 weeks of anti-TNF-alpha treatment. 16 patients were treatment responders, as defined by improvement in disease activity score in 28 joints (DAS28) by more than 1·2 from baseline. Nine patients were non-responders (change in DAS28 score Findings ELISPOT analysis showed a significant increase in circulating IL17-producing cells 12 weeks after anti-TNF initiation (baseline vs 12 weeks: mean 466 spSFC/106 [SD 277] vs 759 [510]; p=0·003). Fluorescence-activated cell sorting analysis confirmed significant increase in CD4+IL17+ cells at treatment week 12 (baseline vs 12 weeks: mean 0·78% [0·5] vs 1·1 [0·5]; p=0·01). The dynamics of changes in circulating Th17 cells during anti-TNF-alpha treatment were the same in treatment responders and non-responders and in patients treated with different types of anti-TNF alpha agents, suggesting a class effect. The increase in circulating Th17 cells during treatment correlated with reduction in synovial vascularity ( r =−0·68, p=0·007) and synovial thickening ( r =−0·39; p=0·04) as determined by PDUS. Higher numbers of circulating Th17 cells at baseline were associated with poorer response to anti-TNF-alpha treatment as defined by DAS28 score and ultrasonographic measures. Interpretation This is the first study, to our knowledge, that links changes in circulating Th17 cells evaluated by cellular assays with resolution of ultrasonographic features of synovitis during anti-TNF treatment. The findings could mean that Th17 cells are redistributed from inflamed joints during treatment or that TNFα could have a role in the regulation of Th17 cell production. Funding The Kennedy Trust for Rheumatology Research, Imperial College Healthcare Charity, UK Medical Research Council.

Dear Sir, It is well recognised that patients with autoimmune disease have an increased risk of infection both through virtue of their underlying disease and through concomitant drug use. Following the heavily publicised announcement of the H1N1 or ‘swine flu’ pandemic, there has been much concern expressed by patients taking immunosuppressive therapy. The risk of influenza in these patient groups has not been defined. Extrapolation from data in transplant recipients suggests that prevalence of influenza is low (0–2%).1 However, such patients are …

Background Morbidity and mortality in patients with rheumatoid arthritis (RA) are mainly increased by extra-articular manifestations (EA-RA). Studies have suggested that only RA patients with systemic manifestations, as opposed to RA patients without systemic manifestations, have an increased mortality when compared with the general population.[1, 2] Objectives To assess the development of extra-articular manifestations of rheumatoid arthritis (RA) - lung disease, renal disease, nodules and vasculitis - in patients receiving anti-TNF treatment. Methods 152 patients with an established diagnosis of RA, who have received anti-TNF therapy (Infliximab, Etanercept, Adalimumab) were randomly selected from the Charing Cross Hospital (London, UK) Rheumatology department database. Results 110 patients (72.8%) never had extra-articular manifestations of RA, whereas 42 patients (27.2%) did have one of the mentioned extra-articular manifestations of RA before or after commencing anti-TNF therapy. This represents a very high percentage compared to the prevalence of the EA-RA among the RA population previously reported in studies (8-12%).[1-4] Only women developed lung disease, renal impairment or vasculitis, but this could be due to the high prevalence of RA among female population rather than a higher risk for extra-articular manifestations’ development in women. In 22 cases (14.47%), a new extra-articular manifestation developed after starting anti-TNF (8 cases of lung disease; 11 cases of rheumatoid nodules; 3 cases of vasculitis). In 5 cases, there was clear evidence of progression of pre-existing EA-RA (2 lung disease, 3 nodules). Regression was found in 4 cases of nodular RA. Renal disease was found in just one case, and it had a stable evolution throughout the whole anti-TNF treatment period. In the rest of the cases, the evolution of EA-RA remains unclear. The incidence rate of new onset of EA-RA was 7.5 cases per 1000 person-years, which gives a risk of developing new EA-RA of 2.73 cases per person-year. When relating to period of exposure to anti-TNF, the risk was 6.57 cases per person-year. Conclusions Flares and extra-articular disease are still present in patients treated with anti-TNF. In some of the cases, this is due to treatment failure, because of high activity of the disease. In other cases, the development of extra-articular manifestations may be associated with the use of anti-TNFs. References Turesson C, O’Fallon WM, Crowson CS, et al. Occurrence of extraarticular disease manifestations is associated with excess mortality in a community based cohort of patients with rheumatoid arthritis. J Rheumatol. 2002;29:62-67. Turesson C, Jacobsson LT. Epidemiology of extra-articular manifestations in rheumatoid arthritis. Scand J Rheumatol. 2004;33:65-72. Turesson C, Eberhardt K, Jacobsson LT, et al. Incidence and predictors of severe extra-articular disease manifestations in an early rheumatoid arthritis inception cohort. Ann Rheum Dis. 2007;66:1543-1544. Lindqvist E, Saxne T, Geborek P, et al. Ten year outcome in a cohort of patients with early rheumatoid arthritis: health status, disease process, and damage. Ann Rheum Dis. 2002;61:1055-1059. Acknowledgements Sister Angela Smith designed the database. Marie Kelleher provided the hospital notes for the randomised cases. Michael Soljak and Hillary Watt helped with statistical advice. Disclosure of Interest None Declared