ObjectiveDepression and anxiety are not uncommon in Rheumatoid arthritis (RA). It is increasingly recognised that they are associated with high disease activity and worse disease outcomes. We aimed to examine the frequency of depression and anxiety in an early RA inception cohort and to explore associations with disease-related measures.MethodsThe Scottish Early Rheumatoid Arthritis inception cohort recruited newly diagnosed RA patients followed-up 6-monthly. Anxiety and depression were assessed using the hospital anxiety and depression scale. Associations with demographic characteristics and disease-related measures were examined at baseline, 6 months and 12 months.Results848 RA patients were included. The prevalence of anxiety and depression at baseline was 19.0% and 12.2%, respectively. Depression and anxiety scores correlated with DAS28 at all time-points (all p<0.0001). In multivariable linear regression, anxiety score at baseline was associated with younger age and Health Assessment Questionnaire (HAQ) score. Anxiety scores at 6 months and 12 months were associated with low body mass index (BMI), baseline anxiety score and current patient global score and HAQ. Depression score at baseline was associated with younger age, being single and HAQ, while depression scores at 6 months and 12 months were associated with male gender (only at 6 months), baseline anxiety and depression scores and current patient global score, HAQ and C-reactive protein (CRP) levels.ConclusionDepression and anxiety are associated with disease activity, worse functional status and other variables in early RA. There is a close relationship between CRP and depression but not anxiety.
Protease-activated receptor-2 (PAR-2) is known to be pro-inflammatory and increasing evidence points to an inflammatory component in osteoarthritis. This investigation examined the relationship between synovitis and PAR-2 expression, histological and immunohistochemical analysis being performed on synovial samples obtained from OA and RA patients, along with non-arthritic samples obtained by post mortem (PM). Samples were also analysed for PAR-4 expression, this receptor also having putative pro-inflammatory roles. Analysis involved comparison of inflammatory indices (synovial thickness and monocyte infiltration) with expression of PAR-2 and PAR-4. Synovial explants were also analysed for TNFα generation in the presence of a PAR-2 antagonist (ENMD-1068) or vehicle. OA synovia showed heterogeneity of inflammatory indicators, some samples overlapping with those from the RA cohort whilst others appeared similar to the PM cohort. PAR-2 expression, both in the lining layer and the interstitium, correlated strongly and significantly with synovial thickness (r = 0.91) and monocyte infiltration (r = 0.83), respectively (P < 0.001 in both cases), and this remains significant on individual cohort analysis. PAR-2 was co-localised to CD3 and CD68 cells in RA and OA synovium as well as fibroblasts derived from these synovia. PAR-4 was also expressed, but the relationship with inflammatory indicators was substantially weaker. Inflammatory indicators in OA synovia showed considerable variability, but correlated strongly with PAR-2 expression, suggesting PAR-2 upregulation in synovitis. Heterogeneity of inflammatory indicators was paralleled by wide variation in TNFα generation between samples. Secretion of this cytokine was dose-dependently inhibited by ENMD-1068, providing evidence of a functional role for PAR-2 in promoting synovitis.
The pathogenesis of RA is a complex and ever-changing landscape but amid the chaos of the disease process we have found effective treatment regimes. However, our current therapeutics, although targeting various components of both the innate and adaptive immune response, do not result in disease remission. Protein kinase inhibitors are attractive targets due to their ability to influence downstream signalling and their oral bioavailability. Fostamatinib (R788) inhibits spleen tyrosine kinase (Syk) and has been in clinical trials involving both MTX inadequate responders (MTX-IRs) and biologic inadequate responders. Studies on the MTX-IR population revealed ACR20 responses of 67-72% at higher doses (150 mg bd and 100 mg bd), ACR50 responses of 43-57% and ACR70 responses of 28-40%. The trial in the biologic non-responder population showed no efficacy, however, post hoc analyses of the data suggested that a further trial in this population is warranted. The most common adverse events included gastrointestinal effects, hypertension, neutropenia and transaminitis. Many adverse effects were dose responsive and hypertension was amenable to treatment. Upper respiratory tract infections were more likely at higher doses, but no serious infections with tuberculosis, fungi or opportunistic infections were reported. The oral availability of these agents makes them attractive treatment options for our patients, although the literature from the oncology field suggests that patients will only choose the oral route if efficacy is equivalent. Long-term follow-up studies are ongoing and will be critical for rare side effects. The role of these agents in our current arsenal is unclear and economic analyses are awaited.
BackgroundSpondyloarthropathies (SpA) comprise an inflammatory spectrum that can involve peripheral and axial joints, enthesial sites and extra-articular tissues. We hypothesized that oxidation of fibrocartilage matrix proteins collagen type II (CII) at enthesial sites might generate oxidative posttranslational modification (oxPTM)-associated neoepitopes that provoke humoral autoimmunity.Our objectives were to test for the presence and clinical significance of antibodies to oxPTM-CII in patients with SpA. MethodsLevels of antibodies specific to native CII and oxPTM-CII were assessed by enzyme-linked immunosorbent assays (ELISA). Reactivity in serum samples obtained from patients with axial SpA (axSpA, n=242) was compared to reactivity in samples from patients with predominantly peripheral arthritis such as psoriatic arthritis (PsA, n=69), undifferentiated arthritis (UA, n=48) and early rheumatoid arthritis (RA, n=60). Controls included psoriasis without musculoskeletal symptoms (Ps, n=35), fibromyalgia (FM, n=19) and healthy subjects (HC, n=178). 97 th percentile of the healthy individuals cut-off point absorbance units obtained for healthy control samples was used to construct a contingency table of positive binders to oxPTM-CII and tested it by Fishers Exact Test. ResultsIgG binding to oxPTM-CII was observed in serum samples from axSpA (52%) compared to RA (83%), PsA (28%), UA (35%), and FM (15%). Importantly, while strong IgA anti-oxPTM-CII was detected in axSpA and PsA patients, with 47% and 84% respective binders, no IgA anti-oxPTM-CII was detected in RA patients. IgA anti-oxPTM-CII reactivity in axSpA patients treated with biologics was higher and more frequent with 85% binders compared to 9% binders in patients treated with synthetic DMARDs. Sensitivity values for both IgG and IgA anti-oxPTM-CII for RA samples were 3 91% and 32%, respectively. IgG and IgA anti-oxPTM-CII for axSpA were 64% and 80%, respectively. Similartly, sensitivity for IgA anti-oxPTM-CII in PsA was doubled to 87%. Conclusions:Our data implies that axSpA is associated with the presence of antibodies specific for oxPTM-CII, suggesting that there may be a humoral component to disease-associated inflammation that may stratify patients with SpA from RA.
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