No abstract

Background Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. MethodsWe did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. FindingsIn the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo.Interpretation Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases.

Objective. To determine whether the HLA-DRB1 shared epitope (SE) is associated with early mortality and specific causes of death in rheumatoid arthritis (RA).Methods. HLA-DRB1 genotyping was carried out on blood samples from 767 patients recruited for the Early RA Study (ERAS), a multicenter, inception cohort study with followup over 18 years. Dates and causes of death (n ‫؍‬ 186) were obtained from the Office of National Statistics. The association of HLA-DRB1 alleles with risk of mortality was assessed using Cox proportional hazards regression analyses. Multivariate stepwise models were used to assess the predictive value of HLA-DRB1 genotypes compared with other potential baseline risk factors.Results. The SE was not significantly associated with overall mortality. However, the presence of 2 SE alleles was associated with risk of mortality from ischemic heart disease (hazard ratio [HR] 2.02 [95% confidence interval 1.04-3.94], P ‫؍‬ 0.04), and malignancy (HR 2.18 [95% confidence interval 1.17-4.08], P ‫؍‬ 0.01). Analysis of specific SE genotypes (corrected for age and sex) revealed that the HLA-DRB1*0101/*0401 and 0404/*0404 genotypes were the strongest predictors of mortality from ischemic heart disease (HR 5.11 and HR 7.55, respectively), and DRB1*0101/*0401 showed a possible interaction with smoking. Male sex, erythrocyte sedimentation rate, and Carstairs Deprivation Index were also predictive, but the Health Assessment Questionnaire score, rheumatoid factor, nodules, and swollen joint counts were not. Mortality due to malignancy was particularly associated with DRB1*0101 genotypes.Conclusion. The risk of mortality due to ischemic heart disease or cancer in RA is increased in patients carrying HLA-DRB1 genotypes with particular homozygous and compound heterozygous SE combinations.

We investigate a range of clinical factors and anti-rheumatic treatments, for their degree of association with rheumatoid arthritis (RA) fatigue in 557 patients. A range of clinical measures concerning disability, pain and disease activity together with drug history were recorded as part of routine clinical visits. Fatigue was measured using the Functional Assessment of Chronic Illness Therapy (FACIT-F) questionnaire. Spearman's correlation (p < 0.05) evaluated FACIT-F against the other clinical measures. Mean FACIT-F was compared between the treatment groups. Multivariate linear regression analysis investigated association between the clinical measures and FACIT-F in more detail. Correlation (p < 0.05) with FACIT-F was the strongest for Health Assessment Questionnaire (HAQ) (r = -0.68), patient global (r = -0.64) and pain (r = -0.62) visual analogue scores. In multivariate models, DAS28, HAQ and pain explained variability in fatigue the best (R(2) = 0.54). Further analyses, looking at the sub components of DAS28, show that fatigue is mainly associated with tender joint counts and pain rather than swollen joint counts or erythrocyte sedimentation rate. RA fatigue levels were not significantly different between patients on no treatment, disease modifying anti-rheumatic drugs or biologics. Fatigue in established RA is not specifically influenced by the type of treatment used but is associated with tender joint counts, pain and disability. This finding is in contrast to recent trials in early RA that suggest biologics are better than traditional disease modifying anti-rheumatic drugs for fatigue. This difference in result may be because the origins of fatigue are not the same in early compared with established RA.

BackgroundOsteoarthritis (OA) is the fastest growing cause of disability worldwide. Current treatments for OA are severely limited and a large proportion of people with OA live in constant, debilitating pain. There is therefore an urgent need for novel treatments to reduce pain. Synovitis is highly prevalent in OA and is associated with pain. In inflammatory arthritides such as rheumatoid arthritis, methotrexate (MTX) is the gold standard treatment for synovitis and has a well-known, acceptable toxicity profile. We propose that using MTX to treat patients with symptomatic knee OA will be a practical and safe treatment to reduce synovitis and, consequently, pain.Methods/DesignPain Reduction with Oral Methotrexate in knee Osteoarthritis, a pragmatic phase III trial of Treatment Effectiveness (PROMOTE) is an investigator-initiated, multi-centre, randomized, double-blind, pragmatic placebo-controlled trial. A total of 160 participants with symptomatic knee OA will be recruited across primary and secondary care sites in the United Kingdom and randomized on a 1:1 basis to active treatment or placebo, in addition to usual care, for 12 months. As is usual practice for MTX, dosing will be escalated over six weeks to 25 mg (or maximum tolerated dose) weekly for the remainder of the study. The primary endpoint is change in average knee pain during the past week (measured on an 11-point numerical rating scale) between baseline and six months. Secondary endpoints include other self-reported pain, function and quality-of-life measures. A health economics analysis will also be performed. A magnetic resonance imaging substudy will be conducted to provide an explanatory mechanism for associated symptom change by examining whether MTX reduces synovitis and whether this is related to symptom change. Linear and logistic regression will be used to compare changes between groups using univariable and multivariable modelling analyses. All analyses will be conducted on an intention-to-treat basis.DiscussionThe PROMOTE trial is designed to examine whether MTX is an effective analgesic treatment for OA. The MRI substudy will address the relationship between synovitis and symptom change. This will potentially provide a much needed new treatment for knee OA.Trial registrationCurrent Controlled Trials identifier: ISRCTN77854383 (registered: 25 October 2013).