Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

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. Methods We 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. Findings In 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. Funding UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology

[Characteristics and effectiveness of smoking cessation programs in Italy. Results of a multicentric longitudinal study]

Aim: to describe the characteristics and effectiveness of various smoking cessation programs offered by Italian treatment services operating within the National Health Service. Design: prospective longitudinal multicentre study involving 41 smoking cessation services in 16 Italian regions. Study population: the study population includes patients entering smoking cessation programs between April 2003 and June 2004. The "study population" includes 1226 patients (54.2% males and 45.4% females), mean age 47 years. Patients have a middle/high level of education and a long history of smoking; most are highly dependent on nicotine and report previous attempts to quit smoking. Methods: treatment effectiveness in smoking cessation is assessed six months after entering treatment service. Logistic Regression Model was used to determine the predictors of successfiul cessation, independent of treatment typology. The predictors were included as confounding variables in the logistic regression model that was used to evaluate the effectiveness of treatments. Besides the effect of treatment completion on smoking cessation was estimated. Results: predictors of successful smoking cessation are: being male, presence of a partner, strong motivation to quit, previous attempts to give up smoking, mild nicotine dependence, and not suffering from mood disturbances. All treatments are effective in helping people to stop smoking: cessation rate ranges between 25.00% for patients receiving a single session of motivational counselling and 65.3% for those receiving nicotine replacement therapy combined to group therapy. Compared to a single session of motivational counseling, nicotine replacement therapy combined to group therapy is the most effective therapeutic program (OR 5.4; 95%CI 12.5-12.0). Treatment completion is a strong determinant ofsuccess (OR 4.8; 95%CI 3.5-6.4). Conclusion: enrolling people in any type of therapeutic program, in particular nicotine replacement therapy combined with group therapy increases the probability of successfully quitting smoking; moreover, patients that begin a smoking cessation program should be encouraged to complete the therap