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Introduction Ischemic preconditioning (IPC) is protective against future ischemia, with brief cycles of ischemia and reperfusion leading to the release of circulating endogenous compounds from ischemic cells. IPC may increase vasodilatory substances and improve Raynaud's phenomenon (RP). We hypothesized that IPC would be more effective than sham in RP treatment. Sample size required 18 participants to detect 5 fewer RP attacks per week. Methods This was a randomized single-blinded cross-over trial. The IPC intervention of inflating a standard blood pressure cuff on the upper arm (200 mmHg) and sham intervention (60 mmHg) were performed 3 times per week for 2 weeks, with a 2-week washout period between IPC and sham interventions. Cuff inflation was performed 4 times for 2.5 minutes, with 2.5 minutes between cuff inflation. Participants completed a daily diary on RP disease activity. Results Eighteen participants were enrolled (17 with secondary RP and 1 with primary RP); mean age 60.8 (SD 9.4) years, 89% female; and mean number of RP attacks/2 weeks in screen was 16.9 (SD 11.3). With IPC versus sham, results were not significant including an increase of 0.5 RP episodes/week (SD: 10.0; p = 0.84), decrease of 55.6 minutes per week (SD 516.4; p = 0.66), and a decrease in average severity of 0.4 points (on a scale of 0 to 10) (SD 12.9; p = 0.88). Secondary outcomes were also not significant. Conclusions No significant differences in RP disease activity were found between IPC and sham. This could be due to lack of effect of IPC on RP, too few treatments, or sham having a partial effect.

Background:Biological disease modifying anti-rheumatic drugs (bDMARDs) and Janus Kinase inhibitors (JAKi) are both recommended post conventional synthetic disease modifying anti-rheumatic drug (csDMARD) therapy failure in active rheumatoid arthritis (RA), but the data on long-term durability are limited.Objectives:The objective of this study is to analyze a database of patients at the Western University, Rheumatology Center who initiated a bDMARD or JAKi and compare the proportion and characteristics of patients associated with retention of a drug class.Methods:This was a single-center study of 215 adult RA patients (82.76 % females, age 59.8 ± 12.0 years, disease duration 15.5 ± 10.0 years; table 1) failing multiple csDMARDs prior to initiating either bDMARDs (TNF inhibitors, abatacept, rituximab, tocilizumab) or JAKi, between June 2014 (when tofacitinib was approved in Canada) and April 2020. All patients enrolled had failed traditional DMARDs, including methotrexate, hydroxychloroquine, sulfasalazine and/or leflunomide. Durability and predictors of discontinuation were analyzed by Kaplan-Meier and Cox regression analyses for all treatment trials, and for patients receiving bDMARDs/JAKi as a first line after csDMARDs failure.Results:In 215 patients, there were 320 treatment events (148 bDMARDs, 172 JAKi) and 142 discontinuations (53.5% bDMARDs, 46.5% JAKi). Figure 1 represents the Kaplan-Meier survival curve for time to therapy discontinuation in 215 patients receiving bDMARDs vs JAKi. The Cox proportional hazards model was significant with better retention for JAKi, with a hazard ratio (HR) for treatment discontinuation of JAKi compared with bDMARDs of 0.676 (95% CI 0.47-0.97, p=0.034), adjusted for gender, age, disease duration, and line of therapy (Table 1). Moreover, the analysis revealed better retention for both groups as first line advanced therapy compared to later lines of therapy; 57.6% of JAKi and 31.1% of bDMARDs were used as first line advanced therapy. HR for treatment discontinuation for first line vs later lines of therapy was 0.593 (95% CI 0.40-0.88, p=0.01), adjusted for drug class, gender, age, and disease duration (Table 1). The most common reasons for discontinuations were inefficacy (60%), side effects (22%), or other reasons (18%). Inefficacy (58% vs 62%, p=0.8) and side-effects (16% vs 27%, p=0.4) were equally common for bDMARDs and JAKi. Sex, age at treatment onset, and RA duration did not predict discontinuation by Cox regression analyses, and after sub-grouping into bDMARDs and JAKi.Conclusion:EULAR guidelines have placed bDMARDs equal to JAKi as post csDMARD failure therapy in active RA. However, this study demonstrates that JAKi has a greater durability than biologics regardless of gender, age, disease duration, and line of therapy. Therefore, JAKi may be considered as a preferable method of treatment post csDMARD failure in active RA.Figure 1.Kaplan-Meier survival curves for (A) time to discontinuation of therapy in all RA patients receiving bDMARDs versus JAKi; P-value represents Cox regression adjusted for gender, age, disease duration, and line of therapy (B) time to discontinuation of therapy in patients using bDMARDs/JAKi as first line of advanced therapy; P-value represents Cox regression adjusted for drug class, gender, age, and disease durationTable 1.Patient demographics and hazard ratios for discontinuation of bDMARDs versus JAKi by Cox regression modelCharacteristicJAKi (N=172)bDMARD (N=148)MeanAge (years)60.958.559.8Sex (% F)77.888.582.8Disease duration (years)15.315.815.5Line of advanced therapy (% first line)57.631.145.3Drug used (%)Tofacitinib: 93.5Rituximab: 26.4Etanercept: 19.6Adalimumab: 17.6Predictors of Drug DiscontinuationHR (95% CIs)P valuesCrude ModelJAKi vs bDMARDs0.60 (0.43, 0.84)0.003Adjusted modelJAKi vs bDMARDs0.68 (0.47, 0.97)0.034Male vs female0.77 (0.46, 1.31)0.342Age1.01 (0.99, 1.03)0.123RA duration0.99 (0.97, 1.01)0.500Treatment line 1 vs >10.59 (0.40, 0.88)0.010Disclosure of Interests:Karla Machlab: None declared, Samir M. Iskandar: None declared, Tatiana Nevskaya: None declared, Louise Vanderhoek: None declared, Jillian Bylsma: None declared, Sara Hewitt: None declared, Janet Pope Speakers bureau: AbbVie, Amgen, BMS, BI, Gilead, Galapagos, Janssen, Lilly, Medexus, Merck, Novartis, Pfizer, Sanofi, Sandoz, Consultant of: AbbVie, Amgen, BMS, BI, Celltrion, Gilead, Galapagos, Janssen, Lilly, Medexus, Merck, Novartis, Pfizer, Roche, Samsung, Sanofi, Sandoz, Teva, UCB, Grant/research support from: AbbVie, BMS, Merck, Pfizer, Roche, Seattle Genetics

Objective To better understand the feasibility of using imatinib, a tyrosine kinase inhibitor, to treat active diffuse cutaneous systemic sclerosis (dcSSc). Methods We performed a 6-month, randomized, double-blind, placebo-controlled, proof-of-concept pilot study of imatinib in patients with active dcSSc. Data on safety, modified Rodnan skin thickness scores (MRSS), Health Assessment Questionnaire (HAQ) scores, patient's and physician's global assessments (100-mm visual analog scale), and biomarkers in serum and skin biopsy samples were collected. We used a 4:1 randomization strategy (imatinib 200 mg administered twice a day versus placebo), stratifying according to current use of methotrexate. The plan was to enroll 20 dcSSc patients. Results After enrolling 10 patients (9 receiving active drug and 1 receiving placebo), we found poor tolerability and high rates of adverse events with imatinib, and study enrollment was discontinued. There was no significant difference in the mean MRSS in all patients who took imatinib (31.1 at baseline versus 29.4 at 6 months) or in only those who completed 6 months of imatinib (31.0 at baseline versus 30.3 at 6 months), and there was no difference in the C-reactive protein level, erythrocyte sedimentation rate, physician's global assessment, patient's global assessment, response to the Health Transition query, or the HAQ scores between those who did and those who did not complete 6 months of therapy. Side effects were edema, fluid retention, fatigue, nausea, cramps/myalgias, diarrhea, alopecia, and anemia. Most side effects occurred within the first week of treatment, and even when imatinib was reintroduced at a lower dosage (200 mg daily), it was poorly tolerated. Two patients were hospitalized because of side effects of the medication. In general, biomarker levels in plasma and skin did not change. Conclusion Imatinib was poorly tolerated, and this could limit its application in SSc. The study was too small to form conclusions about the efficacy of imatinib in SSc.

OBJECTIVE Data from a small study testing imatinib to treat SSc were used to determine if cytokine changes were related to differences in clinical parameters to model future early phase trials pairing cytokine changes and clinical parameters. METHODS Plasma and punch skin biopsy specimens collected at baseline and 6 months were analysed for levels of 26 fibrotic and inflammatory cytokines using multiplexed immunoassays and ELISA. Seven of nine patients on active treatment had paired data. Biopsies were biopulverized and standardized to protein levels in the tissue homogenate. Plasma was frozen at -80°C and analysed using multiplexed immunoassays or ELISAs standardized to CRP. Correlations between fold changes in cytokines and differences in clinical parameters (skin score, physician and patient global assessments and HAQ) were performed. P < 0.01 was considered significant. RESULTS After 6 months of imatinib treatment, plasma levels of soluble vascular cell adhesion molecule 1 decreased significantly (P < 0.001), while tissue levels of soluble intercellular adhesion molecule 1 increased (P < 0.01). Some significant correlations between fold changes in certain plasma fibrotic and inflammatory cytokines and changes in clinical parameters after 6 months of treatment were found: patient global scores and IL-13 (r = 0.964, P < 0.0001); ESR and IL-12p70 (r = -0.903, P < 0.01); in tissue samples, patient global score and soluble E-selectin (r = 0.913, P < 0.01); and physician global score with sCD40L (r = -0.883, P < 0.01). CONCLUSION Some serum and tissue cytokines may have a role in early phase clinical trials of SSc, correlating with changes in clinical parameters. Serum and tissue samples could be analysed in early phase trials to determine whether they support the clinical observations. TRIAL REGISTRATION http://clinicaltrials.gov/show/NCT01545427.