Practical guidance for managing patients with moderate-to-severe ulcerative colitis using small molecule therapies.

Ulcerative colitis (UC) is a severe and debilitating illness that affects the quality of life and physical health of many Canadians. Given the dynamic and progressive nature of the disease, advanced therapies are required to support its long-term management. The emergence of small molecule therapies offers novel treatment options that target mechanisms central to the immunopathology of UC. Sphingosine-1-phosphate (S1P) receptor modulators and Janus-activated kinase inhibitors are 2 classes of therapies that target unique pathways to attenuate inflammation and modulate the immune response characteristic of UC. This review aims to provide practical guidance on how these therapeutic options can best be used to optimize treatment management and highlight the emerging role of small molecule therapies as a treatment strategy for UC.

Risk factors for prevalent and incident hypertension in rheumatoid arthritis: data from the Canadian Early Arthritis Cohort.

Objective: Hypertension (HTN) is a common comorbidity in RA. This study aimed to explore the prevalence and incidence of HTN and baseline factors associated with incident HTN in early RA (ERA). Methods: Data were from the Canadian Early Arthritis Cohort (CATCH), an inception cohort of ERA patients having <1 year of disease duration. HTN was determined by patient- or physician-reported diagnosis, the use of anti-hypertensives and/or blood pressure. Multivariable logistic regression was performed to determine baseline factors associated with prevalent and incident HTN in this population. Results: The study sample included 2052 ERA patients [mean age 55 years (s.d. 14), 71% female). The prevalence of HTN at study enrolment was 26% (23% in females and 34% in males). In both sexes, prevalent HTN was associated with older age, diabetes and hyperlipidaemia. HTN was associated with being overweight or high alcohol consumption in females. Of the RA patients who did not have HTN at enrolment, 24% (364/1518) developed HTN during the median follow-up period of 5 years (range 1-8). Baseline factors significantly associated with incident HTN were older age, being overweight, excess alcohol consumption and having hyperlipidaemia. Incident HTN was associated with high alcohol consumption in males and with hyperlipidaemia in females. RA-associated disease factors and treatments were not significantly associated with prevalent or incident HTN. Conclusions: Early RA patients had a high incidence of hypertension with the highest risk in older patients with traditional cardiovascular risk factors.

Brentuximab vedotin for skin involvement in refractory diffuse cutaneous systemic sclerosis, an open-label trial.

OBJECTIVE: We explored the efficacy and safety of brentuximab vedotin, a chimeric anti-CD30 antibody drug conjugate, in patients with severe active diffuse cutaneous systemic sclerosis (dcSSc). METHODS: This phase II proof-of-concept, single center, open-label, single arm, investigator-initiated trial included patients ≥18 years, with dcSSc, modified Rodnan skin score (mRSS) ≥15 with <5 years since the first non-Raynaud's symptom and/or skin worsening despite immunosuppression who were treated with intravenous brentuximab vedotin 0.6 mg/Kg q3 weeks for 45 weeks. The primary end point was a decrease in mRSS of ≥ 8 points at 48 weeks. RESULTS: Eleven patients were treated with brentuximab vedotin, with 9 completing the study. The mean mRSS reduction at week 48 was 11.3 (95% CI 6.9, 15.8; p= 0.001), meeting the primary end point in the intention to treat analysis (7/11 had a decrease in mRSS ≥8). The % forced vital capacity increased by 7.8% (12.5). The Composite Response Index in dcSSc (CRISS) suggested a beneficial treatment effect (86% ≥0.6). Most adverse events were mild. No SAEs were attributed to brentuximab vedotin. CONCLUSION: In dcSSc, brentuximab vedotin improved skin and FVC; without safety concerns. A placebo-controlled trial is warranted to corroborate these initial findings.

Retention of triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine compared to combination methotrexate and leflunomide in rheumatoid arthritis.

OBJECTIVE: There are various combination conventional synthetic disease-modifying-antirheumatic drug (csDMARD) treatment strategies used in rheumatoid arthritis (RA). A commonly used csDMARD combination is triple therapy with methotrexate (MTX), sulfasalazine (SSZ) and hydroxychloroquine (HCQ). Another approach is double therapy with MTX and leflunomide (LEF). We compared the real-world retention of these two treatment combinations. METHODS: Patients with RA from the Ontario Best Practices Research Initiative (OBRI) who received triple or double therapy on or after OBRI enrolment were included. Retention rates were compared between these two groups. We also analyzed which medication in the combination was discontinued and the reasons for treatment discontinuation. Disease activity was assessed at baseline, 6 and 12 months after treatment initiation as well as at time of discontinuation. Risk factors for treatment discontinuation were also examined. RESULTS: Six hundred and ninety-two patients were included (258 triple and 434 double therapy). There were 175 (67.8%) discontinuations in the triple therapy group and 287 (66.1%) discontinuations in patients on double therapy. The median survival for triple therapy was longer (15.1 months; 95% CI: 11.2-21.2) compared to double therapy (9.6 months; 95%CI: 7.03-12.2). However, this was not statistically significant. Disease activity at 6 and 12 months, measured by 28-joint count Disease Activity Score based on erythrocyte sedimentation rate (DAS28-ESR) was lower with triple therapy (mean DAS28 at 6 months 3.4 vs. 3.9, P<0.0001 and at 12 months 3.2 vs. 3.5, P=0.0005). CONCLUSION: Patients on triple therapy remained on treatment longer than patients on double therapy. However, this difference was not statistically significant.

Biomarker analysis from the phase 2b randomized placebo-controlled trial of riociguat in early diffuse cutaneous systemic sclerosis.

OBJECTIVE: To examine disease and target engagement biomarkers in the RISE-SSc trial of riociguat in early diffuse cutaneous systemic sclerosis and their potential to predict the response to treatment. METHODS: Patients were randomized to riociguat (n = 60) or placebo (n = 61) for 52 weeks. Skin biopsies and plasma/serum samples were obtained at baseline and week 14. Plasma cyclic guanosine monophosphate (cGMP) was assessed using radio-immunoassay. Alpha smooth muscle actin (αSMA) and skin thickness were determined by immunohistochemistry, mRNA markers of fibrosis by qRT-PCR in skin biopsies, and serum CXC motif chemokine ligand 4 (CXCL-4) and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) by enzyme-linked immunosorbent assay. RESULTS: By week 14, cGMP increased by 94 ± 78% with riociguat and 10 ± 39% with placebo (p < 0.001, riociguat vs placebo). Serum sPECAM-1 and CXCL-4 decreased with riociguat vs placebo (p = 0.004 and p = 0.008, respectively). There were no differences in skin collagen markers between the 2 groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies were associated with a larger reduction of modified Rodnan skin score from baseline at week 52 with riociguat vs placebo (interaction P-values 0.004 and 0.02, respectively). CONCLUSION: Plasma cGMP increased with riociguat, suggesting engagement with the nitric oxide-soluble guanylate cyclase-cGMP pathway. Riociguat was associated with a significant reduction in sPECAM-1 (an angiogenic biomarker) vs placebo. Elevated sPECAM-1 and the presence of αSMA-positive skin cells may help to identify patients who could benefit from riociguat in terms of skin fibrosis. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02283762.

Joint involvement in sarcoidosis: systematic review and meta-analysis of prevalence, clinical pattern and outcome.

OBJECTIVES: To characterize joint involvement (JI) in sarcoidosis, a systematic search of MEDLINE, EMBASE and Cochrane Library was conducted from inception to July 2022 for publications reporting its prevalence, pattern, treatment and outcome. METHODS: The pooled prevalence estimates (PPE) with 95% CI were calculated using binomial distribution and random effects. Meta-regression method was used to examine factors affecting heterogeneity between studies. RESULTS: Forty-nine articles were identified comprising a total of 8574 sarcoidosis patients, where 12% presented with JI (95% CI 10, 14; I2 = 0%). The PPE for sarcoid arthritis (SA) was 19% (95% CI 14, 24; I2 = 95%), and 32% (95% CI 13, 51; I2 = 99%) for arthralgia. Heterogeneity was due to higher JI prevalence reported in Western Asia and the Middle East, in rheumatology clinics and via surveys. Sample size of SA varied from 12 to 117 cases. Ankles were most frequently affected (PPE 80%) followed by knees and wrists. Monoarthritis was uncommon (PPE 1%; 95% CI 0, 2; I2 = 55%). Acute SA prevailed (PPE 79%; 95% CI 72, 88; I2 = 69%) with an equal proportion of oligo and polyarthritis and was frequently accompanied by erythema nodosum (PPE 62%; 95% CI 52, 71; I2 = 16%). Chronic SA was predominantly polyarticular with a higher frequency of the upper extremity joints affected. Most common non-articular manifestations with SA included fever (52%), erythema nodosum (41%), hilar adenopathy (86%) and interstitial lung disease (23%) of which one-third required corticosteroids and/or immunosuppressants. CONCLUSION: SA occurred early in the disease with a PPE of 19% and most frequent pattern of acute oligo- or polyarthritis predominantly affecting the lower extremity large joints.

Performance of DETECT Pulmonary Arterial Hypertension Algorithm According to the Hemodynamic Definition of Pulmonary Arterial Hypertension in the 2022 European Society of Cardiology and the European Respiratory Society Guidelines.

OBJECTIVE: The evidence-based DETECT pulmonary arterial hypertension (PAH) algorithm is frequently used in patients with systemic sclerosis (SSc) to help clinicians screen for PAH by using noninvasive data to recommend patient referral to echocardiography and, if applicable, for a diagnostic right-sided heart catheterization. However, the hemodynamic definition of PAH was recently updated in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines. The performance of DETECT PAH in identifying patients with a high risk of PAH according to this new definition was assessed. METHODS: In this post hoc analysis of DETECT, which comprised 466 patients with SSc, the performance of the DETECT PAH algorithm in identifying patients with a high risk of PAH as defined in the 2022 ESC/ERS guidelines (mean pulmonary arterial pressure [mPAP] >20 mm Hg, pulmonary capillary wedge pressure [PCWP] ≤15 mm Hg, and pulmonary vascular resistance >2 Wood units) was assessed using summary statistics and was descriptively compared to the known performance of DETECT PAH as defined in 2014, when it was developed (mPAP ≥25 mm Hg and PCWP ≤15 mm Hg). RESULTS: The sensitivity of DETECT PAH in identifying patients with a high risk of PAH according to the 2022 ESC/ERS definition was lower (88.2%) compared to the 2014 definition (95.8%). Specificity improved from 47.8% to 50.8%. CONCLUSION: The performance of the DETECT algorithm to screen for PAH in patients with SSc is maintained when PAH is defined according to the 2022 ESC/ERS hemodynamic definition, indicating that DETECT remains applicable to screen for PAH in patients with SSc.

Preventative Care in Scleroderma: What Is the Best Approach to Vaccination?

Systemic sclerosis (SSc) is a rare multisystem autoimmune disease characterized by fibrosis, vasculopathy, and autoimmunity. There are multiple complications inherent to SSc and its management. One of these complications is increased infection risk, which can lead to decreased quality of life and increased morbidity and mortality. Patients with SSc have lower vaccination rates and decreased vaccine seroconversion secondary to immunosuppressive medications compared with the general population. The purpose of this review is to provide clinicians with an approach to vaccinations in SSc.

Preventative Care in Scleroderma: What Is the Best Approach to Bone Health and Cancer Screening?

Systemic sclerosis (SSc) is a rare multisystem autoimmune disease characterized by fibrosis, vasculopathy, and autoimmunity. Lesser known complications inherent to SSc, such as malignancies and osteoporosis, can lead to decreased quality of life and increased morbidity and mortality. Patients with SSc have a greater risk of developing malignancies than the general population. In addition, they are more likely to be vitamin D deficient and are at great risk of osteoporosis-related fractures. However, these complications can be addressed through preventative measures. The purpose of this review is to provide clinicians with an approach to bone health and cancer screening in SSc.

Non-pharmacological interventions in the treatment of rheumatoid arthritis: A systematic review and meta-analysis.

PURPOSE: To investigate the role of non-pharmaceutical therapies on disease activity in rheumatoid arthritis through systematic review and meta-analysis. METHODS: A review of Pubmed, EMBASE, Web of Science, and the Cochrane Library was performed from inception until March 26, 2019. Only randomized controlled trials which assessed oral, non-pharmacological interventions (e.g. diets, vitamins, oils, herbal remedies, fatty acids, supplements, etc.) in adult patients with rheumatoid arthritis, that presented clinically-relevant outcomes (defined as pain, fatigue, disability, joint counts, and/or disease indices) were included in our meta-analysis. Data were analyzed as mean differences between active and placebo and forest plots were performed. Heterogeneity was evaluated using I-squared statistics while funnel plots and Cochrane's risk of bias assessment evaluated bias. RESULTS: 8170 articles were identified in the search and 51 were RCTs were included. The mean difference in DAS28 was significantly improved in experimental group treated with diet (-0.46 [-0.91, -0.02], p = 0.04), zinc sulfate, copper sulphate, selenium, potassium, lipoic acid, turmeric, pomegranate extract, chamomile, and cranberry extract supplements (-0.77 [-1.17, -0.38], p < 0.001), A, B6, C, D, E, and K vitamins (-0.52 [-0.74, -0.29], p < 0.001), and fatty acids (-0.19 [-0.36, -0.01], p = 0.03). Other clinical metrics such as SJC, TJC, HAQ, SDAI, ACR20, and self-reported pain were decreased in the treatment groups. There was significant reporting bias in the studies. CONCLUSION: Some non-pharmacological therapies may modestly improve some clinical outcomes in patients with rheumatoid arthritis. Many identified studies lacked full reporting. Further clinical trials that are well-designed, adequately powered, and sufficiently report ACR improvement criteria or EULAR response criteria outcomes are needed to confirm the efficacy of these therapies.

State-of-the-art evidence in the treatment of systemic sclerosis.

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease with multi-organ involvement, fibrosis and vasculopathy. Treatment in SSc, including early diffuse cutaneous SSc (dcSSc) and the use of organ-specific therapies, has improved, as evident from randomized clinical trials. Treatments for early dcSSc include immunosuppressive agents such as mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab and tocilizumab. Patients with rapidly progressive early dcSSc might be eligible for autologous haematopoietic stem cell transplantation, which can improve survival. Morbidity from interstitial lung disease and pulmonary arterial hypertension is improving with the use of proven therapies. Mycophenolate mofetil has surpassed cyclophosphamide as the initial treatment for SSc-interstitial lung disease. Nintedanib and possibly perfinidone can be considered in SSc pulmonary fibrosis. Pulmonary arterial hypertension is frequently treated with initial combination therapy (for example, with phosphodiesterase 5 inhibitors and endothelin receptor antagonists) and, if necessary, the addition of a prostacyclin analogue. Raynaud phenomenon and digital ulcers are treated with dihydropyridine calcium channel blockers (especially nifedipine), then phosphodiesterase 5 inhibitors or intravenous iloprost. Bosentan can reduce the development of new digital ulcers. Trial data for other manifestations are mostly lacking. Research is needed to develop targeted and highly effective treatments, best practices for organ-specific screening and early intervention, and sensitive outcome measurements.

Systemic Lupus Erythematosus May Be a Risk Factor for Antimalarial-Induced Retinopathy Compared With Other Rheumatologic Diseases.

OBJECTIVE: To describe the pattern and risk factors for antimalarial (AM)-induced retinopathy in patients with rheumatic diseases. METHODS: A retrospective chart review was conducted at an urban Canadian center for patients with AM use of more than 3 months and documented retinopathy screening. Univariate and multivariate regression analyses were performed to determine risk factors for retinopathy. Sensitivity analyses included stratification of analysis by method of screening and by hydroxychloroquine (HCQ) versus chloroquine (CQ). RESULTS: A total of 613 patients were included in the final analysis, with systemic lupus erythematosus (SLE) (n = 259) as the most common diagnosis. Definite AM-induced retinal toxicity was observed in 12 patients, 11 of whom had SLE. The earliest diagnosis of toxicity occurred after 5.4 years of AM therapy, and the prevalence beyond 5 years was 3.1%. In univariate analysis, a diagnosis of SLE (P = 0.009; odds ratio [OR]: 15.66; 95% confidence interval [CI]: 2.01-122.05), the daily weight-based dose of HCQ (P = 0.044; OR: 1.49; 95% CI: 1.01-2.20), cumulative CQ dose (P = 0.014; OR: 4.80; CI: 1.37-16.84), and daily CQ weight-based dose (P = 0.0001; OR: 5.70; 95% CI: 2.41-13.49) were significantly associated with toxicity. In multivariate analysis, diagnosis of SLE (P = 0.022; OR: 12.14; 95% CI: 1.44-102.44) and daily CQ weight-based dose (P = 0.005; OR: 1.83; 95% CI: 1.83-26.75) were significant after adjusting for standard covariates. CONCLUSION: The risk of AM-induced retinopathy increases after 5 years of therapy. There may be higher rates of toxicity in patients with SLE because of longer duration of treatment, higher weight-based dosages, and more CQ use in this population, and SLE may be an independent risk factor.

"From Where I Stand": using multiple anchors yields different benchmarks for meaningful improvement and worsening in the rheumatoid arthritis flare questionnaire (RA-FQ).

PURPOSE: The Rheumatoid Arthritis Flare Questionnaire (RA-FQ) is a patient-reported measure of disease activity in RA. We estimated minimal and meaningful change from the perspective of RA patients, physicians, and using a disease activity index. METHODS: Data were from 3- to 6-month visits of adults with early RA enrolled in the Canadian Early Arthritis Cohort. Participants completed the RA-FQ, the Patient Global Assessment of RA, and the Patient Global Change Impression at consecutive visits. Rheumatologists recorded joint counts and MD Global. Clinical Disease Activity Index (CDAI) scores were computed. We compared mean RA-FQ change across categories using patients, physicians, and CDAI anchors. RESULTS: The 808 adults were mostly white (84%) women (71%) with a mean age of 55 and moderate-high disease activity (85%) at enrollment. At V2, 79% of patients classified their RA as changed; 59% were better and 20% were worse. Patients reporting they were a lot worse had a mean RA-FQ increase of 8.9 points, whereas those who were a lot better had a -6.0 decrease. Minimal worsening and improvement were associated with a mean 4.7 and - 1.8 change in RA-FQ, respectively, while patients rating their RA unchanged had stable scores. Physician and CDAI classified more patients as worse than patients, and minimal and meaningful RA-FQ thresholds differed by group. CONCLUSION: Thresholds to identify meaningful change vary by anchor used. These data offer new evidence demonstrating robust psychometric properties of the RA-FQ and offer guidance about improvement or worsening, supporting its use in RA care, research, and decision-making.

Measuring the Impact of MyLupusGuide in Canada: Results of a Randomized Controlled Study.

OBJECTIVE: This study was undertaken to assess the effects of a web-based program, MyLupusGuide, developed to facilitate self-management in systemic lupus erythematosus (SLE). METHODS: In this randomized controlled online study, participants received either immediate access to the MyLupusGuide site or delayed access starting on month 3. The primary outcome was the patient activation measure (PAM) score. Secondary outcomes included measurements of health status, self-efficacy, coping, perceived patient-physician relationship, and medication adherence. Outcomes were measured at the baseline visit and at the 3-month and 6-month follow-up visits. We used linear mixed modeling to compare PAM scores between the 2 groups at months 3 and 6. RESULTS: There were 541 participants included in this study. The mean ± SE age was 50 ± 14 years; 93% were female and 74% were White. The mean ± SE disease duration was 17 ± 12 years, and 56% visited MyLupusGuide at least once. The baseline mean ± SE PAM score was 61.2 ± 13, with 36% scoring low for perceived self-management skills. After 3 months of exposure to MyLupusGuide, there were no differences in terms of PAM scores between groups. In exploratory analyses, we found significant improvement in PAM scores in those who had low PAM scores at baseline and in male individuals. We observed significant improvements in self-efficacy before and after access to MyLupusGuide and delayed improvements at month 6 compared to month 3 in terms of mental health and emotional coping. CONCLUSION: MyLupusGuide increases self-efficacy but not patient activation. A total of 56% of participants visited the MyLupusGuide site during the study period. Individuals with lupus need support to become activated toward self-management behaviors.

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update.

OBJECTIVES: To provide an update of the EULAR rheumatoid arthritis (RA) management recommendations addressing the most recent developments in the field. METHODS: An international task force was formed and solicited three systematic literature research activities on safety and efficacy of disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs). The new evidence was discussed in light of the last update from 2019. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned to and participants finally voted on the level of agreement with each item. RESULTS: The task force agreed on 5 overarching principles and 11 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); GCs; biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab including biosimilars), abatacept, rituximab, tocilizumab, sarilumab and targeted synthetic (ts) DMARDs, namely the Janus kinase inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib. Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering in sustained clinical remission is provided. Safety aspects, including risk of major cardiovascular events (MACEs) and malignancies, costs and sequencing of b/tsDMARDs were all considered. Initially, MTX plus GCs is recommended and on insufficient response to this therapy within 3-6 months, treatment should be based on stratification according to risk factors; With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD should be added to the csDMARD; after careful consideration of risks of MACEs, malignancies and/or thromboembolic events tsDMARDs may also be considered in this phase. If the first bDMARD (or tsDMARD) fails, any other bDMARD (from another or the same class) or tsDMARD (considering risks) is recommended. With sustained remission, DMARDs may be tapered but should not be stopped. Levels of evidence and levels of agreement were high for most recommendations. CONCLUSIONS: These updated EULAR recommendations provide consensus on RA management including safety, effectiveness and cost.