Shahin Jamal

Biologic Therapy for Systemic Sclerosis: A Systematic Review

Objective. Biologic agents are increasingly used in the rheumatic diseases. Their role in patients with systemic sclerosis (SSc) is uncertain. Our aim was to evaluate the effectiveness and safety of biologic agents in SSc. We review the evidence for the use of biologic agents to improve inflammatory arthritis, disability, and skin score, and we review adverse effects with biologic agents in patients with SSc. Methods. A systematic literature review was performed to identify studies evaluating the use of biologic agents in SSc. Medline, Embase, CINAHL, and Cochrane Database of Systematic Reviews were searched. A standardized abstraction form was used to extract biologic agent, study design, sample size, treatment effect, and adverse effects. Results. A total of 23 studies from 1413 citations were evaluated. Three studies evaluated infliximab, 3 evaluated etanercept, 3 evaluated antithymocyte globulin, 3 evaluated imatinib, 6 evaluated rituximab, and 1 study each evaluated interferon-γ (IFN-γ), IFN-α, relaxin, delipidated, deglycolipidated Mycobacterium vaccae, human anti-transforming growth factor ß1 antibody, and oral type I collagen. Studies of etanercept and infliximab suggest improvements in inflammatory arthritis and Health Assessment Questionnaire Disability Index (HAQ-DI). None of the other biologic agents demonstrated reproducible, statistically significant improvements in joint count, HAQ-DI, or skin score. Conclusion. Anti-tumor necrosis factor-α agents may improve inflammatory arthritis and disability in SSc. The effect on skin score is uncertain. Adequately powered trials are needed to evaluate efficacy, and longitudinal studies are needed to evaluate longterm safety of these agents in SSc.

Time to Treatment for New Patients with Rheumatoid Arthritis in a Major Metropolitan City

Objective. To determine the proportion of patients with rheumatoid arthritis (RA) seen by rheumatologists and treated with disease-modifying antirheumatic drugs (DMARD) within 3 months of symptom onset, to determine where treatment delays occur, and to identify contributing factors. Methods. A retrospective cohort study in which adult patients with RA, diagnosed between January 1, 2003, and May 31, 2006, were recruited from rheumatologists’ offices to participate in a telephone survey and chart review. The percentage treated with DMARD within 3 months of symptom onset was determined, along with median times for delay. Factors contributing to the delay were explored using multivariable logistic regression. Results. Our study included 204 patients. Within 3 months of symptoms, 22.6% (95% CI 16.8%, 28.3%) received DMARD and within 6 months, 47.6% (95% CI 40.7%, 54.4%). The median time from symptom onset to DMARD was 6.4 months [interquartile range (IQR) 3.3, 12.0] with a median time from RA diagnosis by a rheumatologist to DMARD of 0.0 months (IQR 0.0, 1.0). Higher baseline swollen joint counts resulted in earlier treatment. Age, sex, education, comorbidity, rheumatologist practice type, and years since the physician’s graduation did not affect time to treatment. Conclusion. Fewer than 25% of patients referred to rheumatologists were treated within 3 months of symptom onset. Identification of inflammatory arthritis and referral to rheumatologists are the key factors in timely care, because once patients are seen there is no delay to treatment. Future resources should be focused on development and evaluation of interventions to facilitate rapid triage, referral, and assessment by a rheumatologist.

The Canadian Early Arthritis Cohort (CATCH): Patients with New-onset Synovitis Meeting the 2010 ACR/EULAR Classification Criteria But Not the 1987 ACR Classification Criteria Present with Less Severe Disease Activity

Objective. Our objective was to describe characteristics of Canadian patients with early arthritis and examine differences between those fulfilling 1987 and 2010 rheumatoid arthritis (RA) classification criteria. Methods. The Canadian Early Arthritis Cohort (CATCH) is a national, multicenter, observational, prospective cohort of patients with early inflammatory arthritis, receiving usual care, recruited since 2007. Inclusion criteria include age > 16 years; symptom duration 6–52 weeks; swelling of ≥ 2 joints or ≥ 1 metacarpophalangeal/proximal interphalangeal joint; and 1 of rheumatoid factor ≥ 20 IU, positive anticitrullinated protein antibodies (ACPA), morning stiffness ≥ 45 min, response to nonsteroidal antiinflammatory drug, or positive metatarsophalangeal joint squeeze test. Data from patients enrolled to March 15, 2011, were analyzed. Results. In total, 1450 patients met the eligibility criteria (1187 were followed). At baseline, mean age was 53 ± 15 years, symptom duration was 6.1 ± 3.2 months, Disease Activity Score (DAS28) was 4.9 ± 1.6, Health Assessment Questionnaire-Disability Index was 1.0 ± 0.7. Forty-one percent (n = 450) of patients had moderate (3.2 < DAS28 ≤ 5.1) and 46% (n = 505) had high (DAS28 > 5.1) disease activity; 28% of those with baseline radiographs (n = 250/908) had radiographic evidence of erosions. ACPA status was available for 70% (n = 831) of patients; 55% (n = 453) tested positive. Sixty percent (n = 718) of patients were treated with methotrexate (MTX) initially. Of 612 patients without erosions, 63% and 83% fulfilled 1987 and 2010 RA classification criteria, respectively. Seventy-three percent (n = 166) of those who did not fulfill 1987 criteria were newly identified by the 2010 criteria. These patients had less severe disease and more were MTX-naive compared to those satisfying the 1987 criteria. Forty-seven percent of all patients achieved remission at 1 year. Conclusion. Patients with early RA present with moderate high disease activity; < 50% achieve remission at 1 year, despite MTX treatment in the majority. The 2010 RA classification criteria identify more patients with RA who would previously have been designated as having undifferentiated disease. However, these patients have lower disease activity at the time of identification.

The comparative effectiveness of oral versus subcutaneous methotrexate for the treatment of early rheumatoid arthritis

Objective To determine the comparative effectiveness of oral versus subcutaneous methotrexate (MTX) as initial therapy for patients with early rheumatoid arthritis (ERA). Methods Patients with ERA (symptoms ≤1 year) initiating MTX therapy were included from a multicentre, prospective cohort study. We compared the effectiveness between starting with oral versus subcutaneous MTX over the first year. Longitudinal multivariable models, adjusted for potential baseline and time-varying confounders, were used to compare treatment changes due to inefficacy or toxicity and treatment efficacy (Disease Activity Score-28 (DAS-28), DAS-28 remission and Health Assessment Questionnaire-Disability Index (HAQ-DI)). Results 666 patients were included (417 oral MTX, 249 subcutaneous MTX). Patients prescribed subcutaneous MTX were prescribed a higher dose of MTX (mean dose over first three months 22.3 mg vs 17.2 mg/week). At 1 year, 49% of patients initially treated with subcutaneous MTX had changed treatment compared with 77% treated with oral MTX. After adjusting for potential confounders, subcutaneous MTX was associated with a lower rate of treatment failure ((HR (95% CI) 0.55 (0.39 to 0.79)). Most treatment failures were due to inefficacy with no difference in failure due to toxicity. In multivariable models, subcutaneous MTX was also associated with lower average DAS-28 scores (mean difference (−0.38 (95% CI −0.64 to −0.10)) and a small difference in DAS-28 remission (OR 1.2 (95% CI 1.1 to 1.3)). There was no significant difference in sustained remission or HAQ-DI (p values 0.43 and 0.75). Conclusions Initial treatment with subcutaneous MTX was associated with lower rates of treatment changes, no difference in toxicity and some improvements in disease control versus oral MTX over the first year in patients with ERA.

Subsequent entry biologics/biosimilars: a viewpoint from Canada.

We have reviewed the issues surrounding the advent of biosimilars in the rheumatoid arthritis biologic field. Our proposals emphasize the need to focus primarily on patient safety and to assess the outcomes of therapy both in the short and longer term.

Identifying flares in rheumatoid arthritis: reliability and construct validation of the OMERACT RA Flare Core Domain Set

Objective To evaluate the reliability of concurrent flare identification using 3 methods (patient, rheumatologist and Disease Activity Score (DAS)28 criteria), and construct validity of candidate items representing the Outcome Measures in Rheumatology Clinical Trials (OMERACT) RA Flare Core Domain Set. Methods Candidate flare questions and legacy measures were administered at consecutive visits to Canadian Early Arthritis Cohort (CATCH) patients between November 2011 and November 2014. The American College of Rheumatology (ACR) core set indicators were recorded. Concordance to identify flares was assessed using the agreement coefficient. Construct validity of flare questions was examined: convergent (Spearmans r); discriminant (mean differences between flaring/non-flaring patients); and consequential (proportions with prior treatment reductions and intended therapeutic change postflare). Results The 849 patients were 75% female, 81% white, 42% were in remission/low disease activity (R/LDA), and 16–32% were flaring at the second visit. Agreement of flare status was low–strong (κs 0.17–0.88) and inversely related to RA disease activity level. Flare domains correlated highly (rs≥0.70) with each other, patient global (rs≥0.66) and corresponding measures (rs 0.49–0.92); and moderately highly with MD and patient-reported joint counts (rs 0.29–0.62). When MD/patients agreed the patient was flaring, mean flare domain between-group differences were 2.1–3.0; 36% had treatment reductions prior to flare, with escalation planned in 61%. Conclusions Flares are common in rheumatoid arthritis (RA) and are often preceded by treatment reductions. Patient/MD/DAS agreement of flare status is highest in patients worsening from R/LDA. OMERACT RA flare questions can discriminate between patients with/without flare and have strong evidence of construct and consequential validity. Ongoing work will identify optimal scoring and cut points to identify RA flares.

Rheumatologists lack confidence in their knowledge of cannabinoids pertaining to the management of rheumatic complaints

BackgroundArthritis pain is reported as one of the most common reasons for persons using medical herbal cannabis in North America. “Severe arthritis” is the condition justifying legal use of cannabis in over half of all authorizations in Canada, where cannabis remains a controlled substance. As champions for the care of persons with arthritis, rheumatologists must be knowledgeable of treatment modalities both traditional and non-traditional, used by their patients. As study of cannabinoid molecules in medicine is recent, we have examined the confidence in the knowledge of cannabinoids expressed by Canadian rheumatologists.MethodsThe confidence of rheumatologists in their knowledge of cannabinoid molecules and mechanisms relevant to rheumatology, and their ability to advise patients about cannabinoid treatments was recorded by an online questionnaire circulated via email to the entire Canadian Rheumatology Association membership.ResultsOver three quarters of the 128 respondents lacked confidence in their knowledge of cannabinoid molecules. While 45% of respondents believed there was no current role for cannabinoids in rheumatology patient care, only 25% supported any use of herbal cannabis. With 70% never having previously prescribed or recommended any cannabinoid treatment, uncertainty regarding good prescribing practices was prevalent. Concerns about risks of cannabis use were in line with the current literature.ConclusionsRheumatologists lacked confidence in their knowledge of cannabinoid molecules in general and in their competence to prescribe any cannabinoid for rheumatic complaints. In line with this uncertainty, there is reticence to prescribe cannabinoid preparations for rheumatology patients. Guidance is required to inform rheumatologists on the evidence regarding cannabinoids.

Efficacy, Tolerability, and Safety of Cannabinoid Treatments in the Rheumatic Diseases: A Systematic Review of Randomized Controlled Trials.

To assess the efficacy, tolerability, and safety of cannabinoids (phyto‐ and syntheto‐) in the management of rheumatic diseases.

Expanding Medical Marijuana Access in Canada: Considerations for the Rheumatologist

Similar to the enthusiasm for treatment of various ailments that greeted Nicotiana tabacum when brought to Europe from the New World 500 years ago, Cannabis sativa is now hailed as a possible treatment for a multiplicity of symptoms1. Embraced by physicians and the people, from commoners to the aristocracy, the enthusiasm for Nicotiana tabacum was questioned by a discerning few with concerns about the “indiscriminate use of the herb for all diseases in all age groups without specific measured prescriptions”1. Much like for tobacco many years ago, marijuana as the byproduct of Cannabis sativa, with significant financial incentives, requires careful appraisal regarding true therapeutic potential. Cannabinoids are a diverse group of compounds, including in the animal/human system, phytocannabinoids derived from plants, and pharmaceutically prepared synthetocannabinoids. The herbal product is a complexity of over 400 molecules, thereby not allowing for direct comparison or interchangeability with synthetocannabinoids. While the latter are currently available as treatments for some conditions, we will focus on issues pertaining to the use of the phytocannabinoid marijuana (hereafter “herbal cannabis”) in rheumatic diseases. Therapeutic effects have been claimed for various conditions for centuries, but herbal cannabis largely fell into medical disfavor because of variable potency and short shelf life, and was superseded by synthetic analgesic agents that could be reliably dosed and studied2. As pain relief for rheumatic conditions is commonly cited as a reason for medicinal cannabis use, rheumatologists are increasingly caring for patients who are either selfmedicating or requesting advice regarding use. Legislators worldwide are currently debating the merits of expanding access to herbal cannabis for medicinal purposes. In some countries such as Canada, physicians will now be required to write a prescription for herbal cannabis. With increasing pressure from legislators, driven by public advocacy, there exists a discord between … Address correspondence to Dr. Mary-Ann Fitzcharles, Montreal General Hospital, 1650 Cedar Avenue, H3G 1A4, Montreal, Quebec, Canada. E-mail: mary-ann.fitzcharles{at}muhc.mcgill.ca

Heterogeneous Disease Trajectories Explain Variable Radiographic, Function and Quality of Life Outcomes in the Canadian Early Arthritis Cohort (CATCH).

Our objective was to identify distinct trajectories of disease activity state (DAS) and assess variation in radiographic progression, function and quality of life over the first two years of early rheumatoid arthritis (ERA). The CATCH (Canadian early ArThritis CoHort) is a prospective study recruiting ERA patients from academic and community rheumatology clinics in Canada. Sequential DAS28 scores were used to identify five mutually exclusive groups in the cohort (n = 1,586) using growth-based trajectory modeling. Distinguishing baseline sociodemographic and disease variables, treatment required, and differences in radiographic progression and quality of life measures over two years were assessed. The trajectory groups are characterized as: Group 1 (20%) initial high DAS improving rapidly to remission (REM); Group 2 (21%) initial moderate DAS improving rapidly to REM; Group 3 (30%) initial moderate DAS improving gradually to low DAS; Group 4 (19%) initial high DAS improving continuously to low DAS; and Group 5 (10%) initial high DAS improving gradually only to moderate DAS. Groups differed significantly in age, sex, race, education, employment, income and presence of comorbidities. Group 5 had persistent steroid requirements and the highest biologic therapy use. Group 2 had lower odds (OR 0.22, 95%CI 0.09 to 0.58) and Group 4 higher odds (OR 1.94, 95%CI 0.90 to 4.20) of radiographic progression compared to Group 1. Group 1 had the best improvement in physical function (Health Assessment Questionnaire 1.08 (SD 0.68) units), Physical Component Score (16.4 (SD 10.2) units), Mental Component Score (9.7 (SD 12.5) units) and fatigue (4.1 (SD 3.3) units). In conclusion, distinct disease activity state trajectories explain variable outcomes in ERA. Early prediction of disease course to tailor therapy and addressing social determinants of health could optimize outcomes.