Initial Disease-modifying Antirheumatic Drug Research Articles

E008 I feel a bit happier about going on it now: exploring the information needs of people starting methotrexate

Abstract Background/Aims Methotrexate (MTX) is recommended as initial disease-modifying anti-rheumatic drug (DMARD) therapy for people with rheumatoid arthritis (RA). Rheumatology nurses provide information about benefits, risks and safety monitoring requirements for methotrexate during DMARD counselling, which may be provided in different formats. This study sought to explore the information needs and experiences of people with RA commencing MTX. Methods Seventy-six adults with RA referred for MTX DMARD counselling attending two rheumatology units in the West Midlands were invited to take part in qualitative semi-structured interviews (either by phone or video) before and after receiving information about MTX. Research partners with RA helped to develop interview topic guides. Interviews were digitally recorded, transcribed and analysed using reflexive thematic analysis. Results Nineteen participants, (11 male, 8 female, White British, age 45-76 years, disease duration 6 weeks - 35 years) took part in telephone (n17) or video (n2) interviews (duration 34-82 minutes). Three main themes were identified: information delivery, necessity of MTX and concerns about MTX. Information delivery: most participants received telephone DMARD counselling which was helpful for people with mobility issues or work commitments. However, most acknowledged a preference for, and the importance of face-to-face communication. Information tended to be provided in a generic manner, using a checklist, and could feel rushed. Written MTX leaflets were received but not used by all participants. Some participants felt well informed whilst others felt overwhelmed with information. Many had difficulty recalling important safety information. Unmet information needs about monitoring, prescribing and follow-up arrangements were frequently reported. Inconsistent information about MTX from different sources could increase concerns. Rheumatology helplines were valued as a direct route to information and care. Necessity of MTX: most participants wanted more information on why they should take MTX, how and when MTX would help them and how long they would be required to take MTX for. Some wanted to know about other drug treatment options. Concerns about MTX: all participants had concerns about the likelihood and severity of side-effects including mouth ulcers, nausea and hair loss. Worries about the use of MTX as a cancer treatment were frequently reported. Whilst concerns remained about MTX most participants accepted the risk of side-effects because of the need to improve their symptoms. Conclusion DMARD counselling was valued by people with RA when starting MTX but was not always responsive to information needs. Addressing individual concerns about the necessity for MTX, concerns about side-effects and prioritising essential safety information is recommended. Practical issues around obtaining supplies of MTX, monitoring, follow-up arrangements and a follow-up telephone call may help address unmet information needs for some. Disclosure S.J. Logan: None. S. Hider: None. J. Green: None. S. Ryan: None.

Clinical predictors of response to methotrexate in patients with rheumatoid arthritis: a machine learning approach using clinical trial data

BackgroundMethotrexate is the preferred initial disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis (RA). However, clinically useful tools for individualized prediction of response to methotrexate treatment in patients with RA are lacking. We aimed to identify clinical predictors of response to methotrexate in patients with rheumatoid arthritis (RA) using machine learning methods.MethodsRandomized clinical trials (RCT) of patients with RA who were DMARD-naïve and randomized to placebo plus methotrexate were identified and accessed through the Clinical Study Data Request Consortium and Vivli Center for Global Clinical Research Data. Studies with available Disease Activity Score with 28-joint count and erythrocyte sedimentation rate (DAS28-ESR) at baseline and 12 and 24 weeks were included. Latent class modeling of methotrexate response was performed. The least absolute shrinkage and selection operator (LASSO) and random forests methods were used to identify predictors of response.ResultsA total of 775 patients from 4 RCTs were included (mean age 50 years, 80% female). Two distinct classes of patients were identified based on DAS28-ESR change over 24 weeks: “good responders” and “poor responders.” Baseline DAS28-ESR, anti-citrullinated protein antibody (ACPA), and Health Assessment Questionnaire (HAQ) score were the top predictors of good response using LASSO (area under the curve [AUC] 0.79) and random forests (AUC 0.68) in the external validation set. DAS28-ESR ≤ 7.4, ACPA positive, and HAQ ≤ 2 provided the highest likelihood of response. Among patients with 12-week DAS28-ESR > 3.2, ≥ 1 point improvement in DAS28-ESR baseline-to-12-week was predictive of achieving DAS28-ESR ≤ 3.2 at 24 weeks.ConclusionsWe have developed and externally validated a prediction model for response to methotrexate within 24 weeks in DMARD-naïve patients with RA, providing variably weighted clinical features and defined cutoffs for clinical decision-making.

Innovative strategies for treatment of rheumatoid arthritis

Besides excellent guidelines and newly developed highly effective drugs, evidence-based strategic use of these new drugs has especially contributed to enormous advances in rheumatoid arthritis treatment, apparent especially since 2000. Currently, the treat-to-target (T2T) strategy has proven to be the most successful in several studies and systematic reviews. The target is to achieve remission, which should be reached and sustained for an optimal outcome (i.e. stable over a long time period). If the initial disease-modifying antirheumatic drug (DMARD) treatment fails, the best strategy for continuing treatment is controversial, with swap or switch being open to debate (change within a class of drugs or change in the mechanism of action). Recent studies seem to indicate that switching to another mechanism of action is the most successful approach. A hotly discussed topic is the question whether DMARD treatment can or should be tapered when sustained remission has been achieved? Many patients wish for a reduction of drugs in cases of stable remission; however, the stable disease control might become destabilized by tapering. The main priority is the reduction or tapering of glucocorticoid treatment. When the decision for reduction of DMARD treatment is made together with the patient, a complete cessation bears a high risk of a flare, therefore, a careful step by step reduction of DMARD treatment should be preferred. In the case of a running combination, the question whether the conventional DMARD (mostly methotrexate), the biological (b)DMARD or targeted synthetic (ts)DMARD should be reduced first, must be decided on an individual basis. Most patients prefer to first reduce methotrexate and transfer to a monotherapy.

Development and validation of the Methotrexate Experience Questionnaire, a new methotrexate oral treatment adherence tool in rheumatoid arthritis

ObjectiveDespite the development of new biologic therapies, methotrexate (MTX) remains the preferred initial disease-modifying anti-rheumatic drug to treat rheumatoid arthritis (RA). Adherence to disease-modifying anti-rheumatic drugs is suspected to be highly variable potentially leading to reduced treatment effectiveness. This work aimed to develop and validate the Methotrexate Experience Questionnaire (MEQ), a tool to identify and characterize non-adherence to oral MTX.MethodsMEQ development included a literature review and qualitative interviews with RA patients and physicians in the United States. A retrospective, cross-sectional study using data from Optimum Patient Care Research Database, a large primary care database of electronic medical records in the United Kingdom, was conducted to finalize the MEQ and evaluate its psychometric properties.ResultsThree hundred seven e-consented subjects (66% women, mean age of 65 years) completed the MEQ remotely, and were included in this analysis. Item-convergent and divergent validity were generally supportive of the construct validity of the MEQ and Cronbach’s alpha of 0.87 supported its reliability. The MEQ Total score presented statistically significant correlations of small to medium size with all selected concurrent scales, as expected; the highest correlation was obtained between the general acceptance score of ACCEPT and the MEQ Total score (0.55, p < 0.001). Known-groups validity was demonstrated as a logical pattern of higher MEQ scores was obtained for patients considered adherent with both the 6- and 12-month Proportion of Days Covered (mean MEQ total score 82.7 for 12-month PDC ≥ 80% against 76.3 for 12-month PDC < 80%, p< 0.0001). Additionally, a pattern of lower MEQ scores was obtained for patients with more severe disease assessed with Routine Assessment of Patient Index Data 3.ConclusionThe 24-item MEQ is a reliable and valid instrument to assess the adherence of RA patients taking MTX, potentially improving over historical refill rate metrics by providing insights into the individual reasons for lack of adherence. This information should facilitate clinician-patient discussions and help inform treatment decisions.

Heterogeneity in Patient Characteristics and Differences in Treatment Across 4 Canadian Rheumatoid Arthritis Cohorts.

To compare clinical characteristics and treatment of patients with rheumatoid arthritis (RA) across 4 Canadian cohorts. The 4 longitudinal cohorts included the following: the Canadian Early Arthritis Cohort (CATCH; n = 2878), Ontario Best Practices Research Initiative (OBRI; n = 3734), RHUMADATA (Quebec, n = 2890), and the Rheum4U Precision Health Registry (Calgary, Alberta, n = 709). Data were from cohort inception (range 1998-2016) to 2020. Clinical characteristics and drug treatments were summarized descriptively. In total, 10,211 patients with RA were included. The percentage of patients who entered the cohort with early RA (2 yrs of disease at enrollment) ranged from 29% (Rheum4U) to 100% (CATCH). Mean age (55 yrs), sex (74% female), and seropositivity (69%) were similar between cohorts. At the time of initial disease-modifying antirheumatic drug (DMARD) use, median Disease Activity Score in 28 joints (DAS28) varied, ranging from 2.99 (Rheum4U) to 5.19 (CATCH), but were more similar at the time of the first DMARD switch (range 3.57-5.03), first biologic (bDMARD) or targeted synthetic DMARD (tsDMARD) use (range 4.01-4.67), and second bDMARD or tsDMARD (range 3.71-4.39). The initial DMARD was most commonly methotrexate, either in monotherapy (32%, range 18-40%) or dual therapy (34%, range 29-42%). The first DMARD switch was to another DMARD monotherapy in 20% (range 10-32%), dual therapy in 49% (range 39-56%), and bDMARD or tsDMARD in 24% (range 15-28%). The first bDMARD was an anti-tumor necrosis factor in 79% (range 78-82%). Canadian RA cohorts demonstrate some heterogeneity in treatment, which could reflect differences in inclusion criteria, calendar year, or regional differences. This project is a first step toward conducting harmonized analyses across Canadian RA cohorts.

TP2 INITIAL PRESCRIBING PATTERNS TRENDS IN NEWLY DIAGNOSED CHILDREN WITH NON-SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS IN US: ANALYSIS OF ELECTRONIC MEDICAL RECORDS FROM 2009 TO 2018

The study describes patterns of initial medication prescriptions among children newly diagnosed with non-systemic forms of juvenile idiopathic arthritis (JIA), and its association with the disease activity outcomes from 2009- 2018. Using a pediatric hospital’s electronic medical record (EMR) between 2009 to 2018, we identified all patients with newly diagnosed JIA. Five subtypes of JIA were considered: oligoarticular JIA, polyarticular JIA, juvenile psoriatic arthritis, enthesitis-related arthritis, and undifferentiated arthritis. We examined patient baseline characteristics and initial prescribing patterns. The disease outcomes of initial prescribing patterns were described. A total of 821 patients were included in the analysis. Most patients were female (66.3%) and white race (88.9%). The median age was 11 years (IQR: 5–14). The proportion of patients who had an initial disease-modifying antirheumatic drugs (DMARD) prescription increased substantially from 2009 to 2018. The most common initial prescriptions were conventional synthetic (cs)DMARD and non-steroidal anti-inflammatory drugs (NSAIDs). For patients who were prescribed DMARD as initial therapy, csDMARDs monotherapy (57.3%) was most frequently used, followed by biologic agents and csDMARDs combination therapy (28.3%), and biologic (b)DMARDs monotherapy (14.4%). Methotrexate was the most commonly prescribed csDMARD throughout the study period, comprising more than 90% of monotherapy or combination therapy. Etanercept (56.3%) was the most prescribed bDMARDs, followed by adalimumab (36.6%). Nearly half (43.3%) of polyarticular JIA patients received a bDMARD prescription as initial therapy. The proportion of intra-articular glucocorticoid users increased considerably from 1.1% in 2009 to 25.6% in 2018. csDMARDs and NSAIDs appear to be the mainstay of first-line treatment initiated among non-systemic JIA patients over the past decade. However, biologic DMARDs are increasing in use, especially for treating children with polyarticular JIA.

Clinical characteristics associated with drug-free sustained remission in patients with rheumatoid arthritis: Data from Korean Intensive Management of Early Rheumatoid Arthritis (KIMERA)

ObjectivesThere is limited information on treatment withdrawal in patients with rheumatoid arthritis (RA). This study investigated the clinical course after stopping disease-modifying anti-rheumatic drugs (DMARDs) in patients with well-controlled RA and the clinical features associated with disease flare. MethodsAmong patients in the Korean Intensive Management of Early Rheumatoid Arthritis (KIMERA) cohort, discontinuation of DMARDs was determined by a shared decision between patient and rheumatologist. Drug-free remission was defined as (1) non-use of DMARDs and corticosteroids, (2) Disease Activity Score in 28 joints (DAS28) <2.6, and (3) no evidence of synovitis. The maintenance rate of drug-free remission and the predictors for flare were evaluated using Cox proportional hazard models. ResultsOf 234 patients, 50 patients discontinued DMARDs. All but one using etanercept were treated with conventional synthetic DMARDs. The median follow-up duration was 30 months, and 31 patients (62%) experienced disease flare after stopping DMARDs. The maintenance rate of drug-free remission was 94.0%, 86.7%, and 46.1% at 12, 24, and 48 months, respectively. Disease flare was correlated with longer time to remission, failure of initial DMARDs, and longer duration of disease and higher disease activity at DMARD withdrawal (P = 0.001, 0.022, 0.010 and 0.037, respectively). In multivariate analyses, longer duration of disease (>24 months) and higher disease activity (DAS28 >2.26) at DMARD withdrawal was independently associated with disease flare. ConclusionDrug-free remission was feasible in selected patients with well-controlled RA. Patients with early RA and lower disease activity at DMARD withdrawal are more likely to maintain the drug-free remission.

Treatment Patterns with Disease-Modifying Antirheumatic Drugs in U.S. Veterans with Newly Diagnosed Rheumatoid Arthritis, Psoriatic Arthritis, or Ankylosing Spondylitis.

Delays in treatment for inflammatory arthritis (IA) are associated with unfavorable outcomes, including impaired quality of life, irreversible joint damage, and disability. To characterize treatment initiation patterns in veterans with newly diagnosed rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS). ICD-9/10-CM codes and natural language processing were used to identify incident cases of RA, PsA, or AS between January 1, 2007, and December 31, 2015, in patients enrolled in the Veterans Health Administration. Patterns of treatment initiation and nontreatment with disease-modifying antirheumatic drugs (DMARDs) were assessed in the 12-month follow-up period after the incident diagnosis. Outcomes included the percentage of veterans treated with a DMARD, the mean time to the initial DMARD after diagnosis, and the percentage of veterans who accessed rheumatology care before DMARD initiation. To assess outcomes over time, veterans were grouped by year of initial IA diagnosis. Additionally, outcomes were compared between nonbiologic and biologic DMARDs and among IA subtypes (RA, PsA, and AS). Groups were statistically compared with 95% confidence intervals. The population consisted of 12,118 IA veterans (9,711 RA, 1,472 PsA, and 935 AS), with 91.3% males and a mean age of 63.7 years. The percentage of veterans treated with ≥ 1 DMARD (nonbiologic or biologic) during the 12-month follow-up period increased from 48.8% in 2007 to 66.4% in 2015. In veterans diagnosed with IA in 2015, DMARD treatment was more common for PsA patients (72.9%) and RA patients (68.6%) than for AS patients (28.9%). In the subset treated with a DMARD within 12 months after diagnosis, the mean time to the initial DMARD after diagnosis did not change throughout the observation period (35.5 days for RA, 43.9 days for PsA, and 59.5 days for AS). Rheumatology specialty care was accessed by 87.4% of veterans treated with a nonbiologic DMARD and 92.2% of veterans treated with a biologic DMARD, in patients diagnosed in 2015. DMARD treatment rates during the initial 12 months after diagnosis increased between 2007 and 2015, but nontreatment remained common, particularly in veterans with AS. The time to treatment after diagnosis was stable over time; it was shortest for RA, intermediate for PsA, and longest for AS. DMARD treatment was uncommon in veterans who did not access rheumatology specialty care. AbbVie Pharmaceuticals and Marriott Daughters Foundation funded this study via investigator-initiated grants. Data analyses were completed by investigators independent of AbbVie and Marriott Daughters Foundation. Walker, Clewell, and Douglas are employed by, and stockholders in, Abbvie. Halwani reports grants from BMS, Kyowa Hakko Kirin, Seattle Genetics, Roche-Genentech, Miragen, Immunedesign, Takeda, Amgen, Pharmacyclics, and Abbvie. The other authors have nothing to disclose.

Impact of the combined presence of erosions and ACPA on rheumatoid arthritis disease activity over time: results from the METEOR registry

ObjectiveTo investigate associations between baseline presence of erosions and/or anti-citrullinated protein antibodies (ACPA) on functional ability, disease activity and treatment survival over time.MethodsReal life data from newly diagnosed rheumatoid arthritis...

Delay in initiation of DMARD or anti-inflammatory therapy in patients newly diagnosed with rheumatoid arthritis: An analysis of United States Military Health System TRICARE beneficiaries

ObjectiveTo investigate factors associated with delay in initiation of initial disease-modifying antirheumatic drug (DMARD) in patients newly diagnosed with rheumatoid arthritis (RA). MethodsWe performed a retrospective cohort descriptive study using administrative data from the US military's TRICARE program (2007–2012). We identified incident RA cases using billing codes and initial DMARD receipt using prescription fill date. We quantified the time between RA presentation and initial DMARD receipt, evaluated temporal changes in delay over the study period, and investigated predictors of treatment delay (> 90 days) using logistic regression. ResultsWe identified 16,680 patients with incident RA that were prescribed DMARDs and mean age was 47.2 (SD 13.5) years. The mean time from initial RA presentation to first DMARD prescription receipt was 125.3days (SD 175.4). Over one-third (35.6%) of incident RA patients initiated DMARD > 90days after presentation. There was less treatment delay in later years of the study (mean days to DMARD of 144.7days in 2007; 109.7days in 2012). Patients prescribed opioids had mean time to DMARD of 212.8days (SD 207.4) compared to mean of 77.3days (SD 132.3) for those who did not use opioids (p < 0.0001). Patients prescribed opioids between RA presentation and initial DMARD receipt were more likely to have delay in initial DMARD (OR 4.07, 95% CI: 3.78–4.37). ConclusionIn this large US nationwide study, delays in initial DMARD receipt for incident RA were common but time to treatment improved in recent years. While further analysis using clinical data is warranted, these findings suggest that limiting opioid use in patients newly presenting with RA may decrease delay in initiating DMARDs.

Overweight, Obesity, and the Likelihood of Achieving Sustained Remission in Early Rheumatoid Arthritis: Results From a Multicenter Prospective Cohort Study.

Obesity is implicated in rheumatoid arthritis (RA) development, severity, outcomes, and treatment response. We estimated the independent effects of overweight and obesity on ability to achieve sustained remission (sREM) in the 3 years following RA diagnosis. Data were from the Canadian Early Arthritis Cohort, a multicenter observational trial of early RA patients treated by rheumatologists using guideline-based care. sREM was defined as Disease Activity Score in 28 joints (DAS28) <2.6 for 2 consecutive visits. Patients were stratified by body mass index (BMI) as healthy (18.5-24.9 kg/m2 ), overweight (25-29.9 kg/m2 ), and obese (≥30 kg/m2 ). Cox regression was used to estimate the effect of the BMI category on the probability of achieving sREM over the first 3 years, controlling for age, sex, race, education, RA duration, smoking status, comorbidities, baseline DAS28, Health Assessment Questionnaire disability index, C-reactive protein level, and initial treatment. Of 982 patients, 315 (32%) had a healthy BMI, 343 (35%) were overweight, and 324 (33%) were obese; 355 (36%) achieved sREM within 3 years. Initial treatment did not differ by BMI category. Compared to healthy BMI, overweight patients (hazard ratio [HR] 0.75 [95% confidence interval (95% CI) 0.58-0.98]) and obese patients (HR 0.53 [95% CI 0.39-0.71]) were significantly less likely to achieve sREM. Rates of overweight and obesity were high (69%) in this early RA cohort. Overweight patients were 25% less likely, and obese patients were 47% less likely, to achieve sREM in the first 3 years, despite similar initial disease-modifying antirheumatic drug treatment and subsequent biologic use. This is the largest study demonstrating the negative impact of excess weight on RA disease activity and supports a call to action to better identify and address this risk in RA patients.

Patterns of Systemic Treatment for Psoriatic Arthritis in the US: 2004-2015.

To examine trends in the use of systemic disease-modifying antirheumatic drugs (DMARDs) among patients with psoriatic arthritis (PsA) in the US. Using claims data (2004-2015) from a large US commercial health plan, we identified patients with PsA who initiated DMARD therapy. We examined baseline patient characteristics and initial treatment patterns. We then assessed changes in the DMARD regimen over the 12-month period after the first DMARD initiation date. Using Poisson regression, we estimated age- and sex-adjusted incidence rates of treatment changes in each calendar year. We identified 9,222 PsA patients who initiated DMARD therapy (42.8% biologic DMARDs [bDMARDs] and 57.2% conventional synthetic DMARDs [csDMARDs]). Initiators of bDMARDs were younger than those initiating csDMARDs (mean ± SD age 48 ± 13 versus 52 ± 14 years) and generally had fewer comorbidities, but a higher proportion of bDMARD initiators received nonsystemic treatments for psoriasis at baseline. Methotrexate was the most frequently used DMARD, constituting 80.6% of csDMARD initiations. Etanercept (49.1%) was the most commonly prescribed bDMARD, followed by adalimumab (34.4%). During the 12-month followup after the first DMARD initiation, 20.1% of bDMARD initiators and 31.1% of csDMARD initiators had their initial DMARD regimen modified, with an increasing trend in treatment modifications over the 11-year study period (P = 0.03). Overall, 5.3% of patients discontinued treatment, but the rates of discontinuation decreased over time (P < 0.001). In this large cohort of PsA patients with DMARD initiation, more than 40% were treated with a bDMARD. We found an increasing trend in treatment modification after use of the initial DMARD and a decreasing trend in complete DMARD discontinuation over the past decade.

Starting of biological disease modifying antirheumatic drugs may be postponed in rheumatoid arthritis patients with multimorbidity: Single center real life results.

The objective of this study was to assess the frequency of comorbidities and multimorbidities in rheumatoid arthritis (RA) patients under biologic therapy and their effects on biological disease modifying antirheumatic drugs (DMARDs) choice, timing, and response.Hacettepe University Biologic Registry (HUR-BIO) is single center biological DMARD registry. Cardiovascular, infectious, cancer, and other comorbidities were recorded with face to face interviews. Multimorbidity is defined as >1 comorbidity. Disease duration, initial date of biological DMARDs, initial and overall biological DMARD choice were recorded. Disease activity score-28 (DAS-28) responses were compared to comorbidity presence and multimorbidity.Total of 998 RA patients were enrolled into the study. The mean age was 53.1 (12.5) and mean disease duration (standard deviation [SD]) was 11.7 (7.5) years. At least 1 comorbidity was detected in 689 (69.1%) patients, 375 (37.9%) patients had multimorbidity. Patients had mean 1.36 ± 1.32 comorbidity. The median durations of first biological DMARDs prescription were 60 (3–552) months after RA diagnosis. For multimorbidity patients, the median first biological prescription duration was longer than the duration for patients without multimorbidity (72 [3–552] vs 60 [3–396] months, P < .001). The physicians prescribe tumor necrosis factor inhibitor (TNFi) biological drugs less frequently than other biological DMARDs in patients with at least 1 comorbidity (66.2% vs 74.5%, P = .007) or multimorbidity (34.6% vs 43.5%, P = .006). Patients with comorbidities and multimorbidity achieved DAS-28 remission less frequently than patients without comorbidity (31.6% vs 42.6%, P = .012 and 27.2% vs 39.7%, P = .001, respectively).In real life, physicians may postpone to prescribe biological DMARDs and less frequently choose TNFi biological drugs in patients with multimorbidity. Furthermore, comorbidity may have a negative effect on the treatment response.

Disease activity trajectories in early rheumatoid arthritis following intensive DMARD therapy over 3 years: association with persistence to therapy.

To identify the disease activity trajectories during intensive triple disease modifying anti-rheumatic drug (DMARD) therapy over 3 years in rheumatoid arthritis (RA) patients and to evaluate the association with treatment persistence. Disease Activity Score in 28 joints, baseline risk factors and medication usage were obtained from a longitudinal observational cohort of early RA patients, most of whom were treated with combination DMARD therapy consisting of methotrexate, sulfasalazine and hydroxychloroquine. Persistence of each DMARD was defined as the duration of time from initiation to cessation. A group-based trajectory modelling technique was used to identify disease activity trajectories. Three disease activity trajectories (good [43.8%], moderate [39.7%] and poor [16.5%]) were identified in a cohort of 297 patients. Most baseline risk factors, medication usage, the rate of treatment persistence and the effect of persistence on disease activity differed among patients in each of the three trajectories. Although the rate of persistence was higher in the trajectory with a good outcome, the association with persistence was more pronounced among patients who were in the poor outcome trajectory. Persistence with at least two or all three baseline DMARDs was associated with a decrease in disease activity to a broadly similar degree in all trajectories. After correction for other baseline prognostic factors, persistence with initial DMARDs contributes to heterogeneity in disease activity trajectory and there was an association between persistence with initial DMARD therapy and lower long-term disease activity.

Leflunomide is equally efficacious and safe compared to low dose rituximab in refractory rheumatoid arthritis given in combination with methotrexate: results from a randomized double blind controlled clinical trial

BackgroundThe standard dose of rituximab used in rheumatoid arthritis (RA) is 1000 mg but recent studies have shown that low dose (500 mg) is also effective. Efficacy of low dose rituximab in rheumatoid arthritis (RA) refractory to first-line non-biologic Disease Modifying Anti Rheumatic Drugs (DMARDs), compared to leflunomide is unknown. In a tertiary care referral setting, we conducted a randomized, double blind controlled clinical trial comparing the efficacy and safety of low-dose rituximab-methotrexate combination with leflunomide-methotrexate combination.MethodsPatients on methotrexate (10-20 mg/week) with a Disease Activity Score (DAS) > 3.2 were randomly assigned to rituximab (500 mg on days 1 and 15) or leflunomide (10-20 mg/day). The primary end-point was ACR20 at 24 weeks. Sample of 40 had 70% power to detect a 30% difference. ACR50, ACR70, DAS, EULAR good response, CD3 + (T cell), CD19 + (B cell) and CD19 + CD27+ (memory B cell) counts, tetanus and pneumococcal antibody levels were secondary end points.ResultsBaseline characteristics were comparable in the two groups. At week 24, ACR20 was 85% vs 84% (p = 0.93), ACR50 was 60% vs. 64% (p = 0.79) and ACR70 was 35% vs 32% (P = 0.84), in rituximab and in leflunomide groups respectively. Serious adverse events were similar.With rituximab there was significant reduction in B cells (p < 0.001), memory B cells (p < 0.001) and pneumococcal antibody levels (P < 0.05) without significant changes in T cells (p = 0.835) and tetanus antibody levels (p = 0.424) at 24 weeks. With leflunomide, significant reduction in memory B cells (p < 0.01) and pneumococcal antibody levels (p < 0.01) occurred without significant changes in B cells (P > 0.05), T cells (P > 0.05) or tetanus antibody levels (P > 0.05).ConclusionsLeflunomide-methotrexate combination is as efficacious as low-dose rituximab-methotrexate combination at 24 weeks, in RA patient’s refractory to initial DMARDs. The high responses seen in both groups have favorable cost implications for patients in developing countries. Changes in immune parameters with leflunomide are novel and need further characterization.Trial registrationThe trial was registered with the Sri Lanka Clinical Trials Registry (SLCTR), a publicly accessible primary registry linked to the registry network of the International Clinical Trials Registry Platform of the WHO (WHO-ICTRP) (registration number: SLCTR/2008/008 dated 16th May 2008).

Brief Report: Intensification to Triple Therapy After Treatment With Nonbiologic Disease-Modifying Antirheumatic Drugs for Rheumatoid Arthritis in the United States From 2009 to 2014.

Several trials suggest that triple therapy (methotrexate, sulfasalazine, and hydroxychloroquine) and biologic disease-modifying antirheumatic drugs (DMARDs) have similar efficacy in patients with rheumatoid arthritis (RA). This study was undertaken to investigate intensification to triple therapy after initial nonbiologic prescription among patients with RA. The use of triple therapy among patients with RA in 2009-2014 was evaluated using US insurance claims data. Patients with a health care visit for RA and an initial nonbiologic DMARD prescription were included. Frequencies of intensification to triple therapy or a biologic DMARD and rates of intensification per 6-month time period were calculated. Using Cox regression, we evaluated whether sociodemographic, temporal, geographic, clinical, and health care utilization factors were associated with intensification to triple therapy. Among those patients whose therapy was intensified, we investigated factors associated with triple therapy use by logistic regression. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) for intensification to triple therapy in relation to various clinical and demographic factors were calculated. There were 24,576 patients with a mean ± SD age of 50.3 ± 12.3 years, and 78% were female. During the study period, treatment was intensified to biologic DMARDs in 2,739 patients (11.1%) compared to 181 patients (0.7%) whose treatment was intensified to triple therapy. There was no significant change in triple therapy use across calendar years. Patients whose treatment was intensified to triple therapy were more likely to receive glucocorticoids (HR 1.91 [95% CI 1.41-2.60]) compared to patients who did not use glucocorticoids and were more likely to use nonsteroidal antiinflammatory drugs (NSAIDs) (HR 1.48, 95% CI 1.10-1.99 versus no NSAID use). Among those patients whose treatment was intensified to triple therapy or biologic DMARDs, factors significantly associated with triple therapy use included older age, US region (with the highest odds for triple therapy use in the West and lowest odds for triple therapy use in the Northeast), glucocorticoid use, and lower number of outpatient visits within 180 days of initial nonbiologic DMARD prescription. Despite reports published during the study period suggesting equivalent efficacy of triple therapy and biologic DMARDs for RA, the use of triple therapy was infrequent and did not increase over time in this large nationwide study.

Initial combination therapy versus step-up therapy in treatment to the target of remission in daily clinical practice in early rheumatoid arthritis patients: results from the DREAM registry.

BackgroundTreat to target (T2T) is widely accepted as the standard of care for patients with rheumatoid arthritis (RA) and has been shown to be more effective than traditional routine care. The objective of this study was to compare the effectiveness of two T2T strategies in patients with early RA: a step-up approach starting with methotrexate (MTX) monotherapy (cohort I) versus an initial disease-modifying antirheumatic drug combination approach (cohort II).MethodsA total of 128 patients from cohort II were case–control-matched with 128 patients from cohort I on gender, age, and baseline disease activity. Twelve-month follow-up data were available for 121 patients in both cohorts. The primary outcome was the proportion of patients having reached at least one 28-joint Disease Activity Score (DAS28) score <2.6 (remission) during 12 months of follow-up. Secondary outcomes were time until remission was achieved and mean DAS28 scores at 6- and 12-month follow-up.ResultsAfter 12 months of follow-up, remission was reached at least once in 77.3 % of the patients in cohort II versus 71.9 % in cohort I (P = 0.31). Median time until first remission was 17 weeks in cohort II versus 27 weeks in cohort I (P = 0.04). A significant time by strategy interaction was found in mean DAS28 scores. Post hoc analysis revealed a significant difference in mean DAS28 scores between both cohorts at 6 months (P = 0.04), but not at 12 months (P = 0.36).ConclusionsThe initial combination strategy resulted in a comparable remission rate after 1 year but a significantly shorter time until remission. At 6 months, mean DAS28 scores were lower in patients with initial combination treatment than in those with step-up therapy. At 12 months, no significant differences remained in mean DAS28 scores or the proportion of patients in remission.

The influence of age at disease onset on disease activity and disability: results from the Ontario Best Practices Research Initiative.

This study aims to compare characteristics between late-onset rheumatoid arthritis (RA) and young-onset RA and determine the association between age at disease onset and disease severity. We cross-sectionally studied 971 patients at the time of entry into the Ontario Best Practices Research Initiative, a registry of RA patients followed up in routine care. We restricted patients to ≤5 years of disease duration. Late-onset RA was defined as an onset ≥60 years of age and young-onset RA <60 years. Group differences were compared, and multivariate linear regression models were used to test the influence of age at onset on Disease Activity Score in 28 Joints with erythrocyte sedimentation rate (DAS28-ESR), Clinical Disease Activity Index (CDAI), and Health Assessment Questionnaire (HAQ) scores. The swollen joint count (6.2 vs. 5.3), acute phase reactants (C-reactive protein (CRP) 17.4 vs. 11.8 mg/L, ESR 30.6 vs. 21.5 mm/h), and comorbidity burden were higher in late-onset RA compared to young-onset RA (p < 0.01). Mean DAS28-ESR (4.6 vs. 4.3) and HAQ (1.2 vs. 1.1) scores were higher in late-onset RA patients (p < 0.05). Late-onset RA patients received more initial disease-modifying antirheumatic drug (DMARD) monotherapy and corticosteroids in comparison to greater DMARD/biologic combination therapy in young-onset RA patients (p < 0.05). Adjusted multivariate analyses showed that late-onset RA was independently associated with higher mean DAS28-ESR and HAQ scores, but not CDAI. Late-onset RA patients have greater disease activity that may contribute to disability early in the disease course. Despite this, initial treatment consists of less combination DMARD and biologic use in late-onset RA patients. This may have implications for future response to therapy and development of joint damage, disability, and comorbidities in this group.

Two-year clinical and radiologic follow-up of early RA patients treated with initial step up monotherapy or initial step down therapy with glucocorticoids, followed by a tight control approach: lessons from a cohort study in daily practice

The objective of the study was to evaluate the effect of initial disease-modifying antirheumatic drug (DMARD) combination therapy with steroids (ICTS) and DMARD monotherapy (IMT) on the clinical and radiologic evolution of patients with early rheumatoid arthritis (RA) over a 2-year treatment period, applying tight control (TC) in daily practice. Seventy-four DMARD-naive early RA patients received ICTS or IMT in a TC setting. Baseline and year 1 and year 2 X-rays of hands and feet were scored according to Sharp/van der Heijde. Rapid radiographic progression (RRP) was defined as total Sharp score (TSS) of >5 units/year. At year 1, both treatment groups achieved 50 % remission. At year 2, 37 % of IMT and 60 % of ICTS patients were in remission, despite ICTS patients having initially a more severe RA profile. RRP was found in 4/74 patients at year 1: 3 IMT and 1 ICTS patients. Remarkably, three of these four patients had no radiographic progression in the second year. Five other patients had RRP in the second year: four IMT and one ICTS patients. In a TC setting, ICTS and IMT can prevent radiographic progression in the majority of patients in the daily practice of a Belgian academic hospital over 2 years. ICTS seems to be more effective than IMT in achieving higher remission rates and less radiographic progression.

Validation of the Methotrexate‐First Strategy in Patients With Early, Poor‐Prognosis Rheumatoid Arthritis: Results From a Two‐Year Randomized, Double‐Blind Trial

Methotrexate (MTX) taken as monotherapy is recommended as the initial disease-modifying antirheumatic drug for rheumatoid arthritis (RA). The purpose of this study was to examine outcomes of a blinded trial of initial MTX monotherapy with the option to step-up to combination therapy as compared to immediate combination therapy in patients with early, poor-prognosis RA. In the Treatment of Early Rheumatoid Arthritis (TEAR) trial, 755 participants with early, poor-prognosis RA were randomized to receive MTX monotherapy or combination therapy (MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine). Participants randomized to receive MTX monotherapy stepped-up to combination therapy at 24 weeks if the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) was ≥3.2. Attrition at 24 weeks was similar in the MTX monotherapy and combination groups. Of the 370 evaluable participants in the initial MTX group, 28% achieved low levels of disease activity and did not step-up to combination therapy (MTX monotherapy group). The mean ± SD DAS28-ESR in participants continuing to take MTX monotherapy at week 102 was 2.7 ± 1.2, which is similar to that in participants who were randomized to immediate combination therapy (2.9 ± 1.2). Participants who received MTX monotherapy had less radiographic progression at week 102 as compared to those who received immediate combination therapy (mean ± SD change in modified Sharp score 0.2 ± 1.1 versus 1.1 ± 6.4). Participants assigned to initial MTX who required step-up to combination therapy at 24 weeks (72%) demonstrated similar DAS28-ESR values (3.5 ± 1.3 versus 3.2 ± 1.3 at week 48) and radiographic progression (change in modified Sharp score 1.2 ± 4.1 versus 1.1 ± 6.4 at week 102) as those assigned to immediate combination therapy. The results for either of the immediate combination approaches, whether triple therapy or MTX plus etanercept, were similar. These results in patients with early, poor prognosis RA validate the strategy of starting with MTX monotherapy. This study is the first to demonstrate in a blinded trial that initial MTX monotherapy with the option to step-up to combination therapy results in similar outcomes to immediate combination therapy. Approximately 30% of patients will not need combination therapy, and the 70% who will need it are clinically and radiographically indistinguishable from those who were randomized to receive immediate combination therapy.