Which advanced treatment should be used following the failure of a first-line anti-TNF in patients with rheumatoid arthritis? 15 years of evidence from the Quebec registry RHUMADATA.

BACKGROUND: Since 2000, advanced therapies (AT) have revolutionized the treatment of moderate to severe rheumatoid arthritis (RA). Randomized control trials as well as observational studies together with medication availability often determine second-line choices after the failure of first Tumor Necrosis Factor inhibitors (TNFi). This led to the observation that specific sequences provide better long-term effectiveness. We investigated which alternative medication offers the best long-term sustainability following the first TNFi failure in RA. METHODS: Data were extracted from RHUMADATA from January2007. Patients were followed until treatment discontinuation, loss to follow-up, or November 25, 2022. Kaplan-Meier and Cox regression models were used to compare discontinuation between groups. Missing data were imputed, and propensity scores were computed to reduce potential attribution bias. Complete, unadjusted, and propensity score-adjusted imputed data analyses were produced. RESULTS: 611 patients (320 treated with a TNFi and 291 treated with molecules having another mechanism of action (OMA)) were included. The mean age at diagnosis was 44.5 and 43.9 years, respectively. The median retention was 2.84 and 4.48 years for TNFi and OMAs groups. Using multivariable analysis, the discontinuation rate of the OMA group was significantly lower than TNFi (adjHR: 0.65; 95% CI: 0.44-0.94). This remained true for the PS-adjusted MI Cox models. In a stratified analysis, rituximab (adjHR: 0.39; 95% CI: 0.18-0.84) had better retention than TNFi after adjusting for patient characteristics. CONCLUSION: Switching to an OMA, especially rituximab, in patients with failure to a first TNFi appears to be the best strategy as a second line of therapy.

Trial of Upadacitinib or Abatacept in Rheumatoid Arthritis.

BACKGROUND: Upadacitinib is an oral selective Janus kinase inhibitor to treat rheumatoid arthritis. The efficacy and safety of upadacitinib as compared with abatacept, a T-cell costimulation modulator, in patients with rheumatoid arthritis refractory to biologic disease-modifying antirheumatic drugs (DMARDs) are unclear. METHODS: In this 24-week, phase 3, double-blind, controlled trial, we randomly assigned patients in a 1:1 ratio to receive oral upadacitinib (15 mg once daily) or intravenous abatacept, each in combination with stable synthetic DMARDs. The primary end point was the change from baseline in the composite Disease Activity Score for 28 joints based on the C-reactive protein level (DAS28-CRP; range, 0 to 9.4, with higher scores indicating more disease activity) at week 12, assessed for noninferiority. Key secondary end points at week 12 were the superiority of upadacitinib over abatacept in the change from baseline in the DAS28-CRP and the percentage of patients having clinical remission according to a DAS28-CRP of less than 2.6. RESULTS: A total of 303 patients received upadacitinib, and 309 patients received abatacept. From baseline DAS28-CRP values of 5.70 in the upadacitinib group and 5.88 in the abatacept group, the mean change at week 12 was -2.52 and -2.00, respectively (difference, -0.52 points; 95% confidence interval [CI], -0.69 to -0.35; P<0.001 for noninferiority; P<0.001 for superiority). The percentage of patients having remission was 30.0% with upadacitinib and 13.3% with abatacept (difference, 16.8 percentage points; 95% CI, 10.4 to 23.2; P<0.001 for superiority). During the treatment period, one death, one nonfatal stroke, and two venous thromboembolic events occurred in the upadacitinib group, and more patients in the upadacitinib group than in the abatacept group had elevated hepatic aminotransferase levels. CONCLUSIONS: In patients with rheumatoid arthritis refractory to biologic DMARDs, upadacitinib was superior to abatacept in the change from baseline in the DAS28-CRP and the achievement of remission at week 12 but was associated with more serious adverse events. Longer and larger trials are required in order to determine the effect and safety of upadacitinib in patients with rheumatoid arthritis. (Funded by AbbVie; SELECT-CHOICE Clinicaltrials.gov number, NCT03086343.).

Effects of Disease-Worsening Following Withdrawal of Etanercept or Methotrexate on Patient-Reported Outcomes in Patients With Rheumatoid Arthritis: Results From the SEAM-RA Trial.

BACKGROUND/OBJECTIVE: The effect of treatment withdrawal on patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) whose disease is in sustained remission has not been well described. This analysis aimed to compare PRO changes in patients with RA following medication withdrawal and disease worsening. METHODS: SEAM-RA (Study of Etanercept and Methotrexate in Combination or as Monotherapy in Subjects With Rheumatoid Arthritis) was a phase 3, multicenter, randomized withdrawal, double-blind controlled study in patients with RA taking methotrexate plus etanercept and in remission (Simple Disease Activity Index ≤3.3). Patient's Global Assessment of Disease Activity, Patient's Assessment of Joint Pain, Health Assessment Questionnaire-Disability Index, and 36-Item Short-Form Health Survey were evaluated for 48 weeks following methotrexate or etanercept withdrawal. Treatment differences for patients with versus without disease worsening were evaluated using a 2-sample t test for continuous end points and log-rank test for time-to-event end points. RESULTS: Of 253 patients, 121 experienced disease worsening and 132 did not. All PRO scores were similar to those of a general population at baseline and deteriorated over time across the study population. The PtGA and Patient's Assessment of Joint Pain values deteriorated less in those on etanercept monotherapy compared with methotrexate monotherapy. More patients with versus without disease worsening experienced deterioration that was greater than the minimal clinically important difference (MCID) for all PROs tested. In patients with disease worsening, PtGA deterioration more than the MCID preceded Simple Disease Activity Index disease worsening. CONCLUSIONS: Etanercept monotherapy showed benefit over methotrexate in maintaining PRO scores. Patients with disease worsening experienced a more rapid worsening of PtGA beyond the MCID versus patients without disease worsening.Categories: autoinflammatory disease, biological therapy, DMARDs, rheumatoid arthritis.

An open-label randomized controlled trial of DMARD withdrawal in RA patients achieving therapeutic response with certolizumab pegol combined with DMARDs.

OBJECTIVES: The objective of this trial was to compare effectiveness of certolizumab pegol added to conventional synthetic DMARDs (csDMARDs) in RA patients, followed by continuing vs discontinuing background csDMARDs after treatment response. METHODS: Patients with active RA who had certolizumab pegol added to their existing csDMARD regimen due to inadequate response were eligible. At 3 or 6 months, patients who achieved a change (Δ) in DAS28 of ⩾1.2 were randomized to continue combination therapy (COMBO) or withdraw csDMARD therapy (MONO) (unblinded). The primary outcome was non-inferiority of stopping vs continuing csDMARD(s) in terms of maintaining ΔDAS28 ⩾ 1.2 or achieving DAS28 low disease activity at 18 months (non-inferiority margin: 15 percentile units). RESULTS: A total of 125 patients were enrolled, 88 randomized to COMBO (n = 43) or MONO (n = 45). No significant differences were observed between groups in baseline age, gender, race, RF status or prior biologics (16% vs 11%). Although the rate of ΔDAS28 ⩾ 1.2 and/or DAS28 low disease activity achievement at 18 months was clinically comparable between the two groups (72% vs 69%), non-inferiority assumptions were not met [absolute risk difference (upper limit of 90% CI): 2.6% (19.1%)]. Similar baseline-adjusted improvements were seen in DAS28 (COMBO vs MONO: -2.3 vs -2.1; P = 0.49) and all endpoints were not statistically different including 59% vs 56% achieved DAS28 low disease activity, 69% vs 59% ΔDAS28 ⩾ 1.2, and 41% each remission. CONCLUSION: Among RA patients achieving a therapeutic response on combination therapy with certolizumab pegol and csDMARDs, withdrawing csDMARDs was not non-inferior to maintaining csDMARDs but improvements were sustained in both groups at 18 months.

Experience with tofacitinib in Canada: patient characteristics and treatment patterns in rheumatoid arthritis over 3 years.

OBJECTIVES: To describe characteristics, treatment patterns and persistence in patients with RA treated with tofacitinib, an oral Janus kinase inhibitor, in Canadian clinical practice between 1 June 2014 and 31 May 2017. METHODS: Data were obtained from the tofacitinib eXel support programme. Baseline demographics and medication history were collected via patient report/special authorization forms; reasons for discontinuation were captured by patient report. Treatment persistence was estimated using Kaplan-Meier methods, with data censored at last follow-up. Cox regression was applied to analyse baseline characteristics associated with treatment discontinuation. RESULTS: The number of patients with RA enrolled from 2014 to 2017 was 4276; tofacitinib utilization increased during that period, as did the proportion of biologic (b) DMARD-naïve patients prescribed tofacitinib. Of patients who initiated tofacitinib, 1226/3678 (33.3%) discontinued, mostly from lack of efficacy (35.7%) and adverse events (26.9%). Persistence was 62.7% and 49.6% after 1 and 2 years of treatment, respectively. Prior bDMARD experience predicted increased tofacitinib discontinuation (vs bDMARD-naïve, P < 0.001). Increased retention was associated with older age (56-65 years and >65 years vs ⩽45 years; P < 0.05), and time since diagnosis of 15 to <20 years (vs <5 years; P < 0.01). In bDMARD-naïve, post-1 bDMARD, post-2 bDMARD and post-⩾3 bDMARD patients, median survival was >730, 613, 667 and 592 days, respectively. CONCLUSION: Since 2014, tofacitinib use in Canadian patients with RA increased, especially among bDMARD-naïve/post-1 bDMARD patients. Median drug survival was ∼2 years. Likelihood of persistence increased for bDMARD-naïve (vs bDMARD-experienced) patients and those aged ⩾56 (vs ⩽45) years.

Dose reduction of baricitinib in patients with rheumatoid arthritis achieving sustained disease control: results of a prospective study.

OBJECTIVES: This study investigated the effects of dose step-down in patients with rheumatoid arthritis (RA) who achieved sustained disease control with baricitinib 4 mg once a day. METHODS: Patients who completed a baricitinib phase 3 study could enter a long-term extension (LTE). In the LTE, patients who received baricitinib 4 mg for ≥15 months and maintained CDAI low disease activity (LDA) or remission (REM) were blindly randomised to continue 4 mg or taper to 2 mg. Patients could rescue (to 4 mg) if needed. Efficacy and safety were assessed through 48 weeks. RESULTS: Patients in both groups maintained LDA (80% 4 mg; 67% 2 mg) or REM (40% 4 mg; 33% 2 mg) over 48 weeks. However, dose reduction resulted in small, statistically significant increases in disease activity at 12, 24 and 48 weeks. Dose reduction also produced earlier and more frequent relapse (loss of step-down criteria) over 48 weeks compared with 4 mg maintenance (23% 4 mg vs 37% 2 mg, p=0.001). Rescue rates were 10% for baricitinib 4 mg and 18% for baricitinib 2 mg. Dose reduction was associated with a numerically lower rate of non-serious infections (30.6 for baricitinib 4 mg vs 24.9 for 2 mg). Rates of serious adverse events and adverse events leading to discontinuation were similar across groups. CONCLUSIONS: In a large randomised, blinded phase 3 study, maintenance of RA control following induction of sustained LDA/REM with baricitinib 4 mg was greater with continued 4 mg than after taper to 2 mg. Nonetheless, most patients tapered to 2 mg could maintain LDA/REM or recapture with return to 4 mg if needed.

Vaccination Guidelines for Patients With Immune-Mediated Disorders on Immunosuppressive Therapies.

BACKGROUND:: Patients with immune-mediated diseases on immunosuppressive therapies have more infectious episodes than healthy individuals, yet vaccination practices by physicians for this patient population remain suboptimal. OBJECTIVES:: To evaluate the safety and efficacy of vaccines in individuals exposed to immunosuppressive therapies and provide evidence-based clinical practice recommendations. METHODS:: A literature search for vaccination safety and efficacy in patients on immunosuppressive therapies (2009-2017) was conducted. Results were assessed using the Grading of Recommendation, Assessment, Development, and Evaluation system. RESULTS:: Several immunosuppressive therapies attenuate vaccine response. Thus, vaccines should be administered before treatment whenever feasible. Inactivated vaccines can be administered without treatment discontinuation. Similarly, evidence suggests that the live zoster vaccine is safe and effective while on select immunosuppressive therapy, although use of the subunit vaccine is preferred. Caution regarding other live vaccines is warranted. Drug pharmacokinetics, duration of vaccine-induced viremia, and immune response kinetics should be considered to determine appropriate timing of vaccination and treatment (re)initiation. Infants exposed to immunosuppressive therapies through breastmilk can usually be immunized according to local guidelines. Intrauterine exposure to immunosuppressive agents is not a contraindication for inactivated vaccines. Live attenuated vaccines scheduled for infants and children ⩾12 months of age, including measles, mumps, rubella, and varicella, can be safely administered as sufficient time has elapsed for drug clearance. CONCLUSIONS:: Immunosuppressive agents may attenuate vaccine responses, but protective benefit is generally maintained. While these recommendations are evidence based, they do not replace clinical judgment, and decisions regarding vaccination must carefully assess the risks, benefits, and circumstances of individual patients.

Head-to-head comparison of certolizumab pegol versus adalimumab in rheumatoid arthritis: 2-year efficacy and safety results from the randomised EXXELERATE study.

BACKGROUND: To date, head-to-head trials comparing the efficacy and safety of biological disease-modifying antirheumatic drugs within the same class, including TNF inhibitors, in patients with active rheumatoid arthritis despite methotrexate therapy are lacking. We aimed to compare the efficacy and safety of two different TNF inhibitors and to assess the efficacy and safety of switching to the other TNF inhibitor without a washout period after insufficient primary response to the first TNF inhibitor at week 12. METHODS: In this 104-week, randomised, single-blind (double-blind until week 12 and investigator blind thereafter), parallel-group, head-to-head superiority study (EXXELERATE), eligible patients from 151 centres worldwide were aged 18 years or older with a diagnosis of rheumatoid arthritis at screening, as defined by the 2010 ACR/EULAR criteria, and had prognostic factors for severe disease progression, including a positive rheumatoid factor, or anti-cyclic citrullinated peptide antibody result, or both. Participants were randomly assigned (1:1) via an interactive voice and web response system with no stratification to receive certolizumab pegol plus methotrexate or adalimumab plus methotrexate. All study staff were kept masked throughout the study and participants were masked until week 12. At week 12, patients were classified as responders (by either achieving low disease activity [LDA] according to Disease Activity Score 28-erythrocyte sedimentation rate [DAS28-ESR] ≤3·2 or DAS28-ESR reduction ≥1·2 from baseline) or as non-responders. Non-responders to the first TNF inhibitor to which they were randomised were switched to the other TNF inhibitor with no washout period. Primary endpoints were the percentage of patients achieving a 20% improvement according to the American College of Rheumatology criteria (ACR20) at week 12 and LDA at week 104 (week 12 non-responders were considered LDA non-responders). This study is registered with ClinicalTrials.gov, number NCT01500278. FINDINGS: Between Dec 14, 2011, and Nov 11, 2013, 1488 patients were screened of whom 915 were randomly assigned; 457 to certolizumab pegol plus methotrexate and 458 to adalimumab plus methotrexate. No statistically significant difference was observed in ACR20 response at week 12 (314 [69%] of 454 patients and 324 [71%] of 454 patients; odds ratio [OR] 0·90 [95% CI 0·67-1·20]; p=0·467) or DAS28-ESR LDA at week 104 (161 [35%] of 454 patients and 152 [33%] of 454 patients; OR 1·09 [0·82-1·45]; p=0·532) between certolizumab pegol plus methotrexate and adalimumab plus methotrexate, respectively. At week 12, 65 non-responders to certolizumab pegol were switched to adalimumab and 57 non-responders to adalimumab were switched to certolizumab pegol; 33 (58%) of 57 patients switching to certolizumab pegol and 40 (62%) of 65 patients switching to adalimumab responded 12 weeks later by achieving LDA or a DAS28-ESR reduction 1·2 or greater. 389 [75%] of 516 patients who received certolizumab pegol plus methotrexate and 386 [74%] of 523 patients who received adalimumab plus methotrexate reported treatment-emergent adverse events. Three deaths (1%) occurred in each group. No serious infection events were reported in the 70-day period after treatment switch. INTERPRETATION: These results show that certolizumab pegol plus methotrexate is not superior to adalimumab plus methotrexate. The data also show the clinical benefit and safety of switching to a second TNF inhibitor without a washout period after primary failure to a first TNF inhibitor. FUNDING: UCB Pharma.

The effect of rheumatoid arthritis-associated autoantibodies on the incidence of cardiovascular events in a large inception cohort of early inflammatory arthritis.

Objective: . RA is associated with an increased risk of cardiovascular events (CVEs). The objective was to estimate independent effects of RA autoantibodies on the incident CVEs in patients with early RA. Methods: Patients were enrolled in the Canadian Early Inflammatory Arthritis Cohort, a prospective multicentre inception cohort. Incident CVEs, including acute coronary syndromes and cerebrovascular events, were self-reported by the patient and partially validated by medical chart review. Seropositive status was defined as either RF or ACPA positive. Multivariable Cox proportional hazards survival analysis was used to estimate the effects of seropositive status on incident CVEs, controlling for RA clinical variables and traditional cardiovascular risk factors. Results: . A total of 2626 patients were included: the mean symptom duration at diagnosis was 6.3 months ( s . d . 4.6), the mean age was 53 years ( s . d . 15), 72% were female and 86% met classification criteria for RA. Forty-six incident CVEs occurred over 6483 person-years [incidence rate 7.1/1000 person-years (95% confidence interval 5.3, 9.4)]. The CVE rate did not differ in seropositive vs seronegative subjects and seropositivity was not associated with incident CVEs in multivariable Cox regression models. Baseline covariates independently associated with incident CVEs were older age, a history of hypertension and a longer duration of RA symptoms prior to diagnosis. Conclusion: The rate of CVEs early in the course of inflammatory arthritis was low; however, delays in the diagnosis of arthritis increased the rate of CVEs. Hypertension was the strongest independent risk factor for CVEs. Results support early aggressive management of RA disease activity and co-morbidities to prevent severe complications.

Thresholds for the 28-joint disease activity score (DAS28) using C-reactive protein are lower compared to DAS28 using erythrocyte sedimentation rate in early rheumatoid arthritis.

OBJECTIVES: The 28-Joint Disease Activity Score (DAS28) using C-reactive protein (CRP) and DAS28 using erythrocyte sedimentation rate (DAS28-ESR) may not be interchangeable. We sought to compare and estimate optimal thresholds for the DA28-CRP for use in early rheumatoid arthritis (ERA). METHODS: Patients from the Canadian Early Arthritis Cohort with baseline and 12 months' data for both DAS28-ESR and DAS28-CRP were examined for correlations and differences between DAS28-CRP and DAS28-ESR across their range of values. Receiver operating characteristic analysis identified thresholds for DAS28-CRP that best corresponded to established thresholds for the DAS28-ESR using the total sample, then stratified by age and sex. Agreement between DAS28-CRP and DAS28-ESR thresholds was assessed with the kappa statistic. RESULTS: The sample included 995 patients with mean (SD) age of 53.7 (14.5) years, 5.8 (2.9) months of symptom duration and 74% were female. DAS28-CRP and DAS28-ESR scores were highly correlated (r= 0.92, p<0.0001), however DAS28-CRP values were consistently lower than DAS28-ESR values. Calculated thresholds for DAS28-CRP were lower with 2.5 for remission, 2.9 for low disease activity, and 4.6 for high disease activity but showed moderate agreement with the DAS28-ESR thresholds (kappa=0.70). CONCLUSIONS: In this large sample of ERA patients, newly estimated thresholds for DAS28-CRP were consistently lower than DAS28-ESR thresholds across the spectrum of disease activity. This may have important clinical implications if inflammatory markers are used interchangeably. Additional external validation of our findings is needed.

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.

Evidence for treating rheumatoid arthritis to target: results of a systematic literature search update.

OBJECTIVE: A systematic literature review (SLR; 2009-2014) to compare a target-oriented approach with routine management in the treatment of rheumatoid arthritis (RA) to allow an update of the treat-to-target recommendations. METHODS: Two SLRs focused on clinical trials employing a treatment approach targeting a specific clinical outcome were performed. In addition to testing clinical, functional and/or structural changes as endpoints, comorbidities, cardiovascular risk, work productivity and education as well as patient self-assessment were investigated. The searches covered MEDLINE, EMBASE, Cochrane databases and Clinicaltrial.gov for the period between 2009 and 2012 and separately for the period of 2012 to May of 2014. RESULTS: Of 8442 citations retrieved in the two SLRs, 176 articles underwent full-text review. According to predefined inclusion/exclusion criteria, six articles were included of which five showed superiority of a targeted treatment approach aiming at least at low-disease activity versus routine care; in addition, publications providing supportive evidence were also incorporated that aside from expanding the evidence provided by the above six publications allowed concluding that a target-oriented approach leads to less comorbidities and cardiovascular risk and better work productivity than conventional care. CONCLUSIONS: The current study expands the evidence that targeting low-disease activity or remission in the management of RA conveys better outcomes than routine care.

Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force.

BACKGROUND: Reaching the therapeutic target of remission or low-disease activity has improved outcomes in patients with rheumatoid arthritis (RA) significantly. The treat-to-target recommendations, formulated in 2010, have provided a basis for implementation of a strategic approach towards this therapeutic goal in routine clinical practice, but these recommendations need to be re-evaluated for appropriateness and practicability in the light of new insights. OBJECTIVE: To update the 2010 treat-to-target recommendations based on systematic literature reviews (SLR) and expert opinion. METHODS: A task force of rheumatologists, patients and a nurse specialist assessed the SLR results and evaluated the individual items of the 2010 recommendations accordingly, reformulating many of the items. These were subsequently discussed, amended and voted upon by >40 experts, including 5 patients, from various regions of the world. Levels of evidence, strengths of recommendations and levels of agreement were derived. RESULTS: The update resulted in 4 overarching principles and 10 recommendations. The previous recommendations were partly adapted and their order changed as deemed appropriate in terms of importance in the view of the experts. The SLR had now provided also data for the effectiveness of targeting low-disease activity or remission in established rather than only early disease. The role of comorbidities, including their potential to preclude treatment intensification, was highlighted more strongly than before. The treatment aim was again defined as remission with low-disease activity being an alternative goal especially in patients with long-standing disease. Regular follow-up (every 1-3 months during active disease) with according therapeutic adaptations to reach the desired state was recommended. Follow-up examinations ought to employ composite measures of disease activity that include joint counts. Additional items provide further details for particular aspects of the disease, especially comorbidity and shared decision-making with the patient. Levels of evidence had increased for many items compared with the 2010 recommendations, and levels of agreement were very high for most of the individual recommendations (≥9/10). CONCLUSIONS: The 4 overarching principles and 10 recommendations are based on stronger evidence than before and are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA.

Two-year radiographic and clinical outcomes from the Canadian Methotrexate and Etanercept Outcome study in patients with rheumatoid arthritis.

OBJECTIVE: To evaluate radiographic and clinical outcomes up to 24 months in patients with RA enrolled in the Canadian Methotrexate and Etanercept Outcome study. METHODS: In this open-label non-inferiority trial, patients with inadequate response to MTX received etanercept plus MTX for 6 months and then were randomized to either etanercept monotherapy or continued etanercept plus MTX until 24 months. Radiographic data were analysed using the modified total Sharp score (mTSS), joint space narrowing and erosion scores. Secondary outcomes included the 28-joint DAS with ESR (DAS28-ESR), Simplified Disease Activity Index, Clinical Disease Activity Index, HAQ Disability Index (HAQ-DI) and safety. RESULTS: Two hundred five of 258 patients enrolled were randomized (98 etanercept, 107 etanercept plus MTX). At month 24, the mean increase from baseline to month 24 for the etanercept and etanercept plus MTX arms, respectively, for the mTSS were 0.4 (s.d. 1.9) and 0.0 (s.d. 1.4); for joint space narrowing, 0.1 (s.d. 0.6) and 0.0 (s.d. 0.7) and for erosion, 0.3 (s.d. 1.5) and 0.0 (s.d. 1.0). At month 24, the mean increase from month 6 mean scores/count increases for DAS28-ESR were 0.56 (s.d. 1.26) and 0.08 (s.d. 1.50); for Simplified Disease Activity Index, 4.7 (s.d. 13.1) and 0.9 (s.d. 12.5); for Clinical Disease Activity Index, 4.1 (s.d. 12.3) and 1.0 (s.d. 12.3) and for HAQ-DI, 0.20 (s.d. 0.45) and 0.02 (s.d. 0.54). Patients with DAS28-ESR low disease activity (LDA)/remission at month 6 had numerically better outcomes at month 24 than patients with moderate to high disease activity at month 6. In patients with LDA/remission at month 6, outcomes were similar at month 24 between etanercept monotherapy and etanercept plus MTX, whereas patients with moderate to high disease activity at month 6 had numerically better outcomes with etanercept plus MTX than etanercept at month 24. There were no new safety signals and serious adverse events were not different between groups. CONCLUSION: These results support the possibility of discontinuing MTX in patients who have tolerability issues with MTX if they achieve LDA/remission. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov/; NCT00654368).

Self-reported comorbidity is common in early inflammatory arthritis and associated with poorer function and worse arthritis disease outcomes: results from the Canadian Early Arthritis Cohort.

OBJECTIVE: Comorbid medical conditions may influence treatment and contribute to poor outcomes in early RA. We aimed to assess the association of baseline comorbidity with outcomes in early inflammatory arthritis using data from the Canadian Early Arthritis Cohort. METHODS: Patients (n = 2090) with early inflammatory arthritis (symptom duration of < 1 year) reported comorbid medical conditions at baseline. Functional status (HAQ), detailed clinical assessments and treatment were assessed. Treatment is not protocolized but participating rheumatologists aim for remission. The influence of comorbidity on clinical outcomes was determined using multivariate models. RESULTS: At least one comorbid condition was reported by 76% of patients. Patients with comorbidity were older (mean age 56 vs 44 years, P < 0.0001) and had worse baseline function [median (interquartile range, IQR) HAQ score (0.88 (1) vs 0.75(1), P < 0.0001] compared with those without comorbidity even after controlling for age, sex and symptom duration. At 1 year, patients with baseline comorbidity were less likely to achieve remission (odds ratio, OR = 0.67; 95% CI: 0.51, 0.88, P = 0.004) and had higher HAQ [median (IQR) 0.25 (1) vs 0 (0), P < 0.0001] and pain scores [median (IQR) 2.85 (4) (out of 10) vs 1 (4), P < 0.0001] than patients without comorbidity after adjusting for age, sex, symptom duration, baseline disease activity and arthritis treatment. CONCLUSION: Comorbidity is common in early inflammatory arthritis and associated with higher disease activity, worse functional status and greater pain scores during the first year of follow-up. While the mechanisms for this association require investigation, addressing comorbidity may improve clinical outcomes in early RA.

Psoriasis and Smoking: A Systematic Literature Review and Meta-Analysis With Qualitative Analysis of Effect of Smoking on Psoriasis Severity.

BACKGROUND: Smoking has been associated with psoriasis prevalence and severity. OBJECTIVE: To evaluate prevalence of smoking in patients with psoriasis and to examine the relationship between smoking and psoriasis severity. METHODS: MEDLINE, EMBASE, and Cochrane databases (1960-2012) and conference proceedings (2010-2012) were systematically searched using keywords relevant to psoriasis and smoking. Controlled studies addressing psoriasis and smoking status were included. A meta-analysis for the relative risk of smoking in psoriasis patients was performed. RESULTS: Meta-analysis identified a significant association between smoking and psoriasis with a relative risk of 1.88 (95% CI, 1.66-2.13) for smoking in patients with psoriasis versus patients without psoriasis. Eight articles of 11 with data on smoking and psoriasis severity suggested that severity increases with smoking status. CONCLUSIONS: This literature review is in favor of a positive association between the prevalence of smoking and psoriasis as well as an association between smoking and severity of psoriasis.

The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis.

The objective of this systematic literature review was to determine the association between cardiovascular events (CVEs) and antirheumatic drugs in rheumatoid arthritis (RA) and psoriatic arthritis (PsA)/psoriasis (Pso). Systematic searches were performed of MEDLINE, EMBASE and Cochrane databases (1960 to December 2012) and proceedings from major relevant congresses (2010-2012) for controlled studies and randomised trials reporting confirmed CVEs in patients with RA or PsA/Pso treated with antirheumatic drugs. Random-effects meta-analyses were performed on extracted data. Out of 2630 references screened, 34 studies were included: 28 in RA and 6 in PsA/Pso. In RA, a reduced risk of all CVEs was reported with tumour necrosis factor inhibitors (relative risk (RR), 0.70; 95% CI 0.54 to 0.90; p=0.005) and methotrexate (RR, 0.72; 95% CI 0.57 to 0.91; p=0.007). Non-steroidal anti-inflammatory drugs (NSAIDs) increased the risk of all CVEs (RR, 1.18; 95% CI 1.01 to 1.38; p=0.04), which may have been specifically related to the effects of rofecoxib. Corticosteroids increased the risk of all CVEs (RR, 1.47; 95% CI 1.34 to 1.60; p<0.001). In PsA/Pso, systemic therapy decreased the risk of all CVEs (RR, 0.75; 95% CI 0.63 to 0.91; p=0.003). In RA, tumour necrosis factor inhibitors and methotrexate are associated with a decreased risk of all CVEs while corticosteroids and NSAIDs are associated with an increased risk. Targeting inflammation with tumour necrosis factor inhibitors or methotrexate may have positive cardiovascular effects in RA. In PsA/Pso, limited evidence suggests that systemic therapies are associated with a decrease in all CVE risk.

Maintenance of remission following 2 years of standard treatment then dose reduction with abatacept in patients with early rheumatoid arthritis and poor prognosis.

OBJECTIVES: To evaluate maintenance of response while reducing intravenous abatacept dose from ~10 mg/kg to ~5 mg/kg in patients with early rheumatoid arthritis (RA) who achieved disease activity score (DAS)28 (erythrocyte sedimentation rate, ESR) <2.6. METHODS: This 1-year, multinational, randomised, double-blind substudy evaluated the efficacy and safety of ~10 mg/kg and ~5 mg/kg abatacept in patients with early RA with poor prognosis who had reached DAS28 (ESR) <2.6 at year 2 of the AGREE study. The primary outcome was time to disease relapse (defined as additional disease-modifying antirheumatic drugs, ≥2 courses high-dose steroids, return to open-label abatacept ~10 mg/kg, or DAS28 (C reactive protein) ≥3.2 at two consecutive visits). RESULTS: 108 patients were randomised (~10 mg/kg, n=58; ~5 mg/kg, n=50). Three and five patients, respectively, discontinued, and four per group returned to open-label abatacept. Relapse over time and the proportion of patients relapsing were similar in both groups (31% (~10 mg/kg) vs 34% (~5 mg/kg); HR: 0.87 (95% CI 0.45 to 1.69)). Mean steady-state trough serum concentration for the ~10 mg/kg group was 20.3-24.1 µg/mL, compared with 8.8-12.0 µg/mL for the ~5 mg/kg group. CONCLUSIONS: This exploratory study suggests that abatacept dose reduction may be an option in patients with poor prognosis early RA who achieve DAS28 (ESR) <2.6 after ≥1 year on abatacept (~10 mg/kg). TRIAL REGISTRATION NUMBER: NCT00989235.

The Canadian methotrexate and etanercept outcome study: a randomised trial of discontinuing versus continuing methotrexate after 6 months of etanercept and methotrexate therapy in rheumatoid arthritis.

OBJECTIVE: To determine if withdrawing methotrexate (MTX) after 6 months of combination etanercept (ETN)+MTX, in MTX-inadequate responders with active rheumatoid arthritis (RA), is non-inferior to continuing ETN+MTX. METHODS: Tumour necrosis factor-inhibitor naïve RA patients with disease activity score 28 (DAS28)≥3.2, swollen joint count≥3, despite stable MTX, were treated with ETN+MTX for 6 months, followed by randomisation to either continue ETN+MTX or switch to ETN monotherapy for an additional 18 months. The primary endpoint was change in DAS28 from 6-month randomisation to 12 months. The non-inferiority margin of change in DAS28 was 0.6, with prespecified analyses (DAS28<3.2 vs DAS28≥3.2). RESULTS: 205 patients were randomised. DAS28 was stable in patients on ETN+MTX and increased slightly in patients on ETN monotherapy from 6 to 12 months. Non-inferiority was not achieved, with an adjusted difference of 0.4 (0.1 to 0.7) between the ETN and the ETN+MTX groups, for the month 6-12 change in DAS28. However, patients who achieved low disease activity (LDA; DAS28<3.2) at 6 months had a similar disease activity at 12 months, whether on monotherapy or combination therapy (DAS28 change 0.7 ETN vs 0.57 ETN+MTX, p=0.8148). Conversely, for patients who did not reach LDA at 6 months, those on ETN monotherapy had increased disease activity at 12 months, while disease activity continued to decrease for patients on combination therapy, at 12 months (DAS28 change 0.4 ETN vs -0.4 ETN+MTX, p=0.0023). CONCLUSIONS: Non-inferiority was not achieved. Withdrawing MTX after 6 months of continuation ETN+MTX in MTX inadequate responders did not yield the same degree of improvement between 6 and 12 months compared with continuing ETN+MTX. TRIAL REGISTRATION: ClinicalTrials.gov-NCT00654368.

Physician global assessment at 3 months is strongly predictive of remission at 12 months in early rheumatoid arthritis: results from the CATCH cohort.

OBJECTIVE: The objective of this study was to determine predictors of 1-year remission in early RA (ERA) using baseline and 3-month data. METHODS: The Canadian Early Arthritis Cohort (CATCH) patients were included if baseline, 3- and 12-month data were available. Regression analyses for four different definitions of remission at 12 months were done to determine baseline and 3-month predictors of remission. RESULTS: Five hundred and sixty-two patients had complete data at 12 months (mean age 53.4 years, disease duration 6.2 years, 73% female). The factors at baseline associated with all four remission outcomes at 12 months were age, gender, income, education, tender joint count (TJC), patient global assessment (PtGA), HAQ and pain. Baseline ESR was associated with the 28-joint DAS (DAS28) remission only. At 3 months, all four remission definitions were associated with TJC, swollen joint count, physician global assessment (PGA), PtGA, HAQ, pain, ESR and CRP in univariate analyses. In the regression model, variables associated with Simple Disease Activity Index remission were PGA [odds ratio (OR) 0.77, P < 0.001), pain (OR 0.85, P = 0.004), age (OR 0.98, P = 0.006) and HAQ (OR 0.49, P = 0.011); Clinical Disease Activity Index remission was associated with PGA (OR 0.77, P < 0.001), pain (OR 0.85, P = 0.003), age (OR 0.98, P = 0.015) and CRP (OR 0.80, P = 0.031). DAS28 remission was predicted by ESR (OR 0.95, P < 0.001), PGA (OR 0.76, P < 0.001), age (OR 0.98, P = 0.001), HAQ (OR 0.57, P = 0.006) and male gender (OR 2.01, P = 0.005), whereas Boolean remission was associated with pain (OR 0.79, P = 0.009), age (OR 0.98, P = 0.016), PtGA (OR 0.83, P = 0.025) and PGA (OR 0.86, P = 0.038). CONCLUSION: A low PGA at 3 months was consistently associated with 1-year remission in ERA.