Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy: a critical review

Conventional disease-modifying antirheumatic drugs such as methotrexate are the mainstay of treatment for rheumatoid arthritis. More recently, biologic agents such as etanercept, infliximab and adalimumab, which act by inhibiting tumour necrosis factor (TNF), have become available. TNF inhibitors have proved to be very effective in patients not responding to conventional disease-modifying antirheumatic drugs. However, about 20% to 40% of patients treated with a TNF inhibitor fail to achieve a 20% improvement in American College of Rheumatology criteria, and more lose response over time (secondary failure or acquired therapeutic resistance) or experience adverse events following treatment with a TNF inhibitor. In this group of patients, therapeutic options were limited until recently and an established treatment approach was to switch from one TNF inhibitor to another. In recent years, therapeutic options in these patients have increased with the introduction of biologic agents with novel mechanisms of action, such as rituximab and abatacept. This review outlines the current evidence in support of the available treatment strategies in patients with an inadequate response or intolerance to an initial TNF inhibitor

Avaliação à medida no Segundo HAREM

Objectives This study compared the efficacy and safety of subcutaneous (SC) versus intravenous (IV) formulations of tocilizumab in patients with rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs (DMARD). Methods Patients (n=1262) were randomly assigned to receive tocilizumab-SC 162mg weekly+placebo-IV every 4weeks or tocilizumab-IV 8mg/kg every 4weeks+placebo-SC weekly in combination with traditional DMARD. The primary outcome was to demonstrate the non-inferiority of tocilizumab-SC to tocilizumab-IV with regard to the proportion of patients in each group achieving an American College of Rheumatology (ACR) 20 response at week 24 using a 12% non-inferiority margin (NIM). Secondary outcomes were disease activity score using 28 joints (DAS28), ACR responses, health assessment questionnaire scores and safety assessments. Results At week 24, 69.4% (95% CI 65.5 to 73.2) of tocilizumab-SC-treated patients versus 73.4% (95% CI 69.6 to 77.1) of tocilizumab-IV-treated patients achieved an ACR20 response (weighted difference between groups -4.0%, 95% CI -9.2 to 1.2); the 12% NIM was met. ACR50/70 responses, DAS28 and physical function improvements were comparable between the tocilizumab-SC and tocilizumab-IV groups. The safety profiles of tocilizumab-SC and tocilizumab-IV were similar, and the most common adverse event was infection. Injection-site reactions (ISR) occurred more frequently in the tocilizumab-SC group than in the tocilizumab-IV (placebo-SC) group. No anaphylaxis was reported over the 24weeks. Conclusions Tocilizumab-SC 162mg weekly demonstrated comparable efficacy to tocilizumab-IV 8mg/kg. The safety profile of tocilizumab-SC is consistent with the known and well-established safety profile of tocilizumab-IV, with the exception of a higher incidence of ISR, which were more common with tocilizumab-SC administration

Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial

OBJECTIVES: The efficacy of tocilizumab (TCZ), an anti-interleukin-6 receptor antibody, has not previously been evaluated in a population consisting exclusively of patients with early rheumatoid arthritis (RA). METHODS: In a double-blind randomised controlled trial (FUNCTION), 1162 methotrexate (MTX)-naive patients with early progressive RA were randomly assigned (1:1:1:1) to one of four treatment groups: 4 mg/kg TCZ+MTX, 8 mg/kg TCZ+MTX, 8 mg/kg TCZ+placebo and placebo+MTX (comparator group). The primary outcome was remission according to Disease Activity Score using 28 joints (DAS28-erythrocyte sedimentation rate (ESR) \u3c 2.6) at week 24. Radiographic and physical function outcomes were also evaluated. We report results through week 52. RESULTS: The intent-to-treat population included 1157 patients. Significantly more patients receiving 8 mg/kg TCZ+MTX and 8 mg/kg TCZ+placebo than receiving placebo+MTX achieved DAS28-ESR remission at week 24 (45% and 39% vs 15%; p \u3c 0.0001). The 8 mg/kg TCZ+MTX group also achieved significantly greater improvement in radiographic disease progression and physical function at week 52 than did patients treated with placebo+MTX (mean change from baseline in van der Heijde-modified total Sharp score, 0.08 vs 1.14 (p=0.0001); mean reduction in Health Assessment Disability Index, -0.81 vs -0.64 (p=0.0024)). In addition, the 8 mg/kg TCZ+placebo and 4 mg/kg TCZ+MTX groups demonstrated clinical efficacy that was at least as effective as MTX for these key secondary endpoints. Serious adverse events were similar among treatment groups. Adverse events resulting in premature withdrawal occurred in 20% of patients in the 8 mg/kg TCZ+MTX group. CONCLUSIONS: TCZ is effective in combination with MTX and as monotherapy for the treatment of patients with early RA. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT01007435

Sustained inhibition of progressive joint damage with rituximab plus methotrexate in early active rheumatoid arthritis: 2-year results from the randomised controlled trial IMAGE

Background In the IMAGE study, rituximab plus methotrexate (MTX) inhibited joint damage and improved clinical outcomes at 1 year in MTX-naive patients with early active rheumatoid arthritis. Objective The aim of this study was to assess joint damage progression and clinical outcomes over 2 years. Methods Patients (n=755) were randomised to receive rituximab 2x500 mg+MTX, 2x1000 mg+MTX or placebo+MTX. The placebo-controlled period continued to week 104. Two-year end points were defined as secondary or exploratory and included change in total Genant-modified Sharp score (mTSS), total erosion score and joint space narrowing score from baseline to week 104. Clinical efficacy and physical function end points were also assessed. Results At 2 years, rituximab 2x1000 mg+MTX maintained inhibition of progressive joint damage versus MTX alone (mTSS change 0.41 vs 1.95; p <0.0001 (79% inhibition)), and a higher proportion of patients receiving rituximab 2x1000 mg+MTX had no radiographic progression over 2 years compared with those receiving MTX alone (57% vs 37%; p <0.0001). Contrary to 1-year results, exploratory analysis of rituximab 2x500 mg+MTX at 2 years showed that progressive joint damage was slowed by similar to 61% versus placebo+MTX (mTSS, exploratory p=0.0041). Improvements in clinical signs and symptoms and physical function seen after 1 year in rituximab-treated patients versus those receiving placebo were maintained at year 2. Safety profiles were similar between groups. Conclusions Treatment with rituximab 2x1000 mg+MTX was associated with sustained improvements in radiographic, clinical and functional outcomes over 2 year

Effect of disease duration and other characteristics on efficacy outcomes in clinical trials of tocilizumab for rheumatoid arthritis

Objective: To determine the extent to which disease duration, alone or in combination with other baseline clinical and non-clinical factors, explains variations in outcome of tocilizumab initiated in biologic-naïve patients with established RA. Methods: In this pooled analysis of phase 3 and 4 clinical trials conducted by the sponsor, predictors of response, including demographics, disease characteristics at baseline (start of tocilizumab dosing) and study characteristics (e.g. patient inclusion criteria, tocilizumab dosing regimen) were evaluated. Response was measured as change from baseline to week 24 in Clinical Disease Activity Index (CDAI) and HAQ-Disability Index (HAQ-DI) scores and as the proportions of patients who experienced ≥50% improvement based on ACR criteria (ACR50) and CDAI remission (≤2.8) rates at week 24. Results: Improvements in all outcomes investigated were observed in patients receiving tocilizumab. Although disease duration was statistically significant in the models, it accounted for <2% of variation in CDAI and HAQ-DI score changes from baseline to week 24; baseline CDAI and HAQ-DI values accounted for 32% and 15% of variations, respectively. Doubling of disease duration reduced the odds of achieving an ACR50 response by only 9%, and each additional 5-year period of disease duration decreased the odds of achieving CDAI remission by only 15%. Conclusion: RA duration, alone or in combination with other baseline characteristics, had a statistically significant but clinically small effect on the outcomes of tocilizumab initiated in biologic-naïve patients with established RA

Anti-CD74 autoantibodies in axial spondyloarthritis as biomarkers for activity and severity of disease but not for tumour necrosis factor inhibitor retention: data from the Swiss Clinical Quality Management in rheumatic diseases cohort

OBJECTIVES: Anti-CD74 antibodies (Abs) have been proposed as a diagnostic biomarker in axial spondyloarthritis (axSpA). The aims of this study were to evaluate the association of these Abs with disease activity parameters in axSpA and to assess their predictive value for tumour necrosis factor inhibitor (TNFi) treatment effectiveness. METHODS: Patients diagnosed with axSpA in the Swiss Clinical Quality Management registry with available biosamples and a measurement of IgA anti-CD74 Abs were included in this cohort study. We used a cut-off of 15 U/ml to define anti-CD74 Abs elevation. Associations of important disease characteristics with anti-CD4 Abs elevation and anti-CD74 Abs levels were evaluated using logistic and linear regression, respectively. For patients with an available biosample before TNFi initiation, we evaluated drug retention and estimated the hazard ratio of treatment discontinuation depending on anti-CD74 Abs elevation. RESULTS: Elevated IgA anti-CD74 Abs were found in 383/722 (53%) patients with axSpA and were significantly associated with older age, male sex, and elevated C-reactive protein (CRP). Among 310 patients starting TNFi treatment, no significant difference in drug retention was found between patients with and without elevated anti-CD74 Abs (HR 0.91, 95% CI 0.66 to 1.25). An increased Bath Ankylosing Spondylitis Disease Activity Index was found to be associated with a reduced TNFi retention whereas an elevated CRP was associated with a prolonged retention. CONCLUSIONS: Although elevated IgA anti-CD74 Abs are associated with CRP elevation, we could not demonstrate an additional value of this biomarker for predicting response to treatment with TNFi beyond CRP measurement

Canakinumab for Treatment of Adult-Onset Still's Disease to Achieve Reduction of Arthritic Manifestation (CONSIDER): phase II, randomised, double-blind, placebo-controlled, multicentre, investigator-initiated trial

Background: Inhibition of interleukin (IL)-1 represents a promising treatment option in adult-onset Still's disease (AOSD). Objective: To investigate the efficacy and safety of canakinumab in patients with AOSD and active joint involvement by means of a multicentre, double-blind, randomised, placebo-controlled trial. Methods Patients with AOSD and active joint involvement (tender and swollen joint counts of >= 4 each) were treated with canakinumab (4 mg/kg, maximum 300 mg subcutaneous every 4 weeks) or placebo. The primary endpoint was the proportion of patients with a clinically relevant reduction in disease activity at week 12 as determined by the change in disease activity score (Delta DAS28>1.2). Results At enrolment, patients had high active disease with a mean DAS28(ESR) of 5.4 in the canakinumab and 5.3 in the placebo group, respectively. In the intention-to-treat analysis, 12 patients (67%) in the canakinumab group and 7 patients (41%) in the placebo group fulfilled the primary outcome criterion (p=0.18). In the per-protocol analysis, significantly higher American College of Rheumatology (ACR) 30% (61% vs 20%, p=0.033), ACR 50% (50% vs 6.7%, p=0.009) and ACR 70% (28% vs 0%, p=0.049) response rates were observed in the canakinumab group compared with the placebo group. Two patients in the canakinumab group experienced a serious adverse event. Conclusion Although the study was terminated prematurely and the primary endpoint was not achieved, treatment with canakinumab led to an improvement of several outcome measures in AOSD. The overall safety findings were consistent with the known profile of canakinumab. Thus, our data support indication for IL-1 inhibition with canakinumab in AOSD

Abatacept used in combination with non-methotrexate disease-modifying antirheumatic drugs: a descriptive analysis of data from interventional trials and the real-world setting

Background Methotrexate (MTX) remains the anchor drug in rheumatoid arthritis (RA) treatment, but is poorly tolerated or contraindicated in some patients. There is a wealth of data supporting the use of abatacept in combination with MTX, but data on alternative conventional synthetic disease-modifying antirheumatic drug (csDMARD) combinations with abatacept are scarce. Methods In this post-hoc exploratory analysis, efficacy and safety data were extracted from abatacept RA studies in which combination with csDMARDs other than MTX was permitted: three interventional trials (ATTAIN, ASSURE, and ARRIVE) and one real-world study (ACTION). Patients with moderate-to-severe RA received abatacept in combination with MTX, hydroxychloroquine, sulfasalazine, azathioprine, or leflunomide for 6 months to 2 years according to the study design. Change from baseline in physical function (Health Assessment Questionnaire—Disability Index (HAQ-DI); all studies) and 28-joint Disease Activity Score (C-reactive protein) (DAS28 (CRP); ATTAIN, ARRIVE, and ACTION), American College of Rheumatology response rates (ATTAIN), and safety were assessed for individual and pooled csDMARD combinations for each trial. A meta-analysis was also performed on pooled data for HAQ-DI and DAS28 (CRP) across interventional trials. Results Across all four studies, 731 patients received abatacept plus one non-MTX csDMARD (hydroxychloroquine n = 152; sulfasalazine n = 123; azathioprine n = 59; and leflunomide n = 397) and 2382 patients received abatacept plus MTX. Mean changes from baseline in HAQ-DI scores for abatacept plus MTX (all csDMARDs pooled) vs abatacept plus a non-MTX csDMARD were –0.54 vs –0.44 (ATTAIN), –0.43 vs –0.43 (ASSURE), and –0.39 vs –0.36 (ARRIVE). Mean changes from baseline in DAS28 (CRP) and ACR response rates were also similar with abatacept plus MTX or non-MTX csDMARDs. Data for individual non-MTX csDMARDs (pooled across studies) and real-world data were consistent with these findings. Rates of treatment-related adverse events and serious adverse events, respectively, for abatacept plus one non-MTX csDMARD vs abatacept plus MTX were 35.7% vs 41.7% and 2.4% vs 2.3% (ATTAIN), 58.0% vs 55.9% and 4.2% vs 1.7% (ASSURE), and 38.1% vs 44.3% and 0.6% vs 2.9% (ARRIVE). Conclusions Abatacept in combination with non-MTX csDMARDs is clinically effective and well tolerated in patients with moderate-to-severe RA, providing similar benefits to those seen with abatacept plus MTX. Trial registration ClinicalTrials.gov NCT00048581. Registered 2 November 2002. ClinicalTrials.gov NCT00048932. Registered 11 November 2002. ClinicalTrials.gov NCT00124982. Registered 30 June 2005. ClinicalTrials.gov NCT02109666. Registered 8 April 2014

Plasma processes in pulsar magnetospheres and eclipsing binary pulsar systems

Background: Upadacitinib (UPA), a selective JAK1 inhibitor, has demonstrated efficacy and safety in patients with rheumatoid arthritis (RA) as monotherapy and in combination with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) such as methotrexate (MTX).1,2 However, UPA monotherapy has not been compared directly with UPA combination therapy in the Phase 3 program. Objectives: To compare the efficacy of UPA monotherapy and UPA in combination with MTX using data from two Phase 3 trials of RA patients with an inadequate response (IR) to prior MTX therapy. Methods: In SELECT-MONOTHERAPY, 648 MTX-IR patients were randomized to receive UPA 15 mg or 30 mg monotherapy once daily (QD), or continue with MTX monotherapy (cMTX; given as a blinded study drug), for 14 weeks. In SELECT-NEXT, 661 csDMARD-IR patients were randomized to receive UPA 15 mg or 30 mg QD or placebo (PBO) for 12 weeks on a background of csDMARDs. Only patients receiving concomitant MTX (with or without additional csDMARDs) at baseline in SELECT-NEXT were included in this analysis. The primary endpoints of both studies were the proportion of patients achieving ACR20 and DAS28(CRP) ≤3.2. Additional endpoints included ACR50/70, DAS28(CRP) <2.6, CDAI remission (≤2.8), CDAI low disease activity (LDA; ≤10), and change from baseline in HAQ-DI. Logistic regression or ordinary least squares analyses were used to compare outcomes with monotherapy versus combination therapy, adjusting for demographics and baseline disease characteristics. Results: A total of 1114 patients were included in the analysis, of whom 648 received monotherapy in SELECT-MONOTHERAPY and 466 received combination therapy in SELECT-NEXT. Of the patients receiving combination therapy, 338 (72.5%) were receiving MTX background therapy only and 128 (27.5%) were receiving MTX plus other csDMARDs. Baseline characteristics were generally similar between the study cohorts; the majority of patients in both studies were female and of white ethnicity, with a mean age of approximately 55 years and a mean MTX dose of approximately 17 mg/week. Consistent with previously reported results from SELECT-MONOTHERAPY1 and SELECT-NEXT,2 both UPA monotherapy and UPA combination therapy led to significant improvements in efficacy outcomes versus cMTX/PBO+MTX (Table). No significant differences were observed between UPA monotherapy and UPA combination therapy across a range of clinical endpoints, including ACR20/50/70 responses and measures of LDA and remission. In addition, improvements in quality of life as measured by HAQ-DI were similar with UPA monotherapy and combination therapy. Efficacy was comparable between the two UPA doses in the combination therapy group, whereas in the monotherapy group numerically higher responses were observed with UPA 30 mg versus UPA 15 mg.No Full Tex

Concurrent Oral 1 - Therapy of rheumatic disease: OP4. Effectiveness of Rituximab in Rheumatoid Arthritis: Results from the British Society for Rheumatology Biologics Register (BSRBR)

Background: Rituximab (RTX) in combination with methotrexate (MTX) has been licensed since 2006 for the management of severe active rheumatoid arthritis (RA) in patients who have failed at least one anti-tumour necrosis factor (anti-TNF) therapy. Published clinical trials have demonstrated the efficacy of RTX in improving both clinical symptoms and patients' physical function. This study aimed to assess the effectiveness of RTX in RA patients treated in routine clinical practice by examining clinical and patient reported outcomes six months after receiving a first course of RTX. Methods: The analysis involved 550 RA patients registered with the BSRBR, who were starting RTX and were followed up for at least 6 months. Change in Disease Activity Score (DAS28) and European League Against Rheumatism (EULAR) response were used to assess the clinical response while change in Health Assessment Questionnaire (HAQ) score was used to assess the physical function of the patients 6 months after starting RTX. The change in DAS28 and HAQ was compared between seronegative and seropositive patients and anti-TNF naïve patients versus anti-TNF failures. The response was also compared between patients receiving RTX in combination with MTX, other non-biologic disease modifying anti-rheumatic drugs (nbDMARDs) or no nbDMARDs. Results: The mean (s.d.) age of the cohort was 59 (12) years and 78% of the patients were females. The patients had a mean (s.d.) of 15 (10) years of disease duration. 16% were biologic naïve while 84% were anti-TNF failures. 32% of the patients were seronegative and 68% were seropositive. The mean (95% CI) DAS28 at baseline was 6.2 (6.1, 6.3) which decreased to 4.8 (4.7, 4.9) at 6 months of follow up. 16% were EULAR good responders, 43% were moderate responders and 41% were non responders. The mean (95% CI) change in HAQ was −0.1 (−0.2, −0.1) (Table 1). The mean change in DAS28 was similar in seropositive and seronegative patients (p = 0.18) while the anti-TNF naïve patients showed a greater reduction in DAS28 scores than anti-TNF failures (p = 0.05). Patients receiving RTX in combination with MTX showed similar changes in DAS28 and HAQ compared to patients receiving RTX alone or with other nbDMARDs. Conclusions: RTX has proven to be effective in the routine clinical practice. Anti-TNF naïve patients seem to benefit more from RTX treatment than anti-TNF failures. Disclosure statement: The authors have declared no conflicts of interes