Therapies for Active Rheumatoid Arthritis after Methotrexate Failure

O'Dell, James Robert; Mikuls, Ted R.; Taylor, Thomas H.; Ahluwalia, Vandana; Brophy, Mary; Warren, Stuart; Lew, Robert A.; Cannella, Amy C.; Kunkel, Gary; Phibbs, Ciaran S.; Anis, Aslam H.; Leatherman, Sarah; Keystone, Edward

doi:10.1056/nejmoa1303006

Cited by 330 publications

(265 citation statements)

References 36 publications

(76 reference statements)

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“…(TNF) inhibitors, abatacept, rituximab, tocilizumab] or newer generation kinase inhibitors (e.g., tofacitinib), which have demonstrated significant efficacy in controlling joint damage and improving physical function and quality of life 2,3,4 . Despite this, substantial proportions of patients discontinue biologic treatment because of inadequate efficacy or adverse events (AE) 5 .…”

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confidence: 99%

Results from a Phase IIA Parallel Group Study of JNJ-40346527, an Oral CSF-1R Inhibitor, in Patients with Active Rheumatoid Arthritis despite Disease-modifying Antirheumatic Drug Therapy

et al. 2015

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Objective.To assess the efficacy and safety of JNJ-40346527, a selective inhibitor of colony-stimulating factor-1 (CSF-1) receptor kinase that acts to inhibit macrophage survival, proliferation, and differentiation in patients with active rheumatoid arthritis (RA) despite disease-modifying antirheumatic drug (DMARD) therapy.Methods.In this randomized, double-blind, placebo-controlled, parallel group study, adults were randomized (2:1) to receive oral JNJ-40346527 100 mg or placebo twice daily through Week 12. Patients with RA had disease activity [≥ 6 swollen/≥ 6 tender joints, C-reactive protein (CRP) ≥ 0.8 mg/dl] despite DMARD therapy for ≥ 6 months. The primary endpoint was change from baseline at Week 12 in the 28-joint Disease Activity Score with CRP (DAS28-CRP). Pharmacokinetic/pharmacodynamic analyses were also performed, and safety was assessed through Week 16.Results.Ninety-five patients were treated (63 JNJ-40346527, 32 placebo); 8 patients discontinued treatment (6 JNJ-40346527, 2 placebo) through Week 12. Mean improvements in DAS28-CRP from baseline to Week 12 were 1.15 for the JNJ-40346527 group and 1.42 for the placebo group (p = 0.30); thus, a statistically significant difference was not observed for the primary endpoint. Pharmacokinetic exposure to JNJ-40346527 and its active metabolites was above the projected concentration needed for pharmacologic activity, and effective target engagement and proof of activity were demonstrated by increased levels of CSF-1 and decreased CD16+ monocytes in JNJ-40346527–treated, but not placebo-treated, patients. Thirty-seven (58.7%) JNJ-40346527–treated and 16 (50.0%) placebo-treated patients reported ≥ 1 adverse event (AE); 1 (1.6%) JNJ-40346527–treated and 3 (9.4%) placebo-treated patients reported ≥ 1 serious AE.Conclusion.Although adequate exposure and effective peripheral target engagement were evident, JNJ-40346527 efficacy was not observed in patients with DMARD-refractory active RA. ClinicalTrials.gov identifier: NCT01597739. EudraCT Number: 2011-004529-28.

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confidence: 99%

Results from a Phase IIA Parallel Group Study of JNJ-40346527, an Oral CSF-1R Inhibitor, in Patients with Active Rheumatoid Arthritis despite Disease-modifying Antirheumatic Drug Therapy

et al. 2015

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“…Among Medicare enrollees, adding HCQ to oral MTX was associated with a reduced likelihood of subsequently receiving a biologic agent, and trends were similar numerically but not significant (although perhaps underpowered) in the younger, commercially insured patients. While this could represent a true benefit of treatment strategies that include HCQ (22), a cautious interpretation of this result is warranted because of the possibility of confounding by indication. In other words, less active RA patients might preferentially receive HCQ, a drug that could be perceived as less toxic, albeit somewhat less effective, and thus more suitable for patients who do not need more aggressive treatment.…”

Section: Discussionmentioning

confidence: 97%

Use of Oral and Subcutaneous Methotrexate in Rheumatoid Arthritis Patients in the United States

Curtis

Zhang

Xie

et al. 2014

Arthritis Care & Research

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Objective. To examine the patterns of methotrexate (MTX) use among rheumatoid arthritis (RA) patients. Methods. Using data from RA patients enrolled in a US commercial health plan and the US Medicare program, we identified RA patients initiating oral MTX. Persistence with MTX (oral or subcutaneous [SC]) was defined as no gap for >90 days. Results. New oral MTX users in Medicare (n ‫؍‬ 20,431) were 76.9% women, had a mean ؎ SD age of 69.7 ؎ 11.7 years, and contributed a median followup of 2.6 years (interquartile range 1.7-3.5 years). Only 38% received dosages >20 mg/week at any time. Approximately 50% of patients discontinued MTX at 1 year, although more than one-third of patients subsequently restarted. New commercially insured oral MTX users (n ‫؍‬ 4,048) were similar to Medicare patients, except for age. Among Medicare patients, 19% starting oral MTX subsequently initiated a biologic agent, mostly anti-tumor necrosis factor (85%). Of these, only 50% received MTX at a dosage of >20 mg/week, and only 21% of individuals switched to SC MTX (4%) or received hydroxychloroquine (8%), sulfasalazine (5%), or leflunomide (8%) prior to biologic agents. In commercially insured patients, 35% initiated a biologic agent, mostly anti-tumor necrosis factor therapies (90%). Of these, 43% never received MTX >20 mg/week. Conclusion. Titration to a higher-dose oral MTX and use of SC MTX among RA patients were infrequent and may have been underutilized. Further work to optimize MTX dosing before patients are switched to a biologic agent may be warranted.

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“…This bias involved 2 studies, which were performed in Asia and Latin America, in patients with long disease duration, an inadequate response to previous DMARDs, and no treatment with a course of GC (11,12,16). In contrast, the other studies (3,4,9,10,13,15) were performed in North America and Europe, and generally in DMARD-naive early arthritis patients.…”

Section: Discussionmentioning

confidence: 99%

Combination Therapy With and Without Tumor Necrosis Factor Inhibitors in Rheumatoid Arthritis: A Meta‐Analysis of Randomized Trials

Graudal

Hubeck-Graudal

Faurschou

et al. 2015

Arthritis Care & Research

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Objective. The costs of biologic treatment per patient with rheumatoid arthritis (RA) are approximately 100 times the costs of treatment with a combination of conventional disease-modifying antirheumatic drugs (DMARDs). Despite this, biologic agents have not been proven superior. We compared the effects of combination DMARD therapies with and without biologic agents as therapy for patients with RA. Methods. Eight randomized controlled trials published in 10 articles were selected from a systematic literature search of 1,674 identified studies and integrated in a meta-analysis. These trials compared combinations of DMARDs versus a tumor necrosis factor (TNF) inhibitor plus methotrexate. Two reviewers independently entered data into standardized extraction forms. The combined effect measures were compared by means of the inverse variance method (continuous data) and the Mantel-Haenszel method (dichotomous data) using a random-effects model. Results. The primary outcome, radiographic progression score, did not differ between the combination DMARD group and the TNF inhibitor group, neither during the second year (20.09 units [20.61, 0.44]) of treatment or during the first 2 years (0.66 units [20.12, 1.43]). There were significant differences in the radiographic progression score, the American College of Rheumatology criteria for 50% improvement (ACR50), and the ACR70 response criteria at 6 months in favor of TNF inhibitor treatment, but these differences were not present in patients treated with an initial steroid course and disappeared at 24 months, irrespective of the use of steroids. Conclusion. The difference between DMARD combination treatments, including or excluding TNF inhibitors, is small. Due to the enormous cost differences, RA guidelines should recommend combination DMARD treatment before initiation of TNF inhibitors.

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Therapies for Active Rheumatoid Arthritis after Methotrexate Failure

Cited by 330 publications

References 36 publications

Results from a Phase IIA Parallel Group Study of JNJ-40346527, an Oral CSF-1R Inhibitor, in Patients with Active Rheumatoid Arthritis despite Disease-modifying Antirheumatic Drug Therapy

Results from a Phase IIA Parallel Group Study of JNJ-40346527, an Oral CSF-1R Inhibitor, in Patients with Active Rheumatoid Arthritis despite Disease-modifying Antirheumatic Drug Therapy

Use of Oral and Subcutaneous Methotrexate in Rheumatoid Arthritis Patients in the United States

Combination Therapy With and Without Tumor Necrosis Factor Inhibitors in Rheumatoid Arthritis: A Meta‐Analysis of Randomized Trials

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