Long-term use of adalimumab as monotherapy after attainment of low disease activity with adalimumab plus methotrexate in patients with rheumatoid arthritis

Abstract

Objective: To evaluate long-term clinical, functional and radiographic outcomes in an open-label extension (OLE) study in patients with rheumatoid arthritis (RA) receiving adalimumab monotherapy or adalimumab+methotrexate following attainment of low disease activity (LDA) with adalimumab+methotrexate.

Methods: Methotrexate-naive patients with early RA were randomised to adalimumab, methotrexate or adalimumab +methotrexate in a double-blind, 2-year study. Patients who completed the study and achieved LDA (28-joint Disease Activity Score using C reactive protein (DAS28(CRP)<3.2) could receive adalimumab monotherapy for up to 8 additional years in the OLE; open-label methotrexate could be added per investigator's discretion. This post hoc analysis included data up to OLE year 3 (study year 5) from patients receiving adalimumab+methotrexate who achieved LDA at year 2 followed by adalimumab monotherapy or methotrexate reinitiation. Normal physical function was defined as Disability Index of the Health Assessment Questionnaire <0.5 and radiographic non-progression as change in modified total Sharp score ≤0.5.

Results: Of 140 patients initiating adalimumab monotherapy, 84 (60%) received adalimumab only (methotrexate non-use) and 56 (40%) reinitiated methotrexate (methotrexate use) during OLE treatment. Median (IQR) time to first methotrexate use was 5.1 (0.1-31.4) weeks. Among methotrexate users, 61% retained LDA, 48% achieved DAS28(CRP) <2.6, 45% had normal physical function and 46% had no radiographic progression at year 5; for non-users, 63%, 50%, 58% and 50%, respectively, achieved these milestones. Adverse event rates were similar between methotrexate non-use and use patients.

Conclusions: Adalimumab monotherapy effectively maintained good clinical, functional and radiographic outcomes for up to 3 additional years in ≥50% of patients who attained LDA after 2 years of adalimumab+methotrexate therapy.

Trial registration number: NCT00195663; Post-results.

Keywords: anti-tnf; methotrexate; rheumatoid arthritis.

Conflict of interest statement

Competing interests: ECK has received consulting fees or other remuneration from, and served on advisory boards on behalf of, Abbott Laboratories, AstraZeneca Pharma, Biotest, Bristol-Myers Squibb Company, Crescendo Bioscience, F. Hoffmann-La Roche Inc., Genentech Inc., Janssen Inc., Lilly Pharmaceuticals, Merck and Pfizer Pharmaceuticals; has received research grants from Abbott Laboratories, Amgen Inc., AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, F. Hoffmann-La Roche Inc., Janssen Inc., Lilly Pharmaceuticals, Novartis Pharmaceuticals, Pfizer Pharmaceuticals and Sanofi-Aventis and has speaker honoraria agreements with Abbott Laboratories, Amgen, AstraZeneca LP, Bristol-Myers Squibb Canada, F. Hoffmann-La Roche Inc., Janssen Inc., Pfizer Pharmaceuticals and Sanofi Genzyme. FCB has received consulting fees or other remuneration from Centocor, Schering-Plough, Amgen/Wyeth and Abbott. HK, YL, IS and SF are employees of AbbVie and may own AbbVie stock and/or stock options.

Figures

Figure 1

Patient disposition of responders to adalimumab+methotrexate at year 2 (OLE entry) from the primary study who were in methotrexate non-use or use groups during the OLE. AE, adverse event; ELISA, enzyme-linked immunosorbent assay; LDA, low disease activity; MTX, methotrexate; OLE, open-label extension. *Patients entering the OLE received open-label adalimumab 40 mg every other week and could receive MTX at the investigator’s discretion. †In the MTX non-use group, eight patients discontinued because of AEs (stage III malignant melanoma (n=1); squamous cell carcinoma of the tongue (n=1); mycobacterium marinum skin infection (n=1); mycobacterium avium complex infection (n=1); cholecystitis and gastric adenocarcinoma (n=1); alternations of cardiac rhythm (n=1); psoriasis-like eczema and severe bone marrow puncture due to lymphocytosis (n=1) and anaemia, fever and aortic valve endocarditis (n=1). ‡In the MTX use group, five patients discontinued because of AEs (cognitive impairment and a positive ELISA test (n=1); neutropenia (n=1); dyspnoea on exertion (n=1); nasal ulcer (n=1) and atrial fibrillation, encephalopathia, Gram-negative sepsis, septic shock, multiorgan failure, haemophagocytic syndrome, respiratory insufficiency, melena and Epstein-Barr virus infection (n=1). §Reflects the percentages of year 2 LDA responders who were in MTX non-use or use groups during the OLE and completed OLE year 3 (year 5 of the study).

Figure 2

Association of disease parameters at the time of methotrexate reinitiation during the OLE based on propensity score matching. (A) Mean values for the indicated disease parameters at the time of MTX reinitiation (MTX use) versus matched controls (MTX non-use); (B) ORs (95% CIs) of MTX reinitiation for the indicated disease parameters. CRP, C reactive protein; MTX, methotrexate; OLE, open label extension; PGA, Physician Global Assessment; PtGA, Patient Global Assessment; SJC66, swollen joint count based on 66 joints; TJC68, tender joint count based on 68 joints. *One case (MTX use) could have multiple matched controls (MTX non-use); two of 56 MTX use patients had no matches, so total cases=54. †P<0.01.

Figure 3

Clinical, functional and radiographic outcomes following up to 3 years of open-label adalimumab as monotherapy after 2 years of adalimumab+methotrexate. (A) Percentages of MTX non-use and MTX use patients with remission (DAS28(CRP)