Combination therapy of a tumor necrosis factor inhibitor plus methotrexate inhibited both joint erosion and joint space narrowing independent of disease activity in a 2-year, randomized, controlled trial of 638 patients with early, progressive rheumatoid arthritis.
While joint erosion (JE) has been perceived to be the most critical indicator of permanent disability in RA patients, recent data suggest that joint space narrowing (JSN) may be more important early in the disease process as a predictor of irreversible physical disability (Ann. Rheum. Dis. 2011;70:733-9). "Preventing the onset or worsening of JSN probably represents a critical aspect of effective disease management of early rheumatoid arthritis patients," Dr. Josef S. Smolen of the Medical University of Vienna and Hietzing Hospital, also in Vienna, and his associates wrote online in Annals of the Rheumatic Diseases (2012 [doi 10.1136/annrheumdis-2012-201620]).
The data came from patients enrolled in Abbott’s PREMIER trial, a 2-year, active-controlled, double-blind study of 799 methotrexate-naive patients with early, progressive RA. They were randomly assigned to either combination treatment with subcutaneous adalimumab (ADA; 40 mg every other week) plus oral methotrexate (MTX; titrated to 20 mg/week by week 8, as tolerated), adalimumab monotherapy, or methotrexate monotherapy. Study patients were 18 years of age or older, with RA duration of less than 3 years, 8 or more swollen joints, and 10 or more tender joints.
Of the 799 patients originally randomly assigned in PREMIER, the current analysis included 229 patients in the ADA plus MTX combination group, 205 on ADA monotherapy, and 204 MTX monotherapy patients, all of whom had one or more post-baseline time-averaged disease activity (DAS28) measurements and underwent radiography at baseline and week 52 and/or week 104.
At both the 52 and 104 week time points, the patients receiving combination therapy using ADA and MTX had greater mean reductions from baseline in DAS28 (–3.6 at 52 weeks, –3.8 at 104 weeks) than did those receiving patients receiving ADA monotherapy (–2.8 and –3.1, respectively) or MTX monotherapy (–2.8 and –3.1, respectively). This pattern of treatment responses was evident at week 2 and maintained throughout the 104 weeks of the trial, Dr. Smolen and his associates said.
Approximately half of the patients receiving combination therapy were in the lowest tertile of time–averaged 28-joint disease activity score (TA-DAS28), while patients receiving either adalimumab or methotrexate monotherapy were clustered in the higher TA-DAS28 tertiles. Whereas the radiographic progression of both JE and JSN increased significantly with increasing disease activity in the two monotherapy groups – more so with MTX than ADA – there was far less of a relationship between radiographic progression and disease activity in the combination treatment group, and even less so for JSN than for JE. These findings suggest that ADA plus MTX therapy may have even stronger inhibitory effects on JSN progression than on JE progression despite persistent inflammation, they commented.
While JE scores were not associated with health assessment questionnaire (HAQ-DI) scores at any of the time points examined, JSN scores were positively associated with HAQ-DI scores at both 52 and 104 weeks but not at baseline.
Of 649 patients for whom employment status was known, the presence of JSN was associated with being employed at baseline and at weeks 52 and 104 (P = .02, .007, and .04, respectively) but JE was not. The percentages of employed patients generally decreased with increasing baseline values of JE or JSN, but the relationship was more apparent for JSN (P =.02 vs. P less than .001 for the overall differences among JE and JSN tertiles, respectively). These data indicate that progression of JSN plays a more prominent role than does JE in determining employment status, Dr. Smolen and his associates said.
"Patients with RA frequently lose their jobs early in the course of the disease, with 20%-30% experiencing permanent work disability during the first 2-3 years after diagnosis (Clin. Exp. Rheumatol. 2003;21:S71-4). These data indicate that early control of JSN progression is important not only to protect patients’ physical functioning but [also] to help them maintain the lifestyle they had before RA diagnosis," the investigators said.
"Because of the clinical implications of JSN progression for disability and work impairment, protection from the onset or worsening of JSN should be an important factor when choosing between therapeutic modalities," they concluded.
The study was sponsored by Abbott. Dr. Smolen has financial relationships with Abbott, Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Glaxo, Lilly, MSD (Schering-Plough), Novo-Nordisk, Pfizer (Wyeth), Roche, Sandoz, and UCB. His coauthors have similar disclosures, and four are full-time employees of Abbott.