Background/Purpose:

Insulin resistance (IR), N-terminal pro-brain natriuretic peptide (NT-proBNP) and total cholesterol/high density lipoprotein cholesterol ratio (TC/HDL-C) profiles have been proposed as surrogate measures of CVD in RA, with some improving with suppression of disease activity. In early RA, few randomised controlled trials (RCTs) have compared the effects of DMARDs with TNFi on these biomarkers. A recent cohort study has linked TNFi to a reduced risk of diabetes. We aimed to determine whether TNFi had greater influence over DMARDs on homeostasis model assessment of IR (HOMA-IR), NT-proBNP and TC/HDL-C.

Methods:

The Infliximab as Induction therapy for Early rheumatoid Arthritis (IDEA) multicentre double-blind RCT recruited 112 DMARD-naïve RA patients (pts) (1987 ACR criteria; 3-12 months duration). Pts were randomised 1:1 to IFX+MTX or MTX with single-dose 250mg IV methylprednisolone (MP) as induction therapy. Treatment was blinded to week 26 then guided using a treat to target (T2T) approach. 120mg IM MP was given in both groups at weeks 6, 14 and 22 if DAS>2.4 at that visit.  A single centre conducted the CV sub-study. Fasting glucose, lipids, insulin and NT-proBNP were measured at baseline, week 26 (w26) and 78 (w78). Multiple imputation by chained equations, using predictive mean matching, created 20 datasets; linear regression analyses adjusted for baseline values. HOMA-IR (glucose*insulin/405) and NT-proBNP values were ln-transformed prior to analysis.

Results:

CV biomarker data were available for 86 pts; 7 had known CVD and were excluded from the subsequent analysis. Of the 79 pts included (age 51.6 [range 19-75], 71% female, 57% RF+ve, 72% ACPA+ve), 38 received IFX and 41 MP. Baseline clinical characteristics were similar between the two groups, including CV risk factors.  DAS44 remission rates did not differ between TNFi and DMARD groups at w26 (32% vs. 37%, p=0.956) and w78 (43% vs. 54%, p=0.593).  In both groups the three surrogate CVD markers improved on average at w26 and w78 (see Table 1). TC/HDL-C or NT-proBNP did not differ, but the TNFi group showed greater improvement in HOMA-IR at w78. Adjusting for IA/IM steroid injection dose did not alter the result.

Conclusion:

Treatment of early RA was associated with improvement in TC/HDL-C, IR and NT-proBNP.  To our knowledge this is the first double-blinded RCT to compare the change in HOMA-IR with TNFi versus non-TNFi in early DMARD-naive RA.  We determined a greater long-term improvement in HOMA-IR in those treated with TNFi; on average at w78 HOMA-IR values were around half (0.51 times) as high as those treated with MTX/IV steroid. When implementing a T2T approach, there appears to be an advantage with the use of TNFi.  Longer term follow up is underway to determine if these findings translate into reduced overt CVD.

Table 1: Changes in surrogate measures of CVD over 78 weeks

*it was not possible to calculate SD in original units for log-transformed variables