Background/Purpose: Initial combination therapy has proven to be effective in early rheumatoid arthritis (RA) patients. To determine which patients benefit from initial combination therapy. 

Methods: In the BeSt study, 508 patients were randomized to 4 treatment strategies: 1 Sequential monotherapy 2 Step-up therapy 3 Initial combination with a tapered high dose prednisone 4 Initial combination with infliximab. For this subanalysis, groups 1 & 2 (methotrexate monotherapy) were compared to groups 3 & 4 (initial combination therapy).

Clinical assessments were performed every 3 months and radiographs of hands and feet yearly. Radiographs were assessed by 2 independent blinded readers using the Sharp van der Heijde Score (SHS).

High risk was defined as ≥ 3 of 4 features present at baseline: Swollen Joint Count ≥ 10, erosions ≥ 4, Disease Activity Score (DAS) ≥ 3.7, both rheumatoid factor and anti-citrullinated peptide autoantibodies positive.

Chi square and T-tests were used to test differences between the groups and regression analysis was performed to calculate odds ratios (OR) and risk ratios (RR).

Results: Baseline characteristics were similar among the groups. 417 of 508 patients could be categorized into high or non-high risk with available data, of which 192 were identified as having high risk for progression. At 3 months, high risk patients who started with combination therapy significantly more often than those who started with monotherapy fulfilled ACR 20 (33 vs 20%), 50 (22 vs 7%) and 70 (11 vs 2%) response criteria, and achieved more DAS-remission (DAS < 1.6) (8 vs 3%) and more functional improvement (median 0.750 vs 0.375 decrease in HAQ). At 1 year, differences in DAS-remission and ACR 20 response criteria were sustained. Also, high risk patients who started combination therapy showed significant less RRP (≥ 5 points increase in SHS) than who started with monotherapy (5 vs 14%).

Also non-high risk patients who started with combination therapy at 3 months significantly more often than who started with monotherapy met the ACR 20 (40 vs 19%), 50 (27 vs 6%) and 70 (9 vs 1%) response criteria, achieved more DAS-remission (10 vs 3%) and more functional improvement (median 0.625 vs 0.375 improvement in HAQ).  At 1 year, differences remained for ACR 20 and 50 response and functional improvement. There was less RRP in non-high risk patients, without a significant difference between initial monotherapy and initial combination therapy patients (2 vs 5%). ORs and RRs are shown in table 1.

Table 1: Regression analyses: initial monotherapy was set as reference.

		High risk		Non-high risk
Logistic regression	OR	95% CI	OR	95% CI
DAS remission
at 3 months	3.67	1.28 to 10.56	2.96	1.21 to 7.22
at 1 year	2.06	1.07 to 3.95	0.99	0.57 to 1.73
ACR20 response
at 3 months	3.94	2.09 to 7.43	3.11	1.73 to 5.63
at 1 year	3.08	1.16 to 8.20	2.24	1.12 to 4.48
ACR50 response
at 3 months	6.29	3.00 to 13.20	6.25	3.08 to 12.70
at 1 year	1.84	0.98 to 3.46	1.99	1.12 to 3.56
ACR70 response
at 3 months	7.08	2.31 to 21.68	6.39	1.84 to 22.23
at 1 year	1.81	0.967 to 3.38	1.33	0.74 to 2.38
Poisson regression	RR	95% CI	RR	95% CI
RRP at 1 year	0.351	0.20 to 0.62	0.62	0.32 to 1.21
Linear regression	Beta	95% CI	Beta	95% CI
Δ HAQ
at 3 months	-0.42	-0.61 to -0.24	-0.33	-0.51 to -0.15
at 1 year	-0.16	-0.36 to 0.04	-0.21	-0.40 to -0.01

Conclusion: High risk as well as non-high risk patients benefit from initial combination therapy. To avoid RRP, high risk patients benefit the most from combination therapy. However, taking into account the clinical outcome measurements, non-high risk patients also do benefit by achieving earlier ACR response, DAS-remission and functional improvement when starting treatment with a combination therapy.

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