Background/Purpose: Methotrexate (MTX) is used as first line therapy for treatment of rheumatoid arthritis (RA). Current recommendations state that therapy should be adjusted if patients (pts) fail to attain remission or low disease activity (LDA) after 6 mo of MTX, and TNF inhibitors could be considered for pts with high risk of aggressive disease. The objective of this post hoc analysis was to identify the benefits of treatment adjustment vs no treatment adjustment in pts who did not achieve a stable LDA after 6 mo of MTX.

Methods: A post hoc analysis from OPTIMA and PREMIER was conducted in MTX-naïve, early RA pts. In OPTIMA, non-achievers (NAs) were defined as pts failing to achieve a stable LDA target of DAS28(CRP) <3.2 at weeks (wks) 22 and 26 following placebo (PBO)+MTX for 26 wks. Pts who were NAs to MTX switched to open-label (OL) ADA+MTX for an additional 52 wks. In PREMIER, following MTX monotherapy, NAs were defined as pts failing to achieve a stable LDA target at wks 20 and 24; however, these pts continued MTX monotherapy up to 104 wks. Clinical and functional outcomes were evaluated at wk 78 and 76 for OPTIMA and PREMIER, respectively, while radiographic outcomes were evaluated at wk 78 for OPTIMA and both wks 52 and 104 for PREMIER. Additionally, ANOVA and logistic regression analysis was conducted on continuous and dichotomized endpoints, respectively, with the following baseline characteristics as variables: age, sex, RA duration, RF status, previous DMARD use, tender joint count, swollen joint count, C-reactive protein, DAS28 score, HAQ-DI, mTSS, erosion score, and estimated annual TSS progression.

Results: 348 out of 517 total pts in OPTIMA and 172 out of 257 total pts in PREMIER did not achieve a stable LDA target of DAS28(CRP) <3.2 after 26 and 24 wks of MTX monotherapy. In those NAs, mean disease duration at baseline was 0.3 and 0.8 for OPTIMA and PREMIER, respectively. In OPTIMA, the mean DAS28(CRP), HAQ-DI, and mTSS at baseline for NAs were 6.1, 1.7, and 11.7, respectively. In comparison, the mean DAS28(CRP) at baseline from the NAs in the PREMIER trial was 6.4, while the HAQ-DI and mTSS were 1.6 and 23.4, respectively. There was a significant decrease compared to baseline in the clinical and functional outcomes for both pts who were given OL ADA+MTX as well as pts who remained on MTX monotherapy; however, compared with pts who continued MTX, there was a significant increase in the percentage of pts achieving LDA and remission, according to all scores used, for those who switched to combination therapy with ADA+MTX (Table). Additionally, a larger proportion of pts showed no radiographic progression in the OPTIMA trial, where pts were switched to OL ADA+MTX after 26 wks.

Table. Clinical, Functional, and Radiographic Outcomes at Week 78 and 76 for Patients who were Non-Achievers to MTX Monotherapy in OPTIMA and PREMIER
	OPTIMAa	PREMIERb	P-Value
n (%)	N=348c	N=172c
DAS28(CRP), mean (SD)	2.9 (1.2)	3.7 (1.2)	<0.001d
DAS28(CRP) <2.6	138 (39.7)	23 (13.4)	<0.001e
DAS28(CRP) <3.2	185 (53.2)	51 (29.7)	<0.001e
SDAI ≤3.3	92 (26.4)	11 (6.4)	0.006e
CDAI ≤2.8	94 (27.0)	11 (6.4)	0.005e
HAQ-DI, mean (SD)	0.7 (0.6)	0.8 (0.7)	0.062d
HAQ-DI <0.5	125 (35.9)	49 (28.5)	0.091e
DHAQ-DI ≤0.22 from week 26	161 (46.3)	36 (20.9)	0.016e
mTSS, mean (SD)	12.6 (18.2)	29.6 (25.6)	<0.001d
DmTSS ≤0.5 from week 26	237 (68.1)	63 (36.6)	<0.001e
CDCf from week 26	77 (22.1)	7 (4.1)	<0.001e
CDAI, clinical disease activity index; CDC, comprehensive disease control; CRP, C-reactive protein; DAS28, 28-joint disease activity score; HAQ-DI, disability index of the health assessment questionnaire; mTSS, modified total Sharp score; SDAI, simplified disease activity index. aClinical, functional, and radiographic outcomes at week 78. bClinical and functional outcomes at week 76 and radiographic and CDC outcomes shown for week 52. cN consists of patients treated with PBO+MTX who do not achieve a DAS28(CRP) <3.2 at week 24/26 or week 20/24 for OPTIMA and PREMIER, respectively. dp-values derived from ANCOVA model adjusted for baseline values. ep-values based upon the difference between the OPTIMA and PREMIER study using a logistic regression model adjusted for baseline characteristics. fCDC is defined as DmTSS ≤0.5, DAS28(CRP) <2.6, and HAQ-DI <0.5.

Conclusion: Not adjusting treatment in pts who did not receive a stable LDA after 6 mo of initial MTX appears to result in worse long-term clinical, functional, and structural outcomes compared to pts whose treatment was adjusted by adding ADA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/long-term-clinical-structural-and-functional-consequences-of-not-adopting-treatment-in-mtx-suboptimal-responders/