Background/Purpose:  Active rheumatoid arthritis (RA) is commonly associated with impairment of physical function and health-related quality of life (QoL), as well as work disability. The importance of patient-reported outcomes (PROs) in evaluating the impact of RA treatment on function, QoL, and the ability to work is well recognized. Patients with early (mean symptom duration, 6 months), moderate-to-severe RA who previously received induction therapy and achieved DAS28 remission with etanercept (ETN) 50 mg/methotrexate (MTX) in the 52-week, open-label Phase 1 of the PRIZE study received ETN 25 mg/MTX, MTX alone, or no treatment in the 39-week, randomized, double-blind Phase 2. The results of Phase 1//2 demonstrated a statistically significant and clinically meaningful favorable impact/sustained effect of biologic therapy on PROs.¹ Patients were subsequently included in a 26-week, observational, treatment-free Phase 3 if they had DAS28 ≤3.2 to assess the impact of complete therapy withdrawal.

Methods:  Patients achieving response at end of Phase 2 (week 91: DAS28 ≤3.2) to treatment with ETN/MTX, MTX/placebo (PBO) injection, or PBO capsules/PBO injection continued to 26-week drug-free Phase 3. MTX was tapered to 0 by 5-mg weekly decrements. At week 117, the following PROs were assessed: the Health Assessment Questionnaire disability index (HAQ-DI); EuroQol-5 Dimensions utility score (EQ-5D); Short Form Health Survey Physical/Mental Component Summary (SF-36 PCS/MCS); Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue); Work Productivity and Activity Impairment Questionnaire (WPAI:RA); and Work Instability Scale for Rheumatoid Arthritis (RA-WIS).

Results:  After withdrawal of treatment in patients who responded to ETN/MTX and MTX/PBO therapy at week 91, worsening of most PROs was observed (Table 1). At week 117, the proportions of patients who achieved the following endpoints were not significantly different between the ETN/MTX and MTX/PBO groups after treatment withdrawal: normal HAQ-DI or EQ-5D VAS; clinically relevant improvements in EQ-5D utility and SF-36 PCS; and low risk of work disability. Whereas worsening of most PROs plateaued among patients who were treatment free in both Phases 2 and 3, sharper declines were observed among patients withdrawn from ETN/MTX and MTX/PBO treatment in Phase 3.

 

Table 1. Effects of Biologic Treatment Withdrawal on PROs in PRIZE Phase 3 (LOCF)
		Patients, %			Pairwise Comparison P value§
		ETN/MTX (n=63)	MTX/PBO(n=65)	PBO (n=65)	ETN/MTX vs MTX/PBO	ETN/MTX vs PBO/PBO	MTX/PBO vs PBO/PBO
HAQ-DI ≤0.5*	Wk 91	77.8	72.3	44.6	0.543	0.0001	0.002
	Wk 117	66.7	58.5	40.0	0.366	0.003	0.053
EQ-5D utility improvement ≥0.05†	Wk 91	76.2	73.8	53.8	0.839	0.010	0.028
	Wk 117	68.3	67.7	52.3	1.000	0.073	0.107
EQ-5D VAS >82*	Wk 91	71.4	58.5	32.3	0.142	<0.0001	0.005
	Wk 117	55.6	38.5	32.3	0.076	0.012	0.582
SF-36 PCS improvement ≥5†	Wk 91	79.4	76.6	42.2	0.831	<0.0001	0.0001
	Wk 117	58.7	62.5	34.4	0.718	0.008	0.003
SF-36 MCS improvement ≥5†	Wk 91	58.7	46.9	35.9	0.215	0.013	0.282
	Wk 117	60.3	39.1	39.1	0.021	0.021	1.000
Low risk RA-WIS ≤9‡	Wk 91	86.1	84.4	62.1	1.000	0.041	0.050
	Wk 117	80.6	71.1	58.6	0.438	0.062	0.319
*“Normal” value, data shown for mITT population; †improvement from Phase 1 baseline mITT population (LOCF), representing clinically relevant improvement; ‡low risk of work disability; §based on 2-sided pairwise Fishers’ exact tests.

Conclusion:  Withdrawal of ETN/MTX therapy in Phase 3 of the PRIZE study resulted in loss of favorable impact on PROs.

Reference: 1. Emery P, et al. Ann Rheum Dis 2013;72(Suppls3):765.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/impact-of-etanercept-methotrexate-treatment-withdrawal-on-patient-reported-outcomes-in-patients-with-early-rheumatoid-arthritis-prize-trial/