Of 3035 unique articles identified in electronic searches and 2077 articles screened from secondary sources, we included 43 articles in the systematic review of the prevalence of sustained remission/LDA after discontinuation and 37 studies in the scoping review of predictors (Fig. 1). Of the 43 articles in the systematic review, 22 articles reported induction-withdrawal studies and 22 articles reported studies of maintenance TNFi discontinuation, with 1 article including both groups [22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64]. Data on predictors were reported in 12 induction-withdrawal articles [27, 33,34,35,36, 39, 41, 43, 65,66,67,68] and 22 maintenance discontinuation articles [44, 46, 47, 49,50,51,52, 54,55,56, 59,60,61,62, 64, 69,70,71,72,73,74,75,76].

Flow diagram of study inclusion. Error bars represent 95% confidence intervals

These studies included 5 double-blind controlled trials [22,23,24,25,26], 1 open-label trial [27], and 16 studies in which TNFi discontinuation was observational [28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43] (Table 1 and Supplemental Table 3).

The criterion for TNFi discontinuation was DAS28 < 3.2 in 9 studies, DAS28 < 2.6 in 9 studies, and other indicators in 4 studies. The number of patients who discontinued TNFi ranged from 2 to 200 (median 34; total 1183), with larger samples in the trials. Seven studies examined etanercept, 5 examined infliximab, 5 examined adalimumab, 2 examined certolizumab, and 3 examined various TNFi. Follow-up varied from 24 to 96 weeks. Thirteen studies reported results at 37–52 weeks after TNFi discontinuation, and 6 studies reported results at 24–36 weeks. The proportion of patients with sustained remission/LDA after TNFi discontinuation varied widely (Table 1).

In the pooled analysis, 58% had DAS28 < 3.2 and 52% had DAS28 < 2.6 at 37–52 weeks after discontinuation, with high heterogeneity among studies (Fig. 2 and Supplemental table 4).

Pooled proportions having sustained remission/low disease activity at 37–52 weeks after either discontinuation or continuation of tumor necrosis factor inhibitor treatment in induction-withdrawal studies. Circles represent the DAS28 < 3.2 outcome, squares represent the DAS28 < 2.6 outcome, and triangles represent the SDAI ≤ 3.3 outcome. Closed symbols represent tumor necrosis factor inhibitor discontinuation arms, and open symbols represent continuation arms. Error bars represent 95% confidence intervals

Only four studies reported SDAI-based results, and 40% of patients had SDAI ≤ 3.3 after discontinuation. The proportion remaining in remission/LDA was therefore lower with more stringent definitions of remission. At 24–36 weeks after TNFi discontinuation, 36% of patients maintained DAS28 < 3.2, 73% had DAS28 < 2.6, and 12% had SDAI ≤ 3.3 (Supplemental table 4).

The double-blind controlled trials were rated as having a low or moderate risk of bias, while the open-label trial was rated as having a high risk of bias (Supplemental Fig. 1). Seven observational studies were judged as having a serious risk of bias (Supplemental Fig. 2). In the sensitivity analysis, pooled results were similar when only studies with low or moderate risk of bias were examined (Fig. 2 and Supplemental table 4).

We explored potential heterogeneity by disease activity, duration of RA, and study design among the 9 studies that reported DAS28 < 2.6 outcomes at 37–52 weeks. Among the six studies that required DAS28 < 2.6 at the time of discontinuation [23, 27, 28, 32, 36, 39], the proportion with DAS28 < 2.6 at follow-up 1 year later was 58% (95% CI 33, 82), compared to 42% (95% CI 20, 67) among the three studies that required DAS28 < 3.2 at TNFi discontinuation [22, 24, 26] (p = 0.42). Among the six studies in early RA [22, 23, 26,27,28, 32], the pooled proportion with DAS28 < 2.6 at follow-up was 63% (95% CI 42, 82), compared to 32% (95% CI 17, 49) in three studies in established RA [24, 36, 39] (p = 0.05). Among the five controlled trials [22,23,