Introduction
Guideline | Method for reviewing and rating quality of evidence | Recommendation | Quality of evidence |
---|---|---|---|
2015 ACR Guideline for the Treatment of Rheumatoid Arthritis [3] | GRADEa methodology was used to evaluate the literature | For patients with established RA who are in remission: | Conditional recommendation |
Taper DMARD therapy | Low | ||
Taper TNF-I, non-TNF biologic or tofacitinib | Moderate to very low | ||
EULAR recommendations for the management of RA: 2013 update [6] | Most evidence came from three SLRs; provides levels of evidence, grades of recommendations, and strengths of recommendations | If a patient persists in remission after tapering glucocorticoids, then the clinician can consider tapering bDMARDs, especially if combined with a csDMARD | LoE:b 2b GoR: B SoR: 8.7 ± 1.8 Votes: 100% |
APLAR RA treatment recommendations [7] | The ADAPTE framework was used to identify and review international RA guidelines, and the AGREE II instrument was used to assess the quality of the guidelines | Tapering of bDMARDs can be considered for patients in extended remission (>12 months) | LoE: 2 Strength: B |
Methods
Search strategy
Study selection
Eligibility criteria and data extraction
Risk of bias assessment
Results
Literature search
Efficacy studies
Study citation and type | Dose of biologic | Efficacy outcome | Comments/author conclusions |
---|---|---|---|
Smolen et al. [20] PRESERVE RCT | OL: ETN50 + MTX qw for 36 wk, N = 834 then DB: ETN50 + MTX qw, n = 202 or ETN25 + MTX qw, n = 202 or PBO + MTX qw, n = 200 | LDA at wk 88: ETN50 + MTX qw: 166/201 (82.6%) ETN25 + MTX qw: 159/201 (79.1%) PBO + MTX qw: 84/197 (42.6%)
p < 0.0001, ETN25 or ETN50 vs PBO | Author conclusions: ETN standard or reduced dose plus MTX is more effective at maintaining LDA than MTX alone |
Emery et al. [15] PRIZE RCT | OL: ETN50 + MTX qw for 52 wk, N = 306 then DB for 39 wk: ETN25 + MTX qw, n = 63 or MTX qw, n = 65 or PBO, n = 65 | Sustained remission at end of DB phase: ETN25 + MTX qw: 40/63 (63%) MTX qw: 26/65 (40%) PBO: 15/65 (23%)
p = 0.009, ETN25 + MTX vs MTX
p < 0.001, ETN25 + MTX vs PBO | Author conclusions: Following early, aggressive treatment, some patients in remission or LDA may be considered for reduction or withdrawal of the biologic; patients should be closely monitored |
Mariette et al. [18] SMART RCT | RTX 1000 mg + MTX on days 1 and 15, overall population, N = 224 At wk 24: RTX 1000 mg + MTX on day 1, PP n = 51 RTX 1000 mg + MTX on days 1 and 15, PP n = 49 | Over 104 wks, the adjusted mean difference in DAS28-CRP AUC was 51.4 (95% CI −131.2 to 234). This was within the non-inferiority margin of 20% of the reference data (mean ± SD = 2218 ± 967; 20% = 444), indicating non-inferiority between the two doses | Author conclusions: For patients with a EULAR good or moderate response, decreasing the subsequent dose of RTX is non-inferior to administering the standard dose |
Keystone et al. [16] Open-label extension of RAPID 1 | 400 mg CZP q2w decreased to 200 mg q2w, N = 436 | Improvements in ACR response rates and DAS28-ESR were maintained over 192 weeks | – |
Borras-Blasco [12] Observational |
N = 24 pts with DAS28 <2.6 switched from ETN50 qw to ETN25 qw |
n = 17 pts have continued ETN25 for a median of 3.5 ± 2.5 year
n = 7 pts discontinued after 1.8 ± 1.2 year: n = 2 pts had adverse event n = 5 pts flared: 4 of these resumed ETN50 and one switched to ADA; all returned to clinical remission | Small number of patients in study Author conclusions: ETN25 may be considered in patients who have maintained remission on ETN50 for ≥1 year and have had slow worsening of structural changes. However, the appropriate patients have not been defined |
Observational | ADA Standard dose (S): n = 39 Reduced dose (R): n = 14 ETN: (S): n = 59 (R): n = 22 INF: (S): n = 16 (R): n = 2 | Remission (DAS28 <2.6) ADA (S): 41.0%, ADA (R): 64.3% ETN (S): 45.8%, ETN (R): 50.0% INF (S): 37.5%, INF (R): 50.0% LDA (DAS28 2.6–3.2) ADA (S): 20.5%, ADA (R): 7.1% ETN (S): 10.2%, ETN (R): 27.3% INF (S): 6.3%, INF (R): 0% MDA (DAS28 3.2–5.1) ADA (S): 33.3%, ADA (R): 21.4% ETN (S): 37.3%, ETN (R): 9.1% INF (S): 43.8%, INF (R): 0% HDA (DAS28 >5.1) ADA (S): 5.1%, ADA (R): 7.1% ETN (S): 6.8%, ETN (R): 13.6% INF (S): 12.5%, INF (R): 50% | Efficacy was measured at 1 visit; patients had been receiving an anti-TNF for ≥12 months; dose taper was allowed for patients in remission or LDA ≥12 months Author conclusions: For patients who have responded clinically, it is reasonable to attempt a dose decrease; controlled trials are needed to determine when the dose can be titrated and which patients are appropriate |
van den Bemt [21] Observational |
N = 18 pts decreased INF from 5 mg/kg to 3 mg/kg and were followed for 3 infusions | 16/18 successfully down-titrated 1/18 had persistent flare following first low-dose infusion. The flare subsided after the INF dose was increased 1/18 discontinued due to adverse event | Small number of patients in study; three infusions may not allow enough time to assess progression of RA activity Author conclusions: Most patients can decrease the dose of INF from 5 mg/kg to 3 mg/kg; the DAS28 score should be monitored |
van der Maas [22] Observational |
N = 51 pts attempted down-titration of INF. From 3 mg/kg dose decreased by 25% every 8–12 wk for 1 year until discontinued or disease flare | 23/51 (45%) successfully down-titrated: 3 decreased by 25% 12 decreased by 50% 8 decreased by 75% 8/51 (16%) were able to stop INF 20/51 (39%) failed down-titration due to flare | Author conclusions: Most patients with stable LDA can decrease or discontinue INF |
TNF inhibitors
Rituximab
Economic outcomes
Discussion
1. A homogeneous patient population with similar levels of disease activity, duration of disease, and prior use of DMARDs and biologics |
2. An established definition of disease flare |
3. A clear statement on how improvement or relapse is being measured |
4. Established definitions of low disease activity, remission, moderate disease activity, partial remission, high disease activity, and/or relapse |
5. A statistical comparison of the efficacy of the standard dose and the titrated dose |
6. Safety and pharmacoeconomic data |