Literature search and study characteristics
The details of the search program in this study are shown in Fig. 1. In total, 5800 articles were retrieved from PubMed, Embase, and the Cochrane Library after the initial implementation of the search strategy, and 3581 remained after duplicates were removed. After screening the titles and abstracts, 308 articles remained. Ultimately, 28 studies with 14500 randomized RA patients met the eligibility criteria of the meta-analysis. Among these studies, efficacy was evaluated after treatment with jakinibs, including baricitinib (5 trials) [19–23], decernotinib (2 trials) [24, 25], filgotinib (3 trials) [26–28], peficitinib (3 trials) [29–31], tofacitinib (10 trials) [32–41], and upadacitinib (5 trials) [42–46]. In these trials, most RA patients were treated with jakinib monotherapy or jakinibs in combination with DMARDs, especially methotrexate, in the treatment arms and placebo with or without DMARDs in the control arms; patients received methotrexate monotherapy in the control arms in only one study [37]. The characteristics of the selected trials and Jadad scores are summarized in Table 1.
Table 1
Baseline study characteristics of randomized, placebo-controlled double-blinded trials of Jakinibs in rheumatoid arthritis.
Author (trial name) | Year | Phase | No. of centers | Randomised subjects | Jakinibs regimen | Jakinibs dosage | Control | Time (wk) | Jadad score |
Baricitinib (JAK-1, 2) | | | | | | | | | |
Dougados (RA-BUILD) | 2017 | III | 182 | 684 | Baricitinib + MTX | 2 and 4 mg qd | PLA + MTX | 12, 24 | 5 |
Fleischmann (RA-BEGIN) | 2017 | III | 198 | 588 | Baricitinib + MTX | 4 mg qd | PLA + MTX | 24 | 5 |
Genovese (RA-BEACON) | 2016 | III | 178 | 527 | Baricitinib + MTX | 2 and 4 mg qd | PLA + MTX | 12, 24 | 5 |
Keystone | 2015 | IIb | 69 | 301 | Baricitinib + MTX | 1, 2, 4 and 8 mg qd | PLA + MTX | 12 | 4 |
Taylor (RA-BEAM) | 2017 | III | 281 | 1307 | Baricitinib + MTX | 4 mg qd | PLA + MTX | 12, 24 | 5 |
Decernotinib (JAK-3) | | | | | | | | | |
Fleischmann and Damjanov | 2015 | IIa | 54 | 206 | Decernotinib + 1 DMARDs | 25, 50, 100, or 150 mg bid | PLA + 1 DMARDs | 12 | 5 |
Genovese and van Vollenhoven | 2016 | IIb | 103 | 359 | Decernotinib + MTX | 100, 150 or 200 mg qd; 100 mg bid | PLA + MTX | 12, 24 | 4 |
Filgotinib (JAK-1) | | | | | | | | | |
Genovese (FINCH 2) | 2019 | III | 114 | 449 | Filgotinib + 1–2 DMARDs | 100, or 200 mg qd | PLA + 1–2 DMARDs | 12 | 5 |
Kavanaugh (DARWIN 2) | 2016 | IIb | 59 | 287 | Filgotinib | 50, 100, or 200 mg qd | PLA | 12 | 5 |
Westhovens (DARWIN 1) | 2017 | IIb | 106 | 599 | Filgotinib | 50, 100, or 200 mg qd; 25, 50, or 100 mg bid | PLA | 12, 24 | 4 |
Peficitinib (JAK-1, 3) | | | | | | | | | |
Kivitz | 2017 | IIb | 43 | 379 | Peficitinib + MTX | 25, 50, 100, or 150 mg qd | PLA + MTX | 12 | 3 |
Takeuchi (RAJ4) | 2019 | III | 161 | 519 | Peficitinib + MTX | 100, or 150 mg qd | PLA + MTX | 12 | 5 |
Takeuchi and Tanaka | 2016 | IIb | 43 | 281 | Peficitinib | 25, 50, 100, or 150 mg qd | PLA | 12 | 4 |
Tofacitinib (JAK-1, 3) | | | | | | | | | |
Burmester (ORAL Step) | 2013 | III | 82 | 399 | Tofacitinib + MTX | 5, 10 mg bid | PLA + MTX | 12 | 5 |
Fleischmann (ORAL Solo) | 2012 | III | 94 | 611 | Tofacitinib | 5, 10 mg bid | PLA | 12 | 5 |
Fleischmann and Cutolo | 2012 | IIb | 63 | 386 | Tofacitinib | 1, 3, 5, 10, 15 mg bid | PLA | 12, 24 | 4 |
Kremer (ORAL Sync) | 2013 | III | 114 | 795 | Tofacitinib + ≥ 1 DMARDs | 5, 10 mg bid | PLA + ≥ 1 DMARDs | 12 | 5 |
Kremer and Cohen | 2012 | IIb | 72 | 509 | Tofacitinib + MTX | 1, 3, 5, 10, 15 mg bid; 20 mg qd | PLA + MTX | 12 | 5 |
Lee | 2014 | III | 151 | 958 | Tofacitinib | 5, 10 mg bid | MTX | 24, 48, 96 | 4 |
Tanaka and Suzuki | 2011 | II | 19 | 140 | Tofacitinib + MTX | 1, 3, 5, 10 mg bid | PLA + MTX | 12 | 4 |
Tanaka and Takeuchi | 2015 | II | 47 | 318 | Tofacitinib | 1, 3, 5, 10, 15 mg bid | PLA | 12 | 4 |
van der Heijde (ORAL Scan) | 2013 | III | 111 | 797 | Tofacitinib + MTX | 5, 10 mg bid | PLA + MTX | 24 | 5 |
van Vollenhoven (ORAL Standard) | 2012 | III | 115 | 717 | Tofacitinib + MTX | 5, 10 mg bid | PLA + MTX | 24 | 5 |
Upadacitinib (JAK-1) | | | | | | | | | |
Burmester (SELECT-NEXT) | 2018 | III | 150 | 661 | Upadacitinib | 15, 30 mg qd | PLA | 12 | 5 |
Genovese (BALANCE 2) | 2016 | IIb | 63 | 300 | Upadacitinib | 3, 6, 12, or 18 mg bid, or 24 mg qd | PLA | 12 | 5 |
Genovese (SELECT-BEYOND) | 2018 | III | 153 | 499 | Upadacitinib | 15, 30 mg qd | PLA | 12 | 5 |
Kremer (BALANCE 1) | 2016 | IIb | 123 | 276 | Upadacitinib | 3, 6, 12, or 18 mg bid | PLA | 12 | 4 |
Smolen (SELECT-MONOTHERAPY) | 2019 | III | 138 | 648 | Upadacitinib + MTX | 15, 30 mg qd | PLA + MTX | 14 | 5 |
JAK; Janus kinase; MTX, methotrexate; DMARDs, disease-modifying antirheumatic drugs; PLA, Placebo. |
Overall efficacy
Efficacy outcomes for all included studies are summarized in Table 2. Twenty-four trials with a total of 10,923 patients (7,885 RA patients treated with jakinibs and 3,038 controls) assessed the efficacy of jakinibs in RA patients at week 12. A pooled analysis demonstrated that treatment with jakinibs was associated with improvement in the clinical response of ACR20 (OR = 3.79, 95% CI 3.14–4.59, P < 0.001, χ2 = 5.84, I2 = 14.3%), ACR50 (OR = 3.83, 95% CI 3.29–4.46, P < 0.001, χ2 = 25.06, I2 = 24%), and ACR70 (OR = 4.63, 95% CI 3.61–5.95, P < 0.001, χ2 = 25.97, I2 = 27%) compared to control treatment (online supplementary figures S1). At week 24, 10 trials focusing on the efficacy of jakinib treatment in RA patients revealed that jakinib treatment also significantly improved the clinical response of ACR20 (OR = 3.08, 95% CI 2.49–3.80, P < 0.001, χ2 = 29.07, I2 = 66%), ACR50 (OR = 3.46, 95% CI 2.74–4.37, P < 0.001, χ2 = 21.87, I2 = 59%), and ACR70 (OR = 3.96, 95% CI 3.11–5.05, P < 0.001, χ2 = 12.75, I2 = 29%) compared with control treatment (online supplementary figure S2). The subgroup analysis based on different types of jakinibs illustrated that only peficitinib treatment had no impact on improvement in ACR50 (OR = 3.32, 95% CI 0.93–11.89, P = 0.06, χ2 = 17.86, I2 = 89%) or ACR70 (OR = 3.69, 95% CI 0.93–14.59, P = 0.06, χ2 = 8.17, I2 = 76%) at week 12. Heterogeneity testing showed a moderate degree of heterogeneity, with I2 > 85% (Phetero<0.05). Publication bias was evaluated by a funnel plot, which showed no significant evidence of asymmetry (online supplementary figures S3, 4).
Table 2
Summary of the clinical efficacy outcomes of Jakinibs in rheumatoid arthritis.
Author (trial name) | Time (wk) | Dosage | ACR20 | ACR50 | ACR70 |
Baricitinib | | | | | |
Dougados (RA-BUILD) | 12 | Placebo | 90/228 (39.5) | 29/228 (12.7) | 7/228 (3.1) |
| | 2 mg qd | 151/229 (65.9) | 77/229 (33.6) | 41/229 (17.9) |
| | 4 mg qd | 140/227 (61.7) | 76/227 (33.5) | 41/227 (18.1) |
| 24 | Placebo | 96/228 (42.1) | 49/228 (21.5) | 18/228 (7.9) |
| | 2 mg qd | 140/229 (61.1) | 95/229 (41.5) | 58/229 (25.3) |
| | 4 mg qd | 148/227 (65.2) | 100/227 (44.1) | 55/227 (24.2) |
Fleischmann (RA-BEGIN) | 24 | Placebo | 130/210 (61.9) | 91/210 (43.3) | 45/210 (21.4) |
| | 4 mg qd | 168/215 (78.1) | 136/215 (63.3) | 85/215 (39.5) |
| 52 | Placebo | 117/210 (55.7) | 79/210 (37.6) | 53/210 (25.2) |
| | 4 mg qd | 156/215 (72.6) | 133/215 (61.9) | 99/215 (46.0) |
Genovese (RA-BEACON) | 12 | Placebo | 48/176 (27.3) | 14/176 (8.0) | 4/176 (2.3) |
| | 2 mg qd | 85/174 (48.9) | 35/174 (20.1) | 22/174 (12.6) |
| | 4 mg qd | 98/177 (55.4) | 50/177 (28.2) | 20/177 (11.3) |
| 24 | Placebo | 48/176 (27.3) | 23/176 (13.1) | 6/176 (3.4) |
| | 2 mg qd | 78/174 (44.8) | 40/174 (23.0) | 23/174 (13.2) |
| | 4 mg qd | 82/177 (46.3) | 52/177 (29.4) | 30/177 (16.9) |
Keystone | 12 | Placebo | 40/98 (40.8) | 10/98 (10.2) | 2/98 (2.0) |
| | 2 mg qd | 28/52 (53.8) | 9/52 (17.3) | 4/52 (7.7) |
| | 4 mg qd | 39/52 (75.0) | 18/52 (34.6) | 12/52 (23.1) |
Taylor (RA-BEAM) | 12 | Placebo | 196/488 (40.2) | 82/488 (16.8) | 23/488 (4.7) |
| | 4 mg qd | 339/487 (69.6) | 219/487 (45.0) | 92/487 (18.9) |
| 24 | Placebo | 179/488 (36.7) | 94/488 (19.3) | 39/488 (8.0) |
| | 4 mg qd | 360/487 (73.9) | 246/487 (50.5) | 145/487 (29.8) |
Decernotinib | | | | | |
Fleischmann and Damjanov | 12 | Placebo | 12/41 (29.3) | 3/41 (7.3) | 1/41 (2.4) |
| | 25 mg bid | 16/41 (39.0) | 7/41 (17.1) | 3/41 (7.3) |
| | 50 mg bid | 25/41 (61.0) | 13/41 (31.7) | 5/41 (12.2) |
| | 100 mg bid | 26/40 (65.0) | 15/40 (37.5) | 7/40 (17.5) |
| | 150 mg bid | 27/41 (65.9) | 20/41 (48.8) | 9/41 (22.0) |
Genovese and van Vollenhoven | 12 | Placebo | 13/71 (18.3) | 5/71 (7.0) | 2/71 (2.8) |
| | 100 mg qd | 33/71 (46.5) | 16/71 (22.5) | 7/71 (9.9) |
| | 150 mg qd | 48/72 (66.7) | 28/72 (38.9) | 8/72 (11.1) |
| | 200 mg qd | 41/72 (56.9) | 25/72 (34.7) | 7/72 (9.7) |
| | 100 mg bid | 49/72 (68.1) | 28/72 (38.9) | 16/72 (22.2) |
| 24 | Placebo | 12/71 (16.9) | 5/71 (7.0) | 2/71 (2.8) |
| | 100 mg qd | 43/71 (60.6) | 27/71 (38.0) | 12/71 (16.9) |
| | 150 mg qd | 44/72 (61.1) | 28/72 (38.9) | 13/72 (18.1) |
| | 200 mg qd | 44/72 (61.1) | 29/72 (40.3) | 11/72 (15.3) |
| | 100 mg bid | 45/72 (62.5) | 34/72 (47.2) | 18/72 (25.0) |
Filgotinib | | | | | |
Genovese (FINCH 2) | 12 | Placebo | 46/148 (31.1) | 22/148 (14.9) | 10/148 (6.8) |
| | 100 mg qd | 88/153 (57.5) | 49/153 (32.0) | 22/153 (14.4) |
| | 200 mg qd | 97/147 (66.0) | 63/147 (42.9) | 32/147 (21.8) |
| 24 | Placebo | 51/148 (34.5) | 28/148 (18.9) | 12148 (8.1) |
| | 100 mg qd | 84/153 (54.9) | 54/153 (35.3) | 31/153 (20.3) |
| | 200 mg qd | 102/147 (69.4) | 67/147 (45.6) | 47/147 (32.0) |
Kavanaugh (DARWIN 2) | 12 | Placebo | 21/72 (29.2) | 8/72 (11.1) | 2/72 (2.8) |
| | 50 mg qd | 48/72 (66.7) | 25/72 (34.7) | 6/72 (8.3) |
| | 100 mg qd | 46/70 (65.7) | 26/70 (37.1) | 13/70 (18.6) |
| | 200 mg qd | 50/69 (72.5) | 30/69 (43.5) | 9/69 (13.0) |
Westhovens (DARWIN 1) | 12 | Placebo | 38/86 (44.2) | 13/86 (15.1) | 7/86 (8.1) |
| | 50 mg qd | 46/82 (56.1) | 27/82 (32.9) | 13/82 (15.9) |
| | 100 mg qd | 54/85 (63.5) | 32/85 (37.6) | 18/85 (21.2) |
| | 200 mg qd | 59/86 (68.6) | 37/86 (43.0) | 21/86 (24.4) |
| | 25 mg bid | 49/86 (57.0) | 24/86 (27.9) | 12/86 (14.0) |
| | 50 mg bid | 51/85 (60.0) | 29/85 (34.1) | 16/85 (18.8) |
| | 100 mg bid | 66/84 (78.6) | 46/84 (54.8) | 26/84 (31.0) |
| 24 | Placebo | 36/86 (41.9) | 14/86 (16.3) | 8/86 (9.3) |
| | 50 mg qd | 45/82 (54.9) | 29/82 (35.4) | 18/82 (22.0) |
| | 100 mg qd | 52/85 (61.2) | 40/85 (47.1) | 28/85 (32.9) |
| | 200 mg qd | 63/86 (73.3) | 43/86 (50.0) | 25/86 (29.1) |
| | 25 mg bid | 48/86 (55.8) | 30/86 (34.9) | 18/86 (20.9) |
| | 50 mg bid | 51/85 (60.0) | 30/85 (35.3) | 20/85 (23.5) |
| | 100 mg bid | 67/84 (79.8) | 46/84 (54.8) | 33/84 (39.3) |
Peficitinib | | | | | |
Kivitz | 12 | Placebo | 32/72 (44.4) | 19/72 (26.4) | 8/72 (11.1) |
| | 25 mg qd | 29/66 (43.9) | 12/66 (18.2) | 6/66 (9.1) |
| | 50 mg qd | 48/78 (61.5) | 26/78 (33.3) | 12/78 (15.4) |
| | 100 mg qd | 39/84 (46.4) | 28/84 (33.3) | 14/84 (16.7) |
| | 150 mg qd | 45/78 (57.7) | 29/78 (37.2) | 15/78 (19.2) |
Takeuchi (RAJ4) | 12 | Placebo | 37/170 (21.8) | 13/170 (7.6) | 4/170 (2.4) |
| | 100 mg qd | 102/174 (58.6) | 52/174 (29.9) | 21/174 (12.1) |
| | 150 mg qd | 112/174 (64.4) | 80/174 (46.0) | 41/174 (23.6) |
Takeuchi and Tanaka | 12 | Placebo | 6/56 (10.7) | 3/56 (5.4) | 1/56 (1.8) |
| | 25 mg qd | 13/55 (23.6) | 4/55 (7.3) | 0/55 (0.0) |
| | 50 mg qd | 18/57 (31.6) | 5/57 (8.8) | 1/57 (1.8) |
| | 100 mg qd | 30/55 (54.5) | 17/55 (30.9) | 9/55 (16.4) |
| | 150 mg qd | 38/58 (65.5) | 17/58 (29.3) | 7/58 (12.1) |
Tofacitinib | | | | | |
Burmester (ORAL Step) | 12 | Placebo | 32/131 (24.4) | 11/131 (8.4) | 2/131 (1.5) |
| | 5 mg bid | 55/132 (41.7) | 35/132 (26.5) | 18/132 (13.6) |
| | 10 mg bid | 64/133 (48.1) | 37/133 (27.8) | 14/133 (10.5) |
Fleischmann (ORAL Solo) | 12 | Placebo | 33/122 (27) | 15/122 (12.3) | 7/122 (5.7) |
| | 5 mg bid | 145/243 (59.7) | 76/243 (31.3) | 37/243 (15.2) |
| | 10 mg bid | 161/245 (65.7) | 90/245 (36.7) | 50/245 (20.4) |
Fleischmann and Cutolo | 12 | Placebo | 13/59 (22) | 6/59 (10.2) | 2/59 (3.4) |
| | 1 mg bid | 17/54 (31.5) | 6/54 (11.1) | 3/54 (5.6) |
| | 3 mg bid | 20/51 (39.2) | 12/51 (23.5) | 6/51 (11.8) |
| | 5 mg bid | 29/49 (59.2) | 18/49 (36.7) | 6/49 (12.2) |
| | 10 mg bid | 43/61 (70.5) | 27/61 (44.3) | 15/61 (24.6) |
| | 15 mg bid | 41/57 (71.9) | 29/57 (50.9) | 15/57 (26.3) |
| 24 | Placebo | 15/59 (25.4) | 6/59 (10.2) | 4/59 (6.8) |
| | 1 mg bid | 13/54 (24.1) | 4/54 (7.4) | 3/54 (5.6) |
| | 3 mg bid | 19/51 (37.3) | 14/51 (27.5) | 7/51 (13.7) |
| | 5 mg bid | 25/49 (51.0) | 17/49 (34.7) | 10/49 (20.4) |
| | 10 mg bid | 40/61 (65.6) | 27/61 (44.3) | 23/61 (37.7) |
| | 15 mg bid | 38/57 (66.7) | 31/57 (54.4) | 19/57 (33.3) |
Kremer (ORAL Sync) | 12 | Placebo | 43/159 (27.0) | N/A | N/A |
| | 5 mg bid | 235/315 (74.6) | N/A | N/A |
| | 10 mg bid | 260/318 (81.8) | N/A | N/A |
Kremer and Cohen | 12 | Placebo | 23/69 (33.3) | N/A | N/A |
| | 1 mg bid | 32/70 (45.7) | N/A | N/A |
| | 3 mg bid | 36/68 (52.9) | N/A | N/A |
| | 5 mg bid | 36/71 (50.7) | N/A | N/A |
| | 10 mg bid | 43/74 (58.1) | N/A | N/A |
| | 15 mg bid | 42/75 (56.0) | N/A | N/A |
| | 20 mg qd | 43/80 (53.8) | N/A | N/A |
Lee | 24 | Placebo | 94/186 (50.5) | 49/186 (26.3) | 22/186 (11.8) |
| | 5 mg bid | 266/373 (71.3) | 174/373 (46.6) | 141/373 (37.8) |
| | 10 mg bid | 302/397 (76.1) | 224/397 (56.4) | 101/397 (25.4) |
| 48 | Placebo | 95/186 (51.1) | 63/186 (33.9) | 28/186 (15.1) |
| | 5 mg bid | 253/373 (67.8) | 186/373 (49.9) | 142/373 (38.1) |
| | 10 mg bid | 284/397 (71.5) | 221/397 (55.7) | 114/397 (28.7) |
| 96 | Placebo | 79/186 (42.5) | 53/186 (28.5) | 28/186 (15.1) |
| | 5 mg bid | 239/373 (64.1) | 184/373 (49.3) | 128/373 (34.3) |
| | 10 mg bid | 255/397 (64.2) | 195/397 (49.1) | 149/397 (37.5) |
Tanaka and Suzuki | 12 | Placebo | 4/28 (14.3) | N/A | N/A |
| | 1 mg bid | 18/28 (64.3) | N/A | N/A |
| | 3 mg bid | 21/27 (77.8) | N/A | N/A |
| | 5 mg bid | 26/27 (96.3) | N/A | N/A |
| | 10 mg bid | 21/26 (80.8) | N/A | N/A |
Tanaka and Takeuchi | 12 | Placebo | 8/52 (15.4) | N/A | N/A |
| | 1 mg bid | 20/53 (37.7) | N/A | N/A |
| | 3 mg bid | 36/53 (67.9) | N/A | N/A |
| | 5 mg bid | 38/52 (73.1) | N/A | N/A |
| | 10 mg bid | 45/53 (84.9) | N/A | N/A |
| | 15 mg bid | 49/54 (90.7) | N/A | N/A |
van der Heijde (ORAL Scan) | 24 | Placebo | 40/160 (25) | 13/160 (8.1) | 2/160 (1.3) |
| | 5 mg bid | 165/321 (51.4) | 104/321 (32.4) | 47/321 (14.6) |
| | 10 mg bid | 195/316 (61.7) | 138/316 (43.7) | 70/316 (22.2) |
van Vollenhoven (ORAL Standard) | 24 | Placebo | 30/106 (28.3) | N/A | N/A |
| | 5 mg bid | 101/196 (51.5) | N/A | N/A |
| | 10 mg bid | 103/196 (52.6) | N/A | |
Upadacitinib | | | | | |
Burmester (SELECT-NEXT) | 12 | Placebo | 79/221 (35.7) | 33/221 (14.9) | 13/221 (5.9) |
| | 15 mg qd | 141/221 (63.8) | 84/221 (38.0) | 46/221 (20.8) |
| | 30 mg qd | 145/219 (66.2) | 94/219 (42.9) | 59/219 (26.9) |
Genovese (BALANCE 2) | 12 | Placebo | 23/50 (46) | 9/50 (18.0) | 3/50 (6.0) |
| | 3 mg bid | 31/50 (62.0) | 19/50 (38.0) | 11/50 (22.0) |
| | 6 mg bid | 34/50 (68.0) | 23/50 (46.0) | 14/50 (28.0) |
| | 12 mg bid | 40/50 (80.0) | 25/50 (50.0) | 8/50 (16.0) |
| | 18 mg bid | 32/50 (64.0) | 20/50 (40.0) | 13/50 (26.0) |
| | 24 mg qd | 37/49 (75.5) | 19/49 (38.8) | 11/49 (22.4) |
Genovese (SELECT-BEYOND) | 12 | Placebo | 48/169 (28.4) | 20/169 (11.8) | 11/169 (6.5) |
| | 15 mg qd | 106/164 (64.6) | 56/164 (34.1) | 19/164 (11.6) |
| | 30 mg qd | 93/165 (56.4) | 59/165 (35.8) | 30/165 (18.2) |
Kremer (BALANCE 1) | 12 | Placebo | 19/56 (33.9) | 9/56 (16.1) | 2/56 (3.6) |
| | 3 mg bid | 29/55 (52.7) | 13/55 (23.6) | 7/55 (12.7) |
| | 6 mg bid | 32/55 (58.2) | 20/55 (36.4) | 14/55 (25.5) |
| | 12 mg bid | 39/55 (70.9) | 23/55 (41.8) | 12/55 (21.8) |
| | 18 mg bid | 37/55 (67.3) | 21/55 (38.2) | 12/55 (21.8) |
Smolen (SELECT-MONOTHERAPY) | 14 | Placebo | 89/216 (41.2) | 32/216 (14.8) | 6/216 (2.8) |
| 15 mg qd | 148/217 (68.2) | 91/217 (41.9) | 50/217 (23.0) |
| | 30 mg qd | 153/215 (71.2) | 112/215 (52.1) | 71/215 (33.0) |
Safety profile
The safety profile of jakinibs compared to that of placebo during the placebo-controlled periods was reported in all the included trials and is summarized in Table 3. At week 12, infectious diseases were significantly increased after jakinib treatment compared with placebo (OR = 1.21, 95% CI 1.03–1.42, P = 0.02, χ2 = 11.85, I2 = 7%). The commonly reported infections were upper respiratory tract infections, nasopharyngitis, or herpes zoster infections. Apart from these, there were no significant differences between jakinibs and the placebo with regard to treatment-emergent adverse events (TEAEs) (OR = 1.11, 95% CI 1.00-1.23, P = 0.05, χ2 = 22.81, I2 = 17%), SAEs (OR = 0.97, 95% CI 0.70–1.35, P = 0.87, χ2 = 23.48, I2 = 15%), discontinuations due to adverse events, (OR = 1.02, 95% CI 0.78–1.33, P = 0.90, χ2 = 22.47, I2 = 11%), or serious infection (OR = 1.18, 95% CI 0.66–2.12, P = 0.57, χ2 = 11.39, I2 = 0%) (online supplementary figure S5). At week 24, however, an enhanced risk of both TEAEs (OR = 1.27, 95% CI 1.07–1.51, P = 0.007, χ2 = 16.23, I2 = 38%) and infectious diseases (OR = 1.47, 95% CI 1.26–1.71, P < 0.001, χ2 = 6.16, I2 = 0%) in response to jakinibs compared to placebo was observed in RA patients. In contrast, no increase in the risk of SAEs (OR = 0.84, 95% CI 0.62–1.13, P = 0.25, χ2 = 11.36, I2 = 12%), discontinuations due to adverse events (OR = 1.18, 95% CI 0.90–1.54, P = 0.23, χ2 = 8.80, I2 = 0%), or serious infection (OR = 0.92, 95% CI 0.58–1.46, P = 0.74, χ2 = 2.58, I2 = 0%) was observed in comparisons between treatment with jakinibs and treatment with placebo in these RA patients (online supplementary figure S6).
Table 3
Summary of the safety profile of Jakinibs in rheumatoid arthritis.
Author (trial name) | Time (wk) | Dosage | TEAE | SAE | Discontinuation* | Infection disease | Serious infection |
Baricitinib | | | | | | | |
Dougados (RA-BUILD) | 12 | Placebo | 133/228 (58.3) | 8/228 (3.5) | 8/228 (3.5) | 53/228 (23.2) | 3/228 (1.3) |
| | 2 mg qd | 122/229 (53.3) | 4/229 (1.7) | 7/229 (3.1) | 45/229 (19.7) | 1/229 (0.4) |
| | 4 mg qd | 135/227 (59.5) | 4/227 (1.8) | 8/227 (3.5) | 66/227 (29.1) | 2/227 (0.9) |
| 24 | Placebo | 161/228 (70.6) | 11/228 (4.8) | 10/228 (4.4) | 79/228 (34.6) | 4/228 (1.8) |
| | 2 mg qd | 154/229 (67.2) | 6/229 (2.6) | 10/229 (4.4) | 70/229 (30.6) | 2/229 (0.9) |
| | 4 mg qd | 162/227 (71.4) | 12/227 (5.3) | 12/227 (5.3) | 96/227 (42.3) | 4/227 (1.8) |
Fleischmann (RA-BEGIN) | 24 | Placebo | 136/210 (64.8) | 9/210 (4.3) | 5/210 (2.4) | 58/210 (27.6) | 3/210 (1.4) |
| 4 mg qd | 146/215 (67.9) | 8/215 (3.7) | 15/215 (7.0) | 74/215 (34.4) | 4/215 (1.9) |
| 52 | Placebo | 151/210 (71.9) | 20/210 (9.5) | 11/210 (5.2) | 80/210 (38.1) | 8/210 (3.8) |
| | 4 mg qd | 167/215 (77.7) | 17/215 (7.9) | 23/215 (10.7) | 108/215 (50.2) | 5/215 (2.3) |
Genovese (RA-BEACON) | 12 | Placebo | 96/176 (54.5) | 7/176 (4.0) | 4/176 (2.3) | 35/176 (19.9) | 3/176 (1.7) |
| 2 mg qd | 107/174 (61.5) | 3/174 (1.7) | 7/174 (4.0) | 61/174 (35.1) | 3/174 (1.7) |
| | 4 mg qd | 119/177 (67.2) | 11/177 (6.2) | 9/177 (5.1) | 48/177 (27.1) | 3/177 (1.7) |
| 24 | Placebo | 112/176 (63.6) | 13/176 (7.4) | 7/176 (4.0) | 55/176 (31.3) | 5/176 (2.8) |
| | 2 mg qd | 123/174 (70.7) | 7/174 (4.0) | 7/174 (4.0) | 76/174 (43.7) | 4/174 (2.3) |
| | 4 mg qd | 137/177 (77.4) | 18/177 (10.2) | 11/177 (6.2) | 70/177 (39.5) | 6/177 (3.4) |
Keystone | 12 | Placebo | 45/98 (45.9) | 3/98 (3.1) | 5/98 (5.1) | N/A | 0/98 (0.0) |
| | 2 mg qd | 24/52 (46.2) | 3/52 (5.8) | 1/52 (1.9) | N/A | 2/52 (3.8) |
| | 4 mg qd | 22/52 (42.3) | 0/52 (0.0) | 1/52 (1.9) | N/A | 0/52 (0.0) |
Taylor (RA-BEAM) | 24 | Placebo | 295/488 (60.5) | 22/488 (4.5) | 17/488 (3.5) | 134/488 (27.5) | 7/488 (1.4) |
| | 4 mg qd | 347/487 (71.3) | 23/487 (4.7) | 24/487 (4.9) | 176/487 (36.1) | 5/487 (1.0) |
Decernotinib | | | | | | | |
Fleischmann and Damjanov | 12 | Placebo | 19/41 (46.3) | 1/41 (2.4) | 2/41 (4.9) | 7/41 (17.1) | 0/41 (0.0) |
| 25 mg bid | 12/41 (29.3) | 0/41 (0.0) | 0/41 (0.0) | 5/41 (12.2) | 0/41 (0.0) |
| | 50 mg bid | 18/41 (43.9) | 1/41 (2.4) | 1/41 (2.4) | 5/41 (12.2) | 0/41 (0.0) |
| | 100 mg bid | 25/40 (62.5) | 5/40 (12.5) | 7/40 (17.5) | 10/40 (25.0) | 3/40 (7.5) |
| | 150 mg bid | 22/41 (53.7) | 2/41 (4.9) | 5/41 (12.2) | 8/41 (19.5) | 2/41 (4.9) |
Genovese and van Vollenhoven | 24 | Placebo | 30/71 (42.3) | 4/71 (5.6) | N/A | N/A | N/A |
| 100 mg qd | 37/71 (52.1) | 3/71 (4.2) | N/A | N/A | N/A |
| | 150 mg qd | 44/72 (61.1) | 6/72 (8.3) | N/A | N/A | N/A |
| | 200 mg qd | 49/72 (68.1) | 5/72 (6.9) | N/A | N/A | N/A |
| | 100 mg bid | 42/72 (58.3) | 7/72 (9.7) | N/A | N/A | N/A |
Filgotinib | | | | | | | |
Genovese (FINCH 2) | 12 | Placebo | 80/148 (54.1) | 4/148 (2.7) | 3/148 (2.0) | 27/148 (18.2) | 2/148 (1.4) |
| | 100 mg qd | 77/153 (50.3) | 6/153 (3.9) | 6/153 (3.9) | 29/153 (19.0) | 1/153 (0.7) |
| | 200 mg qd | 82/147 (55.8) | 4/147 (2.7) | 4/147 (2.7) | 34/147 (23.1) | 1/147 (0.7) |
| 24 | Placebo | 100/148 (67.6) | 5/148 (3.4) | 3/148 (2.0) | 38/148 (25.7) | 2/148 (1.4) |
| | 100 mg qd | 97/153 (63.4) | 8/153 (5.2) | 6/153 (3.9) | 52/153 (34.0) | 1/153 (0.7) |
| | 200 mg qd | 102/147 (69.4) | 6/147 (4.1) | 5/147 (3.4) | 53/147 (36.1) | 3/147 (2.0) |
Kavanaugh (DARWIN 2) | 12 | Placebo | 28/72 (38.9) | 1/72 (1.4) | 4/72 (5.6) | N/A | 0/72 (0.0) |
| 50 mg qd | 29/72 (40.3) | 1/72 (1.4) | 1/72 (1.4) | N/A | 1/72 (1.4) |
| | 100 mg qd | 23/70 (32.9) | 0/70 (0.0) | 0/70 (0.0) | N/A | 0/70 (0.0) |
| | 200 mg qd | 30/69 (43.5) | 3/69 (4.3) | 1/69 (1.4) | N/A | 1/69 (1.4) |
Westhovens (DARWIN 1) | 24 | Placebo | 32/56 (57.1) | 4/56 (7.1) | 2/56 (3.6) | 1/56 (1.8) | 1/56 (1.8) |
| 50 mg qd | 33/63 (52.4) | 0/63 (0.0) | 2/63 (3.2) | 4/63 (6.3) | 0/63 (0.0) |
| | 100 mg qd | 37/85 (43.5) | 4/85 (4.7) | 5/85 (5.9) | 4/85 (4.7) | 3/85 (3.5) |
| | 200 mg qd | 50/86 (58.1) | 2/86 (2.3) | 3/86 (3.5) | 7/86 (8.1) | 1/86 (1.2) |
| | 25 mg bid | 37/69 (53.6) | 1/69 (1.4) | 5/69 (7.2) | 5/69 (7.2) | 0/69 (0.0) |
| | 50 mg bid | 46/85 (54.1) | 0/85 (0.0) | 2/85 (2.4) | 7/85 (8.2) | 0/85 (0.0) |
| | 100 mg bid | 45/84 (53.6) | 3/84 (3.6) | 3/84 (3.6) | 7/84 (8.3) | 1/84 (1.2) |
Peficitinib | | | | | | | |
Kivitz | 12 | Placebo | 34/72 (47.2) | 0/72 (0.0) | 1/72 (1.4) | N/A | 0/72 (0.0) |
| | 25 mg qd | 28/66 (42.4) | 0/66 (0.0) | 0/66 (0.0) | N/A | 0/66 (0.0) |
| | 50 mg qd | 39/78 (50.0) | 0/78 (0.0) | 0/78 (0.0) | N/A | 0/78 (0.0) |
| | 100 mg qd | 40/84 (47.6) | 2/84 (2.4) | 3/84 (3.6) | N/A | 1/84 (1.2) |
| | 150 mg qd | 39/78 (50.0) | 1/78 (1.3) | 4/78 (5.1) | N/A | 1/78 (1.3) |
Takeuchi (RAJ4) | 12 | Placebo | 84/170 (49.4) | 4/170 (2.4) | 7/170 (4.1) | N/A | 0/170 (0.0) |
| | 100 mg qd | 89/174 (51.1) | 5/174 (2.9) | 5/174 (2.9) | N/A | 6/174 (3.4) |
| | 150 mg qd | 104/174 (59.8) | 3/174 (1.7) | 5/174 (2.9) | N/A | 6/174 (3.4) |
Takeuchi and Tanaka | 12 | Placebo | 36/56 (64.3) | 1/56 (1.8) | 10/56 (17.9) | 12/56 (21.4) | 0/56 (0.0) |
| | 25 mg qd | 39/55 (70.9) | 1/55 (1.8) | 7/55 (12.7) | 18/55 (32.7) | 0/55 (0.0) |
| | 50 mg qd | 37/57 (64.9) | 2/57 (3.5) | 5/57 (8.8) | 14/57 (24.6) | 0/57 (0.0) |
| | 100 mg qd | 29/55 (52.7) | 3/55 (5.5) | 6/55 (10.9) | 7/55 (12.7) | 0/55 (0.0) |
| | 150 mg qd | 39/58 (67.2) | 0/58 (0.0) | 4/58 (6.9) | 17/58 (29.3) | 0/58 (0.0) |
Tofacitinib | | | | | | | |
Burmester (ORAL Step) | 12 | Placebo | 75/132 (56.8) | 6/132 (4.5) | 7/132 (5.3) | N/A | 0/132 (0.0) |
| 5 mg bid | 71/133 (53.4) | 2/133 (1.5) | 8/133 (6.0) | N/A | 0/133 (0.0) |
| | 10 mg bid | 76/134 (56.7) | 2/134 (1.5) | 6/134 (4.5) | N/A | 0/134 (0.0) |
Fleischmann (ORAL Solo) | 12 | Placebo | 67/122 (54.9) | 6/122 (4.9) | 5/122 (4.1) | N/A | 0/122 (0.0) |
| 5 mg bid | 124/243 (51.0) | 1/243 (0.4) | 2/243 (0.8) | N/A | 0/243 (0.0) |
| | 10 mg bid | 139/245 (56.7) | 5/245 (2.0) | 6/245 (2.4) | N/A | 1/245 (0.4) |
Fleischmann and Cutolo | 24 | Placebo | 16/34 (47.1) | 2/34 (5.9) | 1/34 (2.9) | 6/34 (17.6) | 1/34 (2.9) |
| 1 mg bid | 19/37 (51.4) | 1/37 (2.7) | 4/37 (10.8) | 11/37 (29.7) | 2/37 (5.4) |
| | 3 mg bid | 18/34 (52.9) | 2/34 (5.9) | 3/34 (8.8) | 7/34 (20.6) | 0/34 (0.0) |
| | 5 mg bid | 27/49 (55.1) | 1/49 (2.0) | 1/49 (2.0) | 17/49 (34.7) | 0/49 (0.0) |
| | 10 mg bid | 36/61 (59.0) | 0/61 (0.0) | 1/61 (1.6) | 21/61 (34.4) | 0/61 (0.0) |
| | 15 mg bid | 35/57 (61.4) | 5/57 (8.8) | 3/57 (5.3) | 19/57 (33.3) | 1/57 (1.8) |
Kremer (ORAL Sync) | 12 | Placebo | 97/159 (61.0) | 6/159 (3.8) | 2/159 (1.3) | N/A | 0/159 (0.0) |
| | 5 mg bid | 166/315 (52.7) | 9/315 (2.9) | 13/315 (4.1) | N/A | 2/315 (0.6) |
| | 10 mg bid | 169/318 (53.3) | 8/318 (2.5) | 13/318 (4.1) | N/A | 4/318 (1.3) |
Kremer and Cohen | 24 | Placebo | 29/51 (56.9) | 0/51 (0.0) | 3/51 (5.9) | 3/51 (5.9) | 0/51 (0.0) |
| | 1 mg bid | 29/49 (59.2) | 1/49 (2.0) | 3/49 (6.1) | 7/49 (14.3) | 0/49 (0.0) |
| | 3 mg bid | 38/55 (69.1) | 2/55 (3.6) | 2/55 (3.6) | 11/55 (20.0) | 2/55 (3.6) |
| | 5 mg bid | 47/71 (66.2) | 4/71 (5.6) | 3/71 (4.2) | 16/71 (22.5) | 1/71 (1.4) |
| | 10 mg bid | 50/74 (67.6) | 7/74 (9.5) | 5/74 (6.8) | 13/74 (17.6) | 1/74 (1.4) |
| | 15 mg bid | 57/75 (76.0) | 6/75 (8.0) | 10/75 (13.3) | 14/75 (18.7) | 0/75 (0.0) |
| | 20 mg qd | 41/67 (61.2) | 2/67 (3.0) | 6/67 (9.0) | 13/67 (19.4) | 1/67 (1.5) |
Lee | 24 | Placebo | 147/186 (79.0) | 22/186 (11.8) | 25/186 (13.4) | N/A | 5/186 (2.7) |
| | 5 mg bid | 297/373 (79.6) | 40/373 (10.7) | 40/373 (10.7) | N/A | 11/373 (2.9) |
| | 10 mg bid | 334/397 (84.1) | 43/397 (10.8) | 41/397 (10.3) | N/A | 8/397 (2.0) |
Tanaka and Suzuki | 12 | Placebo | N/A | 0/28 (0.0) | 2/28 (7.1) | 6/28 (21.4) | 0/28 (0.0) |
| | 1 mg bid | N/A | 1/28 (3.6) | 0/28 (0.0) | 3/28 (10.7) | 0/28 (0.0) |
| | 3 mg bid | N/A | 1/27 (3.7) | 2/27 (7.4) | 8/27 (29.6) | 0/27 (0.0) |
| | 5 mg bid | N/A | 1/27 (3.7) | 4/27 (14.8) | 3/27 (11.1) | 0/27 (0.0) |
| | 10 mg bid | N/A | 2/26 (7.7) | 4/26 (15.4) | 11/26 (42.3) | 0/26 (0.0) |
Tanaka and Takeuchi | 12 | Placebo | 23/52 (44.2) | 1/52 (1.9) | 2/52 (3.8) | N/A | 0/52 (0.0) |
| | 1 mg bid | 21/53 (39.6) | 0/53 (0.0) | 0/53 (0.0) | N/A | 0/53 (0.0) |
| | 3 mg bid | 23/53 (43.4) | 3/53 (5.7) | 1/53 (1.9) | N/A | 0/53 (0.0) |
| | 5 mg bid | 29/52 (55.8) | 2/52 (3.8) | 2/52 (3.8) | N/A | 0/52 (0.0) |
| | 10 mg bid | 32/53 (60.4) | 2/53 (3.8) | 3/53 (5.7) | N/A | 0/53 (0.0) |
| | 15 mg bid | 28/54 (51.9) | 1/54 (1.9) | 0/54 (0.0) | N/A | 0/54 (0.0) |
van der Heijde (ORAL Scan) | 12 | Placebo | 73/160 (45.6) | 5/160 (3.1) | 5/160 (3.1) | N/A | 0/160 (0.0) |
| 5 mg bid | 157/321 (48.9) | 12/321 (3.7) | 15/321 (4.7) | N/A | 2/321 (0.6) |
| | 10 mg bid | 171/316 (54.1) | 10/316 (3.2) | 14/316 (4.4) | N/A | 2/316 (0.6) |
van Vollenhoven (ORAL Standard) | 12 | Placebo | 51/108 (47.2) | 2/108 (1.9) | 3/108 (2.8) | N/A | 1/108 (0.9) |
| 5 mg bid | 106/204 (52.0) | 12/204 (5.9) | 14/204 (6.9) | N/A | 3/204 (1.5) |
| | 10 mg bid | 94/201 (46.8) | 10/201 (5.0) | 10/201 (5.0) | N/A | 4/201 (2.0) |
| 24 | Placebo | 16/59 (27.1) | 2/59 (3.4) | 0/59 (0.0) | N/A | 0/59 (0.0) |
| | 5 mg bid | 7/28 (25.0) | 0/28 (0.0) | 1/28 (3.6) | N/A | 0/28 (0.0) |
Upadacitinib | | | | | | | |
Burmester (SELECT-NEXT) | 12 | Placebo | 108/221 (48.9) | 5/221 (2.3) | 7/221 (3.2) | 47/221 (21.3) | 1/221 (0.5) |
| 15 mg qd | 125/221 (56.6) | 9/221 (4.1) | 7/221 (3.2) | 64/221 (29.0) | 1/221 (0.5) |
| | 30 mg qd | 118/219 (53.9) | 6/219 (2.7) | 13/219 (5.9) | 69/219 (31.5) | 3/219 (1.4) |
Genovese (BALANCE 2) | 12 | Placebo | 13/50 (26.0) | 0/50 (0.0) | 1/50 (2.0) | 7/50 (14.0) | 0/50 (0.0) |
| 3 mg bid | 20/50 (40.0) | 0/50 (0.0) | 1/50 (2.0) | 10/50 (20.0) | 0/50 (0.0) |
| | 6 mg bid | 23/50 (46.0) | 2/50 (4.0) | 1/50 (2.0) | 7/50 (14.0) | 0/50 (0.0) |
| | 12 mg bid | 29/50 (58.0) | 1/50 (2.0) | 1/50 (2.0) | 12/50 (24.0) | 1/50 (2.0) |
| | 18 mg bid | 25/50 (50.0) | 3/50 (6.0) | 5/50 (10.0) | 11/50 (22.0) | 0/50 (0.0) |
| | 24 mg qd | 17/49 (34.7) | 2/49 (4.1) | 1/49 (2.0) | 9/49 (18.4) | 0/49 (0.0) |
Genovese (SELECT-BEYOND) | 12 | Placebo | 95/169 (56.2) | 0/169 (0.0) | 9/169 (5.3) | 51/169 (30.2) | 0/169 (0.0) |
| 15 mg qd | 91/164 (55.5) | 8/164 (4.9) | 4/164 (2.4) | 54/164 (32.9) | 1/164 (0.6) |
| | 30 mg qd | 111/165 (67.3) | 12/165 (7.3) | 15/165 (9.1) | 55/165 (33.3) | 4/165 (2.4) |
Kremer (BALANCE 1) | 12 | Placebo | 25/56 (44.6) | 2/56 (3.6) | 2/56 (3.6) | 13/56 (23.2) | 1/56 (1.8) |
| | 3 mg bid | 26/55 (47.3) | 1/55 (1.8) | 0/55 (0.0) | 11/55 (20.0) | 0/55 (0.0) |
| | 6 mg bid | 31/55 (56.4) | 2/55 (3.6) | 6/55 (10.9) | 12/55 (21.8) | 0/55 (0.0) |
| | 12 mg bid | 37/55 (67.3) | 2/55 (3.6) | 2/55 (3.6) | 22/55 (40.0) | 0/55 (0.0) |
| | 18 mg bid | 39/55 (70.9) | 1/55 (1.8) | 2/55 (3.6) | 21/55 (38.2) | 0/55 (0.0) |
Smolen (SELECT-MONOTHERAPY) | 14 | Placebo | 102/216 (47.2) | 6/216 (2.8) | 6/216 (2.8) | 57/216 (26.4) | 0/216 (0.0) |
| 15 mg qd | 103/217 (47.5) | 11/217 (5.1) | 8/217 (3.7) | 42/217 (19.4) | 1/217 (0.5) |
| | 30 mg qd | 105/215 (48.8) | 6/215 (2.8) | 6/215 (2.8) | 54/215 (25.1) | 1/215 (0.5) |
TEAE, treatment-emergent adverse event; SAE, serious adverse event; PLA, Placebo.*Discontinuations due to adverse events; N/A, not applicable. |