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Abstract
Objective
Rheumatoid arthritis (RA) patients suffer from an increased risk of herpes zoster (HZ) partially due to immunosuppressant medications. This study investigated HZ in RA patients treated with biologic disease-modifying antirheumatic drugs (bDMARDs), as compared with conventional DMARDs (cDMARDs).
Methods
This retrospective case series study assembled record information of 277 RA patients who received bDMARDs after failure of at least one cDMARDs at Seoul National University Hospital between August 2003 and February 2015. Following capture of baseline information and identification of HZ episodes, crude HZ incidence rates per 100 patient-years (95% confidence intervals) were calculated.
Results
For 718 treatment courses, 277 (38.6%) comprised cDMARDs, 66 (9.2%) infliximab, 175 (24.4%) etanercept, 95 (13.2%) adalimumab, 9 (1.3%) golimumab, 41 (5.7%) rituximab, 31 (4.3%) abatacept, and 24 (3.3%) tocilizumab. There were 37 HZ episodes, 16 during cDMARD treatment courses, and 21 accompanying bDMARDs, two with infliximab, eight with etanercept, five with adalimumab, and three each with rituximab and abatacept. The crude HZ incidence rate per 100 patient-years was 2.4 (1.4∼3.9) for cDMARDs, 2.2 (0.3∼7.9) for infliximab, 1.8 (0.8∼3.6) for etanercept, 3.7 (1.2∼8.4) for adalimumab, 3.9 (0.8∼11.0) for rituximab, and 8.5 (1.8∼23.1) for abatacept.
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Table 1.
Baseline characteristics of study patients at the time point of RA diagnosis
| Variable | Patient (n=277) |
|---|---|
| Age at RA diagnosis (yr) | 46.8 (13.6) |
| Sex (female), n (%) | 596 (83.0) |
| Underlying disease, n (%) | |
| Diabetes milletus | 75 (10.5) |
| Hypertension | 198 (27.7) |
| Malignancy | 32 (4.5) |
| Laboratory findings∗ | |
| RF, titer (IU/mL) (n=273) | 80.4 (99.2) |
| Anti-CCP antibody, titer (IU/mL) (n=289) | 124.2 (166.8) |
| ESR (mm/h) (n=253) | 49.4 (34.7) |
| CRP (mg/dL) (n=271) | 2.4 (4.1) |
| Conventional DMARD after RA diagnosis, n (%) | |
| Methotrexate | 201 (75.0) |
| Leflunomide | 46 (17.2) |
| Hydroxychloroquine | 126 (47.0) |
| Sulfasalazine | 88 (32.8) |
| Corticosteroids | 215 (80.2) |
| Prednisolone, dose* (mg/d) | 5.4 (4.5) |
Table 2.
Comparison of characteristics and demographics at the time point of starting between cDMARD and bDMARD treatment period
| Variable | cDMARDs period (n = 277) |
bDMARDs (post-cDMARDs period) |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Total bDMARDs (n = 441) | Anti-TNF α antibodies∗ (n = 170) | Infliximab (n = 66) | Adalimumab (n = 95) | Golimumab (n = 9) | Etanercept (n= 175) | Rituximab (n=41) | Abatacept (n = 31) | Tocilizumab (n = 24) | ||
| Age (yr) | 49.7 (12.7) | 52.9 (13.2) | 53.4 (13.0) | 56.2 (12.4) | 51.4 (13.3) | 53.7 (10.7) | 51.8 (12.8) | 55.1 (12.4) | 51.8 (14.3) | 54.6 (18.0) |
| Sex (female), n (%) | 229 (82.7) | 367 (83.2) | 145 (85.3) | 57 (86.4) | 80 (84.2) | 8 (88.9) | 144 (82.3) | 34 (82.9) | 26 (83.9) | 18 (75.0) |
| Treatment duration (yr) | 2.4 (2.3) | 1.8 (1.9) | 1.4 (1.5) | 1.4 (1.4) | 2.5 (2.3) | 1.4 (1.6) | 1.2 (1.4) | 1.9 (1.6) | 1.1 (1.2) | 0.8 (0.5) |
| Laboratory findings | ||||||||||
| ESR (mm/h) | 49.4 (34.7) | 56.5 (28.7) | 54.1 (26.8) | 55.2 (28.4) | 54.5 (26.5) | 41.5 (11.3) | 57.8 (28.7) | 71.5 (32.3) | 43.5 (23.7) | 54.4 (30.0) |
| CRP (mg/dL) | 2.4 (4.1) | 2.6 (2.8) | 2.2 (2.5) | 2.4 (2.6) | 2.2 (2.4) | 0.6 (0.86) | 2.9 (3.1) | 3.9 (3.6) | 1.8 (1.9) | 2.0(1.8) |
| Concomitant cDMARD, n (%) | ||||||||||
| Methotrexate | 201 (75.0) | 289 (65.5) | 123 (72.4) | 50 (75.8) | 68 (71.6) | 5 (55.6) | 113 (64.6) | 25 (61.0) | 15 (48.4) | 12 (50.0) |
| Leflunomide | 46 (17.2) | 28 (6.4) | 14 (8.2) | 8 (12.1) | 6 (6.3) | 0 (0) | 10 (5.7) | 3 (7.3) | 1 (3.2) | 0 (0) |
| Hydroxychloroquine | 126 (47.0) | 41 (9.3) | 12 (7.1) | 7 (10.6) | 5 (5.3) | 0 (0) | 24 (13.7) | 3 (7.3) | 2 (6.5) | 0 (0) |
| Sulfasalazine | 88 (32.8) | 40 (9.1) | 9 (5.3) | 4 (6.1) | 5 (5.3) | 0 (0) | 22 (12.6) | 8 (19.5) | 1 (3.2) | 0 (0) |
| Prednisolone | 215 (80.2) | 378 (85.7) | 147 (86.5) | 63 (95.5) | 80 (84.2) | 4 (44.4) | 149 (85.1) | 37 (90.2) | 27 (87.1) | 18 (75.0) |
| Prednisolone, dose∗ (mg/d) | 5.4 (4.5) | 5.3 (3.3) | 5.2 (3.1) | 6.1 (2.8) | 4.7 (3.0) | 2.1 (3.4) | 5.0 (3.0) | 6.7 (4.4) | 5.7 (4.2) | 4.7 (3.5) |
Values are presented as mean (standard deviation) or number (%). n: the number of treatment episodes receiving cDMARD and/or bDMARD therapies. cDMARD: conventional disease-modifying antirheumatic drug, bDMARD: biologic disease-modifying antirheumatic drug, TNF: tumor necrosis factor, ESR: erythrocyte sedimentation rate, CRP: C-reactive protein.
Table 3.
Crude incidence rates of herpes zoster events per 100 patient-years
| Treatment | Observed patient-years | HZ cases | Crude incidence rates (95% CI) |
|---|---|---|---|
| cDMARDs (n=277) | 662.1 | 16 | 2.4 (1.4∼3.9) |
| bDMARDs (n=441) | 808.1 | 21 | 2.6 (1.6∼4.0) |
| Anti-TNFα antibodies* (n=170) | 236.9 | 7 | 2.9 (2.2∼6.0) |
| Infliximab (n=66) | 89.8 | 2 | 2.2 (0.3∼7.9) |
| Adalimumab (n=95) | 135.9 | 5 | 3.7 (1.2∼8.4) |
| Golimumab (n=9) | 11.2 | 0 | 0.0 (0∼28.5) |
| Etanercept (n=175) | 440.3 | 8 | 1.8 (0.8∼3.6) |
| Rituximab (n=41) | 77.1 | 3 | 3.9 (0.8∼11.0) |
| Abatacept (n=31) | 35.5 | 3 | 8.5 (1.8∼23.1) |
| Tocilizumab (n=24) | 18.3 | 0 | 0.0 (0∼18.5) |
Table 4.
Clinical characteristics of herpes zoster cases in bDMARD users
| Patient no. | Age (yr) | Sex | Disease duration at HZ occurrence (yr) | Biologics | MTX (mg/wk) | PD*(mg/d) | N'th biologics at HZ occurrence | Total number of biologics use |
|---|---|---|---|---|---|---|---|---|
| 1 | 39 | F | 7.2 | ETA | 10 | 1.25 | 1 | 2 |
| 2 | 78 | F | 9.0 | ADA | 12.5 | 0 | 2 | 4 |
| 3 | 54 | F | 1.4 | RTX | 0 | 5 | 2 | 2 |
| 4 | 45 | F | 4.4 | ADA | 15 | 0 | 1 | 3 |
| 5 | 52 | F | 7.3 | ABT | 15 | 0 | 2 | 3 |
| 6 | 57 | F | 9.1 | IFX | 15 | 2.5 | 1 | 1 |
| 7 | 50 | F | 18.3 | ETA | 17.5 | 2.5 | 1 | 2 |
| 8 | 56 | F | 7.8 | RTX | 0 | 5 | 2 | 2 |
| 9 | 37 | F | 14.8 | ETA | 15 | 5 | 1 | 1 |
| 10 | 41 | F | 12.4 | ETA | 0 | 0 | 1 | 1 |
| 11 | 42 | F | 12.7 | ETA | 0 | 0 | 1 | 1 |
| 12 | 51 | F | 1.1 | ADA | 15 | 5 | 1 | 2 |
| 13 | 59 | F | 2.2 | ETA | 0 | 5 | 1 | 1 |
| 14 | 66 | M | 2.1 | ETA | 10 | 2.5 | 1 | 1 |
| 15 | 74 | F | 12.1 | IFX | 15 | 5 | 2 | 2 |
| 16 | 75 | F | 18.0 | ADA | 12.5 | 5 | 1 | 1 |
| 17 | 42 | F | 8.3 | ETA | 0 | 2.5 | 2 | 2 |
| 18 | 56 | F | 13.3 | ABT | 0 | 0 | 2 | 2 |
| 19 | 65 | F | 22.2 | RTX | 12.5 | 5 | 3 | 3 |
| 20 | 73 | F | 3.1 | ABT | 0 | 5 | 2 | 2 |
| 21 | 51 | F | 2.1 | ADA | 15 | 1.5 | 1 | 1 |
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