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.
REFERENCES
1. Geraldino-Pardilla L, Bathon JM. Management of rheumatoid arthritis: synovitis. Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, editors. Hochberg Rheumatology. 6th ed.Philadelphia: Elsevier;2015. p. 802–8.
2. Law SC, Street S, Yu CH, Capini C, Ramnoruth S, Nel HJ, et al. T-cell autoreactivity to citrullinated autoantigenic peptides in rheumatoid arthritis patients carrying HLA-DRB1 shared epitope alleles. Arthritis Res Ther. 2012; 14:R118.
3. Mitchell DM, Spitz PW, Young DY, Bloch DA, McShane DJ, Fries JF. Survival, prognosis, and causes of death in rheumatoid arthritis. Arthritis Rheum. 1986; 29:706–14.
4. Wolfe F, Mitchell DM, Sibley JT, Fries JF, Bloch DA, Williams CA, et al. The mortality of rheumatoid arthritis. Arthritis Rheum. 1994; 37:481–94.
5. Symmons DP, Jones MA, Scott DL, Prior P. Longterm mortality outcome in patients with rheumatoid arthritis: early presenters continue to do well. J Rheumatol. 1998; 25:1072–7.
6. Hayward AR, Herberger M. Lymphocyte responses to varicella zoster virus in the elderly. J Clin Immunol. 1987; 7:174–8.
7. Cohen JI. Clinical practice: Herpes zoster. N Engl J Med. 2013; 369:255–63.
8. Smitten AL, Choi HK, Hochberg MC, Suissa S, Simon TA, Testa MA, et al. The risk of herpes zoster in patients with rheumatoid arthritis in the United States and the United Kingdom. Arthritis Rheum. 2007; 57:1431–8.
9. Schmajuk G, Trivedi AN, Solomon DH, Yelin E, Trupin L, Chakravarty EF, et al. Receipt of disease-modifying antirheumatic drugs among patients with rheumatoid arthritis in Medicare managed care plans. JAMA. 2011; 305:480–6.
10. Wolfe F, Michaud K, Chakravarty EF. Rates and predictors of herpes zoster in patients with rheumatoid arthritis and non-inflammatory musculoskeletal disorders. Rheumatology (Oxford). 2006; 45:1370–5.
11. McDonald JR, Zeringue AL, Caplan L, Ranganathan P, Xian H, Burroughs TE, et al. Herpes zoster risk factors in a national cohort of veterans with rheumatoid arthritis. Clin Infect Dis. 2009; 48:1364–71.
12. Veetil BM, Myasoedova E, Matteson EL, Gabriel SE, Green AB, Crowson CS. Incidence and time trends of herpes zoster in rheumatoid arthritis: a population-based cohort study. Arthritis Care Res (Hoboken). 2013; 65:854–61.
13. Winthrop KL, Baddley JW, Chen L, Liu L, Grijalva CG, Delzell E, et al. Association between the initiation of antitumor necrosis factor therapy and the risk of herpes zoster. JAMA. 2013; 309:887–95.
14. Sakai R, Komano Y, Tanaka M, Nanki T, Koike R, Nagasawa H, et al. Time-dependent increased risk for serious infection from continuous use of tumor necrosis factor antagonists over three years in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012; 64:1125–34.
15. Winthrop KL, Yamanaka H, Valdez H, Mortensen E, Chew R, Krishnaswami S, et al. Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis. Arthritis Rheumatol. 2014; 66:2675–84.
16. Yun H, Xie F, Delzell E, Chen L, Levitan EB, Lewis JD, et al. Risks of herpes zoster in patients with rheumatoid arthritis according to biologic disease-modifying therapy. Arthritis Care Res (Hoboken). 2015; 67:731–6.
17. Antonelli MA, Moreland LW, Brick JE. Herpes zoster in patients with rheumatoid arthritis treated with weekly, low-dose methotrexate. Am J Med. 1991; 90:295–8.
18. Strangfeld A, Listing J, Herzer P, Liebhaber A, Rockwitz K, Richter C, et al. Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. JAMA. 2009; 301:737–44.
19. Galloway JB, Mercer LK, Moseley A, Dixon WG, Ustianowski AP, Helbert M, et al. Risk of skin and soft tissue infections (including shingles) in patients exposed to anti-tumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2013; 72:229–34.
20. Serac G, Tubach F, Mariette X, Salmon-Céron D, Ravaud P, Lioté F, et al. Risk of herpes zoster in patients receiving an-ti-TNF-α in the prospective French RATIO registry. J Invest Dermatol. 2012; 132:726–9.
21. Mélet J, Mulleman D, Goupille P, Ribourtout B, Watier H, Thibault G. Rituximab-induced T cell depletion in patients with rheumatoid arthritis: association with clinical response. Arthritis Rheum. 2013; 65:2783–90.
22. Lavielle M, Mulleman D, Goupille P, Bahuaud C, Sung HC, Watier H, et al. Repeated decrease of CD4+ T-cell counts in patients with rheumatoid arthritis over multiple cycles of rituximab treatment. Arthritis Res Ther. 2016; 18:253.
23. Schiff M, Weinblatt ME, Valente R, van der Heijde D, Citera G, Elegbe A, et al. Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: two-year efficacy and safety findings from AMPLE trial. Ann Rheum Dis. 2014; 73:86–94.
Table 1.
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.
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.
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.
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 |