Received：March 12, 2015, Revised：June 4, 2015, Accepted：June 5, 2015
Corresponding to：Yong-Gil Kim, Division of Rheumatology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea. E-mail : [email protected]
*The first two authors contributed equally to this work.
pISSN: 2093-940X, eISSN: 2233-4718
Copyright ⓒ 2015 by The Korean College of Rheumatology. All rights reserved.
This is a Free Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.
The Incidence of Uveitis in Ankylosing Spondylitis Patients Undergoing Tumor Necrosis Factor Inhibiting Therapy in Korea
Bon San Koo1*, Seokchan Hong2*, You Jae Kim2, Chang-Keun Lee2, Bin Yoo2, Yong-Gil Kim2
1Division of Rheumatology, Department of Internal Medicine, Konkuk University Chungju Hospital, Konkuk University College of Medicine, Chungju, 2Division of Rheumatology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Objective. The purpose of this study is to evaluate the outcome of uveitis in ankylosing spondylitis (AS) during tumor necrosis factor (TNF)-inhibiting therapy and to compare the incidence rate of uveitis in infliximab, adalimumab, and etanercept.
Methods. A retrospective evaluation was performed in AS patients who had started TNF-inhibiting therapy from June 2003 to June 2011. The clinical characteristics of patients with documented uveitis were evaluated. Results. Among 316 patients treated with TNF inhibitor, 26 patients (8%) had experienced uveitis during TNF-inhibiting therapy. Among them, 15 patients were treated with etanercept, eight with adalimumab, and three with infliximab. The overall incidence rate of uveitis flare during therapy with TNF inhibitor was 46 per 1,000 person-years (pys) (95% confidence interval [CI], 32 to 64). The incidence rate did not differ between TNF inhibitors, with 54/1,000 pys (95% CI, 34 to 81) for etanercept, 46/1,000 pys (95% CI, 21 to 87) for adali- mumab, and 22/1,000 pys (95% CI, 5 to 64) for infliximab. Fourteen patients experienced a first episode of uveitis. The overall incidence rate of new onset-uveitis after therapy with TNF inhibitor was 19 per 1,000 pys (95% CI, 10 to 31). The incidence rate for etanercept was 24/1,000 pys (95% CI, 12 to 45); adalimumab, 15/1,000 pys (95% CI, 3 to 45); and infliximab, 7/1,000 pys (95% CI, 0 to 40). There was no statistical difference in the incidence of uveitis flare or the cumulative uveitis-free rate among the three TNF inhibitors. Conclusion. The relative rate of uveitis, including the first episode, was determined using the TNF inhibitor. However, there was no difference in the incidence rate of uveitis among the three TNF inhibitors. (J Rheum Dis 2015;22:288-292)
Key Words. Tumor necrosis factor, Ankylosing spondylitis, Uveitis
INTRODUCTION
Uveitis is the most common extra-articular manifes- tation occurring in patients with ankylosing spondylitis (AS) [1,2]. Patients with AS have a 20% to 30% chance of developing uveitis during the course of their disease, and 85% of the AS patients who experience uveitis are diag- nosed with acute anterior uveitis [1]. It generally affects men and is unilateral, painful, and self-limiting.
Tumor necrosis factor (TNF) inhibitors have been known to be effective agents in treating articular as well as extra-articular manifestations of AS. However, differ-
ing from monoclonal antibodies, concerns have been raised that etanercept may have a less protective effect on uveitis flare [3-7]. Although the pathogenic mechanisms have not yet been fully identified, a recombinant soluble receptor to TNF might be related to lack of its effect on uveitis flare or its paradoxically adverse effect of ocular inflammation.
In our study, we investigated the incidence rate of uveitis in AS patients treated with TNF inhibitors in Korea. We also compared the incidence rate of uveitis in patients treated with infliximab, adalimumab, and etanercept.
Table 1. Comparison of the clinical characteristics of AS patients treated with infliximab, adalimumab, or etanercept
Characteristic Total†
(n=316)
Infliximab (n=85)
Adalimumab (n=148)
Etanercept
(n=142) p-value
Age at the start of TNFi (yr) 36.1±11.8 36.4±11.6 36.3±11.6 36.4±12.4 0.987
Male (%) 81 77 74 83 0.189
HLA-B27 positivity (%) 95 95 94 95 0.901
AS disease duration (mo) 75.7±52.9 86.1±54.8 58.63±50.1 86.8±51.1 0.000
Duration of TNFi exposure (mo) 23.9±19.4 19.5±15.0 16.1±12.5 34.6±22.6 0.001
Body mass index (kg/m2) 24.2±3.9 23.9±3.5 24.5±4.3 24.1±4.0 0.598
Previous history of uveitis 42 (13) 6 (7) 21 (14) 15 (11) 0.252
Uveitis during TNFi therapy 26 (8) 3 (4) 8 (5) 15 (11) 0.000
Uveitis during TNFi therapy (episode) 34 (11) 3 (4) 9 (6) 22 (15) 0.004
Incidence rate of uveitis during TNFi therapy (per 1,000 pys)
46 (32∼64) 22 (5∼64) 46 (21∼87) 54 (34∼81) 0.257*
New onset of uveitis during TNFi therapy
14 (4) 1 (1) 3 (2) 10 (7) 0.029
Incidence rate of new onset of uveitis during TNFi therapy (per 1,000 pys)
19 (10∼31) 7 (0∼40) 15 (3∼45) 24 (12∼45) 0.357*
Values are presented as mean±standard deviation, percent only, number (%), or median (95% CI). AS: ankylosing spondylitis, HLA: human leukocyte antigen, TNFi: tumor necrosis factor inhibitor, CI: confidence interval, pys: person-years. *Using Poisson regression; †including 59 patients who were treated with second or third TNFi.
MATERIALS AND METHODS
We retrospectively reviewed the electronic medical re- ports (EMR) of 316 AS patients treated with TNF-inhibit- ing therapy in a tertiary care center in Korea from June 2003 to June 2011. All of the patients had been previously diagnosed as having AS which satisfied the modified New York criteria [8] and had received at least one TNF in- hibitor, including etanercept, adalimumab or infliximab, due to the lack of efficacy or the adverse effect of non-ster- oidal, anti-inflammatory drugs and disease–modifying, anti-rheumatic drugs. This study was approved by the Asan Medical Center Institutional Review Board (IRB 2013-0882).
A previous history of uveitis was evaluated at the first medical examination and it was recorded in the EMR. We defined uveitis patients as those with at least one episode of uveitis diagnosed by an ophthalmologist. Clinical data, including patient age, sex, disease duration, human leu- kocyte antigen (HLA)-B27 allele, body-mass index, and duration of TNF inhibitor exposure, were collected.
When comparing the three TNF inhibitors, the chi-square test or Kruskal-the Wallis test was performed.
The incidence rates of uveitis were calculated as the num- ber of events or patients per 1,000 person-years (pys) of follow-up with a 95% confidential interval (CI) in the in- fliximab, adalimumab, and etanercept groups. To esti-
mate the difference in the uveitis risk in the three groups, a survival analysis was performed using the Kaplan-Meier method and Cox proportional hazards model. The log-rank test was used to compare survival curves. A p＜0.05 was considered statistically significant. All stat- istical analyses were performed using Predictive Analytics Software SPSS Statistics ver. 17.0 (SPSS Inc., Chicago, IL, USA).
RESULTS
Among the 316 AS patients treated with TNF inhibitor, 42 patients (13%) experienced uveitis before TNF-in- hibiting therapy. Table 1 shows a comparison of the in- fliximab, adalimumab, and etanercept groups. Infliximab was used for 85 patients, adalimumab for 148 patients, and etanercept for 142 patients. Male predominance and high HLA-B27 positivity were similar in all of the groups.
As each TNF inhibitor was approved by Korean National Health Insurance at points in time, the exposure duration differed in each group.
In patients treated with infliximab and adalimumab, the number of patients who experienced uveitis was de- creased following their treatment, although not in those treated with etancercept. The overall incidence rate of uveitis flare in all TNF inhibitors was 46 per 1,000 pys (95% CI, 32 to 64). The incidence rate for etanercept was
Figure 1. Cumulative uveitis-free survival rate after tumor necrosis fator (TNF) inhibitors (A) in all patients and (B) in patients who had never experienced uveitis before TNF-inhibiting therapy.
54/1,000 pys (95% CI, 34 to 81) for adalimumab, 46/1,000 pys (95% CI, 21 to 87), and for infliximab, 22/1,000 pys (95% CI, 5 to 64). The incidence rate of uveitis flare did not different among the three groups even in cases of new onset.
Of the 42 patients who experienced uveitis, nine pa- tients were changed to another TNF inhibitor, i.e. five due to uveitis, three due to the lack of efficacy of axial symp- toms, and one due to an injection site reaction.
Interestingly, among the five patients who switched the TNF inhibitor due to uveitis, four patients changed etan- cercept to adalimumab and one changed etanercept to infliximab. And after alternative TNF-inhibiting therapy, they never suffered from uveitis again. Among the three patients who changed their TNF inhibitor due to its lack of efficacy, one suffered from uveitis flare after changing adalimumab to etancercept.
Fourteen patients experienced their first episode of uveitis after TNF-inhibiting therapy and which was ob- served more often in the etanercept group (10 patients) and also in the adalimumab group (three patients) and the infliximab group (one patient). The overall incidence rate of new onset uveitis after TNF-inhibiting therapy was 19 per 1,000 pys (95% CI, 10 to 31). The incidence rate for etanercept was 24/1,000 pys (95% CI, 12 to 45), that for adalimumab was 15/1,000 pys (95% CI, 3 to 45), and that for infliximab was 7/1,000 pys (95% CI, 0 to 40), respectively. The incidence rate of patients who used eta- nercept was 1.6 to 3.4 times higher than that of infliximab and adalimumab; however, there was statistically no dif- ference of incidence rate in three TNF inhibitors. The du-
ration of TNF-inhibiting therapy before the new onset of uveitis was not statistically different.
The cumulative, uveitis-free rate was analyzed in the three TNF inhibitors and there was no difference in the development of uveitis (Figure 1A). Moreover, the rate of developing uveitis in patients who had not previously ex- perienced it before starting the TNF inhibitor also did not differ between them (Figure 1B). The risk of developing uveitis and new onset of uveitis during TNF inhibiting therapy increased with treatment with adalimumab and etanercept without significant difference (Table 2). The hazard ratio adjusted for disease duration and duration of TNF inhibitor exposure was also analyzed (hazard ratio 0.9 to 3.1) and there was no significant difference.
DISCUSSION
In our AS cohort, 26 patients (8%) developed uveitis and 14 patients (4%) experienced new onset of uveitis during TNF-inhibiting therapy. Although there have been pre- vious reports regarding uveitis flare during etanercept therapy, in our study there was no difference in the rate of developing uveitis in the three TNF inhibitors.
The TNF inhibitor is a highly effective agent for control- ling the activity of AS, including extra-articular manifes- tations (EAM). The TNF inhibitor can also decrease the incidence of uveitis flare which is a major EAM of AS [9-11]. Although our study did not compare numerous episodes of uveitis flare before and after each TNF in- hibitor exposure, the number of patients who developed uveitis during TNF-inhibitor therapy was low (8%) com-
Table 2. Cox proportional hazard analysis for uveitis of ankylosing spondylitis patients treated with infliximab, adalimumab, or etanercept
Characteristic Infliximab (n=85) Adalimumab (n=148) Etanercept (n=142)
95% CI p 95% CI p
HR developing uveitis during TNFi therapy Reference 2.0 (0.5∼7.8) 0.295 1.6 (0.5∼5.8) 0.461 Adjusted HR developing uveitis during TNFi
therapy*
Reference 1.8 (0.4∼7.9) 0.429 1.7 (0.4∼6.5) 0.443 HR of new onset of uveitis Reference 2.8 (0.3∼28.2) 0.37 2.8 (0.3∼22.7) 0.336 Adjusted HR of new onset of uveitis* Reference 0.9 (0.1∼12.3) 0.98 3.1 (0.3∼27.0) 0.312 CI: confidence interval, HR: hazard ratio, TNFi: tumor necrosis factor inhibitor. *Adjusted for ankylosing spondylitis disease duration and duration of TNFi exposure.
pared to AS patients in general, who usually have a 20%
to 30% chance of developing uveitis [1]. However, some studies have reported that etanercept did not reduce the incidence of uveitis differently from that of TNF mono- clonal antibodies. Guignard et al. [11] reported a differ- ence in the efficacies of the three TNF inhibitors in 46 spondyloarthropathy patients who had at least one uvei- tis flare. They suggested that etanercept did not reduce the number of flares, whereas infliximab and adalimu- mab greatly reduced the number of flares. However, it has also been seen in AS clinical trials that etanercept is effec- tive for lowering the uveitis flare rate in AS patients [12].
Our study showed that developing a uveitis flare and the new onset of uveitis did not statistically differ in the three TNF inhibitors. However, five of our patients who were previously treated with etanercept were switched to in- fliximab or adalimumab alternatively after their uveitis flare, and after which they experienced no subsequent flare. Considering the results of previous reports related to TNF inhibitor and uveitis, these clinical experiences support the supposition that etanercept might be less ef- fective for treating uveitis compared to the other TNF inhibitors.
Etanercept is a soluble TNF receptor molecule, whereas infliximab and adalimumab are monoclonal antibodies.
Because their mechanisms of antagonizing TNF-α differ, there are pharmacodynamic and pharmacokinetic differ- ences between the TNF inhibitors that may potentially contribute to their action in different disease states [4,13,14]. This evidence suggests that the monoclonal antibodies may be more appropriate than etanercept for treating EAM, including uveitis [15]. Although our study showed that there was no difference in the uveitis flare among the three TNF inhibitors, changing from eta- nercept to a monoclonal antibody, including infliximab
and adalimumab, could be effective for preventing uveitis flare in patients experienced uveitis before.
Even if the cohort was small, our patients’ character- istics showed a male predominance and a high percentage of HLA-B27 positivity similar to that seen in other reports of AS patients who developed uveitis during TNF-inhibit- ing therapy [4,5,12,16]. In addition, most studies report- ing uveitis onset stated that the duration of TNF-in- hibitor exposure was from one to 96 months [16]. In our study, with regard to the new onset of uveitis, the mean duration of TNF-inhibiting therapy was 30.5 months and the range was four to 71 months.
Our study has several limitations. First, because of ret- rospective study in single center, small number of pa- tients and loss of follow-up might be influence the in- cidence rate of uveitis. Second, we could not determine the cause for developing uveitis during TNF-inhibiting therapy and whether it was an adverse effect or the lack of efficacy of the TNF inhibitor. Third, the physician’s pref- erence for patients, based on their age and comorbidity, could have affected the choice of TNF inhibitor.
CONCLUSION
In conclusion, a considerable proportion of the AS pa- tients experienced uveitis flare and approximately half of them developed new uveitis onset even during their treat- ment with the TNF inhibitor. Although there was no dif- ference in the uveitis flare in the three TNF inhibitors in our study, it might be helpful for patients developing uveitis during etanercept therapy to change to mono- clonal antibodies.
CONFLICT OF INTEREST
No potential conflict of interest relevant to this article was reported.
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