Decreased incidence of anterior uveitis in patients with ankylosing spondylitis treated with the anti–tumor necrosis factor agents infliximab and etanercept

Authors


Abstract

Objective

To estimate the incidence of anterior uveitis in patients with ankylosing spondylitis (AS) who underwent anti–tumor necrosis factor (anti-TNF) therapy, using data from recently performed trials.

Methods

Data from 4 placebo-controlled studies with anti-TNF agents in AS (2 with etanercept and 2 with infliximab) and 3 open-label studies were analyzed for the prestudy prevalence and the incidence of reported flares of anterior uveitis.

Results

A total of 717 patients who received treatment for anterior uveitis during the course of published clinical studies were identified by a systematic literature search using Medline. Followup information on the course of anterior uveitis was available for 397 patients. Of these, 297 were exposed to etanercept and 90 were exposed to infliximab for a total of 430 and 146.4 years, respectively. Among 190 patients who received placebo, the overall exposure was 70.5 years. The frequency of flares of anterior uveitis in the placebo group was 15.6 per 100 patient-years (95% confidence interval 7.8–27.9), while the patients treated with anti-TNF agents had a mean of only 6.8 anterior uveitis flares per 100 patient-years (P = 0.01). Flares of anterior uveitis occurred less frequently (although not significantly) in patients treated with infliximab than in patients treated with etanercept (3.4 per 100 patient-years and 7.9 per 100 patient-years, respectively).

Conclusion

Treatment of AS patients with biologic agents directed against TNFα is associated with a significant decrease in the number of anterior uveitis flares. This reduction was slightly more marked among patients treated with infliximab, but the difference was not significant.

Ankylosing spondylitis (AS) is a frequently occurring chronic inflammatory rheumatic disease that causes inflammation at diverse sites, such as the spine, peripheral joints, and entheses. The most frequently occurring extraspinal involvement is inflammation of the uvea. In fact, the prevalences reported for anterior uveitis in patients with AS range from 30% to 40% (1). Tumor necrosis factor α (TNFα) is believed to play a major role in the pathogenesis of AS and other spondylarthritides. Treatment strategies involving anti-TNF agents have recently proven rather successful (2–4). Both infliximab and etanercept have been approved for the treatment of patients with active AS, both in Europe and in the US. Based on data from trials of infliximab and etanercept, it became clear that the main symptoms of AS, i.e., inflammatory back pain, peripheral arthritis, and enthesitis, are highly responsive to this therapy. However, the data for anterior uveitis are less clear.

The aim of this study was to analyze the cumulative recent experience in terms of the incidence of anterior uveitis among patients with AS who were treated with anti-TNF agents and placebo.

PATIENTS AND METHODS

Although the total number of published reports of controlled trials with anti-TNFα agents is already quite substantial, the number of reports that describe the history of anterior uveitis or the incidence of flares during treatment is small. We performed a systematic PubMed search to identify all articles on this topic published up to October 10, 2004. The search terms used were as follows: ankylosing spondylitis, infliximab, etanercept, and incidence and prevalence of anterior uveitis. In addition, information from 2 studies was available on the basis of co-authorship (4, 5). No other data were obtained from investigators or pharmaceutical companies.

Information was collected on the number of patients included in the studies; the number of cases in which a history of anterior uveitis was reported; the cumulative exposure time to infliximab, etanercept, or placebo; the incidence of anterior uveitis flares in the treatment groups during the placebo-controlled phases; and the number of flares of anterior uveitis that occurred during the open-label phase of the studies. All data were analyzed for the different phases of the studies. Anterior uveitis was usually defined in the studies as “as diagnosed by an ophthalmologist.”

The number of flares of anterior uveitis depends on the time period of observation (exposure time). For subjects who completed the trials, these exposure times were obtained from the data in the original publications (2–4, 6–9). The exposure time for the subjects who withdrew was calculated by using the published data (2, 3, 6, 8) or by estimation, using the mean of the time period during which the withdrawal occurred (4, 9). The total exposure time was calculated by summing the observation times for every patient into person-years of followup. The number of flares that occurred during exposure to both drugs was related to the corresponding total number of available person-years of followup.

Fisher's exact test was applied to compare the proportions of patients who experienced a flare of anterior uveitis. Exact Poisson fiducial confidence limits were calculated for the anterior uveitis rates per 100 patient-years.

RESULTS

Overall, 14 references that matched the search for the prevalence and incidence of anterior uveitis in AS patients were identified by a PubMed search. Seven clinical trials included useful data on the history of anterior uveitis (5–11) (n = 717 patients). In 4 of these studies (6–9), followup data on the incidence of anterior uveitis (n = 397 patients) were additionally available.

History of anterior uveitis. The reported prevalence of anterior uveitis before the treatment period of the trial was higher among patients who received infliximab (35.6%; 146 of 410 patients) compared with the prevalence among patients who received etanercept (29.3%; 90 of 307 patients) (P = 0.08). The reported prevalences of anterior uveitis are presented in Table 1. For all studies combined, a history of anterior uveitis was reported in 236 (32.9%) of 717 patients (95% confidence interval [95% CI] 29.5–36.5). In studies with available followup data, a history of anterior uveitis was reported in 127 (32.0%) of 397 patients (95% CI 27.4–36.8) (Table 1).

Table 1. History of AU in studies that were assessed for the prevalence of pretreatment AU*
Author, year (ref.)No. of patients in study populationNo. (%) of patients with history of AU95% CI
  • *

    AU = anterior uveitis; 95% CI = 95% confidence interval.

  • Followup information was available for calculation of the incidence of AU.

  • All patients for whom followup information was available, including the 10 patients who withdrew from one study (4).

Randomized controlled trials   
 Braun et al, 2002 (8)6932 (46.4)35.1–58.0
 Brandt et al, 2003 (6)308 (26.7)14.2–44.4
 Davis et al, 2003 (9)27782 (29.6)24.5–35.2
 Van der Heijde et al, 2005 (5)27997 (34.8)29.4–40.5
Observational studies   
 Brandt et al, 2005 (3)112 (18.2)5.1–47.7
 Stone et al, 2001 (7)215 (23.8)10.6–45.1
 Temekonidis et al, 2003 (11)3010 (33.3)19.2–51.2
Total, all studies717236 (32.9)29.5–36.5
Total, studies with followup information397127 (32.0)27.4–36.8

Incidence of anterior uveitis during the placebo-controlled phase of the studies. Overall, 190 patients were initially treated with placebo. The duration of placebo therapy ranged from 6 weeks to 24 weeks. The cumulative observation time was 70.5 years. During placebo treatment, flares of anterior uveitis occurred in 11 patients, for an incidence of 15.6 per 100 patient-years (95% CI 7.8–27.9) (Table 2).

Table 2. AU flares according to type of treatment and type of study*
Agent used, type of study, author, year (ref.)No. of patientsCumulative exposure, yearsNo. of AU flaresNo. of AU flares per 100 patient-years
  • *

    AU = anterior uveitis; RCT = randomized controlled trial (double-blind, placebo-controlled); anti-TNF = anti–tumor necrosis factor.

  • Included among the 69 patients in the open-label phase.

  • One hundred twenty-eight of these patients were included in the open-label phase.

  • §

    Thirteen of these patients were included among the 29 patients in the open-label phase.

  • Calculated as 257 + 29 + 10 + 1 patients; the latter patient had withdrawn from the study before the open-label phase began.

  • #

    Includes all patients receiving current treatment with anti-TNF agents. The number differs from the total of 397 patients shown in Table 1, which includes 10 patients who withdrew from one study (4).

Placebo, RCT    
 Braun et al, 2002 (8)358.1337.2
 Davis et al, 2003 (9)13960.6813.2
 Brandt et al, 2003 (6)161.800
 Total placebo treatment19070.51115.6
Infliximab, RCT    
 Braun et al, 2002 (8)347.8112.8
Infliximab, open-label    
 Braun et al, 2005 (2)69133.332.2
 Stone et al, 2001 (7)215.3118.9
 Total infliximab treatment90146.453.4
Etanercept, RCT    
 Davis et al, 2003 (9)13860.834.9
 Brandt et al, 2003 (6)14§1.600
Etanercept, open-label    
 Davis et al, 2005 (4)257315.5268.2
 Brandt et al, 2003 (6)2952.159.6
 Total etanercept treatment297430347.9
Anti-TNF agents, total387#576.4396.8

Incidence of anterior uveitis during the open-label phase of the studies. During the double-blind and open-label phases of the studies, 387 patients received anti-TNF therapy for 14 to 156 weeks. Overall, 90 patients were treated with infliximab for a cumulative exposure time of 146.4 years, and 297 patients were treated with etanercept for a cumulative exposure time of 430 years.

Among patients treated with infliximab, the incidence of anterior uveitis flares was 3.4 per 100 patient-years (95% CI 1.1–8.0). In comparison, among patients treated with etanercept, the incidence of anterior uveitis flares was 7.9 per 100 patient-years (95% CI 5.5–11.1) (Table 2).

The difference between the incidence of anterior uveitis flares during placebo treatment and the incidence during treatment with anti-TNFα agents was significant (P = 0.01). This trend was somewhat stronger for infliximab (P = 0.005) than for etanercept (P = 0.05). However, the differences between infliximab and etanercept did not reach statistical significance (P = 0.08).

DISCUSSION

This study shows that anti-TNF therapy prevents flares of anterior uveitis in a clinically relevant number of patients with severe AS. This positive effect of anti-TNF therapy on the incidence of flares of anterior uveitis could be shown for the currently available agents, infliximab and etanercept, while data on adalimumab are still lacking. Because the patient numbers in the individual trials were too small to allow valuable conclusions to be reached, a combined analysis of all studies was necessary.

In comparison with the numbers reported in previous trials, the incidence of flares of anterior uveitis was reduced in those trials with anti-TNF agents in which data on eye involvement were available. The incidence of anterior uveitis in the trials with infliximab was as low as 3.4 per 100 patient-years. Although the direct comparison of infliximab with etanercept did not reveal a statistically significant difference, it must be taken into account that in the etanercept studies, the prestudy prevalence of anterior uveitis was relatively low. This difference most probably can be explained only by chance, because the inclusion criteria in the studies were similar. However, it is possible that the allowance of sulfasalazine, methotrexate, and corticosteroid treatment in some trials with etanercept (4), but not in those with infliximab (5, 8), may have influenced that difference. At least for sulfasalazine, a preventive effect on flares of anterior uveitis has been shown (12).

Nevertheless, based on the data presented here, the value of anti-TNF therapy for the prevention of anterior uveitis in patients with AS seems to be proven. This was recently indicated in a brief report on patients with AS who were receiving etanercept (13). However, it must be stressed that clearly not all patients in the studies have had benefit in terms of anterior uveitis, because a small number of patients did have a flare of anterior uveitis. No information is available regarding whether the severity of the flares differed and whether these flares represented new onset or relapses of anterior uveitis. There is also no information on the correlation between the efficacy of anti-TNF therapy on spinal symptoms and uveitis.

There was no major difference in the incidence of anterior uveitis in the early phases of the studies compared with the later periods, in the open extension phase (data not shown). Because after several months, the number of withdrawals from trials increases steadily, in the patients treated with infliximab (7, 8) somewhat more frequently than in the patients treated with etanercept (4, 6), it is possible that the calculated proportion of patients with a flare was falsely low because patients who were prone to experiencing a flare had already dropped out of the study.

Overall, the prevalence of anterior uveitis reported for the pretreatment periods of the studies was similar to the prevalence reported in the periodical literature (1) and in textbooks, with a range of 30–40% of patients with AS. Because of the weak association between disease severity and reported flares of anterior uveitis (14), the prevalence in the studies could have been even higher, but this apparently was not the case. In future studies, it will be interesting to examine the clinical severity of anterior uveitis in relation to both the prevalence and the incidence, as well as in relation to the efficacy of treatment, of anterior uveitis in patients with rheumatic manifestations, as compared with patients with anterior uveitis without concomitant rheumatic symptoms.

There is some evidence from open-label studies that infliximab is effective for the treatment of posterior uveitis in patients with Behçet's disease (15) and in treatment-resistant active uveitis in other patients (16). The reported efficacy of etanercept in children with active uveitis (17) was not confirmed in a recent controlled study (18). In contrast to such severe cases, in which uveitis often leads to compromised vision, the anterior uveitis associated with AS and HLA–B27 is mostly unilateral and rather transient and mild in the majority of cases (15, 19). However, some cases of severe anterior uveitis have been successfully treated with infliximab (20). More study is needed to define the role of anti-TNF agents in the treatment of severe anterior uveitis.

  • 1

    Dr. Braun has received honoraria of less than $10,000 from Centocor, Schering-Plough, Wyeth, Amgen, and Abbott.

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