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Comparison of infliximab versus ciclosporin during the initial 6-month treatment period in Behçet disease
  1. Yukiko Yamada,
  2. Sunao Sugita,
  3. Hiroyuki Tanaka,
  4. Koju Kamoi,
  5. Tatsushi Kawaguchi,
  6. Manabu Mochizuki
  1. Department of Ophthalmology & Visual Science, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan
  1. Correspondence to Professor Manabu Mochizuki, Department of Ophthalmology & Visual Science, Tokyo Medical and Dental University Graduate School of Medicine, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan; m.manabu.oph{at}tmd.ac.jp

Abstract

Aim To compare the efficacy and safety of infliximab versus ciclosporin A (CsA) in refractory uveoretinitis in Behçet disease.

Methods In this retrospective clinical chart review of patients with Behçet disease who were treated with CsA or infliximab, we collected information on the number of uveitis attacks, visual acuity and adverse side effects that occurred during the 6 months prior to and after the initiation of CsA (n=20) or infliximab (n=17).

Results The number of acute episodes of uveitis during the 6 months before and after initiation of CsA were 3.3±2.4 and 1.2±1.2, and those of infliximab were 3.1±2.7 and 0.4±1.0, respectively (p<0.005). The number of episodes after infliximab administration was significantly lower than that seen for CsA (p<0.05). During the 6-month treatment period, there were no significant differences noted in the improvement of the visual acuity between the two therapies. After CsA administration, neurological symptoms and renal toxicity were seen in one patient each, while after the infliximab administration, an infusion reaction and leucopenia were seen in one patient each.

Conclusion During the initial 6 months of treatment, infliximab proved to be more effective in reducing acute episodes of uveitis in Behçet disease.

  • Behçet disease
  • anti-TNF-α
  • antibody
  • uveoretinitis
  • ciclosporin A
  • immunology
  • inflammation
  • treatment medical

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Introduction

Behçet disease is one of the most serious sight-threatening clinical entities of uveitis and can be accompanied by recurrent oral aphthous ulcers, genital ulcers, skin symptoms and many other systemic inflammatory lesions. Recurrent episodes of obstructive uveoretinitis and retinal vasculitis can cause irreversible changes in neural retina and optic disc, resulting in visual loss. This refractory condition of intraocular inflammation in Behçet disease has been treated with both systemic corticosteroids and many immunosuppressive agents, including ciclosporin, which is a selective immunosuppressive agent of T lymphocytes. However, management of the intraocular inflammation in Behçet disease remains unsatisfactory.

Recent advances in immunology and immunopharmacology have made it possible to apply various biological agents, including the antitumour necrosis factor-α (TNF-α) monoclonal antibodies and infliximab. TNF-α is a well-known proinflammatory cytokine that plays a significant role in immune responses and inflammation. TNF-α has been shown to be high in the serum of patients with Behçet disease with active uveitis.1 2 Anti-TNF-α antibody has been proven to be effective in suppressing experimental autoimmune uveitis in animals.3 Infliximab is a chimeric monoclonal antibody to TNF-α that can minimise the immunological response when it is used in humans.4 It is composed of an antigen-binding variable region from mice with high affinity to human TNF-α.4 Infliximab neutralises membrane binding TNF-α as well as soluble TNF-α in addition to suppressing TNF-α production by macrophages. Clinically, infliximab has been used to treat rheumatoid arthritis,5 6 Crohn disease7 and some refractory uveitis with non-infectious aetiologies, including Behçet disease.8–14 In Japan, multicentre clinical trials have been carried out with satisfactory results,10 with the agent being approved for refractory retinochoroiditis therapy in Behçet disease by the Ministry of Health, Labor and Welfare of Japan in January 2007.

Although the efficacy of infliximab has been well documented in previous studies,8–14 a comparison between infliximab and conventional immunosuppressive agents for their efficacy in Behçet disease in the early phase of the treatments has yet to be reported. Therefore, the present study was aimed at comparing the effects of infliximab and ciclosporin on recurrent episodes of uveitis that occur during the 6-month periods before and after the initiation of each of these agents.

Material and methods

Patients

Clinical charts of 122 consecutive patients with Behçet disease who were treated at the Tokyo Medical and Dental University Hospital Ophthalmology Department between 1998 and 2008 were retrospectively reviewed. The diagnosis of Behçet disease was made based on the criteria of the Behçet disease Research Committee, which is part of the Ministry of Health and Welfare of Japan.15 16 To compare the efficacy of infliximab and ciclosporin during the early phases of the treatment of recurrent episodes of uveitis, we used the following two inclusion criteria: (1) patients had to be completely followed by our group for a period of 6 months before and after the initiation of the administration of each of the agents, and (2) patients had to continue receiving a therapeutic dosage of each agent (5 or 10 mg/kg for infliximab, 3–5 mg/kg for ciclosporin) for 6 months or longer. Although we found a total of 41 patients who were treated with ciclosporin and 24 patients who were treated with infliximab between 1988 and 2008 at our uveitis clinic, the number of patients who met the aforementioned inclusion criteria was only 20 for ciclosporin A (CsA) and 17 for infliximab.

Methods

Based on each patient's clinical chart, we counted the number of acute episodes of uveitis (uveitis attack) during the 6 months before (pretreatment period) and 6 months after (treatment period) CsA or infliximab initiation. The best-corrected visual acuity (BCVA) values at remission during the pretreatment period as well as during the treatment period were also collected. CsA was given orally at 3–5 mg/kg daily, while infliximab intravenous infusions were administered using doses of 5 mg/kg (16 patients) or 10 mg/kg (one patient) at 0, 2 and 6 weeks, after which the infusions were then administered every 8 weeks. Any adverse side effects noted during the 6-month treatment periods were compared.

The majority of patients in this study had received prior treatment, with the CsA patient group previously administered colchicine with or without systemic corticosteroids and the infliximab group given CsA with or without systemic corticosteroids. These previous treatments were converted to either CsA or infliximab due to the side effects or because of a poor response to the original therapy. Once it was decided to switch to a different therapy, the agents being administered were discontinued or tapered slowly prior to giving the new agents to the patients.

Before we started infliximab, all patients underwent a chest x-ray and were given a purified protein derivative (PPD) skin test. If a patient had a strong positive skin test, an abnormal chest x-ray or any risk factors such as a family history of tuberculosis, we gave an antituberculosis agent (isoniazid) with the infliximab.

The research followed the tenets of the Declaration of Helsinki, with the study approved by the Institutional Ethics Committee of the Tokyo Medical and Dental University.

Statistical analysis

Statistical analysis was performed using the Mann–Whitney U test or Wilcoxon signed-ranks test. A p value <0.05 was considered to indicate statistical significance.

Results

The characteristics of 17 patients with Behçet disease who treated with infliximab are illustrated in table 1. There were 15 men and two women, ranging in age from 25 to 63 years (mean age: 37.6 years). The table includes the interval between the onset of uveitis and infliximab therapy, treatment before infliximab, number of uveitis attacks in the 6 months before and after treatment, concomitant treatment along with infliximab and the reason for conversion to infliximab treatment. The characteristics of 20 patients with ciclosporin A (CsA, n=20) treatment are illustrated in table 2.

Table 1

Characteristics of patients with Behçet disease treated with infliximab (IFX)

Table 2

Characteristics of patients with Behçet disease treated with ciclosporin A (CsA)

The number of acute episodes of uveitis that occurred at 6 months before the initiation of CsA or infliximab was 3.3±2.4 (mean±SD: standard deviation) or 3.1±2.7, respectively (figure 1). There was no statistically significant difference between the CsA and infliximab groups with regard to the number of uveitis attacks that occurred prior to the initiation of each agent, which indicates that the uveitis activity was similar in these two groups. CsA treatment significantly reduced the number of uveitis attacks from 3.3±2.4 to 1.2±1.2 during the 6 months after the CsA initiation (p<0.005). Infliximab also significantly reduced the number of uveitis attacks from 3.1±2.7 to 0.4±1.0 (p<0.005). In addition, the number of uveitis attacks during the 6 months after the initiation of the treatments was significantly lower in the infliximab group than with the CsA group (p<0.05, figure 1). This finding indicates that infliximab therapy is more efficacious as compared with CsA in treating uveitis attacks during the initial 6-month treatment period.

Figure 1

Frequency of acute uveitis episodes at 6 months before and after each treatment. Acute uveitis episodes during the 6-month period before the treatment were 3.1±2.7 in the infliximab group and 3.3±2.4 in the CsA group. During the 6-month period after the initiation of the treatment, the number of episodes was 0.4±1.0 in the infliximab group and 1.2±1.2 in the CsA group. Statistical analysis was performed using the Mann–Whitney U test or Wilcoxon signed-ranks test. *p<0.05, **p<0.005, compared with two groups. ns, not significant.

Out of the 20 patients treated with CsA, nine patients (45%) had no acute episodes of uveitis during the 6 months they were given CsA, while two patients had one episode, seven patients had two, one patient had three, and one patient had four episodes. On the other hand, out of the 17 patients treated with infliximab, 14 patients (82%) had no ocular inflammatory episodes during the 6-month infliximab administration, while two patients had one episode, and one patient had four episodes (table 1).

BCVA values at remission during the 6 months before and after the initiation of CsA and infliximab are shown in figure 2. A total of 97% eyes of the patients in the infliximab group and 93% eyes in the CsA group exhibited visual improvement (two or more lines of improvement). However, there was no significant difference in the amount of improvement between these two groups.

Figure 2

Visual acuity changes seen for each therapy. Best-corrected visual acuity (BCVA) was measured at the initiation point and 6 months after the administration. With infliximab, the vision improved or was unchanged in 97% of the eyes, compared with 93% in the CsA group. Open circle, more than two lines of improvement; black square, unchanged; open triangle, a decrease of less than two lines. Statistical analysis was performed using the Mann–Whitney U test.

As for the adverse side effects that were seen during the 6 months after the initiation of CsA, one patient developed neurological symptoms, while another patient developed renal toxicity, which required a reduction of the CsA dosage in both patients. In the infliximab group, nine patients had skin symptoms (eruption, itching and recurrence of atopic dermatitis), and an infusion reaction and leucopenia were noted in one patient each. All the infliximab-related skin symptoms were well controlled by topical therapy. In the patient with the infusion reaction, since the reaction was considered to be mild, a lowering of the speed of the intravenous infusion of infliximab along with the addition of antiallergic agents made it possible to continue the treatment. In the patient who developed leucopenia 1 month after the initiation of the treatment (Case 8 in table 1), this patient was also being treated with concomitant immunosuppressive agents (azathioprine, colchicine and systemic corticosteroids, 10 mg/day). Once these other agents were discontinued, it became possible to control the leucopenia, and the treatment was continued. During the initial 6 months of the therapy, there were no serious adverse events observed, such as tuberculosis or bacterial infections.

Discussion

The present study demonstrated that both CsA and infliximab can reduce the number of uveitis attacks effectively and significantly in Behçet disease during the initial 6-month treatment period. In addition, the present study also showed that infliximab was much more effective than CsA.

Similar to the current study, previous reports have also documented that infliximab is more effective than CsA in the treatment of Behçet disease.8–14 However, the interpretations of the data in these previous reports were based on the fact that patients who are resistant to CsA are well controlled by the use of infliximab. It is a well-known fact that the efficacy of CsA decreases with time and that a certain proportion of such patients will become resistant to the therapy. In order to avoid this bias, the current study was designed to compare the effects of these two drugs on Behçet disease only during the early phases of each treatment. Thus, the current study demonstrated that infliximab was much more effective than CsA during the initial 6 months of therapy. The data are also noteworthy in that more than 80% of the patients treated with infliximab were completely free of intraocular inflammatory attacks during this initial 6 months of therapy. However, we also found that there was a small proportion of patients who did not respond well to the infliximab treatment. During this initial 6-month infliximab treatment period, a total of three out of 17 patients had uveitis attacks, with two patients each having a single uveitis attack and one patient having four attacks (see table 1). The reason why a small proportion of patients did not respond well to infliximab is currently unknown. However, the infliximab serum concentrations were not examined in these patients as well as in the other patients who responded to the infliximab administration. Examinations of these concentrations in the future may very well be able to provide an answer that could explain these differences.

The effects of the two treatments on the visual acuity were not significantly different during this short treatment period. The majority of our patients in the infliximab group had been previously treated with CsA for a period of time but, due to the ineffectiveness or side effects of the CsA, were changed to the infliximab treatment. Therefore, many of the eyes in these patients could have already developed irreversible changes in the retina or optic nerve by the time infliximab treatment was actually initiated. If the infliximab therapy had been initiated at a much earlier stage, a better visual outcome would have been observed in these patients. Infliximab was not administered as the first-line therapy because the majority of the patients in this study were subjects of a multicentre clinical trial of infliximab on Behçet disease in Japan. According to the inclusion criteria of this clinical trial, the patients must be previously treated with CsA or another immunosuppressive agent in addition to having had three or more ocular inflammatory attacks within 28 weeks, while they were on these treatments.10 After the Ministry of Health, Labor and Welfare of Japan approved infliximab for use in uveoretinitis therapy in Behçet disease, infliximab is allowed to be used only if conventional immunosuppressive agents have been proven to be ineffective. The present study, however, strongly suggests that infliximab should be used as the first-line therapy in patients with Behçet disease who have intense sight-threatening uveoretinitis.

With regard to adverse effects, no serious side effects were seen in both CsA and infliximab. In the CsA group, only one patient had neurological symptoms and renal toxicity that required a dose reduction. In the infliximab group, leucopenia and an infusion reaction were seen in one patient each. All other infliximab-related skin symptoms were mild and only needed topical treatment. However, there was one other patient, not included in the present study, who also developed leucopenia. Unfortunately, in this patient, the cell count decreased to 2800 cells, which required discontinuation of the infliximab at 2 months after the initiation of the drug administration. In the current study, no serious systemic infections such as tuberculosis or Pneumocystis pneumonia were seen. However, in one other previous study, these systemic infections have been reported to occur in infliximab-treated rheumatoid arthritis patients.17 Many of these patients were elderly patients, and the adverse events usually occurred within 1 or 2 months after initiation of the treatment. In the current study, our patients with Behçet disease were much younger than the patients with rheumatoid arthritis and thus were not likely to be a high-risk group for these systemic infections. Even so, for all patients we perform a very detailed medical history that carefully looks for previous tuberculosis; in addition, we perform a purified (tuberculin) protein derivative (PPD) skin test, and all patients undergo a chest x-ray before the initiation of infliximab. If a patient has any risk factors for tuberculosis, such as a family history of tuberculosis, a strong positive skin test or an abnormal chest x-ray, we coadminister an antituberculosis agent with the infliximab. Our current study included three such patients who were PPD-positive (>20 mm), as none of their chest x-rays were found to be abnormal. However, these PPD-positive patients did receive the antituberculosis agent (eg, isoniazid) for 9 months. In such cases, a much longer observation period is necessary to ensure patient safety, and so we routinely follow these patients for extended periods of time.

Limitations of the present study include the study design and the relatively short follow-up that was performed after the initiation of the treatments. The design of this study was not a randomised control study but was a retrospective comparative study. A randomised control study would indeed be the most powerful method to use in order to obtain a definitive conclusion on the efficacy and safety of this new treatment. In this study, however, because of the limitation of the number of new patients who have Behçet disease with refractory uveitis who had not been previously treated with CsA, a randomised control study comparing CsA and infliximab would have been difficult to set up, even with a multicentre study in Japan. Therefore, this is why we chose to perform a retrospective study. It is also true that the efficacy and safety of a new drug need to be evaluated based on a long-term follow-up. The follow-up period of this study, however, was only designed to be 6 months, as the aim of this study was to compare the early effects of these two treatments shortly after the initiation of the therapies. The overall aim of our study was not to investigate the long-term effects and safety of infliximab. A separate analysis on the long-term effects is currently ongoing and will be reported in a future study.

In conclusion, infliximab and ciclosporin significantly suppressed the number of acute episodes of intraocular inflammation in Behçet disease. During the 6-month period after the initial administration, infliximab proved to be a much more effective therapy than with the currently available conventional therapies such as CsA.

References

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Footnotes

  • Competing interests None.

  • Ethics approval Ethics approval was provided by the Institutional Ethics Committee of Tokyo Medical and Dental University Hospital.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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