APLAR Journal of Rheumatology 2004; 7: 141–145

©Asia Pacific League of Associations for Rheumatology

Blackwell Publishing, Ltd.LECTURENew and innovative therapies for Behcet’s disease

New and innovative therapies for Behcet’s diseaseFereydoun DAVATCHI

Rheumatology Research Center, Tehran University for Medical Sciences, Shariati Hospital, Tehran, Iran

AbstractBackground: Behcet’s disease (BD) is a vasculitis progressing by attacks and remissions. Not all patients willrespond even to the classical treatments. New treatments are emerging with the hope to overcome this failure.

Biologic agents: Interferon-α (IFN-α), anti-tumour necrosis factor-α (TNF-α), and tolerization have been usedin BD.

IFN-α is mainly used for ocular manifestations of BD. The result seems impressive, 92% of cases had goodor excellent results. It was less impressive for mucocutaneous and joint manifestations. The dosage is 6–9 million IU/day for 4 weeks, then 4.5 million daily for 4 weeks, and then 3 million/day. The maintenancedose is 3 millions, three times/week, to continue for 8 weeks after complete remission.

Etanercept (anti-TNF-α) was effective in mucocutaneous lesions of BD at the dosage of 25 mg twice weeklyfor 3 months (double-blind control study). Attacks relapsed after discontinuation. Etanercept was ineffectivein ocular lesions (open study).

Infliximab (anti-TNF-α) was very effective in many studies of ocular lesions. It dramatically suppressed theinflammatory attack. The dosage is one injection of 5 mg/kg (intravenous infusion) at weeks 0, 2, 6, and thenevery 8 weeks.

Tolerization with oral administration of HSP peptide 336–351 seems to protect from uveitis relapse.Pentoxifylline is not particularly effective unless for oral aphthae (50% response rate).Pimecrolimus ointment may be of help in resistant genital aphthosis, reducing the healing time.

Key words: anti-TNF, Behcet’s disease, interferon-α, pentoxifylline, pimecrolimus.

INTRODUCTION

Behcet’s disease (BD) is a vasculitides of unknownorigin. It is rare in Western countries and in the southhemisphere. It is mainly seen in Asian countries,especially Japan, Korea, China, Iran and Turkey, alongthe Silk Road.1

Behcet’s disease is characterized by multisysteminvolvement of different organs, mainly mucocutane-ous, eyes, joints, gastro-intestinal tract and nervoussystem.2,3 The organ involvement is characterized byrecurrent attacks followed by remission. In manyorgans the remission is usually achieved by a completehealing of the lesion, without any sequela (mucocuta-neous lesions, articular manifestations). Theoreticallythere is no need to treat these lesions, because theyheal spontaneously (oral aphthae, genital aphthae,skin aphthae, BD pustulosis, erythema nodosum,arthralgia, sub-acute arthritis, etc.). However, if thelesion is too painful, or the rate of recurrence is high,or the duration of the attack is long, treatmentis warranted. Colchicine, levamisole, NSAID, localtreatments (steroids, antibiotics, etc.) are the main

Correspondence: Fereydoun Davatchi, MD. Professor and Head, Rheumatology Research Center, Shariati Hospital, Tehran University for Medical Sciences. Kargar Avenue, Tehran 14114, Iran.Email: fddh@davatchi.net

This is a version of a paper originally delivered at the Annual Conference of the Indian Rheumatology Association, New Delhi 28–30 November, 2003.

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therapeutic agents for this. Other lesions (eyes, centralnervous system, etc.) also progress by attack andremission, but the healing process is usually slow andprogress toward severe sequela. These lesions needaggressive treatment. The gold standard is immuno-suppressive drugs (mono or combination therapy)along with corticosteroids.4

Not all patients respond favourably to the classicaltreatment, especially those necessitating cytotoxic drugs.There is therefore a constant search for new therapiespromising better outcome.

BIOLOGICAL AGENTS

As some of the auto-immune mechanisms of BD seemto be impaired natural killer cells cytotoxicity, increasednumber of γ-δ CD3 T-cells, overproduction of TNF, andelevation of IL-8, it was natural to turn to biologicalagents for help.

Interferon-αααα (INF-α-2a and INF-α-2b) was the firstbiological agent used in BD. It was introduced in thetreatment of BD by Tsambaos et al. in 1986.5 Interferonwas first used in milder forms of BD such as muco-cutaneous lesions and articular manifestations. Later,ocular lesions too were treated by INF. The dosage isnot standardized (from 3 million IU three times/week,to 9 million IU/day). Kotter et al.6 in a very interestingreview of all works done on interferon, recommendstarting the treatment with higher dosages, 6–9 millionIU/day in subcutaneous injections. After 4 weeks thedosage is reduced to 4.5 million daily, and after another4 weeks to 3 million/day. After complete remission, itis recommended to reduce the dosage to 3 million threetimes/week as a maintenance dose. It is recommendedto continue INF at least for 8 weeks after completeremission. Side-effects are numerous, mainly a flu-likesyndrome necessitating the use of NSAIDs to overcomethe reaction. The local reaction on the site of injectionis very frequent, from a rash to pyoderma gangrenosum,although the latter is exceptional. A case of pathergyreaction has also been reported on the site of injec-tion.7 Results on eye lesions (from different reports)seem very good. The highest number of patients isreported by Kotter et al. (50 patients). The response ratewas 92%. The mean visual acuity rose from 0.46 to0.81 at 6 months.8 Results on mucocutaneous andarticular manifestations are less impressive and lesscomplete.9,10 Many recurrences are seen during thetreatment. Kotter et al. conclude that INF should bereserved for more serious lesions of the disease, such asocular lesions.6

Anti-TNF-αααα has recently been used in BD. There aresparse reports on few cases.

Etanercept is a soluble receptor intercepting circulat-ing TNF-α before it reaches its receptors on the cellsurface. There is only one report on a double-blindcontrol study of etanercept in mucocutaneous lesions.11

The study was done by Melikoglu et al. from Istanbul(Turkey). Patients received 25 mg injections twiceweekly for 3 months. There was a statistically signific-ant reduction in mucocutaneous and articular attacksduring the therapy. It is important to note that: (i) notall lesions responded to the treatment; and (ii) afterdiscontinuation, there was an exacerbation of attacks.The latter will limit largely the use of etanercept in BDbecause the disease is chronic and lasting for severaldecades. The same authors tested etanercept for ocularlesions in an open study on 10 cases.12 Patients werealready receiving azathioprine, cyclosporin and pred-nisolone. All medication continued with the adjunc-tion of etanercept, except cyclosporin. The result after6 months of etanercept was not satisfactory. There wasno statistically significant improvement of visual acuity(mean before 0.34, mean after 0.54).

Infliximab, a chimeric monoclonal antibody againstTNF-α, was used by Sablé-Fourtassou et al. as 5 mg/kgin infusion, on weeks 1, 2, 6 and then every 8 weeks for5–9 months in three patients. The result was excellent.Visual acuity improved significantly in all of them,reaching nearly the normal value.13 It is interesting tonote that these patients had used interferon-α and wereobliged to stop it due to side-effects or inefficacy. Trioloet al. had three patients, two with ocular manifestationsand one with neurological involvement.14 They usedthe same protocol and had complete remission of allsymptoms. Joseph et al. experienced three cases ofuveitis with infliximab. The same protocol was used andthe result was excellent like those before.15 Morris et al.experienced one case of uveitis resistant to differentcytotoxics and interferon-α. They had a good short-timeresponse.16 Sfikakis et al. presented their short-termresult with infliximab on uveitis in five patients. Theimmediate response was dramatic.17 Katsiari et al. pres-ented the mid-term experience of two cases of BD, onewith uveitis.18 This patient was refractory to azathioprine,cyclosporin and prednisolone. Cyclosporine was con-tinued while on infliximab. The visual acuity becamenormal in one eye and improved largely in the secondeye. The follow-up was for one-and-a-half years. Behrenset al.19 presented a case of resistant Behcet’s disease whoimproved partially with infliximab. Infliximab is alsoeffective in the treatment of gastro-intestinal BD.20–22

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As seen by the above experiences, etanercept maybe partially effective in mucocutaneous lesions of BD,but not effective in ocular manifestations. Infliximabwas effective in short and mid-term studies of ocularmanifestations. However, all the presented experiencesare on few cases and on practically short-time treat-ment. Attacks of ocular lesions in BD continue for manyyears. It is important to have a control study on severalpatients and several years to judge the real efficacy ofinfliximab, like the studies done for cytotoxic drugs. Fornow, the best indication of anti-TNF therapy will be thecontrol of intractable ocular attack, mainly the retinalvasculitis. After resolution of the attack, it is better toprevent future attacks with cytotoxic drugs, keeping theanti-TNF for future intractable attacks.

Specific immuno-tolerance induction is a muchmore interesting idea for ocular lesions of BD. Lehneret al. showed that oral administration of peptide 336–351 of HSP 60 induced the uveitis of BD in 72% ofLewis rats. Administration of the peptide covalentlylinked to recombinant cholera toxin B subunit (CTB)decreased the rate of uveitis from 72% to 20%.23 Prelim-inary results from a phase 1 clinical study in humans24

suggest that oral administration of P336-351 linked toCTB can prevent relapses of uveitis, in patients in whomremission was induced first by immunosuppressivedrugs and then gradually withdrawn. No adverse effectshave so far been detected. The data is very interesting;however, these were patients who responded well toimmunosuppressive drugs. Tolerization permitted tostop the immunosuppressive drug without relapse ofthe eye disease. There is no experience to show thattolerization with P336-351-CTB can improve an attackof uveitis or retinitis.

The induction of tolerance is an interesting idea,dealing directly with the mechanism of the disease (themultisystem immunopathology of BD might be gener-ated by an over-reaction to microbial stress proteins).We are testing, in a double-blind control study, thesame idea of tolerization, but with protein S extractedfrom bovine retinal cells. Our goal is to induceremission in ocular manifestations of BD withoutcytotoxic agents, instead of maintaining an inducedremission by cytotoxic drugs.

PENTOXIFYLLINE

Pentoxifylline (PTX) was assessed by sending question-naires to American and Canadian rheumatologists.25

Pentoxifylline was used by 135 rheumatologists fortheir 274 BD patients. The average dose was 400 mg,

three times/day. The response was partial (fewer attacks,shorter attacks). It was obtained in 50% of oral aphthae,39% of genital aphthae, 34% of other symptoms, andin 13% of ocular lesions. Side-effects were frequent,45%, as GI upset, nausea, and diarrhea. Among thepatients, 40% received concomitantly colchicines withsynergistic effect. The effect of PTX seems to be thecontrol of γ-δ T-cell expansion, as demonstrated invitro by Triolo et al.26

LOCAL TREATMENT

Iontophoresis is a transcleral introduction of methyl-prednisolone in the eye.27 The method was used fortwo eyes by Ben Ezra et al. with a complete remissionof the inflammation. No information is available forthe long-term outcome of the method.

Pimecrolimus is an anti-inflammatory topical,steroid-free crème.28,29 It is an ascomycin macrolactamderivative, extracted from streptomyces hygroscopicus,having similar action as cyclosporin. It inhibits locallythe production of inflammatory cytokines by bindingto the protein receptor macrophilin-12 (FKBP-12),inhibiting calcineurin, resulting in the blockade ofsignal transduction in the target cell. It is mainly usedin atopic dermatitis. We have started to use it in resistantgenital aphthosis and skin aphthosis. In daily practice,if aphthosis resists to the classical treatment of colchi-cine or levamisole, the next step is the use of generalsteroids or cytotoxic drugs. Thalidomide and dapsoneare more experimental than routine drugs. Pimecrolimusis a good alternative before taking the step towardgeneral steroids or cytotoxic drugs. Pimecrolimus isapplied twice daily on the lesion. We had good responsein resistant attacks of genital aphthosis in six patients,shortening significantly the duration of the attack.However, it does not prevent new attacks. A double-blind control study on the effect of pimecrolimus ongenital aphthosis is actually on the way in the Behcet’sDisease Research Unit. Pimecrolimus in our experiencedoes not seem to work on oral aphthosis.

Tacrolimus is a macrolide derived from streptomycesstukubaensis.30 It greatly resembles pimecrolimus andhas similar action.

CONCLUSION

Classical treatments of BD, although not effective in allcases, have the advantage of being easy to use and aremuch cheaper. The latter is a major factor in countrieswhere BD is seen most frequently, especially most of

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the Asian and North African countries. Behcet’s disease,being characterized by periodical relapses over decades,it is important to keep in mind that no treatment willprotect from new attacks once it is discontinued. Sometreatments like INF for ocular lesions seem to protectfor a while, which is also seen with cytotoxic drugs.However, this ability varies widely from one patient toanother and seems to be related more to the diseaseability to relapse than to the treatment itself. Therefore,it appears logical to start the treatment with the lessaggressive and the least expensive treatment, andreserve the more aggressive and the more expensive forresistant cases.

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