Part 5 • Uveitic Conditions not Caused by Active Infection Chapter 26 Behçet’s Disease

disease were tested for a possible link between a specific tumor necrosis factor SNP and the disease. Although HLA-B51 was again found to be strongly linked with the disease, no TNF gene polymorphisms were found to be associated.107 TNF-α SNP −1031C was found associated with the disease in a study performed in the United Kingdom.108 In Turks, an association with the disease has been reported with the IL-1A −889 allele and the IL-1B +5887 haplotype.109 Another portion of the genome that has been investigated has been a novel family of the major histocompatibility complex (MHC) class I genes, located near the HLA B gene and termed MIC (MHC class I chain-related genes). Yabuki and associates110 reported an association between one MICA (one of the transmembrane regions) microsatellite polymorphism A6 in patients with Behçet’s disease compared with control subjects (86.8% vs 50%). However, Salvarani and coworkers111 did not find such a linkage. No association was seen in CTLA (cytotoxic T-lymphocyte associated antigen 4, an adhesion molecule important in cell trafficking) SNPs distributions between controls and Behçet’s patients.112

Various investigators have attempted to identify an exogenous cause for this disease, particularly a viral one. The incidence of the disease is greater in the northern portions of Japan, although there is no known genetic difference, such as a higher incidence of HLA-B51, between the people in the north of Japan as opposed to those in the south. A somewhat dated report emphasized that there had been no documented cases of the disease in Nisei living in Hawaii,113 suggesting that an exogenous source may indeed act at least as a triggering mechanism. As mentioned above, Turks living in Germany have a much smaller chance of developing the disease than those living in Anatolia.6

The search for the presence of live virus in the retina has not been successful, and therapeutic approaches with this concept as its underlying logic have not been rewarding (see later discussion). Denman and colleagues114 offered a more provocative theory on the role of virus in this disorder. They noted that mononuclear cells from these patients have a high concentration of the interferon-induced enzyme 2´,5´-oligoadenylate synthetase, which is suggestive, but not confirmatory, of a viral infection.115 They speculate that the virus may act as a ‘promoter’ by stimulating the expansion of clones of abnormal lymphocytes that will induce disease. Bonass and coworkers,116 using DNA dot-blotting techniques, found evidence of the presence of herpes simplex virus type 1 DNA in a high percentage of patients with Behçet’s disease. More recent work has centered on the possible role of streptococcal-related antigens as an etiologic agent of this disease. Hirohata and colleagues117 showed that when Streptococcus sanguis-related antigens (RRE KTH-1 anti­ gens) were added to T cells of patients with Behçet’s disease in in vitro cultures, the amount of IL-6, an ‘inflammatory’ cytokine, is higher than that produced by T cells from control subjects stimulated in a similar fashion. This suggests that a hypersensitivity response to these bacterial antigens could be a triggering mechanism for this disease. Tanaka and co­ workers118 reported finding titers of the 65-kDa heat shock protein of Streptococcus in patients with Behçet’s disease. Pervin and colleagues119 demonstrated a responsiveness of T-cell clones from patients with Behçet’s disease to four peptide determinants within the 65-kDa heat shock proteins derived from Mycobacterium tuberculosis. The inflammatory

response seen in these patients could in part be due to a heightened response to bacterial antigens.120 The potential role of these findings still needs to be elucidated. Recently, Kurhan-Yavuz and coworkers121 have shown a relationship to an endogenous antigen, a common sequence found in various HLA-B molecules that is shared by HLA-B7 and HLA-B51 (B27PD). Increased amounts of IL-2 and TNF-2 were seen in the supernatants from lymphocytes of patients with Behçet’s disease after stimulation with this molecule.

No truly specific tests for the diagnosis of Behçet’s disease exist. The skin-prick test looking for evidence of pathergy has been suggested to be highly diagnostic for Behçet’s disease by some, particularly the Turkish. Skin hyperreactivity has not been a markedly striking feature in the patients we have seen in the United States. Wechsler and colleagues122 have applied immunofluorescence techniques to skin from which biopsy specimens were obtained after an intradermal injection of distilled water. About 60% of those thought to have Behçet’s disease had complement and/or IgM deposition, compared to 14% of control subjects. There was no concordance with HLA-B5. Dogan and colleagues123 found that total serum sialic acid levels, as well as the proportion of total serum sialic acid to total protein levels, can help to distinguish Behçet’s disease from other uveitic entities. Michaelson and coworkers124 investigated the presence of anticytoplasmic antibodies in this disease by means of an indirect immunofluorescence technique, using guinea pig lip as the tissue substrate. Although eight of eight American patients with Behçet’s disease had positive test reactions, only 10 of 16 Turkish patients showed positivity. Anticardiolipin antibodies, which have been observed in several patients with lupus erythematosus accompanied by retinal vascular disease, were reported to be present in high serum titers in one patient with neuro-Behçet’s disease.125 These antibodies were looked for in patients with Behçet’s with uveitis, and no correlation could be made by Efthimiou and coworkers,126 but Bergman and colleagues127 claimed that IgM isotypes were increased in these patients. However, Aydintug and coworkers128 found no evidence of anticardiolipin or antineutrophil cytoplasmic antibodies in 72 Turkish patients they screened. Rather, they found that 18% had evidence of antiendothelial cell antibodies (AECAs), which did not induce complement-mediated cytotoxicity; nor was the binding due to immune complexes. However, they did find that those with evidence of AECAs were more apt to develop acute thrombotic events and retinal vasculitis.

Therapy

The responsibility of the ophthalmologist in the treatment of Behçet’s disease is a heavy one. The visual course of the patient is often a major factor in the evaluation of whether therapy is successful, or should be altered or stopped. Because of the difficulty in treating the posterior pole aspects of this disorder, a litany of therapies has been proposed. Despite these sometimes intensive attempts, loss of useful visual acuity may occur in about three-quarters of the eyes 6–10 years after the initiation of ocular symptoms.129

The most commonly used agents in the past have been systemic corticosteroids, cytotoxic agents (alkylating agents),

colchicine, and ciclosporin and tacrolimus (FK506). More recently, IFN-a and anti-TNF therapy have begun to be used. So far, most of these latter medications have been used in a noncontrolled fashion in relatively small numbers of patients, and in case reports with relatively short follow-up. It is important to remember that few medications have been evaluated in randomized studies, and even fewer in the ocular realm. An evaluation of evidenced-based studies shows 21 randomized controlled studies (Table 26-10). To date, only azathioprine and ciclosporin have been shown to be effective for the ocular complications of Behçet’s disease. At the time of writing IFN-a has been shown in a controlled trial to be effective against mucocutaneous lesions, whereas none have been reported for anti-TNF-α agents.130 This may change in the near future.

Systemic corticosteroids

Although Behçet’s disease may initially respond to systemic corticosteroids, it will invariably become ‘resistant,’ with a further drop in vision and the need for additional thera­ peutic modes.129 Reed131 has given high-dose intravenous methylprednisolone followed by oral immunosuppressive therapy to rapidly reverse retinal disease. Some Japanese observers never give corticosteroids for this disease because they believe that in the long term the addition of these agents will result in an even worse visual prognosis.

Cytotoxic and antimetabolic agents

In several reports from the Mediterranean basin the efficacy of cytotoxic agents (particularly alkylating agents) in the treatment of the ocular component of Behçet’s disease has been demonstrated.132–134 Mamo132 noted no ocular recurrences in most patients treated. In a retrospective clinical study Pivetti-Pezzi and coworkers135 found that the visual prognosis for patients treated with chlorambucil early in their disease course was considerably better than that for those treated early with steroid. A reappraisal by Tabbara136 of the role of chlorambucil in the treatment of this disorder was considerably less favorable. He underlined the significant side effects seen with the drug, and noted that threequarters of the eyes studied had a visual acuity of 20/200 or less when chlorambucil was used as the sole therapeutic agent. Kazokoglu and coworkers137 evaluated the long-term effects of cyclophosphamide and colchicine and concluded that in their 64 patients there was no statistically significant positive change in visual acuity or the attack rate compared with the posttreatment period. These observations essentially corroborate those of BenEzra and Cohen129 as well as ours. A disturbing report by Takeuchi and Takeuchi138 found an increased frequency of chromosomal aberrations (dicentrics) in patients with Behçet’s disease treated with cytotoxic agents as well as colchicine. Another approach has been to use intravenous pulse cyclophosphamide therapy (which may have fewer side effects) to treat Behçet’s disease, an approach similar to that used for severe renal disease. Our experience with this method has not been especially promising, whereas Hamza and colleagues139 reported some advantage with this method over pulse steroid therapy. Yazici and colleagues140 reported that azathioprine was superior to placebo in the treatment of this disease. Although any controlled trial deserves attention, it has been noted that

Therapy

maintenance of visual acuity was a goal that was met with only modest success.141,142 However, long-term results demonstrated that maintenance of visual acuity was better achieved in the azathioprine-treated group than in the control group.143 Greenwood and coworkers144 reported their experience with the use of azathioprine in treating the ocular manifestations of Behçet’s disease and found that it was only partially effective in allowing a reduction of steroid dosage, and overall was not overwhelmingly effective.

Colchicine

Because the results of leukocyte migration studies showed abnormalities, the use of colchicine was thought ideal because it would inhibit such migration.145 Most practitioners use it to prevent recurrences, not to treat active disease. Hijikata and colleagues134 found that the visual prognosis for patients receiving colchicine was better than that for those receiving steroid. A masked, randomized study in Turkey, in which patients received colchicine or placebo, demonstrated no differences between the groups.146

A randomized (colchicine versus placebo) study147 treating active mucocutaneous disease demonstrated that the colchicine-treated group had a reduced incidence of genital ulcers, erythema nodosum, and arthritis. This effect was seen particularly in women. This medication is being used less and less, as other medications for ocular disease, at least, seem to give better control.

Interferon-α

The use of interferon-α in the treatment of the ocular complications of Behçet’s disease has been reported. Kötter and colleagues148 used an initial dose of 6 × 106 IU subcutaneously daily and then 3 × 106 IU every day for 1 month, followed by 3 × 106 IU subcutaneously every other day. This group saw an improvement in all seven patients treated. Pivetti-Pezzi and associates149 and Wechsler and coworkers150 used a dose of 3 × 106 IU three times a week. PivettiPezzi and associates saw a 50% reduction of ocular relapses. In two patients the medication was stopped, and there was a recurrence of disease. All patients had a flu-like illness during therapy. Sakane and Takeno151,152 stressed the potential secondary effects of this therapy, such as immune reactivity, thyroiditis, and a Behçet’s disease-like retinopathy, all having been associated with IFN-a therapy.

Ciclosporin and tacrolimus (FK506)

Our observation early on in using ciclosporin suggested clearly that patients with Behçet’s disease appeared to have a particularly positive therapeutic response to this agent.153 These observations were confirmed in a randomized, double-masked multicenter study in Japan, in which ciclosporin was found to be superior to the original standard therapy.154 In their study, Ando and associates26 wrote: ‘The introduction of ciclosporin in 1985 is probably responsible for the improvement of the visual prognosis in Behçet’s disease patients.’ Observations have been made in Israel, where the drug was compared with cytotoxic agents in a masked study,155 as well as in Turkey.156 Özyazgan and colleagues,157 in a single masked study, compared 5 mg/kg/day of ciclosporin with intravenous administration of 1 g

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No suggestion that daclizumab was beneficial. However, low attack rate for both arms limited ability to make a definitive comparison.

Mat CM et al.191 (2006)

Effective for erythema nodosum in females but not in males. The drug is more effective among females, similar to colchicine trial.

Melikoglu M et al.192 (2005)

Alpsoy E et al.193 (2002)

Masuda K et al.154 (1989)

Davies UM et al.171(1988)

cyclophosphamide (Cytoxan) per month. In this small study of 23 patients, they found that the ciclosporin group had a significantly marked improvement of their vision compared to the other group, but at 24 months it was not clear whether this improvement was sustained, leaving the observers with the call for further long-term studies. Kotake and colleagues158 treated 20 Japanese patients with Behçet’s disease with low doses of ciclosporin (5 mg/kg/day), and found it to be effective in 70%. Chavis and coworkers159 in Saudi Arabia reported a salutary effect of ciclosporin on loss of vision due to papillitis, optic neuritis, macular neuro­ retinitis, and retinal phlebitis, but not with retinal arteritis. Their approach to therapy is different from the one we have outlined here, with a taper of ciclosporin therapy once clinical improvement is seen; this is therefore intermittent lowdose therapy, as opposed to continuous low-dose ciclosporin therapy as described by us. We have reported our long-term results with ciclosporin in 19 patients with Behçet’s disease.160 We found that combined ciclosporin and prednisone therapy appeared to be an effective means to treat this disorder. The combination permits the use of lower doses of both medications, thereby helping to reduce the possibility of untoward secondary effects. Also of interest was the positive therapeutic effect of ciclosporin therapy reported by Elidan and colleagues161 on the hearing loss that occurred during Behçet’s disease.

With a mechanism that is essentially the same as that of ciclosporin, it is logical to assume that tacrolimus would be a useful therapy for this disorder. It has been used in the treatment of presumed pulmonary vasculitis due to Behçet’s disease, with resolution of the pulmonary lesion, as well as amelioration of the uveitis.162

Anti-TNF therapy (infliximab)

Infliximab, a chimeric monoclonal antibody directed against TNF-α was reported effective in treating five patients with Behçet’s disease. When one dose was given at the last relapse, remission was evident within 24 hours. However, remission is the natural history of this disease even without therapy, but several reports have appeared suggesting its usefulness. Abu El-Asrar et al.163 reported the response over a relatively long period (16–36 months). When given at 5 mg/kg at time 0, week 2 and then week 6, followed by every 8 weeks, they found that three of six patients were attack free, but that two developed positive ANAs. This reflects our general experience. One patient has been infused for 4 years,164 and another’s optic disc neovascularization regressed with this therapy165 (no real surprise if the neovascularization is inflammatorily driven). It appears useful, but just to what degree remains to be determined. Sakellariou et al.166 described a Behçet’s patient who developed scleromalacia perforans while receiving infliximab. The implication is that the disease was not necessarily caused by the medication, but rather that it was not effective in controlling the full span of the disease; we see this in all medications as they are more widely used. It is important to remember that it is a chimeric antibody (see Chapter 7) and therefore more prone to the devleopment of antibody reactions; it is often given in conjunction with methotrexate in order to minimize these responses. Further, it is contraindicated in patients with suspected multiple sclerosis,167 and there have been several

Therapy

alerts calling attention to the risk of systemic infection (tuberculosis and fungal disease). Like many of the biologics, it is not cheap, with the annual cost for rheumatoid arthritis treatment estimated at £11,000 sterling.168 Finally, others have begun to examine the role of humanized antibodies directed against the same cytokine, using adalimumab (Humira). Mushtaq et al.169 transferred three patients from infliximab to adalimumab and achieved control of their disease. The same caveats apply here, in that it is a small series and we need to see whether this antibody is generally as effective as the one it might replace.

Other approaches

Brief comments should be made about some of the other therapeutic approaches suggested for Behçet’s disease. The use of agents that augment the immune response appears not to be based on any recent information dealing with potential mechanisms for this disease. Plasmapheresis may be a helpful adjunct in an emergency, but in our mind is not practical for long-term use and must usually be accompanied by immunosuppressive therapy. Bonnet and colleagues170 treated seven patients with plasma exchange to remove circulating immune complexes and simultaneously gave high doses of aciclovir, with most discouraging results. The use of antiviral agents cannot currently be supported by information in the literature. However, a randomized study using aciclovir for the treatment of Behçet’s disease showed no value, at least for the orogenital ulcers.171 Some centers both inside and outside the United States have used thalidomide to treat various components of Behçet’s disease. Although some aspects of the disease may respond positively to this approach,172 the ocular lesions do not seem particularly amenable.173 An interesting observation has been the use of thalidomide in the treatment of a patient with neuro-Behçet’s disease, in whom no relapses were seen when this agent was added to chlorambucil and prednisone.174 Stuebiger and associates175 reported regression of neovascularization with IFN-α therapy. Oral prostaglandin E1, a potent vasodilator, has been used to treat the leg ulcers sometimes seen with the peripheral vascular complications of Behçet’s disease.176 Rituximab, an antibody directed against CD20, a marker for B cells, induced a 24-month remission in one patient.177 Additionally, a clinical trial using CAMPATH-1H directed to the CD52 marker, a marker for T cells, induced tolerance in the majority of 18 Behçet’s disease patients treated.178 A randomized study looking at the usefulness of daclizumab in treating the ocular manifestations of the disease did not show it effective as a sole agent. However, the relatively few recurrences in randomized groups prevented an indepth evaluation.179

Our approach to the patient with Behçet’s disease who has severe ocular involvement is as follows (Fig. 26-12). For patients with bilateral disease having their first attack, we usually use systemically administered prednisone and then slowly taper the medication. We know that long-term therapy of this nature will not protect the patient, but our diagnosis may still be wrong or the patient may indeed have only one attack, although this happens rarely. In some cases it might be useful to observe the patient, particularly if one has not witnessed the attack at its peak and sees only

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Part 5 • Uveitic Conditions not Caused by Active Infection Chapter 26 Behçet’s Disease

Ciclosporin Anti-Lymphokine/Lymphokine R therapy (αTNF, αIL-2 therapy)

Cytotoxic agents Colchicine ?anti-Chemokine therapy

Unilateral disease

Figure 26-12.  General outline for treatment of ocular complications of Behçet’s disease.

minimal residua. If the attacks become repetitive, or if the initial attack is particularly severe, then alternative therapeutic agents should be considered. Based on our experience and that of several groups worldwide, we believe that ciclosporin is the initial drug to consider for this disorder, but only after an evaluation determining the feasibility of its use. The goal of therapy is to prevent the recurrent explosive episodes affecting the posterior portion of the globe, and if this is not met we might then consider additional immunosuppressive agents, and then finally add infliximab. Others may turn to IFN-α first, but we have not done so over recent years.

It must be stressed that many agents we use are not approved for the treatment of this disorder in the United States, but certainly some have become standard of care. The patient must be fully aware of the side effects, which one hopes can be minimized. If good control is achieved, it may be that the patient needs to be treated for an extended period, that is, 1–4 years, during which time there can certainly be an attempt to slowly taper the medication. An additional secondary effect of ciclosporin therapy needs to be mentioned here – so far one that has been noted only in patients with Behçet’s disease in Japan. In those patients, CNS symptoms, including pleocytosis in the spinal fluid, have been noted. Because uveitis and neuro-Behçet’s disease are not commonly seen together, these findings are thought to be due to the ciclosporin. Indeed, Kotter and colleagues180 carried out a retrospective review of their patients treated with a variety of agents and found that all of those who developed CNS involvement were receiving ciclosporin. Retrospective studies are difficult to evaluate without randomization. Were the most difficult to control cases receiving ciclosporin? Is ciclosporin adequate for ocular disease but simply not effective in treating CNS involvement? We have not so far recognized this in the patients we have treated, nor was this seen in the randomized study comparing ciclosporin to colchicine.154

If an alternative therapeutic approach is needed, the practitioner might consider the use of colchicine. The usefulness of colchicine for this disorder is still in doubt, and strict criteria for its continuation or stoppage must be established. We have not used it for bilateral sight-threat- ening disease. Alternatively, cytotoxic agents should be considered as well. The vast bulk of the literature supports the use of alkylating agents (chlorambucil or cyclophosphamide) for both the uveitis and the CNS findings in this disease.181 Once again, patients need to know about the potential side effects of these drugs, and the appropriate authorities, if necessary, need to be apprised of the situation. The place of monoclonal antibody therapy still needs to be defined.

In instances of unilateral disease, we usually observe this rare patient with just one attack. If the disease becomes unilaterally recurrent, we might continue to observe the patient if the vision is already markedly diminished because of previous attacks. However, if intervention appears indicated, we would consider using either a periocular steroid or colchicine. Some practitioners have reported the use of intravitreal traimacinolone injections, often giving them repeatedly.182,183 This should not be considered for long-term treatment, but can be used to deal with acute problems needing immediate action. Constant local steroid therapy is not necessarily benign. Ufret-Vincently et al.184 reported the development of cytomegalovirus retinitis in an eye from a Behçet’s disease patient who received a fluorocinolone implant. For these patients we generally do not use ciclosporin. The alternative argument is that most will develop bilateral disease, and the eye initially involved may ultimately be the better one. These are difficult questions that both practitioner and patient must consider on an individual basis.

Surgery is usually not part of the initial therapeutic approach for these patients. In one report of 26 eyes from patients with Behçet’s disease needing vitreoretinal surgery, 15 (58%) had an improvement in vision after surgery, whereas 11 eyes (41%) had no change over a mean followup of 23 months. Ahn et al.185 also suggest that vitrectomy resulted in an improvement in visual acuity and inflammation in the Behçet’s patients they operated on. Evaluating nonrandomized data, and in particular vitrectomy studies, is exceptionally difficult, as medical therapy is usually part of the treatment strategy. The important measure is that Behçet patients need surgery but that it should be performed with under-aggressive immunosuppressive coverage; just what the ideal coverage is not defined. For our group it is any combination that renders the patient’s ocular activity quiescent and that recurrences have not occurred over the past 3 months or longer. There are numerous reports in the literature regarding the need for adequate immunosup­ pressive coverage, including the use of IFN-α.186 Park and colleagues report the large number of postoperative complications in Behçet’s patients.187 Kawaguchi and co­ workers188 reported that such patients had significantly worse outcomes after phacoemulsification and IOL placement than did other uveitis patients, and 35% of the Behçet’s patients suffered relapses. Retinal tears, some at the periphery of an active lesion, may occur and membrane removal may be necessary.181,189 Laser surgery can be performed if the patient is adequately immunosuppressed.