Infliximab for Beh¿et's disease with severe uveitis

July 13, 2004

Jul 13, 2004

Portland, OR - The TNF inhibitor infliximab (Remicade, Centocor) is the drug of choice for ocular Beh¿et's disease (BD), which has proven refractory to older immunosuppressants, says an expert in the field, Dr James T Rosenbaum (Casey Eye Institute, Oregon Health & Science University, Portland).





In an editorial in the July 2004 issue of the Journal of Rheumatology [ 1 ], Rosenbaum discusses the pros and cons of TNF-alpha inhibitor therapy for refractory uveitis associated with Beh¿et's disease and why he believes infliximab is currently the best option.

"A lot of people are impressed with infliximab for Beh¿et's disease," he told rheumawire .

A lot of people are impressed with infliximab for Beh¿et's disease.

Also in the journal is a study by Dr Shigeaki Ohno (Hokkaido University Graduate School of Medicine, Sapporo, Japan) and colleagues [ 2 ], which found that administration of infliximab to patients with Beh¿et's disease and refractory uveitis suppressed the frequency of ocular attacks.

Uveitis is often the dominant clinical finding of BD

Beh¿et's disease typically begins when patients are in their 20s or 30s. A rare, chronic disorder that involves inflammation of blood vessels throughout the body, it is characterized by recurrent oral ulcers, recurrent genital ulcers, and eye inflammation. The disorder may also cause various types of skin lesions, arthritis, bowel inflammation, and meningitis and has the potential to affect all organs, including the central nervous system. Beh¿et's disease is most common in Japan and China as well as countries such as Turkey and Iran.

"Intraocular inflammation, or uveitis, typifies Beh¿et's disease, and it is often the dominant clinical finding," explains Rosenbaum.

In the new study by Ohno et al, infliximab was given 4 times, at weeks 0, 2, 6, and 10 at doses of 5 mg/kg or 10 mg/kg by intravenous infusion to 13 patients with Beh¿et's disease accompanied by uveoretinitis that was resistant to cyclosporine.

The mean numbers of ocular attacks—converted to frequency per 14 weeks—were 3.96 times for the 5-mg/kg group and 3.79 times for the higher-dose group during the observation period. Following treatment with infliximab, attacks decreased to 0.98 times and 0.16 times, respectively. One serious adverse event—tuberculosis—was seen in the 10-mg/kg group.

These findings are "consistent with other favorable reports about treating the uveitis associated with Beh¿et's disease with a monoclonal antibody to TNF, including publications from Greece, England, and Spain as well as case reports and abstracts," says Rosenbaum.

He continues: "In the largest series published to date [the Greek study], 24 of 25 patients with ocular Beh¿et's disease experienced a prompt remission of the eye disease after a single infusion." In 15 of these patients, infusions were repeated periodically for 32 weeks, and 60% of those receiving sustained therapy had no further attacks during treatment, he notes.

Many questions remain

But despite these encouraging observations, many questions remain, says Rosenbaum. "Is TNF inhibition safe in treating BD?" for example. While the report of Ohno et al is "encouraging" in this respect, despite 1 case of tuberculosis, the study size is too small to exclude the possibility of unique toxicities associated with this disease, he notes. "The effect of TNF inhibition on infectious complications, on thrombosis, and on the neurological manifestations of BD especially deserves careful scrutiny."

Rosenbaum told rheumawire that in his own previous open-label study with infliximab for various forms of severe uveitis, "we observed serious side effects -- both pulmonary embolism and lupuslike reactions -- during the course of therapy."

We observed serious side effects. . . . This should signal caution to someone in a solo practice.

"We don't know whether patients who have localized inflammatory disease might have more toxicity [with TNF inhibitors]; this should signal caution to someone in a solo practice," Rosenbaum said.

How should infliximab be given? What about other agents?

Also, it is not known whether it's necessary or desirable to give infliximab with other immunosuppressive agents, Rosenbaum says. "At the moment, we are using infliximab with azathioprine and cyclosporine, but I am more reticent to use it with cyclophosphamide, as there are preliminary data in vasculitis that this combination could lead to more toxicity," he notes.

In addition, the optimal dose of infliximab and the optimal frequency of therapy remain unclear. "Since BD is episodic, should treatment be given only with each attack? Or will that approach promote synthesis of neutralizing antibodies?"

Rosenbaum says he currently uses a dose of 3 mg/kg of infliximab if a patient is already taking another immunosuppressant and uses the same regimen as in rheumatoid arthritis -- loading doses at 0, 2, and 6 weeks and then repeated infusions every 2 months. If the patient is not taking any other immunosuppressant, a dose of 5 mg/kg is used.

With respect to other agents, etanercept (Enbrel, Amgen/Wyeth), another TNF inhibitor, does not seem to be as effective for this indication, says Rosenbaum. But the newer TNF inhibitor adalimumab (Humira, Abbott Laboratories) -- which is a monoclonal antibody like infliximab -- holds promise. "There are published data on adalimumab for uveitis in juvenile arthritis, and it seems encouraging," he says, adding, "We hope to be looking at it in the future."

There has also been an optimistic report on interferon-alpha in 50 patients with ocular BD in which a response rate of 92% was seen, Rosenbaum notes, but he says in his experience "interferon-alpha is not pleasant to receive—people feel sick, they get myalgias and fever."

Even with these caveats in mind, my current belief is that infliximab is the drug of choice for ocular BD.

In conclusion, Rosenbaum says that "untreated ocular BD frequently leads to blindness in less than 4 years from its onset." Caution is required in using a TNF inhibitor in a patient with central-nervous-system disease or a thrombotic diathesis, and patients should be active participants in the choice of therapy, he says. "But even with these caveats in mind, my current belief is that infliximab is the drug of choice for ocular BD. The study by Ohno and colleagues in this issue strongly supports this conclusion."

Sources

  1. Rosenbaum JT. Blind insight: Eyeing anti-tumor necrosis factor treatment in uveitis associated with Beh¿et's disease. J Rheumatol 2004; 31:1241-1243. Abstract

  2. Ohno S, Nakamura S, Hori S, et al. Efficacy, safety and pharmacokinetics of multiple administration of infliximab in Beh¿et's disease with refractory uveitis. J Rheumatol 2004; 31:1362-1368. Abstract

 

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