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Current Therapy in BehÁetís Disease

T. Sakane, MD, PhD and Mitsuhiro Takeno MD, PhD
Departments of Immunology and Medicine, St. Marianna University School of Medicine, Kawasaki, Japan

ABSTRACT

BehÁetís disease is an inflammatory disorder of unknown cause. There is often involvement of the gastrointestinal system, the central nervous system and large vessels, which can be life-threatening. As well, ocular lesions can cause blindness. Mucocutaneous symptoms are self-limiting but more frequent. Almost all the patients have recurrent oral aphthous ulcers, and more than 70% of the patients have genital ulcers and skin symptoms, which include erythema nodosum, pseudofolliculitis, papulopustular lesions, acneiform nodules and a positive pathergy test. The pathergy test is felt to reflect cutaneous hypersensitivity. In general, topical treatment using corticosteroids is satisfactory for these mucocutaneous lesions unless eye and vital organs are involved.

Key Words: BehÁetís disease, pathergy test, topical treatment, systemic treatment, cyclosporin A

BehÁetís disease (BD) is an inflammatory disorder, characterized by recurrent oral aphthous ulcers, genital ulcers, uveitis, and skin lesions1. BD patients cluster along the ancient Silk-Road, which extends from eastern Asia to the Mediterranean basin. The prevalence of BD in the countries along the Silk-Road ranges from 13.5 to 380 cases per 100,000, whereas the prevalence in western countries is less than one per 100,0001. This unique geographic distribution suggests possible genetic and environmental factors in the development of BD. It is well established that susceptibility of BD is strongly associated with the HLA-B51 allele2. There is also accumulating evidence that microbial infections trigger cross-reactive autoimmune responses, leading to overt BD. Thus, BD is neither a hereditary disease nor an infectious disease, but is multifactorial.

Vascular injuries, neutrophil infiltration, and hypercoagulability characterize pathological findings of BD lesions. The autoimmune responses against heat shock protein 60 (hsp60) may be involved in the pathological processes, though it remains to be determined whether the autoimmune mechanism is a primary or a secondary event in the development of BD1,2.

There is no established standard therapeutic regimen for BD. Because this condition has a broad spectrum of clinical features, the choice of the treatment depends on the patientís clinical manifestations. This article outlines the clinical features and therapies for BD, focusing on mucocutaneous symptoms.

Diagnosis of BehÁetís Disease

Because BD does not have any specific symptoms and laboratory findings, the diagnosis is made on the basis of the criteria proposed by the International Study Group for BehÁetís Disease in 1990. These criteria require recurrent oral ulceration as an essential symptom, plus any two or more of the following symptoms: genital ulceration, eye lesions, skin lesions, and a positive pathergy test. The pathergy test is performed by piercing a sterile needle subcutaneously into the forearm. It is judged as positive when the puncture leaves an aseptic erythematous nodule or pustule of more than 2mm in diameter after 24-48 hours. The differential diagnosis includes chronic oral aphthosis, herpes simplex virus infection, Sweetís syndrome and HLA-B27-related syndromes such as ankylosing spondylitis. Analysis of HLAphenotypes and the measurement of serum IgD levels may help to make a diagnosis (patients with active BD often have elevated levels of serum IgD)1.

Clinical Manifestations

Oral ulceration is usually an initial symptom that is seen in all patients during the course of the disease. This symptom may be a genetic predisposition, because it frequently precedes other manifestations and is often seen in some of the patientís family members. Painful oral ulcers appear in the gingiva, tongue, buccal, and labial mucosal membranes. The typical lesion is round, with a sharp, erythematous border and the surface is covered with a yellowish pseudomembrane. The lesions heal within 10 days and do not leave scars.

Genital ulcers preferentially recur on the scrotum and penis in men and on the vulva in women. They are painful and morphologically similar to oral ulcers, but they are usually larger and deeper and have an irregular margin. The lesions recur and usually leave scars.

Erythema nodosum is common in female patients and usually occurs on the front of the legs. The lesions are painful. They resolve spontaneously, leaving deeply pigmented areas, and sometimes ulcerations. Pseudofolliculitis and acneiform nodules are common in male patients and are distributed on the back, face, and neck, especially along the hairline. The presence of acneiform nodules in adolescents or in patients who are receiving corticosteroids cannot be used in the diagnosis. Superficial migratory thrombophlebitis of the arms and legs is more common in male patients than in female patients. Because of the irritability of the skin of BD patients, shaving often causes pseudofolliculitis, and intravenous punctures can lead to local thrombophlebitis.

Ocular lesions occur in the uvea and retina. Patients present with sudden attacks of visual loss, blurred vision, floaters, and associated eye pain. Hypopyon, a visible layer of pus in the anterior ocular chamber, is easily recognized, even by nonophthamalogical physicians. The most serious ocular problem in BD is retinal disease, which can cause blindness.

Arthritis is seen in about half of the patients. Epididymitis is seen in some of the patients. Involvement of the gastrointestinal system, the central nervous system and large vessels can lead to serious clinical problems.

Current Treatments

Therapeutic priority is given to the treatment of vital organ lesions, which requires high dose corticosteroids and/or immunosuppressants, and sometimes needs surgical intervention. Treatment of ocular lesions requires more careful consideration than that of the mucocutaneous symptoms.

Topical Treatment

Mucocutaneous lesions, especially genital ulcers, must be kept clean to avoid contaminated secondary infection. Oral and genital ulcers are treated with topical corticosteroids (i.e., triamcinalone acetonide, and corticosteroids in combination with antibiotics). Another topical approach would be the use of a tetracycline solution, which is made by dissolving in the contents of a 250mg capsule in 5ml of water, for aphthous lesions.

Systemic Treatment

Colchicine 1-1.5mg/day has beneficial effects for the mucocutaneous symptoms, presumably by inhibiting neutrophil functions. Systemic corticosteroids are prescribed for erythema nodosum refractory to colchicine. Furthermore, the following drugs have been documented to be effective for treating mucocutaneous lesions: thalidomide1,3, dapsone1, pentoxifylline1, azathioprine1, interferon-alpha1,4, and rebamipide5. However, the mucocutaneous symptoms of BD are self-limiting, and overtreatment should be avoided.

Treatment Dose Indication

Topical Treatment:

Triamcinolone acetonide ointment

3 times/day

Oral ulcers

Betamethasone ointment

3 times/day

Genital ulcers

Tetracycline

250mg in water solution, once/day

Oral ulcers

Systemic Treatment:

Colchicine

0.5-1.5mg/day orally

Oral ulcers, genital ulcers, pseudofolliculitis, erythema nodosum

Prednisone

5-20mg/day orally

Erythema nodosum

Thalidomide

100-300mg/day orally

Oral ulcers, genital ulcers, pseudofolliculitis

Dapsone

100mg/day orally

Oral ulcers, genital ulcers, pseudofolliculitis, erythema nodosum

Pentoxifylline

300mg/day orally

Oral ulcers, genital ulcers, pseudofolliculitis, erythema nodosum

Azathioprine

100mg/day orally

Oral ulcers, genital ulcers, pseudofolliculitis, erythema nodosum

Interferon-alpha

Remission induction: 6x106 IU/day SC for one month; Maintenance: 3x106IU/day SC

Oral ulcers, genital ulcers, pseudofolliculitis, erythema nodosum

Table 1: Current therapies for mucocutaneous lesions.

Ocular Lesions

Colchicine is first prescribed to prevent both anterior and posterior uveitis. Topical mydriatics and corticosteroid drops are given for the treatment of anterior uveitis. Topical injection, in some cases with systemic administration, of corticosteroids is used for the acute attacks of posterior uveitis. Cyclosporin A becomes the first line therapy for uveitis1,6, while conventional cytotoxic agents such as azathioprine, chlorambucil and cyclophosphamide are other alternatives1. Recent trials using interferon-alpha (IFN-alpha) to treat BD have produced encouraging results1,4.

Involvement of Vital Organs

The treatments for inflammatory bowel diseases are also applicable for the gastrointestinal lesions found in BD. Sulfasalazine and corticosteroids are the principal drugs. High doses of corticosteroids with cytotoxic immunosuppressants are administered for neurological involvement. A combination therapy of corticosteroids and cytotoxic agents, supplemented with anticoagulants and antiplatelet agents is used for vascular lesions.

Surgical approaches should be considered for gastrointestinal perforation, uncontrollable intestinal bleeding, or rupture of an aneurysm.

Conclusion

Local treatment with corticosteroids is satisfactory in most of the mucocutaneous lesions. Colchicine is useful to prevent the attacks of individual symptoms. Overtreatment should be avoided for mucocutaneous lesions unless they are complicated by more serious symptoms.

References

  1. Sakane T, Takeno M, Suzuki N, Inaba G. BehÁetís disease. N Engl J Med 341(17):1284-91 (1999 Oct).
  2. Sakane T. New perspective on BehÁetís disease. Int Rev Immunol 14(1):89-96 (1997).
  3. Hamuryudan V, Mat C, Saip S, et al. Thalidomide in the treatment of the mucocutaneous lesions of the BehÁet syndrome: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 128(6):443-50 (1998 Mar).
  4. Zouboulis CC, Orfanos CE. Treatment of Adamantiades-BehÁet disease with systemic interferon-alpha. Arch Dermatol 134(8):1010-6 (1998 Aug).
  5. Kaklamani VG, Vaiopoulos G, Kaklamanis PG. BehÁetís disease. Semin Arthritis Rheum 27(4):197-217 (1998 Feb).
  6. Masuda K, Nakajima A, Urayama A, Nakae K, Kogure M, Inaba G. Doublemasked trial of cyclosporin versus colchicine and long-term open study of cyclosporin in BehÁetís disease. Lancet 1(8647):1093-6 (1989 May)

In this issue:

  1. Vitiligo Management Update
  2. Current Therapy in BehÁetís Disease
  3. Update on Drugs and Drug News - Number 6 1999