Behcet's disease M35.2

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 31.01.2021

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Synonym(s)

Adamantiades-Behcet disease; Adamantiades-Behcet's disease; Aphthose large; Aphthosis Behçet; Aphthouses Touraine; Behçet aphthae; Behcet's disease; Behcet's syndrome; Behçet's syndrome; bipolar aphthaesia; Bipolar aphthosis; cutaneous muco-uveal syndrome; Gilbert Syndrome; Grande Aphthose Touraine; Hypopyoniritis; iridocyclitis septica (Gilbert); large aphthose; malignant aphthaemia; malignant aphthouses; Neuro-Behçet; Ophthalmia lenta; recurrent; Trisymptom complex

History
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Gilbert, 1925; Adamantiades, 1931; Behçet, 1937

Definition
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Chronic, inflammatory, intermittent systemic disease with multiple organ involvement in the context of generalized vasculitis. The main clinical symptom is the triad: aphthae of the oral mucosa, aphthous genital ulcers, peripheral retinitis.

Occurrence/Epidemiology
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Mainly Eastern Mediterranean countries (Turkey, Greece), Middle East, Japan. Incidence (Turkey): 300-400/100.000 inhabitants/year. Incidence (Federal Republic of Germany): 1-2/100,000 inhabitants/year.

Etiopathogenesis
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The exact cause is unknown; it is suspected that there is a defect in cellular immunity. Association with HLA-B5, -B27, -B12, B-51.

Manifestation
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Mostly between the ages of 20 and 40, men are affected significantly more often than women.

Clinical features
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A distinction is made between major and minor symptoms. The diagnosis of M. Behçet's disease can be confirmed if at least two main and two secondary symptoms are present (percentages in brackets indicate the frequency of symptoms).

  • Main symptoms:
    • Disseminated, multiple, often very painful aphthae of the oral mucosa (100%).
    • Painful, smeary, ulcerative genital lesions (90%).
    • Ocular involvement (50%): Painful photophobia, rarely retinitis, uveitis, evidence of cells in the vitreous, hemorrhages of the vitreous and at the fundus. Any recurrence leads to an initially temporary, later permanent reduction in vision. Usually development of amaurosis. Characteristic is the marked painfulness of recurrent retinitis.
  • Secondary symptoms:
    • Recurrent erythema nodosum (80%)
    • Sterile pustules (80%)
    • Pathergy phenomenon: Local hyperergic reaction of the skin when traumatized, e.g. formation of inflammatory induration at puncture sites.
    • Increased fragility, hemorrhages of the skin and mucous membranes, recurrent thrombosis and thrombophlebitis (25%).
    • Arthralgias and rheumatoid factor negative polyarthritides (40-50%)
    • epididymitis, orchitis
    • Rare development of chronic meningoencephalitis with poor prognosis (= so-called neuro-Behçet complex)
    • Pulmonary involvement (rare) with hilar reactions, infiltrations, aphthae and haemorrhages of the trachea and bronchi, haemoptysis.
    • Gastrointestinal manifestations (10-25%): Ulcerative oesophagitis and (ileocecal) colitis with bleeding of the gastrointestinal tract.
    • Others: haematuria, swelling of the salivary and lacrimal glands.

Depending on the predominant manifestation, the disease is divided into mucocutaneous, arthritic, neurological and ocular type.

Laboratory
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Depending on the severity of the disease, unspecific signs of inflammation can vary in severity. Eosinophilia is possible.

Diagnosis
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Nonspecific signs of inflammation in blood test; positive pathergy test (appearance of a papule or pustule after intracutaneous injection of 0.1 ml NaCl on the forearm polar side); the OKT4:OKT8 ratio is decreased; C9 is increased. Ophthalmological, neurological, rheumatological, gastroenterological examination.

Differential diagnosis
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Sarcoidosis; seronegative arthritis of other causes; chronic inflammatory bowel diseases; multiple sclerosis; gingivostomatitis herpetica; habitual aphthae.

Therapy
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No standard therapy available. The individual organ manifestations show different responses to medication, see Table 1.

General therapy
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Diet for aphthous changes: Acid and spice free; no fruit acids because of strong burning; little salt; no pepper or paprika.

External therapy
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  • Genital ulcers: Combination of fluorinated glucocorticoids and antiseptics in a cream base (e.g. Locacorten-Vioform, Duogalen). For painful scrotal ulcers, external anaesthetics in the form of a gel or cream can be helpful, such as 2-5% lidocaine (e.g. Xylocaine Viscous Ointment), 1.5% mepivacaine (e.g. Meaverin Gel) or combination preparations with polidocanol (e.g. Scandicain Gel).
  • Aphthae: Antiseptic and antiphlogistic with hexiditine (e.g. Hexoral Lsg.), dexpanthenol (e.g. Bepanthen Lsg./Lutschtbl.) or camomile extracts (e.g. Kamillosan Lsg.). Local anaesthetic topicals (e.g. Dynexan A mouth gel). Topical glucocorticoids: e.g. irrigation with prednisolone (1 tbl. prednisolone 20-50 mg dissolved in 200 ml tap water; rinse 4 minutes), triamcinolone acetonide ointment (e.g. Volon A ointment) or mouth gel for night use. Alternatively, put "Clobetasol mice" (small cotton swabs soaked with Clobegalen cream on the aphthae twice a day for 10 minutes). S.a.u. Aphthae, habituelle.

Internal therapy
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  • Mucocutaneous:
    • Internal therapy for severe forms of the mucocutaneous variant or if there is no improvement following external treatment. Glucocorticoids such as prednisolone (e.g. Decortin H) 40-60 mg/day p.o. over several weeks in decreasing doses is the first choice.
    • Since glucocorticoids are often not sufficiently effective as monotherapy, if necessary combination with azathioprine p.o. (e.g. Imurek) 100 mg/day or Thalidomide 100-400 mg/day Cave! Off-Label-Use! Continuation for 2-3 months until the systemic glucocorticoid can be discontinued. Followed by monotherapy with azathioprine or thalidomide.
    • Alternative: Especially for erythema nodosum DADPS (e.g. Dapson-Fatol) 100-150 mg/day p.o. for 4-7 months. Cave! Determination of glucose-6-phosphate dehydrogenase before starting therapy!
    • Alternatively colchicine (e.g. Colchicum-Dispert) initial 1-2 mg/day p.o. in 2-3 ED, afterwards 0.5-1 mg every 1-2 days for 2 months to 2 years or maintenance dose according to clinic. Cave! Contraception!
    • Alternative: Newer treatment approaches with interferon alfa-2a (e.g. Roferon) show good results and are trend-setting; dosage: 3 times/week 3-4 million IU s.c. over 6 months.
    • Additive: In severe cases Indometacin (e.g. Amuno) 100 mg/day can be effective for 3 months.

  • Ocular (Immunosuppressive drugs such as Ciclosporin A, Azathioprine and glucocorticoids are first choice, but can at best halt the decline in vision. In case of uveitis remission > 2 years, no further therapy is necessary):
    • Ciclosporin A (e.g. Sandimmun): Systemic therapy with 5-6 mg/kg bw/day p.o. in 2 ED over 3 months is the most effective procedure in case of eye manifestation. Serum level should be 50-150 ng/ml. In case of rapid reduction rebound phenomena are to be expected. In case of non-response, combination with glucocorticoids like prednisolone (e.g. Decortin H) 0.2-0.4 mg/kg bw/day p.o. is possible.
    • Azathioprine (e.g. Imurek): 1-2.5 mg/kg bw/day p.o. can be used as monotherapy or in combination with glucocorticoids. In the case of monocular symptoms it has a preventive effect on infestation of the other eye.
    • High-dose glucocorticoids, e.g. prednisolone (Solu-Decortin H) as pulse therapy 1000/750/500/250 mg/day, each as a short infusion, can improve the inflammation, but have no influence on the recurrence frequency and overall prognosis of the uveitis.
  • Neurological:
    • The only safe treatment is high-dose glucocorticoids like prednisolone 100-150 mg/day i.v. with slow dose reduction. Alternatively, cyclophosphamide as bolus therapy once/week 1000 mg i.v. or chlorambucil (e.g. Leukeran) 0.1 mg/kg bw/day p.o. can be effective.
  • vascular:
    • Glucocorticoids such as prednisolone (e.g. Decortin H) 100-250 mg/day p.o. in combination with azathioprine (e.g. Imurek) 200 mg/day p.o. are agents of choice. Anticoagulants for acute superficial thrombophlebitis and phlebothrombosis. Cave! Anticoagulants for pulmonary vasculitis!
    • Gastrointestinal: sulfasalazine (e.g. azulfidine) in gastrointestinal ulcerations. Because of intolerance therapy should be started slowly, initially 0.5 g/day p.o., weekly increase by 0.5 g/day, maintenance dose 2 g/day. Intermediate increase to 3 g/day possible.
  • Articular:
    • Non-steroidal anti-inflammatory drugs such as indomethacin (e.g. Amuno) 100 mg/day p.o. for 3 weeks or prednisolone 4-8 mg/day p.o. Intra-articular glucocorticoids (e.g. Lederlon) in case of infestation of individual joints. Therapy trial with colchicine (e.g. Colchicum-Dispert) initial 1-2 mg/day p.o. in 2-3 ED, maintenance dose with 0.5-1 mg p.o. every 1-2 days for 2 months to 2 years depending on the symptoms. Cave! Contraception! Combination with glucocorticoids possible if symptoms persist.
  • Experimental: In a double-blind, placebo-controlled study over 4 weeks 40 subjects were treated with Etanercept 2 times/day 25 mg. Already after the first week of treatment significant clinical improvements were seen, at the end of the study significantly less disease foci were documented.

Progression/forecast
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Chronic relapsing course.

Tables
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Range of action of various drugs in the symptom spectrum of Behçet's disease (modified according to Orfanos)

Clinical manifestations

Mucocutaneous

Ocular

Neurological

Vascular

Articulate

Gastrointestinal

External treatment

+++

+++

-

-

-

+a

Thalidomide

++

-

-

-

-

-

Indomethacin

+b

-

-

-

+++

-

Colchicine

++

-

-

-

+++

-

Dapson

+

-

-

-

-

-

Glucocorticoids

+++

+

+++

+++

+++

-c

Azathioprine

++

+

-

+++

-

-c

cyclophosphamide, chlorambucil

-

-

+

-

-

-

Ciclosporin A

-

+++

-

+

-

-

Sulfasalazine

+++

Interferon e

++

-

-

-

++

-

Anticoagulants

-

-

-

+/- d

-

-

Literature
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  1. Adamantiades B (1931) Sur un cas d'iritis à hypopyon récidivant. Annales d'oculistique (Paris) 168: 271-278
  2. Alpsoy E et al (2002) Interferon alfa-2a in the treatment of Behcet disease: a randomized placebo-controlled and double-blind study. Arch Dermatol 138: 467-471
  3. Alpsoy E et al (1999) The use of sucralfate suspension in the treatment of oral and genital ulceration of Behcet disease: a randomized, placebo-controlled, double-blind study. Arch Dermatol 135: 529-532
  4. Batioglu F (2003) Factor V Leiden and prothrombin gene G20210A mutations in ocular Behcet disease. Acta Ophthalmol Scand 81: 283-285
  5. Behçet H (1937) On recurrent, aphtous ulcers of the mouth, eye and genitals caused by a virus Dermatological weekly (Hamburg) 105: 1152-1163
  6. Gilbert W (1925) About a chronic form of metastatic ophthalmia ("Ophtalmia lenta"). Archive for Ophthalmology (Wiesbaden) 96: 119-130
  7. Melikoglu M et al (2005) Short-term trial of etanercept in Behcet's disease: a double blind, placebo controlled study. J Rheumatol 32: 98-105
  8. Yazici H (2001) Behcet disease. Curr Opin Rheumatol 13: 18-22
  9. Zouboulis CC et al (1993) Therapeutic use of systemic recombinant interferon-alpha-2a. Dermatologist 44: 440-445

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Last updated on: 31.01.2021