Behcet's disease M35.2

Author: Prof. Dr. med. Peter Altmeyer

All authors of this article

Last updated on: 22.11.2021

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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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The ABD prevalence in the total German population calculated from new data (2018) is 4.7 per 100,000. The highest prevalence is found in Turkey with 20/100,000 inhabitants (in some places it even rises up to 420). Turks living in Germany have a significantly higher risk of contracting the disease than the general German population. But the prevalence among Turks living in Germany is lower than in Turkey.

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 cream base (e.g. Locacorten-Vioform, Duogalen). For painful scrotal ulcers, external anesthetics in gel or cream form may be helpful such as 2-5% lidocaine (e.g. Xylocaine Viscös Ointment), 1.5% mepivacaine (e.g. Meaverin Gel) or combination preparations with polidocanol (e.g. Scandicain Gel).

Aphthae: Antiseptic and antiphlogistic with hexiditin (e.g. Hexoral Lsg.), dexpanthenol (e.g. Bepanthen Lsg./Lutschtbl.) or camomile extracts (e.g. Kamillosan Lsg.). Local anaesthetic externals (e.g. Dynexan A mouth gel). Topical glucocorticoids: e.g. rinses with prednisolone (1 tbl. prednisolone 20-50 mg dissolved in 200 ml tap water; rinse for 4 minutes), triamcinolone acetonide adhesive ointment (e.g. Volon A adhesive ointment) or oral gel applied at night. Alternatively, insert "clobetasol mice" (apply small cotton swabs soaked in clobegal cream to the aphthae 2 times/day for 10 minutes). S.a.u. Aphthae, habituelle.

Internal therapy
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  • Mucocutaneous:
    • Internal therapy in severe courses of the mucocutaneous variant or if there is no improvement on external treatment. Glucocorticoids such as prednisolone (e.g. Decortin H) 40-60 mg/day p.o. for several weeks in descending doses is the first choice.
    • Since glucocorticoids are often not sufficiently effective as monotherapy, combination with azathioprine p.o. if necessary. (e.g. Imurek) 100 mg/day or thalidomide 100-400 mg/day Caution! Off-label use!. Continue for 2-3 months until systemic glucocorticoid can be discontinued. Subsequently monotherapy with azathioprine or thalidomide.
    • Alternative: DADPS (e.g. dapsone-fatol) 100-150 mg/day p.o. for 4-7 months, especially for erythema nodosum. Caution! Determine glucose-6-phosphate dehydrogenase before starting therapy!
    • Alternatively colchicine (e.g. Colchicum-Dispert) initially 1-2 mg/day p.o. in 2-3 ED, then 0.5-1 mg every 1-2 days for 2 months to 2 years or maintenance dose according to clinic. Caution. Contraception!
    • Alternative: Newer treatment approaches with interferon alfa-2a (e.g. Roferon) show good success and are forward-looking; dosage: 3 times/week 3-4 million IU s.c. over 6 months.
    • Alternative: Biologics such as the TNF-alpha inhibitors adalimumab (approved since June 2016 in the indication uveitis, panuveitis), etanercept and infliximab can be used successfully in Behcet's disease.

    • The oral low-molecular inhibitor of phosphodiesterase-4 (PDE-4) apremilast (Otezla®), which has already proven its worth as a modulator of inflammatory mediators in psoriasis, has also been approved for Behcet's disease since April 2020.

    • Additive: In severe cases, indomethacin (e.g. Amuno) 100 mg/day for 3 months may also be effective.

  • Ocular (immunosuppressants such as ciclosporin A, azathioprine, and glucocorticoids are first-line agents, but can at best halt the decline in vision. If the uveitis is in remission > 2 years, therapy is no longer necessary):
    • Ciclosporin A (e.g. Sandimmune): Systemic therapy with 5-6 mg/kg bw/day p.o. in 2 ED for 3 months is the most effective approach for ocular manifestations. Serum levels should be 50-150 ng/ml. Rebound phenomena are to be expected with rapid reduction. In case of non-response, combination with glucocorticoids such as 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. Prevents infestation of the other eye in monocular symptoms.
    • High doses of glucocorticoids, e.g. prednisolone (Solu-Decortin H) as pulse therapy 1000/750/500/250 mg/day, each as short infusion, can improve the inflammation, but have no influence on recurrence frequency and overall prognosis of uveitis.
  • Neurologic:
    • The only reliable treatment is high-dose glucocorticoids such as prednisolone 100-150 mg/day i.v. with slow dose reduction. Alternatively: cyclophosphamide as bolus therapy 1 time/week 1000 mg i.v. or chlorambucil (e.g. Leukeran) 0.1 mg/kg bw/day p.o. may 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. Caveat. Anticoagulants in pulmonary vasculitis!
    • Gastrointestinal: Sulfasalazine (e.g. azulfidine) in gastrointestinal ulcerations. Because of intolerance, slowly introduce therapy, 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) if individual joints are affected. Therapy trial with colchicine (e.g. Colchicum-Dispert) initially 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 symptoms. Caution! Contraception! Combination with glucocorticoids possible if symptoms persist.

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 genitalia caused by a virus. Dermatologische Wochenschrift (Hamburg) 105: 1152-1163
  6. Gilbert W (1925) On a chronic course of metastatic ophtalmia ("Ophtalmia lenta"). Archives of Ophthalmology (Wiesbaden) 96: 119-130.
  7. Huhn CK et al. (2019) Skin inflammation associated with arthritis, synovitis and enthesitis. Part 1: psoriatic arthritis, SAPHO syndrome, Still's disease, Behçet's disease. J Dtsch Dermatol Ges 17:43-64.
  8. 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
  9. Yazici H (2001) Behcet's disease. Curr Opin Rheumatol 13: 18-22
  10. Zouboulis CC et al (1993) Therapeutic use of systemic recombinant interferon-alpha-2a. Dermatologist 44: 440-445

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Authors

Last updated on: 22.11.2021