Behçet's Disease

History and Epidemiology

Behçet’s disease — also known as Behçet’s syndrome, Behçet’s vasculitis, Adamantiades-Behçet’s syndrome, and Silk Road disease — is a chronic inflammatory disorder affecting multiple systems throughout the body. Symptoms of Behçet’s disease may have been described as early as the 5^th century by Hippocrates¹ and were reported by Adamantiades, another Greek physician, in 1931.²

However, Behçet’s disease was named after Turkish dermatologist and scientist Hulusi Behçet, the first to recognize the key triad of symptoms contributing to the disease in 1937.³ Behçet’s disease is most prevalent throughout the Middle East and East Asia (370 patients per 100,000 in Turkey, 80 per 100,000 in Iran, and 14 per 100,000 in China) but is rarer in the United States (5.2 per 100,000), Europe (0.64 per 100,00 in the United Kingdom), and Africa (7.6 per 100,000 in Egypt).⁴

Behçet’s Disease Diagnosis & Presentation

Behçet’s disease causes inflammation in blood vessels throughout the body, with veins more commonly affected than arteries.⁴ The International Study Group (ISG) for Behçet disease criteria are the most widely used.⁵ To meet these criteria, patients much have recurrent oral ulcers (at least three times over a 12-month period), as well as two of the following symptoms:

Recurrent genital ulcers
Eye lesions (eg, retinal vasculitis)
Skin lesions (eg, erythema nodosum)
A positive pathergy test

Despite their widespread usage, the ISG criteria are not without limitations. Eighty percent of patients used to formulate the ISG criteria were from the Middle East, where gastrointestinal symptoms and involvement is less common compared to in other parts of the world. Furthermore, these criteria do not consider the prevalence of symptoms.⁶ Additional diagnostic criteria for Behçet disease have been developed,⁷ but the new criteria have lower specificity than the ISG criteria.⁸

Additional symptoms of Behçet’s disease include pericarditis, arthritis (especially in the lower limbs), abdominal pain, hemoptysis, and pleuritis.^9,10 Neurological involvement — dubbed neuro-Behçet disease — is less frequent compared to other symptoms but is considered a more devastating manifestation. Three quarters of patients with neurological involvement display parenchymal nervous system lesions and may present with hemiparesis, dysarthria, ataxia, cranial neuropathies, and severe headache.^11,12

Diagnostic Workup

There is no single laboratory test used to diagnose Behçet’s disease. The diagnostic workup typically begins by taking a detailed history, completing a systematic examination and workup — including serology and laboratory tests (blood and urine tests, skin biopsies) — and referring to the ISG diagnostic criteria specified above (i.e., recurrent genital ulcers, eye/skin lesions, and a positive pathergy test.¹³

Almost all patients with Behçet’s disease (97% to 99%) present with multiple, painful, and recurrent oral ulcers affecting the soft palate, hard palate, tongue, lips, tonsils, buccal mucosa, and gingiva. Genital lesions are slightly less common (seen in more than 80% of patients), occurring on the scrotum in males and on the vulva or vagina in females.¹⁴

Imaging can assist in determining the extent of organ involvement in Behçet’s disease:

X-rays or arthrocentesis for arthritis
CT (including angiography) for bleeding, thrombosis, and aneurysms or vessel involvement in the chest and abdomen
MRI for neurological involvement
Echocardiography for cardiac involvement
Ultrasonography for differentiation of lesions and biopsies
Retinal imaging for peripheral lesions
Optical coherence tomography to confirm macular edema.⁶

Gastrointestinal involvement can be determined using fecal calprotectin levels.⁶ A lumbar puncture can evaluate if meningitis is present.

Behçet’s Disease Differential Diagnosis

The diagnosis of Behçet’s disease can be challenging due to the lack of specific or characteristic laboratory findings. Consequently, laboratory tests and investigations are undertaken to rule out other conditions. The symptoms of Behçet’s disease can appear similar other conditions, including:

Inflammatory bowel disease (IBD)
Seronegative arthritis
Systemic lupus erythematosus (SLE)
Herpetic infections²³

Behçet’s Disease Management

The management of Behçet’s disease aims to control symptoms and prevent organ damage by decreasing inflammation and/or suppressing the immune system.^17,18 Consequently, it is difficult to define a standard treatment for Behçet’s disease, as the management approach will be dictated by symptom presence and severity, as well as other patient and provider factors.⁶ However, most patients with Behçet’s disease display an undulating pattern of disease activity, where they improve over time as their symptoms become milder.¹⁹

Table 1. Range of management approaches used in Behçet disease.^6,15

Symptom	Treatment(s)
Ulcers and arthritis	Colchicine (effective for arthritis, conflicting evidence for oral ulcers)²⁰ Mouthwash containing local anesthetic (for oral ulcers) NSAIDS Apremilast Immunosuppressive or biological agents (eg, azathioprine, thalidomide, adalimumab, IFNα, and etanercept) Monoclonal antibodies (ustekinumab, secukinumab) TNF inhibitors (certolizumab, golimumab) Topical corticosteroids
Thrombotic complications	Rest and limb elevation Compression stockings Topical antibiotics TNF inhibitors
Arterial and nervous system involvement	Methylprednisolone pulses prior to oral prednisolone and immunosuppressives Cyclophosphamide TNF inhibitors
Ocular disease	Immunosuppressive or biological agents Infliximab, adalimumab Dexamethasone implants Aspirin Retinal laser photocoagulation Vitrectomy Topical (cortico)steroids (eg, fluocinolone acetonide)
Gastrointestinal involvement	Mesalazine Corticosteroids Immunomodulators (azathioprine, 6- mercaptopurine) TNF inhibitors (infliximab, adalimumab)

Monitoring Behçet’s Disease Side Effects

The prevention of post-thrombolytic complications in Behçet’s disease is controversial. If patients develop an arterial aneurysm, the bleeding can be fatal.⁶ It is not uncommon for patients to rapidly develop cataracts following local steroid use for ocular symptoms, but the treatment remains highly effective. The larger risk associated with steroid use is the development of secondary glaucoma. Close follow-ups are required.⁶

Adalimumab, while shown to be an effective treatment, is associated with infections and injection site reactions.²¹ Other drugs, such as IFNα, can lead to a reduced quality of life due to the frequency of adverse events associated with these medications.²²

References

1. Feigenbaum A. Description of Behçet’s Syndrome in the Hippocratic Third Book of Endemic Diseases. Br J Ophthalmol. 1956;40(6):355–357. doi: 10.1136/bjo.40.6.355

2. Adamantiades B. Sur un case d’iritis á hypopyon récidivant. Ann Oculist (Paris). 1931;168:271–278.

3. Behçet H. Über rezidiverende, apthöse durch ein Virus verursachte Geschwüre am Mund, am uge und an der Genitalen. Dermatol Wochenschr. 1937;105:1152–1157.

4. Yazici H, Seyahi E, Hatemi G, Yazici Y. Behçet syndrome: a contemporary view. Nat Rev Rheumatol. 2018;14(2): 107–119. doi: 10.1038/nrrheum.2017.208

5. International Study Group for Behçet’s Disease. Criteria for diagnosis of Behçet’s disease. Lancet. 1990;335(8697):1078-1080.

6. Yazici Y, Hatemi G, Bodaghi B, et al. Behçet syndrome. Nat Rev Dis Primers. 2021;7(1):67. doi: 10.1038/s41572-021-00301-1

7. International Team for the Revision of the International Criteria for Behçet’s Disease (ITR-ICBD). The International Criteria for Behçet’s Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria. J Eur Acad Dermatol Venereol. 2014;28(3):338-347. doi: 10.1111/jdv.12107

8. Blake T, Pickup L, Carruthers D, et al. Birmingham Behçet’s service: classification of disease and application of the 2014 International Criteria for Behçet’s Disease (ICBD) to a UK cohort. BMC Musculoskelet Disord. 2017;18(1):101. doi: 10.1186/s12891-017-1463-y

9. Bolster MB. MKSAP 15 Medical Knowledge Self-assessment Program: Rheumatology. Philadelphia: American College of Physicians; 2009.

10. Hatemi G, Seyahi E, Fresko I, Hamuryudan V. Behçet’s syndrome: a critical digest of the recent literature. Clin Exp Rheumatol. 2012;33(6 Suppl 94):S3-14.

11. Al-Araji A, Kidd DP. Neuro-Behçet’s disease: epidemiology, clinical characteristics, and management. Lancet Neurol. 2009;8(2): 192–204. doi:10.1016/S1474-4422(09)70015-8

12. Uygunoğlu U. & Siva A. Nervous system involvement in Behçet’s syndrome. Curr Opin Rheumatol. 2019;31(1):32-39. doi: 10.1097/BOR.0000000000000562

13. Davatchi F. Diagnosis/Classification Criteria for Behcet’s Disease. Patholog Res Int. 2012;2012:607921. doi: 10.1155/2012/607921

14. Adil A, Goyal A, Quint JM. Behcet Disease. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022.

15. Behçet’s Syndrome. Rare Disease Database. Published 2018. Accessed 22 July 2022.

16. Kiafar M, Faezi ST, Kasaeian A, et al. Diagnosis of Behçet’s disease: clinical characteristics, diagnostic criteria, and differential diagnoses. BMC Rheumatol. 2021;5(1):2. doi: 10.1186/s41927-020-00172-1

17. Shahneh F, Mohammadian M, Babaloo Z, Baradaran B. New approaches in immunotherapy of behçet disease. Adv Pharm Bull. 2013;3(1):9-11. doi: 10.5681/apb.2013.002

18. Alpsoy E, Akman A. Behçet’s disease: an algorithmic approach to its treatment. Arch Dermatol Res. 2009;301(10):693-702. doi: 10.1007/s00403-009-0990-2

19. Kural- Seyahi E, Fresko I, Seyahi N, et al. The long-term mortality and morbidity of Behçet syndrome: a 2-decade outcome survey of 387 patients followed at a dedicated center. Medicine. 2003;82(1):60-76. doi: 10.1097/00005792-200301000-00006

20. Leccese P, Ozguler Y, Christensen R, et al. Management of skin, mucosa and joint involvement of Behçet’s syndrome: A systematic review for update of the EULAR recommendations for the management of Behçet’s syndrome. Semin Arthritis Rheum. 2019;48(4):752-762. doi: 10.1016/j.semarthrit.2018.05.008

21. Suzuki Y, Hagiwara T, Kobayashi M, et al. Long-term safety and effectiveness of adalimumab in 462 patients with intestinal Behçet’s disease: results from a large real-world observational study. Intest Res. 2021;19(3):301-312. doi: 10.5217/ir.2020.00013

22. Ozguler Y, Leccese P, Christensen R, et al. Management of major organ involvement of Behçet’s syndrome: a systematic review for update of the EULAR recommendations. Rheumatology. 2018;57(12):2200-2212. doi: 10.1093/rheumatology/key242

23. Adil A, Goyal A, Quint JM. Behcet Disease. In: StatPearls. NCBI Bookshelf version. StatPearls Publishing; 2022. Accessed August 2, 2022.

Author Bio

Lincoln Tracy, PhD, is a researcher and freelance writer based in Melbourne, Australia. You can follow him on Twitter @lincolntracy.