Residency · Residency · Rheumatology

Behcet Disease and Relapsing Polychondritis

Introduction

Behcet disease and relapsing polychondritis are rare systemic inflammatory diseases with distinct pathophysiologic mechanisms that require a high index of clinical suspicion due to their heterogeneous presentations. Behcet disease is classified as a variable-vessel vasculitis, unique in its capacity to affect vessels of any size and type, and is characterized by recurrent oral and genital ulcers, uveitis, and vascular involvement. Relapsing polychondritis is an autoimmune disease targeting cartilaginous structures throughout the body, including the ears, nose, larynx, trachea, and joints.

Behcet Disease

Epidemiology

Behcet disease exhibits a striking geographic distribution with the highest prevalence along the ancient Silk Road, peaking in Turkey at approximately 420 per 100,000, with significant prevalence also in Iran, Iraq, Japan, Korea, and China. The male-to-female ratio is approximately equal, though males tend to have more severe disease, particularly with respect to vascular and ocular manifestations. Peak onset occurs between 20 and 40 years of age. HLA-B51 is the strongest genetic risk factor, with an odds ratio of 5 to 6, and is positive in 50 to 60 percent of patients in endemic regions.

Pathogenesis

Behcet disease is classified as a variable-vessel vasculitis because it can affect arteries and veins of any size, a feature unique among the vasculitides. Neutrophilic inflammation is central to the pathology, and the pathergy reaction reflects an exaggerated neutrophil response to minor tissue injury. Innate immune activation features enhanced neutrophil function and elevated levels of IL-1 beta, TNF, and IL-6. The adaptive immune response is characterized by Th1 and Th17 predominance, with gamma-delta T cells identified in mucosal lesions. Genetic susceptibility involves HLA-B51 as the primary risk allele, along with IL-10, IL-23R-IL-12RB2, STAT4, and ERAP1 polymorphisms. Environmental triggers may include microbial antigens from Streptococcus sanguis and herpes simplex virus.

Clinical Manifestations

Mucocutaneous (>95%)

Oral ulcers are the most common and often first symptom, presenting as painful, round, well-demarcated lesions with an erythematous halo. They are classified as minor ulcers, the most common form at less than 10 millimeters, major ulcers exceeding 10 millimeters that are deep and may scar, and herpetiform ulcers that present as multiple small lesions. Oral ulcers typically heal within 1 to 3 weeks and recur at least 3 times per year. Genital ulcers affect the scrotum in males and vulva in females, are painful, and often scar, a feature that distinguishes them from oral ulcers and provides an important diagnostic clue as to chronicity. Cutaneous manifestations include erythema nodosum-like lesions, papulopustular or acneiform lesions, and superficial thrombophlebitis. The pathergy test, in which a sterile pustule forms at the site of a needle prick at 24 to 48 hours, has low sensitivity in Western populations at approximately 40 to 50 percent but higher sensitivity in Turkey and the Middle East.

Ocular (50-70%)

Anterior uveitis may present with hypopyon, a layer of pus in the anterior chamber, which is a classic though not pathognomonic finding. Posterior uveitis with retinal vasculitis is the most vision-threatening manifestation and can lead to blindness. Panuveitis is the most common pattern and is bilateral in 80 percent of cases. Retinal vasculitis involving both arteries and veins is a unique feature. Without treatment, blindness develops in 25 to 50 percent of patients within 5 years of onset. Males experience more severe ocular disease with a worse visual prognosis.

Vascular (15-40%)

Venous thrombosis is the predominant vascular manifestation and includes deep vein thrombosis, cerebral venous sinus thrombosis, Budd-Chiari syndrome, IVC thrombosis, and superficial thrombophlebitis. A critical conceptual point is that thrombosis in Behcet disease is inflammatory rather than thromboembolic: vessel wall inflammation produces adherent thrombus, which explains why pulmonary embolism is paradoxically rare despite frequent DVT. Treatment is therefore directed at immunosuppression rather than anticoagulation alone. Arterial manifestations include aneurysms, with pulmonary artery aneurysm being pathognomonic and potentially fatal, aortitis, and arterial occlusion. Pulmonary artery aneurysm presenting with hemoptysis demands urgent immunosuppression and represents an absolute contraindication to anticoagulation due to the risk of fatal hemorrhage. Hughes-Stovin syndrome, comprising pulmonary artery aneurysm with DVT, is considered a variant of Behcet disease.

Neurologic (5-30%)

Parenchymal neuro-Behcet, accounting for 80 percent of neurologic involvement, produces brainstem and diencephalic lesions manifesting as headache, hemiparesis, cranial neuropathy, and behavioral changes. MRI reveals T2 hyperintense lesions in the brainstem and basal ganglia that may mimic multiple sclerosis. Non-parenchymal disease, comprising 20 percent, involves cerebral venous sinus thrombosis with intracranial hypertension. CSF analysis shows neutrophilic or lymphocytic pleocytosis with elevated protein. Parenchymal disease carries a worse long-term neurologic outcome.

Musculoskeletal (40-60%)

A non-erosive oligoarthritis affecting knees, ankles, and wrists occurs with self-limited episodes and no joint destruction.

GI (10-50%, varies by region)

Ileocecal ulcers are deep and discrete with potential for perforation. GI-Behcet disease mimics Crohn disease but is distinguished by round or oval ulcers rather than the linear ulcers of Crohn disease, absence of granulomas, and HLA-B51 positivity.

Diagnosis

The 2014 International Criteria for Behcet Disease employ a scoring system in which a score of 4 or greater classifies as Behcet disease. Point values are assigned as follows: oral ulcers (2 points), genital ulcers (2 points), ocular lesions (2 points), skin lesions (1 point), vascular manifestations (1 point), neurologic involvement (1 point), and positive pathergy test (1 point). These criteria achieve a sensitivity of 94.8 percent and specificity of 90.5 percent. There is no pathognomonic laboratory test, and the diagnosis remains fundamentally clinical. HLA-B51 testing is supportive but not diagnostic.

<image>A clinical overview illustration of Behcet disease showing a male figure with labeled arrows to all major manifestations. Head: Painful oral aphthous ulcers on buccal mucosa (round, well-demarcated with erythematous halo), hypopyon uveitis (layered white pus in anterior chamber on slit-lamp view), and MRI showing T2 hyperintense brainstem lesion (neuro-Behcet). Genitals: Genital ulcer on scrotum with scarring. Skin: Erythema nodosum-like lesion on shin and papulopustular acneiform lesion on trunk; positive pathergy test on forearm (pustule at needle insertion site). Vascular: DVT in lower extremity, pulmonary artery aneurysm on CT angiography. Joints: Oligoarticular knee swelling. GI: Ileocecal ulcer (round, deep) on colonoscopy view. Include the ICBD scoring system in a corner box.</image>

Management

Mucocutaneous Disease

Topical glucocorticoids such as triamcinolone paste are applied for oral ulcers. Colchicine at 1 to 2 milligrams daily is the first-line systemic agent for mucocutaneous disease and arthritis. Apremilast at 30 milligrams twice daily, validated by the RELIEF trial, reduced oral ulcers significantly and received FDA approval for Behcet disease oral ulcers in 2019. Azathioprine at 2.5 milligrams per kilogram per day is effective for mucocutaneous disease and additionally prevents eye disease, as demonstrated in the landmark Turkish trial by Yazici and colleagues. Dapsone is an alternative for mucocutaneous manifestations. Thalidomide is effective for severe oral and genital ulcers but carries risks of teratogenicity and peripheral neuropathy.

Ocular Disease

Ocular involvement constitutes a medical emergency, as untreated posterior uveitis progresses to blindness. Azathioprine is the first-line maintenance agent for preventing ocular attacks. Infliximab or adalimumab is recommended for severe or refractory posterior uveitis or retinal vasculitis, supported by strong observational data and the VISUAL trials for non-infectious uveitis. Interferon-alpha 2a is an alternative for refractory ocular disease and may induce sustained remission. Cyclosporine at 3 to 5 milligrams per kilogram per day is effective but carries a neurotoxicity risk and must not be used in neuro-Behcet. Intravitreal glucocorticoids serve as a bridge therapy but are not sufficient alone. The 2018 EULAR/ACR recommendations emphasize early aggressive immunosuppression for posterior and panuveitis.

Vascular Disease

Immunosuppression is the primary treatment for vascular Behcet disease, reflecting the inflammatory rather than thromboembolic nature of the thrombotic process. For DVT, glucocorticoids combined with azathioprine or cyclophosphamide are used, with anticoagulation being controversial but potentially added if no pulmonary artery aneurysm is present. For pulmonary artery aneurysm, glucocorticoids combined with cyclophosphamide or infliximab are indicated, with anticoagulation absolutely contraindicated due to the risk of fatal hemorrhage. Arterial aneurysms are treated with glucocorticoids plus cyclophosphamide, with surgical repair as needed, though the restenosis risk is high and perioperative immunosuppression is essential.

Neuro-Behcet

Parenchymal disease is treated with glucocorticoids plus azathioprine for mild cases and glucocorticoids plus cyclophosphamide or infliximab for severe or refractory disease. Cerebral venous sinus thrombosis is managed with glucocorticoids plus anticoagulation, representing a distinct approach from arterial vascular involvement.

Relapsing Polychondritis

Epidemiology

Relapsing polychondritis is very rare, with an incidence of approximately 3.5 per million per year. Peak age of onset is between 40 and 60 years, with an equal sex distribution. Approximately 30 percent of patients have coexistent autoimmune disease, including myelodysplastic syndrome, rheumatoid arthritis, systemic lupus erythematosus, and vasculitis. The MAGIC syndrome represents the overlap of Behcet disease and relapsing polychondritis.

Pathogenesis

The pathogenic process involves autoimmune destruction of proteoglycan-rich cartilage. Anti-type II collagen antibodies are found in approximately 30 to 50 percent of patients but lack sufficient sensitivity for diagnosis. Anti-matrilin-1 antibodies are more specific and are associated with airway involvement. Both T cell-mediated and humoral immunity contribute to cartilage destruction. The progression follows a pattern of cartilage loss, fibrosis, and ultimately structural collapse.

Clinical Manifestations

Auricular Chondritis (85-95%)

Auricular chondritis is the most common and often presenting feature, manifesting as a painful, red, swollen pinna that characteristically spares the non-cartilaginous earlobe. The inflammation is bilateral in 40 percent of cases. Recurrent episodes lead to cauliflower ear deformity with a floppy, collapsed ear. Conductive hearing loss results from external auditory canal collapse, while sensorineural hearing loss may develop from inner ear inflammation.

Nasal Chondritis (50-70%)

Nasal cartilage destruction produces the saddle-nose deformity, accompanied by rhinitis, nasal pain, and epistaxis. Unlike GPA, relapsing polychondritis does not produce granulomatous inflammation, an important histologic distinction.

Airway Involvement (20-50%)

Airway involvement is the most dangerous manifestation and the leading cause of relapsing polychondritis-related death. Laryngotracheal chondritis produces stridor, hoarseness, and dyspnea. Tracheobronchial chondritis leads to tracheobronchomalacia with airway collapse on expiration. Dynamic CT with inspiratory and expiratory phases demonstrates the airway collapse. Bronchoscopy reveals edematous, inflamed tracheal rings with dynamic collapse. Management may require tracheostomy, stenting, or CPAP/BiPAP support.

Ocular (50-65%)

Ocular manifestations include episcleritis, scleritis which may be necrotizing, proptosis from orbital inflammation, uveitis, and retinal vasculitis.

Musculoskeletal (50-85%)

A non-erosive polyarthritis or oligoarthritis with episodic flares is common. Costochondritis causes anterior chest pain from rib cartilage involvement and may lead to pectus excavatum. Both large and small joints can be affected.

Cardiovascular (15-25%)

Aortic regurgitation results from aortic root dilation due to destruction of the cartilaginous ring. Aortitis and aortic aneurysm may develop. Mitral valve regurgitation and conduction abnormalities are additional cardiovascular manifestations.

Other

Cutaneous features include erythema nodosum, livedo reticularis, and purpura. Renal involvement with mesangial glomerulonephritis is rare. Neurologic manifestations including cranial neuropathies and meningoencephalitis occur rarely.

Diagnosis

The diagnosis is clinical, based on the modified McAdam criteria (Damiani/Levine), which require 3 of 6 features: bilateral auricular chondritis, non-erosive seronegative polyarthritis, nasal chondritis, ocular inflammation, respiratory tract chondritis, and audiovestibular damage. Alternative diagnostic pathways include 1 criterion plus histologic confirmation, or chondritis at 2 or more separate sites with response to glucocorticoids. Biopsy demonstrates loss of basophilic staining of the cartilage matrix, perichondrial lymphocytic and neutrophilic infiltrate, and cartilage destruction with fibrotic replacement. CT and MRI reveal tracheal wall thickening, airway narrowing, and dynamic collapse on expiratory CT. Pulmonary function testing with flow-volume loops may show variable intrathoracic or extrathoracic obstruction with flattening of the inspiratory or expiratory limb.

Management

Mild disease involving auricular, nasal, or joint manifestations is managed with NSAIDs, colchicine, low-dose glucocorticoids at prednisone 10 to 20 milligrams daily, or dapsone at 50 to 100 milligrams daily. Moderate to severe disease involving the airway, aorta, or eyes requires glucocorticoids at prednisone 0.5 to 1 milligram per kilogram per day for acute flares, followed by steroid-sparing agents including methotrexate, azathioprine, mycophenolate mofetil, or cyclosporine. Biologics including infliximab, adalimumab, tocilizumab, and abatacept have been reported effective in case series, though no randomized controlled trials exist. Rituximab has shown benefit in case reports.

Airway management is particularly challenging. Intraluminal stenting is used for focal stenosis. Tracheostomy may be necessary for severe subglottic stenosis. CPAP or BiPAP provides support for tracheobronchomalacia. Intubation should be avoided if possible as it may worsen airway damage. MDS-associated relapsing polychondritis may respond to MDS-directed therapy with azacitidine or lenalidomide.

<image>A clinical progression illustration of relapsing polychondritis showing the three most affected cartilaginous structures. (1) Ear: Three stages - normal ear anatomy → acute auricular chondritis (red, swollen pinna with spared earlobe) → chronic cauliflower ear deformity (floppy, collapsed cartilage). (2) Nose: Normal nasal bridge → nasal chondritis (swollen, red nose) → saddle-nose deformity from septal cartilage loss. (3) Airway: Cross-section of normal trachea with intact C-shaped cartilage rings → inflamed tracheal wall with perichondrial inflammation → tracheomalacia showing collapsed, softened tracheal rings on expiration (dynamic airway collapse). Include an inset of an expiratory CT scan showing anteroposterior tracheal narrowing. Label all stages and pathologic changes.</image>

Key Clinical Pearls

• Behcet disease is the only vasculitis that can affect vessels of ALL sizes (arteries and veins)
• Pulmonary artery aneurysm in BD: Do NOT anticoagulate; immunosuppress instead (risk of fatal hemorrhage)
• BD venous thrombosis is inflammatory, not thromboembolic; PE is paradoxically rare despite frequent DVT
• Relapsing polychondritis spares the earlobe (no cartilage); inflammation of the pinna with earlobe sparing is characteristic
• Airway involvement is the leading cause of death in RP; monitor PFTs and dynamic CT for tracheobronchomalacia
• Cyclosporine should NOT be used in neuro-Behcet (neurotoxicity risk)

References

1. Hatemi G, et al. 2018 Update of the EULAR recommendations for the management of Behcet's syndrome. Ann Rheum Dis. 2018;77(6):808-818.
2. International Team for the Revision of the International Criteria for Behcet's Disease (ITR-ICBD). Revision of the International Criteria for Behcet's Disease (ICBD). Clin Exp Rheumatol. 2014;32(4 Suppl 84):S136-S141.
3. Hatemi G, et al. Trial of apremilast for oral ulcers in Behcet's syndrome (RELIEF). N Engl J Med. 2019;381(20):1918-1928.
4. Borgia F, et al. Relapsing polychondritis: An updated review. Biomedicines. 2018;6(3):84.
5. Dion J, et al. Relapsing polychondritis can frequently present as an isolated feature with need for prolonged treatment. Arthritis Res Ther. 2019;21(1):72.

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