Use of Upadacitinib in Refractory Behcet’s Disease: Case Report and Systematic Literature Review

Behçet’s Disease (BD) is a chronic, relapsing and remitting, systemic neutrophilic vasculitis. The syndrome is characterized by recurrent oral aphthous ulcers (98.1%), genital ulcers (76.9%), uveitis (53.7%), and cutaneous lesions (71.9%) such as folliculitis, erythema nodosum and thrombophlebitis.¹ Rarely, there may also be neuro-ocular, gastrointestinal, pulmonary, urogenital, and large vessel involvement that carry high morbidity and mortality.¹

First described by a Turkish physician, Dr. Huluci Behçet in 1937, the disease is endemic in populations along the ancient “Silk Road” in countries such as Turkey, Iran, Japan, and Korea.¹ While BD can affect men and women of all ages, young males appear to present with the most severe forms of BD, perhaps due to neutrophil-promoting effects of testosterone.¹

While the etiology of BD is largely unknown, etiology of the disease is likely multifactorial with genetic and infectious components affecting both the innate and adaptive immune systems. The most widely accepted risk factor for BD is the HLA-B*51 MHC-I allele.² HLA-B*51 is present in approximately 60% of BD cases with HLA-B*51 positive patients having an increased propensity for oral, genital, and skin involvement.² HLA-B*51 has also been reported to affect both the innate and adaptive immune response via its association with CD8+ T cell activation, Th1/Th17 axis, neutrophil dysfunction, and chemotaxis.² Cytokine studies have found increased levels of IL-1ß, IL-4, IL-17A, IL-21, IL-22, IL-31, IFN-γ, sCD40L, and TNFα in patients with BD. Further studies have also shown mutations in IL-10, IL-23 receptor, and IL-12 receptor beta genes in patients with BD.⁴ Microbial triggers such as streptococcus and herpes simplex virus-1 infections have also been implicated in disease pathogenesis.⁵ Molecular mimicry and cross-reaction likely lead to the formation of the anti-endothelial cell autoantibodies seen in BD.¹

To date, there are no diagnostic laboratory tests or pathognomonic histology features that confirm BD diagnosis. Therefore, BD relies on clinical criteria such as the International Criteria for Behçet’s Disease (ICBD).⁶ The ICBD ascribes points to the most common signs or symptoms of BD. For example, two points are awarded to a patient for each of the following: ocular lesions, genital aphthosis, and oral aphthosis. Skin lesions, neurological manifestations, vascular manifestations, or a positive pathergy test are each worth one point. BD is diagnosed if a patient score is >4 points.⁵

Treatment of BD is widely variable and individualized to treat patient symptom, organ involvement, and severity.¹ Patients with disease limited to skin and mucosa are often treated with topical corticosteroids and colchicine.¹ Ocular, arthritic, gastrointestinal, and serious large vessel involvement is treated with immunosuppressive therapies: cyclosporine, methotrexate, cyclophosphamide, thalidomide and azathioprine and immunomodulatory agents: IFN-γ, apremilast, and anti-TNF agents.¹ Lastly, systemic glucocorticoids may be added for rapid relief of acute flares.¹

Here, we present a case of a 38-year-old male with refractory BD treated with a JAK inhibitor (JAKi), upadacitinib.