Bullous pemphigoid (BP) is a chronic autoimmune blistering disease characterized by the formation of autoantibodies against hemidemosomlein in the basement membrane region. This disease is most common in older people and manifests as erythema or tension bullae on normal**, usually affecting the trunk and extremities with marked pruritus. Timely intervention can** erosive lesions and reduce morbidity and mortality (e.g., secondary infection). Depending on the degree of involvement, topical or systemic corticosteroids have traditionally been used as first-line, and systemic immunosuppressive drugs, such as methotrexate or mycophenolate mofetil, have been deployed as second-line agents in patients with extensive or persistent disease.
Janus kinase (JAK) inhibitors are currently used for conditions such as rheumatoid arthritis and atopic dermatitis (AD), and are expected to be used for other inflammatory diseases in the future. However, the use of these drugs in autoimmune bullous diseases has not been extensively studied. We present an 81-year-old woman with BP who did not respond completely to a course of prednisone but achieved complete regression with upadacitinib**.
Case reports
An 81-year-old woman presents to our **Department Fast Track clinic for 4 months with a severe itchy rash. The rash initially begins as a urticarial patch on the trunk and spreads to all aspects of the extensor surface of the arms and forelimbs of the thighs. Tense bullae cover erythema and normal adjacents**. She acknowledges the presence of painful oral lesions, but no ocular or gastrointestinal symptoms. Her medical history includes hypertension, dyslipidemia, osteoarthritis, and endometriosis. She was taking aspirin, amlodipine, perindopril and rosuvastatin at the time of the rash, which were all long-term medications.
Figure 1Bullous pemphigoid after 1 month of systemic corticosteroid use. A, there are many tense bullae and hemorrhagic erosions on the background of annular urticaria plaques fused on the right flank and abdomen.
A bullous biopsy of the anterior thigh completed by the GP prior to the consultation shows an inflammatory process showing many eosinophils in the subepidermal blisters that are histologically consistent with BP. Her family doctor started taking prednisone 50 mg daily and had been taking prednisone for 1 month at the time of her visit. Prednisone led to some improvement in itching; However, she still has fairly extensive ** involvement (figure 1). Perilesional biopsy for direct immunofluorescence shows linear IgG and C3 at the dermal-epidermal junction, confirming the diagnosis of BP. Her white blood cell count is elevated, neutrophils predominant, but her complete blood count is normal. Serum immunoglobulin E is 2887 and C-reactive protein is normal. Our institute does not offer the BP180 BP230 ELISA assay.
The patient reported that the itching associated with BP had the greatest impact on her life. Further probing of her ** medical history at this point and she did confirm pruritic eczema-like lesions prior to the onset of BP. Because of its rapid pruritus AD relief and clinical benefit, it was finally decided to start 15 mg of upadacitinib orally daily, and she gradually shed prednisone over 20 days. At the 2-month follow-up, she had been away from prednisone for more than a month and was only taking upadacitinib. She experienced a complete regression of the disease. Since starting upadacitinib, she has not formed any new blisters, and her itching has disappeared completely (Figure 2). Further follow-up after 3 months (5 months of upadacitinib) showed **sustained response,** further healing, complete resolution of the disease, and no **or flare-ups of the disease. So far, the drug has been well tolerated by patients, with no significant adverse events.
Figure 2Bullous pemphigoid response to upadacitinib. A, 2 months after initiation of upadacitinib, the right arm showed mild erythema, no erosions, no bullae, and no urticarial lesions. B, right arm 5 months after initiation of upadaci-tinib showing post-inflammatory hyperpigmentation without bullae.
Discuss
Upadacitinib is a second-generation JAK inhibitor that is selective for the JAK1 enzyme. JAK enzymes phosphorylation of signal transducers and activator of transcription (STAT) to regulate gene transcription in immune cells (i.e., the JAK STAT pathway). Inhibition of these enzymes prevents inflammatory cytokines from enhancing immune cell function using the JAK STAT pathway. Upadacitinib, which was originally approved for severe rheumatoid arthritis, is now used for severe AD and has shown faster and improved disease resolution compared to dupilumab, an interleukin-4 (IL-4) IL-13 inhibitor. A wider range of inflammatory markers signaling using JAK1 (e.g., IL-4, IL-13, IL-22, and IL-31) and involved in the pathogenesis of AD are interfered with by JAK1 inhibition.
Although the inflammatory signaling involved in the pathogenesis of BP is not fully understood, type 2 T helper cytokines, such as IL-4 and IL-13, do appear to play a role. An increase in the number of cells producing these cytokines has been found in the bullae of BP patients, and there is now a growing body of clinical data supporting the use of dupilumab in BP. Inhibition of broader cytokine perturbations by JAK is beneficial when the pathogenesis of the disease is complex and unclear, and because our patients have a history of pruritic eczema lesions prior to the onset of BP, this provides an opportunity to **both conditions and to assess the efficacy of upadacitinib for **bp.
Xiao et al. have also reported the use of JAK inhibitors in BP, and they have successfully used the JAK1 JAK2 inhibitor baricitinib in patients with psoriasis and BP. Elevated expression of JAK STAT protein was found in lesions of patients with BP and dermatitis herpetiformis, and Xiao et al. hypothesized that disruption of the JAK STAT signaling pathway may inhibit the autoimmune response of BP and subsequently reduce the development of bullae. Baricitinib has also been shown to stop the progression of mucous membrane pemphigoid, a related disease in patients who have failed other systemic medications.
As more and more is understood about the immunopathogenesis of BP, this provides more potential targets. For this condition, there is a need for improved, safer medications, as it often affects older patients with multiple other comorbidities. Further investigation into the use of JAK inhibitors, such as upadacitinib, would have the potential to broaden the options for this condition**.