Th-17 and the lack of efficacy of ustekinumab in pemphigus vulgaris
Published Web Locationhttps://doi.org/10.5070/D39hw6p904
Th-17 and the lack of efficacy of ustekinumab in pemphigus vulgaris1. Servicio de Dermatología, Hospital General de México
Tirado-Sánchez Andrés1,2 MD MSc, Ponce-Olivera Rosa María1 MD MSc, Vazquez-González Denisse1 MD, Bonifaz Alexandro1 MSc
Dermatology Online Journal 19 (3): 15
2. Instituto Mexicano del Seguro Social
Systemic corticosteroids represent an effective treatment for pemphigus vulgaris (PV). However, this treatment is related to many adverse side effects. Herein, we report a case of PV treated with ustekinumab.
|Figure 1. Changes in aDsg3 and interleukin levels during the treatment with ustekinumab|
A 44-year-old man, had developed nonhealing erosions on face, oral and genital mucosa, and trunk diagnosed as PV, based on suprabasal acantholysis, and honeycomb-like intercellular deposition of IgG and C3. Previous treatments included prednisone, azathioprine, methotrexate, dexamethasone, dapsone, and thalidomide, with unsatisfactory control of the disease and/or severe adverse events with long-term use. Based on its effects on Th17 cells, ustekinumab 45 mg subcutaneously (SC) was introduced and previous therapy was progressively reduced. The treatment was well tolerated and no side effects were observed. One month later, good clinical improvement was observed (reepithelization of > 30% of body surface affected, neither new blisters nor Nikolsky sign were present). Oral lesions also improved (figure not shown), but no improvement was seen in serum antidesmoglein 3 (aDsg3) and IL-10 levels. However, IL-12, IL-17, IFN-γ, and IL-6 levels showed significant decrease (Figure 1). We decided to increase the dose from 45 to 90 mg SC (100 kg) and new blisters and oral erosions over hard and soft palate were detected and Nikolsky sign was positive again; aDsg3 and IL-10 levels were still high and IL-12, IL-17, IFN-γ, and IL-6 levels were persistently decreased. One month later, with 90 mg SC, a complete clinical relapse was observed (skin and mucosal lesions) along with persistently increased aDsg3 and IL-10 levels. Low serum concentrations of IL-12, IL-17, IFN-γ, and IL-6 were observed. We assumed a lack of efficacy of ustekinumab in controlling pemphigus.
ELISA was performed to detect IgG antibodies against Dsg3 (MBL Co., Nagoya, Japan); IL-10 and IL-12 (Diaclone ELISA biotinylated assay, France); IL-17 (eBioscience, ESP); IL-6 and IFNγ (R&D Systems, Minneapolis, MN, USA).
Recent evidence suggests that Th17-cells may be involved in the pathogenesis of PV. However, it is not clear if lesional Th17-cells may be the cause of the autoimmune mechanism (related to the presence of IL-6) and/or may be complimentary to the effect of pathogenic antibodies. In addition, the findings may simply be a result of disease activity, like a protective response to maintain the homeostasis of the epithelial barrier . Ustekinumab, a fully human IgG1α monoclonal antibody, binds to the p40 subunit of IL-12/IL-23, thereby preventing binding to the IL-12β1 receptor on the surface of T cells. Thus ustekinumab inhibits IL-12 induced activation of Th1 cells and subsequently the release of proinflammatory cytokines (IL-2, TNFα, IFNγ). Ustekinumab also reduces IL-23-induced activation of Th17-cells and the secretion of the proinflammatory cytokine IL-17  and thus might be expected to be effective in treating pemphigus.
To date, the exact mechanism of acantholysis has not been fully elucidated. Some reports point at ICAM-1, TNF-α, IL-1, IL-10, or IL-6 as players involved in this mechanism [3, 4]. Other studies revealed that a synergistic cooperation of pemphigus antibodies with IL-12, IFN-γ, IL-6 and TNF-α results in acantholysis . The disease can be mediated in part by the activation of B-cells with the increase in antibody response, and on the other hand, by the activation of Th-1, the imbalance with Th-2 cytokines,  and probably Th-17 cells , with the increase in proinflammatory mediators like IL-21, IL-22, IFN-γ, TNF-α, IL-17 and IL . The latter is considered a useful marker of activity in PV . These mechanisms are important in disease presentation. However, the B-cell activation mechanism seems to be the most important and persistent through disease course [3, 4]. The significant decrease in the cytokine levels after therapy suggests that ustekinumab may have a beneficial effect on PV, but did not decrease IL-10 levels, which has itself an inhibitory effect on the Th1 population.
Ustekinumab was unable to prevent relapse of PV during active treatment. We believe that this apparent lack of therapeutic effect is because Th17 and the other cytokines involved are not solely responsible for pemphigus pathogenesis. Moreover, the intervention of IL-10 could partially explain such outcome. Thus, ustekinumab plus glucocorticoids (e.g., dexamethasone) may contribute in achieving faster and prolonged remission; such a combination is based on the effect of the latter to reduce the levels of IL-10 . More studies are needed to demonstrate the real importance of Th17/IL-17 as a new therapeutic target in PV and the efficacy profile of ustekinumab in treating PV.
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