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OblIgEd to search for steroid-sparing agents in treating bullous pemphigoid

DII small banner By Warren R. Heymann, MD
Jan. 19, 2017

I’m always anxious to learn about alternative approaches for treating bullous pemphigoid (BP). Perhaps it’s my imagination, but most of my patients with BP are elderly, diabetic, hypertensive, and anticoagulated. It is impossible to prescribe rituximab out of the shoot, doxycycline causes gastrointestinal tract distress or interacts with their warfarin, and clobetasol applications are difficult to apply on extensive disease. Other immunosuppressive agents such as mycophenolate mofetil don’t display their clinical benefit for months. So, with reluctance, prednisone is prescribed, fingers are crossed hoping that the comorbidities don’t go haywire, and that no hips are broken. The steroid-sparing frenzy for the right drug starts on day one of therapy. There has been a spate of reports that omalizumab may be valuable for BP. Does it fit the bill?

In BP two hemidesmosomal components, the transmembrane collagen XVII (BP180 or BPAG2) and the plakin family protein BP230 (BPAG1), are targeted by autoimmunity. Collagen XVII (COL17) is thought to be a major autoantigen, with IgG autoantibodies playing a key role in the pathogenesis of BP. The disorder also shows distinct features, including pruritic urticarial erythema and eosinophilic infiltration, which may be independent of IgG-mediated autoimmunity. Recently, it has been revealed that sera from certain patients with BP contain IgE autoantibodies to COL17 and that IgE autoantibodies bind to the perilesional dermal-epidermal junction. Mouse models have demonstrated that IgE antibodies to COL17 induce erythema and eosinophilic infiltration in skin, suggesting that both IgG and IgE autoantibodies to COL17 may be involved in the BP pathogenesis (1).

In a study of 117 patients with BP (69 women and 48 men), anti-BP180 NC16A serum IgE was detected in 47 (40.2%) which correlated with disease activity as measured by the total bullous pemphigoid disease activity index (BPDAI) (r = 0.918; P = .06). An intraindividual correlation of anti-BP180 NC16A serum levels with the total BPDAI was observed during the course of the disease in 10 randomly selected patients with BP (r = 0.983; P = .003). Although no association of circulating BP180 NC16A IgE antibodies with urticarial or erythematous lesions was observed (r = 0.481; P = .31), the presence of IgG anti-BP180 NC16A antibodies was associated with the occurrence of erosions and blisters (r = 0.985; P = .006) but not urticarial and erythematous lesions (r = 0.632; P = .23). The authors concluded that the correlation of serum anti-BP180 NC16A IgE levels with disease activity in BP supports the notion that anti-BP180 IgE is of pathogenic relevance. The detection of serum anti-BP180 IgE may be relevant for therapeutic decisions (e.g., the use of anti-IgE treatment) (2).

Current hypotheses on the pathomechanism(s) of IgE in BP focus on IgE autoantibodies binding to the surface of cutaneous mast cells via the high affinity IgE receptor, FcɛRI. Binding of the antigenic NC16A domain of BP180 to IgE causes receptor cross-linking and mast cell degranulation with subsequent release of mediators including histamine, cytokines and proteases. This incites an immunologic cascade, recruiting eosinophils and neutrophils resulting in further destruction of the basement membrane zone (BMZ). Alternatively, free IgE autoantibodies can bind via their variable region directly to NC16A expressed by basal keratinocytes. It has been demonstrated in vitro that the direct effects of IgE autoantibodies contribute to inflammation and fragility of the BMZ. (3)
To date, there have been 10 reported cases of BP treated with omalizumab. Yu et al treated 6 patients with BP using omalizumab and followed up their disease for up to 42 months. Five of 6 of their patients responded to treatment and none had adverse reactions to the drug. In 3 patients, omalizumab was sufficient as monotherapy. In one patient, discontinuation and reinstitution of omalizumab seemed to correlate with clinical disease exacerbations and subsequent disease remissions, suggesting that continuous therapy with omalizumab may be superior to intermittent dosing. In 2 other patients omalizumab was used successfully as a steroid-sparing agent in the induction and maintenance of remission. One patient was able to reduce their steroids while on omalizumab, but the BP exacerbated when omalizumab became unavailable (4). Balakirski et al utilized omalizumab (300 mg subcutaneously every 3 weeks) in 2 patients with therapy-resistant BP. Both patients experienced significant improvement of their disease with almost complete resolution of pruritus. The treatment was well tolerated (3).

As always, in the absence of appropriate randomized, double-blinded, controlled, prospective studies, it is difficult to reach definitive conclusions about the role of omalizumab in treating BP. Currently, I would consider it a reasonable steroid-sparing adjunctive agent. For the lucky few, it can be used as monotherapy. Omalizumab should be considered in recalcitrant BP patients with elevated levels of IgE and an eosinophilia. I view BP as a potential collision at home plate between the baserunner (BP) and catcher (prescribing physician). In this case, both a simultaneous call of safe (drug) and out (the disease) by the umpire is optimal (obviously, something you’ll never see in baseball). We are oblIgEd to seek out streroid-sparing agents for our patients. While not the ultimate answer, omalizumab appears to be a step in the right direction.

1. Ujiie H. IgE autoantibodies in bullous pemphigoid: Supporting role, or leading player? J Dermatol Sci 2015; 78: 5-10.
2. van Beek N, et al. Correlation of serum levels of IgE autoantibodies against BP180 with bullous pemphigoid disease activity. JAMA Dermatol 2017: 153: 30-8.
3. Balakirski G, et al. Successful treatment of bullous pemphigoid with omalizumab as corticosteroid-sparing agent: Report of two cases and review of literature. J Eur Acad Dermatol Venereol 2016; 30: 1778-82.
4. Yu KK, et al. Omalizumab therapy for bullous pemphigoid. J Am Acad Dermatol 2014; 71: 468-74.

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