From the Cochrane Library: Interventions for Pemphigus Vulgaris and Pemphigus Foliaceus

Introduction

Cochrane systematic reviews are rigorous in methodology and contribute to our understanding of evidence-based treatments of diseases. Among these diseases is pemphigus, a group of acquired autoimmune vesiculobullous diseases (pemphigus vulgaris [PV], pemphigus foliaceus [PF], and pemphigus paraneoplastic [PNP]), characterized by B-cell–mediated immunoglobulin G antibodies against desmogleins 1 and 3. Cutaneous bullae cause loss of barrier function and pain, dehydration, superimposed infections, and psychological distress. Due to a lack of expert consensus and the poor efficacy of previous therapies, a Cochrane systematic review of randomized controlled trials (RCTs) sought to define the best treatment for pemphigus [1]. Here, we highlight takeaways from the review [1] and discuss advances in therapy. PNP was excluded from the review due to its rarity and because its management depends on the underlying malignancy.

Methods

A total of 11 RCTs were analyzed to assess efficacy and safety among treatments for PV and PF. The primary outcomes were death and disease remission, with secondary outcomes including disease severity indexes, time to disease control, cumulative glucocorticoid dose, serologic markers, and the proportion of patients achieving disease control and relapse. The RCTs used various combinations and doses of steroid-sparing agents with or without corticosteroids. We contrasted therapies, outcomes, and comparison effect size and conducted 4 meta-analyses.

Results

A recent (2021) network meta-analysis [2] found rituximab (Table 1), a CD20 B-cell–depleting therapy, as the most effective therapy for key outcomes like disease relapse, withdrawal from adverse events, remission, and cumulative glucocorticoid dose. The right-most column of Table 1 contrasts therapies relative to rituximab among the 4 key outcomes evaluated. Although the included trials [2] risked bias due to inadequate allocation concealment and lack of participant, personnel, and outcome blinding, the results align with emerging expert consensus and other important clinical trials [3] directly comparing rituximab to other therapies like mycophenolate.

Induction dosing for rituximab was two 1 g intravenous infusions 2 weeks apart followed by a 6-month prednisone taper of 1 mg/kg/day. Additionally, 2 novel higher-affinity CD20-blocking agents, ofatumumab and veltuzumab, demonstrated efficacy in isolated cases of rituximab-resistant pemphigus. Ofatumumab and veltuzumab are not used for pemphigus outside of clinical trials and for compassionate use. In addition, trials are underway for other immunotherapies targeting the fragment crystallizable region, B-cell–activating factor, and Bruton tyrosine kinase [4]. The meta-analyses revealed that some interventions were superior for certain outcomes: improved disease remission with mycophenolate relative to azathioprine, a steroid-sparing effect with azathioprine and cyclophosphamide, and a decreased time to erosion control with topical epidermal growth factor (Table 2). At the time of the 2009 study, systematic analysis including rituximab and clinical trials including intravenous immunoglobulin were ongoing [5].

Discussion

With an increasing understanding of the immune system, B-cell physiology, and the pathogenesis of pemphigus, therapies continue to emerge, making previous therapies obsolete. Here, we placed important Cochrane review findings in the context of recent advancements in the treatment of pemphigus. Further studies are needed to determine therapeutic regimens, safety, and efficacy of novel medical therapies for pemphigus.