Treatment considerations for patients with pemphigus during the COVID-19 pandemic

To the Editor: COVID-19, a serious pulmonary illness caused by the highly contagious novel coronavirus, severe acute respiratory syndrome (SARS) coronavirus 2, is a global pandemic. COVID-19–related mortality risk factors include advanced age, male sex, and certain comorbidities, including immunosuppression.¹ Besides direct viral-induced injury, the host cytokine-mediated antiviral response potentiates tissue damage.¹

Pemphigus, a mucocutaneous autoimmune blistering disease, increases infection risk via multiple mechanisms, including epithelial barrier breakdown and therapy-related immunosuppression. Given the need to balance appropriate pemphigus treatment with reduction of COVID-19–associated mortality risk, we have outlined treatment considerations for this particularly vulnerable patient population below.

Rituximab, a chimeric CD20 monoclonal antibody and the only United States Food and Drug Administration (FDA)-approved medication for moderate to severe pemphigus, is considered first-line therapy based on its well-documented efficacy and safety profile.² However, its effect on B-cells is irreversible. Reconstitution of B-cell immunity can take months, which could be problematic for patients who contract COVID-19. In addition, logistics of intravenous infusions may not be feasible when limits on nonemergent medical care are mandated. We have taken the approach of postponing rituximab infusions temporarily, with the aim of delaying peak patient immunosuppression during peak COVID-19 incidence to reduce the risk of adverse outcomes.

Besides rituximab, the mainstay of pemphigus treatment is glucocorticoids, due to their rapid onset, efficacy, and low cost. However, their nonspecific immunosuppressive effects increase infection risk, among other complications, in a dose-dependent manner. A basic therapeutic principle with particular importance during the pandemic is that glucocorticoids and steroid-sparing immunosuppressive agents, such as azathioprine and mycophenolate mofetil, should be tapered to the lowest effective dose. In active COVID-19 infection, immunosuppressive steroid-sparing medications should be discontinued when possible, although glucocorticoid cessation often cannot be considered due to risk for adrenal insufficiency.

Effective as adjuvant treatment in both pemphigus³ and COVID-19,⁴ intravenous immunoglobulin supports immunity and therefore may be useful in this setting. In addition, hydroxychloroquine can be used to treat pemphigus in the elderly⁵ and in pregnancy and has been proposed in the treatment of COVID-19. Although proof of plasmapheresis efficacy is mainly anecdotal in pemphigus and COVID-19, it could also be considered. The effect of convalescent plasma, a FDA-approved COVID-19 treatment under active investigation, on pemphigus is unknown.

Emerging selective agents for pemphigus may offer certain pharmacologic advantages. For example, a new oral Bruton tyrosine kinase inhibitor (PRN1008; currently in phase 3 clinical trials; NCT02704429) works via reversible covalent binding and therefore has a self-limited immunomodulatory effect. Compassionate access to this agent under these extraordinary circumstances would be very useful.

In addition, ofatumumab, a fully human monoclonal CD20 antibody, is shorter acting than rituximab. Despite early promise of this agent in pemphigus, a phase 3 clinical trial (NCT01920477) was prematurely terminated due to changing sponsor priorities. Tocilizumab, a humanized monoclonal antibody against interleukin 6, has been proposed to treat the inflammatory phase of COVID-19 and has been reported anecdotally to help pemphigus.

Until sufficient experience with pemphigus and COVID-19 is available to guide therapeutic decision making, we advocate for thoughtful pharmacologic selection as well as adherence to basic infection-prevention principles, such as social distancing, hand washing, and reduction of iatrogenic immunosuppression as feasible.