Treatment of pemphigus vulgaris: part 2 – emerging therapies

ABSTRACT

Introduction: Corticosteroids and immunosuppressive agents have been the mainstay for the treatment of pemphigus vulgaris (PV). While they have benefited patients, they have been associated with the risks of prolonged immune suppression and a high incidence of significant and catastrophic side effects. Relapses are common. Novel agents promising targeted therapies, that may provide better outcomes, are being studied.

Areas covered: Recently rituximab with corticosteroids has been recommended as the first-line treatment for PV. A number of known and new therapeutic agents currently investigated are BAFF, P13K, BTK inhibitors along with the use of IVIg and CAR-T therapy. The possible role of these therapeutic targets in the pathophysiology appears to be the rationale for the treatment of this potentially fatal disease.

Expert opinion: While there is significant enthusiasm for these therapies, certain concerns and consequences are being under-discussed. None of the current clinical trials in progress are specific for PV, except possibly CAR-T therapy. The major issue(s) that are unclear is whether these therapies would be successful in providing long-term clinical remissions. Will these therapies require additional agents to be effective? Will the benefits be limited in duration? The answers to many questions will determine their final place in the algorithm for the treatment of PV.

KEYWORDS:

• BAFF
• Biologic therapy
• BTK inhibitors
• CAR-T therapy
• corticosteroids
• FcRn
• immunosuppression
• IVIg
• pemphigus vulgaris
• PI3K
• Rituximab

Article Highlights

• In order to provide long-term remission to pemphigus vulgaris (PV) patients, therapies must address both the production and consumption of autoantibodies.

• Anti-CD20 therapy with shorter durations of corticosteroids has recently been suggested as first-line therapy for PV. Other protocols specific for PV patients have induced long-term remission.

• Targeted therapies for PV are promising in that they may possibly avoid the risks of blanket immunosuppression produced by corticosteroids and immunosuppressive agents.

• Targeted therapies that have been successful for other autoimmune diseases may not produce the same results in PV patients. Each autoimmune disease probably has unique pathophysiology. This pathophysiology should be taken into account when considering the proposed mechanisms of action of therapies under investigation.

• CAR-T therapy has been explored for the targeted eradication of cancer cells. PV patients may benefit from analogous destruction of pathogenic autoimmune B cells from CAR-T therapy that targets PV auto-antigen displaying cells.

• The ultimate aim of any therapy should be to produce a complete, long term, sustained clinical remission off therapy per consensus terminology guidelines. In practical terms, it means no disease and no drugs. None of the investigators who are leading the clinical trials in PV, discussed in this manuscript, have addressed this issue.

• None of the new emerging therapies are specific for PV. All of them are therapies attempted in other autoimmune diseases or cancer therapy, with a hope that they may be effective in PV.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This study was supported in part by an educational grant from Dysimmune Diseases Foundation (Plantation, FL, USA).