In pursuit of a prime drug for Pemphigus Vulgaris

Monika R, PSG College of Technology, Coimbatore

Derived from the Greek word pemphix, pemphigus means “vesicle” or “blister”. There are many different types of pemphigus, all involving vesicle formation at some stage, but Pemphigus Vulgaris (autoimmune disease) is the most common of all and is characterized by blistering and erosions of mucous membranes and skin. 

Pemphigus Vulgaris involves acantholysis, in which IgG autoantibody binds to a membrane antigen (glycoprotein) and release protease which breaks the intercellular connections between keratinocytes through an autoantibody-mediated response. The PV antigens are a member of the cadherin family of Ca2+-dependent cell adhesion molecules. Blister formation after antibody binding to the PV antigen might be related to antibody inhibition of cadherin interactions and may involve activation of the complement cascade and/or plasminogen activators. 

There are two different variants of Pemphigus Vulgaris: the mucocutaneous variant and the mucosal dominant variant. The mucosal dominant variant of PV involves autoantibodies against only desmoglein 3, and with disease progression, the distribution of lesions shifts from mucosal to mucocutaneous variant, which involves autoantibodies against both desmoglein 1 and 3, which are responsible for cell-cell adhesion. 

Pemphigus diseases have four levels of disease activity: early endpoints, late endpoints, relapse or flare, and treatment failure. 

• Early endpoints: These include the following stages of disease activity: baseline, control of disease activity, and end of the consolidation phase. 
• Late Endpoints: These include complete remission off/on therapy, partial remission off/on therapy. 
• Relapse/flare: If a patient’s established lesions start getting worse instead of healing, then it’s the Relapse disease activity stage. 
• Treatment failure: The final stage in which despite using the maximum therapeutic doses, there is a failure of bringing the patient to the “control of disease activity”.

Knowing the disease activity level of PV can aid physicians to begin the treatment in the course of the disease. The identification of effective and safe therapy for the individual pemphigus patient is a challenge and often requires time, which is reflected by a high number of therapy changes. PV used to be an indefinitely fatal disease before the introduction of corticosteroids as the primary form of treatment. The main treatment for PV includes systemic corticosteroids and immunosuppressive agents, but due to adverse reactions and therapeutic failure, new drugs such as rituximab and mycophenolate mofetil have been used.

Rituximab & Mycophenolate Mofetil

Patients with PV require high-dose, long-term corticosteroids/immunosuppressant drugs and are often slow in achieving remission. It may also cause severe life-threatening side-effects in patients with PV. There is increasing evidence for First-line use of Rituximab as adjuvant therapy, which can decrease the treatment side effects of corticosteroids and could also improve the proportion of patients achieving complete remission off-therapy. Rituximab is also effective in the treatment of patients with severe recalcitrant pemphigus and patients with newly diagnosed pemphigus. In the remaining refractory cases, the B-cell depleting Rituximab has been recently introduced as a highly effective rescue medication. Rituximab is a chimeric IgG1 mAb and is against CD20. Rituximab exerts B-cell cytolytic activity through Ab-dependent cell-mediated cytotoxicity. Since it is involved in B-cell depletion (responsible for the production of autoimmune antibodies), Rituximab is used to treat moderate-to-severe PV. Rituximab exerts adverse events early (eg, fever, cough, and dyspnea) or late (eg, agranulocytosis or severe infection). Severe adverse events are also rare, whereas the other drug MMF is a safe steroid-sparing agent that is recommended to treat PV as a first-line adjuvant immunosuppressant as it exerts a wide range of actions, including both immunosuppressive effects and anti-inflammatory activity. MMF is rapidly absorbed following oral administration and hydrolyzed to its active metabolite mycophenolic acid (MPA), which selectively inhibits inosine monophosphate dehydrogenase, which results in inhibition of the de novo pathway in T and B cells. This mechanism results in the inhibition of lymphocyte proliferation because lymphocytes rely on the de novo pathway and this causes suppression of both cellular and humoral immunity. The limitation of this agent is its relatively high cost and lack of availability as compared to other immunosuppressive agents. Gastrointestinal side-effects like gastritis, nausea, and abdominal cramping, are commonly observed. The most common side-effect documented was lymphopenia. MMF-treated patients show faster and more durable responses. Thus, MMF may be a potentially useful agent in patients with mild or moderate PV.

Rituximab vs Mycophenolate Mofetil

Most of the cases indicate that Rituximab and MMF are safe, effective drugs, with lasting results, revealing themselves as valuable therapeutic options for severe and refractory PV. But while comparing Rituximab with MMF, Rituximab seemed to be superior, because Mycophenolate mofetil was not effective in controlling the PV patient reporting with occult HBV infection. But when this patient received Rituximab, he went into remission without any adverse effect. Rituximab has also been reported to be a successful therapy for EBV-related lymphoproliferative disease and as such, it may be a viable option in the management of PV patients with positive EBV serologies, whereas in this case, MMF is not much effective. Rituximab is also more effective than MMF in producing sustained complete remission in many cases. Most of the literature supports a greater reduction in anti-Dsg3 autoantibodies with Rituximab than with MMF. Rituximab also produces a greater steroid-sparing effect than MMF. 

PV treatment also usually comprises 2 phases: the induction of remission and the maintenance of remission. Rituximab has revolutionized the treatment of pemphigus, indicating a complete remission off therapy and maintaining remission. Treatment of PV during the pandemic of COVID-19 infection is included in the study. Rituximab may be used in the treatment of PV during the COVID-19 pandemic if its use is absolutely necessary. In addition, physicians should also consider risk-benefit ratios in individual cases, before initiating treatment and during treatment. 

Until sufficient evidence as a guideline for pemphigus and COVID-19 treatment is available, caution is advocated in commencing Rituximab.

Also read:Takotsubo cardiomyopathy – “Breaking hearts” linked to Covid

Source:

Werth, V., P., et al. (2021). Rituximab versus mycophenolate mofetil in patients with pemphigus vulgaris, N Engl J Med. doi: http://10.1056/NEJMoa2028564.

Kridin, K. (2018). Emerging treatment options for the management of pemphigus vulgaris. Therapeutics and Clinical Risk Management, Volume 14, 757–778. doi:http://10.2147/tcrm.s142471

Antonucci, R., Locci, C., Biondi, G., Manconi, A., Mannazzu, R., Abis, L., … Montesu, M. A. (2020). Mycophenolate mofetil in the treatment of childhood pemphigus vulgaris. Pediatrics International, 62(9), 1123–1124. doi:http://10.1111/ped.14327

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