Therapeutic Plasma Exchange-A New Dawn in the Treatment of Pemphigus Vulgaris.

Pemphigus vulgaris is an autoimmune disorder that involves intraepithelial blistering and sores of skin and mucous membrane. It generally correlates with the levels of circulating autoantibodies; their removal seems a reasonable therapeutic approach. Therapeutic plasma exchange is hypothesized to remove pathogenic autoantibodies and has been used in refractory or severe cases. It may be considered for rapid control of severe or recalcitrant pemphigus vulgaris and should be combined with use of concomitant immuno-suppressive.

What was known?

Pemphigus Vulgaris is managed worldwide with corticosteroids with or without adjuvant therapies like immunosuppressives and immunomodulators and therapeutic plasma exchange can be used as standard therapy or who require unacceptably high doses of steroids or immunosuppressants.

Introduction

Pemphigus vulgaris (PV) is an autoimmune disease characterized by blisters and erosion on skin and mucous membrane due to acantholysis. It is caused by autoantibodies against desmosomal caderins desmoglein 3 (Dsg 3) which are cell adhesion molecules.[1] The incidence of pemphigus has varied widely from 0.09% to 1.8%. It affects men and woman equally and usually occurs in the fifth and sixth decade.[2] The mainstay of treatment remains to be corticosteroids with or without adjuvant therapies which may include immunosuppressive, anti-inflammatory and immunomodulatory procedures. Due to the variation in severity, varied response to the conventional treatment protocols and severe side effects, now dermatologists all over the world have ventured into new modalities of adjuvant therapies, like intravenous immunoglobulins (IVIG), therapeutic plasma exchange (TPE) and rituximab to grapple the increasing number of patients with severe PV who show little or no response with conventional steroid treatment.[3]

We herewith report a case of severe PV, who was resistant to corticosteroids pulse therapy, cyclophosphamide and was successfully treated with TPE, an option hardly being considered in Indian scenario.

Case Report

A 65-year-old male presented to the emergency with multiple blisters and erosions all over his body including oral mucosa, scalp with superadded maggot infection since last 6 months. He had previous episodes of such lesions which subsided within 3-4 months after treatment with steroids and some unknown generic medications from outside last 1 year. The patient again developed lesions all over the body over the period of 6 month which gradually worsened and was brought to our tertiary hospital.

On physical examination, he was febrile and had numerous flaccid blisters and erosions covering more than 85% of body surface area with some of them covered with slough and maggots [Figure 1]. Nikolsky sign was strongly positive and the diagnosis of PV was confirmed by a skin biopsy [Figure 2] and tzanck smear. He was put on intravenous (IV) dexamethasone pulse (120 mg) along with supportive care such as fluids, fresh frozen plasma (FFP) and dressings on admission for three consecutive days, once routine blood investigation were normal and blood and urine cultures were sterile. Intravenous antibiotics (Piperacillin/Tazobactam and Teicoplanin) were given according to the pus culture and sensitivity. Adjuvant immunosuppressors were held back because of infection. Due to extensive lesions and high susceptibility to further infections the patient was shifted to isolation intensive care unit. There was still oozing from skin ulcerations and hemorrhagic excoriation with peeling of skin was present. He was maintained on 1 mg/kg of oral methyl prednisolone after the pulse but there was no improvement in the skin lesions and general condition of the patient worsened further with hypoproteinemia and developed pleural effusion on day 7. Blood culture showed enterobacter and pus culture from erosions show Staphylococcus aureus and Proteus mirabilis. Based on sensitivity intravenous Tigecycline and vancomycin was started. The erosions still persisted and did not show any sign of re-epithelialization, perilesional Nikolsky sign was still positive and he continued to develop new blisters. As he was in sepsis with persistent high grade fever, albumin levels fell to 2.1 mg, it was considered to hold the “Pulse therapy” of IV methyl prednisolone and cyclophosphamide. Keeping this in mind, the plan for one TPE cycle was made. TPE was performed using a single volume plasma exchange with intermittent cell separator (Haemonetics MCS plus, kit 980/790) machines based on centrifugation by femoral access using a 12-French double lumen dialysis catheter. It was scheduled preferably on alternate-day intervals for five sessions over a period of 10 days. Anticoagulation with citrate (ACD) was systematically used. Replacement of plasma removed during the procedure was done with isotonic sterile saline, to make up one-half of the volume and with 4% purified human albumin and FFP to complete it. A careful monitoring of hemodynamic parameters was done and complications during or following procedure were rapidly recognized and reverted by rationale interventions. Indications for TPE, number of cycles and sessions, duration of each session, volume of plasma exchanged and patient tolerance to the procedure were systematically recorded. 10 ml of 10% calcium gluconate was administered through the procedure to avoid citrate toxicity and hemogram, serum electrolytes, total protein, albumin were monitored daily.

Figure 1

Extensive blisters and non-healing erosions on face and neck

Figure 2

Histopathology of a skin biopsy from erosion showing an acantholytic cleft separates the upper part of the epidermis from the basal keratinocytes (H and E, ×40)

The amount of plasma to be exchanged must be determined in relation to the estimated plasma volume (EPV). A simple means of estimating the EPV can be done from the patient's weight and hematocrit using the formula: EPV= [0.065 × wt (kg)] × [1-Hct].[4] A total of 12.75 L of plasma was removed in five sessions in ICU. After the third session of TPE, Nikolsky sign became negative and no new lesions appeared. The exudation from the lesions reduced drastically and dressings also started to remain dry. The lesions showed 60-70% re-epithelization and 90% healing after the last sessions [Figure 3]. The oral lesions also healed completely though little erosions on back, anterior aspect of thigh and buttocks persisted. Serum antibody levels before and after TPE sessions could not be done as the patient could not afford it.

Figure 3

Healing of erosions over the head and neck after five sessions of TPE

In order to prevent the “rebound” antibody synthesis, the patient was given “Pulse therapy” of IV methyl prednisolone (1 gm/day) and cyclophosphamide (500 mg/day) for three consecutive days. At the end of Pulse therapy, there was further improvement in the lesions and the patient was clinically stable. To achieve further improvement as evident by previous, plan was to given one more TPE cycles for three sessions but due to cost restraint it was not done and patient was discharged on maintained dose of monthly IV dexamethosone pulse along with daily oral prednisolone (60 mg/day).

Discussion

TPE is an extracorporeal blood purification technique in which the plasma is separated from blood, discarded in total, and replaced with a substitution fluid such as albumin or with plasma collected from healthy donors. This is generally performed to remove high-molecular-weight substances such as pathogenic auto antibodies, immune complexes, cryoglobulins and toxins that have accumulated in the plasma. Usually it is combined with immunosuppressive treatment, such as IVIG, prednisone and azathioprine, to avoid rebound effect and to maintain the improvement. It is used for various autoimmune diseases like Goodpasture syndrome, myasthenia gravis, Guillain-Barre syndrome, systemic lupus erythematosus, PV and bullous pemphigoid etc.[5] The first therapeutic implications of TPE in PV were described by Cotterill.[6] Since then, it has been described as an effective adjuvant therapy in PV patients in controlling disease activity by reducing serum levels of autoantibodies.[7] Even though, there is no standardized protocol for the number of cycles and frequency of sessions, it is commonly believed that four or five sessions of plasma exchanges over a period of 7 to 10 days constitutes an adequate short-term therapy, to remove 90% of the total initial body immunoglobulin.[8]

TPE is relatively safe and the risk of infections associated with it is mainly due to the steroids and immunosuppressives given along with it. The overall incidence of adverse reaction reported in the literature range for 1.6% to 2.5% with severe reaction occurring in 0.5-3.1%. Sagi et al. studied the role of TPE as steroid sparing therapy in seven patients and found 86% response rate with three sessions of TPE per week along with monthly IV dexamethasone pulse, without any major adverse effects.[9] We could safely practice TPE in our patient despite evidence of sepsis and a similar observation was made by Saraceno et al. in a 63-year-old male who developed Nocardia asteroides infection when on conventional therapy and responded well to TPE.[10] While immuno-adsorption is superior to plasma exchange in terms of efficacy and safety but the high cost of the adsorbers is the major limiting factor. It is a useful intervention in patients with PV who are not responding to standard therapy or who require unacceptably high doses of steroids or immunosuppressant.[11] While the cost of four injections of rituximab or one cycle of IVIG could be approximately 1.2 to 1.5 lakh rupees in India, five to six sessions of TPE will cost less than half of the same with better results.[12] The use of TPE has changed in recent years, given advances in medical technology that have allowed a wider clinical application in the critical care setting.

What is new?

Therapeutic plasma exchange improves outcome in patients of pemphigus vulgaris who experience the exacerbations in spite of treatment with steroids and oral immunosuppressives. It may considered as treatment options especially in developing countries like India as it is comparatively less costly and as equally effective.