Management of pemphigus vulgaris during acute phase

Introduction

Pemphigus vulgaris (PV) is a chronic autoimmune blistering disease of skin and mucous membrane. Prior to the advent of corticosteroids, the majority of patients with pemphigus vulgaris died usually from overwhelming sepsis.[1],[2] Survival of the patients has improved dramatically since systemic corticosteroids were introduced.′,′ However, the high doses of corticosteroids required to suppress blistering frequently caused steroid related side effects and death.′,′ Morbidity and mortality from pemphigus today is often directly proportional to the dose of corticosteroids administered.[5] Because of the problem of corticosteroid related side effects, adjuvant immunosuppressive agents have been added to the treatment of pemphigus vulgaris to attain a steroid-sparing effect. In the last two decades, a variety of agents have been used including gold, dapsone, azathioprine, methotrexate and cyclophosphamide.[6] With the combination of corticosteroids and immunosuppressive agents, morbidity and mortality from pemphigus vulgaris has decreased even further.[7],[8] In this study we have made an attempt to study the efficacy of systemic corticosteroids and cyclophosphamide therapy in pemphigus vulgaris during acute phase.

Materials and Methods

We have seen 21 cases of pemphigus vulgaris from 1991 to 2001. All patients were admitted in ICU for initial assessment and treatment. Many of them (70%) were readmitted several times with recurrence of the disease. Details of history, physical findings, laboratory data, treatment and follow up were recorded. The diagnosis was confirmed by histopathological examination. Patients were treated in ICU till the acute phase of the disease subsided with fluid replacement, nutritional support, a coherent antibacterial therapy along with corticosteroids and immunosuppressants like cyclophosphamide, till the relief of symptoms or lesions subsided. Patients were monitored clinically. Repeated laboratory investigations like blood for Hb%, TLC, DLC, platelet count, serum electrolytes, blood sugar, serum creatinine, blood urea, LFT, urine RE, microscopic examination and culture, and repeated bacteriological culture of skin lesions were carried out in each patient.

When allowed by their general condition, patients were given bath once or twice a day in 1:10000 potassium permanganate solutions. When oozing from the skin lesions subsided the lesions were treated with 1 % framycetin cream dressing. Efficacy of antibiotic therapy was monitored by bacterial culture from several sites of affected skin once in every two days. The corticosteroid was administered as a single dose, prednisolone 1 mg/kg/day. Cyclophosphamide was given orally at an initial dose of 50mg/day and the dose was escalated to 100mg depending on patient′s tolerance. Complete blood cells count, platelet count and urinalysis were performed prior to therapy and monitored weekly. The dose of corticosteroids required to control disease activity were maintained until approximately 80% of the lesions were healed and there was no itching, a subtle sign of disease activity. Once the bulk of the lesions healed the dose of corticosteroids was gradually lowered by approximately 50% every two weeks till it was tapered off. Patients were given oral cyclophosphamide 100 mg OD as a maintenance dose.

Results

Out of 28 patients with various types of pemphigus, 21 (75%) had pemphigus vulgaris,[2] (7.1 %) pemphigus vegetans, 2 (7.1 %) pemphigus foliaceous and 3 (10.7%) had pemphigus erythematosus. Age groups of patients suffering from pemphigus vulgaris ranged from 25-24 years [Table - 1]. Eighteen (85.7%) were young adults, 30-40 years of age. Fifteen (71.4%) were men and 6 (28.6%) were women. All had extensive disease. Out of 21 patients receiving corticosteroids, immunosuppressants and other supportive therapy all but one (95%) had undergone clinical resolution of the disease. During follow up study for another two years 15(71.4% patients remained symptom free and undergone clinical remission [Table - 2]. Five (23.8%) patient: had relapse, which was mild in nature, and the lesions were localized. They required treatment with prednisolone 15 mg per day and remained symptom free. There was one case of death in our study.

Discussion

The management of pemphigus vulgaris during active phase of the disease necessitates intensive care preferably in ICU till the main disease responsible for acute skin failure is under control.[7] In PV, in addition to the exudates there is increased evaporation of ′free water′ without proteins or electrolytes. Electrolyte and fluid losses combined with hypoalbuminemia lead to the reduction of intravascular volumes. If not corrected hypovolaemia may lead to haemodynamic changes, renal failure and increase the risk of aseptic shock.[8] All the water and electrolyte needs of patients with pemphigus (PV) are maintained by a nasogastric silicone tube and venous access is used only a few hours a day for a discontinuous supply of macromolecules. The intravenous fluids given in the first 24 hours include 1 mI/kg weight/body surface area involved of macromolecules, preferably human albumin diluted to 40g/l in isotonic saline solution rather than fresh frozen plasma because of the risk of virus transmission, plus 0.7 ml/kg body weight/% body surface area involved of isotonic saline solution. Intravenous fluids are supplemented with potassium phosphate in order to correct hypophosphataemia, which may worsen insulin resistance, alter the neurological status and impair diaphragmatic function. In addition all patients are given 1500ml of nasogastric feeding during the first 24 hours. On the following days fluids are required to be decreased.[7],[8]

Aggressive nutritional support is needed as soon as possible to minimize the protein losses and to promote tissue synthesis during the healing of cutaneous lesions.[9] In patients who are able to eat, discontinuous tube feeding supplements are administered during the night. In all cases oral alimentation is preferable to parenteral therapy considering the risk of venous line contamination. It is ideal to begin with 1500 or 2000 calories in 1500-2000 ml for the first twelve hours and increase the intake by 500 calories daily up to 3500-4000 calories per day.[10] The diet is high protein with 2-3 g/kg body weight of protein daily in adults. Residual gastric volume is checked by periodic aspiration, and feeding is stopped if more than 50 ml are present.

Infection is the main cause of death in all widespread skin involvement in PV. Routine prophylactic systemic antibiotics do not prevent infection but rather lead to the emergence of resistant bacterial strains and of fungi as the cause of severe sepsis.[4] When allowed by their general condition patients are bathed once or twice a day with 1 in 10000 potassium permanganate solution. In between, the skin lesions are painted every 4 hours in with 0.05% aqueous chlorhexidine. When oozing from the skin lesions subside the lesions are treated with 1% silver suphadiazine cream or sofratulle dressing. Efficiency of antiseptic therapy is monitored by bacterial sampling on several sites of altered strains present on the skin. At the beginning of the hospital stay Staph aureus is the main suspect while later pseudomonas and enterobacteriaceae are the most likely responsible.

Environment temperature should be raised to 30-32°C. This will reduce calorie losses through the skin and the resultant shivering and stress. Patients with extensive skin lesions usually have fever and shivering, even in the absence of infection. Interleukin I, which is produced by epidermal cells, plays a key role in inducing fever. Lowering of the central body temperature by antipyretics will contribute to the reduction of cutaneous heat losses and improve the cardiac index.[8] The temperature of antiseptic baths should be carefully monitored and set to 35-38°C. Infrared lamps and an air-fluidised bed are of great help to keep the patients warm.[8]

Corticosteroids are the mainstay of therapy for patients with pemphigus vulgaris.[9],[10],[11],[12],[13],[14],[15] The aim of therapy is to find the lowest possible dosage of prednisolone, which will control the majority of the patient′s symptoms.[5] Corticosteroids are usually administered as a single dose in the morning. The dosage of corticosteroid is highly dependent on the patient and the severity of disease. For example, patients with mild disease may respond to as little as 20mg/day of prednisolone, while those with more severe and extensive involvement tend to require higher dosage, such as 60 to 80 mg/day (1 to 1.5 mg/ kg/day).[8] Recent studies have confirmed a direct correlation between the number of blisters and the time to control disease in patients with pemphigus vulgaris.[9] In patients whose disease fails to respond to the initial dose of prednisolone, the dosage is increased by 50 percent every four to five days until initial control is reached. Patients whose skin continues to blister while they are receiving relatively high dosages of prednisolone (120 mg/day) may try split doses, e.g. 80 mg in the morning and 40 mg in the evening for better control. Once new blistering has ceased, the dosage of prednisolone is maintained until the majority of the erosions are healed. Once the majority of lesions have healed, slow judicious tapering of the prednisolone dosage can begin.[12]

Long term side effects associated with corticosteroid used include osteoporosis, peptic ulcer disease, aseptic vascular necrosis, cataract formation and unmasking of diabetes mellitus.[6] Strategies to minimize these side effects include alternate day therapy, administration of corticosteroid sparing agents and the use of adjuvant to decrease the corticosteroid dependency.[6],[7],[8],[9],[10] Current agents used to mitigate against osteoporosis include vitamin D2, 400 IU per day and calcium carbonate 1 gm/day.[8]

Adjuvant therapy[6] is meant to comple-ment but not substitute for treatment with corticos-teroids. Some investigators believe that the course of the disease is shortened and morbidity is less with the aggressive use of immunosuppressants early in the disease course. The use of immuno-suppressants must be tailored to the individual patient. Immunosuppressants most commonly used in the treatment of autommune blistering diseases are azathioprine and cyclophosphamide. Patients do not respond to immunosuppressant until six to eight weeks after initiating therapy, so adequate dosages of steroids should be maintained. Cyclo-phosphamide has been reported to be effective both as a first line adjuvant in patients with pem-phigus and in the treatment of those whose dis-ease has previously failed to respond to azathio-prine.[13] Cyclophosphamide, an alkylating agent, is one of the most potent chemical immunosup-pressants available. Cyclophosphamide has been used for a variety of autoimmune diseases includ-ing systemic lupus erythematosus and pemphi-gus.[14],[15],[16],[17],[18] Cyclophosphamide is usually used in a single oral dose of 2 to 3 mg/kg/day. Toxic effects specially associated with cyclophosphamide include infertility, amenorrhoea, hemorrhagic cystitis, and bladder cancer. The risk of hemorrhagic cystitis is lessened considerably by adequate rehydration and frequent urination.

[Table - 3] summarizes the results of the larger studies[13],[14],[15],[16],[17] of patients with pemphigus treated with cyclophosphamide. Almost all patients were also treated concurrently with systemic corticosteroids. The average mortality was only 12% [Table - 3]. In our study there was one mortal-ity (4.7%) among patients suffering from pemphi-gus vulgaris. In our study we have not observed any serious side effects of cyclophosphamide in-cluding toxic effect on bone marrow and liver and hemorrhagic cystitis. Perhaps most worrisome is the growing evidence that the long term adminis-tration of immnosuppressive drugs is associated with an increased risk of cancer.[6] However, we have not come across any incidence of cancer in our series of cases.

Until the introduction of system corticosteroids, PV was an almost invariably fatal disease with a mortality rate of up to 90%.[1],[2] After the advent of corticosteroids in the 1950s, the mortality rate decreased dramatically. Mortal rates continued to decline, more slowly in the 1970s to an average of 60% and have remain essentially unchanged during the past 2 decade between 5 and 15%.[2],[5] The results of the present study are consistent with these trends. The other parameter commonly used to judge response therapy on PV is the induction of a remission. A remission occurs when a patient is completely free of lesions of pemphigus and is not receiving a systemic therapy.[18] Many workers[4],[9] believe the remission in pemphigus vulgaris are of she duration. The incidence of remission increase somewhat to an average of 23.3%, following the introduction of adjuvants.[14],[15],[16],[17],[18] Review of all major studies[4],[9] of pemphigus conducted during the pc 4 decades describes these as occurring in less the one third of patients. The average incidence remissions in the more recent studies[11] is 61% The possibility that remissions occur more oft now than they did in the past because patients a diagnosed and treated more quickly, however, cannot be excluded.[11]

These results indicate that the outlook pemphigus vulgaris is more favorable than currently believed.[18],[19],[20] The disease can be converted in to an inactive state in the majority of the patients. Most patients will eventually enter a complete and durable remission that permits systemic therapy to be safely discontinued without an exacerbation of disease severity. The remaining patients will usually have only mild disease controllable with low doses of prednisolone or an adjuvant.