Pulse Therapy in Pemphigus: Ready Reckoner

Abstract

Pulse therapy for the treatment of pemphigus has been in vogue for several years and is administered by many dermatologists across the world. However, even though there is enough evidence about its efficacy and methodology, there continue to be doubts and questions regarding the rationale of use of high dose intravenous steroids and steroid-sparing immunosuppressants. This article has aimed to provide clarity to young dermatology residents on the administration of pulse therapy, and the various controversies and modifications that have been mentioned in literature over the past couple of years.

What was known?

• The efficacy and methodology of administration of pulse therapy

• The modifications of pulse therapy and dexamethasone. cyclophosphamide pulse therapy.

Introduction

The treatment of pemphigus has been a long-standing burning issue in India particularly as it happens to be severer and occurs at a younger age as compared to the Western population. Earlier, pemphigus was commonly treated with prednisolone, which resulted in severe side effects of steroids. However, Pasricha and Gupta[1] introduced the dexamethasone-cyclophosphamide pulse (DCP) therapy in 1984,[1,2] and thereafter, plenty of literature on the management of pemphigus in India is based on this method. Even Western literature on the use of DCP showed studies conducted in UK, South Africa, and Serbia, which were efficacious.[3,4,5]

Rationale

The administration of suprapharmacologic doses of drugs in an intermittent manner is known as “pulse therapy.”[2,6] In pemphigus, pulse therapy refers to intravenous (IV) infusion of high doses of steroids for one or more days for quicker, better efficacy, and to decrease the side effects of long-term steroids.[7]

Glucocorticoids (GCs) have an immunosuppressive and anti-inflammatory effect on cells.[8] Studies have shown that steroids act on cells via two mechanisms: Genomic and nongenomic. Depending on the concentration of steroids used the effect seen is as follows:[9]

• At low concentrations (genomic effect): GC form complexes with cytosolic GC receptors (GCR) to form GCR complex which activates the MAPK signaling pathway. The activated GCR complex moves to the nucleus that activates the GC-responsive element which results in anti-inflammatory and immunosuppressive effects

• At high concentrations (genomic and nongenomic effects): GC intercalates with the cell membrane GCR causing rapid immunosuppression via apoptosis and induction of lipomodulin (which inhibits prostaglandins and leukotrienes). At high doses steroids inhibit nuclear factor kappaB via “transrepression” (direct interaction of GC with transcription factors).

Administration of Intravenous High dose Corticosteroids

Medications[10]

Dexamethasone (100 mg) or methylprednisolone (20–30 mg/kg). Reason for dexamethasone use in DCP is because it is a cheaper option. The reason for administration of dexamethasone in dextrose instead of normal saline is because steroids cause hypernatremia and hypokalemia.

Precautions

1. Before starting therapy:

   • Before the administration of corticosteroids, the patient should be free from systemic infections. Minor upper respiratory tract, gastrointestinal, or skin infections are not a contraindication to pulse therapy
   • Blood pressure must be under control
   • Counts, blood sugar, urea, creatinine, electrolytes, and urine routine should be done
   • In elderly patients, cardiac assessment should be done
   • Direct immunofluorescence (DIF) and histopathological examination help in the diagnosis of pemphigus. However, DIF specifically helps in monitoring disease activity and for prognosis and hence should be recorded before initiating pulse therapy.

2. During and after therapy:

   • Monitor pulse, respiratory rate, and blood pressure every 15–30 min
   • In case of an arrhythmia, the infusion is discontinued. Electrocardiography and electrolytes are measured, and abnormalities are corrected
   • Check regular blood levels of sugar and electrolytes daily.

Steps of pulse therapy as shown in Table 1.[11]

Table 1.

Steps of pulse therapy

Phases of pulse therapy as shown in Table 2.[11]

Table 2.

Phases of pulse therapy

Modifications

According to literature, modifications in the basic DCP have been proposed in the regimen for pulse therapy for pemphigus:

• Use of oral antibiotics and antifungals to control superadded infections which delay the healing of lesions[12]

• Thorough cleaning of skin and scalp lesions with soap and shampoo and maintenance of oral hygiene[12]

• Addition of daily oral steroids to control the disease activity during Phase 1, with progressive tapering as lesions heal (patient is shifted to Phase 2 only when all lesions healing and no new lesions while off oral steroids)[12]

• “Intermittent pulse” may also be given at shorter intervals (fortnightly) if disease is very severe[13]

• Instead of a total of 18 months for Phases 2 and 3; based on clinical severity, IF, and response to therapy, the duration may be shortened or extended in quick/slow responders[14]

• Individualization of the duration of Phase 2 and 3 based on IF results. The relapse rate is 13–27% if DIF is negative at the end of treatment but increases to 4–100% if DIF is positive[14]

• To replace a daily dose of cyclophosphamide of 50 mg in Phase 2 and 3 with a bolus dose of 500 mg every 4 weeks. The modified Phase 2 will consist of bolus dose of dexamethasone (100 mg for 3 days) and cyclophosphamide (500 mg on day 2) for 9 months. The modified Phase 3 will consist of only bolus dose of cyclophosphamide 500 mg IV every 4 weeks for 9 months instead of oral daily 50 mg[14]

• Cyclophosphamide-induced hemorrhagic cystitis is prevented infusion of 500 ml of 5% dextrose on day 2 of IV cyclophosphamide. On day 2 of cyclophosphamide infusion, the patient is advised to empty the bladder half hourly during infusion until 2 h after the infusion[15]

• Bladder toxicity is reduced by administration of IV mesna during IV doses of cyclophosphamide. The dose of mesna is equivalent to cyclophosphamide dose in 5 divided doses over 24 h[14]

• The duration of infusion of CP according to Pasricha[16] is 2 h and according to Balachandran[17,18] is 3–4 h. However, half-life is 7 h, and hence, it should be given over maximum 2 h to maintain the maximum concentration over a short-time[19]

• Prevention of steroid-induced osteoporosis by administration of calcium supplementation (500 mg/day), Vitamin D (400 IU/day), and bisphosphonate (e.g., alendronate).[11,12,15]

Modifications including regimens other than DCP:[15]

• Dexamethasone-azathioprine pulse (DAP): Cyclophosphamide is replaced by daily oral azathioprine. No bolus dose of azathioprine is given during the pulse

• Dexamethasone-methotrexate pulse (DMP): Cyclophosphamide is replaced by 7.5 mg of oral weekly methotrexate (three doses of 2.5 mg at 12 h apart), during the three phases of pulse therapy

• Rituximab is also given for pemphigus according to the rheumatoid arthritis protocol as 2 doses of 1 g, 2 weeks apart and according to the lymphoma protocol as 375 mg/m² weekly for 4 weeks.

DAP is recommended for unmarried patients who have not completed their family.

DMP is recommended for patients not responding to DCP/DAP after 12 pulses in Phase 1.

Complications according to severity:[11,15,20]

• Immediate: Anaphylactic reactions, seizures, arrhythmias, bradycardia sudden death, hypotension, hypertension electrolyte shifts, acute psychosis, sleep disturbance, infections, weakness, lethargy, flushing, palpitations, hiccups, numbness, polyuria, diffuse maculopapular rash, shivering, shooting pain along thighs, soreness of the mouth, conjunctival congestion, breathlessness, limb edema, and ecchymoses over the forearms

• Late: Hypothalamic-pituitary-adrenal axis suppression, avascular necrosis, osteoporotic fractures, cataracts, coronary artery disease, stroke, myopathy, diabetes, hypertension, peptic ulceration, osteoporosis, gonadal failure (amenorrhea, azoospermia), hemorrhagic cystitis, diffuse hyperpigmentation, obesity, squamous and transitional cell bladder carcinoma, loss of hair, headache, blurring of vision, menstrual disorder, dysgeusia, and nail discoloration.

The most common side effects are:[21,22]

• Mood and behavior altearation, hyperactivity, psychosis, disorientation, and sleep disturbances are seen in about 10% patients

• Hyperglycemia, hypokalemia, and infections

• Hiccups, facial flushing, diarrhea, weakness, generalized swelling, myalgia, arrhythmias, and shock.

Controversies

According to Singh et al.[23] who critically analyzed Pasricha's methodology of pulse therapy for pemphigus:

• Patients with diabetes were given the pulse in 5% glucose resulting in further hyperglycemia

• Unmarried patients and those who had not completed their families were given 50 mg cyclophosphamide daily resulting in gonadal failure at a cumulative dose of 30 g and 12 g in women and men, respectively.[24] Ramam[24] therefore opined that cyclophosphamide should be completely avoided in such patients

• Although dual-energy X-ray absorptiometry was not done, it was mentioned that osteoporosis is not common with pulse therapy

• Pulse therapy can result in cardiac arrhythmias and sudden death during and even days after pulse therapy; however, patients are discharged within 3 days of hospitalization

• Patients receive antibiotics especially cephalosporins in view of bacterial skin infection, until the skin lesions heal, however, cephalosporins aggravate pemphigus.[25] Furthermore, long-term use of antibiotics can cause antibiotic resistance. Ramam[24] found that antibiotics should be used until the infection clears and not until lesions heal

• According to a study by Sethy et al.,[26] a trial of DCP and daily cyclophosphamide (DCP + C) versus CP and daily oral prednisolone (CP + P) was conducted. In CP + P early remission was achieved, but relapse rates and side effects were comparable for both groups

• There is no standardized objective method for assessing severity of disease before and after treatment

• According to a study by Shahidi-Dadras et al.,[27] a trial of pulse versus oral steroid therapy, therapeutic responses, remission, relapse, and complications were similar in both study groups.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

What is new?

A simple and easy 1st time reading for a beginner to have an understanding of the reason for pulse steroids over daily steroids in pemphigus.