Emerging treatment options for the management of pemphigus vulgaris

Figures & data

Table 1 Adverse events of systemic corticosteroids divided by body systems

System	Remarks
Musculoskeletal
Osteoporosis	Occurs in 30%–50% of all patients undergoing chronic treatment.^Citation138 A rapid decline in bone mineral density arises within the first 3 months of treatment, with a peak rate of loss at 6 months.^Citation139 Postmenopausal Caucasian women are at highest risk for complications such as fractures, as they have the lowest bone mass before treatment initiation.^Citation140
Avascular bone necrosis	Uncommon but serious complication. Mainly affects the proximal femur, although the distal femur or humeral head may also be involved. Most patients have been treated for at least 6–12 months, corresponding to the time required to induce changes in bone marrow fat deposition.^Citation141
Proximal myopathy	Uncommon. Most often affecting the lower extremities. It typically begins many weeks to months following therapy initiation, usually in patients treated with >40 mg/day of predniso(lo)ne.^Citation142
Growth retardation	A major concern in pediatric patients.^Citation143
Ophthalmologic
Posterior subcapsular cataract	The main ophthalmic concern in chronic corticosteroid therapy. This adverse effect can be observed in patients receiving as little as 10 mg/day of prednisone for 1 year.^Citation140
Others: glaucoma, infections, hemorrhage, and exophthalmos	Other uncommon ophthalmologic complications. Ophthalmologic examinations are recommended every 6–12 months for patients on long-term systemic corticosteroid therapy.^Citation144
Metabolic^Citation140
Hyperglycemia	Elevation of preexisting or subclinical glucose intolerance frequently occurs under treatment. New-onset diabetes mellitus usually occurs only with high-dose therapy. Most patients will return to their prior glucose status within few months of corticosteroid therapy discontinuation.
Hyperlipidemia	Hypertriglyceridemia is most frequently observed. Elevations of high- or low-density lipoproteins may also occur.
Weight gain with central redistribution	Leading to the classic “buffalo hump” and “moon face” habitus.
Cardiovascular
Hypertension	May occur in 20% of patients. More frequent in patients with preexisting hypertension or decreased renal function, in the elderly, and when high mineralocorticoid activity-corticosteroids are used.^Citation145
Atherosclerosis	Accelerated atherosclerosis occasionally develops in association with long-term systemic corticosteroid therapy.^Citation140
Others	Thromboembolic complications and atrioventricular conduction disturbances have also been reported under long-term corticosteroid treatment.^Citation140
Gastrointestinal
Peptic ulcer disease (PUD)	Increased incidence in patients treated concomitantly with NSAIDs or aspirin.^Citation146 As corticosteroids may mask symptoms of inflammation and inhibit wound healing, PUD is more susceptible to complications of hemorrhage or perforation. The administration with food and concomitant use of H2 receptor antagonists or proton pump inhibitors in higher-risk individuals, decreases the likelihood of PUD.^Citation140
Nausea, vomiting, and gastroesophageal reflux	The risk for these events may be diminished by the administration with food and/or taking acid-suppressing medications.^Citation140
Candidal esophagitis	Requires oral antifungal treatment.^Citation140
Fatty liver and pancreatitis	Associated with glucocorticoid-induced hypertriglyceridemia.^Citation140
Infections
Increased overall susceptibility to many bacterial, viral, fungal, and parasitic infections^Citation140	• Fever and signs of inflammation may be attenuated in patients receiving corticosteroids, impeding early recognition of infectious diseases. • Reactivation of tuberculosis is a concern in patients receiving chronic corticosteroid therapy. Screening is advocated prior to treatment initiation. • An increased risk of Pneumocystis jiroveci pneumonia (Pneumocystis carinii pneumonia [PCP]) mainly in patients on high doses for >1 month and in those with additional causes for immunodeficiency. A recent study observed low incidence of PCP among patients with autoimmune bullous diseases that does not require prophylaxis.^Citation147 • HIV-positive patients with CD4^+ counts <200/mm^3 should routinely receive trimethoprim–sulfamethoxazole prophylaxis.^Citation140 • Due to insufficient antibody responses to immunizations, live-virus vaccines should be avoided during or within a month after discontinuing corticosteroid therapy at a dose equivalent to ≥20 mg/day of predniso(lo)ne for more than 2 weeks.^Citation140
Nervous system^Citation140
Most frequent: mood changes, anxiety, and insomnia	Common and dose-related adverse events.
Depression	Not uncommon during the tapering phase of corticosteroid therapy. Patients with a prior history of personality disorders are at a greater risk for corticosteroid-related neuropsychiatric symptoms.
Psychosis	Uncommon side effect that is dose related and tends to develop in patients with prior psychiatric condition.
Pseudotumor cerebri	A possible complication of high-dose or long-term therapy. Occurs typically subsequent to rapid tapering or discontinuation of treatment.
Seizures	Infrequent. Primarily among seizure-prone individuals on high corticosteroid doses.
Others	Peripheral neuropathy, electroencephalographic changes, and enhancement of preexisting tremor.
Hypothalamus–pituitary–adrenal (HPA) axis suppression^Citation140
Secondary adrenal insufficiency	• Related to both the dose and duration of treatment. Usually occurs following 4 weeks of systemic treatment with doses above physiologic levels and even earlier with higher doses. • Attenuated by administering the corticosteroid as a single morning dose and decreased even more by using an intermediate-acting agent on alternate mornings. • Full recovery of the adrenal glands with the reversion of normal serum cortisol levels may require an extended duration, sometimes up to 1 year. Screening tests are warranted prior to the discontinuation of long-term steroidal therapy. Morning serum cortisol level is the primary screening test for basal function of the entire axis. Adrenal function can be examined by using the more specific ACTH stimulation test.
Cutaneous
Systemic	Purpura, telangiectasias, atrophy, striae, pseudoscars, acneiform or rosacea-like eruptions, and facial plethora. In a prospective study including 88 patients, 46.2% of patients developed skin changes after 3 months of treatment with a mean prednisone dosage of 30 mg/day.^Citation148
Topical	Localized telangiectasias, atrophy, and hypopigmentation, especially following long-term daily application of potent agents or use under occlusion.^Citation140

Abbreviations: NSAIDs, nonsteroidal anti-inflammatory drugs; ACTH, adrenocorticotropic hormone.

Table 2 Randomized controlled trials of therapeutic interventions in pemphigus vulgaris

Study	Treatments compared	Blinding	Number of participants	Follow-up duration	Main findings
Ratnam et al^Citation21	1) Low prednisolone dose (45–60 mg) 2) High prednisolone dose (120–180 mg)	No	22	5 years	No significant differences in death, disease control, relapse, and adverse events between doses
Chrysomallis et al^Citation68	1) Adjuvant oral cyclophosphamide (100 mg/day) 2) Adjuvant cyclosporine (5 mg/kg/day) 3) Prednisolone alone (40 mg/day)	No	28	5 years	No significant differences in time until remission and relapse rate between arms. Complications were higher in combination therapy
Mentink et al^Citation12	1) Adjuvant pulsed dexamethasone (300 mg/day for three consecutive days) 2) Prednisolone (initially 80 mg/day) and azathioprine (3 mg/kg/day) alone	Double blind	20	1 year	The dexamethasone group had more adverse events. Its effect on remission, death, and relapse rates were inconclusive
Chams-Davatchi et al^Citation27	1) Adjuvant azathioprine (2.5 mg/kg/day) 2) Adjuvant MMF (2 g/day) 3) Adjuvant intravenous cyclophosphamide pulses (1 g/month) 4) Prednisolone (2 mg/kg/day)	No	120	1 year	Significant corticosteroid-sparing effect in Group 1 compared with groups 2 and 4. Group 2 had higher corticosteroid-sparing effect compared with Group 4. Similar side effects and remission rate in all groups
Tabrizi et al^Citation149	1) Topical epidermal growth factor 2) Placebo	Double blind	20	9 months	The topical epidermal growth factor group had faster healing by a median of 6 days
Arnold et al^Citation78	1) Adjuvant IVIg 2) Placebo infusion	Double blind	1	1 year	Lower disease activity and anti-Dsg1 and anti-Dsg3 levels while on IVIg compared with placebo
Sethy et al^Citation70	1) IV dexamethasone (100 mg on three consecutive days) in combination with IV cyclophosphamide (500 mg) every 4 weeks; and oral cyclophosphamide (50 mg/day) between the pulses 2) IV cyclophosphamide (15 mg/kg/day) every 4 weeks and oral prednisolone (1.5 mg/kg/day)	No	28	1 year	Faster healing (8.4 vs 13 weeks) but greater corticosteroid-induced adverse effect in Group 2
el-Darouti et al^Citation150	1) IV cycles of methyl-prednisolone (500 mg on five consecutive days) and cyclophosphamide (500 mg on Day 1) every 2–4 weeks with daily oral cyclophosphamide (100 mg) and oral prednisone (60 mg twice per week) between the cycles plus daily pentoxifylline (3 × 400 mg/day) and sulfasalazine (3 × 500 mg/day) 2) IV cycles of methyl-prednisolone (500 mg on 5 consecutive days) and cyclophosphamide (500 mg on day 1) every 2–4 weeks with daily oral cyclophosphamide (100 mg) and oral prednisone (60 mg twice per week) in between the cycles plus placebo	Double blind	64	8 months	Group 1 had more clinical improvement and lower TNF-α levels
Beissert et al^Citation25	1) Adjuvant MMF (2 g/day) 2) Adjuvant MMF (4 g/day) 3) Prednisolone alone (1–2 mg/day)	Double blind	96	52 weeks	Similar response rates but earlier and more durable response with longer time to relapse in groups 1 and 2
Iraji et al^Citation151	1) Pimecrolimus 1% cream 2) Placebo  • Both groups were treated concomitantly with prednisolone and azathioprine	Double blind	11	30 days	Better epithelization index in group 1; lesion size was smaller by Day 15 (2.86 vs 3.14 cm) and day 30 (2.67 vs 3.67 cm)
Fiorentino et al^Citation152	1) Etanercept (50 mg once weekly for 16 weeks) 2) Placebo	Double blind	8	35 days	The effect of etanercept on the number of lesions and adverse events was inconclusive
Nazemi-Tabrizi et al^Citation153	1) Tacrolimus 0.1% ointment 2) Placebo	Single-blinded	15	2 weeks	The effect of tacrolimus on pain scores and total erosive surface area was not significant
Hall et al^Citation154	1) Adjuvant infliximab (5 mg/kg at weeks 0, 2, 6 and 14) 2) Prednisolone alone	Double blind	20	26 weeks	Dsg1 antibodies levels showed a significant decrease at Week 18. No significant difference in clinical response, adverse events, and B-cell levels between the two arms
Iraji et al^Citation155	1) Adjuvant acyclovir 2) Prednisolone and azathioprine alone	No	30	1 month	No significant difference in disease severity, remission, hospitalization time, and adverse effects between the two arms
Sharma and Khandpur^Citation69	1) Adjuvant pulsed IV cyclophosphamide (15 mg/kg once a month) 2) Prednisolone alone (initial dose of 1 mg/kg/day)	No	60	1 year	No significant differences in time until response/remission/relapse, remission and relapse rates, cumulative steroid doses, and adverse events between the two arms
Parmar et al^Citation71	1) IV dexamethasone (100 mg on three consecutive days) in combination with IV cyclophosphamide (500 mg) every 4 weeks; and oral cyclophosphamide (50 mg/day) between the pulses 2) Oral cyclophosphamide (50 mg/day) alone	No	19	9 months	No significant differences in relapse rate, Dsg1 and -3 levels, and DIF grading between the two arms
Chams-Davatchi et al^Citation23	1) Adjuvant azathioprine (2.5 mg/kg/day) 2) Prednisolone alone (2 mg/kg/day)	Double blind	56	1 year	The effect of azathioprine on severity score, cumulative corticosteroid dose and mean daily prednisolone dose was significant in the last 3 months of the 1-year trial. Its effect was inconclusive in the first 9 months of the trial
Kanwar et al^Citation156	1) High-dose rituximab (1,000 mg on days 0 and 15) 2) Low-dose rituximab (500 mg on days 0 and 15)  • Patients in both groups also received oral corticosteroids depending on the severity of the disease and clinical judgment	Single-blind	22	48 weeks	No significant difference in early and late clinical end points, and total cumulative dose of corticosteroids between the two arms. Patients in the low-dose group received a significantly higher cumulative dose of azathioprine. The ELISA indices of Dsg1 and Dsg3 showed a statistically significant decline in the high-dose group only. B-cell repopulation occurred earlier in the low-dose group by 8 weeks
Dastgheib et al^Citation157	1) Adjuvant azathioprine (2.5 mg/kg/day) 2) Adjuvant tacrolimus (0.05 mg/kg/day)  • Patients in both groups also received prednisolone (1 mg/kg/day)	No	46	6 months	No significant difference in duration taken to cease formation of new bulla and time to start steroid tapering between the two groups. Group 1 had more severe adverse events
El-Darouti et al^Citation158	1) Interferon retard SC (60 µg/week for 4 weeks) 2) Placebo  • Both groups were treated concomitantly with IV methyl-prednisolone and IV cyclophosphamide pulses every 2–4 weeks in combination with oral cyclophosphamide, sulphasalazine and pentoxifylline	Double blind	30	1 year	Group 1 patients showed a statistically significant greater improvement in the PAAS score. Complete resolution was significantly higher both at 4 and 12 weeks IFN-γ levels were elevated significantly and IL-4 were dropped significantly in Group 1 compared to Group 2
Joly et al^Citation52	1) Rituximab IV (1,000 mg on days 0 and 14, and 500 mg at months 12 and 18) in combination with prednisone (0.5 or 1.0 mg/kg/day tapered over 3 or 6 months) 2) Prednisolone alone (1.0 or 1.5 mg/kg/day tapered over 12 or 18 months)	No	91	3 years	Higher “complete remission off-therapy” rate following 24 months in Group 1 More severe adverse events of grade 3–4 were reported in Group 2

Abbreviations: MMF, mycophenolate mofetil; IVIg, intravenous immunoglobulin; IV, intravenous; SC, subcutaneous; PAAS, Pemphigus Area and Activity Score.

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