British Association of Dermatologists' Guidelines for the Management of Pemphigus Vulgaris 2017

K.E. Harman; D. Brown; L.S. Exton; R.W. Groves; P.J. Hampton; M.F. Mohd Mustapa; J.F. Setterfield; P.D. Yesudian


The British Journal of Dermatology. 2017;177(5):1170-1201. 

In This Article

Comparisons of Systemic Adjuvant Drugs

Azathioprine and Mycophenolate Mofetil

In an unblinded multicentre RCT, 40 patients with pemphigus (33 PV and seven PF) were randomized to receive mycophenolate mofetil (1 g twice daily, n = 21) or azathioprine (2 mg kg−1 per day, n = 18), both in combination with a standardized corticosteroid regimen (methylprednisolone, initial dose 2 mg kg−1 per day); they were followed up for 2 years. There were no significant differences in efficacy, adverse event profile or cumulative corticosteroid dose between the two arms. There was a trend towards azathioprine achieving faster clinical remission, although more patients achieved remission with mycophenolate mofetil (95%, 20 of 21) after a mean of 91 days vs. azathioprine (72%, 13 of 18) after a mean of 74 days, and there were fewer grade 3 or 4 adverse events with mycophenolate mofetil (19% vs. 33% for azathioprine). However, the study was small with wide confidence intervals.[71]

In a further unblinded single-centre RCT, mycophenolate mofetil and azathioprine were compared as adjuvant drugs, in addition to pulsed cyclophosphamide.[53] In total 120 patients with PV were randomized to four groups of 30 patients: prednisolone alone (initial dose 2 mg kg−1 per day); prednisolone plus azathioprine (2·5 mg kg−1 per day for 2 months followed by 50 mg daily); prednisolone plus mycophenolate mofetil (2 g per day); and prednisolone plus intravenous cyclophosphamide (1 g monthly for 6 months, then 1 g every 2 months). In total 111 patients completed the 1-year follow-up. Efficacy and adverse events were similar in all four arms, but the cumulative corticosteroid dose was significantly higher in the prednisolone-only arm compared with the combined adjuvant groups. The lowest cumulative dose was in the azathioprine arm (azathioprine < intravenous cyclophosphamide < mycophenolate mofetil) and there was a significant difference between the azathioprine and mycophenolate mofetil arms, favouring azathioprine.

In a Cochrane systematic review[52] of these two studies comparing mycophenolate mofetil with azathioprine,[53,71] the combined data showed that azathioprine had a significantly better corticosteroid-sparing effect, measured as cumulative corticosteroid dose. However, they concluded that the Beissert et al. study[71] showed that mycophenolate mofetil was more effective than azathioprine at achieving a higher proportion of patients with disease control.[52]

Azathioprine and Oral Cyclophosphamide

A retrospective study of 101 patients included 20 treated with prednisolone alone and three groups treated with combinations of prednisolone and immunomodulatory drugs: 51 treated with cyclophosphamide 100 mg daily (1·1–1·5 mg kg−1), 16 with azathioprine (100 mg daily initial dose) and 14 with ciclosporin (2·5–3 mg kg−1 per day). The time to clinical remission was significantly shorter in the cyclophosphamide arm compared with the other three groups. The cyclophosphamide group also had a lower cumulative corticosteroid dose and a shorter time to immunological remission (no detectable antibodies). This study suggests that cyclophosphamide plus prednisolone is more effective than prednisolone alone and is superior to azathioprine plus prednisolone and ciclosporin plus prednisolone.[94]

Azathioprine and Intravenous Cyclophosphamide

In a small, multicentre RCT of 22 patients with pemphigus (16 PV) a regimen of oral methylprednisolone (initial dose 2 mg kg−1) and azathioprine (2–2·5 mg kg−1) was compared with a DCP regimen. The DCP regimen comprised pulses of 3 × 100-mg intravenous dexamethasone and 500-mg intravenous cyclophosphamide on day 1, repeated every 2–3 weeks initially, dropping down in frequency to every 6 weeks. Oral cyclophosphamide 50 mg daily was given between pulses but stopped after 6 months. Cyclophosphamide pulses were stopped when there was no relapse at 6 weeks from the last dose, but dexamethasone pulses were continued every 12 weeks. Patients were followed up for 2 years and there were no significant differences in either efficacy or adverse effects in the two treatment arms.[70]

Another study has compared a modified DCP regimen (each course included 1000-mg intravenous methylprednisolone for 4 days plus 500-mg intravenous cyclophosphamide for 1 day) with oral prednisolone (1–2 mg kg−1 initial dose) plus azathioprine (100–150 mg daily). Only three monthly pulses were given, with oral cyclophosphamide 50 mg daily and oral prednisolone, initially 30 mg daily, between pulses. It was not randomized, with 72 patients in the pulse arm and 51 in the control arm. Most outcome measures were similar in both groups, although at 1 year, cumulative corticosteroid doses and weight gain were significantly greater in the azathioprine arm, suggesting superiority of the DCP regimen compared with oral prednisolone and azathioprine.[72]

In the nonblind single-centre RCT that recruited 120 patients with PV and is described in section 18·1, efficacy and adverse effects were similar in the pulsed cyclophosphamide and azathioprine arms.[53] The cumulative corticosteroid dose was lower in the azathioprine arm but it was not significantly different from that in the cyclophosphamide arm. However, a Cochrane systematic review of these data indicated that the difference in cumulative corticosteroid dose was significant, favouring azathioprine as an adjuvant drug.[52]

Intravenous Cyclophosphamide and Mycophenolate Mofetil

Only one study comparing cyclophosphamide pulses with mycophenolate mofetil has been described (see section 18·1). In this study 30 patients with PV were recruited to each arm. There were no significant differences in efficacy or adverse events.[53] Both arms showed a corticosteroid-sparing effect, measured as cumulative prednisolone dose, but the difference between the cumulative corticosteroid dose in the two arms was reported by the authors as not significant using anova. A Cochrane systematic review of these data indicated that the difference in cumulative corticosteroid dose was significant, favouring pulsed cyclophosphamide as an adjuvant drug.[52]