Published on in Vol 6 (2023)

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From the Cochrane Library: Interventions for Pemphigus Vulgaris and Pemphigus Foliaceus

From the Cochrane Library: Interventions for Pemphigus Vulgaris and Pemphigus Foliaceus

From the Cochrane Library: Interventions for Pemphigus Vulgaris and Pemphigus Foliaceus

Research Letter

1Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States

2Department of Dermatology, St George Hospital, Sydney, Australia

3Dermatology Service Rocky Mountain Regional VA Medical Center, Eastern Colorado Health Care System, Aurora, CO, United States

4Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, United States

Corresponding Author:

Robert P Dellavalle, MSPH, MD, PhD

Department of Dermatology

University of Colorado Anschutz Medical Campus

1665 Aurora Ct

3rd Floor

Aurora, CO, 80045

United States

Phone: 1 720 289 0247


Cochrane systematic reviews are rigorous in methodology and contribute to our understanding of evidence-based treatments of diseases. Among these diseases is pemphigus, a group of acquired autoimmune vesiculobullous diseases (pemphigus vulgaris [PV], pemphigus foliaceus [PF], and pemphigus paraneoplastic [PNP]), characterized by B-cell–mediated immunoglobulin G antibodies against desmogleins 1 and 3. Cutaneous bullae cause loss of barrier function and pain, dehydration, superimposed infections, and psychological distress. Due to a lack of expert consensus and the poor efficacy of previous therapies, a Cochrane systematic review of randomized controlled trials (RCTs) sought to define the best treatment for pemphigus [1]. Here, we highlight takeaways from the review [1] and discuss advances in therapy. PNP was excluded from the review due to its rarity and because its management depends on the underlying malignancy.

A total of 11 RCTs were analyzed to assess efficacy and safety among treatments for PV and PF. The primary outcomes were death and disease remission, with secondary outcomes including disease severity indexes, time to disease control, cumulative glucocorticoid dose, serologic markers, and the proportion of patients achieving disease control and relapse. The RCTs used various combinations and doses of steroid-sparing agents with or without corticosteroids. We contrasted therapies, outcomes, and comparison effect size and conducted 4 meta-analyses.

A recent (2021) network meta-analysis [2] found rituximab (Table 1), a CD20 B-cell–depleting therapy, as the most effective therapy for key outcomes like disease relapse, withdrawal from adverse events, remission, and cumulative glucocorticoid dose. The right-most column of Table 1 contrasts therapies relative to rituximab among the 4 key outcomes evaluated. Although the included trials [2] risked bias due to inadequate allocation concealment and lack of participant, personnel, and outcome blinding, the results align with emerging expert consensus and other important clinical trials [3] directly comparing rituximab to other therapies like mycophenolate.

Table 1. Summary of interventions, outcomes assessed, and effect size from 2009 (left) and 2021 (right).
InterventionEffect size: RRa (95% Cl)OutcomesEffect size: pooled ORb (95% CI)

Rituximab vs intervention
Prednisolone (1mg/kg vs 0.5 mg/kg)Steroid alone

1Not estimableDisease controlc

20.7 (0.43 to 1.14)Relapse0.38 (0.12 to 1.15)

3Not estimableWithdrawal due to adverse event0.05 (0 to 0.083)
Pulsed oral dexamethasone vs placeboSteroid alone

11.91 (0.68 to 5.33)Relapse (after discontinuing or stopping)

22.45 (0.31 to 19.74)Withdrawal due to adverse event
Azathioprine vs glucocorticoid (prednisolone) alone

11.04 (0.8 to 1.36)Remission14.45 (4.71 to 43.68)Steroid alone

2–3.91 (–6.71 to –1.12)Cumulative glucocorticoid dose–11.10 (–14.08 to –9.57)Steroid alone

32 (0.19 to 20.9)Withdrawal due to adverse event0.02 (0 to 0.56)Azathioprine
Cyclophosphamide vs glucocorticoid (prednisone/prednisolone) aloneAzathioprine

10.96 (0.71 to 1.28)Remission10.10 (2.67 to 38.23)

20 (0)Disease control

30.5 (0.05 to 4.67)Relapse0.60 (0.10 to 3.63)

4–3.35 (–6.14 to –0.56)Cumulative glucocorticoid dose­–8.79 (–11.60 to –5.98)

50.33 (0.01 to 7.87)Withdrawal due to adverse events
Cyclosporine vs glucocorticoid (prednisone/methylprednisolone) aloneCyclophosphamide

10 (0)Remission9.59 (2.42 to 37.96)

21.06 (0.86 to 1.32)Disease control

30.92 (0.23 to 3.65)Relapse0.42 (0.08 to 2.28)

4–0.05 ( –0.18 to 0.081)Cumulative glucocorticoid dose–9.36 (–12.16 to –6.55)

50 (0)Withdrawal due to adverse event0.10 (0 to 4.20)
Dapsone vs placeboCyclophosphamide

11.85 (0.61 to 5.63)Remission (<7.5 mg prednisone) at 12 months

20.37 (0.05 to 2.95)Withdrawal due to adverse event
Mycophenolate vs glucocorticoid (prednisolone) aloneDexamethasone-cyclophosphamide (6 and 12 months)

10.91 (0.67 to 1.24)Remission47.11 (4.99 to 445.07), 6 months

2–1.83 (–4.94 to 1.28)Cumulative glucocorticoid dose

31.0 (0.07 to 15.26)Withdrawal due to adverse events0.06 (0 to 7.06), 6 months
Plasma-exchange vs controlDexamethasone-cyclophosphamide (6 and 12 months)

17.43 (0.43 to 129.55)Death

21.12 (0.70 to 1.78)Disease control (study definition involving relative healing time)

344.38 (–222.43 to 311.19)Reduction antibody titer (baseline to end protocol, mean difference)

47.2 (0.42 to 124.08)Withdrawal due to adverse events
Azathioprine vs cyclophosphamide

11.09 (0.82 to 1.44)Remission5.48 (0.71 to 42.02), 12 monthsDexamethasone-cyclophosphamide (6 and 12 months)

21.8 (0.89 to 3.64)Disease control (healing of >50% of lesions and/or occurrence of <5 blisters/month)Dexamethasone-cyclophosphamide (6 and 12 months)

31.0 (0.53 to 1.88)Relapse0.67 (0.04 to 11.13)Dexamethasone-cyclophosphamide (6 and 12 months)

41.0 (0.53 to 1.88)Relapse0.063 (0.12 to 3.47)Mycophenolate

5–5.64 (–1.04 to –0.79)Cumulative glucocorticoid doseMycophenolate

63.91 (0.45 to 33.66)Withdrawal due to adverse events0.05 (0 to 1.18)Mycophenolate
Azathioprine vs mycophenolateMycophenolate

11.14 (0.85 to 1.53)Remission10.80 (3.07 to 38.05)

20.72 (0.52 to 0.99)Disease control

3–2.07 (–3.54 to –0.60)Cumulative glucocorticoid dose–11.10 (–13.70 to –8.49)

43.01 (0.48 to 18.97)Withdrawal due to adverse events
Cyclophosphamide vs cyclosporine

10 (0)Remission (<10 mg prednisone equivalent) at 5 yearsMycophenolate

20 (0)Disease controlMycophenolate

30.4 (0.04 to 3.66)Relapse0.81 (0.05 to 13.72)Cyclosporine

40 (0)Withdrawal due to adverse events0.04 (0 to 5.92)Cyclosporine
Cyclophosphamide vs mycophenolateCyclosporine

11.05 (0.76 to 1.44)Remission11.96 (1.92 to 74.49)

2–1.52 (–2.98 to –0.056)Cumulative glucocorticoid dose–11.77 (–14.04 to 9.51)

30.33 (0.01 to 7.87)Withdrawal due to adverse events
Topical epidermal growth factor vs placebo2.35 (1.62 to 3.41)Time to control (hazard ratio)Cyclosporine
Traditional Chinese Medicine0.75 (–1.12 to 2.62)Antibody titerCyclosporine

aRR: relative risk.

bOR: odds ratio.

cThe 2021 network review assessed withdrawal due to adverse events, remission, relapse, and cumulative glucocorticoid dose. Other measures were not available.

Induction dosing for rituximab was two 1 g intravenous infusions 2 weeks apart followed by a 6-month prednisone taper of 1 mg/kg/day. Additionally, 2 novel higher-affinity CD20-blocking agents, ofatumumab and veltuzumab, demonstrated efficacy in isolated cases of rituximab-resistant pemphigus. Ofatumumab and veltuzumab are not used for pemphigus outside of clinical trials and for compassionate use. In addition, trials are underway for other immunotherapies targeting the fragment crystallizable region, B-cell–activating factor, and Bruton tyrosine kinase [4]. The meta-analyses revealed that some interventions were superior for certain outcomes: improved disease remission with mycophenolate relative to azathioprine, a steroid-sparing effect with azathioprine and cyclophosphamide, and a decreased time to erosion control with topical epidermal growth factor (Table 2). At the time of the 2009 study, systematic analysis including rituximab and clinical trials including intravenous immunoglobulin were ongoing [5].

Table 2. Summary of conclusive secondary outcomes (2009).
TherapeuticSecondary outcome
Mycophenolate mofetilImproved disease control compared to azathioprine (RRa 0.72, 95% CI 0.52 to 0.99; NNTb 3.7)
AzathioprineDecreased the cumulative glucocorticoid dose (MWDc –3919 mg prednisolone, 95% CI –6712 to –1126)
CyclophosphamideDeceased the cumulative glucocorticoid dose compared to prednisolone alone (MWD –3355 mg prednisolone, 95% CI –6144 to –566)
Topical epidermal growth factorDecreased time to erosion healing compared to the control intervention (HRd 2.35, 95% CI 1.62-3.41)

aRR: relative risk.

bNNT: number needed to treat.

cMWD: difference in means.

dHR: hazard ratio.

With an increasing understanding of the immune system, B-cell physiology, and the pathogenesis of pemphigus, therapies continue to emerge, making previous therapies obsolete. Here, we placed important Cochrane review findings in the context of recent advancements in the treatment of pemphigus. Further studies are needed to determine therapeutic regimens, safety, and efficacy of novel medical therapies for pemphigus.


RPD receives editorial stipends (JMIR Dermatology), royalties (UpToDate), and expense reimbursement from Cochrane. TES receives fellowship funding from Pfizer (grant 25B1519; principal investigator [PI]: Stanca Birlea) and the National Institutes of Health (NIH; grant 2T32AR00741136A1; PI: Dennis Roop). RR receives fellowship funding from the NIH (grant 2T32AR00741131A1; PI: Dennis Roop). The authors would like to thank Linda Martin for reviewing and providing feedback on the manuscript.

Conflicts of Interest

RPD is editor-in-chief of JMIR Dermatology and Cochrane Council cochair. TES serves as an editorial board member-at-large for JMIR Dermatology. RR is an editorial fellow for JMIR Dermatology. DM serves on the advisory boards or is an investigator for ArgenX, Roche, Lilly, Principiabio, Sanofi, and Janssen. DM is also the cocreator of the Pemphigus Disease Area Index and the creator of the Autoimmune Bullous Disease Quality of Life (ABQOL) and Treatment Autoimmune Bullous Disease Quality of Life (TABQOL) questionnaires.

Editorial notice: This article is based on a Cochrane Review previously published in the Cochrane Database of Systematic Reviews 2009, Issue 1, DOI: 10.1002/14651858.CD006263.pub2 (see for information). Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and Cochrane Database of Systematic Reviews should be consulted for the most recent version of the review.

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  5. Atzmony L, Hodak E, Gdalevich M, Rosenbaum O, Mimouni D. Treatment of pemphigus vulgaris and pemphigus foliaceus: a systematic review and meta-analysis. Am J Clin Dermatol. Dec 2014;15(6):503-515. [CrossRef] [Medline]

PF: pemphigus foliaceus
PNP: pemphigus paraneoplastic
PV: pemphigus vulgaris
RCT: randomized controlled trial

Edited by R Alhusayen; submitted 26.02.23; peer-reviewed by D Di Stasio, S Norouzi, L Wheless; comments to author 23.05.23; revised version received 19.06.23; accepted 23.07.23; published 15.12.23.


©Ramiro Rodriguez, Torunn E Sivesind, Dedee Murrell, Robert P Dellavalle. Originally published in JMIR Dermatology (, 15.12.2023.

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