Elsevier

The Lancet

Volume 389, Issue 10083, 20–26 May 2017, Pages 2031-2040
The Lancet

Articles
First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial

https://doi.org/10.1016/S0140-6736(17)30070-3Get rights and content

Summary

Background

High doses of corticosteroids are considered the standard treatment for pemphigus. Because long-term corticosteroid treatment can cause severe and even life-threatening side-effects in patients with this disease, we assessed whether first-line use of rituximab as adjuvant therapy could improve the proportion of patients achieving complete remission off-therapy, compared with corticosteroid treatment alone, while decreasing treatment side-effects of corticosteroids.

Methods

We did a prospective, multicentre, parallel-group, open-label, randomised trial in 25 dermatology hospital departments in France (Ritux 3). Eligible participants were patients with newly diagnosed pemphigus aged 18–80 years being treated for the first time (not at the time of a relapse). We randomly assigned participants (1:1) to receive either oral prednisone alone, 1·0 or 1·5 mg/kg per day tapered over 12 or 18 months (prednisone alone group), or 1000 mg of intravenous rituximab on days 0 and 14, and 500 mg at months 12 and 18, combined with a short-term prednisone regimen, 0·5 or 1·0 mg/kg per day tapered over 3 or 6 months (rituximab plus short-term prednisone group). Follow-up was for 3 years (study visits were scheduled weekly during the first month of the study, then monthly until month 24, then an additional visit at month 36). Treatment was assigned through central computer-generated randomisation, with stratification according to disease-severity (severe or moderate, based on Harman's criteria). The primary endpoint was the proportion of patients who achieved complete remission off-therapy at month 24 (intention-to-treat analysis). This study is registered with ClinicalTrials.gov, number NCT00784589.

Findings

Between May 10, 2010, and Dec 7, 2012, we enrolled 91 patients and randomly assigned 90 to treatment (90 were analysed; 1 patient withdrew consent before the random assignment). At month 24, 41 (89%) of 46 patients assigned to rituximab plus short-term prednisone were in complete remission off-therapy versus 15 (34%) of 44 assigned to prednisone alone (absolute difference 55 percentage points, 95% CI 38·4–71·7; p<0·0001. This difference corresponded to a relative risk of success of 2·61 (95% CI 1·71–3·99, p<0·0001), corresponding to 1·82 patients (95% CI 1·39–2·60) who would need to be treated with rituximab plus prednisone (rather than prednisone alone) for one additional success. No patient died during the study. More severe adverse events of grade 3–4 were reported in the prednisone-alone group (53 events in 29 patients; mean 1·20 [SD 1·25]) than in the rituximab plus prednisone group (27 events in 16 patients; mean 0·59 [1·15]; p=0·0021). The most common of these events in both groups were diabetes and endocrine disorder (11 [21%] with prednisone alone vs six [22%] with rituximab plus prednisone), myopathy (ten [19%] vs three [11%]), and bone disorders (five [9%] vs five [19%]).

Interpretation

Data from our trial suggest that first-line use of rituximab plus short-term prednisone for patients with pemphigus is more effective than using prednisone alone, with fewer adverse events.

Funding

French Ministry of Health, French Society of Dermatology, Roche.

Introduction

Pemphigus is a life-threatening autoimmune blistering disease affecting the skin and mucosa.1, 2, 3, 4, 5 It is mediated by pathogenic autoantibodies directed against the desmoglein 1 and desmoglein 3 adhesion molecules of the epidermis that are responsible for the cohesion between keratinocytes in the skin and mucosa.6, 7, 8 High doses of systemic corticosteroids are considered the standard treatment for patients with pemphigus,9, 10 and little evidence supports the use of conventional immunosuppressants as first-line treatment of this disease.11, 12, 13, 14, 15, 16, 17, 18, 19

Research in context

Evidence before this study

Pemphigus is a life-threatening autoimmune blistering disease affecting the skin and mucosa. The combination of high doses of systemic corticosteroids and conventional immunosuppressive drugs, mostly azathioprine and mycophenolate mofetil, is regarded as standard treatment for severe cases of pemphigus. However, only 50% of patients achieve complete remission off-therapy. Many patients relapse and require a maintenance corticosteroid therapy, leading to high cumulative doses of corticosteroids and accompanying side effects. We searched PubMed for articles published from 2002–2015 with the terms “pemphigus” and “rituximab”. We identified more than 400 patients with severe types of pemphigus refractory to conventional immunosuppressive drugs, who were treated with rituximab as second-line or third-line treatment. A few studies compared the first-line use of adjuvant immunosuppressive drugs as steroid-sparing agents versus placebo. Unfortunately, none of the findings from these studies showed a clear beneficial effect from the addition of conventional immunosuppressants to corticosteroids alone. High rates of short-term complete remission between 70% and 80% were reported with good tolerance, but with a 30%–60% relapse rate. Given this high efficacy of rituximab in the refractory type of pemphigus, results from a few case reports have suggested that its use as first-line treatment in pemphigus might permit rapid tapering of corticosteroid doses. Because long-term corticosteroid treatment is responsible for severe and even life-threatening side-effects in patients with pemphigus, we did a randomised trial comparing treatment with a high dose of prednisone alone given for 12 to 18 months with a regimen of rituximab plus lower initial doses of prednisone, rapidly tapered over 3 to 6 months. Our aim was to assess whether first-line rituximab plus short-term prednisone could substantially improve the occurrence of long-term complete remission off-therapy in patients with pemphigus, while allowing a decrease in cumulative doses of prednisone and a reduction of severe treatment adverse events, compared with prednisone alone.

Added value of this study

This is the first trial of patients with pemphigus that compared a regimen of high doses of corticosteroids alone with a regimen of rituximab plus low dose of corticosteroids. The findings showed that first-line use of rituximab with short-term prednisone resulted in an increase in achievement of complete remission off-therapy at month 24 of almost three times compared with a corticosteroid-alone regimen. Additionally, median cumulative duration of complete remission-off-therapy was more than seven times higher in patients assigned to rituximab plus short-term prednisone. Patients in the rituximab plus short-term prednisone group also took about one-third of the prednisone cumulative dose that the corticosteroid-alone group took, and had about half as many severe adverse events.

Implications of all the available evidence

Data from our trial suggest that a regimen of rituximab plus low dose corticosteroids could be used as first-line treatment in patients with moderate to severe pemphigus. The regimen is highly effective, allows rapid tapering of corticosteroids, and causes fewer treatment adverse events than a regimen using corticosteroid doses alone.

Rituximab, a monoclonal antibody directed against the CD20 antigen of B-lymphocytes, has been shown to be effective in severe types of pemphigus.20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 Findings from some uncontrolled case series have suggested that the use of rituximab as first-line treatment of pemphigus permits rapid tapering of corticosteroid doses.21, 32, 33, 34, 35 Because long-term corticosteroid treatment is responsible for severe and even life-threatening side-effects in patients with pemphigus,36, 37, 38 we did a randomised trial comparing a standard corticosteroid regimen of high-dose prednisone given for 12 to 18 months with a regimen of rituximab plus lower initial doses of prednisone, rapidly tapered over 3 to 6 months. The aim of our study was to assess whether the regimen of rituximab plus short-term prednisone could substantially improve the number of patients with pemphigus who achieved long-term complete remission off-therapy, and enable a decrease in cumulative doses of prednisone and a reduction of severe treatment adverse events, compared to prednisone alone.

Section snippets

Study design and participants

We did a prospective, multicentre, parallel-group, open-label, randomised trial in 25 dermatology hospital departments in France (Ritux 3). The Ethics Committee (CPP Nord-Ouest1) approved the study. The references of the trial (ClinicalTrials.gov number, NCT00784589) and full protocol are in the appendix.

We recruited consecutive patients with newly diagnosed pemphigus aged between 18 and 80 years if they fulfilled the following criteria: clinical features suggestive of pemphigus vulgaris or

Results

Between May 10, 2010, and Dec 7, 2012, we enrolled 91 patients the study. One patient withdrew their consent before randomisation, leaving 90 patients randomly assigned to treatment (46 to rituximab plus short-term-prednisone and 44 to prednisone alone (figure 1). 74 (82%) of 90 patients in total had pemphigus vulgaris. Mean weight loss before treatment in the 71 (79%) patients who had oral (mucosal) lesions was 6·7 kg (SD 4·5). The two groups were well balanced except for sex and for PDAI

Discussion

The results from our study show that first-line use of rituximab plus a short prednisone regimen was more effective than prednisone alone for patients with pemphigus on all primary and secondary endpoints. Despite the study not being powered to detect a difference for pemphigus subtypes, the beneficial effect of rituximab was observed not only in pemphigus patients as a whole, but also in patients with the subtype pemphigus vulgaris, which is often considered to be a more severe condition than

References (49)

  • AR Ahmed et al.

    First line treatment of pemphigus vulgaris with a novel protocol in patients with contraindications to systemic corticosteroids and immunosuppressive agents: preliminary retrospective study with a seven year follow-up

    Int Immunopharmacol

    (2016)
  • YA Leshem et al.

    Opportunistic infections in patients with pemphigus

    J Am Acad Dermatol

    (2014)
  • N Almugairen et al.

    Assessment of the rate of long-term complete remission off therapy in patients with pemphigus treated with different regimens including medium- and high-dose corticosteroids

    J Am Acad Dermatol

    (2013)
  • M Rosenbach et al.

    Reliability and convergent validity of two outcome instruments for pemphigus

    J Invest Dermatol

    (2009)
  • DF Murrell et al.

    Consensus statement on definitions of disease, end points and therapeutic response for pemphigus

    J Am Acad Dermatol

    (2008)
  • JR Stanley

    Pemphigus and pemphigoid as paradigms of organ-specific, autoantibody-mediated diseases

    J Clin Invest

    (1989)
  • GJ Anhalt et al.

    Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease

    N Engl J Med

    (1982)
  • JR Stanley et al.

    Pemphigus, bullous impetigo, and the staphylococcal scalded-skin syndrome

    N Engl J Med

    (2006)
  • SM Langan et al.

    Bullous pemphigoid and pemphigus vulgaris incidence and mortality in the UK: population based cohort study

    BMJ

    (2008)
  • H Wu et al.

    Protection against pemphigus foliaceus by desmoglein 3 in neonates

    N Engl J Med

    (2000)
  • M Hertl et al.

    T cell control in autoimmune bullous skin disorders

    J Clin Invest

    (2006)
  • P Berkowitz et al.

    p38MAPK inhibition prevents disease in pemphigus vulgaris mice

    Proc Natl Acad Sci USA

    (2006)
  • CY Zhao et al.

    Pemphigus vulgaris: an evidence-based treatment update

    Drugs

    (2015)
  • WF Lever et al.

    Treatment of pemphigus vulgaris with methotrexate

    Arch Dermatol

    (1969)
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