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Rituximab as first-line treatment of pemphigus
Comment
Rituximab as first-line treatment of pemphigus Pemphigus is a rare, life-threatening autoimmune blistering disorder with an incidence of one to seven new cases per million inhabitants per year in Europe and the USA. The two major pemphigus subtypes— pemphigus vulgaris and pemphigus foliaceus—account for about 75% and 20% of cases, respectively. The desmosomal cadherins desmoglein 1 and 3 have been identified as autoantigens in pemphigus vulgaris (desmoglein 1 has been identified in pemphigus foliaceus). Desmoglein 1 and 3 mediate adhesion between neighbouring keratinocytes and are targeted by autoantibodies in more than 95% of patients with pemphigus (figure).1–3 Although non-desmoglein antibodies have been described,4 serum concentrations of anti-desmoglein IgG correlate with disease activity.2,3 Injection of anti-desmoglein IgG in mice reproduces major clinical and immunopathological features of the human disease—ie, intercellular deposits of IgG in the epidermis or epithelium, acantholysis (loss of cell adhesion between neighbouring keratinocytes), intraepidermal or epithelial splitting, and flaccid blisters occurring after mechanical friction.3 The advent of corticosteroids in the early 1950s resulted in a decrease in mortality from pemphigus from 75% to 30%.5 Mortality is still three times higher in individuals with pemphigus than in age-matched and sex-matched controls, which can be at least partly attributed to the immunosuppressive medication. Long-term use of highdose systemic corticosteroids (prednisolone ≥1·0 mg/kg per day) is effective and induces complete remission in 30–50% of patients;5 however, data for the effectiveness of other immunosuppressants or immunomodulants on pemphigus are scarce. The results from clinical trials of azathioprine, mycophenolate mofetil, and a combination of sulfasalazine and pentoxifylline, respectively, combined with different regimens of systemic corticosteroids showed only a few clinical effects.6 At present, most clinicians choose systemic corticosteroids alone or combined with azathioprine, mycophenoles, or (for example, in India and Egypt) with cyclophosphamide as first-line treatment of pemphigus. Thus, there is a high, so far unmet, medical need for effective, safe, and more specific therapies for pemphigus. Given the direct pathogenic effect of autoantibodies in pemphigus, their removal from the circulation seems
a rational and promising therapeutic approach. In fact, findings from a trial with an escape-from-treatment design showed that a single cycle of high-dose intravenous immunoglobulin (2 g/kg) was clinically effective and significantly reduced the serum concentrations of antidesmoglein antibodies.6 Results of a trial assessing the efficacy and safety of adjuvant immunoadsorption are currently being analysed (DRKS00000566). The monoclonal antibody rituximab binds to CD20 and removes CD20-expressing B lymphocytes from the circulation for 6–12 months. Rituximab was first used for pemphigus vulgaris and pemphigus foliaceus in the early 2000s; by 2007 the first case series had appeared,7–9 resulting in the off-label treatment of thousands of patients with pemphigus worldwide. Most of these patients had previously been refractory to treatment, and the European Academy of Dermatology and Venereology guideline from 2015 recommends rituximab as a third-line therapy. Treatment of pemphigus with rituximab leads to a rapid decline of anti-desmoglein serum autoantibodies, whereas total IgG and the ratio of IgG to antimicrobial-recall antigens remain largely unchanged. From an analysis10 of all reported cases and case series with many different adjuvant therapies, healing of pemphigus lesions appeared to start within a few weeks after rituximab infusion and complete remission on therapy was
Published Online March 22, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)30787-0 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(17)30070-3
Keratin filaments Desmosomal plaque
Cell membranes
Desmoglein 1
Desmoglein 3
Figure: Immunopathological characteristics of pemphigus vulgaris Autoantibodies bind to the extracellular portion of desmoglein 3, a transmembranous cadherin of the epidermal desmosome that mediates adhesion between two neighbouring keratinocytes. The cellular mechanisms that mediate lesion formation after binding of anti-desmoglein 3 IgG are complex and yet incompletely understood, involving direct inhibition of desmoglein 3 transinteraction, depletion of desmosomal proteins from the keratinocyte surface, and signal-transduction events via p38MAPK, protein kinase C, and epidermal growth factor receptor.1
www.thelancet.com Published online March 22, 2017 http://dx.doi.org/10.1016/S0140-6736(17)30787-0
1
Comment
achieved in about 80% of patients after 3–6 months. However, the proportion of patients who relapsed was around 40–60%. Now, thanks to the trial by Pascal Joly and colleagues in The Lancet,11 the clinical efficacy of rituximab has been shown at a high level of evidence. The investigators compared first-line use of rituximab combined with short-term prednisone versus prednisone alone in 90 newly diagnosed, untreated patients with pemphigus. Intravenous rituximab was given at a dose of 1 g on days 0 and 14 and 500 mg at months 12 and 18. Prednisone was given at tapering doses of 0·5 mg/kg per day for 3 months (for moderate disease) or 1·0 mg/kg per day for 6 months (in severe disease). In the corticosteroid-alone group, patients were treated with 1·0 mg/kg per day and 1·5 mg/kg per day for moderate and severe disease, respectively, tapered over 12 or 18 months. The most striking result of Joly and colleagues’ trial was the assessment of the primary endpoint of the proportion of patients who achieved complete remission off-therapy 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). Additionally, patients in the rituximab group took a third of the cumulative prednisone dose that patients assigned to prednisone alone took, and the number of severe adverse events of grade 3 or 4 was lower in the rituximab group than in the prednisone group (53 events in 29 patients in the prednisone-alone group; mean 1·20 [SD 1·25]; 27 events in 16 patients in the rituximab plus prednisone group; mean 0·59 [1·15]; p=0·0021). 26% of rituximab-treated patients had a relapse within 36 months, two-thirds of them between months 6 and 12.11 The findings from this study show that rituximab plus prednisone is effective in pemphigus and thus, anti-CD20 therapy can be regarded as the most important advance after the advent of corticosteroids in the treatment of this devastating disease. Joly and colleagues’ study will have implications for clinicians, since most will have applied rituximab as second-line or third-line therapy in refractory patients, but may now face the challenge to also use rituximab, although off-label, in treatment-naive patients. This strategy 2
now needs to be considered in future international and national guidelines. The results from the trial also provoke new questions: are corticosteroids still required for pemphigus? What are the roles of other immunosuppressants, intravenous immunoglobulin, and immunoadsorption? Is there a subgroup of patients that can be treated without rituximab? What can be done to reduce the number of severe adverse events? (27 severe adverse events occurred in 40% of rituximab-treated patients.)10 What is the optimal dose and frequency of rituximab infusions? Do we need a fixed schedule of rituximab infusions in addition to the initial cycle to prevent relapses, or should retreatment be better reserved for relapses? And how do we treat the 10% of patients who do not adequately respond to rituximab, and those who require a high number of repeated rituximab infusions? Further trials are required to address these questions and new treatment methods are already on the horizon. These include desmoglein-specific immunoadsorption,12 and the chimeric autoantibody receptor (CAAR) technology that engineers human T cells to express a CAAR consisting of desmoglein 3 fused to a CD137–CD3ξ signalling domain that enables selective depletion of autoreactive B cells.13 Enno Schmidt Department of Dermatology, University of Lübeck, Lübeck, D-23538, Germany; and Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany [email protected] I declare no competing interests. 1 2 3 4 5 6 7 8 9
Waschke J, Spindler V. Desmosomes and extradesmosomal adhesive signaling contacts in pemphigus. Med Res Rev 2014; 34: 1127–45. Stanley JR, Amagai M. Pemphigus, bullous impetigo, and the staphylococcal scalded-skin syndrome. N Engl J Med 2006; 355: 1800–10. Schmidt E, Groves R. Immunobullous diseases. In: Griffith C, Barker J, Chalmers, Bleiker T, Creamer D (eds). Rook’s textbook of dermatology, 9th edn. Chichester: Wiley-Blackwell 2016; 1–56. Sajda T, Hazelton J, Patel M, et al. Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus. Proc Natl Acad Sci USA 2016; 113: 1859–64. Bystryn JC, Steinman NM. The adjuvant therapy of pemphigus. An update. Arch Dermatol 1996; 132: 203–12. Martin LK, Werth VP, Villaneuva EV, Murrell DF. A systematic review of randomized controlled trials for pemphigus vulgaris and pemphigus foliaceus. J Am Acad Dermatol 2011; 64: 903–08. Ahmed AR, Spigelman Z, Cavacini LA, Posner MR. Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med 2006; 355: 1772–79. Joly P, Mouquet H, Roujeau JC, et al. A single cycle of rituximab for the treatment of severe pemphigus. N Engl J Med 2007; 357: 545–52. Schmidt E, Seitz CS, Benoit S, Brocker EB, Goebeler M. Rituximab in autoimmune bullous diseases: mixed responses and adverse effects. Br J Dermatol 2007; 156: 352–56.
www.thelancet.com Published online March 22, 2017 http://dx.doi.org/10.1016/S0140-6736(17)30787-0
Comment
10 Wang HH, Liu CW, Li YC, Huang YC. Efficacy of rituximab for pemphigus: a systematic review and meta-analysis of different regimens. Acta Derm Venereol 2015; 95: 928–32. 11 Joly P, Maho-Vaillant M, Prost-Squarcioni C, et al. 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. Lancet 2017; published online March 22. http://dx.doi.org/10.1016/S0140-6736(17)30070-3.
12 Langenhan J, Dworschak J, Saschenbrecker S, et al. Specific immunoadsorption of pathogenic autoantibodies in pemphigus requires the entire ectodomains of desmogleins. Exp Dermatol 2014; 23: 253–59. 13 Ellebrecht CT, Bhoj VG, Nace A, et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 2016; 353: 179–84.
www.thelancet.com Published online March 22, 2017 http://dx.doi.org/10.1016/S0140-6736(17)30787-0
3
Rituximab as first-line treatment of pemphigus Pemphigus is a rare, life-threatening autoimmune blistering disorder with an incidence of one to seven new cases per million inhabitants per year in Europe and the USA. The two major pemphigus subtypes— pemphigus vulgaris and pemphigus foliaceus—account for about 75% and 20% of cases, respectively. The desmosomal cadherins desmoglein 1 and 3 have been identified as autoantigens in pemphigus vulgaris (desmoglein 1 has been identified in pemphigus foliaceus). Desmoglein 1 and 3 mediate adhesion between neighbouring keratinocytes and are targeted by autoantibodies in more than 95% of patients with pemphigus (figure).1–3 Although non-desmoglein antibodies have been described,4 serum concentrations of anti-desmoglein IgG correlate with disease activity.2,3 Injection of anti-desmoglein IgG in mice reproduces major clinical and immunopathological features of the human disease—ie, intercellular deposits of IgG in the epidermis or epithelium, acantholysis (loss of cell adhesion between neighbouring keratinocytes), intraepidermal or epithelial splitting, and flaccid blisters occurring after mechanical friction.3 The advent of corticosteroids in the early 1950s resulted in a decrease in mortality from pemphigus from 75% to 30%.5 Mortality is still three times higher in individuals with pemphigus than in age-matched and sex-matched controls, which can be at least partly attributed to the immunosuppressive medication. Long-term use of highdose systemic corticosteroids (prednisolone ≥1·0 mg/kg per day) is effective and induces complete remission in 30–50% of patients;5 however, data for the effectiveness of other immunosuppressants or immunomodulants on pemphigus are scarce. The results from clinical trials of azathioprine, mycophenolate mofetil, and a combination of sulfasalazine and pentoxifylline, respectively, combined with different regimens of systemic corticosteroids showed only a few clinical effects.6 At present, most clinicians choose systemic corticosteroids alone or combined with azathioprine, mycophenoles, or (for example, in India and Egypt) with cyclophosphamide as first-line treatment of pemphigus. Thus, there is a high, so far unmet, medical need for effective, safe, and more specific therapies for pemphigus. Given the direct pathogenic effect of autoantibodies in pemphigus, their removal from the circulation seems
a rational and promising therapeutic approach. In fact, findings from a trial with an escape-from-treatment design showed that a single cycle of high-dose intravenous immunoglobulin (2 g/kg) was clinically effective and significantly reduced the serum concentrations of antidesmoglein antibodies.6 Results of a trial assessing the efficacy and safety of adjuvant immunoadsorption are currently being analysed (DRKS00000566). The monoclonal antibody rituximab binds to CD20 and removes CD20-expressing B lymphocytes from the circulation for 6–12 months. Rituximab was first used for pemphigus vulgaris and pemphigus foliaceus in the early 2000s; by 2007 the first case series had appeared,7–9 resulting in the off-label treatment of thousands of patients with pemphigus worldwide. Most of these patients had previously been refractory to treatment, and the European Academy of Dermatology and Venereology guideline from 2015 recommends rituximab as a third-line therapy. Treatment of pemphigus with rituximab leads to a rapid decline of anti-desmoglein serum autoantibodies, whereas total IgG and the ratio of IgG to antimicrobial-recall antigens remain largely unchanged. From an analysis10 of all reported cases and case series with many different adjuvant therapies, healing of pemphigus lesions appeared to start within a few weeks after rituximab infusion and complete remission on therapy was
Published Online March 22, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)30787-0 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(17)30070-3
Keratin filaments Desmosomal plaque
Cell membranes
Desmoglein 1
Desmoglein 3
Figure: Immunopathological characteristics of pemphigus vulgaris Autoantibodies bind to the extracellular portion of desmoglein 3, a transmembranous cadherin of the epidermal desmosome that mediates adhesion between two neighbouring keratinocytes. The cellular mechanisms that mediate lesion formation after binding of anti-desmoglein 3 IgG are complex and yet incompletely understood, involving direct inhibition of desmoglein 3 transinteraction, depletion of desmosomal proteins from the keratinocyte surface, and signal-transduction events via p38MAPK, protein kinase C, and epidermal growth factor receptor.1
www.thelancet.com Published online March 22, 2017 http://dx.doi.org/10.1016/S0140-6736(17)30787-0
1
Comment
achieved in about 80% of patients after 3–6 months. However, the proportion of patients who relapsed was around 40–60%. Now, thanks to the trial by Pascal Joly and colleagues in The Lancet,11 the clinical efficacy of rituximab has been shown at a high level of evidence. The investigators compared first-line use of rituximab combined with short-term prednisone versus prednisone alone in 90 newly diagnosed, untreated patients with pemphigus. Intravenous rituximab was given at a dose of 1 g on days 0 and 14 and 500 mg at months 12 and 18. Prednisone was given at tapering doses of 0·5 mg/kg per day for 3 months (for moderate disease) or 1·0 mg/kg per day for 6 months (in severe disease). In the corticosteroid-alone group, patients were treated with 1·0 mg/kg per day and 1·5 mg/kg per day for moderate and severe disease, respectively, tapered over 12 or 18 months. The most striking result of Joly and colleagues’ trial was the assessment of the primary endpoint of the proportion of patients who achieved complete remission off-therapy 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). Additionally, patients in the rituximab group took a third of the cumulative prednisone dose that patients assigned to prednisone alone took, and the number of severe adverse events of grade 3 or 4 was lower in the rituximab group than in the prednisone group (53 events in 29 patients in the prednisone-alone group; mean 1·20 [SD 1·25]; 27 events in 16 patients in the rituximab plus prednisone group; mean 0·59 [1·15]; p=0·0021). 26% of rituximab-treated patients had a relapse within 36 months, two-thirds of them between months 6 and 12.11 The findings from this study show that rituximab plus prednisone is effective in pemphigus and thus, anti-CD20 therapy can be regarded as the most important advance after the advent of corticosteroids in the treatment of this devastating disease. Joly and colleagues’ study will have implications for clinicians, since most will have applied rituximab as second-line or third-line therapy in refractory patients, but may now face the challenge to also use rituximab, although off-label, in treatment-naive patients. This strategy 2
now needs to be considered in future international and national guidelines. The results from the trial also provoke new questions: are corticosteroids still required for pemphigus? What are the roles of other immunosuppressants, intravenous immunoglobulin, and immunoadsorption? Is there a subgroup of patients that can be treated without rituximab? What can be done to reduce the number of severe adverse events? (27 severe adverse events occurred in 40% of rituximab-treated patients.)10 What is the optimal dose and frequency of rituximab infusions? Do we need a fixed schedule of rituximab infusions in addition to the initial cycle to prevent relapses, or should retreatment be better reserved for relapses? And how do we treat the 10% of patients who do not adequately respond to rituximab, and those who require a high number of repeated rituximab infusions? Further trials are required to address these questions and new treatment methods are already on the horizon. These include desmoglein-specific immunoadsorption,12 and the chimeric autoantibody receptor (CAAR) technology that engineers human T cells to express a CAAR consisting of desmoglein 3 fused to a CD137–CD3ξ signalling domain that enables selective depletion of autoreactive B cells.13 Enno Schmidt Department of Dermatology, University of Lübeck, Lübeck, D-23538, Germany; and Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany [email protected] I declare no competing interests. 1 2 3 4 5 6 7 8 9
Waschke J, Spindler V. Desmosomes and extradesmosomal adhesive signaling contacts in pemphigus. Med Res Rev 2014; 34: 1127–45. Stanley JR, Amagai M. Pemphigus, bullous impetigo, and the staphylococcal scalded-skin syndrome. N Engl J Med 2006; 355: 1800–10. Schmidt E, Groves R. Immunobullous diseases. In: Griffith C, Barker J, Chalmers, Bleiker T, Creamer D (eds). Rook’s textbook of dermatology, 9th edn. Chichester: Wiley-Blackwell 2016; 1–56. Sajda T, Hazelton J, Patel M, et al. Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus. Proc Natl Acad Sci USA 2016; 113: 1859–64. Bystryn JC, Steinman NM. The adjuvant therapy of pemphigus. An update. Arch Dermatol 1996; 132: 203–12. Martin LK, Werth VP, Villaneuva EV, Murrell DF. A systematic review of randomized controlled trials for pemphigus vulgaris and pemphigus foliaceus. J Am Acad Dermatol 2011; 64: 903–08. Ahmed AR, Spigelman Z, Cavacini LA, Posner MR. Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med 2006; 355: 1772–79. Joly P, Mouquet H, Roujeau JC, et al. A single cycle of rituximab for the treatment of severe pemphigus. N Engl J Med 2007; 357: 545–52. Schmidt E, Seitz CS, Benoit S, Brocker EB, Goebeler M. Rituximab in autoimmune bullous diseases: mixed responses and adverse effects. Br J Dermatol 2007; 156: 352–56.
www.thelancet.com Published online March 22, 2017 http://dx.doi.org/10.1016/S0140-6736(17)30787-0
Comment
10 Wang HH, Liu CW, Li YC, Huang YC. Efficacy of rituximab for pemphigus: a systematic review and meta-analysis of different regimens. Acta Derm Venereol 2015; 95: 928–32. 11 Joly P, Maho-Vaillant M, Prost-Squarcioni C, et al. 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. Lancet 2017; published online March 22. http://dx.doi.org/10.1016/S0140-6736(17)30070-3.
12 Langenhan J, Dworschak J, Saschenbrecker S, et al. Specific immunoadsorption of pathogenic autoantibodies in pemphigus requires the entire ectodomains of desmogleins. Exp Dermatol 2014; 23: 253–59. 13 Ellebrecht CT, Bhoj VG, Nace A, et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 2016; 353: 179–84.
www.thelancet.com Published online March 22, 2017 http://dx.doi.org/10.1016/S0140-6736(17)30787-0
3