S2k guidelines for the treatment of pemphigus vulgaris/foliaceus and bullous pemphigoid: 2019 update

Abstract

The present S2K guidelines are an update of the most recent edition of the German guidelines from 2015 3, 4. The complete guidelines (including methodology) are available at www.awmf.org. As this is an update, some sections from the previous version have been adopted without any changes. The methodology of this update of the most recent version of these S2k guidelines (2015) follows the specifications issued by the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft Wissenschaftlicher Medizinischer Fachgesellschaften, AWMF) 5. The level of development remains unchanged (S2k). Using a structured nominal group process (consensus conferences), the recommendations contained in these guidelines were developed by a representative interdisciplinary group of experts. The present update is valid until Dec 31, 2022. This article is a short version of the updated guidelines. The long version (see AWMF guideline registry) includes additional information. This includes information on the group of experts, on how to use these guidelines, on target audience and objectives, financial support, implementation and circulation, as well as on the handling of conflicts of interests (www.awmf.org). Uniform wording was used in an effort to standardize the guideline recommendations (Table 1). “is recommended” or “… shall …” “may be recommended” or “… should …” “is not recommended” “… shall not …” ▸ ≤ 1 cm2 of mucous membranes affected (only in pemphigus vulgaris) ▸ ≤ 1 % of normal skin affected ▸ no pain, no significant impairment of quality of life ▸ PDAI score ≤ 15 ▸ PDAI score > 15 ▸ severe pain and significant impairment of quality of life The differentiation between mild and moderate-to-severe pemphigus is based on the cutoff value between the first and the second quartile of the PDAI score in a large prospective multicenter study of 96 newly diagnosed PV und PF patients 6. Strong consensus (100 %)** Strong consensus (100 %) Abstention: patient representative Consensus (90 %)** Consensus (90 %)** It is recommended to combine corticosteroids with an immunosuppressive agent (see recommended regimens for induction therapy). Strong consensus (100 %) Abstention: patient representative Besides our own experience, the recommendation for dapsone is based on a case series of nine patients and a dozen individual case reports of patients with pemphigus foliaceus 7-9. In the aforementioned case series, five patients showed complete remission after 2 weeks 10. In the various case reports, approximately 70 % of patients received dapsone monotherapy, which resulted in a good clinical response and/or complete remission 7-9. For initial treatment of moderate-to-severe pemphigus vulgaris/foliaceus, systemic therapy, it is recommended to use: or Strong consensus (100 %) Abstention: patient representative Strong consensus (100 %) Abstention: patient representative Strong consensus (100 %) Abstention: patient representative Strong consensus (100 %) Abstention: patient representative Strong consensus (100 %) Abstention: patient representative The following alternative may also be considered: Consensus (77 %) Abstention: patient representative Majority consensus (62 %) Abstention: patient representative Strong consensus (100 %) Abstention: patient representative The following therapies may be recommended for treatment-resistant and particularly severe disease: The following therapy may be recommended for treatment-resistant disease: Strong consensus (100 %) Abstention: patient representative Strong consensus (100 %) Abstention: patient representative The intensity of treatment for pemphigus vulgaris/foliaceus is generally guided by disease severity and acuity and on treatment-relevant comorbidities. The objective of induction therapy is control of disease activity, defined as the absence of new lesions concurrent with improvement of existing lesions. Switching to maintenance therapy requires that no new lesions appear within a two-week consolidation phase and that approximately 80 % of initial lesions have healed. Rituximab, a monoclonal anti-CD20 antibody, causes depletion of CD20-positive B cells from the peripheral blood; the effect lasts for approximately 6–12 months. In 2001, rituximab was introduced in the treatment of paraneoplastic pemphigus. Only a short time thereafter, the agent was first employed in the treatment of patients with recalcitrant pemphigus vulgaris/foliaceus 11-13. Subsequently, various case series using different treatment protocols and adjuvant therapies reported on the clinical effectiveness of rituximab in patients with severe pemphigus 14-20. In two meta-analyses of more than 500 pemphigus patients treated with rituximab, complete remission was achieved in 80–90 % of patients 21, 22. A recent controlled prospective trial of 90 patients with new-onset pemphigus vulgaris/foliaceus provided conclusive evidence for the superiority of rituximab (two initial doses of 1 g, followed by 0.5 g after 12 and 18 months) in combination with short-term use of prednisolone (0.5–1.0 mg/kg/day for 3–6 months) over treatment with prednisolone alone (1.0–1.5 mg/kg/day for 12–18 months) 23. After two years, 89 % of patients in the rituximab group were in complete remission with no further treatment required, compared to only 34 % in the prednisolone group (p < 0.0001). Moreover, the cumulative prednisolone dose was three times lower and the number of severe adverse events twice lower in the rituximab arm than in the prednisolone arm (p < 0.0001 and p = 0.0084, respectively) 23. Severe adverse events, primarily infections, were observed in 4–10 % of patients treated with rituximab. The mortality rate was between 1.3 % and 1.9 % 16, 19 21, 22 24. In nearly all cases, rituximab was combined with systemic corticosteroids and/or other immunosuppressive agents. To date, there has been no reported case of progressive multifocal leukoencephalopathy in pemphigus patients; this condition is known to be associated with rituximab therapy, particularly in individuals with lymphoproliferative disorders 25. Using data from approximately 350,000 patients with rheumatoid arthritis, it has been calculated that the risk of developing progressive multifocal leukoencephalopathy following rituximab therapy is 2.5/100,000 cases 26. Based on the data published by Joly et al. 23, rituximab was approved for the treatment of moderate-to-severe pemphigus vulgaris by the FDA in 2018 and by the EMA in 2019. A number of international experts have recommended the use of rituximab as first-line treatment for patients with moderate-to-severe pemphigus 27, 28. Clinical studies have shown that immunosuppressive agents such as azathioprine, mycophenolate mofetil, mycophenolic acid, methotrexate, and cyclophosphamide have a steroid-sparing effect in the treatment of patients with pemphigus vulgaris/foliaceus 29-37. A recent retrospective analysis revealed that the initial prednisolone dose (≤ 0.5 mg/kg or ≥ 1.0 mg/kg per day) had no effect on the rate of complete clinical remission off therapy. The median follow-up period in this study was 77 ± 64 months 38. In a controlled prospective trial from Japan that investigated the use of high-dose intravenous immunoglobulins (IVIGs) in 61 pemphigus patients, a dose of 2 g/kg was superior to 1 g/kg IVIGs and to placebo 39. In an unusual study design, clinical efficacy was evaluated based on the period of time during which patients were able to “escape” the treatment protocol. While there are still no controlled prospective trials on the effects and efficacy of immunoapheresis in patients with pemphigus, there is some evidence from monocenter studies that adjuvant immunoadsorption therapy may result in a rapid decrease in circulating anti-Dsg antibodies and may thus be effective in severe and/or recalcitrant cases 40, 41, 43, 44. There is no trial data on the use of topical corticosteroids in the treatment of pemphigus vulgaris/foliaceus; calcineurin inhibitors may be considered for topical treatment of oral/genital erosions (tacrolimus 0.1 %). In order to avoid bacterial superinfection, antibacterial/antiseptic treatment is recommended (including fusidic acid, triclosan 1 %, octenidine). All published randomized controlled trials on the treatment of pemhigus have been summarized in a recent review 45. *Control of disease activity is defined as the absence of new lesions concurrent with improvement of existing lesions; **relapse: > 3 new lesions (blisters or erosions) per month that do not heal spontaneously within one week; or progression of existing lesions in patients who previously achieved control of disease activity; ***no new vote, as this recommendation was adopted from the previous guideline version. Strong consensus (100 %) Strong consensus (100 %) Consensus (92 %) Abstention: 1 expert Consensus (92 %) Abstention: 1 expert In the aforementioned controlled prospective trial of 90 patients with new-onset PV and PF, all patients again received rituximab (500 mg) after 12 and 18 months, following an initial dose of 1 g given twice. The 500 mg dose was chosen because the sponsor of the trial only provided a total of 3 g of rituximab per patient, and two doses were scheduled to be administered after the initial dose 23. Smaller studies and case series have shown that a rituximab dose of 500 mg is likewise clinically effective 46, 47. Thus, it is currently impossible to issue a clear recommendation as to the rituximab dose to be administered for repeat treatment. In the controlled prospective trial conducted by Joly et al., eight of eleven relapses in the rituximab group occurred between months 6 and 12 23. It is therefore recommended that patients undergo maintenance therapy after 6 and 12 months. Given the lack of consensus in the literature, it remains up to each individual center/physician whether to initiate hydrocortisone replacement therapy or perform an ACTH stimulation test (Synacthen test) prior to complete discontinuation of long-term systemic corticosteroid treatment (the decision should likely be made in cooperation with endocrinologists). There is no generally accepted classification of disease severity for bullous pemphigoid; the classification presented herein (mild, moderate, and severe disease) reflects the consensus of the guideline group (Table 2). Studies have shown topical treatment with clobetasol at a daily dose of 40 g 48 as well as of 10–30 g to be equally effective as systemic prednisolone in the treatment of localized and moderate bullous pemphigoid, while causing fewer systemic adverse effects. A substantial limitation to topical treatment is its practicability; in older bullous pemphigoid patients, twice-daily topical application on large areas of skin is usually not feasible. With respect to topical tacrolimus as a substitute for topical corticosteroids, there have only been individual case reports, which presently do not warrant a treatment recommendation. In order to avoid bacterial superinfection of erosions, topical antiseptic treatment is recommended, including chlorhexidine, triclosan 1 % and octenidine; atraumatic wound dressings should be used for large wounds. It is recommended to puncture large or otherwise bothersome blisters in a sterile manner. Leaving the blister roof intact provides additional protection from infection. Strong consensus (100 %)* Alternatively, the following drugs may be recommended either as monotherapy or as adjuvant treatment in combination with corticosteroids: (strictly alphabetical order): Strong consensus on the choice of therapeutic options (100 %) Majority consensus regarding alphabetic order (54 %) (the other participants advocated for giving preference to dapsone and doxycycline or abstained from voting) Abstentions: 3 experts Strong consensus (100 %)* Strong consensus (100 %)* Unlike pemphigus, initial doses of > 1.0 mg/kg/day of prednisolone equivalent show little additional benefit for patients with bullous pemphigoid. There is only limited evidence for the effectiveness of the various therapies used in the treatment of bullous pemphigoid. In the Cochrane review by Kirtschig et al., there was no difference in terms of disease control between azathioprine in combination with prednisone and prednisone alone (one study), between prednisolone in combination with azathioprine and prednisolone in combination with plasmapheresis (one study), between prednisolone in combination with mycophenolate mofetil or in combination with azathioprine (one study), and between tetracycline in combination with nicotinamide and prednisolone (one study) 1. One study that was published after the aforementioned Cochrane review showed non-inferiority of doxycycline to prednisolone after 6 weeks (end point: number of patients with fewer than three blisters). However, the acceptable predefined margin of non-inferiority was very large (37 %). With respect to severe adverse events after 52 weeks, doxycycline showed a relevant benefit over prednisolone 2. Another study that compared dapsone (1.5 mg/kg/day) versus azathioprine (1.5–2.5 mg/kg/day), each in combination with methylprednisolone (0.5 mg/kg/day), defined the time until complete tapering of methylprednisolone as primary end point and the overall methylprednisolone dose required as secondary end point 42. The primary end point was not reached, as only very few patients (5 on azathioprine and 3 on dapsone) achieved this goal. The cumulative dose of methylprednisolone was lower in the dapsone group than in the azathioprine group (p = 0.06). There was no significant difference in the number of adverse events (18 in the azathioprine arm and 13 in the dapsone arm) including fatalities (3 in the azathioprine group and 1 in the dapsone group) 42. Strong consensus (100 %)*** Strong consensus (100 %)*** Strong consensus (100 %)*** Strong consensus (100 %)*** Consensus (92 %) Abstention: 1 expert Consensus (92 %) Abstention: 1 expert Bullous pemphigoid frequently runs a chronic course. Patients should be clinically examined on a regular basis (initially at 14-day intervals and subsequently every 3–6 months, depending on clinical activity) until they achieve complete clinical remission or until treatment is discontinued. The goals of maintenance therapy include control of disease activity, tapering of systemic corticosteroids and, if applicable, of adjuvant immunosuppressive agents as quickly as possible while avoiding relapses, as well as regular monitoring for treatment-related adverse effects (clinical presentation, lab tests). Follow-up intervals should be guided by disease activity; initially every 14 days, followed by every 3–6 months for patients with low disease activity or remission.

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