Current therapy of the pemphigus group
Introduction
In most autoimmune bullous disorders, disease activity can be sufficiently controlled by systemic corticosteroids in combination with further immunosuppressants/immunomodulants, such as azathioprine, mycophenolate mofetil, dapsone, methotrexate, or doxycycline.1 In contrast, although considerable advances have been made in the past decade, treatment of pemphigus, including pemphigus vulgaris (PV), pemphigus foliaceus (PF), paraneoplastic pemphigus, and immunoglobulin (Ig) A pemphigus, remains challenging and in some patients, conventional immunosuppressive therapy is not sufficient to induce clinical remission.1 In addition, this long-term immunosuppressive treatment is associated with severe side effects and may significantly increase both morbidity and mortality,2 warranting new treatment modalities for this disease. Although the therapeutic backbone of pemphigus is still systemic corticosteroids in combination with other immunosuppressants, much progress has been achieved in establishing newer adjuvant therapeutic options, including high-dose intravenous immunoglobulins (IVIGs), immunoadsorption (IA), and rituximab, which have changed the prognosis of this disease. Knowledge on the efficacy and safety of pemphigus treatment still mainly relies on data from case series and meta-analyses.1, 3
Due to the rarity of the disease, only slow progress in randomized controlled prospective studies is observed (Table 1). In many of these studies, patient numbers were low, which may explain why significant differences between study arms were often not observed. Larger prospective randomized controlled studies are, therefore, highly needed.
Section snippets
Systemic corticosteroids
Systemic corticosteroids are still the most frequently used drugs and best-established therapy in pemphigus. As PF is usually less resistant to treatment than PV, prednisolone can often be started at lower doses. In general, however, the dosing schedule of systemic corticosteroids in pemphigus is largely empirical. In one controlled trial, patients randomized to treatment with either low-dose oral prednisolone (1 mg/kg/d) or high-dose oral prednisolone (2.0-2.5 mg/kg/d) showed no significant
Adjuvant immunosuppressive drugs
Adjuvant drugs are usually administered in combination with systemic corticosteroids so as to reduce corticosteroid-related side effects and increase efficacy. To directly explore the benefit of corticosteroid-sparing agents in pemphigus, 5 prospective controlled studies have been performed investigating the effects of adjuvant drugs compared with corticosteroid monotherapy (Table 1). In one study6 3 groups were compared: 1 group received only corticosteroids at a daily dosage of 40 mg of
High-dose intravenous immunoglobulin
IVIG was first applied in 3 patients with pemphigus at a dosage of 2 g/kg in 1989. A single cycle of IVIG was applied, no adjuvant medication was given, and no effect was observed.56 One year later, another case series showed that application of 6 cycles of IVIG in combination with prednisolone (70 mg/d) was capable of inducing clinical remission in patients with pemphigus.57 Until 2009, only case reports and small uncontrolled studies analyzing IVIG in pemphigus have been reported. Recent
Plasmapheresis and immunoadsorption
As with IVIG, rapid removal of circulating autoantibodies can be achieved by plasmapheresis or, more recently, by IA. In 1978, plasmapheresis was first used in pemphigus.68 Although small trials have demonstrated the potential of plasmapheresis in obtaining partial or complete remission,69, 70, 71, 72 results from the controlled prospective multicenter trial4 revealed that plasmapheresis with low-dose corticosteroids is ineffective as treatment for pemphigus. In the 34 patients with pemphigus
Rituximab
Rituximab is a monoclonal humanized antibody to the B-cell–specific cell-surface antigen CD20, which is not expressed by plasma cells, stem cells, or B-cell progenitors. Originally developed for the treatment of B-cell malignancies, its potential to deplete B cells by a combination of complement, antibody, and cytotoxic activities is being increasingly used in different autoimmune disease, including autoimmune bullous diseases.78, 79 In addition, because of the close interaction between B and T
Topical treatment
Randomized, double-blind, placebo-controlled trials showed that topical treatment of cutaneous pemphigus lesions with epidermal growth factor (10 μg/g) or nicotinamide gel 4%, as well as oral pemphigus lesions with pimecrolimus 1% cream can significantly accelerate healing time in these patients.13, 20, 21 In addition, topical or intralesional injections with class III or IV corticosteroids in combination with antiseptic additives may be helpful. For oral pemphigus, topical analgetics are
Conclusions
Corticosteroids alone or in combination with corticosteroid-sparing immunosuppressive agents remain the first-line therapy for pemphigus. Azathioprine, mycophenolate mofetil, and cyclophosphamide are most frequently used as corticosteroid-sparing agents with higher adverse reactions in the cyclophosphamide-treated patients. As our understanding of autoimmune bullous diseases has progressed within recent years, the therapeutic arsenal has been extended by newer drugs and interventions, which
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