Intravenous immunoglobulin G in the treatment of autoimmune bullous disease

Immunobullous diseases are autoimmune diseases where patients develop blisters on the skin, over months to years, without an inciting event. Bullae are present in either in the epidermis or at the epidermal-dermal junction, and autoantibodies against skin antigens are present. The diseases are very rare, with only a handful of dermatologists worldwide having the treatment of these conditions as their clinical focus. Immunobullous diseases can be divided into two categories: pemphigus and pemphigoid. Pemphigus lesions are mucosal or mucocutaneous and are usually painful. Bullous pemphigoid occurs at the epidermal-dermal junction and patients more often complain of itching. The classic clinical presentation of pemphigus is painful, flaccid, non-intact blisters. These conditions usually occur in patients aged 50–60 years, and the pathogenic autoantibodies responsible are directed against cadherin molecules desmoglein 1 (Dsg1) and desmoglein 3 (Dsg3) which are responsible for intercellular adhesion between keratinocytes. The oral cavity is the most common site of lesions, with 60% of patients experiencing oral involvement initially; approximately half of those patients will then develop mucocutaneous disease involving the nasopharynx, oesophagus or ocular mucosa. Further complications which can develop include verrucous plaques or superinfection. Prior to the advent of systemic steroids, pemphigus was a universally fatal condition; it is now possible to control severe, progressive disease, but the morbidity of steroid treatment is a leading cause of mortality. Most patients present with moderate to severe disease. Patients with minimal disease can be treated locally with intralesional steroids, whereas more severe disease requires systemic steroids combined with immunosuppressants. The use of intravenous immunoglobulin (IVIg) and rituximab is also becoming increasingly commonplace. In contrast, bullous pemphigoid presents as large, active, tense blisters usually located on urticarial plaques. Patients are typically elderly, meaning that there are usually multiple co-morbidities that contraindicate certain therapies; thus IVIg is a preferred treatment option. In pemphigoid, autoantibodies are directed against the hemidesmosome, specifically the bullous pemphigoid (BP) antigens BP230 and BP180. Patients may present with urticarial plaque, and as time goes on blisters develop within urticarial plaques. All patients receive topical steroid treatment and in addition some will receive low-dose systemic steroids. Other treatments include tetracycline and niacinamide (nicotinamide), and when patients are refractory to treatment or have contraindications, IVIg is used with or without rituximab. An experimental approach that we use to target the allergic pathogenesis of this disease is omalizumab, which inhibits immunoglobulin E (IgE) binding to, and degranulation of, mast cells and basophils. Although the question of whether IVIg is an effective treatment for both pemphigus and pemphigoid has been examined in retrospective and case-control studies, to date there has been only one randomized controlled trial 1. This double-blind study (n = 61) was conducted on pemphigus patients in Japan, where IVIg is used as a first-line treatment for the condition. The primary end-point was the time for which the patients remained on protocol; patients who did not respond well to therapy and withdrew from protocol were switched back to conventional therapy. Patients were assigned randomly to receive either a single cycle of high-dose IVIg 400 (n = 20) or 200 (n = 21) mg/kg daily for 5 consecutive days or placebo (n = 20). IVIg-treated patients stayed on protocol significantly longer than those on placebo (P < 0·001), and a dose-response relationship was observed between the three treatment groups (P < 0·001). Patients in the active treatment groups also experienced a significant decline in levels of pathological autoantibodies. The effect of a single cycle of IVIg (2 g/kg) was evaluated in a study of 12 patients with active and severe pemphigus vulgaris unresponsive to high-dose systemic steroids with or without cytotoxic therapy 2. The primary end-points included healing of skin lesions, changes in intercellular autoantibodies and change in steroid doses. In most patients, the condition was controlled within 1 week; within 2 weeks, patients' autoantibody levels were reduced by an average of 70%; and within 3 weeks following a single cycle of IVIg, the systemic steroid dose was reduced by 40%. As a control, levels of protective autoantibodies against varicella-herpes zoster virus were also measured. Unlike the pathogenic autoantibodies, the levels of the protective autoantibodies did not decrease, showing that the elimination of pathogenic autoantibodies was selective. In a retrospective study (n = 20), we evaluated patients with pemphigus vulgaris or pemphigus foliaceus who had received IVIg either alone or in combination with immunosuppressants 3. Levels of pathogenic autoantibodies were recorded at baseline, 1 week after treatment and 1 month after treatment. One week after the last IVIg cycle, patients who had received combination therapy had a significantly greater mean decrease in their antibody levels than those who had received IVIg alone (−77 versus −48%, P = 0·054), and this effect was maintained at 1 month (−90 versus −43%, P = 0·03). Recently, we initiated a randomized controlled trial in patients with very severe pemphigus (n = 7) treated with either IVIg alone (n = 4) or IVIg in combination with cyclophosphamide (n = 3) (manuscript in preparation). Cyclophosphamide is not usually a first-line treatment for pemphigus, but is sometimes used in very aggressive, difficult-to-treat cases. The end-points of our study were changes from baseline in pemphigus antibody titres, prednisone dose required (prednisone being the first-line treatment for pemphigus) and change in disease severity score. Our preliminary data suggest that the combination of IVIg and cyclophosphamide produced a greater decline in the levels of pathogenic autoantibodies than IVIg alone 1 week after the last IVIg cycle (Dsg1: −71 versus −34%; Dsg3: −55 versus −27%). In addition, the prednisone dose was reduced by 21% in the IVIg plus cyclophosphamide group compared to 7% in the IVIg alone group. In this small cohort, disease severity also improved more in terms of score reduction by the combination treatment than IVIg alone (−38 versus −15%). In addition to pemphigus, we have studied the effect of IVIg in combination with a cytotoxic agent in a 78-year-old patient with autoantibody-mediated bullous pemphigoid 4. The patient had multiple cycles of IVIg treatment, with or without immunosuppressants on an alternating schedule, over a period of 20 months. We observed that the patient experienced a greater decline in pathogenic autoantibody levels with the combination treatment than IVIg alone. In summary, the available data suggest that IVIg is an appropriate treatment for immunobullous disease. IVIg decreases the levels of pathogenic autoantibodies rapidly and selectively. We have observed that IVIg is best used as adjuvant therapy in combination with an immunosuppressive agent. This combination reduced and maintained low levels of pathogenic intercellular autoantibodies, we were able to taper the patients' steroid treatment much faster and patients experienced a more rapid decrease in disease severity compared with IVIg treatment alone. Rituximab may be added to the treatment regimen if the patient does not respond to the combination of IVIg and an immunosuppressant, although its role in immunobullous disease requires evaluation in a prospective study.