IgA vasculitis, formerly known as Henoch-Schönlein purpura, is a systemic IgA-mediated vasculitis of the small vessels that is common in children. The major clinical features of IgA vasculitis are palpable purpura, arthritis, abdominal pain, and nephritis [1]. The natural history of IgA vasculitis is generally self-limiting; however, one-third of patients experience symptom recurrence and a refractory course [2]. Patients with renal disease are more likely to experience recurrence, and the long-term prognosis of IgA vasculitis is related to nephritis [1-5].

However, the treatment for IgA vasculitis has not been established. Steroids can manage abdominal pain symptoms but are unsuitable for the prevention of nephropathy [2]. Joint pain is managed with nonsteroidal anti-inflammatory drugs and steroids in severe cases [2]. Cutaneous symptoms respond to steroids and dapsone [2]. Some studies reported that immunosuppressive therapy could be considered for IgA vasculitis with nephropathy; however, the treatment of nephritis remains controversial [2]. Treatment with steroids and immunosuppressive therapy such as cyclophosphamide, cyclosporine, and azathioprine is beneficial for IgA vasculitis nephritis [1,2,6]. Some reports showed that colchicine and dapsone may be useful for treating chronic IgA vasculitis [6].

Among the diverse armamentarium of therapeutic options, dapsone has been used in several severe cases. Although it is not considered a standard treatment for IgA vasculitis, purpuric rash, abdominal pain, and arthritis in IgA vasculitis respond to it [7]. Dapsone, known as an antileprosy drug, has antioxidant scavenger effects and may suppress the production of toxic free radicals by neutrophils. It also inhibits prostaglandin D2 production and the synthesis of IgG and IgA antibodies [8]. It also inhibits IgA-neutrophil interactions, which may explain the potential efficacy of dapsone in the management of IgA vasculitis [7,9]. Therefore, in the absence of clinical trials, this systematic review aimed to elucidate the characteristics of dapsone use in refractory IgA vasculitis.

IgA vasculitis is a systemic IgA-mediated vasculitis characterized by palpable cutaneous purpura, arthritis, abdominal pain, gastrointestinal bleeding, and nephritis [1]. Although IgA vasculitis is usually a self-limiting disease, one report showed that 33% of patients experience a relapse [19]. The aim of drug therapy in IgA vasculitis is rapid symptomatic relief because the symptoms of IgA vasculitis are generally self-limiting with the exception of renal disease, which might become a long-term complication [1]. Steroids are considered the mainstay of treatment because they seem to have a relief effect on abdominal [20,21] and joint pain [21]. In one study of 417 patients, corticosteroids and nonsteroidal antiinflammatory drugs were commonly prescribed [22]. One report showed that azathioprine can be used to treat recurrent IgA vasculitis [23]. Factor XIII may have diagnostic value in patients with severe gastrointestinal symptoms without cutaneous rash; the infusion of activated factor XIII can be an adjunctive therapy in such patients [24]. Similarly, factor XIII and intravenous immunoglobulin therapy can be effective in IgA vasculitis patients with severe abdominal symptoms [25,26].

Despite various attempts, a standardized treatment for recurrent IgA vasculitis is lacking. Corticosteroids have various side effects; corticosteroid-resistant patients with IgA vasculitis have been treated effectively with mizoribine or cyclosporine A [27,28]. Drugs such as azathioprine, factor XIII, and intravenous immunoglobulin are expensive or exhibit potential severe side effects. In contrast, dapsone is safe and available in pill form. However, only a few cases of recurrent IgA vasculitis were treated with dapsone.

The use of dapsone in IgA vasculitis appears rela tively unfamiliar to clinicians compared to that of steroids, although the first case of IgA vasculitis treated with dapsone was reported in 1983 [29]. Dapsone is an antileprosy drug that can be used for dermatological diseases associated with the deposition of antibodies and accumulation of neutrophils [30]. Dapsone is an alter native, especially in relapsed IgA vasculitis, considering that IgA vasculitis is an IgA-mediated vasculitis and that the IgA-neutrophil interaction could be inhibited by dapsone [7,9].

The World Health Organization (WHO) regimens are the standard treatment for leprosy. The WHO recommends using dapsone 100 mg daily for 6 months in cases of paucibacillary leprosy and 100 mg daily for at least 2 years and to smear negativity in cases of multibacillary leprosy [30]. One study showed that peak serum concentrations of dapsone of 1.10–2.33 mg/L were reached within 0.5–4 hours after 100 mg was orally administered to 25 healthy volunteers [31]. However, in severe leprosy patients, absorption could be decreased [32]. In leprosy, the therapeutic range of dapsone is 0.5–5 mg/L; the adverse effect of dapsone is rare at plasma levels below 5 mg/L [33]. The most common adverse effect is methemoglobinemia, which is usually not a serious problem except at doses exceeding 200 mg/day [34]. Hemolysis and frank anemia is another well-known side effect [35]. Increasing age and the daily dose of dapsone were related to increased magnitude of hemolysis in dapsone therapy [35]. Thus, it is recommended not to exceed 1.5 mg/kg body weight or 100 mg in normal healthy persons [36]. Agranulocytosis is a fatal adverse effect of dapsone [37]. Another rare side effect is a hypersensitivity syndrome, called dapsone syndrome, which is characterized by fever, rash, and internal organ involvement [38,39]. Other side effects include neurotoxicity such as peripheral neuropathy (rare, typically at doses exceeding 300 mg/day) and psychosis (rare, at doses below 100 mg/day), which is dose-independent [40-43].

In our reviewed patients, no treatment exceeded 100 mg/ day or 1.5 mg/kg. One patient who stopped dapsone because of dizziness at 100 mg/day did not report dizziness at 150 mg/day after IgA vasculitis recurrence. This means that the side effect of dapsone is somewhat unpredictable and dose-independent. However, although many side effects of dapsone may be doseindependent, to minimize the adverse effect, the dose should not exceed 100 mg/day or 1.5 mg/kg. In our reviewed patients, treatment discontinuation without tapering seems related to relapse because 15 patients reported prompt recurrence, whereas the tapering group reported fewer relapses.

This study has the limitation that only 26 patients were reviewed. Because of the small number of patients, it is difficult to explain the use of dapsone in detail such as how to taper its use. Of our reviewed patients, 19.0% did not require dose tapering; however, because of the small number of patients, our results cannot confirm what percentage of people will need it or why.

To best of our knowledge, this is the first systematic review to summarize the efficacy of dapsone in IgA vasculitis. Since several side effects should be noted, most patients with recurrent or refractory disease should be counseled about the side effects by clini cians and start on dapsone according to the risks and benefits. However, our study will increase awareness that dapsone is an effective treatment for recurrent IgA vasculitis pati ents. Multicenter randomized placebo-controlled clinical trials are necessary to determine the standard dapsone use or dosage as a treatment option at the time of treatment initiation or tapering in refractory IgA vasculitis patients and evaluate whether it has a significant benefit compared to steroids or other medications.