Treatment of adult hyper-IgD syndrome with canakinumab

Abstract

Hyper-IgD and periodic fever syndrome (HIDS) is a rare, autosomal-recessive autoinflammatory disease characterized by lifelong recurrent episodes of systemic inflammation. HIDS frequently presents in infancy with intermittent fevers lasting from 4 to 7 days, recurring every 4 to 6 weeks. Febrile episodes may be unprovoked or precipitated by factors including infections, vaccinations, or stress. Associated symptoms may include abdominal pain, diarrhea, rashes, arthralgias, aphthous ulcers, and lymphadenopathy. During acute attacks, patients may exhibit leukocytosis, elevations in acute-phase reactants, and elevated levels of proinflammatory cytokines such as IL-1, IL-6, and TNF-a. At baseline, affected individuals may have elevated IgD levels; however, increases in IgD levels are not universal, particularly in very young patients. If clinical suspicion is high, HIDS should be considered despite normal serum IgD levels. Patients with HIDS may exhibit increased rates of infection, particularly with S pneumoniae; this may be secondary to infrequent IgG hypogammaglobulinemia or host conditions that may be permissive for persistence of this organism. HIDS is part of a clinical spectrum caused by decreased activity of mevalonate kinase, an enzyme involved in isoprenoid biosynthesis. Four mutations in MVK, the gene encoding mevalonate kinase (V377I, I268T, H20P/N, and P167L), account for more than 70% of the cases associated with HIDS. Lack of isoprenoid end products due to abnormal metabolism increases IL-1b secretion from mevalonate kinaseedeficient PBMCs, making IL-1 signaling a promising therapeutic target. Previous studies have shown inconsistent benefits of treatments including colchicine, cyclosporine, and statins. Many patients respond well to oral steroids, but the frequency of exacerbations makes a steroid-sparing therapy desirable. Biologic therapies have been successful in the treatment of other periodic fever syndromes. The cryopyrin-associated periodic syndromes are a group of fever disorders including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS). These conditions are also mediated through excessive IL-1b production. Canakinumab, a fully human antie IL-1b mAb, has been shown to induce rapid remission of symptoms in patients with cryopyrin-associated periodic syndromes and is approved by the Food and Drug Administration for the treatment of FCAS and MWS. Biologics including etanercept, adalimumab, and anakinra have all been shown to decrease the frequency and severity of febrile episodes in patients with HIDS. Small numbers of patients with HIDS treated with canakinumab have also shown clinical improvement. Here, we describe the case of a patient with HIDS who had significant clinical improvement with initiation of canakinumab therapy.