To the Editor:
We read with interest the recent report that described a dramatic response of some autoinflammatory syndromes to anakinra (1). We describe a patient with severe and refractory Schnitzler syndrome that responded dramatically to interleukin-1 (IL-1) blockade with anakinra. The similarities between Schnitzler syndrome and some hereditary periodic syndromes suggest that these entities belong to a group of disorders in which IL-1 plays a dominant role.
The patient, a 42-year-old man, was remitted for evaluation in May 2002. He reported a 1-year history of high spiking fever accompanied by a widespread urticarial and pruritic rash, together with severe bone pain. The laboratory studies revealed an erythrocyte sedimentation rate of 23 mm/1 hour and a C-reactive protein level of 2.5 mg/dl (normal <0.5 mg/dl). The serum electrophoresis revealed an IgM kappa gammopathy (790 mg/dl; normal 60–370 mg/dl). The abdominal radiograph showed a condesant lesion on the right iliac bone, and the skin biopsy yielded findings compatible with urticaria.
The patient was diagnosed as having Schnitzler syndrome (2) and was treated with celecoxib, high-dose corticosteroids, azathioprine, pamidronate, rituximab, cyclosporin A, interferon alpha, infliximab plus methotrexate, intravenous inmunoglobulins, and phototherapy. All of these treatments were discontinued because of inefficacy or side effects. In April 2004, anakinra (100 mg/day subcutaneously) plus methotrexate (5 mg/week) was started as a compassionate therapy. Within 1 week, the patient was asymptomatic. Ten months later, his condition remained stable on 100 mg/day of anakinra plus methotrexate (5 mg/week).
A number of rare autoinflammatory disorders with rheumatic manifestations have recently been found to be associated with mutations in NALP3 and Nod2 (3–5). Another member of this family, NALP1, has also been suggested to play an important role in mediating inflammatory responses and secretion of IL-1β (5). Therefore, in this patient, we searched for mutations in the coding region of NALP1, NALP3, and Nod2 and found no sequence alterations.
Schnitzler syndrome is a rare and probably underrecognized disorder. The presence of the chronic urticarial lesions and the monoclonal IgM component, which define the syndrome, are virtually constant. Intermittent fever, joint symptoms, and the increase in acute-phase reactants are also very frequent, albeit nonspecific, characteristics of this entity (2). The clinical course of the disease is usually chronic, with no spontaneous remissions, and treatment is difficult and often ineffective (2). Due to the severity of the clinical features in our patient, he was administered most of the different therapies that have been reported to be effective in isolated cases of Schnitzler syndrome (2). Based on the effectiveness of rituximab and tumor necrosis factor antagonists in other systemic inflammatory disorders, these agents were also used as compassionate therapies in this patient, without any significant benefit. However, the patient responded dramatically to treatment with anakinra, suggesting that IL-1 plays a predominant role in Schnitzler syndrome. Due to the rarity of this condition, the pathophysiology of the disease remains unknown. An increased frequency of IgG autoantibodies to IL-1α has been reported (6), and those authors suggested that an antibody-mediated prolongation of the half-life of IL-1 might account for some of the symptoms and signs of Schnitzler syndrome (6).
Human autoinflammatory diseases are a heterogeneous group of genetically determined conditions that are characterized by seemingly unprovoked inflammation in the absence of infection or autoimmunity (7). Although each of these entities presents genetic and phenotypic peculiarities, globally these conditions share an intermittent expression in the form of acute attacks of fever variably associated with serosal, synovial, and/or cutaneous inflammation, which is usually self-limiting (7). Although Schnitzler syndrome does not begin in childhood, it shares many of the clinical features of these autoinflammatory syndromes. Based on this, we analyzed NALP1, NALP3, and Nod2, which are members of a gene family associated with autoinflammatory disorders with rheumatic manifestations (5). Although these NALP family members are likely candidates as susceptibility genes in Schnitzler syndrome, we could not find mutations in any of them. However, this family contains at least 19 members and it may be that the association is established with one of the genes that we have not studied. Alternatively, because the penetrance of these mutations is not complete, it could be that our patient has no genetic association with this family of inflammation-regulatory genes. In addition to the clinical features that are shared by Schnitzler syndrome and the hereditary periodic syndromes, it seems that all these entities also share a predominant role of IL-1 in their pathogenesis. In fact, recent reports have described a dramatic response of some of these disorders to anakinra (1, 8, 9).