Adult-onset Still's disease and chronic recurrent multifocal osteomyelitis: A hitherto undescribed manifestation of autoinflammation
Department of Medicine 3, University Erlangen-Nuremberg, Krankenhausstr. 12, 91054, Erlangen, Germany.Rheumatology International (Impact Factor: 1.52). 07/2011; 32(6):1827-9. DOI: 10.1007/s00296-011-2020-x
Still's disease and chronic recurrent multifocal osteomyelitis (CRMO) are febrile rheumatic diseases of unknown etiology, which predominantly affect children but can also have their initial manifestation in adults. Both can present as intermittent, relapsing episodes and are considered potential candidates within the expanding spectrum of autoinflammatory disorders, although no genetic abnormalities have been described for either of them. Here, we describe a man with an initial manifestation of abacterial multifocal osteitis at the age of 41. During a relapsing-remitting course of his illness, he increasingly developed symptoms of adult-onset Still's disease (AOSD), and the diagnosis was established according to the Yamaguchi criteria. When treated with anakinra, not only the acute symptoms disappeared promptly, but also the osteitis went into complete remission. This is to our knowledge the first description of a simultaneous occurrence of these two manifestations of autoinflammation in adulthood.
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ABSTRACT: Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory disorder that primarily affects children. Its hallmark is recurring episodes of sterile osteomyelitis. The clinical presentation is insidious onset of bone pain with or without fever. Laboratory studies typically reveal nonspecific evidence of inflammation. Radiologic imaging and histologic appearance resemble those of infectious osteomyelitis. There is a strong association with inflammatory disorders of the skin and intestinal tract in affected individuals and their close relatives, suggesting a shared pathophysiology and supporting a genetic component to disease susceptibility. Two genetic syndromes have CRMO as a prominent phenotype-Majeed syndrome and deficiency of the interleukin-1 receptor antagonist-and suggest that interleukin-1 may be a key cytokine in disease pathogenesis. This review briefly summarizes the main clinical and radiologic aspects of the disease and then focuses on genetics and pathophysiology and provides an update on treatment.
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ABSTRACT: Background and objective: Majeed syndrome is an autosomal recessive disorder characterised by the triad of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anaemia and a neutrophilic dermatosis that is caused by mutations in LPIN2. Long-term outcome is poor. This is the first report detailing the treatment of Majeed syndrome with biological agents and demonstrates clinical improvement with IL-1blockade. Methods: We describe the clinical presentation, genetic analysis, cytokine profiles and response to biological therapy in two brothers with Majeed syndrome. Results: Both boys were homozygous for a novel 2-base pair deletion in LPIN2 (c.1312_1313delCT; p.Leu438fs+16X), confirming the diagnosis. Their bone disease and anaemia were refractory to treatment with corticosteroids. Both siblings had elevated proinflammatory cytokines in their serum, including tumour necrosis factor α (TNF-α), however a trial of the TNF inhibitor etanercept resulted in no improvement. IL-1 inhibition with either a recombinant IL-1 receptor antagonist (anakinra) or an anti-IL-1β antibody (canakinumab) resulted in dramatic clinical and laboratory improvement. Conclusions: The differential response to treatment with TNF-α or IL-1 blocking agents sheds light into disease pathogenesis; it supports the hypothesis that Majeed syndrome is an IL-1β dependent autoinflammatory disorder, and further underscores the importance of IL-1 in sterile bone inflammation.
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