Anti-TNFRSF11A monoclonal antibody, clone 0B836 [PE]

Context: A middle-aged woman with recent-onset painful swollen fingers and widespread periostitis, elevated serum alkaline phosphatase ( ALP) activity and erythrocyte sedimentation rate, and accelerated skeletal turnover was found not to have mutations in the gene sequences for exon 1 of receptor activator of nuclear factor-kappa B ( RANK), osteoprotegerin ( OPG), or sequestosome-1. Introduction: Hyperphosphatasia refers to disorders that feature elevated serum ALP activity ( hyperphosphatasemia) usually from excesses of the bone isoform of ALP. Such conditions include familial expansile osteolysis, expansile skeletal hyperphosphatasia, and a familial form of early-onset Paget's disease of bone ( PDB2), all from constitutive activation of RANK, and juvenile Paget's disease from OPG deficiency. Patient and Methods: A 38-yr-old woman developed painful swollen fingers and achy bones after an episode of unexplained pericarditis and restrictive lung disease. Sequence analysis of exon 1 of TNFRSF11A encoding RANK, TNFRSF11B encoding OPG, and SQSTM1 encoding sequestosome-1 searched for mutations responsible for familial expansile osteolysis, expansile skeletal hyperphosphatasia, or PDB2, juvenile Paget's disease, or Paget's disease of bone ( PDB), respectively. Results: Serum ALP and osteocalcin and urinary hydroxyproline were increased. Radiographs showed widespread, symmetric hyperostosis in the limbs where bone scintigraphy demonstrated enhanced radionuclide uptake. Iliac crest histology revealed accelerated skeletal turnover. No mutations were detected in the three genes examined. Three years of therapy with 70 mg alendronate orally once weekly improved symptoms, radiographic abnormalities, and biochemical markers. Conclusions: Our patient manifested a unique, sporadic hyperphosphatasia syndrome. Unexplained, transient inflammation seemed to cause her pericarditis, restrictive lung disease, and periostitis with accelerated skeletal turnover that responded well to antiinflammatory drugs and alendronate therapy.

Objective. Autoinflammatory disorders are caused by a primary dysfunction of the innate immune system. Among these disorders are hereditary recurrent fevers, which are characterized by recurrent episodes of fever and inflammatory manifestations affecting multiple tissues. Hereditary recurrent fevers often lack objective diagnostic criteria, thereby hampering the identification of disease-causing genes. This study was undertaken to identify a gene responsible for hereditary recurrent fevers. Methods. Copy number variations and point mutations were sought by array-comparative genomic hybridization and polymerase chain reaction sequencing, respectively. Serum cytokine levels were measured using Luminex technology. The effect of TNFRSF11A molecular defects on NF-kappa B signaling in cells expressing wild-type and mutated forms of the receptor was evaluated by luciferase assay. Results. A patient with multiple congenital anomalies and hereditary recurrent fever was found to carry a de novo heterozygous complex chromosomal rearrangement encompassing a duplication of TNFRSF11A, a gene known to regulate fever in rodents. We also identified a heterozygous frameshift mutation (p. Met416Cysfs*110) in TNFRSF11A in a mother and daughter with isolated hereditary recurrent fever. This mutation was associated with increased secretion of several inflammatory cytokines (tumor necrosis factor alpha [TNF alpha], interleukin-18 [IL-18], IL-1 receptor antagonist, interferon-gamma) and altered the biologic effects of the receptor on NF-kappa B signaling. The disease in the patients described herein exhibits striking clinical similarities to TNF receptor-associated periodic syndrome, another hereditary recurrent fever involving a gene of the same family (TNFRSF1A). Conclusion. The involvement of TNFRSF11A in hereditary recurrent fever highlights the key role of this receptor in innate immunity. The present results also suggest that TNFRSF11A screening could serve as a new diagnostic test for autoinflammatory disorders.