Elizabeth Drewe

The present report describes and expands the clinical and genetic spectrum of the autoinflammatory disorder, tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS). A total of 20 mutations have been identified since our initial discovery of 6 missense mutations in TNF receptor super family 1A (TNFRSF1A) in 1999. Eighteen of the mutations result in amino acid substitutions within the first 2 cysteine-rich domains (CRDs) of the extracellular portion of the receptor. A single splicing mutation also affects the first CRD by causing the insertion of 4 amino acids. Haplotype analysis of the most commonly occurring and ethnically heterogeneous mutation, R92Q, demonstrates an ancient founder; however, analysis of the T50M mutation, another commonly occurring mutation in Irish and Scottish families, does not, suggesting that T50M is a recurring mutation. Mutations that result in cysteine substitutions demonstrate a higher penetrance of the clinical phenotype (93% versus 82% for noncysteine residue substitutions), and also increase the probability of developing life-threatening amyloidosis (24% versus 2% for noncysteine residue substitutions). Retrospective and prospective evaluation of more than 50 patients, representing 10 of the 20 known mutations, allows us to expand and better define the clinical spectrum of TRAPS. Recurrent episodes of fever, myalgia, rash, abdominal pain, and conjunctivitis that often last longer than 5 days are the most characteristic clinical features of TRAPS. Defective shedding of TNFRSF1A can only partially explain the pathophysiologic mechanism of TRAPS, since some mutations have normal shedding. Consequently, other mechanisms may be mediating the observed phenotype. We are currently investigating other possible mechanisms using stable and transiently transfected cell systems in vitro, as well as developing a knockin mouse model. Preliminary data suggest that etanercept may be effective in decreasing the severity, duration, and frequency of symptoms in TRAPS patients. Additionally, it provides a viable therapeutic alternative to glucocorticoid therapy, which has numerous serious, long-term adverse effects. Two clinical trials are being conducted to evaluate the efficacy of etanercept in decreasing the frequency and severity of symptoms in TRAPS. Lastly, we have summarized data that R92Q and P46L, and probably as yet undiscovered substitutions, represent very low penetrance mutations that may play a much larger role in more broadly defined inflammatory diseases such as rheumatoid arthritis. Our laboratories are currently undertaking both clinical and basic research studies to define the role of these mutations in more common inflammatory diseases.

BACKGROUND: The genetic cause of primary immunodeficiency disease (PID) carries prognostic information. OBJECTIVE: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource-Rare Diseases cohort. METHODS: In the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses. RESULTS: B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases. CONCLUSION: We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.

OBJECTIVE: To assess the effects prospectively of tumour necrosis factor (TNF) receptor superfamily (TNFRSF) fusion proteins TNFRSF1B (etanercept) and TNFRSF1A (p55TNFr-Ig) in patients with TNF receptor associated periodic syndrome (TRAPS). METHODS: Seven patients with a clinical and genetic diagnosis of TRAPS received subcutaneous etanercept for 24 weeks. One of these patients had previously received an intravenous infusion of p55TNFr-Ig. Therapeutic response was assessed by comparing corticosteroid requirement, acute-phase response and an established scoring system over 20 weeks, both on and off etanercept. RESULTS: Etanercept was well tolerated. The five corticosteroid-responsive patients required significantly less corticosteroids and demonstrated reductions in acute-phase reactants on etanercept. The two patients not requiring corticosteroids had small reductions in disease activity scores. The effect of p55TNFr-Ig in a single patient with TRAPS remains unclear. CONCLUSIONS: Etanercept does not abolish inflammatory attacks but improves disease activity allowing corticosteroid reduction. Etanercept may be clinically useful in replacing or reducing steroid requirements in the treatment of TRAPS. A formal trial of etanercept to establish its role in clinical management is indicated.

To the Editor: The tumor necrosis factor (TNF) receptor–associated periodic syndrome is a dominantly inherited, chronic inflammatory condition characterized by lifelong febrile attacks of abdominal and musculoskeletal pain associated with skin lesions. The attacks vary in severity and in frequency, usually last from 3 to 21 days, and respond to high-dose corticosteroids. Soluble TNF receptors can inhibit TNF activity by binding and preventing the interaction of TNF-α (TNFSF2) with its cell-surface receptor. Recombinant human TNF receptor (TNFRSF1B) (p75):Fc fusion protein (etanercept) inhibits the activity of TNF in vitro and reduces inflammation in animal models.1 We evaluated a woman with the . . .