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ObjectiveAutoantibodies against proteins encoded by human endogenous retrovirus K (HERV-K) have been reported in patients with rheumatoid arthritis (RA), but their relevance, if any, has remained unresolved. We revisited this question and tested if such autoantibodies may react with citrullinated epitopes on the envelope (Env) protein of HERV-K.MethodsImmunoblotting and ELISAs were conducted with unmodified Env protein and with Env citrullinated by protein arginine deiminase 4 (PAD4). Sera from 100 patients with RA, plasma from 32 patients with juvenile idiopathic arthritis (JIA), and healthy adult and pediatric controls were included. Antibody reactivity was evaluated for correlations with clinical and laboratory variables of the patients.ResultsWe replicated and expanded upon published data suggesting that patients with RA or JIA have autoantibodies against HERV-K Env, some with high titers. Anti-HERV-K antibodies correlated with cigarette smoking and with circulating myeloperoxidase-DNA complexes indicative of nonapoptotic neutrophil cell death. Further, most of the patients with RA, but not those with JIA, had autoantibodies that reacted more strongly with Env that was citrullinated by PAD4. These anticitrullinated Env autoantibodies correlated with seropositivity and tended to be higher in patients with erosive disease.ConclusionOur data suggest that anti-HERV-K immunity is elevated in RA and JIA and may have a connection with pathogenic protein citrullination in RA.

Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory disease that causes bone destruction, soft tissue swelling, and bone pain1. Diagnosis and treatment are hindered by a lack of a reliable laboratory test to assess disease activity. Bone inflammation in CNO is associated with increased osteoclastic activity and bone resorption, causing focal accelerated breakdown of bone collagen. This may be measured through elevated urinary N-terminal telopeptide (NTx). Miettunen, et al reported rapid decline of urinary NTx in children with CNO after pamidronate treatment and subsequent rise of NTx was correlated with disease flare2. The initial NTx from patients with CNO was not different from that of healthy children. Correlation of NTx with disease activity in patients with CNO not treated with pamidronate has not been investigated. We sought to determine if NTx values correlate with CNO disease activity in children treated without a bisphosphonate. Children with a CNO diagnosis made by a pediatric rheumatologist as well as their nonadult healthy siblings were recruited from the rheumatology clinics after written informed consent was obtained (approved by Seattle Children’s Hospital, IRB 14426, and University of Iowa, IRB 200308051). Inclusion criteria consisted of a clinical diagnosis of CNO, … Address correspondence to Dr. Y. Zhao[4][1], 4800 Sand Point Way NE, Seattle, WA 98105, USA. Email: yongdong.zhao{at}seattlechildrens.org. [1]: #ref-4

Objective.Little is known about the genetic etiology of systemic lupus erythematosus (SLE) in individuals of African ancestry, despite its higher prevalence and greater disease severity. Overproduction of nitric oxide (NO) and reactive oxygen species are implicated in the pathogenesis and severity of SLE, making NO synthases and other reactive intermediate-related genes biological candidates for disease susceptibility. We analyzed variation in reactive intermediate genes for association with SLE in 2 populations with African ancestry.Methods.A total of 244 single-nucleotide polymorphisms (SNP) from 53 regions were analyzed in non-Gullah African Americans (AA; 1432 cases and 1687 controls) and the genetically more homogeneous Gullah of the Sea Islands of South Carolina (133 cases and 112 controls). Single-marker, haplotype, and 2-locus interaction tests were computed for these populations.Results.The glutathione reductase geneGSR(rs2253409; p = 0.0014, OR 1.26, 95% CI 1.09–1.44) was the most significant single SNP association in AA. In the Gullah, the NADH dehydrogenaseNDUFS4(rs381575; p = 0.0065, OR 2.10, 95% CI 1.23–3.59) and NO synthase geneNOS1(rs561712; p = 0.0072, OR 0.62, 95% CI 0.44–0.88) were most strongly associated with SLE. When both populations were analyzed together,GSRremained the most significant effect (rs2253409; p = 0.00072, OR 1.26, 95% CI 1.10–1.44). Haplotype and 2-locus interaction analyses also uncovered different loci in each population.Conclusion.These results suggest distinct patterns of association with SLE in African-derived populations; specific loci may be more strongly associated within select population groups.

Objective.Granulomatosis with polyangiitis (Wegener’s; GPA) and other antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are rare in childhood and are sometimes difficult to discriminate. We compared use of adult-derived classification schemes for GPA against validated pediatric criteria in the ARChiVe (A Registry for Childhood Vasculitis e-entry) cohort, a Childhood Arthritis and Rheumatology Research Alliance initiative.Methods.Time-of-diagnosis data for children with physician (MD) diagnosis of AAV and unclassified vasculitis (UCV) from 33 US/Canadian centers were analyzed. The European Medicines Agency (EMA) classification algorithm and European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society (EULAR/PRINTO/PRES) and American College of Rheumatology (ACR) criteria for GPA were applied to all patients. Sensitivity and specificity were calculated (MD-diagnosis as reference).Results.MD-diagnoses for 155 children were 100 GPA, 25 microscopic polyangiitis (MPA), 6 ANCA-positive pauciimmune glomerulonephritis, 3 Churg-Strauss syndrome, and 21 UCV. Of these, 114 had GPA as defined by EMA, 98 by EULAR/PRINTO/PRES, and 87 by ACR. Fourteen patients were identified as GPA by EULAR/PRINTO/PRES but not by ACR; 3 were identified as GPA by ACR but not EULAR/PRINTO/PRES. Using the EMA algorithm, 135 (87%) children were classifiable. The sensitivity of the EMA algorithm, the EULAR/PRINTO/PRES, and ACR criteria for classifying GPA was 90%, 77%, and 69%, respectively, with specificities of 56%, 62%, and 67%. The relatively poor sensitivity of the 2 criteria related to their inability to discriminate patients with MPA.Conclusion.EULAR/PRINTO/PRES was more sensitive than ACR criteria in classifying pediatric GPA. Neither classification system has criteria for MPA; therefore usefulness in discriminating patients in ARChiVe was limited. Even when using the most sensitive EMA algorithm, many children remained unclassified.