Key Points: A recombinant antibody recognizing the D1 domain of β2 glycoprotein I induces fetal loss and clot formation in animal models. The CH2-deleted antibody fails to activate complement and prevents the procoagulant and proabortive effects of patient antibodies.

Objective: It has been suggested that only antibodies against domain 1 (D1) of β₂‐glycoprotein I (β₂GPI) are pathogenic and diagnostic. The role of antibodies against other β₂GPI domains is still debated. This study was undertaken to evaluate the clinical relevance of domain specificity profiling of anti‐β₂GPI IgG antibodies in antiphospholipid syndrome (APS) patients and in control groups of patients with systemic autoimmune rheumatic diseases and in asymptomatic antiphospholipid antibody (aPL) carriers.Methods: We evaluated 159 subjects with persistently positive, medium or high‐titer anti‐β₂GPI IgG, including 56 patients with thrombotic (obstetric or nonobstetric) primary APS, 31 women with obstetric primary APS, 42 aPL‐positive patients with systemic autoimmune rheumatic diseases, and 30 asymptomatic aPL carriers. One hundred healthy donors were included. Anti‐β₂GPI D1 and D4/5 IgG were tested on research enzyme‐linked immunosorbent assays containing recombinant β₂GPI domains.Results: As compared to other groups, aPL carriers displayed higher frequency/titer of anti‐D4/5 IgG. Unlike anti‐D4/5, anti‐D1 IgG antibodies were more frequent and at higher titer in triple than in single or double aPL‐positive subjects. An anti‐D1 to anti‐D4/5 ratio of ≥1.5 was predictive of systemic autoimmunity (odds ratio 3.25 [95% confidence interval 1.45–7.49], P = 0.005). Neither anti‐D1 nor anti‐D4/5 antibodies were associated with APS clinical criteria.Conclusion: Anti‐D1 IgG is the preferential specificity not only in vascular and obstetric primary APS, but also in patients with systemic autoimmune rheumatic disease with no clinical features of APS. Conversely, aPL carriers do not have a polarized profile toward D1. Combined testing for anti‐β₂GPI IgG with different domain specificity allows a more accurate aPL profiling, with polarization toward anti‐D1 IgG as a possible fingerprint of systemic autoimmunity.

Objective: Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder with pubertal delay, normal (normoosmic-IHH, nIHH) or defective sense of smell (Kallmann syndrome, KS). Other reproductive and non-reproductive anomalies might be present although information on their frequency are scanty, particularly according to the age of presentation. Design: Observational cohort study carried out between January 2008 and June 2016 within a national network of academic or general hospitals. Methods: We performed a detailed phenotyping of 503 IHH patients with: (1) manifestations of hypogonadism with low sex steroid hormone and low/normal gonadotropins; (2) absence of expansive hypothalamic/pituitary lesions or multiple pituitary hormone defects. Cohort was divided on IHH onset (PPO, pre-pubertal onset or AO, adult onset) and olfactory function: PPO-nIHH (n = 275), KS (n = 184), AO-nIHH (n = 36) and AO-doIHH (AO-IHH with defective olfaction, n = 8). Results: 90% of patients were classified as PPO and 10% as AO. Typical midline and olfactory defects, bimanual synkinesis and familiarity for pubertal delay were also found among the AO-IHH. Mean age at diagnosis was significantly earlier and more frequently associated with congenital hypogonadism stigmata in patients with Kallmann’s syndrome (KS). Synkinesis, renal and male genital tract anomalies were enriched in KS. Overweight/obesity are significantly associated with AO-IHH rather than PPO-IHH. Conclusions: Patients with KS are more prone to develop a severe and complex phenotype than nIHH. The presence of typical extra-gonadal defects and familiarity for PPO-IHH among the AO-IHH patients indicates a common predisposition with variable clinical expression. Overall, these findings improve the understanding of IHH and may have a positive impact on the management of patients and their families.

Objective: To evaluate the 12‐year survival of the first tumor necrosis factor inhibitor (TNFi) treatment in a cohort of rheumatoid arthritis (RA) patients, comparing the between‐groups discontinuation rates for infliximab, etanercept, and adalimumab.Methods: RA patients treated with their first TNFi were investigated from a local registry. Before and after adjusting for propensity scores, overall and by individual TNFi 12‐year drug retention was evaluated. Drug survival rates were calculated using the Kaplan‐Meier method and compared by the Cox extended model. Subanalyses were performed according to concomitant methotrexate (MTX) and discontinuation reasons.Results: Of 583 patients, 222 were treated with infliximab, 179 with etanercept, and 182 with adalimumab; 33.7% and 26% discontinued the first TNFi because of inefficacy or adverse events, respectively. The overall 12‐year drug survival rate for the unmatched population was 23.4%. In the propensity score–adjusted population, the hazard ratio (HR) for treatment discontinuation was significantly greater for adalimumab and infliximab versus etanercept (HR 2.89 [95% confidence interval (95% CI) 2.2–3.78] and HR 2.56 [95% CI 1.92–3.4], respectively), and no difference was found between and for adalimumab versus infliximab (HR 1.16 [95% CI 0.91–1.47]). The incidence of withdrawal due to secondary inefficacy was stable from 3 to 12 years for etanercept, but progressively increased for the monoclonal antibodies. Concomitant MTX significantly increased the survival of both adalimumab and etanercept (HR 1.48 [95% CI 1.18–1.86]).Conclusion: The overall 12‐year drug survival rate was 23.4%, being significantly higher for etanercept than adalimumab and infliximab. Etanercept discontinuations for inefficacy did not increase from 3 to 12 years. Concomitant MTX increased adalimumab and etanercept drug survival.

Autoantibody against phospholipase A2 receptor (anti-PLA2R) is a sensitive and specific biomarker of idiopathic membranous nephropathy (iMN), being found in approximately 70% of iMN patients and only occasionally in other glomerular diseases. However, whereas its diagnostic specificity vs. normal controls and other glomerulonephritides (GN) has been firmly established, its specificity vs. membranous nephropathy associated with various diseases (sMN) has given inconsistent results. The aim of our study was to evaluate the prevalence of anti-PLA2R antibodies in iMN in comparison with various control groups, including sMN. A total of 252 consecutive iMN patients, 184 pathological and 43 healthy controls were tested for anti-PLA2R antibody using indirect immunofluorescence (PLA2R IIFT, Euroimmun). Anti-PLA2R autoantibodies were detectable in 178/252 iMN patients, 1/80 primary GN, 0/72 secondary GN, 9/32 sMN and 0/43 healthy controls, with a diagnostic sensitivity of 70.6%. The diagnostic specificity of anti-PLA2R antibody vs. normal and pathological controls was 100 and 94.6% respectively. However, when the diagnostic specificity was calculated only vs. secondary forms of MN, it decreased considerably to 71.9%. Interestingly enough, 9 out of 10 anti-PLA2R positive patients in the disease control groups had membranous nephropathy associated with various diseases (7 cancer, 1 Crohn’s disease, 1 scleroderma). In conclusion, anti-PLA2R positivity in a patient with MN, should not be considered sufficient to abstain from seeking a secondary cause, especially in patients with risk factors for neoplasia. The causal relationship between tumors and anti-PLA2R-induced MN remains to be established, as well as the possible mechanisms through which malignancies provoke autoimmunity.