Purpose Biomarkers for outcome after immune-checkpoint blockade are strongly needed as these may influence individual treatment selection or sequence. We aimed to identify baseline factors associated with overall survival (OS) following pembrolizumab treatment in melanoma patients. Experimental design Serum lactate dehydrogenase (LDH), routine blood count parameters, and clinical characteristics were investigated in 616 patients. Endpoints were OS and best overall response following pembrolizumab. Kaplan-Meier analysis and Cox regression were applied for survival analysis. Results Relative eosinophil count (REC) ≥1.5%, relative lymphocyte count (RLC) ≥17.5%, ≤2.5-fold elevation of LDH, and the absence of metastasis other than soft-tissue/lung were associated with favorable OS in the discovery (n=177) and the confirmation (n=182) cohort and had independent positive impact (all P<0.001). Their independent role was subsequently confirmed in the validation cohort (n=257; all P<0.01). The number of favorable factors was strongly associated with prognosis. One-year-OS probabilities of 83.9% vs 14.7% and response rates of 58.3% vs 3.3% were observed in patients with four out of four compared to those with none out of four favorable baseline factors present, respectively. Conclusions High REC and RLC, low LDH, and absence of metastasis other than soft-tissue/lung are independent baseline characteristics associated with favorable OS of patients with melanoma treated with pembrolizumab. Presence of four favorable factors in combination identifies a subgroup with excellent prognosis. In contrast, patients with no favorable factors present have a poor prognosis, despite pembrolizumab, and additional treatment advances are still needed. A potential predictive impact needs to be further investigated.

Multiple sclerosis (MS) is a chronic inflammatory, likely autoimmune disease of the central nervous system with a combination of genetic and environmental risk factors, among which Epstein-Barr virus (EBV) infection is a strong suspect. We have previously identified increased autoantibody levels toward the chloride-channel protein Anoctamin 2 (ANO2) in MS. Here, IgG antibody reactivity toward ANO2 and EBV nuclear antigen 1 (EBNA1) was measured using bead-based multiplex serology in plasma samples from 8,746 MS cases and 7,228 controls. We detected increased anti-ANO2 antibody levels in MS (P = 3.5 × 10−36) with 14.6% of cases and 7.8% of controls being ANO2 seropositive (odds ratio [OR] = 1.6; 95% confidence intervals [95%CI]: 1.5 to 1.8). The MS risk increase in ANO2-seropositive individuals was dramatic when also exposed to 3 known risk factors for MS: HLA-DRB1*15:01 carriage, absence of HLA-A*02:01, and high anti-EBNA1 antibody levels (OR = 24.9; 95%CI: 17.9 to 34.8). Reciprocal blocking experiments with ANO2 and EBNA1 peptides demonstrated antibody cross-reactivity, mapping to ANO2 [aa 140 to 149] and EBNA1 [aa 431 to 440]. HLA gene region was associated with anti-ANO2 antibody levels and HLA-DRB1*04:01 haplotype was negatively associated with ANO2 seropositivity (OR = 0.6; 95%CI: 0.5 to 0.7). Anti-ANO2 antibody levels were not increased in patients from 3 other inflammatory disease cohorts. The HLA influence and the fact that specific IgG production usually needs T cell help provides indirect evidence for a T cell ANO2 autoreactivity in MS. We propose a hypothesis where immune reactivity toward EBNA1 through molecular mimicry with ANO2 contributes to the etiopathogenesis of MS.

BackgroundInfection with cytomegalovirus (CMV) remains asymptomatic in most immunocompetent hosts, but is the leading cause of congenital viral infection worldwide and can be life-threatening in immunocompromised individuals. We aimed to assess CMV seroprevalence in a nationally representative sample of adults in Germany and to identify sociodemographic factors associated with CMV seropositivity.MethodsBlood samples from 6552 participants (18–79 years) of the “German National Health Interview and Examination Survey 1998”, a population-based sample of the adult population in Germany, were tested for the presence of CMV antibodies using an Ig-multiplex assay. Weighted seroprevalence was calculated and weighted binomial regression was used to identify factors associated with CMV seropositivity.ResultsOverall CMV seroprevalence was 56.7% (95%CI: 54.8–58.7%), with a higher seroprevalence in women (62.3%) than in men (51.0%). Seroprevalence increased with age: from 31.8% to 63.7% in men and from 44.1% to 77.6% in women when comparing the 18–29 with the 70–79 year age-group, respectively. CMV seroprevalence in women of childbearing age (18–45 years) was 51.7%. Factors significantly associated with CMV seropositivity were age, country of birth, smoking status, education, living in northern Germany and number of household members. In addition, having attended child care was associated with seropositivity in men, and number of siblings and living in East Germany in women.ConclusionOur results indicate that half the women of childbearing age were susceptible for primary CMV infection during pregnancy. CMV screening during pregnancy and informing seronegative women about CMV risk reduction measures could prevent congenital CMV infections with its serious consequences.