We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.

Objective. We developed interferon-␣-kinoid (IFN-K), a drug composed of inactivated IFN␣ coupled to a carrier protein, keyhole limpet hemocyanin. In human IFN␣-transgenic mice, IFN-K induces polyclonal antibodies that neutralize all 13 subtypes of human IFN␣. We also previously demonstrated that IFN-K slows disease progression in a mouse model of systemic lupus erythematosus (SLE). This study was undertaken to examine the safety, immunogenicity, and biologic effects of active immunization with IFN-K in patients with SLE.Methods. We performed a randomized, doubleblind, placebo-controlled, phase I/II dose-escalation study comparing 3 or 4 doses of 30 g, 60 g, 120 g, or 240 g of IFN-K or placebo in 28 women with mild to moderate SLE.Results. IFN-K was well tolerated. Two SLE flares were reported as serious adverse events, one in the placebo group and the other in a patient who concomitantly stopped corticosteroids 2 days after the first IFN-K dose, due to mild fever not related to infection. Transcriptome analysis was used to separate patients at baseline into IFN signature-positive and -negative groups, based on the spontaneous expression of IFNinduced genes. IFN-K induced anti-IFN␣ antibodies in all immunized patients. Notably, significantly higher anti-IFN␣ titers were found in signature-positive patients than in signature-negative patients. In IFN signature-positive patients, IFN-K significantly reduced the expression of IFN-induced genes. The decrease in IFN score correlated with the anti-IFN␣ antibody titer. Serum complement C3 levels were significantly increased in patients with high anti-IFN␣ antibody titers.Conclusion. These results show that IFN-K is well tolerated, immunogenic, and significantly improves disease biomarkers in SLE patients, indicating that further studies of its clinical efficacy are warranted.

Extracellular vesicles (EVs), including exosomes and microvesicles, derived from mesenchymal stem/stromal cells (MSCs) exert similar effects as their parental cells, and are of interest for various therapeutic applications. EVs can act through uptake by the target cells followed by release of their cargo inside the cytoplasm, or through interaction of membrane-bound ligands with receptors expressed on target cells to stimulate downstream intracellular pathways. EV-based therapeutics may be directly used as substitutes of intact cells or after modification for targeted drug delivery. However, for the development of EV-based therapeutics, several production, isolation, and characterization requirements have to be met and the quality of the final product has to be tested before its clinical implementation. In this review, we discuss the challenges associated with the development of EV-based therapeutics and the regulatory specifications for their successful clinical translation.

Our study indicates that synovial activation rapidly drives anti-inflammatory and protective effects of intra-articularly deposited ASCs in experimental OA which is reflected by decreased S100A8/A9 levels.

Objective. To investigate the safety and efficacy of ofatumumab, a novel human anti-CD20 monoclonal antibody (mAb), in patients with active rheumatoid arthritis (RA) whose disease did not respond to >1 disease-modifying antirheumatic drug.Methods. This combined phase I/II study investigated the safety and efficacy of 3 doses of ofatumumab. In part A (phase I), 39 patients received 2 intravenous (IV) infusions of ofatumumab (300 mg, 700 mg, or 1,000 mg) or placebo in a 4:1 ratio 2 weeks apart, using a specified premedication and infusion regimen. In part B (phase II), 225 patients received study treatment as per phase I in a 1:1:1:1 ratio. Safety was assessed by adverse events (AEs) and laboratory parameters. Efficacy was assessed by the American College of Rheumatology 20% criteria for improvement (ACR20), the Disease Activity Score in 28 joints, and the European League Against Rheumatism (EULAR) response criteria. B cell pharmacodynamics were also investigated.Results. AEs were predominantly reported at the first infusion and were mostly mild to moderate in intensity. Rapid and sustained peripheral B cell depletion was observed in all dose groups. In phase II, patients in all ofatumumab dose groups had significantly higher ACR20 response rates (40%, 49%, and 44% for the 300 mg, 700 mg, and 1,000 mg doses, respectively) than did patients receiving placebo (11%) at week 24 (P < 0.001). Overall, 70% of patients receiving ofatumumab had a moderate or good response according to the EULAR criteria at week 24.Conclusion. Our findings indicate that ofatumumab, administered as 2 IV infusions of doses up to 1,000 mg, is clinically effective in patients with active RA.Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease characterized by symmetric inflammation of synovial joints, leading to progressive ClinicalTrials.gov identifier: NCT00291928.

Objective. To determine the prevalence of hepatitis C virus (HCV) infection in patients with sicca syndrome, and to determine the clinical, immunologic, and genetic characteristics of sicca syndrome associated with HCV.Methods. We conducted a prospective study in a university hospital immunology-rheumatology department. Sixty-two consecutive patients with sicca syndrome according to the European criteria for Sjogren's syndrome were included. HCV infection was diagnosed in patients with positive recombinant immunoblot assay findings and the presence of viral RNA in serum and saliva. Rheumatoid factor (RF), cryoglobulins, antinuclear antibodies, and anti-SS-NSS-B antibodies were sought. HLA typing was performed on all patients.Results. The prevalence of HCV infection in patients with sicca syndrome was 19%. The incidence of neurologic involvement was significantly increased in patients with sicca syndrome associated with HCV infection (24% versus 4%; P c 0.03), as was elevations in transaminase levels (87.5% versus 16%; P < 0.0001). RF and cryoglobulins were more frequent in HCV-positive sicca syndrome patients (62% versus 30%; P C 0.03, and 56% versus 10%; P c 0.001, respectively). In contrast, anti-SS-NSS-B antibodies were present in 38% of HCVnegative sicca syndrome patients, but in only 1 HCVpositive sicca syndrome patient (P c 0.01). No significant difference in HLA type was observed. Viral RNA

Objective-To investigate the influence of breast feeding, use of the oral contraceptive pill (OCP), and parity on rheumatoid arthritis (RA). Methods-One hundred and seventy six women with RA were compared with 145 control subjects; all had at least one child. RA patients were classified as having severe (n = 82) or mild disease (n = 89) according to clinical joint evaluation, radiological score, biological inflammation, and the presence of HLA-DR1 or -DR4 alleles. Results-The mean age ofRA patients was 58 years, and the mean age at the time of diagnosis of RA was 46 years. The mean time between onset of RA and the first birth was 23-6 (SD 3.8) years. The OCP user rates were 33% in the RA group and 47-6% in the control group (p < 0.02). OCP use was related to the mother's year of birth. The relative risk for developing RA was 0-598 (95% confidence interval (CI) 0-33 to 1

Objective. To assess the effects of antibiotic treatment of urethritis or cervicitis on the incidence of recurrences of articular symptoms in Reiter's syndrome patients.Methods. Retrospective evaluation of the medical charts of 109 patients living in Greenland.Results. Thirty-seven percent of the episodes of genitourinary tract inflammation that were not treated or were treated with penicillin were followed by arthritis, compared with 10% of those treated with tetracycline or erythromycin. Conclusion. Antibiotics active against Chlamydia-____