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Objective: To evaluate the significance of antibodies against cyclic citrullinated peptide (anti-CCP) and rheumatoid factors (RFs), before the onset of rheumatoid arthritis and when presenting as early disease (baseline), for disease activity and progression. Methods: 93 of a cohort of 138 patients with early rheumatoid arthritis (<12 months of symptoms) had donated blood before symptoms of rheumatoid arthritis (defined as pre-patients) and were identified from among blood donors within the Medical Biobank of northern Sweden. Disease activity (erythrocyte sedimentation rate (ESR), C reactive protein, joint score, global visual analogue scale) and radiological destruction in hands and feet (Larsen score) were assessed at baseline and after two years. Anti-CCP antibodies and RFs were analysed using enzyme immunoassays. HLA shared epitope (SE) alleles (DRB1*0401/0404) were identified. Results: Patients with anti-CCP antibodies before disease onset had significantly higher Larsen score at baseline and after two years. In multiple regression analyses baseline values of anti-CCP/IgA-RF/IgG-RF/IgM-RF, swollen joint count, and Larsen score significantly predicted radiological outcome at two years. In logistic regression analyses, baseline values of anti-CCP antibodies/IgA-RF, therapeutic response at six months, and swollen joint count/ESR significantly predicted radiological progression after two years. The baseline titre of anti-CCP antibodies was higher in patients with radiological progression and decreased significantly in those with response to therapy. SE allele carriage was associated with a positive test for anti-CCP antibodies in pre-patients and in early rheumatoid arthritis. Conclusions: Presence of anti-CCP antibodies before disease onset is associated with more severe radiological damage. The titre of anti-CCP antibodies is related to disease severity.

Measurement of two groups of autoantibodies, rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) have gained increasing significance in the diagnosis and classification of rheumatoid arthritis (RA) over the last 65 years. Despite this rising importance of autoimmune serology in RA, there is a palpable lack of harmonization between different commercial RF and ACPA tests. While a minimal diagnostic specificity has been defined for RF tests, which almost always are related to an international reference preparation, neither of this applies to ACPA. Especially assays with low diagnostic specificity are associated with very low positive predictive values or post-test probabilities in real world settings. In this review we focus on issues of practical bearing for the clinical physician diagnosing patients who potentially have RA, or treating patients diagnosed with RA. We advocate that all clinically used assays for RF and ACPA should be aligned to a common diagnostic specificity of 98-99% compared to healthy controls. This high and rather narrow interval corresponds to the diagnostic specificity seen for many commercial ACPA tests, and represents a specificity that is higher than what is customary for most RF assays. Data on antibody occurrence harmonized in this way should be accompanied by test result-specific likelihood ratios for the target diagnosis RA on an ordinal or interval scale, which will provide the clinical physician with more granular and richer information than merely relating numerical values to a single cut-off point. As many physicians today are used to evaluate autoantibodies as positive or negative on a nominal scale, the introduction of test result-specific likelihood ratios will require a change in clinical mindset. We also discuss the use of autoantibodies to prognosticate future arthritis development in at-risk patients as well as predict severe disease course and outcome of pharmacological treatment.

In this paper, a joint adaptive sampling interval and power allocation (JASIPA) scheme based on chance-constraint programming (CCP) is proposed for maneuvering target tracking (MTT) in a multiple opportunistic array radar (OAR) system. In order to conveniently predict the maneuvering target state of the next sampling instant, the best-fitting Gaussian (BFG) approximation is introduced and used to replace the multimodal prior target probability density function (PDF) at each time step. Since the mean and covariance of the BFG approximation can be computed by a recursive formula, we can utilize an existing Riccati-like recursion to accomplish effective resource allocation. The prior Cramér-Rao lower boundary (prior CRLB-like) is compared with the upper boundary of the desired tracking error range to determine the adaptive sampling interval, and the Bayesian CRLB-like (BCRLB-like) gives a criterion used for measuring power allocation. In addition, considering the randomness of target radar cross section (RCS), we adopt the CCP to package the deterministic resource management model, which minimizes the total transmitted power by effective resource allocation. Lastly, the stochastic simulation is embedded into a genetic algorithm (GA) to produce a hybrid intelligent optimization algorithm (HIOA) to solve the CCP optimization problem. Simulation results show that the global performance of the radar system can be improved effectively by the resource allocation scheme.

ObjectivesAn increased prevalence of periodontitis and perturbation of the oral microbiome has been identified in patients with rheumatoid arthritis (RA). The periodontal pathogen Porphyromonas gingivalis may cause local citrullination of proteins, potentially triggering anti-citrullinated protein antibody production. However, it is not known if oral dysbiosis precedes the onset of clinical arthritis. This study comprehensively characterised the oral microbiome in anti-cyclic citrullinated peptide (anti-CCP) positive at-risk individuals without clinical synovitis (CCP+at risk).MethodsSubgingival plaque was collected from periodontally healthy and diseased sites in 48 CCP+at risk, 26 early RA and 32 asymptomatic healthy control (HC) individuals. DNA libraries were sequenced on the Illumina HiSeq 3000 platform. Taxonomic profile and functional capability of the subgingival microbiome were compared between groups.ResultsAt periodontally healthy sites, CCP+at risk individuals had significantly lower microbial richness compared with HC and early RA groups (p=0.004 and 0.021). Microbial community alterations were found at phylum, genus and species levels. A large proportion of the community differed significantly in membership (523 species; 35.6%) and structure (575 species; 39.1%) comparing CCP+at risk and HC groups. Certain core species, including P. gingivalis, had higher relative abundance in the CCP+at risk group. Seventeen clusters of orthologous gene functional units were significantly over-represented in the CCP+at risk group compared with HC (adjusted p value <0.05).ConclusionAnti-CCP positive at-risk individuals have dysbiotic subgingival microbiomes and increased abundance of P. gingivalis compared with controls. This supports the hypothesis that the oral microbiome and specifically P. gingivalis are important in RA initiation.

ObjectivesRheumatoid arthritis (RA)-specific anti-citrullinated protein/peptide antibodies (ACPAs) appear before disease onset and are associated with bone destruction. We aimed to dissect the role of ACPAs in osteoclast (OC) activation and to identify key cellular mediators in this process.MethodsPolyclonal ACPA were isolated from the synovial fluid (SF) and peripheral blood of patients with RA. Monoclonal ACPAs were isolated from single SF B-cells of patients with RA. OCs were developed from blood cell precursors with or without ACPAs. We analysed expression of citrullinated targets and peptidylarginine deiminases (PAD) enzymes by immunohistochemistry and cell supernatants by cytometric bead array. The effect of an anti-interleukin (IL)-8 neutralising antibody and a pan-PAD inhibitor was tested in the OC cultures. Monoclonal ACPAs were injected into mice and bone structure was analysed by micro-CT before and after CXCR1/2 blocking with reparixin.ResultsProtein citrullination by PADs is essential for OC differentiation. Polyclonal ACPAs enhance OC differentiation through a PAD-dependent IL-8-mediated autocrine loop that is completely abolished by IL-8 neutralisation. Some, but not all, human monoclonal ACPAs derived from single SF B-cells of patients with RA and exhibiting distinct epitope specificities promote OC differentiation in cell cultures. Transfer of the monoclonal ACPAs into mice induced bone loss that was completely reversed by the IL-8 antagonist reparixin.ConclusionsWe provide novel insights into the key role of citrullination and PAD enzymes during OC differentiation and ACPA-induced OC activation. Our findings suggest that IL8-dependent OC activation may constitute an early event in the initiation of the joint specific inflammation in ACPA-positive RA.

ObjectivesTo evaluate the association between long-term dietary quality, measured by the 2010 Alternative Healthy Eating Index, and risk of rheumatoid arthritis (RA) in women.MethodsWe prospectively followed 76 597 women in the Nurses' Health Study aged 30–55 years and 93 392 women in the Nurses' Health Study II aged 25–42 years at baseline and free from RA or other connective tissue diseases. The lifestyle, environmental exposure and anthropometric information were collected at baseline and updated biennially. Cumulative follow-up rates were more than 90% for both cohorts. The primary outcome was RA alone with two subtypes of the disease: seropositive and seronegative RA.ResultsDuring 3 678 104 person-years, 1007 RA cases were confirmed. In the multivariable-adjusted model, long-term adherence to healthy eating patterns was marginally associated with reduced RA risk. To assess potential effect modification by age at diagnosis, we stratified by age. Among women aged ≤55 years, better quality diet was associated with lower RA risk (HRQ4 vs Q1: 0.67; 95% CI 0.51 to 0.88; p trend: 0.002), but no significant association was found for women aged >55 years (p interaction: 0.005). When stratifying by serostatus, the inverse association among those aged ≤55 years was strongest for seropositive RA (HRQ4 vs Q1: 0.60; 95% CI 0.42 to 0.86; p trend: 0.003).ConclusionsA healthier diet was associated with a reduced risk of RA occurring at 55 years of age or younger, particularly seropositive RA.

ObjectiveAn interesting and so far unexplained feature of chronic pain in autoimmune disease is the frequent disconnect between pain and inflammation. This is illustrated well in rheumatoid arthritis (RA) where pain in joints (arthralgia) may precede joint inflammation and persist even after successful anti-inflammatory treatment. In the present study, we have addressed the possibility that autoantibodies against citrullinated proteins (ACPA), present in RA, may be directly responsible for the induction of pain, independent of inflammation.MethodsAntibodies purified from human patients with RA, healthy donors and murinised monoclonal ACPA were injected into mice. Pain-like behaviour was monitored for up to 28 days, and tissues were analysed for signs of pathology. Mouse osteoclasts were cultured and stimulated with antibodies, and supernatants analysed for release of factors. Mice were treated with CXCR1/2 (interleukin (IL) 8 receptor) antagonist reparixin.ResultsMice injected with either human or murinised ACPA developed long-lasting pronounced pain-like behaviour in the absence of inflammation, while non-ACPA IgG from patients with RA or control monoclonal IgG were without pronociceptive effect. This effect was coupled to ACPA-mediated activation of osteoclasts and release of the nociceptive chemokine CXCL1 (analogue to human IL-8). ACPA-induced pain-like behaviour was reversed with reparixin.ConclusionsThe data suggest that CXCL1/IL-8, released from osteoclasts in an autoantibody-dependent manner, produces pain by activating sensory neurons. The identification of this new pain pathway may open new avenues for pain treatment in RA and also in other painful diseases associated with autoantibody production and/or osteoclast activation.

ObjectivesTo determine whether ultrasound can identify anti-cyclic citrullinated peptide (anti-CCP) antibody-positive patients without clinical synovitis (CS) who progress to inflammatory arthritis (IA).MethodsIn a prospective study, anti-CCP-positive patients without CS underwent ultrasound imaging of 32 joints (wrists, metacarpophalangeal joints, proximal interphalangeal joints and metatarsophalangeal joints (MTPs)) and were monitored for the development of IA. Associations between baseline ultrasound findings (grey scale (GS), power Doppler (PD) and erosions) and (1) progression to IA and (2) development of CS within an individual joint were measured.ResultsConsecutive anti-CCP-positive patients (n=136; mean age 51 years, 100 women) were followed up for median of 18.3 months (range 0.1–79.6). At baseline 96% had GS, 30% had PD and 21% had one or more erosions. IA developed in 57 patients (42%) after median of 8.6 months (range 0.1–52.4). Ultrasound abnormalities (GS ≥2, PD ≥1 or erosion ≥1) were found in 86% at baseline compared with 67% of non-progressors (χ2=6.3, p=0.012). Progression to IA was significantly higher in those with ultrasound findings in any joint (excluding MTPs for GS) (GS ≥2: 55% vs 24%, HR (95% CI) 2.3 (1.0 to 4.9), p=0.038; PD ≥2: 75% vs 32%, 3.7 (2.0 to 6.9), p<0.001 and erosion ≥1: 71% vs 34%, 2.9 (1.7 to 5.1), p<0.001). Furthermore, progression occurred earlier with PD ≥2 (median 7.1 vs 52.4 months) and erosion ≥1 (15.4 vs 46.5). At the individual joint level, the trend for progression to CS was more significant for GS and PD (GS ≥2: 26% vs 3%, 9.4 (5.1 to 17.5), p<0.001; PD ≥2: 55% vs 4%, 31.3 (15.6 to 62.9), p<0.001).ConclusionUltrasound features of joint inflammation may be detected in anti-CCP-positive patients without CS. Ultrasound findings predict progression (and rate of progression) to IA, with the risk of progression highest in those with PD signal.Trial registration numberNCT02012764; Results.

Background Histone deimination regulates gene function and contributes to antimicrobial response, allowing the formation of neutrophil extracellular traps (NETs). Deiminated proteins are target of anti-citrullinated peptides antibodies (ACPA) in rheumatoid arthritis (RA). Objective The objective of this paper is to test the hypothesis that RA sera react with deiminated histones contained in NETs. Methods Neutrophils from peripheral blood were stimulated with A23187 and acid treated; NETosis was induced by phorbol myristate acetate, and NET proteins were isolated. Sera were tested by immunoblot on acid extracted proteins from neutrophils and from NETs, and by ELISA on deiminated histone H4 or H4-derived peptides. Bands reactive with RA sera were excised from gels, digested with trypsin and subjected to matrix-assisted laser desorption/ionisation time of flight (MALDI-TOF) analysis, before and after derivatisation to detect citrullinated peptides. Results RA sera reacted with a deiminated antigen of 11 KDa from activated neutrophils, recognised also by anti-H4 and antideiminated H4 antibodies. A similar reactivity was observed with NET proteins. The antigen from neutrophils or NETs was identified as citrullinated H4 by MALDI-TOF analysis. By ELISA, RA sera bound in vitro citrullinated H4. Citrullinated H4 14–34 and 31–50 peptides detected antibodies in 67% and 63% of RA sera and in less than 5% of controls; antibody titre was correlated with anti-CCP2. Conclusions Citrullinated H4 from activated neutrophils and NETs is a target of antibodies in RA, and synthetic citrullinated H4-derived peptides are a new substrate for ACPA detection. As NETosis can generate antigens for ACPA, these data suggest a novel connection between innate and adaptive immunity in RA.

Background Celiac disease (CD) and rheumatoid arthritis (RA) are multisystem autoimmune diseases affecting 1% of general populationa. Both diseases share genetic and immunological features. Aim In this retrospective study, we aim to determine the frequency of auto‐antibodies of RA in adult patients with CD. Materials and methods Seventy seven adult patients with active CD were included in the present study. Ninety healthy blood donors (HBD) served as control group. Anti‐cyclic citrullinated peptides antibodies (CCP‐Ab) and rheumatoid factors (RF; IgA, IgG and IgM) were determined by enzyme linked immunosorbent assay (ELISA) for patients and control group. For statistical analysis, we used Chi‐square or Fisher's exact test. Results Our study included 77 adult patients with active celiac disease (57 female, 20 male). Twenty‐four (31.2%) active celiac patients and 7 (7.8%) blood donors had CCP‐Ab or RF (31.2% vs 7.8%, p < 10–4). Only two patients (2.6%) had both CCP‐Ab and RF. IgA was the predominant isotype of RF in celiac patients (n = 18; 23.4%) while none of healthy blood donors had RF‐IgA (23.4% vs 0.0%, p < 10–4). Conclusion The current study has shown that CD is associated with a high frequency of RF‐IgA suggesting that celiac patients could be at a higher risk of developing RA. Seventy seven adult patients with active celiac disease (CD) and ninety healthy blood donors were tested for rheumatoid arthritis (RA) autoantibodies. The frequency of rheumatoid factors IgA (RF‐IgA) were significantly higher in celiac disease patients than in control group.