Objectives. To examine the value of anti‐cyclic citrullinated peptide (anti‐CCP) antibodies, anti‐keratin antibodies (AKA) and immunoglobulin M rheumatoid factors (IgM RF) in discriminating between ...rheumatoid arthritis (RA) and other rheumatic diseases, and to determine whether the clinical manifestations or severity of erosions in RA are associated with anti‐CCP positivity. Methods. In a cross‐sectional study, we determined the concentrations or titres of these three markers in 179 RA patients and 50 controls. Erosions were quantified using the Larsen score in 129 patients. Results. Sensitivity was highest for IgM RF (75%), followed by anti‐CCP antibodies (68%) and AKA (46%). Specificity was highest for anti‐CCP antibodies (96%), followed by AKA (94%) and IgM RF (74%). A correlation with clinical manifestations and severity of erosions was observed mainly for IgM RF positivity. Conclusions. With their excellent specificity, anti‐CCP antibodies can be useful in establishing the diagnosis of RA, but IgM RF is a better predictor of disease severity.
Background The diagnosis of Spondylarthritis remains a challenge (1). We present a case series of patients with overlaping clinical manifestations of Spondylarthritis and autoinflammatory Syndromes ...making the diagnosis difficult. Objectives We hypothesized that SpA and other autoinflammatory syndromes may coexist. Methods We provide a brief clinical description of several patients initially diagnosed only as SpA. We performed a genetic analysis of these patients and of their family members, focusing on well-characterized hereditary autoinflammatory syndromes. Results Patient (P1) presented with undifferentiated arthritis and exhibited some clinical and radiological characteristics of Spondyloarthritis (SpA), including inflammatory back pain, inflammatory arthralgias, sacro-iliitis on MRI, high acute-phase response (CRP and ESR), but negative HLA B-27. The disease activity and acute-phase response remained high despite anti-TNF and c-DMARD therapy. Because the patient also complained of abdominal pain, myalgia and urticaria, we searched for an immunodeficiency and found high levels of IgD. Two other patients (P2 and P3) were consequently identified with similar clinical and laboratory features, including inflammatory back pain and arthralgias, high acute-phase response, negative HLA B-27, high serum IgD levels and only limited responsiveness to c-DMARDs and TNF-inhibitors. P1 was found to have a heterozygous mutation in the MEFV- Gene (K695R) suggestive of FMF. P2 carries a heterozygous mutation in the TNFRSF1A gene (R92Q) and a heterozygous mutation in the MEFV-gene (E148Q), suggestive of FMF and TRAPS. No mutations were found for P3. In family of P1 (SpA & FMF), the same mutation was found in the mother, the sister and 3 nieces. Of note, the sister also has SpA and one of the nieces, also displays high IgD, arthralgias, abdominal pains and severe aphthosis. In family of P2 (SpA-FMF-TRAPS), both mutations were found in his/her mother and two sisters. His/her father displayed typical features of SpA, the mother had episodes of pleuritis and abdominal pain and the two sisters had similar, though less severe, clinical manifestations as the index patient. Conclusions Our findings support the presence of overlapping clinical manifestations between SpA and periodic fever syndromes in some patients. These patient's low penetration genetic mutations may have influenced the clinical manifestations of SpA. SpA in general does have some autoimmune but also some autoinflammatory features (2). High serum levels of IgD are commonly reported in some autoinflammatory diseases and may represent a useful biomarker for these overlap presentations between SpA and autoinflammatory diseases. References Are Spondylarthritides related but distinct conditions or a single disease with heterogeneous phenotype? Dominique Baeten, Maxime Breban, Rik Lories, Georg Schett and Joachin Sieper. Arthritis and Rheumatism Vol. 65, No 1, January 2013, pp 12-20 Pathogenesis of Spondyloarthritis: autoimmune or autoinflammatory? C. Ambarus et al. Curr Opin Rheumatol 2012, 24:000-000 Diagnostic value of serum immunoglobulinaemia D level in patients with a clinical suspicion of hyper IgD syndrome. W. Ammouri et al. Rheumatology 2007;46: 1597-1600. Disclosure of Interest I. von Mühlenen Grant/research support: Novartis, A. Finckh Grant/research support: Novartis, P. Roux-Lombard Grant/research support: Novartis, C. Gabay Grant/research support: Novartis DOI 10.1136/annrheumdis-2014-eular.3669
Liver kidney microsomal type 1 (LKM‐1) antibodies have been shown to decrease the CYP2D6 activity in vitro and are present in a minority of patients with chronic hepatitis C infection. We ...investigated whether LKM‐1 antibodies might reduce the CYP2D6 activity in vivo. All patients enrolled in the Swiss Hepatitis C Cohort Study and tested for LKM‐1 antibodies were assessed (n = 1723): 10 eligible patients were matched with patients without LKM‐1 antibodies. Patients were genotyped for CYP2D6 variants to exclude individuals with a poor metabolizer genotype. CYP2D6 activity was measured by a specific substrate using the dextromethorphan/dextrorphan metabolic ratio to classify patients into four activity phenotypes. All patients had a CYP2D6 extensive metabolizer genotype. The observed phenotype was concordant with the CYP2D6 genotype in most LKM‐negative patients, whereas only three LKM‐1 positive patients had a concordant phenotype (six presented an intermediate and one a poor metabolizer phenotype). The median DEM/DOR ratio was sixfold higher in LKM‐1 positive than in LKM‐1 negative patients (0.096 vs. 0.016, P = 0.004), indicating that CYP2D6 metabolic function was significantly reduced in the presence of LKM‐1 antibodies. In chronic hepatitis C patients with LKM‐1 antibodies, the CYP2D6 metabolic activity was on average reduced by 80%. The impact of LKM‐1 antibodies on CYP2D6‐mediated drug metabolism pathways warrants further translational studies.
BackgroundIdentifying pre-clinical phases of rheumatoid arthritis (RA) is challenging. Musculoskeletal ultrasound (US) is more sensitive than clinical assessment for the detection of synovitis. US ...abnormalities have been associated with subsequent joint inflammation in patients with anti-citrullinated peptide antibodies (ACPA) without clinical synovitis (SJ)1.ObjectivesTo identify US abnormalities associated with the recognized phases of RA development2 in individuals at increased risk for RA.MethodsThis is a nested cohort study within an ongoing prospective study of individuals genetically at risk of developing RA, namely first degree relatives of patients with RA (FDR). Individuals without clinical evidence of RA were enrolled, and then followed-up yearly. We included in this analysis all individuals with available ACPA status (anti-CCP 2, 3.0, or 3.1) and US assessment. The US examination was conducted according to the validated SONAR score3 and performed by US trained rheumatologists blinded to clinical and biological data. According to previous publications4, inflammatory activity on US (active US) was defined as a Bmode score ≥9 and at least one synovitis of grade 2 or 3, or a Doppler score ≥2. We used logistic regression to analyze univariable and multivariable associations between US findings and specific phases preceding RA development and other patient characteristics.ResultsA total of 269 FDRs were analyzed, of which 97 (36%) had an active US as defined above. Individuals with an active US tended to be older (years median (IQR): 51 (41–59) vs 47 (35–57), OR: 1.0, 95% CI: 1.0–1.0, p<0.05), with no difference in sex, body mass index and tobacco smoking. In univariable analyses, there was a strong correlation between an active US and the presence of 'unclassified arthritis' (≥1 SJ on physical examination) (OR:2.6, 95% CI:1.4–4.9). No association was demonstrated with genetic risk factors (presence of shared epitope), systemic autoimmunity (ACPA positivity) or self reported symptoms in the absence of arthralgia or SJ (Table 1). In the multivariable analyses, the relation between US and 'unclassified arthritis' remained significant (OR:2.4, 95% CI:1.3–4.5).ConclusionsIn individuals at risk of RA, active US was strongly associated with the presence of “unclassified arthritis”. There was no association between US findings and earlier identified phases of RA development. These data suggest that in individuals at increased risk for RA, without obvious disease, US may identify imminent RA. These findings support the usefulness of US in a screening strategy for imminent RA.ReferencesNam JL et al. Ann Rheum Dis. 2016 Jan 22.Gerlag DM et al. Ann Rheum Dis. 2012 May;71(5):638–41. 3.Zufferey P. Joint Bone Spine 2014;81(3):222–7. 4.Zufferey P et al. Swiss Med Wkly.2013;143.Disclosure of InterestNone declared
BackgroundA significant proportion of patients with Rheumatoid Arthritis (RA) are negative for rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). There is a unmet need for new ...biomarkers to better define the severity and prognosis of RA.ObjectivesTo study the sensitivity and specificity of numerous auto-antibodies and calprotectin in RA patients compared with patients with spondyloarthritis (SpA) and to investigate the relationship between these biomarkes and measures of disease activity and severity.MethodsData was obtained from the “Swiss Clinical Quality Management” (SCQM) registry which recruits adults with RA, psoriatic arthritis (PsA) and axial spondylarthritis (axSpA). All patients with a Biobank sample were tested for RF (IgM and IgA, QUANTA Flash (QF), Inova), ACPA (anti-CCP2 (Eurodiagnostica) and anti-CCP3 (IgG QF and QUANTA Lite (QL) and IgA QF, Inova), anti-carbamylated proteins (anti-CarP, carbamylated fetal calf serum, prototype ELISA, Inova), anti-peptidyl arginine deiminase type-3 antibodies (anti-PAD3-E.Coli QF and anti-PAD3-insect QF, Inova) and serum calprotectin (QL prototype ELISA, Inova). The control group consisted of patients with PsA (CASPAR criteria positive) and axSpA (ASAS criteria positive). In univariable analyses we tested for associations between the biomarkers and the 28-joint disease activity score (DAS28) and the presence of erosive disease at inclusion. Multivariable analyses were corrected for age, sex, disease duration and anti-CCP2 positivity.ResultsA total of 1471 patients were included, 969 with RA and 502 in the SpA control group (317 with axSpA and 185 with PsA). Statistical measures of the biomarkers for the diagnosis of RA are shown in Table 1. In univariable analyses, RA patients positive for anti-PAD3-E.Coli, anti-PAD3-insect or calprotectin were significantly more likely to have a moderate to high DAS28 (DAS28>3.2) than patients with negative values (68.2% vs. 54.8%, p=0.001, 67.7% vs. 56.0%, p=0.027 and 70.4% vs. 56.2%, p=0.020 respectively). RA patients positive for anti-CarP, anti-PAD3-E.Coli or anti-PAD3-insect were significantly more likely to demonstrate joint erosions compared with patients with negative values (66.3% vs. 57.7%, p=0.037, 68.5% vs. 57.7%, p=0.015 and 71.6% vs. 58.3%, p=0.020 respectively). In multivariable analyses, the odd ratios (and 95% confidence intervals) for the association of anti-PAD3-E.Coli, anti-PAD3-insect or calprotectin with a moderate to high DAS28 were 1.65 (1.15, 2.39), 1.64 (1.02, 2.64) and 1.90 (1.08, 3.35) respectively, and for the association of anti-CarP, anti-PAD3-E.Coli or anti-PAD3-insect with joint erosions were 1.32 (0.90, 1.93), 1.43 (0.95, 2.15) and 1.82 (1.05, 3.15) respectively.ConclusionsAlthough anti-PAD3 and calprotectin are only present in a minority of RA patients, they are significantly associated with more active disease and anti-PAD3-insect is significantly associated with the presence of joint erosions, independently of ACPA (anti-CCP2).Disclosure of InterestNone declared
BackgroundMany controversies exist about the role of sex hormones and reproductive factors in the development of rheumatoid arthritis (RA). Post-menopause is a period of important hormonal and ...immunologic changes and has been associated with increased risk of seronegative-RA (1). Earlier age at menopause has been associated with increased risk of RA (2), therefore factors related to menopause may be relevant for the development of preclinical phases of RA.ObjectivesTo study the association between reproductive and menopausal factors and the risk of development systemic autoimmunity associated with RA, in particular of anti-citrullinated protein antibodies (ACPA), in women at increased risk for RA.MethodsThis is a nested cohort study within an ongoing prospective study of individuals genetically at risk of developing RA, namely first degree relatives of patients with RA (FDRs). Individuals without clinical evidence of RA were enrolled, and followed-up yearly with clinical and laboratory assessments. We included all women with available ACPA status (anti-CCP 2, 3.1 or 3.0). Reproductive and menopausal factors were self-reported. We operationally defined perimenopausal women as those with recent menopause (<3 years) or aged between 47 to 53 years with menopause-related symptoms. Total ovulatory years were estimated by substracting the age at menarche from the age at menopause minus one year for every childbirth and the total years of oral contraceptive use as previously described (3). We used logistic regression to analyze univariable and multivariable associations between ACPA-positivity and menopause factors.ResultsOf the 809 FDR women analyzed, 50 (6%) were ACPA-positive and had a median age of 46 (interquartile range (IQR): 34–56) years. Characteristics of FDR women are shown in Table 1. In univariable analysis, older age, ≥1 tender joint on examination, post-menopausal status and total ovulatory years were significantly associated with ACPA positivity. Perimenopausal status tended to be associated with ACPA status (OR:1.8, 95%CI:0.9–3.4), but did not reach significance. Other menopausal factors, such as age at menopause, earlier menopause or surgical menopause were not associated with ACPA positivity. Due to high correlation between age and menopausal status (r=0.73), we included tobacco smoking, post-menopausal status and having ≥1 tender joint on examination in the multivariable adjusted analyses, post-menopausal status and ≥1 tender joint on examination remained independently associated with ACPA positivity.ConclusionsPost-menopausal FDR women have an increased risk of ACPA positivity, suggesting menopausal hormonal changes are associated with the development of ACPAs, which may be linked to previously described increase of pro-inflammatory cytokines during menopause (4).ReferencesBengtsson C, et al. Arthritis Rheumatol 2014;66:S1261.Beydoun HA, et al. Menopause 2013;20:930–5.Costenbader KH, et al 2007; 56(4):1251–62.Kim OY, et al. Age 2012;34:415–2.Disclosure of InterestNone declared
•Patients with anorexia nervosa show few abnormalities in cytokine expression.•Of chemokines measured, RANTES showed elevations in some patients.•Despite depression in many patients, levels of TNF-α ...or IL-6 were not elevated.•Low body weight may alter cytokine expression in psychiatric disease.
Anorexia nervosa (AN) is a serious, potentially life-threatening disorder characterized by severe weight loss, dysregulated eating, and often excessive exercise. While psychiatric illnesses such as depression are associated with increased levels of pro-inflammatory mediators, evidence for such disturbances in patients with AN has been less clear. In an exploratory study of possible disturbances in immune responses in AN, we assayed a panel of cytokines and chemokines in the blood of patients undergoing inpatient treatment, testing the hypothesis that metabolic disturbances in this disease would lead to a pattern of immune disturbances distinct from that of other psychiatric diseases. For this purpose, we evaluated patients by the Beck Depression Inventory-II (BDI-II) and the Eating Disorders Examination-Questionnaire and assessed cytokines and chemokines by enzyme-linked immunosorbent assays. Patients reported a moderate level of depression (mean BDI-II=22.6) but exhibited few immunologic abnormalities of the kind associated with major depressive disorder e.g., increased interleukin (IL)-6; RANTES showed the most frequent elevations and was increased in 4 of the patients studied. Together, these findings suggest that features of AN such as loss of adipose tissue and excessive exercise may attenuate cytokine production and thus modulate the experience of illness that impacts on core features of disease.
BackgroundThe etiopathogenesis of rheumatoid arthritis (RA) is viewed as a multi-step process whereby environmental factors induce pathologic activation of the immune system that eventually leads to ...clinical onset of RA in genetically susceptible individuals. Systemic autoimmunity associated with RA is one of the phases preceding the development of the disease. The role of female hormonal factors is controversial and their relation in the transition to systemic autoimmunity has not been studied. Recently, observational studies have suggested differences in the role of female reproductive factors between anti-citrullinated protein antibodies (ACPA) negative and positive RA.ObjectivesTo analyze the association between female reproductive factors and the development of systemic autoimmunity associated with RA.MethodsThis is a prospective cohort study of first degree relatives (FDRs) of patients with established RA. Only individuals without clinical evidence of RA are enrolled and followed-up yearly. We included in this analysis only female participants with available ACPA status (anti-CCP 2.0 or 3.1) and full information on reproductive factors. The outcome of interest was the presence of ACPA. The predictor of interest was the cumulative lifetime estrogen (CLE) exposure as previously described (1). This composite score integrates a history of menarche ≤10 years, 3 or more pregnancies, hysterectomy, hormonal contraceptive or replacement therapy and age at menopause ≥53 years. Based on the CLE score, women were categorized as being low, moderate or high estrogen exposed. We used logistic regression to analyze univariate and multivariate associations between ACPA positive status, CLE exposure and other specific reproductive factors.ResultsA total of 583 women FDRs were analyzed, of which 93 (16%) were ACPA-positive. Characteristics were balanced between ACPA positive and negative FDRs with a mean age of 48.3 and 44.9 years and heavy tobacco smoking (>10 pack-years) in 45 and 46% respectively. Positive shared epitope (SE) in 8 and 10% and positive rheumatoid factor in 17% of subjects in both groups. In a multivariate adjusted analysis, low CLE exposure was associated with ACPA positivity (OR 1.88, p=0.03). High CLE exposure was also numerically associated with an increased risk of ACPA (OR 1.57, p=0.36), even though not significantly. We found no significant association between ACPA positivity and SE, ever smoking, obesity, breastfeeding or postmenopausal status.ConclusionsIn women at increased risk of RA, the development of ACPAs was found to be associated with low lifetime exposure to estrogens, however high lifetime estrogen exposure also tended to increase the risk of ACPAs positivity, suggesting a non-linear association between estrogenic exposure and the development of ACPAs. We plan to replicate these findings in a separate cohort. If this non-linear association was confirmed it could explain some discordant findings in the literature.ReferencesGatto NM et al. Parkinsonism Relat Disord 2014; 20(11):1149-56.Disclosure of InterestNone declared
OBJECTIVE To determine the prevalence of myositis specificautoantibodies (MSAs) and several myositisassociated autoantibodies (MAAs) in a large group of patients with myositis. METHODS A total of 417 ...patients with myositis from 11 European countries (198 patients with polymyositis (PM), 181 with dermatomyositis (DM), and 38 with inclusion body myositis (IBM)) were serologically analysed by immunoblot, enzyme linked immunosorbent assay (ELISA) and/or immunoprecipitation. RESULTS Autoantibodies were found in 232 sera (56%), including 157 samples (38%) which contained MSAs. The most commonly detected MSA was anti-Jo-1 (18%). Other anti-synthetase, anti-Mi-2, and anti-SRP autoantibodies were found in 3%, 14%, and 5% of the sera, respectively. A relatively high number of anti-Mi-2 positive PM sera were found (9% of PM sera). The most commonly detected MAA was anti-Ro52 (25%). Anti-PM/Scl-100, anti-PM/Scl-75, anti-Mas, anti-Ro60, anti-La, and anti-U1 snRNP autoantibodies were present in 6%, 3%, 2%, 4%, 5%, and 6% of the sera, respectively. Remarkable associations were noticed between anti-Ro52 and anti-Jo-1 autoantibodies and, in a few sera, also between anti-Jo-1 and anti-SRP or anti-Mi-2 autoantibodies. CONCLUSIONS The incidence of most of the tested autoantibody activities in this large group of European patients is in agreement with similar studies of Japanese and American patients. The relatively high number of PM sera with anti-Mi-2 reactivity may be explained by the use of multiple recombinant fragments spanning the complete antigen. Furthermore, our data show that some sera may contain more than one type of MSA and confirm the strong association of anti-Ro52 with anti-Jo-1 reactivity.
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