Search

Objective: This study aimed to explore whether phenotypic characteristics of patients with chronic widespread pain (CWP) and fibromyalgia (FM) can be aggregated into definable clusters that may help to tailor treatments., Method: Baseline variables (sex, age, education, marital/employment status, pain duration, prior CWP/FM diagnosis, concomitant rheumatic disease, analgesics, tender point count, and disease variables derived from standardized questionnaires) collected from 1099 patients (93.4% females, mean age 44.6 years) with a confirmed CWP or FM diagnosis were evaluated by hierarchical cluster analysis. The number of clusters was based on coefficients in the agglomeration schedule, supported by dendrograms and silhouette plots. Simple and multiple regression analyses using all variables as independent predictors were used to assess the likelihood of cluster assignment, reported as odds ratios (ORs) with 95% confidence intervals (CIs)., Results: Only one cluster emerged (Cluster 1: 455 patients). Participants in this cluster were characterized as working (OR 66.67, 95% CI 7.14 to 500.00), with a medium-term/higher education (OR 16.80, 95% CI 1.94 to 145.41), married/cohabiting (OR 14.29, 95% CI 1.26 to 166.67), and using mild analgesics (OR 25.64, 95% CI 0.58 to > 999.99). The odds of being an individual in Cluster 1 were lower when having a worse score on the PDQ (score ≥ 18) (OR < 0.001, 95% CI < 0.001 to 0.02)., Conclusion: We identified one cluster, where participants were characterized by a potentially favourable clinical profile. More studies are needed to evaluate whether these characteristics could be used to guide the management of patients with CWP and FM.

The structure of solvent molecules within zeolite pores influences the rates and selectivities of catalytic reactions by altering the free energies of reactive species. Here, we examine the consequences of these effects on the kinetics and thermodynamics of 1,2-epoxybutane (C 4 H 8 O) ring-opening with methanol (CH 3 OH) in acetonitrile (CH 3 CN) cosolvent over Lewis acidic (Zr-BEA) and Brønsted acidic (Al-BEA) zeolites of varying (SiOH) x density. Despite ostensibly identical reaction mechanisms across materials, turnover rates depend differently on (SiOH) x density between acid types. (SiOH) x -rich Zr-BEA (Zr-BEA-OH) provides ∼10 times greater rates than a (SiOH) x -poor material (Zr-BEA-F), while Al-BEA-OH and Al-BEA-F give turnover rates within a factor of 2. Zr-BEA-OH shows more positive activation enthalpies and entropies than Zr-BEA-F across the range of [CH 3 OH], which reflect the displacement of solvent molecules and lead to greater rates in Zr-BEA-OH due to the dominant role of entropic gains. Measurements of the density and composition of solvent within the pores show that the (SiOH) x nests within Zr-BEA-OH promote hydrogen-bonded solvent structures distinct from Zr-BEA-F, while the Brønsted acid sites confer interactions similar to (SiOH) x nests and give solvent structures within Al-BEA-F that resemble those within Al-BEA-OH. Correlations between apparent activation enthalpies and C 4 H 8 O adsorption enthalpies show that interactions with solvent molecules give proportional changes to both C 4 H 8 O adsorption and ring-opening transition state formation. The differences in intrapore environment carry consequences for both rates and regioselectivities of epoxide ring-opening, as demonstrated by product regioselectivities that increase by a factor of 3 in response to changes in solvent composition and the type of acid site in the *BEA structure (i.e., Lewis or Brønsted). These results demonstrate the ability to control rates, regioselectivities, and adsorption thermodynamics relevant for industrially relevant liquid-phase reactions through the design of noncovalent interactions among solvating molecules, reactive species, and (SiOH) x functions., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Brønsted acidic zeolites are ubiquitous catalysts in fuel and chemical production. Broadening the catalytic diversity of a given zeolite requires strategies to manipulate the acid site placement at framework positions within distinct microporous locations. Here, we combine experiment and theory to elucidate how intermolecular interactions between organic structure-directing agents (OSDAs) and framework Al centers influence the placement of H + sites in distinct void environments of MFI zeolites and demonstrate the catalytic consequences of active site location on kinetically controlled (403 K) toluene methylation to xylene regioisomers. Kinetic measurements, interpreted using mechanism-derived rate expressions and transition state theory, alongside density functional theory (DFT) calculations show that larger intersection environments similarly stabilize all three xylene isomer transition states without altering well-established aromatic substitution patterns ( ortho / para / meta ∼ 60%:30%:10%), while smaller channel environments preferentially destabilize transition states that form bulkier ortho - and meta -isomers, thereby resulting in high intrinsic para -xylene selectivity (∼80%). DFT calculations reveal that the flexibility of nonconventional OSDAs (e.g., 1,4-diazabicyclo[2.2.2]octane) to reorient within MFI intersections and their ability to hydrogen-bond to form protonated complexes favor the placement of Al in smaller channel environments compared to conventional quaternary OSDAs (e.g., tetra- n -propylammonium). These molecular-level insights establish a mechanistic link between OSDA structure, active site placement, and transition state stability in MFI zeolites and provide active site design strategies that are orthogonal to crystallite design approaches harnessing complex reaction-diffusion phenomena to enhance regioisomer selectivity in the industrial production of valuable polymer precursors.

Objective: Patient education is recommended as an integral component of the therapeutic plan for the management of chronic widespread pain (CWP) and fibromyalgia (FM). The key purpose of patient education is to increase the patient's competence to manage his or her own health requirements, encouraging self-management and a return to desired everyday activities and lifestyle. The aim of this systematic review was to evaluate the evidence for the benefits and potential harms associated with the use of patient education as a stand-alone intervention for individuals with CWP and FM through randomized controlled trials (RCTs)., Method: On 24 November 2021 a systematic search of PubMed, MEDLINE, Embase, CENTRAL, PsycINFO, CINAHL, ClinicalTrials.gov, American College of Rheumatology, European League Against Rheumatism, and the World Health Organization International Clinical Trials Registry Platform identified 2069 studies. After full-text screening, five RCT studies were found to be eligible for the qualitative evidence synthesis., Results: Patient education as a stand-alone intervention presented an improvement in patients' global assessment (standardized mean difference 0.79, 95% confidence interval 0.13 to 1.46). When comparing patient education with usual care, no intervention, or waiting list, no differences were found for functioning, level of pain, emotional distress in regard to anxiety and depression, or pain cognition., Conclusion: This review reveals the need for RCTs investigating patient education as a stand-alone intervention for patients with FM, measuring outcomes such as disease acceptance, health-related quality of life, enhancement of patients' knowledge of pain, pain coping skills, and evaluation of prioritized learning outcomes.

Introduction: The association between chronic widespread pain (CWP) and disability is well established. Although research support large interindividual differences in functional outcomes, limited studies are available on the socio-economic consequences of offering stratified treatment based on prognostic factors. Identification of predictors of long-term functional outcomes such as work disability as a critical consequence, could assist early and targeted personalised interventions. The primary objective of this cohort study is to identify prognostic factors for the primary endpoint work status (employed and working vs not working) in patients with CWP assessed 3 years from baseline, that is, at referral for specialist care., Methods and Analyses: Data are collected at the diagnostic unit at Department of Rheumatology, Frederiksberg Hospital. The first 1000 patients ≥ 18 years of age registered in a clinical research database (DANFIB registry) with CWP either 'employed and working' or 'not working' will be enrolled. Participants must meet the American College of Rheumatology 1990 definition of CWP, that is, pain in all four body quadrants and axially for more than 3 months and are additionally screened for fulfilment of criteria for fibromyalgia. Clinical data and patient-reported outcomes are collected at referral (baseline) through clinical assessment and electronic questionnaires. Data on the primary endpoint work status at baseline and 3 years from baseline will be extracted from the Integrated Labour Market Database, Statistics Denmark and the nationwide Danish DREAM database. Prognostic factor analysis will be based on multivariable logistic regression modelling with the dichotomous work status as dependent variable., Ethics and Dissemination: Sensitive personal data will be anonymised according to regulations by the Danish Data Protection Agency, and informed consent are obtained from all participants. Understanding and improving the prognosis of a health condition like CWP should be a priority in clinical research and practice. Results will be published in international peer-reviewed journals., Trial Registration Number: NCT04862520., Competing Interests: Competing interests: MH: Advisory Board member at the Thuasne Group. LEK: received fees for speaking and/or consultancy from Pfizer, AbbVie, Amgen, UCB, Celgene, BMS, Biogen, Sanofi, MSD, Novartis, Eli Lilly, Janssen Pharmaceuticals. PHD, HL, EEW, RC, KT, HB and KA: none., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

INTRODUCTION The multi-organ disease Lyme borreliosis can cause mainly large joint arthritis. No guideline exists describing how to diagnose Lyme arthritis (LA). The incidence of LA in Denmark remains unknown, but it is considered to be low. The primary aim of this study was to quantify the number of Borrelia burgdorferi serological tests requested from primary and secondary care; secondly, to examine how often LA is diagnosed. METHODS this was a register-based study including B. burgdorferi serological tests analysed at the department of clinical microbiology at Hvidovre and Herlev Hospitals during a two-year period. The results of the tests were categorised into primary and secondary care. A medical record review was made covering all newly referred rheumatological patients with B. burgdorferi serological tests analysed the Department of Clinical Microbiology, Hvidovre Hospital. A model was set up to diagnose LA. RESULTS Most tests were requested by primary care. A total of 146 rheumatology patients were tested for B. burgdorferi of whom 118 were newly referred. Using our model to diagnose LA, we found that three patients had possible LA, whereas one had likely LA, but none were given a final LA diagnosis. Overdiagnosis was not common among rheumatologists. CONCLUSION. The number of requested B. burgdorferi serological tests was highest in primary care. A clear guideline describing how to diagnose LA is needed in primary and secondary care alike. FUNDING none. TRIAL REGISTRATION Under current Danish law, no formal ethical approval was required for this study. Approval for this study was obtained from the Danish Data Protection Agency (no. 2012-58-0004)., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Objectives: To determine the diagnostic potential of simultaneous presence of serum anti-SSA/Ro and upregulated salivary protein biomarkers in patients with primary Sjögren's syndrome (pSS)., Methods: Previous proteomics data on the intensity of neutrophil elastase, calreticulin, tripartite motif containing protein 29 (TRIM29), clusterin and vitronectin provided basis for performing extended analysis. Protein data was obtained by liquid chromatography tandem mass spectrometry technique in whole saliva from 24 patients with pSS and 16 patients having symptoms of pSS, but not fulfilling the American College of Rheumatology/European League against Rheumatism classification criteria (non-pSS). Serum anti-SSA/Ro antibody was measured using enzyme-linked immunosorbent assays. Receiver operating characteristic curve (ROC) value was calculated for combined biomarkers., Results: Simultaneous presence of serum anti-SSA/Ro and upregulated salivary TRIM29 provided the most optimal combination with an area under curve (AUC) of 0.995 (95% CI 0.98-1.00, p = 2.0E-7 and standard error 0.007) and combinations of sensitivity and specificity within the interval of 91-100%. ROC analysis showed that salivary levels of TRIM29 alone enabled differentiation between pSS and non-pSS with an area under curve (AUC) of 0.88 (95%CI 0.77-1.00). All patients with pSS and 3 non-pSS patients were serum anti-SSA/Ro positive., Conclusions: Simultaneous presence of serum anti-SSA/Ro and upregulated salivary TRIM29 provided a high diagnostic accuracy exceeding that of currently available tools used in pSS diagnostics. This biomarker combination represents a promising less invasive diagnostic tool for pSS. The clinical applicability of TRIM29 needs further testing in independent cohorts using relevant analytical techniques., Competing Interests: The authors have declared that no competing interests exist.

Objectives: Increasing evidence suggests that aberrant expression of microRNAs (miRNAs) is involved in the pathogenesis of primary Sjögren's syndrome (pSS). The aim was thus to characterize the miRNA profile in saliva, salivary gland tissue, and plasma from patients with pSS and compare findings with those of patients having Sjögren-like disease (non-pSS). In addition, to correlate miRNA levels and clinicopathological features of pSS., Methods: miRNA real-time quantitative polymerase chain reaction was performed on saliva, plasma, and salivary gland tissue samples from 24 patients with pSS and 16 non-pSS in 384-well plates. T test was used for comparison of miRNA profiles, followed by Benjamini-Hochberg correction. The discriminatory power of miRNAs was evaluated by receiver-operating characteristic curves, and Pearson/Spearman correlation was used for correlation analyses., Results: In saliva, 14 miRNAs were significantly differentially expressed between pSS and non-pSS, including downregulation of the miR-17 family in pSS. In salivary gland tissue of patients with pSS, miR-29a-3p was significantly upregulated. Plasma miRNAs did not differ between the two groups, although the miR-17 family tended to be downregulated. The combination of miR-17-5p and let-7i-5p in saliva yielded an area under curve of 97% (CI 92%-100%). Several miRNAs correlated significantly with one another and with salivary flow rates and histopathology., Conclusion: Our findings indicate that the miRNA expression profile in saliva may enable to discriminate between pSS and non-pSS patients. However, further validation in larger cohorts is needed as well as functional analyses of the miRNAs of interest., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: Glucocorticoid treatment is fundamental in polymyalgia rheumatica (PMR) and giant cell arteritis (GCA), but carries a risk of glucocorticoid-induced adrenal insufficiency. Adrenal insufficiency can cause reluctance to stop glucocorticoid treatment after disease remission as symptoms can resemble PMR/GCA flare. We aimed to determine the prevalence of adrenal insufficiency in prednisolone-treated patients with PMR/GCA., Methods: We included 47 patients with PMR (n = 37), GCA (n = 1) or both (n = 9), treated with prednisolone for ≥5.4 months, current dose 2.5-10 mg/day. Adrenal function was evaluated using a corticotropin (Synacthen®) stimulation test following 48 h prednisolone pause. Two years' clinical follow-up data are provided., Results: Seven patients (15%) had adrenal insufficiency, 4 (11%) of the 37 patients with PMR alone, and 3 (30%) of the 10 patients with GCA. Corticotropin-stimulated P-cortisol was significantly associated with current prednisolone dose, mean daily dose the last 3 and 6 months before testing, and basal P-cortisol, but not with total dose or treatment duration. Adrenal insufficiency occurred with all current prednisolone doses (2.5-10 mg/day). Five (71%) of the glucocorticoid-insufficient patients could discontinue prednisolone treatment; two of them recovered glucocorticoid function, whereas three still needed hydrocortisone replacement 2 years later. Two patients experienced in total four acute hospital admissions with symptoms of adrenal crises., Conclusion: Glucocorticoid-induced adrenal insufficiency occurred in 15% of patients with PMR/GCA. Mean prednisolone dose the last 3 months and basal P-cortisol were the best and simplest predictors of adrenal function. Most of the glucocorticoid-insufficient patients could discontinue prednisolone with appropriate treatment for adrenal insufficiency., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The aim of this study was to characterize and compare the proteome in whole saliva, plasma, and salivary gland tissue in patients with primary Sjögren's syndrome (pSS) and patients having symptoms of pSS, but not fulfilling the classification criteria, and to search for diagnostic biomarker candidates for pSS., Methods: Liquid chromatography tandem mass spectrometry was conducted on whole saliva, plasma, and labial salivary gland tissue samples from 24 patients with pSS and 16 non-Sjögren control subjects (non-pSS). Gene Ontology (GO)-terms and Kyoto Encyclopedia of Genes and Genomes (KEGG)-pathways were applied for functional annotation., Results: 1013 proteins were identified in whole saliva, 219 in plasma, and 3166 in salivary gland tissue. In saliva, 40 proteins differed significantly between the two groups. In pSS, proteins involved in immunoinflammatory processes were upregulated, whereas proteins related to salivary secretion were downregulated. The combination of neutrophil elastase, calreticulin, and tripartite motif-containing protein 29 yielded a receiver-operating characteristic (ROC) value of 0.97 (CI 0.93-1.00). Protein expression in plasma and salivary gland tissue did not differ between the patient groups., Conclusion: The salivary proteome of patients with pSS differed from that of non-pSS patients, indicating that saliva proteomics represents a promising non-invasive diagnostic tool for pSS., Significance: Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune disease, which clinically may present with a wide variety of symptoms and signs. Symptoms of dry eyes and dry mouth due to lacrimal and salivary gland dysfunction are prominent, but not pathognomonic, and an extensive diagnostic work-up including blood tests and labial salivary gland biopsy is often required to distinguish pSS from non-pSS. In this study, we used high throughput proteomics and identified a non-invasive biomarker candidate comprising a combination of three different upregulated salivary proteins, which enables differentiation between patients with pSS and non-pSS patients with an accuracy of 97%. In the future, this could contribute to earlier, more accurate and less costly diagnosis of pSS., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: To investigate whether tumour necrosis factor alpha inhibitors (TNFis) are associated with an increased risk of neuroinflammatory diseases among patients with arthritic diseases., Methods: Cohorts of patients with rheumatoid arthritis (RA, n=25 796), psoriatic arthritis (PsA, n=8586) and ankylosing spondylitis (AS, n=9527) who initiated a TNFi treatment year 2000-2017 were identified from nationwide clinical rheumatology registers in Sweden and Denmark. Information on demyelinating disease and inflammatory neuropathy diagnoses was retrieved from prospective linkage to National Patients Register. A Cox proportional hazard model was used to estimate HRs and 95% CI comparing TNFi exposed and non-exposed, by disease and country., Results: Among 111 455 patients with RA, we identified 270 (Sweden) and 51 (Denmark) events (all types of neuroinflammatory diseases combined), corresponding to crude incidence rates (per 1000 person-years) of 0.37 (Sweden) and 0.39 (Denmark) in TNFi-treated patients vs 0.39 (Sweden) and 0.28 (Denmark) in unexposed patients, and an age-sex-calendar-period-adjusted HR (95% CI) of 0.97 (0.72 to 1.33) (Sweden) and 1.45 (0.74 to 2.81) (Denmark) in TNFi exposed compared with non-exposed patients. For a total of 64 065 AS/PsA patients, the corresponding numbers were: 196 and 32 events, crude incidence rates of 0.59 and 0.87 in TNFi-treated patients vs 0.40 and 0.19 in unexposed patients, and HRs of 1.50 (1.07 to 2.11) and 3.41 (1.30 to 8.96), for Sweden and Denmark, respectively. For multiple sclerosis, the patterns of HRs were similar., Conclusions: Use of TNFi in AS/PsA, but not in RA, was associated with increased risk of incident neuroinflammatory disease, though the absolute risk was below one in 1000 patients/year., Competing Interests: Competing interests: MM has received grants from Novartis and Biogen, and has received personal fees from Novartis, Biogen, Merck, Sanofi Genzyme and Teva. FS has received grants and personal fees from Biogen, Merck, Novartis, Sanofi Genzyme and Roche. JA has received grants from Abbvie, BMS, Eli Lilly, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi and UCB. LD has received grants from BMS and has received personal fees from Eli Lilly and Galderma. TIK, BD, EVA, RKJ, EHI, RLC, HL and DVJ have nothing to disclose., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective : To characterize and compare the salivary microbiota in patients with pSS and patients with non-Sjögren's-related sicca, and to relate the findings to their oral health status and saliva flow rates. Methods : Twenty-four patients fulfilled the 2016 classification criteria for pSS and 34 did not (non-pSS). A clinical examination included registration of decayed, missing and filled teeth/-surfaces and collection of whole saliva. The microbiota was characterized using next-generation sequencing of the V1-V3 region of the 16S rRNA gene. Data were annotated against the eHOMD database. Results : A total of 509 different bacterial taxa were identified. There were no statistically significant differences between the groups with regard to the abundance of predominant genera, bacterial diversity and relative abundance on the genus or species level. The two groups did not differ with regard to general health, including intake of xerogenic medication and polypharmacy, oral health status or unstimulated and stimulated whole saliva flow rates. Conclusion : The salivary microbiota and oral health status, as well as salivary flow rate in patients with pSS resemble that of non-pSS patients. Our findings indicate that changes in the salivary microbiota do not appear to be determined by the disease entity pSS itself.

Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology. The majority of individuals with RA are positive for the disease-specific anti-citrullinated protein antibodies (ACPAs). These antibodies are primarily of cross-reactive nature, hence, the true autoantigen to ACPA remains unidentified. In this study, we analyzed the reactivity of RA sera to several post-translationally modified epitopes, in order to further characterize the specific nature of ACPAs by immunoassays. Substituting citrulline with other amino acids, e.g., D-citrulline, homo-citrulline and methyl-arginine illustrated that ACPAs are utmost specific for citrullinated targets. Collectively, these findings support that ACPAs and citrullinated targets are specific for RA, making citrulline-containing peptide targets the most effective assays for detection of ACPAs.

Background: Ankylosing spondylitis (AS) results from the combined effects of susceptibility genes and environmental factors. Polymorphisms in genes regulating inflammation may explain part of the heritability of AS., Methods: Using a candidate gene approach in this case-control study, 51 mainly functional single nucleotide polymorphisms (SNPs) in genes regulating inflammation were assessed in 709 patients with AS and 795 controls. Data on the patients with AS were obtained from the DANBIO registry where patients from all of Denmark are monitored in routine care during treatment with conventional and biologic disease modifying anti-rheumatic drugs (bDMARDs). The results were analyzed using logistic regression (adjusted for age and sex)., Results: Nine polymorphisms were associated with risk of AS (p < 0.05). The polymorphisms were in genes regulating a: the TNF-α pathway (TNF -308 G > A (rs1800629), and - 238 G > A (rs361525); TNFRSF1A -609 G > T (rs4149570), and PTPN22 1858 G > A (rs2476601)), b: the IL23/IL17 pathway (IL23R G > A (rs11209026), and IL18-137 G > C (rs187238)), or c: the NFkB pathway (TLR1 743 T > C (rs4833095), TLR4 T > C (rs1554973), and LY96-1625 C > G (rs11465996)). After Bonferroni correction the homozygous variant genotype of TLR1 743 T > C (rs4833095) (odds ratios (OR): 2.59, 95% confidence interval (CI): 1.48-4.51, p = 0.04), and TNFRSF1A -609 G > T (rs4149570) (OR: 1.79, 95% CI: 1.31-2.41, p = 0.01) were associated with increased risk of AS and the combined homozygous and heterozygous variant genotypes of TNF -308 G > A (rs1800629) (OR: 0.56, 95% CI: 0.44-0.72, p = 0.0002) were associated with reduced risk of AS., Conclusion: We replicated associations between AS and the polymorphisms in TNF (rs1800629), TNFRSF1A (rs4149570), and IL23R (rs11209026). Furthermore, we identified novel risk loci in TNF (rs361525), IL18 (rs187238), TLR1 (rs4833095), TLR4 (rs1554973), and LY96 (rs11465996) that need validation in independent cohorts. The results suggest that genetically determined high activity of the TNF-α, IL23/IL17, and NFkB pathways increase risk of AS.

Background: Evidence is emerging that pain in rheumatoid arthritis (RA) exists without underlying inflammation. Our objective was to evaluate the prognostic value of pain classification at treatment initiation using the painDETECT questionnaire (PDQ). Outcomes were change in DAS28-CRP and RAMRIS synovitis score., Methods: RA patients initiating a disease-modifying anti-rheumatic drug (DMARD) or initiating/ switching a biological agent were included. Follow-up time was 4 months. Clinical examination, imaging (MRI, dynamic contrast-enhanced MRI (DCE-MRI)), and patient-reported outcomes were undertaken. The PDQ was used to differentiate pain mechanisms. Mean change (95% CI) was calculated using ANCOVA. Multivariable regression models were used to determine a prognostic value., Results: A total of 102 patients were included; 75 were enrolled for MRI. Mean changes in baseline variables were greatest in the high PDQ classification group (> 18), while limited in the intermediate group (13-18). The 12 patients with high baseline PDQ score all changed pain classification group. No prognostic value of PDQ pain classification was found in relation to change of DAS28-CRP, RAMRIS score, or VAS pain. In the unadjusted model, RAMRIS score at baseline was associated with change in DAS28-CRP. The exploratory variables of DCE-MRI did not differ from other inflammatory variables., Conclusions: In RA patients a high PDQ score (non-nociceptive pain) at baseline was not associated with worse outcomes, in fact these patients had numerically greater improvement in DAS28-CRP. However, pain classification by PDQ was not independently associated with change in DAS28-CRP, RAMRIS score, or VAS pain in the prognostic models. Furthermore, patients classified with a high baseline PDQ score changed pain classification group. Patients with unclear pain mechanism had reduced numerically treatment response., Trial Registration: The study was approved by the Regional Ethics Committee of the Capital of Denmark April 18 2013; identification number H-3-2013-049 .

Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology. A characteristic feature of RA is the presence of anti-citrullinated protein antibodies (ACPA). Since ACPAs are highly specific for RA and are often present before the onset of RA symptoms, they have become valuable diagnostic and prognostic. As a result, several assays for detection of ACPAs exist, which vary in sensitivity and specificity. In this study, we analyzed the reactivity of RA sera to selected peptides by solid-phase immunoassays in order to develop an ACPA assay with improved sensitivity and specificity. ACPA levels were determined with respect to sensitivity and specificity in 332 serum samples using the newly developed peptide panel, which was compared to the commercial assays CCPlus (Eurodiagnostica) and CCP3.1 (Inova Diagnostics). A primary panel (peptides 814, 33062 and 33156) was identified, which obtained a sensitivity of 71%, while the complete peptide panel reacted with 79% of RA sera screened. Total specificities of 89% and 80% were obtained for the primary peptide panel and the complete peptide panel. Sensitivities for the commercial assays ranged between 71% and 76% and specificities between 88% and 90%. These findings indicate that the generated peptide panel is optimal for ACPA detection and able to compete with commercial available assays. Collectively, this study may contribute to characterize autoimmunity towards citrullinated proteins and to the development of new and improved diagnostic assays for detection of ACPA and determination of RA., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Anti-citrullinated protein antibodies (ACPA) are crucial for the serological diagnosis of RA, where Epstein-Barr virus (EBV) has been suggested to be an environmental agent in triggering the onset of the disease. This study aimed to analyse antibody reactivity to citrullinated EBV nuclear antigen-2 (EBNA-2) peptides from three different EBV strains (B95-8, GD1 and AG876) using streptavidin capture enzyme-linked immunosorbent assay. One peptide, only found in a single strain (AG876), obtained a sensitivity and specificity of 77% and 95%, respectively and showed high sequence similarity to the filaggrin peptide originally used for ACPA detection. Comparison of antibody reactivity to commercial assays found that the citrullinated peptide was as effective in detecting ACPA as highly sensitive and specific commercial assays. The data presented demonstrate that the citrullinated EBNA-2 peptide indeed is recognised specifically by RA sera and that the single peptide is able to compete with assays containing multiple peptides. Furthermore, it could be hypothesized that RA may be caused by (a) specific strain(s) of EBV.

Several genetic variants in Toll-like receptor (TLR) and nuclear factor (NF)-κB signalling pathways have been reported associated with responsiveness to tumour necrosis factor inhibitor (anti-TNF) treatment in rheumatoid arthritis (RA). The present study was undertaken to replicate these findings. In a retrospective case-case study including 1007 Danish anti-TNF-treated RA patients, we genotyped 7 previously reported associated single-nucleotide polymorphisms (SNPs) in these pathways. Furthermore, 5 SNPs previously reported by our group were genotyped in a subcohort (N=469). Primary analyses validated the IRAK3 rs11541076 variant as associated (odds ratio (OR)=1.33, 95% confidence interval (CI): 1.00-1.77, P-value=0.047) with a positive treatment response (EULAR (European League Against Rheumatism) good/moderate vs none response at 4±2 months), and found the NLRP3 rs461266 variant associated (OR=0.75, 95% CI: 0.60-0.94, P=0.014) with a negative treatment response. Meta-analyses combining data from previous studies suggested smaller effect sizes of associations between variant alleles of CHUK rs11591741, NFKBIB rs3136645 and rs9403 and a negative treatment response. In conclusion, this study validates rs11541076 in IRAK3, a negative regulator of TLR signalling, as a predictor of anti-TNF treatment response, and suggests true positive associations of previously reported SNPs within genes encoding activators/inhibitors of NF-κB (CHUK, MYD88, NFKBIB, and NLRP3).

Objective: To describe the distribution of specific mitochondrial DNA (mtDNA) haplogroups (hgs) in a cohort of patients with rheumatoid arthritis (RA)., Methods: Two-hundred nineteen consecutive patients with RA had mtDNA isolated from their blood, sequenced and haplotyped. Patients were diagnosed according to the American College of Rheumatology (ACR)/European league against Rheumatism (EULAR) criteria. Demographic and clinical data were retrieved from the Danish nationwide database (DANBIO). Logistic regression analyses were performed to test for associations., Results: One-hundred eighty-four patients were eligible for analysis. Haplogroup frequencies were: H (n = 88; 47.8%), U (n = 37; 20.1%), T (n = 22; 12.0%), J (n = 16; 8.7%), K (n = 11; 5.9%), HV (n = 6; 3.3%) and V (n = 4; 2.2%). The distribution of individual hgs was identical to the background population. Radiographic erosions were significantly associated with hg clusters JT (OR = 2.37, 95% confidence interval (CI): 1.07-5.53, p = 0.038). Significantly fewer patients from hg cluster JT received biological treatment (OR = 0.17, 95% CI: 0.03-0.87, p = 0.038). Albeit, none of these associations were significant when corrected for multiple tests., Conclusion: There was no significant association between mtDNA hgs and presence of RA or disease manifestations. There was an, albeit insignificant, overrepresentation of patients with hg JT among patients with erosive disease; however, slightly fewer patients in the JT group were treated with biological drugs.

Objective: Patients receiving long-term glucocorticoid treatment are at risk of developing adrenal insufficiency during treatment. We investigated the prevalence of prednisolone-induced adrenal insufficiency in the particular clinical situation where patients receive ongoing low-dose (5 mg/day) prednisolone treatment, a dose by itself too low to cover glucocorticoid needs during stress., Design and Methods: Cross-sectional study in 42 patients with rheumatoid arthritis (29 women, aged 36-86 years) treated with 5 mg prednisolone/day, who had received prednisolone for ≥6 months (median: 66, range: 6-444 months). Adrenal function was evaluated by a 250 μg Synacthen test performed after mean 48.7 h prednisolone pause. Local assay-specific cut-off for normal adrenal function was P-cortisol ≥420 nmol/L 30 min after Synacthen injection., Results: Overall, 20 of the 42 patients (48%, 95% CI: 33-62%) had an insufficient adrenal response to the Synacthen test. Including only patients who had not received concomitant treatment with any other glucocorticoid formulas within the last 3 months, 13 of 33 patients (39%, 95% CI: 25-56%) had an insufficient response. Adrenocorticotrophic hormone (ACTH) concentrations were generally low and anti-adrenal antibodies were negative indicating secondary adrenal insufficiency as the most likely diagnosis. There was no correlation between duration of treatment and 30 min P-cortisol ( P  = 0.62). Adrenal function did not depend on sex or seropositivity of rheumatoid arthritis., Conclusion: We demonstrate a high prevalence of adrenal insufficiency during ongoing low-dose prednisolone treatment. The results urge to increase focus on the condition to ensure identification and correct management of insufficient patients during stress and withdrawal. Strategies for adrenal function evaluation during ongoing low-dose glucocorticoid treatment need to be established., (© 2017 European Society of Endocrinology.)

Rheumatoid arthritis (RA) is an autoimmune disease of complex etiology. A characteristic feature of a subset of RA is the presence of anti-citrullinated protein antibodies (ACPA), which correlate with a progressive disease course. In this study, we employed streptavidin capture enzyme-linked immunosorbent assay to analyze ACPA reactivity. Using the pro-filaggrin peptide HQCHQEST-Cit-GRSRGRCGRSGS, as template, we analyzed the reactivity of RA sera and healthy donor sera to various peptides in order to determine the physical characteristics of the citrullinated pro-filaggrin epitope and to examine whether biotin labelling influence antibody recognition. The full-length cyclic pro-filaggrin peptide and a linear form with a N-terminal biotin, was recognized to the same level, whereas, a notable difference in ACPA reactivity to the linear peptides with a C-terminal biotin was found, probably due to steric hindrance. Screening of linear and cyclic truncated peptides, revealed that small cyclic peptides containing 10-12 amino acids are favored over the linear. Moreover, the charged amino acids C-terminal to citrulline were found to be essential for antibody reactivity, most important was the charged amino acid in position 4 C-terminal to citrulline. Collectively, peptide structure, length, the presence of charged amino acids and biotin labelling markedly influence antibody reactivity. In relation to the clinical diagnostics of ACPA, these findings may reflect the differences in diagnostic assays used for detection of ACPA, which relates to differences in sensitivity and specificity dependent on the assay applied., Competing Interests: The authors have declared that no competing interests exist.

Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA) and represent an important tool for the serological diagnosis of RA. In this study, we describe ACPA reactivity to overlapping citrullinated Epstein-Barr virus nuclear antigen-1 (EBNA-1)-derived peptides and analyze their potential as substrates for ACPA detection by streptavidin capture enzyme-linked immunosorbent assay. Using systematically overlapping peptides, containing a 10 amino acid overlap, labelled with biotin C-terminally or N-terminally, sera from 160 individuals (RA sera (n=60), healthy controls (n=40), systemic lupus erythematosus (n=20), Sjögren's syndrome (n=40)) were screened for antibody reactivity. Antibodies to a panel of five citrullinated EBNA-1 peptides were found in 67% of RA sera, exclusively of the IgG isotype, while 53% of the patient sera reacted with a single peptide, ARGGSRERARGRGRG-Cit-GEKR, accounting for more than half of the ACPA reactivity alone. Moreover, these antibodies were detected in 10% of CCP2-negative RA sera. In addition, 47% of the RA sera reacted with two or three citrullinated EBNA-1 peptides from the selected peptide panel. Furthermore, a negative correlation between the biotin attachment site and the location of citrulline in the peptides was found, i.e. the closer the citrulline was located to biotin, the lower the antibody reactivity. Our data suggest that citrullinated EBNA-1 peptides may be considered a substrate for the detection of ACPAs and that the presence of Epstein-Barr virus may play a role in the induction of these autoantibodies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To determine whether genetic variation within genes related to the Toll-like receptor, inflammasome and interferon-γ pathways contributes to the differences in treatment response to tumour necrosis factor inhibitors (anti-TNF) in patients with rheumatoid arthritis (RA)., Methods: In a retrospective case-case study, we assessed 23 functional single nucleotide polymorphisms (SNPs) in 15 genes. We included 538 anti-TNF naïve Danish RA patients from the nationwide DANBIO database. Multivariable logistic regression analyses were performed to detect associations (p-value<0.05) between genotypes and European League Against Rheumatism (EULAR) treatment responses. False Discovery Rate corrections for multiple testing (q-value) and stratified analyses were performed to investigate association with individual therapies and IgM-rheumatoid factor (RF) status., Results: Six of twenty successfully genotyped polymorphisms were nominally associated with EULAR treatment response. Three of these were in weak to moderate linkage disequilibrium with polymorphisms previously reported associated with anti-TNF treatment response. TLR5(rs5744174) variant allele carriers (odds ratio(OR) = 1.7(1.1-2.5),p = 0.010,q = 0.46) and TLR1(rs4833095) homozygous variant carriers (OR = 2.8(1.1-7.4),p = 0.037,q = 0.46) had higher odds for a positive treatment response. NLRP3(rs10754558) variant allele carriers (odds ratio(OR) = 0.6(0.4-1.0),p = 0.045,q = 0.46) were more likely to have a negative treatment response. The association in TLR5(rs5744174) remained significant after correction for multiple comparisons among patients negative for RF (OR = 6.2(2.4-16.3),p = 0.0002,q = 0.024). No other association withstood correction for multiple testing. Post hoc analyses showed that change in Patient Global score on a visual analogue scale (VAS) and change in pain VAS were the main factors responsible for the association., Conclusions: We reproduced previously reported associations between genetic variation in the TLR10/1/6 gene cluster, TLR5, and NLRP3 loci and response to anti-TNF treatment in RA. Changes in VAS pain and patient global scores were the main contributors to the association found for TLR5. Furthermore, we identified other candidate genes that require replication in independent cohorts.

Introduction: Pain in rheumatoid arthritis (RA) is traditionally considered to be of inflammatory origin. Despite better control of inflammation, some patients still report pain as a significant concern, even when being in clinical remission. This suggests that RA may prompt central sensitisation-one aspect of chronic pain. In contrast, other patients report good treatment response, although imaging shows signs of inflammation, which could indicate a possible enhancement of descending pain inhibitory mechanisms. When assessing disease activity in patients with central sensitisation, the commonly used disease activity scores (eg, DAS28-CRP (C reactive protein)) will yield constant high total scores due to high tender joint count and global health assessments, whereas MRI provides an isolated estimate of inflammation. The objective of this study is, in patients with RA initiating anti-inflammatory treatment, to explore the prognostic value of a screening questionnaire for central sensitisation, hand inflammation assessed by conventional MRI, and the interaction between them regarding treatment outcome evaluated by clinical status (DAS28-CRP). For the purpose of further exploratory analyses, dynamic contrast-enhanced MRI (DCE-MRI) is performed., Method and Analysis: The painDETECT Questionnaire (PDQ), originally developed to screen for a neuropathic pain component, is applied to indicate the presence of central sensitisation. Adults diagnosed with RA are included when either (A) initiating disease-modifying antirheumatic drug treatment, or (B) initiating or switching to biological therapy. We anticipate that 100 patients will be enrolled, tested and reassessed after 4 months of treatment., Data Collection Includes: Clinical data, conventional MRI, DCE-MRI, blood samples and patient-reported outcomes., Ethics and Dissemination: This study aims at supporting rheumatologists to define strategies to reach optimal treatment outcomes in patients with RA based on chronic pain prognostics. The study has been approved by The Capital region of Denmark's Ethics Committee; identification number H-3-2013-049. The results will be published in international peer-reviewed journals., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: Many patients with rheumatoid arthritis (RA) benefit from tumor necrosis factor-α blocking treatment (anti-TNF), but about one third do not respond. The objective of this study was to replicate and extend previously found associations between anti-TNF treatment response and genetic variation in the TNF-, NF-κB- and pattern recognition receptor signalling pathways., Methods: Forty-one single nucleotide polymorphisms (SNPs), including 34 functional, in 28 genes involved in inflammatory pathways were assessed in 538 anti-TNF naive Danish RA patients with clinical data. Multivariable logistic regression analyses were performed to test associations between genotypes and treatment response at 3-6 months using the European League Against Rheumatism (EULAR) response criterion. American College of Rheumatology treatment response (ACR50) and relative change in 28-joint disease activity score (relDAS28) were used as secondary outcomes. Subgroup analyses were stratified according to smoking status, type of anti-TNF drug and IgM-Rheumatoid Factor (IgM-RF) status. False discovery rate (FDR) controlling was used to adjust for multiple testing., Results: Statistically significant associations with EULAR response were found for two SNPs in NLRP3(rs4612666) (OR (odds ratio) for good/moderate response = 0.64 (95% confidence interval: 0.44-0.95), p = 0.025, q = 0.95) and INFG(rs2430561) (OR = 0.40 (0.21-0.76), p = 0.005, q = 0.18) and among IgM-RF positive patients for TNFRS1A(rs4149570) (0.59 (0.36-0.98), p = 0.040, q = 0.76). Current smokers who carried the NLRP3(rs4612666) variant allele were less likely to benefit from anti-TNF treatment (OR = 0.24 (0.10-0.56), p = 0.001, q = 0.04)., Conclusions: In a population of Danish RA patients, we confirm the NLRP3 gene as associated with EULAR anti-TNF response as previously reported. The NLRP3 variant (T) allele is associated with lower treatment response, in particular among current smokers. Furthermore, we find that a functional polymorphism in the interferon-γ gene is associated with anti-TNF response. All findings should be tested by replication in independent validation cohorts and augmented by assessing cytokine levels and activities of the relevant gene products.

Biological treatment with inhibitors of the pro-inflammatory cytokine TNF-alpha has dramatically improved the disease course of several chronic rheumatologic conditions. Adverse events (AEs) are primarily infections and hypersensitivity reactions. Demyelinizing neurological symptoms resembling multiple sclerosis (MS) have been described as a rare AE. During about 10-year use of anti TNF-alpha, the Danish Medicines Agency has recorded eight cases of MS like AEs. The objective of this study was to estimate the incidence of demyelinizing AEs both in the central and peripheral nervous system after treatment with anti TNF-alpha in a cohort of patients from a large rheumatologic outpatient clinic in Copenhagen. In a 4-year period from January 2008 to December 2011, approximately 550 patients annually were undergoing treatment with anti TNF-alpha inhibitors in our department. We collected data on all patients who developed neurological symptoms during this time period. We found six patients with signs of demyelinizing neurological disorders: four resembling MS, one MS-like condition, and one multifocal motor neuropathy. During a relatively short time period, we found a remarkably high number of neurological demyelinizing AEs probably linked to anti TNF-alpha treatment. The AEs were not associated with a single anti TNF-alpha agent and were thus presumably a class effect. The data presented suggest that neurological AEs may be underreported. We advocate that physicians handling patients during treatment with TNF inhibitors are aware of this potentially serious AE and report these events to the proper medical authorities.

Introduction: Chronic pain is common in rheumatoid arthritis (RA) and may still persist despite regression of objective signs of inflammation. This has led researchers to hypothesise that central pain sensitisation may play a role in the generation of chronic pain in RA. Application of the disease activity score DAS28 can classify some patients with active RA solely based on a high tender joint count and poor patient global health score. In such cases, intensified treatment with anti-inflammatory drugs would be expected to yield poorer results than in cases with DAS28 elevation due to a high score for swollen joints and C reactive protein (CRP). Evaluation of central pain sensitisation in patients with few inflammatory indices may be a predictive tool regarding the effect of anti-inflammatory treatment. Computerised pneumatic cuff pressure algometry (CPA) is a method for assessing temporal summation (ie, degree of central sensitisation). The main objective of this study was to examine the prognostic values of pressure pain-induced temporal summation, ultrasound Doppler activity and the interaction between them in relation to treatment response (DAS28-CRP change) in patients with RA initiating any anti-inflammatory therapy., Method and Analysis: 120 participants ≥18 years of age will be recruited. Furthermore, they must be either (1) diagnosed with RA, untreated with disease-modifying antirheumatic drugs for at least 6 months and about to initiate disease-modifying antirheumatic drug treatment or (2) about to begin or switch treatment with any biological drug for their RA. Data (clinical, imaging, blood samples, patient reported outcomes and CPA measurements) will be collected from each participant at baseline and after 4 months of anti-inflammatory treatment., Ethics and Dissemination: This study has been approved by the ethics committee for the Copenhagen region (H-4-2013-007). Dissemination will occur through presentations and publication in international peer-reviewed journals.

Background: Centromere protein-F (CENP-F) is a large nuclear protein of 367 kDa, which is involved in multiple mitosis-related events such as proper assembly of the kinetochores, stabilization of heterochromatin, chromosome alignment and mitotic checkpoint signaling. Several studies have shown a correlation between CENP-F and cancer, e.g. the expression of CENP-F has been described to be upregulated in cancer cells. Furthermore, several studies have described a significant correlation between the expression of autoantibodies to CENP-F and cancer., Methods: Autoantibodies to CENP-F were detected in a small number of samples during routine indirect immunofluorescence (IIF) analysis for anti-nuclear antibodies (ANA) using HEp-2 cells as substrate. Using overlapping synthetic peptides covering a predicted structural maintenance of chromosomes (SMC) domain, we developed an enzyme-linked immunosorbent assay (ELISA) for detection of CENP-F antibodies., Results: Analyzing the reactivity of the sera positive in IIF for CENP-F antibodies to overlapping CENP-F peptides, we showed that autoantibodies to several peptides correlate with the presence of antibodies to CENP-F and a diagnosis of cancer, as increased CENP-F antibody expression specific for malignant cancer patients to five peptides was found (A9, A12, A14, A16, A27). These antibodies to CENP-F in clinical samples submitted for ANA analysis were found to have a positive predictive value for cancer of 50%. Furthermore, the expression of cancer-correlated CENP-F antibodies seemed to increase as a function of time from diagnosis., Conclusion: These results conform to previous findings that approximately 50% of those patients clinically tested for ANA analyses who express CENP-F antibodies are diagnosed with cancer, confirming that these antibodies may function as circulating tumor markers. Thus, a peptide-based CENP-F ELISA focused on the SMC domain may aid in identifying individuals with a potential cancer.

The role of Campylobacter jejuni cytolethal distending toxin (CDT) on clinical outcome after gastroenteritis was investigated. Clinical data, blood serum samples, and Campylobacter spp. isolated, from each of 30 patients were collected over a period of 6 months. The CDT encoding genes, cdtABC, characterized by PCR, revealed that all but one of the C. jejuni strains had the wild-type sequence. Sequencing of cdtABC from this strain showed two major deletions. From all of the strains, CDT titers were determined, and toxin neutralizing antibodies were documented using an in vitro assay. Three of the thirty clinical isolates, including the one with the mutant cdtABC coding genes, did not have a detectable CDT activity. Analyzing the relationship between CDT titer, serum neutralization of CDT, and the clinical outcome showed that campylobacteriosis caused by CDT-negative strains was clinically indistinguishable from that of patients infected with an isolate that produced high levels of CDT. These results suggest that CDT does not solely determine severity of infection and clinical outcome., (© 2011 The Authors. APMIS © 2011 APMIS.)

Individuals with Turner syndrome (TS) are prone to develop autoimmune conditions such as coeliac disease (CD), thyroiditis and type 1 diabetes (T1DM). The objective of the present study was to examine TS of various karyotypes for autoantibodies and corresponding diseases. This was investigated in a prospective cross-sectional study of Danish TS patients (n = 107, median age 36.7 years, range: 6-60 years). A medical history was recorded and a blood sample was analysed for autoantibodies against gliadin, transglutaminase, adrenal cortex, intrinsic factor, anti-thyroid peroxidase (anti-TPO) and glutamic-acid-decarboxylase 65 (GAD-65). Autoantibodies were present in 58% (n = 61) of all patients, whereof 18% (11) had autoantibodies targeting more than one organ. Patients with autoantibodies were significantly older than those without (P = 0.001). Anti-TPO was present in 45% (48) of patients, of whom 33% (16) were hypothyroid. Overall, 18% (19) presented with CD autoantibodies, of whom 26% (five) had CD. Anti-TPO and CD autoantibodies co-existed in 9% (10). Immunoglobulin A deficiency was found in 3% (three) of patients, who all had CD autoantibodies without disease. Among four patients with anti-GAD-65 none had T1DM, but two were classified as having T2DM. One patient had adrenocortical autoantibodies but not adrenal failure. Autoantibodies against intrinsic factor were absent. Anti-GAD-65 was increased in isochromosomal karyotypes (3/23 versus 1/84, P = 0.008) with no other association found between autoantibodies and karyotype. In conclusion, TS girls and women face a high prevalence of autoimmunity and associated disease with a preponderance towards hypothyroidism and CD. Thus, health care providers dealing with this patient group should be observant and test liberally for these conditions even before clinical symptoms emerge.

Background and Aims: The etiology of the inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC) remains unknown. We aimed to investigate the influence of genetic, serological, and environmental factors on phenotypic presentation of IBD at diagnosis in a population-based Danish inception cohort from 2003-2005., Methods: Three-hundred-forty-seven (62%) of 562 cohort patients were genotyped. ASCA and p/c-ANCA were determined and patients answered a questionnaire concerning environmental factors with possible influence on IBD., Results: Fourteen percent of CD patients vs. 11% of controls were positive for common CARD15 mutation (ns), whereas more CD patients than healthy controls were homozygous for the OCTN-TC haplotype (p=0.03). ASCA was more common in CD (22%) than UC (14%) (p=0.045) and was related to age and localization of CD. p-ANCA was more frequent in UC (p=0.00001) but was related to pure colonic CD (p=0.0001). Sugar consumption was significantly higher in CD patients than in UC patients (p=0.0001) and more CD patients than UC patients had undergone appendectomy prior to IBD diagnosis (p=0.03). A possible relation between tonsillectomy and disease severity in CD, and a relation between use of oral contraception and disease localization of UC to rectum/left-sided colon were found., Conclusions: In this cohort of unselected IBD patients we found a very low frequency of mutations in IBD susceptibility genes and observed a greater impact of ASCA and ANCA than of genetic factors on disease phenotypes. In addition, several environmental factors seemed to influence disease occurrence and disease presentation in both UC and especially CD.

Objective: To compare sensitivity and specificity of autoantibodies to alpha-fodrin with conventional anti-Ro and anti-La antibodies in patients with primary Sjögren's syndrome (pSS). Data on internal organ manifestations were correlated with presence of autoantibodies., Methods: We collected clinical and laboratory data from 321 patients with pSS (Copenhagen criteria), of which 205 fulfilled the new American-European 2002 consensus criteria. Sera were tested for autoantibodies against alpha-fodrin and recombinant Ro-52, Ro-60, and La proteins., Results: Antibodies to alpha-fodrin were not diagnostically superior to conventional anti-Ro/La testing. IgG anti-La had the highest specificity (97%). A highly significant association was found between presence of anti-La and internal organ manifestations (OR 6, 95% CI 2.99-12.03) or hematological abnormalities. The pattern of autoantibodies was relatively independent of disease duration, indicating that these antibodies appeared early in pSS, probably even years before the first symptoms were manifest., Conclusion: We could not confirm that antibodies to alpha-fodrin had higher specificity or sensitivity than anti-Ro/La. Anti-La antibodies were strongly correlated to organ involvement and cytopenias, and thus could serve as a prognostic marker in pSS.

Objective: We conducted a case-case comparison study to estimate the attack-rate of reactive joint pain (JPrea) following intestinal infections, and evaluated whether the susceptibility and severity of joint symptoms was associated with the tissue-type HLA-B27., Methods: Consecutive patients with positive fecal culture for Salmonella, Campylobacter, Yersinia, Shigella, and E. coli were addressed by questionnaires inquiring about gastrointestinal (GI) symptoms and the occurrence of joint pain in a previously healthy joint within 4 weeks after onset of infection. A blood sample was requested for HLA-B27 typing., Results: Of 3146 patients invited, 2105 (67%) responded to the survey questionnaire. The triggering infections were Campylobacter, 1003; Salmonella, 619; E. coli, 290; Shigella, 102; and Yersinia, 91. JPrea was reported by 294 subjects: Campylobacter, 131 (13.1%); Salmonella, 104 (16.8%); Yersinia, 21 (23.1%); Shigella, 10 (9.8%); and E. coli, 28 (9.7%). There was a significant association between severity of gastroenteritis and development of arthralgia (p = 0.001). The odds ratio (OR) for JPrea in an HLA-B27-positive individual was 2.62 (95% CI 1.67-3.93) for the entire group. A significant association between JPrea and HLA-B27 was found for Salmonella, Shigella, and Yersinia; not, however, for Campylobacter and E. coli. HLA-B27-positive patients had a significantly increased risk for severe joint symptoms., Conclusion: Our study shows that JPrea after GI infection is positively correlated to severity of GI symptoms. HLA-B27 is not associated with joint pain after Campylobacter. Intestinal E. coli seems to be an arthritogenic pathogen. A significant association between HLA-B27 and severity of joint pain was observed.

We correlated the distribution and levels of serum anti-cardiolipin (aCL) and anti-beta(2)-glycoprotein-1 antibodies (anti-beta(2)-GPI) of the IgG and IgM isotypes to the clinical spectrum of recent (<6 months) thrombo-embolic events in a cohort of 162 patients. Clinical information was obtained by questionnaires from the referring physicians. Cerebro-vascular infarction (CVI) had taken place in 82 patients, deep venous thrombosis (DVT) in 34, pulmonary embolism (PE) in 14, myocardial infarction (MI) in four, and other thromboses in 28 patients. SLE was the most commonly associated rheumatic disease and accounted for 20 (12%) patients. In 124 (77%) patients no underlying rheumatic disease was identified. Isolated IgG aCL was found in 31 of 48 patients with DVT/PE (65%), but in only 21 of 82 patients with CVI (26%); p<0.0001. IgG anti-beta(2)-GPI were detected in 23 (48%) DVT/PE patients, but in only 13 (16%) CVI patients; p<0.001. The IgG class anti-beta(2)-GPI positive patients had significantly higher levels of IgG aCL (mean 65 units) compared to IgG anti-beta(2)-GPI negative patients (mean 29 units); p<0.0001. In contrast, isolated IgM aCL was found in nine (19%) patients with DVT/PE, but in 46 (56%) CVI patients; p<0.0001. Only ten patients had IgM anti-beta(2)-GPI. The present study shows that the IgG and IgM aCL isotypes seem to define different clinical subsets of patients with thrombo-embolic events with IgG aCL being most prevalent in the group having DVT/PE, IgM aCL being found primarily among CVI patients.

We evaluated the prevalence of anti-beta2-glycoprotein I (a-beta2-GPI), anti-phosphatidylserine/prothrombin (a-PP), anti-prothrombin (a-PT), and anti-oxidised low-density lipoprotein (a-oxLDL) antibodies in a cohort of patients with a recent thrombotic event. Among consecutive sera sent to an autoimmune laboratory for routine testing for anti-cardiolipin antibodies (aCL) 473 were found positive for IgG and/or IgM aCL. The referring physicians were requested for clinical information about thrombo-embolic events occurring within 6 months prior to testing. One hundred and sixty-three individuals of which 82 had suffered from cerebro-vascular infarction and 49 from deep venous thromboses or pulmonary emboli were included in the study. Ninety-four sera were positive for IgG aCL and 69 were negative. There was a strong correlation between the presence of IgG aCL and the three other phospholipid-related antibodies: a-beta2-GPI, a-PP, and a-PT. However, IgG a-oxLDL antibodies were almost equally distributed among sera positive and negative for IgG aCL. The presence of antibodies of all subgroups was most pronounced among patients with venous thrombo-embolic disease. In this cohort antibodies to beta2-GPI, PP, PT seem to coexist with aCL. However, a-oxLDL antibodies appear to define a subset of patients, who were older, had more arterial vascular disease, and with no apparent association to the presence of IgG aCL.

Background: Periodontitis shares several clinical and pathogenic characteristics with chronic arthritis, and there is some degree of coexistence. The aims of this study were to elucidate whether patients with localized aggressive periodontitis (LAgP), generalized aggressive periodontitis (GAgP), juvenile idiopathic arthritis (JIA), and rheumatoid arthritis (RA) share periodontal and hematological characteristics distinguishing them from individuals free of diseases., Methods: The study population consisted of white adults (or=4 mm, CAL>or=2 mm, and ABL>or=2 mm compared to controls. The percentage of sites with CAL>or=2 mm significantly correlated with the levels of IgM-RF and IgA-RF. Missing teeth in JIA and RA patients were not lost due to periodontitis. Patients with GAgP showed higher levels of leukocytes, including neutrophils, and CRP compared to controls. In part, JIA and RA patients showed similar results., Conclusions: Young adults with RA may develop periodontal destruction, and these patients require professional attention. Both differences and similarities in periodontal and hematological variables were seen in individuals with periodontitis, JIA, and RA.