Peptides Bearing Multiple Post-Translational Modifications as Antigenic Targets for Severe Rheumatoid Arthritis Patients.

Rheumatoid arthritis (RA) is characterized by the presence of autoantibodies that are of paramount importance for the diagnosis and prognosis of the disease and have been implicated in its pathogenesis. Proteins resulting from post-translational modifications (PTMs) are capable of triggering autoimmune responses important for the development of RA. In this work, we investigate serum antibody reactivity in patients with an established RA against a panel of chimeric peptides derived from fibrin and filaggrin proteins and bearing from one to three PTMs (citrullination, carbamylation and acetylation) by home-designed ELISA tests (anti-AMPA autoantibodies). The role of anti-AMPAs as biomarkers linked to the presence of a more severe RA phenotype (erosive disease with radiological structural damage) and to the presence of interstitial lung disease (ILD), a severe extra-articular manifestation in RA patients entailing a high mortality, was also analyzed. In general, the association with the clinical phenotype of RA was confirmed with the different autoantibodies, and especially for IgA and IgM isotypes. The prevalence of severe joint damage was only statistically significant for the IgG isotype when working with the peptide bearing three PTMs. Furthermore, the median titers were significantly higher in patients with RA-ILD, a finding not observed for the IgG isotype when working with the single- and double-modified peptides.

ACPA-positive versus ACPA-negative rheumatoid arthritis: two distinct erosive disease entities on radiography and ultrasonography.

The objective of this study is to assess the prevalence, localization, and severity of bone erosions on radiography (RX) and ultrasonography (US) according to ACPA status in patients with rheumatoid arthritis (RA). 78 patients with ACPA-positive (ACPA+) RA and 30 patients with ACPA-negative (ACPA-) RA fulfilling the ACR 1987 and/or ACR/EULAR 2010 criteria were consecutively included. On RX, a modified Sharp erosion score (SHSe) was evaluated by two blinded readers and one adjudicator for discordant cases (number of eroded joints ≤ three). On US, erosions were scored on six bilateral joints (MCP2, 3, 5; MTP2, 3, 5) with a four-point scale to calculate the total US score for erosions (USSe). The mean total SHSe and USSe were 3.7 and 4.4 times higher in the ACPA+ group than in the ACPA- group, respectively (P < 0.001). On both RX and US, the most discriminating joint between the two groups was MTP5, especially in cases with bilateral erosion. Based on multivariate analyses, ACPA + status was associated with erosive RA on RX according to the EULAR 2013 definition criteria [OR 4.4 (95% CI 1.2-16.4)], and on US according to the following two definitions: the presence of at least two eroded joint facets [OR 3.7 (95% CI 1.4-9.9)] or at least one grade 2 joint facet erosion [OR 9.0 (95% CI 2.8-28.4)]. Compared to ACPA- RA, ACPA + RA is associated independently with more severe erosive disease on RX and US. Both US and RX bilateral erosions in MTP5 joints are highly discriminant for ACPA + RA patients (97.8% in US and 100% in RX).

Long-term fracture risk in rheumatoid arthritis: impact of early sustained DAS28-remission and restored function, progressive erosive disease, body mass index, autoantibody positivity and glucocorticoids. A cohort study over 10 years.

BACKGROUND: Risk of fragility fractures in patients with rheumatoid arthritis (RA) is increased. Disease-related inflammation in RA is associated with low Bone Mineral Density (BMD). However, effects of specific disease factors on fracture occurrence and whether or not such disease effects are independent of BMD are unknown. METHODS: Analysis of fracture outcome in the prospective cohort of 2557 patients with early RA (67% women, mean age 58.1 ± 15.6 years) during an observation period of 10.6 ± 4.7 years. In 602 patients BMD was measured at baseline. The first major fragility fractures were considered. Kaplan-Meier and Cox regression analysis, adjusted for traditional factors, prior fracture, disease activity and period of inclusion, were used to estimate the risk of the outcome. RESULTS: During follow-up fracture occurred in 352 patients (13.8%), a rate of 13/1000 p-y. A proportional risk reduction for the outcome was associated with Body Mass Index (BMI) at baseline, BMI ≥ 30 kg/m2, and over the first two years sustained Disease Activity Score (DAS28)-remission, DAS28-low disease activity and Health Assessment Questionnaire (HAQ) ≤ 0.5. The proportional risk elevation for fractures was associated with BMI ≤ 20 kg/m2, DAS28 at baseline, 6-month and at 1-year, cumulative DAS28 over the two years, RF, erosion score progression at 2-year, HAQ score and HAQ ≥ 1 at 6-month and 1-year and showed a trend for ACPA positivity. The estimated fracture risk was increased in users of glucocorticoids (GC), associated with a higher GC-dosage at follow-ups and a higher cumulative dosage over two years, independently of disease activity. With adjustment for BMD, there was no difference in fracture outcome by exposure to GC. The effects of a higher BMI, DAS28-remission and low HAQ ≤ 0.5 attained at 6-month of treatment initiation and sustained up to 2 years, RF, ACPA, and erosion score progression at 2-year were independent of low BMD. CONCLUSIONS: This analysis supports importance of RA-specific risk factors in early RA for future major fragility fractures. Treat-to-target strategy and restored functional capacity in early RA-disease are important to prevent fractures. Autoantibody positivity, progressively erosive disease, and low weight could have additional value for personalized fracture preventive strategies in early RA.

Analysis of the patients with nonvariceal upper gastrointestinal bleeding and comparison of Rockall and Glasgow-Blatchford scores.

BACKGROUND: Nonvariceal upper gastrointestinal bleeding (UGB) has important morbidity and mortality. Predicting high-risk patients for mortality and rebleeding is necessary for a treatment plan. In the present study, we aimed to define the epidemiological and etiological characteristics of patients presenting with nonvariceal UGB and to observe mortality and morbidity rates. We also aimed to compare Rockall and Glasgow-Blatchford scoring systems in predicting rebleeding and mortality. METHODS: Subjects presenting with nonvariceal UGB over a 3-year period were included. Demographic characteristics, symptoms, and signs on physical examination, laboratory data, endoscopic signs and diagnosis, interventions during hospitalization and follow-up period were recorded. Glasgow-Blatchford and Rockall scores were calculated for every participant at the first day of the admission. RESULTS: A total of 709 patients were enrolled in the study. A total of 490 of them (69.1%) were men. The mean age of the women and men was 60.7±1.2 and 58.6± 0.7 years, respectively. Melena was the most common presenting symptom. Duodenal ulcer (31%), gastric ulcer (20.7%), and erosive disease (17.6%) were the most common causes of bleeding. History of use of aspirin and/or nonsteroidal anti-inflammatory drug use were present in 63.7% of the subjects. All patients were followed up for 30th-day mortality. Overall, rebleeding and mortality rates were 11% and 7%, respectively. A Rockall score greater than 6 was the most important predictor of mortality (odds ratio:39.1) and rebleeding (odds ratio:4.7). CONCLUSION: Nonvariceal UGB patients with a Rockall score greater than 6 should undergo aggressive endoscopic treatment and inpatient care.

Chemokine and Cytokine Profiles in Patients with Hand Osteoarthritis.

BACKGROUND: The development of hand osteoarthritis (HOA) and its progression into the erosive subset are unclear, but inflammation is suspected to be the main source. To verify the involvement of inflammation in HOA pathogenesis, we evaluate serum inflammatory mediators and their association with HOA-related clinical features in patients. METHODS: 153 participants (50 non-erosive HOA patients, 54 erosive HOA patients, and 49 healthy control subjects) were included in this study. All patients underwent clinical examination, which included assessment of tender and swollen small hand joints, ultrasound (US) examination, and self-reported measures (e.g., AUSCAN or algofunctional indexes). Serum inflammatory mediators were quantified using human cytokine 27-plex immunoassay. We employed linear modelling, correlation analysis, and resampling statistics to evaluate the association of these mediators to HOA. RESULTS: We identified increased levels of nine inflammatory mediators (e.g., eotaxin, monocyte chemoattractant protein 1, interleukin-8, and tumour necrosis factor) in HOA patients compared to healthy controls. Increased mediators correlated with ultrasound findings as well as with clinically tender and swollen joint counts in patients with erosive HOA. However, none of the mediators distinguished between erosive and non-erosive HOA subtypes. CONCLUSION: Our findings support the hypothesis on the involvement of inflammation in HOA.

The Utility and Experience with Disease Biomarkers in Juvenile Onset Arthritis vs. Adult Onset Arthritis.

Juvenile idiopathic arthritis (JIA) is the most common but extremely heterogeneous group of rheumatic diseases of childhood. There are no reliable, well-researched and published biomarkers for diagnosis or monitoring in juvenile idiopathic arthritis as there are for rheumatoid arthritis (RA) in adults. Biomarkers are not utilized in classifying JIA as they are in adult RA, making the JIA classifications less clinically effective and informative. The situation presents a lost opportunity for early aggressive therapy in JIA patients. Various researchers have used diverse biomarkers anecdotally in JIA and more systematically in RA patients and have drawn inferences on their utility from their experiences. The experience with biomarkers from RA patients cannot necessarily be extrapolated for JIA patients because they are dissimilar diseases. This article reconnoiters the comparative utility of various arthritis biomarkers in adult as well as in JIA patients. In contrast to RA, JIA is in itself a diverse group of arthritis with clinically overlapping subgroups with diverse etiology. The difference in the etiopathogenesis of arthritis subgroups demands identifying subgroup-specific biomarkers for diagnosis/monitoring and subgroup-specific therapies for management. The diagnostic/prognostic value of the individual biomarker could be different in different types of arthritis and in different types of hosts. Understanding the utility of individual biomarkers and careful selection of the assay are important to achieve the best disease outcomes.

Assessment of Cardiovascular Disease Risk and Therapeutic Patterns among Urban Black Rheumatoid Arthritis Patients.

Rheumatoid arthritis (RA) patients have nearly twice the risk of cardiovascular disease (CVD) compared to the general population. We aimed to assess, in a predominantly Black population, the prevalence of traditional and RA-specific CVD risk factors and therapeutic patterns. Utilizing ICD codes, we identified 503 RA patients ≥18 years old who were seen from 2010 to 2017. Of them, 88.5% were Black, 87.9% were women and 29.4% were smokers. CVD risk factors (obesity, diabetes, hypertension, dyslipidemia) were higher than in previously reported White RA cohorts. Eighty-seven percent of the patients had at least one traditional CVD risk factor, 37% had three or more traditional CVD risk factors and 58% had RA-specific risk factors (seropositive RA, >10 years of disease, joint erosions, elevated inflammatory markers, extra-articular disease, body mass index (BMI) < 20). CV outcomes (coronary artery disease/myocardial infarction, heart failure, atrial fibrillation and stroke) were comparable to published reports. Higher steroid use, which increases CVD risk, and lesser utilization of biologics (decrease CV risk) were also observed. Our Black RA cohort had higher rates of traditional CVD risk factors, in addition to chronic inflammation from aggressive RA, which places our patients at a higher risk for CVD outcomes, calling for revised risk stratification strategies and effective interventions to address comorbidities in this vulnerable population.

Assessment of interstitial lung disease among black rheumatoid arthritis patients.

BACKGROUND: Conflicting reports exist regarding the racial and the gender distribution of rheumatoid arthritis-related interstitial lung disease (RA-ILD). In a major population study of predominately Whites, RA-ILD was reported mainly among smoker middle-aged men. However, recent data suggest that the disease is that of elderly women. Our study aimed to assess the prevalence and identify the gender differences and clinical characteristics of RA-ILD in a predominantly Black population. METHODS: Cross-sectional analysis of data obtained from the records of 1142 patients with RA diagnosis by ICD codes of which 503 cases met the inclusion criteria for the study. Eighty-six patients had chronic respiratory symptoms of cough and dyspnea and were further assessed by our multidisciplinary group of investigators. Thirty-two subjects with an established diagnosis of rheumatoid arthritis met the diagnostic criteria for interstitial lung disease. RESULTS: Of the 32 patients with RA-ILD, mean age was 62.6 ± 2.2 (± SEM), 93.7% were females, and 89% Blacks with a BMI = 29.2 (Kg/m2). Usual interstitial pneumonia (UIP) was found in 24/32 (75%) of the cases. Seventy-two percent of the RA-ILD patient had seropositive RA. Smoking history was reported in 31.3% of the cohort, gastroesophageal reflux disease (GERD) in 32.3%, and cardiovascular disease (CVD) risk factors in 65.6%. CONCLUSION: Our study indicates RA-ILD among Blacks is predominantly a disease of elderly females with higher rates of GERD and CVD risk factors. Further studies are needed to identify the pathogenetic differences accounting for the gender distribution of RA-ILD among Black and White populations.Key Points• First study to assess ILD among predominantly Black RA patients.• The prevalence of RA-associated ILD was 6.36%, affecting mostly women in their sixth decade with seropositive disease.• COPD was the most common airway disease among non-RA-ILD Black population.• GERD was found in approximately one-third of patients with RA-associated ILD versus one-fifth of those RA patients without any lung disease.

Pentosidine, an advanced glycation end-product, may reflect clinical and morphological features of hand osteoarthritis.

The study investigates pentosidine levels, an advanced glycation end-product, in patients with erosive and non-erosive hand osteoarthritis (HOA) and determine its potential association with clinical findings and imaging-defined joint damage.Pentosidine was measured by HPLC in serum and urine of 53 females with HOA (31 erosive and 22 non-erosive HOA) and normalised to the total serum protein or urinary creatinine, respectively. Pain, joint stiffness and disability were assessed by the Australian/Canadian OA hand index (AUSCAN). The hand radiographs scored according to the Kallman grading scale were assessed to determine a baseline value and reassessed after two years.The levels of urine pentosidine, but not of serum pentosidine, were higher in patients with erosive HOA than in non-erosive HOA (p=0.039). Urinary pentosidine correlated with CRP (r=0.302, p=0.031), ESR (r=0.288, p=0.041) and AUSCAN (r=0.408, p=0.003). Serum pentosidine, but not in urine, significantly correlated with the Kallman radiographic score in erosive HOA at the baseline (r=0.409, p=0.022) and after 2 years (r=0.385, p=0.032). However, when corrected for age and disease duration, only correlation between urine pentosidine and AUSCAN remained significant (r=0.397, p=0.004).Our data suggest that serum and urine pentosidine levels may relate to the distinctive clinical and morphological features of HOA.