Immunogenetic Risks of Anti-Cyclical Citrullinated Peptide Antibodies in a North American Native Population with Rheumatoid Arthritis and Their First-degree Relatives

Objective.To determine the prevalence of anti-cyclic citrullinated peptide (anti-CCP) antibodies in unaffected relatives of North American Native probands with rheumatoid arthritis (RA); and the associations of the shared epitope (SE) and HLA-DRB1*0901 with RA and anti-CCP antibodies.Methods.The subjects were RA probands, affected relatives, unaffected first-degree (FDR) and more distant relatives, and unaffected controls from the same population. HLA-DRB1 typing was determined by DNA sequencing and anti-CCP antibodies were determined by ELISA.Results.DRB1*0901, SE, and SE/DRB1*0901 genotypes were all associated with RA. SE/DRB1*0901, but not other SE genotypes, was associated with disease onset at age < 16 years. The frequency of anti-CCP antibodies was 82% in RA probands, 17% in FDR, 11% in more distant relatives, and 3% in controls. Among unaffected relatives, a significant increased risk of anti-CCP was associated with SE/DRB1*0901 genotype, but not with SE.Conclusion.An independent association of the non-SE allele DRB1*0901 with RA was confirmed in this population, and this allele in combination with a SE allele was associated with younger age at disease onset. FDR of RA probands have a higher prevalence of anti-CCP antibodies than more distant relatives and unrelated controls, suggesting a gradient of risk for disease development. Immunogenetic risks may act early in disease pathogenesis at the level of initiation of RA autoantibody formation; however, it is not clear what additional genetic and environmental risks are involved in progression to clinical disease.

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Mortality following new-onset Rheumatoid Arthritis: has modern Rheumatology had an impact?

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2017-212131 ◽

2017 ◽

Vol 77 (1) ◽

pp. 85-91 ◽

Cited By ~ 25

Author(s):

Marie Holmqvist ◽

Lotta Ljung ◽

Johan Askling

Keyword(s):

Rheumatoid Arthritis ◽

General Population ◽

Excess Mortality ◽

Disease Onset ◽

Mortality Rates ◽

Calendar Time ◽

Risk Of Death ◽

Quality Register ◽

Increased Risk ◽

New Onset

ObjectiveTo investigate if, and when, patients diagnosed with rheumatoid arthritis (RA) in recent years are at increased risk of death.MethodsUsing an extensive register linkage, we designed a population-based nationwide cohort study in Sweden. Patients with new-onset RA from the Swedish Rheumatology Quality Register, and individually matched comparators from the general population were followed with respect to death, as captured by the total population register.Results17 512 patients with new-onset RA between 1 January 1997 and 31 December 2014, and 78 847 matched general population comparator subjects were followed from RA diagnosis until death, emigration or 31 December 2015. There was a steady decrease in absolute mortality rates over calendar time, both in the RA cohort and in the general population. Although the relative risk of death in the RA cohort was not increased (HR=1.01, 95% CI 0.96 to 1.06), an excess mortality in the RA cohort was present 5 years after RA diagnosis (HR after 10 years since RA diagnosis=1.43 (95% CI 1.28 to 1.59)), across all calendar periods of RA diagnosis. Taking RA disease duration into account, there was no clear trend towards lower excess mortality for patients diagnosed more recently.ConclusionsDespite decreasing mortality rates, RA continues to be linked to an increased risk of death. Thus, despite advancements in RA management during recent years, increased efforts to prevent disease progression and comorbidity, from disease onset, are needed.

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Radiological outcome in rheumatoid arthritis is predicted by presence of antibodies against cyclic citrullinated peptide before and at disease onset, and by IgA-RF at disease onset

Annals of the Rheumatic Diseases ◽

10.1136/ard.2005.041376 ◽

2006 ◽

Vol 65 (4) ◽

pp. 453-458 ◽

Cited By ~ 147

Author(s):

E Berglin

Keyword(s):

Rheumatoid Arthritis ◽

Disease Onset ◽

Radiological Outcome ◽

Cyclic Citrullinated Peptide ◽

Citrullinated Peptide

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Plasma 25,OH Vitamin D Concentrations Are Not Associated with Rheumatoid Arthritis (RA)-related Autoantibodies in Individuals at Elevated Risk for RA

The Journal of Rheumatology ◽

10.3899/jrheum.080764 ◽

2009 ◽

Vol 36 (5) ◽

pp. 943-946 ◽

Cited By ~ 32

Author(s):

MARIE FESER ◽

LEZLIE A. DERBER ◽

KEVIN D. DEANE ◽

DENNIS C. LEZOTTE ◽

MICHAEL H. WEISMAN ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Vitamin D ◽

Elevated Risk ◽

Rheumatoid Factors ◽

Increased Risk ◽

Vitamin D Levels ◽

25 Oh Vitamin D ◽

Negative Controls ◽

Citrullinated Peptide ◽

Peptide Antibodies

Objective.To evaluate the association between rheumatoid arthritis (RA)-related autoantibodies and plasma 25,OH vitamin D in subjects at risk for RA.Methods.In 1210 subjects without RA, 76 were positive for anti-cyclic citrullinated peptide antibodies or for at least 2 rheumatoid factors (RF; by nephelometry: RF-IgM, RF-IgG, RF-IgA). 25,OH vitamin D was measured in these cases and 154 autoantibody-negative controls from this cohort.Results.25,OH vitamin D levels did not differ between cases and controls (adjusted OR 1.23, 95% CI 0.93–1.63).Conclusion.Vitamin D concentrations are not associated with RA-related autoimmunity in unaffected subjects at increased risk for RA.

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Exposure to passive smoking and rheumatoid arthritis risk: results from the Swedish EIRA study

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2018-212973 ◽

2018 ◽

Vol 77 (7) ◽

pp. 970-972 ◽

Cited By ~ 12

Author(s):

Anna Karin Hedström ◽

Lars Klareskog ◽

Lars Alfredsson

Keyword(s):

Rheumatoid Arthritis ◽

Passive Smoking ◽

Population Based ◽

Rheumatoid Arthritis Risk ◽

Increased Risk ◽

Study Population ◽

Never Smokers ◽

Incident Cases ◽

Citrullinated Peptide ◽

Control Study

IntroductionSmoking has consistently been associated with increased risk of developing rheumatoid arthritis (RA). The aim of this study was to estimate the influence of passive smoking on the risk of developing anti-cyclic citrullinated peptide antibodies (ACPA)-positive and ACPA-negative RA.MethodsA population-based case–control study using incident cases of RA was performed in Sweden, and the study population in this report was restricted to include never-smokers (589 cases, 1764 controls). The incidence of RA among never-smokers who had been exposed to passive smoking was compared with that of never-smokers who had never been exposed, by calculating the OR with a 95% CI employing logistic regression.ResultsNo association was observed between exposure to passive smoking and RA risk (OR 1.0, 95% CI 0.8 to 1.2 for ACPA-positive RA, and OR 0.9, 95% CI 0.7 to 1.2, for ACPA-negative RA). No suggestion of a trend between duration of passive smoking and RA risk was observed.DiscussionsNo association was observed between exposure to passive smoking and RA risk, which may be explained by a threshold below which no association between smoke exposure and RA occurs.

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Rheumatoid Arthritis in a North American Native Population: Longitudinal Followup and Comparison with a White Population

The Journal of Rheumatology ◽

10.3899/jrheum.091452 ◽

2010 ◽

Vol 37 (8) ◽

pp. 1589-1595 ◽

Cited By ~ 37

Author(s):

CHRISTINE A. PESCHKEN ◽

CAROL A. HITCHON ◽

DAVID B. ROBINSON ◽

IRENE SMOLIK ◽

CHERYL R. BARNABE ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

North American ◽

Disease Onset ◽

Health Assessment ◽

Joint Involvement ◽

Tender Joint ◽

Academic Center ◽

Large Joint ◽

Treatment Data ◽

White Patients

Objective.To describe differences in phenotype and outcomes in North American Native (NAN) patients with rheumatoid arthritis (RA) followed prospectively and compared to white patients with RA.Methods.Patients from a single academic center were followed over 20 years using a custom database. Data included diagnoses, year of disease onset, ethnicity, modified Health Assessment Questionnaire (mHAQ) score, patient and physician global scores, tender and swollen joint counts, treatment, serology, and erythrocyte sedimentation rate (ESR). Records of all white (n = 1315) and NAN (n = 481) patients with RA were abstracted. Cumulative treatment data and clinical measures were compared.Results.Disease duration was longer in white patients compared to NAN patients (16 ± 11 vs 14 ± 10 years, respectively; p = 0.03). Onset age was 34 years for NAN patients and 43 years for white patients (p < 0.001). NAN patients were more frequently positive for rheumatoid factor (89% vs 74%; p < 0.001) and antinuclear antibody (57% vs 21%; p < 0.001). Although mean tender joint counts and swollen joint counts were similar, NAN patients had higher Lansbury scores (weighted joint count; 66.5 vs 49.7; p < 0.001), mHAQ scores (1.1 vs 0.9; p = 0.001), and ESR (31 vs 25 mm/h; p < 0.012). NAN patients had more frequent knee (53% vs 34%; p < 0.001) and elbow (62% vs 48%; p = 0.007) involvement. Compared to white patients, NAN patients took a higher lifetime number of disease-modifying antirheumatic drugs (3.2 ± 1.9 vs 2.2 ± 1.7; p < 0.001), had more combination therapy (38% vs 29%; p = 0.002), and had more frequent prednisone use (55% vs 39%; p < 0.001).Conclusion.Compared to white patients, NAN patients with RA develop disease earlier, are more frequently seropositive, have greater large joint involvement, and greater disease burden, although treatment is more aggressive. These differences are present early and persist throughout the disease course.

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Validation of a prediction rule for development of rheumatoid arthritis in patients with early undifferentiated arthritis

Annals of the Rheumatic Diseases ◽

10.1136/ard.2008.092676 ◽

2008 ◽

Vol 68 (9) ◽

pp. 1482-1485 ◽

Cited By ~ 30

Author(s):

B Kuriya ◽

C K Cheng ◽

H M Chen ◽

V P Bykerk

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Functional Status ◽

Rheumatoid Factor ◽

Prediction Rule ◽

Undifferentiated Arthritis ◽

Increased Risk ◽

Baseline Characteristics ◽

Poor Functional Status ◽

Citrullinated Peptide

Objective:To validate a model which predicts progression from undifferentiated arthritis (UA) to RA, in a Canadian UA cohort.Methods:The prediction rule, comprising variables which are scored from 0 to 13, with higher scores reflecting an increased risk of RA, was applied to baseline characteristics of all patients with UA. Progression to RA was determined at 6 months.Results:105 patients were identified. By 6 months, 80 (76%) had developed RA while 25 (24%) had developed another diagnosis. Number of tender and swollen joints, rheumatoid factor positivity, anti-cyclic citrullinated peptide positivity, poor functional status and high disease activity were associated with development of RA (p<0.01). Median prediction score was 8.0 for progressors, 5.0 for non-progressors. With these cut-off points, 18 (72%) patients with scores ⩽5 did not develop RA, while 35 (97%) with scores ⩾8 did develop RA.Conclusions:High scores in our cohort predicted those who progressed to RA by 6 months. Baseline scores ⩾8 corresponded with higher rates of progression.

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Comparison of Threshold Cutpoints and Continuous Measures of Anti-Cyclic Citrullinated Peptide Antibodies in Predicting Future Rheumatoid Arthritis

The Journal of Rheumatology ◽

10.3899/jrheum.080895 ◽

2009 ◽

Vol 36 (4) ◽

pp. 706-711 ◽

Cited By ~ 64

Author(s):

LORI B. CHIBNIK ◽

LISA A. MANDL ◽

KAREN H. COSTENBADER ◽

PETER H. SCHUR ◽

ELIZABETH W. KARLSON

Keyword(s):

Rheumatoid Arthritis ◽

Conditional Logistic Regression ◽

Menopausal Status ◽

Reproductive Factors ◽

Continuous Variable ◽

Health Study ◽

Cyclic Citrullinated Peptide ◽

Increased Risk ◽

Sensitivity Specificity ◽

Citrullinated Peptide

Objective.Anti-cyclic citrullinated peptide (anti-CCP) antibodies are strongly associated with increased risk of rheumatoid arthritis (RA).While the anti-CCP level is commonly dichotomized for clinical use, the best threshold for and utility of the titer as a continuous variable to predict development of RA are uncertain.Methods.Using data from the Nurses’ Health Study and Nurses’ Health Study II longitudinal cohorts, we examined the sensitivity, specificity, and hazard of RA at various thresholds of the anti-CCP. Incident RA was confirmed using the Connective Tissue Disease Screening Questionnaire and medical record review in 93 women from among 62,437 participants with blood samples. Three controls per case were randomly chosen, matching on cohort, age, and menopausal status. Stored plasma was tested for anti-CCP antibodies with the second-generation Diastat™ ELISA. Five threshold values were assessed for sensitivity, specificity, and time to diagnosis of RA. Hazard of RA was assessed with conditional logistic regression models adjusting for smoking and reproductive factors.Results.Using the suggested threshold of > 5 U/ml for anti-CCP positivity, specificity was 100%, but sensitivity was only 28%. A threshold of > 2 U/ml had a higher sensitivity (51%), and similar specificity (80%), with an odds ratio of 11.2 (95% confidence interval 4.7–26.9) for RA. Anti-CCP level as an ordinal variable was strongly associated with time to RA onset, with higher values predicting shorter time to RA onset.Conclusion.A lower threshold for anti-CCP positivity was more sensitive in predicting RA development. Higher ranges of the level were informative in predicting time to RA onset.

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The Multifaceted Aspects of Interstitial Lung Disease in Rheumatoid Arthritis

BioMed Research International ◽

10.1155/2013/759760 ◽

2013 ◽

Vol 2013 ◽

pp. 1-13 ◽

Cited By ~ 41

Author(s):

Lorenzo Cavagna ◽

Sara Monti ◽

Vittorio Grosso ◽

Nicola Boffini ◽

Eva Scorletti ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Interstitial Lung Disease ◽

Lung Disease ◽

Interstitial Pneumonia ◽

Usual Interstitial Pneumonia ◽

Disease Process ◽

Tnf Alpha ◽

Increased Risk ◽

Nonspecific Interstitial Pneumonia ◽

Citrullinated Peptide

Interstitial lung disease (ILD) is a relevant extra-articular manifestation of rheumatoid arthritis (RA) that may occur either in early stages or as a complication of long-standing disease. RA related ILD (RA-ILD) significantly influences thequoad vitamprognosis of these patients. Several histopathological patterns of RA-ILD have been described: usual interstitial pneumonia (UIP) is the most frequent one, followed by nonspecific interstitial pneumonia (NSIP); other patterns are less commonly observed. Several factors have been associated with an increased risk of developing RA-ILD. The genetic background plays a fundamental but not sufficient role; smoking is an independent predictor of ILD, and a correlation with the presence of rheumatoid factor and anti-cyclic citrullinated peptide antibodies has also been reported. Moreover, bothexnovooccurrence and progression of ILD have been related to drug therapies that are commonly prescribed in RA, such as methotrexate, leflunomide, anti-TNF alpha agents, and rituximab. A greater understanding of the disease process is necessary in order to improve the therapeutic approach to ILD and RA itself and to reduce the burden of this severe extra-articular manifestation.

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Autoantibody profiling in patients with very early rheumatoid arthritis: a follow-up study

Annals of the Rheumatic Diseases ◽

10.1136/ard.2008.100677 ◽

2009 ◽

Vol 69 (01) ◽

pp. 169-174 ◽

Cited By ~ 33

Author(s):

V Nell-Duxneuner ◽

K Machold ◽

T Stamm ◽

G Eberl ◽

H Heinzl ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Final Diagnosis ◽

Early Arthritis ◽

Erosive Disease ◽

Follow Up Study ◽

Number Of Patients ◽

Increased Risk ◽

Time Courses ◽

Citrullinated Peptide

Objective:To investigate time courses of autoantibody profiles in patients with early arthritis.Patients and methods:A total of 200 patients with very early arthritis (<3 months duration), among them 102 patients with a final diagnosis of rheumatoid arthritis (RA) and 98 with other rheumatic diseases, were followed up for several years. First follow-up testing was performed in all patients (mean 5 months from baseline), and 82 patients with RA and 35 patients without RA were available for last follow-up testing (mean 32 months from baseline). IgM-rheumatoid factor (RF) was measured by nephelometry, IgA-RF, IgG-RF and anti-cyclic citrullinated peptide antibodies (ACPA) by ELISA, and anti-RA33 antibodies were determined by immunoblotting.Results:At baseline, IgA-RF was detectable in 29% and IgG-RF in 14% of patients with RA while IgM-RF>50 IU/ml (RF50) was positive in 45% of the patients; specificities were 97%, 99% and 96%, respectively. However, the vast majority of patients positive for IgA-RF or IgG-RF were also positive for RF50 or ACPA. During follow-up, the prevalence of ACPA slightly increased while prevalence of all RF subtypes and anti-RA33 decreased. Remarkably, the number of patients positive for RF50 and/or ACPA remained constant, and these patients had a highly increased risk for developing erosive disease in contrast to patients solely positive for anti-RA33.Conclusions:Testing for RF subtypes did not provide additional diagnostic information. Patients positive for RF50 and/or ACPA had an unfavourable prognosis, irrespectively of changes in the antibody profile during follow-up, whereas anti-RA33 positivity was inversely associated with erosiveness at baseline and at later time points.

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