Palindromic rheumatism: Evidence of four subtypes of palindromic-like arthritis based in either MEFV or RF/ACPA status

Objective.To analyze longterm progression to rheumatoid arthritis (RA) and the predictive value of anticitrullinated peptide/protein antibodies (ACPA) in palindromic rheumatism (PR).Methods.We selected all patients in our clinic with PR who had at least 1 ACPA measurement. We included only patients with pure PR, defined as no evidence of associated rheumatic disease at the first serum ACPA measurement. Clinical characteristics, serum ACPA levels, duration of PR until serum ACPA measurement, and total followup time were recorded. The outcome variable was the definitive diagnosis of RA. The prognostic value of ACPA status in pure PR for a definite diagnosis of RA was analyzed by different statistical methods.Results.Seventy-one patients (54 women/17 men) with a PR diagnosis were included. Serum ACPA were positive in 52.1%. After a mean followup of 7.6 ± 4.7 years since the first ACPA measurement, 24 patients (33.8%) progressed to chronic disease: 22% RA, 5.6% systemic lupus erythematosus, and 5.6% other diseases. The positive likelihood ratio of ACPA status for RA was 1.45, and the area under the receiver-operating characteristic curve of ACPA titers was 0.60 (95% CI 0.45−0.75). Progression to RA was more frequently seen in ACPA-positive than in ACPA-negative patients (29.7% vs 14.7%), but the difference was not significant (hazard ratio 2.46, 95% CI 0.77−7.86). Mean ACPA levels of patients with pure PR did not differ significantly from those of patients who progressed to RA.Conclusion.ACPA are frequently found in the sera of patients with PR, and a significant proportion of these patients do not progress to RA in the long term.

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Palindromic Rheumatism: Autoimmunity, Inflammation or Both? Evidence for Four Subtypes of Palindromic-Like Arthritis Based in Either MEFV or RF/ACPA Status

SSRN Electronic Journal ◽

10.2139/ssrn.3762515 ◽

2021 ◽

Author(s):

Andrea M. Cuervo ◽

Raimon Sanmarti ◽

Julio Ramírez ◽

Raúl Castellanos ◽

José Inciarte-Mundo ◽

...

Keyword(s):

Palindromic Rheumatism ◽

Acpa Status

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Is There Subclinical Synovitis in Patients with Palindromic Rheumatism in the Intercritical Period? A Clinical and Ultrasonographic Study According to Anticitrullinated Protein Antibody Status

The Journal of Rheumatology ◽

10.3899/jrheum.131545 ◽

2014 ◽

Vol 41 (8) ◽

pp. 1650-1655 ◽

Cited By ~ 9

Author(s):

Sonia Cabrera-Villalba ◽

Julio Ramirez ◽

Georgina Salvador ◽

Virginia Ruiz-Esquide ◽

M. Victoria Hernández ◽

...

Keyword(s):

Clinical Phenotype ◽

Power Doppler ◽

Disease Onset ◽

Control Group ◽

Palindromic Rheumatism ◽

Younger Age ◽

Healthy Control ◽

Acpa Status ◽

Active Synovitis ◽

Subclinical Synovitis

Objective.To investigate the presence of subclinical synovitis by ultrasound (US) and the clinical phenotype in patients with palindromic rheumatism (PR) according to anticitrullinated protein antibody (ACPA) status.Methods.Fifty-four patients with PR were studied. Clinical, demographic, serological, and therapeutic characteristics were compared in ACPA-positive and ACPA-negative patients. US searching for synovial hypertrophy (SH) and power Doppler signal (PDUS) in 22 joints of the hands was performed in the intercritical period. The results were compared according to ACPA status and with a healthy control group (n = 30). In 10 patients, US was performed during the joint attack.Results.Most patients were female (63%) with a mean disease duration of 11.6 ± 10.7 years. Thirty-six patients (66.7%) were ACPA-positive. ACPA-positive patients had a shorter duration of attacks, a younger age, and less knee involvement at disease onset. US examination showed SH grade ≥ 1 in 79.6% of patients with PR and 50% of controls. Significant US results (SH ≥ 2 or PDUS) were observed in 2.7% and 1.4% of joints assessed and in 33% and 25.9% of patients with PR, respectively. Only 4 patients (7.4%) had US active synovitis (SH ≥ 2 plus PDUS) in at least 1 joint. US assessment showed no significant differences between ACPA-positive and ACPA-negative patients. PDUS was observed in 7 out of 10 patients during attacks.Conclusion.Some differences emerged in the clinical phenotype of PR according to ACPA status. Most patients with PR do not have US subclinical synovitis in the intercritical period, even those who are ACPA-positive.

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High disease activity is associated with higher blood pressure in recent onset rheumatoid arthritis patients, post-hoc analyses of IMPROVED study

European Journal of Preventive Cardiology ◽

10.1093/eurjpc/zwab061.388 ◽

2021 ◽

Vol 28 (Supplement_1) ◽

Author(s):

M Gegenava ◽

SA Bergstra ◽

H Maassen ◽

CF Allaart

Keyword(s):

Rheumatoid Arthritis ◽

Blood Pressure ◽

Disease Activity ◽

Classification Criteria ◽

Recent Onset ◽

American College Of Rheumatology ◽

Cardiovascular Morbidity And Mortality ◽

The Difference ◽

Post Hoc ◽

Acpa Status

Abstract Funding Acknowledgements Type of funding sources: None. Background Rheumatoid arthritis (RA) is a chronic autoimmune disease with a high prevalence of cardiovascular morbidity and mortality. Purpose: purpose of our project was to investigate the association between disease activity and systolic and diastolic blood pressure (SBP, DBP) in patients with recent-onset rheumatoid arthritis (RA 2010 criteria) or undifferentiated arthritis (UA) who were treated to target disease activity score (DAS)<1.6 in the IMPROVED study. Methods: The associations between disease activity and SBP/DBP were tested for 610 patients (364 RA, 246 UA), cross-sectionally and over time. GEE analyses were performed with both SBP and DBP as outcome measures and disease activity categories (DAS<1.6;>1.6 but ≤2.4; >2.4), CRP level, treatment arms or the number of visits on a certain drug as potential predictors in separate analyses. Separate analyses tested potential contributions of gender, anti-cyclic citrullinated peptide antibodies (ACPA) status, and fulfilling the 2010 ACR/EULAR (American college of rheumatology/ European league against rheumatism) classification criteria. In addition association of BP with various levels of disease activity was tested with T-test. Results: At the baseline mean (SD) SBP was 133 (20) and DBP mean (SD) was 80 (10). SBP > 140mm Hg was observed in 40% of patients and DBP > 90 mm Hg in 21% of patients. SBP and DBP statistically significantly decreased during 5 years follow up (mainly during year 1), but the difference in mm Hg was small. Estimates from GEE analysis showed that patients with high DAS >2.4 (HDAS) had a statistically significantly higher SBP (average 3 mm Hg higher, 95% CI 1.7; 4.2, p < 0.01), than the patients in with DAS ≤2.4. ANOVA analyses showed a statistically significant association between SBP and DAS. In addition, post hoc analyses showed that patients with HDAS had a statistically significantly higher SBP (mean (SD) 132 (19) than the patients with DAS < 1.6 (remission) (mean (SD) 129 (20), p < 0.01), and patients in LDAS but DAS≥1.6 had a statistically significantly higher SBP (mean (SD) 131 (19) than the patients in remission (mean (SD) 129 (20), p = 0.02) (Figure 1), whereas no association was found between DAS category and DBP. Gender, ACPA status or fulfilling the 2010 classification criteria did not influence the relation between DAS and blood pressure. Conclusions: In patients with RA or UA, a higher DAS is associated with higher blood pressure, but the clinical impact is unclear. Abstract Figure 1

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POS0387 ACPA STATUS CORRELATES WITH DIFFERENTIAL IMMUNE PROFILE OF RHEUMATOID ARTHRITIS PATIENTS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.1885 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 423.2-424

Author(s):

A. Floudas ◽

M. Canavan ◽

T. McGarry ◽

V. Krishna ◽

S. Nagpal ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Synovial Tissue ◽

Peripheral Blood ◽

Flow Cytometric Analysis ◽

Algorithm Analysis ◽

Treat To Target ◽

Tnf Α ◽

Acpa Status

Background:Rheumatoid arthritis (RA) is a progressive erosive autoimmune disease that affects 1% of the world population. Anti-citrullinated protein autoantibodies (ACPA) are routinely used for the diagnosis of RA, however 20-30% of patients are ACPA negative. ACPA status is a delineator of RA disease endotypes with similar clinical manifestation but potentially different pathophysiology. Elucidating the underlying mechanisms of disease pathogenesis could inform a treat to target approach for both ACPA-positive and ACPA-negative RA patients.Objectives:To identify peripheral blood and synovial tissue immune population differences that associate with RA disease endotype.To identify unique RA patient synovial tissue gene signatures and enriched pathways that correlate with ACPA status.Methods:Detailed high dimensionality flow cytometric analysis with supervised and unsupervised algorithm analysis of ACPApos and ACPAneg RA patient peripheral blood and synovial tissue single cell suspensions. Ex vivo peripheral blood and synovial tissue T cell stimulation and cytokine production characterisation. RNAseq analysis with specific pathway enrichment analysis of APCApos and ACPAneg RA patient synovial tissue biopsies.Results:Detailed profiling based on high dimensionality flow cytometric analysis of key peripheral blood and synovial tissue immune populations including B cells, T follicular helper (Tfh) cells, T peripheral helper cells (Tph) and CD4 T cell proinflammatory cytokine responses with supervised and unsupervised algorithm analysis revealed unique RA patient peripheral blood B cell and Tfh cell profiles. ACPApos RA patients were characterised by significantly (*P=0.03) increased frequency of Tfh (CXCR5+CD4+) cells and distinct clustering influenced by increased switched (IgD-CD27+) and DN (IgD-CD27-) memory B cells compared to APCAneg RA patients. Surprisingly synovial tissue B cell subpopulation distribution was similar between ACPAneg and ACPApos RA patients, with significant accumulation of switched and double negative memory B cells, highlighting a key role for specific B cell subsets in both disease endotypes. Interestingly, synovial tissue CD4 T cell proinflammatory cytokine (TNF-α, IFN-γ, IL-2, GM-CSF, IL-17A, IL-22, IL-4) production was markedly different between ACPAneg and APCApos RA patients with hierarchical clustering and PCA analysis revealing endotype specific cytokine profiles with ACPAneg RA patient synovial T cells showing increased TNF-α (P=0.01) expression. RNAseq analysis of RA patient synovial tissue revealed significant disease endotype specific gene signatures with specific enrichment for B cell receptor signalling and T cell specific pathways in ACPApos compared to ACPAneg RA patients. Additionally, significantly different chemokine receptor expression based on RA patient ACPA status was observed with increased CXCR3 (P<0.001), CCR7 (P=0.002), and CCR2 (P=0.004) but decreased CXCR7 (P=0.007) expression in APCApos compared to ACPAneg RA patient synovial biopsies.Conclusion:ACPA status associates with unique synovial tissue immune cell and gene profile signatures highlighting differences in the underlying immunological mechanisms involved, therefore reinforcing the need for a treat to target approach for both endotypes of RA.Figure 1.RNAseq analysis of synovial tissue biopsies revealed specific T cell related pathway enrichment in ACPA positive compared to ACPA negative RA patients (n=50, analysis performed with the DESq2 and pathfindeR pipelines in R).Disclosure of Interests:Achilleas Floudas: None declared, Mary Canavan: None declared, Trudy McGarry Employee of: Novartis, Vinod Krishna Employee of: Janssen, Sunil Nagpal Employee of: Janssen, GSK, Douglas Veale Speakers bureau: Abbvie, Janssen, Novartis, MSD, Pfizer, UCB, Consultant of: Abbvie, Janssen, Novartis, MSD, Pfizer, UCB, Grant/research support from: Janssen, Abbvie, Pfizer, UCB, Ursula Fearon Speakers bureau: Abbvie, Grant/research support from: Janssen, Abbvie, Pfizer, UCB

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OP0073 RISK OF DEVELOPING RHEUMATIC DISEASES IN PATIENTS WITH PALINDROMIC RHEUMATISM IN SOUTH KOREA: A NATION-WIDE POPULATION-BASED STUDY

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3664 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 49.2-49

Author(s):

J. K. Ahn ◽

J. Hwang ◽

J. Lee ◽

H. Kim ◽

G. H. Seo

Keyword(s):

Health Insurance ◽

South Korea ◽

Rheumatic Diseases ◽

Index Date ◽

Claims Data ◽

Population Based ◽

Palindromic Rheumatism ◽

Psoriatic Arthropathy ◽

Increased Risk ◽

The Mean

Background:Palindromic rheumatism (PR) has known to be three patterns of disease course: clinical remission of attacks, persistent attacks, and evolution to chronic arthritis or systemic disease. The spectrum in progression to chronic diseases of PR, however, is quite variable; rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjögren’s syndrome (SjS), ankylosing spondylitis (AS), relapsing polychondritis (RP), Behçet’s disease (BD), sarcoidosis, and psoriatic spondylitis and arthropathy. Because of the small numbers in case-control studies and too aged investigations, now we needs to shed new light on the fate of PR.Objectives:The aim was to investigate the epidemiology of PR and the risk of developing various rheumatic diseases compared with non-PR individuals, employing the National Health Insurance Service (NHIS) medical claims data, which covers all medical institutions of South Korea.Methods:The study used 2007-2018 claims data from the Korean Health Insurance Review and Assessment Service (HIRA). The identified 19,724 PR patients from 2010 to 2016 were assessed for the incidence rate (IR) compared with the population in the given year by 100,000 person-year (py). The date of diagnosis was the index date. After matching with non-PR individuals (1:10) for age, sex and the year of index date, we calculated the hazard ratios (HRs) with 95% confidence intervals (CIs). The risk of developing the various rheumatic diseases and adult immunodeficiency syndrome (AIDS) as the outcome diseases in PR cohort was estimated. This risk was compared with that of matched non-PR cohort.Results:Of 19,724 PR patients (8,665 males and 11,059 females), the mean age was 50.2 ± 14.9 years (47.7 ± 14.4 years in males and 52.6 ± 14.9 years in females,p< 0.001). The ratio of male to female patients with PR was approximately 1:1.28. The annual IR of PR was 7.02 (6.92-7.12) per 100,000 py (6.22 (6.09-6.35) and 7.80 (7.66-7.95) per 100,000 py in males and females, respectively). The mean duration to develop the outcome diseases was significantly shorter in PR cohort compared that of non-PR cohort (19.4 vs. 35.8 months,p< 0.001). The most common outcome disease was RA (7.34% of PR patients; 80.0% of total outcome diseases), followed by AS, SLE, BD, SjS, MCTD, DM/PM, SSc, RP, psoriatic arthropathy, and AIDS in PR cohort. The patients with PR had an increased risk of RA (HR 46.6, 95% CI [41.1-52.7]), psoriatic arthropathy (44.79 [15.2-132.4]), SLE (24.5 [16.2-37.2]), MCTD (22.0 [7.7-63.3]), BD (21.0 [13.8-32.1]), SjS (12.4 [8.5-17.9]), AS (9.0 [6.7-12.2]), DM/PM (6.1 [2.6-14.8]), and SSc (3.8 [1.5-9.6]) but not of AIDS. The risk of developing RA was greater in male patients (HR 58.9, 95% CI [45.6-76.2] vs. 43.2 [37.4-49.8],pfor interaction = 0.037) while female patients encountered a higher risk of developing AS (15.8 [8.9-28.1] vs. 7.2 [5.0-10.3],pfor interaction = 0.023). The risk of developing RA, SLE, SjS, and BD were significantly more highly affected in younger age (pfor interaction < 0.001, = 0.003, 0.002, and 0.017, at each).Conclusion:This nationwide, population-based cohort study demonstrated that patients with PR had an increased risk of developing various rheumatic diseases, not only RA but also psoriatic arthropathy. Therefore, patients with PR needs to be cautiously followed up for their potential of diverse outcome other than RA: RA, SLE, SjS, and BD in younger patients, RA in males, and AS in females, in particular.Disclosure of Interests:None declared

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POS0392 PRESENCE OF FOUR SERUM AUTOANTIBODIES ASSOCIATES WITH THE ACPA STATUS IN EARLY RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2514 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 425.3-426

Author(s):

L. Lourido ◽

C. Ruiz-Romero ◽

L. Collado ◽

M. Hansson ◽

L. Klareskog ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Early Diagnosis ◽

Specific Antigen ◽

Coiled Coil ◽

Population Based ◽

Mitogen Activated Protein Kinase ◽

Absolute Deviation ◽

Swedish Population ◽

Early Ra ◽

Acpa Status

Background:The presence of anti-citrullinated protein antibodies (ACPAs) is a hallmark of rheumatoid arthritis (RA) that precede the development of the disease by years and is used for its clinical diagnosis. However, there are RA subjects that test negative for ACPA and thus the early diagnosis on these patients may be delayed. Furthermore, the presence or absence of ACPA in RA supports the hypothesis that on these two subsets of patients underlie different pathogenesis and clinical outcomes.Objectives:In this work, we searched for serum autoantibodies useful to assist the early diagnosis of ACPA-seronegative RA and its management.Methods:We profiled the serum autoantibody repertoire of 80 ACPA-seronegative and 80 ACPA-seropositive RA subjects from the Swedish population-based Epidemiological Investigation of RA (EIRA) cohort. A suspension bead array platform built on protein fragments within Human Protein Atlas and selected from an initial untargeted screening using arrays containing 2660 total antigens was employed to identify IgG and IgA serum autoantibodies. A validation phase on antigen suspension bead arrays was carried out on another set of samples from EIRA containing 386 ACPA-seropositive, 358 ACPA-seronegative and 372 randomly selected control subjects of the same age and sex. A sample-specific threshold based on 20 times the median absolute deviation plus the median of all signals was selected to determine the reactivity of samples. The Wilcoxon rank sum test and Fisher’s test were applied for the comparison of autoantibody levels and reactivity frequencies between the groups.Results:Our data revealed four antigens associated with the ACPA status (Table 1). Testis-specific Y-encoded-like protein 4 (TSPYL4) showed significantly higher IgG reactivity frequency in ACPA-seronegative subjects compared to ACPA-seropositive (8% vs. 3%; P<0.05). Significant differences at IgG autoantibody levels (P<0.05) were also observed between ACPA-seronegative subjects and controls for this specific antigen. Significantly higher IgG autoantibody levels (P<0.05) towards another antigen, dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6), were also observed in ACPA-seronegative subjects compared to ACPA-seropositive and controls. In contrast, we found significantly higher IgG autoantibody levels (P<0.05) in ACPA-seropositive individuals compared to ACPA-seronegative and controls towards two antigens, anosmin-1 (ANOS-1) and muscle related coiled-coil protein (MURC). ANOS-1 shows also significantly higher IgG reactivity frequency in ACPA-seropositive individuals compared to ACPA-seronegative and controls (22%, 9% and 6% respectively; P<0.05). Interestingly, three out of the four antigens discovered to be associated with the ACPA status in early RA are highly expressed in lungs and heart, two of the main extraarticular sites affected in RA. No significant differences were observed at IgA levels for any of the antigens analyzed.Table 1.Scheme of the different phases of the study, the features within each phase and the results. The reactivity to four antigens allows to distinguish ACPA-seronegative (ACPA-), ACPA seropositive (ACPA+) and controls.PhasesUntargeteddiscoveryTargeteddiscoveryTargetedvalidationNumber of samples80 ACPA-80 ACPA-358 ACPA-372 Controls80 ACPA+80 ACPA+386 ACPA+Antigen arrayplatformPlanararraysSuspensionbead array 1Suspensionbead array 2Number of antigens26606227Number of candidatebiomarkers6227 4 (TSPYL4,MAP2K6,ANOS1,MURC)Conclusion:Upon further validation in other early RA sample cohorts, our data suggest the measurement of these four autoantibodies may be useful for the early diagnosis of ACPA-seronegative RA and give insight into the pathogenesis of the different RA subsets.Characters from table content including title and footnotes:Disclosure of Interests:None declared

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