Utility of testing for third-generation anticyclic citrullinated peptide (anti-CCP3) antibodies in individuals who present with new musculoskeletal symptoms but have a negative second-generation anticyclic citrullinated peptide (anti-CCP2) antibody test.

OBJECTIVES: To investigate the role of third-generation anticyclic citrullinated peptide (anti-CCP3) antibodies in predicting progression to inflammatory arthritis (IA) in individuals with new musculoskeletal (MSK) symptoms and a negative second-generation anti-CCP antibody test (anti-CCP2-). METHODS: 469 anti-CCP2- individuals underwent baseline anti-CCP3 testing (QUANTA Lite CCP3; Inova Diagnostics) and received a post enrolment 12-month questionnaire. A rheumatologist confirmed or excluded diagnosis of IA. Univariable/multivariable analyses were performed to assess the value of anti-CCP3 in predicting IA development in these anti-CCP2- individuals. RESULTS: Only 16/469 (3.4%) anti-CCP2- individuals had a positive anti-CCP3 test. Of these 16 individuals, 4 developed IA. In addition, 61/469 (13.0%) anti-CCP2- individuals self-reported, to have developed, IA. Progression was confirmed in 43/61 of them (70.5%); of whom 30/43 (69.8%) and 13/43 (30.2%) were given a diagnosis of IA and rheumatoid arthritis (RA), respectively. In qualitative univariable analysis, anti-CCP3 positivity was associated with self-reported progression (p<0.01) and IA (p=0.03), but not with RA. Anti-CCP3 levels differed significantly between progressors and non-progressors (p<0.01) for all three categories. At the manufacturer's cut-off, OR for progression ranged from 2.4 (95% CI 0.5 to 18.6; RA) to 7.5 (95% CI 2.3 to 24.0; self-reported progression). Interestingly, when cut-offs for anti-CCP3 were optimised, lower values (≥5 units) significantly increased the OR for progression in all three categories. In multivariable analysis, anti-CCP3 positivity at the manufacturer's cut-off did not remain associated with IA progression, while this lower cut-off value (≥5 units) was associated with diagnosis of RA (p=0.02). CONCLUSIONS: Anti-CCP3 testing could improve the prediction of IA development in anti-CCP2- individuals with new MSK symptoms.

Factors associated with resolution of ultrasound subclinical synovitis in anti-CCP-positive individuals with musculoskeletal symptoms: a UK prospective cohort study.

BACKGROUND: Subclinical synovitis occurs in a third of individuals at risk of rheumatoid arthritis. The objective of this study was to assess the reversibility of subclinical synovitis in individuals at risk of rheumatoid arthritis who are positive for anti-cyclic citrullinated peptide (CCP) antibody with musculoskeletal symptoms and investigate factors associated with its resolution within 12 months. METHODS: We conducted a single-centre, prospective, cohort study in the UK, recruiting individuals aged 18 years or older who were anti-CCP-positive with a new non-specific musculoskeletal symptom but no clinical synovitis. Referrals were made through primary or secondary care. Participants attended a baseline visit, which included a clinical assessment, blood tests, patient questionnaires, and a musculoskeletal ultrasound scan (ie, of wrists and metacarpophalangeal, proximal interphalangeal, and metatarsophalangeal joints), and then follow-up visits every 3 months for the first year, with a repeat ultrasound scan every 12 months. Participants with subclinical synovitis (ie, grey scale ≥1 and power Doppler ≥1) in at least one joint at baseline were selected for this analysis. Investigation of good prognostic factors by 12 months was done first using univariable analysis to identify significant factors in participants with no missing data. Then receiver operating characteristic (ROC) curves were used to establish the optimal cutoffs for significant continuous variables. Finally, a modified Poisson regression approach was performed to identify the best prediction model and was adjusted for confounders, using data from all participants, with missing values imputed. This study is registered with ClinicalTrials.gov, NCT02012764. FINDINGS: Between June 30, 2008, and Feb 24, 2020, 451 participants consented to participate in the CCP study and 122 (27%) individuals had subclinical synovitis at baseline, of whom 90 (74%) had data available at 12 months. Mean age was 54·1 years (SD 12·5), and 63 (70%) of 90 participants were women and 27 (30%) were men. Subclinical synovitis resolved in 43 (48%) of 90 participants, whereas subclinical synovitis persisted in 47 (52%) participants, 27 (57%) of whom developed clinical synovitis within 12 months. In the multivariable analysis, low anti-CCP titre (relative risk [RR] 1·52, 95% CI 1·04-2·22), negative rheumatoid factor (1·54, 0·92-2·58), subclinical synovitis in only one joint (1·62, 1·04-2·50), and an erythrocyte sedimentation rate of 15 mm/h or lower (1·82, 1·15-2·87) were predictors of subclinical synovitis resolution within 12 months (ie, good prognostic factors). ROC curve showed an area under the curve of 0·84 (95% CI 0·76-0·92; p<0·0001). Resolution occurred in seven (100%) of seven participants with all four factors present, and in only one (7%) of 14 participants with none of the factors present. INTERPRETATION: In individuals who were anti-CCP-positive, subclinical synovitis disappeared in approximately half of the participants by 12 months and was associated with the presence of good prognostic factors. Subclinical synovitis should be interpreted in the context of these additional factors. FUNDING: National Institute for Health Research Leeds Biomedical Research Centre.

Ultrasound in anti-CCP+ at-risk individuals without clinical synovitis: development of a novel 6-joint protocol for feasible risk prediction.

OBJECTIVES: To investigate, in anti-cyclic citrullinated peptide antibody positive individuals with musculoskeletal symptoms but no clinical synovitis (CCP+ at-risk), the additional value of ultrasound (US) for the prediction of inflammatory arthritis (IA). Furthermore, to define a concise US protocol for feasible risk prediction. METHODS: Demographic and clinical data were collected in 417 CCP+ at-risk (Leeds CCP cohort) with a baseline US scan assessing synovitis and bone erosions in 36 joints, and a follow-up duration ≥24 months. Multivariable binary regression models for IA development at 24 months evaluated routine clinical variables associated with IA alone ("clinical" model) and combined with a 36-joint US scanning protocol ("clinical-US extended" model). A "clinical-US short" model was developed. RESULTS: At 24 months, 92/417 (22.1%) CCP+ at-risk developed IA (median time: 7 months, IQR : 3-12). The "clinical-US extended" model performed better than the "clinical" model (AUC 0.788 vs AUC 0.731 respectively, p< 0.001) with an odds ratio for IA development of 3.18 (95% IC 1.80-5.63) for US synovitis and 2.54 (95% IC 1.21-5.37) for bone erosions. The "clinical-US short" model, which retained the wrists, knees and MTP5 joints, performed better (AUC 0.782) than the "clinical" model (p< 0.001) and similarly (difference in Akaike information criteria <2) to the "clinical-US extended" model. CONCLUSIONS: US provides valuable information for predicting progression to IA in CCP+ individuals both alone and in addition to clinical variables. US synovitis was associated with a threefold increase risk of IA development. A concise US protocol of 6 joints provides clinically feasible risk prediction in CCP+ at-risk.

Lymphocyte subset phenotyping for the prediction of progression to inflammatory arthritis in anti-citrullinated-peptide antibody-positive at-risk individuals.

OBJECTIVES: Inflammatory arthritis (IA) is considered the last stage of a disease continuum, where features of systemic autoimmunity can appear years before clinical synovitis. Time to progression to IA varies considerably between at-risk individuals, therefore the identification of biomarkers predictive of progression is of major importance. We previously reported on the value of three CD4+T-cell subsets as biomarkers of progression. Here, we aim to establish the value of 18 lymphocyte subsets (LS) for predicting progression to IA. METHODS: Participants were recruited based on a new musculoskeletal complaint and being positive for anti-citrullinated-peptide Antibody. Progression (over 10 years) was defined as the development of clinical synovitis. LS analysis was performed for lymphocyte lineages, naïve/memory subsets, inflammation-related cells (IRC), and regulatory cells (Treg/B-reg). Modelling used Logistic/Cox regressions. RESULTS: Of 210 patients included, 93 (44%) progressed to IA, 41/93 (44%) within 12 months (rapid progressors). 5/18 LS were associated with progression (Treg/CD4-naïve/IRC (adjusted p < 0.0001), CD8 (p = 0.021), B-reg (p = 0.015)) and 3 trends (NK-cells/memory-B-cells/plasmablasts).Unsupervised hierarchical clustering using these 8 subsets segregated 3 clusters of patients, one cluster being enriched (63/109(58%)) and one poor (10/45(22%)) in progressors.Combining all clinical and LS variables, forward logistic regression predicted progression with accuracy=85.7% and AUC=0.911, selecting smoking/Rheumatoid-Factor/HLA-Shared-Epitope/Tender-Joint-Count-78 and Treg/CD4-naive/CD8/NK-cells/B-reg/plasmablasts.To predict rapid progression, a Cox regression was performed resulting in a model combining smoking/rheumatoid factor and IRC/CD4-naïve/Treg/NK-cells/CD8+T-cells (AUC=0.794). CONCLUSION: Overall, progression was predicted by specific LS, suggesting potential triggers for events leading to the development of IA, while rapid progression was associated with a different set of subsets.

Predicting Inflammatory Arthritis in At-Risk Persons: Development of Scores for Risk Stratification.

BACKGROUND: Inflammatory arthritis (IA) is an immune-related condition defined by the presence of clinical synovitis. Its most common form is rheumatoid arthritis. OBJECTIVE: To develop scores for predicting IA in at-risk persons using multidimensional biomarkers. DESIGN: Prospective observational cohort study. SETTING: Single-center, Leeds, United Kingdom. PARTICIPANTS: Persons with new musculoskeletal symptoms, a positive test result for anticitrullinated protein antibodies, and no clinical synovitis and followed for 48 weeks or more or until IA occurred. MEASUREMENTS: A simple score was developed using logistic regression, and a comprehensive score was developed using the least absolute shrinkage and selection operator Cox proportional hazards regression. Internal validation with bootstrapping was estimated, and a decision curve analysis was done. RESULTS: Of 455 participants, 32.5% (148 of 455) developed IA, and 15.4% (70 of 455) developed it within 1 year. The simple score identified 249 low-risk participants with a false negative rate of 5% (and 206 high-risk participants with a false-positive rate of 72%). The comprehensive score identified 119 high-risk participants with a false-positive rate of 29% (and 336 low-risk participants with a false-negative rate of 19%); 40% of high-risk participants developed IA within 1 year and 71% within 5 years. LIMITATIONS: External validation is required. Recruitment occurred over 13 years, with lower rates of IA in later years. There was geographic variation in laboratory testing and recruitment availability. CONCLUSION: The simple score identified persons at low risk for IA who were less likely to need secondary care. The comprehensive score identified high-risk persons who could benefit from risk stratification and preventive measures. Both scores may be useful in clinical care and should also be useful in clinical trials. PRIMARY FUNDING SOURCE: National Institute for Health and Care Research Leeds Biomedical Research Centre.

Added value of multiple autoantibody testing for predicting progression to inflammatory arthritis in at-risk individuals.

BACKGROUND: Predicting progression to clinical arthritis in individuals at-risk of developing rheumatoid arthritis is a prerequisite to developing stratification groups for prevention strategies. Selecting accurate predictive criteria is the critical step to define the population at-risk. While positivity for anti-citrullinated protein antibodies (ACPA) remains the main recruitment biomarker, positivity for other autoantibodies (AutoAbs) identified before the onset of symptoms, may provide additional predictive accuracy for stratification. OBJECTIVE: To perform a multiple AutoAbs analysis for both the prediction and the time of progression to inflammatory arthritis (IA). METHODS: 392 individuals were recruited based on a new musculoskeletal complaint and positivity for ACPA or rheumatoid factor (RF). ELISAs were performed for ACPA, RF, anti-nuclear Ab, anti-carbamylated protein (anti-CarP) and anti-collagen AutoAbs. Logistic and COX regression were used for analysis. RESULTS: Progression to IA was observed in 125/392 (32%) of cases, of which 78 progressed within 12 months. The AutoAbs ACPA, RF, anti-CarP were individually associated with progression (p<0.0001) and improved prediction when combined with demographic/clinical data (Accuracy >77%; area under the curve (AUC) >0.789), compared with prediction using only demographic/clinical data (72.9%, AUC=0.760). Multiple AutoAbs testing provided added value, with +6.4% accuracy for number of positive AutoAbs (AUC=0.852); +5.4% accuracy for AutoAbs levels (ACPA/anti-CarP, AUC=0.832); and +6.2% accuracy for risk-groups based on high/low levels (ACPA/RF/anti-CarP, AUC=0.837). Time to imminent progression was best predicted using ACPA/anti-CarP levels (AUC=0.779), while the number of positive AutoAbs was/status/risk were as good (AUC=0.778). CONCLUSION: We confirm added value of multiple AutoAbs testing for identifying progressors to clinical disease, allowing more specific stratification for intervention studies.

Effectiveness of SARS-CoV-2 vaccination in patients with rheumatoid arthritis (RA) on DMARDs: as determined by antibody and T cell responses.

OBJECTIVES: To assess antibody and T cell responses to SARS-CoV-2 vaccination in patients with rheumatoid arthritis (RA) on disease-modifying antirheumatic drugs (DMARDs). METHODS: This prospective study recruited 100 patients with RA on a variety of DMARDs for antibody and T cell analysis, pre-vaccination and 4 weeks post-vaccination. Positive antibody response was defined as sera IgG binding to ≥1 antigen. Those that remained seronegative after first vaccination were retested 4 weeks after second vaccination; and if still seronegative after vaccination three. A T cell response was defined an ELISpot count of ≥7 interferon (IFN)γ-positive cells when exposed to spike antigens. Type I IFN activity was determined using the luminex multiplex assay IFN score. RESULTS: After vaccine one, in patients without prior SARS-CoV-2 exposure, 37/83 (45%) developed vaccine-specific antibody responses, 44/83 (53%) vaccine-specific T cell responses and 64/83 (77%) developed either antibody or T cell responses. Reduced seroconversion was seen with abatacept, rituximab (RTX) and those on concomitant methotrexate (MTX) compared to 100% for healthy controls (p<0.001). Better seroconversion occurred with anti-tumour necrosis factor (TNF) versus RTX (p=0.012) and with age ≤50 (p=0.012). Pre-vaccine SARS-CoV-2 exposure was associated with higher quantitative seroconversion (≥3 antibodies) (p<0.001). In the subgroup of non-seroconverters, a second vaccination produced seroconversion in 54% (19/35), and after a third in 20% (2/10). IFN score analysis showed no change post-vaccine. CONCLUSION: Patients with RA on DMARDs have reduced vaccine responses, particularly on certain DMARDs, with improvement on subsequent vaccinations but with approximately 10% still seronegative after three doses.

Prioritising referrals of individuals at-risk of RA: guidance based on results of a 10-year national primary care observational study.

BACKGROUND: Musculoskeletal (MSK) symptoms are among the commonest reasons for primary care assessments; however, few individuals will be diagnosed with an inflammatory arthritis (IA) within the following year. The purpose of this study was to investigate, in individuals with new MSK symptoms, the association between patient factors and risk of progression to IA, in order to optimise primary care referrals to rheumatology. METHODS: Individuals ≥16 years old with new non-specific MSK symptoms and no clinical synovitis were recruited by primary care across the UK from July 2007 until May 2019. Those testing positive for the anti-CCP2 assay (anti-CCP+) were invited to Leeds for follow-up. Subjects with a negative result (anti-CCP-) were sent a 1-year questionnaire, and general practitioners were contacted to confirm whether the individual had been diagnosed with an IA by a rheumatologist. Predictors for progression were assessed using multivariable regression analysis. RESULTS: Six thousand seven hundred eighty individuals were recruited: 3% were anti-CCP+, of whom 45% progressed to IA, predominantly rheumatoid arthritis. Anti-CCP+ participants with high antibody levels had an odds ratio (OR) for progression to IA of 9.42 [P < 0.001, 95% CI (3.13-28.30)], hand pain, OR 2.74 [P = 0.043, 95% CI (1.03-7.27)] and foot pain, OR 4.10 [P = 0.003, 95% CI (1.59-10.54)]. In low-level anti-CCP+ individuals, absence of pain in hands or feet had a negative predictive value of 96% for progression to IA. One-year follow-up data were available for 5640 anti-CCP- individuals, of whom 53 were diagnosed with IA (0.93%). Pain in hands, OR 2.51 [P = 0.018, 95% CI (1.17-5.39)] or knees, OR 3.03 [P = 0.003, 95% CI (1.47-6.25)] were associated with development of IA within 12 months. CONCLUSIONS: This is the largest prospective primary care study of individuals at risk of IA, and the first one to prospectively investigate the outcome of MSK symptoms in a large anti-CCP- cohort. High anti-CCP levels and pain in hands/feet indicated an increased likelihood of progression to IA. In patients with low anti-CCP level and no pain in the hands/feet, progression is unlikely. In anti-CCP- patients, those with hand or knee pain were at increased risk of progression. This study demonstrates that routinely available tests and joint symptoms provide useful discrimination that may be used to prioritise referrals to rheumatology and avoid a delayed diagnosis. TRIAL REGISTRATION: NCT, NCT02012764 . Registered 25 January 2007.

Ultrasound subclinical synovitis in anti-CCP-positive at-risk individuals with musculoskeletal symptoms: an important and predictable stage in the rheumatoid arthritis continuum.

OBJECTIVES: To investigate whether anti-CCP2-positive at-risk individuals with musculoskeletal (MSK) symptoms but without clinical synovitis (CCP2+ at-risk) develop US subclinical synovitis before inflammatory arthritis and if US subclinical synovitis can be predicted. METHODS: First, US scans of CCP2+ at-risk individuals who developed inflammatory arthritis ('progressors') were reviewed for subclinical synovitis prior to inflammatory arthritis development. Patients in whom the pre-progression US scan was negative but the scan was conducted >6 months before progression were excluded. Subsequently, regression analyses were performed to identify predictors of US synovitis in CCP2+ at-risk individuals without baseline US abnormalities who had one or more longitudinal US scan and a complete dataset. RESULTS: US subclinical synovitis was detected in one or more scan in 75 of 97 progressors (77.3%) {median time to inflammatory arthritis development from first evidence of US synovitis 26.5 weeks [interquartile range (IQR) 7-60]}, in whom one or more scan was available, excluding those with a negative scan >6 months from inflammatory arthritis development (n = 38). In 220 CCP2+ at-risk individuals with normal baseline US scans, who had one or more longitudinal US scan and a complete dataset, US synovitis was detected in 69/220 (31.4%) [median time to first developing US synovitis 56.4 weeks (IQR 33.0-112.0)]. In the multivariable analysis, only anti-CCP3 antibodies were predictive for the development of US synovitis [odds ratio 4.75 (95% CI 1.97, 11.46); P < 0.01]. CONCLUSIONS: In anti-CCP2+ at-risk individuals, a stage of subclinical synovitis usually precedes the development of inflammatory arthritis. Anti-CCP2+/CCP3+ individuals without clinical or US subclinical synovitis may represent the optimal window of opportunity for intervention to prevent joint disease.

In anti-CCP+ at-risk individuals, radiographic bone erosions are uncommon and are not associated with the development of clinical arthritis.

OBJECTIVES: To investigate the prevalence, distribution and predictive value for the development of inflammatory arthritis (IA) of conventional radiography (CR) bone erosions (BE) in anti-CCP positive (CCP+) at-risk individuals with musculoskeletal (MSK) symptoms but without clinical synovitis. METHODS: Baseline CR of the hands and feet of 418 CCP+ at-risk individuals were analysed. The presence of US-BE was explored in the anatomical areas in which CR-BE were reported. Hands and feet CR at the time of progression were analysed in a subset of individuals who developed IA (73/123, 59.3%). Logistic regression analyses were performed to calculate the predictive value of baseline CR-BE for the development of IA in 394 CCP+ individuals with ≥1 follow-up visit. RESULTS: BE were detected in 17/418 (4.1%) CCP+ at-risk individuals (median Simple Erosions Narrowing Score-BE = 2.0, IQR: 1.0-2.0; median Sharp van der Heijde score-BE = 4.0, IQR: 3.0-8.5), most frequently in the foot joints (11/17, 64.7% individuals). A total of 123/394 (31.2%) CCP+ at-risk individuals developed IA; 7/17 (41.2%) with, and 116/377 (30.8%) without BE on CR (P = 0.37). US-BE were found in 4/7 (57.1%) individuals with CR-BE who developed IA, but only in 1/10 (10.0%) who did not. At the time of progression, new BE were detected in 4/73 (5.5%) CCP+ individuals on repeated CR. In the regression analyses, baseline CR-BE were not predictive for the development of IA. CONCLUSIONS: In CCP+ at-risk individuals with MSK symptoms, CR-detected BE are uncommon and do not predict the development of IA.

Anti-carbamylated protein antibodies: are they useful for the diagnosis of rheumatoid arthritis?

OBJECTIVES: ACR/EULAR-2010 classification criteria for rheumatoid arthritis (RA) rely heavily on the presence of anti-citrullinated peptide antibody (ACPA). The role of anti-carbamylated protein antibodies (anti-CarP) in this context is uncertain. We aimed to investigate the value of anti-CarP for RA classification in patients with early inflammatory arthritis. METHODS: Patients (n=402) were recruited from an early arthritis clinic and followed for 24 months. Healthy controls (n=95) were included. An anti-CarP ELISA was performed (aU/mL). Statistical analysis used regression and AUC analysis. RESULTS: The criteria for RA were met by 195/402 patients at inclusion; 28 developed RA during follow-up and 179 had other diagnosis (non-RA). 97/195 (49%) RA patients were anti-CarP+ (median 250 uA/mL [IQR 25-762]). In the group that progressed to RA, 7/28 (25%) were positive (82 uA/mL [13-235]) compared to non-RA (p=0.001) with 13/179 (7%) positive (26 uA/mL [5-80]). Being anti-CarP+ alone was observed in 17 patients of whom 7 (41%) were RA. Levels/positivity were not associated with other parameters. Anti-CarP+ had an odds ratio (OR) 6.5 for predicting RA (OR=17.1 for ACPA+ and OR=2.5 for RF+). In ACPA- patients, anti-CarP+ was also predictive of RA (OR=2.39). Being ACPA+/anti-CarP+/RF+ had a high predictive value for RA (OR=29.9 sensitivity/specificity (sen/spe) 33%/99%, positive/negative predictive values (ppv/npv) 97%/54%), however, being ACPA+/anti-CarP+ was superior (OR=36.1 sen/spe=41%/99%, ppv/npv=98%/57%) while being ACPA+/RF+ was inferior (OR=11.9, sen/spe=54%/95%, ppv/npv=94%/62%). CONCLUSIONS: For RA classification, anti-CarP+ was less sensitive than ACPA, but more specific than RF. Anti-CarP+ may prove useful, classifying early arthritis patients, notably ACPA- patients.

The Role of Ultrasound Across the Inflammatory Arthritis Continuum: Focus on "At-Risk" Individuals.

In individuals at-risk of developing inflammatory arthritis, the value of an ultrasound (US) scan assessment to predict progression has been demonstrated repeatedly. However, depending on recruitment criteria, these individuals may be at different stages in the arthritis development continuum, therefore representing a heterogeneous population. As a consequence, the predictive value of ultrasound results may differ between cohorts. As other reviews have focused on the challenges in population recruitment or have combined biomarkers predicting value according to one recruitment pathway, we wanted to focus on the sole use of ultrasound assessment and its variation according to population recruitment criteria. In this review, we discuss the use of ultrasound in the different at-risk populations across the inflammatory arthritis disease continuum. This review demonstrates that although some sub-population data is scarce, ultrasound is best predictive in three at-risk populations: those with a positive ACPA test in the context of non-specific MSK symptoms, those with clinically suspect arthralgia and those with palindromic rheumatism. We consider that ultrasound assessment will be a cornerstone in prediction risk modeling and prevention studies of the preclinical phases of IA in the future.

Third-Generation Anti-Cyclic Citrullinated Peptide Antibodies Improve Prediction of Clinical Arthritis in Individuals at Risk of Rheumatoid Arthritis.

OBJECTIVE: To 1) determine the prevalence of anti-cyclic citrullinated peptide 3 (anti-CCP3) antibodies in anti-CCP2 antibody-positive (anti-CCP2+) at-risk individuals, and 2) explore the additional value of anti-CCP3 antibodies in anti-CCP2+ at-risk individuals for predicting progression to inflammatory arthritis. METHODS: Stored serum samples obtained from 347 anti-CCP2+ (BioPlex 2200; Bio-Rad) at-risk individuals without clinical synovitis were tested for anti-CCP3 antibodies. Anti-CCP2 titers were categorized as low or high, and anti-CCP3 titers were categorized as negative, low, or strong. Progression to inflammatory arthritis was defined as the development of clinical synovitis in ≥1 joint. Only subjects with ≥1 follow-up visit were included in the progression analysis (n = 291). RESULTS: In the 347 samples included, anti-CCP3 antibody titers tended to be either negative (n = 138 [39.7%]) or strongly positive (n =189 [54.4%]), with very few subjects showing a low titer (n = 20 [5.7%]). In contrast, for anti-CCP2 antibodies, more low titers were observed (n = 103 [29.7%]). Eighty-eight of 291 subjects (30.2%) developed inflammatory arthritis. The rate of progression to inflammatory arthritis in the low-titer anti-CCP2 group and the high-titer anti-CCP2 group fell from 7.5% to 3.3% and from 38.9% to 9.8%, respectively, when anti-CCP3 was negative. Progression in the high-titer anti-CCP2 group increased from 38.9% to 48.4% when anti-CCP3 was strongly positive. The area under the curve was 0.72 for anti-CCP2 (95% confidence interval [95% CI] 0.66, 0.78) and 0.76 for anti-CCP3 (95% CI 0.70, 0.81) for assessment of progression. In the multivariable analysis, the odds ratio for the development of inflammatory arthritis in anti-CCP3+ subjects was 1.73 (95% CI 1.20, 2.51) (P < 0.01). CONCLUSION: Anti-CCP3 antibodies improve the prediction of inflammatory arthritis in anti-CCP2+ at-risk individuals. The impact of anti-CCP3 antibody status for the risk stratification of individuals with high-titer anti-CCP2 is particularly notable.

Ultrasound erosions in the feet best predict progression to inflammatory arthritis in anti-CCP positive at-risk individuals without clinical synovitis.

OBJECTIVES: To investigate, in anti-cyclic citrullinated peptide antibody positive (CCP+) at-risk individuals without clinical synovitis, the prevalence and distribution of ultrasound (US) bone erosions (BE), their correlation with subclinical synovitis and their association with the development of inflammatory arthritis (IA). METHODS: Baseline US scans of 419 CCP+ at-risk individuals were analysed. BE were evaluated in the classical sites for rheumatoid arthritis damage: the second and fifth metacarpophalangeal (MCP2 and MCP5) joints, and the fifth metatarsophalangeal (MTP5) joints. US synovitis was defined as synovial hypertrophy (SH) ≥2 or SH ≥1+power Doppler signal ≥1. Subjects with ≥1 follow-up visit were included in the progression analysis (n=400). RESULTS: BE were found in ≥1 joint in 41/419 subjects (9.8%), and in 55/2514 joints (2.2%). The prevalence of BE was significantly higher in the MTP5 joints than in the MCP joints (p<0.01). A significant correlation between BE and US synovitis in the MTP5 joints was detected (Cramer's V=0.37, p<0.01). The OR for the development of IA (ever) was highest for the following: BE in >1 joint 10.6 (95% CI 1.9 to 60.4, p<0.01) and BE and synovitis in ≥1 MTP5 joint 5.1 (95% CI 1.4 to 18.9, p=0.02). In high titre CCP+ at-risk individuals, with positive rheumatoid factor and BE in ≥1 joint, the OR increased to 16.9 (95% CI 2.1-132.8, p<0.01). CONCLUSIONS: In CCP+ at-risk individuals, BE in the feet appear to precede the onset of clinical synovitis. BE in >1 joint, and BE in combination with US synovitis in the MTP5 joints, are the most predictive for the development of clinical arthritis.

Safety evaluation of adalimumab in immune-mediated inflammatory disorders: a rheumatological point of view.

INTRODUCTION: Immune-mediated inflammatory disorders (IMIDs) are systemic conditions which arise secondary to complex immune mechanism defects and can affect many organs. While previous therapies based on steroids and immunosuppressive agents had a poor risk/benefit balance, TNFα-specific inhibitors such as adalimumab have revolutionized the course of many diseases and patient outcomes. However, concerns were raised regarding the increased risk of infectious diseases and neoplasia due to potential prospective loss of immune control. This is especially true when considering that IMIDs concerns elderly/frail populations, with multiple co-morbidities, organ damage and often long-term steroid therapy. Areas covered: Now prescribed for more than 15 years for a diverse range of indications, long-term data highlighting the efficacy and safety are available and led to recommendations for the daily practice that will be discussed. Expert opinion: The efficacy of adalimumab changed the therapeutic paradigm of many diseases. Its tolerance is good and it is the most widely prescribed therapy in IMIDs. It is now the standard of care arm in head to head trials. In the long term, adalimumab dominant role might be weakened by more targeted therapies but its varied indications among IMIDs should secure its position as an important tool in our future practice.

The initiation of autoimmunity at epithelial surfaces: a focus on rheumatoid arthritis and systemic lupus erythematosus.

It is well established that the autoantibodies that characterize both rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are present systemically years before patients develop disease. In both these autoimmune rheumatic diseases, evidence is growing that local autoimmune processes occur at epithelial surfaces potentially initiating localized autoimmunity. For RA, these are mucosal surfaces including the oral mucosa, lung, and gut. At the oral mucosa and lung, risk factors such as periodontal disease and smoking may contribute to autoimmunity by driving the local generation of citrullinated autoantigens. For SLE, the skin may be integral in pathogenesis. It is proposed that defective clearance of apoptotic debris leads to initial innate immune responses preceding autoimmunity. Many tissues may be implicated but the frequency of skin disease, even without autoantibodies, and the role of UV light as a trigger suggest that keratinocytes may be a key site of initiation. In both diseases, a local break in immune tolerance could lead to systemic autoimmunity, and, in the gut, bacterial organisms that colonize the intestine may influence the localized gut immune response through T-cells and promote the development of systemic autoimmunity. In this review, we discuss the evidence for localized epithelial autoimmunity in those at risk of RA and SLE and early disease. Localized autoimmunity at the oral mucosa, lung, gut, and skin will be considered as potential initiating sites of ARD-related autoimmunity.