Objectives: Predictors of arthritis development are highly warranted among patients with anti-citrullinated protein antibodies (ACPAs) and musculoskeletal symptoms to optimize clinical management. We aimed to identify clinical and laboratory predictors of arthritis development, including biochemically assessed alcohol consumption, among ACPA-positive patients with musculoskeletal pain. Method: 82 ACPA-positive individuals with musculoskeletal pain but no clinical arthritis were followed for a median of 72 months (interquartile range 57-81 months). We evaluated the prognostic value of baseline clinical and laboratory factors including smoking, symptom duration, age, gender, shared epitope, rheumatoid factor (RF), anti-carbamylated protein antibodies, ACPA levels, erythrocyte sedimentation rate, C-reactive protein levels, tender joint count, patient-reported general well-being, 28-joint Disease Activity Score, and alcohol consumption as measured by phosphatidyl ethanol (PEth) levels in whole blood. Results: During follow-up, 48% developed at least one arthritis. Multivariable analysis revealed an increased risk of arthritis development with RF positivity [hazard ratio (HR) = 2.3, 95% confidence interval (CI) 1.1-4.8, p = 0.028] and higher ACPA levels (HR = 1.0, 95% CI 1.000-1.001, p = 0.002). High levels of RF (HR = 4.4, 95% CI 1.7-11) entailed the highest HR in this ACPA-positive population. Neither clinical characteristics nor alcohol consumption measured by PEth conferred significant prognostic value. Conclusions: ACPA levels and concurrent presence of RF are independent predictors of arthritis development among ACPA-positive patients with musculoskeletal pain. The results are compatible with a dose-response relationship between RA-related autoantibodies and risk of arthritis development.

Anti-citrullinated protein antibodies (ACPA) often precede onset of rheumatoid arthritis (RA) by years, and there is an urgent clinical need for predictors of arthritis development among such at-risk patients. This study assesses the prognostic value of ultrasound for arthritis development among ACPA-positive patients with musculoskeletal pain. We prospectively followed 82 ACPA-positive patients without clinical signs of arthritis at baseline. Ultrasound at baseline assessed synovial hypertrophy, inflammatory activity by power Doppler, and erosions in small joints of hands and feet. We applied Cox regression analyses to examine associations with clinical arthritis development during follow-up (median, 69 months; range, 24–90 months). We also compared the ultrasound findings among the patients to a control group of 100 blood donors without musculoskeletal pain. Clinical arthritis developed in 39/82 patients (48%) after a median of 6 months (range, 1–71 months). One or more ultrasound erosions occurred in 13/82 patients (16%), with none in control subjects (p < 0.001). Clinical arthritis development was more common among patients with baseline ultrasound erosions than those without (77 vs. 42%, p = 0.032), and remained significant in a multivariable Cox regression analysis that included previously described prognostic factors (HR 3.9, 95% CI 1.6–9.4, p = 0.003). Ultrasound-detected tenosynovitis was more frequent among the patients and associated with clinical arthritis development in a univariable analysis (HR 2.5, 95% CI 1.1–5.7, p = 0.031), but did not remain statistically significant in multivariable analysis. Thus, bone erosions detected by ultrasound are independent predictors of clinical arthritis development in an ACPA-positive at-risk population.Trial Registration: Regional Ethics Committee in Linköping, Sweden, Dnr M220-09. Registered 16 December 2009, https://etikprovningsmyndigheten.se/.

BackgroundIndividuals with anti-citrullinated peptide antibodies (ACPA) and arthralgia are at increased risk of developing rheumatoid arthritis (RA). Predictors of disease development are important within this category of patients in order to improve treatment and follow-up decisions. Although excessive use of alcohol is well-known to cause harmful medical and social consequences, an inverse association between alcohol consumption and RA development has been proposed. Phosphatidylethanol (PEth) has shown to be a reliable biomarker to measure recent (up to four weeks) alcohol consumption with high specificity.ObjectivesThe aim of this study was to, in relation to other possible clinical and laboratory predictors, pinpoint the association between biochemically determined alcohol consumption and development of arthritis in ACPA-positive individuals with musculoskeletal pain.MethodsThe study was performed as part of an observational prospective cohort (TIRx), including 104 ACPA-positive individuals with musculoskeletal pain and maximally one arthritis upon clinical examination. Exclusion criteria were >1 clinical arthritis, previous inflammatory rheumatic disease, and oral or intraarticular corticosteroid treatment within 6 weeks prior to screening. Participants were enrolled between 2010 and 2013 and were carefully followed during 72 months in median (range 23-91). The primary outcome measure was development of arthritis upon clinical examination. In baseline samples, we assessed ACPA levels in serum (2nd generation cyclic citrullinated peptides (CCP) as antigen), rheumatoid factor (RF), and the presence of shared epitope. PEth 16:0/18:1 was measured by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) in whole blood from baseline, and the results were categorized into three groups: no/low, moderate, or high consumption. Cox regression analyses were performed adjusting for smoking, symptom duration, age, sex, shared epitope, RF, and treatment with disease modifying antirheumatic drugs (DMARDs) and oral glucocorticoids.ResultsIn TIRx, 82 patients had no swollen joints at inclusion, of whom 39 (48%) developed arthritis during follow-up after median 6 months (range 1-71). Of those, 48 (59%) patients were classified according to PEth values with no/low alcohol consumption, 28 (34%) with moderate consumption and 5 (6%) patients with high alcohol consumption. There was no significant difference in PEth values between patients with one baseline arthritis compared to those without (p=0.09). Neither were there any significant differences in arthritis-free survival across PEth categories versus arthritis development (p=0.64). Unadjusted hazard ratios (HRs) were numerically, but not significantly, increased among moderate (HR 1.22 95% CI 0.63-2.37, p=0.56) and high consumers (HR 1.69 95%CI 0.50-5.68, p=0.40) as compared to those classified as no/low consumers.There was an increased risk of arthritis development regarding RF positivity (adjusted HR 3.13, 95% CI 1.36-7.19, p=0.007) and higher ACPA levels (adj...

BackgroundAnti-citrullinated protein antibodies (ACPA) are associated with an increased risk of developing rheumatoid arthritis (RA), and in particular erosive disease. Detection of joint inflammation prior to clinical synovitis may improve treatment decisions in early disease.ObjectivesWe sought to determine the value of ultrasound (US) to predict arthritis development among ACPA positive patients with musculoskeletal (MSK) pain.MethodsWe prospectively followed 82 ACPA-positive patients with MSK pain but without arthritis upon baseline clinical examination (mean follow-up 68 months, range 23-91). US at baseline assessed joint erosions, synovial hypertrophy in grey scale (GS), and inflammatory activity judged by power Doppler (PD) in 36 small joints in hands and feet. We used a ProFocus system (BK Medical) with pulse repetition frequency 0.8 kHz for PD grading. The US and PD results were blinded to patients and treating rheumatologists during the initial 3 years. US findings among patients were compared to 100 age-matched healthy blood donors. Arthritis development during follow-up of patients was determined by clinical examination by an experienced rheumatologist. Associations between baseline US findings and arthritis development were tested by Cox regression analysis with adjustment for sex, age, symptom duration, smoking habits, erythrocyte sedimentation rate, C-reactive protein level, rheumatoid factor, and ACPA levels.ResultsSignificantly more patient joints had synovial hypertrophy (GS score >0) compared to control joints in metacarpophalangeal (MCP) (5.2% vs. 2.5%; p<0.001) and proximal interphalangeal (PIP) joints 2-5 (6.6 vs. 1.5%; p<0.001). In contrast, metatarsophalangeal (MTP) joints 1-5 of the controls were more often scored GS>0 compared to patient joints (49% vs. 24%; p<0.001). Positive PD (>0) occurred significantly more often in patient joints compared to the controls in all joint areas (p<0.05). At patient level, the mean sum score of all investigated joints was higher among patients than controls, regarding GS as well as PD (p<0.001 for both). 13 patients (16%), but none of the controls, had erosions detected on US (p<0.001). During follow-up of patients, 39 (48%) developed arthritis after median 25 weeks (range 5-302). Arthritis development was significantly more common among patients with baseline US erosions (10 out of 13; 77%) compared to those without (29 out of 69; 42%, p=0.032). This remained significant also in Cox regression adjusting for potential confounders (Hazard ratio =4.2, 95% CI 1.7-10.4, p=0.002). Out of the 13 erosions detected on US, 4 could be identified on conventional radiographs. Neither GS nor PD findings were significantly associated with arthritis development.ConclusionArthritis-related US findings are more common among patients at increased risk of RA compared to healthy controls, but with site-specific differences. Erosions detected on US predicted arthritis development. Thus, US assessment of erosions improves risk-stratification of ACPA-positive patients without s...

BackgroundTo assess the prognostic value of ultrasound for clinical arthritis development among anti-citrullinated peptide antibody (ACPA)-positive patients with musculoskeletal (MSK) pain.MethodsWe prospectively followed 82 ACPA-positive patients with MSK pain without clinical signs of arthritis at baseline. Ultrasound examination at baseline assessed synovial hypertrophy (SH), and inflammatory activity by power Doppler (PD) in 36 small joints and 6 tendons, and erosions in 18 joints. We applied Cox regression analyses to examine associations with clinical arthritis development during follow-up (median, 69 months; range, 24–90 months). We also compared the ultrasound findings among the patients to a control group of 100 blood donors without MSK pain.ResultsClinical arthritis developed in 39/82 patients (48%) after a median of 6 months (range, 1–71 months). One or more ultrasound erosions occurred in 13/82 patients (16%), with none in control subjects (p < 0.001). Clinical arthritis development was more common among patients with baseline ultrasound erosions than those without (77% vs 42%, p = 0.032), and remained significant in a multivariable Cox regression analysis that included previously described prognostic factors (HR 3.9, 95% CI 1.6–9.4, p = 0.003). Ultrasound-detected tenosynovitis was more frequent among the patients and associated with clinical arthritis development in a univariable analysis (HR 2.5, 95% CI 1.1–5.7, p = 0.031), but did not remain statistically significant in multivariable analysis. Neither SH nor PD was associated with arthritis development.ConclusionsBone erosions detected by ultrasound are independent predictors of clinical arthritis development in an ACPA-positive at-risk population.Trial registrationRegional Ethics Committee in Linköping, Sweden, Dnr M220-09. Registered 16 December 2009, https://etikprovningsmyndigheten.se/