Anti-cyclic Citrullinated Peptide Antibody Predicts the Development of Rheumatoid Arthritis in Patients with Undifferentiated Arthritis
Undifferentiated arthritis (UA) is a common type of inflammatory arthritis that cannot be classified as a specific rheumatic disease at the time of diagnosis. The clinical outcomes of UA are diverse, with nearly half of the patients achieving spontaneous remission without treatment, while less than half eventually develop rheumatoid arthritis (RA). Identifying predictive markers at the onset of UA is crucial for determining which patients are at high risk of progressing to RA and would benefit from early intervention. Conversely, patients with a lower likelihood of progression could avoid unnecessary treatment. This study aimed to analyze the clinical outcomes of UA and identify predictors for the development of RA.
The study was conducted as a prospective, multi-center investigation involving Chinese patients diagnosed with UA across 22 tertiary-care hospitals from January 2013 to October 2016. Patients were included if they were aged over 18 years and had persistent arthritis lasting between 6 and 24 weeks. Exclusion criteria included pregnancy, uncontrolled hypertension, abnormal heart, liver, or renal function, and alcohol addiction. None of the patients had received treatment with glucocorticoids, disease-modifying anti-rheumatic drugs (DMARDs), or biologic agents prior to enrollment.
A total of 234 patients were recruited, with 17 (7.3%) failing to follow up during the study period. Among the 217 patients who completed the study, 83 (38.2%) went into remission after 2 years of follow-up. Of these, 50 (60.2%) were treated with total glucosides of paeony, 30 (36.1%) underwent symptomatic treatment, and 2 (2.4%) achieved remission without any treatment. Among the remaining patients, 20 (9.2%) developed RA, 10 (4.6%) developed osteoarthritis (OA), and 2 (0.9%) developed psoriatic arthritis (PsA). Other diagnoses included systemic lupus erythematosus (SLE), dermatomyositis, Rhupus syndrome, and reactive arthritis (ReA), each occurring in 1 (0.5%) patient.
The baseline characteristics of the patients were as follows: the mean age was 44.2 years, and 74.7% were female. Morning stiffness was reported in 59.4% of patients, and the median number of tender and swollen joints were 2 and 1, respectively. The most commonly affected joints were the proximal interphalangeal joints and the wrists. The positivity rates for anti-cyclic citrullinated peptide (CCP) antibody and rheumatoid factor (RF) were 16.1% and 19.4%, respectively. Hypertension was the most common underlying disease, present in 6.9% of patients, and 6.9% had a family history of RA. Smoking and periodontitis were documented in 6.9% and 5.1% of patients, respectively, while 8.8% had a history of infection.
The study found that UA patients who developed RA had significantly higher rates of RF positivity (42.9% vs. 16.8%), anti-CCP antibody positivity (66.7% vs. 10.7%), and double-positivity for both RF and anti-CCP antibody (38.1% vs. 4.1%) compared to those who did not develop RA. Multivariate Cox proportional hazards regression analysis revealed that anti-CCP antibody, but not RF, was an independent predictor for RA development, with a hazard ratio of 18.017 and a 95% confidence interval of 5.803–55.938.
The importance of anti-CCP antibody as a predictor for RA has been a subject of debate. Some studies suggest that a high titer of anti-CCP antibody is associated with radiographic progression and worsening disease activity in RA patients. However, other studies have found no correlation between the titer of anti-CCP antibody and disease outcome in early arthritis. In this study, anti-CCP antibody emerged as a strong predictor for RA development, emphasizing its clinical utility in identifying UA patients at high risk of progressing to RA.
RF, a traditional serologic marker for inflammatory arthritis, has been associated with RA development in some studies but not in others. In this study, RF positivity was not an independent predictor for RA progression, although it was more common in patients who developed RA. The double-positivity for RF and anti-CCP antibody was also significantly higher in patients who developed RA, but it was not an independent predictor for RA development.
Smoking and periodontitis have been previously associated with RA. Smoking is known to increase the RF titer in patients with inflammatory polyarthritis, and periodontitis has been linked to RA due to the citrullination of antigens by Porphyromonas gingivalis. However, in this study, neither smoking nor periodontitis was significantly associated with RA development, possibly due to the relatively low prevalence of these factors in the study cohort.
The study had two major limitations. First, the number of participants was relatively small, which may limit the generalizability of the findings. Second, the study did not include early treatment with DMARDs in UA patients. Previous studies have shown that early methotrexate treatment can prevent the development of RA in UA patients, and initial triple-DMARD therapy can reduce disease activity and the need for biologics. Biological DMARDs, such as abatacept, have also been shown to slow the progression of UA.
In conclusion, this study demonstrated that only a small proportion of UA patients progress to RA, and anti-CCP antibody is a strong and independent predictor for RA development. Testing for anti-CCP antibody at the onset of UA is recommended to identify patients at high risk of developing RA, who may benefit from early intervention with DMARDs to prevent disease progression. The findings underscore the importance of using simple, clinically relevant parameters to predict RA development in UA patients, thereby improving clinical outcomes and reducing unnecessary treatment in low-risk patients.
doi.org/10.1097/CM9.0000000000000570
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