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Anticarbamylated protein antibodies: The new clinically relevant antibody system in rheumatoid arthritis
Department of Rheumatology, All India Institute of Medical Sciences, New Delhi, India
Department of Rheumatology, All India Institute of Medical Sciences, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
Rheumatoid arthritis (RA) affects 0.5%–1% of adults. Early diagnosis and treatment prevents joint damage and leads to better long-term results. Therefore, reliable biomarkers are needed to make the diagnosis, assess prognosis, and achieve better disease control.
The presence of autoantibodies is an important feature of RA. Rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPAs) are the two autoantibody systems commonly used as an aid for diagnosing/classifying RA. They have been shown to precede the onset of symptoms, predict a more severe disease course, and have a pathogenic role in RA. Their importance was emphasized by the inclusion of ACPA alongside the previously included RF in ACR/EULAR 2010 RA classification criteria.
Recently, a new autoantibody system, characterized by antibodies against carbamylated proteins, i.e., proteins containing homocitrulline residues (anti-carbamylated protein [anti-CarP] antibodies), has been described in RA, independent of ACPA. Anti-CarP antibodies may be detected in ACPA-negative patients and vice versa.,
ACPAs target proteins with citrullination, which is one of the posttranslational modifications of proteins, in which arginine is converted to citrulline by the catalysis of peptidylarginine deiminase. Similarly, carbamylation is a posttranslational modification, in which a neutral amino acid replaces a positively charged amino acid. The most common carbamylation process is the conversion of lysine into homocitrulline. Homocitrulline is one methylene group longer than citrulline., In contrast to citrullination, carbamylation is a nonenzymatic chemical reaction, which involves cyanate in the conversion of lysine into homocitrulline. Under normal physiological conditions, extensive carbamylation does not take place due to low cyanate levels. However, conditions such as renal disease, inflammation, and smoking increase the level of cyanate [Figure 1]. Cyanate is in equilibrium with urea in blood; hence, the carbamylation of proteins commonly occurs in end-stage renal disease patients. Thiocyanate is taken into the body by cigarette smoking, increasing the concentration of cyanate. However, most carbamylation likely occurs under inflammatory conditions, when myeloperoxidase is released from neutrophils, which converts thiocyanate to cyanate, in turn leading to increased carbamylation. Excess carbamylation leads to protein and cellular dysfunction. In certain individuals, extensive carbamylation possibly provides the trigger for the development of autoimmunity against carbamylated proteins. Albumin and alpha-1 antitrypsin have been identified as anti-CarP-specific antigens.
In the study by Mohamed et al., anti-CarP antibody levels were measured in 96 RA patients (56 patients with early disease and 40 patients with established disease) and 60 healthy controls. Of 96 RA patients, 74 (77.1%) were positive for anti-CarP antibody including 47 (83.9%) patients with early RA, whereas only 5 (8.3%) patients in control group were positive. The sensitivity for the diagnosis of RA using anti-CarP antibody was found to be 85.4% and specificity was 93.3%. Receiver operating curve analysis showed an area under the curve as 0.95. When the anti-CarP antibody was included in the RA diagnosis, 50 (89.2%) of early RA patients became seropositive versus 46 (82.1%) when only ACPA and RF were used for diagnosis, reducing the serological gap by about 7%. The current study shows the positivity of anti-CarP antibodies in RA at a higher level than previously reported. According to meta-analysis, sensitivity and specificity of anti-CarP were 42% and 96%, respectively. Anti-CarP antibodies may occur in 16%–30% of ACPA-negative patients (16% immunoglobulin G [IgG] and 30% IgA anti-CarP). The presence of anti-CarP antibodies is associated with higher disease activity and higher disability in patients with RA, and statistically significant associations were seen independent of ACPA status. Anti-CarP IgG antibodies also seem to be associated with a more severe radiological progression in ACPA-negative RA. Similar to ACPA and RF, these autoantibodies can be detected more than 10 years before disease onset., The presence of anti-CarP antibodies has also been shown to predict the development of RA in patients with arthralgia independently of ACPA. Therefore, anti-CarP antibodies might be a useful biomarker to identify ACPA-negative “preclinical RA” patients and newly diagnosed RA patients who require early and aggressive clinical intervention. These antibodies were not found in patients with other rheumatic conditions or normal healthy individuals, suggesting a high specificity of anti-CarP antibodies. However, one study showed that anti-CarP antibodies are detectable in the serum of patients with active psoriatic arthritis and were also reported in 16.7% of juvenile idiopathic arthritis patients.
In conclusion, anti-CarP antibodies have shown potential in diagnosis and predicting disease progression of RA independent of ACPA. It could be available for commercial use in the coming years. It also has a potential role in making treatment decisions. Rituximab is currently the cheapest biologic available in our country (India), and it is more effective in seropositive RA patients than seronegative RA patients. If anti-CarP antibodies can narrow the serological gap as suggested by Mohamed et al. and put more patients in the seropositive basket than seronegative, more patients can be considered for rituximab therapy after failing to respond to conventional disease-modifying drugs.
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