Indian Journal of Rheumatology

: 2019  |  Volume : 14  |  Issue : 2  |  Page : 102--103

Anticarbamylated protein antibodies: The new clinically relevant antibody system in rheumatoid arthritis

Sajal Ajmani 
 Department of Rheumatology, All India Institute of Medical Sciences, New Delhi, India

Correspondence Address:
Dr. Sajal Ajmani
Department of Rheumatology, All India Institute of Medical Sciences, New Delhi - 110 029

How to cite this article:
Ajmani S. Anticarbamylated protein antibodies: The new clinically relevant antibody system in rheumatoid arthritis.Indian J Rheumatol 2019;14:102-103

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Ajmani S. Anticarbamylated protein antibodies: The new clinically relevant antibody system in rheumatoid arthritis. Indian J Rheumatol [serial online] 2019 [cited 2020 Nov 28 ];14:102-103
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Rheumatoid arthritis (RA) affects 0.5%–1% of adults. Early diagnosis and treatment prevents joint damage and leads to better long-term results.[1] 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.[2]

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.[3],[4]

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.[4],[5] 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].[6] Cyanate is in equilibrium with urea in blood; hence, the carbamylation of proteins commonly occurs in end-stage renal disease patients.[4] 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.[4] 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.[4] Albumin and alpha-1 antitrypsin have been identified as anti-CarP-specific antigens.[7]{Figure 1}

In the study by Mohamed et al.,[8] 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.[9] Anti-CarP antibodies may occur in 16%–30% of ACPA-negative patients (16% immunoglobulin G [IgG] and 30% IgA anti-CarP).[10] 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.[4] Anti-CarP IgG antibodies also seem to be associated with a more severe radiological progression in ACPA-negative RA.[10] Similar to ACPA and RF, these autoantibodies can be detected more than 10 years before disease onset.[3],[11] The presence of anti-CarP antibodies has also been shown to predict the development of RA in patients with arthralgia independently of ACPA.[11] 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.[12] However, one study showed that anti-CarP antibodies are detectable in the serum of patients with active psoriatic arthritis[13] and were also reported in 16.7% of juvenile idiopathic arthritis patients.[14]

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.[15] 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.


1Moeez S, John P, Bhatti A. Anti-citrullinated protein antibodies: Role in pathogenesis of RA and potential as a diagnostic tool. Rheumatol Int 2013;33:1669-73.
2Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62:2569-81.
3Verheul MK, Fearon U, Trouw LA, Veale DJ. Biomarkers for rheumatoid and psoriatic arthritis. Clin Immunol 2015;161:2-10.
4Shi J, van Veelen PA, Mahler M, Janssen GM, Drijfhout JW, Huizinga TW, et al. Carbamylation and antibodies against carbamylated proteins in autoimmunity and other pathologies. Autoimmun Rev 2014;13:225-30.
5Burska AN, Hunt L, Boissinot M, Strollo R, Ryan BJ, Vital E, et al. Autoantibodies to posttranslational modifications in rheumatoid arthritis. Mediators Inflamm 2014;2014:492873.
6de Brito Rocha S, Baldo DC, Andrade LE. Clinical and pathophysiologic relevance of autoantibodies in rheumatoid arthritis. Adv Rheumatol 2019;59:2.
7Nakabo S. Clinical and etiological meaning of anti-carbamylated protein antibodies in rheumatoid arthritis. Immunol Med 2018;41:147-53.
8Mohamed AH, Enein A, Abdelsalam N, Balata M, Abdellatif S, Rizk E, et al. Utility of anti-carbamylated protein antibodies in the diagnosis of early rheumatoid arthritis. Indian J Rheumatol 2019;14:37.
9Li L, Deng C, Chen S, Zhang S, Wu Z, Hu C, et al. Meta-analysis: Diagnostic accuracy of anti-carbamylated protein antibody for rheumatoid arthritis. PLoS One 2016;11:e0159000.
10Shi J, Knevel R, Suwannalai P, van der Linden MP, Janssen GM, van Veelen PA, et al. Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc Natl Acad Sci U S A 2011;108:17372-7.
11Shi J, van de Stadt LA, Levarht EW, Huizinga TW, Toes RE, Trouw LA, et al. Anti-carbamylated protein antibodies are present in arthralgia patients and predict the development of rheumatoid arthritis. Arthritis Rheum 2013;65:911-5.
12Scinocca M, Bell DA, Racapé M, Joseph R, Shaw G, McCormick JK, et al. Antihomocitrullinated fibrinogen antibodies are specific to rheumatoid arthritis and frequently bind citrullinated proteins/peptides. J Rheumatol 2014;41:270-9.
13Chimenti MS, Triggianese P, Nuccetelli M, Terracciano C, Crisanti A, Guarino MD, et al. Auto-reactions, autoimmunity and psoriatic arthritis. Autoimmun Rev 2015;14:1142-6.
14Muller PC, Anink J, Shi J, Levarht EW, Reinards TH, Otten MH, et al. Anticarbamylated protein (anti-CarP) antibodies are present in sera of juvenile idiopathic arthritis (JIA) patients. Ann Rheum Dis 2013;72:2053-5.
15Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 2006;54:2793-806.