Can anticyclic citrullinated peptide antibodies be used to successfully monitor treatment in rheumatoid arthritis patients?

Rheumatoid arthritis (RA) is a systemic, inflammatory autoimmune disease characterized by joint inflammation that often leads to joint destruction, severe disability and increased mortality. Up to 40% of patients with rheumatoid arthritis experience progression toward an erosive pattern in the early stages of the disease. (1) It is known that most joint erosions occur within the first two years of the disease, and there is growing evidence that only therapeutic intervention early in the course of the disease leads to satisfactory disease control, less joint damage, and a better prognosis. As the current therapeutic strategies in rheumatoid arthritis recommend increasingly aggressive regimens early in the course of the disease, diagnostic tests with high specificity are desirable for choosing the optimal treatment. If, in addition, this test could be used both to monitor disease activity and to indicate adequate treatment, it would be an irreplaceable diagnostic and prognostic tool.

The introduction of biologic agents into the therapy of rheumatoid arthritis has opened a new era for rheumatologists to fulfill the desired conceptions of early disease control and prevention of joint damage. Despite an impressive overall clinical impact, more than one quarter of patients still have a poor response to these biologic agents on the basis of both clinical and radiological evaluation. (2) So far, no reliable indices have been identified as possible predictive factors for the clinical response in patients undergoing therapy with biologic agents. An important topic in view of these new biologic treatments, such as TNF [alpha] blockade, is therefore the identification of biomarkers that predict response to treatment.

Circulating antibodies are the main effector molecules of the humoral immune system and, at present, the only practical indices for monitoring the immune response in certain autoimmune diseases. The value of the different RA-associated antibodies as diagnostic markers has been broadly analyzed in the past and comparison clearly indicates that anticyclic (anti-CCP) antibodies show a better diagnostic and prognostic performance than RF. (3) The role of anti-CCP as an early predictor for identifying patients at risk of more aggressive and erosive disease is of great importance, as it has been suggested that early and aggressive treatment, even with the use of biologic agents, can prevent the progression of joint damage. (2) The arising question is if anti-CCP can also be used to successfully monitor treatment, especially with biologic agents, in rheumatoid arthritis patients. So far, only a few studies have analyzed the variations in the titer of anti-CCP antibodies and RF during treatment with TNF[alpha] inhibitors, with inconsistent results.

A correlation between RF titers and clinical disease activity has been reported. (4) Because RF titers decrease with successful treatment, particularly methotrexate, this suggests an indirect link with disease activity. (4) Allessandri et al (5) showed a significant decrease in the titer of anti-CCP and RF in sera of patients after 24 weeks of infliximab treatment. De Rycke et al (6) found different effects of infliximab treatment on IgM-RF and anti-CCP: RF titers decreased significantly, but concentrations of anti-CCP antibodies did not change. Both the differential effect of infliximab treatment on IgM-RF and the anti-CCP antibodies, as well as the different correlation to acute phase reactants during infliximab treatment, support the emerging evidence that RF and anti-CCP antibodies are two different, independent auto-antibody systems in RA.

The use of anti-CCP as diagnostic marker is undisputed these days. Its use to successfully monitor treatment seems to depend on the patients, response to therapy and the disease duration. However, it might not be suitable for all RA patients. To monitor the clinical course of the disease, the combined use of RF-isotypes and CCP still seems to be the most powerful prognostic and diagnostic approach and has the greatest value for the clinician to choose a more aggressive treatment early in the course of the disease to delay articular damage and preserve joint function.

References

1. Plant MJ, Jones PW, Saklatvala J, et al. Patterns of radiological progression in early rheumatoid arthritis: results of an 8 year prospective study. J Rheumatol 1998;25:417-426.

2. St. Clair EW. Infliximab treatment for rheumatic disease: clinical and radiological efficacy. Ann Rheum Dis 2002;(Suppl 2):ii67-ii69.

3. De Rycke L, Peene I, Hoffman IEA, et al. Rheumatoid factor and anticitrullinated protein antibodies in rheumatoid arthritis: diagnostic value, associations with radiological progression rate, and extra-articular manifestations. Ann Rheum Dis 2004;63:1587-1593.

4. Alarcon GS, Schrohenloher RE. Bartolucci AA, et al. Suppression of rheumatoid factor production by methotrexate in patients with rheumatoid arthritis. Evidence for differential influences of therapy and clinical status on IgM and IgA rheumatoid factor expression. Arthritis Rheum 1990;33:1156-1161.

5. Alessandri C, Bombardieri M, Papa N, et al. Decrease of anti-cyclic citrullinated peptide antibodies and rheumatoid factor following anti-TNFalpha therapy (infliximab) in rheumatoid arthritis is associated with clinical improvement. Ann Rheum Dis 2004:63:1218-1221.

6. De Rycke L, Verhelst X, Kruithof E, et al. Rheumatoid factor, but not anti-cyclic citrullinated peptide antibodies, is modulated by infliximab treatment in rheumatoid arthritis. Ann Rheum Dis 2005;64:299-302.

A nation which does not remember what it was yesterday does not know
where it is today
--Robert E. Lee

From the Department of Rheumatology and Clinical Immunology, Krankenhaus Munchen-Bogenhausen, Munich, Germany.

Reprint requests to I.I. Vallbracht, Krankenhaus Munchen-Bogenhausen, Rheumatology / Clinical Immunology, Englschalkingerstr. 77, 81925 Munich, Germany. Email: [e-mail]

Accepted June 29, 2006.