| May 2006 - CRA Journal Club Review by Dr. Morton A. KAPUSTA | The HLA-DRB1 Shared Epitope Alleles Are Primarily a Risk Factor for Anti-Cyclic Citrullinated Peptide Antibodies and Are Not an Independent Risk Factor for Development of Rheumatoid Arthritis. van der Helm-van Mil AHM, Verpoort KN, Breedveld FC, Huizinga TWJ, Toes REM, and de Vries RRP. Arthritis Rheum 2006; 54: 1117-1121.
Morton A. Kapusta
M.D., FRCPC, FACP |
Editorial:
By Dr. MORTON A. KAPUSTA
MY PREVIOUS REVIEW
Posted on this site, in March of 2006 (1), presented a Swedish paper which studied the relationship between Shared Epitope (SE), antibodies to Citrullinated Protein/Peptides and smoking in the development of Rheumatoid Arthritis (RA) in patients with Early Arthritis. This review also presented an introductory discussion of HLA, SE and the chemistry of Citrullination.
The posted paper demonstrated that, in the presence of antibodies to Citrullinated Protein/Peptides, there is an increased relative risk of developing RA in the presence of SE and smoking. This relationship does not exist in the absence of these antibodies.
The authors pointed out that Citrullination of Protein/Peptides can result from a variety of insults.
| However, only patients with RA have the ability to make antibodies against them. They postulated that an insult, such as a viral infection, involving the synovial membrane, would result in the production of Citrullinated Protein/Peptides. The production of antibodies directed against these Protein/Peptides would perpetuate the inflammatory process as RA.
THE PRESENT STUDY
From the Netherlands, also involved patients with early Arthritis. Those (N=177) who evolved into RA after 1 year were compared to those who didn’t (N=393).
They were studied for antibodies against Citrullinated Protein/Peptides, using Cyclic Citrullinated Protein as Antigen (CCP), Rheumatoid Factor and the SE *0401, *0404, *0405, *0408, *0410 and *1001, alleles.
Univariate analysis demonstrated that SE, Antibodies to CCP, and Rheumatoid Factor were all associated with an increased likelihood of developing RA. SE increased the likelihood of antibodies to CCP, both in the presence or absence of Rheumatoid Factor. Therefore, SE predisposes toward the development of antibodies to CCP, which is unrelated to the presence of Rheumatoid Factor.
There was a strong correlation between SE, antibodies to CCP and the development of RA. This raises the question as to which of these two has the direct relationship to the development of RA.
This question was addressed in Table 2. The population of patients with non-RA, or RA, were subdivided into those with, and without, SE. These two SE groups were further subdivided into those with, and those without, antibodies to CCP. This resulted in the RA, and the non-RA, group, both, being subdivided into 4 subpopulations.
The upper portion of Table 2 compares the subpopulations of the non-RA and the RA patients stratified according the presence, or absence, of anti CCP antibodies.
The percentages of four identical subpopulations of the RA and the non-RA patients were compared. If SE predisposes to the development of RA, the percentage of the SE positive groups in RA should be greater than the SE positive groups in the non-RA population. This was not the case. Therefore, SE does not directly predispose to RA.
The same subpopulations were restratified according to SE status, to determine the role of antibodies against CCP in the development of RA.
The percentage of the two subpopulations with the anti-CCP antibodies was much higher in the RA, as compared to the equivalent non-RA, Anti CCP Antibody subpopulations. This was true both in the presence, or absence, of SE.
The authors concluded that, “these data indicate that the SE alleles primarily predispose to the presence of anti-CCP Antibodies and are not an independent risk factor for the development of Rheumatoid Arthritis”.
The titer of the antibodies to CCP was the same, whether the individual had one, or two, alleles for SE.
A previous study (2) demonstrated that Citrullinated vimentin had 100; 90 and 20 fold higher affinity for *0101, *0401, and *0404 SE alleles respectively, as compared to non-citrullinated protein. These authors proposed that this high degree of binding could result in a higher density of peptide-MHC complexes on antigen presenting cells, resulting in the activation of disease producing T-Cells.
LEARNING OBJECTIVE
These two studies were discussed together in this review because they are mutually complementary in elaborating the role of SE, and antibodies to Citrullinated Protein/Peptides in the pathogenesis of RA. The learning objective of these two combined reviews is to demonstrate the following points:
(A) Antibodies to Citrullinated Protein/Peptides are found in the majority of patients
with RA.
(B) Only patients with RA can make these antibodies.
(C) The ability to make these antibodies may play an important role in the pathogenesis of RA.
REFERENCES
- March 2006 – CRA Journal Club Review by Dr. Morton A. Kapusta A New Model for an Etiology of Rheumatoid Arthritis: Smoking May Trigger HLA-DR (Shared Epitope) – Restricted Immune Reactions to Autoantigens Modified by Citrullination. Klareskog L, Stolt P, Lundberg K, et al. Arthritis Rheum 2006; 54: 38-46.
- Hill JA, Southwood S, Sette A, et al. Cutting Edge: The Conversion of Arginine To Citrulline Allows for a High-Affinity Peptide Interaction with the Rheumatoid Arthritis – Associated HLA-DRB1*0401 MHC Class II Molecule. J. Immunol 2003; 178: 538-541.
ABSTRACT
The HLA-DRB1 shared epitope alleles are primarily a risk factor for anti-cyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis
Annette H. M. van der Helm-van Mil *, Kirsten N. Verpoort, Ferdinand C. Breedveld, Tom W. J. Huizinga, René E. M. Toes, René R. P. de Vries
Leiden University Medical Center, Leiden, The Netherlands
email: Annette H. M. van der Helm-van Mil (AvdHelm@lumc.nl)
*Correspondence to Annette H. M. van der Helm-van Mil, Department of Rheumatology, Leiden University Medical Center, PO Box 9600, 2300RC Leiden, The Netherlands
Funded by:
Leids Universitair Fonds
Gratama stichting
Abstract
Objective
The shared epitope (SE)-containing HLA-DRB1 alleles represent the most significant genetic risk factor for rheumatoid arthritis (RA). Recent studies indicate that the SE alleles are associated with only RA that is characterized by the presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies, and not with anti-CCP-negative disease. In this study we investigated whether the SE alleles contribute to the development of anti-CCP-positive RA, or whether they are associated solely with the presence of anti-CCP antibodies. We therefore determined the influence of the SE alleles and anti-CCP antibodies on the progression from recent-onset undifferentiated arthritis (UA) to RA.
Methods
Patients with recent-onset UA at the 2-week visit (n = 570) were selected from the Leiden Early Arthritis Cohort. SE alleles, rheumatoid factor (RF) status, and anti-CCP antibody levels were determined. Progression to RA or other diagnoses was monitored.
Results
One hundred seventy-seven patients with UA developed RA during the 1-year followup, whereas the disease in 393 patients remained unclassified or was given other diagnoses. The SE alleles correlated with the presence of anti-CCP antibodies, but not with the presence of RF. Both in SE-positive and in SE-negative patients with UA, the presence of anti-CCP antibodies was significantly associated with the development of RA. More intriguingly, however, no apparent contribution of the SE alleles to the progression to RA was found when analyses were stratified according to the presence of anti-CCP antibodies. In patients with anti-CCP-positive disease, the presence of SE alleles was associated with significantly higher levels of anti-CCP antibodies, suggesting that the SE alleles act as classic immune response genes.
Conclusion
The SE alleles do not independently contribute to the progression to RA from UA, but rather contribute to the development of anti-CCP antibodies.
Received: 24 August 2005; Accepted: 30 December 2005
Full article (PDF) |
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CRA Forum : May 2006, Review by Dr. MORTON A. KAPUSTA
Topic: Review By Dr. M. Kapusta
