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OptimalHealthResearch.com
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Are you
already using CCP to diagnose early RA in your patients? |
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What: CCP—cyclic
citrullinated protein antibodies; anticitrullinated protein antibodies:
this is a relatively new auto-antibody marker that shows great promise
and specificity for the early diagnosis of rheumatoid arthritis (RA).
The test often becomes positive/present in asymptomatic patients years
before the onset of clinical manifestations of RA.
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How:
anti-CCP antibodies are directed toward several native proteins (e.g.,
filaggrin, fibrinogen, and vimentin) that have become
posttranslationally modified by a uncharged citrulline in contrast to
the normal positively charged arginine. This “citrullination” is
catalyzed by a calcium-dependent enzyme, peptidylarginine deiminase
(PAD). These changes in protein charge and sequence make the native
protein a target of auto-antibody attack by IgG antibodies in RA.[1]
However, this does not necessarily imply that citrullination of native
proteins is “the cause” of RA because citrullination of native proteins
can also occur de novo in inflamed joints, which are then further
targeted for inflammatory destruction. Until more information is
available, we should withhold final judgment as to the ultimate role and
origin of anti-CCP antibodies and in the meanwhile view them as a very
strong and sensitive association with RA that facilitates the early
diagnosis of this disease.
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Importance:
Anti-CCP antibodies have 98% specificity for RA[2] and is likely to
become the future laboratory standard in the diagnosis and prognosis of
RA.[3] Anti-CCP antibodies with a positive rheumatoid factor (RF) is
termed “composite seropositivity” and appears to be more specific than
isolated anti-CCP antibodies or RF.[4]
The best current data indicates
that anti-CCP antibodies are sensitive and specific for RA[5], and
clinicians should begin using this test to diagnose and confirm RA;
however, continue to monitor research on this test as its value is
verified or questioned in future reports.
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Finding:
Healthy people do not generally have anti-CCP antibodies. Asymptomatic
patients with anti-CCP antibodies are at increased risk for clinical RA
and are probably en route to the manifestation of clinical
autoimmunity—RA, Sjogren’s disease, or SLE; holistically intervene.
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Perspectives:
Given that the test is still somewhat new, clinicians should
periodically survey the news and literature on this test to see if
perspectives change either positively or negatively in the next few
years as clinical experience with this marker accumulates. We must also
recall however the speed with which laboratory markers can rise from
obscurity to fame; take for example CRP, which was still very new to
most clinicians in 1999 and by 2001—only 2 years later—the test had
rapidly become a daily component of clinical care. I hypothesize that
PAD may become upregulated in synovial joints exposed to allergens,
xenobiotics, bacterial debris/toxins/lipopolysaccharides and that the
subsequent citrullination of joint proteins may lead to an autoimmune
arthropathy that persists, perhaps despite removal of the inciting
immunogen. More obviously, given that PAD is calcium-dependent, it may
be upregulated secondary to intracellular hypercalcinosis secondary to
vitamin D deficiency, magnesium deficiency, or fatty acid imbalance.[6]
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[1] Hill J, Cairns E, Bell DA. The joy of citrulline: new insights into the
diagnosis, pathogenesis, and treatment of rheumatoid arthritis. J Rheumatol.
2004 Aug;31(8):1471-3
http://www.jrheum.com/subscribers/04/08/1471.html
[2] Hill J, Cairns E, Bell DA. The joy of citrulline: new insights into the
diagnosis, pathogenesis, and treatment of rheumatoid arthritis. J Rheumatol.
2004 Aug;31(8):1471-3
[3] "We conclude that, at present, the antibody response directed to
citrullinated antigens has the most valuable diagnostic and prognostic
potential for RA." van Boekel MA, Vossenaar ER, van den Hoogen FH, van
Venrooij WJ. Autoantibody systems in rheumatoid arthritis: specificity,
sensitivity and diagnostic value. Arthritis Res. 2002;4(2):87-93
http://arthritis-research.com/content/4/2/87
[4] “…our findings suggest that a positive anti-CCP antibody result does not
necessarily exclude SLE in African American patients presenting with
inflammatory arthritis. In such patients, the additional assessment of
IgA-RF or IgM-RF isotypes may be of added value since composite
seropositivity appears to be nearly exclusive to patients with RA.” Mikuls
TR, Holers VM, Parrish L, Kuhn KA, Conn DL, Gilkeson G, Smith EA, Kamen DL,
Jonas BL, Callahan LF, Alarcon GS, Howard G, Moreland LW, Bridges SL Jr.
Anti-cyclic citrullinated peptide antibody and rheumatoid factor isotypes in
African Americans with early rheumatoid arthritis. Arthritis Rheum. 2006
Sep;54(9):3057-9
[5] "Serum antibodies reactive with citrullinated proteins/peptides are a
very sensitive and specific marker for rheumatoid arthritis." Migliorini P,
Pratesi F, Tommasi C, Anzilotti C. The immune response to citrullinated
antigens in autoimmune diseases. Autoimmun Rev. 2005 Nov;4(8):561-4
[6] See
http://optimalhealthresearch.com/archives/intracellular-hypercalcinosis
and
www.naturopathydigest.com/archives/2006/sep/vasquez.php for
additional discussion
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Copyright
Ó
2006
Alex Vasquez and Integrative and
Biological Medicine Research and Consulting LLC.
http://OptimalHealthResearch.com
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