since its appearance on the market in the second half of 2002 , the diagnostic properties of the ccp2 test have been studied by many laboratories .
the accumulated data , including only papers that appeared in pubmed till december 2006 , are given in table  1 .
it is clear that the accumulated data confirm the earliest reports on specificity and sensitivity of the ccp2 test .
the anti - ccp2 test demonstrates an rf - like sensitivity with a very high specificity for ra ( see also recent reviews : [ 2 , 3 ] ) .
it is also commonly recognized that anti - ccp2 antibody may be present in up to 40% of rf - negative ra sera [ 4 , 5 ] . 

table  1cumulative anti - ccp2 diagnostic data published between 2002 and 2006patient groupnumberccp2+sensitivity ( % ) specificity ( % ) ra total14,18310,13571.5  early3,8762,36561.0  established10,3077,77075.4controls15,1566834.595.6  non - ra11,5026475.694.4  healthy3,654361.099.0 in total , 122 independent studies were included .
cumulative anti - ccp2 diagnostic data published between 2002 and 2006 in total , 122 independent studies were included .
the anti - ccp2 test enables clinicians to distinguish ra patients from other arthritic diseases , especially in cases where the rf test is not discriminative .
this is , for example , the case with chronic hepatitis c virus ( hcv ) infection , a disease that can easily be misdiagnosed as it often reveals ra - like arthropathies and , in many cases , is accompanied by a positive rf .
recently , there is also an interest to compare the diagnostic potential of anti - ccp2 with novel tests based on the use of a citrullinated antigen ( for example , mcv  =  anti - mutated citrullinated vimentin , cpa  =  citrullinated protein antibodies , vcp  =  anti - viral citrullinated protein , antihuman fibrinogen alpha [ 9 , 10 ] , and ccp3 ) .
for a reliable comparison of these tests , it is essential that their performance is assessed under the same conditions , e.g. , the sensitivities of the tests should be determined at the same level of specificity .
good examples of such stratified studies have been carried out recently by van der cruijssen et al .   and dejaco et al . .
for example , dejaco et al .   showed , in a large cohort of patients ( > 600 ) , that at a specificity of 98.7% , being the specificity of the anti - ccp2 test , the sensitivity of the anti - mcv test is 53.7% as opposed to 70.1% for the anti - ccp test .
compared several commercial tests , including a very recent ccp3 test from inova . at the cut - offs recommended by the various manufacturers ,
the positive predictive value of the three commercial ccp2 tests is about 90% with a specificity of around 96% .
the specificity of the other tests ( ccp3  =  88% , mcv  =  90% , cpa  =  94% ) is lower as are their positive predictive values .
these numbers may improve a little bit when the cut - off values are adjusted to more realistic data ; nevertheless , the data allow the statement that , in absolute percentages , none of the tests performs better than the anti - ccp2 test .
they also seem to indicate that some tests detect ra patient groups that are negative in the anti - ccp test , illustrating again that the autoantibody repertoire of ra patients is very heterogeneous . another risk for
the specificity of a test that is based on a citrullinated antigen is the possibility that antibodies are not directed exclusively to the citrulline - containing epitope but also to other possibly overlapping epitopes present in the substrate antigen .
this is particularly important when citrullinated versions of proteins like vimentin or fibrinogen are used .
for example , it is known that antibodies to vimentin are present in several diseases different from ra [ 12 , 13 ] .
they used elisa plates containing the control ccp2 antigens ( arg instead of cit in the same peptide context ) , produced and made available by euro - diagnostica , arnhem , the netherlands , in parallel to the normal ccp2 test .
the results of these comparative studies showed that in ra and most non - ra rheumatic disease sera , anti - ccp reactivity indeed is citrulline - dependent .
however , in some patients , particularly autoimmune hepatitis patients , citrulline - independent reactivity with the antigen may occur .
a positive ccp test in a rheumatic disease ( almost always citrulline - specific ) may thus suggest the future development of ra as has been suggested by several studies [ 15 , 16 ] .
a positive test in a nonrheumatic disease ( very often not citrulline - specific ) , for example , liver disease , should be interpreted with care .
because ra patients at first presentation often do not fulfill the criteria for the diagnosis / classification of ra , an early , highly predictive marker would greatly assist the clinician in reaching an early diagnosis .
there are several studies indicating that the anti - ccp2 test provides this help ( reviewed by ) . in the recently published eular recommendations for the management of early arthritis
these factors include : number of swollen and tender joints , esr or crp , level of rf and anti - ccp antibodies , and radiographic erosions .
most of these factors were also mentioned as being important in the prediction of early erosive ra ( visser et al . ) .
subsequent studies by the same group gave an indication of the relative importance of these factors . when expressed as odds ratios ( or )
, the data was as follows : arthritis of three or more joints , 5.0 ; radiographic erosions , 8.7 ; positive igm - rf , 1.7 ; and positive anti - ccp2 , 38.6 . these and other data ( see also ) clearly show that the presence of anti - ccp antibodies is an important and independent prognostic factor for radiographic progression in not only early arthritis but also in early rheumatoid arthritis [ 16 , 20 ] .
recently , it has also been shown that igm - ccp is present in early samples from both patients with undifferentiated arthritis ( ua ) and patients with ra as well as in follow - up samples from patients with ra .
these data indicate the development of the anti - ccp isotype repertoire into full usage early in the course of arthritis and a continuous ( re)activation of the ra - specific anti - ccp response during the further development of the disease .
it is , however , evident that besides the clinical and laboratory parameters mentioned above , some genetic factors are important as well .
the effect of the hla shared - epitope alleles on the development of acpa has been firmly established .
because such dying cells are generally removed from the environment via clearance by phagocytes , a process that is regulated by many genes , the immune system will normally not encounter citrullinated proteins .
however , it has been shown that during inflammation , citrullinated proteins are detectable in the inflamed tissue , both in ra and non - ra patients .
this is probably caused by inefficient clearance of the massive numbers of dying cells , a process already described to occur in sle .
this inefficient clearing could , in principal , also be the consequence of altered genes , i.e. , the genetic background .
the mere presence of citrullinated antigens in inflamed synovial tissue does not necessarily result in the occurrence of anti - ccp antibodies in serum or synovial fluid , neither in humans nor in mouse models of arthritis [ 24 , 22 ] . hill et al
.   showed that the generation of anticitrulline antibody in mice actually is linked to the expression of the ra shared epitope ( se ) , and a similar link was also found in patients because the combination of se , and anti - ccp has a very high predictive value for the future development of ra .
the specific structure of hla molecules obviously plays an important role in the induction of autoimmunity to citrullinated proteins .
these studies were extended by huizinga et al .   who found that hla - drb1 alleles encoding the se were only associated with anti - ccp positive ra and not with anti - ccp negative ra .
in contrast , anti - ccp negative ra appeared to be associated with hla - dr3 .
therefore , the presence of citrullinated antigens , together with the appropriate genetic background ( the se and probably other types of hla ) , appears to be the minimum requirement for an immune response to citrullinated polypeptides to be generated .
next to that , other sensitizing genetic settings resulting from polymorphisms ( e.g. , ptpn22 ) might , given their association , aid in triggering of acpa .
the present literature describes and confirms that the anti - ccp2 test is a very useful marker for the early and accurate diagnosis of ra .
anti - ccp antibody is very specific for ra and has a sensitivity comparable to that of rf .
these antibodies can be detected very early in disease and may be used as an indicator for the progression and prognosis of ra .
initially , the test was available principally as a manual elisa method through euro - diagnostica and axis - shield and their partners .
more recently , fully automated anti - ccp assays have also been made available from phadia ( unicap elia ccp ) and abbott diagnostics ( axsym anti - ccp ) .
a very novel format is the ccpoint , a point - of - care test for the detection of these antibodies in whole blood in 10  min .
a small drop of whole blood is applied onto the sample well followed by the addition of four drops of running buffer .
after 10  min , the result is read by visual inspection of the detection zone for staining of the antigen line . as no special equipment
is required to perform the assay , this test will bring the detection of anti - ccp antibodies into the office of the family doctor , facilitating a very fast referral to the rheumatologist when the test gives a positive answer .
such new applications will undoubtedly further enhance the utility of the anti - ccp autoantibody system in clinical practice .
 the literature of the last 4  years confirms that the anti - ccp2 test is a very useful marker for the early and specific diagnosis of rheumatoid arthritis ( ra ) . 
 the anti - ccp2 test is very specific for ra ( 9599% ) and has sensitivity comparable to that of the rheumatoid factor ( 7075% ) . 
 the antibodies can be detected very early in the disease and can be used as an indicator for the progression and prognosis of ra . in this review , 
 these interesting properties and some future possibilities of this diagnostic test are discussed . 
The CCP2 Test is Sensitive and Highly Specific for RA
Anti-CCP2 Antibodies are Present Early in Disease and have Predictive Potential
Conclusions and Future Perspectives