Hi Maximilian, 

Thank you for your helpful answer. What would you suggest how to discriminate these patients in clinical routine? There are about three cases published of patients with longstanding RA who developed antisynthetase syndrome (or showed ass later and ccp are really markers of erosion?). The clinical picture alone often is consistent with the ACR classification criteria.  

Best, 

Peter

My impression is that ACPA responses may not be due to a single immunological error. Jo Cambridge found ACPA, of a different subclass pattern, in males with coronary artery disease (greater than controls). So I think it may be unwise to redefine 'diseases' by autoantibody, however much that might seem desirable as a mechanistic classification. I think ACPA-ve  RA should still be considered RA in the clinic and I suspect the effector mechanism is still much the same as in ACPA +ve RA. 

I suspect early reports of specificity for RA were partly driven by commerical concerns with assays. And of course sensitivity and specificity claims do not have to include anyone with another rare disease. I certainy found ACPA in people with a variety of other rheumatic syndromes occasionally, but not often enough to look at statistics. One thing we have been interested in is the idea that you may actually need more than one antibody population to drive autoimmune diseases. The two populations may just recognise different epitopes on a single antigen but it may be more complex than that. So I guess it is possible that ACPA can 'partner' more than just rheumatoid factors, but maybe with different isotype profiles or dominant specificities for cit- fibronogen, enolase etc.

Dear Max,

Your point about non-specific responses is of course important. But mice and lupus patients have always been a source of confusion when it comes to ELISA plates. Our CAD study has indeed been followed up with detailed analyses of fine specificities but these are not yet released. 

I did not want to deny that autoantibodies are pathogenic in autoimmune disease and that a mechanistic classification should be autoantibody based - I was really just suggesting that things may be a bit subtle. In our lab autoantibodies are TOTALLY responsible, for both the perpetuation of the immune dysregulation and effector mechanisms of tissue damage (near enough). There is nothing wrong with the T cells. But our impression is that clinical classification may map more closely to effector mechanisms - size of immune complex etc - than to antibody specificity, at least in RA (not so much for antinucleoprotein antibodies maybe). We suspect that certain autoantigens get caught up in the dysregulatory process in more than one way. Rheumatoid factor is the obvious example - those in RA are different from those in Sjogren's for instance. it looks as if an ACPA response can contribute in different ways too. That may depend on epitope specificity, relative affinity for one or other host protein as citrulline substrate, Vh gene usage or on class switching history. In fact my suspicion is that differences in Vh gene usage and abnormal patterns of class switching may be more relevant than epitope specificity.

At least we are now in an era when autoantibodies are taken seriously. For thirty years  everyone was obsessed with an imaginary loss of T cell tolerance! 

Hi Peter

We dis a study on Palindromic Rheumatism. Anti CCP was positive in 42% of patients.A multiicenter study of clinical and laboratory findings of

palindromic rheumatism in Iran. International Journal of Rheumatic Diseases 2012

You will find it as attached file.

Best regards

Alireza Khabbazi

Dear Peter,

i believe that the presence of any antibody needs to be seen in the clinical context. anti ccp may be present long before the onset of symptoms. if the pt of say systemic sclerosis has anti ccp but no arthritis, it would not have much clinical significance at the present time, but it is to be kept in mind that the disease may evolve.

i liken autoimmune diseases as a tree with a thick trunk with many branches. one never knows fro certain to which branch(es) the disease may evolve at a later stage.

Dear Max,

This is the work that led us to use rituximab in RA and get proof of concept for efficacy in autoimmunity. Its a long story scattered over a large number of papers with G Cambridge. The complex size issue goes back to Kunkel's work in the 1960s that nobody ever reads now but is far better than anything since in terms of physical chemistry. RA lesions map to the distribution of FcgRIII, which is good at generating TNF in response to low numbers of cross links. Circulating complexes cannot explain RA lesions through complement activation because it they bound complement they would be cleared in the circulation. Moreover, synovium has the highest level of complement inhibitory proteins of any tissue. Kunkel's people, and later Peters and co didn't twig to the significance of the paradoxical role of complement inside and outside vessels. Its a long a complicated set of arguments, but it explains the TNF in RA a lot better than T cells! The data on differences in rheumatoid factors I cannot honestly remember where we published - the isotype profiles in Sjogren's were quite different from RA I remember. But there is a whole lot of earlier work from people like Natvig and Thompson on fine specificities and Vh usage etc etc to show that RA rheumatoid factors are different from normal rheumatoid factors and those in other diseases. I am afraid I have lost touch with much of this since I retired.

Positive or elevated anti-CCP antibodies have been described in psoriatic arthritis, and interestingly enough, in mycobacterial infections. These are rare instances, however. For all practical purposes, a positive anti-CCP is seen in patients with RA for the most part.

thats the point, they are seen in RA for the MOST part. However, we have seen quite a few patients with ccp antibodies consistent with RA (according to the ACR criteria) who developed another autoimmune disease (per classification) later. the interesting thing here is to 1. explain the underlying mechanisms of two autoimmune diseases in one patient 2. maybe further define the role of ccp ab (are they really specific for RA or specific for erosive arthritis?. This is in an interesting topic which in my view warrants more research in these "overlap" patients. 

thans to everybody for your effort and your answersm they have been very thoughprovoking and helpful! 

That's correct; anti-CCP antibodies seem to be markers of more aggresssive and erosive RA. In addition, anti-CCP seropositivity precedes clinical disease by an average of 2.5 years or so. I have a couple of patients positive for anti-CCP for several years yet without clinical RA. What do you do with and for them in the meantime? That's another question. As far as other autoimmune disorders, there is an overlap syndrome of RA with lupus, often called "rhupus". Also, not uncommonly, RA tends to overlap with inflammatory myopathy, e.g., poly/dermatomyositis. We need more data about the role of anti-CCP antibodies in these subsets of patients.  

these are overlapping diseases

Since there are different commercially available anti-CCP ELISA on the market, it is important to state the actual autoantigenic targets used in the assay of interest. We have experience with second generation cyclic citrullinated peptides (CCP) described by Walter von Venrooij. We published a comparative analysis of APCA and found little reactivity with CCP in an extensive control group consisting of patients with non-RA joint inflammation (Conrad et al. Autoimmun Rev 2009;9:431-5). In contrast, the prevalence of autoantibodies to citrullinated proteins such as vimentin was higher in this group. It seems that citrullination is a pathognomonic feature of RA and provides posttranslationalyl modified autoantigenic epitopes.   

I am beginning to suspect that anti-CCP positivity may also be seen in certain patients with erosive hand osteoarthritis (OA). Over the last few years, I have a seen a number of patients with erosive hand OA who repeatedly display a positive anti-CCP test. Yet, these folks have not shown much evidence for RA at all on follow-up. What's going on? Could it be that a positive anti-CCP may also be part of erosive inflammatory hand OA in the absence of bona fide RA? We need more data here,

Dear Emilio,

this is an interesting Observation indeed. I personally am not aware of such cases by experience. I think that the presence of ccp-antibodies is more likely associated with erosive disease rather than the disease itself. We see also patients with systemic sclerosis who are ccp negative and have erosive arthritis on MRI but not radiologically, so there seem to be additional pathophysiologc processes.

In our recent study, Anti-CCP titer was positive in 16.3% patients with brucellosis. You can find the detail of our study in following link:

https://www.ncbi.nlm.nih.gov/pubmed/26781780  

Thank you for this remark. Indeed, ACPA have been found also in other infectious diseases (Tbc etc.). Do you have any pathophysiological explanation for ACPA and RF? In your study, however, the presence of ACPA was not different for patients vs. controls.