Re: Autoantibodies found in blood years before onset of RA

[Guest guest]

This is very interesting. Probably 15 years ago, I ran an RA titer on myself

just out of curiosity, since my dad had it. I had no real symptoms then, but my

titer was a low positive. It wasn't enough positive to be serious, but right on

the borderline.

So when I did start having problems, and my titer was really positive, it really

didn't come as a surprise.

Noreen

[ ] Autoantibodies found in blood years before onset of RA

Rheumawire

Mar 4, 2004

Autoantibodies found in blood years before onset of RA

Amsterdam, the Netherlands - A second study has shown that many patients

with rheumatoid arthritis (RA) have autoantibodies typically associated

with RA circulating in their bloodstream several years before they

experienced any symptoms [1]. The finding opens up the possibility of

using interventions to prevent the development of RA, particularly in

high-risk individuals, say the researchers.

The latest study, reported by Dr Markus Nielen (Jan van Breemen

Institute, Amsterdam, the Netherlands) and colleagues in the February

2004 issue of Arthritis & Rheumatism, has very similar findings to those

reported by Dr Solbritt Rantapaa-Dahlqvist (Umea University, Sweden) and

colleagues last October in the same journal [2]. Both groups traced RA

patients who had been blood donors long before they developed the

diseases and tested early blood samples for antibodies against

anti-cyclic citrullinated proteins (anti-CCP) and also against

immunoglobulin rheumatoid factor (the Dutch group tested for IgM-RF; the

Swedes tested for IgG-RF, IgM-RF, and IgA-RF).

Both groups found autoantibodies in the blood of manybut not allof the

RA patients long before they showed symptoms of the disease.

In the Dutch study, 39 of 79 patients (49%) had at least 1 positive test

for anti-CCP/IgM-RF, found at a median of 4.5 years (range 0.1-13.8)

before symptom onset. The researchers note that the patients who had

autoantibodies before developing symptoms were significantly younger and

went on to have more radiographic damage than those who didn't.

The Swedish researchers studied 83 RA patients, of whom 33.7% had

anti-CCP antibodies: 16.9% had IgG-RF, 19.3% had IgM-RF, and 33.7% had

IgA-RF antibodies. The longest time between onset of symptoms and the

finding of these autoantibodies was 22 years for IgA-RF, 19 years for

IgG-RF and IgM-RF, and 9 years for anti-CCP.

Nielen tells rheumawire that the findings of both studies were similar

but points out that the study he and his colleagues conducted is the

first to report on findings from serial blood samples. There have been

previous reports of autoantibodies found long before disease

development, but all of these have been from single blood samples, and

even the Swedish findings are based on only 1 or 2 samples from each

patient (a total of 98 samples obtained for 83 subjects). In contrast,

their study tested a total of 1188 samples for 79 patients, with a

median of 8 samples per individual.

This serial blood testing allows a glimpse into the time sequence of

events involved in the pathogenesis of RA, Nielen et al comment. " An

unknown trigger activates B lymphocytes to produce RA-specific

autoantibodies several years before the appearance of a level of

inflammation that is perceived as symptoms. In the majority of patients,

seropositivity, once established, is stable. "

" The production of autoantibodies in itself is not essential for

clinical disease, since it occurred in only half of the patients before

onset of symptoms, " the researchers note. " Still, these patients proved

to be more severely affected in terms of radiologic findings, and the

prevalence of antibodies increased over time and was highest in the year

before symptoms appeared. Apparently, the conversion to

RF-seropositivity continued after the onset of symptoms and reached the

commonly reported prevalence level of 67% after 6 years. "

" Our findings indicate that it may be possible to predict RA development

in high-risk populations, " say Nielen and colleagues, and they raise the

possibility of medical intervention to prevent the development of the

disease in these individuals.

One group to target with such an approach would be multicase family

members, who already have 2 or more first-degree relatives with RA.

Previous reports have estimated that such an individual has a 3.9% risk

of developing RA in the next 5 years. However, from their findings,

Nielen et al calculate that if such a family member tests positive for

anti-CCP, the 5-year risk of developing RA rises to 69.4%. " We believe

this figure is high enough to consider a clinical trial of a medical

intervention to prevent the development of RA in these individuals, "

they comment. Other groups to target include patients with arthralgia

and positive serologic findings, they add.

Nielen tells rheumawire his group is now planning a clinical trial in

about 100 high-risk individuals, people who have 1 first-degree relative

with RA or those who have painful but not swollen joints who also test

positive for anti-CCP or IgM-RF or both. The aim is to try to prevent RA

from developing in these individuals, but how to do this is still being

discussed. Nielen says that it would not be suitable to use a drug such

as methotrexate or any of the disease-modifying antirheumatic drugs

(DMARDs) in such healthy individuals because of their toxicity, but 1

option may be to use a steroid such as prednisolone.

The Dutch researchers also comment that the tests for both

autoantibodies were found to be highly specific in their study, which

implies that the finding of an elevated serum level of IgM-RF or

anti-CCP or both signifies a high risk for the development of RA in

healthy persons up to age 70 years (the upper age limit of the blood

donors).

In the earlier paper, the Swedish researchers concluded that anti-CCP

antibodies and RF (particularly IgA-RF) predate the development of RA by

up to several years and that the presence of anti-CCP antibody has a

strong predictive value for later development of RA.

Rantappaa-Dalhlqvist and colleagues report that combining the presence

of anti-CCP antibodies and the presence of any of the RF isotopes in

blood samples predating the onset of symptoms resulted in high

specificity, with increases to 99% and 100%. In the general population,

for which the prevalence of RA is estimated at 1%, the positive

predictive value based on a combination of anti-CCP antibody and RF

isotypes was around 20%. This is of the same order of magnitude as

mammography screening for breast cancer, which has a PPV of 12% to 46%.

However, the PPV would be much higher in an at-risk group (eg, patients

attending an early arthritis clinic), they note. For instance, for

individuals with pain syndromes (in whom the occurrence of RA would be

estimated at 8%), the PPV of anti-CCP alone was 62% and rose to 63% to

70% for a combination of anti-CCP with any RF isotype.

They conclude that serologic screening for autoantibodies is feasible

and would be of " considerable help in the clinical management of

patients in whom RA is predicted to develop. "

Zosia Chustecka

Sources

1. Nielen MM, van Schaardenburg D, Reesink HW, et al. Specific

autoantibodies precede the symptoms of rheumatoid arthritis: a study of

serial measurements in blood donors. Arthritis Rheum 2004 Feb;

50(2):380-6.

2. Rantapaa-Dahlqvist S, de Jong BA, Berglin E, et al. Antibodies

against cyclic citrullinated peptide and IgA rheumatoid factor predict

the development of rheumatoid arthritis. Arthritis Rheum 2003 Oct;

48(10):2741-9.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org