Statistics from Altmetric.com
We read with interest the editorial by Soltys and colleagues about rheumatoid factors (RFs).1 They correctly stated that most naturally occurring RFs were of the IgM isotype while IgG RFs were thought to be associated with rhematoid arthritis (RA). It should be pointed out in this context that it is very difficult to measure IgG RF and this RF isotype can only be detected in approximately 50% of RA patients whereas IgA RF, usually in combination with IgM RF, can be detected in most patients with seropositive RA.2-4 It should also be noted that increased IgA RF is associated with severe manifestations in RA and this has been extensively reported by several different groups in the last 15 years.5-10
Furthermore, several reports have shown that RFs may be increased in serum many months or even years before clinical symptoms of RA appear,11-13 and it has also been reported that symptom free people with an increase in IgA RF or IgG RF have an increased risk of developing RA.14 This indicates that both IgA RF and IgG RF may have a primary role in the pathogenesis of RA.
Recent studies have shown that a combined increase in IgM and IgA RF, with or without IgG RF, is the most common RF pattern found in patients with RA.2-4 14 Thus, a combined increase in IgM and IgA RF is very specific for RA and rarely found in symptom free people or patients with other rheumatic disorders.3 15 It should also be noted that IgG RF and IgM RF are more frequently raised than IgA RF in symptom free members of families with multicase RA.16 This indicates that an increase in IgA RF is more specific for RA than an increase in IgM RF or IgG RF. Thus, switching from IgM RF to IgA RF may be at least as important in the pathogenesis of RA as switching to the IgG class.
Several studies have shown that RA patients with an increase in IgA RF develop a more severe disease, with bone erosions or extra-articular manifestations, or both, than patients without IgA RF.5-10 17-21 Table 1 summarises some published studies on the association between disease manifestations in RA and different RF isotypes. Not all studies have agreed2 18 but different findings can at least in part be explained by technical differences in RF testing.24 25
Measurement of individual RF isotypes is clinically useful, both in terms of diagnostic and prognostic evaluation of patients with RA. Furthermore, it is probable that RF has a primary role in the pathogenesis of RA and this may apply even more to IgA RF than IgG RF.
We are most grateful to Drs Jonsson and Valdimarsson for their additional comments with regard to rheumatoid factors and their definite pathogenic associations with disease mechanisms in rheumatoid arthritis.
Their take home message is that perhaps we should be measuring other rheumatoid factor isotypes, as well as IgM, as they may be more prognostically relevant. This may indeed be the case but, at present, IgM rheumatoid factor is the only isotype that can be precisely measured using techniques such as nepholometry where additionally there is an accepted primary (WHO) standard. IgG and IgA rheumatoid factors are often measured by enzyme linked immunosorbent assay and this is where problems may occur. IgM rheumatoid factors can interfere with the assay by binding to the antigen and then subsequently to the detection antibody to give false positive results. Use of F(ab)2 gets over this to some extent, but IgM can still form complexes that may interfere. Currently there is no agreed international reference standard to make assays comparable between laboratories and in the UK there is no national quality assurance programme; other than for IgM. This means that there can be no independent assessment of laboratory performance of IgG and IgA rheumatoid factors if these were to be applied to clinical samples. The advice from Professor Pam Riches of the Protein Reference Unit at St George’s Hospital Medical School is that, at present, she would not recommend the use of non-standardised unvalidated assays other than for research.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.