Background/Purpose: Rheumatoid factor (RF) and Anti-Citrullinated Protein antibodies (ACPA) are the most specific diagnostic markers of rheumatoid arthritis (RA). These antibodies are predominantly of the IgM (RF) or IgG (ACPA) isotype. The presence of IgA subtypes was reported but their added diagnostic and prognostic value has still not been fully elucidated. It was therefore the objective of this study to (i) determine the prevalence of IgA-RF and IgA-ACPA in patients with RA and (ii) to investigate their potential predictive value regarding response to treatment with methotrexate (MTX) and TNF inhibitors.

Methods:

To determine the diagnostic sensitivity and specificity sera from 255 RA patients, 258 disease controls and 100 healthy subjects were tested for the presence of IgA-RF and IgA-ACPA by EliA (Thermo Fisher Scientific). IgM-RF and IgG-ACPA were routinely measured by nephelometry and the anti-CCP EliA, respectively. Therapeutic responses to MTX and TNF inhibitors (TNFi) were analyzed in an inception cohort (n=104) who had started their DMARD therapy at our clinic. To define therapeutic responses simplified disease activity score (SDAI) and American College of Rheumatology (ACR) responses were calculated.

Results:

Diagnostic specificity was 95% for IgA-RF and 98% for IgA-ACPA, respectively. Among the 255 RA patients, 49% had at least one type of IgA antibody: 45% were IgA-RF positive (as compared to 61% IgM-RF positivity) and 31% were IgA-ACPA positive (56% IgG-ACPA positivity). Importantly, 10.5% of IgA-RF positive patients (i.e. 5% of the total cohort) were negative for IgM-RF (and half of also them for IgG-ACPA) while – apart from two exceptions- all IgA-ACPA positive patients had also IgG-ACPA. Thus, the added diagnostic value of IgA-RF was approximately 5% whereas IgA-ACPA only marginally increased the sensitivity of ACPA testing. Remarkably, the percentage of patients showing a SDAI50 response to TNFi was significantly lower in patients positive for IgA-RF and/or IgA-ACPA (p<0.0001) compared to IgA negative patients: while 58% of IgA negative (but IgM-RF and/or IgG-ACPA positive) patients showed a SDAI50 response only 25% of the IgA positive ones were responders. Interestingly, IgA-ACPA positive/IgA-RF negative patients were the poorest responders with only one out of nine patients showing a SDAI50 response whereas 4/13 IgA-RF positive/IgA-ACPA negative patients were responders. Seronegative patients also showed a significantly decreased SDAI50 response (p<0.001) to TNFi compared to IgM-RF/IgG-ACPA positive patients without IgA antibodies. Similar results were obtained when ACR20 was used as primary response criteria. Interestingly, no difference between the various groups was seen with respect to treatment with MTX.

Conclusion: Apart from a moderate added diagnostic value of IgA-RF, IgA subtypes and particularly IgA-ACPA appear to be strongly associated with a diminished therapeutic response to TNF blocking biological drugs, irrespectively of IgM-RF and IgG-ACPA. Therefore their determination may help in further stratification of RA patients and therapeutic decision making.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-prognostic-value-of-iga-subtypes-of-rheumatoid-factor-and-anti-citrullinated-protein-antibodies-acpa-for-prediction-of-therapeutic-responses-to-tnf-inhibitory-therapy-in-patients-with-rheu/