The main findings in the present study are that positive ANA status before the initiation of treatment with infliximab and use of infliximab without methotrexate in patients with RA are independent risk factors for developing infusion reactions; and that the risk is considerably increased in patients with a combination of both factors. The risk is most pronounced in ANA-positive patients treated with infliximab as monotherapy, suggesting that concomitant treatment with DMARDs, preferably methotrexate, should be encouraged before initiation of infliximab in RA patients. Concerning DMARDs other than methotrexate, use of sulphasalazine, of azathioprine and of all other DMARDs as a group were not associated with infusion reactions.
The association between new appearances of ANAs during infliximab treatment and the clinical consequences of these have been addressed in several studies [7
]. However, to our knowledge, the present study is the first to report the predictive value of baseline ANA status for development of infusion reactions. ANA status is usually known or can be determined before the initiation of biologic treatments. Our results suggest that the presence of ANAs should be taken into account when infliximab treatment is considered.
The observation that combined treatment with infliximab and methotrexate was associated with reduced induction of anti-infliximab antibodies raised the hypothesis that concomitant methotrexate treatment reduces immunogenicity against monoclonal antibodies [2
]. Also, patients with Crohn's disease experienced less frequent infusion reactions if infliximab treatment was given in combination with other immunosuppressive agents [6
]. Our findings are in accordance with those reports and suggest that continuous methotrexate treatment should be encouraged in RA patients treated with inflximab and probably other monoclonal antibodies as well.
We found no association between baseline ANA status and use methotrexate and subsequent development of infliximab-related infusion reactions in patients with SpA. However, this finding must be interpreted with caution because of limited statistical power. In our study, concomitant treatment with methotrexate was used to a lesser extent in patients with SpA than in patients with RA, probably because methotrexate is not a prerequisite therapy in SpA patients. Furthermore, more frequent use of infliximab as monotherapy in SpA (48.9% versus 21.6%; Table ) could be one possible explanation for the significant shorter duration of treatment at the moment of infusion reaction (4.3 months and 11.5 months for SpA and RA, respectively).
Additionally, more RA than SpA patients developed infusion reactions during the treatment. However, no significant difference in frequency of infusion reactions was observed between RA and SpA patients, possibly also reflecting the problem of statistical power. Provided that the same underlying mechanism is responsible for development of infusion reactions in both RA and SpA, the use of infliximab as monotherapy in a large proportion of SpA patients might have contributed to the nonsignificant difference.
In case of insufficient clinical response after 3 months, infliximab dosage could be increased. In a substantial proportion of both RA and SpA patients, infliximab dosage was increased over time but no clear association between increased dosage and infusion reactions could be detected.
A further interesting observation in the study is the unexpected high frequency (25%) of ANA positivity at baseline in SpA patients. In a recently reported review article by De Rycke and coworkers [9
], which includes an overview of the studies investigating autoantibody profile during treatment with infliximab, ANAs were detected in between 4% and 17% of SpA patients before initiation of treatment. One possible explanation might be the use of different methods to detect ANAs. An advantage of international guidelines for clinical use of immunofluorescence assay for determination of ANAs is that comparisons of the results from different studies should be possible [17
]. The method applied in our study is accredited and used routinely at Lund University Hospital. The prevalence of ANAs in our RA patients (27.9%) is comparable with that reported in the literature [9
The mechanism underlying the association between ANA positivity and infusion reactions remains unknown. Immunological mechanisms are thought to be responsible for many of the toxic reactions to some DMARDs [12
]. Furthermore, Panayi and coworkers found a positive correlation between HLA-DR phenotype and toxic complications of some DMARDs [14
]. The findings of increased risk for developing infusion reactions in ANA-positive RA patients in our study support the plausibility of underlying immunogenetic mechanisms of drug-related side effects.
One weakness of this work is that determination of anti-infliximab antibodies was not performed. In a previously reported study including infliximab-treated patients with Crohn's disease, development of anti-infliximab antibodies of IgG type was found to be associated with increased risk for infusion reactions [6
]. Our pilot study of development of anti-infliximab antibodies and infusions reactions in selected patients with RA [21
] showed that antidrug antibodies were mostly of IgG and not of IgE type, despite clinical symptoms indicating type I allergic reactions. The clinical relevance of measuring these antibodies is currently being investigated.
In summary, RA patients in whom ANA positive status is present at treatment initiation with infliximab and who are treated without methotrexate are at increased risk for developing infusion reactions. The possible protective effects of DMARDs other than methotrexate against such infusion reactions remain to be studied.