Abstract
BackgroundMethotrexate (MTX) is the standard first-line therapy in rheumatoid arthritis (RA) with variable clinical efficacy that is difficult to predict. The glycosylation status of immunoglobulin G (IgG) is altered in RA and influenced by MTX treatment. We aimed to further investigate if IgG glycosylation in untreated early RA can predict therapeutic response to MTX.MethodsWe used a shotgun proteomic approach to screen for the Fc glycopeptides in the serum of 12 control subjects and 59 untreated patients with early RA prior to and following MTX initiation. MTX treatment response was defined according to the European League Against Rheumatism at a median of 14 weeks (range 13–15) after treatment initiation. Seropositive patients were defined as those testing positive for anticitrullinated protein antibodies and/or rheumatoid factor at baseline (n = 44). Data analysis was performed using uni- and multivariate statistics.ResultsWe could confirm a low abundance of galactosylated glycans in untreated patients with early RA compared with control subjects that was partially restored by MTX treatment. This was more evident among future nonresponders than among responders to MTX treatment. Results were further validated and confirmed by multivariate statistical analysis of the baseline Fc glycan, proteomic, and clinical data. We found that the ratio between the main agalactosylated (FA2) and main mono- and di-galactosylated Fc glycans (FA2G1 and FA2G2) of IgG1 ranked as the most prominent factor distinguishing responders from nonresponders. A low baseline ratio of FA2/[FA2G1 + FA2G2]-IgG1 was associated with nonresponse (OR 5.3 [1.6–17.0]) and was able to discriminate future nonresponders from responders to MTX therapy with a sensitivity of 70% (95% CI 46–88%) and a specificity of 69% (95% CI 52–83%). For seropositive patients (n = 44), this trend was improved with a sensitivity of 73% (95% CI 45–92%) for nonresponse and a specificity of 79% (95% CI 60–92%).ConclusionsWe show that the FA2/[FA2G1 + FA2G2] of IgG1 is a biomarker candidate that is significantly associated with nonresponding patients and has potential value for prediction of MTX clinical response.
Highlights
Methotrexate (MTX) is the standard first-line therapy in rheumatoid arthritis (RA) with variable clinical efficacy that is difficult to predict
To test the influence that the different fragment crystallizable (Fc) glycan sugar types have on the RA patient profile and their potential as biomarkers for response to treatment, the IgG1- and IgG2-Fc glycans were grouped as galactosylated, agalactosylated, afucosylated, bisected, and sialylated
Baseline Main agalactosylated Fc glycan (FA2)/(FA2G1 + Main digalactosylated Fc glycan (FA2G2)) of IgG1 can predict response to MTX treatment in early RA Because uni- and multivariate data analyses indicated that the baseline Fc glycan ratio of FA2/(FA2G1 + FA2G2) of IgG1 was the top candidate for distinguishing between MTX responders and nonresponders, we further investigated this marker’s performance in predicting therapeutic response (Table 3)
Summary
Methotrexate (MTX) is the standard first-line therapy in rheumatoid arthritis (RA) with variable clinical efficacy that is difficult to predict. Effector functions of antibodies are mediated largely through the fragment crystallizable (Fc) portion, such as phagocytosis; cell cytotoxicity; complement activation; and, more recently, osteoclast activation [1, 2]. These functions are dependent on the glycan structures present on the constant heavy chains of the Fc portion of immunoglobulin G (IgG). The more complex the glycan is ( if the glycan contains galactose and sialic acid), the less likely it is for antibodies to have a proinflammatory effect [3,4,5,6]. ACPA IgGs have a perturbed pattern of Fc glycans compared with the total IgG pool [10,11,12]
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