POS0647 DOES TNF INHIBITOR MOLECULAR STRUCTURE MATTER? ANALYSIS OF IMPACT OF BASELINE RHEUMATOID FACTOR TITERS ON DRUG LEVELS IN PATIENTS WITH RHEUMATOID ARTHRITIS

Abstract

BackgroundElevated rheumatoid factor (RF) in patients with rheumatoid arthritis (RA) is associated with higher disease activity and increased risk for disease progression1.Recent publications indicate significantly lower efficacy of TNF inhibitors (TNFi) in RA patients with high RF levels compared with low/negative RF subgroup2,3. Fab therapy with Certolizumab pegol (CZP), a PEGylated, Fc-free monoclonal antibody (mAb), has shown comparable efficacy and consistent serum levels irrespective of baseline RF4.RF binds the Fc region of IgG1, the subtype used to engineer the majority of mAbs5. Formation of large immune complexes may likely explain the inceased clearance of mAbs in patients with high RF titers and reported reduced TNFi efficacy.ObjectivesWe aimed to evaluate in clinical practice whether RF levels in RA patients influence serum drug levels of 3 TNFi with different molecular structures.MethodsWe evaluated retrospectively a cohort of RA patients from La Paz University Hospital (RA-Paz Registry, 1999-2019) treated with Infliximab (IFX), Adalimumab (ADA) or CZP. Clinical and demographic data were collected at baseline (T0) and after 6 months (T6) of treatment. RF titers and serum drug levels were measured at T0 and T6 using nephelometry and ELISA respectively. Association between baseline RF titers and drug levels was assessed using non-parametric test (Mann-Whitney).Results168 patients were evaluated: 90 received IFX, 48 ADA and 32 CZP. Characteristics at T0 are shown in Table 1. All patients had active disease at baseline and 76% were RF positive: ADA subgroup had lower percentage of positive RF than IFX and CZP subgroups. Patients were stratified into quartiles based on baseline RF titers: low (20-57 IU/ml), medium (57-380 IU/ml), high (>380 IU/ml) and seronegative (<20 IU/ml).Table 1.Baseline characteristics.CharacteristicsTotal (n=168)IFX (n=90)ADL (n=48)CZP (n=32)p valueAge, years*55.5(45.3-66)57(46-65)50(42-64)61(47-70)0.08Body mass index, Kg/m2*24.5(21.7-29)24.2(21.8-27.7)24.7(21.5-30.3)24.6(22.2-30.3)0.3Male, n(%)28(17%)14(15%)9(19%)5(17%)0.2Disease duration, years*8.7(4.5-14.3)8.4 (4.4-14.3)8.8 (3.9-16)9.7(5-12)0.06Smoking status, n(%)0.03Currently/ex-smoker66(39%)29(32%)22(48%)16(57%)Non-smoker96(57%)61(68%)24(52%)12(43%)RF, n(%)128(76%)75(83%)28(58%)25(81%)0.002ACPA, n(%)134(80%)73(81%)35(73%)27(84%)0.3DAS28**5.1(1.3)5.4(1.3)4.5(1.3)4.9(1.3)0.002CRP levels*7.8(3-21.8)10.3(3.2-25.2)5.1(1.4-10.1)7.8(2.3-18.2)0.1Prior bDMARDs, n(%)26(15%)10 (11%)10 (21%)6(20%)0.2Monotherapy, n(%)16(10%)8(9%)8(17%)00.2csDMARDS, n(%)152(90%)82(91%)82(91%)32(100%)Methotrexate, n(%)112(67%)64(78%)33(83%)17(53%)0.2Other csDMARDs, n(%)24(24%)18(22%)7(18%)15(50%)0.0008Prednisone, n(%)85(51%)49(54%)21(44%)16(50%)0.6*Median and interquartile range;**mean and standard deviationDrug levels of IFX and ADA at T6 were significantly lower in those patients who had higher RF titers at T0 compared to seronegative. In contrast, CZP levels remained stable irrespectively of baseline RF titers, without significant differences among quartiles (Figure 1).ConclusionHigher baseline RF titers are associated with lower IFX and ADA levels at T6 in a cohort of RA patients. A concentration-response association has been clearly established for TNFi, and baseline RF levels appear to influence drug levels.Reduced immune complexes formation with CZP may result in a limited impact of baseline RF titers on drug levels.