FIRST is an exploratory, multi-center, open label, uncontrolled phase IIIb study evaluating the efficacy of Rituximab (RTX) in RA after inadequate response to a single TNFα inhibitor (TNFi). 302 patients were treated with 1000 mg RTX on days 1 and 15 and observed up to 2 years. In a substudy, it was intended to investigate B cell markers and to identify B cell populations predictive of response at week 16.
In the substudy (n=154) rheumatoid factor (RF), RF-isotypes, peripheral CD19+ B cells and CD19+ B cell subpopulations using marker combinations of IgD, CD10, CD38, CD27 and CD20 were determined. Their impact on EULAR response rates (ER) was analysed univariately and multivariately. Stepwise forward logistic regression including the significant (p<0.1) B cell markers (logarithms) was used with entry and stay criterion of 10%. Odds ratios (OR) and their 95% confidence intervals [in brackets] were determined for the final model.
Baseline characteristics: n=154, age [mean ± s.d.] = 54.9 ± 9.9 years, female 77.9%, RF+ 71.4%, RFIgA 103.9 ± 118.7 [IU/mL]. At week 16 112 patients (72.7%) achieved ER (good response 26.6%). DAS28 changed from initial 5.8 ± 1.0 to 4.0 ± 1.2 (week 16). About half of the patients (49.4%) showed an improvement in ACR 20, 18.8% in ACR 50 and 6.5% in ACR 70. According to predictors identified, the observed ER were: for RF+ patients 80.0%, RF- 56.1%, RFIgA+ 81.4%, RFIgA- 63.5%, for normal or above normal CD19 B cells [%] (CD19+) 75.7%, for low CD19 [%] (CD19-) 62.2%.
Multivariate analysis (MVA) yielded higher ER for RFIgA+ (p = 0.0154, OR=2.576 [1.198, 5.540]) and for CD19+ [%] (p = 0.0517, OR=2.186 [0.994, 4.807]). Observed ER were 83.9% (RFIgA+/CD19+), 73.1% (RFIgA+/CD19-), 69.0% (RFIgA-/CD19+) and 47.4% (RFIgA-/CD19-). Further MVA intending to differentiate specific B cell subpopulations yielded that ER is influenced by “double negative” CD27-IgD- B cells (27-D-) (p=0.0174, OR=1.989 [1.129, 3.506]). Observed ER for CD27-IgD- B cells (≥5/μL) were 81.8% and for low CD27-IgD- B cells (<5/μL) 62.9%. Combining RF and CD27-IgD- B cells resulted in ER for RF+ patients with 90.9% (RF+/27-D-(≥5) and 72.5% (RF+/27-D-(<5)). In RF negative patients the RF-/27-D-(≥5) group achieved 61.9% and the RF-/27-D-(<5) group 41.2% ER.
Among the different B cell markers in addition to RF positivity, normal or high values of B cells (CD19) and higher values of “double negative” CD27-IgD- B cells proved to be predictive of better EULAR responses to a first course of RTX+MTX. This was true among RF+ as well as among RF- patients. Particularly in RF negative patients the determination of CD19+ or “double negative” CD27-IgD- B cells may prove useful to select responding patients.
Disclosure: H. P. Tony, None; P. Roll, None; H. Mei, None; L. Gnuegge, Roche Pharma AG, 3 ; M. Kobialko, Roche Pharma AG, 3 ; T. Dörner, None.