Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.

Identification of Biomarkers for Enhanced Benefit to Rituximab in Rheumatoid Arthritis: Role of Autoantibodies and Inflammatory Markers

Silverman¹, G. J., Schwartzman², Sergio, Townsend³, M., Su³, Z., Holweg³, C., Read⁴, S., Yocum³, D.

UCSD, La Jolla, CA,
Hosp for Special Surgery, New York, NY,
Genentech, South San Francisco, CA,
Roche, United Kingdom

Purpose:

Rituximab has been shown to significantly improve the signs and symptoms of rheumatoid arthritis (RA) as well as slow the progression of joint damage. The purpose of this analysis was to examine serologic markers in randomized clinical trials (RCT) and identify biomarkers that best distinguish patient subsets with high hurdle clinical responses (ACR 50 at 24 weeks) to rituximab therapy.

Methods:

With baseline samples from the REFLEX trial of 517 RA patients with previous inadequate response to TNF inhibitors, a threshold sensitivity method was used to identify candidate biomarkers that enriched for placebo corrected ACR50 response at 24 weeks, and which represented at least 20% of subjects. Of 19 serological markers and 9 clinical features examined, we identified the best four biomarkers, which included levels of IgA isotype of rheumatoid factor (RF), sCD25, and IgG anti-CCP3 antibodies, as determined by ELISA, and of C-reactive protein (CRP), as determined by nephelometry. These biomarkers and five of their two-biomarker combinations as well as levels of IgM and IgG isotypes of RF were then further investigated following a pre-specified diagnostic plan using data from the SERENE RCT of 501 RA patients with an inadequate response to methotrexate. We then also calculated odds ratios for achieving an ACR50 response at 24 weeks compared to placebo, as well as additional summary statistics for biomarker positive/negative subgroups (Table 1).

Table. Efficacy difference (95% CI) between Rituximab and placebo treated patients at Week 24 in the SERENE trial.

	²amp; ACR50*	ACR50 O.R.	²amp; ACR20	²amp; EULAR good/moderate	²amp; mean DAS change from baseline
Biomarker(+)
CRP>2.9 mg/dL & RF IgA**>25 U/ml	34%	10.4	44%	55%	-1.54
22% population	(20%, 48%)	(2.9, 37.2)	(28%, 60%)	(39%, 71%)	(-2.00, -1.08)
Biomarker(-)	13%	2.7	26%	25%	-0.82
78% population	(6%, 20%)	(1.4, 5.2)	(16%, 36%)	(15%, 35%)	(-1.11, -0.53)
*²amp; is between active and placebo. Permutation p-value=0.02, unadjusted for the number of biomarkers considered.
**Similar enhanced benefit to rituximab in the biomarker (+) group was observed when any other isotype of RF or Total RF was substituted for RF IgA.

Results:

In discovery studies we found that, compared to seronegative patients, seropositivity for any isotypes of RF or IgG anti-CCP antibodies was associated with a higher rate of placebo controlled ACR50 responses at 24 weeks. Patients with elevated levels of CRP also demonstrated more frequent clinical benefit. These findings were independently reiterated in the SERENE patient populations. The greatest enhancement was seen in patients with both elevated baseline CRP (>2.9 mg/dL) and positivity for RF of any isotypes or IgG anti-CCP. These patients had better clinical responses across a spectrum of clinical outcome measures (ACR responses, delta DAS, and EULAR response).

Conclusion:

In the REFLEX and SERENE RCT, the presence of autoantibodies and elevated CRP identified a subgroup of RA patients with an enhanced benefit to rituximab. However, these findings need to be verified in large independent data sets.

To cite this abstract, please use the following information:
Silverman, G. J., Schwartzman, Sergio, Townsend, M., Su, Z., Holweg, C., Read, S., et al; Identification of Biomarkers for Enhanced Benefit to Rituximab in Rheumatoid Arthritis: Role of Autoantibodies and Inflammatory Markers [abstract]. Arthritis Rheum 2009;60 Suppl 10 :1680
DOI: 10.1002/art.26754

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