Two Biomarkers May Predict Rituximab Response in RA

Major Finding: Response rate to rituximab is highest in RA patients with elevated CRP and RF positivity.

Data Source: Post hoc analysis of data from REFLEX and SERENE trials.

Disclosures: The study was supported by Genentech Inc., F. Hoffmann-LaRoche Ltd., and Biogen Idec Inc. Dr. Faraawi reported receiving research grants from Roche, Pfizer Inc., UCB, Schering-Plough Corp., and Wyeth.

QUEBEC CITY — Baseline serologic biomarkers offer rheumatologists the possibility of tailoring rheumatoid arthritis medications to fit various subgroups of patients, thereby increasing the likelihood of achieving a good response to treatment, said Dr. Rafat Faraawi at the annual meeting of the Canadian Rheumatology Association.

In a sea of pharmaceuticals for RA, with no clear understanding of why some patients respond to one agent and not to another, biomarkers are a potential tool for predicting treatment response, Dr. Faraawi said in an interview with

“We still don't have guidelines on how to select pharmaceuticals. More or less, [the drugs] all have the same efficacy. There are minor differences, and then the selection depends on many factors.

“We depend on personal preference, physician experience, certain peculiarities of the drugs, mechanism of action,” according to Dr. Faraawi.

In a post hoc analysis of two large trials of rituximab, his group discovered that a subgroup of patients with high serum levels of C-reactive protein (CRP) as well as seropositivity for rheumatoid factor (RF) had the highest response to rituximab. “If you want to select patients who will get a response to this expensive biologic, then those with positive rheumatoid factor and an elevated C-reactive protein most likely will show a better response than [will] seronegative patients or those with low CRP.

“And if they have a combination of both, that is even better,” said Dr. Faraawi, who is a rheumatologist at McMaster University in Kitchener, Ont.

He presented the data as a poster at the meeting.

The investigators used data from REFLEX (Randomized Evaluation of Long-Term Efficacy of Rituximab in RA) and SERENE (Study Evaluating Rituximab's Efficacy in Methotrexate Inadequate Responders).

Both are randomized, placebo-controlled trials of rituximab in patients with inadequate response to either tumor necrosis factor inhibitors or methotrexate, respectively (Arthritis Rheum. 2006;54:2793-806; ACR 2008, abstract 364).

Both trials reported ACR 50 response rates for rituximab, compared with placebo, after 24 weeks.

The REFLEX trial (n = 517) showed an ACR 50 response of 27% in the treated group, compared with 5% in placebo. And the SERENE trial (n = 501) showed an ACR 50 response of 26% in the treated group, compared with 9% in placebo.

For both trials, baseline levels of 19 serologic markers and 9 clinical features were recorded.

After an analysis of baseline and outcome data from both trials, Dr. Faraawi's study identified four serologic biomarkers—RF, CRP, IgG anti–cyclic citrullinated peptide 3 (CCP3) antibodies, and soluble cluster of differentiation 25 (CD25)—that were predictive of response to rituximab, he explained.

Of these, seropositivity for RF and CRP were the most predictive, and this was further enhanced when both biomarkers were presented.

For example, in the REFLEX trial, the overall ACR 50 response rate was 27% in the treated group, whereas the subgroup of patients with CRP levels above 2.9 mg/dL and positive RF of any isotope (defined as IgA RF greater than 25 U/mL, IgG RF greater than 20 U/mL, IgM RF greater than 20 U/mL, total RF greater than 20 IU/mL) had an ACR 50 response rate of 31% (placebo, 1%).

Similarly, in the SERENE trial, the overall ACR 50 response rate was 26% in the treated group, whereas the response rate was 39% in the same subgroup of patients who were positive for RF and had an elevated CRP (placebo, 7%).

Rituximab is a monoclonal antibody that selectively targets CD20-positive B cells, which secrete rheumatoid factor, said Dr. Faraawi.

“That is why, for this particular drug, patients with positive rheumatoid factor respond well. That doesn't mean this agent does not work for patients with low markers. It still works. But the likelihood of response is greater with positive markers.”

He said that large trials are needed to further clarify which markers can help in the selection of agents for specific patients.

Major Finding: Response rate to rituximab is highest in RA patients with elevated CRP and RF positivity.

Data Source: Post hoc analysis of data from REFLEX and SERENE trials.

Disclosures: The study was supported by Genentech Inc., F. Hoffmann-LaRoche Ltd., and Biogen Idec Inc. Dr. Faraawi reported receiving research grants from Roche, Pfizer Inc., UCB, Schering-Plough Corp., and Wyeth.

QUEBEC CITY — Baseline serologic biomarkers offer rheumatologists the possibility of tailoring rheumatoid arthritis medications to fit various subgroups of patients, thereby increasing the likelihood of achieving a good response to treatment, said Dr. Rafat Faraawi at the annual meeting of the Canadian Rheumatology Association.

In a sea of pharmaceuticals for RA, with no clear understanding of why some patients respond to one agent and not to another, biomarkers are a potential tool for predicting treatment response, Dr. Faraawi said in an interview with

“We still don't have guidelines on how to select pharmaceuticals. More or less, [the drugs] all have the same efficacy. There are minor differences, and then the selection depends on many factors.

“We depend on personal preference, physician experience, certain peculiarities of the drugs, mechanism of action,” according to Dr. Faraawi.

In a post hoc analysis of two large trials of rituximab, his group discovered that a subgroup of patients with high serum levels of C-reactive protein (CRP) as well as seropositivity for rheumatoid factor (RF) had the highest response to rituximab. “If you want to select patients who will get a response to this expensive biologic, then those with positive rheumatoid factor and an elevated C-reactive protein most likely will show a better response than [will] seronegative patients or those with low CRP.

“And if they have a combination of both, that is even better,” said Dr. Faraawi, who is a rheumatologist at McMaster University in Kitchener, Ont.

He presented the data as a poster at the meeting.

The investigators used data from REFLEX (Randomized Evaluation of Long-Term Efficacy of Rituximab in RA) and SERENE (Study Evaluating Rituximab's Efficacy in Methotrexate Inadequate Responders).

Both are randomized, placebo-controlled trials of rituximab in patients with inadequate response to either tumor necrosis factor inhibitors or methotrexate, respectively (Arthritis Rheum. 2006;54:2793-806; ACR 2008, abstract 364).

Both trials reported ACR 50 response rates for rituximab, compared with placebo, after 24 weeks.

The REFLEX trial (n = 517) showed an ACR 50 response of 27% in the treated group, compared with 5% in placebo. And the SERENE trial (n = 501) showed an ACR 50 response of 26% in the treated group, compared with 9% in placebo.

For both trials, baseline levels of 19 serologic markers and 9 clinical features were recorded.

After an analysis of baseline and outcome data from both trials, Dr. Faraawi's study identified four serologic biomarkers—RF, CRP, IgG anti–cyclic citrullinated peptide 3 (CCP3) antibodies, and soluble cluster of differentiation 25 (CD25)—that were predictive of response to rituximab, he explained.

Of these, seropositivity for RF and CRP were the most predictive, and this was further enhanced when both biomarkers were presented.

For example, in the REFLEX trial, the overall ACR 50 response rate was 27% in the treated group, whereas the subgroup of patients with CRP levels above 2.9 mg/dL and positive RF of any isotope (defined as IgA RF greater than 25 U/mL, IgG RF greater than 20 U/mL, IgM RF greater than 20 U/mL, total RF greater than 20 IU/mL) had an ACR 50 response rate of 31% (placebo, 1%).

Similarly, in the SERENE trial, the overall ACR 50 response rate was 26% in the treated group, whereas the response rate was 39% in the same subgroup of patients who were positive for RF and had an elevated CRP (placebo, 7%).

Rituximab is a monoclonal antibody that selectively targets CD20-positive B cells, which secrete rheumatoid factor, said Dr. Faraawi.

“That is why, for this particular drug, patients with positive rheumatoid factor respond well. That doesn't mean this agent does not work for patients with low markers. It still works. But the likelihood of response is greater with positive markers.”

He said that large trials are needed to further clarify which markers can help in the selection of agents for specific patients.

Major Finding: Response rate to rituximab is highest in RA patients with elevated CRP and RF positivity.

Data Source: Post hoc analysis of data from REFLEX and SERENE trials.

Disclosures: The study was supported by Genentech Inc., F. Hoffmann-LaRoche Ltd., and Biogen Idec Inc. Dr. Faraawi reported receiving research grants from Roche, Pfizer Inc., UCB, Schering-Plough Corp., and Wyeth.

QUEBEC CITY — Baseline serologic biomarkers offer rheumatologists the possibility of tailoring rheumatoid arthritis medications to fit various subgroups of patients, thereby increasing the likelihood of achieving a good response to treatment, said Dr. Rafat Faraawi at the annual meeting of the Canadian Rheumatology Association.

In a sea of pharmaceuticals for RA, with no clear understanding of why some patients respond to one agent and not to another, biomarkers are a potential tool for predicting treatment response, Dr. Faraawi said in an interview with

“We still don't have guidelines on how to select pharmaceuticals. More or less, [the drugs] all have the same efficacy. There are minor differences, and then the selection depends on many factors.

“We depend on personal preference, physician experience, certain peculiarities of the drugs, mechanism of action,” according to Dr. Faraawi.

In a post hoc analysis of two large trials of rituximab, his group discovered that a subgroup of patients with high serum levels of C-reactive protein (CRP) as well as seropositivity for rheumatoid factor (RF) had the highest response to rituximab. “If you want to select patients who will get a response to this expensive biologic, then those with positive rheumatoid factor and an elevated C-reactive protein most likely will show a better response than [will] seronegative patients or those with low CRP.

“And if they have a combination of both, that is even better,” said Dr. Faraawi, who is a rheumatologist at McMaster University in Kitchener, Ont.

He presented the data as a poster at the meeting.

The investigators used data from REFLEX (Randomized Evaluation of Long-Term Efficacy of Rituximab in RA) and SERENE (Study Evaluating Rituximab's Efficacy in Methotrexate Inadequate Responders).

Both are randomized, placebo-controlled trials of rituximab in patients with inadequate response to either tumor necrosis factor inhibitors or methotrexate, respectively (Arthritis Rheum. 2006;54:2793-806; ACR 2008, abstract 364).

Both trials reported ACR 50 response rates for rituximab, compared with placebo, after 24 weeks.

The REFLEX trial (n = 517) showed an ACR 50 response of 27% in the treated group, compared with 5% in placebo. And the SERENE trial (n = 501) showed an ACR 50 response of 26% in the treated group, compared with 9% in placebo.

For both trials, baseline levels of 19 serologic markers and 9 clinical features were recorded.

After an analysis of baseline and outcome data from both trials, Dr. Faraawi's study identified four serologic biomarkers—RF, CRP, IgG anti–cyclic citrullinated peptide 3 (CCP3) antibodies, and soluble cluster of differentiation 25 (CD25)—that were predictive of response to rituximab, he explained.

Of these, seropositivity for RF and CRP were the most predictive, and this was further enhanced when both biomarkers were presented.

For example, in the REFLEX trial, the overall ACR 50 response rate was 27% in the treated group, whereas the subgroup of patients with CRP levels above 2.9 mg/dL and positive RF of any isotope (defined as IgA RF greater than 25 U/mL, IgG RF greater than 20 U/mL, IgM RF greater than 20 U/mL, total RF greater than 20 IU/mL) had an ACR 50 response rate of 31% (placebo, 1%).

Similarly, in the SERENE trial, the overall ACR 50 response rate was 26% in the treated group, whereas the response rate was 39% in the same subgroup of patients who were positive for RF and had an elevated CRP (placebo, 7%).

Rituximab is a monoclonal antibody that selectively targets CD20-positive B cells, which secrete rheumatoid factor, said Dr. Faraawi.

“That is why, for this particular drug, patients with positive rheumatoid factor respond well. That doesn't mean this agent does not work for patients with low markers. It still works. But the likelihood of response is greater with positive markers.”

He said that large trials are needed to further clarify which markers can help in the selection of agents for specific patients.