New Biomarkers Identify Tocilizumab Responders Super Early

BERLIN – Novel serologic biomarkers of cartilage degradation and synovial tissue destruction in rheumatoid arthritis patients permit discrimination between eventual responders and nonresponders to the interleukin-6 inhibitor tocilizumab after just 2-4 weeks of treatment.

Given that early introduction of effective therapy for rheumatoid arthritis (RA) is the key to preventing joint destruction, use of these new biomarkers for early differentiation between likely tocilizumab responders and nonresponders will provide value to patients and payers alike, Anne C. Bay-Jensen, Ph.D., predicted at the annual European Congress of Rheumatology.

She investigated early changes in a slew of serum biomarkers of cartilage, bone, synovium, and systemic inflammation in response to tocilizumab treatment as a means of discriminating treatment responders from nonresponders months before the clinical impact becomes apparent.

The biomarkers included several novel tissue-specific end products of tissue turnover, providing unique information about the state of the tissue of interest. These markers included matrix metalloproteinase-mediated degradation of type II collagen (C2M) or type III collagen (C3M); matrix metalloproteinase-mediated C-reactive protein (CRPM); citrullinated and matrix metalloproteinase-degraded vimentin (VICM); and matrix metalloproteinase-destroyed type I collagen (ICTP).

The key point is that while C-reactive protein (CRP), for example, is produced in the liver, CRPM is produced specifically in the joint and reflects joint-specific tissue inflammation, as Dr. Bay-Jensen and her coworkers have previously demonstrated (Arthritis Res. Ther. 2011;13:215 [doi: 10.1186/ar3280]).

In addition to this set of novel biomarkers, she evaluated several traditional biomarkers: CRP, along with osteocalcin and CTX-1 (C-terminal telopeptide of type I collagen ) as markers of bone formation and resorption, respectively.

The biomarkers, new and old, were evaluated in a secondary analysis of the 2-year, phase III, double-blind LITHE trial, in which 1,196 RA patients with inadequate response to methotrexate were randomized to tocilizumab (Actemra) at 8 mg/kg or 4 mg/kg or to placebo on top of background methotrexate therapy.

The substudy involved 206 patients on the higher dose of tocilizumab plus methotrexate and 211 on placebo plus methotrexate. The tocilizumab group included 91 responders and 29 nonresponders at week 16 of treatment, explained Dr. Bay-Jensen, a cartilage scientist at Nordic Bioscience in Herlev, Denmark.

Levels of CRPM dropped by 33% from baseline at week 4 and by 40% by week 52 in responders to dual therapy and by significantly lesser amounts in the nonresponders. Levels remained unchanged over time in the methotrexate-plus-placebo arm.

The same pattern followed for C2M, C3M, ICM, and ICTP.

Indeed, an 11% decrease in CRPM from baseline at week 4 of treatment with tocilizumab plus methotrexate was associated with a fourfold increased likelihood of clinical response at week 16. A 7.4% reduction in C2M at week 2 indicated a 5.8-fold increased odds of a week-16 response. And a 28% decline in C3M was associated with a 9.6-fold increased likelihood of subsequent clinical response.

In contrast, the conventional marker of systemic inflammation, high-sensitivity CRP, dropped by about 35% in both responders and nonresponders, rendering it useless as a predictive tool. Osteocalcin and CTX-1 were of no value, either.

The next step in this research project will be to see if these novel biomarkers of cartilage and synovial turnover and within-joint inflammation are able to discriminate responders from nonresponders to other biologic agents that address targets other than interleukin-6, she continued.

To put these new findings in perspective, today on average physicians have to treat 3.5 rheumatoid arthritis patients with biologic therapy in order to obtain 1 good response.

"Tomorrow, using serologic biomarker profiles, there might be 10 potential candidates, 1.5 patients selected for treatment, and 1.5 responders," Dr. Bay-Jensen said.

Data from the LITHE study were supplied by Genentech. Dr. Bay-Jensen’s biomarker analysis was supported by the Danish Research Foundation. She reported having no financial conflicts.

BERLIN – Novel serologic biomarkers of cartilage degradation and synovial tissue destruction in rheumatoid arthritis patients permit discrimination between eventual responders and nonresponders to the interleukin-6 inhibitor tocilizumab after just 2-4 weeks of treatment.

Given that early introduction of effective therapy for rheumatoid arthritis (RA) is the key to preventing joint destruction, use of these new biomarkers for early differentiation between likely tocilizumab responders and nonresponders will provide value to patients and payers alike, Anne C. Bay-Jensen, Ph.D., predicted at the annual European Congress of Rheumatology.

She investigated early changes in a slew of serum biomarkers of cartilage, bone, synovium, and systemic inflammation in response to tocilizumab treatment as a means of discriminating treatment responders from nonresponders months before the clinical impact becomes apparent.

The biomarkers included several novel tissue-specific end products of tissue turnover, providing unique information about the state of the tissue of interest. These markers included matrix metalloproteinase-mediated degradation of type II collagen (C2M) or type III collagen (C3M); matrix metalloproteinase-mediated C-reactive protein (CRPM); citrullinated and matrix metalloproteinase-degraded vimentin (VICM); and matrix metalloproteinase-destroyed type I collagen (ICTP).

The key point is that while C-reactive protein (CRP), for example, is produced in the liver, CRPM is produced specifically in the joint and reflects joint-specific tissue inflammation, as Dr. Bay-Jensen and her coworkers have previously demonstrated (Arthritis Res. Ther. 2011;13:215 [doi: 10.1186/ar3280]).

In addition to this set of novel biomarkers, she evaluated several traditional biomarkers: CRP, along with osteocalcin and CTX-1 (C-terminal telopeptide of type I collagen ) as markers of bone formation and resorption, respectively.

The biomarkers, new and old, were evaluated in a secondary analysis of the 2-year, phase III, double-blind LITHE trial, in which 1,196 RA patients with inadequate response to methotrexate were randomized to tocilizumab (Actemra) at 8 mg/kg or 4 mg/kg or to placebo on top of background methotrexate therapy.

The substudy involved 206 patients on the higher dose of tocilizumab plus methotrexate and 211 on placebo plus methotrexate. The tocilizumab group included 91 responders and 29 nonresponders at week 16 of treatment, explained Dr. Bay-Jensen, a cartilage scientist at Nordic Bioscience in Herlev, Denmark.

Levels of CRPM dropped by 33% from baseline at week 4 and by 40% by week 52 in responders to dual therapy and by significantly lesser amounts in the nonresponders. Levels remained unchanged over time in the methotrexate-plus-placebo arm.

The same pattern followed for C2M, C3M, ICM, and ICTP.

Indeed, an 11% decrease in CRPM from baseline at week 4 of treatment with tocilizumab plus methotrexate was associated with a fourfold increased likelihood of clinical response at week 16. A 7.4% reduction in C2M at week 2 indicated a 5.8-fold increased odds of a week-16 response. And a 28% decline in C3M was associated with a 9.6-fold increased likelihood of subsequent clinical response.

In contrast, the conventional marker of systemic inflammation, high-sensitivity CRP, dropped by about 35% in both responders and nonresponders, rendering it useless as a predictive tool. Osteocalcin and CTX-1 were of no value, either.

The next step in this research project will be to see if these novel biomarkers of cartilage and synovial turnover and within-joint inflammation are able to discriminate responders from nonresponders to other biologic agents that address targets other than interleukin-6, she continued.

To put these new findings in perspective, today on average physicians have to treat 3.5 rheumatoid arthritis patients with biologic therapy in order to obtain 1 good response.

"Tomorrow, using serologic biomarker profiles, there might be 10 potential candidates, 1.5 patients selected for treatment, and 1.5 responders," Dr. Bay-Jensen said.

Data from the LITHE study were supplied by Genentech. Dr. Bay-Jensen’s biomarker analysis was supported by the Danish Research Foundation. She reported having no financial conflicts.

BERLIN – Novel serologic biomarkers of cartilage degradation and synovial tissue destruction in rheumatoid arthritis patients permit discrimination between eventual responders and nonresponders to the interleukin-6 inhibitor tocilizumab after just 2-4 weeks of treatment.

Given that early introduction of effective therapy for rheumatoid arthritis (RA) is the key to preventing joint destruction, use of these new biomarkers for early differentiation between likely tocilizumab responders and nonresponders will provide value to patients and payers alike, Anne C. Bay-Jensen, Ph.D., predicted at the annual European Congress of Rheumatology.

She investigated early changes in a slew of serum biomarkers of cartilage, bone, synovium, and systemic inflammation in response to tocilizumab treatment as a means of discriminating treatment responders from nonresponders months before the clinical impact becomes apparent.

The biomarkers included several novel tissue-specific end products of tissue turnover, providing unique information about the state of the tissue of interest. These markers included matrix metalloproteinase-mediated degradation of type II collagen (C2M) or type III collagen (C3M); matrix metalloproteinase-mediated C-reactive protein (CRPM); citrullinated and matrix metalloproteinase-degraded vimentin (VICM); and matrix metalloproteinase-destroyed type I collagen (ICTP).

The key point is that while C-reactive protein (CRP), for example, is produced in the liver, CRPM is produced specifically in the joint and reflects joint-specific tissue inflammation, as Dr. Bay-Jensen and her coworkers have previously demonstrated (Arthritis Res. Ther. 2011;13:215 [doi: 10.1186/ar3280]).

In addition to this set of novel biomarkers, she evaluated several traditional biomarkers: CRP, along with osteocalcin and CTX-1 (C-terminal telopeptide of type I collagen ) as markers of bone formation and resorption, respectively.

The biomarkers, new and old, were evaluated in a secondary analysis of the 2-year, phase III, double-blind LITHE trial, in which 1,196 RA patients with inadequate response to methotrexate were randomized to tocilizumab (Actemra) at 8 mg/kg or 4 mg/kg or to placebo on top of background methotrexate therapy.

The substudy involved 206 patients on the higher dose of tocilizumab plus methotrexate and 211 on placebo plus methotrexate. The tocilizumab group included 91 responders and 29 nonresponders at week 16 of treatment, explained Dr. Bay-Jensen, a cartilage scientist at Nordic Bioscience in Herlev, Denmark.

Levels of CRPM dropped by 33% from baseline at week 4 and by 40% by week 52 in responders to dual therapy and by significantly lesser amounts in the nonresponders. Levels remained unchanged over time in the methotrexate-plus-placebo arm.

The same pattern followed for C2M, C3M, ICM, and ICTP.

Indeed, an 11% decrease in CRPM from baseline at week 4 of treatment with tocilizumab plus methotrexate was associated with a fourfold increased likelihood of clinical response at week 16. A 7.4% reduction in C2M at week 2 indicated a 5.8-fold increased odds of a week-16 response. And a 28% decline in C3M was associated with a 9.6-fold increased likelihood of subsequent clinical response.

In contrast, the conventional marker of systemic inflammation, high-sensitivity CRP, dropped by about 35% in both responders and nonresponders, rendering it useless as a predictive tool. Osteocalcin and CTX-1 were of no value, either.

The next step in this research project will be to see if these novel biomarkers of cartilage and synovial turnover and within-joint inflammation are able to discriminate responders from nonresponders to other biologic agents that address targets other than interleukin-6, she continued.

To put these new findings in perspective, today on average physicians have to treat 3.5 rheumatoid arthritis patients with biologic therapy in order to obtain 1 good response.

"Tomorrow, using serologic biomarker profiles, there might be 10 potential candidates, 1.5 patients selected for treatment, and 1.5 responders," Dr. Bay-Jensen said.

Data from the LITHE study were supplied by Genentech. Dr. Bay-Jensen’s biomarker analysis was supported by the Danish Research Foundation. She reported having no financial conflicts.