Biomarker score not predictive of successful TNF inhibitor tapering in RA

A multi-biomarker disease activity score in patients with longstanding rheumatoid arthritis and low disease activity prior to tapering adalimumab or etanercept did not predict flare-related outcomes in an 18-month, open-label, randomized clinical trial.

These findings seemed “robust and valid, at least in this specific context,” said investigators led by Chantal A. M. Bouman, MD, of Sint Maartenskliniek Nijmegen (the Netherlands), because multiple other outcomes measured in the trial, including discontinuation of biologic and radiographic progression, were not predicted by the multi-biomarker disease activity (MBDA) score, which is derived from an algorithm using a biomarker panel of 12 serum proteins and is marketed under the name Vectra DA.

The researchers sought to determine if measurement of disease activity using biomarkers with the MBDA score has a potential for smaller measurement error, compared with clinical decision making, in predicting the effects of dose tapering of biologic disease-modifying antirheumatic drugs by examining blood samples taken from 171 people with longstanding RA with low disease activity who were participating in the Dutch Dose Reduction Strategies of Subcutaneous TNF inhibitors (DRESS) trial (Rheumatology [Oxford]. 2017 Feb 22. doi: 10.1093/rheumatology/kex003).

The use of biomarkers could potentially overcome some of the drawbacks of the most widely used and extensively validated measure of RA disease activity, the Disease Activity Score in 28 joints (DAS28), which relies on “clinical assessments [that] are subject to interobserver variability, resulting in measurement error and suboptimal precision,” the investigators wrote. “Also, DAS28 can be influenced by factors other than RA disease activity (e.g., OA, [fibromyalgia], or other causes of inflammation, such an infection), resulting in clinical misclassification of disease activity state.”

The randomized DRESS trial investigated the noninferiority of a dose reduction strategy of adalimumab or etanercept (n = 115), compared with usual care (n = 56), on the rate of flare, defined as a DAS28 (using C-reactive protein) increase of more than 1.2 or 0.6 if the current DAS was more than or equal to 3.2. A major flare was one lasting more than 3 months despite treatment intervention.

The baseline MBDA score did not predict successful tapering based on an area under the receiver operating characteristic (AUROC) of 0.53 (95% confidence interval, 0.41-0.66), nor did it predict the discontinuation of either biologic (AUROC = 0.51; 95% CI, 0.36-0.66) or the occurrence of flare (AUROC = 0.50; 95% CI, 0.41-0.59 for both groups combined) or major flare (AUROC = 0.46; 95% CI, 0.32-0.65 for both groups combined).

Although the authors found a borderline positive predictive value of baseline MBDA score for major flare in the usual care group (AUROC = 0.72; 95% CI, 0.56-0.88), they said the finding should be “interpreted cautiously” as multiple testing may have resulted in false-positive findings.

The researchers also discovered that, in contrast to findings from five studies in four cohorts of patients with established or early RA, the MBDA did not predict radiographic progression (AUROC = 0.53 for predicting radiographic progression of more than 0.5 Sharp–van der Heijde points; 95% CI, 0.43-0.63 for both groups combined).

The inability of the MBDA score to predict radiographic outcomes “might be attributable to the low frequency and severity of radiographic progression in our study, with only a small difference in favor of the [usual care] group. It might reflect the strict tight control that was applied to patients who were already in low disease activity or remission,” the investigators suggested.

They also said that, in spite of the findings, the MBDA score may have predictive value in other groups of patients, such as those with early rheumatoid arthritis, higher disease activity, or suboptimal disease control, and suggested that the study’s findings be validated in further studies.

The study received no specific funding. However, one author is an employee of Crescendo Bioscience and reported receiving stock grants from its parent company, Myriad Genetics. Several authors reported relationships with industry.

A multi-biomarker disease activity score in patients with longstanding rheumatoid arthritis and low disease activity prior to tapering adalimumab or etanercept did not predict flare-related outcomes in an 18-month, open-label, randomized clinical trial.

These findings seemed “robust and valid, at least in this specific context,” said investigators led by Chantal A. M. Bouman, MD, of Sint Maartenskliniek Nijmegen (the Netherlands), because multiple other outcomes measured in the trial, including discontinuation of biologic and radiographic progression, were not predicted by the multi-biomarker disease activity (MBDA) score, which is derived from an algorithm using a biomarker panel of 12 serum proteins and is marketed under the name Vectra DA.

The researchers sought to determine if measurement of disease activity using biomarkers with the MBDA score has a potential for smaller measurement error, compared with clinical decision making, in predicting the effects of dose tapering of biologic disease-modifying antirheumatic drugs by examining blood samples taken from 171 people with longstanding RA with low disease activity who were participating in the Dutch Dose Reduction Strategies of Subcutaneous TNF inhibitors (DRESS) trial (Rheumatology [Oxford]. 2017 Feb 22. doi: 10.1093/rheumatology/kex003).

The use of biomarkers could potentially overcome some of the drawbacks of the most widely used and extensively validated measure of RA disease activity, the Disease Activity Score in 28 joints (DAS28), which relies on “clinical assessments [that] are subject to interobserver variability, resulting in measurement error and suboptimal precision,” the investigators wrote. “Also, DAS28 can be influenced by factors other than RA disease activity (e.g., OA, [fibromyalgia], or other causes of inflammation, such an infection), resulting in clinical misclassification of disease activity state.”

The randomized DRESS trial investigated the noninferiority of a dose reduction strategy of adalimumab or etanercept (n = 115), compared with usual care (n = 56), on the rate of flare, defined as a DAS28 (using C-reactive protein) increase of more than 1.2 or 0.6 if the current DAS was more than or equal to 3.2. A major flare was one lasting more than 3 months despite treatment intervention.

The baseline MBDA score did not predict successful tapering based on an area under the receiver operating characteristic (AUROC) of 0.53 (95% confidence interval, 0.41-0.66), nor did it predict the discontinuation of either biologic (AUROC = 0.51; 95% CI, 0.36-0.66) or the occurrence of flare (AUROC = 0.50; 95% CI, 0.41-0.59 for both groups combined) or major flare (AUROC = 0.46; 95% CI, 0.32-0.65 for both groups combined).

Although the authors found a borderline positive predictive value of baseline MBDA score for major flare in the usual care group (AUROC = 0.72; 95% CI, 0.56-0.88), they said the finding should be “interpreted cautiously” as multiple testing may have resulted in false-positive findings.

The researchers also discovered that, in contrast to findings from five studies in four cohorts of patients with established or early RA, the MBDA did not predict radiographic progression (AUROC = 0.53 for predicting radiographic progression of more than 0.5 Sharp–van der Heijde points; 95% CI, 0.43-0.63 for both groups combined).

The inability of the MBDA score to predict radiographic outcomes “might be attributable to the low frequency and severity of radiographic progression in our study, with only a small difference in favor of the [usual care] group. It might reflect the strict tight control that was applied to patients who were already in low disease activity or remission,” the investigators suggested.

They also said that, in spite of the findings, the MBDA score may have predictive value in other groups of patients, such as those with early rheumatoid arthritis, higher disease activity, or suboptimal disease control, and suggested that the study’s findings be validated in further studies.

The study received no specific funding. However, one author is an employee of Crescendo Bioscience and reported receiving stock grants from its parent company, Myriad Genetics. Several authors reported relationships with industry.

A multi-biomarker disease activity score in patients with longstanding rheumatoid arthritis and low disease activity prior to tapering adalimumab or etanercept did not predict flare-related outcomes in an 18-month, open-label, randomized clinical trial.

These findings seemed “robust and valid, at least in this specific context,” said investigators led by Chantal A. M. Bouman, MD, of Sint Maartenskliniek Nijmegen (the Netherlands), because multiple other outcomes measured in the trial, including discontinuation of biologic and radiographic progression, were not predicted by the multi-biomarker disease activity (MBDA) score, which is derived from an algorithm using a biomarker panel of 12 serum proteins and is marketed under the name Vectra DA.

The researchers sought to determine if measurement of disease activity using biomarkers with the MBDA score has a potential for smaller measurement error, compared with clinical decision making, in predicting the effects of dose tapering of biologic disease-modifying antirheumatic drugs by examining blood samples taken from 171 people with longstanding RA with low disease activity who were participating in the Dutch Dose Reduction Strategies of Subcutaneous TNF inhibitors (DRESS) trial (Rheumatology [Oxford]. 2017 Feb 22. doi: 10.1093/rheumatology/kex003).

The use of biomarkers could potentially overcome some of the drawbacks of the most widely used and extensively validated measure of RA disease activity, the Disease Activity Score in 28 joints (DAS28), which relies on “clinical assessments [that] are subject to interobserver variability, resulting in measurement error and suboptimal precision,” the investigators wrote. “Also, DAS28 can be influenced by factors other than RA disease activity (e.g., OA, [fibromyalgia], or other causes of inflammation, such an infection), resulting in clinical misclassification of disease activity state.”

The randomized DRESS trial investigated the noninferiority of a dose reduction strategy of adalimumab or etanercept (n = 115), compared with usual care (n = 56), on the rate of flare, defined as a DAS28 (using C-reactive protein) increase of more than 1.2 or 0.6 if the current DAS was more than or equal to 3.2. A major flare was one lasting more than 3 months despite treatment intervention.

The baseline MBDA score did not predict successful tapering based on an area under the receiver operating characteristic (AUROC) of 0.53 (95% confidence interval, 0.41-0.66), nor did it predict the discontinuation of either biologic (AUROC = 0.51; 95% CI, 0.36-0.66) or the occurrence of flare (AUROC = 0.50; 95% CI, 0.41-0.59 for both groups combined) or major flare (AUROC = 0.46; 95% CI, 0.32-0.65 for both groups combined).

Although the authors found a borderline positive predictive value of baseline MBDA score for major flare in the usual care group (AUROC = 0.72; 95% CI, 0.56-0.88), they said the finding should be “interpreted cautiously” as multiple testing may have resulted in false-positive findings.

The researchers also discovered that, in contrast to findings from five studies in four cohorts of patients with established or early RA, the MBDA did not predict radiographic progression (AUROC = 0.53 for predicting radiographic progression of more than 0.5 Sharp–van der Heijde points; 95% CI, 0.43-0.63 for both groups combined).

The inability of the MBDA score to predict radiographic outcomes “might be attributable to the low frequency and severity of radiographic progression in our study, with only a small difference in favor of the [usual care] group. It might reflect the strict tight control that was applied to patients who were already in low disease activity or remission,” the investigators suggested.

They also said that, in spite of the findings, the MBDA score may have predictive value in other groups of patients, such as those with early rheumatoid arthritis, higher disease activity, or suboptimal disease control, and suggested that the study’s findings be validated in further studies.

The study received no specific funding. However, one author is an employee of Crescendo Bioscience and reported receiving stock grants from its parent company, Myriad Genetics. Several authors reported relationships with industry.