In the JournalsPerspective

Patients treated late, women at higher risk for refractory RA

Manuel Bécède

A delayed initial treatment, as well as female sex and a higher disease activity, are major predictors of refractory rheumatoid arthritis, according to data published in Seminars in Arthritis and Rheumatism.

“Despite the fact that treatment of RA has experienced tremendous innovations over the past 20 years, a subgroup of patients remains to pose a challenge to rheumatologists,” Manuel Bécède, MD, of the Medical University of Vienna, told Healio Rheumatology. “These patients are characterized by a lack of clinical response to numerous consecutive therapeutic interventions and may exhibit significant progression of joint damage and irreversible disability. This group of patients is currently poorly defined and is sometimes referred to as ‘difficult’ or ‘problematic’ RA, or simply as ‘refractory.’”

“Without knowing risk factors for refractory RA, the clinical recognition of a patient’s course as refractory inherently comes too late, and physicians may find themselves recognizing that more aggressive initial treatment strategies would potentially have been beneficial to avert the refractory course of the disease,” Bécède added. “Refractory patients are still underrepresented in clinical trials.”

 
Delayed initial treatment, as well as female sex and a higher disease activity, are major predictors of refractory RA, according to data.
Source: Adobe

To analyze the predictors of refractory RA, Bécède and colleagues reviewed information from a longitudinal academic clinical database, established more than 15 years ago at the Medical University of Vienna’s rheumatology department. They identified 412 patients for inclusion in their study. Of these patients, 70 met the criteria for refractory RA, which the researchers defined as failing to reach at least low disease activity with three or more disease-modifying antirheumatic drug courses, including one or more biological, during a total of 18 months or more.

Those patients were compared to a control group of 102 participants who did response within the first two treatments — these patients were classified as “treatment amenable.” The remaining 240 patients met neither definition. The researchers completed logistic regression analysis to find risk factors for refractory disease courses. They also used sensitivity analyses regarding various definitions of refractory RA, to help confirm their results.

According to the researchers, 92.9% of the patients with refractory RA were women, compared with 70.6% in the control group (P < .001). In addition, patients with refractory RA were younger at disease onset, with a median age of 44.37 years, compared with 51.14 years in the control group (P=.002). They also demonstrated higher disease activity at first onset compared with controls, with a median Clinical Disease Activity Index (CDAI) of 26.06 among those with refractory RA vs. 15.39 for those who were treatment amenable (P < .001).

Lastly, delays in initial treatment were significantly longer among patients with refractory RA, with a median delay of 3.17 years, compared with 1.45 years in the control group (P =.001). Following multivariable analyses, only treatment delay, female sex and higher CDAI remained as independent predictors of refractory disease course.

“The matrix risk model, which includes the identified risk factors of female gender, treatment delay and disease activity, provides a novel tool for the determination of a risk to become a refractory RA patient, thus informing rheumatologists and patients on the potential necessity of a particularly intensive treatment approach,” Bécède said. “We can also conclude on the conceptual and practical presence of the window of opportunity in RA regarding the ability of rheumatologists to change the course of the disease in patients with RA. Thus, delay of DMARD treatment start is a major risk factor of a subsequent therapeutic failure.” – by Jason Laday

Disclosure: Bécède reports no relevant financial disclosures. Please see the study for all other relevant financial disclosures.

Manuel Bécède

A delayed initial treatment, as well as female sex and a higher disease activity, are major predictors of refractory rheumatoid arthritis, according to data published in Seminars in Arthritis and Rheumatism.

“Despite the fact that treatment of RA has experienced tremendous innovations over the past 20 years, a subgroup of patients remains to pose a challenge to rheumatologists,” Manuel Bécède, MD, of the Medical University of Vienna, told Healio Rheumatology. “These patients are characterized by a lack of clinical response to numerous consecutive therapeutic interventions and may exhibit significant progression of joint damage and irreversible disability. This group of patients is currently poorly defined and is sometimes referred to as ‘difficult’ or ‘problematic’ RA, or simply as ‘refractory.’”

“Without knowing risk factors for refractory RA, the clinical recognition of a patient’s course as refractory inherently comes too late, and physicians may find themselves recognizing that more aggressive initial treatment strategies would potentially have been beneficial to avert the refractory course of the disease,” Bécède added. “Refractory patients are still underrepresented in clinical trials.”

 
Delayed initial treatment, as well as female sex and a higher disease activity, are major predictors of refractory RA, according to data.
Source: Adobe

To analyze the predictors of refractory RA, Bécède and colleagues reviewed information from a longitudinal academic clinical database, established more than 15 years ago at the Medical University of Vienna’s rheumatology department. They identified 412 patients for inclusion in their study. Of these patients, 70 met the criteria for refractory RA, which the researchers defined as failing to reach at least low disease activity with three or more disease-modifying antirheumatic drug courses, including one or more biological, during a total of 18 months or more.

Those patients were compared to a control group of 102 participants who did response within the first two treatments — these patients were classified as “treatment amenable.” The remaining 240 patients met neither definition. The researchers completed logistic regression analysis to find risk factors for refractory disease courses. They also used sensitivity analyses regarding various definitions of refractory RA, to help confirm their results.

According to the researchers, 92.9% of the patients with refractory RA were women, compared with 70.6% in the control group (P < .001). In addition, patients with refractory RA were younger at disease onset, with a median age of 44.37 years, compared with 51.14 years in the control group (P=.002). They also demonstrated higher disease activity at first onset compared with controls, with a median Clinical Disease Activity Index (CDAI) of 26.06 among those with refractory RA vs. 15.39 for those who were treatment amenable (P < .001).

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Lastly, delays in initial treatment were significantly longer among patients with refractory RA, with a median delay of 3.17 years, compared with 1.45 years in the control group (P =.001). Following multivariable analyses, only treatment delay, female sex and higher CDAI remained as independent predictors of refractory disease course.

“The matrix risk model, which includes the identified risk factors of female gender, treatment delay and disease activity, provides a novel tool for the determination of a risk to become a refractory RA patient, thus informing rheumatologists and patients on the potential necessity of a particularly intensive treatment approach,” Bécède said. “We can also conclude on the conceptual and practical presence of the window of opportunity in RA regarding the ability of rheumatologists to change the course of the disease in patients with RA. Thus, delay of DMARD treatment start is a major risk factor of a subsequent therapeutic failure.” – by Jason Laday

Disclosure: Bécède reports no relevant financial disclosures. Please see the study for all other relevant financial disclosures.

    Perspective
    David A. McLain

    David A. McLain

    One of the most difficult things we deal with in rheumatology practice is refractory disease. With the advent of newer targeted biologics, our job has become easier in rheumatoid arthritis, but we are still encountering patients who fail to respond or have adverse drug reactions and whose RA becomes refractory. We also have the problem of having restrictions on our list of available agents that we can use and the order in which we can use them by insurance companies and pharmacy benefit managers.

    Bécède et al have reviewed their longitudinal academic database to compare what they define as refractory RA with “treatment amenable” RA, which responds to the first two treatments. The researchers define refractory RA as failing to reach the treatment target of at least low disease activity with three DMARD courses, including one biological, over a total of 18 months.

    Their findings demonstrated the refractory RA patients were more likely to be female (93% vs. 71%), younger (44 years vs. 51 years), and exhibited a high CDAI on first presentation (26 vs. 15). The delay of treatment was also higher in the refractory than the “treatment-amenable” groups (3.2 vs 1.5 years). Of interest is the fact that known risk factors for severe disease, seropositivity and pre-existing erosions were not statistically different between the refractory and “treatment-amenable” groups. The researchers also performed a validation analysis between their academic center and a community rheumatology setting which confirmed findings for high CDAI on presentation and delay in treatment as risk factors for refractory RA — again, delay in treatment has been shown to affect outcome.

    In the United States, the shortage of rheumatologists, which leads to long wait times for both and returning patients, has now been compounded by a delay in utilization of the best therapies by insurance, pharmacy benefit manager rules and red tape. The researchers have also created a matrix risk model for the probability of refractory RA, which as a visual graphic, may be of value in discussing risk with insurers, especially when selecting therapies. Using this model, we would be able to select those patients at highest risk to receive the best therapy —  regardless of cost — early in their disease, when we know it makes the most difference.

    • David A. McLain, MD, FACP, FACR
    • Executive director, Alabama Society for the Rheumatic Diseases
      Symposium director, Congress of Clinical Rheumatology

    Disclosures: McLain reports no relevant financial disclosures.