Introducing Multiple Biomarkers for Personalized Rheumatoid Arthritis Medicine

On the final day of the National Association of Managed Care Physicians’ Spring Managed Care Forum 2014 in Orlando, Jeffrey Curtis, MD, director, Arthritis Clinical Intervention Program at the University of Alabama, Birmingham, gave a clinical presentation of studies that focused on using multiple biomarkers to assess treatments of rheumatoid arthritis (RA). In his presentation, “Introducing Personalized Medicine to Rheumatology: Optimizing the Treatment of Rheumatoid Arthritis,” Dr Curtis first described RA etiology and then compared it to the more common osteoarthritis (OA).

Dr Curtis pointed out that most people get OA simply due to gravity at some point in their lives. More physical activity with an OA patient typically leads to more pain. By contrast, RA patients typically respond more positively to physical activity and will experience less pain. OA is more of a wear and tear disease, while RA is a disease largely characterized by excessive inflammation occurring in the joint capsules that can result in the classic rheumatoid nodules. The inflammatory environment leads to the destruction of bones and tendons, which can lead to multiple joint replacements.

There are also a wide variety of extra-articular features potentially connected with RA. These can include pericardial effusions, lung fibrosis, neuropathies, and even blindness or paralysis, if left untreated. Every joint in the body except for those in the lower back can be affected, according to Dr Curtis. And due to cardiovascular disease associated with RA, life expectancy for RA patients is typically reduced by 5 to 10 years. The annual cost burden for RA patients approaches $9000, on average, and approximately 30% of RA patients will apply for disability within 10 years of initial diagnosis, according to data presented by Dr Curtis.

The inflammatory cascade that leads to RA begins with antigen-presenting cells, which progress to T cells and B cells, to cytokines, and then generally to RA. The process is complex and not completely understood, but there is good news: any of a wide range of targets in this chain can be disrupted using biologicals to successfully lead to a remission of the disease.

Remission is typically an oncology term, but RA is similarly a disease involving the same type of hyperproliferation as cancer—and people immediately understand this term. Twenty years ago, “remission” was not even used because successful recovery was never observed. Tremendous progress has been made in this field.

The range of pharmacotherapeutic targets in the treatment of RA includes TNF-alpha, IL1, and IL6, B cells, T cell costimulators, and most recently, Janus kinase. All of these tend to work, but they are also all very expensive. Generally, biologicals cost between $3000 and $4000 per month, and it is not known for how long remission can last once the drugs are stopped. For many patients, due to the high cost of these drugs, their only chance at accessing them is through an active clinical trial.

Thus, it is most valuable to be able to predetermine which patients are most likely to benefit from treatment. Toward this end, a multi-biomarker disease activity (MBDA) score was developed, and it has now been validated as a predictor of radiographic disease progression. After consideration of over 100 potential biomarkers, Dr Curtis and his team were able to narrow this down to 12 biomarkers that correlated with disease activity.

Several case studies were also presented. One patient with normal C-reactive protein (CRP) but a high MBDA score was followed. The MBDA score successfully correlated with radiographic progression of the disease, thus validating this biomarker approach. Will physicians actually change their approach if given MBDA data? The answer, 38% of the time, was yes.

A case study of a 72-year-old woman who would only take prednisone was considered. Dr Curtis strongly advised against prednisone, as it is highly damaging. She had high disease activity; a swollen joint count of 7 and a tender joint count of 5, with moderate pain scores and normal CRP, but her MBDA was high at 55. Methotrexate dosage changes were recommended, but little outcome changes were seen at follow-up. But the patient confessed to not actually having taken the methotrexate. Then she decided to actually take it and her MBDA dropped to 40. They were just about to start this patient on very expensive biologicals, but they were able to avoid this. Close monitoring of this patient helped save money, and also increased safety from adverse events.

In summary, RA clinical assessment remains largely subjective today, where “MBDA is emerging as a great complement,” according to Dr Curtis. We still have huge gaps in our understanding of whether patients can stop taking their biologics. Based on limited data, for patients in remission that stopped taking their biologicals, about 60% of them were still in remission after 1 year. However, we still do not know how long this cure can last, and these studies are not being supported much. Moreover, there is the added complication that irregular administration of biologics can lead to the development of antidrug antibodies. Finally, there have also been truly exciting developments in the PCORI architecture that is providing tremendous funding for comparative effectiveness research of RA. This includes real-time data monitoring and social networking as RA research continues to take the lead in reporting medical monitoring data.