Time is Bone: Unchecked Rheumatoid Arthritis Affects More Than Joints

While rheumatoid arthritis (RA) is commonly perceived as a condition that only impacts bone and joint health, realistically, it can elevate the risk for several comorbidities that can lead to death, underscoring the need for consistent monitoring. During an educational symposium for health care professionals at the Asembia Specialty Pharmacy Summit 2017, Kevin Mange, MD, MSCE, head of North America Medical Immunology at Sanofi, gave a comprehensive overview that emphasized RA is more than a disease that just impacts the joints.

“RA is disease that affects multiple organ systems,” Dr Mange said during the session. “This relatively new concept has been integrated into the American College of Rheumatology [ACR] guidelines of treating patients with RA to a level of severity.”

RA currently affects approximately 1.5 million adults in the United States, typically in their 40s and 50s, at a female-to-male ratio of approximately 3 to 1.

“If you sit and talk with a patient after they’ve been diagnosed with RA and ask, ’What were your earliest symptoms you had?’ their symptoms at presentation relate to how stoic that patient is,” Dr Mange said. “It relates to their pain tolerance, or intolerance as the case may be, and also how active that individual is.

“What they will say consistently is that when they wake up in the morning, they’re stiff. It takes a while for them to get going.”

In describing the early symptoms of RA, Dr Mange described how inflammation of the joint lining causes patients to experience stiffness that progresses to tenderness, which puts stress on the joints. This stress limits motion and causes pain and swelling, ultimately impairing daily activity.

“If we’re talking about a couch potato, they are going to present a bit later,” Mange said. “Why? Because they’re not moving and when they start to move, they have pain. So, it’s kind of a negative reinforcement.”

Mange also noted that a significant minority of patients experience chronic inflammation that manifests in their ankles and feet, which creates a diagnosis challenge for physicians.

Updated ACR Guidelines Direct Early RA Treatment

In their recent guidelines update, the ACR specified that patients with early RA should be addressed with a treat-to-target strategy instead of a non­targeted therapeutic approach. The ACR guidelines recommend the early target treatments should be low disease activity or remission.

“After 2015, the ACR recommended that clinicians providing care to patients with RA need to regularly measure the level of disease activity,” Dr Mange said. “Doing it once a year is no longer adequate. Why? Because there is a state of chronic inflammation.”

For patients with low disease activity who have never taken a disease-modifying anti-rheumatic drug (DMARD), the ACR guidelines recommend DMARD monotherapy versus double or triple DMARD therapy. Meanwhile, for the majority of patients with early, active RA, methotrexate is the preferred initial therapy.

For patients on DMARD monotherapy who still show moderate or high disease activity, the ACR guidelines recommend switching to a DMARD combination treatment regimen or a tumor necrosis factor (TNF) inhibitor or non-TNF biologic, with or without methotrexate.

Early diagnosis and treatment can lessen the risk of comorbidities

Active adults are often slow to recognize or receive treatment for their inflammation. In these cases, the risks that accompany RA intensify greatly. Chronic inflammation causes erosion in the bone and leads to narrowing of the joint space, which is a significant determinate of disability. Inflammatory joint symptoms determine disability in the early course of the disease, while the subsequent effect of joint destruction dominates disability late in the disease, Dr Mange noted.

“If that chronic inflammation goes unchecked, then joint damage occurs,” Dr Mange said. “It’s important to recognize that joint damage is irreparable. It should not be allowed to progress. RA is a disease of the joints, but that’s not the full story. RA, as a disease, affects several other organ systems.”

Mange pointed to the data from Consortium of Rheumatology Researchers of North America (CORRONA) database of information collected from rheumatologists and patients, beginning in 2002, to illustrate the risks of multiple comorbidities that may impact patients with RA. These include diabetes, cardiovascular and lung diseases, osteoporosis that elevates the risk for bone fracture, certain types of cancer, and greater rates of hospitalization.

“When RA patients have these additional comorbidities, certainly they are more ill,” Dr Mange said. “As a marker, once again, these patients do not do as well as someone in the absence of these comorbidities, perhaps, because that impacts the therapeutic strategy that the physician can do with that patient.”

Because there are limited therapeutic options for these patients’ associated comorbidities, RA can cause multiple conditions to worsen. Dr Mange noted that the inflammatory state caused by RA can be an independent marker or independent risk for the development of cardiovascular disease; events that can present atypically. Silent myocardial infarctions are common, in which patients do not experience chest pain, but the event shows on an electrocardiogram.

RA patients also have a greater risk of sudden cardiac death because of their high inflammatory state. A 2015 study published in Arthritis & Rheumatology used data from CORRONA to analyze the correlation between RA disease activity and treatment regimen with cardiovascular risk. The study authors evaluated 24,989 patients with RA for 2.7 years following their baseline visit to the clinician until they were lost to follow-up, experienced an initial cardiovascular event, or died.

Of these patients, 61% were administered a nonsteroidal anti-inflammatory drug or a COX-2 inhibitor, 84% were administered methotrexate, and 48% were administered a TNF-antagonist. As the RA disease activity was lowered, the authors found a significantly diminished risk of cardiovascular events. The results showed a 21% reduced cardiovascular event risk for each 10-point drop in the Clinical Disease Activity Index, and a 53% decrease in cardiovascular risk from high disease activity to remission. The study results further bolster the importance of monitoring and controlling RA disease activity to avoid not only joint pain, but to reduce the mortality risk from cardiovascular events as well.

“Recent data from CORRONA of over 25,000 US patients also confirms that the risk of cardiovascular events in an RA patient increases as their severity of RA increases,” Dr Mange said.

Autopsies show that nearly half of RA patients also experience rheumatologic processes in their lungs, such as inflammation of the chest cavity. Dr Mange noted that between 8% and 15% of RA patients may have interstitial lung disease, a condition that results in an oxygenation problem that may require additional therapy.

Rheumatoid nodules also present a challenge for patients with RA that extends beyond the unsightly appearance. One-third of patients with RA will develop rheumatoid nodules around their elbows and hands. Dr Mange explained that skin disease in RA is not simply a cosmetic problem. Rheumatoid nodules can interfere with normal muscle function, ulcerate, and become infected, ultimately requiring surgical intervention.

Nodules also lead to joint destruction that severely impacts a patient’s functional capacity, especially if a patient’s job requires working with their hands.

“If someone has extra-articular manifestations in another organ system than the joints, you can imagine that the therapeutic strategy to treat that patient’s lung disease or heart disease is very different than someone who has joint-limited disease. Monitoring for that organ system is very different than joint disease,” Dr Mange said.

RA can also lead to peripheral neuropathy; which, while not severe, adds another layer of complexity to the disease, including a greater risk of falls. Trauma caused by an incident such as a slip-and-fall or a minor car accident can cause the joint to become unstable, and could lead to the development of spinal cord problems, according to Dr Mange. He further noted that RA patients with extra-articular manifestations, which make up 40% of the RA population, are at a greater risk of mortality than RA patients without extra-articular manifestations.

Dr Mange recommended these patients should be managed broadly in a very different way than someone who has joint-limited disease. Because unchecked joint damage is irreparable and patients with RA are at a high risk of extra­ articular manifestations, ACR guidelines emphasize the importance of a therapeutic strategy for disease activity measurement after 3 months. At that point, if the patient is not in a state of low disease activity or remission, clinicians need to decide whether they need to escalate or intensify immune suppression efforts or think about changing therapies within the same drug class.

“If you let that person continue to go unchecked with that level of inflammation, it’s going to put them at a greater risk for joint disease and extra-articular manifestations,” Mange said.

It’s important to consider the additional costs comorbidities add in treating RA

Because of the widespread impact of RA on the patient’s body and the subsequent danger to other organ systems, the cost of the disease on the health care system is significant. In 2010, the incremental, annual direct cost attributed to RA in the United States was $11.4 billion, with another estimated $14.8 billion in indirect costs. A 2012 study in Arthritis Care & Research examined a sample of respondents from the Medical Expenditure Panel Survey conducted in 2008 to compare a cohort of patients with RA and a control cohort without RA.

The adjusted average annual total expenditure in the cohort of patients with RA in 2008 US dollars (USD) was $13,012 compared with $4950 in the control cohort. Furthermore, the annual pharmacy expenditure in the RA cohort was $5825, which was $1380 higher than the control group. The study authors found a total incremental expenditure in the United States among all RA patients of $22.3 billion in 2008 USD.

“RA as a disease garners a lot of attention; not just simply because it’s an intellectual curiosity, but in part because it’s an expensive disease,” Dr Mange said, adding that the higher the disease activity in RA, the higher the use of health care utilization and health care resources.

Act now: Use the ACR Guidelines to help prevent additional damage caused by RA

Ultimately, with the significant risks that unchecked RA poses to other organ systems, the irreparable damage to joint systems, and the high costs incurred from RA and related conditions, the importance of following ACR guidelines is magnified. The more time that passes without taking prompt action in the treatment of RA equates to damage that cannot be repaired long-term.

“Time is bone; it’s irreparable. If you continue with unchecked inflammation, you’re going to have other organ systems involved,” Dr Mange concluded. “Make a decision, that’s what the ACR guidelines are really emphasizing.”