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"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

It's widely recognized that the risk for cardiovascular (CV) disease is increased about 1.5 to 2 times compared with that of the general population among patients with rheumatoid arthritis (RA), and that CV disease is a leading cause of mortality for patients with systemic inflammatory diseases. And while much of the CV risk in the general population derives from modifiable risk factors such as smoking, dyslipidemia, and obesity, the situation in RA is considerably more complex. Researchers are striving to address and clarify the various issues involved, including risk assessment, the role of inflammation, the "lipid paradox," and differences among medications.

Risk Assessment Tools

In the general population, several tools are available for evaluating CV risks, such as the and , both of which calculate 10-year risk of CV events based on individual factors such as age, sex, cholesterol levels, blood pressure, and smoking. However, because the elevated CV risk in RA is believed to relate to long-term exposure to high levels of inflammation, these tools -- which do not adjust for inflammation -- have been shown to underestimate CV risk in RA by as much as twofold.

Accordingly, various groups have attempted to develop RA-specific risk calculators to more clearly identify which patients are at greatest risk. The European Alliance of Associations for Rheumatology has recommended the use of a "" on the Framingham Risk Score or SCORE for patients who have longstanding disease or are positive for rheumatoid factor. The Consortium of Rheumatology Researchers of North America developed an based on an analysis of almost 24,000 RA patients, determining that specific RA factors could help predict risk, including disease activity and duration, disability, and daily prednisone use.

In 2019, the American College of Cardiology/American Heart Association published on CV disease prevention, which classified systemic inflammatory diseases including rheumatoid arthritis as "risk enhancers," conditions that should lower the threshold for initiating treatment with a statin.

"Screening for cardiovascular disease in patients with rheumatoid arthritis is something we're all thinking about right now," said Katherine P. Liao, MD, of Harvard University and Brigham and Women's Hospital in Boston. "Patients with RA should be aware of their risk, and clinicians should at least follow the general population recommendations for cardiovascular screening and consider the underlying risk-enhancing inflammatory condition during discussions about starting a statin."

Another option, Liao said, which is not yet included in guidelines for patients who may be at increased risk and may be at the borderline for initiating statin therapy is to perform a cardiac scan looking for coronary artery calcium, which is a sign of plaque. "That can provide another piece of information suggesting that it's time to start a statin," she said.

Inflammation and Lipids

"Classically, rheumatoid arthritis has been thought of as a condition of the joints, but we now know that it's a chronic systemic inflammatory condition," Liao continued. "But 'inflammation' is very broad, and in RA the question is what aspect of inflammation are we trying to target and control."

For instance, are there specific inflammatory pathways that provide the best targets in RA? "We're still trying to disentangle how we should be dealing with this -- target a specific pathway such as IL [interleukin]-6, or should we be very aggressive in treatment overall, more so than we would just for the joints?" Liao said.

Further complicating matters is the effect of inflammation on the pattern of lipids in RA, known as the lipid paradox. While lipids are routinely evaluated for general CV risk assessment and high levels of total cholesterol and low-density lipoprotein (LDL) cholesterol are considered risk factors, that observation does not appear to apply in RA.

Patients with RA, it has been observed, actually have lower total cholesterol and LDL cholesterol than age- and sex-matched individuals in the general population. How this paradox correlates with actual CV risk, however, remains uncertain.

The observation that inflammation influences lipid levels has been supported by findings showing that changes in inflammation are accompanied by changes in lipid levels. For instance, measurement of lipids before and after the initiation of tumor necrosis factor (TNF) inhibitors have shown that total cholesterol and LDL cholesterol levels rise by as much as 30%, despite the satisfactory control of inflammation with the use of these drugs.

Studies with other RA therapies such as tocilizumab (Actemra) and tofacitinib (Xeljanz) also have shown similar increases in total and LDL cholesterol levels, along with heterogeneous changes in high-density lipoprotein (HDL) cholesterol. For tocilizumab, the labeling recommends checking lipids 4 to 8 weeks after starting treatment and every 6 months thereafter. For tofacitinib, lipid screening is recommended 4 to 8 weeks after the start of treatment.

The mechanisms involved in lipid levels and changes in RA have been explored in studies using radioactive tracers on LDL to evaluate the effects of treatment.

In those studies, the fractional catabolic rate has been used to measure the metabolic clearance of cholesterol. This catabolism -- breakdown and clearance of specific molecules -- is an attempt to maintain homeostasis, Liao explained. "What happens with inflammation is that there seems to be a higher catabolic rate, meaning that the lipids are broken down faster, but when you treat the inflammation the catabolic rate goes back to normal. It looks like the lipids are coming back up but really they are just not being broken down as fast."

In a , 36 patients with RA and 33 healthy controls were given stable isotope tracers to examine cholesterol and lipoprotein kinetics and metabolism resulting from inflammation suppression with this JAK inhibitor. At baseline, HDL, LDL, total cholesterol, and apolipoprotein A-I were lower in RA patients. Also at baseline, the rate of catabolism of cholesterol esters was higher in the RA patients than in controls. After tofacitinib treatment, 10 mg twice daily for 6 weeks, the cholesterol ester fractional catabolic rate fell and cholesterol levels increased.

And in a , the fractional catabolic rate of LDL was measured before and after three infusions of this IL-6 inhibitor, 8 mg/kg, in 11 patients with severe, active RA. At baseline, the fractional catabolic rate was in the hypercatabolic range, "suggestive of markedly active turnover," Liao and a colleague wrote in . But after treatment, the catabolic rate decreased to what would be expected in the general population.

Moreover, changes in lipids that occur in response to control of inflammation may not necessarily reflect an actual increase in CV risks, Liao noted. In one recent open-label study, patients who had one or more CV risk factors and who had previously had an inadequate response to a conventional disease-modifying drug were randomized to receive tocilizumab 8 mg/kg/month or etanercept (Enbrel) 50 mg/week. During a mean follow-up of 3.2 years, and despite higher levels of lipids in the tocilizumab group, no differences were observed in the time to occurrence of a first major CV event.

"When RA patients are treated and control of inflammation is improved, the metabolic clearance of lipids is reduced, and thus total cholesterol and LDL cholesterol levels increase, which may not necessarily portend worse outcomes," she said. An important implication of lipid studies in RA is that the optimal time to assess CV risks is when the patient's disease is under good control and lipids are likely to be in a steady state.

What About Medications?

How CV risk should figure into medication choice is an evolving area of research, according to Liao. "Observational studies suggested that patients with RA who were on methotrexate had fewer cardiovascular events compared with those not on methotrexate," she said. However, in a of low-dose methotrexate for the prevention of atherosclerotic events in patients who had a previous cardiac event, there was no reduction in the rate of cardiac events.

In that study, the median C-reactive protein (CRP) level (indicating levels of inflammation) was slightly over 1.50 mg/L, whereas in a RA population, the mean CRP typically is 8 to 10 mg/L, "so you're looking at a different scale of inflammation," Liao said. "So is it that methotrexate is helping or just controlling inflammation? I think that question is still out there."

So there is now a focus on the individual biologics and targeted synthetic drugs currently available, where it is clear what is being targeted and how that might influence CV risks, whether it's IL-6 for tocilizumab and sarilumab (Kevzara), the TNF pathway for agents such as adalimumab (Humira), and the JAK-STAT pathway for JAK inhibitors such as tofacitinib. "This is where all the action is right now," Liao commented.

Thus far, with the exception of the JAK inhibitors, meta-analyses seem to suggest that there are few major differences among the various types of currently available medications with regard to CV risk, according to Liao. Some agents, such as tocilizumab, may be slightly more protective, but overall the drugs appear to be roughly equivalent in reducing CV risk, she said.

"That said, with any of these observational studies you have to take it with a grain of salt, because people are on a specific drug for certain reasons -- these are not randomized trials," she cautioned. Patient factors including age and comorbidities are likely to have influenced choice of medication in the observational studies.

The JAK Factor

Following the approval of tofacitinib in 2012, the FDA required the manufacturer Pfizer to conduct a safety study known as the , because reports had arisen during drug development of increases in lipid levels and certain cancers. Oral Surveillance was a noninferiority trial that prospectively compared tofacitinib with a TNF inhibitor (adalimumab or etanercept), and was published in the New England Journal of Medicine in early 2022.

During a median of 4 years of follow-up, the event rates for both major CV events and cancer were higher for tofacitinib, with hazard ratios of 1.33 (95% CI 0.91-1.94) for CV events and 1.48 (95% CI 1.04-2.09) for cancer.

"In this noninferiority study for safety, the criteria for higher CV events in tofacitinib versus a TNF inhibitor were met," Liao said. "But we still have to understand what this means, because the signal was not just for CV disease but also for malignancy and infections, so you wonder whether the risk is specific for CV events."

This returns to the question of whether the risk can be ameliorated simply by interfering with the inflammation. In this study, inflammation was controlled by two different drugs, yet there was a signal between the two for a safety difference, she noted.

It's still not clear what the specific mechanism in JAK inhibition might be for CV disease. "We know there is a higher rate of deep venous thrombosis with JAK inhibition, and thrombotic risk is often associated with cardiovascular disease. So I think we are still trying to unpack what the mechanism might be," she said.

The FDA accordingly has required that the , baricitinib (Olumiant) and upadacitinib (Rinvoq), carry boxed warnings about heart-related events and cancer.

"But remember that the first thing we're trying to do is manage our patients' RA so that they can do what they want to do, including exercise, which is good for their cardiovascular risk," Liao said. "But now the paradigm has shifted a little and we're not just generally trying to reduce inflammation but also thinking about their comorbidities. So for patients who are older and have CV risk factors, it makes us think more about IL-6 or TNF inhibitors."

Read previous installments in this series:

Part 1: RA Beginnings: Before the Painful Joints

Part 2: RA: Still a Clinical Diagnosis

Part 3: RA: Choosing Initial Treatment

Part 4: Case Study: Patient With RA Develops Dangerous Symptoms

Part 5: Second-Line Treatment of Rheumatoid Arthritis: What Are the Options?

Part 6: Managing Rheumatoid Arthritis in the Time of COVID

Part 7: Reproductive Health in Rheumatoid Arthritis

Part 8: Case Study: A Struggle to Maintain Mobility But Not for the Reason Everyone Thought

Part 9: Psychological and Emotional Health in Rheumatoid Arthritis