Paradoxes and Unanswered Questions in RA

As I reflect on the last day of EULAR 2015, I am again reminded of two paradoxes in RA. The first being that of cachexia at the onset of RA when both CRP and TNF are elevated, resulting in weight loss. Later in the disease when treatment has been initiated and levels of inflammation fall, BMI seems to normalize.

A review of data from two UK-based, multicentre, observational studies in RA patients (n=2701) found that being overweight or obese provided a protective effect, or at least showed no increase in the risk of mortality. This is a paradox compared to a healthy population but consistent with other conditions such as heart failure and end stage renal function. The authors indicated the need for further research on the role of weight and obesity on disease progression and outcomes in RA.

The second paradox is one of lipids where higher levels of HDL are associated with higher cardiovascular risk. Other markers of cardiovascular disease are then needed to make accurate predictions and to determination the need for treatment. Dr. Zoltan Szekaneczh from Hungary presented additional options for better predicting the progression of CVD. The first was Apo B/Apo AI ratio. Hyperuricemia is also a cardiovascular risk factor in RA patients without symptoms of gout, yet how often is it checked? It is known that more severe disease activity will increase CV risk as will disease duration, and acute flares are now known to further increase that risk.

There are also genes that have been identified in RA that increase cardiovascular risk. HLA-DR-B1 is a SNP that is highly sensitive for coronary atherosclerosis and is related to an OPG gene polymorphism. NT pro-BNP is a marker of CVD mortality and is also associated with insulin resistance. IL-6 appears to be a driver of NT pro-BNP. Both IL-6 and TNF inhibition help reduce this level.

Non-invasive assessments appear to be helpful predictors of CV risk when used in combination. Carotid U/S assessment for both intima media thickness and plaque analysis are more predictive than either alone. Of note, patients with RA have more unstable plaque than calcified plaque. 

An additional cardiovascular concern is the increased risk of arrhythmia due to QT prolongation. Prolonged QT interval also predicts all-cause mortality in RA. Many medications have now been identified that cause QT prolongation; this is usually only a risk if multiple medications with this effect are taken simultaneously and if the person already has some degree of prolongation. Adding an ECG to assess QT interval was suggested as part of a complete cardiovascular risk assessment.

Statins are known to reduce CRP in addition to their direct benefits on plaque reduction and stabilization. During a poster tour, Dr. George Kitas of the UK presented results of the TRACE-RA trial, which asssessed atorvastatin for the primary prevention of CV events in patients with RA. This multicentre RCT included patients with RA who were over 50 years of age or who had RA for greater than 10 years and who did not have known atherosclerosis, diabetes, or myopathy, and were not taking statin therapy. It included 2986 patients who were randomized to atorvastatin 40 mg or placebo and followed for a median of 2.5 years. Both groups were well matched for severity, seropositivity, RA duration, BP, etc. However, the placebo group included fewer current smokers than the active treatment arm (14.5% vs. 18.4%).

The atorvastatin group showed a 34% risk reduction for a major CVD event compared to placebo, however, due to early discontinuation of the trial and because the overall event rate was lower than expected, this positive change was still not statistically significant.

The early discontinuation was a big disappointment to this trial, which set out to answer an important question.

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