ASCVD Risk in Rheumatic Diseases: A Bold New Frontier

Dear Sir,

The article by Malaviya et al. in the June 2024 issue of IJR is interesting and timely. ¹ The authors have adequately highlighted the hidden burden of atherosclerotic cardiovascular disease (ASCVD) risk among patients of rheumatoid arthritis (RA) in remission. The message to rheumatologists to identify the hidden inflammation and control all ASCVD risk factors among these patients is well taken. A significant proportion of the study population had a high inflammatory and cholesterol burden; that 82% of the study population were females and 16% of study population who were below 45 years of age should make us pay attention to this (traditionally considered low risk for ASCVD) group of patients. Another worrying observation was that the higher the ASCVD risk category of the patient, the higher was the proportion of patients who had a residual cholesterol risk (RCR), thus suggesting a wider gap between their target and actual low-density lipoprotein (LDL) cholesterol levels and a greater need to bring it down. The recent approval of low-dose colchicine 0.5 mg daily by the United States Food and Drug Administration for the purpose of cardiovascular event reduction for both secondary prevention and primary prevention in individuals with multiple risk factors now provides a way for addressing residual inflammatory risk (RIR). ²

An aggressive approach is needed towards identification, risk stratification and risk reduction among patients of inflammatory rheumatic disease in Indian population. Indians tend to develop ASCVD a decade earlier than the Western population; In the INTERHEART study, the median age of MI among Indians was 53.0 years compared to 58.1 years in other countries. ³ Thirty-three per cent Indians develop coronary artery disease (CAD) at less than 50 years of age ⁴ and it has been reported that more than 50% of CAD-associated deaths in India occur before the age of 50 years and 25% of myocardial infarctions occur before the age of 40 years. ⁵ Hence, most of the individuals who require primary prevention are young or middle-aged. In these age groups, atherosclerosis is relatively less abundant, but the mere presence of atherosclerosis indicates high lifetime risk of ASCVD events. Early onset ASCVD in India has several important implications for disease prevention. First, the young age of onset renders conventional clinical ASCVD risk assessment tools (like FRS-CVD, QRISK3) less relevant because in all of them, age has an overriding influence on the estimated risk. Second, it also raises questions about the relevance of 10-year estimated ASCVD risk and instead emphasises the importance of assessing lifetime ASCVD risk. Third, the high incidence of early onset ASCVD necessitates early institution of aggressive preventive measures to protect the young population prior to development of ASCVD events. Thus, the thresholds of LDL cholesterol for risk classification and treatment targets recommended for Western population are mostly applicable to older individuals, and are less applicable for Indians. When seeing patients, as we calculate DAS28/CDAI/CDAI scores, a ASCVD risk score should be calculated and documented.

It is increasingly becoming clear that what is widely perceived as ‘remission’ for RA patients is a very narrow definition, which needs to be broadened. Rheumatologists should aim for holistic outcomes including sustained deep remission, radiological absence of or minimal synovitis, satisfactory control of vascular inflammation and lipids, identifying and controlling ASCVD risk factors (hypertension, diabetes, smoking, lifestyle, obesity, high hsCRP levels), restoration of bone health, return to normal activities of daily living/productivity and addressing mental health issues. An analogy can be taken with the multi-targeted management paradigms in diabetes mellitus, where adequate attention is given to factors other than blood glucose control, namely blood pressure, diet, lipids, weight control, vascular inflammation, ASCVD assessment, identifying triopathies and control of other components of the metabolic syndrome. RA patients too need such an approach to achieve ‘true remission’.

The Lipid Association of India 2023 update on cardiovascular risk assessment and lipid management in Indian patients: Consensus statement IV’ provides a new risk stratification algorithm and valuable insights. ⁶ The 2020 LAI risk assessment algorithm and corresponding recommendations for LDL cholesterol lowering were critically reviewed and updated by the LAI expert panel in accordance with current understanding of ASCVD risk in Indians. Importantly, the recommendations focus on lifetime risk reduction necessitating early introduction of preventive measures. The LAI recommends targeting LDL cholesterol as the primary target, non-high-density lipoprotein (HDL) cholesterol as a co-primary target and Apo(B) as a secondary target. A notable advance in this update is that RA, psoriasis and spondyloarthropathies are included as risk modifiers and the presence of any of them places a patient in the moderate or high ASCVD risk category. If used, all patients in this study would be re-classified as, at least, moderate-to-high ASCVD risk and none would be in the low-risk category (58 such patients in the current study), as per the LAI risk algorithm. This would consequently lower the target cholesterol levels, making them candidates for aggressive statin (ezetimibe or even PCSK-9 inhibitor) therapy, in turn reducing their RCR and RIR.

An interesting proposition in the updated LAI risk stratification algorithm is identifying ‘subclinical atherosclerosis’—by using modalities such as Coronary Artery Calcium Score (CACS), carotid/femoral ultrasound and ankle-brachial pressure index (ABPI). As per the recommendations therein, ‘assessment for subclinical atherosclerosis is recommended for persons aged 30 years and over for whom treatment decisions may be uncertain after consideration of risk scoring and additional risk factors and high-risk features, especially in Individuals considered to be in the moderate risk and high risk group as per the LAI risk algorithm’—this would mean ALL patients of RA, PsA and SpA are candidates for the assessment for subclinical atherosclerosis (as discussed above). Here it should be noted that widespread availability of the CACS could be a problem in India. However, the carotid ultrasound can easily be performed in OPDs—what with so many rheumatologists having access to ultrasound in their chambers. Compared with CACS, carotid/femoral ultrasonography has the advantages of being less expensive, more widely available and radiation free. The relatively low cost of ABPI measurement warrants its consideration for further ASCVD risk assessment, particularly when CACS or carotid/femoral assessment is not available and/or in situations where peripheral arterial disease may be suspected. Even so, these are parameters easily captured with minimal training

Several female-specific high-risk factors for ASCVD have also been incorporated in the updated LAI algorithm, namely polycystic ovarian disease (affects 4%-22% of reproductive age Indian women ⁷ ) which is associated with insulin resistance and visceral adiposity, late menarche, pre-eclampsia during pregnancy, gestational diabetes mellitus and premature menopause—implying that the largely female patient population of RA should be evaluated for these factors, by taking a complete reproductive history.

Another way of looking at (pure) RCR and RIR among RA patients is to assess those who do not have any co-morbidities such as diabetes, smoking, obesity and hypertension—these are all factors which could, per se, increase inflammation and lipid levels in RA patients. In the study by Malaviya et al., 98 RA patients had some form of co-morbidity and there were 32 RA patients without any co-morbidity. A sub-group analysis, comparing the proportion of RA patients with RIR and RCR, between these 2 groups would be interesting. A regression analysis can be done to analyse the factors affecting RIR (as measured by hsCRP) among RA patients. Further, if any or all of these 32 RA patients were categorised low ASCVD risk, as per the QRISK3 score (data not provided in the study), it remains to be seen how many of these would be upgraded to high or very high ASCVD risk categories, if assessed per the updated LAI risk algorithm. The author of this letter has recently conducted a study (unpublished data), as a postgraduate thesis, studying ASCVD risk among 52 RA patients. These were all female, non-smokers, non-hypertensive, non-diabetic and 45 of these patients were below 50 years of age. Twenty-five patients (49%) were in remission or low disease activity state. Yet, out of the 52 patients, 48 (92%) had a mean hsCRP of ≥2 mg/dL, signifying a significant RIR among this group of RA patients without any other traditional risk factor for ASCVD. When analysed by carotid ultrasound, 11 patients of RA had increased carotid intimo-medial thickness and/or carotid plaques. We also compared the ASCVD risk, for the whole group, as calculated by the QRISK3 score and the updated LAI risk algorithm. Surprisingly, all 11 patients of RA who had increased carotid intimo-medial thickness and/or carotid plaques were classified as low ASCVD risk by the QRISK3 score, while the updated LAI risk algorithm (using carotid ultrasound in place of CACS) classified all 11 of these patients as high ASCVD risk. In fact, an additional eight patients of high ASCVD risk were identified by the updated LAI risk algorithm, among whom increased carotid intimo-medial thickness and/or carotid plaques could not be detected. Thus, attesting to the fact that among Indian patients of RA who are predominantly young to middle age non-smoking females, non-hypertensive and non-diabetic, the updated LAI risk algorithm is more sensitive at identifying high ASCVD risk.

While the QRISK3 score relies heavily on conventional risk factors for ASCVD, namely age, smoking, diabetes, hypertension and cholesterol levels, the updated LAI risk algorithm is more broad-based and includes additional simple clinical markers like presence of metabolic syndrome, female reproductive factors, waist circumference, HIV infection, pre-diabetes (IFG), air pollution and laboratory markers like Lipoprotein (B), Apo(a) and hsCRP> 2 mg/L. Also, the updated LAI algorithm incorporates the QRISK 3 calculator to assess lifetime ASCVD risk, but using a single cut-off, that is, 30% to define low versus moderate ASCVD risk. The QRISK3 score is a validated, easy, online tool suited for busy clinicians, while the updated LAI algorithm is a slightly cumbersome tool with more variables to consider, not yet validated in Indian patients, and may incur challenges of availability and costs while ordering laboratory and radiological investigations.

In another review by Malaviya and Kapoor, published online in IJR on 17 October 2024, the authors echo the very ideas above and opine that ‘a significant limitation of the QRISK-3 is its failure to account for systemic inflammation…the LAI recommendations, which factor in systemic inflammation and include conditions like RA and spondyloarthritis, offer a more comprehensive approach for ASCVD risk assessment in these patients’. ⁸ Ours is, perhaps, the first study from India comparing the performance of these two risk scores in RA patients, albeit the population studied was a selected one. In spite of its shortcomings, the updated LAI risk algorithm is likely to capture the ‘true’ RIR and RCR among Indian patients of RA. Nevertheless, more studies comparing the QRISK3 score with the updated LAI risk algorithm are needed among Indian patients with RA, PsA and SpA, so that the true inflammatory burden and ASCVD risk may be determined. At the same time, better ASCVD risk scores, designed specifically for Indian patients of RA, SLE, PsA, SpA etc. is the need of the hour.