Guest Editorial: Lipid Management in Patients with Chronic Inflammatory Conditions

Introduction

Immune system activation – i.e., systemic inflammation, plays an essential role in all stages of atherosclerosis, from the development of the fatty streak to acute plaque rupture.¹ Autoimmune diseases are common, with a prevalence of up to 8% of the United States (US) adult population. Diseases such as rheumatoid arthritis (RA), psoriasis, systemic lupus erythematosus (SLE), rare conditions such as the inflammatory myopathies (IMs), and states of chronic inflammation such as human immunodeficiency virus (HIV), all increase the risk of atherosclerotic cardiovascular disease (ASCVD) greater than 50% over controls.^2-4
 
Lipid management in patients with chronic inflammatory disease poses several challenges. Traditional cardiovascular (CV) risk scoring systems underestimate risk in patients with inflammatory conditions and few primary prevention guidelines are available that are specific to these patients.³ Additionally, serum lipid levels fluctuate in parallel with inflammation and its suppression. Thus, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) are sometimes low during disease flares and increase with treatment.⁵ Certain anti-inflammatory therapies may further modulate lipid levels as well as the patient’s level of CV risk. Lastly, statin hesitancy is a concern in this population of patients who are oftentimes more likely to experience side effects. This review discusses important considerations for lipid management in patients with chronic inflammatory conditions including HIV, psoriasis, RA, SLE, and IM.

HIV

Until the advent of antiretroviral therapy (ART), HIV infected individuals progressed to acquired immunodeficiency syndrome (AIDS) and typically death within three years due to opportunistic infections.⁶ As the life expectancy of patients with HIV has increased, ASCVD has emerged as the most significant complication. The risk of ASCVD is up to twice as high among persons with HIV as compared to the general population.⁷ In developed nations, the prevalence of traditional CV risk factors is higher in patients with HIV than in the general population, but increased CV risk persists after controlling for these factors.⁸ This increased risk therefore likely relates to traditional risk factors in the setting of residual inflammation and immune activation, leading to vascular dysfunction and atherothrombosis.⁹ Underlying inflammation leads to a lipid panel characterized by the “lipid triad” of hypertriglyceridemia, increase in small LDL-C particles, and lower HDL-C.10,11 In this setting, it is worthwhile to obtain an apolipoprotein B (apoB) level and/or LDL particle number (LDL-P) to facilitate treatment decisions, as LDL-C may be falsely low and may not adequately represent atherogenic risk.
 
At this time there is no validated 10-year risk score specifically for people with HIV. The NLA suggests using either the Framingham Risk Score or ACC/AHA 2013 Pooled Cohort Equation along with considering HIV an additional CV risk enhancing factor to guide treatment initiation and lipid target goals.¹¹ The recently published Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) provided convincing evidence that statin therapy effectively reduces CV risk in primary prevention patients with HIV who are on ART. In this trial, treatment with pitavastatin 4 mg daily led to a significant 35% lower risk of major adverse cardiovascular events (MACE) versus placebo.¹² This was a larger reduction than that predicted by the Cholesterol Treatment Trialists’ Collaboration based on LDL-C reduction, suggesting an additional mechanism of benefit such as an anti-inflammatory effect.

When utilizing statin therapy in patients with HIV, drug interactions with ART must be considered. Due to their efficacy, atorvastatin and rosuvastatin are first-line agents (with appropriate dose adjustments depending on the type of ART used [Table 1]).¹¹ Pravastatin and pitavastatin do not interact significantly with ART. On the other hand, lovastatin and simvastatin should not be used.¹¹

Psoriasis

Studies have demonstrated an approximate 50% increased risk of ASCVD in patients with psoriasis, while severe psoriasis increases CV mortality¹³ by 40%. Key cytokine abnormalities pronounced in psoriasis, such as interleukin (IL)-17, IL-6, and tumor necrosis factor (TNF)α, share a link with atherosclerosis development.¹⁴ Inflammation in psoriasis drives several lipid abnormalities including reduced HDL-C and HDL-C efflux capacity, as well as reduced LDL-C size, increased LDL-P, and increased oxidized LDL-C (oxLDL).^15,16 Additionally, traditional CV risk factors are highly prevalent, under-recognized, and undertreated in psoriasis.¹⁷ ASCVD development in psoriasis can therefore be attributed to a combination of immune system activation, pan-arterial inflammation, and concomitant cardiometabolic conditions.¹⁸

When risk stratifying patients with psoriasis, a history of moderate-to-severe psoriasis should be considered a significant CV risk enhancing factor.^18,19 Some guidelines suggest a 1.5 multiplication factor to a 10-year CV risk score.20 Studies evaluating statin therapy for primary prevention in psoriatic patients are limited; but given the increased CV risk in psoriasis, an aggressive approach to both lifestyle and medication therapy is warranted.^3,18

Observational data suggests that targeting inflammation in psoriasis could reduce CV risk. In one study of psoriasis patients treated with a TNFα inhibitor, myocardial infarction was reduced by 50%.²¹ Randomized placebo-controlled trials (RCTs) have had mixed results.18 Current evidence on TNFα, IL-12/IL-23(p40), IL-23(p19), and IL-17 inhibitors leans towards a CV benefit, but further work is needed.²²

Rheumatoid Arthritis

CV risk is 1.5- to 2-fold higher in patients with RA compared to individuals from the general population.²³ The underlying chronic inflammation in RA is similar to the processes involved in the initiation of atherosclerotic plaques and thus leads to accelerated atherosclerosis.²⁴ During active flares of RA, inflammation suppresses levels of TC, HDL-C, and LDL-C.⁵ There is an interesting “lipid paradox,” whereby RA patients with the lowest LDL-C levels have the highest coronary calcium scores and risk for CV events, with risk comparable to or exceeding that observed in RA patients with the highest LDL-C levels.^25,26 A proposed mechanism of this paradox is increased lipoprotein oxidation resulting in increased vascular LDL-C uptake and plaque formation.²⁷ Consequently, if a patient has lipid levels checked during an RA flare, it is recommended that lipids be rechecked when their disease is controlled.¹¹

As with psoriasis, guidelines suggest considering RA an additional CV risk factor ^3,28 or multiplying the 10-year CV risk score by 1.5. Statins appear to be safe and effective in the RA population²⁹ with evidence for an additional anti-inflammatory effect.³⁰ In a large primary prevention RCT of RA patients, treatment with atorvastatin 40 mg daily led to a 34% lower risk of MACE versus placebo.³¹ Most experts therefore argue for a low threshold to statin initiation.^3,30
 
The role of anti-inflammatory therapies—particularly IL-6 inhibition—in the reduction of residual CV risk is an area of active research.³² The IL-6 inhibitor tocilizumab increases TC, HDL-C, and LDL-C levels, but it has also been shown to modify HDL-C particles towards an anti-inflammatory composition and to reduce lipoprotein(a) (Lp(a)) levels.³³ This dual effect of both decreased inflammation and Lp(a) may improve ASCVD outcomes.³⁴ On the other hand, there is concern regarding the CV safety of janus kinase (JAK) inhibitors.³⁵ In the ORAL Surveillance trial, treatment with the JAK inhibitor tofacitinib increased the risk of MACE and failed to demonstrate noninferiority versus TNFα inhibitors.³⁶ Post-hoc analyses suggest that this increased risk may disproportionately affect individuals with CV risk factors or established ASCVD.³⁵ JAK inhibitors are also associated with increased levels of TC, HDL-C, LDL-C, and triglycerides, though statins can normalize these changes.^37,38 CV risk stratification prior to initiating therapy as well as aggressive CV risk factor mitigation during therapy are crucial. Of note, selective tyrosine kinase 2 (TYK2) inhibitors, a novel subclass of JAK inhibitors, have not been associated with significant changes in serum lipid levels or risk of MACE.³⁵

Systemic Lupus Erythematosus

There is a several fold increase in the risk of ASCVD in patients with SLE, and younger females with SLE have the greatest relative risk compared to age- and sex-matched controls.³⁹ Early onset ASCVD in SLE patients can be attributed to a combination of traditional cardiac risk factors, chronic inflammation, and disease-specific factors.³ In particular, higher disease activity, glucocorticoid use, and the presence of antiphospholipid antibodies are associated with increased CV risk.³⁹ Patients with SLE have increased platelet activity and subsequent endothelial cell activation, which may represent a key mechanism of accelerated ASCVD.⁴⁰ Inflammation in SLE also promotes the transformation of normal, protective HDL-C to proinflammatory HDL-C, which enhances the oxidation of LDL-C and attracts monocytes to engulf oxLDL.^41,42 This process, together with endothelial dysfunction, initiates atherosclerotic plaque formation.
 
Guidelines for risk stratification in patients with SLE are limited, and no society ‘risk multiplier’ recommendations exist.³ The evidence for or against statin therapy is also mixed. Although a retrospective observational study did find a benefit⁴³, in one RCT atorvastatin 40 mg daily did not reduce subclinical measures of atherosclerosis, disease activity, or biochemical measures of inflammation.44 Nevertheless, diligent CV risk factor identification and mitigation is necessary.³
 
Hydroxychloroquine, a cornerstone in the treatment of SLE, may be protective against ASCVD via improvements in glycemic control, reduction in lipid levels, inhibition of proatherogenic inflammatory pathways, and reduction in thromboembolic events.^45,46 

Azathioprine and glucocorticoids have been associated with increased CV risk, but these relationships are confounded by the fact that patients requiring these medications have higher disease activity.³⁹

Inflammatory Myopathies

As with other inflammatory conditions, the IMs increase ASCVD risk likely through interactions between proinflammatory cytokines and an increased prevalence of traditional risk factors.⁴⁷ Lipid profiles in patients with dermatomyositis and polymyositis are characterized by increased triglycerides, decreased HDL-C, and increased TC/HDL-C ratio.^48,49 Impaired HDL-C antioxidant function, which is linked to accelerated atherosclerosis in SLE and RA⁴², has also been observed.⁵⁰
 
There is understandable hesitancy to prescribe statins to patients with IM due to concerns about statin-associated muscle symptoms (SAMS) or an exacerbation of IM-associated muscle symptoms. However, observational studies have shown that statins are fairly well-tolerated in patients with IM.⁵¹ In one study of 33 patients with IM who were prescribed statins, there were no significant changes in muscle disease activity or assessments of inflammation as compared to a control group with IM not on statin therapy.⁵² For patients who do develop SAMS, one could consider using a lower dose statin or a decreased dosing frequency in combination with ezetimibe or bempedoic acid. In patients with IM who are statin-intolerant or who remain symptomatic from their IM, it may be reasonable to defer statin therapy and proceed directly to proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor monoclonal antibodies.⁵¹

SAMS should be distinguished from statin-induced necrotizing autoimmune myopathy (SINAM). This rare and life-threatening condition may present with severe symmetric proximal muscle weakness and CK levels >1000 IU/L any time after statin initiation and is thought to be mediated by antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR).^53,54 Whereas SAMS typically improve with statin discontinuation, SINAM may persist or worsen after statin discontinuation and usually requires immunotherapy for improvement.⁵³ Though anti-HMGCR antibodies are strongly associated with statin exposure, about one third of patients with anti-HMGCR antibodies are statin-naïve.⁵³ Nonetheless, if SINAM is suspected the statin should be immediately discontinued and alternative lipid-lowering therapy, such as a PCSK9 inhibitor, should be considered.

Conclusions

There are several important considerations for lipid management in patients with chronic inflammatory conditions. These conditions increase ASCVD risk and should be considered risk-enhancing factors that guide treatment initiation and lipid target goals. Lipid levels may be affected by both the degree of disease activity and the use of anti-inflammatory therapies. Finally, as outlined, certain disease-modifying therapies may positively or negatively impact CV risk.

Dr. Sherry has no financial relationships to disclose. Dr. Garshick has received honorarium from BMS, Agepha, Kiniksa, Horizon, and grant support from Pfizer. 

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