Dyslipidemia in Women with Autoimmune Diseases: Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Beyond

Inflammation-driven lipid alterations

Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and type I interferons profoundly affect lipid metabolism. TNF-α and IL-6 upregulate hepatic very low-density lipoprotein (VLDL) production while simultaneously inhibiting lipoprotein lipase activity, leading to hypertriglyceridemia. IL-6 also accelerates hepatic clearance of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), often resulting in paradoxically low levels during active inflammation. Despite these apparently favorable lipid concentrations, the risk of atherosclerosis is heightened, a phenomenon termed the “lipid paradox” in RA.^[4] In addition, systemic inflammation promotes oxidative modification of low-density lipoprotein (LDL) particles, creating oxidized LDL (oxLDL), which is more atherogenic due to enhanced uptake by macrophages and stimulation of endothelial dysfunction [Figure 1].

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Figure 1:

Effect of inflammation in autoimmune diseases. (TNF: Tumor necrosis factor, IL: Interleukin, VLDL: Very low density lipoprotein, LPL: Lipoprotein lipase.)

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Autoantibody-mediated mechanisms

High-density lipoprotein (HDL) normally exerts anti-atherogenic effects by facilitating reverse cholesterol transport and exerting anti-inflammatory and antioxidant actions. In SLE, however, the presence of autoantibodies against apolipoprotein A1 (ApoA1) and HDL leads to structural and functional impairment, converting HDL into a pro-inflammatory HDL particle. This dysfunctional HDL loses its protective capacity and instead promotes oxidative stress within the vasculature.^[5,6] Similar phenomena are described in RA and Sjögren’s syndrome, where HDL exhibits reduced paraoxonase-1 activity, impairing its antioxidant function.^[7-9]

Hormonal and gender-specific influences

An increasing number of studies have explored the role of sex on the immune system, and there is a considerable amount of evidence in the literature suggesting that estrogens play a significant part in autoimmunity.^[10] Sex hormones modulate lipid metabolism. Estrogen typically raises HDL cholesterol (HDL-C) and lowers LDL-C, contributing to the lower CV risk in premenopausal women. In autoimmune diseases, however, chronic systemic inflammation blunts estrogen’s protective effects, while premature menopause, common in SLE and RA due to both disease activity and cytotoxic therapies, accelerates adverse lipid changes.^[11] Menopause can induce the development of autoimmunity and can alter the course of immune-rheumatic diseases.^[12] This interaction explains, in part, why women with ARDs lose their expected hormonal CV protection and exhibit disproportionately high atherosclerotic risk.

Therapy-related factors

Medications significantly modulate lipid profiles in autoimmune diseases.

• Glucocorticoids: Commonly used in SLE and RA, increase LDL-C and triglycerides (TGs) in a dose-dependent manner while lowering HDL-C at higher doses.

• Hydroxychloroquine: Improves lipid profiles by lowering LDL and TG s while raising HDL.

• Methotrexate: Exerts indirect cardioprotective effects via inflammation reduction.

• Biologic agents (TNF inhibitors, IL-6 blockers): May raise TC and LDL-C but also improve HDL function and reduce vascular inflammation, resulting in net CV benefit.

Epidemiology

Among traditional atherosclerotic risk factors, dyslipidemia is believed to decisively affect the long-term prognosis of lupus patients with regard to CV events Dyslipidemia is highly prevalent in SLE, affecting up to 30–60% of patients.^[13]

Characteristic lipid profile

The “lupus pattern” of dyslipidemia includes:

• Low HDL-C

• Elevated TGs

• Elevated oxLDL

• Normal or slightly increased TC and LDL-C

• Altered apolipoproteins: Reduced ApoA1 (HDL’s main protein component) and elevated ApoB are frequently observed.

Disease activity and lipid changes

Active disease exacerbates lipid abnormalities through enhanced cytokine release. During remission, partial improvement in lipid levels is observed, though abnormalities often persist.^[14]

CV outcomes

With regard to the impact of dyslipidemia on clinical CVD, several studies have shown that increased TC is an independent predictor for CV events, including myocardial infarction and stroke^[1,15-18] as well as subclinical atherosclerosis. The dyslipidemia in SLE, combined with chronic inflammation and traditional risk factors, contributes significantly to this burden, necessitating vigilant monitoring and aggressive risk management. Importantly, CV events often occur despite “normal” lipid levels, reflecting the impact of dysfunctional HDL and oxLDL.

Renal outcomes

Dyslipidemia in patients with SLE can alter the course of disease severity majority of patients with SLE have renal involvement. There is mounting evidence that dyslipidemia can, in fact, aggravate renal injury. The levels of TNF receptors are increased in patients with SLE nephritis. Hyperlipidemia may interact with these TNF receptors and aggravate renal damage.

Epidemiology

Dyslipidemia is common in RA, affecting nearly 50% of patients during the disease course. The CV research in Rheumatoid patients study reported a two-fold increase in CV events among RA patients compared with the general population, despite lower LDL-C concentrations.^[19] Large registries such as Quantitative Patient Questionnaires in standard monitoring of patients with Rheumatoid arthritis (QUEST)-RA and population-based cohorts confirm this elevated risk.^[20] While conventional risk factors contribute, RA-specific lipid changes and inflammation-driven alterations explain much of the residual CV burden. The association between CVD and RA was greater in females and younger individuals.^[21] Studies suggest that female RA patients have lower HDL-C and more adverse lipid ratios compared with men. Furthermore, post-menopausal women with RA exhibit accelerated atherogenesis due to the combined loss of estrogen’s cardioprotective effects and heightened systemic inflammation.

The “lipid paradox”

One of the most striking features of RA-associated dyslipidemia is the so-called “lipid paradox.” Unlike classic dyslipidemia, where higher TC and LDL cholesterol (LDL-C) strongly predict CVD, RA patients often exhibit low TC, LDL-C, and HDL-C levels during periods of high disease activity—yet their CV risk is paradoxically elevated. This paradox is explained by:

• Inflammation-induced lipid lowering: Pro-inflammatory cytokines such as TNF-α and IL-6 accelerate LDL clearance and reduce cholesterol synthesis, resulting in lower circulating lipid levels.

• Qualitative lipid dysfunction: Despite reduced absolute concentrations, LDL particles are more atherogenic (small, dense, oxidized), while HDL becomes dysfunctional, losing its antioxidant and reverse cholesterol transport capacity.

• Inflammation as the true driver: CVD risk is closely linked to systemic inflammation rather than absolute lipid levels, explaining why lowering inflammation often normalizes lipids while simultaneously reducing risk.

Gender differences

Female RA patients display more adverse lipid profiles, including lower HDL-C and more dysfunctional HDL compared with male patients. Menopause compounds this effect.

CV risk

The paradoxical association of low cholesterol with higher CV risk underscores the centrality of inflammation. Effective suppression of RA activity improves both lipid levels and outcomes, emphasizing the need for integrated management. The European League Against Rheumatism (EULAR) recommends multiplying standard CVD risk scores by 1.5 in RA patients with additional risk factors.^[22]

Psoriasis and PsA

The inflammatory milieu in psoriasis and PsA exerts profound effects on lipid homeostasis. Pro-inflammatory cytokines such as TNF-α, IL-6, and IL-17 disrupt normal lipid metabolism, leading to an atherogenic lipid profile.

Patients with psoriasis and PsA often have elevated TGs, low HDL-C, and increased LDL-C. The overlap with metabolic syndrome is strong.^[23] The severity and duration of psoriasis correlate with the degree of lipid abnormalities, suggesting that sustained systemic inflammation amplifies metabolic dysregulation.

Sjögren’s syndrome

Dyslipidemia in Sjögren’s syndrome represents an important but often underrecognized contributor to CVD. Driven by chronic inflammation, immune dysregulation, and oxidative stress, lipid abnormalities in Sjögren’s syndrome extend beyond quantitative changes to involve functional alterations that accelerate atherosclerosis. Carotid intima-media thickness (cIMT) and endothelial dysfunction have been observed in Sjögren’s syndrome patients, often independent of traditional CV risk factors.^[24] Compared with RA or SLE, the CV risk in Sjögren’s syndrome is less extensively studied, but emerging evidence highlights a similar pattern of premature vascular aging and subclinical atherosclerosis.

SSc

Dyslipidemia in SSc arises from a complex interplay of systemic inflammation, endothelial dysfunction, and metabolic disturbances. Patients with SSc exhibit increased rates of subclinical atherosclerosis, as reflected by cIMT, impaired flow-mediated vasodilation, and arterial stiffness. Dyslipidemia acts synergistically with immune-mediated endothelial injury, Raynaud’s phenomenon-related vascular stress, and microangiopathy to accelerate atherothrombosis. Consequently, SSc patients are at higher risk for ischemic heart disease, CVD, and CV mortality compared with the general population. While pulmonary arterial hypertension and myocardial fibrosis dominate clinical attention, dyslipidemia represents a modifiable contributor to CV risk that should not be overlooked. Disease duration, diffuse cutaneous subtype, and systemic involvement (particularly interstitial lung disease and renal dysfunction) are associated with more pronounced dyslipidemia. Compared to SLE or RA, the literature on dyslipidemia in SSc is relatively limited, yet available data indicate a similarly heightened cardiometabolic burden.

AITDs

AITDs, including Hashimoto’s thyroiditis and Graves’ disease, are characterized by immune-mediated thyroid dysfunction, manifesting as hypothyroidism, hyperthyroidism, or fluctuating thyroid states. Beyond the endocrine manifestations, AITD is increasingly recognized as a systemic condition associated with metabolic derangements, particularly dyslipidemia. The thyroid gland plays a central role in lipid metabolism by regulating cholesterol synthesis, clearance, and lipoprotein activity. In hypothyroidism due to Hashimoto’s thyroiditis, reduced thyroid hormone levels impair LDL receptor activity in the liver, slowing LDL clearance and raising circulating cholesterol. Lipoprotein lipase activity is also reduced, leading to elevated TGs. Furthermore, oxidative stress and systemic inflammation inherent to autoimmunity modify lipoproteins, producing oxLDL and dysfunctional HDL, which exacerbate atherogenesis. In contrast, hyperthyroidism (often due to Graves’ disease) accelerates LDL clearance, typically resulting in hypocholesterolemia, though chronic inflammation and treatment-induced hypothyroidism may paradoxically contribute to dyslipidemia. Various patterns of lipid abnormalities in autoimmune diseases described above are summarized in Table 1.

Screening and risk assessment

Regular lipid screening is recommended in all patients with autoimmune diseases, particularly women with active disease or those receiving corticosteroids. EULAR guidelines advise baseline lipid profiling at diagnosis and periodically.^[25] Conventional CV risk calculators (e.g., Framingham, systematic coronary risk evaluation [SCORE], atherosclerotic cardiovascular disease [ASCVD]) underestimate risk in autoimmune populations. EULAR recommends multiplying calculated risk scores by 1.5 in RA if additional risk factors (disease duration >10 years, seropositivity, extra-articular disease) are present. Similar adjustments are likely necessary in SLE, although no validated formula currently exists.

Lifestyle interventions

Lifestyle modification is a cornerstone of management. Interventions include:

• Dietary changes: Mediterranean-style diet rich in omega-3 fatty acids, fiber, and antioxidants.

• Physical activity: Regular aerobic and resistance exercise, adapted to joint function and fatigue levels.

• Smoking cessation: Critical in RA and SLE, where smoking exacerbates both inflammation and CVD risk.

• Weight management: Essential in PsA and other conditions closely linked to metabolic syndrome.

Control of systemic inflammation

Inflammation control is central to correcting lipid abnormalities.

• Glucocorticoids improve disease activity but worsen lipid profiles; the lowest effective dose should be used.

• Hydroxychloroquine (in SLE) improves lipid parameters by lowering LDL-C and TGs, and increasing HDL-C, making it both disease-modifying and cardioprotective.

• Methotrexate in RA has indirect cardioprotective benefits through inflammation suppression.

• Biologic agents (TNF inhibitors, IL-6 receptor blockers, rituximab) improve lipid function and vascular inflammation despite sometimes raising TC. Net effect is CV risk reduction.

Pharmacologic lipid-lowering therapy

Statins remain the mainstay of therapy. They effectively reduce LDL-C and TGs while modestly increasing HDL-C. Beyond lipid-lowering, statins may exert anti-inflammatory effects, potentially improving endothelial function in autoimmune diseases. Many autoimmune patients have normal LDL-C but elevated C reactive protein (CRP)/high sensitive C reactive protein (hs-CRP). Justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin (JUPITER) proved that rosuvastatin reduces CV events in patients with normal LDL but elevated hsCRP, confirming the inflammation–atherosclerosis link and providing rationale for statin therapy in these patients, even in the absence of overt hyperlipidemia.^[26]

Lupus Atherosclerosis Prevention Study (LAPS) trial tested atorvastatin 40 mg daily versus placebo over 2 years in 200 SLE patients without clinical CVD, showed atorvastatin significantly lowered LDL in SLE but did not reduce subclinical atherosclerosis progression over 2 years, underscoring that lupus-related vascular risk extends beyond cholesterol. LAPS suggests that statins alone may not fully prevent lupus-related vascular damage, highlighting the need for comprehensive risk management (tight disease control, steroid minimization, control of blood pressure,and diabetes).^[27]

The atherosclerosis prevention in pediatric lupus erythematosus (APPLE) trial found that atorvastatin safely lowered LDL-C in pediatric SLE but did not reduce cIMT progression overall. Statins should be considered in pediatric SLE patients with dyslipidemia or other strong CV risk factors.^[28]

The trial of atorvastatin in rheumatoid arthritis (TARA) trial demonstrated that atorvastatin can improve both lipid parameters and markers of systemic inflammation in RA. Importantly, atorvastatin also led to modest improvements in disease activity, suggesting a dual CV and anti-rheumatic benefit. The magnitude of disease activity score (DAS)28 reduction was smaller than that typically achieved with Disease Modifying anti Rheumatic drugs (DMARDs) or biologics, but clinically meaningful given statins’ safety, low cost, and widespread availability.^[29]

Trial of atorvastatin for the primary prevention of cardiovascular events (TRACE) RA confirmed that atorvastatin significantly improves lipid levels in RA and showed a non-significant trend toward CV event reduction. It could not prove a definitive reduction in CV outcomes since the trial was underpowered (early termination after fewer-than-expected events). Importantly, the trial demonstrated the safety of high-dose atorvastatin in RA, supporting broader use in high-risk patients.^[30]

• Ezetimibe can be added if statin monotherapy is insufficient or not tolerated.

• Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors offer potent LDL-C reduction in high-risk patients, though data in autoimmune diseases are limited.

• Fibrates may be considered for severe hypertriglyceridemia, particularly in lupus patients on corticosteroids [Table 2].

Gender and pregnancy considerations

The American College of cardiology (ACC)/American heart association (AHA) guidelines recommend the consideration of “RISK ENHANCERS” including female-specific factors such as pregnancy outcomes (e.g., Preeclampsia), polycystic ovarian disease (PCOD), premature menopause, and autoimmune/inflammatory diseases (such as SLE and RA). The presence of this risk-enhancing factors would reclassify women into a higher risk group and favor the initiation of statin therapy or intensification of therapy, particularly for borderline risk groups for whom there may be more uncertainty about actual CVD risk. In such cases of uncertainty, a coronary artery calcium (CAC) score based on non-contrast computed tomography (CT) can help refine risk estimates and guide decision-making for the need for pharmacological intervention. Statin therapy is recommended for CAC score ≥ 100 Agatston units or at or above ≥75^th age-sex percentile. Management of women of reproductive age requires special attention. Statins and PCSK9 inhibitors are contraindicated in pregnancy due to teratogenic risk. Hydroxychloroquine, in contrast, is safe and should be continued throughout pregnancy. For women planning conception, discontinuation of statins with transition to non-teratogenic options (diet, lifestyle, possibly bile acid sequestrants) is recommended. Post-menopausal women often require more intensive lipid-lowering therapy due to the loss of estrogen’s protective effects.

Integrated multidisciplinary care

The management of dyslipidemia in autoimmune diseases is distinct from that in the general population. It requires a dual focus on suppressing systemic inflammation and implementing evidence-based lipid-lowering strategies, tailored to the unique risks faced by predominantly female patients. Optimal management requires collaboration among rheumatologists, cardiologists, and primary care physicians. Comprehensive strategies should integrate disease control, CV risk stratification, and reproductive counseling. Patient education is crucial to improve adherence, particularly since asymptomatic dyslipidemia may be overshadowed by active autoimmune disease manifestations. Future directions include the use of PCSK9 inhibitors and development of autoimmune-specific CV risk calculators to guide therapy more precisely.

SLE (mostly young women) → high dyslipidemia burden

An Eastern India prospective cohort (n = 101; 96% female; mean age 27) found dyslipidemia in 57.4%: hypertriglyceridemia 54.4%, low HDL and higher LDL versus controls; steroids did ot significantly change the pattern in this dataset.^[31]

“Lupus pattern” echoes in Indian cohorts

Elevated TG/VLDL with low HDL predominates in active disease; Indian data mirror this phenotype versus matched controls.^[31]

Subclinical atherosclerosis is common

Indian SLE and RA cohorts show increased cIMT versus controls; older Indian studies and a 2023 East-India SLE paper support higher CIMT/plaque burden in these patients.^[32,33]

RA in India → frequent low HDL and dyslipidemia

Indian RA series report dyslipidemia with low HDL as the most common abnormality; disease activity correlates inversely with HDL. Early Indian data (Hadda et al.) and newer Indian RA cohorts (Telangana; 2024–2025) reinforce this and show higher CIMT tied to age/disease activity.^[34,35]

Lipid Association of India (LAI) 2023/2024 update

Recognizes high ASCVD risk in Indians and supports aggressive LDL-C lowering (statin ± ezetimibe; early re-testing at 2 weeks for intensification). These principles are applicable to patients with chronic inflammatory diseases like RA/SLE, where calculated risk may underestimate true risk.^[36]

Screen early and repeatedly

Fasting lipid panel at diagnosis, after disease control, and at 3–6 months post-therapy changes; then annually (more often if active disease or therapy changes). Under-testing misses risk in RA/SLE.

Aim low on LDL-C

Treat RA/SLE patients as at least “risk-enhanced” in many, manage like high-risk Indians as per LAI: Start moderate–high intensity statin; add ezetimibe if not at goal; consider PCSK9 when available/affordable for very-high risk.

Check subclinical atherosclerosis where risk feels “under-called”

CIMT/carotid plaque can reclassify risk when calculators look “normal” but disease is active/long-standing or other enhancers exist.^[37,38]

Mind disease activity and steroids

Active SLE/RA worsens TG/HDL; optimize disease modifying anti rheumatic drugs (DMARDs) and steroid-sparing regimens to improve the lipid pattern. Indian SLE data did not find a clear steroid signal in that cohort, but overall literature supports activity-linked dyslipidemia.

Women’s health specifics

• Pregnancy: Coordinate obstetric-rheumatology care; avoid statins in pregnancy; address TG surges.

• Vitamin D/HDL interplay in RA: Indian data note low HDL with Vitamin D deficiency and higher disease activity—address deficiencies.^[39]