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Autoimmune rheumatic diseases (AIRDs) therapies that better regulate lipid metabolism could significantly reduce the harmful side-effects caused by conventional treatments, according to a new large-scale review led by University College London (UCL) researchers.

For the study, published in the Journal of Clinical Investigation, researchers carried out a literature review of more than 200 studies, to assess and interpret what is known regarding the on-target/off-target effects and mechanisms of action of current AIRD therapies on lipid metabolism, immune cell function, and cardiovascular disease (CVD) risk.

AIRDs affect millions globally and include rheumatoid arthritis, lupus, and Sjögren’s syndrome – all of which have high rates of morbidity. These conditions occur when the immune system mistakenly attacks and damages its own tissues. But the pathogenesis of these conditions is still ill-defined and delivering targeted therapeutic strategies is challenging.

As a result, current treatments for AIRDs are primarily designed to suppress the major symptom, which is inflammation. But many of these drugs may also have unintended side-effects, including causing changes to cell metabolism (such as lipids) and function, putting patients at greater risk of comorbidities such as cardiovascular disease.

Lead author Dr George Robinson (Center for Rheumatology Research, UCL Division of Medicine) said, “While the mechanisms that cause rheumatic diseases are ill-defined, some recent research indicates cell metabolism may play an important role in triggering or worsening their onset or effect.

“In this review we therefore sought to understand the effect of both conventional and emerging therapies on lipid metabolism in patients with AIRDs.”

Conventional therapies for AIRDS with low target specificity can have effects on cell metabolism that are less predictable. For example, current therapies can improve or exacerbate dyslipidemia. Many conventional drugs also require in vivo metabolism for their conversion into therapeutically beneficial products.

However, drug metabolism often involves the additional formation of toxic by-products, and rates of drug metabolism that can be heterogeneous between patients. As a result, new research is targeting alternative metabolic pathways that can be more specifically targeted to reduce inflammation but also to prevent undesirable off-target metabolic consequences of conventional anti-inflammatory therapies.

Explaining the findings of their study, Robinson said: “Our review found that current AIRD therapies can both improve or worsen lipid metabolism, and either of these changes could cause inflammation and increased CVD risk.

“Many conventional drugs also require cell metabolism for their conversion into therapeutically beneficial products; however drug metabolism often involves the additional formation of toxic by-products, and rates of drug metabolism can be different between patients.”

The review noted that better control of inflammation using optimal combinations of immunosuppressive treatments could lead to an improved metabolic/lipid profile in AIRDs.

However, it also revealed many studies have shown that lipid lowering drugs (such as statins) are not sufficient to reduce CVD risk in some AIRDs, potentially because they cannot completely restore the anti-inflammatory properties

Robinson added, “The unfavorable off-target adverse effects of current therapies used to treat AIRDs provides an opportunity for optimal combination co-therapies targeting lipid metabolism that could reduce immune complications and potential increased CVD risk in patients.

“New therapeutic technologies and research have also highlighted alternative metabolic pathways that can be more specifically targeted to reduce inflammation but also to prevent undesirable off-target metabolic consequences of conventional anti-inflammatory therapies.”

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