Psoriasis is a chronic autoimmune condition characterized by overactive skin cell multiplication, resulting in the development of painful rashes and inflammation. Unfortunately, there is no outright cure for psoriasis, but there are a number of treatment options available. These include creams containing tar, retinol, steroids, light therapy, and oral immune regulators such as methotrexate, cyclosporine, and injectable biologics. Conversely, certain medications can also cause psoriasis flare-ups. Beta-blockers, including metoprolol, used to treat high blood pressure and anxiety, are known to increase the risk of flare-ups. Similarly, lithium, anti-malarial drugs, and a number of others can also predispose one to a flare-up or, in rare cases, induce psoriasis. Additionally, stopping oral corticosteroids abruptly may worsen psoriasis symptoms. Recent genetic analysis has confirmed the connection between high cholesterol levels and psoriasis risk. This opens a new way to improve psoriasis treatment by using cholesterol-lowering medications.

How do we know that cholesterol-lowering medications are effective for psoriasis?

Studies have found that psoriasis is comorbid with hyperlipidemia (high cholesterol).  This is because certain genes that cause high cholesterol also increase the risk of developing psoriasis. A large study found that mutations in genes that lower cholesterol levels also affect psoriasis risk. Researchers have studied how cholesterol-lowering drugs can affect psoriasis symptoms in people with genetically reduced enzyme activity or deficiency. This research provides insight into how these drugs can help psoriasis patients with high cholesterol.

Statins are medications that can help lower cholesterol levels. They do this by blocking the activity of an enzyme called 3-hydroxy-3-methylglutaryl CoA reductase, which is encoded by the HMGCR gene. Research shows that people who carry genetic variants that cause loss of function of the HMGCR gene have a lower risk of developing psoriasis. In fact, their odds of developing psoriasis are 0.71 times lower than those of people without these variants. Statins also have a broad anti-inflammatory effect and can reduce the risk of cancer and improve longevity.

Cholesterol absorption inhibitors including ezetimibe (Zetia), block Niemann-Pick C1–like 1 cholesterol transporter (NPC1L1). People with mutations in the NPC1L1 gene, which encodes this enzyme, have >50% lower incidence of psoriasis compared to controls (OR 0.48). Although ezetimibe has a moderate impact on cholesterol levels, genetic results suggest that it may have the most potent effect among cholesterol medications for treating psoriasis. To achieve greater clinical impact, ezetimibe is commonly prescribed in combination with statins such as atorvastatin (Liptruzet) or simvastatin (Vytorin). When taken in conjunction, the medications are expected to have a greater benefit for psoriasis than either statins or ezetimibe alone.

Proprotein convertase inhibitors such as alirocumab (Praluent) and evolocumab (Repatha) are injectable medications used to significantly reduce low-density lipoprotein (LDL) cholesterol levels, also known as “bad cholesterol”. Similarly, the incidence of psoriasis was substantially lower among people with loss-of-function mutations in the PCSK9 gene (OR 0.51) and in the LDL gene (OR 0.58).

Which cholesterol-lowering drug would work best for me?

If you have psoriasis and are considering augmenting your treatment with one of these medications, it is important to know that the selection of cholesterol-lowering drugs should be done with consideration of a variety of factors, including your cholesterol levels, heart disease risk, and DNA.
If you have normal cholesterol levels, starting with ezetimibe may be the best route. The use of stronger cholesterol-lowering medications is associated with significant health risks. Lowering cholesterol levels too far can create a deficiency, as your body needs cholesterol for hormone synthesis and for building protective lipid layers in your nervous system.

If you have moderately elevated cholesterol, statins might be needed in addition to diet modification. However, statins are known to increase the risk of muscle and joint pain. The selection of specific medication and dose is also impacted by your DNA.  Pharmacogenetic tests, such as Pillcheck, can help you and your doctor select a statin that will be safe and effective for you.

If you have a family history of extremely high cholesterol levels, known as familial hypercholesterolemia, it is likely due to a gain-of-function mutation (a genetic mutation that causes abnormal or enhanced function, and can lead to elevated levels of the products of that gene) in one of the genes mentioned above. In such cases, you may require a combination of biological cholesterol-lowering medication along with a statin to manage both your risk of heart disease and psoriasis effectively.

How can pharmacogenetics help to guide my psoriasis therapy?

It is important to note that taking multiple medications increases a person’s risk of drug-induced complications. Some drugs, including topical creams, may cause severe side effects. Using DNA-guided dosing based on your personal genetic profile can make prescribing other non-biological psoriasis therapies safer.

Methotrexate is a powerful immune regulator for treating various autoimmune conditions, including severe psoriasis. The SLCO1B1 gene encodes the transporter that metabolizes methotrexate and all statins. Genetic variations in this gene can increase the risk of methotrexate toxicity and statin intolerance. For people with a normal SLCO1B1 gene, it may be possible to combine methotrexate with a low dose of statins. However, for people with reduced function, significant dose adjustments are recommended for both medications, and it is best to avoid combining them.

Cyclosporine is an immunoregulator used to treat severe psoriasis, metabolized by enzymes CYP3A4 and CYP3A5. CYP3A5 activity varies among different populations. Many people of European descent lack this enzyme, but it is active in most of African descent. Since early clinical trials included predominantly people of European origin, the standard drug dosing is better suited for this ancestry. Individuals with African, Middle Eastern, or mixed ancestry may require higher doses of a certain drug to achieve its desired effect. Some people have a lower activity of the CYP3A4 enzyme, which can increase their chances of experiencing cyclosporin toxicity, especially when taking statins. Therefore, it is important to determine the ideal dosage of cyclosporin based on your genetic profile and any other medications you may be taking.

Thioguanine is an oncological medicine sometimes used in people who cannot tolerate other therapies. Genetic variations in the TPMT and NUD15 genes impact the risk of side effects of azathioprine, mercaptopurine and thioguanine. Clinical guidelines recommend pharmacogenetic testing before prescribing these medications to improve safety.

Coal tar ointment and shampoo may increase CYP1A2 activity and affect the response to some mental health medications in certain individuals with psoriasis.

UV light therapies are also commonly recommended, but long-term use may increase your risk of melanoma.

Biological therapies block specific inflammatory cytokines and are quite effective for some individuals, but there are currently no predictive tests to assess response to these drugs. Because the risk of drug interactions is low, biological medicines can be combined with ezetimibe and statins to augment your treatment.

Summary

• Due to shared genetic links between cholesterol metabolism and psoriasis, cholesterol-lowering medication can help to treat both conditions.
• The selection and dosing of cholesterol-lowering medications are determined by your DNA. A pharmacogenetic test result can help you and your doctor to select the appropriate medication and dose.
• If you did not respond to biological medication and need an immunosuppressant, pharmacogenetic testing is highly recommended to reduce your risk of drug-induced side effects.
• Pharmacogenetics is now covered by many workplace insurance plans as part of extended health benefits.

Selected references

Zhao SS et al., Association of Lipid-Lowering Drugs With Risk of Psoriasis A Mendelian Randomization Study JAMA Dermatol. 2023;159(3):275-280.

Xiao Y et al., Serum Lipids and Risk of Incident Psoriasis: A Prospective Cohort Study from the UK Biobank Study and Mendelian Randomization Analysis. J Invest Dermatol. 2022 Dec;142(12):3192-3199.e12.

Gonzalez-Cantero A et al., Statins and psoriasis: Position statement by the Psoriasis Task Force of the European Academy of Dermatology and Venerology. J Eur Acad Dermatol Venereol. 2023 Sep;37(9):1697-1705.