A new treatment for DSAP at Skin Plus Compounding Pharmacy

Disseminated Superficial Actinic Porokeratosis (DSAP) is a skin disorder characterised by scaly pink or brown spots usually on areas of sun-exposed skin. It is a chronic condition for which there is no definitive cure. Instead, the aim of medical treatment is to reduce the severity and number of lesions. However, existing traditional treatments used to manage DSAP have yielded variable results and have often caused unwanted side effects. 

In recent years, there has been promising research on the combined use of lovastatin and cholesterol on patients suffering from DSAP. While the exact mechanism of action has yet to be determined, evidence on its effectiveness continues to grow. 

Here we present important findings on the use of topical statins with cholesterol in alleviating DSAP clinical signs. To fully appreciate the implications of this novel treatment option, it is important to understand the disorder it helps to manage.

What is DSAP?

DSAP is one of several porokeratotic conditions that cause keratinocyte dysregulation. It is primarily associated with a loss-of-function mutation on the genes that encode for key enzymes in the mevalonate pathway. This complex metabolic process is crucial to skin cell proliferation, differentiation, and apoptosis. Its end product is cholesterol, one of the components of the epidermal lipid matrix on which the most superficial layer of the skin cells rest. This medium helps minimise the escape of water and electrolytes from the surface of the skin.

Decreased production of enzymes involved in the mevalonate pathway lead to disordered keratinization of the skin. The reduced amount of cholesterol compromises barrier integrity, leaving the surface of the body with poor protection and impaired ability to heal.

The manifestation of this pathogenesis is evident in the clinical signs. Affected patients have a large number of dry, scaly, brown-to--red plaques with distinct borders. Histologically, the border is made of a column of parakeratotic cells called the coronoid lamella. The presence of these nucleated keratinocytes in the superficial layer of the skin is abnormal, as the cells in this area should be anucleate. 

The plaques of DSAP are typically found in the lower arms and legs, with bilateral distribution. The unsightly marks often cause embarrassment and emotional stress on the patient. At times, the plaques may be pruritic, leading to discomfort and irritation. However, the most concerning aspect of DSAP to patients is the increased risk of cancer, particularly squamous cell carcinoma and basal cell carcinoma. 

Clinical signs are most often noticed at 30-40 years of age. DSAP can happen to anyone, but it appears to be slightly more prevalent among women and among people of European descent. Genetic mutations that lead to DSAP are autosomal dominant traits, which means that there is a 50% chance that a patient’s children will inherit the condition. Though DSAP is considered a hereditary condition, it has also been known to occur in immunocompromised people, including those who have undergone organ transplants and experienced systemic infection. Unprotected exposure to UV light has also been implicated as a trigger for DSAP.

What are the conventional treatment options for DSAP?

There are a variety of treatment options for DSAP that have been used throughout the years.

One method is to destroy the abnormal keratinocytes. Fluorouracil cream, ingenol mebutate gel, and photodynamic therapy use this mechanism of action. On the other hand, alpha hydroxy acids, and laser therapy promote continuous exfoliation of the skin surface. Cryotherapy, dermabrasion, and curettage are used to remove the lesion entirely.

Inhibiting the proliferation of abnormal keratinocytes is how calcipotriol and acitretin are believed to work on DSAP patients. Retinoids may also help as these counteract UV damage, which has been associated in the occurrence of DSAP.

Immune response modifiers such as imiquimod and diclofenac gel appear to have a positive effect on DSAP lesions, though the mechanism is not fully understood.

While these treatments have proven helpful, results are variable, side effects are prevalent, and recurrence is often observed. The therapeutic procedures including use of lasers and cryotherapy may be expensive and difficult to do on patients with wide distribution of lesions across their body. With these factors in mind, researchers are continuously searching for DSAP therapy, and it seems that lovastatin/cholesterol may be a strong contender.

Lovastatin/cholesterol for DSAP

The use of lovastatin/cholesterol for DSAP makes sense when the pathogenesis of the disorder is taken into consideration. The majority of studies on this combination have come out within the last year and a half. While much research is still needed to confirm its effectiveness, the initial results have so far confirmed that its mechanism of action works.

What is lovastatin?

Lovastatin is a secondary metabolite produced by the fungus Aspergillus terreus. This drug is part of the statin group of medications that have been used since the 1980s to decrease the levels of low density lipoproteins (LDL) in hypercholesterolemic individuals and those at risk of cardiovascular disease. It was the first of the statins to be approved for therapeutic use. 

Lovastatin and other statin drugs act as a potent inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HmG-CoA reductase), a major rate-limiting enzyme in the mevalonate pathway (Alberts, 1988). This enzyme is primarily produced in the liver, as this is the major site of cholesterol synthesis. HmG-CoA reductase is an enzyme that is responsible for the conversion of acetoacetyl-CoA to mevalonate. Mevalonate is then acted on in a stepwise manner by several mevalonate enzymes.  These are the very same enzymes that are defectively produced in patients suffering from DSAP.

Lovastatin is a prodrug, that is, its effect can only be manifested once it undergoes an enzymatic reaction within the body, specifically the liver. Once absorbed, lovastatin enters the bloodstream and passes through the liver, where it is metabolised and converted into its active form, which is a beta-hydroxyacid. The structure of this compound is very similar to the molecule that HmG-CoA reductase reacts with. Instead of binding to the substrate and transforming it into mevalonate, the enzyme instead binds with lovastatin’s beta-hydroxyacid form. Therefore, the reaction does not proceed and ultimately, cholesterol is not produced.

What is the mechanism of action of lovastatin/cholesterol?

The landmark study of Atzmony et al. (2020) hypothesized that the combined use of lovastatin and cholesterol would target important contributors to the pathogenesis of porokeratotic disorders. The following studies were noted as the basis of this hypothesis.

Accumulation of mevalonate appears to play a role in inflammation. A study by Bekkering et al. (2018) on patients with hyper immunoglobulin D syndrome (HIDS) finds that mevalonate activates the inflammatory pathway. Similar to DSAP, this disorder also results from deficiency of mevalonate-acting enzymes. Without these enzymes, mevalonate--a substance that is only supposed to be an intermediate along the biochemical pathway--accumulates. Too much mevalonate in the system is believed to contribute to the sterile episodes of inflammation that HIDS patients experience. The same study found that administration of fluvastatin, another member of the statin family, was able to downregulate the inflammatory substances associated with mevalonate accumulation. 

A study by Paller et al. (2011) on another autosomal dominant disorder affecting the cholesterol synthesis, Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects (CHILD) syndrome. Believing that cholesterol deficiency was the main factor in the pathogenesis of skin lesions, the team treated the patients with topical 10% cholesterol in hydrophilic ointment twice a day for 3 months. No significant improvement was observed. Ultrastructural analysis of the patients’ skin biopsy samples showed that affected skin had depleted cholesterol levels and accumulation of toxic metabolites. Guided by this finding, the researchers administered 2% lovastatin/2% cholesterol lotion twice a day for the 3 months. 

The idea was that the lovastatin would prevent the progress of the mevalonate pathway by inhibiting one of the first enzymes involved, HmG-CoA reductase. This way, the mevalonate intermediates are not formed and do not accumulate. Meanwhile, the administration of cholesterol would supply the needs of the skin. This way, the toxic substances from the incomplete mevalonate pathway are prevented from forming, but the end product of the pathway, cholesterol, is still made available for use in the skin.

The results provide strong evidence for this treatment. As early as 4-6 weeks starting treatment, the two patients involved in the study showed decreased scaling, skin thickening, and inflammation. At the end of the 3-month period, severity scores decreased by above 70% and ultrastructural analysis of the skin reflected the same improvements. The two patients were followed up over a year later as they continued the treatment, and found that the skin had continued to improve, with no adverse effects.

Studies on lovastatin/cholesterol on DSAP patients

The case series conducted by Atzmony et al. (2020) involved a total of 5 patients with porokeratosis disorders: 1 with DSAP, 2 with porokeratosis palmaris et plantaris disseminata (PPPD), and 2 with linear porokeratosis (LP). Genetic sequencing found that DSAP and PP patients had genetic mutations affecting the mevalonate kinase enzyme, while the LP patients had genetic mutations affecting the phosphomevalonate kinase enzyme. 

The patients administered a 2% cholesterol/2% lovastatin on a unilaterally defined treatment area for a total of 6 weeks to 3 months, with four using ointment form, and one using lotion form. Both were applied with occlusion. One patient used 2% cholesterol ointment on other affected areas outside of the defined treatment area.

All patients showed a marked improvement in lesion appearance. The adverse effects typically associated with topical drugs, including itchiness, redness, irritation, or dermatitis, were not reported among the participants in the study.

The patient with DSAP had a noticeable decrease in redness, scaling, and lesion size in the treatment area (right arm) as early as 4 weeks into the treatment. In an effort to see if cholesterol alone would have the same effect, the patient was tasked to administer 2% cholesterol on the left arm. After 4 weeks of this treatment, there was no clinical improvement in that area. On the other hand, the right arm continued to improve with the administration of the lovastatin/cholesterol combination, such that only small red macules were left by the end of the 3-month study period.

Patients with PPPD experienced decreased redness and scaling within 4 weeks, however there were no changes to the size or number of lesions by the end of 8 weeks. Meanwhile, patients with LP had a dramatic decrease in skin thickness and scaling. 

It is important to note that this is a case series with a small number of patients. The authors emphasize the need for randomised clinical trials with a larger sample size.

While the study and cases mentioned employed the lovastatin/cholesterol therapy, there is a case report that showed lovastatin monotherapy appears to be just as efficacious as the 2% lovastatin/2% cholesterol combination (Ugwu, Choate, & Atzmony, 2020). The DSAP patient’s proximal left limb was treated with 2% lovastatin/2% cholesterol twice a day for 4 weeks and achieved significant improvement. At the same time, a different part of the patient’s body was then treated with 2% cholesterol alone twice a day. No improvement was observed within 4 weeks.  The researchers then had the distal left limb treated with 2% lovastatin alone, and by 6 weeks, there were no lesions left. 

This finding is being investigated further. A clinical trial sponsored by the Medical University of South Carolina is currently in process at the time of writing (September 2021).  The study is reported to enroll 31 participants diagnosed with DSAP, with each applying 2% lovastatin/2% cholesterol on one arm and 2% lovastatin on the other arm, both with occlusion, twice a day for 12 weeks. The measures of improvement will include changes in the size of lesions, presence or absence of coronoid lamella under dermoscopy, the Actinic Keratosis Field Assessment Scale, Patient Quality of Life survey, and Physician Global Assessment Scale. 

The results of this clinical trial may uncover more information about the efficacy and safety of lovastatin and lovastatin/cholesterol on DSAP patients.

Use of simvastatin/cholesterol on DSAP patients

Simvastatin is a chemically modified version of lovastatin. Though the two substances share similar molecular structures and mechanism of action, simvastatin is known to have improved intrinsic inhibitory potency (Alberts, 1990). A study by Farmer et al. (1992) found that 20 mg of simvastatin decreased low density lipoprotein and total cholesterol factions in patients with hypercholesterolemia as compared to 40 mg of lovastatin.

A case letter to the Australasian Journal of Dermatology by Jerjen, Koh, & Sinclair (2020) documented two DSAP patients treated with 2% simvastatin/2% cholesterol, as lovastatin is difficult to come by in Australia. Both patients showed marked improvement after 3 months using objective and subjective measures. It appears that using simvastatin in place of lovastatin has the same general effect on DSAP lesions. 

A study by Byth & Byth (2021) echoed these findings. Eight patients contributing 13 affected limb pairs were involved in this split-body clinical trial. In each pair, one limb would receive 2% simvastatin/2% cholesterol, while its partner limb would receive bland emollients. The study found that the simvastatin/cholesterol combination significantly decreased lesion number, redness, and scale.

Conclusion

The use of statins and cholesterol appears to address the factors contributing to DSAP pathogenesis. Initial studies and case reports show promising results, but more rigorous clinical studies are needed to solidify the evidence. Research on identifying the toxic precursors involved in the DSAP-impaired mevalonate pathway is also warranted. It is also worth studying the effects of other statin drugs on this disorder.

However, comparing statin/cholesterol combinations with current treatment therapies, it is easy to see why the former would be a viable option for DSAP patients. Its excellent safety profile, low cost, marked improvement in clinical signs, and absence of adverse side effects make topical statin/cholesterol combinations a treatment worth pursuing. 

Lovastin 2% /cholesterol 2% or Simvastatin 2% / cholesterol 2% can be compounded at Skin Plus Compounding Pharmacy.  Contact us for further information. 

Sources: 

Alberts A. W. (1988). Discovery, biochemistry and biology of lovastatin. The American journal of cardiology, 62(15), 10J–15J. https://doi.org/10.1016/0002-9149(88)90002-1

Alberts A. W. (1990). Lovastatin and simvastatin--inhibitors of HMG CoA reductase and cholesterol biosynthesis. Cardiology, 77 Suppl 4, 14–21. https://doi.org/10.1159/000174688

Atzmony, L., Lim, Y. H., Hamilton, C., Leventhal, J. S., Wagner, A., Paller, A. S., & Choate, K. A. (2020). Topical cholesterol/lovastatin for the treatment of porokeratosis: A pathogenesis-directed therapy. Journal of the American Academy of Dermatology, 82(1), 123–131. https://doi.org/10.1016/j.jaad.2019.08.043

Bekkering, S., Arts, R., Novakovic, B., Kourtzelis, I., van der Heijden, C., Li, Y., Popa, C. D., Ter Horst, R., van Tuijl, J., Netea-Maier, R. T., van de Veerdonk, F. L., Chavakis, T., Joosten, L., van der Meer, J., Stunnenberg, H., Riksen, N. P., & Netea, M. G. (2018). Metabolic Induction of Trained Immunity through the Mevalonate Pathway. Cell, 172(1-2), 135–146.e9. https://doi.org/10.1016/j.cell.2017.11.025

Farmer, J. A., Washington, L. C., Jones, P. H., Shapiro, D. R., Gotto, A. M., Jr, & Mantell, G. (1992). Comparative effects of simvastatin and lovastatin in patients with hypercholesterolemia. The Simvastatin and Lovastatin Multicenter Study Participants. Clinical therapeutics, 14(5), 708–717.

Ugwu, N., Choate, K. A., & Atzmony, L. (2020). Two percent lovastatin ointment as a pathogenesis-directed monotherapy for porokeratosis. JAAD case reports, 6(10), 1110–1112. https://doi.org/10.1016/j.jdcr.2020.08.017

https://clinicaltrials.gov/ct2/show/NCT04359823

https://onlinelibrary.wiley.com/doi/epdf/10.1111/ajd.13473

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