

Topical Simvastatin as Treatment of Digital Ulcer in Systemic

Scleroderma

Tuntas Rayinda, Ika Rizki, Yohanes Widodo Wirohadidjojo

Department of Dermatology and Venereology, Faculty of Medicine, Universitas Gadjah Mada / RSUP Dr. Sardjito,

Yogyakarta Indonesia

Keywords: systemic scleroderma, digital ulcer, statin, topical simvastatin.

Abstract: Systemic Scleroderma (SS) is a connective tissue disease characterized by extensive fibrosis, vascular

damage, immunologic disorder, and organ involvement.

digital ulcer (DU) is a common clinical condition

in SS which occurred in 30% of the patients. Simvastatin, a HMG-CoA reductase competitive inhibitor, is

known to have anti-inflammatory potency and could accelerate the healing of chronic wound. We report a

case of UD in SS that improved with topical simvastatin treatment. A 61 years old woman came to the

clinic with a complaint of wounds on the tip of fingers and toes that has not healed for two weeks. The

wound initially appeared at the tip of finger, extended, and then similar wound appeared at the tip of toe.

The patient was diagnosed with systemic scleroderma since three years ago and treated with

methylprednisolone and a vasodilator agent. From physical examination, there were shallow ulcers at the

right middle toe and left thumb sized 1x1-2 cm, with irregular border and covered with necrotic tissues. DU

management in SS consisted of non-pharmacological, pharmacological, and operative methods.

Simvastatin, a statin class drug, was proven to have anti-inflammatory, immune modulatory, and wound

healing effects in several studies. The benefit of statin in wound healing process was shown by its ability to

improve vascularization in chronic wound through increased VEGF concentration which is disturbed in

abnormal wound healing process. Topical simvastatin was also proven to have antimicrobial effect which

could potentially prevent bacteria from disrupting epithelialization and wound healing process. The patient

was given normal saline compression twice daily followed by application of 0.5% simvastatin in

gentamicin ointment twice daily after saline compression. After two weeks of treatment, the ulcers on both

fingers and toes improved.

1 INTRODUCTION

Systemic scleroderma (SS) is a rare connective

tissue disorder characterized by extensive fibrosis,

vascular damage, immunologic disorder, and various

organ involvement (Barsotti et al., 2016). Two of the

most common clinical symptoms in SS are Raynaud

phenomenon (RP) and digital ulcer (DU). Digital

ulcer is defined as ischemic tissue that undergo

denudation with clear margin, loss of epidermis and

dermis, and found on the fingertips. The ulcer could

be found above bone protrusion such as proximal

phalanx, but it could also occur due to secondary

causes such as trauma. The ulcer is often very

painful and disturb hand function (Abraham, 2015;

Marvi and Chung, 2010).

Digital ulcer occurred in 30% of SS patient. In

addition, 66% of DU patients experienced more than

one episode of recurrence albeit utilization of

vasodilator (Steen et al., 2009). In March 2016-April

2017, there were 17 SS patients on maintenance

therapy in the Dermatology and Venereal Disease

Clinic of Dr. Sardjito Hospital, Yogyakarta. Four

(23.5%) of the SS patients also had DU.

Simvastatin, a plasma cholesterol lowering drug,

is a competitive inhibitor of HMG-CoA reductase

and is known to have anti-inflammatory potency and

could accelerate chronic wound healing

(Stojadinovic et al., 2014). Topical simvastatin had

been reported to have efficacy in healing chronic

venous ulcer and diabetic ulcer (Asai et al., 2012;

Raposio et al., 2016).

This manuscript will report a case of DU in SS

that improved after treatment with topical

simvastatin. The discussion will focus on

simvastatin’s mechanism of action in chronic wound

Rayinda, T., Rizki, I. and Wirohadidjojo, Y.

Topical Simvastatin as Treatment of Digital Ulcer in Systemic Scleroderma.

DOI: 10.5220/0008159804650468

In Proceedings of the 23rd Regional Conference of Dermatology (RCD 2018), pages 465-468

ISBN: 978-989-758-494-7

465

healing. The purpose of this manuscript is to

understand simvastatin’s mechanism of action as an

effective drug in the management of chronic ulcer in

SS patients.

2 CASE

A 61 years old woman came with the complaint of

wounds on the tips of fingers and toes that has not

healed for two weeks. The wound initially appeared

at the tip of finger, extended, and similar wound also

appeared at the tip of toe. The wound was widened

after being hit by shower handle. The wound was

painful and occasionally wet. The wound had been

treated with normal saline compression and fusidic

acid but there was no improvement.

In the past five years, the patient started to

complain stiffness in the skin and joints all over her

body. Three years later, the patient went to Dr.

Sardjito Hospital and was diagnosed with SS based

from clinical, laboratory, and histopathological

examination. The patient was treated with

maintenance therapy of methylprednisolone 8 mg/2

days, pentoxifylline 400 mg/day, nifedipine 10

mg/day, aspilet 80 mg/day, and emollient.

The patient’s general appearance and vital

signs were within normal limit. In dermatological

examination, there were dry skin with sclerotic

impression in the whole body and salt and pepper

appearance in several skin areas of the body. There

was fish mouth appearance on the face. The fingers

and toes appeared sclerotic and there were shallow

ulcers sized 1x1-2 cm, covered with necrotic tissue,

and irregular border on the right middle toe and left

thumb.

The working diagnosis of DU in SS was

confirmed by clinical examination. DU was treated

with normal saline compression twice daily,

followed by application of 0.5% simvastatin in

gentamycin ointment twice daily after saline

compression. After two weeks of treatment, there

was an improvement in both finger and toe ulcers

3 DISCUSSION

Fibroproliferative and microvascular endothelial cell

vasculopathy is one of the primary process in the

pathophysiology of SS. Those vascular abnormality

and dysfunction caused RP, DU, and capillary

abnormality on nail fold which are early

manifestation and key diagnosis of SS

(Postlethwaite, 2015). The change in nail fold

capillaroscopy proved that there is a severe

angiogenesis disturbance in SS patients. The loss of

blood capillary also occurs at end stage of the

disease. However, before end stage of the disease

occur, various levels of angiogenesis disturbance

manifest as various morphological changes of blood

vessels. The change in angiogenesis process will

contribute to chronic oxygen supply reduction and

ischemic tissue manifestation such as ulcers at

fingertips (Distler et al., 2002).

Figure 1: A). Before treatment (B). 1 week (C). 2

weeks (D). 3 weeks after application of topical simvastatin.

A B

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Management of DU in SS consisted of

nonpharmacological, pharmacological, and operative

therapies. Although there are several treatment

modalities that could be used, there is no strong

evidence because of the difficulties in conducting

clinical trial (Abraham, 2015). Administration of

oral statin therapy for DU in SS patient had shown

satisfying result (A et al., 2008). In this case, we

used topical statin in ointment base for treating DU

in SS patient.

Simvastatin is one of statin class drug which is

often usedto treat hypercholesterolemia. In addition,

statin is known to have immunomodulatory,

neurotropic, and wound healing effect. Its pleotropic

effect, safety profile, and low cost made this drug a

promising alternative in SS patient. A study by

Abou-Raya et al. showed a decrease in DU number,

its degree of severity, and pain score in SS patient

who were treated with systemic statin (A et al.,

2008).

Statins are known to have anti-inflammatory

effect through several mechanisms in the

inflammatory pathway. Through inhibition of HMG-

CoA reductase in mevalonate pathway, statin would

decrease synthesis of mevalonate which then

decrease bioavailability of two important isoprenoid

intermediates, namely farnesyl pyrophosphate (FPP)

and geranylgeranyl diphosphate (GGPP) (Laufs and

Liao, 2009). With low bioavailability of the two

molecules, statin would increase vascular reactivity,

coagulation, and affect inflammatory pathway.

Important anti-inflammatory effects of statin are

decreased C-reactive protein, chemokine, adhesion

molecule, and cytokine release and to modulation of

T cell activity. Additionally, statin also act as

immunomodulator and antioxidant which protect

endothelial function by decreasing eNOS, monocyte

tissue factor, and PAI-1 expression. Statin could also

stimulate the activation of heme oxygenase and

tissue plasminogen activator (Laufs & Liao, 2009;

Vukelic et al., 2010).

In wound healing process, statin also regulate

FPP. Farnesyl pyrophosphate is known to inhibit

wound healing and epithelialization process through

glucocorticoid receptor. In vitro, decreased

endogenous FPP was proved to stimulate migration

of keratinocytes. In addition, decreased FPP, which

is glucocorticoid receptor agonist and could repress

keratin 6, was proved to stimulate epithelialization

and wound closure in Human Skin Organ Culture

Wound Model and Histology ex vivo. Through

similar mechanism, application of topical mevastatin

was proved to stimulated epithelialization ex vivo.

Therefore, decreased FPP in epidermis that was

treated with statin would be beneficial for

epithelialization process during wound healing

(Vukelic et al., 20100.

The benefit of statin in wound healing is also

shown by its ability to improve chronic wound

vascularization. Statin could reduce vasoconstriction

by decreasing angiotensin-2 response and decreasing

the concentration of preproendothelin-1 mRNA

which would decrease synthesis of endothelin-1, a

strong vasoconstrictor ( Hernandez-perera et al.,,

1998; Vukelic et al., 2010). Statin also stimulated

vascular relaxation through inhibition of Rho

geranyl-granylation which would increase the

expression of endothelial nitrite oxide synthase

(eNOS). In addition, statin could stimulate

neovascularization in ischemic tissues by increasing

the activity of endothelial progenitor cells in chronic

wound. Statin administration could also increase

VEGF concentration which was disturbed in

abnormal wound healing process. However, statin’s

effect on VEGF depends on dose and length of

administration. In high dose and long administration,

statin did not increase VEGF concentration. Statin’s

ability in improving angiogenesis became the basis

for its utilization to treat DU in SS patient as in this

case study (Hernandez-perera et al., 1998; Weis et

al., 2002; A A-R, et al., 2008; Laugs & Liao, 2009;

Vukelic et al., 2010).

Besides several abilities described above, topical

simvastatin was proved to possess antimicrobial

effect on wound. Bacteria play a role in slowing

wound healing process; hence, decreased bacteria

concentration in the wound could accelerate

epithelialization and wound healing process. Open

wounds in rats that were treated using topical

simvastatin did not show the presence of

polymicrobial infection as occurred in the group that

were not treated with simvastatin (Weis et al., 2002).

Utilization of topical simvastatin were reported

in several clinical trials in experimental animals or

human. A study on experimental animals by Asai et

al. found that statin could accelerate wound healing

process in rats with diabetes model through

angiogenesis and limphangiogenesis acceleration.

Raposio et al. reported the effect of simvastatin on

patients with chronic vascular ulcer. In the study, the

group treated with 0.5% topical simvastatin in cream

base showed faster wound healing compared to

control group, although the difference was not

statistically significant. Until now, there was no

report on utilization of topical simvastatin for

treatment of DU in SS (Weis et al., 2002;

Khoshneviszadeh et al., 2014).

Topical Simvastatin as Treatment of Digital Ulcer in Systemic Scleroderma

467

2% simvastatin gel was proved to accelerate

wound healing in experimental animal through its

anti-inflammatory effect and its influence on

granulation tissue formation and reepithelialization.

Those stereologic results from experimental animals

studies showed that simvastatin gel could increase

the number of fibroblasts, collagen, and blood

vessels formation which are important in wound

healing process (Khoshneviszadeh et al., 2014).

In this case, DU in SS showed improvement in

lesion morphology and pain scale after

administration of 0.5% topical simvastatin in

gentamicin ointment base. Until now, there is no

case report or research on topical simvastatin to treat

DU in SS. Its effect on wound healing, safety

profile, and low cost could make topical simvastatin

an alternative topical therapy for DU in SS.

4 CONCLUSION

We reported a case of DU in SS that improved after

application of topical simvastatin. Beside its anti-

inflammatory potential, simvastatin could accelerate

chronic ulcer healing through decrease in farnesyl

pyrophosphate, facilitation of vascular relaxation,

acceleration of neovascularization, and decreased

bacteria concentration. Topical simvastatin could be

used as an alternative topical pharmacological

therapy for DU in SS.

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