ORIGINAL ARTICLE

A Double-blind, Randomized Controlled Trial of Ciplukan
(Physalis angulata Linn) Extract on Skin Fibrosis,
Inflammatory, Immunology, and Fibrosis Biomarkers in
Scleroderma Patients
Sumartini Dewi1, Harry Isbagio2, Erni H. Purwaningsih3, Nyoman Kertia4,
Rianto Setiabudy5, Siti Setiati2
Department of Internal Medicine, Faculty of Medicine, Padjadjaran University - Hasan Sadikin Hospital,
Bandung, Indonesia.
2
Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo Hospital,
Jakarta, Indonesia.
3
Department of Pharmacy, Universitas Indonesia, Jakarta, Indonesia.
4
Department of Internal Medicine, Faculty of Medicine, University of Gadjah Mada, Yogyakarta, Indonesia.
5
Department of Pharmacology, Universitas Indonesia, Jakarta, Indonesia.
1

Corresponding Author:
Sumartini Dewi, MD. Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Padjadjaran
University - Hasan Sadikin Hospital. Jl. Pasteur No. 38 Bandung, Indonesia 40161. email: sppd_dewi@yahoo.co.id.
ABSTRAK
Latar belakang: skleroderma merupakan penyakit autoimun yang resisten terhadap pengobatan standar,
penambahan ekstrak herba ciplukan (Physalis angulata Linn) diduga dapat memperbaiki fibrosis kulit skleroderma.
Penelitian ini bertujuan mengkaji peran ekstrak herba Ciplukan sebagai terapi ajuvan untuk fibrosis kulit
skleroderma yang mendapat terapi standar, berdasarkan MRSS, biomarker inflamasi, imunologi dan fibrosis
serum. Metode: uji klinis acak tersamar ganda pada pasien skleroderma stabil yang berobat jalan di RSCM dan
RSHS sejak November 2015−Maret 2017 yang memenuhi kriteria inklusi dan menerima terapi standar. Subjek
secara random terbagi dua: kelompok uji yang mendapat ekstrak herba C iplukan 3x 250 mg/hari selama 12
minggu dan kelompok plasebo. Pemeriksaan MRSS, LED, P1NP, BAFF dan sCD40L dilakukan setiap 4 minggu
hingga akhir penelitian. Hasil: lima puluh sembilan subjek menyelesaikan penelitian, 29 subjek kelompok uji dan
30 subjek kelompok plasebo, rerata usia 41 (SB 9) tahun, proporsi wanita : pria = 9 : 1. Ditemukan perbaikan
fibrosis kulit bermakna pada kelompok uji dengan penurunan relatif MRSS sebesar 35,9% dibandingkan plasebo
6,3% dengan p < 0,001 dan penurunan relatif bermakna kadar P1NP sebesar 17,8% dibandingkan plasebo 0,7%
dengan p = 0,002. Tidak ditemukan penurunan kadar LED, BAFF dan sCD40L pada kedua kelompok. Terdapat
korelasi positif bermakna antara MRSS dengan kadar P1NP (r = 0,236, p = 0,036). Kesimpulan: pemberian
ekstrak etanol herba ciplukan dosis 3 x 250 mg selama 12 minggu sebagai terapi ajuvan pada skleroderma dalam
terapi standar, secara klinis dan statistik menunjukkan perbaikan kelainan fibrosis kulit berdasarkan MRSS dan
biomarker fibrosis P1NP serum secara bermakna dibandingkan kontrol.
Kata kunci: Physalis angulata Linn, modified Rodnan’s skin score (MRSS), erythrocyte sedimentation rate
(ESR), procollagen type-1 N terminal proteinase (P1NP), skleroderma.
ABSTRACT
Background: scleroderma is an autoimmune disease characterized by organ fibrosis, resistant to standard
treatment. It is suggested that he addition of Physalis angulata Linn. (Ciplukan) extract as adjuvant therapy can
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improve the scleroderma skin fibrosis. The aim at this study is to evaluate the effect of ciplukan extract as adjuvant on
scleroderma skin fibrosis in standard therapy, based on modified Rodnan skin scale (MRSS), inflammatory biomarkers,
immunology and serum fibrosis. Methods: double-blind, randomized clinical trial was performed in scleroderma
patients with stable disease at Cipto Mangunkusumo hospital and Hasan Sadikin hospital during November 2015−
March 2017 who met the selection criteria and continued to receive standard therapy. The subjects were randomly
allocated into two groups: the study group received the ciplukan extract 3 x 250 mg / day for 12 weeks and the
placebo group. Examination of MRSS, ESR, P1NP, BAFF and sCD40L was performed every 4 weeks until the end
of the study. Results: fifty-nine subjects completed the study. They consisted of 29 subjects of the treatment group and
30 of the placebo group, with an average age of 41 (SD 9) years, the proportion of women: male = 9 : 1. There was
a significant improvement of skin fibrosis in the study group with a highly significant decrease in MRSS (35.9% VS
6.3%, p <0.001) and a relative decrease in P1NP levels (17.8% VS 0.7%, p = 0.002). No decrease in ESR, BAFF
and sCD40L levels were observed in both groups. There was a weak but significant positive correlation between
MRSS with P1NP levels (r=0.236, p=0.036). Conclusion: Ciplukan extract with dose 3 x 250 mg for 12 weeks as
adjuvant on scleroderma standard therapy alleviates skin fibrosis significantly based on MRSS and P1NP levels.
Keywords: Physalis angulata Linn, modified Rodnan’s skin score (MRSS), erythrocyte sedimentation rate
(ESR), procollagen type-1 N terminal proteinase (P1NP), scleroderma.
INTRODUCTION

Scleroderma is an autoimmune connective
tissue disease involving fibrosis of the skin, which
is characterized by the excessive accumulation
of extracellular matrix (ECM) proteins, vascular
injuries, and immune abnormalities. In early
stages of scleroderma, activated fibroblasts in the
affected areas produce high amounts of collagen.1
Numerous studies have demonstrated the crucial
role of several fibrogenic cytokines released
from immunocytes in initiating the sequence of
events leading to fibrosis in the pathogenesis of
scleroderma.1,2 Moreover, vascular injury and
apoptosis, extracellular matrix overproduction,
oxidative stress (reactive oxygen species)
also played role.1,2,3-5 The standard therapy for
scleroderma is modifying disease anti-rheumatic
drugs (DMARD).6 However, there are some
problems such as high risk of drugs resistance;
drug side effects, and price of the drug.2,6 Some
immunosuppresant agents are not covered by
the national health insurance. Therefore, some
patients discontinue the treatment, resulting
in disease progresses, higher morbidities, and
mortality. Some new medicines are still under
research and not accessible. Others are too
expensive for most of Indonesian communities.
Ciplukan herb (Physalis angulata Linn.)
is known widely as a medicinal plant. It
grows in Indonesia and has been known

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for its efficacy to stimulate the activity of
lymphocyte, and modulate the immune system
in human.7-8 Ciplukan herb is also known for
its antiinflamatory, antiproliferative, antiangiogenesis, and anti-cancer activities because
it contains phenol, secosteroid (physalin,
withanguline, and others), and saponin. It has
three major pathways in immunomodulatory. The
first pathway is phenol components in Ciplukan
herb, such as flavonoid, tannin, phenylpropane,
and other simple phenol compounds which
show antioxidant and immunomodulating
effects that control the autoimmune activity.8-10
The second and third pathways are due to
secosteroid and saponin compounds which have
anti-inflammatory and antiproliferative effects
that is thought to inhibit the fibrosis process in
scleroderma.10-12 Ciplukan herb is proved to be
safe in human. No side effects were reported in
long-term use.8-9
There are no published clinical trials
regarding the effects of ciplukan herb on
scleroderma, in terms of skin fibrosis changes
based on MRSS and the level of biomarkers
serum in scleroderma. The aim of this study to
evaluate the effect of the addition ciplukan extract
as adjuvant to scleroderma standard therapy in
suppressing inflammatory, immunological,
and fibrosis processes to accelerate clinical
improvement of skin fibrosis based on MRSS in

Vol 51 • Number 4 • October 2019 A double blind, randomized controlled trial of ciplukan extract on skin fibrosis

scleroderma patients (primary outcome).13-14 We
evaluated disease activity based on erythrocyte
sedimentation rate for inflammatory biomarker;
the levels of B-cell activation factor (BAFF)
and soluble CD40 ligand (sCD40L) serum
for immunological biomarkers; and the level
of procollagen Type I N-Terminal Propeptide
(P1NP) serum for biomarker of fibrotic process
(secondary outcome).15-22
METHODS

This was a randomized, double blind,
placebo controlled trial. Subjects were recruited
consecutively from January 2016 to March 2017.
This study has been approved by the Ethical
Research Comission of Faculty of Medicine
Universitas Indonesia and Research unit of
Cipto Mangunkusumo Hospital (25/UN2.F1/
ETIK/2016).
Subjects

Inclusion criteria were limited and diffused
type of scleroderma patients in rheumatology
outpatient clinic in Cipto Mangunkusumo
Hospital (RSCM) or Hasan Sadikin Hospital
(RSHS) Bandung, aged 15−60 years old,
received standard therapy with stable dose in
the last 3 months. Exclusion criteria were not
willing to participate in the study, impaired liver
function or cirrhosis, impaired renal function,
overlap syndrome, active tuberculosis, heart
disease, allergy to Ciplukan herb or history of
hypersensitivity to certain drugs, hypotension
and hypoglycemia.
Subjects with consent for clinical trials were
randomly assigned into 2 groups: intervention
group (ciplukan herb 250 mg TID) or control
group (placebo containing amylum 250 mg TID).
Subjects were observed for 12 weeks. Allocation
was done using block permuted randomization
technique with block size combination 4.
The result was put in sealed envelopes. The
researchers, responsible physicians, and study
subjects did not know the allocation group until
the end of the study (double-blind).
Data Collection and Analysis

Collected data included demographic data
(age, sex, weight, height, blood pressure),
clinical data (duration of illness, history of illness

and medication), skin fibrosis examination based
on MRSS, and laboratory examination: ESR,
the levels of P1NP, BAFF and sCD40L serum,
complete blood count, transaminase enzyme,
creatinine, blood glucose, sodium, potassium
and urinalysis. All data were collected every 4
weeks during the visit. We also assessed subjects’
compliance and adverse event during treatment.
Normally distributed data was presented
in mean (SD); otherwise, presented in median
(interquartile range). A 95% confidence interval
(95% CI) was calculated around sclerodermaprevalence. Comparison between groups was
done using Mann-Whitney U test. Data were
analyzed using SPSS program. Drop out subjects
were removed from the analysis (per protocol)
to see the main output. Efficacy of the drugs
was represented using the result of intention to
treat (ITT) and number needed to harm (NNH).
The main outcome of clinical assessment,
improvement of skin fibrosis based on MRSS
was analyzed using unpaired t-test, to assess the
different effects between ciplukan herb group
and placebo group. For the secondary outcome,
numeric variables such as the level of ESR,
BAFF, sCD40L, P1NP, and the relative changes
of those variables after 12 weeks of treatment
were analyzed using Wilcoxon test.
This study was conducted based on the
principles of the “Guideline for Good Clinical
Practice” of the ICH Tripartite Guideline (ICHGCP). This study has been registered in the
registry of clinical trial data at www.clinicaltrials.
gov with ClinicalTrials.gov ID: NCT03141125
identification number to ensure the public
scientific knowledge of this research.
RESULTS
Baseline Characteristics

There were 61 subjects randomly allocated
into 2 groups. After 12 weeks of observation,
one subject dropped out in ciplukan group due
to loss to follow-up. In placebo group, one
subject dropped out due to severe hypoglycemia.
(Figure 1)
From 59 subjects, 92.1% were females
with mean age of 41 (9) years old. Duration
of scleroderma was 12 months to 88 months

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Figure 1. Flow of subjects

with the median of 34 months. Subjects were
categorized into 35 subjects (59%) diffuse type
scleroderma and 24 subjects (41%) limited type
scleroderma. Diffuse type scleroderma were
higher in intervention group (65.5%) than in
placebo group (53.3%), the other subjects were
categorized into limited-type scleroderma. (Table
1)
The most common encountered ACR EULAR
diagnostic criteria 2013 clinical symptoms
were finger fibrosis (100%), and Raynaud’s
phenomenon (100%), followed by scars in
36 (61%) subjects, finger ulcers in 32 (54%)
subjects, salt and pepper appearance in 32 (54%)
subjects, finger edema in 54 (91.5%) subjects, and
telangiectasia in 17 (28.8%) subjects.
Initial assessment of modified Rodnan’s Skin
Score (MRSS) showed higher score in ciplukan
group (median 19, range 8−34) compared to
placebo group (median 15, range 6−36). This
is caused by the diffuse type of scleroderma
subjects in ciplukan group were higher than
in placebo group with the ratio of 19:16. This
is consistent with the extent of skin fibrosis
predilection in diffuse type than in the limited
type of scleroderma.
The result of laboratory tests at the baseline
of the study were as followed: the average of
ESR was 38 (22) mm/hour; P1NP level was 56.8

306

(31.8) ng/mL; BAFF level was 1,258 (5,473) pg/
mL; and serum sCD40L level was 6,505 (3,415)
pg/mL.
Response to Ciplukan Herb

Changes in skin abnormalities in the study
subjects marked by a decrease in MRSS were
shown in Figures 2 and 3.
MRSS decreased 35.9% in the ciplukan
group, while it only decreased 6.3% in placebo
group after 12 weeks. It means that Ciplukan herb
can improve skin fibrosis clinically (Figure 4).
Further decrease of serum P1NP levels
were also found in ciplukan herb group (17.8%)
compared to the placebo group (0.7%) after 12
weeks (Figure 5). The response was better than
the standard therapy alone.
There were no significant changes of the ESR
value, serum BAFF, and sCD40L level in both
groups. However we found that in placebo group,
those values tend to increase compared to the
baseline, but it was not statistically significant.
Bivariate analysis of skin fibrosis based on
MRSS showed a weak correlation with serum
P1NP level (r = 0.236; p = 0.036).
DISCUSSION

The previous study at Laboratorium
Penelitian dan Pengujian Terpadu Universitas

Vol 51 • Number 4 • October 2019 A double blind, randomized controlled trial of ciplukan extract on skin fibrosis
Table 1. Baseline characteristics
Characteristic

Physalis
angulata
Group (n = 29)

Control
Group
(n =30)

41 (9)

41 (9)

Mean age,
years (SD)
Gender, n (%)
-- Male

0 (0.0)

2 (9.5)

-- Female

29 (100)

29 (90.5)

-- Limited type

10 (34.5)

14 (46.7)

Type of Scleroderma, n (%)
-- Difuse type

19 (65.5)

16 (53.3)

Onset of the disease
(months), median
(IQR)

34 (12–88)

31 (13–72)

BMI (kg/m2),
mean (SD)

20.7 (3.7)

20.1 (2.5)

-- metothrexate

28 (96.6)

28 (93.3)

-- sulphasalazine

1 (3.4)

1 (3.3)

-- mycophenolat
mofetil

1 (3.4)

1 (3.3)

Figure 2. Skin of scleroderma patients before study.

Standard Therapy, n (%)

-- colchicine

2 (6.8)

2 (6.6)

-- nifedipin

12 (41.4)

14 (46.7)

-- diltiazem

6 (20.7)

5 (16.7)

-- amlodipine

11 (37.9)

10 (33.3)

-- methylprednisolon:
< 10 mg/day

15 (51.7)

16 (53.3)

-- aspirin

24 (82.7)

22 (73.3)

-- clopidogrel

3 (10.3)

4 (13.3)

-- cilostazol

2 (6.8)

1 (3.3)

-- folic acid

28 (96.6)

28 (93.3)

MRSS, median (IQR)

19 (8–34)

15 (6–36)

ESR (mm/hour),
mean (SD)

35 (19)

40 (25)

BAFF (pg/mL),
mean (SD)

1,132 (435)

1,380 (621)

P1NP (ng/mL),
mean (SD)

50.5 (24.5)

62.9 (37)

sCD40L (pg/mL),
mean (SD)

6,870 (4,125)

6,151 (2,576)

SD= Standard deviation; ESR= Erythrocyte sedimentation
rate; MRSS= Modified Rodnan’s Skin Score; BAFF= β cell
activating factor; P1NP= Procollagen type-1 N terminal
proteinase; sCD40L= soluble cluster of differentiation 40
Ligand.

Gadjah Mada (LPPT UGM) Yogyakarta,
Ciplukan herb contained unspecific compounds,
such as: Betasitosterols, tannins, phenols,
saponins, flavonoids, and alkaloids.
Phenolic compounds like flavonoid,
tannin, phenilpropan, and other phenols have
immunomodulatory activity with complement

Figure 3. The skin of a scleroderma patient after completion
of clinical trials (archive after open label) in the Ciplukan
group.

system or intracellullar biochemistry reaction.
Ethanol extract is capable of extracting more
phenols, flavonoids, and tannins than methanol
and hexsane do. This study used 50% ethanol
extract, which contains the highest total phenols
compared to other solvents. The saponins
component in herbal plants is known to have a
potentiating effect on chemotherapy drugs such
as methotrexate.25
Several studies have shown that ethanol
extract from ciplukan herb has a strong
antioxidant effect due to the flavonoid content.
Phenol derivatives of ciplukan herb have an
important role as natural theurapeutic substances
that can inhibit oxidative stress in chronic

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inflammatory diseases such as scleroderma.26-27
Inflammatory processes and oxidative stress have
been shown to play a role in the pathogenesis of
scleroderma. The antioxidant ability of phenols
can also protect lymphocytes from the adverse
effects of reactive oxygen molecules. The
component is soluble in a polar solvent, inducing
leukocytes proliferation, increased lymphocytes
proliferation is influenced by several factors
such as the phenols content attached to proteins
forming a protein complex that binds to the
hydrogen ions. Sitosterol in ciplukan herb,
has a strong anti-inflammatory effect and may
contribute to the clinical improvement of
scleroderma patients.11-12
The exact role of proinflammatory markers
in ciplukan herb such as thromboxane B2
(TXB2) and leukotriene B4 (LTB4) remains
to be elucidated. TXB2 has the ability to
increase platelet aggregation and LTB4 has a

chemotaxis effect on neutrophils, causing direct
damage to the cells.12 Other proinflammatory
markers that need further investigation are
Interleukin-6 and C-reactive protein (CRP),
which increase in the inflammatory phase.
Assessment of cyclooxygenase-1 (COX-1)
and cyclooxygenase-2 (COX-2) activities
may also be considered for follow-up studies,
because both of them are involved in the
inflammatory process. Inhibition of this COX
enzyme causes a decrease in arachidonic acid
levels, by alteration of arachidonic acid into
eicosanoid, prostaglandin and thromboxane in
the inflammatory pathway.11,12
There are several novelties and strengths in
this study. First, to the best of our knowledge,
this is the first clinical trial in the world that
investigated the effects of ciplukan herb extract
as adjuvant therapy, i.e. adding traditional herb
to the standard therapy on scleroderma patients.

Figure 4. Difference of MRSS changes from Physalis angulata and placebo group.

Figure 5. Difference of P1NP changes from Physalis angulata and Placebo group.

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Second, ethanol extract has the highest content
of phenols, flavonoids, tannins compared to
methanol extract and hexane extract.8,9 Third,
in this ciplukan extract contains saponins
substances that are not found in ciplukan plants
abroad.16 Fourth, clinical and laboratory data
support antifibrotic effects of ethanol extract
of ciplukan herb for scleroderma. The addition
of ciplukan herb has been proven to accelerate
clinical improvement based on decreased MRSS
values in assessing skin fibrosis. In general,
standard scleroderma treatment needs longer
time to reduce MRSS values from the baseline,
up to 2 years.13,14 In this study, the reduction
of MRSS to 6 points lower than the baseline
was achieved within 3 months. We also found
a significant decrease in serum P1NP level
clinically and statistically as the evidence of
fibrosis process of improvement.
Eventhough the correlation was weak
between MRSS and P1NP levels, our finding
supports the theory that P1NP has a role in skin
fibrosis process of scleroderma patients who
show an excessive synthesis of collagen and
release its metabolite products to the circulation.
We found no correlation between MRSS and the
result of ESR value, serum BAFF and CD40L
levels in both groups. ESR, as the biomarker
for inflammation used in this study, failed to
indicate the presence of inflammation process in
scleroderma due to less sensitive. Further study
using other inflammatory markers are needed to
prove the anti-inflamation effects of Ciplukan
herb. There were no significant changes of serum
BAFF and sCD40L levels.
The outcome of this study was analyzed
per protocol. Although there were 2 subjects
excluded from the study, the number of our
study subjects (29 and 30 for the treatment and
the control group, respectively) still exceeded
the minimum sample size from the calculated
sample size, i.e. at least 27 subjects for each
group. The number of samples in this study has
met the criteria, thus the result of the research
outcomes analysis is valid, with good research
power (80%).
The ciplukan extract is suggested to
have synergic effects as antifibrotic on skin
scleroderma, by its antioxidant, antiinflammatory,

antiproliferative effects, and saponins content in
ciplukan herb may also have a similar effect
to methotrexate action, with the end result
of clinical improvement of scleroderma skin
fibrosis.10-12,25-27
CONCLUSION

Our results suggested that administration
of 3x250 mg per day dose of ciplukan herb
extract as adjuvant therapy in scleroderma
standard therapy for 12 weeks, was statistically
significant and clinically important in alleviating
skin fibrosis based on assessment of MRSS and
P1NP levels.
ACKNOWLEDGMENTS

The authors of this study wish to thank to
the Chairman and Staff of the Rheumatology
Division, Department of Internal Medicine,
Faculty of Medicine, in University of Padjadjaran/
Hasan Sadikin Hospital Bandung, and University
of Indonesia/Cipto Mangunkusumo Hospital,
Jakarta, for their support during the first author’s
doctoral study. The author also would like to
thank to Prof. Dr. Mae Sri Hartati W, M.Sc., Apt.
along with staff at The Herbal Medicine Center,
Faculty of Medicine, University of Gadjah Mada,
Yogyakarta who have provided the ciplukan and
placebo capsules.
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