Effects of shock wave therapy in the skin of patients with progressive systemic sclerosis: A pilot study

Abstract

Vasculopathy, immunological abnormalities, and excessive tissue fibrosis are key elements in the pathogenesis of progressive systemic sclerosis (SSc). Extracorporeal shock waves (ESW) have anti-inflammatory and regenerative effects on different tissues. We hypothesized that ESW can reduce endothelial cell damage and skin fibrosis in patients with SSc. We enrolled 30 patients affected by SSc, 29 females and 1 male. Rodnan Skin Score (RSS) and Visuo-Analogical Scale (VAS) for skin wellness were performed before and immediately after ESW therapy (ESWT) and at 7, 30, 60, and 90 days after the treatment. Sonographic examination of the patients' arms was performed before and 7, 30, 60, 90 days after treatment. Blood samples were obtained before and 30 and 60 days after treatment to measure serological levels of von Willebrand factor, vascular endothelial growth factor, intracellular adhesion molecule-1, monocyte chemotactic protein-1. The number of endothelial progenitor cells (EPCs) and circulating endothelial cells (CECs) were determined at the same time points. After ESWT we observed a rapid and persistent reduction of RSS and decrease of VAS. There was no difference in skin thickness before and after ESWT; however, we observed a more regular skin structure and an improvement in skin vascularization 90 days after treatment. EPCs and CECs increased 60 and 90 days after treatment, while serological biomarkers showed no variation before and after therapy. In conclusion, ESWT resulted in an improvement of VAS, RSS, and of skin vascular score, and in an increase of CECs and EPCs.

Full text

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Effects of Shock Wave Therapy in the skin of patients with Progressive Systemic
Sclerosis: a pilot study.
Elisa Tinazzi MD1*, Ernesto Amelio MD2*, Elettra Marangoni MD1, Claudio Guerra
MD2, Antonio Puccetti MD3, Orazio Michele Codella MD1, Sara Simeoni MD1,
Elisabetta Cavalieri PhD4, Martina Montagnana MD5, Roberto Adani MD2, Roberto
Corrocher MD1 and Claudio Lunardi MD1.
1 Department of Clinical and Experimental Medicine, University of Verona, P.le L.A.
Scuro 10, 37134 Verona, Italy
2 Shock Wave Unit-Hand Surgery Section, University Hospital of Verona, P.le
L.A.Scuro 10, 37134 Verona, Italy
3 Department of Experimental medicine, University of Genova and Institute G.
Gaslini, L.go G. Gaslini 5, 16148 Genova, Italy
4 Department of Morphological and Technical Sciences, University of Verona, St. Le
Grazie 8, 37134 Verona
5 Department of Morphological and Biomedical Sciences, University of Verona, P.le
L.A.Scuro 10, 37134 Verona, Italy
* These two authors equally contributed to the work
Corresponding Author:
Professor Claudio Lunardi
Department of Clinical and Experimental Medicine, University of Verona,
P.le L.A. Scuro 10, 37134 Verona, Italy
Phone number: +390458124759
Fax n.: +39-045-8027473
E-mail: claudio.lunardi@univr.it

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Abstract
Objectives: Vasculopathy, immunological abnormalities and excessive tissue fibrosis
are key elements in the pathogenesis of progressive systemic sclerosis (SSc).
Extracorporeal shock waves (ESW) have anti-inflammatory and regenerative effects
on different tissues. We hypothesized that ESW can reduce endothelial cell damage
and skin fibrosis in patients with SSc.
Methods: We enrolled 30 patients affected by SSc, 29 females and 1 male. Rodnan
Skin Score (RSS) and Visuo-Analogical Scale (VAS) for skin wellness were
performed before and immediately after ESW therapy (ESWT) and at 7, 30, 60 and
90 days after the treatment. Sonographic examination of the patients’ arms was
performed before and 7, 30, 60, 90 days after treatment. Blood samples were obtained
before and 30 and 60 days after treatment to measure serological levels of von
Willebrand factor, vascular endothelial growth factor, intracellular adhesion
molecule-1, monocyte chemotactic protein-1; the number of endothelial progenitor
cells (EPCs) and circulating endothelial cells (CECs) were determined at the same
time points.
Results: After ESWT we observed a rapid and persistent reduction of RSS and
decrease of VAS. There was no difference in skin thickness before and after ESWT;
however we observed a more regular skin structure and an improvement in skin
vascularization 90 days after treatment. EPCs and CECs increased 60 and 90 days
after treatment, while serological biomarkers showed no variation before and after
therapy.
Conclusions: ESWT resulted in an improvement of VAS, RSS and of skin vascular
score. An increase of CECs and EPCs was also observed after therapy.
Key words: ESWT: extracorporeal shock wave therapy; SSc: progressive systemic
sclerosis; skin fibrosis; endothelial cell damage.

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Introduction
Progressive systemic sclerosis (SSc) is an autoimmune disease characterized by
excessive deposition of collagen in the skin and visceral organs. Pathogenesis of the
disease is complex: the pivotal steps are endothelial cell damage, immune activation
and collagen production by fibroblasts [1]. Endothelial involvement is associated
with the increase of some circulating markers including von Willebrand factor
(vWF), vascular endothelial growth factor (VEGF), intracellular adhesion molecule-1
(ICAM-1), monocyte chemotactic protein-1 (MCP-1) [2,3].
The treatment of SSc is still disappointing since it is not able to modify the course of
the disease. Conventional therapies are directed to improve peripheral blood
circulation, to prevent the synthesis and release of harmful cytochines and possibly to
inhibit or reduce fibrosis [4].
Extracorporeal shock waves (ESW) are defined as a sequence of sonic pulses
characterized by high peak pressure (up to 100 MPa), fast pressure rise (10-100 ns)
and short lifecycle. First applied in 1980 for the treatment of kidney stones, during
the last 10 years this tecnique was found to induce an immediate anthalgic and anti-
inflammatory effect and a long-term tissue regeneration together with increase of
angiogenesis [5-9].
ESW have found widespread use in orthopaedics. ESW have a positive influence on
both calcifying tendonitis of the shoulder and fracture healing [10-11]. Moreover,
low-energy shock waves therapy is used for persistent tennis elbow syndrome and
painful heel with significant positive clinical results [12-13].
Recently Nishida et al performed extracorporeal shock wave application on the
ischemic myocardial region (200 shots/spot for 9 spots at 0,09 mJ/mm2) in a porcine
model of chronic myocardial ischemia [14]. The cardiac shock wave therapy
intervention improved global and regional myocardial functions in the treated
animals as well as regional perfusion measured as myocardial blood flow of the
chronic ischemic region without any adverse effects. No rise in CK, CkmB or
Troponin was observed in that study. Vascular density increased in the shock wave

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treated area and VEGF production was enhanced in the ischemic myocardium in vivo
[14].
The aim of this work was to investigate whether ESWT applied to limited skin area
might reduce fibrosis and increase vascularization in patients affected by systemic
sclerosis.
Matherials and methods
Patients selection
From January to April 2008 we enrolled 30 patients affected by systemic sclerosis, 29
female and 1 male, aged 27-76 years old (mean age 55.9 yrs), 19 with limited
cutaneous disease, 10 with diffuse cutaneous disease and 1 with overlap syndrome
polymiositis/systemic sclerosis; disease duration varied from 11 months to 23 years
(mean duration 6,7 yrs).
All patients were treated with calcium channel blockers and antiplatelet aggregation
drugs (acetyl-salicylic acid) and monthly infusion of prostanoids for 8 hours.
Written informed consent was obtained from all patients before entering the study.
Treatment regimen
An electromagnetic lithotriptor (DUOLITH SD1 device; Storz Medical AG,
Switzerland) was used for ESWT. The electromagnetic generator of the device
consists of a cylindrical wire wound coil, a metallic membrane and a concentric
paraboloid reflector. Swithching an electrical pulse in the kilo amperes range to a
cylindrical coil which is surrounded by the metallic membrane, strong eddy currents
are induced and the membrane is elongated, emitting a cylindrical acoustic wave in
water. This wave is not yet a shock wave. It is focused by the reflector and it is
steepening on its way to the focus.
Treatment protocol consisted of three sittings. The pressure pulses were focused on
the volar and dorsal side of the forearm and on the hand and the fingers of one upper

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arm, following this protocol: 2000 shots along the dorsal forearm, 2000 shots along
the volar forearm, 1000 shots along the dorsal side of the hand and fingers, 1000
shots along the volar side of the hand and fingers. The other upper arm and hand were
used as controls. Defocused energy applied was 0.20/0.25 mJ/mm2 with a repetition
frequency of 4Hz. Treatment did not require any kind of anaesthetic.
Twenty-eight patients completed the entire treatment, while two patients received
only two sittings.
Clinical evaluation
Skin involvement was determined by the modified Rodnan skin score (mRSS) [with
palpation of 17 anatomical sites and scoring on a 0-3 scale, where 0= normal skin, 1=
slight thickening, 2= moderate thickening, 3= hidebound skin sclerosis].
A visual-analogic scale (VAS) was used to asses skin wellness; it assessed skin
elasticity and softness and oedema, sensitivity and pain of the hand scoring on a 0-
100 scale (0= the best possible condition, 100= the worst possible condition)
RSS and VAS were performed before, immediately after the first ESWT and then at
7, 30, 60, 90 days after the end of the treatment.
Ultrasonographic evaluation
Skin thickness and vascularity were measured with a high frequency ultrasound
scanner (LOGIQ Book XP ultrasound machine; GE Healthcare, UK) using a 12 MHz
transducer (I12L) and an ultrasound pad to increase ultrasonographic signal. Scans
were obtained form volar and dorsal side of upper harm 10 cm distal from elbow;
total skin thickness (expressed in centimetres) was calculated as mean of these two
measures. Skin vascularity was obtained by colorDoppler analysis and represented on
an arbitrary scale ranging from 1 (scarse) to 3 (elevate); total vascular score was the
mean of values obtained for dorsal and volar side of upper harm.
Sonographic examination was performed before ESWT and at 7, 30, 60 and 90 days
after the end of the treatment.

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Biochemicals markers and circulating endothelial cells
Blood samples were obtained before and 30, 60 days after the end of ESWT. Among
the markers of endothelial cell disfunction we have tested vWF, VEGF, ICAM-1 and
MCP-1 which is also a marker of fibrosis. vWF-Ag was measured by an automated
quantitative enzyme linked immunosorbent assay (ELISA) on the mini Vidas
(BioMeriuex, Marcy L’Etoile, France). Determination of VEGF (R&D System
Quantikine ®; Minneapolis, MN, USA), MCP-1 and ICAM-1 (Endogen Thermo
Scientific®; Rockford, Illinois, USA) were carried out using commercially available
kits following the manufacturer’s instructions.
The number of endothelial progenitor cells (EPCs) and circulating endothelial cells
(CECs) was determined at the same time points. CECs and EPCs were detected by
flow-cytometry by lyse-no-wash method. Two hundred μL of each sample were
incubated with a panel of monoclonal antibodies for 20 minutes at room temperature.
Fluorescein isothiocyanate (FITC)-conjugated anti-CD45 (10 μl), R-Phycoerythrin
(PE)-conjugated anti-CD34,-CD31 and -CD146 (10 μl) or isotype-matched control
(IgG1), allophyco-cyanine (APC) anti-CD3, -CD16, -CD19 and -CD33 (5 μl) were
used. 7-amino-actinomycin (7-AAD) was added for dead cells exclusion. Samples
were also stained with anti-CD45 FITC, anti-CD34, -CD31 and -CD146 PE, anti-
CD106 or anti-VEGFR2 APC and peridin chlorophill protein (PerCP)-conjugated
anti-CD3, -CD16, -CD19 and -CD33. All reagents were purchased from Becton
Dickinson (San Jose, CA, USA), except for anti-CD16 (Caltag, Burlingame, CA,
USA), anti-CD106 (Biolegend, San Diego, CA, USA) and anti-VEGFR2-APC (R&D
System, Minneapolis, MN, USA). After labeling, red blood cells were lysed by
incubation with 2 ml of Ammonium Chloride lysis solution and then the sample was
analysed on a FACS Calibur cytometer (Becton Dickinson). The sensitivity of
fluorence detectors was set and monitored using Calibrite Beads (Becton Dickinson)
according to the manufacturer’s recomendations; 500.000 cells per sample were
acquired in live gating. Data were analyzed with CellQuest software (Becton

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Dickinson). Appropriate analysis gates, designed to remove dead cells, platelet
aggregates and debris, and to exclude CD45+ and CD3+/CD16+/CD19+/CD33+
hematopoietic cells (dump channel), were used to enumerate total CECs and EPCs .
Nitric Oxide evaluation
In 3/30 patients levels of nitric oxide were measured before and during ESWT at time
2 and 4 minutes after beginning of treatment. Enzymatic Griess assay on
deproteinated serum was used to determine nitric oxide values (kit Cayman
Chemical; Ann Arbor, Michigan, USA) [15].
Statystical analysis
Calculations were performed with the SPSS16 statistical package. For statistical
analysis Student’s t test was used and a p<0,05 was considered statistically
significant.
Results
Clinical evaluation
Rodnan Skin Score showed a statistically significant reduction (p<0,001)
immediately after the first sitting of ESWT and 7 and 30 days after treatment
compared to the basal value, while VAS showed a statistically significant decrease at
all time points (p= 0,03 90 days after the end of treatment), as shown in table 1.
Ultrasonographic evaluation
No significant changes were observed in both skin thickness and vascularity at time
7, 30, 60 and 90 days after ESW therapy compared to the basal scores. However we
observed a more regular skin structure, as shown in figure 1. Moreover, the vascular
score 90 days after treatment was increased compared to the basal score nearly

8
reaching a statistical significant difference (p=0.06). Table 2 shows the results of
ultrasonographic examination.
Biochemical markers and circulating endothelial cells
The baseline evaluation of biochemical parameters gave the following results: vWF
103.3 ± 54.9 mg/L, VEGF 710.4 ± 592.1 pg/mL, ICAM-1 291±139.1 ng/mL, MCP-1
323.7 ± 213 pg/mL. No significant changes were observed at time 30 and 60 days
after the end of treatment (table 3).
Both EPCs and CECs showed a significant increase 30 and 60 days after the end of
treatment compared to the basal (p< 0,05) as shown in table 4.
Nitric Oxide evaluation
In 2 out of the 3 patients examined nitric oxide dosage showed an increase after 2
minutes from the beginning of ESW therapy (data not shown).
Discussion
The present study demonstrates that, in patients affected by SSc, skin application of
extracorporeal shock waves causes a rapid and persistent improvement of clinical
parameters (RSS and VAS for skin wellness) and a late increase in skin
vascularization and in number of EPCs and CECs.
Shock waves were used since 1980’s to treat kidney stones. During the last 10 years
this tecnique was found to induce an immediate anthalgic and anti-inflammatory
effect and a long-term tissue regeneration together with increase of angiogenesis [5-9,
16]. One of the possible mechanisms of action of the anti-inflammatory effect of
ESWT may be related to the ability of ESW to keep local NO contents at a
physiological level in the early phase of inflammatory response, enhancing either a
non-enzymatic or enzymatic production of NO [15]. Therefore induction of NO

9
synthesis has been suggested to be one of the most important mechanism implicated
in the anti-inflammatory effect of ESWT, while increased expression of VEGF and
the consequent mobilization of endothelial progenitor cells can explain the
proangiogenic action [6-8, 17]. It has been recently demonstrated that, in addition to
angiogenesis due to migration and proliferation of endothelial cells in situ, EPCs
contribute to neovascularization in ischemic tissue through a vasculogenetic
mechanism and through secretion of a variety of angiogenic factors [18-19]. Finally,
recent studies have marked out that ESW are able to recruit stem cells and to
stimulate their differentiation in various damaged tissues inducing reparative
phenomena [20-22].
On these scientific bases, we studied the effect of low-energy ESWT on skin and
serological biomarkers in patients affected by SSc.
Our results showed both a short-term and a long-term effect of ESW: we observed a
rapid improvement of skin elasticity as measured by RSS and VAS, with a persistent
effect during the time (until 30 days after the treatment for RSS and until 90 days for
VAS).
Ultrasonographic evaluation of the skin showed no significant difference of skin
thickness before and after ESWT, and after ESWT compared to the untreated
controlateral arm. However we observed a regularization of skin structure with more
defined skin layers; the lack of statistical significance is probably due to the limited
number of patients analyzed. Moreover the modification of the skin structure may be
responsible for the improvement of RSS and VAS. Finally we are evaluating whether
a modification in skin thickness is detectable by ultrasonography in a longer period of
observation.
The increasing of vascular score 90 days after the end of treatment is concordant with
the hypothesis of ESW-induced neoangiogenesis. However, our study did not
demonstrate an increase in serological levels of VEGF or a decrease of other
biomarkers (vWF, MCP-1, ICAM-1) indicative of endothelial cell damage; this is
possibly related to the application of ESW to a very limited skin area. On the contrary

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the pro-angiogenetic and reparative effect of ESW is demonstrated by the persistent
increase of CECs and EPCs, which remains elevated until 60 days from the end of
treatment.
Nitric oxide measurement was limited to only three patients because of difficulties in
maintaining a venous access during ESW sitting. The increased values found in 2/3
patients is in accordance with literature [6, 7, 17], but further studies are needed.
For all paramethers considered, we found no significant difference both between
patients with limited and diffuse skin involvement or between patients with or
without digital ulcerations, although the absence of differences may depend on the
limited number of patients enrolled in each subgroup.
In conclusion, the results of our study suggest that ESWT is a novel and efficacious
treatment that can be added to the pharmacological therapy in order to decrease
endothelial cell damage and skin fibrosis in patients affected by SSc. This treatment
is well tolerated and can be repeated without side effects; in the majority of cases it
determines a rapid improvement of skin elasticity and skin wellness, even if the
effects tend to reduce during the time.
We are now planning to evaluate the time of retreatment and the effects of ESWT
applied to more extensive skin areas, such as face and neck, to ameliorate both
functional and aesthetic aspects. Moreover we are performing skin biopsy with
immunohistochemical analysis prior to and after ESWT.
Acknowledgment
We thanks Dr. Ernst Marlinghaus for his invaluable technical support.

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Table 1. Rodnan Skin Score (RSS) and Visual-analogic Scale (VAS) before and after
ESW therapy.
Measure
RSS
VAS (0-100)
Pre-ESWT
28.62 ± 7.56
47.2 ± 14.9
After Ist sitting
27.14 ± 8.24 *
27.2 ± 13.3 *
After 7 days
27.98 ± 6.29 *
31.4 ± 16.8 *
After 30 days
28.09 ± 6.30 *
31.4 ± 17.3 *
After 60 days
28.21 ± 6.14
40.7 ± 18.1 *
After 90 days
27.96 ± 7.25
42.8 ± 16.2 *
* p <0,05
Table 2. Skin thickness and vascular score measured by ultrasound.
Measure
Skin thickness (cm)
Vascular score
Pre-ESWT and
controlateral untreated
arm (any time point)
2.7 ± 0.3
1.78 ± 0.65
After 7 days
2.6 ± 0.3
1.76 ± 0.51
After 30 days
2.6 ± 0.2
1.62 ± 0.58
After 60 days
2.5 ± 0.3
1.55 ± 0.47
After 90 days
2.6 ± 0.3
1.42 ± 0.37*
*p =0,06

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Table 3. Biochemical markers measured before and after ESWT.
Measure
VWF
(mg/L)
sVEGF
(pg/mL)
sICAM-1
(ng/mL)
sMCP-1
(pg/mL)
Pre-ESWT
103.3 ± 54.9
710.4 ± 592.1
291 ± 139.1
323.7 ± 213
After 30 days
121.6 ± 111
698.6 ± 382.2
279.4 ± 116.8
408.1 ± 185.4
After 60 days
98.7 ± 65.3
702 ± 370.5
290.9 ± 129.7
396.7 ± 196.4
Table 4. Number of Endothelial Progenitors Cells (EPCs) and Circulating Endothelial
Cells (CECs) before and after ESW therapy.
Measure
CECs/mm3
EPCs/mm3
Pre-ESWT
586 ± 356
121 ± 86
After 30 days
798 ± 452
168 ± 100
After 60 days
775 ± 382
186 ± 104
* p <0,05

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Figure 1. Ultrasonographic examination of foreharm skin before (A) and after (B)
ESWT in one of the treated patients: similar findings were found in the other patients.
A more regular skin structure is clearly present in panel B.