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\begin{document}

\title{INTRALESIONAL LOW DOSE METHYLPREDNISOLONE FOR THE TREATMENT OF ACTIVE
PHASE PEYRONIE'S DISEASE: A SINGLE CENTER, PRELIMINARY PROSPECTIVE
NON-RANDOMISED STUDY}



\author[1]{iyimser üre}%
\author[1]{ata özen}%
\affil[1]{Eskişehir Osmangazi Üniversitesi Tıp Fakültesi}%


\vspace{-1em}



  
  \date{May 17, 2024}


\begingroup
\let\center\flushleft
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\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Aim There are few types of drugs that can be used in the active phase of
Peyronie's disease. Methylprednisolone is a corticosteroid with a strong
anti-inflammatory effect. In this study, we aimed to evaluate the effect
of intralesional low dose methylprednisolone treatment on patients in
the active phase of Peyronie's disease. Patients and Methods Forty-eight
patients suffering from Peyronie's disease active phase symptoms were
included in the study. Methylprednisolone was administered
intralesionally for 8 weeks, once per week, at a dose of 40 mg. The
injection was applied into the plaques, which causes maximum curvature.
Patients were evaluated before and after treatment for plaque size,
angle of curvature, and erectile dysfunction according to the
International Index of Erectile Function-5 and Peyronie's Disease
Questionnaire. Results The mean age of the patients was 61.1 (43-78)
years. Mean duration of the symptoms was 3.4 (0-9) months. The average
plaque size before treatment was 13.6 mm (7.1-16.8) and after treatment,
this value decreased to 10.8 mm (4.3-14.6) (p:0.025). The average scores
of Peyronie's Disease Questionnaire elements; symptom severity, penile
pain and bother/discomfort were 12.3, 19.1 and 6.2, respectively before
the treatment. These scores were decreased to 8.9, 9.6 and 4.4,
respectively after treatment. All subgroups of Peyronie's Disease
Questionnaire scores were significantly improved after treatment
(p:0.001, p\textless{}0.001, p:0.045, respectively). No adverse events
were observed during or after treatment. Conclusion In order to recover
the symptoms and signs, new and easily accessible drugs are required for
use in the acute period of Peyronie's disease. In this context,
treatment with intralesional low dose methylprednisolone in acute phase
Peyronie's Disease is a promising and safe treatment option.%
\end{abstract}%



\sloppy


\textbf{INTRALESIONAL LOW DOSE METHYLPREDNISOLONE FOR THE TREATMENT OF
ACTIVE PHASE PEYRONIE'S DISEASE: A SINGLE CENTER, PRELIMINARY
PROSPECTIVE NON-RANDOMISED STUDY}

\textbf{Running Title: Methylprednisolone for treatment of Peyronie's
disease}

Dr. Iyimser URE, M.D.*

Dr. Ata OZEN, M.D.*

*Osmangazi University, Faculty of Medicine, Department of Urology,
Eskisehir, TURKEY

\textbf{Corresponding Author:}

Iyimser URE, M.D.

Osmangazi Universitesi, Tip Fakultesi, Uroloji AD

Eskisehir / TURKIYE

\emph{iyimserure@yahoo.com}

+90 530 347 3301

\textbf{Key Words:} Peyronie's disease; Methylprednisolone; Treatment



\textbf{ABSTRACT}

\emph{Aim}

There are few types of drugs that can be used in the active phase of
Peyronie's disease. Methylprednisolone is a corticosteroid with a strong
anti-inflammatory effect. In this study, we aimed to evaluate the effect
of intralesional low dose methylprednisolone treatment on patients in
the active phase of Peyronie's disease.

\emph{Patients and Methods}

Forty-eight patients suffering from Peyronie's disease active phase
symptoms were included in the study. Methylprednisolone was administered
intralesionally for 8 weeks, once per week, at a dose of 40 mg. The
injection was applied into the plaques, which causes maximum curvature.
Patients were evaluated before and after treatment for plaque size,
angle of curvature, and erectile dysfunction according to the
International Index of Erectile Function-5 and Peyronie's Disease
Questionnaire.

\emph{Results}

The mean age of the patients was 61.1 (43-78) years. Mean duration of
the symptoms was 3.4 (0-9) months. The average plaque size before
treatment was 13.6 mm (7.1-16.8) and after treatment, this value
decreased to 10.8 mm (4.3-14.6) (p:0.025). The average scores of
Peyronie's Disease Questionnaire elements; symptom severity, penile pain
and bother/discomfort were 12.3, 19.1 and 6.2, respectively before the
treatment. These scores were decreased to 8.9, 9.6 and 4.4, respectively
after treatment. All subgroups of Peyronie's Disease Questionnaire
scores were significantly improved after treatment (p:0.001,
p\textless{}0.001, p:0.045, respectively). No adverse events were
observed during or after treatment.

\emph{Conclusion}

In order to recover the symptoms and signs, new and easily accessible
drugs are required for use in the acute period of Peyronie's disease. In
this context, treatment with intralesional low dose methylprednisolone
in acute phase Peyronie's Disease is a promising and safe treatment
option.



\textbf{INTRODUCTION}

Peyronie's disease is a condition characterized by the formation of
plaque due to collagen accumulation inside the tunica albuginea that
surrounds the structures of the penile corpus cavernosum. This plaque
can cause deformities such as penile shortening and curvature {[}1{]}.
Penile pain and discomfort may occur during the active period of the
disease, sexual functions are negatively affected, and erectile
dysfunction may occur {[}2{]}. The incidence of Peyronie's disease was
found to be 3.2-8.9\% {[}3{]}. Although young men are also affected
occasionally, the disease is more common among older men---specifically,
those over the age of 45---and its incidence increases with age {[}4{]}.

Surgical treatment is not recommended in the active period of the
disease. In this period, it is aimed to stop the formation of new
plaques, avoid the plaque growth, to eliminate the pain. Approaches to
treatment include the use of oral treatment agents and intralesional
agents {[}5{]}. Oral therapies being used today include vitamin E,
carnitine, colchicine, potassium amino benzoate, and phosphodiesterase
type 5 inhibitors. However, none of these agents' effectiveness has been
fully proven {[}6{]}.

Molecules such as corticosteroids, verapamil, interferon, and
collagenase clostridium histolyticum are commonly used in intralesional
therapy {[}5{]}. Among these, collagenase clostridium histolyticum
stands out as the most effective agent, and there are many studies that
have proven its effectiveness {[}1,7--9{]}. However, in some countries,
this drug is difficult to obtain, and the cost of treatment protocols
with this drug can be excessive. In addition, collagenase was withdrawn
from the European market for commercial reasons. Therefore, there is a
search for more accessible treatment methods that can be used during
Peyronie's active period, especially in developing countries.

Methylprednisolone is a corticosteroid with a strong anti-inflammatory
effect. It is used in the treatment of rheumatic diseases, acute/chronic
inflammatory diseases, and allergic reactions {[}10{]}. It is a fairly
inexpensive drug and easy to obtain. Since systemic and local side
effects are also rare, it is probably that methylprednisolone could
serve as an alternative treatment option in the acute period of
Peyronie's disease where inflammatory reactions are at the forefront
{[}11{]}.

The purpose of our study was to investigate the effectiveness and safety
of intralesional methylprednisolone treatment in patients presenting in
the acute period of Peyronie's disease.

\textbf{MATERIALS AND METHODS}

\emph{Study Design}

This is a prospective non-randomized preliminary study for observing the
effectiveness and safety of using intralesional methylprednisolone to
treat patients in the active phase of Peyronie's disease. Patients who
applied to our clinic for Peyronie's disease and who were in the active
phase of the disease between 2018 and 2020 were included in the study.
To confirm that the disease was in the acute phase, we used the
following criteria for inclusion: (1) less than 12 months passed since
the onset of complaints; (2) absence of calcified plaque in penile
duplex doppler ultrasound; (3) symptoms of painful erection; and (4)
recent change in penile curvature. Patients who had completed the acute
phase and progressed to the chronic phase disease stage, who had the
presence of calcified plaque, who had prior medical or surgical
treatment for Peyronie's disease, who had a history of extra corporeal
shock wave therapy (ESWT), who had hourglass and hinge deformity, and
who were not sexually active were excluded from the study. Apart from
hourglass and hinge deformity, patients with all types of curvature were
included in the study.

\emph{Pre Treatment work-up}

After erection was achieved by intracavernosal alprostadil injection,
the maximum plaque size was measured before and after treatment by
performing penile duplex doppler ultrasound in all patients. During the
same procedure, the physician investigated whether there was calcified
plaque. During erection, curvature angle was measured using a goniometer
protractor. The point of injection was determined by marking the maximal
curvature point, and the necessity of erection was eliminated before
each procedure. To determine the point of maximum curvature, starting at
the base of the penis, a straight line was drawn through the center of
the straight portion of the penile shaft proximal and distal to the
point of maximum curvature. The intersection of these lines was accepted
as the maximal point of curvature, and the degree of curvature was
determined by measuring the angle between these lines.

Before the first injection and one month after the last injection, all
patients were assessed with Peyronie's Disease Questionnaire (PDQ),
consisting of 15 questions, and the International Index of Erectile
Function (IIEF-5), consisting of 5 questions {[}12{]}. The score
obtained from questions 1-6 of the PDQ questionnaire evaluates symptom
severity (PDQS), questions 7-9 evaluate penile pain (PDQP), and
questions 10-15 evaluate bother/discomfort symptoms (PDQB) {[}13{]}.

\emph{Treatment Protocol}

The treatment protocol was designed as an intralesional injection of 40
mg methylprednisolone to the maximum curvature point; this injection was
repeated once a week for 8 weeks. No local anesthesia was performed
before injection, but patients were allowed to use non-steroidal
anti-inflammatory drugs and pain killers after injection. A 23G needle
was used for injection. The dosage was 40 mg of the drug in its pure
form (no dilution), which was loaded into a syringe and then inserted
into the plaque at a right angle. The drug was then injected at
different points of the plaque by slightly moving the needle around the
injection point.

During the protocol, treatment was terminated and the patient was
excluded from the study in cases of an unexpected side effects or
worsening disease symptoms. All adverse events were recorded during the
study period. All procedures were performed by a single experienced
urologist.

All patients voluntarily signed their consent to participate in the
study. The study was approved by the Ethics Committee of Eski\selectlanguage{polish}ş\selectlanguage{english}ehir
Osmangazi University Faculty of Medicine.

\emph{Statistical Analysis}

Statistical analysis was done with IBM SPSS V23.0 Software. No power
analysis were performed. Continuous variables are reported as means,
standart deviation and range. The Student's t test for unpaired data was
used to compare means. Changes in plaque size, penile curvature, PDQ,
and IIEF-5 scores from baseline to end of therapy were analyzed using
ranked one-way analysis of variance (ANOVA). P values less than 0.05
were considered statistically significant.

\textbf{RESULTS}

Of the 61 patients who were admitted to our clinic for Peyronie's
disease, 48 patients who met the inclusion criteria were included in the
study. All patients completed the 8-week treatment protocol. No patients
were excluded from the study because no serious side effects or
worsening of symptoms were observed during the protocol. The mean age
was 61.1 (43-78). The average time from the onset of complaints was 3.4
months (0-9). Curvature was dorsal in 19 (39.6\%) patients, ventral in 5
(10.4\%) patients, lateral in 12 (25\%) patients, and dorsolateral in 12
(25\%) patients. The average plaque size before treatment was 13.6 mm
(7.1-16.8), and after treatment, this value decreased to 10.8 mm
(4.3-14.6) (p = 0.025) (Figure 1). In 35 (72.9\%) of the 48 patients, a
decrease in plaque size was seen after treatment. Plaque size did not
increase in for any of the patients after treatment. The mean curvature
angle was 55.7 degrees (35-85) before treatment, whereas this value
decreased to 52.5 degrees (33-85) after treatment. In 8 (16.7\%) of the
48 patients, the curvature angle was reduced, but this decrease was not
statistically significant (p:0.07) (Figure 2). In five patients
(10.4\%), curvature angle was increased. This increase was no more than
10 degrees. The changes in plaque size and curvature angle did not show
any statistically significant difference with respect to curvature
direction (p = 0.145). No local or systemic side effects or
complications were observed during or after drug administration,
excluding pain resulting from the injection of the drug.

The average IIEF-5 score before treatment was 18.1 (10-25). This score
increased to 20.2 (10-25) after treatment. However, this rise was not
statistically significant (p = 0.069). The PDQS score was 12.3 (4-18) on
average, and this value decreased significantly to 8.9 (0-14) after
treatment (p = 0.001). The PDQP score average was 19.1 (12-26) before
treatment and significantly decreased to 9.6 (0-21) after treatment (p
\textless{} 0.001). Finally, the PDQB score decreased significantly
after treatment, as did the other scores. Before treatment, this value
was 6.2 (4-12), and after treatment, it was 4.4 (2-10) (p = 0.045)
(Figure 3).

\textbf{DISCUSSION}

Surgical treatment modalities of Peyronie's disease are continually
being explored and increasing in diversity. However, surgical procedures
can be performed only in the chronic phase of the disease {[}4{]}. In
the acute phase in which inflammation is in progress, there are not many
treatment methods with proven effectiveness {[}5{]}. Today, the most
effective acute phase treatment is provided with collagenase clostridium
histolyticum. This is the only treatment method licensed by the FDA. The
effectiveness of Collagenase clostridium histolyticum has been proven by
many recent studies {[}14--16{]}. However, especially in developing
countries, using this agent can be very costly and the procurement of
the drug can be difficult.

There are many studies about the etiology and physiopathology of
Peyronie's disease in the literature. These studies generally focus on
genetic, traumatic, and inflammatory processes {[}17--19{]}. However,
regardless of the underlying cause, the inflammatory process that occurs
later in the disease forms the basis of plaque formation. In the course
of inflammation, Peyronie's disease occurs due to the production of
inducible nitric oxide synthase (iNOS), which leads to an increase of
nitric oxide and a corresponding increase in production of peroxynitrite
anion. These processes result in the proliferation of fibroblasts and
myo-fibroblasts and excessive production of collagen between the layers
of the tunica albuginea, which is called penile plaque {[}20{]}.

Corticosteroids are frequently considered to be an acute phase treatment
modality of Peyronie's disease due to their intense anti-inflammatory
effects {[}21{]}. However, few studies have investigated the
intralesional use of steroids. Of those that have, positive results were
obtained with intralesional steroid use in terms of improving penile
curvature angle, plaque size, and penile pain and discomfort during
erection {[}22,23 However, the use of these drugs has not become
widespread, and this is largely due to the systemic side effects caused
by the use of high doses of steroids and the local side effects that
appear around the area of application. As far as we know, this study is
the first research to consider low dose methylprednisolone in the
treatment of Peyronie's Disease. In our study, statistically significant
improvements were found for this treatment, especially in plaque size,
severity of symptoms, and penile pain and discomfort during erection. We
believe that the use of the drug in a low dose of 40 mg and with
one-week intervals between injections would prevent the expected
complications of steroids.

PDQ is a questionnaire that has been used many times to investigate the
effectiveness of treatment methods used in Peyronie's disease. Its
reliability and effectiveness have been proven {[}24,25{]}. It is a
scale that assesses the patient's perspective on the disease, not just
in the physical sense, but also in the psychosexual perception. It was
observed that the complaint of pain---one of the typical findings of
Peyronie's disease, which disturbs the patient and occurs during
erection---decreased significantly after methylprednisolone treatment.
Naturally, the sexual performance of patients will improve with the
reduction of this complaint. Our study showed an increase in IIEF-5
scores after treatment; however, this increase was not statistically
significant. This may be due to the low number of patients in our study.
Another reason could be that basal IIEF-5 values are already high, so
there may be no significant increase after treatment.

\emph{Study Limitations}

The main limitation of the current study was the low number of patients.
Additionally, it is not a placebo-controlled randomized study. However,
we believe that the results obtained from our study are likely to be
replicated in comprehensive double-blind randomized placebo-controlled
studies that should be done in the future. One of the methodological
limitations was the preferred method of plaque size measuring. Using
ultrasound for measuring the plaque size is easy but not reliable
because the variable and subjective measurement depends on the person
who performs the ultrasound. In order to minimize this subjectivity, all
ultrasound procedures were performed by same clinician. Finally, the
short follow up time after treatment protocol negatively affected the
expected change in IIEF scores because IIEF is made to evaluate erectile
function in the past six months.

\emph{Conclusion}

The etiology of Peyronie's disease has not been fully elucidated, but
the inflammatory process has an important place in the disease's
physiopathology. The fact that the only drug that is licensed for the
acute phase of the disease is collagenase clostridium histolyticum, and
that the effectiveness of other previously-attempted methods has not
been fully proven, makes us predict that new treatment modalities will
be investigated in the future as well. Our study shows that
intralesional usage of low dose methylprednisolone is effective for
improving symptoms and signs during the active period of Peyronie's
disease. Thus, it may lead to a more progressive transition of the
disease from the acute phase to the chronic phase, resulting in less
penile deformity and less subsequent complicated correctional surgeries
for affected patients.

\textbf{DISCLOSURE STATEMENT}

Authors declare no conflict of interest

\textbf{REFERENCES}

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{[}2{]} Lipshultz LI, Goldstein I, Seftel AD, et al. Clinical efficacy
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{[}6{]} Talib RA, Ibrahim MA, Cang\selectlanguage{ngerman}üven Ö. Nonsurgical treatment options
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{[}7{]} Abdel Raheem A, Capece M, Kalejaiye O, et al. Safety and
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{[}8{]} Yan S, Yap T, Minhas S. Collagenase clostridium histolyticum
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{[}9{]} Bazzi M, Jamil ML, Dabaja AA. Outcomes of Surgery in Peyronie's
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{[}11{]} Evaniew N, Belley-Côté EP, Fallah N, et al. Methylprednisolone
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{[}12{]} Turunç T, Deveci S, Güvel S, et al. The assessment of turkish
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{[}14{]} Capece M, Cocci A, Russo G, et al. Collagenase clostridium
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{[}15{]} Cocci A, Cito G, Urzì D, et al. Sildenafil 25 mg ODT~+
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{[}19{]} Gunes M, Aslan R, Ery\selectlanguage{polish}ı\selectlanguage{english}lmaz R, et al. Levels of serum trace
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\textbf{Table 1.} Characteristics of the patients.\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
& Mean & Min & Max & SD (\selectlanguage{ngerman}±)\tabularnewline
\midrule
\endhead
Age & 61.1 & 43 & 78 & 11.8\tabularnewline
Disease duration (months) & 3.4 & 0 & 9 & 2.3\tabularnewline
Baseline curvature (\selectlanguage{ngerman}°) & 55.7 & 35 & 85 & 24.3\tabularnewline
Baseline plaque size (mm) & 13.6 & 7.1 & 16.8 & 3.7\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2.} Baseline values according to direction of the
curvature.\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Dorsal (n:19)\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Ventral (n:5)\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Lateral (n:12)\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Dorsolateral (n:12)\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
p\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Age (mean\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
63.3\selectlanguage{ngerman}±12.1\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
53.2\selectlanguage{ngerman}±5.4\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
65.3\selectlanguage{ngerman}±7.8\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
56.9\selectlanguage{ngerman}±11.1\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.135\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Plaque Size (mm) (mean\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
11.9\selectlanguage{ngerman}±3.1\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
15.6\selectlanguage{ngerman}±1.2\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
15.9\selectlanguage{ngerman}±2.4\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
13.3\selectlanguage{ngerman}±2.3\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.065\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Angle of Curvature (\selectlanguage{ngerman}°) (mean±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
50.4\selectlanguage{ngerman}±12.9\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
62\selectlanguage{ngerman}±8.4\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
54.5\selectlanguage{ngerman}±10.1\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
62.7\selectlanguage{ngerman}±20.5\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{0.045}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}



\textbf{Figure Legends}

\textbf{Figure 1.} Improvement in plaque size after treatment.

\textbf{Figure 2.} Improvement in curvature angle after treatment.

\textbf{Figure 3.} Changes in questionnaire scores after treatment.
IIEF-5: Five question version of International Index of Erectile
Fuction; PDQS: Peyronie's Disease Questionnaire Symptom Severity; PDQP:
Peyronie's Disease Questionnaire Penile Pain; PDQB: Peyronie's Disease
Questionnaire Bother/Discomfort.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure-1/figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure-2/figure-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure-3/figure-3}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

