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364Pakistan Oral & Dental Journal Vol 35, No. 3 (September 2015)
ORAL SUBMUCOUS FIBROSIS: COMPARISON OF DIFFERENT TREATMENT MODALITIES
1OMAR ARSHAD2KHALID MAHMOOD SIDDIQI
3ZAHOOR AHMAD RANA
ABSTRACT
Oral submucous fibrosis (OSMF) is a chronic, insidious, fibrotic disease that predominantly affects people of South-East Asian origin. The majority of patients present with an intolerance to spicy food, rigidity of lip, tongue and palate leading to varying degrees of limitation of mouth opening and tongue movement. The use of areca nut has been strongly implicated as the principal etiological factor in the pathogenesis of OSMF which involves cytokine mediated collagen synthesis and deposition and reduced collagen degradation. Various modalities have been proposed for the management of OSMF. Aimed primarily at increasing oral opening, surgical treatments have been hampered by relapse and medical agents have yielded limited success. In this prospective comparative study we tested a hypothesis that a combination of intralesional steroid and oral antioxidant would prove to be of maximal efficacy than either of the two agents used alone. Forty five patients with a clinical and histologic diagnosis of OSMF were randomly divided into three treatment groups of fifteen patients each. Patients in group ‘A’ received monthly intralesional injections of methylprednisolone acetate, those in group ‘B’ were put on daily lycopene supplements while the ones in group ‘C’ received monthly intralesional injections of methylprednisolone acetate and concurrently were put on daily lycopene supplements as well. Mouth opening values for patients showed an average increase of 3.46 mm, 2.46 mm and 7 mm for groups A, B and C respectively. The difference in mouth openings at the end of treatment was found to be statistically insignificant between groups A and B (p > 0.05), significant between groups A and C (p < 0.05) while it was very significant between groups B and C (p ≤ 0.01). We therefore conclude that the most favorable response in terms of clinical efficacy was derived from the combination of intralesional steroid and oral antioxidant therapy in patients abstaining from areca nut habit and indulging in rigorous physiotherapy. We further suggest that this modality may be used as a frontline therapy for the pharmacologic and physiotheraputic management of oral submucous fibrosis.
Key Words: Mouth Opening, Areca Nut, Fibrous Bands, Oral Submucous Fibrosis.
Original article
For correspondence: 1Dr Omar Arshad, BDS, MDS, Assistant Professor and Head, Department of Dental and Maxillofacial Surgery, Pakistan Atomic Energy Commission (PAEC) General Hospital, Islamabad Email: [email protected]
Cell: 0321-95494662 Dr Khalid Mahmood Siddiqi, BDS, MDS, Assistant Professor and
Head Department of Oral and Maxillofacial Surgery, Islamabad Medical and Dental College, Bahria University, Islamabad
Email: [email protected] Cell: 0321-50322033 Dr Zahoor Ahmed Rana, BDS, MDS, Professor and Chairman,
Department of Oral and Maxillofacial Surgery, Pakistan Institute of Medical Sciences, Islamabad
Email: [email protected] Cell: 051-9261170 Received for Publication: July 28, 2015 Revised: August 24, 2015 Approved: September 10, 2015
Oral & MaxillOfacial Surgery
INTRODUCTION
Oral Submucous Fibrosis (OSMF) is a debilitating but preventable oral disease.1 A condition similar to OSMF was described as early as 600 BC by Sushruta, who named it “Vidari” which presented as progressive narrowing of the mouth, depigmentation of the oral
mucosa and pain during eating. The first documen-tation of this disease during recent times came from Schwartz in 1952, who described a similar entity in five Indian females from Kenya and he designated the term “AtropicaI diopathica Mucosae Oris”’ to this condition. In 1953, Joshi described this condition as “Submucous fibrosis”.2
Oral Submucous Fibrosis (OSMF) is a chronic dis-ease of insidious onset affecting the oral mucosa with progressive involvement of the pharynx and esopha-gus.3 Patients frequently present with a history of oral pain, intolerance to spicy food and gradual reduction of oral opening.4 Areca nut usage has strongly been implicated in the development of this condition. Review of literature on OSMF reveals a condition where main burden of disease lies in developing countries of Asia and the Indian Subcontinent.5 Other causes of reduced mouth opening including odontogenic infections, TMJ
365Pakistan Oral & Dental Journal Vol 35, No. 3 (September 2015)
Oral submucous fibrosis
ankylosis and myositis ossificans traumatica must be set apart from OSMF.6,7
The clinical criteria used for diagnosing OSMF is the presence of palpable fibrous bands which give a leathery texture, leading to a blanching and yellow-ish-white discoloration of the oral mucosa.8 Mouth opening is limited, which can be categorized on the basis of its clinical and functional severity.9 Although provisional diagnosis is made by clinical examination, the disorder is confirmed and graded histopathologically with quantification of the collagen fibers and presence of hyalinization in the lamina propria.10
No known treatment for OSMF is curative, although some conservative and surgical interventions may re-sult in improvement of oral function.11,12 Steroids are said to inhibit fibroblast proliferation at high doses.13 Lycopene, a naturally occurring carotenoid responsible for tomato’s bright red color has shown to have potent anti-carcinogenic and antioxidant properties and inhi-bition of human fibroblast activity in vitro. It has been used in the treatment of OSMF in some studies and found efficacious.14,15
Improved oral opening is an important objective of OSMF treatment and whichever modality of manage-ment is used; the core concept relies on the cessation of the quid habit and vigorous physiotherapy to exploit the accelerated tissue remodeling potential of the disease to advantage.16
Although there have been several reports on the institution of diverse treatment protocols in the man-agement of OSMF, especially in Indian and Sri Lankan populations, no clinical reports are available for Paki-stani patients. This study was done after the approval of ethical committee which presents the experience of randomized uncontrolled trial at the Department of Oral and Maxillofacial Surgery, Pakistan Institute of Medical Sciences, Islamabad, Pakistan, with intrale-sional methyl prednisolone or oral lycopene alone and in combination along with conservative measures like discontinuation of quid habit and rigorous jaw stretch-ing exercises to improve mouth opening in OSMF patients.
METHODOLOGY
Forty five patients with a diagnosis of oral submu-cous fibrosis presenting to the Department of Oral & Maxillofacial Surgery, Pakistan Institute of Medical Sciences were selected as the study sample. After in-formed consent participants were randomly distributed into one of the three treatment groups (15 patients each) using computer lottery system at Random Sequence Generator at “www.random.org”. Patients not willing
to participate in study or not ready to quit the use of quid were excluded from study. Patients having clinical or histological evidence of malignant change, extension of the disease either onto the pharynx or floor of mouth were also excluded. Patients having history of recent myocardial infarction, uncontrolled hypertension, dia-betes, peptic ulcer, tuberculosis, cirrhotic liver disease and current pregnancy were all excluded as steroids can potentially worsen the aforementioned conditions.
After a clinical diagnosis, the case was discussed with patients in detail and risk-benefit ratio explained. Those who wished to participate in the study were designated a numeric identification in sequence. A specially designed proforma containing demographics and clinical findings was filled for every patient. A vernier caliper was used to measure the maximum unaided inter incisal opening in millimeters. Oral hy-giene improvement measures were employed and they were instructed and strongly counseled to discontinue the quid habit. An incisional biopsy was carried out in all participants under local anesthesia (LA) to confirm clinical diagnosis.
After confirmation of diagnosis histopathological-ly, patients falling in group “A” were administered intralesional methyl prednisolone, group “B” were prescribed oral lycopene and group “C” were given a combination of both intralesional methyl prednisolone and oral lycopene. Methyl prednisolone (Depo-Medrol; Pharmacia & Upjohn Company, Puurs, Belgium) 20 mg/0.5 ml preparation was injected every month, at a single site on the buccal mucosa, bilaterally (40 mg in total) to patients in groups “A” and “C” for a total duration of six months.
Lycopene 10 mg soft gels (Lycopene; General Nutri-tion Corporation, Pittsburgh, PA, USA) were advised to all the patients of groups “B” and “C” as a single daily dose for six months. Patients were assessed monthly for six months and after that, bi-monthly for a total of one year and interincisal opening assessed. During this one year period, an aggressive physiotherapy regimen consisting of rigorous jaw stretching (wooden spatula) exercises was instituted.
All the data collected was entered in SPSS and analyzed accordingly. The qualitative variables in the demographic data (e.g. gender, predictor and outcome variable) are presented as percentages and proportions and quantitative data presented as means and standard deviations. All the groups were compared with each other using student t-test and intra-group pre and post-treatment interincisal opening was compared using paired sample t-test. A p-value of less than 0.05 is considered significant with a confidence interval of 95%.
366Pakistan Oral & Dental Journal Vol 35, No. 3 (September 2015)
Oral submucous fibrosis
62.2% (n-28) female and 37.8% (n-17) male patients as shown in figure1 and Fig 2. Duration of their quid chewing habit is shown in Fig 3.
The median inter-incisal opening (MIIO) open-ing was recorded at the start (MIIO1) of treatment and there on, every month for a period of six months (MIIO2-6). Form the seventh month onwards the MIIO was recorded at two month intervals till the completion of study duration at twelve months (MIIO7-9).
The mean MIIO at the start of study (MIIO1) of all 45 patients was 16.87±5.33 mm while it was 21.18±6.27 mm at the end of study (MIIO9). In group “A” MIIO1 was 15.67±6.46 mm while MIIO9 was 19.13±6.79 mm. In group “B” MIIO1 was 17.07+4.2 mm while MIIO9 was 19.53±4.54 mm. In group “C” MIIO1 was 17.87±5.23 mm while MIIO9 was 24.87+5.9 mm as shown in Table 1.
The difference between MIIO at the start (MIIO1) and completion (MIIO9) of study was statistically high-ly significant in all the study groups (p < 0.001). The difference in mouth openings at the end of study was found to be statistically insignificant between groups “A” and “B” (p > 0.05), significant between groups “A” and “C” (p < 0.05) while it was highly significant between groups “B” and “C” (p ≤ 0.01).
DISCUSSION
OSMF is a chronic, debilitating and a well-recog-nized potentially malignant condition associated with areca nut chewing, an ingredient of betel quid and is prevalent in South Asian population. Pathogenesis is not yet established but is believed to be multifactorial; hence the treatment of OSMF presents a major chal-lenge for oral and maxillofacial surgeons. Patients’ age in present study ranges from 13 to 75 years with a mean of 36.49±11.82 years. Majority are in 4th decade followed by the 3rd. It is very interesting to note that only two patients (4%) presented in second decade. This might be considered indicative of the time dependent and insidious pathogenesis of the disorder. Other re-searchers also found a comparable mean age in their studies.1,2,3,4
There was a distinct preponderance of females in our study, with a female to male ratio of 1.6:1. Maher et al in their two different studies conducted in Karachi found the female to male ratio to be 1.6:1 and 2:1.5.18,19 Isaac et al in a study reported a contrasting predomi-nance of men.20 Male preponderance was also observed in studies by other researchers.10,5,6 Rana et al however, in an earlier study to evaluate the risk factors for the development of oral precancers in patients presenting to the oral and maxillofacial surgery department of PIMS, Islamabad, found the female to male ratio to be 1.4:1.7 If one closely observes the demographic data regarding oral submucous fibrosis in Pakistan, distinct
RESULTS
Patients of OSMF were between 13-75 years of age with a mean of 36.49±11.82 years and majority (38%) in (31-40) year age bracket followed by 25% in (21-30) years. Females predominated over males. There were
Male
38%
Female
62%
Fig 1: Gender distribution in total sample
10
8
6
4
2
0
Group (A)
Group (B)
Group (C)
13% 13%
11%
20% 20%
22%
Male Female
Fig 2: Gender distribution in different groups
Fig 3: Duration of quid chewing habit
11-15 Years
42%1-5 Years
31%
6-10 Years
27%
367Pakistan Oral & Dental Journal Vol 35, No. 3 (September 2015)
Oral submucous fibrosis
TA
BL
E 1
: ME
DIA
N I
NT
ER
-IN
CIS
AL
OP
EN
ING
(MII
O1-
9) -
TR
EA
TM
EN
T G
RO
UP
S
Pos
t-O
p-
erat
ive
Inte
r-in
cisa
l O
pen
ing
at o
ne
Mon
th
Pos
t-O
p-
erat
ive
Inte
r-in
cisa
l O
pen
-in
g at
2
mon
ths
Pos
t-O
p-
erat
ive
Inte
r-in
cisa
l O
pen
-in
g at
3
Mon
ths
Pos
t-O
p-
erat
ive
Inte
r-in
cisa
l O
pen
-in
g at
4
mon
ths
Pos
t-O
p-
erat
ive
Inte
r-in
cisa
l O
pen
-in
g at
5
mon
ths
Pos
t-O
p-
erat
ive
Inte
r-in
cisa
l O
pen
-in
g at
6
mon
ths
Pos
t-O
p-
erat
ive
Inte
r-in
cisa
l O
pen
-in
g at
8
mon
ths
Pos
t-O
p-
erat
ive
Inte
r-in
cisa
l O
pen
ing
at 1
0 m
onth
s
Pos
t-O
p-
erat
ive
Inte
r-in
cisa
l O
pen
ing
at 1
2 m
onth
s
Group A
NV
alid
1515
1515
1515
1515
15
Mis
sing
00
00
00
00
0
Mea
n15
.67
15.8
016
.47
17.2
018
.00
18.7
319
.00
19.2
719
.13
Med
ian
13.0
014
.00
14.0
016
.00
17.0
018
.00
18.0
019
.00
19.0
0
Std
. Dev
iati
on6.
466
6.54
96.
770
6.89
96.
782
6.80
86.
887
6.87
16.
791
Ran
ge20
2020
2020
2021
2121
Min
imum
66
77
88
88
8
Max
imum
2626
2727
2828
2929
29
Group B
NV
alid
1515
1515
1515
1515
15
Mis
sing
00
00
00
00
0
Mea
n17
.07
17.0
717
.40
17.9
318
.47
19.1
319
.47
19.5
319
.53
Med
ian
17.0
017
.00
17.0
018
.00
19.0
020
.00
20.0
020
.00
20.0
0
Std
. Dev
iati
on4.
200
4.20
04.
256
4.48
04.
518
4.48
64.
373
4.54
94.
549
Ran
ge16
1616
1717
1716
1616
Min
imum
88
88
89
1010
10
Max
imum
2424
2425
2526
2626
26
Group A
NV
alid
1515
1515
1515
1515
15
Mis
sing
00
00
00
00
0
Mea
n17
.87
18.6
719
.73
21.4
722
.67
24.0
724
.87
24.9
324
.87
Med
ian
18.0
019
.00
19.0
020
.00
22.0
023
.00
25.0
025
.00
25.0
0
Std
. Dev
iati
on5.
235
5.44
75.
574
6.03
46.
137
6.15
86.
300
6.01
75.
902
Ran
ge22
2324
2627
2728
2726
Min
imum
66
78
89
910
10
Max
imum
2829
3134
3536
3737
36
368Pakistan Oral & Dental Journal Vol 35, No. 3 (September 2015)
Oral submucous fibrosis
female predilection in this region will be found.18,19 This might be due to the practice that women locally tend to sit at home and have more time on hands to indulge in habits like areca nut chewing; also areca chewing is considered a more socially acceptable habit than (for example) smoking, especially in women.
Mouth opening is an objectively verifiable criterion by which the severity of oral submucous fibrosis can be assessed. The involvement of submucosal tissues in the oral cavity by severe fibrosis tends to significantly de-crease the elasticity of oral tissues, thereby disallowing stretch on them while the jaw is opened. It is logical to believe therefore, that severer disease activity would mean a more debilitating effect on mouth opening. Inter-incisal distance may successfully be used as an outcome measure of response to intervention and it is less likely to be affected by observer bias than other criteria used for physically examining a patient with OSMF. In the present study, inter-incisal opening was assessed using a graduated vernier caliper at start and throughout the study. Patients in all three groups, who received Lycopene or methyl prednisolone alone or in combination showed a statistically significant (p < 0.001) improvement in their mouth opening. Comparatively speaking, the group which received a combination ther-apy consisting of both agents had the most significant increase in their mouth opening. Ariyawardana et al8 concluded that 86% of patients showed significant improvement in mouth opening after six months with intralesional methylprednisolone. In another study, Lai et al8 reported improvement in 83% of patients receiving submucosal injections of steroid with hyaluronidase. Kumar et al9 carried out a study to demonstrate the efficacy of lycopene, alone and in combination with intralesional steroids for the management of OSMF. They reported statistically significant mouth opening values in patients, an average increase of 3.4 mm (Ly-copene) and 4.6 mm (Lycopene + Steroid).
All the patients had reportedly discontinued areca chewing habit and indulged in physiotherapy, which are believed to be the core requisites for any treatment to be efficacious in the management of OSMF. A particularly remarkable finding, when comparing our results with these studies8,17,25,10 was that none of the other authors, except Lai et al24 included physiotherapy as part of their treatment regimen, which is believed to be a fundamen-tal requirement in the quest for a successful, stable, long-term results. Cox and Zoellner,16 in probably the only study of its kind, quite astonishingly demonstrated physiotherapy to be efficacious as the primary/only treatment option for OSMF. However, there is plenty of anecdotal evidence from fellow maxillofacial surgery colleagues about the lack of efficacy of mouth opening exercises alone in the management of OSMF. There is
a need of longer follow up and larger sample size study to be conducted in different settings.
CONCLUSION
This study was able to address the fundamental pathogenic mechanisms of OSMF and devise a therapy that targeted the basic disease process leading to limit-ed mouth opening, in patients who were not subjected further to noxious stimulation by areca nut constituents due to cessation of the habit and participated in their own recovery through mouth opening exercises. The authors were thus able to achieve results that were statistically significant, encouraging and point towards a definitive role of this multi-modality approach towards alleviation of this debilitating condition.
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CONTRIBUTION BY AUTHORS
1 Omar Arshad & Khalid Mahmood Siddiqi: Made substantial contributions to conception and design of the manuscript as well as data acquisition.
2 Khalid Mahmood Siddiqi: Were involved in drafting and revising the manu-script.
3 Zahoor Ahmad Rana: Also made the statistical analysis.