Download Treatment of cyclosporin-induced gingival hyperplasia with

Nephrol Dial Transplant (1997) 12: 2694–2697
Nephrology
Dialysis
Transplantation
Clinical Report
Treatment of cyclosporin-induced gingival hyperplasia
with azithromycin
E. Gómez, M. Sánchez-Nuñez, J. E. Sánchez, C. Corte, S. Aguado, C. Portal, J. Baltar
and J. Alvarez-Grande
Nephrology Service, Hospital Central de Asturias, Oviedo, Spain
Abstract
Background. Gingival hyperplasia is a known complication of cyclosporin therapy. Although plaque control has been shown to be of benefit, gingival surgery
is occasionally necessary. The aim of this study was to
review the effect of a short-course therapy with azithromycin in renal transplant patients with cyclosporininduced gingival hyperplasia.
Methods. Thirty-eight patients received 500 mg/day of
azithromycin for 3 consecutive days. The degree of
gingival hyperplasia was classified as: 0, no gingival
overgrowth; 1, mild overgrowth; 2, moderate overgrowth, and 3, severe overgrowth. Gingival bleeding
and evolution of gingival hyperplasia were determined
at 0 (pretreatment), 7, 30, 90 and 180 days.
Cyclosporin, serum creatinine and ALT levels were
simultaneously determined on the same days.
Results. Seven patients were excluded, leaving a total
of 31 included in the trial. Eleven had a score of 3, 17
a score of 2, and 3 a score of 1. The degree of gingival
hyperplasia was unrelated to the dose and levels of
cyclosporin. Gingival hyperplasia improved in all
patients (P<0.001, Friedman test). The degree of
improvement was better when the degree of hyperplasia
was lower. In 27 patients gingival hyperplasia remained
absent 6 months later, 3 patients required a second
course of treatment, and another required gingival
surgery. Gingival bleeding, present in 28 patients when
diagnosed, disappeared in all cases in 2.2±1.2 (1–7)
days. No adverse effects were observed. Cyclosporin,
serum creatinine, and ALT levels were not affected by
treatment.
Conclusions. Azithromycin improves cyclosporinassociated gingival hyperplasia, especially when administered early in the process.
Key words: azithromycin; cyclosporin; gingival hyperplasia; renal transplant
Correspondence and offprint requests to: Dr Ernesto Gómez, Servicio
de Nefrologia, Hospital Central de Asturias, C/ Celestino Villamil
s/n, E-33006 Oviedo, Spain.
Introduction
Gingival hyperplasia is a known complication of cyclosporin therapy, affecting 21–35% of renal transplant
patients [1]. It appears in all cases as an essentially
papillary process affecting labial, buccal, palatal, and
lingual tissues in all parts of the mouth. Onset is
invariably rapid, with a clinical picture that takes 1 or
2 weeks to develop. In some patients with uncontrolled
hyperplastic changes and poor plaque control, alveolar
bone loss is significant and tooth loss follows [2].
Plaque control and removal of local irritants has
been shown to be of some benefit [3]. However, no
effective medical treatment is available and gingival
surgery is sometimes necessary. Recently Walhstrom
et al. [4] have described improvement of gingival
hyperplasia following treatment with azithromycin, an
azalide antimicrobial agent derived from the macrolide
antibiotic erythromycin.
The aim of this study was to evaluate short-course
azithromycin therapy in renal transplant patients with
cyclosporin-induced gingival hyperplasia.
Subjects and methods
Thirty-eight consecutive renal transplant patients with gingival hyperplasia were examined between April 1995 and
March 1996. Patients were excluded for any of the following
reasons: a follow-up period less than 6 months, introduction
of calcium-channel blockers or phenytoin therapy during the
study (with exceptions if they were taking those drugs before
entering the study and provided that they continued taking
the drugs), and patients with impairment of renal function
due to rejection, urinary tract obstruction, or any other cause.
The degree of gingival overgrowth was classified into four
categories: no gingival overgrowth, (0); mild overgrowth,
blunting of marginal gingiva (1); moderate overgrowth,
overgrowth extending to the middle of the tooth crown (2);
severe overgrowth, overgrowth bearing two-thirds of the
tooth crown or where the whole attached gingiva was affected
(3) (Figure 1).
All patients received azithromycin because of gingival
hyperplasia. A dose of 500 mg/day was given for 3 consecutive days. Symptomatic features, such as gingival bleeding
© 1997 European Renal Association–European Dialysis and Transplant Association
Treatment of cyclosporin-induced gingival hyperplasia with azithromycin
2695
Significance was established using GraphPAD Prism 2.0
(GraphPAD Software, CA, USA).
Results
Fig. 1. Examples of gingival overgrowth scoring system: (A) score
1, mild gingival overgrowth; (B) score 2, moderate overgrowth; and
(C ) score 3, severe overgrowth.
and evolution of gingival hyperplasia were determined on
days 0 (pretreatment), 7, 30, 90 and 180. The degree of
gingival bleeding was determined using triangular toothpicks
(5) at day 0. The day bleeding ceased was determined by the
patient, and this was verified using the same method on the
day 7 visit. The degree of oral hygiene at the beginning of
treatment was noted as poor or good and the patients were
instructed on adequate oral hygiene (brushing, flossing)
during the period of the study. Other bleeding indexes and
plaque index were not determined. Analytic determinations
including cyclosporin blood levels (monoclonal antibodies,
Tdx, Abbott), serum creatinine, and ALT were simultaneously carried out.
The groups (score 3 vs score 2) were compared using the
Student’s test for unpaired samples. The statistical significance of the differences between proportions was determined
using Fisher’s exact test. Statistical analysis of repeated
measures (e.g. creatinine, cyclosporin levels, cyclosporin
doses, ALT ) was performed by analysis of variance for
normally distributed variables, and the Friedman test was
employed for non-normally-distributed variables (evolution
of score of gingival overgrowth throughout the study).
Evolution of the disease after 7 and 180 days of treatment
was analysed using Wilcoxon signed rank test. Results are
expressed as the mean±SD. Differences were considered
significant when the two-tailed P value was <0.05.
Seven patients were excluded (five with serum creatinine greater than 2 mg/dl, one who did not return for
visits, and another because of the incorporation of
calcium-channel blockers after azithromycin treatment). Details of the 31 patients included in the trial
are given in Table 1; 19/31 (61%) and 1/31 (3%)
patients received calcium-channel blockers or phenytoin respectively during the whole study.
At the beginning of therapy, 11 patients had a
gingival hyperplasia score of 3, 17 had a score of 2,
and 3 a score of 1. The mean maintenance dose of
cyclosporin during the previous month (mg/kg/day)
was 3.01±1.28 (0.85–6.80). The degree of gingival
hyperplasia was unrelated to cyclosporin dose
(2.67±0.7 mg/kg/day for score 3 vs 3.4±1.5
mg/kg/day for score 2, P=0.1), or to cyclosporin
blood levels (153±30 ng/ml for score 3 vs
147±31 ng/ml for score 2, P=0.66). The cyclosporin
dose was kept constant throughout the period of study
(3±1.2, 3±1.1, 3±1.1, 2.9±1.1, and 2.9±1.1
mg/kg/day at baseline, 7, 30, 90 and 180 days respectively, P=0.7).
Twelve patients had poor and 19 had good oral
hygiene when enrolled in the study; 66% (8/12) of the
patients with poor oral hygiene had a score of 3, vs
21% (4/19) of patients with good oral hygiene (P=
0.02).
Gingival hyperplasia improved in all treated patients
throughout the study (P<0.0001, F=95.96, Friedman
test). Improvement was evident 7 days after the beginning of therapy in all except two patients who had an
initial score of 3. All patients, however, showed
improvement at the 30th and 180th days, including the
two previous patients without initial improvement
( Table 2). The degree of improvement was enhanced
with a lower degree of initial hyperplasia.
On the 7th day of therapy, 9/11 patients with an
initial score of 3 improved to classification 2, with two
patients remaining at 3. In the group of patients with
an initial score of 2, 15/17 were scored at 1, and 2/17
Table 1. Patient data
Sex (male/female)
Age (years)
Time from transplant at therapy (months)
Number of transplants
Immunossuppression
Prednisone+cyclosporin+azathioprine
Prednisone+cyclosporin
Cyclosporin+azathioprine
Cyclosporin only
Calcium-channel blockers
Nifedipine
Amlodipine
Phenytoin
14/17
48±11 (25–72)
34±26 (2–86)
27 one, 4 two
13
5
2
11
13
6
1
2696
E. Gómez et al.
Table 2. Gingival hyperplasia scores for 31 patients over the course
of treatment with azithromycin
Pretreatment
3
3
3
3
3
3
3
3
3
3
3
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
1
1
mmol/l, P=0.58), and ALT (24±13, 27±16, and
29±19 U/l, P=0.16) did not change between days 0,
7 and 30.
Post-treatment days
7
30
90
180
2
2
2
2
3
2
2
3
2
2
2
1
1
1
1
1
1
1
1
1
1
0
1
0
1
1
1
1
0
0
0
1
1
1
1
2
1
1
2
1
2
1
1
1
1
1
1
1
1
1
1
1
0
1
0
0
0
0
0
0
0
0
1
2
1
0
1
1
1
1
0
3*
0
1
0
1
1
1
1
1
1
1
1
0
0
0
0
0
0
0
0
0
0
1
0
1
0
0
1
1
1
0
—
0
1
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
*Deterioration at 90 days, requiring surgery.
improved to a score of 0. All three patients with an
initial score of 1 improved to a score of 0 (P<0.0001,
Wilcoxon signed rank test). At the end of the study
(180th day), only 45% (5/11) patients with an initial
score of 3 achieved a final score of 0, while 88% (15/17)
of those with an initial score of 2 and 100% (3/3) of
those with an initial score of 1 were without gingival
hyperplasia (P<0.0001, Wilcoxon signed rank test).
The degree of oral hygiene also affected the response
to treatment. At the end of study, only 50% (6/12) of
patients with poor oral hygiene developed a score of
0, as opposed to 90% (17/19) of those with good oral
hygiene (P=0.03, Fisher’s exact test).
In 27 patients gingival hyperplasia did not recur,
while three patients needed a second course of treatment, and 1 patient needed gingival surgery after an
initial phase of improvement. The latter 4 patients had
pre-treatment scores of 3.
Twenty eight patients suffered gingival bleeding after
brushing their teeth. All of them stopped bleeding after
2.2±1.2 days (range 1–7).
Azithromycin was well tolerated and no adverse
effects were observed. The levels of cyclosporin
(139±36, 153±37, and 146±38 ng/dl, P=0.06),
serum creatinine (120±29, 121±28 and 122±27
Discussion
The results of this descriptive study, which lacks a
control group, clearly suggest that azithromycin
improves cyclosporin-associated gingival hyperplasia.
Treatment is undoubtedly very simple and cheap, and
effective in a short period of time, avoiding gingival
surgery in a large number of patients. Moreover, the
fast disappearance of gingival bleeding results in oral
hygiene. The drug is well tolerated and does not modify
the cyclosporin, creatinine, or ALT levels. However,
therapy should be started as early as possible, since
the greater the degree of initial hyperplasia, the lower
the benefits. After short-term therapy (7 days after the
beginning of treatment), no patient with an initial
score of 3, only 11% of those with an initial score of
2, and all those with an initial score of 1, achieved a
score of 0. After long-term therapy (180 days) only
45% of patients with an initial score of 3, 88% of those
with an initial score of 2, and 100% of those with an
initial score of 1 achieved a final score of 0.
The improvement in the degree of hyperplasia could
also be modified by a better degree of oral hygiene, as
was recommended to all patients during the study. For
some authors, plaque accumulation is essential for
initiation of drug-induced gingival overgrowth [6,7],
but other authors claim that this factor can only
modify the severity of the process [3,8]. Poor oral
hygiene does not seem to be the only cause of hyperplasia, since several patients with excellent oral hygiene
had an initial score of 3, as others authors have also
noted [8].
There are only two articles about the improvement
of gingival overgrowth with drug therapy. In 1994,
Wong and colleagues [9] described four cases of cyclosporin-induced gingival hyperplasia which resolved
after 7 day treatment with 400 mg/day of metronidazole. Gingival hyperplasia disappeared after 3–4 weeks
of treatment. In two of these patients gingival hyperplasia recurred 1 year later, but then it responded again
to a second course of metronidazole therapy.
Wahlstrom and colleagues [4] described two further
cases of gingival hyperplasia that improved after treatment with azithromycin. Therapy consisted of a 5-day
course of azithromycin (at an initial dose of 500 mg,
followed by a daily dose of 250 mg for 4 days).
Azithromicin was used for other reasons, and the
regression of the gum overgrowth was noted incidentally a few months later.
The mechanism by which these drugs may improve
gingival hyperplasia is unknown. Although both have
an antibacterial effect, they belong to different groups
with different mechanisms of action. Moreover, no
pathogen was identified in gum scrapings [10], and
this disease does not appear in patients treated with
other immunosuppressive drugs [11]. On the other
Treatment of cyclosporin-induced gingival hyperplasia with azithromycin
hand, some drugs with completely different mechanism
of action can induce gingival hyperplasia such as
phenytoin [12] and nifedipine [13,14] which do not
have any immunosuppressive effect. These findings
suggest that the action of azithromycin is unrelated to
its antimicrobial effect, although some authors have
found that its use reduces the growth of pigmented
anaerobes and spirochetes [15].
The predominant histological feature found in the
hyperplastic tissue is a proliferation of collagen fibres
in the corium. Azithromycin has been shown to reach
high concentrations in human fibroblasts [16 ], and it
is supposed that it has some action there. It is possible
that drugs such as azithromycin or metronidazole have
a common action which can inhibit the proliferation
of collagen fibres. In this sense, it is interesting that
tacrolimus, a macrolide antibiotic employed as an
immunossuppressive and whose mechanism of action
is similar to that of cyclosporin, does not produce
gingival hyperplasia [17,18]. However, contrary to
cyclosporin [19], tacrolimus may competitively interfere with TGF-b1 (transforming growth factor-beta)
signalling, the most important cytokine involved in
fibrogenesis [20], whose synthesis is increased in druginduced gingival hyperplasia [21]. Gum biopsies were
not obtained, and therefore it is unclear whether the
effect of azithromycin in our patients was due to an
improvement in inflammation of the tissue alone, or
to a reduction in the accompanying hyperplasia.
Usually, gingival inflammation appears to be associated with gingival hyperplasia [7].
Seventy-two per cent (8/11) of the patients with a
gingival hyperplasia score of 3 were receiving calciumchannel blockers, which, especially nifedipine, can also
induce gingival hyperplasia in association with cyclosporin [7,22], although other authors do not find this
kind of association [1,23]. Azithromycin is also useful
in these patients.
In conclusion, azithromycin appears to be useful in
the treatment of cyclosporin-induced gingival hyperplasia, particularly when administered early in the
process. Treatment is simple, cheap, and without
known adverse effects and useful even in patients
receiving other drugs such as nifedipine or phenytoin
that induce gingival hyperplasia. However, more controlled studies are needed to determine the exact role
of this drug in the treatment of cyclosporin-induced
gingival hyperplasia.
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Received for publication: 3.10.96
Accepted in revised form: 11.7.97