James JA, Marley JJ, Jamal S, Campbell BA, Short CD, Johnson RWG, Hull PS,. Spratt H, Irwin CR, Boomer S, Maxwell AP, Linden GJ: The calcium channel.
Copyright C Munksgaard 2000
J Clin Periodontol 2000; 27: 109–115 Printed in Denmark . All rights reserved
ISSN 0303-6979
The calcium channel blocker used with cyclosporin has an effect on gingival overgrowth
J. A. James1, J. J. Marley2, S. Jamal1, B. A. Campbell4, C. D. Short4, R. W. G. Johnson4, P. S. Hull1, H. Spratt2, C. R. Irwin2, S. Boomer2, A. P. Maxwell3 and G. J. Linden2 1 Turner Dental School, University of Manchester, Higher Cambridge Street, Manchester M15 6FH, UK; 2School of Clinical Dentistry, 3Department of Medicine, The Queen’s University of Belfast, Grosvenor Road, Belfast, BT12 6BP Northern Ireland, UK; 4The Renal Transplant Unit, Manchester Royal Infirmary, Central Manchester Healthcare Trust, Oxford Road, Manchester M13 9WL, UK
James JA, Marley JJ, Jamal S, Campbell BA, Short CD, Johnson RWG, Hull PS, Spratt H, Irwin CR, Boomer S, Maxwell AP, Linden GJ: The calcium channel blocker used with cyclosporin has an effect on gingival overgrowth. J Clin Periodontol 2000; 27: 109–115. C Munksgaard, 2000. Abstract Background/aims: To investigate whether the choice of calcium channel blocker, used in conjunction with cyclosporin A, affected the prevalence of gingival overgrowth. Method: A cohort of 135 renal transplant recipients who had been medicated with cyclosporin A in combination with either nifedipine (89) or amlodipine (46) since transplant, took part in the study. The inclusion criteria were that eligible subjects had been in receipt of a kidney transplant for at least 12 months, had at least 10 teeth and had not received specialist periodontal treatment. The age, gender, current drug regimen and dosage were recorded for each participant and alginate impressions taken of both arches. The presence and severity of gingival overgrowth were scored from plaster models. Results: A higher proportion (72%) of the amlodipine group were categorised as having gingival overgrowth compared with only 53% of the nifedipine group, c2Ω4.5, p∞0.05. Logistic regression analysis was used to explore the relationship between the presence or absence of gingival overgrowth (dependent variable) and age, gender, time since transplant, dose of cyclosporin A, centre in which the patient was treated, and the calcium channel blocker used (independent variables). Independent predictors of gingival overgrowth in this multivariate analysis were whether the individual was treated with amlodipine or nifedipine (pΩ0.01) and whether the individual was young or old (pΩ0.01). Within the multivariate analysis, the odds ratio for amlodipine to be associated with gingival overgrowth compared with nifedipine was 3.0 (confidence interval 1.3–6.9). Conclusions: The prevalence of gingival overgrowth in renal transplant recipients maintained on cyclosporin A and nifedipine is lower than those treated with cyclosporin A and amlodipine.
Cyclosporin A (CsA) has been the immunosuppressant of choice for organ transplantation over the last decade. It has also been commonly prescribed in the management of several immunologically based diseases including diabetes mellitus, Bechet’s disease, psoriasis, multiple sclerosis, erosive lichen planus
and systemic lupus erythematosus (Seymour & Jacobs 1992). Unfortunately, CsA is associated with a number of side effects, including enlargement of the gingival tissues. In a recent well controlled study the prevalence of gingival overgrowth resulting from monotherapy with CsA was found
Key words: gingival overgrowth; cyclosporin A; calcium channel blockers Accepted for publication 13 April 1999
to be 21% (Hefti et al. 1994). Although not life threatening the gingival changes are aesthetically disfiguring and often have psychological implications for affected individuals. On occasions the overgrowth can be so severe that it interferes with mastication, occlusion and speech. Other serious side effects of
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James et al. oedematous and haemorrhagic (Daley & Wysocki 1984, James & Linden 1992). The use of CsA in combination with a calcium channel blocker has been shown to be associated with increased prevalence and severity of gingival overgrowth compared with monotherapy with CsA (Slavin & Taylor 1987, Pan et al. 1992, Thomason et al. 1993, Spratt et al. 1999). It has been demonstrated recently in patients with hypertensive heart disease that monotherapy with a ‘new generation’ calcium channel blocking agent such as amlodipine induces less gingival overgrowth than an ‘established’ first generation type such as nifedipine (Jørgensen 1997). The aim of the present study was to investigate whether the choice of calcium channel blocker, either amlodipine or nifedipine, used in conjunction with cyclosporin A affects the prevalence of gingival overgrowth in renal transplant patients.
cyclosporin include nephrotoxicity, hepatotoxicity and hypertension. The nephrotoxicity is caused by arteriolar vasoconstriction due to local release of thromboxane A2 (Bennett 1996). Calcium channel blockers such as nifedipine and amlodipine have been used to mitigate the renal vasoconstriction caused by CsA and thus relieve hypertension. Research suggests that calcium channel blockers not only reduce nephrotoxicity but also enhance the immunosuppressive potency of CsA (Weir 1991). It has been shown that calcium channel blockers can independently induce gingival overgrowth albeit with an apparently lower prevalence than CsA (Barclay et al. 1992, Miller & Damm 1992, Jørgensen 1997). The overgrowths induced clinically by both CsA and the calcium channel blockers are virtually indistinguishable and can range from being firm and fibrous to obviously
Table 1. Characteristics of renal transplant recipients being treated in Manchester compared with those treated in Belfast Manchester male female
Belfast c2Ω0.16 pΩ0.69
41 (76%) 13 (24%)
59 (73%) 22 (27%)
age mean years (SD)
42.1 (11.5)
42.2 (14.3)
tΩ0.07 pΩ0.95
time since transplant mean months (SD)
68.5 (37.2)
40.8 (19.2)
tΩ5.65 pΩ∞0.0001
no. teeth mean (SD)
24.3 (5.3)
24.7 (5.2)
tΩ0.42 pΩ0.68
340.6 (116.6)
292.1 (79.2)
tΩ2.84 pΩ0.005
cyclosporin dose mean mg/day (SD)
Table 2. Characteristics of renal transplant recipients being treated with nifedipine compared with those treated with amlodipine Nifedipine male female age mean years (SD) time since transplant mean months (SD) no. teeth mean (SD) cyclosporin dose mean mg/day (SD)
70 19 41.4 52.2 24.3 322.4
Amlodipine
(79%) (21%) (13.4) (32.5) (5.7) (105.5)
30 16 43.6 46.5 24.8 282.3
(65%) (35%) (12.9) (25.1) (4.1) (73.3)
Table 3. Overgrowth scores for nifedipine compared with amlodipine treated renal transplant recipients; all data shown as mean (SD) Nifedipine upper buccal/labial upper palatal lower buccal/labial lower lingual all teeth
2.5 1.9 2.3 1.7 2.1
(1.2) (1.4) (1.1) (1.2) (1.1)
Amlodipine 2.7 2.1 2.6 2.3 2.4
(1.0) (1.1) (0.9) (1.1) (0.8)
t
p
0.89 0.98 1.64 2.96 1.6
0.37 0.32 0.10 0.004 0.11
Material and Methods
Consecutive groups of renal transplant recipients attending the Renal Transplant Units in Manchester Royal Infirmary and Belfast City Hospital took part in this study. All participants gave informed consent. The inclusion criteria were that eligible subjects had been in receipt of a kidney transplant for at least 12 months, had at least ten teeth and had not received specialised periodontal treatment for any gingival changes which had occurred since their transplant. All those recruited had been medicated with CsA in combination with either nifedipine or amlodipine since transplant. The age, gender, current drug regimen and dosage were recorded for each participant and alginate impressions were taken of both upper and lower arches. The extent and severity of gingival overgrowth for each of the subjects was scored on plaster models using an expanded version of the gingival overgrowth index developed by Seymour et al. (1985) and described by Thomason et al. (1996a). Briefly, each interdental papilla, either buccal or palatal/lingual in both arches was assessed. The maximum number of interdental papillae per dentate patient with 32 teeth is 60. Papillae were scored only if there were two contacting adjacent teeth. The gingival tissue distal to the last standing molar was not scored. The interdental papillae were classified by the teeth mesially and distally to them (e.g. 18/17, 17/16 etc.). Each papilla was graded in relation to how much it encroached towards the incisal edge of the tooth (score 0–3) and how thickened it was bucco-palatally/ lingually (score 0–2). The maximum score for each papilla was 5. The models were scored by one investigator (SJ), who was blind to the drug regimens. A mean overgrowth score was calculated and a value of 2 or more was used to identify renal transplant recipients with clinically significant overgrowth.
Statistical analysis
All data were entered into a statistical package (Statview 4.1) on an Apple PowerMac for subsequent analysis. The subject was taken as the statistical unit of analysis. The Student t-test or c2 analyses were used with the level of sig-
Calcium channel blockers and gingival overgrowth
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nificance set at p∞0.05. Multivariate analysis was carried out using logistic regression to identify possible predictors of gingival overgrowth. Results
In total 135 renal transplant recipients immunosuppressed with cyclosporin A and concomitantly taking either nifedipine or amlodipine since transplant were recruited into the study (54 in Manchester, 81 in Belfast). The ratio of males : females was similar in both centres (∂3:1). The age of the subjects and the number of teeth were comparable between the two centres (Table 1). The average time since transplantation and the mean dose of CsA were significantly higher in Manchester compared with Belfast (Table 1). The renal transplant recipients were divided into two distinct groups on the basis of the calcium channel blocker used since transplantation. A nifedipine group was made up of 89 subjects and an amlodipine group of 46 subjects. The members of the nifedipine group were taking a significantly higher daily dose of CsA than those in the amlodipine group (p∞0.05), however, there were no other differences between the two groups (Table 2).
Fig. 1. The distribution of gingival overgrowth related to buccal/labial interdental papillae.
Gingival overgrowth
The average overgrowth score in the amlodipine group was not significantly different from that in the nifedipine group (Table 3). Figs. 1, 2 show that the mean papillary overgrowth scores were consistently higher in the amlodipine compared with the nifedipine group. Overgrowth was most severe in the buccal tissues related to the upper and lower canines and lateral incisors (Figs. 1, 2). There was significantly more overgrowth affecting the lingual aspects of the lower teeth in the amlodipine compared with the nifedipine group (Table 3). A higher proportion (72%) of the amlodipine group were categorised as having gingival overgrowth compared with only 53% of the nifedipine group, c2Ω4.5, p∞0.05. In this comparison gingival overgrowth was categorised as being present when a subject had a mean overgrowth score of >2. The odds ratio for gingival overgrowth to be present in the amlodipine compared with nifedipine group was 2.27 (confidence interval 1.1 to 4.9). The effects of vari-
Fig. 2. The distribution of gingival overgrowth related to palatal/lingual interdental papillae.
ous factors on the prevalence of overgrowth are shown in Table 4. To correct for confounding effects, all the independent variables in Table 4 were included in a logistic regression analysis with the dependent variable being whether a subject had overgrowth as evidenced by a mean overgrowth score of >2. Within this analysis subjects who were under 35 years of age were categorised as young, a recent transplant was one which had been in situ for less than 3 years, and a low dose of CsA was categorised as
