James JA, Boomer S, Maxwell AP, Hull PS, Short CD, Campbell BA, Johnson. RWG, Irwin CR, Marley JJ, Spratt H, Linden GJ: Reduction in gingival overgrowth.
Copyright C Munksgaard 2000
J Clin Periodontol 2000; 27: 144–148 Printed in Denmark . All rights reserved
ISSN 0303-6979
Case Report
Reduction in gingival overgrowth associated with conversion from cyclosporin A to tacrolimus
J. A. James1, S. Boomer3, A. P. Maxwell4, P. S. Hull1, C. D. Short2, B. A. Campbell2, R. W. G. Johnson2, C. R. Irwin3, J. J. Marley3, H. Spratt3 and G. J. Linden3 1
Turner Dental School, University of Manchester, Higher Cambridge Street, Manchester M15 6FH, UK; 2The Renal Transplant Unit, Manchester Royal Infirmary, Central Manchester Healthcare Trust, Oxford Road, Manchester M13 9WL, UK; 3School of Clinical Dentistry, 4 Department of Medicine,The Queen’s University of Belfast, Grosvenor Road, Belfast BT12 6BP, Northern Ireland, UK
James JA, Boomer S, Maxwell AP, Hull PS, Short CD, Campbell BA, Johnson RWG, Irwin CR, Marley JJ, Spratt H, Linden GJ: Reduction in gingival overgrowth associated with conversion from cyclosporin A to tacrolimus. J Clin Periodontol 2000; 27: 144–148. C Munksgaard, 2000. Abstract Background: Unsightly gingival overgrowth affects many individuals immunosuppressed with cyclosporin A (CsA). Current management involves repeated periodontal surgery and intensive hygienist support. Tacrolimus is an effective alternative immunosuppressive agent for renal transplantation which does not appear to produce gingival enlargement. Aims: The purpose of the present study was to monitor the gingival response of 4 renal transplant patients (RTPs), with clinically significant CsA-induced gingival overgrowth, after their immunosuppressive therapy was switched to tacrolimus. Methods: Intra-oral photographs and alginate impressions were taken both prior to the drug conversion and again, 6 to 9 months later. Gingival overgrowth scores were determined, from plaster models on both these occasions. Results: All of the RTPs experienced significant resolution of their gingival enlargement within the time period studied; however, only one had complete regression. Conclusion: It is concluded that conversion of RTPs with gingival overgrowth from CsA to tacrolimus may provide an effective management strategy for this clinical problem.
Disfiguring overgrowth of the gingival tissues occurs frequently in organ transplant recipients immunosuppressed with the endecapeptide, cyclosporin A (CsA) (Hassell & Hefti 1991). The reported prevalence of overgrowth resulting from monotherapy with CsA varies between 8 and 81% (Laupacis 1983, Friskopp & Klintmalm 1986). In one well controlled investigation the overall prevalence was reported to be 21% (Hefti et al. 1994). Recent reports show that the prevalence and severity of gingival overgrowth (GOG) is increased when individuals taking CsA are concomitantly treated with a calcium chan-
nel blocking agent (Thomason et al. 1993, Spratt et al. 1999). These drugs are prescribed to alleviate the hypertension associated with CsA-induced nephrotoxicity. CsA-induced GOG may be so severe that it interferes with normal oral function and can cause profound psychological problems for those affected. Despite gingival surgery and post-operative hygienist support recurrence is often inevitable. Cessation of drug therapy is not a clinical option, as organ transplant recipients must be treated with some form of immunosuppressant in order to maintain graft function.
Key words: gingival overgrowth; cyclosporin A; tacrolimus Accepted for publication 19 March 1999
Tacrolimus or FK506, is a macrolide molecule which has been shown to have major potential as an alternative immunosuppressant to CsA. Over the last decade it has been used successfully to prevent renal (Pirsch et al. 1997), liver (Cox & Fresse 1996) and cardiac (Pham et al. 1996) allograft rejection. Tacrolimus and CsA have been associated with several similar side effects including nephrotoxicity, neurotoxicity and the induction of a diabetic state. Although there have been case reports linking tacrolimus with GOG (Adams & Famili 1991), most clinical trials investigating the effectiveness of tacrol-
Tacrolimus and gingival overgrowth imus after cadaveric organ transplantation suggest the immunosuppressant does not cause gingival overgrowth. Recently, there have been qualitative accounts of rapid resolution of gingival enlargement, within a period of a few months, following conversion of renal transplant recipients (RTPs) from CsA to tacrolimus (Dodd 1997, Bader et al. 1998, Busque et al. 1998). However, it remains unclear whether there is resolution in all RTPs changing from CsA particularly those with severe, well-established fibrous GOG. It remains difficult therefore to give both affected patients and their physicians evidencebased advice on the likely gingival changes resulting from switching to tacrolimus. The purpose of the present report was to quantify the short-term effects of the conversion from CsA to tacrolimus in four RTPs with clinically significant GOG and to assess the benefit of this approach in the management of fibrous GOG-induced by CsA. Case Reports Patient no. 1
A 24-year-old female RTP was reviewed over an 8-month period in the Periodontal Department, School of Clinical Dentistry, Queen’s University Belfast. The patient received a cadaveric renal allograft in 1994 and had subsequently maintained satisfactory graft function. At initial dental assessment in January 1998 the patient had generalised moderate gingival overgrowth. Medication comprised CsA (100 mg b.d.), amlodip-
ine (10 mg/ day), prednisolone (5 mg alt days). The patient was distressed about the appearance of her gums. Intra-oral photographs and alginate impressions of both arches were taken for clinical records (Fig. 1). The patient was switched from CsA to tacrolimus (5 mg bd) in February 1998 with no change in other medication. During the following 6 months, the patient received hygienist support and throughout maintained excellent oral hygiene. At review in August 1998 her dose of tacrolimus had been reduced to 3 mg b.d., amlodipine had been reduced to 5 mg/day with no change in prednisolone dose. Although there was reduction in the severity of gingival overgrowth over the 6-month period some residual swelling was present (Fig. 2). However, the patient was satisfied with the appearance of her gingivae and did not want to undergo surgical treatment. The patient remains under review and her gingival swelling is continuing to resolve, albeit slowly. Patient no. 2
In February 1998 a 16-year-old male RTP attended the Periodontal Department, School of Clinical Dentistry, Queen’s University Belfast for an initial dental assessment. The patient had received a cadaveric kidney transplant in May 1994. Medication comprised CsA 150 mg bd, nifedipine 20 mg/ day, prednisolone 5 mg alt days. Clinical examination showed generalised, moderately severe fibrous overgrowth of the gingival tissues, which in localised
Fig. 1. Plaster model demonstrating moderate CsA-induced GOG in the lower anterior labial region at initial examination of patient no. 1.
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areas was interfering with mastication and occlusion. Intra-oral photographs and alginate impressions were taken for clinical records. The patient was switched to tacrolimus (9 mg/day) in February 1998 with no change in other medication. Over a 9-month period he had hygiene phase therapy but despite oral hygiene instruction his plaque control remained poor. His treatment was complicated by his delayed development and his mental age of 7 or 8 years. At review in November 1998 the only change in his medication was a reduction in tacrolimus dose to 8 mg/ day. Clinical photographs and alginate impressions were recorded. The GOG had improved, particularly where there had been localised sites of severe gingival swelling; however, it had not completely regressed within the nine month period. Patient no. 3
In January 1998 a 53-year-old female RTP underwent a dental examination at the Renal Transplant Clinic, Manchester Royal Infirmary. She had received a cadaveric kidney transplant in 1990, which was functioning satisfactorily. Medication comprised CsA (175 mg/ day), atenolol (100 mg/day), frusemide (80 mg/day) and allopurinol (100 mg/ day). She presented with generalised moderate gingival overgrowth and was very concerned about the appearance of her gums. She had previously undergone repeated periodontal surgery (6 ¿) to reduce generalised gingival en-
Fig. 2. Plaster model demonstrating partial regression of GOG in the lower anterior labial region for patient 1, 6 months following the switch from CsA to tacrolimus.
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Fig. 3. Clinical photographs showing mild CsA-induced GOG for patient no. 4 at initial presentation. Note the prominent papillary hyperplasia of the hard palate.
Fig. 4. Clinical photographs of the same patient, 9 months following change in immunosuppressive therapy to tacrolimus. Note the regression of GOG particularly in the lower anterior labial gingiva but the persistence of the papillary hyperplasia on the hard palate.
largement, however, the overgrowth had always recurred within a few months. Intra-oral photographs and alginate impressions were taken for clinical records. The patient was switched the same day to tacrolimus (8 mg bd) with no change in other medication. At review 9 months later, her dose of tacrolimus had been reduced to 1mg bd and the only other change was the addition of calciferol (0.25 mg/day). The patient was delighted that her gingival overgrowth had regressed to what she called ‘normal gums’! However, she had noticed that her hair was not as thick as it had been prior to starting the CsA therapy after transplantation in 1990. Patient no. 4
In February 1998, a 44-year-old male RTP was seen in the Unit of Periodontics, Turner Dental School, Uni-
versity of Manchester. Clinical examination showed marked generalised gingival overgrowth with multiple papillary nodules, of various sizes, on the hard and soft palate. The largest nodule was approximately 10 mm in diameter. The patient had received a cadaveric kidney transplant in December 1990 and was medicated with CsA (400 mg/day), nifedipine (40 mg/day), prednisolone (8 mg/day), atenolol (25 mg/ day) and ranitidine (150 mg/day). He also had a history of smoking 20 cigarettes per day for nearly 30 years. Intraoral photographs and dental impressions were recorded (Figs. 3). The patient was switched to tacrolimus (20 mg/day) within one week, with no change in other medication. The patient regularly attended his own general dental practitioner and was reviewed in the Periodontal Clinic eight months later. At review his dose of tacrolimus had
been reduced to 8 mg/day, however, his other medication remained unchanged. The patient was satisfied that his gingival swelling had decreased to an acceptable level aesthetically but was still aware that some nodules remained on his palate. During the 8-month interval the patient had continued to smoke (20 cigarettes/day) despite advice to stop. Intra-oral photographs and alginate impressions were taken for follow-up records (Figs. 4). Assessment of gingival overgrowth
The extent and severity of gingival overgrowth for each of the four RTPs was scored on plaster models using an expanded version of the gingival overgrowth index developed by Seymour et al. (1985) and described previously by Thomason et al. (1996). Briefly, each interdental papilla, either buccal or pala-
Tacrolimus and gingival overgrowth Table 1. Mean overgrowth scores for the 4 RTPs studied. Scores were measured prior to (initial) and 6–9 months after (final) switching to tacrolimus Patient no.
Sex
Age (years)
Initial score
Final score
% reduction
1 2 3 4
F M F M
24 16 53 44
2.5 3.94 3.10 2.96
1.81 2.96 0.55 1.13
27.8 24.9 82.3 61.8
tal/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 buccopalatally/lingually (score 0–2). The maximum score for each papilla was 5. A mean overgrowth score was calculated for all the papillae. The models were scored by one investigator (JJ). Results
There was a reduction in overgrowth in the four RTPs who switched from CsA to tacrolimus. The decrease in mean overgrowth scores ranged from 24.9% to 82.3% (Table 1). Discussion
Within the 6- to 9-month study period, all of the patients experienced reduction in the severity of gingival overgrowth following conversion from CsA to tacrolimus. Although all of the patients reported improvement to an acceptable level, three had some residual enlargement. Only one patient reported a return to normal evidenced by a reduction of greater than 80% in the severity of gingival overgrowth which was equated with complete regression. These results support the view that switching to tacrolimus may be beneficial in the management of severe GOG related to the use of CsA. 2 of the patients had professional cleaning and instruction in oral hygiene during the study period. Improvements in gingival health may have contributed to the reduction in gingival overgrowth in these cases. Somacerra et al. (1997) reported a mean reduction of 12% in GOG as a result of professional
cleaning. In the present study the patients who had hygiene phase treatment were those who had the least favourable response to tacrolimus with reductions in GOG of only 25% and 28%. The lack of complete regression in 3 of the RTPs studied may be due to a number of factors. The study was short-term being limited to between 6 and 9 months. Within this time frame it may not be possible for physiological remodelling, with breakdown of large numbers of extracellular matrix macromolecules, to restore clinically normal gingival architecture in all cases of well established fibrous overgrowth. Indeed this may never happen and in such cases periodontal surgery may be required to restore normal gingival contour. However, for many patients a reduction in swelling may result in acceptable aesthetic and functional outcomes. This was the case for the 4 patients in the present study. The patient who experienced complete regression did not take a calcium channel blocker in addition to her immunosuppressive therapy. GOG has been associated with calcium channel blockers, particularly nifedipine and amlodipine. In addition, research has shown that patients treated with the combination of CsA and a calcium channel blocker have an increased prevalence and severity of gingival overgrowth (Thomason et al. 1993, Spratt et al. 1999). It may be that the persistence of overgrowth in 3 out of the 4 RTPs in the present study resulted from the continued use of calcium channel blocking agents over the study period to relieve hypertension. Clinical trials which have compared CsA with tacrolimus in the management of allograft rejection have reported inconsistent results in relation to the occurrence of GOG in patients treated with tacrolimus. GOG was not found in tacrolimus treated liver transplant patients (Cox & Freese 1996) or paediatric heart transplant patients (Asante-Korang et al. 1996). In contrast, other studies have reported GOG
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in organ transplant patients taking tacrolimus, albeit less frequently than in comparable patients taking CsA (Spencer et al. 1997). It is interesting to note that these latter studies failed to comment whether those with GOG were concomitantly prescribed a calcium channel blocking agent in addition to tacrolimus. In a recent health-related quality of life assessment of RTPs taking either tacrolimus or CsA, it was found using an appearance scale to measure side effects such as GOG, that the results favoured the use of tacrolimus (Shield et al. 1997). Taken together these findings support the view that tacrolimus has substantially less association with GOG than CsA. There is a need for a prospective clinical study detailing the changes in the gingival health of patients which result from treatment with tacrolimus. All the RTPs investigated in this report maintained stable kidney function. This was an important clinical factor supporting the use of tacrolimus as a safe and effective alternative to CsA for primary immunosuppression in RTPs. Previous related research has demonstrated that tacrolimus is capable of reducing the incidence and severity of acute kidney rejection episodes leading to its increased use in organ transplantation (Pirsch et al. 1997). However, studies comparing tacrolimus and CsA have shown that both drugs produce significant adverse effects. For example, CsA is associated with nephrotoxicity, hepatotoxicity, hypertrichosis, lymphoma, fibrosis of pulmonary, pericardial and renal tissues and GOG (Pirsch et al. 1997). Tacrolimus is commonly associated with a high incidence of neurologic events such as tremor and paraesthesia, post transplantation diabetes mellitus, gastro-intestinal disorders, pruritus and alopecia (Pirsch et al. 1997). In the present short-term investigation three of the patients had no significant clinical problems associated with tacrolimus therapy. Unfortunately the lady who experienced almost complete resolution of her GOG was affected by excessive hair loss. She had previously suffered from hypertrichosis whilst on CsA therapy. This hair loss, which is currently being monitored by her renal physician, emphasises that conversion to tacrolimus may not be suitable for all patients requiring immunosuppression. In a related study patients switched from CsA to tacrolimus did not resolve all pre-existing
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side-effects such as nephrotoxicity, hypertension and hyperlipidemia despite graft function remaining stable (Pratschke et al. 1997). It is concluded from the results of this preliminary study that conversion to tacrolimus may be beneficial for suitable patients with marked GOG related to immunosuppressive therapy with CsA. However, in the short-term at least, while the use of tacrolimus may be associated with a substantial reduction in the severity of gingival overgrowth it may only be in a minority of cases that there will be almost complete regression. Longer longitudinal clinical trials are indicated to establish the benefits for patients with established GOG of switching from CsA to tacrolimus. Zusammenfassung Reduktion der gingivalen Wucherung durch Medikationsa¨nderung von Cyclosporin A zu Tacrolimus Unansehnliche gingivale Wucherungen betreffen viele Personen, deren Immunsystem mit Cyclosporin A (CsA) supprimiert wird. Das gegenwa¨rtige Management schließt wiederholte parodontale und intensive Hygieneunterstu¨tzung ein. Tacrolimus ist ein effektives alternatives Immunsuppressivum fu¨r Nierentransplantationen, das keine gingivale Wucherungen zu verursachen scheint. Der Zweck der vorliegenden Studie war es, die gingivale Reaktion bei 4 nierentransplantierten Patienten (RTPs) mit klinisch signifikanten CsA-induzierten gingivalen Wucherungen zu beobachten, nachdem ihre immunsuppressive Therapie zu Tacrolimus gewechselt wurde. Intraorale Fotos und Alginatabformungen wurden vor der Medikationsa¨nderung und 6 bis 9 Monate spa¨ter vorgenommen. Die gingivalen Wucherungswerte wurden von Gipsmodellen an allen diesen Gelegenheiten bestimmt. Alle RTPs zeigten eine signifikante Verringerung ihrer gingivalen Wucherungen innerhalb der Zeit dieser Studie, jedoch nur 1 Patient hatte eine komplette Regression. Es wird geschlossen, daß die Medikationsa¨nderung von CsA zu Tacrolimus bei RTPs mit gingivalen Wucherungen eine effektive Strategie fu¨r dieses klinische Problem unterstu¨tzen kann.
Re´sume´ Re´duction de l’hypertrophie gingivale lors de la substitution de la ciclosporine A par le tacrolimus Beaucoup de sujets en immunosuppression par la ciclosporine A (CsA) souffrent d’hypertrophies gingivales (GOG) inesthe´tiques. Le traitement employe´ actuellement comporte des interventions de chirurgie parodontale re´pe´te´es et un traitement de soutien intensif par hygie´niste. Le tacrolimus est un agent im-
munosuppresseur pouvant servir d’alternative efficace lors des transplantations re´nales, et il ne semble pas produire d’hypertrophie gingivale. La pre´sente e´tude se proposait de surveiller chez 4 patients transplante´s re´naux (RTP) pre´sentant des signes cliniques significatifs d’hypertrophie gingivale due a` la CsA, la re´ponse gingivale apre`s substitution de cet immunosupresseur par le tacrolimus. Des photographies endo-buccales et des empreintes a` l’alginate ont e´te´ pratique´es avant le changement de me´dicament, et de nouveau 6 a` 9 mois plus tard. Les scores de l’hypertrophie gingivale ont e´te´ de´termine´s a` partir des mode`les de plaˆtre a` ces deux occasions. Chez tous les RTP on constatait une re´solution significative de l’hypertrophie gingivale au cours de la pe´riode e´tudie´e, mais une re´gression comple`te n’a e´te´ atteinte que chez un seul d’entre eux. En conclusion, la substitution de la CsA par le tacrolimus chez les RTP atteints d’hypertrophie gingivale pourrait repre´senter une strate´gie efficace pour re´soudre ce proble`me clinique.
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