Cyclosporine A-induced gingival hyperplasia pemphigus vulgaris: literature review and report of a case

Gingival hyperplasia appears in 8% to 85% of patients treated with cyclosporine. Most studies show an association between oral hygiene status and the prevalence and severity of this gingival overgrowth. Thus, besides attempting to substitute this drug with another whenever possible, treatment usually involves maintenance of strict oral hygiene coupled with scaling and root planing and removal of iatrogenic factors. Sometimes a second treatment phase involving periodontal surgery is necessary. Cyclosporine-induced gingival overgrowth has been mainly described in post-organ transplant patients. The present case describes, for the first time, a severe form of cyclosporine-induced gingival overgrowth arising in a 15 year-old male with pemphigus vulgaris. Periodontal treatment included oral hygiene and scaling and root planing under local anesthesia. There was a significant reduction in gingival enlargement, as well as a reduction in plaque levels and inflammation. Cessation of drug administration, combined with continuous periodontal treatment, brought further improvement. This successful conservative treatment of cyclosporine-induced gingival overgrowth in a pemphigus vulgaris patient suggests that early diagnosis and comprehensive treatment of these lesions may yield good response and reduce the need for periodontal surgery.     

Incidence and severity of phenytoin-induced gingival overgrowth in epileptic patients in General Medical Practice

This investigation examines the incidence of phenytoin-induced gingival overgrowth in a population of epileptic patients who attend General Medical Practices for treatment of their epilepsy and compares the gingival changes with an otherwise healthy group of patients. The plaque score, gingival index, and gingival overgrowth did not differ significantly between the two groups (P > 0.05). A significant correlation was observed between plaque score and gingival overgrowth in the phenytoin-treated patient, but in this group there was no correlation between gingival overgrowth and salivary concentration of the drug. The overall incidence of clinically significant overgrowth (13%) is considerably less than in other studies.     

Risk factors conditioning the incidence and severity of cyclosporine A-induced gingival overgrowth and methods of prevention

Cyclosporin A (CsA) induced gingival overgrowth is one of the major side-effects conditioning the quality of life of the patient under immunosuppressive therapy. This adverse effect has been first reported in 1983 and affects almost 30% of treated patients. Several papers have been published concerning the cellular/molecular mechanisms by which CsA may induce, at the same time, an immunosuppressive and proliferative action. In this review various factors concerning the patient and his milieu that account for the different prevalence of the severity of gingival overgrowth in clinical studies are analyzed and briefly discussed. In particular, age, sex, pharmacokinetic properties, pharmaceutical preparation, genetic predisposition, association with other drugs and the parodontal conditions before transplantation are considered. In addition, a unique approach to the patients with gingival overgrowth as well as effective methods of prevention and therapy are suggested.     

Tacrolimus is not associated with gingival overgrowth in renal transplant patients

BACKGROUND: Cyclosporin A is used extensively to prevent the rejection of allogenic renal transplants. However, it is associated with a variety of undesirable side effects including gingival overgrowth. Tacrolimus (FK506), has been marketed as an effective alternative immunosuppressant to cyclosporin A and recent subjective reports suggest patients taking it complain infrequently of gingival problems. This clinical investigation was undertaken to confirm whether or not tacrolimus adversely affected the gingival health of renal transplant recipients. METHODS: Renal transplant patients (RTPs) under the care of the Renal Transplantation Service at the Manchester Royal Infirmary, who had received a renal allograft at least 18 months earlier, were recruited for this study. All but one of the RTPs had been taking tacrolimus since transplantation. The other had commenced tacrolimus therapy two months after receiving her allograft. A hospital based control group was recruited from non transplanted individuals attending the Turner Dental School, Manchester. Each patient underwent a detailed dental assessment and had dental impressions taken. The extent of gingival overgrowth was determined from plaster models. RESULTS: 25 renal transplant recipients and 26 control patients were included in the study. None of the individuals in either the tacrolimus or control groups had clinically significant overgrowth. The patients in the tacrolimus group with the highest overgrowth scores were those also taking calcium antagonists as treatment for hypertension. CONCLUSION: This study demonstrates that tacrolimus has no adverse effects on the gingival tissues and thus has potential as an alternative immunosuppressant for individuals susceptible to developing cyclosporin A-induced gingival overgrowth.     

Relationship between IL-1A polymorphisms and gingival overgrowth in renal transplant recipients receiving Cyclosporin A

AIM: Levels of interleukin-1alpha (IL-1alpha) are elevated in periodontal inflammation. IL-1A gene polymorphisms are associated with inflammatory diseases. This study aimed to investigate IL-1A gene polymorphism in Cyclosporin A (CsA)-treated renal transplant patients and investigate the association between this polymorphism and gingival crevicular fluid (GCF) levels of several cytokines. MATERIALS AND METHODS: Fifty-one renal transplant patients on CsA treatment (25 with and 26 without gingival overgrowth) and 29 healthy controls were recruited for the study. Demographic, pharmacological and periodontal parameters were recorded and gingival overgrowth was assessed. RESULTS: Multiple regression analysis showed that genotype was significantly associated with gingival overgrowth (p=0.02). Carriage of the IL-1A (-889) T allele was strongly protective [95% confidence interval (CI): 0.046-0.77], although not significantly associated with IL-1alpha protein levels in GCF. IL-1alpha, IL-1beta and IL-8, but not IL-6, were detected in GCF of CsA-treated patients, but none of them was significantly associated with gingival overgrowth. CONCLUSIONS: This study is the first to associate a gene polymorphism as a risk factor for CsA-induced gingival overgrowth in renal transplant patients, demonstrating that IL-1A polymorphism might alter individual susceptibility to CsA. However, there was no association between GCF cytokine levels and the presence of gingival overgrowth or patient IL-1A genotype.     

Photographic scoring of gingival overgrowth

BACKGROUND: A wide range of methods have been employed to determine the severity of gingival overgrowth resulting in uncertainty regarding the prevalence of the side-effect. There is no simple, non-invasive, objective, blind method for assessing gingival overgrowth. AIM: This article aims to describe a method which is suitable for use in large-scale population studies. MATERIALS AND METHODS: Photographs were taken of the anterior, buccal gingivae and teeth of 925 patients medicated with calcium channel blockers. In addition, each patient was ascribed a clinical gingival overgrowth score. 100 patients had repeat photographs, and a further 10 patients had alginate impressions taken. The models were scored for severity of gingival overgrowth using a described technique. The slides were scored using a modification of this technique. RESULTS: When photographic and study model scores were compared, photographic scores were consistently higher, and as a result, a photographic score of 38.6% was considered to represent a significant overgrowth. There was good agreement between clinically determined scores and photographic scores (kappa=0.71). CONCLUSIONS: The results indicate that this method is suitable for large-scale population studies where it also has the advantage of providing a continuous scale of gingival changes for subsequent statistical analysis.     

Plasma TGF-beta1 as a risk factor for gingival overgrowth

BACKGROUND AND AIMS: Induction of the pro-fibrotic growth factor TGF-beta1 has been suggested as a possible mechanism through which immunosuppressant drugs may induce gingival overgrowth. This study aims to investigate plasma levels of TGF-beta1 and relate them to the development and severity of gingival overgrowth in immunosuppressed transplant patients. MATERIALS AND METHODS: One hundred and thirty-two ciclosporin-treated and 13 tacrolimus-treated transplant patients and 24 drug-free control subjects underwent a full periodontal examination including a determination of the presence and severity of gingival overgrowth. RESULTS: Plasma TGF-beta1 concentrations were determined by ELISA, and were found to be significantly elevated in samples from the transplant patients (mean=29.1 ng/ml) as compared with controls (mean=6.1 ng/ml, p<0.0001). There was no significant difference between the levels of plasma TGF-beta1 in the ciclosporin- and tacrolimus-treated patient groups. CONCLUSIONS: Furthermore, concomitant treatment with calcium channel blockers did not influence the levels of plasma TGF-beta1 in the patients group. The relationship between gingival overgrowth, independent periodontal variables and TGF-beta1 plasma concentrations was examined using univariate and multivariate regression analyses; low TGF-beta1 plasma concentrations were found to be a risk factor for gingival overgrowth in immunosuppressed patients concomitantly receiving a calcium channel blocker.     

Primary gingival pseudoepitheliomatous hyperplasia with periodontal findings: a rare case report

Background: This paper is the first‐ever report, to our knowledge, of a case of generalized primary gingival pseudoepitheliomatous hyperplasia(PEH) with significant periodontal findings in a 23‐year‐old Indian female patient. It explains the need to differentiate PEH from squamous cell carcinoma in diagnosis and treatment planning. The present article also reviews current immunohistologic staining methods used to differentiate PEH from squamous cell carcinoma. Methods: A two‐stage surgical approach was used to eliminate the lesion by gingivectomy and gingivoplasty under local anesthesia. Histopathologic examination of excised tissue was done to differentiate it from squamous cell carcinoma. Results: After 1‐year follow‐up, there was uneventful gingival healing and no recurrence of the lesion. Conclusions: Differentiation of PEH from squamous cell carcinoma of the gingiva is important for diagnosis and treatment. It is also important to consider PEH as a rare condition of gingival overgrowth.     

The effect of a plaque control program on the development of phenytoin-induced gingival overgrowth

The effect of a plaque control program on the development of phenytoin(PHT)-induced gingival overgrowth was studied in 16 epileptic children, 8-16 years of age during a 2-year longitudinal study. The parameters studied were: visible plaque index (VPI), gingival bleeding index (GBI), probing depth and gingival overgrowth. A preventive program was instituted before the start of the PHT-medication and included oral hygiene instruction and frequent professional tooth cleaning during the observation period. When gingival overgrowth was evaluated on the basis of probing depth, no patients on PHT therapy for 2 years developed pseudopockets (greater than or equal to 4 mm). During the 2-year observation period, there was a statistically significant increase (p less than 0.01) in the thickness of the marginal gingiva bucco-lingually in all patients. This gingival enlargement was already evident (p less than 0.01) after 1 month. The degree of gingival enlargement in this patient group did not increase significantly after the 1st year of PHT-medication and was not significantly correlated to the plasma concentration of PHT. The results of this study show that the development of PHT-induced gingival overgrowth could not be prevented by this specific plaque control program.     

Treatment of gingival overgrowth induced by manidipine administration. A case report

BACKGROUND: It is well known that severe gingival overgrowth (GO) is induced in patients taking certain calcium channel blockers (CCB) for the treatment of hypertension, angina pectoris, and other diseases. No case has been reported to date of severe GO induced by manidipine hydrochloride (manidipine), a second generation CCB. This case report describes severe GO induced by manidipine in a female patient (43 years old) with hypertension and Sj?gren syndrome (SS). The patient was administered manidipine and carteolol hydrochloride (carteolol) as antihypertensive drugs, together with bromhexine hydrochloride for the treatment of SS. METHODS: At the initial periodontal examination, probing depth (PD, average 4.83 mm), plaque control record (PCR, 84.3%), bleeding on probing (BOP, 100%), and gingival overgrowth index (GOI, 2.42) were assessed. The patient received periodontal treatment without cessation or replacement of the causative drug. Initial treatment included oral hygiene and scaling and root planing (SRP) under local anesthesia. As corrective therapy, remaining pockets were surgically removed and fixed bridges placed to establish proper occlusion. RESULTS: Obvious reductions in PCR (10.0%), PD (1.93 mm), GOI (0.02), and BOP (4.7%), together with a disappearance of GO, were obtained. Salivary secretion was increased after the periodontal and prosthetic treatments. Histological features were similar to those of nifedipine-induced GO. CONCLUSIONS: This case indicated that manidipine may act as a potent inducer of severe GO, and that conventional periodontal treatments without a major change of the causative drugs can yield satisfactory clinical responses.     

Vigabatrin-induced gingival overgrowth

Abstract Vigabatrin is a relatively new medication used in the treatment of epilepsia. The present report concerns the use of vigabatrin by a 19-year-old woman. The patient manifested marked gingival overgrowth compatible clinically and histologically with the overgrowth induced by phenytoin, cyclosporine and calcium channel blockers. This is the 1st report of vigabatrin-induced gingival overgrowth. Clinicians should be aware of similar lesions in patients using new anticonvulsants.     

An investigation into the need for supplementary steroids in organ transplant patients undergoing gingival surgery

Organ transplant patients are frequently medicated with triple immunosuppressive therapy that includes both cyclosporin and the corticosteroid, prednisolone. Many of these patients experience gingival overgrowth that necessitates surgical intervention. Chronic dosing with corticosteroids can lead to suppression of the hypothalamic-pituitary axis, and subsequent adrenocortical suppression. To circumvent possible suppression, supplementary steroids are administered to such patients prior to so-called "stressful events". We have examined the need for supplementary steroids in 20 organ transplant patients undergoing gingival surgery under local anaesthesia to correct their drug-induced gingival overgrowth. All patients were operated upon in the first half of the morning. Prior to gingival surgery, resting blood pressure (BP) and serum ACTH concentrations were determined. Immediately before surgery patients received either intravenous hydrocortisone 100 mg or placebo in random, double-blind order. Each patient required 2 gingivectomies and thus acted as their own placebo control. BP was measured at various time points throughout surgery and upto 2 h postoperatively. On completion of surgery, a further blood sample was taken to determine ACTH concentration. There was no significant difference (p>0.05) between placebo and hydrocortisone treatments for BP and ACTH measurements. No patient experienced any symptoms that were suggestive of adrenocortical suppression. One patient did experience postural hypotension prior to gingival surgery, but this is attributed to his antidepressant medication. We can conclude from this study that immunosuppressed organ transplant patients taking the maintenance dose of prednisolone (5-10 mg/day) do not require corticosteroid cover prior to gingival surgery under local anaesthesia. We would however, advocate monitoring of their blood pressure throughout the procedure.     

Combined treatment approach of gingivectomy and CO2 laser for cyclosporine-induced gingival overgrowth.

The aim of this report is to present a combined treatment approach with gingivectomy and CO2 laser for the management of cyclosporine-induced gingival overgrowth in 4 cases. Four renal transplant patients were surgically treated for marked gingival overgrowth by means of gingivectomy and CO2 laser. Postoperatively, all patients were followed for bleeding, pain, infection during the early healing period, and recurrence of gingival overgrowth for 12 months. The healing was uneventful, and no signs of bleeding, postoperative pain, or infection were observed in any patient during the early healing period. In the 12th postoperative month, there was evidence of mild recurrence in 1 patient, while no sign of recurrence was observed in the other patients during the follow-up period. The advantages of this combined technique include satisfactory bleeding control and clear visibility during the procedure, as well as reduced postoperative pain and swelling.     

Hereditary gingival fibromatosis: a case report

BACKGROUND/AIMS: Hereditary gingival fibromatosis is characterized by various degrees of attached gingival overgrowth. It usually develops as an isolated disorder but can be one feature of a syndrome. A case of a 38-year-old female is reported who presented a generalized severe gingival overgrowth, involving the maxillary and mandibular arches and covering almost all teeth. The clinical differential diagnosis included drug-induced overgrowth as well as idiopathic gingival fibromatosis. TREATMENT: Excess gingival tissue was removed by conventional gingivectomy. As the gingival enlargement was generalized to all quadrants, on both sides, the surgery was carried out under general anaesthesia. The postoperative course was uneventful and the patient's appearance improved considerably. Post-surgical follow-up after 20 months demonstrated a slight recurrence CONCLUSIONS: Hereditary gingival fibromatosis is a rare disorder characterized by the proliferative fibrous overgrowth of the gingival tissue. Resective surgery of the excess tissue is the treatment available. However, recurrence is a common feature.     

Periodontal variables affecting nifedipine sequestration in gingival crevicular fluid

We previously demonstrated the sequestration of nifedipine in gingival crevicular fluid (GCF), especially in patients exhibiting significant gingival overgrowth. The aim of the present study is to determine the role of site specific periodontal factors in this phenomenon. 10 adult patients exhibiting nifedipine induced gingival overgrowth were studied. In each patient GCF was harvested from two sites that demonstrated inflammation and increased probing depth as well as from two clinically healthy sites. The concentration of nifedipine was determined using gas chromatography. Drug concentrations were significantly increased in the presence of inflammation (p=0.004) and plaque (p=0.029) whilst increased probing depths and gingival overgrowth were not significantly related to drug sequestration. We can conclude that inflammatory changes in gingival tissues appear to be a significant determinant for the sequestration of nifedpine in the GCF.     

Diphenylhydantoin-induced gingival overgrowth in man: a clinico-pathological study

In a cross-sectional, epidemiological study of diphenylhydantoin-induced gingival overgrowth (DGO) in 60 epileptic patients, gingival lesion severity was statistically compared with other clinical, laboratory, and histopathological findings. Evident DGO was observed in 50% of patients, and positive correlations were detected between overgrowth severity and oral debris, calculus accumulation, plaque score, gingival inflammation, and probing depth. However, no valid correlation was observed between lesion and patient age, mouth breathing, daily drug dose, plasma diphenylhydantoin level, or duration of drug intake. Also, there were no significant correlations between connective fiber richness and the intensity of epithelial hyperplasia and severity of gingival overgrowth.     

Drug-induced gingival overgrowth: a case with auto-correction of incisor drifting.

Drug-induced gingival overgrowth is an iatrogenic clinical condition, which affects a proportion of patients medicated for conditions such as hypertension, epilepsy and the prevention of organ transplant rejection. Clinical manifestation can vary in severity from minor problems to complete coverage of the standing teeth. Drifting of teeth can also occur, producing further aesthetic and functional problems for the patient. This report documents a case of a renal transplant patient in whom drifting of the upper incisor teeth spontaneously resolved following surgical reduction of the overgrown gingivae. Clinical issues relating to the management of gingival overgrowth are also discussed.     

Disposition of nifedipine in plasma and gingival crevicular fluid in relation to drug-induced gingival overgrowth

The present study investigates the relationship between the pharmacokinetic variables of nifedipine with the incidence and severity of gingival overgrowth in 9 adult male patients medicated with the drug for at least 6 months. Five of the patients had experienced significant gingival changes and were thus designated "responders". The remaining four patients exhibited no gingival overgrowth, and thus acted as a control. A baseline periodontal examination (plaque scores, bleeding index and gingival overgrowth assessment) was carried out on each patient, and confined to the upper and lower anterior teeth. Serial blood and gingival crevicular fluid samples were collected over an eight-hour investigation period. Samples were analyzed for nifedipine by gas chromatography. No significant difference (p>0.05) was seen between responders and non-responders with regard to drug therapy, periodontal parameters or plasma pharmacokinetics of nifedipine. Nifedipine was detected in the gingival crevicular fluid of seven subjects (all responders, and two non-responders). The peak concentration of nifedipine in crevicular fluid was 15–90 fold greater than levels observed in plasma.     

Cyclosporin-induced gingival overgrowth: correlation with dental plaque scores, gingivitis scores, and cyclosporin levels in serum and saliva

Gingival overgrowth, dental plaque, and gingivitis were assessed by means of standardized semiquantitative indices in thirty renal transplant patients undergoing immunosuppression with cyclosporin-A (Cy-A). Radioimmunoassay techniques were used to determine Cy-A in serum samples and in parotid, submandibular, and whole saliva samples from each patient. A significant positive correlation was found between gingival overgrowth scores and both dental plaque and gingivitis scores. A significant positive correlation was found between whole-saliva Cy-A and both plaque and gingival overgrowth scores. No such correlation was found when parotid Cy-A or submandibular Cy-A was considered. This was attributed to differences in saliva-collection methods, and a possible role of dental plaque as a local reservoir of Cy-A is proposed.     

Crevicular fluid levels of TGFbeta1 in drug-induced gingival overgrowth

OBJECTIVE: To determine if local, gingival crevicular fluid (GCF) levels of TGFbeta1 were altered in drug-induced gingival overgrowth. Patients and methods: GCF samples were collected on Periopaper strips from 45 renal transplant recipients who had been medicated with cyclosporin or cyclosporin in combination with other putative overgrowth-inducing drugs for a minimum of 6 months. Twenty-two subjects had gingival overgrowth while the other 23 patients showed no signs of gingival changes and constituted the medicated control group. Non-medicated controls consisted 20 periodontally healthy individuals who had never taken overgrowth-inducing drugs. GCF levels of TGFbeta1 and alkaline phosphatase, a marker of inflammation, were determined by enhanced chemiluminescence ELISA and enzyme activity assays, respectively. RESULTS: TGFbeta1 levels in GCF from overgrowth and non-overgrowth sites in overgrowth sufferers did not differ. However, there were significant differences in median concentration (P = 0.001) and GCF levels of TGFbeta1 per sample (P = 0.05) between study groups with overgrowth patients having higher amounts per sample and lower concentrations than medicated and healthy controls. Median levels of alkaline phosphatase per GCF sample differed between site (P = 0.01) with higher levels present at overgrowth sites. Despite this, the concentration of enzyme in GCF did not differ between site or patient group. CONCLUSIONS: GCF TGFbeta1 detected in overgrowth patients could reflect a higher level of gingival inflammation because of difficulties in plaque control consequent on the development of overgrowth. However, the higher local levels of total TGFbeta1 in overgrowth patients could indicate that it is a risk factor for developing gingival overgrowth.