Role of Cyclosporine in Gingival Hyperplasia: An In Vitro Study on Gingival Fibroblasts.

BACKGROUND: Gingival hyperplasia could occur after the administration of cyclosporine A. Up to 90% of the patients submitted to immunosuppressant drugs have been reported to suffer from this side effect. The role of fibroblasts in gingival hyperplasia has been widely discussed by literature, showing contrasting results. In order to demonstrate the effect of cyclosporine A on the extracellular matrix component of fibroblasts, we investigated the gene expression profile of human fibroblasts after cyclosporine A administration. MATERIALS AND METHODS: Primary gingival fibroblasts were stimulated with 1000 ng/mL cyclosporine A solution for 16 h. Gene expression levels of 57 genes belonging to the "Extracellular Matrix and Adhesion Molecules" pathway were analyzed using real-time PCR in treated cells, compared to untreated cells used as control. RESULTS: Expression levels of different genes were significantly de-regulated. The gene CDH1, which codes for the cell adhesion protein E-cadherin, showed up-regulation. Almost all the extracellular matrix metalloproteases showed down-regulation (MMP8, MMP11, MMP15, MMP16, MMP24, MMP26). The administration of cyclosporine A was followed by down-regulation of other genes: COL7A1, the transmembrane receptors ITGB2 and ITGB4, and the basement membrane constituents LAMA2 and LAMB1. CONCLUSION: Data collected demonstrate that cyclosporine inhibits the secretion of matrix proteases, contributing to the accumulation of extracellular matrix components in the gingival connective tissue, causing gingival overgrowth. Patients affected by gingival overgrowth caused by cyclosporine A need to be further investigated in order to determine the role of this drug on fibroblasts.

Can chlorhexidine mouthwash twice daily ameliorate cyclosporine-induced gingival overgrowth?

BACKGROUND/PURPOSE: Gingival overgrowth can be induced in patients treated with cyclosporine-A (CsA), an immunosuppressant often used following organ transplantation. A pre-existing rat model designed to mimic CsA-induced gingival overgrowth in humans was used to test the effectiveness of frequent application of a chlorhexidine antiplaque solution in reducing the overgrowth. METHODS: Four groups of rats were fed CsA. One group received chlorhexidine mouthwash twice a day, the second group received chlorhexidine mouthwash once a day, the third group received chlorhexidine mouthwash every other day, and the fourth group did not receive chlorhexidine mouthwash all. A fifth negative control group received only mineral oil. Overgrowth was determined by measuring the changes in the gingival probing depth and the keratinized gingival width on molars. A gingival histological examination was performed. RESULTS: Rats treated with mouthwash twice daily exhibited decreased probing depths and gingival widths without statistical significance. Histological examination revealed that CsA treatment caused gingival enlargement, whereas chlorhexidine treatment twice a day diminished the enlargement. CONCLUSION: These findings suggest that chlorhexidine mouthwash used twice daily may reduce the severity of CsA-induced gingival overgrowth. Further research is warranted to determine the optimal dose and treatment regimen.

Conversion to tacrolimus once-daily from ciclosporin in stable kidney transplant recipients: a multicenter study.

This 24-week, open, single-arm, prospective, multicenter study evaluated the effects of conversion from ciclosporin to Tacrolimus QD in adult kidney transplant patients. Stable patients receiving ciclosporin were converted to Tacrolimus QD at 0.1mg/kg/day. Relative change in renal function (primary endpoint) was assessed using estimated creatinine clearance (eCrCl) with a noninferiority margin set at -10%. A total of 346 patients were enrolled; and 301 patients were treated per protocol (PPS) in the hyperlipidemia (n=42), hypertrichosis (n=106), hypertension (n=77) and gingival hyperplasia (n=76) groups. Relative change in eCrCl was -0.6% in all PPS patients (95% CI, -2.2; 0.9) and -5.3% in the hyperlipidemia (CI, -9.59; -0.97), 0.9% in the hypertrichosis (CI, -2.59; 4.45), -0.1% in the hypertension (CI, -3.8; 3.68), and -1% in the gingival hyperplasia groups (CI, -4.63; 2.65) (PPS), meeting noninferiority criteria. There was no acute rejection. Decreases in serum lipids and blood pressure were moderate but without meaningful change in the number of treatment medications. Substantial decreases in severity of ciclosporin-related cosmetic side effects were evident from investigator and patient self-report of symptoms. Renal function remained stable after conversion to Tacrolimus QD. The effect of conversion on cardiovascular parameters was not clinically meaningful, however, marked improvement in ciclosporin-related cosmetic side effects was observed. (ClinicalTrials.gov number: NCT00481481).

Cyclosporine A-Induced Conchal Hyperplasia with Nasal Obstruction in a Patient with Membranous Nephropathy.

BACKGROUND The immunomodulatory and pharmacokinetic effects of cyclosporine A are used to treat diverse disease entities in different medical fields, including organ transplantation and/or autoimmune diseases. It is also applied in patients with nephrotic range proteinuria as an adjunct to steroids and supportive antihypertensive/antiproteinuric medications. Cyclosporine has a small therapeutic window and is dosed with respect to the underlying disease entity and severity via trough level adaptations. Among its most frequent adverse effects are hypertension, nephrotoxicity, neurotoxicity, and electrolyte disturbances. Hypertrichosis and gingival hyperplasia are obvious and widely recognized adverse effects. CASE REPORT We report on a 66-year-old woman who was treated with cyclosporine A for primary membranous nephropathy. During treatment with cyclosporine, she developed hirsutism and gingival hyperplasia. Later, she reported having impaired nasal breathing and dyspnea on mild physical exercise. Clinical, rhinoscopic, and radiological evaluations showed marked conchal hyperplasia as a potential cause of her symptoms. An extensive medical work-up did not show evidence of allergic, immunologic, or other drug adverse effects, suggesting cyclosporine-induced hyperplasia of the turbinates as a hypothetical causative factor. Dose reductions did not lead to resolution of symptoms but resulted in increasing proteinuria. Therefore, cyclosporine was stopped, and the patient was treated with rituximab. Thereafter, hirsutism and gingival and conchal hyperplasia gradually regressed over 2-4 months, showing complete resolution of conchal hyperplasia on computed-tomography follow-up after 6 months. CONCLUSIONS Cyclosporine can not only result in gingival hyperplasia but also in hyperplasia of the turbinates leading to impaired nasal breathing and shortness of breath on exertion. An extensive search for many other known causes of conchal swelling is warranted to finally suggest an adverse effect of cyclosporine. Discontinuation of cyclosporine resulted in complete remission of conchal hyperplasia as well as other adverse effects.

Lamotrigine-Induced Gingival Enlargement: An Older Problem Due to a Newer Drug - A Rare Case Report.

INTRODUCTION: Gingival enlargement (GE) due to anti-epileptic drugs (AEDs) shows a high prevalence rate. However, lamotrigine, a newer AED, has not shown to induce GE. The present case report describes a rare case of GE in a patient with epilepsy under lamotrigine therapy for the past 3 years. CASE PRESENTATION: In this report, successful management of lamotrigine-influenced GE in a 24-year-old patient with epilepsy by gingivectomy followed by stringent oral hygiene protocol is presented. CONCLUSION: The present case report suggests that, even this newer AED can cause GE and the oral hygiene status of the patients could be an important triggering factor.

A Conservative Approach for Localized Spongiotic Gingivitis Hyperplasia Using Photodynamic Therapy: A Case Report and Review of the Literature.

Objective: To describe a clinical case of successful conservative management of Localized Juvenile Spongiotic Gingivitis Hyperplasia (LJSGH) using photodynamic therapy (PDT) and reviews the current literature on this pathology. Background data: LJSGH is a recently described rare disease with controversial treatment results. As of today, 13 publications report surgical treatment approaches. The use of CO2 laser and cryotherapy was reported only in one study. The use of PDT was not previously reported. Patients and methods: A 9-year-old male patient was referred to our institution with the chief complaint of asymptomatic "inflamed gingiva" starting 1 year before. Clinical examination revealed an erythematous line accompanying the gingival contour, with a certain degree of hyperplasia. The diagnosis of LJSGH was performed based on clinical features and later confirmed histopathologically. A novel approach using PDT was then proposed. The photosensitizer was methylene blue, and a semiconductor laser diode was used. Results: One week after starting PDT, gingival hyperplasia was partially reduced. Immediately after the end of treatment, a significant reduction of gingival hyperplasia was observed. PDT proved to be safe, quick and painless, with no esthetic harm. Conclusions: This case illustrates the benefit of a more conservative approach as opposed to surgical procedure, with good clinical response and decreased morbidity over a 2-year follow-up period.

Oral manifestations of Wegener's granulomatosis: a report of three cases and a literature review.

BACKGROUND: Hyperplastic granular gingivitis or "strawberry gingivitis" is a rare manifestation of Wegener's granulomatosis (WG), but it is nearly pathognomonic for this multisystem autoimmune vasculitis. The dentist may be the first health care professional to see patients with symptoms and findings of this condition. Early diagnosis and treatment is the most important factor in the management of this potentially fatal disease. METHODS: The authors present three case reports that demonstrate the disease spectrum and conducted a literature review focused on current understanding of this disease. RESULTS: The first patient had only the classic gingival manifestations of the disease. The second patient had simultaneous typical gingival lesions, as well as dermatologic findings. The third patient had an atypical oral presentation of aphthous ulcers and erythematous gingiva, as well as respiratory and genital involvement. Reaching a definitive diagnosis sometimes is challenging owing to the subtle onset of the disease and variable clinical and laboratory findings. CONCLUSION AND CLINICAL IMPLICATIONS: Clinicians should be familiar with the broad variety of oral and systemic components of WG, as well as strategies to facilitate prompt disease recognition and to provide continued oral health care to these medically complex patients.

The effect of conversion from cyclosporine to tacrolimus on gingival hyperplasia, hirsutism and cholesterol.

UNLABELLED: The use of cyclosporine for immunosuppression in renal transplantation allograft recipients is associated with hypertrichosis, gingival hyperplasia, and hypercholesterolemia. Conversion of patients to tacrolimus may lead to an improvement in these effects with minimal risk of rejection or allograft dysfunction. METHODS: Sixteen renal transplant recipients were prospectively converted from CsA to tacrolimus and followed for 1 year. Gingival hyperplasia index, total cholesterol, and blood pressure were recorded at the outset, 4-, 8-, and 12-month intervals. Glomerular filtration rate was checked before conversion and 1 year later. Photographs documenting hypertrichosis were taken before conversion and 1 year later. Adverse effects from tacrolimus were recorded at 4, 8, and 12 months. RESULTS: Twelve patients with hypertrichosis noted rapid improvement. Mean gingival hyperplasia index decreased from 24 to 6; mean total cholesterol decreased from 237 to 195. Glomerular filtration rate was essentially unchanged (56 to 54). One episode of rejection occurred, three patients developed diarrhea, three noted headaches, and one had a tremor. CONCLUSION: If carefully monitored, patients suffering adverse effects secondary to cyclosporine may be converted to tacrolimus with minimal risk of allograft dysfunction or rejection.

Efficacy of azithromycin in the treatment of cyclosporine-induced gingival hyperplasia in renal transplant recipients.

BACKGROUND: Gingival hyperplasia (GH) is a common side effect of cyclosporine . Azithromycin (Zithromax; AZI) is a macrolide antibiotic reported in case studies to reduce cyclosporine-induced gingival hyperplasia (CIGH) in renal transplant recipients (RTR). METHODS: The efficacy of AZI to treat CIGH in RTR was examined in a double-blind, randomized crossover trial. Patients (n=17) with CIGH were randomized to receive AZI and a matching placebo in alternate order for 5 days, separated by a 2-week washout period. Follow-up visits were conducted at week 6 and week 12. Changes in GH were evaluated by measuring the clinical gingival sulcus depths, tooth length, and the length of the interdental papillae to the cementum-enamel junction of two teeth in each of the four quadrants. RESULTS: Significant improvements were observed in all three types of periodontal measurements, representing reductions of gingival tissue above the medial aspect of the tooth, of the gingival sulcus depth, and of the length of the interdental papillae. Patients reported an improvement in gum bleeding. AZI was well tolerated, and 67% of the patients reported that the treatment was at least somewhat useful. CONCLUSIONS: AZI should be considered for RTR with CIGH.

The effect of urea peroxide on dilantin hyperplasia.

1. A significant inverse relationship was found between the severity of the hyperplasia and the duration of SDH. 2. The severity of hyperplasia and in flammation was found to vary significantly and inversely with oral hygiene scores. 3. Tooth brushing twice a day and the application of Oxygel showed no significant clinical changes on the inflammation and hyperplasia in the test group, whereas the control group using a placebo showed a moderate reduction in gingival inflammation.

Effect of topical application of phenylephrine hydrochloride on hyperplastic gingivitis.

A double blind study was conducted to evaluate the effectiveness of Phenodent Type A (brand of phenylephrine hydrochloride) on decongesting hyperplastic gingivitis. Three solutions were used: a 0.5% a placebo, and a 0.25% concentration of phenylephrine hydrochloride. The periodontal disease index was used to score variables which might have an effect on gingival response to local irritants. Impressions were taken and casts were made on 45 subjects at 0, 1, 3, and 6-week intervals. An instrument with accuracy of 0.001 inch was constructed to measure the changes in the interdental papillae of the stone casts. No significant reduction of gingival volume was established for any of the three solutions.

Gingival overgrowth in kidney transplant recipients treated with cyclosporine and its relationship with chronic graft nephropathy.

Our previous study of a group of renal transplant recipients treated with CsA showed a significantly faster development of chronic graft failure among patients with gingival hyperplasia (GH) compared to unaffected patients. The aim of the present research was to establish the impact of CsA dose and blood levels on the incidence of chronic graft nephropathy and gingival overgrowth as well as to assess risk factors for chronic graft nephropathy. The study included 64 renal graft recipients (32 patients with GH and 32 without GH) transplanted between 1989 and 1994. There were no significant differences between the pretransplant demographic and clinical data of the patients with and without GH. Patients with GH received a significantly higher total yearly dosages of CsA compared those without GH (P <.03). Serum creatinine in the first year posttransplant in patients with GH was 1.9 mg/dL versus 1.6 mg/dL in those without GH. During 9 to 14 years follow-up, end-stage renal failure due to chronic nephropathy occurred in 18 patients (56%) with GH and eight patients (25%) without GH. Ten-year renal graft survival was 35% in GH patients and 69% in patients without GH. Ten-year patient survival was 69% in the GH group and 91% in the group without GH. CsA dosage was a risk factor for GH and for graft loss, which implies a role of CsA toxic effects on the pathological mechanisms of GH and of chronic allograft nephropathy.

Effects of azithromycin on cyclosporine-induced gingival hyperplasia in renal transplant patients.

BACKGROUND: Gingival hyperplasia is a well-known complication of cyclosporine therapy, affecting 21% to 35% of renal transplant patients. Metronidazole, clarithromycin, and azithromycin, all azalid antimicrobial agents derived from the macrolide antibiotic erythromycin, have been used for treatment. Marked improvements in gingival hyperplasia have been recorded in particular with azithromycin. The aim of the present study was to investigate histopathological features of cyclosporine-induced gingival hyperplasia and to evaluate the quantitative efficacy of short-term azithromycin therapy. METHODS: Eighteen renal transplant patients with cyclosporine-induced gingival hyperplasia were included in the study. All patients received azithromycin with a dose of 500 mg/d for 3 consecutive days. Changes in gingival hyperplasia were evaluated by measuring the gingival sulcus depth to the cementum-enamel junction of every tooth in each of the four quadrants on days 0, 7, 30, 90, 180. Gum biopsies were obtained on days 0 and 30; the degree of inflammation was classified as "mild," "intermediate," and "severe". RESULTS: Gingival hyperplasia was reduced in all treated patients throughout the study. The degree of improvement was more significant between 0 to 7 and 7 to 30 days than at other times (respectively, P < .0001 and P < .002). Histopathologically, eight patients had severe and one patient moderate chronic inflammation at the beginning of therapy. Three other biopsies were reported as papilloma, mucosal hyperplasia, and normal gingival tissue biopsy. CONCLUSIONS: Azithromycin appears to be useful to treat cyclosporine-induced gingival hyperplasia in renal transplant patients. Treatment is inexpensive and free from known adverse effects.

Partial regression of advanced cyclosporin-induced gingival hyperplasia after treatment with azithromycin. A case report.

Gingival hyperplasia is a well recognised complication of cyclosporin A therapy. Although its pathogenesis is still debated in several recent reports a second generation macrolide antibiotic-azithromycin induced partial or even complete regression of hyperplasia. We present a patient after kidney transplantation treated with cyclosporin who developed very advanced gigival overgrowth (stage 3+). The patient received a 3-day treatment with azithromycin which was repeated after 3 months. The first course of the drug caused a partial regression of gingival hyperplasia during following months but the repeated treatment did not provide a further regression of the changes.

'Strawberry gums'--a case of Wegener's granulomatosis.

We report a case of Wegener's granulomatosis (WG), localised to the upper aerodigestive tract, which presented as an unusual form of hyperplastic gingivitis in a 36-year-old female. The clinical, serological and histopathological findings are described. The resemblance of the affected gums to over-ripe strawberries is emphasised, in order to draw attention to this characteristic oral manifestation of a rare and potentially life-threatening condition. The response to co-trimoxazole as sole therapy is noted.

A rare case of idiopathic multiple hyperplasia of inflammatory granulation in the oral cavity.

Cases of idiopathic gingival enlargement are so infrequent that the etiology and treatment are subjects of discussion. The case of a 49-year-old woman who presented with a rapidly diffuse enlargement of gingiva, clusters of patches on the buccal mucosa, and a furry-coated tongue within 2 months is reported. Results of various laboratory investigations and additional tests, such as the antineutrophil cytoplasmic antibodies (ANCA) and autoantibody to nuclear antigen (ANA) tests, were all negative. Histopathologic examination showed hyperplasia of inflammatory granulation tissues. Oral steroid therapy was effective. Although cases of multiple hyperplasia of inflammatory granulation in the oral cavity are very rare, clinicians should be aware of such cases and understand the efforts to further delineate the etiology, the management, and the prevention of the recurrence of this condition.