Effectiveness and safety of tacrolimus with or without eltrombopag, as a part of immunosuppressive treatment of aplastic anemia in adults: a retrospective case series.

First-line treatment of aplastic anemia(AA) and for AA patients ineligible for hematopoietic stem cell transplantation (HSCT) has consisted of antithymocyte globulin (ATG), the calcineurin inhibitor cyclosporine A (CsA), and more recently eltrombopag. However, at our institution, we have successfully substituted another calcineurin inhibitor, tacrolimus, as a part of immunosuppressive threatment (IST) for AA due to more favorable toxicity profile. Since there is limited data on the use of tacrolimus in aplastic anemia, we conducted a retrospective review of twenty patients treated with tacrolimus-based immunosuppressive therapy (IST) as a first- or second-line treatment. The overall response rate was comparable to that of patients treated with CsA (18 patients). However, there were no cutaneous side effects observed in patients receiving tacrolimus, a relatively common finding with CsA use. Our data suggest that tacrolimus-based IST is a potential option in AA and might have a more favorable toxicity profile compared to CsA.

Immunoexpression of angiogenesis and proliferation markers in patients treated with cyclosporin A.

AIM: In the present immunohistochemical study, the expression of vascular endothelial growth factor, nitric oxide synthase 1 and 3, and Ki-67 in the gingival tissues of renal transplant patients treated with cyclosporin A was assessed. Gingival overgrowth (GO) frequently occurs in transplant patients receiving immunosuppressive drugs such as cyclosporine and this gingival inflammation might play an important role in the pathogenesis of drug-induced GO. METHODS: Twenty-eight human gingival biopsies were taken from healthy patients with chronic periodontitis (N.=14 control group), and from renal transplant recipients treated with cyclosporin A (N.=14 test group). The retrieved specimens were immunohistochemically processed and stained for vascular endothelial growth factor, nitric oxide synthase 1 and 3, and Ki-67. RESULTS: The levels of vascular endothelial growth factor, nitric oxide synthase 1 and 3, and Ki-67 were found to be significantly different among groups (P>0.001), with patients treated with cyclosporin A showing higher levels of all the analyzed markers compared to control group. CONCLUSION: In summary, the data from this pilot study suggests that the investigated factors have a role in the inflammation processes associated to immunosuppressive therapy. However, further studies with a larger sample population need to be conducted for an exhaustive knowledge of the mechanisms leading to GO.

Aspects related to a periodontal home prevention program for disabled patients: a clinical trial.

AIM: The aim of the present study was to highlight the relationship between the level of oral hygiene and the context in which the patient receives dental treatment, demonstrating that home service is essential and effective to decrease the incidence of periodontal diseases. METHODS: The study was initially conducted on a heterogeneous sample of patients including 48 individuals with psycho-motor deficits. The study included 28 males (58.3%) and 20 females (41.7%) aged between 18 and 50 years, coming from two different sites ("Fa.Di.Vi… e oltre" and "Dentistry Unit, Istituto G. Gaslini" in Genoa). The patients were evaluated during the period 2008-2009. After this first pilot study, a clinical trial was conducted within the educational center "Il Granello", with the participation of 20 patients with disabilities. RESULTS: This study demonstrates that home assistance is essential and effective to decrease the incidence of those periodontal diseases induced by bacterial dental plaque accumulation, and associated with aggravating factors like the repeated use of drugs, such as benzodiazepines, phenylhydantoin, and cyclosporin A, that cause gingival hypertrophia. CONCLUSION: This study was proposed to demonstrate that the availability of a dental service within institutions could improve not only the dental-periodontal conditions of the participants, but also decrease the admission of these subjects to hospitals, contributing to the reduction of public expenditure by the Health Care System.

[Surgical correction of excessive gingival enlargements. Case studies]. / Extrém méretu iatrogén eredetu inyhiperpláziák sebészi korrekciója. Esetsorozat.

INTRODUCTION: Gingival enlargement is a common form of periodontal tissue reaction to several irritating factors. The most common form is the drug related gingival hyperplasia--nevertheless the heredity gingival fibromatosis and hematological cases can also occur and might impose a challenge to periodontists. After a short literature summary three Case reports are presented. The first case is a drug related gingival overgrowth in a young kidney transplant women who took Cyclosporin-A. The excessive mass of fibrotic tissue was removed by a series of internal beveled incision and the oral and buccal gingival flaps were united with sutures. The healing was uneventful and during the follow up patient's compliance and oral hygiene was superb. The second case is a very severe antihypertensive drug related gingival overgrowth in a 62 years old man interfering with the closure of his lip and corrected with a combination of conventional gingivectomy and internal reverse beveled incision both and Ca-channel blockers. The third case is a 42 years old woman with chronic idiopathic hemolytic anemia who presented a sudden onset acute excessive generalized gingival enlargement accompanied with severe pain and fever. At admission she was suspect for leukemia. After obtaining biopsy samples and having negative histology the soft tissue mass was removed under general anesthesia with conventional gingivectomy technique, but after a couple of days the severe pain and gingival swelling recurred. With administering systemic corticosteroid therapy (32 mg Medrol), the gingiva healed in five days and the one year follow-up showed a stable hematological and periodontal status. Today the more conservative internal beveled incision is preferred over the conventional gingivectomy in the most cases because it provides a more predictable healing and better esthetics. The recurrence of the drug related gingival hyperplasia can be anticipated by meticulous postoperative individual oral hygiene and regular supportive therapy. CONCLUSION: The combined conservative and surgical therapy leads to predictable postoperative result even in very severe systematically motivated gingival enlargements, nevertheless the successful patients management needs good cooperation with medical doctors and with the patients themselves.

Reliability of two measurement indices for gingival enlargement.

BACKGROUND AND OBJECTIVE: The objective of this study was to analyze the concordance of the vertical gingival overgrowth index (GOi) and the horizontal Miranda & Brunet index (MBi) and to compare their reliability and reproducibility for an early diagnosis of gingival enlargement. A wide range of methods has been employed to determine the severity of drug-induced gingival enlargement (DIGE) that has resulted in uncertainty with regard to the prevalence of this side effect. In recent studies, different indices have been used to grade DIGE. The large variability observed between studies and the differences between vertical and horizontal gingival-enlargement measurements could be the result of the use of nonreliable indices during the measurement process. Some indices involve invasive procedures that require many measurements, or even a data-processing system, while others are less convenient and technically expensive and complex. In previous studies we used two complementary indices - the vertical GOi and the horizontal MBi. The results of these studies found some differences between both indices, with the MBi rendering higher estimates of DIGE prevalence that was attributed to its greater sensitivity for the detection of minimal changes in gingival thickness. To our knowledge, there are no studies comparing different measurement indices for gingival enlargement that are supported by statistical concordance analysis. MATERIAL AND METHODS: Twelve plaster casts from patients who had worn orthodontic brackets, and who had different degrees of chronic inflammatory gingival enlargement, were analyzed. Three previously trained examiners registered twice the degree of buccal overgrowth, using the GOi and MBi, in all cast models with a minimum interval of 7 d between the first and the second evaluation. In total, from each cast, measurements from 16 gingival sites were taken using the GOi, and from nine gingival units (mesial and distal sites measurements) using the MBi. Concordance analysis of the registered measurements (intra-examiner and among examiners) for each index and between indices was assessed using the nonweighted Kappa index with a confidence interval of 95%. RESULTS: We obtained 648 values for the GOi and the MBi. The overall score 0 (indicating absence of enlargement) was 32.7% and 19.8% for GOi and MBi, respectively, score 1 (light/moderate) was 39.7% and 48.1%, and score 2 (severe) was 27.6% and 32.1%. Concordance analysis for each index showed intra-examiner Kappa values of 0.820 for the GOi and 0.830 for the MBi. Interexaminer Kappa values were 0.720 for the GOi and 0.770 for the MBi. Concordance between indices showed Kappa values for the same examiner of 0.600, whereas concordance among different examiners was 0.550. Discrepancies between indices indicated a systematic skew, with 79-82.1% of discrepancy associated with a higher value for the MBi compared with the GOi. CONCLUSION: Both gingival enlargement indices analyzed are reliable, complementary and applicable for measuring gingival overgrowth. However, the MBi shows, with fewer measurements, a greater sensitivity than the GOi for the detection of the early stages of gingival enlargement, being adequate for the screening of large populations at risk.

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.

Regulation of type I plasminogen activator inhibitor in human gingival fibroblasts with cyclosporine A.

OBJECTIVES: Cyclosporine A (CsA) is used as an immunosuppressive agent and its prominent side effect is the induction of gingival overgrowth. Type I plasminogen activator inhibitor (PAI-1) has shown to play an important role in CsA-induced gingival overgrowth. However, little is known about whether factors can modulate CsA-induced PAI-1 expression. METHODS: Cytotoxicity, reverse transcriptase-polymerase chain reaction, and enzyme-linked immunosorbent assay were used to investigate the effects of Human gingival fibroblasts (HGFs) exposed to CsA. In addition, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, interlukin-1alpha, tumor necrosis factor-alpha, mitogen-activated protein kinase kinase (MEK) inhibitor U0126, signal-regulated protein kinase (ERK) inhibitor PD98059 and cell-permeable glutathione precursor N-acetyl-L-cysteine (NAC) were added to test how they modulated the effects of CsA-induced PAI-1 expression. RESULTS: The concentration of CsA higher than 500 ng ml(-1) demonstrated cytotoxicity to HGFs (P < 0.05). Periodontal pathogens as well as proinflammatory cytokines were found to increase the CsA-induced PAI-1 mRNA and protein expression (P < 0.05). Pharmacological agents NAC, U0126, and PD98059 were found to decrease the CsA-induced PAI-1 mRNA and protein expression (P < 0.05). CONCLUSIONS: Cyclosporine A (CsA) may predispose to gingival overgrowth under inflammatory environments. The regulation of PAI-1 expression induced by CsA might be critically related with the intracellular glutathione and the ERK-MAPK pathway.

[The effect of mycophenolate mofetil and azathioprine on gingival enlargement associated with cyclosporin A use in kidney transplant patients]. / Efecto del micofenolato de mofetilo y azatioprina sobre la hiperplasia gingival asociada al uso de Ciclosporina A en pacientes con trasplante renal.

AIM: To assess gingival overgrowth prevalence and severity in a group of kidney transplant (KT) patients, and analyze the effect of immunosuppressor drugs Cyclosporin A (CsA), Tacrolimus (Tac), Sirolimus (Siro), Azathioprine (Aza) and Mofetil Mycophenolate on this complication. METHODS: Gingival overgrowth presence and severity was classified, and the impact of immunosuppressor drugs, age, oral hygiene, verapamil and nifedipine on this condition was analyzed by multiple logistic regression. RESULTS: 172 KT pts. were examined; 137 used CsA, 25 Tac, 6 Sirolimus, 107 Aza and 56 MMF. Gingival overgrowth prevalence was 59.1% on CsA, 12.0% on Tac, and 16.7% on Sirolimus. CsA odds ratio (OR) 15.2, age <45 OR 5.6, and poor oral hygiene OR 3.2, increased, and Aza OR 0.05 and MMF OR 0.03, decreased GO prevalence. CONCLUSIONS: Aza and MMF effect was a significant protection against GO prevalence in this group of KT patients.

Antigen-presenting cells in human immunosuppressive drug-induced gingival enlargement.

An immunoperoxidase technique was used to compare the number of CD1a+ and factor XIIIa+ dendritic cells (DCs), and CD68+ Macrophages (M) in 30 gingival samples from subjects with clinically healthy periodontitium (HP) and 10 samples from subjects with drug-induced gingival enlargement (DIGE). Fewer CD1a+ and factor XIIIa+ DCs were found in areas with inflammatory infiltration (II) of the lamina propria (LP) in the group with immunosuppressed DIGE (IDIGE) compared to the group with HP. In the sulcular and junctional/pocket epithelia, the number of CD1a+ DCs was decreased in the group with IDIGE (p<0.05). There was a tendency toward a reduced number of CD1a+ DCs and CD68+ M in areas without inflammatory infiltrate of the LP in the group with IDIGE. The alterations in the number of antigen-presenting cells (APCs) may be the reason for the decreased periodontal inflammation and breakdown clinically observed in subjects who are immunosuppressed.

Uso de membrana de celulosa oxidada post-gingivectomía en hiperplasia gingival inducida por fenitoína / Use of oxidized cellulose regenerated post-gingivectomy on ginigival hyperplasia induced by phenytoin

Introducción: La hiperplasia gingival es una condición benigna caracterizada por el aumento de volumen de la encía. Algunos fármacos, factores genéticos, aparatología y placa dentobacteriana son factores que pueden inducir esta condición. Objetivo: Devolver la anatomía a la encía brindando una mejor estética y permitiendo una óptima higiene oral. Material y métodos: Paciente masculino de 20 años de edad con antecedentes de fenitoína presenta aumento de volumen en la encía. Resultados: Se obtuvieron resultados estéticos y funcionales satisfactorios con el tratamiento quirúrgico y el uso de membrana de celulosa oxidada. Conclusión: En el manejo de la hiperplasia gingival es importante el enfoque no quirúrgico como control de placa dentobacteriana y medidas de higiene del mismo paciente (AU)

Introduction: Gingival hyperplasia is a benign condition characterized for the grown on the gingival volume. Some drugs, genetic, orthodontic and dental plaque are some factors that can induce this condition. Objective: To return the gingival anatomy, providing a better aesthetic allowing also good oral hygiene. Material and methods: A male 20 years of age with medical history of phenytoin display grown on the gingival volume. Results: Aesthetic and functional results were achieved with the surgical treatment and the oxidized cellulose membrane. Conclusion: In the gingival hyperplasia management is important de non-surgical approach, as dental plaque control and oral hygiene of the patient (AU)

Gingival overgrowth in renal transplant recipients induced by pharmacological treatment. Review of the literature.

Patients who undergo a renal transplant also require a pharmacological immunosuppressor therapy with cyclosporine (CsA) as well as anti-hypertensive calcium channel-blockers (CCBs); the former suppresses interferon and interleukin-2 production thus interfering with T cell cell-mediated activity, while the latter are used in order to counteract the nephrotoxicity of CsA which causes the local release, of thromboxane A2 with vascular vasoconstriction in the kidney. The use of both these drugs, particularly if used in association, leads to the onset of a clinical picture of variable entity, characterized mainly by a hypertrophy originating usually at the level of interdental papillae, and more pronounced in the anterior maxillary areas and the vestibular surfaces of the teeth, in a more or less symptomatic manner. The therapy is above all preventive, with an appropriate oral hygiene program, both professionally as well as at home, and with the use of substitutive drugs that do not present such side effects.

[Nasotracheal fiberoptic intubation under remifentanil for sedation and analgesia in a boy with a difficult airway due to giant gingival hypertrophy]. / Intubación nasotraqueal con fibroscopio bajo sedoanalgesia con remifentanilo en paciente pediátrico con vía aérea difícil por hipertrofia gingival gigante.

A 9-year-old boy diagnosed with gingival hypertrophy and with a history of West syndrome and associated low platelet levels underwent gingival reduction surgery. Because difficult intubation was foreseen, the fiberoptic tube was inserted through the nose with the patient breathing spontaneously under remifentanil for sedation and analgesia. The procedure was carried out under balanced general anesthesia and with standard monitoring. At the end of gingivectomy, a tracheostomy was performed and the patient was transferred to the pediatric intensive care unit for postoperative observation.

Missing diagnosis: gingival hypertrophy due to amlodipine.

Gingival hypertrophy (GH) is a well-known physical manifestation due to inflammatory conditions, pregnancy, vitamin C deficiency, systemic diseases like leukemia, Wegners granulomatosis, and various drugs like anticonvulsants, immunosuppresant, and calcium channel blockers (CCBs).We present here a case of a 45-year-old woman, who has been taking Amlodipine 10mg once a day together with Atenelol 50mg per day for one and half years, and has subsequently developed gum hypertrophy. This manifestation was reversed after stopping of Amlodipine. Though this case presentation is described in literature, we hereby present it in a pictorial form, to sensitize the treating physician toward it.

A well known and important adverse effect of phenytoin in a neurosurgical patient.

Gum hypertrophy is a well-known and important adverse effect of phenytoin therapy in a neurosurgical patient. We present an interesting case of a 21-year-old man who, following head injury after a road traffic accident, developed status epilepticus diagnosed with gum hypertrophy in the jaws, with ongoing antiepileptics. He was managed conservatively as per hospital protocol.

High-dose oral cyclosporin therapy for recurrent focal segmental glomerulosclerosis in children.

BACKGROUND: Focal segmental glomerular sclerosis (FSGS) has a high propensity for recurrence after renal transplantation, with a 50% risk for graft failure from recurrent disease. METHODS: We report on the efficacy of high-dose oral cyclosporin A (CsA) in the treatment of recurrent FSGS in children. Between August 1991 and January 2003, a total of 24 patients with FSGS underwent transplantation at 1 institution. Sixteen patients (67%) had recurrent disease. In these 16 patients, CsA dose was increased gradually until remission was achieved or there was evidence of renal toxicity. Seven patients also underwent plasma exchange. RESULTS: Thirteen patients (81%) achieved remission. Remission was complete in 11 patients and partial in 2 patients. The CsA dose necessary for inducing remission ranged from 6 to 25 mg/kg/d. Four of these patients also underwent plasma exchange. After remission, CsA dose was reduced gradually toward the standard posttransplantation regimen. Eleven of 13 responders have a functioning graft after a follow-up ranging from 10 months to 12 years. One graft was lost because of recurrent FSGS, and another graft because of recurrence and cellular rejection; noncompliance was a factor in both losses. The 3 patients with disease that did not respond to high-dose CsA therapy lost their grafts because of recurrent FSGS. A common factor in these 3 patients was the inability to increase the CsA dose because of early evidence of nephrotoxicity, evidenced by an increase in serum creatinine level. CONCLUSION: High-dose oral CsA therapy is effective in producing long-lasting remission of recurrent nephrotic syndrome in children with FSGS.

Phenytoin-induced gum hypertrophy in patients with epilepsy.

One hundred and eight patients who had been taking phenytoin for a year or more, either alone or in combination with other drugs, were examined for gum hypertrophy by three observers independently. Approximately 90% of the patients showed either mild or no gum hypertrophy and severe swelling occurred in only 1%. The observed standards of oral hygiene were extremely poor. A tendency for higher serum phenytoin levels to be associated with greater gum hypertrophy was observed. Because the condition was causing no problems in over 90% of patients, it is considered that gum hypertrophy per se should not deter a physician from using phenytoin in the treatment of epilepsy.

CYP2C polymorphisms, phenytoin metabolism and gingival overgrowth in epileptic subjects.

Previous studies suggested that the onset of phenytoin-induced gingival overgrowth depended on serum phenytoin concentration. Cytochrome P450 2C (CYP2C) plays an important role in phenytoin metabolism. Recently, single nucleotide polymorphisms in the coding region of CYP 2C influencing phenytoin metabolism were identified. The purpose of the present study was to see if CYP 2C polymorphisms might relate to the onset and severity of phenytoin-induced gingival overgrowth. Twenty-eight epileptic patients taking phenytoin aged 15 to 75 (mean age: 42.2 years old, 20 males and 8 females) and 56 unrelated healthy subjects aged 30 to 48 (mean age: 36.8 years old, 48 males and 8 females) were examined for CYP 2C polymorphisms. All epileptic subjects were examined for the degree of gingival overgrowth, daily phenytoin dose and serum phenytoin concentration. The results indicated about 7% of the subjects including epileptic and healthy subjects examined were positive for CYP 2C9*3. However, the degree of gingival overgrowth did not directly correlate with CYP 2C polymorphisms. Nevertheless, the subjects with severer gingival overgrowth exhibited significantly higher serum phenytoin concentration, indicating that phenytoin metabolism is an important determinant for the severity of the disease. Additionally, CYP 2C9*3 carriers exhibited significantly higher serum drug concentration to drug dose. Therefore, we concluded although the gene analysis is not directly related to diagnose the disease itself, it can be utilized in estimating serum phenytoin concentration from drug dose, which in turn serves to predict the future development and clinical course of the disease.