tacrolimus and Mouth-Diseases

Systemic non-biologic agents have long been in clinical use in medicine--often with considerable efficacy, albeit with some adverse effects--as with all medications. With the advent of biologic agents, all of which currently are restricted to systemic use, there is a growing need to ensure which agents have the better therapeutic ratio. The non-biologic agents (NBAs) include a range of agents, most importantly the corticosteroids (steroids). Previous articles by us in this series have discussed systemic use of corticosteroids and purine synthesis inhibitors; the other immunomodulating agents (calcineurin inhibitors, thalidomide, dapsone, colchicine and cyclophosphamide) are reviewed in this final article.

Topics: Anti-Infective Agents; Calcineurin Inhibitors; Colchicine; Cyclophosphamide; Cyclosporine; Dapsone; Drug Interactions; Drug Monitoring; Facial Dermatoses; Humans; Immunosuppressive Agents; Mouth Diseases; Tacrolimus; Thalidomide; Tubulin Modulators

Topical immunomodulators have been used for the management of oral mucosal diseases. Topical immunomodulating preparations may have utility in local management of oral disease which is resistant to topical steroids and oral findings of an immunologic-mediated systemic disease with primary or persisting, oral mucosal involvement.. This paper is the first part of a systematic review of topical immunomodulators for the management of various oral indications focused on calcineurin inhibitors. The literature search revealed that data are available for cyclosporine, tacrolimus and pimecrolimus. In addition to the review of scientific evidence, this paper presents the potential market, the mechanism of action, the competitive environment and future development options.. The reader will find weighted conclusions for the topical use of the calcineurin inhibitors in the management of oral diseases.. Topical calcineurin inhibitors may be useful as a second-line treatment in several oral diseases, particularly oral lichen planus.

Topics: Administration, Topical; Animals; Calcineurin Inhibitors; Cyclosporine; Drug Design; Humans; Immunosuppressive Agents; Mouth Diseases; Mouth Mucosa; Tacrolimus

An open-label phase 2 study of topical dexamethasone versus tacrolimus solutions in new-onset oral chronic graft-versus-host disease (cGVHD) revealed the superior efficacy of dexamethasone. The objective of this study was to report long-term patterns of topical therapy utilization and clinical outcomes in this cohort after completing the 30-day trial. A retrospective record review was performed from the date of study completion to January 2017. Topical therapies, systemic immunosuppressive therapies, objective measurements (National Institutes of Health severity score, oral mucosal scores), patient- reported outcomes (dryness, sensitivity, pain), and adverse events were recorded for oral cGVHD-related outpatient visits. Follow-up (FU) periods were defined as FU1 (0-1 month), FU2 (1-3 months), FU3 (3-6 months), FU4 (6-12 months), FU5 (12-18 months), and FU6 (18-24 months). Forty patients (52.5% males, median age, 56 years) completed the clinical trial and were included in the analysis. Topical therapies used were dexamethasone, tacrolimus, clobetasol, or a combination of these agents. At FU1, all 40 patients were receiving topical therapy, which decreased to 54.5% (12 out of 22) at FU6. Clinician-reported oral mucosal scores (0-12) and patient-reported sensitivity scores (0-10) decreased over time from FU1 (median mucosal score, 3; sensitivity, 3) to FU6 (mucosal score, 1; sensitivity, 2). Intralesional steroid therapy was provided to 6 patients for management of refractory oral ulcerations, all within the first year of follow-up. Patients with de novo symptomatic oral cGVHD may require long-term care with topical immunomodulatory therapy for up to 2 years, if not longer. Topical steroid and tacrolimus therapies are safe and effective in managing symptomatic oral cGVHD. Second-line topical therapy for refractory oral cGVHD requires further investigation.

Topics: Chronic Disease; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Male; Middle Aged; Mouth Diseases; Retrospective Studies; Tacrolimus

The objective of this study was to evaluate the safety and efficacy of single-agent dexamethasone or tacrolimus topical solution as first-line treatment for symptomatic oral chronic graft-versus-host disease (cGVHD). This was a prospective, single-center, open-label, randomized phase II trial of patients with symptomatic oral cGVHD without prior topical therapy. Subjects were randomly assigned 1:1 to either topical dexamethasone (.5 mg/mL) or tacrolimus (.5 mg/mL) solution and instructed to rinse with 5 mL for 5 minutes, 4 times a day, for 4 weeks. Oral cGVHD assessments (National Institutes of Health [NIH] criteria) were completed at baseline and end of treatment (NIH criteria, global response, and tolerability). The primary endpoint was the response rate defined as ≥3-point reduction in patient-reported sensitivity score (range, 0 to 10). A parallel 2-stage design was employed so that a less efficacious arm could be terminated early. The accrual goal was 60 evaluable patients; 30 in each arm), accruing 14 in the first stage and 16 in the second stage. If both arms were regarded as efficacious, a "pick-the-winner" method would be employed to choose a better treatment for future investigation. Forty-six subjects were randomized to receive either dexamethasone (n = 28) or tacrolimus (n = 18). Six subjects were excluded from the analysis because of changes in systemic immunosuppression (dexamethasone  = 1, tacrolimus  = 3) or lack of end-of-treatment visit (1 per arm). After the first stage evaluation, the tacrolimus arm was terminated because of lack of activity (3 of 14 responses; response rate, 21%). Twenty-six subjects in the dexamethasone arm completed both study visits and were included in the response analysis, with a 58% (15 of 26) response rate, compared with 21% (3 of 14) in the tacrolimus arm (P = .05). The response rates according to the NIH score in the dexamethasone and tacrolimus arms were 50% (13 of 26) and 2% (2 of 14), respectively (P = .04). From the onset of therapy, 31% versus 21% patients reported feeling "much better" and 38% versus 36% reported feeling "slightly better," giving an overall global response rate ("much better" or "slightly better") of 81% (21 of 26) versus 71% (10 of 14), in the dexamethasone and tacrolimus arms, respectively. Dexamethasone rinses were well tolerated and taste was reported as "very pleasant" or "tolerable" in most subjects (96%). Intensive topical therapy with dexamethasone solution is effective for man

Topics: Adult; Child; Child, Preschool; Dexamethasone; Female; Graft vs Host Disease; Humans; Male; Mouth Diseases; Stomatitis; Tacrolimus; Treatment Outcome; Young Adult

The aim of this study was to evaluate patients with complete response of oral chronic graft-versus-host disease to immunosuppressive treatment.. A total of 29 patients submitted to allogeneic hematopoietic stem cell transplantation, with oral chronic graft-versus-host disease, were enrolled in this retrospective study, from September 2012 to February 2018. Patients were treated with combined topical dexamethasone solution and topical tacrolimus ointment, combined topical dexamethasone and topical tacrolimus, systemic immunosuppressive medication, and topical dexamethasone only.. The mean time of complete response of lichenoid lesions, erythema, and ulcers using dexamethasone and systemic immunosuppressive medication was of 105, 42 and 42 days, respectively (p=0.013).When we associated dexamethasone, tacrolimus and systemic immunosuppressive medication, the mean time of complete response of lichenoid lesions, erythema and ulcers was of 91,84 and 77 days (p=0.011). When dexamethasone was used alone, the mean time of complete response of lichenoid lesions, erythema and ulcers was 182, 140, 21 days, respectively (p=0.042).. Our study shows that lichenoid lesions require more time to heal. Notably, lichenoid lesions tend to respond better to dexamethasone combined with tacrolimus and systemic immunosuppressive medication, whereas erythema and ulcers respond better to dexamethasone combined with systemic immunosuppressive medication and dexamethasone only, respectively.

Topics: Chronic Disease; Graft vs Host Disease; Humans; Immunosuppressive Agents; Mouth Diseases; Retrospective Studies; Tacrolimus

To characterize the immunohistopathological features of oral chronic graft-versus-host disease (cGVHD), and the impact of topical immunomodulatory therapy on the infiltrating cells.. Paired oral cGVHD biopsies obtained before (n = 12) and 1 month after treatment (n = 12) with topical dexamethasone (n = 8) or tacrolimus (n = 4) were characterized by immunohistochemistry using a panel of CD1a, CD3, CD4, CD8, CD20, CD31, CD62E, CD103, CD163, c-kit, and FoxP3. Controls included acute GVHD (aGVHD; n = 3), oral lichen planus (OLP; n = 5), and normal tissues (n = 5).. Oral cGVHD specimens prior to treatment were mainly characterized by basal cell squamatization, lichenoid inflammation, sclerosis, apoptosis, and lymphocytic exocytosis. The infiltrating cells in oral cGVHD primarily consisted of CD3. The high expression of CD3, CD4, CD8, CD103, CD163, and FoxP3 confirms that oral cGVHD is largely T-cell-driven with macrophage participation. The impact of topical immunomodulatory therapy was variable, reducing histological inflammatory features, but with a weak clinicopathological correlation. Topical dexamethasone reduced the expression of CD4 and CD103, which may offer novel therapeutic targets.

Topics: Administration, Topical; Adult; Aged; Antigens, CD; Dexamethasone; Female; Forkhead Transcription Factors; Glucocorticoids; Graft vs Host Disease; Humans; Immunohistochemistry; Immunomodulation; Immunosuppressive Agents; Macrophages; Male; Middle Aged; Mouth Diseases; T-Lymphocytes; Tacrolimus; Young Adult

Extracorporeal photopheresis (ECP) is a second-line therapy for steroid-refractory chronic graft-versus-host disease (cGVHD).. We describe the long-term efficacy and tolerability of ECP according to the cutaneous phenotype of cGVHD and report on the reduced need for immunosuppressant drugs in this setting.. Fourteen patients (8 females) with cutaneous and/or mucosal cGVHD, treated with ECP between October 2010 and May 2016 within a single center, were included. Final analyses included patients who had received ECP for at least 12 months. We prospectively evaluated the efficacy of ECP using lesion-specific clinical scores and by recording changed doses of systemic immunosuppressants.. Of the 14 patients, sclerotic skin lesions were present in 10 (71%). The mRODNAN score decreased in all patients from month 9 onwards, with 40 and 77% reductions at 12 and 36 months, respectively. Six patients (43%) presented with cutaneous lichenoid lesions: this score was reduced in all patients by month 3, reaching a 93% reduction by month 12. Five patients (36%) experienced oral mucosal lichenoid lesions: these scores were decreased by 55% at month 12 and by 100% by month 33. The use of systemic immunosuppressants was reduced in all patients; 4 patients could stop all immunosuppressant drugs after 2 years. ECP was stopped in 3 patients after a complete response. No major ECP-associated adverse effects were observed.. ECP was an effective long-term therapy for oral and cutaneous cGVHD: consequently, dose levels of therapeutic immunosuppression could be reduced.

Topics: Adult; Chronic Disease; Cyclosporine; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lichenoid Eruptions; Male; Middle Aged; Mouth Diseases; Mouth Mucosa; Mycophenolic Acid; Photopheresis; Prednisone; Sclerosis; Skin; Tacrolimus

Oral lichen planus is a common, chronic mucosal disease associated with T-cell-mediated immunological dysfunction. The disease is classified in a painful red form with erosions and ulcerations and a less painful to painless white form with reticular, papular and plaque lesions. In a small proportion of cases, the lesions may develop into a squamous cell carcinoma. Corticosteroids are the mainstay of the therapy; the combination of systemic and topical corticosteroids is often very effective. Topical calcineurin inhibitors, especially tacrolimus, have produced long-term responses in clinical studies. We describe a patient with excellent response to therapy with tacrolimus mouthrinse and systemic corticosteroids.

Topics: Administration, Oral; Administration, Topical; Adrenal Cortex Hormones; Anti-Inflammatory Agents; Clobetasol; Drug Therapy, Combination; Humans; Injections, Intravenous; Lichen Planus, Oral; Male; Middle Aged; Mouth Diseases; Tacrolimus; Treatment Outcome

The authors present a case demonstrating the success of topical tacrolimus (TAC) therapy with custom trays in the treatment of oral chronic graft-versus-host disease (cGVHD). The 41-year-old male patient initially responded to topical steroid therapy (clobetasol propionate 0.05% ointment) applied both topically and with flexible carrier trays, but later became refractory to this potent topical agent. Topical TAC therapy with flexible carrier trays and systemic prednisone therapy was initiated.. The patient responded favorably with the change to topical TAC therapy with custom trays (and oral prednisone). His oral cGVHD lesions resolved within a period of 4 weeks. The improvement has remained stable at 14 months of follow-up.. This is the first case reported with regard to the successful resolution of steroid recalcitrant cGVHD successfully treated with topical TAC with custom trays.

Topics: Administration, Topical; Adult; Clobetasol; Drug Carriers; Follow-Up Studies; Glucocorticoids; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Mouth Diseases; Myelodysplastic Syndromes; Recurrence; Tacrolimus

Lichen sclerosus is a chronic inflammatory disease of unknown origin, which affects mostly women in the fifth and sixth decades of life, but can also occur in men and children. The involvement of the oral mucosa alone or together with other forms of presentation is extremely rare, requiring a differential diagnosis with other diseases of the oral cavity, particularly lichen planus. There are less than 30 cases of lichen sclerosus in the oral mucosa described in the literature and there are no reports on malignant transformation so far. We describe a patient with skin, oral and genital lesions of lichen sclerosus.

Topics: Administration, Topical; Aged; Diagnosis, Differential; Female; Genital Diseases, Female; Humans; Immunosuppressive Agents; Lichen Sclerosus et Atrophicus; Mouth Diseases; Tacrolimus

Gran versus Host Disease (GVHD) is a common complication in allogenic bone marrow transplants and in some cases, it involves the oral mucosa. Therefore, the appropriate diagnosis and timely treatment is essential to prevent local complications which interfere with normal oral functions and facilitate infection spread. We report a 17 years old woman with GVHD associated to lichenoid and ulcerative lesion in the oral mucosa, which responded to the topical administration of a 0.1% tacrolimus ointment.

Topics: Adolescent; Anemia, Aplastic; Bone Marrow Transplantation; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Mouth Diseases; Mouth Mucosa; Tacrolimus

Topics: Administration, Topical; Adult; Combined Modality Therapy; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Male; Middle Aged; Mouth Diseases; Photopheresis; Tacrolimus

Topics: Adult; Chronic Disease; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mouth Diseases; Tacrolimus

Oral chronic graft vs. host disease (GVHD) frequently presents in patients with sclerotic features of skin GVHD and is often associated with considerable limitations of oral food intake and decreased quality of life. Systemic tacrolimus is efficacious for prophylaxis and treatment of acute and chronic GVHD and topical tacrolimus has shown activity in chronic GVHD skin lesions. We therefore initiated a pilot study to investigate the safety and efficacy of topical tacrolimus ointment in children with oral GVHD. Six patients suffering from oral GVHD (five chronic and one acute) were included in the study. Tacrolimus ointment 0.1% was applied twice daily using sterile gauze. The only side-effects observed were a slight burning discomfort after the first application in one patient and after food intake in another patient. Tacrolimus was absorbed systemically in four of six patients. Of six patients, we observed a complete response in two, a very good partial response (VGPR) in two, and a PR in two patients, respectively. We conclude that topical application of tacrolimus ointment holds promise as a safe and efficacious treatment for oral GVHD in children. The Food and Drug Administration has recently issued a health advisory about a potential cancer risk associated with topical tacrolimus treatment of the skin; therefore, its benefits should be weighed against its potential risks and diligent long-term follow-up should be carried out especially in children.

Topics: Administration, Topical; Adolescent; Child; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Mouth Diseases; Ointments; Pilot Projects; Tacrolimus; Treatment Outcome

Topics: Administration, Topical; Adult; Erythema; Humans; Immunosuppressive Agents; Male; Mouth Diseases; Phototherapy; Psoriasis; Severity of Illness Index; Tacrolimus

Erosive oral lichen planus (OLP) is a painful chronic inflammatory disease that is sometimes resistant to systemic or topical therapies. Topical steroids remain the mainstay of therapy, but topical tacrolimus has recently been used to treat OLP resistant to topical corticosteroids. Topical tacrolimus appears as an effective and safe treatment of symptomatic OLP. We report the first histopathologically documented case of oral mucosa pigmentation after OLP treatment with topical tacrolimus. The relation between tacrolimus treatment and staining was suggested by the appearance of pigmentation during topical tacrolimus treatment and its clinical disappearance when treatment was stopped. Histopathology showed an increase in melanocyte numbers and melanogenesis.

Topics: Administration, Cutaneous; Aged; Diagnosis, Differential; Female; Humans; Hyperpigmentation; Immunosuppressive Agents; Lichen Planus, Oral; Mouth Diseases; Mouth Mucosa; Tacrolimus

Oral cicatricial pemphigoid is a chronic autoimmune blistering disease which affects predominantly the gingiva and the buccal mucosa. The pathogenesis of this disease is still incompletely understood; however, there is compelling evidence that cicatricial pemphigoid might be mediated by T lymphocytes. Therefore, we performed immunomodulatory therapy with topical tacrolimus in patients with long-standing, therapy-resistant oral cicatricial pemphigoid. Following 3 months of treatment, complete healing and ongoing remission could be achieved.

Topics: Aged; Autoimmune Diseases; Facial Dermatoses; Female; Humans; Immunosuppressive Agents; Male; Mouth Diseases; Ointments; Pemphigoid, Bullous; Tacrolimus; Time Factors; Treatment Outcome

Oral involvement of chronic graft-versus-host disease (GvHD) is a most distressing and disabling complication of hematopoietic cell transplantation, for which systemic immunosuppression as well as topical corticosteroid treatment may offer only limited symptomatic relief. Here we report encouraging preliminary results with the application of tacrolimus (FK-506) as a 0.1% ointment in three patients with severe oral chronic GvHD, heavily pretreated without success, who experienced rapid, consistent, complete or at least marked, subjective and objective improvement with topical tacrolimus.

Topics: Administration, Topical; Adult; Chronic Disease; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Mouth Diseases; Tacrolimus; Treatment Outcome

Topics: Administration, Topical; Aged; Female; Gingival Diseases; Humans; Immunosuppressive Agents; Male; Mouth Diseases; Pemphigoid, Benign Mucous Membrane; Tacrolimus

Immunosuppression by cyclosporin A (CsA) is associated with adverse side-effects, including nephrotoxicity, neurotoxicity and gingival overgrowth. Tacrolimus (TAC/FK506) is a new immunosuppressive agent, recently approved for use in solid-organ transplants. The mode of action of TAC is similar to that of CsA and the toxicity profile of CsA is duplicated by TAC. The effect of TAC on the gingival tissue is not yet conclusive.. Gingival overgrowth was assessed in 30 liver transplant children, 20 boys and 10 girls, aged 2-19 years. Seventeen children (10 boys, seven girls) were on a CsA-based immunosuppressive regimen whereas 13 children (10 boys, three girls) were on TAC for at least 1 year (mean 4.3 +/- 2.7).. In the CsA group, 35% of children exhibited gingival overgrowth characterized by one or more units with increased sulcus probing depth (> or = 4 mm), i.e. pseudopockets. In contrast to the CsA group, none of the children in the TAC group exhibited gingival overgrowth. The occurrence of enamel hypoplasia was observed in 11 children (36%) and enamel opacities were found in 23 children (76%). Six of the 12 children (50%) with hyperbilirubinaemia biliary atresia exhibited a marked greenish discoloration of the teeth. Caries experience (dmft/DMFT) among these children was 2.0 +/- 2.8.. No difference in caries experience or enamel defect was observed between the CsA and TAC group.

Topics: Adolescent; Adult; Biliary Atresia; Child; Child, Preschool; Cyclosporine; Dental Enamel; Dental Enamel Hypoplasia; Dental Plaque Index; DMF Index; Female; Follow-Up Studies; Gingival Overgrowth; Gingivitis; Humans; Hyperbilirubinemia; Immunosuppressive Agents; Liver Transplantation; Male; Mouth Diseases; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Statistics as Topic; Statistics, Nonparametric; Tacrolimus; Tooth Discoloration; Tooth Diseases

Crohn's disease of the mouth or perineum is more common in young people, and notably resistant to treatment. However, there is increasing evidence that topical therapy with tacrolimus (FK506) may be effective in skin diseases resistant to cyclosporin because of its high uptake in inflamed skin and subsequent reduction in keratinocyte chemokine production.. Tacrolimus ointment was made up inhouse from the intravenous or oral formulation and suspended in appropriate vehicles for perioral or perianal administration at an initial concentration of 0.5 mg/g. This was administered open label to eight children (aged 5-18 years) with treatment resistant oral (three patients) and/or ulcerating perineal (six patients) Crohn's disease.. Marked improvement was seen in 7/8 patients within six weeks and healing within 1-6 months. One child with gross perineal and colonic disease showed little response. Two of the responders showed rebound worsening when tacrolimus was stopped or the dosage reduced rapidly, and one of these eventually required proctectomy. Slower weaning of drug concentration has been successful in 6/8 patients, with four receiving intermittent treatment and two on regular reduced dosage (0.1-0.3 mg/g) with follow up times of six months to 3.5 years. Serum concentrations of tacrolimus were undetectable in all patients.. Topical tacrolimus at low concentrations (0.5 mg/g) shows promise in the management of childhood perineal and oral Crohn's disease, with no evidence of significant systemic absorption. However, rapid weaning or abrupt cessation of therapy may cause rebound worsening of disease. Further controlled studies are required to assess the efficacy and safety of this treatment.

Topics: Administration, Topical; Adolescent; Child; Child, Preschool; Crohn Disease; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Male; Mouth Diseases; Perineum; Tacrolimus; Treatment Outcome

Topics: Cyclosporine; Female; Gingival Diseases; Humans; Immunosuppressive Agents; Male; Mouth Diseases; Skin Diseases; Tacrolimus