tacrolimus and Corneal-Diseases

Ocular graft-versus-host disease (GvHD) following allogeneic blood stem cell transplantation leads to immunologically induced alterations in many ocular tissues, particularly at the ocular surface. Within the framework of the main topic, this article focuses primarily on corneal complications in chronic ocular GvHD.. This article aims to promote understanding of the influencing factors, diagnostics, and therapeutic options pertaining to corneal complications in ocular GvHD. Furthermore, the possibilities for prevention are discussed.. This analysis is based on a literature review as well as on data from the Ophthalmology Clinic at the University Hospital Essen.. Corneal complications often occur secondarily in ocular GvHD, as a consequence of severe inflammatory alterations of the conjunctiva or eyelid. Spontaneous corneal perforations associated with only mild symptoms are less common during the course of disease. From the ophthalmologist's perspective, it is important that the inflammatory activity of all the different ocular tissues is considered. Treatment may follow a stepwise scheme that includes substitution, immunosuppression, and surgical rehabilitation.. Systematic diagnosis of ocular GvHD helps to prevent corneal complications or support early therapeutic intervention. An interdisciplinary approach to diagnosis and treatment planning is recommended, in order to optimize local and systemic immunosuppressive therapy.

Topics: Adrenal Cortex Hormones; Chronic Disease; Combined Modality Therapy; Corneal Diseases; Corneal Ulcer; Cyclosporine; Diagnosis, Differential; Eye Diseases; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Interdisciplinary Communication; Intersectoral Collaboration; Keratoplasty, Penetrating; Limbus Corneae; Ophthalmic Solutions; Tacrolimus

To evaluate the efficacy of topical tacrolimus 0.05% as adjuvant therapy to corticosteroids in the treatment of acute endothelial rejection of a penetrating keratoplasty (PKP) graft.. Patients with the clinical diagnosis of acute endothelial rejection of a PKP graft were randomized into 2 groups-group 1: receiving topical tacrolimus 0.05% as adjuvant therapy to corticosteroid treatment and group 2: receiving only corticosteroid treatment. Main outcome measures were rejection reversal, time to rejection reversal, and recurrence of rejection.. Thirty-one eyes of 31 patients (17 and 14 eyes in group 1 and 2, respectively) were included in the study. The rejection episode completely resolved in 88.2% of patients in group 1 and 85.7% of patients in group 2 [hazard ratio = 0.60, 95% confidence interval (CI) = 0.28-1.29, P = 0.191]. After adjusting for preoperative factors using the inverse-probability weighting method, the time to resolution of rejection was significantly shorter in group 1 than group 2 (average treatment effect = 16, 95% CI, 3.7-28.7, P = 0.013). The recurrence rate of rejection was significantly higher in group 2 (39.7, 95% CI, 12.8-92.6 per 1000 months of follow-up) than in group 1 (3.6, 95% CI, 0.05-19.9 likewise); risk ratio: 11.1, 95% CI, 1.3-95.0, P = 0.028.. Topical tacrolimus 0.05% as an adjunct to steroids can hasten the resolution of endothelial rejection of a PKP graft and potentially decreases the recurrence of rejection. However, it may not improve rejection reversal success.

Topics: Acute Disease; Administration, Topical; Adolescent; Adrenal Cortex Hormones; Adult; Aged; Chemotherapy, Adjuvant; Corneal Diseases; Female; Graft Rejection; Humans; Immunosuppressive Agents; Keratoplasty, Penetrating; Male; Middle Aged; Ophthalmic Solutions; Prednisolone; Recurrence; Tacrolimus; Young Adult

To evaluate the safety and efficacy of topical tacrolimus 0.05% versus topical methylprednisolone 0.5% in patients with ocular graft-versus-host disease (GVHD).. Phase 1/2 prospective, randomized, double-masked clinical trial.. Eighty eyes of 40 patients diagnosed with chronic ocular GVHD were enrolled.. Forty patients with ocular GVHD were randomized; 24 patients were treated with topical tacrolimus 0.05% and 16 patients were treated with topical methylprednisolone 0.5% twice daily for 10 weeks, in addition to continuing their baseline treatment regimen.. Safety was evaluated based on occurrence of adverse events. Tolerability was assessed based on subject reports of discomfort after drop instillation. Intraocular pressure (IOP) was monitored. The main efficacy end points were corneal fluorescein staining (CFS), tear film break-up time (TBUT), Schirmer test results, and expression of the ocular surface inflammatory markers human leukocyte antigen-DR (HLA-DR) and intercellular adhesion molecule-1 (ICAM-1). Symptoms were evaluated using the Ocular Surface Disease Index (OSDI).. After 10 weeks of treatment, no major adverse events occurred in either treatment group, and there was no significant difference in the composite tolerability scores between the 2 groups (P = 0.06). However, burning sensation was more pronounced with tacrolimus (P = 0.002). Topical tacrolimus was more effective than methylprednisolone in reducing the CFS score at week 10 (55% vs. 23% reduction, respectively; P = 0.01) and achieved significant improvement in TBUT when compared with baseline (P < 0.001). Reduction in OSDI score achieved statistical significance with tacrolimus (27% reduction; P = 0.02), but was marginal with methylprednisolone (32% reduction; P = 0.06). Expression of ICAM-1 by ocular surface epithelium decreased significantly in both groups (tacrolimus, P = 0.003; methylprednisolone, P = 0.008), whereas HLA-DR expression decreased significantly only in the tacrolimus group (P = 0.03). Schirmer test scores did not change significantly in either group during the study; IOP increased significantly with methylprednisolone at week 10 (P = 0.04).. Topical tacrolimus 0.05% is safe, generally well tolerated, and effective for the treatment of ocular GVHD without the hypertensive effects of topical corticosteroids.

Topics: Administration, Topical; Adult; Aged; Anti-Inflammatory Agents; Conjunctival Diseases; Corneal Diseases; Double-Blind Method; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Male; Methylprednisolone; Middle Aged; Prospective Studies; Tacrolimus

To describe the outcomes of allograft ocular surface stem cell transplantation (OSST) and the complication profile of systemic immunosuppression (SI) in pediatric patients with limbal stem cell deficiency.. This was a retrospective interventional case series from a single tertiary referral institution of 20 eyes from 13 patients who 1) underwent allograft OSST surgery, 2) were 18 years or less at time of OSST, and 3) received SI with 4) a minimum of 12-months follow-up. The main outcome measures were ocular surface stability, visual acuity, and SI adverse events.. The mean age of patients was 15.1 ± 3.2 years (range 9-18 years). The mean follow-up was 5.6 ± 5.0 years after OSST. At the last follow-up, 15 eyes (75%) had a stable ocular surface, 1 eye (5%) developed partial failure, and 4 eyes (20%) developed total surface failure. Preoperative mean logarithm of the minimum angle of resolution visual acuity 1.5 improved to 1.1 at the last follow-up (P = 0.1); when 4 eyes of 3 nonadherent patients were excluded, the results were more pronounced and statistically significant (1.5 improved to 1.0, P = 0.002). SI was tolerated well by all patients with minimal adverse events.. OSST provides a stable ocular surface and is a successful treatment option for pediatric patients with limbal stem cell deficiency. SI is well-tolerated with a minimal complication profile.

Topics: Adolescent; Allografts; Child; Corneal Diseases; Drug Combinations; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Limbus Corneae; Male; Mycophenolic Acid; Retrospective Studies; Stem Cell Transplantation; Stem Cells; Tacrolimus; Treatment Outcome; Visual Acuity

Topics: Adenovirus Infections, Human; Corneal Diseases; Humans; Keratoconjunctivitis; Tacrolimus

To report a case of local transmission of invasive lobular carcinoma from a donor to a recipient in a keratolimbal allograft after cessation of systemic immunosuppressive therapy.. This is a case report including the clinicopathologic findings. Sections of the donor breast tumor and recipient conjunctival lesions were stained with hematoxylin and eosin. Immunohistochemical studies were performed using pancytokeratin, CK7, CK20, CAM 5.2, CD138, TTF1, estrogen receptor, progesterone receptor, GATA-3, GCDFP-15, and mammaglobin. Polymerase chain reaction-based DNA profiling of tumor cells was performed.. Histopathologic examination revealed an infiltrate of atypical cells with large hyperchromatic nuclei consistent with carcinoma. Immunohistochemical analysis showed pancytokeratin, CK7, CAM 5.2, GATA-3, and estrogen receptor positivity and progesterone receptor absence, consistent with the previously determined phenotype of the donor's breast carcinoma. Results of polymerase chain reaction analysis were also consistent with the donor's tumor. After reduced dosing of tacrolimus and mycophenolate mofetil, 2 limbal tumors occurred in the recipient. The immunosuppressive treatment had been stopped completely before the appearance of the third lesion. The recipient had no history of malignancy, and she had routine screenings for breast cancer.. We report a case of donor-derived breast carcinoma in a keratolimbal allograft recipient. The grafted tissue harbored donor-derived tumor cells for more than 4 years after surgery even after systemic immunosuppression was discontinued. Although no similar reports of tumor transfer could be found in the literature, this case suggests the need for increased stringency in donor selection and heightened surveillance for such tumor transmission.

Topics: Aged; Allografts; Biomarkers; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Lobular; Conjunctival Neoplasms; Corneal Diseases; DNA Fingerprinting; Female; GATA3 Transcription Factor; Humans; Immunohistochemistry; Immunosuppressive Agents; Keratin-7; Keratins; Limbus Corneae; Mycophenolic Acid; Polymerase Chain Reaction; Receptors, Estrogen; Stem Cell Transplantation; Tacrolimus; Tissue Donors

To report a case of probable donor-derived cytomegalovirus (CMV) infection after keratolimbal allograft (KLAL) transplantation.. Observational case report.. A 41-year-old man with a history of aniridic keratopathy and limbal stem cell deficiency underwent KLAL in his right eye. Preoperatively, he was negative for CMV IgG and IgM. Postoperatively, he was maintained on tacrolimus and mycophenolate mofetil for systemic immunosuppression; he was also on prophylactic valganciclovir (for CMV) and trimethoprim/sulfamethoxazole (for pneumocystis pneumonia) for 1 month. Approximately 5 weeks postoperatively, he developed a nonproductive cough, rhinorrhea, and dyspnea. His condition did not improve with oral azithromycin or levofloxacin. He developed worsening symptoms over the next 2 weeks despite therapy. The serum CMV polymerase chain reaction was positive, and he was readministered valganciclovir with subsequent resolution of symptoms.. We present the first case of CMV disease in a seronegative patient who received a presumed CMV-seropositive donor KLAL. Similar to solid organ transplantation, prophylactic and therapeutic management of CMV infection is necessary in the setting of systemic immunosuppression.

Topics: Adult; Allografts; Antiviral Agents; Corneal Diseases; Cytomegalovirus Infections; Drug Therapy, Combination; Eye Infections, Viral; Ganciclovir; Humans; Limbus Corneae; Male; Mycophenolic Acid; Stem Cell Transplantation; Tacrolimus; Tissue Donors; Valganciclovir

Psoriasis is a common chronic inflammatory skin disease. Ocular manifestations, which occur in 10% to 20% of cases of psoriasis, are usually bilateral and often present during an exacerbation of the psoriasis. Serious corneal involvement is rare but can be devastating.. Two cases of sterile corneal infiltrates secondary to an exacerbation of psoriasis are presented. Treatment involved the use of 0.02% topical tacrolimus ointment, which resulted in resolution of the symptoms and infiltrates.. Topical tacrolimus may be considered as an alternative treatment option to corticosteroids in sterile corneal infiltrates.

Topics: Administration, Topical; Adult; Corneal Diseases; Humans; Immunosuppressive Agents; Male; Ointments; Psoriasis; Tacrolimus

To investigate the effectiveness of topical tacrolimus treatment on herpetic stromal keratitis (HSK) in a rat model.. The development of HSK was monitored for 14 days after the inoculation of rats with herpes simplex type 1 virus. Rats that developed HSK were divided into four groups as follows: (1) topical antiviral treatment (control), (2) topical antiviral and 1% prednisolone acetate, (3) topical antiviral and 0.03% tacrolimus ointment, and (4) topical antiviral plus 0.1% tacrolimus ointment. After 14 days of treatment, the severity levels of HSK were scored and compared with the levels before the treatment. The expression of CD3, CD4, and CD8 was evaluated by flow cytometry. The development of the disease was evaluated clinically and histologically.. Significant improvement in vascularization was observed in the groups with the drug treatment in addition to the antiviral agent (P<0.05), but there was no obvious difference within groups 2, 3, and 4 in the vascularization severity. The regression of corneal edema was 8.05%±6% in group 1, 25.17%±14.55% in group 2 (P=0.01), 36.40%±21.69% in group 3 (P=0.03), and 46.39%±14.96% in group 4 (P=0.00). A significant decrease in the number of inflammatory cells in the groups with the drug treatment was evaluated by immunohistochemical staining and confirmed by flow cytometry analysis.. Topical tacrolimus treatment caused a significant decrease in corneal vascularization accompanied by a lower number of inflammatory cells in the experimental HSK corneal edema model. Therefore, topical tacrolimus has the potential to be used in the treatment of HSK.

Topics: Administration, Topical; Animals; CD3 Complex; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Corneal Diseases; Corneal Stroma; Disease Models, Animal; Eye Infections, Viral; Flow Cytometry; Glucocorticoids; Herpesvirus 1, Human; Immunosuppressive Agents; Keratitis, Herpetic; Ophthalmic Solutions; Prednisolone; Prospective Studies; Rats; Rats, Wistar; Tacrolimus

Nephropathic cystinosis is a rare disorder causing the accumulation of intracellular cystine crystals in tissues. The damage to the proximal tubules of the kidneys results in Fanconi syndrome, and patients with cystinosis experience the progression of chronic kidney disease, resulting in the need for kidney transplantation. Treatment of cystinosis with cysteamine has proven to be effective; however, it has many gastrointestinal side effects that are concerning for transplant specialists during the immediate post-transplant period. Transplant specialists routinely discontinue cysteamine therapy for up to six weeks to ensure proper immunosuppressant absorption. This practice is worrisome because it communicates the acceptability of lapses of cysteamine treatment to patients. It may be better to re-initiate cysteamine therapy shortly after transplantation while the patient is followed more closely by the transplant team. This report presents two pediatric patients with nephropathic cystinosis who successfully restarted cysteamine therapy in the immediate post-transplant period without issue in regard to immunosuppression absorption or gastrointestinal side effects. These cases challenge current practice of discontinuing cysteamine therapy during kidney transplantation, and immediate re-initiation of cysteamine therapy in cystinosis patients post-transplant should be considered.

Topics: Adolescent; Child; Corneal Diseases; Cysteamine; Cystinosis; Drug Administration Schedule; Fanconi Syndrome; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Inpatients; Kidney Transplantation; Male; Postoperative Period; Renal Insufficiency; Tacrolimus; Treatment Outcome

The objective of this study was to investigate the efficacy of topical 0.1% tacrolimus in treating refractory allergic conjunctivitis with proliferative lesions and/or corneal involvement.. This prospective observational study included 1436 patients with refractory allergic conjunctivitis whose condition had responded poorly to conventional antiallergic drugs and/or topical steroids and/or topical cyclosporine. All patients received tacrolimus eye drops twice daily during the study period. Ten clinical signs and six clinical symptoms were rated on a four-grade scale. The primary endpoint was the change from baseline in total clinical signs and symptoms score at the last observation or following 6 months of treatment.. Total signs and symptoms score significantly decreased after 1 month of treatment (p<0.001). Giant papillae and corneal lesions were also reduced by tacrolimus eye drop use (p<0.001). The drug proved effective in patients whose condition did not respond well to topical cyclosporine therapy. About 50% of all patients using topical steroids were weaned. The most common adverse reaction was a transient burning sensation (3.20%).. Tacrolimus eye drops are highly effective in treating refractory allergic conjunctivitis with proliferative lesions and/or corneal involvement, and may reduce or replace topical steroid use.. UMIN 000008640.

Topics: Adolescent; Adult; Child; Conjunctivitis, Allergic; Corneal Diseases; Female; Humans; Immunosuppressive Agents; Male; Ophthalmic Solutions; Prospective Studies; Tacrolimus; Young Adult

To report postoperative complications of keratolimbal allograft (KLAL) transplantation in patients with bilateral total limbal stem cell deficiency.. In this retrospective observational case series, medical charts of 45 patients with at least 6 months of follow-up were reviewed. The main outcome measure was postoperative complications including graft-related issues (thickness, position, and alignment) and immunologic rejection.. Sixty-six KLALs were performed on 45 eyes. The mean follow-up period was 26.1 ± 11.8 months (range, 6-48 months). Primary failure occurred in 5 eyes primarily as a result of ocular surface exposure and severe dry eyes. Graft-related complications included misalignment (4 eyes), buttonhole (4), inner-edge tear (4), inadvertent limbal trephination (2), and thick KLAL (2). Postoperatively, regional thinning of the graft was observed in 8 KLALs as a result of exposure, regional ischemia, and after epithelial rejection. Acute rejection was diagnosed 16 times in 8 eyes, whereas chronic rejection was observed in 24 eyes. At last follow-up, 12 cases (26.6%) had failed because of recurrent acute rejection (4), chronic rejection (5), refractory herpetic keratitis (1), exposure (1), and refractory papillomavirus keratitis (1).. KLAL may be complicated by several adverse events. The most important complications are immunologic rejections, chronic ocular surface exposure, and graft-related complications.

Topics: Adolescent; Adult; Cell Transplantation; Child; Corneal Diseases; Drug Therapy, Combination; Epithelium, Corneal; Female; Graft Rejection; Humans; Immunosuppressive Agents; Limbus Corneae; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Stem Cell Transplantation; Tacrolimus; Tissue Donors; Transplantation, Homologous; Young Adult

The administration of topical tacrolimus (FK506) eye drops or ointment is effective in treating certain immunologic corneal diseases and in the prevention of rejection of high-risk corneal grafts. The purpose of this study is to determine the optimal formulation of tacrolimus 0.06% eye drops. A procedure for preparation is presented and discussed.. Tacrolimus monohydrate powder and virgin castor oil are used in this new formulation. The manufacturing process guarantees consistency of product sterility. Measurement by high-performance liquid chromatography allows precise control of the concentration of tacrolimus.. The manufacture and packaging of tacrolimus 0.06% eye drops involve numerous controls allowing for guaranteed sterility and stability. The drops remained sterile and stabile for 28 days after opening regardless of storage conditions and can be stored for 3 months after manufacture. Tolerability studies are currently being performed.

Topics: Castor Oil; Chromatography, High Pressure Liquid; Corneal Diseases; Humans; Immunosuppressive Agents; Ophthalmic Solutions; Osmolar Concentration; Powders; Tacrolimus

To describe the systemic immunosuppression protocol used at the Cincinnati Eye Institute and University of Cincinnati, and to evaluate the success, tolerability, and side effects of systemic immunosuppression in patients undergoing ocular surface stem cell transplantation (OSST).. Retrospective study of all patients who had OSST from 1997 to 2007 and received follow-up for systemic immunosuppression at the Cincinnati Eye Institute. Patients were analyzed for demographics, systemic immunosuppression exposure, ocular surface stability, efficacy, and toxicity variables.. A total of 225 eyes from 136 patients with a mean age of 43.6 years (range, 8.9-80.6 years) underwent OSST with systemic immunosuppression. The most common systemic immunosuppression regimen consisted of tacrolimus, mycophenolate mofetil, and a short course (1-3 months) of prednisone (102/136 patients, 75%). Prophylactic valganciclovir and trimethoprim/sulfamethoxazole (dapsone if sulfa allergy was present) were also used. Mean duration of immunosuppression was 42.1 months (range, 3.6-128 months) and mean follow-up time after OSST was 53.9 months (range, 3.6-147.3 months). At the patients' final follow-up visit, 105/136 patients (77.2%) had a stable ocular surface. There were 3 severe adverse events in 2 patients (1.5%) and 21 minor adverse events in 19 patients (14.0%). Of the 21 patients with adverse events, 10 (47.6%) had systemic comorbidities at initial presentation.. The prevention of graft rejection with the use of systemic immunosuppression after OSST is crucial and should be approached with the same rigor as in solid organ transplantation. With appropriate long-term monitoring by the cornea specialist and transplant physician, the risk of irreversible toxicity at current dosages of systemic immunosuppression in this population is minimal.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Corneal Diseases; Drug Therapy, Combination; Epithelium, Corneal; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Limbus Corneae; Male; Middle Aged; Mycophenolic Acid; Prednisone; Retrospective Studies; Stem Cell Transplantation; Tacrolimus; Time Factors; Young Adult

To determine the long-term outcomes of keratolimbal allograft (KLAL).. Scores of such risks as infrequent blinking, blink-related microtrauma, conjunctival inflammation, elevated intraocular pressure, dry eye, symblepharon, lagophthalmos, and previous KLAL or penetrating keratoplasty (PKP) failure were calculated and recorded before, during, and after KLAL. Prolonged oral mycophenolate mofetil and tacrolimus and short-term prednisone and acyclovir were administered in 12 eyes (10 consecutive patients) with total limbal stem cell deficiency after KLAL. Ten eyes underwent subsequent PKP.. More corrective measures were required in eyes with higher risk scores. During a follow-up of 61.2 months (standard deviation [SD], 18.2; range, 36-91 months) after KLAL, postoperative epithelial breakdown due to exposure occurred late in the period after PKP and remained a primary risk. Mean daily doses of 1.4 g of mycophenolate mofetil and 1.6 mg of tacrolimus were administered for 52.7 months (SD, 22.5; range, 23-91 months) with few adverse effects and reached trough levels of 1.6 microg/mL (SD, 0.6 microg/mL) and 4.5 ng/mL (SD, 2 ng/mL), respectively. Keratolimbal allograft and PKP rejection was noted in 2 and 3 eyes, respectively, though there was a reversal in 1 eye in each group, yielding final KLAL and PKP survivals in 10 and 8 eyes, respectively, and ambulatory visual acuity of up to 20/20 in 10 eyes for 67.2% of the entire follow-up period.. Correction of ocular surface deficits combined with an immunosuppressive regimen further improves the long-term outcome of KLAL in eyes with total limbal stem cell deficiency.

Topics: Adult; Aged; Amnion; Combined Modality Therapy; Corneal Diseases; Drug Therapy, Combination; Epithelial Cells; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Limbus Corneae; Male; Middle Aged; Mycophenolic Acid; Risk Factors; Stem Cell Transplantation; Stem Cells; Suture Techniques; Tacrolimus; Transplantation, Homologous; Treatment Outcome

The purpose of our study was to compare the effectiveness of immunosuppressive drugs on the prevention of allograft rejection in a murine model of low-risk and high-risk keratoplasty. The therapy included FK 506 (tacrolimus; 0.2 mg/kg), mycophenolate mofetil (30 mg/kg), aminoguanidine (0.1 g/kg), and combination of FK506 + mycophenolate mofetil or FK506 + aminoguanidine. The results obtained from the Gray's survival model stratified according to the type of subjects suggest that a major rejection risk reduction was achieved using FK506; good results also were obtained for mycophenolate mofetil. Although the point estimates of both the survival and relative risk of rejection suggest a deferred effect of the combination FK506 + mycophenolate mofetil, this finding did not prove statistically significant.

Topics: Animals; Corneal Diseases; Corneal Transplantation; Disease Models, Animal; Drug Combinations; Female; Graft Rejection; Graft Survival; Guanidines; Immunosuppressive Agents; Male; Mice; Mycophenolic Acid; Risk Factors; Tacrolimus; Transplantation, Homologous