tacrolimus and Behcet-Syndrome

Myelodysplastic syndrome (MDS) in children is often associated with chromosomal anomalies and trisomy 8 is a characteristic karyotypic feature in up to 20% of the cases. Behçet disease is a rare multisystem inflammatory disorder characterized by recurrent mouth and genital ulcers. MDS with trisomy 8 has been observed in adult patients with Behçet syndrome with some cases developing prior to the clinical manifestations of the latter. We present a female with a similar association and explain the importance of identifying the coexisting conditions. The immunological abnormalities, which may be observed in MDS and their possible mechanisms, are also discussed.

Topics: Adolescent; Anemia, Refractory; Behcet Syndrome; Chromosomes, Human, Pair 8; Female; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Karyotyping; Oral Ulcer; Tacrolimus; Thalidomide; Trisomy

Experimental autoimmune uveoretinitis (EAU) induced by immunization with retinal antigen (Santigen or interphotoreceptor retinoid-binding protein; IRBP) serves as an animal model of human uveoretinitis. As the first stage, we demonstrated the similarities between EAU and ocular inflammation in Behçet's disease by investigating anti-retinal antibodies, leukocyte migration inhibition by retinal antigen, immunogenic antigens, aberrant functions of neutrophils, and dominant Th1 lymphocyte reaction. From these findings, we verified that EAU, which is not associated with the systemic disorders observed in Behçet's disease, is an appropriate model for translational research targeting ocular inflammation. In the second stage, we set 3 therapeutic strategies for uveitis in Behçet's disease to be conducted in the translational research: (1) intraocular administration of an immunosuppressive drug; (2) inhibition of Th1 lymphocytes; and (3) activation of immunoregulatory cells. In strategy 1, our studies indicated that intravitreal injection of 10 microg of tacrolimus (FK 506) was not harmful to the retina and was predominantly effective in suppressing ongoing EAU in rats. In strategy 2, two approaches were adopted to prevent differentiation of Thl cells. One is anti-cytokine antibody therapy using anti-IL-12 monoclonal antibodies(mAb). The other is blockade of co-stimulatory signals, especially the ICOS-B7RP-1 pathway. Administration of anti-IL-12 mAb at the time of IRBP immunization completely inhibited development of EAU, and antagonistic anti B7RP-1 mAb suppressed the severity of EAU even when administered after development of EAU. In strategy 3, adoptive transfer of antigen presenting cells treated with a neuropeptide (vasoactive intestinal peptide or calcitonin gene-related peptide) or CD 4+ CD 25+ regulatory T cells suppressed EAU. We look forward to the day when therapies that are being developed in our translational research using EAU will become available for treating intraocular inflammation in Behçet's disease.

Topics: Adoptive Transfer; Animals; Antibodies, Monoclonal; Antigens, Differentiation, T-Lymphocyte; Autoimmune Diseases; Behcet Syndrome; CD28 Antigens; CD4-Positive T-Lymphocytes; Disease Models, Animal; Humans; Inducible T-Cell Co-Stimulator Protein; Interleukin-12; Interleukin-2 Receptor alpha Subunit; Neuropeptides; Rats; Retinitis; Tacrolimus; Th1 Cells; Uveitis

Behçet's disease (BD) is a chronic, relapsing, systemic inflammatory vasculitis of unknown aetiology with a myriad of immunological and pathological consequences. Patients with BD are clustered along the ancient silk road, extending from Far-East Asia to Turkey. The disease affects both genders of all ages from infants to the elderly. It is a long-term, cyclical disease and such patients may have symptom-free periods of weeks, months or years that are interrupted by exacerbations of varying intensities lasting a few days, weeks or months. Clinical features include oral aphthae, genital ulcers, ocular inflammation, skin lesions, as well as articular, vascular, neurological, pulmonary, gastrointestinal, renal and genitourinary manifestations. The main histopathological finding is a widespread vasculitis of the arteries and veins of any size or thrombophilia according to the site of involvement. BD may start with just one or two small symptoms but other symptoms may gradually appear over the years. Recurrent ocular inflammation, which occurs in approximately 50% of cases, is the major morbidity that may eventually lead to blindness. The treatment of BD is usually symptomatic and palliative. Therefore, the main objectives are to relieve symptoms associated with mucocutaneous lesions and arthritis, to modify the course of the disease, to control inflammatory eye disease, clinically suppress the inflammation and vasculitis, to prevent recurrences and thus, prevent irreversible damage. The choice of treatment is based on the severity of systemic involvement, clinical presentation and the site affected. The preferred treatment modalities are combined drug therapy and include topical therapies as well as systemic corticosteroids, NSAIDs, colchicine, dapsone and immunosuppressive and cytotoxic agents. Such therapies are tailored to the individual patient depending on clinical manifestations. Thalidomide, tacrolimus, IFN-alpha and anti-TNF monoclonal antibody have recently attracted attention as novel therapeutic approaches.

Topics: Behcet Syndrome; Humans; Interferon-alpha; Tacrolimus; Thalidomide; Tumor Necrosis Factor-alpha; Turkey

Topics: Behcet Syndrome; Chaperonin 60; Cyclosporine; Cytokines; Drug Administration Schedule; Female; HLA-B Antigens; HLA-B51 Antigen; Humans; Immunosuppressive Agents; Male; Tacrolimus

In this review we summarize selected articles that have been published about immunosuppressive agents in the past year. These studies fall into three major categories: 1) use of pulse cyclophosphamide in autoimmune diseases other than systemic lupus erythematosus; 2) use of newer immunosuppressive agents such as cyclosporine and FK506 in a variety of rheumatic diseases; and 3) toxicity.

Topics: Adult; Arthritis, Juvenile; Azathioprine; Behcet Syndrome; Child; Cladribine; Cyclophosphamide; Cyclosporine; Drug Therapy, Combination; Granulomatosis with Polyangiitis; Humans; Hydroxychloroquine; Immunosuppressive Agents; Liver; Lung; Lung Injury; Lupus Erythematosus, Systemic; Methotrexate; Pemphigoid, Benign Mucous Membrane; Retina; Tacrolimus; Thalidomide

Behçet's disease is an inflammatory disorder affecting many organs including the eye and one of the most common sight-threatening causes in countries around the Mediterranean basin and in the Asia including Japan, Korea and China. A number of clinical and laboratory findings suggest the significant involvement of the immune alterations in the pathophysiology and the pathogenic mechanisms of Behçet's disease. The immune alterations demonstrated in the disease include the alteration of the T cell circuitry and abnormal functions of the leukocyte. Because immunologic processes are believed to be in the chain of events in the manifestation of Behçet's disease, various agents capable of modulating the immune responses have been used to treat the disease. These drugs include corticosteroids, colchicine, cytotoxic agents, and immunophilin ligands (cyclosporine and FK506). This paper reviews the experimental and clinical investigations to analyze the immunopharmacological activities of these immunosuppressive agents in animal models and in patients with Behçet's disease.

Topics: Adrenal Cortex Hormones; Animals; Antineoplastic Agents; Behcet Syndrome; Colchicine; Cyclosporine; Humans; Immunosuppressive Agents; Immunotherapy; Ligands; Tacrolimus; Uveitis

The ocular complications of Behçet's disease are considered one of the major criteria upon which the diagnosis is based. Its complications are frequently sight threatening and require constant attention. The ocular disease is characterized by repeated, explosive ocular inflammatory attacks which get better by themselves, so that in-between attacks there is little or no evidence of inflammatory disease in the eye. The anterior segment can be involved alone, most frequently presenting as a severe anterior uveitis, frequently with hypopyon. This is not associated with a poor visual outcome, and usually treated with topical medication to make the patient more comfortable. However, the anterior segment disease is usually accompanied by recurrent retinal vaso-occlusive disease which is sight threatening if repeated attacks occur. Treatment is with systemic medications, including corticosteroids, cyclosporine, FK506, anti-metabolites, and cytotoxic agents. Complications of the inflammation can include retinal and optic atrophy, vitreous hemorrhage, neovascular glaucoma, and retinal detachment.

Topics: Adrenal Cortex Hormones; Anterior Eye Segment; Behcet Syndrome; Cataract; Colchicine; Cyclosporine; Humans; Tacrolimus; Uveitis; Vitreous Body

To elucidate the role played by HLA-B51 in the neutrophil hyperfunction of Behcet's disease, we determined the superoxide production by purified peripheral blood neutrophils from Behcet's disease patients, from HLA-B51 positive healthy individuals, and from HLA-B51 transgenic mice. As a result, a significant correlation between the neutrophil hyperfunction and the possession of HLA-B51 phenotype, regardless of the presence of the disease, was observed in humans. FMLP-stimulated neutrophils (without in vitro priming) from HLA-B51 transgenic mice, but not those from HLA-B35 transgenic mice or from nontransgenic mice, produced substantial amounts of superoxide. The HLA-B51 molecule itself may thus be responsible, at least in part, for neutrophil hyperfunction in Behcet's disease. CD4+ alphabeta T cells in this disease proliferated vigorously in response to specific peptide derived from human heat shock protein (HSP)-60; however, CD4+ alphabeta T cells from normal subjects or patients with rheumatoid arthritis did not. This peptide has the amino acid sequence 336-351 of human HSP60, which is similar, but not identical to specific peptide of mycobacterial HSP-65. To clarify whether the peptide stimulates patients' T cells as a polyclonal activator, a specific antigen or superantigen-like substance, we have also analyzed TCR usage of responsive T cells by means of TCR Vbeta subfamily-specific mAbs and PCR single strand conformation polymorphism-based technique. We found that T cells with specific TCR Vbeta subfamilies proliferated and increased in number in response to the peptide by an antigen-specific fashion. The result of recurrent exposure to the HSP may break the tolerance to self HSP, and provoke T cell responses to self and microbial HSP. Such T cells may produce Th1-like proinflammatory cytokines and lead to tissue injury possibly via delayed-type hypersensitivity reaction, macrophage activation, and activation and/or recruitment of neutrophils. Our data shed a new light on the autoimmune nature of Behcet's disease; a novel multistep molecular mimicry mechanism may induce and/or exacerbate Behcet's disease by bacterial antigens that activate T cells previously educated by self-peptide(s) of HSP. This would lead to positive selection of autoreactive T cells in this disease.

Topics: Animals; Behcet Syndrome; Cyclosporine; Female; Heat-Shock Proteins; HLA-B Antigens; Humans; Immunosuppressive Agents; Male; Neutrophils; Reference Standards; T-Lymphocytes; Tacrolimus

To determine whether the addition of 26 weeks of subcutaneous peginterferon-α-2b could reduce the requirement for systemic corticosteroids and conventional immunosuppressive medication in patients with Behçet's disease (BD).. We conducted a multicentre randomised trial in patients with BD requiring systemic therapy. Patients were randomised to 26 weeks of peginterferon-α-2b in addition to their standard care or to standard care only and followed 6-monthly for 3 years with BD activity scores and quality of life questionnaires. Patients at one centre had blood taken to measure regulatory T cells (Tregs) and Th17 cells.. 72 patients were included. At months 10-12, while among the entire patient population there was no difference in the corticosteroid dose or immunosuppression use between the treatment groups (adjusted OR 1.04, 95% CI 0.34 to 3.19), post hoc analysis revealed that in patients who were on corticosteroids at baseline the corticosteroid requirement was significantly lower in the peginterferon-α-2b (6.5 (5-15) mg/day) compared with the non-interferon group (10 (8.25-16.5) mg/day, p=0.039). Furthermore, there was a trend towards an improved quality of life that became significant by 36 months (p=0.008). This was associated with a significant rise in Tregs and a decrease in Th17 cells which was still present at 1 year and 6 months after the interferon was stopped. The safety profile was similar with adverse events in 10% in both groups.. The addition of peginterferon-α-2b to the drug regime of BD patients did not significantly reduce their corticosteroid dose required at 1 year. However, in those on corticosteroids at baseline post hoc analysis demonstrated that the addition of peginterferon-α-2b did result in a significant reduction in corticosteroid dose with a significantly improved quality of life and trend to reduce other required immunosuppressive agents. This effect was seen at 1 year and associated with a rise in Tregs suggesting a possible mode for interferon action.. ISRCTN 36354474; EudraCT 2004-004301-18.

Topics: Adrenal Cortex Hormones; Adult; Antiviral Agents; Azathioprine; Behcet Syndrome; Cyclosporine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Lymphocyte Count; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Polyethylene Glycols; Quality of Life; Recombinant Proteins; Single-Blind Method; Surveys and Questionnaires; T-Lymphocytes, Regulatory; Tacrolimus; Th17 Cells; Treatment Outcome

Genital aphthous ulcers of Behcet's disease (BD) are painful and usually resistant to local treatments. Pimecrolimus is an ascomycin macrolactam, used in inflammatory skin diseases.. To discover if pimecrolimus can accelerate the healing of BD genital aphthous ulcers.. Ninety patients with genital aphthous ulcers were enrolled. Only patients treated with colchicine alone were selected. All patients signed a written consent form. Patients were randomly assigned to pimecrolimus or placebo cream, applied twice daily for 1 week. The primary outcome was the healing period. Up to 7 days, it was considered as a positive result. Results were compared by chi-square test. The mean healing time was compared by analysis of variance. Analyses were done both by the 'intention-to-treat' and 'treatment-completed' methods.. Both groups were similar at the entry (gender, age, ulcer size, pain intensity and treatment delay). By intention-to-treat analysis, in the pimecrolimus group, 18 patients had positive and 27 negative results. In the control group, four had positive and 41 negative results. The difference was significant (chi(2) = 10.167, P = 0.001). By treatment-completed analysis, with pimecrolimus, 18 patients had positive and 22 negative results. With placebo, four had positive, and 41 negative results. The difference was significant (chi(2) = 12.574, P = 0.0004). Comparison of mean healing time in the pimecrolimus versus placebo group, demonstrated a significant acceleration both in intention-to-treat analysis (10.7 vs. 20.7 days, F = 17.466, P < 0.0001) and treatment-completed analysis (8.3 vs. 20.7 days, F = 29.289, P < 0.0001).. Pimecrolimus is safe and efficient in the treatment of BD genital ulcers, by accelerating the healing process.

Topics: Administration, Cutaneous; Adolescent; Adult; Behcet Syndrome; Chi-Square Distribution; Dermatologic Agents; Double-Blind Method; Female; Genital Diseases, Female; Genital Diseases, Male; Humans; Iran; Male; Middle Aged; Placebo Effect; Stomatitis, Aphthous; Tacrolimus; Time Factors; Treatment Outcome; Wound Healing; Young Adult

Recurrent and painful genital ulcers are the hallmark of Behçet's disease.. To determine the efficacy of pimecrolimus (PIM) cream on the pain and healing time of genital ulcers.. A total of 76 patients were randomized to either receive PIM cream plus colchicine (COL) tablets (1-2 g/day) or COL tablets (1-2 g/day) alone for 1 month. Clinical evaluations were performed in 68 patients at the baseline and on the 3rd, 7th, 10th, 14th and 28th days of treatment. Also, genital ulcer pain was evaluated using a verbal pain score at each visit. Safety was monitored through adverse event reporting and laboratory tests.. The mean healing time of genital ulcers was shorter in the PIM + COL group (4.2 +/- 1.5 days) than the COL group (4.7 +/- 1.8 days), without statistical significance (p = 0.399). Visual analog scale scores decreased in both groups significantly. Neither of the treatment modalities was found to be superior to the other; however, pain was relieved in 4.2 +/- 0.5 days in PIM + COL group and in 5.5 +/- 1.2 days in COL group in the intention to treat population (p = 0.023). Observed adverse events were transient.. Compared to COL alone, COL + PIM cream shortens the pain duration without any significant effect on healing time.

Topics: Adult; Behcet Syndrome; Colchicine; Dermatologic Agents; Drug Therapy, Combination; Emollients; Female; Genital Diseases, Female; Genital Diseases, Male; Humans; Male; Pain; Pain Measurement; Retrospective Studies; Scrotum; Tablets; Tacrolimus; Treatment Outcome; Turkey; Ulcer; Vagina

A multicenter open study was conducted to investigate optimum dose schedule of FK506 on refractory uveitis associated with Behçet's disease and allied conditions. Fifty-three patients (41 with Behçet's and 12 with allied conditions) were enrolled in this study. A daily oral dose of FK506 was initially 0.05, 0.1, 0.15 or 0.2 mg/kg, but adjusted in more than half patients during the study based on clinical conditions of patients and/or adverse effects of FK506. The improvement rate of initial daily dose as well as final improvement rate were evaluated in the study. The improvement rate of initial daily dose was increased dose-dependently; 37.5% with 0.05 mg/kg initial daily dose group, 60.0% with 0.1 mg/kg, 91.7% with 0.15 mg/kg and 78.6% with 0.2 mg/kg. The final improvement rate was 76.5%. In patients with Behçet's disease, ocular symptoms improved in 30 (75.0%) of 40 patients evaluable for efficacy and the frequency of ocular attacks was significantly reduced. In eight (66.7%) of 12 patients with Behçet's disease in whom cyclosporin treatment had been failed, their ocular symptoms improved by FK506. Main adverse reactions of FK506 were renal impairment (28.3%), neurologic symptoms (22.6%), gastrointestinal symptoms (20.8%), hypomagnesemia (28.3%), hyperkalemia (13.2%), and hyperglycemia (13.2%. Most of the adverse effects disappeared or ameliorated after FK506 dose reduction or withdrawal from FK506 therapy. It seems that the incidence of the adverse effects depends on the dosage of FK506. The lower dosage (0.05 and 0.1 mg/kg) caused a relatively small number of adverse effects, and the higher dosage (0.15 and 0.2 mg/kg) caused them more frequently. Through level is recommended to maintain between 15-25 ng/ml during early days of treatment based on the safety and efficacy. It is also recommended that a initial daily dose is 0.15 mg/kg on the basis of the efficacy and safety results, and then adjusted based on symptoms of patients and whole blood through level of FK506.

Topics: Administration, Oral; Adolescent; Adult; Aged; Behcet Syndrome; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Tacrolimus; Uveitis

We studied the clinical effects of the immunosuppressive agent FK506 in patients with noninfectious uveitis.. This study was designed as a multicenter open clinical trial in Japan. Sixteen patients with noninfectious uveitis who had visited the Uveitis Survey Clinic of the Yokohama City University Hospital were given FK506. Eight had Behçet's disease; five, Vogt-Koyanagi-Harada syndrome; one, sympathetic ophthalmia; one, retinal vasculitis; and one, sarcoidosis. In patients with Behçet's disease, ocular attack score before and after therapy was compared to judge clinical status. For the other diseases, the ocular inflammatory symptoms were observed after the initiation of FK506 treatment. All patients underwent blood and urine examinations, electrocardiography, and chest x-rays before and after FK506 treatment.. Of the patients with Behçet's disease, five improved, one remained unchanged, one deteriorated, and the status of one could not be determined. Of the patients with Vogt-Koyanagi-Harada syndrome, four improved, and one remained unchanged. The patient with sympathetic ophthalmia improved, the patient with retinal vasculitis remained unchanged, and the status of the patient with sarcoidosis could not be determined. Major adverse effects were sensations of warmth, hypomagnesemia, renal dysfunction, glucose intolerance, nausea, vomiting, and disorders of the central nervous system. All adverse effects disappeared or improved when FK506 was stopped or when the dosage was decreased. Renal dysfunction and glucose intolerance appeared when the blood level of FK506 was high.. FK506 was effective in patients with uveitis, but it is important to monitor the occurrence of adverse effects.

Topics: Adult; Aged; Behcet Syndrome; Endophthalmitis; Female; Humans; Male; Middle Aged; Retinitis; Tacrolimus; Uveitis; Uveomeningoencephalitic Syndrome; Vasculitis

Efficacy of a new immunosuppressive agent, FK506, in refractory uveitis was studied in 8 patients: 5 with Behcet's disease and 3 with idiopathic retinal vasculitis. The agent was given by oral administration every 12 hours. The previous therapy with systemic corticosteroids or immunosuppressive agents including cyclosporine failed to subside uveitis in these cases. During the observation period of 21.6 +/- 7.8 weeks (mean +/- SD) under FK506 at doses with 0.05, 0.1, 0.15 or 0.2 mg/kg/day, the visual acuity was increased in 44% of treated eyes, unchanged in 44% and decreased in 12%. The inflammatory activity in the ocular fundus was improved in 69% and unchanged in 6% of treated eyes. The effects of FK506 on uveitis by the criteria of improvement of visual acuity and uveitis activity was dose-dependent: 0.05 and 0.1 mg/kg/day were ineffective but 0.15 and 0.2 mg/kg/day were effective in most cases. One patient with Behcet's disease converted from cyclosporine developed moderate renal impairment in 4 weeks under FK506 and the therapy was discontinued in 8 weeks, though the uveitis activity as well as visual acuity was markedly improved. Other 7 cases had no side effect of FK506. Although the number of cases was small and observation period was short, the present clinical data indicate that FK506 is effective to treat refractory uveitis.

Topics: Administration, Oral; Adult; Aged; Animals; Antigens; Arrestin; Autoantigens; Autoimmune Diseases; Behcet Syndrome; Drug Evaluation, Preclinical; Eye Proteins; Female; Humans; Injections, Intraperitoneal; Male; Middle Aged; Rats; Rats, Inbred Lew; Tacrolimus; Uveitis; Vasculitis; Visual Acuity

Topics: Adolescent; Adult; Behcet Syndrome; Child; Child, Preschool; Creatinine; Female; Humans; Male; Tacrolimus; Uveitis

Topics: Behcet Syndrome; Humans; Stomatitis, Aphthous; Tacrolimus

The coexistence of acute myeloid leukemia (AML) with Behçet's disease (BD) is rare. The optimum treatment for AML-associated BD has not been established. We herein report a patient with BD who developed AML with myelodysplasia-related changes. Induction chemotherapy caused complete remission of the AML but worsened the BD. Thereafter, AML was treated with azacitidine. The BD was steroid-dependent. Tacrolimus was added, which improved the BD. The patient underwent allogeneic hematopoietic stem cell transplantation (HSCT) and remains in complete remission for both diseases. Allogeneic HSCT was found to be a potent therapeutic option for AML-associated BD. In addition, azacitidine and tacrolimus were shown to be a suitable bridging regimen before HSCT.

Topics: Adult; Antimetabolites, Antineoplastic; Asian People; Azacitidine; Behcet Syndrome; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Remission Induction; Tacrolimus; Transplantation, Homologous; Treatment Outcome

We herein describe the case of a 60-year-old man with a history of Behçet's disease and myelodysplastic syndrome who received cord blood transplantation (CBT). The patient was given anti-thymocyte globulin conditioning and tacrolimus to prevent graft-versus-host disease. Two months after CBT, his blood Tac concentration measured by an antibody-conjugated magnetic immunoassay (ACMIA) was found to have increased >4-fold, even after the Tac treatment was stopped. This false response was caused by the interference of endogenous heterophilic antibodies with ACMIA. Therefore, physicians must be aware of possible false ACMIA results for patients with a history of autoimmune disease and/or treated by xenogeneic antibody therapy.

Topics: Behcet Syndrome; Cord Blood Stem Cell Transplantation; Cyclosporine; False Positive Reactions; Graft vs Host Disease; Humans; Immunoassay; Immunosuppressive Agents; Male; Middle Aged; Myelodysplastic Syndromes; Tacrolimus

Topics: Administration, Oral; Adult; Behcet Syndrome; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Tacrolimus

Topics: Acute Disease; Adult; Behcet Syndrome; Diarrhea; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Oral Ulcer; Recurrence; Tacrolimus

We investigated the concentration of tacrolimus in aqueous humor, and serum of patients with ocular Behçet's disease after topical application in 11 patients. All received 1 drop of isotonic tacrolimus solution 0.3% every 6 hours for 3 days. The mean tacrolimus concentration in the aqueous and serum, as measured by microparticle enzyme immunoassay, were 12.49 and 0.76 ng/mL, respectively. Tacrolimus may be a promising treatment modality in anterior uveitis in Behçet's disease by topical application.

Topics: Absorption; Administration, Topical; Adult; Aqueous Humor; Behcet Syndrome; Female; Humans; Male; Tacrolimus

The aim of this paper is to provide a summary of clinical findings regarding the safety of tacrolimus in pregnancy. From 1992 to 1998 data were collected on 100 pregnancies from 84 mothers who received tacrolimus systemically; 83 cases of solid organ transplantation, and 1 case of Behçet's disease. Maternal mean age at conception was 28 years and pregnancy outcome was live birth in 68%, spontaneous abortion in 12%, induced abortion in 12%, stillbirth/perinatal death in 3%, ongoing pregnancy in 2%, and lost to follow up in 3%. Fifty-nine percent of the neonates were delivered prematurely (< 37 weeks of gestation). Birth weight was appropriate for the gestational age in 90% of the cases. Malformations occurred in 4 neonates: case 1, meningocele and urogenital defects; case 2, alcoholic embryopathy; case 3, ear defect, cleft palate and hypospadia; case 4, multicystic dysplastic kidney. There was no consistent pattern of malformations and 2 mothers subsequently delivered a healthy neonate while on tacrolimus therapy. Nearly 70% of pregnancies following systemic tacrolimus administration resulted in a favourable outcome without any significant effect on intrauterine growth. The incidence of malformations was similar to that reported with other immunosuppressants in transplant recipients.

Topics: Adolescent; Adult; Behcet Syndrome; Birth Weight; Congenital Abnormalities; Female; Gestational Age; Humans; Immunosuppressive Agents; Infant, Newborn; Infant, Premature; Kidney Transplantation; Liver Transplantation; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Retrospective Studies; Tacrolimus; Transplantation Immunology

To elucidate the profile of cytokine-producing T cells in patients with active or inactive Behçet's disease (BD), the frequencies of type 1 (Interleukin- [IL] 2, interferon-gamma [IFN-gamma]) and type 2 (IL-4) cytokine-producing CD4+ and CD8+ cells in peripheral blood were investigated, and the effect of immunosuppressive drugs on the profile of cytokine-producing cells was evaluated.. Fifty-two patients with BD (32 with active and 20 with inactive BD) and 33 healthy control subjects were the subjects in this study. Patients were or were not treated with immunosuppressive drugs. Peripheral blood mononuclear cells were fixed, permeabilized, and stained for intracellular cytokines in combination with cell surface markers CD4 and CD8 for flow cytometric analysis.. In nontreated patients with BD, the frequencies of IL-2- and IFN-gamma-producing CD4 and CD8+ cells in active patients were significantly higher than those in inactive patients. Conversely, the frequencies of IL-4 producing CD4+ and CD8+ cells in nontreated patients with active BD were comparable with those in patients with inactive disease and in control subjects. Patients with inactive BD who were treated with immunosuppressive drugs showed significantly lower frequencies of IL-2- and IFN-gamma-producing CD4+ and CD8+ cells than did treated patients with active BD.. The frequencies of type 1 cytokine-producing CD4+ and CD8+ cells increased in patients with active BD. Effective immunosuppressive treatments decreased the population of type 1 cytokine-producing CD4+ and CD8+ cells. These results suggest that type 1 cytokine-producing cells play an important role in the immunopathogenesis of the inflammation in BD.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Behcet Syndrome; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cells, Cultured; Cyclosporine; Female; Flow Cytometry; Humans; Immunosuppressive Agents; Interferon-gamma; Interleukin-2; Interleukin-4; Kinetics; Male; Middle Aged; Tacrolimus

To examine the in vivo mechanisms of suppression of T lymphocyte function in patients with Behçet's disease (BD) undergoing long-term treatment with tacrolimus (FK-506).. Intracellular proteins were analyzed by immunoprecipitation and Western blotting. Messenger RNA expression was studied by a polymerase chain reaction-based technique.. Interleukin-2 production was suppressed in patients treated with tacrolimus. This suppression was found to be due to inhibition of interactions between activated calcineurin (Cn) and nuclear factor of activated T cells (NF-AT), inhibition of cleavage of the autoinhibitory domain of the CnA subunit, and inhibition of heterodimer formation by CnA and CnB subunits, resulting in the absence of NF-AT in nuclei of the T cells. We found that T lymphocytes in some BD patients treated with tacrolimus had reduced amounts of FK-506 binding protein (FKBP) in their cytoplasm.. Tacrolimus reduces the Cn activity of T cells in vivo by the cumulative effects of several distinct mechanisms. It is plausible that reduced amounts of FKBP may be associated with diminished clinical efficacy in some BD patients receiving prolonged treatment with tacrolimus.

Topics: Adult; Behcet Syndrome; Blotting, Western; Calcineurin; Calmodulin-Binding Proteins; Carrier Proteins; Dimerization; DNA-Binding Proteins; Female; Genetic Variation; Heat-Shock Proteins; Humans; Immunosuppressive Agents; Interleukin-2; Lymphocyte Activation; Male; Middle Aged; Nuclear Proteins; Phosphoprotein Phosphatases; Precipitin Tests; T-Lymphocytes; Tacrolimus; Tacrolimus Binding Proteins

Topics: Adult; Behcet Syndrome; Brain Diseases; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Pons; Tacrolimus

Behçet's disease (BD) affects the lung as well as the intestine, central nervous system, kidney, and other organs. Pulmonary vasculitis is one of the most severe complications in BD because it can cause fatal bleeding. Corticosteroids and other immunosuppressive drugs have been used to treat pulmonary vasculitis, but the efficacy of these agents has not yet been established. We administered FK506, a novel immunosuppressive agent, as a treatment for BD. A 21-year-old woman presented definitive symptoms of BD, ie, repeated oral and genital ulcers, folliculitis, and panuveitis. The patient showed localized pulmonary infiltrates on her chest x-ray film that were histologically proved to be venulitis consistent with BD. These pulmonary infiltrates evanesced after the oral administration of FK506 for 8 weeks; in addition, the skin lesions and uveitis improved. This clinical observation indicates that FK506 is an effective agent in the treatment of pulmonary vasculitis associated with BD.

Topics: Adult; Behcet Syndrome; Female; Humans; Lung; Lung Diseases; Tacrolimus; Vasculitis; Venules