tacrolimus and Crohn-Disease

Nowadays, non-biological treatments remain valuable approaches among the therapeutic armamentarium of inflammatory bowel disease (IBD). Mesalamine is the core treatment of mild‑to‑moderate ulcerative colitis (UC) and corticosteroids are crucial for the induction of remission of moderate‑to‑severe flares in both UC and Crohn's disease (CD). Even approaches as cyclosporine, tacrolimus, azathioprine, methotrexate, and surgery still have a nuclear position as strategies to induce and/or maintain remission in IBD. Due to their particularities and to the accumulated evidence, each of these strategies conquered peculiar roles in the overall IBD strategy, all of them contributing to better outcomes. This review emphasizes the particular roles that non-biological treatments gained over time: recent mesalamine formulations to increase adhesion rates, higher doses of 5-ASA for high-risk patients, MMX technology to improve drug release and attain higher bowel concentrations, cyclosporine as a bridge to vedolizumab, tacrolimus as a potential alternative to thiopurines or infliximab, azathioprine in combination therapy with infliximab and dubious in monotherapy, and surgery as a mean to a "better end".

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Digestive System Surgical Procedures; Gastrointestinal Agents; Humans; Mesalamine; Methotrexate; Tacrolimus; Treatment Outcome

Topics: Administration, Topical; Biopsy, Needle; Blood Chemical Analysis; Crohn Disease; Facial Dermatoses; Follow-Up Studies; Humans; Immunohistochemistry; Infliximab; Male; Photosensitivity Disorders; Psoriasis; Risk Assessment; Tacrolimus; Treatment Outcome; Tumor Necrosis Factor-alpha; Young Adult

Only a few randomized controlled trials (RCTs) and some uncontrolled trials have reported the efficacy and adverse events (AEs) of tacrolimus (Tac) in patients with refractory Crohn's disease (CD). The aim of this study was to undertake a systematic review and meta-analysis of the therapeutic efficacy and AEs of Tac in patients with CD.. We investigated studies reporting the therapeutic efficacy of Tac in patients with CD from 1950 until December 2017. Study subjects were categorized into three groups: systemic administration of Tac for patients with luminal CD (Group 1); systemic administration of Tac for patients with perianal CD (Group 2); and topical administration of Tac for patients with localized CD (Group 3). The primary endpoint of this study was the remission rate. Secondary endpoints were partial response rate, factors related to remission, and the incidence of AEs.. The remission rate of Group 1, 2, and 3 was 37.1, 32.0, and 22.7%, respectively. The partial response rate of those was 42.3, 42.9, and 44.3%, respectively. In addition, the incidence of AEs of those was 50.9, 65.5, and 40.0%, respectively. No life-threatening AEs were observed in any study.. This systematic review and meta-analysis demonstrated that Tac therapy was effective for subpopulation of CD patients and that the incidence of AEs was tolerable. Therefore, Tac therapy should be considered an option for patients with CD. However, there have been few well-designed RCTs on this subject and further studies are required.

Topics: Crohn Disease; Humans; Immunosuppressive Agents; Remission Induction; Tacrolimus; Treatment Outcome

Topics: Adalimumab; Adolescent; Adrenal Cortex Hormones; Anti-Bacterial Agents; Antibodies, Monoclonal, Humanized; Azathioprine; Colitis, Ulcerative; Crohn Disease; Enteral Nutrition; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Mesalamine; Methotrexate; Sulfasalazine; Tacrolimus

Crohn's disease (CD) is a complex disorder with important incidence in North America. Perianal fistulas occur in about 20% of patients with CD and are almost always classified as complex fistulas. Conventional treatment options have shown different success rates, yet there are data indicating that these approaches cannot achieve total cure and may not improve quality of life of these patients. Fibrin glue, fistula plug, topical tacrolimus, local injection of infliximab, and use of hematopoietic stem cells (HSC) and mesenchymal stem cells (MSC) are newly suggested therapies with variable success rates. Here, we aim to review these novel therapies for the treatment of complex fistulizing CD. Although initial results are promising, randomized studies are needed to prove efficacy of these approaches in curing fistulizing perianal CD.

Topics: Crohn Disease; Cutaneous Fistula; Fibrin Tissue Adhesive; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infliximab; Mesenchymal Stem Cell Transplantation; Rectal Fistula; Tacrolimus; Tumor Necrosis Factor-alpha

Topics: Adalimumab; Adult; Anti-Inflammatory Agents; Breast; Cellulitis; Crohn Disease; Diagnosis, Differential; Female; Groin; Humans; Immunosuppressive Agents; Recurrence; Skin Diseases; Tacrolimus; Treatment Outcome

Inflammatory bowel diseases are chronic conditions that frequently affect patients during their childbearing years. Considering the characteristics of disease and the medications used to treat it, several issues arise in the care of these patients when they attempt or achieve conception. We review the most current evidence concerning fertility and pregnancy outcomes in patients with inflammatory bowel diseases. With the exception of those women who undergo pelvic surgery, patients with inflammatory bowel diseases have no decreased fertility. Sulfasalazine decreases fertility in men. When looking at obstetrical outcomes, active disease at conception is associated with an increased risk of preterm delivery and low birth weight. While most medications used to treat inflammatory bowel diseases are low risk, some precautions need to be taken and the risk-to-benefit ratio needs to be considered on an individualized basis. In general, aminosalicylates and thiopurines should be continued, but methotrexate is contraindicated. Anti-tumour necrosis factor agents are considered safe to continue but full monoclonal antibodies do cross the placenta. As a general rule, the it is important to counsel women that conception is optimal when disease is in remission, as adverse obstetrical outcomes are directly associated with disease activity. Clinicians need to educate patients before, during and after conception, emphasizing treatment compliance.

Topics: Adalimumab; Adrenal Cortex Hormones; Aminosalicylic Acids; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Breast Feeding; Certolizumab Pegol; Colitis, Ulcerative; Contraindications; Crohn Disease; Cyclosporine; Female; Fertility; Humans; Immunoglobulin Fab Fragments; Immunosuppressive Agents; Infliximab; Mercaptopurine; Methotrexate; Natalizumab; Polyethylene Glycols; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Tacrolimus

Topics: Crohn Disease; Humans; Immunosuppressive Agents; Proctitis; Tacrolimus

Intravenous cyclosporine A (CsA) is an effective treatment for patients with severe, steroid-refractory ulcerative colitis (UC). Like the response to CsA, clinical trials have shown that two-thirds of patients with refractory UC respond to tacrolimus therapy. However, it is unclear how/when this agent should be used for patients with active UC.. We reviewed the results of previous studies regarding calcineurin inhibitors in UC patients. We examined the best way to use tacrolimus to obtain maximum efficacy by comparing the results from clinical trials with those from a recent survey in Japan.. Calcineurin inhibitors are useful to induce remission in patients with refractory UC; however, the long-term prognosis has not been shown to be improved by CsA. Early intervention with CsA/tacrolimus may improve the long-term prognosis of UC patients just as infliximab does for Crohn's disease patients. Recent studies have indicated that a fasting state and administration of a higher dosage of tacrolimus at the beginning of therapy are critical in ensuring that the target trough concentration of the agent is reached.. The use of higher initial doses of tacrolimus ensured that patients achieved their target levels. Further studies will be needed to elucidate the efficacy of top-down therapy with tacrolimus in patients with UC. Physicians must know how to use calcineurin inhibitors to obtain maximum efficacy.

Topics: Anti-Inflammatory Agents; Antibodies, Monoclonal; Calcineurin Inhibitors; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Humans; Immunosuppressive Agents; Infliximab; Tacrolimus

Inflammatory bowel disease (IBD) is a non-curable disease. Although we seem to have a definitive surgical solution for ulcerative colitis, patients are at risk of suffering from acute and chronic pouchitis as well as peri- and postoperative complications. In Crohn's disease medical treatment is able to prolong surgery-free survival, but no definitive healing strategy is as yet at hand. Moreover, effective medication exposes patients to potentially life-threatening complications. The severely compromised patient in particular needs careful surveillance and requires a balanced treatment strategy endorsed by gastroenterologists and surgeons. Treatment is still aimed at suppressing immune mechanisms and is far from being causal. Nevertheless, this approach has resulted in a reduction in surgical procedures and hospitalizations. The following overview covers special issues related to strategies for severe and fulminant flares of inflammatory bowel disease.

Topics: Algorithms; Anti-Inflammatory Agents; Antibodies, Monoclonal; Colitis, Ulcerative; Critical Care; Crohn Disease; Cyclosporine; Humans; Immunosuppressive Agents; Infliximab; Interdisciplinary Communication; Patient Care Team; Tacrolimus; Tumor Necrosis Factor-alpha

BACKGROUND  Several published studies have evaluated the efficacy of tacrolimus in the management of Crohn's disease with variable conclusions. AIM  To review systematically the evidence examining the efficacy and safety of tacrolimus in treating Crohn's disease. METHODS  The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (PUBMED) and EMBASE (1984 to January 2011) were searched. Also, references from selected articles were examined. Case series (five or more patients), cohort and randomised controlled trials were eligible for inclusion, incorporating oral, intravenous or topical tacrolimus therapy. The primary outcome was induction of remission of active Crohn's disease. RESULTS  Eleven studies met the inclusion criteria which included 163 patients, of which 127 received tacrolimus therapy. In patients with luminal Crohn's disease, the crude pooled remission rate for tacrolimus was 44.3% (range, 7-69%) and the crude pooled response rate was 37.1% (range, 14-57%). For patients with perianal disease using systemic tacrolimus, crude pooled remission rate was 28.6% (range, 0-64%) and crude pooled response rate was 38.8% (range, 0-57%). Combining data from two studies using topical tacrolimus, 35.7% of patients achieved remission and 28.6% partial response. Nonserious adverse effects are common, particularly tremor, paraesthesia and headache. Reversible nephrotoxity occurred in 16% of patients. CONCLUSIONS  The current evidence; although of a poor quality, appears to support the use of tacrolimus in Crohn's disease. High quality randomised controlled trials are needed.

Topics: Crohn Disease; Humans; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Tacrolimus; Treatment Outcome

Topical tacrolimus and pimecrolimus are indicated for treatment of atopic dermatitis, but they have been studied in many off-label uses. Double-blind and open studies have shown favorable results with topical tacrolimus and pimecrolimus in oral lichen planus. In 1 study of oral lichen planus, blood tacrolimus was detected in 54% of patients, but there were no signs of systemic toxicity. Double-blind and open studies of vitiligo have shown favorable results with tacrolimus in combination with excimer laser, especially for lesions over bony prominences and on extremities. Similarly, double-blind studies of vitiligo have shown favorable results when pimecrolimus is combined with narrow-band UVB, especially for facial lesions. Double-blind and open studies of psoriasis have shown favorable results for tacrolimus and pimecrolimus, especially for inverse psoriasis. Topical calcineurin inhibitors have been effective in many other cutaneous disorders, and further studies would help clarify their roles.

Topics: Administration, Cutaneous; Calcineurin Inhibitors; Child; Child, Preschool; Crohn Disease; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Female; Humans; Lichen Planus, Oral; Lupus Erythematosus, Cutaneous; Male; Off-Label Use; Psoriasis; Rosacea; Skin Diseases; Tacrolimus; Therapies, Investigational; Vitiligo

Management of inflammatory bowel disease in childhood poses great challenges. Apart from the disease complications, the drugs' adverse affects, especially corticosteroids, are significant. In the past decade major progress was made in elucidating the pathogenesis of IBD, which led to new treatment options aiming to achieve better control of the disease and decrease the various complications of current therapy. In this review we provide an overview of novel therapies for IBD, their efficacy, safety and their current use in children.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Basiliximab; Child; Crohn Disease; Enzyme Inhibitors; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Integrin alpha4; Mycophenolic Acid; Natalizumab; Probiotics; Receptors, Interleukin-6; Recombinant Fusion Proteins; Tacrolimus; Treatment Outcome

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Antibodies, Monoclonal; Ciprofloxacin; Crohn Disease; Cutaneous Fistula; Endosonography; Female; Humans; Hyperbaric Oxygenation; Infliximab; Magnetic Resonance Imaging; Male; Metronidazole; Perineum; Randomized Controlled Trials as Topic; Rectal Fistula; Rectovaginal Fistula; Tacrolimus

Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Cytapheresis; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Male; Tacrolimus

Topics: Adrenal Cortex Hormones; Adult; Aminosalicylic Acids; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Azathioprine; Budesonide; Colitis, Ulcerative; Colonoscopy; Controlled Clinical Trials as Topic; Crohn Disease; Diagnosis, Differential; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Magnetic Resonance Imaging; Mercaptopurine; Methotrexate; Metronidazole; Pouchitis; Remission Induction; Tacrolimus; Time Factors; Tomography, X-Ray Computed; Ultrasonography

Biologic and other novel therapies targeted to specific pathogenic processes offer the potential for improved treatment outcomes in patients with Crohn's disease and alteration of the course of the disease. Therapies targeted to tumor necrosis factor alpha (TNF-alpha) include anti-TNF-alpha monoclonal antibodies (infliximab and CDP-571), TNF-binding neutralizing fusion proteins (etanercept), and TNF-alpha production inhibitors (thalidomide). In placebo-controlled trials, infliximab has rapidly induced clinical response and remission in patients with moderately to severely active Crohn's disease refractory to conventional therapy and patients with fistulizing Crohn's disease, with minimal toxicity; retreatment with infliximab in patients who experienced an initial response maintained their clinical improvement. Clinical experience suggests that infliximab may also be effective when administered as corticosteroid-sparing therapy. Infliximab is the only anti-TNF-alpha therapy currently available in clinical practice for the treatment of active Crohn's disease. Controlled trials of the investigational anti-TNF-alpha agent CDP-571 show benefit for induction of clinical improvement and steroid-sparing, but further investigation is needed. A pilot study of etanercept suggested a beneficial effect, but its efficacy was not confirmed in a controlled trial. In open-label trials, thalidomide has demonstrated efficacy in patients with refractory Crohn's disease; however, the therapeutic potential of thalidomide may be severely limited by the high incidence of drug-induced side effects. Other novel agents, including anti-alpha4 integrin antibodies, interleukin (IL)-10 and IL-11, and the immunomodulators tacrolimus and mycophenolate mofetil have been evaluated as treatment in patients with severely active or fistulizing Crohn's disease in open-label and controlled trials, with varied results reported to date. The development of these new therapies is an exciting advance that promises to improve the management of Crohn's disease and expand current knowledge of underlying pathophysiologic mechanisms.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antigens, CD; Cell Adhesion Molecules; Clinical Trials as Topic; Crohn Disease; Cytokines; Drugs, Investigational; Etanercept; Gastrointestinal Agents; Humans; Immunoglobulin G; Immunologic Factors; Immunosuppressive Agents; IMP Dehydrogenase; Infliximab; Integrin alpha4; Mycophenolic Acid; Receptors, Tumor Necrosis Factor; Recombinant Proteins; Tacrolimus; Thalidomide; Treatment Outcome; Tumor Necrosis Factor-alpha

To determine the efficacy of 0.1% tacrolimus ointment in patients with perianal Crohn's disease (CD).. This prospective randomized trial enrolled 20 patients with perianal CD as anal fissures and rectal fistulas. The inclusion criteria were rectovaginal or extrasphincteric fistulas and purulent leakages. A study group comprised 11 patients, including 9 with anal fissures and 2 with fistulas. A control group included 9 patients, including 8 with fissures and 1 with fistulas. The study group received systemic therapy with azathioprine 2 mg/kg/day and tacrolimus ointment 2 mg/day; the control group had systemic therapy with azathioprine 2 mg/kg/day, hormone ointment 1 mg/day, and metronidazole suppositories 250 mg/day. Control examination and perianal CD activity index (PCDAI) determination were done 6 and 12 weeks after therapy initiation.. At 6 weeks after beginning the study, local examination revealed the signs of anal fissure epithelialization in 5 (45.5%) of the 11 patients in the study group and in 3 (33.3%) of the 9 patients in the control one. At 12 weeks, fissure epithelialization and fistula obliteration were stated in 6 (54%) patients in the study group and in 3 (33%) of the 9 patients in the control group. At 12 weeks, PCDAI in the study and control groups was 2.00 and 4.44 scores (p = 0.01).. The findings suggest that topical 0.1% tacrolimus ointment versus antibacterial suppositories and hormone ointments is effective in treating patients with perianal CD. Topical 0.1% tacrolimus ointment therapy caused a reduction in PCDAI.. Цель исследования. Определить эффективность мази такролимус (0,1%) у больных с перианальными поражениями при болезни Крона (БК). Материалы и методы. В проспективное рандомизированное исследование включили 20 больных БК с перианальными поражениями в виде трещин анального канала и свищей прямой кишки. Критериями исключения являлись ректовагинальные свищи, экстрасфинктерные свищи и наличие гнойных затеков. Основную группу составили 11 пациентов, из которых трещины анального канала отмечались у 9, свищи - у 2. В контрольную группу входили 9 пациентов, из которых трещины имелись у 8, свищи - у 1. Пациенты основной группы получали системную терапию азатиоприном (2 мг/кг/сут) и мазь такролимус (1 мг/сут), пациенты контрольной группы - системную терапию азатиоприном (2 мг/кг/сут), гормональную мазь (1 мг/сут) и свечи с метронидазолом (250 мг/сут). Контрольный осмотр и определение индекса активности перианальной БК (PCDAI) проводили через 6 и 12 нед от начала терапии. Результаты. Через 6 нед от начала исследования при местном осмотре у 5 (45,5%) из 11 пациентов основной группы и у 3 (33,3%) из 9 контрольной отмечалось появление признаков эпителизации анальной трещины. Через 12 нед эпителизация трещин и облитерация свищей констатированы у 6 (54%) больных из 11 основной группы и у 3 (33%) из 9 больных контрольной. PCDAI через 12 нед в основной группе составил 2,00 балла, в контрольной группе - 4,44 балла (р=0,01). Заключение. По результатам проведенного исследования выявлена эффективность местного использования мази такролимус (0,1%) у больных с перианальными поражениями при БК по сравнению с антибактериальными свечами и гормональными мазями. Местная терапия такролимусом (0,1%) способствовала снижению PCDAI.

Topics: Adult; Anal Canal; Colitis; Crohn Disease; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Prospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Several small retrospective studies have reported encouraging response rates in patients with Crohn's disease (CD) treated with tacrolimus.. We conducted a retrospective study of the use of oral tacrolimus for severe CD refractory to anti-tumor necrosis factor agents. Response was defined as a clinician's assessment of improvement after at least 7 days of treatment of one or more of the following: bowel movement frequency, fistula output, rectal bleeding, abdominal pain, extraintestinal manifestations, or well-being. Remission required all of the following: <3 stools per day, no bleeding, abdominal pain or extraintestinal manifestations, and increased well-being.. Twenty-four eligible patients were treated with tacrolimus for a median of 4 months. Approximately 37% were steroid dependent or steroid refractory. Response and steroid-free remission rates were 67% and 21%, respectively, and lasted for a median of 4 months. Approximately 42% of patients were able to stop steroids and 54% of patients ultimately required surgery within a median of 10 months after starting tacrolimus. Patients with mean tacrolimus trough levels of 10 to 15 ng/mL had the highest rates of response (86%) and remission (57%). Surgery seemed to be postponed in this group compared with others. An adverse event occurred in 75% of patients. Eight of these events (33%) required dose reduction and 6 (25%) led to treatment discontinuation. There were no irreversible side effects or deaths attributable to tacrolimus over a median follow-up of 56 months.. Oral tacrolimus seems to be safe and effective in some patients with severe CD refractory to anti-tumor necrosis factor therapy, particularly at a mean trough level of 10 to 15 ng/mL.

Topics: Administration, Oral; Adult; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Crohn Disease; Drug Resistance; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Infliximab; Male; Middle Aged; Prognosis; Retrospective Studies; Salvage Therapy; Tacrolimus; Tumor Necrosis Factor-alpha; Young Adult

Patients with inflammatory bowel disease who are refractory to standard therapies frequently require surgery. The long-term efficacy of tacrolimus in patients who fail standard immunosuppressive and antitumor necrosis factor α therapy is unknown.. Thirty-five patients (11 Crohn's disease and 24 ulcerative colitis) with medication-resistant disease were treated with oral tacrolimus and reviewed retrospectively. Patients were commenced on tacrolimus 0.1 mg/kg/day, with a trough level targeted between 8 and 12 ng/mL. Clinical response or remission at 30 days, 90 days, and 1 year was assessed. The overall risk of requiring surgery and predictive factors were also assessed.. All patients had failed a thiopurine, 5 (14%) had also failed methotrexate, while 90% had a primary or secondary nonresponse, or an incomplete response, to an antitumor necrosis factor α agent. The proportions that achieved a clinical response at 30 days, 90 days, and 1 year was 65.7%, 60%, and 31.4%, respectively, whereas the corresponding proportions in remission were 40%, 37.1%, and 22.9%. The cumulative risk of requiring surgery was 40.4% at 1 year and 59.3% at 2 years with a median time to surgery of 22 months (range, 0.5-84 months). Patients who were steroid refractory, or dependent, before starting tacrolimus were more likely to have surgery (P = 0.006), whereas patients who were able to achieve or maintain a clinical response with tacrolimus by 90 days were less likely (P = 0.004).. Tacrolimus is able to induce a clinical response in a third and remission in a fifth of medically refractory patients with inflammatory bowel disease at 1 year. A 90-day therapeutic trial is worthwhile in difficult to treat patients.

Topics: Administration, Oral; Adolescent; Adult; Biological Products; Colitis, Ulcerative; Crohn Disease; Drug Resistance; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Prognosis; Remission Induction; Retrospective Studies; Salvage Therapy; Survival Rate; Tacrolimus; Young Adult

Cutaneous Crohn's Disease is a notoriously difficult condition to treat and causes significant morbidity, impacting heavily on quality of life. This is the first study in adults examining the effect of topical tacrolimus on the different cutaneous manifestations of Crohn's Disease.. This open label observational study of 20 patients with heterogeneous forms of cutaneous Crohn's disease used topical tacrolimus 0.1% ointment once daily to affected areas for 12 weeks with a maximal total dose of 90g. Therapy was stopped at 12 weeks to assess whether the condition relapsed. Thereafter relapsing patients optionally continued an open label extension of topical tacrolimus therapy and were observed for a total of 12 months.. Of seventeen patients completing the twelve-week study, fifteen improved using a specifically designed physicians' global severity scale. One patient cleared, four showed a pronounced improvement (51-75%) and ten demonstrated a mild (1-25%) or moderate improvement (25-50%) in twelve weeks. Over twelve months eleven patients remained in the study, nine of which improved, one cleared and one showed no change. Perineal disease responded better with two out of twelve clearing, four showing pronounced benefit and four mild to moderate improvement. Long-term application of 0.1% tacrolimus applied to broken skin and mucosa was safe and serum levels of tacrolimus were undetectable in all subjects throughout the study.. 0.1% tacrolimus ointment was safe and effective in treating cutaneous manifestations of Crohn's disease, particularly perineal disease and pyoderma gangrenosum, yet it seldom cleared the condition.. ClinicalTrials.gov Protocol Registration System ID: 33000332.

Topics: Administration, Topical; Adolescent; Adult; Aged; Child; Crohn Disease; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Skin Diseases; Tacrolimus; Young Adult

The aim of this study is to evaluate the efficacy of topical tacrolimus in treating perianal Crohn's disease.. Nineteen patients, stratified into 7 with ulcerating, and 12 with fistulizing, perianal Crohn's disease were randomized to topical tacrolimus 1 mg/g (1 g ointment twice a day [bid]) or placebo for 12 weeks. Sixteen patients had been on, or were currently taking, azathioprine/6-MP, and 6 had received infliximab. The primary outcome in ulcerating disease was global improvement in perianal/anal lesions, as assessed by the attending physician; for fistulas, it was reduction of > or =50% of actively draining fistulas on 2 consecutive visits. Blood tacrolimus levels and adverse events were assessed.. Three of 4 patients treated with topical tacrolimus for ulcerating disease improved compared with none of 3 in the placebo group. Complete healing was not achieved. In fistulizing disease, topical tacrolimus was not beneficial. Two tacrolimus-treated patients developed perianal abscesses, 1 after improvement in fistula drainage. Adverse events were otherwise infrequent and mild. Whole blood tacrolimus levels were detectable in only 2 patients and were low.. These preliminary data suggest that topical tacrolimus is effective and safe in the treatment of perianal or anal ulcerating Crohn's disease. This therapy is unlikely to be beneficial in fistulizing perianal Crohn's disease, although a larger study is required to confirm this.

Topics: Administration, Topical; Adult; Crohn Disease; Double-Blind Method; Female; Fissure in Ano; Humans; Immunosuppressive Agents; Male; Rectal Fistula; Tacrolimus

To evaluate efficacy and safety of oral tacrolimus in cases of fistulizing Crohn's disease (FCD), which is refractory to conventional therapy including infliximab.. Patients with fistulas, previously and unsuccessfully treated with all conventional therapy (i.e., antibiotics, azathioprine, or 6-mercaptopurine and infliximab), were enrolled in a prospective, uncontrolled, open-label study of long-term treatment with oral tacrolimus (0.05 mg/kg every 12 h). The evaluation of the clinical response was complemented by use of the perianal Crohn's disease activity index (PCDAI) and magnetic resonance imaging-based score (MRS) with determined periodicity.. Ten patients were included in the study (enterocutaneous fistula, 3 patients; perianal fistula, 4 patients; rectovaginal fistula, 3 patients) with 6 to 24 months of follow-up. Five patients were steroid-dependent, and 4 patients needed maintenance treatment with immunosuppressant agents. Four patients (40%) achieved complete clinical responses, which were verified by PCDAI and MRS. Five patients (50%) achieved partial responses (i.e., important decreases in fistula drainage, size, discomfort, and PCDAI/MRS values). Decreases in both the PCDAI and MRS were statistically significant (P < 0.05). All steroid-dependent patients stopped therapy with prednisone, and concomitant immunosuppressive therapy was tapered. The response was maintained, and no new flare-up of the disease was observed. Only mild adverse events were detected (1 patient withdrew from treatment due to headache), and no case of nephrotoxicity or diabetes was detected. One patient had received no benefit from therapy after 6 months.. Oral tacrolimus could be an effective and safe treatment for patients with FCD, even if there has been no response to infliximab treatment. Randomized studies are needed to compare oral tacrolimus with infliximab in terms of efficacy, safety, and costs.

Topics: Administration, Oral; Aged; Antibodies, Monoclonal; Crohn Disease; Digestive System Fistula; Drug Administration Schedule; Drug Resistance; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Male; Middle Aged; Prospective Studies; Tacrolimus; Treatment Outcome

This study determined the effectiveness of tacrolimus for the treatment of Crohn's disease fistulas.. The study was a randomized, double-blind, placebo-controlled, multicenter clinical trial. Forty-eight patients with Crohn's disease and draining perianal or enterocutaneous fistulas were randomized to treatment with oral tacrolimus 0.2 mg. kg(-1). day(-1) or placebo for 10 weeks. The primary outcome measure was fistula improvement as defined by closure of >/=50% of particular fistulas that were draining at baseline and maintenance of that closure for at least 4 weeks. A secondary outcome measure was fistula remission as defined by closure of all fistulas and maintenance of that closure for at least 4 weeks.. Forty-three percent of tacrolimus-treated patients had fistula improvement compared with 8% of placebo-treated patients (P = 0.004). Ten percent of tacrolimus-treated patients had fistula remission compared with 8% of placebo-treated patients (P = 0.86). Adverse events significantly associated with tacrolimus, including headache, increased serum creatinine level, insomnia, leg cramps, paresthesias, and tremor, were managed with dose reduction.. Oral tacrolimus 0.2 mg. kg(-1). day(-1) is effective for fistula improvement, but not fistula remission, in patients with perianal Crohn's disease. Adverse events associated with tacrolimus can be managed by dose reduction. Lower doses of tacrolimus should be evaluated.

Topics: Adolescent; Adult; Aged; Child; Crohn Disease; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Intestinal Fistula; Male; Middle Aged; Tacrolimus

To report the results of a prospective, open-label, uncontrolled study in 13 patients affected by Crohn's disease with resistance to steroids.. The patients were treated long-term with oral tacrolimus, aiming to both resolve acute attacks and maintain remission. Tacrolimus was administered at the dose of 0.1--0.2 mg.day/kg and adjusted in order to achieve levels of 5--10 ng/mL; only mesalazine was continued concomitantly. Steroids and total parenteral nutrition were tapered when appropriate.. Median treatment was 27.3 months. Only one patient dropped out due to adverse events. Crohn's disease activity index score significantly decreased after 6 months in 11 patients; for 1 year in nine of them, and 7 years in two of them. The inflammatory bowel disease life-quality questionnaire score significantly increased over the same periods. A marked drop in hospitalizations was recorded. In three out of six patients complete closure of fistulas occurred. Tacrolimus allowed total parenteral nutrition to be withdrawn in three out of five patients. Supplementation with low-dose steroids was required in five patients. Two patients underwent surgery.. Tacrolimus therapy appears to be associated with both short- and long-term benefits, and may represent a therapeutic option in Crohn's disease when conventional therapies fail. This study encourages its use in controlled trials.

Topics: Administration, Oral; Adult; Crohn Disease; Drug Resistance; Female; Hospitalization; Humans; Immunosuppressive Agents; Male; Middle Aged; Quality of Life; Steroids; Tacrolimus; Treatment Outcome

Topics: Adult; Analysis of Variance; Crohn Disease; Female; Humans; Immunosuppressive Agents; Male; Patient Selection; Prospective Studies; Quality of Life; Tacrolimus; Treatment Outcome

To evaluate the efficacy of oral tacrolimus as an induction agent in steroid-refractory severe colitis.. Open-label, multicenter trial of oral tacrolimus in patients with severe colitis. Patients not responding to conventional therapy received tacrolimus, 0.1 mg/kg/dose given twice a day, and the dosage was adjusted to achieve blood levels between 10 and 15 ng/mL. Response was defined as improvement in a number of clinical parameters (including abdominal pain, diarrhea, rectal bleeding, and cessation of transfusions). Patients who responded by 14 days continued to receive tacrolimus, and 6-mercaptopurine or azathioprine was added as a steroid-sparing agent 4 to 6 weeks after the tacrolimus was instituted.. Fourteen patients were enrolled in the study. One patient elected to withdraw after 48 hours. Of the 13 remaining, 9 (69%) responded and were discharged. Tacrolimus was continued for 2 to 3 months in the responders, except for 1 patient who was given tacrolimus for 11 months. After 1 year of follow-up, only 5 (38%) patients were receiving maintenance therapy; the other 4 responders had undergone colectomy.. Although tacrolimus is effective induction therapy for severe ulcerative or Crohn's colitis, fewer than 50% of patients treated will successfully achieve a long-term remission.

Topics: Adolescent; Adult; Azathioprine; Child; Child, Preschool; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Infant; Male; Mercaptopurine; Prospective Studies; Remission Induction; Severity of Illness Index; Tacrolimus

Our aim was to report the clinical experience with combination treatment using tacrolimus and either azathioprine (AZA) or 6-mercaptopurine (6MP) in patients with Crohn's disease (CD) perianal fistulae. The medical records of all patients with Crohn's disease perianal fistulae seen at the Mayo Clinic from 1996-1998 who were treated with tacrolimus were reviewed. Clinical response was classified as: complete response, partial response, and nonresponse. Eleven patients were treated with oral tacrolimus for a mean duration of 22 weeks. The initial oral dose of tacrolimus ranged from 0.15 to 0.31 mg/kg/day. Azathioprine or 6MP was continued in combination with tacrolimus in seven patients and initiated simultaneously with tacrolimus in four patients. All patients improved clinically, seven had a complete response, and four had a partial response. The mean time to initial improvement was 2.4 weeks, and the mean time to complete response was 12.2 weeks. The most frequent adverse events were nausea, paresthesias, nephrotoxicity, and tremor. Patients with nephrotoxicity had a significantly higher mean initial tacrolimus dose (0.31 mg/kg/day) compared with patients who did not have nephrotoxicity (0.25 mg/kg/day) (p = 0.035); however, there was not a statistically significant association between the starting dose or mean blood level and clinical response. Combination therapy with oral tacrolimus and AZA or 6MP may be effective treatment for CD perianal fistulae. Higher initial tacrolimus doses increase the risk of nephrotoxicity without improving clinical response.

Topics: Administration, Oral; Adolescent; Adult; Azathioprine; Crohn Disease; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Rectal Fistula; Recurrence; Tacrolimus; Treatment Outcome

Intestinal barrier loss is a Crohn's disease (CD) risk factor. This may be related to increased expression and enzymatic activation of myosin light chain kinase 1 (MLCK1), which increases intestinal paracellular permeability and correlates with CD severity. Moreover, preclinical studies have shown that MLCK1 recruitment to cell junctions is required for tumour necrosis factor (TNF)-induced barrier loss as well as experimental inflammatory bowel disease progression. We sought to define mechanisms of MLCK1 recruitment and to target this process pharmacologically.. Protein interactions between FK506 binding protein 8 (FKBP8) and MLCK1 were assessed in vitro. Transgenic and knockout intestinal epithelial cell lines, human intestinal organoids, and mice were used as preclinical models. Discoveries were validated in biopsies from patients with CD and control subjects.. MLCK1 interacted specifically with the tacrolimus-binding FKBP8 PPI domain. Knockout or dominant negative FKBP8 expression prevented TNF-induced MLCK1 recruitment and barrier loss in vitro. MLCK1-FKBP8 binding was blocked by tacrolimus, which reversed TNF-induced MLCK1-FKBP8 interactions, MLCK1 recruitment and barrier loss in vitro and in vivo. Biopsies of patient with CD demonstrated increased numbers of MLCK1-FKBP8 interactions at intercellular junctions relative to control subjects.. Binding to FKBP8, which can be blocked by tacrolimus, is required for MLCK1 recruitment to intercellular junctions and downstream events leading to immune-mediated barrier loss. The observed increases in MLCK1 activity, MLCK1 localisation at cell junctions and perijunctional MLCK1-FKBP8 interactions in CD suggest that targeting this process may be therapeutic in human disease. These new insights into mechanisms of disease-associated barrier loss provide a critical foundation for therapeutic exploitation of FKBP8-MLCK1 interactions.

Topics: Animals; Caco-2 Cells; Crohn Disease; Humans; Intestinal Mucosa; Mice; Mice, Knockout; Myosin-Light-Chain Kinase; Tacrolimus; Tacrolimus Binding Proteins; Tight Junctions; Tumor Necrosis Factor-alpha

Topics: Antibodies, Monoclonal; Crohn Disease; Gastrointestinal Agents; Humans; Infliximab; Intestinal Fistula; Tacrolimus; Treatment Outcome

Tacrolimus is a calcineurin inhibitor commonly used for prophylaxis of rejection in renal and liver transplantation. There are limited but favourable data regarding its possible use in patients with inflammatory bowel disease (IBD).. To evaluate the efficacy and safety of tacrolimus in patients with IBD in clinical practice.. We performed a retrospective, multicentre study in 22 centres in Spain. All adult patients who received oral tacrolimus for luminal or perianal IBD were included. Clinical response was assessed by Harvey-Bradshaw index and partial Mayo score after 3 months. Perianal disease was evaluated by fistula drainage assessment.. One hundred and forty-three patients were included (mean age 38 years; 51% male; median disease duration 110 months). In ulcerative colitis (UC) (n = 58), the partial Mayo score decreased after 3 months from median 6 to 3 (P = 0.0001), whereas in Crohn's disease (CD) (n = 85), the Harvey-Bradshaw index decreased after 3 months from median 9 to 7 (P = 0.011). In CD patients, blood tacrolimus concentrations during induction (>10 ng/mL vs <10 ng/mL; odds ratio 0.23, 95% CI 0.05-0.87) and the concomitant use of thiopurines (odds ratio 0.18, 95% CI 0.04-0.81) were associated with lower clinical disease activity at 3 months. Of 62 patients with perianal disease, complete closure was observed in 8% (n = 5) of patients with perianal fistulas, with 34% (n = 21) showing partial response. Treatment was maintained for a median of 6 months (IQR, 2-16). After a median clinical follow-up of 24 months (IQR, 15-57), the rate of treatment-related adverse events was 34%, correlating with blood drug concentrations (P = 0.021). Finally, 120 patients (84%) discontinued tacrolimus, usually due to absence or loss of response. Three patients (2%) were subsequently diagnosed with cancer. The overall rate of surgery was 39%, with a 33% colectomy rate in UC.. Tacrolimus shows a clinical benefit in both CD and UC after 3 months of treatment, but its long-term effectiveness and frequent adverse events remain relevant issues in clinical practice.

Topics: Adult; Colectomy; Colitis, Ulcerative; Crohn Disease; Female; Humans; Inflammatory Bowel Diseases; Male; Middle Aged; Recurrence; Retrospective Studies; Spain; Tacrolimus; Time Factors; Treatment Outcome

Topics: Administration, Oral; Antibiotics, Antineoplastic; Crohn Disease; Drug Therapy, Combination; Female; Humans; Ileostomy; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mycophenolic Acid; Ointments; Proctocolectomy, Restorative; Pyoderma Gangrenosum; Tacrolimus; Treatment Outcome; Young Adult

Topics: Child, Preschool; Colonoscopy; Crohn Disease; Diagnosis, Differential; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Male; Methotrexate; Prolidase Deficiency; Tacrolimus

Tacrolimus is an immunosuppressive agent that has been proposed in the treatment of severe ulcerative colitis. The present study examined the effectiveness and safety of tacrolimus in treating refractory Crohn disease (CD) colitis in children.. All children treated by oral tacrolimus for CD colitis at a tertiary pediatric center were included in the study. All patients were refractory to steroids and infliximab. Clinical response (decreased pediatric CD activity index [PCDAI] >15 and PCDAI <30) and remission (PCDAI <10) were monitored at 2, 4, 6, 12, and 24 months after induction. Tacrolimus blood levels and adverse effects were also noted.. Among 220 patients with CD, 8 children (including 3 girls, median age 14 [9.5-18] years) were registered with a median PCDAI of 58.7 (32.5-65) before tacrolimus initiation. In patients treated with tacrolimus, the overall clinical response rates were 6/8, 3/8, 2/8, 2/8, and 1/8 with a remission rate of 4/8, 0/8, 0/8, 2/8, and 0/8 at 2, 4, 6, 12, and 24 months, respectively. At 2 months, the PCDAI scores were lower than those at induction (median 11.2; P = 0.004) with the mean whole plasma level of tacrolimus being 8.75 ng/mL (5.9-10 ng/mL). Adverse events occurred in 6 of 8 patients, including renal dysfunction, insulin-dependent diabetes, paresthesia, and tremor. Tacrolimus interruption was required in 2 cases.. Tacrolimus could be considered to transiently treat refractory CD colitis. Tacrolimus could be used as a "bridge" toward another medical option in pediatric CD, although its adverse events are frequent.

Topics: Acute Disease; Administration, Oral; Adolescent; Child; Colitis; Crohn Disease; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Retrospective Studies; Severity of Illness Index; Tacrolimus; Treatment Outcome

Although tacrolimus (TAC) can induce remission in children with refractory inflammatory bowel disease (IBD) or autoimmune gastroenteropathy (AGE), its use in maintenance therapy remains controversial. The aim of this study was to investigate the potential nephrotoxic nature of prolonged TAC use.. This retrospective study reviewed children with gastrointestinal disorder who underwent kidney biopsy for the evaluation of renal damage during TAC therapy for >1 year. The clinical and histological features of renal damage were evaluated in this single-institution cohort.. Eighteen of 121 children with IBD and two children with AGE followed at a national children hospital in Tokyo, Japan, received TAC between August 2006 and April 2013. Among them, five (Crohn's disease, n = 3; autoimmune gastropathy, n = 1; autoimmune enteropathy, n = 1) received TAC for >1 year, and underwent kidney biopsy. All five had achieved remission on TAC, but had histological evidence of chronic nephrotoxicity. Renal damage in one patient with relatively low TAC trough level remained mild. Estimated glomerular filtration rate (eGFR) at the time of kidney biopsy was lower than at the initiation of TAC in all four available patients. Among them, eGFR improved in one patient after the decrease or discontinuation of TAC.. TAC appeared to be effective in children with refractory gastrointestinal disorder, but long-term use seems to cause irreversible renal damage. Rigorous monitoring of eGFR and kidney biopsy in selected cases should be considered for the proper adjustment of TAC.

Topics: Autoimmune Diseases; Biopsy; Child; Crohn Disease; Female; Gastroenteritis; Humans; Immunosuppressive Agents; Infant; Kidney; Maintenance Chemotherapy; Male; Renal Insufficiency; Retrospective Studies; Tacrolimus; Treatment Outcome

Systemic steroids, in association or not with cyclosporin, are indicated for the treatment of large or widespread Pyoderma gangrenosum (PG). We report the case of a 27-year-old woman with a 15-year history of severe Crohn's disease, who developed a severe and disseminated PG, refractory to multiple lines of treatment. Infliximab and adalimumab were contraindicated, either because of allergy or of ineffectiveness on Crohn's disease. The addition of certolizumab pegol to the baseline treatment, associating systemic steroids and tacrolimus, finally allowed the complete healing of PG. Oral prednisone was stopped and tacrolimus was decreased, without any cutaneous or digestive relapse. Certolizumab pegol could be an alternative therapy in the treatment of PG in case of intolerance or ineffectiveness of the other anti-tumor necrosis factor (anti-TNF) therapies.

Topics: Adult; Certolizumab Pegol; Crohn Disease; Female; Humans; Prednisone; Pyoderma Gangrenosum; Recurrence; Remission Induction; Tacrolimus; Tumor Necrosis Factor-alpha

Topics: Absorption, Physiological; Administration, Topical; Crohn Disease; Female; Humans; Immunosuppressive Agents; Middle Aged; Skin Ulcer; Tacrolimus

Inflammatory bowel disease is a chronic disorder of the gastrointestinal tract. Tacrolimus is a calcineurin inhibitor used in the prophylaxis of rejection after a solid organ transplant. There is some evidence for its use in inflammatory bowel disease, although there is a lack of information about the patients who will benefit the most with this drug and the prognostic factors for a favorable response.. We performed a multicentric retrospective study evaluating all the patients who have received tacrolimus in the last 10 years as a treatment for IBD in our area.. A total of 20 patients, 12 with Crohn's disease and 8 with ulcerative colitis, were included in four hospitals. The two most common indications were steroid-dependency and fistulizing Crohn's disease. The median time receiving tacrolimus was 11 months. In 12 patients the treatment was stopped. The main reasons for drug withdrawal were absence or loss of response. The median clinical follow-up was 35.5 months. Overall, a 25% achieved clinical remission and 40% were in partial response. Biologics-naïve patients demonstrated a significantly better remission rate as compared with those that were not (80 vs 7%). Patients who achieved remission were more likely to have a significant reduction in C-reactive protein values 1 month after starting the drug. Seven patients required surgery during the follow- up period.. Patients naïve to biologics showed a significantly better response to tacrolimus. A reduction in C-reactive protein one month after starting this drug was associated with clinical remission.

Topics: Adolescent; Adult; Biological Products; C-Reactive Protein; Child; Crohn Disease; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Retrospective Studies; Tacrolimus; Treatment Outcome; Young Adult

To report a case of successful use of infliximab (IFX) and tacrolimus (TAC) in a patient with Crohn's disease (CD).. A 42-year-old man with no significant previous medical history was referred to our emergency department because of a 3-month history of weight loss, severe abdominal pain, and bloody diarrhea. His Harvey Bradshaw Index was 39. Ileocolonoscopic revealed severe Crohn colitis. Treatment with IFX 5 mg/kg, azathioprine 2.5 mg/kg/day and corticosteroids was started. After a second IFX infusion, he remained with symptoms with a Harvey Bradshaw Index of 17. An IFX dose intensification of 10 mg/kg every 8 weeks was prescribed. After 16 weeks, a new colonoscopic examination revealed multiple deep ulcerations in sigma and rectum. IFX was intensified to 10 mg/kg every 6 weeks. After 4 doses of IFX intensified dose, the patient's clinical condition was not improved, with a Harvey Bradshaw Index of 10. Azathioprine (AZA) 2.5 mg/kg/day was suspended. Tacrolimus 0.2 mg/kg/day as a compassionate use was added to IFX 10 mg/kg every 6 weeks. After 6 months of combination therapy, the patient was in clinical remission. His Harvey Bradshaw Index was 3. After 1 year on combination IFX and TAC therapy, the patient continued in clinical remission.. This case documents that the combination therapy of IFX and TAC could be selected as an effective approach for patients with CD refractory to IFX dose-intensification plus AZA. However, further studies need to be performed to evaluate the efficacy of this combination therapy.

Topics: Adult; Antibodies, Monoclonal; Compassionate Use Trials; Crohn Disease; Drug Therapy, Combination; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Male; Remission Induction; Tacrolimus; Time Factors; Treatment Outcome

Currently, limited data of the outcome of inflammatory bowel disease (IBD) in patients after solid organ transplantation (SOT) are available. We aimed to analyze effects of SOT on the IBD course in a large IBD patient cohort.. Clinical data from 1537 IBD patients were analyzed for patients who underwent SOT (n = 31) between July 2002 and May 2014. Sub-analyses included SOT outcome parameters, IBD activity before and after SOT, and efficacy of IBD treatment.. 4.74% of patients with ulcerative colitis (UC) and 0.84% of patients with Crohn's disease (CD) underwent SOT (p = 2.69 x 10(-6), UC vs. CD). 77.4% of patients with SOT underwent liver transplantation (LTx) with tacrolimus-based immunosuppressive therapy after SOT. All LTx were due to primary sclerosing cholangitis (PSC) or PSC overlap syndromes. Six patients (19.4%) required renal transplantation and one patient (3.2%) heart transplantation. A survival rate of 83.9% after a median follow-up period of 103 months was observed. Before SOT, 65.0% of patients were in clinical remission and 5 patients received immunosuppressive therapy (16.1%). After SOT, 61.0% of patients were in remission (p = 1.00 vs. before SOT) and 29.0% required IBD-specific immunosuppressive or anti-TNF therapy (p = 0.54 vs. before SOT). 42.9% of patients with worsening of IBD after SOT were at higher risk of needing steroid therapy for increased IBD activity (p = 0.03; relative risk (RR): 10.29; 95% CI 1.26-84.06). Four patients (13.0%) needed anti-TNF therapy after SOT (response rate 75%).. SOT was more common in UC patients due to the higher prevalence of PSC-related liver cirrhosis in UC. Despite mainly tacrolimus-based immunosuppressive regimens, outcome of SOT and IBD was excellent in this cohort. In this SOT cohort, concomitant immunosuppressive therapy due to IBD was well tolerated.

Topics: Adult; Aged; Colitis, Ulcerative; Crohn Disease; Female; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Survival Rate; Tacrolimus; Treatment Outcome; Tumor Necrosis Factor-alpha

Appropriate influenza vaccination is important for patients with inflammatory bowel disease under immunosuppressive therapy. The purpose of this study was to evaluate the influence of immunosuppressive therapy on the immune response to the trivalent influenza vaccine in adult patients with inflammatory bowel disease.. In this cohort study, 91 participants received a single dose of influenza vaccine for the 2010/2011 season. Serum samples were collected at 3 different times (pre-vaccination, 3 weeks post-vaccination, and after flu season) to measure hemagglutination inhibition antibody titers. Immune responses were compared based on immunosuppressive therapy.. Among the 88 subjects who completed the study, the influenza vaccine induced a more than 4-fold increase in the mean antibody level for all flu strains. The overall seroprotection proportion (post-vaccination titer ≥ 1:40) was 81% for H1N1, 61% for H3N2, and 86% for B. Treatment with an immunomodulator reduced the immune response to the H1N1 strain (OR=0.20, p=0.01), and treatment with infliximab reduced the immune response to the other strains (H3N2 strain: OR=0.37, p=0.02; B strain: OR=0.18, p=0.03). Combination therapy with azathioprine/6-mercaptopurine and infliximab significantly inhibited the immune response to H1N1 (OR=0.056, p=0.02).. Infliximab and/or immunomodulators inhibit immune responses to some strains of trivalent influenza vaccination in adults with inflammatory bowel disease. For optimization of the trivalent influenza vaccination for patients with adult inflammatory bowel disease treated with immunosuppressive agents, establishing an effective vaccination method is crucial.

Topics: Adrenal Cortex Hormones; Adult; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Viral; Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunity, Active; Immunosuppressive Agents; Infliximab; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza Vaccines; Male; Mercaptopurine; Methotrexate; Middle Aged; Prospective Studies; Tacrolimus

Topics: Administration, Cutaneous; Crohn Disease; Granuloma; Humans; Immunosuppressive Agents; Male; Penile Diseases; Recurrence; Skin Diseases; Tacrolimus; Young Adult

We report a case of an orofacial lesion in Crohn's disease successfully treated with tacrolimus ointment. A 22-year-old woman with Crohn's disease presented with a discharging lesion on the right side of her face. Intraorally, there was a resultant loss of the sulcal depth. She reported a 1-year history of variable right-sided facial swelling for which she had undergone extraoral incision and drainage, resulting in localized paresthesia and nonhealing of the incision site. Following exclusion tests, a treatment of twice-daily extraoral application of tacrolimus 0.1% ointment was commenced. Upon review, the lesion had reduced in size, with minimal discharge. Further improvement over 12 months of tacrolimus use resulted in a satisfactory cosmetic result as well as resolution of the intraoral features and reestablishment of the full sulcal depth. This case illustrates the successful use of topical tacrolimus to treat a cutaneous manifestation of Crohn's disease.

Topics: Administration, Topical; Crohn Disease; Facial Dermatoses; Female; Humans; Immunosuppressive Agents; Ointments; Tacrolimus; Young Adult

Topics: Adalimumab; Adult; Antibodies, Monoclonal, Humanized; Biological Products; Crohn Disease; Humans; Immunocompromised Host; Immunosuppressive Agents; Liver Transplantation; Male; Tacrolimus; Tumor Necrosis Factor-alpha

Topics: Administration, Topical; Anus Diseases; Crohn Disease; Dizziness; Female; Humans; Immunosuppressive Agents; Nausea; Paresthesia; Tacrolimus; Young Adult

Pyoderma gangrenosum (PG) is often associated with inflammatory bowel disease even after bowel surgery, but it remains an extremely rare pathology. The purpose of this study was to investigate the clinical features and treatment of PG and to consider proper management for peristomal PG.. Demographic data for patients who underwent colorectal surgery with ostomy creation at Hyogo College of Medicine between July 2007 and July 2011 were prospectively collected. The main outcome measures were postoperative occurrence of peristomal PG by type: explosive and rapidly spreading type (type R) and indolent and gradually spreading type (type G).. Overall prevalence was 11/738 (1.5%), with type R in 5 patients and type G in 6. Type R and type G were significantly more common in ulcerative colitis and Crohn's disease, respectively (p = 0.01). Type R developed within 6 days after surgery. Type G developed a mean of 52 days after surgery. Complete healing required a long time in both types, with means of 69 days for type R and 48 days for type G.. Although peristomal PG was a rare complication after surgery, differences in the development of PG were observed between ulcerative colitis and Crohn's disease. Careful observation and knowledge of PG are needed.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents; Colitis, Ulcerative; Crohn Disease; Enterostomy; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Prednisolone; Pyoderma Gangrenosum; Risk Factors; Surgical Stomas; Surgical Wound Infection; Tacrolimus

Topics: Crohn Disease; Humans; Immunosuppressive Agents; Interleukin-12; Interleukin-23; Rectal Fistula; Tacrolimus

The introduction of immunosuppressants and biologic agents has led to active debate and research about optimal therapeutic strategies considering risk factors and predictors of clinical outcome in inflammatory bowel disease (IBD). Data about gender-specific treatment differences and risk factors is lacking for IBD. The aim of the present study was to evaluate gender-related differences in the treatment of a distinct IBD patient population treated in the Rhein-Main region, Germany.. Data about past medical history, disease status and medical treatment of 986 outpatients treated in ten gastroenterological practices and three hospitals were collected from November 1st 2005-July 31st 2007 and analyzed with regard to gender-related differences in therapy and disease management.. With the exception of an extended disease duration in women, no significant gender-related differences in demographic and clinical characteristics were observed. Men showed a significantly higher remission rate than women (p=0.025), while women received significantly less immunosuppressive medication compared to men (p=0.011). In addition, treatment with immunosuppressants was not different in women with child-bearing potential compared to menopausal women.. Our investigation demonstrates for the first time gender-specific differences in the therapeutic management in a large cohort of IBD patients.

Topics: Adrenal Cortex Hormones; Adult; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Azathioprine; Budesonide; Colitis, Ulcerative; Crohn Disease; Cross-Sectional Studies; Cyclosporine; Female; Germany; Humans; Immunosuppressive Agents; Infliximab; Male; Mercaptopurine; Mesalamine; Methotrexate; Middle Aged; Practice Patterns, Physicians'; Prospective Studies; Remission Induction; Severity of Illness Index; Sex Factors; Tacrolimus

The Budd-Chiari syndrome (BCS) is characterized by hepatic venous outflow obstruction involving the hepatic veins, inferior vena cava, or both. BCS has occasionally been reported in the literature as a very rare complication of ulcerative colitis. However, association of Crohn's disease (CD) and BCS is extremely rare with only a single case reported in the world literature to date. We report a case of a young woman with chronically active, therapy-resistant CD who developed massive ascites, elevation of liver enzymes, and coagulopathy in the course of her disease. She was subsequently diagnosed with BCS for which a successful liver transplantation was performed. Chronically active therapy resistant CD and methylenetetrahydrofolate reductase gene mutation have been identified as possible risk factors for development of BCS in this patient.

Topics: Adrenal Cortex Hormones; Ascites; Budd-Chiari Syndrome; Crohn Disease; Female; Hepatic Veins; Humans; Immunosuppressive Agents; Liver; Liver Transplantation; Methylenetetrahydrofolate Reductase (NADPH2); Mutation; Phlebography; Risk Factors; Tacrolimus; Tomography, X-Ray Computed; Vena Cava, Inferior; Warfarin; Young Adult

Crohn's disease is a chronic granulomatous inflammatory bowel disorder, often associated with cutaneous manifestations, termed metastatic Crohn's. Here we present two cases of paediatric metastatic Crohn's disease involving the penis, focusing on clinical presentation, histological diagnosis and treatment.

Topics: Anti-Infective Agents; Child; Child, Preschool; Circumcision, Male; Crohn Disease; Diagnosis, Differential; Drug Therapy, Combination; Follow-Up Studies; Foreskin; Humans; Immunosuppressive Agents; Male; Metronidazole; Ointments; Penile Diseases; Tacrolimus

Recent evidence indicates that intravenous or oral therapy with tacrolimus (FK-506) is effective in treating patients with Crohn's disease. We evaluated the usefulness of tacrolimus therapy for Japanese patients with refractory Crohn's disease.. Fourteen adult Japanese patients with Crohn's disease that was refractory to conventional therapies, including prednisolone (n = 5), azathioprine (n = 6), and infliximab (n = 5), were enrolled. Treatment with tacrolimus was started orally or intravenously and aimed for serum trough levels of 10-15 ng/ml. After the patients achieved clinical improvement, tacrolimus maintenance therapy was administered to maintain the trough level at 5-10 ng/ml.. All patients achieved remission or significant improvement 40 days after starting tacrolimus treatment. By 120 days after the start of therapy, 9 (64%) patients achieved remission, 2 patients (14%) achieved significant improvement, and only 3 patients (21%) relapsed. The relapsed patients were treated with infliximab therapy and achieved remission. Steroids were discontinued by the 5 patients who had taken steroids before the study began. Adverse effects of tacrolimus included a temporary increase in serum creatinine concentration (n = 1, 7%), hyperkalemia (n = 1, 7%), and tremor (n = 1, 7%).. Tacrolimus therapy is effective and well tolerated in patients with Crohn's disease that is refractory to conventional therapies.

Topics: Adult; Asian People; Cohort Studies; Crohn Disease; Drug Administration Schedule; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Japan; Male; Middle Aged; Retrospective Studies; Secondary Prevention; Tacrolimus; Treatment Outcome

The published experience regarding the use of tacrolimus in Crohn's disease (CD) and ulcerative colitis (UC) refractory to more commonly used medical therapy has been fairly limited. Our objective was to describe our experience with its use in a cohort of patients which, to our knowledge, represents the largest North American cohort described to date.. This was a retrospective, single-center chart analysis. Patients were identified by compiling all hospital discharges with principle diagnoses of ICD-9 codes for 555.0-555.9 (regional enteritis) and 556.0-556.9 (ulcerative colitis) from January 1, 2000, to October 31, 2005, and then cross-referencing the electronic charts for tacrolimus serum concentrations ordered during this time period. Additional patients were identified through verbal communication with participating clinicians. Information abstracted included proportion with clinical response and remission (using a modified disease activity index), ability to wean from steroids, need for surgery / time to surgery, and side-effect profile.. In all, 32 UC patients and 15 CD patients were identified. The mean disease duration was: UC 81 months (range, 1 month to 37 years), CD 100 months (range, 1 month to 35 years). The disease distribution for UC was: pancolitis 12 (37.5%), extensive colitis 6 (18.8%), left-sided 11 (34.4%), and proctitis 3(9.4%). For CD this was: TI 2 (13.3%), small bowel 2 (13.3%), colonic 3 (20.7%), ileocolonic 7(46.7%), and perianal 1 (6.7%). The duration of tacrolimus treatment for UC was mean, 29 weeks. For CD it was mean, 9.9 weeks. In all, 30/32 UC and 7/15 CD patients were on steroids; 4/30 UC and 0/7 CD patients were able to subsequently wean off steroids. In all, 12/32 UC patients proceeded to colectomy. Mean time to colectomy was 28 weeks and 6/15 CD patients proceeded to a resective surgery. The mean time to surgery was 22 weeks. In all, 22/32 UC patients achieved a clinical response; 3/32 achieved remission and 8/15 CD patients achieved a clinical response; 1/15 achieved remission. Adverse reactions were generally mild. In 6 patients the drug had to be discontinued because of an adverse reaction. There were no opportunistic infections identified, no cases of renal insufficiency related to drug administration, and no deaths while on the medicine.. Our experience with tacrolimus in UC and CD indicates that it is safe and relatively well tolerated, although its clinical efficacy is quite variable. More prospective studies assessing its use are necessary.

Topics: Cohort Studies; Colitis, Ulcerative; Crohn Disease; Female; Humans; Male; North America; Retrospective Studies; Tacrolimus; Treatment Outcome

This study aimed to evaluate the efficacy of oral tacrolimus in patients with inflammatory bowel disease (IBD) refractory to conventional therapy, including azathioprine, 6-mercaptopurine, and infliximab.. Retrospective review of all patients with IBD treated with oral tacrolimus was undertaken. Tacrolimus was administered t an initial dose of 0.05 mg/kg twice daily, aiming for serum trough levels of 5-10 ng/mL. We evaluated clinical response, a retrospective estimated Crohn's disease activity index (CDAI) for Crohn's disease (CD), modified Truelove-Witts index for ulcerative colitis (UC), and modified pouch disease activity index (mPDAI) for pouchitis. Patients had been monitored clinically for benefit and side effects and by whole blood tacrolimus level approximately every 4 weeks for the duration of treatment. Clinical remission was defined as an estimated CDAI <150 (CD), an inactive disease score on the Truelove-Witts index (UC), and mPDAI <5 (pouchitis).. Twelve patients with CD, six with UC, and one with pouchitis, all resistant to previous therapies, were treated for a median of 5 months. After 4 weeks 10 CD (83%), four UC (67%) patients, and one pouchitis patient had a clinical response. There was a median reduction of the estimated CDAI of 108 points (range 35-203; P = 0.002) and stool frequency of three per day at week 4. Remission was achieved in 42% (5/12) of CD and 50% (3/6) of UC patients at the end of follow-up. Side effects included temporary elevated creatinine (n = 1), tremor (n = 3), arthralgia (n = 1), insomnia (n = 1), and malaise (n = 1). Four patients discontinued treatment due to side effects. CONCLUSION-: Oral tacrolimus is well tolerated and effective in patients with refractory IBD in the short- to medium-term. Further controlled, long-term evaluation is warranted.

Topics: Administration, Oral; Adolescent; Adult; Aged; Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Intestinal Fistula; Male; Middle Aged; Pouchitis; Tacrolimus; Treatment Outcome

The prevalence of inflammatory bowel disease (IBD) after renal transplantation is affected by the immune tolerance and the modality of immunosuppression. Mycophenolate mofetil (MMF) may have a promoting effect on the development of posttransplantation erosive enterocolitis and a Crohn's disease-like pattern of colitis. We have presented a 40-year-old man with end-stage renal disease due to chronic glomerulonephritis who commenced hemodialysis for 2 months before receipt of a live unrelated renal transplant. He developed early posttransplantation diabetes mellitus and an anti graft rejection episode, which responded to a methylprednisolone pulse and OKT3 treatment. His immunosuppressive regimen included prednisolone, MMF, and tacrolimus. Three years after transplantation, he developed mild constitutional symptoms, mouth ulcerations, and chronic intermittent bloody diarrhea. Colonoscopy showed active segmental colitis with aphthous ulcers, involving the proximal descending colon and the splenic flexure. Colonic biopsies showed distended and branched crypts in the ascending colon, moderate active chronic colitis with regenerative atypia, skipping appearance, and ulceration in the splenic flexure and descending colon. The edematous crypts were associated with ulcerations in the sigmoid colon and rectum. The features were highly suggestive of Crohn's disease. He was successfully treated with high-dose steroids and 5-aminosalicylic acid. Subsequently, he developed chronic transplant glomerulopathy and restarted hemodialysis. We concluded that de novo Crohn's disease may develop in renal transplant recipients despite immunosuppressive therapy especially with MMF immunosuppression.

Topics: Adult; Crohn Disease; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Renal Dialysis; Tacrolimus

We and others have reported the use of tacrolimus in refractory inflammatory bowel disease (IBD). Little is known about its long-term efficacy and safety.. In this retrospective, observational single center study the charts of 53 adult patients with steroid-dependent (n = 18) or steroid-refractory (n = 35) IBD, Crohn's disease (CD) (n = 11), ulcerative colitis (UC) (n = 40), or pouchitis (PC) (n = 2) were reviewed. Tacrolimus (0.1 mg/kg body weight per day) was administered orally in all and initially intravenously in 2 patients (0.01 mg/kg body weight per day), aiming for serum trough levels of 4-8 ng/mL. Forty-one of 53 (77.1%) patients were receiving concomitant azathioprine. The mean treatment duration was 25.2 +/- 4.6 SD months (0.43-164 months). Patients were followed for a mean of 39 +/- 4.1 SD months (5-164 months). Response was evaluated using a modified clinical activity index (M-CAI).. Thirty-one UC (78%), 10 CD (90.1%), and both PC (100%) patients experienced an immediate clinical response or went into remission at 30 days. A statistically significant drop on the M-CAI was documented for UC and CD patients. Nine UC patients (22.5%) underwent colectomy between 1.6 and 41.3 months following initiation. Mean colectomy-free survival was 104.8 +/- 15.5 (95% CI 74.4-135.2) months (limited to 164.4 months). Cumulative colectomy-free survival was estimated 56.5% at 43.8 months. Steroids were reduced or discontinued in 40 of 45 UC and CD patients (90%) taking steroids. Side effects included a temporary rise of creatinine (n = 4, 7.6%), tremor or paresthesias (n = 5, 9.4%), hyperkalemia (n = 1, 1.9%), hypertension (n = 1, 1.9%), and opportunistic infections (n = 2, 3.8%).. Long-term tacrolimus therapy appears safe and effective in refractory IBD.

Topics: Adult; Aged; Azathioprine; Colectomy; Colitis, Ulcerative; Crohn Disease; Drug Resistance; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Pouchitis; Remission Induction; Retrospective Studies; Steroids; Tacrolimus; Treatment Outcome

(1) Tacrolimus (FK-506) is an immunosuppressant that is being investigated for use in patients with Crohn's disease, mainly in those with refractory illness and fistulizing patterns of the disease. (2) Evidence from a small, randomized controlled trial indicates that, compared with placebo, tacrolimus is associated with higher rates of improvement and similar rates of remission in those with fistulizing patterns of disease. (3) Nephrotoxicity, which has been reported with the use of tacrolimus in clinical trials, seems to improve with dose reduction, but may be associated with irreversible histologic changes. (4) More studies are needed to determine the optimal dose and duration of therapy, and whether the drug is beneficial to patients with non-fistulizing patterns of Crohn's disease.

Topics: Canada; Crohn Disease; Digestive System Fistula; Drug Approval; Drug Costs; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Prevalence; Randomized Controlled Trials as Topic; Tacrolimus; Treatment Outcome

Topics: Adult; Colonic Diseases; Colonoscopy; Crohn Disease; Duodenal Diseases; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Injections, Intravenous; Intestinal Fistula; Tacrolimus

Tacrolimus, a relatively new therapeutic option for patients with corticosteroid-refractory Crohn's disease or ulcerative colitis, is a substrate for the apically directed efflux transporter P-glycoprotein (P-gp). Duodenal biopsy specimens obtained from a patient with corticosteroid-refractory Crohn's disease and with significantly higher-than-average tacrolimus dose requirements were analyzed for P-gp by Western blot. The P-gp content in this patient was more than double that in specimens obtained from 9 of 10 healthy subjects. Elevated intestinal P-gp could have resulted in decreased tacrolimus absorption, thereby leading to decreased blood concentration and decreased efficacy in this patient. The cause and prevalence of this phenomenon are unknown.

Topics: Abdominal Pain; Adult; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biomarkers; Biopsy, Needle; Blotting, Western; Crohn Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Gastrointestinal Hemorrhage; Humans; Immunohistochemistry; Immunosuppressive Agents; Intestinal Mucosa; Prognosis; Sensitivity and Specificity; Severity of Illness Index; Tacrolimus

Topics: Administration, Oral; Antibodies, Monoclonal; Crohn Disease; Drug Resistance; Gastrointestinal Agents; Humans; Infliximab; Intestinal Fistula; Retreatment; Tacrolimus

Topics: Azepines; Cholinergic Agents; Colitis, Ulcerative; Crohn Disease; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Isoquinolines; Pyridazines; Tacrolimus; Thiazoles

Pyoderma gangrenosum is a rare idiopathic skin disorder associated with other diseases, including inflammatory bowel disease. The commonest site is the skin, but sometimes it can occur in the parastomal region. Most of these cases respond to treatment with systemic corticosteroids and cyclosporin or local Kenalog injections.. The following are two cases of parastomal pyoderma in patients not responding to the standard measures. These patients were treated with topical tacrolimus.. These patients showed dramatic improvement in one week with complete resolution and re-epithelialization of skin within two weeks.. Pyoderma gangrenosum is a difficult problem to manage and its early resolution is important. In these two reported cases, the improvement was dramatic, therefore topical tacrolimus should be considered early in the management.

Topics: Administration, Topical; Adult; Aged; Crohn Disease; Humans; Ileostomy; Immunosuppressive Agents; Male; Pyoderma Gangrenosum; Tacrolimus; Treatment Outcome

Topics: Absorption; Administration, Topical; Adolescent; Crohn Disease; Female; Herpes Zoster; Humans; Immunosuppressive Agents; Tacrolimus

Topics: Absorption; Administration, Topical; Crohn Disease; Humans; Immunosuppressive Agents; Mouth Mucosa; Tacrolimus

We describe the cases of two patients with Crohn's disease affected by severe perineal fistulae resistant to conventional therapies, successfully treated with FK 506, a new immunomodulatory drug. It is well absorbed from diseased bowel and preliminary experiences have indicated its short-term use in complicated Crohn's disease. The first patient was a 24-year-old male with perineal fistula and severe skin ulceration (8 cm of external opening diameter). He had undergone colectomy and ileostomy because of severe pancolitis refractory to medical treatment and had been treated with azathioprine and metronidazole. Two months after starting FK 506, a dramatic improvement made further surgical operation unnecessary. Local and general benefit was observed during the following 26 months, until FK 506 was withdrawn. The second patient was a 28-year-old male with a diagnosis of ulcerative pancolitis changed to Crohn's disease two months after the onset of a perineal fistula, recurring despite drainage procedures, steroid therapy, and total parenteral nutrition. FK 506 was administered for two months with a complete healing of fistula. Successively, it was stopped and corticosteroids (associated to enteral nutrition) were given because of recurrent rectal bleeding. Our experience encourages the use of oral FK 506 in complicated Crohn's disease and suggests the possibility of a long-term primary therapy other than the use as a "bridge" to other treatments.

Topics: Administration, Oral; Adult; Crohn Disease; Fistula; Humans; Immunosuppressive Agents; Male; Perineum; Tacrolimus

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

Steroid treatment failure in acute Crohn's disease and ulcerative colitis frequently necessitates surgical intervention. Several alternative therapeutic strategies have been raised. The most promising so far has been intravenous cyclosporine, but the results in the long term have been discouraging. We assessed the efficacy and safety of the new macrolide immunomodulator tacrolimus as an alternative to cyclosporine A.. Eleven patients with steroid-refractory disease (six ulcerative colitis, two indeterminate colitis, two Crohn's disease, one pouchitis) and severe activity according to the Truelove and Witts criteria or Crohn's disease activity index > 150, respectively, were eligible for the study. All patients were treated with intravenous tacrolimus for 7-10 days followed by oral treatment over a median period of 7 months (range 0.25-16). Azathioprine and mesalamine were given concomitantly. Steroids were tapered according to clinical activity.. Seven of 11 patients achieved remission rapidly, whereas a modest improvement was noted in two. Only two patients required an early and one a delayed colectomy. Moreover, a rectovaginal fistula closure in a case of Crohn's disease and an improvement of pouchitis was observed. A tapering to low dose steroids was possible during oral tacrolimus therapy in all nine responders and remission was maintained in five of them (mean follow-up 9.2 months). The drug was well tolerated and side effects were managed conservatively.. Tacrolimus induced rapid remission in steroid resistant inflammatory bowel disease in the majority of cases. It appears to be an effective treatment modality that may be superior to cyclosporine with respect to maintenance of remission.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Pilot Projects; Prospective Studies; Remission Induction; Steroids; Tacrolimus; Time Factors; Treatment Failure

Tacrolimus (FK506) has a mechanism of action similar to cyclosporine. Unlike standard oral cyclosporine, tacrolimus is well absorbed orally, even from diseased small bowel mucosa.. To report the use of oral tacrolimus in three patients with complicated proximal small bowel or fistulizing Crohn's disease as a "bridge" to methotrexate or 6-mercaptopurine.. Oral tacrolimus was started at doses of 0.15-0.29 mg/kg/day and adjusted to a whole blood tacrolimus concentration range of 10-20 ng/ml. Case 1: Gastroenterostomy for gastroduodenal Crohn's disease complicated by recurrent gastrointestinal hemorrhage from persistent duodenal ulceration. Case 2: Diffuse jejunoileal Crohn's disease, seven prior stricturoplasties, and a postoperative small intestinal fistula causing an abdominal abscess. Case 3: Perianal and pouch-vaginal fistulae after colectomy and ileal pouch-anal anastomosis in a patient with Crohn's disease. All three patients had good oral absorption of tacrolimus, rapid clinical improvement of their Crohn's disease, and began long-term remission maintenance treatment with either methotrexate (n = 2) or 6-mercaptopurine (n = 1). Dose dependent side effects resulting from tacrolimus therapy occurred in all three patients (nephrotoxicity, hyperkalemia, diarrhea, nausea, flushing, headache, tremor, paresthesias, and insomnia).. Oral tacrolimus (0.15-0.29 mg/kg/day) is well absorbed in patients with Crohn's disease with proximal small bowel involvement or fistulae and appears to be of clinical benefit as a rapidly acting "bridge" to long-term therapy with methotrexate or 6-mercaptopurine.

Topics: Administration, Oral; Adolescent; Adult; Crohn Disease; Female; Humans; Immunosuppressive Agents; Intestinal Absorption; Intestinal Fistula; Intestine, Small; Male; Tacrolimus

Topics: Azathioprine; Cholangitis, Sclerosing; Colitis, Ulcerative; Crohn Disease; Cyclophosphamide; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Liver Transplantation; Male; Middle Aged; Muromonab-CD3; Retrospective Studies; Steroids; Tacrolimus