mycophenolic-acid and Colitis

Immune checkpoint inhibitors (ICI) have become a pillar of cancer therapy for many people around the world. However, up to two-thirds of all patients undergoing ICI therapy will have immune-related adverse events (irAEs), including immune-checkpoint inhibitor colitis (ICIC). This review summarizes the most valuable and currently available information about the mechanism, diagnosis, and management of ICIC.. Recent findings include several developments on the leading theories for the mechanisms of ICIC such as the role of the gut microbiome. New emerging therapy strategies include tocilizumab, ustekinumab, mycophenolate mofetil, and calcineurin inhibitors.. The occurrence of irAEs remains a limiting factor for the use of immunotherapy in cancer treatment. Prompt diagnosis of ICIC with endoscopy and histologic confirmation can lead to early utilization of known effective treatments such as corticosteroids, infliximab, vedolizumab, and other emerging therapy strategies. We summarize the key points of this review article in our abstract video, Supplemental Digital Content 1, http://links.lww.com/COG/A44.

Topics: Colitis; Gastrointestinal Microbiome; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Mycophenolic Acid

Gastrointestinal complications are common after renal transplantation, and they have a wide clinical spectrum, varying from diarrhoea to post-transplant inflammatory bowel disease (IBD). Chronic immunosuppression may increase the risk of post-transplant infection and medication-related injury and may also be responsible for IBD in kidney transplant re-cipients despite immunosuppression. Differentiating the various forms of post-transplant colitis is challenging, since most have similar clinical and histological features. Drug-related colitis are the most frequently encountered colitis after kidney transplantation, particularly those related to the chronic use of mycophenolate mofetil, while

Topics: Colitis; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid

Despite advances in therapeutic and preventive measures, hematopoietic stem cell transplant recipients remain at risk for a variety of gastrointestinal and liver complications.. To detail the pathologic features of the various gastrointestinal and liver complications occurring after hematopoietic stem cell transplantation in relation to their clinical context. The specific complications covered include graft-versus-host disease, mycophenolate mofetil-induced injury, timeline of infections, neutropenic enterocolitis, gastrointestinal thrombotic microangiopathy, sinusoidal obstruction syndrome, hepatic iron overload, and the controversy around cord colitis syndrome.. The content of this article is based on pertinent peer-reviewed articles in PubMed, relevant textbooks, and on the authors' personal experiences.. The final histopathologic diagnosis requires the integration of clinical and histologic findings and the exclusion of other competing causes of injury. Review of the clinical data, including the original disease pretransplant, the type of transplant, the timing of the gastrointestinal and/or liver manifestations, the timing of the biopsy after transplant, the presence of graft-versus-host disease in other organs and sites, the list of drug regimens, and the clinical and laboratory evidence of infection, is the key to reaching the proper histologic diagnosis.

Topics: Biopsy; Colitis; Enterocolitis, Neutropenic; Gastrointestinal Diseases; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Infections; Liver Diseases; Mucous Membrane; Mycophenolic Acid; Thrombotic Microangiopathies

Immune checkpoint inhibition with the anti-CTLA-4 antibody ipilimumab and the anti-PD-1 antibodies nivolumab and pembrolizumab has improved survival in metastatic melanoma, lung cancer and renal cancer. Use of these agents holds promise in other malignancies. The augmented immune response enabled by these agents has led to a particular group of side effects called immune-related adverse events (irAEs). The main irAEs include diarrhea, colitis, hepatitis, skin toxicities and endocrinopathies such as hypophysitis and thyroid dysfunction. The anti-PD-1 antibodies have a different toxicity profile to ipilimumab with fewer high grade events. This article identifies the rates of common and uncommon irAEs associated with each immune checkpoint inhibitor (ICPI) and their timing of onset, focusing mainly on the experience in melanoma and lung cancer. An approach to management for each class of irAE is provided.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Antineoplastic Agents; Carcinoma, Renal Cell; Chemical and Drug Induced Liver Injury; Colitis; CTLA-4 Antigen; Cyclosporine; Diarrhea; Drug Eruptions; Humans; Immunosuppressive Agents; Infliximab; Ipilimumab; Kidney Neoplasms; Lung Neoplasms; Melanoma; Mycophenolic Acid; Neoplasms; Nivolumab; Pituitary Diseases; Programmed Cell Death 1 Receptor; Skin Neoplasms; Tacrolimus; Thyroiditis

Ipilimumab has been shown to improve overall survival in patients with advanced melanoma. Ipilimumab acts through immune-modulation, and is recognized to cause potentially severe immune-related adverse events (irAEs) including dermatitis, colitis, thyroiditis, hypophysitis, and hepatitis. The acceptance of ipilimumab as a treatment for metastatic melanoma means patients will continue to be treated with this agent and gastroenterologists will be increasingly called upon to assist in managing severe autoimmune-related hepatitis and colitis. To date, the recommendations for managing irAEs secondary to ipilimumab have been steroids at a moderate dose of prednisolone (1 mg/kg) as well as immunosuppressive agents such as mycophenolate mofetil (MMF) for steroid-refractory hepatitis and infliximab in the management of corticosteroid-refractory colitis. However, the dosing and the duration of immunosuppressive therapy have not been systematically studied in the setting of treating ipilimumab-induced irAEs. Therefore, additional immune-modifying agents and/or a change in dosing may be required to manage severe irAEs unresponsive to existing treatment recommendations. We describe a treatment paradigm illustrated by a series of five patients who experienced irAEs. In three cases of metastatic melanoma, ipilimumab-induced hepatitis was successfully treated with high-dose parenteral pulsed methylprednisolone. In two other melanoma patients with ipilimumab-induced colitis, one patient had satisfactory resolution of his colitis with high-dose corticosteroid therapy alone and the other patient required infliximab infusion. We have reviewed the current literature and management algorithms for ipilimumab-induced irAEs. Treatment options and the rationale for their use are discussed, including the use of pulsed high-dose steroids, MMF, azathioprine and calcineurin inhibitors.

Topics: Antibodies, Monoclonal; Azathioprine; Calcineurin Inhibitors; Chemical and Drug Induced Liver Injury; Colitis; Glucocorticoids; Humans; Immunosuppressive Agents; Infliximab; Ipilimumab; Melanoma; Methylprednisolone; Mycophenolic Acid; Patient Care Team; Prednisolone; Pulse Therapy, Drug

Immune checkpoint inhibitor (IO) induced colitis is primarily managed with corticosteroids. Most patients have a rapid resolution of symptoms and do not require additional immunosuppressants. Many patients, however, require prolonged corticosteroid courses to maintain control of toxicity. Mycophenolate mofetil (MMF) is the prodrug of mycophenolic acid; which in turn directly inhibits activated T and B lymphocytes. MMF, in addition to corticosteroids, may enable reduction of corticosteroids without precipitating resurgence of colitis. Metastatic melanoma patients between 1 January 2017 and 31 December 2017 with combination IO-induced colitis were managed with a novel treatment algorithm: upfront oral enteric-coated MMF alongside high-dose corticosteroids. Outcome measures included incidence of colitis flare, time to grade 1 colitis, time to patient-reported normal bowel habit and overall cumulative corticosteroid exposure. Thirteen patients developed high-grade combination IO-induced colitis; 11 were managed with the combination of high-dose corticosteroid and MMF. Median patient age was 59 (range: 28-73) years. Four (36%) developed flare of colitis; flares occurred at a median of 11 (interquartile range: 4.5-16.75) days. All colitis flares responded fully to infliximab (5 mg/kg). The remaining seven patients did not develop colitis flare during corticosteroid wean. All patients were successfully weaned from corticosteroids and none had a resurgence of colitis at 8 weeks following discontinuation of MMF. Concomitant enteric-coated MMF alongside high-dose corticosteroids may hasten the improvement of high-grade colitis to normal bowel habit and reduce the incidence of colitis flare.

Topics: Adrenal Cortex Hormones; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colitis; Disease Management; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Ipilimumab; Male; Melanoma; Middle Aged; Mycophenolic Acid; Nivolumab; Prognosis; Prospective Studies; Skin Neoplasms

Trials of mycophenolate mofetil (MMF) in inflammatory bowel disease (IBD) suggest that it may be useful in patients intolerant of azathioprine. We examined the safety and efficacy of MMF in IBD patients intolerant of or unresponsive to azathioprine. Twelve patients [seven with Crohn's disease (CD); seven women; mean age 40 years, range 14-76 years] were treated with MMF 500 mg b.i.d. for a mean of 12.5 weeks. Intolerance was defined as the development of side effects that resolved on discontinuing MMF. Improvement was described as symptomatic improvement, decreased steroid use, or disease entering endoscopic remission. Four patients responded with symptomatic improvement and reduced steroids or mesalazine requirement. Three patients developed headache, nausea, or arthralgia. Three patients developed profuse bloody diarrhea, and in two cases with previously quiescent ulcerative colitis (UC), the source was shown to be ulcers in a drug-induced colitis with histologic features similar to those previously reported in four renal transplant patients on MMF. There is no clear evidence of efficacy of MMF in the treatment of IBD, and its use in this condition should be confined to a randomized controlled trial. Moreover, as patients with UC may be unduly prone to colonic injury, MMF may not be a suitable drug for its treatment.

Topics: Administration, Oral; Adolescent; Adult; Aged; Colitis; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Middle Aged; Mycophenolic Acid; Treatment Outcome

Topics: Colitis; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid

BACKGROUND Mycophenolic acid is an immunosuppressive drug commonly used in solid organ transplantation to prevent acute and chronic allograft rejection. There are 2 common preparations of mycophenolic acid including mycophenolate mofetil (Cellcept), and enteric-coated mycophenolate sodium (Myfortic) which was developed to reduce the high rate of gastrointestinal side effects seen with Cellcept. Cases of mycophenolate mofetil induced colitis have been described in solid organ transplant patients and rarely in heart transplant patients, but enteric-coated mycophenolate sodium induced colitis is very rare and has not been reported in heart transplant patients. CASE REPORT A 66-year old male with an orthotopic heart transplant was admitted with diarrhea. The patient was on an immunosuppression regimen including mycophenolate mofetil for 10 weeks post-transplantation until complaining of soft stools and bloating. At this time, he was switched to enteric-coated mycophenolate sodium. At week 11 post-transplantation, the patient was admitted to the hospital with worsening diarrhea. Extensive workup was unrevealing. Colonoscopy with biopsy showed features of mycophenolic acid induced colitis. Enteric coated mycophenolate sodium was discontinued, and the patient's diarrhea markedly improved over the next 48 hours. The patient had no signs of colitis or solid organ rejection at 7-month follow up appointment. CONCLUSIONS Although a diagnosis of exclusion, enteric-coated mycophenolate sodium induced colitis should be considered in the differential of an orthotopic heart transplant patient with diarrhea as discontinuing the medication can improve symptoms and avoid costly workups, however, patients should be monitored closely for signs of rebound rejection.

Topics: Aged; Colitis; Colonoscopy; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Tablets, Enteric-Coated; Transplant Recipients

Immunosuppression is necessary after solid organ transplantation. The non-infectious side effects associated with many of these agents are not well understood. We report a case of colitis, most resembling inflammatory bowel disease, that persisted despite withdrawal of tacrolimus and mycophenolate mofetil and transition to alternative agents. The patient was treated for clostridium difficile without improvement. Endoscopic biopsies demonstrated non-specific inflammation without evidence of active infection. An extensive immunologic and oncologic workup was negative. Ultimately, we trialed the administration of infliximab, a monoclonal antibody that inhibits TNF-alpha receptors that is commonly used in the treatment of inflammatory bowel disease. With infliximab treatment, the patient experienced rapid resolution of his disease and has remained in remission.

Topics: Antibiotics, Antineoplastic; Antirheumatic Agents; Biopsy; Child, Preschool; Colitis; Colonoscopy; Drug Therapy, Combination; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Infliximab; Male; Mycophenolic Acid; Tacrolimus

Chronic immunosuppression may increase the risk of post-transplant infection and medication-related injury and may also be responsible for the increased risk of gastrointestinal complications in kidney transplant recipients. Differentiating the various forms of post-transplant colitis is challenging, since most have similar clinical and histological features. This study evaluated the incidence of post-transplant gastrointestinal complications during screening colonoscopy. Kidney transplant recipients undergoing a colonoscopy for any reasons in the period 2014-2018 were included. Among the 134 patients completing the colonoscopy, 74 patients (56%) had an abnormal finding: an adenoma was found in 25 patients (18.6%), while 19 patients (14.1%) had colitis. Mycophenolic acid/related colitis was the most common colitis (6%), while 7 patients (5.2%) developed a

Topics: Adenoma; Age Distribution; Aged; Anemia; Colitis; Colonoscopy; Colorectal Neoplasms; Diarrhea; Diverticulosis, Colonic; Early Detection of Cancer; Female; Gastrointestinal Hemorrhage; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Time Factors

Epithelial to mesenchymal transition (EMT) occurs when cells lose morphological features of epithelial cells, such as cell-to-cell adhesion, and gain features of mesenchymal cells, including elongation and flattening. These cells also lose expression of epithelial immunohistochemical markers. In this report, we present a 55-year-old Caucasian male patient who underwent orthotopic heart transplant and immunosuppressant therapy with tacrolimus and mycophenolic acid. Seven and a half months later, an endomyocardial biopsy revealed a hypercellular, atypical lesion. Evaluation was negative for acute cellular rejection and post-transplant lymphoproliferative disorder. Histopathologic features and immunohistochemical stains were consistent with EMT. We subsequently identified four additional cases of EMT in patients who underwent orthotopic heart transplantation and received a similar immune suppression regimen. EMTs have been reported to occur in lung and kidney allografts; however, this is the first known report describing this entity in a heart transplant recipient.

Topics: Colitis; Diagnosis, Differential; Endocardium; Epithelial-Mesenchymal Transition; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Tacrolimus

Mycophenolate mofetil (MMF) is commonly prescribed and has proven advantages over other immunosuppressive drugs. However, frequent gastrointestinal side effects through an unknown mechanism limit its use. We have found that consumption of MMF alters the composition of the gut microbiota, selecting for bacteria expressing the enzyme β-glucuronidase (GUS) and leading to an up-regulation of GUS activity in the gut of mice and symptomatic humans. In the mouse, vancomycin eliminated GUS-expressing bacteria and prevented MMF-induced weight loss and colonic inflammation. Our work provides a mechanism for the toxicity associated with MMF and a future direction for the development of therapeutics.

Topics: Animals; Bacteria; Bacterial Proteins; Body Weight; Colitis; Disease Models, Animal; Female; Gastrointestinal Microbiome; Gastrointestinal Tract; Glucuronidase; Immunosuppressive Agents; Mice; Mice, Inbred C57BL; Mycophenolic Acid; Up-Regulation; Vancomycin

We present the case of a 44-year-old woman affected by systemic sclerosis (SSc) who was admitted to our department for abdominal pain, nausea, vomiting and fever. Imaging studies showed the presence of a thickened colon wall involving the descending colon and the sigma, while a subsequent endoscopy revealed multiple serpiginous ulcers covered with fibrin and exudates. Under the hypothesis of drug-induced colitis, mycophenolate mofetil (MMF), which she was taking for SSc-related interstitial lung disease (ILD), was readily suspended, with a rapid recovery without further treatment. A follow-up colonoscopy showed the complete resolution of the ulcers. This is the first case of MMF-induced colitis in a patient being treated for SSc-ILD.

Topics: Adult; Colitis; Female; Humans; Lung Diseases, Interstitial; Mycophenolic Acid; Scleroderma, Systemic

In this article, we report a case of a 55-year-old male heart transplant recipient who presented with diarrhoea. An extensive workup for infectious diseases was negative. The patient had a colonoscopy with biopsies showing colitis that mimicked graft-versus-host disease on histopathology. After excluding other potential causes and excluding acute cellular rejection, mycophenolate mofetil was discontinued, and the patient had significant clinical improvement with increased appetite and weight gain.

Topics: Colitis; Colonoscopy; Diagnosis, Differential; Graft Rejection; Heart Transplantation; Humans; Male; Middle Aged; Mycophenolic Acid; Weight Gain

Topics: Adult; Biopsy; Colitis; Colon; Colonoscopy; Diarrhea; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Mycophenolic Acid; Pancreatitis

Topics: Colitis; Colonoscopy; Histoplasmosis; Humans; Ileitis; Immunocompromised Host; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Middle Aged; Mycophenolic Acid; Prednisone; Scleroderma, Systemic

With the recent approval of 5 PD-1/PD-L1 inhibitors for a number of malignancies, PD-1 axis inhibition is drastically changing the treatment landscape of immunotherapy in cancer. As PD-1/PD-L1 are involved in peripheral immune tolerance, inhibition of this immune checkpoint has led to novel immune-related adverse events including colitis, hepatitis, pneumonitis, rash, and endocrinopathies among many others.. In this seminar, we will analyze the incidence of immune-related adverse events for nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. Then, we will discuss the specific management of the most common immune-mediated adverse events including colitis, hepatitis, pneumonitis, rash, endocrinopathies, nephritis, and neurologic toxicities.. Immune-related adverse events are frequently treated with immunosuppressive medication such as steroids and mycofenolate mofetil.. There are specific immune-related adverse events which are frequently seen by the treating oncologist from checkpoint inhibitors. It is essential to understand the recommended treatment options to minimize toxicity and mortality from this important class of anti-neoplastic therapies.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; B7-H1 Antigen; Colitis; Exanthema; Hepatitis; Humans; Immunosuppressive Agents; Immunotherapy; Mycophenolic Acid; Neoplasms; Nephritis; Neurodegenerative Diseases; Nivolumab; Pneumonia; Programmed Cell Death 1 Receptor

Chronic diarrhea after kidney transplantation is often attributed to mycophenolic acid (MPA) toxicity. We hypothesize that intestinal infections contribute to the pathogenesis of chronic MPA-associated diarrhea.. In this retrospective study, all patients (n = 726) receiving a kidney transplant between 2000 and 2010 at the University Hospital Zurich were followed until July 2014 for occurrence of chronic diarrhea (≥4 weeks). Infectious triggers at diarrhea onset were assessed by reviewing medical history, stool microbiology, and histology of colon biopsies.. In 46 patients (6.3% of the cohort), a total of 51 episodes of chronic diarrhea during MPA treatment were documented. The diarrhea episodes were often severe, as confirmed by significant weight loss. The cumulative incidence of chronic diarrhea was uniformly distributed throughout the post-transplant period, with 2.0%, 5.1%, and 9.6% at 1, 5, and 10 years, respectively. Evidence was found for intestinal infection at diarrhea onset in 38 episodes (74.5%). Occurrence of diarrhea onset showed a seasonal distribution with peaks in April and October/November. Specific antimicrobial treatment alone was associated with a 19% resolution rate only, whereas combination with dose reduction of MPA or switch from mycophenolate mofetil to enteric-coated mycophenolate sodium resulted in a 22.7% and 76.5% resolution rate, respectively. Change to an MPA-free regimen was associated with a 100% resolution rate.. These results provide first evidence for a contribution of intestinal infections in chronic post-transplant diarrhea associated with MPA treatment.

Topics: Adult; Area Under Curve; Chronic Disease; Colitis; Colon; Diarrhea; Feces; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Switzerland; Transplant Recipients; Transplantation, Homologous; Weight Loss

Mycophenolate mofetil (MMF) is an alternative immunosuppressive agent that has been reported to be effective and well tolerated for the treatment of refractory inflammatory bowel disease (IBD). The aim of this study was to investigate the therapeutic effect of MMF on intestinal injury and tissue inflammation, which were caused by Crohn's disease (CD). Here, trinitrobenzene sulfonic acid-relapsing (TNBS) colitis was induced in mice; then, we measured the differentiation of Th1/Th2 cells in mouse splenocytes by flow cytometry and the secretion of cytokines in mice with TNBS-induced colitis by real-time polymerase chain reaction and/or enzyme-linked immunosorbent assay (RT-PCR/ELISA). The results show that MMF significantly inhibited mRNA expression of pro-inflammatory cytokines IFN-γ, TNF-α, IL-12, IL-6, and IL-1β in mice with TNBS-induced colitis; however, MMF did not inhibit the expression of IL-10 mRNA. Additionally, ELISA showed that the serum levels of IFN-γ, TNF-α, IL-12, IL-6, and IL-1β were down-regulated in a TNBS model of colitis. Flow cytometric analysis showed MMF markedly reduced the percentages of Th1 and Th2 splenocytes in the CD mouse model. Mycophenolic acid (MPA) also significantly decreased the percentages of splenic Th1 and Th2 cells in vitro. Furthermore, MMF treatment not only significantly ameliorated diarrhea, and loss of body weight but also abrogated the histopathologic severity and inflammatory response of inflammatory colitis, and increased the survival rate of TNBS-induced colitic mice. These results suggest that treatment with MMF may improve experimental colitis and induce inflammatory response remission of CD by down-regulation of pro-inflammatory cytokines via modulation of the differentiation of Th1/Th2 cells.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Differentiation; Colitis; Crohn Disease; Disease Models, Animal; Female; Gene Expression; Immunosuppressive Agents; Interferon-gamma; Interleukin-12; Interleukin-1beta; Interleukin-6; Mice; Mice, Inbred BALB C; Mycophenolic Acid; Spleen; Th1 Cells; Th1-Th2 Balance; Th2 Cells; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Reports on the clinical course of mycophenolic acid (MPA)-related colitis in kidney transplant recipients are scarce. This study aimed at assessing MPA-related colitis incidence, risk factors, and progression after kidney transplantation. All kidney transplant patients taking MPA who had colonic biopsies for persistent chronic diarrhea, between 2000 and 2012, at the Kidney Transplantation Unit of Botucatu Medical School Hospital, Brazil, were included. Cytomegalovirus (CMV) immunohistochemistry was performed in all biopsy specimens. Data on presenting symptoms, medications, immunosuppressive drugs, colonoscopic findings, and follow-up were obtained. Of 580 kidney transplant patients on MPA, 34 underwent colonoscopy. Colonoscopic findings were associated with MPA usage in 16 patients. The most frequent histologic patterns were non-specific colitis (31.3%), inflammatory bowel disease (IBD)-like colitis (25%), normal/near normal (18.8%), graft-versus-host disease-like (18.8%), and ischemia-like colitis (12.5%). All patients had persistent acute diarrhea and weight loss. Six of the 16 MPA-related diarrhea patients (37.5%) showed acute dehydration requiring hospitalization. Diarrhea resolved when MPA was switched to sirolimus (50%), discontinued (18.75%), switched to azathioprine (12.5%), or reduced by 50% (18.75%). No graft loss occurred. Four patients died during the study period. Late-onset MPA was more frequent, and no correlation with MPA dose or formulation was found.

Topics: Adolescent; Adult; Child; Cohort Studies; Colitis; Colonoscopy; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Risk Factors; Treatment Outcome; Young Adult

Serious gastrointestinal complications arising 13 years after the initiation of posttransplant immunosuppressant therapy with mycophenolate mofetil are reported.. Over a three-month period, a male heart transplant recipient who had taken oral mycophenolate mofetil (2 g daily) for 13 years as part of an immunosuppressant maintenance regimen developed diarrhea and weight loss leading to renal failure and metabolic acidosis. There was no evidence of opportunistic infection, and immunostaining for cytomegalovirus yielded negative results. Colonoscopy revealed areas of congested, erythematous, and nodular mucosa. Histological examination of mucosal biopsy specimens revealed pathological abnormalities typical of those seen in cases of mycophenolate mofetil-associated colitis. On discontinuation of mycophenolate mofetil use, the patient's diarrhea resolved and his renal function improved. Colitis, diarrhea, and other gastrointestinal complications are commonly reported in patients receiving mycophenolate mofetil, an immunosuppressant widely used to prevent rejection of solid organ or bone marrow transplants; however, the onset of such symptoms after more than a decade of continuous use of the drug has not been previously reported. This case suggests that mycophenolate mofetil toxicity should be considered in the evaluation of late-onset posttransplant diarrhea regardless of the duration of therapy.. A 33-year-old man maintained on mycophenolate mofetil for 13 years after heart transplantation developed diarrhea, weight loss, and acute kidney injury over a three-month period. Colonoscopy and biopsy revealed pathological changes consistent with mycophenolate mofetil toxicity, and the patient's symptoms resolved after the drug was discontinued.

Topics: Adult; Colitis; Colon; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Tacrolimus

We report a case of a 52-year-old woman, on immunosuppressive treatment with mycophenolate due to a history of giant cell myocarditis (GCM), who presented with new-onset severe blood-tinged diarrhoea after a cytomegalovirus (CMV) primoinfection. An extensively prolonged mycophenolate-related colitis was seen after withdrawal of mycophenolate due to an intestinal Epstein-Barr virus (EBV) infection-a rarely seen event itself. We postulate that colonic toxicity was triggered by CMV infection and perpetuated by intestinal EBV replication/infection.

Topics: Colitis; Cytomegalovirus Infections; Diarrhea; Epstein-Barr Virus Infections; Female; Humans; Immunosuppressive Agents; Middle Aged; Mycophenolic Acid; Severity of Illness Index

The main purpose of this study was to define diagnostic histological characteristics of mycophenolate mofetil (MMF)-related colitis in association with crypt epithelial cell turnover.. The examined material included 43 colonic biopsies from renal transplant recipients with MMF administration and persistent diarrhoea. Thirty-three cases showed MMF-related colitis, while 10 showed no significant changes. The histological findings were scored and correlated with the apoptotic index (AI) and with the proliferation rate (PR) of the crypt epithelium examined by TUNEL assay and Ki-67 immunoexpression. Ten cases of Crohn disease and 10 of ulcerative colitis were used as comparative groups. Crypt distortion and loss as well as increased apoptosis constituted the main features, their degree and combination leading either to an inflammatory bowel disease (IBD)-like (82%) or to a graft-versus-host disease-like pattern (18%). A high AI was associated more frequently with moderate and severe crypt distortion, while the values were significantly higher compared with the control groups (P < 0.01). High PR was noted in 18 of 29 (62.1%) of the cases.. The diagnostic hallmark of MMF-related colitis is an IBD-like histological pattern in association with increased epithelial apoptosis, while apoptotic cell death seems to be a potential pathogenetic factor of mucosa injury.

Topics: Adult; Aged; Aged, 80 and over; Apoptosis; Cell Proliferation; Colitis; Colon; Diarrhea; Female; Humans; Immunosuppressive Agents; Intestinal Mucosa; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid

Topics: Antiviral Agents; Azathioprine; Colitis; Cytomegalovirus Infections; Diarrhea; Female; Ganciclovir; Humans; Immunosuppressive Agents; Middle Aged; Mycophenolic Acid; Treatment Outcome

Mycophenolate mofetil (MMF) is a T-cell inhibitor frequently used in the treatment of acute allograft rejection. MMF may cause colitis that clinically and histologically resembles graft-versus-host disease (GVHD). The aim of this study was to evaluate a wide range of histologic features that may help differentiate MMF from GVHD-induced colitis and to validate significant features on a cohort of bone marrow transplant patients who were also taking MMF as part of their immunosuppressive regimen and developed a diarrheal illness due to colitis. Routinely processed colonic biopsies from 17 patients with MMF colitis and 40 patients with GVHD-induced colitis were evaluated for the overall grade of colitis (grades 1 to 4) and histologically for a wide range of inflammatory, epithelial, and architectural changes in a blinded manner. Statistically significant features were then tested in a cohort of 20 bone marrow transplant patients who also received MMF, and later developed a diarrheal illness. Both univariate and multivariate analyses (including receiver operating characteristic analysis) were performed. Morphologic features shown to be independently associated with MMF include the presence and quantity of lamina propria eosinophils and endocrine cell aggregates and the presence and quantity of apoptotic microabscesses, hypereosinophilic (degenerated) crypts, and crypt distortion. Eosinophils were present in all MMF patients, but apoptotic microabscesses were present in none and endocrine cell aggregates in only 1 case. When a grade-by-grade comparison was made between MMF and GVHD, grade 1 or 2 MMF also showed an increased prevalence rate and quantity of lamina propria neutrophils in comparison with grade 1 or 2 GVHD. By receiver operating characteristic analysis, a combination of lamina propria eosinophils >15 per 10 HPF, combined with a lack of endocrine cell aggregates and apoptotic microabscesses, revealed sensitivity, specificity, and positive and negative predictive values of 76%, 93%, 81%, and 90%, respectively, for identification of MMF colitis. On the basis of these data, we conclude that a variety of histologic features, in particular, eosinophils >15 per 10 HPF, lack of endocrine cell aggregates in the lamina propria, and lack of apoptotic microabscesses, can be used by pathologists to help separate MMF from GVHD-induced colitis in routine clinical practice.

Topics: Adult; Aged; Apoptosis; Biopsy; Colitis; Colon; Diagnosis, Differential; Eosinophils; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Intestinal Mucosa; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Neutrophil Infiltration; Predictive Value of Tests; Reproducibility of Results; ROC Curve

Mycophenolate-associated colitis has been previously reported to show patterns of colonic mucosal injury mimicking a host of conditions, including graft-versus-host disease, ischaemia and inflammatory bowel disease (IBD). The aim of this study is to characterise, semiquantitatively, pathological changes of mycophenolate mofetil (MMF) mucosal injury.. Seven transplant patients receiving MMF who underwent colonoscopic examination and biopsy were identified retrospectively over a 2-year period. Multiple histologic parameters, including architectural distortion, cryptitis, stromal active inflammation, individual damaged crypts (IDC) and crypt apoptotic figures were evaluated in the biopsies semiquantitatively. Where biopsy site was identified, the parameters were assessed separately in biopsies from right and left colon.. All cases showed mixed patterns of mucosal injury. All seven cases showed focal architectural distortion (in 58% of fragments per case), focal cryptitis (mean 3.0 foci per case), increased crypt apoptosis (mean 26.5/100 crypts) and IDC (mean 3.0 foci). Focal changes resembling acute self-limited colitis were noted in three cases. Possible proximal accentuation of some changes was noted with right side biopsies tending to show greater crypt apoptotic activity and more foci of architectural distortion. Three cases showed dual pathology (two with cytomegalovirus (CMV) infection and one with IBD).. Although a wide spectrum of changes may be seen in MMF-associated colitis, important microscopic clues include a mixed pattern of injury (typically a combination of crypt apoptosis, isolated crypt damage and architectural distortion), and possible proximal accentuation of pathologic changes. The need for clinical correlation and follow-up is emphasised by the occurrence of dual pathology in patients treated with MMF.

Topics: Acute Disease; Adult; Apoptosis; Biopsy; Colitis; Colonoscopy; Diagnosis, Differential; Female; Humans; Immunosuppressive Agents; Intestinal Mucosa; Male; Middle Aged; Mycophenolic Acid; Organ Transplantation; Postoperative Complications; Retrospective Studies; Young Adult

Gastrointestinal adverse effects are common with mycophenolate mofetil administration, especially diarrhea. We report a case of mycophenolate mofetil-related colitis in a kidney transplant recipient. Colonoscopy revealed an ulcerative diffuse colitis. The colonoscopic biopsy specimen showed mild crypt distortion, accompanied by cryptitis and focal graft-versus-host disease like changes. The patient's symptoms improved after we discontinued the mycophenolate mofetil. A repeat colonoscopy 2 months after we discontinued the mycophenolate mofetil showed reparative changes. Mycophenolate mofetil is an important drug in organ transplant immune-suppression regimens; however, with its widespread use, additional adverse effects continue to be recognized.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Diarrhea; Graft Rejection; Humans; Kidney Transplantation; Male; Mycophenolic Acid

Topics: Adult; Chronic Disease; Colitis; Diarrhea; Female; Humans; Immunosuppressive Agents; Mixed Connective Tissue Disease; Mycophenolic Acid

Topics: Adult; Aged; Biopsy; Colitis; Colon; Cytomegalovirus Infections; Female; Gastritis; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Stomach

Topics: Antigens, Viral; Colitis; Colonoscopy; Cytomegalovirus; Cytomegalovirus Infections; Diagnosis, Differential; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Methylprednisolone; Mycophenolic Acid; Nocardia Infections; Opportunistic Infections; Pneumatosis Cystoides Intestinalis; Respiratory Tract Infections

Topics: Aged; Biopsy; Colitis; Colon; Colonoscopy; Diagnosis, Differential; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid

To describe a case of cytomegalovirus (CMV) viremia and colitis in a patient on mycophenolate mofetil (MMF) monotherapy for birdshot chorioretinopathy.. Case report.. Retrospective chart review.. Treatment with MMF 1.5 g twice daily for 5 years led to leucopenia and a CD4 count of 299, which resulted in active CMV infection.. Treatment with MMF alone may put otherwise immune-competent individuals at risk for opportunistic CMV infection. Greater awareness of this association may allow for better monitoring, earlier detection, and treatment of future cases.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Antiviral Agents; Birdshot Chorioretinopathy; CD4 Lymphocyte Count; Chorioretinitis; Colitis; Cytomegalovirus Infections; Drug Therapy, Combination; Ganciclovir; Humans; Immunosuppressive Agents; Leukopenia; Male; Mycophenolic Acid; Prednisone; Treatment Outcome; Valganciclovir; Viremia

Topics: Aged; Colitis; Crohn Disease; Cytomegalovirus Infections; Diagnosis, Differential; Diarrhea; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Mycophenolic Acid; Opportunistic Infections; Weight Loss

Mycophenolate mofetil (MMF) was introduced as a new immune-suppression drug in the mid-1990s. It is widely utilized in solid-organ transplantation immune-suppression regimens. Side effects include gastrointestinal (GI) toxicity in the form of nausea, vomiting, and diarrhea. Physicians tend to reduce the dose of MMF or switch their patients to an enterio-coated formula to overcome the side effects. Because GI side effects are well linked to MMF, colonoscopy is not utilized in most of the cases to investigate the diarrhea. However, Crohn's disease-like changes in the colon, erosive enterocolitis, and graft versus host disease-like colonic changes associated with the use of MMF have been reported. Colonic findings in five patients whose symptoms resolved after substituting another agent for MMF are described in the present report. Repeat colonoscopy 4 months following discontinuation of MMF showed reparative changes in one of our patients. MMF is an important drug in organ transplantation immune-suppression regimens; however, with its widespread usage, additional side effects continue to be recognized.

Topics: Adult; Colitis; Colon; Colonoscopy; Diarrhea; Drug Substitution; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Organ Transplantation; Time Factors

A 50-year-old woman with Beçhet's disease presented with episodic diarrhoea and generalised abdominal pain. She was on regular mycophenolate maintenance therapy, being intolerant of both ciclosporin and azathioprine. Previous rectal biopsy was consistent with colitis, probably associated with Beçhet's disease. During this admission, she began passing faecal matter per vaginam. Digital rectal examination confirmed the presence of a large rectovaginal fistula. She underwent urgent laparotomy for a subtotal colectomy with end ileostomy. Although there were no signs of septicaemia preoperatively, small perforations were identified in the caecum and at the splenic flexure on laparotomy. Histopathology confirmed the presence of multiple shallow ulcers throughout the colon with features suggestive of Beçhet's colitis.

Topics: Abdominal Abscess; Abdominal Pain; Behcet Syndrome; Colitis; Colitis, Ulcerative; Colon; Diarrhea; Female; Humans; Ileostomy; Immunosuppressive Agents; Intestinal Perforation; Middle Aged; Mycophenolic Acid; Rectovaginal Fistula

In this study, we used a murine intestinal inflammation model that mimics immunologic characteristics of human Crohn's disease (CD) to investigate the anti-inflammatory effects of mycophenolate mofetil (MMF) on intestinal injury and tissue inflammation. When these colitic mice were pretreated with MMF, we observed a significant decrease in mortality rates and body weight loss as well as an improvement in both wasting and histopathologic signs of colonic inflammation, relative to untreated colitic mice. To determine the mechanisms of action of MMF, we compared various immunological characteristics of the untreated and MMF-pretreated colitic mice. MMF-pretreated colitic mice showed an 18% decrease in the proportion of CD19+ B cells compared with untreated colitic mice 3 days. As a result, MMF pretreatment increases proportion of apoptotic T and B cells, especially CD19+ B cells. Also, down-regulation of Th1 cytokines (TNF-alpha, IFN-gamma) and augmentation of CD4+CD45RB(low) regulatory T (Treg) cells were observed in MMF-pretreated colitic mice compared with untreated colitic mice. Furthermore, mycophenolic acid (MPA) reduced TNF-alpha-stimulated NF-kappaB activation in HT-29 colon epithelial cells. Also, MMF-pretreated colitic mice significantly reduced expression of MD-1 compared with untreated colitic mice on B cells and dendritic cells (DCs). These studies show that MMF pretreatment can improve experimental colitis by down-regulation of expanded B cells population through apoptosis and augmentation of Treg cells. Through these mechanisms, MMF might also be an effective agent for the treatment of other diseases characterized by mucosal inflammation.

Topics: Animals; Antigens, CD19; Antigens, Surface; Apoptosis; B-Lymphocytes; Colitis; Disease Models, Animal; Down-Regulation; Female; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Mycophenolic Acid; NF-kappa B; T-Lymphocytes, Regulatory; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Mycophenolate mofetil (MMF) is widely used for maintenance immunosuppression in solid organ transplantation. Gastrointestinal toxicity, usually manifested as diarrhea, is the most common side effect of MMF. We evaluated colonic biopsies from 20 renal transplant patients with MMF-related diarrhea. The latter was defined by the absence of any other demonstrable etiology and improvement or resolution of symptoms by the discontinuation or reduction of the dose of MMF alone. These biopsies were compared with colon biopsies from patients with the following: acute graft-versus-host disease (GVHD, n=10), inflammatory bowel disease (IBD) or infectious colitis (n=10), and colon biopsies from renal transplant patients not receiving MMF (n=8). Normal colonic segments from surgical specimens served as normal controls (n=5). Colonic biopsies from patients with MMF-related diarrhea showed prominent crypt cell apoptosis and reactive/reparative changes including enterocyte cytologic atypia, increased neuroendocrine cells, and glandular architectural distortion. The changes were similar, although of milder degree to the ones seen in patients with acute intestinal GVHD. This pattern of injury was not seen in controls or in biopsies from transplant patients not receiving MMF, and it was markedly different from the one seen in idiopathic inflammatory or infectious colitis. The severity of histologic changes correlated significantly with the endoscopic degree of "colitis." There was no statistically significant correlation between histologic damage and the dose of MMF (corrected for body weight and renal function). MMF-related colitis is a distinct entity that displays histologic features remarkably similar to the ones associated with intestinal GVHD. This form of injury could be related to either direct toxicity or an "innocent by-stander" phenomenon secondary to the alteration of the immunologic microenvironment of the colon caused by the MMF.

Topics: Apoptosis; Colitis; Diarrhea; Dysentery; Graft vs Host Disease; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Kidney Transplantation; Mycophenolic Acid

Lymphocytes are widely believed to be responsible for persistent intestinal inflammation in inflammatory bowel diseases. Mycophenolate mofetil (MMF) is a potent immunosuppressant that inhibits lymphocyte proliferation and has been shown to be effective in preventing allograft rejection after organ transplantation. The purpose of this study was to assess the modulating effects of MMF on intestinal inflammation in an experimental model of colitis in rats.. Colitis was induced by rectal instillation of trinitrobenzenesulfonic acid (TNBS) in ethanol in male Sprague-Dawley rats. One group of rats (n = 10) was treated with MMF i.p. (25 mg/kg b.w.) daily for 1 week starting 24 h after induction of colitis. A second group of rats (n = 10) was treated with MMF at the same dose 2 days, I day and 1 h prior to induction of colitis. Control animals (n = 10) received vehicle only. After being killed, colonic tissue was macroscopically evaluated for necrosis and microscopically for ulcerations. Sections were stained and examined for the presence of granulocytes.. Administration of MMF after induction of TNBS colitis reduced macroscopic injury by 62% compared to control animals (P = 0.01). Microscopic ulcerations were reduced by 64% compared to controls (P = 0.009). In addition, posttreatment significantly reduced the number of granulocytes. MMF pretreatment did not significantly prevent macroscopic or microscopic tissue damage, or change the number of granulocytes.. Systemic administration of MMF significantly ameliorates tissue damage in a model of experimental colitis in rats suggesting that this compound may play an important role as an immunosuppressant in the therapy of inflammatory bowel diseases.

Topics: Animals; Colitis; Colon; Immunosuppressive Agents; IMP Dehydrogenase; Male; Mycophenolic Acid; Rats; Rats, Sprague-Dawley; Trinitrobenzenesulfonic Acid

Topics: Apoptosis; Biopsy; Colitis; Colon; Diagnosis, Differential; Graft vs Host Disease; Immunosuppressive Agents; Intestinal Mucosa; Kidney Transplantation; Mycophenolic Acid

Topics: Colitis; Colon; Creatinine; Cyclosporine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Ischemia; Kidney Transplantation; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Tacrolimus

Mycophénolate mofétil (MMF) or Cellcept is a potent immunosuppressor that inhibits purin synthesis used to prevent human allograft rejection. The most important secondary effects include haematological and intestinal disorders. Among them, diarrhea is the most common. It is dose-dependant and appears commonly during the first 2 months of treatment. Its physiopathology remains unclear. We reported a case of colitis, 6 months after a kidney transplantation. The patient was treated since day 2 with 2 grams per day of MMF. Morphological analysis showed a diffuse colitis from the coecum to the rectum. Histological samples confirmed a colitis with atrophic crypts but with mucosal secretions and some cryptic abscesses. No granuloma or CMV inclusion was founded. Histochemical immunostaining for CMV was negative. Finally, symptoms regressed within 5 days after tapering down MMF dose in association with metronidazole treatment. The role of MMF in inducing colitis is discussed.

Topics: Aged; Colitis; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Metronidazole; Mycophenolic Acid

Topics: Colitis; Colon; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Care; Prednisone; Serologic Tests