Mycophenolate Mofetil Combination Therapy Research Articles

Refractory optic perineuritis due to granulomatosis with polyangiitis successfully treated with methotrexate and mycophenolate mofetil combination therapy.

Optic perineuritis is an uncommon inflammatory disorder of the optic sheath that causes visual loss or eye pain. There are few case reports of optic perineuritis associated with granulomatosis with polyangiitis. Herein we report the case of a 37-year-old male with granulomatosis with polyangiitis and who presented with headache, blurred vision in the right eye, diplopia, and numbness in the right forehead. Brain magnetic resonance images (MRI) findings revealed hypertrophic pachymeningitis and refractory optic perineuritis. These were manageable only by means of weekly methotrexate and mycophenolate mofetil combination therapy but not with methotrexate, mycophenolate mofetil, intravenous cyclophosphamide, rituximab, azathioprine, or cyclosporine individually.

A novel immunomodulatory treatment involving mycophenolate mofetil and corticosteroids for pediatric autoimmune cytopenias

Successful treatment of both pediatric autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP), specifically those that are refractory to first-line therapies, remains unsatisfactory in terms of long-term remission and medication side effects. Here, we propose a novel combination therapy of mycophenolate mofetil (MMF), an adjunct immunosuppressive, and short-term corticosteroids for the treatment of persistent or chronic autoimmune cytopenias in children. This combination may allow for rapid decrease of steroid usage as well as prolonged count stabilization with minimal toxicity to the patient. Prospective case series of nine patients, six with persistent or chronic ITP and three with persistent or chronic AIHA, between the ages of 5 and 19 years who are being treated with combination therapy consisting of corticosteroids and MMF. All patients with ITP (Patients 4-9) and AIHA (Patients 1-3) met complete response (CR) criteria, as they all initially achieved platelet counts 100 × 109 l-1 or more or hemoglobin level greater than or equal to 10 g/dl, respectively, while on combination therapy and then maintained this level or higher while on MMF alone after steroids were discontinued. Our results are very promising, as MMF appears to be an effective and well-tolerated adjunct immunosuppressant that allows for rapid weaning of steroid usage, minimal adverse side effects to the patients, and long-term stabilization of counts, a goal that has not been achieved successfully with other secondary treatment modalities. Therefore, this novel combination therapy may be an excellent alternative for the treatment of persistent or chronic autoimmune cytopenias in the pediatric population.

Cryptosporidium infection after renal transplantation in an endemic area.

Cryptosporidium is one of the common causes of infective diarrhea in post-transplant patients in endemic areas. However, data are limited on Cryptosporidium infection in recipients of solid organ transplantation. The aim of this study was to determine the incidence, disease manifestation, management, and outcome of Cryptosporidium infection in living-donor renal transplant recipients (RTR). We performed a detailed retrospective review of the data on all RTR who had diarrheal illness requiring evaluation and hospitalization, and Cryptosporidium infection. During the study period, 119/1235 (8.98%) RTR developed diarrhea, and Cryptosporidium was found in 34/119 (28.5%). Nine of 680 (1.3%) patients were on a cyclosporine (CSA)-based regimen, and 25/643 (3.8%) patients were on a tacrolimus (Tac)-based regimen. The relative risk of developing Cryptosporidium infection was lower on the CSA-based regimen, compared with the Tac-based regimen (odds ratio [OR]: 0.35, 95% confidence interval [CI]: 0.17-0.72, P=0.003). Twelve of the 34 patients had acute graft dysfunction, mainly caused by combined Tac toxicity and dehydration. Mean serum creatinine and trough Tac level were 2.04±0.65mg/dL and 8.24±1.19ng/dL, respectively. Nitazoxanide alone was used in 13 patients, and nitazoxanide in combination with fluoroquinolone in 21 patients, with duration of treatment ranging from 16 to 60days. Tac was changed to CSA in 8/11 patients. The clearance of cysts and response to nitazoxanide alone were significantly lower, compared with combination therapy (61.53% vs. 95.23%, P=0.01, 38.46 vs. 85.71%, P=0.004, respectively). The OR for cyst clearance and response was also significantly lower with nitazoxanide alone, in comparison with combination therapy (OR: 0.65, 95% CI: 0.34-0.92, P=0.01, OR: 0.45, 95% CI: 0.21-0.81, respectively). Four (16%) of 24 patients with response had relapse. Patients with Tac and mycophenolate mofetil combination therapy had a significantly high risk of Cryptosporidium infection. Cryptosporidial infection may require prolonged nitazoxanide therapy, either alone or in combination, with or without reduction in immunosuppression.

A Novel Immunomodulatory Treatment Involving Mycophenolate Mofetil and Corticosteroids for Pediatric Autoimmune Cytopenias

Background: Autoimmune cytopenias are defined by immune-mediated destruction of distinct hematopoietic lineages, including white blood cells, red blood cells, and platelets. The destruction of a single lineage in response to an unknown stimulus is known as a primary or idiopathic autoimmune cytopenia. These include immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and autoimmune neutropenia (AIN). The primary treatment modality for all autoimmune cytopenias are drugs that suppress or modulate the immune system. Typically first-line treatment involves the use of corticosteroids. However, this treatment modality often requires prolonged use of steroids, which impacts the quality of life of affected patients and causes multiple adverse side effects. For the treatment of pediatric autoimmune cytopenias, the goal of therapy is to modulate the immune system and hence stabilize counts, while also preventing adverse side effects secondary to medications. Mycophenolate mofetil (MMF) is an immunosuppressive drug that inhibits lymphocyte proliferation and limits the mobilization of leukocytes to sites of inflammation. Here, we propose a novel combination therapy of MMF, an adjunct immunosuppressive, and corticosteroids. This combination may allow for rapid decrease of steroid usage as well as prolonged count stabilization in pediatric patients with autoimmune cytopenias.Objective: To evaluate the efficacy of Mycophenolate mofetil and corticosteroids as a novel combination therapy for stabilizing counts and rapid weaning of steroid usage in pediatric patients with autoimmune cytopenias.Design/Method: Prospective case series of 5 patients, 4 with AIHA and 1 with ITP, between the ages of 2 and 16 that are being treated with the combination therapy of corticosteroids and MMF.Results: All patients (Patients 1-4 with AIHA and Patient 5 with ITP) reached minimal to no corticosteroid use after a few months of being on combination therapy, as seen in Figure 1. Patient 1 sustained Hgb levels above 13g/dl after 20 days of combination therapy and an improvement in IgG mediated AIHA, with a decrease in titers from 4+ to 2+ after five months of therapy. In addition, Patient 1 had a decrease in reticulocyte counts from 21.4% to 0.2% after five months of therapy, as well as a decrease in LDH levels from 714 IU/L to 551 IU/L after two months of therapy. Patient 2 sustained Hgb levels above 13g/dl after one month of combination therapy as well as a normal reticulocyte count of 0.8%. Patient 3 has been on combination therapy for one month and has improved Hgb levels from 11g/dl to 11.4g/dl as well as had a significant reduction in steroid usage. Patient 4 sustained Hgb levels above 12g/dl after six months of combination therapy, an improvement in IgG mediated AIHA, with a decrease in titers from 4+ to 3+ after 16 months of therapy, and a decrease in reticulocyte counts from 43.2% to less than 2% after 12 months of therapy. Patient 5 with ITP had a marked increase in platelet counts from 9k/μl to 418k/μl after only 8 days of combination therapy and has maintained normal platelet counts thereafter. All patients have rapidly decreased steroid doses, maintained targeted MMF doses without toxicities or secondary infections, and not had recurrences of autoimmune cytopenias.Conclusions: Mycophenolate mofetil has been utilized as an adjunct immunosuppressive in a small number of autoimmune diseases and for the treatment of graft-versus-host disease in allogeneic hematopoietic stem cell transplantation. Never before has the combination of MMF and corticosteroids been used to treat pediatric patients with autoimmune cytopenias. The novel combination of MMF and corticosteroids may be an optimal treatment option for pediatric patients with autoimmune cytopenias such as AIHA and ITP. This unique combination of high dose steroids with rapid weaning, coupled with the continued use of MMF mediated immunosuppression allows for prolonged count stabilization with minimal adverse side effects. [Display omitted] *Patient 1’s baseline total daily dose of prednisone is 120mg at time 0 months DisclosuresOff Label Use: Mycophenalate mofetil is an immunosuppressive medication initially utilized in transplantation medicine, and now has been used in a variety of autoimmune diseases. .

AB0616 Efficacy and safety of multi-target therapy with mizoribine and tacrolimus for systemic lupus erythematosus with or without active nephritis

BackgroundPrognosis of systemic lupus erythematosus (SLE) has improved with introduction of various immunosuppressants, but still there is room for improvement as to efficacy and safety. Bao et al. suggested more...

Mycophenolate mofetil combination therapy improves survival after liver transplantation. A single-center retrospective analysis

Because the immunosuppressive regimen is a modifiable risk factor after orthotopic liver transplantation (OLT), physicians are nowadays aiming at an optimized and individualized strategy for each patient. The aim of this retrospective study was to examine the impact of different immunosuppressive regimens on the long-term outcome post-OLT based on routine, real-life situations, with particular focus on the subgroups of patients with HCC or HCV. Our study included 186 patients who underwent OLT between 1999 and 2008 at the University Hospital Heidelberg, Germany with an available minimum follow-up period of 12 months. Data were collected pre-transplantation, and at 3 months, 6 months, and 12 months post-OLT and every 6 months afterwards. We found a statistically significant better 5-year survival in the calcineurin inhibitor (CNI) + mycophenolate mofetil (MMF) group vs. CNI - MMF (p=0.01) in the whole study group, in the HCC group (p=0.008), and in the HCV group (p=0.0163). Furthermore, there was a trend towards a prolonged HCV relapse-free 5-year survival rate in the CNI + MMF group of 85.6% vs. 70.8% in the CNI - MMF group, a trend towards a lower incidence of death secondary to infection (30.8% vs. 69.2%), and a trend towards lower rates of acute rejections (22.6% vs. 29%). The type of CNI administered was irrelevant in all respects. MMF added to immunosuppressive therapy improves patient survival in OLT recipients in general, as well as in patients with HCC and HCV. Prospective studies are needed to determine if a broader application of MMF post-OLT in combination with CNI-tapering could lead to further outcome improvement.

Role of tacrolimus combination therapy with mycophenolate mofetil in the prevention of organ rejection in kidney transplant patients

Several new medications are now available for immunosuppression in the kidney transplant field. Tacrolimus and mycophenolate mofetil were first introduced for immunosuppression in renal transplantation in the mid 1990s. Since then, the combination of tacrolimus and mycophenolate mofetil has been evaluated in numerous clinical trials. The outcomes of these trials have varied due to differences in induction and/or maintenance therapy, drug dosing and monitoring protocols, and study design. The aim of this review is to analyze the literature critically and to provide an overview of tacrolimus and mycophenolate mofetil combination therapy in renal transplantation.

Therapeutic ladder for pemphigus vulgaris: Emphasis on achieving complete remission

Pemphigus vulgaris (PV) is a blistering autoimmune bullous disease that is usually fatal without proper treatment. There are no clear treatment guidelines for PV at this time. We suggest a standard treatment regimen for patients with PV based on the success of our treatment. A retrospective chart review of 18 patients with PV was conducted to assess response to a similar approach using mycophenolate mofetil (MMF) and prednisone. Diagnosis was confirmed through routine histology, direct immunofluorescence, and indirect immunofluorescence, and patients were followed up for a total average of 35.2 months. We achieved complete disease control in 89% of patients using our treatment algorithm. Fourteen of 18 patients achieved complete disease control on therapy with prednisone and MMF. Three of the 4 patients who did not achieve control on MMF and prednisone went on to receive rituximab therapy, and two of those patients achieved disease control on rituximab. The average length of time from initiating therapy to 75% clearance of lesions was 4.5 months. Three of 18 patients were able to discontinue therapy after an average of 3 years and have remained in complete remission for more than 1 year. This was a retrospective chart review with a small patient sample size. The combination therapy of MMF and prednisone is an effective treatment regimen to achieve rapid and complete control of PV. For those patients who fail treatment with MMF and prednisone, rituximab is an efficacious alternative therapy.

Does Calcineurin Inhibitor Plus Mycophenolate Mofetil Combination Therapy Decrease the Risk of Late Acute Rejection after Liver Transplantation?

Does Calcineurin Inhibitor Plus Mycophenolate Mofetil Combination Therapy Decrease the Risk of Late Acute Rejection after Liver Transplantation? Kwan-Woo Kim, M.D., Sung-Gyu Lee, M.D., Shin Hwang, M.D., Ki-Hun Kim, M.D., Chul-Soo Ahn, M.D., Deok-Bog Moon, M.D., Tae-Yong Ha, M.D., Gi-Won Song, M.D., Dong-Hwan Jung, M.D., Nam-Kyu Choi, M.D., Jeong-Ik Park, M.D., Gil-Chun Park, M.D., Young-Dong Yu, M.D., Pyung-Jae Park, M.D. and Young-Il Choi, M.D.

Combination therapy with mycophenolate mofetil and prednisone in steroid-resistant idiopathic membranoproliferative glomerulonephritis

To observe the efficacy of the combination therapy of mycophenolate mofetil (MMF) and glucocorticoids on steroid-resistant idiopathic membranoproliferative glomerulonephritis (IMPGN) with moderate to heavy proteinuria. 13 cases were diagnosed as IMPGN by renal biopsy after excluding secondary etiology. 9 patients had heavy proteinuria and another 4 with moderate proteinuria, 9 with hypertension and 11 with decreased renal function. Before MMF therapy, all of them were resistant to treatment of glucocorticoid (prednisone 1 mg/kg/d) for 8 weeks or more. The initial dose of MMF was 1.5 g/d. Patients were followed up every month, including blood pressure, urine protein excretion, liver and kidney function, complete blood count, and adverse events recorded. At the initiation, the 24-h urine protein excretion was 4.1 +/- 1.4 g, serum creatinine (Scr) 131.0 +/- 44.9 mmol/l, and estimated glomerular filtration rate (eGFR) 63.3 +/- 26.8 ml/min/1.73 m(2). After prednisone therapy for at least 2 months, the 24-h urine protein excretion and eGFR did not change significantly (p > 0.05). After 3 months of the addition of MMF, 24-h urine protein excretion decreased slightly to 3.8 +/- 1.2 g (p < 0.05),Scr decreased to 127.3 +/- 43.7 micromol/l and eGFR elevated to 65.7 +/- 26.8 ml/min/1.73 m(2), (p < 0.05); after 6 months, 24-h urine protein excretion decreased more significantly (2.5 +/- 0.9 g, p < 0.01), with improved kidney function (Scr 97.2 +/- 27.3 mmol/l and eGFR 81.3 +/- 24.2 ml/min/1.73 m(2), p < 0.01); compared with that before MMF treatment. After 12 months, 24-h urine protein excretion decreased further (1.5 +/- 0.6g, p < 0.01) with kidney function remained stable (Scr 95.9 +/- 22.5 micromol/l and eGFR 81.2 +/- 23.8 ml/min/1.73 m(2)). MMF combined with glucosteroids could effectively decrease proteinuria and improve renal function on steroid-resistant IMPGN. Further study with a large sample is needed to evaluate the efficacy and safety of MMF in the treatment of IMPGN.

Is long-term survival of liver transplant recipients improved by mycophenolate mofetil combination therapy?

Is long-term survival of liver transplant recipients improved by mycophenolate mofetil combination therapy?

Mycophenolate mofetil combination therapy improves long‐term outcomes after liver transplantation in patients with and without hepatitis C

To evaluate the impact of mycophenolate mofetil (MMF) on long-term outcomes of tacrolimus and corticosteroids, we analyzed data reported to the Scientific Registry of Transplant Recipients for 11,670 adult patients (3463 with hepatitis C [HCV]) who underwent primary, single-organ, liver transplantation between 1995 and 2001. Patients who were discharged from the hospital on tacrolimus-based immunosuppression with (n = 4466; n = 1323 HCV) or without MMF (n = 7204; n = 2140 HCV) were included in the analysis. Recipients treated at discharge with MMF, tacrolimus, and corticosteroids had significantly increased patient survival (81.0% vs. 77.0% at 4 years, P < 0.0001) and graft survival (76.4% vs. 72.9%, P < 0.0001), and lower rates of acute rejection (29.0% vs. 33.4%, P < 0.001) as compared to recipients treated at discharge with tacrolimus and corticosteroids alone. A trend toward lower rates of death from infection was observed (6.1% at 4 years for MMF vs. 7.1% at 4 years for tacrolimus and corticosteroids, P = 0.0508), but this result did not reach statistical significance. In multiple regression analyses, MMF triple therapy at discharge was associated with a reduced risk of death (hazard ratio [HR] = 0.77, P < 0.001), graft loss (HR = 0.81, P < 0.001), acute rejection (HR = 0.89, P = 0.002), and death from infectious complications (HR = 0.80, P = 0.007). Outcomes were similar for the cohort with HCV.In conclusion, the addition of MMF at discharge to tacrolimus-based immunosuppression is associated with improved long-term outcomes after liver transplantation in patients with and without HCV.

Prolonged survival of rat hindlimb allografts following short-course FK506 and mycophenolate mofetil combination therapy

The immunosuppressive effect of combined therapy using FK506 and mycophenolate mofetil (MMF) was studied in rat limb allotransplantation. Dark Agouti rat donor hindlimbs were orthotopically transplanted into Lewis rat recipients. In total, 38 models of transplantation were performed and divided into 8 groups that were treated individually or in combination with FK506 + MMF therapy. Animals were immunosuppressed for 28 days and then observed for up to 140 days. Graft rejection was evaluated both macroscopically and histologically. Survival times for rat limb allotransplants receiving combination FK506 + MMF therapy were significantly longer than with FK506 or MMF monotherapy, and this was achieved without serious side effects. A histopathological study demonstrated a significantly lower level of rejection with FK506 + MMF combination treatment compared to groups receiving FK506 or MMF monotherapy. Combined FK506 + MMF treatment can prolong the survival of rat limb allografts.

Combination therapy with sirolimus and mycophenolate mofetil: effects on the kidney and on transforming growth factor-beta1.

Sirolimus (SRL) is not nephrotoxic, but it has been shown to increase transforming growth factor (TGF)-beta. We investigated the effect of combining mycophenolate mofetil (MMF) with SRL on renal structure and function and on TGF-beta1. Rats treated with vehicle (VH), MMF 10 mg/kg/d, SRL 0.3 mg/kg/d, or SRL+MMF were killed at 28 days. The physiologic and histologic changes and expression of TGF-beta1, plasminogen activator inhibitor-1, and extracellular matrix proteins were studied. Although SRL alone did not alter renal function and structure, it increased TGF-beta1 mRNA by 44% and protein by 48% (P <0.05 vs. VH). Treatment with MMF did not affect TGF-beta1. When combined with SRL, MMF decreased TGF-beta1 expression to VH levels. A similar trend was observed with plasminogen activator inhibitor-1 and extracellular matrix proteins. The long-term consequence of increased TGF-beta in SRL-treated kidneys remains unknown. However, because MMF can reverse this trend, SRL and MMF combination therapy may be protective.

Study 1: one-year results of the first prospective, randomized, multicenter kidney transplant study comparing tacrolimus and sirolimus versus tacrolimus and mycophenolate mofetil combination therapy

R. Mendez, T. Gonwa, K. Rice, M. Holman, H. Yang, R. Filo, S. Steinberg, S. Weinstein, S. Jensik, B. Philosophe J. Colanna, A. Klein, J. Markowitz, M. Hardy, C. Shield, P.R. Rajagopalan, B. Ketel, G. Barone, W. Concepcion, G. Danovich, S. Tomlanovich, J. Scandling, P. Gores, G. Basadonna, M. Lorber, S. Inokuchi, D. Conti, K. Lake, A. Langnas, M. Kinkhabwala, C. Johnson, M. Johnson, M. Hart, J. Dunn, W. Fitzsimmons, D. Tolzman, G. Harrison, and P. Vanveldhuisen

Combination therapy of mycophenolate mofetil and rapamycin in prevention of chronic renal allograft rejection in the rat1

Chronic rejection is the leading cause of long-term allograft loss. Until now, no therapy has been recognized as being efficient in its prevention. In addition to their immunosuppressive activity, mycophenolate mofetil (MMF) and rapamycin (RAPA) show diverse properties against vascular smooth muscle cell activity, cell-adhesion molecule expression, and ischemia-reperfusion injury. The combination effect of MMF and RAPA was tested to prevent chronic renal allograft rejection in the rat in this study. Nephrectomized Lewis recipients underwent orthotopic transplantation with Fisher (F344) kidneys (allograft groups) or Lewis kidneys (isograft control). The initial episode of acute rejection was controlled with a short course of cyclosporine A (CsA) (1.5 mg/kg/day for 10 days). From weeks 4 to 20, animals were thereafter treated every other day either with vehicle, MMF (20 mg/kg), RAPA (0.8 mg/kg), or MMF (20 mg/kg) plus RAPA (0.8 mg/kg) in combination. Animals were sequentially killed at serial intervals over a follow-up of 50 weeks, and histologic study was performed on harvested kidneys according to the Banff working classification for allograft pathology. Animals treated with MMF or RAPA alone showed a Banff sum score similar to the allograft control group (6.31+/-1.01 and 7.27+/-1.14 vs. 7.21+/-1.14, respectively; P>0.05). When the recipient rats were treated with MMF and RAPA in combination, it resulted in a clinically and statistically significant reduction of Banff sum score (4.21+/-0.79, P<0.01), with specific inhibition of vascular fibrous intimal thickening, allograft glomerulopathy, and interstitial fibrosis. Over a 50-week study, concomitant therapy of MMF and RAPA prevents chronic renal allograft rejection, probably through reduction of ischemic and cytotoxic degenerative changes. These results warrant further investigation in the combination of MMF and RAPA as anti-chronic rejection therapy in clinical transplantation.

Chronic sclerodermic graft-versus-host disease refractory to immunosuppressive treatment responds to UVA1 phototherapy

Graft-versus-host disease is a frequent complication of allogenic bone marrow transplantation. Approximately 10% of patients suffering from chronic graft-versus-host disease develop sclerodermic graft-versus-host disease of the skin, which often does not respond to conventional immunosuppressive therapy. An alternative to immunosuppressive treatment is photochemotherapy. We describe a patient with chronic sclerodermic graft-versus-host disease who did not respond to a combination therapy of cyclosporine and prednisone and later mycophenolate mofetil plus prednisone. A combination therapy of mycophenolate mofetil (2 g/day) and low-dose UVA1 therapy (single dose, 20 J/cm2, 4 times per week over 6 weeks) resulted in striking clinical improvement of sclerodermic graft-versus-host disease. (J Am Acad Dermatol 2000;42:134-6.)

Fresh venous allografts in peripheral arterial reconstruction in dogs: Effects of histocompatibility and of short-term immunosuppression with cyclosporine A and mycophenolate mofetil

To date, no arterial substitute has been shown to be as effective as the autologous saphenous vein in peripheral revascularization procedures. In the present study, the venous allograft was evaluated as a vascular substitute in terms of patency and induction of host immune reactivity, whether used in major histocompatibility complex–incompatible, major histocompatibility complex–compatible, or immunosuppressed major histocompatibility complex–incompatible dogs. The immunosuppressive drug therapies were given for a period of 31 days, beginning 1 day before transplantation, and consisted of the use of cyclosporine A, mycophenolate mofetil, or a combination of both. All histoincompatible allografts were thrombosed at 4 or 8 weeks after transplantation with antibody development and cell-mediated cytotoxicity in the graft, whereas histocompatible allografts showed late stenosis without immunologic reactions directed toward donor cells. Given alone, neither cyclosporine A nor mycophenolate mofetil improved the overall patency of venous allografts; thrombosis occurred shortly after cessation of immunosuppression. Still, the cyclosporine A–mycophenolate mofetil combination therapy led to a 100% patency rate at 20 weeks after implantation and immune reactions were markedly reduced. This study shows that the fresh vein allograft is still an attractive and functional alternative to the autologous saphenous vein if the host immunologic reactions are controlled by cyclosporine A–mycophenolate mofetil immunosuppression. (J T HORAC C ARDIOVASC S URG 1995;110:1732-42)