Months Of Mycophenolate Mofetil Therapy Research Articles

ODP352 Steroid-sparing immunosuppressive therapy controls refractory headaches due to lymphocytic hypophysitis: a case report

Abstract Background Systemic glucocorticoid therapy has been used to control headaches associated with lymphocytic hypophysitis (LH), a rare autoimmune inflammation of the pituitary gland and stalk. Steroid-sparing immunosuppressive therapies, like mycophenolate mofetil (MM), have proven to be effective for patients with many systemic inflammatory and rheumatological conditions. However, the safety and efficacy of steroid-sparing immunosuppressive therapies for LH has not been studied. Clinical Case Here we report a case of a 31-year-old male who presented with worsening headache, fatigue, polyuria, insomnia, low libido, and decreased appetite. His laboratory results were consistent with central diabetes insipidus (DI), central hypothyroidism, central adrenal insufficiency, and hypogonadotropic hypogonadism without evidence of growth hormone deficiency. Initial pituitary MRI revealed pituitary enlargement and thickening of the stalk. He was started on desmopressin, levothyroxine, testosterone cypionate, and physiologic glucocorticoid replacement with prednisone 5mg daily. He continued to endorse incapacitating occipital headaches not relieved by ibuprofen, topiramate, gabapentin, amitriptyline, sumatriptan, or rizatriptan, and only temporary relieved by occipital nerve blocks. A pituitary biopsy confirmed the diagnosis of LH. Given his persistent, debilitating headaches, prednisone was increased to supraphysiologic doses. Headaches resolved on prednisone 40mg daily but recurred two months after tapering down to prednisone 5mg daily. Pituitary MRI after 4 months revealed a mild interval increase in enhancement and thickening of the pituitary stalk. Prednisone was increased to 20mg daily, and he was started on MM for progressive inflammation. Prednisone was tapered down to 5mg daily over the course of 3 months as MM dose was increased to 1000mg twice a day. Headaches completely resolved. After 4 months of MM therapy, pituitary MRI showed decrease in size of pituitary stalk thickening and pituitary, consistent with treatment effect. After 6 months of MM therapy, MRI brain showed further decrease in pituitary size and resolution of pituitary stalk thickening. He did not experience any adverse effect on MM. Serial complete blood counts, liver function tests, and basic metabolic panels were normal. Two years after diagnosis and one year on MM therapy, his DI resolved, his adrenal insufficiency was well managed with prednisone 4mg daily, he was euthyroid on levothyroxine 75mcg daily, and his hypogonadism was treated adequately with testosterone cypionate 50mg weekly with improved libido and energy. Conclusion MM was effective in treating intractable headaches caused by biopsy-proven LH. Radiologic signs of improvement in pituitary inflammation coincided with patient's report of headache relief and initiation of MM, without concurrent use of supraphysiologic glucocorticoids. Treatment was well-tolerated with no reported adverse effect. Steroid-sparing immunosuppressive therapy like MM may be considered as a therapy for LH, particularly in patients who depend on prolonged courses of supraphysiologic glucocorticoid treatment to alleviate symptoms. Presentation: No date and time listed

Mycophenolate Mofetil Treatment of Systemic Sclerosis Reduces Myeloid Cell Numbers and Attenuates the Inflammatory Gene Signature in Skin

Fewer than half of patients with systemic sclerosis demonstrate modified Rodnan skin score improvement during mycophenolate mofetil (MMF) treatment. To understand the molecular basis for this observation, we extended our prior studies and characterized molecular and cellular changes in skin biopsies from subjects with systemic sclerosis treated with MMF. Eleven subjects completed ≥24 months of MMF therapy. Two distinct skin gene expression trajectories were observed across six of these subjects. Three of the six subjects showed attenuation of the inflammatory signature by 24 months, paralleling reductions in CCL2 mRNA expression in skin and reduced numbers of macrophages and myeloid dendritic cells in skin biopsies. MMF cessation at 24 months resulted in an increased inflammatory score, increased CCL2 mRNA and protein levels, modified Rodnan skin score rebound, and increased numbers of skin myeloid cells in these subjects. In contrast, three other subjects remained on MMF >24 months and showed a persistent decrease in inflammatory score, decreasing or stable modified Rodnan skin score, CCL2 mRNA reductions, sera CCL2 protein levels trending downward, reduction in monocyte migration, and no increase in skin myeloid cell numbers. These data summarize molecular changes during MMF therapy that suggest reduction of innate immune cell numbers, possibly by attenuating expression of chemokines, including CCL2.

A Prospective Observational Study of Mycophenolate Mofetil Treatment in Progressive Diffuse Cutaneous Systemic Sclerosis of Recent Onset

A prospective observational study of mycophenolate mofetil (MMF) treatment in patients with diffuse progressive cutaneous systemic sclerosis (SSc) of recent onset. Twenty-five previously untreated consecutive patients with recent-onset (< 24 mo) diffuse progressive cutaneous SSc received MMF as the only disease-modifying therapy. Modified Rodnan skin score (mRSS) and affected body surface area (BSA) were compared from initiation of MMF to study end. Pulmonary function tests performed at the same institution before therapy and at study end were available in 15 patients. Histopathology and real-time PCR assessment of fibrosis-related gene expression were performed before and after treatment in skin biopsies from 3 patients. At 18.2 ± 8.73 months of MMF therapy (median 2000 mg/day) the mRSS decreased from 24.56 ± 8.62 to 14.52 ± 10.9 (p = 0.0004) and the affected BSA from 36% ± 16% to 14% ± 13.3% (p = 0.00001). Pulmonary function tests remained stable from initiation of MMF to the end of the study. Skin histopathology showed a remarkable reduction in accumulation of fibrotic tissue. Real-time PCR of skin biopsies demonstrated a marked decrease in expression of fibrosis-related genes. Patients with diffuse progressive cutaneous SSc of recent onset treated with MMF experienced marked improvement in skin involvement and stabilization of pulmonary function. Skin biopsies from 3 patients demonstrated histopathological improvement and decreased expression of fibrosis-related genes.

Mycophenolate Mofetil Therapy Is a Steroid Sparing In Childhood and Young Adult Chronic ITP and Evans Syndrome.

AbstractAbstract 1441Chronic ITP and Evans syndrome are diseases characterized by autoantibody formation with resultant destruction of platelets or both platelets and red blood cells on neutrophils, respectively. Affected patients are at risk of life threatening bleeding complications and/or life threatening anemia. Conventional therapies are often ineffective or transiently effective and have significant toxicity. One of the most commonly used therapeutic strategies employs chronic corticosteroid administration with the attendant weight gain, hypertension, hyperglycemia, bone loss, infection risk, mood changes and protean other undesirable side effects. Mycophenolate Mofetil (MMF) is an immunosuppressive agent with a favorable side effect profile. It is converted to the active metabolite, mycophenolic acid, and interferes with purine metabolism in T-lymphocytes, effectively killing many of these cells and down-regulating autoimmune phenomena. With approval of our local IRB /HIC we retrospectively reviewed the charts of 11 chronic ITP/Evans syndrome patients who had received MMF, all such patients treated at a large urban Children's Hospital. Clinical variables included age, sex, duration of disease, steroid use, IVIG use, Anti-D use, platelet counts, hemoglobin concentrations and reticulocyte percentages. These data were analyzed using paired t-tests, one-sample t-test and descriptive statistics. The 11 patients ranged in age from 9–22 years old, with a mean age of 15 years. The mean time from diagnosis of disease was 41.8 months with a range of 6–95 months. There were 5 female subjects, 6 Evans syndrome patients and 5 with chronic ITP alone. The median platelet count over the 6 months prior to MMF was 70×109/L, (18-223), with a median of 90×109/L with (27-145) during the first 6 months of MMF therapy (p=0.4). In the Evans syndrome group, the mean hemoglobin prior to MMF was 10.9 g/dL, (9.1-14.6), with a mean of 12.1 g/dL, (6.9-16.7) on MMF (p=0.54). Similarly, the mean reticulocyte percentage was 2.7%, (0.5-14) prior to MMF, with a mean of 2.3%, (0.3-8.9) during MMF therapy. The mean total dose of steroids used in the 6 months prior to MMF was 84.2 mg/kg (prednisone equivalent), (11.2-170), compared to 62.2 mg/kg, (0-193.8) on MMF. 9 of 11 patients had reductions in steroid requirement by an average of 49.3% (p=0.0013). During the first 6 months of MMF both IVIG and anti-D usage decreased from total doses for the entire group of 17 and 3 doses to 8 and 1 dose, respectively. None of the patients experienced severe bleeding episodes or side effects more serious than a transient rash while on MMF. These data suggest that MMF may have a role as a steroid sparing therapy in the treatment of chronic ITP and Evans syndrome. Disclosures:Off Label Use: mycophenolate mofetil for ITP Evans syndrome.

Mycophenolate mofetil: A possible therapeutic agent for children with juvenile dermatomyositis

To determine if mycophenolate mofetil (MMF) diminishes skin and muscle disease activity in children with juvenile dermatomyositis (DM), thereby permitting a decrease in corticosteroid dose. A retrospective data review for 50 children with juvenile DM (mean ± SD age 12.2 ± 5.0 years) who had received MMF for 12 months identified the following characteristics: 38 (76%) were girls, 39 (78%) were white, 10 (20%) were Hispanic, and 1 (2%) was African American. The MMF dose and frequency, type of infection, white blood cell (WBC) count, corticosteroid dose, and the validated disease activity score (DAS) subscores for skin (DAS-S) and muscle (DAS-M) were obtained. Twelve months after the start of MMF, the mean ± SD DAS-S decreased from 5.24 ± 0.29 to 3.72 ± 0.29 (P = 0.001), and the mean ± SD DAS-M decreased from 2.44 ± 0.39 to 1.17 ± 0.28 (P = 0.002). The mean ± SD prednisone dosage decreased from 0.39 ± 0.06 to 0.23 ± 0.02 mg/kg/day (P = 0.0001), with resumption of linear growth (P = 0.008). The WBC/lymphocyte count was unchanged over the 12 months on MMF. The infection rate was assessed in a subset of 26 children with juvenile DM who were observed for 12 months before the start of MMF and then compared with the ensuing 12 months of MMF therapy. There was no significant difference between the pretreatment period and the first 6 months of MMF therapy (P = 0.44), but the infection rate decreased in months 7-12 (P = 0.001). MMF appears to be worthy of consideration as an additional therapeutic modality for treatment of children with juvenile DM. These data suggest that the use of MMF decreases skin and muscle disease activity and is steroid sparing. MMF appears to be well tolerated, but patients should be monitored for infection.

The effect of mycophenolate mofetil on primary and secondary treatment of primary glomerulonephritis and lupus nephritis

Mycophenolate mofetil (MMF) has shown to be a reliable choice in the treatment of glomerulonephritis. We retrospectively reviewed the clinical course and response to MMF therapy in 49 patients with primary glomerulopathy (37 patients) and lupus nephritis [class III (five patients) and IV (seven patients)]. Patients were treated with MMF for more than 6 months as a primary (18 patients) or an adjunctive treatment (31 patients). Patients were also on methylprednisolone (2-20 mg/day) and angiotensin converting enzyme inhibitor/angiotensin receptor blocker. The mean age of the patient cohort was 33.69 +/- 12.4 years (range 19-59 years). Twenty-four-hour urinary protein excretion was reduced from 3.50 +/- 3.08 g prior to the commencement of MMF drug therapy to 1.21 +/- 1.44 and 0.99 +/- 1.34 g at the sixth and 12th months of MMF therapy, respectively (P < 0.05 for all). During this same period, significant increases in serum total protein (from 5.92 +/- 1.38 to 6.59 +/- 0.79 and 6.81 +/- 0.77 g/dl) and albumin levels (from 3.23 +/- 1.10 to 3.93 +/- 0.67 and 4.21 +/- 0.50 g/dl) were detected, whereas total cholesterol and low-density lipoprotein levels were found to be significantly decreased (P < 0.05 for all). Serum creatinine levels did not significantly change. The efficacy of MMF in reducing proteinuria was similar in both first line and an adjunctive therapy. The efficacy of MMF therapy began at the third month of treatment and continued through to the 12th month. Mycophenolate mofetil therapy was found to be useful in achieving improvements in proteinuria and nephrotic syndrome and stabilizing renal function. It was also a well-tolerated drug by the majority of the patients. Based on our results, we suggest that MMF may be alternative therapy for resistant/relapsing primary glomerulopathies and lupus nephritis.

Pilot Study of Mycophenolate Mofetil for Treatment of Kidney Disease due to Congenital Urinary Tract Disorders in Children

Congenital uropathies account for nearly half the chronic kidney disease in children. Immune-mediated injury may contribute to progressive loss of kidney function in affected patients. Open-label uncontrolled pilot study to determine the feasibility of treatment with the immunosuppressive drug mycophenolate mofetil (MMF) to prevent a decrease in kidney function in pediatric patients with congenital uropathies. Children treated in an outpatient tertiary-care center were eligible if they had: (1) age of 3 to 16 years, (2) glomerular filtration rate (GFR) less than 50 mL/min/1.73 m(2), and (3) a congenital genitourinary tract abnormality. After a 2-month run-in period, patients were prescribed MMF, 600 mg/m(2)/dose, twice daily for a 24-month treatment period. The primary end point was feasibility based on the ability to recruit and retain subjects and lack of unanticipated adverse events. The secondary end point was change in GFR. Patients were monitored by using standard clinical laboratory tests, and GFR was determined by means of iothalamate clearance. 12 patients aged 8.9 +/- 4.8 years (10 boys, 2 girls) were treated with MMF for 18.6 +/- 8.0 months; 7 patients completed the entire treatment period. MMF dosage at the final study visit was 381 +/- 241 mg/m(2) twice daily. Gastrointestinal symptoms were the most common adverse effect. There was only 1 serious adverse event, an episode of fever and neutropenia requiring parenteral antibiotic therapy after 21 months of MMF therapy. GFR remained stable throughout the treatment period. Nutritional status, blood pressure, and serum calcium, phosphorus, and cholesterol levels were unchanged during this period. Insufficient power to assess the safety or efficacy of MMF therapy for patients with congenital uropathies. It is feasible to study MMF as an adjunctive therapy to retard the progression of kidney disease in children with congenital uropathies. A multicenter randomized clinical trial is warranted to determine the efficacy of this novel treatment strategy.

Activation of the Purine Salvage Pathway in Mononuclear Cells of Cardiac Recipients Treated with Mycophenolate Mofetil

The objective of this study was to investigate purine nucleotide metabolism in peripheral blood mononuclear cells (PBMC) of cardiac transplant recipients switched from azathioprine to mycophenolate mofetil (MMF). Concentrations of guanosine 5'triphosphate (GTP) and adenosine 5'triphosphate (ATP), the activities of inosine monophosphate dehydrogenase (IMPDH), guanine phosphoribosyltransferase (GPRT), and hypoxanthine phosphoribosyltransferase (HPRT) were determined in PBMC of 27 cardiac transplant recipients before switch to MMF and 3, 6, and 12 months thereafter. There was no difference in the activities of IMPDH and salvage pathway enzymes GPRT and HRPT as well as in intracellular GTP and ATP concentrations between the patients before switch to MMF and healthy controls. The GTP and ATP concentrations in PBMC of cardiac recipients did not change during the entire observation period. Although the MPA trough level remained similar, IMPDH activity declined from 897 to 316 pmol/10(6)PBMC/h 3 months after MMF onset, was almost completely inhibited after 6 months, and partially restored to 143 pmol/10(6)PBMC/h 12 months after switch to MMF. In contrast, GPRT activity increased after 3, 6, and 12 months of MMF therapy and HPRT activity 3 and 6 months after switch to MMF. We demonstrated for the first time an induction of salvage pathway enzyme activities in PBMC under MMF therapy. This probably accounts for the maintenance of intracellular purine nucleotide pools and prevents the GTP depletion.

Mycophenolate mofetil is effective in reducing lupus glomerulonephritis proteinuria

Mycophenolate mofetil (MMF) significantly reduces proteinuria in experimental model of human membranous nephropathy (Heymann nephritis). Twenty consecutive SLE patients with persistent isolated severe proteinuria and/or proteinuric flare were studied for 18 months of MMF therapy. All of them presented stable renal function and 12 had biopsy proven membranous glomerulonephritis (WHO class V). The starting daily dose for MMF was 1.5 g to a maximum of 3 g. Patients were divided into: partial response, >or=50% decrease of baseline proteinuria; complete response, normal proteinuria levels (less than 0.3 g/24 h); flare, increase of at least 50% of the mean baseline proteinuria. All 20 SLE patients (100%) presented a 50% reduction of baseline proteinuria which was achieved in 8.2+/-3.3 months of MMF therapy, at a mean daily dose of 2.3+/-0.5 g. A significant decrease in 24-h protein excretion was observed compared to entry (3.47+/-1.26 vs. 1.33+/-0.67 g, P<0.0001) as well as a correspondent increase of serum albumin (3.2+/-0.4 vs. 3.7+/-0.4 mg/dl, P=0.02) and reduction of prednisone dose (33.7+/-20.0 to 18.6+/-14.1 mg/day, P=0.01). Complete response was observed in 11 SLE patients (55%) in 12.2+/-3.0 months of therapy with a significant decrease in proteinuria (P<0.0001), prednisone dose (P<0.0001) and an increase of serum albumin (P=0.003). Interestingly, initial proteinuria or serum albumin levels did not identify patients with complete response and those with partial response at the end of the study (P=0.543 and 0.657, respectively). Our pilot prospective study suggests that MMF appears to be effective in reducing severe persistent proteinuria in lupus glomerulonephritis, even in patients unresponsive to other immunosuppressive treatments.

Mycophenolate mofetil as first-line treatment improves clinically evident early scleroderma lung disease

To find an effective, safe immunosuppressive regimen as an alternative to cyclophosphamide (Cy) for the treatment of clinically evident diffuse scleroderma (dSSc)-associated alveolitis of recent onset. Five consecutive patients with dSSc and recent-onset alveolitis were enrolled and treated with mycophenolate mofetil (MMF) and small (< or =10 mg/day) doses of predinisolone in this open-label trial. One patient with long-standing fibrosing alveolitis was later added to our cohort. Pulmonary function tests [carbon monoxide diffusing capacity (DLCO) and forced vital capacity (FVC)], pulmonary high-resolution computed tomography (HRCT) scans and clinical assessment were performed before and at specified time-points after enrolment. Cases of significant infections, leucopenia and abdominal pain were recorded. After 4-6 months of MMF therapy, DLCO improved significantly compared with pre-treatment (mean DLCO 75.4% vs 64.2% of predicted value, respectively, P = 0.033). Values of FVC also improved, with the difference almost reaching levels of statistical significance (mean FVC 76.2% vs 65.6% of predicted value, P = 0.057). Ground glass opacities cleared in three of four patients with recent-onset alveolitis and were reduced in one patient after 6-8 months of treatment. Breathlessness and cough improved by 3 months. A possible treatment failure was seen in one patient. However, in five patients functional and clinical improvement was sustained during the study period. No adverse events were recorded in this ongoing clinical trial. Our preliminary data suggest that in patients with dSSc and recent, clinically apparent alveolitis, early treatment with MMF and small doses of corticosteroids (CS) may represent an effective, well-tolerated and safe alternative therapy.