mycophenolic-acid and Pulmonary-Fibrosis

Although interstitial lung disease accounts for the majority of deaths of patients with systemic sclerosis, treatment options for this manifestation of the disease are limited. Few high-quality, randomized, controlled trials exist for systemic sclerosis-related interstitial lung disease, and historically, studies have favored the use of cyclophosphamide. However, the benefit of cyclophosphamide for this disease is tempered by its complex adverse event profile. More recent studies have demonstrated the effectiveness of mycophenolate for systemic sclerosis-related interstitial lung disease, including Scleroderma Lung Study II. This review highlights the findings of this study, which was the first randomized controlled trial to compare cyclophosphamide with mycophenolate for the treatment of systemic sclerosis-related interstitial lung disease. The results reported in this trial suggest that there is no difference in treatment efficacy between mycophenolate and cyclophosphamide; however, mycophenolate appears to be safer and more tolerable than cyclophosphamide. In light of the ongoing advances in our understanding of the pathogenic mechanisms underlying interstitial lung disease in systemic sclerosis, this review also summarizes novel treatment approaches, presenting clinical and preclinical evidence for rituximab, tocilizumab, pirfenidone, and nintedanib, as well as hematopoietic stem cell transplantation and lung transplantation. This review further explores how reaching a consensus on appropriate study end points, as well as trial enrichment criteria, is central to improving our ability to judiciously evaluate the safety and efficacy of emerging experimental therapies for systemic sclerosis-related interstitial lung disease.

Topics: Cyclophosphamide; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lung; Lung Diseases, Interstitial; Lung Transplantation; Mycophenolic Acid; Pulmonary Fibrosis; Randomized Controlled Trials as Topic; Respiratory Function Tests; Scleroderma, Systemic; Treatment Outcome

Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis (SSc) and mainly encountered in patients with diffuse disease and/or anti-topoisomerase 1 antibodies. ILD develops in up to 75% of patients with SSc overall. However, SSc-ILD evolves to end-stage respiratory insufficiency in only a few patients. Initial pulmonary function tests (PFT) with measurement of carbon monoxide diffusing capacity, together with high-resolution computed tomography, allows for early diagnosis of SSc-ILD, before the occurrence of dyspnea. Unlike idiopathic ILD, SSc-ILD corresponds to non-specific interstitial pneumonia in most cases, whereas usual interstitial pneumonia is less frequently encountered. Therefore, the prognosis of SSc-ILD is better than that for idiopathic ILD. Nevertheless, ILD represents one of the two main causes of death in SSc patients. To detect SSc-ILD early, PFT must be repeated regularly, every 6 months to 1 year, depending on disease worsening. Conversely, broncho-alveolar lavage is not needed to evaluate disease activity in SSc-ILD but may be of help in diagnosing opportunistic infection. The treatment of SSc-ILD is not well established. Cyclophosphamide, which has been used for 20 years, has recently been evaluated in two prospective randomized studies that failed to demonstrate a major benefit for lung function. Open studies reported mycophenolate mofetil, azathioprine and rituximab as alternatives to cyclophosphamide. On failure of immunosuppressive agent treatment, lung transplantation can be proposed in the absence of other major organ involvement or severe gastro-esophageal reflux.

Topics: Antibodies, Monoclonal, Murine-Derived; Autoantibodies; Azathioprine; Contraindications; Cyclophosphamide; DNA Topoisomerases, Type I; Four-Dimensional Computed Tomography; Gastroesophageal Reflux; Humans; Immunosuppressive Agents; Lung; Lung Diseases, Interstitial; Lung Transplantation; Mycophenolic Acid; Prognosis; Pulmonary Fibrosis; Randomized Controlled Trials as Topic; Respiratory Function Tests; Rituximab; Scleroderma, Systemic

At present, no approved pharmacotherapies are available for unclassifiable interstitial lung disease (ILD), which is characterised by progressive fibrosis of the lung. We aimed to assess the efficacy and safety of pirfenidone in patients with progressive fibrosing unclassifiable ILD.. We did a multicentre, double-blind, randomised, placebo-controlled phase 2 trial at 70 centres in Australia, Belgium, Canada, Czech Republic, Denmark, Germany, Greece, Ireland, Israel, Italy, Poland, Portugal, Spain, and the UK. Eligible patients (aged ≥18-85 years) had progressive fibrosing unclassifiable ILD, a percent predicted forced vital capacity (FVC) of 45% or higher and percent predicted carbon monoxide diffusing capacity (DLco) of 30% or higher, more than 10% fibrosis on high-resolution CT, and a high-resolution CT from the previous 12 months. Patients were randomly assigned (1:1) to 2403 mg oral pirfenidone daily or placebo using a central validated interactive voice or web-based response system, stratified by concomitant mycophenolate mofetil use and presence or absence of interstitial pneumonia with autoimmune features. Investigators, site personnel, and patients were masked to treatment assignment. The primary endpoint was mean predicted change in FVC from baseline over 24 weeks, measured by daily home spirometry. Secondary endpoints were change in FVC measured by site spirometry, proportion of patients who had a more than 5% or more than 10% absolute or relative decline in percent predicted FVC measured by clinic-based spirometry, change in percent predicted DLco, change in 6-min walk distance (6MWD), change in University of California San Diego-Shortness of Breath Questionnaire (UCSD-SOBQ) score, change in Leicester Cough Questionnaire score, change in cough visual analogue scale, and changes in total and subscores of the St George's Respiratory Questionnaire (SGRQ), all of which were compared with baseline. Additional secondary endpoints included proportion of patients who had non-elective hospitalisation (respiratory and all-cause) and acute exacerbations, and progression-free survival. Efficacy was analysed in the intention-to-treat (ITT) population, which included all randomly assigned patients. Safety was assessed in the safety analysis set, which included all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03099187, and is no longer recruiting.. Between May 15, 2017, and June 5, 2018, 253 patients were randomly assigned to receive 2403 mg pirfenidone (n=127) or placebo (n=126) and were included in the ITT analysis set. Analysis of the primary endpoint was affected by intraindividual variability in home spirometry values, which prevented application of the prespecified statistical model. Over 24 weeks, predicted median change in FVC measured by home spirometry was -87·7 mL (Q1-Q3 -338·1 to 148·6) in the pirfenidone group versus -157·1 mL (-370·9 to 70·1) in the placebo group. Over 24 weeks, predicted mean change in FVC measured by site spirometry was lower in patients given pirfenidone than placebo (treatment difference 95·3 mL [95% CI 35·9 to 154·6], p=0·002). Compared with the placebo group, patients in the pirfenidone group were less likely to have a decline in FVC of more than 5% (odds ratio [OR] 0·42 [95% CI 0·25 to 0·69], p=0·001) or more than 10% (OR 0·44 [0·23 to 0·84], p=0·011). At week 24, mean change in DLco from baseline was -0·7% (SD 7·1) for the pirfenidone group and -2·5% (8·8) for the placebo group, and mean change in 6MWD from baseline was -2·0 m (68·1) for the pirfenidone group and -26·7 m (79·3) for the placebo group. Changes from baseline in UCSD-SOBQ, Leicester Cough Questionnaire score, cough visual analogue scale, and SGRQ scores were similar between the pirfenidone and placebo groups at week 24. Analysis of acute exacerbations, hospital admissions, and time to death from respiratory causes during the study yielded no meaningful results due to a small number of events. No differences in progression-free survival were identified between the pirfenidone and placebo groups, irrespective of the definition of progression-free survival used. Treatment-emergent adverse events were reported in 120 (94%) of 127 patients in the pirfenidone group and 101 (81%) of 124 patients in the placebo group. Serious treatment-emergent adverse events were reported in 18 (14%) patients in the pirfenidone group and 20 (16%) patients in the placebo group. The most common treatment-related treatment-emergent adverse events were gastrointestinal disorders (60 [47%] in the pirfenidone group vs 32 [26%] in the placebo group), fatigue (16 [13%] vs 12 [10%]), and rash (13 [10%] vs nine [7%]).. Although the planned statistical model could not be applied to the primary endpoint data, analysis of key secondary endpoints suggests that patients with progressive fibrosing unclassifiable ILD could benefit from pirfenidone treatment, which has an acceptable safety and tolerability profile. These findings support further investigation of pirfenidone as an effective treatment for patients with progressive fibrotic unclassifiable ILD.. F Hoffmann-La Roche.

Topics: Aged; Double-Blind Method; Drug Therapy, Combination; Europe; Female; Humans; Lung; Lung Diseases, Interstitial; Male; Middle Aged; Mycophenolic Acid; Progression-Free Survival; Pulmonary Fibrosis; Pyridones; Respiratory Function Tests; Treatment Outcome; Vital Capacity

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.

Topics: Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Prospective Studies; Pulmonary Diffusing Capacity; Pulmonary Fibrosis; Scleroderma, Diffuse; Tomography, X-Ray Computed; Treatment Failure; Vital Capacity

Topics: Adult; Bronchiolitis Obliterans; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Reoperation; Tacrolimus; Time Factors

BACKGROUND Mycophenolate mofetil (MMF) induced lung disease has been described in only a few isolated reports. We report a case of fatal respiratory failure associated with MMF after kidney transplantation. CASE REPORT A 50-year-old Hispanic male with a history of end-stage renal disease secondary to hypertension underwent deceased donor kidney transplantation. His preoperative evaluations were normal except for a chest x-ray which showed bilateral interstitial opacities. Tacrolimus and MMF were started on the day of surgery. His postoperative course was uneventful and he was discharged on postoperative day 5. One month later, he presented with shortness of breath and a cough with blood-tinged sputum. His respiratory condition deteriorated rapidly, requiring intubation. Chest computer tomography (CT) demonstrated patchy ground-glass opacities with interlobular septal thickening. Comprehensive pulmonary, cardiac, infectious, and immunological evaluations were all negative. Open lung biopsy revealed extensive pulmonary fibrosis with no evidence of infection. He temporarily improved after discontinuation of tacrolimus and MMF, however, on resuming MMF his respiratory status deteriorated again and he subsequently died from hypoxic respiratory failure. CONCLUSIONS An awareness of pulmonary lung disease due to MMF is important to prevent adverse outcomes after organ transplantation. MMF must be used with utmost care in recipients with underlying lung disease as their pulmonary condition might make them more susceptible to any harmful effects of MMF.

Topics: Fatal Outcome; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pulmonary Fibrosis

Polyomavirus nephropathy is commonly seen in the renal allograft setting but is uncommon in native kidneys. This paper describes polyomavirus nephropathy that developed in the native kidneys of a patient following immunosuppressive therapy for rheumatoid arthritis/Sjögren's syndrome associated lung disease. The patient presented with dyspnoea and a slow steady rise in serum creatinine. Owing to chronic immunosuppression, calcineurin-inhibitor toxicity was suspected. However, renal biopsy revealed polyomavirus nephropathy. The treatment of choice, lowered immunosuppression, was complicated by exacerbation of the patient's lung disease. This case highlights features of polyomavirus nephropathy in the native kidney, as well as the difficulty in its treatment when immunosuppressive treatment is necessary for medical comorbidities.

Topics: Arthritis, Rheumatoid; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Middle Aged; Mycophenolic Acid; Opportunistic Infections; Polyomavirus; Polyomavirus Infections; Pulmonary Fibrosis; Tacrolimus

The purpose of this study was to assess the impact of enteric-coated mycophenolate sodium (EC-MPS) on skin and pulmonary manifestations of patients with progressive systemic sclerosis (Ssc). A prospective, open-label single-centre trial with EC-MPS 2 × 720 mg/day over 12 months and a long-term follow-up of 50 months were conducted. Modified Rodnan skin score (mRSS) was used to assess the skin and pulmonary function tests to assess the pulmonary involvement. In order to quantify the extent of alveolitis/fibrosis via densitometry, the high attenuation value, median lung density and percentiles of lung tissue densities were obtained by high-resolution computed tomography. Eleven patients were included. Three patients had to stop medication before month 6 (2× side effects, 1× progression). For the remaining eight patients, the median mRSS was non-significantly reduced from 13.5 at baseline to 11 at month 12. According to the CT histography, median lung density and high attenuation values remained stable. However, the course of percentiles -200 to -300 and particularly -300 to -400 Hounsfield units slightly increased in seven of eight patients after 12 months, suggesting worsening of pulmonary involvement. Accordingly, median diffusing capacity for carbon monoxide showed a tendency to decline (75.1 % vs. 70.2) while forced vital capacity non-significantly improved (78.0 vs. 85.5 %) during the study. Four patients are still on EC-MPS without clinical signs of progression after 50 months follow-up. EC-MPS showed non-significant improvement of the skin. Pulmonary fibrosis remained stable with only a slight tendency towards progression which might be ascribed to the medication as well as the natural course of the disease. CT histography appears to be a sensitive method for the detection of progression of pulmonary fibrosis and therefore should be considered for further studies in Ssc.

Topics: Adult; Aged; Carbon Monoxide; Disease Progression; Female; Follow-Up Studies; Humans; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Pulmonary Fibrosis; Respiratory Function Tests; Scleroderma, Diffuse; Skin; Tablets, Enteric-Coated; Time Factors; Tomography, X-Ray Computed

Rheumatoid arthritis (RA) is the most common systemic autoimmune disease in the United States, affecting 1% to 2% of the adult population. Although joints and synovium are the primary targets in this disorder, extra-articular manifestations involving the lungs can lead to significant morbidity and excess mortality. Among the various pulmonary complications that occur in RA, interstitial lung disease (ILD) is the most damaging, with effects ranging from subclinical inflammation/scarring to end-stage pulmonary fibrosis. New insights during the past several years have underscored the epidemiologic impact of clinically/functionally significant RA-associated ILD (RA-ILD) and have begun to identify factors contributing to the pathogenesis of this potentially devastating complication of RA. Despite these advancements, the complexity of RA-ILD and the lack of reliable predictors for disease progression highlight the need for improved biomarker development. Establishing such detailed molecular signatures will ultimately guide the application and timing of therapeutic agents that include immunomodulators as well as newly studied antifibrotic agents.

Topics: Adrenal Cortex Hormones; Antimetabolites; Arthritis, Rheumatoid; Biomarkers; Citrulline; Cyclophosphamide; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Mycophenolic Acid; Proteins; Pulmonary Fibrosis; Radiography; Smoking

Acute fibrinous and organizing pneumonia (AFOP) has recently been identified as an unusual variant of acute lung injury. We describe a man with rapidly progressive lung disease who had AFOP detected via surgical lung biopsy. The patient acutely decompensated while in the hospital and required mechanical ventilation as well as a prolonged ICU stay. He responded poorly to initial treatment and progressively worsened, but he subsequently responded very well to combined therapy with mycophenolate mofetil and methylprednisolone. The combination of corticosteroids and mycophenolate may provide a safe and effective treatment strategy for severe forms of this newly defined pulmonary syndrome.

Topics: Adrenal Cortex Hormones; Cryptogenic Organizing Pneumonia; Humans; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Pulmonary Fibrosis; Treatment Outcome

We describe a case of chronic mineralizing pulmonary elastosis in a seven-yr-old boy following DD renal transplantation for Wilms tumour. Fourteen months post-transplantation he developed respiratory symptoms with lung biopsy demonstrating chronic mineralizing pulmonary elastosis thought to be secondary to immunosuppression with MMF. Symptomatic resolution occurred following MMF cessation.

Topics: Calcinosis; Chronic Disease; Humans; Immunosuppressive Agents; Infant; Kidney; Kidney Neoplasms; Kidney Transplantation; Male; Mycophenolic Acid; Nephrectomy; Pulmonary Fibrosis; Remission Induction; Renal Dialysis; Tomography, X-Ray Computed; Wilms Tumor

Posttransplant lymphoproliferative disorder is a rare and often difficult diagnosis in patients with only cutaneous symptoms. A stepwise approach to diagnosis and classification can lead to successful treatment. We report a case of an EBV-associated posttransplant lymphoproliferative disorder (PTLD) occurring on the face with a primary cutaneous presentation. The appropriate diagnosis was made only after multiple biopsies and special stains. There was near complete resolution with decreased levels of iatrogenic immunosuppression. The diagnosis of Posttransplant lymphoproliferative disorder can be difficult to establish. A proper workup will aid in making an accelerated diagnosis and choosing appropriate treatment options.

Topics: Dose-Response Relationship, Drug; Epstein-Barr Virus Infections; Face; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lung Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Mycophenolic Acid; Prednisone; Pulmonary Fibrosis; Sirolimus; Skin Diseases

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Pulmonary Fibrosis; Scleroderma, Diffuse

Idiopathic pulmonary fibrosis (IPF) is an inflammatory disorder of the lungs of unknown etiology, with no effective treatment. Besides the recent finding of utility of mycophenolate mofetil (MMF) in a case of refractory interstitial lung disease associated with ulcerative colitis, I suggest that there are at least three other reasons to consider MMF for IPF. Previously, MMF has been found to be effective as salvage therapy in a number of diseases. MMF might work for IPF not only by white cell suppression, but also in vivo against proliferation of primary human pulmonary fibroblasts. There is one group of patients for whom, logically, MMF should be most strongly considered--those with a high likelihood of receiving a lung transplant. As MMF is often part of the post-transplant immunosuppressive regimen in these patients, logic would seem to dictate MMF should be considered for use before subjecting the patient to major surgery.

Topics: Humans; Immunosuppressive Agents; Lung Transplantation; Mycophenolic Acid; Pulmonary Fibrosis

Topics: Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pulmonary Fibrosis

We report the first documented case of pulmonary toxicity to mycophenolate mofetil in this article.. A 51-year-old woman experienced systemic reactions beginning 10 days after cadaveric renal transplantation.. Recurrent respiratory failure and documented progressive pulmonary fibrosis ensued. Cultures were negative and other agents were discontinued. It was not until the mycophenolate was stopped did the patient improve.. Mycophenolate mofetil can cause acute respiratory failure simulating opportunistic infection or pulmonary edema. If not recognized, this may lead to the rapid development of severe pulmonary fibrosis, some of which may not be reversible.

Topics: Biopsy; Bronchoscopy; Female; Humans; Immunosuppressive Agents; Lung; Middle Aged; Mycophenolic Acid; Pulmonary Fibrosis; Respiratory Insufficiency