mycophenolic-acid and Hypertension--Pulmonary

Clinical heterogeneity, unpredictable course and flares are characteristics of systemic lupus erythematosus (SLE). Although SLE is-by and large-a systemic disease, occasionally it can be organ-dominant, posing diagnostic challenges. To date, diagnosis of SLE remains clinical with a few cases being negative for serologic tests. Diagnostic criteria are not available and classification criteria are often used for diagnosis, yet with significant caveats. Newer sets of criteria (European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019) enable earlier and more accurate classification of SLE. Several disease endotypes have been recognised over the years. There is increased recognition of milder cases at presentation, but almost half of them progress overtime to more severe disease. Approximately 70% of patients follow a relapsing-remitting course, the remaining divided equally between a prolonged remission and a persistently active disease. Treatment goals include long-term patient survival, prevention of flares and organ damage, and optimisation of health-related quality of life. For organ-threatening or life-threatening SLE, treatment usually includes an initial period of high-intensity immunosuppressive therapy to control disease activity, followed by a longer period of less intensive therapy to consolidate response and prevent relapses. Management of disease-related and treatment-related comorbidities, especially infections and atherosclerosis, is of paramount importance. New disease-modifying conventional and biologic agents-used alone, in combination or sequentially-have improved rates of achieving both short-term and long-term treatment goals, including minimisation of glucocorticoid use.

Topics: Anemia, Hemolytic, Autoimmune; Antibodies, Monoclonal, Humanized; Autoantibodies; Azathioprine; Calcineurin Inhibitors; Cardiovascular Diseases; Cyclophosphamide; Disease Management; Female; Glucocorticoids; Heart Valve Diseases; Humans; Hydroxychloroquine; Hypertension, Pulmonary; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Lupus Vasculitis, Central Nervous System; Macrophage Activation Syndrome; Methotrexate; Mycophenolic Acid; Myocarditis; Outcome Assessment, Health Care; Pericarditis; Phenotype; Pregnancy; Pregnancy Complications; Prognosis; Purpura, Thrombocytopenic, Idiopathic; Quality of Life; Recurrence; Rituximab; Severity of Illness Index; Survival Rate; Uterine Cervical Neoplasms

Topics: Adrenal Cortex Hormones; Anemia, Hemolytic; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Cyclophosphamide; Cyclosporine; Hypertension, Pulmonary; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid; Plasma Exchange

Pulmonary arterial hypertension (PAH) and interstitial pneumonia (IP) are relatively rare complications of systemic lupus erythematosus (SLE) and are associated with a poor prognosis. Overcoming these complications is a challenge for improving the prognosis.. In SLE complicated by PAH/IP, reports on the efficacy of MMF are scarce, and our findings suggested that MMF may be a treatment option in such cases.

Topics: Adult; Female; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Lung Diseases, Interstitial; Lupus Erythematosus, Systemic; Mycophenolic Acid; Pulmonary Arterial Hypertension; Skin Ulcer; Tomography, X-Ray Computed

There is a lack of agreement regarding treatment for many aspects of systemic sclerosis (SSc). We undertook this study to generate SSc treatment algorithms endorsed by a high percentage of SSc experts.. Experts from the Scleroderma Clinical Trials Consortium and the Canadian Scleroderma Research group (n = 170) were asked whether they agreed with SSc algorithms from 2012. Two consensus rounds refined agreement; 62, 54, and 48 experts (36%, 32%, and 28%, respectively) completed the first, second, and third surveys, respectively.. For treatment of scleroderma renal crisis, 81% of experts agreed (first-, second-, and third-line treatments were angiotensin-converting enzyme inhibitors, then adding calcium-channel blockers [CCBs], then adding angiotensin receptor blockers [ARBs], respectively). For pulmonary arterial hypertension (PAH), 81% of experts agreed (for mild PAH, treatments were phosphodiesterase 5 [PDE5] inhibitors, then endothelin receptor antagonists plus PDE5 inhibitors, then prostanoids, respectively; for severe PAH, prostanoids were first-line treatment). For mild Raynaud's phenomenon (RP), 79% of experts agreed (treatments were CCBs, then adding PDE5 inhibitors, then ARBs or switching to another CCB, respectively; after the third line of treatment, mild RP was deemed severe). For severe RP, the first- through fourth-line treatments were CCBs, then adding PDE5 inhibitors or prostanoids, then adding PDE5 inhibitors (if not added as second-line treatment) or prostanoids (if not added as second-line treatment), then switching to another CCB, respectively. For active treatment of digital ulcers, 66% of experts agreed (first- and second-line treatments were CCBs and PDE5 inhibitors, respectively). For interstitial lung disease, 69% of experts agreed (for induction therapy, treatments were mycophenolate mofetil [MMF], intravenous cyclophosphamide [IV CYC], and rituximab, respectively; for maintenance, first-line treatment was MMF). For skin involvement, 71% of experts agreed (for a modified Rodnan skin thickness score [MRSS] of 24, first- and second-line treatments were methotrexate [MTX] and MMF, respectively; for an MRSS of 32, first- through fourth-line treatments were MMF, MTX, IV CYC, and hematopoietic stem cell transplantation, respectively). For inflammatory arthritis, 79% of experts agreed (first- through fourth-line treatments were MTX, low-dose glucocorticoids, hydroxychloroquine, and rituximab or tocilizumab, respectively). Algorithms for cardiac and gastrointestinal involvement had ≥75% agreement.. Total agreement for SSc algorithms was considerable. These algorithms may guide treatment.

Topics: Algorithms; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis; Calcium Channels; Cyclophosphamide; Endothelin Receptor Antagonists; Glucocorticoids; Humans; Hydroxychloroquine; Hypertension, Pulmonary; Immunosuppressive Agents; Kidney Diseases; Lung Diseases, Interstitial; Methotrexate; Mycophenolic Acid; Phosphodiesterase 5 Inhibitors; Prostaglandins; Raynaud Disease; Rituximab; Scleroderma, Systemic

Systemic sclerosis-related interstitial lung disease (SSc-ILD) is the leading cause of death in SSc. In this study, we aimed to describe the baseline severity and evolution of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) in patients with SSc-ILD and to assess the baseline clinical, biological and high-resolution CT scan (HRCT) predictors of this evolution. Baseline and serial FVC and DLCO were collected in 75 SSc-ILD patients followed during 6.4±4.2 years (n = 557 individual data). FVC and DLCO evolution was modelled using a linear mixed model with random effect. During follow-up, FVC was stable while DLCO significantly decreased (-1.5±0.3%/year (p<0.0001). Baseline NYHA functional class III/IV, extensive SSc-ILD on HRCT and DLCO<80% were associated with a lower baseline FVC. Absence of digital ulcers extensive SSc-ILD, and FVC<80% and were associated with a lower baseline DLCO. Presence or history of digital ulcers and presence of pulmonary hypertension at baseline or during follow-up were associated with a faster decline of DLCO overtime. Neither age, gender, subtype of SSc nor specificity of autoantibodies were associated with baseline severity or outcome of lung function tests. In this SSc-ILD population, FVC was therefore stable while DLCO significantly declined over time. ILD extension was associated with baseline FVC and DLCO but not with their evolution. Presence or history of digital ulcers and pulmonary hypertension were predictors of a faster decline of DLCO over time.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Carbon Monoxide; Cyclophosphamide; Diffusion; Echocardiography; Female; Fingers; Follow-Up Studies; Humans; Hypertension, Pulmonary; Linear Models; Lung; Lung Diseases, Interstitial; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Pulmonary Diffusing Capacity; Respiratory Function Tests; Scleroderma, Systemic; Ulcer; Young Adult

To analyse the effects of mycophenolate mofetil (MMF) on pulmonary artery pressure (PAP) and the expression of cytokines and their receptors in a rat model of pulmonary arterial hypertension (PAH).. Thirty-eight healthy male inbred Sprague-Dawley rats were divided randomly into four groups: a control group, a monocrotaline (MCT) group, an MMF20 group (MCT+20 mg/kg/day MMF), and an MMF40 group (MCT+40 mg/kg/day MMF). Systolic PAP (SPAP), the right ventricular hypertrophy index (RVI), and the levels of expression of cytokines and their receptors were measured and analysed.. SPAP, RVI, levels of expression of basic fibroblast growth factor (bFGF) in serum and lung homogenates, alveolar arterial wall thickness, and the number of muscular arteries in the MMF20 and MMF40 groups were decreased in comparison with the MCT group.. MMF inhibits the formation of vascular muscle and decreases SPAP and RVI by inhibition of the expression of bFGF, endothelin-1 (ET-1), and their receptors, resulting in the inhibition of smooth muscle proliferation and amelioration of PAH.

Topics: Animals; Blood Pressure; Cell Proliferation; Cytokines; Disease Models, Animal; Endothelin-1; Fibroblast Growth Factor 2; Hypertension, Pulmonary; Lung; Male; Monocrotaline; Muscle, Smooth, Vascular; Mycophenolic Acid; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Cytokine; Receptors, Fibroblast Growth Factor

Topics: Adult; Bosentan; Cyclophosphamide; Familial Primary Pulmonary Hypertension; Fatal Outcome; Female; Humans; Hypertension, Pulmonary; Lupus Erythematosus, Systemic; Middle Aged; Mycophenolic Acid; Steroids; Sulfonamides; Treatment Outcome

Pulmonary arterial hypertension (PAH) is a severe clinical and pathophysiologic syndrome with no effective treatment at present. Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), has been applied widely to the treatment of connective tissue diseases with the effect of immunosuppressant. Its anti-proliferation has been found recently. Thereby, we tried to examine the effects of MMF on rats with PAH which was induced by monocrotaline injection, so as to investigate the mechanisms of treatment on PAH by MMF. The results substantiated that MMF therapy can alleviate thickening of pulmonary arterial walls and inhibit abnormal vascular remodeling, and the MPA concentrations which demonstrated efficacy in this study are within clinical applicable range, suggesting huge potentiality of MMF in the treatment of human PAH.

Topics: Animals; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Hypertension, Pulmonary; Hypertrophy; Immunosuppressive Agents; Male; Monocrotaline; Muscle, Smooth, Vascular; Mycophenolic Acid; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Treatment Outcome

Graves' disease can be associated with other autoimmune disorders. Primary systemic sclerosis (PSS) is such a disease characterised by multi-organ fibrosis. Abnormal thyroid antibody titres and hypothyroidism as well as hyperthyroidism have been observed in PSS patients. Specific and idiopathic inflammatory disorders are an important differential diagnosis in Graves'orbitopathy (GO). Mycophenolate mofetil (MM) is an immunosuppressive drug which depletes guanosin nucleotides in proliferating B-and T-lymphocytes. We describe the effect of MM on the endocrine orbitopathy of a patient with PSS.

Topics: Azathioprine; Bosentan; Cyclophosphamide; Drug Therapy, Combination; Female; Glucocorticoids; Graves Disease; Humans; Hypertension, Pulmonary; Immunoglobulins, Intravenous; Immunosuppressive Agents; Methotrexate; Middle Aged; Mycophenolic Acid; Proteinuria; Raynaud Disease; Scleroderma, Systemic; Sulfonamides

Pulmonary arterial hypertension (PAH) is characterized by abnormal proliferation of smooth muscle cells (SMCs), leading to occlusion of pulmonary arterioles, right ventricular (RV) hypertrophy, and death. We investigated whether mycophenolate mofetil (MMF), a potent immunosuppresssant, prevents the development of monocrotaline (MCT)-induced PAH in rats. MMF effectively decreased RV systolic pressure and RV hypertrophy, and reduced the medial thickness of pulmonary arteries. MMF significantly inhibited the number of proliferating cell nuclear antigen (PCNA)-positive cells, infiltration of macrophages, and expression of P-selectin and interleukin-6 on the endothelium of pulmonary arteries. The infiltration of T cells and mast cells was not affected by MMF. In vitro experiments revealed that mycophenolic acid (MPA), an active metabolite of MMF, dose-dependently inhibited proliferation of human pulmonary arterial SMCs. MMF attenuated the development of PAH through its anti-inflammatory and anti-proliferative properties. These findings provide new insight into the potential role of immunosuppressants in the treatment of PAH.

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Cell Proliferation; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Macrophages; Male; Monocrotaline; Mycophenolic Acid; Myocytes, Smooth Muscle; Rats; Rats, Sprague-Dawley

The tuberculostatic compound rifampin (INN, rifampicin) induces the expression of a number of drug metabolism-related genes involved in multidrug resistance (P-glycoprotein and multidrug resistance proteins 1 and 2), cytochromes (cytochrome P450 [CYP] 3A4), uridine diphosphate-glucuronosyltransferases, monoamine oxidases, and glutathione S -transferases. Drugs that depend on these enzymes for their metabolism are prone to drug interactions when coadministered with rifampin. A novel, clinically relevant drug interaction is described between rifampin and mycophenolate mofetil (MMF), a cornerstone immunosuppressive molecule used in solid organ transplantation. Long-term rifampin therapy caused a more than twofold reduction in dose-corrected mycophenolic acid (MPA) exposure (dose-interval area under the concentration curve from 0 to 12 hours [AUC 0-12]) when administered simultaneously in a heart-lung transplant recipient, whereas subsequent withdrawal of rifampin resulted in reversal of these changes after 2 weeks of washout (dose-corrected AUC 0-12 after rifampin withdrawal, 19.7 mg.h.L-1.g -1 versus 6.13 mg.h.L-1.g-1 before rifampin withdrawal [221% change]; dose-uncorrected AUC 0-12 after rifampin withdrawal, 29.6 mg.h/L [daily MMF dose, 3 g] versus 18.4 mg.h/L [daily MMF dose, 6 g] during rifampin administration [60.8% change]). Failure to recognize this drug interaction could potentially lead to MPA underexposure and loss of clinical efficacy. The effect of rifampin on MPA metabolism can, at least in part, be explained by simultaneous induction of renal, hepatic, and gastrointestinal uridine diphosphate-glucuronosyltransferases and organic anion transporters with subsequent functional inhibition of enterohepatic recirculation of MPA.

Topics: Area Under Curve; Chronic Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Enterohepatic Circulation; Glucuronosyltransferase; Heart-Lung Transplantation; Histiocytosis, Langerhans-Cell; Humans; Hypertension, Pulmonary; Male; Metabolic Clearance Rate; Middle Aged; Mycophenolic Acid; Pharmacology, Clinical; Respiratory Insufficiency; Rifampin; Tacrolimus; Time Factors; Uridine Diphosphate; Withholding Treatment

Topics: Azathioprine; Echocardiography; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; POEMS Syndrome; Prednisolone; Treatment Outcome