mycophenolic-acid and Asthma

With the increasing number of options for the treatment of moderate-to-severe atopic dermatitis, clinicians need guidance on a practical approach to selecting a systemic agent for specific patient populations. We convened an expert panel consisting of 12 members to conduct a literature review and summarize relevant data related to six scenarios of clinical interest: comorbid asthma, ocular surface disease, history of cancer, past and ongoing infections of interest (including herpes simplex virus, herpes zoster, hepatitis B, and tuberculosis), pregnancy and lactation, and the elderly. We performed a literature search and examined each clinical scenario with respect to three major categories of available systemic agents: traditional systemics (azathioprine, cyclosporine A, methotrexate, and mycophenolate mofetil), Janus kinase inhibitors (abrocitinib, baricitinib, and upadacitinib), and biologics (dupilumab, lebrikizumab, and tralokinumab). The expert panel and steering committee met virtually to review the data and discuss the drafted consensus statements. A modified Delphi process was used to arrive at a set of final consensus statements related to the systemic treatment of AD in these specific patient populations. To provide practical guidance on the choice of systemic therapy for atopic dermatitis in these six topics of clinical interest, 25 expert consensus statements and a summary of the supporting data are presented herein.

Topics: Aged; Asthma; Cyclosporine; Dermatitis, Atopic; Female; Humans; Methotrexate; Mycophenolic Acid

Torasemide is a loop diuretic with a molecule that is chemically similar to the sulphonamides described as eosinophilic granulomatosis with polyangiitis (EGPA) triggering drugs. The presented case is probably the first description of torasemide-induced vascular purpura in the course of EGPA. Any diagnosis of vasculitis should be followed by an identification of drugs that may aggravate the disease. A 74-year-old patient was admitted to the Department of Dermatology with purpura-like skin lesions on the upper, and lower extremities, including the buttocks. The lesions had appeared around the ankles 7 days before admission to the hospital and then started to progress upwards. The patient complained on lower limb paresthesia and pain. Other comorbidities included bronchial asthma, chronic sinusitis, ischemic heart disease, mild aortic stenosis, arterial hypertension, and degenerative thoracic spine disease. The woman had previously undergone nasal polypectomy twice. She was on a constant regimen of oral rosuvastatin 5 mg per day, spironolactone 50 mg per day, metoprolol 150 mg per day, inhaled formoterol 12 μg per day, and ipratropium bromide 20 μg per day. Ten days prior to admission, she was commenced on torasemide at a dose of 50 mg per day prescribed by a general practitioner due to high blood pressure. Doppler ultrasound upon admission to the hospital excluded deep venal thrombosis. The laboratory tests revealed leukocytosis (17.1 thousand per mm3) with eosinophilia (38.6%), elevated plasma level of C-reactive protein (119 mg per L) and D-dimers (2657 ng per mm3). Indirect immunofluorescent test identified a low titer (1:80) of antinuclear antibodies, but elevated (1:160) antineutrophil cytoplasmic antibodies (ANCA) in the patient's serum. Immunoblot found them to be aimed against myeloperoxidase (pANCA). A chest X-ray showed increased vascular lung markings, while high-resolution computed tomography revealed peribronchial glass-ground opacities. Microscopic evaluation of skin biopsy taken from the lower limbs showed perivascular infiltrates consisting of eosinophils and neutrophils, fragments of neutrophil nuclei, and fibrinous necrosis of small vessels. Electromyography performed in the lower limbs because of their weakness highlighted a loss of response from both sural nerves, as well as slowed conduction velocity of the right tibial nerve and in both common peroneal nerves. Both clinical characteristics of skin lesions and histopathology suggested a

Topics: Adolescent; Aged; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Antinuclear; Antihypertensive Agents; Asthma; C-Reactive Protein; Churg-Strauss Syndrome; Eosinophilia; Female; Formoterol Fumarate; Granulomatosis with Polyangiitis; Humans; IgA Vasculitis; Inflammation; Ipratropium; Leukotriene Antagonists; Metoprolol; Mycophenolic Acid; Peroxidase; Prednisone; Purpura; Receptors, Fc; Rosuvastatin Calcium; Sodium Potassium Chloride Symporter Inhibitors; Spironolactone; Sulfanilamides; Torsemide

Topics: Asthma; Female; Forced Expiratory Volume; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Patient Safety; Spirometry; Treatment Outcome; Vasculitis

Topics: Adult; Anti-Allergic Agents; Anti-Inflammatory Agents; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Asthma; Biopsy; Churg-Strauss Syndrome; Eosinophils; Female; Humans; Methylprednisolone; Mycophenolic Acid; Omalizumab; Prednisolone; Treatment Outcome

The bone marrow eosinophilopoiesis makes a major contribution to the chronic airway inflammation in asthmatic animals and patients. Some anti-asthmatic medicines alleviated the asthmatic airway inflammation by inhibiting the bone marrow eosinophilopoiesis. Immunosuppressive agents have been commonly used in patients with glucocorticoid refractory asthma and have been proved to be effective. However, the research on the effect of the immunosuppressive agents on the bone marrow eosinophilopoiesis has seldom been reported. The purpose of the study was to explore the effect of mycophenolate mofetil (MMF) and triptolide (TP) on the bone marrow eosinophilopoiesis and to further investigate the mechanisms of the immunosuppressive agents involved in the anti-asthmatic effect. Balb/c mice were sensitized and challenged by OVA to establish the asthmatic model, and respectively administered orally with sterile saline, MMF, and TP once daily for 2 weeks. Airway inflammation, and inflammatory mediators IL-5 and eotaxin in the peripheral blood and bone marrow were measured by histology and ELISA. Immunocytochemistry combined with in situ hybridization technique and Western blot analysis was performed to estimate the amount of CD34+ IL-5R mRNA+ cells and IL-5R expression in the bone marrow. The count of new produced eosinophils in the bone marrow was detected by anti-BrdU immunocytochemistry. We found that MMF and TP attenuated OVA-induced eosinophil (EOS) recruitment in bronchoalveolar lavage fluid (BALF), inflammatory mediator expression of IL-5 and eotaxin in the peripheral blood, inflammatory cells expressing eotaxin in the lung tissues and the number of new produced EOS in the bone marrow. Also, MMF abated the migration of CD34+ cells from the bone marrow to the peripheral blood, which was associated with a decreased eotaxin expression in the bone marrow and a decreased CCR3 expression on bone marrow cells. While, MMF or TP failed to decrease the amount of CD34+ IL-5R mRNA+ cells (EOS progenitors), and IL-5R expression in the bone marrow of asthmatic model mice. These results demonstrated that MMF and TP reduce the eosinophilopoiesis of the bone marrow; this is associated with a decrease of IL-5 produced by T cells, which contribute to alleviate the allergic airway inflammation in asthma. In addition, MMF decreased the CD34+ cells migration from the bone marrow to the peripheral blood by the reduction of the level of eotaxin in the bone marrow and the expression of

Topics: Animals; Asthma; Bone Marrow; Diterpenes; Eosinophils; Epoxy Compounds; Hematopoiesis; Immunosuppressive Agents; Interleukin-5; Male; Mice; Mice, Inbred BALB C; Mycophenolic Acid; Phenanthrenes; Receptors, CCR3

We have used an optimized, physiologically relevant in vitro assay system to show that in a concentration-dependent fashion the immunomodulatory drugs cyclosporin A, mycophenolate mofetil, and sirolimus (rapamycin), as well as the glucocorticoid dexamethasone, inhibit allergen-driven T-cell proliferation and IL-5 production in PBMCs from allergen-sensitized atopic asthmatic individuals at physiologic concentrations. This effect of cyclosporin A might at least partially account for its established clinical efficacy in sparing systemic glucocorticoid therapy while improving lung function in chronic, severe, glucocorticoid-dependent asthma. The data are also compatible with the hypothesis that the newer immunomodulatory drugs mycophenolate mofetil and sirolimus exert similar effects, perhaps with a more favorable benefit/risk ratio.

Topics: Asthma; Cyclosporine; Dexamethasone; Humans; Immunosuppressive Agents; Interleukin-5; Lymphocyte Activation; Mycophenolic Acid; Sirolimus

We have previously shown that T-lymphocytes from clinically glucocorticoid (GC) resistant asthmatics are more refractory to dexamethasone suppression in vitro than those of GC sensitive asthmatics. We wished to extend these observations to compare three GCs used topically for asthma therapy (budesonide, beclomethasone dipropionate and fluticasone 17 alpha-propionate) and three immunosuppressive drugs (cyclosporin A, FK506 (tacrolimus) and mycophenolate mofetil) with dexamethasone for their antiproliferative effects on T-lymphocytes from GC sensitive and resistant asthmatics, and also to compare the rates of steroid metabolism by T-lymphocytes from these patients. Antiproliferative activity of the drugs was measured on peripheral blood T-lymphocytes activated with phytohaemagglutinin (PHA) and anti-CD3 antibody in vitro. The rates of total steroid metabolism and 20 alpha-hydroxylation by T-cell homogenates were measured using radiolabelled progesterone as an established probe substrate. Over a wide concentration range, T-lymphocytes from GC resistant asthmatics were significantly less inhibited by all four GCs as compared with cells from GC sensitive asthmatics. The median inhibitory concentrations (IC50) for inhibition of T-lymphocytes from the GC resistant asthmatics exceeded those likely to be achieved therapeutically by systemic administration (although higher concentrations might in theory be achieved locally in the bronchial mucosa by inhaled administration). In contrast, all three immunosuppressive drugs at putative therapeutic concentrations inhibited T-lymphocytes both from GC sensitive and resistant asthmatics with equivalent potency. The rates of total metabolism and 20 alpha-hydroxylation of steroid by homogenates of T-lymphocytes from GC sensitive and resistant asthmatics were equivalent. Thus, relative GC resistance in T-lymphocytes from GC resistant as compared with sensitive asthmatics is: 1) manifest with GC molecules of variable molecular structure; 2) not accompanied by elevated intracellular metabolism of steroids; and 3) overcome by immunosuppressive drugs which inhibit T-lymphocytes by non-GC-mediated mechanisms. We conclude that current anti-asthma glucocorticoids at therapeutic concentrations are unlikely to be of benefit for the therapy of glucocorticoid resistant asthma, and that other immunosuppressive drugs may have potential as therapeutic agents in these patients.

Topics: Administration, Topical; Adult; Aged; Androstadienes; Anti-Inflammatory Agents; Asthma; Beclomethasone; Budesonide; CD3 Complex; Cell Division; Cyclosporine; Dexamethasone; Drug Resistance; Female; Fluticasone; Glucocorticoids; Humans; Hydroxylation; Immunosuppressive Agents; Lymphocyte Activation; Male; Middle Aged; Molecular Structure; Mycophenolic Acid; Phytohemagglutinins; Pregnenediones; T-Lymphocytes; Tacrolimus