mercaptopurine and Granulomatosis-with-Polyangiitis

Topics: Antibodies, Antineutrophil Cytoplasmic; Cyclophosphamide; Drug Therapy, Combination; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Mercaptopurine; Methotrexate; Practice Guidelines as Topic; Prednisolone; Prognosis; Pulse Therapy, Drug; Tumor Necrosis Factor-alpha

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Aspirin; Chlorambucil; Cyclophosphamide; Granulomatosis with Polyangiitis; Hepatitis; Humans; Immunosuppressive Agents; Liver Cirrhosis; Lupus Erythematosus, Systemic; Mercaptopurine; Methotrexate; Mice; Mice, Inbred NZB; Multiple Sclerosis; Nephritis; Nephrosis; Nitrogen Mustard Compounds; Penicillins; Psoriasis; Uveitis, Anterior

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Arthritis, Rheumatoid; Azathioprine; Chlorambucil; Colitis, Ulcerative; Crohn Disease; Cyclophosphamide; Granulomatosis with Polyangiitis; Hepatitis; Humans; Immune Complex Diseases; Immunosuppressive Agents; Infections; Liver Cirrhosis, Biliary; Lupus Erythematosus, Systemic; Mercaptopurine; Methotrexate; Nephrotic Syndrome; Ophthalmia, Sympathetic; Psoriasis; Thioguanine; Uveitis

Granulomatosis with polyangiitis (GPA) is an autoimmune disease affecting mainly small blood vessels. B-cells are important in the GPA pathogenesis as precursors of autoantibody-producing cells but likely also contribute (auto)antibody-independently. This has been underlined by the effectiveness of B-cell-depletion (with Rituximab) in inducing and maintaining disease remission. Mycophenolate-mofetil (MMF) and azathioprine (AZA) are immunosuppressive therapies frequently used in GPA-patients. Interestingly, MMF-treated GPA-patients are more prone to relapses than AZA-treated patients, while little is known about the influence of these drugs on B-cells. We investigated whether MMF or AZA treatment (or their active compounds) alters the circulating B-cell subset distribution and has differential effects on in vitro B-cell proliferation and cytokine production in GPA-patients that might underlie the different relapse rate. Circulating B-cell subset frequencies were determined in samples from AZA-treated (n = 13), MMF-treated (n = 12), untreated GPA-patients (n = 19) and matched HCs (n = 41). To determine the ex vivo effects of the active compounds of MMF and AZA, MPA and 6-MP respectively, on B-cell proliferation and cytokine production, PBMCs of untreated GPA-patients (n = 29) and matched HCs (n = 30) were cultured for 3-days in the presence of CpG-oligodeoxynucleotides (CpG) with MPA or 6-MP. After restimulation (with phorbol myristate acetate, calcium-ionophore), cytokine-positive B-cell frequencies were measured. Finally, to assess the effect of MMF or AZA treatment on in vitro B-cell proliferation and cytokine production, PBMCs of MMF-treated (n = 18), and AZA-treated patients (n = 28) and HCs (n = 41) were cultured with CpG. The memory B-cell frequency was increased in AZA- compared to MMF-treated patients, while no other subset was different. The active compounds of MMF and AZA showed in vitro that MPA decreased B-cell proliferation in GPA-patients and HCs. B-cell proliferation in MMF- and AZA-treated patients was not different. Finally, the IL-6+ B-cell frequency was decreased by MPA compared to 6-MP. No differences in IL-10+, IL-6+ or TNFα+ B-cell proportions or proliferation were found in MMF- and AZA-treated patients. Our results indicate that MMF could be superior to AZA in inhibiting B-cell cytokine production in GPA-patients. Future studies should assess the effects of these immunosuppressive drugs on other immune cells to elucidate mechanisms u

Topics: Adult; Aged; Azathioprine; B-Lymphocyte Subsets; B-Lymphocytes; Cell Proliferation; Cytokines; Female; Flow Cytometry; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Interleukin-6; Male; Mercaptopurine; Middle Aged; Mycophenolic Acid

Thirteen patients with Wegener's granulomatosis have been treated with cytotoxic agents. Only one died from the disease whereas two died of infectious complications of therapy and one of heart disease. Seven of the nine survivors are well without medication; one is alive with renal insufficiency and one is in the 5th year of treatment. Cholorambucil was least toxic and should be tried first. Cyclophosphamide was more effective than cholorambucil or azathioprine but, because of side effects, should rarely be used initially. Differentiation of Wegener's granulomatosis from lymphomatiod granumatosis, which it resembles clinically, roentgenologically and pathologically, is important since the latter disease responds differently to cytoxic drug therapy.

Topics: Azathioprine; Cyclophosphamide; Drug Evaluation; Granuloma; Granulomatosis with Polyangiitis; Hodgkin Disease; Humans; Lung Diseases; Mercaptopurine; Prednisone; Prognosis; Remission, Spontaneous

Topics: Azathioprine; Female; Granulomatosis with Polyangiitis; Humans; Mercaptopurine; Middle Aged; Oral Manifestations; Prednisolone; Prednisone; Skin Ulcer

Topics: Adult; Granulomatosis with Polyangiitis; Humans; Hydrocortisone; Male; Mercaptopurine; Prednisolone

Topics: Adult; Aged; Antineoplastic Agents; Azathioprine; Chlorambucil; Female; Granulomatosis with Polyangiitis; Humans; Lung Diseases; Male; Mercaptopurine; Middle Aged; Prednisone; Radiography

Topics: Adrenal Cortex Hormones; Adult; Blood Sedimentation; Drug Synergism; Female; Granulomatosis with Polyangiitis; Humans; Mercaptopurine; Prednisone; Time Factors