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1.
Arthritis Rheumatol ; 67(6): 1629-36, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25776953

ABSTRACT

OBJECTIVE: Nonsevere relapses are more common than severe relapses in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but their clinical course and treatment outcomes remain largely unexamined. We undertook this study to analyze the outcomes of patients with nonsevere relapses in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial who were treated with prednisone according to a prespecified protocol. METHODS: RAVE was a randomized, double-blind, placebo-controlled trial comparing rituximab (RTX) to cyclophosphamide (CYC) followed by azathioprine (AZA) for induction of remission. Patients who experienced nonsevere relapses between months 1 and 18 were treated with a prednisone increase without a concomitant change in their nonglucocorticoid immunosuppressants, followed by a taper. RESULTS: Forty-four patients with a first nonsevere relapse were analyzed. In comparison to the 71 patients who maintained relapse-free remission over 18 months, these patients were more likely to have proteinase 3-ANCAs, diagnoses of granulomatosis with polyangiitis (Wegener's), and a history of relapsing disease at baseline. A prednisone increase led to remission in 35 patients (80%). However, only 13 patients (30%) were able to maintain second remissions through the followup period (mean 12.5 months); 31 patients (70%) had a second disease relapse, 14 of them with severe disease. The mean time to second relapse was 9.4 months (4.7 months in the group treated with RTX versus 13.7 months in the group treated with CYC/AZA; P < 0.01). Patients who experienced nonsevere relapses received more glucocorticoids than those who maintained remission (6.7 grams versus 3.8 grams; P < 0.01). CONCLUSION: Treatment of nonsevere relapses in AAV with an increase in glucocorticoids is effective in restoring temporary remission in the majority of patients, but recurrent relapses within a relatively short interval remain common. Alternative treatment approaches are needed for this important subset of patients.


Subject(s)
Glucocorticoids/therapeutic use , Granulomatosis with Polyangiitis/drug therapy , Microscopic Polyangiitis/drug therapy , Prednisone/therapeutic use , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/drug therapy , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/immunology , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Autoantibodies/immunology , Azathioprine/therapeutic use , Cyclophosphamide/therapeutic use , Double-Blind Method , Female , Granulomatosis with Polyangiitis/immunology , Humans , Immunosuppressive Agents/therapeutic use , Maintenance Chemotherapy , Male , Microscopic Polyangiitis/immunology , Myeloblastin/immunology , Peroxidase/immunology , Recurrence , Remission Induction , Rituximab , Severity of Illness Index , Treatment Outcome
2.
Arthritis Rheumatol ; 66(11): 3151-9, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25047592

ABSTRACT

OBJECTIVE: Disease relapses are frequent in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study was undertaken to evaluate outcomes in patients with AAV who are re-treated with rituximab (RTX) and prednisone for severe disease relapses. METHODS: The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rates of remission induction among patients treated with RTX (n = 99) and patients treated with cyclophosphamide (CYC) followed by azathioprine (AZA) (n = 98). Prednisone was tapered to discontinuation after 5.5 months. After remission was achieved, patients who experienced a severe disease relapse between months 6 and 18 were eligible to receive RTX and prednisone on an open-label basis according to a prespecified protocol. Investigators remained blinded with regard to the original treatment assignment. RESULTS: Twenty-six patients received RTX for disease relapse after remission had initially been achieved with their originally assigned treatment. Fifteen of these patients were initially randomized to receive RTX and 11 to receive CYC/AZA. Thirteen (87%) of the patients originally assigned to receive RTX and 10 (91%) originally assigned to receive CYC/AZA achieved remission again with open-label RTX (an overall percentage of 88%). In half of the patients treated with open-label RTX, prednisone could be discontinued entirely. Patients in this cohort experienced fewer adverse events compared to the overall study population (4.7 adverse events per patient-year versus 11.8 adverse events per patient-year). CONCLUSION: Re-treatment of AAV relapses with RTX and glucocorticoids appears to be a safe and effective strategy, regardless of previous treatment.


Subject(s)
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/drug therapy , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/prevention & control , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Antirheumatic Agents/therapeutic use , Secondary Prevention/methods , Azathioprine/therapeutic use , Cyclophosphamide/therapeutic use , Double-Blind Method , Drug Therapy, Combination , Glucocorticoids/therapeutic use , Humans , Prednisone/therapeutic use , Prospective Studies , Recurrence , Remission Induction/methods , Rituximab , Time Factors , Treatment Outcome
3.
Arthritis Rheum ; 65(9): 2441-9, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23754238

ABSTRACT

OBJECTIVE: To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). METHODS: The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other). RESULTS: Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. CONCLUSION: Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3-ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.


Subject(s)
Antibodies, Monoclonal, Murine-Derived/therapeutic use , Granulomatosis with Polyangiitis/drug therapy , Immunosuppressive Agents/therapeutic use , Microscopic Polyangiitis/drug therapy , Remission Induction/methods , Adult , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Azathioprine/administration & dosage , Azathioprine/therapeutic use , Cross-Over Studies , Cyclophosphamide/administration & dosage , Cyclophosphamide/therapeutic use , Double-Blind Method , Drug Administration Schedule , Drug Therapy, Combination , Female , Humans , Immunosuppressive Agents/administration & dosage , Male , Rituximab , Treatment Outcome
4.
Am J Transplant ; 12(5): 1079-90, 2012 May.
Article in English | MEDLINE | ID: mdl-22420320

ABSTRACT

Control of the alloimmune response requires elimination and/or suppression of alloreactive immune cells. Lymphodepleting induction therapies are increasingly used to accomplish this goal, both as part of tolerance induction protocols or to reduce the requirements for maintenance immunosuppression in the peritransplant setting. However, it is well recognized that lymphopenia induces compensatory proliferation of immune cells, generally termed ``homeostatic proliferation,'' which favors the emergence of memory T cells. Paradoxically therefore, the result may be a situation that favors graft rejection and/or makes tolerance difficult to achieve or sustain. Yet all depletion is not alike, particularly with respect to the timing of reconstitution and the types of cells that repopulate the host. Thus, to design more effective induction strategies it is important to understand the homeostatic mechanisms, which exist to maintain a balanced repertoire of naïve and memory T and B cells in the periphery and how they respond to lymphodepletion. Here we will review the biology of homeostatic proliferation stimulated by lymphopenia, the effects of specific depleting agents on reconstitution of the T- and B-cell immune repertoire, drawing from both from animal models and human experience, and potential strategies to enhance allodepletion while minimizing the adverse effects of homeostatic proliferation.


Subject(s)
Homeostasis/immunology , Immune Tolerance , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Transplantation Immunology , Animals , Humans
5.
J Thorac Imaging ; 16(2): 117-22, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11292203

ABSTRACT

Sarcoidosis is generally not considered in the differential diagnosis of solitary pulmonary nodules. We recently encountered a case in which preoperative awareness of this presentation of sarcoidosis allowed a limited pulmonary resection with resultant lower morbidity and potential preservation of lung function to be performed. Although rare, sarcoidosis should be considered in the differential diagnosis of solitary pulmonary nodules.


Subject(s)
Lung Diseases/diagnostic imaging , Sarcoidosis/diagnostic imaging , Diagnosis, Differential , Humans , Lung Diseases/pathology , Lung Diseases/surgery , Male , Middle Aged , Sarcoidosis/pathology , Sarcoidosis/surgery , Tomography, X-Ray Computed
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