Pulse versus oral cyclophosphamide in the treatment of Wegener's granulomatosis: comment on the article by Guillevin et al.
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Administration, Oral↗
Biomedical subjects
M C Sneller
Publications and source records attributed to M C Sneller.
Pathological findings in human autoimmune lymphoproliferative syndrome.
The defects in lymphocyte apoptosis that underlie the autoimmune lymphoproliferative syndrome (ALPS) are usually attributable to inherited mutations of the CD95 (Fas) gene. In this report, we present the histopathological and immunophenotypic features seen in the lymph nodes (n = 16), peripheral blood (n = 10), bone marrow (n = 2), spleen (n = 3), and liver (n = 2) from 10 patients with ALPS. Lymph nodes showed marked paracortical hyperplasia. Interfollicular areas were expanded and populated by T cell receptor-alphabeta CD3+ CD4-CD8- (double-negative, DN) T cells that were negative for CD45RO. CD45RA+ T cells were increased in all cases studied. The paracortical infiltrate was a result of both reduced apoptosis and increased proliferation, as measured by in situ detection of DNA fragmentation and staining with MIB-1, respectively. The paracortical proliferation may be extensive enough to suggest a diagnosis of malignant lymphoma. Many of the paracortical lymphocytes expressed markers associated with cytotoxicity, such as perforin, TIA-1, and CD57. CD25 was negative. In addition, most lymph nodes exhibited florid follicular hyperplasia, often with focal progressive transformation of germinal centers; in some cases, follicular involution was seen. A polyclonal plasmacytosis also was present. The spleens were markedly enlarged, more than 10 times normal size. There was expansion of both white pulp and red pulp, with increased DN T cells. DN T cells also were observed in liver biopsies exhibiting portal triaditis. In the peripheral blood, the T cells showed increased expression of HLA-DR and CD57 but not CD25. CD45RA+ T cells were increased in the four cases studied. Polyclonal B cell lymphocytosis with expansion of CD5+ B cells was a characteristic finding. Taken together, the histopathological and immunophenotypic findings, particularly in lymph nodes and peripheral blood, are sufficiently distinctive to suggest a diagnosis of ALPS. Of note, two affected family members of one proband developed lymphoma (T-cell-rich B-cell lymphoma and nodular lymphocyte predominance Hodgkin's disease, respectively).
Apoptosis↗
Evaluation, treatment, and prophylaxis of infections complicating systemic vasculitis.
Infection continues to be a major cause of morbidity and mortality in patients with systemic vasculitis. The recognition and treatment of infections in these patients is a particularly difficult task because the spectrum of potential pathogens is broad and the clinical manifestations of infection often mimic those of the underlying disease. This article provides 1) a general overview of the immunosuppressive properties of agents commonly used in the treatment of systemic vasculitis, and 2) a framework for the diagnostic evaluation and treatment of various infectious syndromes in patients with systemic vasculitis.
Evaluation Studies as Topic↗
Polypoid lesions of airways: early experience with computer-assisted detection by using virtual bronchoscopy and surface curvature.
PURPOSE: To test the application of a technique developed by the authors for the computer-assisted diagnosis of polypoid airway lesions from surface rendered virtual bronchoscopic reconstructions. MATERIALS AND METHODS: A computer algorithm was developed to detect polypoid airway lesions by means of segmentation of the bronchial surface with curvature classification. This method was tested with a bronchial phantom, five cadaveric lung specimens, and virtual bronchoscopic studies in 16 patients. RESULTS: For the patient studies, the sensitivity and specificity of the method were 47%-88% and 58%-89%, respectively, depending on the value of an adjustable parameter (the mean curvature threshold). The sensitivity increased (by 20% to 34%) when only lesions larger than 5 mm in diameter were considered. CONCLUSION: With this method, polypoid airway lesions can be detected automatically, although false-positive diagnoses present an important limitation.
Adult↗
Clincal, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis.
Programmed cell death (apoptosis) of activated lymphocytes is critical to immune homeostasis. The cell surface protein Fas (CD95) and its ligand play a pivotal role in regulating lymphocyte apoptosis, and defective expression of either Fas or Fas ligand results in marked over accumulation of mature lymphocytes and autoimmune disease in mice. The results of recent studies suggest that defective lymphocyte apoptosis caused by mutations of the Fas gene can result in a severe autoimmune lymphoproliferative syndrome (ALPS) in humans. To define the clinical, genetic, and immunologic spectrum of ALPS, 9 patients and their families were extensively evaluated with routine clinical studies, lymphocyte phenotyping, genotyping, and in vitro assays for lymphocyte apoptosis. Individual patients were followed up for 3 months to 6 years. ALPS was identified in 9 unrelated children as manifested by moderate to massive splenomegaly and lymphadenopathy, hypergammaglobulinemia, autoimmunity, B-cell lymphocytosis, and the expansion of an unusual population of CD4- CD8- T cells that express the alpha/beta T-cell receptor (TCR). All patients showed defective lymphocyte apoptosis in vitro. Heterozygous mutations of the Fas gene were detected in 8 patients. One ALPS patient lacked a Fas gene mutation. Healthy relatives with Fas mutations were identified in 7 of 8 ALPS kindreds. These relatives also showed in vitro abnormalities of Fas-mediated lymphocyte apoptosis, but clinical features of ALPS were not present in the vast majority of these individuals. ALPS is a unique clinical syndrome in which in vitro abnormalities of lymphocyte apoptosis are associated with abnormal lymphoproliferation and autoimmunity. These findings provide evidence that apoptosis of activated lymphocytes is an important mechanism for maintaining immunologic homeostasis and self-tolerance in humans. Fas gene mutations account for impaired lymphocyte apoptosis in only a subset of patients with ALPS.
Anemia, Hemolytic, Autoimmune↗
ALPS: an autoimmune human lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis.
Apoptosis of activated lymphocytes is critical to immune homeostasis. The cell surface receptor Fas is an important mediator of lymphocyte apoptosis; defective Fas expression causes accumulation of lymphocytes and autoimmune disease in mice. Apoptosis defects due to mutations of Fas have also been found in a rare human autoimmune lymphoproliferative syndrome (ALPS). Nine unrelated children with ALPS had lymphadenopathy, autoimmunity and expansion of a normally infrequent population of CD4-CD8-T cells. All nine exhibited impaired lymphocyte apoptosis in vitro, and eight had heterozygous Fas gene mutations. Thus genetic defects in apoptosis pathways are implicated in the pathogenesis of at least one human autoimmune disorder.
Apoptosis↗
Pathogenesis of vasculitis syndromes.
The pathogenesis of vasculitis is complex and involves a variety of mechanisms acting in concert to bring about necrotizing inflammation of blood vessel walls. In recent years, there has been considerable progress in dissecting the immunologic abnormalities present in specific vasculitis syndromes. The primary immunopathogenic events that initiate the process of vascular inflammation and blood vessel damage, however, are still largely unknown. Although the cause of most vasculitis syndromes remains a mystery, advances in molecular and cellular immunology have defined many of the effector mechanisms that mediate inflammatory vascular damage. In this regard, modulation of the inflammatory response by specific cytokine and adhesion molecule antagonists is now possible and may prove beneficial in the treatment of vasculitis.
Antibodies, Antineutrophil Cytoplasmic↗
Infectious complications of immunosuppressive therapy in patients with rheumatic diseases.
Infection continues to be a significant cause of morbidity and mortality in patients with rheumatic diseases, and, consequently, early diagnosis and treatment of infection is critical to the successful medical management of these patients. The intensity of immunosuppressive therapy is the dominant risk factor for infection in this patient population. Because the manifestations of infection in patients with rheumatic diseases are highly variable, the clinician must always be vigilant about the possibility of infection even if the clinical presentation is highly suggestive of an exacerbation of the underlying disease. We have stressed a systematic and individualized approach in the diagnostic evaluation of suspected infection in these patients. The first part of the evaluation involves forming a list of the most likely pathogens based on a detailed history and physical examination and the intensity and type of immunosuppressive therapy the patient is receiving. The physician must then formulate a plan designed to establish a diagnosis expeditiously and with the least morbidity.
Communicable Diseases↗
Methotrexate use in systemic vasculitis.
Although GS and CYC have been important agents in improving the outcome and survival of patients with systemic vasculitis, they carry their own risk of drug-induced morbidity and mortality. It has also become apparent that these medications are not the final answer in disease management because some forms of vasculitis have the potential to relapse or be treatment resistant. For these reasons, the pursuit of effective, less toxic therapeutic alternatives is critical. Initial results from the use of MTX in systemic vasculitis have been encouraging. Although drug-related toxicity and disease relapse have still been found to occur, MTX appears to be a valuable addition in the treatment of vasculitis. Further studies will be necessary to determine the optimal way that this agent may be used to safely and effectively manage vasculitic disease.
Antirheumatic Agents↗
HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies.
Changes in CD4+ T-cell surface marker phenotype and antigen receptor (TCR) repertoire were examined during the course of HIV infection and following therapy. A preferential decline in naive CD4+ T cells was noted as disease progressed. Following protease inhibitor therapy, naive CD4+ T cells increased only if they were present before initiation of therapy. Disruptions of the CD4+ TCR repertoire were most prevalent in patients with the lowest CD4+ T-cell counts. Antiviral or IL-12 therapy-induced increases in CD4+ T-cell counts led to only minor changes in previously disrupted repertoires. Thus, CD4+ T-cell death mediated by HIV-1 infection may result in a preferential decline in the number of naive CD4+ T cells and disruptions of the CD4+ T-cell repertoire that are not immediately corrected by antiviral or immune-based therapies.
CD4-Positive T-Lymphocytes↗
New developments in the treatment of Wegener's granulomatosis, polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome.
With the opportunity for long-term follow-up, it has been appreciated that disease severity may vary considerably in patients with Wegener's granulomatosis, polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome. Although combined therapy with cyclophosphamide and glucocorticoids continues to be the foundation of treatment, concerns have increased about the toxicities of this regimen. As illustrated by studies on Wegener's-related subglottic stenosis and endobronchial involvement, it has also become apparent that some disease manifestations may not respond to this therapy. Recent therapeutic investigations have therefore focused on identifying approaches that are less toxic and that are based on anatomic involvement and disease severity. The study of polyarteritis nodosa has additionally been affected by proposed changes in classification that would make this condition a separate entity from microscopic polyangiitis. As progress is made in defining the clinical significance of this nomenclature, the prognostic factors in these patients have also been examined, which may be helpful in guiding therapeutic decisions.
Churg-Strauss Syndrome↗
Management of neutralizing antibody to Ceredase in a patient with type 3 Gaucher disease.
OBJECTIVES: The beneficial effects of macrophage-targeted glucocerebrosidase (Ceredase) in patients with Gaucher disease are well established. A minority of recipients develop transient nonneutralizing antibodies to the exogenous enzyme. A 7-year-old patient with type 3 Gaucher disease whose clinical course began to deteriorate while receiving Ceredase developed a progressively increasing titer of IgG antibody that blocked the catalytic activity of Ceredase. We sought to develop a strategy that would restore the benefit of enzyme replacement therapy in this patient. METHODS: The patient was treated with two courses of a combination of plasma exchange, cyclophosphamide, intravenous IgG, and large doses of Ceredase. RESULTS: After the second course of this regimen, the titer of the neutralizing antibody in the blood gradually declined to negligible levels. Clinical parameters that had been deteriorating (reduction of hemoglobin level, increased serum acid phosphates activity, repeated skeletal infarctions, progressive enlargement and infarction of the spleen) all improved. There has been no recurrence of the neutralizing antibody in this patient. CONCLUSIONS: Very few patients with Gaucher disease who are treated with Ceredase develop a neutralizing antibody to the exogenous enzyme. In the rare instances where this phenomenon occurs, it is likely that the strategy we have used (plasma exchange, cyclophosphamide, intravenous IgG, and large doses of enzyme) may provide benefit to such individuals. It is also likely that this technique may be helpful when enzyme replacement therapy is attempted in patients with other disorders in which the genetic mutation abrogates the production of the protein (CRIM-negative individuals).
Antibody Formation↗
Analysis of FcgammaRII gene polymorphisms in Wegener's granulomatosis.
Fcgamma receptors (FcgammaRs) are potent initiators of proinflammatory reactions and tissue injury programs through the oxidative burst, degranulation and the production of a variety of proinflammatory cytokines. Direct experimental evidence indicates that translocation of ANCA target from intracellular granules to the neutrophil membrane and subsequent binding of ANCA enables FcgammaR-mediated neutrophil activation. In the presence of ANCA, these data provide a framework from which to understand the importance of ANCA class, subclass, and titer in Wegener's granulomatosis and other ANCA-positive vasculitides. The well-characterized and functionally important alleles of neutrophil FcgammaR (FcgammaRIIa-H131/R131 and FcgammaRIIIb-NA1/NA2) are possible inheritable genetic elements that may alter disease severity and/or phenotype.
Alleles↗
Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis.
OBJECTIVE: To describe the incidence of, clinical manifestations of, and risk factors for cyclophosphamide-induced urinary bladder toxicity in patients treated for nonmalignant disease. DESIGN: Retrospective analysis of patients followed at the National Institutes of Allergy and Infectious Diseases from 1967 to 1993. SETTING: The Warren G. Magnuson Clinical Center of the National Institutes of Health (NIH). PATIENTS: 145 patients who received cyclophosphamide for the treatment of Wegener granulomatosis and were followed for 0.5 to 27 years (median, 8.5 years), for a total of 1333 patient-years. MEASUREMENTS: Clinical characteristics, cystoscopic findings, results of cytologic examination of urine, surgical pathology, and total dose and duration of cyclophosphamide therapy were recorded and analyzed using a computer-based information retrieval system. RESULTS: Nonglomerular hematuria occurred in 73 of 145 patients treated with cyclophosphamide (50%). Sixty of the 73 patients with nonglomerular hematuria (82%) had cystoscopy at the NIH. Forty-two of the 60 patients (70%) who had cystoscopy had macroscopic changes consistent with cyclophosphamide-induced bladder injury. Seven patients (5%) developed transitional-cell carcinoma of the urinary bladder. In 6 of these 7 patients, the total cumulative cyclophosphamide dose exceeded 100 g, and the cumulative duration of cyclophosphamide therapy exceeded 2.7 years. Before they were given a diagnosis of bladder cancer, all 7 patients had had one or more episodes of microscopic or gross nonglomerular hematuria. In contrast, none of the 72 patients who had never had nonglomerular hematuria developed bladder cancer. Cox proportional hazards regression analysis showed that only microscopic nonglomerular hematuria was a significant risk factor for the development of bladder cancer (P < 0.01). CONCLUSION: Long-term oral cyclophosphamide therapy is associated with substantial urotoxicity, including the development of transitional-cell carcinoma of the urinary bladder. In this cohort of patients, the estimated incidence of bladder cancer after the first exposure to cyclophosphamide was 5% at 10 years and 16% at 15 years. Nonglomerular hematuria was a frequent manifestation of cyclophosphamide-induced cystitis, and it identified a subgroup of patients at high risk for the development of bladder cancer.
Aged↗
Finding a valid model for human Wegener's granulomatosis: comment on the article by Tomer et al.
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Animals↗
Clinical features and therapeutic management of subglottic stenosis in patients with Wegener's granulomatosis.
OBJECTIVE: To determine the clinical features and optimal treatment of subglottic stenosis (SGS) in patients with-Wegener's granulomatosis (WG). METHODS: Review of 43 patients with SGS and treatment of 20 patients with intratracheal dilation-glucocorticoid injection therapy. RESULTS: SGS developed in 43 of 189 patients with WG who were followed up at the National Institutes of Health Clinical Center. The diagnosis of SGS occurred in the absence of other features of active. WG in 21 of 43 patients (49%). In 21 patients (49%), SGS began while the patient was receiving systemic immunosuppressive therapy for disease activity involving other sites. Tracheostomy was required in 10 of 18 patients (56%) who were treated with systemic immunosuppressive therapy. In 20 patients treated with intratracheal therapy, none required tracheostomy and 6 with previous tracheostomies were decannulated. CONCLUSION: SGS often occurs independently of other features of active WG and is frequently unresponsive to systemic immunosuppressive therapy. Intratracheal dilation-injection therapy provides a safe and effective treatment for WG-associated SGS and, in the absence of major organ disease activity, should be used without concomitant systemic immunosuppressive agents.
Adult↗
Cytokine therapy of HIV infection.
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Cytokines↗
Consensus symposium on combined antiviral therapy; overview of interferon and IL-2 combinations for the treatment of HIV infection.
Among the immunomodulatory cytokines that have been evaluated for the treatment of HIV disease, alpha-interferon and interleukin-2 (IL-2) have been the most extensively studied. Monotherapy with alpha-interferon is effective therapy for HIV-associated Kaposi's sarcoma (KS) in patients with CD4 counts > 150 cells/mm3. However, the doses necessary to achieve a significant anti-tumor effect are often poorly tolerated. Combination therapy with alpha-interferon and zidovudine is associated with dose-limiting toxicities and an anti-tumor effect similar to that of higher dose alpha-interferon monotherapy. The combination of alpha-interferon and zidovudine can synergistically inhibit HIV replication in vitro; however, in vivo results suggest the anti-HIV effect of this combination is no greater than that seen with zidovudine monotherapy. Whether combination of interferon-alpha and other antiviral drugs will be useful in the treatment of HIV infection remains to be seen. Recent studies employing intermittent courses of IL-2 combined with continuous antiretroviral therapy indicate that sustained rises in CD4 counts can be achieved. The ability of IL-2 therapy to result in a sustained rise in CD4 counts is critically dependent on the pre-treatment CD4 count. The immunologic and clinical significance of these IL-2-induced increases in CD4 counts is unknown. Larger, controlled trials are currently underway to evaluate the role of intermittent IL-2 therapy in HIV infection.
Acquired Immunodeficiency Syndrome↗