Biomedical subjects
Publications and source records attributed to G S Hoffman.
Wegener's granulomatosis is a chronic debilitating disease with multiple organ system involvement, variable course, and myriad complications that cause morbidity and mortality. We report 2 cases of nasal cavity squamous cell carcinoma occurring in long-standing Wegener's granulomatosis.
OBJECTIVE: To refine and validate the Birmingham Vasculitis Activity Score (BVAS) as a disease-specific activity index for Wegener's granulomatosis (WG). METHODS: Sixteen members of the International Network for the Study of the Systemic Vasculitides (INSSYS) revised the BVAS, with 3 goals: to reduce the redundancy of some component items, to enhance its ability to capture important disease manifestations specific to WG, and to streamline the instrument for use in clinical research. We defined the items and weighted them empirically as either minor (e.g., nasal crusting = 1 point) or major (e.g., alveolar hemorrhage = 3 points). We then validated the new, disease-specific BVAS/WG in 2 simulation exercises and a clinical case series that involved 117 patients with WG. RESULTS: We removed 38 items from the original BVAS, revised 9 items, and added 7 new items. Correlations between the scores on the BVAS/WG and the physician's global assessment (PGA) of disease activity were high, even when patients in remission were excluded. In the clinical case series, Spearman's rank correlation coefficient between the BVAS/WG and the PGA was r = 0.81 (95% confidence interval 0.73-0.87). The interobserver reliability using intraclass (within-case) correlation coefficients in the 2 simulation exercises was r = 0.93 for the BVAS/WG and r = 0.88 for the PGA in the first and r = 0.91 for the BVAS/WG and r = 0.88 for the PGA in the second. There was no significant observer effect in the scoring of the BVAS/WG or the PGA. The discriminant validity of the BVAS/WG was good: r = 0.73 (95% confidence interval 0.43-0.83). CONCLUSION: The BVAS/WG is a valid, disease-specific activity index for WG. Tested in simulation exercises and in actual patients, the BVAS/WG correlates well with the PGA, is sensitive to change, and has good inter- and intraobserver reliability. The INSSYS will use the BVAS/WG to assess the primary outcome in a phase II/III trial of etanercept in WG.
OBJECTIVE: To evaluate the safety of etanercept (Enbrel) in patients receiving conventional treatment for Wegener's granulomatosis (WG). METHODS: We performed a 6-month open-label trial of etanercept (25 mg subcutaneously twice weekly) which was added to standard therapies for WG (glucocorticoids, methotrexate, cyclophosphamide, azathioprine, cyclosporine) and prescribed according to disease severity. Evaluations of clinical response were determined by the Birmingham Vasculitis Activity Score for WG (BVAS/WG) in 20 patients with persistently active disease or with new flares of previously established WG. Fourteen of the 20 patients (70%) had etanercept added as the only new therapeutic variable. RESULTS: Injection site reactions (ISRs) were the most common adverse event related to etanercept (8 episodes in 5 patients [25%]; < 1% of all injections). All ISRs were mild. Two patients had a combined total of 5 hospitalizations (1 patient had 4), but no hospitalizations were attributable solely to etanercept-related adverse events. One patient with severe subglottic stenosis developed pneumococcal tracheobronchitis and subsequently had a localized Herpes zoster infection. Nineteen patients (95%) were still taking etanercept at 6 months, the single exception being a patient who developed progression of orbital (retro-bulbar) disease at 4 months. There were no deaths. The mean BVAS/WG at entry was 3.6 (range 1-8), which decreased at 6 months to 0.6 (P < 0.001, 95% confidence interval [95% CI] -4.0 to -2.1). Among the 14 patients in whom etanercept was the only new treatment variable, the mean daily prednisone dose decreased from 12.9 mg at entry to 6.4 mg at 6 months. This comparison did not achieve statistical significance (difference -6.5; P = 0.19, 95% CI -16.6 to +3.6). Sixteen of the patients (80%) achieved BVAS/WG scores of 0 at some point. However, intermittently active disease was observed in 15 patients (75%). CONCLUSION: In this open-label trial, etanercept used in combination with standard treatments was well-tolerated in patients with WG. Adverse events were few. BVAS/WG scores improved at 6 months, but intermittently active WG (occasionally severe) was common. A randomized, double-masked trial to assess the efficacy of etanercept in WG has begun.
The occurrence, albeit infrequent, of systemic vasculitis in closely related family members suggests that both environmental and genetic factors may play a role in the pathogenesis of these diseases. Malfunction of immune regulation in the systemic vasculitides may indicate a role for genes that encode molecules critical to the immune responses. The extremely polymorphic sequences of MHC molecules may provide a structural basis for associations of MHC genes and systemic vasculitis. This review summarizes recent reports of MHC associations, mechanisms by which MHC may play a role in certain vasculitides, and also examines the role for genes encoding non-MHC molecules, such as Fcgamma receptors, cytokines and T cell co-stimulators. Data suggest that the pathogenesis of systemic vasculitides such as giant-cell arteritis, Takayasu's arteritis and Wegener's granulomatosis might be governed by multiple genes encoding host defence molecules, in conjunction with environmental factors.
OBJECTIVE: To determine 1) the frequency of idiopathic aortitis in a large surgical cohort, 2) how often aortitis was associated with a systemic disease, and 3) whether the findings of aortitis in resected specimens predicted future occurrences of clinically apparent vascular injury due to vasculitis. METHODS: Retrospective chart and pathology review of 1,204 aortic surgical specimens that were gathered over a period of 20 years at a tertiary care medical center. A standardized database was used to compare features of aortitis patients with those of controls in whom inflammation was not present. RESULTS: Among 1,204 aortic specimens, 52 (4.3%) were clinically and pathologically classified as idiopathic aortitis. Sixty-seven percent of patients with idiopathic aortitis were women. In 96% of idiopathic aortitis patients with aneurysm formation, aortitis was present only in the thoracic aorta. Among 383 thoracic aortic aneurysms, 12% had idiopathic inflammatory features. In 96% of patients with idiopathic aortitis, symptoms of systemic illness had not been present at the time of surgery. In 31%, aortitis was associated with a remote history of vasculitis and a variety of other systemic disorders. During a mean followup period of 41.2 months, new aneurysms were identified among 6 of 25 patients who were not treated with glucocorticoids. None were identified among 11 patients who were treated with glucocorticoids (mean followup 35.5 months). CONCLUSION: The frequency of idiopathic aortitis in a large surgical cohort was found to be 4.3%. Thoracic aorta aneurysm formation, in the absence of systemic illness, was the most common manifestation. In the setting of a cardiovascular surgery practice, aortitis may first become apparent only after pathologic evaluation of excised specimens. The appropriate medical treatment for patients with incidentally discovered aortitis is not known. Because 17% of our patients subsequently developed new aneurysms, we suggest that it would be prudent for patients with idiopathic aortitis identified at the time of surgery to be periodically evaluated for recurrent or persistent disease.
BACKGROUND: Systemic vasculitis is an unusual complication of sarcoidosis. Over a 10-year period, the authors have provided care for six patients who had features of both sarcoidosis and vasculitis. Vasculitis could not be attributed to other causes. OBJECTIVES: To report six patients (five children) who had sarcoidosis and systemic vasculitis and compare our experience with previous literature. To better delineate the clinical spectrum of sarcoid vasculitis and its response to therapy. METHODS: Retrospective analysis and a Medline literature review of sarcoid and concurrent vasculitis from 1966. RESULTS: Our six patients had systemic illnesses that included fever, peripheral adenopathy, hilar adenopathy, rash, pulmonary parenchymal disease, musculoskeletal symptoms, and scleritis or iridocyclitis. Biopsies revealed features compatible with the diagnosis of sarcoidosis or necrotizing sarcoid granulomata in either skin, lymph node, lung, synovium, bone, bone marrow, liver, trachea, or sclera. Arteriography showed features of large vessel vasculitis in three patients, all of whom were African American, whereas patients with small vessel vasculitis were white. Prior reports of sarcoid and vasculitis included 14 adults, of whom half had predominantly small vessel disease, and half had medium- or large-sized vessel disease. Eight previously reported children included seven with primarily large vessel sarcoid vasculitis. Racial background was noted in 15 reported cases and included whites (6), African Americans (5), and Asians (4). Among the authors' six patients, four improved when treated with prednisone alone. However, relapses occurred when the drug was tapered or withdrawn. CONCLUSIONS: Sarcoidosis may be complicated by systemic vasculitis that can affect small- to large-caliber vessels. Sarcoid vasculitis can mimic hypersensitivity vasculitis, polyarteritis nodosa, microscopic polyangiitis, or Takayasu's arteritis. African American and Asian patients are disproportionately represented among cases with large vessel involvement. Corticosteroid and cytotoxic therapy is palliative for all forms of sarcoid vasculitis. However, relapses and morbidity from disease and treatment is common.
OBJECTIVE: It is known that renal failure is a poor prognostic marker for survival in Wegener's granulomatosis (WG). We investigated the longterm outcome of patients with WG who have severe renal disease requiring dialysis. METHODS: We performed a retrospective analysis of 104 patients with WG followed at our institution between 1982 and 1997. Twenty-three patients who required dialysis were studied in detail to determine outcomes and factors that influenced survival and restoration of renal function. RESULTS: Of 23 dialysis dependent patients with WG, 11 died (Group 1). 7 either remained dialysis dependent or received successful renal transplants (Group 2), and 5 substantially recovered renal function (Group 3). Mean serum creatinine at the end of a mean followup period of 38.4 months for Group 3 was 1.8 mg/dl. There was no apparent difference between groups in regard to disease profile, e.g., distribution of organ involvement or serum creatinine when renal impairment was first recognized (mean serum creatinine for groups: 1: 3.0 mg/dl; 2: 5.6 mg/dl; 3: 5.5 mg/dl) and peak serum creatinine prior to dialysis (means for groups: 1: 9.5 mg/dl; 2: 10.5 mg/dl; 3: 9.6 mg/dl). Infection secondary to immunosuppression was the leading cause of death in Group I patients. CONCLUSION: Because the clinical profile and degree of renal failure, as judged by serum creatinine, did not differ among patients who did or did not regain dialysis independent renal function, we recommend aggressive immunosuppressive therapy in all cases of active WG with acute rapidly worsening renal failure, regardless of the severity of renal impairment.
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Multicentric reticulohistiocytosis is a rare cutaneous-articular disease that may mimic more common disorders such as rheumatoid arthritis or tophaceous gout. In one fourth of patients, it is a paraneoplastic process. This brief overview is aimed at physicians who care for patients with polyarthritis, to alert them to distinctive features that differentiate multicentric reticulohistiocytosis from the common arthritides.
Wegener's granulomatosis (WG) is a systemic disease characterized by necrotizing granulomatous vasculitis that involves primarily the upper and lower respiratory tracts and, in most cases, the kidneys. Kidney involvement in WG presenting as a mass is recognized, but is very rare. We describe a case of WG presenting with upper and lower respiratory symptoms and a renal mass due to both WG and renal cell carcinoma.
Takayasu's arteritis is an inflammatory process affecting medium to large arteries. In about half of cases, constitutional symptoms and laboratory studies do not correlate with disease activity, confounding therapeutic decision making. We present six representative cases of Takayasu's arteritis in which new magnetic resonance imaging sequences for improved morphological and tissue characterization were useful in identifying aortic wall thickening and acute inflammatory changes, respectively. Specifically, fast spin-echo sequences designed to enhance detection of vessel wall edema were included. This information proved useful in guiding clinical decision making, particularly in regard to initiation and monitoring of therapy in our patients.
Twenty-nine patients with clinically defined Takayasu arteritis and 26 healthy control volunteers were recruited by INSSYS investigators from their clinical practices. Patients with Takayasu arteritis were divided into those with clear-cut clinically active or inactive disease based on Birmingham Vasculitis Activity Scores. Multiple serological tests were performed including ESR, C-reactive protein, tissue factor, von Willebrand factor, thrombomodulin, tissue plasminogen activator, ICAM-1, VCAM-1, E-selectin and PECAM-1. No test was reliably able to distinguish between healthy volunteers and patients with active Takayasu arteritis. At present there is no known serological test which can consistently supplant vascular histopathology in determining the activity of Takayasu arteritis.
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OBJECTIVE: To evaluate the patient-perceived effects of Wegener's granulomatosis (WG) on health, function, income, and interpersonal relationships. METHODS: A self-administered questionnaire, originally designed by the authors and subsequently revised with the aid of a patient focus group, was completed by 60 patients with well-defined features of WG. Patients had WG for a median period of 5 years. RESULTS: Patients with chronic WG experienced substantial medical and functional morbidity and incurred significant socioeconomic losses. A prolonged delay in diagnosis (mean 16.8 months) and the need for multiple consultations prior to initiation of therapy may have contributed to medical morbidity. Although 73% of patients perceived their disease to be in remission following therapy, 78% of these patients required continuing immunosuppressive treatment many years after diagnosis. Eighty percent of patients reported that their normal activities of daily living were compromised. Half of those who were employed prior to diagnosis were required to modify their job or accept total disability (31%). A 26% (median) reduction in income within 1 year after diagnosis was reported. The effects of the disease on interpersonal relationships with a patient's spouse, family, and friends varied considerably. CONCLUSION: Advances in medical care have, for most patients, transformed WG from being a disease with a high potential for short-term mortality to being a chronic illness. This is the first study that has evaluated patients' assessments of the medical, socioeconomic, and quality of life effects of WG and its treatment. The effects of mortality, disability, and outpatient medical expenses indicate that the financial impact alone substantially exceeds prior estimates of $30 million per year in charges for hospitalizations in the US.
Pulmonary vascular inflammation may be seen in a variety of primary lung diseases and in the setting of numerous systemic illnesses. This article reviews those entities in which pulmonary vasculitis represents a central feature of the pathologic process (Wegener's granulomatosis, Churg-Strauss syndrome, and pulmonary capillaritis). In addition, features of pulmonary involvement in other systemic vasculitides (Giant Cell Arteritis, Takayasu's Arteritis, and Behçet's disease) are described. Finally, general principles for the treatment of vasculitis are reviewed.
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