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Gary S Hoffman

Publications and source records attributed to Gary S Hoffman.

15 recordsLinked to original sources
PubMed2004

Anti-tumor necrosis factor therapy in patients with difficult to treat Takayasu arteritis.

OBJECTIVE: Granulomatous inflammation is a typical feature of Takayasu arteritis (TA), and tumor necrosis factor (TNF) is important in the formation of granulomas. In this study, we assessed therapy with anti-TNF agents in patients with TA that was not controlled by glucocorticoid therapy or other immunosuppressants. METHODS: We conducted an open-label trial of anti-TNF therapy at 3 academic medical centers over a period of 4.25 years. Fifteen patients with active, relapsing TA (median 6 years) were selected. Seven received etanercept (later changed to infliximab in 3 patients), and 8 received infliximab. Relapses had occurred in all patients while they were receiving glucocorticoids and, in 13 patients, additional immunosuppressive drugs. No other agents were added to the treatment regimen concurrently with anti-TNF. If patients were receiving cytotoxic agents, the dosage was not increased. Clinical symptoms were recorded, and physical examinations, laboratory studies, and serial magnetic resonance imaging were performed. RESULTS: The median daily dose of prednisone required to maintain remission prior to anti-TNF therapy was 20 mg. Ten of the 15 patients achieved complete remission that was sustained for 1-3.3 years without glucocorticoid therapy. Four patients achieved partial remission, with a >50% reduction in the glucocorticoid requirement. At a median of 12 months of followup, the median dose of prednisone was 0. Therapy failed in 1 patient. In 9 of the 14 responders, an increase in the anti-TNF dosage was required to sustain remission. Two relapses occurred during periods when anti-TNF therapy (etanercept) was interrupted, but remission was reestablished upon reinstitution of therapy. CONCLUSION: In this pilot study of relapsing TA, addition of anti-TNF therapy resulted in improvement in 14 of 15 patients and sustained remission in 10 of 15 patients, who were able to discontinue glucocorticoid therapy. Anti-TNF may be a useful adjunct to glucocorticoids in the treatment of TA. Our results justify a randomized, controlled clinical trial of anti-TNF therapy for TA.

Adolescent↗
PubMed2004

An analysis of CTLA-4 and proinflammatory cytokine genes in Wegener's granulomatosis.

OBJECTIVE: The precipitating event(s) that triggers Wegener's granulomatosis (WG) is unknown. Cytokines, costimulatory molecules, and counterregulatory molecules control the quality and intensity of immune responses. Thus, they are relevant candidates for genetic studies of immune dysregulation in WG, the pathogenesis of which may be facilitated by multiple acquired and/or inherited factors. This study was undertaken to investigate possible genetic associations of various proinflammatory cytokines and CTLA-4, a receptor for T cell inhibition, with WG. METHODS: Using polymerase chain reaction-based DNA genotyping, we investigated the polymorphisms located in the genes encoding a variety of proinflammatory cytokines and CTLA-4 in 117 American patients with WG and 123 ethnically matched healthy controls. RESULTS: Compared with controls, patients with WG had a significantly lower frequency of homozygosity for the shortest allele (designated allele 86) of the Ctla4 microsatellite polymorphism (AT)n located in the 3'-untranslated region (3'-UTR) of exon 3 (47.0% versus 69.9%; P = 0.0005). Significant differences between patients and controls in the allelic and genotypic frequencies of polymorphisms in the other cytokine and cytokine receptor genes studied (tumor necrosis factor alpha [TNFalpha], TNF receptor I [TNFRI], TNFRII, interleukin-1beta [IL-1beta], IL-6) were not found. CONCLUSION: The Ctla4 (AT)n 86 allele has been previously demonstrated to be crucial for maintenance of normal levels of CTLA-4 expression and balance between T cell activation and inhibition. Our results in American patients confirm findings from a Scandinavian cohort in which a positive association between WG and longer alleles of (AT)n in the Ctla4 3'-UTR was demonstrated. Diminished frequencies of the most effective allele for CTLA-4 expression may represent a WG-related susceptibility mutation that accounts, in part, for increased T cell activation and clonal expansion in WG. Blockade of T cell costimulation using CTLA-4Ig might be a useful therapeutic intervention, providing an alternative or complementary approach to conventional treatment with immunosuppressive agents.

Antigens, CD↗
PubMed2004

Identification of candidate microbial sequences from inflammatory lesion of giant cell arteritis.

Giant cell arteritis (GCA) is a granulomatous inflammatory disease of medium and large arteries which is prevalent in the elderly population. The etiology of GCA is unknown, although the immunologic features suggest the possible presence of a microorganism. Our group has examined whether microbial DNA fragments were present at GCA lesions and whether such microbial fragments could be associated with disease pathogenesis. Initial identification of microbial sequences was performed using genomic representational difference analysis (RDA). Laser dissecting microscopy was used to isolate cells from GCA lesions and adjacent uninvolved temporal artery. Using genomic RDA, we isolated 10 gene fragments; three of these sequences had high homology with prokaryotic genes and were considered high-priority candidates for further study. An examination of serum from GCA(+) individuals (in contrast to healthy age-matched controls) showed the presence of IgG which recognized in vitro translated proteins from these clones.

Amino Acid Sequence↗
PubMed2004

Takayasu's arteritis: vascular interventions and outcomes.

OBJECTIVE: To provide an analysis of outcomes of vascular interventions in 20 patients with Takayasu's arteritis (TA) who received care at the Cleveland Clinic Foundation between 1979 and 2001. METHODS: We performed a retrospective chart review. The primary outcome measure of our review was patency of vessels as assessed by repeat invasive angiography or magnetic resonance angiography. The secondary outcome measures included periprocedural complications, morbidity, and mortality. Interventions included bypass grafts, patch angioplasty, endarterectomy, percutaneous transluminal angioplasty (PTA), or stent placement. RESULTS: Sixty-two revascularization procedures were performed in 20 patients. Followup evaluations were available for 52 procedures. Eleven of 31 bypass grafts restenosed or occluded between one day to 168 months after surgery. Three of 7 PTA and 5 of 7 stents restenosed or became occluded after 1-72 months and 2-45 months of followup, respectively. There were no deaths associated with revascularization procedures. CONCLUSION: Despite providing short term benefit, endovascular revascularization procedures are associated with a high failure rate in patients with TA.

Angioplasty, Balloon↗
PubMed2003

Domains of health-related quality of life important to patients with giant cell arteritis.

OBJECTIVE: To determine aspects of quality of life (QOL) important to people with giant cell arteritis (GCA). METHODS: We explored the domains of QOL affected by GCA in audiotaped focus groups. We then created an Importance Rating Questionnaire (IRQ) by constructing questions related to the domains most frequently mentioned. Of 214 GCA patients to whom the IRQ was sent, 145 (68%) responded. We calculated frequencies of responses and then ranked items by the proportion selecting the top category of importance and also according to a mean item rank. We compared the domains of QOL covered by the IRQ with those in the Short Form 12 (SF-12). RESULTS: The highest rated QOL item was "losing sight in both eyes permanently." Of the top 20 items, 12 were in domains not covered directly by the SF-12. CONCLUSION: We have identified aspects of QOL important to GCA patients. Assessment of QOL in GCA should include vision and other domains that are not included in standard QOL questionnaires.

Activities of Daily Living↗
PubMed2003

Prevalence of antineutrophil cytoplasmic antibodies in patients with various pulmonary diseases or multiorgan dysfunction.

OBJECTIVE: To determine the prevalence of antineutrophil cytoplasmic antibodies (ANCA) in patients with diseases that may mimic systemic vasculitides, such as severe multiorgan dysfunction (MOD) and parenchymal pulmonary disorders. METHODS: We conducted a prospective study of patients with MOD admitted to the medical intensive care unit and patients with various lung diseases seen at the outpatient pulmonary clinic of a tertiary care hospital. Patients with a documented diagnosis of Wegener's granulomatosis (WG) served as positive controls. ANCA were determined in serum samples from each patient by a combination of indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assays (ELISAs) for antibodies to proteinase-3 and myeloperoxidase (anti-MPO). RESULTS: Ninety-nine patients with MOD, 29 outpatients with various lung disorders, and 18 patients with WG were included in the study. ANCA were detected by IIF alone in 16% (15/96) of patients with nonvasculitic MOD and 17% (5/29) of outpatients with various pulmonary disorders. The majority of the positive IIF specimens from each group displayed an atypical IIF pattern (73% and 80%, respectively). Only 1 specimen from patients with nonvasculitic disorders was positive for anti-MPO. ANCA by both IIF and ELISA were detected in 78% (12/14) of control patients with WG. CONCLUSION: Detection of ANCA by the combination of IIF and antigen-specific assays for proteinase 3 and myeloperoxidase in diseases that mimic systemic vasculitides is highly specific for WG, microscopic polyangiitis, and Churg-Strauss syndrome.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2003

Treatment of subglottic stenosis, due to Wegener's granulomatosis, with intralesional corticosteroids and dilation.

OBJECTIVE: To determine the longterm efficacy of intralesional long-acting corticosteroid injection plus dilatation (ILCD) for subglottic stenosis (SGS) in Wegener's granulomatosis (WG). METHODS: Since November 1994, all patients with WG who presented with SGS of more than 50% or symptoms of airway compromise were treated with intralesional injection of methylprednisolone acetate, injected directly into the stenotic segment, followed by microsurgical lysis of the stenotic ring and serial dilatation with Maloney bougies or Fogarty catheter balloon. The procedure was repeated at a later date if re-stenosis occurred. Patient outcome was evaluated over a period of 7 years. RESULTS: Twenty-one patients underwent 64 procedures. Mean followup was 40.6 months. Patients who did not have scarring from prior procedures required a mean of 2.4 procedures at mean intervals of 11.6 months to maintain subglottic patency. Patients with established laryngotracheal scarring required a mean of 4.1 procedures at mean intervals of 6.8 months to maintain patency. None of the 21 patients required a new tracheostomy. Only 2 significant complications occurred, both pneumothoraces. There were no adverse longterm sequelae. CONCLUSION: ILCD is effective therapy for SGS due to WG. Best results are obtained when these endoscopic techniques are performed prior to other forms of surgery, which may produce extensive scar formation. Based on this experience, the authors recommend ILCD as the preferred therapy in WG-SGS.

Adult↗
PubMed2003

Relative importance of CCR5 and antineutrophil cytoplasmic antibodies in patients with Wegener's granulomatosis.

OBJECTIVE: Wegener's granulomatosis (WG) is an idiopathic inflammatory condition characterized by upper and lower airway involvement and often renal dysfunction. Sites of tissue injury include pleomorphic cell populations, and classically mononuclear cell infiltrates that may form granulomas. Vascular inflammation (i.e., vasculitis) is often but not always present. Because CCR5 and its ligands influence mononuclear cell trafficking, we sought to identify their expression in pulmonary lesions and to determine whether genetic variations in genes for CCR5 and its ligands influence susceptibility to WG. METHODS: Lung biopsies from 4 patients that had classical features of WG were examined for protein expression of CCR5, RANTES, MIP-1alpha and MIP-1beta using immunohistochemistry. One hundred eighteen Caucasian patients with WG and 127 ethnically matched healthy controls were included in the genetic analysis. Genomic DNA samples were amplified by PCR. CCR5 Delta32 and RANTES -28 and -401 polymorphisms were determined by either specific primers or direct sequencing. RESULTS: CCR5+ cells were enriched in lung lesions from patients with WG. Enhanced protein concentrations of RANTES, MIP-1alpha, and MIP-1beta were present in WG lung lesions, indicating redundancy of ligands for CCR5 in affected tissue. Genetic analyses revealed 3 subsets of patients with WG: (1) circulating antineutrophil cytoplasmic antibody (ANCA) positive and CCR5+/+ (58%); (2) CCR5+/+ and ANCA negative (22%); and (3) CCR5 Delta32 and ANCA positive (20%). Among patients in whom ANCA were repeatedly absent, none was found to carry the CCR5 Delta32 allele. Conversely, patients who possessed the CCR5 Delta32 allele were always ANCA positive. CONCLUSION: CCR5 and its ligands are abundantly present in pulmonary lesions in WG. The absence of a genetic deletion for CCR5 (CCR5 Delta32) in WG patients lacking ANCA suggests that CCR5 may exert a particularly important pathogenetic role in those patients. Another subset of patients (approximately 20%) with WG possessed a genetic deletion for CCR5. That each of these patients was ANCA positive implies that an alternative pathway to CCR5 may exist, for which ANCA may be especially important.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2002

Patients' perceptions of the effects of systemic lupus erythematosus on health, function, income, and interpersonal relationships: a comparison with Wegener's granulomatosis.

OBJECTIVE: To describe the patients' perceptions of the effects of systemic lupus erythematosus (SLE) and Wegener's granulomatosis (WG) on health, function, income, and interpersonal relationships. METHODS: 114 patients with SLE, and 79 patients with WG completed a self-administered questionnaire. Patients had been diagnosed with SLE or WG for a median period of 10 and 5 years, respectively. RESULTS: All patients experienced substantial functional morbidity. Two-thirds of the patients with SLE or WG reported either a periodic or permanent inability to perform daily activities at home and/or at work. Furthermore, SLE as well as WG had a considerable impact upon the psychological and social life, affecting their happiness and altering relationships. CONCLUSION: Our study demonstrates that SLE and WG are associated with substantial medical morbidity resulting in physical and occupational disability. SLE has a profound impact on patients' lives, similar to that experienced in patients with WG.

Activities of Daily Living↗
PubMed2002

Takayasu arteritis: utility and limitations of magnetic resonance imaging in diagnosis and treatment.

OBJECTIVE: Previous studies have confirmed the poor correlation of symptoms, signs, and levels of acute-phase reactants with disease activity in approximately 50% of all patients with Takayasu arteritis (TA). Invasive angiographic studies demonstrate vessel lumen anatomy, but do not provide qualitative information about the vessel wall. Moreover, sequential invasive angiographic studies expose patients to high-dose ionizing radiation and catheter/procedure-related morbidity. The aim of the present study was to determine the utility of new developments in vascular magnetic resonance (MR) technology in patients with TA. METHODS: Electrocardiogram-gated "edema-weighted" MR was used to evaluate the aorta and its primary branches with regard to the vascular lumen, vessel wall anatomy, and vessel wall edema in 24 TA patients (77 studies). Inclusion criteria were age <50 years and features of TA on both clinical examination and invasive angiographic studies. Patients were stratified based on clinical and laboratory indications of having either unequivocally active disease, inactive disease, or uncertain disease status. RESULTS: MR revealed vessel wall edema in 94% (17 of 18), 81% (13 of 16), and 56% (24 of 43) of studies obtained during periods of unequivocally active disease, uncertain disease activity, and apparent clinical remission, respectively. Westergren erythrocyte sedimentation rate and C-reactive protein values did not correlate with either the clinical assessment of disease activity or MR evidence of vascular edema. The frequency of presumed vascular inflammation (edema), as assessed by MR, in patients who appeared to be in remission was similar to the reported frequency of new angiographic lesions and histopathologic evidence of active disease in surgical specimens from patients thought to be in remission. However, the presence of edema within vessel walls did not consistently correlate with the occurrence of new anatomic changes found on subsequent studies. CONCLUSION: Inconsistencies in the presence or absence of vessel edema and subsequent anatomic changes have cast doubt on the utility of edema-weighted MR imaging as a sole guide to disease activity and treatment in TA. In this study, the greatest utility of MR was in providing a safe, noninvasive means of assessing changes in vascular anatomy.

Adolescent↗
PubMed2002

A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis.

OBJECTIVE: To evaluate treatment with methotrexate (MTX) in patients with newly diagnosed giant cell arteritis (GCA) to determine if MTX reduces GCA relapses and cumulative corticosteroid (CS) requirements and diminishes disease- and treatment-related morbidity. METHODS: This was a multicenter, randomized, double-blind study. Over 4 years, 16 centers from the International Network for the Study of Systemic Vasculitides enrolled patients with unequivocal GCA. The initial treatment was 1 mg/kg/day (<or=60 mg every day) prednisone, plus either 0.15 mg/kg/week MTX (increased to 0.25 mg/kg/week, for a maximum weekly dosage of 15 mg) or placebo. Two physicians, both blinded to treatment allocation, evaluated each patient at every trial visit. One physician was responsible for providing global medical care. The other assessed GCA status according to a standard protocol. Treatment failure was defined as 2 distinct relapses or persistence of disease activity after the first relapse, in spite of increased CS therapy. RESULTS: Ninety-eight patients were enrolled. No significant differences between treatment groups were noted with regard to age, frequency of positive findings on temporal artery biopsy (placebo 87%, MTX 79%), or comorbidities at the time of enrollment. The median dosage of MTX was 15 mg/week. The incidence of treatment failure was comparable between groups after 12 months: 57.5% in the MTX group failed treatment (95% confidence interval [95% CI] 41.6-73.4%) compared with 77.3% in the placebo group (95% CI 61.9-92.8%) (P = 0.26). In a Cox regression analysis, MTX was not associated with a reduced risk of treatment failure (relative risk 0.72; 95% CI 0.41-1.28). There were no significant differences between groups with regard to abnormal elevations of the erythrocyte sedimentation rate following initial remissions, serious morbidity due to GCA, cumulative CS dose, or treatment toxicity. In the MTX group, there were fewer cases of GCA relapse heralded by symptoms of isolated polymyalgia rheumatica (1 case versus 5 in the placebo group; P = 0.05). CONCLUSION: The results of this randomized, multicenter trial do not support the adjunctive use of MTX to control disease activity or to decrease the cumulative dose and toxicity of CS in patients with GCA.

Aged↗
PubMed2002

Wegener's granulomatosis: survey of 701 patients in North America. Changes in outcome in the 1990s.

OBJECTIVE: To study the medical and socioeconomic impact of Wegener's granulomatosis (WG) in a large cohort (n = 701) of patients who are members of the international WG Support Group (WGSG). METHODS: Forty questions designed and validated by one of the authors and reviewed by the medical consultants of the WGSG International were mailed to 1690 patients with WG who are members of the WGSG; 701 (41%) patients returned the questions. Diagnosis of WG was self-reported for purpose of this questionnaire. Study domains included demographic features, education, analysis of categories of medical care providers, organ system involvement, delay in diagnosis, frequency and sites of biopsies to assist in diagnosis, treatment outcome, familial association, disability, and financial effect. We compared some of these features in patients whose diagnosis was made in the 1970s, 1980s, or 1990s. RESULTS: In our cohort WG was slightly more prevalent in women (56%), particularly if the disease started at a younger age (9-40 years). Peak age period at disease onset was 45-65 years. Ninety-eight percent of patients were Caucasian. Diagnosis of WG was usually made by a specialist, and the majority of patients received subsequent care by specialists. During the past decade only 7% of patients received a diagnosis of WG upon their first visit to a physician. A period of 3-12 months passed from onset of features of WG to achieving a diagnosis in the majority of patients. Compared to the period 1970-90, in recent years fewer patients had biopsies performed for diagnostic purposes. This observation correlated with increased use of antineutrophil cytoplasmic antibodies. In the 1990s the most common reported therapy was combination of corticosteroids and cyclophosphamide (73%). Patients also reported initial therapy with methotrexate (11%), trimethoprim-sulfamethoxa-zole (32%), and azathioprine (5%). Patients rarely reported other family members with WG. In none of 12 WG patients who had a twin did the twin have WG. The survey did not identify any specific environmental exposure, occupation, or hobby that was overrepresented among patients. One hundred seventy-nine WG patients reported that their disease had a significant financial impact on their lives. CONCLUSION: Information from this survey of 701 patients is consistent with physician reported data about organ involvement, initial manifestations and therapy, and outcomes in WG. More WG patients in the 1990s were diagnosed after first physician encounter. This survey did not reveal any predisposing or inducing environmental or familial factors, and showed fewer patients become disabled and more were able to work full time.

Adolescent↗