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Gary S Hoffman

Publications and source records attributed to Gary S Hoffman.

At least 19 recordsLinked to original sources
PubMed2007

Controversies in small vessel vasculitis--comparing the rheumatology and nephrology views.

Over the past 20 years, remarkable progress has been made in understanding the pathogenesis and treatment of patients with small vessel vasculitis. Nephrologists and rheumatologists play primary roles in the care of these patients. Whilst there are many areas of agreement between these specialists with respect to understanding and practical care of these patients, there are a number of important areas that differ in the practice patterns of nephrologic and rheumatologic practice. These areas include the nomenclature of these diseases, the role of antineutrophil cytoplasmic antibodies in the pathogenesis, the route and duration of initial cyclophosphamide administration, and, most importantly, the total duration of maintenance therapy following disease remission. Two experienced clinicians, a rheumatologist and a nephrologist, spar off in support of their opinions.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2006

Solid malignancies among patients in the Wegener's Granulomatosis Etanercept Trial.

OBJECTIVE: Etanercept is a soluble fusion protein designed to inhibit tumor necrosis factor (TNF). During the Wegener's Granulomatosis Etanercept Trial (WGET), a placebo-controlled trial of etanercept given in addition to standard therapy for remission induction and maintenance, more solid malignancies were observed in the etanercept group than in the group treated with standard therapy alone. This study was undertaken to further explore the potential association between anti-TNF therapy and the development of malignancy in these patients. METHODS: One hundred eighty patients with active WG were enrolled and followed up for a median of 27 months. At enrollment, disease characteristics, treatment history, specific medical history items, and information about previous WG treatments and risk factors for malignancy were recorded. During the trial, the occurrence of malignancies and other adverse events was recorded prospectively. RESULTS: All 6 solid malignancies observed during the WGET occurred in the etanercept group (P = 0.01 versus placebo group); based on a comparison of age- and sex-specific incidence rates, 1.92 solid malignancies would have been expected in this group. The solid malignancies included 2 cases of mucinous adenocarcinoma of the colon, 1 each of metastatic cholangiocarcinoma, renal cell carcinoma, and breast carcinoma, and 1 recurrent liposarcoma. There were no differences between the 2 treatment groups in sex distribution, disease severity, personal or family history of cancer, or tobacco and alcohol use. The etanercept group was older at baseline and less likely to be newly diagnosed with WG at the time of randomization. Patients who developed solid tumors were older than patients who did not. All etanercept-treated patients who developed solid tumors were also treated with cyclophosphamide during the trial. However, there were no differences between the groups in the amount of cyclophosphamide received during the trial or the percentage who had received cyclophosphamide before enrollment. There were also no differences in the mean duration of daily cyclophosphamide therapy or the maximum daily cyclophosphamide dosage before enrollment. CONCLUSION: Data from the WGET, the first substantial reported experience of the combined use of etanercept and cyclophosphamide in the treatment of WG, indicate that the combination of TNF inhibition and cyclophosphamide may heighten the risk of cancer beyond that observed with cyclophosphamide alone.

Aged↗
PubMed2006

Antiplatelet and anticoagulant therapy in patients with giant cell arteritis.

OBJECTIVE: Vision loss and cerebrovascular accidents often complicate giant cell arteritis (GCA). Antiplatelet and anticoagulant therapy reduce the risk of stroke in other populations. We sought to determine whether antiplatelet or anticoagulant therapy reduces ischemic complications in patients with GCA. METHODS: A retrospective chart review for patients with GCA was conducted. Included patients fulfilled modified 1990 American College of Rheumatology criteria for GCA. Collected information included demographic data, dates of antiplatelet or anticoagulant use, vision loss or stroke, and presence of bleeding complications and cerebrovascular risk factors. RESULTS: A total of 143 patients were included with a mean followup period of 4 years. The cohort included 109 women (76%) and 34 men (24%) with a mean age of 71.8 years. A total of 104 patients (73%) had a biopsy-proven diagnosis. Eighty-six patients (60.1%) had received long-term antiplatelet or anticoagulant therapy, including 18 (12.6%) who did not start therapy until after an ischemic event had occurred. Antiplatelet agents or anticoagulants were not used in 57 patients (39.9%). Overall, 11 of 68 patients (16.2%) had an ischemic event while receiving antiplatelet or anticoagulant therapy, compared with 36 of 75 patients (48.0%) not receiving such therapy (P < 0.0005). Univariate analysis failed to show a statistical difference between groups in regard to cerebrovascular risk factors, age, sex, or biopsy-proven diagnosis. Bleeding complications occurred in 2 patients receiving aspirin, 1 patient receiving warfarin, and 5 patients who did not receive anticoagulant or antiplatelet therapy. CONCLUSION: Antiplatelet or anticoagulant therapy may reduce the risk of ischemic events in patients with GCA. An increased risk of bleeding complications was not observed.

Aged↗
PubMed2005

Brief communication: high incidence of venous thrombotic events among patients with Wegener granulomatosis: the Wegener's Clinical Occurrence of Thrombosis (WeCLOT) Study.

BACKGROUND: Venous thrombotic events (VTEs) have been observed in Wegener granulomatosis, but the incidence rate is not known. OBJECTIVE: To measure the incidence of VTEs in patients with Wegener granulomatosis. DESIGN: Prospective, observational cohort study. SETTING: A multicenter, randomized, double-blind, placebo-controlled treatment trial for Wegener granulomatosis. PATIENTS: 180 patients with Wegener granulomatosis enrolled during periods of active disease. MEASUREMENTS: Venous thrombotic events (deep venous thromboses or pulmonary emboli) were documented and confirmed prospectively. Incidence rates were calculated on the basis of time to first VTE. RESULTS: Thirteen patients had VTEs before enrollment. During 228 person-years of prospective follow-up, 16 VTEs occurred in 167 patients with no history of VTE. Median time from enrollment to VTE for patients with an event was 2.1 months. The incidence of VTE among patients with Wegener granulomatosis was 7.0 per 100 person-years (95% CI, 4.0 to 11.4). LIMITATIONS: Although prospectively recorded, screening for VTEs did not occur. CONCLUSIONS: The incidence rate of VTEs in Wegener granulomatosis is high when compared with available rates in the general population, patients with lupus, and patients with rheumatoid arthritis. These results have important implications for clinical care of patients with Wegener granulomatosis.

Double-Blind Method↗
PubMed2005

A serum proteomic approach to gauging the state of remission in Wegener's granulomatosis.

OBJECTIVE: To identify serum ion patterns that distinguish remission from active disease in patients with Wegener's granulomatosis (WG). METHODS: Using sera collected in the WG Etanercept Trial, we selected samples from patients who either were undergoing a period of extended disease remission or had recent flares of active WG. Unfractionated samples were randomized into sets for training and testing, such that remission sera and active disease sera could be analyzed without batch bias. Molecular species within the sera were ionized by high-resolution, matrix-assisted laser desorption ionization time-of-flight mass spectrometry. We then used a bioinformatics pattern-recognition tool to identify optimal combinations of ions. During the training stage, the clinical data (remission versus active disease) were provided in association with the spectral data from each sample. In the testing stage, we performed blinded testing on a previously unexamined set of samples. RESULTS: The most robust model, trained on a total of 82 samples (42 remission, 40 active disease), included 7 key ions with mass:charge ratios of 803.239, 2,171.672, 2,790.574, 3,085.237, 5,051.726, 5,833.989, and 6,630.465. The combined relative amplitudes of these 7 ions identified 5 distinct clusters of either remission or active disease samples during the training stage. In the testing stage, this model segregated 72 samples into the same 5 clusters, including 1 large remission cluster (n = 28) and another large active disease cluster (n = 32). Three smaller clusters of active disease or remission samples were also identified, with remission clusters populated by 2 samples in one cluster and 8 in another, and an active disease cluster populated by 2 samples. The model categorized 35 of 37 remission samples correctly (sensitivity 95%, 95% confidence interval [95% CI] 82.1-99.4) and 32 of 35 active disease samples correctly (specificity 91%, 95% CI 78.1-98.1). CONCLUSION: This serum proteomic profiling approach appears to be useful in distinguishing between states of stable clinical remission and active disease. Further validation and refinement of this strategy may help clinicians apply immunosuppressive therapies more judiciously among their patients, thereby avoiding morbidity and mortality from excessive treatment. Identification of the most robust and clinically useful combinations of ions will permit the rational selection of molecules for sequencing and analysis.

Antirheumatic Agents↗
PubMed2005

Damage caused by Wegener's granulomatosis and its treatment: prospective data from the Wegener's Granulomatosis Etanercept Trial (WGET).

OBJECTIVE: To analyze damage occurring in patients with Wegener's granulomatosis (WG) enrolled in the WG Etanercept Trial (WGET) and to correlate that damage with disease activity, adverse events, and quality of life. METHODS: The Vasculitis Damage Index (VDI) was applied to all 180 patients at trial entry and every 6 months throughout the trial. Items of damage were analyzed by presumed etiology (i.e., secondary to WG, to therapy, or both) and time of occurrence. Spearman's rank correlation coefficients were calculated between VDI scores and the Birmingham Vasculitis Activity Score for WG (BVAS/WG), frequency of flares, number of adverse events, and the patients' quality-of-life assessments. RESULTS: The mean VDI score was 1.3 at the study enrollment and 1.8 at the end of the trial. This increase was due to damage that occurred despite (or because of) therapy, including visual impairment, hearing loss, nasal blockade, pulmonary fibrosis, hypertension, renal insufficiency, peripheral neuropathy, gonadal failure, and diabetes mellitus. Only 11% of the enrolled patients had not sustained a single VDI item after 1 year of enrollment. When adjusted for baseline VDI, the baseline BVAS/WG correlated moderately well with the VDI score at 1 year (r = 0.20, P = 0.015). Increases in adjusted VDI scores also correlated with the number of adverse events, particularly among patients with limited WG (P = 0.06). CONCLUSION: Damage from both active disease and its treatment remain important problems for patients with WG. Despite the dramatic improvements in patient survival achieved over the last several decades, only a few patients with WG emerge from a period of active disease without sustaining some damage from the disease itself, its treatment, or both. An important measure of future therapeutic approaches will be their ability to reduce the damage accrued over time.

Double-Blind Method↗
PubMed2005

Herpes zoster in immunocompromised patients: incidence, timing, and risk factors.

PURPOSE: To evaluate the risk factors for herpes zoster as well as the incidence and timing of this complication in patients who were treated with immunosuppression because of active Wegener's granulomatosis. SUBJECTS AND METHODS: We studied the 180 Wegener's granulomatosis patients in the Wegener's Granulomatosis Etanercept Trial (WGET). Herpes zoster events during WGET were documented prospectively. Follow-up questionnaires were employed to describe the location, treatment, and complication(s) of herpes zoster and its therapy. Univariate and multivariate analyses were performed to evaluate risk factors, including history of herpes zoster, for the occurrence of herpes zoster during the trial. All analyses were based on the time to first occurrence of herpes zoster. RESULTS: Eighteen patients (10% of the WGET cohort) suffered a total of 19 herpes zoster episodes over a mean follow-up period of 27 months. The annual incidence of herpes zoster in the WGET cohort was 45 cases/1000 patient-years (95% confidence interval [CI]: 27, 70). The median time from enrollment to the occurrence of herpes zoster in the subgroup of patients with that complication was 16.5 months (+/- 9.4). Fifteen of the 19 herpes zoster events (79%) occurred between months 6 and 36, many months after the period of most intensive immunosuppression. In univariate analyses, history of serum creatinine > or =1.5 mg/dL before enrollment was associated with a relative risk (RR) of 3.0 (95% CI: 1.1, 7.8) for herpes zoster during WGET (P=.03). In multivariate analyses, serum creatinine > or =1.5 mg/dL was associated with an RR of 6.3 (95% CI: 2.0, 19.8; P=.002), and female sex with an RR of 4.6 (95% CI: 1.6, 13.2; P=.004). CONCLUSION: Renal dysfunction and female sex were consistently strong risk factors for herpes zoster events in this population. Contrary to expectation, most herpes zoster events did not occur during periods of most intensive immunosuppression. These data may inform studies of interventions designed to prevent herpes zoster in patients on treatment for immune-mediated diseases.

Adolescent↗
PubMed2005

Advances in the medical and surgical treatment of Takayasu arteritis.

PURPOSE OF REVIEW: Takayasu arteritis remains a therapeutic challenge. In spite of current treatments, progression of vascular lesions is observed frequently. The purpose of this article is to describe advances in therapeutic strategies for Takayasu arteritis. RECENT FINDINGS: Immunosuppressive agents including methotrexate, mycophenolate mofetil, and azathioprine added to corticosteroids can bring Takayasu arteritis into remission in many patients. Unfortunately, relapse is common when prednisone is tapered to dosages of 15 mg/day or less. A better understanding of pathogenesis has lead to trials with anti-tumor necrosis factor-alpha agents in patients with refractory disease. Preliminary results are encouraging. For patients who require revascularization intervention, both surgical and endovascular procedures can be performed that are safe, with low morbidity and mortality. The best long-term outcomes are achieved with conventional bypass grafts. Percutaneous transluminal angioplasty provides good results for short lesions. In contrast to the results in treating atherosclerosis, the use of conventional stents may not yield long-term vessel patency in Takayasu arteritis. Persistent inflammation and endothelial dysfunction may put patients with Takayasu arteritis at risk for premature atherosclerosis. SUMMARY: In the future, greater therapeutic success may be achieved by addressing both the inflammatory and the myointimal proliferative components of Takayasu arteritis. New drugs that target intimal hyperplasia, as well as drug-eluting stents, deserve to be studied for possible utility as adjuncts to present treatments.

Combined Modality Therapy↗
PubMed2005

Determinants of vessel targeting in vasculitis.

Studies of autoimmune diseases have not yet elucidated why certain organs or vessels become the objects of injury while others are spared. This paper explores the hypothesis that important differences exist in regions of the aorta; these regional variations determine vulnerability to such diseases as atherosclerosis, aortitis, giant-cell arteritis, and Takayasu's disease. The reader is invited to reassess two issues: (1) whether the aorta is indeed a single homogeneous structure; and (2) whether the initial stage of aortitis (and indeed other diseases considered "autoimmune") may primarily be the result of acquired alterations of substrate that influence unique immune profiles, but that by themselves may not be pathogenic. Disease susceptibility and patterns are influenced by many factors that are either inborn or acquired. Examples include genetic background, gender, ethnicity, aging, prior and concomitant illnesses, habits, diet, and exposure to toxins and other environmental hazards. Studies of vascular diseases must assess how such variables affect regional anatomic differences in endothelial cells, subendothelial matrix, and vascular smooth muscle, as well as the response of each to a variety of stimuli.

Aging↗
PubMed2005

Current status of outcome measures in vasculitis: focus on Wegener's granulomatosis and microscopic polyangiitis. Report from OMERACT 7.

The complexity of assessing disease activity, disease status, and damage in the vasculitides reflects the multisystemic pathologic manifestations of these often chronic illnesses. Major progress has been made in the past decade in the development of validated and widely accepted outcome measures for use in clinical trials. Over time, these tools have been regularly revised, expanded, and supplemented with new measures of disease prognosis and damage. As a result clinical research in this area has become increasingly complex. This article critically reviews the current status of tools for assessing disease activity and damage in "ANCA-associated" vasculitides (Wegener's granulomatosis and microscopic polyangiitis), summarizes the current level of validation of each measure, addresses central problems and controversies to be considered during development of new vasculitis assessment tools, and proposes a series of research agendas for consideration by the vasculitis research community.

Clinical Trials as Topic↗
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

Large-vessel vasculitis.

The vasculitides affecting large and medium-sized vessels are heterogeneous. This group includes such disorders as giant cell arteritis, Takayasu's disease, and sarcoidosis. There are several challenges that may arise in the care of patients with these disorders. Diagnosis may be elusive when initially evaluating patients with large-vessel vasculitis. Most serologic markers are not specific, and tissue biopsy is often impractical. We will present data emphasizing the most common disease manifestations, to aid in recognition of a clinical picture suggestive of large-vessel vasculitis. We will also focus on the more common pulmonary manifestations and minimize case reports, which may not reflect the usual course of disease. Large cohort studies and randomized controlled trials to provide an evidence-based approach to therapy in these disorders are uncommon. We have included in this review discussion of those studies that we judged to be most rigorously conducted and clinically relevant. We provide guidelines for initial therapy, with caveats to assist in minimizing potential treatment-related complications and toxicities. Although monitoring of disease activity is often difficult, this is a most crucial element in minimizing disease and treatment-associated morbidity and mortality.

Journal Article↗
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↗