Home Page - About the Arthritis Center -Hopkins Rheumatology - Myositis Center - Vasculitis Center - Scleroderma Center
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| Stuart Levine, M.D.
Pathogenesis Treatments | ||
| Clinical Aspects | ||
Abstract 436 Diagnosing Fever of Unknown Origin: Magnetic Resonance Imaging Angiography Helps to Diagnose Hidden Systemic Vasculitis Abstract 438 Takayasu's Arteritis: Usefulness of Contrast-Enhanced MRI/MRA in Detecting Clinically Unsuspected Lesions Abstract 439 Ultrasound Examination of Carotid Lesions in Takayasu's Arteritis Background: Making the diagnosis of a large vessel vasculitis (especially Takayasu's Arteritis) and monitoring disease activity once the diagnosis has been made are two the great challenges in clinical rheumatology. However, early diagnosis and accurate assessments of disease activity are essential in order to institute appropriate therapy before end-organ damage results. Because early and subclinical disease manifestations are often protean and non-specific, sensitive tools, coupled with the physician's intuition, are essential for making the correct diagnosis. Since it is rarely feasible to obtain tissue from the great vessels, non-invasive biomarkers are required to properly document disease activity. There has been much interest in recent years in non-invasive imaging techniques, such as ultrasound and MRI/MRA, both to document the presence of pathology and to monitor disease progression. These 3 abstracts add additional important data to this developing field. Results: In a retrospective review of 71 patients presenting to a University hospital with a fever of unknown origin (FUO), Wagner et. al. (Abstract #436) report an increase from 8% to 42% (p=0.02) in the patients diagnosed with a systemic vasculitis following the addition of MRI/MRA of the aortic arch and carotid arteries to an already exhaustive diagnostic work-up. In a series of 10 patients previously diagnosed with Takayasu's arteritis, Kissin, et. al. (Abstract #438 and #439) found that 80% had abnormalities on MRA. Strikingly, the MRA demonstrated abnormalities in 4/6 patients with clinically suspected, and in 2/4 with clinically unsuspected active vasculitis. Most importantly, 60% of all abnormal arteries demonstrated pathology such as increased wall thickness, intramural edema, and contrast enhancement that would not be detectable by conventional angiography. These authors then compared the performance of B-mode ultrasonography of the carotid arteries vs. MRA in these same patients and found that no differences in carotid wall thickness or luminal diameter were found between those with and without clinical evidence of inflammation. Editorial Comments: Although these studies were all retrospective and evaluated small numbers of patients, their results bolster the arguments in favor of using non-invasive MRA as both a diagnostic tool in assessing patients with suspected large vessel vasculitis and for monitoring disease activity in patients with established Takayasu's arteritis. More data is needed on the utility of ultrasound in these conditions before it can be recommended routinely in the evaluation of Takayasu's Arteritis. It has become our clinical practice to obtain MRA studies of the aortic arch at regular intervals in our Takayasu's patients to assess disease activity and monitor response to therapy. Abstract 448 Cardiovascular Disease Incidence and Risk Factors in ANCA-Associated Primary Systemic Vasculitis Bakground: Patients with non-vasculitic autoimmune rheumatic diseases such as rheumatoid arthritis and SLE have a markedly increased risk of developing atherosclerotic cardiovascular disease (ASCVD). Many studies in recent years have suggested that this increased cardiovascular risk cannot be explained by an excess in traditional risk factors such as hypertension, diabetes, and hyperlipidemia in these populations. The presence of active inflammation has recently been hypothesized to be responsible for the increased risk, a notion that has been corroborated in studies of non-rheumatic ASCVD, where patients in the highest quartiles of C-reactive protein (CRP) levels have the greatest increased relative risk of developing symptomatic ASCVD. It is logical to assume that patients with vasculitis would also have an increased risk of ASCVD, but this has not been evaluated in a well-characterized group of patients to date. Results: A retrospective analysis was performed on 116 patients with documented ANCA-associated vasculitis seen at 2 University hospitals. Data on traditional ASCVD risk factors, ischemic events, potentially protective medication use such as statin therapy, and smoking were collected, and were compared to those in a previously published background population. 7/116 (6%) patients had an event (3 MI/4 CVA), which was significantly higher than the control population (p< 0.01). While the vasculitis patients had lower incidences of smoking, they were more likely to be diabetic, have hypertension, and be exposed to corticosteroids than the control population. The authors argue that the increased risk of ASCVD events cannot be explained simply on the basis of these increased risk-factors alone, and conclude that vasculitis itself is an important risk factor for the development of ASCVD. Editorial Comments: While these data support the notion that patients with active inflammatory conditions have an increased incidence of ASCVD, the retrospective nature of this data with all of the biases that this kind of analysis contains makes it hard to separate how much of an effect vasculitis itself had on the development and progression of ASCVD. Only a prospective trial with carefully collected data over several years will ultimately answer the question. Until definitive data is available, given what we know about the increased risks of ASCVD in RA and SLE patients, aggressive efforts should be undertaken to try and control both traditional risk factors and disease activity in all vasculitis patients in order to minimize the risk of adverse vascular events in this population. Abstract 1724 High Incidence of Venous Thrombotic Events Among Patients with Wegener's Granulomatosis Background: The small and medium vessel vasculitides have not been previously thought to predispose patients to an increased risk of venous thrombotic events (VTEs). However, during the recruitment phase of the WGET trial, 13 (7.2%) of the patients were found to have had a prior VTE. This surprising finding prompted the development of the Wegener's Granulomatosis Clinical Occurrence of Thrombosis (WeCLOT) study, an ancillary study of the larger WGET trial. The results of WeCLOT are presented in this abstract. Results: The incidence of VTEs in the WGET patient group was compared to that in 4 other cohorts (The Swedish male normal population, the Johns Hopkins Lupus Cohort, the Etanercept RA cohort, and a cohort of patients without rheumatic diseae but with prior VTE). The rate of VTEs was 7.0 per 100 person-years, and there were no differences between the WGET treatment and placebo groups (still blinded at the time of this study). This was markedly increased over the risk of 0.3 and 0.98 per 100 person-years in the general and SLE cohorts respectively. This increased incidence corresponded to a relative risk for the development of a VTE of 7.1 compared to SLE patients, and an incredible 23 compared to the general population and the RA Etanercept cohort. A preliminary look at classic hypercoagulable risk factors does not appear to account for the increased risk in this population. Editorial Comments: The striking increased risk of VTE in patients with Wegener's in the WGET trial raises the possibility that disease-specific changes in the venous system, including venulitis, may be responsible for the documented clot risk. A more complete assessment of hypercoagulable risk factors and of affected tissue will be required to attempt to uncover the mechanism of this association. In the meantime, based on these data, patients with Wegener's Granulomatosis should be closely monitored for the development of VTEs. | ||
| Pathogenesis | ||
Abstract 520 Dendritic Cells Indigenous to the Temporal Artery Wall Control the Breakdown of Self-Tolerance in Giant Cell Arteritis Abstract 1722 Glucocorticoid-Induced Apoptosis Leads to Reduction of Dendritic Cells in Temporal Arteries from Patients with Giant Cell Arteritis Background: Our understanding of the pathogenesis of Giant Cell Arteritis (GCA) has improved dramatically in the last several years with the discovery that antigen-specific T-cell responses are triggered within the adventitial layer of the arterial wall. This specific triggering of CD4+ cells leads clonal expansion, the release of interferon-g, and to an influx of macrophages that all contribute to the development of granulomatous inflammation and intimal hyperplasia in the affected vessels. However, despite an exhaustive search for potential infectious pathogenic triggers of GCA none has yet been found, leaving the question on how the infiltrating T-cells become activated in disease initiation unanswered. These 2 abstracts focus attention on the role that resident dendritic cells (DCs, "professional" antigen-presenting cells) in the arterial wall play in the maintenance of tolerance under normal conditions, and in disease initiation in GCA. Results: An elegant in vivo system using temporal arteries from both normal, PMR, and GCA patients implanted onto the skin of Severe Combined Immunodeficient (SCID) mice was used to study the contributions of resident cell types in the arteries to the development of inflammation (Abstract #520). The SCID system was employed as these mice lack a functional immune system; therefore any antigen-presenting cell (APC)-T cell interaction or clonal proliferation can only be derived from the graft, not from the host organism. The mice were first treated with monoclonal antibodies specific for macrophage and DC markers, as well as a variety of pro-inflammatory cytokines and chemokines. These studies identified a population of resident DCs located in the adventitial layer immediately adjacent to the external elastic lamina. Though inactive in normal grafted temporal arteries, when the mice were treated with ligands that bind and activate Toll-like receptors (activating receptors on APCs), the DCs of PMR arteries became activated and could stimulate adoptively transferred allospecific CD4+ T cells. The most dramatic observation was that DCs in PMR arteries could stimulate T cells from HLA-DR4-matched GCA arteries co-implanted in the same animal, while those from normal arteries could not. Taking these observations to the clinical setting, Wagner et al. (Abstract #1720) performed immunohistochemical analysis on 67 consecutive TA biopsies from 38 patients with GCA. They noted that steroid therapy resulted in a dramatic time-dependent decrease in DC cell number in the biopsy samples, with a significant rise in the number of apoptotic cells seen in the specimen. Editorial Comments: The findings that DCs play such an important role in the pathogenesis of GCA and are specifically depleted by therapeutic steroid treatment provide further concrete evidence that GCA is an antigen-driven autoimmune disease. These data also shed some light on the relationship between PMR and GCA; at least immunologically, PMR appears to be a truly precursor lesion to GCA. At her talk, Dr. Weyand hypothesized that resident DCs in medium sized arteries are tolerogenic under normal circumstances, being able to sample antigen locally and travel to regional lymph nodes where they can anergize potentially autoreactive T cell clones. Therefore, any failure of the DCs to tolerize properly may lead to increased local antigen-presentation, and in the setting of local inflammation in the right host, to increased T cell proliferation and tissue damage. This may also explain the "skip" nature of the GCA lesion, where DCs in different regions of the vessel are able to differentially migrate and anergize T cells. That steroids can reduce DC numbers in the lesions within 1-2 days of therapy provides the tantalizing concept that this treatment "puts out the embers" of the larger fire that is GCA, thus removing the stimulus for continued T cell proliferation and activation at its source. This promises to be an exciting area of investigation in the future, and may ultimately lead to more targeted therapies for GCA. | ||
| Treatments | ||
Abstract 1726 Randomized Trial of Cyclophosphamide Versus Methotrexate for Induction of Remission in "Non-Renal" ANCA-associated Vasculitis Background: The treatment of the ANCA-associated vasculitides (AAV) has been complicated by the heterogeneous nature of the diseases, high relapse rates, and significant drug-related toxicities. The concept of a "milder" induction regimen (ie. one that does not contain cyclophosphamide) is therefore attractive for non-life or organ-threatening disease. This trial therefore asked whether Methotrexate (MTX) could be employed to induce remission in patients with AAV with preserved renal function and non-life threatening disease at baseline. Results: One hundred patients were included in the study and were followed for 18 months. 51 were randomized to receive standard dose oral cytoxan at a dose of 2mg/kg/day and 49 were randomized to receive oral MTX at 15-25 mg/week. All received prednisone at the same dose and tapering schedule, and all drugs were withdrawn completely at 1 year. At 6 months both medications were successful at inducing disease remission (90% MTX and 94% Cytoxan); however, the relapse rates were incredibly and unacceptably high in both groups (70% MTX vs. 45% Cytoxan), with a median time to relapse from study entry between 13 and 15 months. Editorial Comments: This study raises several important practice points for the treatment of patients with AAVs. First, in patients with limited disease, remission induction with MTX is appropriate front-line therapy, and achieves a comparable remission rate to that obtained with Cytoxan at 6 months. Second, this is further evidence that MTX is a truly efficacious agent for low-risk AAV. Finally, the dangers of rapid steroid tapers (6 months or less) and cessation of all therapy at 1 year were made evident by this trial. While the optimal duration of therapy is still controversial, the high relapse rate in both groups of "low-risk" patients in this trial within 1-4 months after discontinuing therapy should give us pause. As in RA, it appears that if patients with AAV are in remission and are tolerating MTX well, they should likely be maintained on this regimen for longer than 1 year, and possibly indefinitely. | ||
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