Vasculitis. A collection of pearls and myths.

Important strides have been made in unraveling the pathophysiologic characteristics of some individual forms of vasculitis, but vasculitides continue to pose enormous challenges for clinicians. Over time, numerous myths and an occasional pearl have arisen from the care of patients with these disorders. In this collection of pearls and myths, we have attempted to pool our knowledge about the clinical care of vasculitis patients.

Treatment of Wegener's granulomatosis.

The two principal aims in the treatment of Wegener's granulomatosis (WG) are to limit the extent and severity of permanent organ damage by controlling the disease promptly and to minimize the short- and long-term morbidity that often results from therapy. Remission is considered to be the absence of disease activity in any organ system. Once the disease has been controlled by the initial treatment regimen, which is dictated by the degree of disease severity, the focus of therapy shifts to maintaining disease remission, often with medications less toxic than those used to induce remission. The description of WG treatments in terms analogous to cancer chemotherapy (i.e., those designed to induce remissions and those intended to maintain them) is useful in the formulation of current disease management strategies and in the investigation of new therapies for WG.

Three-dimensional volume-rendering CT angiography in vasculitis: spectrum of disease and clinical utility.

Spiral computed tomographic angiography (CTA) coupled with three-dimensional volume-rendering image processing is a less invasive alternative to conventional catheter angiography. The technique has been used successfully in a variety of vascular diseases. In this pictorial essay, we review the CTA findings in selected cases of vasculitis. Technical considerations and the potential clinical value of this method are discussed.

Reliability of normal findings on MR imaging for excluding the diagnosis of vasculitis of the central nervous system.

OBJECTIVE: We attempt to determine whether angiography is indicated in patients with suspected central nervous system (CNS) vasculitis who present with negative findings on MR imaging studies. CONCLUSION: MR imaging findings may be negative in the setting of CNS vasculitis confirmed on angiography, indicating that advanced imaging techniques tailored to detect infarction (i.e., fluid-attenuated inversion recovery, diffusion-weighted, and perfusion imaging) may be necessary to enhance the sensitivity of an MR study and that despite the high sensitivity of MR imaging for CNS vasculitis, angiography may still be required to render an accurate diagnosis.

Large artery vasculitis following recombinant hepatitis B vaccination: 2 cases.

We describe 2 women who developed large artery vasculitis shortly after receiving recombinant hepatitis B vaccination. One patient developed Takayasu's arteritis, the other a vasculitis involving subclavian and renal arteries. Both developed renal failure. Whether the vasculitis was caused by the vaccination is not known. Although small vessel vasculitis following hepatitis B vaccination has been reported a number of times, large vessel vasculitis associated with hepatitis B vaccination has been reported only once. These cases suggest that large artery vasculitis should be added to the list of possible side effects of hepatitis B vaccination.

Etanercept combined with conventional treatment in Wegener's granulomatosis: a six-month open-label trial to evaluate safety.

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.

A disease-specific activity index for Wegener's granulomatosis: modification of the Birmingham Vasculitis Activity Score. International Network for the Study of the Systemic Vasculitides (INSSYS).

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.

Primary angiitis of the central nervous system and Alzheimer's disease: clinically and pathologically evident in a single patient.

Two years after being successfully treated for biopsy confirmed primary angiitis of the central nervous system (PACNS), a 69-year-old woman presented with cognitive decline. In contrast to her first presentation, her altered mental function developed gradually, was not associated with headache or abnormal cerebrospinal fluid analysis, and did not improve with immunosuppression. Reevaluation of her original brain biopsy not only confirmed the presence of PACNS, but also revealed neuritic plaques and neurofibrillary tangles, suggesting a concurrent diagnosis of Alzheimer's disease. Cerebral angiogram did not suggest vasculitis and magnetic resonance imaging showed generalized cerebral atrophy supporting the diagnosis of Alzheimer's. This case illustrates that Alzheimer's dementia and PACNS can coexist in a single patient and that Alzheimer's disease should be considered when a patient with successfully treated PACNS presents with cognitive decline months or years after initial diagnosis.

Test characteristics of immunofluorescence and ELISA tests in 856 consecutive patients with possible ANCA-associated conditions.

OBJECTIVE: To examine the test characteristics of immunofluorescence (IF) and enzyme-linked immunosorbent assays (ELISA) in a consecutive series of patients under evaluation for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Using stored sera, we performed a cross-sectional study on 856 consecutive patients tested prospectively for ANCA by IF, Based on guidelines from the 1994 Chapel Hill Consensus Conference (CHCC), we determined each patient's underlying diagnosis by a medical records review without regard to their ANCA status (the CHCC guidelines do not require ANCA as a prerequisite for diagnosis). We grouped patients with forms of vasculitis commonly associated with ANCA into one of 4 types of AAV: Wegener's granulomatosis (n = 45), microscopic polyangiitis (n = 12), Churg-Strauss syndrome (n = 4), and pauci-immune glomerulonephritis (n = 8). We also classified patients without clinical evidence of AAV (92% of all patients tested) into 5 predefined categories of disease (including "other") and an additional category for no identifiable disease. In a blinded fashion, we then performed ELISAs on the stored serum for antibodies to proteinase-3 (PR3) and myeloperoxidase (MPO) and calculated the test characteristics for both ANCA assay techniques. RESULTS: Sixty-nine of the 856 patients (8.1%) had clinical diagnoses of AAV based on CHCC guidelines. The positive predictive value (PPV) of ELISA for AAV was superior to that of IF, 83% versus 45%. For patients with both positive IF tests and positive ELISA tests, the PPV increased to 88%. Both IF and ELISA had high negative predictive values (97% and 96%, respectively). Positive ELISA tests were associated with higher likelihood ratios (LR) than IF (54.2 [95% CI = 26.3, 111.5] versus 9.4 [95% CI = 6.9, 12.7]). The LR of both a positive IF and a positive ELISA was 82.1 (95% CI = 33.3, 202.5). CONCLUSIONS: Compared with IF, an ELISA test fo ANCA was associated with a substantially higher PPV and LR for AAV. This fact, combined with the greater sensitivity of IF, suggests that an effective testing strategy is to perform ELISA tests only on samples that are positive for ANCA by IF.

Validity of a vasculitis activity index for systemic necrotizing vasculitis.

OBJECTIVE: To establish the validity of an index designed to measure activity in systemic necrotizing vasculitis (SNV). METHODS: The Vasculitis Activity Index (VAI) was designed to incorporate appropriately weighted clinical measurements that reflect disease activity in SNV. We performed a pilot study to guide the modification and subsequent testing of the initial design. The data necessary to calculate the VAI are direct ratings by a clinical observer of the degree of activity in 9 organ systems and 3 indirect measures of vasculitis activity. These data are recorded on 0-4 visual analog scales. Physician's global assessment (PGA) is used as the "gold standard" measurement of disease activity. The VAI was validated using 2 independent data sets: the questionnaire data set, derived from test case histories ("paper cases") sent to 100 practicing rheumatologists, and the clinic data set, obtained from use of the VAI in 204 regular care visits of 74 patients with SNV. RESULTS: The VAI correlated highly with the PGA: Pearson's correlation coefficient R = 0.84 (95% confidence interval [95% CI] 0.80-0.88) for the questionnaire data set, and R = 0.92 (95% CI 0.90-0.94) for the clinic data set. The mean of the interobserver coefficients of variation for the test case histories was lower for the VAI than for the PGA (mean difference 0.45; P = 0.002), indicating that the VAI has less interobserver variation than does the PGA. The change in VAI between clinic visits for individual patients correlated highly with the change in PGA (R = 0.88, 95% CI = 0.83-0.91). The VAI data collection form requires about 1 minute to complete, including computation of the score. CONCLUSION: The VAI is a valid measure of vasculitis activity that correlates highly with the PGA. In addition, the VAI has less interobserver variation than the PGA and has a high level of sensitivity to change over time. Additional testing of the VAI appears warranted.

A pilot study of peer review in residency training.

OBJECTIVE: To explore the utility of peer review (review by fellow interns or residents in the firm) as an additional method of evaluation in a university categorical internal medicine residency program. DESIGN/PARTICIPANTS: Senior residents and interns were asked to complete evaluations of interns at the end-of-month ward rotations. MAIN RESULTS: Response rates for senior residents evaluating 16 interns were 70%; for interns evaluating interns, 35%. Analysis of 177 instruments for 16 interns showed high internal consistency in the evaluations. Factor analysis supported a two-dimensional view of clinical competence. Correlations between faculty, senior resident, and intern assessments of interns were good, although varied by domain. CONCLUSIONS: An end-of-year attitude survey found that residents gave high ratings to the value of feedback from peers.

Diaphragmatic paresis as a manifestation of large artery vasculitis.

We describe the initial presentation and followup of a 54-year-old Caucasian woman who presented in 1995 with bilateral arteritis of the axillary arteries and acute onset dyspnea. Chest radiograph, chest fluoroscopy, and pulmonary function studies confirmed the diagnosis of right hemidiaphragmatic paresis. Prednisolone and methotrexate therapy and short term anticoagulation were initiated and she experienced no further sequelae during 2 years of followup.

Cogan's syndrome with refractory abdominal aortitis and mesenteric vasculitis.

Cogan's syndrome is a rare multisystem disease characterized by ocular inflammation, vestibuloauditory dysfunction, and vasculitis. We report a 26-year-old Caucasian woman who died from Cogan's syndrome. Her case illustrates that patients with Cogan's syndrome can have abdominal aortitis and mesenteric vasculitis, and that the vasculitis can be refractory to methotrexate, cyclophosphamide, cyclosporine, and chlorambucil.

Bilateral ocular ischemic syndrome secondary to giant cell arteritis progressing despite corticosteroid treatment.

PURPOSE: To report the development of a bilateral ocular ischemic syndrome despite corticosteroid treatment in a patient with giant cell arteritis. METHOD: Case report. RESULTS: Despite receiving high-dose intravenous methylprednisolone and oral prednisone for biopsy-proven giant cell arteritis that presented as a severe anterior ischemic optic neuropathy in the right eye, a patient developed progressive ocular ischemia in that eye as well as an ocular ischemic syndrome in the fellow eye. CONCLUSIONS: Some patients with giant cell arteritis, possibly patients with other underlying systemic vasculopathies, are refractory to what should be adequate treatment with systemic corticosteroids and may develop a bilateral ocular ischemic syndrome.

CNS vasculitis in autoimmune disease: MR imaging findings and correlation with angiography.

BACKGROUND AND PURPOSE: MR findings in CNS vasculitis and their correlation with angiography have not been clearly defined. We therefore explored three hypotheses regarding CNS vasculitis associated with autoimmune disease: 1) MR imaging is highly sensitive; 2) a typical MR appearance exists; and, 3) MR and angiographic findings correlate well. METHODS: We studied 18 patients with CNS vasculitis associated with autoimmune disease, characterized the MR lesions by type, size, number, and location, and correlated the MR findings with those of angiography. RESULTS: All patients with CNS vasculitis had abnormalities on MR studies. On average, four +/- two lesions per patient were detected on MR images. The lesions were located in the subcortical white matter (n = 20), cortical gray matter (n = 16), deep gray matter (n = 16), deep white matter (n = 9), and cerebellum (n = 9). Only 65% of MR lesions were evident on angiograms; 44% of the lesions revealed on angiograms were detected by MR. CONCLUSION: MR imaging is sensitive for CNS vasculitis. Lesions attributable to CNS vasculitis in autoimmune disease are distributed nearly equally among cortical, subcortical, and deep gray matter structures. The modest correlation between MR imaging and angiography suggests that the two techniques provide different information about CNS vasculitis and that both types of studies are needed for the complete assessment of damage caused by vascular abnormalities.

Development and evaluation of a coordinated, ambulatory rheumatology experience for internal medicine residents.

OBJECTIVE: To develop a compulsory ambulatory rotation in rheumatology for internal medicine residents and to evaluate the educational effect of this rotation. METHOD: All year 2 residents in the program participated in the rotation. The perceived quality of the learning experience was assessed by resident self-evaluation using a visual analog scale. Residents used a similar scale to rate their confidence in managing common rheumatologic problems. A validated multiple choice test was used to measure pre- and post-rotation knowledge of rheumatology and skill in interpreting bone radiographs. RESULTS: On a 1 (no learning) to 5 (superior learning) scale, the mean rating of the rheumatology learning experience was 4.7 +/- 0.5. Residents' confidence in clinical skills significantly increased as well. Scores on the post-rotation rheumatology knowledge test increased 15% compared with pre-rotation scores (P < 0.0001). Confidence and skills in interpreting bone radiology films also significantly improved (P < 0.0001 for both items). CONCLUSION: A relatively brief, subspecialty ambulatory rotation can be developed to expose all residents to a rheumatology curriculum. Such a rotation can increase their confidence, knowledge, and skills in important domains of outpatient rheumatology.