David B. Hellmann

A disease-specific activity index for Wegener's granulomatosis: Modification of the Birmingham Vasculitis Activity Score

OBJECTIVE To refine and validate the Birmingham Vasculitis Activity Score (BVAS) as a disease-specific activity index for Wegeners 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 physicians global assessment (PGA) of disease activity were high, even when patients in remission were excluded. In the clinical case series, Spearmans 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.

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 Wegeners 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.

Fatal Infections in Systemic Lupus Erythematosus: The Role of Opportunistic Organisms

The causes of death were examined in patients with systemic lupus erythematosus (SLE) who were cared for at the University of California, San Francisco and who died after 1969. Of the 44 deaths analyzed, 33 patients had autopsies. Infections were common and often determined to be the cause of death. Overall, infections were present in 55 percent (22/44), and judged to be a cause of death in 30 percent (13/44) of all deaths. The infections could be divided into 2 groups: those due to common bacterial organisms and those due to opportunistic infections. These two types of infections occurred with similar frequency. When compared to common bacterial infections, however, the opportunistic infections were more likely to be first diagnosed at autopsy (p = .001). In only 3 of the 15 patients with an opportunistic infection was the diagnosis made antemortem. Failure to diagnose an opportunistic infection early occurred when the infection simulated active SLE, and when the possibility of an opportunistic infection was not aggressively investigated. The most common opportunistic infections were Candida albicans and Pneumocystis carinii. The most common site of opportunistic infection was the lung. Seventeen patients had 27 common bacterial infections, chiefly sepsis from Staphylococcus aureus and aerobic gram-negative organisms. Eight patients had both a common bacterial and an opportunistic infection. Stepwise linear regression analysis showed that death from infection correlated most strongly with prednisone and cytotoxic drug use in the 3 months before final admission. No measure of lupus activity was found to correlate with death from infection, except that hypocomplementemia correlated with death from bacterial infections.(ABSTRACT TRUNCATED AT 250 WORDS)

Foot and Ankle Problems in Rheumatoid Arthritis

The purpose of this study was to examine the prevalence of foot and ankle problems in 99 patients with clinically proven rheumatoid arthritis. Patients were recruited from outpatient rheumatology clinics; no attempt was made to select patients on the basis of the severity of their disease, duration of disease, or symptom constellation. Each patient was examined by an investigator utilizing a predesigned protocol to assess their functional status, functional capacity, and overall joint involvement. Ninety-three of 99 patients had complaints referable to the foot or ankle at some time since diagnosis of rheumatoid arthritis. Ankle problems were paramount in 42%, forefoot difficulties in 28%, and equal ankle and forefoot problems in another 14%. Only four patients had had any treatment involving foot orthotic devices or special shoe wear. The prevalence of foot and ankle symptoms was related to the duration of systemic illness, but was present in > 50% of patients at any time after diagnosis of rheumatoid arthritis. Patients with longstanding rheumatoid arthritis have a high prevalence of foot and ankle symptoms. Unlike previous reports, the present study found a high prevalence of ankle and hindfoot symptoms, as opposed to forefoot complaints. Despite this finding, the patients had been treated infrequently by either conservative nonoperative management directed at accommodating footwear or surgical intervention to favorably alter their foot and ankle mechanics.

The Frequency of Lupus Anticoagulant in Systemic Lupus Erythematosus: A Study of Sixty Consecutive Patients by Activated Partial Thromboplastin Time, Russell Viper Venom Time, and Anticardiolipin Antibody Level

Recent reviews have suggested a higher frequency of the lupus anticoagulant or related antiphospholipid antibodies in patients with systemic lupus erythematosus (21% to 65%) than was found in earlier studies (6% to 18%). In our study of 60 consecutive patients, we found the frequency of the lupus anticoagulant by Russell viper venom time was 6.7% (95% confidence interval, 16.2 to 1.8) and by anticardiolipin antibody assay was 25% (95% Cl, 37.0 to 15.7), compared with 0% (p = not significant) and 2.5% (p = 0.002), respectively, in the normal control population. The Russell viper venom time (p = 0.0001 by t-test) and anticardiolipin antibody levels (p = 0.01) were significantly associated with presumed thrombotic events (stroke, deep venous thrombosis, and digital gangrene). No association with miscarriage or pulmonary hypertension was detected. The Russell viper venom time was more specific than the anticardiolipin antibody level in the prediction of past presumed thrombotic events, miscarriage, or pulmonary hypertension (100% compared with 84%, p = 0.01).

Gastrointestinal involvement in polyarteritis nodosa (1986–2000):: Presentation and outcomes in 24 patients

PURPOSE Gastrointestinal involvement in polyarteritis nodosa carries a poor prognosis. A 1982 review from our institution reported acute abdominal syndromes in 31% of patients with polyarteritis nodosa, and that all 5 patients with acute surgical abdomens died. We reviewed our more recent experience to determine if outcomes have changed since. SUBJECTS AND METHODS We reviewed the records of all patients with polyarteritis nodosa in our vasculitis database between 1986 and 2000. Inclusion criteria were a diagnosis of polyarteritis nodosa, symptoms or signs of gastrointestinal involvement, and either a mesenteric angiogram consistent with polyarteritis nodosa or histopathologic proof of a medium-vessel vasculitis. We calculated a prognostic (5 factor) score for all patients. RESULTS We identified 24 patients with polyarteritis nodosa who had gastrointestinal involvement during their illness. Thirteen (54%) of the patients developed acute surgical abdomens, 3 of whom died (P = 0.02 by comparison with the historical cohort). Mean (+/- SD) prognostic scores were higher among patients in the acute abdomen group compared with those who did not have acute abdominal syndromes (1.7 +/- 0.9 vs. 0.6 +/- 0.7, P = 0.002), corresponding with the observed mortality in these groups. CONCLUSION Gastrointestinal involvement occurs commonly in polyarteritis nodosa and carries a poor prognosis. Compared with a historical cohort at our institution, mortality from this complication may have decreased, perhaps because of earlier diagnosis.

Giant cell arteritis

Giant cell arteritis (GCA), the most common form of systemic vasculitis in adults, preferentially involves large and medium-sized arteries in patients over the age of 50. The classic manifestations are headache, jaw claudication, polymyalgia rheumatica (PMR), and visual symptoms, but 40% of patients present with a wide range of occult manifestations. Early diagnosis and treatment with prednisone can prevent blindness, the most feared complication of GCA. The pathogenesis of GCA is T-cell dependent and antigen driven. Clinical subsets of GCA appear to result from variable cytokine expression. The risk of developing thoracic aortic aneurysm is increased more than 17-fold in patients with GCA. GCA can also involve large arteries, especially the subclavian and axillary arteries. Color Doppler ultrasound, magnetic resonance imaging, and positron-emission tomography scanning are providing insights into the extent and pathogenesis of the disease but have not replaced temporal artery biopsy as the gold standard for securing the diagnosis. Two recently completed double-blind, placebo-controlled trials concerning whether methotrexate plus prednisone is more effective than prednisone alone reached conflicting conclusions.

Posterior tibial tendon dysfunction in rheumatoid arthritis.

Although hindfoot pathology in rheumatoid arthritis is a significant cause of disability for patients, the etiology of the planovalgus deformity is controversial. The present study surveys 99 patients with clinically proven rheumatoid arthritis for the presence and severity of hindfoot pathology. Specific attention was directed at the function of the posterior tibial tendon, as disruption of this structure has been implicated by some investigators as a cause of hindfoot deformity in rheumatoid arthritis. Assessment of posterior tibial function was by manual testing using two different grading scales, as well as by examination for several signs associated with posterior tibial tendon dysfunction. Between 13% and 64% of the study population could be considered to have posterior tibial tendon dysfunction, depending upon the specific diagnostic criteria used. Using the presence of all three of the most stringent criteria for diagnosis, 11% of patients were believed to have posterior tibial tendon dysfunction. These criteria were loss of the longitudinal arch, inability to perform a heel-rise, and lack of a palpable posterior tibial tendon. This study demonstrates that planovalgus deformity in rheumatoid arthritis can be due to clinically evident dysfunction of the posterior tibial muscle-tendon unit. There is a complex interplay between hindfoot joint disruption due to the inflammatory process and deformity due to tendinous dysfunction. If there is primary subtalar joint instability secondary to the inflammatory process, the posterior tibial tendon is rendered dysfunctional due to deranged hindfoot mechanics, as with primary posterior tibial tendon rupture. Since treatment of either condition (i.e., primary hindfoot instability or primary posterior tibial tendon rupture) is similar, the distinction is not important clinically. What is important is that attention to the specific cause of planovalgus would be expected to improve the overall treatment of rheumatoid feet.

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.

Mononeuritis multiplex: The yield of evaluations for occult rheumatic diseases

We identified 35 patients who had electrodiagnostic evidence of mononeuritis multiplex and did not have diabetes or multiple nerve compressions. Their charts were reviewed to determine the etiologies of the mononeuritis multiplex and to determine how often the laboratory examination revealed a rheumatic disease in patients whose initial history and physical examination did not suggest that a rheumatic disease was present. In 11/35 (31%; CI = 17-49) a disorder capable of causing mononeuritis multiplex was diagnosed before the symptoms of mononeuritis multiplex began. Ten had a rheumatic disease; 1 had lymphoma. Nine of the other patients were suspected, on the basis of the history and physical examination, of having new onset of a rheumatic disease. Subsequent laboratory evaluation showed that 5/9 (56%; CI = 21-86) had a rheumatic disease, and 4/9 (44%; CI = 14-79) were unknowns. In 15/35 (43%; CI = 26-61) patients with mononeuritis multiplex, no rheumatic disease was suspected on the basis of the initial history and physical examination. The subsequent laboratory examination revealed an underlying rheumatic disease in 0/15 (0%; CI = 0-18). Mean clinical follow-up of 16 +/- 16 months in the patients with mononeuritis multiplex of unknown cause also failed to identify a rheumatic disease. Overall 19/35 (54%; CI = 37-71) did not have a rheumatic disease or any other known cause. Of the 14 patients with mononeuritis multiplex associated with a rheumatic disease, 5/14 (36%; CI = 13-15) had systemic lupus erythematosus; an additional patient had both lupus and the CREST syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)