Objective. To assess the efficacy of anakinra treatment in patients with adult-onset Still's disease (AOSD) that is refractory to corticosteroids, methotrexate (MTX), and etanercept.Methods. Four patients with AOSD were treated with prednisone and MTX and 2 patients were also treated with etanercept for worsening symptoms and indicators of systemic inflammation. White blood cells (WBCs), C-reactive protein (CRP) levels and/or erythrocyte sedimentation rate, and ferritin levels were measured and, in 1 patient, serum creatinine levels were determined. Treatment with anakinra at 100 mg/day was initiated.Results. The index patient's disease was refractory to treatment with prednisone (30 mg/day) and MTX, with spiking fevers, rash, synovitis, a serum ferritin level of 8,400 ng/ml (normal <200), and a CRP level of 86 mg/liter (normal <8). Levels of interleukin-1␤ (IL-1␤), IL-1␣, IL-6, IL-1 receptor antagonist, and IL-18 were elevated. Just prior to anakinra treatment, the WBC count was 14,600/mm 3 , the CRP level was 86 mg/liter, and the ferritin level was 573 ng/ml, with daily spiking fevers to 104°F, rash, and swollen joints. Within hours of the first injection, the patient was afebrile and asymptomatic; within days, the WBC count, ferritin level, and CRP level decreased into the normal range.On 2 occasions, anakinra was withheld. Within a few days, the WBC count rose to >20,000/mm 3 with prominent neutrophilia, the CRP level rose to >200 mg/liter, and the ferritin level rose to >3,000 ng/ml. Upon restarting anakinra, the patient became afebrile, the WBC count fell to 8,000/mm 3 , the CRP level fell to <3 mg/liter, and the ferritin level fell to <300 ng/ml. Three additional patients with refractory AOSD who experienced rapid reductions in fever, symptoms, and markers of inflammation when treated with anakinra are reported.Conclusion. Refractory AOSD appears to be IL-1-mediated since anakinra decreases hematologic, biochemical, and cytokine markers and also produces rapid reductions in systemic and local inflammation. Reported efficacy of tumor necrosis factor-blocking therapies in AOSD may be due to a reduction in IL-1.Adult-onset Still's disease (AOSD), a rheumatologic condition found worldwide, is characterized by a variety of clinical features, including intermittent fever, arthritis, evanescent rash, sore throat, leukocytosis, and hepatic dysfunction, polyserositis, lymphadenopathy, splenomegaly, and other systemic symptoms. Because of the diverse presentation (1), classifications have been developed to standardize the diagnosis of AOSD. The most widely accepted criteria set, as presented by Yamaguchi and colleagues (2), is a compilation of major and minor criteria with the exclusion of infections, malignancies, and other rheumatic or systemic diseases. More recently, Fautrel and associates have proposed classification criteria utilizing diagnostic markers of serum ferritin and glycosylated ferritin, thought to be more specific for AOSD (3). These criteria are said to provide a sensitivity of 80.6% and a specifi...

Objective. To determine the safety and efficacy of intravenous (IV) pamidronate treatment in ankylosing spondylitis (AS) patients who have had a suboptimal response to nonsteroidal antiinflammatory drugs (NSAIDs).Methods. Pamidronate at 60 mg was compared with pamidronate at 10 mg rather than placebo in view of the high incidence of transient arthralgias upon first IV exposure to the drug. The drug were given monthly for 6 months in a randomized, double-blind, controlled trial. The inclusion criterion was active disease (Bath AS Disease Activity Index [BASDAI] of >4 or morning stiffness of >45 minutes) despite stable NSAID therapy. The primary outcome measure was the BASDAI, and secondary outcomes included the Bath AS Functional Index (BASFI), Bath AS Global Index (BASGI), Bath AS Metrology Index (BASMI), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and percentage of patients achieving a reduction of >25% in the BASDAI. Outcome assessments were done at ؊2, 0, 12, and 24 weeks, and analysis was by intent to treat. Results. Eighty-four AS patients (67 men and 17women; mean age 39.6 years and mean disease duration 15.1 years) were enrolled. Dosage groups were well matched at baseline for demographics, disease activity, and functional indices. At 6 months, the mean BASDAI had decreased by 2.22 (34.5%) in the 60-mg group and by 0.93 (15%) in the 10-mg group (P ‫؍‬ 0.002). Significantly greater reductions in the 60-mg group were also noted for the BASFI (P < 0.001), BASGI (P ‫؍‬ 0.01), and BASMI (P ‫؍‬ 0.03). Significantly more patients achieved a reduction of >25% in the BASDAI in the 60-mg group versus the 10-mg group (63.4% versus 30.2%; P ‫؍‬ 0.004). Differences in ESR/CRP were not significant (NS). Withdrawals included 9 (20.9%) from the 10-mg group and 3 (7.3%) from the 60-mg group (P NS). Adverse events were confined to transient arthralgias/ myalgias after the first IV infusion, occurring in 68.3% and 46.5% of patients in the 60-mg and 10-mg groups, respectively (P NS).Conclusion. Pamidronate has dose-dependent therapeutic properties in AS.

Objective. To evaluate the efficacy and safety of adding intramuscular (IM) gold to the treatment regimen of patients with rheumatoid arthritis (RA) who have a suboptimal response to methotrexate (MTX).Methods. A randomized, double-blind, doubleobserver, placebo-controlled multicenter trial of 48 weeks was conducted. Sixty-five RA patients who had a suboptimal response to >12 weeks of MTX therapy were randomly assigned to receive weekly IM gold or placebo in addition to MTX. Gold was administered according to a standard protocol developed for the study. The primary outcome measure was the percentage of patients who met the American College of Rheumatology (ACR) 20% improvement criteria (achieved an ACR20 response) at week 48. Secondary outcomes included the percentages of patients achieving ACR50 and ACR70 responses, the individual criteria that make up the primary outcome, quality of life, direct and indirect health care costs, intraarticular steroid use, and adverse events, among other measures. Statistical analyses were based on an intent-to-treat strategy.Results. Sixty-one percent of patients receiving gold achieved an ACR20 response compared with 30% of patients receiving placebo ( 2 ‫؍‬ 6.04, P ‫؍‬ 0.014; logistic regression odds ratio 3.64 [95% confidence interval 1.3, 10.4], P ‫؍‬ 0.016). Twenty-six percent of patients receiving gold achieved an ACR50 response compared with 4% of patients receiving placebo (P ‫؍‬ 0.017), and 21% of patients receiving gold achieved an ACR70 response compared with 0% of patients receiving placebo (P ‫؍‬ 0.011). From both clinical and cost-effectiveness perspectives, gold was the preferred and dominant strategy. Study treatment was discontinued in 23 patients (14 in the placebo group compared with 9 in the gold group; P ‫؍‬ 0.022) due to loss to followup, adverse events, or lack of efficacy.Conclusion. In RA patients with a suboptimal response to MTX, adding weekly IM gold causes significant clinical improvement. Adverse events were minor, and IM gold-related adverse events led to discontinuation in only 11% of the gold group over 48 weeks.Rheumatoid arthritis (RA) affects ϳ1% of North Americans, with profound impact on their quality of life (1) as well as economic consequences for them, their

The BXD2 strain of mice is one of approximately 80 BXD recombinant inbred (RI) mouse strains derived from an intercross between C57BL/6J (B6) and DBA/2J (D2) strains. We have discovered that adult BXD2 mice spontaneously develop generalized autoimmune disease, including glomerulonephritis (GN), increased serum titres of rheumatoid factor (RF) and anti-DNA antibody, and a spontaneous erosive arthritis characterized by mononuclear cell infiltration, synovial hyperplasia, and bone and cartilage erosion. The features of lupus and arthritis developed by the BXD2 mice segregate in F2 mice generated by crossing BXD2 mice with the parental B6 and D2 strains. Genetic linkage analysis of the serum levels of anti-DNA and RF by using the BXD RI strains shows that the serum titers of anti-DNA and RF were influenced by a genetic locus on mouse chromosome (Chr) 2 near the marker D2Mit412 (78 cM, 163 Mb) and on Chr 4 near D4Mit146 (53.6 cM, 109 Mb), respectively. Both loci are close to the B-cell hyperactivity, lupus or GN susceptibility loci that have been identified previously. The results of our study suggest that the BXD2 strain of mice is a novel model for complex autoimmune disease that will be useful in identifying the mechanisms critical for the immunopathogenesis and genetic segregation of lupus and erosive arthritis.

Objective. Timely access to rheumatology consultation is fundamental to appropriate and effective management of patients with musculoskeletal and autoimmune diseases. Yet, for a variety of reasons, limited and delayed access is commonplace. Moreover, information exchange for referral is often inadequate or poorly communicated. The objective of this work was to improve referral from primary care to rheumatology by formulating and testing a clinically coherent, reliable, and non-diagnosis-dependent Priority Referral Score (PRS). Methods. Using a deliberative process, a clinical panel of 10 primary care providers (PCPs) and rheumatology specialists reviewed clinical case scenarios and engaged in a highly iterative process to develop criteria, definitions, and weights for the PRS, a linear 100-point scale to rate the relative urgency of referral. Following tool formulation, clinicians uninvolved with the process tested the PRS against their clinical judgment. Results. The PRS comprises 8 criteria, with 2-4 levels for each criterion, and each having a weight generated through conjoint analysis, which forced choices around the comparative urgency of all of the criteria and levels. The PRS showed a strong correlation between clinical rankings of rheumatologists and PCPs in both the deliberative panel, and the physicians subsequently involved in the testing of the PRS. Conclusion. No standardized priority-setting criteria are available for the full range of primary care referrals to rheumatologists. The PRS had face value with panelists and provided acceptable interrater and intrarater reliability when tested with other rheumatologists and PCPs. Pilot testing with other clinicians and in other settings is justified and prerequisite to use in clinical practice.