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The design of a human immunodeficiency virus–1 (HIV-1) immunogen that can induce broadly reactive neutralizing antibodies is a major goal of HIV-1 vaccine development. Although rare human monoclonal antibodies (mAbs) exist that broadly neutralize HIV-1, HIV-1 envelope immunogens do not induce these antibody specificities. Here we demonstrate that the two most broadly reactive HIV-1 envelope gp41 human mAbs, 2F5 and 4E10, are polyspecific autoantibodies reactive with the phospholipid cardiolipin. Thus, current HIV-1 vaccines may not induce these types of antibodies because of autoantigen mimicry of the conserved membrane-proximal epitopes of the virus. These results may have important implications for generating effective neutralizing antibody responses by using HIV-1 vaccines.

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.

Improved standards for the evaluation of therapeutic interventions in systemic lupus erythematosus (SLE) are needed. The purpose of this study by a committee of the American College of Rheumatology was to define clinically meaningful improvement, no change, or worsening in 6 existing clinical measures of SLE disease activity. This represents an important step in a disease in which some organ symptoms get better and others get worse. It is intended to help investigators develop sample size estimates based on meaningful effect sizes and to gauge the clinical relevance of any observed change in disease activity.Medical records from 310 patients drawn from 3 sources were abstracted into a standard format. Each vignette included clinical and laboratory data obtained during 2-3 visits. Ratings on the following 6 instruments were obtained for the same patients during the visit or retrospectively: the British Isles Lupus Assessment Group (BILAG), the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), the revised Systemic Lupus Activity Measure (SLAM-R), the European Consensus Lupus Activity Measure (ECLAM), the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA)-SLEDAI, and the Responder Index for Lupus Erythematosus (RIFLE). From this pool of vignettes, 5 common vignettes and 10 randomly selected vignettes were rated through a secure Web site by 88 international experts on SLE. The experts, who were blinded to the activity measure scores, were asked to rate each patient's clinical condition as worsened, improved, or unchanged relative to the previous visit. These ratings were transformed by statistical procedures into performance characteristic curves that related a change on a particular SLE activity measure to the physicians' agreement on whether that patient had worsened, improved, or remained the same clinically. These were discussed by the committee members, who were blinded to the actual instrument used. The committee then voted on what level of expert agreement would be used to determine clinically meaningful change.The physician ratings on the 5 common vignettes revealed considerable variation in their clinical appraisals. Overall, the 6 SLE activity measures showed excellent separation of clinical conditions as being worsened, improved, or the same. The committee voted to take 70% agreement by physicians as the point on the performance characteristic curves at which meaningful change in a score could be identified. For each instrument, we computed the units of change required to indicate improvement or worsening.To our knowledge, these are the first response criteria in any disease where a clinically relevant change has been determined a priori and mapped to standardized measures. This criterion should aid the clinical evaluation of new therapies, improve comparability between trials, and facilitate innovative trial designs.

To examine the association between N-acetyl transferase (NAT) genotype (NAT1 and NAT2) and risk of developing systemic lupus erythematosus (SLE).DNA samples were collected from 243 recently diagnosed cases and 298 controls enrolled in a population based case-control study conducted in 60 counties in North Carolina and South Carolina, USA.There was no association between SLE and NAT1 genotype (OR 0.96, 95% CI 0.65, 1.4 for the presence of a *10 allele) or NAT2 genotype (OR 1.1, 95% CI 0.73, 1.6 for the slow- compared with fast-acetylation genotype). We saw some evidence of interaction between NAT genotypes and use of hair dyes (a source of arylamines), with higher risk seen among hair dye users who had both the *10 NAT1 allele and the NAT2 slow-acetylation genotype (OR 2.9, 95% CI 1.2, 6.9 in this subgroup compared with all others).Our results suggest that although there is little overall association between NAT genotypes and risk of developing SLE, the interaction between NAT1 and NAT2 and specific exposures such as hair dyes may be important. This finding highlights the need to consider exposure when assessing genetic susceptibility.

Increasing attention has focused on the early treatment of rheumatoid arthritis (RA) because of the short time lag that can exist between the onset of synovitis and the development of joint damage and loss of function. For optimal benefit, treatment may need to begin in a theoretical 'window of opportunity' that exists within the first few weeks or months of disease onset. Current evidence suggests that early introduction of therapy with disease-modifying antirheumatic drugs (DMARDs) can slow the progression of joint damage and improve long-term outcomes. Moreover, results of several studies suggest that early treatment with two- and three-DMARD combinations can produce superior benefits compared with DMARD monotherapy. Although early DMARD therapy has proven ability to slow the pace of joint destruction, individual treatment decisions are problematic because of the difficulty in accurately predicting individual prognosis and differential responses to therapy. Controlled trials are needed in early disease to investigate these questions and to identify treatment strategies that can effectively induce sustained remission and prevent joint damage.

Objective To evaluate the informed consent process for a clinical trial of intravenous doxycycline for rheumatoid arthritis. Methods Participants completed a self-administered questionnaire about the consent process at baseline and 16 weeks following enrollment in a clinical trial. Results Respondents (n = 30) affirmed voluntary participation in the parent trial. Participants acknowledged hope and altruism as reasons for entering the trial more than expectation of personal benefit or outside influences. Many respondents did not understand randomization (14/30), placebos (15/30), or risks of study medications; 11/30 respondents believed that the study drug was completely safe. Conclusion Respondents generally understood the experimental nature of the trial and confirmed their participation was voluntary. However, gaps existed in participants understanding of trial design, raising the question of whether they were adequately informed about the research study prior to enrollment. Further education of potential participants in clinical trials may be required to achieve valid informed consent.

Multiple genetic factors modulate predisposition to systemic lupus erythematosus (SLE). The glutathione S-transferase (GST) genes GSTM1, GSTT1, and GSTP1 catalyze metabolic pathways for the excretion of reactive oxygen species that may be generated by cellular oxidative stress induced by ultraviolet radiation in sunlight. We hypothesized that risk of SLE associated with occupational sun exposure is modulated by GSTM1, GSTT1, and GSTP1 genotypes.DNA samples and occupational history were collected from 243 cases and 298 controls in the Carolina Lupus Study, a population based case-control study of patients with recently diagnosed SLE.There was no independent association between SLE and presence of the homozygous null GSTM1 or GSTT1 genotype, the homozygous Val/Val or heterozygous Val/Ile GSTP1 genotype, or occupational sunlight exposure. The prevalence of Ro autoantibodies was significantly increased among Caucasians with the GSTM1 null genotype (OR 2.6, 95% CI 1.0, 6.8), but was somewhat weaker among African-Americans (OR 1.5, 95% CI 0.7, 3.5). In the combined analysis of occupational sunlight exposure and GSTM1 genotype, the effect of sun exposure among Caucasians varied depending on GSTM1 genotype. There was a 3-fold increased risk (OR 3.1, 95% CI 0.9, 10.8) of SLE associated with 24 or more months' occupational sun exposure among Caucasians with the GSTM1 null genotype, but sun exposure was not associated with risk among GSTM1 positive Caucasians (OR 0.6, 95% CI 0.3, 1.5). The interaction was statistically significant (p = 0.028).Our results suggest that GSTM1 homozygous null genotype may modify the effect of occupational sun exposure on the risk of SLE in caucasians.

Increased knowledge about the mechanisms of joint inflammation and damage has profoundly shaped the development of new therapies for rheumatoid arthritis (RA). The first stop on this remarkable bench-to-bedside journey has been the biologics targeting tumor necrosis factor-alpha (TNF-alpha) and interleukin 1 (IL-1). These engineered adaptations of naturally occurring molecules function to neutralize the biological activity of proinflammatory cytokines overproduced in the joints of patients with RA. The successful translation of this approach into the clinic has had a substantial effect on the care of patients with RA.

Overproduction of tumor necrosis factor-alpha (TNF) plays a key role in the pathogenesis of rheumatoid arthritis (RA) and other chronic inflammatory diseases. In RA, excessive production of TNF-alpha can drive synovial inflammation and proliferation as well as degradation of articular cartilage and bone. The importance of TNF-alpha in these mechanisms is supported by the results of clinical trials. In these studies, treatment with etanercept and infliximab, two recently approved TNF-alpha inhibitors, has been shown to significantly decrease the signs and symptoms of joint inflammation and slow the progression of radiological joint damage. Although TNF-alpha inhibitors have had acceptable toxicity in clinical trials, commercial use of these agents has produced growing concerns about the potential risk for opportunistic infections, most notably the reactivation of latent tuberculosis. The TNF-alpha inhibitors stand as a powerful example of the therapeutic potential of a targeted biological agent. Longer-term clinical experience with these cytokine antagonists will illuminate their optimal use in RA and other rheumatic diseases.

Objective Estrogen and prolactin may accelerate the progression of murine systemic lupus erythematosus (SLE). In humans, 85% of lupus patients are women, which also suggests the importance of hormonal factors in disease pathogenesis. The purpose of this study was to examine hormonal and reproductive risk factors for lupus among women. Methods This population-based, case–control study included 240 female SLE patients diagnosed between January 1, 1995 and July 31, 1999 who fulfilled the American College of Rheumatology classification criteria. Female controls (n = 321) were identified through driver's license records. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) as measures of association, adjusting for age, state, race, and education. Analyses were limited to exposures before diagnosis. Results Breast-feeding was associated with a decreased risk of developing SLE (OR 0.6, 95% CI 0.4–0.9), with a statistically significant trend for number of babies breast-fed and total weeks of breast-feeding. There were no associations with number of pregnancies or live births. Natural menopause occurred earlier in women with subsequent development of SLE compared with controls (P < 0.001). There was little association between SLE and current use or duration of use of hormone replacement therapy or oral contraceptives, and no association with previous use of fertility drugs. Conclusion We found little evidence that estrogen- or prolactin-related exposures are associated with an increased risk of lupus. The reduced risk observed among women who had breast-fed one or more babies should be examined in other studies. Early natural menopause, rather than decreasing risk of SLE because of reduced estrogen exposure, may be a marker of susceptibility to development of SLE.

Objective To investigate the relationship between serum concentrations of infliximab, a monoclonal anti–tumor necrosis factor α antibody, and clinical improvement from infliximab therapy for rheumatoid arthritis (RA). Methods Multiple blood samples were obtained from each of 428 subjects with active RA who were enrolled in a multicenter, randomized, double-blind, placebo-controlled trial (ATTRACT [Anti–Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy]) evaluating the clinical efficacy and safety of infliximab therapy. Serum levels of infliximab were measured by enzyme-linked immunosorbent assay. Dose-response trends were analyzed using generalized logistic regression techniques. Pharmacokinetic modeling was used to predict the serum concentrations of infliximab after simulated infusions using doses and dosing intervals not evaluated in the trial. Results At week 54, 26% of the subjects receiving 3 mg/kg infliximab every 8 weeks had undetectable trough serum levels of infliximab, a significantly greater proportion than in the other 3 treatment groups (P < 0.001). Increased magnitude of American College of Rheumatology (ACR) response (measured by the ACR-N, a continuous measure of clinical improvement derived from the ACR 20% response criteria) and greater reduction from baseline in serum C-reactive protein level were both associated with higher trough serum concentrations of infliximab (P < 0.001), as was less progression of radiographic joint damage (P = 0.004), providing support for a dose-response relationship. Pharmacokinetic models predicted that decreasing the dosing interval from 8 weeks to 6 weeks would yield higher trough serum levels of infliximab than increasing the dose by 100 mg. Conclusion These results suggest that some patients with RA may benefit from infliximab given at higher doses than 3 mg/kg or more frequently than every 8 weeks.

Systemic vasculitis produces a diverse array of clinical syndromes depending on the size of the affected blood vessels and the predominant sites of organ system involvement. Vasculitis may occur as a primary process in which blood vessel involvement is typically the major component of the disorder, or as a secondary process associated with a connective tissue disease, idiopathic inflammatory disease, toxic exposure, or malignancy. The varied and overlapping clinical, laboratory, and pathological features of the vasculitic disorders have complicated the classification of this group of diseases. A partial listing of primary and secondary vasculitic disorders is shown in Tables 1 and 2. A panel of experts has developed a revised nomenclature for the vasculitic syndromes [248]. In addition, the American College of Rheumatology has established classification criteria for systemic vasculitis [229]. While these criteria distinguish individual diseases from each other with excellent sensitivity and specificity, they have limited diagnostic utility in the clinical setting [406].

Introduction Subjects with primary Sjögren’s syndrome (SjS) have an increased risk of developing B-cell lymphoma and may harbor monoclonal B-cell expansions in the peripheral blood. Expanded B-cell clones could be pathogenic, and their persistence could exacerbate disease or predispose toward the development of lymphoma. Therapy with anti-CD20 (rituximab) has the potential to eliminate expanded B-cell clones and thereby potentially ameliorate disease. This study was undertaken to identify and track expanded B-cell clones in the blood of subjects with primary SjS who were treated with rituximab. Methods To determine whether circulating B-cell clones in subjects with primary SjS emerge or remain after B cell-depleting therapy with rituximab, we studied the antibody heavy-chain repertoire. We performed single-memory B-cell and plasmablast sorting and antibody heavy-chain sequencing in six rituximab-treated SjS subjects over the course of a 1-year follow-up period. Results Expanded B-cell clones were identified in four out of the six rituximab-treated SjS subjects, based upon the independent amplification of sequences with identical or highly similar VH, DH, and JH gene segments. We identified one SjS subject with a large expanded B-cell clone that was present prior to therapy and persisted after therapy. Somatic mutations in the clone were numerous but did not increase in frequency over the course of the 1-year follow-up, suggesting that the clone had been present for a long period of time. Intriguingly, a majority of the somatic mutations in the clone were silent, suggesting that the clone was under chronic negative selection. Conclusions For some subjects with primary SjS, these data show that (a) expanded B-cell clones are readily identified in the peripheral blood, (b) some clones are not eliminated by rituximab, and (c) persistent clones may be under chronic negative selection or may not be antigen-driven. The analysis of sequence variation among members of an expanded clone may provide a novel means of measuring the chronicity and selection of expanded B-cell populations in humans.

RHEUMATOID ARTHRITIS (RA) IS A chronic inflammatory arthritis involving 0.5% to 1% of the US population. This disease affects women twice as often as men and its incidence rises with increasing age. In general, RA causes a symmetric polyarthritis affecting large and small joints in association with systemic manifestations, such as morning stiffness, fatigue, and weight loss. Although considered a joint disease, RA can have widespread effects on the entire body and can impair life expectancy by as much as 5 to 10 years. With progressive disease, patients with RA develop work disability, functional impairment, and radiographic evidence of joint damage. While many conditions can produce polyarthritis, the diagnosis of RA can usually be established by the presence of persistent joint pain, swelling in a symmetric distribution, and prolonged morning stiffness. Supporting the diagnosis are laboratory findings, such as a positive test result for rheumatoid factor. The intensity of joint inflammation often correlates with the erythrocyte sedimentation rate or levels of serum C-reactive protein, but these abnormalities are nonspecific. In the management of RA, the primary care physician plays an important role by ensuring early diagnosis. If unsure about the presence or significance of synovitis, the primary care physician should consult a rheumatologist for this determination. The management of RA has undergone a revolution in the past decade, reflecting a growing armamentarium of drugs and a shift in treatment strategies. While RA is a chronic condition, joint damage occurs at onset for many patients. Thus, in the current strategy, which has replaced the older, more gradualist treatment pyramid, therapy is begun immediately to control disease activity, reduce functional impairment, and prevent irreversible changes in cartilage and bone. Since prompt disease control is a major goal of therapy, the primary care physician should consider referring a patient with suspected RA to a rheumatologist for early treatment. A variety of surgical procedures is also available to reduce joint pain and improve function, but a discussion of these modalities is beyond the scope of this article.

Genetic variation in immunoglobulin γ (GM) and ĸ (KM) chains was associated with systemic lupus erythematosus (SLE) in some studies. However, the data are conflicting, and only one study examined associations in African-Americans. We examined GM and KM allotypes, by race, in a population-based case-control study of SLE. Sera from patients (n = 222) and controls (n = 273) were typed for GM and KM allotypes by a hemagglutination inhibition method. GM phenotypes were not significantly associated with SLE in African-Americans or Caucasians. However, the frequency of KM phenotypes in Caucasian patients was significantly different from that in controls (p = 0.032). KM3,3 was associated with an increased risk, whereas KM1,3 was associated with a lower relative risk of SLE. In African-Americans, however, the pattern of associations with KM phenotypes differed from that in Caucasians, and the overall difference between patients and controls was not statistically significant.

Gabapentin is an antiepileptic agent that is indicated for use as adjunctive therapy for partial seizures. It has a relatively benign side effect profile, but little data exists on massive overdoses with this agent. The authors present a case of a patient who received a massive overdose of this agent but suffered no clinically significant toxicity.

Objective. To investigate the dose tolerance and potential clinical activity of a humanized antilymphocyte monoclonal antibody, CAMPATH-1H (C1H), in patients with active, refractory rheumatoid arthritis (RA). Methods. Thirty adult patients with active, refractory RA were treated in an open-label, 3-center, dose-escalation study of subcutaneously injected C1H. Six patients were assigned to each of 5 dosage groups (0.3, 1.0, 3.0, 10.0 or 30.0 mg/day), and received 10 daily injections of C1H over a 12-day period. Results. Side effects occurred primarily during the first 1–2 days of dosing, and included mild fever, chills, nausea, vomiting, headache, and, in a minority of patients, hypotension. All patients developed some discomfort at the injection site. Self-limited infections occurred in 5 patients during the 6-month study period. Peripheral blood lymphocyte counts fell promptly after initial dosing and recovered slowly, usually over 2–3 months. Serum antibodies to C1H developed in 54% of patients following treatment. Clinical improvement was observed in 56% of patients, based on the composite Paulus criteria, with a median time-to-response of 22 days and a median response duration of 32 days. Conclusion. C1H is a lymphocyte-depleting antibody that exhibits biologic potency when administered subcutaneously to patients with refractory RA. Its use is associated with mild to moderate toxicity and short-term amelioration of disease activity.

The endothelial-specific Angiopoietin-Tie2 ligand-receptor system is an important regulator of endothelial activation. Binding of angiopoietin-2 (Ang-2) to Tie2 receptor renders the endothelial barrier responsive to pro-inflammatory cytokines. We previously showed that circulating Ang-2 correlated with disease severity in a small cohort of critically ill patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. The current study reassessed Ang-2 as a biomarker of disease activity and relapse in AAV. Circulating Ang-2 was measured in 162 patients with severe AAV (BVAS/WG >= 3, with or without glomerulonephritis) in a clinical trial. Ang-2 levels during active AAV were compared to levels in the same patients during remission (BVAS/WG = 0). Levels in clinical subsets of AAV were compared, and association with future disease course was assessed. Ang-2 levels were elevated in severe disease (median 3.0 ng/ml, interquartile range 1.9-4.4) compared to healthy controls (1.2, 0.9-1.5). However, they did not reliably decline with successful treatment (median 2.6 ng/ml, interquartile range 1.9-3.8, median change -0.1). Ang-2 correlated weakly with BVAS/WG score (r = 0.17), moderately with markers of systemic inflammation (r = 0.25-0.41), and inversely with renal function (r = -0.36). Levels were higher in patients with glomerulonephritis, but levels adjusted for renal dysfunction were no different in patients with or without glomerulonephritis. Levels were higher in patients with newly diagnosed AAV and lower in patients in whom treatment had recently been started. Ang-2 levels during active disease did not predict response to treatment, and Ang-2 levels in remission did not predict time to flare. Thus, Ang-2 appears to have limited practical value in AAV as a biomarker of disease activity at time of measurement or for predicting future activity.

Objective. The potential role of cell adhesion molecules in the pathogenesis of Sjogren's syndrome (SS) was assessed by examining their expression in salivary gland (SGL) tissue. Methods. Intercellular adhesion molecule type 1 (ICAM-1), lymphocyte function-associated antigen type 1 (LFA-1), LFA-3, CD2, and CD44 expression were determined using indirect immunofluorescence techniques. Results. In inflamed labial SGL tissue, ICAM-1 expression was evident on infiltrating LFA-1+/CD2+/LFA-3+ mononuclear cells, and to a limited extent on SGL acinar epithelial cells adjacent to sites of intense inflammation. Conclusion. In SS, the SGL microenvironment is characterized by only a modest up-regulation of ICAM-1 expression on epithelial cells, despite the presence of T cells bearing an activated phenotype.

To determine the specificity of antibodies to the (U1) ribonucleoprotein antigen in systemic lupus erythematosus (SLE), patient sera were tested for binding to a recombinant human 70K antigen. By solid-phase immunoassay, we detected anti-70K reactivity in sera from 31 of 96 patients with systemic lupus erythematosus (SLE), demonstrating that anti-70K antibodies may occur in patients with SLE as well as other clinical diagnoses. In sequential sera from 2 of these patients, we found that anti-70K binding varied dramatically over the course of disease. The changes in anti-70K antibody levels did not correlate with clinical events nor evolving antibody reactivity with the Sm-specific antigens.

Background The pathogenic significance of antineutrophilic cytoplasmic antibodies (ANCA) in Wegener's granulomatosis is controversial. Their presence is influenced by the extent, severity, and activity of the disease at the time of sampling. The objective of this study was to determine the frequency of ANCA in patients with active Wegener's granulomatosis and to assess the influence of disease severity on test results. Methods Baseline serum samples from the 180 participants in a multicentric prospective trial were tested for ANCA by indirect immunofluorescence, direct enzyme-linked immunosorbent assay (ELISA), and capture ELISA. Disease activity was measured using the Birmingham Vasculitis Activity Score for Wegener's granulomatosis. All patients had active disease at enrollment. Patients were categorized as having severe (n=128) or limited (n=52) Wegener's granulomatosis. Results When all ANCA detection methods were combined, 166 patients (92%) were ANCA positive, including 96% with severe disease and 83% with limited disease. Conclusion ANCA are detectable in nearly all patients with active severe Wegener's granulomatosis, but approximately 1 of 5 patients with active limited disease are ANCA negative. Immunofluorescence and both direct and capture ELISAs are required for optimal detection, suggesting that ANCA are not recognized equally well by all testing methods.

Nitric oxide (NO) may play important roles in rheumatoid arthritis (RA). RA is an inflammatory disease involving joints and other systems including salivary glands. To assess NO production in RA patients, we compared levels of serum, urine, and salivary nitrite and nitrate (NOx) in patients with RA and normal subjects, and we examined the relationships of these measures to disease activity. Serum, urine, and NOx levels as well as renal creatinine, NOx clearance and fractional excretion rates were compared in 25 RA patients and 20 age- and gender-matched healthy controls. Subjects were hospitalized for 3 days and placed on a NOxrestricted diet. NOx was assayed using nitrate reductase and the Griess reagent. RA activity was assessed using standard clinical and laboratory measures. While consuming a restricted diet for 3 days to eliminate the effects of oral intake of NOx, 24 hour urinary NOx excretion decreased in both RA patients and healthy controls. Urine NOx levels at all time points were not significantly different between RA patients and normal subjects. Serum NOx levels also decreased during the 3 days of NOx restriction, but RA patients had higher serum NOx levels at all time points compared with the control group. Likewise, serum NOx/creatinine ratios were higher in RA patients than in controls. Although basal salivary flow rate and tear flow were lower in RA patients, salivary NOx levels did not differ between normal and RA subjects. While renal creatinine clearance was not different between the two groups, we found that RA patients had lower renal NOx clearance and lower renal NOx fractional excretion. After correction of p values for multiple comparisons, there were no significant relationships for the RA group between measures of disease activity and the urinary NOx, serum NOx, or urinary NOx clearance. Despite interest in the use of NO as a marker of disease activity, alterations in renal NOx clearance and fractional excretion in RA make it difficult to assess in vivo NO production even with strict dietary restriction of NOx intake.

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 ≥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 ≥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.

Venous thrombotic events (VTEs) have been observed in Wegener granulomatosis, but the incidence rate is not known.To measure the incidence of VTEs in patients with Wegener granulomatosis.Prospective, observational cohort study.A multicenter, randomized, double-blind, placebo-controlled treatment trial for Wegener granulomatosis.180 patients with Wegener granulomatosis enrolled during periods of active disease.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.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).Although prospectively recorded, screening for VTEs did not occur.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.

Background: Toxicity limits the use of methotrexate. Objective: To identify risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis. Design: Case-control study. Sett...

▪Objective:To assess the cardiovascular physical examination skills of internal medicine housestaff. ▪Design:Cross-sectional assessment of housestaff performance on three valvular abnormal...

A 66-year-old man with the lupus anticoagulant-hypoprothrombinemia syndrome was treated with cyclophosphamide and prednisone to correct a factor II deficiency prior to elective major surgery. Whereas the lupus anticoagulant activity persisted, functional factor II levels normalized and he underwent surgery without a bleeding diathesis. Immunosuppressive therapy may temporarily normalize factor II levels in patients with the lupus anticoagulant-hypoprothrombinemia syndrome and reduce the risk of excessive hemorrhage. The disparate response of the lupus anticoagulant and hypoprothrombinemia to immunosuppression suggests that the lupus anticoagulant did not directly cause the hypoprothrombinemia.

A purified recombinant La fusion protein was tested in an enzyme-linked immunosorbent assay to quantitate anti-La responses. This protein contained the immunodominant region of the La molecule fused to beta-galactosidase. In solid-phase assays, recombinant La protein was solubilized in urea and bound to polystyrene wells without loss of immunoreactivity. The recombinant-based enzyme-linked immunosorbent assay proved to be a sensitive method for the detection of anti-La binding, and it accurately distinguished anti-La precipitin positive sera from normal sera.

Successful treatment of patients with rheumatoid arthritis demands an understanding of the rationale, clinical use, and side effects of the various antirheumatic modalities. Most patients can be treated effectively with salicylates or other nonsteroidal anti-inflammatory drugs, although some with more serious disease require the addition of a slow-acting agent such as gold, d-penicillamine, or methotrexate.

To investigate patterns of autoreactivity in Sjogren's syndrome, the epitope specificity of anti-La antibodies was determined using recombinant antigens bearing sequences of the amino, middle, and carboxyl portions of the La molecule. Sera from patients with primary as well as secondary Sjogren's syndrome reacted with all three fragments, although the magnitude of the responses varied markedly among individuals. Furthermore, the proportion of antibody binding directed to the different La epitopes showed considerable individual variations, but these patterns were not correlated with specific clinical manifestations. These results suggest that quantitative and qualitative aspects of anti-La responses in Sjogren's syndrome are determined by factors distinct from those determining the clinical expression of disease.

Granulomatosis with polyangiitis (formerly Wegener's) (GPA) and microscopic polyangiitis (MPA) share many clinical and pathological features, including antineutrophil cytoplasmic antibodies (ANCA) directed against either proteinase 3 (PR3) or myeloperoxidase (MPO). These two "ANCA-associated" vasculitides (AAV) are associated with a high mortality in untreated patients, substantial morbidity from standard therapies, and a significant risk of disease relapse. The Rituximab in ANCA-Associated Vasculitis (RAVE) trial is a randomized, double-blind, double-dummy, active- controlled, non-inferiority trial of a new approach to the induction of remission. The RAVE trial represents the first chal- lenge of a biologic agent to CYC as the standard of care for remission induction in AAV. The primary outcome analysis, reported in 2010, compared conventional therapy (the combination of cyclophosphamide (CYC) and glucocorticoids) to the combination of rituximab (RTX) and glucocorticoids. Longer term outcomes to 18 months and beyond have not been reported. The trial aimed to determine if the combination of RTX plus glucocorticoids was non-inferior to the combination of CYC and glucocorticoids. To test this hypothesis, eight clinical centers planned to enroll 200 patients. The randomization was stratified by center and by ANCA subtype. Patients were assigned randomly to each treatment arm in an allocation ratio of 1:1. The primary outcome had two components: 1) the ability of the assigned regimen to induce disease remission by month 6; and, 2) successful discontinuation of prednisone by month 6. All primary analyses were performed on an inten- tion-to-treat basis. A major secondary outcome of interest was the restoration of immune tolerance, defined as disease quiescence and the absence of ANCA following the reconstitution of normal B cell numbers. To meet this definition, pa- tients were required to achieve and maintain disease remissions, complete the prednisone taper, and remain on no immu- nosuppressive medications after discontinuing prednisone. Patients were followed for 18 months after the final patient was enrolled to evaluate the impact of the two treatment regimens on tolerance restoration. In this paper, we describe the development and design of the RAVE trial as a pivotal trial in an orphan disease indication. We illuminate the unique challenges involved in comparing a new treatment approach against an entrenched standard of care in a double-blind, double-dummy trial of a biologic for the treatment of a rare disease.

As the cornerstone of anti-rheumatic therapy in rheumatoid arthritis, high doses of salicylates are frequently employed in combination with methotrexate sodium. Maier and colleagues correctly emphasize the potential clinical importance of interaction between these two drugs. Salicylates may increase serum methotrexate levels by either reducing glomerular filtration or interfering with tubular secretion of methotrexate as Maier and his co-workers explain. Although therapeutic salicylate levels decrease methotrexate binding to serum protein by 20% to 60%, displacement of protein-bound methotrexate by a salicylate probably results in only slight increases in free methotrexate concentration. 1 For displacement from binding sites to be significant, a drug must be greater than 90% bound, and its volume of distribution should not exceed extracellular water. 2 In the case of methotrexate, only about 60% is protein-bound, and the free drug rapidly distributes into total body water. 1 Whether increased or sustained methotrexate serum levels contribute to