Naomi Rothfield, MD, MACR: A Giant Gift in a Small Package.

Naomi Rothfield was truly a pied piper of lupus. She had an abiding interest in the characterization and clinical significance of antinuclear antibodies and anti-DNA antibodies in the serum of systemic lupus erythematosus (SLE) patients. She described the use of serum complement in SLE diagnosis and the association of inherited complement deficiencies with SLE. Under her leadership, numerous professionals focused their clinical and research activities to benefit lupus patients. Naomi was also instrumental in establishing a lupus group to assist lupus patients, which became one of the founding chapters of the Lupus Foundation of America.

A multianalyte assay panel with cell-bound complement activation products demonstrates clinical utility in systemic lupus erythematosus.

OBJECTIVE: To evaluate the clinical utility of the multianalyte assay panel (MAP), commercially known as AVISE Lupus test (Exagen Inc.), in patients suspected of SLE. METHODS: A systematic review of medical records of ANA-positive patients with a positive (>0.1) or negative (<-0.1) MAP score was conducted when the MAP was ordered (T0), when the test results were reviewed (T1) and at a later time (T2, ≥8 months after T1). Confidence in the diagnosis of SLE and initiation of hydroxychloroquine (HCQ) were assessed. RESULTS: A total of 161 patient records from 12 centres were reviewed at T0 and T1. T2 occurred for 90 patients. At T0, low, moderate and high confidence in SLE diagnosis was reported for 58%, 30% and 12% patients, respectively. Confidence in SLE diagnosis increased for the MAP positive, while MAP negative made SLE less likely. Odds of higher confidence in SLE diagnosis increased by 1.74-fold for every unit of increase of the MAP score (p<0.001). Using the MAP-negative/anti-double-stranded DNA-negative patients as reference, the HR of assigning an International Classification of Diseases, Tenth Revision lupus code was 7.02-fold, 11.2-fold and 14.8-fold higher in the low tier-2, high tier-2 and tier-1 positive, respectively (p<0.001). The HR of initiating HCQ therapy after T0 was 2.90-fold, 4.22-fold and 3.98-fold higher, respectively (p<0.001). CONCLUSION: The MAP helps increase the confidence in ruling-in and ruling-out SLE in patients suspected of the disease and informs on appropriate treatment decisions.

A Review of Complement Activation in SLE.

PURPOSE OF REVIEW: Complement activation is a key event in the pathogenesis of tissue inflammation and injury in systemic lupus erythematosus (SLE). This review is aimed at comparing the usefulness of measurement of complement proteins in serum/plasma (C3, C4) to complement activation (split) products in plasma and on circulating blood cells for SLE diagnosis, disease monitoring, and prognosis. RECENT FINDINGS: Complement split products, C3dg, iC3b, and C4d, are elevated in SLE, and C3dg/C3 and iC3b/C3 ratios correlate with active SLE. C4d also is higher in patients with lupus nephritis. An elevated level of the alternative pathway split product, Bb, in early lupus pregnancy is a predictor of adverse outcomes in SLE patients with antiphospholipid antibodies. Elevated levels of cell-bound complement activation products (CB-CAPs), namely, B cell-bound C4d (BC4d) and erythrocyte-bound C4d (EC4d), within a multiparameter assay panel, may predict transition to SLE more than other lupus biomarkers. EC4d better correlates with lupus disease activity than low plasma complement levels. Elevated platelet-bound C4d (PC4d) correlates with thrombosis in SLE. Both EC4d and PC4d are increased in primary and secondary anti-phospholipid syndrome, and anti-beta2glycoproteinI antibodies may directly activate the complement system. Abnormal levels of plasma complement split products and CB-CAPs support complement activation as an important pathogenetic mechanism in SLE and the antiphospholipid syndromes. These tests show promise for the diagnosis of SLE and monitoring of disease activity.

A Multianalyte Assay Panel With Cell-Bound Complement Activation Products Predicts Transition of Probable Lupus to American College of Rheumatology-Classified Lupus.

OBJECTIVE: To evaluate the usefulness of biomarkers to predict the evolution of patients suspected of systemic lupus erythematosus (SLE), designated as probable SLE (pSLE), into classifiable SLE according to the American College of Rheumatology (ACR) classification criteria. METHODS: Patients suspected of SLE were enrolled by lupus experts if they fulfilled three ACR criteria for SLE and were followed for approximately 1-3 years to evaluate transition into ACR-classifiable SLE. Individual cell-bound complement activation products (CB-CAPs), serum complement proteins (C3 and C4), and autoantibodies were measured by flow cytometry, turbidimetry, and enzyme-linked immunosorbent assay, respectively. Blood levels of hydroxychloroquine (HCQ) were measured by mass spectrometry. A multianalyte assay panel (MAP), which includes CB-CAPs, was also evaluated. A MAP of greater than 0.8 reflected the optimal cutoff for transition to SLE. Time to fulfillment of ACR criteria was evaluated by Kaplan-Meier analysis and Cox proportional hazards model. RESULTS: Of the 92 patients with pSLE enrolled, 74 had one or two follow-up visits 9-35 months after enrollment for a total of 128 follow-up visits. Overall, 28 patients with pSLE (30.4%) transitioned to ACR-classifiable SLE, including 16 (57%) in the first year and 12 (43%) afterwards. A MAP score of greater than 0.8 at enrollment predicted transition to classifiable SLE during the follow-up period (hazard ratio = 2.72; P = 0.012), whereas individual biomarkers or fulfillment of Systemic Lupus International Collaborating Clinics criteria did not. HCQ therapy was not associated with the prevention of transition to SLE. CONCLUSION: Approximately one-third of patients with pSLE transitioned within the study period. MAP of greater than 0.8 predicted disease evolution into classifiable SLE.

Evaluation of the Economic Benefit of Earlier Systemic Lupus Erythematosus (SLE) Diagnosis Using a Multivariate Assay Panel (MAP).

OBJECTIVE: Diagnosis of systemic lupus erythematosus (SLE) made by standard diagnostic laboratory tests (SDLTs) has sensitivity and specificity of 83% and 76%, respectively. A multivariate assay panel (MAP) combining complement C4d activation products on erythrocytes and B cells with SDLTs yields a sensitivity and specificity of 80% and 86%, respectively, presumably enabling earlier SLE diagnosis at lower severity, with associated lower health care costs compared with SDLT diagnoses. We compared the payer budget impact of diagnosing SLE using MAP (incremental cost of $108) versus SDLTs. METHODS: We modeled a health plan of 1 million enrollees. SLE diagnosis among suspected patients was 9.2%. The MAP arm assumed 80%/20% of patients were tested with MAP/SDLTs, versus 100% tested with SDLTs in the SDLT arm. Prediagnosis direct costs were estimated from claims data, and postdiagnosis costs were obtained from the literature. Based on improved MAP performance, the assumed hazard ratio for diagnosis rate compared with SDLTs was 1.74 (71%, 87%, 90%, and 91% of patients who develop SLE are diagnosed in years 1 to 4 compared with 53%, 75%, 84%, and 88% of patients diagnosed with SDLTs). RESULTS: Total 4-year pre- and postdiagnosis direct costs for patients with suspected SLE tested with MAP were $59 183 666 compared with $61 174 818 tested by SDLTs, with lower costs in the MAP arm due primarily to prediagnosis savings related to reduced hospital admissions. CONCLUSION: Incorporating MAP into SLE diagnosis results in estimated 4-year direct cost savings of $1 991 152 ($0.04 per member per month). By facilitating earlier diagnosis of SLE, MAP may enhance patient outcomes.

Cell-bound complement activation products associate with lupus severity in SLE.

OBJECTIVES: To evaluate the association between lupus severity and cell-bound complement activation products (CB-CAPs) or low complement proteins C3 and C4. METHODS: All subjects (n=495) fulfilled the American College of Rheumatology (ACR) classification criteria for SLE. Abnormal CB-CAPs (erythrocyte-bound C4d or B-lymphocyte-bound C4d levels >99th percentile of healthy) and complement proteins C3 and C4 were determined using flow cytometry and turbidimetry, respectively. Lupus severity was estimated using the Lupus Severity Index (LSI). Statistical analysis consisted of multivariable linear regression and groups comparisons. RESULTS: Abnormal CB-CAPs were more prevalent than low complement values irrespective of LSI levels (62% vs 38%, respectively, p<0.0001). LSI was low (median 5.44, IQR: 4.77-6.93) in patients with no complement abnormality, intermediate in patients with abnormal CB-CAPs (median 6.09, IQR: 5.31-8.20) and high in the group presenting with both abnormal CB-CAPs and low C3 and/or C4 (median 7.85, IQR: 5.51-8.37). Odds of immunosuppressant use was higher in subjects with LSI ≥5.95 compared with subjects with LSI <5.95 (1.60 vs 0.53, p<0.0001 for both). Multivariable regression analysis revealed that higher LSI scores associated with abnormal CB-CAPs-but not low C3/C4-after adjusting for younger age, race and longer disease duration (p=0.0001), which were also independent predictors of disease severity (global R2=0.145). CONCLUSION: Abnormalities in complement activation as measured by CB-CAPs are associated with increased LSI.

Complement Activation in Patients With Probable Systemic Lupus Erythematosus and Ability to Predict Progression to American College of Rheumatology-Classified Systemic Lupus Erythematosus.

OBJECTIVE: To evaluate the frequency of cell-bound complement activation products (CB-CAPs) as a marker of complement activation in patients with suspected systemic lupus erythematosus (SLE) and the usefulness of this biomarker as a predictor of the evolution of probable SLE into SLE as classified by the American College of Rheumatology (ACR) criteria. METHODS: Patients in whom SLE was suspected by lupus experts and who fulfilled 3 ACR classification criteria for SLE (probable SLE) were enrolled, along with patients with established SLE as classified by both the ACR and the Systemic Lupus International Collaborating Clinics (SLICC) criteria, patients with primary Sjögren's syndrome (SS), and patients with other rheumatic diseases. Individual CB-CAPs were measured by flow cytometry, and positivity rates were compared to those of commonly assessed biomarkers, including serum complement proteins (C3 and C4) and autoantibodies. The frequency of a positive multianalyte assay panel (MAP), which includes CB-CAPs, was also evaluated. Probable SLE cases were followed up prospectively. RESULTS: The 92 patients with probable SLE were diagnosed more recently than the 53 patients with established SLE, and their use of antirheumatic medications was lower. At the enrollment visit, more patients with probable SLE were positive for CB-CAPs (28%) or MAP (40%) than had low complement levels (9%) (P = 0.0001 for each). In probable SLE, MAP scores of >0.8 at enrollment predicted fulfillment of a fourth ACR criterion within 18 months (hazard ratio 3.11, P < 0.01). CONCLUSION: Complement activation occurs in some patients with probable SLE and can be detected with higher frequency by evaluating CB-CAPs and MAP than by assessing traditional serum complement protein levels. A MAP score above 0.8 predicts transition to classifiable SLE according to ACR criteria.

Randomised prospective trial to assess the clinical utility of multianalyte assay panel with complement activation products for the diagnosis of SLE.

OBJECTIVE: We compared the physician-assessed diagnostic likelihood of SLE resulting from standard diagnosis laboratory testing (SDLT) to that resulting from multianalyte assay panel (MAP) with cell-bound complement activation products (MAP/CB-CAPs), which reports a two-tiered index test result having 80% sensitivity and 86% specificity for SLE. METHODS: Patients (n=145) with a history of positive antinuclear antibody status were evaluated clinically by rheumatologists and randomised to SDLT arm (tests ordered at the discretion of the rheumatologists) or to MAP/CB-CAPs testing arm. The primary endpoint was based on the change in the physician likelihood of SLE on a five-point Likert scale collected before and after testing. Changes in pharmacological treatment based on laboratory results were assessed in both arms. Statistical analysis consisted of Wilcoxon and Fisher's exact tests. RESULTS: At enrolment, patients randomised to SDLT (n=73, age=48±2 years, 94% females) and MAP/CB-CAPs testing arms (n=72, 50±2 years, 93% females) presented with similar pretest likelihood of SLE (1.42±0.06 vs 1.46±0.06 points, respectively; p=0.68). Post-test likelihood of SLE resulting from randomisation in the MAP/CB-CAPs testing arm was significantly lower than that resulting from randomisation to SDLT arm on review of test results (-0.44±0.10 points vs -0.19±0.07 points) and at the 12-week follow-up visit (-0.61±0.10 points vs -0.31±0.10 points) (p<0.05). Among patients randomised to the MAP/CB-CAPs testing arm, two-tiered positive test results associated significantly with initiation of prednisone (p=0.034). CONCLUSION: Our data suggest that MAP/CB-CAPs testing has clinical utility in facilitating SLE diagnosis and treatment decisions.

Safety and Efficacy of Belimumab Plus Standard Therapy for Up to Thirteen Years in Patients With Systemic Lupus Erythematosus.

OBJECTIVE: To investigate the long-term safety and efficacy of intravenous (IV) belimumab plus standard of care (SOC) therapy for systemic lupus erythematosus (SLE) in patients with active, autoantibody-positive SLE. METHODS: The study was designed as a multicenter, open-label, continuation study of IV belimumab given every 4 weeks in conjunction with SOC therapy in patients with SLE who completed a phase II, double-blind study. Adverse events (AEs) and laboratory data were monitored from the first belimumab dose (in either study) until 24 weeks after the final dose. Efficacy assessments included SLE Responder Index (SRI) and flare index scores (each assessed at 16-week intervals) and glucocorticoid use (assessed at 4-week intervals). RESULTS: Of the 476 patients in the parent study, 298 (62.6%) entered the continuation study, of whom 96 (32.2%) remained in the study. Patients received belimumab for up to 13 years (median duration of exposure 3,334.0 days [range 260-4,332 days], total belimumab exposure 2,294 patient-years, median number of infusions 115.5 [range 7-155]). The percentage of patients with AEs each year remained stable or decreased. Normal serum IgG levels were maintained in the majority of patients over the study, and the rate of infections remained stable. The percentage of patients who achieved an SRI response increased from 32.8% (year 1) to 75.6% of those remaining on treatment at year 12. The glucocorticoid dose was decreased in patients who had been receiving >7.5 mg/day at baseline. CONCLUSION: This study is the longest to date to assess belimumab treatment in patients with SLE in clinical trials. Belimumab was well tolerated with no new safety concerns, and efficacy was maintained in patients who continued the study. For patients who initially exhibited a satisfactory response to belimumab, the treatment continues to be well tolerated and provides long-term disease control.

Validation of a multi-analyte panel with cell-bound complement activation products for systemic lupus erythematosus.

BACKGROUND: We describe the analytical validation of an assay panel intended to assist clinicians with the diagnosis of systemic lupus erythematosus (SLE). The multi-analyte panel includes quantitative assessment of complement activation and measurement of autoantibodies. METHODS: The levels of the complement split product C4d bound to erythrocytes (EC4d) and B-lymphocytes (BC4d) (expressed as mean fluorescence intensity [MFI]) are measured by quantitative flow cytometry, while autoantibodies (inclusive of antinuclear and anti-double stranded DNA antibodies) are determined by immunoassays. Results of the multi-analyte panel are reported as positive or negative based on a 2-tiered index score. Post-phlebotomy stability of EC4d and BC4d in EDTA-anticoagulated blood is determined using specimens collected from patients with SLE and normal donors. Three-level C4 coated positive beads are run daily as controls. Analytical validity is reported using intra-day and inter-day coefficient of variation (CV). RESULTS: EC4d and BC4d are stable for 2days at ambient temperature and for 4days at 4°C post-phlebotomy. Median intra-day and inter-day CV range from 2.9% to 7.8% (n=30) and 7.3% to 12.4% (n=66), respectively. The 2-tiered index score is reproducible over 4 consecutive daysupon storage of blood at 4°C. A total of 2,888 three-level quality control data were collected from 6 flow cytometers with an overall failure rate below 3%. Median EC4d level is 6 net MFI (Interquartile [IQ] range 4-9 net MFI) and median BC4d is 18 net MFI (IQ range 13-27 net MFI) among 86,852 specimens submitted for testing. The incidence of 2-tiered positive test results is 13.4%. CONCLUSION: We have established the analytical validity of a multi-analyte assay panel for SLE.

Clinical and patient-reported outcomes of bilateral implantation of a +2.5 diopter multifocal intraocular lens.

PURPOSE: To assess the effectiveness and safety of a multifocal intraocular lens (IOL) with +2.5 diopter (D) additional power compared with a monofocal IOL. SETTING: Fifteen sites in the United States. DESIGN: Prospective randomized patient- and observer-masked clinical trial. METHODS: Randomized patients received multifocal or monofocal IOLs bilaterally. Visual acuity (33 cm, 40 cm, 53 cm, 60 cm, 4 m) was measured; safety was assessed through adverse event rates. Patient-reported visual outcomes were evaluated using the Visual Tasks questionnaire. The frequency and severity of visual disturbances were evaluated using the Assessment of Photic Phenomena and Lens EffectS questionnaire. RESULTS: The multifocal IOL (n = 155) provided better corrected distance visual acuity at 53 cm than the monofocal IOL (n = 165) (0.322 versus 0.512 logMAR; between-group difference, -0.190 logMAR; P < .0001) and 40 cm but not at 4 m. Ocular adverse event rates were less than 3.84% in both groups. Serious adverse event rates were comparable between the 2 IOL types. Patients with multifocal IOLs reported less difficulty with near tasks (with and without correction) and intermediate tasks (without correction). Difficulty with extended-intermediate and distance tasks was similar between groups. The most frequently reported self-rated severe phenomena were halos, starbursts, and glare. Most patients (monofocal ≥72%; multifocal ≥73%) reported never experiencing blurred, distorted, or double vision. CONCLUSIONS: The +2.5 D multifocal IOL provided better vision at 40 cm and 53 cm and similar vision at 4 m compared with the monofocal IOL. Safety profiles and visual phenomena were comparable between groups.

Cell-bound complement activation products in systemic lupus erythematosus: comparison with anti-double-stranded DNA and standard complement measurements.

OBJECTIVE: To compare the performance characteristics of cell-bound complement (C4d) activation products (CBCAPS) on erythrocyte (EC4d) and B cells (BC4d) with antibodies to double-stranded DNA (anti-dsDNA) and complement C3 and C4 in systemic lupus erythematosus (SLE). METHODS: The study enrolled 794 subjects consisting of 304 SLE and a control group consisting of 285 patients with other rheumatic diseases and 205 normal individuals. Anti-dsDNA and other autoantibodies were measured using solid-phase immunoassays while EC4d and BC4d were determined using flow cytometry. Complement proteins were determined using immunoturbidimetry. Disease activity in SLE was determined using a non-serological Systemic Lupus Erythematosus Disease Activity Index SELENA Modification. A two-tiered methodology combining CBCAPS with autoantibodies to cellular and citrullinated antigens was also developed. Statistical analyses used area under receiver operating characteristic curves and calculations of area under the curve (AUC), sensitivity and specificity. RESULTS: AUC for EC4d (0.82±0.02) and BC4d (0.84±0.02) was higher than those yielded by C3 (0.73±0.02) and C4 (0.72±0.02) (p<0.01). AUC for CBCAPS was also higher than the AUC yielded by anti-dsDNA (0.79±0.02), but significance was only achieved for BC4d (p<0.01). The combination of EC4d and BC4d in multivariate testing methodology with anti-dsDNA and autoantibodies to cellular and citrullinated antigens yielded 80% sensitivity for SLE and specificity ranging from 70% (Sjogren's syndrome) to 92% (rheumatoid arthritis) (98% vs. normal). A higher proportion of patients with SLE with higher levels of disease activity tested positive for elevated CBCAPS, reduced complement and anti-dsDNA (p<0.03). CONCLUSIONS: CBCAPS have higher sensitivity than standard complement and anti-dsDNA measurements, and may help with the differential diagnosis of SLE in combination with other autoantibodies.

Disease control and safety of belimumab plus standard therapy over 7 years in patients with systemic lupus erythematosus.

OBJECTIVE: To evaluate the efficacy/safety of belimumab plus standard therapy in patients (n = 449) with active systemic lupus erythematosus (SLE) treated up to 7 years (n = 177 currently ongoing). METHODS: Patients (n = 345) who completed a double-blind, placebo-controlled, 52-week study of belimumab 1, 4, or 10 mg/kg and 24-week extension of belimumab (placebo switched to 10 mg/kg; belimumab same dose or switched to 10 mg/kg) could receive belimumab 10 mg/kg in an open-label continuation study (n = 296). Disease activity was analyzed in patients with active SLE at baseline of the initial study. Biomarker and SLE medication changes were evaluated, and adverse events (AE) were monitored throughout the study. RESULTS: Total belimumab exposure over 7 years (double-blind and open-label periods): 1746 patient-years. SLE Responder Index (SRI) response rates at Week 52 in autoantibody-positive patients: placebo, 29%; belimumab, 46% (p < 0.05). In the continuation study, 57% of auto-antibody-positive patients had an SRI response by Year 2 and 65% by Year 7; severe flares occurred in 19% with placebo and 17% with belimumab during the first year, with the annual rate declining to 2%-9% during years 2-7. Anti-dsDNA autoantibodies in patients positive for them at baseline had a progressive decline of 40%-60% from baseline over 2-7 years with belimumab. Corticosteroid use decreased over time with ≥ 50-55% reduction in median dose during years 5-7. Serious and overall annual AE rates, including infections, were generally stable or decreased during 7-year treatment. CONCLUSION: Disease control and safety profile were maintained in patients with active SLE taking belimumab plus standard therapy for up to 7 years. [ClinicalTrials.gov numbers: NCT00071487 and NCT00583362].

Measurement of cell-bound complement activation products enhances diagnostic performance in systemic lupus erythematosus.

OBJECTIVE: To determine the value of cell-bound complement activation products in combination with antinuclear antibody (ANA), anti-double-stranded DNA antibody (anti-dsDNA), and anti-mutated citrullinated vimentin antibody (anti-MCV) for the diagnosis of systemic lupus erythematosus (SLE). METHODS: This was a multicenter cross-sectional study in which 593 subjects were enrolled (210 SLE patients, 178 patients with other rheumatic diseases, and 205 healthy subjects). Complement receptor 1 levels on erythrocytes (ECR1) together with complement C4d levels on erythrocytes (EC4d), platelets (PC4d), and B cells (BC4d) were determined using fluorescence-activated cell sorting. Serologic markers were measured by enzyme-linked immunosorbent assay. Statistical analyses were performed using area under the curve (AUC), logistic regression, and calculations of diagnostic sensitivity and specificity. RESULTS: Anti-dsDNA was an insensitive (30%) but specific (>95%) marker for SLE. Levels of EC4d, BC4d, and PC4d were several times higher, and levels of ECR1 lower, in SLE patients compared to patients with other rheumatic diseases and healthy subjects. Among 523 anti-dsDNA-negative subjects, multivariate logistic regression analysis revealed that SLE was associated with ANA positivity (≥20 units), anti-MCV negativity (≤70 units), and elevated levels of both EC4d and BC4d (AUC 0.918, P < 0.001). A positive index score corresponding to the weighted sum of these 4 markers correctly categorized 72% of SLE patients. Specificity in relation to patients with other rheumatic diseases and healthy controls was >90%. The combination of anti-dsDNA and index score positivity yielded 80% sensitivity for SLE and 87% specificity against other rheumatic diseases. CONCLUSION: An assay panel combining anti-dsDNA, ANA, anti-MCV, EC4d, and BC4d is sensitive and specific for the diagnosis of SLE.

Correlates of axial gout: a cross-sectional study.

OBJECTIVE: A cross-sectional study was undertaken to determine the prevalence of axial gout in patients with established gouty arthritis and to analyze clinical, laboratory, and radiological correlations. METHODS: Forty-eight subjects with a history of gouty arthritis (American College of Rheumatology criteria) for ≥ 3 years under poor control were included. Subjects underwent history, physical examination, laboratory testing, and imaging studies, including radiographs of the hands and feet and computerized tomography (CT) of the cervical and lumbar spines and sacroiliac joints (SIJ). Patients with characteristic erosions and/or tophi in the spine or SIJ were considered to have axial or spinal gout. RESULTS: Seventeen patients (35%) had CT evidence of spinal erosions and/or tophi, with tophi identified in 7 of the 48 subjects (15%). The spinal location of axial gout was cervical in 7 patients (15%), lumbar in 16 (94%), SIJ in 1 (6%), and more than 1 location in 14 (82%). Duration of gout, presence of back pain, and serum uric acid levels did not correlate with axial gout. Extremity radiographs characteristic of gouty arthropathy found in 21 patients (45%) were strongly correlated with CT evidence of axial gout (p < 0.001). All patients with tophi in the spine had abnormal hand or feet radiographs (p = 0.005). CONCLUSION: Axial gout may be a common feature of chronic gouty arthritis. The lack of correlation with back pain, the infrequent use of CT imaging in patients with back pain, and the lack of recognition of the problem of spinal involvement in gouty arthritis suggest that this diagnosis is often missed.