Paloma Vela

Synovial Fluid Analysis for Diagnosis of Intercritical Gout

Patients with gout tend to seek medical attention during gout attacks, at which point the standard diagnostic procedure is to search for monosodium urate crystals in synovial fluid. But patients are often seen during the intercritical periods, when, in the absence of tophi, the diagnosis is made on clinical grounds by applying the preliminary American College of Rheumatology classification criteria (1). However, classification criteria work best in the study of groups of patients, and they often fail in the evaluation of the individual patient (2, 3). A clinical approach for the diagnosis of gout may be problematic (4) and may explain why other conditions are often incorrectly diagnosed and treated as gout (5). Monosodium urate crystals can be found in synovial fluid obtained from asymptomatic gouty joints (6-11). These crystals were found in 36 of 37 asymptomatic but previously inflamed knees from patients with gout who were not receiving hypouricemic agents (12). This finding indicates that after the crystals form, they stay in the joints if serum uric acid levels are not reduced (12). Thus, it has been suggested that identification of crystals in synovial fluid may be used to diagnose gout during intercritical periods (7, 12). We sought to determine whether aspiration of asymptomatic first metatarsophalangeal and knee joints offers a practical approach for the precise diagnosis of gout during intercritical periods. Methods Arthrocentesis was attempted in 101 asymptomatic joints (80 knees and 21 first metatarsophalangeal joints) from 101 patients with gout: 99 men and 2 women 30 to 83 years of age (mean age SD, 55.6 12.5 years). The median disease duration was 5 years (range, 2 months to 37 years; interquartile range, 2.5 to 11 years). In 78 patients, gout had previously been diagnosed by identification of monosodium urate crystals in synovial fluid obtained from inflamed joints; in the remaining 23 patients, the diagnosis was made clinically on the basis of recurrent typical attacks, including podagra and hyperuricemia. All patients fulfilled the preliminary American College of Rheumatology criteria for the classification of gout (1). For each patient, we recorded current serum uric acid levels, time elapsed since the last gout attack, the number of previous attacks in the joint being aspirated, treatment with hypouricemic agents, and duration of this treatment. Patients also received either allopurinol or benzbromarone, but data on the type of treatment were not recorded. All studied joints had been inflamed, and at least 2 months must have elapsed since the resolution of the last attack. The first metatarsophalangeal joint was approached dorsally after the tip of the toe had been pulled to open the joint space; a 25-gauge needle was used for aspiration of this joint. The ethical committee of our hospital approved the study, and each patient provided informed consent. The presence of monosodium urate crystals in synovial fluid samples was investigated immediately after extraction of the fluid by simple polarized light microscopy (magnification, 400); when crystals were detected, their negative bi-refringence was ascertained by using a first-order red compensator (13). To quantify the effort needed to find crystals, we counted the number of microscope fields that had to be examined before a crystal was found. On the basis of our previous experience with searching for crystals in synovial fluid of asymptomatic joints, we decided to count a maximum of 30 fields. When monosodium urate crystals were present in the first microscope field examined, we counted until a maximum of 5 crystals had been identified. Four rheumatologists from three separate sites participated in the study. Statistical Analysis Descriptive statistics are used to present the data. Comparisons were made by using the Pearson chi-square test; the Mann-Whitney U-test; or, if the two populations differed in dispersion, the Kolmogorov-Smirnov two-sample test. All reported P values are two-sided. Analyses were conducted by using SPSS Statistical Package for Windows, release 6.12 (SPSS, Inc., Chicago, Illinois). Results Synovial fluid samples were obtained from 91 of the 101 joints (90%): 73 of 80 knees (91%) and 18 of 21 first metatarsophalangeal joints (86%) (P>0.2). The rate at which synovial fluid was obtained was similar for all participating physicians (between 80% and 93%); only two physicians aspirated more than 1 metatarsophalangeal joint. Crystals were found in all 43 synovial fluid samples (100% [95% CI, 92% to 100%]) obtained from patients not receiving hypouricemic agents (Figure, top). All of these patients had a serum uric acid level greater than 357 mol/L, and 41 (91%) of them had a level that exceeded 416 mol/L. Figure. Presence ( white bars ) or absence ( striped bars ) of monosodium urate crystals in synovial fluid according to the time elapsed since the last gout attack. Top. n Bottom. n P The remaining 48 synovial fluid samples (out of 91 [53%]) were from patients receiving hypouricemic agents. These patients had lower levels of serum uric acid (treated patients: median, 351 mol/L [interquartile range, 280 to 422 mol/L]; untreated patients: median, 500 mol/L [interquartile range, 446 to 559 mol/L]; P<0.001, Kolmogorov-Smirnov two-sample test), although 27% of them had serum uric acid levels greater than 416 mol/L. The median time since the last gout attack in these patients was 10 months (untreated group, 9 months; P>0.2, Kolmogorov-Smirnov two-sample test). In the treated group, monosodium urate crystals were found in 34 of 48 (71% [CI, 56% to 83%]) of the synovial fluid samples; the absence of crystals in synovial fluid correlated positively with more time elapsed since the last attack (P<0.001) (Figure, bottom), lower levels of uric acid, and longer duration of therapy (Table). Table. Characteristics of 48 Patients Receiving Hypouricemic Treatment according to Presence of Crystals in Synovial Fluid Samples from Asymptomatic Joints When we considered all 91 joints from which a synovial fluid sample was obtained, monosodium urate crystals were found in similar proportions in synovial fluid obtained from knees (61 of 73 [84%]) and first metatarsophalangeal joints (16 of 18 [89%]) (P>0.2). Monosodium urate crystals were found in the first microscope field examined in 47 of 77 (61% [CI, 49% to 72%]) of the synovial fluid samples containing these crystals; crystals were found in 90% (CI, 81% to 95%) of joints when the first five microscope fields examined were considered. Furthermore, of the 47 synovial fluid samples in which the crystals were seen in the first field, 38 (81% [CI, 67% to 91%]) contained more than one crystal. We found no relation between synovial fluid obtained from knees or first metatarsophalangeal joints and the number of microscope fields that had to be examined to find crystals. Discussion Our data indicate that arthrocentesis to obtain a synovial fluid sample from asymptomatic knees and first metatarsophalangeal joints is a successful procedure in most cases; no patient had complications. Monosodium urate crystals were found in all 43 synovial fluid samples obtained from patients who did not receive hypouricemic agents. This finding indicates a high sensitivity of this diagnostic approach in these patients; none had low uric acid levels. Similar results in untreated patients have been reported [9, 12]. We found monosodium urate crystals in only 34 of the 48 synovial fluid samples from patients receiving hypouricemic agents. Length of treatment, lower uric acid levels, and longer time since the last attack were related to the absence of crystals. These data are consistent with the following events: 1) As a result of hyperuricemia, monosodium urate crystals form in the joint, remain present while hyperuricemia persists, and can be found in the synovial fluid at any time [12]; and 2) when serum uric acid levels are reduced to normal, the monosodium urate crystals slowly dissolve and finally disappear from the joint, as is noted with crystals that form tophi (14). It is postulated that after crystals disappear from a joint, gout attacks no longer occur unless hyperuricemia recurs and monosodium urate crystals again form in the joint. In a previous study (10), monosodium urate crystals were found in only about half of the synovial fluid samples obtained from asymptomatic knees of patients with gout who received and those who did not receive hypouricemic treatment. However, the mean uric acid level was similar in both groups, and uric acid levels were not elevated in about 50% of both treated and untreated patients (10). Aspiration of the first metatarsophalangeal joint of 23 patients with gout allowed detection of crystals in 16 synovial fluid samples, but some of the joints had never been inflamed and most patients were being treated with allopurinol (8). The possible finding of monosodium urate crystals in never-inflamed joints of patients with gout is well documented (6, 8, 12), and crystals have been identified in the joints of patients with hyperuricemia and renal failure (8). In the synovial fluid samples that contained crystals, crystals were generally abundant. When the first five microscope fields were examined, the crystals were seen in 90% of these samples. The duration of examination of a synovial fluid sample to determine whether it contains crystals has not been critically ascertained, but it has been considered reasonable to search for about 10 minutes before deciding that no crystals are present. We counted microscope fields in an attempt to more objectively quantify the effort needed to find the crystals. Our data support the use of synovial fluid analysis of previously inflamed, asymptomatic knees or first metatarsophalangeal joints as a simple bedside procedure for the diagnosis of intercritical gout. Such an approach may facilitate the diagnosis of gout and help to avoid unnecessary diagnost

Tocilizumab in giant cell arteritis: Multicenter open-label study of 22 patients

OBJECTIVE To assess the efficacy of tocilizumab (TCZ) in giant cell arteritis (GCA) patients with refractory disease and/or with unacceptable side effects due to corticosteroids. METHODS A retrospective multicenter open-label study on 22 GCA patients treated with TCZ at standard dose of 8mg/kg/month. The main outcomes were achievement of disease remission and reduction of corticosteroid dose. RESULTS The mean age ± standard deviation of patients was 69 ± 8 years. The main clinical features at TCZ onset were polymyalgia rheumatica (n = 16), asthenia (n = 7), headache (n =5), constitutional symptoms (n = 4), jaw claudication (n = 2), and visual loss (n = 2). Besides corticosteroids and before TCZ onset, 19 of 22 patients had also received several conventional immunosuppressive and/or biologic drugs. Of 22 patients, 19 achieved rapid and maintained clinical improvement following TCZ therapy. Also, after a median follow-up of 9 (interquartile range: 6-19) months, the C-reactive protein level had fallen from 1.9 (1.2-5.4) to 0.2 (0.1-0.9)mg/dL (p < 0.0001) and the erythrocyte sedimentation rate decreased from 44 (20-81) to 12 (2-20)mm/1st hour (p = 0.001). The median dose of prednisone was also tapered from 18.75 (10-45) to 5 (2.5-10)mg/day (p < 0.0001). However, TCZ had to be discontinued in 3 patients due to severe neutropenia, recurrent pneumonia, and cytomegalovirus infection. Moreover, 1 patient died after the second infusion of TCZ due to a stroke in the setting of an infectious endocarditis. CONCLUSION TCZ therapy leads to rapid and maintained improvement in patients with refractory GCA and/or with unacceptable side effects related to corticosteroids. However, the risk of infection should be kept in mind when using this drug in patients with GCA.

Spanish Rheumatology Society and Hospital Pharmacy Society Consensus on recommendations for biologics optimization in patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis

Objective. The aim of this study was to establish guidelines for the optimization of biologic therapies for health professionals involved in the management of patients with RA, AS and PsA. Methods. Recommendations were established via consensus by a panel of experts in rheumatology and hospital pharmacy, based on analysis of available scientific evidence obtained from four systematic reviews and on the clinical experience of panellists. The Delphi method was used to evaluate these recommendations, both between panellists and among a wider group of rheumatologists. Results. Previous concepts concerning better management of RA, AS and PsA were reviewed and, more specifically, guidelines for the optimization of biologic therapies used to treat these diseases were formulated. Recommendations were made with the aim of establishing a plan for when and how to taper biologic treatment in patients with these diseases. Conclusion. The recommendations established herein aim not only to provide advice on how to improve the risk:benefit ratio and efficiency of such treatments, but also to reduce variability in daily clinical practice in the use of biologic therapies for rheumatic diseases.

Silent Monosodium Urate Crystal Deposits Are Associated With Severe Coronary Calcification in Asymptomatic Hyperuricemia: An Exploratory Study.

To evaluate the association between monosodium urate (MSU) crystal deposits in patients with asymptomatic hyperuricemia and the severity and extension of coronary artery disease (CAD).

Comprehensive Description of Clinical Characteristics of a Large Systemic Lupus Erythematosus Cohort from the Spanish Rheumatology Society Lupus Registry (RELESSER) With Emphasis on Complete Versus Incomplete Lupus Differences

AbstractSystemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ involvement and pronounced racial and ethnic heterogeneity. The aims of the present work were (1) to describe the cumulative clinical characteristics of those patients included in the Spanish Rheumatology Society SLE Registry (RELESSER), focusing on the differences between patients who fulfilled the 1997 ACR-SLE criteria versus those with less than 4 criteria (hereafter designated as incomplete SLE (iSLE)) and (2) to compare SLE patient characteristics with those documented in other multicentric SLE registries.RELESSER is a multicenter hospital-based registry, with a collection of data from a large, representative sample of adult patients with SLE (1997 ACR criteria) seen at Spanish rheumatology departments. The registry includes demographic data, comprehensive descriptions of clinical manifestations, as well as information about disease activity and severity, cumulative damage, comorbidities, treatments and mortality, using variables with highly standardized definitions.A total of 4.024 SLE patients (91% with ≥4 ACR criteria) were included. Ninety percent were women with a mean age at diagnosis of 35.4 years and a median duration of disease of 11.0 years. As expected, most SLE manifestations were more frequent in SLE patients than in iSLE ones and every one of the ACR criteria was also associated with SLE condition; this was particularly true of malar rash, oral ulcers and renal disorder. The analysis—adjusted by gender, age at diagnosis, and disease duration—revealed that higher disease activity, damage and SLE severity index are associated with SLE [OR: 1.14; 95% CI: 1.08–1.20 (P < 0.001); 1.29; 95% CI: 1.15–1.44 (P < 0.001); and 2.10; 95% CI: 1.83–2.42 (P < 0.001), respectively]. These results support the hypothesis that iSLE behaves as a relative stable and mild disease. SLE patients from the RELESSER register do not appear to differ substantially from other Caucasian populations and although activity [median SELENA-SLEDA: 2 (IQ: 0–4)], damage [median SLICC/ACR/DI: 1 (IQ: 0–2)], and severity [median KATZ index: 2 (IQ: 1–3)] scores were low, 1 of every 4 deaths was due to SLE activity.RELESSER represents the largest European SLE registry established to date, providing comprehensive, reliable and updated information on SLE in the southern European population.

Gout treatment: should we aim for rapid crystal dissolution?

Monosodium urate crystal deposition in gout precedes the first attack and, while hyperuricaemia persists, it grows and expands to other sites. Fortunately, it is reversible and slowly dissolves when serum uric acid (SUA) is lowered below its saturation point of about 6.8 mg/dl and with certainty below 6 mg/dl. Crystals finally disappear from joints, taking longer in those patients with longer disease duration, probably because of a larger accumulated load of crystals. The SUA level achieved affects the velocity of crystal dissolution and tophi reduction. Accordingly, by deciding the SUA level cut-off point to be achieved by treatment we are determining the time of crystal disappearance and cure of gout. 6 mg/dl is the usual target level, but lower levels appear appropriate to us, particularly in certain situations.

Criteria for Gout Diagnosis

Diagnosis is the proper classification of an individual patient. Efforts to develop clinical criteria for the classification of gout, which are often used to diagnose individual patients, continue, as the article by Prowse, et al shows in this issue of The Journal 1. A proper approach to gout diagnosis implies that, if possible, (1) all patients presenting with the disease have to be properly diagnosed, and (2) in all cases the diagnosis must be correct, so gout does not go undetected and is not misclassified. Gout results from monosodium urate (MSU) crystal deposition, which is responsible for all clinical consequences of the disease. MSU crystals are large enough to be easily detected and identified by an ordinary microscope fitted with polarized filters, which clearly shows the highly birefringent MSU crystals shining on the dark microscope field. The addition of a first-order red compensator helps in definitive distinction from calcium pyrophosphate (CPP) and other crystals2. Crystals form as a result of elevated serum uric acid (SUA) levels; they slowly dissolve and finally disappear when SUA levels are brought back to normal; thus, the disease is now considered curable3. Because it is associated with an elevated cardiovascular risk4 and, when advanced, can be very disabling, gout cannot be taken as a minor disease. MSU crystals are regularly present in synovial fluid … Address correspondence to Prof. E. Pascual, Rheumatology Section, Hospital General Universitario, Maestro Alonso 109, Alicante, 03010, Spain. E-mail: pascual_eli{at}gva.es

Cardiovascular risk of patients with gout seen at rheumatology clinics following a structured assessment

Objectives Gout-associated cardiovascular (CV) risk relates to comorbidities and crystal-led inflammation. The aim was to estimate the CV risk by prediction tools in new patients with gout and to assess whether ultrasonographic carotid changes are present in patients without high CV risk. Methods Cross-sectional study. Consecutive new patients with crystal-proven gout underwent a structured CV consultation, including CV events, risk factors and two risk prediction tools—the Systematic COronary Evaluation (SCORE) and the Framingham Heart Study (FHS). CV risk was stratified according to current European guidelines. Carotid ultrasound (cUS) was performed in patients with less than very high CV risk. The presence of carotid plaques was studied depending on the SCORE and FHS by the area under the curve (AUC) of receiver operating curves. Results 237 new patients with gout were recruited. CV stratification by scores showed a predominance of very high (95 patients, 40.1%) and moderate (72 patients, 30.5%) risk levels. cUS was performed in 142 patients, finding atheroma plaques in 66 (46.5%, 95% CI 37.8 to 54.2). Following cUS findings, patients classified as very high risk increased from 40.1% up to 67.9% (161/237 patients). SCORE and FHS predicted moderately (AUC 0.711 and 0.683, respectively) the presence of atheroma plaques at cUS. Conclusions The majority of patients presenting with gout may be at very high CV risk, indicating the need for initiating optimal prevention strategies at this stage. Risk prediction tools appear to underestimate the presence of carotid plaque in patients with gout.

A deletion at ADAMTS9-MAGI1 locus is associated with psoriatic arthritis risk

Objective Copy number variants (CNVs) have been associated with the risk to develop multiple autoimmune diseases. Our objective was to identify CNVs associated with the risk to develop psoriatic arthritis (PsA) using a genome-wide analysis approach. Methods A total of 835 patients with PsA and 1498 healthy controls were genotyped for CNVs using the Illumina HumanHap610 BeadChip genotyping platform. Genomic CNVs were characterised using CNstream analysis software and analysed for association using the χ2 test. The most significant genomic CNV associations with PsA risk were independently tested in a validation sample of 1133 patients with PsA and 1831 healthy controls. In order to test for the specificity of the variants with PsA aetiology, we also analysed the association to a cohort of 822 patients with purely cutaneous psoriasis (PsC). Results A total of 165 common CNVs were identified in the genome-wide analysis. We found a highly significant association of an intergenic deletion between ADAMTS9 and MAGI1 genes on chromosome 3p14.1 (p=0.00014). Using the independent patient and control cohort, we validated the association between ADAMTS9-MAGI1 deletion and PsA risk (p=0.032). Using next-generation sequencing, we characterised the 26 kb associated deletion. Finally, analysing the PsC cohort we found a lower frequency of the deletion compared with the PsA cohort (p=0.0088) and a similar frequency to that of healthy controls (p>0.3). Conclusions The present genome-wide scan for CNVs associated with PsA risk has identified a new deletion associated with disease risk and which is also differential from PsC risk.

Febuxostat for Patients With Gout and Severe Chronic Kidney Disease: Which Is the Appropriate Dosage? Comment on the Article by Saag et al.

To the Editor: We read with interest the recent report by Saag et al on the effects of the nonpurine selective xanthine oxidase inhibitor febuxostat on kidney function in patients with gout (1). The main advantage of this treatment is that febuxostat is predominantly metabolized by the liver, enabling reduction of serum uric acid (UA) levels in patients with gout and chronic kidney disease (2). But the exclusion of patients with severe chronic kidney disease (glomerular filtration rate [GFR] ,30 ml/minute) in the pivotal clinical trials of febuxostat led to the recommendation that it be used with caution in these patients (3). The findings in the exploratory trial performed by Saag and colleagues (1) indicate that febuxostat remains safe and effective in patients with GFRs as low as 15 ml/minute (end-stage disease), although the small number of patients studied (n 5 96) precludes the establishment of firm conclusions. We were surprised by the febuxostat dosage used in their study (30 mg twice daily or 40 mg [titrated to 80 mg in 62.5% of cases] once daily. The rationale of these reduced dosages is not stated by the authors and not supported by the findings of preliminary febuxostat studies (4). In the US febuxostat is approved at 40and 80-mg tablets and in Europe at 80 and 120 mg, so it may be difficult to treat patients according to the dosage scheme in the trial. In our practice, febuxostat at usual (European) dosages is safe and serum UA targets are achieved, even in patients with severe chronic kidney disease. We retrospectively reviewed outcomes in febuxostat-treated patients with crystal-proven gout, with a focus on the group with severe chronic kidney disease. We analyzed changes in serum UA levels and rates of achievement of different serum UA cutoffs (6, 5, and 4 mg/dl) after 6 months of febuxostat treatment, and compared patients subgrouped according to GFR (