Agustín Martínez

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

High prevalence of ultrasonographic synovitis and enthesopathy in patients with psoriasis without psoriatic arthritis: a prospective case–control study

OBJECTIVE To investigate the presence of synovitis, tenosynovitis and enthesitis with power Doppler (PD) ultrasonography (US) in patients with psoriasis without musculoskeletal diseases as compared with controls with other skin diseases without musculoskeletal disorders. METHODS A total of 162 patients with plaque psoriasis and 60 age-matched controls with other skin diseases, all without musculoskeletal diseases, were prospectively recruited at 14 centres. They underwent dermatological and rheumatological assessment and a blinded PDUS evaluation. Clinical assessment included demographics, comorbidities, severity of psoriasis, work and sport activities and musculoskeletal clinical examination. PDUS evaluation consisted of the detection of grey scale (GS) synovitis and synovial PD signal in 36 joints, GS tenosynovitis and tenosynovial PD signal at 22 sites, and GS enthesopathy and entheseal PD signal in 18 entheses. RESULTS US synovitis and enthesopathy were significantly more frequent in psoriatic patients than in controls (P = 0.024 and 0.005, respectively). The percentage of joints with US synovitis was 3.2% in the psoriasis group and 1.3% in the control group (P < 0.0005). US enthesopathy was present in 11.6% of entheses in the psoriasis group and 5.3% of entheses in the control group (P < 0.0005). Entheseal PD signal was found in 10 (7.4%) psoriatic patients, whereas no controls showed this finding (P = 0.05). Among demographic and clinical data, having psoriasis was the only significant predictive variable of the presence of US synovitis [odds ratio (OR) 2.1; P = 0.007] and enthesopathy (OR 2.6; P = 0.027). CONCLUSION Psoriatic patients showed a significant prevalence of asymptomatic US synovitis and enthesopathy, which may indicate a subclinical musculoskeletal involvement.

Ultrasound-detected musculoskeletal urate crystal deposition: which joints and what findings should be assessed for diagnosing gout?

Objective The primary objective of this prospective case-control study was to assess the diagnostic value of several intra-articular and periarticular ultrasound (US)-detected abnormalities in the upper and lower limbs in gout. The secondary objective was to test the concurrent validity of US abnormalities using as gold standard the microscopic demonstration of monosodium urate (MSU) crystals. Methods Ninety-one men with gout and 42 age-matched controls were prospectively recruited. All patients with gout and controls underwent US assessment of several US abnormalities in 26 joints, six bursae, eight tendons, 20 tendon compartments, four ligaments, and 18 articular cartilages by experts in US blinded to the patients’ group. Patients with gout and controls with US abnormalities were asked to undergo US-guided aspiration for microscopic identification of MSU crystals. Interobserver and intraobserver reliability of the US assessment was evaluated in a web-based exercise. Results The assessment of one joint (ie, radiocarpal joint) for hyperechoic aggregates (HAGs), two tendons (ie, patellar tendon and triceps tendon) for HAGs and three articular cartilages (ie, first metatarsal, talar and second metacarpal/femoral) for double contour sign showed the best balance between sensitivity and specificity (84.6% and 83.3%, respectively). Intraobserver reliability was good (mean κ 0.75) and interobserver reliability was moderate (κ 0.52). The aspirated material from HAGs was positive for MSU crystals in 77.6% of patients with gout and negative in all controls. Conclusions Our results suggest that US bilateral assessment of one joint, three articular cartilages and two tendons may be valid for diagnosing gout with acceptable sensitivity and specificity.

Gout: the mechanism of urate crystal nucleation and growth. A hypothesis based in facts.

Joint Bone Spine - In Press.Proof corrected by the author Available online since jeudi 27 septembre 2012

Toward personalized medicine in renal transplantation.

BACKGROUND The pharmacokinetics of tacrolimus (TRL) are clearly affected by genetic polymorphisms in drug-metabolizing enzymes, which lead to large interindividual differences in dose-response relations. In addition, TRL has a narrow therapeutic index requiring monitoring of blood levels. The objective of the present observational, retrospective study was to associate maintenance TRL doses with various genetic markers seeking to guide optimization of the initial dose. METHODS Results of DNA samples from 15 kidney transplant patients were correlated retrospectively with clinical information from medical records. Samples were genotyped using PHARMAchip. Association studies were performed with χ2 and Pearson tests and by analysis of variance. The study was carried out in accordance with international ethical standards of the Helsinki Declaration and approved by our ethics committee. RESULTS Two patient groups were identified to show a difference in TRL dose requirements: a control (0.014-0.10 mg/kg/per day) and an high-dose group (0.14-0.15 mg/kg/per day). The presence of CYP3A5*1 and the null allele in GSTM1 were significantly associated (P=.01 and P=.04) with the need for higher immunosuppressive doses (>0.10 mg/kg/per day). There were no differences in plasma levels of TRL or other clinical variables between the patient groups. CONCLUSION Determination of the CYP3A5 genotype might be used to predict initial TRL requirements, although other genetic variants also provide important information to adjust the drug dose.

Whipple's disease diagnosed during anti-tumor necrosis factor alpha treatment: two case reports and review of the literature

IntroductionWhipple’s disease is a rare infectious disease caused by Tropheryma whipplei with protean clinical manifestations. This infection may mimic chronic inflammatory rheumatisms.Case presentationWe report two cases of Whipple’s disease diagnosed in the context of an inflammatory disease with anti-tumor necrosis factor alpha failure. The first patient was a 58-year-old white man with psoriatic spondylarthritis, who was treated with adalimumab, etanercept, infliximab, tocilizumab and golimumab. The second was a 73-year-old white man with rheumatoid arthritis, who received treatment with infliximab, then etanercept and rituximab.ConclusionsWhipple’s disease should be suspected in all patients diagnosed with chronic inflammatory rheumatism, partially controlled or not controlled by treatment with tumor necrosis factor alpha blockers, whose condition worsens after treatment.