Mariano Andrés

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).

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 6.8u2005mg/dl and with certainty below 6u2005mg/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. 6u2005mg/dl is the usual target level, but lower levels appear appropriate to us, particularly in certain situations.

Gout: optimizing treatment to achieve a disease cure.

Gout is one of the most common inflammatory arthritides. The disease is due to the deposition of monosodium urate crystals. These deposits are reversible with proper treatment, suggesting that gout is a curable disease. The main aim in gout is to lower serum uric acid levels to a pre-established target; there are different urate-lowering drugs (xanthine oxidase inhibitors, uricosurics and uricases) through which this can be achieved. Proper treatment of gout also involves correct management of acute flares and their prevention. To ensure treatment adherence it is necessary to explain to the patient what the objectives are.

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.nnGout 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 … nnAddress correspondence to Prof. E. Pascual, Rheumatology Section, Hospital General Universitario, Maestro Alonso 109, Alicante, 03010, Spain. E-mail: pascual_eli{at}gva.es

Incidence, associated factors and clinical impact of severe infections in a large, multicentric cohort of patients with systemic lupus erythematosus

OBJECTIVESnTo estimate the incidence of severe infection and investigate the associated factors and clinical impact in a large systemic lupus erythematosus (SLE) retrospective cohort.nnnMETHODSnAll patients in the Spanish Rheumatology Society Lupus Registry (RELESSER) who meet ≥4 ACR-97 SLE criteria were retrospectively investigated for severe infections. Patients with and without infections were compared in terms of SLE severity, damage, comorbidities, and demographic characteristics. A multivariable Cox regression model was built to calculate hazard ratios (HRs) for the first infection.nnnRESULTSnA total of 3658 SLE patients were included: 90% female, median age 32.9 years (DQ 9.7), and mean follow-up (months) 120.2 (±87.6). A total of 705 (19.3%) patients suffered ≥1 severe infection. Total severe infections recorded in these patients numbered 1227. The incidence rate was 29.2 (95% CI: 27.6-30.9) infections per 1000 patient years. Time from first infection to second infection was significantly shorter than time from diagnosis to first infection (p < 0.000). Although respiratory infections were the most common (35.5%), bloodstream infections were the most frequent cause of mortality by infection (42.0%). In the Cox regression analysis, the following were all associated with infection: age at diagnosis (HR = 1.016, 95% CI: 1.009-1.023), Latin-American (Amerindian-Mestizo) ethnicity (HR = 2.151, 95% CI: 1.539-3.005), corticosteroids (≥10mg/day) (HR = 1.271, 95% CI: 1.034-1.561), immunosuppressors (HR = 1.348, 95% CI: 1.079-1.684), hospitalization by SLE (HR = 2.567, 95% CI: 1.905-3.459), Katz severity index (HR = 1.160, 95% CI: 1.105-1.217), SLICC/ACR damage index (HR = 1.069, 95% CI: 1.031-1.108), and smoking (HR = 1.332, 95% CI: 1.121-1.583). Duration of antimalarial use (months) proved protective (HR = 0.998, 95% CI: 0.997-0.999).nnnCONCLUSIONSnSevere infection constitutes a predictor of poor prognosis in SLE patients, is more common in Latin-Americans and is associated with age, previous infection, and smoking. Antimalarials exerted a protective effect.

Severe gout: Strategies and innovations for effective management.

Severe gout is characterised by frequent polyarticular flares, numerous tophi, joint damage, and musculoskeletal disability. This is a preventable condition and in many cases, represents a disease that has been insufficiently managed for years. Standard management recommendations may be insufficient for patients with severe gout; these patients frequently require intensive individualised pharmacological management with combinations of urate-lowering therapy and anti-inflammatory agents. In this article, we aim to integrate recent therapeutic advances to provide a practical framework for optimal management of severe gout.

Relationship between damage clustering and mortality in systemic lupus erythematosus in early and late stages of the disease: cluster analyses in a large cohort from the Spanish Society of Rheumatology Lupus Registry

OBJECTIVESnTo identify patterns (clusters) of damage manifestations within a large cohort of SLE patients and evaluate the potential association of these clusters with a higher risk of mortality.nnnMETHODSnThis is a multicentre, descriptive, cross-sectional study of a cohort of 3656 SLE patients from the Spanish Society of Rheumatology Lupus Registry. Organ damage was ascertained using the Systemic Lupus International Collaborating Clinics Damage Index. Using cluster analysis, groups of patients with similar patterns of damage manifestations were identified. Then, overall clusters were compared as well as the subgroup of patients within every cluster with disease duration shorter than 5 years.nnnRESULTSnThree damage clusters were identified. Cluster 1 (80.6% of patients) presented a lower amount of individuals with damage (23.2 vs 100% in clusters 2 and 3, P < 0.001). Cluster 2 (11.4% of patients) was characterized by musculoskeletal damage in all patients. Cluster 3 (8.0% of patients) was the only group with cardiovascular damage, and this was present in all patients. The overall mortality rate of patients in clusters 2 and 3 was higher than that in cluster 1 (P < 0.001 for both comparisons) and in patients with disease duration shorter than 5 years as well.nnnCONCLUSIONnIn a large cohort of SLE patients, cardiovascular and musculoskeletal damage manifestations were the two dominant forms of damage to sort patients into clinically meaningful clusters. Both in early and late stages of the disease, there was a significant association of these clusters with an increased risk of mortality. Physicians should pay special attention to the early prevention of damage in these two systems.

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 (

Current advances in therapies for calcium pyrophosphate crystal arthritis.

30 ml/minute or ,30 ml/minute) at the time of treatment initiation, by chi-square test and MannWhitney U test. Safety data were also recorded. Through December 2015, a total of 84 patients with crystal-proven gout had been treated with febuxostat at our unit (70.2% men; mean 6 SD age 72.1 6 13.7 years). Sixty-five percent had received another urate-lowering agent (allopurinol or benzbromarone) before febuxostat. In 20 of the patients (23.8%), febuxostat was started when the GFR was ,30 ml/minute (,15 ml/minute in 1 case). In both groups, 80 mg/day was the most common dosage of febuxostat used (75.0% of the patients with GFR

Methotrexate: should it still be considered for chronic calcium pyrophosphate crystal disease?

30 ml/minute and 70.0% of the patients with GFR ,30 ml/minute). If response was insufficient, the dosage was often escalated to 120 mg/day (23.4% and 15.0% of patients, respectively). Table 1 shows the treatment outcomes according to baseline GFR. Serum UA levels at baseline were numerically higher in the ,30 ml/minute group, and the difference could have reached significance if the number of patients had been larger. After treatment with febuxostat, the magnitude of serum UA reduction achieved was significantly higher in the GFR ,30 ml/minute group (P 5 0.03); however, the proportions of patients in whom the different serum UA end points were reached were similar in the 2 groups. The GFR did not change after 6 months in either group. Febuxostat treatment was discontinued in 6 patients due to adverse events (skin reactions in 4), but the rate of discontinuation did not differ significantly by baseline GFR (P 5 1.00). Our results indicate that the European standard dosages of febuxostat (80 mg/day or 120 mg/day) are effective and safe in gout patients with severe renal impairment. Management of gout and chronic kidney disease may be troublesome and lead to difficult-to-treat cases (5) related to several factors, such as insufficient serum UA reduction due to allopurinol adjustment, use of diuretics, or higher crystal load. A benefit of starting febuxostat at a reduced dosage may be to prevent the occurrence of acute flares, which often happen with this treatment. However, proper and sustained serum UA reduction is needed to ensure crystal dissolution (6). Thus, in cases of insufficient reduction in serum UA levels after treatment according to the reduced dosage scheme (1), our data (from a sample size similar to the one in the study by Saag et al) indicate that the febuxostat dosage can be increased to achieve further serum UA reductions (as we found to occur to an even greater extent in patients with severe