Eliseo Pascual

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).

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.

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 (

Therapy for CPPD: Options and Evidence

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

Editorial: Decreasing Crystal‐Induced Consternation: New Methods of Crystal Identification

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

Decreasing crystal‐induced consternation: New methods of crystal identification

Purpose of ReviewCurrent evidence and accumulated experience for the management of calcium pyrophosphate deposition disease (CPPD) are presented.Recent FindingsContrary to other rheumatic inflammatory conditions that account for high interest and growing research, advances in treating CPPD are still very limited and mostly derive from those achieved in gout.SummaryOnce formed, calcium pyrophosphate crystals cannot be dissolved; therefore, management relies on the control of crystal-derived inflammation. Besides classical agents—such as colchicine, glucocorticoids, or NSAIDs—the use of targeted therapies, mostly against interleukin-1, has provided a relevant relief for refractory CPPD patients in recent years. Meanwhile, former enthusiasm about conventional disease-modifying agents such as methotrexate is currently controversial.

Interleukin-6 pathway blockade as an option for managing refractory cases of crystal arthritis: Two cases report

Daniel J. McCarty, Jr., a major figure in the crystal arthritis field, presented a Heberden Oration lecture in 1982 entitled “Crystals, joints, and consternation” (1). His consternation stemmed from the question of whether control of calcium-containing crystals would prevent the associated inflammatory and degenerative processes which culminate in joint disease. This essential question, along with many other critical questions in the crystal field, remains largely unanswered 30 years after this address and nearly 60 years after the initial visualization of crystals in synovial fluids. A major obstacle to progress in the crystal field is the accurate rapid diagnosis of crystal-induced arthritis. We currently rely on observation of synovial fluid crystals from affected joints under compensated polarizing light microscopy (CPLM). Historically, rheumatologists owe a great deal to CPLM. It is important to remember that prior to 1959, gout was a clinical diagnosis, made without the benefit of visualizing birefringent particulates in synovial fluid aspirates. Indeed, without CPLM, calcium pyrophosphate dihydrate crystal deposition disease (CPDD) might not exist at all. The first descriptions of the pseudogout-type presentation of CPDD relied on CPLM-based examinations of synovial fluid samples from patients with goutlike arthritis whose crystals were resistant to uricase (2). While CPLM has become the standard clinical method of diagnosing crystal-induced arthritis, it is far from perfect. CPLM and expert operators are not available at all locations where patients with acute arthritis often present. This is particularly true in primary care clinics, emergency rooms, and urgent care centers. Ample work suggests that the identification of calcium pyrophosphate dihydrate (CPPD) crystals by CPLM poses more problems than the identification of monosodium urate monohydrate (MSU) crystals (3). CPPD crystals are often very small and may not display birefringence (4). While a short training of the analysts improves this accuracy (5), this type of training is rarely performed. Partially based on these challenges, the sole set of diagnostic criteria for CPPD uses chemical analysis of synovial fluid with Fourier transform infrared (FTIR) spectroscopy or x-ray diffraction to define “definite CPPD.” Sadly, we lack any reliable bedside tests for the detection of basic calcium phosphate (BCP) crystals. Unstained BCP crystals are not visible with CPLM. The only widely available test, alizarin red staining (6), is neither sensitive nor specific for the presence of BCP crystals (7). In this issue of Arthritis & Rheumatology, Li et al (8) describe a shoebox-sized Raman spectroscope they constructed. This device identifies the chemical composition of particulates in synovial fluid and might be adaptable to widespread clinical use. Raman spectroscopy is based on the characteristic absorption and scatter of laser light by a material. When the energy of an incident photon excites a molecule in the material being irradiated, a small portion of the scattered light is shifted in energy with respect to the source beam. Plotting light scatter against frequency produces a Raman spectrum, which is essentially a “fingerprint” of the material’s molecular structure. Use of the device described by Li et al requires some preparation of synovial fluid samples prior to Raman spectroscopy. They treated thawed synovial fluid samples with hyaluronidase to reduce viscosity, diluted the samples with a uric acid–containing buffer to prevent uric acid crystal dissolution, and finally filtered the samples to trap and concentrate crystals. Samples were then subjected to Raman spectroscopy, and based on the presence of characteristic peaks, were identified as containing MSU or CPPD crystals. In addition to high diagSupported by the US Department of Veterans Affairs (1I01CX001143-01). Ann K. Rosenthal, MD: Medical College of Wisconsin and Clement J. Zablocki VA Medical Center, Milwaukee; Eliseo Pascual, MD, PhD: Universidad de Alicante and Hospital General Universitario de Alicante, Alicante, Spain. Address correspondence to Ann K. Rosenthal, MD, Medical College of Wisconsin, Rheumatology Division, FEOB 4th Floor, 9200 West Wisconsin Avenue, Milwaukee, WI 53226. E-mail: arosenthal@ va.gov. Submitted for publication December 26, 2015; accepted in revised form February 9, 2016.

Clinical Images: Hematoidin in Synovial Fluid

Daniel J. McCarty, Jr., a major figure in the crystal arthritis field, presented a Heberden Oration lecture in 1982 entitled “Crystals, joints, and consternation” (1). His consternation stemmed from the question of whether control of calcium-containing crystals would prevent the associated inflammatory and degenerative processes which culminate in joint disease. This essential question, along with many other critical questions in the crystal field, remains largely unanswered 30 years after this address and nearly 60 years after the initial visualization of crystals in synovial fluids. A major obstacle to progress in the crystal field is the accurate rapid diagnosis of crystal-induced arthritis. We currently rely on observation of synovial fluid crystals from affected joints under compensated polarizing light microscopy (CPLM). Historically, rheumatologists owe a great deal to CPLM. It is important to remember that prior to 1959, gout was a clinical diagnosis, made without the benefit of visualizing birefringent particulates in synovial fluid aspirates. Indeed, without CPLM, calcium pyrophosphate dihydrate crystal deposition disease (CPDD) might not exist at all. The first descriptions of the pseudogout-type presentation of CPDD relied on CPLM-based examinations of synovial fluid samples from patients with goutlike arthritis whose crystals were resistant to uricase (2). While CPLM has become the standard clinical method of diagnosing crystal-induced arthritis, it is far from perfect. CPLM and expert operators are not available at all locations where patients with acute arthritis often present. This is particularly true in primary care clinics, emergency rooms, and urgent care centers. Ample work suggests that the identification of calcium pyrophosphate dihydrate (CPPD) crystals by CPLM poses more problems than the identification of monosodium urate monohydrate (MSU) crystals (3). CPPD crystals are often very small and may not display birefringence (4). While a short training of the analysts improves this accuracy (5), this type of training is rarely performed. Partially based on these challenges, the sole set of diagnostic criteria for CPPD uses chemical analysis of synovial fluid with Fourier transform infrared (FTIR) spectroscopy or x-ray diffraction to define “definite CPPD.” Sadly, we lack any reliable bedside tests for the detection of basic calcium phosphate (BCP) crystals. Unstained BCP crystals are not visible with CPLM. The only widely available test, alizarin red staining (6), is neither sensitive nor specific for the presence of BCP crystals (7). In this issue of Arthritis & Rheumatology, Li et al (8) describe a shoebox-sized Raman spectroscope they constructed. This device identifies the chemical composition of particulates in synovial fluid and might be adaptable to widespread clinical use. Raman spectroscopy is based on the characteristic absorption and scatter of laser light by a material. When the energy of an incident photon excites a molecule in the material being irradiated, a small portion of the scattered light is shifted in energy with respect to the source beam. Plotting light scatter against frequency produces a Raman spectrum, which is essentially a “fingerprint” of the material’s molecular structure. Use of the device described by Li et al requires some preparation of synovial fluid samples prior to Raman spectroscopy. They treated thawed synovial fluid samples with hyaluronidase to reduce viscosity, diluted the samples with a uric acid–containing buffer to prevent uric acid crystal dissolution, and finally filtered the samples to trap and concentrate crystals. Samples were then subjected to Raman spectroscopy, and based on the presence of characteristic peaks, were identified as containing MSU or CPPD crystals. In addition to high diagSupported by the US Department of Veterans Affairs (1I01CX001143-01). Ann K. Rosenthal, MD: Medical College of Wisconsin and Clement J. Zablocki VA Medical Center, Milwaukee; Eliseo Pascual, MD, PhD: Universidad de Alicante and Hospital General Universitario de Alicante, Alicante, Spain. Address correspondence to Ann K. Rosenthal, MD, Medical College of Wisconsin, Rheumatology Division, FEOB 4th Floor, 9200 West Wisconsin Avenue, Milwaukee, WI 53226. E-mail: arosenthal@ va.gov. Submitted for publication December 26, 2015; accepted in revised form February 9, 2016.

Persistence of monosodium urate crystals and low-grade inflammation in the synovial fluid of patients with untreated gout

Joint Bone Spine - In Press.Proof corrected by the author Available online since mercredi 31 mai 2017

Crystal Analysis in Synovial Fluid

tion induces skin accumulation of plasmacytoid dendritic cells: a possible role for chemerin. Autoimmunity 2014;47:185–92. 28. Malissen B, Tamoutounour S, Henri S. The origins and functions of dendritic cells and macrophages in the skin. Nat Rev Immunol 2014;14:417–28. 29. Farina GA, York MR, Di Marzio M, Collins CA, Meller S, Homey B, et al. Poly(I:C) drives type I IFNand TGFb-mediated inflammation and dermal fibrosis simulating altered gene expression in systemic sclerosis. J Invest Dermatol 2010;130:2583–93. 30. Lappalainen J, Rintahaka J, Kovanen PT, Matikainen S, Eklund KK. Intracellular RNA recognition pathway activates strong anti-viral response in human mast cells. Clin Exp Immunol 2013;172:121–8. 31. Abe T, Barber GN. Cytosolic-DNA-mediated, STING-dependent proinflammatory gene induction necessitates canonical NF-kB activation through TBK1. J Virol 2014;88:5328–41. 32. Marchlik E, Thakker P, Carlson T, Jiang Z, Ryan M, Marusic S, et al. Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality. J Leukoc Biol 2010;88:1171–80. 33. Gehrke N, Mertens C, Zillinger T, Wenzel J, Bald T, Zahn S, et al. Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing. Immunity 2013;39:482–95. 34. Ahmed NU, Ueda M, Nikaido O, Osawa T, Ichihashi M. High levels of 8-hydroxy-2’-deoxyguanosine appear in normal human epidermis after a single dose of ultraviolet radiation. Br J Dermatol 1999;140:226–31. 35. Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C, de Ravin SS, Smith CK, et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med 2016;22:146–53.