Synovial fluid presepsin as a novel biomarker for the rapid differential diagnosis of native joint septic arthritis from crystal arthritis.

OBJECTIVE: To investigate whether presepsin can be used as a novel biomarker to differentiate between native joint septic arthritis (NJSA) and crystal arthritis (CA). METHODS: This study included 75 patients diagnosed with either NJSA (n = 21) or CA (n = 54). Presepsin in synovial fluid and blood, C-reactive protein, and procalcitonin were measured and compared between the NJSA and CA groups. Receiver operating characteristic (ROC) curve analyses were performed to differentiate between the two groups. RESULTS: Synovial fluid and blood presepsin were significantly higher in the NJSA group than in the CA group (p < 0.0001 and p < 0.01, respectively). The area under the ROC curve for synovial fluid presepsin in the NJSA group compared with the CA group was 0.93 (sensitivity 85.7%, specificity 85.2%, positive predictive value 69.2%, negative predictive value 93.9%, positive likelihood ratio 5.79, negative likelihood ratio 0.17). Among the tests, synovial fluid presepsin was the most accurate. CONCLUSIONS: Measurement of synovial fluid presepsin is reliable for the early diagnosis of NJSA, and synovial fluid presepsin could be used as a novel biomarker for differentiating between NJSA and CA.

Utility of Ultrasound and Dual Energy CT in Crystal Disease Diagnosis and Management.

PURPOSE OF REVIEW: The objective of this review is to critically discuss the latest evidence on the use of ultrasound and dual energy computed tomography (DECT) for the assessment of microcrystalline arthritis. RECENT FINDINGS: Both techniques have been included in the classification and diagnostic criteria for gout, while only ultrasound appears in the diagnostic recommendations for CPPD. Regarding the management of the diseases, there is encouraging evidence for the use of both techniques for the follow-up of gout patients, while very few or null data are available for CPPD. Ultrasound has been adequately validated for the diagnosis of CPPD, while some issues have still to be clarified regarding gout. DECT has also demonstrated to be accurate for gout diagnosis, but very few data are available regarding CPPD. Future research should aim to improve the reliability of both techniques and to create scoring systems for a more accurate follow-up of patients.

[Crystal arthropathies]. / Kristallarthritiden.

Crystals are one of the commonest reasons for acute joint inflammation. The most relevant types of crystals are those of monosodium urate (MSU) and calcium pyrophosphates (CPP). To get proven diagnosis of a crystal arthropathy the microscopic identification of those crystals in synovial fluid is still recommended by the actual guidelines. Whenever arthrocentesis is not feasible, ultrasound or dual-energy-computed tomography might help to visualize specific changes induced especially by MSU crystals. Both types of crystals act as danger signals inducing flares of immediate inflammatory response via activation of the innate immune system. Therefore crystal arthropathies could be seen as an auto-inflammatory condition. As neutrophils, monocytes and macrophages are the key cells and Interleukin 1ß is one of the dominant cytokines the way of blocking inflammation by colchicine and override IL-1ß are specific options in treating inflammation due to the crystals. For gout, causal treatment with urate lowering therapy can result in clearance of urate crystals. Unfortunately, to date there is no causal therapy for CPPD available. The present article summarises the recent knowledge highlighting the news regarding the crystal arthropathies gout and CPPD.

[Haemochromatosis and Arthropathies]. / Hämochromatose-assoziierte Arthropathien.

Arthropathy is the most common and often the earliest clinical manifestation of hereditary hemochromatosis (HH). It is difficult to treat and there is a high risk for early endoprosthetic joint replacement. Research done during the last decade shows that it is a joint disease in its own right. Clinically, there are degenerative articular changes with an atypical pattern of distribution, a crystal arthropathy (CPPD) with congenital joint swelling and synovitis like in RA. The X-ray image shows typical but not exclusive findings. In MRI, groundbreaking subchondral findings are found, especially in the large joints, and ultrasound shows inflammatory lesions in non-arthropathy patients as well. In animal experiments and pathomorphological studies of the synovial membrane, the arthropathy can be differentiated from osteoarthrits and RA. The pathophysiological significance of iron overload can be distinguished from immunohistochemical and cytogenetic investigations in chronic degenerative HH arthropathy and inflammatory-destructive arthropathy in hemophilia. By elucidating the pathophysiology, new therapeutic approaches can be formulated. In addition to colchicine, the IL-1 receptor antagonist anakinra is available for activation of the NLRP3 inflammasome by CPPD crystals and subsequent induction of IL-1ß overproduction. Other manifestations include symptomatic pain therapy and intensive physiotherapy and occupational therapy. To promote further research into hemochromatosis arthropathy, the Hemochromatosis Arthropathy Research Initiative (HARI) was established in 2016.

Disease-Associated Particulates and Joint Inflammation; Mechanistic Insights and Potential Therapeutic Targets.

It is now well established that intra-articular deposition of endogenous particulates, such as osteoarthritis-associated basic calcium phosphate crystals, gout-associated monosodium urate crystals, and calcium deposition disease-associated calcium pyrophosphate crystals, contributes to joint destruction through the production of cartilage-degrading enzymes and pro-inflammatory cytokines. Furthermore, exogenous wear-debris particles, generated from prosthetic implants, drive periprosthetic osteolysis which impacts on the longevity of total joint replacements. Over the last few years, significant insight has been gained into the mechanisms through which these particulates exert their effects. Not only has this increased our understanding of the pathological processes associated with crystal deposition but it has also led to the identification of a number of therapeutic targets to treat particulate-associated disease. In this review, we discuss recent developments regarding the cellular events triggered by joint-associated particulates, as well as future directions in therapy for particulate-related arthropathies.

Emergent nanotherapies in microcrystal-induced arthritis.

The anti-inflammatory and immunomodulatory effects of nanoparticles in several chronic diseases have been extensively researched. The aim of this review is to examine how nanoparticles modulate the inflammatory pathways that characterize the most prevalent forms of microcrystal-induced arthritis, including gout, pseudogout, and BCP-induced arthritis. The nanoparticles of chitosan-coated calcium phosphate, uricase, aceclofenac, and gold have been investigated in crystal-inducedarthritis. The most important results of the studies outlined in this review show that nanoparticles can inhibit the expression and the release of some pro-inflammatory mediators and proteolytic enzymes, and the activity of different transcriptional factors in vitro, as well as decrease the uric acid levels in several studies of in vitro and in vivo models of gout, which show interesting results in terms of decreasing the amount of crystals and tissue damage, respectively. In view of their multiple beneficial effects, nanoparticles can be considered a valuable therapy that contributes to the pharmacological treatment in crystalinduced arthritis.

Discordant American College of Physicians and international rheumatology guidelines for gout management: consensus statement of the Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN).

In November 2016, the American College of Physicians (ACP) published a clinical practice guideline on the management of acute and recurrent gout. This guideline differs substantially from the latest guidelines generated by the American College of Rheumatology (ACR), European League Against Rheumatism (EULAR) and 3e (Evidence, Expertise, Exchange) Initiative, despite reviewing largely the same body of evidence. The Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN) convened an expert panel to review the methodology and conclusions of these four sets of guidelines and examine possible reasons for discordance between them. The G-CAN position, presented here, is that the fundamental pathophysiological knowledge underlying gout care, and evidence from clinical experience and clinical trials, supports a treat-to-target approach for gout aimed at lowering serum urate levels to below the saturation threshold at which monosodium urate crystals form. This practice, which is truly evidence-based and promotes the steady reduction in tissue urate crystal deposits, is promoted by the ACR, EULAR and 3e Initiative recommendations. By contrast, the ACP does not provide a clear recommendation for urate-lowering therapy (ULT) for patients with frequent, recurrent flares or those with tophi, nor does it recommend monitoring serum urate levels of patients prescribed ULT. Results from emerging clinical trials that have gout symptoms as the primary end point are expected to resolve this debate for all clinicians in the near term future.

Update on calcium pyrophosphate deposition.

Calcium pyrophosphate crystal deposition (CPPD) associates with ageing, osteoarthritis (OA), uncommon metabolic diseases, mutations and polymorphisms in the ankylosis human gene (ANKH). CPPD is frequently polyarticular, occurs due to a generalised articular predisposition, and the association between CPPD and OA is joint specific, for example CPPD associates with knee OA, but not with hip OA. Other recently identified associations include knee malalignment (knee CC), low cortical BMD and soft-tissue calcification. CPPD is generally asymptomatic. A recent study reported that knees with OA plus CC at the index joint, or at distant joints (in absence of index joint CC), were more likely to have attrition. CPPD can cause acute CPP crystal arthritis, chronic CPP crystal inflammatory arthritis, and is frequently present in joints with OA. Joint aspiration remains the gold standard for diagnosing CPPD, although other promising techniques are emerging. Patients with polyarticular or young onset CPPD should be screened for underlying metabolic abnormalities, however, such testing can be unrewarding. The treatment of CPPD is symptomatic. Acute CPP crystal arthritis is treated with rest, local application of ice-packs, joint aspiration, colchicine and/or intra-articular corticosteroid injection (once infection is excluded). Colchicine, low-dose corticosteroids, hydroxychloroquine and radiosynovectomy are recommended for the treatment of chronic or recurrent acute CPP crystal arthritis. Recent RCTs did not confirm any benefit from methotrexate, and although there is increasing interest in the use of anti-IL1 agents for acute or chronic CPP crystal arthritis, their efficacy has not been formally examined. Unlike gout, currently there are no treatments to eliminate CPP crystal deposits.