Crystal-induced Arthropathies Research Articles

Imaging of Inflammatory Arthritis: An Overview of Advantages and Limitations

Inflammatory arthritis and crystal-induced arthropathies encompass a diverse range of pathologies characterized by overlapping clinical and laboratory features. Given their potential to cause irreversible joint damage with downstream implications, such as emotional and financial burden, early diagnosis is paramount for initiating timely treatment. With the evolution of various imaging techniques, it becomes crucial for healthcare providers to be well-versed in selecting the most appropriate imaging modality for their specific clinical inquiries. This review highlights commonly employed imaging studies for assessing rheumatic diseases.

Systematic literature review to inform the EULAR recommendations for the use of imaging in crystal-induced arthropathies in clinical practice

ObjectiveTo summarise current data regarding the use of imaging in crystal-induced arthropathies (CiAs) informing a European Alliance of Associations for Rheumatology task force.MethodsWe performed four systematic searches in Embase, Medline...

Ultrasound Features in Gout: An Overview.

The accurate diagnosis of gout frequently constitutes a challenge in clinical practice, as it bears a close resemblance to other rheumatologic conditions. An undelayed diagnosis and an early therapeutic intervention using uric acid lowering therapy (ULT) is of the utmost importance for preventing bone destruction, the main point of managing gout patients. Advanced and less invasive imaging techniques are employed to diagnose the pathology and ultrasonography (US) stands out as a non-invasive, widely accessible and easily reproducible method with high patient acceptability, enabling the evaluation of the full clinical spectrum in gout. The 2023 EULAR recommendations for imaging in diagnosis and management of crystal-induced arthropathies in clinical practice state that US is a fundamental imagistic modality. The guidelines underline its effectiveness in detecting crystal deposition, particularly for identifying tophi and the double contour sign (DCS). Its utility also arises in the early stages, consequent to synovitis detection. US measures of monosodium urate (MSU) deposits are valuable indicators, sensitive to change consequent to even short-term administration of ULT treatment, and can be feasibly used both in current daily practice and clinical trials. This paper aimed to provide an overview of the main US features observed in gout patients with reference to standardized imaging guidelines, as well as the clinical applicability both for diagnosis accuracy and treatment follow-up. Our research focused on summarizing the current knowledge on the topic, highlighting key data that emphasize gout as one of the few rheumatological conditions where US is recognized as a fundamental diagnostic and monitoring tool, as reflected in the most recent classification criteria.

Crystal arthropathies and osteoarthritis-where is the link?

Osteoarthritis (OA) is one of the leading causes of disability worldwide. As our understanding of OA progressively has moved from a purely mechanical "wear and tear" concept toward a complex multi-tissue condition in which inflammation plays a central role, the possible role of crystal-induced inflammation in OA incidence and progression may be relevant. In addition to gout, which affects 4% of the US population, basic calcium phosphate and calcium pyrophosphate deposition both may induce joint inflammation and may play a role in pain in OA. This narrative review article discusses the possible mechanisms underlying the associations between crystal-induced arthropathies and OA, and the important implications of these for clinical practice and future research.

Acute Management of Crystal-Induced Arthropathies: an Overview

Gout and pseudogout are the two major Crystal-induced Arthropathies. Patients with these conditions can experience symptoms such as asymmetric joint pain, swelling, and functional limitation. Acute presentation is due to intra-articular deposition of monosodium urate (Gout) or calcium pyrophosphate (Pseudogout).

Advances in Disease Mechanisms and Translational Technologies: Clinicopathologic Significance of Inflammasome Activation in Autoimmune Diseases.

Autoimmune diseases are characterized by dysregulated immune tolerance to self and inflammatory damage to tissues and organs. The development of inflammation involves multiple innate and adaptive immune pathways. Inflammasomes are multimeric cytosolic protein complexes that form to mediate host immune responses upon recognizing pathogen- or damage-associated molecular patterns via pattern-recognition receptors (PRRs). The accelerating pace of inflammasome research has demonstrated important roles for inflammasome activation in many pathologic conditions, including infectious, metabolic, autoinflammatory, and autoimmune diseases. The inflammasome generally comprises a PRR, procaspase 1, and an adaptor molecule connecting the PRR and procaspase 1. Upon inflammasome activation, procaspase 1 becomes active caspase 1 that converts pro-interleukin-1β (proIL-1β) and proIL-18 into mature and active IL-1β and IL-18, respectively. The cytokines IL-1β and IL-18 have multipotent effects on immune and nonimmune cells and induce and promote systemic and local inflammatory responses. Human studies have shown increased levels of these cytokines, altered activation of inflammasome-related molecules, and/or the presence of inflammasome activators in rheumatic diseases, including systemic lupus erythematosus, rheumatoid arthritis, crystal-induced arthropathies, and Sjögren's syndrome. Such changes are found in the primary target organs, such as the kidneys, joints, and salivary glands, as well as in the cardiovascular system. In animal models of rheumatic diseases, inflammation and tissue damage improve upon genetic or pharmacologic targeting of the inflammasome, supporting its pathogenic role. Herein, we review the clinicopathologic significance and therapeutic targeting of inflammasome activation in rheumatic diseases and related conditions based on recent findings.

Crystal-Induced Joint Disease

The destructive potential of intracellular crystals has been recognized for over a century. The mechanisms by which crystals induce inflammation and bone and cartilage destruction have been elucidated over the past decade. The three most common crystal-induced arthropathies are caused by precipitation of monosodium urate monohydrate, calcium pyrophosphate dihydrate (CPP) and basic calcium phosphate. The definition, epidemiology, pathogenesis and etiology, diagnosis, and treatment of gout and CPP crystal deposition are reviewed, as well as the clinical stages of gout (i.e., acute gouty arthritis, intercritical gout, advanced gout, nonclassic presentations of gout, and other conditions associated with gout). Also reviewed are the clinical manifestations of calcium pyrophosphate dihydrate deposition disease (CPPD), such as asymptomatic CPPD, osteoarthritis with CPPD, acute CPP crystal arthritis, and chronic CPP crystal inflammatory arthritis. Figures illustrate renal transport of urate, monosodium urate crystals, acute gouty flare, advanced gouty arthritis, gouty synovial fluid, radiographic changes of advanced gout, ultrasound appearance of the femoral intercondylar cartilage, pharmacologic management of gout, the effect of gender and age on knee chondrocalcinosis, radiographs of chondrocalcinosis, and compensated polarized microscopy of CPPD. Tables present the major factors responsible for hyperuricemia, characteristics of classic gouty flares, antiinflammatory therapy for gout, and urate-lowering therapy. This chapter contains 90 references. This review contains 11 figures, 12 tables, and 88 references. Keywords: acute gouty arthritis, intercritical gout, advanced gout, asymptomatic CPPD, osteoarthritis with CPPD, acute CPP crystal arthritis, chronic CPP crystal inflammatory arthritis

Crystal-Induced Joint Disease

The destructive potential of intracellular crystals has been recognized for over a century. The mechanisms by which crystals induce inflammation and bone and cartilage destruction have been elucidated over the past decade. The three most common crystal-induced arthropathies are caused by precipitation of monosodium urate monohydrate, calcium pyrophosphate dihydrate (CPP) and basic calcium phosphate. The definition, epidemiology, pathogenesis and etiology, diagnosis, and treatment of gout and CPP crystal deposition are reviewed, as well as the clinical stages of gout (i.e., acute gouty arthritis, intercritical gout, advanced gout, nonclassic presentations of gout, and other conditions associated with gout). Also reviewed are the clinical manifestations of calcium pyrophosphate dihydrate deposition disease (CPPD), such as asymptomatic CPPD, osteoarthritis with CPPD, acute CPP crystal arthritis, and chronic CPP crystal inflammatory arthritis. Figures illustrate renal transport of urate, monosodium urate crystals, acute gouty flare, advanced gouty arthritis, gouty synovial fluid, radiographic changes of advanced gout, ultrasound appearance of the femoral intercondylar cartilage, pharmacologic management of gout, the effect of gender and age on knee chondrocalcinosis, radiographs of chondrocalcinosis, and compensated polarized microscopy of CPPD. Tables present the major factors responsible for hyperuricemia, characteristics of classic gouty flares, antiinflammatory therapy for gout, and urate-lowering therapy. This chapter contains 90 references. This review contains 11 figures, 12 tables, and 88 references. Keywords: acute gouty arthritis, intercritical gout, advanced gout, asymptomatic CPPD, osteoarthritis with CPPD, acute CPP crystal arthritis, chronic CPP crystal inflammatory arthritis

The application of dual-energy computed tomography in the diagnosis of musculoskeletal disorders: a review of current concepts and applications.

With the assistance of innovations in scanner engineering and software design, dual-energy computed tomography (DECT) is an advanced imaging method that has been developed over the last decade. With its unique ability to differentiate materials by their atomic number, DECT has opened new perspectives in imaging. The principal advantages of DECT over conventional CT in the musculoskeletal setting relate to the additional information provided regarding tissue composition, artifact reduction and image optimization. In musculoskeletal imaging, uric acid material decomposition images can help identify articular deposition of uric acid crystals (in addition to the detection of uric acid renal stones). Material separation can also help detect bone marrow edema on CT in the case of trauma, algoneurodystrophy, inflammation (osteitis) or malignant bone marrow infiltrates, such as metastases. DECT also offers means to reduce the radiation exposure of patients by replacing multiphase exams with more specific single acquisitions. The first part of this article reviews the basic principles and technical aspects of DECT. The second part focuses on applications of DECT to musculoskeletal imaging including that of gout and other crystal-induced arthropathies, virtual non-calcium images for the study of bone marrow lesions, the study of collagenous structures, as well as the detection of hemosiderin and metal particles.

Evaluation and Management of Septic Arthritis and its Mimics in the Emergency Department.

Septic arthritis is a dangerous medical condition associated with significant morbidity and mortality. However, the differential diagnosis can be broad with conditions that mimic this disease and require different evaluation and treatment. This narrative review presents the emergency medicine evaluation and management, as well as important medical conditions that may mimic this disease. Septic arthritis commonly presents with monoarticular joint pain with erythema, warmth, swelling, and pain on palpation and movement. Fever is present in many patients, though most are low grade. Blood testing and imaging may assist with the diagnosis, but the gold standard is joint aspiration. Management includes intravenous antibiotics and orthopedic surgery consult for operative management vs. serial aspirations. Clinicians should consider mimics, such as abscess, avascular necrosis, cellulitis, crystal-induced arthropathies, Lyme disease, malignancy, osteomyelitis, reactive arthritis, rheumatoid arthritis, and transient synovitis. While monoarticular arthritis can be due to septic arthritis, other medical and surgical conditions present similarly and require different management. It is essential for the emergency clinician to be aware how to diagnose and treat these mimics.

Metabolic Diseases and Crystal Induced Arthropathies Technic of Non-Staining Histologic Sections - A Comparative Study of Standard Stains and Histochemical Reactions

Arthropathy induced by monosodium salt of uric acid [C5H4N4O3] (MSU) (gout), by calcium pyrophosphate dihydrate [Ca2P2O7.2H₂O] (CPPD) crystals (chondrocalcinosis, pseudogout, pyrophosphate arthropathy) and arthropathy induced by hydroxyapatite [Ca5(PO₄)3(OH)] (HA) crystals (apatite rheumatism, hydroxyapatite arthritis, calcifying tenosynovitis, Milwaukee syndrome, calcific tendinitis, calcific periarthritis) are regarded as distinct clinical entities.

A Brief History of IL-1 and IL-1 Ra in Rheumatology.

The history of what, in 1979, was called interleukin-1 (IL-1), orchestrator of leukocyte inter-communication, began many years before then, initially by the observation of fever induction via the endogenous pyrogen (EP) (1974) and then in rheumatology on the role in tissue destruction in rheumatoid diseases via the induction of collagenase and PGE2 in human synovial cells by a mononuclear cell factor (MCF) (1977). Since then, the family has exploded to presently 11 members as well as many membrane-bound and soluble receptor forms. The discovery of a natural Interleukin-1 receptor antagonist (IL-1Ra) in human biological fluids has highlighted the importance of IL-1 and IL-1Ra in human diseases. Evidence delineating its role in autoinflammatory syndromes and the elucidation of the macromolecular complex referred to as “inflammasome” have been instrumental to our understanding of the link with IL-1. At present, the IL-1blockade as therapeutic approach is crucial for many hereditary autoinflammatory diseases, as well as for adult-onset Still’s disease, crystal-induced arthropathies, certain skin diseases including neutrophil-triggered skin diseases, Behçet’s disease and deficiency of IL-1Ra and other rare fever syndromes. Its role is only marginally important in rheumatoid arthritis and is still under debate with regard to osteoarthritis, type 2 diabetes mellitus, cardiovascular diseases and cancer. This brief historical review focuses on some aspects of IL-1, mainly IL-1β and IL-Ra, in rheumatology. There are many excellent reviews focusing on the IL-1 family in general or with regard to specific diseases or biological discoveries.

Imaging in Gout and Other Crystal-Related Arthropathies.

In this article, the authors consider the manifestations of intraarticular and periarticular crystal deposits. Most cases of crystal deposits are asymptomatic and represent incidental findings at imaging. In symptomatic arthropathies, imaging can play an important role in the diagnosis and assessment of disease progression and the extent of crystal deposits. Conventional radiography is the most common imaging modality. But ultrasound, conventional computerized tomography (CT), dual-energy CT, and MRI play an increasing role. The authors review typical radiographic features of crystal-induced arthropathies and findings that help to differentiate them. The authors also emphasize the increasing role of complementary imaging techniques.

Dual-Energy CT: Basic Principles, Technical Approaches, and Applications in Musculoskeletal Imaging (Part 1).

In recent years, technological advances have allowed manufacturers to implement dual-energy computed tomography (DECT) on clinical scanners. With its unique ability to differentiate basis materials by their atomic number, DECT has opened new perspectives in imaging. DECT has been used successfully in musculoskeletal imaging with applications ranging from detection, characterization, and quantification of crystal and iron deposits; to simulation of noncalcium (improving the visualization of bone marrow lesions) or noniodine images. Furthermore, the data acquired with DECT can be postprocessed to generate monoenergetic images of varying kiloelectron volts, providing new methods for image contrast optimization as well as metal artifact reduction. The first part of this article reviews the basic principles and technical aspects of DECT including radiation dose considerations. The second part focuses on applications of DECT to musculoskeletal imaging including gout and other crystal-induced arthropathies, virtual noncalcium images for the study of bone marrow lesions, the study of collagenous structures, applications in computed tomography arthrography, as well as the detection of hemosiderin and metal particles.

Dual-Energy CT: Basic Principles, Technical Approaches, and Applications in Musculoskeletal Imaging (Part 2).

In recent years, technological advances have allowed manufacturers to implement dual-energy computed tomography (DECT) on clinical scanners. With its unique ability to differentiate basis materials by their atomic number, DECT has opened new perspectives in imaging. DECT has been successfully used in musculoskeletal imaging with applications ranging from detection, characterization, and quantification of crystal and iron deposits, to simulation of noncalcium (improving the visualization of bone marrow lesions) or noniodine images. Furthermore, the data acquired with DECT can be postprocessed to generate monoenergetic images of varying kiloelectron volts, providing new methods for image contrast optimization as well as metal artifact reduction. The first part of this article reviews the basic principles and technical aspects of DECT including radiation dose considerations. The second part focuses on applications of DECT to musculoskeletal imaging including gout and other crystal-induced arthropathies, virtual noncalcium images for the study of bone marrow lesions, the study of collagenous structures, applications in computed tomography arthrography, as well as the detection of hemosiderin and metal particles.

Le pied métabolique et endocrinien (hors pied diabétique)

Among metabolic arthropathies, crystal-induced arthropathies are the main causes of involvement of the foot. Gout, a deposition disease due to chronic hyperuricemia with monosodium urate deposits in and around joints, is the main culprit. Treatment armatorium is large but patient compliance and therapeutic inertia by physicians are responsible for treatment failures. Calcium pyrophosphate depositon disease is a rare cause of foot and ankle involvement but specific radiographic patterns and crystal identification in the synovial fluid will allow diagnosis. Very rarely, apatite crystals deposits are responsible for pseudo-acute gout attack. Other metabolic disorders including haemochromatosis, lipid depositons, and endocrine diseases such as acromegaly, can involve both the ankle and the foot.

Treatment of hyperuricemia, gout and other crystalline arthritidies

Gout is a very common joint disease which is due to chronic hyperuricemia and its related articular involvements. Yet it can be cured when appropriately managed. Comprehensive management of gout involves correct identification and addressing all causes of hyperuricemia, treating and preventing attacks of gouty inflammation (using colchicine NSAIDs, and/or steroids), and lowering serum urate (SUA) to an appropriate target level indefinitely. The ideal SUA target is, at a minimum, less than 6 mg/dL (60 mg/L or 360 μmol/L), or even less than 5 mg/dL in patients with tophi. The SUA target should remain at less than 6 mg/dL for long in all gout patients, especially until tophi have resolved. Patient education and adherence to therapy are key point to the optimal management of gout, aspects which are often neglected. Adherence can be monitored in part by continuing, regular assessment of the SUA level. More difficult cases of gout often need a combination of urate lowering therapy (ULT) for both refractory hyperuricemia and chronic tophaceous arthritis. Chronic tophaceous gouty arthropathy which do not respond adequately to optimized oral ULT might benefit from the use of pegloticase, when this is available in, for example, Italy and other European countries. By contrast, in calcium pyrophosphate (CPP) crystal deposition disease (CPPD), as evidenced by pseudo gout attacks or chronic polyarthritis, similar anti-inflammatory strategies have been recommended, but there have as yet been no controlled trials. Of note, there is no treatment for the underlying metabolic disorders able to control the CPPD. Management of crystal-induced arthropathies (CIA) depends not only on clinical expression, namely acute attacks or chronic arthropathy, but also on the underlying metabolic disorder. We will mainly focus on gout as an archetype of CIA.

Imaging studies of crystalline arthritides

Gout, calcium pyrophosphate dihydrate (CPPD) deposition disease, and calcium hydroxyapatite deposition disease (HADD) are the three most common crystal-induced arthropathies. Multimodality imaging may help in their diagnosis, and is useful for a precise and comprehensive assessment and grading of the related osteoarticular damage. Plain film radiography, due to its low cost and wide availability, is the first imaging technique to be used in crystal deposition diseases, providing well-known and specific findings for CPPD deposition disease and HADD, while it may undergrade the early osteoarticular lesions in gouty patients. Ultrasonography (US) is a radiation-free approach that accurately depicts crystal deposits in cartilage, peri- and intra-articular soft tissues, but it does not give a panoramic view of the affected joints. Cross-sectional imaging techniques can examine crystal deposits in the spine and axial joints. CT has the potential to distinguish monosodium urate (MSU) crystals from calcium containing crystals, due to their different attenuation values. MRI may demonstrate synovitis, erosions and bone marrow edema in gouty patients and it may differentiate tophi from other soft tissue nodules due to its high contrast resolution and power of tissue characterization.

Use of imaging to evaluate gout and other crystal deposition disorders

This review summarizes recent advances in plain radiography and advanced imaging for gout, calcium pyrophosphate dihydrate crystal arthropathy and basic calcium phosphate crystal arthropathy. Plain radiography has diagnostic utility in the crystal-induced arthropathies. A gout radiographic damage index has been recently validated. High-resolution ultrasonography may improve noninvasive diagnosis of the crystal-induced arthropathies, and allow monitoring of intra-articular tophi in clinical trials. Computed tomography provides excellent definition of tophi and bone erosion, and three-dimensional computed tomography assessment of tophus volume is a promising outcome measure in gout. Magnetic resonance imaging is also a reliable method for assessment of tophus size in gout, and has an important role in detection of complications of disease in clinical practice. Emerging imaging techniques include three-dimensional ultrasonography and dual-energy computed tomography. Advanced imaging modalities also offer new insights into the mechanisms of cartilage and bone damage in the crystal-induced arthropathies. Plain radiography and advanced imaging techniques may assist with diagnosis, assessment of disease complications and monitoring of crystal-induced arthropathies. Further study of these techniques will provide significant improvement in patient care and further aid in the understanding of disease pathogenesis.

Arthrocentesis and Synovial Fluid Analysis in Clinical Practice

Joint aspiration, or arthrocentesis, is one of the most useful and commonly performed procedures for the diagnosis and treatment of joint diseases. The synovial fluid aspirated may be examined to evaluate the degree of inflammation and, mainly, to detect the presence of some relevant pathogenic agents, such as crystals or microorganisms. In these cases, synovial fluid analysis still represents the best diagnostic procedure. Arthrocentesis is thus particularly required for the diagnosis and management of the acute "hot red joint," which may be considered a true medical emergency because of the morbidity and mortality related to septic arthritis. The most recent recommendations on arthrocentesis confirm the need for the procedure in the presence of synovial effusion of unknown origin, especially if septic or crystal arthritis is suspected. Owing to the importance of this analysis, it is clearly recommended that ultrasonography should be used to facilitate arthrocentesis in difficult cases. Furthermore, ultrasonography may be useful in revealing the presence of synovial fluid before the joint aspiration and, subsequently, distinguishing some aspects characteristic of crystal-induced arthropathies.