The 2023 ACR/EULAR Classification Criteria for Calcium Pyrophosphate Deposition Disease.

OBJECTIVE: Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease. METHODS: Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort. RESULTS: Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score >56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). CONCLUSION: The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.

The 2023 ACR/EULAR classification criteria for calcium pyrophosphate deposition disease.

OBJECTIVE: Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease. METHODS: Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort. RESULTS: Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score>56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). CONCLUSION: The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.

Agreement Among Multiple Observers on Crystal Identification by Synovial Fluid Microscopy.

OBJECTIVE: Despite the fact that polarized microscopy remains the gold standard for diagnosing crystal arthritis, some uncertainties hamper full implementation in clinical practice. We undertook this study to analyze the agreement among multiple observers in crystal identification using compensated polarized microscopy, as well as to assess potential outcome modifiers. METHODS: This was a cross-sectional, observational study with consecutive synovial fluid sampling. Samples were immediately analyzed when possible or kept refrigerated at 4°C. Five observers analyzed them separately, blinded to clinical data, using a compensated polarized optical microscope (400×), through 3 stages (ordinary, simple polarized, and compensated polarized light) to detect and identify crystals. They recorded the presence and type of crystal (no crystals, monosodium urate [MSU], and calcium pyrophosphate dihydrate [CPP]). Interrater agreement was measured by Cohen's kappa. Subanalyses were performed on visualization delay and cumulative expertise. Discrepancies between each stage of the microscopy and the final decision were also examined. RESULTS: A total of 250 observations from 50 samples completed full assessment. Overall, κ = 0.74 (95% confidence interval [95% CI] 0.64-0.84), indicating good agreement. Agreement for crystal detection was κ = 0.71 (95% CI 0.59-0.82), for MSU was κ = 0.88 (95% CI 0.75-1.0), and for CPP was κ = 0.69 (95% CI 0.56-0.82). Most of the crystal identifications were already made by ordinary light. No differences between observations made before or after 24 hours (P = 0.859) or in expertise on crystal analysis (P = 0.989) were found. Observations performed under ordinary light matched the final diagnosis in 96.8% of cases (242 of 250). CONCLUSION: Compensated polarized microscopy remained consistent in detecting and identifying crystals in synovial fluid, even when examined among multiple observers, confirming its high utility for clinical practice.

Birefringent crystals deposition and inflammasome expression in human atheroma plaques by levels of uricemia.

OBJECTIVE: To verify the monosodium urate (MSU) crystal deposition in artery walls following a structure assessment and to assess NLRP3 inflammasome expression in human atheroma plaques by levels of uricemia. METHODS: Patients with peripheral arterial disease who were candidates for amputation were recruited and classified as normouricemic or hyperuricemic. During surgery, an artery segment from the amputated limb was sampled, divided and fixed separately by cryo-embedding, 100% ethanol or Glyo-fixx. Samples were assessed by compensated polarized-light microscopy to identify MSU crystals on the artery walls. Afterwards, macrophages, neutrophils and NLRP3 inflammasome components at the plaque were categorized by immunostaining and compared between normouricemics and hyperuricemics. RESULTS: Thirty artery samples from 27 patients were studied; 10 (37.0%) participants were hyperuricemic. Birefringent needle-shaped crystals were found in three samples (10.0%), all processed by frozen sectioning. Other methods showed no crystals. No accompanying inflammatory process was noted, and the presence of crystals was equally distributed across ranges of uricemia, making it unlikely they were MSU crystals. Regarding immunostaining, 28 artery samples were available for analysis, with similar infiltration of macrophages and neutrophils. NLRP3 and gasdermin-D expression were significantly greater in hyperuricemics compared to normouricemics (P=0.044 and P=0.017, respectively). ASC content was numerically larger in hyperuricemics as well, while caspase-1 and IL-1beta expression were similar between groups. CONCLUSIONS: The presence of MSU crystals on artery walls was not confirmed. Hyperuricemia was associated with greater NLRP3 and gasdermin-D expression on human atheroma plaques in patients with peripheral artery disease.

Identifying Potential Classification Criteria for Calcium Pyrophosphate Deposition Disease: Item Generation and Item Reduction.

OBJECTIVE: Classification criteria for calcium pyrophosphate deposition (CPPD) disease will facilitate clinical research on this common crystalline arthritis. Our objective was to report on the first 2 phases of a 4-phase process for developing CPPD classification criteria. METHODS: CPPD classification criteria development is overseen by a 12-member steering committee. Item generation (phase I) included a scoping literature review of 5 literature databases and contributions from a 35-member combined expert committee and 2 patient research partners. Item reduction and refinement (phase II) involved a combined expert committee meeting, discussions among clinical, imaging, and laboratory advisory groups, and an item-rating exercise to assess the influence of individual items toward classification. The steering committee reviewed the modal rating score for each item (range -3 [strongly pushes away from CPPD] to +3 [strongly pushes toward CPPD]) to determine items to retain for future phases of criteria development. RESULTS: Item generation yielded 420 items (312 from the literature, 108 from experts/patients). The advisory groups eliminated items that they agreed were unlikely to distinguish between CPPD and other forms of arthritis, yielding 127 items for the item-rating exercise. Fifty-six items, most of which had a modal rating of +/- 2 or 3, were retained for future phases. As numerous imaging items were rated +3, the steering committee recommended focusing on imaging of the knee and wrist and 1 additional affected joint for calcification suggestive of CPP crystal deposition. CONCLUSION: A data- and expert-driven process is underway to develop CPPD classification criteria. Candidate items comprise clinical, imaging, and laboratory features.

Reviewing Disease Activity Indices in Spondyloarthritis From the Sex Perspective: A Systematic Review and Metaanalysis.

OBJECTIVE: To determine whether the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Ankylosing Spondylitis Disease Activity Score (ASDAS) exhibited differences between women and men. METHODS: We systematically searched MEDLINE, Embase, Web of Science, and other sources in English or Spanish from January 1, 1995, to July 31, 2020, to assess the differences according to sex in BASDAI and ASDAS. We performed a comparative analysis by sex using t test and mean difference by sex metaanalyses for BASDAI and ASDAS, as well as a random-effects model using the inverse-variance method. RESULTS: Forty-one studies included BASDAI (6785 women, 12,929 men) and 16 of them included ASDAS (2046 women, 4403 men). Disease activity detected using BASDAI was significantly higher in women than in men (mean 4.9 vs 4.2, P = 0.02), whereas ASDAS did not detect differences between sexes (mean 2.8 women vs 2.8 men). In the metaanalyses, BASDAI detected significant differences between women and men (mean difference = 0.55 [95% CI 0.46-0.65], P < 0.00001), but ASDAS did not identify significant mean difference between sexes (0.04, 95% CI -0.05 to 0.12], P = 0.38). CONCLUSION: The 2 most widely used indices of disease activity in spondyloarthritis (SpA) discriminate differently according to sex by their different evaluations of peripheral disease. The different components and weights in BASDAI and ASDAS influence their values. BASDAI may be affected by fatigue, and in predominantly peripheral manifestations such as enthesitis, ASDAS may not be sensitive enough to detect activity. This may represent a sex bias unfavorable to women, because peripheral SpA is more common in women than in men.

Serum Urate Levels of Hemodialyzed Renal Patients Revisited.

OBJECTIVES: The need of maintaining serum urate (SU)-lowering agents in hemodialysis (HD) patients is an understudied area that requires a review, as it is a common practice. The aims were to assess the SU reduction achieved under HD and to analyze the kinetics of SU in a week of intermittent HD. METHODS: The serum urate levels were determined before and after HD sessions in 96 consecutive patients with end-stage renal disease, and the average SU reduction was assessed. Variables related to HD were analyzed whether they were associated with SU reductions of 80% greater. In addition, a kinetics study was performed on 10 selected patients with hyperuricemia (SU before HD >6.8 mg/dL) throughout intermittent HD sessions in a 1-week period. RESULTS: The mean ± SD age of the patients was 66.5 ± 13.8 years, and 62 of them were male (64.6%). The mean ± SD time on HD replacement was 7.1 ± 7.2 years, and 16 (16.4%) continued with urate-lowering agents. The mean SU reduction immediately after HD was 80.2% (95% confidence interval, 78.4-82.0); 51 patients (56.7%) showed SU reduction of 80% or greater. In the SU kinetics study, SU levels significantly reduced all over the period and persisted below hyperuricemia threshold (p = 0.015). Noteworthy, 6 patients (60%) were hyperuricemic before session 1, but only 1 (10%) before session 2 and none before session 3. CONCLUSIONS: Under HD replacement therapy, the SU levels effectively reduced and persisted below saturation point, suggesting that the SU-lowering therapy would be unnecessary for patients on HD, but necessary in selected cases. The definition of hyperuricemia under HD needs to be revised.

Gout: Where Is the Weak Link?

In the field of rheumatic and musculoskeletal diseases, no other condition has evolved so significantly since the mid-1950s as gout. In this period, the cause of gout has been firmly established; the close relationship with other conditions clarified; a rapid, unequivocal diagnostic test established; and agents effective in dissolving monosodium urate crystals and controlling inflammation made widely available. All these insights have ultimately led to deem gout as curable, an end point formerly considered out of reach. Unfortunately, diagnosis and management of gout in clinical practice have not paralleled the scientific advances and remain far from established quality standards. This paradox is the topic of the present review article, intending to increase the widespread interest of clinicians in gout.

2018 updated European League Against Rheumatism evidence-based recommendations for the diagnosis of gout.

Although gout is the most common inflammatory arthritis, it is still frequently misdiagnosed. New data on imaging and clinical diagnosis have become available since the first EULAR recommendations for the diagnosis of gout in 2006. This prompted a systematic review and update of the 2006 recommendations. A systematic review of the literature concerning all aspects of gout diagnosis was performed. Recommendations were formulated using a Delphi consensus approach. Eight key recommendations were generated. A search for crystals in synovial fluid or tophus aspirates is recommended in every person with suspected gout, because demonstration of monosodium urate (MSU) crystals allows a definite diagnosis of gout. There was consensus that a number of suggestive clinical features support a clinical diagnosis of gout. These are monoarticular involvement of a foot or ankle joint (especially the first metatarsophalangeal joint); previous episodes of similar acute arthritis; rapid onset of severe pain and swelling; erythema; male gender and associated cardiovascular diseases and hyperuricaemia. When crystal identification is not possible, it is recommended that any atypical presentation should be investigated by imaging, in particular with ultrasound to seek features suggestive of MSU crystal deposition (double contour sign and tophi). There was consensus that a diagnosis of gout should not be based on the presence of hyperuricaemia alone. There was also a strong recommendation that all people with gout should be systematically assessed for presence of associated comorbidities and risk factors for cardiovascular disease, as well as for risk factors for chronic hyperuricaemia. Eight updated, evidence-based, expert consensus recommendations for the diagnosis of gout are proposed.

Progresses in the imaging of calcium pyrophosphate crystal disease.

PURPOSE OF REVIEW: Calcium pyrophosphate crystal disease (CPPD) may be considered a neglected disorder, common in clinics and wards, but not receiving enough attention since the time it was recognized as a disease entity. This review aims to highlight the advances occurred in recent years in terms of imaging of CPPD, and their potential aid in diagnosing CPPD. RECENT FINDINGS: The main advances in CPPD imaging have occurred with ultrasound and computed tomography. Ultrasound has been shown as more sensitive than conventional radiography in detecting chondrocalcinosis. OMERACT definitions of ultrasound signs of CPPD have been provided; validations process is still ongoing. Computed tomography has been used to assess CPPD at the spine. Some studies suggest that dual-energy scans could accurately detect chondrocalcinosis and discriminate from other calcified structures. SUMMARY: Ultrasound and computed tomography may have a role in CPPD detection, though the specifics are still unclear. It remains necessary to have studies comparing them with synovial fluid analysis for crystals in a clinical scenario.

Gout, Hyperuricaemia and Crystal-Associated Disease Network (G-CAN) consensus statement regarding labels and definitions of disease states of gout.

OBJECTIVE: There is a lack of standardisation in the terminology used to describe gout. The aim of this project was to develop a consensus statement describing the recommended nomenclature for disease states of gout. METHODS: A content analysis of gout-related articles from rheumatology and general internal medicine journals published over a 5-year period identified potential disease states and the labels commonly assigned to them. Based on these findings, experts in gout were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach agreement on disease state labels and definitions. RESULTS: The content analysis identified 13 unique disease states and a total of 63 unique labels. The Delphi exercise (n=76 respondents) and face-to-face meeting (n=35 attendees) established consensus agreement for eight disease state labels and definitions. The agreed labels were as follows: 'asymptomatic hyperuricaemia', 'asymptomatic monosodium urate crystal deposition', 'asymptomatic hyperuricaemia with monosodium urate crystal deposition', 'gout', 'tophaceous gout', 'erosive gout', 'first gout flare' and 'recurrent gout flares'. There was consensus agreement that the label 'gout' should be restricted to current or prior clinically evident disease caused by monosodium urate crystal deposition (gout flare, chronic gouty arthritis or subcutaneous tophus). CONCLUSION: Consensus agreement has been established for the labels and definitions of eight gout disease states, including 'gout' itself. The Gout, Hyperuricaemia and Crystal-Associated Disease Network recommends the use of these labels when describing disease states of gout in research and clinical practice.