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.

Painful blue fingers.

The patient's history of lupus held the clue to the diagnosis.

Calcium pyrophosphate crystal size and characteristics.

OBJECTIVE: To describe the characteristics of calcium pyrophosphate (CPP) crystal size and morphology under compensated polarized light microscopy (CPLM). Secondarily, to describe CPP crystals seen only with digital enhancement of CPLM images, confirmed with advanced imaging techniques. METHODS: Clinical lab-identified CPP-positive synovial fluid samples were collected from 16 joint aspirates. Four raters used a standardized protocol to describe crystal shape, birefringence strength and color. A crystal expert confirmed CPLM-visualized crystal identification. For crystal measurement, a high-pass linear light filter was used to enhance resolution and line discrimination of digital images. This process identified additional enhanced crystals not seen by raters under CPLM. Single-shot computational polarized light microscopy (SCPLM) provided further confirmation of the enhanced crystals' presence. RESULTS: Of 932 suspected crystals identified by CPLM, 569 met our inclusion criteria, and 293 (51%) were confirmed as CPP crystals. Of 175 unique confirmed crystals, 118 (67%) were rods (median area 3.6 µm2 [range, 1.0-22.9 µm2]), and 57 (33%) were rhomboids (median area 4.8 µm2 [range, 0.9-16.7 µm2]). Crystals visualized only after digital image enhancement were smaller and less birefringent than CPLM-identified crystals. CONCLUSIONS: CPP crystals that are smaller and weakly birefringent are more difficult to identify. There is likely a population of smaller, less birefringent CPP crystals that routinely goes undetected by CPLM. Describing the characteristics of poorly visible crystals may be of use for future development of novel crystal identification methods.

Hypercalcemia-induced acute kidney injury in a Caucasian female due to radiographically silent systemic sarcoidosis.

. Sarcoidosis is a rare autoimmune disease resulting in formation of non-necrotizing "non-caseating" granulomas generally in the lung. The disease classically strikes African American females in their fourth and fifth decades. The resulting hypercalcemia is a result of 1-α hydroxylase overexpression in granulomas with increased 1,25-dihydroxy vitamin D levels. This phenomenon can also be observed in mycobacterial and fungal infections that produce granulomas in infected patients. Thus, chronic infectious diseases are part of differential diagnosis of granulomatous processes. We present an elderly Caucasian female who presented with hypercalcemia with serum calcium of 11 - 14 mg/dL and an elevated ionized calcium of 1.4 - 1.5 mmol/L. Initially cholecalciferol supplements were stopped, but hypercalcemia persisted for more than 2 months. 1,25-dihydroxy vitamin D levels were markedly elevated with low normal 25-hydroxy vitamin D levels, angiotensin-converting enzyme levels were also high, and chest computed tomography (CT) imaging was negative for any lymphadenopathy (including perihilar lymphadenopathy). Malignancy and infectious workups were negative for fungal and mycobacterial infections. Positron emission tomography revealed several small lymph nodes in right upper lobe of lung, and biopsy of bone marrow and lung lymph-nodes revealed non-caseating granulomata. We present an atypical case of occult sarcoidosis presenting mainly with biochemical findings without any definitive imaging findings, making diagnosis a clinical challenge.

Case Report: Patient with Hepatitis C, p-ANCA, and Cryoglobulin Antibodies Presenting with Necrotizing Crescentic p-ANCA Glomerulonephritis.

Hepatitis C (HCV) infection has a prevalence of 3 million infected individuals in the United States, according to recent Center for Disease Control reports, and can have various renal manifestations. Cryoglobulins, antibodies that precipitate at colder temperatures in vitro, are a relatively common cause of renal disease in HCV infection. The cryoglobulin proteins can form occlusive aggregates in small glomerular capillary lumina or deposit in other areas of the glomerulus, resulting in hypocomplementemia, proteinuria, hematuria, and renal injury. The typical biopsy pattern is that of membranoproliferative glomerulonephritis (MPGN). There are, however, other HCV-related patterns of glomerular injury. Anti-neutrophil cytoplasmic antibodies (ANCA) are known to exist in HCV-infected patients. In many reported cases, ANCA serologic testing may appear positive due to cross-reactivity of the immune assays; however, the biopsy findings do not support ANCA-associated crescentic glomerulonephritis (GN)/vasculitis as the primary cause of glomerular injury. There are rare reports of microscopic polyangiitis (MPA) p-ANCA vasculitis, in patients with HCV infection. In comparison with the MPGN pattern of cryoglobulinemic glomerular injury, biopsies from these HCV-infected patients with concomitant MPA revealed a crescentic GN, associated with normal serum complement levels. We present a case of HCV-associated glomerular disease with the surprising biopsy finding of necrotizing and crescentic p-ANCA GN, with a background, low-grade mesangial immune complex GN. Thus, p-ANCA disease should also be considered in HCV-infected patients, in addition to the more typical lesions of MPGN or cryoglobulinemic GN.

Treatment of acute gout: a systematic review.

OBJECTIVE: Acute gout is traditionally treated with NSAIDs, corticosteroids, and colchicine; however, subjects have multiple comorbidities that limit the use of some conventional therapies. We systematically reviewed the published data on the pharmacologic and non-pharmacologic agents used for the treatment of acute gouty arthritis. METHODS: A systematic search was performed using PubMed and Cochrane database through May 2013. We included only randomized controlled trials (RCTs) that included NSAIDs, corticosteroids, colchicine, adrenocorticotropic hormone (ACTH), interleukin-1 (IL-1) inhibitors, topical ice, or herbal supplements. RESULTS: Thirty articles were selected for systematic review. The results show that NSAIDs and COX-2 inhibitors are effective agents for the treatment of acute gout attacks. Systemic corticosteroids have similar efficacy to therapeutic doses of NSAIDs, with studies supporting oral and intramuscular use. ACTH is suggested to be efficacious in acute gout. Oral colchicine demonstrated to be effective, with low-dose colchicine demonstrating a comparable tolerability profile as placebo and a significantly lower side effect profile to high-dose colchicine. The IL-1ß inhibitory antibody, canakinumab, was effective for the treatment of acute attacks in subjects refractory to and in those with contraindications to NSAIDs and/or colchicine. However, rilonacept was demonstrated to be not as effective, and there are no RCTs for the use of anakinra. CONCLUSION: NSAIDs, COX-2 selective inhibitors, corticosteroids, colchicine, ACTH, and canakinumab have evidence to suggest efficacy in treatment of acute gout.

Sensitivity to change of the modified Rodnan skin score in diffuse systemic sclerosis--assessment of individual body sites in two large randomized controlled trials.

OBJECTIVE: The modified Rodnan skin score (MRSS) is a standard outcome measure for skin disease in SSc and calculated by summation of skin thickness in 17 different body sites (total score = 51). Our objective was to evaluate the sensitivity of change over time of individual body sites used in the calculation of total MRSS. METHODS: We analysed two randomized placebo controlled clinical trials investigating the effect of either recombinant human relaxin or type I oral collagen in dcSSc. Both trials used MRSS as the primary outcome measure. We used a change of >10 mm (on a 0-100 VAS) in the patient global assessment (PGA) as the clinically important improvement. We calculated the mean change and the effect size (ES) for each individual body site used in the total MRSS for each study. Magnitude of ES was assessed using Cohen's rule of thumb for ES. RESULTS: In the relaxin and collagen studies, 71 of 199 patients (36%) and 54 of 129 (42%) of patients had an improvement >10 mm on the PGA at 6 and 12 months, respectively. Total MRSS had large ES in both studies (0.85-0.98); the chest, forearms and hands had moderate ES (0.50-0.74); and the lower extremities, face, abdomen and fingers had small ES (0.16-0.49). CONCLUSION: Certain body sites (hands, forearms and chest) are more sensitive to change compared with other body sites in two randomized clinical trials. It remains to be seen whether decreasing the number of body sites by exclusion of relatively static areas would further increase the sensitivity to change over time of the total MRSS.

Tezosentan, a novel endothelin receptor antagonist, markedly reduces rat hepatic ischemia and reperfusion injury in three different models.

This study investigated the effects of dual endothelin (ET) receptor blockade in rat models of liver ischemia and reperfusion injury (IRI). Three models of IRI were used: (1) in vivo total hepatic warm ischemia with portal shunting for 60 minutes with control (saline) and treatment groups (15 mg/kg tezosentan intravenously prior to reperfusion), (2) ex vivo hepatic perfusion after 24 hours of cold storage in University of Wisconsin solution with control and treatment groups (10 mg/kg tezosentan in the perfusate), and (3) syngeneic liver transplantation (LT) after 24 hours of cold storage in University of Wisconsin solution with control and treatment groups (10 mg/kg tezosentan intravenously prior to reperfusion). Tezosentan treatment significantly improved serum transaminase and histology after IRI in all 3 models. This correlated with reduced vascular resistance, improved bile production, and an improved oxygen extraction ratio. Treatment led to a reduction in neutrophil infiltration and interleukin-1 beta and macrophage inflammatory protein 2 production. A reduction in endothelial cell injury as measured by purine nucleoside phosphorylase was seen. Survival after LT was significantly increased with tezosentan treatment (90% versus 50%). In conclusion, this is the first investigation to examine dual receptor ET blockade in 3 models of hepatic IRI and the first to use the parenterally administered agent tezosentan. The results demonstrate that in both warm and cold IRI tezosentan administration improves sinusoidal hemodynamics and is associated with improved tissue oxygenation and reduced endothelial cell damage. In addition, reduced tissue inflammation, injury, and leukocyte chemotactic signaling were seen. These results provide compelling data for the further investigation of the use of tezosentan in hepatic IRI.

A caspase inhibitor, IDN-6556, ameliorates early hepatic injury in an ex vivo rat model of warm and cold ischemia.

This study examined the efficacy of the caspase inhibitor, IDN-6556, in a rat model of liver ischemia-reperfusion injury. Livers from male Sprague-Dawley rats were reperfused for 120 minutes after 24 hours of 4 degrees C cold storage in University of Wisconsin solution. Portal blood flow measurements estimated sinusoidal resistance, and bile production, alanine aminotransferase activities, and Suzuki scores were evaluated as parameters of hepatocyte/liver injury. Treated livers were exposed to 25 or 50 microM of IDN-6556 in University of Wisconsin storage solution and/or the perfusate. All treatment regimens with IDN-6556 significantly improved portal blood flow measured at 120 minutes, and significant improvements were seen as early as 30 minutes when inhibitor was also present in the perfusate (P < 0.01). All treatment groups with IDN-6556 significantly increased bile production by 3-4-fold compared with controls (P < 0.01), and reductions in alanine aminotransferase activities were seen within 90 minutes of reperfusion (P < 0.05). These data were confirmed by improved Suzuki scores (less sinusoidal congestion, necrosis, and vacuolization) in all treated groups. Livers from the IDN-6556-treated groups had markedly reduced caspase activities and TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling)-positive cells, suggesting reductions in apoptosis. IDN-6556 present in cold storage media ameliorated liver injury due to cold ischemia and reperfusion injury and may be a rational therapeutic approach to reduce the risk of liver ischemia in the clinical setting.