Research: Point of Service Testing May Reduce Future Hospital Admissions in Gout and Pseudogout Patients

New research findings presented this week at the American College of Rheumatology Annual Meeting in Boston reveal that Raman spectroscopy (RS) used at point of service could reduce the need for inpatient admission in patients with gout and pseudogout. Gout is a chronic disease that involves painful joint swelling and redness that often strikes joints in the lower extremities including ankles, knees and feet, especially the big toe. Gout occurs when excess uric acid (a normal waste product) collects in the body, and needle‐like urate crystals deposit in the joints. This may happen because uric acid production increases or excretion is reduced, most often if the kidneys cannot remove uric acid from the body well enough.

"The objective of this study was to demonstrate the usefulness of a shoebox sized point of service clinical grade RS instrument in speeding the time to clinical diagnosis of gout and pseudogout while maintaining the accuracy comparable to that attained by microscopic analysis if synovial aspirates," said Nora Singer, MD, professor of rheumatology at Case Western Reserve University School of Medicine.

The diagnosis of gout or pseudogout hinges upon the identification of monosodium urate (MSU) crystals or calcium pyrophosphate dihydrate (CPPD) crystals, respectively, in synovial fluid aspirates from affected joints. Prompt recognition of synovial fluid crystals using polarizing light microscopy (PLM) depends upon a skilled observer''s identifying negatively and/or positively birefringent crystals. Rheumatologists and pathologists routinely examine fluid for crystals using PLM-, however this task is complex, and appropriate personnel to perform and interpret PLM are not always available in urgent cares, ERs and community healthcare settings where patient may present acutely. Failure to promptly diagnose crystalline arthritis results in delay in treatment and even potential hospital admission due to uncertainty about diagnosis.

Investigators developed a desktop instrument specifically for identifying MSU and CPPD crystals to perform RS on synovial fluids. The instrument was used to analyze eighty synovial fluid samples.

MSU crystals were detected by PLM in 19/80 and CPPD crystals in 10/80 samples. Initial measurement using RS detected crystals in 26/29 samples with a sensitivity of 89.7 percent and a specificity of 100 percent. In 80 samples, 2 MSU and 1 CPPD sample were identified by PLM but missed by RS and 3 CPPD containing samples were identified by RS but missed by PLM.

"The value in benchtop RS lies in the ability to quickly and accurately detect the presence of SF MSU and CPPD crystals. Identification of SF MSU as evidence of gout flare facilitates prompt treatment with outpatient follow-up. Limitations of RS include this technique cannot confirm CPPD crystals are intracellular yet, as is required for the diagnosis of pseudogout. However in our hands, RS was at least as sensitive as PLM for crystal detection. Our results suggest that RS used at POS for synovial fluid crystal detection could help guide initiation of targeted outpatient therapy and potentially reduce the need for inpatient admission in patients with joint effusion, in whom diagnosis might otherwise be uncertain. This could potentially improve use of inpatient resources and the overall quality of patient care and should now be tested in a clinical trial" said Dr. Singer.

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The project described was funded by NIAMS award AR# 057812 to OA and supported by National Center for Research Resources, Grant UL1RR024989, and is now at the National Center for Advancing Translational Sciences, Grant UL1TR000439. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Study data were collected and managed using REDCap electronic data capture tools hosted at MetroHealth Medical Center/ CWRU (see footnote). REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies, providing 1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for importing data from external sources.

The American College of Rheumatology is an international professional medical society that represents more than 9,500 rheumatologists and rheumatology health professionals around the world. Its mission is to Advance Rheumatology! The ACR/ARHP Annual Meeting is the premier meeting in rheumatology. For more information about the meeting, visit www.acrannualmeeting.org/ or join the conversation on Twitter by using the official #ACR14 hashtag.

Paper Number: L11

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Raman Spectroscopy: Point of Service Diagnosis Is Sensitive and Specific-a Tool for Improving Accuracy and Reducing Future Hospital Admission.

Nora Singer1, Bolan Li2, Yener Yeni3, Emma Barnboym4, Steven Lewis4, Daniel Oravec3, Donald Haggins3 and Ozan Akkus2, 1MetroHealth Medical Center and CWRU, Cleveland, OH, 2 Case Western Reserve University, Cleveland, OH, 3 Henry Ford Hospital, Detroit, MI, 4 MetroHealth Medical Center, Cleveland, OH.

Background/Purpose: The diagnosis of gout or pseudogout hinges upon identification of monosodium urate (MSU) crystals and calcium pyrophosphate (CPPD) crystals in synovial fluid (SF) aspirates from affected joints. Prompt recognition of SF crystals using polarizing light microscopy (PLM) depends upon a skilled observer identifying negatively and/or positively birefringent crystals. However, appropriate personnel to perform and interpret PLM are not always available. Failure to promptly diagnose crystalline arthritis results in delay in treatment and even hospital admission due to uncertainty about diagnosis.

Methods: We have built a desktop instrument to perform Raman spectroscopy (RS) on synovial fluids that is sensitive and specific for identifying monosodium urate and CPPD crystals, which can be commercialized and developed for point of service (POS) use. Discarded SF from clinically indicated joint aspirates were analyzed using PLM either by a rheumatologist and/or pathologist. Remaining SF was aliquoted and frozen at -80°C. SF was digested with hyaluronidase, Proteinase K, and sodium dodecyl sulfate (SDS) and concentrated for use in RS.

Results: Eighty samples were analyzed. MSU crystals were detected by PLM in 19/80 and CPPD crystals in 10/80 samples. Initial measurement using RS detected crystals in 26/29 samples with a sensitivity of 89.65% and a specificity of 100%. In 80 samples, 2 MSU and 1 CPPD sample were identified by PLM but missed by RS and 3 CPPD containing samples were identified by RS but missed by PLM.

Conclusion: Based on our observations, development of a benchtop point of service clinical grade RS instrument would be useful in speeding the time to, and accuracy of, clinical diagnosis of gout and pseudogout. While the presence of MSU crystals is suspicious for gout even when they are extracellular, the same is not true for CPPD. CPPD found in SF but not in WBC may not be the primary cause of joint inflammation, and therefore diagnosis of pseudogout requires both positive identification of CCPD crystals and demonstration that the CPPD crystals are intracellular. CCPD crystals are typically more difficult to identify than MSU crystals by PLM, but not by RS. Further, pseudogout may accompany infection that can be detected only by microbiological testing. Thus the value in benchtop RS lies in the ability to quickly and accurately detect the presence of SF MSU and CPPD crystals. Identification of SF MSU as evidence of gout flare facilitates prompt treatment with outpatient follow up. Whether hospital admission(s) can be reduced by POS RS diagnosis of gout or potential pseudogout is an open question. While RS facilitates detection of both MSU and CPPD crystals, limitations of the study include the inability of Raman spectroscopy to distinguish intra and extracellular crystals. Nonetheless, RS used at POS for SF crystal detection could reduce the need for inpatient admission in patients with joint effusion and whose diagnosis might otherwise be uncertain, potentially improving use of inpatient resources and improving the quality of patient care. Prospective testing of this RS instrument at POS is a future priority.

The project described was funded by NIAMS award AR# 057812 to OA and supported by National Center for Research Resources, Grant UL1RR024989, and is now at the National Center for Advancing Translational Sciences, Grant UL1TR000439. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Study data were collected and managed using REDCap electronic data capture tools hosted at MetroHealth Medical Center/ CWRU.1 REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies, providing 1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for importing data from external sources.

Footnote: Paul A. Harris, Robert Taylor, Robert Thielke, Jonathon Payne, Nathaniel Gonzalez, Jose G. Conde, Research electronic data capture (REDCap) - A metadata-driven methodology and workflow process for providing translational research informatics support, J Biomed Inform. 2009 Apr;42(2):377-81.




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