Lan X. Chen

Gout: an evidence-based review.

About 1% of individuals studied in Western populations will develop gout during their lifetime. Gout has a wellunderstood pathogenesis and effective treatments, but remains suboptimally managed. This review will emphasize recent developments related to gout epidemiology, pathogenesis, diagnosis, and efficacy of existing therapies. In each of these areas, we identify evidence, persisting gaps in evidence, and address clinical implications.

Developing a provisional definition of flare in patients with established gout

OBJECTIVE Various nonvalidated criteria for disease flare have been used in studies of gout. Our objective was to develop empirical definitions for a gout flare from patient-reported features. METHODS Possible elements for flare criteria were previously reported. Data were collected from 210 gout patients at 8 international sites to evaluate potential gout flare criteria against the gold standard of an expert rheumatologist definition. Flare definitions based on the presence of the number of criteria independently associated with the flare and classification and regression tree approaches were developed. RESULTS The mean ± SD age of the study participants was 56.2 ± 15 years, 207 of them (98%) were men, and 54 of them (26%) had flares of gout. The presence of any patient-reported warm joint, any patient-reported swollen joint, patient-reported pain at rest score of >3 (0-10 scale), and patient-reported flare were independently associated with the study gold standard. The greatest discriminating power was noted for the presence of 3 or more of the above 4 criteria (sensitivity 91% and specificity 82%). Requiring all 4 criteria provided the highest specificity (96%) and positive predictive value (85%). A classification tree identified pain at rest with a score of >3, followed by patient self-reported flare, as the rule associated with the gold standard (sensitivity 83% and specificity 90%). CONCLUSION We propose definitions for a disease flare based on self-reported items in patients previously diagnosed as having gout. Patient-reported flare, joint pain at rest, warm joints, and swollen joints were most strongly associated with presence of a gout flare. These provisional definitions will next be validated in clinical trials.

Efficacy of Acupuncture as a Treatment for Chronic Shoulder Pain

OBJECTIVES The aim of this study was to evaluate the efficacy of acupuncture as a treatment for chronic shoulder pain and to compare the efficacy of individualized acupuncture to fixed, standard point acupuncture treatment. DESIGN The study was a single-blind randomized, controlled trial. SETTINGS/LOCATION The study was conducted in an outpatient rheumatology clinic at the VA Medical Center of Philadelphia. SUBJECTS The participants were adults with shoulder pain for at least 8 weeks with a diagnosis of osteoarthritis or rotator cuff tendonitis and a total Shoulder Pain and Disability Index (SPADI) score of > or =30. INTERVENTIONS Thirty-one (31) subjects were randomized to one of three treatment groups: individualized acupuncture points according to the approaches of Traditional Chinese Medicine; fixed, standard acupuncture points conventionally used for shoulder pain; and sham nonpenetrating acupuncture. Subjects received 12 treatments over 6 weeks and were reassessed using the SPADI at the end of the 6 weeks. OUTCOME MEASURES The primary outcome evaluated was the mean change in total SPADI score in each group from baseline to 6 weeks. RESULTS After 6 weeks of treatment, the mean total SPADI score improved in all three groups, but the change was clinically significant (> or =10 points) only in groups 1 and 2 (-20.3 and -20.4, respectively, versus -6.5 in group 3). The treatment effects of groups 1 and 2 compared to the sham acupuncture group were -13.8 (95% confidence interval: -2.2 to -25.4, p < 0.015) and -13.9 (-2.0 to -25.8, p < 0.013), respectively. There was no difference between the individualized acupuncture and standardized acupuncture treatments. CONCLUSIONS Acupuncture may be an effective treatment for chronic shoulder pain. There may be no difference in efficacy between individualized and standardized acupuncture treatment. This suggests that the use of standard points may make treatment easier for patient care and for further research studies.

A histomorphometric analysis of synovial biopsies from individuals with Gulf War Veterans’ Illness and joint pain compared to normal and osteoarthritis synovium

We compared histologic, immunohistochemical, and vascular findings in synovial biopsies from individuals with Gulf War Veterans Illness and joint pain (GWVI) to findings in normal and osteoarthritis (OA) synovium. The following parameters were assessed in synovial biopsies from ten individuals with GWVI: lining thickness, histologic synovitis score, and vascular density in hematoxylin & eosin-stained sections; and CD68+ lining surface cells and CD15+, CD3+, CD8+, CD20+, CD38+, CD68+, and Ki-67+ subintimal cells and von Willebrand Factor+ vessels immunohistochemically. Comparisons were made to synovial specimens from healthy volunteers (n = 10) and patients with OA or RA (n = 25 each). Histologic appearance and quantitative assessments were nearly identical in the GWVI and normal specimens. Vascular density was between 25% (H & E stains; p = 0.003) and 31% (vWF immunostains; p = 0.02) lower in GWVI and normal specimens than in OA. CD68+ macrophages were the most common inflammatory cells in GWVI (45.3 ± 10.1 SEM cells/mm2) and normal synovium (45.6 ± 7.4) followed by CD3+ T cells (GWVI, 15.1 ± 6.3; normal, 27.1 ± 9.2), whereas there were practically no CD20+, CD38+, and CD15+ cells. All parameters except lining thickness and CD15 and CD20 expression were significantly higher in OA. Five (20%) OA specimens contained significant fractions of humoral immune cells in mononuclear infiltrates, although the overall differences in the relative composition of the OA mononuclear infiltrates did not reach statistical significance compared to GWVI and normal synovium. In summary, the GWVI and normal synovia were indistinguishable from each other and contained similar low-grade inflammatory cell populations consisting almost entirely of macrophages and T cells.

Development and validation of a case ascertainment tool for ankylosing spondylitis.

Ankylosing spondylitis (AS) diagnosis is often delayed. The availability of effective biologic agents for treating AS has increased the importance of early diagnosis. We tested questions derived from a comprehensive literature review and an advisory board in a case–control study designed to identify patients with AS from among patients with chronic back pain (CBP).

Current trends in crystal identification.

Purpose of reviewThis review is an attempt to keep current in the sparse literature addressing the still underutilized area of crystal identification. Recent findingsThe emphasis has been on the subtleties of the microscopic identification of common crystals and other less common potentially confusing crystals. Imaging is noted to provide increasing help, but microscopic crystal identification remains the gold standard. SummaryQuality control is still a concern as is the infrequency of attempted arthrocentesis for crystal identification.

Increased angiogenesis and cellular proliferation as hallmarks of the synovium in chronic septic arthritis.

OBJECTIVE To characterize histologic alterations and inflammatory infiltrates in the synovium of patients with chronic septic arthritis (SeA). METHODS Synovial membranes from patients with SeA (9 specimens; disease duration >4 weeks) were compared with specimens from patients with septic joint prosthesis loosening (septic total arthroplasty [SeTA]; 9 specimens), rheumatoid arthritis (RA; 25 specimens), osteoarthritis (25 specimens), and normal histology (10 specimens). Sections were stained with hematoxylin and eosin, tissue gram stain, and immunostains for von Willebrand factor (vWF; blood vessels), Ki-67 (dividing cells), CD15 (neutrophils), CD3 (T cells), CD20 (B cells), CD38 (plasma cells), and CD68 (macrophages). RESULTS Gram stains were positive in all SeA and SeTA specimens. Mixed polymorphonuclear and mononuclear infiltrates predominated in SeA and SeTA. SeA could be differentiated from RA by higher densities of CD15+ cells (SeA:RA ratio 6.5:1; P < 0.001) or Ki-67+ cells (ratio 2.1:1; P = 0.012). The inflammatory infiltrate of SeTA was similar to SeA but contained fewer CD3+ cells (SeTA versus SeA 0.26:1; P = 0.009) and a tendency toward fewer CD20+ cells. Mean vascular density was strikingly increased in SeA (SeA:normal ratio 3.0:1; P < 0.001) and, to a lesser extent, in the vascularized areas of the SeTA specimens (SeTA:normal ratio 1.9:1). Ki-67/CD31 double immunostains demonstrated proliferating endothelial cells in small subintimal blood vessels, suggesting angiogenesis. Receiver operating characteristic curve analysis identified higher densities of CD15+ and Ki-67+ cells and vWF-positive vessels as histologic markers that differentiated SeA from RA. CONCLUSION This first analysis of the synovium in patients with chronic pyogenic arthritis identified dramatic neovascularization and cell proliferation, accompanied by persistent bacterial colonization and heterogeneous inflammatory infiltrates rich in CD15+ neutrophils, as histopathologic hallmarks.

The time has come to incorporate more teaching and formalized assessment of skills in synovial fluid analysis into rheumatology training programs

Arthrocentesis with synovial fluid analysis can directly dictate the diagnosis and management of previously unexplained joint effusions (1). In addition to its obvious value in confirming the diagnosis of crystal-induced arthritis, fluid analysis can help differentiate among other causes of polyarthritis. This is now particularly relevant, given the potential of overdiagnosing rheumatoid arthritis (RA) using the newer diagnostic algorithms that seem to emphasize sensitivity over specificity (2–4) in order to appropriately encourage the early aggressive therapy of RA. We previously analyzed the accuracy of diagnosis in a series of patients using the 1987 American College of Rheumatology (ACR) criteria for the classification of RA, and noted that the diagnostic specificity could be improved by including synovial fluid analysis (5). In our analysis, 19 of 157 patients diagnosed with RA would have been alternatively classified if synovial fluid findings had been utilized in the diagnostic process. Yet, the 2010 ACR/European League Against Rheumatism classification criteria for the early diagnosis of RA (6), a major international effort that notes the need to exclude other causes of synovitis, do not recognize the diagnostic value of joint aspiration with synovial fluid analysis. We believe that an underemphasis on synovial fluid analysis in clinical training has contributed to an underutilization of the test in clinical practice and an underemphasis in academic writings and practice guidelines. Microscopic examination of synovial fluid for crystals remains the gold standard for the diagnosis of gout and clinically relevant calcium pyrophosphate deposition disease (7–10). Synovial fluid analysis can alter the clinical diagnosis (1,11). Although the concern regarding the inconsistent quality of fluid examination is well-founded (12–15), this can be rectified at least for rheumatologists with appropriate training and a requirement for the demonstration of competency prior to certification. Synovial fluid analysis has been a valuable component of rheumatologic practice for a half-century. It is a skill that is expected by the Accreditation Council for Graduate Medical Education (ACGME) to be learned during rheumatologic training. Yet, only some fellowship programs have well-defined performance measures to assess the skills of their graduating fellows, and synovial fluid analysis is not rigorously assessed on the rheumatology certification examination. An informal survey of program directors and direct observation of our own and other programs indicate that many programs do not explicitly define “competency” to perform synovial fluid analysis. No consensus has been reached on a standardized method for training and evaluating fellows (and staff) in the performance of fluid analysis, nor have outcomes of various utilized teaching approaches been fully evaluated. A number of challenges exist in trying to incorporate a rigorous synovial fluid analysis module into fellowship training (including the lack of experienced mentors in some programs), particularly if it is desired to have uniformity between programs and a shared definition of competency. However, we believe that these challenges can be systematically overcome if the resolve is present. Several educational programs to teach synovial fluid analysis and assess the skills of trainees have been described. For example, we distributed short multiple-choice quizzes on synovial fluid analysis at ACR workshops, but the validity of the quiz and the lasting educational value of the workshop have not been rigorously assessed. A similar quiz (available at http://www.med.upenn.edu/synovium/ sfanalysis.shtml) was developed at the University of Pennsylvania. The questions were designed to assess not only H. Ralph Schumacher, MD: University of Pennsylvania and Philadelphia VA Medical Center, Philadelphia; Lan X. Chen, MD, PhD: Penn Presbyterian Medical Center, Philadelphia, Pennsylvania; Brian F. Mandell, MD, PhD: Cleveland Clinic Foundation, Cleveland, Ohio. Dr. Mandell has received consultant fees, speaking fees, and/or honoraria (less than

Synovial Biopsy Findings in Arthritis Associated with Hepatitis C Virus Infection

10,000 each) from Novartis, Pfizer, and Savient. Address correspondence to Brian F. Mandell, MD, PhD, Cleveland Clinic, A50, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: mandelb@ccf.org. Submitted for publication February 22, 2012; accepted in revised form April 12, 2012. Arthritis Care & Research Vol. 64, No. 9, September 2012, pp 1271–1273 DOI 10.1002/acr.21714

Musculoskeletal Signs and Symptoms

To the Editor: The worldwide prevalence of arthritis presumed to be due to hepatitis C virus (HCV) infection has been reported between 2.4 million and 45.9 million people1,2. Histopathological changes in HCV-associated synovitis have not been examined. We have performed a histological and immunohistochemical analysis of synovial biopsies from the knee joints of 2 patients with HCV infection and arthritis. Laboratory values are summarized in Table 1. Patient 1 was a 56-year-old African American man with joint pain involving hands, wrists, elbows, shoulders, knees, and ankles of 4 months’ duration. There was no history of sexually transmitted diseases or gastroenteritis in the preceding months. Physical examination revealed warmth, swelling, and tenderness over the elbows, wrists, metacarpals, proximal interphalangeal joints, knees, ankles, and metatarsal bones. A closed-needle synovial biopsy was performed on 1 knee joint. At 3 years’ followup, the patient is maintained on low-dose prednisone and continues to have arthralgias but no overt joint swelling. View this table: Table 1. Laboratory values. Patient 2 was a 42-year-old white man with a painful right knee effusion of 1 month’s duration. He denied prior trauma or illness, but reported sweats and chills. There was no recent history of sexually transmitted diseases and no gastroenteritis in the months prior. A closed-needle synovial biopsy was performed on the affected knee joint. Symptoms resolved after an intraarticular injection of triamcinolone hexacetonide and subsequent treatment with nonsteroidal antiinflammatory drugs. Two years later the arthritis has not recurred. Synovial tissue sections from both patients were stained with H&E or immunostained for CD15 (neutrophilic granulocytes), CD3, CD20, CD38, CD68, Ki-67, and von Willebrand factor (vWF) …