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Item does not contain fulltext BACKGROUND: Although there has been major progress in gout imaging, no gout classification criteria currently include advanced imaging techniques. OBJECTIVE: To examine the usefulness of imaging modalities in the classification of gout when compared to monosodium urate (MSU) crystal confirmation as the gold standard, in order to inform development of new gout classification criteria. METHODS: We systematically reviewed the published literature concerning the diagnostic performance of plain film radiography, MRI, ultrasound (US), conventional CT and dual energy CT (DECT). Only studies with MSU crystal confirmation as the gold standard were included. When more than one study examined the same imaging feature, the data were pooled and summary test characteristics were calculated. RESULTS: 11 studies (9 manuscripts and 2 meeting abstracts) satisfied the inclusion criteria. All were set in secondary care, with mean gout disease duration of at least 7 years. Three features were examined in more than one study: the double contour sign (DCS) on US, tophus on US, and MSU crystal deposition on DECT. The pooled (95% CI) sensitivity and specificity of US DCS were 0.83 (0.72 to 0.91) and 0.76 (0.68 to 0.83), respectively; of US tophus, were 0.65 (0.34 to 0.87) and 0.80 (0.38 to 0.96), respectively; and of DECT, were 0.87 (0.79 to 0.93) and 0.84 (0.75 to 0.90), respectively. CONCLUSIONS: US and DECT show promise for gout classification but the few studies to date have mostly been in patients with longstanding, established disease. The contribution of imaging over clinical features for gout classification criteria requires further examination.

Immunohistochemical synovial tissue biomarkers are used increasingly to classify arthropathies, study their pathogenesis, and to measure disease activity in clinical trials. We have used receiver operating characteristic (ROC) analysis to quantify the discriminatory abilities of markers for common inflammatory cells (subintimal CD15, CD68, CD3, CD20, CD38, and lining CD68), proliferating cells (Ki-67) and blood vessels (von Willebrand factor, vWF) among inflammatory (chronic septic arthritis, early arthritis and rheumatoid arthritis (RA)) and degenerative arthropathies (osteoarthritis (OA) and orthopedic arthropathies) and normal synovium. Six of the eight markers distinguished accurately between RA and the degenerative arthropathies (area under the curve (AUC) 0.91-0.97), whereas subintimal CD68 (AUC 0.92) and Ki-67 (AUC 0.87) distinguished best between OA and normal synovium. Fold differences in mean expression correlated only modestly with AUCs (r(2) = 0.44). Multicategory ROC analysis ranked Ki-67, subintimal CD68, and CD15 as discriminating best among all six sample groups, and thus identified them as the most broadly applicable markers.

Recent studies suggest that blockade of the NLRP3 (cryopyrin) inflammasome interleukin 1beta (IL1beta) pathway may offer a new treatment strategy for gout.To explore the potential utility of rilonacept (IL1 Trap) in patients with chronic active gouty arthritis in a proof-of-concept study.This 14-week, multicentre, non-randomised, single-blind, monosequence crossover study of 10 patients with chronic active gouty arthritis included a placebo run-in (2 weeks), active rilonacept treatment (6 weeks) and a 6-week post-treatment follow-up.Rilonacept was generally well tolerated. No deaths and no serious adverse events occurred during the study. One patient withdrew owing to an injection-site reaction. Patients' self-reported median pain visual analogue scale scores significantly decreased from week 2 (after the placebo run-in) to week 4 (2 weeks of rilonacept) (5.0 to 2.8; p0.049), with sustained improvement at week 8 (1.3; p0.049); 5 of 10 patients reported at least a 75% improvement. Median symptom-adjusted and severity-adjusted joint scores were significantly decreased. High-sensitivity C-reactive protein levels fell significantly.This proof-of-concept study demonstrated that rilonacept is generally well tolerated and may offer therapeutic benefit in reducing pain in patients with chronic refractory gouty arthritis, supporting the need for larger, randomised, controlled studies of IL1 antagonism such as with rilonacept for this clinical indication.

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.

To quantify inflammatory changes in synovial membranes from orthopaedic "non-inflammatory" arthropathies (Orth. A).Synovial membranes from patients with femur fracture, avascular necrosis of the femur, plica syndrome, and meniscus and/or ligament injury (n = 23); rheumatoid arthritis (n = 28); osteoarthritis (OA; n = 25); and from normal controls (n = 10) were assessed by light microscopy, a histological synovitis score, immunostaining for CD3, CD20, CD38, CD68, Ki-67 and von Willebrand factor, and with an immunohistochemical inflammation score.Orth. A histology varied between normal and markedly inflamed. Predominant abnormalities were mild lining hyperplasia, scattered inflammatory cells and small perivascular infiltrates. The synovitis score classified Orth. A as "mild synovitis". Inflammatory cells occurred frequently: CD68+ cells in 100% of Orth. A specimens; CD3+, 91%; CD38+, 70%; and CD20+, 39%. Orth. A had 36% greater lining thickness (p = 0.04), 40% higher vascular density (p = 0.009) and 51.3-fold higher CD38+ cell density (p = 0.02) than normal controls; and 60% fewer subintimal Ki-67+ cells (p = 0.003), 42% fewer CD68+ lining cells (p0.01) and 40% fewer subintimal CD68+ cells (p0.01) than OA. The immunohistochemical inflammation score was 2.2-fold higher in Orth. A than in controls (p = 0.048) and similar to OA, with three Orth. A specimens showing marked inflammation.Synovial membranes from "non-inflammatory" arthropathies featured neovascularisation and inflammation intermediate between normal and OA synovium. These results expand previous findings that mechanical joint injury may lead to a mild-to-moderate synovitis.

Background: Rice bodies can occur in the joints in many rheumatic conditions, but they are most common in rheumatoid arthritis. They are generally believed to occur rarely in patients with osteoarthritis, but one study reported rice bodies with apatite crystals. Objective: To report on a series of joint fluids with rice bodies containing apatite clumps and examine their clinical pictures. Methods: All synovial fluid analysis reports for 10 years were reviewed for rice bodies and eight patients were reported on. A series of patients with a variety of diseases with synovial fluid rice bodies found to contain calcific material is described. All were examined by compensated polarised light and alizarin red stain, and four were examined by electron microscopy. Results: The eight patients all had alizarin red S chunks embedded throughout the rice body. Transmission electron microscopy disclosed the presence of a matrix of collagen, fibrin, and amorphous materials containing typical apatite crystals. Clinical diagnoses, radiographic findings, and leucocyte counts varied, but six of the eight patients had had previous repeated corticosteroid injections into the joints. Conclusion: Aggregates of apatites may be more common than previously recognised in rice bodies as they are not routinely sought. Whether they are a result of joint damage or depot steroid injections and whether that might contribute to further joint injury now needs to be investigated.

We report a case of focal calcium pyrophosphate dihydrate (CPPD) arthropathy in a 72-year-old, white woman that occurred in the temporomandibular joint (TMJ), a relatively unusual location for CPPD crystals. The patient underwent surgical exploration and radiation therapy because of histologic interpretation of an initial biopsy specimen as showing metastatic poorly differentiated carcinoma. Further evaluation of the specimen revealed the presence of positively birefringent crystals under compensated polarizing light microscopic examination. Previously reported cases of CPPD affecting the TMJ have also shown that this may mimic neoplastic or infectious conditions. Tophaceous pseudogout at the TMJ is a surprisingly common complication of CPPD deposition disease. As in our patient, it can occur without known CPPD at other sites.

To determine whether alterations in adrenocortical function occur early in the development of inflammatory joint disease, we examined patients with new onset synovitis ( or =45 yr), but similar levels of ACTH, cortisol, DHEA, DHEA sulfate, and total testosterone. In addition, the positive correlations between ACTH-cortisol, ACTH-DHEA, and cortisol-DHEA, observed in the normal controls, were weakened or abolished in the patients (both total and RA subset). No positive relations between inflammatory indices and ACTH or cortisol were noted, yet an inverse correlation between these indices and DHEA and testosterone was observed. Moreover, a steeper age-associated decline in DHEA was observed in our cross-sectional sample of patients with new onset synovitis. We conclude that patients with synovitis (including those fitting criteria for RA) have adrenocortical hormone alterations within a year of disease onset. Paradoxically, these patients have no positive relation between indices of inflammation and ACTH or cortisol, but rather serum androgen levels are inversely correlated with these indices. In addition, the relations between ACTH, the classic stimulus of cortisol and adrenal androgens, and these hormones are weakened or abolished, whereas the negative relation between age and zona reticularis function is steeper than that of controls.

The first descriptions of gout can be traced to the dawn of recorded medical history, yet a number of controversies and unanswered questions remain regarding diagnosis and treatment of gout. Questions can still be posed about the need for crystal identification of all cases, the utility of a 24-hour urine collection for uric acid, and even the difficulty of choosing a technique for measurement of uric acid. Some time has elapsed since Mesner stated in 1623, "Love and gout are incurable." How far have we come? How have we evaluated different treatments for gout? Ongoing reviews of the Cochrane collaboration show that there is still very little reliable information based on randomized controlled trials on which to base treatment decisions in acute and chronic gout.

Rheumatoid arthritis (RA) has been postulated to result from a synovial immune response to an unidentified antigen(s), which should be mirrored by the T cell response. Here we investigate the T cell receptor (TCR) repertoire in the synovial tissue of patients with arthritis of early to moderate duration. We developed a nested polymerase chain reaction (PCR) technique to examine the TCR repertoire of small biopsy specimens, and show that the method is highly sensitive. We apply this technique to synovial biopsies obtained from the knee joints of patients with early to moderate duration arthritis (average duration of arthritis 1 year, range 0.02–2.75 years). We examined biopsies from 5 normal individuals, 32 RA patients, 7 patients with seronegative spondyloarthropathy (Sp), and 12 patients with undifferentiated arthritis (UA). TCR message was detectable in 4/5 normals, 15/32 RA, 5/7 Sp, and 8/11 UA biopsies, with sampling error likely accounting for most negative biopsies. The average numbers of TCR Vβs detected per TCR-positive biopsy were 5.0 ± 3.7 for normals, 12.7 ± 8.4 for RA, 18.0 ± 7.4 for Sp patients, and 14.4 ± 10.2 for UA. Examination of TCR messages by single-stranded conformational polymorphism analysis showed similar proportions of dominant clones in the normals compared with the patients with inflammatory arthritis. Sequence analysis was performed on 33 dominant clones from 16 patients. Sequence alignment of the third hypervariable regions showed some evidence of disease-specific sequence clustering for Sp, while some RA sequences showed similarity to previously described motifs. These data indicate greater TCR heterogeneity in early Sp and UA compared with normal synovium. Disease-specific TCR sequences may occur in early RA and Sp.

This study evaluated measures of metalloproteinase gene expression in synovial biopsies as a means of differentiating the activities of two antirheumatic therapies: piroxicam and tenidap. Synovial biopsies and quantitative in situ hybridization for stromelysin (STR), collagenase (COL), tissue inhibitor of metalloproteinase-1 (TIMP), and actin mRNA were performed in a subset of patients with rheumatoid arthritis in a larger doubleblind randomized crossover trial comparing 120 mg/day of tenidap for 6 weeks with 20 mg/day of piroxicam for 6 weeks. There were no consistent differences between tenidap and piroxicam on COL or TIMP mRNA expression, but STR mRNA was significantly lower after tenidap compared with piroxicam (p = 0.037). There were no significant associations between measures of local or systemic clinical activity and STR, COL, or TIMP gene expression. However, changes in STR gene expression were significantly correlated with changes in serum C-reactive protein (p = 0.016). Because tenidap and piroxicam are both potent inhibitors of prostaglandin production, the effect of tenidap on STR gene expression may be due to its additional cytokine modulating activity. Clinical trials with data from synovial biopsies may be useful in evaluating the potential for disease-modifying effects of antirheumatic drugs.

Previous studies have suggested that monocytes may play a role in the dissemination ofChlamydia trachomatis, and in establishment of persistent infection with this bacterium. Infection of cultured human peripheral blood monocytes withC. trachomatisserovar K produced persistent, non-productive infection. Transmission electron microscopy of such infected cultures revealed single or multipleChlamydiain monocyte inclusions over a culture period of 10 days. Those inclusions were aberrant, and normal reticulate bodies within the inclusions were not observed. Immunoelectron microscopy showed the chlamydial major outer membrane protein and lipopolysaccharide to be associated with the bacterial plasma membrane. Lipopolysaccharide was also identified in the monocyte cytoplasm. Molecular analyses of primary chlamydial rRNA transcripts demonstrated that the organism is viable and metabolically active within monocyte inclusions. However, attempts to overcome chlamydial growth arrest by incubation ofChlamydia-infected monocytes with tryptophan, and antibodies against alpha interferon, gamma interferon, or tumor necrosis factor, were all ineffective, suggesting that known mechanisms of growth inhibition do not hold in human monocytes. These observations indicate that infection of human peripheral blood monocytes withC. trachomatismay be involved in the genesis/maintenance of extra-urogenital inflammation, since non-culturable, metabolically active bacteria persist in those cells.

The objective of this study was to determine the effects of orally administered misoprostol and diclofenac on inflammation caused by particulates in the rat subcutaneous air-pouch model. Subcutaneous air pouches were formed in male Sprague-Dawley rats. The animals were premedicated by gavage with either saline, diclofenac, misoprostol, or both diclofenac and misoprostol. The air pouches were injected with either polymethyl methacrylate particles or monosodium urate crystals, and the pouch fluids were obtained at 1, 6, 24, 48, and 72 h. Leukocyte influx, tumor necrosis factor, neutral metalloprotease activity, and prostaglandin E(2) levels were measured. It was determined that leukocyte influx was inhibited by diclofenac in the acute inflammation caused by monosodium urate crystals only. In all animals receiving diclofenac, prostaglandin E(2) (PGE(2)) levels were reduced, whereas tumor necrosis factor levels were elevated. The elevation of tumor necrosis factor was prevented by the addition of misoprostol. It is concluded that the oral administration of diclofenac or misoprostol can affect levels of specific mediators involved in particulate-induced inflammation in the subcutaneous air pouch.

Background Gout is a quite prevalent disorder in affluent countries, with the prevalence in males being 3–4 times higher than in females [1]. In practice, gout may be perceived as a “males” disorder and it has been suggested that the phenotype of gout differs between males and females, due to selection bias or by nature of the disease. Objectives To analyse whether there are differences between males and females in the phenotype of gout and in the performance of the ACR-EULAR classification criteria. Methods We used the multi-country SUGAR data set in which the ACR-EULAR classification criteria were constructed and validated [2]. In SUGAR, patients with at least one swollen joint or subcutaneous tophus conceivably being due to gout were consecutively included. Presence of MSU crystals in synovial fluid or tophus aspirate was the gold standard for gout, as assessed at inclusion, using microscopy by certified examiners in all included patients. Gout manifestations were standardly assessed without knowing the results of the microscopy. Gout manifestations included in the ACR-EULAR classification criteria were compared between male and female MSU positives. Sensitivity and specificity of the ACR-EULAR criteria, calculated without MSU results, were compared between males and females. To preserve power, the development and validation data sets of SUGAR were combined. Results There were 983 subjects included (71% male), of whom 52% (509/983) were MSU crystal-positive. Sixty-three percent (440/702) of the males and 25% (69/281) of the females were MSU crystal-positive, respectively (p 10%) or significant (p In the complete sample of 983 subjects, the classification system lead to a median (P25-P75) score of 5 (2–8) in females and 9 (6–14) in males (p Conclusions Male and female gout patients are similar on most important aspects of the gout phenotype. The ACR-EULAR classification criteria perform well in both males and females; sensitivity is the same in males and females, while specificity was better in females. References Kuo CF, Grainge M, Zhang W, Doherty M. Nature Rev Rheum. 2015;11:649–662. Neogi T, Jansen T, Dalbeth N, Fransen J, Schumacher HR et al. Ann Rheum Dis 2015;74:1789–1798. Acknowledgement We are grateful for the contributions of all investigators who submitted subjects in the SUGAR study. Disclosure of Interest None declared

Correct early diagnosis of acute and recent-onset arthritis is important to prognosis. The erosive damage done by rheumatoid arthritis occurs earlier in the disease course than previously realized, and more specific therapies to minimize damage are becoming available. Also, arthritis may be the initial clue to a serious systemic disease. Determining whether one, several, or many joints are affected can narrow the diagnostic possibilities. Arthrocentesis and synovial fluid testing provide much information and should be done at initial evaluation if possible. The presence or absence of fever, rash, family history of joint disease, and exposure to infective organisms can further direct diagnostic studies and treatment. In general, to avoid masking clues, drug therapy should be delayed for mild symptoms until diagnosis is complete.

Psoriatic arthritis is an inflammatory arthritis with diverse clinical manifestations. Certain subsets of patients tend to run a more severe course of erosive disease. A few points are noteworthy: When a diagnosis of psoriatic arthritis is being considered, ask if there is any family history of psoriasis and search for skin lesions in all parts of the body, including the scalp, ears, and genital and anal areas. Rule out septic arthritis even in a patient with an established diagnosis of psoriatic arthritis, especially if the presentation is monarticular. In cases of fulminant disease, consider checking for HIV infection. Pharmacologic therapy and physical rehabilitation are used in psoriatic arthritis. Mild cases can be controlled with use of nonsteroidal anti-inflammatory drugs; in more severe cases, treatment with immunosuppressive or disease-modifying agents is needed.

Joint manifestations in patients with rheumatoid arthritis (RA) are usually caused by the rheumatoid disease or, less often, by secondary osteoarthritis or an infection. Effusions related to crystal deposits have been reported but are uncommon. We report on seven patients with quiescent RA who presented with incompletely explained, acute, mostly monoarticular, joint or bursal exacerbations that may have been caused by apatite or lipid crystals or by reactions to tissue and cell debris. In one of these patients, the joint symptoms were related to the development of pigmented villonodular synovitis. Whether or not our hypothesized mechanisms are correct, it is important to be aware that exacerbations in a single or a few sites out of proportion to the rest of the RA need not be because of activity of the RA or infection. This awareness can prevent inappropriate aggressive treatment of the rheumatoid disease or extensive antibiotic therapy. In our cases, careful analysis of the synovial fluid was helpful in ascertaining that active RA was less likely and in identifying some possible causes of the effusions.

A 57-year-old black man with sickle cell disease was admitted to the hospital because of a painful crisis. After a fall with a fracture into the right knee joint, he developed an acutely painful, swollen knee. Synovial fluid from the right knee showed leukocyte counts of up to 154,000/mm3 and was negative for urate and calcium pyrophosphate dihydrate crystals. Gram stains and cultures were negative. Some sickled red cells were seen by light microscopy; electron microscopy revealed crystal-like arrays of sickled hemoglobin tactoids in erythrocytes which were enfolded and phagocytized by the cells of the synovial fluid. We suggest that this phagocytosis of sickled red cells is the likely cause for the otherwise unexplained inflammation.

Introduction: The synovial membrane is the key target of inflammation in chronic arthropathies, and the nature or intensity of the inflammatory infiltrates may vary according to the diagnosis. Traditionally, differences in absolute numbers of cells expressing a certain immunohistochemical marker (e.g.,[for full text, please go to the a.m. URL], GMDS 2012; 57. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V. (GMDS)

Background: Deposition of AL amyloid in multiple myeloma (MM) may lead to an arthropathy resembling rheumatoid arthritis. Due to its low incidence any sustainable knowledge of its natural history would need to come from multicenter case series. However, despite many single case reports and some small[for full text, please go to the a.m. URL], GMDS 2012; 57. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V. (GMDS)

Purpose. We have evaluated the Jebson hand function (JHF) test for use in patients with rheumatoid arthritis (RA). Methods. The JHF test was administered to 25 patients with RA. Results were compared to normative data and related to ability to perform activities of daily living (ADL), pain, and deformity. Results. The JHF test detects differences between patients with RA and normals; all components except for writing show correlations with ADL and deformity. There were no significant correlations with pain. Conclusions. The JHF test is a useful adjunct to evaluation of the hand in RA.

We have described a 45-year-old obese white man found to have myeloperoxidase (MPO) deficiency of the granulocytic and monocytic series. Pancreatic necrosis due to bacterial infection developed as a complication of acute pancreatitis. Subsequently, he died of sepsis. MPO staining of terminal antemortem blood smears and postmortem bone marrow aspirates showed absence of MPO in cells of the myelocytic and monocytic series. Family members' neutrophils and monocytes stained positive for MPO. MPO deficiency associated with severe sepsis is rarely reported. This case serves as a review of the association between hereditary and acquired MPO deficiency and severe infection.

Objective. Reasons for apparent primary deposition of calcium pyrophosphate dihydrate (CPPD) crystals in some synovial membranes have not been systematically examined. We undertook the present study to investigate for and compare possible cellular and matrix factors related to the presence of these crystals in synovium and cartilage. Methods. Ten synovial membrane specimens and 6 cartilage specimens were obtained at the time of joint surgery from 10 patients with CPPD crystal deposition disease, for light microscopic (LM) and electron microscopic (EM) studies. Results. In all synovial and cartilage specimens, we found many of the small CPPD crystals aligned on or in parallel to collagen fibers, as seen by EM. In 9 of the 10 crystal-containing synovia, we found foci of chondrometaplasia adjacent to CPPD, by LM. In 7 of the synovia, including the one without LM evidence of chondrometaplasia, we observed the presence of chondrocyte-like cells by EM. We did not note any predictable relationship between the crystals and matrix vesicles, either in synovium or in cartilage. Conclusion. Our EM findings provide evidence of the relationship of small CPPD-like crystals, presumably early forms, to collagen fibers both in synovium and in cartilage. By LM and EM, we also demonstrate evidence of a close association between chondrometaplasia and CPPD deposits in synovium. We suggest that chondrometaplasia might be responsible for synovial CPPD formation in predisposed patients. Both the collagen fibers and chondrocyte-like cells seem to be involved in the primary formation of CPPD deposits in the synovium as well as in the cartilage.

Objective. There is much evidence indicating that chlamydial antigens in the synovium may be critical in the pathogenesis of Reiter's syndrome (RS), but it is not known whether intact organisms are present in that tissue in any stage of the disease. The present study was undertaken to begin to address this question. Methods. We used a highly specific and sensitive molecular hybridization screening system which detects chlamydial RNA, to examine synovial biopsy samples from 22 patients with various arthropathies, including 9 with RS. Results. Seven of the 9 RS patients were positive for chlamydial RNA, while 3 of the 13 non-RS patients were also positive; positive results in the non-RS patients probably indicate the actual presence of the organism, since these patients had arthritis that was otherwise incompletely explained. Conclusion. The detection of chlamydial RNA, in combination with previous findings of chlamydia-like particles and/or chlamydial antigens in the synovium of RS patients, suggests that whole bacterial cells are present in that tissue.

SUMMARY The etiology of RS is not clear, but there is a strong correlation with infectious episodes and some genetic factor(s). Chlamydia have emerged as the most common pathogen associated with RS. We have presented evidence that chlamydia or its antigens may be present in the synovium and may be important in the pathogenesis of RS. The possibility of latent chlamydial infection has also been discussed. Although previous attempts to treat RS with antibiotics were not encouraging, recent reports suggest some favorable effects from antibiotic therapy. There is still a need to further assess the state of the infectious agent and to consider new, more effective regimens.

Objective To identify, in people known to have gout, the testable, key components of a standard definition of gout flare for use in clinical research. Methods Consensus methodology was used to identify key elements of a gout flare. Two Delphi exercises were conducted among different groups of rheumatologists. A cognitive mapping technique among 9 gout experts with hierarchical cluster analysis provided a framework to guide the panel discussion, which identified the final set of items that should be tested empirically. Results From the Delphi exercises, 21 items were presented to the expert panel. Cluster analysis and multidimensional scaling showed that these items clustered into 5 concepts (joint inflammation, severity of symptoms, stereotypical nature, pain, and gout archetype) distributed along 2 dimensions (objective to subjective features and general features to specific features of gout). Using this analysis, expert panel discussion generated a short list of potential features: joint swelling, joint tenderness, joint warmth, severity of pain, patient global assessment, time to maximum pain, time to complete resolution of pain, an acute-phase marker, and functional impact of the episode. Conclusion A short list of features has been identified and now requires validation against a patient- and physician-defined gout flare in order to determine the best combination of features.

Consensus exercises have identified and prioritized domains of measurement for studies in acute and chronic gout. In parallel, the technical properties of instruments for measurement in many of these domains have been assessed, with the main objective to consider the instruments in the context of the OMERACT filter of truth, discrimination, and feasibility. These data were presented and discussed at OMERACT 9 in the gout workshop, in breakout groups, and at informal meetings of the gout group. In acute gout, instruments for domains of pain, joint swelling, joint tenderness, and patient and physician global assessment have been assessed. In chronic gout, some validation exercises have been performed in instruments for domains serum urate, tophus measurement, health-related quality of life (HRQOL). In voting at OMERACT 9, the Medical Outcomes Study Short-Form 36 was endorsed as a valid instrument for measurement of HRQOL. Methods of tophus measurement were considered to have met some criteria of the OMERACT filter, but these require further work, particularly regarding sensitivity to change over shorter time periods. Priorities for future research include measurement of joint inflammation in acute gout and disability in acute and chronic gout.

Both clinical and epidemiological data suggest that inapparent infection by Chlamydia trachomatis occurs in humans. To confirm and study such infections, we developed a hybridization screening system directed toward chlamydial ribosomal RNA (rRNA). Six restriction endonuclease fragments derived from the cloned rrnA operon of chlamydial serovar L2(434) were tested as hybridization screening probes, but only one fragment encoding the 5' portion of the 16s rRNA gene plus some upstream flanking sequence was both sensitive and highly specific in such experiments. In Northern slot blot assays, hybridization analyses with this fragment as probe routinely detected one picogram or less of chlamydial RNA when that RNA was bound to membranes alone or as part of a mixture with a vast excess of mammalian RNA. The probe did not hybridize to RNA from mammalian and relevant bacterial sources but did hybridize to rRNA from B (ocular) and E (genital) serovars of C. trachomatis. Experiments using RNA from conjunctival biopsies and standard conjunctival swab samples from cynomolgus monkeys showed that the probe reliably distinguishes between known chlamydia-infected and uninfected samples. This suggests that it may be useful for clinical screening. Characterization assays for the RNA-directed probe screening system in this monkey model of trachoma provide initial molecular evidence that ocular Chlamydial infection may persist longer than previously thought, based solely on direct fluorescence antibody assay (DFA) and culture analyses.

Considerable evidence suggests that viable Chlamydia trachomatis are present in joint tissues of patients with Reiter's syndrome/reactive arthritis (RS/ReA), but the use of antibiotics to treat such patients remains controversial. We investigated the continued presence of chlamydia in synovial tissues of patients with RS/ReA; these patients had been treated with antibiotics for relatively extended periods, had shown clinical improvement, but had persistent active disease. Knee synovial tissue was obtained from two patients with RS/ReA and two controls with osteoarthritis (OA). Each sample was screened for chlamydia by culture, direct fluorescent antibody assay (DFA), in situ hybridization (ISH), and polymerase chain reaction (PCR).Synovial tissues from antibiotic-treated RS/ReA patients were negative for chlamydia when analyzed by culture and DFA, but positive when analyzed by ISH for chlamydial RNA and by PCR for chlamydial DNA. Samples from OA patients were negative by all screening methods. Thus, antibiotic treatment does not appear to easily eradicate chlamydia from the joints of RS/ReA patients. Rather, the organism can persist in synovial tissue in a form not detectable by routine laboratory screening methods. Further studies are needed to determine whether antibiotic regimens other than those used here can eradicate synovial chlamydia and to determine how this relates to disease activity. Optimal therapy for patients with RS/ ReA is therefore not yet clear.

We report a patient with Waldenstrom's macroglobulinemia who had diffuse plasmacytoid infiltration in the bone marrow, immunoglobulin M monoclonal gammopathy, wide-spread osteolytic lesions, recurrent pathologic fractures, and diffuse subcutaneous soft tissue calcifications. The bony lesions were even more pronounced than those usually seen with multiple myeloma and are a rare manifestation of this disease. Such malignant plasma-cell dyscrasia with macroglobulinemia and lytic osseous lesions is best handled clinically according to its general presenting features rather than according to whether it is Waldenstrom's macroglobulinemia or an immunoglobulin M myeloma. The bone lesions may require local palliative radiotherapy and orthopedic measures.

Rapidly destructive arthritis with relatively noninflammatory joint fluids has been described at shoulders as well as at other large joints under a variety of names in older persons. Because this syndrome frequently is not recognized, we have reviewed our experience with such cases. After excluding patients with known causes such as avascular necrosis, Paget's disease, neuropathic arthropathy, endocrine disorders, radiographic evidence of chondrocalcinosis, and hemodialysis, we have seen 20 such patients who are described in this report. All were over age 67, and 16 were women. Seventeen patients had shoulders involved; 6 had destructive arthritis at the knees. Many other patients had multiple sites affected. Six patients also had erosive osteoarthritis of small joints.All patients had diffuse cartilage loss and juxta-articular bone destruction. Patients had been symptomatic a mean of 3.5 years at the time of the study. Bony sclerosis on x-ray was more common than reported in previous series. Joint effusions were bloody or clear. All fluids had strongly positive alizarin red S positive chunks; apatites were confirmed in all 7 studied by electron microscopy. Nine had calcium pyrophosphate dihydrate crystals. The latter were somewhat more commonly associated with bony sclerosis, but crystal types did not explain all differences seen in x-ray patterns.Destructive arthropathy of the elderly involves many large joints in addition to the shoulders, and some patients also have erosive osteoarthritis of fingers. Although calcium pyrophosphate dihydrate crystals were present in many patients along with apatites, the role of crystals is not clear. Radiographic patterns may be more diverse than previously suggested by some researchers, so that the spectrum of idiopathic destructive arthritis reported may depend on selection criteria. It is important to be aware of this noninfectious cause of severe joint destruction at a variety of joints.

Gout management requires a comprehensive strategy that considers both acute and chronic aspects of the disease. Acute gout flares should be treated with anti-inflammatory agents as rapidly as possible. The underlying hyperuricemia may be treated with urate-lowering agents initiated at a time appropriate for the individual patient. Successful urate lowering ultimately prevents flares and disease progression and should be started immediately in patients with advanced or tophaceous disease. When urate-lowering therapy is initiated, anti-inflammatory prophylaxis should be used to reduce the risk of flares induced by abrupt changes in urate levels. Regular monitoring of serum urate can ensure therapeutic dosing of urate-lowering agents to achieve levels below 6 mg/dL, which are associated with a reduction in flares and tophi.

An elevated serum urate level, together with local factors, can result in the deposition of urate crystals into the joints. Once crystals are deposited into a joint, they can be released into the joint space and initiate an inflammatory cascade causing acute gouty arthritis. These acute flares resolve, but the crystals remain in the joint. The way to ultimately correct the underlying metabolic problem of hyperuricemia and the crystal deposition is to lower the serum urate level and dissolve the crystal deposits. This will stop both the acute attacks and the progressive joint damage.

Objectives: Ki-67 is expressed in the nuclei of dividing cells and can be used to assess proliferation of synovial inflammatory and stromal cells. We evaluated subintimal Ki-67+ cell density as a tissue biomarker for inflammatory arthropathies and compared it to subintimal CD68, a synovial biomarker of RA. Methods: Subintimal Ki-67+ and CD68+ cell densities were measured immunohistochemically in synovial specimens obtained from patients with rheumatoid arthritis (RA; n = 19), osteoarthritis (OA; n = 18), “non-inflammatory” orthopaedic arthropathies (avascular necrosis, meniscus injury, femur fracture; n = 16), chronic septic arthritis (n = 9), and histologically normal synovium (n = 10). Results were correlated with a histological synovitis score. Utilising the areas under receiver operating characteristic curves (AUCs), we compared the abilities of Ki-67 and CD68 to differentiate among these arthropathies. Results: Ki-67 was expressed widely in the subintima of inflamed specimens and in RA pannus invading hard tissues. Compared to normal controls, it was highly overexpressed in RA (26.6-fold) and chronic septic arthritis (55-fold), and mildly elevated in OA (3.9-fold) and orthopaedic arthropathies (2.1-fold). Ki-67 and CD68 differentiated similarly well between RA and OA (AUC: Ki-67 = 0.91, CD68 = 0.94), Ki-67 better between chronic septic arthritis and RA, and CD68 better between OA and normal controls. Ki-67 ( r = 0.80) and CD68 ( r = 0.79) correlated positively with the synovitis score. Conclusions: Subintimal Ki-67 was overexpressed in inflammatory arthropathies, distinguished among differentially inflamed arthropathies, and correlated positively with the histological severity of synovitis. It may prove useful in synovial tissue classification and as a synovial marker of disease activity in clinical trials when biopsies are available.

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 hematoxylineosin-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% (HE 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/mm(2)) 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.

Objective An unexplained multisymptom illness, Gulf War veterans' illness (GWVI), has been described among allied force veterans of the first Gulf War (1990–1991). It has been proposed that some of its symptoms reflect an immune dysfunction, and rheumatologic symptoms including joint pain and stiffness are reported frequently. However, it is unknown whether synovial inflammation causes the articular symptoms. We examined synovial tissue from individuals with GWVI and joint pain for evidence of inflammation. Methods We compared synovial biopsy samples from 6 individuals with GWVI and joint pain with samples from 9 clinically asymptomatic controls (hematoxylin and eosin [H&E] stains only) and biopsy samples or surgically obtained specimens from 10 patients with rheumatoid arthritis (RA) and 12 with osteoarthritis (OA). Inflammatory changes were quantified in H&E stained sections with a modified synovitis score by immunostaining for CD3, CD20, CD38, CD68, Ki-67, and von Willebrand factor, and with a composite inflammation score based on these markers. Results Normal histology was seen in the GWVI specimens, except for mild focal lining hyperplasia and rare low-grade perivascular infiltrates in 1 specimen each. Mean ± SEM synovitis scores were lowest and nearly identical in control (1.38 ± 0.30) and GWVI specimens (1.41 ± 0.29), intermediate in OA specimens (2.64 ± 0.39), and highest in RA specimens (6.0 ± 0.19). Likewise, inflammatory cells, cell division, vascular density, and composite inflammation score were lowest in the GWVI specimens. Conclusion Despite significant joint pain, the GWVI synovia did not differ from normal controls. These results agree with other studies that have failed to document inflammatory or immunologic etiologies in GWVI.

There has been renewed interest in the treatment of gout with recent reported intervention studies of new agents such as etoricoxib, febuxostat and pegylated-uricase. However, these studies have highlighted the relative paucity of validated outcome measures with which to judge efficacy. This review outlines the published information regarding which endpoints have been measured in randomized clinical trials, what should be measured, what tools or instruments are available for this and the technical properties of such instruments. It highlights recent work that validates measures of tophi, radiographic damage and patient-reported outcomes. The absence of a valid definition of gout-flare or how flare reduction defines response is problematic; this forms the basis for a current ACR-EULAR sponsored project.

Background Arthrocentesis is a common procedure in rheumatology clinical practice, usually to obtain synovial fluid for diagnostic purposes or as a therapeutic procedure for glucocorticoid intra-articular injection. There is a generally held belief amongst rheumatologists that needle arthrocentesis is a safe and well-tolerated procedure. Previous reports of the safety of needle arthrocentesis have been in the context of glucocorticoid injection (1). The safety of diagnostic arthrocentesis has not been previously studied systematically. Objectives To determine the frequency of adverse events of diagnostic arthrocentesis in patients suspected to have gout. Methods Consecutive patients with recent joint swelling or possible tophus underwent arthrocentesis or nodule tissue aspiration as part of a cross-sectional diagnostic study for gout. All patients were evaluated at 6 weeks by telephone or in the clinic to determine any adverse events (AE) following the arthrocentesis. The 95% confidence intervals for the percentage frequency of AE were obtained by bootstrapping. Results Arthrocentesis was performed in 910 patients and 887 of these patients (97.5%) were evaluated for AE. Any adverse event was observed in 12 participants (1.4%, 95%CI 0.6 to 2.1). The commonest AE was pain (5 events), nearly all of which were rated as mild. Other non-serious AE reported were bruising (2 events), and joint swelling (4 events). There was 1 case (0.1%, 95% CI 0 to 0.34) of septic arthritis subsequent to the arthrocentesis who required hospitalization and antibiotics. Conclusions Diagnostic arthrocentesis is safe and associated with a very low frequency of adverse events, which are generally mild. However, septic arthritis rarely occurs with an estimated (bootstrapped 95% CI) frequency of between 0 and 3.4 per 1000 patient-procedures. Acknowledgements This study was supported by the American College of Rheumatology, European League against Rheumatism, Arthritis New Zealand, Association Rhumatisme et Travail, and Asociaciόn de Reumatόlogos del Hospital de Cruces. Disclosure of Interest None declared

This report describes a visit by an international group interested in Rheumatology to the Rheumatology centers and traditional Chinese medicine units in the People's Republic of China. Differing disease patterns and treatment approaches offer opportunities for studies and collaborations. We can also learn from the traditional Chinese approach with individualization of therapy and attention to health maintenance.

This review is an attempt to keep current in the sparse literature addressing the still underutilized area of crystal identification.The 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.Quality control is still a concern as is the infrequency of attempted arthrocentesis for crystal identification.

Objective. Free fragments of synovium have occasionally been seen in synovial fluid but have not been studied systematically. We wished to establish a method for the reliable detection of these fragments in joint and bursa effusions and begin to characterize them by histochemical and immunohistochemical methods. Methods. Cell smears, wet drop preparations and cytospins were prepared from 39 consecutive joint and bursa effusions. Paraffin cell blocks were prepared from a subset. Analysis encompassed standard and polarized light microscopy, histochemistry, immunohistochemistry and transmission electron microscopy (EM). Synovial biopsy tissue from one different patient was examined for comparison. Results. Tissue fragments were not seen in Wright-stained cell smears and only rarely in wet drop preparations. In contrast, variously sized fragments with the histological appearance of hyperplastic synovial lining were detected in ethanol-fixed, haematoxylin/eosin-stained cytospins from bursitis and all arthropathies studied [17/24 (71%) of non-inflammatory and 12/15 (80%) of inflammatory specimens]. Immunostaining revealed CD68 expression in a subset of cells in a pattern characteristic of hyperplastic synovial lining. Juxtaposed cells with morphological features of macrophage-like and fibroblast-like synoviocytes were seen by EM. Conclusions. Synovial lining fragments can be detected in effusions from diverse arthropathies and bursitis. They maintain important properties of the synovial lining and can be analysed by immunohistochemistry. They may afford the opportunity to study a relatively pure preparation of synovial lining cells without the need for cell culture, and to evaluate their possible role in augmenting or perpetuating synovitis or joint damage.

Background: Synovial tissues in patients with Chlamydia associated arthritis are persistently infected by C trachomatis , an organism for which genetic manipulation is not possible. M tuberculosis also engages in persistent infection, and because this bacterium is genetically tractable many groups have been able to define transcriptional characteristics of mycobacterial growth and persistence. Objective: To investigate whether the pattern of gene expression underlying chlamydial persistence is similar to that underlying mycobacterial persistence. Methods: 194 genes in M tuberculosis that are transcriptionally up regulated to support in vivo growth and persistence of that organism have previously been identified. Each of those genes was compared with the C trachomatis genome to identify orthologues. Expression of selected chlamydial orthologues so identified was assessed by real time RT-PCR in an in vitro model of chlamydial persistence and synovial tissues from patients who were PCR positive for C trachomatis at that site. Results: 67 C trachomatis genes were identified as being orthologous to mycobacterial persistence related genes, representing 35% of the genes tested. The chlamydial orthologues fell into similar metabolic and other categories as those in M tuberculosis . Expression of a majority of selected chlamydial orthologues was strongly up regulated in an in vitro model of chlamydial persistence and in synovial tissues of relevant patients, compared with their expression during active infection. Conclusions: These observations provide new insight into the molecular genetic basis underlying chlamydial persistence, and indicate that this information can be obtained, in some instances, by extrapolating observations made in other biological systems and/or organisms.