Ann Rheum Dis. 2009 Sep 9; Dougados M, Jousse-Joulin S, Mistretta F, D'Agostino MA, Backhaus M, Bentin J, Chales G, Chary-Valckenaere I, Conaghan PG, Etchepare F, Gaudin P, Grassi W, van der Heijde D, Sellam J, Naredo E, Szkudlarek M, Wakefield R, Saraux AOBJECTIVES: To evaluate different global ultrasonographic (US) synovitis scoring systems as potential outcome measures of Rheumatoid Arthritis (RA) according to the OMERACT filter. Patients- METHODS: 1. Selected global scoring systems: for both the clinical, B-mode and Power Doppler techniques, the following joints were evaluated: 28 joints (DAS28), 20 joints (MCPs+MTPs) and 38 joints (28+MTPs) using either a binary (yes/no) or a 0-3 grade. 2. Study design: Prospective, 4 months follow-up of 76 RA patients requiring anti-TNF therapy (complete follow-up data: 66 patients) 3. Analysis: 3.a. intra-observer reliability was evaluated using the intra-class coefficient of correlation (ICC), 3.b. validity, 3.b.1. construct validity using the Cronbach's alpha test and 3.b.2. external validity using level of correlation between scoring system and CRP; 3.c. sensitivity to change was evaluated using the Standardized Response Mean; 3.d. discriminating capacity was evaluated using the Standardized Mean Differences in patients considered by the physician as significantly improved or not at the end of the study. RESULTS: Different clinimetric properties of various US scoring systems were at least as good as the clinical scores with as examples intra-observer reliability ranging from 0.61 to 0.97 versus from 0.53 to 0.82, construct validity ranging from 0.76 to 0.89 versus from 0.76 to 0.88, correlation with CRP ranging from 0.28 to 0.34 versus from 0.28 to 0.35, sensitivity to change ranging from 0.60 to 1.21 versus from 0.96 to 1.36 for US versus clinical scoring systems respectively. CONCLUSION: This study suggests that US evaluation of synovitis is an outcome measure at least as relevant as physical examination. Other studies are required in order to achieve optimal US scoring systems for monitoring RA patients both in clinical trials and in clinical practice.

Rheumatology (Oxford). 2009 Sep 10; Carter JD, Kedar RP, Anderson SR, Osorio AH, Albritton NL, Gnanashanmugam S, Valeriano J, Vasey FB, Ricca LRObjective. The aim of this study was to analyse the prevalence of occult destructive arthropathy in subjects with gout and normal plain radiographs by utilizing MRI and ultrasound (US). Methods. The study consisted of two visits. At Visit 1, a plain radiograph of the 'index joint' was obtained. The 'index joint' was defined as a joint that has had the most acute attacks of gout historically. The index joint plain radiograph had to be free of erosive damage in order for the subject to qualify for Visit 2. At Visit 2, the subject had an MRI with contrast and an US of the index joint. Each subject also had an MRI and US of an 'asymptomatic joint'. The 'asymptomatic joint' was defined as a joint that had never experienced an acute attack of gout (determined by standard protocol). The primary endpoint was erosive changes on the MRI and/or US of the index joint. Secondary endpoints included erosive changes on the asymptomatic joint as well as bone marrow oedema (BME) (on MRI), synovial pannus (SP), soft tissue tophi (STT) or oedema (STE) on either the index or asymptomatic joint. Results. Twenty-seven subjects (26 males; 1 female) completed both visits. Their average age and disease duration were 55.1 years (range 21-75 years) and 6.8 years (range 0.25-25 years), respectively. The subjects' average serum uric acid level over the past 5 years was 8.09 mg/dl (range 4.1-12.8 mg/dl); their average on the day of Visit 1 was 7.96 mg/dl (range 4.6-13.9 mg/dl). The first MTP was the most common index joint (17) followed by the ankle (5), mid-tarsal (2), knee (2) and wrist (1). The knee was the most common asymptomatic joint (21) followed by the wrist (3), MTP (2) and ankle (1). All subjects had both MRIs; one subject refused the US. Out of 27 subjects, 15 (56%) had erosions on MRI of their index joint (P < 0.0001); only 1 subject (4%) had erosions identified in the index joint by US (P = NS). Regarding the secondary endpoints on the index joint, the MRI detected SP (13), BME (4), STE (3) and STT (0); the US detected SP (1), STT (1) and STE (0). Regarding the MRI of the asymptomatic joint, positive findings included SP (3), BME (3), STE (2) and erosions (1). There were no positive findings by US in the asymptomatic joint. Conclusions. A large percentage of patients with gout and normal plain radiographs have occult destructive arthropathy that is only detected by advanced imaging such as MRI and/or US. However, MRI appears to be much more sensitive than US at detecting these findings.

J Immunol. 2009 Sep 4; Wenink MH, Santegoets KC, Roelofs MF, Huijbens R, Koenen HJ, van Beek R, Joosten I, Meyer-Wentrup F, Mathsson L, Ronnelid J, Adema GJ, Bonvini E, Koenig S, van den Berg WB, van Riel PL, Radstake TRRheumatoid arthritis (RA) is a common autoimmune disease leading to profound disability and premature death. Although a role for FcgammaRs and TLRs is accepted, their precise involvement remains to be elucidated. FcgammaRIIb is an inhibitory FcR important in the maintenance of tolerance. We hypothesized that the inhibitory FcgammaRIIb inhibits TLR responses on monocyte-derived dendritic cells (DC) and serves as a counterregulatory mechanism to dampen inflammation, and we surmised that this mechanism might be defective in RA. The expression of the inhibitory FcgammaRIIb was found to be significantly higher on DCs from RA patients having low RA disease activity in the absence of treatment with antirheumatic drugs. The expression of activating FcgammaRs was similarly distributed among all RA patients and healthy controls. Intriguingly, only DCs with a high expression of FcgammaRIIb were able to inhibit TLR4-mediated secretion of proinflammatory cytokines when stimulated with immune complexes. In addition, when these DCs were coincubated with the combination of a TLR4 agonist and immune complexes, a markedly inhibited T cell proliferation was apparent, regulatory T cell development was promoted, and T cells were primed to produce high levels of IL-13 compared with stimulation of the DCs with the TLR4 agonist alone. Blocking FcgammaRIIb with specific Abs fully abrogated these effects demonstrating the full dependence on the inhibitory FcgammaRIIb in the induction of these phenomena. This TLR4-FcgammaRIIb interaction was shown to dependent on the PI3K and Akt pathway.

Mol Immunol. 2009 Sep 1; Hamburg JP, de Bruijn MJ, Almeida CR, Dingjan GM, Hendriks RWThe zinc-finger transcription factors Gata3 and ThPOK have both been implicated in positive selection of double positive (DP) thymocytes towards the CD4 lineage. As in the absence of Gata3, expression of ThPOK is lacking, Gata3 may directly regulate ThPOK expression. As ThPOK failed to promote CD4(+) lineage differentiation of Gata3-defcient cells, ThPOK cannot be the only Gata3 target gene essential for the induction of the CD4(+) lineage program. Therefore, it is conceivable that Gata3 is essential for selected DP T cells to reach the developmental stage at which ThPOK expression is induced. Here, we show that Gata3 overexpression does not affect ThPOK expression levels in DP or CD4(+) thymocytes, providing evidence that Gata3 does not directly regulate ThPOK. To identify additional target genes that clarify Gata3 function at the DP thymocyte stage, we performed gene expression profiling assays in wild-type mice and transgenice mice with enforced expression of Gata3, in the presence or absence of the MHC class II-restricted DO11.10 TCR. We found that Gata3 expression in DP cells undergoing positive selection was associated with downregulation of the V(D)J-recombination machinery genes Rag1, Rag2 and TdT. Moreover, Gata3 overexpression was associated with downregulation of many signaling molecules and the induction of modulators of TCR signaling, including Ctla-4 and thrombospondin 2. Together with our previous finding that Gata3 reduces expression of CD5, a negative regulator of TCR signaling, and upregulates TCR expression, these findings indicate that Gata3 in DP cells mainly functions to (i) terminate TCRalpha gene rearrangement, and (ii) regulate TCR signal intensity or duration in cells undergoing positive selection towards the CD4 lineage.

Drugs Aging. 2009; 26(9): 739-50Villa-Blanco JI, Calvo-Alén JElderly onset rheumatoid arthritis (EORA) has been considered a benign form of rheumatoid arthritis (RA). However, it most probably encompasses different subsets of patients with distinct outcomes. According to data reported in the most recent studies directly comparing older and younger RA patients, it seems that, overall, the prognosis of EORA patients is not very different from that of other patients with this disease. However, some cases with negative rheumatoid factor and polymyalgia-like symptoms appear to be a distinct subset with a different genetic basis and a more benign course. The differential diagnosis of EORA from other rheumatological disorders that are prevalent in this stratum of the population, such as polymyalgia rheumatica, crystal-induced arthritis or osteoarthritis, may be complicated because these disorders can present with signs and symptoms similar to those of RA in some circumstances. A prompt diagnosis of true RA is important because early treatment should be implemented. It is recommended that therapy of EORA be tailored according to disease activity, with the aim of achieving clinical remission or the lowest possible level of disease activity in order to minimize potential functional sequelae. Co-morbidities and drug toxicity profiles are major considerations when choosing the most suitable therapy for EORA patients. Prudent use and careful follow-up of all treatments are also required because of the increased risk of adverse events in elderly patients. However, no special contraindications to the use of disease-modifying antirheumatic drugs in this age group apply, and use of biological therapies currently used in younger RA patients has also been described in these patients. Therefore, a therapeutic strategy for first-line and subsequent treatment that is in accordance with the disease activity of patients with EORA is suggested.

J Clin Rheumatol. 2009 Sep; 15(6): 280-283Pineda C, Mansilla-Lory J, Martínez-Lavín M, Leboreiro I, Izaguirre A, Pijoan CINTRODUCTION:: The effect of rheumatic and infectious diseases on skeletal remains provides an important source of information for knowledge of contemporary medicine. Few pathologic conditions have attracted so much interest as treponematoses. One of these, syphilis, was the most feared venereal disease throughout the civilized world until the introduction of penicillin in the 20th century. OBJECTIVE:: To describe paleopathological and ceramic illustrations of treponematoses in ancient Mexico. MATERIALS AND METHODS:: Paleopathological and ceramic material examples from the National Institute of Anthropology and History of Mexico were reviewed. RESULTS:: A unique paleopathologic site for treponemal diseases comprises the La Candelaria Cave skeletal collection from northern Mexico. The cave was used as a burial site and contained the bones of at least 83 adults and 33 subadults. Fifty-one percent of the recovered skulls possess erosions of the vault consistent with treponematoses. Some of these exhibit the impressive frontal bone lytic changes with irregular borders typical of caries sicca. In addition, periostosis of the long bones was found in up to 88% of the study sample, including 6 examples of saber-shin deformity of tibias. Radiocarbon dating (-C) of a bone retrieved from the cave ranges from 1100 to 1300 A.D. Additionally, a Pre-Hispanic ceramic figurine from the Mexican state of Nayarit depicting a lame man with multiple nodular skin lesions that suggest gummatous treponemal infection is described. CONCLUSIONS:: These ancient specimens reinforce the notion that treponemal infection was present on the American Continent before European penetration of the New World. These very advanced paleopathologic lesions and ceramic representations demonstrate the degree to which these diseases wrought devastation before the antibiotic era. In ancient times, treponematoses were true rheumatic diseases that produced profound skeletal abnormalities marked by periosteal accretion and bone destruction.

J Clin Rheumatol. 2009 Sep; 15(6): 275-279Barilla-Labarca ML, Tsang JC, Goldsmith M, Furie RINTRODUCTION:: During a 4-week rheumatology elective at our institution, opportunities for internal medicine residents to perform arthrocentesis were limited, particularly for sites other than the knee. Consequently, residents were inadequately prepared and had less self-confidence to perform such procedures. To overcome these educational deficiencies, an arthrocentesis workshop was developed. We report our quality improvement data that was collected during the first year of workshop implementation. METHODS:: We devised a structured half-day arthrocentesis workshop for rheumatology fellows as well as rotating internal medicine residents. This program consisted of a one hour lecture immediately followed by a hands-on workshop that used mannequin models for 5 anatomic sites. A self-assessment questionnaire and medical knowledge test were administered before and after each session. The accuracy of the self-assessment questionnaire was analyzed by comparing responses to an external objective measure of knowledge in the same content area. Finally, an optional postworkshop survey addressed resident satisfaction. RESULTS:: Thirty-eight trainees participated in the workshop between July 2006 and June 2007. There were statistically significant improvements in self-confidence in 9 content areas (P < 0.0002), cognitive testing (P < 0.0001) and in self-assurance of procedural skill at all anatomic sites. A high degree of discordance was found between the perceived level of competence and the actual performance on the medical knowledge test during the preworkshop analysis. In contrast, the postworkshop analysis displayed modestly higher concordance. All residents completing a postworkshop survey believed that it was a useful exercise, and 96% stated that they would change their practice habits. CONCLUSION:: The arthrocentesis workshop provided a solid foundation from which trainees can learn key concepts of joint injection, increase their self-confidence and refine their motor skills. The accuracy of resident self-reported confidence is poor and should therefore be used only to complement other means of competency assessment and medical knowledge acquisition.

Bone. 2009 Sep 3; Polewski MD, Johnson KA, Foster M, Millán JL, Terkeltaub RIntroduction: The physiologic selectivity of calcification in bone tissue reflects selective co-expression by osteoblasts of fibrillar collagen I and of tissue nonspecific alkaline phosphatase (TNAP), which hydrolyzes the calcification inhibitor pyrophosphate (PP(i)) and generates phosphate (P(i)). Humans and mice deficient in the PP(i)-generating ecto-enzyme NPP1 demonstrate soft tissue calcification, occurring at sites of extracellular matrix expansion. Significantly, the function in osteoblasts of cytosolic inorganic pyrophosphatase (abbreviated iPP(i)ase), which generates P(i) via PP(i) hydrolysis with neutral pH optimum, remains unknown. We assessed iPP(i)ase in Enpp1(-/-) and wild type (WT) mouse osteoblasts and we tested the hypothesis that iPP(i)ase regulates collagen I expression. Methods: We treated mouse calvarial osteoblasts with ascorbate and beta-glycerol phosphate to promote calcification, and we assessed cytosolic P(i) and PP(i) levels, sodium-dependent P(i) uptake, Pit-1 P(i) co-transporter expression, and iPP(i)ase and TNAP activity and expression. We also assessed the function of transfected Ppa1 in osteoblasts. Results: Inorganic pyrophosphatase but not TNAP was elevated in Enpp1(-/-) calvariae in situ. Cultured primary Enpp1(-/-) calvarial osteoblasts demonstrated increased calcification despite flat TNAP activity rather than physiologic TNAP up-regulation seen in WT osteoblasts. Despite decreased cytosolic PP(i) in early culture, Enpp1(-/-) osteoblasts maintained cytosolic P(i) levels comparable to WT osteoblasts, in association with increased iPP(i)ase, enhanced sodium-dependent P(i) uptake and expression of Pit-1, and markedly increased collagen I synthesis. Suppression of collagen synthesis in Enpp1(-/-) osteoblasts using 3,4-dehydroproline markedly suppressed calcification. Last, transfection of Ppa1 in WT osteoblasts increased cytosolic P(i) and decreased cytosolic but not extracellular PP(i), and induced both collagen I synthesis and calcification. Conclusions: Increased iPP(i)ase is associated with "P(i) hunger" and increased calcification by NPP1-deficient osteoblasts. Furthermore, iPP(i)ase induces collagen I at the levels of mRNA expression and synthesis and, unlike TNAP, stimulates calcification by osteoblasts without reducing the extracellular concentration of the hydroxyapatite crystal inhibitor PP(i).

Arthritis Rheum. 2009 Aug 27; 60(9): 2757-2766Burgos PI, Perkins EL, Pons-Estel GJ, Kendrick SA, Liu JM, Kendrick WT, Cook WJ, Julian BA, Alarcón GS, Kew CEOBJECTIVE: To determine the risk factors for recurrent lupus nephritis, allograft loss, and survival among patients with systemic lupus erythematosus (SLE) undergoing kidney transplantation. METHODS: The archival records of all kidney transplant recipients with a prior diagnosis of SLE (according to the American College of Rheumatology criteria) from June 1977 to June 2007 were reviewed. Patients who had died or lost the allograft within 90 days of engraftment were excluded. Time-to-event data were examined by univariable and multivariable Cox proportional hazards regression analyses. RESULTS: Two hundred twenty of nearly 7,000 renal transplantations were performed in 202 SLE patients during the 30-year interval. Of the 177 patients who met the criteria for study entry, the majority were women (80%) and African American (65%), the mean age was 35.6 years, and the mean disease duration was 11.2 years. Recurrent lupus nephritis was noted in 20 patients (11%), allograft loss in 69 patients (39%), and death in 36 patients (20%). African American ethnicity was found to be associated with a shorter time-to-event for recurrent lupus nephritis (hazard ratio [HR] 4.63, 95% confidence interval [95% CI] 1.29-16.65) and death (HR 2.47, 95% CI 0.91-6.71), although, with the latter, the association was not statistically significant. Recurrent lupus nephritis and chronic rejection of the kidney transplant were found to be risk factors for allograft loss (HR 2.48, 95% CI 1.09-5.60 and HR 2.72, 95% CI 1.55-4.78, respectively). In patients with recurrent lupus nephritis, the lesion in the engrafted kidney was predominantly mesangial, compared with a predominance of proliferative or membranous lesions in the native kidneys. CONCLUSION: African American ethnicity was independently associated with recurrent lupus nephritis. Allograft loss was associated with chronic transplant rejection and recurrence of lupus nephritis. Recurrent lupus nephritis is infrequent and relatively benign, without influence on a patient's survival.

J Natl Med Assoc. 2009 Aug; 101(8): 788-92de Azevedo MN, Nunes JV, Pasqualette HA, Tuma Mde F, Nunes LCOBJECTIVE: The objectives of this study were to investigate variations in bone mineral density values in 45-year-old women from a community sample in the City of Rio de Janeiro, in the same-name Brazilian state, and to compare them with US norms and international standards. DESIGN: In this cohort study, the age of 45 years is significant for the design, since clinical observation in this community indicates that it is approximately 5 years before menopause can be confirmed, thus preceding the typical postmenopause acceleration of the rate of bone loss. Nine hundred fifty-nine such women volunteered to participate in the investigation, conducted in 2 Rio de Janeiro teaching hospitals. Informed of procedures, potential risks, and benefits, they were screened for the inclusion criteria: (a) being 45-years-old: (b) being healthy (without obvious or diagnosed systemic disease, metabolic disease, endocrine disease, liver disease, cardiac disease, infectious disease, pulmonary disease, neurologic disease, dermatologic disease, inflammatory bowel disease, kidney disease, hereditary, or congenital conditions); (c) having regular and intact menstrual cycles; (d) having had normal healthy development to date; (e) having had high protein intake from birth to date; (f) having at least completed high school; (g) living in a dwelling equipped with running water, electricity, and public sewer; (h) being nonsmoking and non-drug abusing. Racial distinction was not among the inclusion criteria. After further informed consent, the 146 women who met all inclusion criteria had bone mineral density quantified--using the dual energy x-ray absorptionmetry method--and compared with US-born density norms for L2-L4 and the neck of the femur for young adults and the sample age group, which are endorsed by the World Health Organization and by the International Osteoporosis Foundation. RESULTS: About three-quarters of the sample had normal bone mineral density values, 22.61% had osteopenia, and 2.73% had osteoporosis. CONCLUSION: These findings, obtained from women whose regular and intact menstrual cycles demonstrated premenopausal hormonal levels, seem to attest to the importance of genetic predisposition, yet they warrant the authors' recommendation that interventions be instituted before age 45, specifically aimed at increasing the chances of all women, especially those genetically predisposed, of avoiding osteoporosis and its deleterious consequences.