Santos Castañeda

Osteoarthritis associated with estrogen deficiency

Osteoarthritis (OA) affects all articular tissues and finally leads to joint failure. Although articular tissues have long been considered unresponsive to estrogens or their deficiency, there is now increasing evidence that estrogens influence the activity of joint tissues through complex molecular pathways that act at multiple levels. Indeed, we are only just beginning to understand the effects of estrogen deficiency on articular tissues during OA development and progression, as well as on the association between OA and osteoporosis. Estrogen replacement therapy and current selective estrogen receptor modulators have mixed effectiveness in preserving and/or restoring joint tissue in OA. Thus, a better understanding of how estrogen acts on joints and other tissues in OA will aid the development of specific and safe estrogen ligands as novel therapeutic agents targeting the OA joint as a whole organ.

Subchondral bone microstructural damage by increased remodelling aggravates experimental osteoarthritis preceded by osteoporosis

IntroductionOsteoporosis (OP) increases cartilage damage in a combined rabbit model of OP and osteoarthritis (OA). Accordingly, we assessed whether microstructure impairment at subchondral bone aggravates cartilage damage in this experimental model.MethodsOP was induced in 20 female rabbits, by ovariectomy and intramuscular injections of methylprednisolone hemisuccinate for four weeks. Ten healthy animals were used as controls. At week 7, OA was surgically induced in left knees of all rabbits. At 22 weeks, after sacrifice, microstructure parameters were assessed by micro-computed tomography, and osteoprotegerin (OPG), receptor activator of nuclear factor-κB ligand (RANKL), alkaline phosphatase (ALP) and metalloproteinase 9 (MMP9) protein expressions were evaluated by Western Blot at subchondral bone. In addition, cartilage damage was estimated using the histopathological Mankin score. Mann-Whitney and Spearman statistical tests were performed as appropriate, using SPSS software v 11.0. Significant difference was established at P < 0.05.ResultsSubchondral bone area/tissue area, trabecular thickness and polar moment of inertia were diminished in OPOA knees compared with control or OA knees (P < 0.05). A decrease of plate thickness, ALP expression and OPG/RANKL ratio as well as an increased fractal dimension and MMP9 expression occurred at subchondral bone of OA, OP and OPOA knees vs. controls (P < 0.05). In addition, the severity of cartilage damage was increased in OPOA knees vs. controls (P < 0.05). Remarkably, good correlations were observed between structural and remodelling parameters at subchondral bone, and furthermore, between subchondral structural parameters and cartilage Mankin score.ConclusionsMicrostructure impairment at subchondral bone associated with an increased remodelling aggravated cartilage damage in OA rabbits with previous OP. Our results suggest that an increased subchondral bone resorption may account for the exacerbation of cartilage damage when early OA and OP coexist simultaneously in same individuals.

Subchondral bone as a key target for osteoarthritis treatment.

Osteoarthritis (OA), the most common form of arthritis, is a debilitating and progressive disease that has become a major cause of disability and impaired quality of life in the elderly. OA is considered an organ disease that affects the whole joint, where the subchondral bone (SB) plays a crucial role. Regardless of whether SB alterations precede cartilage damage or appear during the evolution of the disease, SB is currently recognised as a key target in OA treatment. In fact, bone abnormalities, especially increased bone turnover, have been detected in the early evolution of some forms of OA. Systemic osteoporosis (OP) and OA share a paradoxical relationship in which both high and low bone mass conditions may result in induction and/or OA progression. Recent findings suggest that some drugs may be useful in treating both processes simultaneously, at least in a subgroup of patients with OA and OP. This review focuses on the role of SB in OA pathogenesis, describing relevant underlying mechanisms involved in the process and examining the potential activity as disease-modifying anti-osteoarthritic drugs (DMOADs) of certain SB-targeting agents currently under study.

Association of interferon regulatory factor 5 haplotypes, similar to that found in systemic lupus erythematosus, in a large subgroup of patients with rheumatoid arthritis.

OBJECTIVE Previous studies have shown either a lack of effect of IRF5 polymorphisms or an association of the IRF5 gene in only a minor subset of rheumatoid arthritis (RA) patients in whom anti-citrullinated protein antibodies (ACPAs) are absent. The present study was undertaken to investigate the role of genetic variation in IRF5 in susceptibility to RA. METHODS Nine IRF5 single-nucleotide polymorphisms (SNPs) were studied in 1,338 patients with RA and 1,342 control subjects in analyses of exploratory and replication sample collections, with stratification according to sex and by the presence or absence of ACPAs, rheumatoid factor, the shared epitope, the 620W PTPN22 allele, and erosions. A meta-analysis that included results from previous studies was also carried out. RESULTS Our findings together with those from previous studies, in a total of 4,620 RA patients and 3,741 controls, showed a significant association of the rs2004640 IRF5 SNP in RA patients as a whole (odds ratio [OR] 0.88, 95% confidence interval [95% CI] 0.83-0.94; P = 6.5 x 10(-5) versus controls). This association was stronger in ACPA- patients, but was also present in ACPA+ patients (from 3 sample collections). Further analysis of our exploratory sample collection showed that only patients in the ACPA+ and SE- group lacked an association with IRF5 SNPs. All of the remaining RA patients (ACPA- or SE+) showed a strong association with IRF5 SNPs, which followed a complex pattern of opposing effects mediated by independent haplotypes. The susceptibility haplotype showed an OR of 1.8 (95% CI 1.4-2.3; P = 1.2 x 10(-6) versus controls), whereas the protective haplotype showed an OR of 0.76 (95% CI 0.6-0.98; P = 0.046 versus controls). CONCLUSION IRF5 polymorphisms seem to influence RA susceptibility in a large subgroup of patients, following a pattern of association very similar to that described in patients with systemic lupus erythematosus.

Ultrasound-detected musculoskeletal urate crystal deposition: which joints and what findings should be assessed for diagnosing gout?

Objective The primary objective of this prospective case-control study was to assess the diagnostic value of several intra-articular and periarticular ultrasound (US)-detected abnormalities in the upper and lower limbs in gout. The secondary objective was to test the concurrent validity of US abnormalities using as gold standard the microscopic demonstration of monosodium urate (MSU) crystals. Methods Ninety-one men with gout and 42 age-matched controls were prospectively recruited. All patients with gout and controls underwent US assessment of several US abnormalities in 26 joints, six bursae, eight tendons, 20 tendon compartments, four ligaments, and 18 articular cartilages by experts in US blinded to the patients’ group. Patients with gout and controls with US abnormalities were asked to undergo US-guided aspiration for microscopic identification of MSU crystals. Interobserver and intraobserver reliability of the US assessment was evaluated in a web-based exercise. Results The assessment of one joint (ie, radiocarpal joint) for hyperechoic aggregates (HAGs), two tendons (ie, patellar tendon and triceps tendon) for HAGs and three articular cartilages (ie, first metatarsal, talar and second metacarpal/femoral) for double contour sign showed the best balance between sensitivity and specificity (84.6% and 83.3%, respectively). Intraobserver reliability was good (mean κ 0.75) and interobserver reliability was moderate (κ 0.52). The aspirated material from HAGs was positive for MSU crystals in 77.6% of patients with gout and negative in all controls. Conclusions Our results suggest that US bilateral assessment of one joint, three articular cartilages and two tendons may be valid for diagnosing gout with acceptable sensitivity and specificity.

Characterization of a new experimental model of osteoporosis in rabbits

To characterize an experimental model of osteoporosis in rabbits induced either by ovariectomy (OVX), glucocorticoids, or by a combination of both. Thirty-five rabbits were randomly allocated into five groups: bilateral OVX, daily methylprednisolone hemisuccinate (MPH) injections at a 1.5 mg/kg/day dose for 4 consecutive weeks (MPH group), or variable dose of MPH between 0.5 and 2 mg/kg/day in combination with OVX (OVX + MPH at low, medium, and high dose). Twenty-two animals were killed 6 weeks after OVX, and 13 were killed 16 weeks later. Dual-energy X-ray absorptiometry was obtained at baseline and 6 and 16 weeks after OVX. High-resolution magnetic resonance imaging (MRI) was carried out at 0 and 6 weeks after OVX. Glucose, total cholesterol, triglyceride, and oestradiol blood levels before and 16 weeks after OVX were determined. Bone mineral density (BMD) decreased significantly at lumbar spine in MPH and OVX + MPH medium-dose groups, and at global knee and subchondral bone of the knee in MPH, OVX + MPH low- and medium-dosage groups (P < 0.05). BMD variations in OVX rabbits were not significant in any of the three anatomical locations analyzed. BMD variation 16 weeks after OVX was significant at lumbar spine and global knee in the OVX + MPH medium-dose group and only at global knee in the OVX + MPH low-dose group (P < 0.05). MRI did not show bone or cartilage changes. Osteoporosis can be induced experimentally in rabbits through isolated MPH or by a combination of OVX and medium dose corticosteroid for 4 weeks. OVX alone was not sufficient to induce osteoporosis.

Tocilizumab in giant cell arteritis: Multicenter open-label study of 22 patients

OBJECTIVE To assess the efficacy of tocilizumab (TCZ) in giant cell arteritis (GCA) patients with refractory disease and/or with unacceptable side effects due to corticosteroids. METHODS A retrospective multicenter open-label study on 22 GCA patients treated with TCZ at standard dose of 8mg/kg/month. The main outcomes were achievement of disease remission and reduction of corticosteroid dose. RESULTS The mean age ± standard deviation of patients was 69 ± 8 years. The main clinical features at TCZ onset were polymyalgia rheumatica (n = 16), asthenia (n = 7), headache (n =5), constitutional symptoms (n = 4), jaw claudication (n = 2), and visual loss (n = 2). Besides corticosteroids and before TCZ onset, 19 of 22 patients had also received several conventional immunosuppressive and/or biologic drugs. Of 22 patients, 19 achieved rapid and maintained clinical improvement following TCZ therapy. Also, after a median follow-up of 9 (interquartile range: 6-19) months, the C-reactive protein level had fallen from 1.9 (1.2-5.4) to 0.2 (0.1-0.9)mg/dL (p < 0.0001) and the erythrocyte sedimentation rate decreased from 44 (20-81) to 12 (2-20)mm/1st hour (p = 0.001). The median dose of prednisone was also tapered from 18.75 (10-45) to 5 (2.5-10)mg/day (p < 0.0001). However, TCZ had to be discontinued in 3 patients due to severe neutropenia, recurrent pneumonia, and cytomegalovirus infection. Moreover, 1 patient died after the second infusion of TCZ due to a stroke in the setting of an infectious endocarditis. CONCLUSION TCZ therapy leads to rapid and maintained improvement in patients with refractory GCA and/or with unacceptable side effects related to corticosteroids. However, the risk of infection should be kept in mind when using this drug in patients with GCA.

NFKB1-94ATTG ins/del polymorphism (rs28362491) is associated with cardiovascular disease in patients with rheumatoid arthritis

INTRODUCTION Rheumatoid arthritis (RA) is an inflammatory disease associated with increased cardiovascular (CV) mortality. A recent study has disclosed association between NFKB1-94ATTG ins/del polymorphism and higher risk of coronary heart disease in healthy Caucasians. Because of that, we assessed the influence of this polymorphism in the risk of CV disease in RA patients. MATERIAL AND METHODS 1437 Spanish patients with RA were genotyped for the NFKB1-94ATTG ins/del polymorphism. Two hundred and seventy-one of them (18.8%) had experienced CV events. RESULTS After adjusting for sex, age at RA diagnosis and traditional CV risk factors RA patients carrying the NFKB1 del/del genotype had higher risk of CV events than those with ins/ins genotype (Hazard ratio [HR] = 1.76, 95% CI: 1.05-2.97, p = 0.03), while heterozygous patients had an intermediate (but non-significant) risk (HR = 1.31, 95% CI: 0.90-1.92, p = 0.16). CONCLUSION Our results suggest that NFKB1-94ATTG ins/del polymorphism is associated with CV disease in patients with RA.

REDUCTION OF BONE MASS IN WOMEN AFTER BONE MARROW TRANSPLANTATION

Abstract. Osteoporosis is a common disease among patients undergoing transplantation. Its prevalence and complications have been well described in solid organ recipients, especially kidney, liver, and heart. However, studies in bone marrow transplantation (BMT) are scarce. Among the mechanisms invoked in the pathogenesis of BMT osteoporosis are the baseline disease, the use of immunosuppressive drugs and, more remarkably, secondary hypogonadism. We present a study of 27 women who underwent BMT, all of them suffering ovarian failure. We studied different biochemical markers of bone formation/resorption and also evaluated the presence of osteopenia/osteoporosis by dual energy X-ray absorptiometry (DXA) of the lumbar spine. Osteopenia was observed in nine patients (33%) and osteoporosis in another five (18%), according to the World Health Organization criteria. We also detected a subgroup showing elevation of several bone turnover biochemical markers, indicating high osseous remodeling. A remarkable increase in urine hydroxyproline/creatinine was detected in 95% of cases, although an explanation is lacking. We outline a reasonable therapeutic approach for osteoporosis in BMT emphasizing the need to monitor these patients after transplantation.

Recommendations for the management of cardiovascular risk in patients with rheumatoid arthritis: Scientific evidence and expert opinion

OBJECTIVES Last recommendations regarding cardiovascular risk (CVR) in rheumatoid arthritis (RA) patients were developed by the EULAR group in 2010. The aim is to update evidence-based recommendations about this worrying health problem. METHODS We assembled a multidisciplinary workgroup (rheumatologists, endocrinologist, cardiologist, and epidemiologist) and a panel of 28 expert rheumatologists. The study was carried out in two big phases: identifying key areas in the prevention and management of CVR and developing a set of recommendations based on a review of the available scientific evidence and use of the Delphi consensus technique. All this has been developed according to an updating process of evidence-based recommendations. RESULTS Overall, 25 recommendations were made addressing three complementary areas: CVR assessment tools, patient eligibility for assessment, and treatment strategies for control of CVR. The grade of the recommendations was not substantially modified compared to the original EULAR recommendations, except in two of them, which were upgraded from C to B. These two recommendations are the ones related to the use of corticosteroids and smoking cessation. The new developed recommendations address these two areas: CVR assessment and treatment strategies for control of CVR. CONCLUSIONS There are substantial gaps in the current knowledge that do not allow classifying properly RA patients based on their actual CVR and to accurately identify those patients who would benefit from CVR assessment. Consequently, studies designed to determine the causal effects of RA disease characteristics on cardiovascular morbidity/mortality and to identify patients at high risk of cardiovascular disease are still needed.