Rheumatoid Arthritis: Di Munno O

Di Munno O, Delle Sedie A. · U.O. Reumatologia, Dipartimento di Medicina Interna, Università di Pisa, 56126 Pisa, Italy. · J Endocrinol Invest. · Pubmed #18791351 No free full text.

Abstract: Rheumatoid arthritis (RA) is characterized by an extensive dysregulation in skeletal homeostasis recognized as 1) focal articular bone erosions, 2) iuxta-articular osteopenia, 3) systemic osteoporosis (OP) and fractures, as is well documented in both cross-sectional and prospective studies. The disease activity, as a consequence of new insights into the complex interaction between bone cells and a variety of cells of the immune system, has emerged as the main responsible for both focal and systemic bone loss. Given this background, the therapeutic approach to RA has become more aggressive, and a more widespread use of low-dose glucocorticoids (GC), recently categorized as disease modifying antirheumatic drugs (DMARD) because of their additional joint sparing effect on the long-term, has also been recommended from the early stages. Addressing the effects of GC on systemic bone loss in RA, GC are considered, in addition to inflammation and inactivity, the major risk factors for OP and fractures. As a consequence, among the most recent recommendations (i.e. dosing, timing, and tapering strategies) for patients receiving GC for more than 3 months, prevention and treatment of GC-induced OP (i.e. calcium, vitamin D, and bisphosphonates) are included. However, innovative GC, characterized by a more favorable risk/benefit profile such as selective GC receptor agonists (SEGRA), are currently in the pipeline. This article reviews the major points of evidence so far available, regarding the effects of GC on focal and systemic bone loss.

Di Munno O, Delle Sedie A, Rossini M, Adami S. · Department of Internal Medicine, U O Reumatologia, University of Pisa, Pisa, Italy. · Clin Exp Rheumatol. · Pubmed #15895881 No free full text.

Abstract: This article reviews the effects of DMARDs (including biologic agents) on bone metabolism in rheumatoid arthritis (RA). At present there is no evidence that methotrexate, at least at dosages ranging from 5 to 20 mg/week, negatively affects bone mass as measured by DXA (BMD) as documented in both cross-sectional and longitudinal studies. Most studies of cyclosporine (CyA) use reporting a reduction in erosions and joint damage with no adverse effects on bone, did not measure BMD; CyA treatment is associated with a dose-dependent increase of bone turnover as well as a decrease in both animal and human studies; however, its use in RA setting at a dose < or =5 mg/Kg/ day has so far not been associated with clinical relevant adverse effects on bone metabolism. Anti-TNF-alpha agents, infliximab reduced markers of bone turnover in two longitudinal studies. Data on BMD are not available in RA; nevertheless, an increase in BMD has been documented in spondyloarthropathies with infliximab and etanercept. No clinical data concerning BMD are available on leflunomide as well as on the newer biologic agents (adalimumab, rituximab, anakinra).

Morgante M, Di Munno O, Morgante D. · Istituto di Medicina Interna, Università degli Studi, Pisa. · Minerva Med. · Pubmed #10829806 No free full text.

Abstract: In patients with rheumatoid arthritis the serum and synovial fluid levels of a glycoprotein called YKL 40 are correlated to the severity of disease. YKL 40 may be related to disease activity in RA; it is induced by vitamine D and is reduced by TGF b. YKL 40 has been isolated from bovine mammary secretions during non lactating period and from Human osteosarcoma cell line MG-63. Some observations on experimental and clinical studies are presented.

Mazzantini M, Di Munno O, Sinigaglia L, Bianchi G, Rossini M, Mela Q, Del Puente A, Frediani B, Cantatore F, Adami S. · Rheumatology Units of the University of Pisa, Italy. · Clin Exp Rheumatol. · Pubmed #18078618 No free full text.

Abstract: OBJECTIVE: To analyze the influence of cyclosporine A (CYA) on bone using data from a large multicenter, cross-sectional study on bone mineral density (BMD) in rheumatoid arthritis (RA). METHODS: We selected 558 female patients with RA and divided them into two groups on the basis of CYA use: those who had never used CYA (n = 467) and CYA users (n = 91; users for < 24 months n = 50; users for > 24 months n = 41). Demographic, disease and treatment-related variables were collected for each patient. BMD was measured at the lumbar spine and proximal femur using dual x-ray absorptiometry. Data was analyzed by means of a univariate and multivariate statistical procedure. Osteoporosis (OP) was defined as BMD < -2.5 T score. RESULTS: The frequency of OP among non-CYA users and CYA users was 28.2% and 33.3% (p=NS) for the lumbar spine, and 34.2% and 31.3% (p=NS) for the femoral neck, respectively. The prevalence of fragility fractures was not significantly different between the two groups. Mean values for the T-score at either the lumbar spine or the femoral neck were comparable in the two groups, even after adjustment for age, menopausal status, body mass index (BMI), Health Assessment Questionnaire (HAQ) score and steroid use. The generalized linear model showed that age, BMI and the HAQ score were significant independent predictors of BMD at the lumbar and femoral levels, whereas CYA use was not. Logistic analysis showed that only age, the HAQ score and BMI were significantly associated with the risk of OP. However, the duration of CYA therapy > 24 months was associated with an adjusted decreased lumbar BMD and a significantly decreased femoral neck BMD (p = 0.01). The frequency of femoral neck OP in patients on CYA for > 24 months was significantly higher than in patients on CYA for < 24 months: 46.4% vs. 19.44% (p=0.03), while the prevalence of fragility fractures did not differ significantly: 23.1% vs. 16.6%, respectively (p=NS). Logistic analysis showed that CYA use was an independent predictor of osteoporosis at the femoral site. CONCLUSION: Long-term CYA therapy may have negative effects on BMD in female RA patients.

Pasero GP, Di Munno O. · Dipartimento di Medicina Interna, Sezione di Reumatologia, Università degli Studi di Pisa. · Reumatismo. · Pubmed #12404032 links to  free full text

Abstract: OBJECTIVE: To evaluate the therapeutic action and safety of lornoxicam, a new non steroidal anti-inflammatory drug, in 2 oral daily dose regimens of 8 and 16 mg in comparison with oral diclofenac 150 mg/day in patients with rheumatoid arthritis. METHODS: Double blind double-dummy cross-over, controlled trial. The two treatments were given for ten-day periods, separated by a three-day wash-out interval. Patients of both sexes with classical or definite rheumatoid arthritis according to the A.R.A. criteria were enrolled in the study. RESULTS: Fourteen patients (12F, 2M) were admitted, mean age 61.6 years +/- 6.7 (+/-SD), duration of illness 12.7 years +/- 11.9. Lornoxicam 8 and 16 mg/day showed a good therapeutic activity, comparable with diclofenac 150 mg/day. Two patients complained adverse events with diclofenac. CONCLUSIONS: Lornoxicam 16 mg/day was associated with a more sharp action and a better tolerability than diclofenac in rheumatoid arthritis. The twice a day dosage of lornoxicam revealed to be appropriate.

Mazzantini M, Di Munno O, Metelli MR, Bulleri M, Giordani R. · Department of Internal Medicine, University of Pisa, Italy. · Aging Clin Exp Res. · Pubmed #12387527 No free full text.

Abstract: AIMS: The aim of this study was to assess the effects of a single infusion of the bisphosphonate neridronate (N) on parameters of inflammation and bone resorption in rheumatoid arthritis (RA). METHODS: Forty-five patients with active RA were randomly allocated on a double blind basis to receive a single intravenous infusion of either N 25 mg (15 patients), N 50 mg (15 patients), or placebo (15 patients). At baseline and after 7 and 21 days, we assessed the following: erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and Ritchie's articular index as indices of disease activity; and urinary free deoxypyridinoline (DPyr), N-telopeptide of type I collagen (NTx) and hydroxyproline (OHP) as indices of bone resorption. RESULTS: At day 7, N 25 mg significantly decreased ESR compared to N 50 mg (p=0.002), and CRP compared to placebo (p=0.036). With regard to bone resorption markers, at day 7, both N 25 mg and 50 mg compared to placebo significantly decreased NTx (p<0.0005 and p=0.003, respectively) and OHP (p=0.001 and p=0.004, respectively). At day 21, N 50 mg significantly decreased OHP compared to placebo (p=0.017). DPyr levels remained unchanged in the three groups. CONCLUSIONS: N 25 mg and 50 mg exerted different effects on RA activity parameters, since only the lower dose significantly decreased ESR and CRP. Both doses of N inhibited bone resorption, with a transient, significant reduction in urinary NTx and OHP, but without any effect on DPyr.

Mazzantini M, Di Munno O, Incerti-Vecchi L, Pasero G. · Department of Internal Medicine, University of Pisa, Italy. · Clin Exp Rheumatol. · Pubmed #10895369 No free full text.

Abstract: OBJECTIVE: To assess vertebral bone mineral density (BMD) changes in rheumatoid arthritis (RA) patients taking low-dose methotrexate (MTX). METHODS: We evaluated in a 2-year, longitudinal study female RA patients, who had recently started a disease-modifying antirheumatic drug (DMARD), divided into two groups: group A, receiving MTX, and group B, receiving other DMARDs. Lumbar spine BMD was assessed at baseline and every year; RA activity was assessed every 3 months. RESULTS: Sixty-two patients were enrolled in the study; 40 completed the follow-up period: 22 of group A, and 18 of group B. The results after 2 years showed that both groups lost bone significantly vs baseline (p < 0.001) in a comparable fashion: group A (mean +/- SD) -3.9 +/- 4.9% vs group B -3.0 +/- 3.7% (p = NS). The patients who showed active disease lost significantly (p < 0.05) more bone (-5.5 +/- 3.8%) than those with less active disease (-1.1 +/- 3.6%), independently of their DMARD. CONCLUSION: Low-dose MTX in RA does not seem to exert relevant effects on trabecular bone.

Di Munno O, Mazzantini M, Milani S, Pasero G. · Institute of Patologia Medica, University of Pisa, Italy. · Clin Rheumatol. · Pubmed #10357120 No free full text.

Abstract: In order to assess the clinical equivalence between deflazacort oral drops and tablets, 18 patients with active rheumatoid arthritis were enrolled in an open, controlled, randomised ('tablets --> drops' sequence, or vice versa), two-period (21 days each) crossover trial (from tablets to drops, or vice versa). Individual dose titration of deflazacort drops or tablets was made weekly on the basis of clinical need. Primary outcome measures of efficacy were changes in the joint swelling count (JSC), erythrocyte sedimentation rate (ESR), hand-grip strength (HGS), joint pain (JP), duration of morning stiffness (MS), physician's global evaluation and patient's self-assessment. Sixteen patients were available by the end of the study. The formulations were equivalent with respect to HGS and improvement in duration of MS, and close to equivalence with respect to JSC and ESR decrease; the drops seemed to be more effective than tablets with respect to JP reduction. No differences between the two formulations were observed with respect to physician's and patient's assessment. The minimum effective dose of each preparation and the relative potency ratio were also established. Drops and tablets were found to have the same potency.

Frediani B, Rossini M, Adami S, Bianchi G, Di Munno O, Sinigaglia L, Antonelli M, Minisola G, Anonymous00114. · Istituto di Reumatologia, Università di Siena, Ospedale Le Scotte, Siena, Italia. · Reumatismo. · Pubmed #17216021 links to  free full text

Abstract: The fundamental role of Vitamin D has been long known in regulating calcium homeostasis and bone metabolism. An increased contribution of Vitamin D was recently described in association with a lower incidence of Rheumatoid Arthritis (RA). This must not be surprising, as the immunomodulating effects of Vitamin D are clear, which have been attributed protective effects in autoimmune disorders such as some chronic inflammatory bowel diseases, multiple sclerosis and type I diabetes. An interaction was suggested between Vitamin D metabolism and inflammation indexes through mediation of TNF-alpha which is also especially involved in osteoclastic resorption and therefore in bone loss processes. Some preliminary data would indicate an association between seasonal changes of Vitamin D serum levels, latitude and disease activity (DAS28) in RA patients. Consequently, the Osteoporosis and Metabolic Bone Diseases Study Group of SIR believes that there are grounded reasons for assessing the Vitamin D status of RA patients in order to investigate whether this is to be related to physiopathological and clinical aspects of disease other than those of bone involvement. Primary end point of the study will be to assess the levels of 25 OH Vitamin D in RA patients. Secondary endpoints will include correlation with dis-ease activity, densitometry values and bone turnover. The cross-sectional study will enroll patients of both sex genders, age ranging between 30 and 75 years according to the 1988 ACR criteria, onset of symptoms at least 2 years prior to study enrollment. Patients will be excluded suffering from osteo-metabolic diseases, liver and kidney insufficiency and those administered Vitamin D boli in the previous 12 months. Disease activity will be evaluated with the HAQ. Hemato-chemical tests and femoral and lumbar bone densitometry will be performed, unless recently undergone by patients. Blood levels of 25 OH C Vitamin D and PHT and of the two bone remodelling markers (bone alkaline phosphatase and serum CTX) will be measured, as well. Patient enrollment will start on February 2007 and will last 4 months. By the end of 2007 the study will be concluded and results will be published.

Sinigaglia L, Nervetti A, Mela Q, Bianchi G, Del Puente A, Di Munno O, Frediani B, Cantatore F, Pellerito R, Bartolone S, La Montagna G, Adami S. · Department of Rheumatology, Istituto Ortopedico Gaetano, Pini, Milan, Italy. · J Rheumatol. · Pubmed #11093437 No free full text.

Abstract: OBJECTIVE: To determine the frequency of osteoporosis in a large cohort of women with rheumatoid arthritis (RA) and to investigate the main determinants of bone mineral density (BMD) and risk factors for vertebral fractures in this population. METHODS: We recruited 925 consecutive female patients with RA at 21 Rheumatology Centers in Italy. For each patient pre-registered demographic, disease, and treatment-related variables were collected. BMD was measured at lumbar spine and proximal femur by dual x-ray absorptiometry technique. Collected variables underwent a univariate and multivariate statistical procedure. Osteoporosis was defined as BMD > -2.5 T score. RESULTS: The frequency of osteoporosis in the whole sample was 28.8% at lumbar spine and 36.2% at femoral neck and increased linearly from Steinbrocker's functional stage I to IV (p = 0.0001). Patients with spinal or femoral osteoporosis were significantly older (p = 0.0001), had a lower body mass index (BMI) (p < 0.02), a significantly longer disease duration (p < 0.02) and a significantly higher Health Assessment Questionnaire (HAQ) score (p = 0.0001). These differences were significant, even after adjusting for age. Steroid use was associated with significantly lower lumbar and femoral BMD (p = 0.0001) even after adjusting for the main confounding covariates. Analysis of lateral spine radiographs revealed 74 women with at least one vertebral fracture. These women had a significantly lower lumbar and femoral BMD (p = 0.0001). The generalized linear model showed that steroid use, menopause, BMI, age, and HAQ were all significant independent predictors of lumbar and femoral BMD. The logistic procedure showed that age (OR 1.05, 95% CI 1.03-1.07), HAQ (OR 1.3, 95% CI 1.07-1.7), menopause (OR 1.9, 95% CI 1.1-3.2), use of steroids (OR 1.5, 95% CI 1.07-2.1), and BMI (OR 0.8, 95% CI 0.8-0.9) were significantly associated with the risk for osteoporosis. The only variables associated with an increased risk for vertebral fracture were age (OR 1.04, 95% CI 1.01-1.08), HAQ (OR 1.7, 95% CI 1.08-2.09), and cumulative steroid intake (OR for 1 g of prednisone 1.03, 95% CI 1.006-1.07). CONCLUSION: To prevent osteoporosis and its dramatic complications in RA the therapeutic challenge is to preserve functional capacity using the lowest possible dosage of corticosteroids.