Seminars in Arthritis and Rheumatism

Paget's Disease of Bone: Evidence for Complex Pathogenetic Interactions

Pui Yan Jenny Chung, Wim Van Hul — 2011-09-29

Objectives: Paget's disease of bone (PDB), with a prevalence of 2 to 5% in Caucasians >55 years, is the second most frequent metabolic bone disease, after osteoporosis. PDB characteristics are bone lesions with an imbalanced bone remodeling, resulting in disorganized and nonfully fledged new bone. PDB etiology is not completely understood. In this review, current views on the etiology, clinical aspects, and PDB treatment are summarized and discussed. Methods: The PubMed database was searched using the keywords PDB, sequestosome1 (SQSTM1), valosin-containing protein (VCP), receptor activator of nuclear factor-κB (RANK), osteoprotegerin (OPG), RANK ligand (RANKL), mutation, genetic variants, virus, osteosarcoma, bisphosphonates, and denosumab. Results: Environmental evidence (e.g. viruses) and also genetic risk factors have been found for PDB. Until now, SQSTM1 was the only PDB-causing gene identified. However, PDB patients without SQSTM1 mutations seem to have susceptibility genetic polymorphisms in regions containing the CaSR, ESR1, TNFRSF11B (OPG), TNFRSF11A (RANK), CSF1 (M-CSF), OPTN, TM7SF4 (DC-STAMP), VCP, NUP205, RIN3, PML, and GOLGA6A genes, resulting in an increased risk of developing PDB. The nature of these genes indicates that the regulation of osteoclastogenesis is a key process in PDB pathogenesis. Furthermore, with the involvement of SQSTM1 and VCP in autophagy and in forming protein aggregates, this might also indicate that a disturbance of these processes might be a risk factor. Conclusions: Unraveling the PDB genetic background is instrumental to understanding the PDB pathogenesis and the role of slow viruses. Furthermore, it might make early detection and subsequently treatment of risk individuals possible.

Membranous Nephropathy in Systemic Lupus Erythematosus: Long-Term Outcome and Prognostic Factors of 103 Patients

2012-01-27

Objectives: The objective of this study was to evaluate the clinical features, course, outcome, and prognostic indicators in lupus membranous nephritis (LMN) and to compare data of “pure” LMN vs “mixed” forms. Methods: We retrospectively examined medical records and kidney biopsies of 103 patients with a diagnosis of LMN. Results: Sixty-seven patients had “pure” LMN and 36 had “mixed” forms. Patients with mixed LMN had more frequent nephrotic syndrome (66.6 vs 44.7%, P = 0.05), low C3 (83.3 vs 62.6%, P = 0.05) and C4 (80.5 vs 52.2%, P = 0.005), anti-DNA positivity (86.0 vs 62.6%, P = 0.03), and a tendency toward a lower creatinine clearance (93 ± 29 vs 112 ± 50 mL/min, P = 0.07). Moreover, mixed membranous nephritis had a higher activity and chronicity index (6.5 ± 2.1 vs 1.4 ± 2.03, P = 0.005 and 2.4 ± 1.7 vs 1.4 ± 1.8, P = 0.0001, respectively). Methylprednisolone pulses and immunosuppressive therapy were more often used in patients with mixed forms (86.1 vs 60.6%, P = 0.016 and 83.3 vs 57.5%, P = 0.008, respectively). After a mean follow-up of 156.5 ± 104.5 months, there was no difference in the 2 subgroups concerning the number of patients achieving remission and patient/renal survival (94.5 vs 94.0% and 85.8 vs 86% at 10 years). At multivariate analysis, serum creatinine at presentation (P = 0.0013), chronicity index (P = 0.007), failure of achieving remission (P = 0.000001), and occurrence of nephritic flares (P = 0.00167) were independent predictors of chronic renal insufficiency. Conclusions: Despite the differences in clinical and histological presentation, a therapy tailored on the grounds of clinical and histological features may reduce the differences in the outcome of white patients with mixed and pure membranous nephritis.

High Survivin Levels Predict Poor Clinical Response to Infliximab Treatment in Patients with Rheumatoid Arthritis

2011-10-31

Objective: To evaluate if the measurement of survivin in the blood of patients with rheumatoid arthritis (RA) undergoing infliximab treatment has predictive value for treatment response. Methods: The study included 87 consecutive RA patients (age 24-89 years, disease duration 18-526 months) treated with regular infusions of influximab. Survivin levels were measured by enzyme-linked immunosorbent assay and evaluated in relation to the total dose of infliximab, disease activity (DAS28), response to infliximab treatment (change in DAS28 >1.2), and radiographic damage (vdH-Sharp score). Results: Thirty-seven percent of patients were survivin-positive (survivin >0.9 ng/mL) and showed severe radiographic damage at the start of infliximab treatment compared with survivin-negative (P = 0.027). Patients with high survivin levels were unlikely to respond to infliximab treatment (OR 4.02 [1.22-14.61], P = 0.022) and achieve remission (OR 4.32[1.01-30.11], P = 0.048) compared with patients with low survivin levels. Conclusions: High survivin levels are associated with severe radiographic damage at the start of treatment and a poor response to infliximab. Survivin measurement should be considered an additional tool for aiding the selection and follow-up of antirheumatic treatment.

Biological Agents in the Management of Felty's Syndrome: A Systematic Review

2011-11-28

Objective: To review and summarize the information available on the effectiveness and safety of biological therapies in refractory Felty's syndrome (FS). Methods: We describe a case of FS with severe neutropenia and recurrent bacterial infections unresponsive to disease-modifying antirheumatic drug treatment and long-term administration with granulocyte colony-stimulating factor, in which treatment with rituximab (RTX) was useful and resulted in a sustained neutrophil response. Current evidence on the use of biological therapies in FS is also analyzed through a systematic review of the English-language literature, based on a PubMed search. Results: Available data on the use of biological therapies in refractory FS are based only on several case reports and are limited to the use of RTX and some anti-tumor necrosis factor α agents (etanercept, infliximab, and adalimumab). Including the case described here, data are available on 8 patients treated with RTX. A sustained increase in the absolute neutrophil count (>1500/mm3) was observed in 62.5% (5/8) of these patients after 1 cycle of treatment. In most of them, the hematological response was accompanied by a parallel improvement in biological markers of inflammation and other clinical manifestations of FS (arthritis, recurrent infections, systemic symptoms, etc). After a median follow-up of 9 months (range, 6-14), only 1 of these patients relapsed and neutropenia reappeared; in this patient, retreatment was rapidly effective. No significant adverse events related to RTX therapy were reported. Experience with anti-tumor necrosis factor agents is limited to 6 patients, none of whom presented any sustained increase in neutrophil count. Conclusions: Although it is not yet possible to make definite recommendations, the global analysis of all cases reported to date only supports the use of RTX as a second-line therapy in patients with refractory FS.

Subclinical Atherosclerosis and Endothelial Dysfunction in Patients with Early Rheumatoid Arthritis as Evidenced by Measurement of Carotid Intima-Media Thickness and Flow-Mediated Vasodilatation: An Observational Study

2011-10-31

Objective: In this study, we aimed to investigate the frequency of endothelial dysfunction and subclinical atherosclerosis in early rheumatoid arthritis (RA) patients by carotid intima-media thickness (cIMT) and endothelial-dependent flow mediated vasodilatation (ED-FMD) as compared with healthy controls. Methods: The study included 35 early RA patients (disease duration <12 months) and 35 healthy controls. Intima-media thickness of common carotid artery and ED-FMD of brachial artery were measured by high-resolution ultrasonography. Disease activity of RA was assessed by Disease Activity Score and activities of daily living were determined by Health Assessment Questionnaire–Disability Index Score. Results: RA patients (age 38.3 ± 10.6 years) had average disease duration of 0.46 ± 0.28 years and 22 patients (62.9%) were rheumatoid factor (RF) positive (RF titer >9.56 IU/mL). There were no significant differences between age, sex, and lipid profiles of patient and control group. cIMT was significantly higher in RA patients (0.50 ± 0.16 mm) than in controls (0.44 ± 0.09 mm) (P = 0.007). Similarly, FMD% was significantly lower in RA patients [5.26 (2.9-10.6)] as compared with controls [10.34 (7.4-14.3)] (P = 0.004). Age, systolic blood pressure, tender joint count, and swollen joint count had significant correlations with patient cIMT. RF titer came out to be the major risk factor for increased cIMT of the patients. Conclusions: Compared with controls, early RA patients have higher cIMT and lower FMD%, denoting premature atherosclerosis. Our data suggest that early determination of FMD% and cIMT may be useful tools to assess cardiovascular risk even in early RA patients.

Noninvasive Cardiovascular Imaging in Rheumatoid Arthritis: Current Modalities and the Emerging Role of Magnetic Resonance and Positron Emission Tomography Imaging

2011-10-17

Objectives: Rheumatoid arthritis (RA) is associated with premature atherosclerosis and increased prevalence of cardiovascular disease. The objective of this review is to summarize current and emerging imaging modalities for the evaluation of subclinical atherosclerosis in RA, with an emphasis on potential application of novel modalities, high-resolution magnetic resonance imaging and positron emission tomography, as screening tools for early cardiovascular disease risk stratification. Methods: A PubMed literature search was undertaken using the search terms “rheumatoid arthritis” AND “cardiovascular disease” OR “atherosclerosis” OR “plaque” and including all relevant terms for imaging modalities. Results: Two noninvasive imaging modalities have been widely adopted for direct visualization of arterial wall: carotid ultrasonography and cardiac computed tomography. Published studies in the RA population using these 2 modalities are reviewed. Novel cardiovascular imaging modalities are described, with an emphasis on high-resolution magnetic resonance imaging and positron emission tomography. Emerging research tools in vascular imaging, including dynamic and cardiac stress perfusion contrast-enhanced magnetic resonance imaging, are presented. The incremental imaging capabilities to characterize plaque composition and vessel wall inflammation as well myocardial abnormalities and published studies are systematically reviewed. Conclusions: An increasing number of cardiovascular imaging modalities with improved characterization of features associated with plaque vulnerability have been developed. Given the heightened cardiovascular risk profile of the RA population, these novel imaging modalities offer promise for risk stratification and drug safety evaluation.

Cardiopulmonary Complications After Primary Shoulder Arthroplasty: A Cohort Study

Jasvinder A. Singh, John W. Sperling, Robert H. Cofield — 2011-11-07

Objective: To study the frequency and predictors of 90-day cardiopulmonary complications following primary shoulder arthroplasty. Methods: We used prospectively collected data from the Mayo Clinic Total Joint registry from 1976 to 2008. We used univariate and multivariable-adjusted Cox regression analyses to examine the association of age, gender, body mass index, comorbidity assessed by Deyo-Charlson index, American Society of Anesthesiologist class, implant fixation (cemented versus not), and underlying diagnosis with the risk of 90-day cardiopulmonary complications after primary shoulder arthroplasty. Odds ratio (OR) with 95% confidence interval (CI) and P values are presented. Results: A total of 3480 patients underwent 4019 primary shoulder arthroplasties. Ninety-day cardiac and thromboembolic complication rates following primary shoulder arthroplasty were 2.6% (92/3480) and 1.2% (42/3480). After multivariable-adjustment, age >70 years (OR, 2.7; 95% CI: 1.2-5.9; P value = 0.01; relative to age <60), Deyo-Charlson comorbidity index of 1 or more (OR, 3.27; 95% CI:1.9-5.6; P < 0.0001; relative to index of 0), and prior cardiac events (OR, 7.87; 95% CI: 4.89-12.68; P < 0.0001; relative to no prior event) were associated with higher odds of 90-day cardiac complications. Due to a few thromboembolic events, only univariate analyses were performed. Univariately, female gender, age >70 years, body mass index 25 to 29.9 kg/m2, Deyo Charlson index of 1 or more, underlying diagnosis of trauma, prior thromboembolic event, and surgery type were each associated with significantly higher risk of 90-day thromboembolic event (P ≤ 0.03 for all). Conclusions: Cardiac and thromboembolic complications are uncommon after primary shoulder arthroplasty. Patients can be informed of their risk of cardiac complications following shoulder arthroplasty based on the presence of risk factors.

Imaging Approaches for Evaluating Peripheral Joint Abnormalities in Juvenile Idiopathic Arthritis

2011-10-31

Objectives: To assess the usefulness of imaging studies for peripheral joint assessment in children with juvenile idiopathic arthritis (JIA), based on a systematic literature review. Methods: We used PubMed to identify relevant articles published between 2000 and 2011. Results: Plain radiography is still the reference imaging study for monitoring joint destruction in patients with JIA, and the results correlate well with the clinical findings. Radiographs should be obtained routinely during follow-up and in therapeutic trials. Available scoring methods have been validated in children, but no recommendations are available on the intervals between radiographic assessments. Ultrasonography and magnetic resonance imaging (MRI) can detect inflammatory changes that precede bone destruction. Ultrasonography features in JIA are still being studied. Ultrasonography can detect clinically silent synovitis, which has major implications for determining the JIA subtype. MRI is the only imaging study capable of showing bone marrow edema, which predicts joint destruction. Conclusions: Although radiography remains the reference standard imaging study for assessing peripheral joint destruction in JIA, ultrasonography and MRI allow the early detection of predestructive changes, the presence of which affects treatment decisions. Much more work is needed to determine the optimal imaging protocols, the best interval between imaging evaluations during follow-up, and the therapeutic implications of imaging study findings.

Biologics in Relapsing Polychondritis: A Literature Review

Fernando Kemta Lekpa, Virginia B. Kraus, Xavier Chevalier — 2011-11-09

Background: There is no standardized therapeutic protocol for relapsing polychondritis (RP). Emergence of biologics holds much hope in the management of this connective tissue disease. Objectives: To evaluate the efficacy and safety of biologics in patients with active RP. Methods: A systematic review of the literature using PubMed was performed through December 2010. MeSH terms and keywords were used relating to RP and biologics. All papers reporting the efficacy and/or safety of biologics in RP were selected. Reference lists of included papers were also searched. Results: All publications relate to case series or isolated case reports. No randomized controlled trial has been performed. Thirty papers that included 62 patients were published. These patients were treated with TNFα blockers (n = 43), rituximab (n = 11), anakinra (n = 5), tocilizumab (n = 2), and abatacept (n = 1). The endpoint of treatment differs from 1 publication to the other and therefore makes the comparison of efficacy among the various biologics difficult. Biologics were effective in 27 patients, partially effective in 5 patients, and not effective in 29 patients. Safety appeared to be good. However, 4 deaths were recorded (2 sepsis, 1 postoperatively after aortic aneurysm surgery, and 1 after accidental dislocation of the tracheostomy device). Conclusions: The experience with biologics in RP is very limited and their real efficacy and indications need to be better defined. Randomized controlled trials, although difficult to perform because of the rarity of RP, are needed to determine the place of biologics in the treatment strategy of this orphan disease.

Examining How Antiphospholipid Antibodies Activate Intracellular Signaling Pathways: A Systematic Review

Katie Poulton, Anisur Rahman, Ian Giles — 2011-11-07

Objectives: Diverse experimental evidence exists implicating the activation of various different cell surface receptors and intracellular pathways by antiphospholipid antibodies (aPL). This evidence has been generated using a number of different cell types with varying numbers of aPL from different sources and disease subtypes. This experimental variability complicates the comparison of results from different studies. We therefore undertook a systematic review of the literature to provide a critical analysis of the strength of the evidence that specific receptors and signaling pathways are important in the pathogenesis of antiphospholipid syndrome. Methods: We searched PubMed and EMBASE for studies in which the effects of aPL on cell surface receptors or intracellular signaling pathways were measured in vitro or in vivo. Each publication was systematically examined to note the following points: antibody type and source, outcome measures, use of receptor/signaling pathway inhibitors, and cell type and origin. Results: We identified 10 original studies on toll-like receptors (TLR), 14 on protein kinases, and 13 on nuclear factor kappa B (NFκB). There was considerable heterogeneity between studies. Nevertheless, convincing evidence from multiple approaches implicates TLR4, p38 mitogen-activated protein kinase (MAPK), and NFκB in mediating pathogenic effects of antiphospholipid antibodies. Conclusions: TLR4, p38 MAPK and NFκB are involved in mediating pathogenic effects of aPL on different cell types and may be potential therapeutic targets in antiphospholipid syndrome.

Perspectives in Rheumatoid Abstracts from 2011 Meeting Selected Proceedings of the 4th Annual Perspectives in Rheumatic Diseases 2011

Daniel E. Furst, Brian Mandell — 2012-04-01

The 4th annual Perspectives in Rheumatic Diseases 2011 conference presented by Rheumatology News, Family Practice News and Internal Medicine News was held in October 2011 in San Francisco, California. This two-day continuing medical education (CME) conference featured more than 25 presentations and interactive sessions from leading experts in the management of patients with rheumatic diseases, co-morbid conditions and related dermatologic diseases. This conference emphasized the interconnections between rheumatology and dermatology. Practical management approaches to rheumatologic and dermatological diseases and their sequelae were discussed. The conference included an interactive “Rheumatology Jeopardy” session that provided rheumatologist and primary care physician attendees the opportunity to participate in team-based learning.

Introduction: The Value in Musculoskeletal Care Editorial/Introduction to Summary and Recommendations

Kimberly J. Templeton — 2012-04-01

Musculoskeletal diseases can be lifelong and affect and be affected by other health conditions. With their resulting pain and impact on loss of function and mobility, they can affect efforts to control hypertension, diabetes, obesity, and other conditions. They can impact the ability to maximize educational opportunities, earn a living, care for family, and participate in or contribute to other activities associated with a fulfilling life. Tremendous advances have been made in understanding the etiology and identifying treatment options for the vast majority of these conditions. However, understanding and defining the value of these various treatment options to patients, their families, and society are areas that have not been fully examined. Health care reform has drawn our attention to this gaping hole in our knowledge and provides us with an opportunity to look for answers and contribute to the debate that is underway to ensure that resources are allocated to best meet patient needs.

The Value in Musculoskeletal Care: Summary and Recommendations

Steve M. Gnatz, David S. Pisetsky, Gunnar B.J. Andersson — 2012-04-01

This document summarizes key issues and recommendations discussed at the Summit on The Value in Musculoskeletal Care, sponsored by the United States Bone and Joint Initiative (USBJI). This Summit, held in Washington, D.C., on October 12-13, 2011, was attended by 128 invited representatives of the musculoskeletal community, including patients, health care professionals, payers, industry and government.

Erratum

2012-04-01

We regret to report that part of the text was omitted in the article “Reply to Letter to the Editor” [Semin Arthritis Rheum 41(4):e2 to e3] by Arlene Tan Tieng, MD, Cheryl A. Sadow, MD, Jay G. Hochsztein, MD, and Chaim Putterman, MD. The full article is printed below. We apologize for this error.

Masthead

2012-04-01

Current Abstracts

2012-04-01

Seminars in Arthritis and Rheumatism

Paget's Disease of Bone: Evidence for Complex Pathogenetic Interactions

Membranous Nephropathy in Systemic Lupus Erythematosus: Long-Term Outcome and Prognostic Factors of 103 Patients

High Survivin Levels Predict Poor Clinical Response to Infliximab Treatment in Patients with Rheumatoid Arthritis

Biological Agents in the Management of Felty's Syndrome: A Systematic Review

Subclinical Atherosclerosis and Endothelial Dysfunction in Patients with Early Rheumatoid Arthritis as Evidenced by Measurement of Carotid Intima-Media Thickness and Flow-Mediated Vasodilatation: An Observational Study

Noninvasive Cardiovascular Imaging in Rheumatoid Arthritis: Current Modalities and the Emerging Role of Magnetic Resonance and Positron Emission Tomography Imaging

Cardiopulmonary Complications After Primary Shoulder Arthroplasty: A Cohort Study

Imaging Approaches for Evaluating Peripheral Joint Abnormalities in Juvenile Idiopathic Arthritis

Biologics in Relapsing Polychondritis: A Literature Review

Examining How Antiphospholipid Antibodies Activate Intracellular Signaling Pathways: A Systematic Review

Perspectives in Rheumatoid Abstracts from 2011 Meeting Selected Proceedings of the 4th Annual Perspectives in Rheumatic Diseases 2011

Introduction: The Value in Musculoskeletal Care Editorial/Introduction to Summary and Recommendations

The Value in Musculoskeletal Care: Summary and Recommendations

Erratum

Masthead

Table of Contents

Current Abstracts