Allen Anandarajah

Development and Preliminary Validation of a Magnetic Resonance Imaging Joint Space Narrowing Score for Use in Rheumatoid Arthritis: Potential Adjunct to the OMERACT RA MRI Scoring System

Objective. To develop and validate a magnetic resonance imaging (MRI) method of assessment of joint space narrowing (JSN) in rheumatoid arthritis (RA). Methods. Phase A: JSN was scored 0–4 on MR images of 5 RA patients and 3 controls at 15 wrist sites and 2nd–5th metacarpophalangeal (MCP) joints by 8 readers (7 once, one twice), using a preliminary scoring system. Phase B: Image review, discussion, and consensus on JSN definition, and revised scoring system. Phase C: MR images of 15 RA patients and 4 controls were scored using revised system by 5 readers (4 once, one twice), and results compared with radiographs [Sharp-van der Heijde (SvdH) method]. Results. Phase A: Intraobserver agreement: intraclass correlation coefficient (ICC) = 0.99; smallest detectable difference (SDD, for mean of readings) = 2.8 JSN units (4.9% of observed maximal score). Interobserver agreement: ICC = 0.93; SDD = 6.4 JSN units (9.9%). Phase B: Agreement was reached on JSN definition (reduced joint space width compared to normal, as assessed in a slice perpendicular to the joint surface), and revised scoring system (0–4 at 17 wrist sites and 2nd–5th MCP; 0: none; 1: 1–33%; 2: 34–66%; 3: 67–99%; 4: ankylosis). Phase C: Intraobserver agreement: ICC = 0.90; SDD = 6.8 JSN units (11.0%). Interobserver agreement: ICC = 0.92 and SDD = 6.2 JSN units (8.7%). The correlation (ICC) with the SvdH radiographic JSN score of the wrist/hand was 0.77. Simplified approaches evaluating fewer joint spaces demonstrated similar reliability and correlation with radiographic scores. Conclusion. An MRI scoring system of JSN in RA wrist and MCP joints was developed and showed construct validity and good intra- and interreader agreements. The system may, after further validation in longitudinal data sets, be useful as an outcome measure in RA.

Role of RANKL in bone diseases

Bone remodeling is a tightly regulated process of osteoclast-mediated bone resorption, balanced by osteoblast-mediated bone formation. Disruption of this balance can lead to increased bone turnover, resulting in excessive bone loss or extra bone formation and consequent skeletal disease. The receptor activator of nuclear factor kappaB ligand (RANKL) (along with its receptor), the receptor activator of nuclear factor kappaB and its natural decoy receptor, osteoprotegerin, are the final effector proteins of osteoclastic bone resorption. Here, I provide an overview of recent studies that highlight the key role of RANKL in the pathophysiology of several bone diseases and discuss the novel therapeutic approaches afforded by the modulation of RANKL.

Effect of adalimumab on joint disease features of patients with psoriatic arthritis detected by Magnetic Resonance Imaging

Background: Bone marrow oedema (BMO), synovitis, effusion and joint erosion on magnetic resonance imaging (MRI) may be used as outcome measures in psoriatic arthritis (PsA). Objective: To assess the impact of adalimumab on BMO, synovitis, effusion and erosions in PsA, as measured by MRI. Methods: Fifteen patients with active PsA (⩾3 tender and ⩾3 swollen joints) were enrolled in an open-label pilot study. Each received adalimumab subcutaneously every other week for 24 weeks. MRI was obtained at baseline and 24 weeks. Results: MRI was available for 11 patients, pre and post-therapy. BMO and effusion scores improved markedly after 24 weeks of adalimumab, while no significant change was noted in erosion score. An unanticipated finding, however, was the lack of improvement in the MRI synovitis score. Conclusions: Improvement in BMO and unchanged erosion scores may explain the “anti-erosive” effects of adalimumab in PsA. Persistence of BMO and synovitis on MRI suggests ongoing disease activity and supports the continuation of long-term anti-TNF therapy.

Decreased influenza-specific B cell responses in rheumatoid arthritis patients treated with anti-tumor necrosis factor

IntroductionAs a group, rheumatoid arthritis (RA) patients exhibit increased risk of infection, and those treated with anti-tumor necrosis factor (TNF) therapy are at further risk. This increased susceptibility may result from a compromised humoral immune response. Therefore, we asked if short-term effector (d5-d10) and memory (1 month or later) B cell responses to antigen were compromised in RA patients treated with anti-TNF therapy.MethodsPeripheral blood samples were obtained from RA patients, including a subset treated with anti-TNF, and from healthy controls to examine influenza-specific responses following seasonal influenza vaccination. Serum antibody was measured by hemagglutination inhibition assay. The frequency of influenza vaccine-specific antibody secreting cells and memory B cells was measured by EliSpot. Plasmablast (CD19+IgD-CD27hiCD38hi) induction was measured by flow cytometry.ResultsCompared with healthy controls, RA patients treated with anti-TNF exhibited significantly decreased influenza-specific serum antibody and memory B cell responses throughout multiple years of the study. The short-term influenza-specific effector B cell response was also significantly decreased in RA patients treated with anti-TNF as compared with healthy controls, and correlated with decreased influenza-specific memory B cells and serum antibody present at one month following vaccination.ConclusionsRA patients treated with anti-TNF exhibit a compromised immune response to influenza vaccine, consisting of impaired effector and consequently memory B cell and antibody responses. The results suggest that the increased incidence and severity of infection observed in this patient population could be a consequence of diminished antigen-responsiveness. Therefore, this patient population would likely benefit from repeat vaccination and from vaccines with enhanced immunogenicity.

The diagnosis and treatment of early psoriatic arthritis

Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disorder associated with a heterogeneous disease presentation, varied disease expression and an unpredictable but often chronically destructive clinical course. Joint damage can occur early in the disease; indeed, several imaging modalities have demonstrated subclinical joint involvement in psoriasis patients without musculoskeletal signs or symptoms. Efforts are underway to validate questionnaires that will enable dermatologists to screen patients with psoriasis for the presence of musculoskeletal disease. To date, the use of therapies in patients with early PsA has not been reported in randomized controlled trials. Moreover, conventional agents are partially effective in established PsA but, in general, trials with DMARDS have not included validated outcome measures for the different manifestations of PsA. Tumor necrosis factor antagonists can alleviate the signs and symptoms of established psoriatic arthritis and inhibit radiographic progression, but the therapeutic impact of early intervention with these agents requires further study. The extent of disease and the presence of comorbidities should be used to guide treatment decisions and to minimize adverse events.

Anti‐RANKL therapy for inflammatory bone disorders: Mechanisms and potential clinical applications

Focal bone loss around inflamed joints in patients with autoimmune disease, such as rheumatoid arthritis, remains a serious clinical problem. The recent elucidation of the RANK/RANK‐ligand/OPG pathway and its role as the final effector of osteoclastogenesis and bone resorption has brought a tremendous understanding of the pathophysiology of inflammatory bone loss, and has heightened expectation of a novel intervention. Here, we review the etiology of inflammatory bone loss, the RANK/RANK‐ligand/OPG pathway, and the clinical development of anti‐RANK‐ligand therapy. J. Cell. Biochem.

Treatment update on spondyloarthropathy

Purpose of reviewThe unexpected success of the tumor necrosis factor antagonists in ankylosing spondylitis and psoriatic arthritis has generated considerable enthusiasm regarding the therapeutic potential of these drugs. By contrast, concerns regarding the high cost and long-term safety of the tumor necrosis factor blocking agents have prompted investigators to take a closer look at more traditional anti-inflammatory agents and to explore novel therapeutic targets. The purpose of this review is to summarize treatment advances in spondylarthropathy over the past year and to discuss potential future therapies. Recent findingsRecent studies indicate that the morbidity of ankylosing spondylitis and PsA are considerably higher than previously reported. Etanercept, infliximab and adalimumab safely and effectively relieved the signs and symptoms of psoriatic arthritis patients in phase III trials. Etanercept and infliximab were also effective in phase III trials in ankylosing spondylitis. Etanercept slowed radiographic progression in psoriatic arthritis trials, but it is not known whether tumor necrosis factor antagonists can prevent structural damage in ankylosing spondylitis. One trial showed that methotrexate may be effective for relieving the pain of axial disease in ankylosing spondylitis but these findings contradict two previous studies. For reactive arthritis and undifferentiated spondylarthropathy, a combination of antibiotics may be more effective than a single antibiotic for the relief of musculoskeletal symptoms. Last, potential therapeutic targets include interleukin-1, interleukin-12, B lymphocytes, accessory molecules on T lymphocytes, and angiogenic factors. SummaryPhase III trials have confirmed that tumor necrosis factor antagonists are effective and safe for the treatment of ankylosing spondylitis and psoriatic arthritis. For patients who do not respond to tumor necrosis factor blockade, several treatment options are under study. Information from these trials will more clearly define the role of disease-modifying antirheumatic drugs, novel therapeutic agents, and antibiotics in the treatment of spondylarthropathy.

Comparative Analysis of Disease Activity Measures, Use of Biologic Agents, Body Mass Index, Radiographic Features, and Bone Density in Psoriatic Arthritis and Rheumatoid Arthritis Patients Followed in a Large U.S. Disease Registry

Objective. To compare disease activity, radiographic features, and bone density in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) matched cohorts. Methods. Disease activity and radiographic data in the Consortium of Rheumatology Researchers of North America database from 2001 to 2008 were compared for 2481 patients with PsA and 17,107 patients with RA subsequently matched for age, gender, and disease duration. Radiographic outcomes included presence of erosions, and joint deformity. In addition, bone mineral density (BMD) scores for lumbar spine (L-spine) and femoral neck were compared using the same matching criteria plus weight and smoking status. Results. Tender (4.5 vs 3.4, p < 0.001) and swollen (4.4 vs 2.9, p < 0.012) joint counts, and modified Health Assessment Questionnaire scores were significantly higher (0.4 vs 0.3, p < 0.001) in patients with RA compared with patients with PsA. Patient general health and pain scores were also higher in patients with RA vs patients with PsA. Joint erosions (47.4% vs 37.6%, p = 0.020) and deformity (25.2% vs 21.6%, p = 0.021) were more prevalent in RA than PsA. In multivariate analysis, a reduced prevalence of erosions in PsA vs RA was noted (OR 0.609, p < 0.001). After matching, T-scores for L-spine (−0.54 vs −0.36, p = 0.077) and femoral neck (−0.88 vs −0.93, p = 0.643) were similar in patients with RA and patients with PsA, although body weight was a major confounder. Conclusion. The level of disease activity and radiographic damage was significantly higher for RA vs PsA subjects, although the magnitude of differences was relatively small. BMD levels were comparable between cohorts. Outcomes in patients with PsA and patients with RA may be more similar than previously reported.

Patients with Rheumatoid Arthritis in Clinical Remission Manifest Persistent Joint Inflammation on Histology and Imaging Studies

Objective. The purpose of our study was to test the hypothesis that synovitis on magnetic resonance imaging (MRI) and ultrasound (US) observed in patients with rheumatoid arthritis (RA) who meet remission criteria reflects active inflammation on histopathology. Methods. We analyzed 15 synovial specimens obtained during surgical procedures from 14 patients with RA in clinical remission as defined by the American College of Rheumatology criteria. Histological specimens were scored for hyperplasia of synovial lining and synovial stroma, inflammation, lymphoid follicles, and vascularity. The histology scores were classified as minimal, mild, moderate, or severe disease activity. US and MRI performed within a 4-month period of surgery were scored for disease activity. The correlation between histology and imaging scores was examined. Results. Four of 14 patients were receiving anti-tumor necrosis factor (TNF) therapy, 4 were receiving methotrexate (MTX) alone, 4 were taking MTX and hydroxychloroquine (HCQ), and 1 was taking HCQ and sulfasalazine. Four specimens had severe, 6 moderate, 3 mild, and 2 minimal disease activity on histology. Three of 4 specimens with minimal and mild histology were observed in subjects receiving anti-TNF therapy. Synovitis was noted on greyscale in 80% of joints and Doppler signal in 60%. MRI demonstrated synovitis and bone marrow edema in 86% of images. Positive but not significant correlations were noted between histology and synovitis scores on US. Conclusion. Despite clinical remission, histology and imaging studies documented a persistently active disease state that may explain the mechanism for radiographic progression.

Bone Loss in the Spondyloarthropathies: Role of Osteoclast, RANKL, RANK and OPG in the Spondyloarthropathies

Bone loss is a common finding in the spondyloarthropathies. It may be localized and present as erosions or be generalized and cause osteoporosis. The pathogenesis of bone loss in the spondyloarthropathies is yet to be fully understood. There is however increasing evidence to support a role for the osteoclasts in bone erosions. Similarly a balance between the receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) levels is thought to regulate osteoclastic activity and therefore bone loss in the inflammatory arthritides. In this chapter we will review the recent literature on the role of osteoclasts and the RANKL/OPG system in the various spondyloarthropathies and try to formulate a hypothesis for the possible mechanism of bone loss in this group of inflammatory rheumatic disease.