Helena Marzo-Ortega

Defining active sacroiliitis on Magnetic Resonance Imaging (MRI) for classification of axial spondyloarthritis –a consensual approach by the ASAS/ OMERACT MRI Group

Background: Magnetic resonance imaging (MRI) of sacroiliac joints has evolved as the most relevant imaging modality for diagnosis and classification of early axial spondyloarthritis (SpA) including early ankylosing spondylitis. Objectives: To identify and describe MRI findings in sacroiliitis and to reach consensus on which MRI findings are essential for the definition of sacroiliitis. Methods: Ten doctors (two radiologists and eight rheumatologists) from the ASAS/OMERACT MRI working group reviewed and discussed in three workshops MR images depicting sacroiliitis associated with SpA and other conditions which may mimic SpA. Descriptions of the pathological findings and technical requirements for the appropriate acquisition were formulated. In a consensual approach MRI findings considered to be essential for sacroiliitis were defined. Results: Active inflammatory lesions such as bone marrow oedema (BMO)/osteitis, synovitis, enthesitis and capsulitis associated with SpA can be detected by MRI. Among these, the clear presence of BMO/osteitis was considered essential for defining active sacroiliitis. Structural damage lesions such as sclerosis, erosions, fat deposition and ankylosis can also be detected by MRI. At present, however, the exact place of structural damage lesions for diagnosis and classification is less clear, particularly if these findings are minor. The ASAS group formally approved these proposals by voting at the annual assembly. Conclusions: For the first time, MRI findings relevant for sacroiliitis have been defined by consensus by a group of rheumatologists and radiologists. These definitions should help in applying correctly the imaging feature “active sacroiliitis by MRI” in the new ASAS classification criteria for axial SpA.

European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies

Background Psoriatic arthritis (PsA) is a clinically heterogeneous disease. Clear consensual treatment guidance focused on the musculoskeletal manifestations of PsA would be advantageous. The authors present European League Against Rheumatism (EULAR) recommendations for the treatment of PsA with systemic or local (non-topical) symptomatic and disease-modifying antirheumatic drugs (DMARD). Methods The recommendations are based on evidence from systematic literature reviews performed for non-steroidal anti-inflammatory drugs (NSAID), glucocorticoids, synthetic DMARD and biological DMARD. This evidence was discussed, summarised and recommendations were formulated by a task force comprising 35 representatives, and providing levels of evidence, strength of recommendations and levels of agreement. Results Ten recommendations were developed for treatment from NSAID through synthetic DMARD to biological agents, accounting for articular and extra-articular manifestations of PsA. Five overarching principles and a research agenda were defined. Conclusion These recommendations are intended to provide rheumatologists, patients and other stakeholders with a consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes, based on combining evidence and expert opinion. The research agenda informs directions within EULAR and other communities interested in PsA.

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10−8 in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10−6 overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27–positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

Efficacy of etanercept in the treatment of the entheseal pathology in resistant spondylarthropathy: a clinical and magnetic resonance imaging study.

OBJECTIVE To determine the effect of tumor necrosis factor alpha (TNFalpha) blockade with etanercept on the clinical manifestations of resistant spondylarthropathy (SpA) and on axial and peripheral entheseal lesions using magnetic resonance imaging (MRI). METHODS We performed a descriptive longitudinal study of 10 SpA patients, all of whom had active inflammatory back pain and peripheral involvement. Patients were treated with 25 mg subcutaneous etanercept twice weekly for 6 months. Clinical assessments included entheseal count, visual analog scale (VAS) scores for spinal pain during the day and night, VAS scores for entheseal pain, the Bath Ankylosing Spondylitis Functional Index (BASFI), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and the Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire. MRI scans of sacroiliac (SI) joints, the lumbar spine, and affected peripheral joints were performed using a 1.5T scanner employing T1-weighted, T2-weighted fat-suppressed (FS), and T1-weighted FS postgadolinium sequences at baseline and at 6 months. Enthesitis and associated osteitis were scored semiquantitatively in pre- and posttreatment scans. RESULTS There was a statistically significant improvement in all clinical and functional parameters (P = 0.008 for VAS spinal pain score during the day and for VAS spinal pain score during the night, P = 0.008 for the BASFI, and P = 0.005 for the BASDAI) as well as in quality of life (P = 0.005 for the ASQoL) at 6 months. Nine patients had a total of 44 MRI-detectable entheseal lesions. These were seen in the SI joints in 6 patients (n = 15 lesions), in the lumbar or cervical spine in 9 patients (n = 22 lesions), and in peripheral joints in 5 patients (n = 7 lesions). Overall, 86% of MRI-detected entheseal lesions either regressed completely or improved. No new lesions developed. CONCLUSION These findings suggest that TNFalpha blockade with etanercept is markedly effective in controlling the clinical manifestations of SpA that is resistant to disease-modifying antirheumatic drugs. This is associated with marked improvement of enthesitis and associated osteitis pathology as determined by MRI.

European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update

Background Since the publication of the European League Against Rheumatism recommendations for the pharmacological treatment of psoriatic arthritis (PsA) in 2012, new evidence and new therapeutic agents have emerged. The objective was to update these recommendations. Methods A systematic literature review was performed regarding pharmacological treatment in PsA. Subsequently, recommendations were formulated based on the evidence and the expert opinion of the 34 Task Force members. Levels of evidence and strengths of recommendations were allocated. Results The updated recommendations comprise 5 overarching principles and 10 recommendations, covering pharmacological therapies for PsA from non-steroidal anti-inflammatory drugs (NSAIDs), to conventional synthetic (csDMARD) and biological (bDMARD) disease-modifying antirheumatic drugs, whatever their mode of action, taking articular and extra-articular manifestations of PsA into account, but focusing on musculoskeletal involvement. The overarching principles address the need for shared decision-making and treatment objectives. The recommendations address csDMARDs as an initial therapy after failure of NSAIDs and local therapy for active disease, followed, if necessary, by a bDMARD or a targeted synthetic DMARD (tsDMARD). The first bDMARD would usually be a tumour necrosis factor (TNF) inhibitor. bDMARDs targeting interleukin (IL)12/23 (ustekinumab) or IL-17 pathways (secukinumab) may be used in patients for whom TNF inhibitors are inappropriate and a tsDMARD such as a phosphodiesterase 4-inhibitor (apremilast) if bDMARDs are inappropriate. If the first bDMARD strategy fails, any other bDMARD or tsDMARD may be used. Conclusions These recommendations provide stakeholders with an updated consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes in PsA, based on a combination of evidence and expert opinion.

A systematic literature review of drug therapies for the treatment of psoriatic arthritis: current evidence and meta-analysis informing the EULAR recommendations for the management of psoriatic arthritis

Objectives To review the available evidence for the efficacy and safety of non-steroidal anti-inflammatory drugs (NSAIDs), synthetic and biological drug therapies for the different clinical manifestations of psoriatic arthritis (PsA) in order to provide data for the development of treatment recommendations by the European League Against Rheumatism (EULAR) taskforce. Methods A systematic literature review (SLR) of available treatments for PsA was performed using the largest electronic databases (MEDLINE, EMBASE and COCHRANE) by two working groups formed within the EULAR taskforce. This comprised a comprehensive sample of rheumatologists, dermatologists, epidemiologists and patients. The available evidence was reviewed for NSAIDs, synthetic disease modifying antirheumatic drugs (DMARDs), local and systemic corticosteroids and biologic drugs. All articles and abstracts published between 1962 and January 2010 were reviewed and considered and a meta-analysis of data on biological therapies was performed. Results While little data are available on NSAIDs, glucocorticoids and synthetic DMARDs, the available evidence suggests an acceptable efficacy and safety profile of both NSAIDs and synthetic DMARDs (methotrexate, cyclosporine A, sulfasalazine and leflunomide) in PsA. More evidence is available (level 1B) supporting the efficacy of anti-tumour necrosis factor (anti-TNF) agents (adalimumab, etanercept, golimumab and infliximab) in treating the signs and symptoms of PsA as well as reducing radiographic progression. Registry data show no new safety concerns, although the numbers studied to date are relatively small. Conclusions This SLR reveals some evidence to support the use of NSAIDs and synthetic DMARDs and good evidence for the efficacy of anti-TNF therapy in PsA.

Persistence of mild, early inflammatory arthritis: the importance of disease duration, rheumatoid factor, and the shared epitope.

OBJECTIVE To determine the factors that predict clinical outcome at 6 months for patients with mild, early inflammatory arthritis. METHODS Sixty-three patients with mild, untreated, early arthritis were given a single dose of corticosteroids at presentation. Administration was intramuscular if disease was polyarticular (n = 53) or intraarticular if patients had <5 synovitic joints (n = 10). The primary outcome measure was clinical disease remission or persistence of arthritis at 6 months following injection. RESULTS At 6 months following injection, 49 of the 63 patients (78%) had persistent inflammatory joint disease. The other 14 (22%) had clinical disease remission. Regression analysis showed that only disease duration was significantly associated with persistent arthritis (P < 0.05). The other significant factor (by chi-square test) was the presence of the shared epitope (SE). Of the patients fulfilling the American College of Rheumatology (ACR) criteria at presentation (51% of the total), 53% with disease duration of < or = 12 weeks at presentation had persistent disease 6 months later, compared with 94% of those who presented with disease duration of >12 weeks. CONCLUSION The strongest predictor of persistent disease was a disease duration of >12 weeks. Rheumatoid factor and SE were also predictors to a lesser extent. Patients who both fulfilled the ACR classification criteria for rheumatoid arthritis (RA) and had a short disease duration included some with an excellent prognosis. Therefore, 12 weeks may be a more appropriate disease duration to use for the RA classification criteria. Administering a bolus of corticosteroids may be a useful diagnostic/therapeutic approach.

Histological assessment of the early enthesitis lesion in spondyloarthropathy

Objectives: To describe the histological changes in acute enthesopathy in early spondyloarthropathies (SpA). Methods: Clinically evident acute enthesopathy was confirmed by magnetic resonance imaging and ultrasonography in four cases of plantar fasciitis and one case of patellar tendon enthesitis. Ultrasound guided biopsy of insertional points was carried out with a Jamshedi needle. Control tissue was obtained from two subjects undergoing spinal grafting surgery. Standard histochemistry and immunohistochemistry analysis using the avidin-biotin immunoperoxidase complex method employing markers against CD3, CD8, CD34, and CD68 was used to determine cellular infiltrates at the insertion point. Results: The enthesis architecture was abnormal in the SpA group, with increased vascularity and cellular infiltration compared with normal subjects. The predominant infiltrating cell at the enthesis fibrocartilage was the macrophage, but there was a paucity of lymphocytes at the insertion point. Conclusion: These preliminary findings have implications for a better understanding of the pathology in early SpA.

The development of candidate composite disease activity and responder indices for psoriatic arthritis (GRACE project)

Objective To develop new composite disease activity indices for psoriatic arthritis (PsA). Methods Data from routine clinic visits at multiple centres were collected in a systematic manner. Data included all domains identified as important in randomised controlled trials in PsA. Decisions to change treatment were used as surrogates for high disease activity. New indices were developed by multiple linear regression (psoriatic arthritis disease activity score: PASDAS) and empirically, utilising physician-defined cut-offs for disease activity (arithmetic mean of desirability functions: AMDF). These were compared with existing composite measures: Composite Psoriatic arthritis Disease Activity Index (CPDAI), Disease Activity for PSoriatic Arthritis (DAPSA), and Disease Activity Score for rheumatoid arthritis (DAS28). Results 161/503 (32%) subjects had treatment changes. Although all measures performed well, compared with existing indices, PASDAS was better able to discriminate between high and low disease activity (area under receiver operating curves (ROC)) curve with 95% CI: PASDAS 0.773 (0.723, 0.822); AMDF 0.730 (0.680, 0.780); CPDAI 0.719 (0.668, 0.770); DAPSA 0.710 (0.654, 0.766); DAS28 0.736 (0.680, 0.792). All measures were able to discriminate between disease activity states in patients with oligoarthritis, although area under the receiver operating curves (AUC) were generally smaller. In patients with severe skin disease (psoriasis area and severity index >10) both nonparametric and AUC curve statistics were nonsignificant for all measures. Conclusions Two new composite measures to assess disease activity in PsA have been developed. Further testing in other datasets, including comparison with existing measures, is required to validate these instruments.

Enthesitis in spondyloarthropathy.

Inflammation at the insertions of ligaments, tendons, or joint capsules to bone, which is termed enthesitis, is a characteristic feature of spondyloarthropathy. Because of the relative inaccessibility of the enthesis, the inflammatory, microbiologic, and immunologic events at that site have been poorly defined. Recent magnetic resonance imaging studies have drawn attention to the ubiquitous nature of enthesitis in spondyloarthropathies, especially adjacent to synovial joints. This may have implications for the mechanisms of synovitis in spondyloarthropathies. Magnetic resonance imaging studies also suggest that enthesitis lesions may be extensive, which could explain the diffuse nature of bone changes seen in some patients with spondyloarthropathies. The importance of enthesitis as a skeletal phenomenon in spondyloarthropathies has gained further support from transgenic models in which either tumor necrosis factor-alpha or bone morphogenetic protein-6 overexpression result in entheseal-associated polyarthropathy.