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1.
Semin Arthritis Rheum ; 51(6): 1342-1349, 2021 12.
Article En | MEDLINE | ID: mdl-34489113

BACKGROUND: The current core outcome set for ankylosing spondylitis (AS) has had only minor adaptations since its development 20 years ago. Considering the significant advances in this field during the preceding decades, an update of this core set is necessary. OBJECTIVE: To update the ASAS-OMERACT core outcome set for AS into the ASAS-OMERACT core outcome set for axial spondyloarthritis (axSpA). METHODS: Following OMERACT and COMET guidelines, an international working group representing key stakeholders (patients, rheumatologists, health professionals, pharmaceutical industry and drug regulatory agency representatives) defined the core domain set for axSpA. The development process consisted of: i) Identifying candidate domains using a systematic literature review and qualitative studies; ii) Selection of the most relevant domains for different stakeholders through a 3-round Delphi survey involving axSpA patients and axSpA experts; iii) Consensus and voting by ASAS; iv) Endorsement by OMERACT. Two scenarios are considered based on the type of therapy investigated in the trial: symptom modifying therapies and disease modifying therapies. RESULTS: The updated core outcome set for axSpA includes 7 mandatory domains for all trials (disease activity, pain, morning stiffness, fatigue, physical function, overall functioning and health, and adverse events including death). There are 3 additional domains (extra-musculoskeletal manifestations, peripheral manifestations and structural damage) that are mandatory for disease modifying therapies and important but optional for symptom modifying therapies. Finally, 3 other domains (spinal mobility, sleep, and work and employment) are defined as important but optional domains for all trials. CONCLUSION: The ASAS-OMERACT core domain set for AS has been updated into the ASAS-OMERACT core domain set for axSpA. The next step is the selection of instruments for each domain.


Axial Spondyloarthritis , Spondylarthritis , Spondylitis, Ankylosing , Consensus , Humans , Outcome Assessment, Health Care , Rheumatologists , Spondylarthritis/diagnosis , Spondylarthritis/drug therapy , Spondylitis, Ankylosing/drug therapy
2.
Semin Arthritis Rheum ; 51(5): 1089-1098, 2021 10.
Article En | MEDLINE | ID: mdl-34311986

Magnetic resonance imaging (MRI) is an increasingly important tool for identifying involvement of the sacroiliac joints (SIJ) in juvenile idiopathic arthritis (JIA). The key feature for diagnosing active sacroiliitis is bone marrow edema (BME), but other features of active arthritis such as joint space inflammation, inflammation in an erosion cavity, capsulitis and enthesitis can be seen as well. Structural changes may also be seen. Systematic MRI assessment of inflammation and structural damage may aid in monitoring the disease course, choice of therapeutics and evaluating treatment response. In this pictorial essay, we illustrate normal MRI findings and growth-related changes of the SIJ in the pediatric population, as well as the different MRI features of SIJ inflammation. This atlas demonstrates fundamental MRI disease features of active inflammation in a format that can serve as a reference for assessing SIJ arthritis according to the updated preliminary JAMRIS (Juvenile Idiopathic Arthritis MRI Score) scoring system proposed by the MRI in JIA working group of Outcome Measures in Rheumatology and Clinical Trials (OMERACT). The atlas is intended to be read in conjunction with its companion Part 2, Structural Lesions.


Arthritis, Juvenile , Rheumatology , Sacroiliitis , Arthritis, Juvenile/diagnostic imaging , Child , Humans , Magnetic Resonance Imaging , Outcome Assessment, Health Care , Sacroiliac Joint/diagnostic imaging , Sacroiliitis/diagnostic imaging
3.
Semin Arthritis Rheum ; 51(5): 1099-1107, 2021 10.
Article En | MEDLINE | ID: mdl-34311987

Magnetic resonance imaging (MRI) is the imaging modality of choice for identifying sacroiliitis in juvenile idiopathic arthritis (JIA). Besides active lesions of sacroiliitis, of which bone marrow edema (BME) is the key feature, structural damage lesions can also be detected. Structural changes include erosion, sclerosis, fat lesion, backfill and ankylosis, and are more common at later stages. Systematic MRI assessment of inflammation and structural damage may aid in monitoring the course of the disease and evaluating treatment options. In this pictorial essay, we illustrate normal MRI findings and growth-related changes of the SIJ in the pediatric population, as well as the different MRI features of structural damage of sacroiliitis. This atlas can serve as a reference for assessing structural lesions of SIJ arthritis according to the updated preliminary JAMRIS (Juvenile Idiopathic Arthritis MRI Score) scoring system proposed by the MRI in JIA working group of Outcome Measures in Rheumatology and Clinical Trials (OMERACT). The atlas is intended to be read in conjunction with its companion Part 1, Active Lesions.


Arthritis, Juvenile , Rheumatology , Sacroiliitis , Arthritis, Juvenile/complications , Arthritis, Juvenile/diagnostic imaging , Child , Humans , Magnetic Resonance Imaging , Outcome Assessment, Health Care , Sacroiliac Joint/diagnostic imaging , Sacroiliitis/diagnostic imaging
4.
Sci Rep ; 10(1): 3733, 2020 02 28.
Article En | MEDLINE | ID: mdl-32111860

Childbearing women with rheumatoid (RA) and psoriatic arthritis (PsA) have significant peripartum issues. A retrospective anonymous RedCAP survey of peripartum period in females with RA/PsA in the RAPPORT registry was performed. Completed analyses included descriptive statistics, Chi-square and Fisher's exact test. 162 patients (133 RA/29 PsA) completed the survey (103 women having 234 pregnancies), 164 pregnancies occurring before and 70 pregnancies occurring after diagnosis. Pregnancy outcomes from 103 patients included: 96% live births, 1.9% stillbirths, 23% miscarriages, and 15% therapeutic abortions. A third of patients had fewer children than desired due to disease activity, medications and other reasons. For 63 pregnancies after diagnosis: (1) 49% of pregnancies received pre-conception counseling; (2) 65% described good disease control during pregnancy but 74% flared in the first 3 months postpartum; (3) 79% of pregnancies discontinued IA medications; (4) 35% of pregnancies occurred on biologic therapy at or prior to conception. Gestational age at time of delivery was 37-40 weeks in 58% (33/57) post-arthritis vs 66% (83/126) pre-arthritis pregnancies. No statistically significant differences occurred between pregnancies before or after RA/PsA diagnosis for: pregnancy planning, fertility treatment, pregnancy and labour/delivery complications, birth defect frequency or neonatal complications. Neonatal ICU admissions were significantly lower in pre- compared to post-arthritis pregnancies (3.2% vs 14.5%). No pregnancy complications were noted in 24/54 pregnancies on medications compared to 6/9 pregnancies not on medications. The impact of RA/PsA before, during and after pregnancy varied considerably in this cohort emphasizing the importance of informed-decision making at all stages.


Arthritis, Psoriatic/epidemiology , Arthritis, Rheumatoid/epidemiology , Pregnancy Complications/epidemiology , Adolescent , Adult , Arthritis, Psoriatic/diagnosis , Arthritis, Psoriatic/immunology , Arthritis, Psoriatic/physiopathology , Arthritis, Rheumatoid/diagnosis , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/physiopathology , Canada , Female , Humans , Middle Aged , Peripartum Period/immunology , Pregnancy , Pregnancy Complications/diagnosis , Pregnancy Complications/immunology , Pregnancy Complications/physiopathology , Pregnancy Outcome , Prospective Studies , Registries/statistics & numerical data , Retrospective Studies , Young Adult
6.
Scand J Rheumatol ; 48(2): 121-127, 2019 Mar.
Article En | MEDLINE | ID: mdl-30112959

OBJECTIVE: To assess the risk of hospitalized infection among initiators of disease-modifying anti-rheumatic drugs (DMARDs) and/or anti-tumour necrosis factor (anti-TNF) agents in ankylosing spondylitis (AS). METHOD: We studied AS patients, new users of anti-TNF drugs and/or DMARDs between 1 January 2001 and 31 December 2011. Cohort entry was defined as the date of first prescription of any of these drugs. We used Cox regression with three time-varying drug exposures: current use of DMARDs without biologics, current use of anti-TNF agents alone or in combination with DMARDs (anti-TNF ± DMARDs), and current non-use. Models were adjusted for baseline patient sociodemographic characteristics, comorbidity, outpatient visits and procedures, previous infection, non-steroidal anti-inflammatory drugs, and corticosteroids. Hospitalized infection was defined on the basis of hospitalization discharge diagnoses (primary or non-primary) coding for infection. RESULTS: The cohort included 747 AS patients, with a mean age of 51.1 years (sd 14.6), and 466 (62.4%) were men. During the median follow-up of 1.98 years, 57 hospitalized infections occurred, for an incidence rate of 2.9/100 person-years. The adjusted hazard ratio of infection (relative to unexposed) was 1.00 [95% confidence interval (CI) 0.47-2.11] for the anti-TNF ± DMARDs group and 0.96 (95% CI 0.45-2.04) for DMARDs alone. Use of healthcare, corticosteroids, and previous hospitalized infections were associated with infection. CONCLUSION: We found no clear evidence that the risk of hospitalized infection was linked to DMARD and/or anti-TNF drug use. Because of scarce published literature on infection risk in AS patients, our results have important implications for clinicians.


Antirheumatic Agents/adverse effects , Infections/chemically induced , Spondylitis, Ankylosing/drug therapy , Cohort Studies , Female , Hospitalization , Humans , Male , Middle Aged , Tumor Necrosis Factor-alpha/antagonists & inhibitors
7.
RMD Open ; 3(1): e000399, 2017.
Article En | MEDLINE | ID: mdl-28469937

OBJECTIVE: We tested the hypothesis that fat metaplasia on MRI of the sacroiliac joints (SIJ) increases the propensity for new bone formation in the spine of patients with spondyloarthritis. METHODS: We assessed baseline T1-weighted and short τ inversion recovery SIJ MRIs from patients in the Follow Up Research Cohort in Ankylosing Spondylitis (FORCAST). Radiographic progression was assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Structural and inflammatory lesions were scored using the Spondyloarthritis Research Consortium of Canada (SPARCC) SIJ structural and SPARCC SIJ inflammation scores, respectively. Radiographic progression was compared in cases with and without definite MRI lesions (score ≥2 or <2) and the extent of MRI lesions at baseline was compared in patients with and without radiographic progression. The predictive capacity of MRI SIJ lesions for radiographic progression in the spine was assessed in univariate and multivariate regression analyses. RESULTS: The extent of MRI structural lesions in the SIJ at baseline was significantly greater in those patients who had spinal radiographic progression on follow-up (p=0.003, 0.02, 0.003 for fat metaplasia, backfill and ankylosis, respectively). Also, radiographic progression was significantly greater in cases with definite baseline SIJ ankylosis (p=0.008). In multivariate regression that included all types of MRI lesions and was adjusted for age, sex, symptom duration, duration of follow-up, CRP, baseline mSASSS and treatment, the extent of SIJ fat metaplasia and ankylosis at baseline were independently associated with radiographic progression. CONCLUSIONS: SIJ ankylosis and fat metaplasia but not inflammatory lesions increase the propensity for radiographic progression in the spine.

8.
RMD Open ; 2(2): e000311, 2016.
Article En | MEDLINE | ID: mdl-27752358

INTRODUCTION: The Assessments of SpondyloArthritis international society Health Index (ASAS HI) measures functioning and health in patients with spondyloarthritis (SpA) across 17 aspects of health and 9 environmental factors (EF). The objective was to translate and adapt the original English version of the ASAS HI, including the EF Item Set, cross-culturally into 15 languages. METHODS: Translation and cross-cultural adaptation has been carried out following the forward-backward procedure. In the cognitive debriefing, 10 patients/country across a broad spectrum of sociodemographic background, were included. RESULTS: The ASAS HI and the EF Item Set were translated into Arabic, Chinese, Croatian, Dutch, French, German, Greek, Hungarian, Italian, Korean, Portuguese, Russian, Spanish, Thai and Turkish. Some difficulties were experienced with translation of the contextual factors indicating that these concepts may be more culturally-dependent. A total of 215 patients with axial SpA across 23 countries (62.3% men, mean (SD) age 42.4 (13.9) years) participated in the field test. Cognitive debriefing showed that items of the ASAS HI and EF Item Set are clear, relevant and comprehensive. All versions were accepted with minor modifications with respect to item wording and response option. The wording of three items had to be adapted to improve clarity. As a result of cognitive debriefing, a new response option 'not applicable' was added to two items of the ASAS HI to improve appropriateness. DISCUSSION: This study showed that the items of the ASAS HI including the EFs were readily adaptable throughout all countries, indicating that the concepts covered were comprehensive, clear and meaningful in different cultures.

9.
Arthritis rheumatol ; 68(2)Feb. 2016.
Article En | BIGG | ID: biblio-964633

OBJECTIVE: To provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946-2014), PubMed (1966-2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. RESULTS: In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. CONCLUSION: These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.(AU)


Humans , Spondylitis, Ankylosing/drug therapy , Spondylitis, Ankylosing/therapy , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antirheumatic Agents/therapeutic use , Spondylarthritis/drug therapy , Glucocorticoids/therapeutic use , Physical Therapy Modalities , Tumor Necrosis Factor-alpha/therapeutic use , Adalimumab/therapeutic use , Infliximab/therapeutic use , Etanercept/therapeutic use
10.
Arthritis Rheumatol ; 67(10): 2702-12, 2015 Oct.
Article En | MEDLINE | ID: mdl-26139307

OBJECTIVE: Axial spondyloarthritis (SpA) is a chronic inflammatory disease characterized by back pain and stiffness. The objective of this study was to determine whether golimumab is superior to placebo in patients with nonradiographic axial SpA. METHODS: This phase III, double-blind, randomized, placebo-controlled trial was performed to evaluate subcutaneous golimumab (50 mg) versus placebo in patients ages ≥18 years to ≤45 years who had active nonradiographic axial SpA according to the Assessment of SpondyloArthritis international Society (ASAS) criteria for ≤5 years since diagnosis, high disease activity, and an inadequate response to or intolerance of nonsteroidal antiinflammatory drugs. Patients were randomized 1:1 to receive golimumab or placebo subcutaneously every 4 weeks. The primary end point was 20% improvement according to the ASAS criteria (ASAS20) at week 16. Key secondary end points were an ASAS40 response, ASAS partial remission, 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and change in the Spondyloarthritis Research Consortium of Canada (SPARCC) magnetic resonance imaging (MRI) index for sacroiliac (SI) joint inflammation (SPARCC score). RESULTS: Of the 198 patients randomized, 197 were treated (97 received golimumab, and 100 received placebo). The mean age of the patients was 31 years, and 57.1% were male. At baseline, the mean ± SD BASDAI was 6.5 ± 1.5, the mean ± SD ASDAS was 3.5 ± 0.9, and the mean ± SD SPARCC score was 11.3 ± 14.0. The primary end point, an ASAS20 response, was achieved by significantly more patients in the golimumab group compared with the placebo group (71.1% versus 40.0%; P < 0.0001). An ASAS40 response was also achieved by significantly more patients in the golimumab group compared with the placebo group (56.7% versus 23.0%; P < 0.0001). The incidence of adverse events did not differ meaningfully between groups. CONCLUSION: Patients with active nonradiographic axial SpA treated with golimumab had significantly greater improvement in symptoms compared with patients treated with placebo. Golimumab was well tolerated and had a favorable risk/benefit profile.


Antibodies, Monoclonal/therapeutic use , Antirheumatic Agents/therapeutic use , Axis, Cervical Vertebra , Severity of Illness Index , Spondylarthritis/drug therapy , Adult , Antibodies, Monoclonal/administration & dosage , Antirheumatic Agents/administration & dosage , Double-Blind Method , Endpoint Determination , Female , Humans , Injections, Subcutaneous , International Cooperation , Longitudinal Studies , Male , Risk Assessment , Spondylarthritis/diagnosis , Treatment Outcome , Tumor Necrosis Factor-alpha/immunology
11.
Arthritis Rheumatol ; 67(3): 668-77, 2015 Mar.
Article En | MEDLINE | ID: mdl-25470228

OBJECTIVE: Previous reports of the RAPID-axSpA trial (NCT01087762) described the efficacy and safety of certolizumab pegol (CZP) over 24 weeks in patients with axial spondyloarthritis (SpA), including ankylosing spondylitis (AS) and nonradiographic axial SpA. We report efficacy and safety data up to week 96 of the study. METHODS: The RAPID-axSpA trial is double-blind and placebo-controlled to week 24, dose-blind to week 48, and open-label to week 204. Outcome variables included Assessment of SpondyloArthritis international Society criteria for 20% and 40% improvement in disease activity (ASAS20/40), ASAS partial remission responses (analyzed by nonresponder imputation), AS Disease Activity Score (ASDAS), ASDAS inactive disease, ASDAS major improvement, Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), and Bath AS Metrology Index (BASMI) linear score (analyzed by the last observation carried forward method). Safety data were collected for patients treated with ≥1 dose of CZP. RESULTS: Of the 325 patients who were randomized, 218 received CZP from week 0. Of these, 93% completed week 24, 88% completed week 48, and 80% completed week 96. Improvements in ASAS responses were maintained to week 96 (for ASAS20, 67.4%, 72.0%, and 62.8% at weeks 24, 48, and 96, respectively), as well as improvements in ASDAS, BASDAI (mean score 3.3, 3.1, and 3.0 at weeks 24, 48, and 96, respectively), BASFI, and BASMI linear score. Comparable improvements were observed with both dosing regimens (200 mg every 2 weeks or 400 mg every 4 weeks) and in patients with AS and those with nonradiographic axial SpA. In the safety set, adverse events occurred in 279 patients (88.6%) and serious adverse events in 41 (13.0%). No deaths or malignancies were reported. CONCLUSION: Clinical improvements to week 24 in both CZP dosing regimens were sustained to week 96. Similar sustained improvements were observed in AS and nonradiographic axial SpA subpopulations. The safety profile was consistent with previous reports from RAPID-axSpA, with no new safety signals observed with longer exposure.


Antibodies, Monoclonal, Humanized/therapeutic use , Immunoglobulin Fab Fragments/therapeutic use , Immunosuppressive Agents/therapeutic use , Polyethylene Glycols/therapeutic use , Spondylarthritis/drug therapy , Adult , Aged , Antibodies, Monoclonal, Humanized/adverse effects , Certolizumab Pegol , Double-Blind Method , Female , Humans , Immunoglobulin Fab Fragments/adverse effects , Immunosuppressive Agents/adverse effects , Male , Middle Aged , Polyethylene Glycols/adverse effects , Spondylarthritis/physiopathology , Treatment Outcome
12.
Ann Rheum Dis ; 74(7): 1387-93, 2015 Jul.
Article En | MEDLINE | ID: mdl-24651623

OBJECTIVE: To identify genetic associations with severity of radiographic damage in ankylosing spondylitis (AS). METHOD: We studied 1537 AS cases of European descent; all fulfilled the modified New York Criteria. Radiographic severity was assessed from digitised lateral radiographs of the cervical and lumbar spine using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). A two-phase genotyping design was used. In phase 1, 498 single nucleotide polymorphisms (SNPs) were genotyped in 688 cases; these were selected to capture >90% of the common haplotypic variation in the exons, exon-intron boundaries, and 5 kb flanking DNA in the 5' and 3' UTR of 74 genes involved in anabolic or catabolic bone pathways. In phase 2, 15 SNPs exhibiting p<0.05 were genotyped in a further cohort of 830 AS cases; results were analysed both separately and in combination with the discovery phase data. Association was tested by contingency tables after separating the samples into 'mild' and 'severe' groups, defined as the bottom and top 40% by mSASSS, adjusted for gender and disease duration. RESULTS: Experiment-wise association was observed with the SNP rs8092336 (combined OR 0.32, p=1.2×10(-5)), which lies within RANK (receptor activator of NFκB), a gene involved in osteoclastogenesis, and in the interaction between T cells and dendritic cells. Association was also found with the SNP rs1236913 in PTGS1 (prostaglandin-endoperoxide synthase 1, cyclooxygenase 1), giving an OR of 0.53 (p=2.6×10(-3)). There was no observed association between radiographic severity and HLA-B*27. CONCLUSIONS: These findings support roles for bone resorption and prostaglandins pathways in the osteoproliferative changes in AS.


Bone Resorption/genetics , Cervical Vertebrae/diagnostic imaging , Genetic Association Studies , Lumbar Vertebrae/diagnostic imaging , Osteogenesis/genetics , Spondylitis, Ankylosing/diagnostic imaging , Spondylitis, Ankylosing/genetics , Adult , Cyclooxygenase 1/genetics , Exons/genetics , Female , Genotype , Haplotypes/genetics , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Radiography , Receptor Activator of Nuclear Factor-kappa B/genetics , Severity of Illness Index
13.
Ann Rheum Dis ; 74(5): 830-5, 2015 May.
Article En | MEDLINE | ID: mdl-24399232

OBJECTIVES: The burden of disease in patients with ankylosing spondylitis (AS) can be considerable. However, no agreement has been reached among expert members of Assessment of SpondyloArthritis International Society (ASAS) to define severity of AS. Based on the International Classification of Functioning, Disability and Health (ICF), a core set of items for AS has been selected to represent the entire spectrum of possible problems in functioning. Based on this, the objective of this study was to develop a tool to quantify health in AS, the ASAS Health Index. METHODS: First, based on a literature search, experts' and patients' opinion, a large item pool covering the categories of the ICF core set was generated. In several steps this item pool was reduced based on reliability, Rasch analysis and consensus building after two cross-sectional surveys to come up with the best fitting items representing most categories of the ICF core set for AS. RESULTS: After the first survey with 1754 patients, the item pool of 251 items was reduced to 82. After selection by an expert committee, 50 items remained which were tested in a second cross-sectional survey. The results were used to reduce the number of items to a final set of 17 items. This selection showed the best reliability and fit to the Rasch model, no residual correlation, and absence of consistent differential item function and a Person Separation Index of 0.82. CONCLUSIONS: In this long sequential study, 17 items which cover most of the ICF core set were identified that showed the best representation of the health status of patients with AS. The ASAS Health Index is a linear composite measure which differs from other measures in the public domain.


Activities of Daily Living , Adaptation, Psychological , Health Status Indicators , Quality of Life , Spondylitis, Ankylosing/physiopathology , Adult , Aged , Consensus , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Spondylitis, Ankylosing/psychology , Surveys and Questionnaires
14.
Clin Exp Rheumatol ; 32(5 Suppl 85): S-35-9, 2014.
Article En | MEDLINE | ID: mdl-25365087

14-3-3 proteins are a conserved family of 7 isoforms with diverse cellular functions found predominantly intracellularly. The 14-3-3η isoform is expressed extracellularly in the joints of patients with rheumatoid arthritis (RA) and expression in both serum and joint fluid correlates strongly with expression of metalloproteinases. 14-3-3η activates proinflammatory signalling cascades and inflammatory mediators relevant to the pathogenesis of RA. A new ELISA based assay has diagnostic utility for RA with sensitivity of 63.6% and specificity of 92.6% using the optimal cut-off from ROC analysis of 0.19ng/ml. Adding 14-3-3η to anti-cyclic citrullinated peptide antibodies (ACPA) resulted in an identification rate of 72% compared to 59% for ACPA alone. Adding rheumatoid factor (RF) to ACPA increased diagnostic capture from 59% to 72% and this increased further to 78% when 14-3-3η was added. Positive 14-3-3η status is also significantly associated with radiographic progression in early RA at years 1, 3 and 5 indicating prognostic utility. Extracellular 14-3-3η elicits the production of autoantibodies to the native protein, which also possess diagnostic utility. These do not correlate with expression of the protein and have complementary diagnostic utility. The presence of either the protein or its autoantibodies is observed in 90% of patients with early RA. Together with RF and/or ACPA this may result in identification of 95% of patients with early RA.


14-3-3 Proteins/blood , Arthritis, Rheumatoid/diagnosis , 14-3-3 Proteins/immunology , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/immunology , Biomarkers/blood , Enzyme-Linked Immunosorbent Assay , Humans , Peptides, Cyclic/immunology , Predictive Value of Tests , Prognosis , ROC Curve , Rheumatoid Factor/blood , Severity of Illness Index
15.
Osteoarthritis Cartilage ; 22(10): 1639-50, 2014 Oct.
Article En | MEDLINE | ID: mdl-25278073

OBJECTIVE: We sought to develop a comprehensive scoring system for evaluation of pre-clinical models of osteoarthritis (OA) progression, and use this to evaluate two different classes of drugs for management of OA. METHODS: Post-traumatic OA (PTOA) was surgically induced in skeletally mature rats. Rats were randomly divided in three groups receiving either glucosamine (high dose of 192 mg/kg) or celecoxib (clinical dose) or no treatment. Disease progression was monitored utilizing micro-magnetic resonance imaging (MRI), micro-computed tomography (CT) and histology. Pertinent features such as osteophytes, subchondral sclerosis, joint effusion, bone marrow lesion (BML), cysts, loose bodies and cartilage abnormalities were included in designing a sensitive multi-modality based scoring system, termed the rat arthritis knee scoring system (RAKSS). RESULTS: Overall, an inter-observer correlation coefficient (ICC) of greater than 0.750 was achieved for each scored feature. None of the treatments prevented cartilage loss, synovitis, joint effusion, or sclerosis. However, celecoxib significantly reduced osteophyte development compared to placebo. Although signs of inflammation such as synovitis and joint effusion were readily identified at 4 weeks post-operation, we did not detect any BML. CONCLUSION: We report the development of a sensitive and reliable multi-modality scoring system, the RAKSS, for evaluation of OA severity in pre-clinical animal models. Using this scoring system, we found that celecoxib prevented enlargement of osteophytes in this animal model of PTOA, and thus it may be useful in preventing OA progression. However, it did not show any chondroprotective effect using the recommended dose. In contrast, high dose glucosamine had no measurable effects.


Cyclooxygenase 2 Inhibitors/therapeutic use , Disease Models, Animal , Osteoarthritis, Knee/diagnosis , Osteoarthritis, Knee/drug therapy , Pyrazoles/therapeutic use , Sulfonamides/therapeutic use , Animals , Anterior Cruciate Ligament/surgery , Bone Cysts/diagnosis , Bone Cysts/drug therapy , Bone Cysts/etiology , Bone Marrow Diseases/diagnosis , Bone Marrow Diseases/drug therapy , Bone Marrow Diseases/etiology , Cartilage, Articular/diagnostic imaging , Cartilage, Articular/pathology , Celecoxib , Disease Progression , Glucosamine/therapeutic use , Knee Injuries , Magnetic Resonance Imaging , Osteoarthritis, Knee/etiology , Osteophyte/diagnosis , Osteophyte/drug therapy , Osteophyte/etiology , Rats , Reproducibility of Results , Severity of Illness Index , Synovitis/diagnosis , Synovitis/drug therapy , Synovitis/etiology , X-Ray Microtomography
16.
Ann Rheum Dis ; 73(1): 39-47, 2014 Jan.
Article En | MEDLINE | ID: mdl-24013647

OBJECTIVES: To evaluate the efficacy and safety of certolizumab pegol (CZP) after 24 weeks in RAPID-axSpA (NCT01087762), an ongoing Phase 3 trial in patients with axial spondyloarthritis (axSpA), including patients with ankylosing spondylitis (AS) and non-radiographic axSpA (nr-axSpA). METHODS: Patients with active axSpA were randomised 1:1:1 to placebo, CZP 200 mg every 2 weeks (Q2W) or CZP 400 mg every 4 weeks (Q4W). In total 325 patients were randomised. Primary endpoint was ASAS20 (Assessment of SpondyloArthritis international Society 20) response at week 12. Secondary outcomes included change from baseline in Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and Bath Ankylosing Spondylitis Metrology Index (BASMI) linear. RESULTS: Baseline disease activity was similar between AS and nr-axSpA. At week 12, ASAS20 response rates were significantly higher in CZP 200 mg Q2W and CZP 400 mg Q4W arms versus placebo (57.7 and 63.6 vs 38.3, p≤0.004). At week 24, combined CZP arms showed significant (p<0.001) differences in change from baseline versus placebo in BASFI (-2.28 vs -0.40), BASDAI (-3.05 vs -1.05), and BASMI (-0.52 vs -0.07). Improvements were observed as early as week 1. Similar improvements were reported with CZP versus placebo in both AS and nr-axSpA subpopulations. Adverse events were reported in 70.4% vs 62.6%, and serious adverse events in 4.7% vs 4.7% of All CZP versus placebo groups. No deaths or malignancies were reported. CONCLUSIONS: CZP rapidly reduced the signs and symptoms of axSpA, with no new safety signals observed compared to the safety profile of CZP in RA. Similar improvements were observed across CZP dosing regimens, and in AS and nr-axSpA patients.


Antibodies, Monoclonal, Humanized/administration & dosage , Immunoglobulin Fab Fragments/administration & dosage , Immunosuppressive Agents/administration & dosage , Polyethylene Glycols/administration & dosage , Spondylarthritis/drug therapy , Spondylitis, Ankylosing/drug therapy , Adult , Antibodies, Monoclonal, Humanized/adverse effects , Certolizumab Pegol , Double-Blind Method , Female , Humans , Immunoglobulin Fab Fragments/adverse effects , Immunosuppressive Agents/adverse effects , Male , Middle Aged , Placebos , Polyethylene Glycols/adverse effects , Spondylarthritis/diagnosis , Spondylitis, Ankylosing/diagnosis , Treatment Outcome
17.
Clin Radiol ; 68(8): 785-91, 2013 Aug.
Article En | MEDLINE | ID: mdl-23561226

AIM: To analyse the imaging findings at the sterno-costo-clavicular (SCC) joint region using whole-body (WB) magnetic resonance imaging (MRI) in healthy individuals to minimize misinterpretation as changes due to spondyloarthritis (SpA). MATERIALS AND METHODS: As part of a cross-sectional study of 122 SpA patients, 75 healthy individuals (42/33 males/females; median age 30.3 years; range 17.7-63.8 years) were scanned using sagittal and coronal WB short tau inversion recovery (STIR) and T1-weighted MRI sequences. The SCC region was analysed independently by seven readers for bone marrow oedema (BMO), erosions, subchondral fat signal intensity (FSI), and joint fluid accumulation. RESULTS: SCC changes simulating inflammation were reported by four or more of the seven readers in 15 (20%) healthy individuals (12 male/three female; median age 32.1 years; range 20.2-48 years). Thirteen individuals (17%) had changes at the manubriosternal joint (MSJ); five had BMO, one BMO + erosion, four erosion, two erosion + FSI, and one FSI only. Changes at the sternoclavicular joint occurred in three individuals (4%) encompassing erosion, erosion + FSI + BMO, and joint fluid accumulation, respectively. One patient had both MSJ and sternoclavicular joint changes. CONCLUSIONS: Findings mimicking inflammatory changes occurred in healthy individuals, particularly in the MSJ. Awareness of this is important in recognition of SCC inflammation in SpA.


Magnetic Resonance Imaging/methods , Spondylarthritis/diagnosis , Sternoclavicular Joint/pathology , Whole Body Imaging , Adolescent , Adult , Asymptomatic Diseases , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Sensitivity and Specificity , Sternoclavicular Joint/anatomy & histology
18.
Clin Biochem ; 46(15): 1601-6, 2013 Oct.
Article En | MEDLINE | ID: mdl-23623829

OBJECTIVE: Cathepsin K plays essential roles in bone resorption and is intensely investigated as a therapeutic target for the treatment of osteoporosis. Hence an assessment of the active form of cathepsin K may provide important biological information in metabolic bone diseases, such as osteoporosis or ankylosing spondylitis. METHODS: Presently there are no robust assays for the assessment of active cathepsin K in serum, and therefore an ELISA specifically detecting the N-terminal of the active form of cathepsin K was developed. RESULTS: The assay was technically robust, with a lowest limit of detection (LOD) of 0.085 ng/mL. The average intra- and inter-assay CV% were 6.60% and 8.56% respectively. The dilution recovery and spike recovery tests in human serum were within 100±20% within the range of the assay. A comparison of latent and active cathepsin K confirmed specificity towards the active form. Quantification of the levels of active cathepsin K in supernatants of purified human osteoclasts compared to corresponding macrophages showed a 30-fold induction (p<0.001). In contrast, in serum samples from osteoporotic women on estrogen or bisphosphonate therapy and from ankylosing spondylitis patients no clinically relevant differences were observed. CONCLUSION: In summary, we have developed a robust and sensitive assay specifically detecting the active form of cathepsin K; however, while it monitors osteoclasts with high specificity in vitro, it appears that circulating levels of active cathepsin K do not reflect bone changes under these circumstances.


Cathepsin K/blood , Enzyme-Linked Immunosorbent Assay/methods , Osteoclasts/enzymology , Osteoporosis/blood , Spondylitis, Ankylosing/blood , Animals , Antibodies, Monoclonal/chemistry , Bone Density Conservation Agents/therapeutic use , Bone and Bones/enzymology , Bone and Bones/pathology , Diphosphonates/therapeutic use , Enzyme Activation , Female , Humans , Macrophages/cytology , Macrophages/enzymology , Mice , Middle Aged , Osteoclasts/cytology , Osteoporosis/drug therapy , Osteoporosis/enzymology , Osteoporosis/pathology , Sensitivity and Specificity , Spondylitis, Ankylosing/enzymology , Spondylitis, Ankylosing/pathology
19.
Rheum Dis Clin North Am ; 38(3): 613-33, 2012 Aug.
Article En | MEDLINE | ID: mdl-23083759

Tumor necrosis factor α inhibitors (TNF blockers) have revolutionized the treatment of patients with anklyosing spondylitis. Despite clinical efficacy, there are questions and controversies treating rheumatologists face, which this review discusses: whether there are specific indications for specific TNF blockers; whether the dose of TNF blockers can be decreased; whether immunogenicity plays a role; what the role of residual active inflammation MRI might be; and whether there is a window of opportunity to treat patients with anklyosing spondylitis and prevent radiographic progression. This article summarizes evidence for switching between TNF blockers and addresses the question of malignancies.


Antibodies, Monoclonal/therapeutic use , Antirheumatic Agents/therapeutic use , Spondylitis, Ankylosing/drug therapy , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Dose-Response Relationship, Drug , Drug Substitution , Humans , Inflammation/drug therapy , Inflammation/immunology , Inflammation/pathology , Joints/pathology , Magnetic Resonance Imaging , Severity of Illness Index , Spondylitis, Ankylosing/immunology , Spondylitis, Ankylosing/pathology , Time Factors , Treatment Outcome
20.
Osteoarthritis Cartilage ; 20(7): 694-702, 2012 Jul.
Article En | MEDLINE | ID: mdl-22498029

OBJECTIVE: To employ elemental Strontium as a tracer of bone turnover, in the presence (or absence) of the bisphosphonate drug Alendronate, in order to spatially map osteophytogenesis and other bone turnover in rats developing post-traumatic secondary osteoarthritis (PTOA). METHODS: PTOA was induced in rats by medial meniscectomy surgery. We utilized in-vivo microfocal computed tomography (CT) to follow bony adaptations in groups for 8 weeks after surgery, either with or without alendronate treatment. Electron probe microanalysis (EPMA) was used to detect Strontium incorporation in mineralizing tissues. Histologic studies were conducted on the same samples using Safranin-O/fast green and Tetrachrome staining of decalcified sections to examine articular cartilage health and osteophyte formation at the sites of elemental Strontium deposition. RESULTS: EPMA revealed uniform incorporation of Strontium over actively remodeling trabecular surfaces in normal control rats. That pattern was significantly altered after meniscectomy surgery resulting in greater Strontium signal at the developing osteophyte margins. Alendronate treatment inhibited osteophyte development by 40% and 51% quantified by micro-CT volumetric measurements at 4 and 8 weeks after surgery, respectively. Osteophytes in the alendronate group were more cartilaginous in composition [i.e., lower bone mineral density (BMD)] compared to the untreated group. Histological analysis confirmed the osteophyte inhibitory effect of alendronate, and also verified reduced degeneration of the articular cartilage compared to untreated rats. CONCLUSION: Our study confirmed that alendronate administration will reduce osteophyte formation in a rat model of post-traumatic osteoarthritis, partially through the inhibition of secondary remodeling of osteophytes. Our study is the first to employ elemental Strontium as a tracer of bone turnover in the pathogenesis of osteoarthritis and to assess the efficacy of bisphosphonate antiresorptive drug interventions on osteophytogenesis.


Alendronate/therapeutic use , Arthritis, Experimental/prevention & control , Bone Density Conservation Agents/therapeutic use , Osteoarthritis/prevention & control , Osteophyte/prevention & control , Animals , Arthritis, Experimental/diagnostic imaging , Arthritis, Experimental/etiology , Drug Evaluation, Preclinical/methods , Electron Probe Microanalysis/methods , Female , Organometallic Compounds , Osteoarthritis/diagnostic imaging , Osteoarthritis/etiology , Osteogenesis/drug effects , Osteophyte/diagnostic imaging , Osteophyte/etiology , Rats , Rats, Sprague-Dawley , Thiophenes , Tibial Meniscus Injuries , X-Ray Microtomography/methods
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