NMR-Based Serum Metabolomics Revealed Distinctive Metabolic Patterns in Reactive Arthritis Compared with Rheumatoid Arthritis.

Reactive arthritis (ReA) is a member of seronegative spondyloarthropathy (SSA), which involves an acute/subacute onset of asymmetrical lower limb joint inflammation weeks after a genitourinary/gastrointestinal infection. The diagnosis is clinical because it is difficult to culture the microbes from synovial fluid. Arthritis patients with a similar clinical picture but lapsed history of an immediate preceding infection that do not fulfill the diagnostic criteria of other members of SSA, such as ankylosing spondylitis, psoriatic arthritis, and arthritis associated with inflammatory bowel disease, are labeled as peripheral undifferentiated spondyloarthropathy (uSpA). Both ReA and uSpA patients show a strong association with class I major histocompatibility complex allele, HLA-B27, and a clear association with an infectious trigger; however, the disease mechanism is far from clear. Because the clinical picture is largely dominated by rheumatoid-arthritis (RA)-like features including elevated levels of inflammatory markers (such as ESR, CRP, etc.), these overlapping symptoms often confound the clinical diagnosis and represent a clinical dilemma, making treatment choice more generalized. Therefore, there is a compelling need to identify biomarkers that can support the diagnosis of ReA/uSpA. In the present study, we performed NMR-based serum metabolomics analysis and demonstrated that ReA/uSpA patients are clearly distinguishable from controls and further that these patients can also be distinguished from the RA patients based on the metabolic profiles, with high sensitivity and specificity. The discriminatory metabolites were further subjected to area under receiver operating characteristic curve analysis, which led to the identification of four metabolic entities (i.e., valine, leucine, arginine/lysine, and phenylalanine) that could differentiate ReA/uSpA from RA.

The performance of classification criteria for juvenile spondyloarthropathies.

Juvenile spondyloarthropathies (JSpA) are a group of rheumatologic diseases with a disease onset before 16; characterized with enthesitis, lower extremity oligoarthritis, involvement of the axial skeleton and HLA B27 positivity. The diversity of classification criteria along with the phenotype heterogeneity makes the classification of JSpA challenging. The aim of our study was to evaluate the performance of the pre-determined and recently proposed classification criteria for JSpA. The study group consisted of 113 patients with JSpA and 150 patients with juvenile idiopathic arthritis (JIA). Eligible criteria for JSpA were applied to all of the enrolled patients. The analysis of sensitivity, specificity and the kappa index were used to verify the performance of the JSpA criteria. The Amor criteria showed the highest sensitivity (98.2%) while the ASAS criteria for the axial SpA had highest specificity (100%). The sensitivity and specificity of the remaining criteria were: 93.8 and 63.8% for ESSG, 95.6 and 62.7% for Garmisch-Partenkirchen, 91.2 and 75.3% for ASAS criteria for peripheral SpA, respectively. Criteria proposed by our group showed the high sensitivity, specificity and kappa value: 90.3, 90.7, 0.843%, respectively. We suggest that criteria proposed by us could be used in the classification of JSpA. However, neither the pre-determined nor the new criteria are totally adequate and efficacious for the classification and diagnosis of this disease. The evaluation of the validity and reliability of proposed criteria in multicentric studies are mandatory, to increase its utility in routine clinical practice.

Axial spondyloarthritis classification criteria: the debate continues.

PURPOSE OF REVIEW: The Assessment of Spondyloarthritis International Society (ASAS) axial spondyloarthritis (axSpA) classification criteria marked a major step forward in SpA research, distinguishing axial from peripheral disease, and allowing earlier identification through MRI. This facilitated all aspects of research including epidemiology, therapeutics and patient outcomes. RECENT FINDINGS: The ASAS axSpA classification criteria have been applied broadly in research, and were validated in a recent meta-analysis of international studies. Concerns arose because of clinical differences between the clinical and imaging arms, which imply different risk for radiographic progression, and perform differently in validation studies. Low specificity of the MRI finding of sacroiliac joint bone marrow edema may lead to misclassification in populations with low axSpA prevalence. We suggest methodology to improve upon the criteria, including rigorous assessment of potential candidate criteria sets, discrete choice experiments to allow consideration of feature weights, and validation. Separately, assessment of structural and inflammatory MRI abnormalities should be performed to refine the MRI definition of sacroiliitis. SUMMARY: The debate regarding the validation and modification of the ASAS axSpA classification criteria should lead to international efforts to build upon the gains made by these criteria, to further refine the axSpA population definitions for research and ultimately improve patient outcomes.

Performance of the ASAS classification criteria for axial and peripheral spondyloarthritis: a systematic literature review and meta-analysis.

OBJECTIVE: To summarise the evidence on the performance of the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial spondyloarthritis (axSpA) (also imaging and clinical arm separately), peripheral (p)SpA and the entire set, when tested against the rheumatologist's diagnosis ('reference standard'). METHODS: A systematic literature review was performed to identify eligible studies. Raw data on SpA diagnosis and classification were extracted or, if necessary, obtained from the authors of the selected publications. A meta-analysis was performed to obtain pooled estimates for sensitivity, specificity, positive and negative likelihood ratios, by fitting random effects models. RESULTS: Nine papers fulfilled the inclusion criteria (N=5739 patients). The entire set of the ASAS SpA criteria yielded a high pooled sensitivity (73%) and specificity (88%). Similarly, good results were found for the axSpA criteria (sensitivity: 82%; specificity: 88%). Splitting the axSpA criteria in 'imaging arm only' and 'clinical arm only' resulted in much lower sensitivity (30% and 23% respectively), but very high specificity was retained (97% and 94% respectively). The pSpA criteria were less often tested than the axSpA criteria and showed a similarly high pooled specificity (87%) but lower sensitivity (63%). CONCLUSIONS: Accumulated evidence from studies with more than 5500 patients confirms the good performance of the various ASAS SpA criteria as tested against the rheumatologist's diagnosis.

Imaging in Axial Spondyloarthritis: Evaluation of Inflammatory and Structural Changes.

The primary use of imaging focuses on diagnostic evaluation, and pelvic radiography is still the primary modality for evaluation of disease in the sacroiliac joints. Its unreliability and inability to directly assess inflammation has led to increasing use of MRI, which directly assesses inflammatory changes as well as the structural changes associated with inflammation. Both radiography and MRI have therefore been incorporated into new classification criteria designed to capture both early and established spondyloarthritis. Fat metaplasia on T1-weighted MRI is an important intermediary tissue on the pathway from inflammation to ankylosis in both the sacroiliac joints and spine.

Imaging Scoring Methods in Axial Spondyloarthritis.

Inflammatory and chronic structural changes are objective signs of axial spondyloarthritis. In the sacroiliac joints (SIJs), inflammation (sacroiliitis) can be visualized as bone marrow edema, whereas chronic structural changes are visualized as fat metaplasia, erosions, sclerosis, or ankylosis in the area of the SIJ. In the spine, bone marrow edema in the vertebral bodies represents spondylitis but can also affect the facet and the costovertebral and costotransverse joints (arthritis), whereas structural changes are visualized as fat metaplasia, sclerosis or syndesmophytes and ankylosis at the vertebral edges.

[General concepts and pathogenesis of the spondyloarthropathies]. / Concept général et pathogenèse des spondylarthropathies.

The spondyloarthritides are a group of interrelated diseases with a close association with the HLA-B27 antigen that share many common articular and extra-articular features. This paper summarizes the different classification criteria that are currently in use. While the exact pathogenesis of these diseases is not yet clearly elucidated, there are a number of hypotheses relating to HLA-B27, modifications of the microbiome and biomechanical stresses. This in turn leads to upregulation of various proinflammatory cytokines such as TNF-alpha, IL-17, IL-22 and IL-23, which results in further inflammation and osteoproliferation.

Espondiloartropatía juvenil: una visión desde la pediatría / Juvenile spondyloarthropathy: a view from pediatrics

La espondiloartropatía juvenil (EAPj) representa un grupo de artropatías crónicas que se inician en la infancia y que corresponden a entidades cuyas clasificaciones se han modificado en el transcurso de las décadas. Las clasificaciones actuales las incluyen sólo parcialmente. Las manifestaciones clínicas incluyen compromiso articular periférico asimétrico, entesis, sacroilíaco y menos frecuentemente de columna han permitido agruparlas en cinco categorías entre el que se encuentra la forma anquilosante juvenil relacionada con HLA B27 (+), el prototipo de EAPj y que podría representar a la forma de inicio de espondiloartropatía anquilosante del adulto. Los recientes avances en los estudios genéticos, en la patogenia, el desarrollo de mejores técnicas de imagenología tales como la ecografía musculo-esquelética y resonancia magnética aplicada a la Reumatología pediátrica podrían contribuir a generar criterios de clasificación de manera tal que faciliten la comunicación científica con los Reumatólogos de adultos. Un diagnóstico precoz, la aplicación de medidas de actividad de la enfermedad validadas y el oportuno manejo terapéutico obtendrán un pronóstico más favorable. Los resultados terapéuticos en EAPj presentan evidencia limitada aún requiriéndose mayor tiempo de evolución para obtener resultados a largo plazo.

Juvenile spondyloarthropathy (EAPj) represents a heterogeneous group of juvenile articular inflammatory entities and their classification have been changed during the last decades. The current classifications include only partially. The clinical manifestations of diseases involves peripheral joints, enthesis, sacroiliac and less frequently spine and they are classified in five specific subgroups among which is the juvenile ankylosing HLA B27 (+); the EAPj’s prototype and that may represent one of ankylosing spondyloarthropathy adult diseases. Recently, novel insights into the epidemiology, pathogenesis, and development of the imaging techniques such as muscle-skeletal ultrasound and magnetic resonance applied to pediatric rheumatology could be contributing to new classification criteria in order to facilitate the scientific communication with Rheumatologist of adult patients. An early diagnosis a validated measures of disease activity and treatment can change the course and outcome of disease.

Relationship of Psoriatic Arthritis to Other Spondyloarthritides.

In the early 1970s, Moll and co-workers formulated the unified concept of spondyloarthritides, a group of conditions sharing similar clinical features. Subsequently, criteria for their classification have been proposed by Amor and coworkers, the European Spondylarthropathy Study Group, and the Assessment in SpondyloArthritis international Society. Opinion, however, is divided between those who believe that the different entities of the complex represent the variable expression of the same disease ("lumpers") and those who think that these should be considered separately but under the same umbrella ("splitters"). Several sets of criteria have been proposed for psoriatic arthritis (PsA), the most recent being the ClASsification for Psoriatic Arthritis (CASPAR) criteria. According to some authors, there are persuasive arguments to support the view of PsA as a distinct entity.

Anti-tumor necrosis factor drug survival in axial spondyloarthritis is independent of the classification criteria.

To compare the impact of meeting specific classification criteria [modified New York (mNY), European Spondyloarthropathy Study Group (ESSG), and Assessment of SpondyloArthritis international Society (ASAS) criteria] on anti-tumor necrosis factor (anti-TNF) drug retention, and to determine predictive factors of better drug survival. All patients fulfilling the ESSG criteria for axial spondyloarthritis (SpA) with available data on the axial ASAS and mNY criteria, and who had received at least one anti-TNF treatment were retrospectively retrieved in a single academic institution in Switzerland. Drug retention was computed using survival analysis (Kaplan-Meier), adjusted for potential confounders. Of the 137 patients classified as having axial SpA using the ESSG criteria, 112 also met the ASAS axial SpA criteria, and 77 fulfilled the mNY criteria. Drug retention rates at 12 and 24 months for the first biologic therapy were not significantly different between the diagnostic groups. Only the small ASAS non-classified axial SpA group (25 patients) showed a nonsignificant trend toward shorter drug survival. Elevated CRP level, but not the presence of bone marrow edema on magnetic resonance imaging (MRI) scans, was associated with significantly better drug retention (OR 7.9, ICR 4-14). In this cohort, anti-TNF drug survival was independent of the classification criteria. Elevated CRP level, but not positive MRI, was associated with better drug retention.

Classification criteria: peripheral spondyloarthropathy and psoriatic arthritis.

Recent proposals for re-classification of spondyloarthropathies according to the predominance of peripheral and axial manifestations and for non-radiographic ankylosing spondylitis to be re-named axial spondyloarthritis are reviewed. It is argued that such proposals are less likely to advance knowledge in the study of spondyloarthopathies and that accurate classification criteria for defined diseases, for example psoriatic arthritis, remain as necessary now as they ever did. The CASPAR criteria remain the best performing classification criteria for psoriatic arthritis.

[Spondyloarthritis - the novel concept. An introduction to the diagnosis and treatment of axial spondyloarthritis]. / Spondyloarthritiden - das neue Konzept. Eine Einführung zu Diagnostik und Therapie der axialen Spondyloarthritis.

The characteristic features of spondyloarthritis are inflammation in the axial skeleton (sacroiliitis, spondylitis) and inflammation in peripheral joints (arthritis) and entheses (enthesitis). According to the leading clinical symptom SpA is today differentiated in the either predominant axial or the peripheral form. The axial SpA are further subdivided in ankylosing spondylitis and non-radiographic axial SpA. This subset is characterized by the absence of structural changes on conventional x-rays. In this review we describe the clinical symptoms, the diagnosis and therapy of patients with axial SpA.

[Degenerative diseases of the spine]. / Degenerative Erkrankungen der Wirbelsäule.

Degenerative alterations of the spine are among the most common causes of complaints of the musculoskeletal system. Imaging procedures are an established component of diagnostics and differential diagnoses. A reduction in height of the intervertebral space and sclerotization of the basal and covering plates are part of the first radiological alterations and in the further course can be accompanied by formation of spondylophytes, arthrosis of the intervertebral joints and degenerative vertebral surface gliding. However, early changes of the mobile segments can often not be visualized in x-ray images. Computed tomography (CT) and magnetic resonance imaging (MRI) substantially improve the diagnostic options. Using MRI the spinal column and the surrounding soft tissues can be visualized in 3-D and a differential diagnostic differentiation between inflammatory, traumatized or neoplastic processes is possible. A lack of correlation between the imaging findings and clinical symptoms remains problematic. A meaningful interpretation of x-ray images and MRI can only be made with the appropriate knowledge of the symptoms and possible diseases.

Enthesitis in seronegative spondyloarthropathies with special attention to the knee joint by MRI: a step forward toward understanding disease pathogenesis.

Seronegative spondyloarthropathies are a unique group of disorders sharing similar clinical characteristics (e.g., inflammatory back pain, spondylitis, sacroiliitis, uveitis, inflammatory bowel disease, skin rashes, and enthesitis). Clinical and genetic similarities suggest that they also share similar causes or pathophysiologies. Rheumatoid factor (RF) is characteristically negative in this group of disorders, hence collectively termed seronegative spondyloarthropathies (SpA). They include psoriatic arthritis, ankylosing spondylitis, reactive arthritis, ulcerative colitis, and Crohn's disease. "Enthesitis", the term used to describe inflammation at tendon, ligament, or joint capsule insertions, is considered a common feature in this domain and was included in the European Spondyloarthropathy Study Group criteria for the classification of SpA. Evaluation of entheseal-related changes at different joints by MRI became an important item on the research agenda in both differentiated and undifferentiated arthritis. Most of the research focused on MRI findings in the hand and wrist joints among patients with RA and SpA and support two patterns of inflammation "RA" phenotype where synovial involvement is the primary target of inflammation and "SpA" pattern where enthesitis comes first followed by synovitis. In this review, we summarize the literature on enthesitis in SpA and focus on MRI findings in the knee joint in the SpA group of disorders and subclinical synovitis among patients with skin psoriasis.

Current evidence of the management of undifferentiated spondyloarthritis: a systematic literature review.

OBJECTIVE: To examine the efficacy of available drugs in undifferentiated spondyloarthritis (u-SpA). METHODS: Systematic review of studies retrieved from Medline (1961-July 2009), Embase (1961-July 2009), and Cochrane Library (up to July 2009). A complementary hand search was also performed. The selection criteria were as follows: (population) u-SpA patients; (intervention) nonsteroidal anti-inflammatory agents, disease-modifying antirheumatic drugs, anti-tumor necrosis factor α, anakinra, abatacept, biphosphonates, or thalidomide; (outcome) pain, function, structural damage and quality of life; (study design) randomized controlled trials (RCT), cohort studies, and case reports; (level of evidence) according to The Oxford Centre for Evidence-based Medicine (update 2009). An additional narrative review was performed to analyze the effects of drug therapies in patients with spondyloarthritis according new Assessment of Spondyloarthritis International Society criteria. RESULTS: The following 7 studies were included: 2 RCT, 1 cohort study, and 4 case reports, which included 117 patients with u-SpA (mostly young men). No evidence related to the effect of nonsteroidal anti-inflammatory agents or disease-modifying antirheumatic drugs on u-SpA patients was found. Infliximab and etanercept showed some benefit regarding clinical outcomes, function, and quality of life. Two RCT reported important benefit of infliximab and adalimumab also in patients with predominantly axial spondyloarthritis. Rifampicin plus doxycycline improved some clinical outcomes but ciprofloxacin had no benefit. Anecdotal positive evidence was reported with pamidronate. No serious adverse events were reported in the retrieved studies. CONCLUSION: Low-quality evidence suggests a benefit of tumor necrosis factor α blockers in u-SpA and good-quality evidence in predominantly axial spondyloarthritis. The use of antibiotics remains controversial. High-quality trials are needed to definitively assess the effect of available drugs in these patients.