To update and integrate the recommendations for ankylosing spondylitis and the recommendations for the use of tumour necrosis factor inhibitors (TNFi) in axial spondyloarthritis (axSpA) into one set applicable to the full spectrum of patients with axSpA. Following the latest version of the European League Against Rheumatism (EULAR) Standardised Operating Procedures, two systematic literature reviews first collected the evidence regarding all treatment options (pharmacological and non-pharmacological) that were published since 2009. After a discussion of the results in the steering group and presentation to the task force, overarching principles and recommendations were formulated, and consensus was obtained by informal voting. A total of 5 overarching principles and 13 recommendations were agreed on. The first three recommendations deal with personalised medicine including treatment target and monitoring. Recommendation 4 covers non-pharmacological management. Recommendation 5 describes the central role of non-steroidal anti-inflammatory drugs (NSAIDs) as first-choice drug treatment. Recommendations 6-8 define the rather modest role of analgesics, and disprove glucocorticoids and conventional synthetic disease-modifying antirheumatic drugs (DMARDs) for axSpA patents with predominant axial involvement. Recommendation 9 refers to biological DMARDs (bDMARDs) including TNFi and IL-17 inhibitors (IL-17i) for patients with high disease activity despite the use (or intolerance/contraindication) of at least two NSAIDs. In addition, they should either have an elevated C reactive protein and/or definite inflammation on MRI and/or radiographic evidence of sacroiliitis. Current practice is to start with a TNFi. Switching to another TNFi or an IL-17i is recommended in case TNFi fails (recommendation 10). Tapering, but not stopping a bDMARD, can be considered in patients in sustained remission (recommendation 11). The final two recommendations (12, 13) deal with surgery and spinal fractures. The 2016 Assessment of SpondyloArthritis international Society-EULAR recommendations provide up-to-date guidance on the management of patients with axSpA

Objective. To investigate mechanisms involved in inflammation and new bone formation in the sacroiliac (SI) joints of patients with ankylosing spondylitis (AS).Patients and methods. Computed tomographyassisted biopsy of the SI joint was performed in 5 patients with AS with a mean disease duration of 4.5 years and radiographic stage 2-3 disease. Immunohistologic studies were performed with the alkaline phosphatase-anti-alkaline phosphatase technique, and cytokine messenger RNA (mRNA) was detected by in si tu hybridization.Results. Dense cellular infiltrates with varying amounts of CD3+ cells (mean f SD 53.3 f 24.1%), CD4+ cells (29.7 f 17.6%), CDS+ cells (15.8 f 11.4%), CD14+ cells (23.6 f 16.9%), CD45RO+ cells (48.4 f 23.6%), and CD45RA+ cells (4.5 f 2.9%) were found in the synovial portion of the SI joints of all 5 patients. In these infiltrates a high amount of tumor necrosis factor a (TNFa) mRNA and, near the site of new bone formation, a lower amount of transforming growth factor / 3 (TGFP) mRNA, were detected, while no message for interleukin-1 was found in the 3 patients examined by this technique.Conclusion.

A major immunoregulatory mechanism in inflammatory infections and allergic dies Is the control of the balance of cytokines secreted by Thl/Th2 subsets of T helper (Th) cells. This might also be true in autoimmune diseas; a Th2 pattern that prevents an effective immune response in infections with intracellular bacteria may favor immunosuppression in autoimmune disease. The pattern of cytokine expression was compared in the synovial tissue from patients with a typical autoimmune disease, rheumatoid arthritis, and with a disorder with similar synovial pathology but driven by persisting exogenous antigen, reactive arthritis. We screened 12 rheumatoid and 9 reactive arthritis synovial tissues by PCR and in situ hybridization for their expression of T-cell cytokines. The cytokine pattern differs significantly between the two diseases; rheumatoid arthritis samples express a Thllike pattern whereas in reactive arthritis interferon y expression is accompanied by that of interleukin 4. Studying the expression of cytokines by in situ hybridization confimed the results found by PCR; they also show an extremely low frequency of cytokine-transcribing cells. In a double-staining experiment, it was demonstrated that interleukin 4 is made by CD4 cells. These experiments favor the possibility of therapeutic intervention in inflammatory rheumatic diseases by means of inhibitory cytokines.The control of the balance of cytokines secreted by differing T-cell subsets is emerging as a major immunoregulatory mechanism (1, 2). The division ofT helper (Th) cells into Thl [secreting interferon y (IFN-y) and interleukin (IL) 2] and Th2 (secreting IL-4 and IL-5) found in the mouse (3) holds good for humans (2), provided that attention is focused on IL-4 (4). Cytokines of the Thl spectrum are generally elevated in successful responses to a variety of intracellular pathogens (5), and Th2 cytokines are elevated in allergic diseases and in helminth infections (6, 7). The balance appears to be maintained not only by the cytokines considered originally to be of Thl/Th2 type but also by other inhibitory cytokines such as transforming growth factor (3 and I1-10, which are not confined to one ofthe original subsets and can additionally be secreted by non-T cells (8,9). In this context the pattern of T-cell cytokines in reactive and rheumatoid arthritis is of particular interest. Not only is rheumatoid arthritis among the commonest of the candidate autoimmune diseases, it also offers easy access to the site of inflammation. Reactive and rheumatoid arthritis are sister diseases, in the sense that both are characterized by inflammation of joints and the development of similar synovial pathology. Reactive arthritis is triggered by intracellular bacteria that persist in the joint (10,11), whereas for rheumatoid arthritis, the triggering events are unknown but thought not to involve persistent infection. Comparison ofthe two diseases should be informative.The importance of T cells in initiating and maintaining inflammation in the rheumatic diseases...

The basic helix-loop-helix transcriptional repressor twist1, as an antagonist of nuclear factor κB (NF-κB)–dependent cytokine expression, is involved in the regulation of inflammation-induced immunopathology. We show that twist1 is expressed by activated T helper (Th) 1 effector memory (EM) cells. Induction of twist1 in Th cells depended on NF-κB, nuclear factor of activated T cells (NFAT), and interleukin (IL)-12 signaling via signal transducer and activator of transcription (STAT) 4. Expression of twist1 was transient after T cell receptor engagement, and increased upon repeated stimulation of Th1 cells. Imprinting for enhanced twist1 expression was characteristic of repeatedly restimulated EM Th cells, and thus of the pathogenic memory Th cells characteristic of chronic inflammation. Th lymphocytes from the inflamed joint or gut tissue of patients with rheumatic diseases, Crohn's disease or ulcerative colitis expressed high levels of twist1. Expression of twist1 in Th1 lymphocytes limited the expression of the cytokines interferon-γ, IL-2, and tumor necrosis factor-α, and ameliorated Th1-mediated immunopathology in delayed-type hypersensitivity and antigen-induced arthritis.

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These finding suggest an association between bacterial infection and inflammatory arthritides in some patients. Further research is required to determine the role of these organisms in the pathogenesis and whether such patients might respond to prolonged antibiotic therapy.

Ankylosing spondylitis (AS) is the prototype of the spondyloarthritides (SpA). AS is a disease subset but also a possible outcome of SpA. Early diagnosis of sacroiliitis, the most frequent clinical symptom frequently accompanied by inflammatory back pain and other inflammatory lesions of the spine such as spondylitis and spondylodiscitis, can be visualized early by magnetic resonance imaging (MRI). Spinal inflammation can be demonstrated by MRI using either the fat-saturating short tau inversion recovery (STIR) technique or by application of the contrast agent gadolinium-diethylenetriamine pentaacetic acid (DTPA). This is especially useful in early and active disease, in young women and in children, and for the differential diagnosis of septic sacroiliitis. Because of the efficacy of the novel biological agents directed against tumour necrosis factor-alpha (TNF-alpha) - such as infliximab and etanercept - in SpA there is a need for spinal imaging techniques more sensitive than conventional X-rays. The available scoring tools are reviewed and novel approaches using MRI are presented.