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.
Anti-tumor necrosis factor-alpha (TNF-alpha) therapy can induce reactivation of tuberculosis and an increase of other infections in patients with ankylosing spondylitis (AS). This raises the question ...if an alteration of T cell function can be detected by in vitro analysis to identify patients who might be more at risk of acquiring such infectious diseases.
We examined peripheral blood from AS patients without history of tuberculosis before and after 10-14 and 24-36 weeks of therapy with adalimumab (n = 8) or infliximab (n = 10). Fresh peripheral blood mononuclear cells were stimulated with cytomegalovirus antigens and with the Mycobacterium tuberculosis antigen purified protein derivative and early secretory antigen target 6. Interferon-gamma production of CD4+ T cells was assessed after in vitro antigen-specific stimulation by intracellular cytokine staining and flow cytometry.
There was no significant change, either decrease or increase, of the T cell response to recall antigens during therapy compared to controls without treatment, if the mean values of all patients treated with adalimumab or infliximab were compared at the given timepoints. However, analysis on the individual patient level of such T cell responses revealed 1 adalimumab-treated patient and 2 infliximab-treated patients with a clear decrease of T cell response during therapy. Longterm analysis indicated that such a decrease of T cell responsiveness is generally transient and reconstituted at the latest after 52 weeks.
Some patients treated with adalimumab or infliximab showed a decrease of T cell responsiveness, which seems to be transient. These patients in particular might be at risk for intracellular infections.
The basic helix-loop-helix transcriptional repressor twist1, as an antagonist of nuclear factor kappaB (NF-kappaB)-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-kappaB, 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-gamma, IL-2, and tumor necrosis factor-alpha, and ameliorated Th1-mediated immunopathology in delayed-type hypersensitivity and antigen-induced arthritis.
Epigenetic modifications, including DNA methylation, profoundly influence gene expression of CD4(+) Th-specific cells thereby shaping memory Th cell function. We demonstrate here a correlation ...between a lacking fixed potential of human memory Th cells to re-express the immunoregulatory cytokine gene IL10 and its DNA methylation status. Memory Th cells secreting IL-10 or IFN-gamma were directly isolated ex vivo from peripheral blood of healthy volunteers, and the DNA methylation status of IL10 and IFNG was assessed. Limited difference in methylation was found for the IL10 gene locus in IL-10-secreting Th cells, as compared with Th cells not secreting IL-10 isolated directly ex vivo or from in vitro-established human Th1 and Th2 clones. In contrast, in IFN-gamma(+) memory Th cells the promoter of the IFNG gene was hypomethylated, as compared with IFN-gamma-nonsecreting memory Th cells. In accordance with the lack of epigenetic memory, almost 90% of ex vivo-isolated IL-10-secreting Th cells lacked a functional memory for IL-10 re-expression after restimulation. Our data indicate that IL10 does not become epigenetically marked in human memory Th cells unlike effector cytokine genes such as IFNG. The exclusion of IL-10, but not effector cytokines, from the functional memory of human CD4(+) T lymphocytes ex vivo may reflect the need for appropriate regulation of IL-10 secretion, due to its potent immunoregulatory potential.
There is no agreement on how to classify and diagnose reactive arthritis (ReA) and it is also unclear what kind of specific clinical and laboratory investigations are appropriate. We define relevant ...points of agreement and identify points of disagreement among an international group of experts in the field.
Prior to the 4th International Workshop on Reactive Arthritis, Berlin, July 1999, we sent questionnaires to 42 experts identified by personal knowledge and recent publications.
The response rate was 81% (n = 34). There was agreement on the nomenclature and recommendation to use the term "reactive arthritis" only if the clinical picture and the microbes involved are HLA-B27 and spondyloarthropathy (SpA) associated, whereas the term "infection related arthritis" is used for all other arthritides related to or associated with infections. A differentiation between acute and chronic ReA with a cutoff of 6 months is recommended. The history of a preceding symptomatic infection is thought to be most relevant for a diagnosis of ReA. The minimal interval between preceding symptoms and arthritis is proposed to be 1-7 days, maximally 4 weeks. The joint pattern in ReA is asymmetrical, with predominance of the lower limbs. SpA related symptoms may contribute to the diagnosis. A search for chlamydia in urine/urethra/cervix is recommended, while in the case of diarrhea enterobacteria should be searched for in stool and antibodies against them in serum. There were also areas of disagreement, such as: Is arthritis essential for the diagnosis of ReA?, Is it oligoarthritis or any arthritis?, What are the role and value of polymerase chain reaction investigation?, The role and value of serology?, Is the diagnostic sensitivity of microbiological tests for ReA increased by HLA-B27 determination?
The points of agreement will support better communication in this area, and clarification of the disagreements will lead to further studies and discussion.
Magnetic resonance imaging (MRI) of the sacroiliac (SI) joints and the spine is increasingly important in the assessment of inflammatory activity and structural damage in clinical trials with ...patients with ankylosing spondylitis (AS). We investigated inter-reader reliability and sensitivity to change of several scoring systems to assess disease activity and change in disease activity in patients with AS. Twenty sets of consecutive MRI, derived from a randomized clinical trial comparing an active drug with placebo and selected on the basis of the presence of activity at baseline, were presented electronically to 7 experienced readers from different countries (Europe, Canada). Readers scored the MRI by 3 different methods including: a global score (grading activity per SI joint); a more comprehensive global score (grading activity per SI joint per quadrant); and a detailed scoring system Spondyloarthritis Research Consortium of Canada (SPARCC) scoring system, which scores 6 images, divided into quadrants, with additional scores for "depth" and "intensity." A fourth and a fifth scoring system were constructed afterwards. The fourth method included the SPARCC score minus the additional scores for "depth" and "intensity," and the fifth method included the SPARCC slice with the maximum score. Inter-reader reliability was investigated by calculating intraclass correlation coefficients (ICC) for all readers together and for all possible reader pairs. Sensitivity to change was investigated by calculating standardized response means (SRM) on change scores that were made positive. Overall inter-reader ICC per method were between 0.47 and 0.58 for scoring status, and between 0.40 and 0.53 for scoring change. ICC per possible reader pairs showed much more fluctuation per method, with lowest observed values close to zero (no agreement) and highest observed values over 0.80 (excellent agreement). In general, agreement of status scores was somewhat better than agreement of change scores, and agreement of the comprehensive SPARCC scoring system was somewhat better than agreement of the more condensed systems. Sensitivity to change differed per reader, but in general was somewhat better for the comprehensive SPARCC system. This experiment under "real life," far from optimal conditions demonstrates the feasibility of scoring exercises for method comparison, provides evidence for the reliability and sensitivity to change of scoring systems to be used in assessing activity of SI joints in clinical trials, and sets the conditions for further validation research in this field.
New classification criteria for axial spondyloarthritis (SpA) have been developed and validated. MRI of the sacroiliac joints is an important feature in these criteria. This is rightfully so, as MRI ...can identify active lesions in the subchondral bone marrow that are thought to be related to the underlying pathophysiological process at the cartilage-bone junction. Follow-up studies using various imaging techniques, including MRI, in unselected patients with undiagnosed back pain of short symptom duration will provide more information on the differential diagnostic capacity of MRI and its predictive value for long-term outcomes. Even longer-term follow-up (>10 years) is necessary to provide reliable data; however, the validity of MRI in the diagnostic process can only be approximated, as it will never cover the entire gestalt of SpA.
To evaluate computed tomography (CT) guided corticosteroid injections of inflamed sacroiliac (SI) joints in patients with spondyloarthropathies (SpA), and to evaluate dynamic magnetic resonance ...imaging (DMRI) of the SI joints in serial examinations of these patients, who had different degrees of inflammatory back pain.
We examined and treated 30 patients with ankylosing spondylitis (n = 9) or undifferentiated SpA (n = 11) (14 women and 16 men, mean age 36.5 +/- 13.4 years, mean disease duration 5.4 +/- 4.0 years) who had severe inflammatory back pain for more than 3 months. All patients had DMRI of the SI joints before and 4-6 months after a CT guided injection of 40 mg triamcinolone acetonide into SI joints (n = 54; 24 patients received injections in both joints). Enhancement of the contrast agent gadolinium-DTPA was quantified by calculating the enhancement of the contrast agent gadolinium-DTPA was quantified by calculating the enhancement gradient Fenh. A subjective index with a visual analog scale (0 = no pain, 10 = very severe pain) was used for assessment of back pain. Followup visits were done every 3 months for a maximum of 18 months.
There was significant improvement of inflammatory back pain and sacroiliitis at 5.2 +/- 1.3 months after therapy in 25/30 patients (83.3%). The differences between the Fenh values before (98.2 +/ 56.1) and after (44.3 +/- 31.2) therapy and of the subjective pain index (8.5 +/- 1.5 and 3.0 +/- 2.3, respectively) were statistically significant. Subjective improvement lasted a mean of 8.9 +/- 5.3 months.
CT guided corticosteroid injection of inflamed SI joints is a useful option in therapy for sacroiliitis in patients with SpA. Different degrees of inflammation in the SI joints can be quantitatively assessed by DMRI.
Magnetic resolution imaging (MRI) is a promising tool in the assessment of inflammation and structural damage in clinical trials in ankylosing spondylitis (AS). The ASAS/OMERACT MRI in AS working ...group, a collaborative initiative of rheumatologists and musculoskeletal radiologists with a special interest in this field, collected data on all available scoring methods for both sacroiliac (SI) joints and spine, and tested them with respect to the OMERACT filter. These data were presented together with the technical specifications of all methods at the OMERACT 7 conference. In addition, the results of 2 separate experiments on the inter-reader reliability of scoring methods to assess activity in SI joints, and on the comparison of STIR sequence versus T1 post-gadolinium (Gd) sequence for the spine, were presented. Thereafter, 8 groups discussed these data and proposed a research agenda, each on a different topic. This information was reported back to all participants and a prioritized research agenda was compiled by voting. Research on scoring methods for assessing disease activity, in both the spine and SI joints, was considered most important. Research on assessing structural damage was considered less important. The specific process and results of this initiative are discussed.
AS and other spondyloarthritides (SpA) are mostly chronic inflammatory rheumatic diseases characterised by a strong association with HLA B27. Recent data from our group have suggested that AS ...patients have a diminished secretion capacity of inflammatory cytokines, possibly associated with HLA B27. The aim of this study was to identify CD4+ and CD8+ T cell subsets responsible for the observed lower cytokine secretion capacity in HLA B27-positives.
Highly purified (> 98%) CD4+ and CD8+ T cells of HLA B27-positive AS patients (n = 13), healthy HLA B27-positive (n = 7) and -negative controls (n = 9) were stimulated for 6h with PMA/ Ionomycin and, after fixation, stained for surface markers CD45RA and CD27 and cytokines TNFalpha, IFNgamma, IL-4 and IL-10.
CD27+ CD45RA- memory CD8+ T cells of HLA B27-positive subjects showed a significantly lower percentage of TNFalpha (median 71.4%) and IFNgamma production (median 69.7%) than HLA B27-negative controls (TNFalpha 85.1%; p < or = 0.027; IFNgamma 82.7%, p < or = 0.026). A similar result was also detected in CD27- CD45RA+ effector CD8+ T cells of which 43.2% produced TNFalpha and 66.3% IFNgamma in HLA B27-positive subjects, respectively, compared to 75.6% TNFalpha and 84.4% IFNgamma producing T cells in HLA B27-negatives (p < or = 0.045 and p < or = 0.062, respectively). For all CD4+ T cell subsets no significant differences between HLA B27-positive and HLA B27-negative donors were observed, regarding neither the frequency of IFNgamma, TNFalpha, IL-4 or IL-10 producers nor the coexpression of IFNgamma and IL-4 in memory subsets.
HLA B27-positive subjects are characterized by a low proinflammatory cytokine production in CD8+ effector and memory T cell subsets. This suggests an influence of HLA B27 on cytokine production in antigen-experienced CD8+ T cells.
PDF
