2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis.

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.

Justification for including MRI as a tool in the diagnosis of axial SpA.

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.

Autoregulation of Th1-mediated inflammation by twist1.

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.

In vitro observations of T cell responsiveness to recall antigens during tumor necrosis factor-alpha-blocking therapy in patients with ankylosing spondylitis.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

IL-10 is excluded from the functional cytokine memory of human CD4+ memory T lymphocytes.

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.

Congenital absence of the portal vein with splenomegaly and hypersplenism in a young woman.

Congenital absence of portal vein (CAPV) with a systemic shunt of enteric blood is a rare malformation. Twenty-seven cases have been reported to date; with the exception of 4 patients all cases had either liver anomalies or cardiac anomalies. CAPV is usually diagnosed before the age of 18 (25/27 cases). Here we present the case of a 33-year-old woman with CAPV without further anomalies. Beside suffering from circumscript scleroderma, splenomegaly and hypersplenism, the patient was otherwise healthy. Diagnosis was based on histological findings, angiography and CT scan. The liver biopsy showed portal tracts with inconspicuous arteries and bile ducts, but with severe loss of portal vein branches and minimal proliferation of bile ductules. In addition, the perivenular sinusoids were slightly dilated with focal parenchymal atrophy. Angiography showed a missing portal vein system and a missing splenic vein with drainage of the enteric blood through dilated perisplenic and perigastric collaterals to the azygos vein system. A CT scan revealed an empty liver hilus without portal vein. Here we discuss clinical aspects of this patient, show radiologic and histopathologic findings, and compare them to other cases in the literature.