Clinical and functional characterisation of a novel TNFRSF1A c.605T > A/V173D cleavage site mutation associated with tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), cardiovascular complications and excellent response to etanercept treatment.

Objectives: To study the clinical outcome, treatment response, T-cell subsets and functional consequences of a novel tumour necrosis factor (TNF) receptor type 1 (TNFRSF1A) mutation affecting the receptor cleavage site. Methods: Patients with symptoms suggestive of tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and 22 healthy controls (HC) were screened for mutations in the TNFRSF1A gene. Soluble TNFRSF1A and inflammatory cytokines were measured by ELISAs. TNFRSF1A shedding was examined by stimulation of peripheral blood mononuclear cells (PBMCs) with phorbol 12-myristate 13-acetate followed by flow cytometric analysis (FACS). Apoptosis of PBMCs was studied by stimulation with TNFa in the presence of cycloheximide and annexin V staining. T cell phenotypes were monitored by FACS. Results: TNFRSF1A sequencing disclosed a novel V173D/ p.Val202Asp substitution encoded by exon 6 in one family, the c.194–14G.A splice variant in another and the R92Q/p.Arg121Gln substitution in two families. Cardiovascular complications (lethal heart attack and peripheral arterial thrombosis) developed in two V173D patients. Subsequent etanercept treatment of the V173D carriers was highly effective over an 18-month follow-up period. Serum TNFRSF1A levels did not differ between TRAPS patients and HC, while TNFRSF1A cleavage from monocytes was significantly reduced in V173D and R92Q patients. TNFa-induced apoptosis of PBMCs and T-cell senescence were comparable between V173D patients and HC. Conclusions: The TNFRSF1A V173D cleavage site mutation may be associated with an increased risk for cardiovascular complications and shows a strong response to etanercept. T-cell senescence does not seem to have a pathogenetic role in affected patients

Imaging in diagnosis, outcome prediction and monitoring of large vessel vasculitis : a systematic literature review and meta-analysis informing the EULAR recommendations

Objectives: To perform a systematic literature review on imaging techniques for diagnosis, outcome prediction and disease monitoring in large vessel vasculitis (LVV) informing the European League Against Rheumatism recommendations for imaging in LVV. Methods: Systematic literature review (until 10 March 2017) of diagnostic and prognostic studies enrolling >20 patients and investigating ultrasound, MRI, CT or positron emission tomography (PET) in patients with suspected and/or established primary LVV. Meta-analyses were conducted, whenever possible, obtaining pooled estimates for sensitivity and specificity by fitting random effects models. Results: Forty-three studies were included (39 on giant cell arteritis (GCA), 4 on Takayasu arteritis (TAK)). Ultrasound (‘halo’ sign) at temporal arteries (8 studies, 605 patients) and MRI of cranial arteries (6 studies, 509 patients) yielded pooled sensitivities of 77% (95% CI 62% to 87%) and 73% (95% CI 57% to 85%), respectively, compared with a clinical diagnosis of GCA. Corresponding specificities were 96% (95% CI 85% to 99%) and 88% (95% CI 81% to 92%). Two studies (93 patients) investigating PET for GCA diagnosis reported sensitivities of 67%–77% and specificities of 66%–100% as compared with clinical diagnosis or temporal artery biopsy. In TAK, one study each evaluated the role of magnetic resonance angiography and CT angiography for diagnostic purposes revealing both a sensitivity and specificity of 100%. Studies on outcome prediction and monitoring disease activity/damage were limited and mainly descriptive. Conclusions: Ultrasound and MRI provide a high diagnostic value for cranial GCA. More data on the role of imaging for diagnosis of extracranial large vessel GCA and TAK, as well as for outcome prediction and monitoring in LVV are warranted

EULAR Points to Consider for the use of imaging to guide interventional procedures in patients with rheumatic and musculoskeletal diseases (RMDs)

OBJECTIVES: To develop evidence-based Points to Consider (PtC) for the use of imaging modalities to guide interventional procedures in patients with rheumatic and musculoskeletal diseases (RMDs). METHODS: European Alliance of Associations for Rheumatology (EULAR) standardised operating procedures were followed. A systematic literature review was conducted to retrieve data on the role of imaging modalities including ultrasound (US), fluoroscopy, MRI, CT and fusion imaging to guide interventional procedures. Based on evidence and expert opinion, the task force (25 participants consisting of physicians, healthcare professionals and patients from 11 countries) developed PtC, with consensus obtained through voting. The final level of agreement was provided anonymously. RESULTS: A total of three overarching principles and six specific PtC were formulated. The task force recommends preference of imaging over palpation to guide targeted interventional procedures at peripheral joints, periarticular musculoskeletal structures, nerves and the spine. While US is the favoured imaging technique for peripheral joints and nerves, the choice of the imaging method for the spine and sacroiliac joints has to be individualised according to the target, procedure, expertise, availability and radiation exposure. All imaging guided interventions should be performed by a trained specialist using appropriate operational procedures, settings and assistance by technical personnel. CONCLUSION: These are the first EULAR PtC to provide guidance on the role of imaging to guide interventional procedures in patients with RMDs

Apoptotic Effects of Antilymphocyte Globulins on Human Pro-inflammatory CD4+CD28− T-cells

BACKGROUND: Pro-inflammatory, cytotoxic CD4(+)CD28(-) T-cells with known defects in apoptosis have been investigated as markers of premature immuno-senescence in various immune-mediated diseases. In this study we evaluated the influence of polyclonal antilymphocyte globulins (ATG-Fresenius, ATG-F) on CD4(+)CD28(-) T-cells in vivo and in vitro. PRINCIPAL FINDINGS: Surface and intracellular three colour fluorescence activated cell sorting analyses of peripheral blood mononuclear cells from 16 consecutive transplant recipients and short-term cell lines were performed. In vivo, peripheral levels of CD3(+)CD4(+)CD28(-) T-cells decreased from 3.7 ± 7.1% before to 0 ± 0% six hours after ATG-F application (P = 0.043) in 5 ATG-F treated but not in 11 control patients (2.9 ± 2.9% vs. 3.9 ± 3.0%). In vitro, ATG-F induced apoptosis even in CD4(+)CD28(-) T-cells, which was 4.3-times higher than in CD4(+)CD28(+) T-cells. ATG-F evoked apoptosis was partially reversed by the broad-spectrum caspase inhibitor benzyloxycarbonyl (Cbz)-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk) and prednisolon-21-hydrogensuccinate. ATG-F triggered CD25 expression and production of pro-inflammatory cytokines, and induced down-regulation of the type 1 chemokine receptors CXCR-3, CCR-5, CX3CR-1 and the central memory adhesion molecule CD62L predominately in CD4(+)CD28(-) T-cells. CONCLUSION: In summary, in vivo depletion of peripheral CD3(+)CD4(+)CD28(-) T-cells by ATG-F in transplant recipients was paralleled in vitro by ATG-F induced apoptosis. CD25 expression and chemokine receptor down-regulation in CD4(+)CD28(-) T-cells only partly explain the underlying mechanism

Definition of remission and relapse in polymyalgia rheumatica: data from a literature search compared with a Delphi-based expert consensus

OBJECTIVE: To compare current definitions of remission and relapse in polymyalgia rheumatica (PMR) with items resulting from a Delphi-based expert consensus. METHODS: Relevant studies including definitions of PMR remission and relapse were identified by literature search in PubMed. The questionnaire used for the Delphi survey included clinical (n=33), laboratory (n=54) and imaging (n=7) parameters retrieved from a literature search. Each item was assessed for importance and availability/practicability, and limits were considered for metric parameters. Consensus was defined by an agreement rate of ≥80%. RESULTS: Out of 6031 articles screened, definitions of PMR remission and relapse were available in 18 and 34 studies, respectively. Parameters used to define remission and/or relapse included history and clinical assessment of pain and synovitis, constitutional symptoms, morning stiffness (MS), physician's global assessment, headache, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), blood count, fibrinogen and/or corticosteroid therapy. In the Delphi exercise a consensus was obtained on the following parameters deemed essential for definitions of remission and relapse: patient's pain assessment, MS, ESR, CRP, shoulder and hip pain on clinical examination, limitation of upper limb elevation, and assessment of corticosteroid dose required to control symptoms. CONCLUSIONS: Assessment of patient's pain, MS, ESR, CRP, shoulder pain/limitation on clinical examination and corticosteroid dose are considered to be important in current available definitions of PMR remission and relapse and the present expert consensus. The high relevance of clinical assessment of hips was unique to this study and may improve specificity and sensitivity of definitions for remission and relapse in PMR