In inflammatory myopathies, dropped head/bent spine syndrome is associated with scleromyositis: an international case-control study.

BACKGROUND: Some myopathies can lead to dropped head or bent spine syndrome (DH/BS). The significance of this symptom has not been studied in inflammatory myopathies (IM). OBJECTIVES: To assess the significance of DH/BS in patients with IM. METHODS: Practitioners from five IM networks were invited to report patients with IM suffering from DH/BS (without other known cause than IM). IM patients without DH/BS, randomly selected in each participating centre, were included as controls at a ratio of 2 to 1. RESULTS: 49 DH/BS-IM patients (DH: 57.1%, BS: 42.9%) were compared with 98 control-IM patients. DH/BS-IM patients were older (65 years vs 53 years, p<0.0001) and the diagnosis of IM was delayed (6 months vs 3 months, p=0.009). Weakness prevailing in the upper limbs (42.9% vs 15.3%), dysphagia (57.1% vs 25.5%), muscle atrophy (65.3% vs 34.7%), weight loss (61.2% vs 23.5%) and loss of the ability to walk (24.5% vs 5.1%) were hallmarks of DH/BS-IM (p≤0.0005), for which the patients more frequently received intravenous immunoglobulins (65.3% vs 34.7%, p=0.0004). Moreover, DH/BS-IM patients frequently featured signs and/or complications of systemic sclerosis (SSc), fulfilling the American College of Rheumatology/European Alliance of Associations for Rheumatology criteria for this disease in 40.8% of the cases (vs 5.1%, p<0.0001). Distribution of the myopathy, its severity and its association with SSc were independently associated with DH/BS (p<0.05). Mortality was higher in the DH/BS-IM patients and loss of walking ability was independently associated with survival (p<0.05). CONCLUSION: In IM patients, DH/BS is a marker of severity and is associated with SSc (scleromyositis).

NKG2D ligands in inflammatory joint diseases: analysis in human samples and mouse models.

OBJECTIVES: NKG2D ligands (NKG2DLs) are stress-inducible molecules involved in multiple inflammatory settings. In this work, we quantified MICA, an NKG2DL, in the synovial fluid of patients suffering various arthritides and measured Nkg2dLs gene expression in murine models of acute joint inflammation. METHODS: Soluble MICA (sMICA) was quantified by ELISA is synovial fluids harvested from patients suffering osteoarthritis, rheumatoid arthritis, psoriatic arthritis, calcium pyrophosphate crystal arthritis, urate crystal arthritis and reactive arthritis. Transcripts encoding murine NKG2DLs were quantified by RT-qPCR in the joints of mouse models of rheumatoid arthritis, urate crystal arthritis and osteoarthritis. RESULTS: Marked overproduction of sMICA was observed in the synovial fluid of RA patients. Mouse studies highlighted the complex transcriptional regulation of Nkg2d ligands encoding genes depending on the inflammatory setting and microenvironment CONCLUSIONS: sMICA quantification could be an interesting biomarker to identify acute inflammation in RA patients in whom classical markers (i.e. anti-citrullinated protein antibodies, ACPA) are undetectable.

Mitochondria: An Organelle of Bacterial Origin Controlling Inflammation.

Inflammation is a cellular and molecular response to infection and/or tissues injury. While a suited inflammatory response in intensity and time allows for killing pathogens, clearing necrotic tissue, and healing injury; an excessive inflammatory response drives various diseases in which inflammation and tissues damages/stress self-sustain each other. Microbes have been poorly implied in non-resolving inflammation, emphasizing the importance of endogenous regulation of inflammation. Mitochondria have been historically identified as the main source of cellular energy, by coupling the oxidation of fatty acids and pyruvate with the production of high amount of adenosine triphosphate by the electron transport chain. Mitochondria are also the main source of reactive oxygen species. Interestingly, research in the last decade has highlighted that since its integration in eukaryote cells, this organelle of bacterial origin has not only been tolerated by immunity, but has also been placed as a central regulator of cell defense. In intact cells, mitochondria regulate cell responses to critical innate immune receptors engagement. Downstream intracellular signaling pathways interact with mitochondrial proteins and are tuned by mitochondrial functioning. Moreover, upon cell stress or damages, mitochondrial components are released into the cytoplasm or the extra cellular milieu, where they act as danger signals when recognized by innate immune receptors. Finally, by regulating the energetic state of immunological synapse between dendritic cells and lymphocytes, mitochondria regulate the inflammation fate toward immunotolerance or immunogenicity. As dysregulations of these processes have been recently involved in various diseases, the identification of the underlying mechanisms might open new avenues to modulate inflammation.

Grade and location of power Doppler are predictive of damage progression in rheumatoid arthritis patients in clinical remission by anti-tumour necrosis factor α.

Objectives: To investigate power Doppler (PD) signal, grade and location and their association with radiographic progression in RA patients in remission. Methods: A prospective observational study was conducted in 125 consecutive RA patients in stable 28-joint DAS (DAS28) remission (⩾6 months) achieved on anti-TNF-α. At baseline, patients in stable remission underwent radiographic and US examination of the wrists and MCP, PIP and MTP joints. Semi-quantitative PD scoring (0-3) was recorded. We scored PD according to two locations: capsular or within synovial tissue without bone contact (location 1) and with bone contact or penetrating bone cortex (location 2). Radiographic progression was evaluated at the 1 year follow-up and defined as a change in van der Heijde-modified total Sharp score >0. Risk ratios (RRs) of radiographic progression according to presence, grade and location of PD were calculated. Results: Four patients were excluded because of missing data. At baseline, 59/121 (48.7%) patients had a PD signal in one or more joints. PD location 2 was found in 74.6% patients (44/59). At the 1 year follow-up, 17/121 patients experienced radiographic progression: all had PD signal in one or more joints at baseline (RR 2.47, P < 0.0001). Radiographic progression was associated with the following baseline US features: PD grade 2 (RR 4.58, P < 0.01), PD grade 3 (RR 3.49, P < 0.05), total PD score ⩾2 (sum of all PD scores) (RR 3.19, P < 0.0001) and PD location 2 (RR 3.49, P < 0.0001). Conclusion: Higher PD grades and PD in contact with/or penetrating bone are associated with radiographic progression in patients in DAS28 remission.

Self-reported flares are predictors of radiographic progression in rheumatoid arthritis patients in 28-joint disease activity score remission: a 24-month observational study.

BACKGROUND: Disease flares are common in rheumatoid arthritis (RA) and are related to structural damage. However, few data on the impact of flares reported by patients on radiographic progression are available. Our aim was to investigate whether overall flares (OF), self-reported flares (SRF) and short flares assessed at the visit (SF) predict radiographic progression in RA patients in DAS28 (28-joint disease activity score) remission. METHODS: We reviewed the records of RA patients included in our database. We considered all patients who had a period of at least 24 months in remission (DAS28 < 2.6), stable biologic and synthetic disease-modifying anti-rheumatic drug treatment, no missing follow-up visits and hands and feet radiographs at the start and at the end of the 24-month follow up. Radiographic progression was considered as an increase in the van der Heijde modified total Sharp score >0. Patients were assessed every 3 months and flares were recorded. We defined SRF as any worsening of the disease reported by patients occurring in the time between visits and SF as an increase in DAS28 ≥ 2.6 or >0.6 from the previous visit assessed by the physician in one isolated visit. The impact of SRF, SF and OF on radiographic progression was assessed through multivariate regression analysis. RESULTS: One hundred forty-nine patients were included. The median number (interquartile range) of OF was 1.00/year (0.50; 1.38), of SRF was 0.50/year (0.14; 1.00), and of SF was 0.34/year (0; 0.50). Eighteen patients (12.1 %) experienced a progression of radiographic damage. OF and SRF were significant predictors of radiographic progression: OR 3.27, 95 % CI 1.30, 8.22 and OR 3.63, 95 % CI 1.16, 11.36, respectively. CONCLUSIONS: OF and SRF are predictors of structural damage. Flares assessed at the visit, SF, do not impact on radiographic progression as they might underestimate the actual number of flares.

Effects of half dose etanercept (25 mg once a week) on clinical remission and radiographic progression in patients with rheumatoid arthritis in clinical remission achieved with standard dose.

OBJECTIVES: This prospective long-term follow-up study evaluated the effects of half-dose etanercept (25 mg weekly) on clinical remission and radiographic progression in a large cohort of patients with rheumatoid arthritis (RA) in clinical remission after etanercept 25 mg bi-weekly. METHODS: 524 biologic-naïve RA patients were treated with etanercept 25 mg bi-weekly after failure of conventional drugs. Patients achieving remission (DAS28 <2.6) for ≥12 months were randomised to receive etanercept 25 mg weekly or 25 mg bi-weekly. Patients were assessed at baseline and every 12 weeks. Remission rates, radiographic progression, incidence of infections and costs of the regimens were compared. RESULTS: After a mean follow-up of 18±11 months, 347 patients (66.2%) achieved DAS28 remission; 323 were randomised to one of two dose regimens: etanercept 25 weekly (group A, 159 patients) and etanercept 25 mg bi-weekly (group B, 164 patients). At the end of follow-up, 81.8% patients of group A maintained remission for a mean of 3.6±1.5 years. Radiographic progression occurred in a small number of patients of group A and the rate of radiographic progression (TSS >0) was not significantly different in the two groups (18.85% vs. 19.0% after the first year and 16.9% vs. 21.6% after the second year, respectively). The incidence ratio of severe infections was 2.3/1.000 patient-years in group A. Etanercept half-dose regimen resulted in a saving of €3.190.545 with a cost saving up to €827.318 per year. CONCLUSIONS: Clinical remission and arrest of radiographic progression persisted in a substantial percentage of patients with RA even after reduction of standard-dose etanercept.

Inefficacy or paradoxical effect? Uveitis in ankylosing spondylitis treated with etanercept.

Ankylosing spondylitis (AS) is presented with axial and peripheral articular involvement. Uveitis is a severe and rather specific manifestation of AS. Biologics targeting tumor necrosis factor (TNF) α are effective on both articular and ocular manifestations of disease. The occurrence of uveitis in patients that never had eye involvement or the relapse of uveitis is described during anti-TNF α treatment. The frequency of these events is slightly higher during therapy with etanercept. The available TNF α blockers show different pharmacokinetics and pharmacodynamics yielding different biological effects. There is an ongoing debate whether uveitis during anti-TNF α has to be considered as paradoxical effect or an inadequate response to therapy. Here, we present a case report and review what the evidences for the two hypotheses are.

MR and CEUS monitoring of patients with severe rheumatoid arthritis treated with biological agents: a preliminary study.

PURPOSE: This study was done to propose a study protocol for patients with rheumatoid arthritis (RA) treated with biological agents, by evaluating the contribution of contrast-enhanced magnetic resonance (CE-MR) imaging, a software programme that calculates the volume of synovitis on CE-MR images, and contrast-enhanced ultrasound (CEUS). MATERIALS AND METHODS: Sixteen patients with RA receiving treatment with biologics were analysed. The patients underwent clinical examination, CE-MR imaging and CEUS on the same day. Images were postprocessed with the software and evaluated independently by three physicians in terms of RAMRIS (Rheumatoid Arthritis Magnetic Resonance Imaging Score), SAMIS (Simplified Rheumatoid Arthritis Magnetic Resonance Imaging Score) and CEUS grade. The techniques were correlated statistically. RESULTS: The RAMRIS and SAMIS scores were found to correlate statistically. CE-MR imaging correlated with the clinical data (p < 0.05), whereas CEUS did not. The data provided by the software did not correlate statistically with the other techniques. The most painful joint was consistently found to be the joint with most synovitis. CONCLUSIONS: CE-MR imaging may be used prior to treatment and for long-term follow-up. CEUS might be useful in the short-term follow-up, as it seems to provide an indication of the presence or absence of disease, though not of its severity. The software is a very useful tool that can supplement, but not replace, the other techniques.

Methods used to assess remission and low disease activity in rheumatoid arthritis.

The aim of the treatment in rheumatoid arthritis (RA) is to prevent articular damage and functional loss by decreasing the activity of the disease. The overall goal is the full suppression of the activity of the disease, also called clinical remission. The most reliable indices to assess RA activity were defined by the American College of Rheumatology (ACR), the European League Against Rheumatism (EULAR) and the International League Against Rheumatism (ILAR) and are habitually used for the evaluation of remission. The Food and Drug Administration (FDA) established three increasingly restrictive categories of disease remission: complete clinical response, major clinical response, and remission. Then, OMERACT (Outcome Measures in Rheumatoid Arthritis Clinical Trials) advanced the concept of low disease activity state (LDAS) or minimal disease activity (MDA). Thus, those reported by FDA are the only criteria for remission which consider radiographic arrest of the disease. This review aims to describe the criteria for RA remission and to discuss their advantages and limitations.