Bone marrow mesenchymal stem cells (BM-MSCs) can dampen inflammation in animal models of inflammatory rheumatisms and human osteoarthritis. They are expected to be a solution for numerous human ...conditions. However, in rheumatoid arthritis (RA) and spondyloarthritis (SpA), subsets of subchondral BM-MSCs might conversely fuel synovitis and enthesitis.
Abnormal behaviour of BM-MSCs and/or their progeny has been found in RA and SpA. BM-MSCs also contribute to the ossifying processes observed in ankylosing spondylitis. Some synovial fibroblastic stem cells probably derive from BM-MSCs, but some stem cells can also migrate through the bare zone area of joints, not covered by cartilage, into the synovium. BM-MSCs can also migrate in the synovium over tendons. Sub-populations of bone marrow stem cells also invade the soft tissue side of enthesis via small holes in the bone cortex. The present review aims (1) to make a focus on these two aspects and (2) to put forward the hypothesis that lasting epigenetic changes of some BM-MSCs, induced by transient infections of the bone marrow close to the synovium and/or entheses (i.e. trained immunity of BM-MSCs and/or their progeny), contribute to the pathogenesis of inflammatory rheumatisms. Such hypothesis would fit with (1) the uneven distribution and/or flares of arthritis and enthesitis observed at the individual level in RA and SpA (reminiscent of what is observed following reactive arthritis and/or in Whipple's disease); (2) the subchondral bone marrow oedema and erosions occurring in many RA patients, in the bare zone area; and (3) the frequent relapses of RA and SpA despite bone marrow transplantation, whereas most BM-MSCs resist graft preconditioning.
Some BM-MSCs might be more the problem than the solution in inflammatory rheumatisms. Subchondral bone marrow BM-MSCs and their progeny trafficking through the bare zone area of joints or holes in the bone cortex of entheses should be thoroughly studied in RA and SpA respectively. This may be done first in animal models. Mini-arthroscopy of joints could also be used in humans to specifically sample tissues close to the bare zone and/or enthesis areas.
Objective
To evaluate the usefulness of 2‐18F‐fluoro‐2‐deoxy‐d‐glucose–positron emission tomography/computed tomography (FDG‐PET/CT) in IgG4‐related disease (IgG4‐RD) for the staging of the disease ...and the followup under treatment.
Methods
All patients included in the French IgG4‐RD registry who underwent ≥1 FDG‐PET/CT scan were included in the study. Clinical, biologic, pathologic, radiologic, and FDG‐PET/CT qualitative and quantitative findings were retrospectively collected and analyzed.
Results
Twenty‐one patients were included in the study and 46 FDG‐PET/CT examinations were evaluated. At either diagnosis or relapse, all evaluated patients presented abnormal 18F‐FDG uptake in typical IgG4‐RD localizations. In most cases, FDG‐PET/CT was more sensitive than conventional imaging to detect organ involvement, especially in arteries, salivary glands, and lymph nodes. In few cases (small‐sized lesions and brain or kidney contiguous lesions), false‐negative results were noted. Evaluation before and after treatment showed in most cases a good correlation of FDG‐PET/CT results with treatment response and disease activity.
Conclusion
This large retrospective study shows that FDG‐PET/CT imaging is useful for the staging of IgG4‐RD. Moreover, FDG‐PET/CT is useful to assess the response to treatment during followup.
Upon recognition of microbial DNA or self-DNA, the cyclic-GMP-AMP synthase (cGAS) of the host catalyzes the production of the cyclic dinucleotide cGAMP. cGAMP is the main activator of STING, ...stimulator of interferon genes, leading to interferon synthesis through the STING-TBK1-IRF3 pathway. STING is also a hub for activation of NF-κB and autophagy. The present review details the striking similarities between T and B cell responses in severe coronavirus disease 2019 (COVID-19) and both animal or human models of STING gain of function (SAVI syndromes: STING-associated vasculopathy with onset in infancy). Those similarities may be further clues for a delayed activation of STING in severe COVID-19 patients, due to DNA damages following severe acute respiratory syndrome coronaviruses (SARS-CoV-2) infection and unusual role of STING in SARS-CoV-2 control. In early stages, Th2 differentiation are noticed in both severe COVID-19 and SAVI syndromes; then, CD4+ and CD8+ T cells functional exhaustion/senescent patterns due to TCR hyper-responsiveness are observed. T cell delayed over-responses can contribute to pneumonitis and delayed cytokine secretion with over-production of IL-6. Last, STING over-activation induces progressive CD4+ and CD8+ T lymphopenia in SAVI syndromes, which parallels what is observed in severe COVID-19. ACE2, the main receptor of SARS-CoV-2, is rarely expressed in immune cells, and it has not been yet proven that some human lymphocytes could be infected by SARS-CoV-2 through CD147 or CD26. However, STING, expressed in humans T cells, might be triggered following excessive transfer of cGAMP from infected antigen presenting cells into activated CD4+ and CD8+ T cells lymphocytes. Indeed, those lymphocytes highly express the cGAMP importer SLC19A1. Whereas STING is not expressed in human B cells, B cells counts are much less affected, either in COVID-19 or SAVI syndromes. The recognition of delayed STING over-activation in severe COVID-19 patients could prompt to target STING with specific small molecules inhibitors already designed and/or aspirin, which inhibits cGAS.
IgG4‐Related Disease (IgG4‐RD) results from tissue infiltration by IgG4‐expressing plasma cells and lymphocytes, leading to fibrosis and organomegaly. Clinical presentation is remarkably variable ...according to organ involvement, and high IgG4 serum concentration, initially considered a diagnostic hallmark of IgG4‐RD, tends to be forgone as an indispensable criterion for its diagnosis; it can indeed be absent in some patients, highlighting the diversity of presentation of this dysimmune condition. Nevertheless, elevation of IgG4 serum concentration in suggestive settings remains an argument in favour of IgG4‐RD, and while other IgG subclasses can be elevated, this biological feature lacks any diagnostic value. We retrospectively studied 9 patients (5 females, 4 males, 31–81 years old) for whom a diagnosis of IgG4‐RD had been considered, based on clinical, imaging or histological criteria, but appeared to display abnormally high serum IgG2 while IgG4 levels were normal. Increased serum IgG1 in one case and increased IgG3 in another one were also noticed. Immunohistochemical analyses of intracellular immunoglobulins could be performed on tissue lymph node biopsies from 2 patients, which demonstrated strong infiltration with IgG2‐expressing plasma cells. Thus, overexpression of IgG2 subclass may highlight cases of dysimmune disorders resembling IgG4‐RD, although the disease trigger might be different, notably infectious. We suggest measuring all serum IgG subclass levels in patients with features consistent with IgG4‐RD.
Objective
To validate the measurement properties and the detection performance of the FLARE‐RA questionnaire in a longitudinal prospective study.
Methods
To validate the FLARE‐RA self‐administered ...questionnaire, we conducted a prospective trial in rheumatoid arthritis (RA) patients to document: 1) content and construct validity by factor analysis, convergent validity by Pearson's correlation with routine assessment of patient index data (Routine Assessment of Patient Index Data 3 RAPID‐3 questionnaire), RA Impact of Disease (RAID) score, Disease Activity Score in 28 joints (DAS28), and Health Assessment Questionnaire (HAQ), 2) reliability (intraclass correlation coefficient ICC and Bland‐Altman plot), and 3) feasibility of use. Patients were examined and questionnaires were collected at baseline and 3 months, and every week in between for RAPID‐3.
Results
We recruited 138 patients from 13 centers: 81.9% women, mean age 57.4 years, mean DAS28 2.9, mean C‐reactive protein level 6.2 mg/liter, 84.4% rheumatoid factor positive, 78.0% anti–citrullinated protein antibody positive, and 78.8% with erosive disease. At baseline, the mean ± SD FLARE‐RA score was 2.3 ± 2.3. The content and construct validity of FLARE‐RA was good. A substantial floor effect, but no ceiling effect, was observed. Principal components analysis revealed 1 domain disentangled in 2 subdomains: physical and emotional. The FLARE‐RA total score was correlated with the DAS28 (r = 0.63, P < 0.001), RAID (r = 0.80, P < 0.001), RAPID‐3 (r = 0.77, P < 0.001), and HAQ (r = 0.53, P < 0.001). The ICC for reliability was 0.94 (95% confidence interval 0.92–0.96).
Conclusion
The FLARE‐RA self‐administered questionnaire represents a valid and valuable instrument to detect RA flare between visits to the physician.
The object of the paper is to investigate the effects of staking sequences and hybridation on the damping properties of flax–carbon twill epoxy composites. Various staking sequences of these hybrid ...laminates were manufactured by platen press process. Next, dynamic properties were investigated using beam test specimens and an impulse technique. Damping modelling was implemented by using a finite element analysis to evaluate the dissipated energies in each layer of carbon–flax laminates. The obtained results show a good agreement between the experimental damping coefficients and those deduced from modelling. It is also shown that the position of flax layers within the hybrid composites plays a major role on their bending stiffness and damping properties.
We previously made the hypothesis that STING contributes to COVID-19. The present review detail new arguments for over-activation of STING pathways in COVID-19, following the description of ...hyper-coagulability and Kawasaki-like diseases in children. Indeed, Kawasaki disease is induced by overreaction of innate cells following exposition to various viruses, including herpes viruses which trigger STING. It predisposes to diffuse vasculitis and aneurysms, whereas STING is over-expressed in arterial aneurisms. The redness at the inoculation site of bacillus Calmette-Guérin, a specific feature of Kawasaki disease, is reproduced by activation of the STING pathway, which is inhibited upstream by aspirin, intravenous immunoglobulins, and Vitamin-D. SARS-CoV2 binding to ACE2 can lead to excessive angiotensin II signaling, which activates the STING pathway in mice. Over-activation of the STING-pathway promotes hyper-coagulability through release of interferon-β and tissue factor by monocytes-macrophages. Aspirin and dipyridamole, besides their anti-platelet activity, also reduce tissue factor procoagulant activity, and aspirin inhibits the STING pathway upstream of STING. Aspirin and dipyridamole may be used, in combination with drugs blocking downstream the activation of the STING pathway, like inhibitors of IL-6R and JAK/STAT pathways. The risk of bleeding should be low as bleeding has not been reported in severe COVID-19 patients.
Triggering of the STING pathway by alien or self cytosolic DNA, can activate (from right to left): IRF-3 (partly inhibited by IVIgs after linking of FcγRIIa
38
), NK-κB, and the inflammasome NLRP3
9
.
This might occur even more frequently in COVID-19 patients with simultaneous enhancement of STING synthesis following excess of angiotensin II on cell membrane, secondary to the ACE1/2 imbalance (more pronounced in males), induced by the binding of SARS-CoV2 to ACE2
42-45
.
STING can contribute to Kawasaki disease, an innate overimmune response disorder following viral insults, in several ways. The mainstays of Kawasaki disease treatment, IVIgs and aspirin, both inhibit the STING pathway
38
,
39
, which is also down-regulated by Vitamin-D
37
.
Excessive triggering of the STING pathway can also lead to pyroptosis of monocyte-macrophages, and release of the highly prothrombotic tissue factor
54-57
, also found in excess in lung tissues of severe COVID-19 patients
49
.
Tocilizumab in refractory adult Still's disease Puéchal, Xavier; DeBandt, Michel; Berthelot, Jean‐Marie ...
Arthritis care & research (2010),
January 2011, Letnik:
63, Številka:
1
Journal Article
Recenzirano
Objective
There is an unmet need for the treatment of adult Still's disease (ASD), the pathogenesis of which may involve interleukin‐6 (IL‐6). We report the first series of patients with ASD treated ...with tocilizumab (TCZ), a humanized anti–IL‐6 receptor antibody.
Methods
All ASD patients treated with TCZ in France between July 2006 and July 2009 after failure to all available therapies were included in this cohort study. The main outcome measures were the European League Against Rheumatism (EULAR) improvement criteria and resolution of systemic symptoms at the 3‐ and 6‐month followup periods.
Results
Fourteen patients with refractory ASD were included. At the start of TCZ treatment, despite a mean prednisone dosage of 23.3 mg/day, based on a 28‐joint count, mean tender joints were 10.5, mean swollen joints were 7.9, and the mean Disease Activity Score in 28 joints was 5.61. Recurrent systemic involvement, including fever and rash, was present in 7 patients. TCZ was administered at 5–8 mg/kg every 2 or 4 weeks (8 mg/kg/month, n = 9). Eleven patients successfully completed the 6‐month study; 1 withdrew due to necrotizing angiodermatitis, another due to chest pain at each TCZ infusion, and a third due to systemic flare. A good EULAR response was observed in 64% of patients (9 of 14) at 3 months and EULAR remission was observed in 57% (8 of 14) at 6 months. Systemic symptoms were resolved in 86% of patients (6 of 7). Moreover, corticosteroid dose was reduced by 56%. No other severe adverse effects occurred.
Conclusion
TCZ is a promising new treatment for ASD.
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![Usefulness of 2‐[18F]‐fluor...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/2151-464X/small "Usefulness of 2‐[18F]‐fluoro‐2‐deoxy‐d‐glucose–Positron Emission Tomography/Computed Tomography for Staging and Evaluation of Treatment Response in IgG4‐Related Disease: A Retrospective Multicenter Study")
