Psoriatic Arthritis Ritchlin, Christopher T; Colbert, Robert A; Gladman, Dafna D
The New England journal of medicine,
03/2017, Letnik:
376, Številka:
10
Journal Article
Here we report on the antibody and memory B cell responses of a cohort of 20 volunteers who received the Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) vaccine against SARS-CoV-2
. Eight weeks ...after the second injection of vaccine, volunteers showed high levels of IgM and IgG anti-SARS-CoV-2 spike protein (S) and receptor-binding-domain (RBD) binding titre. Moreover, the plasma neutralizing activity and relative numbers of RBD-specific memory B cells of vaccinated volunteers were equivalent to those of individuals who had recovered from natural infection
. However, activity against SARS-CoV-2 variants that encode E484K-, N501Y- or K417N/E484K/N501-mutant S was reduced by a small-but significant-margin. The monoclonal antibodies elicited by the vaccines potently neutralize SARS-CoV-2, and target a number of different RBD epitopes in common with monoclonal antibodies isolated from infected donors
. However, neutralization by 14 of the 17 most-potent monoclonal antibodies that we tested was reduced or abolished by the K417N, E484K or N501Y mutation. Notably, these mutations were selected when we cultured recombinant vesicular stomatitis virus expressing SARS-CoV-2 S in the presence of the monoclonal antibodies elicited by the vaccines. Together, these results suggest that the monoclonal antibodies in clinical use should be tested against newly arising variants, and that mRNA vaccines may need to be updated periodically to avoid a potential loss of clinical efficacy.
The HLA-B27 gene is a major risk factor for clinical diseases including ankylosing spondylitis, acute anterior uveitis, reactive arthritis, and psoriatic arthritis, but its mechanism of risk ...enhancement is not completely understood. The gut microbiome has recently been shown to influence several HLA-linked diseases. However, the role of HLA-B27 in shaping the gut microbiome has not been previously investigated. In this study, we characterize the differences in the gut microbiota mediated by the presence of the HLA-B27 gene. We identified differences in the cecal microbiota of Lewis rats transgenic for HLA-B27 and human β2-microglobulin (hβ2m), compared with wild-type Lewis rats, using biome representational in situ karyotyping (BRISK) and 16S rRNA gene sequencing. 16S sequencing revealed significant differences between transgenic animals and wild type animals by principal coordinates analysis. Further analysis of the data set revealed an increase in Prevotella spp. and a decrease in Rikenellaceae relative abundance in the transgenic animals compared to the wild type animals. By BRISK analysis, species-specific differences included an increase in Bacteroides vulgatus abundance in HLA-B27/hβ2m and hβ2m compared to wild type rats. The finding that HLA-B27 is associated with altered cecal microbiota has not been shown before and can potentially provide a better understanding of the clinical diseases associated with this gene.
Understanding how HLA-B27 contributes to the pathogenesis of spondyloarthritis continues to be an important goal. Current efforts are aimed largely on three areas of investigation; peptide ...presentation to CD8T cells, abnormal forms of the HLA-B27 heavy chain and their recognition by leukocyte immunoglobulin-like receptors on immune effector cells, and HLA-B27 heavy chain misfolding and intrinsic biological effects on affected cells. In this chapter we review our current understanding of the causes and consequences of HLA-B27 misfolding, which can be defined biochemically as a propensity to oligomerize and form complexes in the endoplasmic reticulum (ER) with the chaperone BiP (HSPA5/GRP78). HLA-B27 misfolding is linked to an unusual combination of polymorphisms that identify this allele, and cause the heavy chain to fold and load peptides inefficiently. Misfolding can result in ER-associated degradation (ERAD) of heavy chains, which is mediated in part by the E3 ubiquitin ligase HRD1 (SYVN1), and the ubiquitin conjugating enzyme UBE2JL. Upregulation of HLA-B27 and accumulation of misfolded heavy chains can activate ER stress signaling pathways that orchestrate the unfolded protein response. In transgenic rats where HLA-B27 is overexpressed, UPR activation is prominent. However, it is specific for heavy chain misfolding, since overexpression of HLA-B7, an allele that does not misfold, fails to generate ER stress. UPR activation has been linked to cytokine dysregulation, promoting lL-23, IFNβ, and lL-1α production, and may activate the IL-23/IL-17 axis in these rats. IL-1α and IFNβ are pro- and anti-osteoclastogenic cytokines, respectively, that modulate osteoclast development in HLA-B27-expressing transgenic rat monocytes. Translational studies of patient derived cells expressing HLA-B27 at physiologic levels have provided evidence that ER stress and UPR activation can occur in peripheral blood, but this has not been reported to date in isolated macrophages. Inflamed gastrointestinal tissue reveals evidence for HLA-B27 misfolding, ERAD, and autophagy, without acute UPR activation. A more complete picture of conditions that impact HLA-B27 folding and misfolding, the full spectrum and time course of consequences of ER stress, and critical cell types involved is needed to understand the role of HLA-B27 misfolding in spondyloarthritis pathogenesis.
Rheumatic diseases represent a heterogeneous group of inflammatory conditions, many of which involve chronic activation of both innate and adaptive immune responses by multiple genetic and ...environmental factors. These immune responses involve the secretion of excessive amounts of cytokines and other signalling mediators by activated immune cells. The endoplasmic reticulum (ER) is the cellular organelle that directs the folding, processing and trafficking of membrane-bound and secreted proteins, including many key components of the immune response. Maintaining homeostasis in the ER is critical to cell function and survival. Consequently, elaborate mechanisms have evolved to sense and respond to ER stress through three main signalling pathways that together comprise the unfolded protein response (UPR). Activation of the UPR can rapidly resolve the accumulation of misfolded proteins, direct permanent changes in the size and function of cells during differentiation, and critically influence the immune response and inflammation. Recognition of the importance of ER stress and UPR signalling pathways in normal and dysregulated immune responses has greatly increased in the past few years. This Review discusses several settings in which ER stress contributes to the pathogenesis of rheumatic diseases and considers some of the therapeutic opportunities that these discoveries provide.
Objective
To assess patient‐reported symptoms and burden of disease in relapsing polychondritis (RP).
Methods
Patients with RP completed a disease‐specific online survey to identify symptoms ...attributed to illness. Patients were divided into subgroups based upon presence or absence of ear/nose, airway, or joint involvement. Pathway to diagnosis, treatment, and disease‐related complications were assessed within each subgroup.
Results
Data from 304 respondents were included in this analysis. Prior to diagnosis, most patients with RP went to the emergency room (54%), saw > 3 physicians (54%), and had symptoms for >5 years (64%). A concomitant diagnosis of fibromyalgia and absence of ear/nose or joint involvement was associated with diagnostic delay >1 year. Common diagnoses prior to RP diagnosis included asthma in patients with airway involvement (35% versus 22%; P = 0.03) and ear infection in patients with ear/nose involvement (51% versus 6%; P < 0.01). Patients with joint involvement were more likely to receive a glucocorticoid‐sparing agent (85% versus 13%; P < 0.01). Most patients reported a major complication, including disability (25%), tracheomalacia (16%), or hearing loss (34%). Patients with airway involvement reported more tracheomalacia (20% versus 4%; P < 0.01). Disability (24% versus 7%; P < 0.01) and hearing loss (39% versus 11%; P < 0.01) were prevalent in the joint involvement subgroup.
Conclusion
Patient‐reported data in RP highlight a significant burden of disease. Patterns of organ involvement may lead to diagnostic delay and influence treatment decisions, ultimately impacting the development of disease‐related complications. Timely diagnosis, standardization of treatment approaches, and prevention of disease‐related complications are major unmet needs in RP.
Objective
To investigate whether HLA–B27–mediated experimental spondyloarthritis (SpA) is associated with a common gut microbial signature, in order to identify potential drivers of pathogenesis.
...Methods
The effects of HLA–B27 on 3 genetic backgrounds, dark agouti (DA), Lewis, and Fischer, were compared, using wild‐type littermates and HLA–B7–transgenic Lewis rats as controls. Cecum and colon tissue specimens or contents were collected from the rats at 2, 3–4, and 6–8 months of age, and histologic analysis was performed to assess inflammation, RNA sequencing was used to determine gene expression differences, and 16S ribosomal RNA gene sequencing was used to determine microbiota differences.
Results
Both HLA–B27–transgenic Lewis rats and HLA–B27–transgenic Fischer rats developed gut inflammation, while DA rats were resistant to the effects of HLA–B27, and HLA–B7–transgenic rats were not affected. Immune dysregulation was similar in affected Lewis and Fischer rats and was dominated by activation of interleukin‐23 (IL‐23)/IL‐17, interferon, tumor necrosis factor, and IL‐1 cytokines and pathways in the colon and cecum, while DA rats exhibited low‐level cytokine dysregulation without inflammation. Gut microbial changes in HLA–B27–transgenic rats were strikingly divergent on the 3 different host genetic backgrounds, including different patterns of dysbiosis in HLA–B27–transgenic Lewis and HLA–B27–transgenic Fischer rat strains, with some overlap. Interestingly, DA rats lacked segmented filamentous bacteria that promote CD4+ Th17 cell development, which may explain their resistance to disease.
Conclusion
The effects of HLA–B27 on gut microbiota and dysbiosis in SpA are highly dependent on the host genetic background and/or environment, despite convergence of dysregulated immune pathways. These results implicate an ecological model of dysbiosis, with the effects of multiple microbes contributing to the aberrant immune response, rather than a single or small number of microbes driving pathogenesis.
Spondyloarthritis (SpA) refers to a spectrum of immune-mediated inflammatory diseases with overlapping features, which differ from other types of inflammatory arthritis in genetic predisposition, ...pathogenesis and outcome. SpA frequently involves the axial skeleton, and can result in abnormal bone formation with eventual ankylosis of the spine, resulting in substantial disability. SpA often begins as an 'undifferentiated' disease, the presentation of which differs in children and adults; most notably, spinal involvement is uncommon, while hip arthritis and enthesitis are frequently seen in juvenile-onset disease. Currently, the classification of SpA in adults and children is approached differently. Using the International League of Associations for Rheumatology (ILAR) system for juvenile idiopathic arthritis, most childhood SpA is classified as enthesitis-related arthritis. However, in contrast to adult SpA classification, the presence of, or a family history of, psoriasis dictates a separate category of juvenile idiopathic arthritis. More importantly, the ILAR system does not specifically recognize the presence of axial disease in juvenile SpA. Resolution of these issues will improve communication and the transitioning of patients from pediatric to adult clinics, will facilitate research in genetics and pathogenesis, and will be particularly important in the evaluation of tumor necrosis factor inhibitors and other biologic agents for early, axial SpA.
Objective
To provide evidence‐based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA).
Methods
A core group led the ...development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946–2014), PubMed (1966–2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework.
Results
In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS.
Conclusion
These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.
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