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Study design. Retrospective. Objective. We aimed to describe a magnetic resonance imaging (MRI)-based grading system of inflammatory features of the lumbar facet joints using an atlas and assess its reliability. Summary of Background Data. Chronic low back pain is often caused by facet joint arthropathy. Inflammatory features are often evident on MRI. While several grading systems of facet arthropathy have been described, there is scant data on the reliability of these systems, and none focus exclusively on inflammatory features. Materials and Methods. We describe a grading system that assesses facet joint effusion, bone marrow edema, and soft tissue edema. Each feature was graded from 0 to 3 (facet edema) or 0 to 2 (bone marrow edema intensity and extent, soft tissue edema intensity and extent). Four spine experts graded MRIs of 50 subjects at the bilateral L3/4, L4/5, and L5/S1 levels. All subjects had symptomatic facet arthropathy and received therapeutic facet joint injections. We assessed the intra-reader and inter-reader reliability of each feature at each joint and summarized across all six joints. Results. The mean age of subjects was 56 years (SD = 17), and 48% were female. The injections occurred at the L3/4 level in 12% of cases, at L4/5 in 88%, and at L5/S1 in 80% of cases. The intra- reader reliability kappa's for each feature ranged from 0.42 to 0.81. In contrast, the inter-reader reliability kappa values for each feature ranged from 0.37 to 0.54. Conclusion. MRI inflammatory features of the lumbar facet joints are often noted in patients with low back pain. The proposed grading system is reliable and could serve as a research tool for studies assessing the clinical relevance and prognostic value of these features. [ABSTRACT FROM AUTHOR]

The disease activity of axSpA after initiating anti-TNF agents for inflammatory bowel diseases (IBD) is poorly understood. We sought to examine the disease activity of axial spondyloarthritis (axSpA) after initiation of anti-tumor necrosis factor (TNF) agents among patients with IBD. This retrospective cohort study included adults with IBD and axSpA who initiated anti-TNF agents between 1/1/2012-10/1/2021 at a large academic center. The primary outcome was symptom resolution (SR) of axSpA at 12 months ("0/10 pain" or "no pain" or "controlled pain" with no morning stiffness and no use of daily NSAIDs). The secondary outcome was clinical remission (CR) of IBD at 12 months (simple clinical colitis activity index <3, Harvey-Bradshaw Index <5, or provider assessment with no use of oral/IV steroids for 30 days). Associations between baseline characteristics and SR of axSpA were examined using logistic regression. 82 patients with axSpA and IBD initiated anti-TNF agents. At 12 months, 52% and 74% achieved SR of axSpA and CR of IBD, respectively. IBD duration <5 years (OR 3.0, 95% CI 1.2-7.5) and adalimumab use (reference: all other anti-TNFs; OR 2.7, 95% CI 1.002-7.1) were associated with SR of axSpA at 12 months. 52% of patients with axSpA and IBD achieved SR of axSpA at 12 months after initiating anti-TNF therapy. Shorter disease duration and adalimumab use may be associated with higher odds of SR. Larger studies are needed to confirm these findings, examine additional clinical predictors of SR, and identify more effective therapeutics for this population. [ABSTRACT FROM AUTHOR]

Mouse and human data implicate the NOD1 and NOD2 sensors of the intestinal microbiome and the associated signal transduction via the receptor interacting protein kinase 2 (RIPK2) as a potential key signaling node for the development of inflammatory bowel disease (IBD) and an attractive target for pharmacological intervention. The TRUC mouse model of IBD was strongly indicated for evaluating RIPK2 antagonism for its effect on intestinal inflammation based on previous knockout studies with NOD1, NOD2, and RIPK2. We identified and profiled the BI 706039 molecule as a potent and specific functional inhibitor of both human and mouse RIPK2 and with favorable pharmacokinetic properties. We dosed BI 706039 in the spontaneous TRUC mouse model from age 28 to 56 days. Oral, daily administration of BI 706039 caused dose-responsive and significant improvement in colonic histopathological inflammation, colon weight, and terminal levels of protein-normalized fecal lipocalin (all P values <0.001). These observations correlated with dose responsively increasing systemic levels of the BI 706039 compound, splenic molecular target engagement of RIPK2, and modulation of inflammatory genes in the colon. This demonstrates that a relatively low oral dose of a potent and selective RIPK2 inhibitor can modulate signaling in the intestinal immune system and significantly improve disease associated intestinal inflammation. NEW & NOTEWORTHY The RIPK2 kinase at the apex of microbiome immunosensing is an attractive target for pharmacological intervention. A low oral dose of a RIPK2 inhibitor leads to significantly improved intestinal inflammation in the murine TRUC model of colitis. A selective and potent inhibitor of the RIPK2 kinase may represent a new class of therapeutics that target microbiome-driven signaling for the treatment of IBD. [ABSTRACT FROM AUTHOR]

Objectives This study aimed to compare comorbidities and biologic DMARD (bDMARD) use between AS and non-radiographic axial SpA (nr-axSpA) patients, using a large cohort of patients from routine clinical practice in the United States. Methods We performed a cross-sectional study using electronic medical records from two academic hospitals in the United States. Data were extracted using automated searches (⩾3 ICD codes combined with text searches) and supplemented with manual chart review. Patients were categorized into AS or nr-axSpA according to classification criteria. Disease features, comorbidities (from a list of 39 chronic conditions) and history of bDMARD prescription were compared using descriptive statistics. Results Among 965 patients identified, 775 (80%) were classified as having axSpA. The cohort was predominantly male (74%) with a mean age of 52.5 years (s. d. 16.8). AS patients were significantly older (54 vs 46 years), more frequently male (77% vs 64%) and had higher serum inflammatory markers than those with nr-axSpA (median CRP 3.4 vs 2.2 mg/dl). Half of all patients had at least one comorbidity. The mean number of comorbidities was 1.5 (s. d. 2.2) and similar between AS and nr-axSpA groups. A history of bDMARD-use was seen in 55% of patients with no difference between groups. The most commonly prescribed bDMARDs were adalimumab (31%) and etanercept (29%). Ever-prescriptions of individual bDMARDs were similar between AS and nr-axSpA. Conclusion Despite age differences, nr-axSpA patients had similar comorbidity burdens as those with AS. Both groups received comparable bDMARD treatment in this United States clinic-based cohort. [ABSTRACT FROM AUTHOR]

Retro-odontoid pseudotumor, or mass-like retro-odontoid soft tissue thickening, is an uncommon but important imaging finding that may be associated with rheumatoid arthritis, crystal deposition diseases, as well as non-inflammatory conditions such as cervical degenerative changes and mechanical alterations. Retro-odontoid pseudotumor is commonly associated with atlantoaxial microinstability or subluxation. MRI and CT have an important role in the detection and diagnosis of retro-odontoid pseudotumor. However, due to a wide range of imaging characteristics and ambiguous etiology, it is a frequently misunderstood entity. The purpose of this article is to review relevant anatomy of the craniocervical junction; describe various imaging appearances, pathophysiology and histology in both rheumatoid and non-rheumatoid etiologies; and discuss differential diagnosis of retro-odontoid pseudotumor in order to help guide clinical management. [ABSTRACT FROM AUTHOR]

Study design. Retrospective. Objective. We aimed to assess the frequency of facet joint inflammatory features noted in routine radiology reports of lumbar spine magnetic resonance imaging (MRI) studies among patients with chronic low back pain. Summary of Background Data. Facet joint arthropathy is one of the most common causes of chronic low back pain. It may encompass various inflammatory imaging characteristics, such as facet joint effusion, bone marrow edema, and soft tissue edema. The extent to which radiology reports mention inflammatory features of the lumbar facet joints and the accuracy of these reports have not been investigated. Materials and Methods. The authors performed a chart review on 49 subjects with previous facet-related interventions (i.e. medial branch blocks or intra-articular facet joint injection) and MRI available in the medical record. One senior musculoskeletal radiologist and a musculoskeletal radiology fellow graded the inflammatory features using a published facet joint inflammation grading system [Gold Standard (GS)]. The authors identified the inflammatory markers mentioned in the radiology reports and calculated the sensitivity and positive predictive value of the radiology reports compared with GS readings. Results. Compared with the GS, the sensitivity of radiology reports for facet joint effusion, bone marrow, and soft tissue edema ranged from 6% to 22%, and the positive predictive value ranged from 25% to 100%. L4/5 had the highest number of cases with inflammatory features noted on the reports. Conclusion. Inflammatory findings, such as facet joint effusion, bone marrow edema, and soft tissue edema, are not commonly identified in radiology reports. Further investigations are needed to determine the clinical importance of MRI-detected lumbar facet joint inflammatory features as a potential mechanism of nociception and as a predictor of outcomes following injections or other therapies. [ABSTRACT FROM AUTHOR]

The article discusses the use of mouse models in studying disease pathogenesis which highlights the conflicting results of studies that fuel negative sentiments on the validity and relevance of mouse models. It highlights the separate studies conducted by HJ Wu and colleagues, and JL Auger and colleagues which yield conflicting results on the role of T helper cells in the formation of arthritis antibodies in mouse models.

Biomarkers are needed to guide treatment decisions for patients with rheumatic diseases. Although the phenotypic and functional analysis of immune cells is an appealing strategy for understanding immune-mediated disease processes, immune cell profiling currently has no role in clinical rheumatology. New technologies, including mass cytometry, gene expression profiling by RNA sequencing (RNA-seq) and multiplexed functional assays, enable the analysis of immune cell function with unprecedented detail and promise not only a deeper understanding of pathogenesis, but also the discovery of novel biomarkers. The large and complex data sets generated by these technologies--big data--require specialized approaches for analysis and visualization of results. Standardization of assays and definition of the range of normal values are additional challenges when translating these novel approaches into clinical practice. In this Review, we discuss technological advances in the high-dimensional analysis of immune cells and consider how these developments might support the discovery of predictive biomarkers to benefit the practice of rheumatology and improve patient care. [ABSTRACT FROM AUTHOR]

Recent advances have dramatically increased our understanding of how organ systems interact. This has been especially true for immunology and bone biology, where the term “osteoimmunology” was coined to capture this relationship. The importance of the microbiome to the immune system has also emerged as a driver of health and disease. It makes sense therefore to ask the question: how does the intestinal microbiome influence bone biology and does dysbiosis promote bone disease? Surprisingly, few studies have analyzed this connection. A broader interpretation of this question reveals many mechanisms whereby the microbiome may affect bone cells. These include effects of the microbiome on immune cells, including myeloid progenitors and Th17 cells, as well as steroid hormones, fatty acids, serotonin and vitamin D. As mechanistic interactions of the microbiome and skeletal system are revealed within and without the immune system, novel strategies to optimize skeletal fitness may emerge. [ABSTRACT FROM AUTHOR]

Study design. A scoping review. Objective. We aimed to identify and describe the factors associated with the patient-reported response after lumbar intra-articular facet joint (FJ) injections or medial branch blocks (MBBs). Summary of Background Data. FJ osteoarthritis is among the most common causes of chronic low back pain. Management often includes FJ intra-articular injection and MBBs (which may be followed by radiofrequency ablation of the nerves innervating these joints). However, the success of these approaches is variable, prompting interest in identifying patient characteristics (imaging features, clinical signs, and among others) associated with response to these types of facet injections. Materials and Methods. We performed a literature search on factors associated with patient-reported outcomes after lumbar FJ intra-articular injections or MBBs for patients with low back pain published in English or Spanish between 2000 and 2023. We excluded duplicate papers that did not describe factors associated with outcomes or those describing other interventions. We collected data on the association of these factors with patient-reported outcomes. Results. Thirty-seven studies met the inclusion criteria and were analyzed. These studies evaluated factors, such as age, depression, and single photon emission computed tomography (SPECT), and among variables. Age and imaging findings of facet arthropathy were the most frequently described factors. Imaging findings of FJ arthropathy and positive SPECT were often associated with positive results after intra-articular FJ injections or MBBs. In contrast, younger age and smoking were frequently associated with less favorable clinical outcomes. Conclusion. Numerous factors were considered in the 37 studies included in this review. Imaging findings of facet arthropathy, duration of pain, and positive SPECT were consistently associated with favorable results after facet interventions. [ABSTRACT FROM AUTHOR]

The genetic basis of human autoimmune diseases remains incompletely understood, despite significant progress from genome-wide association studies (GWAS). In this review we outline how studies in mice may help filling these knowledge gaps. Forward genetic approaches including mutagenesis screens and quantitative trait locus (QTL) mapping studies can identify candidate genes for in depth analysis in human patient populations. Reverse genetic approaches utilize genetically engineered mice to analyze the function of disease-associated genes and their variants. Inbred strains are a distinctive feature of mouse genetics and we discuss their history, advantages and disadvantages. Three factors need to be considered when comparing experimental results from studies in mice and humans: In addition to species-specific differences, phenotypes are affected by the genetic background of the mouse strain being analyzed, and by microbial factors. Despite of these complexities, mice are essential discovery tools in the post GWAS era. [ABSTRACT FROM AUTHOR]

Genetic modifier loci influence the phenotypic expression of many Mendelian traits; insight into disease pathogenesis gained from their identification in animal disease models may impact the treatment of human multigenic disorders. We previously described an innate immune-driven model of spontaneous ulcerative colitis in T-bet-/- .Rag2-/- double-deficient mice that resembles human ulcerative colitis. On a BALB/c background, this disease is highly penetrant and results in the development of colorectal cancer. However, we observed that colitis in T-bet-/-.Rag2-/- mice on a CS7BL/6 background was significantly less severe. Quantitative trait locus analysis using an N2 backcross strategy revealed a single major quantitative trait locus on chromosome 3 that mapped to the Cdcs1 (cytokine deficiency-induced colitis susceptibility-1) locus previously identified in the II10-/- and Gnai2-/- colitis models. Congenic introduction of the susceptible Cdcs1 interval from C3H/He into the C57BL/6 background restored colitis severity. Bone marrow reconstitution experiments further mapped the effect of host genetics on disease severity to the hematopoietic compartment. There were distinct differences in the expression of several Cdcs1 genes in bone marrow-derived dendritic cells from Cdcs1 congenic mice. We conclude that the Cdcs1 locus controls colitis severity in T-bet-/-.Rag2-/- mice through innate immune cells. [ABSTRACT FROM AUTHOR]

We have developed a multiplexed reverse phase protein (RPP) microarray platform for simultaneous monitoring of site-specific phosphorylation of numerous signaling proteins using nanogram amounts of lysates derived from stimulated living cells. We first show the application of RPP microarrays to the study of signaling kinetics and pathway delineation in Jurkat T lymphocytes. RPP microarrays were used to profile the phosphorylation state of 62 signaling components in Jurkat T cells stimulated through their membrane CD3 and CD28 receptors, identifying a previously unrecognized link between CD3 crosslinking and dephosphorylation of Raf-1 at Ser259. Finally, the potential of this technology to analyze rare primary cell populations is shown in a study of differential STAT protein phosphorylation in interleukin (IL)-2-stimulated CD4+CD25+ regulatory T cells. RPP microarrays, prepared using simple procedures and standard microarray equipment, represent a powerful new tool for the study of signal transduction in both health and disease. [ABSTRACT FROM AUTHOR]

Study Design.: A scoping review. Objective.: We aimed to identify and characterize grading systems of the inflammatory features of the lumbar facet joints (FJs) noted on magnetic resonance imaging and summarize their reliability. Summary of Background Data.: Chronic low back pain is one of the most common causes of disability worldwide and is frequently accompanied by FJ osteoarthritis. Inflammatory changes in the lumbar FJs are commonly noted in imaging studies of patients with FJ osteoarthritis and low back pain. Several grading systems for these inflammatory changes have been developed. However, these grading system's features and reliability have yet to be reviewed. Materials and Methods.: We performed a literature search of studies reporting grading systems for FJ inflammatory changes published in English or Spanish between 1985 and 2022. We collected data on reported interreader reliability measures of each grading system. Finally, we compared the features of inflammation described by each system. Results.: Six studies met the inclusion criteria and were used in our analysis. Features commonly graded in these systems are the hyperintensity signal noted within the FJ, bone marrow edema, and the extent of the soft-tissue edema surrounding the FJs. We found that the interreader reliability measures ranged from 0.56 to 0.96. Conclusions.: Only 6 studies have reported methods for documenting inflammation in the FJs. Studies varied in the precise tissues and phenomena included in the grading systems. However, the systems were generally reliable. Future studies should document the reliability of these methods when independent investigators are not involved in developing the classification schemes. Further work might combine one or more of these measures to establish a standard and reliable grading system for inflammatory changes in the FJs, including signal intensity within the joint, bone marrow edema, and soft-tissue inflammation. [ABSTRACT FROM AUTHOR]

In this Overview, common themes of the accompanying News & Views on RA, SLE, IDDM, thyroiditis and MS are discussed. A unifying concept for the development of these and other autoimmune diseases should incorporate genetic predisposition, environmental factors and immune dysregulation. [ABSTRACT FROM AUTHOR]

The concept of specialized suppressor T cells called regulatory T cells which was abandoned by most immunologists in the early 1980's, was rescued by the description of a marker for their identification, however the marker is also induced on conventional T cells after activation. A major paradigm of current immunology is that the initiation of an immune receptor GITR on the surface of the marker could modulate Treg function. There appears to be a hierarchy of cosmulatory ligand or receptor pairs. The general implication is that the initiation of a T cell response involves the interaction of three different cell types.

An abstract of the article "Nod/Ripk2 signaling in dendritic cells activates IL-17A-secreting innate lymphoid cells and drives colitis in T-bet~/~.Rag2~/~(TRUC) mice," by Joerg Ermann and colleagues is presented.

Mature donor T cells cause graft-versus-host disease (GVHD), but they are also the main mediators of the beneficial graft-versustumor (GVT) activity of allogeneic bone marrow transplantation. Suppression of GVHD with maintenance of GVT activity is a desirable outcome for clinical transplantation. We have previously shown that donor-derived CD4[sup +]CD25[sup +] regulatory T cells inhibit lethal GVHD after allogeneic bone marrow transplantation across major histocompatibility complex (MHC) class I and II barriers in mice. Here we demonstrate that in host mice with leukemia and lymphoma, CD4[sup +]CD25[sup +] regulatory T cells suppress the early expansion of alloreactive donor T cells, their interleukin-2-receptor (IL-2R) α-chain expression and their capacity to induce GVHD without abrogating their GVT effector function, mediated primarily by the perforin lysis pathway. Thus, CD4[sup +]CD25[sup +] T cells are potent regulatory cells that can separate GVHD from GVT activity mediated by conventional donor T cells. [ABSTRACT FROM AUTHOR]

Background: Overexpression of IL-23 in adult mice by means of hydrodynamic tail vein injection of IL-23 minicircles has been reported to result in spondyloarthritis-like disease. The impact of genetic background and sex on the disease phenotype in this model has not been investigated. Methods: We compared male B10.RIII mice with male C57BL/6 mice, and male with female B10.RIII mice after hydrodynamic injection of IL-23 enhanced episomal vector (EEV) at 8–12 weeks of age. We monitored clinical arthritis scores, paw swelling, and body weight. Animals were euthanized after two weeks and tissues were harvested for histology, flow cytometry and gene expression analysis. Serum cytokine levels were determined by ELISA. Findings: Male B10.RIII mice developed arthritis in the forepaws and feet within 6 days after IL-23 EEV injection; they also exhibited psoriasis-like skin disease, colitis, weight loss, and osteopenia. In contrast to previous reports, we did not observe spondylitis or uveitis. Male C57BL/6 mice injected with IL-23 EEV had serum IL-23 levels comparable with B10.RIII mice and developed skin inflammation, colitis, weight loss, and osteopenia but failed to develop arthritis. Female B10.RIII mice had more severe arthritis than male B10.RIII mice but did not lose weight. Conclusions: The phenotype of IL-23 induced disease in mice is controlled by genetic background and sex of the animals. The development of extra-articular manifestations but absence of arthritis in C57BL/6 mice suggests that organ-specificity of IL-23 driven inflammation is genetically determined. The mechanisms behind the strain-specific differences and the sexual dimorphism observed in this study may be relevant for human spondyloarthritis and warrant further exploration. [ABSTRACT FROM AUTHOR]

Objectives To develop classification algorithms that accurately identify axial SpA (axSpA) patients in electronic health records, and compare the performance of algorithms incorporating free-text data against approaches using only International Classification of Diseases (ICD) codes. Methods An enriched cohort of 7853 eligible patients was created from electronic health records of two large hospitals using automated searches (⩾1 ICD codes combined with simple text searches). Key disease concepts from free-text data were extracted using NLP and combined with ICD codes to develop algorithms. We created both supervised regression-based algorithms—on a training set of 127 axSpA cases and 423 non-cases—and unsupervised algorithms to identify patients with high probability of having axSpA from the enriched cohort. Their performance was compared against classifications using ICD codes only. Results NLP extracted four disease concepts of high predictive value: ankylosing spondylitis, sacroiliitis, HLA-B27 and spondylitis. The unsupervised algorithm, incorporating both the NLP concept and ICD code for AS, identified the greatest number of patients. By setting the probability threshold to attain 80% positive predictive value, it identified 1509 axSpA patients (mean age 53 years, 71% male). Sensitivity was 0.78, specificity 0.94 and area under the curve 0.93. The two supervised algorithms performed similarly but identified fewer patients. All three outperformed traditional approaches using ICD codes alone (area under the curve 0.80–0.87). Conclusion Algorithms incorporating free-text data can accurately identify axSpA patients in electronic health records. Large cohorts identified using these novel methods offer exciting opportunities for future clinical research. [ABSTRACT FROM AUTHOR]

Abstract Serum bone turnover markers show diurnal variation in humans, suggesting that circadian rhythms contribute to normal bone physiology. This conclusion is corroborated by bone phenotypes in mice with genetic disruption of the circadian molecular clock mechanism, for instance via deletion of the transcription factor Brain and Muscle Arntl-like 1 (Bmal1). To dissect the contribution of circadian molecular clocks in individual bone cell types, we generated mice with conditional deletion of Bmal1 in osteoclasts (Ctsk-cre) and in mesenchymal cells of the limbs (Prx1-cre). We report that deletion of Bmal1 in osteoclasts had no effect on trabecular or cortical bone parameters in vivo or on osteoclast differentiation in vitro. In contrast, Bmal1 f/f .Prx1-cre mice had significantly less trabecular and cortical bone than Bmal1 f/f littermate controls, recapitulating the bone phenotype of Bmal1 germline deficient mice. The number of osteoblast precursors in the bone marrow of Bmal1 f/f .Prx1-cre mice was similar to wild-type controls, while the in vitro differentiation capacity of Bmal1 -deficient osteoblast precursors, measured as induction of alkaline phosphatase activity, was significantly lower. Despite this, serum procollagen type 1 N-terminal propeptide (P1NP), a measure of bone formation in vivo , was higher in Bmal1 f/f .Prx1-cre mice than in Bmal1 f/f mice. Consistent with a high bone turnover state in the mutant mice, the bone resorption marker serum C-terminal telopeptides of Type I collagen (CTX-I) was also elevated, and Bmal1 f/f .Prx1-cre mice had a higher number of tartrate resistant acid phosphatase (TRAP) positive osteoclasts than Bmal1 f/f controls. These results demonstrate that adult bone mass in mice is controlled by the intrinsic circadian molecular clock in mesenchymal cells but not osteoclasts. The effect of the mesenchymal cell clock on bone turnover appears to involve osteoblast-osteoclast cross-talk. Highlights • Bmal1 −/− mice with genetic disruption of the circadian molecular clock have a low bone mass phenotype. • The bone phenotype of Bmal1 −/− mice is recapitulated in mice with conditional Bmal1 deletion in mesenchymal cells (Bmal1 f/f .Prx1-cre). • Bmal1 f/f .Prx1-cre mice exhibit high bone turnover with enhanced bone resorption and bone formation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Schmid metaphyseal chondrodysplasia (MCDS) involves dwarfism and growth plate cartilage hypertrophic zone expansion resulting from dominant mutations in the hypertrophic zone collagen, Col10a1. Mouse models phenocopying MCDS through the expression of an exogenous misfolding protein in the endoplasmic reticulum (ER) in hypertrophic chondrocytes have demonstrated the central importance of ER stress in the pathology of MCDS. The resultant unfolded protein response (UPR) in affected chondrocytes involved activation of canonical ER stress sensors, IRE1, ATF6, and PERK with the downstream effect of disrupted chondrocyte differentiation. Here, we investigated the role of the highly conserved IRE1/XBP1 pathway in the pathology of MCDS. Mice with a MCDS collagen X p.N617K knock-in mutation (ColXN617K) were crossed with mice in which Xbp1 was inactivated specifically in cartilage (Xbp1CartΔEx2), generating the compound mutant, C/X. The severity of dwarfism and hypertrophic zone expansion in C/X did not differ significantly from ColXN617K, revealing surprising redundancy for the IRE1/XBP1 UPR pathway in the pathology of MCDS. Transcriptomic analyses of hypertrophic zone cartilage identified differentially expressed gene cohorts in MCDS that are pathologically relevant (XBP1-independent) or pathologically redundant (XBP1-dependent). XBP1-independent gene expression changes included large-scale transcriptional attenuation of genes encoding secreted proteins and disrupted differentiation from proliferative to hypertrophic chondrocytes. Moreover, these changes were consistent with disruption of C/EBP-β, a master regulator of chondrocyte differentiation, by CHOP, a transcription factor downstream of PERK that inhibits C/EBP proteins, and down-regulation of C/EBP-β transcriptional co-factors, GADD45-β and RUNX2. Thus we propose that the pathology of MCDS is underpinned by XBP1 independent UPR-induced dysregulation of C/EBP-β-mediated chondrocyte differentiation. Our data suggest that modulation of C/EBP-β activity in MCDS chondrocytes may offer therapeutic opportunities. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an autoimmune arthritis, for which treatment options remain limited. This study investigated the potential role of adoptive cellular gene therapy as a novel means for treating the RA animal model collagen-induced arthritis (CIA). Adoptive transfer of antigen-specific T-cell hybridomas retrovirally transduced to express IL-4 1 day before booster immunization significantly reduced the number of inflamed joints. Cell transfer after clinical onset of disease had no therapeutic effect. Bioluminescence imaging showed that the hybridomas migrated to the inflamed joints, thus delivering the regulatory protein locally at the site of inflammation. The homing was, at least in part, due to chemotaxis in response to proinflammatory chemokines that are expressed in inflamed joints. There were no significant changes in the cytokine milieu of the draining lymph nodes, nor in the systemic levels of anti-collagen antibodies in treated mice. We conclude that the beneficial clinical effects observed in our model were most likely based on the local action(s) of IL-4 in the inflamed joints and that the local delivery (and effects) of regulatory cytokines, like IL-4, constitutes a novel and effective method of preventing organ-specific autoimmune disease and of minimizing systemic adverse effects. [Copyright &y& Elsevier]