Potential therapeutic targets of fibrosis in inflammatory rheumatic diseases.

Fibrosis is commonly associated with chronic rheumatic diseases, and causes substantial morbidity and mortality. Treatment of fibrosis is extremely challenging but is badly needed, as approved antifibrotic therapies fibrosis do not halt its progression, which will be discussed with a focus on pulmonary fibrosis. Findings from recent studies indicate several therapeutic targets for treating fibrosis. Interleukin-11 is emerging as a fibrogenic cytokine whose activity can be blocked with neutralizing monoclonal antibodies. Fibroblast activation protein (FAP) is highly expressed by activated fibroblasts in inflammatory and fibrotic tissues. Targeting FAP with different modalities has been extensively explored as adjunct treatment for cancer, which can also apply to treating fibrosis in rheumatic diseases.

Advances and challenges in management of large vessel vasculitis.

Glucocorticoids (GC) remains the mainstay for management of large vessel vasculitis (LVV). Recent introduction of interleukin-6 signaling blocker, tocilizumab has substantially changed the practice in management of patients with LVV, in particular, giant cell arteritis (GCA). Benefit of tocilizumab to patients with Takayasu arteritis (TAK) is supported by observational studies, but randomized clinical trials are lacking. Addition of tocilizumab enables reduction of the total amount of GC in patients with GCA, but GC burden remains high and to be further reduced. Ongoing studies aim at minimal use of GC or even GC-free. Tumor necrosis factor inhibitors appear to be beneficial to TAK despite their ineffectiveness to GCA. Randomized clinical trials are undergoing to target other inflammatory cytokines in both GCA and TAK. Janus kinase inhibitors alone or in combination with conventional disease modifying anti-rheumatic drugs showed promising results in treatment of TAK.

mRNA vaccine against fibroblast activation protein ameliorates murine models of inflammatory arthritis.

Objective: Synovial fibroblasts in patients with rheumatoid arthritis (RA) contribute substantially to the perpetuation of synovitis and invasion to cartilage and bone, and are potential therapeutic targets. Fibroblast activation protein (FAP) is highly expressed by RA synovial fibroblasts and the expression is relatively specific. We tested whether FAP can serve as a molecular target to modulate synovial fibroblasts for therapy in experimental arthritis. Methods: mRNA encoding consensus FAP (cFAP) was encapsulated in lipid nanoparticles (LNP) and was injected intramuscularly as vaccine prior to induction of collagen-induced arthritis (CIA) and collagen antibody induced arthritis (CAIA) in mice. Development of CIA and CAIA was assessed clinically and by histology. Results: cFAP mRNA-LNP vaccine provoked immune response to cFAP and mouse FAP (mFAP); prevented onset of CIA in 40% of mice and significantly reduced the severity of arthritis. In CAIA, cFAP mRNA-LNP did not prevent onset of arthritis but significantly reduced the severity of arthritis. Conclusion: cFAP mRNA-LNP vaccine was able to provoke immune response to mFAP and suppress inflammatory arthritis.

Animal models for large vessel vasculitis - The unmet need.

Our understanding of the pathogenesis of large vessel vasculitis (LVV) are mainly achieved by studying the arteries taken from temporal artery biopsy in giant cell arteries (GCA) or surgical or autopsy specimens in Takayasu arteritis (TAK). These artery specimens provide invaluable information about pathological changes in these conditions that GCA and TAK are similar but are distinctly different in immune cell infiltrate and distribution of inflammatory cells in anatomical locations. However, these specimens of established arteritis do not provide information of the arteritis initiation and early events which are impossible to obtain in human artery specimens. Animal models for LVV are needed but not available. Here, several approaches are proposed for experimentation to generate animal models to aid in delineating the interaction of immune reaction with arterial wall components.

Toll-like receptors 7 and 9 regulate the proliferation and differentiation of B cells in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune illness marked by the loss of immune tolerance and the production of autoantibodies against nucleic acids and other nuclear antigens (Ags). B lymphocytes are important in the immunopathogenesis of SLE. Multiple receptors control abnormal B-cell activation in SLE patients, including intrinsic Toll-like receptors (TLRs), B-cell receptors (BCRs), and cytokine receptors. The role of TLRs, notably TLR7 and TLR9, in the pathophysiology of SLE has been extensively explored in recent years. When endogenous or exogenous nucleic acid ligands are recognized by BCRs and internalized into B cells, they bind TLR7 or TLR9 to activate related signalling pathways and thus govern the proliferation and differentiation of B cells. Surprisingly, TLR7 and TLR9 appear to play opposing roles in SLE B cells, and the interaction between them is still poorly understood. In addition, other cells can enhance TLR signalling in B cells of SLE patients by releasing cytokines that accelerate the differentiation of B cells into plasma cells. Therefore, the delineation of how TLR7 and TLR9 regulate the abnormal activation of B cells in SLE may aid the understanding of the mechanisms of SLE and provide directions for TLR-targeted therapies for SLE.

Lateral cerebellothalamic tract activation underlies DBS therapy for Essential Tremor.

BACKGROUND: While deep brain stimulation (DBS) therapy can be effective at suppressing tremor in individuals with medication-refractory Essential Tremor, patient outcome variability remains a significant challenge across centers. Proximity of active electrodes to the cerebellothalamic tract (CTT) is likely important in suppressing tremor, but how tremor control and side effects relate to targeting parcellations within the CTT and other pathways in and around the ventral intermediate (VIM) nucleus of thalamus remain unclear. METHODS: Using ultra-high field (7T) MRI, we developed high-dimensional, subject-specific pathway activation models for 23 directional DBS leads. Modeled pathway activations were compared with post-hoc analysis of clinician-optimized DBS settings, paresthesia thresholds, and dysarthria thresholds. Mixed-effect models were utilized to determine how the six parcellated regions of the CTT and how six other pathways in and around the VIM contributed to tremor suppression and induction of side effects. RESULTS: The lateral portion of the CTT had the highest activation at clinical settings (p < 0.05) and a significant effect on tremor suppression (p < 0.001). Activation of the medial lemniscus and posterior-medial CTT was significantly associated with severity of paresthesias (p < 0.001). Activation of the anterior-medial CTT had a significant association with dysarthria (p < 0.05). CONCLUSIONS: This study provides a detailed understanding of the fiber pathways responsible for therapy and side effects of DBS for Essential Tremor, and suggests a model-based programming approach will enable more selective activation of lateral fibers within the CTT.

Complement-targeted therapy for autoimmune diseases.

The success and safety seen in treating complement-mediated hemolysis conditions has sparked the development of targeted therapies for rare autoimmune diseases, with expansion to more common autoimmune conditions. Various classes of drugs, including small molecules, peptides, monoclonal antibodies, and small interfering RNA (siRNA), are undergoing development to specifically address complement activity. A dual approach targeting both complement and other immune components may be required for autoimmune diseases characterized by inflammation and complex pathogenic mechanisms. siRNA, which suppresses complement production, is emerging as a potent therapeutic tool. Combining a complement-blocking siRNA drug with a treatment that reduces autoantibodies could prove clinically feasible and impactful in managing these conditions.

Contribution of Impaired DNASE1L3 Activity to Anti-DNA Autoantibody Production in Systemic Lupus Erythematosus.

Anti-DNA autoantibodies are pathogenic in systemic lupus erythematosus (SLE). Cell-free chromatin associated long DNA fragments are antigens for anti-DNA antibodies. In health state, released by cell death and actively secreted by live cells, these cell-free DNA are cleared by deoxyribonucleases (DNASES). In SLE, cell-free DNA are accumulated. The defective clearance of long fragments of cell-free DNA in SLE is largely attributed to impaired deoxyribonuclease 1 like 3 (DNASE1L3). DNASE1L3 null mutation results in monogenic SLE. The SLE risk single-nucleotide polymorphism (rs35677470) encodes R260C variant DNASE1L3, which is defective in secretion, leading to reduced levels of DNASE1L3. In addition, neutralizing autoantibodies to DNASE1L3 are produced in SLE to inhibit its enzymatic activity.

3D macroporous CUPC/g-C3N4 heterostructured composites for highly efficient multifunctional solar evaporation.

Solar-driven interfacial evaporation is a promising technology for water recycling and purification. A sustainable solar evaporation material should have not only high photothermal conversion efficiency, but also an ecofriendly fabrication process as well as pollutant degradation and sterilization properties. We present in this work a solar evaporator based on graphitic carbon nitride (g-C3N4) and copper phthalocyanine (CUPC) composites with typical type-I heterojunctions. Superhydrophilic three-dimensional macroporous g-C3N4 was obtained by self-assembly of precursors in aqueous solution followed by thermal polycondensation. By adding various weight ratios (0.15%, 1.5% and 7.5%) of CUPC, the composites exhibited a strong absorption in the region of red and infrared light. The CUPC-CN 7.5% composite achieved a photothermal conversion efficiency of 98.5% in nanofluids with an interfacial solar evaporation efficiency of 93.6% for artificial sea water and 98.7% for deionized water, which are among the highest reported to date. Besides, the composite materials demonstrated superior water purification capabilities by decomposing dye molecules and E. coli bacteria in aqueous solution. Our work established a novel approach for the development of multifunctional interfacial evaporators based on macroporous organic semiconductor heterostructures.

Sulfonylureas or biguanides is associated with a lower risk of rheumatoid arthritis in patients with diabetes: A nationwide cohort study.

Objective: Diabetes mellitus (DM) is associated with immune dysregulation, while sulfonylureas or biguanides have been linked to anti-inflammatory mechanisms. In this study, we aimed to examine the occurrence rate of rheumatoid arthritis (RA) among DM patients and its incidence rate between different treatments. Methods: This cohort study used the Taiwan National Health Insurance Research Database between 1997 and 2013 to evaluate the primary outcomes of the preventive role of sulfonylureas or biguanides in the development of RA. We used the Chi-square test for categorical variables and Cox proportional hazard regression and log-rank test to explore the time for development of RA in DM patients. Logistic regression was adopted to estimate the odds ratio of RA in different dosages of medication exposure. Results: Our cohort study included 94,141 DM cases. The risk of RA development of non-sulfonylureas/biguanides users among the DM group in each analysis was set as the reference, and the adjusted hazard ratio of RA in DM patients who were using sulfonylureas or biguanides was 0.73 (95% confidence interval 0.60-0.90). Within 1 year before the index date, compared with no-biguanides users, patients with more than 180 days of prescription of biguanides had a significantly lower RA risk. Similarly, the significantly lower risk of RA was still observed in DM patients who had more than 365 days of prescription of sulfonylurea within 2 or 3 years before the index date of first RA visit (all p < 0.05). Conclusion: Our data suggest that sulfonylureas or biguanides are associated with a lower rate of RA development in patients with DM; the effect of biguanides appeared more rapid than that of sulfonylureas, but the sulfonylureas might have a longer effect on lowering RA development incidence.

Highlights of Strategies Targeting Fibroblasts for Novel Therapies for Rheumatoid Arthritis.

Synovial fibroblasts of rheumatoid arthritis (RA) play a critical role in perpetuation of chronic inflammation by interaction with immune and inflammatory cells and in cartilage and bone invasion, but current therapies for RA are not directly targeted fibroblasts. Selectively fibroblast targeted therapy has been hampered because of lack of fibroblast specific molecular signature. Recent advancement in technology enabled us to gain insightful information concerning RA synovial fibroblast subpopulations and functions. Exploring fibroblast targeted therapies have been focused on inducing cell death via fibroblast associated proteins; interrupting fibroblast binding to matrix protein; blocking intercellular signaling between fibroblasts and endothelial cells; inhibiting fibroblast proliferation and invasion; promoting cell apoptosis and inducing cellular senescence, and modulating fibroblast glucose metabolism. Translation into clinical studies of these fibroblast targeted strategies is required for evaluation for their clinical application, in particular for combination therapy with current immune component targeted therapies. Here, several strategies of fibroblast targeted therapy are highlighted.

Schnitzler syndrome and Schnitzler-like syndromes.

ABSTRACT: Schnitzler syndrome is a rare disease of adult-onset with main features including chronic urticarial rash, recurrent fever, arthralgia or arthritis, monoclonal gammopathy of undetermined significance (MGUS), and marked systemic inflammation. Schnitzler syndrome is often underdiagnosed. Patients with Schnitzler syndrome may present to dermatologists and allergists for urticaria, hematologists for MGUS, or rheumatologists for arthritis. It is important to recognize Schnitzler syndrome for its remarkable response to interleukin (IL)-1 blockade. Besides, many cases of Schnitzler-like syndromes do not meet the diagnostic criteria of classical Schnitzler syndrome but display excellent response to IL-1 inhibitors. The overly produced IL-1 is the result of a somatic mosaic gain of function mutation of NLRP3 (nucleotide-binding oligomerization domain [NOD]-like receptor [NLR] family pyrin domain containing 3) gene in some patients with Schnitzler-like syndromes. Inflammasome activation is evident in patients with classical Schnitzler syndrome although no NLRP3 gene mutation is identified. Collectively, Schnitzler syndrome and Schnitzler-like syndromes represent a spectrum of IL-1 mediated adult-onset autoinflammatory diseases.

RNA isolation from micro-quantity of articular cartilage for quantitative gene expression by microarray analysis.

Isolation of quality RNA from articular cartilage has been challenging due to low cellularity and the high abundance of extracellular matrix and proteoglycan proteins. Recently developed methods for isolation of high quality RNA from cartilage are more applicable to larger cartilage specimens typically weighing at least 25 mg. While these methods generate RNA suitable for analysis, they are less successful with smaller tissue inputs. For the study of small focal defect cartilage specimens an improved RNA extraction method is needed. Here we report a protocol for direct RNA isolation from less than 3 mg of wet weight rabbit articular cartilage for quantitative microarray gene profiling. This protocol is useful for identifying differentially expressed genes in chondrocytes following focal cartilage repair and can potentially be adopted for gene expression analysis of cartilage biopsy specimens from human joints.

Prediction of treatment response: Personalized medicine in the management of rheumatoid arthritis.

Highly efficacious drugs are widely available for treating rheumatoid arthritis (RA). However, accurately selecting a likely effective drug for individual RA patients has been challenging. Biomarkers are required since clinical phenotypes are not reliable to guide the choice of drugs. Previously identified genetic variants for predicting treatment response have failed in replication in independent cohorts of RA patients. Recent studies aimed at the discovery of biomarkers to predict treatment response have focused on integrative omics analysis, expanded to the microbiome, and further finer definition of synovial pathotypes. Treatment responders and non-responders of RA patients can be distinguished by distinct signatures at baseline in their gut microbiota compositions, peripheral blood transcriptome profiling or histomorphological and molecular pathotypes of synovitis. These distinct biological signatures are promising for developing clinically applicable tools for decision in the selection of drugs for RA, albeit further validations in independent cohorts are required.