Disease Modification in Gout: A Qualitative Study of Gout Expert Rheumatologists

Objective To examine healthcare provider views of disease modification in gout to potentially derive a provisional set of domains for disease modification in gout. Methods We performed a qualitative nominal group (NG) study with 20 gout experts (15 were authors/expert panel members of the 2012 and/or 2020 ACR gout guidelines, and/or 2015 ACR/EULAR gout classification criteria) about what constitutes “disease modification” in gout – “What sorts of things do you think constitute a change in the course of disease in gout? (positive); What are all the ways in which gout as a disease can be modified?” Results Decrease in gout flares was rated #1 rank in all six NGs as indicative of disease modification in gout, followed by serum urate (SU) lowering, which was rated #1 rank in 1 of the 6 NGs (tied score with flares in one NG). Other components of gout disease modification were to improve quality of life/productivity; restore function; reduce/eliminate pain; reduce tophi burden; and joint preservation or resolution of joint damage. Potential additional components that were not ranked in the top 3 votes within each NG were: Decrease healthcare cost/utilization; cardiovascular/renal morbidity/mortality reduction; and stop urate crystals formation. Conclusion This qualitative study provides a provisional set of domains for disease modification in gout. Future studies for the development of thresholds for disease modification domains, and wider consensus on this definition are needed.

Propionibacterium freudenreichii Inhibits RANKL-Induced Osteoclast Differentiation and Ameliorates Rheumatoid Arthritis in Collagen-Induced Arthritis Mice

Osteoclast differentiation is crucial for bone absorption, and osteoclasts are involved in bone destruction in rheumatoid arthritis (RA). Dairy Propionibacterium freudenreichii is used as a cheese starter and possesses prebiotic and postbiotic properties. It is known to stimulate the growth of bifidobacteria and produces valuable metabolites, such as vitamin B12 and propionic acid. However, limited information is available on the beneficial effects of P. freudenreichii on human disease. Herein, we aimed to investigate the inhibitory effect of P. freudenreichii MJ2 (MJ2) isolated from raw milk on osteoclast differentiation and evaluate the improvement in RA. The murine macrophage cell line, RAW 264.7, and a collagen-induced arthritis (CIA) mouse model were used to perform in vitro and in vivo studies, respectively. Heat-killed P. freudenreichii MJ2 (hkMJ2)-treated cells significantly inhibited RANKL-induced osteoclast differentiation and TRAP activity. HkMJ2-treated cells exhibited significantly decreased expression of genes and proteins related to RANKL-induced osteoclast differentiation. MJ2 administration decreased the arthritic score in the CIA mouse model. Live and dead MJ2 inhibited bone loss and afforded protection against bone erosion and joint damage in CIA mice. MJ2 decreased the levels of collagen-specific antibodies and inflammatory cytokines and the expression of osteoclast differentiation-related genes and proteins in CIA mice. Interestingly, live and dead MJ2 showed similar RA improvement effects in CIA mice. In conclusion, P. freudenreichii MJ2 inhibited osteoclast differentiation by inhibiting the NF-κB signaling pathway and ameliorated CIA.

Molecular Modeling Insights into Upadacitinib Selectivity upon Binding to JAK Protein Family

Rheumatoid arthritis (RA) is a chronic disease characterized by bone joint damage and incapacitation. The mechanism underlying RA pathogenesis is autoimmunity in the connective tissue. Cytokines play an important role in the human immune system for signal transduction and in the development of inflammatory responses. Janus kinases (JAK) participate in the JAK/STAT pathway, which mediates cytokine effects, in particular interleukin 6 and IFNγ. The discovery of small molecule inhibitors of the JAK protein family has led to a revolution in RA therapy. The novel JAK inhibitor upadacitinib (RinvoqTM) has a higher selectivity for JAK1 compared to JAK2 and JAK3 in vivo. Currently, details on the molecular recognition of JAK1 by upadacitinib are not available. We found that characteristics of hydrogen bond formation with the glycine loop and hinge in JAKs define the selectivity. Our molecular modeling study could provide insight into the drug action mechanism and pharmacophore model differences in JAK isoforms.

14-3-3η Promotes Invadosome Formation via the FOXO3–Snail Axis in Rheumatoid Arthritis Fibroblast-like Synoviocytes

Erosive destruction of joint structures is a critical event in the progression of rheumatoid arthritis (RA), in which fibroblast-like synoviocytes (FLS) are the primary effectors. We previously reported that the ability of RA FLS to degrade extracellular matrix (ECM) components depends on the formation of actin-rich membrane protrusions, called invadosomes, through processes that remain elusive. 14-3-3η belongs to a family of scaffolding proteins involved in a wide range of cellular functions, and its expression is closely related to joint damage and disease activity in RA patients. In this study, we sought to assess the role of 14-3-3η in joint damage by examining its contribution to the invadosome formation phenotype of FLS. Using human primary FLS, we show that 14-3-3η expression is closely associated with their ability to form invadosomes. Furthermore, knockdown of 14-3-3η using shRNAs decreases the level of invadosome formation in RA FLS, whereas addition of the recombinant protein to FLS from healthy individuals promotes their formation. Mechanistic studies suggest that 14-3-3η regulates invadosome formation by increasing Snail expression, a mechanism that involves nuclear exclusion of the transcription repressor FOXO3. Our results implicate the 14-3-3η–FOXO3–Snail axis in promoting the aggressive ECM-degrading phenotype of RA FLS, and suggest a role for this scaffolding protein in cartilage degradation.

A COMPARATIVE CLINICAL STUDY OF MATRAVASTI AND PICHU WITH RASNA TAILA IN SANDHIGATAVATA W.S.R TO OSTEOARTHRITIS

Sandhigata Vata (Osteoarthritis) is a type of Vatavyadhi (degenerative disease) that mainly occurs in Vrid- dhavastha (Old age) due to Dhatukshaya (cellular degeneration). Vagabhatta has also considered Vata Vyadhi as a Maharoga. It appears from the point of view of modern medical sciences that Sandhigata vata can be simulated with Osteoarthritis in its clinical appearance. Osteoarthritis is the most common articular disorder that begins asymptomatically in the 2nd and 3rddecades and is extremely common by age 70. Almost all persons by age 40 have some pathologic change in the weight-bearing joint. 25% of females and 16% males have symptomatic OA. This disease has been described in Ayurveda from ancient times. The disease Arthritis causes work disability. It limits everyday activities such as walking, dressing, bathing etc, thus making individuals handicapped. No treat- ment is available which can prevent the disease process. In western medical science, mainly analgesics, anti- inflammatory drugs or surgery are the options for the treatment of Osteoarthritis; don’t provide remarkable recov- ery but causes great adverse effect. Researchers are trying their level best for making drugs that can prevent or slow down or reverse joint damage. Panchakarma therapy is one of the important branches of Ayurveda, which deals mainly with the purification of the aggravated Doshas from the human system. This is the reason behind the selection of the topic entitled “A COMPARATIVE CLINICAL STUDY OF MATRA VASTI AND PICHU WITH RASNA TAILA IN SANDHIGATA VATA W.S.R TO OSTEOARTHRITIS”. We have used Panchakarma treatment procedure. Panchakarma treatment is believed to help in the radical elimi- nation of the disease-causing factors and maintain the equilibrium of doshas. The selection of Matravasti and pichu both are based on repeated recommendations of different Acharyas on Sandhigatavata. We used Rasna taila. Keywords: Sandhigata vata, Osteoarthritis, MatraVasti, Pichu, Rasna taila

Peptides Bearing Multiple Post-Translational Modifications as Antigenic Targets for Severe Rheumatoid Arthritis Patients

Rheumatoid arthritis (RA) is characterized by the presence of autoantibodies that are of paramount importance for the diagnosis and prognosis of the disease and have been implicated in its pathogenesis. Proteins resulting from post-translational modifications (PTMs) are capable of triggering autoimmune responses important for the development of RA. In this work, we investigate serum antibody reactivity in patients with an established RA against a panel of chimeric peptides derived from fibrin and filaggrin proteins and bearing from one to three PTMs (citrullination, carbamylation and acetylation) by home-designed ELISA tests (anti-AMPA autoantibodies). The role of anti-AMPAs as biomarkers linked to the presence of a more severe RA phenotype (erosive disease with radiological structural damage) and to the presence of interstitial lung disease (ILD), a severe extra-articular manifestation in RA patients entailing a high mortality, was also analyzed. In general, the association with the clinical phenotype of RA was confirmed with the different autoantibodies, and especially for IgA and IgM isotypes. The prevalence of severe joint damage was only statistically significant for the IgG isotype when working with the peptide bearing three PTMs. Furthermore, the median titers were significantly higher in patients with RA-ILD, a finding not observed for the IgG isotype when working with the single- and double-modified peptides.

Juvenile Idiopathic Arthritis: A Review of Novel Diagnostic and Monitoring Technologies

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of childhood and is characterized by an often insidious onset and a chronic relapsing–remitting course, once diagnosed. With successive flares of joint inflammation, joint damage accrues, often associated with pain and functional disability. The progressive nature and potential for chronic damage and disability caused by JIA emphasizes the critical need for a prompt and accurate diagnosis. This article provides a review of recent studies related to diagnosis, monitoring and management of JIA and outlines recent novel tools and techniques (infrared thermal imaging, three-dimensional imaging, accelerometry, artificial neural networks and fuzzy logic) which have demonstrated potential value in assessment and monitoring of JIA. The emergence of novel techniques to assist clinicians’ assessments for diagnosis and monitoring of JIA has demonstrated promise; however, further research is required to confirm their clinical utility.

Gender characteristics of gout and differences in response to taking xanthioxidase inhibitors

Introduction. To date, there is no consensus regarding the gender characteristics of the course of gout. There is little data on the possible difference between men and women in response to uric acid-lowering therapy.Aim. To compare the clinical characteristics of the course of gout and evaluate the differences in response to urate-lowering therapy (ULT) with allopurinol and febuxostat in men and women.Material and methods. The retrospective cohort study included 279 men and 83 women diagnosed with gout (ACR/EULAR, 2015). The comparative analysis of the clinical characteristics of gout, as well as responses to the intake of xanthioxidase (XO) inhibitors in representatives of different sexes, was carried out. We compared the gender characteristics of obtaining a positive response to ULT, defined as achieving a target serum uric acid (sUA) level of < 360 μmol / l within 6 months of treatment, while taking allopurinol and febuxostat.Results. By the age at which the onset of gout took place, women were older than men, the duration of the disease in them was shorter. Men showed a shorter duration of the first attack of arthritis. Chronic arthritis was diagnosed in 56% of men and 35% of women (p < 0.05). The process involved the joints of both the lower and upper extremities. However, more often the joints of the lower extremities were affected in men, and in the upper extremities in women. Tophus were detected in 35% of patients, of whom 30.3% were men, 4.7% were women (p < 0.05). Allopurinol was prescribed to 216 men and 54 women, and febuxostat was prescribed to 63 men and 29 women. After six months, the proportion of women who achieved the target sUA was 57.5% and 65.8%, the proportion of men – 60.4% and 76.2% for allopurinol and febuxostat, respectively.Conclusion. The clinical manifestations of gout in men and women differ. Due to the pronounced increase in the level of uric acid, men develop more severe joint damage due to the tendency to chronicity. However, the study did not reveal gender differences in the response to XO inhibitors, which indicates that there is no need to choose therapy depending on the patient’s gender.

Micro RNA-23b as a potential biomarker in rheumatoid arthritis disease activity and severity: clinical, laboratory, and radiological cross-sectional study

Background Rheumatoid arthritis (RA) is an autoimmune inflammatory disease. It is characterized by an inflammatory polyarthritis that preferentially affects the small joints leading to joint damage and eventual deformity and disability, and can also present with extra-articular manifestations. Micro RNA (miRNA) is a class of non-coding RNAs which negatively regulate messenger RNA (mRNA) expression. Several studies had shown that miRNA-23b has a close relationship with inflammation and autoimmune diseases. An increasing evidence has suggested that miRNA-23b is closely associated with many inflammatory and autoimmune diseases. The current study aimed to evaluate the plasma expression of miRNA-23b in rheumatoid arthritis (RA) patients and to explore its potential association with diseases activity. Results RA patients had a significantly higher plasma miRNA-23b expression than controls (P < 0.001). The miRNA-23b plasma expression was significantly associated with the clinical and laboratory indices of RA activity as well as with the DAS28-ESR score (P = 0.009) and grades (P < 0.001). The miRNA-23b plasma expression was significantly correlated with the radiological severity of RA (P = 0.002). Conclusions Plasma expression of miRNA-23b is significantly increased in patients with RA than controls. In RA patients, plasma expression of miRNA-23b was significantly correlated with the activity and radiological severity of RA. miRNA-23b may represent a potential therapeutic target that can retard progression of RA.