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Pathogenic responses of bradykinin system in chronic inflammatory rheumatoid disease

Sharma JN, Buchanan WW

Exp. Toxicol. Pathol., 1994 Dec;46(6):421-33.
PMID: 7703672 DOI: 10.1016/S0940-2993(11)80053-9

Excessive release of kinin (BK) in the synovial fluid can produce oedema, pain and loss of functions due to activation of B1 and B2 kinin receptors. Activation of the kinin forming system could be mediated via injury, trauma, coagulation pathways (Hageman factor and thrombin) and immune complexes. The activated B1 and B2 receptors might cause release of other powerful non-cytokine and cytokine mediators of inflammation, e.g., PGE2, PGI2, LTs, histamine, PAF, IL-1 and TNF, derived mainly from polymorphonuclear leukocytes, macrophages, endothelial cells and synovial tissue. These mediators are capable of inducing bone and cartilage damage, hypertrophic synovitis, vessel proliferation, inflammatory cell migration and, possibly, angiogenesis in pannus formation. These pathological changes, however, are not yet defined in the human model of chronic inflammation. The role of kinins and their interacting inflammatory mediators would soon start to clarify the detailed questions they revealed in clinical and experimental models of chronic inflammatory diseases. Several B1 and B2 receptor antagonists are being synthesized in an attempt to study the molecular functions of kinins in inflammatory processes, such as rheumatoid arthritis, periodontitis, inflammatory diseases of the gut and osteomyelitis. Future development of specific potent and stable B1 and B2 receptor antagonists or combined B1 and B2 antagonists with y-IFN might serve as a pharmacological basis for more effective treatment of joint inflammatory and related diseases.

Matched MeSH terms: Arthritis, Rheumatoid/metabolism*
Fulltext Osteoimmunology: Major and Costimulatory Pathway Expression Associated with Chronic Inflammatory Induced Bone Loss

Crotti TN, Dharmapatni AA, Alias E, Haynes DR

J Immunol Res, 2015;2015:281287.
PMID: 26064999 DOI: 10.1155/2015/281287

The field of osteoimmunology has emerged in response to the range of evidences demonstrating the close interrelationship between the immune system and bone metabolism. This is pertinent to immune-mediated diseases, such as rheumatoid arthritis and periodontal disease, where there are chronic inflammation and local bone erosion. Periprosthetic osteolysis is another example of chronic inflammation with associated osteolysis. This may also involve immune mediation when occurring in a patient with rheumatoid arthritis (RA). Similarities in the regulation and mechanisms of bone loss are likely to be related to the inflammatory cytokines expressed in these diseases. This review highlights the role of immune-related factors influencing bone loss particularly in diseases of chronic inflammation where there is associated localized bone loss. The importance of the balance of the RANKL-RANK-OPG axis is discussed as well as the more recently appreciated role that receptors and adaptor proteins involved in the immunoreceptor tyrosine-based activation motif (ITAM) signaling pathway play. Although animal models are briefly discussed, the focus of this review is on the expression of ITAM associated molecules in relation to inflammation induced localized bone loss in RA, chronic periodontitis, and periprosthetic osteolysis, with an emphasis on the soluble and membrane bound factor osteoclast-associated receptor (OSCAR).

Matched MeSH terms: Arthritis, Rheumatoid/metabolism
Salivary and serum cathelicidin LL-37 levels in subjects with rheumatoid arthritis and chronic periodontitis

Cheah CW, Al-Maleki AR, Vadivelu J, Danaee M, Sockalingam S, Baharuddin NA, et al.

Int J Rheum Dis, 2020 Oct;23(10):1344-1352.
PMID: 32743970 DOI: 10.1111/1756-185X.13919

INTRODUCTION: Rheumatoid arthritis (RA) is associated with chronic periodontitis (CP) due to shared risk factors, immuno-genetics and tissue destruction pathways. Human cathelicidin LL-37 has been suggested as a possible mechanistic link for these diseases. This study investigated the levels of salivary and serum LL-37 in subjects with RA and CP and their correlation with disease parameters.
METHOD: Subjects were allocated into RA (n = 49) or non-RA (NRA) (n = 55) groups, where 3 subgroups were further established; chronic periodontitis (CP), gingivitis (G) and periodontal health (H). Demographic and periodontal parameters were collected. Rheumatology data were obtained from hospital records. Serum and salivary LL-37 levels were measured using enzyme-linked immunosorbent assay and compared for all groups.
RESULTS: For salivary LL-37, RA-CP was significantly higher than NRA-G and NRA-H (P = .047). For serum LL-37, all RA and NRA-CP were significantly higher than NRA-G and NRA-H (P = .024). Salivary LL-37 correlated negatively with clinical attachment loss (CAL) (P = .048), but positively with erythrocyte sedimentation rate (ESR) in RA-H (P = .045). Serum LL-37 showed positive correlation with ESR (P = .037) in RA-G, with C-reactive protein (P = .017) in RA-H, but negative correlation with number of teeth (P = .002) in NRA-CP. Rheumatology data correlated positively with periodontal parameters in RA-CP group.
CONCLUSION: NRA-CP subjects with high serum LL-37 should receive comprehensive periodontal therapy. Positive correlation between rheumatology data and periodontal parameters showed that RA disease stability may be obtained by assessing the periodontal condition. Periodontal therapy is necessary to compliment RA treatment to achieve optimum outcome for RA patients with concurrent CP.

Matched MeSH terms: Arthritis, Rheumatoid/metabolism*
The effect of disease activity on fat-free mass and resting energy expenditure in patients with rheumatoid arthritis versus noninflammatory arthropathies/soft tissue rheumatism

Arshad A, Rashid R, Benjamin K

Mod Rheumatol, 2007;17(6):470-5.
PMID: 18084698 DOI: 10.1007/s10165-007-0628-1

Rheumatoid arthritis (RA) is a chronic joint disease of undetermined cause that is associated with significant disability. Low-grade fever, anemia, and weight loss are recognized extra-articular features associated with increased disease activity. Weight loss and cachexia are well-established features of RA. The mechanism behind weight loss in RA is not known and may be multifactorial. Reduced energy intake and hypermetabolism are the major two factors frequently implicated in the etiology of RA cachexia. One would expect the effect of the above two factors to be highest during increased disease activity and lowest during remission. The purpose of this study was: (a) to establish whether in RA patients changes in body composition mirror changes in disease activity, (b) to investigate the relation between the energy expenditures and weight loss, (c) to examine the dietary energy intake and its role in weight loss in RA patients, and (d) to investigate the relation between the cytokine interleukin (IL)-6 and other variables including resting energy expenditure (REE), body composition, and acute phase reactants. Fourteen patients with RA were age-, sex-, and race-matched with 14 controls from patients with noninflammatory diseases/soft tissue rheumatism. The measurements included the following: disease activity assessment, anthropometric measurements, indirect calorimetry, and measurements of dietary intake. Blood was collected to measure the acute-phase reactants and IL-6 levels. We demonstrated that loss of fat-free mass (FFM) might accelerate during times of increased disease activity and is only partially restored during periods of reduced disease activity. This probably means that the extent of cachexia in RA patients is determined by the frequency and intensity of disease activity (flare) for a given disease duration. Hypermetabolism with increased REE was more evident during increased disease activity. Hypermetabolism in the face of increased energy intake continued to cause loss of the FFM. Interleukin-6 correlates with increased REE and erythrocyte sedimentation rate. There was no direct association between IL-6 level and low FFM. We conclude that loss of FFM is common in RA, cytokine production in RA is associated with altered energy metabolism, and preservation of FFM is important in maintaining good quality of life in patients with RA.
Study site: Rheumatology clinic, Putra Specialist Centre, Kedah

Matched MeSH terms: Arthritis, Rheumatoid/metabolism
Rheumatoid arthritis: Recent advances on its etiology, role of cytokines and pharmacotherapy

Alam J, Jantan I, Bukhari SNA

Biomed Pharmacother, 2017 Aug;92:615-633.
PMID: 28582758 DOI: 10.1016/j.biopha.2017.05.055

An autoimmune disease is defined as a clinical syndrome resulted from an instigation of both T cell and B cell or individually, in the absence of any present infection or any sort of distinguishable cause. Clonal deletion of auto reactive cells remains the central canon of immunology for decades, keeping the role of T cell and B cell aside, which are actually the guards to recognize the entry of foreign body. According to NIH, 23.5 million Americans are all together affected by these diseases. They are rare, but with the exception of RA. Rheumatoid arthritis is chronic and systemic autoimmune response to the multiple joints with unknown ethology, progressive disability, systemic complications, early death and high socioeconomic costs. Its ancient disease with an old history found in North American tribes since 1500 BCE, but its etiology is yet to be explored. Current conventional and biological therapies used for RA are not fulfilling the need of the patients but give only partial responses. There is a lack of consistent and liable biomarkers of prognosis therapeutic response, and toxicity. Rheumatoid arthritis is characterized by hyperplasic synovium, production of cytokines, chemokines, autoantibodies like rheumatoid factor (RF) and anticitrullinated protein antibody (ACPA), osteoclastogensis, angiogenesis and systemic consequences like cardiovascular, pulmonary, psychological, and skeletal disorders. Cytokines, a diverse group of polypeptides, play critical role in the pathogenesis of RA. Their involvement in autoimmune diseases is a rapidly growing area of biological and clinical research. Among the proinflammatory cytokines, IL-1α/β and TNF-α trigger the intracellular molecular signalling pathway responsible for the pathogenesis of RA that leads to the activation of mesenchymal cell, recruitment of innate and adaptive immune system cells, activation of synoviocytes which in term activates various mediators including tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-8), resulting in inflamed synovium, increase angiogenesis and decrease lymphangiogensis. Their current pharmacotherapy should focus on their three phases of progression i.e. prearthritis phase, transition phase and clinical phase. In this way we will be able to find a way to keep the balance between the pro and anti-inflammatory cytokines that is believe to be the dogma of pathogenesis of RA. For this we need to explore new agents, whether from synthetic or natural source to find the answers for unresolved etiology of autoimmune diseases and to provide a quality of life to the patients suffering from these diseases specifically RA.

Matched MeSH terms: Arthritis, Rheumatoid/metabolism
Osteonecrosis with renal damage in HIV patients undergoing HAART

Chitra P, Bakthavatsalam B, Palvannan T

Biomed Pharmacother, 2014 Sep;68(7):881-5.
PMID: 25194446 DOI: 10.1016/j.biopha.2014.07.017

Rheumatoid arthritis in HIV patients undergoing HAART is associated with increased risk of side effect. Elevation of uric acid (UA) is important in tissue damage, deposition of crystal in joints leads to the development of rheumatoid arthritis in the HAART complaint group. This study was carried out to investigate the relationship of uric acid, RA factor, ANA, ESR, cystatin C, urea and creatinine in the HAART complaint group. Moreover; the ratio of uric acid/cystatin C, uric acid/urea and uric acid/creatinine were also studied. To analyze the progression of HIV, the immunological parameters were correlated with uric acid. Our result showed a statistically high significant increase in uric acid, RA factor, ANA, ESR, cystatin C, urea and creatinine in the HAART complaint group when compared to HAART non-complaint group, early stage and control. The ratio of uric acid/cystatin C, uric acid/urea, uric acid/creatinine were significantly increased in the HAART complaint group. Statistically significant positive correlation was observed between uric acid and cystatin C, urea, creatinine, absolute CD4 and CD8 count. The increased level of uric acid, RA factor, ANA, ESR, cystatin C and increased ratio of uric acid/cystatin C in the HAART complaint group might conclude the mechanism underlying the increased risk for rheumatoid arthritis in the HAART complaint group which may relate to the combined effects of low-grade inflammation and renal dysfunction.

Study done in India

Matched MeSH terms: Arthritis, Rheumatoid/metabolism
Fulltext Molecular modulators of celastrol as the keystones for its diverse pharmacological activities

Ng SW, Chan Y, Chellappan DK, Madheswaran T, Zeeshan F, Chan YL, et al.

Biomed Pharmacother, 2019 Jan;109:1785-1792.
PMID: 30551432 DOI: 10.1016/j.biopha.2018.11.051

In the recent years, much attention has been focused on identifying bioactive compounds from medicinal plants that could be employed in therapeutics, which is attributed to their potent pharmacological actions and better toxicological profile. One such example that has come into the light with considerable interest is the pentacyclic triterpenoid, celastrol, which has been found to provide substantial therapeutic properties in a variety of diseases. In an effort to further accelerate its potential to be utilized in clinical practice in the future; along with advancing technologies in the field of drug discovery and development, different researchers have been investigating on the various mechanisms and immunological targets of celastrol that underlie its broad spectrum of pharmacological properties. In this review, we have collated the various research findings related to the molecular modulators responsible for different pharmacological activities shown by celastrol. Our review will be of interest to the herbal, biological, molecular scientist and by providing a quick snapshot about celastrol giving a new direction in the area of herbal drug discovery and development.

Matched MeSH terms: Arthritis, Rheumatoid/metabolism
The effects of TNF α antagonist therapy on bone metabolism in rheumatoid arthritis: a systematic review

Sakthiswary R, Das S

Curr Drug Targets, 2013 Dec;14(13):1552-7.
PMID: 23848441

Osteoporosis is a common complication observed in rheumatoid arthritis (RA). Accelerated bone loss is always a matter of concern. The pathogenesis of RA may be important for better understanding of the bone loss. The mechanism involved in the bone loss in RA is not well understood although cytokines such as interleukin 1 and tumour necrosis factor α (TNF α) have been strongly implicated. TNF α antagonists have revolutionised the treatment of RA in the recent years. Beyond the control of disease activity in RA, accumulating evidence suggests that this form of therapy may provide beneficial effects to the bone metabolism and remodeling. An extensive search of the literature was performed in the Medline, Scopus and EBSCO databases to evaluate the documented research on the effects of TNF α antagonists in RA on bone mineral density and bone turnover markers. The available data based on our systematic review, depict a significant association between TNF α antagonists treatment and suppression of bone resorption.

Matched MeSH terms: Arthritis, Rheumatoid/metabolism
Fulltext Clinical Aspects of Janus Kinase (JAK) Inhibitors in the Cardiovascular System in Patients with Rheumatoid Arthritis

Kotyla PJ, Islam MA, Engelmann M

Int J Mol Sci, 2020 Oct 07;21(19).
PMID: 33036382 DOI: 10.3390/ijms21197390

Janus kinase (JAK) inhibitors, a novel class of targeted synthetic disease-modifying antirheumatic drugs (DMARDs), have shown their safety and efficacy in rheumatoid arthritis (RA) and are being intensively tested in other autoimmune and inflammatory disorders. Targeting several cytokines with a single small compound leads to blocking the physiological response of hundreds of genes, thereby providing the background to stabilize the immune response. Unfortunately, blocking many cytokines with a single drug may also bring some negative consequences. In this review, we focused on the activity of JAK inhibitors in the cardiovascular system of patients with RA. Special emphasis was put on the modification of heart performance, progression of atherosclerosis, lipid profile disturbance, and risk of thromboembolic complications. We also discussed potential pathophysiological mechanisms that may be responsible for such JAK inhibitor-associated side effects.

Matched MeSH terms: Arthritis, Rheumatoid/metabolism
Dietary Phytochemicals: Natural Swords Combating Inflammation and Oxidation-Mediated Degenerative Diseases

Islam MA, Alam F, Solayman M, Khalil MI, Kamal MA, Gan SH

Oxid Med Cell Longev, 2016;2016:5137431.
PMID: 27721914

Cumulatively, degenerative disease is one of the most fatal groups of diseases, and it contributes to the mortality and poor quality of life in the world while increasing the economic burden of the sufferers. Oxidative stress and inflammation are the major pathogenic causes of degenerative diseases such as rheumatoid arthritis (RA), diabetes mellitus (DM), and cardiovascular disease (CVD). Although a number of synthetic medications are used to treat these diseases, none of the current regimens are completely safe. Phytochemicals (polyphenols, carotenoids, anthocyanins, alkaloids, glycosides, saponins, and terpenes) from natural products such as dietary fruits, vegetables, and spices are potential sources of alternative medications to attenuate the oxidative stress and inflammation associated with degenerative diseases. Based on in vitro, in vivo, and clinical trials, some of these active compounds have shown good promise for development into novel agents for treating RA, DM, and CVD by targeting oxidative stress and inflammation. In this review, phytochemicals from natural products with the potential of ameliorating degenerative disease involving the bone, metabolism, and the heart are described.

Matched MeSH terms: Arthritis, Rheumatoid/metabolism

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