You're using an outdated browser. Please upgrade to a modern browser for the best experience.
Medicinal and Aromatic Plants against Obesity and Arthritis: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Rheumatology | Integrative & Complementary Medicine
Contributor: Alok Paul

Obesity is a significant health concern, as it causes a massive cascade of chronic inflammations and multiple morbidities. Rheumatoid arthritis and osteoarthritis are chronic inflammatory conditions and often manifest as comorbidities of obesity. Adipose tissues serve as a reservoir of energy as well as releasing several inflammatory cytokines (including IL-6, IFN-γ, and TNF-α) that stimulate low-grade chronic inflammatory conditions such as rheumatoid arthritis, osteoarthritis, diabetes, hypertension, cardiovascular disorders, fatty liver disease, oxidative stress, and chronic kidney diseases. Dietary intake, low physical activity, unhealthy lifestyle, smoking, alcohol consumption, and genetic and environmental factors can influence obesity and arthritis. Current arthritis management using modern medicines produces various adverse reactions. Medicinal plants have been a significant part of traditional medicine, and various plants and phytochemicals have shown effectiveness against arthritis and obesity; however, scientifically, this traditional plant-based treatment option needs validation through proper clinical trials and toxicity tests. In addition, essential oils obtained from aromatic plants are being widely used for complementary therapy (e.g., aromatherapy, smelling, spicing, and consumption with food) against arthritis and obesity; scientific evidence is necessary to support their effectiveness.

  • rheumatoid arthritis
  • obesity
  • spice
  • medicinal plant
  • aromatic plant
  • essential oil
  • osteoarthritis
  • comorbidity

1. Introduction

Obesity can be characterized as a body mass index (BMI) of 25 or more in adults, who are classified as overweight, or a BMI of 30 or more, classified as obesity [1]. In 2016, around 1.9 billion adults (aged > 18 years) were overweight, but >650 million people were obese. According to the WHO, the cause of obesity is an increased consumption of foods that are high in fat and sugars, along with the progressively sedentary nature of modern lifestyles, reduced physical work, lack of exercise, and urbanization [1]. An increased waist circumference of more than 40 inches in men (35 inches in women) is known as visceral adiposity, and can be a cause for concern even when BMI is at a normal level. Obesity and overweight also cause other diseases as comorbidities, such as musculoskeletal disorders (e.g., arthritis) [2], cardiovascular diseases [3], diabetes [4], and cancer [5].

1.1. Obesity and Inflammation

Obesity is caused by various factors, including imbalance between energy intake and expenditure, sedentary lifestyle, genetics, and many other causes [6]. In terms of cellular mechanisms, adipocytes (cells responsible for the storage of lipids from food and synthesized from de novo lipogenesis) and macrophages secrete adipokines, and excess secretion of adipokines causes low-grade inflammation in some obese people [6][7]. In addition, triglycerides present in adipocytes hydrolyze into free fatty acids, and are transported into the blood circulation of obese people. Lipid deposition in hepatocytes can be seen in disease conditions such as non-alcoholic fatty liver disease (NAFLD) and other comorbidities related to obesity [7]. Heymsfield and Thomas described how obesity is strongly connected to the pathogenesis of several chronic diseases, such as coronary artery disease (CAD), NAFLD, osteoarthritis (OA), gastroesophageal reflux disease, obstructive sleep apnea, stroke, and chronic kidney disease [6]. Immune dysfunction derived from obesity is caused by excess secretion of inflammatory adipokines [8]. A clinical study revealed that obesity was firmly connected with various proinflammatory cytokines, such as interleukins (ILs: IL-5, -10, -12, and -13), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α), and obese patients displayed elevated plasma levels of IL-4, -10, and -13 [9]. Thus, obesity is not simply a result of high energy intake and low energy expenditure; it is multifaceted, and inflammatory cytokines (increased TNF-α, IL-4, and IL-6; reduced IL-10), adipokines (e.g., adiponectin, leptin, resistin, and visfatin), and many other factors are involved in the pathogenesis of obesity [10][11]. The interaction between adipocytes and hepatic lipid metabolism, along with imbalance in the synthesis of de novo synthesis, causes obesity and associated comorbidities [12][13]. Adipocytes release adipokinomes or adipokines that control energy metabolism and dietary intake [14]. Adipokinomes regulate the secretion of adipose cells, releasing fatty acids and prostaglandins, adipsin, proinflammatory cytokines such as IL-1β, -6, -8, and -10, and tumor necrosis factor-α (TNF-α) [10][15][16]. Excess plasma IL-6 levels trigger the release of C-reactive proteins by hepatocytes, which indicate the levels of chronic inflammation and the risk of cardiovascular disorders [17]. Collectively, these processes lead to lipid deposition (obesity), vascular hemostasis, insulin resistance, chronic metabolic diseases such as type 2 diabetes, and inflammation, as the proinflammatory cytokines transform into inflammatory cytokines [17][18][19]. Inflammatory processes also stimulate the development or progression of psoriasis, cancer, and kidney diseases [17]. Increased plasma contents of IL-6, IL-10, and IL-18 are observed among obese patients [20][21]. Thus, obesity is not merely a metabolic disease; rather, it is a chronic inflammatory disorder, where dietary intake inflicts or triggers the pathogenesis of obesity and diabetes [11][22].

1.2. Influence of Dietary Habits during Childhood on Obesity and Inflammation

As mentioned in the previous section, there are possible correlations between obesity and adult diet. Similarly, childhood diet may influence the possibility of obesity and other comorbidities in later life. Breastfeeding (intake of colostrum and milk) at an earlier age (from birth to 6 months of age) reduces plasma proinflammatory cytokine levels compared to formula feeding [23] (Figure 1). Breast milk is an ideal food for children, naturally supplemented with various bioactive immunomodulatory substances such as immunoglobulins (e.g., secretory IgA), oligosaccharides, cytokines (e.g., IL-1, IFN-α, IL-6, and TNF-α help in the development and functions of the mammary gland), growth factors (e.g., transforming growth factor β2), food antigens, and essential microbiota supplements (e.g., non-sterile breast milk contains long-chain polyunsaturated fatty acids (LCPUFAs), which impede the production of proinflammatory cytokines [24][25][26] (Figure 1). Human milk intake in infancy can also protect children against various pathogens, including but not limited to Bordetella pertussis, Campylobacter, Haemophilus, Salmonella, Streptococcus, Shigella, Vibrio cholerae, and respiratory viruses [23][27][28]. Noticeably, formula-fed children show reduced transforming growth factor β2 compared to breast milk-fed children; instead, they display higher levels of plasma proinflammatory cytokines (e.g., IL-2 and TNF-α) than breast-fed children [29]. Inadequate intake of LCPUFAs in the body/diet can influence the development of obesity and arthritis (Figure 1). Resistin—an adipokine—along with other senescence-associated secretory phenotype factors, regulates glucose metabolism, oxidative stress, inflammatory responses, and autoimmune diseases. [30][31]. High plasma resistin concentrations can increase the possibility of inflammation, insulin resistance, and the aging process [30]. Resistin possibly interacts with TLR-4 receptors, influences the transcription of proinflammatory genes, inflammatory cytokines, and chemokines, and causes osteoclastogenesis via the NF-κB pathway [30]. Sedentary lifestyle and increased calorie intake are related to the progression of adipocyte hypertrophy and low-grade inflammation via the recruitment of antigen-producing cells in adipose tissues [31][32]. Resistin, adiponectin, TNF-α (released by adipocytes), and proinflammatory cytokines (e.g., IL-1β, IL-6) derived from adipokines increase muscle and bone metabolism [30][32]. This biological pathway is responsible for the generation of several chronic diseases, including obesity, diabetes, and arthritis [32].
Nutrients 14 00985 g001 550
Figure 1. Mechanisms of obesity and rheumatoid arthritis (RA). Abbreviations—APC: antigen-presenting cell; GI: gastrointestinal: GIT: gastrointestinal tract; IL: interleukin; LCPUFAs: long-chain polyunsaturated fatty acids: TNF-α: tumor necrosis factor alpha; IFN-γ: interferon gamma; M-cell: microfold cell; Th: T helper cell; T-cell: T-cell lymphocytes: B-cell: B-cell lymphocytes; red rod-shaped bacteria: Prevotella spp.; SCFA: short-chain fatty acid. This figure was made with www.biorender.com (accessed on 25 January 2022).

2. Arthritis and Inflammation

2.1. Osteoarthritis and Inflammation

There are various types of arthritis, and these are multifactorial, with the common features of chronic intense pain and inflammation [33]. Osteoarthritis (OA) is a chronic painful disorder that increases with age and is common in adults aged over 55 years [34]. The mechanisms of OA are not completely understood, but its clinical features include irreversible age-related damage to the joint cartilage, pain, and low-grade inflammation over a period of many years [35]. The pathogenesis of OA can also be caused by cellular stress produced by the activation of endogenous cytosolic proteins such as nucleotide-binding domain, leucine-rich repeat/pyrin domain-containing-3 (NALP3) inflammasome [36][37][38][39][40], proinflammatory cytokines released by macrophages [41][42][43], or the production of proinflammatory cytokines induced by uric-acid-crystal-induced inflammasome assembly [40]. There is a positive correlation between osteoarthritis (OA) severity, uric acid levels (in synovial fluid), and proinflammatory cytokines (e.g., IL-18, IL-1β) [38][44]. Monosodium uric acid (MSU) can accumulate in joints as crystals when its plasma concentrations exceed its solubility (≥70 mg/L) [45], stimulating the synthesis of different inflammatory cytokines [46]. The inflammatory processes are also triggered by chemokines, proteases, and oxidative materials that cause osteoporosis, cartilage degradation, and inflammation in the synovial joints [44][47]. This process is further exaggerated when toll-like receptors recognize MSU (monosodium urate crystals), and when lymphocytes and macrophages in synovial fluids uptake MSU. These interactions ultimately release various inflammatory cytokines (especially IL-1β, IL-6, TNF-α, and IL-18) via nucleotide-binding domain and the leucine-rich repeat/pyrin domain-containing-3 (NALP3) inflammasome [36][37][38][39][40]. OA is also influenced by calcium-oxalate-containing crystals that stimulate the production of IL-1β, causing cartilage damage [48]. OA is also caused by mutations of genes encoding collagens (e.g., types II, IV, V, and VI) [33][49]. The pathogenesis of OA can cause neuronal damage in joint tissues, causing intense pain, limited mobility, depression, and anxiety in elderly people (Figure 2) [50][51]. People experiencing OA also often have multiple comorbidities, such as obesity [52][53][54], diabetes [4], cardiovascular diseases [3], cancers [5], and musculoskeletal disorders [2].
Nutrients 14 00985 g002 550
Figure 2. Osteoarthritis (OA) and associated comorbidities. Abbreviations—COPD: chronic obstructive pulmonary disease. This figure was made with www.biorender.com (accessed on 25 January 2022).
Currently, analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are used to manage OA, but these drugs have no effect on the prevention of OA’s pathogenesis, and they are mainly for symptomatic management. In addition, these drugs have adverse effects on the gut, liver, kidneys, and heart [55][56][57][58]. Long-term use of NSAIDs to manage arthritis provides poor pain relief, major discomfort for patients, and can lead to invasive procedures, such as surgeries [59][60][61]. A clinical study showed that paracetamol alone provided insufficient analgesia in OA, but an NSAID such as diclofenac (0.15 g daily) showed noticeable efficacy in OA management [62]. It is also important to note the adverse effects of diclofenac, including gastrointestinal toxicity, liver toxicity, and renal impairment. Another study reported that celecoxib (an NSAID) caused lower cardiovascular, renal, and gastrointestinal adverse reactions than ibuprofen or naproxen (NSAIDs), which was similar in patients experiencing OA or RA [63]. It is understood that there are significant variations between drugs within a group of drugs (e.g., NSAIDs), and the efficacy of a particular drug may depend on its molecular structure, formulation, route of administration, dosage, and duration of treatment [64]. The bioactivity and efficacy of a drug also depend on its metabolic capabilities (e.g., hepatic or renal impairment, aging-related) and bioavailability at the target site. Importantly, chronic treatment with NSAIDs for OA can result in adverse outcomes and cause adverse events in older adults [65][66]. Opioids are not recommended to manage OA [51][67], but these drugs are widely used in OA-related chronic pain management for older adults, despite their potential adverse effects—such as addiction, dependence, analgesic tolerance, respiratory depression, and behavioral disorders over long-term usages [66][68][69][70][71].

2.2. Brief Pathophysiology of Rheumatoid Arthritis (RA)

2.2.1. RA and Inflammation

Despite differences in the initiation and progression mechanisms between OA and RA—the latter of which is another type of arthritis that is multifactorial, and whose root causes remain to be elucidated—long-term low-grade inflammation is the common ground in the pathogenesis of obesity, OA, and RA [52][53][54][72]. As with the pathogenesis of OA, RA manifests with increased secretion of proinflammatory cytokines (e.g., IL-1, IL-6, IL-12, IL-17, IL-18, and TNF-α). In parallel, secretion of immunomodulatory cytokines (e.g., IL-10, IL-11, and IL-13) is reduced in the blood, along with stiffness, swollen joints, and impaired movement of the affected person [73][74][75][76] (Figure 1). Defensive cells, such as T helper 1 (Th1) and T helper 17 (Th17) cells, produce an inflammatory response via IL-17A, IFN-γ, and TNF-α, leading to the pathogenesis of RA [77][78]. Toll-like receptors (TLRs) regulate the functions of the nuclear factor kappa B ligand (NF-κB), osteoclastogenesis, and generation of proinflammatory cytokines [79][80][81]. As a result, joint pain, inflamed joints, and damage to cartilage can be seen during clinical symptoms of RA [82]. Inflammatory cytokines such as IL-17 or TNF-α can influence the upregulation of matrix metalloproteinase (MMP) enzymes, which irreversibly damage the extracellular matrix and the cartilage of joints [74][83] (Figure 1). Apart from inflammatory or genetic mechanisms, fat-rich food intake, smoking, and periodontal infections also affect the generation and progression of RA [84][85]. Women are more prone to RA than men. Citrullination of proteins in lung macrophages, along with neuropathic pain and osteoporosis, can potentially influence the pathogenesis of RA [84][86][87][88].

2.2.2. RA, Gut Dysbiosis, and Inflammation

RA also manifests as a result of excess inflammatory cytokines, with the influence of major changes in the microbial population of the gut. For example, Faecalibacterium spp. are a part of the healthy gut microbiota that is responsible for butyrate production [89][90][91], and helps in the secretion of mucin—a natural lubricator of gut epithelial cells. If the abundance of Faecalibacterium spp. decreases, other opportunistic bacteria such as Collinsella, Eggerthella, Haemophilus, Prevotella, and Streptococcus can grow and produce inflammatory cytokines and/or cause citrullination of proteins, leading to RA [90][92].
Prevotella copri (P. copri) is a part of people normal gut microbiota and oral cavity, and can grow massively with the influence of change in diet, stress, lack of oral hygiene, and microbial infection [85][93][94][95]. As a result, P. copri can cause increased production of T helper cells (e.g., Th1, Th17) and inflammatory cytokines (e.g., IL-1β, IL-6, IL-17, and IL-23), leading to an inflammatory response in the gut, and can possibly migrate to inflammatory joint tissues [96][97] (Figure 1). Prevotella spp. can produce increased prostaglandin E2 in joint tissues, and has been observed in RA, causing joint pain, inflammation, and bone degradation [98][99] (Figure 1). The simultaneous growth of Porphyromonas gingivalis in the mouth and P. copri in the intestine are noticed in RA patients [100]. P. gingivalis possibly translocates to synovial joints via phagocytosis, causes citrullination of proteins in joints, and increases inflammatory cytokine production [101][102]. Proper management and restoration of healthy gut microbiota by using probiotic supplements as food can reduce the population of Prevotella spp. and increase the gut population of Lactobacillus spp. [95].

3. Relationships between Obesity and Arthritis

OA and RA are both prevalent in older adults (>55 years), and especially in the elderly with frailty syndromes (e.g., falls, immobility, delirium, incontinence, and adverse effects of medications) [72][103]. Obesity is also a common comorbidity of this population cohort for various reasons, including inactivity, diet, diabetes, and aging [104][105]. Tumor necrosis factor α (TNF-α)—a proinflammatory cytokine—from the adipose tissues of obese animals can cause low-grade inflammation in adipocytes [52][106]. Adipose tissues mainly produce inflammatory biomarkers such as TNF-α, and macrophages and other immune cells are partially responsible for oxidative damage and low-grade inflammation in the body [52][106][107]. NLRP3 (nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3)—a polyprotein complex inflammasome found in macrophages—is also responsible for releasing proinflammatory cytokines. NLRP3 is stimulated by the activation of NF-κB (nuclear factor kappa B, which TNF-α stimulates), and causes the secretion of the proinflammatory cytokines pro-IL-1β and pro-IL-18 [108] (Figure 3). NLRP3 is matured by PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns) or lipopolysaccharides. NLRP3 maturation stimulates the release of cytokines (e.g., IL (interleukin)-1β, IL-6, and IL-18) and low-grade inflammation in multiple organs, including joints (Figure 3) [109].
Nutrients 14 00985 g004 550
Figure 3. Relationships between the pathogenesis of osteoarthritis (OA), obesity, and rheumatoid arthritis (RA) in older adults. Abbreviations—↑: increase; ROS: reactive oxygen species; TNF-α: tumor necrosis factor α: TLR: toll-like receptor; IL: interleukin; NADPH: nicotinamide adenine dinucleotide phosphate oxidase; IFNγ: interferon gamma; NF-κB: nuclear factor kappa B; NLRP3: nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 inflammasome; PAMPs: pathogen-associated molecular patterns; DAMPs: damage-associated molecular patterns; MHC-II: major histocompatibility complex class II. This figure was made with www.biorender.com (accessed on 25 January 2022), and partially reproduced from Paul et al. [107].
Clinical studies show strong positive connections between obesity, osteoarthritis, and rheumatoid arthritis [52][53][110][111][112] (Figure 3). People with a body mass index of >30 kg/m2 show higher incidence of knee OA than people of normal weight, and it is recommended to reduce weight in order to improve clinical symptoms of OA in obese patients [113][114]. A clinical study showed that obesity was present (33.4%) in RA patients (n = 11,406) at a significantly higher rate than obesity (31.6%) in the control group (n = 54,701) [112]. Obesity causes inflammation and autoimmune conditions in RA patients [112]. Obese RA patients experience more tender joints and swelling in joints than non-obese RA patients [115]. Obesity is a common comorbidity of RA patients, and it also reduces the efficacy of drugs working against TNF-α, but losing body weight improves the success of treatment with these drugs [111]. Importantly, no association with BMI was found in this review with drugs other than anti-TNF-α drugs, such as biologics that act against IL-6, CD4, or CD20 [111]. Studies have reported that the RA patients experience lower grip strength and fatigue (40–80%), and these decrease their strength and their interest in being involved in various physical activities [116][117]. Similarly, a later study showed that patients who also experienced RA displayed fatigue (40%) and anxiety/depression (52%) as comorbidities [118]. Obese RA patients experienced less remission (improvement of symptoms and pain relief) and lower disease activity scores than non-obese (control) RA patients [110]. Van Beers-Tas et al. mentioned that reduced smoking increased arthritis remission, but obesity increased arthritis progression and delayed its remission [119]. Another study on a small number (n = 19) of obese RA patients (aged 55 years on average; range: 34–71) observed that reduction in dietary energy intake and moderate physical exercise led to a 9% reduction in fat mass and improved physical fitness of the participants [120]. Conversely, another study with a comparatively large number (n = 192) of participants (aged 64.5 years on average, range: 50–78) in a similar weight-reduction program did not improve structural joint damage, muscle strength, or knee joint alignment, but achieved some benefits in terms of overall health improvement [121]. Noticeably, age was an important factor in the performance of the participants, and there were differences in the measurements of performance, as the previous study measured outcomes such as the capability to ride a bicycle, whereas the later study investigated using MRI and radiographs [120][121]. Collectively, management of obesity may improve the clinical symptoms of obese OA and RA patients.

4. Current Drugs for the Management of Obesity and Arthritis

A few anti-obesity drugs have now been approved for human use, and most of these show various side effects. According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the United States Food and Drug Administration (USFDA) has so far approved five drugs—namely, orlistat, phentermine/topiramate, lorcaserin, naltrexone/bupropion, and liraglutide—to treat obesity [122]. Importantly, the European Medicines Agency (EMA) has approved three drugs to fight symptoms of obesity: orlistat, bupropion/naltrexone, and liraglutide [123]. Orlistat reduces intestinal absorption of fat content from food, as it is a pancreatic lipase inhibitor; side effects of this drug include diarrhea, oily stools, abdominal pain and, less frequently, cholelithiasis, cholestatic hepatitis, and subacute hepatitis [124]. People feel less hungry when using the drug combination phentermine/topiramate, as phentermine decreases one’s appetite, while topiramate reduces seizures and migraine headaches. Noticeably, this drug combination can cause serious side effects, including dysgeusia (taste alteration), paresthesia (burning sensation in hands and feet), hypoesthesia (loss of sensation of a body part), attention deficiency, dizziness, constipation, and dry mouth [125]. There are serious safety concerns with respect to the long-term efficacy of anti-obesity medications; the European Medicines Agency refused the approval of phentermine/topiramate, while for lorcaserin, authorization was previously withdrawn for a low overall benefit/risk ratio [126]. Lorcaserin (for the risk of cancer), rimonabant, and sibutramine have been withdrawn from the US market for safety concerns [126][127]. Mitral regurgitation is a serious side effect of lorcaserin, and may lead to other complications, such as increased risk of cardiovascular complications [127][128]. The naltrexone/bupropion drug combination has little effect against obesity individually. Long-term opioid treatment causes various behavioral adverse effects, addiction, and tolerance, but naltrexone—as an opioid antagonist—shows efficacy against dependency on opioids and alcoholic beverages [64][69][122][129]. Patient management using these analgesics should also consider the reduced metabolic capability of people such as the elderly, or people suffering from chronic kidney or liver diseases [70][130][131][132][133]. Bupropion is used for treating depression and for help with giving up smoking. Individually, these drugs have no or little effect on obesity; used in combination, they form a safe anti-obesity polypharmacy drug with no serious side effects except for nausea [134][135].
Liraglutide—an anti-diabetic drug—works as an anti-obesity drug as well, and shows side-effects such as nausea, diarrhea, abdominal pain, and constipation. Acute pancreatitis and rare thyroid tumors are severe adverse effects that may arise from the use of liraglutide [136].
Rheumatoid arthritis (RA) is currently treated with disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate, non-steroidal anti-inflammatory drugs (such as paracetamol, ibuprofen, naproxen, diclofenac, indomethacin, ketoprofen, and meloxicam), Janus kinase (JAK) inhibitors (e.g., baricitinib and upadacitinib), anti-malarial drugs (e.g., hydroxychloroquine and chloroquine), TNF-α inhibitors, and glucocorticoids (e.g., prednisone, hydrocortisone, and dexamethasone). All of these drug types produce severe adverse effects (Figure 4), limiting their efficacy, and scientists are looking for safe alternative drugs or food supplements for the prevention or cure of RA [95][137][138][139].
Nutrients 14 00985 g005 550
Figure 4. Common problems associated with long-term treatment of arthritis with current anti-arthritic drugs. Abbreviations—NSAIDs: non-steroidal anti-inflammatory drugs; DMARDs: disease-modifying anti-rheumatic drugs; GI: gastrointestinal. The purple-colored text indicates common routes of administration of various anti-arthritic drugs. 
Overall, anti-obesity drugs are effective in reducing body weight, but in consideration of their adverse effect profiles, the only possible alternative to these drugs is bariatric surgery, which also increases the risk of developing alcohol use disorders [140]. Thus, scientists, naturopaths, and traditional medicinal practitioners are investigating some suitable plants that have the ability to reduce weight. A single plant may contain hundreds of secondary metabolites, a few of which may be effective against obesity. Plants are readily available from nature; many plants can be cultivated and extracted to isolate active ingredients for various purposes.

This entry is adapted from the peer-reviewed paper 10.3390/nu14050985

References

  1. World Health Organization. Obesity and Overweight. 9 June 2021. Available online: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight (accessed on 11 August 2021).
  2. Kortt, M.; Baldry, J. The association between musculoskeletal disorders and obesity. Aust. Health Rev. 2002, 25, 207–214.
  3. Poirier, P.; Després, J.-P. Obésité et maladies cardiovasculaires. M/S Méd. Sci. 2003, 19, 943–949.
  4. Parmar, M.Y. Obesity and type 2 diabetes mellitus. Integr. Obes. Diabetes 2018, 4, 1–2.
  5. Basen-Engquist, K.; Chang, M. Obesity and cancer risk: Recent review and evidence. Curr. Oncol. Rep. 2010, 13, 71–76.
  6. Heymsfield, S.B.; Wadden, T.A. Mechanisms, pathophysiology, and management of obesity. N. Engl. J. Med. 2017, 376, 254–266.
  7. Tchkonia, T.; Thomou, T.; Zhu, Y.; Karagiannides, I.; Pothoulakis, C.; Jensen, M.D.; Kirkland, J.L. Mechanisms and metabolic implications of regional differences among fat depots. Cell Metab. 2013, 17, 644–656.
  8. Redinger, R.N. The pathophysiology of obesity and its clinical manifestations. Gastroenterol. Hepatol. 2007, 3, 856–863.
  9. Schmidt, F.M.; Weschenfelder, J.; Sander, C.; Minkwitz, J.; Thormann, J.; Chittka, T.; Mergl, R.; Kirkby, K.C.; Faßhauer, M.; Stumvoll, M.; et al. Inflammatory cytokines in general and central obesity and modulating effects of physical activity. PLoS ONE 2015, 10, e0121971.
  10. Trayhurn, P.; Wood, I.S. Adipokines: Inflammation and the pleiotropic role of white adipose tissue. Br. J. Nutr. 2004, 92, 347–355.
  11. Lee, H.; Lee, I.S.; Choue, R. Obesity, inflammation and diet. Pediatr. Gastroenterol. Hepatol. Nutr. 2013, 16, 143–152.
  12. Knebel, B.; Fahlbusch, P.; Poschmann, G.; Dille, M.; Wahlers, N.; Stühler, K.; Hartwig, S.; Lehr, S.; Schiller, M.; Jacob, S.; et al. Adipokinome signatures in obese mouse models reflect adipose tissue health and are associated with serum lipid composition. Int. J. Mol. Sci. 2019, 20, 2559.
  13. Eissing, L.; Scherer, T.; Tödter, K.; Knippschild, U.; Greve, J.W.; Buurman, W.A.; Pinnschmidt, H.O.; Rensen, S.S.; Wolf, A.M.; Bartelt, A.; et al. De novo lipogenesis in human fat and liver is linked to ChREBP-β and metabolic health. Nat. Commun. 2013, 4, 1528.
  14. Adolph, T.E.; Grander, C.; Grabherr, F.; Tilg, H. Adipokines and non-alcoholic fatty liver disease: Multiple interactions. Int. J. Mol. Sci. 2017, 18, 1649.
  15. Frühbeck, G.; Gomez-Ambrosi, J.; Muruzabal, F.J.; Burrell, M. The adipocyte: A model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am. J. Physiol. Metab. 2001, 280, E827–E847.
  16. Trayhurn, P.; Beattie, J.H. Physiological role of adipose tissue: White adipose tissue as an endocrine and secretory organ. Proc. Nutr. Soc. 2001, 60, 329–339.
  17. Ellulu, M.S.; Patimah, I.; KhazáAi, H.; Rahmat, A.; Abed, Y. Obesity and inflammation: The linking mechanism and the complications. Arch. Med. Sci. 2017, 13, 851–863.
  18. Das, U. Is obesity an inflammatory condition? Nutrition 2001, 17, 953–966.
  19. Hill, J.O. A new way of looking at obesity. Nutrition 2001, 17, 975–976.
  20. Vozarova, B.; Weyer, C.; Hanson, K.; Tataranni, P.A.; Bogardus, C.; Pratley, R.E. Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion. Obes. Res. 2001, 9, 414–417.
  21. Esposito, K.; Pontillo, A.; Ciotola, M.; Di Palo, C.; Grella, E.; Nicoletti, G.; Giugliano, D. Weight loss reduces interleukin-18 levels in obese women. J. Clin. Endocrinol. Metab. 2002, 87, 3864–3866.
  22. Rodríguez-Hernández, H.; Simental-Mendía, L.E.; Rodríguez-Ramírez, G.; Reyes-Romero, M.A. Obesity and inflammation: Epidemiology, risk factors, and markers of inflammation. Int. J. Endocrinol. 2013, 2013, 678159.
  23. Palmeira, P.; Carneiro-Sampaio, M. Immunology of breast milk. Rev. Assoc. Méd. Bras. 2016, 62, 584–593.
  24. Burris, A.D.; Pizzarello, C.; Järvinen, K.M. Immunologic components in human milk and allergic diseases with focus on food allergy. Semin. Perinatol. 2020, 45, 151386.
  25. Dain, A.; Repossi, G.; Diaz-Gerevini, G.T.; Vanamala, J.; Das, U.N.; Eynard, A.R. Long chain polyunsaturated fatty acids (LCPUFAs) and nordihydroguaiaretic acid (NDGA) modulate metabolic and inflammatory markers in a spontaneous type 2 diabetes mellitus model (Stillman Salgado rats). Lipids Health Dis. 2016, 15, 205.
  26. Das, U.N. Long-chain polyunsaturated fatty acids and diabetes mellitus. Am. J. Clin. Nutr. 2002, 75, 780–781.
  27. Hanson, L.; Korotkova, M. The role of breastfeeding in prevention of neonatal infection. Semin. Neonatol. 2002, 7, 275–281.
  28. Quinello, C.; Quintilio, W.; Carneiro-Sampaio, M.; Palmeira, P. Passive Acquisition of protective antibodies reactive with Bordetella pertussis in newborns via placental transfer and breast-feeding. Scand. J. Immunol. 2010, 72, 66–73.
  29. Kainonen, E.; Rautava, S.; Isolauri, E. Immunological programming by breast milk creates an anti-inflammatory cytokine milieu in breast-fed infants compared to formula-fed infants. Br. J. Nutr. 2012, 109, 1962–1970.
  30. Acquarone, E.; Monacelli, F.; Borghi, R.; Nencioni, A.; Odetti, P. Resistin: A reappraisal. Mech. Ageing Dev. 2019, 178, 46–63.
  31. Xie, C.; Chen, Q. Adipokines: New therapeutic target for osteoarthritis? Curr. Rheumatol. Rep. 2019, 21, 71.
  32. Kirk, B.; Feehan, J.; Lombardi, G.; Duque, G. Muscle, bone, and fat crosstalk: The biological role of myokines, osteokines, and adipokines. Curr. Osteoporos. Rep. 2020, 18, 388–400.
  33. Senthelal, S.; Li, J.; Goyal, A.; Bansal, P.; Thomas, M.A. Arthritis. In Statpearls; StatPearls Publishing: Treasure Island, FL, USA, 2022.
  34. Wallace, J.L. Polypharmacy of osteoarthritis: The perfect intestinal storm. Am. J. Dig. Dis. 2013, 58, 3088–3093.
  35. Xia, B.; Chen, D.; Zhang, J.; Hu, S.; Jin, H.; Tong, P. Osteoarthritis pathogenesis: A review of molecular mechanisms. Calcif. Tissue Res. 2014, 95, 495–505.
  36. So, A. Developments in the scientific and clinical understanding of gout. Arthritis Res. Ther. 2008, 10, 221.
  37. Goo, B.; Lee, J.; Park, C.; Yune, T.; Park, Y. Bee venom alleviated edema and pain in monosodium urate crystals-induced gouty arthritis in rat by inhibiting inflammation. Toxins 2021, 13, 661.
  38. Leung, Y.Y.; Yao Hui, L.L.; Kraus, V.B. Colchicine—Update on mechanisms of action and therapeutic uses. Semin. Arthritis Rheum. 2015, 45, 341–350.
  39. Stannus, O.; Jones, G.; Cicuttini, F.; Parameswaran, V.; Quinn, S.; Burgess, J.; Ding, C. Circulating levels of IL-6 and TNF-α are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults. Osteoarthr. Cartil. 2010, 18, 1441–1447.
  40. Martinon, F.; Petrilli, V.; Mayor, A.; Tardivel, A.; Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006, 440, 237–241.
  41. Guo, H.; Callaway, J.B.; Ting, J.P.-Y. Inflammasomes: Mechanism of action, role in disease, and therapeutics. Nat. Med. 2015, 21, 677–687.
  42. Millerand, M.; Berenbaum, F.; Jacques, C. Danger signals and inflammaging in osteoarthritis. Clin. Exp. Rheumatol. 2019, 37 (Suppl. 120), 48–56.
  43. Zhao, L.; Xing, R.; Wang, P.; Zhang, N.; Yin, S.; Li, X.; Zhang, L. NLRP1 and NLRP3 inflammasomes mediate LPS/ATP-induced pyroptosis in knee osteoarthritis. Mol. Med. Rep. 2018, 17, 5463–5469.
  44. Denoble, A.E.; Huffman, K.M.; Stabler, T.V.; Kelly, S.J.; Hershfield, M.S.; McDaniel, G.E.; Coleman, R.E.; Kraus, V.B. Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation. Proc. Natl. Acad. Sci. USA 2011, 108, 2088–2093.
  45. Fiddis, R.W.; Vlachos, N.; Calvert, P.D. Studies of urate crystallisation in relation to gout. Ann. Rheum. Dis. 1983, 42 (Suppl. 1), 12–15.
  46. Wilson, L.; Saseen, J.J. Gouty Arthritis: A review of acute management and prevention. Pharmacother. J. Hum. Pharmacol. Drug Ther. 2016, 36, 906–922.
  47. Richette, P.; Doherty, M.; Pascual, E.; Barskova, V.; Becce, F.; Castaneda, J.; Coyfish, M.; Guillo, S.; Jansen, T.; Janssens, H.; et al. 2018 updated European league against rheumatism evidence-based recommendations for the diagnosis of gout. Ann. Rheum. Dis. 2019, 79, 31–38.
  48. Sokolove, J.; Lepus, C.M. Role of inflammation in the pathogenesis of osteoarthritis: Latest findings and interpretations. Ther. Adv. Musculoskelet. Dis. 2013, 5, 77–94.
  49. Reginato, A.M.; Olsen, B.R. The role of structural genes in the pathogenesis of osteoarthritic disorders. Arthritis Res. Ther. 2002, 4, 337–345.
  50. Held, F.P.; Blyth, F.; Gnjidic, D.; Hirani, V.; Naganathan, V.; Waite, L.M.; Seibel, M.J.; Rollo, J.; Handelsman, D.J.; Cumming, R.G.; et al. Association rules analysis of comorbidity and multimorbidity: The concord health and aging in men project. J. Gerontol. A Biol. Sci. Med. Sci. 2016, 71, 625–631.
  51. Hunter, D.J.; Bierma-Zeinstra, S. Osteoarthritis. Lancet 2019, 393, 1745–1759.
  52. Wang, T.; He, C. Pro-inflammatory cytokines: The link between obesity and osteoarthritis. Cytokine Growth Factor Rev. 2018, 44, 38–50.
  53. Kulkarni, K.; Karssiens, T.; Kumar, V.; Pandit, H. Obesity and osteoarthritis. Maturitas 2016, 89, 22–28.
  54. Hawker, G.A. Osteoarthritis is a serious disease. Clin. Exp. Rheumatol. 2019, 37, 3–6.
  55. Wang, Z.; Singh, A.; Jones, G.; Winzenberg, T.; Ding, C.; Chopra, A.; Das, S.; Danda, D.; Laslett, L.; Antony, B. Efficacy and safety of turmeric extracts for the treatment of knee osteoarthritis: A systematic review and meta-analysis of randomised controlled trials. Curr. Rheumatol. Rep. 2021, 23, 11.
  56. Scarpignato, C.; Hunt, R.H. Nonsteroidal antiinflammatory drug-related injury to the gastrointestinal tract: Clinical picture, pathogenesis, and prevention. Gastroenterol. Clin. N. Am. 2010, 39, 433–464.
  57. Scarpignato, C. Piroxicam-β-cyclodextrin: A GI safer piroxicam. Curr. Med. Chem. 2013, 20, 2415–2437.
  58. Wehling, M. Non-steroidal anti-inflammatory drug use in chronic pain conditions with special emphasis on the elderly and patients with relevant comorbidities: Management and mitigation of risks and adverse effects. Eur. J. Clin. Pharmacol. 2014, 70, 1159–1172.
  59. Van Laar, M.; Pergolizzi, J.V., Jr.; Mellinghoff, H.-U.; Merchante, I.M.; Nalamachu, S.; O’Brien, J.; Perrot, S.; Raffa, R.B. Pain treatment in arthritis-related pain: Beyond NSAIDs. Open Rheumatol. J. 2012, 6, 320–330.
  60. Courtney, P. Key questions concerning paracetamol and NSAIDs for osteoarthritis. Ann. Rheum. Dis. 2002, 61, 767–773.
  61. Pelletier, J.-P.; Martel-Pelletier, J.; Rannou, F.; Cooper, C. Efficacy and safety of oral NSAIDs and analgesics in the management of osteoarthritis: Evidence from real-life setting trials and surveys. Semin. Arthritis Rheum. 2015, 45, S22–S27.
  62. Da Costa, B.R.; Reichenbach, S.; Keller, N.; Nartey, L.; Wandel, S.; Jüni, P.; Trelle, S. Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: A network meta-analysis. Lancet 2017, 390, e21–e33.
  63. Solomon, D.H.; Husni, M.E.; Mph, K.E.W.; Rn, L.M.W.; Borer, J.S.; Graham, D.Y.; Libby, P.; Lincoff, A.M.; Lüscher, T.F.; Menon, V.; et al. Differences in safety of nonsteroidal antiinflammatory drugs in patients with osteoarthritis and patients with rheumatoid arthritis. Arthritis Rheumatol. 2017, 70, 537–546.
  64. Paul, A.K.; Gueven, N.; Dietis, N. Morphine dosing strategy plays a key role in the generation and duration of the produced antinociceptive tolerance. Neuropharmacology 2017, 121, 158–166.
  65. Malfait, A.-M.; Schnitzer, T.J. Towards a mechanism-based approach to pain management in osteoarthritis. Nat. Rev. Rheumatol. 2013, 9, 654–664.
  66. Ragni, E.; Mangiavini, L.; Viganò, M.; Brini, A.T.; Peretti, G.M.; Banfi, G.; De Girolamo, L. Management of osteoarthritis during the COVID-19 pandemic. Clin. Pharmacol. Ther. 2020, 108, 719–729.
  67. The Royal Australian College of General Practitioners. Guideline for the Management of Knee and Hip Osteoarthritis, 2nd ed.; The Royal Australian College of General Practitioners: East Melbourne, Australia, 2018.
  68. Alamanda, V.K.; Wally, M.K.; Seymour, R.B.; Springer, B.D.; Hsu, J.R.; Beuhler, M.; Bosse, M.J.; Gibbs, M.; Griggs, C.; Jarrett, S.; et al. Prevalence of opioid and benzodiazepine prescriptions for osteoarthritis. Arthritis Care Res. 2019, 72, 1081–1086.
  69. Paul, A.K.; Smith, C.M.; Rahmatullah, M.; Nissapatorn, V.; Wilairatana, P.; Spetea, M.; Gueven, N.; Dietis, N. Opioid analgesia and opioid-induced adverse effects: A review. Pharmaceuticals 2021, 14, 1091.
  70. Paul, A.K.; Lewis, R.J. Pain management in older adults: Facts to consider. Pain 2022, 163, e497–e498.
  71. Mushtaq, S.; Choudhary, R.; Scanzello, C.R. Non-surgical treatment of osteoarthritis-related pain in the elderly. Curr. Rev. Musculoskelet. Med. 2011, 4, 113–122.
  72. Serhal, L.; Lwin, M.N.; Holroyd, C.; Edwards, C.J. Rheumatoid arthritis in the elderly: Characteristics and treatment considerations. Autoimmun. Rev. 2020, 19, 102528.
  73. Xu, L.; Feng, X.; Tan, W.; Gu, W.; Guo, D.; Zhang, M.; Wang, F. IL-29 enhances Toll-like receptor-mediated IL-6 and IL-8 production by the synovial fibroblasts from rheumatoid arthritis patients. Arthritis Res. Ther. 2013, 15, R170.
  74. Thompson, C.; Davies, R.; Choy, E. Anti cytokine therapy in chronic inflammatory arthritis. Cytokine 2016, 86, 92–99.
  75. Kishimoto, T. Discovery of IL-6 and Development of anti-IL-6R antibody. Keio J. Med. 2019, 68, 96.
  76. Mateen, S.; Zafar, A.; Moin, S.; Khan, A.Q.; Zubair, S. Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis. Clin. Chim. Acta 2016, 455, 161–171.
  77. Van Hamburg, J.P.; Tas, S.W. Molecular mechanisms underpinning T helper 17 cell heterogeneity and functions in rheumatoid arthritis. J. Autoimmun. 2018, 87, 69–81.
  78. Alam, J.; Jantan, I.; Bukhari, S.N.A. Rheumatoid arthritis: Recent advances on its etiology, role of cytokines and pharmacotherapy. Biomed. Pharmacother. 2017, 92, 615–633.
  79. Chen, J.-Q.; Szodoray, P.; Zeher, M. Toll-like receptor pathways in autoimmune diseases. Clin. Rev. Allergy Immunol. 2015, 50, 1–17.
  80. McGarry, T.; Veale, D.J.; Gao, W.; Orr, C.; Fearon, U.; Connolly, M. Toll-like receptor 2 (TLR2) induces migration and invasive mechanisms in rheumatoid arthritis. Arthritis Res. Ther. 2015, 17, 153.
  81. Piccinini, A.M.; Williams, L.; McCann, F.E.; Midwood, K.S. Investigating the role of toll-like receptors in models of arthritis. In Toll-Like Receptors; Springer: Berlin/Heidelberg, Germany, 2016; Volume 1390, pp. 351–381.
  82. McInnes, I.B.; Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 2011, 365, 2205–2219.
  83. Malemud, C.J. Matrix metalloproteinases and synovial joint pathology. Prog. Mol. Biol. Transl. Sci. 2017, 148, 305–325.
  84. Klareskog, L.; Stolt, P.; Lundberg, K.; Källberg, H.; Bengtsson, C.; Grunewald, J.; Rönnelid, J.; Harris, H.E.; Ulfgren, A.K.; Rantapää-Dahlqvist, S.; et al. A new model for an etiology of rheumatoid arthritis: Smoking may trigger HLA–DR (shared epitope)–restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006, 54, 38–46.
  85. Möller, B.; Kollert, F.; Sculean, A.; Villiger, P.M. Infectious triggers in periodontitis and the gut in rheumatoid arthritis (RA): A complex story about association and causality. Front. Immunol. 2020, 11, 1108.
  86. Favalli, E.G.; Biggioggero, M.; Crotti, C.; Becciolini, A.; Raimondo, M.G.; Meroni, P.L. Sex and management of rheumatoid arthritis. Clin. Rev. Allergy Immunol. 2018, 56, 333–345.
  87. Islander, U.; Jochems, C.; Lagerquist, M.K.; Forsblad-D’Elia, H.; Carlsten, H. Estrogens in rheumatoid arthritis; the immune system and bone. Mol. Cell. Endocrinol. 2011, 335, 14–29.
  88. Fert-Bober, J.; Darrah, E.; Andrade, F. Insights into the study and origin of the citrullinome in rheumatoid arthritis. Immunol. Rev. 2019, 294, 133–147.
  89. Ferreira-Halder, C.V.; de Sousa Faria, A.V.; Andrade, S.S. Action and function of Faecalibacterium prausnitzii in health and disease. Best Pract. Res. Clin. Gastroenterol. 2017, 31, 643–648.
  90. Chen, J.; Wright, K.; Davis, J.M.; Jeraldo, P.; Marietta, E.V.; Murray, J.; Nelson, H.; Matteson, E.L.; Taneja, V. An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome Med. 2016, 8, 43.
  91. He, X.; Zhao, S.; Li, Y. Faecalibacterium prausnitzii: A next-generation probiotic in gut disease improvement. Can. J. Infect. Dis. Med. Microbiol. 2021, 2021, 6666114.
  92. Chu, X.-J.; Cao, N.-W.; Zhou, H.-Y.; Meng, X.; Guo, B.; Zhang, H.-Y.; Li, B.-Z. The oral and gut microbiome in rheumatoid arthritis patients: A systematic review. Rheumatology 2020, 60, 1054–1066.
  93. Tanaka, S.; Yoshida, M.; Murakami, Y.; Ogiwara, T.; Shoji, M.; Kobayashi, S.; Watanabe, S.; Machino, M.; Fujisawa, S. The Relationship of Prevotella intermedia, Prevotella nigrescens and Prevotella melaninogenica in the supragingival plaque of children, caries and oral malodor. J. Clin. Pediatr. Dent. 2008, 32, 195–200.
  94. Ceccarelli, F.; Saccucci, M.; Di Carlo, G.; Lucchetti, R.; Pilloni, A.; Pranno, N.; Luzzi, V.; Valesini, G.; Polimeni, A. Periodontitis and rheumatoid arthritis: The same inflammatory mediators? Mediat. Inflamm. 2019, 2019, 6034546.
  95. Paul, A.K.; Paul, A.; Jahan, R.; Jannat, K.; Bondhon, T.A.; Hasan, A.; Nissapatorn, V.; Pereira, M.L.; Wilairatana, P.; Rahmatullah, M. Probiotics and amelioration of rheumatoid arthritis: Significant roles of Lactobacillus casei and Lactobacillus acidophilus. Microorganisms 2021, 9, 1070.
  96. Maeda, Y.; Kurakawa, T.; Umemoto, E.; Motooka, D.; Ito, Y.; Gotoh, K.; Hirota, K.; Matsushita, M.; Furuta, Y.; Narazaki, M.; et al. Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine. Arthritis Rheumatol. 2016, 68, 2646–2661.
  97. Larsen, J.M. The immune response to Prevotella bacteria in chronic inflammatory disease. Immunology 2017, 151, 363–374.
  98. Guan, S.-M.; Fu, S.-M.; He, J.-J.; Zhang, M. Prevotella intermedia induces prostaglandin E2 via multiple signaling pathways. J. Dent. Res. 2010, 90, 121–127.
  99. Dubois, R.N.; Abramson, S.B.; Crofford, L.; Gupta, R.A.; Simon, L.S.; Van De Putte, L.B.; Lipsky, P.E. Cyclooxygenase in biology and disease. FASEB J. 1998, 12, 1063–1073.
  100. Drago, L.; Zuccotti, G.V.; Romanò, C.L.; Goswami, K.; Villafañe, J.H.; Mattina, R.; Parvizi, J. Oral–gut microbiota and arthritis: Is there an evidence-based axis? J. Clin. Med. 2019, 8, 1753.
  101. Jung, H.; Jung, S.M.; Rim, Y.A.; Park, N.; Nam, Y.; Lee, J.; Park, S.-H.; Ju, J.H. Arthritic role of Porphyromonas gingivalis in collagen-induced arthritis mice. PLoS ONE 2017, 12, e0188698.
  102. Carrion, J.; Scisci, E.; Miles, B.; Sabino, G.J.; Zeituni, A.E.; Gu, Y.; Bear, A.; Genco, C.A.; Brown, D.L.; Cutler, C.W. Microbial carriage state of peripheral blood dendritic cells (DCs) in chronic periodontitis influences DC differentiation, atherogenic potential. J. Immunol. 2012, 189, 3178–3187.
  103. Salaffi, F.; Farah, S.; Di Carlo, M. Frailty syndrome in rheumatoid arthritis and symptomatic osteoarthritis: An emerging concept in rheumatology. Acta Bio-Med. Atenei Parm. 2020, 91, 274–296.
  104. Han, T.; Tajar, A.; Lean, M.E.J. Obesity and weight management in the elderly. Br. Med Bull. 2011, 97, 169–196.
  105. Han, T.; Wu, F.; Lean, M. Obesity and weight management in the elderly: A focus on men. Best Pr. Res. Clin. Endocrinol. Metab. 2013, 27, 509–525.
  106. Tzanavari, T.; Giannogonas, P.; Karalis, K.P. TNF-α and obesity. TNF Pathophysiol. 2010, 11, 145–156.
  107. Paul, A.K.; Hossain, K.; Mahboob, T.; Nissapatorn, V.; Wilairatana, P.; Jahan, R.; Jannat, K.; Bondhon, T.A.; Hasan, A.; Pereira, M.D.L.; et al. Does oxidative stress management help alleviation of COVID-19 symptoms in patients experiencing diabetes? Nutrients 2022, 14, 321.
  108. Vandanmagsar, B.; Youm, Y.-H.; Ravussin, A.; Galgani, J.E.; Stadler, K.; Mynatt, R.L.; Ravussin, E.; Stephens, J.M.; Dixit, V.D. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 2011, 17, 179–188.
  109. Ding, S.; Xu, S.; Ma, Y.; Liu, G.; Jang, H.; Fang, J. Modulatory mechanisms of the NLRP3 inflammasomes in diabetes. Biomolecules 2019, 9, 850.
  110. Liu, Y.; Hazlewood, G.; Kaplan, G.G.; Eksteen, B.; Barnabe, C. Impact of obesity on remission and disease activity in rheumatoid arthritis: A systematic review and meta-analysis. Arthritis Care Res. 2016, 69, 157–165.
  111. Moroni, L.; Farina, N.; Dagna, L. Obesity and its role in the management of rheumatoid and psoriatic arthritis. Clin. Rheumatol. 2020, 39, 1039–1047.
  112. Dar, L.; Tiosano, S.; Watad, A.; Bragazzi, N.L.; Zisman, D.; Comaneshter, D.; Cohen, A.; Amital, H. Are obesity and rheumatoid arthritis interrelated? Int. J. Clin. Pr. 2017, 72, e13045.
  113. King, L.K.; March, L.; Anandacoomarasamy, A. Obesity & osteoarthritis. Indian J. Med. Res. 2013, 138, 185–193.
  114. Coggon, D.; Reading, I.; Croft, P.; McLaren, M.; Barrett, D.; Cooper, C. Knee osteoarthritis and obesity. Int. J. Obes. 2001, 25, 622–627.
  115. Kaeley, G.S.; MacCarter, D.K.; Pangan, A.L.; Wang, X.; Kalabic, J.; Ranganath, V.K. Clinical Responses and synovial vascularity in obese rheumatoid arthritis patients treated with adalimumab and methotrexate. J. Rheumatol. 2018, 45, 1628–1635.
  116. Stebbings, S.; Treharne, G.J. Fatigue in rheumatic disease: An overview. Int. J. Clin. Rheumatol. 2010, 5, 487.
  117. Vlietstra, L.; Stebbings, S.; Meredith-Jones, K.; Abbott, J.H.; Treharne, G.; Waters, D.L. Sarcopenia in osteoarthritis and rheumatoid arthritis: The association with self-reported fatigue, physical function and obesity. PLoS ONE 2019, 14, e0217462.
  118. Tournadre, A.; Pereira, B.; Gossec, L.; Soubrier, M.; Dougados, M. Impact of comorbidities on fatigue in rheumatoid arthritis patients: Results from a nurse-led program for comorbidities management (COMEDRA). Jt. Bone Spine 2018, 86, 55–60.
  119. Van Beers-Tas, M.H.; Turk, S.A.; Van Schaardenburg, D. How does established rheumatoid arthritis develop, and are there possibilities for prevention? Best Pr. Res. Clin. Rheumatol. 2015, 29, 527–542.
  120. Engelhart, M.; Kondrup, J.; Høie, L.H.; Andersen, V.; Kristensen, J.H.; Heitmann, B.L. Weight reduction in obese patients with rheumatoid arthritis, with preservation of body cell mass and improvement of physical fitness. Clin. Exp. Rheumatol. 1996, 14, 289–293.
  121. Gudbergsen, H.; Boesen, M.; Lohmander, S.; Christensen, R.; Henriksen, M.; Bartels, E.; Rindel, L.; Aaboe, J.; Danneskiold-Samsøe, B.; Riecke, B.; et al. Weight loss is effective for symptomatic relief in obese subjects with knee osteoarthritis independently of joint damage severity assessed by high-field MRI and radiography. Osteoarthr. Cartil. 2012, 20, 495–502.
  122. NIDDK. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Prescription Medications to Treat Overweight & Obesity. Available online: https://www.niddk.nih.gov/health-information/weight-management/prescription-medications-treat-overweight-obesity (accessed on 15 August 2021).
  123. Yumuk, V.; Tsigos, C.; Fried, M.; Schindler, K.; Busetto, L.; Micic, D.; Toplak, H. European guidelines for obesity management in adults. Obes. Facts 2015, 8, 402–424.
  124. Filippatos, T.D.; Derdemezis, C.S.; Gazi, I.F.; Nakou, E.S.; Mikhailidis, D.P.; Elisaf, M.S. Orlistat-associated adverse effects and drug interactions. Drug Saf. 2008, 31, 53–65.
  125. Lei, X.; Ruan, J.; Lai, C.; Sun, Z.; Yang, X. Efficacy and safety of phentermine/topiramate in adults with overweight or obesity: A systematic review and meta-analysis. Obesity 2021, 29, 985–994.
  126. Siebenhofer, A.; Winterholer, S.; Jeitler, K.; Horvath, K.; Berghold, A.; Krenn, C.; Semlitsch, T. Long-term effects of weight-reducing drugs in people with hypertension. Cochrane Database Syst. Rev. 2021, 2021, CD007654.
  127. Tak, Y.J.; Lee, S.Y. Long-term efficacy and safety of anti-obesity treatment: Where do we stand? Curr. Obes. Rep. 2021, 10, 14–30.
  128. Di Nicolantonio, J.J.; Chatterjee, S.; O’Keefe, J.H.; Meier, P. Lorcaserin for the treatment of obesity? A closer look at its side effects. Open Heart 2014, 1, e000173.
  129. Paul, A.; Gueven, N.; Dietis, N. Profiling the effects of repetitive morphine administration on motor behavior in rats. Molecules 2021, 26, 4355.
  130. Paul, A.K.; Gueven, N.; Dietis, N. Data on prolonged morphine-induced antinociception and behavioral inhibition in older rats. Data Brief 2018, 19, 183–188.
  131. Paul, A.K.; Gueven, N.; Dietis, N. Age-dependent antinociception and behavioral inhibition by morphine. Pharmacol. Biochem. Behav. 2018, 168, 8–16.
  132. Andreasen, P.B.; Hutters, L. Paracetamol (acetaminophen) clearance in patients with cirrhosis of the liver. Acta Med. Scand. 2009, 205, 99–105.
  133. Ochs, H.R.; Schuppan, U.; Greenblatt, D.J.; Abernethy, D.R. Reduced distribution and clearance of acetaminophen in patients with congestive heart failure. J. Cardiovasc. Pharmacol. 1983, 5, 697–699.
  134. Verpeut, J.L.; Bello, N.T. Drug safety evaluation of naltrexone/bupropion for the treatment of obesity. Expert Opin. Drug Saf. 2014, 13, 1–11.
  135. McIntyre, R.S.; Paron, E.; Burrows, M.; Blavignac, J.; Gould, E.; Camacho, F.; Barakat, M. Psychiatric Safety and Weight loss efficacy of naltrexone/bupropion as add-on to antidepressant therapy in patients with obesity or overweight. J. Affect. Disord. 2021, 289, 167–176.
  136. Onge, E.S.; Miller, S.A.; Motycka, C. Liraglutide (Saxenda®) as a treatment for obesity. Food Nutr. Sci. 2016, 07, 227–235.
  137. Therapeutic Guidelines Limited. Principles of Nonsteroidal Anti-Inflammatory Drug Use for Musculoskeletal Conditions in Adults. In eTG Complete Melbourne; Therapeutic Guidelines Limited: West Melbourne, Australia. Available online: https://tgldcdp.tg.org.au/index (accessed on 29 December 2020).
  138. Schrezenmeier, E.; Dörner, T. Mechanisms of action of hydroxychloroquine and chloroquine: Implications for rheumatology. Nat. Rev. Rheumatol. 2020, 16, 155–166.
  139. Wang, W.; Zhou, H.; Liu, L. Side effects of methotrexate therapy for rheumatoid arthritis: A systematic review. Eur. J. Med. Chem. 2018, 158, 502–516.
  140. Bramming, M.; Becker, U.; Jørgensen, M.B.; Neermark, S.; Bisgaard, T.; Tolstrup, J.S. Bariatric surgery and risk of alcohol use disorder: A register-based cohort study. Int. J. Epidemiol. 2020, 49, 1826–1835.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Academic Video Service
Feedback