Inflammatory phenotype of osteoarthritis and its potential therapies
Published Online: 10 January 2022
Abstract
Introduction:
Osteoarthritis (OA) is the most common joint disorder in the world but there are no approved therapies to slow disease progression. Historically, OA has been considered a wear and tear joint disease and efforts to identify and develop disease modifying therapies have primarily focused on inhibiting cartilage degradation directly. However, increasing studies have suggested that inflammation is a key player of joint pathology in some OA patients and also a link between obesity and OA. Therefore, targeting inflammation in these patients could be a promising therapeutic strategy.
Areas Covered:
In this review, we collate the latest evidence on the relationship between inflammation and OA which allows to propose the inflammatory phenotype of OA, and summarize major results of some emerging therapies targeting this phenotype in clinical trials which could implicate future directions for OA treatment.
Expert Opinion:
The authors believe early diagnosis, phenotyping OA patients and precise therapies would expedite the development of DMOADs targeting OA inflammatory phenotype. In the future, well-designed clinical trials including appropriate subgroups or phenotypes of patients according to underlying causes and mechanisms of OA are expected for investigational therapies.
Abstract
Highlights
•
This review summarize the major results of some emerging therapies targeting inflammatory phenotype in clinical trials, implying future directions for OA treatment.
•
This work provide a new perspective to develop true DMOADs that target the OA inflammatory phenotype.
Abstract
Highlights
•
This review summarize the major results of some emerging therapies targeting inflammatory phenotype in clinical trials, implying future directions for OA treatment.
•
This work provide a new perspective to develop true DMOADs that target the OA inflammatory phenotype.
Graphical Abstract
OA phenotypes and emerging therapies for the inflammatory phenotype.
1 | INTRODUCTION
Osteoarthritis (OA) is viewed as a whole-organ disease of the joint, including degradation of cartilage, remodeling of subchondral bone, formation of ectopic bone, meniscal damage, deterioration of tendons and ligaments, and inflammation of the synovial lining.1,2,3 It is associated with chronic pain, joint function impairment, and disability, resulting in worsened quality of life and significant socioeconomic burdens worldwide.4,5 On the basis of its multiple pathological features, OA is divided into different phenotypes, such as synovial inflammatory phenotype, osteoporotic phenotype, articular cartilage degradation phenotype, and metabolic phenotype.6,7 Although the pathogenesis of OA is unclear, growing evidence indicates that inflammation plays an integral role in its pathogenesis.8,9 In other words, OA is a whole-joint disease in which inflammation can lead to many pathological changes in certain patients (Figure 1).
The inflammation in OA differs from that in rheumatoid arthritis and other autoimmune diseases, because it is chronic, low-grade, and predominantly mediated by the innate immune system.10,11 Current therapies mainly concentrate on pain management together with rehabilitation and exercise strategies. For advanced cases, joint replacement surgery is the only option.12,13,14 Hence, there is an unmet need to develop effective and safe drugs that can prevent or slow the progression of OA. Given the critical role of low-grade inflammation in OA, novel anti-inflammatory therapeutic agents could offer new opportunities for the treatment of this disease.15,16 In OA-related research, there has been a strong focus on the identification of OA inflammation that contributes to the balance between anabolism and catabolism in articular cartilage in the inflammatory phenotype.
2 | INFLAMMATORY PHENOTYPE OF OA
The inflammatory process has been overlooked for many years in research on the pathogenesis of OA.9,17 Recent studies have consistently revealed that both local and systemic inflammation play critical roles in the onset and progression of OA.18 Synovial fluid effusion and synovitis represent partial inflammation within the knee joint and are universal in patients with symptomatic and radiographic knee OA.19,20 Effusion-synovitis visualized on magnetic resonance imaging and ultrasonography is closely correlated with structural and clinical measures of OA, including total knee replacement.21,22,23 Likewise, Hoffa-synovitis can strongly predict the development of incident radiographic knee OA.24
In addition to local inflammation in the joint, systemic inflammation has an important role in OA pathogenesis.9 For example, obesity can predispose individuals to OA,17,25,26 not only by increasing the mechanical load on joints but also by causing chronic systemic inflammation through inflammatory mediators (proinflammatory cytokines, adipokines, alarmins) that are produced by adipose tissue and released into the bloodstream.27,28 Proinflammatory cytokines, including interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6, contributed to progressive cartilage loss in OA29 and were positively associated with changes in knee pain.30 A meta-analysis demonstrated that serum high-sensitivity C-reactive protein was upregulated in OA patients compared with control participants.31 Moreover, weight loss was associated with significantly lower systemic levels of C-reactive protein and IL-6 in OA patients, and may prevent OA onset or alleviate existing OA symptoms.32 Furthermore, serum IL-17F and IL-23 predicted increased knee bone marrow lesion (BML) scores in women, suggesting involvement of inflammation in BML pathogenesis in knee OA, particularly in women.33 Our preliminary research results suggested that serum S100A8/A9 in patients with knee OA was positively correlated with total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, cartilage defects, and serum matrix metalloproteinase 3 (MMP3).34 Our recently published article indicated that serum IL-10 and IL-12 were associated with increased cartilage volume and decreased effusion-synovitis and WOMAC scores, while leptin, adipsin, and C-reactive protein were positively associated with WOMAC scores.35 Thus, it is possible that systemic inflammation, which is associated with chronic inflammatory states like obesity and certain chronic diseases, promotes local inflammation in joints that ultimately leads to the inflammatory phenotype of OA.
3 | ANTI-INFLAMMATORY THERAPEUTIC AGENTS FOR OA
Because efforts to develop effective disease-modifying OA therapies against major inflammatory targets have not borne fruit, ongoing research is essential to better understand the inflammatory response in OA joint tissues and identify new drug targets.6,16 A number of different therapeutic approaches are currently under investigation that may eventually provide effective anti-inflammatory therapies for OA patients (Table 1). These approaches are summarized below.
| Type of drug | Route of administration | Major findings | The current phase of development | References | |
|---|---|---|---|---|---|
| Agents targeting cytokines | |||||
| IL-17-NAb | Intra-articular | Il-17-NAb could significantly reduce joint degeneration and relieve pain in the OA animal model | - | [36] | |
| IL-36Ra/RN | Intra-articular | IL-36Ra/RN showed greater improvements in OA development in mice and human OA chondrocytes | - | [37] | |
| Tocilizumab | Intraperitoneal injection | Tocilizumab contributed to cartilage preservation and increased bone volume in the ischemic osteonecrosis mice model, and reduced cartilage damage and synovitis in a mouse model of DMM-induced OA | - | [38] | |
| hIL-10var pDNA | Intra-articular | hIL-10var pDNA was safe, and significantly improved pain symptoms | - | [39] | |
| Lutikizumab | Subcutaneous | Lutikizumab was generally well tolerated in patients with knee OA and elicited an anti-inflammatory response. | Phase I trial | [40,41,42] | |
| Canakinumab | Intra-articular | The clinical trial was completed, but the results have not been released | Phase II trial | [43,44] | |
| Diacerein | Intra-articular | Diacerein has shown a reduction in synovitis in animal models of OA | - | [45] | |
| Oral | Diacerein was noninferior to celecoxib in reducing pain, stiffness, or functional limitations | Phase III | [46] | ||
| Adalimumab | Intra-articular | Adalimumab showed a significant improvement from baseline in VAS pain, WOMAC pain, stiffness, and function scores as well as physician assessments | - | [47,48] | |
| Corticosteroids | |||||
| FX006 (Zilretta) | Intra-articular | FX006 (Zilretta) markedly improved WOMAC scores for pain, stiffness, and physical function, and knee injury and KOOS-QOL scores compared with both placebo and TA crystal suspensions | Phase III | [49,50,51] | |
| MTX | Oral | MTX remarkably reduced pain and improved synovitis in patients with symptomatic knee OA | - | [52] | |
| The effect of oral MTX on pain and synovitis in patients with mid-to late-stage knee OA with effusion-synovitis is ongoing | Phase III | [53] | |||
| Vitamin D | Oral | Vitamin D showed significant effects on WOMAC total score, WOMAC function, VAS knee pain, and increase in BMLs, and might be beneficial for foot pain and depressive symptoms. | Phase III | [54,55,56] | |
| Oral | Both supplementation of vitamin D and maintaining vitamin D sufficiency had dramatical effects on knee joint effusion-synovitis in knee OA patients | Phase III | [57,58] | ||
| Curcumin | Oral | Curcumin was more effective than placebo for knee pain but did not affect knee effusion-synovitis or cartilage composition | Phase II | [59] | |
| The clinical trial is ongoing | Phase III | ||||
TABLE 1 Anti-inflammatory agents for the treatment of OA
Abbreviations: BML, bone marrow lesion; DMM, destabilization of medial meniscus; IL, interleukin; KOOS-QOL, knee injury and osteoarthritis outcome score quality of life; MTX, methotrexate; Nab, neutralizing antibody; OA, osteoarthritis; TA, triamcinolone acetonide; VAS, visual analog scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.
3.1 | Agents targeting cytokines
Inflammation is part of the OA process and inflammatory cytokines released by different articular cells are involved in pain and joint degradation.30,60,61 Several promising agents have shown disease-modifying effects on low-grade inflammation in animal models of OA that require confirmation in human clinical trials.62,63 For example, intra-articular (IA) injection of an IL-17-neutralizing antibody in mice decreased cyclin-dependent kinase inhibitor 1A and MMP13 expression and increased expression of IL-4, thereby reducing joint degeneration and relieving pain.36 In addition to neutralizing antibodies, receptor blockers appeared to be effective in experimental OA studies. A study found that IA injection of mouse IL-36 receptor (IL-36R) antagonists attenuated OA development in mice, while human IL-36R antagonists reduced MMP13 in human OA chondrocytes.37 Tocilizumab, an IL-6R blocker, contributed to cartilage preservation and increased bone volume in a mouse model of ischemic osteonecrosis, and reduced cartilage damage and synovitis in a mouse model of medial meniscus destabilization-induced OA.38 An experimental study on a plasmid DNA containing a human IL-10 transgene variant (hIL-10var pDNA) was conducted to examine its effects on pain measures in companion (pet) dogs with naturally occurring OA.39 The results revealed that IA injection of hIL-10var pDNA led to significant improvements in pain measures in vivo without toxicological effects, suggesting that IL-10var pDNA was well tolerated as a therapeutic option. Therefore, therapies targeting cytokines may be useful in OA with inflammatory features. Nevertheless, well-designed randomized controlled trials are required to confirm the findings obtained in these experimental studies.
Lutikizumab, an anti-IL-1α/β dual variable domain immunoglobulin, provided limited improvement in knee pain and synovitis in a Phase II trial but reduced neutrophil levels and plateaued high-sensitivity C-reactive protein levels when applied as a 100-mg injection subcutaneously every 2 weeks for 50 weeks.40 Two Phase I clinical studies of lutikizumab demonstrated an anti-inflammatory response and good tolerance in healthy subjects and patients with mild-to-moderate knee OA (NCT01668511).41,42 In patients with symptomatic, radiographic, and inflammatory knee OA, lutikizumab decreased WOMAC pain score at Week 16 (NCT02087904). Canakinumab, a humanized monoclonal antibody that blocks IL-1βR and is considered a disease-modifying antirheumatic drug (DMARD), showed symptom improvement for juvenile idiopathic arthritis and rheumatoid arthritis, with decreased cartilage destruction.43 A posthoc analysis in a randomized, double-blind, placebo-controlled trial (NCT01327846) was performed to determine the effects of canakinumab on incident hip and knee replacement. The results revealed significantly lower incidence rates for total hip or total knee replacement during a median follow-up of 3.7 years in participants receiving canakinumab compared with participants receiving placebo.44 The results supported further investigation of canakinumab for the treatment of large-joint OA. Another Phase II study (NCT01160822) on the safety, tolerability, pharmacokinetics, and pain effects of a single IA injection of canakinumab in patients with knee OA has been completed, but the results have not yet been released.
Diacerein is an inhibitor of IL-1β, and has an anticatabolic effect on OA tissues, and reduces MMP generation. In animal models of OA, diacerein has generally shown limited long-term effects on cartilage composition or pathology, but there is some evidence for a reduction in synovitis.45 Meanwhile, an international, multicenter, double-blind, randomized study reported that diacerein was noninferior to celecoxib in reducing pain, stiffness, and functional limitations.46 Adalimumab, a fully human anti-TNF-α monoclonal antibody, binds specifically to TNF-α and neutralizes its biological function by blocking the interactions with tumor necrosis factor receptor 1 (TNFR1) and TNFR2 receptors. An open-label randomized controlled trial concluded that there were significant improvements from baseline in visual analog scale (VAS) pain score, WOMAC pain, stiffness, and function scores and physician assessments after IA injection of adalimumab.47,48 A Phase-2 clinical trial has evaluated the safety and efficacy of a single injection of XT-150 (formally hIL-10var pDNA) for the treatment of patients with knee OA (NCT04124042), and is estimated to be completed in 2022.
3.2 | Corticosteroids
Corticosteroids are the most widely used anti-inflammatory agents worldwide, especially in the treatment of inflammatory diseases such as rheumatoid arthritis and gout. IA corticosteroids are commonly used for OA, with most trials focusing on knee OA, because they offer the opportunity to target inflammation at the joint level, thereby reducing systemic exposure to the drugs and the associated complications. However, corticosteroid injections have only short-term effects on knee pain and function, and treatments with sustained efficacy are needed.62 Furthermore, long-term (2 years) IA corticosteroid injections were reported to result in greater cartilage loss and no effects on pain compared with saline injection.49 FX006 (Zilretta), a novel type of extended-release triamcinolone acetonide (TA) formulation in 75:25 polymicrospheres, is designed to prolong conventional TA residence in the joint.50 FX006 significantly improved WOMAC scores for pain, stiffness, and physical function, as well as a knee injury and osteoarthritis outcome score quality of life scores for quality of life at 12 weeks, compared with both placebo and TA crystal suspensions.51 Owing to its reduced blood glucose elevation compared with standard TA crystal suspensions in patients with type 2 diabetes, FX006 was licensed by the Food and Drug Administration in October 2017 for the treatment of OA-related knee pain.
3.3 | Methotrexate
Methotrexate (MTX) has an anti-inflammatory effect by curbing the inflammatory functions of neutrophils, macrophages, monocytes, dendritic cells, and lymphocytes through adenosine release, thereby suppressing the secretion of inflammatory cytokines such as TNF-α and IL-6.52 In an open-label study on moderate-dose oral MTX for symptomatic knee OA, a high proportion of participants had a significant reduction in pain, suggesting that MTX could be a therapeutic option for knee OA.52 However, a systematic review published in 2018 found that DMARDs, including MTX, showed poor efficacy.64 These results suggest that MTX may be particularly effective for OA patients with effusion-synovitis. A multicenter randomized controlled trial to investigate the effects of oral MTX on pain and synovitis in patients with mid-to-late-stage knee OA with effusion-synovitis (NCT03815448) is ongoing, and further data are expected soon.53 Overall, more evidence is needed to clearly define the role of MTX in OA treatment.
3.4 | Vitamin D
Vitamin D supplementation did not prevent tibial cartilage loss or relieve WOMAC knee pain score over 2 years but had significant effects on WOMAC total score, WOMAC function score, VAS knee pain score, and BML increase, and may be beneficial for foot pain and depressive symptoms.54,55,56 Interestingly, both supplementation of vitamin D and maintenance of vitamin D sufficiency had significant effects on knee joint effusion-synovitis in patients with knee OA.57,58
3.5 | Curcumin
Curcumin is a natural phenol (diferuloylmethane) responsible for the yellow color of turmeric and is derived from the Curcuma longa root.65 Preclinical research showed that curcumin exhibited anti-inflammatory, antioxidant, and anticatabolic effects on chondrocytes by inhibiting expression of the inflammatory mediators IL-6, inducible nitric oxide synthase, and cyclooxygenase-2.65 Curcumin also blocked expression of MMPs and a disintegrin and metalloproteinase with thrombospondin motifs and increased expression of SOX-9 and production of collagen II, thus attenuating cartilage degradation.66,67 We performed a randomized, double-blind, placebo-controlled trial to determine the efficacy of curcumin extract (CL) treatment for 3 months in reducing knee symptoms and effusion-synovitis in patients with symptomatic knee OA with effusion-synovitis.59 The results suggested that CL was more effective than placebo for knee pain but did not affect knee effusion-synovitis or cartilage composition. Thus, there is a need for multicenter and well-conducted randomized trials using larger samples to assess their efficacy.
4 | CONCLUSION
OA is a complex, heterogeneous, and whole-joint disease with multiple etiologies.1,68 As the nature of its pathophysiology has become clearer, it has become increasingly common to see OA described in phenotypes.69 OA phenotyping has the potential to make important and impactful contributions to the development of more effective and/or disease-modifying interventions for OA.13,16,70 Further knowledge of the heterogeneity of many aspects around OA can help to refine the design of future trials for potential disease-modifying osteoarthritis drugs (DMOADs), better delineate potential treatment targets, improve the ability to select appropriate patients for tested interventions, and adapt outcome measures to the situation.71 Thus, further work is needed to identify effective inhibitors of the low-grade inflammation in OA, and to determine whether therapies that target inflammation can prevent or slow the onset and progression of this disease with the inflammatory phenotype and eventually lead to transformative therapies.
5 | PERSPECTIVES
The marked variations in disease expression and pathobiological manifestations in OA suggest the significant value of personalized and precision medicine from the therapeutic perspective.12,69,72 Personalized medicine is used to treat patients on the basis of their individual clinical characteristics, taking account of the diversity of symptoms, severity, and genetic defects.73 In precision medicine, molecular information maximizes the accuracy of patient classification and treatment, typically applying large amounts of data for the identification of patient phenotypes that share specific relevant characteristics to predict diagnosis, progression, or treatment response and utilize appropriate therapeutic targets.74,75 Clinical phenotypes, endotypes, and molecular and imaging biomarkers are being identified, but their exact interactions and the underlying mechanisms remain to be elucidated.69,76 While these biomarkers may have potential benefits in detecting patients at the greatest risk for structural progression, their use needs to be translated into efficient clinical trial designs and widespread clinical applications. Several recent clinical trials have utilized effusion-synovitis, an imaging biomarker, as a selection criterion and an endpoint to test the effects of anti-inflammatory agents on knee OA progression.53,59 Such precise clinical trials will eventually help to develop true DMOADs that target the OA inflammatory phenotype.
Acknowledgments
No other people was involved in this paper.
ETHICS STATEMENT
Ethics approvement was not required.
AUTHOR CONTRIBUTIONS
All authors contributed to the article and approved the submitted version.
REFERENCES
1.
Hunter D, Bierma-Zeinstra S. Osteoarthritis. Lancet. 2019;393: 1745-1759. doi:https://doi.org/10.1016/s0140-6736(19)30417-9
2.
Goldring S, Goldring M. Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage-bone crosstalk. Nat Rev Rheumatol. 2016;12:632-644. doi:https://doi.org/10.1038/nrrheum.2016.148
3.
Goldring M, Goldring S. Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Ann N Y Acad Sci. 2010; 1192:230-237. doi:https://doi.org/10.1111/j.1749-6632.2009.05240.x
4.
Palazzo C, Nguyen C, Lefevre-Colau M, Rannou F, Poiraudeau S. Risk factors and burden of osteoarthritis. Ann Phys Rehabil Med. 2016;59:134-138. doi:https://doi.org/10.1016/j.rehab.2016.01.006
5.
Katz J, Arant K, Loeser R. Diagnosis and treatment of hip and knee osteoarthritis: a review. JAMA. 2021;325:568-578. doi:https://doi.org/10.1001/jama.2020.22171
6.
Van Spil W, Kubassova O, Boesen M, Bay-Jensen A, Mobasheri A. Osteoarthritis phenotypes and novel therapeutic targets. Biochem Pharmacol. 2019;165:41-48. doi:https://doi.org/10.1016/j.bcp.2019.02.037
7.
Zhu Z, Li J, Ruan G, Wang G, Huang C, Ding C. Investigational drugs for the treatment of osteoarthritis, an update on recent developments. Expert Opin Invest Drugs. 2018;27:881-900. doi:https://doi.org/10.1080/13543784.2018.1539075
8.
Ansari M, Ahmad N, Haqqi T. Oxidative stress and inflammation in osteoarthritis pathogenesis: role of polyphenols. Biomed Pharmacother. 2020;129:110452. doi:https://doi.org/10.1016/j.biopha.2020.110452
9.
Liu-Bryan R, Terkeltaub R. Emerging regulators of the inflammatory process in osteoarthritis. Nat Rev Rheumatol. 2015; 11:35-44. doi:https://doi.org/10.1038/nrrheum.2014.162
10.
Robinson WH, Lepus CM, Wang Q, et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat Rev Rheumatol. 2016;12:580-592. doi:https://doi.org/10.1038/nrrheum.2016.136
11.
Lopes E, Filiberti A, Husain S, Humphrey M. Immune contributions to osteoarthritis. Curr Osteoporos Rep. 2017;15:593-600. doi:https://doi.org/10.1007/s11914-017-0411-y
12.
Latourte A, Kloppenburg M, Richette P. Emerging pharmaceutical therapies for osteoarthritis. Nat Rev Rheumatol. 2020;16: 673-688. doi:https://doi.org/10.1038/s41584-020-00518-6
13.
Cai X, Yuan S, Zeng Y, Wang C, Yu N, Ding C. New trends in pharmacological treatments for osteoarthritis. Front Pharmacol. 2021;12:645842. doi:https://doi.org/10.3389/fphar.2021.645842
14.
Oo W, Little C, Duong V, Hunter D. The development of disease-modifying therapies for osteoarthritis (DMOADs): the evidence to date. Drug Des Devel Ther. 2021;15:2921-2945. doi:https://doi.org/10.2147/dddt.s295224
15.
Philp A, Davis E, Jones S. Developing anti-inflammatory therapeutics for patients with osteoarthritis. Rheumatology. 2017;56: 869-881. doi:https://doi.org/10.1093/rheumatology/kew278
16.
Conaghan P, Cook A, Hamilton J, Tak P. Therapeutic options for targeting inflammatory osteoarthritis pain. Nat Rev Rheumatol. 2019;15:355-363. doi:https://doi.org/10.1038/s41584-019-0221-y
17.
Ioan-Facsinay A, Kloppenburg M. Osteoarthritis: inflammation and fibrosis in adipose tissue of osteoarthritic joints. Nat Rev Rheumatol. 2017;13:325-326. doi:https://doi.org/10.1038/nrrheum.2017.53
18.
Scanzello C. Role of low-grade inflammation in osteoarthritis. Curr Opin Rheumatol. 2017;29:79-85. doi:https://doi.org/10.1097/bor.0000000000000353
19.
Scanzello C, Goldring S. The role of synovitis in osteoarthritis pathogenesis. Bone. 2012;51:249-257. doi:https://doi.org/10.1016/j.bone.2012.02.012
20.
Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat Rev Rheumatol. 2010; 6:625-635. doi:https://doi.org/10.1038/nrrheum.2010.159
21.
Wang X, Blizzard L, Halliday A, et al. Association between MRI-detected knee joint regional effusion-synovitis and structural changes in older adults: a cohort study. Ann Rheum Dis. 2016;75: 519-525. doi:https://doi.org/10.1136/annrheumdis-2014-206676
22.
Guermazi A, Roemer FW, Hayashi D, et al. Assessment of synovitis with contrast-enhanced MRI using a whole-joint semi-quantitative scoring system in people with, or at high risk of, knee osteoarthritis: the MOST study. Ann Rheum Dis. 2011;70:805-811. doi:https://doi.org/10.1136/ard.2010.139618
23.
Oo WM, Linklater JM, Bennell KL, et al. Are OMERACT knee osteoarthritis ultrasound scores associated with pain severity, other symptoms, and radiographic and magnetic resonance imaging findings? J Rheumatol. 2021;48:270-278. doi:https://doi.org/10.3899/jrheum.191291
24.
Atukorala I, Kwoh CK, Guermazi A, et al. Synovitis in knee osteoarthritis: a precursor of disease? Ann Rheum Dis. 2016;75: 390-395. doi:https://doi.org/10.1136/annrheumdis-2014-205894
25.
Wang T, He C. Pro-inflammatory cytokines: the link between obesity and osteoarthritis. Cytokine Growth Factor Rev. 2018;44: 38-50. doi:https://doi.org/10.1016/j.cytogfr.2018.10.002
26.
Urban H, Little C. The role of fat and inflammation in the pathogenesis and management of osteoarthritis. Rheumatology. 2018;57:iv10-iv21. doi:https://doi.org/10.1093/rheumatology/kex399
27.
Lee R, Kean W. Obesity and knee osteoarthritis. Inflammopharmacology. 2012;20:53-58. doi:https://doi.org/10.1007/s10787-011-0118-0
28.
Berenbaum F, Eymard F, Houard X. Osteoarthritis, inflammation and obesity. Curr Opin Rheumatol. 2013;25:114-118. doi:https://doi.org/10.1097/BOR.0b013e32835a9414
29.
Larsson S, Englund M, Struglics A, Lohmander L. Interleukin-6 and tumor necrosis factor alpha in synovial fluid are associated with progression of radiographic knee osteoarthritis in subjects with previous meniscectomy. Osteoarthritis Cartilage. 2015;23: 1906-1914. doi:https://doi.org/10.1016/j.joca.2015.05.035
30.
Stannus O, Jones G, Blizzard L, Cicuttini F, Ding C. Associations between serum levels of inflammatory markers and change in knee pain over 5 years in older adults: a prospective cohort study. Ann Rheum Dis. 2013;72:535-540. doi:https://doi.org/10.1136/annrheumdis-2011-201047
31.
Jin X, Beguerie JR, Zhang W, et al. Circulating C reactive protein in osteoarthritis: a systematic review and meta-analysis. Ann Rheum Dis. 2015;74:703-710. doi:https://doi.org/10.1136/annrheumdis-2013-204494
32.
Vincent H, Heywood K, Connelly J, Hurley R. Obesity and weight loss in the treatment and prevention of osteoarthritis. PM R. 2012; 4:S59-S67. doi:https://doi.org/10.1016/j.pmrj.2012.01.005
33.
Zhu Z, Otahal P, Wang B, et al. Cross-sectional and longitudinal associations between serum inflammatory cytokines and knee bone marrow lesions in patients with knee osteoarthritis. Osteoarthritis Cartilage. 2017;25:499-505. doi:https://doi.org/10.1016/j.joca.2016.10.024
34.
Ruan G, Xu J, Wang K, et al. Associations between serum S100A8/S100A9 and knee symptoms, joint structures and cartilage enzymes in patients with knee osteoarthritis. Osteoarthritis Cartilage. 2019;27:99-105. doi:https://doi.org/10.1016/j.joca.2018.08.020
35.
Zhu J, Ruan G, Cen H, et al. Association of serum levels of inflammatory markers and adipokines with joint symptoms and structures in participants with knee osteoarthritis. Rheumatology. 2021;keab479. doi:https://doi.org/10.1093/rheumatology/keab479
36.
Faust HJ, Zhang H, Han J, et al. IL-17 and immunologically induced senescence regulate response to injury in osteoarthritis. J Clin Invest. 2020;130:5493-5507. doi:https://doi.org/10.1172/jci134091
37.
Li T, Chubinskaya S, Esposito A, et al. TGF-β type 2 receptor-mediated modulation of the IL-36 family can be therapeutically targeted in osteoarthritis. Sci Transl Med. 2019;11:eaan2585. doi:https://doi.org/10.1126/scitranslmed.aan2585
38.
Kamiya N, Kuroyanagi G, Aruwajoye O, Kim H. IL6 receptor blockade preserves articular cartilage and increases bone volume following ischemic osteonecrosis in immature mice. Osteoarthritis Cartilage. 2019;27:326-335. doi:https://doi.org/10.1016/j.joca.2018.10.010
39.
Watkins LR, Chavez RA, Landry R, et al. Targeted interleukin-10 plasmid DNA therapy in the treatment of osteoarthritis: toxicology and pain efficacy assessments. Brain Behav Immun. 2020;90: 155-166. doi:https://doi.org/10.1016/j.bbi.2020.08.005
40.
Fleischmann RM, Bliddal H, Blanco FJ, et al. A phase II trial of lutikizumab, an anti-interleukin-1α/β dual variable domain immunoglobulin, in knee osteoarthritis patients with synovitis. Arthritis Rheumatol. 2019;71:1056-1069. doi:https://doi.org/10.1002/art.40840
41.
Wang SX, Abramson SB, Attur M, et al. Safety, tolerability, and pharmacodynamics of an anti-interleukin-1α/β dual variable domain immunoglobulin in patients with osteoarthritis of the knee: a randomized phase 1 study. Osteoarthritis Cartilage. 2017; 25:1952-1961. doi:https://doi.org/10.1016/j.joca.2017.09.007
42.
Kosloski MP, Goss S, Wang SX, et al. Pharmacokinetics and tolerability of a dual variable domain immunoglobulin ABT-981 against IL-1α and IL-1β in healthy subjects and patients with osteoarthritis of the knee. J Clin Pharmacol. 2016;56:1582-1590. doi:https://doi.org/10.1002/jcph.764
43.
Sota J, Vitale A, Insalaco A, et al. Safety profile of the interleukin-1 inhibitors anakinra and canakinumab in real-life clinical practice: a nationwide multicenter retrospective observational study. Clin Rheumatol. 2018;37:2233-2240. doi:https://doi.org/10.1007/s10067-018-4119-x
44.
Schieker M, Conaghan PG, Mindeholm L, et al. Effects of interleukin-1β inhibition on incident hip and knee replacement: exploratory analyses from a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2020;173:509-515. doi:https://doi.org/10.7326/m20-0527
45.
Eladawy N, Morsi N, Shamma R. Diacerein-loaded hyaluosomes as a dual-function platform for osteoarthritis management via intra-articular injection: in vitro characterization and in vivo assessment in a rat model. Pharmaceutics. 2021;13. doi:https://doi.org/10.3390/pharmaceutics13060765
46.
Pelletier JP, Raynauld JP, Dorais M, et al. An international, multicentre, double-blind, randomized study (DISSCO): effect of diacerein vs celecoxib on symptoms in knee osteoarthritis. Rheumatology. 2020;59:3858-3868. doi:https://doi.org/10.1093/rheumatology/keaa072
47.
Wang J. Efficacy and safety of adalimumab by intra-articular injection for moderate to severe knee osteoarthritis: an open-label randomized controlled trial. J Int Med Res. 2018;46:326-334. doi:https://doi.org/10.1177/0300060517723182
48.
Maksymowych WP, Russell AS, Chiu P, et al. Targeting tumour necrosis factor alleviates signs and symptoms of inflammatory osteoarthritis of the knee. Arthritis Res Ther. 2012;14:R206. doi:https://doi.org/10.1186/ar4044
49.
McAlindon TE, LaValley MP, Harvey WF, et al. Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial. JAMA. 2017;317:1967-1975. doi:https://doi.org/10.1001/jama.2017.5283
50.
Conaghan PG, Cohen SB, Berenbaum F, Lufkin J, Johnson JR, Bodick N. Brief report: a phase IIb trial of a novel extended-release microsphere formulation of triamcinolone acetonide for intraarticular injection in knee osteoarthritis. Arthritis Rheumatol. 2018;70:204-211. doi:https://doi.org/10.1002/art.40364
51.
Conaghan PG, Hunter DJ, Cohen SB, et al. Effects of a single intra-articular injection of a microsphere formulation of triamcinolone acetonide on knee osteoarthritis pain: a double-blinded, randomized, placebo-controlled, multinational study. J Bone Joint Surg Am. 2018;100:666-677. doi:https://doi.org/10.2106/jbjs.17.00154
52.
Wenham CY, Grainger AJ, Hensor EM, Caperon AR, Ash ZR, Conaghan PG. Methotrexate for pain relief in knee osteoarthritis: an open-label study. Rheumatology. 2013;52:888-892. doi:https://doi.org/10.1093/rheumatology/kes386
53.
Zhu Z, Yu Q, Leng X, et al. Can low-dose methotrexate reduce effusion-synovitis and symptoms in patients with mid- to late-stage knee osteoarthritis? Study protocol for a randomised, double-blind, and placebo-controlled trial. Trials. 2020;21:795. doi:https://doi.org/10.1186/s13063-020-04687-3
54.
Jin X, Jones G, Cicuttini F, et al. Effect of vitamin D supplementation on tibial cartilage volume and knee pain among patients with symptomatic knee osteoarthritis: a randomized clinical trial. JAMA. 2016;315:1005-1013. doi:https://doi.org/10.1001/jama.2016.1961
55.
Zheng S, Tu L, Cicuttini F, et al. Effect of vitamin D supplementation on depressive symptoms in patients with knee osteoarthritis. J Am Med Dir Assoc. 2019;20:1634-1640. doi:https://doi.org/10.1016/j.jamda.2018.09.006
56.
Tu L, Zheng S, Cicuttini F, et al. Effects of vitamin D supplementation on disabling foot pain in patients with symptomatic knee osteoarthritis. Arthritis Care Res. 2021;73:781-787. doi:https://doi.org/10.1002/acr.24371
57.
Wang X, Cicuttini F, Jin X, et al. Knee effusion-synovitis volume measurement and effects of vitamin D supplementation in patients with knee osteoarthritis. Osteoarthritis Cartilage. 2017;25: 1304-1312. doi:https://doi.org/10.1016/j.joca.2017.02.804
58.
Zheng S, Jin X, Cicuttini F, et al. Maintaining vitamin D sufficiency is associated with improved structural and symptomatic outcomes in knee osteoarthritis. Am J Med. 2017;130:1211-1218. doi:https://doi.org/10.1016/j.amjmed.2017.04.038
59.
Wang Z, Jones G, Winzenberg T, et al. Effectiveness of Curcuma longa extract for the treatment of symptoms and effusion-synovitis of knee osteoarthritis: a randomized trial. Ann Intern Med. 2020;173:861-869. doi:https://doi.org/10.7326/m20-0990
60.
Panina SB, Krolevets IV, Milyutina NP, et al. Circulating levels of proinflammatory mediators as potential biomarkers of post-traumatic knee osteoarthritis development. J Orthop Traumatol. 2017;18:349-357. doi:https://doi.org/10.1007/s10195-017-0473-8
61.
Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier J, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol. 2011;7:33-42. doi:https://doi.org/10.1038/nrrheum.2010.196
62.
Atiquzzaman M, Karim M, Kopec J, Wong H, Anis A. Role of nonsteroidal antiinflammatory drugs in the association between osteoarthritis and cardiovascular diseases: a longitudinal study. Arthritis Rheumatol. 2019;71:1835-1843. doi:https://doi.org/10.1002/art.41027
63.
Ghouri A, Conaghan P. Update on novel pharmacological therapies for osteoarthritis. Ther Adv Musculoskelet Dis. 2019;11: 1-11. doi:https://doi.org/10.1177/1759720x19864492
64.
Persson M, Sarmanova A, Doherty M, Zhang W. Conventional and biologic disease-modifying anti-rheumatic drugs for osteoarthritis: a meta-analysis of randomized controlled trials. Rheumatology. 2018;57:1830-1837. doi:https://doi.org/10.1093/rheumatology/key131
65.
Henrotin Y, Clutterbuck AL, Allaway D, et al. Biological actions of curcumin on articular chondrocytes. Osteoarthritis Cartilage. 2010;18:141-149. doi:https://doi.org/10.1016/j.joca.2009.10.002
66.
Zhao P, Cheng J, Geng J, et al. Curcumin protects rabbit articular chondrocytes against sodium nitroprusside-induced apoptosis in vitro. Eur J Pharmacol. 2018;828:146-153. doi:https://doi.org/10.1016/j.ejphar.2018.03.038
67.
Jiang C, Luo P, Li X, Liu P, Li Y, Xu J. Nrf2/ARE is a key pathway for curcumin-mediated protection of TMJ chondrocytes from oxidative stress and inflammation. Cell Stress Chaperones. 2020; 25:395-406. doi:https://doi.org/10.1007/s12192-020-01079-z
68.
Loeser R, Collins J, Diekman B. Ageing and the pathogenesis of osteoarthritis. Nat Rev Rheumatol. 2016;12:412-420. doi:https://doi.org/10.1038/nrrheum.2016.65
69.
Mobasheri A, Batt M. An update on the pathophysiology of osteoarthritis. Ann Phys Rehabil Med. 2016;59:333-339. doi:https://doi.org/10.1016/j.rehab.2016.07.004
70.
Berenbaum F, Walker C. Osteoarthritis and inflammation: a serious disease with overlapping phenotypic patterns. Postgrad Med. 2020;132:377-384. doi:https://doi.org/10.1080/00325481.2020.1730669
71.
Deveza L, Nelson A, Loeser R. Phenotypes of osteoarthritis: current state and future implications. Clin Exp Rheumatol. 2019; 37:64-72.
72.
Tonge D, Pearson M, Jones S. The hallmarks of osteoarthritis and the potential to develop personalised disease-modifying pharmacological therapeutics. Osteoarthritis Cartilage. 2014;22: 609-621. doi:https://doi.org/10.1016/j.joca.2014.03.004
73.
Jiang X, Nelson AE, Cleveland RJ, et al. Precision medicine approach to develop and internally validate optimal exercise and weight-loss treatments for overweight and obese adults with knee osteoarthritis: data from a single-center randomized trial. Arthritis Care Res. 2021;73:693-701. doi:https://doi.org/10.1002/acr.24179
74.
Tsimberidou A, Müller P, Ji Y. Innovative trial design in precision oncology. Semin Cancer Biol. 2020;S1044-579X(20):30195-4. doi:https://doi.org/10.1016/j.semcancer.2020.09.006
75.
Malone E, Oliva M, Sabatini P, Stockley T, Siu L. Molecular profiling for precision cancer therapies. Genome Med. 2020;12:8. doi:https://doi.org/10.1186/s13073-019-0703-1
76.
Kalunian K. Current advances in therapies for osteoarthritis. Curr Opin Rheumatol. 2016;28:246-250. doi:https://doi.org/10.1097/bor.0000000000000273
Information & Authors
Information
Published In
Rheumatology & Autoimmunity
Volume 01 • Number 02 • 30 December 2021
Pages: 92 - 100
Copyright
© 2021 Chinese Medical Association. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CC BY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
History
Received: 23 August 2021
Accepted: 29 October 2021
Published online: 10 January 2022
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Data Availability Statement
No data was used in this review paper.
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Conflict of Interests
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
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