Musculoskeletal pain: determination of clinical phenotypes and the rational treatment approach

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Personalized treatment is one of the basic principles of modern medicine. When administering a treatment, one should consider individual patient characteristics, comorbidities and, what is most important, the prevailing symptoms, as well as the clinical phenotype of a disease. This is directly related to chronic musculoskeletal pain (MSP), which occurs with underlying most prevalent joint and vertebral disorders. At present, MSP is considered to be an independent clinical syndrome.
Predominant mechanisms of MSP pathophysiology allow for determination of its special phenotypes: “inflammatory”, “mechanical”, related to enthesopathy and central sensitization. Treatment strategies for MSP phenotypes should obviously be differentiated and based on a tailored and pathophysiologically sound of medical agents and non-medical measures with different mechanisms of pharmacological effects. Effective treatment of the “inflammatory” phenotype requires the use of non-steroidal anti-inflammatory drugs, topical glucocorticoids, disease modifying anti-inflammatory agents. The “mechanical” phenotype necessitates the correction of biomechanical abnormalities, the use of hyaluronic acid containing agents, whereas the “enthesopathic” phenotype is treated with local therapy. Treatment of the phenotype with central sensitization is performed with agents effective for neuropathic pain (anticonvulsants, anti-depressants).

About the authors

A. E. Karateev

V.A. Nasonova Research Institute of Rheumatology, Russian Academy of Medical Sciences

Author for correspondence.
ORCID iD: 0000-0002-1391-0711

Andrei E. Karateev – MD, PhD, Head of the Laboratory of the Pathophysiology of Pain and Polymorphism of Musculoskeletal Diseases

34A Kashirskoe shosse, Moscow, 115522

Russian Federation


  1. van Meurs JB, Boer CG, Lopez-Delgado L, Riancho JA. Role of Epigenomics in Bone and Cartilage Disease. J Bone Miner Res. 2019;34(2): 215–30. doi: 10.1002/jbmr.3662.
  2. Casanova JL. Human genetic basis of interindividual variability in the course of infection. Proc Natl Acad Sci U S A. 2015;112(51):E7118– 27. doi: 10.1073/pnas.1521644112.
  3. Felson DT. Identifying different osteoarthritis phenotypes through epidemiology. Osteoarthritis Cartilage. 2010;18(5): 601–4. doi: 10.1016/j.joca.2010.01.007.
  4. Babatunde OO, Jordan JL, Van der Windt DA, Hill JC, Foster NE, Protheroe J. Effective treatment options for musculoskeletal pain in primary care: A systematic overview of current evidence. PLoS One. 2017;12(6):e0178621. doi: 10.1371/journal.pone.0178621.
  5. Bruyere O, Honvo G, Veronese N, Arden NK, Branco J, Curtis EM, Al-Daghri NM, HerreroBeaumont G, Martel-Pelletier J, Pelletier JP, Rannou F, Rizzoli R, Roth R, Uebelhart D, Cooper C, Reginster JY. An updated algorithm recommendation for the management of knee osteoarthritis from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO). Semin Arthritis Rheum. 2019 Apr 30. pii: S0049-0172(19)30043-5. doi: 10.1016/j.semarthrit.2019.04.008.
  6. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100): 1211–59. doi: 10.1016/S0140-6736(17)32154-2.
  7. O'Neill TW, McCabe PS, McBeth J. Update on the epidemiology, risk factors and disease outcomes of osteoarthritis. Best Pract Res Clin Rheumatol. 2018;32(2): 312–26. doi: 10.1016/j.berh.2018.10.007.
  8. Vos T, Flaxman AD, Naghavi M. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859): 2163–96. doi: 10.1016/S0140-6736(12)61729-2.
  9. Cisternas MG, Murphy L, Sacks JJ, Solomon DH, Pasta DJ, Helmick CG. Alternative Methods for Defining Osteoarthritis and the Impact on Estimating Prevalence in a US Population-Based Survey. Arthritis Care Res (Hoboken). 2016;68(5): 574–80. doi: 10.1002/acr.22721.
  10. Здравоохранение в России. 2017. Статистический сборник. М.: Росстат; 2017. 170 с. [Интернет]. Доступно на:
  11. Bastick AN, Belo JN, Runhaar J, Bierma-Zeinstra SM. What Are the Prognostic Factors for Radiographic Progression of Knee Osteoarthritis? A Meta-analysis. Clin Orthop Relat Res. 2015;473(9): 2969–89. doi: 10.1007/s11999015-4349-z.
  12. de Rooij M, van der Leeden M, Heymans MW, Holla JF, Hakkinen A, Lems WF, Roorda LD, Veenhof C, Sanchez-Ramirez DC, de Vet HC, Dekker J. Prognosis of pain and physical functioning in patients with knee osteoarthritis: a systematic review and meta-analysis. Arthritis Care Res (Hoboken). 2016;68(4): 481–92. doi: 10.1002/acr.22693.
  13. Schaible HG, Ebersberger A, Von Banchet GS. Mechanisms of pain in arthritis. Ann N Y Acad Sci. 2002;966:343–54. doi: 10.1111/j.17496632.2002.tb04234.x.
  14. Robinson WH, Lepus CM, Wang Q, Raghu H, Mao R, Lindstrom TM, Sokolove J. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat Rev Rheumatol. 2016;12(10): 580–92. doi: 10.1038/nrrheum.2016.
  15. Mathiessen A, Conaghan PG. Synovitis in osteoarthritis: current understanding with therapeutic implications. Arthritis Res Ther. 2017;19(1): 18. doi: 10.1186/s13075-0171229-9.
  16. McWilliams DF, Walsh DA. Pain mechanisms in rheumatoid arthritis. Clin Exp Rheumatol. 2017;35 Suppl 107(5): 94–101.
  17. Bidad K, Gracey E, Hemington KS, Mapplebeck JCS, Davis KD, Inman RD. Pain in ankylosing spondylitis: a neuro-immune collaboration. Nat Rev Rheumatol. 2017;13(7): 410–20. doi: 10.1038/nrrheum.2017.92.
  18. Straub RH, Bijlsma JW, Masi A, Cutolo M. Role of neuroendocrine and neuroimmune mechanisms in chronic inflammatory rheumatic diseases – the 10-year update. Semin Arthritis Rheum. 2013;43(3): 392–404. doi: 10.1016/j.semarthrit.2013.04.008.
  19. Arnbak B, Hendricks O, Horslev-Petersen K, Jurik AG, Pedersen SJ, Ostergaard M, Hermansen LT, Loft AG, Jensen TS, Manniche C. The discriminative value of inflammatory back pain in patients with persistent low back pain. Scand J Rheumatol. 2016;45(4): 321–8. doi: 10.3109/03009742.2015.1105289.
  20. Pan F, Jones G. Clinical perspective on pain and pain phenotypes in osteoarthritis. Curr Rheumatol Rep. 2018;20(12): 79. doi: 10.1007/s11926-018-0796-3.
  21. Nees TA, Rosshirt N, Reiner T, Schiltenwolf M, Moradi B. Inflammation and osteoarthritis-related pain. Schmerz. 2019;33(1): 4–12. doi: 10.1007/s00482-018-0346-y.
  22. Ledford C. Spine Conditions: Mechanical and Inflammatory Low Back Pain. FP Essent. 2017;461:15–20.
  23. Dell'Isola A, Allan R, Smith SL, Marreiros SS, Steultjens M. Identification of clinical phenotypes in knee osteoarthritis: a systematic review of the literature. BMC Musculoskelet Disord. 2016;17(1): 425. doi: 10.1186/s12891016-1286-2.
  24. Haugen IK, Mathiessen A, Slatkowsky-Christensen B, Magnusson K, Boyesen P, Sesseng S, van der Heijde D, Kvien TK, Hammer HB. Synovitis and radiographic progression in non-erosive and erosive hand osteoarthritis: is erosive hand osteoarthritis a separate inflammatory phenotype? Osteoarthritis Cartilage. 2016;24(4): 647–54. doi: 10.1016/j.joca.2015.11.014.
  25. Attur M, Belitskaya-Levy I, Oh C, Krasnokutsky S, Greenberg J, Samuels J, Smiles S, Lee S, Patel J, Al-Mussawir H, McDaniel G, Kraus VB, Abramson SB. Increased interleukin-1β gene expression in peripheral blood leukocytes is associated with increased pain and predicts risk for progression of symptomatic knee osteoarthritis. Arthritis Rheum. 2011;63(7): 1908– 17. doi: 10.1002/art.30360.
  26. Daghestani HN, Pieper CF, Kraus VB. Soluble macrophage biomarkers indicate inflammatory phenotypes in patients with knee osteoarthritis. Arthritis Rheumatol. 2015;67(4): 956–65. doi: 10.1002/art.39006.
  27. van Spil WE, Jansen NW, Bijlsma JW, Reijman M, DeGroot J, Welsing PM, Lafeber FP. Clusters within a wide spectrum of biochemical markers for osteoarthritis: data from CHECK, a large cohort of individuals with very early symptomatic osteoarthritis. Osteoarthritis Cartilage. 2012;20(7): 745–54. doi: 10.1016/j.joca.2012.04.004.
  28. Poddubnyy D, Callhoff J, Spiller I, Listing J, Braun J, Sieper J, Rudwaleit M. Diagnostic accuracy of inflammatory back pain for axial spondyloarthritis in rheumatological care. RMD Open. 2018;4(2):e000825. doi: 10.1136/rmdopen-2018-000825.
  29. Kivity S, Gofrit SG, Baker FA, Leibushor N, Tavor S, Lidar M, Eshed I. Association between inflammatory back pain features, acute and structural sacroiliitis on MRI, and the diagnosis of spondyloarthritis. Clin Rheumatol. 2019;38(6): 1579–85. doi: 10.1007/s10067-01904432-5.
  30. Paholpak P, Dedeogullari E, Lee C, Tamai K, Barkoh K, Sessumpun K, Wang JC, Buser Z. Do modic changes, disc degeneration, translation and angular motion affect facet osteoarthritis of the lumbar spine. Eur J Radiol. 2018;98:193– 9. doi: 10.1016/j.ejrad.2017.11.023.
  31. O'Leary SA, Paschos NK, Link JM, Klineberg EO, Hu JC, Athanasiou KA. Facet joints of the spine: structure-function relationships, problems and treatments, and the potential for regeneration. Annu Rev Biomed Eng. 2018;20:145–70. doi: 10.1146/annurev-bioeng-062117-120924.
  32. Gellhorn AC, Katz JN, Suri P. Osteoarthritis of the spine: the facet joints. Nat Rev Rheumatol. 2013;9(4): 216–24. doi: 10.1038/nrrheum.2012.199.
  33. Nguyen QT, Jacobsen TD, Chahine NO. Effects of inflammation on multiscale biomechanical properties of cartilaginous cells and tissues. ACS Biomater Sci Eng. 2017;3(11): 2644–56. doi: 10.1021/acsbiomaterials.6b00671.
  34. Boyer KA. Biomechanical response to osteoarthritis pain treatment may impair long-term efficacy. Exerc Sport Sci Rev. 2018;46(2): 121–8. doi: 10.1249/JES.0000000000000141.
  35. Walter BA, Purmessur D, Moon A, Occhiogrosso J, Laudier DM, Hecht AC, Iatridis JC. Reduced tissue osmolarity increases TRPV4 expression and pro-inflammatory cytokines in intervertebral disc cells. Eur Cell Mater. 2016;32:123–36. doi: 10.22203/eCM.
  36. O'Conor CJ, Leddy HA, Benefield HC, Liedtke WB, Guilak F. TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading. Proc Natl Acad Sci U S A. 2014;111(4): 1316–21. doi: 10.1073/pnas.1319569111.
  37. Birmingham TB, Marriott KA, Leitch KM, Moyer RF, Lorbergs AL, Walton DM, Willits K, Litchfield RB, Getgood A, Fowler PJ, Giffin JR. Association Between Knee Load and Pain: Within-Patient, Between-Knees, Case-Control Study in Patients With Knee Osteoarthritis. Arthritis Care Res (Hoboken). 2019;71(5): 647–50. doi: 10.1002/acr.23704.
  38. Felson DT, Niu J, Gross KD, Englund M, Sharma L, Cooke TD, Guermazi A, Roemer FW, Segal N, Goggins JM, Lewis CE, Eaton C, Nevitt MC. Valgus malalignment is a risk factor for lateral knee osteoarthritis incidence and progression: findings from the Multicenter Osteoarthritis Study and the Osteoarthritis Initiative. Arthritis Rheum. 2013;65(2): 355–62. doi: 10.1002/art.37726.
  39. Wyndow N, Collins N, Vicenzino B, Tucker K, Crossley K. Is There a Biomechanical Link Between Patellofemoral Pain and Osteoarthritis? A Narrative Review. Sports Med. 2016;46(12): 1797–808. doi: 10.1007/s40279-016-0545-6.
  40. Gross KD, Felson DT, Niu J, Hunter DJ, Guermazi A, Roemer FW, Dufour AB, Gensure RH, Hannan MT. Association of flat feet with knee pain and cartilage damage in older adults. Arthritis Care Res (Hoboken). 2011;63(7): 937–44. doi: 10.1002/acr.20431.
  41. Miyagi M, Fukushima K, Inoue G, Nakazawa T, Imura T, Saito W, Takahira N, Takaso M. Hip-spine syndrome: cross-sectionalstudy of spinal alignment in patients with coxalgia. Hip Int. 2019;29(1): 21–5. doi: 10.1177/1120700018803236.
  42. Schett G, Lories RJ, D'Agostino MA, Elewaut D, Kirkham B, Soriano ER, McGonagle D. Enthesitis: from pathophysiology to treatment. Nat Rev Rheumatol. 2017;13(12): 731–41. doi: 10.1038/nrrheum.2017.188.
  43. Slobodin G, Rimar D, Boulman N, Kaly L, Rozenbaum M, Rosner I, Odeh M. Entheseal involvement in systemic disorders. Clin Rheumatol. 2015;34(12): 2001–10. doi: 10.1007/s10067015-3068-x.
  44. Каратеев АЕ, Каратеев ДЕ, Орлова ЕС, Ермакова ЮА. «Малая»ревматология: несистемная ревматическая патология околосуставных мягких тканей верхней конечности. Часть 1. Современная ревматология. 2015;9(2): 4–15. doi: 10.14412/19967012-2015-2-4-15.
  45. McGonagle D, Hermann KG, Tan AL. Differentiation between osteoarthritis and psoriatic arthritis: implications for pathogenesis and treatment in the biologic therapy era. Rheumatology (Oxford). 2015;54(1): 29–38. doi: 10.1093/rheumatology/keu328.
  46. Binks DA, Bergin D, Freemont AJ, Hodgson RJ, Yonenaga T, McGonagle D, Radjenovic A. Potential role of the posterior cruciate ligament synovio-entheseal complex in joint effusion in early osteoarthritis: a magnetic resonance imaging and histological evaluation of cadaveric tissue and data from the Osteoarthritis Initiative. Osteoarthritis Cartilage. 2014;22(9): 1310–7. doi: 10.1016/j.joca.2014.06.037.
  47. McGonagle D, Aydin SZ, Tan AL. The synovioentheseal complex and its role in tendon and capsular associated inflammation. J Rheumatol Suppl. 2012;89:11–4. doi: 10.3899/jrheum.120233.
  48. Mantel PY, Schmidt-Weber CB. Transforming growth factor-beta: recent advances on its role in immune tolerance. Methods Mol Biol. 2011;677:303–38. doi: 10.1007/978-1-60761869-0_21.
  49. van Lent PL, Blom AB, van der Kraan P, Holthuysen AE, Vitters E, van Rooijen N, Smeets RL, Nabbe KC, van den Berg WB. Crucial role of synovial lining macrophages in the promotion of transforming growth factor beta-mediated osteophyte formation. Arthritis Rheum. 2004;50(1): 103–11. doi: 10.1002/art.11422.
  50. Lories RJ, Luyten FP. Bone morphogenetic protein signaling in joint homeostasis and disease. Cytokine Growth Factor Rev. 2005;16(3): 287–98. doi: 10.1016/j.cytogfr.2005.02.009.
  51. Lee YC. Effect and treatment of chronic pain in inflammatory arthritis. Curr Rheumatol Rep. 2013;15(1): 300. doi: 10.1007/s11926-0120300-4.
  52. Salaffi F, Giacobazzi G, Di Carlo M. Chronic Pain in Inflammatory Arthritis: Mechanisms, Metrology, and Emerging Targets – A Focus on the JAK-STAT Pathway. Pain Res Manag. 2018;2018:8564215. doi: 10.1155/2018/8564215.
  53. Arendt-Nielsen L, Morlion B, Perrot S, Dahan A, Dickenson A, Kress HG, Wells C, Bouhassira D, Mohr Drewes A. Assessment and manifestation of central sensitisation across different chronic pain conditions. Eur J Pain. 2018;22(2): 216–41. doi: 10.1002/ejp.1140.
  54. Chen G, Zhang YQ, Qadri YJ, Serhan CN, Ji RR. Microglia in pain: detrimental and protective roles in pathogenesis and resolution of pain. Neuron. 2018;100(6): 1292–311. doi: 10.1016/j.neuron.2018.11.009.
  55. Olesen AE, Nielsen LM, Feddersen S, Erlenwein J, Petzke F, Przemeck M, Christrup LL, Drewes AM. Association Between Genetic Polymorphisms and Pain Sensitivity in Patients with Hip Osteoarthritis. Pain Pract. 2018;18(5): 587–96. doi: 10.1111/papr.12648.
  56. Abella V, Scotece M, Conde J, Pino J, GonzalezGay MA, Gomez-Reino JJ, Mera A, Lago F, Gomez R, Gualillo O. Leptin in the interplay of inflammation, metabolism and immune system disorders. Nat Rev Rheumatol. 2017;13(2): 100–9. doi: 10.1038/nrrheum.2016.209.
  57. Kohler O, Krogh J, Mors O, Benros ME. Inflammation in depression and the potential for anti-inflammatory treatment. Curr Neuropharmacol. 2016;14(7): 732–42. doi: 10.2174/1570159X14666151208113700.
  58. Steyaert A, Lavand'homme P. Prevention and treatment of chronic postsurgical pain: A narrative review. Drugs. 2018;78(3): 339–54. doi: 10.1007/s40265-018-0866-x.
  59. Dougados M, Perrot S. Fibromyalgia and central sensitization in chronic inflammatory joint diseases. Joint Bone Spine. 2017;84(5): 511–3. doi: 10.1016/j.jbspin.2017.03.001.
  60. Lee YC, Lu B, Boire G, Haraoui BP, Hitchon CA, Pope JE, Thorne JC, Keystone EC, Solomon DH, Bykerk VP. Incidence and predictors of secondary fibromyalgia in an early arthritis cohort. Ann Rheum Dis. 2013;72(6): 949–54. doi: 10.1136/annrheumdis-2012-201506.
  61. Walsh DA, Stocks J. New Therapeutic Targets for Osteoarthritis Pain. SLAS Discov. 2017;22(8): 931–49. doi: 10.1177/2472555217716912.
  62. Favero M, Ramonda R, Goldring MB, Goldring SR, Punzi L. Early knee osteoarthritis. RMD Open. 2015;1(Suppl 1):e000062. doi: 10.1136/rmdopen-2015-000062.
  63. Filardo G, Kon E, Longo UG, Madry H, Marchettini P, Marmotti A, Van Assche D, Zanon G, Peretti GM. Non-surgical treatments for the management of early osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2016;24(6): 1775– 85. doi: 10.1007/s00167-016-4089-y.
  64. Wenham CY, Grainger AJ, Hensor EM, Caperon AR, Ash ZR, Conaghan PG. Methotrexate for pain relief in knee osteoarthritis: an open-label study. Rheumatology (Oxford). 2013;52(5): 888–92. doi: 10.1093/rheumatology/kes386.
  65. 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(1): 326– 34. doi: 10.1177/0300060517723182.
  66. Chevalier X, Goupille P, Beaulieu AD, Burch FX, Bensen WG, Conrozier T, Loeuille D, Kivitz AJ, Silver D, Appleton BE. Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2009;61(3): 344–52. doi: 10.1002/art.24096.
  67. Wu PI, Diaz R, Borg-Stein J. Platelet-Rich Plasma. Phys Med Rehabil Clin N Am. 2016;27(4): 825–53. doi: 10.1016/j.pmr.2016.06.002.
  68. Kuffler DP. Variables affecting the potential efficacy of PRP in providing chronic pain relief. J Pain Res. 2018;12:109–16. doi: 10.2147/JPR.S190065.

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