The role of clinical parameters and cathepsin S gene expression in predicting the development of postoperative pain in patients with hip osteoarthritis

 Objective: to evaluate the significance of clinical indicators, expression of pain syndrome genes cathepsin S and pro-inflammatory cytokines in peripheral blood for predicting the development of postoperative pain (POP)  in patients with hip osteoarthritis (HOA) before total arthroplasty (TA).
Material and methods. The study included 31 patients with stages III–IV of HOA (mean age 61.3±9.8 years) who underwent TA and 26 healthy volunteers (control group). Depending on the presence or absence of POP,  patients were divided into two subgroups: with POP (1st subgroup, n=12) and without POP (2nd subgroup, n=19). Patients were examined before and 6  months after surgery.
Prior to TA, the level of pain was determined in all patients using the visual analogue scale (VAS), as well as using the DN4 and PainDETECT neuropathic pain questionnaires. Functional status was assessed by the WOMAC index. The development of POP ≥30 mm according to VAS was assessed 6 months after TA.
Total RNA was isolated from whole blood and used to evaluate gene  expression for cathepsin S, interleukin 1 (IL1 ), tumor necrosis factor α (TNFα), and cyclooxygenase 2 (COX2) by quantitative real-time polymerase chain  reaction. 

Results and discussion. Complaints of pain persisted in 12 (38.7%) patients 6 months after TA. Before surgery, the expression of cathepsin S, IL1 , TNFα, and COX2 genes was significantly higher in patients of both subgroups compared to healthy controls. In addition, in patients with POP who were not satisfied with the outcome of TA, the rates of neuropathic pain according to  the DN4 questionnaire and cathepsin S gene expression were significantly  higher than in other patients. At the same time, there was no significant  difference in the expression of genes of pro-inflammatory cytokines in  patients of the studied subgroups before TA.
Conclusion. The development of POP in patients with HOA may be partially associated with its perception mechanisms disturbance, and an increase in the expression of the cathepsin S gene in the peripheral blood prior to TA can serve as its prognostic biomarker. 

1. Salmon JH, Rat AC, Sellam J, et al. Economic impact of lower-limb osteoarthritis worldwide: a systematic review of cost-ofillness studies. Osteoarthritis Cartilage. 2016 Sep;24(9):1500-8. doi: 10.1016/j.joca.2016.03.012. Epub 2016 Mar 23.

2. Pivec R, Johnson AJ, Mears SC, Mont MA. Hip arthroplasty. Lancet. 2012 Nov 17;380(9855):1768-77. doi: 10.1016/S0140-6736(12)60607-2. Epub 2012 Sep 26.

3. Inacio MCS, Graves SE, Pratt NL, et al. Increase in Total Joint Arthroplasty Projected from 2014 to 2046 in Australia: A Conservative Local Model With International Implications. Clin Orthop Relat Res. 2017 Aug; 475(8):2130-7. doi: 10.1007/s11999-017-5377-7. Epub 2017 May 9.

4. Hammett T, Simonian A, Austin M, et al. Changes in Physical Activity After Total Hip or Knee Arthroplasty: A Systematic Review and Meta-Analysis of Six- and Twelve-Month Outcomes. Arthritis Care Res (Hoboken). 2018 Jun;70(6):892-901. doi: 10.1002/acr.23415. Epub 2018 Apr 16.

5. Beswick AD, Wylde V, Gooberman-Hill R, et al. What proportion of patients report longterm pain after total hip or knee replacement for osteoarthritis? A systematic review of prospective studies in unselected patients. BMJ Open. 2012 Feb 22;2(1):e000435. doi: 10.1136/bmjopen-2011-000435. Print 2012.

6. Singh JA, Lewallen DG. Predictors of activity limitation and dependence on walking aids after primary total hip arthroplasty. J Am Geriatr Soc. 2010 Dec;58(12):2387-93. doi: 10.1111/j.1532-5415.2010.03182.x.

7. Aggarwal A, Naylor JM, Adie S, et al. Preoperative Factors and Patient-Reported Outcomes After Total Hip Arthroplasty: Multivariable Prediction Modeling. J Arthroplasty. 2022 Apr;37(4):714-20.e4. doi: 10.1016/j.arth.2021.12.036. Epub 2022 Jan 3.

8. Harris WH. Traumatic arthritis of the hip after dislocation and acetabular fractures: treatment of mold arthroplasty. An end-result study using a new method of result evaluation. J Bone Joint Surg Am. 1969 Jun;51(4):737-55.

9. Wood TJ, Gazendam AM, Kabali CB; Hamilton Arthroplasty Group. Postoperative Outcomes Following Total Hip and Knee Arthroplasty in Patients with Pain Catastrophizing, Anxiety, or Depression. J Arthroplasty. 2021 Jun;36(6):1908-14. doi: 10.1016/j.arth.2021.02.018. Epub 2021 Feb 11.

10. Vranceanu AM, Barsky A, Ring D. Psychosocial aspects of disabling musculoskeletal pain. J Bone Joint Surg Am. 2009 Aug;91(8): 2014-8. doi: 10.2106/JBJS.H.01512.

11. Chetina EV, Glemba KE, Markova GA, et al. Prediction of the development of postoperative pain in patients with late-stage knee osteoarthritis based on the expression of genes for degradation of the extracellular matrix, inflammation and apoptosis in the blood. Sovremennaya revmatologiya = Modern Rheumatology Journal. 2022;16(3):42-9. (In Russ.). doi: 10.14412/1996-7012-2022-3-42-49.

12. Kellgren JH, Lawrence JS. Radiological assessment of osteoarthrosis. Ann Rheum Dis. 1957 Dec;16(4):494-502. doi: 10.1136/ard.16.4.494.

13. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singap. 1994 Mar;23(2):129-38.

14. Bellamy N. WOMAC Osteoarthritis Index: A User’s Guide. London: University of Western Ontario; 1995.

15. Freynhagen R, Baron R, Gockel U, Tolle TR. PainDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin. 2006 Oct;22(10):1911-20. doi: 10.1185/030079906X132488.

16. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983 Jun;67(6):361-70. doi: 10.1111/j.1600-0447.1983.tb09716.x.

17. Macario A, McCoy M. The pharmacy cost of delivering postoperative analgesia to patients undergoing joint replacement surgery. J Pain. 2003 Feb;4(1):22-8. doi: 10.1054/jpai.2003.2.

18. Grieshaber-Bouyer R, Kämmerer T, Rosshirt N, et al. Divergent Mononuclear Cell Participation and Cytokine Release Profiles Define Hip and Knee Osteoarthritis. J Clin Med. 2019 Oct 5;8(10):1631. doi: 10.3390/jcm8101631.

19. Chaudhary MA, Dalton MK, Koehlmoos TP, et al. Identifying Patterns and Predictors of Prescription Opioid Use After Total Joint Arthroplasty. Mil Med. 2021 May 3; 186(5-6):587-592. doi: 10.1093/milmed/usaa573.

20. Patel DV, Bawa MS, Haws BE, et al. PROMIS Physical Function for prediction of postoperative pain, narcotics consumption, and patient-reported outcomes following minimally invasive transforaminal lumbar interbody fusion. J Neurosurg Spine. 2019 Feb 1; 1-7. doi: 10.3171/2018.9.SPINE18863. Online ahead of print.

21. Bolland BJ, Culliford DJ, Maskell J, et al. The effect of hip and knee arthroplasty on oral anti-inflammatory use and the relationship to body mass index: results from the UK general practice research database. Osteoarthritis Cartilage. 2011 Jan;19(1):29-36. doi: 10.1016/j.joca.2010.10.012. Epub 2010 Oct 27.

22. Brindisino F, Silvestri E, Gallo C, et al. Depression and Anxiety Are Associated With Worse Subjective and Functional Baseline Scores in Patients With Frozen Shoulder Contracture Syndrome: A Systematic Review. Arthrosc Sports Med Rehabil. 2022 May 21; 4(3):e1219-e1234. doi: 10.1016/j.asmr.2022.04.001. eCollection 2022 Jun.

23. Debbi EM, Krell EC, Sapountzis N, et al. Predicting Post-Discharge Opioid Consumption After Total Hip and Knee Arthroplasty in the Opioid-Naпve Patient. J Arthroplasty. 2022 Aug;37(8S):S830-S835.e3. doi: 10.1016/j.arth.2022.02.011. Epub 2022 Feb 11.

24. Izumi M, Petersen KK, Laursen MB, et al. Facilitated temporal summation of pain correlates with clinical pain intensity after hip arthroplasty. Pain. 2017 Feb;158(2):323-32. doi: 10.1097/j.pain.0000000000000764.

25. Bjurström MF, Bodelsson M, Irwin MR, et al. Decreased pain sensitivity and alterations of cerebrospinal fluid and plasma inflammatory mediators after total hip arthroplasty in patients with disabling osteoarthritis. Pain Pract. 2022 Jan;22(1):66-82. doi: 10.1111/papr.13051. Epub 2021 Jul 24.

26. Suokas AK, Walsh DA, McWilliams DF, et al. Quantitative sensory testing in painful osteoarthritis: a systematic review and metaanalysis. Osteoarthritis Cartilage. 2012 Oct; 20(10):1075-85. doi: 10.1016/j.joca.2012.06.009. Epub 2012 Jul 13.