Expert Review of Proteomics
ISSN: 1478-9450 (Print) 1744-8387 (Online) Journal homepage: http://www.tandfonline.com/loi/ieru20
Emerging applications of proteomics in hip and knee arthroplasty Herbert John Cooper To cite this article: Herbert John Cooper (2014) Emerging applications of proteomics in hip and knee arthroplasty, Expert Review of Proteomics, 11:1, 5-8 To link to this article: http://dx.doi.org/10.1586/14789450.2014.865522
Published online: 18 Dec 2013.
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Date: 13 September 2015, At: 03:16
Editorial
Emerging applications of proteomics in hip and knee arthroplasty Expert Rev. Proteomics 11(1), 5–8 (2014)
Downloaded by [117.27.136.66] at 03:16 13 September 2015
Herbert John Cooper Department of Orthopaedic Surgery, Adult Reconstructive Orthopaedic Surgery, Lenox Hill Hospital, 130 East 77th Street New York, NY 10075, USA [email protected]
Total hip and knee arthroplasties are commonly performed orthopedic procedures that involve a complex interaction between the prosthetic device and its surrounding biological environment. Recent developments in the field of proteomics have enabled a better understanding of these interactions in patients with a total joint arthroplasty and have the potential to lead to development of novel diagnostic and therapeutic modalities that may improve the care of these patients, particularly those who have developed complications of wear, osteolysis, loosening and periprosthetic joint infection. This article reviews several of the areas of active research that are occurring at the intersection of the fields of proteomics and total joint arthroplasty.
Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are widely used surgical procedures. In the USA alone, the number of hip and knee arthroplasties performed yearly is currently over one million and is expected to surpass four million by 2030. Both surgical procedures are very effective treatments for patients with degenerative joint disease and various other conditions, providing long-term pain relief and restoration of function with high degrees of success. The field of proteomics offers much promise in improving the ability to treat patients undergoing or who have undergone THA or TKA. As the understanding of these procedures has become more refined, the importance of the cellular and molecular mechanisms in play has become better understood. Proteomics will likely have a significant impact on diagnosis and treatment of various failure mechanisms such as wear, osteolysis, aseptic loosening and periprosthetic joint infection, and will additionally offer the opportunity to improve perioperative care of patients undergoing these procedures. Wear, osteolysis & loosening
Hip and knee arthroplasties are mechanical devices that consist of articulating
surfaces where motion occurs. A number of different materials are being used at this bearing surface, including metal (typically a cobalt-chromium or titanium alloy), highly cross-linked polyethylene (XLPE) or ceramic. Metal-on-XLPE, metal-onmetal, ceramic-on-ceramic, ceramic-onXLPE have all been commonly used as bearing couples, and each bearing couple releases different types of micron to submicron sized wear particles that can have a range of effects on the surrounding biological environment. Despite substantial advances in bearing surface technology, wear particles are still released from the joint surface. Bone resorption secondary to the release of wear debris can manifest as osteolysis or aseptic loosening of the implant and still remains a clinical concern. Therapeutic options to treat osteolysis and bone resorption remain limited at this time, and accordingly revision surgery to place new components is the treatment of choice for most patients. A number of studies have identified molecular pathways of bone resorption at the bone-implant interface, which may eventually allow the development of therapeutic or preventative strategies to limit bone resorption secondary to the release of wear debris. Cellular
KEYWORDS: biomarker • cytokine • loosening • osteolysis • periprosthetic joint infection • total hip arthroplasty • total knee arthroplasty
www.expert-reviews.com
10.1586/14789450.2014.865522
2014 Informa UK Ltd
ISSN 1478-9450
5
Downloaded by [117.27.136.66] at 03:16 13 September 2015
Editorial
Cooper
interaction with wear debris is the key event leading to osteolysis, with the pathways often mediated through release of proinflammatory cytokines such as IL-1a, IL-1b, IL-6, IL-8 and TNF-a. These cytokines can, in turn, recruit osteoclast precursors to resorb bone [1–3]. Proteomic tools such as flow cytometry, ELISA [2] and high-throughput protein chips [1] have provided much of the understanding for these cytokine-driven cascades, and will aid in identification and evaluation of potential targets for blockage and augmentation in the future. Systemic levels of certain proteins such as RANKL, osteoprotegerin and adiponectin can also be measured in the serum via immunoenzymatic assays [4,5] and these biomarkers may have the potential to be used for monitoring the stability of the implant and for predicting aseptic loosening. Additionally, proteins found in synovial fluid, such as monocyte chemotactic protein 1, IL-1a, IL-1b, IL-6, IL-8 and IL-10 may also be elevated in patients with osteolysis and are potentially predictive of bone loss that might be found at revision surgery [6,7]. Periprosthetic joint infection
Deep periprosthetic joint infection (PJI) is an uncommon but potentially devastating complication of THA and TKA, with an incidence of approximately 0.9% [8]. While the diagnosis of PJI is often readily apparent, at times it remains elusive when using traditional diagnostic tools such as serum erythrocyte sedimentation rate, C-reactive protein (CRP) and synovial fluid white blood cell count and differential, particularly in patients with low-grade, chronic PJI [9]. Notably, high- and lowsensitivity serum CRP have recently demonstrated equivalent utility in the diagnosis of PJI [10]. Proteomics offers the potential to improve diagnostic accuracy in many of these cases, and several new tests have emerged in recent years that will undoubtedly improve the ability to care for these patients. Synovial fluid CRP was found, via a multiplex ELISA analysis, to be more accurate in diagnosing PJI than the standard serum CRP assay in 66 patients undergoing revision TKA [11] and is currently being investigated further in ongoing studies. Other synovial fluid biomarkers may offer even greater sensitivity and specificity, and may be more widely utilized as diagnostic testing becomes more readily available to the surgeons treating these patients. One recent study investigated 23 potential biomarkers for PJI, and found 12 of them to be predictive of infection, including proteins such as IL-1a, IL-1b, IL-6, IL-17, granulocyte colony-stimulating factor and skin-derived antileukoproteinase, with both IL-1b and IL-6 offering 100% sensitivity and specificity for a diagnosis of PJI [12]. A follow-up study analyzed 46 different synovial fluid proteins, and found that IL-6, IL-8, a2-macroglobulin, CRP and VEGF each demonstrated good-to-excellent levels of diagnostic accuracy for PJI [13]. A third study that used ELISA to investigate serum and synovial fluid levels antimicrobial peptides and proinflammatory cytokines found significant elevations in human b-defensin-3 and cathelicidin LL-37 in the synovial fluid of patients with PJI when compared with a control group of 6
patients with aseptic loosening of their implants [14]. The authors demonstrated a lower accuracy for diagnosis of PJI in systemic serum levels of the various peptides and cytokines, somewhat dampening enthusiasm for blood testing compared with synovial fluid analysis. Finally, two current studies have found high levels of sensitivity and specificity (95–98%) for diagnosis of PJI for both Toll-like receptors (TLRs) 1 and 6 [15] and a-defensin, neutrophil elastase 2, bactericidal/ permeability increasing protein, neutrophil gelatinase-associated lipocalin and lactoferrin [16]. Perioperative care
Proteomics may also enhance the ability to care for patients in the perioperative period around THA and TKA. Recent research has shown various markers to be potentially predictive of perioperative complications such as cardiac events [17] and venous thromboembolic disease [18] through measuring levels of platelet-bound CD40 ligand and cross-linked fibrin degradation products by leukocyte elastase, respectively. Additionally, various biomarkers such as creatine kinase, CRP, IL-6, IL-1b, TNF-a, muscle atrophy F-Box and muscle RING finger 1 have been used as research tools to quantify muscle damage and surgical stress during THA and TKA [19,20]. Expert commentary
THA and TKA are the most successful orthopedic procedures performed today, providing the vast majority of patients an excellent clinical result by restoring function and alleviating pain, and the need for both procedures is expected to increase dramatically over the next several decades. Although many complications of THA and TKA are readily apparent, there are a number of patients with persistent pain where the diagnosis and reason for clinical failure remains elusive. New proteomic tests are readily being developed which may aid in the treatment of these patients, and these tests will be a welcome addition to the current diagnostic armamentarium that is often limited in its ability to provide an accurate, straightforward and timely answer. At present, only a small number of these tests are available to practicing orthopedic surgeons, which makes their widespread utility quite limited. As the equipment and methodology necessary to perform these tests becomes more accessible, costs will come down, the understanding of the scope and interpretation of these tests will improve, and they will undoubtedly become more widely adopted in the treatment of patients with THA and TKA. For example in the last 2 years, synovial fluid CRP has quickly become adopted as a powerful diagnostic test for PJI by many orthopedic surgeons, as this test can typically be performed on the same laboratory equipment that is readily available for the serum test of the same biomarker. Five-year view
Diagnosis of PJI through various synovial fluid biomarkers is an active area of clinical and commercial interest. Expert Rev. Proteomics 11(1), (2014)
Downloaded by [117.27.136.66] at 03:16 13 September 2015
Emerging applications of proteomics in hip & knee arthroplasty
Presently, most cases rely on serum inflammatory markers such as erythrocyte sedimentation rate and CRP in combination with synovial fluid white blood cell count, differential and cultures. Synovial fluid biomarkers offer the potential for more accurate diagnosis than these more widely used tests, although additional studies will need to be performed to determine which of these has the most utility for widespread adoption. Additionally, the technology and equipment to perform these tests quickly and economically will need to be more widely distributed. This is a current focus of those studying PJI, and some of these tests will be increasingly adopted and may gain widespread acceptance over the next 5 years. As proteomics further enables understanding of the mechanisms that drive periprosthetic bone resorption, therapeutic interventions aimed at diminishing or preventing osteolysis may begin to enter the field through early clinical trials. If successful, these interventions could obviate the need for revision surgery in some
Editorial
patients where wear, osteolysis and loosening are a significant clinical concern. Additionally, further proteomic research may allow physicians to better risk-stratify patients for specific perioperative complications such as cardiopulmonary complications or venous thromboembolic disease, which may allow targeted intervention to reduce the incidence of these complications. Financial & competing interests disclosure
The author is a paid consultant for Smith & Nephew Orthopaedics. The author has no other 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 apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are commonly performed and widely successful orthopedic procedures. • Wear, osteolysis and mechanical loosening are known long-term limitations of these devices. • Research tools such as flow cytometry, ELISA and high-throughput protein chips have allowed a better understanding of the cytokinedriven cascades that mediate the cellular pathways of wear, osteolysis and loosening. • Various proteins, cytokines and biomarkers are elevated in either the serum or synovial fluid of patients with aseptic loosening or periprosthetic osteolysis. • Periprosthetic joint infection remains a significant clinical problem following THA and TKA, and a diagnosis of low-grade infection can often be elusive using traditional testing modalities. • Synovial fluid biomarker analysis has identified a number of proteins that offer excellent sensitivity, specificity and accuracy in the diagnosis of periprosthetic joint infection, which hold significant clinical promise as testing for these becomes more widely available. • Proteomics may offer the potential to identify and predict the risk of various perioperative complications following total joint arthroplasty. • Measurement of serum biomarkers and proteins that serve as a surrogate for surgical stress and muscle damage has allowed comparison of various surgical techniques for performing THA and TKA, which has provided some definitive evidence toward the benefit of minimally invasive surgical approaches for THA and TKA.
References 1
2
3
4
Shanbhag AS, Kaufman AM, Hayata K, Rubash HE. Assessing osteolysis with use of high-throughput protein chips. J. Bone Joint Surg. Am. 89, 1081–1089 (2007). Wang CT, Lin YT, Chiang BL, Lee SS, Hou SM. Over-expression of receptor activator of nuclear factor-kappaB ligand (RANKL), inflammatory cytokines, and chemokines in periprosthetic osteolysis of loosened total hip arthroplasty. Biomaterials 31, 77–82 (2010). Purdue PE, Koulouvaris P, Potter HG, Nestor BJ, Sculco TP. The cellular and molecular biology of periprosthetic osteolysis. Clin. Orthop. Relat. Res. 454, 251–261 (2007).
www.expert-reviews.com
5
6
7
Granchi D, Pellacani A, Spina M et al. Serum levels of osteoprotegerin and receptor activator of nuclear factor-kappaB ligand as markers of periprosthetic osteolysis. J. Bone Joint Surg. Am. 88, 1501–1509 (2006). Landgraeber S, Wegner A, Canbay A, von Knoch M. Serum levels of adiponectin in patients with aseptic loosening after total hip replacement. J. Biomed. Mater. Res. A 93, 748–752 (2010). Dasa V, Kramer JM, Gaffen SL, Kirkwood KL, Mihalko WM. Is monocyte chemotactic protein 1 elevated in aseptic loosening of TKA? A pilot study. Clin. Orthop. Relat. Res. 470, 1879–1884 (2012). Beraudi A, Stea S, Cremonini S, Visentin M, Toni A. Assessment of five interleukins in human synovial fluid as
possible markers for aseptic loosening of hip arthroplasty. Artif. Organs 33, 538–543 (2009). 8
Kurtz SM, Lau E, Schmier J, Ong KL, Zhao K, Parvizi J. Infection burden for hip and knee arthroplasty in the United States. J. Arthroplasty 23, 984–991 (2008).
9
Cooper HJ, Della Valle CJ. Advances in the diagnosis of periprosthetic joint infection. Expert Opin. Med. Diagn. 7, 257–263 (2013).
10
Milone MT, Kamath AF, Israelite CL. Converting between high- and low-sensitivity C-reactive protein in the assessment of periprosthetic joint infection. J. Arthroplasty doi:10.1016/j. arth.2013.09.015 (2013) (Epub ahead of print).
7
Editorial
Cooper
11
Parvizi J, Jacovides C, Adeli B, Jung KA, Hozack WJ. Mark B. Coventry Award: Synovial C-reactive protein: a prospective evaluation of a molecular marker for periprosthetic knee joint infection. Clin. Orthop. Relat. Res. 470, 54–60 (2012).
12
Deirmengian C, Hallab N, Tarabishy A et al. Synovial fluid biomarkers for periprosthetic infection. Clin. Orthop. Relat. Res. 468, 2017–2023 (2010).
13
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8
15
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Jacovides CL, Parvizi J, Adeli B, Jung KA. Molecular markers for diagnosis of periprosthetic joint infection. J. Arthroplasty 26(6 Suppl.), 99–103 (2011). Gollwitzer H, Dombrowski Y, Prodinger PM et al. Antimicrobial peptides and proinflammatory cytokines in periprosthetic joint infection. J. Bone Joint Surg. Am. 95, 644–651 (2013).
17
Cipriano C, Maiti A, Hale G, Jiranek W. The host response: toll like receptor expression in periprosthetic tissues as a biomarker for deep joint infection. Presented at: American Association of Hip and Knee Surgeons, 23rd Annual Meeting. Dallas, TX, USA, 8–10 November 2013. Deirmengian C, Cameron A, Schiller K, Parvizi J, Kilmartin P, Kardos K. Diagnosing periprosthetic joint infection: the era of the biomarker has arrived. American Association of Hip and Knee Surgeons, 23rd Annual Meeting. Dallas, TX, USA, 8–10 November 2013. Ray MJ, Calabro LJ, Sirisena T, Crawford SA, Crawford RW, Walters DL. Pre-operative platelet-bound CD40 ligand is probably associated with peri-operative cardiac events in hip and knee arthroplasty. Eur. J. Clin. Invest. 40, 497–503 (2010).
18
Watanabe H, Madoiwa S, Sekiya H et al. Predictive blood coagulation markers for early diagnosis of venous thromboembolism after total knee joint replacement. Thromb. Res. 128, e137–e143 (2011).
19
Bergin PF, Doppelt JD, Kephart CJ et al. Comparison of minimally invasive direct anterior versus posterior total hip arthroplasty based on inflammation and muscle damage markers. J. Bone Joint Surg. Am. 93, 1392–1398 (2011).
20
Bailey AN, Hocker AD, Vermillion BR et al. MAFbx, MuRF1, and the stress-activated protein kinases are upregulated in muscle cells during total knee arthroplasty. J. Physiol. Regul. Integr. Comp. Physiol. 303, R376–R386 (2012).
Expert Rev. Proteomics 11(1), (2014)
ISSN: 1478-9450 (Print) 1744-8387 (Online) Journal homepage: http://www.tandfonline.com/loi/ieru20
Emerging applications of proteomics in hip and knee arthroplasty Herbert John Cooper To cite this article: Herbert John Cooper (2014) Emerging applications of proteomics in hip and knee arthroplasty, Expert Review of Proteomics, 11:1, 5-8 To link to this article: http://dx.doi.org/10.1586/14789450.2014.865522
Published online: 18 Dec 2013.
Submit your article to this journal
Article views: 47
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ieru20 Download by: [117.27.136.66]
Date: 13 September 2015, At: 03:16
Editorial
Emerging applications of proteomics in hip and knee arthroplasty Expert Rev. Proteomics 11(1), 5–8 (2014)
Downloaded by [117.27.136.66] at 03:16 13 September 2015
Herbert John Cooper Department of Orthopaedic Surgery, Adult Reconstructive Orthopaedic Surgery, Lenox Hill Hospital, 130 East 77th Street New York, NY 10075, USA [email protected]
Total hip and knee arthroplasties are commonly performed orthopedic procedures that involve a complex interaction between the prosthetic device and its surrounding biological environment. Recent developments in the field of proteomics have enabled a better understanding of these interactions in patients with a total joint arthroplasty and have the potential to lead to development of novel diagnostic and therapeutic modalities that may improve the care of these patients, particularly those who have developed complications of wear, osteolysis, loosening and periprosthetic joint infection. This article reviews several of the areas of active research that are occurring at the intersection of the fields of proteomics and total joint arthroplasty.
Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are widely used surgical procedures. In the USA alone, the number of hip and knee arthroplasties performed yearly is currently over one million and is expected to surpass four million by 2030. Both surgical procedures are very effective treatments for patients with degenerative joint disease and various other conditions, providing long-term pain relief and restoration of function with high degrees of success. The field of proteomics offers much promise in improving the ability to treat patients undergoing or who have undergone THA or TKA. As the understanding of these procedures has become more refined, the importance of the cellular and molecular mechanisms in play has become better understood. Proteomics will likely have a significant impact on diagnosis and treatment of various failure mechanisms such as wear, osteolysis, aseptic loosening and periprosthetic joint infection, and will additionally offer the opportunity to improve perioperative care of patients undergoing these procedures. Wear, osteolysis & loosening
Hip and knee arthroplasties are mechanical devices that consist of articulating
surfaces where motion occurs. A number of different materials are being used at this bearing surface, including metal (typically a cobalt-chromium or titanium alloy), highly cross-linked polyethylene (XLPE) or ceramic. Metal-on-XLPE, metal-onmetal, ceramic-on-ceramic, ceramic-onXLPE have all been commonly used as bearing couples, and each bearing couple releases different types of micron to submicron sized wear particles that can have a range of effects on the surrounding biological environment. Despite substantial advances in bearing surface technology, wear particles are still released from the joint surface. Bone resorption secondary to the release of wear debris can manifest as osteolysis or aseptic loosening of the implant and still remains a clinical concern. Therapeutic options to treat osteolysis and bone resorption remain limited at this time, and accordingly revision surgery to place new components is the treatment of choice for most patients. A number of studies have identified molecular pathways of bone resorption at the bone-implant interface, which may eventually allow the development of therapeutic or preventative strategies to limit bone resorption secondary to the release of wear debris. Cellular
KEYWORDS: biomarker • cytokine • loosening • osteolysis • periprosthetic joint infection • total hip arthroplasty • total knee arthroplasty
www.expert-reviews.com
10.1586/14789450.2014.865522
2014 Informa UK Ltd
ISSN 1478-9450
5
Downloaded by [117.27.136.66] at 03:16 13 September 2015
Editorial
Cooper
interaction with wear debris is the key event leading to osteolysis, with the pathways often mediated through release of proinflammatory cytokines such as IL-1a, IL-1b, IL-6, IL-8 and TNF-a. These cytokines can, in turn, recruit osteoclast precursors to resorb bone [1–3]. Proteomic tools such as flow cytometry, ELISA [2] and high-throughput protein chips [1] have provided much of the understanding for these cytokine-driven cascades, and will aid in identification and evaluation of potential targets for blockage and augmentation in the future. Systemic levels of certain proteins such as RANKL, osteoprotegerin and adiponectin can also be measured in the serum via immunoenzymatic assays [4,5] and these biomarkers may have the potential to be used for monitoring the stability of the implant and for predicting aseptic loosening. Additionally, proteins found in synovial fluid, such as monocyte chemotactic protein 1, IL-1a, IL-1b, IL-6, IL-8 and IL-10 may also be elevated in patients with osteolysis and are potentially predictive of bone loss that might be found at revision surgery [6,7]. Periprosthetic joint infection
Deep periprosthetic joint infection (PJI) is an uncommon but potentially devastating complication of THA and TKA, with an incidence of approximately 0.9% [8]. While the diagnosis of PJI is often readily apparent, at times it remains elusive when using traditional diagnostic tools such as serum erythrocyte sedimentation rate, C-reactive protein (CRP) and synovial fluid white blood cell count and differential, particularly in patients with low-grade, chronic PJI [9]. Notably, high- and lowsensitivity serum CRP have recently demonstrated equivalent utility in the diagnosis of PJI [10]. Proteomics offers the potential to improve diagnostic accuracy in many of these cases, and several new tests have emerged in recent years that will undoubtedly improve the ability to care for these patients. Synovial fluid CRP was found, via a multiplex ELISA analysis, to be more accurate in diagnosing PJI than the standard serum CRP assay in 66 patients undergoing revision TKA [11] and is currently being investigated further in ongoing studies. Other synovial fluid biomarkers may offer even greater sensitivity and specificity, and may be more widely utilized as diagnostic testing becomes more readily available to the surgeons treating these patients. One recent study investigated 23 potential biomarkers for PJI, and found 12 of them to be predictive of infection, including proteins such as IL-1a, IL-1b, IL-6, IL-17, granulocyte colony-stimulating factor and skin-derived antileukoproteinase, with both IL-1b and IL-6 offering 100% sensitivity and specificity for a diagnosis of PJI [12]. A follow-up study analyzed 46 different synovial fluid proteins, and found that IL-6, IL-8, a2-macroglobulin, CRP and VEGF each demonstrated good-to-excellent levels of diagnostic accuracy for PJI [13]. A third study that used ELISA to investigate serum and synovial fluid levels antimicrobial peptides and proinflammatory cytokines found significant elevations in human b-defensin-3 and cathelicidin LL-37 in the synovial fluid of patients with PJI when compared with a control group of 6
patients with aseptic loosening of their implants [14]. The authors demonstrated a lower accuracy for diagnosis of PJI in systemic serum levels of the various peptides and cytokines, somewhat dampening enthusiasm for blood testing compared with synovial fluid analysis. Finally, two current studies have found high levels of sensitivity and specificity (95–98%) for diagnosis of PJI for both Toll-like receptors (TLRs) 1 and 6 [15] and a-defensin, neutrophil elastase 2, bactericidal/ permeability increasing protein, neutrophil gelatinase-associated lipocalin and lactoferrin [16]. Perioperative care
Proteomics may also enhance the ability to care for patients in the perioperative period around THA and TKA. Recent research has shown various markers to be potentially predictive of perioperative complications such as cardiac events [17] and venous thromboembolic disease [18] through measuring levels of platelet-bound CD40 ligand and cross-linked fibrin degradation products by leukocyte elastase, respectively. Additionally, various biomarkers such as creatine kinase, CRP, IL-6, IL-1b, TNF-a, muscle atrophy F-Box and muscle RING finger 1 have been used as research tools to quantify muscle damage and surgical stress during THA and TKA [19,20]. Expert commentary
THA and TKA are the most successful orthopedic procedures performed today, providing the vast majority of patients an excellent clinical result by restoring function and alleviating pain, and the need for both procedures is expected to increase dramatically over the next several decades. Although many complications of THA and TKA are readily apparent, there are a number of patients with persistent pain where the diagnosis and reason for clinical failure remains elusive. New proteomic tests are readily being developed which may aid in the treatment of these patients, and these tests will be a welcome addition to the current diagnostic armamentarium that is often limited in its ability to provide an accurate, straightforward and timely answer. At present, only a small number of these tests are available to practicing orthopedic surgeons, which makes their widespread utility quite limited. As the equipment and methodology necessary to perform these tests becomes more accessible, costs will come down, the understanding of the scope and interpretation of these tests will improve, and they will undoubtedly become more widely adopted in the treatment of patients with THA and TKA. For example in the last 2 years, synovial fluid CRP has quickly become adopted as a powerful diagnostic test for PJI by many orthopedic surgeons, as this test can typically be performed on the same laboratory equipment that is readily available for the serum test of the same biomarker. Five-year view
Diagnosis of PJI through various synovial fluid biomarkers is an active area of clinical and commercial interest. Expert Rev. Proteomics 11(1), (2014)
Downloaded by [117.27.136.66] at 03:16 13 September 2015
Emerging applications of proteomics in hip & knee arthroplasty
Presently, most cases rely on serum inflammatory markers such as erythrocyte sedimentation rate and CRP in combination with synovial fluid white blood cell count, differential and cultures. Synovial fluid biomarkers offer the potential for more accurate diagnosis than these more widely used tests, although additional studies will need to be performed to determine which of these has the most utility for widespread adoption. Additionally, the technology and equipment to perform these tests quickly and economically will need to be more widely distributed. This is a current focus of those studying PJI, and some of these tests will be increasingly adopted and may gain widespread acceptance over the next 5 years. As proteomics further enables understanding of the mechanisms that drive periprosthetic bone resorption, therapeutic interventions aimed at diminishing or preventing osteolysis may begin to enter the field through early clinical trials. If successful, these interventions could obviate the need for revision surgery in some
Editorial
patients where wear, osteolysis and loosening are a significant clinical concern. Additionally, further proteomic research may allow physicians to better risk-stratify patients for specific perioperative complications such as cardiopulmonary complications or venous thromboembolic disease, which may allow targeted intervention to reduce the incidence of these complications. Financial & competing interests disclosure
The author is a paid consultant for Smith & Nephew Orthopaedics. The author has no other 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 apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are commonly performed and widely successful orthopedic procedures. • Wear, osteolysis and mechanical loosening are known long-term limitations of these devices. • Research tools such as flow cytometry, ELISA and high-throughput protein chips have allowed a better understanding of the cytokinedriven cascades that mediate the cellular pathways of wear, osteolysis and loosening. • Various proteins, cytokines and biomarkers are elevated in either the serum or synovial fluid of patients with aseptic loosening or periprosthetic osteolysis. • Periprosthetic joint infection remains a significant clinical problem following THA and TKA, and a diagnosis of low-grade infection can often be elusive using traditional testing modalities. • Synovial fluid biomarker analysis has identified a number of proteins that offer excellent sensitivity, specificity and accuracy in the diagnosis of periprosthetic joint infection, which hold significant clinical promise as testing for these becomes more widely available. • Proteomics may offer the potential to identify and predict the risk of various perioperative complications following total joint arthroplasty. • Measurement of serum biomarkers and proteins that serve as a surrogate for surgical stress and muscle damage has allowed comparison of various surgical techniques for performing THA and TKA, which has provided some definitive evidence toward the benefit of minimally invasive surgical approaches for THA and TKA.
References 1
2
3
4
Shanbhag AS, Kaufman AM, Hayata K, Rubash HE. Assessing osteolysis with use of high-throughput protein chips. J. Bone Joint Surg. Am. 89, 1081–1089 (2007). Wang CT, Lin YT, Chiang BL, Lee SS, Hou SM. Over-expression of receptor activator of nuclear factor-kappaB ligand (RANKL), inflammatory cytokines, and chemokines in periprosthetic osteolysis of loosened total hip arthroplasty. Biomaterials 31, 77–82 (2010). Purdue PE, Koulouvaris P, Potter HG, Nestor BJ, Sculco TP. The cellular and molecular biology of periprosthetic osteolysis. Clin. Orthop. Relat. Res. 454, 251–261 (2007).
www.expert-reviews.com
5
6
7
Granchi D, Pellacani A, Spina M et al. Serum levels of osteoprotegerin and receptor activator of nuclear factor-kappaB ligand as markers of periprosthetic osteolysis. J. Bone Joint Surg. Am. 88, 1501–1509 (2006). Landgraeber S, Wegner A, Canbay A, von Knoch M. Serum levels of adiponectin in patients with aseptic loosening after total hip replacement. J. Biomed. Mater. Res. A 93, 748–752 (2010). Dasa V, Kramer JM, Gaffen SL, Kirkwood KL, Mihalko WM. Is monocyte chemotactic protein 1 elevated in aseptic loosening of TKA? A pilot study. Clin. Orthop. Relat. Res. 470, 1879–1884 (2012). Beraudi A, Stea S, Cremonini S, Visentin M, Toni A. Assessment of five interleukins in human synovial fluid as
possible markers for aseptic loosening of hip arthroplasty. Artif. Organs 33, 538–543 (2009). 8
Kurtz SM, Lau E, Schmier J, Ong KL, Zhao K, Parvizi J. Infection burden for hip and knee arthroplasty in the United States. J. Arthroplasty 23, 984–991 (2008).
9
Cooper HJ, Della Valle CJ. Advances in the diagnosis of periprosthetic joint infection. Expert Opin. Med. Diagn. 7, 257–263 (2013).
10
Milone MT, Kamath AF, Israelite CL. Converting between high- and low-sensitivity C-reactive protein in the assessment of periprosthetic joint infection. J. Arthroplasty doi:10.1016/j. arth.2013.09.015 (2013) (Epub ahead of print).
7
Editorial
Cooper
11
Parvizi J, Jacovides C, Adeli B, Jung KA, Hozack WJ. Mark B. Coventry Award: Synovial C-reactive protein: a prospective evaluation of a molecular marker for periprosthetic knee joint infection. Clin. Orthop. Relat. Res. 470, 54–60 (2012).
12
Deirmengian C, Hallab N, Tarabishy A et al. Synovial fluid biomarkers for periprosthetic infection. Clin. Orthop. Relat. Res. 468, 2017–2023 (2010).
13
Downloaded by [117.27.136.66] at 03:16 13 September 2015
14
8
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Expert Rev. Proteomics 11(1), (2014)
