Advertisement

Autologous Interleukin 1 Receptor Antagonist Blood-Derived Products for Knee Osteoarthritis: A Systematic Review

      Purpose

      To systematically review the available clinical data regarding the use of autologous IL-1 receptor antagonist blood products (AILBPs) and their validity as an alternative intra-articular (IA) therapy for symptomatic knee osteoarthritis (OA).

      Methods

      The PubMed, MEDLINE, Embase, and Cochrane Library databases were searched from inception to June 2018. All randomized controlled trials (RCTs) and noncomparative studies that evaluated the clinical efficacy of AILBPs (i.e., autologous protein solution and autologous conditioned serum) for knee OA were included. The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index. The secondary outcomes measured were the Knee Injury and Osteoarthritis Outcome Score, visual analog scale score, Short Form 36 (SF-36) score, radiographic scores, and adverse events, which were qualitatively analyzed.

      Results

      We included 8 studies, comprising 3 RCTs (Level II) and 5 noncomparative studies (Level IV), with a total of 592 patients (mean age, 56.4 years; 49.7% male patients). The RCTs represented high methodologic quality, whereas the noncomparative studies represented moderate to good quality. With AILBPs, 2 of 4 studies (50%) showed improvements in the Knee Injury and Osteoarthritis Outcome Score symptom and sport subscales, 5 of 7 studies (71%) achieved improvements in the Western Ontario and McMaster Universities Osteoarthritis Index score, and 4 of 5 studies (80%) attained improvements in the visual analog scale pain score from baseline to final follow-up. Most adverse events associated with AILBPs were mild to moderate in severity and were primarily localized to the injection site.

      Conclusions

      Limited evidence substantiates that AILBPs are a safe and tolerable IA injection therapy that may improve pain parameters and functionality for mild to moderate knee OA patients and may be an effective adjunct for those unresponsive to traditional IA therapies.

      Level of Evidence

      Level IV, systematic review of Level II through IV studies.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Arthroscopy
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Berenbaum F.
        Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!).
        Osteoarthritis Cartilage. 2013; 21: 16-21
        • Fernandes J.C.
        • Pelletier J.P.
        The role of cytokines in osteoarthritis pathophysiology.
        Biorheology. 2002; 39: 237-246
        • Kapoor M.
        • Martel-Pelletier J.
        • Lajeunesse D.
        • Pelletier J.P.
        • Fahmi H.
        Role of proinflammatory cytokines in the pathophysiology of osteoarthritis.
        Nat Rev Rheumatol. 2011; 7: 33-42
        • Kobayashi M.
        • Squires G.R.
        • Mousa A.
        • et al.
        Role of interleukin-1 and tumor necrosis factor alpha in matrix degradation of human osteoarthritic cartilage.
        Arthritis Rheum. 2005; 52: 128-135
        • Attur M.
        • Belitskaya-Levy I.
        • Oh C.
        • et al.
        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: 1908-1917
        • Larsson S.
        • Englund M.
        • Struglics A.
        • Lohmander L.S.
        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
        • Livshits G.
        • Zhai G.
        • Hart D.J.
        • et al.
        Interleukin-6 is a significant predictor of radiographic knee osteoarthritis: The Chingford Study.
        Arthritis Rheum. 2009; 60: 2037-2045
        • Stannus O.
        • Jones G.
        • Cicuttini F.
        • et al.
        Circulating levels of IL-6 and TNF-α are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults.
        Osteoarthritis Cartilage. 2010; 18: 1441-1447
        • Jotanovic Z.
        • Mihelic R.
        • Sestan B.
        • et al.
        Role of interleukin-1 inhibitors in osteoarthritis: An evidence-based review.
        Drugs Aging. 2012; 29: 343-358
        • Dinarello C.
        • van der Meer J.
        Treating inflammation by blocking interleukin-1 in humans.
        Semin Immunol. 2013; 25: 469-484
        • Hannum C.
        • Wilcox C.
        • Arend W.
        • et al.
        Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor.
        Nature. 1990; 343: 336-340
        • Frisbie D.
        • Ghivizzani S.
        • Robbins P.
        • et al.
        Treatment of experimental equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor antagonist gene.
        Gene Ther. 2002; 9: 12-20
        • Arrich J.
        • Piribauer F.
        • Mad P.
        • Schmid D.
        • Klaushofer K.
        • Mullner M.
        Intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee: Systematic review and meta-analysis.
        CMAJ. 2005; 172: 1039-1043
        • Bannuru R.R.
        • Natov N.S.
        • Dasi U.R.
        • Schmid C.H.
        • McAlindon T.E.
        Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis—Meta-analysis.
        Osteoarthritis Cartilage. 2011; 19: 611-619
        • Bannuru R.R.
        • Natov N.S.
        • Obadan I.E.
        • Price L.L.
        • Schmid C.H.
        • McAlindon T.E.
        Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treatment of knee osteoarthritis: A systematic review and meta-analysis.
        Arthritis Rheum. 2009; 61: 1704-1711
        • Bellamy N.
        • Campbell J.
        • Robinson V.
        • Gee T.
        • Bourne R.
        • Wells G.
        Viscosupplementation for the treatment of osteoarthritis of the knee.
        Cochrane Database Syst Rev. 2006; : CD005321
        • Nguyen C.
        • Lefevre-Colau M.M.
        • Poiraudeau S.
        • Rannou F.
        Evidence and recommendations for use of intra-articular injections for knee osteoarthritis.
        Ann Phys Rehabil Med. 2016; 59: 184-189
        • Hepper T.H.
        • Duncan S.
        • Gregory A.
        • Dunn W.
        • Spindler K.
        The efficacy and duration of intra-articular corticosteroid injection for knee osteoarthritis: A systematic review of Level I studies.
        J Am Acad Orthop Surg. 2009; 17: 638-646
        • Bellamy N.C.
        • Welch V.
        • Gee T.L.
        • Bourne R.
        • Wells G.A.
        Intraarticular corticosteroid for treatment of osteoarthritis of the knee (review).
        Cochrane Database Syst Rev. 2006; : 1-221
        • Petrella R.
        • Petrella M.
        A prospective, randomized, double-blind, placebo controlled study to evaluate the efficacy of intraarticular hyaluronic acid for osteoarthritis of the knee.
        J Rheumatol. 2006; 33: 951-956
        • Lo G.H.
        • LaValley M.
        • McAlindon T.
        • Felson D.
        Intra-articular hyaluronic acid in treatment of knee osteoarthritis: A meta-analysis.
        JAMA. 2003; 290: 3115-3121
        • Wang C.L.
        • Chang C.
        • Lin Y.
        • Hou S.
        Therapeutic effects of hyaluronic acid on osteoarthritis of the knee: A meta-analysis of randomized controlled trials.
        J Bone Joint Surg Am. 2004; 86: 538-545
        • Rutjes A.
        • Juni P.
        • da Costa B.
        • et al.
        Viscosupplementation for osteoarthritis of the knee: A systematic review and meta-analysis.
        Ann Intern Med. 2012; 157: 180-191
        • McAlindon T.
        • LaValley M.
        • Harvey W.
        • et al.
        Effect of intra-articular triamcinolone vs saline on knee cartilage volume and in patients with knee osteoarthritis: A randomized clinical trial.
        JAMA. 2017; 317: 1967-1975
        • Filardo G.
        • Kon E.
        • Buda R.
        • et al.
        Platelet-rich plasma intra-articular knee injections for the treatment of degenerative cartilage lesions and osteoarthritis.
        Knee Surg Sports Traumatol Arthrosc. 2011; 19: 528-535
        • Meheux C.J.
        • McCulloch P.C.
        • Lintner D.M.
        • Varner K.E.
        • Harris J.D.
        Efficacy of intra-articular platelet-rich plasma injections in knee osteoarthritis: A systematic review.
        Arthroscopy. 2016; 32: 495-505
        • Sheth U.
        • Simunovic N.
        • Klein G.
        • et al.
        Efficacy of autologous platelet-rich plasma use for orthopaedic indications: A meta-analysis.
        J Bone Joint Surg Am. 2012; 94: 298-307
        • Zhang H.F.
        • Wang C.G.
        • Li H.
        • Huang Y.T.
        • Li Z.J.
        Intra-articular platelet-rich plasma versus hyaluronic acid in the treatment of knee osteoarthritis: A meta-analysis.
        Drug Des Devel Ther. 2018; 12: 445-453
        • Khoshbin A.L.
        • Wasserstein D.
        • Marks P.
        • et al.
        The efficacy of platelet-rich plasma in the treatment of symptomatic knee osteoarthritis: A systematic review with quantitative synthesis.
        Arthroscopy. 2013; 29: 2017-2048
        • Filardo G.
        • Di Matteo B.
        • Di Martino A.
        • et al.
        Platelet-rich plasma intra-articular knee injections show no superiority versus viscosupplementation: A randomized controlled trial.
        Am J Sports Med. 2015; 43: 1575-1582
        • Cole B.J.
        • Karas V.
        • Hussey K.
        • Pilz K.
        • Fortier L.A.
        Hyaluronic acid versus platelet-rich plasma: A prospective, double-blind randomized controlled trial comparing clinical outcomes and effects on intra-articular biology for the treatment of knee osteoarthritis.
        Am J Sports Med. 2017; 45: 339-346
        • Frisbie D.D.
        • McCarthy H.E.
        • Archer C.W.
        • Barrett M.F.
        • McIlwraith C.W.
        Evaluation of articular cartilage progenitor cells for the repair of articular defects in an equine model.
        J Bone Joint Surg Am. 2015; 97: 484-493
        • O'Shaughnessey K.
        • Matuska A.
        • Hoeppner J.
        • et al.
        Autologous protein solution prepared from the blood of osteoarthritic patients contains an enhanced profile of anti-inflammatory cytokines and anabolic growth factors.
        J Orthop Res. 2014; 32: 1349-1355
        • Bertone I.A.
        • Zekas L.J.
        • Wellman M.L.
        • et al.
        Evaluation of a single intra-articular injection of autologous protein solution for treatment of osteoarthritis in horses.
        Am J Vet Res. 2014; 75: 141-151
        • Frisbie D.D.
        • Werpy N.M.
        • Park R.D.
        • McIlwraith C.W.
        Clinical, biochemical, and histologic effects of intra-articular administration of autologous conditioned serum in horses with experimentally induced osteoarthritis.
        Am J Vet Res. 2007; 68: 290-296
        • Wanstrath A.W.
        • Hettlich B.F.
        • Su L.
        • et al.
        Evaluation of a single intra-articular injection of autologous protein solution for treatment of osteoarthritis in a canine population.
        Vet Surg. 2016; 45: 764-774
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        • PRISMA Group
        Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement.
        Ann Intern Med. 2009; 6: e1000097
        • Detsky A.N.
        • O'Rourke K.
        • McGeer A.
        • L'Abbe K.
        Incorporating variations in the quality of individual randomized trials into meta-analysis.
        J Clin Epidemiol. 1992; 45: 255-265
        • Slim K.N.
        • Forestier D.
        • Kwiatkowski F.
        • Panis Y.
        • Chipponi J.
        Methodological index for non-randomized studies (MINORS): Development and validation of a new instrument.
        ANZ J Surg. 2003; 73: 712-716
        • Auw Yang K.G.
        • Raijmakers N.J.
        • van Arkel E.R.
        • et al.
        Autologous interleukin-1 receptor antagonist improves function and symptoms in osteoarthritis when compared to placebo in a prospective randomized controlled trial.
        Osteoarthritis Cartilage. 2008; 16: 498-505
        • Baltzer A.W.
        • Moser C.
        • Jansen S.A.
        • Krauspe R.
        Autologous conditioned serum (Orthokine) is an effective treatment for knee osteoarthritis.
        Osteoarthritis Cartilage. 2009; 17: 152-160
        • Kon E.
        • Engebretsen L.
        • Verdonk P.
        • Nehrer S.
        • Filardo G.
        Clinical outcomes of knee osteoarthritis treated with an autologous protein solution injection: A 1-year pilot double-blinded randomized controlled trial.
        Am J Sports Med. 2018; 46: 171-180
        • King W.
        • van der Weegen W.
        • Van Drumpt R.
        • Soons H.
        • Toler K.
        • Woodell-May J.
        White blood cell concentration correlates with increased concentrations of IL-1ra and improvement in WOMAC pain scores in an open-label safety study of autologous protein solution.
        J Exp Orthop. 2016; 3: 9
        • Rutgers M.
        • Creemers L.B.
        • Auw Yang K.G.
        • Raijmakers N.J.
        • Dhert W.J.
        • Saris D.B.
        Osteoarthritis treatment using autologous conditioned serum after placebo.
        Acta Orthop. 2015; 86: 114-118
        • Barreto A.
        • Braun T.R.
        A new treatment for knee osteoarthritis: Clinical evidence for the efficacy of Arthrokinex autologous conditioned serum.
        J Orthop. 2017; 14: 4-9
        • Hix J.
        • Klaassen M.
        • Foreman R.
        • et al.
        An autologous anti-inflammatory protein solution yielded a favorable safety profile and significant pain relief in an open-label pilot study of patients with osteoarthritis.
        Biores Open Access. 2017; 6: 151-158
        • van Drumpt R.A.
        • van der Weegen W.
        • King W.
        • Toler K.
        • Macenski M.M.
        Safety and treatment effectiveness of a single autologous protein solution injection in patients with knee osteoarthritis.
        Biores Open Access. 2016; 5: 261-268
        • Weinberger T.
        Clinical experience with ACS/Orthokine/IRAP in horses.
        Equine Sports Med. 2008; 3: 1-5
        • Baselga Garcia-Escudero J.
        • Miguel Hernandez Trillos P.
        Treatment of osteoarthritis of the knee with a combination of autologous conditioned serum and physiotherapy: A two-year observational study.
        PLoS One. 2015; 10: e0145551
        • Fathalla M.
        • Abd-El Motaal F.
        • Abdulkareem O.
        • Elganzoury A.
        Low-dose intra-articular autologous conditioned serum in treatment of primary knee osteoarthritis.
        Egypt Rheumatol Rehabil. 2014; 41: 98-102
        • Baltzer A.D.
        • Granrath M.
        • Godde G.
        • Klein W.
        • Wehling P.
        Intraarticular treatment of osteoarthritis using autologous interleukine-1 receptor antagonist (IL-1Ra) conditioned serum.
        Dtsch Z Sportmed. 2003; 54: 209-211
        • Woodell-May J.
        • Matuska A.
        • Oyster M.
        • Welch Z.
        • O'Shaughnessey K.
        • Hoeppner J.
        Autologous protein solution inhibits MMP-13 production by IL-1beta and TNFalpha-stimulated human articular chondrocytes.
        J Orthop Res. 2011; 29: 1320-1326
        • Murphy G.
        • Lee M.H.
        What are the roles of metalloproteinases in cartilage and bone damage?.
        Ann Rheum Dis. 2005; 64: iv44-iv47
        • Asanbaeva A.
        • Masuda K.
        • Thonar E.J.
        • Klisch S.M.
        • Sah R.L.
        Regulation of immature cartilage growth by IGF-I, TGF-beta1, BMP-7, and PDGF-AB: Role of metabolic balance between fixed charge and collagen network.
        Biomech Model Mechanobiol. 2008; 7: 263-276
        • Athanasiou K.A.
        • Shah A.R.
        • Hernandez R.J.
        • LeBaron R.G.
        Basic science of articular cartilage repair.
        Clin Sports Med. 2001; 20: 223-247
        • Patil A.S.
        • Sable R.B.
        • Kothari R.M.
        An update on transforming growth factor-beta (TGF-beta): Sources, types, functions and clinical applicability for cartilage/bone healing.
        J Cell Physiol. 2011; 226: 3094-3103
        • Denker A.N.
        • Tuan R.
        Formation of cartilage-like spheroids by micromass cultures of murine C3HlOTU2 cells upon treatment with transforming growth factor-pl.
        Differentiation. 1995; 59: 25-34
        • Rubin B.R.
        Insulin-like growth factor-I receptor. Its role in cell proliferation, apoptosis, and tumorigenicity.
        Lab Invest. 1995; 73: 311-331
        • Nixon A.B.-T.
        • Bent S.
        • Saxer R.
        • Wilke M.
        • Robbins P.
        • Evans C.
        Insulinlike growth factor-I gene therapy applications for cartilage repair.
        Clin Orthop Relat Res. 2000; 379: 201-213
        • Montaseri A.
        • Busch F.
        • Mobasheri A.
        • et al.
        IGF-1 and PDGF-bb suppress IL-1beta-induced cartilage degradation through down-regulation of NF-kappaB signaling: Involvement of Src/PI-3K/AKT pathway.
        PLoS One. 2011; 6: e28663
        • Schmidt M.B.
        • Chen E.H.
        • Lynch S.E.
        A review of the effects of insulin-like growth factor and platelet derived growth factor on in vivo cartilage healing and repair.
        Osteoarthritis Cartilage. 2006; 14: 403-412
        • Jia H.
        • Ma X.
        • Tong W.
        • et al.
        EGFR signaling is critical for maintaining the superficial layer of articular cartilage and preventing osteoarthritis initiation.
        Proc Natl Acad Sci U S A. 2016; 113: 14360-14365
        • Shepard J.B.
        • Jeong J.W.
        • Maihle N.J.
        • O'Brien S.
        • Dealy C.N.
        Transient anabolic effects accompany epidermal growth factor receptor signal activation in articular cartilage in vivo.
        Arthritis Res Ther. 2013; 15: R60
        • Zhang X.
        • Zhu J.
        • Liu F.
        • et al.
        Reduced EGFR signaling enhances cartilage destruction in a mouse osteoarthritis model.
        Bone Res. 2014; 2: 14015
        • King W.J.
        • Woodell-May J.E.
        Comparison of the cellular and cytokine concentrations in the output of the autologous protein solution, Orthokine, and Onoccomed 2 Device Systems.
        Osteoarthr Cartil. 2014; 22: S484
        • Arakawa T.
        • Prestrelski S.J.
        • Kenney W.C.
        • Carpenter J.F.
        Factors affecting short-term and long term stabilities of proteins.
        Adv Drug Deliv Rev. 2001; 46: 307-336
        • Saltzman B.
        • Leroux T.
        • Meyer M.
        • et al.
        The Therapeutic effect of intra-articular normal saline injections for knee osteoarthritis: A meta-analysis of evidence level 1 studies.
        Am J Sports Med. 2017; 45: 2647-2653