BR-112019016182-B1 - METHOD FOR DIAGNOSING IMPLANT-RELATED REVISION RISK

BR112019016182B1BR 112019016182 B1BR112019016182 B1BR 112019016182B1BR-112019016182-B1

Abstract

The present invention relates generally to the field of implant-related revision risk, in particular implant-related revision risk not caused by an infection or metal-on-metal reaction. The present invention provides methods for diagnosing implant-related revision risk, use of kits for such diagnostic purposes, and compositions for use in the treatment of implant-related revision risk, in particular implant-related revision risk not caused by an infection or metal-on-metal reaction.

Inventors

Stein LIAN
Jarle MIKALSEN
Eric BENDIKSEN
Anders EINUNG HANSEN

Assignees

LYFSTONE B.V

Dates

Publication Date: 20260310
Application Date: 20180207
Priority Date: 20170207

Claims (4)

1. Method for diagnosing implant-related revision risk, characterized in that the method comprises the following steps: - detecting a calprotectin level in a biological sample from a subject with an implant; and - comparing the calprotectin level in the biological sample with the calprotectin level in a control sample; the control sample being a synovial fluid sample from a subject not suffering from implant-related revision risk; wherein - an increased calprotectin level is indicative of a diagnosis of implant-related revision risk; wherein - a calprotectin level < 4 mg/L is indicative of the absence of implant-related revision risk, - a level in the range of 4-50 mg/L of calprotectin is indicative of implant-related revision risk at an initiating stage of pathology; a calprotectin level > 50 mg/L is indicative of implant-related revision risk in an acute pathology stage; wherein: - the biological sample is synovial fluid from the implant site; - the calprotectin to be detected is a secreted polypeptide and not the intracellular polypeptide of intact cells present in the sample; - the implant is a joint implant; - implant-related revision risk in an initiating pathology stage is selected from the group consisting of aseptic loosening, implant displacement, osteolysis and/or any combination thereof; and - implant-related revision risk in an acute pathology stage is selected from the group consisting of implant-associated infection and metal-on-metal reaction, wherein implant-associated infection is selected from the group consisting of septic loosening, chronic joint infection, biofilm infection and/or any combination thereof.
2. Method according to claim 1, characterized in that the subject to be diagnosed fails to show any perceptible symptoms with which the risk of implant-related revision is associated.
3. Method according to claim 1, characterized in that the implant is a joint prosthesis.
4. Method according to claim 1, characterized in that the implant is a hip prosthesis and the biological sample is synovial fluid from the hip joint; or the implant is a knee prosthesis and the biological sample is synovial fluid from the knee joint.

Description

FIELD OF THE INVENTION [001] The present invention relates generally to the field of implant-related revision risk, in particular to implant-related revision risk not caused by an infection or metal-on-metal reaction. The present invention provides methods for diagnosing implant-related revision risk, use of kits for such diagnostic purposes, and compositions for use in the treatment of implant-related revision risk, in particular implant-related revision risk not caused by an infection or metal-on-metal reaction. FUNDAMENTALS OF THE INVENTION [002] Approximately 1.5 million total hip replacement (total hip arthroplasty - THA) operations are performed annually worldwide. This will likely increase to approximately 3 million per year worldwide within the next decade. In addition, other types of implants and joint replacements, such as knee, shoulder, foot, ankle, hand, wrist, elbow, craniomaxillofacial and dental, are also being used in increasing quantities. [003] Prostheses for hip replacement often consist of two components. An artificial socket, or acetabular component (Figure 3), is located in a prepared cavity in the acetabulum of the pelvis (Figures 2 and 3). This articulates with a femoral component comprising a femoral head attached to a femoral stem (Figure 3), which is inserted into a prepared cavity in the femoral medulla. There are many variations of both components, and they can be retained with or without cement. The goals of hip replacement are to increase mobility, improve hip joint function, and relieve pain. Although notwithstanding its success as a surgical procedure, hip replacement is still considered a last resort treatment because it requires excision of the entire femoral head. It is this major alteration of the femur that often makes revision replacement difficult. [004] Although the THA procedure has a prosthesis survival rate of 90% or more in elderly patients (who typically do not survive the implant), implant lifespans are significantly shorter in younger, more active patients. As a result, younger patients face the prospect of multiple difficult revisions in their lifetime. Typically, a hip prosthesis is preserved for at least 15 to 20 years before needing to be replaced. The presumed failure rate of prosthetic implants during the first 10 years is approximately 3-5%, and the failure rate increases during the following 10 years. In Norway, data from 2012 show that revisions constitute 8.5% of all hip prosthetic operations. [005] Osteolysis and subsequent aseptic joint loosening, both categorized as an initiating pathology condition, are the most common causes for joint revision. In an early stage, this condition is typically associated with micromovement at the implant-bone interface causing progressive bone destruction. Initially, this condition is often painless, and because of this asymptomatic period, bone loss can be massive before patients seek advice. By then, conditions for a revision procedure may be unfavorable, and the expected survival time for a new prosthesis is reduced. Furthermore, if the initiating pathology is diagnosed before progression to a more acute pathology, the condition may be favorably treated, for example, by the use of anti-inflammatory drugs. If treatment is successful, it may not be necessary to proceed with a revision procedure. [006] Therefore, there is a need for methods that allow the diagnosis of implant loosening at the early stage, that is, the initiation of pathology, even in asymptomatic patients. [007] Furthermore, there is also a need for cost-effective methods that allow the identification of patients who are at risk for revision; that is, the identification of those patients who need treatment. [008] Diagnostic and prognostic biomarkers have the potential to provide early, accurate, and non-invasive diagnosis of these undesirable developments, and also to help plan interventions to prevent some of these complications, especially aseptic loosening, implant displacement, and osteolysis. Numerous studies have been reported discussing the use of biomarkers to diagnose aseptic loosening. [009] Int. J. Clin. Exp. Pathol. 2016;9(2):1954-1960 suggests that osteoclastic morphology and activity in peripheral blood and MCP-1 expression levels can be used for early diagnosis of aseptic loosening after total hip replacement. [0010] Int. Orthop. 2013 Jun; 37(6): 1025-1031 refers to a study indicating that there was a significant alteration in the plasma level of multiple biomarkers, including PICP, OPG, TNF-α, NTX, RANKL, and IL-1β, in patients with aseptic prosthetic loosening. [0011] J Arthroplasty. 2005 Dec;20(8):1049-54 demonstrates that both IL-6 and IL-8 are associated with aseptic loosening. [0012] Although suitable biomarkers for diagnosing implant loosening after total hip replacement have been discussed in the previous technique, there is still a need for other biomarkers and, in particular, for biomarkers that are easily detectable at an