Serological biomarkers in hemophilic arthropathy: Can they be used to monitor bleeding and ongoing progression of blood-induced joint disease in patients with hemophilia?

Abstract

In patients with hemophilia, levels of uCTX-II and sCS846 increase 5 days after joint hemorrhage with respect to the initial value. In other words, in patients with established hemophilic arthropathy, the aforesaid biomarkers of joint tissue damage augment shortly after the first joint hemorrhage. In patients with hemophilia treated on demand, a correlation has been found between magnetic resonance imaging scores and the CS846 biomarker. Patients with hemophilia having more than one joint with advanced arthropathy have shown high levels of circulating soluble vascular cell adhesion molecule-1 (sVCAM-1). In addition, sVCAM-1 levels in these patients are associated with the severity of hemophilic arthropathy. In patients with hemophilia, cartilage degradation is increased by 25% compared with controls, as measured by some biomarkers (C2M, CTX-II and COMP). Levels of the cartilage degradation enzyme, ADAMTS5, are 10% lower in patients with hemophilia. Bone formation (PINP) is 25% lower in patients with hemophilia, whereas bone resorption (CTXI) is 30% greater. Acute inflammation (hsCRP) is 50% greater, whereas chronic inflammation (CRPM) is 25% lower. The hsCRP/CRPM ratio is 60% higher in patients with hemophilia than in controls. A panel of biomarkers that combines C2M, CRPM and ADAMTS5 can distinguish patients with hemophilia from controls with 85.3% accuracy. No strong correlation between biomarkers and the radiological and physical examination of the joint has been found.

Introduction

Finding diagnostic methods that can be used to identify patients at high risk of development or progression of joint damage in the initial phases of hemophilic arthropathy is important. The usual diagnostic methods include plain radiography, ultrasonography (US) and magnetic resonance imaging (MRI) [[1], [2], [3], [4], [5], [6]]. An alternative diagnostic method is the use of biomarkers (in serum or urine), which serve to assess joint tissue turnover; i.e., they have the ability to reflect dynamic changes in joint tissue [7,8]. Biomarkers can be useful to better treat our patients and to better assess the progression of their disease and the effectiveness of treatments.

Biomarkers can be clinically useful in people with destructive joint diseases to assess changes in cartilage and bone turnover. In osteoarthritis (OA) and rheumatoid arthritis (RA), biomarkers (in urine, blood and synovial fluid) related to the degradation of cartilage, bone and synovial tissue have been studied, with a dual purpose: to assess the severity and progression of joint damage, and control the effects of treatments [[9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21]]. Although biomarkers have been shown to be useful for assessing joint damage in OA and RA, there are few data on biomarkers in hemophilic arthropathy.

Hemophilia is a hereditary disease caused by deficiency of a coagulation factor (factor VIII [FVIII]: hemophilia A; factor IX [FIX]: hemophilia B), and the disease is characterized by spontaneous bleeding or trauma-related bleeding. Over time, recurrent joint bleeds produce inflammation, synovitis and subsequent destruction of cartilage and bone (i.e., hemophilic arthropathy, which is characterized by soft tissue contractures, muscle atrophy, angular deformities and articular pain) [[22], [23], [24], [25], [26], [27], [28], [29], [30]]. The development of hemophilic arthropathy can be prevented or delayed by means of regular prophylactic intravenous infusions of FVIII or FIX products, whose purpose is to avoid joint hemorrhages and their sequelae [[31], [32], [33], [34], [35], [36], [37], [38], [39], [40]]. Hemophilic arthropathy has some characteristics similar to OA (degenerative joint disease) and RA (inflammatory joint disease). However, there are currently few reports on the use of biomarkers for the evaluation of hemophilic arthropathy. In patients with hemophilic arthropathy, Oldenburg et al. have studied the applicability of several biomarkers found to be useful in patients with OA and RA [41]. Table 1 summarizes the main biomarkers of joint turnover reported in the literature thus far [42,43]. Fig. 1 shows the main cartilage-derived soluble biomarkers. Various experimental and clinical studies on the role of biomarkers in hemophilic arthropathy will be reviewed below.

The purpose of this article was to investigate whether serological biomarkers in patients with hemophilia could be used to monitor bleeding and ongoing progression of blood-induced joint disease (hemophilic arthropathy).