The combination of urinary CTX‐II and serum CS‐846: Promising biochemical markers to predict radiographic progression of haemophilic arthropathy—An exploratory study

In haemophilia patients, recurrent haemarthroses result in haemophilic arthropathy (HA), causing major morbidity. In general, the bleeding tendency is inversely correlated with the clotting factor level, so HA is mainly seen in patients with severe haemophilia. The severity of damage upon a joint bleeding differs between patients, as does the development of HA. It would be of great value to identify those patients susceptible to (fast) progressive joint damage as this might have therapeutic implications, especially early in the disease. Currently, imaging techniques such as plain radiography, ultrasonography and magnetic resonance imaging are used to monitor joint damage. The information obtained is static, providing the cumulative result of a dynamic process over time. Biochemical markers, measured in blood or urine, reflect dynamic changes in joint tissue turnover at a certain point in time. Although promising in theory, research has thus far not yielded a (set of) biochemical marker(s) with sufficient prognostic value for joint damage progression over time at the level of an individual patient. A previous study conducted by our group indicated that levels of the biomarkers uCTXII (urinary Cterminal telopeptide of type II collagen), sC1,2C (serum cartilage cleavage product C1,2C) and sCS846 (serum chondroitin sulphate 846) correlated with overall joint damage using the Pettersson score, 1 and with the joint space narrowing component specifically, reflecting cartilage thinning. 2 The combination of uCTXII, sCOMP (serum cartilage oligomeric matrix protein) and sCS846 correlated best with the degree of arthropathy. In an additional study in haemophilia patients, it was demonstrated that uCTXII and sCS846 increased shortly after a joint bleeding, supporting their dynamic value. 3 uCTXII is a biomarker of type II collagen degradation considered representative for cartilage degradation, 4 as well as bone metabolism. 5 sCS846 is an aggrecan synthesis marker. 6 In rheumatoid arthritis (RA) and osteoarthritis (OA), joint diseases sharing characteristics with HA, these 2 biomarkers were associated with radiographic progression. 7,8 Unfortunately, these findings on group level do not yield diagnostic or prognostic value for an individual haemophilia patient. Considering the responsiveness of uCTXII and sCS846 to a joint bleeding—the clear trigger to develop HA—and the results in RA and OA, the potential prognostic value of these biochemical markers was explored in this study. This study comprises a followup on our previous crosssectional study, 2 in which 8 biomarkers including uCTXII and sCS846 were measured in 36 haemophilia patients with various degrees of HA. Radiographs of the ankles, knees and elbows were evaluated for the degree of joint damage using the Pettersson score. As part of routine care, followup radiographs were made every 5 years. The Pettersson scores on both time points were assessed by a trained observer, in a blinded manner. 9 The progression rate per year was calculated by dividing the delta Pettersson score by the followup time in years. Fast progression of HA was defined as ≥0.4 points per year, based on the mean progression rate in a larger cohort of haemophilia patients treated in our clinic. 10 Natural log transformation of the biomarker values was performed to achieve a normal distribution. In order to give the same weight to each biomarker in the combined score of uCTXII and sCS846, the mean level of the biomarker at group level was calculated. For each patient, the ratio of the individual value to that mean value was determined. The combined score consisted of the mean of these ratios in each patient. To explore differences between slow and fast progressors, logistic regression was performed. Of the original 36 patients, followup was available in 34 patients (lost to followup n = 1, deceased n = 1). Three patients were excluded due to the absence of followup radiographs (n = 1) or a Pettersson score of ≥60 points at baseline (n = 2) as the high baseline score limits progression towards the maximum score of 78. The majority of patients had haemophilia A (87.1%, n = 27) and had the severe type (90.3%, n = 28; Table 1 ). The mean age at inclusion was 35.1 years (SD ± 10.1), the median delta Pettersson score was 1.0 points (IQR 0.02.0), and the mean followup was 6.5 years (range 3.99.7; Table 1 ). The median progression rate was 0.2 points/year (IQR 0.00.3). Seven of 31 (22.6%) patients showed progression of