Joint pain has been reported as a major problem in people with haemophilia (PwH). Therefore, haemophilia in adults seems clinically more related to a musculoskeletal disorder than a bleeding disorder, with many patients reporting a pain intensity exceeding 6/10 on a visual analogue scale. However, although the complexity of joint pain has been studied in chronic joint pain conditions such as low back pain, osteoarthritis or rheumatoid arthritis, until present only very limited research has been done on joint pain within PwH. Therefore, exploring the underlying mechanisms and the functional implications of this intense joint pain is urgently needed. As such, the main aim of the current prospective observational study is to gain more insights in joint pain in PwH enabling us to move towards adequate pain management in PwH.
In this study, adult patients with moderate or severe Haemophilia from the Haemophilia Treatment Centers will be invited to participate in the study. Patients willing to participate will be asked to complete a battery of questionnaires in the week prior to the study. Patients will undergo a comprehensive baseline evaluation after their regular appointment with their treating hematologist. During the baseline assessment, the structure of ankle and knee joints will be assessed, using respectively magnetic resonance imaging (MRI) and ultrasound evaluation. Besides, patients will be asked to perform some active movements to quantify the physical functions of the lower limb and will undergo an extensive pain assessment. During one month following baseline assessment, patients will be closely monitored. They will be asked to fill in a diary linked to their usual logbook in which they indicate the minimal and maximal intensity of pain, location of pain, intake of regular or additional (in case of bleeding) clotting factors, intake of analgesics, occurrence and location of assumed bleeding. Patients will be asked to wear an activity tracker to register the number of steps during this month.The short version of the International Physical Activity Questionnaire (IPAQ) will be used to evaluate the self-reported estimation of weekly physical activity. During the next 11 months, patients will be asked to fill in three online pain-related questionnaires: the Brief Pain Inventory, Brief Illness Perception Questionnaire and the EQ-5D-5L questionnaire once a month.
Study Type
OBSERVATIONAL
Enrollment
104
At baseline (T0) patients underwent the somatosensory pain assessment, joint structure and function assessment and filled in all questionnaires. During one month after baseline (T1) patients wore an activity tracker and filled in the Illness Perceptions Questionnaire and the International Physical Activity questionnaire. During one year after the baseline assessment (T2) patients filled in every month The Brief Pain Inventory, Illness Perceptions Questionnaire and the EQ-5D-5L quality of life questionnaire.
University Hospital Antwerp
Edegem, Antwerp, Belgium
Cliniques universitaires Saint-Luc
Brussels, Belgium
Pain localisation
The body chart of the Brief Pain Inventory (BPI) was used to investigate painful body sites.
Time frame: At baseline (T0)
Pain localisation
The body chart of the Brief Pain Inventory (BPI) was used to investigate painful body sites.
Time frame: At one year follow-up (T2)
Pain severity
The BPI was used to evaluate the individual's pain experience within the last 24 hours by four items, resulting in a total pain severity score. Minimum score 0, maximum score 10. The higher te score, the higher the pain severity.
Time frame: At baseline (T0)
Pain severity
The BPI was used to evaluate the individual's pain experience within the last 24 hours by four items, resulting in a total pain severity score. Minimum score 0, maximum score 10. The higher te score, the higher the pain severity.
Time frame: At one year follow-up (T2)
Pain interference
The BPI was used to evaluate how much pain interferes with patient's daily activities. This was assessed by seven items, resulting in a total pain interference score. Minimum score 0, maximum score 10. The higher the score, the more pain interference.
Time frame: At baseline (T0)
Pain interference
The BPI was used to evaluate how much pain interferes with patient's daily activities. This was assessed by seven items, resulting in a total pain interference score. Minimum score 0, maximum score 10. The higher the score, the more pain interference.
Time frame: At one year follow-up (T2)
Signs of neuropathic pain
The Douleur Neuropathique en 4 questions (DN4) was applied as a screening tool for the presence of a neuropathic pain component. Minimum score 0, maximum score 10, a score of ≥4/10 was used as a cut-off.
Time frame: At baseline (T0)
Signs of central sensitization
The Central Sensitisation Inventory (CSI) part A was used to identify signs of central sensitization (CS) i.e. increased sensitivity of nociceptive neurons in the central nervous system.The presence of 25 pain-related psychological, cognitive and functional signs are scored from 0 (never) to 4 (always). A total score exceeding ≥40/100 indicated central sensitization.
Time frame: At baseline (T0)
Pain Catastrophizing
The Pain Catastrophizing Scale (PCS) asked participants to reflect on previous painful experiences and to rate their degree of catastrophic thinking in the content domains of rumination, magnification and helplessness. A score of 0 (not at all) to 4 (all the time) was indicated for each of the 13 items, resulting in a total score range of 0-52. Higher scores were associated with higher levels of pain catastrophizing.
Time frame: At baseline (T0)
Anxiety and Depression
The Hospital Anxiety and Depression Scale (HADS) was used to establish symptoms of anxiety and depression. This 14-item questionnaire consists of two subscales each including 7 items, the first to identify anxiety and the second depression. Individual items were scored from 0 to 3, resulting in a total range score of 0-21 for each subscale. A score of ≥8/21 was determined as a cut-off, indicating anxiety and depression.
Time frame: At baseline (T0)
Fear Avoidance and Beliefs
The fear avoidance and beliefs questionnaire (FABQ) will be used to assess fear avoidance behaviors. The first five items question physical activity, the other 11 activities work. A minimum score is 0, maximum 24. Higher scores indicate fear avoidance behaviors.
Time frame: At baseline (T0)
Life quality
The EQ-5D-5L was used to assess quality of life. From five items investigating the impact of their disease, a health utility score was calculated. Additionally, the questionnaire consists of a visual analogue scale (VAS) labelled from 0: "worst imaginable health state," to 100 "best imaginable health state" providing the EQ-VAS.
Time frame: At baseline (T0)
Life quality
The EQ-5D-5L was used to assess quality of life. From five items investigating the impact of their disease, a health utility score was calculated. Additionally, the questionnaire consists of a visual analogue scale (VAS) labelled from 0: "worst imaginable health state," to 100 "best imaginable health state" providing the EQ-VAS.
Time frame: At one year follow-up (T2)
Haemophilia Activity Limitations
The Haemophilia Activity List (HAL) was used to assess activity limitations and participation restrictions people with haemophilia suffer with. A sum score and component scores can be calculated, resulting in scores ranging from 0-100. Lower scores represent higher levels of participation restrictions.
Time frame: At baseline (T0)
Physical endurance ability
The 2 minutes walking test (2MWT) was used as a performance-based test to assess their functional activity. Subjects were asked to walk as far as possible for two minutes in a 30 meters flat corridor, resulting in the walking distance in meters.
Time frame: At baseline (T0)
Physical functioning
The Timed Up \& Go (TUG) consists of asking the patient to sit on a standard armchair; stand up and walk 3 meters; turn around at the line and walk back to the chair and sit down at a normal pace.
Time frame: At baseline (T0)
Joint structure US
Ultrasound (US) examinations will be performed with a linear probe (3-13 MHz) Esaote, type MyLab Gamma, Genova, Italy).The Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) scanning procedure and scoring method will be performed by one of our investigators. A score of 0/8 (normal bone 0/2, normal cartilage 0/4, absent hypertrophic synovium 0/2) is considered normal. A score above 1/8 is considered as abnormal.
Time frame: At baseline (T0)
Joint structure MRI
Magnetic Reasoning Imaging (MRI) of the ankles will be performed with a 3T-magnet (GE Signa Premier, GE Healthcare, Milwaukee, USA).Joint images will be classified with the international Prophylaxis Study Group (IPSG) scale. Joints will be classified as abnormal if talocrural joints or subtalar joints were positive at IPSG-score. Joints will be considered healthy if the total score was of 1/17.
Time frame: At baseline (T0)
Illness perceptions
The illness perceptions questionnaire (B-IPQ) includes nine items ranging from 0 (minimum) to 10 (maximum) and questions the perceptions related to the patients disease. No total score exists, as each item is scored individually. Higher scores indicate more negative or unhelpful illness perceptions. A change score between baseline (T0) and one year follow-up (T2) will be calculated.
Time frame: At baseline (T0)
Illness perceptions
The illness perceptions questionnaire (B-IPQ) includes nine items ranging from 0 (minimum) to 10 (maximum) and questions the perceptions related to the patients disease. No total score exists, as each item is scored individually. Higher scores indicate more negative or unhelpful illness perceptions. A change score between baseline (T0) and one year follow-up (T2) will be calculated.
Time frame: At one year follow-up (T2)
Physical activity
The International Physical Activity Scale (IPAQ) questions the hours of physical activity over the last week (Higher scores are higher levels of physical activity). Based on the patient's answers a MET-minute score is calculated (MET-minutes x weight in kilograms/60kilograms)
Time frame: At baseline (T0)
Physical activity
The International Physical Activity Scale (IPAQ) questions the hours of physical activity over the last week. Based on the patient's answers a MET-minute score is calculated (MET-minutes x weight in kilograms/60kilograms)
Time frame: At one month follow-up (T1)
Joint function
Joint function of the ankles, knees and ankles was assessed with the HJHS 2.1. Minimum score is 0, maximum, 20. The higher the score the more functional limitations. HJHS scores are considered positive when scores reach 1/20.
Time frame: At baseline (T0)
Warm and cold detection threshold
Thermal hyper or hypo esthesia were assessed with a thermode attached at the dominant wrist by use of a validated Quantitative Sensory testing protocol with the Medoc TSA-2 device.
Time frame: At baseline (T0)
Warm and cold pain thresholds
Thermal hyper or hypo algesia were assessed with a thermode attached at the dominant wrist by use of a validated Quantitative Sensory testing protocol with the Medoc TSA-2 device.
Time frame: At baseline (T0)
Mechanical pain thresholds
Mechanical local and widespread hyperalgesia indicated by lower pressure pain thresholds were assessed with a digital algometer at the knee joints, ankle joints and forehead. This by use of a validated quantitative sensory testing protocol.
Time frame: At baseline (T0)
Temporal summation of pain
Temporal summation (or bottom-up sensitization) of pain was assessed by use of a 60g Von Frey monofilament at the medial knee and dorsal side of the wrist of the dominant side.
Time frame: At baseline (T0)
Conditioned Pain Modulation
Dysfunctional endogenous pain inhibition (as form of central pain processing) was assessed by a validated protocol applying the Medoc TSA-2 device with thermodes attached at both wrists.
Time frame: At baseline (T0)
Pain interference change
The BPI was used to evaluate how much pain interferes with patient's daily activities. This was assessed by seven items, resulting in a total pain interference score. Minimum score 0, maximum score 10. The higher the score, the more pain interference.A change score between baseline and one year follow-up will be calculated.
Time frame: Change from baseline (T0) to one year follow-up (T2)
Pain severity change
The BPI was used to evaluate the individual's pain experience within the last 24 hours by four items, resulting in a total pain severity score. Minimum score 0, maximum score 10. The higher te score, the higher the pain severity.A change score between baseline (T0) and one year follow-up (T2) will be calculated.
Time frame: Change from baseline (T0) to one year follow-up (T2)
Fear Avoidance and beliefs change
The fear avoidance and beliefs questionnaire (FABQ) will be used to assess fear avoidance behaviors. The first five items question physical activity, the other 11 activities work. A minimum score is 0, maximum 24. Higher scores indicate fear avoidance behaviors. A change score between baseline (T0) and one year follow-up (T2) will be calculated.
Time frame: Change from baseline (T0) to one year follow-up (T2)
Anxiety and Depression change
The Hospital Anxiety and Depression Scale (HADS) was used to establish symptoms of anxiety and depression. This 14-item questionnaire consists of two subscales each including 7 items, the first to identify anxiety and the second depression. Individual items were scored from 0 to 3, resulting in a total range score of 0-21 for each subscale. A score of ≥8/21 was determined as a cut-off, indicating anxiety and depression.A change score between baseline (T0) and one year follow-up (T2) will be calculated.
Time frame: Change from baseline (T0) to one year follow-up (T2)
Illness Perceptions change
The illness perceptions questionnaire (B-IPQ) includes nine items ranging from 0 (minimum) to 10 (maximum) and questions the perceptions related to the patients disease. No total score exists, as each item is scored individually. Higher scores indicate more negative or unhelpful illness perceptions. A change score between baseline (T0) and one year follow-up (T2) will be calculated.
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Time frame: Change from baseline (T0) to one year follow-up (T2)
Pain Catastrophizing change
The Pain Catastrophizing Scale (PCS) asked participants to reflect on previous painful experiences and to rate their degree of catastrophic thinking in the content domains of rumination, magnification and helplessness. A score of 0 (not at all) to 4 (all the time) was indicated for each of the 13 items, resulting in a total score range of 0-52. Higher scores were associated with higher levels of pain catastrophizing. A change score between baseline (T0) and one year follow-up (T2) will be calculated.
Time frame: Change from baseline (T0) to one year follow-up (T2)
Pain localisation change
The body chart of the Brief Pain Inventory was used to investigate painful body sites. A change score between baseline (T0) and one year follow-up (T2) will be calculated.
Time frame: Change from baseline (T0) to one year follow-up (T2)