
==== Front
BMJ Open
BMJ Open
bmjopen
bmjopen
BMJ Open
2044-6055
BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR

39260833
10.1136/bmjopen-2023-082204
bmjopen-2023-082204
Original Research
Haematology (Incl Blood Transfusion)
1700
1506
Assessment of joint health in patients receiving prophylaxis for haemophilia A: a cross-sectional survey in five European countries
http://orcid.org/0000-0002-9179-201X
De la Corte-Rodríguez Hortensia 1hortensiadelacorterodriguez@yahoo.es

http://orcid.org/0000-0002-9787-7866
Bystrická Linda 2linda.bystricka@sobi.com

http://orcid.org/0000-0002-4150-1106
Ball Nathan 3nathan.ball@adelphigroup.com

http://orcid.org/0000-0002-8911-0155
Olsen Stevie 3stevie.olsen@adelphigroup.com

http://orcid.org/0000-0002-8340-6430
Golden Keisha 3keisha.golden@adelphigroup.com

http://orcid.org/0000-0001-5835-8599
Hakimi Zalmai 2zalmai.hakimi@sobi.com

http://orcid.org/0000-0002-9222-4479
Kragh Nana 2nana.kragh@sobi.com

1 La Paz University Hospital, Madrid, Spain
2 Swedish Orphan Biovitrum AB, Stockholm, Sweden
3 Adelphi Real World, Bollington, UK
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

HDlC-R reports consultancy/advisory, honoraria, expert testimony fees and support for meeting attendance from Bayer, CSL-Behring, Novo Nordisk, Pfizer, Roche, Sobi and Takeda. LB, ZH and NK are employees of and shareholders in Sobi. NB, SO and KG are employees of Adelphi Real World.

Mrs; nana.kragh@sobi.com
2024
6 9 2024
14 9 e08220416 11 2023
26 7 2024
Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Abstract

Objectives

To evaluate joint health, pain and health-related quality of life (HRQoL) in patients with moderate/severe haemophilia A in Europe.

Design

Multinational, cross-sectional survey, with retrospective data collection. Data were taken from the Adelphi Real World Haemophilia Disease Specific Programme Wave II, using surveys completed by physicians and patients between February 2020 and May 2021.

Setting

Haematologists/haemato-oncologists and their patients in France, Germany, Italy, Spain and the UK.

Participants

Males aged ≥18 years with moderate or severe haemophilia A (baseline clotting factor level ≤5%), without existing inhibitors and currently receiving prophylaxis. Patients were grouped into those with or without haemophilia-affected joints (HAJs) based on bleeding, radiographic, surgical, mobility and joint pain data.

Primary outcome measure

Characterisation of humanistic and clinical outcomes in patients with or without HAJs.

Results

A total of 120 physicians provided data for 351 eligible patients; 209 (59.5%) patients had HAJs and 142 (40.5%) had no HAJs. Pain/discomfort was significantly different (p=0.01) and reported more frequently in the HAJ (85.7%) vs non-HAJ group (53.3%). Pain medication use was significantly higher in the HAJ versus non-HAJ group (73.2% vs 60.6%; p=0.01). Up to half of the patients with HAJs had synovitis (49.8%) or arthropathy (48.4%), and one-third had undergone joint surgery (35.4%). Overall health status was significantly worse in the HAJ versus non-HAJ group (mean (SD) EuroQol Visual Analogue Scale score: 65.5 (19.3) vs 81.1 (14.6); p=0.01).

Conclusions

In this multinational real-world study, nearly two-thirds of adults with moderate/severe haemophilia A without inhibitors experienced HAJs despite prophylaxis. Individuals with HAJs had higher rates of pain and pain medication use, and lower HRQoL compared with those without HAJs. These data indicate that HAJs represent a clinically relevant burden and early identification/monitoring and management of affected joints should be an important consideration to help prevent long-term joint morbidity.

bleeding disorders & coagulopathies
primary prevention
surveys and questionnaires
pain management
quality of life
Sobi Not applicable
==== Body
pmcSTRENGTHS AND LIMITATIONS OF THIS STUDY

This study captures real-world data for adult males with moderate/severe haemophilia A receiving prophylaxis from five European countries (France, Germany, Italy, Spain and the UK).

Data were collected from surveys completed by both physicians (haematologists or haemato-oncologists) and their patients, using a standardised methodology (as part of the Haemophilia DSP Wave II) over a 15-month period between 2020 and 2021.

Although this study adopted a comprehensive definition of haemophilia-affected joints capturing bleeding, radiographic, surgical, mobility and joint pain data, a standardised approach to measure joint health has not been established.

This study was a cross-sectional survey with retrospective data collection, and there was a possibility of recall bias in the physician-reported and patient-reported data.

Introduction

Early factor VIII (FVIII) prophylaxis is standard of care for patients with haemophilia A (PwHA) to prevent musculoskeletal bleeding episodes and subsequent complications, including joint damage and joint pain.1 Recurrent joint bleeds (haemathroses) are the most common clinical manifestation in patients with moderate or severe haemophilia A,2 3 reported to account for up to 80% of all bleeding episodes.147

Repeated haemathroses can lead to synovial inflammation and progressive damage to the cartilage and bone, resulting in joint degeneration and remodelling (haemophilic arthropathy).24 810 Joint problems are more common with increasing severity of haemophilia A and are the most frequent long-term complication in moderate or severe disease.2 3 11

Haemophilic joint disease represents a substantial humanistic and economic burden,12 including pain, impaired mobility and diminished health-related quality of life (HRQoL).4 6 8 9 13 Joint pain, which can be acute or chronic, is experienced by up to two-thirds of patients with severe haemophilia.4 7 10 14 Appropriate pain management is required to improve joint function, mobility and HRQoL;15 multimodal strategies include non-surgical techniques (eg, rehabilitation, braces/orthotics), pharmacotherapy (eg, systemic analgesics, intra-articular injections), psychosocial support, orthopaedic surgery and other complementary/alternative treatments.17 11 1416 HRQoL impacts may include physical functioning, daily functioning, mental health and participation in social and work activities.6 7 9

Therapeutic advances in haemophilia A, such as extended half-life (EHL) FVIII products improve bleeding protection, via higher trough levels and fewer bleeds, than standard half-life (SHL) FVIII products in routine clinical practice.1720 In addition, prophylaxis with FVIII mimetics is associated with low bleeding rates in phase III clinical trials,21 but real-world data show spontaneous bleeds in 0%–51% of patients2224 and joint bleeds account for 42%–66% of all bleeding events.2426 Adeno-associated virus-mediated gene therapy has most recently become available for the treatment of adults with severe haemophilia A,27 although long-term and real-world bleeding data are limited. Despite the effectiveness of current treatments, PwHA may still experience bleeding and joint problems (bleeding-related arthropathy and chronic pain).2 14 Consequently, maintaining joint health remains a key challenge in the management of haemophilia.28

Real-world assessments of joint health in PwHA in the setting of current treatment options are limited. To address this knowledge gap, this study aimed to evaluate joint health, pain and HRQoL in patients with moderate or severe haemophilia A receiving prophylaxis as reported by physicians and patients in Europe.

Methods

Data source

Cross-sectional survey with retrospective data collection, of joint health in PwHA in Europe. Data were taken from the Adelphi Real World Haemophilia Disease Specific Programme (DSP) Wave II, a multinational cross-sectional survey of physicians and their patients in France, Germany, Italy, Spain, the UK and the USA. DSPs are large, multinational surveys conducted in clinical practice that describe current disease management, disease-burden impact and treatment effects (clinical and physician perceived).29 The Haemophilia DSP Wave II database held (as of May 2021) real-world data for ~1500 PwH submitted by ~250 physicians.

Procedures

Data were collected using two questionnaires—a patient-record form (PRF) completed by physicians and a patient self-completion (PSC) form. Both forms consisted of questions with predefined answer alternatives (eg, Likert-scale questions) plus open-ended questions and were translated into local languages.

Physicians (haematologists or haemato-oncologists) completed an electronic PRF for patients who were consecutively consulted (to avoid selection bias) and met the inclusion criteria (ie, males diagnosed with haemophilia A or B, with/without inhibitors). PRFs were completed using information collated following the most recent routine care visit. The PRFs included questions on patient demographics, concomitant conditions, consultation history, evaluation/testing, haemophilia treatment, bleeding episodes, joint health (Pettersson score and/or Haemophilia Joint Health Score (HJHS) at the last assessment), pain and medications for haemophilia-related pain, hospitalisations and patients’ HRQoL.

At the end of the consultation, physicians invited in-person each patient with a completed PRF to complete a printed PSC form within the physician’s practice; patients completed the PSC independently and participation was voluntary. The PSC contained questions on their demographics, clinical characteristics, haemophilia treatment and HRQoL (including the EuroQol 5-dimensions 5-levels (EQ-5D-5L)). EQ-5D-5L is a generic HRQoL measurement of patients’ self-rated health, which generates a health index score (using a descriptive system of five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and five levels (no problems to extreme problems)) and a Visual Analogue Scale (VAS) score.30 Linguistic-validated versions of EQ-5D-5L were provided to patients. In this study, the index values were derived from a UK crosswalk value set; the health index and VAS scores ranged from −0.594 to 1.000 and 0 to 100, respectively (higher scores represent better overall health).31 Other validated generic or disease-specific tools (eg, Brief Pain Inventory or Haemophilia Activities List) were excluded to avoid increased survey completion time and respondent fatigue. Informed consent was obtained from physicians via the completion of an online screener and from patients via completion of the PSC form.

Physician-reported data from the PRF were included in the database even if the corresponding patient-reported data were not available from the PSC. The survey was designed to facilitate understanding of current real-world clinical practice, and thus physicians could only report on data they had available at the time of consultation; no tests/investigations or treatments were initiated specifically for this survey. The number of PRFs completed was dependent on the physician caseload during the data collection period.

Study population

Data in this analysis were collected from France, Germany, Italy, Spain and the UK, from surveys completed between February 2020 and May 2021. Deidentified data from the Haemophilia DSP Wave II were used to retrospectively identify eligible patients: adult males (≥18 years) with moderate or severe haemophilia A (baseline clotting factor level ≤5%), without existing inhibitors, and receiving prophylaxis at the time of the survey.

Eligible patients were grouped into those with or without haemophilia-affected joints (HAJs). In this current analysis, patients were considered to have HAJs if the PRF reported one or more of the following: history or presence of haemophilia-related joint problems; existing haemophilic arthropathy; history of synovitis in any joints (tenderness/pain, swelling); history of joint surgery due to haemophilia-related joint damage; ≥1 existing target joint (>3 bleeds in a joint during any 6-month period); or Pettersson score ≥1 or HJHS >3 at last assessment.

Statistical analysis

Analyses included all eligible patients and data from the five countries were combined. In the main analysis, patients with moderate or severe haemophilia were combined; exploratory analyses were performed to assess outcomes in patients with moderate versus severe haemophilia. Patients were included in any analysis for which they had evaluable data. Missing data were not imputed and adjustments for multiplicity were not performed.

Descriptive analyses (mean, SD, median and range) and statistical testing were performed to compare patients with and without HAJs. Pearson’s χ2, Fisher’s exact or Mann-Whitney U tests were used for categorical variables, while Student’s t-test was used for continuous variables. All analyses were performed by using Stata V.17 (StataCorp).

Patient and public involvement

Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Results

Study population

A total of 120 physicians completed PRFs for 351 patients with a confirmed diagnosis of moderate or severe haemophilia A without existing inhibitors and currently receiving prophylaxis. Physicians reported 209 (59.5%) patients had HAJs and 142 (40.5%) had no HAJs; sociodemographic and clinical characteristics are presented in table 1.

Table 1 Patient sociodemographic and clinical characteristics (physician reported)

	All patients	Moderate haemophilia	Severe haemophilia	
HAJ (n=209)	Non-HAJ (n=142)	P value	HAJ (n=74)	Non-HAJ (n=81)	P value	HAJ (n=135)	Non-HAJ (n=61)	P value	
Country, n (%)*										
N	209	142	0.01†	74	81	0.07†	135	61	0.01†	
 France	44 (21.1)	30 (21.1)		10 (13.5)	19 (23.5)		34 (25.2)	11 (18.0)		
 Germany	20 (9.6)	18 (12.7)		11 (14.9)	10 (12.3)		9 (6.7)	8 (13.1)		
 Italy	63 (30.1)	25 (17.6)		29 (39.2)	19 (23.5)		34 (25.2)	6 (9.8)		
 Spain	49 (23.4)	29 (20.4)		16 (21.6)	15 (18.5)		33 (24.4)	14 (23.0)		
 UK	33 (15.8)	40 (28.2)		8 (10.8)	18 (22.2)		25 (18.5)	22 (36.1)		
Ethnicity, n (%)										
N	209	142	0.78†	74	81	0.85†	135	61	0.85†	
 White	190 (90.9)	131 (92.3)		69 (93.2)	75 (92.6)		121 (89.6)	56 (91.8)		
 Asian-Indian subcontinent	1 (0.5)	1 (0.7)		0 (0)	0 (0)		1 (0.7)	1 (1.6)		
 Chinese	1 (0.5)	2 (1.4)		1 (1.4)	2 (2.5)		0 (0)	0 (0)		
 Hispanic/Latino	6 (2.9)	4 (2.8)		3 (4.1)	2 (2.5)		3 (2.2)	2 (3.3)		
 Middle Eastern	5 (2.4)	3 (2.1)		1 (1.4)	2 (2.5)		4 (3.0)	1 (1.6)		
 Afro-Caribbean	2 (1.0)	0 (0)		0 (0)	0 (0)		2 (1.5)	0 (0)		
 Other	4 (1.9)	1 (0.7)		0 (0)	0 (0)		4 (3.0)	1 (1.6)		
Age										
N	209	142	<0.01‡	74	81	0.03‡	135	61	p<0.01‡	
 Years, mean (SD)	34.7 (13.8)	29.0 (11.7)		36.1 (15.0)	31.0 (13.8)		34.0 (13.0)	26.4 (7.4)		
BMI										
N	209	142	0.13‡	74	81	0.24‡	135	61	0.12‡	
 kg/m2, mean (SD)	25.5 (8.2)	24.4 (2.8)		26.2 (13.0)	24.5 (2.9)		25.1 (3.2)	24.4 (2.7)		
Employment status, n (%)										
N	206	139	0.01†	74	80	0.49†	132	59	0.02†	
 Working full time	86 (41.7)	44 (31.7)		33 (44.6)	28 (35.0)		53 (40.2)	16 (27.1)		
 Working part time	31 (15.0)	21 (15.1)		11 (14.9)	14 (17.5)		20 (15.2)	7 (11.9)		
 Long-term sick leave	8 (3.9)	1 (0.7)		2 (2.7)	1 (1.3)		6 (4.5)	0 (0)		
 Homemaker	1 (0.5)	0 (0)		0 (0)	0 (0)		1 (0.8)	0 (0)		
 Student	57 (27.7)	58 (41.7)		18 (24.3)	28 (35.0)		39 (29.5)	30 (50.9)		
 Retired	13 (6.3)	3 (2.2)		6 (8.1)	3 (3.8)		7 (5.3)	0 (0)		
 Unemployed	10 (4.9)	12 (8.6)		4 (5.4)	6 (7.5)		6 (4.5)	6 (10.2)		
Inhibitor status, n (%)										
N	209	142	0.01§	74	81	0.22§	135	61	0.07§	
 No prior inhibitors	168 (80.4)	129 (90.8)		62 (83.8)	74 (91.4)		106 (78.5)	55 (90.2)		
 Prior, but no current inhibitors	41 (19.6)	13 (9.2)		12 (16.2)	7 (8.6)		29 (21.5)	6 (9.8)		
Time since last treatment switch										
N	106	36	0.42‡	22	21	0.09‡	84	15	0.13‡	
 Months, mean (SD)	38.1 (56.6)	30.1 (29.3)		23.2 (26.1)	39.1 (34.0)		42.0 (61.7)	17.5 (14.4)		
* PRFs were completed by 120 physicians from France (n=26), Germany (n=14), Italy (n=40), Spain (n=21) and the UK (n=19).

† Pearson’s chi-squaredχ2.

‡ Student’s t-test.

§ Fisher’s exact test.

BMI, body mass index; HAJ, haemophilia-affected joint; PRF, patient-record form

Patients in the HAJ group were ~6 years older than the non-HAJ group (mean (SD) age 34.7 (13.8) vs 29.0 (11.7) years; p<0.01). Prior inhibitor status was significantly different between the two groups (p=0.01); prior inhibitors were more frequent in the HAJ group (19.6%) than the non-HAJ group (9.2%).

Haemophilia treatment patterns

Haemophilia treatments in the whole cohort (n=351) included EHL FVIII, SHL FVIII and FVIII mimetics. EHL FVIII treatment and FVIII mimetics were used more frequently in the HAJ group (23.0% and 32.5%, respectively) than the non-HAJ group (16.2% and 25.4%, respectively) while SHL FVIII (44.5% and 58.5%) was used more frequently in the non-HAJ group. The mean (SD) time since the last treatment switch was 38.1 (56.6) months in the HAJ group and 30.1 (29.3) months in the non-HAJ group (table 1).

Joint health in the HAJ group

Among the 209 patients with HAJs, 74 (35.4%) had moderate haemophilia and 135 (64.6%) had severe haemophilia (table 2). Overall, mean (SD) age at first presentation of joint damage was 23.9 (13.5) years, including 22.6 (13.1) years in severe haemophilia and 26.4 (14.0) years in moderate haemophilia (table 2).

Table 2 Joint health status in patients with HAJs (physician reported)

	All patients (n=209)	Moderate haemophilia (n=74)	Severe haemophilia (n=135)	
Age at first presentation of joint damage	
N	100	34	66	
 Years, mean (SD)	23.9 (13.5)	26.4 (14.0)	22.6 (13.1)	
Joint health status at last switch, n (%)	
N	118	29	89	
 No problems	9 (7.6)	2 (6.9)	7 (7.9)	
 Mild problems	35 (29.7)	9 (31.0)	26 (29.2)	
 Moderate problems	57 (48.3)	15 (51.7)	42 (47.2)	
 Severe problems	17 (14.4)	3 (10.3)	14 (15.7)	
Joint health status at last assessment, n (%)	
N	186	64	122	
 No problems	5 (2.7)	0 (0)	5 (4.1)	
 Mild problems	97 (52.2)	42 (65.6)	55 (45.1)	
 Moderate problems	68 (36.6)	20 (31.3)	48 (39.3)	
 Severe problems	16 (8.6)	2 (3.1)	14 (11.5)	
Haemophilic arthropathy*	
N	186	64	122	
 No, n (%)	96 (51.6)	42 (65.6)	54 (44.3)	
 Yes, n (%)	90 (48.4)	22 (34.4)	68 (55.7)	
  Shoulder	4 (2.2)	1 (2.2)	3 (2.5)	
  Elbow	33 (17.7)	4 (6.3)	29 (23.8)	
  Hip	16 (8.6)	7 (10.9)	9 (7.4)	
  Knee	62 (33.3)	17 (26.6)	45 (36.9)	
  Ankle	41 (22.0)	9 (14.1)	32 (26.2)	
  Wrist	2 (1.1)	1 (2.2)	1 (0.8)	
N	90	22	68	
 Joints, mean (SD)	1.8 (0.8)	1.8 (1.0)	1.8 (0.8)	
Synovitis in joint, n (%)	
N	209	74	135	
 No	105 (50.2)	47 (63.5)	58 (43.0)	
 Yes	104 (49.8)	27 (36.5)	77 (57.0)	
Joint surgery, n (%)	 	 	 	
N	209	74	135	
 No	135 (64.6)	54 (73.0)	81 (60.0)	
 Yes	74 (35.4)	20 (27.0)	54 (40.0)	
  Synovectomy	12 (5.7)	3 (4.1)	9 (6.7)	
  Arthrodesis	7 (3.3)	3 (4.1)	4 (3.0)	
  Arthroplasty	21 (10.0)	2 (2.7)	19 (14.1)	
  Joint aspiration	43 (20.6)	13 (17.6)	30 (22.2)	
Target joints*	 	 	 	
N	186	64	122	
 No, n (%)	45 (24.2)	8 (12.5)	37 (30.3)	
 Yes, n (%)	141 (75.8)	56 (87.5)	85 (69.7)	
  Shoulder	11 (5.9)	6 (9.4)	5 (4.1)	
  Elbow	31 (16.7)	11 (17.2)	20 (16.4)	
  Hip	15 (8.1)	6 (9.4)	9 (7.4)	
  Knee	90 (48.4)	36 (56.3)	54 (44.3)	
  Ankle	48 (25.8)	14 (21.9)	34 (27.9)	
  Wrist	8 (4.3)	4 (6.3)	4 (3.3)	
  Finger(s)	1 (0.5)	1 (1.6)	0 (0)	
N	141	56	85	
 Joints, mean (SD)	1.5 (0.7)	1.4 (0.7)	1.5 (0.7)	
* Left and right joints combined.

HAJhaemophilia-affected joint

In the HAJ group overall, the mean (SD) Pettersson score (n=34) and HJHS (n=48) were 20.1 (19.4) and 42.6 (35.8), respectively, at the last assessment. Joint problems at the last assessment were mostly of mild (52.2%) or moderate (36.6%) severity (table 2). Joint problems were observed in both moderate and severe haemophilia; the proportion of patients with moderate or severe joint problems was greater in those with severe (39.3% and 11.5%, respectively) than moderate haemophilia (31.3% and 3.1%, respectively) (table 2). The overall proportion of patients with joint problems was 97.3% at the last assessment compared with 92.4% at the last treatment switch (table 2).

Physicians reported 49.8% of patients with HAJs had a history of synovitis, which was more common in severe (57.0%) than moderate haemophilia (36.5%) (table 2). Existing target joints were reported in 75.8% of the HAJ group and were more common in patients with moderate (87.5%) than severe haemophilia (69.7%) (table 2). Patients in the HAJ group overall had a mean (SD) of 1.5 (0.7) target joints; knee (48.4%), ankle (25.8%) and elbow (16.7%) were most common. Existing haemophilic arthropathy was reported in 48.4% of patients and was more common in severe (55.7%) than moderate haemophilia (34.4%) (table 2). Overall, patients had a mean (SD) of 1.8 (0.8) joints with haemophilic arthropathy; knee (33.3%), ankle (22.0%) and elbow (17.7%) were most common. A history of joint surgery was reported in 35.4% of patients and was more common in severe (40.0%) than moderate haemophilia (27.0%) (table 2); the most common procedures were joint aspiration (20.6%) and arthroplasty (10.0%).

Pain

Physician-reported pain (any, ie, not restricted to joints) was significantly different between the HAJ and non-HAJ groups (p<0.01); any pain was reported in a greater proportion of patients in the HAJ group (82.8%) than the non-HAJ group (73.2%) (figure 1). Similarly, moderate and severe pain were reported more frequently in the HAJ group (31.6% and 13.9%, respectively) than the non-HAJ group (15.5% and 0%, respectively). In addition, physician-reported pain was significantly different between the two groups in both patients with moderate (p=0.01) or severe (p<0.01) haemophilia (online supplemental figure 1). Similarly, patient-reported pain/discomfort (any, ie, not restricted to joints) was significantly different between the two groups (p=0.01); any pain/discomfort was reported more frequently by patients in the HAJ group (85.7%) than the non-HAJ group (53.3%) (figure 2). The rates of moderate (28.6% vs 20.0%) and severe (17.1% vs 0%) pain/discomfort were greater in patients with HAJs than without HAJs.

Figure 1 Pain in patients with moderate or severe haemophilia (physician reported). †Pearson’s χ2. ‡No physicians reported any patients with very severe pain. HAJ, haemophilia-affected joint.

Figure 2 EQ-5D-5L dimensions in patients with moderate or severe haemophilia (patient reported). †Mann-Whitney U test. ‡No patients reported extreme problems. EQ-5D-5L, EuroQol 5-dimensions 5-levels; HAJ, haemophilia-affected joint.

Physicians reported a significantly greater proportion of patients with HAJs were currently receiving medication to treat haemophilia-related pain compared with those without HAJs (73.2% vs 60.6%; p=0.01) (table 3). The most common medications were paracetamol (42.6% vs 23.9%; p<0.01), non-steroidal anti-inflammatory drugs (NSAIDs) (37.8% vs 23.2%; p=0.01) and opioids (24.9% vs 20.4%; p=0.37). Medication was used to treat chronic (42.8% (paracetamol, 35.8%; NSAIDs, 37.8%; opioids, 51.2%; other, 87.5%)) or acute pain (57.2% (paracetamol, 64.2%; NSAIDs, 62.3%; opioids, 48.9%; other, 12.5%)). Patients with HAJs received a significantly higher mean (SD) number of drug classes (1.1 (0.9) vs 0.7 (0.6); p<0.01) and number of drugs (1.2 (1.0) vs 0.7 (0.6); p<0.01) to treat haemophilia-related pain compared with those without HAJs. Pain medication use within the moderate and severe haemophilia groups is shown in online supplemental table 1. Physicians reported a significantly greater proportion of patients with HAJs were using at least one walking aid (eg, orthotics, brace) due to their haemophilia compared with those without HAJs (24.9% vs 7.0%; p<0.01).

Table 3 Pain medication currently used in patients with moderate or severe haemophilia (physician reported)

	HAJ (n=209)	Non-HAJ (n=142)	P value	
Pain medication, n (%)	 	 	0.01*	
 Yes	153 (73.2)	86 (60.6)	 	
 No	56 (26.8)	56 (39.4)	 	
Total treatment classes	 	 	<0.01†	
 Mean (SD)	1.1 (0.9)	0.7 (0.6)	 	
 Median (range)	1.0 (0–3.0)	1.0 (0–3.0)	 	
Total drugs	 	 	<0.01†	
 Mean (SD)	1.2 (1.0)	0.7 (0.6)	 	
 Median (range)	1.0 (0–5.0)	1.0 (0–3.0)	 	
Treatment, n (%)	 	 	 	
 Paracetamol	89 (42.6)	34 (23.9)	<0.01*	
 NSAIDs	79 (37.8)	33 (23.2)	0.01*	
  Celecoxib	15 (7.2)	0 (0)	<0.01*	
  Diclofenac	12 (5.7)	5 (3.5)	0.45*	
  Etoricoxib	11 (5.3)	3 (2.1)	0.17*	
  Ibuprofen	27 (12.9)	25 (17.6)	0.28*	
  Indomethacin	2 (1.0)	0 (0)	0.52*	
  Meloxicam	1 (0.5)	0 (0)	1*	
  Naproxen	12 (5.7)	1 (0.7)	0.02*	
 Opioids	52 (24.9)	29 (20.4)	0.37*	
  Buprenorphine	1 (0.5)	1 (0.7)	1*	
  Butorphanol	1 (0.5)	0 (0)	1*	
  Codeine	7 (3.3)	23 (16.2)‡	<0.01*	
  Dihydrocodeine	2 (1.0)	0 (0)	0.52*	
  Fentanyl	12 (5.7)	1 (0.7)	0.02*	
  Hydrocodone	1 (0.5)	0 (0)	1*	
  Hydrocodone+paracetamol	1 (0.5)	0 (0)	1*	
  Hydromorphone	1 (0.5)	0 (0)	1*	
  Levomethadyl	1 (0.5)	1 (0.7)	1*	
  Morphine	3 (1.4)	1 (0.7)	0.65*	
  Oxycodone	7 (3.4)	0 (0)	0.04*	
  Oxycodone+paracetamol	1 (0.5)	0 (0)	1*	
  Oxycodone+naloxone	1 (0.5)	0 (0)	1*	
  Tapentadol	2 (1.0)	0 (0)	0.52*	
  Tramadol	16 (7.7)	2 (1.4)	0.01*	
 Other	16 (7.7)	0 (0)	<0.01*	
  IACI	14 (6.7)	0 (0)	<0.01*	
  Other	2 (1.0)	0 (0)	0.52*	
* Fisher’s exact test.

† Student’s t-test.

‡ 22/23 patients who received codeine were from the UK.

HAJ, haemophilia-affected joint; IACI, intra-articular corticosteroid injection; NSAID, non-steroidal anti-inflammatory drug

Health-related quality of life

The voluntary PSC form was completed by 50/351 eligible patients (n=49 for EQ-VAS). Overall health status was significantly lower (worse) in the HAJ group (n=35) vs the non-HAJ group (n=14) based on mean (SD) EQ-VAS (65.5 (19.3) vs 81.1 (14.6); p=0.01) and EQ-5D-5L index (0.64 (0.21) vs 0.80 (0.17); p=0.01) scores. The ability to perform usual activities was significantly different between the HAJ and non-HAJ groups (p<0.01); a higher proportion of patients with HAJs had problems performing usual activities (74.3%) vs those without HAJs (26.7%) (figure 2). A higher proportion of patients had mobility problems in the HAJ group (60.0%) vs the non-HAJ group (46.7%), although mobility was not significantly different between the groups (p=0.10). No significant between-group differences were observed for self-care (p=0.19) or anxiety/depression (p=0.20).

Discussion

This study provides clinically relevant insights into joint health, pain and HRQoL in adult males with moderate or severe haemophilia A receiving prophylaxis in Europe within a real-world setting. Overall, 60% of this patient population were found to have HAJs, with joint problems predominantly described as mild or moderate. Additionally, up to half of the patients with HAJs had synovitis or arthropathy, and patients with HAJs were more likely to experience pain, use pain medication and have impaired HRQoL compared with those without HAJs. Overall, the data indicate that joint problems still represent a substantial burden in the care of haemophilia A.

HAJs were reported in our study despite all patients receiving current prophylaxis. However, the survey did not include questions to determine when patients first received prophylaxis and whether prophylaxis was primary, secondary or tertiary. Randomised trials have shown primary prophylaxis significantly reduces joint damage versus on-demand therapy in patients with severe haemophilia,3234 although some patients on primary prophylaxis still experience joint damage.33 Overall, these data indicate an unmet need for more effective therapies or better utilisation of existing therapies via targeting higher FVIII levels.35 36

A standardised definition of HAJs has not been established. Target joints may be employed as an indicator of joint morbidity based on evidence that repeated haemathroses lead to complications such as chronic synovitis and haemophilic arthropathy.1 8 37 However, using target joints alone may lead to underdiagnosis as they do not account for underlying joint issues that can occur with/without persistent bleeding.37 An alternative definition for a problem joint was recently proposed: chronic joint pain and/or limited range of movement due to compromised joint integrity (chronic synovitis and/or haemophilic arthropathy) with/without persistent bleeding.38 However, this does not capture the extent of damage to individual joints.38 In our study, HAJs were defined using several criteria, including haemophilic arthropathy, synovitis, joint surgery, target joints, Pettersson score and/or HJHS. As such, it offers a comprehensive definition capturing bleeding data, radiographic assessments, mobility issues and joint pain; however, it has not been validated.

A major finding of our study was that >80% of patients with HAJs reported pain/discomfort. Pain was rated as moderate or severe in ~40% of cases, suggesting patients perceived it to be bothersome. Other studies suggest up to 90% of adults with severe haemophilia experience some level of daily pain in ≥1 joint.4 8 11 Appropriate analgesics are often required to control pain in PwH1 and significantly more patients received pain medication in the HAJ group versus the non-HAJ group. Patients with HAJs used >1 pain medication on average; paracetamol (42.6%), NSAIDs (37.8%) and opioids (24.9%) were most common. NSAID use, including selective COX-2 inhibitors, was high, especially in patients with HAJs; NSAID use was proportionally higher in Germany and Italy versus the other countries. Opioid use was unexpectedly high in the non-HAJ group (20.4%), compounded by 23/29 patients (22 from the UK) who received codeine; this result may be an anomaly due to organisational level guidelines or physician preference in the UK. Analgesics may be used according to a pain ladder, where non-opioids are typically used first line for chronic pain.3 16 However, opioid use may be under-reported, most often prescribed for acute pain by non-haemophilia treatment centres (HTCs); this indicates HTCs should primarily evaluate and manage pain (advocating non-opioid options) for PwH.39

Previous studies show PwHA, particularly those with haemophilic arthropathy, have an impaired HRQoL with negative impacts on multiple aspects of life, including physical health, social and sports activities, and education/employment.6 11 40 41 In our study, patients with HAJs had a significantly lower overall health status compared with those without HAJs, including a significant impact on the ability to perform usual activities (eg, work, study, housework, family or leisure). Other observational studies have reported the presence of ≥1 target joint, ≥1 problem joint or indicators of joint disease have a negative impact on HRQoL in PwH.5 13 37 Pain adds to the burden of disease and affects daily activities/ability to function for PwH.4

Key factors associated with joint health deterioration include age of first haemarthrosis, severe haemophilia, joint type, synovitis and increased joint bleeding.4244 In our study, physicians reported first signs of joint damage on average during the second decade of life. However, structural changes probably start much earlier, typically after the first haemarthrosis as children with severe haemophilia begin to crawl/walk;1 35 42 and ~90% will have developed joint disease in ≥1 major joint by 20–40 years of age.11 45 In exploratory analyses of joint health in moderate versus severe haemophilia, we found that patients with severe disease first presented with joint damage at an earlier age and had higher rates of moderate/severe joint problems and haemophilic arthropathy compared with those with moderate haemophilia.

This study provides real-world evidence reported by both physicians and patients, conducted over a 15-month period and collected using a standardised methodology (as part of the Haemophilia DSP Wave II). Other strengths include the identification of patients with moderate or severe haemophilia based on a confirmed diagnosis from experienced physicians and data are representative of clinical practice in Europe.

Limitations include the cross-sectional nature of the data, which cannot be used to demonstrate causality. The patient population consisted of successive patients presenting with haemophilia in physicians’ practices in Europe; therefore, the sample is not truly random, may not represent the overall haemophilia population and the results cannot be generalised outside Europe. Relatedly, the Haemophilia DSP Wave II also captured data from the USA, but these data were excluded from the current analysis due to overarching differences in healthcare systems versus the European countries,46 which could have biased the outcome data. As data collection overlapped the COVID-19 pandemic, the population may consist of a higher proportion of patients with severe haemophilia than otherwise expected. Physician-reported and patient-reported data used in the assessment of HAJs and outcome data may be subject to recall bias. The type of evaluation and the medical function who performed the examinations when assessing joint problems were not captured in the survey, but it likely varied across the different clinics. Data were not adjusted for multiple testing so any significant p values close to 0.05 should be handled with caution. The sample size for patient-reported data was smaller than for the physician-reported data, potentially because completion of the PSC form was voluntary and without formal physician follow-up. The number of joint bleeds during a 6-month period used to define a target joint (>3 bleeds) was slightly different from that used in treatment guidelines (≥3 bleeds);1 additional studies will be required to determine whether this difference had an impact on the study results. Finally, pain medication use may have been underestimated in our study due to the possible use of over-the-counter medications, which physicians were unaware of when completing the PRF for a patient. In addition, the potential use of postoperative (orthopaedic surgery) analgesia was not specifically captured in the PRF, but this may have overlapped with the pain medications already reported.

Conclusions

Overall, nearly two-thirds of adult patients with moderate or severe haemophilia A receiving prophylaxis had HAJs, predominantly of mild/moderate severity; first signs of joint damage were observed by the second decade of life. Individuals with HAJs were slightly older, had higher rates of pain and pain medication use, and lower HRQoL compared with those without HAJs. These data, which reflect current clinical practice in Europe, indicate that patients with moderate or severe haemophilia A without existing inhibitors experience HAJs despite current prophylaxis and that HAJs represent a clinically relevant burden for PwHA. Early identification/monitoring and management of affected joints should be an important consideration to help prevent long-term joint morbidity.http://creativecommons.org/licenses/by-nc/4.0/

supplementary material

10.1136/bmjopen-2023-082204 online supplemental file 1

Acknowledgements

The Haemophilia Disease Specific Programme Wave II is owned by Adelphi. Sobi and Sanofi reviewed and provided feedback on the content. The authors would like to thank Sarah Weatherby of Adelphi Real World for analysis of data and statistical support, and Tyrone Daniel of Genesis Medical Writing for medical writing support.

Data availability statement

Data are available on reasonable request.

Review Process File
6 9 2024

Funding: The study and medical writing support were supported by Sobi.

Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2023-082204).

Provenance and peer review: Not commissioned; externally peer reviewed.

Patient consent for publication: Not applicable.

Ethics approval: The DSP methodology (protocol number AG8709) was reviewed and approved by the Western Institutional Review Board. Patients who contributed data to the Adelphi Real World Haemophilia Disease Specific Programme Wave II provided informed consent and they had the right to opt out at any time. All collected data were aggregated and deidentified before receipt. All information provided by patients and physicians remained confidential and only reported when combined with other respondents’ data; consequently, physicians and patients could not be identified directly. Respondents were informed that all data collected will be saved for as long as it is needed for legitimate business purposes in accordance with applicable laws and regulations; the results may be analysed by academic researchers and analysts within pharmaceutical companies; and the results may be used for market research purposes and publication in scientific journals. As this was a retrospective analysis that used deidentified data previously collected, patient participants were not required to provide formal consent to release information forms for the current analyses; the original consent from those who provided data in the DSP covered the planned analyses in this study. Physicians received fair market value compensation for completing the PRFs. A small donation was made to a relevant charity on behalf of each patient who completed a PSC.

Data availability free text: All data that support the findings of this study are the intellectual property of Adelphi Real World. All requests for access should be addressed directly to KG at keisha.golden@adelphigroup.com.

Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
==== Refs
References

1 Srivastava A Santagostino E Dougall A et al WFH guidelines for the management of hemophilia, 3rd edition Haemophilia 2020 26 1 158 10.1111/hae.14046 32744769
2 Gualtierotti R Solimeno LP Peyvandi F Hemophilic arthropathy: Current knowledge and future perspectives J Thromb Haemost 2021 19 2112 21 10.1111/jth.15444 34197690
3 Di Minno MND Santoro C Corcione A et al Pain assessment and management in Italian Haemophilia Centres Blood Transfus 2021 19 335 42 10.2450/2020.0085-20 33263519
4 Auerswald G Dolan G Duffy A et al Pain and pain management in haemophilia Blood Coagul Fibrinolysis 2016 27 845 54 10.1097/MBC.0000000000000571 27439216
5 O’Hara J Walsh S Camp C et al The impact of severe haemophilia and the presence of target joints on health-related quality-of-life Health Qual Life Outcomes 2018 16 84 10.1186/s12955-018-0908-9 29720192
6 Curtis R Manco-Johnson M Konkle BA et al Comorbidities, health-related quality of life, health-care utilization in older persons with Hemophilia-Hematology Utilization Group Study Part VII (HUGS VII) J Blood Med 2022 13 229 41 10.2147/JBM.S354526 35585877
7 Stromer W Pabinger I Ay C et al Pain management in hemophilia: expert recommendations Wien Klin Wochenschr 2021 133 1042 56 10.1007/s00508-020-01798-4 33661391
8 Riley RR Witkop M Hellman E et al Assessment and management of pain in haemophilia patients Haemophilia 2011 17 839 45 10.1111/j.1365-2516.2011.02567.x 21645179
9 Gouw SC Timmer MA Srivastava A et al Measurement of joint health in persons with haemophilia: A systematic review of the measurement properties of haemophilia-specific instruments Haemophilia 2019 25 e1 10 10.1111/hae.13631 30427100
10 Rodriguez-Merchan EC Treatment of musculo-skeletal pain in haemophilia Blood Rev 2018 32 116 21 10.1016/j.blre.2017.09.004 28943040
11 Brown LJ La HA Li J et al The societal burden of haemophilia A. I - A snapshot of haemophilia A in Australia and beyond Haemophilia 2020 26 Suppl 5 3 10 10.1111/hae.14102
12 Chowdary P Nissen F Burke T et al The humanistic and economic burden of problem joints for children and adults with moderate or severe haemophilia A: Analysis of the CHESS population studies Haemophilia 2023 29 753 60 10.1111/hae.14766 36897517
13 Soucie JM Grosse SD Siddiqi AE et al The effects of joint disease, inhibitors and other complications on health‐related quality of life among males with severe haemophilia A in the United States Haemophilia 2017 23 e287 93 10.1111/hae.13275 28574229
14 Santoro C Di Minno MND Corcione A et al Improving assessment and management of pain in hemophilia: an Italian Delphi consensus statement Blood Rev 2022 51 100885 10.1016/j.blre.2021.100885 34544642
15 De la Corte-Rodriguez H Rodriguez-Merchan EC Chronic pain in haemophilia: assessment and analgesic treatment Blood Coagul Fibrinolysis 2023 34 S1 4 10.1097/MBC.0000000000001199 37254721
16 Gualtierotti R Tafuri F Arcudi S et al Current and emerging approaches for pain management in hemophilic arthropathy Pain Ther 2022 11 1 15 10.1007/s40122-021-00345-x 35020184
17 Khair K Pollard D Harrison C et al HOw Patients view Extended half-life products: Impressions from real-world experience (The HOPE study) Haemophilia 2019 25 814 20 10.1111/hae.13803 31365176
18 Peyvandi F Garagiola I Boscarino M et al Real‐life experience in switching to new extended half‐life products at European haemophilia centres Haemophilia 2019 25 946 52 10.1111/hae.13834 31418967
19 Brennan Y Parikh S McRae S et al The Australian experience with switching to extended half-life factor VIII and IX concentrates: On behalf of the Australian Haemophilia Centre Directors’ Organisation Haemophilia 2020 26 529 35 10.1111/hae.13970 32243027
20 Ay C Feistritzer C Rettl J et al Bleeding outcomes and factor utilization after switching to an extended half-life product for prophylaxis in haemophilia A in Austria Sci Rep 2021 11 12967 10.1038/s41598-021-92245-5 34155229
21 Callaghan MU Negrier C Paz-Priel I et al Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies Blood 2021 137 2231 42 10.1182/blood.2020009217 33512413
22 Barg AA Avishai E Budnik I et al Emicizumab prophylaxis among infants and toddlers with severe hemophilia A and inhibitors-a single-center cohort Pediatr Blood Cancer 2019 66 e27886 10.1002/pbc.27886 31348595
23 Barg AA Livnat T Budnik I et al Emicizumab treatment and monitoring in a paediatric cohort: real-world data Br J Haematol 2020 191 282 90 10.1111/bjh.16964 32656767
24 Levy-Mendelovich S Brutman-Barazani T Budnik I et al Real-world data on bleeding patterns of hemophilia A patients treated with emicizumab J Clin Med 2021 10 4303 10.3390/jcm10194303 34640320
25 Ebbert PT Xavier F Seaman CD et al Emicizumab prophylaxis in patients with haemophilia A with and without inhibitors Haemophilia 2020 26 41 6 10.1111/hae.13877 31746522
26 Warren BB Chan A Manco-Johnson M et al Emicizumab initiation and bleeding outcomes in people with hemophilia A with and without inhibitors: A single-center report Res Pract Thromb Haemost 2021 5 e12571 10.1002/rth2.12571 34377887
27 Valentino LA Kaczmarek R Pierce GF et al Hemophilia gene therapy: first, do no harm J Thromb Haemost 2023 21 2354 61 10.1016/j.jtha.2023.06.016 37353081
28 Schmidt DE Michalopoulou A Fischer K et al Long-term joint outcomes in adolescents with moderate or severe haemophilia A Haemophilia 2022 28 1054 61 10.1111/hae.14636 35925557
29 Anderson P Benford M Harris N et al Real-world physician and patient behaviour across countries: Disease-Specific Programmes - a means to understand Curr Med Res Opin 2008 24 3063 72 10.1185/03007990802457040 18826746
30 Herdman M Gudex C Lloyd A et al Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L) Qual Life Res 2011 20 1727 36 10.1007/s11136-011-9903-x 21479777
31 EuroQol Value sets. Available https://euroqol.org/information-and-support/resources/value-sets/
32 Manco-Johnson MJ Abshire TC Shapiro AD et al Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia N Engl J Med 2007 357 535 44 10.1056/NEJMoa067659 17687129
33 Warren BB Thornhill D Stein J et al Young adult outcomes of childhood prophylaxis for severe hemophilia A: results of the Joint Outcome Continuation Study Blood Adv 2020 4 2451 9 10.1182/bloodadvances.2019001311 32492157
34 Gringeri A Lundin B von Mackensen S et al A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study) J Thromb Haemost 2011 9 700 10 10.1111/j.1538-7836.2011.04214.x 21255253
35 Berntorp E Hermans C Solms A et al Optimising prophylaxis in haemophilia A: The ups and downs of treatment Blood Rev 2021 50 100852 10.1016/j.blre.2021.100852 34243987
36 Skinner MW Nugent D Wilton P et al Achieving the unimaginable: Health equity in haemophilia Haemophilia 2020 26 17 24 10.1111/hae.13862 31724316
37 Burke T Rodriguez-Santana I Chowdary P et al Humanistic burden of problem joints for children and adults with haemophilia Haemophilia 2023 29 608 18 10.1111/hae.14731 36574369
38 O’Hara J Khair K McLaughlin P et al “Problem Joint” a more patient relevant definition for joint morbidity in haemophilia Haemophilia 2019 25 35 188 Available https://onlinelibrary.wiley.com/doi/full/10.1111/hae.13666
39 Peltier SJ Mazepa MA Freese RL et al Opioid exposure in haemophilia patients is common and underreported Haemophilia 2020 26 251 6 10.1111/hae.13950 32100423
40 Fischer K de Kleijn P Negrier C et al The association of haemophilic arthropathy with Health-Related Quality of Life: a post hoc analysis Haemophilia 2016 22 833 40 10.1111/hae.13120 27785891
41 Schnohr C Ekholm O Poulsen LH et al Health and quality of life of patients with haemophilia: A national study of 124 Danish men Haemophilia 2023 29 538 44 10.1111/hae.14751 36729615
42 van Dijk K Fischer K van der Bom JG et al Variability in clinical phenotype of severe haemophilia: the role of the first joint bleed Haemophilia 2005 11 438 43 10.1111/j.1365-2516.2005.01124.x 16128885
43 Goren R Pullenayegum E Blanchette VS et al Patterns of joint damage in severe haemophilia A treated with prophylaxis Haemophilia 2021 27 666 73 10.1111/hae.14345 34015166
44 Kuijlaars IAR Timmer MA de Kleijn P et al Monitoring joint health in haemophilia: Factors associated with deterioration Haemophilia 2017 23 934 40 10.1111/hae.13327 28873289
45 Oldenburg J Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens Blood 2015 125 2038 44 10.1182/blood-2015-01-528414 25712992
46 Lamb CC Wolfberg A Lyytinen K UK vs US physician decision-making in the treatment of haemophilia Haemophilia 2019 25 616 25 10.1111/hae.13766 31056808
