Efficacy of rehabilitation interventions on functioning in patients with hemophilic arthropathy: A systematic review with meta-analysis

Abstract

BACKGROUND:

Hemophilic arthropathy is a detrimental condition that crucially affects functional outcomes in hemophilic patients. In recent years, due to the advances in systemic therapies, growing attention has been raised in the rehabilitation field in order to improve functional outcomes of hemophilic patients. However, the optimal rehabilitation modalities in these patients are far from being fully characterized.

OBJECTIVE:

The present study aimed to assess the effects of different rehabilitation interventions on physical functioning and health-related quality of life of hemophilic arthropathic patients.

METHODS:

The review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Five databases were systematically searched for randomized controlled trials (RCTs) published until June 22nd, 2023. The selection criteria included adult patients with hemophilia A and B receiving rehabilitation interventions. The outcomes were muscle strength, physical function, pain intensity, physical performance, and health-related quality of life.

RESULTS:

Out of 1,743 identified records, 17 studies were included in the qualitative synthesis. Rehabilitation interventions were categorized into exercise intervention, fascial therapy, and multimodal intervention. The findings suggested positive outcomes in terms of muscle modifications, range of motion improvements, joint health enhancements, pain intensity reduction, and quality of life improvements. More in detail, meta-analyses showed significant improvements in pain intensity [ES: $-$ 1.10 cm ( $-$ 1.37, $-$ 0.82), $p<$ 0.00001], joint health [ES: $-$ 1.10 ( $-$ 1.38, $-$ 0.82), $p<$ 0.00001], In accordance, exercise interventions showed significant benefits in terms of joint health [ES: $-$ 2.54 ( $-$ 3.25, $-$ 1.83), $p<$ 0.00001)] and quality of life [ES: 1.17 (0.48, 1.86), $p<$ 0.0000)].

CONCLUSION:

Rehabilitation interventions have a positive impact on functional outcomes and health-related quality of life of hemophilic arthropathic patients. Further studies are needed to better elucidate the role of a comprehensive intervention combining different rehabilitation approaches to treat hemophilic arthropathy.

Keywords

Hemophilia rehabilitation fascial therapy physical exercise muscle hemophilic arthropathy

1. Introduction

Hemophilia is an X-linked recessive disorder characterized by the deficit of coagulation factors VIII (hemophilia A) or coagulation factors IX (hemophilia B). The disease leads to blood coagulation impairment with a severity related to the percentage of active clotting factor [1]. Patients with hemophilia might complain frequent internal or external bleeding episodes that might be associated with major or minor traumas [2]. Interestingly, it has been estimated that approximately 85% of bleeding episodes might affect the musculoskeletal system, leading to intrafascial hematomas or hemarthrosis [3]. Frequent bleeding episodes in the joints might promote the onset of hemophilic arthropathy, a disabling disorder related to significant functional impairment and reduced independence of activity of daily living [4]. The mechanisms promoting this detrimental condition are strictly linked to the number of intra-articular recurrent hemorrhages, promoting synovial membrane inflammation, joint degeneration and joint pain [5, 6, 7].

As a result, inactivity is a common consequence of hemophilic arthropathy leading to periarticular muscle atrophy and joint instability, with detrimental consequences on skeletal muscle health of hemophilic patients [7, 8]. Moreover, recent reports underlined that functional impairment and reduced physical performance might significantly worsen social participation and independence in activities of daily living of these patients, with detrimental consequences on health-related quality of life (HR-QoL) [9, 10, 11, 12].

Rehabilitation might play a pivotal role in preventing or minimizing musculoskeletal issues of hemophilic arthropathy [3, 13]. Recent research highlighted that physical exercise might significantly improve physical and psychosocial well-being of hemophilic patients with potential positive implications also in terms of improvement of muscle trophism and reduction of joint bleeding [14, 15, 16]. Several rehabilitation techniques have been proposed for the correct rehabilitative management of hemophilic arthropathic patients, including aerobic training, strength training, proprioceptive and balance training and mobilization techniques [17, 18, 19, 20]. Although several rehabilitation approaches have been recently suggested, the optimal rehabilitation strategy to counteract musculoskeletal consequences of hemophilic arthropathy is far from being fully characterized. Interestingly, the recent systematic review by Pacheco-serrano et al. [21] assessed the effectiveness of physical rehabilitation intervention in patients with hemophilic arthropathy, reporting promising results in different physical outcome measures. However, only two studies were included in the meta-analysis and quantitative data were reported only for skeletal muscle pain. Thus, to the best of our knowledge, no previous meta-analysis assessed the multidimensional effects of different rehabilitation strategies on hemophilic arthropathic patients.

Therefore, the present systematic review of randomized controlled trials aimed at summarizing the current evidence about the impact of different rehabilitation interventions on functional and HR-QoL outcomes in hemophilic arthropathic patients. This could provide clinically useful indications to guide clinicians in the precise prescription of an evidence-based rehabilitation plan to treat this burdensome and highly disabling condition.

2. Methods

2.1 Registration and search strategy

This systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement [22]. The study protocol has been prospectively submitted before study initiation to the international prospective register of systematic reviews (PROSPERO) and was accepted with registration number CRD42023389366.

Five different databases were systematically searched for RCTs published until June 22^nd, 2023 by two different reviewers independently. More in detail, PubMed, Scopus, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and PEDro were searched adopting the search strategies shown in Supplementary Table 1. Lastly, reference lists of relevant studies were screened for any other RCT potentially eligible and not retrieved by the search strategy. The reference list screening was performed by two different reviewers independently.

2.2 Selection criteria

After duplicate removal, two authors (LL, AT) screened the resulting studies for title and abstract. The agreement was achieved by discussion between the two authors, or by consulting a third author (AdS) if consensus was not achieved. The studies potentially eligible were screened in full-text by the same two Authors. In accordance, if a consensus was not achieved by collegial discussion, the discrepancy was solved by a third author (AdS).

According to the PICO model [23], we considered for eligibility the studies to meet the following criteria:

P) Participants: adult patients (age $\geqslant$ 18 years old) with hemophilia A and B;

I) Intervention: rehabilitation intervention including physical exercise, fascial therapy, physical therapies, and educational interventions, alone or combined with other therapies;

C) Comparator: any comparator, including no treatment, placebo, or other pharmacological or non-pharmacological treatments;

O) Outcomes: skeletal muscle modifications (in terms of muscle strength, function, and mass), joint pain, physical function, physical performance, and HR-QoL.

We considered only RCTs in English language published in peer-reviewed international journals. On the other hand, the studies were excluded if: a) language was other than English; b) study design was different from RCTs; c) the study assessed animal models; d) participants with other pathological conditions potentially affecting functional outcomes; e) other treatments than rehabilitation assessed as main intervention.

2.3 Data extraction and synthesis

Two authors (LL, AT) performed independently full-text assessments and data extraction. Any disagreements were solved by discussion between the two authors. A third author (AdS) was asked in case of further disagreement.

The following data were extracted: 1) title; 2) authors; 3) publication year; 4) nationality; 5) participants (number, mean age and age range, gender, body mass index - BMI); 6) interventions’ characteristics; 7) comparator; 8) study results.

The data were synthesized by two independent authors (LL, AT) from full-text articles. Any disagreement between the two authors was solved by discussion or asking a third author (AdS). Data were synthesized in the main text and tables to provide a qualitative summary and explanation of study characteristics and findings. A specific subgroup analysis was performed based on the rehabilitation treatment assessed by the study included.

2.4 Quality assessment and risk of bias

The quality of the RCTs included was assessed by two of the authors (LL, AT) independently, according to the Jadad scale [24]. Discordance between the two authors was resolved collegially among the research team. The Jadad scale is composed of five items, with a total score ranging from zero to five, The items assessed were the following: a) random sequence generation; b) appropriate randomization; c) blinding of participants or personnel; d) blinding of outcome assessors; e) withdrawals and dropouts. A Jadad score between three to five points was considered high quality.

The risk of bias was assessed by the Cochrane risk-of-bias tool for randomized trials (RoBv.2) [25]. Bias was classified as low, high, or unclear based on the item of the RoBv.2. In particular, the following domains were assessed by RoBv.2: a) randomization process; b) deviations from the intended interventions; c) missing outcome data; d) measurement of the outcome; e) selection of the reported result.

Figure 1.

From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372: n71. doi: 10.1136/bmj.n71. For more information, visit: http://www.prisma-statement.org/.

3. Results

3.1 Study characteristics

Altogether, 1,743 records were identified from the 5 databases. After duplication removal, 998 studies were assessed for eligibility and screened for title and abstract. Therefore, 952 records were excluded, and 46 full-text studies were screened. Subsequently, 29 articles were excluded for inconsistency with the eligibility criteria. Supplementary Table 2 reported the list of excluded studies along with the reasons for exclusion. Lastly, 17 studies [26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42] were included in the qualitative synthesis. Further details of the search process are shown in the PRISMA flow diagram depicted in Fig. 1. The studies included in this systematic review were published between 2014 [27, 41, 42] and 2022 [29, 31, 36, 37, 40].

The mean age of the subjects included ranged from 24.5 (IQR 9) years [34] to 46.79 $\pm$ 4.42 years [37]. Parhampour et al. [41] did not report the age of the participants included, but only reported the range of age in the inclusion criteria (20–35 years).

It should be noted that Runkel et al. [38] and Tat et al. [34] did not characterize the participants included in the analysis for the type of hemophilia. As a result, based on the remaining 583 participants, the sample of the present study was composed of 503 patients with hemophilia A and 80 with hemophilia B. On the other hand, only the study of Runkel et al. [38] did not characterize hemophilia severity. As a result, based on the remaining 600 participants, the sample was composed of 466 patients with severe hemophilia, 112 patients with moderate hemophilia, and 22 patients with mild hemophilia.

Table 1
Main characteristics of the studies included

Abbreviations: BB: Biceps Brachii; BMI: body mass index; CG: Control group; CT: Combined training; ET: endurance training; HAL: Haemophilia Activities List; HEP-Test-Q: Questionnaire for the assessment of subjective physical functioning; HAEM-A-QoL: disease-specific health-related quality of life; HJHS: Haemophilia Joint Health Score; IG: Intervention group; MG: Medial Gastrocnemius; MHR: maximum heart rate; MT: Muscle Thickness; PA: Pennation Angle; RM: repetition maximum; RPE: rate of perceived exertion; SF-36: Short Form Health Survey-36; ST: strength training; TB: Triceps Brachii; VM: Vastus Medialis; VL: Vastus Lateralis.

Table 2

Main characteristics of the studies included

Abbreviations: BMI: body mass index; CG: Control group; IG: Intervention group; ROM: range of motion; SF-36: Short Form Health Survey-36.

Table 3

Main characteristics of the studies included with two intervention groups

Abbreviations: CG: Control group; FISH: Functional Independence Score in Hemophilia; HJHS: Haemophilia Joint Health Score; IG: Intervention group; IQR: interquartile range; QoL: quality of life; ROM: range of motion.

In 14 studies (82.4%) [26, 27, 28, 29, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40] the rehabilitation intervention was compared to usual daily activities. In contrast, 2 RCTs compared 2 different intervention groups [27, 34], 2 studies [27, 28] assessed the effects of two different intervention groups compared to a control group, and 1 study assessed the effects of three different intervention groups compared to a control group [41]. The characteristics of these studies are presented in detail in Tables 1, 2, and 3.

3.2 Intervention characteristics

We summarized the different rehabilitation interventions into exercise intervention, fascial therapy and multimodal intervention. More in detail, exercise intervention was characterized as resistance training (RT), combined training (CT), home-based exercise program, and Programmed Sports Therapy (PST). Fascial therapy was characterized by mobilization techniques, joint traction techniques, gliding techniques, passive muscle stretching, and myofascial release techniques. Lastly, multimodal interventions were characterized by the combination of different types of rehabilitation interventions.

3.2.1 Physical exercise

Exercise intervention:

Resistance training (RT): four studies [35, 36, 37, 41] assessed the effects of RT. The exercise intensity was tailored to subject characteristics, based on the Repetition Maximum (RM) method [35, 36, 37, 41]. The duration of the training protocols ranged from 6 [37, 41] to 8 [35, 36] weeks, with a training frequency that ranged from 2 [35, 36] to 3 [37, 41] sessions/week. The exercise volume ranged from 1 [37, 41] to 3 [35, 36] sets.

Combined training (CT): was assessed in the study of Parhampour et al. [37] combining both aerobic and RT, while two studies [38, 39] assessed the effects of Programmed Sports Therapy, consisting of CT in supervised groups. More in detail, programs included strength training, mobility, and endurance exercises.

Home exercise program: two studies [32, 34] assessed the effects of home exercise programs performed alone without a combination with any type of other treatment.

3.2.2 Fascial therapy

Six studies [26, 29, 30, 31, 33, 40] assessed fascial therapy considering different types of intervention: mobilization techniques, joint traction techniques, gliding techniques, passive muscle stretching and myofascial release techniques. In the study of Cuesta-Barriuso et al. [26] the fascial therapy protocol included knee joint traction in knee flexion and extension, gliding techniques towards knee flexion and extension and passive muscle stretching of the quadriceps and hamstrings muscles. In the remaining 4 studies performed by Cuesta-Barriuso et al. [29, 30, 31] and Donoso-Úbeda et al. [33], the effects of specific fascial therapy combined with usual fascial therapy treatment were assessed.

In the study of Donoso-Úbeda et al. [32], the protocol included 4 superficial maneuvers, while in the study of Pérez-Llanez et al. [40], the protocol included superficial and deep maneuvers. The frequency of the fascial therapy sessions ranged from 1 [29, 30, 31, 33, 40] to 2 [26] sessions/week, with a protocol duration ranging from 3 [29, 30, 31, 33, 40] to 12 [26] weeks. The duration of session ranged from 45 [33, 40] to 60 [26] minutes.

3.2.3 Multimodal rehabilitative intervention

Multimodal rehabilitative intervention was assessed in 5 studies [27, 28, 34, 41]:

Mobilization techniques $+$ exercise intervention: was assessed in the study by Cuesta-Barriuso et al. [27]. The study protocol included superficial thermotherapy, passive mobilizations, resisted exercises, active stretching, proprioception exercises with open and closed eyes and cryotherapy. The frequency of the treatment sessions was 2 sessions/week, with a protocol duration of 6 weeks. The duration of session was 60 minutes.

Pulsed electromagnetic fields + exercise intervention: were assessed in the study of Parhampour et al. [41]. The study protocol included for the intervention group pulsed electromagnetic fields (PEMF) combined with RT. Exercise intervention consisted of 10 repetitions for each exercise for lower and upper limbs, with an intensity of 50–60% 1RM, for 30–40 minutes. The frequency of this protocol was 1 session/week.

Educational sessions $+$ exercise intervention: was assessed in 2 studies [27, 28], with similar rehabilitation protocols including stretching, isometric and isotonic exercises, proprioceptive exercises, aerobic exercises, active exercises for mobility, and educational sessions. The frequency of the treatment sessions was 7 sessions/week [27, 28], and the frequency of the educational sessions was 1 session every two weeks [27, 28]. The protocol duration was 12 weeks [27, 28]. The duration of session was 60 minutes.

Fascial therapy $+$ exercise intervention combination was assessed in 4 studies [27, 28, 34], and the protocols included superficial thermotherapy, joint tractions, active exercise of strength with thera band, passive muscle stretching, isometric and resisted exercises, soft tissue mobilizations, mulligan’s mobilization, proprioception exercises with open and closed eyes, and cryotherapy. The frequency of the treatment sessions ranged from 2 [27, 28] to 3 [34] sessions/week, and the protocol duration ranged from 5 [34] to 12 [27, 28] weeks.

All rehabilitation programs assessed in the present systematic review have been summarized in detail in Tables 1, 2, and 3.

3.3 Main findings

3.3.1 Muscle modifications

The effects of the different interventions on muscle modifications were assessed in terms of: a) muscle strength; b) muscle architecture; c) muscle circumference.

Muscle Strength: Calatayud et al. [35] assessed muscle strength with a portable hand-held dynamometer (Nicholas Manual Muscle Tester, Lafayette Instruments, Lafayette, IN, USA) with tests performed against a fixed resistance. In particular, the study showed significant strength improvements in patients performing RT protocols in terms of right-elbow flexion ( $p=$ 0.019), left-elbow extension ( $p=$ 0.015), right-elbow extension ( $p=$ 0.001), left-knee extension ( $p=$ 0.002), right-knee extension ( $p<$ 0.0001), and left-knee flexion ( $p<$ 0.0001) [35]. On the other hand, in the study of Parhampour et al. [37] muscle strength was assessed by 10-RM, showing significant improvements in muscle strength in the RT and CT groups compared to the controls ( $p<$ 0.001). Moreover, the study conducted by Runkel et al. [38] assessed maximal complex isometric strength performance by a mobile strength sensor (KD 9363 including DMS measuring amplifier GVS-2 from ME-measuring systems GmbH, Hennigsdorf, Germany). The authors reported significant improvement in triceps brachii ( $p\leqslant$ 0.0001), the biceps brachii ( $p\leqslant$ 0.0001), the latissimus dorsi ( $p\leqslant$ 0.0001), rectus abdominis ( $p\leqslant$ 0.0001), the biceps femoris ( $p=$ 0.001) and the quadriceps femoris (right: $p=$ 0.003 and left: $p=$ 0.001) in patients performing the PST program. In the study of Tat et al. [34] knee flexors and extensors were assessed by applying resistance over the malleolus with a digital dynamometer in a sitting position with hip and knee in 90^∘ flexed position. The authors reported significant improvements in the strength of plantar flexors in the group that followed fascial therapy & exercise protocol ( $p<$ 0.05), compared to the home exercise group.

Muscle architecture: only one study [37] assessed muscle architecture modifications induced by RT or CT protocols in hemophilic patients. In particular, it assessed muscle thickness and muscle pennation of vastus medialis (VM), vastus lateralis (VL), medial gastrocnemius (MG), biceps brachii (BB) and triceps brachii (TB) through musculoskeletal ultrasonography. The authors reported that the main finding is the significant increase in muscle thickness and pennation angle of VM, VL, and MG in both RT and CT groups ( $p\leqslant$ 0.001). Compared to the control group, significant increases were observed in the muscle thickness and muscle pennation angle of BB and TB in the RT group and the muscle thickness of BB and TB in the CT group ( $p\leqslant$ 0.001).

Muscle circumference: in two studies [27, 42] gastrocnemius muscle circumference was measured through a tape measure placed in the middle of the muscular belly of the gastrocnemius circumference. Moreover, in another study [28], the arm perimeter was assessed by a tape measure that was placed in the middle of the muscular belly of the biceps brachii. The fascial therapy & exercise treatment significantly improved the gastrocnemius muscle circumference ( $p<$ 0.05) [27, 42], while the circumference of the arm did not change significantly after both treatments [28].

Taken together, these findings suggested that rehabilitation interventions in hemophilic patients might provide significant effects in terms of muscle modifications. In particular, positive outcomes were reported in terms of muscle strength across various muscle groups, modifications in muscle architecture and muscle circumference improvements in lower legs. Further details are shown in Tables 1, 2, and 3.

3.3.2 Range of motion

Range of motion modifications after rehabilitation were assessed in 6 studies [26, 27, 28, 31, 34, 35]. More in detail, in the study of Calatayud et al. [35], the intervention group reported a statistically significant improvement in knee flexion ROM ( $p=$ 0.021) compared to the control. Moreover, in the study of Cuesta-Barriuso et al. [26], patients in the intervention group showed significant improvements in knee flexion ROM ( $p<$ 0.001) and loss of extension ( $p<$ 0.001). On the other hand, the study of Cuesta-Barriuso et al. [31] assessed the effect of fascial therapy on the elbow joint flexion and extension ROM, reporting significant differences ( $p<$ 0.001) in the repeated measures analysis. The study of Cuesta-Barriuso et al. [27] compared the effects of fascial therapy & exercise protocol with mobilizations & exercise protocol, showing that both treatments significantly improved ankle plantar and dorsal flexion, eversion, and inversion ROM ( $p<$ 0.05). In addition, the study of Cuesta-Barriuso et al. [28] analyzed the effect of fascial therapy & exercise, educational sessions and home exercise protocols on the elbow ROM. The authors reported significant improvements in elbow flexion ( $p=$ 0.022) following the fascial therapy & exercise protocol, while there were no significant changes after the educational sessions and home exercises protocol. In one study [34] the elbow range of motion was assessed to determine the effects of fascial therapy & exercises compared to home exercise protocols. In the study of Tat et al. [34], the authors reported significant improvements in the fascial therapy & exercise group in ankle ROM ( $p<$ 0.05). In the study by Pérez-Llanes et al. [40] the IG showed significant improvements in flexion ( $p<$ 0.01) of the right elbow, following fascial therapy.

In conclusion, rehabilitation interventions showed a significant improvement in ROM across multiple joints. Knee and elbow flexion ROM showed consistent improvement after the rehabilitation intervention. Fascial therapy and exercise protocols yielded positive outcomes on ankle and elbow ROM, emphasizing the positive impact of rehabilitation interventions on joint mobility. Further details are shown in Tables 1, 2, and 3.

3.3.3 Joint health

Joint health and joint status were assessed in 10 studies [26, 29, 30, 33, 34, 35, 37, 38, 40, 41]. In particular, in the study of Calatayud et al. [35] the Hemophilia Joint Health Score 2.1 (HJHS 2.1) was used to evaluate joint health in patients performing an RT protocol. The results showed significant improvements in HJHS 2.1 ( $p=$ 0.027). Moreover, the study of Parhampour et al. [37] reported a significant decrease in HJHS 2.1 score in CT and RT groups ( $p<$ 0.001). In accordance, four studies [26, 29, 30, 33] showed significant changes in joint status ( $p<$ 0.001) assessed by HJHS 2.1 after fascial therapy rehabilitation treatments. In addition, the study of Pérez-Llanes et al. [40] reported significant improvements in joint condition ( $p=$ 0.04) of the right elbow, assessed with HJHS 2.1 score, in IG treated with fascial therapy.

In one study [34], joint health was assessed to determine the effects of fascial therapy & exercises compared to home exercise protocols. In this study [34] fascial therapy & exercise protocols improved significantly the HJHS 2.1 score compared to home exercise programs ( $p<$ 0.05). In the study of Parhampour et al. [41] the Modified Colorado Hemophilia Pediatric Physical Examination Scale [43] was used to evaluate joint health in patients performing an RT protocol or RT combined with pulsed electromagnetic fields. After the six-week intervention, the total score of the modified Colorado Questionnaire (for all joints of the right and left sides) was significantly improved in the RT and RTPEMF groups compared with the PEMF alone and control groups ( $p\leqslant$ 0.05). This score was significantly improved ( $p\leqslant$ 0.05) in both ankles and the right knee in the PEMF group but only the right knee showed a significant improvement ( $p\leqslant$ 0.05) compared with the control group.

Lastly, in the study conducted by Runkel et al. [38], joint health was assessed with the orthopedic joint score developed by Gilbert [44]. In this study, there were reported significant differences in the right knee joint score ( $p=$ 0.048) in the PST group.

Overall, rehabilitation interventions showed consistent improvements on joint health and joint function. A Decrease in HJHS 2.1 scores and positive changes in joint condition were observed across multiple studies. These findings support the effectiveness of fascial therapy, resistance training and comprehensive rehabilitation treatments in enhancing joint health and improving the overall joint function. Further details are shown in Tables 1, 2, and 3.

3.3.4 Pain intensity

Pain intensity was assessed in 11 studies [26, 27, 28, 29, 30, 32, 33, 34, 35, 41, 42]. In particular, Cuesta-Barriuso et al. [32] reported significant improvements in terms of Visual Analogue Scale (VAS) ( $p=$ 0.007) after a home exercise protocol combined with an educational program.

Moreover, significant changes in terms of VAS were reported after fascial therapy ( $p<$ 0.001) [29, 33], fascial therapy ( $p<$ 0.05) [27, 28], fascial therapy combined with passive stretching protocol ( $p<$ 0.001) [26] and fascial therapy combined with fascial release ( $p<$ 0.001) [30].

In two studies [34, 42], pain intensity was assessed to determine the effects of fascial therapy & exercises compared to home exercise protocols, reporting significant decrease in VAS score ( $p<$ 0.05) in the fascial therapy & exercise program group. In the study by Pérez-Llanes et al. [40] the IG showed significant pain reduction assessed with VAS score of both elbows ( $p<$ 0.01 and $p=$ 0.03, in right and left elbow, respectively) after fascial therapy treatment.

Lastly, in the study of Calatayud et al. [35] the patient’s global impression of pain modification was evaluated by asking the following question: “Since the start of the study, my overall pain status is”: (1) very much improved, (2) much improved, (3) minimally improved, (4) no change, (5) minimally worse, (6) much worse, and (7) very much worse. The results showed a significantly greater overall pain reduction ( $p=$ 0.037) after the RT protocol.

Taken together, these findings suggested that rehabilitation interventions might lead to a significant improvement on joint pain intensity after home exercise programs, fascial therapy, fascial therapy and passive stretching protocol in hemophilic patients. Further details are shown in Tables 1, 2, and 3.

3.3.5 Quality of life

Quality of life was assessed in 6 studies [27, 29, 32, 35, 36, 39]. In particular, Cuesta-Barriuso et al. [32] reported positive significant differences ( $p<$ 0.05) of the A36 Hemophilia-QoL questionnaire and the Illness Behavior Questionnaire (IBQ) after a home exercise program combined with an educational session program. In accordance, Cruz-Montecinos et al. [36] reported significant improvements ( $p=$ 0.015) in the A36 Hemophilia-QoL questionnaire after a resistance exercise program. Similarly, passive mobilization & exercise protocol was assessed by Cuesta-Barriuso [27], reporting significant improvements ( $p<$ 0.05) in terms of the A36 Hemophilia-QoL questionnaire after this intervention.

Interestingly, Runkel et al. [39] assessed generic health-related quality of life by the Short Form-36 Health Survey (SF-36), and the hemophilia-specific health-related quality of life by the Haem-A-QoL. A significant difference in the domains ‘general health perceptions’ ( $p=$ 0.005) and ‘mental health’ ( $p=$ 0.001) was detected between the IG (performing PST) and the CG intervention.

Similarly, Cuesta-Barriuso et al. [29] reported significant improvements in terms of physical and mental domains of the SF-36 ( $p<$ 0.001).

Lastly, in the study of Calatayud et al. [35] general health status was evaluated on a 3-point scale of “worsened”, “unchanged”, or “improved”. The authors reported a significant improvement in self-rated overall status ( $p=$ 0.037) after an RT protocol.

Altogether, rehabilitation interventions might have a positive impact on the quality of life assessed by different questionnaires in these patients. Positive changes were reported on physical and mental domains, general health perceptions, and overall health status, suggesting a beneficial impact of rehabilitation on quality of life in hemophilic patients. Further details are shown in Tables 1, 2, and 3.

3.3.6 Physical function

Physical function was assessed in 7 studies [31, 34, 35, 36, 37, 38, 39]. In particular, the study by Cuesta-Barriuso et al. [31] reported significant improvements ( $p<$ 0.001) in terms of Disabilities of Arm, Shoulder and Hand (DASH) questionnaire after fascial therapy.

Similarly, Tat et al. [34] showed significant improvements ( $p<$ 0.05) in terms of the Functional Independence Score in Hemophilia (FISH) only in fascial therapy & exercise group.

In the study of Calatayud et al. [35], the Timed Up and Go (TUG) and the sit-to-stand (STS) tests were used to measure functional capacity of these patients. The author reported a significant improvement in TUG and STS tests ( $p=$ 0.009 and $p=$ 0.006, respectively) in hemophilic patients performing RT.

Moreover, the study by Cruz-Montecinos et al. [36] showed significant improvements ( $p=$ 0.006) in terms of functional abilities assessed by the Hemophilia Activities List (HAL) after an RT intervention.

In the study by Parhampour et al. [37], significant improvements were reported in the 42-item hemophilia activities list (HAL) for both the RT and CT groups ( $p<$ 0.001). No significant differences were observed between the intervention groups.

In the two studies by Runkel et al. [38, 39], the effects of PST on physical functional capacity were assessed. In one study [38], walking capacity was investigated with the 12-min walking test, and balance was evaluated with the one-leg stand test. The results showed an increase in the distance covered in the 12-min walking test ( $p=$ 0.011) in the IG group. Regarding the one-leg stand test, a significant improvement ( $p=$ 0.037) was observed in the IG after the intervention.

Lastly, the study by Runkel et al. [39] assessed the perceived functionality using the Subjective physical performance (HEP-Test-Q). The authors reported significant improvements in ‘endurance’ ( $p<$ 0.0001) in IG, in the HEP-Test-Q compared to the CG.

Overall, rehabilitation interventions showed significant improvement on physical function, functional capacity, mobility, functional abilities and perceived functionality, assessed by different outcome measures. Further details are shown in Tables 1, 2, and 3.

3.3.7 Frequency of hemarthrosis

Figure 2.

Forest plot comparing Fascial Therapy to Control in terms of pain intensity (VAS).

Figure 3.

Forest plot comparing Fascial Therapy to Control in terms Hemophilia Joint Health Score 2.1 (HJHS 2.1).

Four studies [26, 30, 31, 33] assessed the frequency of hemarthrosis. In the study of Cuesta-Barriuso et al. [26], the frequency of hemarthrosis was significantly different after fascial therapy intervention combined with passive stretching compared to control group ( $p<$ 0.001). Three studies [30, 31, 33] assessed the effects of fascial therapy on the frequency of hemarthrosis. In particular, the study by Cuesta-Barriuso et al. [30], reported significant changes in the repeated measures factor in the frequency of hemarthrosis ( $p<$ 0.001). The authors found a group interaction in the frequency of hemarthrosis ( $p<$ 0.001), and there were significant changes ( $p<$ 0.01) in the pairwise comparison analysis between the pretreatment assessment and the posttreatment and follow-up assessments. In addition, the study by Cuesta-Barriuso et al. [31], reported significant differences ( $p<$ 0.001) in the repeated measures analysis for frequency of elbow clinical hemarthrosis, and significant group interaction ( $p<$ 0.001). Moreover, the study by Donoso-Úbeda et al. [33], reported significant improvements ( $p<$ 0.001) in the frequency of joint bleeding at baseline, after 3 weeks of treatment, and after 5 months of follow-up in the IG, compared to the control group. Moreover, there was a significant improvement in the experimental group after follow-up compared to the baseline in frequency of bleeding ( $p<$ 0.001).

In conclusion, rehabilitation interventions showed a significant effect in reducing the frequency of hemarthrosis in hemophilic patients. Further details are shown in Tables 1, 2, and 3.

3.4 Meta-analysis

According to the Cochrane Handbook for Systematic Review of Intervention [45], a meta-analysis has been performed only for homogeneous studies in terms of samples, interventions and outcomes.

A significant improvement was highlighted in adult patients treated with fascial therapy in terms of pain intensity. More in detail, an overall significant MD% decrease was underlined in the quantitative syntheses after fascial therapy intervention [ES: $-$ 1.10 cm ( $-$ 1.37, $-$ 0.82), $p<$ 0.00001]. Figure 2 shows further details of the meta-analysis.

In accordance, a meta-analysis was performed to assess the effects of fascial therapy in terms of joint health assessed by the HJHS 2.1. The results of the meta-analysis showed an overall significant MD% improvement in joint health [ES: $-$ 1.10 ( $-$ 1.38, $-$ 0.82), $p<$ 0.00001]. See Fig. 3 for further details.

Figure 4.

Forest plot comparing Exercise Therapy to Control in terms of the Haemophlia Joint Health Score 2.1 (HJHS 2.1).

Moreover, exercise training therapy showed similar benefits in terms of HJHS 2.1. It should be noted that the study by Parhampour et al. [37] assessed 2 different exercise training therapy interventions compared with a control group. Thus, the effects of both interventions were included in the meta-analysis. The results of the quantitative analysis showed an overall significant MD% decrease in HJHS 2.1 score [ES: $-$ 2.54 ( $-$ 3.25, $-$ 1.83), $p<$ 0.00001)] in adult patients with emophilia receiving exercise training therapy (Fig. 4).

Figure 5.

Forest plot comparing Exercise Therapy to Control in terms of Quality of Life (A36 Hemofilia-QoL).

Lastly, significant benefits were shown in terms of quality of life assessed by the A36 Hemophilia-QoL questionnaire, showing an overall significant MD% improvement score [ES: 1.17 (0.48, 1.86), $p<$ 0.0000)]. For further details see Fig. 5.

Figure 6.

Risk of bias of the included studies according to the RoB2.

3.5 Quality assessment and risk of bias

According to the Jadad scale [22], 16 studies (94.1%) of the RCTs included [26, 27, 38, 40, 41] resulted of high-quality, while only one resulted of low-quality [39]. Table 2 shows in detail the score of each subitem of the Jadad scale for the RCTs included.

The risk of bias was assessed by the RoBv.2 [23]. The process showed that 12 studies (70.6%) [26, 27, 28, 29, 32, 34, 35, 36, 37, 38, 39, 41] ensured correct randomization, while 5 [27, 30, 31, 33, 40] studies showed some concerns in this item due to baseline group differences. Six studies [33, 34, 38, 39, 40, 41] (35.3%) showed some concerns in the fourth domain due to the lack of details about the blinding of the study operators and assessors. All studies ( $n=$ 17, 100%) showed a low risk of bias in missing outcome data and deviations from the intended interventions domain [26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41]. See Fig. 6 for further details.

4. Discussion

Rehabilitation is a cornerstone in the therapeutic management of functional decline related to hemophilic arthropathy, a burdensome condition leading to increased disability and poor HR-Qol [9, 10, 11, 12]. However, to date, the optimal rehabilitation approach to manage adult hemophilic patients is far from being completely understood and several rehabilitative interventions have been proposed to treat these patients.

In light of these considerations, the present meta-analysis assessed the effectiveness of different rehabilitation approaches in terms of skeletal muscle modifications, muscle strength, functional performance, pain intensity, and HR-QoL.

Interestingly, the meta-analysis showed significant benefits of fascial therapy in terms of pain intensity [ES: $-$ 1.10 cm ( $-$ 1.37, $-$ 0.82), $p<$ 0.00001]. Joint pain is one of the most common symptoms affecting physical function and quality of life of patients with emophilia [46]. Interestingly, VAS improvement underlined by this meta-analysis reached the minimum detectable change (MDC) of VAS score, lasting 0.08 cm [47]. However, the improvements were far from being over the minimum clinically important difference (MCID) lasting at 3.0 cm [48]. Despite fascial therapy techniques employed across the six studies [26, 29, 30, 31, 33, 40] included different maneuvers and treatment durations, clinicians should be aware that fascial therapy alone might be not enough in the management of joint pain in patients with hemophilic arthropathy. Thus, a comprehensive intervention should be considered to provide clinically important benefits in patients with emophilia.

However, our findings showed a significant improvement in joint health assessed by HJHS 2.1 [ES: $-$ 1.10 ( $-$ 1.38, $-$ 0.82), $p<$ 0.00001]. In accordance, it has been proposed that fascial therapy might improve joint status through different mechanisms, including modulation of the autonomic nervous system and improvement of nitric oxide plasma levels, and consequent increased tissue vascularization [49, 50]. Despite these considerations, our quantitative synthesis showed significant improvements in HJHS 2.1 after physical exercise intervention, with a greater MD% change [ES: $-$ 2.54 ( $-$ 3.25, $-$ 1.83), $p<$ 0.00001)]. These results are in line with growing research focusing on the multicomponent effect of physical exercise intervention modulating inflammation biomarkers [51, 52], bone turnover biomarkers [53], bioenergetics and oxidative response [54, 55], and pain sensitivity [56]. As a result, is not surprising that joint health can be significantly affected by physical exercise interventions. In addition, several RCTs included in the present review underlined that physical exercise might be effective in improving muscle strength [34, 35, 37, 38], muscle quality [37], and muscle mass [27, 28].

Table 4
Quality assessment of the studies included in the present systematic review

Articles	Domain					Score
	Random sequence generation	Appropriate randomization	Blinding of participants or personnel	Blinding of outcome assessors	Withdrawals and dropouts
Calatayud et al. 2020	1	1	0	1	1	4
Cruz-Montecinos et al. 2022	1	1	0	1	1	4
Cuesta-Barriuso et al. 2014 (1)	1	0	0	1	1	3
Cuesta-Barriuso et al. 2014 (2)	1	1	0	1	1	4
Cuesta-Barriuso et al. 2017	1	1	0	1	1	4
Cuesta-Barriuso et al. 2018	1	1	0	1	1	4
Cuesta-Barriuso et al. 2020	1	1	0	1	1	4
Cuesta-Barriuso et al. 2021	1	1	0	1	1	4
Cuesta-Barriuso et al. 2022 (1)	1	1	0	1	1	4
Cuesta-Barriuso et al. 2022 (2)	1	1	0	1	1	4
Donoso-Úbeda et al. 2020	1	1	0	0	1	3
Pérez-Llanes et al. 2020	1	1	0	0	1	3
Parhampour et al. 2014	1	1	0	0	1	3
Parhampour et al. 2022	1	1	0	1	1	4
Runkel et al. 2016 (1)	1	1	0	0	1	3
Runkel et al. 2016 (2)	1	0	0	0	1	2
Tat NM et al. 2021	1	1	0	0	1	3

Points were awarded as follows: study described as randomized, 1 point; appropriate randomization, 1 point; subjects blinded to intervention, 1 point; evaluator blinded to intervention, 1 point; description of withdrawals and dropouts, 1 point.

Lastly, the meta-analysis showed significant results in terms of quality of life, supporting the positive benefits of physical exercise interventions [ES: 1.17 (0.48, 1.86), $p<$ 0.0000)]. On the other hand, the exercise programs varied significantly in terms of type, intensity, duration, and frequency as shown in Table 1, which may limit the ability to draw definitive conclusions about the comparative effectiveness of the interventions.

Unfortunately, to date, no data comparing exercise therapy to fascial therapy alone were available thus a meta-analysis comparing these two different rehabilitation interventions was not performed. On the other hand, the study by Tat et al. [34] showed a significant improvement in patients treated with a multimodal intervention including both fascial therapy and exercises in terms of HJHS 2.1 score compared to home exercise program alone.

Taken together, these findings suggested that a comprehensive rehabilitation program including a multicomponent intervention might be the best option to improve joint health in hemophilic adult patients.

These results are in line with previous systematic reviews suggesting promising effects of different rehabilitation interventions in hemophilic patients [13, 21, 57]. More in detail, the recent meta-analysis by Haghpanah et al. [13] assessed the effects of myofascial therapy, reporting significant effects in terms of joint status and pain intensity. However, the authors focused only on myofascial therapy without considering other rehabilitation interventions. Moreover, just 4 studies were included and the quality assessment has been performed with the old version of the Cochrane Collaboration RoB tool.

In accordance, the meta-analysis by Elshennawy et al. [57] assessed the effects of different physical therapy interventions in hemophilic patients, reporting significant results in joint status and pain relief. However, the authors included also pediatric patients and did not consider other rehabilitation interventions, without characterizing the potential implications of a multicomponent approach to manage hemophilic arthropathy.

This systematic review with meta-analysis is not free from limitations. In particular, the different rehabilitative interventions were grouped according to different rehabilitation modalities. However, the heterogeneity of rehabilitation protocols poses challenges in drawing strong conclusions from meta-analysis. Although rehabilitation interventions were categorized for comparison to perform a meta-analysis, the treatments were similar but not the same. However, our approach aligns with several studies in rehabilitation field [57, 58, 59] and this quantitative synthesis was combined with a detailed qualitative synthesis including a precise rehabilitation protocol description as presented in Tables 1, 2, and 3.

However, to the best of our knowledge, this is the first systematic review with meta-analysis focusing on different rehabilitation interventions in hemophilic patients. Our findings provided a broad overview of the different therapeutic interventions targeting multilevel disability related to hemophilic arthropathy. Moreover, quantitative data about evidence-based approaches have been provided in order to guide clinicians in a precise rehabilitation prescription tailored to patients’ characteristics, targeting the impaired physical and psychological domains characteàrizing disability of people with hemophilic arthropathy.

5. Conclusions

In the past decade, growing literature has been emphasized the need for a precise rehabilitation management of hemophilic arthropathy due to its detrimental effects on physical and psychological domains and on the overall functioning of hemofilic patients. However, to date, the optimal rehabilitation strategy to precisely manage these patients is far from being fully clarified. Taken together, the results of the present meta-analysis highlighted the positive effects of multimodal rehabilitative interventions in improving several functional and HrQoL related outcomes in these patients.

Further good-quality observational studies comparing different rehabilitation modalities are still needed to better characterize the optimal rehabilitation strategy to counteract the multidimensional functional impairment of people affected by hemophilic arthropathy.

Author contributions

Conceptualization, L.L., A.d.S., and M.I.; methodology, L.L., A.d.S., and M.I.; investigation, L.L., and A.T.; writing – original draft preparation, L.L. and A.T.; writing – review and editing, A.d.S, and M.I.; visualization, R.M.S., M.P., A.A., and A.F.; supervision, A.d.S. and M.I. All authors have read and agreed to the published version of the manuscript.

Data availability statement

The data can be shared up on request.

Ethical approval

Not applicable.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Informed consent

Not applicable.

Supplementary data

The supplementary files are available to download from https://dx-doi-org.web.bisu.edu.cn/10.3233/BMR-230320.

Footnotes

Acknowledgments

None to report.

Conflict of interest

The authors declare that they have no conflict of interest.

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Efficacy of rehabilitation interventions on functioning in patients with hemophilic arthropathy: A systematic review with meta-analysis

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

1. Introduction

2. Methods

2.1 Registration and search strategy

2.2 Selection criteria

2.3 Data extraction and synthesis

2.4 Quality assessment and risk of bias

3.1 Study characteristics

Table 1 Main characteristics of the studies included

3.2.1 Physical exercise

3.2.2 Fascial therapy

3.2.3 Multimodal rehabilitative intervention

3.3 Main findings

3.3.1 Muscle modifications

3.3.2 Range of motion

3.3.3 Joint health

3.3.4 Pain intensity

3.3.5 Quality of life

3.3.6 Physical function

3.3.7 Frequency of hemarthrosis

4. Discussion

Table 4 Quality assessment of the studies included in the present systematic review

Author contributions

Data availability statement

Ethical approval

Funding

Informed consent

Supplementary data

Footnotes

Acknowledgments

Conflict of interest

References

Table 1
Main characteristics of the studies included

Table 4
Quality assessment of the studies included in the present systematic review