Joint evaluation instruments for children and adults with haemophilia.

With the heightened interest in protocols to prevent or treat complications of haemophilia related to recurrent haemarthroses, there is a need for sensitive joint-evaluation tools. The World Federation of Haemophilia (WFH) Physical Joint Examination instrument, which was developed for persons with haemophilia worldwide, is not sensitive enough to detect early structural or functional abnormalities. Therefore, we have expanded the WFH instrument to detect more subtle abnormalities of joint structure and function, and in addition, developed a new scale specifically tailored to the dynamic growth and gait development of children. We compared the original and three new instruments in 43 children with haemophilia. The three new scales all showed better correlation with the WFH pain instrument than did the original WFH physical examination instrument (P < 0.01 for each of the new instruments vs. P > 0.05 for the WFH instrument). In addition, results of the new child physical examination instrument best conformed to a normal distribution (P=0.35) and this instrument had better overall statistical performance. This instrument should be studied further in prospective, longitudinal clinical trials of young children.     

Prevalence of clinical hip abnormalities in haemophilia A and B: an analysis of the UDC database

Clinical hip abnormalities, secondary to recurrent joint and/or muscle bleeding in persons with haemophilia, have not been well characterized and have the potential for significant morbidity. We aimed to examine the prevalence of clinical hip abnormalities in the US haemophilia population and to explore associations between these findings and putative risk factors. We conducted a study of hip abnormalities of 8192 subjects aged 2–69 years with haemophilia A and haemophilia B (54% of haemophilia A and haemophilia B are severe) currently enrolled in the Universal Data Collection (UDC) database. Associations between hip abnormality and type/severity of haemophilia A/B, current age, history of high‐titre (≥5 BU) inhibitor (HTinh), concomitant ankle (AA) and knee arthropathy (KA), overweight and obesity and prophylaxis were examined using logistic regression. Overall prevalence of hip abnormality at the last recorded UDC visit for all subjects was 16.7%. Haemophilia A (aOR = 1.3, 1.0–1.4), severe haemophilia (aOR = 1.3, 1.0–1.5), a history of HTinh (aOR = 1.4, 1.1–1.7), and concomitant AA (aOR = 1.7, 1.4–1.9) were each independently associated with hip abnormality. Older age (45–69 years) was significantly associated with hip abnormality prevalence only in subjects with KA (aOR = 3.4, 1.9–5.9). The presence of overweight (aOR = 1.4, 1.1–1.8) and obesity (aOR = 2.1, 1.6–2.8) was associated with hip abnormality only among subjects without KA. Hip abnormality prevalence was not influenced by prophylaxis (aOR = 0.9, 0.8–1.1). These data suggest that hip abnormalities in US patients with haemophilia are associated with haemophilia severity and type, HTinh, concomitant AA and, depending on the presence or absence of KA, advancing age and obesity.     

When to start and when to stop primary prophylaxis in patients with severe haemophilia

Summary.  Primary prophylactic treatment of patients with severe haemophilia has been shown to reduce the number of bleeding episodes and to minimize the development of arthropathy. However, since the use of clotting factor concentrates is associated with considerable cost and not all patients with severe haemophilia have a severe bleeding phenotype, there is still no consensus about when to start prophylaxis, which dosing regimen to use, and if or when the treatment should be stopped when the patient becomes elderly. Some care providers are also concerned about the use of central venous lines in very young children. Even though most available data indicate that prophylaxis should be started during the first years of life, it may be possible to adjust the dose and dose interval depending on the bleeding pattern. The use of an individualized prophylactic regimen may also improve cost-effectiveness and make the use of this treatment modality more feasible. Studies to further address this issue are warranted.     

Renal disease among males with haemophilia

Haematuria is common among persons with haemophilia (PWH), but its long-term effects on the kidney and renal function are not well defined. In addition, infection with human immunodeficiency virus (HIV) or hepatitis C, or exposure to nephrotoxic agents as therapy for these infections may place PWH at increased risk for renal disease. To examine factors associated with chronic renal disease (CRD) and acute renal disease (ARD) in PWH, we analysed data collected from the medical records of 3422 males with haemophilia living in six US states from 1993 to 1998. Renal disease cases were ascertained from among 2075 persons who were hospitalized at least once over the 6-year period. Of these, 60 (2.9%) were diagnosed during one or more hospitalizations with either ARD (29/60) or CRD (31/60). In multivariate analyses, we examined associations between renal disease and demographic and clinical factors including age, race, haemophilia type and severity, hypertension, diabetes, history of recent renal bleeds, presence of an inhibitor, and infection with hepatitis C or HIV. HIV infection and hypertension were strongly associated with both ARD and CRD. PWH who had ARD were also more likely to have an inhibitor than those without this diagnosis. PWH who had CRD were more likely to be older and non-white and to have had a recent admission for a kidney bleed than those without diagnosed CRD. In summary, we found that HIV infection and haemophilia-related factors including inhibitors and kidney bleeds were associated with renal disease in a cohort of males with haemophilia.     

When to start and when to stop primary prophylaxis in patients with severe haemophilia

Summary. Primary prophylactic treatment of patients with severe haemophilia has been shown to reduce the number of bleeding episodes and to minimize the development of arthropathy. However, since the use of clotting factor concentrates is associated with considerable cost and not all patients with severe haemophilia have a severe bleeding phenotype, there is still no consensus about when to start prophylaxis, which dosing regimen to use, and if or when the treatment should be stopped when the patient becomes elderly. Some care providers are also concerned about the use of central venous lines in very young children. Even though most available data indicate that prophylaxis should be started during the first years of life, it may be possible to adjust the dose and dose interval depending on the bleeding pattern. The use of an individualized prophylactic regimen may also improve cost‐effectiveness and make the use of this treatment modality more feasible. Studies to further address this issue are warranted.     

Correlation between clinical, radiological and ultrasonographical image of knee joints in children with haemophilia

The aims of the study were to evaluate the clinical, radiological and ultrasonographical images of knee joints in children with severe haemophilia and von Willebrand's disease, to determine the correlation between these images and to assess the usefulness of ultrasonography (USG) in evaluating the intensity of haemophilic arthropathy. Thirty-nine boys were included in the study, all of them with a past history of knee bleeds. The average age of the children was 10.02 +/- 3.01 years. In patients with slight (1-3 points) and moderate (4-7 points) radiological changes in knee joint bones, an increase in synovial fluid, considerable hypertrophy and inflammation of the synovium were observed in USG. In haemophilic patients with severe (8-13 points) bone changes, the amount of fluid was usually normal and there was slight inflammation but considerable hypertrophy of the synovium. Radiological evaluation of haemophilic arthropathy was made according to the Pettersson classification. A good correlation between the degree of cartilage damage in USG and the progression of bone changes in radiographs was found. Cartilage and bone damage progressed with the increase in the number of intra-articular haemorrhages into the knee joint. In our opinion USG is useful in evaluating the fluid, synovium and cartilage of joints in haemophiliacs.     

Improved joint health in subjects with severe haemophilia A treated prophylactically with recombinant factor VIII Fc fusion protein

Introduction

Joint arthropathy is the long‐term consequence of joint bleeding in people with severe haemophilia.

Aim

This study assessed change in joint health over time in subjects receiving recombinant factor VIII Fc fusion protein (rFVIIIFc) prophylaxis.

Methods

ALONG is the phase 3 pivotal study in which the benefit of rFVIIIFc as a prophylactic treatment for bleeding control was shown in previously treated severe haemophilia patients ≥12 years of age (arm 1: 25‐65 IU/kg every 3‐5 days, arm 2: 65 IU/kg weekly and arm 3: episodic). After completing ALONG, subjects had the option to enrol into the extension study (ASPIRE). This interim, post hoc analysis assessed changes in joint health over ~2.8 years in these patients.

Results

Forty‐seven subjects had modified Haemophilia Joint Health Score (mHJHS) data at A‐LONG baseline, ASPIRE baseline and ASPIRE Year 1 and Year 2. Compared with A‐LONG baseline (23.4), mean improvement at ASPIRE Year 2 was ?4.1 (95% confidence interval [CI], ?6.5, ?1.8; P = .001). Regardless of prestudy treatment regimen, subjects showed continuous improvement in mHJHS from A‐LONG baseline through ASPIRE Year 2 (prestudy prophylaxis: ?2.4, P = .09; prestudy episodic treatment: ?7.2, P = .003). Benefits were seen in subjects with target joints (?5.6, P = .005) as well as those with severe arthropathy (?8.8, P = .02). The mHJHS components with the greatest improvement at ASPIRE Year 2 were swelling (?1.4, P = .008), range of motion (?1.1, P = .03) and strength (?0.8, P = .04).

Conclusions

Prophylaxis with rFVIIIFc may improve joint health over time regardless of prestudy prophylaxis or episodic treatment regimens.     

Total knee replacement in haemophilia

We believe that total knee replacement (TKR) is a safe and effective procedure for the management of haemophiliac joint arthropathy; however, the increased risk of infection and non-infective complications remain a cause for concern. TKR in haemophilic patients carries with it an increased risk of post-operative infection in comparison to non-haemophiliac patients. Those patients at particular risk are the HIV-positive haemophiliac patients whose CD4 count is less than 200 cells mm-3. The latest techniques have gone a long way to reducing the complication rate and to achieving results that match those of a similar non-haemophiliac population.     

Somatosensory profile of patients with haemophilia

Introduction

Patients with haemophilia (PwH) suffer from an enhanced pain sensitivity due to repetitive joint bleedings. A comprehensive, quantitative examination of the somatosensory system has not been performed in this population to date.

Material and methods

Thirty patients with moderate or severe haemophilia A or B and 30 healthy controls were examined by means of Quantitative Sensory Testing to assess the function of the somatosensory system. Detection (DT) and pain thresholds (PT) were determined, amounting to a total of 13 parameters. Both knee joints and the hand as reference were examined in order to assess both joint‐specific as well as general changes in the somatosensory profile.

Results

Analysing DT and PT, a significant main effect was found for group × stimulus interaction (P ≤ .001). Post hoc tests revealed significant differences in DT between PwH and controls for thermal stimuli across both knees (cold DT: P < .001; warm DT: P < .01) and the hand (cold DT: P < .01; warm DT: P < .05). Mechanical DT was increased in PwH at both knee joints (left knee: P ≤ .05; right knee: P ≤ .01). Furthermore, pressure PT was decreased in PwH at both knees (P ≤ .001).

Conclusion

Haemophilic arthropathy leads to alterations of the somatosensory profile in PwH. Our results reveal initial evidence of a combination of peripheral sensitization, indicated by decreased pressure PT and mechanical DT at the knee joints, as well as general changes of the somatosensory system, shown by reduced thermal DT at affected sites and remote from these. Therefore, both mechanisms have to be considered regarding the pain management in PwH.     

Septic arthritis of the sternoclavicular joint in healthy adults

Septic arthritis of the sternoclavicular joint (SCJ) is a rare disorder, and is usually associated with predisposing factors such as contiguous foci of infection, heroin addiction, rheumatoid arthritis and diabetes mellitus. Three cases in previously healthy adults are reported here. The aetiology, clinical manifestations and treatment are briefly reviewed. The considerable difficulty in diagnosing this disorder in adults is emphasized. In summary, diagnosis of septic arthritis of the SCJ in adults requires a high index of suspicion, and must be considered not only in patients with predisposing factors, but also in previously healthy adults.     

Long-term outcome of individualized prophylactic treatment of children with severe haemophilia

The development of arthropathy is a serious complication of severe haemophilia. With the use of prophylaxis, bleeds can be prevented and arthropathy delayed. We investigated whether an individually tailored prophylactic regimen can prevent arthropathy and whether it had a similar effect on orthopaedic outcome compared with that of a high-dose regimen. Efficacy was determined clinically and by radiographs of six major joints. Prophylaxis was started in 70 patients at a mean age of 4.1 years. Mean follow-up was 15.6 years (range 8-24.5 years). The mean factor VIII consumption was 2319 IU/kg/year. The mean number of joint bleeds was 3.5/year and the mean clinical score (maximum score 90) was 1.0, with a mean Pettersson joint score (maximum score 78) of 3.0 at a mean age of 13.5 years. In conclusion, long-term, early-onset, individualized prophylaxis in haemophilia is feasible and prevents arthropathy.     

Prophylactic therapy for haemophilia: early experience

Summary.  During the 1960s, it was reported from Sweden that haemophiliacs with factor levels above 1% rarely develop arthropathy. This observation suggested that severe haemophilia could be converted to a milder form by regular infusions with factor concentrate. After several earlier publications, a report was published in 1992 that detailed 25 years' experience with prophylaxis in 60 patients from the Malmö centre. The results showed that starting prophylaxis early in life with a dose regimen that would prevent factor VIII or IX plasma levels from falling below 1% could prevent the development of haemophilic arthropathy. Also, older age groups who had received less intensive treatment, and who started prophylaxis later in life, were still in a much better condition than historic controls. In the 1970s several small but well-controlled studies from the USA, Germany and Italy clearly showed the benefit of prophylaxis in reducing bleeding frequency. Early experience from the Netherlands was published in 1971. Since these early studies, the results have been corroborated from many countries and in a large multinational study. Although the benefits of prophylaxis seem unquestionable, several research questions remain to be better elucidated, such as when to start and when to stop, dosing and dose interval, and how to assess the long-term treatment effects. These issues are of great economic importance, and the need for health economical studies is obvious.     

Identification and long-term observation of early joint damage by magnetic resonance imaging in clinically asymptomatic joints in patients with haemophilia A or B despite prophylaxis

Severe haemophilia is associated with recurrent joint bleeds, which can lead to haemophilic arthropathy. Subclinical joint bleeds have also been associated with joint damage detected using magnetic resonance imaging (MRI). We investigated the development of early changes in clinically asymptomatic joints using MRI in haemophilia A or B patients receiving prophylactic therapy. In this single-centre retrospective cohort study, patients with clinical evidence of joint damage in one ankle and one clinically asymptomatic ankle, in which we performed an MRI scan of both ankles in one session, were enrolled. MRI findings were graded using a 4-point scoring system (0 = normal findings and III = severe joint damage). Since 2000, 38 MRIs in 26 patients have been performed. Starting at a median age of 4 years, 23 patients received prophylaxis 2-3 times weekly. On-demand treatment was performed in three patients. Eight patients (31%) presented with an MRI score of 0, 12 (46%) had a score of I, four (15%) had a score of II, and two (8%) had a score of III in the clinically unaffected ankle. The six patients with MRI scores of II and III had started regular prophylaxis between the ages of 2 years and 15 years; none had developed an inhibitor or experienced a clinically evident bleed in the asymptomatic ankle. During our study, five of 26 patients had a worsening of MRI findings without experiencing a joint bleed. Early morphological changes in clinically asymptomatic ankles can be detected using MRI, despite adequate prophylaxis.     

Ankle muscle activation in people with haemophilia

Since normative surface EMG (SEMG) values for muscles acting at the knee joint are available for people with haemophilia, increasing interest is noticeable for other joints affected by haemophilic arthropathy. Adequate activity of shank muscles is an important key for appropriate postural control. The aim of this study was to determine differences in muscle activation patterns of lower leg muscles between people with and without haemophilia during upright standing. SEMG of tibialis anterior (TA), fibularis longus (FL), lateral (LG) and medial (MG) heads of gastrocnemius, and soleus (SO) muscles of both sides were recorded in 25 haemophilic patients (H) and 25 non‐haemophilic control subjects (C) while standing on even ground. The Gilbert‐Score was used to assign sides to major (H‐MA) and minor (H‐MI) affected ankle joints in H. To normalize the SEMG amplitudes, amplitude ratios (percentage of cumulated activity) were calculated. Compared to controls, TA ratios showed higher and MG reduced levels in both H groups (P < 0.01). In the H‐MA subgroup of H, FL also joined the TA behaviour whereas SO had similar activation direction as MG. Although possible descending influences from the knee joints cannot be excluded, this can be interpreted as a compensational mechanism due to the severity of the orthopaedic status of the ankle, which with increasing heaviness is accompanied by reduced plantar flexion capability. However, ankle joint integrity appears to be reduced in H, with TA and MG seeming to play key roles for neuromuscular control of upright posture.