Contexte

Bienvenue à la deuxième partie de la discussion sur les cas d’hypophosphatasie (HPP) 2022.

Entre octobre 2021 et janvier 2022, un questionnaire d’évaluation des besoins auquel ont répondu des spécialistes de toutes les régions du Canada a permis de recueillir des renseignements sur les perceptions et les modèles de pratique actuels.

Principaux enseignements pertinents dans le cadre de ce numéro tirés de l’évaluation :
  • On s’accorde à dire que les symptômes de l’HPP peuvent avoir des répercussions importantes sur la qualité de vie (84 %).

Dans quelle mesure êtes-vous d’accord avec les énoncés suivants concernant le fardeau de la maladie et le soutien à dispenser :
[1 = pas du tout d’accord, 3 = sans opinion, 5 = tout à fait d’accord]

  • Il n’existe pas d’approche cohérente/définie pour évaluer le fardeau de la maladie dans la plupart des centres (69 %).

Existe-t-il une approche cohérente/définie pour évaluer le fardeau de la maladie dans votre centre?

Voir l’annexe pour consulter plus de données issues de l’évaluation du traitement et du fardeau de la maladie.

Cette série en deux parties a pour but de clarifier les lacunes en matière d’éducation que l’évaluation a permis d’identifier.  Chaque numéro présente une étude de cas et fournit des données supplémentaires sur les meilleures pratiques.

La première partie a exploré les avantages et les difficultés de la mise en œuvre de la cartographie familiale dans la pratique canadienne dans le contexte de l’HPP.

La deuxième partie se concentre sur l’instauration appropriée du traitement sur la base des symptômes cliniques et d’une évaluation cohérente du fardeau.

Nous remercions la Dre Aliya Khan (Université McMaster) et la Dre Sarah Khan (hôpital Credit Valley) pour le contenu du présent issue.

Introduction

Nous avons appris dans la première partie que :
  • L’HPP est un trouble héréditaire rare, potentiellement mortel, du métabolisme osseux et minéral, causé par des mutations entraînant une perte de fonction dans le gène ALPL.
  • Les principaux indicateurs de diagnostic comprennent des variantes génétiques du gène ALPL, un faible taux d’ALP sérique spécifique à l’âge et des niveaux accrus de substrats (PPi, PLP, PEA) ainsi que les caractéristiques cliniques de l’HPP.
  • L’utilisation de la cartographie familiale peut améliorer la détection de l’HPP et réduire les retards dans le diagnostic et la prise en charge.
  • L’HPP est une maladie très hétérogène dans sa présentation et son degré de gravité.
L’HPP est une maladie multisystémique 

L’HPP est une maladie multisystémique dont les effets délétères peuvent apparaître à différents âges et progresser avec le temps. Les principales caractéristiques susceptibles de se manifester chez les enfants et les adultes sont présentées dans le tableau 1. Le tableau clinique chez les enfants et les adultes peut être extrêmement variable et l’évolution naturelle est mal comprise, en particulier chez les adultes.

Tableau. Caractéristiques clés de l’HPP¹

Il se peut que les symptômes de l’HPP ne soient pas reconnus, car ils font partie d’une constellation de caractéristiques d’une maladie multisystémique, ce qui entraîne des retards dans le diagnostic et un traitement inapproprié qui peut être néfaste, comme le traitement par bisphosphonates. Le traitement par bisphosphonates dans l’HPP peut en outre entraîner des altérations de la minéralisation osseuse, aggravant l’ostéomalacie sous-jacente.

Évaluation du fardeau de la maladie – meilleures pratiques

On dispose de peu de données sur le fardeau de la maladie sur la fonction physique et la qualité de vie.  Une évaluation minutieuse du patient est nécessaire et une intervention pharmacologique doit être envisagée chez les personnes répondant aux critères de traitement.

Le traitement pharmacologique est fondé sur la gravité de l’HPP.  L’étude de cas suivante concentre sur l’instauration appropriée du traitement sur la base des symptômes cliniques et d’une évaluation cohérente du fardeau. Elle est présentée, ainsi que la discussion qui suit, dans la langue de l’auteur.

¹ Table adapted from Khan, Aliya & Josse, R. & Kannu, Peter & Villeneuve, J. & Paul, T. & van uum, Stan & Greenberg, C.R.. (2019). Hypophosphatasia: Canadian update on diagnosis and management. Osteoporosis International. 30. 10.1007/s00198-019-04921-y.

Case Study

ID: 37-year-old female with hypophosphatasia

Past Medical History:

  1. Hypophosphatasia diagnosed at the age of 2 based on early tooth loss and delayed gross motor development and low ALP levels. She did not have any skeletal deformities or respiratory issues in infancy. DNA analysis confirmed HPP with heterozygous mutation in N400S in ALPL gene.  No further treatment was provided, and patient was recently referred to endocrinology for evaluation.
  2. Depression

Medications: escitalopram, iron, Vit D

Family History: Father has hypophosphatasia

Social History: Non-smoker, occasionally drinks alcohol, currently unemployed due to debilitating pain

Allergies: NKDA

Case: Her active symptoms included significant muscle weakness, gait instability and joint pains. Patient has been unable to stay employed due to ongoing fatigue and generalized pain. She had no history of fractures. Further clinical assessment revealed her quality of life to be significantly impacted as assessed in clinic by the SF-36 scoring system. She was only able to walk 450 m during the 6-minute walk test (for her age, weight, and height the expected walk should be at least 675 m).  She rated her pain between 8-10 on the Wong-Baker FACES scale.

Her baseline labs were as follows:

Baseline bone density was normal. Skeletal X-rays did not show evidence of chondrocalcinosis but did reveal moderate mid-lower cervical kyphosis.  No nephrocalcinosis noted on kidney ultrasound.

Given her significant MSK pain, poor mobility, and decreased quality of life she was started on asfotase alpha treatment.

Following initiation of enzyme replacement therapy, a significant improvement was noted in her mobility as well as a reduction in her chronic MSK pain. She was able to begin employment and reduce the dose of the SSRI that she was using for anxiety and depression. Her SF-36 scoring shows that she noticed a significant improvement in physical, emotional, social functioning as well as an improvement in her energy levels. Her Wong-Baker faces pain rating scale post-treatment was between 0-2 which was a significant improvement compared to her pre-treatment scores which were between 6-8.

Discussion

Considerations for treatment initiation

The primary treatment for hypophosphatasia is enzyme replacement therapy (ERT) with asfotase alfa, a recombinant ALP enzyme replacement drug.

In 2015 the enzyme replacement therapy (ERT), asfotase alfa, was approved by Health Canada for use in patients of any age with pediatric-onset HPP. Access to asfotase alfa is determined by clinical criteria and varies from province to province.

Canadian recommendations advise that adults with HPP be considered for treatment with ERT in the presence of the following criteria¹:

  1. Osteomalacia and complications of osteomalacia
  2. Pseudofractures
  3. Intractable musculoskeletal pain requiring or unresponsive to opioids.
  4. Presence of chondrocalcinosis with intractable pain
  5. Major osteoporotic fractures
  6. Delayed or incomplete fracture healing
  7. Individuals with significant impairment in function with impaired gait and mobility

Prior to initiation of treatment with ERT a confirmed diagnosis of HPP is required.

Because of the systemic presentation of HPP, a coordinated, multidisciplinary, team-based, patient-focused approach is recommended in the management of patients receiving treatment.

 

Considerations for assessing burden of disease

Limited evidence on the patient-reported burden of HPP and its impact on an individual’s HRQoL exists in the literature.

Data from the Global HPP Registry suggest that adults with HPP have a substantial burden of illness that is associated with reduced patient-reported HRQoL, regardless of age of disease onset (i.e. pediatric vs. adult-onset) highlighting limitations of categorizing HPP by age of onset.²

The efficacy of ERT for HPP is assessed primarily based on improvements in clinical symptoms and manifestations of HPP.

The goals of therapy vary on the severity of the condition as well as the patients age. In perinatal and infantile patients the goal is to optimize respiratory status and control seizures. In children the goal is to improve growth and mobility and ensure that developmental milestones are being met. Oral health also must be evaluated and optimized.  In adults the goal is to optimize bone mineralization and bone strength and prevent fractures as well as improve muscle function and mobility and control MSK pain.

Monitoring recommendations for patients with HPP vary by age.

It is recommended to evaluate the laboratory profile measuring calcium corrected for albumin, phosphate, 25OH vitamin D, PTH , CBC, ALT, ALP , creatinine, and 24-hour urine for calcium and creatinine at baseline. Following initiation of therapy the lab profile can be repeated at 2 weeks and then every 3 months for the 1st year.³

The substrates of TNSALP can be measured by evaluating vitamin B6 levels which reflect pyridoxal 5’phosphate (PLP) Urinary PEA can be measured commercially. Inorganic pyrophosphate PPi is not available commercially. The substrates of TNSALP are elevated prior to starting therapy with asfotase alfa. Following asfotase alfa therapy dramatic rises in ALP levels are seen up to several thousand units per liter.  The substrates of TNSALP may not be detectable on asfotase alfa as the substrates are hydrolyzed in the test tubes on therapy.

Physical examination can be completed every 3 – 6 months evaluating muscle mass and muscle function as well as gait speed, timed up and go test, 6-minute walk test as well as growth velocity with monitoring of height, weight, BMI in children and head circumference and shape in infants.

Quality of life can be evaluated by the SF 36 scale at baseline and then again at 6-12 months after starting enzyme replacement therapy.

Skeletal x-rays are advised at baseline with repeat imaging at 3, 6, and 12 months in children.  BMD is recommended by DXA assessment at baseline and then annually thereafter. Eye examination for ectopic calcification is recommended at baseline and this can be followed every 2 yrs. A renal US can be completed at baseline and can be repeated in 2-3 years evaluating nephrocalcinosis or occult nephrolithiasis.

Baseline and routine dental visits are recommended to assess for premature tooth loss, dental caries or abnormal dentition.

Treatment with asfotase alfa therapy in adults and adolescents with HPP showed reduction in the substrates of TNALP (PLP and PPi). Previous studies have shown that treatment improved walking ability, muscle strength and running speed in patients who received treatment compared to the control group. Adverse reactions to monitor for on treatment include injection site reactions, lipodystrophy, local skin discoloration, ophthalmic and renal ectopic calcifications.

Upon treatment initiation patients should be monitored at each visit to assess for potential adverse events to treatment which include an accurate history that evaluates hypersensitivity reactions, signs, and symptoms of ophthalmic and renal ectopic calcifications and for changes in vision or renal function and lipodystrophy.

For children <5 years of age periodic evaluations for craniosynostosis (including fundoscopy) are also recommended.

Additional recommended patient assessments are based on patient age and include monitoring of biochemistry, skeletal radiographs, respiratory function, growth, pain, mobility and motor function, and quality of life.³

Annexe : Rétroaction sur l’évaluation des besoins – fardeau de la maladie et traitement

 

The HPP needs assessment survey developed in collaboration with Dr. Aliya Khan was distributed to Canadian specialists with an interest/focus in the category. Response at final analysis: n=15.

Responder Demographics

Type of Practice:

Specialty Breakdown:

Provinces represented:

  • British Columbia
  • Alberta
  • Manitoba
  • Ontario
  • Québec
  • Nova Scotia
Burden of Disease and Treatment 

To what extent do you agree with the following statements on disease burden and support:
[1 being strongly disagree, 3 being neutral and 5 being strongly agree]

Is there is a consistent/defined approach for evaluating burden of disease within your centre?

If yes, what is it?
[Responders selected all that apply]

To what extent do you agree with the following statements on treatment:
[1 being strongly disagree, 3 being neutral and 5 being strongly agree]

Have you maintained management/treatment with any patients transitioning from pediatric over to adult?

If yes, on a scale of 1-5 how easy was this process?
[1 being difficult, 3 being neutral, 5 being easy]

Further explanation on barrier that exists with transition included:

  • Identifying consistent primary care MDs for overall health
  • lack of adult carers

Have you treated any HPP patients with STRENSIQ® (asfotase alfa)?

If yes, the percent that were pediatric vs. adult is as follows:

  • All/100% pediatric (60% of responders to this question)
  • 70% pediatric (20% of responders to this question)
  • 20% pediatric (20% of responders to this question)
What do you perceive as the largest barriers/challenges with use of STRENSIQ® (asfotase alfa)?

Explanations received:

  • Cost/Access due to cost and coverage constraints/Funding (64%)
  • Haven’t needed to access it yet. The issue with it will be that I deal with several provinces that have different mechanisms [for approval] (9%)
  • Lack of clear guideline regarding use (9%)
  • Approval for adult populations (9%)
  • Lack of additional well controlled clinical trials (9%)
(Click on Images to Enlarge)

¹ Khan, Aliya & Josse, R. & Kannu, Peter & Villeneuve, J. & Paul, T. & van uum, Stan & Greenberg, C.R.. (2019). Hypophosphatasia: Canadian update on diagnosis and management. Osteoporosis International. 30. 10.1007/s00198-019-04921-y.

² Seefried, L., Dahir, K., Petryk, A., Högler, W., Linglart, A., Martos-Moreno, G.Á., Ozono, K., Fang, S., Rockman-Greenberg, C. and Kishnani, P.S. (2020), Burden of Illness in Adults With Hypophosphatasia: Data From the Global Hypophosphatasia Patient Registry. J Bone Miner Res, 35: 2171-2178. https://doi.org/10.1002/jbmr.4130

³ Kishnani PS, Rush ET, Arundel P, Bishop N, Dahir K, Fraser W, Harmatz P, Linglart A, Munns CF, Nunes ME, Saal HM, Seefried L, Ozono K. Monitoring guidance for patients with hypophosphatasia treated with asfotase alfa. Mol Genet Metab. 2017 Sep;122(1-2):4-17. doi: 10.1016/j.ymgme.2017.07.010. Epub 2017 Jul 25. PMID: 28888853.

Kishnani PS, Rockman-Greenberg C, Rauch F, Bhatti MT, Moseley S, Denker AE, Watsky E, Whyte MP (2019) Five-year efficacy and safety of asfotase alfa therapy for adults and adolescents with hypophosphatasia. Bone 121:149–162

Le support pour cette série de cas est fourni par Alexion, AstraZeneca Rare Disease.