POS0336 PROSPECTIVE STUDY ON PREVALENCE AND DIAGNOSTIC ALGORITHMS FOR HYPOPHOSPHATASIA DETECTION IN ADULT RHEUMATOLOGY PATIENTS - THE COHIR STUDY

Background:

Hypophosphatasia (HPP) is a rare genetic disorder (1-3/300,000 severe cases in Europe) caused by one or more mutations in the alkaline phosphatase (ALP) gene. Hypomineralization results in symptoms such as arthralgias, insufficiency fractures, and poor dental status beginning in childhood. In cases of early childhood manifestation, a fatal course is possible. Consistent with the musculoskeletal complaint pattern, HPP is far more common in the rheumatology patient population than in the general population [1]. However, HPP is still frequently misdiagnosed as some other form of bone disease (e.g., rickets, osteomalacia, or osteoporosis). Therefore, implementation of a clinically applicable algorithm for early HPP detection is needed.

Objectives:

The principal aim of this study is to prospectively ascertain the prevalence of HPP in adult rheumatology patients. Concurrently, this research seeks to evaluate and refine a proposed protocol for the early identification of HPP, distinguishing it from other, more prevalent rheumatologic conditions.

Methods:

For all patients with musculoskeletal complaints and suspected rheumatological disease who present at the University Hospital Bonn beginning February 28, 2023, the ALP values prospectively obtained during routine diagnostics are continuously analyzed. The aim is to screen at least 3500 patients. Patients with reduced ALP (below sex-adjusted normal range) will receive an additional ALP measurement after informed consent. In case of persistently low ALP, abnormalities of calcium and phosphate levels and other causes of secondary hypophosphatemia are excluded (by laboratory diagnostics, by recording specific symptoms of the entire course of the disease since childhood, and by evaluating the patient history). Finally, to confirm the diagnosis of HPP, genetic testing of the ALP gene is performed.

Results:

As of October 06, 2023, 2780 patients with musculoskeletal complaints and suspected rheumatological disease have been screened for low serum ALP levels. Persistently low ALP levels were found in 30 patients (1.08%). The first batch analysis of 12 patients with persistently lowered ALP levels revealed pathogenic ALPL gene mutations consistent with HPP diagnosis in six out of 12 patients. Results from extended laboratory diagnostics of these 12 patients showed higher pyridoxal-5'-phosphate, lower bone-specific alkaline phosphatase (BAP) concentrations, lower BAP/ procollagen type I N propeptide (PINP) ratio and lower ALP/PINP ratio in HPP patients compared to patients without pathogenic mutations [see Table 1].

Conclusion:

The objective of the COHIR study is twofold: First, to offer prospective prevalence data on HPP among adult rheumatology patients, a first in this field. Second, the study focuses on developing and clinically implementing a protocol for early detection of HPP, which includes both laboratory and clinical diagnostics. This is crucial as the journey to a correct diagnosis in HPP patients is often protracted, incurring significant costs. Interim analysis and existing literature suggest that laboratory and clinical diagnostics can serve as valuable indicators of HPP prior to genetic testing.

REFERENCES:

[1] Karakostas P, Dolscheid-Pommerich R, Hass MD, et al. Prevalence of hypophosphatasia in adult patients in rheumatology. Z Rheumatol 2022; 81: 513–519. doi:10.1007/s00393-021-00994-5. Table 1. Interim analysis of 12 patients with persistently lowered ALP levels [ALP = alkaline phosphatase ACMG = American College of Medical Genetics and Genomics BAP = bone-specific alkaline phosphatase PINP = procollagen type I N propeptide SD = standard deviation]

Acknowledgements:

We thank Alexion Germany Pharma GmbH for the provision of financial support for this project. Alexion was not involved in the study design, data collection, analysis, or data interpretation.

Disclosure of Interests:

Claus Juergen Bauer Alexion Pharma Germany GmbH, Clara Niesing: None declared, Pantelis Karakostas: None declared, Ramona Dolscheid-Pommerich: None declared, Birgit Stoffel-Wagner: None declared, Sandra Pasternack-Ziach: None declared, Markus Noethen: None declared, Valentin S. Schaefer Alexion Pharma Germany GmbH.