Start ERT in Symptomatic Late-onset Pompe Patients, Study Says

Patients with late-onset Pompe disease (LOPD) should be followed regularly and start on enzyme replacement therapy (ERT) if they develop symptoms, according to an analysis of available guidelines.

The study, “Comparison of recent pivotal recommendations for the diagnosis and treatment of late-onset Pompe disease using diagnostic nodes — the Pompe disease burden scale,” appeared in the Journal of Neurology.

ERT has led to significant improvements in exercise capacity and stabilization of respiratory function in LOPD patients in a clinical trial. Still, about one-third of these patients may not benefit from this treatment, which, along with its high cost, has led to a lack of uniform recommendations on when to start ERT, treatment duration and the best time to stop.

A team from Switzerland, Germany and Australia used a software tool to compare guidelines across countries and continents. The investigators searched an online database for recommendations between January 2013 and December 2018, which resulted in the inclusion of five studies, three of which were directly or indirectly sponsored by industry.

One of the main areas identified was confirmation of diagnosis. All five studies state that characteristic clinical manifestations are needed for suspicion of LOPD, recommending screening of GAA enzyme activity, which is absent or altered in Pompe disease patients.

Four studies recommend the dried blood spot assay for this purpose and three advise genetic confirmation. In case of doubt, four studies recommend a second GAA activity assay, while the European consensus recommends a combination of a GAA assay with genetic confirmation as the gold standard.

The criteria for ERT start varied significantly across the studies. According to stricter recommendations, only symptomatic patients may qualify for treatment, while others support ERT also in patients with clinical signs such as increased levels of creatine kinase, a biomarker of muscle damage.

Based on their analysis, the scientists developed a “Pompe Disease Burden Scale” (PDBS) with four stages (I-IV). Stage I includes those with no symptoms or signs (I), diagnosed via newborn screening or after diagnosis of an affected sibling. Those at stage II have clinical signs but are still presymptomatic.

Stage III is subdivided into “a” and “b” categories depending on whether the patients are able to walk and need invasive ventilatory support. Stage IV includes severely affected patients with no relevant residual muscle function.

Two studies — the Canadian guidelines and the European consensus — recommend at least minimal functionally relevant and measurable muscle function as a key criterion for ERT start in stages III and IIIb. Two recommend ERT in pre-symptomatic patients with a definitive diagnosis and objective clinical signs — stage II — while all support such an approach for patients in stage III.

Overall, “we propose to follow the patients of PDBS I and II by regular assessment every 6–12 months and initiate ERT if symptoms arise (progression to PDBS III),” the team stated.

The most important criterion for stopping ERT is its inefficacy. The Middle East and North Africa and the Brazilian consensuses recommended a 12-month treatment course in severely affected patients. Yet most criteria were vague, the scientists noted, and only two studies stated the need for adherence to infusion intervals and regular assessment procedures. These studies also mentioned that high levels of anti-GAA antibodies may limit ERT efficacy and induce immune responses.

As for guidelines in pregnancy, existing studies indicate that staying on ERT may be important and not harmful to the fetus. Yet further evidence is needed, the researchers cautioned.

“According to this investigation, further clinical research should concentrate on ERT in pre-symptomatic and severely affected LOPD patients and on cessation criteria for ERT as these issues are areas of international uncertainty and discordance,” they said.