Response to Letter to the Editor: Effect of Nusinersen on Respiratory and Bulbar Function in Children with Spinal Muscular Atrophy

We are delighted by the interest in our article, appreciate the valuable comments on our study, and welcome the opportunity to comment on them.

The purpose of our study was to evaluate the real-life impact of nusinersen in patients affected by spinal muscular atrophy (SMA) and followed up in our pediatric hospital. We did not include adult patients who were seen in the adult clinic. SMA is a rare disease.[1] In Spain, it affects approximately 1 in 10,000 births and, before the advent of treatment, it was the leading cause of infant mortality in children under 2 years of age due to genetic disease. Although 28 patients seems like a small number, it is above what is expected for the pediatric population in the area where we provide health care services. In the literature, SMA type 1 accounts for approximately 60% of all cases, while in our series, it is close to 40%.[1] In our ongoing research, we are increasing the number of patients and hope to soon recruit a population that reflects the true prevalence of all pediatric types of SMA.

All patients included in our study received standard care according to functional status, as proposed by available international guidelines, and were reassessed at each visit.[2] [3] Because of this, we did not consider standard care as a confounding variable in our study and no patient had a significant underlying medical condition different from those expected from SMA itself. We and others have shown that real-world studies (RWS) reflect actual practices with respect to how patients react to treatment in terms of tolerability and efficacy. It is worth noting that RWS may have several advantages over the randomized clinical trial (RCT): RWS cost less and require fewer resources than RCTs; RWS allow better assessment of the natural history of the disease and infrequent side effects than RCTs do, as RCT are conducted in a uniform population and with a shorter duration.[4] On the other hand, to suggest that “future research could use a RCT comparing nusinersen with a placebo group” is unethical at this stage, at least in a pediatric population, when three treatments have clearly been shown to increase survival in SMA patients.[5] Conducting a placebo-controlled trial would involve withholding life-saving treatment from children, which violates ethical principles, especially when established therapies are available that significantly improve both life expectancy and quality of life. In such a vulnerable population, the focus should now shift to optimizing treatment protocols, rather than questioning their efficacy in comparison to a placebo.

The importance of vascular head function (bulbar function) in the quality of life of SMA patients wasn't one of the aims of our study; however, in our future research, we will consider the need for further investigation into this component of patient care.

Finally, we are aware that our study does not provide a “complete picture of the long-term safety and efficacy of nusinersen,” but it adds to what is already known and published.[6] We have a longer follow-up for all patients included in the study and we continue to observe no significant side effects, but of course the picture is not entirely complete. In our ongoing research, we are looking at the impact of nusinersen on the physical growth, brain function, and overall health of children with SMA. As for the “best time to start treatment,” the available data demonstrate the importance of early and accurate diagnosis and prompt treatment, as soon as the diagnosis is genetically confirmed, preferably at a presymptomatic stage of the disease. To this end, universal neonatal screening programs are being implemented in several countries.[7]

Publication History

Received: 10 September 2024

Accepted: 03 October 2024

Article published online:
08 November 2024

• References

• 1 Verhaart IEC, Robertson A, Wilson IJ. et al. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy - a literature review. Orphanet J Rare Dis 2017; 12 (01) 124
• 2 Mercuri E, Finkel RS, Muntoni F. et al. SMA Care Group. Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord 2018; 28 (02) 103-115
• 3 Finkel RS, Mercuri E, Meyer OH. et al; SMA Care group. Diagnosis and management of spinal muscular atrophy: part 2: pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord 2018; 28 (03) 197-207
• 4 Chodankar D. Introduction to real-world evidence studies. Perspect Clin Res 2021; 12 (03) 171-174
• 5 Mercuri E, Sumner CJ, Muntoni F, Darras BT, Finkel RS. Spinal muscular atrophy. Nat Rev Dis Primers 2022; 8 (01) 52
• 6 Erdos J, Wild C. Mid- and long-term (at least 12 months) follow-up of patients with spinal muscular atrophy (SMA) treated with nusinersen, onasemnogene abeparvovec, risdiplam or combination therapies: a systematic review of real-world study data. Eur J Paediatr Neurol 2022; 39: 1-10
• 7 De Siqueira Carvalho AA, Tychon C, Servais L. Newborn screening for spinal muscular atrophy - what have we learned?. Expert Rev Neurother 2023; 23 (11) 1005-1012