Long-term experience with enzyme replacement therapy (ERT) in MPS II patients with a severe phenotype: an international case series

Because clinical trial data for the use of idursulfase to treat severe (neuropathic) MPS II are lacking, there has been much interest in the long-term clinical course of such patients. In a recent consensus report, a panel of experts pooled their experiences with treating 66 severe patients with ERT and concluded that somatic signs and symptoms were improved in the majority. The panel recommended that a trial of 6 to 12 months’ treatment be offered to severe patients (Muenzer et al 2012). Follow-up examinations are recommended at 6- to 12-month intervals during the trial of treatment (Scarpa et al 2011). In the present case series, the long-term effects of ERT with idursulfase were analyzed in 22 patients with severe MPS II who received ERT for at least 2 consecutive years at five international centers. In agreement with the expert consensus panel, we found that all of our patients experienced improvements in at least four of the somatic signs and symptoms evaluated, and 82 % experienced improvements in five to seven somatic signs and symptoms (Table 2).

Long-term treatment with idursulfase was generally well-tolerated in this case series. The only reported adverse events were IRRs, with 4/22 (18 %) patients experiencing manageable reactions. These included extreme irritability, hypertension, allergic conjunctivitis, urticaria factita, cough, tachypnea, shivering, and vomiting. All resolved with standard care. We did not find a clear connection between IRRs and ADA positivity (Table 1). All four patients who experienced IRRs were successfully premedicated before subsequent infusion visits with prophylactic antihistamines (n = 1) or antihistamines plus steroids (n = 3). Two patients in the latter group were later weaned to antihistamines alone with no further IRRs.

As an MPS II expert consensus panel has previously pointed out, a major challenge in evaluating the response to ERT in severe MPS II patients is the lack of assessment tools that are validated in this population (Muenzer et al 2012). Cognitive decline and behavioral difficulties decrease quality of life for patients with MPS II and their caregivers (Bax and Colville 1995), but it is clear that IV idursulfase treatment does not address these disease features (Muenzer et al 2012; Wraith et al 2008) because the large protein does not appear to cross the blood–brain barrier (Boado et al 2013). Like Muenzer and colleagues (Muenzer et al 2012), we do consider, however, that improvements in somatic signs and symptoms may be experienced by severe patients and can help improve the quality of patients’ and caregivers’ lives. For example, frequent respiratory infections leading to hospitalization are a common finding in MPS II, causing distress for patients and caregivers as well as lost time at work for caregivers (Muhlebach et al 2011; Young et al 1982a). In the current case series, 100 % of patients experienced a reduction in the frequency of respiratory infections with ERT, and 79 % had reductions in the number of disease-related hospitalizations as judged by the managing physician who reviewed patient records (Table 3). In our experience, reductions in organomegaly can improve breathing and reduce abdominal pain, nausea, and early satiety among MPS II patients. All of our patients in this case series experienced reductions in liver and/or spleen size on ERT. Joint contractures and skeletal deformities associated with dysostosis multiplex result in significant restrictions in mobility and progressive disability in MPS II (Link et al 2010; Wraith et al 2008). In the current study, joint range of motion improved in 33 % of patients, and stabilized in 62 % of patients. In addition, 86 % of patients showed stabilization of skeletal disease, which may be considered a benefit of treatment for a progressive disease such as MPS II. It has been previously stated that an important goal of therapy is the improvement in quality of life for the patient and family, so a perception by the family of improved quality of life should be taken into strong consideration when deciding whether or not to continue therapy (Muenzer et al 2012). We agree with this approach and suggest not prohibiting cognitively disabled patients from trying a treatment that may produce clinically relevant improvements in multiple somatic features, thereby lessening the burden of illness for the patient and family.

Urinary GAGs are a useful endpoint in order to observe the biochemical effects of idursulfase treatment. Urinary GAG levels were generally reduced on ERT, with 91 % of patients experiencing a decrease in uGAG levels as compared with baseline (Fig. 1). Two patients experienced an increase in uGAG levels while receiving idursulfase, but this increase did not clearly correspond with ADA, as patient 14 was ADA positive and patient 16 was ADA negative. Both patients experienced four or more somatic improvements on ERT despite increased uGAG levels. It is possible that these patients’ measurements may have been misleading, as individual uGAG measurements vary from day to day and even at different times during the day. The picture is somewhat more complicated for patient 14, who lacks baseline data and whose earliest uGAG test was performed after 6 months of ERT. The result at that point was nearly normal (7.86 mg/mmol creatinine; ULN: 7.70 mg/mmol creatinine). Thus, data from patient 14 should be considered with caution.

As expected for severe patients, cognitive disease progressed in 17/22 (77 %) patients and stabilized in 3/22 (14 %), as assessed by formal developmental evaluation or by investigator impression when formal evaluations were not performed. Slight improvements were reported for two patients. This likely reflects an increased ability of these patients to interact with others and with their environment due to improved mobility, improved sleep, and/or reductions in respiratory disease burden, since idursulfase does not cross the blood–brain barrier (Boado et al 2013). In our experience, families of severe MPS II patients often choose to initiate ERT despite the presence of cognitive impairment because they believe that somatic improvements will improve the quality of the patient’s life. This finding is in keeping with a published survey of MPS families, which found that 77 % of respondents were in favor of starting ERT in a patient with a severe phenotype, even knowing that treatment cannot alter the intellectual deterioration associated with the disease (Coman et al 2008).

In summary, this retrospective case series provides details on our experiences with treating severe MPS II patients with ERT for more than 2 years continuously. Treatment was associated with improvements in somatic signs and symptoms of the disease for all patients, and it was generally well tolerated. While ERT may provide benefits for severe MPS II patients, families should make any treatment decisions in concert with their child’s physician, with open lines of communication regarding the possible benefits and limitations of this treatment (Muenzer et al 2012; Scarpa et al 2011; Wraith et al 2008). Criteria for discontinuation of ERT should be thoroughly outlined before the start of therapy and evaluated again after 6 to 12 months on treatment and every 18 to 24 months thereafter.