*6.1. Treatment Outcome Conundrum*

Before we begin describing treatment options, there is one important point to address. With the multiplicity of therapeutic solutions developed and tested, there has been strong consideration given by both scientists and physicians as to what clinical criteria should be used to reliably evaluate and quantify treatment outcomes for PXE patients. This debate, which has been ongoing for several years, has yet to be settled due to the complexity of the PXE phenotype as multiple organ systems (skin, eyes, cardiovascular, renal, etc. . . . ) are affected with various degree of distribution, severity and considerable inter- and intrafamilial variability [150–152]. Indeed, identical mutations can cause the relatively mild PXE or severe GACI [17] in humans but also in mice [111]. The lack of genotype/phenotype correlation only compounds the problem. However, a very recent clinical study performed with 289 PXE patients found that mixed genotype led to less severe arterial calcification and ocular manifestations than patients with two truncating *ABCC6* variants and suggested that environmental or modifier genes could also contribute to the still unexplained phenotypic variability in PXE [153]. The presence of modifier genes modulating calcification in PXE has been investigated in human and mice but their predictive values for clinical applications are not clear [109,110,147,150,154–156]. Moreover, PXE is a slow and chronic disease with stepwise progression of the phenotype occurring over a period of time measured in years, if not decades [157]. The progression of calcification in *Abcc6*−/<sup>−</sup> mice mirrors that of humans and typically takes many months to develop [18,92]. PPi has been considered as a potential biomarker as it is central to the etiology of PXE [8] but its plasma levels only bring partial information as to the status of the disease [158] (See Figure 2). Furthermore, the daily and long-term natural variations of plasma PPi are not well known. Measuring calcification is an obvious approach but its quantification in a non-invasive or minimally invasive manner is not a trivial task. Invasive biopsies were tested in early trials in semiquantitative evaluations [129,130]. However, these trials did not yield positive conclusions and it is possible that the quantification methodology combined with the heterogeneity of the manifestations may have contributed to the inconclusive results. The capacity of <sup>18</sup>F-sodium fluoride (18F-NaF) positron emission tomography/computed tomography (PET/CT) to identify and evaluate metabolically active osteogenesis in skin and arteries in PXE patients has been demonstrated [159,160]. This method was applied in the recent TEMP clinical trial and was able to discern some phenotypical changes within a year following etidronate administration (*Cf.* Section 6.7.4) [126]. Although the potential of some novel methodology is being investigated, at this time [161], PET/CT scan is probably the best option available to evaluate treatment outcome in PXE patients, but it requires access to well-equipped medical centers. However, it is very likely that a combination of methodology and multiyear trials will be needed to achieve clear and objective results in the future.
