*3.3.2.1 Diflunisal*

*Amyloid Diseases*

**3.3 Treatment of familial ATTR**

*3.3.1 Liver transplantation*

Disease modifying treatments have become available for FAP since 1990s, starting with liver transplantation (**Figure 3**). Treatment strategies include: (1), depleting the source of mutant TTR (liver transplantation); (2), inhibition of formation of TTR (wild type and mutant), by preventing translation of mRNA with antisense oligonucleotide (ASO) or with small interfering RNA (siRNA) technologies; (3), stabilization of TTR tetramere by small molecules (diflunisal and tafamidis); and (4), therapy directed to remove the amyloid deposits [19]. Currently approved disease modifying treatments by US food and drug administration (FDA) include

inotersen and patisiran; with tafamidis approval under FDA review.

Removing the source of mutant TTR (liver) was the first disease modifying treatment for FAP. Liver transplantation, however, involves a major surgery, which is not tolerated with patients with significant underlying cardiovascular disease, and necessitates lifelong immunosuppression. Overall 5 year survival after liver transplantation is ~80% [50]. The 5 and 10 years survival rates post- transplantation were significantly better after Val30Met cases (82 and 74%) than the other mutations [50, 51]. Cardiomyopathy is a major determinant of prognosis with 10-year survival rates of 92 and 64% post-transplantation for patients without and with cardiomyopathy in a previous study [52]. Furthermore, liver transplant is more effective in changing the natural course of the disease in early onset Val30Met than the late onset cases, which could be due to more severe cardiomyopathy in the latter subtype [53]. Liver transplant is not an effective treatment for ATTRwt, leptomeningeal and ocular amyloidosis. Although ~90% of patients with early sensory neuropathy demonstrate disease stability after a liver transplant, organ involvement is not usually reversed, furthermore,

FAP, and specially cardiomyopathy often deteriorate gradually post-transplant due to the deposition of ATTRwt [54, 55]. Advanced age and malnutrition are also risk factors for poor outcome/survival after liver transplantation [53, 56], partly because there is more predisposition to deposition of wild-type TTR in older age.

**96**

**Figure 3.**

*Treatment strategies for fATTR (modified, from [92], with permission).*

In a randomized, double blinded, placebo controlled trial on 130 patients with FAP, diflunisal 250 mg twice a day was well tolerated and slowed the progression of neuropathy over a period of 2 years [57]. In that study, the Neuropathy Impairment +7 (NIS + 7) score increased by an average of 25.0 points in the placebo group versus 8.7 points in the diflunisal group (increase indicates deterioration of neuropathy). On the other hand, diflunisal also had a favorable effect on the quality of life; average of 36-Item Short-Form Health Survey (SF-36) physical scores decreased by 4.9 points in the placebo group and increased by 1.5 points in the diflunisal group. Modified body mass index (BMI), the product of serum albumin concentration (measured in grams per liter) and BMI (calculated as weight in kilograms divided by height in meters squared), which is an indicator of malnutrition and correlates with survival in FAP [58, 59], was the only endpoint which did not show improvement with diflunisal. In another study on 40 Japanese patients with fATTR, diflunisal was effective on neurological and cardiological manifestations after a period of 24 months, 3 patients could not tolerate diflunisal because of declining renal function or thrombocytopenia [60]. Diflunisal is inexpensive and widely available, but some of the potential problems associated with NSAIDs in general, such as gastrointestinal adverse effects including bleeding, limit its use, and caution is to be exercised in its use in the setting of underlying heart or kidney disease [61].
