Berk JL, Suhr OB, Obici L, Sekijima Y, Zeldenrust SR, Yamashita T, Heneghan MA, Gorevic PD, Litchy WJ, Wiesman JF, Nordh E, Corato M, Lozza A, Cortese A, Robinson-Papp J, Colton T, Rybin DV, Bisbee AB, Ando Y, Ikeda S, Seldin DC, Merlini G, Skinner M, Kelly JW, Dyck PJ, Diflunisal Trial Consortium. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA. 2013 Dec 25;310(24):2658-67. PubMed.

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Comments

  1. This study is commendable as a trial of a "repurposed" NSAID that had otherwise lost its clinical relevance. The trial showed both formal efficacy and quality-of-life benefits in patients with a rare but lethal inherited syndrome that leads to multi-organ amyloid deposition. In a particular, fatal form, the disease involves the peripheral nerves. It is important to point out, however, that there are many sources of amyloid, and that the type involved in this disease comes from mis-metabolism of transthyretin, a thyroid hormone carrier protein.

    The paper's discussion section contains the statement "this study provides proof of concept that kinetically stabilizing an amyloidogenic precursor protein (transthyretin) translates to successfully modifying amyloid-related neurological disease progression." While this statement is undoubtedly correct, it would be unwise to interpret these findings as having implications for a role of diflunisal or other NSAIDs in the treatment of Alzheimer's disease (AD) dementia. It is true that impressive epidemiological evidence suggests users of conventional "dual-inhibitor" NSAIDs have reduced frequency of AD dementia, at least among "young-old" individuals (Szekely and Zandi, 2010). Those findings suggest that administration of NSAIDs to individuals in the early pre-symptomatic stages of AD might retard disease progression at that point. One should remember, however, that this notion has never been proven in clinical trials, and that all trials attempting to show a therapeutic effect of NSAIDs (including one cyclo-oxygenase 2 inhibitor) as treatments of symptomatic AD or its prodrome MCI have failed. The largest of these, the ADCS treatment trial with naproxen and rofecoxib, actually showed a trend toward negative (not just null) results in the rofecoxib-treated group (Aisen et al., 2003). Another large trial of rofecoxib in MCI patients showed negative results on the primary outcome of "conversion" to dementia (Thal et al., 2005). Even the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT)—which was intended to examine NSAID treatments for prevention rather than treatment of symptoms—showed a negative treatment effect over its first several years in participants treated with naproxen or celecoxib (Lyketsos et al., 2007). Adverse effects were especially noteworthy in ADAPT participants who (it was later discovered) had entered the trial with MCI (Breitner et al., 2011). At least one large observational study also found increased incidence of AD dementia in prior heavy users of NSAIDs (Breitner et al., 2009). The latter finding was derived from a particularly elderly cohort who might, accordingly, have had a relatively high proportion of individuals with significant pre-symptomatic or early symptomatic Alzheimerization in their brains. If anything, these results suggest that NSAIDs have adverse treatment effects on persons with symptomatic or late pre-symptomatic AD.

    Especially because transthyretrin amyloid is different and the target neural structures are distinct from AD pathology, I consider that this new JAMA paper does not counter that suggestion in any way.

    References:

    Szekely CA, Zandi PP. Non-steroidal anti-inflammatory drugs and Alzheimer's disease: the epidemiological evidence. CNS Neurol Disord Drug Targets. 2010 Apr;9(2):132-9. PubMed.

    Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, Farlow MR, Jin S, Thomas RG, Thal LJ, . Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA. 2003 Jun 4;289(21):2819-26. PubMed.

    Thal LJ, Ferris SH, Kirby L, Block GA, Lines CR, Yuen E, Assaid C, Nessly ML, Norman BA, Baranak CC, Reines SA, . A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacology. 2005 Jun;30(6):1204-15. PubMed.

    ADAPT Research Group, Lyketsos CG, Breitner JC, Green RC, Martin BK, Meinert C, Piantadosi S, Sabbagh M. Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology. 2007 May 22;68(21):1800-8. Epub 2007 Apr 25 PubMed.

    Breitner JC, Baker LD, Montine TJ, Meinert CL, Lyketsos CG, Ashe KH, Brandt J, Craft S, Evans DE, Green RC, Ismail MS, Martin BK, Mullan MJ, Sabbagh M, Tariot PN, . Extended results of the Alzheimer's disease anti-inflammatory prevention trial. Alzheimers Dement. 2011 Jul;7(4):402-11. PubMed.

    Breitner JC, Haneuse SJ, Walker R, Dublin S, Crane PK, Gray SL, Larson EB. Risk of dementia and AD with prior exposure to NSAIDs in an elderly community-based cohort. Neurology. 2009 Jun 2;72(22):1899-905. PubMed.

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