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Familial amyloid polyneuropathy, a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a nonsteroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro.To determine the effect of diflunisal on polyneuropathy progression in patients with familial amyloid polyneuropathy.International randomized, double-blind, placebo-controlled study conducted among 130 patients with familial amyloid polyneuropathy exhibiting clinically detectable peripheral or autonomic neuropathy at amyloid centers in Sweden (Umeå), Italy (Pavia), Japan (Matsumoto and Kumamoto), England (London), and the United States (Boston, Massachusetts; New York, New York; and Rochester, Minnesota) from 2006 through 2012.Participants were randomly assigned to receive diflunisal, 250 mg (n=64), or placebo (n=66) twice daily for 2 years.The primary end point, the difference in polyneuropathy progression between treatments, was measured by the Neuropathy Impairment Score plus 7 nerve tests (NIS+7) which ranges from 0 (no neurological deficits) to 270 points (no detectable peripheral nerve function). Secondary outcomes included a quality-of-life questionnaire (36-Item Short-Form Health Survey [SF-36]) and modified body mass index. Because of attrition, we used likelihood-based modeling and multiple imputation analysis of baseline to 2-year data.By multiple imputation, the NIS+7 score increased by 25.0 (95% CI, 18.4-31.6) points in the placebo group and by 8.7 (95% CI, 3.3-14.1) points in the diflunisal group, a difference of 16.3 points (95% CI, 8.1-24.5 points; P .001). Mean SF-36 physical scores decreased by 4.9 (95% CI, -7.6 to -2.2) points in the placebo group and increased by 1.5 (95% CI, -0.8 to 3.7) points in the diflunisal group (P .001). Mean SF-36 mental scores declined by 1.1 (95% CI, -4.3 to 2.0) points in the placebo group while increasing by 3.7 (95% CI, 1.0-6.4) points in the diflunisal group (P = .02). By responder analysis, 29.7% of the diflunisal group and 9.4% of the placebo group exhibited neurological stability at 2 years (2-point increase in NIS+7 score; P = .007).Among patients with familial amyloid polyneuropathy, the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life. Although longer-term follow-up studies are needed, these findings suggest benefit of this treatment for familial amyloid polyneuropathy.clinicaltrials.gov Identifier: NCT00294671.

Lyme borreliosis is a multisystem inflammatory disorder caused by the tick-borne spirocheteBorrelia burgdorferi. Clinical manifestations are protean, involving the skin, joints, peripheral and central nervous systems, and the heart. However, the presentation of Lyme disease often overlaps with that of other conditions. We describe four patients from a region endemic for Lyme disease who had elevated levels of antibodies reactive toB burgdorferiand whose signs and symptoms were initially attributed to Lyme borreliosis but whose subsequent blood cultures established a diagnosis of nonspirochetal subacute bacterial endocarditis. Although immunoblots on serum samples from three of the four patients were consistent with prior infection fromB burgdorferi, a positive immunoblot does not establish active infection. Similarly, seropositivity toB burgdorferionly indicates possible exposure to this organism. The occurrence of positive serologies toB burgdorferiin the presence of other diseases can lead to diagnostic confusion. (JAMA. 1990;264:2916-2918)

To the Editor.— The following patient was first described in theArchivesin March 1953 (67:429-430) as a case of "essential" cryoglobulinemia. Follow-up evaluation was obtained in the course of a retrospective review of 40 patients with this syndrome seen at our medical center during the past 20 years. 1 This case illustrates the coexistence of clinical features of systemic vasculitis and lymphoproliferative disease in some patients with serum cryoglobulins. Report of a Case.— A 33-year-old woman had recurrent purpura and arthralgias develop three years earlier during pregnancy. The rash was aggravated by cold exposure and initially involved the legs but later spread to the arms and buttocks. A skin biopsy specimen showed leukocytoclastic angiitis. Eventually, a left lateral malleolar leg ulcer developed, but the condition responded gradually to bed rest. Two years previously, hepatosplenomegaly had been noted. A liver biopsy specimen indicated portal infiltration by lymphocytes and plasma cells, consistent