Amyloidosis refers to a clinically heterogeneous group of disorders characterized by the extracellular deposition of amyloid proteins in various tissues of the body. To date, 42 different amyloid proteins that originate from normal precursor proteins and are associated with distinct clinical forms of amyloidosis have been described. Identification of the amyloid type is essential in clinical practice, since prognosis and treatment regimens both vary according to the particular amyloid disease. However, typing of amyloid protein is often challenging, especially in the two most common forms of amyloidosis, i.e., the immunoglobulin light chain amyloidosis and transthyretin amyloidosis. Diagnostic methodology is based on tissue examinations as well as on noninvasive techniques including serological and imaging studies. Tissue examinations vary depending on the tissue preparation mode, i.e., whether it is fresh-frozen or fixed, and they can be carried out by ample methodologies including immunohistochemistry, immunofluorescence, immunoelectron microscopy, Western blotting, and proteomic analysis. In this review, we summarize current methodological approaches used for the diagnosis of amyloidosis and discusses their utility, advantages, and limitations. Special attention is paid to the simplicity of the procedures and their availability in clinical diagnostic laboratories. Finally, we describe new methods recently developed by our team to overcome limitations existing in the standard assays used in common practice.

Objective Amyloid A nephropathy of FMF usually progresses over many years to end-stage renal disease (ESRD). We aim to describe an acute condition, termed here ‘amyloid storm’, typically manifesting with a rapid (≤2 weeks) increase in serum creatinine and urine protein, that has never been characterized in FMF amyloidosis. Methods This retrospective analysis features amyloid storm by comparing between FMF amyloidosis patients who have experienced an episode of amyloid storm (study group) and matched patients who have not (control group). The primary outcome was ESRD or death within 1 year from study entry. Featured data were retrieved from hospital files. Results The study and control groups, each comprising 20 patients, shared most baseline characteristics. However, they differed on the time from FMF onset to reaching serum creatinine of 1.2 mg/dl [26.5 years (s.d. 15.15) vs 41.55 (10.98), P = 0.001] and the time from the onset of proteinuria to study entry [8.8 years (s.d. 6.83) vs 15.75 (13.05), P = 0.04], culminating in younger age at study entry [39.95 years (s.d. 16.81) vs 48.9 (9.98), respectively, P = 0.05] and suggesting an accelerated progression of kidney disease in the study group. Within 1 year from study entry, 16 patients in the study and 3 in the control groups reached the primary endpoint (P = 0.000). The major triggers of amyloid storm were infections, occurring in 17 of 20 patients. Conclusion Amyloid storm is a complication of FMF amyloidosis, induced by infection and associated with poor prognosis and death.

Familial Mediterranean fever (FMF), the most frequent monogenic autoinflammatory disease, is manifested with recurrent and chronic inflammation and amyloid A (AA) amyloidosis, driven by overproduction of interleukin 1 (IL-1) through an activated pyrin inflammasome. Consequently, non-responsiveness to colchicine, the cornerstone of FMF treatment, is nowadays addressed by IL-1- blockers. Each of the two IL-1 blockers currently used in FMF, anakinra and canakinumab, has its own merits for FMF care. Here we focus on anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist, and explore the literature by using PubMed regarding the utility of anakinra in certain conditions of FMF. Occasionally we enrich published data with our own experience. To facilitate insights to anakinra role, the paper briefs some clinical, genetic, pathogenetic, and management aspects of FMF. The clinical settings of FMF covered in this review include colchicine resistance, AA amyloidosis, renal transplantation, protracted febrile myalgia, on- demand use, leg pain, arthritis, temporary suspension of colchicine, pediatric patients, and pregnancy and lactation. In many of these instances, either because of safety concerns or a necessity for only transient and short-term use, anakinra, due to its short half-life, is the preferred IL-1 blocker.

Background: Familial Mediterranean fever (FMF) is an autosomal recessive disease associated with mutations in the Mediterranean fever gene (MEFV) that manifests with recurrent episodes of febrile serositis. Fabry’s disease (FD) is an X-linked lysosomal storage disease caused by mutations in thealpha-galactosidase Agene and presents with a wide range of gastrointestinal, skin, vascular, renal and neurological manifestations. FMF and FD share similar manifestations, which may lead to misdiagnosis of one as the other; mostly FD is misdiagnosed as FMF. Moreover, various overlapping manifestations may stem from comorbidities, commonly coupled to FMF (such as Behcet's disease, inflammatory bowel disease, glomerulonephritis, fibromyalgia, and multiple sclerosis), as well as from colchicine adverse effects, which may add to the diagnostic confusion. Thus, we postulated that screening FMF for FD will lead to the identification of patients falsely diagnosed with FMF or who, in addition to FMF, suffer from FD that was previously missed.Methods: To identify missed FD among the FMF population, we performed chemical and genetic analyses for FD in blood samples obtained from a cohort of FMF patients followed in the specialized FMF center of our institution. To increase the likelihood of detecting patients with FD, we enriched the surveyed FMF population with patients exhibiting manifestations shared by patients with FD or who deviate from the typical FMF presentation.Results and conclusions: Of 172 surveyed FMF patients in a cohort derived from a clinic dedicated to FMF, none had FD. Thus, the postulation of increased odds for detecting FD in patients with FMF was not confirmed. Further exploration for FD in FMF population, is nevertheless recommended.