This clinical case series presents descriptions of 3 patients with familial Mediterranean fever (FMF) who have atypical manifestations and abnormal inheritance mechanisms in terms of Gregor Mendel's laws. Although molecular genetic testing can help with disease diagnosis, it is not always conclusive. The primary need for genetic testing in atypical cases is to explain the mechanism of inflammation and to select the optimal therapy. These clinical observations demonstrate the changes in the spectrum of phenotypic manifestations of FMF in the context of the widespread introduction of molecular genetic methods.

In the history of amyloidosis studying the concept of liquids dyscrasia has been predominated and finally it is resulted in accepting a serum protein-precursor as a leading amyloidogenic factor in the disease pathogenesis. Consequently basic diagnostic and treatment strategy was aimed to find and eliminate this protein from the blood and this approach evidenced high effectiveness in most frequent AA and AL-amyloidosis characterized with anomaly high levels of precursors in the blood. At the same time there are less frequent and slower progressing inheritant forms of systemic amyloidosis including transthyretin induced, which are less depending on amyloidogenecity of amyloid precursor and because of that, in example, the effectiveness of transthyretin stabilizers or blockers of its synthesis is limited comparing with the precursor elimination in AA or AL. Developed in the middle of XX century a theory of local synthesis by macrophages is more preferable to describe the pathogenesis of these forms. And modern proteome analysis using give rise to confirm the key meaning of macrophage in the amyloidogenesis and proves necessity to know deeply mechanisms of macrophagial autophagia – basic tool of maintaining intracellular protein homeostasis. That is why it is difficult to hope on high effectiveness of chemical amyloid solvents in vivo, which being under macrophages regulation never could realize its chemical activities.

Tumour necrosis factor receptor-associated periodic syndrome (TRAPS) belongs to a group of rare hereditary autoinflammatory diseases (familial periodic fevers). TRAPS is characterized by the periodic occurrence of fever, abdominal pain, maculopapular rash, arthralgia/myalgia and laboratory signs of inflammation that persisit for 5 days to 3 weeks. AAamyloidosis can complicate persisting autoinlammation in TRAPS. The authors report two cases of TRAPS and discuss its diagnosis and treatment.

Lysozyme amyloidosis is caused by an amino acid substitution in the sequence of this protein. In our study, we described a clinical case of lysozyme amyloidosis in a Russian family. In our work, we described in detail the histological changes in tissues that appeared as a result of massive deposition of amyloid aggregates that affected almost all organ systems, with the exception of the central nervous system. We determined the type of amyloidosis and mutations using mass spectrometry. Using mass spectrometry, the protein composition of tissue samples of patient 1 (autopsy material) and patient 2 (biopsy material) with histologically confirmed amyloid deposits were analyzed. Amino acid substitutions p.F21L/T88N in the lysozyme sequence were identified in both sets of samples and confirmed by sequencing of the lysozyme gene of members of this family. We have shown the inheritance of these mutations in the lysozyme gene in members of the described family. For the first time, we discovered a mutation in the first exon p.F21L of the lysozyme gene, which, together with p.T88N amino acid substitution, led to amyloidosis in members of the studied family.

Takayasu’s arteritis (TAK) is a systemic large vessel vasculitis that usually develops at young age in females and affects aorta and its branches (pulseless disease). Patients with TAK frequently present with renal artery stenosis associated with renovascular hypertension and ischemic nephropathy, whereas glomerular and interstitial kidney disease is very rare. As any other chronic inflammatory diseases, TAK can be complicated with AA-amyloidosis manifesting by progressive proteinuria, nephrotic syndrome and chronic renal failure. AA-amyloidosis in patients with TAK and other immune-mediated inflammatory disease justifies intensification of immunosuppressive and antiinflammatory therapy (e.g. using interleukin-6 inhibitors) that is essential to prevent progression of kidney amiloidosis.

Transthyretin is primarily synthesized in the liver and transports thyroxine and vitamin A in the body. The transthyretin when dissociated into monomers can misfold and ultimately form amyloid fibrils. There are two types of ATTR amyloidosis: hereditary (caused by mutations in the TTR gene) and wild-type (also referred to as senile systemic amyloidosis). Amyloid cardiomyopathy can develop in patients with both types of ATTR amyloidosis, has a later onset and is characterized by progressive heart failure leading to death within a few years after diagnosis. Tafamidis is an oral-administered small molecule that binds to transthyretin and inhibits transthyretin tetramer dissociation, the rate-limiting step in the amyloidosis. Long-term efficacy and safety of tafamidis were shown in patients with transthyretin familial amyloid polyneuropathy. The objective of the phase 3 international, multicenter, double-blind, placebo-controlled, randomized ATTR-ACT study was to evaluate the efficacy, safety, and tolerability of tafamidis (20 or 80 mg orally QD) in comparison with placebo in 441 patients with hereditary and nonhereditary transthyretin cardiomyopathy (median age 75 years, 90% of males). At month 30, treatment with tafamidis was associated with a lower risk of all-cause mortality (by 30%) and a lower rate of cardiovascular related hospitalizations (by 32%) than placebo and resulted in a lower rate of decline in distance for the 6-minute walk test and a lower rate of decline in KCCQ-OS score. The data from extension study supports tafamidis 80 mg as the optimal dose (bioequivalent to tafamidis free acid 61 mg).

To evaluate diagnostic and treatment issues in patients with familial Mediterranean fever (FMF) and risk factors for AA-amyloidosis.

AA amyloidosis complicates various chronic inflammatory disorders and is characterized by the accumulation of amyloid fibrils composed of serum amyloid A protein, an acute phase reactant. In recent decades, the role of chronic infections and rheumatoid arthritis in the ethiology of AA amyloidosis have decreased significantly as a result of their treatment improvement, whereas both monogenic (familial Meditarranean fever, cryopirin-associated periodic syndrome, etc.) or polygenic (ankylosing spondilitis, psoriatic arthritis, adult onset Still’s disease, etc) autoinflammatory diseases more frequently account for AA-amyloidosis today. Autoinflammatory diseases are a consequence of innate immunity disorders although the latter can contribute to the pathogenesis of autoimmune diseases as well. In patients with autoinflammatory diseases, the suppression of inflammation, even subclinical, is essential to prevent development or progression of AA amyloidosis. The choice of inflammatory agents that can be used to achieve this aim depends on the pathogenesis of autoinflammation, e.g. key mediators that are involved in the activation of inflammatory cascade.

AIM To investigate an influence of the currently changed etiologic structure of AA-amyloidosis on the diagnosis and treatment tactics. MATERIALS AND METHODS In 110 patients with АА-amyloidosis followed during full disease duration (1 month 29 years) etiology, clinical manyfestations and approaches to diagnose and treatment of AA-amyloidosis were evaluated. With ELISA levels of amyloid precursor acute phase inflammation reactant SAA and neutrophil activity marker S100A12 were measured. RESULTS Among the most common causes of AA-amyloidosis at the present stage, in addition to RA (40.3%), a significant place is occupied by a group of diseases with a predominantly autoinflammatory mechanism (53.73%). To confirm the autoinflammatory mechanism of the predisposing disease it is recommended to study a highly sensitive parameter serum protein S100A12. An effective marker of the risk of AA-amyloidosis progression, especially in patients with subclinical activity of inflammatory disease, is a high level of production of amyloidogenic protein-a precursor of SAA.

In a recent study, Deshayes et al used 16S ribosomal RNA gene sequencing to analyse the gut microbiome in patients with familial Mediterranean fever (FMF) complicated or not by AA amyloidosis and in patients with AA amyloidosis of another origin.1 Compared with healthy controls, FMF was associated with decreased α-diversity (ie, microbial richness and evenness) and altered composition of the gut microbiome. Certain operational taxonomy units (OTUs) belonging to the Clostridiales were associated with FMF, whereas two OTUs were overrepresented in AA amyloidosis among FMF patients. The authors suggested that intestinal microorganisms may play a role in the clinical expression and pathogenesis of these diseases. In a similar study, decreased species richness diversity was shown in the microbiome of patients with systemic lupus erythematosus (SLE). Moreover, SLE was associated with intestinal outgrowth of Ruminococcus gnavus of the Lachnospiraceae family that was most pronounced in those with lupus nephritis and correlated with disease activity.2 These and previous studies in spondyloarthritis and rheumatoid arthritis reflect the growing interest of researchers to the role …

The article discusses the current possibilities of postinfectious AA-amyloidosis treatment with dimexide on the example of clinical observation, discribes in detail the problem of functional amyloid and debates the prospects of the principle of amyloid resorption in the treatment of systemic amyloidosis. The history of the use of dimexide in medical practice is given, thenecessary dataon the pharmacology of dimexide are presented.

The article presents the case report of a rare hereditary form of systemic ATTR-amyloidosis in Russian patient with a discussion of approaches to the diagnosis and treatment of this form, also based on the own experience in the management of such patients. Modern ideas about the pathogenesis of the disease as well as detailed information about the clinical manifestations of amyloid cardiopathy and of other organs are presented. The nature of structural and hemodynamic changes in the heart is discussed on the basis of experience, including own, ultrasound examination of the heart in patients with amyloidosis, especially the article focuses the reader's attention on the true infiltrative nature of transtiretin amyloid cardiopathy in contrast to AL-amyloidosis, in which there is a significant inflammatory component that determines a more unfavorable natural course of AL-amyloidosis of the heart. The article discusses the differential diagnosis of different types of amyloidosis, the diagnostic difficulties associated with weak congophilia of transtiretin amyloidosis and at the same time substantiates the need for morphological verification of the diagnosis. Modern methods of treatment of ATTR-amyloidosis are discussed.

"The critical role of chronic kidney disease in the progression of AL-amyloid cardiopathy." Amyloid, 26(sup1), pp. 109–110

The aim of the study was to evaluate the clinical and genetic predictors of AA amyloidosis in patients with familial Mediterranean fever (FMF). We retrospectively studied 170 Armenian patients who were admitted to the two tertiary centers in 2003–2014. The diagnosis of amyloidosis that was suspected clinically (new proteinuria or nephrotic syndrome) was confirmed histologically. Screening for MEFV gene mutations was performed in 70 patients. The most common genotype was M694V/M694V (in 36 % of patients). Biopsy-proven AA amyloidosis was found in 102 (60 %) of 170 patients. AA amyloidosis was diagnosed in 17 (68 %) of 25 patients with homozygous M694V mutation, 17 (53 %) of 32 patients with heterozygous M694V allele and 4 (31 %) of 13 patients with other MEFV gene mutations. The M694V homozygosity and heterozygosity were associated with increased risk of AA amyloidosis, but this association did not reach statistical significance (odds ratio 2.43; 95 % CI 0.87–6.76, and 3.33; 0.91–12.1, respectively). Male gender, early onset of disease, severity of FMF, frequent attacks, peritonitis, pleuritis and erysipelas-like erythema also did not predict AA amyloidosis development. Recurrent arthritis was the only clinical finding that was significantly associated with AA amyloidosis (odds ratio 2.28; 95 % CI 1.17–4.42). Involvement of the joint synovial membrane, that is capable of active serum amyloid A production, is the main predictor of renal amyloidosis in FMF.

Familial Mediterranean fever (FMF) is a hereditary inflammatory disorder. FMF is an autoinflammatory disease caused by mutations in MEFV, a gene which encodes a 781–amino acid protein denoted pyrin. AA-amyloidosis is the main complication of FMF.