Familial Mediterranean fever in the pediatric population

Familial Mediterranean fever (FMF) is the most frequent autoinflammatory disorder characterized by short, repeated, and self-limiting crises of fever and serositis. The disease was described as autosomal recessive hereditary transmission secondary to variants of the MEFV (MEditerranean FeVer) gene, even though a variable proportion of patients only present a heterozygous variant. FMF is very common in certain ethnic groups (Turkish, Armenian, Arab, and Jewish), even though it has been described throughout the Mediterranean and elsewhere in the world. The clinical manifestations are variable, with secondary amyloidosis being the most serious complication of the disorder. Treatment and prophylaxis are mainly based on the administration of colchicine, which prevents the crises and avoids complications in most cases. This study reviews the course of seven pediatric patients diagnosed with FMF during the period 2010–2018 at a district hospital. Most of the patients were of Caucasian origin, with onset at an early age in the form of fever as the main symptom, and some patients moreover presented less frequent manifestations (pericardial effusion, sensorineural hearing loss). Two cases presented plasmatic amyloid A protein elevation that subsided with the treatment. All the patients initially received colchicine, and one of them required prescription of anakinra, which was replaced by canakinumab due to a serious adverse reaction. There were no cases of consanguinity, and all the patients were of Mediterranean origin. The subjects showed a favorable course over the years, which was attributed to the early diagnosis and treatment provided.

Serum amyloid A as a marker of ankylosing spondylitis activity

Serum amyloid A protein A (SAA) is a normal serum protein (serving as a precursor of fibrillar tissue protein AA), synthesized in the liver and a rapidly responding marker of the acute phase of inflammation. A constant high concentration of SAA is one of the factors in the development of AA-amyloidosis. As a rule, secondary amyloidosis develops in patients with long-term and poorly controlled inflammatory diseases, including rheumatic diseases, one of which is ankylosing spondylitis (AS).Objective: to assess the level of SAA in AS patients and its relationship with indicators of disease activity.Patients and methods. The study included 124 patients with AS who met the modified New York 1984 criteria. The disease activity and functional status of patients were assessed according to the recommendations of Russian experts. SAA and CRP, ESR in blood serum were measured in all patients.Results and discussion. The median SAA concentration was 12.5 mg/L [4; 71.6]. Of 124 patients, 31% had SAA levels <5 mg/L and 69% had >5 mg/L. A strong correlation was found between the levels of SAA and CRP (r=0.80, p<0.000001), no significant relationship was found between SAA and ESR (r=0.31, p=0.92). The correlation between the AS activity according to the BASDAI index and SAA was weak (r=0.3, p<0.002), the correlation with ASDAS-CRP was moderate (r=0.54, p<0.00001).Conclusion. A statistically significant relationship was found between SAA and CRP levels, as well as the AS activity indices. Research has shown that SAA can be used as one of the markers of inflammation in AS.

Amyloidosis and Glomerular Diseases in Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is a genetic autoinflammatory disease with autosomal recessive transmission, characterized by periodic fever attacks with self-limited serositis. Secondary amyloidosis due to amyloid A renal deposition represents the most fearsome complication in up to 8.6% of patients. Amyloidosis A typically reveals a nephrotic syndrome with a rapid progression to end-stage kidney disease still. It may also involve the cardiovascular system, the gastrointestinal tract and the central nervous system. Other glomerulonephritis may equally affect FMF patients, including vasculitis such as IgA vasculitis and polyarteritis nodosa. A differential diagnosis among different primary and secondary causes of nephrotic syndrome is mandatory to determine the right therapeutic choice for the patients. Early detection of microalbuminuria is the first signal of kidney impairment in FMF, but new markers such as Neutrophil Gelatinase-Associated Lipocalin (NGAL) may radically change renal outcomes. Serum amyloid A protein (SAA) is currently considered a reliable indicator of subclinical inflammation and compliance to therapy. According to new evidence, SAA may also have an active pathogenic role in the regulation of NALP3 inflammasome activity as well as being a predictor of the clinical course of AA amyloidosis. Beyond colchicine, new monoclonal antibodies such as IL-1 inhibitors anakinra and canakinumab, and anti-IL-6 tocilizumab may represent a key in optimizing FMF treatment and prevention or control of AA amyloidosis.

Association of ulcerative colitis and IgA nephropathy: A case report

The extradigestive manifestations of chronic inflammatory bowel disease most often affect the articulations, skin, eyes, liver and bile ducts. Renal involvement is rare, and manifests as kidney stones, glomerulonephritis, tubulointerstitial nephritis, and secondary amyloidosis. In this context of chronic inflammatory bowel disease, in particular ulcerative colitis, renal involvement is very often secondary to nephrotoxicity of the basic treatment of digestive pathology, and very rarely an authentic extradigestive manifestation of intestinal disease. We report a case of IgA nephropathy as an extra-digestive manifestation of ulcerative colitis. The objective of this study is not to neglect the IgA nephtopathy as an extradigestive manifestation of IBD which, even though rare, remains a condition to be looked for by clinicians during the follow-up of IBD.

A case of effective use of interleukin 6 inhibitors in patients with ankylosing spondylitis with secondary amyloidosis

Ineffectiveness of interleukin 6 inhibitors (iIL6), tocilizumab (TCZ) and sarilimumab in ankylosing spondylitis (AS) was shown in randomized clinical trials. However, there is ample evidence that IL6 is actively involved in the pathogenesis of this disease. In addition, the efficacy of iIL6 in patients with secondary AA-amyloidosis was established.Objective: to analyze the results of TCZ administration in AS, complicated by secondary AA-amyloidosis.Patients and methods. The analysis included 6 patients with AS with secondary AA-amyloidosis. All patients were HLA-B27 positive male. The average age of patients was 44±9.2 years, the average age of the disease onset was 16.3±7.9 years, the average duration of AS was 26.0±7.5 years. All 6 patients had pathomorphologic confirmed secondary AA-amyloidosis: all had kidney affection, 5 patients also had gastrointestinal tract affection and 2 had heart affection. As a first biological drug TCZ was prescribed in 2 patients, and 4 patients had previously received one or more inhibitors of tumor necrosis factor α. The average duration of TCZ treatment was 27.6 [3.0; 36.0] months.Results and discussion. During TCZ therapy, the level of CRP (M±σ) significantly decreased: from 81.1±74.5 to 1.2±0.8 mg/L (p<0.05), as well as daily proteinuria (Me [25th ; 75th percentile]): from 1.8 [1.0; 2.1] to 0.2 [0.1; 0.3] g/day (p<0.05) and AS activity indices – BASDAI (M±σ): from 6.2±1.6 to 3.3±0.9 (p<0.05 ); ASDAS-CRP (M±σ) from 4.6±1.1 to 2.04±0.7 (p<0.05). Positive dynamics was also noted in relation to a decrease in the number of patients with inflammatory back pain, arthritis and coxitis. A case of clinical and laboratory remission of AS on TCZ treatment is described. Conclusion. The presented data show that in certain clinical situations iIL6 can be highly effective in AS.

Difficulties of biological therapy in the patient with active rheumatoid arthritis and secondary renal amyloidosis: A report of clinical case

A clinical case of a patient with active rheumatoid arthritis (RA) resistant to standard basic therapy is presented, which served as the reason for the appointment of the target drug – Janus kinase, tofacitinib (Jaquinus) and then biological therapy using anti-IL6 receptor antibody tocilizumab (Actemra). This clinical example demonstrates the patient with the presence of several complications, both the course of the disease – amyloid nephropathy with the development of nephrotic syndrome (NS) as a manifestation of secondary amyloidosis with kidney damage, as well as basic therapy – the presence of comorbid infections with hospital pneumonia and infectious (septic) knee arthritis.An additional contribution of NS to the development of infectious complications in patients with RA receiving immunosuppressive therapy is supposed. Current treatment options for resistant RA and the feasibility of early use of biologics before the development of irreversible complications, as well as the difficulties of therapy and the complications associated with immunosuppression are discussed. Preventive measures for immunization with the anti-pneumococcal vaccine and the need to correct hemostatic disorders in patients with RA and NS are important.

Nephrotic Syndrome Following Resection of an Adrenal Incidentaloma:A Case Report

A 69 year old man had a 5 cm right adrenal lesion discovered incidentally while being investigated for a deterioration in previously well-controlled hypertension. Routine investigations including serum albumin were normal. Further investigation confirmed a non-functioning adrenal lesion. MRI revealed a ‘non-fat-containing T1 hyperintense indeterminate adrenal lesion with speckling of T2 hyperintensity, not typical for adenoma, hyperplasia, myelolipoma, haemangioma or pheochromocytoma’. An uncomplicated laparoscopic adrenalectomy was performed. Histology revealed a 118 g adrenal neoplasm, modified Weiss score 0, with abundant hyaline deposits.3 months later the patient complained of peripheral oedema. Investigations revealed a serum albumin of 24 g/L and 14 g of proteinuria in 24 hours. Serum protein electrophoresis revealed a monoclonal IgA type lambda band. Renal biopsy revealed amorphous material displaying apple green birefringence on staining with Congo Red, which stained with antibodies to lambda light chains, confirming AL amyloid. Therefore the patient’s resected adrenal specimen was retrieved and stained with Congo Red, revealing apple green birefringence in the walls of the blood vessels, confirming the presence of amyloidosis. Although adrenal gland involvement in secondary amyloidosis is common, adrenal involvement in primary amyloidosis is less well described. This case illustrates the indolent nature of primary amyloidosis, prior to the development of often catastrophic symptoms. Consideration should be given to Congo Red staining of resected pathologic specimens containing hyaline deposition, to potentially allow for earlier recognition of this devastating disease. A pathophysiologic link between the patient’s incidentaloma, adrenalectomy, and onset of nephrotic syndrome remains a matter for conjecture.

Successful Treatment of AA Amyloidosis in Ankylosing Spondylitis Using Tocilizumab: Report of Two Cases and Review of the Literature

Historically, secondary amyloidosis has been a feared complication of chronic inflammatory conditions. The fibril protein AA derives from the acute phase reactant serum amyloid A (SAA). Long-term elevation of SAA levels remains a major risk factor for the development of AA amyloidosis in rheumatic diseases, and the prognosis may be unpredictable. Nowadays, with increased availability of effective biological agents, the incidence of AA amyloidosis seems to be declining. Still, genetically predisposed subjects with slowly progressive disease and mild symptoms combined with ongoing systemic inflammation may be at risk. Interleukin-6 (IL-6) is one of the drivers of SAA release and effectiveness of the humanized anti-IL-6 receptor antibody tocilizumab (TCZ) for the treatment of AA amyloidosis has been observed in some rheumatic conditions. Herein, we report two male subjects with longstanding ankylosing spondylitis (AS) complicated by renal amyloidosis who received TCZ with rapid and beneficial effects regarding inflammation and proteinuria. To the best of our knowledge, the use of TCZ in AS patients with this extra-articular manifestation has not previously been described. The paper includes histopathology, clinical follow-up, and longitudinal data of the two cases along with a comprehensive review of relevant literature. Mechanisms behind amyloid-mediated tissue damage and organ dysfunction are discussed. Altogether, our data highlight that blocking IL-6 signaling may represent a promising therapeutic option in patients with renal AA amyloidosis.