Paraprotein-related renal disease

Paraprotein-related renal disease represents a diverse group of rare diseases characterized by distinct renal injury caused by the direct or indirect effects of a nephrotoxic paraprotein secreted by a clone of B cells. Early diagnosis and use of rapidly effective chemotherapy agents have improved patient and renal outcomes for these disorders. Patients can present with proteinuric renal impairment or tubular dysfunction. Diagnosis is often challenging because of the wide range of disease manifestations, difficulties with detection of the pathogenic clone and the common finding of an incidental paraprotein in elderly individuals. A renal biopsy along with haematological work-up is required to link a paraprotein with kidney disease. Chemotherapy directed at the plasma cell clone can halt the production of the paraprotein, which can in turn benefit renal function

Amyloidosis and the lungs and airways

Amyloidosis can both complicate long-standing respiratory conditions and be deposited within the respiratory system itself. In acquired systemic amyloidosis, control of the underlying condition that is producing the circulating amyloid precursor protein is paramount. Systemic AA amyloidosis can result from unremitting chronic inflammation or infection such as in bronchiectasis. Control of the inflammation is paramount to amyloid regression. For systemic AL amyloidosis, treatment requires the use of chemotherapy or novel immunotherapies targeting the underlying plasma cell dyscrasia or lymphoproliferative disease that produce the abnormal amyloidogenic light chain. Localised amyloidosis can occur anywhere along the respiratory tract and can present with marked heterogeneity. In localised amyloidosis, management generally involves resection or ablation of symptomatic deposits. On occasion, localised pulmonary amyloidosis can be a manifestation of underlying Sjögren syndrome. Novel treatments are beginning to become available, including specific drug therapies to prevent translation of amyloidogenic proteins, stabilise amyloid precursor proteins and interfere with amyloid fibrillogenesis

Periodic fever syndromes

Periodic fever syndromes are autoinflammatory diseases. The majority present in infancy or childhood and are characterised by recurrent episodes of fever and systemic inflammation that occur in the absence of autoantibody production or identifiable infection. The best recognised disorders include CAPS, FMF, TRAPS and MKD. Understanding the molecular pathogenesis of these disorders provides unique insights into the regulation of innate immunity. Diagnosis relies on clinical acumen and is supported by genetic testing. With the exception of FMF, which is prevalent in populations originating from the Mediterranean, these syndromes are rare and easily overlooked in the investigation of recurrent fevers. Disease severity varies from mild to life threatening, and one of the most feared complications is AA amyloidosis. Effective therapies are available for many of the syndromes, including colchicine, IL-1 blockade and anti-TNF therapies, and there is an increasing interest in blocking interferon pathways

Systemic amyloidosis in England: an epidemiological study.

Epidemiological studies of systemic amyloidosis are scarce and the burden of disease in England has not previously been estimated. In 1999, the National Health Service commissioned the National Amyloidosis Centre (NAC) to provide a national clinical service for all patients with amyloidosis. Data for all individuals referred to the NAC is held on a comprehensive central database, and these were compared with English death certificate data for amyloidosis from 2000 to 2008, obtained from the Office of National Statistics. Amyloidosis was stated on death certificates of 2543 individuals, representing 0·58/1000 recorded deaths. During the same period, 1143 amyloidosis patients followed at the NAC died, 903 (79%) of whom had amyloidosis recorded on their death certificates. The estimated minimum incidence of systemic amyloidosis in the English population in 2008, based on new referrals to the NAC, was 0·4/100 000 population. The incidence peaked at age 60-79 years. Systemic AL amyloidosis was the most common type with an estimated minimum incidence of 0·3/100 000 population. Although there are various limitations to this study, the available data suggest the incidence of systemic amyloidosis in England exceeds 0·8/100 000 of the population

Cryopyrin-Associated Periodic Fever Syndrome and the Nervous System

PURPOSE OF REVIEW: The purpose of this review is to highlight the molecular and clinical characteristics of the cryopyrin-associated periodic fever syndrome (CAPS) and its management. CAPS is an autosomal dominantly inherited autoinflammatory disorder associated with mutations in the NLRP3 gene, which ultimately lead to excessive production of interleukin-1β (IL-1β) and systemic inflammation. Typical systemic features include fever, urticarial rash and arthralgia, and ultimately amyloidosis. There are also multiple neurological manifestations including, but not restricted to, headache, sensorineural hearing loss, aseptic meningitis, myalgia and optic nerve involvement. RECENT FINDINGS: Since the recognition of CAPS as a single disease entity and discovery of the underlying causative gene, there has been a major breakthrough in terms of its treatment by pharmacological IL-1β inhibition. Highly targeted therapies against IL-1 have been shown to be remarkably effective in the treatment of CAPS and make early diagnosis of this condition crucial. It is hoped that starting pharmacological intervention in a timely manner will prove neuroprotective. There are three drugs licensed for treatment of CAPS; canakinumab, anakinra and rilonacept. The former two are widely used: canakinumab is a fully humanised anti-IL-1β monoclonal antibody administered as a subcutaneous injection once every 8 weeks starting at a dose of 150 mg in patients weighing more than 40 kg. Anakinra is a recombinant form of the IL-1 receptor antagonist and the adult daily dose is 100 mg subcutaneously. CAPS is a highly debilitating disorder characterised by unregulated IL-1β production driven by autosomal dominantly inherited mutations in the NLRP3 gene. Effective therapies targeted against IL-1 are now available and are vital to prevent long-term complications

Senile Systemic Amyloidosis: Clinical Features at Presentation and Outcome

Background Cardiac amyloidosis is a fatal disease whose prognosis and treatment rely on identification of the amyloid type. In our aging population transthyretin amyloidosis (ATTRwt) is common and must be differentiated from other amyloid types. We report the clinical presentation, natural history, and prognostic features of ATTRwt compared with cardiac‐isolated AL amyloidosis and calculate the probability of disease diagnosis of ATTRwt from baseline factors. Methods and Results All patients with biopsy‐proven ATTRwt (102 cases) and isolated cardiac AL (36 cases) seen from 2002 to 2011 at the UK National Amyloidosis Center were included. Median survival from the onset of symptoms was 6.07 years in the ATTRwt group and 1.7 years in the AL group. Positive troponin, a pacemaker, and increasing New York Heart Association (NYHA) class were associated with worse survival in ATTRwt patients on univariate analysis. All patients with isolated cardiac AL and 24.1% of patients with ATTRwt had evidence of a plasma cell dyscrasia. Older age and lower N‐terminal pro‐B‐type natriuretic peptide (NT pro‐BNP) were factors significantly associated with ATTRwt. Patients aged 70 years and younger with an NT pro‐BNP <183 pmol/L were more likely to have ATTRwt, as were patients older than 70 years with an NT pro‐BNP <1420 pmol/L. Conclusions Factors at baseline associated with a worse outcome in ATTRwt are positive troponin T, a pacemaker, and NYHA class IV symptoms. The age of the patient at diagnosis and NT pro‐BNP level can aid in distinguishing ATTRwt from AL amyloidosis

Cardiovascular disease risk assessment in patients with familial Mediterranean fever related renal amyloidosis

Chronic inflammation and proteinuria is a risk factor for cardiovascular disease (CVD) in patients with chronic kidney diseases and rheumatologic disorders. Our aim was to investigate the CVD events (CVDEs) and survival between the patients with FMF-related AA amyloidosis and glomerulonephropathies (GN) to define possible predictors for CVDEs. A prospective follow-up study with FMF-amyloidosis and glomerulonephropathy (GN) was performed and patients were followed for CVDEs. Flow-mediated dilatation (FMD), FGF-23, serum lipid, hsCRP levels, BMI and HOMA were assessed. A Cox regression analysis was performed to evaluate the risk factors for CVDEs. There were 107 patients in the FMF-amyloidosis group and 126 patients with GN group. Forty-seven CVDEs were observed during the 4.2-years follow up; all 28 patients in the FMF-amyloidosis group and 14/19 patients with GN developed CVDEs before the age of 40 (p = 0.002). CVD mortality was 2.8 times higher (95% CI 1.02–7.76) in patients with FMF-amyloidosis. Across both groups, FMD and FGF23 (p < 0.001) levels were independently associated with the risk of CVDEs. Patients with FMF-amyloidosis are at increased risk of early CVDEs with premature mortality age. FGF 23, FMD and hsCRP can stratify the risk of early CVD in patients with FMF-related AA amyloidosis

Trapped without a diagnosis: Tumour necrosis factor receptor-associated periodic syndrome (TRAPS)

Tumour necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant condition caused by mutations in the TNFRSF1A gene. It is characterised by recurrent episodes of myalgia, followed by prolonged fever, migratory rashes, headache, serositis, arthralgia, abdominal pain and periorbital oedema. We describe a 49-year-old man with a self-limiting episode of paraparesis who reported recurrent bouts of abdominal symptoms and headaches since childhood. He had a persistent inflammatory response with night sweats and weight loss. We diagnosed TRAPS 2 years after having identified a TNFRSF1A gene mutation. His symptoms and inflammatory response resolved dramatically with the interleukin-1 receptor antagonist anakinra