Treatment of renal amyloidosis with etanercept in tumour necrosis factor receptor-associated periodic syndrome

E. Drewe, M. L. Huggins, A. G. Morgan, M. J. D. Cassidy and R. J. Powell

Correspondence to: E. Drewe, Clinical and Molecular Immunology, University Hospital, Nottingham NG7 2UH, UK. E-mail: liz.drewe{at}nottingham.ac.uk


    Abstract
 Top
 Abstract
 Introduction
 Case 1
 Case 2
 Discussion
 References
 
Objective. To describe the effect of Etanercept treatment in systemic AA amyloidosis in tumour necrosis factor receptor-associated periodic syndrome (TRAPS).

Methods. Etanercept therapy was given to a 27 year old woman, with systemic amyloidosis and nephrotic syndrome, and to her 51 year old father, also affected by TRAPS, who had previously undergone renal transplant for amyloidosis. Serum SAA levels, plasma cytokines, glomerular filtration rate and serum amyloid P scanning were monitored.

Results. Etanercept treatment resulted in initial clinical resolution of nephrotic syndrome in the 27 year old female. Both subjects demonstrated improvements in GFR and initial reduction or stabilisation of amyloid deposits on SAP scanning.

Conclusion. Etanercept may reverse or slow the progression of systemic AA amyloidosis in subjects with C33Y TNFRSF1A mutation. Treatment may however need to be continuous and life-long to prevent progression to end stage disease.

KEY WORDS: TRAPS (TNF receptor-associated periodic syndrome), Amyloid, Etanercept, Nephrotic syndrome, SAA (serum amyloid A), GFR (glomerular filtration rate)


    Introduction
 Top
 Abstract
 Introduction
 Case 1
 Case 2
 Discussion
 References
 
Tumour necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory disease, or hereditary periodic fever syndrome, which is caused by mutations in TNFRSF1A (TNFR1) [1]. Other diseases in this cateogry include familial Mediterranean fever, hyper-immunoglobulin (Ig) D syndrome, Muckle-Wells syndrome and familial cold autoinflammatory syndrome. TRAPS is characterized by attacks lasting 1–4 weeks. Clinical manifestations include serositis, migratory myalgia and erythema, arthralgia and conjunctivitis. Amyloidosis occurs in 14% of subjects with TRAPS [2] and is also common in FMF and Muckle–Wells syndrome.


    Case 1
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 Abstract
 Introduction
 Case 1
 Case 2
 Discussion
 References
 
A 27-yr-old woman presented in May 1999 with nephrotic syndrome [3]. She had suffered with TRAPS, due to C33Y TNFRSF1A mutation, characterized by recurrent attacks of fever and abdominal pain since 18 months of age, requiring intermittent oral prednisolone. In the 6 months prior to presentation, she had reported an increase in the frequency and severity of attacks. Twenty-four hour urinary protein excretion was 10.3 g, serum albumin 24 g/l (normal range 30–48 g/l) and serum IgG 2.7 g/l (normal range 6–15 g/l). Serum amyloid P (SAP) scan suggested amyloid in the kidneys and spleen. Systemic AA amyloidosis had complicated her father's illness (case 2). In October 1999, she commenced twice-weekly subcutaneous injections of 25 mg of etanercept. After 4 months of treatment, clinical improvement of the nephrotic syndrome was apparent, 24-h urinary protein falling to 2.1 g, serum albumin rising to 30 g/l and IgG 5 g/l. SAP scan suggested regression of amyloidosis and the glomerular filtration rate (GFR) rose from 43 to 59 ml/min/1.73 m2. Improvement of the nephrotic syndrome was maintained by etanercept therapy for 2 yr and was accompanied by a dramatic reduction in inflammatory symptoms. Significant reductions in CRP and ESR occurred and serum amyloid A (SAA) levels fell to less than 10 mg/l (Fig. 1). Detectable plasma TNF-{alpha} levels rose on etanercept therapy, with no other differences in a cytokine panel measured by cytometric bead array both on and off etanercept (Table 1).



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FIG. 1. SAA levels (mg/l) in case 1. Arrow marks the start of etanercept treatment.

 

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TABLE 1. Cytokines (pg/ml) in cases 1 and 2, who were well whilst on and off etanercept

 
After 2 yr of treatment and whilst discussing future treatment plans, the patient stopped the etanercept. Within 6 weeks she had a further inflammatory attack and relapse of the nephrotic syndrome, with 24-h urinary protein 9.9 g, serum albumin 20 g/l and serum IgG 2.3 g/l. Within 3 months of reintroducing etanercept, further improvement occurred, 24-h urinary protein falling to 3.6 g and serum albumin and IgG rising to 28 and 4.9 g/l respectively. A period of non-compliance 4 yr after initiating etanercept followed by inadvertently taking a cough preparation containing aspirin resulted in nephrotic syndrome and a significant deterioration in renal function, GFR falling to 11 ml/min/1.73 m2. Renal function did not improve on treatment with etanercept 25 mg three times weekly and the subject required renal dialysis. The subject is currently awaiting renal transplantation and remains on etanercept 25 mg twice weekly to mitigate extrarenal deposition of amyloidosis.


    Case 2
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 Abstract
 Introduction
 Case 1
 Case 2
 Discussion
 References
 
This 54-yr-old male (the father of case 1) with TRAPS presented with chronic renal failure aged 46 yr. Renal biopsy demonstrated AA amyloidosis and SAP scan suggested amyloid deposition in the liver, kidneys and spleen. His TRAPS had also manifested in early childhood, with febrile abdominal attacks and subsequent features that included purpuric rash, chest pain and myalgia. Treatment prior to renal failure had included prednisolone and thalidomide. His course was complicated by Salmonella enteritidis septicaemia and a thigh abscess, presumably associated with hypogammaglobulinaemia secondary to urinary protein loss. Treatment with oral chlorambucil followed by cyclophosphamide produced improvement in TRAPS but not renal impairment, which subsequently required haemodialysis. Aged 49 yr, he underwent successful cadaveric renal transplantation and subsequent immunosuppression consisted of prednisolone, azathioprine and cyclosporin. Two years after transplantation, SAP scan suggested amyloid involving the renal transplant. He was commenced on subcutaneous etanercept 25 mg twice weekly without complication. During 2 yr of follow-up his renal function has improved, creatinine falling from 258 to 165 µmol/l and GFR rising from 19 to 83/min/1.73m2, and the SAP scan has stabilized.


    Discussion
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 Abstract
 Introduction
 Case 1
 Case 2
 Discussion
 References
 
Amyloidosis represents the most severe complication of TRAPS. Risk factors include mutations involving the cysteine residues of TNFRSF1A and a positive family history. The two cases described represent the only subjects with amyloidosis from an extended family of 13 subjects with C33Y TRAPS. Other genetic and environmental factors may therefore modulate susceptibility to amyloidosis in TRAPS. SAA genotype as well as specific mutations in the MEFV gene have been linked to susceptibility to renal amyloidosis in FMF [4].

Amyloidosis in TRAPS usually presents with nephrotic syndrome and treatment of early renal involvement (e.g. proteinuria) with corticosteroids, colchicine, azathioprine or chlorambucil fails to prevent end-stage renal failure [5, 6]. Renal transplantation for AA amyloidosis is associated with mortality from sepsis and extrarenal amyloidosis (e.g. cardiac arrhythmia), but survival may not be worse than with other indications for transplantation [7]. Recurrent amyloidosis may, however, occur in the transplanted kidney in TRAPS, despite immunosuppression to prevent rejection [5].

The soluble TNFRSF1B-linked Fc human IgG1 recombinant fusion protein etanercept significantly reduces the acute-phase response and corticosteroid use in some patients with TRAPS [8]. The role and dosing regime of etanercept in the long-term management of TRAPS is, however, unestablished. Etanercept was well tolerated in both the cases described, neither subject experiencing infections or neurological symptoms. The rapid clinical resolution of nephrotic syndrome in case 1 was unexpected.

Nephrotic syndrome in association with renal amyloidosis may occasionally regress, despite persisting histological evidence of renal amyloidosis, with treatment of the underlying disease (e.g. infection) or spontaneously [9, 10]. Whilst spontaneous remission of nephrotic syndrome cannot be excluded in case 1, the recurrence of nephrotic syndrome coinciding with stopping etanercept on two occasions makes this unlikely. Serial renal biopsies were not undertaken in case 1, but the finding of amyloid regression on SAP scan suggests that etanercept may have reduced the amyloid load.

There have recently been several reports that anti-TNF agents may affect nephrotic syndrome or amyloidosis in TRAPS as well as other inflammatory diseases. Etanercept has been effective in preventing the recurrence of amyloidosis, as assessed by repeat liver biopsy, in a patient with C33G mutation TRAPS who underwent liver transplantation for treatment of AA amyloid-induced hepatic failure. A patient with C52F mutation, however, took etanercept for more than 2 yr with dramatic improvement of TRAPS, but developed nephrotic syndrome with renal amyloidosis which may have reflected failure to adequately suppress SAA levels [11]. A 37-yr-old woman with adult Still's disease also had a progressive regression of nephrotic syndrome over a 17-month treatment period with etanercept [12]. The anti-TNF-{alpha} monoclonal antibody infliximab has also been associated with clinical remission of nephrotic syndrome in a 39-yr-old woman with seropositive arthritis within weeks of starting treatment [13]. In this subject, SAP scan had stabilized at 1 yr. Response to anti-TNF agents is variable, however. A retrospective study of 15 subjects with AA amyloidosis secondary to inflammatory arthritides demonstrated 24-h proteinuria and/or GFR worsening in seven patients, stabilizing in five patients and dramatically improving in three patients during treatment with etanercept or infliximab [14].

A previous central role for TNF-{alpha} in the pathogenesis of amyloidosis was suggested by a case of renal amyloidosis that remitted following resection of a hepatic adenoma producing large quantities of TNF-{alpha} [15]. Whilst the pathogenesis of amyloid formation is incompletely understood, there are a number of possible mechanisms by which anti-TNF therapy could reduce the amyloid load. SAA is the precursor of AA amyloid fibrils and its transcription is under the control of TNF-{alpha}. Reduction of SAA to less than 10 mg/l is associated with regression of amyloid deposits by SAP scanning [16], and this initially occurred in case 1. TNF-{alpha} may also play a role in the proteolysis of SAA to AA in acidic intracellular vesicles following SAA-HDL endocytosis by macrophages. Macrophages in amyloid deposits also have increased expression of receptor advanced glycation end products (RAGE), which may bind AA, resulting in a signalling cascade that causes sustained activation of NF-{kappa}B [17, 18]. TNF-{alpha} also signals via NF-{kappa}B and anti-TNF agents could potentially disrupt RAGE-induced propagation of amyloidogenesis. The increased detectable plasma TNF-{alpha} levels in both cases could reflect the detection of immobilized TNF-{alpha} bound to circulating etanercept by the bead assay. As etanercept has a long half-life, accumulation of bound TNF-{alpha} is possible; hence, levels of plasma TNF-{alpha} appear to increase during etanercept treatment.

In rheumatoid arthritis, etanercept reduces levels of the cytokine-modulated metalloproteinase (MMP) enzymes involved in homeostasis of the extracellular matrix [19]. MMPs may participate in amyloidogenesis by influencing SAA production, SAA and AA proteolysis or by remodelling the extracellular matrix after AA deposition. This last explanation could be supported by the finding that etanercept may also influence regression of AL amyloid [20].

Whilst we have demonstrated amyloid regression by SAP scanning, amyloid quantification by SAP scanning correlates poorly with organ dysfunction [21]. Mechanisms other than amyloid reduction could therefore have contributed to the observed improvements in renal function. Serum TNF-{alpha} levels may be elevated in a wide range of renal diseases, such as membranous and IgA nephropathy and focal and segmental glomerulosclerosis [22, 23]. Mononuclear phagocytes may infiltrate and adhere to mesangial cells prior to functional and structural changes associated with renal injury [24]. Subsequent TNF-{alpha} production by macrophages, and to a lesser extent intrinsic glomerular cells, may be central to subsequent glomerular inflammation and glomerular membrane dysfunction. In vitro models antagonizing TNF-{alpha} may inhibit glomerular disease. In vitro animal models have suggested that TNF-{alpha} may enhance glomerular albumin permeability, favouring the development of proteinuria [25]. Proposed mechanisms include mesangial cell production of superoxide, resulting in alterations in the glomerular epithelial cell membrane, cytoskeleton or intercellular junctions.

The eventual development of end-stage renal failure in case 1 after stopping etanercept on the second occasion may have been related to cyclooxygenase inhibition by aspirin. Patients with nephrotic syndrome rely on increased prostaglandin production to maintain renal blood flow and glomerular filtration. The reintroduction of etanercept as a higher three-times-a-week dose was unable to reverse this damage. NSAIDs are also associated with tubulointerstitial nephritis, but this was not thought to be present in this case.

In summary, we have described two cases demonstrating initial regression and stabilization of amyloidosis by etanercept in TRAPS. Treatment may, however, need to be continuous and life-long to prevent progression to end-stage disease. This report provides further evidence for the dynamic turnover of amyloidosis despite its inherent insolubility. It is currently unclear how our experience relates to the treatment of amyloidosis in other cases of TRAPS and other inflammatory diseases. TNFRSF1A mutation and genes affecting amyloidogenesis and the response to etanercept may all be relevant.


    Acknowledgments
 
We are grateful to Professor P. N. Hawkins of the National Amyloidosis Centre, University College London, for performing SAP scans.

The authors have declared no conflicts of interest.


    References
 Top
 Abstract
 Introduction
 Case 1
 Case 2
 Discussion
 References
 

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Submitted 18 December 2003; revised version accepted 6 July 2004.