Academic Rheumatology Unit, University Hospital Aintree, Liverpool L9 7AL,
1 Blackburn Royal Infirmary, Bolton Road, Blackburn BB2 3LR and
2 National Amyloidosis Centre, Department of Medicine, Royal Free and University College Medical School, Royal Free Campus, London NW3 2PF, UK
Abstract
Psoriatic spondyloarthropathy (PSA) can occasionally be complicated by AA amyloid, and renal amyloidosis should be suspected in patients with PSA who have unexplained proteinuria. The diagnosis of amyloidosis can be made either histologically or by radiolabelled serum amyloid P component (SAP) scintigraphy. Prognosis is determined by the extent of organ involvement and associated impairment of function, and by the degree of response of the underlying disease to anti-inflammatory therapy. A review of the literature identified less than a dozen cases of AA amyloidosis complicating PSA, and the outcome in most cases was poor. We report here the favourable clinical course of a middle-aged Caucasian male patient with severe PSA who developed renal AA amyloidosis, in whom treatment with oral chlorambucil led to stabilization of the amyloid deposits and resolution of the associated nephrotic syndrome. We review the diagnosis and treatment of AA amyloidosis, including the management of patients with underlying inflammatory spondyloarthropathies, and propose the possible role of a therapeutic trial of anti-tumour necrosis factor in patients with amyloid complicating inflammatory rheumatic diseases.
KEY WORDS: Psoriatic spondyloarthropathy, AA amyloidosis, Chlorambucil, Anti-TNF.
Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited as abnormal, insoluble fibrils that cause disease by disrupting normal tissue structure and function [1]. Some 20 different unrelated proteins can form amyloid in vivo, and amyloidosis is classified clinically according to the fibril protein type (Table 1). AA amyloid fibrils are derived from an N-terminal cleavage fragment of acute-phase reactant serum amyloid A protein (SAA), and AA (reactive systemic) amyloidosis is a potential complication of chronic inflammatory diseases that stimulate a sustained and substantial acute-phase response. The most frequent predisposing conditions are idiopathic inflammatory rheumatic diseases. A major determinant of outcome in reactive systemic AA amyloidosis is the effectiveness with which the underlying inflammatory disease can be suppressed [2], but disease-modifying anti-rheumatic drugs are often of limited efficacy in patients with spondyloarthropathies. Oral chlorambucil has been used successfully in patients with AA amyloidosis complicating rheumatoid arthritis and juvenile idiopathic arthritis, but its role has not been studied systematically in patients with inflammatory spondyloarthropathies. We report here a patient with severe psoriatic spondyloarthropathy who developed AA amyloidosis, in whom treatment with oral chlorambucil led to stabilization of the amyloid deposits and resolution of the associated nephrotic syndrome.
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Discussion
This is the first detailed report of the response of a patient with an HLA-B27-associated psoriatic spondyloarthropathy to chlorambucil therapy. AA amyloidosis develops during the course of rheumatoid arthritis in up to 20% of patients in certain populations, and probably in 15% of cases generally by the time of death [3]. AA amyloid deposits can be distributed widely without causing clinical symptoms, but may nevertheless contribute to morbidity and mortality. The presenting clinical feature in more than 90% of patients is non-selective proteinuria due to glomerular amyloid deposition, and nephrotic syndrome may develop before progression to end-stage renal failure. Haematuria, isolated tubular defects, nephrogenic diabetes insipidus and diffuse renal calcification occur rarely. Although the kidneys may be enlarged, it is usually normal or even (in advanced cases) reduced. Acute and often irreversible renal failure, even in the presence of well-preserved renal function, may be precipitated by hypotension and/or salt and water depletion following surgery, excessive use of diuretics or intercurrent infection. In practice, renal vein thrombosis occurs rarely, and the risk probably does not justify the use of prophylactic anticoagulants. The second most common presentation is with organ enlargement, such as hepatosplenomegaly or occasionally thyroid goitre, with or without overt renal abnormality, but in every case vascular amyloid deposits, at least, are always widespread at the time of presentation. Involvement of the heart rarely causes functional impairment or echocardiographic abnormalities. Gastrointestinal dysfunction is common in advanced disease, and presents most often with bleeding and diarrhoea.
AA amyloidosis may cause clinically evident disease within as little as 1 yr of developing a chronic inflammatory disorder, and the incidence increases with the duration of the underlying condition. The typical duration of chronic inflammatory disease prior to diagnosis of amyloid is about 10 yr, but in about 5% of cases the underlying disorder is covert, for example in patients with cytokine-secreting Castleman's disease tumours. The prognosis is closely related to the degree of renal dysfunction and the effectiveness of treatment for the underlying inflammatory condition. In the presence of persistent, uncontrolled inflammation, 50% of patients with AA amyloid die within 10 yr of the amyloid being diagnosed, but if the acute-phase response can be kept suppressed proteinuria can resolve, renal function may be retained or improve, and the long-term prognosis is excellent [4]. The availability of chronic haemodialysis and transplantation prevents early death from uraemia per se, but amyloid deposition in extrarenal tissues is responsible for a less favourable prognosis than in other causes of end-stage renal failure. The diagnosis of amyloidosis is traditionally confirmed histologically [5]. The pathognomonic tinctorial property of amyloidotic tissue is apple green/red birefringence when stained with Congo red dye and viewed under intense cross-polarized light, and immunohistochemical staining of amyloid-containing tissue sections is the most accessible method for characterizing the amyloid fibril protein type. However, histology cannot provide information about the overall whole-body load or distribution of amyloid deposits, nor does it permit monitoring of the natural history of amyloidosis or its response to treatment. Radiolabelled human SAP is a specific, non-invasive, quantitative in vivo tracer for amyloid deposits, and serial studies have shown that the deposits are far from inert but are actually turned over quite rapidly in many patients [4, 6, 7].
The apparent rarity of AA amyloidosis in psoriatic spondyloarthropathy [8] is probably due to the relatively modest acute-phase response that is usually stimulated by this particular disease. However, acute-phase responsiveness' varies widely among patients whose inflammatory disease activity appears to be similar clinically. AA amyloid fibrils are derived from circulating SAA, and AA amyloidosis occurs in patients who have sustained elevation of their plasma SAA concentration, as part of the acute-phase response to a wide range of diseases (Table 3) [9]. SAA is an apolipoprotein of high-density lipoprotein particles and is the polymorphic product of a set of genes located on the short arm of chromosome 11. It is highly conserved in evolution and is a major acute-phase reactant. Most of the SAA in plasma is produced by hepatocytes, in which its synthesis is under transcriptional regulation by cytokines, especially interleukin (IL)-1, IL-6 and tumour necrosis factor. After secretion, SAA rapidly associates with high-density lipoproteins, from which it displaces apolipoprotein A-I. The circulating concentration can rise from normal levels of up to 3 mg/l to over 1500 mg/l within 2448 h of an acute stimulus, and with ongoing chronic inflammation can remain persistently high. Although certain isoforms of SAA may be more inherently amyloidogenic than others, the only known prerequisite for the development of AA amyloidosis is a substantially elevated serum SAA concentration. Most patients with AA amyloidosis among the 250 cases evaluated at the National Amyloidosis Centre have had serum SAA concentrations greater than 100 mg/l when their underlying inflammatory diseases have been active.
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Although the rationale and objectives of treatment of AA amyloidosis are now clear, the ability to suppress the underlying inflammatory disease adequately is frequently difficult in practice. Most patients who develop AA amyloidosis are, by definition, those whose inflammatory disease activity has been controlled insufficiently by conventional therapies, or are those with diseases for which effective treatment is not available. Chlorambucil was first prescribed to patients with AA amyloidosis over 30 yr ago, for refractory juvenile rheumatoid arthritis. The prognosis of these children has improved dramatically following this approach [10], 80% of those treated with chlorambucil remaining alive 10 yr after diagnosis of amyloid compared with 23.5% of patients who are not treated with this agent. More than half of adult patients with AA amyloidosis complicating RA also respond extremely well to chlorambucil treatment [4]. The protocol for treatment with oral chlorambucil used in our centre comprises a starting dose of 2 mg daily, increasing by 2 mg increments every 68 weeks, up to a dose of 68 mg daily, until the plasma SAA concentration has fallen substantially or until leucopenia or thrombocytopenia occurs. A response may take up to 6 months, failing which the drug should be discontinued. Among responders, it is reasonable to begin tapering the dose after remission has been maintained for 1 yr. Chlorambucil is remarkably well tolerated on a symptomatic basis, cheap to prescribe, and simple to monitor with monthly full blood counts, but side-effects include myelosuppression, which is much more frequent in older patients, sterility in all males, premature ovarian failure, and, in the longer term, development of myelodysplasia or leukaemia in some cases. Potential recipients of chlorambucil need to be counselled appropriately and informed that chlorambucil is not licensed for this indication in the UK. Sperm banking should be offered. Fewer treatments are known to suppress inflammatory disease activity in the spondyloarthropathies than in rheumatoid arthritis, and, indeed, a therapeutic trial of disease-modifying anti-rheumatic drugs is frequently not even performed in many patients with predominantly spinal disease. The clinical and serological response to chlorambucil in our patient was rapid and sustained, despite his disease having proved refractory to numerous other disease-modifying anti-rheumatic drugs. The potential risks of this therapy were rapidly countered by resolution of his nephrotic syndrome and cessation of amyloid deposition. Although chlorambucil has also proved to be effective in suppressing the inflammatory disease activity in some patients with AA amyloidosis complicating Crohn's disease, there is no evidence that it has any direct beneficial effect on either the production of SAA or on the amyloid deposits themselves. For example, in our own practice chlorambucil has not been efficacious in patients with AA amyloidosis complicating Castleman's disease and the MuckleWells syndrome.
Treatment with biological agents that neutralize the proinflammatory effects of tumour necrosis factor (TNF-
) have proven to be highly effective in a substantial proportion of patients with rheumatoid arthritis and juvenile idiopathic arthritis. These agents are lately also emerging as efficacious in patients with spondyloarthropathies [1114]. The relative freedom from toxicity of anti-TNF-
drugs, their rapid mode of action and the frequency with which they can abolish the acute-phase plasma protein response provides a compelling argument for their application to patients with AA amyloidosis complicating these various inflammatory disorders, and our preliminary experience in this setting has been very favourable. Indeed, the acute-phase response resolves rapidly in some patients following neutralization of TNF-
even when their clinical symptoms fail to improve. It is possible that other biological drugs currently under development, for example agents that neutralize the effects of IL-1 and IL-6, might also reduce SAA production and AA amyloid deposition. Novel treatments that may have a direct effect on the amyloid deposits themselves have lately entered clinical trials. These include low molecular weight polysulphonated compounds that inhibit the association of glycosaminoglycans with amyloid fibrils, and a drug that depletes serum amyloid P component from the amyloid deposits [15].
In conclusion, we have demonstrated the therapeutic efficacy of oral chlorambucil in a patient with AA amyloidosis complicating psoriatic spondyloarthropathy. Treatment strategies in patients with AA amyloidosis should generally be guided by frequent measurement of serum SAA concentration, with the aim of lowering SAA to healthy values. Although chlorambucil therapy achieves this objective in a substantial proportion of patients with inflammatory rheumatic diseases, its potential for producing serious adverse effects restricts its suitability to patients whose disease cannot be suppressed by other agents. The efficacy and rapidity with which anti-TNF- can suppress the acute-phase response in some patients with rheumatic disease supports consideration of a therapeutic trial of infliximab or etanercept in this group of patients before resorting to chlorambucil.
Acknowledgments
We thank our colleagues for referring patients and supporting our clinical service. This work was supported in part by grants from the Medical Research Council (UK), The Wellcome Trust and by NHS Research and Development Funds.
Notes
Correspondence to: S. Mpofu. E-mail: tsujoy{at}aol.com
References