Royal National Hospital for Rheumatic Diseases, Bath and 1Royal Free Hospital, London, UK
Correspondence to: A. K. Bhalla, Royal National Hospital for Rheumatic Diseases, Upper Borough Walls, Bath BA1 1RL, UK. E-mail: ashok.bhalla{at}rnhrd-tr.swest.nhs.uk
SIR, We read with interest the grand round of Mpofu et al. of cases of amyloidosis complicating psoriatic arthritis successfully treated with chlorambucil [1]. In their discussion they hypothesized that anti-tumour necrosis factor (TNF-
) treatment may have a role in the treatment of AA or reactive amyloidosis complicating inflammatory rheumatic diseases and may be an attractive alternative to immunosuppressive drugs, which are associated with myelosuppression. There have since been reports of TNF-
blockade used to reduce proteinuria in patients with rheumatoid arthritis and spondyloarthropathy complicated by AA amyloidosis [2, 3]. These reports had mean follow-up periods of up to 1 yr and describe the stabilization of renal function. We report a case of rheumatoid arthritis with secondary Sjögrens syndrome and Feltys syndrome complicated by AA amyloidosis and nephrotic syndrome treated with TNF-
blockade for 2 yr. There was a significant reduction in proteinuria as well as a sustained stabilization of renal function. In addition, there was a suggestion of regression of AA amyloid, as quantified by scintigraphy of radio-iodinated serum amyloid P (SAP). Interestingly, in this patient there was no change in the neutropenia associated with her Feltys syndrome.
The patient is now 74 yr old. She first developed symptoms of seropositive rheumatoid arthritis in 1970 and presented to the Royal National Hospital for Rheumatic Diseases Trust in 1972, having been treated with non-steroidal anti-inflammatory drugs (NSAIDs), hydroxychloroquine and intramuscular gold. In 1978 she was switched to penicillamine following prolonged active disease. At that time her neutrophil count was noted to be low. Her bone marrow showed hypercellularity with active granulopoiesis, consistent with Feltys syndrome. She became intolerant to penicillamine, with mouth ulcers and weight loss. Methotrexate induced pancytopenia within weeks and was stopped. A repeat bone marrow examination in 1996 showed dyserythropoiesis. Following consultation with a haematologist, it was deemed risky to subject her to further myelosuppressive treatments. Her rheumatoid disease was managed with NSAIDs and intravenous methylprednisolone. Her symptoms remained moderate and she continued to live alone independently with no assistance. She subsequently developed secondary Sjögrens syndrome, right corneal melt and osteoporosis, as defined by DEXA scanning.
In 1997 a 24-h urinary collection revealed 0.2 g of protein (0.1 g/l). This deteriorated to 1.4 g in 2000 and was accompanied by reduced creatinine clearance. A diagnosis of AA amlyoidosis secondary to her chronic rheumatoid arthritis was made following a renal biopsy. An SAP scan demonstrated deposits in her spleen and kidneys. Her rheumatoid disease at that time was also active and her C-reactive protein (CRP) was 90 mg/l. She was commenced on etanercept (25 mg subcutaneously twice weekly; Enbrel) in October 2001. Etanercept was seen to reduce her urinary protein leak over the course of 6 months. This was accompanied by a reduction in her CRP. As her urinary protein was nearly 6 g over 24 h she was changed to monotherapy with infliximab (5 mg/kg; Remicade) in June 2002, as it was felt that she had had only a partial response (Figs 1 and 2). Loading doses at 0, 2 and 6 weeks were given before establishing an 8-weekly maintenance regime. Further significant reductions in her proteinuria were noted. Her renal function remained stable throughout, as indicated by a 24-h creatinine clearance of between 39 and 47 ml/min on repeated measurements. A repeat SAP scan demonstrated no increase in these deposits, with possibly some regression. Her Feltys syndrome did not appear to respond to TNF- blockade, her neutrophil count remaining persistently low (Fig. 3). Her clinical course was complicated by an osteoporotic fracture of the hip and subsequent surgery that caused a transient increase in her CRP. She remains on infliximab monotherapy 2 yr after commencing etanercept.
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TNF- is thought to have protean effects that are relevant to the pathogenesis of AA amyloid and possibly nephrotic syndrome. TNF-
stimulates the production of SAA by hepatocytes. TNF-
may also play a direct role in renal damage. TNF-
was significantly elevated in a study of cytokine profiles in the urine and plasma of patients with primary nephrotic syndrome when compared with controls [10]. TNF-
can result in monocyte proliferation and differentiation within the mesangium as well as an increase in glomerular permeability to protein when studied in vitro [11].
TNF- blockade has been used to treat nephrotic syndrome due to renal AA amyloid in a patient with TNF receptor-associated periodic syndrome [12]. There is now growing evidence to suggest that TNF-
blockade has a similar role in rheumatic diseases. In separate studies, Gottenberg et al. [2] and Elkayam et al. [3] report a reduction of proteinuria and the stabilization of renal function in patients with rheumatoid arthritis and spondyloarthritis treated with TNF-
blockade using both etanercept and infliximab. These studies had follow-up periods of up to 1 yr. In our patient treated with anti-TNF-
for 2 yr, we found a reduction in proteinuria and a sustained stabilization of renal function. There was a suggestion of regression of amyloid deposits on the repeat SAP scan after 12 months, which showed a slight reduction of SAA deposit. Proteinuria stabilized and perhaps improved after the introduction of etanercept. However, it is interesting to note that the reduction in proteinuria continued to improve on infliximab. There are biological differences between the two compounds. Infliximab binds both monomeric and trimeric forms of soluble TNF-
. Etanercept binds only the trimeric form. Furthermore, infliximab binds to form more stable complexes than etanercept. TNF-
released from the unstable etanercept complexes is still biologically active. Infliximab also binds to transmembrane TNF-
with higher avidity than etanercept. These different molecular mechanisms may explain the clinical differences between these two agents.[13]
In this patient, however, we observed no sustained response in the neutropenia during treatment with TNF- blockade. There were fluctuations in the neutrophil count, but this may well have been multifactorial and the latest counts are all below normal. We found one report in which etanercept was tried in Feltys syndrome but had to be discontinued because of a severe allergic cutaneous reaction after 2 weeks. There was no improvement in the neutropenia [14]. Several mechanisms have been proposed for the neutropenia in Feltys syndrome; these include excessive margination of neutrophils, anti-neutrophil antibodies and immune complex-mediated destruction or splenic sequestration of neutrophils [1516]. Cytokines, including TNF-
, have also been investigated for their role in Feltys syndrome as they can influence neutrophil maturation and function as well as affecting colony stimulating factor production. Meliconi et al. [17], however, found no specific role for TNF-
in Feltys syndrome, and this was reflected in the lack of improvement in neutropenia in our patient.
These case reports have suggested that TNF- blockade may be an effective treatment of AA amyloid and nephrotic syndrome, but not Feltys syndrome, in rheumatoid arthritis. Larger numbers of patients with longer durations of treatment are required to ascertain whether they have reduced morbidity and improved survival in this uncommon but serious complication of rheumatoid arthritis.
The patient has given consent for this material to appear in Rheumatology.
The authors have declared no conflicts of interest.
References