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Reactive systemic AA amyloidosis is a severe complication of rheumatoid arthritis (RA), occurring in 2–5% of RA patients (1). Infliximab, a monoclonal antibody against tumor necrosis factor α (TNFα), is successfully used in the treatment of RA (2). TNFα plays a key role in inducing the synthesis of the hepatic acute-phase reactant protein serum amyloid A, the precursor of tissue AA amyloid.

There have been reports of TNFα blockade treatment in patients with rheumatic diseases complicated by renal AA amyloidosis (3, 4). The major concern with infliximab is the possible increase of infections, and no established data have been presented on the safety of infliximab in patients with hepatitis B virus (HBV) infection. This report describes the case of a patient with RA, renal amyloidosis, and HBV-related chronic hepatitis in whom infliximab improved renal function with the disappearance of HBV replication.

CASE REPORT

  1. Top of page
  2. CASE REPORT
  3. DISCUSSION
  4. REFERENCES

The patient, a 36-year-old woman with RA and HBV-related chronic hepatitis that was diagnosed when she was 7 years old, presented to our hospital in March 2003 for treatment of nephrotic syndrome and renal failure. She had been treated with corticosteroids and disease-modifying antirheumatic drugs, which had been discontinued due to inefficacy and/or intolerability. Laboratory investigation revealed a serum creatinine level of 2.8 mg/dl, creatinine clearance of 20 ml/minute, proteinuria of 6 gm/24 hours (Figure 1A), an aspartate aminotransferase level of 11 units/liter, an alanine aminotransferase (ALT) level of 26 units/liter (Figure 1B), a C-reactive protein level of 5.2 mg/dl, and an erythrocyte sedimentation rate of 132 mm/hour. Hepatitis B surface antigen (HBsAg), anti-HBe, and anti-HBc antibodies (IgG) were positive, while hepatitis B e antigen (HBeAg) and anti-HBs antibodies (IgG) were negative. HBV DNA was measured at a level of 2,720 IU/ml using an in-house real-time polymerase chain reaction assay with a lower detection cutoff of 200 IU/ml.

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Figure 1. Laboratory results during 1 year of infliximab treatment. A, The patient showed a decrease in daily proteinuria and a significant improvement of renal function. B, A progressive increase in the alanine aminotransferase (ALT) level was also seen, but studies for serum hepatitis B virus (HBV) DNA yielded negative results. i.v. = intravenous.

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A renal biopsy showed mesangial deposition of homogeneous, amorphous material that was Congo red positive with apple green birefringence under polarization; immunofluorescence showed AA amyloid fibrils in the mesangium and in the vessel walls. These findings were consistent with AA amyloidosis secondary to RA.

A liver biopsy was not performed because of the high hemorrhagic risk due to vascular damage by AA amyloid deposition. In June 2003, infliximab was initiated at a dosage of 3 mg/kg at weeks 0, 2, and 6, and every 8 weeks thereafter. After the second infusion of infliximab, an improvement in disease activity occurred, including a reduction of the severity of morning stiffness and the number of tender and swollen joints. After 1 year of treatment, proteinuria decreased from 6.0 gm/24 hours to 0.87 gm/24 hours and a partial recovery of renal function was observed, with an increase in creatinine clearance from 20 ml/minute to 40 ml/minute and a decrease in the serum creatinine level from 2.8 mg/dl to 1.3 mg/dl (Figure 1A). HBsAg, anti-HBe, anti-HBc IgG, HBeAg, and anti-HBs IgG were not modified, and despite the positivity of anti–hepatitis delta virus (HDV) IgG, anti-HDV IgM was negative. Interestingly, although ALT levels increased, serum HBV DNA levels were negative after both 6 months and 1 year of treatment (Figure 1B).

DISCUSSION

  1. Top of page
  2. CASE REPORT
  3. DISCUSSION
  4. REFERENCES

As has been reported by Gottenberg and colleaques (3), infliximab is a valid option in the treatment of RA patients with renal amyloidosis, particularly in patients with hepatopathy, in which the use of other immunosuppressive drugs, such as methotrexate (MTX), can be hazardous. But, inhibition of TNFα is associated with the development of serious infectious diseases (5). TNFα antiviral activity has long been recognized, and the inhibition of this cytokine might lead to an increase of viral replication due to an escape from the host antiviral mechanism.

Whether infliximab activates viral replication in patients with RA and HBV infection is a matter of debate. Ostuni and colleagues (6) described a case of HBV reactivation in a patient with RA who was treated with infliximab and low doses of MTX, whereas Oniankitan and colleagues (7) reported the case of a patient with ankylosing spondylitis in whom infliximab induced a dramatic benefit without activation of the chronic viral liver disease. Michel and associates (8) reported a case of fulminating hepatitis after treatment with infliximab in a patient with HBV and Still's disease, with no evidence of HBV reactivation. Our patient had a complete and prolonged disappearance of HBV DNA after 1 year of treatment with infliximab, and improved renal function with a reduction of daily proteinuria. However, continued laboratory and clinical monitoring is required.

REFERENCES

  1. Top of page
  2. CASE REPORT
  3. DISCUSSION
  4. REFERENCES
  • 1
    Gillmore JD, Hawkins PN, Pepys MB. Amyloidosis: a review of recent diagnostic and therapeutic developments [review]. Br J Haematol 1997; 99: 24556.
  • 2
    Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al, and the Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis With Concomitant Therapy Study Group. Infliximab (chimeric anti-tumour necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet 1999; 354: 19329.
  • 3
    Gottenberg JE, Merle-Vincent F, Bentaberry F, Allanore Y, Berenbaun F, Fautrel B, et al. Anti–tumor necrosis factor α therapy in fifteen patients with AA amyloidosis secondary to inflammatory arthritides: a followup report of tolerability and efficacy. Arthritis Rheum 2003; 48: 201924.
  • 4
    Elkayam O, Hawkins PN, Lachmann H, Yaron M, Caspi D. Rapid and complete resolution of proteinuria due to renal amyloidosis in a patient with rheumatoid arthritis treated with infliximab. Arthritis Rheum 2002; 46: 25713.
  • 5
    FDA. Safety update on TNF-α antagonists: infliximab and etanercept. FDA, Center for Biologics Evaluation and Research; 2001. URL: http://www.fda.gov/ohrms/dockets/ac/01/ briefing/3779b2.htm.
  • 6
    Ostuni P, Botsios C, Punzi L, Sfriso P, Todesco S. Hepatitis B reactivation in a chronic hepatitis B surface antigen carrier with rheumatoid arthritis treated with infliximab and low dose methotrexate [letter]. Ann Rheum Dis 2003; 62: 6867.
  • 7
    Oniankitan O, Duvoux C, Challine D, Mallat A, Chevalier X, Pawlotsky JM, et al. Infliximab therapy for rheumatic diseases in patients with chronic hepatitis B or C. J Rheumatol 2004; 31: 1079.
  • 8
    Michel M, Duvoux C, Hezode C, Cherqui D. Fulminant hepatitis after infliximab in a patient with hepatitis B virus treated for an adult onset Still's disease. J Rheumatol 2003; 30: 16245.