Development of systemic lupus erythematosus in a patient with rheumatoid arthritis following treatment conversion of infliximab to adalimumab

Journal of Drugs in Dermatology, August, 2008 by Jamaiya Havel, Sina Aboutalebi, Lauren Doughty, Marla Wiges

ABSTRACT: Systemic lupus erythematosus (SLE)-like syndromes and the development of lupus-related autoantibodies are known to occur during treatment with certain medications. Here a case of complete SLE conversion in a patient with rheumatoid arthritis following sequential treatment with infliximab and adalimumab is reported. Potential mechanisms for development of SLE with this treatment regimen are discussed, as well as the need for further exploration into autoimmune phenomenon with the use of immunobiologic agents.

INTRODUCTION

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by autoantibody formation to nuclear, cytoplasmic, and cell-surface autoantigens resulting in multisystem disease. Clinical manifestations of SLE include leukopenia, thrombocytopenia, proteinuria, immune-complex glomerulonephritis, nonerosive polyarthritis, skin rash, photosensitivity, serositis, and mucocutaneous ulceration. Development of the lupus-related autoantibody anti-double-stranded DNA (anti-dsDNA) has occasionally been observed in patients treated with the tumor necrosis factor (TNF)-inhibitor infliximab (Remicade[R]). However, development of a clinical SLE-like syndrome rarely follows antibody conversion in this population. (1) Even more rare, is the development of SLE or lupus-like syndrome in patients treated with the fully human anti-TNF antibody, adalimumab (Humira[R]). (2) Infliximab and adalimumab are both immunomodulators currently employed in the management of psoriasis and rheumatoid arthritis (RA). The therapeutic effects of TNF-[alpha] antibodies in RA result from the downregulation of pro-inflammatory cytokines interleukin (IL)-1 and IL-6, the chemokine, IL-8, and decreased leukocyte trafficking. (3) Here, the authors report a case of a patient with RA who developed a positive anti-dsDNA titer while on infliximab and clinical SLE upon subsequent initiation of adalimumab therapy.

CASE REPORT

A 47-year-old African American female with a history of RA first diagnosed in 1998, had been treated with methotrexate (MTX) on and off for the past 9 years. Labs at the onset of therapy were significant for a positive rheumatoid factor (RF), positive anti-nuclear anti-nuclear antibodies (ANA) and an elevated erythrocyte sedimentation rate (ESR). Complete blood count (CBC) levels were within normal limits and anti-dsDNA antibodies were not detectable. In May 2005, infliximab was added to her treatment regimen for better control of her arthritis. Six months later, the patient discontinued infliximab due to a change in her insurance. She reestablished care at our university hospital again after 3 months in February 2006. At this time, she had active RA as evident by clinical exam and radiological findings. Rheumatoid factor and ANA levels remained positive; however, now anti-dsDNA and anti-Ro antibodies were also detectable. The patient was restarted on infliximab. After 3 infusions, the patient developed severe pruritus and an urticarial eruption on the chest and back. Infliximab was discontinued. After a wash out period of roughly 12 weeks, the patient was started on subcutaneous adalimumab 40 mg every 2 weeks while continuing oral MTX 20 mg weekly.

Approximately 6 weeks after therapy with adalimumab, the patient developed fatigue, photosensitivity, oral ulcerations, continued active polyarthritis, and erythematous crusted papules and plaques across the face, chest, back, and upper extremities (Figure 1). Laboratory studies revealed a decreased platelet count, an elevated ANA titer and elevated ESR. Curiously, anti-dsDNA antibody levels were not detected this time, but anti-Ro antibodies remained positive. Renal function, CBC, and liver function tests were all within normal limits.

[FIGURE 1 OMITTED]

Biopsies taken from skin lesions were consistent with lupus erythematosus (Figure 2). As a result, treatment with adalimumab was discontinued due to the diagnosis of SLE.

[FIGURE 2 OMITTED]

DISCUSSION

Prior reports of nucleosomal autoantibody formation following infliximab treatment have proposed several mechanisms for this process. Binding of infliximab to TNF-[alpha] located on cell surfaces may induce apoptosis, thus releasing nuclear autoantigens and contributing to the formation of anti-dsDNA as well as anti-ANA, anti-Smith, antiribonucleoprotein, and anti-ssDNA antibodies in genetically susceptible individuals. (1) Additionally, infliximab has been shown to significantly decrease human C-reactive protein (CRP) levels in vivo. Previous studies using the serum amyloid P (SAP), knockout mouse, which lacks the murine equivalent of CRP, showed aberrant chromatin clearance leading to autoantibody formation against nucleosomal proteins. Thus treatment with infliximab may potentiate autoimmunity by slowing clearance of nuclear material by CRP. (4)

In patients with RA treated with infliximab, decreased lymphocyte homing occurs secondary to downregulation of cell-surface adhesion molecules such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and endothelial leukocyte adhesion molecule-1. The result is a peripheral lymphocytosis of predominately Th1-type CD4 T cells. (3) This subset of T cells is responsible for the secretion of interferon (IFN)-Y (involved in activation of antigen presenting cells and differentiation of Th 1 T cells) and IL-2 (involved in immunoglobulin production and cytotoxic T-cell differentiation and proliferation).