The immunoregulatory role of TNF was first clearly shown in an autoimmune mouse model, specifically the F1 hybrid of New Zealand black and New Zealand white (NZB/W) mouse (see “Mouse Model,” below). Surprisingly, these mice showed low levels of TNF and had a reduction of disease manifestations when TNF was administered. These findings suggested that TNF inhibited rather than stimulated autoreactivity, a marked difference from the action of this cytokine in other disease models such as collagen-induced arthritis, where, in contrast to SLE, autoantigen may largely be accessible because of the inflammatory process. Although the paradoxical effect of TNF was primarily observed with the NZB/W mice among lupus models, these findings nevertheless raised an alarm bell about the use of TNF blockers in treating human lupus, causing caution in exploring this approach, even in patients with refractory disease.
In a clinical setting, an analogous effect occurred when patients developed antibodies to double-stranded DNA (dsDNA) and, sometimes, drug-induced lupus-like syndromes when treated with TNF blockade for rheumatoid arthritis (RA) or Crohn’s disease (see “TNF Blockade and Findings of Lupus,” p. 17).1,2 In these settings, drug-induced lupus resulting from a TNF blocker is typically mild and only rarely results in internal organ manifestations, such as lupus nephritis. Importantly, drug-induced lupus is self-limited upon cessation of TNF blocker therapy. Nevertheless, these two sets of observations, one from mouse and one from man, sparked heated debate when TNF blockade was considered as a potential treatment for SLE.
In addition to findings in murine lupus mouse models and clinical use in RA, the limited clinical experience with infliximab in SLE also suggested immunoregulatory effects of TNF that could have an impact on autoreactivity. Thus, levels of both anti-dsDNA antibodies and anti-cardiolipin antibodies increased, albeit transiently, when the first seven patients with this disease were treated in an early clinical trial of four infliximab infusions (300mg fixed dose, approximately 5mg/kg for most patients, at Weeks 0, 2, 6, and 10) in combination with azathioprine (or methotrexate).3 In fact, one patient with antiphospholipid syndrome developed venous thrombosis associated with such an increase.1 In contrast, no clinical flares have been observed by any of us or reported by any other group in SLE patients with increasing anti-dsDNA antibodies following TNF blockade.
Given the collective experience with the potent and beneficial effects of TNF blockade in diseases such as RA, psoriatic arthritis, and ankylosing spondylitis, modern-day rheumatologists are well aware that TNF is a strong inflammatory mediator in those diseases. In contrast, the role of TNF in the pathogenesis of SLE and lupus nephritis is far from clear, but the field has been beset by strong feelings, opinions, and worries arising from the existing data, which are actually quite limited.
Mouse Model
In the NZB/W F1 mice, the lupus phenotype in part depends on TNF deficiency stemming from the NZW parent.15 High-dose administration of TNF early in their life can delay disease, but long-term administration does not prevent lupus.16 These findings were more recently reiterated in TNF-deficient NZB mice, and most recently in TNF-receptor double-deficient NZB/W mice, all of which also developed severe disease.17,18
