Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a wide variety of autoantibodies (1–5), some of which are pathogenic. The disease is often chronic and incurable, and it is associated with substantial mortality. Given that there have been no major therapeutic advances over more than 2 decades and that the current nonspecific immunosuppressive measures are linked with significant adverse events and disability, there is a need to find new therapies. Many of the novel approaches are targeted toward particular molecules or disease mechanisms (6).
The pathologic events in SLE are mediated by the formation of immune complexes (7–9), activation of the complement cascade, and engagement of cellular Fc and complement receptors (10). The ensuing inflammatory process may then lead to progressive tissue destruction and organ damage, such as lupus nephritis, a common and serious manifestation of SLE (11–13). While interference with both complement activation and with Fcγ receptor function have been shown to ameliorate experimental SLE (14–16), the role of proinflammatory cytokines in the pathogenesis of SLE as well as the effect of cytokine blockade are still unknown.
Tumor necrosis factor (TNF) is an important proinflammatory cytokine with pleiotropic properties (17–19), including the activation of a cascade of inflammatory events that lead to tissue destruction (20–22). In most studies, TNF is found to be markedly increased and appears to be bioactive in the sera of patients with active SLE, and levels of TNF have been shown to correlate with SLE disease activity (23–29). Moreover, TNF is present in renal tissue in all types of lupus glomerulonephritis and is associated with renal disease activity (30–33). These data and the finding that immune complexes induce TNF (34) indicate that blockade of TNF might have beneficial effects on organ inflammation in SLE.
However, in rheumatoid arthritis and Crohn's disease, TNF blockade leads to the formation of antinuclear autoantibodies (ANAs) in 30–40% of patients and to the formation of autoantibodies to double-stranded DNA (anti-dsDNA) in ∼15% of patients, which is occasionally associated with a transient drug-induced lupus–like syndrome (35–38). Anticardiolipin antibodies (aCL) have also been observed during TNF-blocking therapy (39). Even if many patients with SLE may be in need of new therapies because of toxicity or insufficient efficacy of their current treatments, blockade of TNF has not hitherto been considered to be an option because of the above observations as well as the controversy stemming from experimental models of the disease.
In some experimental models, TNF has been shown to have beneficial effects. The offspring of NZB/NZW mice were found to express low levels of TNF (40), and application of high doses of TNF was shown to delay disease onset in this lupus-prone mouse strain (40). There have also been recent suggestions of an important role of TNF in the down-regulation of the immune response (41). However, it was found that prolonged administration of TNF does not prevent the occurrence of nephritis in NZB/NZW mice (42). In addition, low-dose TNF administered late in the disease course was shown to cause a deterioration of nephritis (43, 44). Moreover, the kidneys of MRL/lpr lupus-prone mice contain high levels of TNF (45, 46), and serum levels of TNF in these mice correlate with disease activity (47), similar to the findings in humans (26).
Taken together, the data suggest that anti-TNF therapy may be beneficial in interfering with the organ inflammation in patients with SLE, although its potential to induce autoantibodies and to inhibit other possibly beneficial immunologic effects of TNF might constitute a significant safety issue. Before it would be ethically acceptable to start a controlled trial to evaluate the benefit of such therapy, it appears necessary to test the safety of TNF blockade in SLE patients in an open-label approach. This was the focus of the present investigation in 6 patients with SLE.
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- PATIENTS AND METHODS
TNF blockade as therapy for SLE is a highly controversial issue. The main concerns derive from some data in experimental models of the disease (53) and from the induction of ANAs, anti-dsDNA, and aCL antibodies and some rare cases of drug-induced lupus–like syndromes in patients treated with anti-TNF agents (35–39). Indeed, among the 6 SLE patients we treated with infliximab, 4 had an increase in anti-dsDNA antibodies. In addition, aCL antibodies increased in 3 of these 4 patients and in an additional patient. This increase in both anti-dsDNA and aCL antibodies during anti-TNF therapy suggests that TNF, in fact, may down-modulate autoantibody responses.
However, neither clinical deterioration of the underlying disease nor a drug-induced lupus–like syndrome was observed. One could argue that the observed relapses of arthritis in the 3 patients with polyarthritis were signs of lupus flares. However, SLE disease activity did not increase to levels higher than they were before therapy, there was no new organ involvement, renal disease remained improved in the patient with concurrent arthritis and nephritis, and most important, rechallenge with another infusion of infliximab in patient 6 had the same beneficial clinical effect. Complement levels did not decrease, but rather, improved in some of the patients, further supporting the notion that SLE activity did not increase following infliximab. As with previous experience indicating that autoantibodies (and even lupus-like episodes) observed in rheumatoid arthritis and Crohn's disease patients usually resolve with cessation of anti-TNF treatment, the anti-dsDNA antibodies did not further increase or decrease during the followup observation period after the fourth (and last) infusion.
None of the patients had to terminate the study prematurely, and none had an infusion reaction. However, 3 patients experienced a urinary tract infection, and the infection was complicated by E coli bacteremia in 1 of them. Although all 3 patients had a history of recurrent urinary tract infections, the observation made is consistent with an increased risk of infection during treatment with anti-TNF agents, which confirms previous indications of such an effect.
This study was primarily designed as a first open trial to examine the safety of infliximab in SLE and not to prove its efficacy. However, the observed clinical findings under TNF blockade suggest that infliximab may have a therapeutic effect in patients with SLE. In particular, the reduction of proteinuria by ≥60% within a few weeks, including normalization of urinary protein in patient 1 and a striking effect even on nephrotic-range proteinuria and the consequent nephrotic syndrome in patient 2, is noteworthy. Of interest, proteinuria and hematuria, which had been present in all 6 patients for many months or years prior to this study, did not recur in any of them during an observation period of up to 52 weeks (and up to >8 months off infliximab therapy). Evidence of the potential clinical benefit of infliximab is further supported by the effects on hitherto refractory lupus arthritis, which completely remitted in all 3 affected patients, although it recurred after cessation of infliximab treatment.
The courses of the disease before infliximab therapy suggest that the observed improvement in nephritis and arthritis were not the results of mere chance or of treatment with the other therapeutic agents. In particular, except for 1 patient, immunosuppressive therapy had been stable for several months before the initiation of anti-TNF therapy. Moreover, the consistent improvement in objective laboratory measures, such as proteinuria, in all of the patients with nephritis and within a short time after the first infusion of infliximab speak for a true clinical benefit—with all caveats in mind. Further indications of clinical benefit are the stable serum creatinine levels and stable or improving serum C3c levels as well as the overall clinical improvement observed. All of these findings must be interpreted with great caution given the open nature of this study. However, small open trials have provided important clinical information that has led the way to infliximab therapy in rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis (54–56), and similar trials in SLE have laid the groundwork for subsequent clinical trials (57).
Thus, our data allow us to speculate that anti-TNF therapy could suppress the local tissue destruction in SLE. However, at the same time, and unassociated with clinical consequences, TNF blockade may lead to increased autoantibody formation (53, 58). These 2 differential effects, taken together with the finding of a very rapid and sustained improvement in renal disease, suggest that anti-TNF agents may be, but possibly should only be, used as rescue therapy in patients with refractory forms of the disease.
In summary, although no firm conclusions can be drawn from this open-label study of TNF-blocking therapy with infliximab in SLE, 2 patterns seem to emerge. First, it appears likely that a short course of anti-TNF therapy may be effective in SLE, perhaps as a consequence of its antiinflammatory effects. Second, and not unexpectedly, there is a trend toward increased autoantibody production, although there is no indication in these patients that the enhanced autoreactivity caused clinically untoward effects, at least during an observation period of up to 52 weeks (42 weeks after the last infliximab infusion). Despite the efficacy observed, these data must be interpreted with all necessary caution, since previous uncontrolled trials in lupus have been misleading in this respect. Moreover, the present study was small and was limited to patients with nephritis and/or arthritis and low-to-moderate overall disease activity. Thus, to sufficiently address the potential value of TNF-blocking therapy in SLE, larger and controlled clinical trials are necessary. The data presented here justify such trials.