ReviewTherapeutic blockade of TNF in patients with SLE—Promising or crazy?
Introduction
TNF is a pro-inflammatory cytokine that is involved in essentially all inflammatory processes. Accordingly, TNF blockade has been tried in a wide variety of diseases [1], [2], [3], [4], [5], [6], [7], [8], [9]. For several rheumatic diseases, such as rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis or ankylosing spondylitis, TNF blockers have become a mainstay of therapy for refractory disease [10]. Other than with regard to serious infections, especially with intracellular pathogens [11], [12], [13], TNF blockers proved remarkably safe over the last ten years.
SLE organ disease likewise constitutes an inflammatory process. In fact, in murine models of SLE, deficiency in receptors for immunoglobulin or interferon-γ could prevent this inflammatory process despite the occurrence of autoantibodies and the deposition of immune complexes [14], [15]. Given this inflammatory phenotype, as well as the fact that immune complexes induce TNF production (Fig. 1 and Ref. [16]), it is not entirely surprising that TNF also is involved in SLE inflammatory organ disease.
Section snippets
TNF in lupus inflammatory organ disease
TNF is overexpressed in renal as well as skin lesions of patients with SLE [17], [18], [19], [20], [21], [22]. High levels of TNF are also found in serum of SLE patients, where they correlate closely with disease activity [23], [24], [25], [26]. Despite an association with very high levels of soluble TNF receptors [23], [26], this serum TNF is in fact bioactive [27]. Since the presence of a strong proinflammatory mediator in inflamed organs likely reflects a role of this mediator in the ongoing
TNF and autoimmunity in murine lupus
However, other bits of data cautioned against such approach. Importantly, there is the autoimmune phenotype of the NZB/W mouse. This mouse displays a deficiency in producing TNF, which stems from the NZW parent. The resulting lack of TNF clearly is involved in the development of autoantibodies in NZB/W mice, and TNF substitution can delay autoimmunity [35], [36]. The same phenotype developed when, more recently, NZB mice were made TNF deficient [37]. Finally, it took deficiency in both TNF
Emergence of autoantibodies under TNF blockade
The occurrence of autoantibodies to nuclear antigens in patients treated with TNF blockers constitutes additional evidence in this direction. Depending on the detection system and the patient population, anti-nuclear antibodies (ANA) and even antibodies to dsDNA developed in up to more than half of the studied patient populations [38]. More specific methods, such as CLIFT and RIA, still found anti-dsDNA antibodies in 14% and 5%, respectively, in the study by Charles et al. [39]. Most patients
Autoimmunity safety data on TNF blockade in SLE
Before discussing the available data on TNF blockade in SLE patients, it is important to stress that no controlled trials have been published and that the number of patients treated is still very limited. In addition, there may be reporting bias influencing the overall picture. Therefore, no firm conclusions can be drawn. Nevertheless, the available data are of interest in that they not only provide a rationale for controlled trials, but also add to our understanding of the role of TNF in SLE,
Infections and lymphoma under TNF blockade in SLE
Bacterial infections are another issue. Three cases of pneumonia have been reported, with one Legionella pneumonia ending fatal in a young woman after long-term infliximab therapy [62], [64], [65], [66]. Infections of the urinary tract were more benign, but rather common in our sample [61], and have also been reported in lupus nephritis patients treated in Japan [63] and Kuwait [64]. These urinary tract infections could be influenced by direct anti-TNF effects in the urinary tract, given the
Preliminary efficacy data on TNF blockade in SLE
The concerns regarding the very limited data set, the open label character of all studies published so far and potential reporting bias favoring good outcomes are of even greater importance when looking for signals of efficacy. However, TNF blockade mostly was used as a last resort, and some of the responses seen in our patients were impressive indeed [61].
In our hands, about two thirds of patients with lupus nephritis had rapid improvement with impressive reduction of proteinuria under and
Conclusions and outlook
Taken together, there are data suggesting efficacy of an induction regimen of TNF blockers, combined with azathioprine, for refractory lupus nephritis, while lupus arthritis would require long term therapy, as for rheumatoid arthritis. Hemophagocytic syndrome, interstitial lung disease, and refractory severe skin disease may likewise respond to TNF blockade. However, it is important to reiterate that there are no controlled trial results available yet. Nevertheless, the available evidence
Conflict of interest
Dr. Aringer and Dr. Smolen have received grant support and support for a controlled trial of infliximab in SLE by Centocor, the manufacturer of infliximab and have received occasional honoraria from companies distributing TNFα blockers.
Take-home messages
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TNF has both proinflammatory and immunoregulatory properties and various murine models reflect either side.
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If TNF-blocker induced lupus-like syndromes occur, they are transient after stop of therapy.
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TNF is overexpressed in human SLE.
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Clinical experience with TNF blockade is limited and does not allow for firm conclusions. However, flares have not been seen and long-term renal remissions of lupus nephritis, hemophagocytic syndrome, and interstitial lung disease were seen after TNF blocker
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