Elsevier

Autoimmunity Reviews

Volume 11, Issue 5, March 2012, Pages 321-325
Autoimmunity Reviews

Review
Therapeutic blockade of TNF in patients with SLE—Promising or crazy?

https://doi.org/10.1016/j.autrev.2011.05.001Get rights and content

Abstract

TNF is an important mediator of inflammation, but is also involved in the control of autoimmunity. The latter has been demonstrated in a murine model of SLE (NZB/W) and by the occurrence of autoantibodies to nuclear antigens as well as occasional, transient lupus-like syndromes in patients under TNF blockade. In contrast, data on increased TNF levels in serum, kidney and skin samples of SLE patients as well as results in other mouse models of the disease point to an inflammatory role of TNF in SLE organ disease. Despite all due caution, given these two sides of the cytokine, TNF blockade has by now been employed for several years in single cases and open label studies; data on more than fifty patients have meanwhile been published, for the vast majority of which infliximab was employed. These clinical data have to be very cautiously interpreted, as always with data on single cases or open label trials. However, some consistent pieces of information emerge and may inform controlled clinical trials: (i) While antibodies to double-stranded DNA commonly showed transient increases, lupus flares have not been seen so far and thus apparently are at least not the rule; (ii) in contrast, increases in anti-phospholipid antibodies may be associated with vascular adverse events; (iii) bacterial infections, pneumonia and urinary tract infections in particular, have been observed; (iv) short term induction therapy appears relatively safe, while long-term TNF blockade may confer significant risks in SLE; (v) TNF blocker induction therapy may lead to long-term remission in patients with lupus nephritis, hemophagocytic syndrome, and interstitial lung disease; (vi) patients with lupus arthritis often respond to TNF-blockade but symptoms recur after cessation of therapy, necessitating longer term therapy, which is more risky than short term treatment.

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

  • TNF has both proinflammatory and immunoregulatory properties and various murine models reflect either side.

  • If TNF-blocker induced lupus-like syndromes occur, they are transient after stop of therapy.

  • TNF is overexpressed in human SLE.

  • 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

References (78)

  • C. Antoni et al.

    Open-label study of infliximab treatment for psoriatic arthritis: clinical and magnetic resonance imaging measurements of reduction of inflammation

    Arthritis Rheum

    (2002)
  • P. Lamprecht et al.

    Effectiveness of TNF-alpha blockade with infliximab in refractory Wegener's granulomatosis

    Rheumatology (Oxford)

    (2002)
  • E. Drewe et al.

    Prospective study of anti-tumour necrosis factor receptor superfamily 1B fusion protein, and case study of anti-tumour necrosis factor receptor superfamily 1A fusion protein, in tumour necrosis factor receptor associated periodic syndrome (TRAPS): clinical and laboratory findings in a series of seven patients

    Rheumatology (Oxford)

    (2003)
  • A.K. Tausche et al.

    Severe gouty arthritis refractory to anti-inflammatory drugs: treatment with anti-tumour necrosis factor alpha as a new therapeutic option

    Ann Rheum Dis

    (2004)
  • R.P. Baughman et al.

    Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement

    Am J Respir Crit Care Med

    (2006)
  • D.E. Furst et al.

    Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2008

    Ann Rheum Dis

    (2008)
  • J. Keane et al.

    Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent

    N Engl J Med

    (2001)
  • J.H. Lee et al.

    Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept

    Arthritis Rheum

    (2002)
  • N.R. Slifman et al.

    Listeria monocytogenes infection as a complication of treatment with tumor necrosis factor alpha-neutralizing agents

    Arthritis Rheum

    (2003)
  • D. Balomenos et al.

    Theofilopoulos AN Interferon-gamma is required for lupus-like disease and lymphoaccumulation in MRL-lpr mice

    J Clin Invest

    (1998)
  • R. Clynes et al.

    Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis

    Science

    (1998)
  • J.M. Debets et al.

    Fc-receptor cross-linking induces rapid secretion of tumor necrosis factor (cachectin) by human peripheral blood monocytes

    J Immunol

    (1988)
  • T. Takemura et al.

    Cellular localization of inflammatory cytokines in human glomerulonephritis

    Virchows Arch

    (1994)
  • T.J. Neale et al.

    Tumor necrosis factor-alpha is expressed by glomerular visceral epithelial cells in human membranous nephropathy

    Am J Pathol

    (1995)
  • R. Herrera-Esparza et al.

    Renal expression of IL-6 and TNFalpha genes in lupus nephritis

    Lupus

    (1998)
  • M. Aringer et al.

    Cytokine expression in lupus kidneys

    Lupus

    (2005)
  • S. Zampieri et al.

    Tumour necrosis factor alpha is expressed in refractory skin lesions from patients with subacute cutaneous lupus erythematosus

    Ann Rheum Dis

    (2006)
  • A. Studnicka-Benke et al.

    Tumour necrosis factor alpha and its soluble receptors parallel clinical disease and autoimmune activity in systemic lupus erythematosus

    Br J Rheumatol

    (1996)
  • M. Aringer et al.

    Serum interleukin-15 is elevated in systemic lupus erythematosus

    Rheumatology (Oxford)

    (2001)
  • C.P. Maury et al.

    Tumor necrosis factor in the serum of patients with systemic lupus erythematosus

    Arthritis Rheum

    (1989)
  • C. Gabay et al.

    Circulating levels of tumor necrosis factor soluble receptors in systemic lupus erythematosus are significantly higher than in other rheumatic diseases and correlate with disease activity

    J Rheumatol

    (1997)
  • M. Aringer et al.

    Increased bioactive TNF in human systemic lupus erythematosus: associations with cell death

    Lupus

    (2002)
  • J.M. Boswell et al.

    Increased tumor necrosis factor and IL-1 beta gene expression in the kidneys of mice with lupus nephritis

    J Immunol

    (1988)
  • D.C. Brennan et al.

    Tumor necrosis factor and IL-1 in New Zealand Black/White mice. Enhanced gene expression and acceleration of renal injury

    J Immunol

    (1989)
  • Y. Deguchi et al.

    Tumour necrosis factor/cachectin plays a key role in autoimmune pulmonary inflammation in lupus-prone mice

    Clin Exp Immunol

    (1991)
  • C.K. Edwards et al.

    Inhibition of superantigen-induced proinflammatory cytokine production and inflammatory arthritis in MRL-lpr/lpr mice by a transcriptional inhibitor of TNF-alpha

    J Immunol

    (1996)
  • X. Su et al.

    Reduction of arthritis and pneumonitis in motheaten mice by soluble tumor necrosis factor receptor

    Arthritis Rheum

    (1998)
  • R. Segal et al.

    Suppression of experimental systemic lupus erythematosus (SLE) in mice via TNF inhibition by an anti-TNFalpha monoclonal antibody and by pentoxiphylline

    Lupus

    (2001)
  • C.O. Jacob et al.

    Tumour necrosis factor-alpha in murine autoimmune 'lupus' nephritis

    Nature

    (1988)
  • Cited by (107)

    • Interferons and cytokines in SLE pathogenesis and therapy

      2021, Lahita’s Systemic Lupus Erythematosus
    View all citing articles on Scopus
    View full text