Inflammatory responses in SLE can be favored and/or sustained by the availability of cytokines that are overexpressed systemically and/or in local tissues. Proinflammatory cytokines such as TNF-α, IL-1, -6, -12, -15, -18 and IFN-α and -γ are upregulated in SLE and play important roles in the inflammatory processes that leads to tissue and organ damage. Thus, many of these cytokines have been considered potential targets for the reduction of chronic inflammation in SLE. Blockade of these cytokines has been studied in preclinical models, with the acknowledged caveat that murine lupus models and human SLE may not fully share patho genetic mechanisms. For some cytokines – which are reviewed below – specific biologics have been developed and tested in clinical trials.
The role of TNF-α in SLE is controversial. TNF-α promotes apoptosis and significantly affects the activity of B cells, T cells and dendritic cells (DCs). In different strains of lupus mice, the expression of TNF-α is often variable, and beneficial effects on the disease can be observed either after administration of TNF or upon TNF blockade [2
]. In kidney inflammation, the renal expression of TNF is usually increased [5
]. In lupus mice, skin disease may be TNF dependent, and anti-TNF treatment can deteriorate nephritis. In humans, some studies have found relatively low concentrations of serum TNF-α, while other studies have found elevated amounts or no significant differences between SLE patients and healthy controls. Similarly, high TNF-α has been described in both active and inactive SLE [6
]. Furthermore, TNF-α levels might correlate with clinical disease because they are increased in lupus nephritis in relation to the activity of renal disease [9
Infliximab & etanercept
The TNF blockers that have been successful in the management of RA, Crohn's disease and psoriasis are known to induce autoantibodies and lupus-like syndromes. Thus, their use in SLE is controversial [10
]. Although with the cessation of the administration of TNF inhibitors, the lupus-like symptoms and most auto-antibodies disappear (they are IgM and possibly are not pathogenic), it has been reported that a few RA patients who use TNF-blockers can develop nephritis [13
In SLE, the use of anti-TNF antibodies has been associated with amelioration of poly-arthritis, cutaneous manifestations, disease activity, proteinuria and nephritis, but also severe infusion reaction [15
]. An open-label study of infliximab in a small number of SLE patients with arthritis and/or lupus nephritis that were refractory to standard therapy has shown clinical improvement and an increased risk of infection [17
]. However, it appears that anti-TNF treatment is not promising in SLE, after the termination of studies on TNF blockade in a Phase II/III multicenter trial where infliximab was combined with azathioprine in lupus membranous nephritis, and also in a randomized, double-blind, multicenter Phase II study that evaluated safety and tolerability of etanercept in patients with active lupus nephritis.
Both type I (IFN-α) and type II (IFN-γ) interferons have been implicated in the pathogenesis of SLE, with IFN-α being a key player in inflammation and immune hyperactivity in the disease owing to its ability to directly affect T cells and B cells and induce the activation of peripheral DCs.
DNA-containing immune complexes in lupus serum stimulate plasmacytoid DCs to produce IFN-α [18
]. IFN-α levels often correlate with anti-dsDNA antibody production, complement activation and IL-10 production [20
]. This cytokine promotes activation, differentiation, survival and antibody production in B cells. In SLE, patients can have increased levels of IFN-α, which in turn promotes the expression of interferon-regulated inflammatory genes in the peripheral blood mononuclear cells of the SLE patients (a characteristic often referred to as the ‘interferon signature’).
This human antibody that blocks multiple IFN-α subtypes is currently being tested in Phase Ib and IIa clinical trials, to evaluate safety and tolerability of multiple intravenous and subcutaneous doses in SLE.
This humanized mAb against IFN-α (rhuMAb IFN-α) is in a Phase II, randomized, double-blind, placebo-controlled trial that evaluates the efficacy and safety in patients with moderately to severely active SLE.
The role of IFN-γ in SLE is not fully elucidated. IFN-γ is elevated in (New Zealand Black [NZB] × New Zealand White [NZW])F1
(NZB/W) lupus mice, where it correlates with disease. In addition, administration of IFN-γ accelerates murine lupus, while anti-IFN-γ antibody (or soluble IFN-γ receptor or IFN-γ receptor-immunoglobin) delays the disease [21
]. Finally, late treatment with IFN-γ in MRL/lpr mice accelerates SLE, while early treatment protects from disease [24
In humans, elevated serum IFN-γ correlates with disease activity and kidney involvement in SLE patients [25
]. However, some studies show an increase of IFN-γ in SLE patients and other studies find decreased titers of IFN-γ in lupus nephritis [26
The safety, tolerability, pharmacokinetics and pharmacodynamics of multiple doses of this human mAb to IFN-γ are under investigation in a Phase Ib, randomized, multicenter study in SLE patients with and without glomerulonephritis.
IL-1 includes the proinflammatory cytokines IL-1α and IL-1β. IL-1 binds to IL-1 receptor (IL-1R). The IL-1R antagonist (IL-1Ra) competes for receptor binding with IL-1α and IL-1β, thus blocking these cytokines.
IL-1 is overexpressed in inflamed kidneys of MRL/lpr and NZB/W lupus mice, and low-dose administration of IL-1 accelerates renal disease in the latter strain of mice [3
]. IL-1R deficiency causes arthritis in mice, and MRL/lpr mice with nephritis do not respond to therapy with IL-1Ra [3
In human SLE, IL-1α and -1β are increased in glomerulonephritis, and IL-1β is increased in the serum and cerebrospinal fluid of patients with CNS lupus [29
]. Although kidney involvement associates with low serum levels of IL-1Ra, some reports have shown an increase of IL-1Ra during active disease and a decrease during disease flares [30
This nonglycolated version of the human IL-1Ra (which neutralizes the biological activity of IL-1) has shown both safety and efficacy in improving arthritis in an open trial on four SLE patients, with only short-lasting therapeutic effects in two patients [32
IL-6 induces B-cell differentiation to plasma cells, hyperactivity and secretion of antibodies, and also promotes T-cell proliferation, cytotoxic T-cell differentiation and local inflammation. IL-6 can be induced by TNF-α and IL-1, and signals through the ligand-binding membrane-bound IL-6R and the nonligand-binding signal transducer gp130. A soluble form of IL-6R, which lacks transmembrane and cytoplasmic domains (and can form a complex with soluble IL-6) is elevated in SLE patients and in experimental lupus nephritis.
Blockade of IL-6R improves renal disease [33
]. Similarly, treatment with IL-6 promotes disease, while anti-IL-6 therapy delays lupus nephritis in NZB/W mice [34
In the serum of active SLE patients, IL-6 is elevated and correlates with disease activity [35
]. IL-6 is found in lupus kidneys and in the urine of patients with lupus nephritis [29
]. Finally, IL-6 is elevated during cardiopulmonary complications of SLE and in the cerebrospinal fluid of SLE patients with neuropsychiatric symptoms [37
By binding both the membrane-bound IL-6R and the soluble form of IL-6R, this humanized mAb inhibits IL-6 signaling. An open-label Phase I dosage-escalation study with tocilizumab in SLE patients with mild-to-moderate disease demonstrated improved disease activity scores and amelioration of arthritis, in addition to a decrease in the frequency of circulating plasma cells and reduced IgG and anti-dsDNA a ntibody titers, but also induced neutropenia [39
IL-10 is generally considered an inhibitory cytokine for T cells and contrasts the activity of other proinflammatory cytokines such as IFN-γ, TNF-α and GM-CSF. In B cells, IL-10 promotes differentiation and antibody production.
New Zealand Black/White lupus mice treated with anti-IL-10 mAb have reduced anti-DNA antibody titers and a delay in the onset of proteinuria and glomerulonephritis. Conversely, their treatment with IL-10 associates with accelerated disease [40
]. However, these effects appear to be strain dependent [41
IL-10 levels are elevated in sera of SLE patients and correlate with clinical and sero-logical disease activities [42
]. Treatment of cells from lupus patients with anti-human IL-10 antibody reduces antibody production [43
]. Interestingly, the dysregulation of IL-10 in SLE patients is linked to certain genetic polymorphisms [44
In the absence of a human (or humanized) mAb to IL-10, the murine anti-IL-10 mAb B-N10 was used to neutralize IL-10 in a small uncontrolled, open-label study in patients with relatively mild disease [45
]. Disease activity improved and inactivity was observed in SLE patients up to 6 months after treatment [45
]. However, all patients developed antibodies against the murine mAb [45