Tumor necrosis factor (TNF) is a critical cytokine, which contributes to both physiological and pathological processes. It is one of multiple proteins capable of inducing necrosis (death) of tumor cells that possess a wide range of proinflammatory actions. Abbreviated TNF. TNF is a multifunctional cytokine with effects on lipid metabolism, coagulation, insulin resistance, and the function of endothelial cells lining blood vessels. Drugs that block the action of TNF have been shown to be beneficial in reducing the inflammation in inflammatory diseases such as PM , DM and rheumatoid arthritis.
Histologic studies of the muscles suggest that cytokines are involved in inflammatory myopathy. The therapeutic effects of cytokine blockade are controversial, with anecdotal reports of clinical efficacy. IL-1 and TNF blockade ameliorated CIM (C protein–induced myositis) after disease onset and should potentially be a new strategy for the treatment of inflammatory myopathy. As IL-1 blockade, treatment with anti–IL-1R monoclonal antibody appeared more feasible than the other approaches.(1)
An accumulated body of evidence supports the notion that the pathology of PM is driven by cytotoxic CD8 T cells , but the event that initiates the inflammatory processes has not been identified. Currently, patients with PM are treated primarily with nonspecific immunosuppressants, including high-dose corticosteroids, methotrexate, and/or other small-molecule immunosuppressants. Because the administration of therapeutic agents can elicit a wide variety of adverse reactions, treatments that address the specific pathology of PM need to be developed. (2)
Updates
In the development of new therapeutic approaches to human diseases, animal models have served as a means with which to identify therapeutic targets and to test the effect of new treatments . Despite the known limitations, experiments in animals with collagen-induced arthritis (CIA) have facilitated development of new treatments for rheumatoid arthritis (RA). Treatment approaches such as blockade of interleukin-1 (IL-1), tumor necrosis factor α (TNFα), and IL-6 have had an enormous effect in modulating the disease course of RA . (3)
Elevation of IL-15, sIL2-R and sTNF-R1 in active patients provides preliminary evidence for the activation of inflammatory response during PM/DM flares. Further studies may be needed to explain the mechanisms driving these diseases.(4)
What s next?
Because of the availability of biologic anticytokine reagents for clinical use, these reagents have been anecdotally tested for the treatment of patients with PM and patients with dermatomyositis (DM) who did not respond to conventional treatment. In this regard, results of animal experiments using anticytokine reagents will represent a rationale for conducting controlled clinical studies in humans.
Footnotes:
Naoko O. Therapeutic effects of interleukin-6 blockade in a murine model of polymyositis that does not require interleukin-17ª. Article first published online: 30 JUL 2009DOI: 10.1002/ar.24689. view
Takahiko S. Interleukin-1 and tumor necrosis factor α blockade treatment of experimental polymyositis in mice. Article first published online: 27 JUL 2012DOI: 10.1002/art.34465. American college of Rheumatology. view
Grundtman C,. Immunolocalization of interleukin-1 receptors in the sarcolemma and nuclei of skeletal muscle in patients with idiopathic inflammatory myopathies. Arthritis Rheum2007; 56: 674–87 .view
Marzena O. Serum concentration of interleukin 15, interleukin 2 receptor and TNF receptor in patients with polymyositis and dermatomyositis: correlation to disease activity. Rheumatology International March 2012, Volume 32, Issue 3, pp 639-643. view
TNF receptors
Cytokines are implied in polymyositis/dermatomyositis (PM/DM) pathogenesis. Several studies have as their aim to evaluate the serum levels of interleukin-15 (IL-15), soluble receptors for IL-2 (sIL-2R) and TNF-alpha type 1 receptor (sTNF-R1) in PM/DM patients and their relation to disease activity and clinical symptoms. Thirty-eight patients who met definite or probable criteria of Bohan and Peter for DM/PM were included into one study. Results in patients with active (41 observations) and inactive disease (24 observations) were compared with control (15 subjects). There were significantly higher serum levels of these cytokines in active patients than in control subjects (for sIL-2R P = 0.05, CI95% 0.4–331; and sTNF-R1 P = 0.031, CI95% 15.1–321.5). The interleukin levels did not differ between inactive patients and controls. Elevation of IL-15, sIL2-R and sTNF-R1 in active patients provides preliminary evidence for the activation of inflammatory response during PM/DM flares. Further studies may be needed to explain the mechanisms driving these diseases. (1)
Therapeutic targets
The therapeutic effects of cytokine blockade are controversial, with anecdotal reports of clinical efficacy. The aim of another study was to discern the significance of interleukin-1 (IL-1) and tumor necrosis factor α (TNFα) as therapeutic targets in polymyositis (PM) by studying their involvement and the effects of their blockade in C protein–induced myositis (CIM), a murine model of PM. C57BL/6 mice were immunized with recombinant skeletal C protein fragments to induce CIM. The expression of IL-1 and TNFα in the muscles of mice with CIM was detected using immunohistochemical and real-time polymerase chain reaction analyses. IL-1α– and TNFα-positive macrophages were observed in the muscle tissue of mice with CIM as early as 7 days after immunization. IL-1α, IL-1β, and TNFα expression in the muscles increased as the severity of myositis peaked, at both the messenger RNA and protein levels. IL-1 and TNF blockade ameliorated CIM after disease onset and should potentially be a new strategy for the treatment of inflammatory myopathy. As IL-1 blockade, treatment with anti–IL-1R monoclonal antibody appeared more feasible than the other approaches. (2)
Visfatin is an adipocytokine that supports B-lymphocyte precursor maturation, and also takes part in regulation of inflammation. Anti-histidyl-tRNA syntethase antibodies (anti-Jo-1) are the most frequent myositis specific autoantibodies. We have shown increased serum levels of B-cell activating factor of the TNF family (BAFF) in dermatomyositis (DM) and anti-Jo-1-positive polymyositis (PM) patients and its association with disease activity. Serum visfatin and BAFF levels were significantly higher in myositis patients (medians 1.9 and 1.4 pg/l) compared to healthy controls (1.3 and 1.0 pg/l; p < 0.02 and p = 0.003) and were associated with clinical muscle activity (rs = 0.39; p < 0.02 and rs = 0.34; p = 0.04). Trend for correlation of both visfatin and BAFF with the global disease activity was present. These results demonstrate that serum levels of visfatin, similarly to BAFF, associate with disease activity in patients with myositis. Increased visfatin levels and expression in inflamed muscle tissues support its potential role in the pathogenesis of idiopathic inflammatory myopathies. (3)
Recent findings: The most promising biological treatment in polymyositis, dermatomyositis and juvenile dermatomyositis is B-cell blockade by rituximab. Anti-Jo or anti-Mi-2 antibodies were predictors of response suggesting different molecular pathways in different subsets of myositis. T-cell blockade with abatacept is a new possibility, as is blockade of interleukin-1, interleukin-6, TNF or type I interferon, but controlled studies are needed. Metabolic abnormalities may contribute to muscle impairment, lending support to combine pharmacological therapy with exercise in patients with polymyositis and dermatomyositis. (4)
Footnotes:
Marzena O. Serum concentration of interleukin 15, interleukin 2 receptor and TNF receptor in patients with polymyositis and dermatomyositis: correlation to disease activity. Rheumatology International March 2012, Volume 32, Issue 3, pp 639-643. view
Takahiko S. Interleukin-1 and tumor necrosis factor α blockade treatment of experimental polymyositis in mice. Article first published online: 27 JUL 2012DOI: 10.1002/art.34465. American college of Rheumatology. view
Hulejom. H. Serum Levels of Visfatin and B-Cell Activating Factor of the TNF Family Correlate with Disease Activity in Patients with Myositis . Ann Rheum Dis 2013;72:A29 doi:10.1136/annrheumdis-2013-203217.15.view
