Alpha Blockade

Overview

Raised levels of TNF-α have been demonstrated both in serum of patients with chronic DM and inside the calcium deposits (calcinosis cutis) . It has also been reported that the soluble forms of the receptors TNF-R55 and TNF-R75 are increased in DM/PM sera [1]. The induction of INF-alpha can be the result of immune complexes containing anti-Ro or anti-Jo-1 antibodies and RNA that activate IFN-α production in plasmacytoid dendritic cells . Biological agents, in particular TNF-α blocking agents, have been proposed as potential steroid-sparing agents and as long-term therapies in addition or substitution to corticosteroid therapy . [2]

Findings

In one control series study Improvement of DM/PM after anti-TNF-α therapy suspension was recorded in 15 cases; only partial improvement was seen in one patient and there was no available information regarding outcome and/or complications in 5 cases. In all of the available cases with outcomes, therapy with other immunosuppressors was required to control the DM/PM flare [3].

There is a specific subset of patients affected by DM/PM, where the presence of antisynthetase antibodies (Jo-1, PL-7, PL-12, EJ, OK, KS, YRS, and Zo) with the addition of some specific clinical findings as, ILD and/or arthralgia/arthritis constitute a clinical entity called antisynthetase syndrome [36–38]. In such patients, other clinical findings such as fever, Raynaud’s phenomenon, and mechanic’s hands can be present [4].

Between the 20 cases examined herein, one developed a subset of DM/PM called antisynthetase syndrome after the introduction of anti-TNF-α therapy. In the other five patients (three with previous positive anti-Jo-1 antibodies, one with anti-PL-7, and another one with anti PL-12) the emergence of PM/DM and the aggravation of the clinical picture previously compatible with RA associated with interstitial lung disease was compatible with a full development of an antisynthetase syndrome, probably unmasked by the use of anti-TNF-α agents. Interestingly, anti-TNF-α therapy has been associated also with the new onset or exacerbation of ILD mainly in patients affected by RA, being the TNF-α, a vital cytokine implicated in the development of pulmonary fibrosis [5].

Therapy

The use of anti-TNF-α therapies has been postulated in the treatment of DM/PM, in particular the use of etanercept as steroid-sparing agent [10–12]. Mainly case reports and series descriptions have been conducted; only one RCT is retrievable and larger studies are not available [11]. The muscle study group published in 2011, a randomized, double-blind, placebo-controlled trial evaluating the use of etanercept (50 mg subcutaneously weekly) for 52 weeks in DM affected patients [5].

TNF-α blockage may induce autoimmune phenomena in individuals with some genetic background as confirmed by the onset of autoantibodies (50% of antinuclear antibodies and 15% of anti-DNA antibodies), drug induced lupus, vasculitis, antiphospholipid syndrome, and other autoimmune entities .Anti-TNF-α therapy inhibits the cytotoxic T lymphocyte response that would normally suppress the autoreactive B-cell response, promoting humoral autoimmunity and increasing the type-I interferon system, that has been implicated in the pathogenesis of DM and PM .The accumulation of apoptotic cells and the release of antigenic particles might stimulate autoimmunity . The increased infections-rate in patients treated with anti-TNF-α drugs may lead to polyclonal B lymphocyte activation and autoantibody production.

The blockage of TNF-α causes the exacerbation or prolongation of preexisting autoimmune diseases, such as multiple sclerosis. [6].

Relevance

In conclusion, the emergence of DM/PM and a specific subset of such diseases as the antisynthetase syndrome seem to be associated with the use of anti-TNF-α agents, especially in patients with chronic inflammatory diseases (mainly RA but also AS and Crohn’s disease). physicians should pay attention to patients affected by RA with positive antisynthetase antibodies (in particular anti-Jo-1 antibodies) and/or history of ILD. In those cases the use of the TNF-α blocking agents may trigger the onset of PM, DM, and antisynthetase syndrome or may aggravate or trigger the lung disease.

Footnotes:

1. B. De Paepe, K. K. Creus, and J. L. De Bleecker, “The tumor necrosis factor superfamily of cytokines in the inflammatory myopathies: potential targets for therapy,” Clinical and Developmental Immunology, vol. 2012, Article ID 369432, 10 pages, 2012.

2. R. J. Walsh, W. K. Sek, Y. Yao et al., “Type I interferon-inducible gene expression in blood is present and reflects disease activity in dermatomyositis and polymyositis,” Arthritis and Rheumatism, vol. 56, no. 11, pp. 3784–3792, 2007.

3. M. Ramos-Casals, P. Brito-Zerón, M.-J. Soto, M.-J. Cuadrado, and M. A. Khamashta, “Autoimmune diseases induced by TNF-targeted therapies,” Best Practice and Research, vol. 22, no. 5, pp. 847–861, 2008.

4. J. Solomon, J. J. Swigris, and K. K. Brown, “Myositis-related interstitial lung disease and antisynthetase syndrome,” Jornal Brasileiro de Pneumologia, vol. 37, no. 1, pp. 100–109, 2011. R. Perez-Alvarez, M. Perez-de-Lis, C. Diaz-Lagares et al., “Interstitial lung disease induced or exacerbated by TNF-targeted therapies: analysis of 122 cases,” Seminars in Arthritis and Rheumatism, vol. 41, no. 2, pp. 256–264, 2011.

5. A. Amato, “A randomized, pilot trial of etanercept in dermatomyositis,” Annals of Neurology, vol. 70, no. 3, pp. 427–436, 2011. View at Publisher · View at Google Scholar ·

6. P. A. Gordon, J. B. Winer, J. E. Hoogendijk, and E. H. Choy, “Immunosuppressant and immunomodulatory treatment for dermatomyositis and polymyositis,” Cochrane Database of Systematic Reviews, vol. 15, no. 8, 2012.