Dermatomyositis and Immune-Mediated Necrotizing Myopathies: A Window on Autoimmunity and Cancer

Abstract

Autoimmune myopathies (myositides) are strongly associated with malignancy. The link between myositis and cancer, originally noticed by Bohan and Peter in their classification in 1975 (1), has been evidenced by large population-based cohort studies and a recent meta-analysis. The numerous reports of cases in which the clinical course of myositis reflects that of cancer and the short delay between myositis and cancer onset support the notion that myositis may be an authentic paraneoplastic disorder. Thus, cancer-associated myositis raises the question of cancer as a cause rather than a consequence of autoimmunity. Among myositides, dermatomyositis and more recently, although to a lesser extent, immune-mediated necrotizing myopathies are the most documented forms associated with cancer. Interestingly, the current diagnostic approach for myositis is based on the identification of specific antibodies where each antibody determines specific clinical features and outcomes. Recent findings have shown that the autoantibodies anti-TIF1γ, anti-NXP2 and anti-HMGCR are associated with cancers in the course of myositis. Herein, we highlight the fact that the targets of these three autoantibodies involve cellular pathways that intervene in tumor promotion and we discuss the role of cancer mutations as autoimmunity triggers in adult myositis.

Keywords: TIF1gamma; autoantibody; autoimmunity; cancer; myositis.

Figure 1

Clinical and histological features of dermatomyositis (DM). (A) Gottron’s sign: erythematous scaly papules over the metacarpophalangeal joints. (B) «V sign» in a white European male patient with DM. (C) Poikiloderma (i.e., erythema, atrophy, variable pigmentary changes) on the upper trunk of an African Caribbean female patient with DM. (D) Typical centripetal flagellate erythema affecting the upper trunk of a male patient with DM. (E,F) Periungual erythema and telangiectatic capillary loops in patients with DM. (G–I) Histological feature of a Gottron’s papule. (G) Slight hyperkeratosis, basal cell vacuolar degeneration, upper dermal edema, and perivascular inflammatory cell infiltrate with enlarged capillaries (HES staining, ×20). (H) DM interface dermatitis with vacuolar changes of the basal cell layer, perivascular inflammatory cell infiltrate with capillary dilatation, endothelial cell turgescence, and pigmentary incontinence (HES staining, ×40). (I) Positive alcian-blue staining attesting dermal mucin deposits (×20).

Figure 2

Muscle biopsy of dermatomyositis. (A) Perifascicular atrophy. (B) Area of contiguous necrotic myofibers (arrow) corresponding to a microinfarct. (C) Punch-out vacuoles within myofibers (arrows) assessing focal myosinolysis. (D) Ubiquitous myofiber reexpression of MHC-class I with perifascicular reinforcement. (E) Neural cell adhesion molecule (NCAM) immunostaining showing large areas of positive myofibers indicating muscle ischemia. (F) Platelet endothelial cell adhesion molecule (PECAM) immunostaining for endothelial cells showing marked endomysial capillary drop out. (G) Complement activation assessed by the presence of membrane attack complex deposits at the level of endomysial capillaries (arrows). Frozen sections, light microscopy; hematoxylin-eosin (A–C), immunoperoxydase technique (D–G), HLA-ABC (D), CD56/NCAM (E), CD31/PECAM (F), and C5b-9 (G).

Figure 3

Hypothetical model of specific antitumoral response as a trigger of dermatomyositis through the example of TIF1γ. According to this model, TIF1γ (or NXP2, or HMGCR) is modified in the tumor (gene mutation, overexpression, ectopic expression, posttranslational modification), leading to the development of a TIF1γ- (or NXP2-, or HMGCR-) specific T and B cell antitumor response. Secondarily, breakage of tolerance results from cross-reactivity and/or epitope spreading, promoting a response against muscle and skin.