We found angiogenesis in the fascia in patients with DM but not in patients with PM. Although some researchers have provided data on the number of blood vessels or neovascularization in the muscle of patients with DM and PM, they did not report the data on the fascia [7, 8, 11]. Grundtman et al. reported that there was no significant difference in the number of CD31-expressing capillaries in muscle among patients with PM and DM and healthy controls. Similarly, in the present study, there was also no significant difference in the number of CD31-expressing vessels in muscle in the DM and PM groups. However, our previous study  and our present study showed that the number of CD31-expressing blood vessels in the fascia in patients with DM was significantly greater than in patients with PM, regardless of the number of CD31-expressing blood vessels in muscle. This suggests that the pathogenesis of the fascia differs markedly between DM and PM.
In the present study, immunohistochemical staining showed that the number of VEGF-expressing cells in the fascia in patients with DM was greater compared with that in patients with PM. In contrast, the number of VEGF-expressing cells within muscle in patients in the PM and DM groups did not differ to a statistically significant extent. Grundtman et al. showed that the total protein expression of VEGF in muscle in patients with PM and DM was significantly increased in comparison to healthy control subjects. However, there was no difference in the expression of VEGF within muscle in patients in the PM and DM groups . This finding is in line with our results. VEGF, which is a major mediator of pathological angiogenesis , has a predominant role in both tumor-induced and inflammation-induced angiogenesis . In the present study, the number of VEGF-expressing cells in the fascia was positively correlated with the AS, suggesting that VEGF is a principal angiogenic factor in DM-associated fasciitis.
In the early-phase DM, increased AS and number of VEGF-expressing cells were found in the fascia rather than in muscle. Conversely, in the late phase, the AS and the number of VEGF-expressing cells in the fascia and muscle did not differ to a statistically significant extent. We previously showed the possibility that inflammatory cell infiltration progressed from the fascia into muscle in patients with DM . Moreover, PDUS predominantly detected increased blood flow signals in the fascia rather than in muscle . Our data suggest that the angiogenesis induced by VEGF may progress from the fascia into muscle in patients with DM. Any lack of findings of inflammation and angiogenesis histologically detected in the muscle tissue at a site with muscle symptoms, such as myalgia, may be due in part to DM-associated fasciitis in the early phase before the progression of inflammation and angiogenesis to muscle.
We previously showed that DM is frequently associated with fasciitis, whereas no such association is noted with PM [4,5,6]. In the present study, fasciitis, including mild fasciitis, was detected in all patients with DM regardless of the presence of myositis-specific/associated antibodies, suggesting that fasciitis results from the properties of DM. In contrast, mild fasciitis, which had perivascular inflammatory cell infiltration, was detected in four patients with PM, two of whom were positive for anti-ARS antibodies, but not in patients with PM in whom inflammatory infiltrates predominantly surrounded the endomysium within the fascicles. In general, inflammatory infiltrates are predominantly found at perivascular sites or in the interfascicular septa in DM, while they surround and invade non-necrotic muscle fibers expressing major histocompatibility class I antigens within the fascicles in PM [2, 3]. Noguchi et al. showed that in antisynthetase syndrome, inflammatory infiltrates were present at perimysial sites, normally perivascular sites, but that they did not surround the endomysium or invade into non-necrotic muscle fibers within the fascicles, as typically observed in PM . Their study suggests that the sites of inflammatory cell infiltration in antisynthetase syndrome are similar to those in DM. We therefore believe that fasciitis can be frequently detected in anti-ARS antibody-positive patients without typical skin rash who are diagnosed with PM according to the Bohan and Peter criteria; however, fasciitis is rarely detected in patients who are diagnosed with PM based on the typical histological findings of PM.
In the patients with DM in the present study, angiogenesis was accompanied by inflammatory cell infiltration. The TVIS in the fascia in the DM group was significantly greater compared with the PM group, which included a larger number of patients than in our previous report.  The degree of inflammation (TVIS) and angiogenesis in the fascia were both significantly increased during early-phase DM compared with those in muscle. Furthermore, there was significant positive correlation between the TVIS and the AS in the fascia in patients with DM. Grundtman et al. also showed that the number of capillaries expressing CD31 in muscle was significantly higher in patients with PM/DM with inflammatory cell infiltrates before treatment than in those without inflammatory cell infiltrates. In chronic inflammatory disorders, hypoxia is associated with the accumulation of inflammatory cells and the overexpression of hypoxia-inducible factor, which promotes the transcription of several angiogenic genes, including VEGF, and consequently induces angiogenesis [15,16,17,18]. For instance, in patients with rheumatoid arthritis, hypoxia mainly occurs due to hyperplasia of the synovial lining and the augmented infiltration of immune cells [19,20,21]. In our study, the marked proliferation of blood vessels in the fascia and hyperplasia of the fascia were present at the sites of intense inflammatory cell infiltration in patients with DM. Local inflammatory processes are considered a potential source of angiogenesis in DM-associated fasciitis.
TNF-α is generally considered to be a proinflammatory cytokine that plays a principal role in initiating the cascade of activation of other cytokines and growth factors in the inflammatory response. VEGF is produced in response to stimulation by proinflammatory cytokines . Although Kuru et al. and Lundberg et al. previously reported that TNF-α was expressed in muscle in patients both with PM and with DM, the expression levels in patients with PM and DM did not differ to a significant extent [23, 24]. In the present study, the number of TNF-α-expressing cells in the fascia in patients with DM was significantly higher than in patients with PM, whereas the number in muscle in patients with PM and DM did not differ to a statistically significant extent as they previously reported. Furthermore, the number of TNF-α-expressing cells was positively correlated with the TVIS and the number of VEGF-expressing cells in the fascia of patients with DM. TNF-α enhanced the expression of angiogenic ligands, such as VEGF, basic fibroblast growth factor (bFGF), and IL-8 . Anti-VEGF antibodies inhibit TNF-α-induced angiogenesis in the rabbit cornea . These reports and our data suggest that TNF-α is a potential angiogenesis factor in the fascia of patients with DM, which increases the expression of VEGF.
With regard to patients with IIM, there are conflicting reports about the responses to TNF-α blocking agents. Datmalchi et al. reported that infliximab treatment was not effective in treating refractory inflammatory myopathies in an open pilot study . Brunasso et al. concluded in their systematic literature review that the use of the TNF-α blocking agents had the potential to trigger the onset of PM, DM, and antisynthetase syndrome in patients with chronic inflammatory diseases . However, several case reports and case series have suggested the beneficial effects of TNF-α blocking agents such as infliximab, etanercept, and adalimumab in patients with DM or PM [28,29,30,31,32]. It appears that anti-TNF-α treatment could be of benefit to a subset of patients with IIM, especially those with early-stage DM with interstitial lung disease [30,31,32]. A further study would be needed to clarify the effects of anti-TNF-α therapy in the different subsets of DM.
The present study had the limitation of having a small study population. A further study of a larger cohort of patients with PM and DM is needed to clarify the findings.