Vasculopathy in dermatomyositis

To the Editor: Dermatomyositis (DM) is a rare autoimmune disease characterized by specific cutaneous manifestations and proximal muscle weakness, in which abnormalities of nailfold capillary (NFC) and serum levels of vascular biomarkers are common. Dynamic changes in vascular lesions play an important role in the occurrence and development of DM and reflect the disease activity and treatment efficacy. Due to the diversity of clinical manifestations in DM patients, vascular involvement is often under-evaluated, causing the treatment of refractory vascular damage challenging. This review aims to explore the mechanisms, clinical manifestations, and treatment options of vasculopathy in DM to achieve early recognition and improve prognosis. The precise underlying autoimmune mechanism of DM remains poorly understood. There is considerable evidence showing that pathological complement activation plays a role in DM, leading to endothelial cell activation and damage. Membrane attack complex (MAC) depositions are often observed in the vessel walls of patients' muscle biopsy samples. Microvascular complement deposition is a feature of DM pathology. In addition, interferon (IFN) has been considered a key cytokine in the pathogenesis of DM. The levels of IFNs in the serum of DM patients are significantly higher than those in healthy controls and are associated with the features of vasculopathy. Capillary loss and perifascicular atrophy in DM have been attributed to the enhanced expression of myxovirus resistance protein 1, interferon-stimulated gene 15, and oligoadenylate synthase 1 induced by type 1 IFN (IFN-1). Many studies have documented that vasculopathy is a predominant feature of the DM and the followings clinical manifestations are associated with the existence of vascular involvement. Cutaneous involvement: The characteristic skin lesions of DM include heliotrope rash, Gottron's sign, V sign rash, and shawl sign rash. Histological findings in DM skin specimens revealed evidence of vasculopathy characterized by interface dermatitis with mucin accumulation and perivascular inflammation.[1] Dilated capillary loops and hemorrhagic nailfold infarction are commonly observed periungual changes in DM. Moreover, Raynaud's phenomenon, skin ulcers, and calcinosis are not rare in DM and are associated with vascular damage due to skin vasculitis. Musculoskeletal involvement: Vasculopathy is also associated with muscle involvement in DM patients, and inflammation around blood vessels can be found in biopsy specimens, particularly in the interfascicular septa or the periphery of muscle fascicles. A close relationship between the extent of capillary loss and the severity of muscle involvement in DM has been reported[2] and severe degeneration of myofiber might even further impair angiogenesis. Cardiac involvement: DM patients had an increased risk of cardiovascular complications, especially in the first year following DM diagnosis. Feng et al[3] reported that irreversible damage, such as myocardial fibrosis and necrosis, could be found in DM patients without obvious clinical symptoms after laboratory or imaging examination and suggested that this might be a consequence of the progressively deleted microvessels caused by local immune or inflammatory reactions and replaced by regions of fibrosis and ischemia. Gastrointestinal tract involvement: DM patients may have variable gastrointestinal manifestations, such as persistent abdominal pain, diarrhea, and even bleeding and perforation. Vasculopathy can occur in any part of the gastrointestinal tract, and microscopic examinations have found significant vascular changes, including non-inflammatory luminal occlusion in small arteries by intimal hyperplasia and prominent infiltration of lymphocytes around and within the venous walls. Other organ involvement: Vasculopathy has also been detected in several other organs. DM is associated with a significantly increased risk of cerebrovascular events that may be attributed to vasculitis, leading to local hypoperfusion, thrombosis, and infarction. Retinopathy and vision loss in DM patients may attribute to atypical central retinal artery occlusion following endothelial damage and platelet thrombi, indicating potential microangiopathy. Recent studies have pointed out that severe microangiopathies are often present in DM, of which NFC changes reflect the degree of systemic vascular abnormality and can be measured by nailfold video-capillaroscopy (NVC), a non-invasive, inexpensive imaging technique. NVC findings are associated with myositis-specific autoantibodies, which correlate with specific clinical manifestations and treatment outcomes in DM patients. The prevalence of NFC abnormalities was significantly higher in DM patients with anti-melanoma differentiation-associated protein 5 (MDA5) and anti-transcriptional intermediary factor-1γ (TIF-1γ) compared to those with anti-synthase syndrome (ASS).[4] In MDA5+ DM patients, microhemorrhage and capillary disorganization were shown to correlate with known poor prognostic factors such as serum ferritin, C-reactive protein, and Krebs von den lungen-6 levels, and chest high-resolution computed tomography findings.[5] Enlarged capillaries, giant capillaries, and hemorrhages can be detected in the NVC of anti-TIF-1γ positive DM patients.[6] NFC abnormalities are not rare in ASS, however, large capillaries, disturbances, and major capillary loss are observed in DM but not in ASS patients, and ASS NFC alterations are different from DM.[7] Research found that NFC abnormalities in DM seem to be more changeable and even reversible. [4] The disappearance or improvement of NFC abnormalities could be detected in patients with stable DM after 1 year of immunosuppressive therapy.[4] The persistence of ramified capillaries, a manifestation of neoangiogenesis, could appear in patients with longstanding disease and represents a form of recovery from microvascular damage in DM patients. Therefore, NVC findings could be implemented as effective markers for assessing disease activity in DM patients. Although the ability to detect subclinical early vascular lesions and disease activity is still limited, there is accumulating evidence supporting a significant association between specific markers in the serum of DM patients and vascular inflammation. IFN‑related biomarkers: IFN-1 could induce the antiangiogenic properties of endothelial progenitor cells by upregulating the interleukin-1 (IL-1) receptor antagonist and promoting the activation of IL-18. When exposed to proangiogenic stimulation, decreased circulating endothelial progenitor cells (CEPCs) have been observed in a significant proportion of DM patients, which may be attributed to the IFN-1/IL-18 axis. The inverse correlation of the number of CEPCs with muscle function and disease activity confirmed that CEPCs serve as effective biomarkers for DM.[8] Galectin (Gal) family members, IFN-related immunomodulators, are involved in many biological processes, including angiogenesis and immune regulation; and Gal-9 has been identified as a specific biomarker of endothelial activation and dysfunction in DM.[9] Angiogenic factors: Angiogenesis occurs as a result of growth factors driving endothelial cell proliferation, migration, and differentiation. Serum levels of angiogenin and vascular endothelial growth factor-1 (VEGF1) were found to be highly expressed in DM patients.[10] VEGF involves physiological and pathological angiogenesis, and high levels of VEGF appear to be associated with severe vascular lesions. Although VEGF and soluble VEGF receptor 1 have been observed to be increased during active DM, reflecting disease activity in patients,[9] the serum levels of VEGF in MDA5+ DM patients were found to be similar to healthy controls.[11] Complement system, vascular cell adhesion molecule, and coagulation factors: Circulating complement fragments C1q, C3b, C4b, and MAC were higher in the serum of patients with active DM compared to inactive DM patients, and these could be used as potential serological biomarkers.[12] Similarly, markers of endothelial cell activation such as intercellular adhesion molecule and vascular-cell adhesion molecule (VCAM) have been considered to be related to disease activity, and serum level of VCAM-1 has recently been considered a useful biomarker for reflecting the severity of pulmonary disease in patients with DM. Elevated levels of endothelin-1, a marker of defective vascular tone control, and von Willebrand factor, which reflects coagulation disorders, were observed in MDA5+ DM patients with cutaneous ulcers and/or interstitial lung diseases. Currently, systemic glucocorticoids (GCs) and immunosuppressive drugs, such as cyclophosphamide and calcineurin inhibitors (CNIs), are commonly used in the treatment of DM. Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate (MTX), azathioprine, and mycophenolate mofetil, are also beneficial for the improvement and maintenance of disease remission. However, conventional immunosuppressive therapy, including GCs, MTX, hydroxychloroquine, or other DMARDs, may not sufficiently target anti-angiogenic IFN signaling, and vascular lesions such as ulceration and NFC abnormalities are refractory to immunosuppressive therapy. In addition, CNIs, including tacrolimus and cyclosporine A, may hinder VEGF-mediated angiogenesis. Kawamoto et al[13] reported a case of DM patient who developed secondary thrombotic microangiopathy which may be associated with CNIs, although the association is considered to be low. Janus kinase (JAK) inhibitors are considered a therapeutic option for refractory DM. Ruxolitinib, which selectively inhibits JAK1 and JAK2, could abolish the pathogenic effects of IFN during the angiogenesis of endothelial cells and muscles in vitro. In juvenile DM, JAK inhibitors showed significant effects in reversing severe vasculopathy in muscles or skin tissues. In DM patients, a steady decline in the frequency of classic DM rashes, such as Gottron's sign and heliotrope, was observed after rituximab (RTX) therapy, and the degree of cutaneous involvement was improved faster in patients who received RTX early. In addition, RTX has the unique function of targeting microvasculature and reversing NFC damage in DM patients, indicating that it could be used to treat and repair pathogenic vascular injury. Intravenous immunoglobulin (IVIG) could improve calcinosis in patients with DM, especially those with cutaneous and musculoskeletal involvement. Non-immunosuppressants, including bisphosphonates, sodium thiosulfate, calcium channel blockers, and intravenous prostaglandins, have been reported to be effective in improving clinical symptoms associated with vasculopathy in DM patients.[14] Notably, exercise is a part of the treatment of DM patients, as endurance exercise has been indicated to promote muscle growth, suppress muscular inflammatory response, and increase capillary density. Obviously, csDMARDs are necessary to control the active disease but are often insufficient to target vascular lesions in DM patients. JAK inhibitors, IVIG, and RTX have been tried with some success; however, the dosage and timing of these therapeutic interventions and the prevention of severe vasculopathy remain an unmet research need. In conclusion, vasculopathy is an important characteristic of DM. It may change over the course of the disease and has been associated with refractory clinical manifestations and life-threatening organ involvement. Abnormal complement activation and marked upregulation of IFN pathways play an important role in the development of vasculopathy in DM. NVC and several serum vascular biomarkers, such as IFN-induced immunomodulatory cytokines, can be used to evaluate disease activity and response to therapy. Conventional immunosuppressants are effective for DM patients and vasodilation are available for treating vasculopathy in DM. However, predicting and monitoring the progression of vascular lesions throughout the disease process remain challenging as current therapeutic regimes cannot effectively control disease activity in patients with severe vasculopathy. Therefore, early identification and aggressive treatment of vasculopathy in DM are important for improving patient outcomes. Funding This work was supported by grants from the China International Medical Foundation (No. Z-2018-40), the Nantong Science and Technology Bureau Project (Nos. MSZ18108, JCZ20058, and JCZ2022026), and the Special Clinical Basic Research Key Project of Nantong University (No. 2019JZ001). Conflict of Interest None.