Patients with anti-MDA5 antibody-positive DM have various clinical manifestations, and the severity is different. Some patients with atypical clinical manifestations are often missed or misdiagnosed, and patients with anti-MDA5 antibody-positive DM are more common with ILD or RPILD with high mortality rate and poor prognosis. Therefore, it is especially important to have a good knowledge of the clinical features for anti-MDA5 antibody-positive DM.
According to the results of an epidemiological survey made by Hiroyuki Tomimitsu[21] in Japan in 2016 to 17,000 DM patients, the male/female ratio was about 1:2.7, and the majority of patients has an onset age between 40 and 60 years old. Among the 109 patients included in the study, the total male/female ratio was 1:2.3, and the onset age of anti-MDA5 antibody-positive group and antibody-negative group was approximately 40-60 years old with Japanese flow. The results were consistent. There was no difference in age, onset age, and gender between the two groups. There were 58 patients with anti-MDA5 antibody-positive DM, and the positive rate was 53.21%, being consistent with Wang Kaige[15]. By analyzing the subtypes of patients with MDA5 antibody-positive DM, only one patient with clinical myositis dermatomyositis was found to be inconsistent with the literature[15], and the fact might be that only inpatient information was collected in this study. Some outpatients or patients in other departments such as Dermatology had incomplete information collection, so leading to certain selection bias. It was found that the difference in disease duration between the two groups was obvious. Patients with anti-MDA5 antibody-positive DM had a shorter course of disease, which may be related to the rapid progression of the disease and the severity of the disease for patients with positive MDA5 antibody.
Common skin lesions of DM have Gottron sign, Heliotrope rash, V-shaped shawl sign, holster sign, technician hand, skin ulcer, and nail erythema, which are heterogeneous for each patient. The Gottron sign refers to the rash that occurs on the lateral side of the joint. In this study, patients with anti-MDA5 antibody-positive DM tended to have the Gottron sign, met with reports made by Li[18], but the pathogenesis of the Gottron sign have not yet been clearly illustrated. Whether there is correlation between them or not, a larger amount of samples are needed. The incidence of pruritus is common for DM patients. The incidence of Heliotrope rash in this study is 60.55%, which conforms to Kazandjieva’s reports[22]. The V-shaped sign marks the V-shaped erythematous rash in the anterior and upper chest, while the shawl sign shows a change in the skin of the scalp, shoulder and upper back. Sun[23] uncovered the negative correlation between V-shaped sign and the occurrence of ILD. The study conducted by Wu[24] showed that the shawl sign is irrelevant to the occurrence of ILD. However, this study revealed that patients with anti-MDA5-positive DM had fewer V-type shawl signs, which accords with Sun’s findings. However, whether the V-shaped shawl sign is indeed negatively correlated with anti-MDA5 antibody requires numerous data to further confirm. It is not common for DM patients to suffer from skin ulcers. In this study, there were 18 patients with skin ulcers (13.53%), same with the reported incidence of 3-19% by Narang[25]. So, DM patients with skin ulcers should be highly alert to whether they have anti-MDA5 antibody-positive and pulmonary interstitial lesions, and should regularly screen for myositis antibody and lung high-resolution CT. Perlungual erythematosus is often neglected in DM and fewer studies have reported that anti-MDA5 antibodies are associated with it. This study found that patients with positive anti-MDA5 antibodies are more prone to perlungual erythematosus. Therefore, it should be observed in the clinical diagnosis and treatment for patients with perlungual erythematosus. The performance of the technician hands and holster sign is relatively rare. The technician hands are mainly found in patients with anti-synthetase antibody syndrome[26] and closely related to anti-JO-1 antibody, while the holster sign refers to the outside of the buttocks or thighs rash. There are few reports on the occurrence of holster signs, because they may be misdiagnosed as other skin damage such as body lice for its occultity.
Joint swelling and pain are non-specific manifestations of connective tissue disease and can be found in a variety of connective tissue diseases, including rheumatoid arthritis, systemic lupus erythematosus, idiopathic inflammatory myopathy, and seronegative spondyloarthropathy. This study demonstrated that anti-MDA5 antibodies are associated with joint pain/swell, but the exact mechanism remains unclear.
Dyspnea, cough, and cough are the main clinical manifestations of respiratory involvement. This study displayed that anti-MDA5 antibody-positive patients are prone to dyspnea, cough symptoms, usually dry cough, no obvious cough and other discomfort, which may be associated with anti-MDA5 antibody-positive DM patients with ILD[19, 20], involving the respiratory system and causing respiratory muscle fatigue.
There is few report about anti-MDA5 antibodies that is associated with abnormal liver function. Besides liver, transaminase has other sources, including muscle, heart, kidney, and red blood cells. Studies have shown that alanine aminotransferase is relatively liver-specific, while aspartate aminotransferase lacks organ specificity and is abundant in liver, kidney, heart, muscle and other tissues, especially in myocardial and skeletal muscle. Patients with myositis can be combined with elevated transaminase. This study gave the information that anti-MDA5 antibody-positive DM patients are prone to elevated transaminase, but the specific mechanism of action is still not clear. It was discovered that the level of creatine kinase, creatine kinase isoenzyme and myoglobin is different between the two groups. However, in studies performed by Taborda[27],it was clear that the level of muscle enzyme is negatively correlated with the prognosis of patients with DM/PM. However, patients with positive anti-MDA5 antibodies have a worse prognosis, which is deferent from it.
More than half of the patients in this study had pulmonary interstitial lesions (57.80%), and there was a significant difference in ILD and RPILD between the two groups. Patients with anti-MDA5 antibody-positive patients were more likely to suffer from ILD and RPILD. Numerous literatures[28-35] have analyzed the relationship between anti-MDA5 antibodies and ILD, and the relationship between anti-MDA5 antibody and RPILD was analyzed by a number of literature[13, 14, 16, 33, 35-39], suggesting that anti-MDA5 antibody is closely related to the occurrence of ILD and RPILD. However, the mechanism of how MDA5 participates in pulmonary interstitial lesions is not clear.
Both domestic and foreign studies have reviled that it is easy for myositis to combine with tumors[40, 41], with the incidence rate of 10.9-35.8%, significantly higher than the normal population, and DM is the most common one. Tumors can develop before and after the diagnosis of myositis or at the same time, and about 60% of patients suffer from tumors more than 1 year after the diagnosis of myositis[42]. Grau[43] pointed out that pulmonary interstitial lesions are negatively correlated with tumors. That means patients with pulmonary interstitial lesions should have fewer tumors. The results in this study accords with this, and patients with anti-MDA5-positive DM have fewer tumors. Further analysis to patients in this study with other myositis-specific antibodies revealed significant difference in the anti-TIF1γ antibody and anti-NXP2 antibody positive between the two groups, namely, the anti-MDA5 antibody-positive group was less anti-TIF1γ antibody and anti-NXP2 antibody. Positive. Hoshino[28] reported that among 12 anti-TIF1γ antibody-positive patients, 7 patients had tumors (58%), manifesting that anti-TIF1γ antibodies are associated with tumors in patients with myositis. According to Albayda[44], 5 patients with anti-NXP2 antibody-positive DM (9%) had tumors, much higher than the normal population. Therefore, in recent years, anti-TIF1γ antibody and anti-NXP2 antibody were considered to be biomarkers of tumors for patients with myositis. In this study, patients were followed up for 1 year to 3 years. Some patients were not followed up for a long time, occurring missed tumor diagnosis.
DM/PM is prone to ILD, and patients with ILD usually have a poor prognosis. Anti-MDA5 antibodies are closely related to ILD and RPILD, and most patients with anti-MDA5 antibody-positive DM have a poor prognosis. Gono[45] reported 24 patients with DM, complicated with pulmonary interstitial lesions, 14 of whom were positive for anti-MDA5 antibody, with 60% of 10-month survival rate. Meanwhile, ferritin, anti-MDA5 antibody, etc. were found, closely related to prognosis. Xu[46] also reported that anti-MDA5 antibody titer, skin ulcer, lymphocyte count, and ferritin are prognostic indicators for CADM patients. In this study, it was also discovered that patients with positive anti-MDA5 antibodies have a significantly increased case fatality rate and poor prognosis. Most patients with poor prognosis are associated with RPILD and may be due to respiratory failure. Therefore, for patients with first-episode DM, in order to provide further reference for future diagnosis, treatment and prognosis, the detection of myosin antibody spectrum should be actively improved. For patients with anti-MDA5-positive DM, they should be more watchful. If RPILD is combined, poor prognosis may happen at any time.