Anti-MDA5-associated DM, which is a rare subtype of DM that presents with unique mucocutaneous features, including Gottron’s sign, Heliotrope rash, V sign, Shawl sign, Periungual erythema, Mechanic’s hand and skin ulcer. It is gaining increasing attention due to its complication of RP-ILD and high mortality. The incidence of anti-MDA5 + DM associated ILD varies in different regions. The prevalence was 11%-75% in Europeans and United States while it was 92%-100% in Asians[1]. According to previous studies, about 40%-70% of MDA5 associated DM cases developed RP-ILD and died of respiratory failure during half year after admission due to the progressive course and a poor response to the treatment[2]. However, in our case, the patient with positive of anti-MDA5 had a good treatment effect and maintained remission for more than half year. There are several reflections about why she had a good outcome and why her prognosis modified.
Timely diagnosis and multi-combination therapy are important
We made a rapid and accurate diagnosis at the early stage. The woman was highly suspected CADM with her outstanding skin manifestations, few myositis evidence, and nonspecific interstitial pneumonia. The diagnosis was finally verified after several myositis-specific antibodies exhibited positive like anti-MDA5, anti-EJ and anti-Ro52. The timely intervention with triple combination therapy of GCs, immunosuppressants in induction phase were extremely important. With consideration of her disease severity and relative chronic disease progression, we applied a moderate-dose GCs and alternate-day intravenous cyclophosphamide further to avoid many common side effects because of high dose. In remission phase, we gradually decreased oral prednisone, meanwhile combining oral cyclophosphamide and tacrolimus to get a long-term maintenance. These triple combination continuous therapies have improved her survival rates and prolonged her recurrence-free survival.
Completely learning of clinical conditions is helpful for predicting outcome
A current meta-analysis included 29 cohorts with 2645 patients found that old age, male sex, hypoxemia, low FVC, lymphocytopenia, and high levels of ferritin, CRP, creatine kinase, and LDH predicted poor prognosis in patients with MDA5 + DM[3]. In a large Chinese cohort study of patients with MDA5-DM, patients were classified into three subgroups according to peripheral lymphocyte count. The results proved severe lymphopenia is strongly associated with high mortality, and a normal peripheral lymphocyte number at baseline predicts a better prognosis[4]. However, a single indicator fails to accurately predict a particular outcome, a prediction model incorporating several relevant risk factors may enhance predictive power. Therefore, several prediction models for monitoring the disease severity or prognosis in MDA5-DM were emerged (Table 3). The CROSS model is one of the prediction models, four variables were included: C-reactive protein (CRP) levels, anti-Ro52 antibody positivity, short disease duration, and male sex. And a point scoring system was used to classify anti-MDA5 + DM patients into moderate, high, and very high risk of RP-ILD. After one-year follow-up, the incidence of RP-ILD in the very high- risk group was about 70–80%, significantly higher than those in the high-risk group (30–40%) and moderate-risk group (6–9%)[5]. The CRAFT model also included 4 variables, CRP-to-albumin ratio, red blood cell distribution width-coefficient of variation, fever status, and CD3 + T cells[6]. FLAIR score is a prediction model for mortality risk, which included 5 variables: ferritin, LDH, anti-MDA5 antibody titers, CT imaging score and RP-ILD[7]. According to these predictors or models, our case was all belonged to a mild or moderate group, indicating a relatively good outcome.
Table 3
Several prediction models for RP-ILD risk or mortality in anti-MDA5 + DM patients
| Variables | Subgroups score | Prediction risk |
CROSS model | CRP (abnormal,1; normal,0) Ro-52 antibody (positive,1; negative,0) Disease duration (<3 months,2;≥3months,0) Sex (male,1; female,0) | Moderate:0–2 High:3–4 Very high:5–6 | RP-ILD risk | Moderate:6.67% High:41.69% Very high:85.71% |
CRAFT model | CRP-to-albumin ratio, red blood cell distribution width-coefficient of variation, fever status, and CD3 + T cells | | RP-ILD risk | Sensitivity:0.81 Specificity:0.91 |
FLAIR score | Ferritin(<636ng/ml,0;≥636ng/ml,2) LDH(<355U/L,0;≥355U/L,2) anti-MDA5 antibody titers(negative,0;+,2;++,3;+++,4) CT imaging score*(< 133,0;≥133,3) RP-ILD (non-RP-ILD,0;RP-ILD,2) | Low:0–4 Medium:5–9 High:10–13 | Mortality risk | Low:0% Medium:7.7% High:85% |
* CT imaging score were evaluated based on the method described by Ichikado et al[8].
Some protective factors may be essential to balance the negative effects.
The majority of researchers stated that the coexistence of anti-MDA5 and anti-Ro52 antibodies led to a worse prognosis and lower survival rates[9][10]. Besides, a large retrospective case-control study revealed that CAMD was associated with higher rates of mortality, 1-year mortality and RP-ILD than classic DM[11]. Similarly, some other studies also proved patients with CADM exhibit relatively worse symptoms and prognosis, which doesn’t accord with our case. Some special features for instance onset of black skin maybe one of protective factors. A study identified three different subgroups in MDA5-DM: Patients with RP-ILD show the highest mortality rate, those with skin vasculopathy and clinical myositis exhibit an intermediate prognosis and sole dermato-rheumatologic symptoms were associated with the best outcome[12]. A report systematically analyses histopathological findings in two MDA-5 + CADM patients with fatal RP-ILD. These two patients both had none or subtle skin changes and no overt muscle symptoms until hospitalization. Noteworthy, the muscle autopsy showed characteristic signs of muscle inflammation, and the lung autopsy showed massive interstitial and alveolaroedema, hyaline membranes and intraluminal fibrinoid deposits[13].Thus, the different symptoms in skin may illustrate different pathologies in muscle and lung and then probably affect prognosis. The chronic blacken skin symptom before affected respiratory system may help avoiding disease progression. Moreover, anti-EJ antibody positive may another protective factor. One Chinese retrospective research compared anti-MDA5 and anti-aminoacyl-tRNA synthetase antibody (anti-ARS, including anti-PL-12, anti-PL-7, anti-EJ and anti-Jo1) double-positive dermatomyositis patients (Anti-MDA5+/ARS + group) to single anti-MDA5 positive (Anti-MDA5+/ARS- group) and single anti-ARS positive patients (Anti-MDA5-/ARS + group). The result presented that anti-MDA+/ARS + group had higher ferritin levels than Anti-MDA5-/ARS + group and higher CD4 + T-cell counts than Anti-MDA5+/ARS- group. Individuals with anti-MDA+/ARS + antibodies combined the features of anti-MDA5 + and anti-ARS + individuals and respond well to glucocorticoid therapy[14]. A latest review summarized the lung manifestations of MDA5 + DM, commonly including organizing pneumonia, which typically presents with subpleural consolidation during the early stage of the disease, non-specific interstitial pneumonia and non-specific interstitial pneumonia–organizing pneumonia overlap[2], while grid shadows and pleura thicken seldom appeared as our case. Perhaps the special HRCT images play another important role to change prognosis. High-quality prospective studies are required to confirm our findings.