Clinical features and poor prognostic factors of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with rapid progressive interstitial lung disease
- By Sei-ichiro Motegi,
- Akiko Sekiguchi,
- Sayaka Toki,
- Chikako Kishi,
- Yukie Endo,
- Masahito Yasuda,
- Hidekazu Ikeuchi,
- Toru Sakairi,
- Kenichiro Hara,
- Koichi Yamaguchi,
- Toshitaka Maeno,
- Keiju Hiromura
- and Osamu Ishikawa
Pages 511 to 517
Cite this article
- MOTEGI, Sei-ichiro,
- SEKIGUCHI, Akiko,
- TOKI, Sayaka,
- KISHI, Chikako,
- ENDO, Yukie,
- YASUDA, Masahito,
- IKEUCHI, Hidekazu,
- SAKAIRI, Toru,
- HARA, Kenichiro,
- YAMAGUCHI, Koichi,
- MAENO, Toshitaka,
- HIROMURA, Keiju
- and ISHIKAWA, Osamu,
- Motegi, Sei-ichiro.,
- et al.
- Motegi, S.-i.,
- Sekiguchi, A.,
- Toki, S.,
- Kishi, C.,
- Endo, Y.,
- Yasuda, M.,
- Ikeuchi, H.,
- Sakairi, T.,
- Hara, K.,
- Yamaguchi, K.,
- Maeno, T.,
- Hiromura, K.
- and Ishikawa, O.
https://doi.org/10.1684/ejd.2019.3634
Cite this article
- Motegi, S.-i.,
- Sekiguchi, A.,
- Toki, S.,
- Kishi, C.,
- Endo, Y.,
- Yasuda, M.,
- Ikeuchi, H.,
- Sakairi, T.,
- Hara, K.,
- Yamaguchi, K.,
- Maeno, T.,
- Hiromura, K.
- and Ishikawa, O.
- Motegi, Sei-ichiro.,
- et al.
- MOTEGI, Sei-ichiro,
- SEKIGUCHI, Akiko,
- TOKI, Sayaka,
- KISHI, Chikako,
- ENDO, Yukie,
- YASUDA, Masahito,
- IKEUCHI, Hidekazu,
- SAKAIRI, Toru,
- HARA, Kenichiro,
- YAMAGUCHI, Koichi,
- MAENO, Toshitaka,
- HIROMURA, Keiju
- and ISHIKAWA, Osamu,
https://doi.org/10.1684/ejd.2019.3634
1 Dermatomyositis (DM) is an autoimmune, idiopathic inflammatory disease affecting muscles and skin. Clinical features of DM patients are heterogeneous, revealing various degrees of skin manifestations, myositis, and pulmonary involvement, which are considerably associated with severity and prognosis [1, 2]. Interstitial lung disease (ILD) and internal malignancy are important complications that determine the prognosis in DM patients [3]. Therefore, the identification of clinical features and biomarkers to predict patients' prognosis could increase the efficiency of screening and diagnostic resources [2, 4]. Myositis-specific autoantibodies (MSAs) including anti-aminoacyl-tRNA synthetases (ARS), anti-clinically amyopathic DM (CADM)-140/melanoma differentiation-associated gene 5 (MDA5), anti-Mi-2, anti-transcriptional intermediary factor 1 gamma (TIF-1γ), and anti-nuclear matrix protein 2 (NXP2) antibody (Ab) are detected in the serum of patients with DM [4, 5]. Because each Ab is closely associated with certain clinical features and prognosis, the identification of autoantibodies is important for classification of the clinical subsets of patients with DM [4, 5].
2 The anti-MDA5 Ab was first reported in 2005 as the anti-CADM-140 Ab which was thought to bind to a 140-kDa protein in the cytoplasm [6]. Thereafter, it was revealed that it bound to MDA5, and was renamed as anti-MDA5 Ab [7]. MDA5 is a cytoplasmic retinoic acid inducible gene-I like receptor involved in viral dsRNA recognition, and its stimulation leads to the induction of type 1 interferon and inflammatory cytokines [8]. Anti-MDA5 Ab has been shown to be significantly associated with a subset of DM patients, CADM (defined as the presence of cutaneous features of DM without clinical muscle weakness), and rapidly progressive ILD (RP-ILD) [1, 2]. The prognosis of RP-ILD is extremely poor and is often resistant to various treatments at the stage when respiratory symptoms develop [1, 4]. Therefore, early diagnosis and treatment are required for anti-MDA5 Ab-positive DM patients. In this study, we retrospectively analysed the clinical features of anti-MDA5 Ab-positive DM patients and investigated risk factors that are potentially associated with a poor prognosis.
Materials and methods
Patients
3 We analysed 75 Japanese DM patients (53 female and 22 male; aged 46.1 ± 1.8 years) who visited Gunma University Hospital from 2000 to 2017. All patients fulfilled the criteria for DM, proposed by Bohan and Peter (1975) [9, 10], or CADM, proposed by Sontheimer (1999) [11]. A total 75 patients, including 50 (66.7%) DM patients and 25 (33.3%) CADM patients were enrolled. This study was approved by the institutional review board of Gunma University (#1687), and was conducted according to the principles of the Declaration of Helsinki.
Clinical and laboratory assessments
4 Clinical data, including patient demographics, clinical manifestations, laboratory data, treatments, and outcomes were collected retrospectively for all the patients by reviewing their clinical medical records. Skin manifestations were evaluated by physical examination by dermatologists (OI and SM). A malignancy survey was performed for all patients based on computed tomography (CT) and/or 18F-fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT). ILD was diagnosed by pulmonologists based on clinical symptoms, physical examination findings, and high-resolution CT (HRCT) imaging findings. ILD was classified as RP-ILD when respiratory failure developed within three months from the initial respiratory symptoms or the initial visits [12], and was classified as chronic ILD when it developed over three months [13]. Anti-MDA5 Ab was measured using an enzyme immunoassay (EIA) (Medical & Biological Laboratories, Nagoya, Japan), however, we could not compare the levels of anti-MDA5 Ab, because Ab levels in some old blood samples could not be measured correctly if greater than 500 index. The levels of serum ferritin, Krebs von den Lungen-6 (KL-6), and creatine kinase (CK), at the time when the diagnosis of DM was established, were analysed.
Statistical analysis
5 P values were calculated based on the Student's t-test or χ2-test analysis; p < 0.05 was considered statistically significant.
Results
Comparison of demographic and clinical characteristics of DM patients with and without anti-MDA5 antibody
6 We examined the clinical and laboratory features of 75 Japanese DM patients with or without anti-MDA5 Ab (table 1). Among the 75 DM patients, 28 patients (37.3%; 28/75) were positive for anti-MDA5 Ab. The mean age and male:female ratio were similar between the two groups. The frequency of CADM was significantly higher in the anti-MDA5 Ab-positive group (53.6% vs 21.3%; p < 0.01). With regards to skin manifestations, the frequency of Gottron's papules/signs was significantly higher in patients with anti-MDA5 Ab compared to patients without anti-MDA5 Ab (96.4% vs 74.4%; p < 0.01) (a representative image of Gottron's papules/signs in patients with anti-MDA5 Ab is shown in figure 1A). In addition, the prevalence of palmar violaceous macules in DM patients with anti-MDA5 Ab was markedly higher than that in DM patients without anti-MDA5 Ab (82.1% vs 25%; p < 0.01) (a representative image of palmar violaceous macules in patients with anti-MDA5 Ab is shown in figure 1B). Furthermore, antihelix/helix violaceous macules were observed more frequently in the patients with anti-MDA5 Ab (40.7% vs 18.6%; p < 0.05) (a representative image of antihelix/helix violaceous macules in patients with anti-MDA5 Ab is shown in figure 1C). The frequency of skin ulcers on the skin lesions of the whole body in patients with anti-MDA5 Ab tended to be higher than in patients without anti-MDA5 Ab, but this difference did not reach statistical significance. The frequency of heliotrope rash and mechanic's hand was similar between the two groups.
Demographic and clinical characteristics of DM patients with or without anti-MDA5 antibody.
| Anti-MDA5 Ab-positive group (37.3%, n = 28) | Anti-MDA5 Ab-negative group (62.7%, n = 47) | p | |
|---|---|---|---|
| Age (years, mean ± SE) | 51.9 ± 3.0 | 51.3 ± 3.6 | 0.877 |
| Sex | |||
| Male | 28.6% (8/28) | 29.8% (14/47) | |
| Female | 71.4% (20/28) | 70.2% (33/47) | 0.911 |
| CADM | 53.6% (15/28) | 21.3% (10/47) | <0.01** |
| Skin lesions | |||
| Heliotrope rash | 53.6% (15/28) | 53.5% (23/43) | 0.995 |
| Gottron's papules/signs | 96.4% (27/28) | 74.4% (32/43) | <0.01** |
| Palmar violaceous macules | 82.1% (23/28) | 25 % (7/28) | <0.01** |
| Mechanic's hand | 25% (7/28) | 26.2% (11/42) | 0.911 |
| Antihelix/helix violaceous macules | 40.7% (11/27) | 18.6% (8/43) | <0.05* |
| Skin ulcers | 25% (7/28) | 8.6% (3/35) | 0.076 |
| Complications | |||
| ILD | 100% (28/28) | 43.5% (20/46) | <0.01** |
| RP-ILD | 57.1% (16/28) | 2.2% (1/46) | <0.01** |
| Internal malignancy | 3.6% (1/28) | 14.9% (7/47) | 0.124 |
| Dysphagia | 13.6% (3/22) | 22.9% (8/35) | 0.39 |
| Laboratory finding | |||
| Ferritin (ng/mL, mean ± SE) | 725.6 ± 122.1 | 212.6 ± 39.1 | <0.01** |
| KL-6 (U/mL, mean ± SE) | 1001.3 ± 123 | 477.3 ± 52.3 | <0.01** |
| PaO2 (mmHg, mean ± SE) | 74.1 ± 2.5 | 81.9 ± 3.9 | 0.102 |
| CK (IU/L, mean ± SE) | 195 ± 34.1 | 1347.3 ± 364.9 | <0.01** |
Demographic and clinical characteristics of DM patients with or without anti-MDA5 antibody.
*p < 0.05, **p < 0.01; SE: standard error; MDA5: melanoma differentiation associated gene 5; CADM: clinically amyopathic dermatomyositis; ILD: interstitial lung disease; RP-ILD: rapid progressive ILD; KL-6: Krebs von den Lungen-6; PaO2: partial pressure of arterial oxygen; CK: creatine kinase. “Skin ulcers” refers to skin ulcers on skin lesions of the whole body.7 Regarding complications, all patients with anti-MDA5 Ab had ILD. The prevalence of ILD in patients with anti-MDA5 Ab was significantly increased compared with anti-MDA5 Ab-negative patients (100% vs 43.5%; p < 0.01). In addition, the frequency of progression to RP-ILD was significantly higher in patients with anti-MDA5 Ab compared to patients without anti-MDA5 Ab (57.1% vs 2.2%; p < 0.01). There was no significant difference in prevalence of internal malignancy or dysphagia between the two groups. Based on laboratory findings, serum ferritin levels were significantly higher in the anti-MDA5 Ab-positive group (725.6 ± 122.1 vs 212.6 ± 39.1 ng/mL; p < 0.01). In addition, serum KL-6 levels were also significantly elevated in DM patients with anti-MDA5 Ab (1001.3 ± 123 vs 477.3 ± 52.3 U/mL; p < 0.01). In contrast, the levels of serum CK were significantly lower in patients with anti-MDA5 Ab (CK: 195 ± 34.1 vs 1347.3 ± 364.9 IU/L; p < 0.01). The levels of partial pressure of arterial oxygen (PaO2) at first visit tended to be lower in patients with anti-MDA5 Ab (PaO2: 74.1 ± 2.5 vs 81.9 ± 3.9 mmHg; p = 0.102). These results suggest that anti-MDA5 Ab might be closely associated with CADM, ILD, progression to RP-ILD, high serum ferritin levels, and skin manifestations including Gottron's papules/signs, palmar violaceous macules, and antihelix/helix violaceous macules.
Clinical features of anti-MDA5 Ab-positive DM patients with RP-ILD
8 Anti-MDA5 Ab is reported to be associated with a subset of patients with RP-ILD with poor prognosis [1, 2, 7]. Next, we examined the clinical features of anti-MDA5 Ab-positive DM patients with and without RP-ILD. Among the 28 anti-MDA5 Ab-positive DM patients, 16 patients (57.1%; 16/28) developed RP-ILD. The complications concerning clinical characteristics of the anti-MA5 Ab-positive DM patients with or without RP-ILD are summarized in table 2. The mean age and male:female ratio were similar between the two groups. The proportion of CADM was not significantly different between anti-MDA5 Ab-positive DM patients with or without RP-ILD. There was no significant difference in frequency of skin lesions including heliotrope rash, Gottron's sign, palmar violaceous macules, mechanic's hand, and skin ulcers. The frequency of internal malignancy or dysphagia was not significantly different between anti-MDA5 Ab-positive DM patients with or without RP-ILD. Based on laboratory findings of DM patients with anti-MDA5 Ab, serum ferritin level was markedly higher in patients with RP-ILD than without RP-ILD (849 ± 172 vs 453 ± 133 ng/mL; p < 0.01). Additionally, the levels of PaO2 at first visit were significantly lower in patients with anti-MDA5 Ab (PaO2: 67.7 ± 2.8 vs 82.8 ± 2.8 mmHg; p < 0.01). However, there was no significant difference in the serum KL-6 or CK levels between patients with and without RP-ILD. These results suggest that high serum ferritin level and low PaO2 at first visit in anti-MDA5 Ab-positive DM patients might be associated with the development RP-ILD
Clinical features of anti-MDA5 antibody-positive DM patients with or without RP-ILD.
| Anti-MDA5 Ab-positive patients (n = 28) | p | ||
|---|---|---|---|
| RP-ILD (+) (57.1%, n = 16) | RP-ILD (-) (42.9%, n = 12) | ||
| Age (years, mean ± SE) | 54.8 ± 3.3 | 48.1 ± 5.6 | 0.29 |
| Sex | |||
| Male | 31.3% (5/16) | 25% (3/12) | |
| Female | 68.8% (11/16) | 75% (9/12) | 0.71 |
| CADM | 62.5% (10/16) | 41.7% (5/12) | 0.27 |
| Skin lesions | |||
| Heliotrope rash | 50% (8/16) | 58.3% (7/12) | 0.66 |
| Gottron's papules/signs | 100% (16/16) | 100% (12/12) | 0.9 |
| Palmar violaceous macules | 87.5% (14/16) | 75% (9/12) | 0.39 |
| Mechanic's hand | 25% (4/16) | 0% (0/12) | 0.72 |
| Skin ulcers | 31.3% (5/16) | 9.1% (1/11) | 0.17 |
| Complications | |||
| Internal malignancy | 6.3% (1/16) | 0% (0/12) | 0.378 |
| Dysphagia | 23.1% (3/13) | 0% (0/10) | 0.1 |
| Laboratory finding | |||
| Ferritin (ng/mL, mean ± SE) | 849 ± 172 | 453 ± 133 | <0.01** |
| KL-6 (U/mL, mean ± SE) | 775.5 ± 105.7 | 1302 ± 243.1 | 0.06 |
| PaO2 (mmHg, mean ± SE) | 67.7 ± 2.8 | 82.8 ± 2.8 | <0.01** |
| CK (IU/L, mean ± SE) | 260 ± 51 | 112.9 ± 30.8 | 0.15 |
| Prognosis | |||
| Survivors | 56.3% (9/16) | 100% (12/12) | <0.01** |
Clinical features of anti-MDA5 antibody-positive DM patients with or without RP-ILD.
*p < 0.05, **p < 0.01; SE: standard error; MDA5: melanoma differentiation associated gene 5; CADM: clinically amyopathic dermatomyositis; ILD: interstitial lung disease; RP-ILD: rapid progressive ILD; KL-6: Krebs von den Lungen-6; PaO2: partial pressure of arterial oxygen; CK: creatine kinase. “Skin ulcers” refers to skin ulcers on skin lesions of the whole body.Clinical and laboratory features and prognosis in anti-MDA5 Ab-positive DM patients with RP-ILD
9 Among 16 anti-MDA5 Ab-positive DM patients with RP-ILD, seven patients (43.8%; 7/16) died of respiratory failure. The clinical features of anti-MDA5 Ab-positive DM patients with RP-ILD who did and did not survive are summarized in table 3. The mean age was significantly higher in non-survivors with anti-MDA5 Ab and RP-ILD than in survivors (62.8 ± 4.3 vs 48.4 ± 3.6 years; p < 0.05). The male:female ratio was similar between the two groups. There was no difference in the proportion of CADM between non-survivors and survivors. No significant difference in the frequency of skin lesions was observed. Based on laboratory findings, serum ferritin level in non-survivors was significantly higher than in survivors (1183.6 ± 238.7 vs 514.6 ± 187 ng/mL; p < 0.05). PaO2 at first visit was significantly lower in non-survivors than survivors (60.8 ± 1.4 vs 72.4 ± 3.7 mmHg; p < 0.05). In contrast, there was no significant difference in serum KL-6 or CK levels between the two groups. These results suggest that elderly age, high serum ferritin level, and low PaO2 might be associated with a poor outcome in patients with anti-MDA5 Ab and RP-ILD.
Clinical features of anti-MDA5 antibody-positive DM non-survivors and survivors with RP-ILD.
| Anti-MDA5(+) Ab-positive patients with RP-ILD (n = 16) | p | ||
|---|---|---|---|
| Non-survivors (43.8%, n = 7) | Survivors (56.2%, n = 9) | ||
| Age (years, mean ± SE) | 62.8 ± 4.3 | 48.4 ± 3.6 | <0.05 |
| Sex | |||
| Male | 14.3% (1/7) | 44.4% (4/9) | 0.197 |
| Female | 85.7% (6/7) | 55.6% (5/9) | 0.515 |
| CADM | 71.4% (5/7) | 55.6% (5/9) | |
| Skin lesions | |||
| Heliotrope rash | 57.1% (4/7) | 55.6% (5/9) | 0.949 |
| Gottron's papules/signs | 85.7% (6/7) | 100% (9/9) | 0.242 |
| Palmar violaceous macules | 85.7% (6/7) | 88.9% (8/9) | 0.89 |
| Mechanic's hand | 14.3% (1/7) | 33.3% (3/9) | 0.38 |
| Skin ulcers | 28.6% (2/7) | 33.3% (3/9) | 0.838 |
| Complications | |||
| Internal malignancy | 14.3% (1/7) | 0% (0/9) | |
| Dysphagia | 0% (0/7) | 22.2% (2/9) | 0.18 |
| Laboratory finding | |||
| Ferritin (ng/mL, mean ± SE) | 1183.6 ± 238.7 | 514.6 ± 187 | <0.05* |
| KL-6 (U/mL, mean ± SE) | 793.6 ± 152 | 752.3 ± 155.3 | 0.852 |
| PaO2 (mmHg, mean ± SE) | 60.8 ± 1.4 | 72.4 ± 3.7 | <0.05* |
| CK (IU/L, mean ± SE) | 253 ± 67.5 | 269.3 ± 84 | 0.883 |
| Initial treatment | |||
| PSL or PSL + TAC/CsA | 71.4% (5/7) | 11.1% (1/9) | <0.05* |
| PSL + TAC/CsA + IVCY | 28.6% (2/7) | 88.9% (8/9) | <0.05* |
Clinical features of anti-MDA5 antibody-positive DM non-survivors and survivors with RP-ILD.
*p < 0.05, **p < 0.01; SE: standard error; MDA5: melanoma differentiation associated gene 5; CADM: clinically amyopathic dermatomyositis; ILD: interstitial lung disease; RP-ILD: rapid progressive ILD; KL-6: Krebs von den Lungen-6; PaO2: partial pressure of arterial oxygen; CK: creatine kinase; PSL: prednisolone; TAC: tacrolimus; CsA: cyclosporine; IVCY: intermittent pulse intravenous cyclophosphamide therapy. “Skin ulcers” refers to skin ulcers on skin lesions of the whole body.10 The treatment and prognosis of individual patients with anti-MDA5 Ab and RP-ILD are summarised in table 4. Among nine patients who survived with anti-MDA5 Ab and RP-ILD, eight patients received intensive immunosuppressive triple therapy, a combination of high-dose prednisolone (PSL), calcineurin inhibitor (tacrolimus or cyclosporine), and intravenous cyclophosphamide (IVCY) as an initial treatment. However, two of seven non-survivors received triple therapy as an initial treatment. Therefore, the frequency of triple therapy as initial treatment was significantly lower in non-survivors than in survivors (28.6% vs 88.9%; p < 0.05) (table 3). However, the number of patients initially treated with PSL only or both PSL and calcineurin inhibitor (tacrolimus or cyclosporine) in the non-survivor group was significantly higher than that in the survivor group (71.4% vs 11.1%; p < 0.05). Among seven non-survivors, five received PSL only or both PSL and calcineurin inhibitor treatment as initial treatment. As RP-ILD did not improve, four patients subsequently received treatment with IVCY and/or intravenous immunoglobulin (IVIG). These results suggest that a lack of triple therapy, as initial treatment, is associated with poor prognosis of RP-ILD in DM patients with anti-MDA5 Ab.
Treatments and prognosis of anti-MDA5 antibody-positive DM patients with RP-ILD.
| No | Age | Sex | Diagnosis | Initial treatment | Additional treatment | Days from PSL + TAC/CsA to IVCY | Prognosis |
|---|---|---|---|---|---|---|---|
| 1 | 70 | F | DM | Steroid pulse, PSL, TAC, IVCY | IVIG, Rituximab | 0 | Survived |
| 2 | 45 | M | CADM | PSL, TAC | − | Survived | |
| 3 | 38 | F | DM | Steroid pulse, PSL, TAC, IVCY | Rituximab | 0 | Survived |
| 4 | 42 | F | CADM | Steroid pulse, PSL, TAC, IVCY | 0 | Survived | |
| 5 | 57 | F | CADM | Steroid pulse, PSL, TAC, IVCY | 0 | Survived | |
| 6 | 55 | F | CADM | Steroid pulse, PSL, TAC, IVCY | 0 | Survived | |
| 7 | 44 | M | DM | Steroid pulse, PSL, TAC, IVCY | 0 | Survived | |
| 8 | 51 | M | DM | Steroid pulse, PSL, TAC, IVCY | IVIG | 0 | Survived |
| 9 | 34 | M | CADM | Steroid pulse, PSL, CsA, IVCY | 0 | Survived | |
| 10 | 43 | F | DM | Steroid pulse, PSL | CsA | − | Deceased |
| 11 | 72 | M | CADM | Steroid pulse, PSL | TAC, IVCY, IVIG | 49 | Deceased |
| 12 | 65 | F | DM | Steroid pulse, PSL, TAC, IVCY | 0 | Deceased | |
| 13 | 54 | F | CADM | Steroid pulse, PSL | TAC, IVCY, IVIG | 9 | Deceased |
| 14 | 66 | F | CADM | Steroid pulse, PSL, TAC, IVCY | 0 | Deceased | |
| 15 | 77 | F | CADM | Steroid pulse, PSL, TAC | IVCY, IVIG | 42 | Deceased |
| 16 | 63 | F | CADM | Steroid pulse, PSL, TAC | IVCY | 28 | Deceased |
Treatments and prognosis of anti-MDA5 antibody-positive DM patients with RP-ILD.
F: female; M: male; DM: dermatomyositis; CADM: clinically amyopathic dermatomyositis; PSL: prednisolone; TAC: tacrolimus; CsA: cyclosporine; IVCY: intermittent pulse intravenous cyclophosphamide therapy; IVIG: intravenous immunoglobulin.Discussion
11 In this study, we examined the clinical characteristics of DM patients with anti-MDA5 Ab, and identified several clinical characteristics that are potentially associated with a poor prognosis. Numerous studies have reported an association between anti-MDA5 Ab and CADM and RP-ILD [1, 2, 4, 14]. Abe et al. assessed 105 DM patients including 24 patients with anti-MDA5 Ab and reported that the frequency of CADM was significantly higher in the anti-MDA5 Ab-positive group than in the Ab-negative group (100% vs 46%; p < 0.01) [14]. Furthermore, the frequency of ILD and RP-ILD was higher in patients with anti-MDA5 Ab than those without (ILD: 100% vs 74%; p < 0.01, RP-ILD: 71% vs 6%; p < 0.01) [14]. Consistent with previous reports, our study confirms that the prevalence of CADM, ILD, and RP-ILD in DM patients with anti-MDA5 Ab is significantly higher than that in DM patients without anti-MDA5 Ab. Several studies have evaluated the cutaneous characteristics of DM patients with anti-MDA5 Ab. Cutaneous ulcers, palmar violaceous papules/macules, alopecia, and painful oral ulcers are reportedly associated with the presence of anti-MDA5 Ab [15-19]. Furthermore, Okiyama et al. reported that antihelix/helix violaceous macules are one of the characteristic cutaneous manifestations in DM patients with anti-MDA5 Ab [20]. Consistent with these reports, we identified a significant association of palmar violaceous macules and antihelix/helix violaceous macules in DM patients with anti-MDA5 Ab, and skin ulcers tended to be associated with the presence of anti-MDA5 Ab in DM patients.
12 The prognosis for DM patients with anti-MDA5 Ab with comorbid RP-ILD is extremely poor, and such patients are often resistant to various treatments upon development of respiratory symptoms [1, 4]. Therefore, identification of clinical features and biomarkers associated with RP-ILD in anti-MDA5 Ab-positive patients is very important in order to improve patient prognosis. We found that serum ferritin levels at the time of diagnosis were markedly higher in DM patients with anti-MDA5 Ab than DM patients without anti-MDA5 Ab. In addition, we found that serum ferritin levels at diagnosis were markedly higher in patients with RP-ILD than patients without RP-ILD among anti-MDA5 Ab-positive DM patients. These results suggest that high serum ferritin levels might be potentially associated with the presence of the anti-MDA5 Ab, especially, in cases of comorbid RP-ILD.
13 Previous studies have identified several risk factors potentially associated with a poor prognosis in patients with anti-MDA5 Ab complicated by ILD/RP-ILD. Several studies reported that serum ferritin levels are a prognostic marker of RP-ILD in DM patients [21-23]. For example, Tanizawa et al. reported that a ferritin level of ≥500 ng/mL is associated with a poor prognosis of RP-ILD in DM patients [23]. Consistent with these reports, we confirmed that serum ferritin levels at diagnosis were markedly higher in non-survivors than survivors, who were anti-MDA5 Ab-positive with RP-ILD. Accordingly, high serum ferritin levels might be associated with a poor prognosis of RP-ILD in DM patients with anti-MDA5 Ab.
14 In addition to serum ferritin levels, several factors are reportedly associated with a poor prognosis of RP-ILD in DM. It has been reported that a high fever, anti-MDA5 Ab titre, and specific CT shadows (especially lower consolidation) are associated with a poor prognosis [23]. Nakashima et al. assessed anti-MDA5 Ab-positive patients with ILD and determined that the prognosis was poor in elderly patients or in patients with a long period from appearance of skin lesions to diagnosis of ILD [1]. Yamaguchi et al. reported that patients with CADM, who have both anti-MDA5 Ab and myositis-associated autoantibodies (MAAs) (which characterize other connective tissue diseases, such as rheumatoid arthritis and Sjögren's syndrome), have a lower incidence of RP-ILD and a lower mortality rate than patients with CADM who have anti-MDA5 Ab alone [24]. In addition to these findings, we found that non-survivors revealed lower PaO2 at first visit than survivors among patients with anti-MDA5 Ab and RP-ILD
15 Several studies have examined the association between cutaneous symptoms and prognosis in DM patients with anti-MDA5 Ab. Fiorentino et al. reported that anti-MDA5 Ab-positive DM patients presenting cutaneous ulcerations and/or palmar papules were at an increased risk of RP-ILD [15]. In contrast, Hamaguchi et al. pointed out that anti-MDA5 Ab was closely associated with cutaneous ulcers, with no association with prognosis [4]. In this study, the frequency of cutaneous symptoms, including heliotrope rash, Gottron's papules/signs, palmar violaceous macules, mechanic's hand, and skin ulcers, was not significantly different between survivors and non-survivors, suggesting that cutaneous manifestations might not be associated with the prognosis of RP-ILD in DM patients with anti-MDA5 Ab.
16 Many previous studies suggest that an intensive immunosuppressive therapy, a combination of high-dose PSL, calcineurin inhibitor (tacrolimus or cyclosporine), and IVCY might improve the prognosis of RP-ILD in DM patients with anti-MDA5 Ab [25-27]. Nakashima et al. reported that combined immunosuppressive therapy markedly improved the mortality of anti-MDA5 Ab-positive patients, from 28.6% to 75% [25]. Yamasaki et al. reported that treatment with IVCY (combined immunosuppressive therapy), more than six times, was effective for DM patients with RP-ILD [28]. In our study, the frequency of triple therapy as initial treatment was significantly lower in non-survivors compared to survivors. In contrast, the frequency of PSL-only treatment or an oral combination of PSL and calcineurin inhibitor as initial treatment was significantly higher in non-survivors compared to survivors. Our results suggest that the prognosis of RP-ILD might be poor if triple therapy is not introduced as initial treatment. In particular, early administration of IVCY is considered to be important in order to improve prognosis. A limitation of our study is the small sample size and the retrospective design, therefore, large-scale prospective studies are warranted to investigate the prognosis of RP-ILD in DM patients with anti-MDA5 Ab.
17 In conclusion, our results suggest that anti-MDA5 Ab might be associated with CADM, ILD, progression to RP-ILD, high serum ferritin levels, and certain skin manifestations. Additionally, high serum ferritin levels and low PaO2 at first visit are potentially associated with the development of RP-ILD and a poor prognosis among patients with anti-MDA5 Ab. Awareness of these characteristics of DM patients with anti-MDA5 Ab is important for dermatologists and rheumatologists in order to make an early diagnosis and initiate appropriate treatment. Finally, our results suggest that early administration of triple therapy, including IVCY, may be promising in an effort to improve prognosis.
Disclosure
18 Financial support: none. Conflicts of interest: none.
- [1] Nakashima R., Imura Y., Kobayashi S. The RIG-I-like receptor IFIH1/MDA5 is a dermatomyositis-specific autoantigen identified by the anti-CADM-140 antibody. Rheumatology (Oxford). 2010;49:433-440.
- [2] Chen Z., Cao M., Plana M.N. Utility of anti-melanoma differentiation-associated gene 5 antibody measurement in identifying patients with dermatomyositis and a high risk for developing rapidly progressive interstitial lung disease: a review of the literature and a meta-analysis. Arthritis Care Res (Hoboken). 2013;65:1316-1324.
- [3] Qiang J.K., Kim W.B., Baibergenova A., Alhusayen R. Risk of malignancy in dermatomyositis and polymyositis. J Cutan Med Surg. 2017;21:131-136.
- [4] Hamaguchi Y., Kuwana M., Hoshino K. Clinical correlations with dermatomyositis-specific autoantibodies in adult Japanese patients with dermatomyositis: a multicenter cross-sectional study. Arch Dermatol. 2011;147:391-398.
- [5] Mimori T., Imura Y., Nakashima R., Yoshifuji H. Autoantibodies in idiopathic inflammatory myopathy: an update on clinical and pathophysiological significance. Curr Opin Rheumatol. 2007;19:523-529.
- [6] Sato S., Hirakata M., Kuwana M. Autoantibodies to a 140-kd polypeptide, CADM-140, in Japanese patients with clinically amyopathic dermatomyositis. Arthritis Rheum. 2005;52:1571-1576.
- [7] Sato S., Hoshino K., Satoh T. RNA helicase encoded by melanoma differentiation-associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis: association with rapidly progressive interstitial lung disease. Arthritis Rheum. 2009;60:2193-2200.
- [8] Kato H., Takeuchi O., Sato S. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature. 2006;441:1015-1019.
- [9] Bohan A., Peter J.B. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292:344-348.
- [10] Bohan A., Peter J.B. Polymyositis and dermatomyositis (second of two parts). N Engl J Med. 1975;292:403-407.
- [11] Sontheimer R.D. Cutaneous features of classic dermatomyositis and amyopathic dermatomyositis. Curr Opin Rheumatol. 1999;11:475-482.
- [12] Moghadam-Kia S., Oddis C.V., Sato S., Kuwana M., Aggarwal R. Aggarwal, anti-melanoma differentiation-associated gene 5 is associated with rapidly progressive lung disease and poor survival in US patients with amyopathic and myopathic dermatomyositis. Arthritis Care Res. 2016;68:689-694.
- [13] Matsushita T., Mizumaki K., Kano M. Antimelanoma differentiation-associated protein 5 antibody level is a novel tool for monitoring disease activity in rapidly progressive interstitial lung disease with dermatomyositis. Br J Dermatol. 2017;176:395-402.
- [14] Abe Y., Matsushita M., Tada K., Yamaji K., Takasaki Y., Tamura N. Clinical characteristics and change in the antibody titres of patients with anti-MDA5 antibody-positive inflammatory myositis. Rheumatology (Oxford). 2017;56:1492-1497.
- [15] Fiorentino D., Chung L., Zwerner J., Rosen A., Casciola-Rosen L. The mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to MDA5 (CADM-140): a retrospective study. J Am Acad Dermatol. 2011;65:25-34.
- [16] Tansley S.L., Betteridge Z.E., Gunawardena H. Anti-MDA5 autoantibodies in juvenile dermatomyositis identify a distinct clinical phenotype: a prospective cohort study. Arthritis Res Ther. 2014;16:R138.
- [17] Narang N.S., Casciola-Rosen L., Li S., Chung L., Fiorentino D.F. Cutaneous ulceration in dermatomyositis: association with anti-melanoma differentiation-associated gene 5 antibodies and interstitial lung disease. Arthritis Care Res (Hoboken). 2015;67:667-672.
- [18] Koguchi-Yoshioka H., Okiyama N., Iwamoto K. Intravenous immunoglobulin contributes to the control of antimelanoma differentiation-associated protein 5 antibody-associated dermatomyositis with palmar violaceous macules/papules. Br J Dermatol. 2017;177:1442-1446.
- [19] Kurtzman D.J.B., Vleugels R.A. Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis: a concise review with an emphasis on distinctive clinical features. J Am Acad Dermatol. 2018;78:776-785.
- [20] Okiyama N., Inoue S., Saito A. Antihelix/helix violaceous macules in Japanese patients with anti-melanoma differentiation-associated protein 5 (MDA5) antibody-associated dermatomyositis. Br J Dermatol. 2019;180:1226-1227.
- [21] Xu Y., Yang C.S., Li Y.J. Predictive factors of rapidly progressive-interstitial lung disease in patients with clinically amyopathic dermatomyositis. Clin Rheumatol. 2016;35:113-116.
- [22] Gono T., Sato S., Kawaguchi Y. Anti-MDA5 antibody, ferritin and IL-18 are useful for the evaluation of response to treatment in interstitial lung disease with anti-MDA5 antibody-positive dermatomyositis. Rheumatology. 2012;51:1563-1570.
- [23] Tanizawa K., Handa T., Nakashima R. The prognostic value of HRCT in myositis-associated interstitial lung disease. Respir Med. 2013;107:745-752.
- [24] Yamaguchi K., Yamaguchi A., Kashiwagi C. Differential clinical features of patients with clinically amyopathic dermatomyositis who have circulating anti-MDA5 autoantibodies with or without myositis-associated autoantibodies. Respir Med. 2018;140:1-5.
- [25] Nakashima R., Mimori T. Anti-MDA5 (melanoma differentiation-associated gene 5) antibody and dermatomyositis with rapidly progressive interstitial pneumonia. Nihon Rinsho Meneki Gakkai Kaishi. 2013;36:711-716.
- [26] Morisset J., Johnson C., Rich E., Collard H.R., Lee J.S. Management of myositisrelated interstitial lung disease. CHEST. 2016;150:1118-1128.
- [27] Kameda H., Nagasawa H., Ogawa H. Combination therapy with corticosteroids, cyclosporin A, and intravenous pulse cyclophosphamide for acute/subacute interstitial pneumonia in patients with dermatomyositis. J Rheumatol. 2005;32:1719-1726.
- [28] Yamasaki Y., Yamada H., Yamasaki M. Intravenous cyclophosphamide therapy for progressive interstitial pneumonia in patients with polymyositis/dermatomyositis. Rheumatology (Oxford). 2007;46:124-130.