Clinically amyopathic dermatomyositis with anti-transcriptional intermediary factor 1-γ autoantibody positivity

Rheumatology key message

• Patients with clinically amyopathic dermatomyositis with anti-TIF1γ antibody may have a low prevalence of malignancy.

Sir, Unique autoantibody specificities are associated with distinct clinical phenotypes. Among Japanese patients with dermatomyositis (DM), the marked feature among adults who are positive for anti-transcriptional intermediary factor 1-γ antibody (anti-TIF1γ Ab) is that the prevalence of malignant tumour complications is high (44–68%) [1, 2]. In the clinical setting, adults with DM with anti-TIF1γ Ab demonstrate obvious muscle weakness and severe skin symptoms. In contrast, patients with clinically amyopathic DM (CADM) demonstrate lower prevalence of malignancy and higher incidence of complications of rapidly progressive interstitial pneumonia resistant to treatment [1, 2]. In this study, we evaluated the clinical features of Japanese patients with anti-TIF1γ Ab-positive DM, especially of patients with CADM.

Thirty-four DM patients with anti-TIF1γ Ab who met Bohan and Peter’s criteria [3] were included. CADM was diagnosed based on the criteria proposed by Sontheimer [4]. CADM cases were extracted from the anti-TIF1γ Ab-positive DM cases, and clinical features, such as skin manifestations, prevalence of malignancy and/or interstitial lung disease, and level of anti-TIF1γ Ab were evaluated. Patients with complications of malignancy detected within 3 years before and after diagnosis of DM were included. The serum anti-TIF1γ Ab level was measured using enzyme-linked immunosorbent assay (MESACUP anti-TIF1-γ Ab test, MBL, Nagoya, Japan) in which the cut-off level for anti-TIF1γ Ab was set to 32 index calculated based on the receiver operating characteristic analysis [5]. No other myositis-specific autoantibodies, such as anti-aminoacyl-tRNA synthetase, anti-melanoma differentiation-associated gene 5 and anti-Mi-2 Abs, were detected in any of the enrolled patients. The study was approved by the Institutional Review Board of Yokohama City University (approval number: B190800045). Comparisons between two groups were tested for statistical significance using the Mann–Whitney U-test. Fisher’s exact test was used to compare the categorical data. P < 0.05 was considered significant.

There were nine (26.5%) patients with CADM among 34 DM patients positive for anti-TIF1γ Ab. No significant differences in the age at disease onset and sex were noted between the patients with and without myositis (Table 1). The prevalence of malignancy was 60.0% (15/25) and 11.1% (1/9) in the anti-TIF1γ Ab-positive non-CADM and CADM patients, respectively, and the difference was statistically significant (P = 0.02). Interstitial lung disease was observed in four out of nine patients with CADM (44.1%), which was higher than that noted in non-CADM patients (12.0%, P = 0.06). None of the patients had rapidly progressive disease type. Furthermore, the serum anti-TIF1γ Ab levels were significantly lower among CADM patients than among non-CADM cases (71.6 ± 39.7 and 106.8 ± 33.8, respectively, P = 0.04; Table 1). Although there was no significant difference in skin manifestations between the two groups, Gottron’s sign and heliotrope rash were more frequently observed in the CADM patients than in the DM patients (Table 1). Although anti-TIF1γ Ab positivity was noted, CADM patients had a significantly lower rate of malignancy and lower levels of anti-TIF1γ Ab than non-CADM patients. Interstitial lung disease was also more common among CADM patients than among non-CADM patients. These observations may be distinct from the recognized features of anti-TIF1γ Ab-positive DM.

Table 1

Clinical comparison between the anti-TIF1γ antibody-positive CADM and non-CADM patients

Characteristics	Non-CADM patients	CADM patients	P-value
Patients, n	25	9
Age, mean (s.d.), years	64.7 (16.0)	64.3 (13.1)	0.78
Sex, n (%)
Female	19 (76.0)	5 (55.6)
Male	6 (24.0)	4 (44.4)
Concomitant malignancy, n (%)	15 (60.0)	1 (11.1)	0.02*
Interstitial lung disease, n (%)	3 (12.0)	4 (44.4)	0.06
Cutaneous manifestation, n (%)
Heliotrope rash	7 (28.0)	5 (55.6)	0.22
Gottron’s sign	10 (40.0)	6 (66.7)	0.25
Gottron’s papule	21 (84.0)	9 (100.0)	0.55
Flagellate erythema	8 (32.0)	1 (11.1)	0.39
Periungual erythema	18 (72.0)	8 (88.9)	0.4
Skin ulcer	1 (4.0)	1 (11.1)	0.47
Inverse Gottron’s sign	1 (4.0)	0 (0.0)	>0.99
Shawl sign	9 (36.0)	3 (33.3)	>0.99
V neck sign	11 (44.0)	4 (44.4)	>0.99
Level of anti-TIF1γ Ab, mean (s.d.), index'a	106.8 (33.8)	71.6 (39.7)	0.04*

a

Serums were available for analysis in 22 non-CADM patients and seven CADM patients. CADM: clinically amyopathic DM; TIF1γ Ab: transcriptional intermediary factor 1-γ antibody. *P < 0.05.

The aetiological implication of this result is unknown yet, but this observation may be related to the pathological significance of anti-TIF1γ Ab production in the presence or absence of malignant tumour and/or myositis. Recent studies revealed higher autoantigen expression in muscles from patients with autoimmune myositis [6]. Myositis autoantigen expression is markedly increased in several types of cancer, which may induce an immune response [7]. Increased TIF1γ expression was noted in some malignant tumours and was significantly higher in tumours and muscles from anti-TIF1γ Ab-positive DM patients than in DM patients without this antibody [5]. Genetic alterations in TIF1 genes were more frequently noted in tumours from anti-TIF1γ Ab-positive DM patients; thus, the hypothesis that TIF1 gene mutations in tumours with high expression of TIF1γ may trigger autoimmune response, myositis and antibody production was proposed [6]. These findings may support our observations that low anti-TIF1γ Ab titres and low prevalence of malignancies were found in CADM patients who express this antibody. We are currently analysing the direct association of anti-TIF1γ Ab levels and activity of myositis and malignancies in the clinical setting.

Regarding the skin manifestations, heliotrope rash and Gottron’s papule/sign were more frequently observed among the anti-TIF1γ Ab-positive patients than among the anti-TIF1γ Ab-negative patients [5]. Our findings indicate that anti-TIF1γ Ab-positive CADM patients tend to show Gottron’s signs and heliotrope rash more often than non-CADM patients. While anti-TIF1γ Ab-positive CADM patients have poor myositis, skin eruptions may be more characteristic.

In recent years, genetic factors have been reported in DM, and it is thought that there is considerable racial difference. Our results are for Japanese patients and may not apply to other races. This study included a small sample population and further studies with larger sample population are required to validate the findings.

Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.

Disclosure statement: The authors have declared no conflicts of interest.