Occurrence of cholangiocarcinoma, three years after negative seroconversion of anti-TIF1γ antibody, in a dermatomyositis patient

概要

CORRESPONDENCE
Occurrence of cholangiocarcinoma three years after negative
seroconversion of anti-TIF1γ antibody in a dermatomyositis patient

Short title: Anti-TIF1-positive DM complicated with cancer

Ken Horisaki, Yoshinao Muro, Mariko Ogawa-Momohara, Yuta Yamashita, Haruka
Koizumi, Takuya Takeichi, Masashi Akiyama
Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya,
466-8550, Japan
Corresponding Author:
Yoshinao Muro, M.D., Ph.D.
Department of Dermatology, Nagoya University Graduate School of Medicine
65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, JAPAN
TEL: 81-52-744-2314 / FAX: 81-52-744-2318
E-mail: ymuro@med.nagoya-u.ac.jp
699 words, 1 figure, 7 references

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Editor
It is widely known that anti-TIF1γ antibody-positive dermatomyositis (DM) often occurs
in association with internal malignancies; therefore, thorough screening for underlying
malignancies is performed for anti-TIF1γ antibody-positive adult patients upon DM
diagnosis. However, it is unclear how long we should continue cancer screening after the
diagnosis if no malignancy is found.

Here, we report a 73-year-old anti-TIF1γ antibody-positive Japanese man with DM in
whom no malignancy was found at the time of DM diagnosis. Cancer screening had been
continued annually while the DM was inactive, with the negative seroconversion of antiTIF1γ antibody. Unfortunately, a malignant tumor was found 4 years after the diagnosis
of DM. We reported the detailed clinical features at onset and during the initial therapy,
including intramuscular hemorrhage, in the present patient in this journal [1]. He
presented with a 3-month history of skin erythema including heliotrope rash and
Gottron’s sign, and symmetric muscle weakness. Serum levels of creatine kinase (CK)
and aldolase were elevated and anti-TIF1γ antibody was positive with an index of 70
(cutoff value: 32) (MBL, Nagoya, Japan). We performed various examinations, including
CT imaging, endoscopies, and serum biomarker tests, but no malignancy was noted. He
received two courses of steroid pulse therapy (methylprednisolone 500 mg/day for 3 days),
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and then oral prednisolone 25 mg/day and azathioprine 50 mg/day. About 6 months after
the diagnosis, the anti-TIF1γ antibody became negative (index value: 26), the serum
levels of CK normalized, and the DM symptoms disappeared. Since he showed no
elevated anti-TIF1γ antibody titers, no other blood test abnormalities including elevated
serum CK levels, and no relapse of DM symptoms, the oral prednisone dose was further
reduced. Finally, his disease activity was well controlled with prednisolone at 1 mg/day
and azathioprine at 100 mg/day (Fig. 1A).

However, approximately 4 years after the diagnosis of DM, liver enzymes were suddenly
elevated, and cholangiocarcinoma with peritoneal dissemination was discovered. No
elevation of anti-TIF1γ antibody (index value: 20) nor relapse of DM symptoms was
observed before the elevation of liver enzymes; however, after the malignancy was noted,
the anti-TIF1γ antibody titer did increase to become positive (index value: 73). Even so,
the DM symptoms did not relapse even up to death. The cholangiocarcinoma was treated
with a combination of cisplatin and gemcitabine, but the treatment was ineffective, and
the patient died 6 years after the diagnosis of DM (Fig. 1B). TIF1γ expression was not
elevated in the cancer tissue as determined by immunohistochemistry (data not shown).

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Two previous meta-analyses reported several risk factors for malignancy in DM patients:
age >45 years, male, skin necrosis, anti-TIF1γ positivity, dysphagia, and elevated
erythrocyte sedimentation rate [2, 3]. Other reports suggested the following risk factors
associated with malignancy: age >52 years at diagnosis, skin necrosis, periungual
erythema, hypocomplementemia, and the rapid onset of cutaneous and muscular
symptoms [4]. Our patient had plural risk factors for cancer complications. As for the
timing of malignancy discovery, we reported that the majority of patients with anti-TIF1γ
antibody-positive DM develop visceral malignancies within 2 years before and after the
diagnosis of DM [5]. Another report revealed that no malignancies occurred from 2.5 to
7.5 years after the diagnosis of anti-TIF1γ antibody-positive DM [6]. However, in our
patient, cholangiocarcinoma was discovered approximately 4 years after the diagnosis of
DM, suggesting that this case is atypical. A recent study [7] showed the following trends
in titer changes of anti-TIF1γ antibodies in DM: i) anti-TIF1γ antibodies became negative
with treatment of both malignancy and DM, ii) patients with advanced cancer who had
no treatment option never demonstrated negative seroconversion. Our patient had no
cancer complications at the time of DM diagnosis and the anti-TIF1γ antibody became
negative after the DM was treated. Since he had had no recurrence of DM symptoms nor
re-elevation of the antibody titers for more than 3 years, we did not perform any imaging
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tests, such as CT scans, during that period. No previous reports have shown the elevation
of anti-TIF1γ antibodies associated with malignancy but without DM eruptions.

Anti-TIF1γ antibodies are not always useful biomarkers for the early detection of
malignancy in DM and that tumor screening should be performed with great caution even
several years after DM diagnosis, especially in high-risk cases.

Disclosure
Financial support: None.
Conflicts of interest: None.

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References
1. Adachi R, Muro Y, Kono M, et al. Intramuscular haemorrhage in a patient with
dermatomyositis and anti-TIF1γanti-bodies. Eur J Dermatol 2018;28:116-118.
2. Lu X, Yang H, Shu X, et al. Factors predicting malignancy in patients with
polymyositis and dermatomyostis: a systematic review and meta- analysis. PLoS One
2014;9:e94128.
3. Wang J, Guo G, Chen G, et al. Meta-analysis of the association of dermatomyositis
and polymyositis with cancer. Br J Dermatol 2013;169:838-47.
4. Fardet L, Dupuy A, Gain M, et al. Factors associated with underlying malignancy in
a retrospective cohort of 121 patients with dermatomyositis. Medicine (Baltimore)
2009;88:91-7.
5. Ogawa-Momohara M, Muro Y, Mitsuma T et al. Strong correlation between cancer
progression and anti-transcription intermediary factor 1γ antibodies in dermatomyositis
patients. Clin Exp Rheumatol 2018:36;990-5.
6. Oldroyd A, Sergeant JC, New P, et al. The temporal relationship between cancer and
adult onset anti-transcriptional intermediary factor 1 antibody-positive dermatomyositis.
Rheumatology (Oxford) 2019;58:650-5.
7. Ikeda N, Yamaguchi Y, Kanaoka M, et al. Clinical significance of serum levels of
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anti-transcriptional intermediary factor 1-γ antibody in patients with dermatomyositis. J
Dermatol. 2020;47:490-6.

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Figure 1.

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Figure legend
Figure 1. Clinical course of the present DM patient complicated with
cholangiocarcinoma. A) The 3-year period from the time of DM diagnosis (Day 1). B)
The 3-year period from the diagnosis of DM to the patient’s death. Elevated anti-TIF1γ
antibodies were observed after cholangiocarcinoma diagnosis.
The broken lines at 32 denote a cutoff value of anti-TIF1γ antibody in ELISA.
AZT: azathioprine; CK: creatinine kinase; PSL: prednisolone. ...

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