Clinical profile of anti-transcription intermediary factor-1 gamma-positive adults from a single tertiary care center

Avanish Jha; John Mathew; John Antony Jude Prakash; Susmitha Karunasree Perumalla

doi:10.4103/cmi.cmi_6_22

CASE SERIES

Year : 2022 | Volume : 20 | Issue : 2 | Page : 99-103

Clinical profile of anti-transcription intermediary factor-1 gamma-positive adults from a single tertiary care center

Avanish Jha¹, John Mathew¹, John Antony Jude Prakash², Susmitha Karunasree Perumalla²
¹ Department of Clinical Immunology and Rheumatology, Christian Medical College, Vellore, Tamil Nadu, India
² Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu, India

Date of Submission	19-Jan-2022
Date of Decision	20-Feb-2022
Date of Acceptance	03-Mar-2022
Date of Web Publication	07-May-2022

Correspondence Address:
Dr. John Mathew
Department of Clinical Immunology and Rheumatology, CMC, Vellore - 632 004, Tamil Nadu
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/cmi.cmi_6_22

Abstract

Anti-transcription intermediary factor-1 γ (TIF-1 γ) antibody is a myositis-specific antibody. These cases had specific clinical features in the past studies. There is no published data on such patients from South Asia. We retrospectively looked at data from patients with positive anti-TIF-1 γ antibodies from our hospital database between May 2019 and October 2020. Their clinical presentation, muscle and extra muscular involvement, investigations, presence of malignancy, and treatment with subsequent follow-up were retrieved using the electronic medical records. TIF-1 γ was rare at our center and was 2.46% out of the total positive myositis immunoblot results. Seven adult patients had significant anti-TIF-1 γ positivity. Five out of them had clinical muscle weakness; none had severe or respiratory muscle weakness. No patients had cancer-associated myositis. The skin was the most common extra muscular organ involved. The absence of cancer-associated myositis with anti-TIF-1 γ subjects in our series may represent the difference in phenotype in the South Asian population.

Keywords: Anti-transcription intermediary factor-1 gamma, dermatomyositis, myositis

How to cite this article:
Jha A, Mathew J, Prakash JA, Perumalla SK. Clinical profile of anti-transcription intermediary factor-1 gamma-positive adults from a single tertiary care center. Curr Med Issues 2022;20:99-103

How to cite this URL:
Jha A, Mathew J, Prakash JA, Perumalla SK. Clinical profile of anti-transcription intermediary factor-1 gamma-positive adults from a single tertiary care center. Curr Med Issues [serial online] 2022 [cited 2023 Mar 30];20:99-103. Available from: https://www.cmijournal.org/text.asp?2022/20/2/99/344936

Introduction

Idiopathic Inflammatory myositis (IIM) is a group of autoimmune disorders characterized by predominant feature of muscle involvement. There are 16 myositis-specific and associated antibodies identified and used in clinical practice.^[1] Anti-transcription intermediary factor-1 γ (TIF-1 γ) is a myositis-specific autoantibody which was first recognized in 2006 by Targoff against a 155 kd protein.^[2] This protein has an important role in transforming the growth factor-beta and WNT/beta-catenin pathways. It is also involved in the cell cycle by being a part of mitotic checkpoint complex and is believed to have both tumor suppressor and oncogene-like features depending on the type and state of the cell.^[3] Anti-TIF-1 γ-positive cases constitute up to 41% of cases of dermatomyositis in different cohorts.^[2],[4],[5] The observed variations are due to the immunological assays used their varying sensitivity and the inclusion criteria used in different studies. Immunoprecipitation was a test of choice for confirming myositis antibodies in the past. It is expensive, time-consuming, and needs expertise. Immunoblot assays overcome these limitations. These assays are also more reliable than immunoprecipitation for the detection of TIF-1 γ autoantibodies.^[6] There is, however, only a moderate correlation between the two methods for anti-TIF-1 γ antibody (K = 0.56) but most clinical laboratories use immunoblot-based assays in the current times.^[1]

According to a recent meta-analysis, anti-TIF-1 γ-positive patients had a diagnostic odd of 9.37 for having a malignancy.^[7] They also have lesser constitutional features, interstitial lung disease (ILD), Raynaud's phenomenon, and calcinosis as per previously reported literature. Skin involvement with characteristic findings of hyperkeratosis of palms, psoriasiform lesions, and red on white lesions have been seen. They also have a lower serum creatine phosphokinase (CPK) as compared to other dermatomyositis cases.^[4] There is a paucity of data on adult anti-TIF-1 γ patients from the South Asian population.

Case Series

We retrospectively recruited all adult cases of anti-TIF-1 γ positivity from our hospital database between May 2019 and October 2020. The kit used in our institute is a Euroline Autoimmune Inflammatory Myopathies 16 Antigens (IgG) immunoblot assay (EUROIMMUN Lubeck, Germany). It detects anti-TIF-1 γ antibody in addition to 15 other antibodies and has been in use ever since May 2019 at our center. Patients' demographic features, clinical symptoms, examination findings, and investigations were retrieved from the electronic medical records. The study was approved by the institutional review board (IRB Min No 13886 dated March 03, 2021). Informed consents were waived as ours is a retrospective case series. Individual patient identities were not revealed.

There were 264 antibodies detected on the myositis immunoblot assays during the study period of 18 months. A report was considered significant positive only if the intensity on the reader was 11 or more as advised by the manufacturer. There were seven adult patients with significant anti-TIF-1 γ positivity.

Clinical feature

All these patients were women, suggesting a female preponderance. The median age of presentation was 53 years (range 33–69). Five of the seven patients had clinical muscle weakness. Four of those were diagnosed with dermatomyositis. Another patient presented with polymyositis, ILD, and nonerosive arthritis. None of these patients had a respiratory or pharyngeal weakness. One subject had no clinical muscle weakness but had electromyography (EMG) features of myositis with elevated lactate dehydrogenase (LDH) but normal CPK and was thus diagnosed to have hypomyopathic dermatomyositis. The last patient was already known to have seropositive rheumatoid arthritis in the past and presented with constitutional features, joint pains, and specific skin rash of dermatomyositis. Patient was thus considered as an overlap syndrome of rheumatoid arthritis and amyopathic dermatomyositis [Table 1]. The median manual muscle testing 8 score was 61 (range 38–80).

Table 1: Clinical characteristics and laboratory features of patients

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Constitutional features were present in five patients and two of them had a history of fever.

Skin

Six cases had skin involvement. Five had a dermatomyositis-specific skin involvement as per the 2017 EULAR/ACR criteria for IIM.^[8] Two patients each had palmar hyperkeratosis and psoriasiform lesions over the trunk and one had telangiectatic – “red on white” lesions over the face. Three individuals also reported significant alopecia. One of them had a scarring alopecia noted by the physician. Two individuals had a sheet-like calcinosis.

Pulmonary

Two out of seven patients had ILD. Usual interstitial pneumonia and organizing pneumonia were the patterns observed on high-resolution computed tomography (CT) thorax. The former case also had strong Ro52 positivity. The same patient had features suggestive of pulmonary hypertension on echocardiography.

Arthritis

Three patients had joint pains. Only one had features of inflammatory arthritis. The patient with inflammatory arthritis had rheumatoid factor and anti-citrullinated protein antibodies in high titers.

Gastrointestinal involvement-two had gastroesophageal reflux symptoms; one had dysphagia.

Malignancy

All patients had age-and gender-specific malignancy screens. Only one patient had a history of malignancy. She had a breast carcinoma history, which was treated 8 years back with no recurrence at the time of diagnosis of dermatomyositis.

Investigations

Laboratory evaluation revealed a baseline median CPK of 83 units/liter (interquartile range [IQR] = 106–66; normal range 31–145 U/L). None of the patients had an elevated CPK at baseline despite five of them having clinical muscle weakness. LDH elevation was found in all six patients with either clinical or EMG features of muscle involvement.

A skin biopsy was done for one of the patients. It showed interface dermatitis and perivascular infiltrates in the dermis. One patient had a muscle biopsy. It showed focal endomysial, perifascicular lymphocytic infiltrates, and perivascular infiltrates.

Four out of seven cases had a positive antinuclear antibody (ANA) (nuclear-speckled pattern). Two cases also had a strong Ro52 positivity. There was no other significant cross-reactivity with other myositis-specific antibodies. Two of the patients had a positron emission tomography/CT done as a part of their malignancy evaluation. Both of them showed increased fluorodeoxyglucose uptake in muscles.

Four patients underwent needle EMG. All of them had myopathic changes. Spontaneous fibrillations, polyphasic reduced motor unit action potentials, and increased interference patterns were the common findings. One patient had positive sharp waves noted on the EMG.

Treatment

All seven patients received corticosteroids. Patients with muscle weakness received 0.5–1 mg/kg prednisolone equivalent of steroid initially. One patient received a lower dose of corticosteroid given the mild disease and concomitant tuberculosis at the point of the initial evaluation. The hypomyopathic patient with ILD and pulmonary hypertension received 0.5 mg/kg prednisolone initially. The steroid dose was later increased to 1 mg/kg due to poor response. The overlap patient received an initial dose of 10 mg prednisolone equivalent for skin and joint symptoms.

All patients received steroid-sparing agents. Mycophenolate mofetil was started in four patients (2 g/day) and methotrexate (20 mg/week) in one case as the initial steroid-sparing agent. The other two received azathioprine (2 mg/kg/day). Two of the patients with skin rashes were also given hydroxychloroquine in addition to the mentioned agents.

The patient not on high-dose corticosteroid for nonsevere disease and active tuberculosis later received adjunct rituximab. The indication was the worsening calcinosis despite being on treatment. She had also received mycophenolate and three cycles of 3 monthly intravenous bisphosphonates therapy prior to rituximab administration. One patient with worsening ILD received pulsed cyclophosphamide later.

Follow-up and outcome

Six out of the seven patients followed up after the initial visit. One patient was lost to follow-up. The median follow-up was 15 months with IQR from 10 to 17.5 months.

All patients who had at least a single follow-up had a stable or improved muscle power. One patient had worsening ILD needing an increased dose of steroid and pulsed cyclophosphamide. She had a stable condition after three doses of the same. There was mild activity in the form of active skin lesions in one patient at the most recent follow-up. There were no deaths or new malignancies reported at the last follow-up.

Discussion

We present the first set of data on adult anti-TIF-1 γ antibody-positive cases from South Asia. Our center uses Euroline immunoblot assay used the world over in diagnostic laboratories.^[9] Our anti-TIF-1 γ positivity of 2.46% was low compared to the series previously reported from Japan (17%) and the United States of America (41%).^[4],[10] This contradicts the previously reported negative association of anti-TIF-1 γ prevalence with the latitude that would have suggested a higher prevalence in our area.^[11]

All adult cases of anti-TIF-1 γ were females. This gender predisposition was reported previously but was more marked in our series with no male patients reported.^[10],[12] Severe muscle weakness or respiratory muscle weakness was absent in all cases. CPK was not elevated in any of the cases instead LDH was found raised at baseline. Similar findings of normal or lower CPK despite muscle weakness or involvement on magnetic resonance imaging have been reported in previous cases of anti-TIF-1 γ positivity.^[4],[13] This may represent the mild muscle involvement seen. LDH may be a more sensitive marker in such cases. However, more studies are needed.

Skin involvement was common with characteristic palmar hyperkeratosis, psoriasiform rash, and “red on white” lesions as previously described in the literature.^[4] Typical rash of dermatomyositis was more common than the abovementioned specific findings of anti-TIF-1 γ skin lesions.

We had only one patient with malignancy in our series. Her breast cancer history preceded myositis by 8 years. This patient did not have any malignancy recurrence at the time of dermatomyositis diagnosis or follow-up. The previous anti-TIF-1 γ cohorts have shown high rates of malignancies.^{[4],[10],[14],[15]} The two largest cohorts showed high rates of cancers- 22% (10 out of 46) and 65% (48 of 74).^[4],[10] The definition of cancer-associated malignancy used by Love et al.(1991) was malignancy within 1 year of dermatomyositis diagnosis. None of our patients who followed up had this.^[16] We add a point of caution in interpreting this data as patients had a short follow-up and cases need to be followed up serially for any malignancy in future. [Table 2] shows a comparison of data from other previously reported TIF-1 γ antibody-positive series. All our patients had a treatment response by the last follow-up. Although two cases needed either rituximab or cyclophosphamide due to resistant disease. This suggests a relatively good prognosis of anti-TIF-1 γ-positive adults in our population.

Table 2: Comparison of features of transcription intermediary factor-1 gamma cases-past series to present study

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Our study design was retrospective in nature. The number of cases was small and follow-up period was short. This is, however, to our knowledge, the first case series of adult anti-TIF-1 γ antibody cases from a South Asian population. Prospective study of patients with IIM looking at their phenotypes and clinical association with different myositis specific and associated antibodies in our region is the need of the hour.

Conclusion

Adult anti-TIF-1 γ cases were rare in our setting. Such patients most commonly had skin involvement, with dermatomyositis as a common clinical presentation. Muscle weakness was not severe. CPK rise was not seen even in cases with clinical weakness and LDH may be a better marker of muscle involvement in these cases. There was no cancer-associated myositis in our series of anti-TIF-1 γ cases.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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