Anti-signal recognition particle-positive interstitial lung disease accompanied by metastatic duodenal adenocarcinoma: a case report

doi:10.21203/rs.3.rs-3223428/v1

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Case Report

Anti-signal recognition particle-positive interstitial lung disease accompanied by metastatic duodenal adenocarcinoma: a case report

https://doi.org/10.21203/rs.3.rs-3223428/v1

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Background: Anti-signal recognition particle (anti-SRP) antibodies are one of the two most commonly identified antibodies in immune-mediated necrotizing myopathies (IMNMs), a disease characterized by proximal muscular weakness. Anti-SRP-positive IMNMs predominantly affect middle-aged women; extra-muscular manifestations, such as interstitial lung disease (ILD), are not frequent and often mild. Malignancy is not a major concern for patients with IMNMs, especially those who are anti-SRP-positive.

Case presentation: We present the case of a 64-year-old male who tested positive for anti-SRP antibodies and presented with ILDinstead of myopathy. This was accompanied by metastatic duodenal adenocarcinoma, and the patient experienced rapidly progressive interstitial lung disease (RP-ILD) during anticancer therapy. We chose low-dose immunosuppressive therapy after surgical removal of the metastatic cancerous lesion. The patient exhibited a positive response, whose respiratory condition gradually improved throughout the 2-year follow-up period. But the primary lesion appeared two years later than the site of metastasis, and the patient developed extensive metastases finally.

Conclusions: The rare form of ILD in this patient highlights the significance of cancer screening and surveillance in atypical anti-SRP-positive patients. Low-dose immunosuppressive therapy following anticancer therapy resulted in significant improvement in ILD, serving as a treatment reference for paraneoplastic RP-ILD.

Interstitial lung disease

Anti-signal recognition particle antibodies

Duodenal adenocarcinoma

Immune-mediated necrotizing myopathies

Immune-mediated necrotizing myopathies (IMNMs) represent a distinct subgroup of idiopathic inflammatory myopathies characterized by inflammatory involvement of skeletal muscle. Two specific autoantibodies, which are anti-signal recognition particle (SRP) antibodies and anti-3-hydroxyl-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies, are closely associated with IMNMs and exhibit distinct clinical features [1, 2]. Compared with anti-HMGCR antibodies, anti-SRP antibodies are more significantly associated with progressive muscle weakness, and resistance to glucocorticoid treatment [3, 4]. Malignancy was found to occur more rarely in IMNMs that were anti-SRP positive than in IMNMs that were seronegative and anti-HMGCR positive [5].

Nevertheless, we present an exceptional case of a 64-year-old patient who tested positive for anti-SRP antibodies and was diagnosed with metastatic duodenal adenocarcinoma. Surprisingly, this patient predominantly exhibited interstitial lung disease (ILD) rather than the typical muscle weakness observed in anti-SRP-positive individuals. This case deviates from the usual clinical presentation of anti-SRP-positive patients and highlights a unique manifestation of the disease.

A previously healthy 64-year-old male was admitted to our department in May 2020. His initial complaints included mild proximal myasthenia and myalgia that persisted for a period of two months, followed by the development of noticeable breathlessness. No additional symptoms such as fever, rash, Raynaud phenomenon, joint pain, morning stiffness, or weight loss were noted. On physical examination, Velcro-type bibasilar crackles were detected in the lung bases, but no significant muscle weakness was observed. A slight elevation of serum CK levels (488 U/L, [reference, 55–170 U/L]) revealed mild muscle injury. The patient tested positive for only anti-SRP antibodies among the myositis-specific antibodies at a high level (+++), while other immunological blood tests, including antinuclear antibodies, anti-neutrophil cytoplasmic antibodies, and rheumatoid factor, were negaSRPtive. Arterial blood gas (ABG) analysis showed a PaO2 of 71 mmHg, and a PaCO2 of 44 mmHg, with no oxygen therapy. High-resolution computed tomography (HRCT) revealed ILD with prominent involvement at the basal and subpleural regions (Fig. 1).

Pulmonary function tests indicated a forced vital capacity of 51% predicted, while diffusing capacity could not be measured due to the patient's inability to cooperate. Tumor markers were evaluated to rule out various types of cancer. Carbohydrate antigen 15 − 3 was found to be elevated at 44.87 U/ml (reference range: <32 U/ml), while other results fell within the normal range (carbohydrate antigen 19 − 9, alpha-fetoprotein, prostate-specific antigen). Abdominal computed tomography (CT) scan did not reveal any noticeable lesions, whereas 18F-FDG positron emission tomography-computed tomography (PET/CT) indicated a grossly suspicious mass in the vicinity of the uncinate process of the pancreas, with no additional suspicious masses observed (Fig. 2).

To confirm the findings, endoscopic ultrasonography (EUS) was performed, which revealed an encapsulated, hypoechoic lesion with a regular shape adjacent to the pancreatic head (Fig. 3).

With regard to treatment, the priority was to surgically remove the grossly suspicious lesion, while the treatment for ILD was temporarily postponed. On June 5, 2020, the mass was laparoscopically resected, and the pathological examination confirmed the presence of poorly differentiated adenocarcinoma metastases in the retroperitoneal lymph node. Positive immunohistochemical staining of the intestinal epithelium (AE1/AE3, CDX2) suggested the possibility of gastrointestinal cancer in this patient (Fig. 4). However, due to the unknown primary site, no chemotherapy or radiotherapy was administered.

Shortly after the operation, the patient experienced rapid-onset dyspnea. ABG analysis indicated rapid respiratory failure, with a PaO2 of 60 mmHg. The extent of ILD on HRCT imaging rapidly increased, with no evidence of infection (Fig. 1). Interestingly, the patient's muscle weakness did not worsen, and the levels of CK even decreased compared to baseline. The diagnosis of rapidly progressive interstitial lung disease (RP-ILD) was established, and aggressive immunosuppression therapy was deemed necessary. The initial dosage of methylprednisolone was 120 milligrams per day (mg/day) and that of mycophenolate mofetil (MMF) was 1.0 grams per day (g/day). However, considering the possibility of cancer with an unknown primary site, the corticosteroid dosage was quickly tapered down to 20 mg/day of prednisolone as soon as improvement was observed. After 2 months, a follow-up HRCT showed reduced reticulation and resolution of consolidation (Fig. 1). The prednisolone dosage was further reduced to 10 mg/day and the MMF dosage to 0.5 g/day for maintenance therapy. Throughout the 2-year follow-up period, the patient's respiratory condition gradually improved (Fig. 1). Abdominal CT scan was conducted for cancer surveillance; however, no significant primary site was detected.

In May 2022, the patient presented with fatigue and a reduced appetite. Liver function tests revealed an obstructive pattern, with a significant elevation in alkaline phosphatase (884.2 U/L [reference, 10–60 U/L]) and direct bilirubin (46.8 µmol/L [reference, 0.1–6.8 µmol/L]). Serum CK levels were within the normal range, and the ILD remained stable. Due to concerns about potential liver injury, MMF was discontinued, and the patient continued with a low dosage of 10 mg/day of prednisolone. As no correlation was found between serum transaminases and CK levels and the patient had an unknown primary gastrointestinal cancer, malignant obstructive jaundice was suspected. Abdominal CT scan and EUS revealed a suspicious mass in the duodenal papilla, accompanied by dilatation of the biliary and pancreatic ducts (Fig. 3). An EUS-guided biopsy was performed for accurately diagnose the mass, and histological examination confirmed malignancy. Preoperative PET/CT scan showed no signs of metastasis (Fig. 5), leading to the performance of laparoscopic radical pancreatoduodenectomy.

The postoperative pathological examination confirmed poorly differentiated adenocarcinoma of the duodenum. Chemotherapy consisting of 5-fluorouracil plus calcium folinate was initiated, but after three cycles, it had to be discontinued due to a gastrointestinal perforation that occurred in September 2022. The patient discontinued treatment and subsequently developed extensive metastases (in the lung and liver) in April 2023.

IMNMs is a rare disease with an annual incidence of approximately 1 in 100,000 individuals. It primarily affects middle-aged females and can be triggered by connective diseases, virus infection, statin usage, and malignancy [3, 6]. It represents the most severe form of myopathy, characterized by extremely elevated serum CK levels in the thousands of units/liter (U/L). Malignancy is not a major concern for patients with IMNMs, especially those who are anti-SRP-positive [7, 8]. However, our patient exhibited atypical anti-SRP-positive manifestations: not in the susceptible group, with mild muscle weakness but ILD, and subsequent findings confirmed the diagnosis of metastatic duodenal adenocarcinoma even in the absence of any symptoms of malignancy.

A PubMed search was conducted for all published case reports of anti-SRP-positive IMNMs comorbid with malignancy in the past 10 years, with the main search term “anti-signal recognition particle” and combined with the comprised terms related to “cancer”. Only three cases were found in total. Hara et al. reported an 87-year-old female comorbid with colon carcinoma presenting with heart failure as the initial clinical symptom [9]. Nawata et al. reported a 58-year-old female with a predominant presentation of cutaneous lesions but mild muscle injury, ultimately diagnosed with pulmonary adenocarcinoma [10]. Sehara et al. reported a 72-year-old female who presented with a progressively worsening muscle injury comorbid with gastric cancer [11]. Although the incidence of malignancy in anti-SRP-positive patients is low, screening for malignancy in atypical patients, especially those aged 50 years or older, is necessary, with FDG-PET/CT being the preferred method of screening [10, 12]. The primary lesion in our patient appeared two years later than the site of metastasis, highlighting the importance of malignancy surveillance during follow-up. The presence of anti-SRP antibodies and atypical presentation may be a consequence of a paraneoplastic syndrome resulting from immune tolerance disruption induced by malignancy [13].

Extra-muscular manifestations, such as ILD, are not frequent and often mild in anti-SRP-positive IMNMs. Nonspecific interstitial pneumonia is the principal form of ILD identified in these patients [3]. RP-ILD is more likely to occur in dermatomyositis patients rather than IMNMs patients [14]. However, in our patient, ILD was aggressive and progressed to RP-ILD within a short period, characterized by acute and progressive dyspnea requiring supplemental oxygen, an increase in interstitial abnormalities on HRCT by more than 20%, and respiratory failure as suggested by ABG analysis [15]. The cause could be related to the resection of the metastatic lymph node or a manifestation of paraneoplastic syndrome.

RP-ILD is generally refractory to treatment and its management relies heavily on experience and expert opinion, with a poor prognosis [16]. High-dose corticosteroid therapy is the main treatment approach due to the aggressive nature of RP-ILD, often supplemented with additional immunosuppressants such as MMF, cyclophosphamide, cyclosporine A, or tacrolimus [17, 18]. However, in our patient's case, as RP-ILD occurred during anticancer therapy and aggressive immunosuppression therapy could potentially impact the cancer prognosis [19, 20], we chose to implement a transient high-dose corticosteroid therapy and rapidly taper it to a low-dose maintenance, deviating from the recommended approach. We also decided to maintain MMF at a low dose for the same reason. Previous reports have shown a high relapse rate when tapering therapy for RP-ILD [21, 22]. However, our patient exhibited a positive response to low-dose immunosuppression therapy, leading to significant relief of ILD symptoms. This suggests that treating the underlying malignancy is of utmost importance in the paraneoplastic type. In previous studies, paraneoplastic idiopathic inflammatory myopathies may be in remission when malignancy treatment was administered without the need for immunosuppression therapy [11, 23, 24]. With the use of low-dose corticosteroids alone, our patient's ILD remained stable, indicating the difference between paraneoplastic and other types. We plan to attempt corticosteroid discontinuation once complete relief of ILD is achieved.

In summary, this case highlights an exceedingly rare form of ILD in anti-SRP-positive patients. Physicians should be aware of the potential occurrence of cancer in these atypical cases, and FDG-PET/CT is the recommended method for cancer screening. Furthermore, these findings emphasize the importance of prioritizing cancer therapy in INMNs comorbid with malignancy, which may be complemented by mild immunosuppression therapy.

Ethics approval and consent to participate

Written informed consent was obtained from the patient. The ethics committee of The First People’s Hospital of Changzhou, Third Affiliated Hospital of Soochow University reviewed and approved this case report.

Consent for publication

The patient gave written informed consent for publication of this case and accompanying images.

Availability of data and materials

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Funding

None.

Authors’ contributions

WX and MW conceived of the work and gave final approval of the version to be published. WLJ performed the data analysis and drafted the manuscript. PRZ and TX revised the manuscript. LZ, LX, LM and SLZ performed the data collection and follow-up surveillance. All authors contributed to the article and approved the submitted version.

Acknowledgments

The authors wish to acknowledge Dr. Yue Zhang of the Department of Hepatobiliary and Pancreatic Surgery, The First People’s Hospital of Changzhou, Third Affiliated Hospital of Soochow University, for providing the analysis of Abdominal CT.

Watanabe Y, Uruha A, Suzuki S, Nakahara J, Hamanaka K, Takayama K, et al. Clinical features and prognosis in anti-SRP and anti-HMGCR necrotising myopathy. J Neurol Neurosurg Psychiatry. 2016;87(10):1038–44.
Allenbach Y, Benveniste O, Stenzel W, Boyer O. Immune-mediated necrotizing myopathy: clinical features and pathogenesis. Nat Rev Rheumatol. 2020;16(12):689–701.
Suzuki S, Nishikawa A, Kuwana M, Nishimura H, Watanabe Y, Nakahara J, et al. Inflammatory myopathy with anti-signal recognition particle antibodies: case series of 100 patients. Orphanet J Rare Dis. 2015;10:61.
Pinal-Fernandez I, Parks C, Werner JL, Albayda J, Paik J, Danoff SK, et al. Longitudinal Course of Disease in a Large Cohort of Myositis Patients With Autoantibodies Recognizing the Signal Recognition Particle. Arthritis Care Res (Hoboken). 2017;69(2):263–70.
Allenbach Y, Keraen J, Bouvier AM, Jooste V, Champtiaux N, Hervier B, et al. High risk of cancer in autoimmune necrotizing myopathies: usefulness of myositis specific antibody. Brain. 2016;139(Pt 8):2131–5.
Khan NAJ, Khalid S, Ullah S, Malik MU, Makhoul S. Necrotizing Autoimmune Myopathy: A Rare Variant of Idiopathic Inflammatory Myopathies. J Investig Med High Impact Case Rep. 2017;5(2):2324709617709031.
Aussy A, Boyer O, Cordel N. Dermatomyositis and Immune-Mediated Necrotizing Myopathies: A Window on Autoimmunity and Cancer. Front Immunol. 2017;8:992.
Yang HX, Tian XL, Jiang W, Li WL, Liu QY, Peng QL, et al. [Clinical and pathological characteristics of immune mediated necrotizing myopathy]. Beijing Da Xue Xue Bao Yi Xue Ban. 2019;51(6):989–95.
Hara A, Amano R, Yokote H, Ijima M, Zeniya S, Uchihara T, et al. Secondary cardiac involvement in anti-SRP-antibody-positive myopathy: an 87-year-old woman with heart failure symptoms as the first clinical presentation. BMC Neurol. 2020;20(1):29.
Nawata T, Kubo M, Mitsui H, Oishi K, Omoto M, Kanda T, et al. Dermatomyositis Complicated by Digital Ischemia and Lung Adenocarcinoma in a Patient with Positive Anti-signal Recognition Particle Antibodies. Intern Med. 2018;57(6):883–6.
Sehara Y, Tsuchiya K, Nishino I, Sato H, Ando Y. Resection of Gastric Cancer Remitted Anti-signal Recognition Particle Myopathy. Intern Med. 2022;61(16):2509–15.
Shelly S, Beecher G, Milone M, Liewluck T, Ernste F, Triplett J, et al. Cancer and immune-mediated necrotizing myopathy: a longitudinal referral case-controlled outcomes evaluation. Rheumatology (Oxford). 2022;62(1):281–9.
Yang H, Peng Q, Yin L, Li S, Shi J, Zhang Y, et al. Identification of multiple cancer-associated myositis-specific autoantibodies in idiopathic inflammatory myopathies: a large longitudinal cohort study. Arthritis Res Ther. 2017;19(1):259.
Selva-O'Callaghan A, Pinal-Fernandez I, Trallero-Araguas E, Milisenda JC, Grau-Junyent JM, Mammen AL. Classification and management of adult inflammatory myopathies. Lancet Neurol. 2018;17(9):816–28.
You H, Wang L, Wang J, Lv C, Xu L, Yuan F, et al. Time-dependent changes in RPILD and mortality risk in anti-MDA5 + DM patients: a cohort study of 272 cases in China. Rheumatology (Oxford). 2023;62(3):1216–26.
Wang H, Lv J, He J, Wu W, Zhong Y, Cao S, et al. The prevalence and effects of treatments of rapidly progressive interstitial lung disease of dermatomyositis/polymyositis adults: A systematic review and meta-analysis. Autoimmun Rev. 2023;22(8):103335.
Barba T, Fort R, Cottin V, Provencher S, Durieu I, Jardel S, et al. Treatment of idiopathic inflammatory myositis associated interstitial lung disease: A systematic review and meta-analysis. Autoimmun Rev. 2019;18(2):113–22.
Jablonski R, Bhorade S, Strek ME, Dematte J. Recognition and Management of Myositis-Associated Rapidly Progressive Interstitial Lung Disease. Chest. 2020;158(1):252–63.
Thet Z, Lam AK, Ranganathan D, Aung SY, Khoo TK. Cancer risks along the disease trajectory in antineutrophil cytoplasmic antibody associated vasculitis. Clin Rheumatol. 2020;39(9):2501–13.
Hellemans R, Pengel LHM, Choquet S, Maggiore U, for EWotTLJp. Managing immunosuppressive therapy in potentially cured post-kidney transplant cancer (excluding non-melanoma skin cancer): an overview of the available evidence and guidance for shared decision-making. Transpl Int. 2021;34(10):1789–800.
McPherson M, Economidou S, Liampas A, Zis P, Parperis K. Management of MDA-5 antibody positive clinically amyopathic dermatomyositis associated interstitial lung disease: A systematic review. Semin Arthritis Rheum. 2022;53:151959.
Teel A, Lu J, Park J, Singh N, Basharat P. The Role of Myositis-Specific Autoantibodies and the Management of Interstitial Lung Disease in Idiopathic Inflammatory Myopathies: A Systematic Review. Semin Arthritis Rheum. 2022;57:152088.
Lin C, Ying Z, Sijing C. Spontaneous resolution of dermatomyositis associated with fallopian-tube carcinoma following staging surgery: A case report. Med (Baltim). 2019;98(10):e14530.
Klukas J, Pudszuhn A, Kusch K, Obermueller T, Hofmann VM. [Dermatomyositis as a paraneoplastic syndrome of head-neck-cancer: Case series & literature review]. Laryngorhinootologie. 2021;100(7):542–9.

No competing interests reported.

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Anti-signal recognition particle-positive interstitial lung disease accompanied by metastatic duodenal adenocarcinoma: a case report

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Abstract

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Background

Case presentation

Discussion and Conclusions

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Ethics approval and consent to participate

Consent for publication

Availability of data and materials

Competing interests

Funding

Authors’ contributions

Acknowledgments

References

Additional Declarations

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