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REVIEW ARTICLE
Ahead of print publication  

Cancer in myositis


 Department of Medicine, Systemic Autoimmune Diseases Unit, Vall d'Hebron General Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain

Date of Submission26-Jun-2020
Date of Acceptance16-Jul-2020

Correspondence Address:
Albert Selva-O'Callaghan,
Department of Medicine, Systemic Autoimmune Diseases Unit, Vall d'Hebron General Hospital, Universitat Autonoma de Barcelona, C/Siracusa n° 12 BIS “A”, Barcelona 08012
Spain
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_168_20

  Abstract 


There is an intriguing relationship between cancer and myositis. The immunosuppressive agents commonly used to treat myositis patients are known to favor the development of cancer, but this factor does not seem to be the main cause of the association. Most myositis patients who develop cancer are considered to have cancer-associated myositis, which suggests that there are some types of etiopathogenic relationship between these two conditions. The malignancy usually appears within 3 years of the myositis diagnosis, and the risk of cancer depends on the myositis phenotype, with classic or amyopathic dermatomyositis (DM) and immune-mediated necrotizing myopathy being the main associated phenotypes. Several considerations regarding the pathogenesis of this association and strategies to detect occult malignancy in these patients are discussed here, with special emphasis on the role of autoantibodies as markers of this condition. Anti- TIF1g (Transcription Intermediary Factor 1 gamma) antibodies have been extensively studied in patients with cancer-associated DM. In addition, we discuss the peculiarities of treating patients with cancer-associated myositis and suggest some good treatment options, and finally, we examine the cancer–myositis relationship with regard to the recently described concept of myositis as an immune-related adverse event derived from the use of checkpoint immune inhibitors to treat cancer.

Keywords: Anti-TIF1g, cancer-associated myositis, dermatomyositis, immune-mediated necrotizing myopathy



How to cite this URL:
Selva-O'Callaghan A, Terrones-Peinador M, Marques-Soares JR, Gil-Vila A. Cancer in myositis. Indian J Rheumatol [Epub ahead of print] [cited 2020 Dec 4]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=298855




  Introduction Top


The relationship between cancer and myositis is manifested in several ways.[1],[2] The most commonly reported is classic cancer-associated myositis, in which there is a close temporal relationship between the two conditions. When managing a patient with myositis, delineation of the myositis phenotype is of the utmost importance to establish the risk of associated cancer.[3] It is well recognized that patients with classic or amyopathic dermatomyositis (DM) are at the highest risk, in particular those testing positive for certain specific autoantibodies, such as anti-TIF1g. antibody.[4],[5],[6],[7] The second most frequent phenotype associated with cancer is seronegative immune-mediated necrotizing myopathy (IMNM), referred to as seronegative because the two most common autoantibodies related to IMNM, anti-signal recognition particle (SRP) and anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), are not present in this form. Although some researchers have found that IMNM patients who test positive for anti-HMGCR also have some risks of developing cancer, it is minor in comparison to seronegative patients.[8]

Cancer and myositis can behave in different manners.[9] One is the elimination phase, in which our immune defense system develops a strong response against cancer and eradicates it. When this response fails, cancer can appear, but the immune system may be able to contain the neoplastic cells, establishing a balance known as the equilibrium phase that can last for years but can also be disrupted in one way or another. Occasionally, the equilibrium phase is of short duration, and after a certain period, usually <3 years, cancer overcomes our immune system and becomes clinically apparent, generally as a full-blown neoplasm. This is the situation termed cancer-associated myositis or paraneoplastic myositis. Considering all these circumstances, some authors have stated that patients with DM, the most common phenotypes associated with cancer are actually “cancer survivors.”[10]

Throughout this review, we will discuss several cancer-related issues in myositis patients with DM, the most common phenotype associated with cancer.


  What Do We Know About the Pathogenesis of the Association? Top


Several theories have been launched to explain the complex relationship between cancer and myositis. One of them is based on the fact that tumors and muscle share certain antigens, and the association between the two diseases would be explained by what is known as molecular mimicry.[11] A good example is overexpression of Mi2 antigen in muscle and in some type of tumors, such as breast and lung malignancies. Anti-Mi2 antibodies are a well-recognized specific myositis autoantibody. Thus, it is plausible that antibodies directed against the tumor could produce an immune response that attacks muscle and leads to the clinical features of myositis.

A recent study reported that certain genetic alterations – mutations and a loss of heterozygosity – in TIF1 (transcription intermediary factor 1) cancer genes are more frequent in DM patients with anti-(transcription intermediary factor 1) TIF1g antibodies, a well-known biomarker of cancer-associated DM, than in those without.[12] (transcription intermediary factor 1) TIF1g, also known as TRIM33, is a highly represented molecule in several types of cancer. It participates in transcription, cellular proliferation, and apoptosis, all processes involved in carcinogenesis. In human cancer, loss of heterozygosity is a favorable mechanism in which a mutant allele is lost in an attempt to avoid the body's immune response against an immunogenic protein. Taken together, these data suggest that mutations in tumor TIF1 genes may result in an immune response against the mutated TIF1 protein detected by the presence of anti- (transcription intermediary factor 1) TIF1g antibodies. Depending on the ability of the tumor to avoid or not the immune response against the mutated protein by a loss of heterozygosity, the clinical features of DM will develop or not.

Two additional scenarios illustrate the complex relationship between cancer and myositis. The first concerns the immunosuppressive drugs that myositis patients currently receive to improve their clinical manifestations. Although epidemiological data do not support the idea that immunosuppression is a relevant factor for developing malignancy in myositis patients,[2] sometimes, clinicians encounter patients who develop a type of cancer typically related with immunosuppression (illustrated in the clinical problem, below). This could well be the case of some types of Epstein–Barr virus (EBV)-related lymphomas, which typically arise in posttransplanted patients as posttransplantation lymphoproliferative disease.[13] The second scenario, which can be considered the other side of the coin and will be discussed later, is the well-recognized myositis that appears after treatment of some types of malignancies with checkpoint inhibitors.[14],[15]


  The Clinical Problem Top


A 62-year-old woman diagnosed with classic DM 10 years earlier was attended for a state of confusion. One week before this presentation, she experienced dizziness and “slow thinking”. She also forgot to take her medication, and her husband reported that her mood was highly depressive. At the time of the DM diagnosis when she was 51 years of age, the patient presented with typical skin lesions, Gottron papules, and periorbital heliotrope rash [Figure 1], as well as proximal muscle weakness and mild dysphagia. Muscle biopsy disclosed perifascicular atrophy and perimysial lymphocyte infiltration [Figure 2]. At onset, she received prednisone p. o. (60 mg/d) at a decreasing dose and tacrolimus at a dose of 2 mg/12 h. Positron-emission tomography and computed tomography (PET/CT) cancer screening at that time showed no malignancy, and the autoantibody profile was positive for anti-small ubiquitin-like modifier activating enzyme and negative for anti-NXP2 and anti-TIF1g antibodies. The patient did well with treatment. Six years later, that is, 4 years before the current admission, while under treatment with low-dose prednisone (5 mg/d) and tacrolimus 2 mg/12 h, she developed dyspnea and dry bibasilar lung crackles that had not been present before. High-resolution CT examination showed probable cryptogenic organizing pneumonia with a restrictive pattern (FVC 51%). The patient declined fibrobronchoscopy with bronchoalveolar lavage and cryobiopsy. Prednisone was transiently increased to 40 mg/d and tacrolimus to 3 mg/12 h. The lung disease stabilized, but subsequently, kidney function was impaired; hence, tacrolimus was switched to mycophenolate mofetil, which had been her regular treatment until the current admission.
Figure 1: Gottron papules (a) and Heliotrope rash (b)

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Figure 2: Perifascicular atrophy (arrows) and perimysial inflammatory infiltrate (arrowhead) (Contributed by Prof. Josep Maria Grau-Junyent, Hospital Clinic Barcelona, Universitat de Barcelona) Be aware of the arrows

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Cranial CT, performed on admission to the emergency department, showed multiple nodular lesions suggestive of metastasis. Dexamethasone was started because of perilesional edema, and the confusional state improved. Whole-body PET/CT detected no suspicious lesions. Thereafter, gadolinium-enhanced MRI of the brain revealed pseudonodular lesions affecting the choroid plexus and small microhemorrhagic foci with high gadolinium uptake [Figure 3]. Primary central nervous system (CNS) lymphoma was suspected and stereotaxic biopsy confirmed the diagnosis. HIV serology was negative.
Figure 3: Contrast-enhanced magnetic resonance imaging of the brain shows periependymal enhancement and mainly periventricular multifocal nodular lesions (arrows)

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  Corollary Top


In the case reported, the final diagnosis was diffuse, large B-cell lymphoma, which is classically related to immunosuppression.[16] Most patients with this condition are HIV positive or, as likely occurred in this case, cancer develops due to iatrogenic immunosuppression. The patient had been diagnosed with DM 10 years previously and had now developed a lymphoma. Given the lengthy time interval between the two processes, it would be difficult establish an association. It would be more reasonable to consider this a case of cancer associated with immunosuppression than cancer-associated DM. Given the nature of this specific autoimmune disease, it is uncertain whether DM patients are more prone to develop this complication of immunosuppressive therapy.


  Cancer Screening When, How, and How Often? Top


Considering that cancer is highly associated with myositis, cancer screening is recommended in patients who develop inflammatory myopathy,[17],[18],[19] mainly those with classic or amyopathic DM or IMNM.[20] The first step in the strategy used in these myositis phenotypes in clinical practice includes a thorough history taking, complete general physical examination, determination of myositis autoantibodies, such as anti- TIF1g (transcription intermediary factor 1) (only useful in DM), anti-NXP2, and anti-HMGCR, and PET/CT imaging study.[21] DM patients testing positive to anti- TIF1g (transcription intermediary factor 1) antibodies should then have 1 PET/CT scan every year for 3 years. An excellent study[22] performed in Manchester (United Kingdom) demonstrated that DM patients with anti- TIF1g (transcription intermediary factor 1) who do not develop cancer during the first 3 years following the DM diagnosis will not do so in future, at least not more often than the general population. Thus, it seems that the 3-year window is critical for the development of associated cancer in this patient population. Positive status to anti-NXP2[23] and anti-HMGCR[8] is also associated with a risk of cancer-associated myositis, but it seems to be less intense than the case of anti- TIF1g (transcription intermediary factor 1) in DM patients. Anti-NXP2 is a useful marker not only in DM but also in other phenotypes, and anti-HMGCR is especially useful in those with IMNM, in whom the risk of malignancy is higher in anti-SRP- and anti-HMGCR-negative patients.

Muscle biopsy may show characteristic vacuolated fibers corresponding to irregularly shaped areas of myofibrillar loss, mainly in anti- (transcription intermediary factor 1) TIF1g -positive patients with cancer-associated myositis [Figure 4]. These pathological findings are also helpful to support a possible association with malignancy and can be easily differentiated from the rimmed vacuoles usually seen in sporadic inclusion body myositis.[24]
Figure 4: Histopathology findings in a patient with anti-TIF1γ antibody positive cancer-associated dermatomyositis (modified Gomori trichrome staining; bar: 50

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We propose the acronym EUCLIDES as an overall strategy for cancer screening in myositis patients.[19] The E refers to epidemiologic features that take into account the prevalence of malignancies in different countries (e.g., the high prevalence of EBV-related nasopharyngeal cancer in Asian countries). UCL refers to useful clinical and laboratory data, including the clinical phenotype, findings on clinical examination, and laboratory results (the autoantibody profile with anti (transcription intermediary factor 1) TIF1g, NXP2, HMGCR). The I in the acronym refers to imaging. We prefer a single PET/CT study, but whole-body CT or MRI can also be performed, as well as “double check” complementary techniques, represented by DES (development screening). A flowchart for cancer screening in patients with myositis is reported in [Figure 5].
Figure 5: Algorithm for cancer screening in patients with idiopathic inflammatory myopathy.IMNM: immune-mediated necrotizing myopathy. FDG-PET/CT [18F] = Fluorodeoxyglucose PET/computed tomography, CAM = Cancer-associated myositis, MSA = Myositis-specific antibody. *If available. The Anti-NXP2 and anti-HMGCR association with cancer requires further investigation

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  Treatment in Cancer-Associated Myositis Top


Treatment for patients with cancer-associated myositis is similar to that of other myositis patients. Nevertheless, some particularities should be pointed out. First, surgical therapy for cancer (e.g., localized colon cancer) can lead to total remission of myositis in some patients, with DM behaving as a true paraneoplastic syndrome. Second, aggressive chemotherapy, such as CHOP-R (cyclophosphamide, hydroxydaunorubicin, oncovin [vincristine], and prednisone-rituximab) used to treat some types of lymphomas, may lead to remission of the myositis not necessarily because of fading of the tumor but because of severe immunosuppression. Third, cancer induction therapy does not always improve myositis. On the contrary, occasionally, a cancer patient without myositis develops full-blown inflammatory muscle disease shortly after chemotherapy treatment. This is interpreted as tumour antigen spread yielding to an intensive immune response expressed as myositis. Fourth, it is of utmost importance to establish a strong link with oncologists to avoid undesirable interactions between drugs used in patients with myositis and drugs used by the oncologist for treating cancer.

Beyond these considerations, a good therapeutic strategy in patients with cancer-associated myositis includes administration of triple therapy with prednisone, an immunosuppressive drug, and intravenous immunoglobulin in an attempt to promptly improve their clinical condition. Intravenous immunoglobulin is a good option in these cases, as it can improve myositis while avoiding immunosuppression. The immunosuppressive drugs mentioned are those usually administered in myositis patients, such as methotrexate, azathioprine, mycophenolate mofetil, or calcineurin antagonists (cyclosporine or tacrolimus). Rituximab is also a good therapeutic option, which we generally use as an “add-on” drug.


  Can Immune Checkpoint Inhibitor-Induced Myositis Be Included in Cancer-Associated Myositis? Top


Immune checkpoint inhibitors are a family of monoclonal antibodies that act by blocking programmed cell death 1 (PD-1), its ligand (PD-1 L), or cytotoxic T-lymphocyte antigen 4 (CTLA-4), which are natural inhibitors of the immune system. Immune checkpoint inhibitors have a proven beneficial effect in several types of cancer, such as melanoma and nonsmall cell lung cancer due to strong immune activation against the disease.[25],[26] Nevertheless, a toll to pay for activating the immune system against cancer is the development of immune-related adverse events; for example, myositis.[13],[27] Could there be a multidirectional link between the checkpoint inhibitor pathway, cancer, and myositis? Some data point in this direction. Researchers have found that the soluble form of PD-1 L seems to be a marker of occult cancer in myositis patients, as higher values of this molecule were found in DM patients with cancer-associated myositis than in those who did not harbor malignant disease.[28] Thus, downregulation of the immune system by activation of the PD-1/PD-1 L pathway could favor escape of the tumor from immune vigilance, and blocking this pathway by immune checkpoint inhibitors could contribute to abating the cancer but at the price of developing an immune-related adverse event such as myositis. It is important to increase our knowledge of the complex relationship between these factors to gain insight into the pathogenesis of carcinogenesis and establish new therapies for patients with these conditions.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Casciola-Rosen L, Nagaraju K, Plotz P, Wang K, Levine S, Gabrielson E, et al. Enhanced autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy. J Exp Med 2005;201:591-601.  Back to cited text no. 11
    
12.
Pinal-Fernandez I, Ferrer-Fabregas B, Trallero-Araguas E, Balada E, Martínez MA, Milisenda JC, et al. Tumour TIF1 mutations and loss of heterozygosity related to cancer-associated myositis. Rheumatology (Oxford) 2018;57:388-96.  Back to cited text no. 12
    
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Selva-O'Callaghan A, Palacios A, Solans-Laque R, Labirua A, Salcedo-Allende T, Vilardell-Tarrés M. Epstein-Barr virus-associated lymphoma in patients with dermatomyositis. Be aware of double immunosuppression. Rheumatology (Oxford) 2009;48:1462-3.  Back to cited text no. 13
    
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Touat M, Maisonobe T, Knauss S, Salem OB, Hervier B, Auré K, et al. Immune checkpoint inhibitor-related myositis and myocarditis in patients with cancer. Neurology 2018;91:E985-94.  Back to cited text no. 14
    
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Matas-García A, Milisenda JC, Selva-O'Callaghan A, Prieto-Gonzalez S, Padrosa J, Cabrera C, et al. Emerging PD-1 and PD-1 L inhibitors-associated myopathy with a characteristic histopathological pattern. Autoimmun Rev 2020;19:102455.  Back to cited text no. 15
    
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21.
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Johansen A, Christensen SJ, Scheie D, Højgaard JLS, Kondziella D. Neuromuscular adverse events associated with anti-PD-1 monoclonal antibodies: Systematic review. Neurology 2019;92:663-74.  Back to cited text no. 27
    
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Chen H, Peng Q, Yang H, Yin L, Shi J, Zhang Y, et al. Increased levels of soluble programmed death ligand 1 associate with malignancy in patients with dermatomyositis. J Rheumatol 2018;45:835-40.  Back to cited text no. 28
    


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