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Immune checkpoint inhibitors (ICIs)-related ocular myositis
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Immune checkpoint inhibitors (ICIs)-related ocular myositis Matteo Garibaldi , Fabio Calabro` , Gioia Merlonghi , Silvia Pugliese , Marco Ceccanti , Lara Cristiano , Tommaso Tartaglione , Antonio Petrucci PII: DOI: Reference:
S0960-8966(20)30039-0 https://doi.org/10.1016/j.nmd.2020.02.013 NMD 3807
To appear in:
Neuromuscular Disorders
Received date: Revised date: Accepted date:
25 June 2019 15 January 2020 18 February 2020
Please cite this article as: Matteo Garibaldi , Fabio Calabro` , Gioia Merlonghi , Silvia Pugliese , Marco Ceccanti , Lara Cristiano , Tommaso Tartaglione , Antonio Petrucci , Immune checkpoint inhibitors (ICIs)-related ocular myositis, Neuromuscular Disorders (2020), doi: https://doi.org/10.1016/j.nmd.2020.02.013
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier B.V.
ICIs-related ocular myositis Highlights
Clinically isolated ocular involvement can occur during ICIs treatment Muscle biopsy showed subclinical generalized myositis despite normal muscle MRI Ocular myositis represents a peculiar subgroup of generalized Checkpoint Inhibitors-related Myositis (irMyositis) Extraocular muscles can be predominantly involved in autoimmune processes Autoimmune ocular myositis could exist among unexplained ptosis/ophthalmoplegia
1
ICIs-related ocular myositis
Immune checkpoint inhibitors (ICIs)-related ocular myositis Authors and institutional affiliations: Matteo Garibaldi1, Fabio Calabrò2, Gioia Merlonghi1, Silvia Pugliese3, Marco Ceccanti4, Lara Cristiano5, Tommaso Tartaglione5, Antonio Petrucci6 1. Neuromuscular Disease Centre, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), SAPIENZA University of Rome, Sant'Andrea Hospital, Rome, Italy 2. Department of Medical Oncology, San Camillo Forlanini Hospital, Rome, Italy 3. Department of Radiology, Policlinico Tor Vergata, Rome, Italy 4. Rare Neuromuscular Diseases Centre, Department of Human Neuroscience, SAPIENZA University, Rome, Italy 5. Department of Radiology, Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy. 6. Department of Neuroscience, San Camillo-Forlanini Hospital, Rome, Italy
Total word count: 889 Corresponding author: Matteo GARIBALDI, MD, PhD Unit of Neuromuscular Diseases Department of Neurology Mental Health and Sensory Organs (NESMOS) Faculty of Medicine and Psychology SAPIENZA University of Rome Sant'Andrea Hospital Via di Grottarossa 1035-1039 00189 Roma Tel. +39 06 33775937 Fax: +39 06 33775900 Mail: [email protected]
Contribution and disclosures: MG: study concept, design and supervision, acquisition and interpretation of data, manuscript writing, responsibility for the integrity of the study; GM: histoenzymologyl and immunohistochemisty studies, analysis and interpretation of the data; SP, LC, TT: muscle and orbital imaging studies, analysis and interpretation of the data; FC, MC, AP: study concept, acquisition of clinical data, critical revision of the manuscript for intellectual content. All authors read and approved the final manuscript. None of the authors has conflicts of interest that could influence the work. 2
ICIs-related ocular myositis
Abstract We present extensive clinical, serological, morphological and muscle imaging data of a 66 years old man with isolated bilateral ptosis and external ophthalmoplegia secondary to Immune check point inhibitors (Pembrolizumab). He had elevated CK level (>5000 UI/L). No facial, bulbar, proximal, distal or axial muscular weakness was observed. Electromyography (EMG) showed myopathic pattern, with spontaneous activity. Myositis specific antibodies and anti-striational antibodies were negative. Cardiac and respiratory functions were preserved. Muscle MRI was unremarkable, whereas orbital MRI revealed bilateral hyperintensities in inferior rectus, medial rectus and superior oblique muscles in both T1 and STIR sequences, with mild muscle atrophy. Muscle biopsy showed endomysial inflammatory infiltrates, MHC-1 expression was observed in clusters of non-necrotic cells. CD56 positive cells were observed in perifascicular regions. Patient discontinued Pembrolizumab and received corticosteroid treatment with progressive clinical improvement and CK normalization. Our findings support this clinical entity, suggesting that isolated ocular myositis represents a subgroup of generalised myositis with predominant ocular symptoms. Keywords: Ocular myositis Immune checkpoint inhibitors-related Myositis (irMyositis) Idiopathic inflammatory myopathies Immune checkpoint inhibitors (ICIs) Anti-PD-1 Pembrolizumab Care Report Introduction Immune check point inhibitors (ICIs) are a novel class of anti-tumor agents which have been linked to several neurological adverse event (irAE) including myositis (irMyositis), myocarditis and myasthenia.(1,2) Overlapping irMyositis with myocarditis or myasthenia has been reported in approximately 32% and 5% of cases respectively.(3) Conversely, while ocular involvement has been frequently observed in patients with generalized irMyositis and/or myasthenia, (4–6) only few 3
ICIs-related ocular myositis
cases have been reported with isolated ocular myositis.(6-8) We report extensive clinical, serological, histological and neuroimaging data from a patient with clinically isolated ICIs-related ocular myositis, supporting the evidence of a more generalized muscle involvement underlying clinical presentation. Case Report A 66-years-old man was addressed to our attention because of subacute presentation of painless ophthalmoplegia and bilateral eyelid ptosis. He was receiving Pembrolizumab - Lenvatinib association for 6 weeks, because of metastatic renal carcinoma (Fuhrman score: 2; pTNM:1b). Routine laboratory analysis, including CK level, tested until few days after the second infusion of Pembrolizumab, were unremarkable. He started to complain about ocular symptoms 2 weeks after the second infusion of Pembrolizumab. CK level raised up to to 5.026 UI/L. Thyroid function assessed by circulating free thyroxines (T3 and T4) was constantly normal with negative antithyroglobulin and thyroperoxidase antibodies. Only a transitory and mild elevation of TSH was observed. Clinical examination showed complete, non-fluctuating, external ophthalmoplegia with bilateral eyelid ptosis without orbicularis oculi weakness (Fig.1,A). No proximal, distal or axial muscular weakness was detected. Electromyography showed short and small motor unit action potential (MUAP) in orbicularis oculi and proximal muscles with spontaneous activity, consistent with myopathic pattern. Neuromuscular transmission defect was ruled out by evidence of normal repetitive nerve stimulation and single fibre-EMG performed on orbicularis oculi muscle, and negative anti-acetylcholine receptor and anti- muscle specific kinase (MuSK) antibodies. Full panels of myositis specific antibodies (MSA) and myositis associated antibodies (MAA) were negative, as well as antibodies associated to paraneoplastic syndromes, including anti-striational antibodies. Cardiac and respiratory evaluations were unremarkable. Whole body muscle MRI did not show significant fibro-fatty replacement in T1 sequences nor positive STIR images, whereas orbital MRI still showed bilateral hyperintensities in inferior rectus, medial rectus and superior 4
ICIs-related ocular myositis
oblique muscles in both T1 and STIR sequences with mild muscle atrophy (Fig.1,B). Deltoid muscle biopsy showed mixed lymphocytic/macrophagic endomysial inflammatory infiltrates, with prevalent CD8 and CD68 cells, sometimes expressing PD-1 or PD-L1 antigens. Sarcolemmal and cytoplasmic MHC-I overexpression was observed in clusters of non-necrotic cells. CD56 positive cells were also observed in perifascicular regions (Fig.2). Patient discontinued Pembrolizumab and received corticosteroid treatment with progressive clinical improvement and CK normalization. Discussion Overall incidence of neurological irAE during ICIs treatments ranges from 0.2 to 12% depending on severity of irAE.(1) Neuromuscular side-effects occurs in about 1% of patients treated by ICIs.(3) irMyositis seems to occur more frequently in association with anti-PD1 agents, in particular Pembrolizumab,(3) whereas isolated ocular myositis has been reported in few reports after anti-PD1 or -CTLA4 treatments.(6–8) Ocular involvement is frequently observed among both irMyositis and irMyasthenia. Careful clinical examination, searching for signs of fatigability, is mandatory to distinguish between ocular symptoms related to neuromuscular transmission defect or to primary muscle inflammation. Our patient showed a external ophthalmoplegia, improved after treatment, without signs of fatigability and negative AChR and MuSK antibodies. Anti-striational antibodies, recently reported in association with irMyositis (68% of patients) but resulted negative in our patient, had also been previously associated with Myasthenia-Myositis association with thymoma.(4) It leads to suppose a possible common pathogenic pathway between ICIs- and thymoma-associated myositis/myasthenia, as autoimmune-iatrogenic response in the former and paraneoplastic in the latter, both associated to anti-striational antibodies.(9) Isolated ocular myositis represents a peculiar manifestation of irMyositis and has been rarely reported as irAE. Interestingly, in our patient the muscle biopsy collected from an asymptomatic and STIR negative muscle showed inflammatory infiltrates. In accordance to previous observations, these findings suggest that a subclinical, generalised myositis occurs also in patients with clinically isolated ocular 5
ICIs-related ocular myositis
myositis (9), as also recently observed by Touat et al. in one patient (p7) of their cohort, showing isolated ocular myositis and inflammation at muscle biopsy.(6) Unfortunately, none of the other cases of ocular myositis reported in literature included extensive muscle biopsy data.(7,8) In this prospective, isolated ocular myositis should be considered a subgroup of irMyositis with predominant ocular presentation. This hypothesis is also supported by the evidence that isolated ocular myositis can be associated with myocarditis(8) or irMyositis.(6) It could be assumed that predominant ocular involvement could be due to the presence of specific autoantigens expressed in extraocular muscles, consistently with evidence that extraocular muscle are specifically affected or spared in several inherited muscle diseases, suggesting a specific pattern of gene expression in extraocular muscles. The occurrence of ICIs-related ocular myositis suggests that ocular muscles could be specifically involved in autoimmune processes, leading to speculate that autoimmune aetiology could also exist among patients with unexplained eyelid ptosis and ophthalmoplegia. In fact, idiopathic ocular myositis is a not well investigated clinical entity, most often reported in association with other autoimmune diseases (such as sarcoidosis, systemic lupus erythematosus, Crohn’s disease or vasculitis), thyroid pathology, infectious diseases or malignancy.(10) Conclusions Our findings suggest that isolated ocular myositis during ICIs treatment represents a subgroup of generalised irMyositis with predominant ocular symptoms. ICIs-related ocular myositis proves that extraocular muscles can be electively involved in autoimmune processes. More evidences are warranted to support these data in order to better understand this probably underrecognized clinical entity. References 1. Touat M, Talmasov D, Ricard D, Psimaras D. Neurological toxicities associated with immunecheckpoint inhibitors. Curr Opin Neurol. 2017 Dec;30(6):659–68. 2. Suzuki S, Ishikawa N, Konoeda F, Seki N, Fukushima S, Takahashi K, et al. Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan. Neurology. 2017 Sep 12;89(11):1127–34. 6
ICIs-related ocular myositis
3. Moreira A, Loquai C, Pföhler C, Kähler KC, Knauss S, Heppt MV, et al. Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors. Eur J Cancer. 2019 Jan;106:12–23. 4. Seki M, Uruha A, Ohnuki Y, Kamada S, Noda T, Onda A, et al. Inflammatory myopathy associated with PD-1 inhibitors. J Autoimmun. 2019 Jun;100:105–13. 5. Kamo H, Hatano T, Kanai K, Aoki N, Kamiyama D, Yokoyama K, et al. Pembrolizumabrelated systemic myositis involving ocular and hindneck muscles resembling myasthenic gravis: a case report. BMC Neurol. 2019 Aug 5;19(1):184. 6. Touat M, Maisonobe T, Knauss S, Ben Hadj Salem O, Hervier B, Auré K, et al. Immune checkpoint inhibitor-related myositis and myocarditis in patients with cancer. Neurology. 2018 Sep 4;91(10):e985–94. 7. Pushkarevskaya A, Neuberger U, Dimitrakopoulou-Strauss A, Enk A, Hassel JC. Severe Ocular Myositis After Ipilimumab Treatment for Melanoma: A Report of 2 Cases. J Immunother. 2017;40(7):282–5. 8. Hellman JB, Traynis I, Lin LK. Pembrolizumab and epacadostat induced fatal myocarditis and myositis presenting as a case of ptosis and ophthalmoplegia. Orbit. 2018 Jul 9;1–4. 9. Garibaldi M, Fionda L, Vanoli F, Leonardi L, Loreti S, Bucci E, et al. Muscle involvement in myasthenia gravis: Expanding the clinical spectrum of myasthenia-myositis association from a large cohort of patients. Autoimmunity Reviews. 2020 Feb 14;102498. 10. Fraser CL, Skalicky SE, Gurbaxani A, McCluskey P. Ocular myositis. Curr Allergy Asthma Rep. 2013 Jun;13(3):315–21.
7
ICIs-related ocular myositis
Fig.1. Clinico-radiological findings. A: Clinical presentation before (left) and post (right) corticosteroid treatment. B: ocular MRI showing bilateral mild STIR hyperintensity of medial rectus, inferior rectus and superior oblique muscles (arrows), and focal T1signal in superior oblique and inferior rectus muscle with mild atrophy of all muscles.
8
ICIs-related ocular myositis
Fig.2. Muscle biopsy. A-F: transverse (frozen) and longitudinal (paraffin) sections form deltoid muscle biopsy showing endomysial inflammatory infiltrates (A,B) with prevalent CD8 (C) and CD68 (D) positive cells, showing occasional PD-1 positive lymphocytes (E) and PD-L1 positive macrophages (F); perimysial CD56 positive muscle cells (G); sarcolemmal and sarcoplasmic MHCI expression in muscle fibres (H).
9
Immune checkpoint inhibitors (ICIs)-related ocular myositis Matteo Garibaldi , Fabio Calabro` , Gioia Merlonghi , Silvia Pugliese , Marco Ceccanti , Lara Cristiano , Tommaso Tartaglione , Antonio Petrucci PII: DOI: Reference:
S0960-8966(20)30039-0 https://doi.org/10.1016/j.nmd.2020.02.013 NMD 3807
To appear in:
Neuromuscular Disorders
Received date: Revised date: Accepted date:
25 June 2019 15 January 2020 18 February 2020
Please cite this article as: Matteo Garibaldi , Fabio Calabro` , Gioia Merlonghi , Silvia Pugliese , Marco Ceccanti , Lara Cristiano , Tommaso Tartaglione , Antonio Petrucci , Immune checkpoint inhibitors (ICIs)-related ocular myositis, Neuromuscular Disorders (2020), doi: https://doi.org/10.1016/j.nmd.2020.02.013
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier B.V.
ICIs-related ocular myositis Highlights
Clinically isolated ocular involvement can occur during ICIs treatment Muscle biopsy showed subclinical generalized myositis despite normal muscle MRI Ocular myositis represents a peculiar subgroup of generalized Checkpoint Inhibitors-related Myositis (irMyositis) Extraocular muscles can be predominantly involved in autoimmune processes Autoimmune ocular myositis could exist among unexplained ptosis/ophthalmoplegia
1
ICIs-related ocular myositis
Immune checkpoint inhibitors (ICIs)-related ocular myositis Authors and institutional affiliations: Matteo Garibaldi1, Fabio Calabrò2, Gioia Merlonghi1, Silvia Pugliese3, Marco Ceccanti4, Lara Cristiano5, Tommaso Tartaglione5, Antonio Petrucci6 1. Neuromuscular Disease Centre, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), SAPIENZA University of Rome, Sant'Andrea Hospital, Rome, Italy 2. Department of Medical Oncology, San Camillo Forlanini Hospital, Rome, Italy 3. Department of Radiology, Policlinico Tor Vergata, Rome, Italy 4. Rare Neuromuscular Diseases Centre, Department of Human Neuroscience, SAPIENZA University, Rome, Italy 5. Department of Radiology, Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy. 6. Department of Neuroscience, San Camillo-Forlanini Hospital, Rome, Italy
Total word count: 889 Corresponding author: Matteo GARIBALDI, MD, PhD Unit of Neuromuscular Diseases Department of Neurology Mental Health and Sensory Organs (NESMOS) Faculty of Medicine and Psychology SAPIENZA University of Rome Sant'Andrea Hospital Via di Grottarossa 1035-1039 00189 Roma Tel. +39 06 33775937 Fax: +39 06 33775900 Mail: [email protected]
Contribution and disclosures: MG: study concept, design and supervision, acquisition and interpretation of data, manuscript writing, responsibility for the integrity of the study; GM: histoenzymologyl and immunohistochemisty studies, analysis and interpretation of the data; SP, LC, TT: muscle and orbital imaging studies, analysis and interpretation of the data; FC, MC, AP: study concept, acquisition of clinical data, critical revision of the manuscript for intellectual content. All authors read and approved the final manuscript. None of the authors has conflicts of interest that could influence the work. 2
ICIs-related ocular myositis
Abstract We present extensive clinical, serological, morphological and muscle imaging data of a 66 years old man with isolated bilateral ptosis and external ophthalmoplegia secondary to Immune check point inhibitors (Pembrolizumab). He had elevated CK level (>5000 UI/L). No facial, bulbar, proximal, distal or axial muscular weakness was observed. Electromyography (EMG) showed myopathic pattern, with spontaneous activity. Myositis specific antibodies and anti-striational antibodies were negative. Cardiac and respiratory functions were preserved. Muscle MRI was unremarkable, whereas orbital MRI revealed bilateral hyperintensities in inferior rectus, medial rectus and superior oblique muscles in both T1 and STIR sequences, with mild muscle atrophy. Muscle biopsy showed endomysial inflammatory infiltrates, MHC-1 expression was observed in clusters of non-necrotic cells. CD56 positive cells were observed in perifascicular regions. Patient discontinued Pembrolizumab and received corticosteroid treatment with progressive clinical improvement and CK normalization. Our findings support this clinical entity, suggesting that isolated ocular myositis represents a subgroup of generalised myositis with predominant ocular symptoms. Keywords: Ocular myositis Immune checkpoint inhibitors-related Myositis (irMyositis) Idiopathic inflammatory myopathies Immune checkpoint inhibitors (ICIs) Anti-PD-1 Pembrolizumab Care Report Introduction Immune check point inhibitors (ICIs) are a novel class of anti-tumor agents which have been linked to several neurological adverse event (irAE) including myositis (irMyositis), myocarditis and myasthenia.(1,2) Overlapping irMyositis with myocarditis or myasthenia has been reported in approximately 32% and 5% of cases respectively.(3) Conversely, while ocular involvement has been frequently observed in patients with generalized irMyositis and/or myasthenia, (4–6) only few 3
ICIs-related ocular myositis
cases have been reported with isolated ocular myositis.(6-8) We report extensive clinical, serological, histological and neuroimaging data from a patient with clinically isolated ICIs-related ocular myositis, supporting the evidence of a more generalized muscle involvement underlying clinical presentation. Case Report A 66-years-old man was addressed to our attention because of subacute presentation of painless ophthalmoplegia and bilateral eyelid ptosis. He was receiving Pembrolizumab - Lenvatinib association for 6 weeks, because of metastatic renal carcinoma (Fuhrman score: 2; pTNM:1b). Routine laboratory analysis, including CK level, tested until few days after the second infusion of Pembrolizumab, were unremarkable. He started to complain about ocular symptoms 2 weeks after the second infusion of Pembrolizumab. CK level raised up to to 5.026 UI/L. Thyroid function assessed by circulating free thyroxines (T3 and T4) was constantly normal with negative antithyroglobulin and thyroperoxidase antibodies. Only a transitory and mild elevation of TSH was observed. Clinical examination showed complete, non-fluctuating, external ophthalmoplegia with bilateral eyelid ptosis without orbicularis oculi weakness (Fig.1,A). No proximal, distal or axial muscular weakness was detected. Electromyography showed short and small motor unit action potential (MUAP) in orbicularis oculi and proximal muscles with spontaneous activity, consistent with myopathic pattern. Neuromuscular transmission defect was ruled out by evidence of normal repetitive nerve stimulation and single fibre-EMG performed on orbicularis oculi muscle, and negative anti-acetylcholine receptor and anti- muscle specific kinase (MuSK) antibodies. Full panels of myositis specific antibodies (MSA) and myositis associated antibodies (MAA) were negative, as well as antibodies associated to paraneoplastic syndromes, including anti-striational antibodies. Cardiac and respiratory evaluations were unremarkable. Whole body muscle MRI did not show significant fibro-fatty replacement in T1 sequences nor positive STIR images, whereas orbital MRI still showed bilateral hyperintensities in inferior rectus, medial rectus and superior 4
ICIs-related ocular myositis
oblique muscles in both T1 and STIR sequences with mild muscle atrophy (Fig.1,B). Deltoid muscle biopsy showed mixed lymphocytic/macrophagic endomysial inflammatory infiltrates, with prevalent CD8 and CD68 cells, sometimes expressing PD-1 or PD-L1 antigens. Sarcolemmal and cytoplasmic MHC-I overexpression was observed in clusters of non-necrotic cells. CD56 positive cells were also observed in perifascicular regions (Fig.2). Patient discontinued Pembrolizumab and received corticosteroid treatment with progressive clinical improvement and CK normalization. Discussion Overall incidence of neurological irAE during ICIs treatments ranges from 0.2 to 12% depending on severity of irAE.(1) Neuromuscular side-effects occurs in about 1% of patients treated by ICIs.(3) irMyositis seems to occur more frequently in association with anti-PD1 agents, in particular Pembrolizumab,(3) whereas isolated ocular myositis has been reported in few reports after anti-PD1 or -CTLA4 treatments.(6–8) Ocular involvement is frequently observed among both irMyositis and irMyasthenia. Careful clinical examination, searching for signs of fatigability, is mandatory to distinguish between ocular symptoms related to neuromuscular transmission defect or to primary muscle inflammation. Our patient showed a external ophthalmoplegia, improved after treatment, without signs of fatigability and negative AChR and MuSK antibodies. Anti-striational antibodies, recently reported in association with irMyositis (68% of patients) but resulted negative in our patient, had also been previously associated with Myasthenia-Myositis association with thymoma.(4) It leads to suppose a possible common pathogenic pathway between ICIs- and thymoma-associated myositis/myasthenia, as autoimmune-iatrogenic response in the former and paraneoplastic in the latter, both associated to anti-striational antibodies.(9) Isolated ocular myositis represents a peculiar manifestation of irMyositis and has been rarely reported as irAE. Interestingly, in our patient the muscle biopsy collected from an asymptomatic and STIR negative muscle showed inflammatory infiltrates. In accordance to previous observations, these findings suggest that a subclinical, generalised myositis occurs also in patients with clinically isolated ocular 5
ICIs-related ocular myositis
myositis (9), as also recently observed by Touat et al. in one patient (p7) of their cohort, showing isolated ocular myositis and inflammation at muscle biopsy.(6) Unfortunately, none of the other cases of ocular myositis reported in literature included extensive muscle biopsy data.(7,8) In this prospective, isolated ocular myositis should be considered a subgroup of irMyositis with predominant ocular presentation. This hypothesis is also supported by the evidence that isolated ocular myositis can be associated with myocarditis(8) or irMyositis.(6) It could be assumed that predominant ocular involvement could be due to the presence of specific autoantigens expressed in extraocular muscles, consistently with evidence that extraocular muscle are specifically affected or spared in several inherited muscle diseases, suggesting a specific pattern of gene expression in extraocular muscles. The occurrence of ICIs-related ocular myositis suggests that ocular muscles could be specifically involved in autoimmune processes, leading to speculate that autoimmune aetiology could also exist among patients with unexplained eyelid ptosis and ophthalmoplegia. In fact, idiopathic ocular myositis is a not well investigated clinical entity, most often reported in association with other autoimmune diseases (such as sarcoidosis, systemic lupus erythematosus, Crohn’s disease or vasculitis), thyroid pathology, infectious diseases or malignancy.(10) Conclusions Our findings suggest that isolated ocular myositis during ICIs treatment represents a subgroup of generalised irMyositis with predominant ocular symptoms. ICIs-related ocular myositis proves that extraocular muscles can be electively involved in autoimmune processes. More evidences are warranted to support these data in order to better understand this probably underrecognized clinical entity. References 1. Touat M, Talmasov D, Ricard D, Psimaras D. Neurological toxicities associated with immunecheckpoint inhibitors. Curr Opin Neurol. 2017 Dec;30(6):659–68. 2. Suzuki S, Ishikawa N, Konoeda F, Seki N, Fukushima S, Takahashi K, et al. Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan. Neurology. 2017 Sep 12;89(11):1127–34. 6
ICIs-related ocular myositis
3. Moreira A, Loquai C, Pföhler C, Kähler KC, Knauss S, Heppt MV, et al. Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors. Eur J Cancer. 2019 Jan;106:12–23. 4. Seki M, Uruha A, Ohnuki Y, Kamada S, Noda T, Onda A, et al. Inflammatory myopathy associated with PD-1 inhibitors. J Autoimmun. 2019 Jun;100:105–13. 5. Kamo H, Hatano T, Kanai K, Aoki N, Kamiyama D, Yokoyama K, et al. Pembrolizumabrelated systemic myositis involving ocular and hindneck muscles resembling myasthenic gravis: a case report. BMC Neurol. 2019 Aug 5;19(1):184. 6. Touat M, Maisonobe T, Knauss S, Ben Hadj Salem O, Hervier B, Auré K, et al. Immune checkpoint inhibitor-related myositis and myocarditis in patients with cancer. Neurology. 2018 Sep 4;91(10):e985–94. 7. Pushkarevskaya A, Neuberger U, Dimitrakopoulou-Strauss A, Enk A, Hassel JC. Severe Ocular Myositis After Ipilimumab Treatment for Melanoma: A Report of 2 Cases. J Immunother. 2017;40(7):282–5. 8. Hellman JB, Traynis I, Lin LK. Pembrolizumab and epacadostat induced fatal myocarditis and myositis presenting as a case of ptosis and ophthalmoplegia. Orbit. 2018 Jul 9;1–4. 9. Garibaldi M, Fionda L, Vanoli F, Leonardi L, Loreti S, Bucci E, et al. Muscle involvement in myasthenia gravis: Expanding the clinical spectrum of myasthenia-myositis association from a large cohort of patients. Autoimmunity Reviews. 2020 Feb 14;102498. 10. Fraser CL, Skalicky SE, Gurbaxani A, McCluskey P. Ocular myositis. Curr Allergy Asthma Rep. 2013 Jun;13(3):315–21.
7
ICIs-related ocular myositis
Fig.1. Clinico-radiological findings. A: Clinical presentation before (left) and post (right) corticosteroid treatment. B: ocular MRI showing bilateral mild STIR hyperintensity of medial rectus, inferior rectus and superior oblique muscles (arrows), and focal T1signal in superior oblique and inferior rectus muscle with mild atrophy of all muscles.
8
ICIs-related ocular myositis
Fig.2. Muscle biopsy. A-F: transverse (frozen) and longitudinal (paraffin) sections form deltoid muscle biopsy showing endomysial inflammatory infiltrates (A,B) with prevalent CD8 (C) and CD68 (D) positive cells, showing occasional PD-1 positive lymphocytes (E) and PD-L1 positive macrophages (F); perimysial CD56 positive muscle cells (G); sarcolemmal and sarcoplasmic MHCI expression in muscle fibres (H).
9