- Email: [email protected]
Sporadic inclusion body myositis: Diagnostic value of p62 immunostaining
Med Clin (Barc). 2019;153(11):437–440
www.elsevier.es/medicinaclinica
Clinical report
Sporadic inclusion body myositis: Diagnostic value of p62 immunostaining José C. Milisenda a,∗,1 , Ana Matas García a,1 , Cristina Jou b,c , Iago Pinal-Fernandez d , Albert Selva O’Callaghan e , Josep María Grau a a Muscle Research Unit, Internal Medicine Service, Hospital Clínic de Barcelona, Universidad de Barcelona and Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain b Department of Neurology, Neuromuscular Units, Hospital Sant Joan de Déu, Instituto de Salud Carlos III, Barcelona, Spain c Center for Biomedical Research on Rare Diseases (CIBERER), Institute of Pediatric Research Sant Joan de Déu, Madrid, Spain d National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA e Internal Medicine Service, Hospital Universitari Vall d’Hebron, Barcelona, Spain
a r t i c l e
i n f o
Article history: Received 29 March 2019 Accepted 4 April 2019 Available online 26 June 2019 Keywords: sIBM Polymyositis Inflammatory myopathies P62 Myositis
a b s t r a c t Background and objectives: Sporadic inclusion body myositis (sIBM) diagnosis is frequently delayed or confused with another class of disorders, and misdiagnosis is common. Sometimes, we have problems diagnosing an sIBM in the early stages or predicting when a PM is going to become an sIBM. In this sense, we believe that p62 immunostaining could help clinicians. Case report: We report the case of a 61-year-old patient with sIBM who six years earlier had been diagnosed with polymyositis (PM). After muscle biopsies analyses, we showed the natural history of sIBM by p62 expression. Results: When we looked for p62 aggregates retrospectively we could see small dotted p62 aggregates in the muscle fibres of the first muscle biopsy. Six years later, the patient presented with the typical clinical picture of sIBM, also the muscle biopsy was characteristic, with large p62 aggregates. Conclusions: Probably p62 immunostaining could help to distinguish PM patients that are going to become sIBM, but to date there has been no systematic study to clarify p62 utility in myositis. ˜ S.L.U. All rights reserved. © 2019 Elsevier Espana,
Miositis con cuerpos de inclusión: valor de la inmunohistoquímica para p62 en su diagnóstico r e s u m e n Palabras clave: MCI Polimiositis Miopatías inflamatorias P62 Miositis
Fundamento y objetivo: El diagnóstico de la miositis por cuerpos de inclusión en su forma esporádica (MCI) con frecuencia se retrasa o se confunde con otra clase de trastornos. En ocasiones, surgen problemas para diagnosticar una MCI en estadios iniciales. En este sentido, pensamos que la inmunohistoquímica para p62 podría ser una herramienta de gran utilidad para el diagnóstico. ˜ con MCI que seis anos ˜ antes recibió Observación clínica: Presentamos el caso de un paciente de 61 anos el diagnóstico de polimiositis (PM). Después de analizar las biopsias musculares realizadas, mostramos la historia natural de la MCI a través de la expresión de p62. ˜ agregados Resultados: Cuando buscamos los agregados de p62 retrospectivamente pudimos ver pequenos ˜ más tarde, coincidiendo con el cuadro de p62 en las fibras musculares de la primera biopsia. Seis anos de presentación clínica, típico de MCI, la biopsia muscular resultó característica, mostrando grandes agregados de p62.
∗ Corresponding author. E-mail address: [email protected] (J.C. Milisenda). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.medcli.2019.04.022 ˜ S.L.U. All rights reserved. 2387-0206 0025-7753/© 2019 Elsevier Espana,
438
J.C. Milisenda et al. / Med Clin (Barc). 2019;153(11):437–440
Conclusiones: Probablemente la inmunotinción para p62 ayudaría a distinguir los pacientes con diagnóstico de PM que posteriormente van a convertirse en MCI, pero hasta ahora no hay un estudio sistemático para dilucidar la utilidad de p62 en miositis. ˜ S.L.U. Todos los derechos reservados. © 2019 Elsevier Espana,
Introduction
Discussion
In 1975 Bohan and Peter1 did not recognize sporadic inclusion body myositis (sIBM) as a specific entity and such patients would have been probably classified as having polymyositis. Now, we know that sIBM is distinguished from other inflammatory myopathies by its clinical (progressive course, the selective pattern of muscle involvement and poor response to immune therapies) and histopathological (combination of inflammatory and myodegenerative features) characteristics. The sensitivity and specificity of existing criteria for sIBM have been reviewed recently and found to have high specificity but variable sensitivity, with problems to the diagnosis of sIBM in early stages or to predict when polymyositis (PM) is going to become an sIBM.2 In this sense, most studies have analyzed SMI-131, TDP43 and p62 immunostainings, and it seems that p62 is the most useful. Here, we report an sIBM case, showing p62 expression both at the beginning of the disease, when the patient received the diagnosis of PM, and 6 years later when he clinically configured the typical phenotype of sIBM.
There have been multiple attempts for developing sIBM diagnostic criteria using certain pathological and clinical features. The most widely used criteria for the diagnosis of polymyositis and dermatomyositis, which are Bohan and Peter criteria, came from 1975. These include two clinical features (symmetric proximal muscle weakness and typical DM rash), one laboratory finding (elevated serum muscle enzymes) and one electrodiagnostic feature (myopathic changes in EMG). Four of these criteria are required for a definite diagnosis, three for a probable disease and only two criteria for a possible disease, either DM or PM, and the skin rash, which distinguish PM from DM.3 It was not until 1995 when the ‘Griggs criteria’ became the established formal diagnostic criteria for sIBM. Differently from the Bohan and Peter criteria, Griggs criteria were heavily biased towards pathological features and diagnosis can only be made if all three pathological features were present, that is, (inflammatory infiltrate with partial invasion of muscle cells, rimmed vacuoles, and either amyloid deposits or 15–18-nm tubofilaments, independent of the clinical features) (picture C in Fig. 3). In the absence of pathological features, only a possible diagnosis of sIBM can be considered if characteristic clinical features are present. Nevertheless, since each individual pathological feature is not specific for sIBM, diagnostic problems could appear when an uncomplete histological pattern is found, requiring diagnosis confirmation by repeating the muscle biopsy.2,4 In concordance with this, an overweight of histopathological changes instead of clinical features leads to an underdiagnosis of sIBM and overdiagnosis of PM.5 Since the Griggs criteria, a number of diagnostic criteria for IBM have been put forward. The most recent is the European Neuromuscular Centre 2011 criteria (ENMC) that allow a diagnosis of sIBM in the absence of the classically considered essential pathological features. The ENMC criteria divided sort patients into two large subgroups, those with typical clinical and pathological features (‘clinico-pathologically defined sIBM’), and those with typical clinical features but limited pathological changes (‘clinically defined sIBM’). Also, patients presenting characteristic upper or lower limb pattern of weakness, but not both, could be recognized as having a (‘probable sIBM’). In fact, in 2013 Brady et al. demonstrated that 88% of patients receiving a certainty sIBM diagnosis fulfilled the ENMC criteria, but only 27% fulfilled the Griggs criteria.6 Putting everything into account, it seems that clinical features considered in the diagnostic criteria can be as specific in diagnosing sIBM as pathological features and have substantially greater sensitivity at the time of presentation. As discussed above, after two decades of clinical experience, the main drift has been for increased importance to be given to specific clinical features since in many cases long-term follow-up of patients presenting clinical features in the absence of pathological ones leaves the clinician in no doubt about the correct diagnosis. We believe the present case represents the “natural history” of a typical case of sIBM, starting as a PM and becoming an sIBM some years later. This is an interesting case from the histopathological point of view since the patient did not have distal weakness
Case report A 61-year-old male with a medical history of hypertension, dyslipidemia, and asymptomatic hyperuricemia started six years before the present evaluation with progressive proximal muscle weakness, along with increased muscle damage markers. A muscle biopsy was performed, receiving the diagnosis of PM based on endomysial and perivascular inflammatory infiltrate with partial invasion cell of non-necrotic fibres by T lymphocytes in deltoid muscle biopsy. At the beginning he remained stable, he refused to take any medication, and we lost the follow-up. Four years later, he came back to the visit, with severe proximal weakness of upper and lower limbs, so treatment with prednisone and methotrexate was started with poor response. Six years later, the patient was reevaluated due to the progressive proximal and distal weakness in both upper (deltoid 5/5, biceps 4/5) and lower (right quadriceps 2/5, left quadriceps 3/5, gastrocnemius 4/5) limbs, with involvement of finger flexors (2/5) (pictures A and B in Figs. 1 and 2). Also, marked dysphagia to liquids and solids, and frequent falls with difficulty to get up off the ground were objectivated. A mildly elevated creatine kinase (CK) levels (470 UI/L) and aldolase (8.7 UI/L) was also noticed. In addition, during the followup, positivity to antibody anti-cN1A was demonstrated. Whereas in the first biopsy a PM pattern was observed (picture A in Fig. 3), a second muscle biopsy showed the typical sIBM picture with prominent rimmed vacuoles with inflammatory features (picture C in Fig. 3). When we looked for the p62 aggregates retrospectively, we could see small dotted p62 aggregates in the muscle fibres that were predominantly expressed in the vacuoles (picture B in Fig. 3). After performing a second biopsy six years later, we found a significant positivity for p62, with small positive dots distributed throughout the sarcoplasm of a high number of fibres forming large p62 aggregates into the muscle fibres (picture D in Fig. 3).
J.C. Milisenda et al. / Med Clin (Barc). 2019;153(11):437–440
439
Fig. 1. (A, B) The typical clinical picture of sIBM. Quadriceps muscle and finger flexor atrophy (arrows).
Fig. 2. Muscle weakness distribution. (A) At initial diagnosis (PM). (B) Six years later (sIBM). Proximal weakness ( weakness (
); dysphagia (
); distal weakness (
); asymmetric
).
(picture A in Fig. 2) and in his first muscle biopsy, a clear PM pattern was observed (picture A in Fig. 3). When we looked for the p62 aggregates retrospectively we could see small dotted p62 aggregates in the muscle fibres (picture B in Fig. 3). Six years later, the patient presented with the typical clinical picture of sIBM (pictures A and B in Fig. 1, and B in Fig. 2), also the muscle biopsy was characteristic, and we could see large p62 aggregates (picture D in Fig. 3). Also, p62% of the muscle area was quantified at the beginning and six years later (Fig. 4). There is still a debate as to whether sIBM is primarily autoimmune in origin or a degenerative myopathy with a secondary
inflammatory/immune response.7 Because the physiopathological mechanism is unknown, there is not a gold standard for its diagnosis and some controversies regarding the classification criteria are still present. A combination of rimmed vacuoles, a characteristic pattern of p62 staining, and increased sarcolemmal and sarcoplasmic MHC I expression had a sensitivity of 93% and a specificity of 100% for sIBM. Characteristic p62 staining in the absence of rimmed vacuoles had a specificity of 91% for sIBM, but a sensitivity of only 44%.7-9 So, the main problem is to identify patients with sIBM in the early stages. Probably p62 immunostaining could help the clinicians in
440
J.C. Milisenda et al. / Med Clin (Barc). 2019;153(11):437–440
Fig. 3. (A and B) Muscle biopsy at the beginning of the disease. (A) Cross-sectional H&E stained muscle-biopsy sample with endomysial inflammatory infiltrate invading non-necrotic cells (arrows). PM Pattern. (B) Double-immunofluorescence with an antibody against p62 (green) combined with an antibody for spectrin (red). Little dots inside of some muscle fibres can be seen (arrows). (C and D) Muscle biopsy six years after the first one. (C) Cross-sectional H&E stained muscle-biopsy sample with numerous rimmed vacuoles (arrows). (D) Double-immunofluorescence with an antibody against p62 (green) combined with an antibody for spectrin (red). Large p62 aggregates into the muscle fibres (arrows).
p62 Expression (% muscle area)
Informed consent
5
Written informed consent was obtained from the patient described in the case report. The patient has also agreed on publishing the pictures included in this manuscript.
4
Conflict of interest
3
The authors declare no conflicts of interest.
2
References 1
0
PM diagnosis
Six years later
Fig. 4. p62% of the muscle area, at the beginning and six years later. The amount of p62 in the biopsies was quantified using “Image J” software.
order to distinguish PM patients that are going to become sIBM, but there are a lot of questions to answer before we really know the true diagnostic value of this histological marker is, such as if there’s a typical and unique pattern of p62 in sIBM, or what is the positivity in other inflammatory and non-inflammatory myopathies. Until now there is not a systematic study to dilucidated the utility of p62 in myositis, however, further revision of diagnostic criteria is now necessary given the new immunological, and possibly imaging, developments.
1. Bohan A, Peter JB. Polymyositis and dermatomyositis. N Engl J Med. 1975;292:344–7. 2. Hilton-Jones D, Brady S. Diagnostic criteria for inclusion body myositis. J Intern Med. 2016;280:52–62. 3. Raychaudhuri S, Mitra A. Polymyositis and dermatomyositis: disease spectrum and classification. Indian J Dermatol. 2012;57:366. 4. Greenberg SA. Inclusion body myositis. Contin Lifelong Learn Neurol. 2016;22:1871–88. 5. Chahin N, Engel AG. Correlation of muscle biopsy, clinical course, and outcome in PM and sporadic IBM. Neurology. 2008;70:418–24. 6. Brady S, Squier W, Hilton-Jones D. Clinical assessment determines the diagnosis of inclusion body myositis independently of pathological features. J Neurol Neurosurg Psychiatry. 2013;84:1240–6. 7. Mastaglia FL, Needham M. Inclusion body myositis: a review of clinical and genetic aspects, diagnostic criteria and therapeutic approaches. J Clin Neurosci. 2015;22:6–13. 8. Lloyd TE, Mammen AL, Amato AA, Weiss MD, Needham M, Greenberg SA. Evaluation and construction of diagnostic criteria for inclusion body myositis. Neurology. 2014;83:426–33. 9. Brady S, Squier W, Sewry C, Hanna M, Hilton-Jones D, Holton JL. A retrospective cohort study identifying the principal pathological features useful in the diagnosis of inclusion body myositis. BMJ Open. 2014;4:e004552.
www.elsevier.es/medicinaclinica
Clinical report
Sporadic inclusion body myositis: Diagnostic value of p62 immunostaining José C. Milisenda a,∗,1 , Ana Matas García a,1 , Cristina Jou b,c , Iago Pinal-Fernandez d , Albert Selva O’Callaghan e , Josep María Grau a a Muscle Research Unit, Internal Medicine Service, Hospital Clínic de Barcelona, Universidad de Barcelona and Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain b Department of Neurology, Neuromuscular Units, Hospital Sant Joan de Déu, Instituto de Salud Carlos III, Barcelona, Spain c Center for Biomedical Research on Rare Diseases (CIBERER), Institute of Pediatric Research Sant Joan de Déu, Madrid, Spain d National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA e Internal Medicine Service, Hospital Universitari Vall d’Hebron, Barcelona, Spain
a r t i c l e
i n f o
Article history: Received 29 March 2019 Accepted 4 April 2019 Available online 26 June 2019 Keywords: sIBM Polymyositis Inflammatory myopathies P62 Myositis
a b s t r a c t Background and objectives: Sporadic inclusion body myositis (sIBM) diagnosis is frequently delayed or confused with another class of disorders, and misdiagnosis is common. Sometimes, we have problems diagnosing an sIBM in the early stages or predicting when a PM is going to become an sIBM. In this sense, we believe that p62 immunostaining could help clinicians. Case report: We report the case of a 61-year-old patient with sIBM who six years earlier had been diagnosed with polymyositis (PM). After muscle biopsies analyses, we showed the natural history of sIBM by p62 expression. Results: When we looked for p62 aggregates retrospectively we could see small dotted p62 aggregates in the muscle fibres of the first muscle biopsy. Six years later, the patient presented with the typical clinical picture of sIBM, also the muscle biopsy was characteristic, with large p62 aggregates. Conclusions: Probably p62 immunostaining could help to distinguish PM patients that are going to become sIBM, but to date there has been no systematic study to clarify p62 utility in myositis. ˜ S.L.U. All rights reserved. © 2019 Elsevier Espana,
Miositis con cuerpos de inclusión: valor de la inmunohistoquímica para p62 en su diagnóstico r e s u m e n Palabras clave: MCI Polimiositis Miopatías inflamatorias P62 Miositis
Fundamento y objetivo: El diagnóstico de la miositis por cuerpos de inclusión en su forma esporádica (MCI) con frecuencia se retrasa o se confunde con otra clase de trastornos. En ocasiones, surgen problemas para diagnosticar una MCI en estadios iniciales. En este sentido, pensamos que la inmunohistoquímica para p62 podría ser una herramienta de gran utilidad para el diagnóstico. ˜ con MCI que seis anos ˜ antes recibió Observación clínica: Presentamos el caso de un paciente de 61 anos el diagnóstico de polimiositis (PM). Después de analizar las biopsias musculares realizadas, mostramos la historia natural de la MCI a través de la expresión de p62. ˜ agregados Resultados: Cuando buscamos los agregados de p62 retrospectivamente pudimos ver pequenos ˜ más tarde, coincidiendo con el cuadro de p62 en las fibras musculares de la primera biopsia. Seis anos de presentación clínica, típico de MCI, la biopsia muscular resultó característica, mostrando grandes agregados de p62.
∗ Corresponding author. E-mail address: [email protected] (J.C. Milisenda). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.medcli.2019.04.022 ˜ S.L.U. All rights reserved. 2387-0206 0025-7753/© 2019 Elsevier Espana,
438
J.C. Milisenda et al. / Med Clin (Barc). 2019;153(11):437–440
Conclusiones: Probablemente la inmunotinción para p62 ayudaría a distinguir los pacientes con diagnóstico de PM que posteriormente van a convertirse en MCI, pero hasta ahora no hay un estudio sistemático para dilucidar la utilidad de p62 en miositis. ˜ S.L.U. Todos los derechos reservados. © 2019 Elsevier Espana,
Introduction
Discussion
In 1975 Bohan and Peter1 did not recognize sporadic inclusion body myositis (sIBM) as a specific entity and such patients would have been probably classified as having polymyositis. Now, we know that sIBM is distinguished from other inflammatory myopathies by its clinical (progressive course, the selective pattern of muscle involvement and poor response to immune therapies) and histopathological (combination of inflammatory and myodegenerative features) characteristics. The sensitivity and specificity of existing criteria for sIBM have been reviewed recently and found to have high specificity but variable sensitivity, with problems to the diagnosis of sIBM in early stages or to predict when polymyositis (PM) is going to become an sIBM.2 In this sense, most studies have analyzed SMI-131, TDP43 and p62 immunostainings, and it seems that p62 is the most useful. Here, we report an sIBM case, showing p62 expression both at the beginning of the disease, when the patient received the diagnosis of PM, and 6 years later when he clinically configured the typical phenotype of sIBM.
There have been multiple attempts for developing sIBM diagnostic criteria using certain pathological and clinical features. The most widely used criteria for the diagnosis of polymyositis and dermatomyositis, which are Bohan and Peter criteria, came from 1975. These include two clinical features (symmetric proximal muscle weakness and typical DM rash), one laboratory finding (elevated serum muscle enzymes) and one electrodiagnostic feature (myopathic changes in EMG). Four of these criteria are required for a definite diagnosis, three for a probable disease and only two criteria for a possible disease, either DM or PM, and the skin rash, which distinguish PM from DM.3 It was not until 1995 when the ‘Griggs criteria’ became the established formal diagnostic criteria for sIBM. Differently from the Bohan and Peter criteria, Griggs criteria were heavily biased towards pathological features and diagnosis can only be made if all three pathological features were present, that is, (inflammatory infiltrate with partial invasion of muscle cells, rimmed vacuoles, and either amyloid deposits or 15–18-nm tubofilaments, independent of the clinical features) (picture C in Fig. 3). In the absence of pathological features, only a possible diagnosis of sIBM can be considered if characteristic clinical features are present. Nevertheless, since each individual pathological feature is not specific for sIBM, diagnostic problems could appear when an uncomplete histological pattern is found, requiring diagnosis confirmation by repeating the muscle biopsy.2,4 In concordance with this, an overweight of histopathological changes instead of clinical features leads to an underdiagnosis of sIBM and overdiagnosis of PM.5 Since the Griggs criteria, a number of diagnostic criteria for IBM have been put forward. The most recent is the European Neuromuscular Centre 2011 criteria (ENMC) that allow a diagnosis of sIBM in the absence of the classically considered essential pathological features. The ENMC criteria divided sort patients into two large subgroups, those with typical clinical and pathological features (‘clinico-pathologically defined sIBM’), and those with typical clinical features but limited pathological changes (‘clinically defined sIBM’). Also, patients presenting characteristic upper or lower limb pattern of weakness, but not both, could be recognized as having a (‘probable sIBM’). In fact, in 2013 Brady et al. demonstrated that 88% of patients receiving a certainty sIBM diagnosis fulfilled the ENMC criteria, but only 27% fulfilled the Griggs criteria.6 Putting everything into account, it seems that clinical features considered in the diagnostic criteria can be as specific in diagnosing sIBM as pathological features and have substantially greater sensitivity at the time of presentation. As discussed above, after two decades of clinical experience, the main drift has been for increased importance to be given to specific clinical features since in many cases long-term follow-up of patients presenting clinical features in the absence of pathological ones leaves the clinician in no doubt about the correct diagnosis. We believe the present case represents the “natural history” of a typical case of sIBM, starting as a PM and becoming an sIBM some years later. This is an interesting case from the histopathological point of view since the patient did not have distal weakness
Case report A 61-year-old male with a medical history of hypertension, dyslipidemia, and asymptomatic hyperuricemia started six years before the present evaluation with progressive proximal muscle weakness, along with increased muscle damage markers. A muscle biopsy was performed, receiving the diagnosis of PM based on endomysial and perivascular inflammatory infiltrate with partial invasion cell of non-necrotic fibres by T lymphocytes in deltoid muscle biopsy. At the beginning he remained stable, he refused to take any medication, and we lost the follow-up. Four years later, he came back to the visit, with severe proximal weakness of upper and lower limbs, so treatment with prednisone and methotrexate was started with poor response. Six years later, the patient was reevaluated due to the progressive proximal and distal weakness in both upper (deltoid 5/5, biceps 4/5) and lower (right quadriceps 2/5, left quadriceps 3/5, gastrocnemius 4/5) limbs, with involvement of finger flexors (2/5) (pictures A and B in Figs. 1 and 2). Also, marked dysphagia to liquids and solids, and frequent falls with difficulty to get up off the ground were objectivated. A mildly elevated creatine kinase (CK) levels (470 UI/L) and aldolase (8.7 UI/L) was also noticed. In addition, during the followup, positivity to antibody anti-cN1A was demonstrated. Whereas in the first biopsy a PM pattern was observed (picture A in Fig. 3), a second muscle biopsy showed the typical sIBM picture with prominent rimmed vacuoles with inflammatory features (picture C in Fig. 3). When we looked for the p62 aggregates retrospectively, we could see small dotted p62 aggregates in the muscle fibres that were predominantly expressed in the vacuoles (picture B in Fig. 3). After performing a second biopsy six years later, we found a significant positivity for p62, with small positive dots distributed throughout the sarcoplasm of a high number of fibres forming large p62 aggregates into the muscle fibres (picture D in Fig. 3).
J.C. Milisenda et al. / Med Clin (Barc). 2019;153(11):437–440
439
Fig. 1. (A, B) The typical clinical picture of sIBM. Quadriceps muscle and finger flexor atrophy (arrows).
Fig. 2. Muscle weakness distribution. (A) At initial diagnosis (PM). (B) Six years later (sIBM). Proximal weakness ( weakness (
); dysphagia (
); distal weakness (
); asymmetric
).
(picture A in Fig. 2) and in his first muscle biopsy, a clear PM pattern was observed (picture A in Fig. 3). When we looked for the p62 aggregates retrospectively we could see small dotted p62 aggregates in the muscle fibres (picture B in Fig. 3). Six years later, the patient presented with the typical clinical picture of sIBM (pictures A and B in Fig. 1, and B in Fig. 2), also the muscle biopsy was characteristic, and we could see large p62 aggregates (picture D in Fig. 3). Also, p62% of the muscle area was quantified at the beginning and six years later (Fig. 4). There is still a debate as to whether sIBM is primarily autoimmune in origin or a degenerative myopathy with a secondary
inflammatory/immune response.7 Because the physiopathological mechanism is unknown, there is not a gold standard for its diagnosis and some controversies regarding the classification criteria are still present. A combination of rimmed vacuoles, a characteristic pattern of p62 staining, and increased sarcolemmal and sarcoplasmic MHC I expression had a sensitivity of 93% and a specificity of 100% for sIBM. Characteristic p62 staining in the absence of rimmed vacuoles had a specificity of 91% for sIBM, but a sensitivity of only 44%.7-9 So, the main problem is to identify patients with sIBM in the early stages. Probably p62 immunostaining could help the clinicians in
440
J.C. Milisenda et al. / Med Clin (Barc). 2019;153(11):437–440
Fig. 3. (A and B) Muscle biopsy at the beginning of the disease. (A) Cross-sectional H&E stained muscle-biopsy sample with endomysial inflammatory infiltrate invading non-necrotic cells (arrows). PM Pattern. (B) Double-immunofluorescence with an antibody against p62 (green) combined with an antibody for spectrin (red). Little dots inside of some muscle fibres can be seen (arrows). (C and D) Muscle biopsy six years after the first one. (C) Cross-sectional H&E stained muscle-biopsy sample with numerous rimmed vacuoles (arrows). (D) Double-immunofluorescence with an antibody against p62 (green) combined with an antibody for spectrin (red). Large p62 aggregates into the muscle fibres (arrows).
p62 Expression (% muscle area)
Informed consent
5
Written informed consent was obtained from the patient described in the case report. The patient has also agreed on publishing the pictures included in this manuscript.
4
Conflict of interest
3
The authors declare no conflicts of interest.
2
References 1
0
PM diagnosis
Six years later
Fig. 4. p62% of the muscle area, at the beginning and six years later. The amount of p62 in the biopsies was quantified using “Image J” software.
order to distinguish PM patients that are going to become sIBM, but there are a lot of questions to answer before we really know the true diagnostic value of this histological marker is, such as if there’s a typical and unique pattern of p62 in sIBM, or what is the positivity in other inflammatory and non-inflammatory myopathies. Until now there is not a systematic study to dilucidated the utility of p62 in myositis, however, further revision of diagnostic criteria is now necessary given the new immunological, and possibly imaging, developments.
1. Bohan A, Peter JB. Polymyositis and dermatomyositis. N Engl J Med. 1975;292:344–7. 2. Hilton-Jones D, Brady S. Diagnostic criteria for inclusion body myositis. J Intern Med. 2016;280:52–62. 3. Raychaudhuri S, Mitra A. Polymyositis and dermatomyositis: disease spectrum and classification. Indian J Dermatol. 2012;57:366. 4. Greenberg SA. Inclusion body myositis. Contin Lifelong Learn Neurol. 2016;22:1871–88. 5. Chahin N, Engel AG. Correlation of muscle biopsy, clinical course, and outcome in PM and sporadic IBM. Neurology. 2008;70:418–24. 6. Brady S, Squier W, Hilton-Jones D. Clinical assessment determines the diagnosis of inclusion body myositis independently of pathological features. J Neurol Neurosurg Psychiatry. 2013;84:1240–6. 7. Mastaglia FL, Needham M. Inclusion body myositis: a review of clinical and genetic aspects, diagnostic criteria and therapeutic approaches. J Clin Neurosci. 2015;22:6–13. 8. Lloyd TE, Mammen AL, Amato AA, Weiss MD, Needham M, Greenberg SA. Evaluation and construction of diagnostic criteria for inclusion body myositis. Neurology. 2014;83:426–33. 9. Brady S, Squier W, Sewry C, Hanna M, Hilton-Jones D, Holton JL. A retrospective cohort study identifying the principal pathological features useful in the diagnosis of inclusion body myositis. BMJ Open. 2014;4:e004552.