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Inclusion body myositis and sarcoid myopathy: Coincidental occurrence or associated diseases
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Case report
Inclusion body myositis and sarcoid myopathy: Coincidental occurrence or associated diseases Oranee Sanmaneechai a,b,*, Andrea Swenson a, Alicia K. Gerke c, Steven A. Moore d, Michael E. Shy a a Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City, Iowa Division of Neurology, Department of Pediatrics, Siriraj Hosptial, Mahidol University, Bangkok, Thailand c Department of Internal Medicine, Pulmonary, Critical Care and Occupational Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa d Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, Iowa Received 27 October 2014; received in revised form 28 November 2014; accepted 11 December 2014 b
Abstract Inclusion body myositis (IBM) is a slowly progressive inflammatory myopathy characterized by selective weakness of finger flexors and quadriceps muscles commonly refractory to treatment. Another chronic inflammatory disorder, sarcoidosis, commonly involves muscle. The comorbidity of inclusion body myositis and sarcoid myopathy is rare. We describe clinical and muscle biopsy findings of a patient with sarcoidosis and inclusion body myositis. A 66-year-old man presented with a 6-year history of progressive, asymmetrical and selective weakness of the quadriceps, biceps and finger flexor muscles; he had a remote history of pulmonary sarcoidosis. A quadriceps muscle biopsy revealed a chronic inflammatory myopathy with ubiquitinated inclusion bodies, rimmed vacuoles, expression of major histocompatibility complex class I, numerous COX-negative fibers and TDP-43 cytoplasmic aggregates (features of IBM) and multiple non-necrotizing granulomata (feature of sarcoidosis). Clinical and histopathologic features of the current illness suggested the patient had sarcoidosis with inclusion body myositis overlap. This patient may represent the coincidental occurrence of both idiopathic inflammatory disorders. Alternatively, sarcoidoisis may promote the development of inclusion body myositis by a similar immune-mediated pathophysiologic process. © 2014 Elsevier B.V. All rights reserved. Keywords: Inclusion body myositis; Sarcoidosis; SARCOID myopathy; Non-caseating granuloma; Muscle biopsy; Rimmed vacuoles
1. Introduction
2. Patient and methods
Sporadic inclusion body myositis (IBM) is a slowly progressive, degenerative inflammatory myopathy characterized by selective finger flexor and quadriceps muscle weakness, rimmed vacuoles in the muscle biopsy, and refractoriness to treatment. The association of IBM with sarcoidosis, a multisystem disease with non-caseating granulomata in affected organs is rare, but has been reported [1–4]. Here, we describe a patient with a remote history of pulmonary sarcoidosis who developed clinical characteristics of IBM. His muscle biopsy showed hallmarks of both IBM and sarcoid myopathy.
A 66-year-old Caucasian man presented with a 6-year history of slowly progressive thigh, arm and hand muscle weakness and atrophy. He had progressive difficulty climbing stairs followed by difficulty in lifting weights, cutting food, and opening bottles and jars. The thigh, arm and forearm muscle atrophy was prominent. He walked with a cane and experienced trips or falls 10–15 times a year. He denied foot drop, but reported numbness, burning and tingling in his toes up to the ankles. He reported swallowing difficulty and choking on both solids and liquids. He had no rash, chest pain, cough or difficulty breathing. His family history was significant for sarcoidosis in a female cousin. He himself was diagnosed with pulmonary sarcoidosis at age 30 years on the basis of chest pain, hilar lymphadenopathy by chest radiographs, and noncaseating granulomata detected in a mediastinal biopsy obtained by mediastinoscopy. At the time of his diagnosis, he denied any muscle weakness and neurological examination was normal. He responded at that time to 2 months treatment with high dose oral corticosteroids and required no further
* Corresponding author. Division of Neurology, Department of Pediatrics, Siriraj Hospital, Mahidol University, 2 Prannok Road, Bangkoknoi, Bangkok, Thailand. Tel.: +662 419 5890; Cell: +6685 333 6777; fax: +662 411 3010; +622 418 2238. E-mail address: [email protected] (O. Sanmaneechai). http://dx.doi.org/10.1016/j.nmd.2014.12.005 0960-8966/© 2014 Elsevier B.V. All rights reserved.
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treatment. In his current evaluation the chest examination was normal. Severe muscle atrophy was noted in biceps, forearm and quadriceps muscles, bilaterally. He had asymmetrical weakness in his upper extremities. There was also weakness in the biceps (R3, L4), wrist extensors (R4, L4−), finger extensors (R4, L4−), finger flexors (R3, L3), hip flexion (R4, L4) and quadriceps (R4−, L4+) muscles by the Medical Research Council (MRC) Scale. Deltoid, triceps, ankle dorsi-flexion, plantar-flexion, toe extension and flexion were of normal strength. Light touch, pinprick and proprioceptive sensation were normal. Vibration sensation was reduced at his toes and normal at his ankles, knees, and upper extremities, bilaterally. Reflexes were 2 + throughout. His gait was waddling. He could not heel, toe or tandem walk. The Romberg sign was negative. A full workup, including complete blood cell count (CBC), chemistry profile, vitamin B1, B6, B12, folate, angiotensinconverting enzyme (ACE), thyroid-stimulating hormone (TSH), erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA), immunoelectrophoresis, and rapid plasma regain (RPR) was performed to exclude possible systemic disorders. These tests were all normal. The serum creatine kinase (CK) level was mildly elevated at 478 U/L (normal range, 40–200 U/L). Electrodiagnostic studies revealed distal axonal sensorimotor polyneuropathy. Peroneal motor and sural sensory responses were absent. Motor and sensory responses at the upper extremity were normal. There was electrophysiologic evidence of myopathic change affecting the forearm muscles.
Chest CT and pulmonary function tests were performed to look for any active evidence of pulmonary sarcoidosis. CT scan of the chest showed extensive calcified lymphadenopathy in the mediastinum and hilar regions, a small focal area of consolidation in the right upper lobe, and bronchiectasis and collapse in the right middle lobe, suggesting post-inflammatory scarring. Pulmonary function tests were normal. MRI of the entire spine was unremarkable. The echocardiogram showed no evidence of pulmonary hypertension. Barium swallow evaluation showed that he had a weak swallow and pharyngeal delay. Esophagram was normal. 3. Results A right quadriceps muscle biopsy revealed multiple, non-necrotizing granulomata in the endomysial, perimysial, and epimysial compartments and a chronic inflammatory necrotizing myopathy with rimmed vacuoles and ubiquitinated inclusion bodies (Fig. 1). Immunofluorescence studies showed strong, diffuse sarcolemmal staining for major histocompatibility complex (MHC) class I. TDP-43-positive cytoplasmic aggregates and TDP-43-negative nuclei were observed by immunoperoxidase staining of paraffin sections (Fig. 2B). Cytochrome C oxidase (COX) staining of cryosections revealed numerous fibers that failed to stain (Fig. 2D). Neither TDP-43-positive cytoplasmic aggregates nor COX-negative fibers were observed in the muscle biopsy from another patient manifesting only sarcoid myopathy (Fig. 2A and
Fig. 1. Muscle biopsy histopathology. Non-necrotizing granulomata were numerous and located in endomysial, perimysial and epimysial compartments of the muscle biopsy. Epitheloid macrophages with lymphocytes (thin arrows) were noted in cryosection H&E stained sections (A), but were best appreciated in paraffin H&E sections (B). Macrophages, lymphocytes, and the sarcolemma of muscle fibers (m) all strongly expressed MHC class I. The granuloma is marked by thin arrows (C). Non-granulomatous myositis was also widespread in the biopsy and associated with active myonecrosis (thick arrows) (D). Rimmed vacuoles (RV) were numerous in several muscle fibers (E). Ubiquitinated inclusion bodies (thin arrows) were easily identified (F). The size marker is 100 µm in panels A–D and 50 µm in panels E–F. Please cite this article in press as: Oranee Sanmaneechai, Andrea Swenson, Alicia K. Gerke, Steven A. Moore, Michael E. Shy, Inclusion body myositis and sarcoid myopathy: Coincidental occurrence or associated diseases, Neuromuscular Disorders (2015), doi: 10.1016/j.nmd.2014.12.005
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Fig. 2. TDP-43 immunoperoxidase and cytochrome C oxidase (COX) enzyme histochemistry. The muscle biopsy from a sarcoid myopathy patient was compared to our patient. In the sarcoid myopathy patient (A), TDP-43 (brown staining) was exclusively in the normal intranuclear location. In contrast, our patient’s biopsy (B) contained several unstained nuclei and numerous cytoplasmic TDP-43-positive aggregates. All muscle fibers from the sarcoid myopathy patient stained positively for COX (C), while numerous COX-negative fibers were observed in our patient (D). The size marker is 50 µm.
C, respectively). The expression of MHC class I at the sarcolemma of muscle fibers in this latter patient was multifocal in a pattern associated with the granulomata (data not shown). Given the unclear relationship between the features suggesting IBM and those suggesting sarcoidosis and the potential responsiveness of sarcoid myopathy to antiinflammatory treatment [5], oral prednisone was initiated and titrated up to the dose of 60 mg daily for two months. After no clinically significant improvement was observed, methotrexate was added to the regimen. Methotrexate was titrated up to 15 mg weekly, along with leucovorin 5 mg weekly. Over 6 months, the corticosteroids are tapered to a dose of 20 mg daily. After the addition of methotrexate to the corticosteroids, the patient improved by history. Muscle strength was improved in biceps (R4+ , L5) and quadriceps (R5, L5) muscles and partially improved in finger flexor muscles (R4−, L4−). Swallowing difficulty was improved by history after medical treatment and speech therapy. 4. Discussion IBM is a slowly progressive degenerative inflammatory myopathy of unknown cause that is particularly common in male patients over the age of 50 years. It is characterized by selective finger flexor and quadriceps muscle weakness, rimmed vacuoles and inclusion bodies in muscle, and refractoriness to treatment [6]. Our patient’s age and clinical findings are suggestive of IBM, although some features such as severe atrophy of the biceps and waddling gait found in this
patient are unusual in sporadic IBM. Surprisingly, a muscle biopsy showed multiple non-necrotizing granulomata in addition to the hallmark histopathology of IBM. Granulomatous myositis is rare and found in only 0.4% of all muscle biopsy specimens in one large reported series; sarcoidosis is the most common cause [7]. Sarcoidosis is a multisystemic inflammatory disorder of unknown etiology, characterized by non-caseating granulomata in affected organs [5]. Muscle involvement is not uncommon in sarcoidosis although this is often asymptomatic; 50–80% of patients with sarcoidosis have demonstrated granulomata on biopsy in some series [8,9]. Symptomatic muscle involvement is less common and can include chronic myopathy as well as acute myositis or nodular involvement [10]. Chronic myopathy from sarcoidosis is characterized by slowly progressive symmetrical proximal muscle weakness and atrophy [10]. To potentially distinguish between sarcoid myopathy and IBM we evaluated TAR DNA-binding protein 43 (TDP-43), cytochrome C oxidase (COX), and MHC class I in the quadriceps biopsy in the patient as compared to a second patient with symptomatic sarcoid myopathy. TDP-43 positive cytoplasmic aggregates are reported to be sensitive markers for IBM [11,12] but have not been reported with sarcoid myopathy. Our patient had multiple TDP-43 aggregates in his biopsy (Fig. 2B). Increased numbers of COX negative fibers are often found in IBM [13] as was the case with our patient (Fig. 2D). Furthermore, MHC class I was strongly positive at the sarcolemma of all muscle fibers in our patient (Fig. 1C),
Please cite this article in press as: Oranee Sanmaneechai, Andrea Swenson, Alicia K. Gerke, Steven A. Moore, Michael E. Shy, Inclusion body myositis and sarcoid myopathy: Coincidental occurrence or associated diseases, Neuromuscular Disorders (2015), doi: 10.1016/j.nmd.2014.12.005
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another characteristic of IBM. Clinically, his pattern of weakness in finger flexors, and the pronounced forearm and biceps atrophy were also suggestive of IBM. Taken together the histolopathologic and clinical studies were consistent with a typical case of IBM, except for the non-caseating granulomata. We think it most likely that the granulomata are residuum of his prior sarcoidosis and not contributing to his current myopathy. However, the presence of distal axonal sensorimotor neuropathies are often associated with sarcoidosis [14] and we cannot exclude the possibility that both disorders were involved in this patient’s overall neuromuscular disease presentation. The association of IBM and sarcoidosis has been reported previously [1–4]. Granulomatous myositis without history or evidence of systemic sarcoidosis that mimics clinical IBM had been previously reported in 3 cases [3]. Vattemi G. et al. identified 27 patients with IBM and 6 patients with pulmonary sarcoidosis from 2952 consecutive muscle biopsies. Seven percent (2/27) of IBM patients had sarcoidosis and 33% (2/6) of sarcoidosis patients had IBM [4]. IBM is associated with various systemic autoimmune disorders in 33% of one series, including autoimmune thyroid disease, rheumatoid arthritis, type I diabetes mellitus, Sjögren disease, psoriasis, vitiligo, celiac disease, and ulcerative colitis [15]. Twenty percent of IBM patients had positive autoantibodies in another series, including: ANA, anti-SSA/Ro, anti-SSb/La, antiribonucleoproteins (RNP), anti-Sm, anticardiolipin (ACA), anti-GM1, and rheumatoid factor (RF) [16]. Similarly, sarcoidosis has been associated with autoimmune diseases such as autoimmune thyroid disease [17], psoriasis [18], and celiac disease [19]. It is unclear in these patients whether sarcoidosis or IBM was the primary disease, but interestingly they do share common immune pathways of disease. IBM and sarcoidosis involve Th1-driven immune reactions and they both have a high level of IL-1 expression [20,21]. The modest clinical improvement following treatment might also suggest a contribution from sarcoidosis to his myopathy. IBM is most often refractory to treatment with corticosteroids, immunosuppressant, immunomodulatory, or IVIG therapy [22,23]. A randomized control trial of oral methotrexate for IBM did not slow progression of muscle weakness but did decrease serum creatine kinase activity [24].On the other hand, sarcoid myopathy has been found to improve by corticosteroids alone or in combination with immunosuppressive drugs [5]. Methotrexate, azathioprine, hydroxychloroquine, leflunomide, infliximab, and thalidomide, have been reported to be useful in treating sarcoid myopathy refractory to corticosteroid therapy [25–27]. The response to medications in our patient supports the interpretation that sarcoid myopathy is a clinically significant component of the pathogenesis. Although IBM and sarcoid myopathy comorbidity is rare, recognizing this condition remains important from both prognostic and therapeutic points of view. Prospective muscle studies of patients with systemic sarcoidosis with or without obvious symptoms and signs of myopathy are needed to better understand the nature of muscle involvement and operative mechanisms involved.
References [1] Bouillot S, Coquet M, Ferrer X, et al. Inclusion body myositis associated with sacroidosis: a report of 3 cases. Ann Pathol 2001;21:334–6. [2] Danon MJ, Perurena OH, Ronan S, et al. Inclusion body myositis associated with systemic sarcoidosis. Can J Neurol Sci 1986;13:334–6. [3] LaRue S, Maisonobe T, Benveniste O, et al. Distal muscle involvement in granulomatous myositis can mimic inclusion body myositis. J Neurol Neurosurg Psychiatry 2011;82:674–7. [4] Vattemi G, Tonin P, Marini M, et al. Sarcoidosis and inclusion body myositis. Rheumatology (Oxford) 2008;47:1433–5. [5] Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007;357:2153–65. [6] Greenberg SA. Inclusion body myositis. Curr Opin Rheumatol 2011;23:574–8. [7] Prayson RA. Granulomatous myositis. Clinicopathologic study of 12 cases. Am J Clin Pathol 1999;112:63–8. [8] Awada H, Abi-Karam G, Fayad F. Musculoskeletal and other extrapulmonary disorders in sarcoidosis. Best Pract Res Clin Rheumatol 2003;17:971–87. [9] Silverstein A, Siltzbach LE. Muscle involvement in sarcoidosis. Asymptomatic, myositis, and myopathy. Arch Neurol 1969;21:235–41. [10] Fayad F, Liote F, Berenbaum F, et al. Muscle involvement in sarcoidosis: a retrospective and followup studies. J Rheumatol 2006;33:98–103. [11] Salajegheh M, Pinkus JL, Taylor JP, et al. Sarcoplasmic redistribution of nuclear tdp-43 in inclusion body myositis. Muscle Nerve 2009;40:19–31. [12] Dubourg O, Wanschitz J, Maisonobe T, et al. Diagnostic value of markers of muscle degeneration in sporadic inclusion body myositis. Acta Myol 2011;30:103–8. [13] Chahin N, Engel AG. Correlation of muscle biopsy, clinical course, and outcome in PM and sporadic IBM. Neurology 2008;70:418–24. [14] Tavee JO, Stern BJ. Neurosarcoidosis. Continuum (Minneap Minn) 2014;20:545–59. [15] Badrising UA, Schreuder GM, Giphart MJ, et al. Associations with autoimmune disorders and HLA class I and II antigens in inclusion body myositis. Neurology 2004;63:2396–8. [16] Koffman BM, Rugiero M, Dalakas MC. Immune-mediated conditions and antibodies associated with sporadic inclusion body myositis. Muscle Nerve 1998;21:115–17. [17] Malli F, Bargiota A, Theodoridou K, et al. Increased primary autoimmune thyroid diseases and thyroid antibodies in sarcoidosis: evidence for an under-recognised extrathoracic involvement in sarcoidosis? Hormones (Athens) 2012;11:436–43. [18] Nikolopoulou M, Katsenos S, Psathakis K, et al. Pulmonary sarcoidosis associated with psoriasis vulgaris: coincidental occurrence or causal association? Case report. BMC Pulm Med 2006;6:26. [19] Ludvigsson JF, Wahlstrom J, Grunewald J, et al. Coeliac disease and risk of sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2007;24:121–6. [20] Authier FJ, Mhiri C, Chazaud B, et al. Interleukin-1 expression in inflammatory myopathies: evidence of marked immunoreactivity in sarcoid granulomas and muscle fibres showing ischaemic and regenerative changes. Neuropathol Appl Neurobiol 1997;23:132–40. [21] Schmidt J, Barthel K, Wrede A, et al. Interrelation of inflammation and APP in sIBM: IL-1 beta induces accumulation of beta-amyloid in skeletal muscle. Brain 2008;131:1228–40. [22] Breithaupt M, Schmidt J. Update on treatment of inclusion body myositis. Curr Rheumatol Rep 2013;15:329. [23] Dalakas MC. Sporadic inclusion body myositis-diagnosis, pathogenesis and therapeutic strategies. Nat Clin Pract Neurol 2006;2:437–47. [24] Badrising UA, Maat-Schieman ML, Ferrari MD, et al. Comparison of weakness progression in inclusion body myositis during treatment with methotrexate or placebo. Ann Neurol 2002;51:369–72. [25] Walter MC, Lochmuller H, Schlotter-Weigel B, et al. Successful treatment of muscle sarcoidosis with thalidomide. Acta Myol 2003;22:22–5. [26] Baughman RP, Costabel U, du Bois RM. Treatment of sarcoidosis. Clin Chest Med 2008;29:533–48. [27] Fujita H, Ishimatsu Y, Motomura M, et al. A case of acute sarcoid myositis treated with weekly low-dose methotrexate. Muscle Nerve 2011;44:994–9.
Please cite this article in press as: Oranee Sanmaneechai, Andrea Swenson, Alicia K. Gerke, Steven A. Moore, Michael E. Shy, Inclusion body myositis and sarcoid myopathy: Coincidental occurrence or associated diseases, Neuromuscular Disorders (2015), doi: 10.1016/j.nmd.2014.12.005
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Case report
Inclusion body myositis and sarcoid myopathy: Coincidental occurrence or associated diseases Oranee Sanmaneechai a,b,*, Andrea Swenson a, Alicia K. Gerke c, Steven A. Moore d, Michael E. Shy a a Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City, Iowa Division of Neurology, Department of Pediatrics, Siriraj Hosptial, Mahidol University, Bangkok, Thailand c Department of Internal Medicine, Pulmonary, Critical Care and Occupational Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa d Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, Iowa Received 27 October 2014; received in revised form 28 November 2014; accepted 11 December 2014 b
Abstract Inclusion body myositis (IBM) is a slowly progressive inflammatory myopathy characterized by selective weakness of finger flexors and quadriceps muscles commonly refractory to treatment. Another chronic inflammatory disorder, sarcoidosis, commonly involves muscle. The comorbidity of inclusion body myositis and sarcoid myopathy is rare. We describe clinical and muscle biopsy findings of a patient with sarcoidosis and inclusion body myositis. A 66-year-old man presented with a 6-year history of progressive, asymmetrical and selective weakness of the quadriceps, biceps and finger flexor muscles; he had a remote history of pulmonary sarcoidosis. A quadriceps muscle biopsy revealed a chronic inflammatory myopathy with ubiquitinated inclusion bodies, rimmed vacuoles, expression of major histocompatibility complex class I, numerous COX-negative fibers and TDP-43 cytoplasmic aggregates (features of IBM) and multiple non-necrotizing granulomata (feature of sarcoidosis). Clinical and histopathologic features of the current illness suggested the patient had sarcoidosis with inclusion body myositis overlap. This patient may represent the coincidental occurrence of both idiopathic inflammatory disorders. Alternatively, sarcoidoisis may promote the development of inclusion body myositis by a similar immune-mediated pathophysiologic process. © 2014 Elsevier B.V. All rights reserved. Keywords: Inclusion body myositis; Sarcoidosis; SARCOID myopathy; Non-caseating granuloma; Muscle biopsy; Rimmed vacuoles
1. Introduction
2. Patient and methods
Sporadic inclusion body myositis (IBM) is a slowly progressive, degenerative inflammatory myopathy characterized by selective finger flexor and quadriceps muscle weakness, rimmed vacuoles in the muscle biopsy, and refractoriness to treatment. The association of IBM with sarcoidosis, a multisystem disease with non-caseating granulomata in affected organs is rare, but has been reported [1–4]. Here, we describe a patient with a remote history of pulmonary sarcoidosis who developed clinical characteristics of IBM. His muscle biopsy showed hallmarks of both IBM and sarcoid myopathy.
A 66-year-old Caucasian man presented with a 6-year history of slowly progressive thigh, arm and hand muscle weakness and atrophy. He had progressive difficulty climbing stairs followed by difficulty in lifting weights, cutting food, and opening bottles and jars. The thigh, arm and forearm muscle atrophy was prominent. He walked with a cane and experienced trips or falls 10–15 times a year. He denied foot drop, but reported numbness, burning and tingling in his toes up to the ankles. He reported swallowing difficulty and choking on both solids and liquids. He had no rash, chest pain, cough or difficulty breathing. His family history was significant for sarcoidosis in a female cousin. He himself was diagnosed with pulmonary sarcoidosis at age 30 years on the basis of chest pain, hilar lymphadenopathy by chest radiographs, and noncaseating granulomata detected in a mediastinal biopsy obtained by mediastinoscopy. At the time of his diagnosis, he denied any muscle weakness and neurological examination was normal. He responded at that time to 2 months treatment with high dose oral corticosteroids and required no further
* Corresponding author. Division of Neurology, Department of Pediatrics, Siriraj Hospital, Mahidol University, 2 Prannok Road, Bangkoknoi, Bangkok, Thailand. Tel.: +662 419 5890; Cell: +6685 333 6777; fax: +662 411 3010; +622 418 2238. E-mail address: [email protected] (O. Sanmaneechai). http://dx.doi.org/10.1016/j.nmd.2014.12.005 0960-8966/© 2014 Elsevier B.V. All rights reserved.
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treatment. In his current evaluation the chest examination was normal. Severe muscle atrophy was noted in biceps, forearm and quadriceps muscles, bilaterally. He had asymmetrical weakness in his upper extremities. There was also weakness in the biceps (R3, L4), wrist extensors (R4, L4−), finger extensors (R4, L4−), finger flexors (R3, L3), hip flexion (R4, L4) and quadriceps (R4−, L4+) muscles by the Medical Research Council (MRC) Scale. Deltoid, triceps, ankle dorsi-flexion, plantar-flexion, toe extension and flexion were of normal strength. Light touch, pinprick and proprioceptive sensation were normal. Vibration sensation was reduced at his toes and normal at his ankles, knees, and upper extremities, bilaterally. Reflexes were 2 + throughout. His gait was waddling. He could not heel, toe or tandem walk. The Romberg sign was negative. A full workup, including complete blood cell count (CBC), chemistry profile, vitamin B1, B6, B12, folate, angiotensinconverting enzyme (ACE), thyroid-stimulating hormone (TSH), erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA), immunoelectrophoresis, and rapid plasma regain (RPR) was performed to exclude possible systemic disorders. These tests were all normal. The serum creatine kinase (CK) level was mildly elevated at 478 U/L (normal range, 40–200 U/L). Electrodiagnostic studies revealed distal axonal sensorimotor polyneuropathy. Peroneal motor and sural sensory responses were absent. Motor and sensory responses at the upper extremity were normal. There was electrophysiologic evidence of myopathic change affecting the forearm muscles.
Chest CT and pulmonary function tests were performed to look for any active evidence of pulmonary sarcoidosis. CT scan of the chest showed extensive calcified lymphadenopathy in the mediastinum and hilar regions, a small focal area of consolidation in the right upper lobe, and bronchiectasis and collapse in the right middle lobe, suggesting post-inflammatory scarring. Pulmonary function tests were normal. MRI of the entire spine was unremarkable. The echocardiogram showed no evidence of pulmonary hypertension. Barium swallow evaluation showed that he had a weak swallow and pharyngeal delay. Esophagram was normal. 3. Results A right quadriceps muscle biopsy revealed multiple, non-necrotizing granulomata in the endomysial, perimysial, and epimysial compartments and a chronic inflammatory necrotizing myopathy with rimmed vacuoles and ubiquitinated inclusion bodies (Fig. 1). Immunofluorescence studies showed strong, diffuse sarcolemmal staining for major histocompatibility complex (MHC) class I. TDP-43-positive cytoplasmic aggregates and TDP-43-negative nuclei were observed by immunoperoxidase staining of paraffin sections (Fig. 2B). Cytochrome C oxidase (COX) staining of cryosections revealed numerous fibers that failed to stain (Fig. 2D). Neither TDP-43-positive cytoplasmic aggregates nor COX-negative fibers were observed in the muscle biopsy from another patient manifesting only sarcoid myopathy (Fig. 2A and
Fig. 1. Muscle biopsy histopathology. Non-necrotizing granulomata were numerous and located in endomysial, perimysial and epimysial compartments of the muscle biopsy. Epitheloid macrophages with lymphocytes (thin arrows) were noted in cryosection H&E stained sections (A), but were best appreciated in paraffin H&E sections (B). Macrophages, lymphocytes, and the sarcolemma of muscle fibers (m) all strongly expressed MHC class I. The granuloma is marked by thin arrows (C). Non-granulomatous myositis was also widespread in the biopsy and associated with active myonecrosis (thick arrows) (D). Rimmed vacuoles (RV) were numerous in several muscle fibers (E). Ubiquitinated inclusion bodies (thin arrows) were easily identified (F). The size marker is 100 µm in panels A–D and 50 µm in panels E–F. Please cite this article in press as: Oranee Sanmaneechai, Andrea Swenson, Alicia K. Gerke, Steven A. Moore, Michael E. Shy, Inclusion body myositis and sarcoid myopathy: Coincidental occurrence or associated diseases, Neuromuscular Disorders (2015), doi: 10.1016/j.nmd.2014.12.005
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Fig. 2. TDP-43 immunoperoxidase and cytochrome C oxidase (COX) enzyme histochemistry. The muscle biopsy from a sarcoid myopathy patient was compared to our patient. In the sarcoid myopathy patient (A), TDP-43 (brown staining) was exclusively in the normal intranuclear location. In contrast, our patient’s biopsy (B) contained several unstained nuclei and numerous cytoplasmic TDP-43-positive aggregates. All muscle fibers from the sarcoid myopathy patient stained positively for COX (C), while numerous COX-negative fibers were observed in our patient (D). The size marker is 50 µm.
C, respectively). The expression of MHC class I at the sarcolemma of muscle fibers in this latter patient was multifocal in a pattern associated with the granulomata (data not shown). Given the unclear relationship between the features suggesting IBM and those suggesting sarcoidosis and the potential responsiveness of sarcoid myopathy to antiinflammatory treatment [5], oral prednisone was initiated and titrated up to the dose of 60 mg daily for two months. After no clinically significant improvement was observed, methotrexate was added to the regimen. Methotrexate was titrated up to 15 mg weekly, along with leucovorin 5 mg weekly. Over 6 months, the corticosteroids are tapered to a dose of 20 mg daily. After the addition of methotrexate to the corticosteroids, the patient improved by history. Muscle strength was improved in biceps (R4+ , L5) and quadriceps (R5, L5) muscles and partially improved in finger flexor muscles (R4−, L4−). Swallowing difficulty was improved by history after medical treatment and speech therapy. 4. Discussion IBM is a slowly progressive degenerative inflammatory myopathy of unknown cause that is particularly common in male patients over the age of 50 years. It is characterized by selective finger flexor and quadriceps muscle weakness, rimmed vacuoles and inclusion bodies in muscle, and refractoriness to treatment [6]. Our patient’s age and clinical findings are suggestive of IBM, although some features such as severe atrophy of the biceps and waddling gait found in this
patient are unusual in sporadic IBM. Surprisingly, a muscle biopsy showed multiple non-necrotizing granulomata in addition to the hallmark histopathology of IBM. Granulomatous myositis is rare and found in only 0.4% of all muscle biopsy specimens in one large reported series; sarcoidosis is the most common cause [7]. Sarcoidosis is a multisystemic inflammatory disorder of unknown etiology, characterized by non-caseating granulomata in affected organs [5]. Muscle involvement is not uncommon in sarcoidosis although this is often asymptomatic; 50–80% of patients with sarcoidosis have demonstrated granulomata on biopsy in some series [8,9]. Symptomatic muscle involvement is less common and can include chronic myopathy as well as acute myositis or nodular involvement [10]. Chronic myopathy from sarcoidosis is characterized by slowly progressive symmetrical proximal muscle weakness and atrophy [10]. To potentially distinguish between sarcoid myopathy and IBM we evaluated TAR DNA-binding protein 43 (TDP-43), cytochrome C oxidase (COX), and MHC class I in the quadriceps biopsy in the patient as compared to a second patient with symptomatic sarcoid myopathy. TDP-43 positive cytoplasmic aggregates are reported to be sensitive markers for IBM [11,12] but have not been reported with sarcoid myopathy. Our patient had multiple TDP-43 aggregates in his biopsy (Fig. 2B). Increased numbers of COX negative fibers are often found in IBM [13] as was the case with our patient (Fig. 2D). Furthermore, MHC class I was strongly positive at the sarcolemma of all muscle fibers in our patient (Fig. 1C),
Please cite this article in press as: Oranee Sanmaneechai, Andrea Swenson, Alicia K. Gerke, Steven A. Moore, Michael E. Shy, Inclusion body myositis and sarcoid myopathy: Coincidental occurrence or associated diseases, Neuromuscular Disorders (2015), doi: 10.1016/j.nmd.2014.12.005
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O. Sanmaneechai et al. / Neuromuscular Disorders ■■ (2015) ■■–■■
another characteristic of IBM. Clinically, his pattern of weakness in finger flexors, and the pronounced forearm and biceps atrophy were also suggestive of IBM. Taken together the histolopathologic and clinical studies were consistent with a typical case of IBM, except for the non-caseating granulomata. We think it most likely that the granulomata are residuum of his prior sarcoidosis and not contributing to his current myopathy. However, the presence of distal axonal sensorimotor neuropathies are often associated with sarcoidosis [14] and we cannot exclude the possibility that both disorders were involved in this patient’s overall neuromuscular disease presentation. The association of IBM and sarcoidosis has been reported previously [1–4]. Granulomatous myositis without history or evidence of systemic sarcoidosis that mimics clinical IBM had been previously reported in 3 cases [3]. Vattemi G. et al. identified 27 patients with IBM and 6 patients with pulmonary sarcoidosis from 2952 consecutive muscle biopsies. Seven percent (2/27) of IBM patients had sarcoidosis and 33% (2/6) of sarcoidosis patients had IBM [4]. IBM is associated with various systemic autoimmune disorders in 33% of one series, including autoimmune thyroid disease, rheumatoid arthritis, type I diabetes mellitus, Sjögren disease, psoriasis, vitiligo, celiac disease, and ulcerative colitis [15]. Twenty percent of IBM patients had positive autoantibodies in another series, including: ANA, anti-SSA/Ro, anti-SSb/La, antiribonucleoproteins (RNP), anti-Sm, anticardiolipin (ACA), anti-GM1, and rheumatoid factor (RF) [16]. Similarly, sarcoidosis has been associated with autoimmune diseases such as autoimmune thyroid disease [17], psoriasis [18], and celiac disease [19]. It is unclear in these patients whether sarcoidosis or IBM was the primary disease, but interestingly they do share common immune pathways of disease. IBM and sarcoidosis involve Th1-driven immune reactions and they both have a high level of IL-1 expression [20,21]. The modest clinical improvement following treatment might also suggest a contribution from sarcoidosis to his myopathy. IBM is most often refractory to treatment with corticosteroids, immunosuppressant, immunomodulatory, or IVIG therapy [22,23]. A randomized control trial of oral methotrexate for IBM did not slow progression of muscle weakness but did decrease serum creatine kinase activity [24].On the other hand, sarcoid myopathy has been found to improve by corticosteroids alone or in combination with immunosuppressive drugs [5]. Methotrexate, azathioprine, hydroxychloroquine, leflunomide, infliximab, and thalidomide, have been reported to be useful in treating sarcoid myopathy refractory to corticosteroid therapy [25–27]. The response to medications in our patient supports the interpretation that sarcoid myopathy is a clinically significant component of the pathogenesis. Although IBM and sarcoid myopathy comorbidity is rare, recognizing this condition remains important from both prognostic and therapeutic points of view. Prospective muscle studies of patients with systemic sarcoidosis with or without obvious symptoms and signs of myopathy are needed to better understand the nature of muscle involvement and operative mechanisms involved.
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Please cite this article in press as: Oranee Sanmaneechai, Andrea Swenson, Alicia K. Gerke, Steven A. Moore, Michael E. Shy, Inclusion body myositis and sarcoid myopathy: Coincidental occurrence or associated diseases, Neuromuscular Disorders (2015), doi: 10.1016/j.nmd.2014.12.005