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Year : 2019  |  Volume : 62  |  Issue : 1  |  Page : 61-66
Juvenile idiopathic inflammatory myopathies: A clinicopathological study with emphasis on muscle histology

1 Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
2 Department of Rheumatology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
3 Department of Neurology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
4 Department of Pediatric Neurology, Rainbow Hospital, Hyderabad, Telangana, India
5 Department of Neurology, Institute of Neurological Sciences, Care Hospital, Hyderabad, Telangana, India

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Date of Web Publication31-Jan-2019


Background: Juvenile idiopathic inflammatory myopathies (JIIM) are rare and heterogeneous. Subtype identification is important for treatment. Materials and Methods: Patients below 18 years diagnosed as idiopathic inflammatory myopathy (IIM) according to the Bohan and Peter criteria between January 2010 and May 2015 were evaluated with muscle biopsy in the four domains: muscle fiber, inflammation, connective tissue, and vascular, with basic panel of histochemical stains as per recommendations of the European Neuromuscular center (ENMC) workshop 2015. Immunohistochemistry with CD 31 was done to assess capillary density. Results: JIIM constituted 15.25% of IIM with juvenile dermatomyositis (JDM) being the most common subgroup (24/27) followed by juvenile overlap myositis (JOM) (3/27) in association with systemic lupus erythematosus (2) and systemic sclerosis (1). Muscle biopsy in JDM was characterized by perifascicular atrophy, necrosis, degeneration, and regeneration in all and the other features included perivascular inflammation (21), lymphoid aggregates (2), mitochondrial abnormalities (9), sarcoplasmic vacuoles (6), capillary dropout (5), capillary dilatation (6), and perimysial fibrosis (14). JOM was characterized by auto-antibodies and perivascular inflammation. Conclusion: JIIMs were rare and JDM was the most common subtype. Muscle biopsy evaluation as per ENMC criteria characterized the subgroups.

Keywords: European Neuromuscular Center criteria, juvenile dermatomyositis, juvenile idiopathic inflammatory myopathy, juvenile overlap myositis, muscle biopsy

How to cite this article:
Challa S, Hui M, Jakati S, Uppin MS, Rajasekhar L, Kannan MA, Lingappa L, Jagarlapudi MM. Juvenile idiopathic inflammatory myopathies: A clinicopathological study with emphasis on muscle histology. Indian J Pathol Microbiol 2019;62:61-6

How to cite this URL:
Challa S, Hui M, Jakati S, Uppin MS, Rajasekhar L, Kannan MA, Lingappa L, Jagarlapudi MM. Juvenile idiopathic inflammatory myopathies: A clinicopathological study with emphasis on muscle histology. Indian J Pathol Microbiol [serial online] 2019 [cited 2021 Apr 18];62:61-6. Available from: https://www.ijpmonline.org/text.asp?2019/62/1/61/251251

   Introduction Top

The juvenile idiopathic inflammatory myopathies (JIIM) are rare and heterogeneous immune mediated muscle disorders.[1] Identification of the subtypes by muscle biopsy is important for diagnosis and prognosis.[1],[2],[3],[4] Recently, the European Neuromuscular Centre (ENMC) international workshop gave recommendations on muscle biopsy evaluation for accurate diagnosis of idiopathic inflammatory myopathies (IIMs).[5] There were limited number of studies on juvenile dermatomyositis (JDM) from India but none using the ENMC criteria in JIIM; hence this study.[6],[7],[8],[9],[10],[11],[12],[13]

   Materials and Methods Top

This was a retrospective review of case records with histological diagnosis of IIM in the juvenile age (<18 years) seen in the Department of Pathology, university hospital in south India between January 2010 and May 2015. This is a referral pathology department for the pathological studies of nerve and muscle diseases in this region. All the patients fulfilled the diagnostic criteria for IIM proposed by Bohan and Peter.[5] The data collected included as follows: demographic details, clinical characteristics, electrodiagnostic data, serum creatine kinase (CK), and lactate dehydrogenase (LDH). Data regarding serum autoantibodies and magnetic resonance imaging muscle imaging were collected wherever they were done.

Muscle biopsy was done by open method from the vastus lateralis muscle in all the patients. The basic panel of histochemical stains recommended by ENMC 2015 for IIMs include as follows: Hematoxylin and eosin (H and E). ATPase/Myosin fast/slow, nicotinamide adenine dinucleotide hydride tetrazolium reductase (NADH-TR), succinate dehydrogenase (SDH), cytochrome c oxidase (COX) or COX/SDH, Gomori trichrome, Periodic acid Schiff (PAS), oil red o (ORO)/Sudan B, acid phosphatase, nonspecific esterase, and Congo red.[14] It is routine practice in our laboratory to do all the above-mentioned stains on cryostat sections except acid phosphatase and nonspecific esterase. In addition to the basic panel of histochemical stains, immunohistochemistry (IHC) with CD31 (BioGenex, California, USA; ready-to-use) was performed to assess the capillary density in the present study.

Muscle biopsy was evaluated in the four domains as proposed by ENMC 2015[14] in the muscle fiber, inflammatory, connective tissue, and vascular domains and the following features were noted:

  1. Muscle fiber domain: The presence of perifascicular atrophy (PFA), necrosis, degeneration, regeneration, internal nuclei, sarcoplasmic vacuoles, fiber type predominance or atrophy, and mitochondrial abnormalities on MGT, SDH, COX, and COX-SDH
  2. Inflammatory domain: The presence of inflammation, its predominant location in the perimysium/perivascular/endomysial region, nature of infiltrate as predominantly lymphocytic or mononuclear, and formation of lymphoid follicle if any
  3. Connective tissue domain: fibrosis in the perimysial or endomysial region and fragmentation of the perimysium if any
  4. Vascular domain: Thickening of vessel wall, dilated capillaries, swollen endothelial cells, and capillary dropout as on CD31.

IHC for membrane attack complex (MAC), major histocompatibility complex-1 (MHC-1), characterization of inflammatory cells, myosin types, and electron microscopic studies were not done. Scoring tools were not applied and disease outcomes were not analyzed.

   Results Top

Of the total 177 histologically confirmed patients with IIMs, JIIM accounted for 27 (15.25%). The subtype of JIIM included as follows: JDM 24 (88.89%) and juvenile overlap myositis (JOM) three (11.11%).

Juvenile dermatomyositis

There were 14 females and ten males and the age ranged between five and 18 (median 10.5) years. The duration of illness before biopsy varied from 15 days to 18 (median 3) months. Myalgia was present in six and contractures in one patient. Constitutional features such as fever and fatigue were present in 12 and joint pains in two patients. Cutaneous manifestations included as follows: erythematous rash (ten), typical heliotrope rash (five), Gottron's papules (five), diffuse hyperpigmentation (three) and periorbital edema, and puffiness (two). Cutaneous ulceration was seen in two patients. None of the patients showed calcinosis cutis. In addition to proximal muscle weakness (pelvic girdle > shoulder girdle), other features included nasal regurgitation in two, and dysphagia in five patients. The other features included lymphadenopathy and pericardial effusion in one patient each. Serum CK levels were >200 IU/L (295–32,169 IU/L) in 22; they were normal in two and the disease duration was 12 months and 8 months, respectively. Elevated LDH (normal 190–270) was present in 12 patients. Antinuclear antibodies (ANA) were positive in four patients. Electromyography was suggestive of primary muscle disease in the 12 patients in whom it was done [Table 1].
Table 1: Demographic, clinical, and laboratory features of juvenile idiopathic inflammatory myopathies

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Muscle biopsy showed changes in all four domains, with muscle fiber and inflammatory domains being the predominantly involved domains. The muscle fiber changes were seen mostly in the perifascicular area in the form of atrophy, degeneration, regeneration, and necrosis. PFA was seen in all patients with JDM and infarction in one. PFA was highlighted on ATPase stains. PFA was prominent near avascular perimysium. Mitochondrial changes in the form of COX-negative fibers but retained SDH activity in the perifascicular area were seen in nine biopsies. There were no red ragged fibers. Sarcoplasmic vacuoles were seen in six biopsies which were negative for glycogen and neutral lipid on PAS and ORO, respectively [Figure 1]. Internal nuclei were seen in regenerating fibers. The inflammation was seen in 21 biopsies, predominantly in the perivascular and perimysial region with extension into endomysium in eight biopsies. The infiltrate was predominantly lymphocytic in 19, predominantly mononuclear in two, and absent in three. Lymphoid aggregates were seen in two biopsies; however, there was no follicle formation [Figure 2]. Perimysial fibrosis was seen in 14 biopsies and concomitant endomysial fibrosis in five. Perimysial fragmentation was not seen. Vascular abnormalities were present in all biopsies with thick vessels in ten biopsies. The capillary dropout was seen predominantly in the perifascicular area in five and neovascularization with dilated capillaries and swollen endothelial cells were seen in six biopsies [Figure 2]. The other features included type 1 predominance in five and type 2 atrophy in two biopsies [Table 2].
Figure 1: Photomicrographs showing (a and b) perifascicular atrophy (H and E and ATPase 9.4 ×100); (c) regenerating fibers with central nuclei (H and E, ×400); (d) sarcoplasmic vacuoles (H and E, ×400); (e) cytochrome c oxidase deficient fibers in perifascicular area (cytochrome c oxidase ×100); (f) retained activity of succinate dehydrogenase in perifascicular fibers (succinate dehydrogenase ×100)

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Figure 2: Photomicrographs showing (a) neovascularization with perivascular lymphomononuclear infiltrate (H and E, ×400); (b) dense lymphoid aggregate (H and E, ×40); (c and d) capillary loss in the perifascicular area CD 31 (×100, ×400); (e) dilated capillaries CD 31 (×400)

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Table 2: Muscle biopsy features in juvenile idiopathic inflammatory myopathies

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Treatment and course

All patients were treated with oral corticosteroids (prednisolone 2 mg/kg/day) and methotrexate (10 mg/m2/week) subcutaneously. Steroids were tapered with improvement in clinical response. Two patients were initially given methylprednisolone (30 mg/kg/day) to induce remission. A total of 14 patients had monocyclic course with complete response and six of them were lost to follow-up after six months; seven patients had chronic relapsing disease, and three had chronic progressive disease. There were no deaths in the study period.

Juvenile overlap myositis

There were three female patients, with associated systemic lupus erythematosus (SLE) in two patients and systemic sclerosis (SSc) in one patient. Both the patients with associated SLE were 10 years old, had severe limb girdle weakness. ANA and anti-dsDNA were positive in both the patients and in addition anti-Sm and antihistone antibodies were positive in one patient. Muscle biopsy in both the patients showed scattered necrotic and regenerating fibers but no PFA. There was perivascular and endomysial inflammation indicating myositis but no specific vascular changes. There was no inflammation surrounding/invading nonnecrotic muscle fibers [Figure 3]. They were treated with oral steroids and hydroxychloroquine with good response [Table 1].
Figure 3: Photomicrograph shows perivascular lymphomononuclear infiltrate extending into endomysium (H and E, ×100)

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The female associated with systemic sclerosis aged 14 years presented with hyperpigmentation, tight skin, and proximal, trunk-and-neck muscle weakness. Anti-PM/Scl antibodies were positive. Muscle biopsy showed scattered atrophic, necrotic, and degenerating fibers. There was no PFA. There was perivascular and sparse endomysial inflammatory infiltrate [Figure 2]. There was no inflammation surrounding/invading nonnecrotic muscle fibers. The patient was treated with oral steroids and methotrexate with good response [Table 1].

   Discussion Top

In this University hospital – based study, histologically confirmed JIIMs accounted for 15.25% of all the histologically confirmed IIMs and were 5.56-fold less common than adult IIMs, similar to the reported frequency in the other series.[1] JDM was the most common subtype in the present study constituting 88.89% of JIIMs; this observation is in agreement with the observations in the other studies.[2],[3],[13],[15] The associated autoimmune diseases with JOM include as follows: SLE, mixed connective tissue disease and less commonly other autoimmune diseases.[2],[3],[13],[16] The associated auto-immune diseases in this study included SLE and systemic sclerosis.

This is probably the first study on JIIM from India which characterized the histological features using the basic panel of histochemical stains in the four domains of muscle: muscle fiber, inflammatory, connective tissue, and vascular, as proposed in the ENMC international workshop 2015.[14] In fact, the evaluation of the four domains in muscle biopsy was done first time in JDM to predict clinical course for stratification of therapeutic regime according to risk for chronic disease [17],[18] and the same has been validated by Varsani et al.[19] The pathological classification and subsequent identification of disease subtypes are extremely important for assessing treatment options and prognosis in the individual patient.[14] In our study, muscle biopsy evaluation in the four domains using the basic panel of histochemical stains helped us to characterize the JIIM subtypes. Additional stains recommended for establishing the IIM diagnosis in doubtful cases include alkaline phosphatase, CD3, CD8, CD68, HLA-ABC/MHC 1, MAC, and p62, and CD31.[14] We have done CD31 to evaluate capillary density to assess the severity of capillary damage. Of the 24 biopsies, capillary dropout was seen in 5 (20.83%) biopsies, predominantly in the perifascicular area. Capillary dropout, muscle infarction, regeneration with internal nuclei, and fibrosis as seen in our study were reported to correlate with the severity of disease.[20] Pestronk suggested a myopathologic classification and described myovasculopathy predominantly in JDM.[21] Mitochondrial abnormalities and sarcoplasmic vacuoles were also described in myovasculopathy.[21] These features and diffuse infiltrates or lymphoid aggregates as observed in our study were reported to be associated with favorable outcome.[21],[22] These observations highlight the importance of detailed evaluation of muscle biopsy.

JOM constitutes 6%–11% of JIIM and the second most common subtype.[1],[2] Overlap myositis in association with SLE and SSc are more frequent in adults than in children.[23],[24] The associated auto-immune disease in our patients was characterized by autoantibodies and muscle biopsy showed evidence of myositis in all the patients.

Using the evaluation of four domains in muscle biopsy, we could not identify any case of pure juvenile polymyositis (JPM). Infantile polymyositis is no longer recognized as a subtype of JIIM, but was found to be congenital muscular dystrophy with laminin alpha2 deficiency.[25],[26] JPM is extremely rare and accounts for 4%–8% of JIIM and tends to occur in preteen or teenage years.[1],[2] However, the diagnosis of JPM is often a misdiagnosis and detailed study of muscle biopsy to exclude other muscle disorders with inflammatory infiltrates is essential before considering the diagnosis.

The strength of the study is that this is probably the first such study in JIIM from India. This study also suggests that subtyping of JIIM is possible with evaluation in the four domains using the basic panel of histochemical stains proposed by the ENMC criteria 2015. There is a need for prospective studies with the use of additional stains and correlating the muscle biopsy findings in the four domains with the severity of the disease and treatment outcome with various treatment regimes.

   Conclusion Top

Muscle biopsy evaluation is important in the subtyping of JIIMs and helps in the treatment options and prognostication.

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Conflicts of interest

There are no conflicts of interest.

   References Top

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Correspondence Address:
Sundaram Challa
Department of Pathology and Laboratory Medicine, Basavatharakam Indo-American Cancer Hospital and Research Institute, Banjara Hills, Hyderabad - 500 034, Telangana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_387_17

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