Rheumatology International (2019) 39:1459–1466 Rheumatology https://doi.org/10.1007/s00296-019-04314-8 INTERNATIONAL CASES WITH A MESSAGE Polymyositis with mitochondrial pathology or atypical form of sporadic inclusion body myositis: case series and review of the literature George K. Papadimas1 · Charalampos Kokkinis2 · Sophia Xirou1 · Margarita Chrysanthou1 · Evangelia Kararizou1 · Constantinos Papadopoulos1 Received: 11 December 2018 / Accepted: 26 April 2019 / Published online: 4 May 2019 © Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract Polymyositis with mitochondrial pathology (PM-Mito) is a rare form of idiopathic infammatory myopathy with no defnite diagnostic criteria and similarities to both PM and sporadic inclusion body myositis (s-IBM). The aim of this study is to address the dilemma of whether PM-Mito is a subtype of infammatory myopathy or represents a disease falling into the spectrum of s-IBM. Herein, we report four female patients diagnosed with PM-Mito, highlighting their rather atypical clini- cal and histopathological characteristics that seem to indicate a diagnosis away from s-IBM. Muscle weakness was rather proximal and symmetrical and lacked the selective pattern observed in s-IBM. Patients had large-scale deletions in mtDNA, refecting the mitochondrial component in the pathology of the disease. Conclusively, our study adds to the limited data in the literature on whether PM-Mito is a distinct form of myositis or represents a prodromal stage of s-IBM. Although the lat- ter seems to be supported by a substantial body of evidence, there are, however, important diferences, such as the diferent patterns of muscle weakness, and the good response to treatment observed in some patients. Larger-scale studies are certainly needed to clarify pathogenesis and clinical characteristics of PM-Mito patients, especially in therapeutic and prognostic terms. Keywords Polymyositis · Mitochondria · mtDNA · Inclusion body myositis Electronic supplementary material The online version of this Introduction article (https ://doi.org/10.1007/s0029 6-019-04314 -8) contains supplementary material, which is available to authorized users. The idiopathic infammatory myopathies (IIMs) are acquired * George K. Papadimas autoimmune disorders characterized by progressive proxi- [email protected] mal muscle weakness and can be mainly grouped into four Charalampos Kokkinis categories: dermatomyositis (DM), polymyositis (PM), [email protected] sporadic inclusion body myositis (s-IBM) and necrotizing Sophia Xirou autoimmune myopathy (NAM). Overlap syndromes refer to [email protected] these disorders in association with cancer or with another Margarita Chrysanthou connective tissue disease [1]. The absence, until recently, [email protected] of diagnostic criteria for infammatory myopathies with Evangelia Kararizou high sensitivity and specifcity and the increasingly rec- [email protected] ognized new subcategories led to the development of the Constantinos Papadopoulos new EULAR–ACR classifcation criteria [2]. However, the [email protected] underlying pathomechanisms still remain to be elucidated. 1 PM and s-IBM share some common histopathological 1st Department of Neurology, Medical School, Eginition features, including endomysial infammation and invasion Hospital, National and Kapodistrian University of Athens, 74, Vas. Sophias Ave, 11528 Athens, Greece by CD8 + T cells of non-necrotic fbers expressing MHC-1 complex. However, the additional presence of rimmed 2 Department of Medical Genetics, Medical School, St. Sofa’s Children’s Hospital, National and Kapodistrian University vacuoles and cytoplasmic and/or intranuclear 15–18 nm of Athens, Athens, Greece tubuloflamentous inclusions is characteristic for s-IBM Vol.:(0123456789)1 3 1460 Rheumatology International (2019) 39:1459–1466 [1]. Mitochondrial pathology may be also observed in IIMs, myositis-specifc antibodies (jo-1, Mi-2, SRP, PL-7, PL-12, especially in s-IBM with a variable extent of cytochrome EJ, OJ) and myositis-associated antibodies (anti-Ro/SSA, c oxidase (COX) defciency and ragged red fbers (RRFs) anti-La/SSB, anti-PM/Scl, anti-Ku, anti-U1RNP), electro- due to mitochondrial DNA (mtDNA) deletions [3–6]. In diagnostic studies with ENMG (electroneuromyography) dermatomyositis, widespread mitochondrial abnormalities and muscle biopsy. The muscle specimens were obtained may be observed in perifascicular regions, distinguishing by open biopsy under local anesthesia and were snap frozen it from other infammatory myopathies, along with skin in liquid nitrogen-cooled isopentane. Six micrometer thick alterations and perimysial connective tissue pathology [6, cryostat sections were used for histological, histochemical, 7]. Polymyositis with COX-defcient fbers, also called PM and immunohistochemical studies, using conventional tech- with mitochondrial pathology (PM-Mito) was frst reported niques. Muscle biopsy was performed for all patients prior in 1997 by Blume et al. [3] as a rare form of infammatory to any corticosteroid use. myopathy sharing common clinical and pathological features Ethical approval was obtained from the Aeginition Hos- with s-IBM, such as later age of onset, slow progressive pital Ethics Committee and all patients have signed written selective weakness of the quadriceps, poor response to cor- informed consent for their data to be used for research pur- ticosteroids, endomysial infammation with focal invasion poses and/or to be published in a scientifc journal. of intact muscle fbers and severe mitochondrial pathology, but lacking the characteristic rimmed vacuoles [3]. Thus, Mitochondrial DNA analysis several reports considered the disease as a possible variant of s-IBM [3, 8] with common pathogenic mechanisms includ- Total DNA was isolated from skeletal muscle biopsy speci- ing disordered autophagy [9]. mens of the four patients and eight age-matched controls There is a scarcity of cases with PM-Mito in the litera- (individuals without evidence of mitochondrial disease) ture to date, and only a few patients have been reported so using a salting-out method based on the procedure described far [3, 8, 9]. So, the aim of the present study is to further by Miller et al. [11], after written informed consent. The expand the limited existing literature regarding PM-Mito, presence of mtDNA rearrangements was examined with by reporting four patients with slow progressive muscular long-range PCR in the major arc, using primers F6951 weakness and myopathological fndings suggestive of the (6951-6972) and R15997 (15997-15975) generating a wild- disease and discuss. type product of 9047 bp (primer numbers refer to NCBI Reference Sequence NC_012920.1). PCR amplifcation was carried out on a Veriti Thermal Cycler (Applied Biosystems) Materials and methods using Phusion DNA Polymerase (ThermoFisher Scientifc) according to the manufacturer’s recommendations. The PCR A retrospective review was carried out at the Department of products were electrophoresed on a 0.8% agarose gel and Myology of the Aeginition University Hospital on muscle imaged using a UVIdoc Gel Documentation System (UVItec biopsies performed in the period from 2010 to 2016, to iden- Ltd, UK). tify cases diagnosed as PM-Mito. Since the above diagnosis is primarily histologic, the selection of patients was based on strict pathological changes, as previously defned [10]. Case reports More specifcally, the muscle biopsy should reveal lympho- cytic endomysial infltrates, especially of CD8+ T cells and/ Clinical/paraclinical manifestations and outcome or macrophages invading non-necrotic fbers, difuse HLA-1 increase and > 1% COX-negative fbers. Rimmed vacuoles The clinical history, the laboratory fndings and the results and cytoplasmic inclusions should be absent. Muscle biop- of the neurophysiological studies for each patient are sum- sies review was performed by two experienced myopatholo- marized in Table 1. A modifed Medical Research Council gists (GKP and CP). The study revealed 4 such patients with (MRC) scale was employed, with grade 5 representing nor- the aforementioned diagnosis out of 805 (Suppl. Fig. 1), mal strength and grade 0 no muscle movement [12]. A sum whose clinical data were retrospectively analyzed. The score ranging from 0 to 100 was calculated for each patient patients’ evaluation was based on muscle strength, labora- by bilateral examination of shoulder abduction, elbow fex- tory testing and neurophysiological studies. They all had a ion, elbow extension, wrist fexion, wrist extension, hip fex- negative family history for neuromuscular diseases and had ion, knee fexion, knee extension, dorsal foot fexion and been investigated for slow progressive muscle weakness. The plantar foot fexion. diagnostic work up included routine laboratory investiga- Patient 1, a 46-year-old female, was referred with a slowly tions, screening for chronic viral infections such as HIV and evolving proximal lower limb muscle weakness with dif- Hepatitis C, blood tests for autoimmune diseases, a panel of fculty in climbing stairs and rising from a chair over the 1 3 Rheumatology International (2019) 39:1459–1466 1461 Table 1 Clinical, laboratory and neurophysiological fndings Patient Gender Age at symp- Age at Symptoms Modifed Comorbidities CK (max EMG number toms’ onset biopsy MRC (sum value) (years) (years) score) (U/L) 1 F 40 46 Swallowing dif- 94 – 697 Myopathic changes fculties, muscle and rare complex weakness initially repetitive discharges in proximal