International Journal of Case Report Clinical Rheumatology

An unusual presentation of inflammatory in a patient on natalizumab treatment for multiple sclerosis: A case report and review of myopathological classification of inflammatory myopathy

Abstract: Acquired immune and inflammatory (IIMs) are traditionally subdivided into Beenish Zulfiqar*1, Jacquelin , , inclusion body (IBM) and necrotizing autoimmune myopathy Chua2, Stacy Weinberg2 & 2 (NAM). Our patient is a 38-year old female who had history of Multiple Sclerosis and was on Natalizumab. Sobia Hassan 1 Almost a year later, she presented with acute proximal bilateral upper extremity with elevated Advocate Illinois Masonic Medical Centre, USA CPK. She was initially labeled as having ‘viral myositis’. Her subsequent two admissions demonstrated 2Rush University Medical Center, Chicago, worsening of with which was initially unresponsive to high dose of IL, USA steroids. She had an EMG which showed irritative myopathy and a muscle biopsy which showed IMPP. She eventually responded to pulse dose of steroids and IVIG and Natalizumab was held. The temporal *Author for correspondence: relationship between the development of inflammatory myopathy in our patient and subsequent [email protected] improvement in her course after discontinuation of the drug suggests that natalizumab may have played a role in our patient’s disease and warrants further investigation and vigilance. In addition to the case report, we hope to elaborate on the myopathological descriptions increasingly being used to describe the IIMs and to explore the potential link between natalizumab and the onset of IIM in our patient.

Keywords: natalizumab myositis • multiple sclerosis • acquired immune and inflammatory myopathies

Introduction Case Acquired immune and inflammatory myopathies We present a case of a 38-year-old female with a (IIMs) are traditionally subdivided into medical history significant for Grave’s disease post- dermatomyositis, polymyositis, inclusion body radioablation, hypertension, and anemia. She myositis (IBM) and necrotizing autoimmune also had a history of Multiple Sclerosis diagnosed myopathy (NAM) [1,2]. The presence of in 2014 when she first presented with impaired myositis specific and myopathological gait and dysarthria after a sinus infection. Her descriptions help to further delineate these MRI brain findings at that time showed several disorders and may help prognostically. We small enhancing lesions in the white matter: left describe an unusual presentation of acute onset cerebellar peduncle, left lateral ventricle, left inflammatory myopathy in a patient who was periventricular white matter, left pons, right on natalizumab treatment for multiple sclerosis and left medial longitudinal fasciculus, and left (MS) and who was initially resistant to high pons. Her course was characterized as relapsing. dose steroids. She was followed by both the She was previously treated with high doses of rheumatology and neuromuscular services steroids and intravenous cyclophosphamide with who characterized her as having an immune improvement. However, in December 2015, myopathy with perimysial pathology (IMPP). In she relapsed and was begun on natalizumab addition to the case report, we hope to elaborate (Tysabri). In September 2016, she began to have on the myopathological descriptions increasingly a headache and neck pain. Work-up including being used to describe the IIMs and to explore MRI of the brain revealed a CSF leak of unknown the potential link between natalizumab and the etiology and she received a blood patch. During onset of IIM in our patient. that time, she also started complaining of

Int. J. Clin. Rheumatol. (2018) 13(3), 197-201 ISSN 1758-4272 197 Case Report Zulfiqar, Chua, Weinberg, et al.

persistent bilateral upper extremity pain and and IV , her swallowing significant arm swelling with proximal muscle and breathing improved. She was sent to weakness. Her exam was notable for 4/5 strength rehabilitation for strength training and recovered in neck flexor and extensors, 5/5 strength in about 75% of her strength on follow-up. bilateral deltoids, 4/5 in bilateral biceps, 4-/5 Prednisone was tapered and she was started on in bilateral triceps, 5/5 strength in bilateral mycophenolate mofetil as a steroid sparing agent hip flexor and extensor and quadriceps. Distal for her myositis. extremity power was normal. Her laboratory Discussion work-up revealed CPK of 3500, 106 mg/dl, AST 126 mg/dl, ALT 53 mg/dl, mildly elevated Adult acquired immune inflammatory RF; otherwise, ANA, inflammatory markers, myopathies are traditionally classified using and complements were normal. EMG findings the Bohan and Peter criterion which was were suggestive of an irritative myopathy. She developed in 1975 [3]. Major advances in was evaluated by rheumatology at that time and knowledge regarding inflammatory myositis it was felt that her presentation was more likely have recognized the limitations of such criteria. to represent a viral myositis than inflammatory Developments of more recent classifications myositis given the sudden onset of symptoms have emerged; one of which emphasized and also because of the temporal relationship clinicoserological profiles, extra muscular organ to symptoms suggestive of a viral infection. She involvement and autoantibodies [4]. These was discharged home with close follow-up. Her newer classifications highlight the heterogeneity symptoms persisted and began to include lower of these myositis syndromes and how this has extremity weakness, pain and swelling. She was implications for prognosis and response to again admitted to the hospital and had a muscle therapy. However, it does not take into account biopsy that showed inflammatory myopathy with the pathological findings which may also have myopathic changes, inflammatory infiltrates, utility for distinguishing between treatable increased labeling of endomysial capillaries and presently untreatable AIM. For example, a for C5b-9 membrane attack complex but no patient with rapidly progressive muscle weakness perifascicular atrophy. Her CPK at this time was with mostly necrosis and little inflammation 2500. Given worsening symptoms, persistent on biopsy may perform poorly despite steroid hyperCKemia and biopsy results, she was started therapy as opposed to one with inflammation on prednisone 60 mg/day. Three weeks later she but little necrosis or fibrosis. Familiarity of returned with resolution of swelling; however, myopathological descriptions, then, can provide her weakness and muscle soreness persisted and insights in to which patients would require she had new symptoms of dyspnea and dysphagia. more aggressive therapy. Myopathological Her proximal upper and lower extremity classification includes description of muscle fiber strength at this time was 3/5 bilaterally. She was pathology, immune characteristics, and types readmitted and started on Methylprednisone of tissues involved [2]. Currently, 6 patterns of 1 g IV × 3 days and IVIG (2 g/kg in divided acquired IIMs have been identified: immune doses over two days). Cancer screening including myopathies with perimysial pathology (IMPP); ovarian ultrasound, CT chest and abdomen, and myovasculopathies; immune polymyopathies; mammogram were unremarkable. Paraneoplastic immune myopathies with endomysial pathology markers were negative. A Myomarker panel was (IM-EP); histiocytic inflammatory myopathy; sent and was noted to be negative for anti-SRP, and inflammatory myopathies with vacuoles, anti Jo-1, EJ, OJ, Mi, Ku, MDA5, Anti HMG aggregates and mitochondrial pathology (IM- Co-A. She was evaluated by the neuromuscular VAMP) Table 1. service who reviewed her muscle biopsy and Specifically, our patient had myopathy consistent felt that her inflammatory changes were subtle with inflammatory myopathy with perimysial and mostly identified in the perimysium region. pathology but with negative myositis antibodies. They labeled her as having an inflammatory IMPP is commonly associated with positive myopathy with perimysial pathology. Due to Anti-Jo1 antibodies. However, autoantibodies her severe and refractory presentation and the can be absent in about 20-40% of patients potential that Natalizumab might have played a in patients with inflammatory myositis [5- role in the development of her myopathy via its 7]. Patients with IMPP and positive anti-Jo-1 immunomodulatory actions, it was discontinued. antibodies can have a constellation of symptoms After she completed her course of IVIG that may include muscle weakness and pain,

198 Int. J. Clin. Rheumatol. (2018) 13(3) An unusual presentation of inflammatory myopathy in a patient on natalizumab Case Report treatment for multiple sclerosis

Table 1. Table illustrating the myopathological classification of IIM [12-15] Antibodies/ Type Myopathological features Disease Associations Comment(s) laboratory findings Dermatomyositis, Common Immune myopathies Fragmentation and histiocyte anti-tRNA synthetase polymyositis, interstitial pattern, Aldolase with perimysial infiltration at the perimysium. antibodies,(Jo-1, PL-7, lung disease, fasciitis, graft selectively high, pathology (IMPP) Myofiber necrosis and regeneration PL-12) vs. host disease, some toxic Not in hereditary myopathies myopathies Dermatomyositis in childhood Perifascicular atrophy and and some adults May be Myovasculopathies vacuolation with little necrosis or associated with calcinosis focal invasion by mononuclear cells Paraneoplastic syndromes CK is very high, Myofibers may have varying stages Differs from of necrosis and regeneration SRP and HMG-CoA Statin use (HMG-CoAR rhabdomyolysis Immune (early stages) or less necrosis and reductase (HMG-CoAR) antibodies) Paraneoplastic in which many polymyopathies regeneration (later stages) No antibodies syndromes damaged fibers have mononuclear cell infiltration a similar stage of pathology Immune and inflammatory Endomysial molecular pathology Brachio-cervical inflammatory myopathies that often requires special stains for myopathy (BCIM) with endomysial demonstration. Pathology (IIM-EP) Granulomatous myopathies, Both MMF and Histiocytic foci in the endomysium i.e. sarcoidosis Macrophagic Histiocytic IMAMs can be related or perimysium. Myofibers are myofasciitis (MMF) inflammatory to immunizations replaced by histiocytic cells and Inflammatory myopathy myopathies and may be clinically endomysial connective tissue. with abundant macrophages silent (IMAMs) Multifocal mononuclear cell inflammatory foci, mostly CD4+ and Disease progression Inflammatory CD8+ T cells, in the endomysium may be more rapid myopathies with in a linear or sinuous pattern. in IM-VAMP with vacuoles, aggregates Perivascular foci may also occur. (IBM) vacuoles than those and mitochondrial Myofibers may contain vacuoles, with mitochondrial pathology (IM-VAMP) aggregates and mislocalized pathology and no proteins or mitochondrial vacuoles pathology.

Raynaud's phenomenon, interstitial lung disease, IMPP syndromes are generally responsive arthritis, and a skin rash, commonly known as to immunomodulatory therapy, including antisynthetase syndrome, different from that and other drugs [9]. Our patient seen in classic dermatomyositis. In a case series, had symmetric proximal muscle weakness but review of charts, muscle biopsies and laboratory also had significant bilateral arm swelling. She records by Mozaffar T et al. [8], features of did not have lung involvement during her myopathology in 11 patients with anti-Jo-1 course. She was initially resistant to high dose associated myopathies were compared steroids but on cessation of her natalizumab with other types of inflammatory myopathies. therapy and with the addition of IVIG and a Electromyography in nine patients tested prolonged course of oral steroids after pulsed showed an irritable myopathy. Muscle biopsies treatment with IV methylprednisolone, she from all 11 patients with antiJo-1 antibodies eventually started to show improvement. By 9 contained regions of fragmented, rarefied months follow-up, her motor strength was 5/5 on perimysial connective tissue. Inflammation was bilateral proximal upper extremities, 4/5 on both less common in endomysial (two of 11; 18%; hip flexors, and 5/5 bilateral hip extensors and p=0.003) and perivascular (one of 11; 9%; thigh adductors and abductors. Our patient had p<0.001) regions of muscles. In another report received Natalizumab for treatment of relapsing high serum aldolase, normal creatine kinase, MS 1 year prior to the onset of her myositis. and systemic features common to antisynthetase Although no prior case reports were found in syndromes were associated with IMPP [8]. our literature review, based on its mechanism Among the biopsies that were reviewed in this of action, it was hypothesized that natalizumab report, 5 were with negative anti-Jo1 antibodies. caused immune dysregulation that may have

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contributed to the development and severity of played a role in our patient’s disease and warrants our patient’s myopathy. Natalizumab works by further investigation and vigilance. targeting cellular adhesion and T cell migration This report also provides a review of the [10,11]. It acts against the a4b1 integrin, VLA4, myopathological classifications of inflammatory on leucocytes, which are fundamental molecules myopathies which are increasingly being for adhesion and transmigration of T cells. It used and can potentially provide additional has been used in Crohn’s disease and multiple information about prognostication and response sclerosis. In the myositis group of diseases, it to therapy. has actually been studied as a treatment for inclusion body myositis. The final results of this References study are not available yet but interim analysis 1. Pestronk A. Acquired immune and inflammatory of a pilot trial showed significant changes in myopathies: pathologic classification. Curr. Opin. muscle biopsies of 2 patients with near complete Rheumatol. 23, 595–604 (2011). elimination of inflammation [10]. No changes in 2. Nozaki KPA. High aldolase with normal creatine the manual muscle testing were noted in these kinase in serum predicts a myopathy with perimysial two patients. Treatment of rare diseases or rare pathology. J. Neurol. Neurosurg. Psychiatry. 80, 904– disease manifestations in rheumatology are often 908 (2009). mirrored on previous experiences of similar more 3. Bohan A, Peter JB. Polymyositis and dermatomyositis common disease presentations. In a review of (first of two parts). N. Engl. J. Med. 292(7), 344–7 (1975). natalizumab, it was suggested that it could be a potential therapy for refractory cases or difficult 4. Senécal JL, Raynauld JP, Troyanov Y. Editorial: A New Classification of Adult Autoimmune Myositis. Arthritis cases of polymyositis, dermatomyositis and & Rheumatology. 69(5), 878–884 (2017). IBM. Limited literature is available in support 5. Dakkalas MC. Inflammatory muscle diseases. N. Engl. of this, however given the temporal relationship J. Med. 372(18), 1734–47 (2015). between starting natalizumab and the onset of 6. Koenig M, Fritzler JM, Targoff IN et al. Heterogeneity our patient’s symptoms, it is postulated that of autoantibodies in 100 patients with autoimmune natalizumab may have played a role in the onset myositis: insights into clinical features and outcomes. or severity of her myositis. It is speculated that Arthritis Research & Therapy. 9(4), 78 (2007). natalizumab, given its mechanism of action, may 7. Aggarwal R, Bandos A, Reed AM et al. Predictors affect the normal trafficking of lymphocytes and of Clinical Improvement in Rituximab-Treated may have perturbed the balance between effector Refractory Adult and and Adult Polymyositis. Arthritis. Rheumatol. 66(3), 740–9 and regulatory T cells. Discontinuation of the (2014). drug and aggressive therapy for her myositis led 8. Mozaffar T, Pestronk A. Myopathy with anti-Jo-1 to a gradual improvement in her symptoms. Even antibodies: pathology in perimysium and neighbouring though the link between our patient’s myositis muscle fibres.J. Neurol. Neurosurg. Psychiatry. 68(4), and natalizumab use is only hypothetical, the 472–8 (2000). fact that natalizumab is being considered as 9. Nozaki K, Pestronk A. High Aldolase with Normal a treatment for refractory or resistant cases Creatine Kinase in serum predicts a Myopathy with of inflammatory myositis should raise some Perimysial Pathology. J. Neurol. Psychiatr. Neurosurg. 80, 829–829 (2009). concern and needs further investigation. 10. Kleinschmidt-DeMasters BK, Tyler KL. "Progressive Conclusion multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for In summary, we report an atypical presentation multiple sclerosis". N. Engl. J. Med. 353(4), 369–74 of adult inflammatory myopathy with perimysial (2005). pathology in the setting of known MS and 11. Zohren F, Toutzaris D, Klarner V et al. "The natalizumab use. We did not find any other case monoclonal anti-VLA4 antibody natalizumab reports implicating natalizumab in the onset mobilizes CD34+ hematopoietic progenitor cells in of inflammatory myopathy. To the contrary, humans". Blood. 111(7), 3893–5 (2008). it has been suggested as a potential treatment 12. Gunawardena H, Wedderburn LR. Autoantibodies for refractory inflammatory myopathy in a few to a 140-kd protein in juvenile dermatomyositis are associated with calcinosis. Arthritis. Rheum. 60(6), studies. However, the temporal relationship 1807–14 (2009). between the development of inflammatory myopathy in our patient and subsequent 13. Bleecker JLD, Lundberg IE. Pathology diagnosis of idiopathic inflammatory myopathies 30 November improvement in her course after discontinuation – 2 December 2012, Naarden, The Netherlands. of the drug suggests that natalizumab may have Neuromuscular Disorders. 23, 945–951 (2013).

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