Case Report: Steroid Responsive Pompe Like Inflammatory Myositis With Complete Recovery After Allogeneic HSCT

Idiopathic inflammatory myositis (IIM) is a group of diseases characterized by muscle weakness due to immune-mediated muscle damage [1]. They are all diagnoses of exclusion; patients should be carefully evaluated for the presence of many conditions such as neurogenic, metabolic, endocrine disorders, malignancies, infectious diseases, and drug-associated myositis before diagnosis [2]. Here, we report a 27-year-old woman with chronic myeloproliferative neoplasm hospitalized for allogeneic hematopoietic stem cell transplantation (HSCT) who suffered from severe muscle weakness. She was successfully treated with corticosteroid and IVIG therapy despite having muscle biopsy findings that mimicked glycogen storage disease and underwent allogeneic HSCT. A 27-year-old woman was evaluated for leukocytosis and abdominal pain. Contrast enhanced computed tomography revealed hepatosplenomegaly accompanied by multiple enlarged lymph nodes in the bilateral axillary and abdominal regions. Bone marrow biopsy demonstrated hypercellular marrow with features overlapping myeloproliferative and myelodysplastic morphology. Molecular analysis identified a CALR mutation, while JAK2 V617F, MPL W515L/K, and BCR-ABL1 (t[9;22]) were negative. Based on these findings, a diagnosis of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) overlap syndrome was considered, and cytoreductive therapy with hydroxyurea was initiated. Hydroxyurea was discontinued in less than a month, and she was hospitalized for allogeneic HSCT. During this period (about 1 month), she developed progressive weakness starting in the upper limbs and extending to the lower limbs, ultimately resulting in an inability to walk. She reported that mild lower limb weakness had already begun around the time of HSCT admission, shortly before hydroxyurea discontinuation. Serum creatine kinase was measured for the first time during this clinical worsening and was found to be markedly elevated; baseline CK levels prior to hydroxyurea exposure were not available. On admission, her vital signs were stable, and she was alert, oriented, and cooperative. Neurological examination revealed symmetric proximal muscle weakness (Medical Research Council grade: upper limbs 3/5, lower limbs 1/5), hypoactive deep tendon reflexes, and preserved sensation without fasciculations or muscle atrophy. Laboratory evaluation revealed severe anemia with a hemoglobin level of 6.5 g/dL (reference 11.9–14.6 g/dL), a white blood cell count of 4.9 × 103/μL, and a platelet count of 154 × 103/μL (reference 170–390 × 103/μL). Serum enzyme levels were markedly elevated: creatine kinase (CK), 8323 U/L (reference < 145 U/L); creatine kinase–MB (CK-MB), 294 U/L (reference 0.6–6.3 U/L); lactate dehydrogenase (LDH), 1441 U/L (reference < 247 U/L); and aspartate aminotransferase (AST), 165 U/L (reference < 35 U/L), with normal renal function. Thyroid function tests and serum vitamin B12 levels were within normal limits. Autoimmune serology, including antinuclear antibody (ANA), anti-double stranded DNA (anti-dsDNA), rheumatoid factor (RF), anti cyclic citrullinated peptide (anti-CCP), and extractable nuclear antigen (ENA) antibodies, all negative except for anti–Scl-70 positivity, was evaluated. The myositis antibody panel, including Mi-2α, Mi-2β, TIF1γ, MDA5, NXP2, SAE1, Ku, PmScl-100, Jo-1, SRP, PL-7, PL-12, EJ, OJ, and Ro-52, was also negative. The patient developed dysphagia. This prompted the immediate start of pulse methylprednisolone (250 mg/day for 3 days) and intravenous immunoglobulin (400 mg/kg/day for 5 days), followed by oral methylprednisolone (40 mg/day). Magnetic resonance imaging (MRI) of the thighs revealed mild atrophy and intra and parafascial edema of the bilateral thigh and gluteal muscles, along with diffuse bone marrow signal alterations but without overt leukemic infiltration. Electromyography (EMG) showed short duration, low amplitude motor unit potentials and fibrillation potentials, consistent with active myopathic involvement. Shortly after treatment, a muscle biopsy was performed from the biceps brachii. Muscle biopsy unexpectedly demonstrated polygonal fiber disarray, round atrophic fibers, scattered necrotic fibers, and subsarcolemmal vacuoles with PAS-positive glycogen and acid phosphatase reactivity, but no inflammatory infiltrates (Figure 1). These findings initially suggested a glycogen storage disease, such as Pompe disease. However, both α-glucosidase and chitotriosidase activities were within normal limits, and the lysosomal storage disorder screening panel was negative. Because the biopsy suggested a possible glycogen storage disorder, targeted next-generation sequencing (NGS) for glycogen storage diseases was performed, but no pathogenic variants were identified. Whole exome sequencing (WES) was then initiated to further explore an immune mediated or secondary autophagic mechanism; however, the WES analysis is still in progress. Her muscle strength improved noticeably within 2 weeks after treatment, her swallowing difficulty resolved, and her creatine kinase levels declined progressively (Figure 2). After a multidisciplinary discussion with hematologists and neurologists, her corticosteroid dose was gradually tapered according to the HSCT protocol, and she subsequently underwent allogeneic HSCT from an HLA-matched sibling donor. After HSCT, her laboratory values normalized, and she experienced complete and sustained recovery of muscle strength, with no recurrence of myopathic symptoms. At her most recent follow-up, she remained clinically stable and fully functional. Here we reported a case with myositis who rapidly responded to immunosuppressive treatment despite having an uncontrolled malignancy and a muscle biopsy compatible with glycogen storage disease. After recovery of myositis, we were able to perform allogenic HSCT for her hematologic malignancy which also helped to control the activity of myositis. At the beginning, we put our patient on steroid and IVIG treatment with preliminary diagnosis of malignancy or drug associated IIM. Though both hematologic malignancies and hydroxyurea have been reported as causes of myositis, to our knowledge, there are no cases associated with MDS/MPN, and our patient was exposed to hydroxyurea for a very short period [3, 4]. In patients with myelodysplastic and myeloproliferative neoplasms, several mechanisms have been proposed to explain associated inflammatory or immune mediated myopathies, including dysregulated cytokine networks and immune cross reactivity driven by the underlying clonal hematopoietic disorder. Cancer related myopathies are thought to occur when the immune system reacts to antigens that are shared by tumor cells and regenerating muscle fibers [5]. Although we cannot demonstrate this mechanism clearly in our case, a very good response to immunosuppressive treatment supports immune-mediated muscle damage. In our patient, anti–Scl-70 antibody positivity also raised the possibility of a systemic sclerosis (SSc) related or overlap syndrome. However, she did not have clinical findings suggestive of SSc, such as Raynaud's phenomenon, skin thickening, gastrointestinal involvement, or abnormal nailfold capillaroscopy. In the absence of supportive clinical features, we did not consider an overlap connective tissue disease diagnosis to be likely. Therefore, anti–Scl-70 positivity was considered an isolated serological finding and was not supported by clinical features of an overlap syndrome. The muscle biopsy result surprised us, demonstrating subsarcolemmal vacuoles with PAS positive glycogen and acid phosphatase activity, which strongly resembled a glycogen storage disorder. She did not have a family history of myositis and blood enzyme levels were in normal range that made a primary metabolic defect such as Pompe disease unlikely. We decided to continue treatment with a diagnosis of immune-mediated myositis. Similar observations have been reported in vacuolar myopathies where altered autophagy and secondary lysosomal activation are consequences of immune-mediated muscle injury instead of a primary enzyme defect [6]. We also did not identify any pathogenic variants by genetic tests. Absence of prominent inflammation in muscle biopsy may be explained by initiation of treatment before procedure. A distinctive aspect of this case is the clinical course after allogeneic hematopoietic stem cell transplantation (HSCT). The patient underwent allogeneic HSCT from HLA-matched sibling donor for her hematologic disease, and thereafter she experienced complete and sustained recovery of muscle strength with no recurrence of myopathic symptoms. HSCT, particularly autologous HSCT, has been increasingly used in severe autoimmune diseases such as systemic sclerosis and refractory inflammatory myopathies, where immune reset and reestablishment of self tolerance are believed to underlie long term remission [7]. The current understanding of HSCT in autoimmune diseases suggests that the elimination of autoreactive lymphocyte clones and the regeneration of a more regulated immune repertoire may play a central role in these outcomes [8]. The steady improvement in her muscle strength and CK levels following the transplant suggests that immune recovery probably helped to bring her myositis under long term control. Overall, this case highlights a few important points. First, the presence of Pompe-like vacuoles on muscle biopsy does not confirm a metabolic glycogen storage disorder on its own; these findings must be interpreted together with enzyme assays, genetic testing, and the patient's clinical response. Second, in patients with hematologic malignancies who develop muscle weakness and marked CK elevation, clinicians should consider paraneoplastic or immune-mediated myositis, even if the biopsy is not typical for an inflammatory myositis. Finally, the strong and sustained improvement after HSCT in this patient suggests that treating the underlying hematologic disease and reestablishing immune balance may help achieve long-term remission of immune-mediated muscle involvement in selected cases. G.S.K.-B. and B.F.-Y. contributed to data organization and drafting of the manuscript. C.E.B.-K. contributed to the collection and interpretation of pathological data and preparation of the images. E.A.-K. contributed to clinical data collection. A.A. and C.E.B.-K. critically reviewed and revised the manuscript. All authors read and approved the final version of the manuscript. The authors have nothing to report. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.