Polymyositis as a manifestation of chronic graft‐versus‐host disease after allo‐HSCT

Key Clinical Message Patients who received allogeneic haematopoietic stem cell transplantation (allo‐HSCT) may develop T cell‐mediated immunologic injury to muscles, recapitulating the characteristics of polymyositis clinically and pahtologically. Polymyositis is a rarely reported complication of graft‐versus‐host disease (GVHD), which often responds well to corticosteroids and immunosuppressive treatment.

Immunohistochemical staining of the sections revealed that the infiltrating lymphocytes were predominantly T cells (mainly CD8+ T cells with a few CD4+ cells), while B lymphocytes were scarce (no CD20+ cells). Major histocompatibility complex class I (MHC-1) was upregulated in some myofibers. In addition, the membrane attack complex (MAC) was deposited in the necrotic myofibers ( Figure 2).
Based on the clinical presentation and the pathologic findings on the biopsied muscle, the polymyositis after allo-HSCT was considered. The patient was initially treated with an increased dosages of prednisone and cyclosporin A (CsA), but no significant improvement was achieved. Thus, rituximab (100 mg) plus a low dose of intravenous immunoglobulin (IVIG, 5-10 g) weekly was applied for consecutive 6 weeks, the patient finally achieved a remarkable improvement of her symptoms with a normal CK level. Until now, the patient has been followed up for one and a half years, and she remained symptom-free on oral prednisone and CsA.

| Patient 2
A 31-year-old woman was diagnosed with AML 20 months ago. A first complete remission of AML was achieved with two courses of chemotherapy (DA regimen: pirarubicin + cytarabine; cytarabine + methylprednisolone). Fifteen months ago, she received allo-HSCT after a reduced intensity conditioning regimen with IDA/Bu/Fu/Me-CCNU. The postoperative regimen was consisted of cyclosporine (25 mg BID) and methylprednisolone (40 mg QD and then gradually reduced the dose to 20 mg QD) for GVHD prophylaxis. She was hospitalized because she had limb weakness and myalgia for 5 months. Five months ago, she felt myalgia in both the lower limbs (MRC graded 4) and later the upper limbs (MRC graded 4-). The muscles on the four extremities were generally tender and slight atrophic. Deep tendon reflexes were slightly decreased. The sensation was normal.
Laboratory tests showed the normal ranges of CK and myoglobin levels. The myositis-specific autoantibodies were not positively detected. The antinuclear antibody (ANA) titer was weakly positive at 1:320 (Table 1). MRI showed high intensities in fat-suppressed T2-weighed image in the supraspinatus, scapular muscles, arm muscle group, as well as the leg muscle group and fascia (Figure 1,C,D). EMG detected myopathic changes. Muscle biopsy of the quadriceps femoris revealed that the degeneration and necrosis of myofibers were evident, with a large number of inflammatory cell infiltrates in the endomysium, similar to those described in the biopsied muscle from the case one. The therapy was shifted from the previous regimen consisting of oral prednisone and CsA to tacrolimus (3 mg QD) combined with oral methylprednisolone (40 mg QD). The symptoms began to relieve in 2 weeks and had disappeared at about 3 months after the new regimen applied. She had been followed up for over 1 year and was in a good condition on the daily dosage of tacrolimus at 3 mg with methylprednisolone at 12 mg.

| DISCUSSION
Polymyositis (PM) is a rare neuromuscular manifestation of chronic GVHD in patients who received allo-HSCT. 1,2 The two cases in our study presented an insidious onset and a slowly progressive mode. The clinical presentation, elevation of CK and/or LDH, myopathic changes in EMG, the abnormal signals on muscular MRI, and the pathological findings in the affected muscles confirmed the diagnosis of PM. 3 That the autoantibodies implying idiopathic inflammatory myopathies, connective tissue diseases or para-neoplastic syndromes were not detected ruled out the possibilities of other diseases.
In order to reduce the occurrence of GVHD, a reduced intensity conditioning regimen before allo-HSCT is often necessary. 4 Although the two cases had received both the standardized pretreatment and sustained immunosuppressants after allo-HSCT, the infused donor's lymphocytes still triggered immune attacks to the host via T-cell pathway. 2,5 Theoretically, the clonally expanded CD8 + cytotoxic T cells invaded the muscle fibers which overexpress MHC class I antigens, in turn led to myofiber necrosis via the perforin pathway 6 and activated complement system. 5 The immunohistochemical staining suggested that the cellular dysimmunity played a key role in the development of GVHD-associated myositis in the two cases. Activation of complement system might have contributed to the pathogenesis since the necrotic myofibers were positive for MAC, which is a marker for complement system activation. [7][8][9] The fact that the case responded well to Rituximab plus small dosage IVIG, signifies that the humoral dysimmunity plays an important role in the development of myositis in addition to cellular autoimmunity, because Rituximab blocks the generation of autoantibodies from B cells. 10 Although no B lymphocytes were infiltrated in the necrotic myofibers in the two cases, the possibility that the activated circulating B cells may act in harmony with T cells and activate complement system to destroy the myofibers is substantiated by the satisfactory responsiveness to Rituximab.
In conclusion, we emphasize that the patients who received allo-HSCT may develop T cell-mediated immunologic injury to muscles which is similar to polymyositis in terms of clinical features and myopathologic changes. Polymyositis as a presentation of chronic GVHD often responds well to corticosteroids and immunosuppressive treatment. Targeting both the T and B cells is effective.