Department of Blood and Marrow Transplantation, University of Texas, MD Anderson Cancer Center, Houston, TX, USA

Correspondence to: Dr D Couriel, The University of Texas, MD Anderson Cancer Center, Department of Blood and Marrow Transplantation, 1515 Holcombe Boulevard, Box 423, Houston, TX 77030, USA

Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic stem cell transplantation. Polymyositis can occur in association with chronic GVHD and mimics the idiopathic form of the disease. We report two cases of chronic GVHD-associated polymyositis and review the published literature. The two patients presented 13 and 19 months after allogeneic transplantation with characteristic features of muscular hypotrophy, proximal muscle weakness, pain, elevated creatine phosphokinase (CPK), aldolase and SGPT. Interestingly, both patients had HLA DR52 genes, which is frequently reported in association with idiopathic polymyositis. Electromyogram (EMG) and muscle biopsy confirmed the diagnosis. Treatment with cyclosporine or tacrolimus resulted in complete and sustained remission of polymyositis in both cases. A review of the literature shows cyclosporine and steroids are well-described treatment options for patients with myositis in post transplant, as well as idiopathic cases. The duration of immunosuppressive treatment has varied in different reports, and there is a risk of recurrence when immunosuppression is tapered.

Bone Marrow Transplantation (2002) 30, 543-546. doi:10.1038/sj.bmt.1703711

GVHD; allogeneic bone marrow/peripheral stem cell transplant; GVHD-associated polymyositis; tacrolimus

GVHD remains a major complication of allogeneic blood and marrow transplantation.^1,2,3 T cells are key mediators of GVHD, as shown in both animal models and humans.^4,5 The diagnosis of chronic GVHD is complex and generally established on the basis of both clinical, and laboratory parameters. Skin is the most frequent site of involvement.^2,6,7 Other sites include ocular, gastrointestinal, hepatic, pulmonary and connective tissues.^8,9 Chronic GVHD may also mimic systemic lupus erythematosus, rheumatoid arthritis, progressive systemic sclerosis, Sjögren syndrome and other autoimmune diseases.^10,11,12,13

We report two cases of chronic GVHD presenting with polymyositis manifestations 13 and 19 months after allogeneic hematopoietic stem cell transplant, successfully treated with corticosteroids and tacrolimus.

Case reports

Patient 1

A 35-year-old female was diagnosed with acute myelogenous leukemia 8 years ago. She underwent allogeneic bone marrow transplantation from her HLA-identical sister, in complete remission. The preparative regimen consisted of etoposide, cyclophosphamide and total body irradiation. She received cyclosporine and methylprednisolone for GVHD prophylaxis. She did not develop any acute GVHD and her early post-transplant period was uneventful. Eleven months post-transplant the patient was off immunosuppressive treatment. Two months later she presented with a 3-week history of diffuse muscle tenderness. On physical examination, the patient had generalized muscle tenderness to palpation. Deep tendon reflexes were slightly decreased but the sensory-motor as well as the rest of the neurological examination was completely normal. Laboratory tests showed an elevated CPK (644 U/l, normal 37-289), aldolase (8.8, normal 0-8.1) and SGPT (177, normal 7-56). EMG findings were compatible with generalized myositis, without evidence of peripheral neuropathy. Muscle biopsy showed mononuclear cell infiltration, consistent with the diagnosis of myositis. The patient was initially treated with methylprednisolone (MP) 1 mg/kg daily for 1 month with normalization of her CPK and transaminase level, and remarkable improvement of her symptomatology in about 2 weeks. The MP was gradually tapered down to 40 mg p.o. every other day over the following 3 months. The manifestations of myositis resolved on MP but the patient developed scleroderma, xerophthalmia and xerostomia while her steroids were being tapered. She was started on cyclosporine 400 mg every other day. She received tapering doses of cyclosporine for the next 18 months along with low doses of methylprednisolone. Steroids were discontinued after a period of 4 years from the diagnosis of myositis. At the last follow-up the patient was leukemia-free and with no recurrence of myositis or chronic GVHD.

Patient 2

A 47-year-old male had Ph+ chronic myelogenous leukemia in accelerated phase. After a short course of treatment with hydroxyurea, followed by interferon and Ara-C, he achieved hematologic, but not cytogenetic remission. He had an allogeneic bone marrow transplant in chronic phase from his HLA-identical sister. The patient received intravenous busulfan and cyclophosphamide as conditioning, and GVHD prophylaxis consisted of tacrolimus and methotrexate. His post transplant course was uneventful and he achieved complete molecular remission. Eight months after his transplant, upon tapering the tacrolimus the patient developed a maculopapular rash on the trunk, which was diagnosed as chronic GVHD. He resumed his therapeutic dose of tacrolimus and was treated with a short course of methylprednisolone with a complete response. After 8 months his immunosuppressive treatment was discontinued and he had no evidence of chronic GVHD. Three months later he experienced severe proximal muscle weakness, more pronounced in the lower extremities. Physical examination was significant for profound muscle atrophy and weakness in all extremities. Deep tendon reflexes and sensory examination were normal. Laboratory examination revealed elevated CPK (2808 U/l, normal 45-235), LDH (1143 U/l, normal 313-618), aldolase (22.6 U/l, normal 0-8.1) and transaminases (SGPT 177 U/l, SGOT 177 U/l). Serum anti-nuclear antibodies were negative. An electromyogram showed abnormal nerve conduction with evidence of active denervation of most of the muscles tested. The test was compatible with mild to moderate necrotizing myopathy. Biopsy of the left biceps muscle showed prominent mononuclear inflammatory infiltrate with regenerating and necrotic fibers suggestive of polymyositis, without evidence of chronic GVHD in any other organ. He was treated with methylprednisolone 1 mg/kg daily for 5 days, followed by gradual tapering over the following 3 months. Tacrolimus was given at doses of 3 to 6 mg/day, to maintain blood levels between 8 and 12 ng/ml. He achieved a complete response after 2 weeks of immunosuppressive treatment. The MP was tapered and he continued tacrolimus for a total of 9 months after the onset of myositis. The patient had no recurrence of any manifestation of chronic GVHD.

Discussion

Polymyositis may occasionally occur in patients with chronic GVHD. We reviewed 36 cases that were published in the literature (Table 1). All of them were case reports or small retrospective series. There are no controlled studies evaluating specific treatments. In 30 of these patients, polymyositis was associated with dermatological changes of GVHD.^{2,12,14,15,16,17,18,19,20,21,22,23,24,25,26} The onset of GVHD-associated polymyositis has been reported to occur between 100 days and 69 months after allogeneic HSCT, and about half of the patients do not have a history of acute GVHD.^21,23 Clinical manifestations of GVHD-associated polymyositis are indistinguishable from those of the idiopathic form polymyositis. The most common presenting symptoms are moderate to severe proximal muscle weakness and myalgias.¹¹ Lower extremities seem to be more commonly involved.^15,26,27 Other signs and symptoms may include fever,^2,20,27,28 contractures,^2,18,23,26 dysphagia^14,24 eosinophilia^13,21 and skin induration over the areas of muscle involvement.²⁶ The majority of patients present with elevated CPK and aldolase enzymes. Elevated titers of antinuclear antibody (ANA) or rheumatoid factor have been inconsistently reported in GVHD-associated polymyositis.¹²

Some HLA types are highly associated with idiopathic polymyositis. HLA DRw52 is present in 75% of patients with idiopathic polymyositis and in >90% of patients with idiopathic polymyositis with anti-Jo-1 antibody.^29,30,31,32 HLA B8, DR3 (DRb*0301) and DQA1*0501 have also been reported more frequently in patients with idiopathic polymyositis.¹² Interestingly, our two patients had HLA DRw52. HLA information from previously reported GVHD-associated polymyositis patients is available on 10 patients, one of whom had the DR3 gene.¹²

EMG study typically shows polyphasic short duration, small amplitude, fibrillation potentials and positive sharp waves. Sensory and motor nerve conduction are preserved.^{11,14,18,22,23,26} The diagnosis of polymyositis can be established on the basis of characteristic clinical and EMG findings. In atypical presentations, a muscle biopsy may be required to confirm the diagnosis. Histopathologic findings on light microscopy are similar to idiopathic polymyositis, demonstrating a mononuclear perimysial inflammatory infiltrate, multiple foci of muscle cell necrosis with phagocytosis and evidence of regeneration.^11,12,13

The majority of cases of GVHD-associated polymyositis respond to immunosuppressive treatment.^11,12,13 Weakness and myalgia usually improve within days of initiation of therapy. CPK levels decrease gradually and may require up to 6 months to return to normal values.

Thirty of 32 evaluable patients reported in the literature were initially treated with prednisone or MP in a wide range of doses and schedules. In 16 cases the steroid was used in combination with a variety of immunosuppressants, including: cyclosporine, intravenous immunoglobulin, azathioprine, antilymphocyte globulin, cyclophosphamide, methotrexate, thalidomide and photopheresis.^{2,12,14,15,16,17,18,24,26,27} Thirteen of 30 evaluable patients failed initial immunosuppression and are summarized in Table 1. Six patients were primarily resistant and seven had recurrent polymyositis while steroids were being tapered.

Our two patients underwent HSCT from an HLA-identical sibling. Both presented with myositis (one as the only manifestation of chronic GVHD) at 13 and 19 months following transplant. Each patient had characteristic elevations in muscle enzymes, EMG and muscle biopsy. They were treated with steroids alone or in combination with tacrolimus, and had an excellent response. Cyclosporine and steroids are well-described treatment options for patients with myositis in post transplant, as well as idiopathic cases. There is very limited experience with the use of tacrolimus,^28,32 but in this case report it was effective in combination with steroids. The duration of immunosuppressive treatment has varied in different reports, but a considerable number of recurrences occur on steroid taper. There is no established standard therapy for this syndrome. A combination of steroids and cyclosporine or tacrolimus with subsequent tapering of immunosuppression as tolerated has been widely applied.

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20 Silverstein L, Davies A, Kelsey S et al. Myositis, polyserositis with a large pericardial effusion and constrictive pericarditis as manifestations of chronic GVHD after non-myeloablative peripheral stem cell transplantation and subsequent donor lymphocyte infusion. Bone Marrow Transplant 2001; 27: 231-233.

21 Reyes M, Noronha P, Thomas W, Heredia R. Myositis of chronic GVHD. Neurology 1983; 33: 1222-1224.

22 Pier N, Dubowitz V. Chronic GVHD presenting with polymyositis. Br Med J 1983; 286: 2024.

23 Tse S, Saunders EF, Silverman E et al. Myasthenia gravis and polymyositis as manifestations of chronic GVHD. Bone Marrow Transplant 1999; 23: 397-399. Article MEDLINE

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Table 1 Treatment results for polymyositis associated with chronic GVHD