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Rheumatology 2003; 42: 34-39
© 2003 British Society for Rheumatology

Polymyositis as a manifestation of chronic graft-versus-host disease

A. M. Stevens1,2,, K. M. Sullivan3 and J. L. Nelson1,2

1 University of Washington and
2 Fred Hutchinson Cancer Research Center, Seattle, WA and
3 Duke University Medical Center, Durham, NC, USA.


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objective. Chronic graft-versus-host disease (GVHD) after haematopoietic stem cell transplantation (HSCT) has similarities to some idiopathic autoimmune diseases, including polymyositis. To investigate the relationship between chronic GVHD and idiopathic myositis we conducted a detailed analysis of all cases of myositis occurring in a large series of HSCT patients.

Methods. We conducted a retrospective chart review of all cases of myositis that developed in 7161 patients who underwent HSCT at the Fred Hutchinson Cancer Research Center between 1969 and 1999.

Results. Among 1859 individuals who developed chronic GVHD, 12 developed myositis. No patients developed myositis without chronic GVHD. Myositis was first identified between 7 and 55 months after transplantation. In histopathology, electromyography, laboratory values and response to immunosuppressive therapy, the cases resembled idiopathic polymyositis. Autoantibodies were found in eight cases.

Conclusions. Myositis in the chronic GVHD population occurred with an incidence higher than expected by chance, suggesting that muscle may be a target tissue for chronic GVHD. Recent studies have implicated allogeneic cells persisting after maternal–fetal cell transfer in selected autoimmune diseases, including myositis. This report lends support to the possibility that both idiopathic myositis and chronic GVHD-related myositis could involve allo-autoimmune responses.

KEY WORDS: Myositis, Autoimmune disease, Stem cell transplantation, Chimerism, Chronic graft-versus-host disease.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Idiopathic polymyositis (PM) is an inflammatory myopathy characterized by the subacute onset of proximal muscle weakness. By definition, patients have no other predisposing factors, such as a family history of neuromuscular disease, endocrinopathy, exposure to myotoxic drugs or toxins, or biochemical muscle disease [1]. Chronic graft-vs-host disease (GVHD) is a diverse syndrome of multi-organ inflammation that develops more than 100 days after allogeneic haematopoietic stem cell transplantation (HSCT) [2, 3]. Chronic GVHD occurs in 33–64% of allogeneic HSCT patients and is more frequent with advancing age and in patients with prior acute GVHD. Aspects of chronic GVHD that are reminiscent of autoimmune diseases include scleroderma, eosinophilic fasciitis, oesophagitis, biliary cirrhosis, sicca syndrome, lymphopenia, thrombocytopenia and antinuclear antibodies (ANA). Here we report the experience of PM in chronic GVHD at the Fred Hutchinson Cancer Research Center (FHCRC) over a 30-yr period. We describe 12 cases of PM that occurred in patients with chronic GVHD who received allogeneic stem cell transplantations in Seattle.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
A retrospective chart review was performed to identify all cases of myositis in patients who underwent HSCT at the FHCRC between 1969 and 1999. A total of 7161 patients received allogeneic (related or unrelated donors) or autologous bone marrow, cord blood or T cell-depleted peripheral stem cells. Of these, 5057 survived at least 100 days, long enough to have developed chronic GVHD. Of all of the patients who survived at least 100 days, 4018 had an allogeneic stem cell donor. Of these, 1859 were known to have developed clinical chronic GVHD and 1700 were known not to have developed chronic GVHD. For 459 patients there was insufficient information to determine whether chronic GVHD occurred, often because the patients died shortly after day 100. Patients were examined at the time of departure from Seattle on day 100. They were then followed by their local physicians and returned to Seattle on the yearly anniversaries of transplantation. Patients with chronic GVHD living in the Pacific Northwest were examined at 3- to 6-month intervals. The median time of continuous follow-up was 7.1 yr, with a range of 100 days to 30.1 yr. The follow-up studies included a thorough physical examination, complete blood count, viral titres and liver, thyroid and pulmonary function tests.

For this study the diagnosis of PM was made on the basis of four generally accepted criteria [4]: (i) proximal muscle weakness; (ii) electromyography showing small, short-duration polyphasic motor unit potentials with or without spontaneous fibrillations; (iii) muscle biopsy demonstrating endomysial lymphocytic infiltrate surrounding or invading individual non-necrotic muscle fibres; and (iv) elevated serum muscle enzymes (creatine kinase, aldolase, transaminases or lactate dehydrogenase). By this definition, the presence of two criteria is designated ‘possible PM’, three criteria ‘probable PM’ and four criteria ‘definite PM’. Skin, muscle and lip biopsies as well as barium swallow oesophograms and ophthalmological exams were performed as clinically indicated to evaluate the extent of disease. Histological assessment of chronic GVHD was based on biopsies of the skin, oral mucosa, salivary glands, liver and oesophagus. Necrosis of individual epithelial cells or lymphoplasmacytic inflammation with destruction of architectural features was considered evidence of active chronic GVHD. Serum samples were tested for ANA at the University of Washington. Sera were also assayed for specific myositis-associated antibodies by Dr Ira Targoff of the University of Oklahoma Research Foundation Clinical Immunology Laboratory by methods previously described [5].


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Among 1859 patients who developed chronic GVHD between 1969 and 1999, 12 were identified who also developed PM (Table 1Go). No patients who had autologous transplantation and no patients without chronic GVHD developed PM. The ages of the patients at the time of transplantation ranged from 4 to 46 yr, which is similar to the general transplantation population. Diseases for which transplants were performed were also similar to the overall transplantation population, consisting of acute and chronic myelogenous leukaemia, acute lymphocytic leukaemia and aplastic anaemia. One patient had pre-existing autoimmune disease: patient 7122 developed leukaemia as a consequence of cyclophosphamide therapy for Cogan's syndrome, Takayasu's arteritis and glomerulonephritis. No patients had been taking medications associated with increased risk of idiopathic PM between the time of transplantation until the time of PM onset. The donor source was a sibling for nine patients, a mother for one and an unrelated donor for two. Patient 1595 was transplanted with bone marrow from a matched sibling and with fetal thymus. All patients were matched with their donors for HLA-A, B, DR and DQ at the serological level, except patient 1603, who differed from her donor for one HLA-B antigen (the donor was B7,12 and the recipient was B7,7).


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  		TABLE 1. Characteristics of HSCT patients with PM

 
Tables 2Go and 3Go summarize the clinical courses of the chronic GVHD-PM patients. As defined by the onset of symptoms (weakness and muscle pain), myositis occurred from 7 to 55 months after transplantation. In five cases PM was part of the original presentation of chronic GVHD. Clinical weakness was present in all patients, and seven of the 10 patients tested had elevated levels of creatine kinase. In these patients the maximum creatine kinase level ranged from 454 to 8400 U/l. Four of six patients tested for aldolase had increased levels, and 11 of 12 had increased lactate dehydrogenase levels. All 11 patients tested for aspartate aminotransferase had increased levels, though the increase was less than two-fold in two patients. Five of six patients tested by electromyography had abnormal results, all of which were consistent with myositis. Seven of eight muscle biopsies performed showed histology typical of PM. By the Bohan and Peter criteria [4, 6], two patients fulfilled criteria for definite PM, eight patients had probable PM, and two possible PM. Of all of the PM criteria tested, only two gave negative results; the lack of criteria in all other cases was due to a lack of testing. Of the two patients with possible PM, patient 1353 had subjective and objective weakness with chronic GVHD as well as elevated liver enzymes, but normal histology by muscle biopsy 6 yr after the onset of symptoms, and the remaining PM criteria were never evaluated. She responded to immunosuppressive therapy, as would be expected in PM; steroid-induced, viral or neuropathic weakness would not be expected to respond to immunosuppression. Patient 5379 had only two criteria tested and responded to empirical treatment. All patients had evidence of chronic GVHD in other organs prior to and during the episode of myositis, including skin, mucous membranes (including sicca syndrome), lungs, liver and oesophagus (Table 2Go). Pulmonary function testing demonstrated that the lung disease was obstructive in two patients and restrictive in four patients. Arthritis, which can accompany idiopathic PM, was found in four patients and morning stiffness without clinical evidence of arthritis in two additional patients.


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  		TABLE 2. The course of PM in chronic GVHD

 

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  		TABLE 3. Diagnostic criteria for PM in chronic GVHD patients

 
Autoantibodies have been demonstrated previously in chronic GVHD patients [7]. Autoantibodies were detected in eight of 12 patients (data not shown). Five patients had ANA, four had anti-smooth muscle antibodies, and one had anti-mitochondrial antibodies. No myositis-specific autoantibodies were found, with the exception of antibodies to the U4/6 small nuclear RNA synthetase complex in one serum. Unidentified bands reflecting antibody reactivity to unidentified proteins were noted in several sera.

The responses of the chronic GVHD-PM patients to immunosuppressive therapy were similar to what has been observed in idiopathic PM: 11 patients responded quickly to prednisone and either azathioprine or cyclosporin A, with clinical remission and/or a normal creatine kinase level within 2–7 months. Patient 1844 relapsed on three separate occasions, but responded quickly each time to increased prednisone doses. One patient had not responded to immunosuppressive therapy by 48 months, the latest date of available follow-up data.

HLA associations have been described with PM and PM-specific antibodies, most frequently the DR3/B8 haplotype [5, 8–11]. We investigated HLA associations in the GVHD-PM patients (Table 4Go). Most patients in this series underwent transplantation prior to the advent of DNA typing techniques, so HLA phenotypes were defined using serological techniques. Among the 12 chronic GVHD-PM patients, one carried the B8/DR3 haplotype (8.3%) whereas in the total transplant population B8/DR3 is present in 23%. Therefore, in the 12 chronic GVHD-PM patients reported here, the strongest myositis-associated HLA phenotype frequency was not increased, although the patient numbers are not large enough to evaluate with significance.


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  		TABLE 4. Serologically determined HLA antigens of patients with myositis and chronic GVHD

 


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
The cases described in this report demonstrate that PM can occur as part of the constellation of manifestations of chronic GVHD. It is unlikely that chronic GVHD-PM occurred in these patients by coincidence, as the incidence of PM found in the HSCT population is higher than in the general population. The incidence in the general population for PM, dermatomyositis and inclusion body myositis combined has been estimated to be 1.8 per 100 000 person-years in a combined population from three independent studies [12] and 0.55 per 100 000 person-years in two large studies performed in different parts of the USA [13, 14]. Among the 4018 allogeneic HSCT recipients who survived at least 100 days there were 12 cases of PM. Considering the mean follow-up time was 13.2 yr, the incidence of PM in the total HSCT population was 23 per 100 000 person-years. Among only the 1859 chronic GVHD patients, the incidence of PM was 49 per 100 000 person-years. Moreover, the incidence of PM in the chronic GVHD population is probably underestimated, as many cases may go unrecognized and patients with severe chronic GVHD may die before developing PM. The incidence of PM in general population studies cannot be compared directly with the incidence in the HSCT or chronic GVHD population because of potential differences in population age, race and sex ratio, all of which affect the risk of PM by two- to three-fold. Nonetheless, it would be difficult to explain the substantially greater incidence in the chronic GVHD population by differences in population characteristics, suggesting a true association between chronic GVHD and PM.

Prior reports have described PM in chronic GVHD [15], but whether PM is a manifestation of chronic GVHD or occurs coincidentally is controversial [16–24]. Most reports have been of single cases. One case series suggested that the frequency of PM in chronic GVHD is too high to be merely coincidental [22]. In this report, 11 cases were found among 705 HSCT patients who survived more than 100 days after transplantation, 318 of whom developed chronic GVHD. Although the follow-up periods are not defined in this report, it appears as if PM occurred more frequently than in our population of chronic GVHD patients. As in our study, the patients in prior reports shared characteristics with idiopathic PM, including the acute or subacute onset of weakness, elevated muscle enzymes, typical pathology noted on muscle biopsy, and electromyographic patterns.

The PM in the chronic GVHD patients described here resembles idiopathic PM in many clinical and laboratory aspects. Each of the diagnostic criteria for idiopathic PM was found in the chronic GVHD patients, including muscle weakness, histology, EMG pattern and elevated muscle enzymes. In addition, in contrast to the obstructive lung disease usually found in association with chronic GVHD, the lung disease found in the chronic GVHD-PM patients was more often restrictive, as can be seen in idiopathic PM patients. Anti-synthetase antibodies were found in one patient. These myositis-associated antibodies are specific for myositis, but the assay has low sensitivity. In one report 49% of PM patients had no detectable myositis-specific antibodies [9]. Because HLA phenotypes have been associated with increased risk of idiopathic myositis, we examined HLA phenotypes in the chronic GVHD-PM patients. The patients described here are too few for HLA associations to be evaluated adequately.

There were no other apparent factors in the patient histories that may have predisposed them to developing myositis, such as thyroid disease, active viral infections or myotoxic medications. It has been suggested that a female donor may be a risk factor for chronic GVHD-related PM by virtue of allosensitization during pregnancy [13]. This could also occur by transfer of persistent allogeneic fetal cells from previous pregnancies along with the HLA-matched donor cells. Although in one initial report nine of 11 donors were female [12], of the total cases reported thus far in the literature, only 14 of 22 donors (63%) were female [16, 17, 19, 20, 22–26]. In our population, however, only six of 12 donors (50%) were female, suggesting no increased risk contributed by female donors.

It is known that in chronic GVHD donor cells infiltrate the skin and mucous membranes. Presumably the lymphocytic infiltration found in chronic GHVD-associated myositis is also composed of donor cells, as the host's circulating cells have been eliminated in the pretransplantation conditioning regimen. In idiopathic PM the foreign cells could come from pregnancy-derived microchimerism: fetal cells in the case of women who have been pregnant and other sources, such as maternal cells, in men, children, and women who have never been pregnant. Maternal cells have been found in muscle tissue of children with PM and dermatomyositis [27, 28], suggesting they may be involved in the disease process. There is experimental evidence to suggest that allogeneic lymphocytes of particular genetic backgrounds may be involved in myositis. Transferring parental splenocytes into some strains of mice can reproduce a disease very similar to human systemic lupus erythematosus with myositis [29]. The mice have ANA and glomerulonephritis, as well as typical myositis-associated electromyography patterns, anti-amino acid tRNA synthetase antibodies, anti-transfer RNP antibodies and lymphocytic lung infiltrates.

In conclusion, the cases reviewed in this report support the hypothesis that muscle tissue is a target for chronic GVHD in HSCT patients. PM occurred more frequently than expected by chance in the chronic GVHD population. The cases of chronic GVHD-related myositis were similar to idiopathic myositis in clinical features and responses to therapy. Recent studies have implicated allogeneic cells persisting after maternal/fetal cell transfer in selected autoimmune diseases, including myositis. This report lends support to the possibility that both idiopathic myositis and chronic GVHD-related myositis could involve allo-autoimmune responses.


   Acknowledgments
 
This work was supported by a grant from the Arthritis National Research Foundation and National Institutes of Health grant NIH-AI-45659.


   Notes
 
Correspondence to: A. M. Stevens, Fred Hutchinson Cancer Research Center, Immunogenetics, D2-100, 1100 Fairview Avenue NE, Seattle, WA 98109, USA. E-mail: astevens{at}fhcrc.org Back


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 13 March 2002; Accepted 21 May 2002


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