Graft-Versus-Host Disease

Steroid myopathy in patients with acute graft-versus-host disease treated with high-dose steroid therapy

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Abstract

High-dose steroids are the first line of treatment for acute graft-versus-host disease (aGVHD). Steroid myopathy is a debilitating steroid-induced complication that significantly impairs a patient's performance status. To determine the frequency and severity of steroid myopathy and other steroid related complications in patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) who developed grade 2 aGVHD after allogeneic hematopoietic stem cell transplantation (HSCT), we performed a retrospective analysis. Patients were included in the analysis if they had a diagnosis of AML/MDS, underwent an allogeneic HSCT between January 1996 and December 2001 and developed grade 2 aGVHD that was treated with 2 mg/kg of methylprednisolone and survived at least 100 days post transplant. A total of 70 patients fulfilled our inclusion criteria. Steroid myopathy was identified in 29 (41%) patients. Steroid myopathy was generally of moderate severity with severe debilitating steroid myopathy seen in only 3% of patients. We concluded that steroid myopathy is a common complication of high-dose steroid therapy after allogeneic HSCT in AML/MDS. Interventions aimed at preventing and treating this complication are warranted and need to be explored in prospective clinical trials.

Introduction

Allogeneic hematopoietic stem cell transplantation (HSCT) is an important and frequently used method for treating hematologic malignancies.1 One of the major complications of allogeneic HSCT is acute graft-versus-host disease (aGVHD).2, 3 Despite receiving cells from a fully matched human leukocyte antigen (HLA) related or unrelated donor and modern immunesuppressive therapy, moderate to severe aGVHD still occurs in up to 30% of patients receiving HCST.4, 5, 6 High-dose steroids are the standard first-line treatment of aGVHD.5, 6, 7, 8 High-dose steroids, while effective, are also associated with a significant incidence of serious and diverse side effects that can increase the morbidity of the transplant procedure and contribute to aGVHD mortality.6, 7

Steroid myopathy, originally described by Cushing8 in 1932, is a serious and debilitating complication of steroid therapy. The clinical presentation is most often insidious, although it can be acute, particularly when high-dose steroids are used. In neuro-oncology patients, the development of steroid myopathy was associated with an increased risk of morbidity and mortality.9

To determine the frequency, spectrum of severity, and potential factors associated with the development of steroid myopathy after allogeneic HSCT, we conducted a retrospective analysis of patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) who underwent allogeneic HSCT and who received high-dose steroids as treatment of aGVHD. Herein are the results of our analysis.

Patients and methods

Patients were considered for analysis if they fulfilled all of the following criteria: received an allogeneic HSCT between January 1996 and December 2001 for AML/MDS; developed aGVHD grade 2; received at least 2 mg/kg of methylprednisolone for the treatment of aGVHD; and survived at least 100 days post transplant.

One hundred seventy-eight patients were transplanted during our study period, of which 70 patients fulfilled all our inclusion criteria and were eligible for retrospective analysis. Information abstracted from the charts and the prospectively maintained BMT database included gender, age, ethnicity, height, weight, history of hypertension, diabetes, as well as disease and transplant-related factors. Steroid dose and duration was scored in all cases. All patients were treated on institutionally approved protocols, and signed written informed consent for therapy. This retrospective analysis was approved by the MDACC IRB according to institutional guidelines.

The following steroid-related complications were scored by chart or database review according to the following criteria:

  1. 1)

    Cataracts if documented by an ophthalmologist.

  2. 2)

    Headaches if documented in the patient's chart by the primary team.

  3. 3)

    Mood swings if pharmacologic therapy was instituted or when diagnosed by a mental health care provider.

  4. 4)

    Hypertension if documented by two consecutive days of blood pressure greater than 140/90 or by the initiation of antihypertensive medication.

  5. 5)

    Gastritis if documented by patient complaint or by endoscopy.

  6. 6)

    Hyperglycemia if documented by a glucose level of 200 mg/dl for two consecutive days or the initiation of a hypoglycemic agent.

  7. 7)

    Steroid myopathy was scored when documented by the attending physician or when evaluated by a physical therapist using the Functional Independence Measure (FIM) or Manual Muscle Exam (MME).

  8. 8)

    Avascular necrosis if documented on radiologic evaluation.

  9. 9)

    Edema if documented in the clinical record.

  10. 10)

    Hypokalemia, if potassium levels were 3.5 meq/dl for two consecutive days or with the introduction of potassium supplementation.

  11. 11)

    Infections were scored if documented in the medical records or as positive blood and tissue cultures.

Assessment of steroid myopathy

Patients with steroid myopathy were referred to physical and occupational therapy for baseline evaluation and therapy. Baseline evaluation included MME and FIM.10, 11, 12, 13 The MME is composed of upper and lower extremity strength tests against full to minimal resistance. The physical therapist examines the patient's ability to move their extremities in full range of motion as well as ability to move against resistance.12 FIM is the assessment of functional movements that are needed for daily activities, such as supine to sit, sit to stand, gait and balance. End points ranged from patient being fully independent (no devices, no caretaker's help) to requiring complete assistance.11, 13

Results

Patient and treatment characteristics

Patient demographics are summarized in Table 1. In brief, the median age was 47 (range 23–76); 80% of patients were Caucasian; 1% were African Americans, and 10% were Hispanic. Forty-three percent of patients received progenitor cells from an HLA-matched sibling, 91% of the patients received tacrolimus/methotrexate for GVHD prophylaxis and 54% received a myeloablative conditioning regimen.

Table 1 Patient and treatment characteristics

Steroid-induced complications

Table 2 summarizes the prevalence of steroid-induced complications in the study population. Thirteen complications were scored from the retrospective chart review. The most common complications were bacterial infection, hypokalemia, viral infections, hypertension and hyperglycemia. Myopathy was documented in 41% of the patient population.

Table 2 Frequency of steroid complications

Severity and characteristics of steroid myopathy

The MME and FIM were evaluated by a physical therapist on patients diagnosed with steroid-induced myopathy and results are shown in Tables 3 and 4. A total of 29 patients were eligible for the physical evaluation but data for three patients were unavailable. Eleven patients had MME scores of 3 in upper extremity MME (movement in full range of motion with gravity eliminated), whereas 13 patients had MME scores of 3 in their lower extremities. These scores constitute moderate myopathy from a functional standpoint as these patients are unlikely to independently transfer or ambulate with this grade of muscle strength. Patients with an MME score of 4 (movement in full range of motion against some resistance) may be able to do both independently, but this is not guaranteed; in this series, 11 and 12 patients had MME scores of 4 in upper and lower extremity testing, respectively.

Table 3 Results of manual muscle testing
Table 4 Results of functional independence measure assessments

As a reflection of the degrees of muscle strength decrease only 31% of patients were totally independent when changing from the supine to sitting position, 28% were totally independent when changing from the sitting to standing position and 14% of patients were totally independent when performing gait examination. However, extremely severe steroid myopathy requiring complete assistance in all three FIM was seen only in 3% of patients.

Steroid-induced myopathy and associated variables

Clinical and demographic characteristics of patients who developed myopathy were compared to the characteristics of those who did not develop this complication using the χ2-test or Fisher's exact test for categorical values and the Wilcoxon rank-sum test for continuous variables. The distribution of clinical and demographic characteristics among patients with and without myopathy to explore potential associations between pre-transplant factors and steroid myopathy is summarized in Table 5. Patient and clinical characteristics were similar in both groups except for a higher median weight among patients who developed myopathy (P=0.06), and a lower prevalence in patients with myopathy among male patients with female donors (P=0.05).

Table 5 Characteristics of patients with and without steroid myopathy

Discussion

High-dose steroid therapy is currently the most effective initial treatment for aGVHD after allogeneic HSCT.5 High-dose steroid therapy is associated with a variety of adverse side effects including infections, hyperglycemia, hypertension, hypokalemia, insomnia and steroid myopathy.14 The spectrum of adverse effects of high-dose steroid therapy as treatment of aGVHD has not been well described; patients with aGVHD may be more prone to steroid-induced side effects than patients with other inflammatory or autoimmune conditions owing to their prior therapy and their underlying immune deficiency.15 This retrospective analysis suggests that the spectrum of steroid-induced complications in the setting of aGVHD is similar to that reported for other inflammatory or autoimmune conditions, although the rates of infection complications are higher.16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 Insomnia and other sleep disturbances were not assessed in this retrospective analysis owing to the difficulty in assessing this complication in patients who were routinely taking sleeping medications before beginning high dose steroids for acute GVHD.

Steroid myopathy is a particular debilitating side effect of high-dose steroid therapy.9 Steroids exert catabolic effects on skeletal muscles by stimulating the ubiquitin–proteasome proteolytic pathway that may ultimately lead to steroid myopathy.31 Proximal lower muscles are commonly involved, quadriceps muscles being most severely affected. The most susceptible fibers to this complication are the fast-twitch glycolytic type IIB.32 No known therapy exists to prevent or enhance recovery after the development of steroid-induced myopathy although physical activity has been reported to prevent its development.33, 34

Our analysis suggests that steroid myopathy is a relatively common complication of high-dose steroid therapy for aGVHD. We limited our analysis to patients with AML/MDS and to patients surviving at least 100 days post transplant to avoid the confounding factors of prior steroid therapy as treatment for the primary malignant disorder, and early deaths from other transplant complications immediately after institution of steroid therapy for aGVHD. The prevalence of 41% is an under-representation of the problem, as some patients may have developed myopathy and died before day 100, but were not included in this analysis. Based on our inclusion criteria, 15 patients who developed acute GVHD and received high-dose steroid therapy died before day 100 and were excluded from this analysis. Only a prospective study can define the true incidence and prevalence of steroid myopathy in this patient population. However, a 41% incidence of steroid myopathy is significant and supports the development of prospective diagnostic and intervention studies in this patient population.

Steroid myopathy was associated with a moderate to severe degree of functional impairment. Only 31% of our patients were able to go from a supine to sitting position independently, and only 28% were able to go from a sitting to a standing position independently. When considered as a time-dependent variable, the hazard rate for death in patients developing any steroid myopathy on univariate analysis is 1.6 (95% confidence interval (CI): 0.8–3.2), the lack of statistical significance should be interpreted with caution as the number of patients is small, and limiting the analysis to patients who survived at least 100 days post transplant could have potentially eliminated patients with the most severe forms of myopathy.

We could not perform a systematic evaluation of predictors of myopathy as this study was retrospective in nature and limited to patients surviving at least 100 days post transplant. However, by describing the observed differences among patients with and without steroid myopathy, it is possible to generate hypothesis that can later be tested either in cohort or prospective studies. In this descriptive exploratory evaluation, patient weight was the only factor seen to be associated with the development of myopathy and warrants further study. The observed difference in the proportion of male patients receiving a female donor in the myopathy group could be related more to the increase in the risk of death before day 100 among this group of patients.

Steroid-induced myopathy usually affects proximal muscles and preferentially affects the lower limbs, quadriceps being the most frequently affected muscles.32 We were unable to observe a significant difference in muscle strength between upper and lower body. However, the number of patients was small, and only a limited number of tests were performed, and the confounding effects of deconditioning that results from prolonged hospitalization could explain these results.

In summary, steroid myopathy is a common complication of high-dose steroid therapy for the treatment of aGVHD in patients with AML/MDS undergoing allogeneic HSCT. It is associated with moderate to severe functional impairment and may be associated with an increased risk of mortality. Prospective studies are needed to further define the incidence and prevalence of this disorder, as well as to define risk factors that would be useful in planning prospective trials for prevention and treatment of this complication.

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Correspondence to S Giralt.

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Lee, H., Oran, B., Saliba, R. et al. Steroid myopathy in patients with acute graft-versus-host disease treated with high-dose steroid therapy. Bone Marrow Transplant 38, 299–303 (2006) doi:10.1038/sj.bmt.1705435

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Keywords

  • steroid complications
  • stem cell transplantation
  • graft-versus-host disease

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