Just Accepted by Modern Rheumatology
Corticosteroid-sparing effect of tacrolimus in the initial treatment of dermatomyositis and polymyositis Yusuke Yokoyama, Shunsuke Furuta, Kei Ikeda, Koichi Hirose, and Hiroshi Nakajima 10.3109/14397595.2015.1029239 Mod Rheumatol Downloaded from informahealthcare.com by University of Connecticut on 04/11/15 For personal use only.
Abstract Objective. In the treatment of polymyositis (PM) and dermatomyositis (DM), muscle inflammation and underlying autoimmunity need to be suppressed promptly; however, catabolic effects of corticosteroids such as myopathy can be detrimental in PM/DM. In this study, we aimed to assess the corticosteroid-sparing effect of tacrolimus in the initial treatment for PM/DM. Methods. We retrospectively identified 19 PM/DM patients who received initial treatment with prednisolone at an initial dose of 1mg/kg/ day (Conventional Monotherapy, our standard therapy before 2008) and 23 patients with tacrolimus plus prednisolone at an initial dose 0.8mg/ kg/day (Tacrolimus Combination, our standard therapy after 2008). Data until 36 months after commencing treatment were collected. Results. There were no statistically significant differences in baseline characteristics between two groups. Median daily dose of prednisolone in the Tacrolimus Combination group was significantly lower than that in the Conventional Monotherapy group at all time during the study period, whereas the proportion of patients who required additional immunosuppressive medications for remission induction was comparable. Remission was achieved in all patients but one who died of refractory interstitial lung disease after receiving Conventional Monotherapy. The time required for creatine kinase normalization and relapse rate were comparable between two groups. The period of hospitalization for initial treatment was significantly shorter and survival without serious infection or relapse tended to be longer in the Tacrolimus Combination than the Conventional Monotherapy. Conclusion. This study provides real-life data which demonstrate that tacrolimus has a corticosteroid-sparing effect and reduces the length of hospitalization period for the initial treatment of PM/DM.
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Original Article
Corticosteroid-sparing effect of tacrolimus in the initial treatment of dermatomyositis and polymyositis
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Yusuke Yokoyama, Shunsuke Furuta, Kei Ikeda, Koichi Hirose, and Hiroshi Nakajima
Department of Allergy and Clinical Immunology, Chiba University Hospital, Japan.
Correspondence to: Dr. Shunsuke Furuta, MD, PhD, Department of Allergy and Clinical Immunology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chibashi, Chiba 260-8670, Japan. E-mail: [email protected]
Short title: Tacrolimus as initial treatment for PM/DM
MORH-D-15-00038 Received: Jan-21-15; Accepted: Mar-11-15
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Abstract Objective. In the treatment of polymyositis (PM) and dermatomyositis (DM), muscle inflammation and underlying autoimmunity need to be suppressed promptly; however, catabolic effects of corticosteroids such as myopathy can be detrimental in PM/DM. In this study, we aimed to assess the corticosteroidsparing effect of tacrolimus in the initial treatment for PM/DM. Methods. We retrospectively identified 19 PM/DM patients who received initial treatment with prednisolone at an initial dose of 1mg/kg/day (Conventional
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Monotherapy, our standard therapy before 2008) and 23 patients with tacrolimus plus prednisolone at an initial dose 0.8mg/kg/day (Tacrolimus Combination, our standard therapy after 2008). Data until 36 months after commencing treatment were collected. Results. There were no statistically significant differences in baseline characteristics between two groups. Median daily dose of prednisolone in the Tacrolimus Combination group was significantly lower than that in the Conventional Monotherapy group at all time during the study period, whereas the proportion of patients who required additional immunosuppressive medications for remission induction was comparable. Remission was achieved in all patients but one who died of refractory interstitial lung disease after receiving Conventional Monotherapy. The time required for creatine kinase normalization and relapse rate were comparable between two groups. The period of hospitalization for initial treatment was significantly shorter and survival without serious infection or relapse tended to be longer in the Tacrolimus Combination than the Conventional Monotherapy. Conclusion. This study provides real-life data which demonstrate that tacrolimus has a corticosteroid-sparing effect and reduces the length of hospitalization period for the initial treatment of PM/DM. Key words: Polymyositis; Dermatomyositis; Tacrolimus; Corticosteroid Introduction Polymyositis (PM) and dermatomyositis (DM) are the major sub-groups of idiopathic inflammatory myopathy [1, 2]. Symmetrical weakness in the proximal muscles and elevated serum levels of skeletal muscle-derived enzymes are the characteristic manifestations of
2
myositis in PM/DM, which is confirmed by electromyogram, imaging, and muscle biopsy [1-4]. For extra-muscular manifestation, DM is further characterized by the presence of skin manifestations and both PM and DM can accompany interstitial lung disease (ILD). The pathogenesis of PM/DM remains largely unknown. However, the association with certain types of human leukocyte antigen (HLA) [5] and the presence of
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disease specific antibodies to self-antigens such as RNA synthetases [6] strongly suggest the involvement acquired immunity in the pathogenesis of PM/DM. Particularly, activated T cells are considered to play a significant role in the process of muscle injury based on the histopathological findings from patients [7] and experiments using human specimens [8,9] and mouse models [10]. PM/DM considerably decreases the patient’s physical function and quality of life and can cause severe disability and death [11]. For the treatment of PM/DM, high-dose corticosteroids have been used to suppress inflammation and underlying autoimmunity [12]. However, a wide range of side effects is accompanied by the corticosteroid therapy, depending on the dose and the period [13], and some of these side effects such as steroid myopathy, osteoporosis, and obesity can substantially affect the patient’s physical function. Given that preventing disability is the major aim of the treatment, a new strategy to reduce the dose and the period of corticosteroids is needed. Tacrolimus is an immunosuppressant which inhibits calcineurin and suppresses T-cell activation and IL-2 transcription. Tacrolimus is efficacious in the management of organ transplant [14] and in the treatment of autoimmune diseases such as systemic lupus erythematosus [15] and rheumatoid arthritis [16]. Successful treatment with tacrolimus in
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patients with PM/DM has also been reported for refractory myositis [17,18] and ILD [1820]. In our institute, the standard initial therapy for PM/DM without severe ILD was a high-dose corticosteroid monotherapy with 1mg/kg/day of prednisolone. At 2008, however, we changed the standard initial therapy to a combination therapy with tacrolimus
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plus 0.8mg/kg/day of prednisolone, aiming to reduce the total dose of corticosteroids and subsequent adverse events. Effectiveness of other immunosuppressants, such as methotrexate or cyclosporine [21], for refractory PM/DM was also reported. However, their efficacy was unproved in randomized controlled trials, and superiority or inferiority of those for PM/DM was still unknown. Tacrolimus was the agent we had the most experience for refractory PM/DM at 2008, therefore we chose tacrolimus as a concomitant with corticosteroids. In the present study, we retrospectively investigated the PM/DM patients who received initial therapy in our institute. We compared the efficacy and safety between treatment with tacrolimus plus a reduced dose of prednisolone and that with a high-dose prednisolone alone to assess the corticosteroid-sparing effect of tacrolimus in the initial treatment for PM/DM. Patients and methods Patients. We reviewed the medical records of patients who were newly diagnosed with PM/DM and were admitted to Department of Allergy and Clinical Immunology, Chiba University Hospital from January 2000 to December 2012. We identified 77 sequential patients who fulfilled the criteria of Bohan and Peter for PM, DM [1], or Southeimer for amyopathic DM
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[22]. Among these patients, 19 patients received treatment with prednisolone at an initial dose of 1mg/kg/day (Conventional Monotherapy group) and 23 patients received treatment with tacrolimus plus prednisolone at an initial dose 0.8mg/kg/day (Tacrolimus Combination group). Thirty-five patients were not able to be categorized to either group for the following reasons: 6 patients received cyclosporine (another calcineurin inhibitor), 2 patients with
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rapidly progressive ILD received methylprednisolone pulse therapy, 7 patients participated a clinical trial, 6 patients received prednisolone at a lower initial dose, 1 patient with dysphagia received intravenous administration of prednisolone, 1 patient could not continue tacrolimus for extremely unstable blood concentration, 3 patients with preceding diagnosis of rheumatoid arthritis were receiving methotrexate, 7 patients had an advanced cancer and received no or less potent therapy, 1 patient with predominant skin manifestation but with minimal muscle and lung involvement did not receive systemic immunosuppressive treatment, and 1 patient refused to receive treatment. These patients were excluded from further analyses. Treatment with prednisolone and tacrolimus. In both the Conventional Monotherapy and the Tacrolimus Combination groups, the dose of prednisolone was kept at the initial dose for 4 to 8 weeks and was tapered with our corticosteroid reducing regimen (-10% every 2 weeks) unless the patient showed any signs of flare. In the Tacrolimus Combination group, the initial daily dose of tacrolimus was 3mg. We adjusted the dose of tacrolimus repeatedly, targeting a trough plasma concentration at 612 ng/ml. Assessment.
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We retrospectively assessed the baseline patient and disease characteristics, including age, sex, body weight, diagnosis, anti Jo-1 antibody positivity, presence of malignancy, presence of ILD, and the serum levels of creatine kinase (CK), aldolase, and KL-6. We also collected data on the use of immunosuppressive medications and the daily prednisolone dose at 0, 6, 12, and 36 months after commencing treatment. The reasons for change in
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immunosuppressive medication were assessed if applicable. In addition, we collected clinical information until 36 months after commencing treatment. For the assessment of treatment response, we collected data on the achievement of remission, the period from initiation of therapy to CK normalization, the period of hospitalization for initial treatment, and the occurrence of relapse. In the patients who achieved CK normalization without worsening of symptoms (e.g. muscle pain, weakness, erythema, dyspnea and cough), remission was subjectively determined by the physicians. Physicians determined the time of hospital discharge considering disease activity and activities of daily living. Relapse was defined as a state in which the physician escalated the immunosuppressive medication due to a new symptom and/or a recurrence of symptoms of PM/DM after once achieving remission. For the safety assessment, we collected data on serious adverse events including serious infection. A serious adverse event was defined as an event which necessitated hospitalization due to any causes. We also analyzed event-free survival which was defined as survival without relapse or serious adverse events as a composite outcome. Statistical analysis. Statistical analysis was performed using SPSS version 22.0 (IBM Japan, Tokyo, Japan). Continuous data were summarized with median and interquartile ranges (IQR) and were compared using Mann-Whitney U test. Categorical data were summarized with percentage
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and were compared using chi-square or Fisher’s exact test. Cumulative event rates were demonstrated using Kaplan-Meier methods and were compared using log-rank test. P values less than 0.05 were considered statistically significant. Ethical approval. The Ethics Committee of Chiba University School of Medicine approved this study. Results
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Patient and disease characteristics at baseline. Table 1 shows the baseline characteristics of the PM/DM patients who received the Conventional Monotherapy and the Tacrolimus Combination therapy. Three patients in the Conventional Monotherapy group and five patients in the Tacrolimus Combination group were classified as clinically amyopathic dermatomyositis. As compared with patients in the Tacrolimus Combination group, those in the Conventional Monotherapy group had a smaller proportion of DM, a younger median age, lower median levels of muscle enzymes, a higher median level of KL-6, a higher prevalence of anti-Jo-1 antibody positivity, and a higher prevalence of ILD. However, all of these numerical differences between the Conventional Monotherapy group and the Tacrolimus Combination group were not statistically significant. At baseline no malignancy was detected in 42 patients in this analysis. Of 35 patients who were excluded from the analysis, 7 patients had malignancy at baseline and recieved no or less potent therapy as mentioned in the Materials and Methods section. Observation period. Of 42 patients analyzed, 31 patients had completed the follow-up period of 36 months. The remaining 11 patients had not completed the follow-up period due to either death (n=1),
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changing hospital (n=2), voluntary discontinuation of therapy after 9 months (n=1), and recent treatment initiation (n=7). Treatment. As shown in Figure 1, the daily dose of prednisolone in the Tacrolimus Combination group was significantly lower than that in the Conventional Monotherapy group at baseline
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(median 40mg vs. 60mg), at 6 months (median 14mg vs. 20mg), at 12 months (median 9mg vs. 15mg), and at 36 months (median 4.75mg vs. 10mg). In the Tacrolimus Combination group, median actual dose of tacrolimus was 3mg/day with a range of 1mg/day to 6mg/day. Tacrolimus was discontinued before 36 months in five patients due to either pregnancy (n=1), adverse events (n=2, one dysgeusia and one posterior reversible encephalopathy syndrome), or insufficient response at early stage (n=2, they started receiving cyclosporine). None of the five patients had disease exacerbation at the time of discontinuation. Proportion of patients who required additional immunosuppressive medications for remission induction of PM/DM tended to be smaller in the Tacrolimus Combination group (n=5, 22 %) than that in the Conventional Monotherapy group (n=6, 32 %) although this did not reach statistical significance (P=0.50, chi-square test). The additional immunosuppressive medications included cyclosporine (n=5), methylprednisolone pulse therapy (n=1), increased dose of prednisolone (n=1), and intravenous cyclophosphamide (n=1) in the Conventional Monotherapy group; and methotrexate (n=4), methylprednisolone pulse therapy (n=2), intravenous immunoglobulin (n=2), and cyclosporine (n=1, tacrolimus was discontinued) in the Tacrolimus Combination group. Treatment response and relapse.
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Table 2 summarizes the outcomes during 36-month follow-up period after commencing treatment in the Conventional Monotherapy group and the Tacrolimus Combination group. Clinical remission was achieved in all patients by the end of study period except for one in the Conventional Monotherapy group who died two months after commencing therapy. As shown in Table 2 and Figure 2, the time period required for CK normalization was
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comparable between Conventional Monotherapy and Tacrolimus Combination. However, hospitalization period for remission induction was significantly shorter in the Tacrolimus Combination group than in the Conventional Monotherapy group (Table 2). The proportion of relapsing patients was also comparable between these two groups (Table 2). Relapse was identified six times in total in five patients in the Conventional Monotherapy group, while none of four patients with relapse in the Tacrolimus Combination group had second relapses. For the treatment of relapse, cyclosporine (n=4), increased dose of prednisolone (n=4), and methylprednisolone pulse therapy (n=1) were used in the Conventional Monotherapy group, whereas increased dose of prednisolone (n=5), methotrexate (n=3), and cyclosporine (n=1) were used in the Tacrolimus Combination group. Serious adverse events. As shown in Table 3, during 36-month follow-up period, serious adverse events were identified in a larger proportion of patients in the Conventional Monotherapy group than in the Tacrolimus Combination group (42% vs. 35%). Serious infections and cataract were also identified in a larger proportion of patients in the Conventional Monotherapy group than in the Tacrolimus Combination group (21% vs. 13%, 16% vs. 9%, respectively). Serious infections consisted of bacterial pneumonia (n=1), pneumocystis pneumonia (n=1),
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cytomegalovirus pneumonia (n=1), and herpes zoster (n=1) in the Conventional Monotherapy group, and bacterial pneumonia (n=3) in the Tacrolimus Combination group. One patient was diagnosed with ovarian cancer 8 months after diagnosis of myositis and given chemotherapy. One patient in the Conventional Monotherapy group had a myocardial infarction, whereas 1 patient in the Tacrolimus Combination group had an episode of
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posterior reversible encephalopathy syndrome. Event-free survival. Difference in the survival without relapse or serious infections during 36-month follow-up period was not statistically significant between the Conventional Monotherapy and the Tacrolimus Combination groups; however, the survival curves tended to favor the Tacrolimus Combination over the Conventional Monotherapy (Figure 3). Discussion This study demonstrates for the first time that tacrolimus combined with a reduced dose of corticosteroid (prednisolone 0.8mg/kg/day) can have therapeutic effectiveness which is comparable to conventional high-dose corticosteroid (prednisolone 1.0mg/kg/day) in the initial treatment for PM/DM without severe ILD. Since the Tacrolimus Combination regimen actually resulted in the administration of smaller doses of prednisolone than did the Conventional Monotherapy regimen throughout the 3-year study period, our data strongly suggest that tacrolimus has a corticosteroid-sparing effect in the standard initial treatment for PM/DM. In this study, “spared” dose of prednisolone was 0.2mg/kg/day, approximately 10mg/day in our patients. Whether this reduction outweighs the cost and the risk of tacrolimus treatment is a matter of debate. Saag KG et al. demonstrated that side effects of
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corticosteroids are largely dose dependent and 10mg difference is clinically important [23]. In fact, patients in the Tacrolimus Combination group in our study less frequently developed serious adverse events which are associated with corticosteroids such as serious infections, cataract, and myocardial infarction than did those in the Conventional Monotherapy group although the differences did not reach a statistical significance probably due to the small
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sample size (Table 3). Moreover, the period of hospitalization for initial treatment was significantly shorter with the Tacrolimus Combination than with the Conventional Monotherapy (Table 2). The cost of hospitalization both for the initial treatment of PM/DM and for adverse events needs to be taken into account when the benefit of tacrolimus coadministration is balanced against its direct cost. On the other hand, tacrolimus also has side effects in common with corticosteroids such as infections and diabetes mellitus and those distinct from corticosteroids such as renal dysfunction and thrombotic microangiopathy [24]. One patient who received the Tacrolimus Combination therapy developed posterior reversible encephalopathy syndrome, a form of thrombotic microangiopathy. Although thrombotic microangiopathy is an infrequently occurring event, possibility of such a severe side effect cannot be ignored. This study has several limitations. First, because this is a retrospective study, we cannot exclude the possible bias in selecting the patients who were treated with regimens which did not fall into either group. Prednisolone tapering schedule may also have been influenced by physician’s opinion on the coadministration of tacrolimus. In a retrospective fashion of collecting data, we could not collect enough data for standardized disease activity measures of myositis such as manual muscle test (MMT), either [25, 26].
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Second, the sample size is small. Although this study only showed the tendency which favored the Tacrolimus Combination in the analyses for adverse events and overall event-free survival, a larger number of patients might have demonstrated statistically significant differences which would verify the advantage of tacrolimus coadministration. A larger sample size would also have allowed for multivariate analysis and subanalysis for
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non-myositis manifestations such as ILD. In summary, this study provides real-life data which demonstrate that the coadministration of tacrolimus has a corticosteroid-sparing effect and reduces the length of hospitalization period for the initial treatment of PM/DM without severe ILD. Our findings provide a rationale for a larger, multicenter, prospective study to verify the benefit of tacrolimus coadministration as a first-line treatment for PM/DM. ACKNOWLEDGEMENTS We thank all staff in Chiba University Hospital for the care and management of patients enrolled in this study and for their support in data collection. Conflict of interest None. References 1
Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med
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Med 1975;292:403-7. 3
Tanaka S, Ikeda K, Uchiyama K, Iwamoto T, Sanayama Y, Okubo A, et al. [18F]FDG
uptake in proximal muscles assessed by PET/CT reflects both global and local muscular
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inflammation and provides useful information in the management of patients with polymyositis/dermatomyositis. Rheumatology (Oxford) 2013; 52:1271-8. 4 Tomasova Studynkova J, Charva F, Jarosova K, Vencovsky J. The role of MRI in the assessment of polymyositis and dermatomyositis. Rheumatology (Oxford) 2007;46:1174–9. 5
O'Hanlon TP, Carrick DM, Arnett FC, Reveille JD, Carrington M, Gao X, et al.
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Immunogenetic risk and protective factors for the idiopathic inflammatory myopathies: distinct HLA-A, -B, -Cw, -DRB1 and -DQA1 allelic profiles and motifs define clinicopathologic groups in caucasians. Medicine (Baltimore) 2005;84:338-49. 6 Hamaguchi Y, Fujimoto M, Matsushita T, Kaji K, Komura K, Hasegawa M, et al. Common and distinct clinical features in adult patients with anti-aminoacyl-tRNA synthetase antibodies: heterogeneity within the syndrome. PLoS One. 2013;8:e60442 7 Dalakas MC. Muscle biopsy findings in inflammatory myopathies. Rheum Dis Clin North Am. 2002;28:779-98. 8
Goebels N, Michaelis D, Engelhardt M, Huber S, Bender A, Pongratz D, et al.
Differential expression of perforin in muscle-infiltrating T cells in polymyositis and dermatomyositis. J Clin Invest 1996;97:2905-10. 9 Fasth AE1, Dastmalchi M, Rahbar A, Salomonsson S, Pandya JM, Lindroos E, et al. T cell infiltrates in the muscles of patients with dermatomyositis and polymyositis are dominated by CD28null T cells. J Immunol. 2009;183:4792-9. 10 Rosenberg NL, Kotzin BL. Aberrant expression of class II MHC antigens by skeletal muscle endothelial cells in experimental autoimmune myositis. J Immunol. 1989;142:428994.
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11 Marie I, Hatron PY, Cherin P, Hachulla E, Diot E, Vittecoq O, et al. Functional outcome and prognostic factors in anti-Jo1 patients with antisynthetase syndrome. Arthritis Res Ther. 2013;15:R149. 12
Marie I, Mouthon L. Therapy of polymyositis and dermatomyositis. Autoimmun Rev
2011;11:6-13.
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Moghadam-Kia S, Werth VP. Prevention and treatment of systemic glucocorticoid side
effects. Int J Dermatol. 2010;49:239–48. 14 Gu J, Wu X, Lu L, Zhang S, Bai J, Wang J, et al. Role of steroid minimization in the tacrolimus-based immunosuppressive regimen for liver transplant recipients: a systematic review and meta-analysis of prospective randomized controlled trials. Hepatol Int. 2014;8:198-215. 15 Lee YH, Lee HS, Choi SJ, Dai Ji J, Song GG. Efficacy and safety of tacrolimus therapy for lupus nephritis: a systematic review of clinical trials. Lupus. 2011;20:636-40. 16 Lee YH, Woo JH, Choi SJ, Ji JD, Bae SC, Song GG. Tacrolimus for the treatment of active rheumatoid arthritis: a systematic review and meta-analysis of randomized controlled trials. Scand J Rheumatol. 2010;39:271-8. 17
Shimojima Y, Ishii W, Matsuda M, Tazawa K, Ikeda S. Coadministration of tacrolimus
with corticosteroid accelerates recovery in refractory patients with polymyositis/ dermatomyositis: a retrospective study. BMC Musculoskelet Disord 2012;13:228. 18
Kurita T, Yasuda S, Oba K, Odani T, Kono M, Otomo K, et al. The efficacy of
tacrolimus in patients with interstitial lung diseases complicated with polymyositis or dermatomyositis. Rheumatology (Oxford) 2015;54:39-44.
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Oddis CV, Sciurba FC, Elmagd KA, Starzl TE. Tacrolimus in refractory polymyositis
with interstitial lung disease. Lancet 1999;353:1762-3. 20
Ando M, Miyazaki E, Yamasue M, Sadamura Y, Ishii T, Takenaka R, et al. Successful
treatment with tacrolimus of progressive interstitial pneumonia associated with amyopathic dermatomyositis refractory to cyclosporine. Clin Rheumatol 2010;29:443-5.
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Aggarwal R, Oddis CV. Therapeutic advances in myositis. Curr Opin Rheumatol.
2012;24:635-41. 22
Sontheimer RD. Would a new name hasten the acceptance of amyopathic
dermatomyositis (dermatomyositis sine myositis) as a distinctive subset within the idiopathic inflammatory dermatomyopathies spectrum of clinical illness? J Am Acad Dermatol 2002;46:626-36. 23 Saag KG, Koehnke R, Caldwell JR, Brasington R, Burmeister LF, Zimmerman B, et al. Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events. Am J Med. 1994;96:115-23. 24
Jacobson P, Uberti J, Davis W, Ratanatharathorn V. Tacrolimus: a new agent for the
prevention of graft-versus-host disease in hematopoietic stem cell transplantation. Bone Marrow Transplant 1998;22:217-25. 25
Isenberg DA, Allen E, Farewell V, Ehrenstein MR, Hanna MG, Lundberg IE, et al.
International consensus outcome measures for patients with idiopathic inflammatory myopathies. Development and initial validation of myositis activity and damage indices in patients with adult onset disease. Rheumatology (Oxford) 2004;43:49-54. 26
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inflammatory myopathies. Ann Rheum Dis 2012;71 Suppl 2:i82-5.
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Table Legends Table 1. Patient and disease characteristics at baseline Conventional
Tacrolimus
Monotherapy
Combination
(n = 19)
(n = 23)
14: 5
20: 3
0.28
13 (68)
15 (65)
0.83
Age [years] , median (range)
47.7 (43.9-58.3)
53.0 (36.3-64.4)
0.53
Body weight [kg], median (range)
54.8 (41.4-80.0)
55.0 (44.0-72.7)
0.97
Creatine kinase [IU/l], median (range)
2491 (443-4429)
2582 (408-5618)
0.97
Aldolase [U/l], median (range)
20.8 (9.2-61.9)
27.8 (11.2-56.4)
0.77
KL-6 [U/ml], median (range)
598 (319-1470)
500 (270-821)
0.39
Anti-Jo-1 antibody positive, n (%)
3 (17)
1 (5)
0.20
Interstitial lung disease, n (%)
13 (68)
12 (51)
0.29
Baseline variables
Dermatomyositis *: Polymyositis Female, n (%)
* including clinically amyopathic dermatomyositis P values were calculated by using chi-square test, Fisher’s exact test, or Mann-Whitney U test.
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P value
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Table 2. Outcomes during 36-month follow-up period Conventional
Tacrolimus
Monotherapy
Combination
(n = 19)
(n = 23)
Time to CK normalization [days], median (range)
55.5 (4-82)
57.5 (4-73)
0.48
Hospitalization period [days], median (range)
79 (74-92)
56 (52-74)
< 0.01
Death *, n (%)
1 (6)
0 (0)
0.35
Patients with relapse *, n (%)
5 (31)
4 (27)
0.78
Outcome measures
CK, creatine kinase. P values were calculated by using chi-square test, Fisher’s exact test, or Mann-Whitney U test. * The patients followed for less than 36 months were excluded from denominators. Table 3. Serious adverse events during 36-month follow-up period Serious adverse events
Conventional Monotherapy
Tacrolimus Combination
(n = 19)
(n = 23)
Events, n
Patients, n (%)
Events, n
Patients, n (%)
24
8 (42%)
15
8 (35%)
Death
1
1 (5%)
0
0
Relapse
6
5 (26%)
4
4 (17%)
Total
17
P value
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Serious infections
4
4 (21%)
3
3 (13%)
Cancer
1
1 (5%)
0
0
Corticosteroid psychosis
1
1 (5%)
0
0
Cataract
5
3 (16%)
3
2 (9%)
Diabetes mellitus
1
1 (5%)
0
0
Hemorrhagic gastric ulcer
1
1 (5%)
0
0
Myocardial infarction
1
1 (5%)
0
0
PRES
0
0
1
1 (4%)
Kidney stones
0
0
1
1 (4%)
Colon polyps
1
1 (5%)
1
1 (4%)
Conjunctivochalasis
2
1 (5%)
0
0
Drug rash
0
0
2
1 (4%)
PRES, Posterior reversible encephalopathy syndrome. Values are the numbers of events and patients (%). The patients followed for less than 36 months were included in denominators.
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Figure legends Figure 1. Dose of prednisolone at indicated time points after commencing treatment Doses of prednisolone are shown in box plots. A bar in the box represents median, a box represents an inter-quartile range, a vertical bar represents a range, and a small circle represents an outlier. Daily dose of prednisolone in the Tacrolimus Combination group was
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significantly lower than that in the Conventional Monotherapy group at all points (baseline, P = 0.01; 6 months, P < 0.01; 12 months, P = 0.01; 36 months, P = 0.02; Mann Whitney U test)
19
Figure 2. Time period from initiation of therapy to CK normalization The time period from initiation of therapy to CK normalization was demonstrated in cumulative incidence curves. The time period required for CK normalization was comparable between the Conventional Monotherapy and the Tacrolimus Combination (P =
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0.48, log-rank test).
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Figure 3. Event free survival after commencing treatment Difference in the event free survival after commencing treatment between the Conventional Monotherapy group and the Tacrolimus Combination group was not statistically significant
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(P = 0.58, log-rank test).
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Corticosteroid-sparing effect of tacrolimus in the initial treatment of dermatomyositis and polymyositis Yusuke Yokoyama, Shunsuke Furuta, Kei Ikeda, Koichi Hirose, and Hiroshi Nakajima 10.3109/14397595.2015.1029239 Mod Rheumatol Downloaded from informahealthcare.com by University of Connecticut on 04/11/15 For personal use only.
Abstract Objective. In the treatment of polymyositis (PM) and dermatomyositis (DM), muscle inflammation and underlying autoimmunity need to be suppressed promptly; however, catabolic effects of corticosteroids such as myopathy can be detrimental in PM/DM. In this study, we aimed to assess the corticosteroid-sparing effect of tacrolimus in the initial treatment for PM/DM. Methods. We retrospectively identified 19 PM/DM patients who received initial treatment with prednisolone at an initial dose of 1mg/kg/ day (Conventional Monotherapy, our standard therapy before 2008) and 23 patients with tacrolimus plus prednisolone at an initial dose 0.8mg/ kg/day (Tacrolimus Combination, our standard therapy after 2008). Data until 36 months after commencing treatment were collected. Results. There were no statistically significant differences in baseline characteristics between two groups. Median daily dose of prednisolone in the Tacrolimus Combination group was significantly lower than that in the Conventional Monotherapy group at all time during the study period, whereas the proportion of patients who required additional immunosuppressive medications for remission induction was comparable. Remission was achieved in all patients but one who died of refractory interstitial lung disease after receiving Conventional Monotherapy. The time required for creatine kinase normalization and relapse rate were comparable between two groups. The period of hospitalization for initial treatment was significantly shorter and survival without serious infection or relapse tended to be longer in the Tacrolimus Combination than the Conventional Monotherapy. Conclusion. This study provides real-life data which demonstrate that tacrolimus has a corticosteroid-sparing effect and reduces the length of hospitalization period for the initial treatment of PM/DM.
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Original Article
Corticosteroid-sparing effect of tacrolimus in the initial treatment of dermatomyositis and polymyositis
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Yusuke Yokoyama, Shunsuke Furuta, Kei Ikeda, Koichi Hirose, and Hiroshi Nakajima
Department of Allergy and Clinical Immunology, Chiba University Hospital, Japan.
Correspondence to: Dr. Shunsuke Furuta, MD, PhD, Department of Allergy and Clinical Immunology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chibashi, Chiba 260-8670, Japan. E-mail: [email protected]
Short title: Tacrolimus as initial treatment for PM/DM
MORH-D-15-00038 Received: Jan-21-15; Accepted: Mar-11-15
1
Abstract Objective. In the treatment of polymyositis (PM) and dermatomyositis (DM), muscle inflammation and underlying autoimmunity need to be suppressed promptly; however, catabolic effects of corticosteroids such as myopathy can be detrimental in PM/DM. In this study, we aimed to assess the corticosteroidsparing effect of tacrolimus in the initial treatment for PM/DM. Methods. We retrospectively identified 19 PM/DM patients who received initial treatment with prednisolone at an initial dose of 1mg/kg/day (Conventional
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Monotherapy, our standard therapy before 2008) and 23 patients with tacrolimus plus prednisolone at an initial dose 0.8mg/kg/day (Tacrolimus Combination, our standard therapy after 2008). Data until 36 months after commencing treatment were collected. Results. There were no statistically significant differences in baseline characteristics between two groups. Median daily dose of prednisolone in the Tacrolimus Combination group was significantly lower than that in the Conventional Monotherapy group at all time during the study period, whereas the proportion of patients who required additional immunosuppressive medications for remission induction was comparable. Remission was achieved in all patients but one who died of refractory interstitial lung disease after receiving Conventional Monotherapy. The time required for creatine kinase normalization and relapse rate were comparable between two groups. The period of hospitalization for initial treatment was significantly shorter and survival without serious infection or relapse tended to be longer in the Tacrolimus Combination than the Conventional Monotherapy. Conclusion. This study provides real-life data which demonstrate that tacrolimus has a corticosteroid-sparing effect and reduces the length of hospitalization period for the initial treatment of PM/DM. Key words: Polymyositis; Dermatomyositis; Tacrolimus; Corticosteroid Introduction Polymyositis (PM) and dermatomyositis (DM) are the major sub-groups of idiopathic inflammatory myopathy [1, 2]. Symmetrical weakness in the proximal muscles and elevated serum levels of skeletal muscle-derived enzymes are the characteristic manifestations of
2
myositis in PM/DM, which is confirmed by electromyogram, imaging, and muscle biopsy [1-4]. For extra-muscular manifestation, DM is further characterized by the presence of skin manifestations and both PM and DM can accompany interstitial lung disease (ILD). The pathogenesis of PM/DM remains largely unknown. However, the association with certain types of human leukocyte antigen (HLA) [5] and the presence of
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disease specific antibodies to self-antigens such as RNA synthetases [6] strongly suggest the involvement acquired immunity in the pathogenesis of PM/DM. Particularly, activated T cells are considered to play a significant role in the process of muscle injury based on the histopathological findings from patients [7] and experiments using human specimens [8,9] and mouse models [10]. PM/DM considerably decreases the patient’s physical function and quality of life and can cause severe disability and death [11]. For the treatment of PM/DM, high-dose corticosteroids have been used to suppress inflammation and underlying autoimmunity [12]. However, a wide range of side effects is accompanied by the corticosteroid therapy, depending on the dose and the period [13], and some of these side effects such as steroid myopathy, osteoporosis, and obesity can substantially affect the patient’s physical function. Given that preventing disability is the major aim of the treatment, a new strategy to reduce the dose and the period of corticosteroids is needed. Tacrolimus is an immunosuppressant which inhibits calcineurin and suppresses T-cell activation and IL-2 transcription. Tacrolimus is efficacious in the management of organ transplant [14] and in the treatment of autoimmune diseases such as systemic lupus erythematosus [15] and rheumatoid arthritis [16]. Successful treatment with tacrolimus in
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patients with PM/DM has also been reported for refractory myositis [17,18] and ILD [1820]. In our institute, the standard initial therapy for PM/DM without severe ILD was a high-dose corticosteroid monotherapy with 1mg/kg/day of prednisolone. At 2008, however, we changed the standard initial therapy to a combination therapy with tacrolimus
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plus 0.8mg/kg/day of prednisolone, aiming to reduce the total dose of corticosteroids and subsequent adverse events. Effectiveness of other immunosuppressants, such as methotrexate or cyclosporine [21], for refractory PM/DM was also reported. However, their efficacy was unproved in randomized controlled trials, and superiority or inferiority of those for PM/DM was still unknown. Tacrolimus was the agent we had the most experience for refractory PM/DM at 2008, therefore we chose tacrolimus as a concomitant with corticosteroids. In the present study, we retrospectively investigated the PM/DM patients who received initial therapy in our institute. We compared the efficacy and safety between treatment with tacrolimus plus a reduced dose of prednisolone and that with a high-dose prednisolone alone to assess the corticosteroid-sparing effect of tacrolimus in the initial treatment for PM/DM. Patients and methods Patients. We reviewed the medical records of patients who were newly diagnosed with PM/DM and were admitted to Department of Allergy and Clinical Immunology, Chiba University Hospital from January 2000 to December 2012. We identified 77 sequential patients who fulfilled the criteria of Bohan and Peter for PM, DM [1], or Southeimer for amyopathic DM
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[22]. Among these patients, 19 patients received treatment with prednisolone at an initial dose of 1mg/kg/day (Conventional Monotherapy group) and 23 patients received treatment with tacrolimus plus prednisolone at an initial dose 0.8mg/kg/day (Tacrolimus Combination group). Thirty-five patients were not able to be categorized to either group for the following reasons: 6 patients received cyclosporine (another calcineurin inhibitor), 2 patients with
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rapidly progressive ILD received methylprednisolone pulse therapy, 7 patients participated a clinical trial, 6 patients received prednisolone at a lower initial dose, 1 patient with dysphagia received intravenous administration of prednisolone, 1 patient could not continue tacrolimus for extremely unstable blood concentration, 3 patients with preceding diagnosis of rheumatoid arthritis were receiving methotrexate, 7 patients had an advanced cancer and received no or less potent therapy, 1 patient with predominant skin manifestation but with minimal muscle and lung involvement did not receive systemic immunosuppressive treatment, and 1 patient refused to receive treatment. These patients were excluded from further analyses. Treatment with prednisolone and tacrolimus. In both the Conventional Monotherapy and the Tacrolimus Combination groups, the dose of prednisolone was kept at the initial dose for 4 to 8 weeks and was tapered with our corticosteroid reducing regimen (-10% every 2 weeks) unless the patient showed any signs of flare. In the Tacrolimus Combination group, the initial daily dose of tacrolimus was 3mg. We adjusted the dose of tacrolimus repeatedly, targeting a trough plasma concentration at 612 ng/ml. Assessment.
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We retrospectively assessed the baseline patient and disease characteristics, including age, sex, body weight, diagnosis, anti Jo-1 antibody positivity, presence of malignancy, presence of ILD, and the serum levels of creatine kinase (CK), aldolase, and KL-6. We also collected data on the use of immunosuppressive medications and the daily prednisolone dose at 0, 6, 12, and 36 months after commencing treatment. The reasons for change in
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immunosuppressive medication were assessed if applicable. In addition, we collected clinical information until 36 months after commencing treatment. For the assessment of treatment response, we collected data on the achievement of remission, the period from initiation of therapy to CK normalization, the period of hospitalization for initial treatment, and the occurrence of relapse. In the patients who achieved CK normalization without worsening of symptoms (e.g. muscle pain, weakness, erythema, dyspnea and cough), remission was subjectively determined by the physicians. Physicians determined the time of hospital discharge considering disease activity and activities of daily living. Relapse was defined as a state in which the physician escalated the immunosuppressive medication due to a new symptom and/or a recurrence of symptoms of PM/DM after once achieving remission. For the safety assessment, we collected data on serious adverse events including serious infection. A serious adverse event was defined as an event which necessitated hospitalization due to any causes. We also analyzed event-free survival which was defined as survival without relapse or serious adverse events as a composite outcome. Statistical analysis. Statistical analysis was performed using SPSS version 22.0 (IBM Japan, Tokyo, Japan). Continuous data were summarized with median and interquartile ranges (IQR) and were compared using Mann-Whitney U test. Categorical data were summarized with percentage
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and were compared using chi-square or Fisher’s exact test. Cumulative event rates were demonstrated using Kaplan-Meier methods and were compared using log-rank test. P values less than 0.05 were considered statistically significant. Ethical approval. The Ethics Committee of Chiba University School of Medicine approved this study. Results
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Patient and disease characteristics at baseline. Table 1 shows the baseline characteristics of the PM/DM patients who received the Conventional Monotherapy and the Tacrolimus Combination therapy. Three patients in the Conventional Monotherapy group and five patients in the Tacrolimus Combination group were classified as clinically amyopathic dermatomyositis. As compared with patients in the Tacrolimus Combination group, those in the Conventional Monotherapy group had a smaller proportion of DM, a younger median age, lower median levels of muscle enzymes, a higher median level of KL-6, a higher prevalence of anti-Jo-1 antibody positivity, and a higher prevalence of ILD. However, all of these numerical differences between the Conventional Monotherapy group and the Tacrolimus Combination group were not statistically significant. At baseline no malignancy was detected in 42 patients in this analysis. Of 35 patients who were excluded from the analysis, 7 patients had malignancy at baseline and recieved no or less potent therapy as mentioned in the Materials and Methods section. Observation period. Of 42 patients analyzed, 31 patients had completed the follow-up period of 36 months. The remaining 11 patients had not completed the follow-up period due to either death (n=1),
7
changing hospital (n=2), voluntary discontinuation of therapy after 9 months (n=1), and recent treatment initiation (n=7). Treatment. As shown in Figure 1, the daily dose of prednisolone in the Tacrolimus Combination group was significantly lower than that in the Conventional Monotherapy group at baseline
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(median 40mg vs. 60mg), at 6 months (median 14mg vs. 20mg), at 12 months (median 9mg vs. 15mg), and at 36 months (median 4.75mg vs. 10mg). In the Tacrolimus Combination group, median actual dose of tacrolimus was 3mg/day with a range of 1mg/day to 6mg/day. Tacrolimus was discontinued before 36 months in five patients due to either pregnancy (n=1), adverse events (n=2, one dysgeusia and one posterior reversible encephalopathy syndrome), or insufficient response at early stage (n=2, they started receiving cyclosporine). None of the five patients had disease exacerbation at the time of discontinuation. Proportion of patients who required additional immunosuppressive medications for remission induction of PM/DM tended to be smaller in the Tacrolimus Combination group (n=5, 22 %) than that in the Conventional Monotherapy group (n=6, 32 %) although this did not reach statistical significance (P=0.50, chi-square test). The additional immunosuppressive medications included cyclosporine (n=5), methylprednisolone pulse therapy (n=1), increased dose of prednisolone (n=1), and intravenous cyclophosphamide (n=1) in the Conventional Monotherapy group; and methotrexate (n=4), methylprednisolone pulse therapy (n=2), intravenous immunoglobulin (n=2), and cyclosporine (n=1, tacrolimus was discontinued) in the Tacrolimus Combination group. Treatment response and relapse.
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Table 2 summarizes the outcomes during 36-month follow-up period after commencing treatment in the Conventional Monotherapy group and the Tacrolimus Combination group. Clinical remission was achieved in all patients by the end of study period except for one in the Conventional Monotherapy group who died two months after commencing therapy. As shown in Table 2 and Figure 2, the time period required for CK normalization was
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comparable between Conventional Monotherapy and Tacrolimus Combination. However, hospitalization period for remission induction was significantly shorter in the Tacrolimus Combination group than in the Conventional Monotherapy group (Table 2). The proportion of relapsing patients was also comparable between these two groups (Table 2). Relapse was identified six times in total in five patients in the Conventional Monotherapy group, while none of four patients with relapse in the Tacrolimus Combination group had second relapses. For the treatment of relapse, cyclosporine (n=4), increased dose of prednisolone (n=4), and methylprednisolone pulse therapy (n=1) were used in the Conventional Monotherapy group, whereas increased dose of prednisolone (n=5), methotrexate (n=3), and cyclosporine (n=1) were used in the Tacrolimus Combination group. Serious adverse events. As shown in Table 3, during 36-month follow-up period, serious adverse events were identified in a larger proportion of patients in the Conventional Monotherapy group than in the Tacrolimus Combination group (42% vs. 35%). Serious infections and cataract were also identified in a larger proportion of patients in the Conventional Monotherapy group than in the Tacrolimus Combination group (21% vs. 13%, 16% vs. 9%, respectively). Serious infections consisted of bacterial pneumonia (n=1), pneumocystis pneumonia (n=1),
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cytomegalovirus pneumonia (n=1), and herpes zoster (n=1) in the Conventional Monotherapy group, and bacterial pneumonia (n=3) in the Tacrolimus Combination group. One patient was diagnosed with ovarian cancer 8 months after diagnosis of myositis and given chemotherapy. One patient in the Conventional Monotherapy group had a myocardial infarction, whereas 1 patient in the Tacrolimus Combination group had an episode of
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posterior reversible encephalopathy syndrome. Event-free survival. Difference in the survival without relapse or serious infections during 36-month follow-up period was not statistically significant between the Conventional Monotherapy and the Tacrolimus Combination groups; however, the survival curves tended to favor the Tacrolimus Combination over the Conventional Monotherapy (Figure 3). Discussion This study demonstrates for the first time that tacrolimus combined with a reduced dose of corticosteroid (prednisolone 0.8mg/kg/day) can have therapeutic effectiveness which is comparable to conventional high-dose corticosteroid (prednisolone 1.0mg/kg/day) in the initial treatment for PM/DM without severe ILD. Since the Tacrolimus Combination regimen actually resulted in the administration of smaller doses of prednisolone than did the Conventional Monotherapy regimen throughout the 3-year study period, our data strongly suggest that tacrolimus has a corticosteroid-sparing effect in the standard initial treatment for PM/DM. In this study, “spared” dose of prednisolone was 0.2mg/kg/day, approximately 10mg/day in our patients. Whether this reduction outweighs the cost and the risk of tacrolimus treatment is a matter of debate. Saag KG et al. demonstrated that side effects of
10
corticosteroids are largely dose dependent and 10mg difference is clinically important [23]. In fact, patients in the Tacrolimus Combination group in our study less frequently developed serious adverse events which are associated with corticosteroids such as serious infections, cataract, and myocardial infarction than did those in the Conventional Monotherapy group although the differences did not reach a statistical significance probably due to the small
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sample size (Table 3). Moreover, the period of hospitalization for initial treatment was significantly shorter with the Tacrolimus Combination than with the Conventional Monotherapy (Table 2). The cost of hospitalization both for the initial treatment of PM/DM and for adverse events needs to be taken into account when the benefit of tacrolimus coadministration is balanced against its direct cost. On the other hand, tacrolimus also has side effects in common with corticosteroids such as infections and diabetes mellitus and those distinct from corticosteroids such as renal dysfunction and thrombotic microangiopathy [24]. One patient who received the Tacrolimus Combination therapy developed posterior reversible encephalopathy syndrome, a form of thrombotic microangiopathy. Although thrombotic microangiopathy is an infrequently occurring event, possibility of such a severe side effect cannot be ignored. This study has several limitations. First, because this is a retrospective study, we cannot exclude the possible bias in selecting the patients who were treated with regimens which did not fall into either group. Prednisolone tapering schedule may also have been influenced by physician’s opinion on the coadministration of tacrolimus. In a retrospective fashion of collecting data, we could not collect enough data for standardized disease activity measures of myositis such as manual muscle test (MMT), either [25, 26].
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Second, the sample size is small. Although this study only showed the tendency which favored the Tacrolimus Combination in the analyses for adverse events and overall event-free survival, a larger number of patients might have demonstrated statistically significant differences which would verify the advantage of tacrolimus coadministration. A larger sample size would also have allowed for multivariate analysis and subanalysis for
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non-myositis manifestations such as ILD. In summary, this study provides real-life data which demonstrate that the coadministration of tacrolimus has a corticosteroid-sparing effect and reduces the length of hospitalization period for the initial treatment of PM/DM without severe ILD. Our findings provide a rationale for a larger, multicenter, prospective study to verify the benefit of tacrolimus coadministration as a first-line treatment for PM/DM. ACKNOWLEDGEMENTS We thank all staff in Chiba University Hospital for the care and management of patients enrolled in this study and for their support in data collection. Conflict of interest None. References 1
Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med
1975;292:344-7. 2
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Med 1975;292:403-7. 3
Tanaka S, Ikeda K, Uchiyama K, Iwamoto T, Sanayama Y, Okubo A, et al. [18F]FDG
uptake in proximal muscles assessed by PET/CT reflects both global and local muscular
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inflammation and provides useful information in the management of patients with polymyositis/dermatomyositis. Rheumatology (Oxford) 2013; 52:1271-8. 4 Tomasova Studynkova J, Charva F, Jarosova K, Vencovsky J. The role of MRI in the assessment of polymyositis and dermatomyositis. Rheumatology (Oxford) 2007;46:1174–9. 5
O'Hanlon TP, Carrick DM, Arnett FC, Reveille JD, Carrington M, Gao X, et al.
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Immunogenetic risk and protective factors for the idiopathic inflammatory myopathies: distinct HLA-A, -B, -Cw, -DRB1 and -DQA1 allelic profiles and motifs define clinicopathologic groups in caucasians. Medicine (Baltimore) 2005;84:338-49. 6 Hamaguchi Y, Fujimoto M, Matsushita T, Kaji K, Komura K, Hasegawa M, et al. Common and distinct clinical features in adult patients with anti-aminoacyl-tRNA synthetase antibodies: heterogeneity within the syndrome. PLoS One. 2013;8:e60442 7 Dalakas MC. Muscle biopsy findings in inflammatory myopathies. Rheum Dis Clin North Am. 2002;28:779-98. 8
Goebels N, Michaelis D, Engelhardt M, Huber S, Bender A, Pongratz D, et al.
Differential expression of perforin in muscle-infiltrating T cells in polymyositis and dermatomyositis. J Clin Invest 1996;97:2905-10. 9 Fasth AE1, Dastmalchi M, Rahbar A, Salomonsson S, Pandya JM, Lindroos E, et al. T cell infiltrates in the muscles of patients with dermatomyositis and polymyositis are dominated by CD28null T cells. J Immunol. 2009;183:4792-9. 10 Rosenberg NL, Kotzin BL. Aberrant expression of class II MHC antigens by skeletal muscle endothelial cells in experimental autoimmune myositis. J Immunol. 1989;142:428994.
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11 Marie I, Hatron PY, Cherin P, Hachulla E, Diot E, Vittecoq O, et al. Functional outcome and prognostic factors in anti-Jo1 patients with antisynthetase syndrome. Arthritis Res Ther. 2013;15:R149. 12
Marie I, Mouthon L. Therapy of polymyositis and dermatomyositis. Autoimmun Rev
2011;11:6-13.
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Moghadam-Kia S, Werth VP. Prevention and treatment of systemic glucocorticoid side
effects. Int J Dermatol. 2010;49:239–48. 14 Gu J, Wu X, Lu L, Zhang S, Bai J, Wang J, et al. Role of steroid minimization in the tacrolimus-based immunosuppressive regimen for liver transplant recipients: a systematic review and meta-analysis of prospective randomized controlled trials. Hepatol Int. 2014;8:198-215. 15 Lee YH, Lee HS, Choi SJ, Dai Ji J, Song GG. Efficacy and safety of tacrolimus therapy for lupus nephritis: a systematic review of clinical trials. Lupus. 2011;20:636-40. 16 Lee YH, Woo JH, Choi SJ, Ji JD, Bae SC, Song GG. Tacrolimus for the treatment of active rheumatoid arthritis: a systematic review and meta-analysis of randomized controlled trials. Scand J Rheumatol. 2010;39:271-8. 17
Shimojima Y, Ishii W, Matsuda M, Tazawa K, Ikeda S. Coadministration of tacrolimus
with corticosteroid accelerates recovery in refractory patients with polymyositis/ dermatomyositis: a retrospective study. BMC Musculoskelet Disord 2012;13:228. 18
Kurita T, Yasuda S, Oba K, Odani T, Kono M, Otomo K, et al. The efficacy of
tacrolimus in patients with interstitial lung diseases complicated with polymyositis or dermatomyositis. Rheumatology (Oxford) 2015;54:39-44.
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Oddis CV, Sciurba FC, Elmagd KA, Starzl TE. Tacrolimus in refractory polymyositis
with interstitial lung disease. Lancet 1999;353:1762-3. 20
Ando M, Miyazaki E, Yamasue M, Sadamura Y, Ishii T, Takenaka R, et al. Successful
treatment with tacrolimus of progressive interstitial pneumonia associated with amyopathic dermatomyositis refractory to cyclosporine. Clin Rheumatol 2010;29:443-5.
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Aggarwal R, Oddis CV. Therapeutic advances in myositis. Curr Opin Rheumatol.
2012;24:635-41. 22
Sontheimer RD. Would a new name hasten the acceptance of amyopathic
dermatomyositis (dermatomyositis sine myositis) as a distinctive subset within the idiopathic inflammatory dermatomyopathies spectrum of clinical illness? J Am Acad Dermatol 2002;46:626-36. 23 Saag KG, Koehnke R, Caldwell JR, Brasington R, Burmeister LF, Zimmerman B, et al. Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events. Am J Med. 1994;96:115-23. 24
Jacobson P, Uberti J, Davis W, Ratanatharathorn V. Tacrolimus: a new agent for the
prevention of graft-versus-host disease in hematopoietic stem cell transplantation. Bone Marrow Transplant 1998;22:217-25. 25
Isenberg DA, Allen E, Farewell V, Ehrenstein MR, Hanna MG, Lundberg IE, et al.
International consensus outcome measures for patients with idiopathic inflammatory myopathies. Development and initial validation of myositis activity and damage indices in patients with adult onset disease. Rheumatology (Oxford) 2004;43:49-54. 26
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inflammatory myopathies. Ann Rheum Dis 2012;71 Suppl 2:i82-5.
15
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Table Legends Table 1. Patient and disease characteristics at baseline Conventional
Tacrolimus
Monotherapy
Combination
(n = 19)
(n = 23)
14: 5
20: 3
0.28
13 (68)
15 (65)
0.83
Age [years] , median (range)
47.7 (43.9-58.3)
53.0 (36.3-64.4)
0.53
Body weight [kg], median (range)
54.8 (41.4-80.0)
55.0 (44.0-72.7)
0.97
Creatine kinase [IU/l], median (range)
2491 (443-4429)
2582 (408-5618)
0.97
Aldolase [U/l], median (range)
20.8 (9.2-61.9)
27.8 (11.2-56.4)
0.77
KL-6 [U/ml], median (range)
598 (319-1470)
500 (270-821)
0.39
Anti-Jo-1 antibody positive, n (%)
3 (17)
1 (5)
0.20
Interstitial lung disease, n (%)
13 (68)
12 (51)
0.29
Baseline variables
Dermatomyositis *: Polymyositis Female, n (%)
* including clinically amyopathic dermatomyositis P values were calculated by using chi-square test, Fisher’s exact test, or Mann-Whitney U test.
16
P value
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Table 2. Outcomes during 36-month follow-up period Conventional
Tacrolimus
Monotherapy
Combination
(n = 19)
(n = 23)
Time to CK normalization [days], median (range)
55.5 (4-82)
57.5 (4-73)
0.48
Hospitalization period [days], median (range)
79 (74-92)
56 (52-74)
< 0.01
Death *, n (%)
1 (6)
0 (0)
0.35
Patients with relapse *, n (%)
5 (31)
4 (27)
0.78
Outcome measures
CK, creatine kinase. P values were calculated by using chi-square test, Fisher’s exact test, or Mann-Whitney U test. * The patients followed for less than 36 months were excluded from denominators. Table 3. Serious adverse events during 36-month follow-up period Serious adverse events
Conventional Monotherapy
Tacrolimus Combination
(n = 19)
(n = 23)
Events, n
Patients, n (%)
Events, n
Patients, n (%)
24
8 (42%)
15
8 (35%)
Death
1
1 (5%)
0
0
Relapse
6
5 (26%)
4
4 (17%)
Total
17
P value
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Serious infections
4
4 (21%)
3
3 (13%)
Cancer
1
1 (5%)
0
0
Corticosteroid psychosis
1
1 (5%)
0
0
Cataract
5
3 (16%)
3
2 (9%)
Diabetes mellitus
1
1 (5%)
0
0
Hemorrhagic gastric ulcer
1
1 (5%)
0
0
Myocardial infarction
1
1 (5%)
0
0
PRES
0
0
1
1 (4%)
Kidney stones
0
0
1
1 (4%)
Colon polyps
1
1 (5%)
1
1 (4%)
Conjunctivochalasis
2
1 (5%)
0
0
Drug rash
0
0
2
1 (4%)
PRES, Posterior reversible encephalopathy syndrome. Values are the numbers of events and patients (%). The patients followed for less than 36 months were included in denominators.
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Figure legends Figure 1. Dose of prednisolone at indicated time points after commencing treatment Doses of prednisolone are shown in box plots. A bar in the box represents median, a box represents an inter-quartile range, a vertical bar represents a range, and a small circle represents an outlier. Daily dose of prednisolone in the Tacrolimus Combination group was
Mod Rheumatol Downloaded from informahealthcare.com by University of Connecticut on 04/11/15 For personal use only.
significantly lower than that in the Conventional Monotherapy group at all points (baseline, P = 0.01; 6 months, P < 0.01; 12 months, P = 0.01; 36 months, P = 0.02; Mann Whitney U test)
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Figure 2. Time period from initiation of therapy to CK normalization The time period from initiation of therapy to CK normalization was demonstrated in cumulative incidence curves. The time period required for CK normalization was comparable between the Conventional Monotherapy and the Tacrolimus Combination (P =
Mod Rheumatol Downloaded from informahealthcare.com by University of Connecticut on 04/11/15 For personal use only.
0.48, log-rank test).
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Figure 3. Event free survival after commencing treatment Difference in the event free survival after commencing treatment between the Conventional Monotherapy group and the Tacrolimus Combination group was not statistically significant
Mod Rheumatol Downloaded from informahealthcare.com by University of Connecticut on 04/11/15 For personal use only.
(P = 0.58, log-rank test).
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