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The efficacy of calcineurin inhibitors for the treatment of interstitial lung disease associated with polymyositis/dermatomyositis T Kurita, S Yasuda, O Amengual and T Atsumi Lupus published online 8 October 2014 DOI: 10.1177/0961203314554849 The online version of this article can be found at: http://lup.sagepub.com/content/early/2014/10/08/0961203314554849
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The efficacy of calcineurin inhibitors for the treatment of interstitial lung disease associated with polymyositis/ dermatomyositis T Kurita, S Yasuda, O Amengual and T Atsumi Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Interstitial lung disease (ILD) in patients with polymyositis (PM) and dermatomyositis (DM) is often resistant to treatment and life threatening, being recognized as one of the severest complication in these autoimmune disorders. Patients with clinically amyopathic dermatomyositis (CADM) or those with anti-CADM140/MDA5 antibody are especially prone to develop rapidly progressive interstitial pneumonia. We retrospectively analyzed 46 patients with PM/DM admitted to our hospital and identified DM, rapidly progressive disease, honeycomb lung, CADM and extensive ILD as risk factors for recurrence or death. In the presence of two or more risk factors, the sensitivity and specificity for the prediction of death or relapse were 81.3% and 76.7%, respectively. Calcineurin inhibitors have been widely used as induction and maintenance therapy for PM/DM-associated ILD. Recently we reported the benefit of tacrolimus on the disease-free survival and event-free survival of the patients with PM/DMassociated ILD. Among those patients treated with tacrolimus, poor prognostic factors for death, recurrence or severe adverse event were identified as acute progression of the disease, honeycomb lung, forced vital capacity (FVC) less than 80% and having DM. The potential effectiveness of an intensive therapy protocol with triple therapy that comprises high-dose corticosteroids, calcineurin inhibitors and cyclophosphamide has been reported. Lupus (2014) 0, 1–7. Key words: Interstitial pneumonia; ciclosporin; tacrolimus; anti-MDA5 antibody
Introduction Polymyositis (PM) and dermatomyositis (DM) are systemic autoimmune disorders affecting skin, skeletal muscles and other organs.1 Among them, pulmonary involvement including interstitial lung disease (ILD), aspiration pneumonia, infections and drug-induced pneumonitis represents one of the most common and serious organ damage in PM/DM, with a reported prevalence up to 65%.2–4 Pulmonary complications are considered to be common determinants of morbidity and mortality in these patients.3,5–12 ILD associated with DM is frequently difficult to treat, being recognized as a
Correspondence to: Olga Amengual, Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, N15 W7, Kita-ku, 060-8638 Sapporo, Japan. Email: [email protected] Received 9 September 2014; accepted 16 September 2014
more refractory disease compared with ILD associated with PM.12,13 Certain patients who have the typical skin manifestations of DM in the absence of clinical manifestations of myositis are referred to as clinically amyopathic dermatomyositis (CADM).14 The frequency of CADM is particularly elevated in Asian regions, and some patients with CADM develop rapidly progressive interstitial pneumonia (RPIP) with lethal respiratory failure. Pathological examinations of the lung lesions in these patients exhibit diffuse alveolar damage.15–21 The basic treatment of PM/DM-associated ILD is corticosteroids in combination with immunosuppressive agents. To improve the prognosis, the identification of patients with PM/DM who eventually develop RPIP would be crucial. In the last decade, calcineurin inhibitors have been widely used as induction and maintenance therapy for ILD associated with PM/DM, and their promising effectiveness should be recognized.
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10.1177/0961203314554849
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In this manuscript, we will review the effects of calcineurin inhibitors on cases of PM/DM. Further, we will evaluate the factors that influence the prognosis of patients with PM/DM, including the myositis-specific autoantibodies.
Characteristics of ILD associated with PM/DM Prognosis The prognosis of ILD associated with PM or DM is poor, with a three-year survival rate of 74.4%5 and 61.6%,22 respectively. In the study by Douglas et al.,5 surgical lung biopsies were performed in 22 out of 58 patients with PM/DM-associated ILD, and organizing diffuse alveolar damage was observed in only two cases. On the other hand, this feature has been demonstrated in a number of autopsy cases of RPIP associated with CADM:12,23 Presumably, its frequency in PM/DM is higher than that reported so far. Unfavorable prognostic factors An unfavorable prognosis of ILD in patients with PM/DM has been associated with the following situations: DM,13 lower values of forced vital capacity (FVC) or diffusing capacity of carbon monoxide at the time of diagnosis,6,24 CADM,25,26 neutrophil alveolitis in the bronchoalveolar lavage,6 pathological evidence of usual interstitial pneumonia,6 skin ulcers,27 Hamman-Rich-like pattern,25,26 absence of Jo-1 anti-amynoacyl-tRNA synthetase (anti-ARS) autoantibodies,28 hyperferritinemia,29–31 and hypoalbuminemia.26 We conducted a multivariate analysis using the Cox proportional hazard model in a cohort of 46 patients with PM/DM attended at the Rheumatology Department in Hokkaido University Hospital. We found that DM, rapidly progressive disease (within two months), honeycomb lung, CADM and extensive ILD affecting more than 50% of the lung represent independent unfavorable prognosis factors for recurrence and death (Figure 1(a)). Further, using combinations of these unfavorable prognosis factors, we generated a receiver operating characteristics (ROC) curve and could accurately predict the relapse and mortality within five years. When the cutoff in the curve was set-up as two or more risk factors, the sensitivity and specificity for the prediction of death or relapse were 81.3% and 76.7%, respectively (Figure 1(b)).
Myositis-specific antibodies Idiopathic inflammatory myopathies (IIM) including PM and DM are a heterogeneous group of disorders with varying degrees of muscle disease, cutaneous manifestations and internal organ involvement. Based on their specificity, autoantibodies detected in patients with IIM are grouped into myositis-specific antibodies and myositis-associated antibodies. Over the last few years, myositis-specific autoantibodies have been better characterized, and these antibodies represent useful tools in IIMs, as they further define more homogeneous subsets. Anti-ARS and anti-MDA5 antibody (namely anti-CADM140 antibody) are the most relevant myositis-specific antibodies. With few exceptions myositis-specific antibodies are mutually exclusive, i.e. only one autoantibody is positive in one patient. Autoantibodies directed to eight different ARS have been described: anti-histidyl (anti-Jo-1),32 antianthreonyl (anti-PL-7),33 anti-alanyl (anti-PL-12),34 anti-glycyl (anti-EJ),35 anti-isoleucyl (anti-OJ),36 anti-asparaginyl (anti-KS),37 anti-phenylalanyl (anti-Zo),38 and anti-tyrosyl (anti-Ha).39 More than 90% of patients with positive anti-ARS antibodies have ILD,40 and among them, those cases with positive anti-PL-7 antibody and anti-PL-12 antibody have more severe prognosis.41 Anti-MDA5 antibody is a myositis-specific antibody strongly correlated with RPIP.42–44 Patients with ILD and anti-MDA5 antibody have a very poor prognosis, with approximately 50% of deaths within six months due to respiratory failure.43
Therapy for PM/DM-associated ILD The optimal treatment for ILD associated with PM/DM has not yet been clearly established. High-dose corticosteroid has been used as a standard first-line therapy for ILD in patients with PM/ DM, although approximately half of cases of ILD are resistant to corticosteroid therapy. In fact, about 20% of patients receiving steroid therapy experience deterioration of ILD. Fifty percent of steroid-resistant ILD patients die of respiratory failure in a relative short period.45 Intravenous cyclophosphamide is the most common immunosuppressive treatment used for ILD associated with PM/DM and may improve the clinical outcome in these patients. Although high clinical efficacy of intravenous cyclophosphamide therapy in PM/DM patients with ILD has been reported in retrospective observational studies
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Figure 1 Identification of prognostic factors in patients with polymyositis (PM)/dermatomyositis (DM)-associated interstitial lung diseases (ILD). (a) Cox regression analysis relating risk for death or recurrence. Candidate risk factors for death or recurrence of the disease were chosen if the p values were less than 0.1. Among these, factors without internal correlation were subjected to multivariate analysis using a Cox proportional hazard model. Closed squares and bars indicate hazard ratios and 95% confidence intervals, respectively. (b) Receiver operating characteristic (ROC) curve for the identified prognostic factors. The ROC curve was created based on the unfavorable prognostic factors identified in the multivariate analysis. Sensitivities and specificities were calculated according to the presence of death or relapse within five years from disease onset. AUC: area under the curve; CADM: clinically amyopathic dermatomyositis; CI: confidence interval; HR: hazard ratio.
or case reports,12,46,47 neither randomized controlled trials nor placebo-controlled studies have been conducted in these patients because of the severity and rarity of the disease.
The effects of other immunosuppressive agents such as azathioprine,5,10 mycophenolate mofetil48 and calcineurin inhibitors such as ciclosporin and tacrolimus in patients with PM/DM-associated Lupus
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ILD have been documented in small-size retrospective studies and case reports. A limited number of studies have shown the potential efficacy of intravenous immunoglobulins,49,50 tumor necrosis factor alpha inhibitors,51 anakinra52 or rituximab.53,54
Effectiveness of calcineurin inhibitors The bronchoalveolar lavage fluid of PM/DM patients with ILD showed a remarkably increased number of CDþ8 lymphocytes,13,55 indicating that the activation of pulmonary T cells plays a role in the pathogenesis of ILD. Therefore, T cells could be a primary therapeutic target for ILD associated with PM/DM. Calcineurin inhibitors exert their major therapeutic effects by inhibiting T cell activation. Calcineurin inhibitors block the dephosphorylation of the nuclear factor of activated T cells by calcineurin,56 showing a strong immune-suppressive effect by inhibiting the production of interleukin (IL)-2, IL-3, IL-4, CD40-ligand and interferon g.57,58 Ciclosporin Ciclosporin has been used for PM/DM-associated ILD since the 1980s. The therapeutic effects of ciclosporin in steroid-resistant patients have been reported in several retrospective studies.13,16,55,59–61 Nagasaka et al.60 retrospectively analyzed 32 patients with PM/DM-associated ILD treated with ciclosporin for two weeks as induction therapy in combination with corticosteroids. A general evaluation performed four weeks after the start of the combination treatment showed that in 29 patients the therapy was ‘‘partially effective,’’ defined as an improvement in only one of the four parameters evaluated, and in eight ‘‘remarkably effective,’’ corresponding to an improvement in at least three out of four evaluated parameters. This study suggests that treatment with ciclosporin during the early stages of ILD in patients with PM/ DM has an important therapeutic effect. Therapy with ciclosporin is often associated with adverse events, in particular renal impairment, gastrointestinal disorders, hypertension and abnormalities in glucose metabolism, but most of these events are preventable by monitoring the blood concentration of ciclosporin.62 The appropriate concentration of ciclosporin to ensure a maximal immunosuppressive effect and to avoid adverse events in patients with PM/DM-associated ILD should reach approximately 150 ng/ml and
1000 ng/ml, at trough and at two hours after administration, respectively.63–65 Tacrolimus Another calcineurin inhibitor, tacrolimus, was developed after ciclosporin, thus reports on the therapeutic effect of tacrolimus for PM/DM-associated ILD are fewer than those of ciclosporin. Since the report by Oddis et al.,66 in 1999, on the efficacy of tacrolimus for the treatment of steroidresistant PM/DM-associated ILD, other studies suggested the high effectiveness of tacrolimus in refractory cases with PM/DM-associated ILD.67–72 Ciclosporin inhibits the activity of calcineurin by binding to cyclophilin whereas tacrolimus exhibits inhibitory activity by binding to the FK binding protein (FKBP). In addition, the pharmacological effect of tacrolimus is 100 times stronger than that of ciclosporin, and its half-life is longer than that of ciclosporin.73 The superiority of tacrolimus to ciclosporin on renal, liver or bone marrow transplantation has been demonstrated in randomized controlled trials.74–77 These results suggested that tacrolimus has some advantages over ciclosporin for the treatment of PM/DM-associated ILD. Takada et al.67 reported five patients with PM/ DM-associated ILD who responded to treatment with tacrolimus rather than to ciclosporin. In our retrospective observational study of 49 patients with PM/DM-associated ILD, the diseasefree survival and event-free survival, using propensity score, were improved by tacrolimus.78 Moreover, we conducted a multivariate analysis in our patients treated with tacrolimus and identified the followings adverse prognosis factors when deaths, recurrences and severe adverse events were set as endpoints: honeycomb lung, DM, FVC not exceeding 80%, and rapid progressiveness (Figure 2). Adverse events of tacrolimus are generally similar to those of ciclosporin.65,79–81 Among them, the frequency of abnormalities in glucose metabolism is higher82 but hypertension or dyslipidemia are lower during the treatment with tacrolimus compared with ciclosporin.83 The appropriate tacrolimus trough levels for the treatment of ILD in PM/DM patients have not been established by clinical trials, but they are set as 5–20 ng/ml on the basis of data from renal and bone marrow transplantation. Triple combination therapy: corticosteroids, calcineurin inhibitors and cyclophosphamide Patients with CADM and anti-MDA5 antibody are prone to have RPIP. In these patients with severe
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Figure 2 Identification of prognostic factors in patients with polymyositis (PM)/dermatomyositis (DM)-associated interstitial lung diseases (ILD) treated with tacrolimus. Factors for death, recurrence of the disease or severe adverse event in PM/DM-associated ILD patients treated with tacrolimus without internal correlation were subjected to multivariate analysis using the Cox proportional hazard model. Closed squares and bars indicate hazard ratios and 95% confidence intervals, respectively. CI: confidence interval; FVC: forced vital capacity; HR: hazard ratio.
disease, the potential effectiveness of intensive therapy protocol with triple therapy (high-dose corticosteroids, calcineurin inhibitors and cyclophosphamide) has been reported.19,84 There is only one observational study with a small number of patients, but this therapy protocol apparently contributed to the better outcome for the patients with RPIP.
Conclusion The effectiveness of tacrolimus both in induction and maintenance therapy for PM/DM-associated ILD is highly promising. The treatment of RPIP in patients with CADM is still difficult, however. The combination therapy, containing calcineurin inhibitors in its protocol, has great potential for the improvement of the prognosis of these patients. Additional reported cases are needed to ascertain the efficacy of this treatment.
Funding This work was supported by grants from the Japanese Ministry of Health, Labor, and Welfare, and the Japanese Ministry of Education, Culture, Sports, Science, and Technology.
Conflict of interest statement S.Y. and T.A. have received honoraria and research support from Astellas Pharma. All the other authors have no conflicts of interest to declare.
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7 51 Park JK, Yoo HG, Ahn DS, Jeon HS, Yoo WH. Successful treatment for conventional treatment-resistant dermatomyositis-associated interstitial lung disease with adalimumab. Rheumatol Int 2012; 32: 3587–3590. 52 Furlan A, Botsios C, Ruffatti A, Todesco S, Punzi L. Antisynthetase syndrome with refractory polyarthritis and fever successfully treated with the IL-1 receptor antagonist, anakinra: A case report. Joint Bone Spine 2008; 75: 366–367. 53 Sem M, Molberg O, Lund MB, Gran JT. Rituximab treatment of the anti-synthetase syndrome: A retrospective case series. Rheumatology 2009; 48: 968–971. 54 Marie I, Dominique S, Janvresse A, Levesque H, Menard JF. Rituximab therapy for refractory interstitial lung disease related to antisynthetase syndrome. Respir Med 2012; 106: 581–587. 55 Kurasawa K, Nawata Y, Takabayashi K, et al. Activation of pulmonary T cells in corticosteroid-resistant and -sensitive interstitial pneumonitis in dermatomyositis/polymyositis. Clin Exp Immunol 2002; 129: 541–548. 56 Schreiber SL, Crabtree GR. The mechanism of action of cyclosporin A and FK506. Immunol Today 1992; 13: 136–142. 57 Kino T, Hatanaka H, Miyata S, et al. FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo) 1987; 40: 1256–1265. 58 Ho S, Clipstone N, Timmermann L, et al. The mechanism of action of cyclosporin A and FK506. Clin Immunol Immunopathol 1996; 80 (3 Pt 2): S40–S45. 59 Gruhn WB, Diaz-Buxo JA. Cyclosporine treatment of steroid resistant interstitial pneumonitis associated with dermatomyositis/polymyositis. J Rheumatol 1987; 14: 1045–1047. 60 Nagasaka K, Harigai M, Tateishi M, et al. Efficacy of combination treatment with cyclosporin A and corticosteroids for acute interstitial pneumonitis associated with dermatomyositis. Mod Rheumatol 2003; 13: 231–238. 61 Cavagna L, Caporali R, Abdi-Ali L, Dore R, Meloni F, Montecucco C. Cyclosporine in anti-Jo1-positive patients with corticosteroid-refractory interstitial lung disease. J Rheumatol 2013; 40: 484–492. 62 Ekberg H, Bernasconi C, Noldeke J, et al. Cyclosporine, tacrolimus and sirolimus retain their distinct toxicity profiles despite low doses in the Symphony study. Nephrol Dial Transplant 2010; 25: 2004–2010. 63 Kotani T, Makino S, Takeuchi T, et al. Early intervention with corticosteroids and cyclosporin A and 2-hour postdose blood concentration monitoring improves the prognosis of acute/subacute interstitial pneumonia in dermatomyositis. J Rheumatol 2008; 35: 254–259. 64 Kotani T, Takeuchi T, Makino S, et al. Combination with corticosteroids and cyclosporin-A improves pulmonary function test results and chest HRCT findings in dermatomyositis patients with acute/subacute interstitial pneumonia. Clin Rheumatol 2011; 30: 1021–1028. 65 Nagai K, Takeuchi T, Kotani T, et al. Therapeutic drug monitoring of cyclosporine microemulsion in interstitial pneumonia with dermatomyositis. Mod Rheumatol 2011; 21: 32–36. 66 Oddis CV, Sciurba FC, Elmagd KA, Starzl TE. Tacrolimus in refractory polymyositis with interstitial lung disease. Lancet 1999; 353: 1762–1763. 67 Takada K, Nagasaka K, Miyasaka N. Polymyositis/dermatomyositis and interstitial lung disease: A new therapeutic approach with T-cell-specific immunosuppressants. Autoimmunity 2005; 38: 383–392.
68 Wilkes MR, Sereika SM, Fertig N, Lucas MR, Oddis CV. Treatment of antisynthetase-associated interstitial lung disease with tacrolimus. Arthritis Rheum 2005; 52: 2439–2446. 69 Ochi S, Nanki T, Takada K, et al. Favorable outcomes with tacrolimus in two patients with refractory interstitial lung disease associated with polymyositis/dermatomyositis. Clin Exp Rheumatol 2005; 23: 707–710. 70 Siekierka JJ, Hung SH, Poe M, Lin CS, Sigal NH. A cytosolic binding protein for the immunosuppressant FK506 has peptidylprolyl isomerase activity but is distinct from cyclophilin. Nature 1989; 341: 755–757. 71 Harding MW, Galat A, Uehling DE, Schreiber SL. A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase. Nature 1989; 341: 758–760. 72 Kang CB, Hong Y, Dhe-Paganon S, Yoon HS. FKBP family proteins: Immunophilins with versatile biological functions. Neurosignals 2008; 16: 318–325. 73 Dumont FJ. FK506, an immunosuppressant targeting calcineurin function. Curr Med Chem 2000; 7: 731–748. 74 Webster AC. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: Meta-analysis and meta-regression of randomised trial data. BMJ 2005; 331: 810. 75 Margreiter R. Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: A randomised multicentre study. Lancet 2002; 359: 741–746. 76 Haddad EM, McAlister VC, Renouf E, Malthaner R, Kjaer MS, Gluud LL. Cyclosporin versus tacrolimus for liver transplanted patients. Cochrane Database Syst Rev 2006; 4: CD005161. 77 Nash RA, Antin JH, Karanes C, et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood 2000; 96: 2062–2068. 78 Kurita T, Yasuda S, Oba K, et al. The efficacy of tacrolimus in patients with interstitial lung diseases complicated with polymyositis or dermatomyositis. Rheumatology (Oxford). Epub ahead of print 24 April 2014. 79 Fung JJ, Alessiani M, Abu-Elmagd K, et al. Adverse effects associated with the use of FK 506. Transplant Proc 1991; 23: 3105–3108. 80 Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group. Transplantation 1997; 63: 977–983. 81 Penninga L, Penninga EI, Møller CH, Iversen M, Steinbru¨chel DA, Gluud C. Tacrolimus versus cyclosporin as primary immunosuppression for lung transplant recipients. Cochrane Database Syst Rev 2013; 5: CD008817. 82 Heisel O, Heisel R, Balshaw R, Keown P. New onset diabetes mellitus in patients receiving calcineurin inhibitors: A systematic review and meta-analysis. Am J Transplant 2004; 4: 583–595. 83 Taylor DO, Barr ML, Radovancevic B, et al. A randomized, multicenter comparison of tacrolimus and cyclosporine immunosuppressive regimens in cardiac transplantation: Decreased hyperlipidemia and hypertension with tacrolimus. J Heart Lung Transplant 1999; 18: 336–345. 84 Tanaka F, Origuchi T, Migita K, et al. Successful combined therapy of cyclophosphamide and cyclosporine for acute exacerbated interstitial pneumonia associated with dermatomyositis. Intern Med 2000; 39: 428–430.
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The efficacy of calcineurin inhibitors for the treatment of interstitial lung disease associated with polymyositis/dermatomyositis T Kurita, S Yasuda, O Amengual and T Atsumi Lupus published online 8 October 2014 DOI: 10.1177/0961203314554849 The online version of this article can be found at: http://lup.sagepub.com/content/early/2014/10/08/0961203314554849
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The efficacy of calcineurin inhibitors for the treatment of interstitial lung disease associated with polymyositis/ dermatomyositis T Kurita, S Yasuda, O Amengual and T Atsumi Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Interstitial lung disease (ILD) in patients with polymyositis (PM) and dermatomyositis (DM) is often resistant to treatment and life threatening, being recognized as one of the severest complication in these autoimmune disorders. Patients with clinically amyopathic dermatomyositis (CADM) or those with anti-CADM140/MDA5 antibody are especially prone to develop rapidly progressive interstitial pneumonia. We retrospectively analyzed 46 patients with PM/DM admitted to our hospital and identified DM, rapidly progressive disease, honeycomb lung, CADM and extensive ILD as risk factors for recurrence or death. In the presence of two or more risk factors, the sensitivity and specificity for the prediction of death or relapse were 81.3% and 76.7%, respectively. Calcineurin inhibitors have been widely used as induction and maintenance therapy for PM/DM-associated ILD. Recently we reported the benefit of tacrolimus on the disease-free survival and event-free survival of the patients with PM/DMassociated ILD. Among those patients treated with tacrolimus, poor prognostic factors for death, recurrence or severe adverse event were identified as acute progression of the disease, honeycomb lung, forced vital capacity (FVC) less than 80% and having DM. The potential effectiveness of an intensive therapy protocol with triple therapy that comprises high-dose corticosteroids, calcineurin inhibitors and cyclophosphamide has been reported. Lupus (2014) 0, 1–7. Key words: Interstitial pneumonia; ciclosporin; tacrolimus; anti-MDA5 antibody
Introduction Polymyositis (PM) and dermatomyositis (DM) are systemic autoimmune disorders affecting skin, skeletal muscles and other organs.1 Among them, pulmonary involvement including interstitial lung disease (ILD), aspiration pneumonia, infections and drug-induced pneumonitis represents one of the most common and serious organ damage in PM/DM, with a reported prevalence up to 65%.2–4 Pulmonary complications are considered to be common determinants of morbidity and mortality in these patients.3,5–12 ILD associated with DM is frequently difficult to treat, being recognized as a
Correspondence to: Olga Amengual, Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, N15 W7, Kita-ku, 060-8638 Sapporo, Japan. Email: [email protected] Received 9 September 2014; accepted 16 September 2014
more refractory disease compared with ILD associated with PM.12,13 Certain patients who have the typical skin manifestations of DM in the absence of clinical manifestations of myositis are referred to as clinically amyopathic dermatomyositis (CADM).14 The frequency of CADM is particularly elevated in Asian regions, and some patients with CADM develop rapidly progressive interstitial pneumonia (RPIP) with lethal respiratory failure. Pathological examinations of the lung lesions in these patients exhibit diffuse alveolar damage.15–21 The basic treatment of PM/DM-associated ILD is corticosteroids in combination with immunosuppressive agents. To improve the prognosis, the identification of patients with PM/DM who eventually develop RPIP would be crucial. In the last decade, calcineurin inhibitors have been widely used as induction and maintenance therapy for ILD associated with PM/DM, and their promising effectiveness should be recognized.
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In this manuscript, we will review the effects of calcineurin inhibitors on cases of PM/DM. Further, we will evaluate the factors that influence the prognosis of patients with PM/DM, including the myositis-specific autoantibodies.
Characteristics of ILD associated with PM/DM Prognosis The prognosis of ILD associated with PM or DM is poor, with a three-year survival rate of 74.4%5 and 61.6%,22 respectively. In the study by Douglas et al.,5 surgical lung biopsies were performed in 22 out of 58 patients with PM/DM-associated ILD, and organizing diffuse alveolar damage was observed in only two cases. On the other hand, this feature has been demonstrated in a number of autopsy cases of RPIP associated with CADM:12,23 Presumably, its frequency in PM/DM is higher than that reported so far. Unfavorable prognostic factors An unfavorable prognosis of ILD in patients with PM/DM has been associated with the following situations: DM,13 lower values of forced vital capacity (FVC) or diffusing capacity of carbon monoxide at the time of diagnosis,6,24 CADM,25,26 neutrophil alveolitis in the bronchoalveolar lavage,6 pathological evidence of usual interstitial pneumonia,6 skin ulcers,27 Hamman-Rich-like pattern,25,26 absence of Jo-1 anti-amynoacyl-tRNA synthetase (anti-ARS) autoantibodies,28 hyperferritinemia,29–31 and hypoalbuminemia.26 We conducted a multivariate analysis using the Cox proportional hazard model in a cohort of 46 patients with PM/DM attended at the Rheumatology Department in Hokkaido University Hospital. We found that DM, rapidly progressive disease (within two months), honeycomb lung, CADM and extensive ILD affecting more than 50% of the lung represent independent unfavorable prognosis factors for recurrence and death (Figure 1(a)). Further, using combinations of these unfavorable prognosis factors, we generated a receiver operating characteristics (ROC) curve and could accurately predict the relapse and mortality within five years. When the cutoff in the curve was set-up as two or more risk factors, the sensitivity and specificity for the prediction of death or relapse were 81.3% and 76.7%, respectively (Figure 1(b)).
Myositis-specific antibodies Idiopathic inflammatory myopathies (IIM) including PM and DM are a heterogeneous group of disorders with varying degrees of muscle disease, cutaneous manifestations and internal organ involvement. Based on their specificity, autoantibodies detected in patients with IIM are grouped into myositis-specific antibodies and myositis-associated antibodies. Over the last few years, myositis-specific autoantibodies have been better characterized, and these antibodies represent useful tools in IIMs, as they further define more homogeneous subsets. Anti-ARS and anti-MDA5 antibody (namely anti-CADM140 antibody) are the most relevant myositis-specific antibodies. With few exceptions myositis-specific antibodies are mutually exclusive, i.e. only one autoantibody is positive in one patient. Autoantibodies directed to eight different ARS have been described: anti-histidyl (anti-Jo-1),32 antianthreonyl (anti-PL-7),33 anti-alanyl (anti-PL-12),34 anti-glycyl (anti-EJ),35 anti-isoleucyl (anti-OJ),36 anti-asparaginyl (anti-KS),37 anti-phenylalanyl (anti-Zo),38 and anti-tyrosyl (anti-Ha).39 More than 90% of patients with positive anti-ARS antibodies have ILD,40 and among them, those cases with positive anti-PL-7 antibody and anti-PL-12 antibody have more severe prognosis.41 Anti-MDA5 antibody is a myositis-specific antibody strongly correlated with RPIP.42–44 Patients with ILD and anti-MDA5 antibody have a very poor prognosis, with approximately 50% of deaths within six months due to respiratory failure.43
Therapy for PM/DM-associated ILD The optimal treatment for ILD associated with PM/DM has not yet been clearly established. High-dose corticosteroid has been used as a standard first-line therapy for ILD in patients with PM/ DM, although approximately half of cases of ILD are resistant to corticosteroid therapy. In fact, about 20% of patients receiving steroid therapy experience deterioration of ILD. Fifty percent of steroid-resistant ILD patients die of respiratory failure in a relative short period.45 Intravenous cyclophosphamide is the most common immunosuppressive treatment used for ILD associated with PM/DM and may improve the clinical outcome in these patients. Although high clinical efficacy of intravenous cyclophosphamide therapy in PM/DM patients with ILD has been reported in retrospective observational studies
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Figure 1 Identification of prognostic factors in patients with polymyositis (PM)/dermatomyositis (DM)-associated interstitial lung diseases (ILD). (a) Cox regression analysis relating risk for death or recurrence. Candidate risk factors for death or recurrence of the disease were chosen if the p values were less than 0.1. Among these, factors without internal correlation were subjected to multivariate analysis using a Cox proportional hazard model. Closed squares and bars indicate hazard ratios and 95% confidence intervals, respectively. (b) Receiver operating characteristic (ROC) curve for the identified prognostic factors. The ROC curve was created based on the unfavorable prognostic factors identified in the multivariate analysis. Sensitivities and specificities were calculated according to the presence of death or relapse within five years from disease onset. AUC: area under the curve; CADM: clinically amyopathic dermatomyositis; CI: confidence interval; HR: hazard ratio.
or case reports,12,46,47 neither randomized controlled trials nor placebo-controlled studies have been conducted in these patients because of the severity and rarity of the disease.
The effects of other immunosuppressive agents such as azathioprine,5,10 mycophenolate mofetil48 and calcineurin inhibitors such as ciclosporin and tacrolimus in patients with PM/DM-associated Lupus
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ILD have been documented in small-size retrospective studies and case reports. A limited number of studies have shown the potential efficacy of intravenous immunoglobulins,49,50 tumor necrosis factor alpha inhibitors,51 anakinra52 or rituximab.53,54
Effectiveness of calcineurin inhibitors The bronchoalveolar lavage fluid of PM/DM patients with ILD showed a remarkably increased number of CDþ8 lymphocytes,13,55 indicating that the activation of pulmonary T cells plays a role in the pathogenesis of ILD. Therefore, T cells could be a primary therapeutic target for ILD associated with PM/DM. Calcineurin inhibitors exert their major therapeutic effects by inhibiting T cell activation. Calcineurin inhibitors block the dephosphorylation of the nuclear factor of activated T cells by calcineurin,56 showing a strong immune-suppressive effect by inhibiting the production of interleukin (IL)-2, IL-3, IL-4, CD40-ligand and interferon g.57,58 Ciclosporin Ciclosporin has been used for PM/DM-associated ILD since the 1980s. The therapeutic effects of ciclosporin in steroid-resistant patients have been reported in several retrospective studies.13,16,55,59–61 Nagasaka et al.60 retrospectively analyzed 32 patients with PM/DM-associated ILD treated with ciclosporin for two weeks as induction therapy in combination with corticosteroids. A general evaluation performed four weeks after the start of the combination treatment showed that in 29 patients the therapy was ‘‘partially effective,’’ defined as an improvement in only one of the four parameters evaluated, and in eight ‘‘remarkably effective,’’ corresponding to an improvement in at least three out of four evaluated parameters. This study suggests that treatment with ciclosporin during the early stages of ILD in patients with PM/ DM has an important therapeutic effect. Therapy with ciclosporin is often associated with adverse events, in particular renal impairment, gastrointestinal disorders, hypertension and abnormalities in glucose metabolism, but most of these events are preventable by monitoring the blood concentration of ciclosporin.62 The appropriate concentration of ciclosporin to ensure a maximal immunosuppressive effect and to avoid adverse events in patients with PM/DM-associated ILD should reach approximately 150 ng/ml and
1000 ng/ml, at trough and at two hours after administration, respectively.63–65 Tacrolimus Another calcineurin inhibitor, tacrolimus, was developed after ciclosporin, thus reports on the therapeutic effect of tacrolimus for PM/DM-associated ILD are fewer than those of ciclosporin. Since the report by Oddis et al.,66 in 1999, on the efficacy of tacrolimus for the treatment of steroidresistant PM/DM-associated ILD, other studies suggested the high effectiveness of tacrolimus in refractory cases with PM/DM-associated ILD.67–72 Ciclosporin inhibits the activity of calcineurin by binding to cyclophilin whereas tacrolimus exhibits inhibitory activity by binding to the FK binding protein (FKBP). In addition, the pharmacological effect of tacrolimus is 100 times stronger than that of ciclosporin, and its half-life is longer than that of ciclosporin.73 The superiority of tacrolimus to ciclosporin on renal, liver or bone marrow transplantation has been demonstrated in randomized controlled trials.74–77 These results suggested that tacrolimus has some advantages over ciclosporin for the treatment of PM/DM-associated ILD. Takada et al.67 reported five patients with PM/ DM-associated ILD who responded to treatment with tacrolimus rather than to ciclosporin. In our retrospective observational study of 49 patients with PM/DM-associated ILD, the diseasefree survival and event-free survival, using propensity score, were improved by tacrolimus.78 Moreover, we conducted a multivariate analysis in our patients treated with tacrolimus and identified the followings adverse prognosis factors when deaths, recurrences and severe adverse events were set as endpoints: honeycomb lung, DM, FVC not exceeding 80%, and rapid progressiveness (Figure 2). Adverse events of tacrolimus are generally similar to those of ciclosporin.65,79–81 Among them, the frequency of abnormalities in glucose metabolism is higher82 but hypertension or dyslipidemia are lower during the treatment with tacrolimus compared with ciclosporin.83 The appropriate tacrolimus trough levels for the treatment of ILD in PM/DM patients have not been established by clinical trials, but they are set as 5–20 ng/ml on the basis of data from renal and bone marrow transplantation. Triple combination therapy: corticosteroids, calcineurin inhibitors and cyclophosphamide Patients with CADM and anti-MDA5 antibody are prone to have RPIP. In these patients with severe
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Figure 2 Identification of prognostic factors in patients with polymyositis (PM)/dermatomyositis (DM)-associated interstitial lung diseases (ILD) treated with tacrolimus. Factors for death, recurrence of the disease or severe adverse event in PM/DM-associated ILD patients treated with tacrolimus without internal correlation were subjected to multivariate analysis using the Cox proportional hazard model. Closed squares and bars indicate hazard ratios and 95% confidence intervals, respectively. CI: confidence interval; FVC: forced vital capacity; HR: hazard ratio.
disease, the potential effectiveness of intensive therapy protocol with triple therapy (high-dose corticosteroids, calcineurin inhibitors and cyclophosphamide) has been reported.19,84 There is only one observational study with a small number of patients, but this therapy protocol apparently contributed to the better outcome for the patients with RPIP.
Conclusion The effectiveness of tacrolimus both in induction and maintenance therapy for PM/DM-associated ILD is highly promising. The treatment of RPIP in patients with CADM is still difficult, however. The combination therapy, containing calcineurin inhibitors in its protocol, has great potential for the improvement of the prognosis of these patients. Additional reported cases are needed to ascertain the efficacy of this treatment.
Funding This work was supported by grants from the Japanese Ministry of Health, Labor, and Welfare, and the Japanese Ministry of Education, Culture, Sports, Science, and Technology.
Conflict of interest statement S.Y. and T.A. have received honoraria and research support from Astellas Pharma. All the other authors have no conflicts of interest to declare.
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