**7. Management of interstitial pneumonia associated with connective tissue disease**

Because of the wide variation in manifestations of ILD in the autoimmune disease of CTD, no simple management strategy is adequate for every possible clinical setting. While a part of patients with CTD-associated ILD have limited and stable disease, not always requiring treatment, the significant proportions have severe and progressive disease which necessitates prompt and appropriate treatment. Essentially, nevertheless, general therapeutic principles in CTDs can be applied to many situations including acute and chronic disease. These include use of corticosteroids, azathioprine (AZA), cyclophosphamide (CYC), methotrexate (MTX), mycophenolate mofetil (MMF), and calcineurin inhibitors [13]. Although there are no specific guidelines for the management of CTD-ILD, general strategies recommended for IPF of IIP are also often applied in some cases of CTD-ILD. Emerging treatments with effects in IPF, e.g., Pirfenidone (a pyridine showing both anti-inflammatory and anti-fibrotic effects) and Nintedanib (a small-molecule tyrosine kinase inhibitor targeting VEGF-, FGF-, PDGFreceptors) may offer additional treatment options, though the efficacy has not been evaluated in CTD-ILD [166]. Basically, in contrast to the dismal prognosis in IPF/UIP of IIP with a median survival since diagnosis of 2–3 years, clinical experience in managing patients has taught us that immunosuppressive drugs in CTD-associated ILDs are capable of benefiting a significant proportion of patients, particularly those with certain histological patterns of disease.

With regard to the clinical study, there have been only two randomized placebo-controlled trials investigating the effect of immunosuppressive treatment in SSc-associated ILD. Briefly, the Scleroderma Lung Study (SLS) and the Fibrosing Alveolitis Scleroderma Trial (FAST), evaluated CYC (given orally at 2 mg/kg for 1 year in SLS and intravenously at a dose of 600 mg/m2 monthly for 6 months, followed by oral AZA for the following 6 months in FAST) for SSc-ILD [72, 73]. Both studies found a slower decline in forced vital capacity (FVC) in the CYC group compared with placebo. Intravenous CYC elicited a lower rate of bone marrow toxicity, severe infections, and gonadal failure compared to oral administration, likely due to higher cumulative dose acquired by daily oral administration [167]. Six months after quitting of immunosuppressant, the recovery in FVC fell into baseline, suggesting the requirement of prolonged immunosuppression therapy to maintain stability of lung function [168]. However, it should be noted that, despite studies supporting the benefit of CYC therapy in preventing deterioration in the lung function and premature death in patients with SSc–ILD, recent systematic review and meta-analysis of RCTs and observational prospective cohort studies failed to validate any clinically significant improvement in pulmonary function in SSc patients treated with CYC [169, 170].

of the pathogenic antigens, which may potentially lead to the development of antigen-specific, molecular-targeted therapies, such as the induction of anergy by peptide analogues similar in

Thus, as a result, the T cell receptor (TCR) repertoire study combined with histological analysis demonstrated substantial CD3+ T cell lung infiltrates with specific oligoclonal TCR usage that differed from those in PBL, suggesting a pivotal role for T cells in the pathogenesis of

**7. Management of interstitial pneumonia associated with connective** 

proportion of patients, particularly those with certain histological patterns of disease.

With regard to the clinical study, there have been only two randomized placebo-controlled trials investigating the effect of immunosuppressive treatment in SSc-associated ILD. Briefly, the Scleroderma Lung Study (SLS) and the Fibrosing Alveolitis Scleroderma Trial (FAST), evaluated CYC (given orally at 2 mg/kg for 1 year in SLS and intravenously at a dose of

for SSc-ILD [72, 73]. Both studies found a slower decline in forced vital capacity (FVC) in the CYC group compared with placebo. Intravenous CYC elicited a lower rate of bone marrow toxicity, severe infections, and gonadal failure compared to oral administration, likely due to higher cumulative dose acquired by daily oral administration [167]. Six months after quitting of immunosuppressant, the recovery in FVC fell into baseline, suggesting the requirement of prolonged immunosuppression therapy to maintain stability of lung function [168]. However, it should be noted that, despite studies supporting the benefit of CYC therapy in preventing deterioration in the lung function and premature death in patients with SSc–ILD,

monthly for 6 months, followed by oral AZA for the following 6 months in FAST)

Because of the wide variation in manifestations of ILD in the autoimmune disease of CTD, no simple management strategy is adequate for every possible clinical setting. While a part of patients with CTD-associated ILD have limited and stable disease, not always requiring treatment, the significant proportions have severe and progressive disease which necessitates prompt and appropriate treatment. Essentially, nevertheless, general therapeutic principles in CTDs can be applied to many situations including acute and chronic disease. These include use of corticosteroids, azathioprine (AZA), cyclophosphamide (CYC), methotrexate (MTX), mycophenolate mofetil (MMF), and calcineurin inhibitors [13]. Although there are no specific guidelines for the management of CTD-ILD, general strategies recommended for IPF of IIP are also often applied in some cases of CTD-ILD. Emerging treatments with effects in IPF, e.g., Pirfenidone (a pyridine showing both anti-inflammatory and anti-fibrotic effects) and Nintedanib (a small-molecule tyrosine kinase inhibitor targeting VEGF-, FGF-, PDGFreceptors) may offer additional treatment options, though the efficacy has not been evaluated in CTD-ILD [166]. Basically, in contrast to the dismal prognosis in IPF/UIP of IIP with a median survival since diagnosis of 2–3 years, clinical experience in managing patients has taught us that immunosuppressive drugs in CTD-associated ILDs are capable of benefiting a significant

structure to culprit antigens [164, 165].

172 Contemporary Topics of Pneumonia

**tissue disease**

600 mg/m2

PM-associated IP via antigen-driven immune mechanisms.

In PM/DM-associated ILD, high-dose steroid is often the first-line drug, although no definite therapeutic recommendation for the disease has been established yet. The other drugs most frequently used are AZA, MMF, hydroxychloroquine, MTX, CYC, and calcineurin inhibitors, e.g., cyclosporine A (CSA) and tacrolimus (TAC). Rituximab, anti-CD20 monoclonal antibody therapy, has lately emerged as a promising remedy of biologics in patients who have failed conventional immunosuppression treatments [171, 172]. Among a variety of immunosuppressants, the efficacy of calcineurin inhibitors for the treatment of PM/DM-associated ILD should be highlighted. CSA, which inhibits T cell proliferation and T cell-mediated cytokine productions at the transcriptional level, has begun to be used for PM/DM-ILD since the 1980s [173–175]. In 1998, the first nation-wide survey for the treatment with CSA in IP associated with CTDs was conducted in Japan, and the efficacy of a combination therapy with CSA and corticosteroids in PM/DM associated IP was indicated [176]. A number of retrospective and open-label studies have supported the benefit of CSA for the treatment of ILD with PM/DM [177–181]. Takada et al. published a retrospective multicenter study of 38 cases with acute ILD with PM/ DM, whereas it was shown that the combination therapy with CSA and corticosteroids started from the early phase of ILD is superior to corticosteroid monotherapy [178]. Today, calcineurin inhibitors are widely used especially in Japan as both an induction and maintenance therapy for PM/DM-ILD, generally resulting in favorable prognostic outcomes. The appropriate serum concentration of CSA to ensure a maximal effect as well as to avoid toxicity in patients with PM/DM-ILD should reach approximately 150 ng/mL and1000 ng/mL, at trough and at 2 hours after administration, respectively [179]. Another calcineurin inhibitor, TAC, which is a 100 fold potent T cell inhibitor compared to CSA, was also introduced into the treatment for PM/ DM-ILD, and its efficacy and tolerability have been demonstrated in retrospective studies and case series since the report by Oddis et al. in 1999 [182–185]. Ochi, et al. described a superior effect of TAC used in two myositis patients with progressive ILD who failed CYC and corticosteroid treatment but successfully recovered with TAC, showing significant improvement in symptoms and radiologic changes [183]. The appropriate tacrolimus trough level for the treatment of ILD in PM/DM patients have not been established by clinical trials, but it is usually set as 5–20 ng/mL on the basis of data from renal and bone marrow transplantation [186].

Given the treatment-effect heterogeneity of the lung disease observed in PM/DM, it is important to prepare novel therapeutics for the challenging cases of ILD which are refractory to conventional formulas. Recently, Suda et al. reported the effectiveness of multitarget therapy for the ILD in two cases of anti-MDA5 antibody-positive DM which is known to be associated with progressive ILD and sometimes has a lethal outcome despite strong immunosuppressive therapy including CYC [187]. They used TAC and mizoribine (MZR, an inosine monophosphate dehydrogenase inhibitor) in combination with corticosteroids. MZR is a nucleoside of the imidazole class, with the same mechanism as MMF: selective inhibition of lymphocyte proliferation by blocking inosine monophosphate dehydrogenase [188]. The safety and steroid-sparing effects of MZR have been shown in various CTDs, and the efficacy of multitarget therapy using TAC and MZR was reported for systemic lupus erythematosus [189, 190].
