cells, with CD8-T cell priming and CD4-T cell-B cell crosstalk, with the production of anti-histidyl-tRNA synthetase autoantibody. Genetic factors can also be involved, such as HLA-B*08.01. The propagation of the disease to other organs remains poorly explained [89].

Measurement of myositis-associated antibodies and myositis-­speci c antibodies levels is required in the initial evaluation of ILD, especially in the presence of skin or muscle clinical features (Table 14.2). The negativity of antinuclear autoantibodies does not rule out the presence of myositis-associated antibodies or myositis-speci c antibodies [90].

Patients with the anti-synthetase syndrome are clinically characterized by arthritis, Raynaud’s phenomenon, mechanics hands, and fever, but can also present with isolated ILD [91, 92].

The anti-synthetase antibodies (anti-Jo1, anti-PL7, anti- ­PL12, anti-KS, anti-OJ, anti-EJ, anti-SC, anti-JS, anti-YRS, anti-Zo) targeting the aminoacyl-tRNA synthetase enzyme are the most frequently found myositis-speci c antibodies, occurring on average in 20% of PM patients and 29% of DM patients (Table 14.2). Anti-PL-7 appears to be associated with ILD preceding the diagnosis of myositis, and anti-PL12 patients have a higher rate of isolated ILD [92]. Anti-MDA5 antibody (previously known as anti-CADM-140) is a myositis-­ speci c antibody associated with pulmonary involvement and is a risk factor for severe and rapidly progressive ILD, with increased mortality [93, 94]. Moreover, it is associated with a higher likelihood of having clinically amyopathic dermatomyositis [95]. Anti-MDA5 antibody detection identi es a subgroup of patients characterized by dermatomyositis skin rash,

a

skin ulcers, calcinosis, mechanic’s hands, ILD, arthralgia/ arthritis, and a high mortality rate [96].

Anti-PM-Scl and anti-Ku are two myositis-associated antibodies associated with a high prevalence of ILD, ranging from 38 to 78% for anti-PM-Scl and 27% for anti-Ku [93].

Pulmonary Manifestations and Treatments

Interstitial Lung Disease

ILD is the most frequent and severe extramuscular involvement of myositis, leading to a signi cant increase in mortality [4, 97]. A prevalence varying between 19.9 and 86% was reported, representing one of the highest prevalence among CTDs (Table 14.1) [98–100]. ILD is particularly frequent in patients with anti-tRNA synthetase [101, 102], anti-MDA5 [49], and anti-PM-Scl antibodies [103–105].

ILD is responsible for estimated excess mortality of 50% in some series [4, 97] and may precede muscular manifestations in up to 20% of cases [106]. Muscular involvement can be subtle or even absent. Rapidly progressive ILD is associated with a poorer prognosis, with a 68% mortality at 3 months (Table 14.3) [107–110].

The most frequent pattern observed on HRCT is an association of consolidations, corresponding to areas of OP, and NSIP features, with bilateral ground-glass opacities, reticulation, and peribronchovascular thickening mostly affecting lower lobes (Fig. 14.8) [111–113]. These features correspond histologically to an overlap pattern of OP and NSIP patterns [114, 115]. HRCT features of ILD are usually unspeci c to a subset of myositis.

b

Fig. 14.8  Organizing pneumonia pattern with consolidation with a peribronchovascular predominance in both lower lobes (Panel a) in a patient with anti-glycyl-tRNA synthetase antibody (anti-EJ). With cor-

ticosteroids, there was a resolution of consolidation with residual ground glass opacities and bronchial distortions (panel b)

Due to the low prevalence of the disease and the high variability in clinical presentation, there is no guideline regarding the treatment of ILD associated with myositis. The choice of immunosuppressive therapy should distinguish between rapidly progressive forms or acute forms associated with respiratory failure, and slowly progressive forms. In rapidly progressive forms or in acute respiratory failure an aggressive treatment should be considered as a rst-line treatment, associating high-dose corticosteroids with cyclophosphamide, rituximab, or a calcineurin inhibitor. In patients with mild disease or chronic presentation, corticosteroids alone or in association with mycophenolate mofetil or azathioprine could be proposed [99, 116].

Corticosteroids represent the cornerstone of the initial treatment of myositis-ILD and are generally used as a rst-­ line strategy [4, 117]. An oral administration of 0.5–1 mg/kg of prednisone for 4–8 weeks is usually admitted, followed by progressive tapering with a duration of treatment that generally exceeds 24 months. In chronic presentations or slowly progressive forms of ILD, a recent meta-analysis reported an improvement rate of 89.2% (95%CI 89.2–93.6) with corticosteroids alone [107]. However, prednisone-resistance is frequent. Corticosteroids alone show a response rate of 50%, suggesting that combined use of immunosuppressive therapies should be preferred in rapidly progressive cases [118– 120]. In a retrospective study, two treatment approaches were compared: an association of immunosuppressive treatment (cyclosporine, cyclophosphamide, azathioprine, or tacrolimus) and prednisone at the treatment initiation (intensive approach), or the adjunction of immunosuppressive therapy when prednisone alone had no favorable response (step-up approach). The intensive approach was associated with better survival [121]. In patients showing initially elevated serum levels of muscle enzymes (creatine phosphokinase), it has been suggested that tapering of corticosteroids should be initiated once enzymes return to normal levels.

Immunosuppressive therapies should be considered in relapsing diseases, or as corticosteroid-sparing agents. Data supporting the effectiveness of azathioprine and mycophenolate mofetil, as maintenance therapy after induction or for patients with mild ILD, are limited to small case series and case reports. Mira-Avendano et al., reported the same ef - cacy on clinical and functional stabilization and corticosteroids daily dose tapering, for oral cyclophosphamide, azathioprine, and mycophenolate mofetil in PM/DM-ILD and anti-synthetase syndrome-ILD [60]. In a recent retrospective study on 66 patients with myositis-associated ILD treated with azathioprine and 44 with mycophenolate mofetil, a signi cant improvement was observed in FVC (%) with both drugs, and DLCO (%) with azathioprine, allowing a tapering of corticosteroids daily dose [122].

Methotrexate is mostly used in case of rheumatic manifestations of myositis. It has been used for the treatment of myositis-associated ILD despite the absence of pulmonary-­ speci c evidence, with a good safety pro le.

Many retrospective studies, regarding both cyclosporine and tacrolimus, suggested that calcineurin-inhibitors may be useful in treating myositis-ILD. Tacrolimus might have an effect on functional and clinical improvement, as well as muscle strength improvement, especially in patients who did not respond to rst-line corticosteroid treatment, with a decrease of prednisone daily dose [123, 124]. Cyclosporine could be suggested in chronic ILD associated with myositis, with a favorable outcome observed when associated with corticosteroids. In acute forms, cyclosporine is associated with a favorable outcome in polymyositis-ILD and in half of ILD associated with dermatomyositis patients, with a better survival rate when cyclosporine and prednisone were associated [125].

The use of cyclophosphamide is currently limited to the aggressive, rapidly progressive, or refractory forms of myositis-­associated ILD with an improvement in survival. A systematic review of 12 studies published in 2015 supported the use of cyclophosphamide in myositisILD, with 58% (34 of 59) of patients showing an improvement in survival rate. In a recent meta-analysis, the global 3-month survival rate was 72.4% (95%CI 6.4–99.0) in rapidly progressive cases [107].

In myositis-ILD, rituximab was shown to have a role as a second-line treatment for refractory ILD in several retrospective studies, with a functional, imaging, and/or clinical improvement [126–129]. Overall, rituximab appears as a drug of choice in the management of refractory myositis-­ ILD and rapidly progressive ILD. Prospective randomized trials are ongoing to assess the ef cacy and tolerability of rituximab in CTD-ILD [130, 131].

Intravenous immunoglobulin combined with steroids is effective in improving muscle strength and decreasing creatine kinase levels in patients with active muscle disease. Data suggesting a bene t in ILD are scarce [132, 133]. However, intravenous immunoglobulin could be discussed in patients with refractory disease associated with muscular involvement or with marked contraindications to immunosuppressive agents.

Respiratory Muscle Weakness

Respiratory muscle weakness is a rare but potentially life-­ threatening complication that can develop independently from skeletal muscle weakness. The management of respiratory muscle involvement is similar to that of peripheral muscle or extramuscular involvement and mostly relies on immunosuppressive therapies [134, 135]. In a retrospective