roids, followed by azathioprine or mycophenolate mofetil as corticosteroids sparing or as add-on agents is the suggested treatment strategy. In refractory or rapidly progressive cases, high doses of steroids as well as rituximab or cyclophosphamide should be considered [43]. Regarding corticosteroids, which are suggested as a rst-line treatment, an initial daily dose of 0.5–1 mg/kg of prednisone has been suggested [58, 59]. The HRCT pattern can help predict the ef cacy of treatment, as NSIP, OP, and LIP have been associated with a better response than the UIP pattern [58, 60]. In the case of an established UIP pattern, it is doubtful whether immunosuppressive treatment ameliorates lung brosis [61]. The use of tocilizumab in SS-ILD has been reported in a case of steroid-­ resistant OP [62].

Prognosis

Pulmonary involvement in SS seems to compromise severely the mortality risk, and in particular, the UIP pattern has been associated with worse survival [42] (Table 14.3). A rare complication of SS as PH or lymphoma also worsens prognosis, with an average 5-year survival in case of lymphoma to be 65–90% [38, 63].

Mixed Connective Tissue Disease

Epidemiology

Mixed Connective Tissue Disease (MCTD) is an autoimmune disorder characterized by the detection of serum anti-­ RNP antibodies associated with features of systemic sclerosis (SSc), SLE, and infammatory myopathies [64, 65].

The prevalence of MCTD is 3.8/100,000 adults [66] while the annual incidence was 1.9/100,000 in a recent study in the

USA [67]. Serositis is common, with an estimated incidence varying from 6% to 50%. ILD occurs in about 36% to 50% of patients and is severe in 19% [68, 69]. PH is a major clinical feature in MCTD, with a prevalence of 10–50% [70–72].

Pathophysiology

Autoantibody production may be driven by distinct subsets of HLA-restricted T cells and HLA DRB1*04: 01 was con-rmed to be a major risk allele for MCTD [73]. Anti-U1-­ small nuclear ribonucleoprotein particle autoantibodies (anti-U1-snRNP) may be pathogenic by different mechanisms of action. First, it could bind to endothelial cells, to U1-RNP peptides presented by the MHC class II, or/and recognize fragments of nucleosome RNP in endothelial cell apoptotic blebs. Anti-U1-snRNP may also contribute to immune complexes that may activate the complement. A recent study proposed that the basophil/IgE/IL-4/CCL11 axis could be involved in the pathogenesis of MCTD, as activated basophils and autoreactive IgE to U1-snRNP were found in MCTD patients [74]. However, further studies are needed to better understand the pathophysiology of MCTD.

Anti-U1-snRNP antibodies are a mandatory criteria for diagnosis of MCTD (Table 14.5) [75]. Although highly sensitive (almost 100%), this marker is characterized by its low speci city and can be found in SLE [70]. Two factors are considered highly indicative of MCTD: the positive IgG anti-U1-RNP with negative IgM anti-U1-RNP and the elevated 70 k anti-U1-RNP titers [76]. In MCTD, the anti-DNA positivity could predict drift to SLE, while rheumatoid factor and anti-CCP seem to associate with arthritis. Anti-U1RNP positivity may be a predictor of more aggressive erosive arthritis [70].