Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)

INTRODUCTION — Interstitial lung disease (ILD) is a frequent complication of systemic sclerosis (SSc) that is often progressive and has a poor prognosis [1-7]. SSc-associated ILD consists of various histopathologic subtypes, most commonly nonspecific interstitial pneumonitis and usual interstitial pneumonitis.

The treatment and prognosis of SSc-ILD will be reviewed here. The clinical presentation and diagnosis of SSc lung disease, the treatment of SSc in general, and the treatment of SSc-associated pulmonary arterial hypertension are discussed separately. (See "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)" and "Overview of pulmonary complications of systemic sclerosis (scleroderma)" and "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults" and "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening".)

TYPES OF INTERSTITIAL LUNG DISEASE — The term interstitial lung disease (ILD) is broadly used to describe a heterogeneous group of disorders that are classified together because of similar clinical, radiographic, physiologic, or pathologic manifestations. In this topic review, we refer broadly to systemic sclerosis (SSc)-ILD and do not distinguish among the histopathologic subtypes.

In the vast majority of patients with SSc-ILD, the lung injury is characterized by a pattern termed nonspecific interstitial pneumonia (NSIP) [8]. Histopathologically, NSIP is characterized by varying degrees of pulmonary inflammation and fibrosis, with some forms being primarily inflammatory (cellular NSIP) and others primarily fibrotic (fibrotic NSIP). Patients with a more fibrosing form of NSIP have worse outcomes compared with those with cellular NSIP [9,10]. (See "Treatment and prognosis of nonspecific interstitial pneumonia" and "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Nonspecific interstitial pneumonia'.)

A minority of patients with SSc-ILD have the histopathologic pattern of UIP [8], the characteristic pattern associated with idiopathic pulmonary fibrosis (IPF). This pattern is characterized by the presence of scattered foci of fibroblast proliferation ("fibroblast foci"), nonuniform distribution of areas of dense fibrosis, scant inflammation, and honeycomb change. While histopathologic pattern of usual interstitial pneumonia (UIP) is less common than NSIP in connective tissue-associated ILD, when present a UIP pattern (histopathologically or radiographically) confers a worse survival compared to NSIP [11]. (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Pathology'.)

INITIATING THERAPY — The optimal treatment for systemic sclerosis-associated interstitial lung disease (SSc-ILD) is not known. Based on the best available evidence, we suggest initiating immunosuppressive therapy in patients with symptomatic SSc-ILD and features suggesting a high likelihood of progression. Mycophenolate mofetil is preferred as initial therapy over cyclophosphamide due to a better safety profile and comparable efficacy as described in the following sections. Azathioprine is an alternative that can be considered for patients with contraindications to or intolerance of cyclophosphamide and mycophenolate. Patients can also be offered the opportunity to participate in a clinical trial (clinicaltrials.gov).

Indications — Exact criteria for initiation of immunosuppressive treatment for SSc-ILD have not been established, and the decision about initiating therapy can be difficult because the benefits of therapy appear to be modest and the toxicities significant. As many patients with SSc-ILD have stable or slowly progressive disease, selection of appropriate therapy requires a balance between avoiding potentially toxic agents in these patients, while providing therapy to those most likely to progress. Features that are associated with progression of lung disease are listed in the table and described below (table 1).

It is thought that patients are more likely to benefit from therapy when it is initiated early in the course of disease, before a substantial loss of lung function has occurred [12-16]. In approximately half of the patients with progressive SSc ILD, the most rapid decline in forced vital capacity (FVC) occurs within the initial three years of disease onset, indicating that lung injury and fibrosis may be early complications [13].

Features associated with ILD progression include the following:

●Duration of ILD – Based on observational data, patients with early SSc-ILD are more likely to have active inflammation and to respond to pharmacologic intervention with immunosuppressive agents than those with long-standing disease [17]. Although there is no uniform agreement on how early disease should be defined, it generally refers to the initial 12 to 24 months of SSc disease before significant irreversible organ fibrosis is established. However, results from the Scleroderma Lung Study (SLS1) showed that in some patients with SSc-ILD, lung disease can show progression even when present for more than four years [18].

●Pulmonary function – No specific pulmonary function test (PFT) values have been validated in SSc-ILD, as triggers for initiating therapy. Serial tests that demonstrate worsening pulmonary function (eg, a ≥10 percent decline in FVC or diffusing capacity for carbon monoxide [DLCO]) are an indication of active disease for which treatment initiation should be considered. Pulmonary function tests demonstrating a restrictive ventilatory defect (ie, reduced total lung capacity, often accompanied by a reduced FVC with a preserved forced expiratory volume in one second [FEV₁] to FVC ratio) and decreased DLCO are consistent with SSc-ILD. However, as noted above, a proportion of patients with SSc-ILD will have normal pulmonary function despite HRCT evidence of ILD [19]. A retrospective analysis of 80 patients with SSc-ILD from the Royal Brompton Hospital (London, United Kingdom) showed that mortality increased with decreasing initial FVC levels and decreasing initial DLCO levels [8]. Characteristic findings on PFTs are described separately. (See "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Pulmonary function testing'.)

Follow-up of patients enrolled in the Scleroderma Lung Studies (SLS) I and II has shown that short-term progression of ILD was a better predictor of mortality than baseline severity of ILD, in particular, patients who experienced a decline in the FVC and DLCO over two years had a substantially increased risk of mortality even after adjusting for treatment arm assignment, as well as baseline disease severity [20].

●High-resolution computed tomography (HRCT) – The proportion of lung affected by ILD can be assessed by HRCT and appears to predict disease progression and mortality (image 1). The presence of radiologic lung fibrosis in SSc patients at baseline confers an increased risk of mortality even among those with a preserved forced vital capacity [21]. In one study, radiographic changes affecting >20 percent of the lung were shown to be predictors of greater mortality [22]. A subsequent study of 172 patients confirmed these results [15]. The finding of widespread honeycombing with SSc-ILD, suggests advanced fibrosis that is unlikely to respond to immunosuppressive therapy. Focal lung scarring, especially in the posterior lung fields, and tree-in-bud opacities may suggest recurrent aspiration that should be treated with measures to prevent aspiration. The typical HRCT findings of SSc-ILD are described separately. (See "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Imaging'.)

●Risk prediction model – It has been shown that three-year mortality risk in SSc-ILD can be estimated using the SADL model (ever Smoking history, Age, and percent predicted Diffusing capacity of the Lung for carbon monoxide) developed in two independent cohorts of patients with SSc-ILD with a total of 225 patients [23].

We do not use the results of bronchoalveolar lavage cell counts to determine the likelihood of response to immunosuppressive therapy, despite earlier small studies that suggested a correlation [24-27]. Similarly, we do not obtain a lung biopsy to determine the histopathology unless unusual features are present, as the majority of patients with SSc-ILD have fibrotic nonspecific interstitial pneumonitis and current treatment is not based on pathologic subtypes.

Choice of initial agent — Once the decision has been made to initiate therapy for ILD, we suggest using mycophenolate mofetil (MMF) rather than cyclophosphamide as initial therapy, based on evidence of comparable efficacy and a better adverse effect profile for MMF. This was illustrated in the Scleroderma Lung Study II (SLS II) that compared MMF with cyclophosphamide and found no significant differences in lung function, but better tolerance of MMF [28]. The details are described below. (See 'Efficacy' below and "General toxicity of cyclophosphamide in rheumatic diseases".)

Tocilizumab is approved by the US Food and Drug Administration (FDA) for slowing the rate of decline in pulmonary function in patients with SSc-ILD and has a good safety profile. Tocilizumab can be considered as an alternative to mycophenolate for initial therapy. Azathioprine is inferior to cyclophosphamide and is generally only used if other initial therapies are not tolerated. (See 'Alternative initial pharmacologic therapy' below.)

Mycophenolate mofetil — MMF is an inhibitor of T and B lymphocyte proliferation that is often used in the treatment of extrapulmonary manifestations of SSc and other rheumatic diseases. Based on results from the SLS II trial described above that compared MMF with oral cyclophosphamide, we suggest MMF as first line therapy in patients with SSc-ILD who are at risk for progressive ILD [28]. (See 'Choice of initial agent' above.)

Dose and duration — The target dose of MMF is generally between 1.5 and 3 g daily, usually given in two divided doses [28]. Starting with lower doses may enhance gastrointestinal tolerance of MMF. The SLS II clinical trial used a designated dose escalation schedule starting at 500 mg twice daily and increasing to the target dose of 1.5 g twice daily over three to four months [28].

The maximal dose of MMF should be reduced in patients with end-stage kidney disease. A number of drug interactions can affect serum concentrations. In particular, proton pump inhibitors and antacids, which are very commonly used in SSc, and mineral supplements can interfere with MMF absorption. Dosing of antacids and mineral supplements should be separated from MMF by least two hours. Dosing and potential drug interactions of MMF are described separately. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Mycophenolate dose and administration' and "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)

The optimal duration of MMF therapy is unknown. In the Scleroderma Lung Study II, treatment with MMF was continued for 24 months, but most experts, including us, continue MMF for several years as maintenance therapy in patients who show stabilization of lung function. (See 'Maintenance therapy' below.)

Monitoring and adverse effects — Bone marrow suppression and gastrointestinal (GI) symptoms are the most commonly observed adverse effects. A complete blood count should be performed one to two weeks after the start of therapy and periodically during dose escalation. If there is no evidence of bone marrow suppression, it is our practice to check complete blood counts every six to eight weeks and gradually extend the period. Gastrointestinal symptoms, such as nausea, diarrhea, and abdominal cramping, are frequent, but may improve with divided dosing (eg, three to four times a day) or a reduction in the total daily dose. Enteric-coated mycophenolate sodium may be an option but requires dose adjustment. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Adverse effects'.)

Because MMF is associated with an increased risk of miscarriage and congenital anomalies, it should be avoided during pregnancy. Reliable contraception should be employed by women of child-bearing potential. MMF is excreted in breast milk and is contraindicated in lactating women. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Mycophenolate mofetil'.)

Pneumocystis prophylaxis is generally not necessary during MMF therapy unless there are other indications. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Pneumocystis jirovecii'.)

Efficacy — The role of MMF in SSc-ILD has been assessed in a randomized trial (SLS II), retrospective reviews, and small prospective case series [28-41]. The consistent finding is of modest improvement or stabilization in lung function and dyspnea. (See "Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)", section on 'Other immunosuppressive agents'.)

●SLS II was a randomized trial that included 142 patients with SSc-ILD, characterized by a forced vital capacity (FVC) <80 percent, but >45 percent of predicted, exertional dyspnea, ground glass opacities on HRCT with or without reticular opacities, and onset of the first non-Raynaud symptom of SSc within the prior seven years [28]. Participants were assigned to MMF 1500 mg twice daily for 24 months or oral cyclophosphamide titrated up to a maximum daily dose of 1.8 to 2.3 mg/kg for 12 months. Both groups demonstrated improvement in adjusted percent predicted FVC from baseline to 24 months: 2.19 percent (95% CI 0.53-3.84) in the MMF group and 2.88 percent (95% CI 1.19-4.58) in the cyclophosphamide group, a nonsignificant difference. Dyspnea improved in both groups based on the Transition Dyspnea Index [42]. MMF was better tolerated than cyclophosphamide based on a longer time to patient withdrawal and a lower incidence of leukopenia and thrombocytopenia. Longer-term toxicities of cyclophosphamide, including gonadal toxicity, hemorrhagic cystitis, and malignancies, were not assessed in the trial.

●Forty-one patients with mild SSc-ILD (FVC ≥70 percent predicted) were randomly assigned to MMF at a total dose of 2 g per day or placebo for 6 months. While the modified Rodnan skin score (mRSS) improved with MMF, dyspnea, DLCO, and 6MWT were similar between groups [41]. Additional study is needed given the small size and short duration of this trial.

●In two retrospective reviews of a combined total of 30 patients with SSc-ILD, MMF treatment for up to 24 months was associated with improved or stable pulmonary function relative to baseline [36,37].

●Small observational studies (total of 39 patients) reported stability or improvement in lung function after initiation of MMF or mycophenolate sodium (MS) [29,32,38].

Alternative initial pharmacologic therapy — Tocilizumab, cyclophosphamide, and azathioprine are alternative initial immunosuppressive agents for patients with SSc-ILD. Compared with placebo, tocilizumab has been shown to reduce lung function decline. Cyclophosphamide itself has been established to have similar efficacy to MMF but has significantly higher toxicity. Azathioprine likely results in inferior outcomes but has been used for many years in patients with SSc-ILD who were felt not appropriate for or did not tolerate other agents.

Tocilizumab — Tocilizumab is a humanized anti-interleukin (IL)-6 receptor antibody of the IgG1 subclass that is used in the treatment of rheumatoid arthritis, giant cell arteritis, and polyarticular juvenile idiopathic arthritis. In SSc, elevated circulating IL-6 is predictive of the progression of ILD, suggesting potential therapeutic benefit to IL-6 antagonism [43]. Based on results from the clinical trials described below, tocilizumab has been approved in the United States for slowing the rate of decline in pulmonary function in adults with SSc-ILD [44]. Tocilizumab is not used to treat SSc skin disease. Tocilizumab has not been directly compared with MMF. While awaiting additional data, tocilizumab is a reasonable treatment alternative to MMF as initial therapy in patients with early diffuse SSc and ILD, particularly in those who are unable to take MMF and have early evidence of ILD progression or prominent musculoskeletal involvement. Tocilizumab is also a reasonable alternative in those with elevated acute phase reactants (eg, platelets and CRP), as it is effective in decreasing these measures; however, we recognize that acute phase reactants are only surrogates of disease activity and that there are no data regarding tocilizumab efficacy specifically in this patient subset.

Dose and administration — For patients with SSc-ILD, the dose of tocilizumab is 162 mg once every week, given subcutaneously. (See "Overview of biologic agents in the rheumatic diseases", section on 'Tocilizumab'.)

Monitoring and adverse effects — Patients should be screened for latent Mycobacterium tuberculosis infection prior to initiation of tocilizumab. A complete blood count, alanine aminotransferase (ALT)/aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin should be obtained prior to therapy, four to eight weeks after start of therapy, and every three months thereafter. Use of tocilizumab is not advised during pregnancy.

The most common adverse effects associated with tocilizumab are upper respiratory infection, headache, hypertension, elevated alanine aminotransferase, and injection site reactions. Interruption of dosing may be needed for laboratory abnormalities such as neutropenia, thrombocytopenia, or elevated liver enzymes. Live vaccines should be avoided during tocilizumab therapy. (See "Overview of biologic agents in the rheumatic diseases", section on 'Tocilizumab'.)

Efficacy — Two randomized trials evaluating tocilizumab versus placebo demonstrated benefit in lung function with treatment:

●An interim report of the randomized clinical trial (faSScinate) of subcutaneous tocilizumab versus placebo for SS skin disease suggested potential benefit in slowing a modest reduction in the decline in forced vital capacity (FVC) at 24 weeks, but not 48 weeks [45,46]. In the open-label extension of this study, fewer subjects receiving tocilizumab experienced a decline in FVC compared with those receiving placebo [47].

●A phase 3 clinical trial (focuSSced) to assess the efficacy of tocilizumab in SSc randomly assigned 210 patients to receive tocilizumab 162 mg or placebo by subcutaneous injection, weekly for 48 weeks [48]. Patients were not on immunomodulatory therapy at enrollment, but a stable dose of oral glucocorticoid was allowed. While there was no difference in the primary endpoint (ie, improvement in skin findings according to the mRSS) between the tocilizumab and placebo-treated groups, a benefit of tocilizumab on lung function was observed at 48 weeks. Among patients with evidence of ILD on baseline HRCT, the mean change in FVC from baseline at 48 weeks was -14 mL with tocilizumab and -255 mL with placebo (LSM difference 241 mL; 95% CI 124-358). A 48-week, open-label extension (181 of the original 212 participants) showed continued preservation of FVC in the continuous tocilizumab group, similar to that seen in the parent study [49]. (See "Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)", section on 'Anticytokine therapy'.)

Cyclophosphamide — We view cyclophosphamide as a less optimal treatment alternative to MMF or tocilizumab for SSc-ILD due to the increased risk of adverse effects associated with cyclophosphamide [28]. When using cyclophosphamide for the treatment of SSc-ILD, we prefer intravenous dosing, given monthly for six months, rather than oral daily dosing for 12 months. In our experience, intravenous therapy allows for lower cumulative dose, less frequent adverse effects, and the ability to ensure adequate hydration prior to dosing (to reduce the risk of bladder toxicity). After completion of cyclophosphamide, patients commonly transition to a maintenance regimen with a less toxic agent (eg, mycophenolate, tocilizumab, or azathioprine). (See "General toxicity of cyclophosphamide in rheumatic diseases" and 'Maintenance therapy' below.)

Evidence in support of cyclophosphamide for SSc-ILD is mixed. Randomized trials (described in the following sections) using both oral and intravenous routes of administration suggest that cyclophosphamide imparts modest benefit in SSc patients with early, symptomatic lung disease [27,28,50,51]. However, a meta-analysis of three randomized trials and six open label studies did not confirm an improvement in pulmonary function (ie, FVC and DLCO) with cyclophosphamide after 12 months [52].

Intravenous cyclophosphamide — While the two Scleroderma Lung Studies (SLS I and SLS II) used daily oral administration of cyclophosphamide [27,28], we prefer monthly intravenous administration, as noted above. The effectiveness of intravenous cyclophosphamide, used in combination with low dose glucocorticoid, at preventing deterioration of lung function in SSc-ILD has been studied in small observational studies and one randomized trial [50,53-57]. In the randomized trial, 45 patients were assigned to receive six monthly infusions of cyclophosphamide plus prednisolone (20 mg on alternate days) [50]. At 12 months, there was a modest improvement of FVC (4.19 percent) in the cyclophosphamide group compared with placebo after adjustment for baseline FVC, but this improvement did not achieve statistical significance. Neither DLCO nor measures of dyspnea showed improvement in either group. (See "General principles of the use of cyclophosphamide in rheumatic diseases" and "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Intermittent (pulse) cyclophosphamide'.)

Oral cyclophosphamide — Oral cyclophosphamide appears to be beneficial for some patients with symptomatic SSc-ILD [27,58,59], although not all studies have confirmed this finding as noted above [52]. Improvement in pulmonary function was demonstrated in a double-blind, multicenter trial (Scleroderma Lung Study I) that randomly assigned 158 patients with early SSc-ILD, dyspnea, an FVC between 45 and 85 percent of the predicted value, and evidence of active alveolar inflammation to receive either oral cyclophosphamide (≤2 mg/kg) or placebo daily for one year [27]. Evidence of active alveolar inflammation included ground-glass opacities on high resolution computed tomography or elevated numbers of neutrophils or eosinophils in bronchoalveolar lavage fluid. Concomitant glucocorticoids were permitted in doses equivalent to ≤10 mg/day of prednisone. Outcomes at 12 months were:

●The cyclophosphamide group had a smaller decline than the placebo group in FVC (-1 versus -2.6 percent of predicted) and total lung capacity (-0.3 versus -2.8 percent of predicted). DLCO was unchanged in both groups.

●The percentage of patients with cough decreased in the cyclophosphamide group from 71 percent at baseline to 56 percent, whereas the percentage of patients with cough in the placebo group remained the same (68 percent) at both baseline and 12 months [60].

●The cyclophosphamide group had less progression of radiographic fibrosis compared to the placebo group [61]. No differences between the groups were noted regarding changes in ground glass opacities or honeycomb cysts. Subsequent analysis found that more severe fibrosis on HRCT was an independent predictor of a response to cyclophosphamide (improvement in forced vital capacity at 18 months) [51].

●More severe SSc based on measures of skin thickness, dyspnea severity, self-reported disability, and health related quality of life also favored cyclophosphamide [62].

A follow-up study reported 24 month outcomes for 93 patients who completed one year of oral cyclophosphamide or placebo plus 52 who completed at least six months of cyclophosphamide or placebo and returned at 24 months or had their 24-month data imputed [63]. Of the 48 patients who had received cyclophosphamide, 12 also received low dose prednisone. The beneficial effects of cyclophosphamide on FVC appeared to persist for six months after stopping the drug. However, by 24 months the improvement in FVC was no longer present, suggesting that the pulmonary response to cyclophosphamide is not durable.

In SLS II, oral cyclophosphamide was initiated at 50 to 150 mg/day (based on weight) and increased gradually over three months to a maximum dose of 1.8 to 2.3 mg/kg [28]. Details of oral cyclophosphamide dosing are provided separately. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Daily oral cyclophosphamide'.)

Monitoring and adverse effects — White blood cell count, renal function, and urinalysis should be monitored monthly during cyclophosphamide therapy. A detailed discussion about monitoring and parameters for withholding cyclophosphamide is provided separately. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Monitoring of oral CYC dosing'.)

Cyclophosphamide has short and long-term potential toxicities, including infertility, opportunistic infections, hemorrhagic cystitis, bladder cancer, neutropenia, and adverse drug interactions [64]. Patients should use effective contraception to prevent pregnancy during cyclophosphamide therapy. (See "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Toxicity'.)

Immunosuppressed patients are at increased risk for Pneumocystis jirovecii pneumonia (PCP, previously called Pneumocystis carinii); thus, we suggest that patients taking cyclophosphamide also receive prophylaxis against PCP, which is described separately. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV".)

Adjuvant glucocorticoids — The role of adjuvant low dose of oral glucocorticoids (equivalent of ≤10 mg/day of prednisone) in combination with cyclophosphamide is unclear. In studies evaluating the efficacy of cyclophosphamide versus placebo in SSc-ILD, many patients also received low dose glucocorticoid [27,50]. However, evidence in support of this practice is lacking, and we reserve low dose glucocorticoids for patients with other indications for glucocorticoids (eg, arthritis, pruritus).

We avoid combining high dose glucocorticoids with cyclophosphamide because of the lack of clinical trial data and the attendant risks of scleroderma renal crisis and opportunistic infection.

Azathioprine — Azathioprine appears less efficacious as initial therapy for SSc-ILD than cyclophosphamide and by extension MMF, although it has not been directly compared with MMF [65]. In an unblinded trial, 60 patients with early diffuse SSc and ILD were randomly assigned to receive either cyclophosphamide (up to 2 mg/kg per day) or azathioprine (2.5 mg/kg per day up to a maximum of 150 mg/day). During the first six months of therapy, patients in both groups also received prednisolone (15 mg/day), which was subsequently tapered. After 18 months, FVC and diffusion capacity were stable in patients treated with cyclophosphamide but had declined in patients treated with azathioprine. Leukopenia was more frequent in the cyclophosphamide group. Azathioprine has not been directly compared with tocilizumab.

A retrospective analysis of eight patients with SSc-ILD who received azathioprine plus prednisone for worsening pulmonary symptoms or declining lung function for a minimum of 12 months showed that five patients had >10 percent improvement of FVC and three patients remained stable [66]. Three other patients discontinued azathioprine due to adverse effects within the first six months of therapy.

Azathioprine dosing and monitoring for adverse effects are discussed separately, along with pretreatment testing for thiopurine S-methyltransferase (TPMT) deficiency. TPMT deficiency confers increased risk of life-threatening immunosuppression with azathioprine therapy. Typically, a complete blood count and liver function tests are obtained monthly for the first few months of therapy, and then every three months once a stable dose is achieved. The dosing of azathioprine, including potential testing for thiopurine S-methyltransferase (TPMT) deficiency, and monitoring for adverse effects are described separately. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacogenetics and azathioprine toxicity'.)

MAINTENANCE THERAPY — After a course of initial therapy, immunomodulatory therapy is usually continued for months to years. Neither the optimal choice of agent for maintenance therapy nor the treatment duration is known.

Part of the rationale for long-term therapy is that the improvements in lung function associated with cyclophosphamide appear to wane in the 12 months after discontinuation of active therapy [63] (see 'Oral cyclophosphamide' above). While both CYC and MMF have been shown to improve pulmonary function up to 24 months, long-term survival was similar in the CYC and placebo groups of SLS I and also in the MMF and CYC groups of SLS II [20,28].

Observational data and clinical experience support the use of mycophenolate (eg, 1.5 to 3 g daily, usually in two divided doses) or azathioprine as maintenance agents [57,67]. In our practice, we generally select MMF over azathioprine due to the evidence of efficacy seen in the Scleroderma Lung Study II (SLS II) [28], unless the patient has previously not tolerated MMF.

Tocilizumab is an alternative to MMF for maintenance therapy, based on long-term use in rheumatoid arthritis, although its long-term use in SSc-ILD has not been formally studied. Maintenance with this agent is reasonable in patients who experience initial benefit with tocilizumab and do not have any adverse effects. (See 'Tocilizumab' above.)

Maintenance therapy is typically continued until the patient has experienced a long period of stability (at least 12 to 24 months) in respiratory symptoms and function or develops progressive disease (prompting consideration of an alternative agent). However, the optimal duration of immunosuppressive treatment is unknown. During maintenance therapy, adjuvant glucocorticoids are usually reserved for patients who have an extrapulmonary indication for them, such as arthritis or pruritus. (See 'Mycophenolate mofetil' above and 'Monitoring response to therapy' below and "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Mycophenolate dose and administration'.)

PROGRESSIVE DISEASE

General approach — Several agents have been used for SSc patients who experience progressive loss of lung function despite treatment with the above drugs. Prior to pursuing other therapies for SSc-ILD, these patients should be reassessed for potential reasons for lack of clinical improvement, such as other disease complications (eg, aspiration pneumonitis, pleural or pericardial disease, pulmonary hypertension) or comorbid disease (eg, thromboembolic disease and chronic obstructive pulmonary disease [COPD]).

For patients whose disease is refractory to immunomodulatory agents, we suggest addition of nintedanib or rituximab to ongoing therapy (eg, mycophenolate, tocilizumab, or cyclophosphamide). Patients with more inflammatory features on imaging may benefit more from rituximab, while those with more fibrosis features may benefit more from nintedanib. In practice, the combination of mycophenolate and nintedanib is often poorly tolerated (typically due to diarrhea), and dose reductions are frequently employed.

Patients with progressive disease and without contraindications should undergo evaluation for lung transplantation.

Patients who are candidates for clinical trials may wish to pursue this option and can be referred to (ClinicalTrials.gov).

Nintedanib — Nintedanib, an inhibitor of multiple tyrosine kinases, slows disease progression in idiopathic pulmonary fibrosis (IPF) and is approved by the US FDA for use in IPF [68] (see "Treatment of idiopathic pulmonary fibrosis", section on 'Nintedanib'), progressive fibrosing ILD [69], and SSc-ILD [70,71]. Randomized trials have demonstrated benefit with nintedanib in the treatment of SSc-ILD, with a reduced rate of loss of forced vital capacity (FVC) [71,72]. Based on these results, nintedanib may be used to slow the progression of SSc-ILD; however, the patients with SSc-ILD most likely to benefit from nintedanib, and the optimal timing of initiation and duration of treatment, remain unknown. It is our opinion that patients with SSc-ILD who demonstrate disease progression despite MMF or cyclophosphamide, especially in the first one to two years of treatment given the association with increased mortality [20], may benefit from the addition of nintedanib to standard therapy [71]. Nintedanib may also be an alternative treatment for SSc-ILD in patients who are unable to take MMF or cyclophosphamide. However, whether it is appropriate to initiate treatment of SSc-ILD with nintedanib as monotherapy has not been determined.

●Dose and administration – The dose of nintedanib is 150 mg twice daily, approximately 12 hours apart. Liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin) should be assessed prior to initiation of nintedanib; patients with moderate or severe hepatic impairment (Child Pugh B or C) should not take nintedanib [70]. Importantly, nintedanib can cause fetal harm. Thus, a pregnancy test should be performed prior to initiation of nintedanib in women of reproductive potential, and highly effective contraception should be used during therapy [70]. While nintedanib does not impair the effectiveness of oral contraceptives, diarrhea and/or vomiting can compromise absorption, which may necessitate use of an alternate contraceptive method. Conception should be avoided until at least three months after the last dose of nintedanib. The dosing and administration of nintedanib are discussed separately. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Dose and administration'.)

●Efficacy – In the SENSCIS trial, 576 subjects with SSc-ILD were randomly assigned to nintedanib 150 mg or placebo twice daily for 52 weeks; approximately half of the patients in each arm of the study were taking mycophenolate (MMF) at baseline [71]. The adjusted annual rate of change in FVC was -52.4 mL/year in the nintedanib-treated group and -93.3 mL/year in the placebo-treated group (difference of 41 mL/year, 95% CI 2.9-79), demonstrating benefit with use of nintedanib. The relative reduction in rate of annual FVC decline was comparable to that seen in the trials of nintedanib in IPF (44 percent versus 49 percent) [68]. A difference in the degree of change in FVC was also observed when comparing patients receiving MMF combined with nintedanib versus MMF alone, although this difference was smaller (-40.2 mL/year and -66.5 mL/year). No significant difference was noted in the mRSS, respiratory symptoms, or health-related quality of life between placebo and nintedanib-treated groups. Diarrhea was the most common adverse effect, reported in 76 percent of patients treated with nintedanib, and was also the most frequent side effect in the prior nintedanib trials in IPF [68]. For those that developed diarrhea, 51.8 percent had the onset of diarrhea within the first 30 days of treatment [73]. A reduced rate of FVC decline was also seen in SSc-ILD patients in the INBUILD trial (-45.4 mL/year versus -166.1 mL/year), although SSc-ILD patients made up a very small portion of that trial population and this difference in FVC decline was not statistically significant [72].

Rituximab — Rituximab is a monoclonal antibody that targets CD20-positive B lymphocytes, leading to prolonged depletion of circulating B cells in most patients. Based on promising results from small clinical trials and some observational studies, rituximab may be an option for SSc-ILD [74-77]. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)

The potential efficacy of rituximab for SSc-ILD was examined in a trial that compared rituximab with cyclophosphamide therapy in 101 patients with various forms of connective tissue disease-associated ILD (40 percent with scleroderma) [78]. Rituximab showed similar efficacy to cyclophosphamide, with both treatments resulting in improvements in FVC at 24 and 48 weeks, six-minute walk distance at 24 weeks, and quality of life at 24 and 48 weeks compared with baseline.

Longer-term outcomes of rituximab were assessed in a much smaller trial of SSc-ILD patients that compared efficacy of rituximab plus "standard therapy" (eg, prednisone, cyclophosphamide and/or mycophenolate) with standard therapy alone [74]. The eight patients in the rituximab group had significantly better forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) at one year than the six patients receiving standard therapy alone [74]. In a follow-up study, the eight patients in the rituximab arm received two additional cycles of rituximab a 12 and 18 months and were reassessed at two years [79]. A significant increase in FVC compared with baseline was noted (median percentage improvement 12.79). DLCO also increased relative to baseline (mean ± SEM: 63.13 ± 7.65 versus 52.25 ± 7.32, respectively, p <0.001).

Although one case series did not observe a benefit to rituximab treatment for SSc-ILD [80], most observational studies have shown stabilization or improvement in lung function following rituximab initiation [80-83]. In a systematic review including two trials and several observational studies of patients with SSc-ILD (575 participants), rituximab resulted in a modest 4.5 percent (95% CI 0.25-8.7) improvement in FVC at six months and a 7.0 percent (95% CI 4.4-9.7) improvement in FVC at 12 months [75].

Lung transplantation — Lung transplantation may be an option for carefully selected SSc patients with severe ILD that is not responsive to pharmacologic interventions [84,85]. However, careful evaluation for extrapulmonary SSc-related disease (eg, uncontrolled aspiration due to esophageal disease, renal or cardiac disease) that might impair tolerance of lung transplantation is essential. While esophageal dysmotility and gastroesophageal reflux require careful evaluation, they need not be a contraindication to transplantation when they are well-controlled [86]. (See "Lung transplantation: General guidelines for recipient selection".)

SSc patients undergoing lung transplantation appear to have morbidity and mortality comparable to patients without SSc undergoing lung transplantation for fibrotic lung disease [87-94], although results vary among studies.

●In a retrospective, single center study, the outcomes of 72 consecutive patients with SSc-ILD who underwent lung transplantation were compared with those of 311 patients with advanced fibrotic lung disease due to idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, or rheumatic diseases other than SSc [91]. Post-transplant survival did not differ at one year or at five years (conditional on one year survival). Pretransplant, esophageal function was assessed by cine esophagram, but only a limited number of patients underwent impedance studies or 24-hour pH probe monitoring. Among 248 patients with SSc-ILD who were referred for consideration for transplant, 146 were evaluated, 89 were listed, and 72 underwent transplantation. The details of reasons that patients were not evaluated or not listed for transplant were not provided.

●Among 90 patients with SSc-ILD who underwent transplantation between 1993 and 2016 at 14 European centers, survival rates at 1, 3, and 5 years were 81, 68, and 61 percent, respectively [95]. The combination of female sex and pulmonary arterial hypertension was associated with poorer survival.  

●In a single center study, lung transplant outcomes were compared among patients with SSc-ILD (n = 35), non-SSc fibrotic lung disease (n = 264), and a non-SSc matched group (n = 109) [90]; 91 percent of the SSc patients received a bilateral lung transplant. The one-, three-, and five-year survivals for SSc-ILD (94, 77, and 70 percent, respectively) were similar to the non-SSc fibrotic lung disease and matched groups. Although 60 percent of the SSc patients had severe esophageal dysfunction, this comorbidity did not appear to adversely affect transplant outcomes. The transplant center used multidisciplinary assessments to determine whether reflux was symptomatically quiescent or nearly so prior to accepting patients for transplant.

●A retrospective cohort study used the United Network for Organ Sharing database to examine the outcome of 229 adults with SSc-ILD who underwent lung transplantation in the United States [84]. The one-year survival of SSc patients was significantly worse compared to patients with IPF, but comparable to that of patients with idiopathic pulmonary arterial hypertension (PAH) unrelated to systemic sclerosis.

●A systematic review that predated the above studies found that the short-term and intermediate-term post-lung transplantation survival was similar in patients with SSc-ILD, PAH, and other forms of ILD [96].

MONITORING RESPONSE TO THERAPY — The optimal tools and timing for assessing treatment response in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) are unknown. Our approach is to evaluate patients initially at least monthly for adverse effects of therapy. In the absence of drug-related adverse effects, we assess respiratory symptoms, subjective exercise tolerance, physical exam, and pulmonary function tests (eg, spirometry, diffusing capacity for carbon monoxide [DLCO], six-minute walk test) at approximately three-month intervals [97,98]. Chest high resolution computed tomography (HRCT) is rarely repeated for monitoring purposes, as there are no data to support the use of serial HRCT in this setting. We generally obtain a follow-up HRCT only in response to a change in symptoms or pulmonary function tests, or when there is concern about lung infection or lung cancer [99].

Assessing the respiratory response to therapy is challenging because:

●Improvement tends to occur slowly

●Small changes in symptoms, lung function, and/or radiographic appearance can be masked by the effect of existing fibrosis

●Stabilization in lung function, rather than improvement, may be the best result that can be expected

Quantitative HRCT, a research tool that uses computer modelling to quantify the extent of reticulation, ground glass, and honeycomb patterns, appears to be a sensitive indicator of disease progression and response to treatment [86,100]. Further study is needed to determine if it has a role in routine monitoring.

It is important to remember that worsening respiratory symptoms or pulmonary function tests in SSc may reflect development of a different disease complication, such as pulmonary hypertension, aspiration, or pleural effusion. The clinical presentation and evaluation of other pulmonary complications of SSc are discussed separately. (See "Overview of pulmonary complications of systemic sclerosis (scleroderma)".)

SUPPORTIVE CARE — Patients with SSc-ILD should receive the same supportive therapies used for the management of other types of ILD. These measures include cigarette smoking cessation, supplemental oxygen as indicated by pulse oxygen saturation, yearly influenza vaccination, SARS-CoV-2 (COVID-19) vaccination, and age-appropriate pneumococcal vaccination (PPS23 and PCV13). While not specifically studied in SSc-ILD, pulmonary rehabilitation may also be of benefit in reducing dyspnea and improving exercise tolerance. (See "Long-term supplemental oxygen therapy" and "Seasonal influenza vaccination in adults" and "COVID-19: Vaccines" and "Pneumococcal vaccination in adults" and "Pulmonary rehabilitation".)

Gastroesophageal reflux and aspiration — Gastrointestinal manifestations of scleroderma are common and include gastrointestinal reflux disease (GERD) and esophageal dysmotility. It is our practice to treat GERD aggressively in SSc-ILD, especially for those with evidence or symptoms of such, and to advise lifestyle modifications (eg, head of bed elevation to 30 degrees, avoidance of meals and alcohol two hours prior to bedtime) for those for whom microaspiration is suspected based on symptoms, presence of a patulous esophagus, or CT findings suggesting aspiration. (See "Gastrointestinal manifestations of systemic sclerosis (scleroderma)" and "Treatment of gastrointestinal disease in systemic sclerosis (scleroderma)".)

In a study of 40 patients with SSc who underwent 24 hours of esophageal pH monitoring, those with SSc-ILD had a higher amount of acid exposure and a greater number of reflux episodes than those without ILD [101]. In a study of 270 SSc patients, increasing diameter of the esophagus was associated with ILD severity and decreased pulmonary function [102]. Further research is needed to understand the interaction between GERD and microaspiration and the development and progression of SSc-ILD.

INVESTIGATIONAL APPROACHES — Several potential therapies for SSc-ILD are under investigation. These include abatacept, intravenous immune globulin (IVIG), and hematopoietic cell transplantation. Additionally, agents that have efficacy in the treatment of idiopathic pulmonary fibrosis (IPF), such as pirfenidone, are undergoing evaluation in SSc-ILD.

Information about clinical trials for patients with SSc-associated lung disease is available at: clinicaltrials.gov

Pirfenidone — Pirfenidone is an antifibrotic agent that is approved for use in idiopathic pulmonary fibrosis, although the precise mechanism of action is not known. In a case series of five patients with SSc-ILD, administration of pirfenidone (1200 to 1800 mg/day) was associated with a reduction in dyspnea and an increase in vital capacity; in four patients, the vital capacity had decreased approximately 10 percent prior to initiation of pirfenidone [103]. The safety and tolerability of pirfenidone in SSc-ILD was evaluated in the LOTUSS study, which was an open-label study of escalating doses of pirfenidone up to 2403 mg/day (the approved dose in IPF) in 63 patients with SSc-ILD [104,105]. Pirfenidone was generally well-tolerated in this group of SSc patients, despite underlying gastrointestinal disease and concomitant use of mycophenolate mofetil. The most common treatment emergent adverse events (>10 percent of patients) were nausea, headache, fatigue, and vomiting, consistent with those previously seen with pirfenidone in IPF. A larger clinical trial to investigate the efficacy of pirfenidone has been initiated.

Abatacept — Abatacept inhibits T-cell (T-lymphocyte) activation by binding to CD80 and CD86 on antigen presenting cells (APCs), thus blocking the required CD28 interaction between APCs and T cells. In a report of two patients with SSc-ILD, both experienced improvements in diffusing capacity for carbon monoxide (DLCO), FVC, and TLC; and one had marked regression of ILD changes on HRCT [106]. However, in an observational study that included six patients with ILD, no improvement in lung function was noted after five months of abatacept 10 mg/kg/month. However, the HRCT was described as showing fibrotic changes and the lung function outcomes were not a main focus of the study. A randomized Phase 2 trial of subcutaneous abatacept in patients with SSc showed no benefit of abatacept on FVC [107].

Hematopoietic stem cell transplantation — Immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) has shown benefit in some patients with severe diffuse cutaneous SSc [108-110]. Given the mortality and morbidity associated with hematopoietic cell transplantation, these procedures are best performed in specialized centers with significant expertise in the procedure. Autologous HSCT for patients with SSc is discussed in greater detail separately. (See "Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)", section on 'Autologous stem cell transplantation'.)

AGENTS UNLIKELY TO BE OF BENEFIT — Many drugs that were previously used for SSc-ILD produced no improvement in lung function. Ineffective drugs include colchicine, para-aminobenzoic acid, chlorambucil, disodium ethylenediaminetetraacetic acid (EDTA), methysergide, and relaxin [111-114]. Additional agents without clear benefit include the following:

●D-Penicillamine – D-Penicillamine is an immunomodulatory agent that inhibits the formation of collagen crosslinks. While it has been used for over four decades to treat SSc, the efficacy of D-penicillamine in SSc remains uncertain, and side effects are common and may be serious. Several retrospective studies demonstrated clinical benefits, including an improved skin score, less new organ involvement, and improved survival [115-117]. However, in a trial that randomly assigned 134 patients with diffuse SSc to receive either standard dose (750 to 1000 mg/day) or low dose (125 mg every other day) D-penicillamine, there was no difference in the extent of skin involvement or survival [118].

●Glucocorticoids – Glucocorticoids, either as monotherapy or in combination with other drugs, have been widely used to treat SSc-ILD with variable benefit [111,119-125]. Given the lack of convincing benefit and the increased risk for scleroderma renal crisis, glucocorticoid monotherapy is not recommended (see "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis", section on 'Risk factors'). However, low dose glucocorticoids (eg, prednisone ≤10 mg/day) are sometimes administered in combination with cyclophosphamide. (See 'Adjuvant glucocorticoids' above.)

●Methotrexate – Methotrexate has been used to treat both SSc and localized forms of scleroderma with modest improvement in skin involvement; however, a beneficial effect on lung involvement has not been demonstrated. Because methotrexate has been occasionally associated with the development of pneumonitis, we do not recommend its use in the treatment of SSc-ILD.

●Tumor necrosis factor-alpha antagonists – Antagonists of tumor necrosis factor (TNF)-alpha have not been beneficial in systemic sclerosis. (See "Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)", section on 'Anticytokine therapy'.)

PROGNOSIS — In patients with systemic sclerosis (SSc), interstitial lung disease (ILD) predicts increased mortality [2,3,6,8,13]. This was illustrated by a retrospective study of 953 patients with SSc; patients with severe ILD had a nine-year survival rate of approximately 30 percent, whereas patients with SSc who did not have severe involvement of an organ system had a nine-year survival rate of 72 percent [13].

A variety of parameters have been examined as predictors of outcome in SSc-ILD:

●In a systematic review of 1616 patients with SSc-ILD, older age, lower forced vital capacity (FVC), and lower diffusing capacity for carbon monoxide (DLCO) predicted mortality in more than one study [126]. In a separate retrospective analysis of two randomized trials, a decline in FVC and DLCO over two years was a better predictor of mortality than baseline FVC or DLCO [20].

●In a database study of 826 patients with SSc-ILD, 219 (27 percent) had a moderate (5 to 10 percent) or significant (>10 percent) decline in lung function over 12 ± 3 months of monitoring [127]. A pattern of slow FVC decline was most common (58 percent), while a rapid, continuous decline in FVC was noted in 8 percent, and stable lung function in 33 percent. Male sex, higher modified Rodnan skin score, and reflux or dysphagia symptoms were the strongest predictors for FVC decline over five years. Male patients have also demonstrated higher rates of FVC decline and increased mortality in randomized trials [128].

●The extent of disease on high resolution computed tomography (HRCT) independently predicted mortality and ILD progression in the systematic review [126]. Furthermore, the presence of combined pulmonary fibrosis and emphysema (CPFE) carries a higher morbidity and mortality in SSc patients than SSc-ILD without coexistent emphysema [129]. In a retrospective case-control series, CPFE SSc patients were more like to have pulmonary hypertension and worse survival compared with SSc-ILD alone.

●The symptomatic and physiologic severity of SSc-ILD are better predictors of outcome than histopathologic subtype. In a retrospective histopathological evaluation of 80 patients with SSc and biopsy proven ILD, 76 percent had nonspecific interstitial pneumonia (NSIP) and 11 percent had usual interstitial pneumonia (UIP) [8]. The five-year survival rate for patients with NSIP and UIP was similar, 82 and 91 percent, respectively. Markers of a worse prognosis included a lower diffusion capacity (DLCO) and a more rapid decline of DLCO over three years.

Bronchoalveolar lavage (BAL) cell counts, once thought to have prognostic value, do not appear to be a reliable indicator of prognosis [8,24-26]. Although one retrospective study reported that increased eosinophils in the BAL fluid was associated with a poorer prognosis, a larger prospective cohort study of 141 patients with SSc-ILD found that the proportion of eosinophils in the BAL fluid did not correlate with mortality, rate of functional deterioration, or progression-free survival [8,24]. An increased proportion of neutrophils in BAL fluid was associated with more extensive lung disease on HRCT, a greater reduction in DLCO, and early mortality (HR 8.40, 95% CI 1.91-36.95), but it did not predict the rate of functional deterioration or progression-free survival [24]. In a prospective clinical trial of 158 patients with early-stage SSc and symptomatic lung involvement, the presence or absence of BAL fluid neutrophilia did not predict rate of worsening or response to therapy [27].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Systemic sclerosis (scleroderma)".)

SUMMARY AND RECOMMENDATIONS

●Indications for therapy – Significant interstitial lung disease (ILD) predicts poor outcome in patients with systemic sclerosis (SSc). The decision to initiate ILD-directed therapy must be made on a case-by-case basis after carefully balancing the potential benefits of treatment and the toxicities of therapy. (See 'Indications' above.)

●Assessing extent and severity of ILD – When deciding whether to initiate treatment for SSc-ILD, the extent and severity of ILD are assessed by a combination of clinical findings (eg, degree of dyspnea), high resolution computed tomography (HRCT), and pulmonary function testing. These tests are used to estimate the extent of disease and likelihood of progression (table 1). Worsening pulmonary function demonstrated by serial testing (eg, a decrease in forced vital capacity or diffusing capacity for carbon monoxide ≥10 percent) may be the most reliable indicator of progressive lung impairment. (See 'Indications' above.)

●Initial therapy – For patients with SSc-ILD who have respiratory symptoms, abnormal and/or declining pulmonary function, imaging evidence of ILD, and no evidence of active infection, we suggest mycophenolate mofetil (MMF) as initial therapy rather than other options (Grade 2C), based on the relatively good side effect profile and length of clinical experience with this agent; however, tocilizumab and cyclophosphamide are reasonable alternatives in selected patients. (See 'Choice of initial agent' above.)

•Mycophenolate – MMF is administered orally in gradually increasing doses to enhance gastrointestinal tolerance, with a target dose of 1.5 to 3 g/day in two divided doses. Dosing of antacids and mineral supplements should be separated from MMF by least two hours. Routine monitoring for bone marrow suppression is required. (See 'Mycophenolate mofetil' above.)

•Tocilizumab – Tocilizumab (162 mg weekly by subcutaneous injection) is an alternative for initial therapy in patients with early-stage SSc-ILD who are not able to take MMF, have elevated levels of acute phase markers, or have other indications for anti-IL6 therapy. While the clinical experience with tocilizumab is less than with cyclophosphamide, tocilizumab has a better safety profile than cyclophosphamide and can be used for both initial and long-term therapy. (See 'Tocilizumab' above.)

•Cyclophosphamide – Cyclophosphamide is administered via monthly intravenous infusions for six months, or via daily oral dosing for 12 months. We prefer monthly intravenous treatments due to the lower cumulative dose, less frequent adverse effects (in our experience), and the ability to ensure adequate hydration prior to dosing. Careful monitoring for adverse effects and drug interactions is essential. (See 'Cyclophosphamide' above and "General principles of the use of cyclophosphamide in rheumatic diseases".)

●Maintenance therapy

•The duration of MMF is not well-established. Typically, maintenance treatment is continued for at least 24 months and often for several years, depending on the patient’s course. (See 'Dose and duration' above.)

•The approach to maintenance therapy in patients treated with an alternative initial agent is discussed above. (See 'Maintenance therapy' above.)

●Progressive disease – For patients whose disease is refractory to the above measures, we suggest addition of nintedanib or rituximab to ongoing therapy (eg, cyclophosphamide or mycophenolate) (Grade 2C). Patients with more fibrosis on lung imaging findings may benefit more from nintedanib, while those with more inflammatory features may benefit more from rituximab. Lung transplantation evaluation should be offered in patients with progressive disease who have no contraindications. Some patients with SSc-ILD may prefer to explore experimental treatment modalities (eg, hematopoietic stem cell transplantation, abatacept, or pirfenidone); information about clinical trials is available at: Clinicaltrials.gov. (See 'Progressive disease' above and 'Investigational approaches' above.)

●Monitoring – Changes in the patient's symptoms, subjective exercise tolerance, and pulmonary function are monitored at approximately three- to six-month intervals. Serial HRCTs are not obtained routinely, only when clinically indicated. For patients whose disease stabilizes or improves, maintenance therapy is continued until the improvement reaches a plateau at which time gradual withdrawal of therapy can be considered. (See 'Monitoring response to therapy' above.)

●Avoidance of pregnancy – Every effort should be made to avoid pregnancy during therapy with MMF, cyclophosphamide, or nintedanib. Information about other rheumatic disease medications is provided separately. (See 'Monitoring and adverse effects' above and 'Monitoring and adverse effects' above and "Safety of rheumatic disease medication use during pregnancy and lactation".)

●Pneumocystis prophylaxis – We advise giving prophylaxis to prevent Pneumocystis jirovecii (previously called Pneumocystis carinii) pneumonia for patients receiving cyclophosphamide as described separately. Such prophylaxis is less clearly needed and less routinely given, for patients receiving MMF or tocilizumab alone. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV" and "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Pneumocystis jirovecii'.)

●Lung transplantation – Selected SSc patients who have severe ILD that is unresponsive to therapy may be referred for lung transplantation. (See 'Lung transplantation' above and "Lung transplantation: General guidelines for recipient selection".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Andrew M Tager, MD, now deceased, who contributed to earlier versions of this topic review.