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Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)
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Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)
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Literature review current through: Oct 2017. | This topic last updated: Jul 18, 2017.

INTRODUCTION — Interstitial lung disease (ILD) is a frequent complication of systemic sclerosis (SSc) that is often progressive and has a poor prognosis [1-4]. In a retrospective study of 619 patients with SSc, 40 percent of patients had a restrictive ventilatory defect (suggesting ILD) either alone or in combination with pulmonary arterial hypertension [5].

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, classification, risk factors, screening, and prognosis".)

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) [6]. 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). Although NSIP may have significant fibrosis, it is usually of uniform temporality. Fibroblast foci and honeycombing, which are hallmarks of usual interstitial pneumonia (UIP), if present, are rare. Patients with a more fibrosing form of NSIP have worse outcomes compared with those with cellular NSIP [7,8]. (See "Idiopathic interstitial pneumonias: Clinical manifestations and pathology", section on 'Nonspecific interstitial pneumonia' and "Treatment and prognosis of nonspecific interstitial pneumonia".)

Few patients with SSc-ILD have the histopathologic pattern of UIP, the pattern that is associated with idiopathic pulmonary fibrosis (IPF). This pattern is characterized by the presence of scattered foci of fibroblast proliferation ("fibroblast foci") and a non-uniform distribution of areas of dense fibrosis, fibroblast foci, scant inflammation, normal lung, and honeycomb change. (See "Idiopathic interstitial pneumonias: Clinical manifestations 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 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 a portion of patients with SSc-ILD have stable or slowly progressive disease, the selection process 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 progressive disease are listed in the table and described below (table 1).

It is thought that patients are more likely to benefit from active therapy when it is initiated early in the course of disease, before a substantial loss of lung function has occurred [9-13]. In approximately half of the patients with progressive 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 are early complications [10].

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 than those with long-standing disease [14]. 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 [15].

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 and might be indications for considering intervention. 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. 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 [16]. 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'.)

High-resolution computed tomography (HRCT) – The proportion of lung affected by ILD can be assessed by HRCT and appears to predict disease progression (image 1). In one study, radiologic changes affecting >20 percent of the lung were shown to be predictors of greater mortality [17]. A subsequent study of 172 patients confirmed these results [12]. The finding of widespread honeycombing, on the other hand, suggests advanced fibrosis that is unlikely to respond to immunosuppressive therapy. Focal scarring may suggest recurrent aspiration that should be treated with measures to prevent aspiration rather than immunosuppressive therapy. 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'.)

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 [18-21]. Similarly, we do not obtain a lung biopsy to determine the histopathology, as the majority of patients with SSc-ILD have fibrotic nonspecific interstitial pneumonitis.

Choice of an agent — Once the decision has been made to initiate immunosuppressive therapy, we suggest using mycophenolate mofetil (MMF) rather than cyclophosphamide 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 included 142 patients with SSc-ILD, characterized by a forced vital capacity (FVC) <80 percent, but >45 percent, of predicted, exertional dyspnea grade 2 or higher on the Mahler Baseline Dyspnea Index [22], ground glass opacities on high resolution computed tomography (HRCT) with or without reticular opacities, and onset of the first non-Raynaud symptom of SSc within the prior 7 years [23]. Participants were randomly 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. No significant difference was noted between groups. Dyspnea improved in both groups based on the Transition Dyspnea Index [24]. MMF was better tolerated than cyclophosphamide based on a longer time to patient withdrawal and a lower incidence of leukopenia and thrombocytopenia.

Mycophenolate mofetil — MMF is an inhibitor of lymphocyte proliferation that is often used in the treatment of extrapulmonary manifestations of SSc and other rheumatic diseases. Based on 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 [23]. (See 'Choice of an agent' above.)

Dose and duration — The target dose of MMF is generally between 1.5 and 3 g daily, usually in two divided doses [23]. Starting with lower doses may improve a patient's gastrointestinal tolerance of MMF. SLS II used a designated dose escalation schedule starting at 500 mg twice daily and increasing to the target dose over three to four months [23].

The maximal dose of MMF should be reduced in patients with end-stage renal disease. A number of drug interactions can affect serum concentrations. In particular, proton pump inhibitors, antacids, and mineral supplements can decrease 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. The Scleroderma Lung Study II continued MMF for 24 months, but most experts, including us, continue MMF for several years as maintenance therapy. (See 'Subsequent 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. If there is no evidence of bone marrow suppression at that time, it is our practice to check complete blood counts every six to eight weeks. 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'.)

MMF is associated with an increased risk of miscarriage and congenital anomalies and 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 antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation", section on 'Mycophenolate mofetil'.)

Efficacy — The role of MMF in SSc-ILD has been assessed in a trial comparing MMF with oral cyclophosphamide (SLS II) (see 'Choice of an agent' above) and in retrospective reviews and small prospective case series [23,25-36]. 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'.)

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 [32,33].

In an observational cohort study, 13 patients with early SSc received anti-thymocyte globulin plus prednisolone for five days, followed by MMF (up to 2 g/day) maintenance therapy for 12 months [25]. Long-term MMF was well tolerated. Although the extent of skin involvement improved, there was no change in mean FVC or diffusion capacity.

In a prospective observational study, 14 consecutive patients with SSc-ILD were treated with mycophenolate sodium (MS) for 12 months [28]. Six patients showed a pulmonary improvement defined as an increase of more than 10 percent in FVC, and 5 out of 14 patients remained stable. In contrast, the median FVC had declined over the 12 months prior to MS treatment.

Among 12 patients with SSc-ILD treated with 12 months of MMF following an inadequate response to cyclophosphamide, FVC improved in three and DLCO in two; HRCT scans showed stable ILD in seven [34].

Cyclophosphamide — We view cyclophosphamide as a second line alternative to MMF for SSc-ILD for the majority of patients, due to the increased risk for adverse effects associated with cyclophosphamide [23]. For those patients in whom cyclophosphamide therapy is deemed more appropriate than MMF, we advocate intravenous dosing, monthly for six months, rather than oral daily dosing for 12 months. The preference for intravenous therapy is based upon the lower cumulative dose, less frequent adverse effects in our experience, and the ability to ensure adequate hydration prior to dosing (to reduce the risk of bladder toxicity).

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 disease [21,23,37,38]. 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 [39].

Intravenous cyclophosphamide — While the Scleroderma Lung Studies used daily oral administration [21,23], 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 patients with SSc-ILD has been studied in small observational studies and one randomized trial [37,40-44]. In the randomized trial, 45 patients were assigned to receive six monthly infusions of cyclophosphamide plus prednisolone (20 mg on alternate days) [37]. 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.

Selection of the initial dose of cyclophosphamide for intravenous infusion is usually based upon estimated body surface area (BSA) expressed in square meters (m2) and is adjusted for advanced age, obesity, and renal function. Subsequent doses are based on the white blood cell nadir and response to therapy. (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 [21,45,46], although not all studies have confirmed this finding as noted above [39]. Improvement in pulmonary function was demonstrated in a double-blind, multicenter trial (the first Scleroderma Lung Study) 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 [21]. 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 the same in both groups.

Cough was a significant symptom in 73 percent of the 158 patients enrolled in the trial. After 12 months of treatment, 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 [47].

In a portion of the patients, HRCT scans were scored for fibrosis (defined as reticular intralobular thickening, traction bronchiectasis, bronchiectasis, or any combination), ground glass opacities, and honeycomb cysts at study onset and again after one year [48]. The cyclophosphamide group had less progression of radiographic fibrosis compared to the placebo group. 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) [38].

More severe SSc based on measures of skin thickness, dyspnea severity, self-reported disability, and health related quality of life also favored cyclophosphamide [49].

Adverse events occurred more frequently in the cyclophosphamide-treated group. Among the 79 patients who received cyclophosphamide, 9 developed hematuria, 19 developed reversible leukopenia, 7 developed neutropenia, and 5 developed pneumonia within the 12 month treatment period. One patient developed severe hemorrhagic cystitis requiring surgery and three patients developed cancer. The duration of this trial was insufficient to assess the true incidence of cyclophosphamide-associated late cancers (bladder, hematological, and skin cancers), which may not become apparent for many years.

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 [50]. 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 respiratory response to cyclophosphamide is not durable. Similarly, the reductions in cough prevalence noted after 12 months of treatment persisted in the cyclophosphamide group compared to the placebo group at 18 months (six months after discontinuation of cyclophosphamide), but treatment-related reductions in cough prevalence were no longer apparent 12 months after discontinuation of cyclophosphamide [47]. In contrast, improvement in dyspnea, as well as in skin induration, persisted in the cyclophosphamide-treated group at 24 months.

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 [23]. 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 duration — 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'.)

While SLS I and II both used a 12 month course of oral therapy [21,23], we prefer a course of six monthly intravenous cyclophosphamide infusions [37]. This preference is based on the ability to ensure adequate hydration with the intravenous infusions and concern about the high rate of adverse effects and early withdrawals in the patients on 12 months of oral cyclophosphamide in SLS II [23].

Thus, we suggest that cyclophosphamide therapy be limited to six months for monthly intravenous administration and 12 months for daily oral administration, because of increasing toxicity over time. Of note, in both SLS I and II, lung function continued to improve in the 12 months following completion of cyclophosphamide [23,50]. After completion of cyclophosphamide, patients commonly transition to a maintenance regimen with a less toxic agent (eg, mycophenolate or azathioprine). (See 'Subsequent maintenance therapy' below.)

Adverse effects and contraindications — Cyclophosphamide has the potential for both short and long term toxicities, including infertility, opportunistic infections, hemorrhagic cystitis, bladder cancer, neutropenia, and adverse drug interactions [51]. (See "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Toxicity'.)

Contraindications – Contraindications to cyclophosphamide include active or suspected infection, pregnancy, nursing, or neutropenia. Patients with a history of cyclophosphamide-related hemorrhagic cystitis should not be prescribed cyclophosphamide again. Contraindications to cyclophosphamide are presented separately. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Contraindications'.)

Pneumocystic prophylaxis – 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 HIV-uninfected patients".)

Reducing risk of hemorrhagic cystitis – Adequate hydration is important to reduce the risk of hemorrhagic cystitis during cyclophosphamide therapy. Patients receiving monthly intravenous cyclophosphamide should receive one liter of intravenous fluid (eg, 0.45 or 0.9 percent saline) over a two- to four-hour period before the infusion. Cyclophosphamide is usually infused over one hour. After the administration of cyclophosphamide, patients should be instructed to drink at least one liter of fluid every six to eight hours for 24 hours afterwards, and to void as frequently as possible. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Prevention of drug-induced cystitis'.)

For patients who are taking daily oral cyclophosphamide, eight 8-ounce glasses of water (approximately two liters) are recommended each day.

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 [21,37]. 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. One observational series described a short-term benefit to high dose compared with low dose glucocorticoids in patients receiving cyclophosphamide for SSc-related ILD but this has not been our experience [52].

Alternative initial therapy — Azathioprine is considered an alternative immunosuppressive agent for SSc patients with early stage ILD who are not candidates for cyclophosphamide for MMF or do not tolerate these agents.

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 [53]. 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.

A retrospective analysis of eight patients 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 [54]. 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 potential pretreatment testing for thiopurine S-methyltransferase (TPMT) deficiency. TPMT deficiency confers greater likelihood of life-threatening immunosuppression with azathioprine therapy. Typically, a complete blood count and liver function tests are obtained monthly for the first few months, and then every three months once a stable dose is achieved. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacogenetics and TPMT testing' and "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Dosing and monitoring'.)

SUBSEQUENT MAINTENANCE THERAPY — As noted, the improvements in lung function associated with cyclophosphamide appear to wane in the 12 months after discontinuation of active therapy [50] (see 'Oral cyclophosphamide' above). However, 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 [44,55]. In our practice, we generally select MMF over azathioprine due to the evidence of efficacy seen in the Scleroderma Lung Study II (SLS II) [23], unless the patient has previously not tolerated MMF.

When these agents are used as maintenance therapy, they are commonly continued until the patient has experienced a period of stability (at least 12 months) in respiratory symptoms and function, or the patient shows progressive disease prompting consideration of an alternative agent. 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'.)

The evidence in favor of azathioprine for maintenance therapy in SSc-ILD after an initial course of cyclophosphamide (in addition to the described role as an alternative to cyclophosphamide) is observational (see 'Azathioprine' above). In a retrospective series of 20 patients with SSc-ILD, stabilization or improvement in pulmonary function tests was noted after a combination of six months of monthly intravenous cyclophosphamide followed by 18 months of azathioprine (2 to 3 mg/kg/day) in 52 percent of participants [44].

The dosing of azathioprine, including potential testing for thiopurine S-methyltransferase (TPMT) deficiency, and monitoring for adverse effects are described separately. (See 'Alternative initial therapy' above and "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacogenetics and TPMT testing' and "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Dosing and monitoring'.)

REFRACTORY DISEASE — A small number of agents have been tried in patients who experience progressive loss of lung function despite the above therapies. Prior to pursuing other therapies for SSc-ILD, these patients are reassessed for other potential reasons for lack of clinical improvement, such as other complications of SSc (eg, aspiration, pleural or pericardial disease, pulmonary hypertension), comorbid disease (eg, thromboembolic disease, chronic obstructive pulmonary disease [COPD]), and end-stage fibrosis.

Patients who are candidates for clinical trials may wish to pursue this option and can be referred to (Clinical Trials). Rituximab and lung transplantation are additional options.

Rituximab — Rituximab is a monoclonal antibody that targets CD20-positive B lymphocytes, leading to long-lived depletion of circulating B cells in most patients. Due to promising results from a small clinical trial and some observational studies, rituximab may be an option for refractory SSc-ILD, although widespread use should await further study, such as a large clinical trial with follow-up for 24 months. (See "Rituximab and other B cell targeted therapies for rheumatoid arthritis", section on 'Rituximab'.)

The potential efficacy of rituximab for SSc-ILD was examined in a small randomized trial that compared rituximab plus "standard therapy" (eg, prednisone, cyclophosphamide and/or mycophenolate) with standard therapy alone [56]. 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 [56]. 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 [57]. 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).

However, observational studies have reported conflicting results [58-61]. Studies suggesting a benefit to rituximab include the following:

In a series of 20 patients treated with rituximab (two infusions of 1000 mg, two weeks apart, with repeat treatment in eight patients) and followed for 12 months, a significant increase was noted in FVC compared with baseline, while the DLCO remained stable [60]. The HRCT scores also remained stable.

A smaller series of eight patients with severe and progressive interstitial lung disease noted an improvement in pulmonary function among seven patients and stability in another over 9 to 12 months of follow-up [59].

A case-control study of nine SSc-ILD patients from the European Scleroderma Trial and Research (EUSTAR) database found that FVC was stable compared with baseline after rituximab treatment for a median of six (4 to 12) months, whereas matched controls showed a decline in FVC [62].

Among eight patients with SSc-ILD treated with one or more cycles of rituximab, six remained stable and two experienced disease progression [63].

On the other hand, a series of 15 patients found no improvement in skin disease and no change in pulmonary function tests (PFTs) six months after two doses of rituximab [58].

Lung transplantation — Lung transplantation may be an option for carefully selected patients with severe SSc-ILD that is not responsive to pharmacologic interventions [64,65]. 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 reflux need careful evaluation, they are not a contraindication to transplantation when they are well-controlled [66]. (See "Lung transplantation: General guidelines for recipient selection".)

SSc patients undergoing lung transplantation appear to have comparable morbidity and mortality to patients undergoing lung transplantation for idiopathic pulmonary fibrosis [67-72], 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 [71]. 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.

In a single center study, lung transplant outcomes of patients with SSc (n = 35) were compared with outcomes of patients with nonSSc fibrotic lung disease (n = 264), and a nonSSc matched group (n = 109) [70]; 91 percent of the SSc patients received a bilateral lung transplant. The one, three, and five year survivals for SSc were 94, 77, and 70, which was similar to the nonSSc fibrotic lung disease and matched groups. Approximately 60 percent of the SSc patients had severe esophageal dysfunction and this characteristic did not appear to adversely affect 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 [64]. 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 [73].

MONITORING RESPONSE TO THERAPY — The optimal tools and timing for assessing the response to therapy in systemic sclerosis-associated interstitial lung disease (SSc-ILD) are unknown. We initially evaluate our patients 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 [74,75]. Chest high resolution computed tomography (HRCT) is repeated less often. 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 possible underlying lung cancer [76].

Assessing the respiratory response to therapy is challenging because:

Improvement tends to be slow

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 [66]. Further study is needed to determine if it has a role in routine monitoring.

It is important to remember that worsening in symptoms or pulmonary function tests may reflect development of a different complication of SSc, such as pleural effusion, pulmonary hypertension, or aspiration. 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, and 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 "Pneumococcal vaccination in adults" and "Pulmonary rehabilitation".)

INVESTIGATIONAL APPROACHES — Several other potential therapies for SSc-ILD are under investigation, including abatacept, tocilizumab, intravenous immune globulin (IVIG), rituximab, and hematopoietic cell transplantation. Additionally, newer agents that had been shown to have efficacy in the treatment of idiopathic pulmonary fibrosis (IPF), including pirfenidone and nintedanib, are undergoing evaluation in SSc-ILD.

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

Hematopoietic stem cell transplantation — Immunosuppressive therapy followed by hematopoietic stem cell transplantation (HSCT) has shown benefit in some patients with severe diffuse cutaneous SSc. Given the high incidence of mortality and morbidity of hematopoietic cell transplantation, these procedures are best performed in specialized centers with expertise in the procedure and in the context of clinical trials (clinicaltrials.gov). 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'.)

Nintedanib — Nintedanib, a receptor blocker for multiple tyrosine kinases has been shown to slow disease progression in idiopathic pulmonary fibrosis and has been approved for use in that disease. It is not known yet whether it would be of benefit in SSc-ILD, but clinical trials to investigate this are being organized. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Nintedanib'.)

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 [77]. 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 [78,79]. 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 is planned.

Tocilizumab — Tocilizumab is a humanized anti-human interleukin (IL)-6 receptor antibody of the IgG1 subclass that is an antagonist of the IL-6 receptor. It is approved for use in rheumatoid arthritis and, in some countries, is approved for juvenile idiopathic arthritis and Castleman's disease. In SSc, elevated serum of IL-6 is predictive of progression of ILD, suggesting potential benefit to IL-6 antagonism [80]. An interim report of a randomized trial of subcutaneous tocilizumab for SS skin disease showed a modest reduction in the decline in forced vital capacity (FVC) at 24 weeks in the tocilizumab group [81], but data at 48 weeks did not show a significant difference in FVC between tocilizumab and control [82]. (See "Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)", section on 'Anticytokine therapy'.)

Abatacept — Abatacept inhibits T-cell (T-lymphocyte) activation by binding to CD80 and CD86 on antigen presenting cells (APC), 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 [83]. 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.

AGENTS WITHOUT CLEAR 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 [84-87]. Additional agents without clear benefit include the following:

D-Penicillamine – D-Penicillamine is an immunomodulatory agent that inhibits the formation of collagen crosslinks. 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 [88-90]. 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 [91].

Glucocorticoids – Glucocorticoids, either as monotherapy or in combination with other drugs, have been widely used to treat SSc-ILD with variable benefit [84,92-98]. Given the lack of convincing benefit and the increased risk for scleroderma renal crisis, glucocorticoid monotherapy is not recommended (see "Renal 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 associated with the development of pneumonitis and, rarely, pulmonary fibrosis, 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 [2-4,10,16]. 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 [10].

In a systematic review of 1616 patients with SSc-ILD, older age, lower forced vital capacity, and lower diffusing capacity for carbon monoxide (DLCO) predicted mortality in more than one study [99]. The extent of disease on high resolution computed tomography (HRCT) independently predicted mortality and ILD progression.

The symptomatic and physiologic severity of the 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) [16]. 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 [16,18-20]. 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 [16,18]. 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 [18]. 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 [21].

SUMMARY AND RECOMMENDATIONS

Significant interstitial lung disease (ILD) predicts poor outcome in patients with systemic sclerosis (SSc). (See 'Indications' above.)

The clinical benefits of immunosuppressive therapy for SSc-ILD appear to be modest and may be associated with substantial toxicity; therefore, the decision to initiate therapy must be made on a case-by-case basis after carefully balancing risk versus potential benefit and the importance of each to the patient. (See 'Indications' above.)

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. Bronchoalveolar lavage appears to have little utility in predicting disease progression or response to therapy. (See 'Indications' above.)

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 initiating treatment with mycophenolate mofetil (MMF) (Grade 2B). We prefer MMF over cyclophosphamide due to its better safety profile and the option for longer term therapy. Careful monitoring for adverse effects and drug interactions is essential. (See 'Choice of an agent' above and 'Mycophenolate mofetil' above.)

As an alternative to MMF, cyclophosphamide can be administered via monthly intravenous infusions for 6 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. White blood cell count, renal function, and urinalysis should be monitored during cyclophosphamide therapy. (See 'Cyclophosphamide' above and "General principles of the use of cyclophosphamide in rheumatic diseases".)

Every effort should be made to avoid pregnancy during MMF or cyclophosphamide therapy. We advise giving prophylaxis to prevent Pneumocystis jirovecii (previously called Pneumocystis carinii) pneumonia for patients receiving cyclophosphamide. Such prophylaxis is less clearly needed and less routinely given, for patients receiving mycophenolate alone. (See "Treatment and prevention of Pneumocystis pneumonia in HIV-uninfected patients".)

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

Patients who receive an initial course of cyclophosphamide are usually transitioned to another agent for maintenance therapy, due to the transient effect of cyclophosphamide. We generally select MMF over azathioprine due to the impression of greater efficacy, but azathioprine is a reasonable alternative for those who do not tolerate MMF. (See 'Subsequent maintenance therapy' above.)

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, just 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.)

Patients whose disease is refractory to the above measures may be candidates for rituximab treatment or may prefer to explore experimental modalities for SSc-ILD (eg, hematopoietic stem cell transplantation, abatacept, nintedanib, or pirfenidone); information about clinical trials is available at: Clinicaltrials.gov. (See 'Investigational approaches' above.)

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 editorial staff at UpToDate would like to acknowledge Andrew M Tager, MD, who contributed to an earlier version of this topic review.

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