Aug 232017


Scleroderma-Related Interstitial Lung Disease

Scleroderma (SSc) is an autoimmune disease characterized by vasculopathy and fibrosis with multi organ involvement. Pulmonary complications such as interstitial lung disease (ILD) and pulmonary hypertension contribute significantly to mortality and morbidity of the disease. Up to 90% patients with scleroderma can have interstitial changes on high resolution CT scan (HRCT) and between 40-75% patients can have pulmonary function test (PFT) abnormalities. Abnormal HRCT and exam findings are often present prior to the patient’s perception of symptoms and early diagnosis requires vigilance in monitoring these patients. This review focuses on diagnosis and management of scleroderma related to interstitial lung disease (scleroderma-ILD).


Clinical Manifestations of Scleroderma-ILD

Patients with mild interstitial lung disease may be asymptomatic in the beginning but often develop dyspnea on exertion and fatigue with worsening lung fibrosis. Whereas exertional dyspnea and fatigue can be suggestive of pulmonary hypertension, dry cough is mostly seen in conjunction with interstitial changes in the lungs. Dry cough often correlates with diffusing capacity and extent of dyspnea. Dry “velcro” crackles at lung bases is a common physical exam finding. Clubbing can be seen in patients with long standing hypoxia.


Imaging of Scleroderma-ILD

High-resolution chest CT scanning is preferred over regular CT or a chest radiograph for better sensitivity. Earliest interstitial change seen on HRCT is an ill-defined subpleural crescent of an increased density in dependent (or posterior) segments of lower lobes. The most common and distinct radiographic pattern seen with SSc-ILD is non-specific interstitial pneumonitis (NSIP) pattern. It is characterized by ground glass opacities in a peripheral and basal distribution. Pulmonary fibrosis with traction bronchiectasis ensues as disease progresses, presenting as a fibrotic NSIP pattern on HRCT. Typical sub pleural sparing of the ground glass opacities is seen in less than 25% of the patients. Although NSIP is the commonly seen pattern, the usual interstitial pneumonitis pattern (UIP) pattern characterized by honeycombing, fibrosis and traction bronchiectasis can also be seen in 25-40% of the cases. Consolidative processes or fibrosis in the dependent areas may also indicate recurrent aspiration associated with esophageal dysmotility in these patients.


Pulmonary Function Tests in Scleroderma-ILD

All patients should have complete pulmonary function testing including spirometry, lung volumes and diffusion capacity for carbon monoxide (DLCO) performed during their initial presentation. Forced vital capacity (FVC) or total lung volume (TLC) less than 80% of predicted suggest restrictive lung disease pattern. Combination of reduced DLCO and reduced lung volumes suggest ILD.

An isolated reduction in DLCO with normal lung volumes can be seen in early asymptomatic disease or in pulmonary hypertension. Similarly, a FVC/DLCO ratio of 1.6 or greater suggests pulmonary hypertension.


Biopsy of Scleroderma-ILD

Biopsy is rarely required to diagnose scleroderma-related ILD. When indicated, an open lung biopsy should be preferred over a transbronchial biopsy. The lung injury pattern most commonly seen in SSc ILD, termed as the NSIP pattern, is characterized by varying degrees of inflammation and fibrosis. Early disease is typically characterized by primarily inflammatory or cellular NSIP pattern.  As the severity of fibrosis progresses, fibrotic NSIP can be the predominant finding. Fibrosis seen with NSIP is of uniform temporality, a feature which differentiates it from fibrosis seen in the UIP pattern. Few patients with SSc ILD have the histopathologic UIP pattern which is usually associated with idiopathic pulmonary fibrosis. This pattern is characterized by scattered fibroblastic foci and scant inflammation interspersed with areas of normal lung.

When to Treat

When to Treat Scleroderma-ILD

Histopathologic patterns do not predict disease course as well as the severity of physiologic and radiographic disease at initial presentation. A simplified classification system has been developed using HRCT findings and PFTs. Early treatment should be considered, especially in patients who present with advanced disease and patients who are at high risk of progression. It can be challenging to identify the latter group but the marginal improvements noted in large, randomized clinical trials must be weighed against the potential for drug toxicity when considering initiation of treatment and while choosing the appropriate agent.

Initial Therapy

Initial Treatment of Scleroderma-ILD

Choosing the appropriate agent requires a balance between the projected modest benefit and potential drug toxicities. Mycophenolate mofetil (MMF) and cyclophosphamide (CYC) are the most commonly used non-selective immunosuppressant for treating scleroderma-ILD. Rituximab is reserved for refractory cases. Lung transplantation can be considered in selected patients with unresponsive disease. Autologous stem cell transplantation and anti-fibrotic agents are under investigation as future therapies.

Cyclophosphamide (CYC) was the first immunosuppressant to be studied and is now the second line agent to MMF for treating scleroderma-ILD.  Evidence behind using cyclophosphamide comes from Scleroderma Lung Study I (SLS I) which compared oral CYC to placebo for 12 months. Patients in the cyclophosphamide group exhibited a modest beneficial effect on lung function, which was maintained till 24 months. Mean difference in FVC at 12 months between cyclophosphamide and placebo groups was 2.53% (Confidence interval (CI) 0.28-4.79, p value <0.03). Patients in the treatment group also reported improved dyspnea and health related quality of life. However, patients in the cyclophosphamide group had a higher rate of adverse events including hematuria, pneumonia, cytopenias and malignancies.

Although clinical trials used weight based oral cyclophosphamide dosing for 12 months, most of the institutions use and recommend monthly intravenous CYC infusions for 6 months to reduce cumulative toxicity over time. Initial dose of cyclophosphamide infusion is based on the body surface area and should be performed only in certified infusion centers. Monthly monitoring of Complete blood count, renal function and urinalysis is required. Patients on CYC therapy should also be considered for PCP prophylaxis. Adjuvant use of low dose glucocorticoids with cyclophosphamide therapy is controversial with some benefit being shown in small observational studies and should be considered on a case to case basis.

Mycophenolate mofetil (MMF) contains mycophenolic acid, which is a lymphocyte inhibitor and has immunomodulatory and antifibrotic properties. It is now considered as first line therapy in patients with scleroderma-ILD based on the results from Scleroderma Lung Study II trial (SLS II). SLS II was conducted to find less toxic, better tolerated and efficacious alternatives to cyclophosphamide.  It was a randomized controlled trial comparing mycophenolate mofetil therapy for 24 months to oral cyclophosphamide therapy for 12 months. Although modest, but both groups demonstrated improvement in percent FVC from baseline and dyspnea scores at 2 years. Percent change in FVC from baseline was 2.19% (CI 0.53-3.84) in the MMF group and 2.88% (CI 1.19-4.58) in the CYC group. Due to the adverse events, 25% patients prematurely stopped treatment in the MMF group as compared to 50% in the CYC group. MMF was better tolerated than CYC based on a longer time to drug discontinuation and lower incidence of leucopenia and thrombocytopenia. Apart from being non-inferior to cyclophosphamide, small non-randomized trials have also shown that MMF may prevent progression of scleroderma-related ILD.  However, absolute effect of MMF against natural progression of disease is hard to estimate as SLS II lacked a placebo arm. To address this limitation, a recent analysis compared patients in MMF group from SLS II (n=69) to patients in the placebo group of SLS I (n=79).  This study showed that after adjusting for disease severity, patients in the MMF group had improvements in FVC, DLCO and dyspnea scores at 2 years as compared to the placebo group, the effect being greatest in the first 12 months. These results further support the use of MMF for treatment of SSc related ILD.

The target dose for mycophenolate mofetil is between 1.5-3 g/day in divided doses. Therapy is usually started at a lower dose (500 mg twice a day) and escalated over 2-3 months to improve patients’ gastrointestinal tolerance. Bone marrow suppression and gastrointestinal symptoms such as nausea, diarrhea and gastritis are the most commonly observed side effects. A complete blood count should be performed 1-2 weeks after starting treatment and 6-8 weeks thereafter, if there is no evidence of cytopenias. Women of child bearing age should be counselled about using contraception as MMF use is associated with increased risk of pregnancy termination and congenital abnormalities. Lactation is a contraindication for MMF use. MMF absorption is hindered by proton pump inhibitors and antacids, hence these medications should not be taken at the same time. We do not routinely check mycophenolate mofetil serum levels as they have not shown to correlate well with clinical response.

Mycophenolate sodium (MS). Mycophenolic acid is also available as MS, commercially marketed as myfortic. Although, there are no randomized trials comparing MS to CYC or placebo, a meta-analysis of small unblinded trials and case studies showed that MS use was associated with modest improvements in FVC. MS has fewer gastrointestinal side effects as compared to MMF and can be considered as an alternative in some patients who are unable to tolerate MMF.

Azathioprine (AZA) is an alternative immunosuppressive agent for patients who are not candidates for CYC or MMF therapy. Azathioprine is less efficacious than CYC as shown in a small unblinded randomized control trial that demonstrated loss of lung function at 18 months in patients on AZA therapy as compared to the cyclophosphamide group.

Patients considered for AZA therapy must undergo testing for thiopurine S-methyltransferase (TPMT) deficiency, which confers greater risk of life threatening immunosuppression with AZA use. Starting dose of AZA ranges from 50mg – 100mg per day depending upon TPMT levels. Complete blood count and hepatic function profile should be checked monthly for the first three months and then every three months once the optimum dose has been achieved.

Rituximab is usually reserved for patients refractory to other immunosuppressive agents.  A small randomized controlled trial involving 14 patients showed that FVC and DLCO improved after a year of treatment with rituximab as compared to placebo.

However, large randomized controlled trials comparing rituximab to placebo or to standard therapy are required to better understand the role of B-cell depletion therapy in SSc related ILD.


Maintenance Therapy for Scleroderma-ILD

Observational data supports the use of mycophenolate mofetil or azathioprine as maintenance therapy. These agents are continued till patient has achieved stability or continues to progress mandating switching to an alternative agent. Response is monitored by clinical improvement and serial lung function testing. Serial testing demonstrating decline in FVC or DLCO more than 10% is an indication of active disease despite therapy. In a recent study of patients with frequent cough from SLS II cohort, cough and cough related QoL parameters were improved with treatment over 2 years irrespective of degree of changes in FVC. Improvement in cough can potentially serve as a surrogate marker of treatment response.

Take Home

Take Home Points: Scleroderma-ILD

Major take home points include:

  • Interstitial lung disease is a common manifestation of scleroderma and carries significant morbidity
  • Diagnosis of scleroderma-ILD is based on symptoms, restriction on PFTs and radiographic findings. Biopsy is rarely required.
  • HRCT is the preferred modality of imaging for scleroderma-ILD. NSIP is the most common radiographic pattern, characterized by peripheral and basilar ground glass opacities and subpleural sparing.
  • Mycophenolate mofetil is the first line agent for treating scleroderma-related ILD and is well tolerated.
  • Response to treatment is monitored by serial lung function testing and symptoms.



Swati Gulati MD, MS. Affiliations: Division of Pulmonary, Allergy, and Critical Care, University of Alabama at Birmingham

Tejaswini Kulkarni MD, MPH. Affiliations: Division of Pulmonary, Allergy, and Critical Care, University of Alabama at Birmingham, Interstitial Lung Disease Program, University of Alabama at Birmingham

Joao A. de Andrade, MD. Affiliations: Division of Pulmonary, Allergy, and Critical Care, University of  Alabama at Birmingham, Interstitial Lung Disease Program, University of Alabama at Birmingham



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Scleroderma-related Interstitial Lung Disease: Diagnosis and Management