A one-year, phase I/IIa, open-label pilot trial of imatinib mesylate in the treatment of systemic sclerosis–associated active interstitial lung disease




Transforming growth factor β (TGFβ) and platelet-derived growth factor (PDGF) may play a critical role in systemic sclerosis (SSc)–related interstitial lung disease (ILD), and imatinib is a potent inhibitor of TGFβ and PDGF production. In this 1-year, phase I/IIa open-label pilot study of imatinib in patients with SSc-related active ILD, our primary aim was to assess the safety of imatinib; we also explored its efficacy.


We recruited 20 SSc patients with a forced vital capacity (FVC) of <85% predicted, dyspnea on exertion, and presence of a ground-glass appearance on high-resolution computed tomography. Patients received oral therapy with imatinib (up to 600 mg/day) for a period of 1 year. Adverse events were recorded, pulmonary function was tested, and the modified Rodnan skin thickness score (MRSS) was assessed every 3 months. The course of changes in lung function, the Health Assessment Questionnaire (HAQ) disability index (DI), and the MRSS were modeled over the period of study to explore treatment efficacy.


The majority of patients were female (65%), Caucasian (75%), and had diffuse cutaneous SSc (70%). At baseline, the mean ± SD FVC % predicted was 65.2 ± 14.0 and the mean ± SD MRSS was 18.7 ± 10.1. The mean ± SD dosage of imatinib was 445 ± 125 mg/day. Of the 20 SSc patients, 12 completed the study, 7 discontinued because of adverse events (AEs), and 1 patient was lost to followup. Common AEs (≥20%) included fatigue, facial/lower extremity edema, nausea and vomiting, diarrhea, generalized rash, and new-onset proteinuria. Treatment with imatinib showed a trend toward improvement in the FVC % predicted (1.74%; P not significant) and the MRSS (3.9 units; P < 0.001).


Use of high-dose daily therapy with imatinib (600 mg/day) in SSc patients with ILD was associated with a large number of AEs. Our experience with AEs suggests that dosages of imatinib lower than 600 mg/day may be appropriate and that further dose ranging analysis is needed in order to understand the therapeutic index of imatinib in SSc.

Systemic sclerosis (SSc)–associated interstitial lung disease (ILD) is present in nearly 70% of patients with SSc, with ∼15% developing severe restrictive lung disease. The pathogenesis of pulmonary fibrosis is mediated through foci of dysregulated fibroblasts driven by profibrotic cytokine signaling (1). In lung biopsy tissues from SSc patients, expression of transforming growth factor β (TGFβ) is increased in the fibrotic areas (2) as is expression of its key mechanism for presentation, integrin αvβ6 (3). In addition, TGFβ and other stimuli can induce the production of connective tissue growth factor, a cytokine that stimulates fibroblast growth and up-regulates the production of collagen and fibronectin (4). These profibrotic cytokines, including platelet-derived growth factor (PDGF), are overexpressed in samples of bronchoalveolar lavage fluid obtained from patients with SSc (5).

Imatinib mesylate (Gleevec; Novartis) is a tyrosine kinase inhibitor that binds to c-Abl and blocks its tyrosine kinase activity; c-Abl is an important downstream signaling molecule of TGFβ (6, 7). In addition, imatinib interferes with PDGF signaling by blocking the tyrosine kinase activity of PDGF receptors. In an in vitro model of bleomycin-induced pulmonary fibrosis, c-Abl inhibition by imatinib was shown to prevent TGFβ-induced extracellular matrix gene expression as well as transformation and proliferation of fibroblasts (7, 8). Similar results were obtained in an in vitro model of radiation-induced pulmonary fibrosis (9, 10) and in mouse models of scleroderma (11, 12).

In chronic myeloid leukemia and gastrointestinal stromal tumors, the Food and Drug Administration (FDA)–approved dosage of imatinib is 400–600 mg/day (see prescribing information). Since our goal was to obtain data on the highest potentially tolerable dose in SSc-related ILD, we attempted to achieve the imatinib dosage of 600 mg/day in an open-label pilot clinical trial. We also explored the efficacy of imatinib therapy in lung physiology and skin fibrosis.


Study population.

We recruited 20 SSc patients who met the American College of Rheumatology classification criteria for SSc (13) at 2 Scleroderma Centers in the US. The inclusion and exclusion criteria (available upon request from the author) were similar to those in a randomized controlled trial comparing daily oral cyclophosphamide versus oral placebo for 1 year in patients with SSc-related ILD (14). The study group consisted of adult patients with SSc of <10 years' duration (defined as the time from the first non–Raynaud's phenomenon sign or symptom), forced vital capacity (FVC; % predicted) <85% of predicted, dyspnea on exertion (grade ≥2 on the Magnitude of Task component of the Mahler Baseline Dyspnea Index) (15), and the presence of ground-glass opacifications on high-resolution computed tomography (HRCT).

Putative disease-modifying medications (e.g., D-penicillamine, cyclophosphamide, azathioprine, methotrexate, and colchicine) were not allowed within 1 month prior to initiation of imatinib. A stable dosage of oral prednisone (or equivalent) of ≤10 mg/day was allowed.

Treatment and assessments.

Eligible patients were administered oral imatinib (up to 600 mg/day; kindly supplied by Novartis) for 1 year. Imatinib was started at a dosage of 100 mg/day and was increased by 100 mg every 2 weeks. A laboratory assessment of safety (complete blood cell count with differential cell count, renal panel, hepatic panel, and urinalysis) was performed every 2 weeks while the dosage was being increased and then monthly thereafter and was reviewed by the investigators.

Patients were seen every 3 months, and data on adverse events (AEs) were collected. Serious adverse events (SAEs) were defined according to the FDA standards.

Pulmonary function tests and patient-reported outcome measures (the Mahler Baseline Dyspnea Index and the disability index [DI] of the Health Assessment Questionnaire [16]) were performed at baseline and every 3 months thereafter. HRCT was performed at baseline and at the 1-year visit (details available upon request from the author).

The primary outcome was the safety of daily administration of imatinib. Secondary and exploratory analyses included changes in the findings on pulmonary function tests, the MRSS, and the patient-reported outcome measures.

The study was approved by local institutional review boards, and each patient signed the written consent form and Health Insurance Portability and Accountability Act form. The clinical trial was conducted under investigational new drug application no. 55,666 and was registered with clinicaltrials.gov (NCT00512902).

Statistical analysis.

Descriptive analysis was done on all baseline data. AEs were grouped by body system and tabulated as numbers and percentages. SAEs were enumerated and described as appropriate. Continuous variables are reported as the mean ± SD and categorical variables as the number with percentage. Efficacy was analyzed using linear mixed-effects modeling of the FVC % predicted, the total lung capacity (TLC) % predicted, the diffusing capacity for carbon monoxide (DLCO) % predicted, and the MRSS. The mixed-effects model used here allows for use of all of the available data and does not assume that data are missing completely at random (details are available upon request from the author).


Clinical characteristics.

We recruited 20 patients with SSc. Their mean ± SD age was 46.1 ± 14.2 years, and their mean ± SD disease duration was 54.2 ± 38.8 months; 65% were female, and 75% were Caucasian (Table 1). The mean ± SD FVC % predicted was 65.2 ± 14.0% and the mean ± SD DLCO % predicted was 50.5 ± 11.4%. All patients had ground-glass opacifications on HRCT; 95% of them had some degree of pulmonary fibrosis, and 37% had honeycomb cysts.

Table 1. Baseline characteristics of the 20 patients with SSc*
  • *

    SSc = systemic sclerosis; dcSSc = diffuse cutaneous SSc; MRSS = modified Rodnan skin thickness score; HAQ = Health Assessment Questionnaire; DI = disability index; DLCO = diffusing capacity for carbon monoxide; RVSP = right ventricular systolic pressure.

  • One high-resolution computed tomography (HRCT) scan was not available for visual interpretation by the thoracic radiologist.

Age, mean ± SD46.1 ± 14.2
No. (%) female13 (65)
Race, no. (%) 
 Caucasian15 (75.0)
 African American3 (15.0)
 Other2 (10.0)
No. (%) with dcSSc14 (70)
Disease duration, mean ± SD months54.2 ± 38.8
MRSS, mean ± SD (range 0–51)18.7 ± 10.1
HAQ DI score, mean ± SD (range 0–3)1.04 ± 0.80
Mahler Baseline Dyspnea Index, mean ± SD (range 0–12)7.69 ± 1.58
Pulmonary function tests, mean ± SD % predicted 
 Forced vital capacity65.2 ± 14.0
 DLco50.5 ± 11.4
 Total lung capacity72.3 ± 11.9
 Ground-glass opacification 
  No. (%) with any ground-glass opacification19 (100)
  Mean ± SD percentage of area affected13.5 ± 12.1
 Reticular changes 
  No. (%) with any reticular changes18 (95)
  Mean ± SD percentage of area affected14.1 ± 15.0
  No. (%) with any honeycombing7 (37)
  Mean ± SD percentage of area affected1.1 ± 2.4
 Estimated RVSP, mean ± SD mm Hg30.6 ± 5.5

Of the group of 20 SSc patients, 12 completed the 1-year study, 7 dropped out because of AEs or progression of SSc-related ILD, and 1 patient was lost to followup (Figure 1).

Figure 1.

Flow diagram showing the distribution of the 20 patients with systemic sclerosis (SSc)–related interstitial lung disease (ILD) from enrollment to completion of the 1-year study of imatinib therapy, including withdrawals, adverse events (AEs), and serious adverse events (SAEs).

The mean ± SD dosage of imatinib was 445 ± 125 mg/day, and the median dosage was 400 mg/day. There was no difference in the mean dosage in patients who discontinued because of AEs (n = 5) and those who completed the study (n = 12) (mean dosage 420 mg versus 475 mg; P = 0.4). There were no significant differences in demographic characteristics between the 2 groups (data not shown). Each investigator was allowed to exercise his or her discretion with regard to decreasing the dosage because of side effects. Only 6 patients (20%) achieved the maximum dosage of 600 mg/day.

Adverse events.

Adverse events requiring discontinuation and thought to be possibly or probably related to imatinib therapy.

There were 5 AEs. The first patient (patient 3, who had an SAE) discontinued the study because of continuing generalized edema that was unresponsive to treatment with daily diuretics. The condition was found to be the result of severe hypothyroidism (thyroid stimulating hormone [TSH] 125 mIU/liter, with undetectable free T4). The other 4 patients discontinued for the following reasons: one because of increasing shortness of breath and diastolic dysfunction noted on right-sided heart catheterization (patient 2, who had an SAE); the second because of generalized rash that disappeared upon stopping imatinib and reappeared after rechallenge with the drug; the third because of elevated aspartate aminotransferase/alanine aminotransferase (twice the upper limit of normal) and severe diarrhea, each of which normalized when imatinib was stopped; and the fourth because of elevated creatine phosphokinase (CPK; 200–400 IU/liter), which normalized over 3 months after discontinuing imatinib (patient 1, who had an SAE). This patient also had SSc-related active gastric antral vascular ectasia (GAVE) and anemia (see below).

Discontinuation thought to be due to the underlying SSc.

Two patients had a >10% decline in the FVC, and both of them discontinued the drug at the end of 3 months. Two patients (who are included in the AEs related to imatinib) were also judged to have discontinued the study due to the underlying SSc. One patient developed GAVE, fatigue, and anemia. This patient (patient 1, who had an SAE) also developed what was thought to be imatinib-related elevation of the CPK level. Another patient developed diastolic dysfunction (patient 2, who had an SAE).

Serious adverse events.

There were 3 SAEs during the study; these occurred in patients 1, 2, and 3. Patient 1 was admitted to the hospital because of marked anemia, fatigue, and marked proximal muscle weakness. Imatinib was discontinued. The patient was diagnosed as having GAVE and scleroderma myopathy (CPK 200–400 IU/liter). Muscle biopsy of the left thigh did not show evidence of active inflammatory myositis, and subsequent assessment of CPK levels showed that they had normalized ∼3 months after she stopped the imatinib. The adverse events in this patient were judged to be related to both the SSc and the imatinib.

Patient 2 experienced worsening dyspnea and generalized edema that continued despite a decrease in the imatinib dosage and the addition of oral loop diuretics. Imatinib was subsequently stopped, but symptoms of increasing shortness of breath continued. His FVC % predicted showed a decline of 6%, and right-sided heart catheterization (performed 1 month later) showed a mean pulmonary artery pressure of 23 mm Hg and a pulmonary wedge pressure of 23 mm Hg, which is suggestive of diastolic dysfunction. There was no evidence of systolic dysfunction. The patient improved with medical management of his diastolic dysfunction. The adverse events in this patient were judged to be related to both the SSc and the imatinib.

At her week 36 visit, patient 3 presented with worsening dyspnea and generalized edema that was resistant to treatment with diuretics. Her serum TSH level was 125 mIU/liter (normal <4.5), with undetectable free T4 (normal range 0.8–1.6 ng/dl). Imatinib therapy was stopped, and levothyroxine was initiated. Her values improved upon treatment with oral levothyroxine, showing a TSH level of 41 mIU/liter and a free T4 level of 0.9 ng/dl after 3 months of therapy. She is currently taking daily levothyroxine, and these values are currently in the normal range. This was considered to be probably related to the imatinib.

Other discontinuations.

One patient was lost to followup.


Treatment with imatinib led to trends toward improvement of 1.74% in the estimated FVC % predicted, 4.17% in the TLC % predicted, and 1.46% in the DLCO % predicted over a 1-year period (P not significant for each comparison). The treatment was also associated with a mean improvement in the MRSS by 3.9 units over the 1-year period (P < 0.001). For sensitivity analyses, the data were reanalyzed using results from only those who completed the study and by imputation of missing data, and the findings were similar (data not shown).

Analysis of individual data for the FVC % predicted showed that the maximum fibrosis identified on HRCT at baseline predicted the decline in the FVC % predicted. The model estimated a mean ± SEM yearly improvement of 4.9 ± 2.1% in the FVC % predicted (P = 0.02) if baseline fibrosis was <20% and a yearly deterioration of 1.3 ± 2.3% (P = 0.56) if baseline fibrosis was ≥20% (P = 0.04 for the between-group difference). (Graphs showing the results of the individual data analysis for the FVC % predicted and the MRSS are available upon request from the author.)

Scores on the HAQ DI demonstrated neither statistically important nor clinically important improvement over the 1-year study period, with a change of –0.11 from the baseline scores (P = 0.11; minimally important difference 0.14 [17]). The Mahler Baseline Dyspnea Index improved statistically, but the improvement was not clinically meaningful, with a change of 0.14 from baseline (P < 0.01; minimally important difference 1.5 [18]).


We present herein the first open-label trial assessing the safety of imatinib in the treatment of SSc-related ILD. We also explored efficacy in this small open-label trial. We found a large number of adverse events, the majority of which were managed with interruption of imatinib treatment or with a decrease in its dosage. Twenty-five percent of our patients developed what were thought to be drug-related AEs; these patients discontinued imatinib therapy. On the other hand, the preliminary analysis suggested a trend toward improvement in the FVC % predicted and the MRSS, which may represent a positive effect of imatinib, or it may represent the natural history of SSc (19).

The AEs seen during the present clinical trial have also been reported in previous clinical trials of imatinib and were anticipated (20, 21). The most common AEs (≥20%) included fatigue, facial/lower extremity edema, nausea/vomiting, diarrhea, generalized rash, and upper respiratory tract infection. The majority of the AEs were dose-related. In the early part of the study (the first 5 patients enrolled), we continued to escalate the dosage of imatinib to reach 600 mg/day, but these patients discontinued therapy. We later allowed de-escalation or stabilization of the dosage so that the patients were able to tolerate the drug. The median dosage was 400 mg/day, and only 6 patients (30%) were able to achieve a dosage of 600 mg/day. In the last 7 patients, the dosage was titrated to a maximum of 400 mg/day, resulting in improved tolerance and no discontinuations. For the study as a whole, the mean ± SD dosage was 445 ± 125 mg/day. In a previously reported study, Gordon and colleagues (22) showed that a dosage of 400 mg/day was well tolerated, and this dosage should be considered for use in future clinical trials.

Six of our patients (30%) developed new-onset mild proteinuria (1+ to 2+ on dipstick urinalysis). We performed 24-hour urinary protein assessment in 3 patients, whose urinary protein levels ranged between 81 mg/dl and 402 mg/dl, but no patient developed worsening of the serum creatinine/creatinine clearance values or renal crisis during the 1-year study. The reason for this AE is not clear. Sunitinib, another tyrosine kinase inhibitor, has been associated with hypertension and sometimes associated with proteinuria (21). We did not notice any significant increase in systemic blood pressure during the trial.

One patient developed elevated CPK levels, which slowly normalized when imatinib was discontinued. The prescribing information reports that elevated CPK levels are a rare side effect of imatinib, having been reported in 0.1–1% of patients participating in clinical trials. In another open trial of imatinib therapy in patients with SSc, 37% had an elevation of CPK levels (22).

Several of the AEs were surprising. One patient developed mild hemoptysis that appeared to be related to the imatinib. This patient did not want to stop imatinib, and he continued in the study. Findings of bronchoscopy and upper endoscopy were unremarkable, and an echocardiogram did not hint of the presence of pulmonary hypertension. The hemoptysis improved after he stopped the medication, but it reappeared after rechallenge. There are no previous reports of hemoptysis or abnormal coagulation with imatinib therapy.

Another patient developed severe hypothyroidism. The current prescribing information for imatinib does report hypothyroidism as an AE, and this AE has frequently been seen with another tyrosine kinase inhibitor, sunitinib. Potential causes include inhibition of iodine uptake by thyroid tissue and destructive thyroiditis (20, 21) or development of autoimmune thyroiditis.

As is usual in SSc studies, 4 patients discontinued treatment as a result of the SSc itself. Two of them had a decline in the FVC of >10%, and the other 2 patients were judged to have had an AE related to the imatinib as well as to progression of the SSc.

We noticed a trend toward improvement in physiologic parameters and the MRSS at the end of 1 year. There was an estimated improvement of 1.74% in the FVC % predicted, 4.17% in the TLC % predicted, and 1.46% in the DLCO % predicted (P not significant for each comparison), and there was an improvement in the MRSS of 3.9 units (P < 0.001). The changes seen in this open-label trial may be related to the effects of imatinib, or they may reflect the natural course of SSc; these possibilities need to be evaluated in a well-controlled trial including a placebo treatment group (19).

Our study is not without limitations. First, this was an open-label trial in a small number of patients, which precludes the drawing of any definitive conclusions about efficacy. Second, we did not perform right-sided heart catheterization at the beginning and end of the study, so we did not definitively exclude pulmonary hypertension, although our patients had undergone routine echocardiograms at the baseline and end-of-study visits, and there were no suggestions of the presence of pulmonary hypertension. It is nevertheless possible that some patients had mild pulmonary hypertension in association with the ILD. Moreover, 7 of the 20 patients where being treated with different immunosuppressive agents 1–3 months before randomization. The Scleroderma Lung Study (18) showed that the efficacy of cyclophosphamide can last up to 6 months following 1 year of therapy, and the previous use of immunosuppressive agents may have affected the efficacy outcome of the study.

In conclusion, the use of daily imatinib in SSc-related ILD was associated with a large number of adverse events. There was also a trend toward improvement in the FVC % predicted and the MRSS. Future controlled studies should further explore lower dosing regimens (400 mg/day) or slower increases in the dosage of imatinib for the treatment of SSc-related ILD. 2

Table 2. Adverse events during the 1-year trial and reasons for discontinuation*
 Adverse eventsDiscontinued
  • *

    Values are the number (%) of patients. FVC = forced vital capacity; AST = aspartate aminotransferase; ALT = alanine aminotransferase; ULN = upper limit of normal; CPK = creatine phosphokinase.

  • Same patient.

  • Same patient.

 Fatigue7 (35)0
 Depression2 (10)0
 Weight loss2 (10)0
 Worsening FVC (>10%)2 (10)2
 Diastolic dysfunction1 (5)1
 Mild hemoptysis1 (5)0
 Hypothyroidism1 (5)1
 New-onset diabetes mellitus1 (5)0
 Nausea/vomiting9 (45)0
 Diarrhea5 (25)1
 Elevated AST/ALT2 (10)1
 Elevated AST/ALT >3× ULN1 (5)0
 Neutropenia (<3.5/μl)2 (10)0
 Hemoglobin (<10 gm/dl)1 (5)0
 Thrombocytopenia (<100,000/μl)1 (5)0
 Upper respiratory tract infection4 (20)0
 Oral thrush1 (5)0
 Urinary tract infection1 (5)0
 Axillary abscess1 (5)0
 Proximal muscle weakness/elevated CPK1 (5)1
 Facial edema7 (35)0
 Pedal edema9 (45)0
 Generalized edema3 (15)1
 New-onset proteinuria6 (30)0
 Generalized rash4 (20)1
Lost to followup1 (5)1


All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Khanna had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Khanna, Mayes, Abtin, Clements, Assassi, Furst.

Acquisition of data. Khanna, Mayes, Abtin, Clements, Assassi, Rajan Saggar, Furst.

Analysis and interpretation of data. Khanna, Rajeev Saggar, Mayes, Abtin, Clements, Maranian, Rajan Saggar, Singh, Furst.


Novartis Pharmaceuticals provided the study drug and partial support for the study. Novartis Pharmaceuticals had no role in the study design or in the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit the manuscript for publication. Publication of this article was not contingent upon approval by Novartis Pharmaceuticals.