Treatment of idiopathic pulmonary fibrosis and progressive pulmonary fibrosis: A position statement from the Thoracic Society of Australia and New Zealand 2023 revision.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease leading to significant morbidity and mortality. In 2017 the Thoracic Society of Australia and New Zealand (TSANZ) and Lung Foundation Australia (LFA) published a position statement on the treatment of IPF. Since that time, subsidized anti-fibrotic therapy in the form of pirfenidone and nintedanib is now available in both Australia and New Zealand. More recently, evidence has been published in support of nintedanib for non-IPF progressive pulmonary fibrosis (PPF). Additionally, there have been numerous publications relating to the non-pharmacologic management of IPF and PPF. This 2023 update to the position statement for treatment of IPF summarizes developments since 2017 and reaffirms the importance of a multi-faceted approach to the management of IPF and progressive pulmonary fibrosis.

Mapping EQ5D utilities from forced vital capacity and diffusing capacity in fibrotic interstitial lung disease.

OBJECTIVES: Fibrotic interstitial lung disease (ILD) includes a large group of conditions that lead to scarring of the lungs. The lack of available 5-level EuroQol 5D (EQ5D) data has limited the ability to conduct economic evaluations in ILD. The purpose of this study was to develop and validate a mapping algorithm that predicts EQ5D utilities from commonly collected pulmonary function measurements (forced vital capacity [FVC] and diffusing capacity of the lung for carbon monoxide [DLCO]) in fibrotic ILDs. METHODS: EQ5D utility and pulmonary function measurements from the Canadian Registry for Pulmonary Fibrosis were included. Ordinary least squares (OLS), beta regression, two-part, and tobit models were used to map EQ5D utilities from FVC or DLCO. Model performance was assessed by comparing the predicted and observed utilities. Subgroup analyses were also conducted to test how well models performed across different patient characteristics. The models were then externally validated in the Australian Idiopathic Pulmonary Fibrosis Registry. RESULTS: The OLS model performed as well as other more complex models (root mean squared error: 0.17 for FVC and 0.16 for DLCO). As with the other models, the OLS algorithm performed well across the different subgroups (except for EQ5D utilities < 0.5) and in the external validation cohort. CONCLUSION: We developed a mapping algorithm that predicts EQ5D utilities from FVC and DLCO, with the intent that this algorithm can be applied to clinical trial populations and real-world cohorts that have not prioritized collection of health-related utilities. The mapping algorithm can be used in future economic evaluations of potential ILD therapies.

Unexpected case of accelerated silicosis in a female quarry worker.

Silicosis is a progressive and irreversible fibrotic occupational lung disease caused by inhalation of respirable crystalline silica (RCS). Recently, outbreaks have been reported in industries involving direct work with high silica-containing materials, such as artificial stone. Here, we describe an unexpected diagnosis made in an asymptomatic 33-year-old female worker employed for 4 years at a quarry for rhyodacite and rhyolite which contain 70% silicon dioxide. Chest computed tomography demonstrated small nodules in the upper lobes and larger ill-defined areas of opacity. Bronchoalveolar lavage revealed fine birefringent material within the cytoplasm of alveolar macrophages, representing silica. Transbronchial biopsies of lung parenchyma and endobronchial ultrasound-guided transbronchial needle aspiration of mediastinal lymph nodes did not reveal features of sarcoidosis, tuberculosis, or malignancy. As such, a diagnosis of accelerated silicosis was confirmed and represents the first reported case in a female worker at a rhyodacite and rhyolite quarry.

Impact of Concomitant Medication Burden on Tolerability of Disease-targeted Therapy and Survival in Interstitial Lung Disease.

Rationale: Multimorbidity is common and leads to substantial concomitant medication burden in patients with interstitial lung disease (ILD), which may affect tolerability of ILD-targeted medications and health outcomes. Objectives: To determine the associations of concomitant medication burden with tolerability of ILD-targeted medications and survival in patients with idiopathic pulmonary fibrosis (IPF) and non-IPF ILD. Methods: Patients with IPF receiving nintedanib or pirfenidone and patients with non-IPF ILD receiving azathioprine or mycophenolate were identified from two Australian and Canadian registries. Baseline concomitant medication burden was evaluated using three measures: medication count, polypharmacy (⩾5 medications), and the medication regimen complexity index (MRCI). Medication intolerance and discontinuation were evaluated at 6 months and 1 year after initiation of ILD-targeted medications, respectively. Cox regression models and likelihood ratio tests were used to determine the prognostic significance of medication burden on transplant-free survival. Results: In 645 treated patients with IPF, 43% experienced adverse reactions leading to intolerance (defined as dose reduction, temporary dose interruption, or permanent drug discontinuation) of antifibrotic medications within 6 months of initiation, with high baseline concomitant medication burden being consistently associated with intolerance (medication count: P = 0.005; polypharmacy: P = 0.006; MRCI: P = 0.004). This association was not observed for immunosuppressive medications in 1,255 treated patients with non-IPF ILD, who also had a lower intolerance (18%). Baseline concomitant medication burden was not independently associated with permanent discontinuation of antifibrotic (29%) and immunosuppressive medications (20%) at 1 year. The MRCI was the only measure of concomitant medication burden associated with transplant-free survival in both cohorts (P < 0.01 for both), which improved prognostication beyond common clinical factors and the ILD-GAP index (P < 0.001 for both). Conclusions: Concomitant medication burden is associated with intolerance of antifibrotic medications in patients with IPF. Medication regimen complexity is superior to simpler evaluation of concomitant medication burden for predicting prognosis in ILD.

Biomarker signatures for progressive idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease in which circulatory biomarkers have the potential for guiding management in clinical practice. We assessed the prognostic role of serum biomarkers in three independent IPF cohorts: Australian Idiopathic Pulmonary Fibrosis Registry (AIPFR), Trent Lung Fibrosis (TLF) and Prospective Observation of Fibrosis in the Lung Clinical Endpoints (PROFILE). METHODS: In the AIPFR cohort, candidate proteins were assessed by ELISA as well as in an unbiased proteomic approach. LASSO (least absolute shrinkage and selection operator) regression was used to restrict the selection of markers that best accounted for the progressor phenotype at 1 year in the AIPFR cohort, and subsequently prospectively selected for replication in the validation TLF cohort and assessed retrospectively in the PROFILE cohort. Four significantly replicating biomarkers were aggregated into a progression index model based on tertiles of circulating concentrations. RESULTS: 189 participants were included in the AIPFR cohort, 205 participants from the TLF cohort and 122 participants from the PROFILE cohort. Differential biomarker expression was observed by ELISA and replicated for osteopontin, matrix metallopeptidase-7, intercellular adhesion molecule-1 and periostin for those with a progressor phenotype at 1 year. Proteomic data did not replicate. The progression index in the AIPFR, TLF and PROFILE cohorts predicted risk of progression, mortality and progression-free survival. A statistical model incorporating the progression index demonstrated the capacity to distinguish disease progression at 12 months, which was increased beyond the clinical GAP (gender, age and physiology) score model alone in all cohorts, and significantly so within the incidence-based TLF and PROFILE cohorts. CONCLUSION: A panel of circulatory biomarkers can provide potentially valuable clinical assistance in the prognosis of IPF patients.

There is detectable variation in the lipidomic profile between stable and progressive patients with idiopathic pulmonary fibrosis (IPF).

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterized by fibrosis and progressive loss of lung function. The pathophysiological pathways involved in IPF are not well understood. Abnormal lipid metabolism has been described in various other chronic lung diseases including asthma and chronic obstructive pulmonary disease (COPD). However, its potential role in IPF pathogenesis remains unclear. METHODS: In this study, we used ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) to characterize lipid changes in plasma derived from IPF patients with stable and progressive disease. We further applied a data-independent acquisition (DIA) technique called SONAR, to improve the specificity of lipid identification. RESULTS: Statistical modelling showed variable discrimination between the stable and progressive subjects, revealing differences in the detection of triglycerides (TG) and phosphatidylcholines (PC) between progressors and stable IPF groups, which was further confirmed by mass spectrometry imaging (MSI) in IPF tissue. CONCLUSION: This is the first study to characterise lipid metabolism between stable and progressive IPF, with results suggesting disparities in the circulating lipidome with disease progression.

Incidence and Prognostic Significance of Hypoxemia in Fibrotic Interstitial Lung Disease: An International Cohort Study.

BACKGROUND: Hypoxemia is a cardinal feature of fibrotic interstitial lung disease (ILD). The incidence, progression, and prognostic significance of hypoxemia in patients with fibrotic ILD currently is unknown. RESEARCH QUESTION: What are the epidemiologic features of hypoxemia and its additive prognostic value in a current risk prediction model of fibrotic ILD? METHODS: We identified 848 patients with fibrotic ILD (258 with idiopathic pulmonary fibrosis [IPF]) in five prospective ILD registries from Australia, Canada, and Switzerland. Cumulative incidence of exertional and resting hypoxemia from the time of diagnosis was estimated at 1-year intervals in patients with baseline 6-min walk tests, adjusted for competing risks of death and lung transplantation. Likelihood ratio tests were used to determine the prognostic significance of exertional and resting hypoxemia for 1-year mortality or transplantation when added to the ILD-GAP model. The cohort was divided into derivation and validation subsets to evaluate performance characteristics of the extended model (the ILD-GAP-O2 model), which included oxygenation status as a predictor. RESULTS: The 1-, 2-, and 5-year overall cumulative incidence was 6.1%, 17.3%, and 40.1%, respectively, for exertional hypoxemia and 2.4%, 5.6%, and 16.5%, respectively, for resting hypoxemia, which were significantly higher in patients with IPF compared with patients without IPF (P < .001 for both). Addition of exertional or resting hypoxemia to the ILD-GAP model improved 1-year mortality and transplantation prediction (P < .001 for both). The ILD-GAP-O2 model showed improved discrimination (C-index, 0.80 vs 0.75) and model fit (Akaike information criteria, 400 vs 422) in the validation cohort, with comparable calibration. INTERPRETATION: Patients with IPF have higher cumulative incidence of exertional and resting hypoxemia than patients without IPF. The extended ILD-GAP-O2 model provides additional risk stratification for 1-year prognosis in fibrotic ILD.

Prognosis of idiopathic pulmonary fibrosis without anti-fibrotic therapy: a systematic review.

In addition to facilitating healthcare delivery planning, reliable information about prognosis is essential for treatment decisions in patients with idiopathic pulmonary fibrosis (IPF). This review aimed to evaluate the prognosis of patients with IPF without anti-fibrotic therapy. We included all cohort studies and the placebo arms of randomised controlled trials (RCTs) in IPF and follow-up of ≥12 months. Two reviewers independently evaluated studies for inclusion, assessed risk of bias and extracted data. A total of 154 cohort studies and 16 RCTs were included. The pooled proportions of mortality were 0.12 (95% CI 0.09-0.14) at 1-2 years, 0.38 (95% CI 0.34-0.42) between 2-5 years, and 0.69 (95% CI 0.59-0.78) at ≥5 years. The pooled mean overall survival was 4 years (95% CI 3.7-4.6) for studies with a follow-up duration of 10 years. At <2 years, forced vital capacity and diffusing capacity of the lung for carbon monoxide declined by a mean of 6.76% predicted (95% CI -8.92 -4.61) and 3% predicted (95% CI -5.14 -1.52), respectively. Although heterogeneity was high, subgroup analyses revealed lower pooled proportions of mortality at 1 year in the RCT participants (0.07 (95% CI 0.05-0.09)) versus cohort study participants (0.14 (95% CI 0.12-0.17)). This review provides comprehensive information on the prognosis of IPF, which can inform treatment discussions with patients and comparisons for future studies with new therapies.

Gastroesophageal reflux and antacid therapy in IPF: analysis from the Australia IPF Registry.

BACKGROUND AND OBJECTIVE: Gastroesophageal reflux disease (GORD) is highly prevalent in idiopathic pulmonary fibrosis (IPF) and may play a role in its pathogenesis. Recent IPF treatment guidelines suggest that all patients with IPF be considered for antacid therapy. However, emerging evidence suggests that antacid therapy does not improve IPF patient outcomes and may increase the risk of pulmonary infection. METHODS: Using prospectively collected data from the Australian IPF Registry including use of antacid therapy, GORD diagnosis and GORD symptoms, the relationship of these GORD variables to survival and disease progression was assessed. The severity of GORD symptoms using the frequency scale for symptoms of GORD (FSSG) and its relationships to outcomes was also assessed for the first time in an IPF cohort. RESULTS: Five hundred eighty-seven (86%) of the 684 patients in the Australian IPF Registry were eligible for inclusion. Patients were mostly male (69%), aged 71.0 ± 8.5 years with moderate disease (FVC 81.7 ± 21.5%; DLco 48.5 ± 16.4%). Most patients were taking antacids (n = 384; 65%), though fewer had a diagnosis of GORD (n = 243, 41.4%) and typical GORD symptoms were even less common (n = 171, 29.1%). The mean FSSG score was 8.39 ± 7.45 with 43% (n = 251) having a score > 8. Overall, there was no difference in survival or disease progression, regardless of antacid treatment, GORD diagnosis or GORD symptoms. CONCLUSIONS: Neither the use of antacid therapy nor the presence of GORD symptoms affects longer term outcomes in IPF patients. This contributes to the increasing evidence that antacid therapy may not be beneficial in IPF patients and that GORD directed therapy should be considered on an individual basis to treat the symptoms of reflux.

Therapeutic burden in interstitial lung disease: Lessons to learn.

BACKGROUND AND OBJECTIVE: Patients with interstitial lung disease (ILD) are often prescribed disease-targeted and symptomatic therapies, both of which can cause significant treatment burden due to polypharmacy and drug-disease interactions. This study aimed to evaluate medication regimen complexity before and after introduction of ILD-specific therapies. Potential drug-disease interactions were evaluated for patients who were prescribed prednisolone. METHODS: In this study, 214 patients with ILD were assessed for demographic information, co-morbidities and medication use. Medication lists were reviewed prior to and after the introduction of ILD-specific therapies. Complexity of treatment regimen was examined using the validated Medication Regimen Complexity Index (MRCI). RESULTS: Of the 214 patients, 75 had idiopathic pulmonary fibrosis (IPF) while the rest had inflammatory ILD (chronic hypersensitivity pneumonitis: 45; connective tissue disease-related ILD: 41). Polypharmacy was common at baseline (IPF: 51%, inflammatory ILD: 63%). Following introduction of ILD-specific therapies, median total MRCI scores significantly increased from 8 (interquartile range (IQR) = 8-15) to 22.5 (17.5-27.5) and 14.5 (8.5-21) to 21.5 (16-30) for IPF and inflammatory ILD groups, respectively (P < 0.0001 for both). Complex dosing instructions contributed the most to total MRCI scores for ILD-specific therapies. Among patients receiving prednisolone (n = 113), 88% had ≥1 co-morbidity which may be impacted. Common co-morbidities included gastrointestinal diseases (56%), obesity (37%), osteoporosis (24%) and diabetes mellitus (18%). CONCLUSION: Polypharmacy and complex medication regimen are common in patients with ILD of different aetiologies. There is a high frequency of potential drug-disease interactions among patients who are prescribed systemic corticosteroids. These findings highlight the need for careful evaluation of the impact of therapeutic complexity and burden in patients with ILD.

Diagnosis and management of idiopathic pulmonary fibrosis: Thoracic Society of Australia and New Zealand and Lung Foundation Australia position statements summary.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease associated with debilitating symptoms of dyspnoea and cough, resulting in respiratory failure, impaired quality of life and ultimately death. Diagnosing IPF can be challenging, as it often shares many features with other interstitial lung diseases. In this article, we summarise recent joint position statements on the diagnosis and management of IPF from the Thoracic Society of Australia and New Zealand and Lung Foundation Australia, specifically tailored for physicians across Australia and New Zealand. Main suggestions: A comprehensive multidisciplinary team meeting is suggested to establish a prompt and precise IPF diagnosis. Antifibrotic therapies should be considered to slow disease progression. However, enthusiasm should be tempered by the lack of evidence in many IPF subgroups, particularly the broader disease severity spectrum. Non-pharmacological interventions including pulmonary rehabilitation, supplemental oxygen, appropriate treatment of comorbidities and disease-related symptoms remain crucial to optimal management. Despite recent advances, IPF remains a fatal disease and suitable patients should be referred for lung transplantation assessment.

Greater endurance capacity and improved dyspnoea with acute oxygen supplementation in idiopathic pulmonary fibrosis patients without resting hypoxaemia.

BACKGROUND AND OBJECTIVE: Supplemental oxygen is commonly prescribed in patients with idiopathic pulmonary fibrosis (IPF), although its benefits have not been proven. The aims of this study were to investigate the effect of oxygen on oxidative stress, cytokine production, skeletal muscle metabolism and physiological response to exercise in IPF. METHODS: Eleven participants with IPF received either oxygen, at an FiO2 of 0.50, or compressed air for 1 h at rest and during a cycle endurance test at 85% of peak work rate. Blood samples collected at rest and during exercise were analysed for markers of oxidative stress, skeletal muscle metabolism and cytokines. The protocol was repeated a week later with the alternate intervention. RESULTS: Compared with air, oxygen did not adversely affect biomarker concentrations at rest and significantly improved endurance time (mean difference = 99 ± 81s, P = 0.002), dyspnoea (-1 ± 1 U, P = 0.02), systolic blood pressure (BP; -11 ± 11 mm Hg, P = 0.006), nadir oxyhaemoglobin saturation (SpO2 ; 8 ± 6%, P = 0.001), SpO2 at 2-min (7 ± 6%, P = 0.003) and 5-min isotimes (5 ± 3, P < 0.001) and peak exercise xanthine concentrations (-42 ± 73 µmol/L, P = 0.03). Air significantly increased IL-10 (5 ± 5 pg/mL, P = 0.04) at 2-min isotime. Thiobarbituric acid-reactive substances (TBARs), IL-6, TNF-α, creatine kinase, lactate, heart rate and fatigue did not differ between the two interventions at any time point. CONCLUSION: In patients with IPF, breathing oxygen at FiO2 of 0.50 at rest seems safe. During exercise, oxygen improves exercise tolerance, alleviates exercise-induced hypoxaemia and reduces dyspnoea. A potential relationship between oxygen administration and improved skeletal muscle metabolism should be explored in future studies.

The evidence of benefits of exercise training in interstitial lung disease: a randomised controlled trial.

BACKGROUND: Uncertainty exists regarding the clinical relevance of exercise training across the range of interstitial lung diseases (ILDs). OBJECTIVE: To establish the impact of exercise training in patients with ILDs of differing aetiology and severity. METHODS: 142 participants with ILD (61 idiopathic pulmonary fibrosis (IPF), 22 asbestosis, 23 connective tissue disease-related ILD (CTD-ILD) and 36 with other aetiologies) were randomised to either 8 weeks of supervised exercise training or usual care. Six-minute walk distance (6MWD), Chronic Respiratory Disease Questionnaire (CRDQ), St George Respiratory Questionnaire IPF-specific version (SGRQ-I) and modified Medical Research Council dyspnoea score were measured at baseline, 9 weeks and 6 months. MEASUREMENTS AND MAIN RESULTS: Exercise training significantly increased 6MWD (25 m, 95% CI 2 to 47 m) and health-related quality of life (CRDQ and SGRQ-I) in people with ILD. Larger improvements in 6MWD, CRDQ, SGRQ-I and dyspnoea occurred in asbestosis and IPF compared with CTD-ILD, but with few significant differences between subgroups. Benefits declined at 6 months except in CTD-ILD. Lower baseline 6MWD and worse baseline symptoms were associated with greater benefit in 6MWD and symptoms following training. Greater gains were seen in those whose exercise prescription was successfully progressed according to the protocol. At 6 months, sustained improvements in 6MWD and symptoms were associated with better baseline lung function and less pulmonary hypertension. CONCLUSIONS: Exercise training is effective in patients across the range of ILDs, with clinically meaningful benefits in asbestosis and IPF. Successful exercise progression maximises improvements and sustained treatment effects favour those with milder disease. TRIAL REGISTRATION NUMBER: Results, ACTRN12611000416998.

Health-related quality of life in idiopathic pulmonary fibrosis: Data from the Australian IPF Registry.

BACKGROUND AND OBJECTIVE: Studies analysing the effect of worsening pulmonary physiological impairment in idiopathic pulmonary fibrosis (IPF) with respect to quality of life have been limited to single centres or highly selected trial populations. The aim of this study was to determine the principal determinants of baseline and longitudinal health-related quality of life (HRQoL) in a large unselected IPF population. METHODS: We used the Australian IPF Registry to examine the relationship between HRQoL, measured using the St George Respiratory Questionnaire (SGRQ), and demographic features, physiological features, co-morbidities and symptoms. Linear regression analysis was performed to identify predictors of baseline HRQoL, linear mixed model analysis to determine the effect of time and forced vital capacity (FVC) on SGRQ and Cox proportional hazards regression to examine the relationship between HRQoL and all-cause mortality. RESULTS: Baseline data from 516 patients were available (347 males; mean (SD) age: 71.3 ± 8.6 years). Univariate analysis showed significant associations between HRQoL and demographic, clinical and physiological features. However, multivariate analysis demonstrated independent associations only between SGRQ and dyspnoea (University of California San Diego Shortness of Breathlessness Questionnaire (UCSD-SOBQ); R2 = 0.71, P < 0.0001), cough severity (visual analogue scale; R2 = 0.06, P < 0.0001) and depression (Hospital Anxiety and Depression Scale; R2 = 0.04, P < 0.0001). Linear mixed-effects modelling of combined baseline and longitudinal data confirmed these associations, as well as for FVC% predicted (P = 0.005). Multivariate Cox proportionate-proportional hazards regression analysis demonstrated no association between HRQoL and risk of mortality. CONCLUSION: Cough, dyspnoea and depression are major symptomatic determinants of HRQoL in IPF. FVC decline is associated with worsening HRQoL.

Agreement and mortality prediction in high-resolution CT of diffuse fibrotic lung disease.

INTRODUCTION: The prognosis of diffuse fibrotic lung disease (DFLD) is known to be variable, but there is a paucity of literature on prognostic markers independent of precise clinical diagnosis. This study aimed to assess the mortality prediction of three high-resolution computed tomography (HRCT) scores in a heterogeneous population of patients with DFLD. A large radiologist and physician reader group was used to determine agreement among readers of varying background in applying these scores. METHODS: Institutional review board approval was obtained. Informed consent was waived for this retrospective study. Eighty HRCTs in 68 patients with DFLD (35 men, mean age 72.9 years) were evaluated retrospectively by 18 readers. Readers included thoracic and general radiologists, respiratory physicians and radiology trainees. Features scored were honeycombing, extent of disease and traction bronchiectasis. Demographics, diagnosis and pulmonary function data were collected. Patients were categorised as having either idiopathic pulmonary fibrosis, fibrosis relating to connective tissue disease, 'miscellaneous' DFLD or 'undefined', where no single entity was felt entirely or confidently to explain the pulmonary disease. Agreement was assessed using the kappa statistic. Associations with mortality were analysed using the Cox marginal model. RESULTS: Agreement was better for honeycombing (kappa = 0.44) and disease extent (kappa = 0.47) than traction bronchiectasis (kappa = 0.24). Honeycombing presence (P < 0.0005) and disease extent >30% (P = 0.002) predicted increased mortality independent of clinical diagnosis. Traction bronchiectasis was non-predictive. Clinical diagnosis was not an independent predictor, but age was independently associated with mortality (P = 0.004). Pulmonary function data were only available for 43 patients, but in a limited subanalysis, the diffusion capacity of carbon monoxide was independently predictive of increased mortality (P = 0.005). CONCLUSIONS: The presence of honeycombing and a greater extent of fibrotic lung disease predict increased mortality independent of clinical diagnosis. Our large, mixed-expertise reader group shows moderate interobserver agreement, comparable with agreement values for these scores in the literature.

Serum interleukin 6 is predictive of early functional decline and mortality in interstitial lung disease associated with systemic sclerosis.

OBJECTIVE: Biomarkers of progression of interstitial lung disease (ILD) are needed to allow early therapeutic intervention in patients with scleroderma-associated disease (SSc-ILD). METHODS: A panel of 8 serum cytokines [interleukin 6 (IL-6), IL-8, IL-10, CCL2, CXCL10, vascular endothelial growth factor, fibroblast growth factor 2, and CX3CL1] was assessed by Luminex bead technology in exploratory cohorts of 74 patients with SSc and 58 patients with idiopathic pulmonary fibrosis (IPF). Mortality and significant lung function decline [forced vital capacity (FVC) ≥ 10%; DLCO ≥ 15%] from date of serum collection were evaluated by proportional hazards analysis. Based on these findings, the prognostic value of serum IL-6, evaluated by ELISA, was assessed in a larger test cohort of 212 patients with SSc-ILD. RESULTS: In the exploratory cohort, only serum IL-6 was an independent predictor of DLCO decline in both IPF and SSc-ILD. The IL-6 threshold level most predictive of DLCO decline within a year was 7.67 pg/ml. In the larger test cohort, serum IL-6 > 7.67 pg/ml was predictive of decline in FVC (HR 2.58 ± 0.98, p = 0.01) and in DLCO (HR 3.2 ± 1.7, p = 0.02) within the first year, and predictive of death within the first 30 months (HR 2.69 ± 0.96, p = 0.005). When stratified according to severity (FVC < 70%), serum IL-6 > 7.67 pg/ml was predictive of functional decline or death within the first year in patients with milder disease (OR 3.1, 95% CI 1.4-7.2, p = 0.007), but not in those with severe ILD. CONCLUSION: In SSc-ILD, serum IL-6 levels appear to be predictive of early disease progression in patients with mild ILD, and could be used to target treatment in this group, if confirmed by prospective studies.

A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma.

OBJECTIVE: The lack of randomized controlled trials (RCTs) in pulmonary fibrosis in systemic sclerosis (SSc) has hampered an evidence-based approach to treatment. This RCT was undertaken to investigate the effects of intravenous (IV) cyclophosphamide (CYC) followed by azathioprine (AZA) treatment in pulmonary fibrosis in SSc. METHODS: Forty-five patients were randomized to receive low-dose prednisolone and 6 infusions (monthly) of CYC followed by oral AZA, or placebo. Primary outcome measures were change in percent predicted forced vital capacity (FVC) and change in single-breath diffusing capacity for carbon monoxide (DLCO). Secondary outcome measures included changes in appearance on high-resolution computed tomography and dyspnea scores. An intent-to-treat statistical analysis was performed. RESULTS: At baseline, there were no significant group differences in factors linked to outcome, including severity of pulmonary fibrosis and autoantibody status. Sixty-two percent of the patients completed the first year of treatment. Withdrawals included 9 patients (6 from the placebo group) with significant decline in lung function, 2 with treatment side effects (both from the active treatment group), and 6 with non-trial-related comorbidity. No hemorrhagic cystitis or bone marrow suppression was observed. Estimation of the relative treatment effect (active treatment versus placebo) adjusted for baseline FVC and treatment center revealed a favorable outcome for FVC of 4.19%; this between-group difference showed a trend toward statistical significance (P = 0.08). No improvements in DLCO or secondary outcome measures were identified. CONCLUSION: This trial did not demonstrate significant improvement in the primary or secondary end points in the active treatment group versus the group receiving placebo. However, for FVC there was a trend toward statistical significance between the 2 groups. This suggests that treatment of pulmonary fibrosis in SSc with low-dose prednisolone and IV CYC followed by AZA stabilizes lung function in a subset of patients with the disease. Therapy was well tolerated with no increase in serious adverse events.