Disease Course of ipf

The disease course is unpredictable in patients with IPF. It’s heterogeneous and difficult to predict but typically involves progressive deterioration of lung function that may have periods of sudden decline.^1-5

• IPF has a heterogeneous disease course that may be slowly progressing or rapidly progressing^2,5
  • Acute exacerbations can cause rapid acceleration of disease progression^6,7
• Disease progression is generally monitored by clinical assessment of a patient’s symptoms¹
• Mortality in IPF is hard to predict¹
  • However, certain factors are associated with poor patient outcomes⁸

IPF HAS MULTIPLE FORMS

The clinical course of IPF may take several forms:^1,5

• Slow physiologic worsening with increasing severity of dyspnea (slowly progressive course)
• Rapid onset of symptoms and progression to death (rapidly progressive course)

Adapted from Raghu G et al.¹

SLOWLY PROGRESSIVE IPF

• The clinical course for many patients is defined by a relatively slow decline in lung function¹
• Patients may experience symptoms, which typically include nonproductive cough and increasing dyspnea, for months or years before they see a physician^2,9,10

RAPIDLY PROGRESSIVE IPF

A subgroup of patients exhibit a rapidly progressive course and have shortened survival compared with patients on a slowly progressive clinical course.⁵

RISK FACTORS FOR RAPIDLY PROGRESSIVE IPF⁵

• Male sex
• Smokers

Rapid and slow forms of IPF look the same on diagnosis. At diagnosis, there are no distinguishing clinical characteristics between patients with the accelerated variant of IPF and those with the more common slowly progressive form.⁵

Gene expression profiles may offer a way to differentiate the various disease courses. One study that evaluated patients’ gene expression profiles found that accelerated disease was associated with upregulation of many genes, including:⁵

• Smooth muscle cell genes
• Cancer-associated genes
• Apoptosis
• Oxidative stress
• Fibroblast genes
• Morphogenesis
• Cell proliferation
• Cell migration

ACUTE EXACERBATIONS CAN ACCELERATE DISEASE PROGRESSION

• Patients with IPF may experience periods of relative stability interspersed with periods of acute decompensation^2,11
• Acute exacerbations are associated with disease progression and in-creased risk of mortality^6,7

Adapted from Raghu G et al.¹

DEFINING DISEASE PROGRESSION

The following changes are considered signs of disease progression in IPF:¹

• Progressive, sustained decrease from baseline in absolute forced vital capacity (FVC)
• Progressive dyspnea (objective assessment)
• Acute exacerbation of IPF (AE-IPF)
• Progression of fibrosis from baseline on high-resolution computed tomography (HRCT)
• Progressive, sustained decrease from baseline in absolute diffusing capacity of carbon monoxide (DL_CO)
• Death from respiratory failure

CLINICAL ASSESSMENT IS THE MOST COMMON WAY TO MONITOR PROGRESSION IN PATIENTS WITH IPF

Changes in patients’ symptoms are the clearest way to mark a worsening of disease.¹

• These symptomatic deteriorations are generally accompanied by reduced physiologic measurements¹

HRCT IS NOT COMMONLY USED TO MONITOR DISEASE PROGRESSION

• There are no official recommendations for routine HRCT scans to monitor IPF progression¹
• Repeat HRCT scans are generally performed at the discretion of the patient’s pulmonologist¹

However, repeat HRCT scans can confirm disease progression.

• Worsening on HRCT has been correlated with increased mortality^12-16
• A patient who presents with worsening breathlessness can undergo HRCT to confirm disease progression or AE-IPF, as well as exclude other causes of dyspnea (e.g., pneumonia, pneumothorax)^1,17

Clinical trials often use surrogate endpoints to measure disease progression. Surrogate endpoints for all-cause mortality allow for smaller samples size to show benefit.¹⁸

Surrogate Endpoints:¹⁸

• Decline in FVC
• Time to acute exacerbation
• 52-week mortality

Questionnaires are a surrogate marker of disease progression in clinical trials. Clinical trials often use questionnaires focused on patient symptoms to define disease progression, although their utility in clinical practice is not established.^19,20

ENDPOINTS USED IN CLINICAL TRIALS MAY NOT BE APPROPRIATE FOR EVALUATING IPF IN THE CLINIC

• While certain parameters appear to be clinically useful, there is still significant debate as to which endpoints are appropriate for patients with IPF¹⁸

Patient-reported outcomes are not prognostic in IPF. Although evidence-based, patient-reported outcome measures of symptoms are prognostic in some other respiratory diseases, these measures have not been validated in IPF.¹⁸

Predicting outcomes in IPF should focus on noting changes to patients’ physiology and symptoms.

The following changes correlate with poor outcomes for individual patients:^6,7,21-23

• Episode(s) of AE-IPF^6,7
• Decreased FVC (≥/10%), recommended by ATS/ERS/JRS/ALAT^22,23
• Desaturation during 6-minute walk test (6MWT) (≤/88%)²¹
• Decreased DL_CO (≥/15%), recommended by ATS/ERS/JRS/ALAT²³

Tracking these changes can facilitate appropriate timing of discussions regarding disease management.

Discussions may include:¹

• Lung transplantation
• Supplemental oxygen therapy
• Palliative care
• Hospice referral

NOTHING CAN CURRENTLY PREDICT MORTALITY IN IPF

• No agreed-upon, evidence-based, surrogate endpoints for all-cause mortality exist for IPF¹⁸

An algorithm may help predict IPF-related mortality

• The gender-age-physiology (GAP) model was developed using competing risks regression modeling⁸
• Potential predictive variables were evaluated retrospectively in a cohort of 228 patients with IPF⁸

THE GAP POINT-SCORE MODEL ASSIGNS VALUES TO SUBGROUPS OF 4 CATEGORIES⁸

Total possible points: 8

Survival decreases with GAP stage⁸

Estimated survival for patients with IPF by GAP stage⁸

(%)