Pharmacologic Interventions in Interstitial Lung Disease

Educational Objectives

The goal of this program is to improve management of interstitial lung disease (ILD). After hearing and assimilating this program, the clinician will be better able to:

1. Modify treatment of ILD among patients who experience disease progression.
2. Evaluate the clinical benefits of antifibrotic agents in the treatment of ILD.
3. Recognize adverse effects associated with immunosuppressive therapies commonly used to treat ILD.

Summary

Hypersensitivity pneumonitis (HP): antigen avoidance (eg, removing the bird, remediation of home mold, moving) is critical in all stages of HP; for patients with mild acute HP, minimal symptoms, and a well-defined antigen, remove the antigen and closely monitor with pulmonary function testing in 6 to 12 wk; for acute or subacute HP, corticosteroids can accelerate recovery, though long-term outcomes might be similar without corticosteroids; off-label indications for medications — for chronic fibrotic HP (ie, inflammation and fibrosis), initiate corticosteroids; if there is a response, initiate mycophenolate mofetil (MMF) as it is better tolerated than azathioprine (although Morisset et al [2017] found equivalent responses); MMF is slower to achieve immunosuppression than corticosteroids, so the therapies are overlapped; consider starting MMF alone in a patient with high risk for corticosteroid adverse effects (AEs) (eg, elevated hemoglobin A_1C, uncontrolled psychiatric disease) and less severe disease; consider a trial of immunosuppressive therapy (data are limited) in patients with fibrosis without inflammation, and continue with a steroid-sparing agent if beneficial; start an antifibrotic agent with progression of fibrosis; antifibrotics are often initiated without MMF if there are no inflammatory features, because it can be difficult to tolerate dual therapy due to gastrointestinal (GI) AEs

Corticosteroids: prednisone is most commonly used in the outpatient setting; the initial dose varies (usually started at 0.5 mg/kg for 2 wk, then tapered); depending on the length of treatment, tapering can be slowed, especially with significant adrenal suppression or adverse effects (eg, hypotension, lightheadedness); medication should be taken with food to reduce GI upset; before prescribing prednisone, check a complete metabolic panel (CMP); blood glucose, blood pressure, weight, and bone mineral density are recommended for ongoing monitoring; coordinate with the patient’s primary care physician; AEs — very common with high-dose (≥20 mg) prednisone over a long period; common AEs include irritability, mood changes, insomnia, increased appetite, hypertension, edema, lipodystrophy, and moon facies; long-term risks include adrenal suppression, osteoporosis, cataracts, peptic ulcers, and opportunistic infections

Mycophenolate mofetil: initiated at 500 mg twice daily for 2 wk and increased by 500 mg every 2 wk until 1000 mg twice daily is reached; the maximum dose is 1500 mg twice daily; it is important to counsel premenopausal women regarding the need for contraception while taking MMF; azathioprine is the preferred alternative to MMF for patients wishing to conceive, as azathioprine levels can be monitored during pregnancy; MMF has only been approved by the United States Food and Drug Administration for patients undergoing organ transplantation; before prescribing MMF, order serum tuberculosis testing or purified protein derivative testing to prevent reactivation of tuberculosis; also check hepatitis C antibody, hepatitis B serology, urine pregnancy test (in premenopausal women), CMP, and complete blood count (CBC); initially monitor CBC every 2 wk, then monthly, to assess for leukopenia; if leukopenia occurs, reduce the dose and recheck in ≈2 wk; common AEs — GI AEs are seen particularly with MMF (might need to switch to mycophenolate sodium); hypertension and swelling are also possible, in addition to increased risk for malignancy

2023 American College of Rheumatology clinical guidelines for connective tissue disease-interstitial lung disease (CTD-ILD): MMF is recommended as first-line therapy for ILD related to systemic sclerosis, myositis, mixed CTD, rheumatoid arthritis, and Sjogren syndrome; tocilizumab is recommended as second-line therapy for systemic sclerosis-associated ILD, and rituximab is often a lower-line therapy; the only disease where glucocorticoids are not recommended for short-term therapy is systemic sclerosis, because of the risk for renal crisis; progression on first-line therapy — rituximab is preferable to azathioprine for patients with antisynthetase syndrome who are taking MMF and have progressive ILD; nintedanib (NTD) can also be used, though the GI AEs overlap with those of MMF and make tolerability an issue; stop NTD and increase immunosuppression in patients who experience GI AEs on NTD; long-term glucocorticoids are not recommended; refer for lung transplantation if disease is progressive and poorly controlled; rapidly progressive ILD — for those with MDA5 or severe disease, admit and start intravenous (IV) glucocorticoids and 1 or 2 additional therapies; guidelines suggest 2 therapies (eg, rituximab, IV immunoglobulin) for patients with MDA5; calcineurin inhibitors (eg, tacrolimus) have been beneficial in small case series, but these patients are often receiving IV therapy and evaluated early for LT

Considerations with immunosuppressive treatment: administer prophylaxis against pneumocystis pneumonia (usually sulfamethoxazole-trimethoprim, dapsone, or pentamidine) when a patient is taking 2 agents or a prednisone dose ≥20 mg for >4 wk; administer immunizations against respiratory syncytial virus, pneumococcus, and COVID-19; avoid administration of live vaccinations in patients taking long-term immunosuppression; rituximab is effective at eradicating immune responses, including those to vaccinations (eg, plan herpes zoster vaccination before initiating rituximab or MMF); manage comorbidities; patients with idiopathic pulmonary fibrosis (IPF) should not be treated with immunosuppression, which increases risks for hospitalization and death (Raghu et al [2012])

Evidence for antifibrotic agents: idiopathic pulmonary fibrosis — the INPULSIS trials (Richeldi et al [2014]) demonstrated slowed declines in lung function and forced vital capacity (FVC) by ≈50% among patients prescribed NTD vs placebo; the ASCEND trial (King et al [2014]) demonstrated a relative reduction of 47.9% among patients who experienced death or an absolute decline of ≥10% in predicted FVC following prescription of pirfenidone (PFD) vs placebo; progressive pulmonary fibrosis (PPF) — the SENSCIS trial (Distler et al [2019]) and INBUILD trial (Flaherty et al [2019]) expanded the indication of NTD to PPF and systemic sclerosis; PFD has not been studied for these indications; exacerbation prevention and treatment — the INPULSIS-2 (not the INPULSIS-1) trial showed NTD delayed time to first acute exacerbation of IPF; other pooled analyses showed reduced respiratory hospitalizations with PFD; small studies have shown benefits with initiating medication during an exacerbation; IPF exacerbations are not treated with corticosteroids; mortality benefit — trials demonstrated increased progression-free survival with NTD and PFD, though demonstrated mortality benefit with only PFD; subsequent post hoc and pooled analyses suggested mortality benefits from NTD and PFD; time to benefit — studies demonstrate >1 yr efficacy with NTD and PFD; benefits with reduced dosing or for patients with life expectancy <1 yr are unclear

Reasons for underprescription of antifibrotic agents: include perceived disease stability (ie, mild disease without progression or exacerbation), young patient age, assumptions about drug tolerability, provider discomfort, concern for AEs, drug cost

Shared decision-making: discuss antifibrotics at the first visit; explain the expected progression of disease if untreated, benefits of antifibrotics, and AEs; offer decision support (eg, patient education websites, discussion with the specialty pharmacy); determine whether patients want to take a preventive or reactive approach to treatment; encourage communication and additional follow-up between visits

Recommendations for prescription: baseline laboratory testing — obtain baseline urine protein and creatinine prior to prescribing NTD (which can cause proteinuria); dosing — unlike NTD, PFD dosing is gradually increased; adverse effects — AEs associated with NTD include bleeding (avoid in patients taking direct oral anticoagulants), increased risk for GI perforation, and diarrhea; AEs associated with PFD include anorexia and photosensitivity; cost — without insurance, NTD costs ≈$16,000/mo, and PFD (generic) costs ≈$500/mo; refer patients to financial assistance programs; ask uninsured patients to enroll in Medicare part D to take advantage of capped out-of-pocket costs; physicians in the United States can write prescriptions for Canadian pharmacies

Readings

Bonella F, Cottin V, Valenzuela C, et al. Meta-analysis of effect of nintedanib on reducing FVC decline across interstitial lung diseases. Adv Ther. 2022;39(7):3392-3402. doi:10.1007/s12325-022-02145-x; Distler O, Highland KB, Gahlemann M, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med. 2019;380(26):2518-2528. doi:10.1056/NEJMoa1903076; Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019;381(18):1718-1727. doi:10.1056/NEJMoa1908681; King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis [published correction appears in N Engl J Med. 2014 Sep 18;371(12):1172]. N Engl J Med. 2014;370(22):2083-2092. doi:10.1056/NEJMoa1402582; Raghu G, Anstrom KJ, King TE Jr, et al. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366(21):1968-77. doi: 10.1056/NEJMoa1113354; Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-2082. doi:10/1056/NEJMoa102584; Witt LJ, Curran JJ, Strek ME. The diagnosis and treatment of antisynthetase syndrome. Clin Pulm Med. 2016;23(5):218-226. doi:10.1097/CPM.0000000000000171.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose. Dr. Witt's lecture includes information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Witt was recorded at Interstitial Lung Disease: The Changing Landscape, held on January 27, 2024, in San Francisco, CA, and presented by the University of California, San Francisco School of Medicine. For information about upcoming CME activities from this presenter, please check https://meded.ucsf.edu/cme. Audio Digest thanks the speakers and the University of California, San Francisco School of Medicine for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

Lecture ID:

IM712102

Qualifies for:

ABIM MOC, Clinical Pharmacology

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.