Pharmacologic Approach to ILD

Transcription

1 Pharmacologic Approach to ILD Brett Ley, MD MAS Assistant Professor Division of Pulmonary and Critical Care Disclosures No relevant financial disclosures I will discuss off-label use of some medications 2 1

2 Objectives To cover practical use of the most commonly used medications in the common ILDs including indications, contraindications, side effects, dosing, and monitoring IPF medications: nintedanib and pirfenidone Immune suppressive medications: mycophenolate and azathioprine Pulmonary hypertension medications: sildenafil Four cases with audience response system I will provide evidence where available, but a lot of what I ll say is expert opinion or my opinion 3 4 2

3 Case 1 67 y/o man with 1 year of dry cough and dyspnea on exertion PMH: GERD, HTN Exposures: former smoker Serologies: negative HRCT: UIP pattern PFTs: FVC 68%, DLCO 45% 5 What treatment would you offer? A. Prednisone B. N-acetylcysteine C. Nintedanib D. Pirfenidone E. Pantoprazole F. No pharmacotherapy, treat with nintedanib or pirfenidone if there is progression over time 6 3

4 PANTHER IPF Trial 35% 30% 25% 20% 15% 10% 5% 0% 10% 9% 1% 1% Death from any cause Placebo Respiratory death 9% 30% Hospitalization 0 6% Acute exacerbation 10% 31% Serious adverse event Prednisone + Azathioprine + N-acetylcysteine 7 NEJM 2012;366(21): Antacid Therapy in IPF Observational data only, studies are mixed: Some suggest reduction in disease progression and mortality 1 Largest study in clinical trial cohort, with meticulous control for confounding found no benefit on disease progression or mortality and suggested increased risk of infections Lancet Respir Med 2013;1(5): Lancet Respir Med 2016;4(5):

5 Nintedanib Main Benefit About half the decline in FVC over 1 year, on average, compared to no treatment Other Possible Benefits Probably reduces risk of acute exacerbations 9 Cost per year $96,000 $94,000 Pirfenidone About half the decline in FVC over 1 year, on average, compared to no treatment Probably reduces 1-year mortality and risk of respiratory hospitalization Administration 1 pill twice daily with food 3 tablets thee times daily with food Tolerance/side effects Loose stools/diarrhea (~2/3) Nausea (~1/4) Weight loss (~1/10) Safety Possible increased risk of myocardial infarction (~1% increase) Abnormal liver tests (5%) Discontinuation (1 year) ~20% ~15% Nausea/vomiting (~1/3) Weight loss (~1/8) Photosensitivity/Rash (~1/4) Fatigue (~1/5) Abnormal liver tests (4%) IPF medications: FAQs Who should be treated? Patients with a confident diagnosis of IPF Patients in whom you favor IPF but not confident? In trials Other forms of progressive fibrotic ILD? In trials Which one do I choose? Unless there is a contraindication, discuss administration details and side effects and let the patient choose When do I start treatment? Generally upon diagnosis for most patients Early or asymptomatic disease? Advanced disease? 10 5

6 IPF medications Manage expectations Slow disease progression May reduce risk of/delay hospitalizations, exacerbations, and death They do not: Improve symptoms such as dyspnea or cough Improve pulmonary function tests Reduce oxygen needs Improve quality of life Increase exercise tolerance 11 Nintedanib Two dosages: 150 mg bid or 100 mg bid, taken with food Loperamide as needed may help manage diarrhea Reduce dose or interrupt treatment for side effects Avoid in: Full dose anticoagulation (expert opinion, no increased risk of bleeding in trials) High risk CAD Ketoconazole, rifampicin, carbamazepine, phenytoin, St John s wart Moderate to severe hepatic impairment May lower thyroid hormone levels, monitor TSH in those on thyroid replacement 12 6

7 Pirfenidone Full dose is three 267 mg capsules taken three times daily with meals Titrate dose over at least 2 weeks, may be extended to improve tolerance Start with 1 capsule TID x 1 week, if tolerating, increase to 2 capsules TID x 1 week, if tolerating, increase to 3 capsules TID thereafter Once tolerating full dose, may switch to three 801 mg tablets TID form Antacids may help with GERD/dyspepsia, anti-emetics/ginger for nausea Reduce dose, interrupt dose, titrate more slowly for side effects My opinion: must tolerate at least 2 capsules TID to continue Sun protection: avoid sun exposure, sun protective clothing, broad spectrum sunscreen Avoid with: fluvoxamine, enoxacin, ciprofloxacin, omeprazole, severe hepatic impairment, end-stage renal disease 13 Monitor LFTs Check LFTs (AST, ALT, bilirubin) at baseline and monthly for 3-6 months then every 3 months Educate patients on signs or symptoms of liver damage AST, ALT Elevation <3x ULN without signs or symptoms of liver damage 3x to 5x ULN without signs or symptoms of liver damage >5x ULN or any elevation with other signs or symptoms of liver damage Action Monitor LFTs more frequently Interrupt treatment or reduce dose temporarily, monitor closely with reintroduction, and dose increase Discontinue 14 7

8 Combination therapy? Pirfenidone + Nintedanib? Small trial tested tolerability of pirfenidone added-on therapy in patients already tolerating nintedanib over 12 weeks More GI side effects (70% vs. 53%), pirfenidone discontinued in 36% Numerically less FVC decline in combination (-13 ml) vs. nintedanib (-41 ml) alone but not statistically significant and not designed to prove efficacy New treatments Several molecules recently demonstrated positive phase II results and will be moving to phase III Will largely be tested on background of approved therapies Future of IPF treatment will involve combination therapies 15 AJRCCM 2018;197(3): Case 1 67 y/o man with 1 year of dry cough and dyspnea on exertion PMH: GERD, HTN Exposures: former smoker Serologies: negative HRCT: UIP pattern PFTs: FVC 68%, DLCO 45% What treatment would you offer? A. Prednisone B. N-acetylcysteine C. Nintedanib OR D. Pirfenidone E. Pantoprazole F. No pharmacotherapy, watch and wait 16 8

9 Case 2 50 y/o woman with 6 weeks of non-productive cough and 4 weeks progressive DOE ROS: New pain, stiffness, and swelling of hands No PMH or medications Exposures: never smoker, no exposure to molds, birds/down Exam: resting sat 93%, desats to 81% with ambulation, mild mechanics hands, basilar crackles HRCT: bilateral GGOs, subpleural sparing, consolidation at bases PFTs: FVC 55%, DLCO 40% Serologies: Jo1+, SSA +, aldolase 9.4 What treatment would you start? A. Prednisone only B. Mycophenolate only C. Prednisone + mycophenolate D. Prednisone + azathioprine E. Rituximab 18 9

10 Connective Tissue Disease Systemic Sclerosis Rheumatoid Arthritis Sjogren s Syndrome Mixed Connective Tissue Disease Dermatomyositis /Polymyositis/A ntisynthetase SLE ILD Occurrence Common Common Possible Common Common Unusual ILD Type NSIP (80-90%), UIP (10-20%) UIP (50-60%), NSIP, OP, DIP NSIP (28-60%), LIP (20%) NSIP, OP NSIP, OP, NSIP/OP overlap, UIP, DAD NSIP, OP DAH Management Mycophenolate Cyclophosphamide Rituximab Antifibrotic Trials Prednisone Mycophenolate Azathioprine Antifibrotic trials Prednisone Mycophenolate Azathioprine Antifibrotic trials Prednisone Mycophenolate Azathioprine Cyclophos. Prednisone Mycophenolate Azathioprine Cyclophosphamide Tacrolimus Rituximab IVIG (muscle) Prednisone Mycophenolate Azathioprine Cyclophosphs. 19 Mycophenolate for CTD-ILDs Retrospective study of 125 CTD- ILD patients treated with MMF Improvements in FVC and DLCO overall Improvement in non-uip Stability in UIP Well-tolerated Only ~10% discontinued over median of ~3 years 20 J Rheumatol 2013;40(5)

11 Mycophenolate for Scleroderma SLS I CYC 1y vs. placebo Improvement in FVC and symptoms SLS II MMF 2y vs CYC 1y Similar improvement in FVC (and symptoms) at 2 years Fewer deaths, adverse events, and discontinuations Post-hoc analysis, similar (small) reduction in extent of ILD by quantitative CT NEJM 2006; 354(25): Lancet Respir Med 2016;4: Mycophenolate 22 Mechanism: inhibits inosine monophosphate (IMP) dehydrogenase, a rate limiting step in purine synthesis of lymphocytes, thus reducing B- and T-cell proliferation and antibody production Two formulations: Mycophenolate mofetil, MMF (Cellcept) & Entericcoated mycophenolate sodium, EC- MPS (Myfortic) MMF 1000mg ~ EC-MPS 720 mg EC-EPS may have improved GI tolerability (released in small bowel) Absorption decreased by high-fat meals, best taken on empty stomach but can take with meals to reduce GI side effects Metabolism: Glucuronidated to inactive metabolite: dose adjustments in severe renal failure, unclear if needed in liver failure Contraindicated in pregnancy Drug interactions: PPIs can reduce absorption of MMF by >=25%, less likely for EC-MPS 11

12 Mycophenolate Dosing: MMF 1000mg Q12h (range 1.5-3g daily) EC-MPS 720 mg Q12h Start at quarter or half-dose then increase every 1-2 weeks to full dose after checking CBC and side effects Usually start with MMF, but may try switching to EC-MPS for GI intolerances Laboratory monitoring: 2 weeks, then monthly but can space out to every 6-8 weeks if no evidence of bone marrow suppression Adverse effects: GI (nausea, diarrhea): generally mild and go away with time, doseadjustments, switching to EC-MPS Bone marrow suppression: monitor CBCs Infection: common infections, herpes zoster, CMV Malignancy: skin, lymphoma Azathioprine Mechanism: Pro-drug, converted to 6-MP by RBC glutathione. Intracellular metabolites inhibit purine synthesis, reducing lymphocyte proliferation Absorption/excretion: Wellabsorbed with biologic half-life of 24h, 45% excreted in urine Metabolism: Xanthine oxidase to inactive metabolite - avoid with XO inhibitors (allopurinol, febuxostat) TPMT, deficiency leads to increased toxicity (11% low activity, 0.3% no activity) TPMT testing: unclear benefit of routine testing vs. starting low dose and monitoring for toxicity Adverse effects: GI: anorexia, nausea/vomiting common, diarrhea uncommon rare, severe GI hypersensitivity reactions LFT elevations (5%) Pancreatitis Bone marrow suppression Infection, malignancy Avoid in pregnancy 12

13 Azathioprine Dosing and Monitoring: Start mg daily x 2 weeks and check CBC, LFTs If tolerating and no lab abnormalities, increase by weekly by 50 mg daily to target dose of mg/kg/day, while monitoring CBC and LFTs every 2 weeks Monitor CBC and LFTs every 4-8 weeks, spacing out with time if no problems Reduce dose by 50% for leukopenia or thrombocytopenia, discontinue if persistent despite dose reduction Lower dose used in renal insufficiency 25 Immune suppression Pre-treatment labs CBC, LFTs (including albumin for MMF), Cr, HBV, HCV, QFT Vaccinations Pneumococcal vaccination per CDC guidelines for immunocompromised Annual inactivated influenza vaccination Non-live recombinant zoster vaccine PCP prophylaxis Prednisone >=20mg daily for >3 weeks controversial on monotherapy with MMF or AZA Higher risk in myositis-associated ILD MMF has activity against PCP and so probably not needed unless also on prednisone and myositis ILD 26 13

14 Mycophenolate vs. Azathioprine Lack of head to head comparisons Mycophenolate generally better tolerated and thus preferred, also stronger evidence base in Scleroderma ILD Some prefer azathioprine in RA-ILD for improved control of arthritis (but PANTHER data gives me pause for RA-UIP) Switching from one to the other for progression is generally not helpful 27 Prednisone: when, how, why? Generally avoided in Scleroderma ILD due to risk of renal crisis Organizing pneumonia, cellular NSIP, LIP, and overlap Higher doses (40-60 mg) tapering over mimimum of 2-3 months as tolerated Some may require chronic low dose Fibrotic NSIP Moderate dose (20-30mg) with initiation of therapy tapering off over 4-8 weeks Start with steroid-sparing agent (MMF or AZA) to cover 4-8 weeks for these to have full effect UIP generally not used End-stage fibrosis: avoid if potential transplant candidate 28 14

15 Case 2 Diagnosis: Anti-synthetase syndrome/inflammatory myositis-associated ILD Treated with prednisone and mycophenolate Off oxygen, prednisone tapered to 10mg (still on for joints), remains on mycophenolate Percent Predicted FVC DLCO Months Case 3 51F with 2 years of dyspnea on exertion ROS: no CTD symptoms Exposures: never smoker, has an African Gray parrot x 10 years Exam: 78% room air, no crackles PFTs: FVC 57%, DLCO 35% Autoimmune serologies negative HRCT: bilateral GGOs, mosaic perfusion, mild peripheral and perbronchovascular reticulation and traction bronchiectasis, air-trapping on expiratory views 30 15

16 In addition to removing the parrot, which of the following treatments would you start? A. No pharmacotherapy, monitor for improvement B. Prednisone only C. Mycophenolate only D. Azathioprine only E. Prednisone plus mycophenolate 31 Treatment of HP Remove/Avoid antigen Acute HP Prednisone may hasten recovery Subacute/Chronic HP Prednisone: 1-3 months if rapid progression and/or prominent CT evidence of inflammation Mycophenolate > Azathioprine 1.2 FVC DLCO For long-term management Reduced adverse events compared to prednisone -- Consider slow taper if (1) at least 1 year treatment, (2) exposure removed, AND (3) stable PFTs/plateau in improvement Chest 2017;151(3): ; 2. ERJ Open Res 2017;3(3) 16

17 Case 3 Diagnosed with chronic hypersensitivity pneumonitis Treatment: Removed parrot and thoroughly cleaned home Prednisone + mycophenolate Supplemental oxygen Course: Improved oxygenation Slight improvement and stabilization in FVC/DLCO Lung transplant evaluation 33 Case 4 76M former smoker with 5 years progressive dyspnea on exertion, more rapid over the past 6 months Exposures: 50 ppy quit 10 years ago Exam: 93% rest, 85% walk, bibasilar crackles, no wheezing PFTs: FVC 82%, FEV1/FVC 71%, DLCO 31%, 2 years ago FVC 85% and DLCO 45% HRCT: Moderate upper lung paraseptal and centrilobular emphysema & basilar predominant, peripheral reticulations, traction bronchiectasis, mild honeycombing; enlarged PA; CT A/P 6 years ago shows minimal reticulation at lung bases TTE: epasp 60, Nl LV size and function, mild RV enlargement 34 17

18 Which of the following treatments would you offer? A. Inhaler therapy for COPD B. Supplemental oxygen C. Pirfenidone or nintedanib D. Sildenafil E. A & B F. A C G. A D 35 Pulmonary hypertension treatment in IPF STEP-IPF trial 1 : sildenafil vs placebo in IPF patients with DLCO < 35% No difference in 6MWD Small, but significant differences in symptoms and quality of life May preserve 6MWD in subgroup with right ventricular systolic dysfunction on TTE 2 INSTAGE trial 3 : Nintedanib + sildenalfil vs nintedanib alone in IPF with DLCO < 35% No difference in change in symptoms or other key outcomes No safety issues Other PAH therapies (ETRAs, riociguat) either failed to show benefit or were harmful Ongoing trial of inhaled treprostinil in RHC confirmed PH secondary to ILD NEJM 2010;363(7): 620-8; 2. Chest 2013.;143(6): ; 3. NEJM 2018;ebub Sept 15 18

19 Pulmonary hypertension treatment in IPF Unclear role for sildenafil in IPF patients with PH 2015 IPF treatment guidelines recommend against sildenafil use in IPF 1 Primary management should be appropriate use of supplemental oxygen, and diuretics If sildenafil is used, probably only for patients with confirmed PH and evidence of RV systolic dysfunction Dosing: 20 mg TID (can start at 10 mg TID) Close monitoring for worsened hypoxemia (VQ mismatching) Discontinue if no clear symptomatic improvement Am J Respir Crit Care Med. 2015;192(2): Case 4 76M former smoker with 5 years progressive dyspnea on exertion, more rapid over the past 6 months Exposures: 50 ppy quit 10 years ago Exam: 93% rest, 85% walk, bibasilar crackles, no wheezing PFTs: FVC 82%, FEV1/FVC 71%, DLCO 31%, 2 years ago FVC 85% and DLCO 45% HRCT: Moderate upper lung paraseptal and centrilobular emphysema & basilar predominant, peripheral reticulations, traction bronchiectasis, mild honeycombing; enlarged PA; CT A/P 6 years ago shows minimal reticulation at lung bases TTE: epasp 60, Nl LV size and function, mild RV enlargement Which of the following treatments would you offer? A. Inhaler therapy for COPD B. Supplemental oxygen C. Pirfenidone or nintedanib D. Sildenafil E. A & B F. A C G. A D 38 19

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