Treatment of ILDs

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Treatment of ILDs

• S. K. Jindal
• Department of Pulmonary Medicine
• Postgraduate Institute of Medical Education and
  Research
• Chandigarh, India

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Spectrum of I.L.D
Connective Tissue Diseases and Pulm-renal
syndromes

Inhalational causes
Inherited causes
I.L.D.
Specific entities

• Granulomatous
• Unknown
• Known

Idiopathic pulmonary fibrosis
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JOB
DRUGS
I P F
C T D
PRIMARY
Schwarz et al In Murray 2000
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Objectives of Treatment of ILDs

1. Symptomatic relief
2. Slow down disease progression
3. Prevent/ Treat complications
4. Prolong survival
5. Improve Quality of Life
6. Prevent drug-induced problems
7. End of Life Care

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Treatment Principles

• I. Secondary ILDs
• Treatment of ILD of a known primary cause
  essentially comprises the treatment of the
  primary disorder.
• Symptomatic
• Anti-inflammatory
• Supportive
• II. Primary ILD (Idiopathic Interstitial
  Pneumonias) and Pulmonary Fibrosis

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General Factors for Treatment

• Primary vs. Secondary
• Age of the patient
• Acute vs Chronic Onset
• Active/Progressive
• Severity of symptoms
• Functional and radiological abnormalities
• Treatment of side effects
• Responsive vs Non-responsive (to tmt)
• Early vs End-stage
• Other considerations

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ACTIVITY ASSESSMENT

• Symptomatology
• Chest radiography
• Pulm. Function Tests
• BAL ? TBLB/Surgical Bx
• Scanning Ga-67,
• TC99m DTPA

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Supportive Treatment

• 1. Underlying cause Identification and
  management
• 2. Oxygen therapy
• 3. Management of pulmonary hypertension and
  cardiac failure
• Pulm. Vasodilators
• Diuretics
• 4. Antibiotics for infections
• 5. Miscellaneous Prevention of disease and
  drug-complications
• 6. Rehabilitation

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Treatment of Idiopathic Interstitial Pneumonias
Garantziotis, J Clin Invest 2004 114 319
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Treatment of IIP/IPF

• Of all IIPs, Idiopathic Pulmonary Fibrosis (IPF)
  i.e. U.I.P. is the most common form.
• It is associated with an extremely poor prognosis
  for survival in most patients.
• Life expectancy after diagnosis varies, but is on
  average less than 5 years.

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Old Treatment Algorithm
Jindal et al, Curr Opin Pulm Med 1999
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Current Drug Treatment

• 1. Corticosteroids
• 2. Immunosuppressive drugs
• Azathioprine
• Cyclophosphamide
• Cyclosporine
• 3. Antifibrotic drugs
• Colchicine
• D-penicillamine
• Pentoxyfylline
• 4. Anti-oxidants
• N. Acetyl-cysteine
• 5. Interferon

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Anti-Inflammatory Therapy

• The mainstay of therapy has been the use of
  corticosteroids with or without immunosuppressive
  drugs.
• Chest 123
  (3) 759 (2002).
• Corticosteroids Prednisolone (1-2 mg/kg)
• Induction (3-6
  mths)
• Maintenance
  (2-5yrs)
• With or without Cytotoxic drugs

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Do Anti-inflammatory Drugs Help?

• Anti-inflammatory therapies continue to be used
  despite there being little evidence of
  inflammation in the pathogenesis of IPF
• Therapies with anti-inflammatory drugs are
  associated with toxicity and do not provide
  objective benefit
• 
  
• Although corticosteroid with or without
  immunosuppressive drugs were the mainstay of
  therapy for IPF for decades, their efficacy is
  unproven and toxicities are substantial .
• Am. J. Respir. Crit. Care Med. 171 (9) 939-940
  (2005).
• Ann. Intern. Med.134136-151 (2001).
• In a majority of IPF, corticosteroid therapy is
  only partially effective, and most patients
  deteriorate despite therapy.

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Should Steroids be Used?

• There is no controlled trial using
  corticosteroids alone for the treatment of IPF
  
• 
  
  Cochrane Database Syst. Rev. 3CD002880 (2003).
  
  
• Any conclusive evidence supporting the use of
  corticosteroid therapy for the treatment of IPF
  is lacking
• 
  
  Eur Respir.
  J.626693-702 (2005).
• Given the poor prognosis and the lack of
  available alternatives or other efficacious
  treatments, a therapeutic trial with
  anti-inflammatory medications is still justified
• 
  
  Thorax 54S1-S30 (1999).
• IPF respond better to therapy if they exhibit
  more inflammation and less fibrosis

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Response to Therapy

• Better
• Younger age
• Shorter duration
• Less severe disease
• Secondary disease
• Assessment of
• 1. Symptomatic
• 2. Chest radiography

• Poor
• Old age
• Acute Exaggeration
• Complicating illnesses
• End stage
• Response
• 3. Spirometry TLC and VC

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Anti-Inflammatory Treatment - Factors
For Against
1. Age Younger (lt 50) Older
2. Stage Less advanced (FVC 60-70 pred.) Severely impaired lung function
3. HRCT Nil or minimal honey combing Extensive honey combing
4. BAL Lymphos. gt 20 Neutropaenic
5. Others Female gender Unclear diagnosis of IIP (6 mths trial) Traction bronchiectasis Recurrent LRTIs/ airway colonization Medical comorbidities
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TREATMENT HYPOTHESES
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TREATMENT BASIS
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ANTI-FIBROTIC AND ANTI-CYTOKINE AGENTS

• The major anti-fibrotic and anti-cytokine agents
  that have been used in the treatment of IPF
  include
• colchicine
• penicillamine
• pirfenidone
• TGF ß antagonist
• anti-tumor necrosis factor a (TNF a)
• interferon-? (IFN- ?) and
• connective tissue growth factor antagonist
• 
  
  Expert Opin.Emerg.
  Drugs 10707-727 (2005).

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Colchicine

• Inhibits collagen formation from fibroblasts and
  may increase collagen degradation .
• Suppresses the release of alveolar
  macrophagederived growth factor and fibronectin
  by alveolar macrophages.
• Clinical studies have not shown it to be more
  effective than glucocorticoids
• 
  
  
  Chest. 1993103101-4.

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D-Penicillamine

• Inhibits collagen synthesis by interfering with
  collagen cross-linking.
• Suppresses T-cell function .
• Reduced fibrosis induced by radiation and
  bleomycin.
• Limited studies have not shown efficacy in
  idiopathic pulmonary fibrosis.
• 
  
• 
  
  
  Semin Respir Crit Care Med. 19941577-96.

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Pirfenidone

• Pirfenidone is an anti-fibrotic agent that
  inhibits TGF- ß induced collagen synthesis in
  vitro.
• Decreases lung fibroblast proliferation, and
  downregulates pro-fibrotic cytokines
• Can diminish BIPF by downregulating
  platelet-derived growth factor (PDGF) expression
• 
  
  Am. J. Respir.
  Crit. Care Med.153A403 (1996).
• In clinical trials, pirfenidone was able to
  stabilize both respiratory function and
  symptomology.

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ANTIOXIDANT AGENTS

• N-acetyl Cystine (NAC)
• Nitric Oxide Synthase Inhibitors (Aminoguanidine)
• Cysteine Pro-drugs

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N-acetyl Cystine (NAC)

• NAC, a derivative of the cysteine amino acid,
  augments anti-oxidant glutathione (GSH)synthesis.
• 
  
  N.
  Engl. J. Med. 3532285-2287 (2005).
• GSH plays an important role for defense against
  intra and extracellular oxidative stress.
• It scavenges free radicals and thus contributes
  to their reduction.
• Used for its contributory role in IPF.

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Potential Therapies

• Receptor Antagonists
• -Decorin
• -Imatinib Mesylate (PDGF Receptor antagonist)
• -Endothelin Receptor 1 Antagonist
• Anti-Apoptosis
• Myofibroblast induced epithelial cell apoptosis
  may promote epithelial injury, aberrant repair
  responses, and progressive fibrosis
• Anti-Angiogenesis
• An imbalance of angiogenic and angiostatic
  chemokines favoring net angiogenesis is
  demonstrated with IPF

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Herbal Remedies for IPF

• Chinese and Japanese granules/ decoctions
• Evidence from bleomycin induced fibrosis
• in rodents / Limited clinical trials
• Symptom-Relief Preserved DLCO
• Qi-dan granules Qi-hong
• Ru-yi-ding-chuan Mai-men-dong
• Fei-kang granules
  Kang-xian
• Cordyceps sinensis
• Kang-xian
• 
  Yang et al, Respirology
  2009

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FUTURE TARGETS FOR THERAPY
SDF 1 Stromal Cellderived Factor-1
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End Stage Disease

• Lung Transplantation
• Palliative End of Life Care
• Domicilliary Oxygen
• Symptomatic relief
• Discontinuation of steroids and immunosuppressive
  drugs
• Other supports

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Lung Transplantation

• Lung transplant is the only therapy of proven
  benefit in IPF, the 5-year survival data approach
  50 percent.
• Transplantation is reserved for advanced stages
  of IPF.
• Many patients show improvement with single lung
  transplantation
• 
  
  
  FASEB J. 152215-2224 (2001).
• Prolongs life and may improve the quality of
  life.
• Complications Rejection, infections, others.
• Unavailable in India because of the shortage of
  donated organs, inadequate infrastructure and
  very high costs.

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Supplemental Oxygen

• For patients with hypoxemia (PaO2 lt 55 mmHg or
  SpO2 lt 88 percent) at rest or during exercise.
• Supplemental oxygen relieves exercise-induced
  hypoxemia and improves exercise performance in
  patients with COPD (? ILD).
• Some studies show no difference in QOL between
  patients receiving supplemental oxygen compared
  to those who were not receiving.

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Pulmonary Rehabilitation

• Overall quality of life is impaired in IPF, with
  specific defects in areas of physical health and
  perceived social independence.
• Therefore, patients with IPF should be encouraged
  to enroll in pulmonary rehabilitation programs.
• Recent evidence suggests the possibility of
  benefit from a tailored exercise program.
• Rehabilitation programs for IPF should be
  designed to include education and psychosocial
  supports with the goal of improving coping skills
  for a better quality of life.

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SUMMARY

• Conventional treatment of IPF with
  corticosteroids and immunosuppressive agents has
  unproven benefit and significant side effects.
• With a better understanding of the pathogenesis
  there is identification of new therapeutic
  approaches.
• Profibrotic growth factors and cytokines act as
  important intermediaries in driving disease
  progression, consequently, modulating their
  activity is an attractive approach.
• Several agents with antifibrotic,
  immunomodulatory, or antioxidant properties are
  being evaluated in randomized, controlled trials
  of patients who have IPF.
• Discontinuation of specific therapy and resorting
  to palliative care is recommended for end-stage
  disease.

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Role of stem cell therapy

• Endogenous tissue stem cells are undifferentiated
  cells that reside in tissues and participate in
  regeneration after injury.
• Adult lung is a vital and complex organ, normally
  turns over slowly.
• Respiratory system regions are derived from
  diverse stem or progenitor cells, differing
  strategies for maintenance and repair.
• There is potential lung tissue derivation from
  extrapulmonary BM-derived stem cells.
• Endothelial, epithelial and mesenchymal elements,
  contribute to repair and regeneration in response
  to injury.
• These cells proliferate from endogenous
  reparative cells of normal lung resident cells or
  may be derived from BM-derived progenitors.

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RECEPTOR ANTAGONIST

• Soluble cytokine receptors or cytokine-binding
  proteins that could compete with cellular
  receptors for any available secreted cytokine
  should effectively inhibit the cytokines
  biological activities.
• -Decorin
• -Imatinib Mesylate (PDGF Receptor antagonist)
• -Endothelin Receptor 1 Antagonist

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ANTI-APOPTOSIS

• Current evidence suggests that increased and
  continuous epithelial cell apoptosis, and
  decreased fibroblast/myofibroblast apoptosis
  occurred in the process of PF
• Myofibroblasts from patients with fibrotic lung
  disease secrete soluble factors (angiotensin
  peptides) that induce apoptosis of human AEC.
• Myofibroblast induced epithelial cell apoptosis
  via an oxidant-mediated mechanism may promote
• epithelial injury,
• aberrant repair responses, and
• progressive fibrosis
• 
  
  
  FASEB J.19854-856 (2005).

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ANTIANGIOGENESIS

• Heterogeneity in vascularization in IPF may, on
  the one hand support fibroproliferation, and on
  the other hand, inhibit normal repair mechanisms.
• If neovascularization plays a key role in
  abnormal matrix remodeling, therapy directed at
  either inhibition of angiogenic or augmentation
  of angiostatic CXC chemokines could be helpful in
  IPF.
• 
  Am. J. Respir. Crit. Care Med.
  170207 (2004).
• An imbalance in the levels of angiogenic
  chemokines as compared with angiostatic
  chemokines favoring net angiogenesis has been
  demonstrated with IPF .
• 
  J. Immunol. 1591437Y1443 (1997).

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Induce Apoptosis in Fibroblasts

• HMG-CoA reductase inhibitors (statins) induce
  apoptosis in normal and fibrotic lung
  fibroblasts.
• Anti-fibrotic effect of statins is related to
  their ability to inhibit the expression of CTGF.
• 
  Am. J. Respir. Crit. Care Med.169A706
  (2004).

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TGF- ß Antagonist

• Anti-TGF- ß antibodies and TGF- ß soluble
  receptors could partially inhibit fibrosis in
  bleomycin model .
• Although efficient in animal models, humans could
  develop immune reactions against the antibodies.
  
• GC1008, an antibody that neutralized TGF ß, is
  being investigated for safety in treating IPF
• 
  Pulm. Pharmacol. Ther.19Mar 3 E Pub (2006).

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IFN- ? -1b

• IFN- ? -1b regulates both macrophage and
  fibroblast function.
• It downregulates molecules associated with
  fibrosis, inflammation, and angiogenesis.
• 
  N. Engl. J. Med. 341(17)
  1302-1304 (1999).
• In addition, IFN- ? therapy reduced TGF ß
  expression in lung biopsies from IPF patients.

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Interleukin-13

• Since epithelial-mesenchymal crosstalk is thought
  to be important for the formation of fibroblastic
  foci, FIZZ-1 may play a significant role in this
  process, downstream of IL-13.
• These data suggest that therapies targeting
  either IL-13 or the IL-13R a 2 receptor may be of
  interest.
• Study in mice has shown that a recombinant fusion
  protein composed of IL-13 and a derivative of
  pseudomonas exotoxin has efficacy in the
  bleomycin model of lung fibrosis.
• 
  J Immunol 2003
  17126842693.

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Between IIPs there are probably large
differences in the role of inflammatory and
fibrotic processes
Markers CRP sIL-2R BAL_lym
Markers KL-6 BAL_neu BAL_eos
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ANTI-FIBROTIC AND ANTI-CYTOKINE AGENTS

• Anti-fibrotic drugs that interfere with or
  modulate further progression of lung fibrosis may
  have potential to improve respiratory function
• 
  Mayo Clin.
  Proc. 72285 (1997)
• Anti-cytokine therapeutic strategies are
  directed at abrogating the activities of the
  targeted cytokines that have diverse regulatory
  activities in several processes that comprise
  fibrosis.
• This has been attempted by targeting one or more
  key steps in cytokine synthesis and binding to
  cognate receptors.

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• THANK YOU