Leukotriene Inhibitors: Uses Beyond Asthma

1
Leukotriene InhibitorsUses Beyond Asthma

• Duane L. Keitel
• Resident Grand Rounds
• January 30, 2001

2
CASE ONE

• 26 y.o. female seen at Hickory Allergy with fall
  seasonal allergic rhinitis without asthma
• Complained of increasing nasal congestion and
  rhinorrhea despite FLONASE and ZYRTEC
• Patient prescribed SINGULAIR
• Is SINGULAIR indicated for allergic rhinitis?

3
CASE TWO

• T.C., 31 y.o. male, new patient visit at GIMA
  complains of years of recurrent hives
• Seen multiple allergists in past
• Often on steroid tapers
• Currently taking ALLEGRA
• Would a leukotriene inhibitor be useful?

4
CASE THREE

• T.S., 74 y.o. male, seen as ED consult in
  November for chest pain
• Has history of COPD, no documented asthma history
• Medication list includes SINGULAIR
• Is SINGULAIR beneficial for this patient?

5
What are Leukotriene Inhibitors Approved Uses?

• Prophylaxis and treatment of chronic asthma

6
Other Uses?

• Allergic Rhinitis
• Chronic Urticaria
• COPD
• Atopic Dermatitis
• Migraine Prophylaxis
• Sinonasal polyposis

7
Table of Contents

• Leukotriene Inhibitors Mechanisms of Action
• Leukotriene Inhibitors for Asthma Therapy Review
• Leukotriene Inhibitors for Allergic Rhinitis
  Therapy
• Leukotriene Inhibitors for Treatment of Atopic
  Dermatitis

8
Table of Contents

• Leukotriene Inhibitors for Treatment of Chronic
  Urticaria
• Leukotriene Inhibitors for Migraine Prophylaxis
• Other Uses for Leukotriene Inhibitors?
• Safety of Leukotriene Inhibitors
• Concluding Thoughts

9
What are the Leukotriene Inhibitors/Modifiers?

• Leukotriene Receptor Antagonists (LTRA)

• 5-lipoxygenase Inhibitor of Leukotriene Synthesis

10
Leukotrienes

• First known as slow-reacting-substances of
  anaphylaxis
• Products of arachidonic acid metabolism in mast
  cells, basophils, eosinophils, macrophages

11
Leukotriene Actions

• inflammatory cell mediator
• smooth muscle contraction, bronchoconstriction
• inflammatory cell chemotaxis
• mucus hypersecretion
• bronchial hyper-responsiveness
• neuronal stimulation
• increased microvascular permeability

12
Leukotriene Synthesis Pathway
13
Leukotriene Receptor Antagonists

• Montelukast (SINGULAIR)
• 10 mg PO qd
• AWP 71.17/ month
• Zafirlukast (ACCOLATE)
• 20 mg PO bid
• AWP 62.16/ month
• Pranlukast (ULTAIR)

14
5-lipoxygenase Inhibitors

• Zileuton (ZYFLO)
• 600 mg PO qid
• AWP 90.90/ month
• blocks production of cysteinyl leukotrienes,
  leukotriene B4, and other products that require
  5-lipoxygenase for synthesis

15
(No Transcript)
16
Leukotriene Modifiers and Asthma

• Ideal as both a bronchoconstriction reliever
  and preventer of leukotriene inflammatory
  activities
• Not addressed in National Heart, Lung, and Blood
  Institute Guidelines (1997)
• Modified guidelines recommends as alternative
  monotherapy for mild persistent asthma and add-on
  therapy for moderate or severe persistent asthma

17
Adult Asthma GuidelinesBusse, JAMA 2000
18
Evidence Review

• RCTs show zafirlukast and montelukast reduce
  asthma exacerbations in mild to moderate
  asthmatics
• RCTs show montelukast effective as monotherapy
  for mild persistent asthma
• Inhaled corticosteroids generally found to be
  superior to LTRA as monotherapy controller agents

19
Evidence Review

• Montelukast effective as add-on therapy
• Montelukast/Beclomethasone Addivity Group Study
• IMPACT will compare to salmeterol (SEREVENT)
• Salmeterol superior to zafirlukast as concurrent
  therapy in previous study

20
Evidence Review

• Montelukast effective in prevention of
  exercise-induced bronchoconstriction
• Superior prevention of FEV1 reduction over
  salmeterol in Exercise Group Study
• Valuable for 10 of chronic asthmatics with
  aspirin sensitivity, possible leukotriene C4
  synthase over-expression

21
Asthma Therapy Summary

• Leukotriene receptor antagonists can be used as
  monotherapy for mild persistent asthma, although
  asthmatics generally respond better to inhaled
  corticosteroids
• Leukotriene receptor antagonists are effective
  add-on therapy to inhaled corticosteroids and are
  currently being studied versus salmeterol
• Leukotriene receptor antagonists should be tried
  in the treatment of aspirin-sensitive asthma
• Montelukast is effective in the treatment of
  exercise-induced bronchoconstriction, and
  possibly superior to salmeterol

22
Asthma Allergic Rhinitis ?

• Concept of one-linked airway disease between
  allergic rhinitis and asthma has lead to
  leukotriene modifiers being prescribed for
  allergic rhinitis
• Clinical Questions Are leukotriene modifiers
  effective therapy for allergic rhinitis? Should
  they be used as first-line therapy?

23
(No Transcript)
24
Allergic Rhinitis

• 20 population affected
• Symptoms include nasal congestion, sneezing,
  rhinorrhea, nasal pruritis
• Allergen exposure induces release of chemical
  mediators, for which histamine and leukotrienes
  are two of the most abundant
• Studies have identified increased levels of
  leukotrienes in nasal lavages after allergen
  challenges

25
Allergic Rhinitis

• Nasal obstruction results from vascular
  engorgement of venous sinusoids within the
  turbinates
• Direct nasal challenge studies with leukotrienes
  have identified no effect on pruritis or sneezing
  in contrast to histamine
• Major leukotriene effects are nasal congestion
  and rhinorrhea from microvascular changes

26
Knapp - NEJM 1990

• First clinical study using oral 5-lipoxygenase
  inhibitor (A-64077) to test effect on nasal
  congestion
• Eight persons with positive nasal-provocative
  screen to ragweed, grasses, or cat dander and no
  allergy medications for 4 weeks were enrolled
• Participants in double-blind fashion dosed either
  with 800mg of A-64077 or placebo, and exposed to
  allergen 3 hours later
• Two allergen challenges were performed at least
  two weeks apart
• Subjects assessed nasal congestion on scale of 0
  (no congestion) to 5 (total occlusion), and
  number of sneezes recorded

27
Knapp- Results

• A statistically significant difference (p lt .02)
  was found between nasal congestion score of the
  A-64077 treated group (3.6) versus placebo group
  (4.6)
• Effect on sneezing was not significant

28
Knapp- Conclusion

• Oral leukotriene synthesis inhibitor reduced
  allergen-induced nasal congestion scores
• Incomplete relief of congestion and no reduction
  in sneezing fits with known biological effects of
  leukotrienes and histamine

29
Donnelly et al.- the walk in the park

• The 1995 the walk in the park study compared
  zafirlukast vs. placebo for treatment of seasonal
  allergic rhinitis
• 185 persons with skin prick positive test to
  ragweed spent 8 hours on two consecutive days in
  an outdoor park during peak ragweed season in
  Iowa
• Subjects assessed hourly symptoms of nasal
  congestion, sneezing, rhinorrhea, and itchy nose,
  throat or palate as well as eye symptoms
• Symptoms were rated based on a detailed scale of
  0 (none) to 4 (severe)

30
Donnelly et al.

• Subjects with sufficient symptoms during a 3-hour
  baseline period on day 1 were randomized to
  treatment with single daily dose of 10, 20, 40,
  100 mg zafirlukast or placebo
• Symptoms were recorded hourly and at night at
  home
• At end of day 2, a global efficacy evaluation to
  rate allergy symptoms was completed on a scale of
  1 (good or substantial) to 5 (aggravated symptoms)

31
Donnelly et al.- Results

• 164 of 169 persons were randomized to treat five
  did not complete the study
• Baseline characteristics were similar
• Statistically significant reductions in nasal
  congestion, sneezing, and rhinorrhea were found
  for the 20 mg and 40 mg zafirlukast treatment
  groups during day and night based on mean symptom
  scores

32
Results
33
Donnelly et al. - Conclusions

• 20mg and 40mg zafirlukast relieved symptoms of
  nasal congestion and rhinorrhea with onset of
  action within 2 hours
• Yet, sneezing also reduced (? a histamine
  response)
• 100mg dosing not effective as in lower airways
• Improved day 2 baseline symptoms suggesting
  prophylactic effect

34
Donnelly et al. - Limitations

• Small population size
• Short study period
• Are the effects lasting?
• Subjective measure of benefit
• Zafirlukast dosed once a day only

35
Grossman et al. (abstract)- Pranlukast also
beneficial for SAR

• A second study of seasonal allergic rhinitis
  relief using pranlukast
• Pranlukast 150mg bid and 300mg bid compared with
  10mg loratadine (CLARITIN) in 4 wk. double-blind,
  placebo-control trial of 484 patients
• At each weekly visit, the mean of 4 highest daily
  symptom scores were calculated

36
Results

• Rhinitis symptoms were reduced compared to
  placebo by 150mg bid pranlukast at weeks 1,3, and
  4. -9, -23, -24 from baseline
• Pranlukast 300mg bid also with statistically
  significant reduction by week one
• Loratadine showed symptom relief at all time
  points

37
Grossman et al.- Limitations

• Study only published in abstract form
• Complete data sets not published
• Provides some additional support to walk in the
  park study
• These studies show a trend toward LTRAs being
  useful for allergic rhinitis therapy

38
Question?

• What is the better therapy
• histamine blocker
• nasal steroid
• leukotriene receptor blocker?

39
Meltzer et al.- LTRA and Anti-histamines

• Montelukast Study Group compared montelukast plus
  loratadine to monotherapy of each agent
• 12 center trial randomized into 5 treatment
  groups with a 1 week run-in period and 2 week,
  double-blind treatment period
• At 3rd visit, patients randomized to 10mg
  montelukast, 20mg montelukast, 10mg loratadine,
  10mg loratadine 10mg montelukast, or placebo

40
Meltzer et al. - Methods

• Daily rhinitis diary card with a 4-point scale
  maintained both day and night
• Rhinoconjunctivitis Quality-of-Life Questionnaire

• Daytime symptoms
• nasal
• eye
• Nighttime congestion on awakenings
• Difficulty going to sleep
• Nighttime awakenings

41
Meltzer et al. - Results

• 460 of 834 screened patients included
• excluded with negative skin tests, on-going use
  of allergy medicines most common
• baseline characteristics similar
• baseline composite symptom score was 1.8
• 26 patients did not complete study
• 7 patients with incomplete data

42
Results
(95 C.I.)
43
Results

• Monotherapy with either 20mg montelukast or 10mg
  loradatine did not show difference from placebo
• 10mg montelukast showed statistically significant
  improvements from placebo with regards to daytime
  eye, nighttime, and composite symptoms
• Monotherapy did show improvement of
  Quality-of-Life scores

44
Results

• Montelukast loratadine improved all endpoints
  significantly

45
Meltzer et al.- Conclusions

• Only combination therapy showed significant
  improvement in all symptom scores
• This is contrary to previous RCTs showing
  effectiveness of loratadine as single agent
  therapy for allergic rhinitis
• Interestingly, all treatment groups had improved
  Quality-of-Life scores despite apparent lack of
  effect on rhinitis symptoms
• For these reasons, others have questioned the
  results of this study

46
Pullerits et al. - LTRA compared to nasal steroids

• Randomized, placebo-controlled trial comparing
  zafirlukast 20mg bid to beclomethasone nasal
  spray 100mcg bid
• 33 patients with positive skin prick test to
  grass pollen enrolled
• Treatment period begun 3 weeks before expected
  grass pollen season
• Daily symptom scores for sneezing, rhinorrhea,
  pruritis, and congestion (0 to 4)

47
Pullerits et al.

• Nasal biopsy performed at start and 6 weeks,
  examined for EG2 eosinophils
• Treatment course of 50 days

48
Results
Mean symptom score increased for all groups
during peak grass pollen season
49
Results

• No difference between placebo and zafirlukast for
  symptom score or EG2 eosinophils

• Significant difference between beclomethasone and
  placebo (p0.005) and beclomethasone and
  zafirlukast (p0.01)
• EG2 cells also lower in beclomethasone treated
  group

50
Conclusions

• Nasal steroid superior to LTRA
• Study was small
• LTRA showed no effect over placebo, concurring
  with previous study
• No comparison of nasal steroid versus LTRA
  anti-histamine

51
Allergic Rhinitis Data Summary

• Few, small studies
• Conflicting results
• nasal steroid gt LTRA H1 blocker gt H1 blocker
  gt LTRA

52
Are Leukotriene Inhibitors Efficacious in
Treating Atopic Dermatitis?
53
Atopic Dermatitis

• Atopic dermatitis is a chronic relapsing T-cell
  mediated inflammatory skin disorder often in
  patients with atopy
• Skin exhibits eczematous changes in flexural
  distributions with extreme pruritis
• Current therapies include topical steroids,
  anti-histamines, and antibiotics for
  superinfections
• Some have proposed leukotriene inhibitors as
  logical choices for therapy given the atopic
  basis of disease

54
Evidence for Therapy

• As of 2000, only two published papers address
  this issue
• Carucci et al. reported a series of 4 cases using
  zafirlukast with observed subjective improvement
• A pilot study using zileuton has also been
  published

55
Woodmansee and Simon- Atopic Dermatitis Pilot
Study

• 9 patients with consistent symptomatic atopic
  dermatitis for at least 3 months enrolled
• All patients received zileuton 600mg PO qid with
  office visits at 0,2,4,6 weeks
• Each visit, pruritis rated on scale of 0 to 10
• Disease dissatisfaction score rated on scale 0
  (satisfied) to 10 (severely dissatisfied)
• Each visit an examiner, blinded to previous skin
  score, scored skin involvement in 20 areas

• 2 of 9 patients did not comply with first
  follow-up
• A third patient withdrew in first 2 weeks
  secondary GI intolerance of zileuton
• Remaining 6 patients completed study

56
Dissatisfaction Score Results

• baseline mean dissatisfaction score 8
• score improved to 4.4 ( p 0.03) after 6 wks.
  therapy
• all reported improvement, but one noted dramatic
  improvement

57
Pruritis Results

• Pruritis scores fell from mean of 7.3 to 4.3 ( p
  0.06) after 6 wks. of therapy

58
Skin Scores Results

• Skin scores were reduced from a baseline mean of
  24 (out of 60) to 14 (p0.03) after 6 weeks of
  therapy

59
Atopic Dermatitis Therapy Conclusions

• Disease dissatisfaction scores and skin scores
  improved, though study has several weaknesses
• small sample size
• open label, no placebo
• 3 subjects not included in analysis
• one subject with much more dramatic response
• Utility of leukotriene inhibitors unclear
  montelukast pilot study recently completed
  larger RCTs needed

60
Are Leukotriene Inhibitors Beneficial in
Treatment of Chronic Urticaria
61
Chronic Urticaria Therapy

• Recurrent urticaria of greater than 6-8 wks.
  duration is termed chronic urticaria
• Often idiopathic
• Anti-histamines mainstay of therapy
• No RCTs published concerning treating chronic
  urticaria with leukotriene modifiers

62
Chronic Urticaria Therapy-whats been published

• Berkun and Shalit reported a case of successfully
  treated steroid-dependent delayed pressure
  urticaria with montelukast
• Ellis reported 2 cases successfully treated with
  zileuton
• Norris and Sullivan reported 9 of 15
  steroid-requiring patients achieved control with
  zafirlukast
• Chiu and Warren noted 8 of 15 subjects responded
  to zafirlukast
• Spector and Tan noted one case controlled by
  zafirlukast and the other by zileuton

63
Chronic Urticaria Therapy-whats been published

• Bensch and Borish performed a retrospective chart
  review and identified 18 patients with chronic
  urticaria treated with leukotriene inhibitors
• Ten had dramatic improvement
• four with montelukast
• five with zafirlukast
• one with both zafirlukast and zileuton
• Improvement seen within 1 week resolution of
  urticaria within one month
• All patients continued various other treatments

64
Chronic Urticaria Therapy Conclusions

• Leukotriene modifiers appear to help some
  patients with chronic urticaria, but not all
• An individual patient may respond better to the
  5-lipoxygenase inhibitors versus the LTRAs
• RCTs are needed

65
Do Leukotriene Inhibitors Prevent Migraines?
66
Leukotriene Modifiers for Migraine Prophylaxis

• Clinical observations noted decreased migraine
  frequency in asthmatics treated with leukotriene
  modifiers
• Leukotrienes have been implicated in the
  pathophysiology of migraines
• Sheftell et al. has published the only study

67
Sheftell et al.- Leukotriene Modifiers for
Migraine Prophylaxis

• 17 patients with diagnosis of migraines without
  aura enrolled
• headache calendars kept for 2 month baseline
  period, then for 3 month open-label treatment
  phase
• montelukast started 10 mg PO qd and increased to
  10 mg bid if patient not responding at 1 month

68
Sheftell et al.- Results

• Number of severe headaches significantly reduced
  (p lt 0.025) with montelukast therapy from 2.78 to
  1.31 per month
• No significant change in number of mild or
  moderate headaches

69
Migraine Prophylaxis Conclusions

• Initial study shows promise for LTRAs in migraine
  prophylaxis
• Severe headache numbers were reduced, while mild
  headaches increased
• maybe a result of montelukast decreasing the
  severity of headaches as opposed to complete
  elimination
• This study is limited secondary to open-label
  design and small sample size
• RCTs are planned to obtain stronger evidence

70
Other Uses for Leukotriene Modifiers

• Case reports and letters have been published with
  regards to the use of leukotriene modifier
  therapy in

• sinonasal polyposis
• sinus symptoms of aspirin triad disease
• eosinophilic lung disease
• eosinophilic gastroenteritis
• inflammatory bowel disease

71
Other Uses for Leukotriene Modifiers

• No published data or reports investigating the
  use of leukotriene modifiers in the treatment of
  COPD

72
Safety of Leukotriene Inhibitors

• Leukotriene inhibitors are being used for many
  conditions for which strong evidence supporting
  their efficacy is lacking
• This class of drug has been considered quite safe
  and well-tolerated
• With more widespread use, toxic side-effects have
  been noted

73
Safety

• Montelukast
• over 2 million users over age 6 by end 1999
• dyspepsia thought to be major side-effect over
  placebo
• elevated transaminases now noted

• Zafirlukast
• similar side-effect profile
• 5 patients with elevated liver enzymes
• 5x liver enzyme increases with doses gt 20 mg bid
• both drugs metabolized by cytochrome P450 hepatic
  pathway

74
Severe Hepatitis with Zafirlukast 20 mg bid

• Report of 3 patients with severe hepatitis
  reported in Annals of Internal Medicine, December
  2000
• Patient 1 recovered spontaneously after
  zafirlukast discontinued
• Patient 2 required liver transplant for
  subfulminant liver failure
• Patient 3 with severe hepatitis (ALT 20,184)
  improved with steroid therapy

75
Churg-Strauss-like Syndrome

• Zafirlukast, pranlukast, montelukast all
  associated with cases of allergic angiitis and
  granulomatosis
• Many cases occurred in steroid-dependent
  asthmatics who were reducing systemic steroid
  therapy after starting LTRA

• Reports of Churg-Strauss exists for LTRAs in
  patients not on steroid therapy
• Suggests LTRAs unmask underlying condition

76
Safety of Zileuton

• 1 in 50 chance of transaminitis
• FDA recommends baseline LFTs and 4 week LFTs
• Also potentiate effects of theophylline and
  warfarin
• These concerns and qid dosing limiting use in the
  United States

77
(No Transcript)
78
Take Home Pearls
79
Conclusions

• Leukotriene Inhibitors Mechanisms of Action
• Montelukast and zafirlukast block binding of
  cysteinyl leukotrienes to the cysLT receptor in
  the extracellular space. Zileuton inhibits
  5-lipoxygenase and therefore all leukotriene
  synthesis within inflammatory cells. Blocking
  the actions of leukotrienes promotes
  bronchodilation and decreases the inflammatory
  response.

80
Conclusions

• Leukotriene Inhibitors for Asthma Therapy
• Guidelines and evidence supports the use of LTRAs
  as monotherapy for mild persistent asthma, as
  add-on therapy to inhaled steroids for moderate
  or severe persistent asthma, and for prevention
  of exercise-induced bronchoconstriction. LTRAs
  also should be used for aspirin-sensitive asthma.

81
Conclusions

• Leukotriene Inhibitors for Allergic Rhinitis
  Therapy
• Limited conflicting data suggests less beneficial
  than nasal steroids, but adds additional benefit
  to oral anti-histamines
• Leukotriene Inhibitors for Treatment of Atopic
  Dermatitis
• With only pilot study available, unclear if
  beneficial in atopic dermatitis

82
Conclusions

• Leukotriene Inhibitors for Treatment of Chronic
  Urticaria
• In case reports, appears to dramatically help
  some patients while others have no response to
  the medication. An individual may have variable
  response to zileuton as compared to a LTRA.
• Leukotriene Inhibitors for Migraine Prophylaxis
• Initial open-label study shows promise for a
  large randomized, placebo-control trial

83
Conclusions

• Other Uses for Leukotriene Inhibitors?
• No reports of treating COPD with leukotriene
  inhibitors are published. Many diseases that
  involve eosinophilic infiltration are being
  treated with a trial of leukotriene inhibitors.

84
Conclusions

• Safety of Leukotriene Inhibitors
• All three medications have associated concerns of
  liver injury and Churg-Strauss-like disease. LFT
  monitoring probably prudent in patients with
  history of excessive alcohol use, known liver
  disease, or co-administered hepatotoxic drugs

85
Conclusions

• Concluding Thoughts
• Limited clinical evidence exists for the use of
  leukotriene modifiers beyond asthma therapy.
  Consequently, at this time a trial-and-error
  approach has been taken with the leukotriene
  modifier class of drugs. Additional research is
  needed to produce stronger evidence to provide
  more specific recommendations. This author would
  recommend short trials (few weeks?) of LTRAs for
  asthma, allergic rhinitis, or chronic urticaria
  not under control by current approved medical
  therapies. When LTRAs have shown effectiveness,
  the response is usually within the first few
  days.

86
Conclusions

• Concluding Thoughts..
• If no response is shown, then discontinue the
  LTRAs secondary to the small risk of liver injury
  and the high drug cost. If prolonged use of a
  LTRA is prescribed, consider periodic liver
  enzyme monitoring as well as warning patients
  about risks and signs of liver injury.

87
Thank You