Immunosuppressive therapy and sarcoidosis - Cleveland Clinic
Transcript of Immunosuppressive therapy and sarcoidosis - Cleveland Clinic
Immunosuppressive
therapy and sarcoidosis
The good, the bad, and the
granulomas
Joseph Barney MD FACP FCCP
Associate Professor
University of Alabama at Birmingham
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General Overview
Who gets treatment
Current therapies
The down side of treatments
The organ involvement approach
New directions in immunosuppressive
treatment
Questions and answers
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Watching and waiting
Many patients with limited disease and no
evidence at diagnosis of organ invasion can
be followed with supportive therapy
As many as 60-80% patients will have
remission of symptoms with supportive care
Decision to start immunosuppressive therapy
should be based on presence of organ
impairment, the degree of symptoms, and the
organ location
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Problems with watching and waiting
Not many reliable prediction criteria on
who will progress to more active disease
Mixed data on whether treatment early
leads to remission vs. observation in
patients with stage II or III sarcoidosis with
limited symptoms
Some symptoms may actually be made
worse by treatment with immune
suppressive medications
Steroids- depression, fatigue, sleep cycle
Methotrexate-fatigue, nausea, depression
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Generally accepted treatment
Decline in FVC<15% and or DLCO <20%
Hypoxemia at time of diagnosis
Central nervous system involvement
Cardiac sarcoidosis
Severe skin involvement (lupus pernio)
Hypercalcemia
Solid organ lesions with evidence of organ
function impairment
Spleen enlargement with severe pain
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What’s available for therapy now
Text ext
Corticosteroids Antimalarials Azathioprine
Cytotoxic agents
(cytoxan)
Methotrexate Other cell cycle
inhibitors
Anti-inflammatory
therapy
Thalidomide anti-TNF alpha
therapies
Non Genomic Effects
Steroids: What they do
Downregulation of
Cytokines
Inhibition of
Inflammatory cells
Gluconeogenesis
Fluid retention
Lymphoid
cell Death
Genomic effects
Non Genomic Effects
Steroids: What they also do
Genomic effects
Central Obesity
Diabetes
Skin Thinning
Cataracts
Osteoporosis
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Corticosteroids: What we know
Cochrane review of studies of oral steroids in
pulmonary sarcoidosis (13 studies)
Improved Chest radiographs
Improved symptoms
Improved functional status
No change in lung function
No definite disease modification
Severe CNS, cardiac, solid organ impairment,
hypercalcemia still first line of treatment
Corticosteroids: What’s still debated
Corticosteroids-suppress the inflammatory
granulomatous reaction that leads to fibrosis
and organ dysfunction vs.
Corticosteroids-prolong an ineffective
inflammatory response and prolong
sarcoidosis activity (worse than watching and
supportive care)
More recent studies for pulmonary sarcoidosis
suggest lower starting doses of corticosteriods
effective with less long term sequela
Antimalarials
Chloroquine and Hydroxychloroquine (slightly
weaker)
Extremely lipophilic and have a presumed wide
volume of distribution
Most commonly used for cutaneous
sarcoidosis patients
Chloroquine studied in small trial of pulmonary
sarcoidosis with favorable results
Work well together with other immune
suppressive therapies
Retinal toxicity monitoring required
Antimalarials: what they do
Allan Genome Biology 2000
Allan, Genome Biology 2000
APC Dendritic Cells
Methotrexate Therapy
Most widely used steroid sparing agent in
sarcoidosis (slow onset of action)
Delivered orally or subcutaneously
Usually taken weekly by patients (Lousy
Monday syndrome)
Reported improvement in
Pulmonary
Cutaneous
Hepatic
Ocular
Cardiac
Neurologic
How it works
Increased
Polyglutamates
Adenosine
Adenosine
Adenosine
Close monitoring of Liver Function tests during initial therapy
For patients with enteral absorption problems Subcutaneous
Drug More effective
Azathioprine and Mycophenolate
Both now commonly used in sarcoid patients
as steroid sparing agents
Little clinical trial data on either
Both function as purine synthesis inhibitors
Probably modulate the immune system
through metabolic impairment of leukocytes
Liver function tests and WBC counts required
Not reported with liver fibrosis
Cyclophosphamide Therapy
Used with some experience in severe
neurosarcoidosis
Extremely potent immune suppressing agent
Alkylating agent cross links DNA-RNA and
inhibits protein synthesis
Monitoring for significant side effects
Hemorrhagic cystitis
Opportunistic infections
Increased risk of bladder cancers
Minocycline
Tetracycline based antibiotic which inhibits
protein synthesis
Most literature for cutaneous sarcoidosis use
Has both antimicrobial effects and anti
inflammatory
In vitro inhibits granuloma formation of
irritated macrophages
Raises the question of whether cell wall
deficient bacteria are related to sarcoidosis
Total body of literature is mixed and trials are
scant on evidence, side effects are low
Anti TNF alpha therapies
Infliximab (remicaid)
Monoclonal antibody against TNF α
Clinical trials on pulmonary function mixed
Shown to be useful in refractory
neurosarcoidosis, ocular, cardiac, cutaneous
Increased risk of tuberculosis and fungal
infection rates
Host antibodies to infliximab can blunt
effectiveness
Anti TNF alpha therapies
Adalimumab (Humira) and Golimumab
(Simponi)
Humanized complete monoclonal antibodies
Subcutaneous delivery
Lower rates of autoantibodies in host
Usually given with another agent
Ustekinumab (Stelara)
Monoclonal antibody that binds IL-12 and IL-
23
Currently approved for psoriasis
Part of recently completed trial
The down side of treatments
Opportunistic infections
Corticosteroids-increased risk of common
infections
UTI’s
Cutaneous fungal infections
Thrush
Combination steroid and DMARDs likely
related to increased infections
Pneumocystis infections seen with higher
doses of prednisone in RA patients
What dose requires prophylaxis (?)
The down side of treatments
Opportunistic infections
DMARDs alone?
Most literature from rheumatoid arthritis
and IBD
Methotrexate and Imuran both low risk of
opportunistic infections without steroids
Anti-TNFα therapies classically associated
with increased risk of fungal and
mycobacterial infections
Increased risk of Pneumocystis infections
when TNF inhibitors used with DMARDs.
The down side of treatments
Sequela of long term therapies
Steroids associated with a multitude
Osteoporosis
Cataracts/Glaucoma
Mood disorders
Central obesity
Acquired diabetes
DMARDs
Hepatic toxicity
Cirrhosis
Symptomatic anemia
The down side of treatments
Concomitant symptom exacerbations
Depression and fatigue often made worse
with corticosteroids
Quality of life scores lower in sarcoid patients
after steroid therapy
Chronic pain from small fiber neuropathy
often does not respond to immune
suppressive therapy
TNF alpha inhibitors have been reported to
cause diffuse granulomatous reactions in lung
The organ involvement approach
Comprehensive investigation into organs
involved and degree of impairment
Pulmonary function testing
Exercise oximetry
Imaging
Laboratory evaluation for organ dysfunction
Screening for chronic infectious diseases
Viral hepatitis screening
Tuberculosis skin testing and quantiferon assay
Sexual history
The Organ Involvement Approach
How many organs are affected by sarcoidosis
Direct involvement (CNS lesions)
Indirect involvement (Obstructing kidney
stones)
Which drugs penetrate the organs involved
Which organs are impaired that will metabolize
immune suppressive drugs
What am I likely to make worse in a specific
patient with treatments
Tandem Therapy
Many immune suppresive agents used for
sarcoidosis complement each other
Different mechanisms of action
Lower doses of each by utilizing two agents
synchronously
Different penetration of organs among
different agents used in sarcoidosis
Different onsets of action
Rapid nongenomic effects of steroids
Slower onset of action of antimetabolites
Tandem Therapy Example
38 year old male with mild hypertension, night
sweats, raised skin lesions on his face and
back, recurrent kidney stones and
hypercalcemia.
Chest radiograph with hilar lymphadenopathy
and upper lobe reticular infiltrates
NKDA
Main complaints are severe joint stiffness,
raised disfiguring skin lesions, and several ER
visits for kidney stones in the past 24 months.
Tandem Therapy
Corticosteroids Hydroxychloroquine
Slower onset of action
Effective for skin lesions and joint pain
Prevents insulin degradation in the
liver and suppresses gluconeogenesis
Increases peripheral utilization of
glucose
Can lower initial starting dose of
prednisone required to treat several
features of sarcoidosis
Rapid onset of action
Usually effective for joint pain
symptoms
Highly effective for lowering
calcium
Activity for skin lesions
Tandem Therapy (other examples)
Methotrexate and Humira used together
Reduces development of host antibodies to
humira and prolongs efficacy
Both effective for skin lesions
Both used for neurosarcoidosis
Prednisone and mycophenolate
Both effective for hepatosplenic sarcoidosis
Neither causes hepatic fibrosis
Doses of both can be lower
Comorbid disorders
General assessment of depression/anxiety
Significant correlation between lung function
and depression scales
Immunosuppression more likely to be
successful when depression/anxiety treated
simultaneously
Specific psychiatric disorders associated with
steroid therapy exacerbations
Bipolar disorder
Schophrenia
Comorbid disorders
General assessment of chronic fatigue and
pain
Newer studies that demonstrated treatment
of chronic fatigue with stimulants improved
quality of life
Chronic pain issues related to small fiber
neuropathy/myopathy often not improved
with immune suppressive therapies
Multidisciplinary treatment with immune
suppressive therapy and pain management
New directions in therapy
Stem cell Immunosuppression Techniques
Randomized trials of Current
immunosuppressive agents not previously
investigated in sarcoidosis
Rapamune and placebo in sarcoidosis (effect
unknown)
Rituximab and placebo in sarcoidosis (effect
unknown)
Anakinra and placebo in sarcoidosis (effect
unknown)
New directions in therapy
NOD like receptors and increased innate
immunity
NOD receptors family of proteins in cells
which detect fragments of bacteria in the host
and activate immunity
NOD gene mutations shared in both Crohn’s
disease and familial forms of sarcoidosis
NOD gene mutations lead to prolonged
immune response after exposure to bacterial
fragments
New Directions in therapy
New Inhibitors of NOD 2
Improved understanding of
Relationships between bacterial
fragments and development of
sarcoidosis
Revisiting the roles of antimicrobials
and their anti inflammatory effects in
treatment of sarcoidosis
Minocycline
Anti mycobacterial drugs
Tattoli I, et al Semin Immunpathol 2007
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