Immunosuppressive therapy and sarcoidosis

Immunosuppressive
therapy and sarcoidosis
The good, the bad, and the
granulomas
Joseph Barney MD FACP FCCP
Associate Professor
University of Alabama at Birmingham
Greetings from the Humidity Belt

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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The patient and Doctor experience
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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
Corticosteroids
Antimalarials
Azathioprine
Cytotoxic agents Methotrexate
(cytoxan)
Other cell cycle
inhibitors
Anti-inflammatory Thalidomide
therapy
anti-TNF alpha
therapies
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Patient experiences in primary care
Corticosteroids ?
?
?
?
?
?
?
?
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If all you have is a hammer…
Steroids: What they do
Genomic effects
Inhibition of
Inflammatory cells
Downregulation of
Cytokines
Gluconeogenesis
Fluid retention
Lymphoid
cell Death
Non Genomic Effects
Steroids: What they also do
Genomic effects
Non Genomic Effects
Central Obesity
Diabetes
Skin Thinning
Cataracts
Osteoporosis
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
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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
APC Dendritic Cells
Allan, Genome Biology 2000
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
Adenosine
Adenosine
Increased
Polyglutamates
Close monitoring of Liver Function tests during initial therapy
For patients with enteral absorption problems Subcutaneous
Drug More effective
Adenosine
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 IL23
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
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

Rapid onset of action

Slower onset of action

Usually effective for joint pain
symptoms

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


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
Questions and Answers?
drbarney@uab.edu
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