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

Greetings from the Humidity Belt

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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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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

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Corticosteroids Antimalarials Azathioprine

Cytotoxic agents

(cytoxan)

Methotrexate Other cell cycle

inhibitors

Anti-inflammatory

therapy

Thalidomide anti-TNF alpha

therapies

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Patient experiences in primary care

Corticosteroids ? ?

? ? ?

? ? ?

If all you have is a hammer…

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



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 (?)



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.


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


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


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

Questions and Answers?

[email protected]

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immunosuppressive therapy and sarcoidosis - cleveland clinic

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