therapy for sarcoidosis

Therapy for Sarcoidosis

Robert P. Baughman MD

Interstitial Lung Disease and Sarcoidosis Clinic

University of Cincinnati

Who needs treatment for sarcoidosis

• Not all patients require therapy for sarcoidosis

• The decision to treat is usually based on symptoms

• Therapy for sarcoidosis has some impact on the long term outcome of disease in the asymptomatic individual with persistent lung infiltrates

What treatment to give for sarcoidosis

• Corticosteroids remain the cornerstone of therapy for sarcoidosis– Always try to treat topically for single organ

involvement

• For patients with chronic disease, steroids sparing agents may prove useful– Chronic is defined by disease more than two years

– Also include patients requiring more than 10 mg a day of prednisone after six months of treatment

Meta Analysis of Steroids for Pulmonary Sarcoidosis: Improving Chest X-ray

Paramothayan and Jones JAMA 2002: 287: 1301-1307

Patient with no pulmonary symptoms, on two years of prednisone. Prednisone recently tapered

20 mg prednisone 10 mg prednisone

Meta Analysis of Steroids for Pulmonary Sarcoidosis: DLCO

Paramothayan and Jones JAMA 2002: 287: 1301-1307

Percent of Patients Requiring Initial Systemic Therapy

0

10

20

30

40

50

60

70

%

Treated

Iowa

PhiladelphiaMilan

Britain

ACCESS

Baughman and Lower Sarcoidosis 1998; 15: 19-20.

Outcome of therapy in Philadelphia

• Patients treated in a standardized fashion– No specific protocol identified

• Patients with drug stopped were then followed for at least two years

• Frequency in which corticosteroids or other therapy reinstituted was noted

Gottlieb et al Chest 1997; 111: 623-631

Outcome of Patients in Philadelphia

Initial EvaluationN=337

Need Systemic TherapyINTIIAL TREATMENT

N=221

No systemic therapyNO INITIAL TREATMENT

N=118

Treat for two years

Continue therapyCHRONIC TREATMENT

RecalcitrantN=116

Stop TherapyN=103

RelapsedCHRONIC TREATMENT

N=77

Remain off therapyACUTE TREATMENT

N=26

Require therapy laterCHRONIC TREATMENT

N=9

Remain off therapyNO TREATMENT

N=109

Results of Therapy in ACCESS*

• Therapy at initial visit, within six month of diagnosis– No therapy– Past therapy– Current systemic therapy

• Repeat evaluation in two years of first third of patients

• ACCESS did not have protocol directing therapy

* ACCESS= A Case Controlled Etiologic Study of SarcoidosisBaughman et al Am J Resp Crit Care Med 2001; 164: 1185-1189

Initial Corticosteroids Associated with Persistent Therapy

0%10%20%30%40%50%60%70%80%90%

% w

ith

Per

sist

ent

The

rapy

Initial Steroids No Initial Steroids

Philadelphia ACCESS

Gottlieb JE et al Chest 1997;111:623-631

Risk Factors At Initial Visit Associated with Need for Treatment at Two Year Follow-up:

Linear Regression Analysis of 205 patients in ACCESS study

Variable Odds Ratio

Age > 40 1.686

African-American 0.908

Female 0.701

% Predicted FVC at baseline 1.003

Cardiac or Neurologic Involvement at Baseline

0.815

Risk Factors At Initial Visit Associated with Need for Treatment at Two Year Follow-up:

Linear Regression Analysis of 205 patients in ACCESS study

Variable Odds Ratio

Dyspnea Level 3 or 4 versus 0 4.042

Dyspnea Level 2 versus 1 2.011

Dyspnea Level 1 versus 0 2.155

Systemic therapy for sarcoidosis at baseline

3.604

For the patient with chronic sarcoidosis:What are the alternatives?

Alternatives to Corticosteroids

• Methotrexate

• Leflunomide

• Azathioprine

• Cyclophosphamide

• Thalidomide

• Infliximab

• Hydroxychloroquine

• Minocycline

Cytotoxic Agents Cytokine Modulators

Antimicrobials

Hydroxychloroquine/Chloroquine

• Antimalarial agent

• Anti-inflammatory agent in rheumatoid arthritis

• Useful in sarcoidosis– Skin disease– Hypercalcemia– ? Neurosarcoidosis

Randomized Trial Chloroquine versus Placebo for Chronic Sarcoidosis

Baltzan M et al. Randomized trial of prolonged chloroquine therapy in advanced pulmonary sarcoidosis. Am J Respir Crit Care Med 1999;160:192-197

Chloroquine Placebo

FVC change

ml/year

-32.9 -144.4

DLCO

mm Hg/min/yr

-0.59 -2.09 *

Relapses 2/10 6/8

* P<0.05

Hydroxychloroquine Therapy for Sarcoidosis

• Initial Laboratory Data– CBC– Hepatic function– Renal Function

• Initial eye examination– Follow-up every 6-12 months

• Initial Dose– 200 mg per day

• Maximum dosage 400 mg per day• Dose limitation is nausea

Use of Tetracyclines for Sarcoidosis

• Twelve patients treated with minocycline or doxycycline

• Follow-up median 26 months– Complete Response =8

– Partial Response = 2

– No Response = 2

• Majority received minocycline at 100 mg bid

Bachelez H, et al. Arch Dermatol 2001;137:69-73

Minocycline:Treating P. acne or Sarcoidosis?

• Minocycline is effective for treating P. acne– Low MICs– Worked in experimental animal model

• Minocycline has anti-inflammatory activity– Suppresses T cell proliferation

• Kloppenburg M, et al. Clin Exp Immunol 1995; 102:635-641

– Inhibition of matrix metalloproteases• Robertson LP, et al. Ann Rheum Dis 2003; 62:267-269

– Anecdotal success in scleroderma and multiple sclerosis• Le CH, et al. Lancet 1998; 352:1755-1756.• Robertson LP, et al. Ann Rheum Dis 2003; 62:267-269


• Methotrexate• Leflunomide

• Azathioprine


• Thalidomide

• Infliximab


• Minocycline


Antimicrobials

Treatment with Methotrexate for >2 YearsU.C. experience of first 54 patients

• Total of 54 patients started on therapy.• Two patients were non compliant and were

withdrawn from therapy.• Remaining patients were evaluated for.

– Response to therapy• 40 patients

– Steroid sparing affect• 25 of 30 patients

Lower, Baughman. Arch Intern Med 1995; 155: 846-851.

Response to Methotrexate

0 10 20 30 40 50 60

Number of Patients

Total

Lung

Skin

Improved No Improvement

Effectiveness of Methotrexate for Specific Organ Involvement

• Neurologic disease – Non responders to

methotrexate usually treated with cyclophosphamide

• Eye disease– Non responders to

methotrexate usually responded to combination cytotoxic drugs

0

10

20

30

40

50

60

# P

atie

nts

CNS Eyes

Improved No Response

Lower et al Arch Intern Med 1997Baughman et al Sarcoidosis

Steroid Sparing Effect of Methotrexatefor Acute Sarcoidosis

• Methotrexate patients had a significant lower prednisone dose in the last six months of study.

• This was associated with significantly less weight gain for patients on MTX 0

510152025303540

0 6 12

Months

Dai

ly P

red

Dos

e

MTX PLA

Baughman et al Sarcoidosis 2000; 17: 60-66

Methotrexate Therapy for Sarcoidosis• Initial and Follow-up Laboratory Data

– CBC– Hepatic function– Renal Function

• Initial Dose– 10 mg per week

• Maximal dose 15-20 mg per week• To reduce toxicity

– Half dose one day, rest next day– Folate 1 mg per day

• Reduction of dose for neutropenia

Ulcer on Tongue of Patient Taking Methotrexate

O b serve

N o F u rth erS ym p tom s

C on tin u eM TX

N o M TXToxic ity

Try A n o th erD ru g

M TXToxic ity

L ive rB iop sy

Im p rovem en t

Try A n o th erD ru g

N o Im p rovem en t

R es ta rt M TX

R ecu rren ceo f S ym p tom s

S top M TXE very 2 years

Trea t w ithM eth o trexa te

20%

5%75%

Baughman and Lower Thorax 1999; 54: 742-746

Results of First 100 Liver BiopsiesNumber of Elevated AST values in prior year

Patients underwent 9 tests during year

0

1

2

3

4

5

6

7

8

9

Num

ber

Tim

es A

ST >

40 in

pas

t ye

ar

Methotrexate Sarcoidosis Negative

Differences between groups by ANOVA, p<0.01.Baughman et al Arch Intern Med 2003; 163: 615-620

Leflunomide (Arava)

• Is an immunomodulatory drug– Inhibits the pyrimidine ribonucleotide uridine

monophosphate (rUMP)

• Similar to methotrexate

• Less gastrointestinal toxicity

• Has been used in combination with methotrexate for rheumatoid arthritis– Kremer JM, et al. Ann Intern Med 2002;137:726-733.

Baughman RP, Lower EE Sarcoidosis 2004;

Results of Therapy

* Number (percent responders)Baughman and Lower Sarcoidosis 2004; 21:43-48

Evaluation Total

Total Number 32

Complete Response 16

Partial Response 9

Complete + Partial Response * 25 (78%)

No Response 4

Toxicity 3

Response Rate for Concurrent Use of Methotrexate and Leflunomide

• Fifteen patients on both methotrexate and leflunomide

• Response seen in 12 (80%)– 9 with complete remission– 3 with partial remission

• Two non responders• One stopped leflunomide because of nausea

but continued on methotrexate

Hematologic abnormalities of sarcoidosis76 consecutive patients

HematologicAbnormality

Number(%)

Anemia 21 (26)

Lymphopenia 41 (55)

Leukopenia 31 (44)

Eosinophilia 12 (16)

Monocytosis 9 (12)

Lower et al.. Sarcoidosis 1988; 5: 512-55.

HepatoSplenic Involvement from Sarc


• Methotrexate

• Leflunomide

• Azathioprine


• Thalidomide

• Infliximab


• Minocycline


Antimicrobials

Tumor Necrosis Factor

• TNF is a central cytokine in chronioc inflammatory conditions

• It is secreted by several effector cells– Especially macrophages

• It has multiple effects in the cytokine cascade– Initiation of the granulomatous reaction– Neutrophil chemotaxtic

APC

HLA Class

II

CD4

T cell antigen receptor

Ag peptide

T cellActivation

IL-2; IFN-; IL-12; IL-18; TNF

APC

HLA Class

II

CD4


Ag peptide

T cellActivation


TNF knock outmouse does notForm granulomas

APC

HLA Class

II

CD4


Ag peptide

T cellActivation

IL-10


TNF; IL-8

RESOLUTION FIBROSIS

Spontaneous Release of TNF by Alveolar Macrophages retrieved by BAL

0

200

400

600

800

1000

1200

1400

Spon

tane

ous

TN

F r

elea

se

Untreated Sarcoidosis

TreatedSarcoidosis

ControlsSmokers

ControlsNonsmokers

Baughman et al J Lab Clin Med 1990 115: 36-42

Effectiveness of Methotrexate versus Prednisone in Sarcoidosis

• Comparison of patients receiving – Prednisone (12 pts)– Methotrexate (12 pts)

• Both groups had improvement in vital capacity with treatment

• Patients underwent BAL before and after 6 months of therapy

0

0.5

1

1.5

2

2.5

3

3.5

VC

(L

)Pred MTX

Pre Rx Post Rx

Baughman, Lower. Am Rev Respir Dis 1990; 142: 1268-1271

Methotrexate and Prednisone Reduced Alveolar Macrophage activity

• Alveolar macrophages retrieved by BAL.

• Spontaneous release of tumor necrosis factor (TNF) measured pre and post therapy.

• Alveolar macrophages from normal subjects release <20 units TNF

0

20

40

60

80

100

120

TN

F u

nits

Pred MTX

Pre Post

TNF release of BAL Retrieved Alveolar Macrophages

0

500

1000

1500

2000

2500

TN

F p

g/m

l/24

hr

Controls No Therapy,Stable

No Therapy,Progressive

On Therapy,Progressive

Ziegenhagen et al Sarcoidosis 2002; 19:185-190.

Drug Suppress AM release of TNF

Treat sarcoidosis

Methotrexate Baughman et al ARRD 1990; 142: 1268-71

Lower et al Arch Intern Med 1995; 155: 846-51

Pentoxifylline Marques et al AJRCCM 1999; 159: 508-511

Zabel et al. AJRCCM 1997; 155: 1665-1669

Azathioprine Muller-Quernheim, J., et al ERJ 1999; 14: 1117-1122.

Muller-Quernheim, J., et al ERJ 1999; 14: 1117-1122

Thalidomide Tavares et al Respir Med 1997; 91: 31-9.

Baughman et al Chest 2002; 122: 227-232

Thalidomide Therapy• Fourteen with skin involvement

– 12 of 14 to 100 mg a day– Remaining 2 required 200 mg a day

• Twelve patients with pulmonary involvement– 2 felt subjectively better– No significant change in VC at end of 4 months of

therapy

• Eight patients with sinus disease– Four had subjective improvement

• No other organ improvement notedBaughman et al Chest 2002; 122: 227-232

Facial sarcoid before and after thalidomide

Biological agents to block TNF

• Developed for treatment of sepsis• Found to be useful for rheumatoid arthritis

and Crohn’s disease• Agents now released in United States

– Etanercept– Infliximab– Adalimumab

• May be useful in treating sarcoidosis

First Three Infliximab PatientsAge, Race, Sex

Index Lesion

Other Organs

Current Therapy

Prior Therapy

46, B, F Skin Sinus, CNS, Eyes

Pred, MTX

Thal,

AZA

55, B, F Skin Sinus, Lungs, Liver, Eyes

Pred Thal, MTX, AZA

47, B, M Lungs Sinus, Skin

Pred, MTX

AZA


First Three Infliximab PatientsChange in Index Lesion

Change in other organs

Initial dose of Prednisone

Dose of prednisone after

12 weeks

Resolution of skin lesion

Sinus- improvement

20 0

Resolution of skin lesion

Sinus- improvement

Lung- improvement

10 0

Improvement of Vital Capacity

Initial: 3.06 L

Follow-up: 3.87 L

Skin- resolution

Sinus- resolution

40 5

Before and After two weeks after first dose of Infliximab (Remicade)


Lupus Pernio after 4th dose Infliximab

Effect of Infliximab on Chest Roentgenogram

Before Infliximab After four cycles of Infliximab

Effect of 2 treatments with Infliximab on Chest Roentgenogram

Before After

• Initial FLAIR (A) and after gadolinium-enhanced (B)

• Post-treatment FLAIR (C) and gadolinium-enhanced (D)

Pettersen JA, et al. Neurology 2002;59:1660-1661.

Toxicity From Infliximab• Allergic reactions

– Anaphylaxis can rarely occur– Patients must be observed during infusion

• Increased risk for infection– Especially tuberculosis

• Keane J et al. N Engl J Med 2001;345:1098-1104.

• Increased mortality for patients with advanced congestive heart failure– NYHC stage 3 or 4

• Possible increased risk for malignancy– No risk yet determined– However most long term studies in patients with inherent risk for malignancy

Rate of M. tuberculosis per 1000 patient years

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Rat

e of

M. t

b /1

000

pati

ent

year

s

Etanercept Infliximab

Total non US US

ProinflammatoryResponse

Macrophage

Etanercept

Etanercept for Sarcoidosis• Not found to be useful in pulmonary sarcoidosis

– 17 patients with stage 2/3 disease– Open label, single agent therapy– Study terminated early because of treatment failures

• Utz et al Chest 2003; 124: 177-185

• Was not successful in double blind randomized trial– For patients with uveitis

Peri Ocular Steroid Injections

Ocular Sarcoidosis Patients failing at least 6 months of Methotrexate

• Patients randomized to– Etanercept 25 mg SQ twice a week– Saline SQ twice a week

• Initial and follow-up visits by ophthalmologist

• No change in methotrexate dosage during study

• Topical therapy frequency and intraocular injections by ophthalmologists

Baughman RP et al Chest in press

Evaluation of Response to Therapy

• Scoring system based on all components of the eye

• Comparison of initial and final systemic and topical corticosteroids– Including intra ocular injections

• Assessment of a single ophthalmologist– Evaluated 18 of the 20 patients in the study

Etanercept Placebo

0

1

2

3

4

5

6

7

Num

ber

of P

atie

nts

Corticosteroid Usage Ophthalmologist's Opinion

Better Same Worse

0

1

2

3

4

5

6

7

Nu

mb

er o

f P

atie

nts

Corticosteroid Usage Ophthalmologist's Opinion

Better Same Worse

No discordance between three scoring systems

Infliximab for Chronic Ocular DiseaseUC Experience

• 14 patients with chronic ocular inflammation studied– 7 with sarcoidosis– 4 with idiopathic uveitis– 2 with Crohn’s disease– 1 with Volt-Koyanagi-Harada (VKH) disease– 1 with Behcet’s

Baughman, R. P., et al. Int.J.Clin.Pharmacol.Ther 2005; 43: 7-11

Other Medications

Therapy Past Current

Methotrexate 4 10

Prednisone 3 7

Azathioprine 2 4

Etanercept 3 0

All patients treated with systemic therapy in addition to infliximab

Response to Infliximab

• 13 of 14 had improvement– Global assessment by ophthalmologist– The one non responder was non compliant

• Prednisone while treated with infliximab– Discontinued in 3 patients– Reduced dose in 4 patients– Not on prednisone 7 patients

Etanercept versus Infliximab

• Three patients had previously received etanercept for six months at 25 mg– No clinical response to etanercept

• All three patients had response to infliximab

Comparison of anti-TNF Agents for Sarcoidosis

• Retrospective study at our institution• All patients were treated for at least one

month of therapy• Treatment with either

– Etanercept• TNF receptor antagonist

– Infliximab• Chimeric anti-TNF antibody

– Adalimumab• Humanized anti-TNF antibody

Response Rate to anti-TNF Therapyat University of Cincinnati Sarcoidosis Clinic

0

5

10

15

20

25

30

35

Num

ber

of P

atie

nts

Infliximab Etanercept Adalimumab

Improved Stable Worsened

Significant difference in response between groups, p<0.0001.

Response Rate to anti-TNF Therapyat University of Cincinnati Sarcoidosis Clinic

0%

20%

40%

60%

80%

100%

Infliximab Etanercept Adalimumab

Num

ber

of P

atie

nts

Improved Stable Worsened

Significant difference in response between groups, p<0.0001.

Patient Treated With Infliximab for 4 months

PRE POST

Patient Treated with Adalimumab for 6 Months

PRE POST

Why aren’t all anti-TNF agents the same in sarcoidosis?

• The drugs work equally well in rheumatoid arthritis

• Difference in effectiveness is noted in Crohns disease– Infliximab >> Adalimumab > Etanercept

Possible Causes of Differences

• Different mechanisms of action– Etanercept is a receptor antagonist

• Dose effect– Intravenous levels lead to high peak dose

• Cell mediated lysis associated with Infliximab– Infliximab has been shown to lyse cells which are

releasing TNF via an antibody dependant cell lysis

• Van den Brande, J et al. Gastroenterology 2003; 124: 1774-1785

ProinflammatoryResponse

Macrophage

InfliximabAdalimumab

InfliximabAdalimumab

Etanercept

Conclusion

• New therapies for sarcoidosis increase options

• A major target of therapy has become TNF

• New options include monoclonal antibodies against TNF

therapy for sarcoidosis

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