Download - 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
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
Alternatives to Corticosteroids
• Methotrexate• Leflunomide
• Azathioprine
• Cyclophosphamide
• Thalidomide
• Infliximab
• Hydroxychloroquine
• Minocycline
Cytotoxic Agents Cytokine Modulators
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
Alternatives to Corticosteroids
• Methotrexate
• Leflunomide
• Azathioprine
• Cyclophosphamide
• Thalidomide
• Infliximab
• Hydroxychloroquine
• Minocycline
Cytotoxic Agents Cytokine Modulators
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
T cell antigen receptor
Ag peptide
T cellActivation
IL-2; IFN-; IL-12; IL-18; TNF
TNF knock outmouse does notForm granulomas
APC
HLA Class
II
CD4
T cell antigen receptor
Ag peptide
T cellActivation
IL-10
IL-2; IFN-; IL-12; IL-18; TNF
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
Baughman and Lower Sarcoidosis 2001; 18: 70-74.
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)
Baughman and Lower Sarcoidosis 2001; 18: 70-74.
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