Therapy for Sarcoidosis

1. Therapy for Sarcoidosis Robert P. Baughman MD Interstitial Lung Disease and Sarcoidosis Clinic University of Cincinnati

2. 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

3. 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

4. Meta Analysis of Steroids for Pulmonary Sarcoidosis: Improving Chest X-ray Paramothayan and Jones JAMA 2002: 287: 1301-1307

5. Patient with no pulmonary symptoms, on two years of prednisone. Prednisone recently tapered 20 mg prednisone 10 mg prednisone

6. Meta Analysis of Steroids for Pulmonary Sarcoidosis: DLCO Paramothayan and Jones JAMA 2002: 287: 1301-1307

7. Percent of Patients Requiring Initial Systemic Therapy Baughman and Lower Sarcoidosis 1998; 15: 19-20.

8. 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

9. Outcome of Patients in Philadelphia

10. 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 Sarcoidosis Baughman et al Am J Resp Crit Care Med 2001; 164: 1185-1189

11. Initial Corticosteroids Associated with Persistent Therapy Gottlieb JE et al Chest 1997;111:623-631

12. Risk Factors At Initial Visit Associated with Need for Treatment at Two Year Follow-up:Linear Regression Analysis of 205 patients in ACCESS study

13. Risk Factors At Initial Visit Associated with Need for Treatment at Two Year Follow-up:Linear Regression Analysis of 205 patients in ACCESS study

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

15. Methotrexate Leflunomide Azathioprine Cyclophosphamide Thalidomide Infliximab Hydroxychloroquine Minocycline Alternatives to Corticosteroids Cytotoxic Agents Cytokine Modulators Antimicrobials

16. Methotrexate Leflunomide Azathioprine Cyclophosphamide Thalidomide Infliximab Hydroxychloroquine Minocycline Alternatives to Corticosteroids Cytotoxic Agents Cytokine Modulators Antimicrobials

17. Hydroxychloroquine/Chloroquine • Antimalarial agent • Anti-inflammatory agent in rheumatoid arthritis • Useful in sarcoidosis • Skin disease • Hypercalcemia • ? Neurosarcoidosis

18. Randomized Trial Chloroquine versus Placebo for Chronic Sarcoidosis * P<0.05 Baltzan M et al. Randomized trial of prolonged chloroquine therapy in advanced pulmonary sarcoidosis. Am J Respir Crit Care Med 1999;160:192-197

19. 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

20. 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

21. 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

22. Methotrexate Leflunomide Azathioprine Cyclophosphamide Thalidomide Infliximab Hydroxychloroquine Minocycline Alternatives to Corticosteroids Cytotoxic Agents Cytokine Modulators Antimicrobials

23. 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.

24. Response to Methotrexate

25. 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 Lower et al Arch Intern Med 1997 Baughman et al Sarcoidosis

26. 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 Baughman et al Sarcoidosis 2000; 17: 60-66

27. 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

28. Ulcer on Tongue of Patient Taking Methotrexate

29. 20% 75% 5% Baughman and Lower Thorax 1999; 54: 742-746

30. Results of First 100 Liver BiopsiesNumber of Elevated AST values in prior yearPatients underwent 9 tests during year Methotrexate Sarcoidosis Negative Differences between groups by ANOVA, p<0.01. Baughman et al Arch Intern Med 2003; 163: 615-620

31. 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;

32. Results of Therapy * Number (percent responders) Baughman and Lower Sarcoidosis 2004; 21:43-48

33. 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

34. Hematologic abnormalities of sarcoidosis76 consecutive patients Lower et al.. Sarcoidosis 1988; 5: 512-55.

35. HepatoSplenic Involvement from Sarc

36. Methotrexate Leflunomide Azathioprine Cyclophosphamide Thalidomide Infliximab Hydroxychloroquine Minocycline Alternatives to Corticosteroids Cytotoxic Agents Cytokine Modulators Antimicrobials

37. 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

38. HLA Class II T cell antigen receptor APC T cell Activation Ag peptide CD4 IL-2; IFN-g; IL-12; IL-18; TNF

39. HLA Class II T cell antigen receptor APC T cell Activation Ag peptide CD4 IL-2; IFN-g; IL-12; IL-18; TNF TNF knock out mouse does not Form granulomas

40. HLA Class II T cell antigen receptor APC T cell Activation Ag peptide CD4 IL-2; IFN-g; IL-12; IL-18; TNF TNF; IL-8 IL-10 RESOLUTION FIBROSIS

41. Spontaneous Release of TNF by Alveolar Macrophages retrieved by BAL Untreated Sarcoidosis Treated Sarcoidosis Controls Smokers Controls Nonsmokers Baughman et al J Lab Clin Med 1990 115: 36-42

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

43. 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

44. TNF release of BAL Retrieved Alveolar Macrophages • Ziegenhagen et al Sarcoidosis 2002; 19:185-190.

46. 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 noted Baughman et al Chest 2002; 122: 227-232

47. Facial sarcoid before and after thalidomide

48. 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

49. First Three Infliximab Patients Baughman and Lower Sarcoidosis 2001; 18: 70-74.

50. First Three Infliximab Patients