1. Making Sense of What we Read about Scleroderma Treatments Kimberly Watkinson September 19, 2014

2. Objectives  Evaluate medical information found on the internet.  Understand some concepts of evidence-based medicine.  Be familiar with evidence behind scleroderma treatments, including stem cell transplantation.  Able to use knowledge to assist with making informed decisions.

3. Evaluating Medical Information on the Internet Who runs the Web site? What is the purpose of the site? What is the original source of the info? How is the info on the site documented? How is info reviewed before it is posted? Good sources: sites end in.gov;.edu;.org

4. Be wary of terminology such as “innovation”, “quick cure”, “miracle cure”, “exclusive product”, “new discovery”, “magical discovery”, “secret formula”, “suppressed by Government ”

5. Evidence Based Medicine (EBM) What is EBM: A decision-making framework that facilitates complex decisions. Considers research and evidence. Concepts: 1. Study design 2. Sources of bias 3. Sample size 4. Measures of precision

6. 1. Study design Descriptive Case study Observational Case-control (retrospective) Follow- up (cohort, longitudinal, prospective) Cross-sectional Experimental comparison groups, investigator **Randomized Controlled Trials (RCT)**

7. 2. Sources of Bias How was the study population selected? How were patients allocated to groups? Were the groups observed differently?

8. Randomization Blinding Single blind: when either the patient or investigator does not know Double blind: neither the investigator nor patient knows which group patient was allocated to. Controlling for bias

9. 3. Sample size (number of patients in study) There is uncertainty introduced by studying a “sample” of the population (random error). The larger the sample size, the more confident that the benefit of a treatment found in the study represents the true effect.

10. Sample size (n) Number of people who respond % responders 41 25 % 20 5 25 % 10025 25% 100025025 %

11. 4. Measures of precision P-values (P= ____) The smaller the P value, the stronger the evidence against the result being a fluke. P < 0.05 is considered “statistically significant”.

12. “Proven Therapies” for scleroderma Interstitial Lung Disease (ILD) Cyclophosphamide Skin Methotrexate Cyclophosphamide

13. OrganDrug Level of Evidence Key benefit Reference (trial) Interstitial lung disease (ILD) Cyclophosphamide Double-blind, randomized, placebo- controlled trial The Scleroderma Lung Study - sample size= 158 - cyclophosphamide oral versus placebo Less lung function decline (FVC) (P < 0.03); total lung capacity, less dyspnea, quality of life. No difference after 2 years. Tashkin, NEJM 2006; 354 (25): 2655- 266. Tashkin, Am J Respir Crit Care Med 2007; 176: 1026-1034. Double-blind, randomized, placebo- controlled trial - sample size= 45 - cyclophosphamide IV monthly plus low-dose prednisone versus placebo for 6 months followed by oral azathioprine Trend towards improvement in FVC (P= 0.08) Hoyles, Arthritis & Rheumatism 2006; 54 (12): 3962-3970. Unblinded, randomized trial - sample size= 60 - cyclophosphamide oral versus azathioprine, plus low-dose prednisone FVC and DLCO did not decline. Nadashkevich, Clin Rheumatol 2006; 25: 205- 212.

14. Scleroderma Lung Study II 2- year course of mycophenolate mofetil compared to 1- year course of oral cyclophosphamide

15. Organ TreatmentLevel of EvidenceKey Benefit Reference (trial) Skin methotrexate Double-blind, randomized, placebo-controlled trial - sample size= 71 - methotrexate oral versus placebo for 12 months Favorable effects on skin scores; improved by 10% in MTX group (P= < 0.009). Re-analyses: - 94% probability that beneficial effect on skin scores Pope, Arthritis & Rheumatism 2001; 44 (6): 1351-1358. Johnson, The Journal of Rheumatology 2009; 36 (2): 323- 329. Double-blind, randomized placebo-controlled trial - sample size= 29 - methotrexate IM versus placebo for one year 53% of the 15 patients in the methotrexate group responded favourably at 24 weeks (P=0.03) Trend towards improvement of total skin score (P= 0.06). Van den Hoogen, British Journal of Rheumatology 1996; 35: 364- 372.

16. Organ TreatmentLevel of EvidenceKey Benefit Reference (trial) Skin cyclophosphamide Double-blind, randomized, placebo- controlled trial The Scleroderma Lung Study - sample size= 158 - cyclophosphamide oral versus placebo Skin thickness score improved at 1 year (P= < 0.05) Tashkin, NEJM 2006; 354 (25): 2655- 266. Unblinded, randomized trial - sample size= 60 - cyclophosphamide oral versus azathioprine, plus low-dose prednisone Improvement of the MRSS at 12 months (P < 0.001) Nadashkevich, Clin Rheumatol 2006; 25: 205- 212.

17. Autologous Bone Marrow Transplantation Rationale: Intense immune suppression followed by an immune reset Alter inflammation and autoimmune component

18. Patient Stem Cell Collection cryopreservation High Dose therapy Autologous Stem Cell transplant Thaw & reinfusion 1.Mobilize stem cells 2.Stem cell collection 3.High Dose therapy 4.Give back stem cells

21. Evidence 3 randomized clinical trials: ASSIST Single center study Non-myeloablative conditioning regimen Results: all ten patients allocated to transplant improved (P= 0.00001) ASTIS Trial ongoing Multi-center study in Europe Non-myeloablative conditioning regimen SCOT Trial ongoing Multi-center study in North America Myeloablative conditioning regimen (includes TBI)

22. Summary Stem cell transplantation Most effective therapy shown to reverse skin fibrosis. Awaiting results of ongoing trials. Appears to change the natural course of scleroderma. Not a cure. Role in therapy likely for select patients: early diffuse systemic sclerosis at risk of early mortality exclusion of high-risk candidates.

23. Interpreting info Is there scientific evidence (not just personal stories) to back up the statements? **** However promising experiments in animals or anecdotal clinical experience, or how widespread, such observations can not predict the results of appropriately designed RCT. ****

24. Antibiotic Protocol (AP) Based on theory that disease caused by mycoplasma infections. Many anecdotal reports of success What is the evidence?

25. Antibiotic Protocol (AP) Open-label trial n= 9 Results at 1 year (Total skin score): 4 pts had complete resolution of their skin disease 2 patients no improvement 1 patient improvement

28. Health Professional perspective Evidence-Based Medicine background Role to recommend therapies with well- established efficacy

29. Patient perspective Don’t care about evidence Importance of hope Sense of control over life Personal preference

30. Reality A lot of research needed Limited evidence for current therapies Huge variability in disease course between patients Right disease to be open minded