Making Sense of What we Read about Scleroderma Treatments

Kimberly WatkinsonSeptember 19, 2014

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.

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

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

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

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)**

2. Sources of Bias

• How was the study population selected?

• How were patients allocated to groups?

• Were the groups observed differently?

•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

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.

Sample size (n) Number of people who respond

% responders

4 1 25 %

20 5 25 %

100 25 25%

1000 250 25 %

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”.

“Proven Therapies” for scleroderma

• Interstitial Lung Disease (ILD)• Cyclophosphamide

• Skin• Methotrexate• Cyclophosphamide

Organ Drug Level of Evidence

Key benefit

Reference (trial)

Interstitial lung disease (ILD)

Cyclophosphamide Double-blind, randomized, placebo-controlled trialThe 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.

Scleroderma Lung Study II

• 2- year course of mycophenolate mofetil

compared to

• 1- year course of oral cyclophosphamide

Organ

Treatment Level of Evidence Key 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.

Organ

Treatment Level of Evidence Key Benefit Reference (trial)

Skin cyclophosphamide Double-blind, randomized, placebo-controlled trialThe 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.

Autologous Bone Marrow Transplantation

Rationale:

•Intense immune suppression followed by an immune reset

• Alter inflammation and autoimmune component

Patient

Stem Cell Collection

cryopreservation

High Dose therapy

Autologous Stem Cell transplantAutologous Stem Cell transplant

Thaw & reinfusion

1. Mobilize stem cells2. Stem cell collection3. High Dose therapy4. Give back stem cells

Evidence3 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)

SummaryStem 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.

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. ****

Antibiotic Protocol (AP)

• Based on theory that disease caused by mycoplasma infections.

• Many anecdotal reports of success

What is the evidence?

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

Health Professional perspective

• Evidence-Based Medicine background

• Role to recommend therapies with well-established efficacy

Patient perspective

•Don’t care about evidence

•Importance of hope

•Sense of control over life

•Personal preference

Reality

• A lot of research needed

• Limited evidence for current therapies

• Huge variability in disease course between patients

• Right disease to be open minded