Scleroderma: Searching for the Cause and the Cure

transcript

SCLERODERMA: Searching for the Cause and the Cure

Maureen D. Mayes, MD, MPH Professor of Medicine

Director of the Scleroderma Program Division of Rheumatology

University of Texas - Houston

RESEARCH

1. Basic Science Research • Genetics

• Skin Biopsy Gene-Expression Studies

• Blood/Serum “biomarker” studies

2. Clinical Treatment Trials • Single-center “proof of concept” trial

• Multicenter, controlled trial to establish effectiveness

What Causes Scleroderma (systemic sclerosis, SSc)?

• Genetic Predisposition

• External “outside” trigger (Initiating Event) – Raynaud’s phenomenon

– Puffy/swollen hands

– Internal organ complications

• Persistence Factors

GENETIC PREDISPOSITION

Does scleroderma run in families?

THE SCLERODERMA REGISTRY AND DNA REPOSITORY

NIH/NIAMS sponsored study to identify susceptibility genes in SSc

Family 0977

201 202

101 102

203 204

SSc LimitedANA 1:80 SpeckledScl 70 -Date Raynaud's: 1991Date Dx: 1996Age Dx: 16

SSc LimitedANA 1:160 SpeckledScl 70 -Date Raynaud's: 1993Date Dx: 1995Age Dx: 22

Family 0766

101 102 103

205201 202 203

ANA +Date Dx: 1978Age Dx: 59

SSc LimitedANA 1:640 Centromere Scl 70 -Date Dx: 1988Age Dx: 47

SLE MS

WHAT GENES ARE INVOLVED?

46 Human

Chromosomes

in 23 pairs

(1 from Mom &

1 from Dad)

Wandstrat and Wakeland: Nature Immunol, 2001.

AUTOIMMUNITY REGIONS FROM GENOME SCANS 2001

GENOME-WIDE SCANS 2009

Genome-Wide Scan of 2,296 SSc patients and 5,171 healthy controls

Nature Genetics 42:426-9 (2010)

GENES in SCLERODERMA (SSc)

1. Immune-function related genes

2. Thus far ~30 recognized genes scattered among the chromosomes

3. Many of these same susceptibility genes are seen in lupus and rheumatoid arthritis

4. Having the “right” combination of genes is NOT ENOUGH to cause disease.

RAYNAUD’S PHENOMENON

RAYNAUD’S PHENOMENON: Pallor Phase

RAYNAUD’S PHENOMENON: Pallor and Cyanosis

What is Raynaud’s phenomenon?

• Spasm of the small blood vessels

• Exaggerated response to cold challenge

• Primary Raynaud’s Disease is common in the general population: 5 – 10% of U.S. adults

• Secondary Raynaud’s phenomenon occurs with scleroderma and other autoimmune diseases

Why do the hands get “puffy?”

• Small blood vessels are damaged and become “leaky”

• Usually involves the hands but sometimes also the feet

• As the blood vessels become more damaged over time, they become less leaky, the hands are less swollen and the skin gets thickened

WHAT CAUSES SKIN THICKENING?

• Increased collagen

• Produced by skin cells (fibroblasts) in the deep skin layers

• In normal conditions, the fibroblasts are only activated to produce collagen if there is a break in the skin scar production

• In scleroderma, the fibroblasts are activated spontaneously and remain so

WHAT CAUSES INTERNAL ORGAN INVOLVEMENT?

• Increased collagen – scar tissue/fibrosis: – Lungs pulmonary fibrosis

– Heart fibrosis in the conduction system or in the heart muscle

– Gastro-intestinal tract muscle is damaged so it no longer moves normally

• Blood vessel damage: – Scleroderma Renal Crisis

– Pulmonary hypertension

WHAT IS THE ROLE OF THE IMMUNE SYSTEM in SSc?

• Normally, the immune system fights off external invaders: bacteria, viruses, etc.

• In auto-immunity, the immune system no longer distinguishes between self and non-self

• In scleroderma, the immune system damages the blood vessels and “drives” the fibroblasts toward activation.

• There are dozens of different types of immune cells and hundreds of soluble factors

RESEARCH

1. Basic Science Research • Genetics

• Skin Biopsy Gene-Expression Studies

• Blood/Serum “biomarker” studies

2. Clinical Treatment Trials • Single-center “proof of concept” trial

• Multicenter, controlled trial to establish effectiveness

SKIN BIOPSY Gene Expression Studies

• Every cell contains ALL of a person’s genes • Not ALL genes are turned on in all tissues • The skin of scleroderma patients have different

genes “turned on” than the skin of healthy controls.

• These gene expression patterns can tell us what pathways to target or “turn off” to get scleroderma skin back to normal

• Medication that gets the skin back to normal should also get the lungs and other organs back to normal.

CLINICAL TREATMENT TRIALS

Why we need “controlled” trials

• The skin score in scleroderma tends to slowly improve over time – even without treatment

• Some patients never get significant internal organ involvement

• Even for those patients with internal organ involvement, sometimes it stabilizes on its own and does not worsen.

• So – we need a group who are on the “standard” therapy to compare with those on the “experimental” therapy

The Evidence: RANDOMIZED, PROSPECTIVE, PLACEBO/CONTROLLED Multicenter TRIALS FOR FIBROSIS

(skin or lung) in SSc

• U.S. D-Penicillamine • European/U.S. Sham-Controlled Photopheresis • U.S./Canadian Oral Methotrexate • U.K. Interferon-Alpha • U.S. Recombinant Human Relaxin • U.S. Oral Collagen Tolerance Trial • U.S. Anti-TGF beta Trial • U.S./Canadian/European BUILD 2 Trial • U.S. Cytoxan - Scleroderma Lung Study (SLS) • The ASTIS Trial of Chemotherapy and Stem-Cell Tx

RANDOMIZED, PROSPECTIVE, MULTI-CENTER CONTROLLED TRIALS FOR FIBROSIS

• U.S. D-Penicillamine (NEGATIVE)

• European/U.S. Sham-Controlled Photopheresis (NEGATIVE)

• U.S./Canadian Oral Methotrexate (NEG for Fibrosis, helpful for inflammatory features)

• U.K. Interferon-Alpha (NEGATIVE)

• U.S. Recomb Human Relaxin (NEGATIVE)

• U.S. Oral Collagen Tolerance Trial (NEGATIVE)

• U.S. Anti-TGF beta Trial (NEGATIVE)

• U.S./Canadian/Euro BUILD 2 Trial (NEGATIVE)

• U.S. Cytoxan - Scleroderma Lung Study (SLS) (POSITIVE)

• ASTIS (POSITIVE)

CURRENT MULTI-CENTER TRIALS

• Scleroderma Lung Study II : Cytoxan versus Mycophenolate (Cellcept)

• SCOT Trial: Cytoxan versus high dose chemotherapy and stem cell rescue

• Rituximab in Scleroderma PAH

• OTHERS

The Causes of SSc

What we know

What we don’t know

The Causes of SSc

What we know:

• Some genes increase susceptibility – but are not enough

• The Immune system is activated

• Small blood vessels start to narrow

• Deep skin cells (fibroblasts) increase collagen production

What we don’t know:

• The external trigger that starts the process

• The key points in the process that can be interrupted to stop the disease

CURRENT STATE of RESEARCH for TREATMENT

• Multiple ongoing clinical trials – more than I have seen in the past 30 years (1981)

• A well organized and collaborative group of dedicated scleroderma researchers

• Interest by pharmaceutical companies to tackle fibrosis in general and scleroderma in particular

WHAT YOU CAN DO

• Learn about the disease

• Keep track of your test results

• Ask questions

• Participate in research

Scleroderma: Searching for the Cause and the Cure

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