HEMATOPOIETIC STEM CELL

TRANSPLANTATION IN AUTOIMMUNE DISEASE

Dominique FargeThomas Kozak

Zora Marjanovic

The European Group for Blood and Marrow Transplantation

Autoimmune Diseases (ADs):

- family of more than 100 heterogeneous diseases, which affect 5 to 8 % of the population worldwide

- characterised by aberrant activation of the immune system with failure of immune regulation to maintain adapted tolerance

- most patients can be treated with drugs suppressing the immune mediated inflammation, but when these fail or are too toxic, alternative strategies are needed

- severe forms of systemic ADs, such as multiple sclerosis (MS), systemic sclerosis (SSc), lupus erythematosus (SLE), Crohn’s disease, inflammatory arthritis as rheumatoid arthritis (RA) or juvenile idiopathic arthritis (JIA) and haematological immune cytopenia (HIC) could be difficult to treat

Dysthyroïdies Arthritis

RA/JIA

Sjögren

PM DM CBI

Scleroderma vasculitis

SLE

INCIDENCE OF AUTOIMMUNE RHEUMATIC DISEASES

Sjögren RA SLE SScSSc CBI Thyr

Prevalence ( pour 100. 000 ) 100 à 200 200 à 500 20 à 30 10

43 2000

Prevalence ( %) sicca syndrome 100 10 à 30 8 à 20 30

70 3

d’ après Sauvezie, Rev Prat 2001

2 MAJOR TYPES OF AD : SystemicOrgan specific

HSCT for treating severe ADsThe first consensus statement concerning the use of HSCT for treating severe ADs in 1995 stipulated:- the basic principles with regard to disease categories, patient selection, mobilisation, in vitro manipulation, conditioning and treatment

- Autologous was largely preferred to allogeneic transplantation due to lower risk of severe toxicity

- Patients should be considered for HSCT if: a) diagnosed with an AD severe enough to have an increased risk of mortality or advanced and irreversible disability; b) the ADs has been unresponsive to conventional treatments; c) the HSCT can be undertaken before irreversible organ damage, so that significant clinical benefit can be achieved

- Standard techniques, as used in autologous HSCT for haematological malignancies were employed

Transplants in 1999

RA28%

MS25%

JCA9%

Unknown2%

Vasculitis 1%

Wegener 2%

AIHA 3%

PM_DM 3%

SLE9%

SSc7%

ITP 2%

IBD1%

Transplants in 2004-2005

MS37%

Wegener1%

ITP 2%

IBD 2%

JCA 2%

RA 2%

Vasculitis 3%

Evan's 3%

SLE9%

SSc 24%

Unknown7%

Disease Breakdown 1999 / 2004-2005

LUPUS ERYTHEMATOSUS

Systemic Lupus Erythematosus (SLESystemic Lupus Erythematosus (SLE)

Cutaneous Lupus Erythematosus

Drug-Induced Lupus

Neonatal Lupus

Types of Lupus

Systemic Lupus Erythematosus - Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease that can be fatal, the immune system attacks the body’s cells and tissue, resulting in inflammation and tissue damage

- SLE can affect any part of the body, but most often harms the heart, joints, skin, lungs, blood vessels, liver, kidneys and nervous system

-The course of the disease is unpredictable, with periods of illness called flares, alternating with remissions

- Can occur at any age, most common in young women (9/1)

SLE

- Cause of the disease remains unknown

- There are three mechanisms by which lupus is thought to develop: genetic predisposition, environmental triggers and drug reaction

SLE

• Common symptoms :- fatigue- hair loss- sensitivity to the sun- painful and swollen joints- unexplained fever- skin rashes- kidney problems

SLEDiagnosis made by a careful review of:

•Current symptoms•Laboratory test results•Medical history•Medical history of close family members

American College of Rheumatology (ACR) ClassificationCriteria (1982)

• 4/11criteria, either at present or in the past - strong chance for lupus

SLEACR 1982 Classification Criteria:

• Malar Rash• Discoid Rash• Photosensitivity• Oral Ulcers• Arthritis• Serositis• Renal Disorder• Neurological Disorder• Hematological Disorder• Immunological Disorder• Antinuclear Antibody

Tan EM, et al. The 1982 Revised Criteria for the Classification of Systemic Lupus Erythematosus. Arthritis Rheum 1982;25:1271-7.

SLE• Antinuclear antibody (ANA) testing and anti-extractable nuclear antigen

(anti-ENA) form the mainstay of serologic testing for SLE

• Several techniques are used to detect ANAs

• Clinically the most widely used method is indirect immunofluorescence

• The pattern of fluorescence suggests the type of antibody present in the patient's serum

• Present in about 5% of the general population

• Indicates that the immune system is altered

• Nearly 100% of people with lupus are ANA positive

• Not everyone with ANAs develops lupus

SLE

As lupus erythematosus is a chronic disease with no known cure, treatment is restricted to dealing with the symptoms

This involves preventing flares and reducing their severity and duration when they occur

SLE• Corticosteroids • Hydroxychlorquine (Plaquenil®)• Aspirin• Antimalarials • Cytotoxics including cyclophosphamide, azathioprine,

methotrexate• Plasmapharesis/PE• Thalidomide• Anticoagulants• Diaminodiphenylsulfone• NSAIDs• DHEA

IMPROVED THERAPY OVER THE LAST 20 YRS in SLE

81% 1st remission, 1/3 relapse,

5- 10 % ERD at 5 - 10 yrs, 10 yr survival : 92 %

TT TOXICITY: infection

+ metabolic, bone, ovary dysfunctions

PROGNOSTIC FACTORS: Compliance,

Response 1st treatment **,

Race, socio-economic factor, HBP

Activity / Chronicity Index, SAPL

Initial Renal failure, Relapse nephritic ∑

0

5

10

15

20

25

30

perc

enta

ge

5 10

years

ESRF

Mortality

All SLE mortality

Survival °n= 207

SLEDAI RR*1-5 1.36-10 2.211-19 4.720+ 14.1

* Cook J Rheumatol 2000

** Houssiau Arth Rheum 2004 ° Doria, Am J Med 2006 (┼35% disease, activity, 64 %infection )

AMELIORATION du PRONOSTIC de la NEPHROPATHIE LUPIQUE: Δ précoce et TT

1980-1989 (group I)

1990-2000 (group II)

p Value

Patients (n) 15 41 Histological classification (WHO)

IV=9, II=2, III=1, V=2, VI=1

IV=32, II=7, V=2

Ns

High chronicy index 5 (33) 4 (10) 0.01 High activiy index 2 (13) 10 (24) 0.03 Crescent 5 (33) 20 (49) 0.04 Interstitial fibrosis 11 (73) 24 (59) 0.03 Tubular atrophy 12 (80) 30 (73) Ns Glomerulosclerosis 10 (67) 17 (41) 0.002

1980-1989(group I)

1990-2000(group II)

pValue

Patients (n) 15 41Cyclophosphamide 8 (53) 25 (61) Ns Oral 2 4 Bolus 6 15 Both 6Corticosteroids 15 (100) 41 (100) Ns Intermediate dose 9 24 Initial bolus 6 17Azathioprine 4 (27) 16 (39) NsCyclosporin A 3 (20) 4 (10) NsHydroxychloroquine 2 (13) 11 (27) NsMycophenolate mofetil - 1 (2)Antihypertensive 12 (80) 21 (51) 0.026ACE inhibitors 3 (20) 11 (27) NsStatins 3 (20) 10 (24) Ns

FIEHN C Ann Rheum Dis 2003; 62 : 435 (n = 56)

20

21

Total score1st January 2003 15 Urinary casts (4)

Proteinuria (4)Pyuria (4)Increased DNA binding (2)Fever (1)

-> New drug given1st February 2003 15 Seizure (8)

Proteinuria (4)Increased DNA binding (2)Leukopenia (1)

1st March 2003 15 Lupus headache (8)Arthritis (4)Increased DNA binding (2)Leukopenia (1)

SLEDAI Score

22

23

BILAG Index: 8 Systems

• General

• Mucocutaneous

• Neurologic

• Musculoskeletal

• Cardio-respiratory

• Vasculitis

• Renal

• Hematology

All features must be attributable to SLE, based on the scoring physicians “intention to treat,” and refer to last 4 weeks compared with prior disease activity.

0=Not present; 1 =Improving; 2=Same; 3=Worse; 4=New or recurrence.Or, Y/N or laboratory value where indicated

SCLERODERMA s +

SCLERODERMA• Scleroderma is a rare, chronic autoimmune

disease characterized by excessive deposits of collagen in the skin or other organs

• The primary finding in scleroderma is thickening and tightening of the skin.

• It is four times as common in women than in men

Raynaud's phenomenon is due to vasoconstriction of the small arteries of exposed peripheries - particularly the hands and feet - in the cold.

It is classically characterised by a triphasic colour change - first white, then blue and finally red on rewarming

Raynaud's phenomenon may precede scleroderma by several years

TWO broad categories:

“localized scleroderma” (not to be confused with limited) which indicates distinct skin lesions

“systemic sclerosis” which indicates similar skin symptoms and the potential for internal organ disease; the terms limited and diffuse refer to the extent of skin involvement.

SCLERODERMA

SCLERODERMA

The limited form is much milder:

- slow onset and progression, - skin hardening is usually confined to the hands

and face- internal organ involvement is less severe- much better prognosis is expected

The limited form is often referred to as CREST syndrome

"CREST" is an acronym for the five main features:

CalcinosisRaynaud’s syndrome Esophageal dysmotility Sclerodactyly Telangiectasia

Diffuse scleroderma or systemic sclerosis, the generalized type of the disease

- can be fatal as a result of heart, kidney, lung or intestinal damage

- in diffuse disease the skin changes can affect the whole body

- tightening of the skin around the fingers, the face and other areas of the body causing contractures (fixed joints) and a small mouth (microstomia), ulceration, dryness and irritation, broken blood vessels (telangiectasia) on the face and hands and calcinosis protruding through the skin

The internal organs can be affected in both limited and diffuse disease

Heart and lung involvement can also be associated with both forms, although the heart is not as commonly affected as the lung

Lung fibrosis is more common in diffuse patients

A small percentage (15%) of patients with limited form will develop pulmonary hypertension (PHT) a condition affecting the vessels taking blood from the right side of the heart to the lungs

The kidneys are rarely affected in limited disease, however approximately 5% - 10% of diffuse patients will incur some form of renal involvement

Organ INVOLVEMENT EXAMINATIONS

SKIN Scleroderma, necrosis Rodnan, ROM

Digestive tract Gatroesophagal reflux, telangiectasies, constipation/diarrhea , malabsorption, fecal incontinence

ENDOSCOPY, Blood cell count, ferritin, serum electrophoresis

LUNG Alvéolitis, fibrosis X RAY, LUNG FUNCTION TEST, WALKING TEST BLOOD GAZ, CT SCANN

PULMONARY VESSELS PHT ++++ Echocardiopgraphy, VIT LVEFG

right catheter if PHT

HEART fibrosis, conduction /rythm disturbances, necrosis, CY tox

EKG, 24 hr Holter EKG, Echocardiopgraphy

KIDNEY HYPERTENSION, RENAL CRISIS, incontinend

BP + Pulse, serum Creatinin, Urinary sediment and 24 hr protenuria

Neurologicla and pscyhiatric Anxio-depression Mental Status

Mucosal Dryness , sclerosis OPH, dental, gynecological

Genital Sclerosis, impotency Clinical examination

Systemic Sclerosis

Diffuse Cutaneous

Lim ited Cutaneous

pulmopnary hypertensionm alabsorption

Interm ediate

jo int contractures,GI, lung, heart, kidney

5 10 20

SK

IN T

HIC

KN

ES

S

Joints destructions in patient with Scleroderma

Lung involvement in Scleroderma

Right ventricular hypertrophy due to pulmonary

fibrosis in Scleroderma

Gastrointestinal System Related Symptoms

peptic stricture, or narrowing of the esophagus near the junction with the stomach due to chronic gastroesophageal reflux, the most common cause of dysphagia, or difficulty swallowing, in scleroderma

barium graphy: lower esophageal sphincter involvement small intestine and colon involvements

SURVIVAL ACCORDING TO VISCERAL SURVIVAL ACCORDING TO VISCERAL INVOLVEMENTINVOLVEMENT

Arthritis and Rhumatism, Altman 1991 Arthritis and Rhumatism, Steen 2000

SSC Treatment• Current therapies use medications that focus on the four

main features of the disease:

- Inflammation (NSAIDs or corticosteroids)

- Autoimmunity (methotrexate, cyclosporine, antithymocyte globulin, mycophenolate mofetil and cyclophosphamide)

- Vascular disease (calcium channel blockers, bosentan, prostacyclin, or nitric oxide)

- Tissue fibrosis (colchicine, para-aminobenzoic acid (PABA), dimethyl sulfoxide, and D-penicillamine)

CROHN’S DISEASE (27–48 per 100,000)

• Chronic, episodic, inflammatory bowel disease (IBD) that affects the entire wall of the bowel or intestines

• Crohn's disease can affect any part of the gastrointestinal tract from mouth to anus

• The disease is characterized by areas of inflammation with areas of normal lining

• The main gastrointestinal symptoms are abdominal pain, diarrhea, constipation, vomiting, weight loss

• Crohn's disease can also cause complications outside of the GIT: skin rashes, arthritis, and inflammation of the eye.

The three most common sites of intestinal involvement in Crohn's disease:ileal , ileocolic and colonic

Crohn's disease in the fundus of the stomach

Crohn's colitis showing deep ulceration Pseudosacculations in Crohn's disease

Crohn's disease

• Crohn's disease may also be classified by the behaviour of disease as it progresses (Vienna classification):

Stricturing disease causes narrowing of the bowel which may lead to bowel obstruction or changes in the caliber of the feces

Penetrating disease creates abnormal passageways (fistulae) between the bowel and other structures such as the skin

Inflammatory disease (or non-stricturing, non-penetrating disease) causes inflammation without causing strictures or fistulae

Crohn's disease• Many patients with Crohn's disease have symptoms for years prior to the

diagnosis

• The usual onset is between 15 and 30 years of age but can occur at any age

• Patients with Crohn's disease will go through periods of flare-ups and remission

• Gastrointestinal symptoms :- abdominal pain - diarrhea which may or may not be bloody,- symptoms caused by intestinal stenosis - vomiting and nausea may indicate the beginnings of small bowel obstruction- fever if abscess - weight loss

Complications:

• Obstruction typically occurs from strictures or adhesions which narrow the lumen, blocking the passage of the intestinal contents

• Fistulae can develop between two loops of bowel, between the bowel and bladder, between the bowel and vagina, and between the bowel and skin

• Abscesses are walled off collections of infection Crohn's disease also increases the risk of cancer in the area of inflammation

• Malnutrition• Malabsorption • Perforation• Hemorrhage

Crohn's disease -Treatment

• 5-aminosalicylic acid

• steroids

• immunomodulators

(azathioprine, mercaptopurine and methotrexate)

• infliximab (Remicade)

• adalimumab (Humira)

• natalizumab (Tysabri)

EBMT registry• The high number of procedures reported to EBMT registry

allows:

- a careful stratification for analysing outcomes on each AD diagnosis

- tight cooperation between transplant teams and the referring specialist is a key factor

- better selection and improved clinical management of the patients

- such a data may be important for further health care decision policy and would support the need for referring centres, with significant levels of activity and resources for adapted clinical care in treating rare ADs

MED-A

MED-A