HEMATOPOIETIC STEM CELL TRANSPLANTATION IN AUTOIMMUNE DISEASE

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• HEMATOPOIETIC
  STEM CELL TRANSPLANTATION IN AUTOIMMUNE
  DISEASE
• Dominique FargeThomas KozakZora Marjanovic

The European Group for Blood and Marrow
Transplantation
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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), Crohns disease,
  inflammatory arthritis as rheumatoid arthritis
  (RA) or juvenile idiopathic arthritis (JIA) and
  haematological immune cytopenia (HIC) could be
  difficult to treat

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• Dysthyroïdies
  Arthritis RA/JIA
• Sjögren
• PM DM CBI
• Scleroderma vasculitis
• 
  SLE

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INCIDENCE OF AUTOIMMUNE RHEUMATIC DISEASES
2 MAJOR TYPES OF AD Systemic Organ specific

• Sjögren RA SLE
  SSc 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

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HSCT for treating severe ADs

• The 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

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Disease Breakdown 1999 / 2004-2005
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LUPUS ERYTHEMATOSUS
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Types of Lupus
Systemic Lupus Erythematosus (SLE) Cutaneous
Lupus Erythematosus Drug-Induced Lupus Neonatal
Lupus
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Systemic Lupus Erythematosus

• - Systemic Lupus Erythematosus (SLE) is a chronic
  autoimmune disease that can be fatal, the immune
  system attacks the bodys 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)

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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

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SLE

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

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SLE

• Diagnosis made by a careful review of
• Current symptoms
• Laboratory test results
• Medical history
• Medical history of close family members
• American College of Rheumatology (ACR)
  Classification
• Criteria (1982)
• 4/11criteria, either at present or in the past
  - strong chance for lupus

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SLE

• ACR 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 1982251271-7.

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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

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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
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SLE

• Corticosteroids
• Hydroxychlorquine (Plaquenil)
• Aspirin
• Antimalarials
• Cytotoxics including cyclophosphamide,
  azathioprine, methotrexate
• Plasmapharesis/PE
• Thalidomide
• Anticoagulants
• Diaminodiphenylsulfone
• NSAIDs
• DHEA

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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 ?

SLEDAI RR 1-5 1.3 6-10
2.2 11-19 4.7 20 14.1
Survival n 207
Cook J Rheumatol 2000 Houssiau Arth Rheum
2004 Doria, Am J Med 2006 (35 disease,
activity, 64 infection )
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AMELIORATION du PRONOSTIC de la NEPHROPATHIE
LUPIQUE ? précoce et TT
FIEHN C Ann Rheum Dis 2003 62 435 (n 56)
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SLEDAI Score
Total score 1st January 2003 15 Urinary
casts (4) Proteinuria (4) Pyuria (4) Incr
eased DNA binding (2) Fever (1) -gt New drug
given 1st February 2003 15 Seizure (8) Proteinu
ria (4) Increased DNA binding (2) Leukopenia
(1) 1st March 2003 15 Lupus headache (8) Arth
ritis (4) Increased DNA binding (2) Leukopen
ia (1)
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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. 0Not present 1 Improving 2Same 3Worse 4New or recurrence. Or, Y/N or laboratory value where indicated
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SCLERODERMA ??????s ?????
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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

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Raynaud's phenomenon may precede scleroderma by
several years

• 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

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SCLERODERMA
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.
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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

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The limited form is often referred to as CREST
syndrome "CREST" is an acronym for the five
main features Calcinosis Raynauds syndrome
Esophageal dysmotility Sclerodactyly
Telangiectasia
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• 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

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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
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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
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Systemic Sclerosis
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Joints destructions in patient with Scleroderma
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Lung involvement in Scleroderma
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Right ventricular hypertrophy due to
pulmonaryfibrosis in Scleroderma
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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
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SURVIVAL ACCORDING TO VISCERAL INVOLVEMENT
Arthritis and Rhumatism, Altman 1991
Arthritis and Rhumatism, Steen 2000
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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)

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CROHNS DISEASE (2748 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.

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The three most common sites of intestinal
involvement in Crohn's disease ileal , ileocolic
and colonic
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Crohn's colitis showing deep ulceration
Pseudosacculations in Crohn's disease
Crohn's disease in the fundus of the stomach
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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

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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

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• 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

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Crohn's disease -Treatment

• 5-aminosalicylic acid
• steroids
• immunomodulators
• (azathioprine, mercaptopurine and
  methotrexate)
• infliximab (Remicade)
• adalimumab (Humira)
• natalizumab (Tysabri)

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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

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MED-A
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MED-A