Curs Reumatologie 14 Mai 2014 Final

Universitatea Titu Maiorescu
Rheumatology
INTRODUCTION

The Painters Family
Jacob Jordaens (1593-1678)

Evidence of:
Rheumatoid Arthritis
The Virgin with Canon van
Der Paele, 1436
Jan van Eyck (1385-1440)

Evidence of:
Temporal (Giant Cell)
Arteritis
Introduction to Rheumatology: Historical Perspective
4
Pierre-Auguste Renior
(1841-1919)
French, impressionist
1892 RA 51 yrs

5
6
Definition:

Rheumatologic (or Rheumatic) Disease:
diseases characterized by pain and inflammation
in joints and connective tissues, often referred to
as collagen-vascular diseases.
Joints (Synovial Joints)
The Normal Synovium
Function of Normal Synovium:
maintenance of intact non-adherent tissue
surface
lubrication of cartilage
control of synovial fluid volume and
composition (plasma and hyaluronan)
nutrition of chondrocytes within joints

General Concepts
Three major functions of the musculoskeletal
system:
Structural support
Motion
Metabolic
The five components of the musculoskeletal
system:
Muscles
Tendons
Ligaments
Cartilage
Bone
The macromolecular building
blocks of connective tissue:
Collagen
Elastin
Adhesion molecules
Proteoglycans
General Concepts
Rheumatology
Connective tissue disease (CTD) is a
major focus of rheumatology.
Rheumatic disease is any disease or
condition involving the
musculoskeletal system.
Arthritis means inflammation of one
or more joints.

Rheumatology (Contd)
Noninflammatory arthritis
(osteoarthritis) is not systemic. OA is not an
autoimmune disease.
Inflammatory arthritis:
Rheumatoid arthritis
Systemic lupus erythematosus
Autoimmune disease
Connective tissue disease that is
inflammatory
Diversity of Rheumatologic Diseases:
Inflammatory and Immune Responses
Inflammatory Diseases (innate immunity)
Osteoarthritis*
Gout*
Pseudogout

Immunologically-Mediated Diseases (adaptive immunity)
Rheumatoid Arthritis*
Systemic Lupus Erythematosus*
Spondyloarthropathies*
Ankylosing spondylitis
Reactive Arthritis (Reiters Syndrome)
Psoriatic Arthritis
Spondylitis associated with IBD
Sjogrens Syndrome
Polymositis/Dematomyositis
Lyme Disease
Rheumatic Fever
Behcets Syndrome
Systemic Sclerosis (Scleroderma)
Wegeners Granulomatosis
Giant Cell Arteritis*

ARA Classification of
Rheumatic diseases:
Systemic connective tissue d.
Vasculitides
Seronegative spondyloarthropathies
Infectious Arthritis
Metabolic, Endocrine, Hematologic
Arthropathies
Bone & Cartilage disorders
Hereditary, Congenital rheumatic d.
Soft tissue rheumatism
Musculoskeletal benign & malignant tumor
Miscellaneous rheumatic diseases

General Concepts
Acute vs Chronic Inflammatory Arthritis

Acute Arthritis
Rapid onset (hours or days)
Severe symptoms
Mediated by components of innate immune response,
especially neutrophils (proteases, leukotrienes,
prostaglandins, etc.)
Can result in rapid joint destruction
Can also evolve into chronic disease
Examples: Gout and Infectious Arthritis


Chronic Arthritis
More gradual onset (days to weeks)
Symptoms are more moderate, AM stiffness is a
prominent symptom
Mediated by the adaptive immune response,
especially T cells and macrophages - a Th1 disease
Cytokines and chronic inflammation lead to joint
remodeling and destruction via erosions

Examples: Rheumatoid Arthritis, Ankylosing
Spondylitis, SLE,
Lyme Disease

Inflammation Drives Arthritis
The inflammatory process results in damage to cartilage & bone
19
20
POLIARTRITA REUMATOID
Cel mai frecvent i mai studiat tip
de reumatism inflamator

Afeciune sistemic cronic
autoimun
articulaiile periferice simetric
simptome generale
afectare extra-articular

Key Features
Symmetric, inflammatory polyarthritis
Autoimmune
Females > Males
Symptoms > 6 wks
Morning stiffness > 1 hr
> 3 joints involved
Spares:
Thoracolumbar spine
DIP of fingers
Chronic autoimmune
disorder
Affects 1% of population
A symmetrical peripheral
polyarthritis of unknown
etiology that leads
to joint deformity &
destruction due to
erosion of cartilage &
bone
Autoimmune and Inflammatory Disorders:

Chronic systemic, inflammatory
disease characterized by recurrent
inflammation of connective tissue, primarily
of joints (diarthroidal) and related
structures.
One of the most common connective tissue
diseases and the most destructive to the
joints
Chronic, progressive, systemic inflammatory
autoimmune disease affecting primarily the
synovial joints
Autoantibodies (rheumatoid factors) formed
that attack healthy tissue, especially
synovium, causing inflammation
Affects synovial tissue of any organ or body
system
Principala leziune inflamaia sinovialei
articulaiilor diartrodiale:
articulaiile minii
articulaia radio-carpian
articulaia genunchiului
articulaiile piciorului

Evolueaz cu distrucia progresiv a
articulaiei i deformri articulare

Prognosticul pe termen lung rezervat
80% din pacieni prezint incapacitate funcional dup 20
ani
sperana de via scade cu 5 10 ani
POLIARTRITA REUMATOID etiologie
Factori genetici
HLA-DR4
HLA-DR1

Factori de mediu

Factori infecioi - ar determina modificri n
sistemul imun, ducnd la autoimunitate
Mycoplasma
virusul Epstein-Barr
virusul rubeolei, etc
etiologie
Statusul hormonal
Hormonii sexuali
afectarea predominent a sexului
feminin
ameliorarea simptomatologiei pe
perioada sarcinii
revenirea/ agravarea
simptomatologiei imediat
postpartum
inciden redus la femeile care
utilizeaz anticoncepionale orale

Hiperprolactinemia factor de risc
etiologie
Factori imunologici
limfocitele Th1 CD4 (produc IL-2 i IFN)

activeaz macrofagele i alte populaii celulare
fibroblastele sinoviale

citokine pro-inflamatorii TNF-, IL-1

inflamaie hiperplazia sinovialei i hiperactivitate
celular

panus (sinoviala inflamat, proliferare)
etiopatogenie
Principalele celule implicate n
patogenez:
1-limfocite Th1 CD4
2-mononucleare
3-fibroblaste
4-osteoclaste
5-neutrofile
6-limfocite B

Producie anormal de:
citokine
chemokine
mediatori ai inflamaiei
Pathophysiology Rheumatoid Arthritis

Normal antibodies (immunoglobulins)
become autoantibodies and attack host
tissues (RF)
Neutrophils, T cells synovial fluid cells acitavted;
Cystokines, interleukin-1 and TNR (tumor
necrosing factor) alpha; chrondroytes attack
cartilage;
Synovium digests cartilage; inflammatory
molecules released containing interleukin-1 and
TNF alpha
Pathogenesis of RA
RA Pathology
Celule B
Celule T
Celule
prezentatoare
de antigen
Celul B sau
macrofag
Sinoviocite
Panus
Cartilaj
Sintez de colagenaze i
alte proteaze neutre
IL-1 i
TNF- a Condrocite
Factor
reumatoid
Factori solubili
i contact
direct
celul-celul
Complexe imune
IL-1,
TNF-
a , etc
Macrofag
IL-1
Arend W. Semin Arthritis Rheum. 2001;30(suppl 2):1-6; Arend WP, Dayer J-M. Arthritis Rheum. 1990;33:305 - 315.
POLIARTRITA REUMATOID-SUMMARY
Stimul
(limfocite T?)
IL-1
TNF-a
IL-8
GM-CSF
IL-6
INFLAMAIE
Pathophysiology: Rheumatoid Arthritis

IgG/RF (HLA)= antigen-antibody
complex
Precipitates in synovial fluid
Inflammatory response
Cartilage connective tissue
primarily affected!

Choy, E. H.S. et al. N Engl J Med 2001;344:907-916
Pathogenesis of Rheumatoid Arthritis
Inflammed synovial tissue (synovitis)
Villous hyperplasia
Intimal cell proliferation
Inflammatory cell infiltration
T cells, B cells, macrophages and
plasma cells
Production of cytokines and proteases
Increased vascularity
Self-amplifying process

Joints changes with RA
Early Pannus
Granulation,
inflammation
at synovial
membrane,
invades joint,
softens and
destroys
cartilage

1-Mod advanced Pannus
joint cartilage disappears,
underlying bone
destroyed, joint
surfaces collapse

2-Fibrous Ankylosis
Fibrous connective tissue
replaces pannus; loss of joint
otion

3-Bony Ankylosis
Eventual tissue and joint
calcification
RA

Neutrofile
Osteoclaste
Os
Cartilaj
Osteoblaste
Condrocite
Os
T N F -
a I L - 1 b
Spaiul
sinovial
IL-6
PGE
2
IL-8
Venule
Membrana
sinovial
Capsula
Panus
Osteoblaste Osteoclaste
PGE
2
= prostaglandina-E
2
Proinflammatory and Anti-inflammatory Cytokines in Rheumatoid Arthritis:
A Primer for Clinicians.
-
Dinarello C, Moldawer L.
3rd ed. Thousand Oaks, CA, USA: Amgen Inc.; 2001; Dinarello C. Blood. 1996;87:2095
-
2147;
Gravallese E, Goldring S. Arthritis Rheum. 2000;43:2143 2151.
.
progresia bolii
Adapted with permission from:
Choy EHS, Panayi GS. N Engl J Med. 2001;344:907916.
Copyright 2001 Massachusetts Medical Society.
Formare de capilare
Membrana
sinovial
hiperplaziat
Sinoviocite
hipertrofice
Neutrofile
Celule T
Celule B
Poliartrita reumatoid precoce
Poliartrita reumatoid stabilizat
Vili sinoviali
Angiogenez
extensiv
Celule plasmatice
Panus
Os erodat
Neutrofile
Articulaie normal - genunchi
Capsula
Os
Membrana
sinovial
Sinoviocite
Cartilaj
Inflamaia sinovialei articulare
Distrucia cartilajului,
eroziuni osoase
Distrucia progresiv a articulaiei,
deformri articulare, invaliditi
Durere
Afectarea calitii vieii
.
www.cks.nhs.uk/.../rheumatoid_arthritis_arc
RHEUMATOID ARTHRITIS

PRESENTATION
LABS
IMAGING
MANAGEMENT
RA-Clinical Features
debut insidios simptome nespecifice + afectare
articular n cursul a ctorva sptmni

debut acut / subacut afectare articular n cteva zile
Tablou clinic
primele manifestri - vagi
simptome generale astenie, inapeten,
scdere ponderal, transpiraii, subfebriliti
parestezii
slbirea forei musculare
artralgii tranzitorii matinale, etc

oligoartrit simetric MCF, IFP
degete II, III
durere + redoare cu caracter inflamator
durere n a doua a nopii ameliorat de
micare
redoare matinal > 30 minute ameliorat de
micare
activiti zilnice reapariia durerii i a redorii
Tablou clinic - debut
semne de inflamaie
tumefiere
degete n fus prin tumefierea IFP
estomparea proeminenelor date de
capetele proximale ale MC cnd
pumnul e strns prin tumefierea MCF

sensibilitate la mobilizare
semn Gaensslen +
mini calde, tremurnde,
nendemnatice

fora de prehensiune

picioare se terge plica de flexie
dorsal de la baza degetelor
monoarticular
genunchiul

poliarticular articulaii
mari

unilateral

Mna reumatoid
Assessment RA
Deformities
that may
occur with
RA
Synotenovitis
Ulnar drift
Swan neck
deformity
Boutonniere
deformity
Mna reumatoid
Deformities with Osteoarthritis
Genuvarus
Herberdens nodes
Carpometacarpocarpal joint of
thumb with subluxation of the
first MCP
MTF degete II, III
dureri la mers
tumefierea dosului piciorului +
perimaleolar + baza degetelor
capetele distale ale MT pot ajunge n
contact cu solul caloziti plantare -
dureroase
IFP flectate n ciocan
deviaie peronier i/sau tibial a degetelor
Piciorul reumatoid
artrit mediotarsian:
picior plat dificultate la mersul cu
picioarele goale
durere la mobilizarea lateral a
piciorului

compromiterea flexiei dorsale mers
trit
Piciorul reumatoid
Piciorul reumatoid
Hammer toes

dureri la extensia antebraului
redoare dureroas n semiflexie +
semipronaie
Cotul
tardiv
dureri bilaterale - accentuate de
presiune
atitudine vicioas antalgic n
adducie + rotaie extern
ridicarea braului - limitat
Umrul
durere inghinal, fesier, lateral
limitarea abduciei, rotaiei
interne, extensiei
fals scurtare a membrului inferoir
oldul
dureri nocturne, la urcatul/
cobortul scrilor
tumefiere global
hidrartroz
extensia limitat
atitudine n flexum
chist Baker
Genunchiul
Mutlans deformity
(rapidly progressing
RA)
Hitch-hiker thumb
Genu valgus
cervicalgii
afectarea artic atlanto-axoidiene
laterale capul are o nclinaie
anteroar
luxaia atlanto-axoidian tergerea
lordozei cervicale + proeminena
apofizei C2 + ridicarea capului e dificil

durere la nivel occipital
parestezii la nivelul minilor i picioarelor
retenie urinar / incontinen
spasme musculare involuntare
Coloana cervical
Rheumatoid Arthritis is Systemic
Inflammatory Disease
Subcutaneous nodules
(disappear and appear
without warning)
RA Joint Involvement
manifestri sistemice nespecifice
astenie, fatigabiliate, inapeten, scdere
ponderal, subfebriliti
Manifestri extraarticulare
Manifestations of RA
Systemically ill
Hematologic
Pulmonary/CV
Neurologic
Ocular symptoms
(Sjorgens)
Skin
Musculoskeletal deformity,
pain
Pain!
Pain!
Pain
Extra-articular features
Neuromuscular
entrapment neuropathy, peripheral neuropathy,
mononeuritis multiplex
Hematologic
Feltys syndrome, large granular lymphocyte
syndrome, lymphomas
Pulmonary
pleuritis, nodules, interstitial lung disease,
bronchiolitis obliterans, arteritis, effusions
Others
Sjogrens syndrome, amyloidosis

tulburri trofice ale pielii la nivelul artic afectate
nodulii reumatoizi subcutanai
n zonele solicitate mecanic zone
extensoare
duri, insensibili, mobili
vasculit + ulceraii
miozit reumatoid mialgii, astenie, atrofie
miopatii iatrogene
pleurezie
plmn reumatoid multinodular
afectarea cilor respiratorii mici, bronit,
broniectazie
cardiomiopatie reumatoid
pericardit
valvulopatii
leziuni renale, digestive
anemie hipocrom, normocitar, hiposideremic
leucopenie + granulocitopenie n sdr Felty
adenopatii
neuropatii - senzitiv, senzitivo-
motorie, vegetativ
afectarea SNC - mielopatii
episclerit, keratit ulcerativ, etc
Sdr Felty splenomegalie + neutropenie
+ adenopatie + anemie +
trombocitopenie
evoluie
0 5 10 15 20 25 30
Durata bolii (ani)
S
e
v
e
r
i
t
a
t
e

Faza
timpurie
Faza
intermediar
Faza
tardiv
Inflamaie
Disfuncii
Radiologic
- evaluare
numrarea articulaiilor afectate tumefiate, respectiv dureroase

evaluarea subiectiv a durerii scala VAS

determinarea activitii bolii DAS

evaluarea strii de sntate, a statusului funcional i a calitii vieii
chestionare HAQ, SF-36, EuroQuol
diagnostic
Criterii revizuite de clasificare a PR (ACR 1987)
I. Principii de clasificare
A. Sunt necesare 4 din 7 criterii pentru a ncadra un pacient n categoria PR
B. Pacienii cu 2 sau mai multe diagnostice nu sunt exclui
II. Criterii*
A. Redoare matinal minim 1h
B. Artrit la 3 regiuni articulare
C. Artrit a articulaiilor minii
D. Artrit simetric
E. Noduli reumatoizi
F. Factor reumatoid n ser
G. Modificri radiografice
* Criteriile A-D trebuie s fie prezente timp de cel puin 6 sptmni. Criteriile
B-E trebuie s fie observate de un medic.
Clasificare clinico-funcional
Clasa I CF nealterat
Clasa II CF normal, dar cu durere i
redoare
Clasa III CF limitat, dar cu capacitatea de
a se autongriji
Clasa IV Infirmitate important
imobilizare la pat, incapacitate de
autongrijire
Stadializare
Stadiul I (precoce) nici un semn Rx
Stadiul II (moderat) osteoporoz distrucii osoase i
cartilaginoase
absena deformrilor articulare
atrofie muscular de vecintate
leziuni extraarticulare
Stadiul III (sever) leziuni distructive osoase + cartilaginoase
deformri axiale, fr anchiloz
atrofie muscular marcat
leziuni extraarticulare - noduli reumatoizi, tenosinovite
Stadiul IV (terminal) + anchiloz fibroas / osoas
Stage I:
Acute: synovial thickening; confined to joint capsule
Stage II:
Persistent inflammation c/c pain, joint damage
Stage III:
Inflammation and damage limiting joint function
Stage IV:
Permanent joint damage and deformity disability

Diagnostic Tests RA

ESR elevated

+ RA, ^ RA titer

Sed rate increased

CBC

C-reactive protein

Dec. serum complement

Synovial fluid inflammation

Joint and bone

Swelling,inflammation
Sdr inflamator
VSH >40-60mm/h
Fibrinogen
CRP
2-globuline, -globuline
Examene de laborator
Sdr disimunitar
Factor reumatoid IgM
Ac antipeptid citric citrulinat
diagnostic precoce naintea aparieiei
simptomelor
diferenierea de alte reumatisme inflamatorii
confirmarea diagn n PR seronegativ
corelaie direct cu evoluia
Ac antinucleari
CIC
complement normal
Examenul lichidului sinovial
lichid opac
leucocite 50 000-60 0000/mm3
75% PMN
ragocite
testul cheagului de mucin negativ
FR
RAAssessments Summary
Psychosocial assessment
Laboratory assessment
rheumatoid factor,
antinuclear antibody titer,
erythrocyte sedimentation rate,
serum complement,
serum protein
electrophoresis,
serum immunoglobulins
Other diagnostic assessmentsx-ray, CT, arthrocentesis,
bone scan
Acute Phase Reactants
Erythrocyte Sedimentation Rate (nonspecific)
C-Reactive Protein (CRP)
Fibrinogen
Serum Amyloid A (SAA)
Ceruloplasmin
Complement (C3, C4)
Haptoglobin
Ferritin
Other indicators: leukocytosis, thrombocytosis,
hypoalbuminemia, anemia of chronic disease
tumefierea prilor moi periarticulare
precoce
ngustarea spaiului articular
osteroporoz subcondral
eroziuni marginale geode,
pseudochiste
deformare articular, dezaxare
anchiloz
Radiologie
98
ABOUT
THE LABORATORY INVESTIGATIONS
IN RHEMATOID ARTHRITIS
We know that:
A negative test never rule out the
Dx
A test may be positive or negative
in a disease
A test may be positive in different
disease
A test may be positive in normal
population

Salehi I.
Lab. tests
Common Rheumatic Tests
Tests Sensitivity Specificity

Rheumatoid 80% 95%
Factor
Antinuclear 98% 93%
Antibody
Uric Acid 63% 96%
Rheumatoid Factor (RF):
Nonscreening for RA
Nonspecific for RA
Seen in many rheumatic and
nonrheumatologic diseases
Seen in normal population:
Young: 5%
Elderly subjects: until 25%
Positive RF nonequal to RA

Salehi I.
Lab. tests
Rheumatoid Factor (RF):
Negative predictive value:
For RA: until 89%
For any Rheumatic d.: until 85%
In higher titer:
Positive predictive value: increases
RF titer > 1/640:
Specificity for RA: 99%
Sensitivity for RA: 8%
It has prognostic value in RA
Salehi I.
Lab. tests
ESR : Introduced by Fahraeus 1918
Mechanisms: Rouleaux formation
Characteristics of RBCs
Shear forces and viscosity of plasma
Bridging forces of macromolecules. High MW fibrinogen tends
to lessen the negative charge between RBCs and promotes
aggregation.
Methods: Westergren method
Low ESR: Polycythemia, Sickle cell, hemolytic anemia,
hemeglobinopathy, spherocytosis, delay, hypofibrinogen,
hyperviscosity (Waldenstroms)
High ESR: Anemia, hypercholesterolemia, female,
pregnancy, inflammation, malignancy,nephrotic syndrome
Erythrocyte Sedimentation Rate (VSH)
Antinuclear Antibodies (ANA)
Virtually present in all SLE patients
Not synonymous with a Dx of SLE
May be present in other conditions:
Drug-induced (procainamide, hydralazine,
quinidine, TCN, TNF inhib.)
Age (3X increase > 65 yrs.)
Autoimmune disease
AIHA, Graves, Thyroiditis, RA, PM/DM,
Scleroderma, Antiphospholipid syndrome
Chronic Renal or Hepatic disease
Neoplasia associated
Ineffective screen for arthritis or lupus
Specificity enhanced when ordered wisely
ANCA: Anti-Neutrophil
Cytoplasmic Antibodies
C-ANCA, P-ANCA, myeloperoxidase (MPO),
proteinase-3 (PR3)
ANCA: antibodies that bind to enzymes
present in the cytoplasm of neutrophils.
Associated with several types of vasculitis.
C-ANCA: cytoplasmic staining. 50% to 90% sensitivity for
Wegener's
P-ANCA exhibits perinuclear staining. Less specific, 60% of
patients with microscopic polyarteritis and Churg-Straus
syndrome.
Anti-Perinuclear Factor Antibody (APF),
Anti-Keratin Antibody (AKA):
The most specific antibodies for
RA
React with CCP in the filaggrin
molecule
Anti-CCP has replaced these tests
More easier to perform than
More standardize than
Salehi I.
Lab. tests
RA Systemic Complications
Weight loss, fever, and extreme fatigue
Exacerbations
Pulmonary complications
Vasculitis
Periungual lesions
Paresthesias
Cardiac complications
RA- Therapy
-
RA
Nonpharmacologic
Interventions
-
RANonpharmacologic
Interventions
Adequate rest
Proper positioning
Ice and heat applications
Plasmapheresis
Gene therapy
Complementary and alternative
therapies
Promotion of self-care
Strategii terapeutice non-farmacologice
repaus reduce inflamaia i durerea articular
kinetoterapie exerciii pentru meninerea forei musculare i
a mobilitii articulare, fr exacerbarea inflamaiei.
managementul durerii masaj, stimulare electric transcutan,
acupunctur, etc.
imobilizare articular - pentru a evita micrile nedorite ale
articulaiilor inflamate i eventuale deformri.
orteze i mecanisme adaptative
educarea pacientului i a familiei acestuia.
modificarea stilului de via.

Puseu acut inflamator
scderea durerii i inflamaiei:
meninerea mobilitii articulare:
meninerea forei i rezistenei musculare
meninerea troficitii i supleei
structurilor capsulo-ligamentare i
tendinoase
repaus articular
repaus total
protejare articular
crioterapie
masaj cu ghea
tehnici de relaxare i reducerea stressului
educarea pacientului
repaus articular
- durerea i inflamaia
- previne deformrile articulare
- evit stresul articular
- redoarea articular

poziii funcionale:
umr abducie 45
art pumnului flexie dorsal 20-30
degete n uoar flexie
old abducie 45 (fr flexie!!)
genunchi extensie
picioare poziie neutr
Stadiu sub-acut
scderea durerii i inflamaiei
meninerea forei i rezistenei musculare
meninerea troficitii i supleei structurilor
capsulo-ligamentare i tendinoase

creterea amplitudinii de mobilizare
Stadiu sub-acut
mobilizri active ale articulaiilor
afectate
mobilizri active ale altor articulaii
contracii izotonice, cu rezisten uoar
Stadiu de inactivitate
termoterapie
antalgic, decontracturant, elasticitatea structurilor
periarticulare
naintea programului de kineto
10-20 min, 1-2x/ zi

electroterapie antalgic

masaj

hidroterapie

hidrokinetoterapie
Stadiu de inactivitate
kinetoterapie
creterea i meninerea mobilitii articulare,
creterea forei i rezistenei musculare,
creterea capacitii aerobice,
ameliorarea funciei biomecanice articulare,
creterea densitii minerale osoase,
ameliorarea funcionalitii,
reeducarea minii,
reeducarea mersului
mbuntirea strii generale a pacientului
Terapie ocupaional
meserii
legatul crilor;
cartonajul;
esutul de covoare;
mpletitul (nuiele sau textile)
munca de artizanat
jocuri cu bile;
sortatul de mrgele pe diferite mrimi;
nirarea mrgelelor pe srm sau a;
cusut, brodat
readaptarea la deprinderile i posturile uzuale, profesionale
(toaleta zilnic, mersul, scrisul, desenul)
reintegrarea n munc
RADrug Therapy
.
RADrug Therapy
Non Steridoian Anti-Inflamatory Drugs-
(NSAIDs)
Biologic response modifiers
Other drugs:
Glucocorticoids
Immunosuppressive agents
Gold therapy
Analgesic drugs
Terapia medicamentoas-Rezumat
AINS
neselective + inhibitori de pomp
protonic
inhibitori de COX-2 Celebrex,
Rofecoxib, Nimesulid,
Meloxicam,
inhibitori de 5-LOX
Terapia de fond
Metotrexat, Azathioprin
Sulfasalazin
Sruri de aur
inhibitorii sintezei de pirimidin!?
Terapii biologice DMARDs
inhibitorii sintezei de pirimidin!?
inhibitorii receptorului solubil de TNF-a
anti-TNF-a
antagonitii receptorului IL-1
Antalgice opioide
Tramal, Codein
Antalgice clasice
Ketoprofen
Co-antalgice
miorelaxante cu
aciune complex
ALGORITM PENTRU TRATAMENTUL
MODERN AL PR (I)
Diagnostic confirmat
(criterii ACR)
Evaluare iniial
(stadializare DAS)
Iniierea tratamentului
Msuri generale
(obligatorii)
Corticoterapie
(facultativ)
general
local
AINS
Clasice + inibitori de
pomp protonic
COX-2 selective
Evaluarea activitii bolii
(ACR, DAS)
6-8 sptmni
New Treatments for

.
Current Therapy of RA
NSAIDs, glucocorticoids
Terapii biologice DMARDs
DMARDS as methotrexate,leflunomide,
plaquenil, sulfasalazine
Newer biological agents with specific
molecular targets in RA pathogenesis:
TNF- antagonist/inhibitor
Interleukin (IL) inhibitor and receptor antagonist
B cell inhibitor (anti-CD20 antibodies)
T cell directed therapies
New molecules targeting JAKs


TNF- (Tumor Necrosis Factors )

antagonist/inhibitor
Introduction of Anti-Tumor
Necrosis Factor (TNF)

/
132
What is TNF?
Mode of TNF Inhibitor Action
Tumor Necrosis Factor:(TNF)
Functions of the Proinflammatory Cytokine
Stimulation of endothelial cells to express adhesion
molecules
Recruitment of white blood cells in inflamed synovium
and skin
Induction of inflammatory cytokine production
(e.g., IL-1, IL-6)
Stimulation of synovial cells to release collagenases
Induction of bone and cartilage resorption
Stimulation of fibroblast proliferation
135
TNF- Inhibitor Drugs
Anti-TNF Agents
Etanercept
Approved in the United States and Europe for
treatment of AS
Dose: 50 mg SC per week as two 25 mg injections
administered on same day or 3 to 4 days apart
Infliximab
Approved in Europe for treatment of AS
Dose: 5 mg/kg IV at week 0, 2, and 6 and every 6 to
8 weeks thereafter
137
TNF- Inhibitor
TNF- inhibitor binds TNF- and prevents
its interaction with its receptors
Many are monoclonal antibodies, some are
receptor fusion proteins
Therapeutic goal is the removal of TNF-
from inflammation sites
The first clinically successful, cytokine-
specific therapy for RA (Lasker Award
2003)
Used in combination with a DMARD
Rapid onset of action (expected effect or
improved symptoms in 1-3 weeks)
Adverse Effects of TNF-
Inhibitors
Injection site reactions
Increased risk of bacterial, viral, and/or
fungal infections
Bone marrow suppression
Generation of antibodies to drugs,
resulting in reduced efficacy over time
Drug-induced lupus-like syndromes
Emergence of lymphoma and skin
cancers over long-term use
Anti-TNF Agents: Summary
Anti-TNF agents target underlying inflammatory process
Alter disease progression
Provide symptomatic relief
Recommended treatment after trial of chronic daily NSAIDs,
physical therapy, and regular exercise
Good safety and tolerability profiles
Long-term data needed
Implement treatment guidelines to ensure proper treatment
given to appropriate patients
Treatment algorithm presented on next two slides
140

Newer biological agents with specific molecular
targets in RA pathogenesis:

Interleukin Receptor Inhibitors

Interleukins
The bodys immune response involves the activation
and release of cytokines (messengers) such as TNF
and interleukins, from macrophages
Leukocytes release a variety of interleukins to
communicate with additional leukocytes (hence the
name)
Perpetuate the immune response (inflammation)
IL-1 and IL-6 are particularly important as these the
both involved in some way with inflammation of the
joints
Macrophage IL-6
Macrophage and T-cells IL-1
142
Interleukin Receptor
Inhibitors
Usually only used if patient has not
improved after using other anti-
inflammatory medication such as
TNF antagonists
Should not be given while still
using TNF antagonists due to
adverse reactions that have been
observed
143
Interleukin Receptor
Inhibitors

Generic Name: Tocilizumab

Brand Name: Actemra
Interleukin receptor inhibitor,
specifically for IL-6 binding
Given intravenously on a per month basis
Dosage: usually 20mg/ml
Adverse Effects Include: risk of contracting
tuberculosis, reduced platelet level in blood, risk of
hypertension
144
Tocilizumab Mode of Action
Drug binds IL-6 receptors
Prevents cytokine IL-6 from binding receptor
Cell-to-cell communication is inhibited
Inhibits production of more T and B cells and aids to
decrease inflammation at the joints
145
Interleukin Receptor Inhibitors
In areas of body where IL are seen to be
uncontrolled and released with no threat from
invader, intensive tissue damage can be seen
IL receptor inhibitors have proved to be quite
successful in individuals with RA in relieving
inflammation
Additionally, shown to have beneficial effect
on preventing bone degradation in RA
patients as well
146


B-Cell Inhibitors

148
Regulating T-cell Activation
T-cell regulation occurs via the
Cytotoxic T-Lymphocyte Associated
Antigen-4 (CTLA-4) molecule
CTLA-4 acts as a negative regulator of
CD28-mediated T-cell stimulation
Antagonizes the CD80/CD86:CD28 binding
pathway by binding CD80/CD86
Greater affinity for CD80/CD86 than CD28
Leads to the down-regulation of T-cell
activation
B-Cell Inhibitors
B-Cell
Type of lymphocyte
Produces antibodies
Express Fc receptors
Express CD20 on cell surface
Phosphoprotein
Spans the membrane four times
Little known except it might function as a Ca
2+
ion channel
B-Cell Inhibitors
Why target B-cells?
Evidence for production of rheumatoid factor
(RF)
Autoantibody which binds to Fc region of IgG
Depletion of B-cells is accompanied by
reduction of inflammation
Secrete cytokines which interact with cells
involved in autoimmune response
Ie. TNF-alpha and chemokines
How to target B-cells?
CD20
Found exclusively on B-cells
Not shed from B cells
Expressed at high levels
B-Cell Inhibitors
Rituximab
Chimeric/fusion
protein
Antibody consisting
of human IgG-1
constant regions and
murine (mouse)
variable regions
Mouse variable regions
come from antibody that
recognizes CD20
Also binds to Fc
receptors
B-Cell Inhibitors
Complement-dependent cytotoxicity
(CDC)
Innate immunity
C1q
Serum protein which binds to Fc region rituximab
Triggers cascade resulting in C5b
C5b triggers membrane attack complex (MAC)
formation
MEC forms transmembrane channels in the
bilayer resulting in cell lysis
B-Cell Inhibitors
Antibody-dependent cell-mediated
cytotoxicity (ADCC)
Adaptive immunity
Natural killer (NK) cells, granulocytes,
macrophages all express Fc receptors of IgG
Once bound, lyse B-cell using respective
effector mechanisms

Induction of apoptosis
Little known about specifics


T-Cell Inhibitors

155
156
Overview of T-Cell Inhibitors
(Abatacept) Mechanism of Action
Blocking CD28-dependent Costimulation
Abatacept is a fusion of the extracellular domain of CTLA-4 (similar to CD28 but with higher affinity for CD80
and CD86) with the Fc fragment of IgG1 (for effector function and to prolong half-life)
From: Moreland
http://www.medscape.com/viewprogram/3415_pnt
158
Abatacept
Classified as a biological disease-modifying anti-
rheumatic drug (DMARD)
Used to treat RA in patients who had failed to
respond to other DMARDs or TNF inhibitors
Consists of the extracellular domain of CTLA-4
and a modified Fc fragment of IgG1 to prevent
antibody dependent cell-mediated cytotoxicity
Has a novel mechanism of action that mimics
CTLA-4s action
22
159
Effects of Abatacept
Inhibits the proliferation of T-cells in vitro
and in vivo
Reduces the amount of circulating
CD8+CD28- T cells, which suppresses the
number of CD4+T cells produced
Reduces adhesion and migratory capacity
of monocytes and the inflammatory activity
of synovial macrophages
Regulates the function of CD4+T cells
24
Orencia (abatacept)
anti-T cell agent


Janus Kinase Inhibitors (JAKs)

Inhibit the activity of the janus kinase (JAK)
family to down regulate inflammatory
reactions

162
Janus Kinase Inhibitors
(JAKs)
New molecular approach to treating RA
Inhibit the activity of the janus kinase
(JAK) family to down regulate
inflammatory reactions
JAK inhibitors include:
Tofacitinib
VX-509 (Vertex)
Baricitinib

Summary of RA Treatment

SUMMARY Therapeutic Strategies
Reagents that blunt inflammation but dont have effects on disease progression:
Aspirin
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Non-selective and selective COX-2 antagonists
Steroids (prednisone)

Disease Modifying Anti-Rheumatic Drugs (DMARDs):
Broad Acting:
Methotrexate
Hydroxychloroquin
Azathoprine
Cyclophosphamide
Cyclosporin
More selective biologics:
TNF antagonists
IL-6R antagonists
IL-1R antagonists
anti-B cell (CD20) therapy
costimulatory inhibitors (CTLA4-Ig)
Intravenous Immunoglobulin (iv Ig)

Biological Therapeutics
Targets, Rationale, Status
Summary

Updated Therapy for RA

1st-Low dose corticosteroids - short/long
term
1st -Methotrexate - long term
2nd - Leflunomide - long term
2nd - Anti-TNF Agents (anti-Tumor
Necrosis Factor) - best overall therapy
3rd - Kineret (anakinra) - IL-1 receptor
3rd - Orencia (abatacept)- anti-T cell
agent
3rd - Rituxan (Rituximab) anti-B cell
therapy
1st-3rd - Corticosteroid joint injections
4th - Reconstructive surgery
Severe
systemic
illness
Bridge therapy
Corticosteroids are not part of the medical
treatment of RA except in very selected
situations as:
RA is an auto-immune disease with upstream mechanisms of activated
macrophages, activated B cells and activated T cells; resulting in
downstream cytokine production and destruction signaling pathways.
Activated macrophages secrete (downstream) inflammatory cytokines
TNF-, and IL-6 and IL-1.
TNF- inhibitors etanercept, infliximab, adalimumab
IL-6 receptor antagonist tocilizumab
IL-1 receptor antagonist anakinra
Activated B cells contribute to inflammation and destruction by
producing autoantibodies (RF) and cytokine IL-6
Bind to CD20 antigen on B Cell and depletes B cells rituximab
Activated (CD4+) T cells activate macrophages and B cells
Upstream regulation of T Cell activation pathway abatacept
Downstream signaling pathways (RANK, MMPs)
JAK inhibitors to down regulate inflammatory responses
tofacitinib

170
Of ,ce greu!
Ankylosing Spondylitis
I. Definiie, generaliti
Boal inflamatorie cronic, ce afecteaz
predominat articulaiile sacroiliace (sacroileit) i
pe cele ale coloanei vertebrale
Spondilatropatie sero-negativ

PREVALENA
0,5-1% n populaia general
raport B:F = 3:1
debut decadele II, III i IV de via
Definitions: chronic
inflammatory
polyarteritis of spine
Affects mostly young
men
Associated with HLA-
B27 antiget positive
antigen (90%)
Pathophysiology &
Manifestations

Like arthritis have
inflammatory changes;
erosion of cartilage,
ossification of joint margins;
scar tissue replaces
Morning backache, flexion
of spine, decreased chest
expansion
Diagnosis
ESR elevation
Positive HLA-B27 antigen
Vertebral changes

II. Etiopatogenia
incomplet cunoscut
terenul genetic
agregare familial
marker HLA B27 (90% din cazuri, fa de 4-7% n
populaia gen.)
factorii de mediu infeciile intestinale (klebsiella)
mecanism imun:
Ig A
reactanii de faz acut
tablou histologic de tip inflamator (Ly CD4+, CD8+)
TNF local
Ag ar putea proveni din cartilaj (proteoglicani)
Ag analog cu tractul uveal, aortic
III. Morfopatologia
Inflamaie cronic articular i periarticular
~ iniial: hipervascularizaie i infiltrare
celular (L, M, fibroblati)
~ eroziuni
~ vindecare: fibroz i osificare

Consecine
- erodarea cartilajelor afectate,
- nlocuirea esutului de granulaie cu fibrocartilaj
de regenerare i osificare ulterioar

Chronic disease that primarily affects
the spine and may lead to stiffness of
the back. The joints and ligaments
that normally permit the back to
move become inflamed. The joints
and bones may grow (fuse) together.
The effects are inflammation and
chronic pain and stiffness in the
lower back that usually starts where
the lower spine is joined to the pelvis
or hip.
Diagnosis is made through: (a)
medical history including symptoms,
(b) X-rays, and possibly (c) blood tests
for HLA-B27 gene
Comparison
of changes
with
ospeoporosis
and
Ankylosing
spondylitis
Identify a
PRIORITY
nursing
concern
related to
ankylosing
spondylitis
Sacroiliitis
Sacroiliitis is an inflammation
of the sacroiliac joint.
Symptoms usually include a fever
and reduced range of motion.
Picture on the bottom right
shows an individual with
sacroiliitis and Ankylosing
Spondylitis. The arrows point to
the inflamed and narrowed SI
joints. They are white due to
bony sclerosis around the joints
Sacroiliitis
Sacroiliitis is an inflammation
of the sacroiliac joint.
Symptoms usually include a fever
and reduced range of motion.
Picture on the bottom right
shows an individual with
sacroiliitis and Ankylosing
Spondylitis. The arrows point to
the inflamed and narrowed SI
joints. They are white due to
bony sclerosis around the joints
Treatment options:
With early diagnosis and
treatment, pain and stiffness
can be controlled and may
reduce fusing. In women, AS
is usually mild and hard to
diagnose.
Exercise
Medications: NSAIDs,
Sulfasalazine
Posture management
Self-help aids
Surgery
art. SI: sacroileita
art. CV: nesinoviale (cartilaginoase): intervertebrale
vertebra patrat
sindesmofitul (prin calcificarea inelului fibros)
calcificarea ligamentului intervertebral anterior
i
sinoviale (diartrodiale): interapofizare
costovertebrale
art. periferice, centurile

Entezita (inflamaia zonelor de inserie pe
os a ligamentelor, aponevrozelor, fasciilor)

manifestri extraarticulare: ochi (uveit
anterioar), cord (insuficien aortic),
colon, plmn, sistem nervos, rinichi
(nefropatie cu IgA, amiloidoz)
Articulaiile
afectate
n
spondilatropatiile
seronegative
IV. Tabloul clinic
Debut :
insidios, la sfritul adolescenei sau la adultul tnr < 40 ani
durere lombosacrat sau fesier, cu caracter inflamator
(diminuat de exerciiu, neameliorat de repaus, apare de
regul n a 2-a jumtate a nopii)
persistent: 3 luni
redoare matinal
+/- radiculalgie sciatic pn n spaiul popliteu, bilateral,
alternant = sciatica nalt, n bascul
artrite periferice (art. mari)- rare
talalgii (entezite)
semne generale: fatigabilitate, anorexie, febr, scdere
ponderal, transpiraii nocturne

Perioada de stare
intensificarea durerilor din faza anterioar i extinderea
teritoriului afectat: lombosacrat toracic cervical
(tardiv)
redoare art. prelungit

Examenul fizic, pe segmentele afectate
tergerea lordozei lombare fiziologice
contracturi ale m. paravertebrale
SacroiIiace: provocarea dureri prin presiune direct

Col. vert. lombar:
- aprecierea indicelui degete - sol
- testul Schober = 2 repere osoase (apofiza spinoasa L5 i
10 cm mai sus) + anteroflexia CV = normal, cretere a
distanei cu > 5 cm
Col. vert. toracica: limitarea expansiunii cutiei toracice: < 5
cm
Col. vert. cervicala: manevre occiput-perete, menton-stern,
nclinri laterale, micri de rotaie
Semne din partea organelor extraarticulare afectate:
uveit anterioar acut: poate precede spondilita, tendina spre
recuren, sechelar (cataract, glaucom)

aortit cu insuficien aortic, BAV grd III

fibroz pulmonar

semne renale

manifestri neurologice (subluxaie atlantoaxoidian)

Stadiul avansat

deformarea CV (cifoz) +/- coxita
anchiloza articular i invaliditate

Ankylosing Spondylosis
Ankylosis= Fusion across a joint
Spondylosis= Inflammation
Sacroiliac and Vertebral joints
Affects Young Males (Age 20-40Yrs), 3-5x>more
common in Men.
Anterior Uveitis (40%), Other Tendon/Joint
involvement
Unknown Aetiology
Hereditary Tendency
HLA-B27 (9/10 with AS are +ve)
196
Ankylosing
Spondylitis
Insidious
onset
Morning
backache
Inflammation
of spine; later
spine
ossification

Oh my back hurts!

198

199
Prognosis
Good..intermittent flare ups, mild-moderate
severity
Regular exercise (Low impact)+ Analgesia to
control symptoms
Gradually increasing stiffness with age
8/10 remain fully independent with limited
disability (despite eventual spinal restriction)
1/10 severe form AS...Anti-TNF Rx promising
Extra-axial:
Lung Fibrosis Restrictive defects, Parasthesia,
Amyloidosis, AR, Enthesopathy etc..

200
V. Explorrile paraclinice
teste inflamatorii: VSH, Fi, PCR, alfa 2
globuline

teste imune: IgA, complexe imune, absena
FR

HLA B27 nu este un test de rutin

HLA-B27
Class I MHC Ag, associated with the
spondyloarthropathies
Ankylosing spondylitis, Reiter's syndrome, Psoriatic
arthritis, and enteropathic arthritis.
HLA-27 is found in up to 8% of normals
3-4% of African-Americans, 1% of Orientals.
Increased risk of spondylitis and uveitis.
Indications: may be used infrequently as a diagnostic test
in AS, Reiters, Psoriatic arthritis
Examenul radiologic
semne precoce: art. sacroiliace i jonciunea dorsolombar
I. Sacroileita bilateral
std I = suspiciune de sacroileit- aspect ters al articulaiei
std II = sacroileit minim- lrgirea spaiului art. (eroziuni
subcondrale de pe cele dou versante art.= ,,margine de
timbru potal)
std III = sacroileit moderat- diminuarea interliniei
articulare (prin osteocondensare)
std IV = anchiloz cu dispariia spaiului articular, prin
fuziunea versanilor art. sacroiliace

II. Coloana vertebral
Sindesmofitul - fin, orientare vertical, se menine n acelai
ax cu CV (osteofitul este grosolan, are orientare transversal
i se ndeprteaz de axul CV)
precoce la T10
calcificarea inelului fibros

Vertebra ptrat - pe rgr. lombar de profil (pierderea
concavitilor, prin eroziunea marginilor corpilor vertebrali)

Rectitudinea coloanei vertebrale

Coloana de bambus = tardiv, sindesmofite + anchiloza art.
interapofizare + calcificarea ligamentelor interspinoase

inele de tramvai cu firul electric

Entezita= spiculi osoi la nivelul calcaneului, crestei iliace,
marelui trohanter, ramurii ischiopubiene

Alte explorri
CT (permite un dg. precoce)
RMN
Scintigrafie cu techneiu (Tc99)
Diagnosis
History:
Persistent, grumbling episodes of Back pain and
Index of suspicion.
Differentiate from Mechanical Back Pain.

Investigations:
Bloods
Inflammatory Markers in acute phase
X ray
Sacroiliitis,Bamboo spine fusion, Delayed changes
MRI
Earlier changes, inflammation of SIJ
209
Criteriile Van der Linden, 1984
Criterii clinice
1. Durere lombar joas i redoare, cu durata de cel puin 3
luni, diminuat de efortul fizic i neameliorat de repaus
2. Limitarea micarilor coloanei lombare, n plan sagital i
frontal
3. Limitarea expansiunii cutiei toracice
Criteriu radiologic
4. Sacroileita bilateral stadiul II-III sau unilateral stadiul III-IV
Diagnostic: prezena sacroileitei + 1 criteriu clinic
VI. Diagnosticul pozitiv
VII. Diagnosticul diferenial
hernia de disc: debut brusc, calmat de repaus, RMN
spondiloz
neoplaziile, discitele, sacroielita septic
ileita condensant
celelalte spondilartropatii seronegative (boala Crohn,
rectocolit ulcero-hemnoragic, psoriazis)

VIII. Evoluia i prognosticul
evoluie indelungat, cu exacerbri i remisiuni (spontane sau
terapeutice), cu att mai grav cu ct debutul bolii este mai precoce

fr tratament: modificri caracteristice ale posturii prin anchiloza
articulaiilor coloanei vertebrale cu: tergerea lordozei lombare, atrofia
m. fesieri, cifoz toracic, aplecarea nainte a capului, flexia
genunchilor compensatorie pentru afectarea oldului

prezena manifestrilor extraarticulare agraveaz prognosticul

complicaii: sindrom de coad de cal, fracturi vertebrale, fibroz
pulmonar, amiloidoz
IX. Tratamentul
Obiective:
1. Sedarea durerii
2. Reducerea inflamaiei
3. Meninerea mobilitii CV
4. Prevenirea anchilozei

Mijloace:
1. Tratament igieno-dietetic
2. Tratament medicamentos
3. Tratament chirurgical
Treatment options:
With early diagnosis and
treatment, pain and stiffness
can be controlled and may
reduce fusing. In women, AS
is usually mild and hard to
diagnose.
Exercise
Medications: NSAIDs,
Sulfasalazine
Posture management
Self-help aids
Surgery
Tratament igienodietetic

regim alimentar bogat n vitamine, hiposodat
n perioada adm. AINS
gimnastic medical, sporturi (notul)
repausul la pat (dormitul) se va face pe un
plan tare

Tratament medicamentos
AINS
neselective
indometacin (75-100 mg/24 de ore), fenilbutazon
diclofenac, piroxicam
selective:
meloxicam (Movalis 7,5-15 mg/24 de ore),
specifice:
celecoxib (Celebrex 200 mg/24 de ore)

Glucocorticoizii
- per os au efecte reduse

- administrai local (intraarticular,
intralezional) au efecte bune

- parenteral, n pulsterapie (metilprednisolon),
rezervat cazurilor cu manifestri severe

- irit-local

Tratament de fond

- n sacroileita cu manifestri periferice
methotrexat (7,5-15 mg/sptmn)
sulfasalazin (2-3g/24 de ore)
ciclofosfamid n pulsterapie ptr. cazurile
severe
Inhibitorii TNF (infliximab, etanercept) foarte
eficieni n remisiunea fenomenelor inflamatorii

Introduction of Anti-Tumor
Necrosis Factor (TNF)

Agents for the Treatment of Ankylosing
Spondylitis

US Modifications of the ASAS International Guidelines
for Use of Anti-TNF Agents
219
Tumor Necrosis Factor:(TNF)
Functions of the Proinflammatory Cytokine
Stimulation of endothelial cells to express adhesion
molecules
Recruitment of white blood cells in inflamed synovium
and skin
Induction of inflammatory cytokine production
(e.g., IL-1, IL-6)
Stimulation of synovial cells to release collagenases
Induction of bone and cartilage resorption
Stimulation of fibroblast proliferation
220
Anti-TNF Agents
Etanercept
Approved in the United States and Europe for
treatment of AS
Dose: 50 mg SC per week as two 25 mg injections
administered on same day or 3 to 4 days apart
Infliximab
Approved in Europe for treatment of AS
Dose: 5 mg/kg IV at week 0, 2, and 6 and every 6 to
8 weeks thereafter
221
Anti-TNF Agents: Summary
Anti-TNF agents target underlying inflammatory process
Alter disease progression
Provide symptomatic relief
Recommended treatment after trial of chronic daily NSAIDs,
physical therapy, and regular exercise
Good safety and tolerability profiles
Long-term data needed
Implement treatment guidelines to ensure proper treatment
given to appropriate patients
Treatment algorithm presented on next two slides
222
Treatment
Ease Pain, reduce stiffness, maintain mobility
Physiotherapy + NSAIDS for flare ups
Immunosuppressant Drugs:
Biological Therapies
TNF-Alpha Blockers Monoclonal AB (Etanercept,
Infliximab)
NICE: Adalimumab/Etanercept for severe AS +
Active spinal disease (assessed 2x 12 weeks apart
Have tried at least 2 NSAIDs ineffectively
Immunomodulators
Suppression of the immune response
(Sulphasalazine) ?Effectiveness in AS

223
Tratament ortopedico-chirurgical
osteotomii
artroplastii (proteze de old)
Systemic Lupus
Erythematous (SLE)
Systemic Lupus Erythematous
(SLE)
Chronic multisystem disease
involving vascular and connective
tissue
Definiie
LES este o boal autoimun cu manifestri
multisistemice, mediate de anticopri
antitisulari i de complexe imune.
Definition
-An inflammatory multisystem disease of unknown etiology
with protean clinical and laboratory manifestations and a
variable course and prognosis
.
-Immunologic aberrations give rise to excessive
autoantibody
production, some of which cause cytotoxic damage, while
others participate in immune complex formation resulting
in immune inflammation.
Systemic Lupus Erythematosus
(Lupus)-Background
Lupus
Systemic lupus erythematosus (also
called SLE, or lupus) is an
autoimmune disease of the body's
connective tissues. Autoimmune
means that the immune system
attacks the tissues of the body. In
SLE, the immune system primarily
attacks parts of the cell nucleus.

SLE affects tissues throughout the
body. Five times as many women as
men get SLE. Most people develop
the disease between the ages of 15
and 40, although it can show up at
any age.

Lupus Anatomy (cont).
The inflammation of SLE can be seen in the
lining, covering, and muscles of the heart.
The heart can be affected even if you are not
feeling any heart symptoms. The most common
problem is bumps and swelling of the
endocardium, which is the lining membrane of
the heart chambers and valves.
SLE also causes inflammation and
breakdown in the skin. Rashes can appear
anywhere, but the most common spot is across
the cheeks and nose.
People with SLE are very sensitive to
sunlight. Being in the sun for even a short
time can cause a painful rash. Some people with
SLE can even get a rash from fluorescent lights.
Rashes caused by SLE are red, itchy, and painful.
The most typical SLE rash is called the
butterfly rash, which appears on the face
particularly the cheeks and across the nose. SLE
can also causes hair loss. The hair usually grows
back once the disease is under control.

Characteristic
butterfly
rash associated
with SLE,
especially
discoid lupus
erythematous
.
,
-
Lupus Anatomy
Lupus can also affect the nervous system
causing headaches, seizures, and organic
brain syndrome.
It can cause anemia due to blood loss or from
the kidney disease (it does not directly effect
the red blood cells).
Pregnancy: the chances of miscarriage,
premature birth, and death of the baby in the
uterus are high.
Etiology and Pathophysiology SLE
Exact etiology unknown: genes
(HLA), hormones, environment
involved
Formation auto-antibodies;
immune complexes deposited
Inflammatory response
triggered by deposition of
immune complexes (kidney,
brain)
Drug induced syndrome similar
to SLE (Procan-SR, hydralazine,
isonaiazid)
Pneumonia, infections, *renal,
CNS involvement!;
Course of disease varies
Mild
Episodic
Rapidly fatal
Epidemiologie
incidena bolii = 4-250 / 100.000
raport femei: brbai= 8/1 - 13/1
grupa de vrst cea mai afectat = decada II-IV de via
Etiologie Necunoscut!

1. Predispoziie genetic
- agregarea familial
- gemeni monozigoi
- asocierea cu HLA-DR2, DR3, A1, B8

2. Factori hormonali
- niveluri mai crescute ale metaboliilor estrogenilor
- agravare dup administrare de contraceptive
Etiologie
3. Factori de mediu
- ageni infecioi (virali, microbieni)
superantigenele microbiene: grup de toxine microbiene ce
acioneaz fr intermediul celulelor prezentatoare de antigeni, induc
activarea LiT, stimularea LiB, eliberarea de limfokine
- radiaii UV
- medicamente: hidralazin, procainamid, izoniazid,
clorpromazin, alfa-metildopa, fenitoin
Patogenie
1. Autoanticorpi
- antinucleari (95%); specifici: AAN ce reacioneaz cu ADN
dublu catenar
- mpotriva unor anitgene nucleare extractibile (anti-RNP, anti-
Sm)
- atc anti SS-A (anti-Ro), anti SS-B (anti-La)
- anticelule sanguine circulante
- antiproteine solubile (anticardiolipin, anticoagulani
circulani, antireceptor de insulin)
Patogenie
2. Leziuni imune
- Produse de autoatc specifici
determin liz celular (celule circulante, renale,
nervoase)

- Produse de complexe imune
- acestea se depun n diverse esuturi, este
afectat epurarea lor
- apare activarea complementului care devine
citotoxic i duce la leziunile inflamatorii
caracteristice
Procesele imune perturbate determin o inflamaie
cronic, localizat n diverse organe i esuturi:
- rinichi: glomerulonefrit mezangial, proliferativ,
membranoas i sclerozant
- vase sanguine
- articulaii
- seroase
- sistem nervos: microinfarcte, hemoragii
- cord: miocardit, endocardit, pericardit, coronarit
- tegumente

Morfopatologie
Leziunile histologice caracteristice:
- corpi hematoxilinici: resturi nucleare ce
provin din necroze celulare, cu aspectul
unor mase rotunde omogene colorate n
rou cu hematoxilin, trstura histologic
specific a LES
-necroza fibrinoid i fibrinoidul: un material
amorf eozinofil, localizat pe vasele sanguine, de-
a lungul fibrelor de colagen, pe suprafaa
seroaselor, n compoziia sa intrnd fibrin,
imunoglobuline, complement i corpi hematoxilinici
Morfopatologie
SLE characterized by periods of
remission and exacerbation.
Stimulated by sunlight, stress,
pregnancy, infections like strep and
some drugs. Some drugs like
apresoline, pronestyl, dilantin,
tetracycline, phenobarbital may cause
a lupus-like reaction which disappears
when drug is stopped.
Tablou clinic
1. Debut
- acut (mai frecvent) sau insidios
- dup expunere la soare, infecii, vaccinri,
sarcin,
- apar
- febr/subfebriliti, astenie, scdere
ponderal, anorexie
- artralgii, artrite, leziuni cutanate

Tablou clinic
Perioada de stare
1. Sindromul febril (constant):
- subfebrilitate sau febr pn la 39-40 grade
Celsius

- orice tip de curb posibil
2. Manifestri cutaneo-mucoase (80%)
- manifestri acute: eritem n fluture la eminenele malare i piramida
nazal, respectnd anul nazo-labial, fotosensibilitate
- leziuni subacute: iniial eritematoase, apoi papuloscuamoase
- leziuni cronice discoide: eritem, urmat de hipercheratoz i atrofie, zonele
afectate rmn hipopigmentate
- leziuni vasculitice: purpur palpabil, eritem periunghial, ulceraii pe
suprafeele de extensie ale antebraului, la pulpa degetelor, erupii
urticariene;
- fenomen Raynaud i livedo reticularis (30% dintre pacieni);
- alopecie: n formele active, frecvent reversibil, poate fi i permanent,
cnd nsoete leziunile discoide;
- pr uscat, lipsit de luciu, friabil;
- leziuni ale mucoaselor: peteii, ulceraii la nivelul palatului dur i moale,
uneori, la nivelul septului nazal, frecvent nedureroase
Tablou clinic
Perioada de stare
eritem in fluture (vespertilio)
Lupus discoid
Tablou clinic
Perioada de stare
3. Manifestri osteo-articulare i musculare
artrit i atralgii (95% dintre pacieni):
- artrit frecvent simetric, afectnd mai ales articulaiile
mici (interfalangiene proximale, metacarpofalangiene,
pumni), dar i coatele sau genunchii

- posibil caracter migrator

- adesea reversibil

- redoare matinal de scurt durat (minute)
Tablou clinic
Perioada de stare
4. Poliserozit
- pleurezie (1/3 dintre bolnavi), deseori bilateral, cu
exsudatul pleural n cantitate mic, biopsia pleural:
corpi hematoxilinici

-pericardit frecvent nediagnosticat, ducnd rar la
tamponad

-peritonit (5-10% dintre pacienii cu pleuropericardit au
concomitent i peritonit): dureri abdominale, anorexie,
varsturi, ascit (rar)
Tablou clinic
Perioada de stare
5. Semne renale (50% dintre pacieni)
- depind de forma morfologic
- cele mai frecvente:
- proteinurie
- hematurie
- insuficien renal
Tablou clinic
Perioada de stare
6. Manifestri cardiovasculare
-pericardit: n cadrul poliserozitei

-miocardit: tahicardie neexplicat de febr sau anemie

-endocardit verucoas Libman-Sacks: n special la valva mitral

-afectarea coronarelor: mai des cauzat de ateroscleroz dect de vasculit

-vasculit: ulceraii la nivelul tegumentului, purpur palpabil, afectarea vasa
nervorum cu manifestri de tip nevritic etc.

-tromboze arteriale: la arterele cerebrale i, rar, la marile trunchiuri arteriale

-tromboze venoase: venele profunde ale membrelor inferioare
Tablou clinic
Perioada de stare
7. Simptome pulmonare
-pneumonia acut lupic: febr, dispnee, tuse,
hemoptizii radiologic: infiltrate bazale sau zone
de atelectazie

-pneumopatia cronic lupic (prin afectarea difuz
a interstiiului pulmonar) de regul,
asimptomatic clinic i, mai rar, cu dispnee de
efort, tuse neproductiv, cianoz, raluri
subcrepitante
radiologic: uneori infiltrate difuze la nivelul
bazelor pulmonare
Tablou clinic
Perioada de stare
8. Manifestri nervoase (30% dintre pacieni)
-tulburri neurologice: convulsii localizate sau generalizate,
cefalee sever, neuropatii periferice, afectarea nervilor
cranieni, accidente vasculare cerebrale, meningit
aseptic limfocitar

-tulburri psihice: psihoze, sindrom organic cerebral
(tulburri de funcie intelectual, orientare, percepie,
memorie)
Tablou clinic
Perioada de stare
9. Manifestri oculare
-corpii citoizi reflect vasculita capilarelor retiniene
i microinfarctele localizate; se ntlnesc n
formele active de boal cu afectarea sistemului
nervos central;

-keratoconjunctivita sicca (uscat) (10% dintre
bolnavi).
Tablou clinic
Perioada de stare
10. Simptome digestive
- interesarea peritoneului, a arterei mezenterice, uneori
pancreatit

-se exprim prin anorexie, grea, vrsturi, dureri abdominale

-hepatomegalie: 30% dintre pacieni, biopsia hepatic poate fi
normal sau poate evidenia ncrcare gras i fibroz

-splenomegalie: prin leziuni arteriolare sau infarcte splenice
Tablou clinic
Perioada de stare
11. Adenopatii
-prezente, uneori, n asociere cu splenomegalia, n forme active

12. Menstruaie i sarcin
- menstruaie abundent
- dup menopauz, LES i reduce activitatea
- avort spontan (25-30% dintre sarcini)
- natere prematur
Investigaii imunologice

- anticorpii antinucleari (AAN) (>95%)
- celula LE = PMN neutrofil cu nucleul mpins la periferie de o mas mare
omogen (colorat n rou cu eozin), ce reprezint nucleul denaturat al altor
leucocite. Nucleul celulei agresate i pierde structura cromatinei, devine
inert i se transform n corpuscul omogen sau corp hematoxilinic. Acesta
este apoi fagocitat de PMN intacte care devin celule LE;
- ali atc: atc mpotriva determinanilor antigenici de suprafa ai celulelor
hematopoetice, atc antifosfolipide (30%), responsabili de apariia
fenomenelor trombotice. Anticorpii din LES sunt, n special, de tip IgG;
- gamaglobulinele: crescute la majoritatea bolnavilor;
- CI circulante i crioglobulinele: cresc n special n perioadele active de boal;
- complementul i fraciile sale (mai ales C3): sczute, reflectnd activarea i
fixarea lor de ctre CI;
- teste fals pozitive pentru sifilis (25%), ce pot aprea cu ani nainte de semnele
clinice ale LES.
Explorri paraclinice
Celula lupic
Teste hematologice
- anemia: urmarea hemolizei autoimune (test Coombs pozitiv), a
unor infecii i/sau a insuficienei renale cronice;
-leucopenia (<4.000 elemente/mm
3
): nsoit de limfopenie,
urmarea aciunii anticorpilor limfocitotoxici, poate lipsi sau,
uneori, exist leucocitoz;
- trombocitopenia (<100.000/mm
3
): produs prin mecanism
autoimun;
- anomaliile coagulrii: urmarea anticoagulanilor circulani (atc.
antifosfolipide). Prezena acestora se asociaz cu prelungirea
APTT, cu detectarea atc. anticardiolipin, cu reacie VDRL fals
pozitiv pentru lues, iar clinic, cu tromboze arteriale i venoase

Teste inflamatorii
- VSH, fibrinogenul, 2 globulinele: frecvent crescute n fazele
acute de boal
- Proteina C reactiv: valori normale chiar n fazele cele mai active
Diagnostic pozitiv criteriile ACR, 1982
Criteriu Definirea criteriului

1. Rash malar Eritem facial fix, plat sau n relief pe suprafeele malare,
respectnd anul nazo-labial
2. Lupus discoid Plci eritematoase cu cruste cheratozice aderente, cu astuparea
foliculilor, uneori atrofie cicatriceal pe leziuni vechi
3. Fotosensibilitate Rash cutanat dup expunere la soare, observat de
medic/pacient
4. Ulceraii orale Ulceraii orale sau nazofaringiene, de obicei nedureroase,
observate de medic
5. Artrit Artrit neeroziv, afectnd dou sau mai multe articulaii
periferice, caracterizat prin durere, tumefacie sau exsudat
6. Serozit a) Pleurit, istoric de durere pleural sau frectur pleural
ascultat de medic sau revrsat pleural
sau
b) Pericardit, afirmat pe ECG, prin frectur pericardic
sau prin identificarea lichidului pericardic
7. Afectare renal a) Proteinurie persistent peste 0,5 g/24 de ore sau peste 3+
dac nu se poate determina cantitativ
sau
b) Cilindri celulari (hematici, granuloi, tubulari, micti)
Diagnostic pozitiv criteriile ACR, 1982
Criteriu Definirea criteriului

8. Afectare a) Convulsii, n absena medicaiei responsabile sau a unor
neurologic cauze metabolice (uremie, cetoacidoz, diselectrolitemii) sau
b) Psihoz, n absena medicaiei responsabile sau a unor
cauze metabolice (uremie, cetoacidoz, diselectrolitemii)
9. Afectare a) Anemie hemolitic cu reticulocitoz sau
hematologic b) Leucopenie (<4.000/mm
3
), la 2 sau mai multe determinri sau
c) Limfopenie (<1.500/mm
3
), la 2 sau mai multe determinri sau
d) Trombocitopenie (<100.000/mm
3
), necauzat de medicaie
10. Anomalii a) Celule LE prezente sau
imunologice b) titru anormal de anticorpi anti ADNds, nativ sau
c) prezena de anticorpi anti-Sm sau
d) teste serologice fals pozitive pentru lues de cel puin 6 luni
11. Anticorpi Titru anormal de AAN determinai prin imunofluorescen sau alt
antinucleari tehnic, n absena medicamentelor ce pot induce lupus

Diagnostic pozitiv
Pentru diagnosticul de LES trebuie s fie
prezente simultan sau succesiv cel puin
4 dintre cele 11 criterii.
Systemic lupus erythematosus classification criteria
(SOAP BRAIN MD)

1. Serositis:
(a) pleuritis, or
(b) pericarditis
2. Oral ulcers
3. Arthritis
4. Photosensitivity

10. Malar rash
11. Discoid rash

5. Blood/Hematologic disorder:
(a) hemolytic anemia or
(b) leukopenia of < 4.0 x 10
9

(c) lymphopenia of < 1.5 x 10
9

(d) thrombocytopenia < 100 X 10
9

6. Renal disorder:
(a) proteinuria > 0.5 gm/24 h or
3+ dipstick or
(b) cellular casts
7. Antinuclear antibody (positive ANA)
8. Immunologic disorders:
(a) raised anti-native DNA
antibody binding or
(b) anti-Sm antibody or
(c) positive anti-phospholipid
antibody work-up
9. Neurological disorder:
(a) seizures or
(b) psychosis
". ..A person shall be said to have SLE if
four or more of the 11 criteria are
present, serially or simultaneously, during
any interval of observation."

Diagnostic Tests
LE cell
Ant-DNA
ANA, titer
Anti-DNA
Complement fixation
decreased
ESR
Other (and CBC, UA)
Kidney biopsy
Criteria to Dx.
malar, discoid rash
photosensitivity
arthritis
renal disorder
immunological
disorder
DNA, ANA
Diagnostic diferenial
-Boli reumatismale inflamatorii:
poliartrit reumatoid (sinovit proliferativ, cu apariia eroziunilor
osoase, complement seric normal, AAN prezeni doar la 10% dintre
pacieni), sindrom Felty (apare, de regul, n cazuri de poliatrit
reumatoid cu evoluie prelungit, cnd diagnosticul este cert),
sclerodermie, reumatism articular acut, polimiozit, vasculite
sistemice;
Boli metabolice:
porfirie (fotosensibilitate, manifestri neurologice, hepatice etc.);
Afeciuni infecioase:
endocardit bacterian, artrite virale (parvovirus B19, hepatita B,
HIV-1), pneumopatii diverse, tuberculoz;
Altele: boli dermatologice
(lichen plan, eritem multiform, psoriazis), boli neuropsihice
(epilepsie, psihoze), nefropatii diverse, tiroidit autoimun,
neoplazii (leucemia), sindroame paraneoplazice
Evoluie i prognostic
- acutizri i remisiuni

- severitatea bolii depinde de: leziuni renale, neurologice i
cardiace

- complicaii tardive: insuficien renal, embolie pulmonar,
tromboze, osteonecroz, tulburri neuropsihice, insuficien
respiratorie

- deces prin: insuficien renal, complicaii vasculare sau
infecii
Anti-Nuclear Antibody (ANA)
Nonspecific for SLE
Seen in:
Systemic autoimmune disease
Specific organ autoimmune disease
Nonautoimmune disease
Normal population
Sensitivity:
SLE: 93%
Scleroderma: 85%
MCTD: 93%
Sjogrens synd.: 48%

Salehi I.
Lab. tests
Anti-Neutrophil Cytoplasmic
Antibody (ANCA):
IF assay: more sensitive
C-ANCA
P-ANCA
Atypical (non-C, non-P) ANCA
ELISA: more specific
PR3-ANCA
MPO-ANCA
C-ANCA: usually PR3-ANCA
P-ANCA: usually MPO-ANCA
Salehi I.
Lab. tests
ANCA:
Positive predictive value of ANCA for
ANCA associated vasculitis:
IF: 45%, ELISA: 83%, IF + ELISA: 88%
in acute or rapidly progressive GN: 98%
in chronic sinusitis: very low for WG
in systemic disease (C-ANCA):
50% for ANCA associated vasculitis
28% for WG

Salehi I.
Lab. tests
Anti-Phospholipid (APL)
Antibodies:
Lupus Anticoagulant (LA)
Anticardiolipin (aCL) antibodies
Anti B2-Glycoprotein-I (B2-GP-I)
Biologic False Positive test for
syphilis:
VDRL, RPR
Low sensitivity, Low specificity
Nonscreening tests for APS
Seen in SLE too
Salehi I.
Lab. tests
Anti-nuclear antibodies lupus cell:
The lupus erythermatosus
(LE) cell:
Is a mature neutrophilic
polymorphonuclear
leukocyte, which has
phagocytized a spherical,
homogeneous-appearing
inclusion, itself derived
from nuclear material of
degenerating leukocytes
and coated with
antinuclear antibody; a
characterisitic of lupus
erythematosus
Therapeutic
Interventions/Management SLE

Tratament
Obiectiv terapeutic: meninerea funcionalitii i prevenirea alterrii
organice

Msuri generale
- interzicerea expunerii la soare sau alte radiaii ultraviolete
- evitarea infeciilor
- evitarea unor medicamente (sulfonamide, penicilin, contraceptive orale,
tetracicline)
- sarcina este permis dup o perioad de inactivitate a bolii de trei ani i
cnd nu exist afectrile severe renale, nervoase sau cardiace (care o
contraindic)

Tratament
Strategia terapeutic - reguli generale:
-anomaliile biologice fr manifestri clinice nu se
trateaz
- formele de boal cu manifestri articulare moderat
active pot beneficia de AINS sau antimalarice
- formele clinice cu atingere visceral necesit
corticoterapie
- imunosupresoarele sunt indicate numai n formele
severe cu afectare renal i neurologic

Tratament
Terapie medicamentoas
Medicamentele folosite (AINS, antimalarice, corticoizi, imunosupresoare)
intervin, probabil, pe cile inflamaiei i interfereaz cu mecanismele
imunologice.

AINS:
- indicate n formele uoare, doar cu febr i manifestri articulare

Antimalaricele de sintez:
- efect favorabil asupra manifestrilor articulare i cutanate
- hidroxiclorochina, 400-600 mg/24 de ore, tratament de lung durat, cu
supraveghere oftalmologic la fiecare 6 luni, deoarece medicamentul poate
produce leziuni retiniene ireversibile

Tratament
Corticoterapia:

- folosit frecvent datorit proprietilor antiinflamatoare i
imunosupresive
- se utilizeaz preparate orale cu durat de aciune medie (prednison,
metilprednisolon, triamcinolon), ele fiind indicate n cazurile febrile
cu interesri viscerale multiple i cnd nu s-a obinut ameliorarea
simptomatologiei cu AINS sau cu antimalarice
- doze: 0,5-2 mg/kg/24 de ore, dup ameliorarea simptomelor, dozele
se reduc treptat
- se poate ntrerupe la 6-12 luni dup dispariia simptomelor
- efectele adverse: frecvente, pentru prevenirea lor este necesar
regimul hiposodat, hipoglucidic, aport suplimentar de potasiu,
administrarea de calciu i alfa D3
Tratament
IIIiiIIimunosupresoarele:

- ciclofosfamida i azatioprina, administrndu-se n situaiile de rezisten la
corticoterapie, n afectrile renale severe sau nervoase i la pacienii
corticodependeni
- ciclofosfamida: cea mai eficient, dar i cea mai toxic. n formele grave, se
face pulsterapie, 1 g/lun, i.v., timp de 6-12 luni. Medicamentul se poate
administra i oral, 1,5-2,5 mg/kg/24 de ore. Efectele adverse sunt: cistita
hemoragice, intolerana digestiv, alopecia, fibroza pulmonar.
- azatioprina: 1-2,5 mg/kg/24 de ore
- metotrexat: 10-25 mg, 1 dat/sptmn, util n special n cazul afectrii
cutanate i articulare

Imunoglobulinele i.v.:
- 400 mg/kg/24 de ore, 5 zile consecutiv
- indicate pentru tratamentul manifestrilor clinice severe, n special pentru
trombopenia refractar la tratament

Androgenii (Danazol) se folosesc n caz de hiperestrogenism
munosupresoarele:
Tratament
Alte modaliti terapeutice

Plasmafereza: util la titruri serice ridicate de CI, AAN,
crioglobuline

Iradierea limfatic total: o terapie de excepie, determin
limfopenie marcat cu depleia LTh (CD4+) care poate
persista civa ani. Riscul complicaiilor infecioase, al
leucemiei acute i al tumorilor solide este crescut.

Anticorpi monoclonali anti CD4, care, prin depleia LTh,
determin scderea produciei de autoanticorpi
Tratament
Tratamentul complicaiilor

Infeciile: trebuie tratate cu promptitudine, macrolidele fiind antibioticele de
elecie pentru infeciile respiratorii banale sau pentru cele din sfera ORL

Trombozele: necesit administrarea de heparin, asociat corticoterapiei,
urmat ulterior de administrarea de anticoagulante orale i antiagregante

Hipertensiunea arterial rspunde la tratamentul cu inhibitori ai canalelor de
calciu

Insuficiena renal cronic sever impune hemodializ i transplant renal
Therapeutic Interventions/Management SLE
Nursing diagnosis
See RA
Impaired skin integrity
Ineffective protection
Impaired health
maintenance

Goal: control inflammation

Emotional support

Life Planning

Required Review
Medications
NSAIDS
(Disease modifying agents)
Antimalarial drugs
Corticosteroids
Immunsuppressive therapy

Antineoplastic drugs such as
Imuran, cytoxan, cyclosporine

Avoid UV
Reduce stress
Monitor/manage to prevent
complications
Treatment of SLE
Arthritis, arthralgias, myalgias:
NSAIDS, anti-malarials (eg.
Plaquenil), Steroids- injections,
oral methotrexate
Photosensitivity, dermatitis avoid Sun
exposure topical
steroids Plaquenil
Weight loss and fatigue
steroids
Abortion, fetal loss
ASA
immunosuppression
Thrombosis
anti-coagulants

Glomerulonephritis
steroids
pulse cytotoxics
mycophenylate mofetil
CNS disease
anti-coagulants for thrombosis
steroids and cytotoxics for
vasculitis
Infarction (secondary to vasculitis)
steroids
cytotoxics
prostacyclin
Cytopenias
steroids
IVIG-short term for
thrombocytopenia
danazol
cytotoxics-if bone marrow status
is known
Some Take Home Messages

Treatment in the future may be driven by the patients
genetic makeup: personalized medicine
The pathogenesis of SLE is complex with
dysregulation of multiple arms of the immune system
Despite improvement in mortality, new treatments are
needed given resistant disease and the side effects of
current immunosuppressives
A number of biologic molecules critical to the lupus
disease process are emerging as logical targets for
treatment
Information about disease pathogenesis is leading to
targeted biologic therapies

SCLERODERMA
(Systemic sclerosis)
Definiie
Este o afeciune cronic a esutului conjunctiv,
caracterizat prin obliterarea arterelor mici i a
capilarelor, cu fibroz i leziuni degenerative,
care intereseaz tegumentul i unele viscere.
Epidemiologie
Incidena anual: 2/100.000 locuitori
Incidena crete cu vrsta (maxim: 20-40 de ani)
Prevalena: 19-75/100.000 locuitori
F/B: >3:1
Etiopatogenie
I. Etiologie
1. Imunologici
- AAN, Ac anticentromer i anti-Scl-70, crete activitatea LTh
(CD4+), scade activitatea LTs (CD8+), crete IL-2
2. Stres nervos
3. Toxici
- expunere la praf de siliciu, policlorur de vinil, hidrocarburi
aromatice, uleiuri toxice, medicamente (bleomicin, pentazocin)
4. Genetici:
- anomalii cromozomiale, anumite antigene HLA (HLA B8)

Etiopatogenie
II. Patogenie
- Anomalii imune
- Alterri vasculare
- Fibroz
- Supraproducia i acumularea de colagen
Morfopatologie
1. Tegumente:
la debut- aspect edemaiat, apoi indurat, infiltrat
2. Tub digestiv:
toate straturile (esofag n 2/3 inferioare, stomac, duoden,
intestin subire i colon): subierea mucoasei, atofierea
musculaturii netede, creterea cantitii de colagen n
submucoas i seroas
3. Plmn:
fibroz interstiial difuz, ngroarea membranei alveolare,
fibroz peribronic
4. Rinichi:
hiperplazie intimal a arterelor interlobulare, necroz
fibrinoid a arteriolelor aferente, ngroarea membranei
bazale glomerulare
5. Cord:
degenerarea fibrelor miocardice, arii neregulate de fibroz
interstiial, fibroz a esutului de conducere, interesarea
pericardului
6. Sistem osteoarticular:
sinovit, colagenizare, osteoliz
7. Sistem muscular:
infiltrate limfocitare perivasculare, interstiiale,
degenerarea fibrelor musculare netede, fibroz interstiial

Morfopatologie
Scleroderma (Systemic Sclerosis)
Chronic, inflammatory, autoimmune
connective tissue disease
Not always progressive
Hardening of the skin
Abnormal amounts of fibrous connective
tissue deposited in skin, blood vissels, lungs,
kidneys, other organs
Can be systemic or localized (CREST)
syndrome

Scleroderma
SclerodermaClinical
Manifestations
Arthralgia
GI tract
Cardiovascular system
Pulmonary system
Renal system
SclerodermaInterventions
Drug therapy
Identify early organ involvement
Skin protective measures
Comfort
GI manifestation
Mobility
Scleroderma
Typical hide-
bound face of
person with
scleroderma
Tissue hardens;
claw-like
fingers; fibrosis
Manifestations & Complications
(systemic)
Female 4:1
Pain, stiffness,
polyartheritis
Nausea, vomiting
Cough
Hypertension
Raynaulds syndrome
Skin atrophy,
hyperpigmented
Scleroderma cont.
Esophageal hypomotility
leads to frequent reflux
GI complaints common
Lung-pleural thickening
and pulmonary fibrosis
Renal disease...leading
cause of death!
Diagnosis/Treatment Scleroderma
R/O autoimmune disease
Radiological: pulmonary
fibrosis, bone resorption,
subcutaneous calcification,
distal esophageal hypomotility
ESR elevated
CBC anemia
Gammaglobulin lelels elevaed;
RA present
Skin biopsy to confirm
What are the KEY
components of care for
the individual with
Scleroderma?
Scleroderma related antibodies:
Anti RNA polymerase
Anti-PM-Scl: Overlap of PM + Scl
Anti-Fibrillin-1: Localized Scl.
Anti-Nucleolus Organizer Region
(NOR-90)
Anti-Nucleolar RNA helicase (Gu):
Scl. + SLE
Salehi I.
Lab. tests
Scleroderma: Patient Care
Medications: based
upon symptoms:
Immunosuppressive agents & steroids &
remitting agents
Ca channels blockers & alpha-adrenergic
blockers
H2 receptor blockers
ACE inhibitors
Broad spectrum antibiotics
CREST Syndrome
Ccalcinosis
RRaynauds phenomenon
Eesophageal dysmotility
Ssclerodactyly
Ttelangiectasia
CREST Syndrome & scleroderma
Sclerodactyl
(localized
scleroderma of
fingers)
Raynauds
disease with
ischemia
Sindrom CREST
Tablou clinic
Debut: necaracteristic
Perioada de stare:
1. Sindrom Raynaud (95%)
- faza sincopal asfixic reacia hiperemic
2. Manifestri tegumentare
- iniial edem al degetelor i minilor, apoi ndurarea i
infiltrarea tegumentului, apariia de ulceraii i cicatrici
- mini n ghear de pasre
- fa de icoan bizantin
- tegument fr pr, sebum i glande sudoripare, uscat
Tablou clinic
3. Manifestri osteoarticulare
- dureri, edeme i redoare la nivelul degetelor
- sindrom de tunel carpian
- artrite ale articulaiilor mici ale minii NEEROZIVE!
4. Manifestri musculare: rare (miozit)
5. Manifestri digestive
- plenitudine gastric, disfagie, arsur retrosternal, regurgitaii
- dilatare gastric
- hipomotilitatea intestinului subire, sindrom de malabsorbie
Tablou clinic
6. Manifestri pulmonare
- dispnee de efort, tuse seac
- pneumonie de aspiraie
- n final: cord pulmonar
7. Manifestri renale
- hipertensiune arterial, uneori malign
- insuficien renal
- hematurie, proteinurie
8. Manifestri cardiace
- pericardit, insuficien cardiac, bloc atrioventricular,
aritmii, angin pectoral
9. Alte:
- uscciunea ochiului i/sau a mucoasei bucale
- nevralgia de trigemen, de nerv median
Sindrom Raynaud
Mn n ghear
Mn cu ulceraie
Fa de icoan bizantin
1. Teste de inflamaie
2. Examen radiologic: pasaj baritat, radiografie pulmonar
3. Anomalii imune
- gamaglobuline, IgG, crioglobuline
- AAN prezeni (95%), atc antitopoizomeraz (Scl 70)
4. Biopsie cutanat:
- proliferri endoteliale intimale, subierea mediei, depunere de
colagen n derm, infilitrat inflamator perivascular
5. Anomalii hematologice: anemie multifactorial
6. Anomalii vasculare
- arteriografie, capilaroscopie, biopsia pulpei degetului
7. Alte explorri: tub digestiv, plmn, cord
Esofag de sticl
Diagnostic pozitiv
Sindrom Raynaud
Esofag de sticl
Sindrom de malabsorie
Serologie imun
Biopsie cutanat
Capilaroscopia patului unghial
1. Poliartit reumatoid
2. Lupus eritematos sistemic
3. Polimiozit
4. Boal mixt a esutului conjunctiv

Forme clinice
1. Sclerodermia cutanat difuz
2. Sclerodermia cutanat limitat (extremiti, fa)
3. Sindromul CREST
Calcinoz subcutan, fenomen Raynaud, disfuncie
Esofagian, Sclerodactilie, Telangiectazii
4. Fibroza pulmonar idiopatic
1. Sindrom Raynaud
- msuri generale, blocante de calciu, unguente cu nitroglicerin,
antagoniti de ketanserin, prostaciclin
2. Modificrile cutanate
- D-penicilamin, vitamina E, colchicin
3. Afectarea esofagian
- antisecretorii, prokinetice
4. Sindromul de malabsorbie
- tetraciclin 2 g/zi
5. Afectarea pulmonar
- corticoterapie, vaccinri
6. HTA
- IECA
7. Afectarea cardiac
- tratamentul insuficienei cardiace, al afectrii corornariene, al
tulburrilor de ritm i de conducere
Tratament
POLIMIOZITA/
DERMATOMIOZITA
Definiie
Polimiozita (PM) i dermatomiozita (DM) sunt
miopatii inflamatorii, n general idiopatice,
caracterizate prin inflamaia difuz, nesupurativ a
muchiului striat, exprimat clinic prin astenie
muscular cu localizare proximal, nedureroas (n
PM), asociat cu rash cutanat (n DM).
Clasificare
Tipul I - PM idiopatic a adultului
Tipul II - DM idiopatic a adultului
Tipul III - DM/PM asociat cu neoplazie
Tipul IV - DM/PM copilului asociat cu vasculit
Tipul V - PM/DM asociat cu alte boli ale esutului
vasculo-conjunctiv
Tipul VI - Miozita cu corpi de incluziune
Tipul VII - Miozita eozinofilic, miozita cu celule
gigante, miozita osifiant
Epidemiologie
Inciden 1/100.000
F:B = 2:1
Vrfuri de inciden
5-15 ani
40-60 ani
Etiopatogenie
1. Terenul genetic
- HLA DR3, HLA B8, HLA DR52
2. Factorii de mediu
- retrovirusuri, Coxsackie B, Epstein-Barr
3. Mecanismul patogenic
- imunologic (umoral DM, celular PM)
- atg: necunoscute (musculare, microvasculare)
- atc:
- anticitoplasmatici: anti-ARN t sintetaze (atc anti
Jo-1, anti PL-7, PL-12, anti OJ, anti EJ), Anti SRP
- antinucleari: anti Mi-2
- ntlnii i n ate boli de esut conjunctiv

Morfopatologie
Biopsia muscular
- inflamaia trstura histologic
- PM: infiltrate cu LiT localizate endomisial, determinnd fagocitoz i
necroz
- DM: inflamaie perimisial, necroz, degenerare, fagocitoz, ducnd la
atrofie perifascicular

Biopsia de piele
- atrofie epidermic
- vacuolizarea celulelor bazale
- dilataie vascular n derm
- infiltrat limfocitar
Tablou clinic
Manifestri musculare:
- astenia muscular nsoit de scderea forei musculare, de regul
nedureroas, este trstura cardinal; ea se instaleaz lent (saptmni, luni,
ani), poate afecta orice muchi i este simetric, aprnd iniial la segmentele
proximale
- localizare:
centura pelvin: frecvent interesat (peste 90%), duce la imposibilitatea flexiei
coapsei pe abdomen i dificulti la urcatul i cobortul treptelor
centura scapular (peste 85% dintre bolnavi) face dificil ridicarea braelor,
pieptnatul etc.
muchii flexori ai cefei: ridicarea capului de pe pern i meninerea poziiei
ortostatice sunt dificile
Examenul neurologic este normal.
Manifestri tegumentare
prezente la aproximativ 40% dintre pacieni, n cadrul DM, i se exprim
prin:
- rash heliotrop (dup expunere la soare), localizat la nivelul feei
(erupie roie sau violaceu-liliachie periorbitar, cu edem al pleoapelor),
gtului (eritem n V) i pe umeri (eritem sub form de al).
- semnul Gottron: erupii eritemato-maculo-papuloase, formate
din pete proeminente de culoare roie-violet, scuamoase, localizate pe
faa dorsal a articulaiilor minilor, metacarpofalangiene i
interfalangiene proximale, coatelor, genunchilor i maleolei externe;
- pat unghial hiperemic, cu teleangiectazii periunghiale, prin
dilatarea anselor capilare
- calcificri n esuturile moi (tegument, esut subcutanat, fascii);
-mini de mecanic: tegumente neregulate, ngroate, cu fisuri,
linii orizontale murdare

Manifestri generale
- febr, stare general alterat, scdere ponderal, sindrom
Raynaud, atralgii

Manifestri articulare
- artralgii, fixitate articular, artrite NEEROZIVE !

Manifestri viscerale:
- gastro-intestinale: disfagie, ulceraii
- pulmonare: afectarea mm. intercostali, a diafragmului, a
interstiiului pulmonar
- cardiace: miocardit, tulburri de ritm i de conducere, HTA,
insuficien cardiac
- neoplazii: ovarian, mamar, pulmonar, colonic, melanom

Rash cutanat
Erupii eritemo-maculo-papuloase
Papule Gottron
Eritem n V la decolteu
Modificri palpebrale - DM
Creterea enzimelor musculare (CPK, ALAT, ASAT, aldolaza)
Creterea excreiei urinare de creatin
Crete mioglobina seric mioglobinuria
Teste inflamatorii: VSH, alfa2-globuline, PCR, fibrinogen
Anomalii imunologice
- atc anti Jo-1, n PM cu afectare pulmonar
- atc Anti Mi-2, n DM cu manifestri cutanate
- atc comuni cu alte boli ale esutului vasculo-conjunctiv
- FR
- CIC
EMG - miopatie inflamatorie (fibrilaii spontane, poteniale de
amplitudine i durat scurt, descrcri pseudomiotonice bizare)

Biopsie muscular

Biopsie tegumentar

Diagnostic pozitiv
CRITERIILE BOHAN & PETER 1975

1. Disfuncie muscular cu slbiciune muscular simetric a musculaturii
centurilor, extremitiilor, gtului, progresiv n sptmni, luni, cu sau fr
disfagie sau afectarea muchilor respiratori
2. Creterea enzimelor serice de origine muscular:
CPK-MM, LDH, GOT, GPT, aldolaz
3. Anomalii electromiografice cu poteniale de scurt durat i amplitudine mic,
fibrilaii spontane de repaus
4. Biopsie muscular: necroza fibrelor musculare, regenerare cu bazofilie, atrofie
perifascicular, exsudat inflamator

Diagnosticul este:
- cert: 4 criterii
- probabil: 3 criterii
- posibil: 2 criterii
- Afeciuni neurologice: scleroz lateral amiotrofic, neuropatii proximale
(porfirie acut intermitent, neuropatie diabetic)

- Afeciuni neuromusculare: miastenia gravis

- Afeciuni musculare: distrofii musculare genetice, distrofia miotonic; boli de
stocaj (glicogen, lipide), miopatii endocrine (hipo- i hipertiroidism), toxice (etilism),
medicamentoase (fibrai, statine), rabdomioliz acut, infecioase (virale: virus
gripal, HIV, bacteriene: streptococ, clostridium, parazitare: trichinella, toxoplasma)

- Polimialgie reumatic
Tratament
Obiectiv:
- suprimarea ct mai precoce a procesului inflamator n vederea reducerii
distruciilor musculare extensive
- depinde de forma clinic de boal

Igieno-dietetic
- repaus la pat n perioadele de activitate

1. Corticoterapie
- Prednison: 1-2 mg/kg corp/24 de ore, cu reducerea treptat a dozelor
2. Imunosupresoare (necesare n 75% dintre cazuri)
- AZT, MTX, CFA, ciclosporin, clorambucil
3. Imunoglobuline i.v.
4. Hidroxiclorochin
- pentru manifestrile cutanate, 400-600mg/24 de ore (cu
supraveghere oftalmologic)

Trepte

- treapta 1: prednison n doz mare
- treapta 2: azatioprin sau metotrexat
- treapta 3: imunoglobuline i.v.
- treapta 4: ciclosporin, clorambucil,
ciclofosfamid, micofenolat
Osteoarthritis
Osteoarthritis (OA)

Osteoarthritis (OA) Noninflammatory
arthritis is not systemic.
OA is not an autoimmune disease.
Arthralgia vs Osteoarthritis
Arthralgia: Joint pain
(there may not be any inflammation)

Arthritis: Inflammation of the Joint

- Pain
- Redness
- Swelling
- Increased warmth
- Fluid accumulation (synovial effusion)
- Stiffness (especially in the AM)

What symptoms/assessment for the patient
with osteoarthritis?
Onset of pain is insidious, individual is
healthy!
Pain is aching in nature; relieved by rest!.
Local signs and symptoms: swelling,
crepitation of joint and joint instability,
asymmetrical joint involvement

Osteoarthritis
Most common type of arthritis
Joint pain and loss of function characterized
by progressive deterioration and loss of
cartilage in the joints
Osteophytes
Synovitis
Subluxation
Osteoarthritis: A Progressive Disease
Osteoarthritis-Diagnosis
Clinical
Supported by X-rays
Non-inflammatory lab data, if any
Degenerative Joint Disease
(Osteoarthritis)
Most common rheumatic disease
and is characterized by
progressive loss of cartilage and
reactive changes at the margins of
the joint and in the subchondral
bone
The disease usually begins in ones
40s
Prevalence increases with age and
the disease becomes almost
universal in individuals aged 65
and older
Primarily affects weight-bearing
joints such as the knees, hips, and
lumbrosacral spine
In early disease, pain
occurs only after joint use
and is relieved by rest

As the disease progresses,
pain occurs with minimal
motion or even at rest

Nocturnal pain is
commonly associated
with severe disease
Treatment and Prognosis of
Meds
Early PT/exercises
Heat/cold therapy
Joint protection
Surgery

Osteoarthritis is a slowly progressive disease
The eventual outcome is complete destruction of
the joint, and ultimately surgical intervention is
required
Osteoarthritis-Treatment
Pain relief
-Analgesics and NSAIDs/Cox-2 Inhibitors
SMOADs (structure modifying osteoarthritis drugs)
-Glucosamine Sulfate -see meta-analysis McAlindon et al. JAMA, 283: 3/2000, p.
1469
-many under development
Non-pharmacologic approaches
-Reduce stress/load on joint
-Strengthen surrounding muscles-PT/OT
-Weight reduction
-Patient education
Limit disability and improve quality of life

Joint Replacement Surgery
-Primarily of knee and hip,
but also available in
hands, shoulders,& elbows
-Indications:
1. pain at rest
2. instability
-patients benefit from
aggressive PT before &
after surgery
Other surgical procedures

Joint Replacement Surgery
-Primarily of knee and hip,
but also available in
hands, shoulders,& elbows
-Indications:
1. pain at rest
2. instability
-patients benefit from
aggressive PT before &
after surgery
Other surgical procedures

Updated Therapy for Osteoarthritis
Glucosamine or
Glucosamine/Chondroitin
supplements
Reduce injury to joint (weight loss,
treat gout, etc).
Acetaminophen and analgesics
Conventional or COX-2 Inhibitor
NSAIDS
IA injections with corticosteroids
IA injections with hyaluronic acid
Reconstructive surgery
Hyaluronate for Intraarticular Injections
First isolated by Palmer and Meyer from
bovine eyes in 1934
Marketed for human use in the early 1980s
using HA derived from rooster comb
Polysaccharide chain made of repeating
Polysaccharide chain made of repeating
disaccharide units of N-acetylglucosamine
and glucuronic acid
Synthesized naturally by Type B
synoviocytes
Injection of Hyaluronate (Hyaluronan)
One-Needle Two Syringe Technique
Chronic Pain: Surgical
Management
Total joint arthroplasty (TJA)
Total joint replacement (TJR)
Arthroscopy
Osteotomy
Total Knee Arthroplasty
Preoperative care
Operative procedures
Postoperative care:
Continuous passive motion machine
Hot/ice device
Pain management
Neurovascular assessment
Heberdens Nodes
Continuous Passive Motion Machine
GOUT
Acute Gout
Hyperuricemia Syndromes

Stage 1 -Asymptomatic hyperuricemia
(uric acid < 7.0 mg/dl)
Stage 2 - Acute gouty arthritis (acute
gout)
Stage 3 - Tophaceous or chronic gout
Uric acid nephrolithiasis
Acute uric acid nephropathy
Chronic sodium urate nephropathy or
interstitial nephritis
Diagnostic Tests for Gout
Serum uric acid x several times
Athrocentesis for crystal
examination
Exclusion of RA, SLE, infection,
CPPD, Reiters syndrome
Hand and foot radiographs
CBC, Cr, uric acid, Ca, Electrolytes
Hepatic enzymes, UA
24 hr urine for creatinine and uric
acid
Gout
Gout Radiography
All joints of hand and wrist possible
(2
nd
-5
th
PIP most common)
Soft tissue swelling
Well demarcated osseous erosions
with sclerotic rims and
overhanging edges
No decrease in bone density
Tophi not calcified
Relative sparing of joint space until
late in the disease
Long latent period between onset
of symptoms and radiographic
changes

Chronic or Tophaceous Gout
More gout
Psoriatic Arthritis
Psoriatic Arthritis
HLA-B27 positive, RF negative
Inflammatory
Seronegative
spondyloarthropathy
Asymmetric and bilateral
Primarily distal involvement
associated with nail changes
No periarticular osteoporosis
Five different patterns
Usually accompanies skin
disease

Psoriatic Arthritis Rad findings
Asymmetric proliferative erosions with ill-
defined margins
Periosteal reaction
Soft tissue swelling
Pencil-in-cup deformity
Resorption of distal phalangeal tufts
Subluxation

376
Psoriatic Arthritis
Psoriatic arthritis
Key Questions
Inflammatory vs. Noninflammatory ?
Acute vs. Chronic ? (< or > 6 weeks)
Articular vs. Periarticular ?
Mono/Oligoarthritis vs Polyarthritis ?
(Focal) (Widespread)

Are there RED FLAGS?

OSTEOPOROZA
Osteoporosis
Has Its Time Come?

Quantitating the Bone Mass

Bone Mineral Density Testing

Practical Definition of Osteoporosis
Literally translates as porous bones
Osteoporosis occurs when the holes between bone become
bigger, making it fragile and liable to break easily

Osteoporosis - Definition
A progressive systematic skeletal disease characterized by low
bone mass and micro-architectural deterioration of bone tissue,
with a consequent increase in bone fragility and susceptibility to
fracture
Risk Factors
1. Hormonal.
Late menarche, early menopause, long hx of
oligomenorrhoea.
During menopause oestrogen deprivation ed
bone resorption, so bone loss.

2. Smoking

3. Excessive alcohol intake

The bones in our
skeleton are made of
a thick outer shell
and a strong inner
mesh filled with
collagen (protein),
calcium salts and
other minerals.

The inside looks like
honeycomb, with
blood vessels and
bone marrow in the
spaces between
bone.
Osteoporosis
Normal bone on left
Osteoporotic bone on right
Osteoporosis Primary Causes
Osteoporosis results from an unhealthy imbalance
between two normal activities of bone: bone
resorption and bone formation.

These activities rely on two major types of cells:
osteoclasts for bone resorption and osteoblasts for
bone formation. The combined processes of bone
resorption and bone formation allow the healthy
skeleton to be maintained continually by the removal
of old bone and its replacement with new bone.

These combined processes are referred to as bone
remodeling or bone turnover. During the first 20-25
years of life, these processes are balanced.
Osteoporosis Primary Causes
Following a period of balanced bone resorption and
bone formation, the destruction of bone begins to
exceed the formation of bone; this imbalance leads to
a net loss of bone, and the beginnings of
osteoporosis.

The risk of fracture increases from 1.5 to 3-fold for
every 10% decrease in bone mass.

Bone mineral density (BMD), a measure of bone mass
divided by bone area, increases with age until peak
bone density is achieved. Bone mineral density is
correlated highly with bone strength and is therefore
used to quantitatively screen and diagnose patients.
Pathogenesis
Diminished bone mass can result from:
1-failure to reach an optimal peak bone mass in early
adulthood
2-increased bone resorption
3-decreased bone formation after peak bone mass has
been achieved
All three of these factors probably play a role in
most elderly persons. Low bone mass, rapid bone
loss, and increased fracture risk correlate with high
rates of bone turnover (ie, resorption and
formation).
In osteoporosis, the rate of formation is inadequate
to offset the rate of resorption and maintain the
structural integrity of the skeleton
Aging vs. Osteoporosis
Bone resorption rates appear to be maintained or
even to increase with age
Bone formation rates tend to decrease.
Loss of template due to complete resorption of
trabecular elements or to endosteal removal of
cortical bone produces irreversible bone loss.
Age-related microdamage and death of osteocytes
may also increase skeletal fragility
HOWEVER, Osteoporosis is NOT an inevitable
consequence of aging; many persons maintain good
bone mass and structural integrity into their 80s
and 90s.
Osteoporosis Vertebral Fractures
A loss of height may indicate a vertebral
compression fracture, which occurs in many
patients without trauma or other acute
precipitant.
A persistent low
backache, or sudden
localized pain, could be
a warning sign of
compression fractures
in the vertebrae of the
spine.

But for many, these
breaks cause little pain,
and may go undetected
for years. For some, the
only tip-off is a
noticeable loss of
height, which can reach
as much as 8 inches.

Osteoporosis Vertebral Body Changes
Normal vertebral bodies on right
Osteoporosis compression fracture.
Trabecular architecture is classic
Osteoporosis Dorsal Hyphosis
Dorsal kyphosis with exaggerated lordosis (dowager's hump)
may result from multiple compression fractures. The
hump caused by spine fractures is disfiguring. This is the
feature of osteoporosis that is the worst thing for most
patients. In severe cases, the ribs can touch the pelvic
bones.
.
Along with the curve in the spine
comes an outward curve of the
stomach. Women do not realize
that the curvature of the spine
means the intestines have
nowhere to go except forwards.

Many women think that they are
getting fat, and they go on a diet
trying to regain their youthful
waistline. If they do successfully
lose weight, it will only increase
their risk for more osteoporotic
fractures.
Atypical Fractures of the Femoral Diaphysis in Postmenopausal Women
Taking Alendronate.
Lenart, Brett; Lorich, Dean; Lane, Joseph

New England Journal of Medicine. 358(12):1304-1306, March 20, 2008.

. Radiographs of Fractures of the Femoral
Shaft Showing the "Simple with Thick
Cortices"
Pattern Panel A shows a fracture of the
femoral shaft in an 83-year-old woman
with a 9-year history of alendronate use.
Panel B shows a similar fracture in a 77-
year-old woman with a 5-year history of
alendronate use.
Atypical Femoral Fracture
Shane et al, JBMR 25:2010;25:22672294.
Conventional AP radiograph of the pelvis (A) shows bilateral focal cortical thickening from
periosteal new bone formation (arrows). Corresponding bone scintigraphy (B)
demonstrates focal increased radionuclide uptake in the proximal lateral femoral cortices
(arrows). MRI images of the femurs (C) demonstrate subtle decreased signal on T1-
weighted and increased signal on T2-weighted images only of the right femur on
this section. Similar findings on AP DXA hip images (D) show focal bilateral cortical
thickening consistent with early, evolving femoral insufficiency fractures.
A B
D C
Osteoporosis Other Fractures
Osteoporotic fractures commonly affect the hip because the elderly
tend to fall sideways or backwards, landing on this joint. Younger,
more agile persons tend to fall forward, landing on the outstretched
wrist, thus fracturing the distal radius
Patient who had a severe fracture and a
moderate fracture in her spine. Three years
later a second xray revealed a new fracture.
These fractures were in the lower spine.

Radiographic Fracture Assessment
Osteoporosis Diagnosis
Without a fracture or bone density screening there
is no way to diagnose the presence of
osteoarthritis.
The goal is to get as much information about
compounding risk factors:
A complete history of menstrual function, pregnancy, and
lactation should be obtained in women, and a history of sexual
function should be obtained in men, in whom decreased libido
and erectile dysfunction may be due to low testosterone levels.
Neurologic deficits and drugs that might increase the risk of
falls should be analyzed.
The family history should include fractures and evidence of
endocrinopathy or renal calculi.
One of the most important predictors of osteoporotic fractures
is a history of a fracture after age 40 due to minimal or
moderate trauma. In such persons, the fracture risk may be
increased severalfold.
The physical examination is often unremarkable. Spinal
deformity and tenderness over the lower back should be sought.
Osteoporosis Screening
1-X-ray findings are generally insufficient for the screening
of primary osteoporosis:
A normal x-ray of bone cannot reliably measure bone
density but is useful to identify spinal factures, explains
back pain, height loss or kyphosis.
X-rays may detect osteopenia only when bone loss is > 30%.
X-ray findings can also suggest other causes of metabolic bone
disease, such as the lytic lesions in multiple myeloma and the
pseudofractures characteristic of osteomalacia.

2-Bone densitometry is the only method for
diagnosing or confirming osteoporosis in the
absence of a fracture
The National Osteoporosis Foundation recommends that
bone densitometry be performed routinely in all women >
65, particularly in those who have one or more risk
factors.
Densitometry can also be used for monitoring the
response to therapy.
Screening - DEXA
Dual energy x-ray absorptiometry (DEXA)
DEXA measures areal density (ie, g/cm2) rather
than true volumetric density.

The test is non-invasive and involves no special
preparation.

Radiation exposure is minimal, and the
procedure is rapid. This is the most popular and
accurate test to date and the test only takes
about 20 to 40 minutes, with a 5 mrem dose of
radiation (a full dental x-ray is 300 mrem).
Screening - DEXA
Can be used to measure bone mineral density in the spine,
hip, wrist, or total body.
However, the standard apparatus is expensive and not
portable. Small DEXA machines that can measure the forearm,
finger, or heel are less expensive and are portable.
Screening - DEXA
DEXA of the proximal femur in a
young woman, age 37, with
unsuspected femoral-neck
osteopenia (T score, -1.6).
DEXA of the lumbar spine in a young
woman, age 37, with unsuspected
lumbar spine osteopenia (T = -1.8)
Screening - DEXA
Screening - DEXA
Screening- Ultrasound Densitometry
Ultrasound densitometry can assess the density and structure of the skeleton
and appears to predict fracture risk in the elderly. The apparatus is relatively
inexpensive, portable, and uses no radiation but can be used only in peripheral
sites (eg, the heel), where bone is relatively superficial. Ultrasound devices
measure the speed of sound (SOS), as well as specific changes in sound waves
(broadband attenuation or BUA) as they pass through bone. QUS measurements
provide information on fracture risk by providing an indication of bone density
and possibly also information on the quality of the bone. Ultrasound devices do
not expose the patient to ionizing radiation.

Osteoporosis Treatment & Prevention
1-Treatment of the patient with osteoporosis frequently involves
management of acute fractures as well as treatment of the underlying
disease

2-Patients should be thoroughly educated to reduce the likelihood of
any risk factors associated with bone loss and falling

3-A large body of data indicates that optimal calcium intake reduces
bone loss and suppresses bone turnover

4-Routine to recommend supplemental vitamin D

5-Exercise in young individuals increases the likelihood that they will
attain the maximal genetically determined peak bone mass. Meta-
analyses of studies performed in postmenopausal women indicate that
weight-bearing exercise prevents bone loss but does not appear to
result in substantial bone gain

6-Osteoporosis does not directly cause death. However, an excess
mortality of 10 to 20% occurs in patients with established osteoporosis,
particularly those with hip fractures.

7-Prevention of osteoporotic fractures is critical to avoid a worldwide,
costly epidemic. Prevention programs should be developed for patients
at risk and for patients with diagnosed osteoporosis.

Antiresorptive therapy: Persons with low bone mass and multiple
risk factors, particularly those who have already had an
osteoporotic fracture, should be considered for antiresorptive
therapy. Antiresorptive drugs include estrogens,
bisphosphonates, selective estrogen receptor modulators, and
calcitonin.

Estrogen can prevent menopausal bone loss in most women.
Estrogen replacement therapy (ERT) is the treatment of choice
for postmenopausal women, particularly those who had an early
menopause, and for women who have had a hysterectomy. ERT
is particularly effective during the first few years after
menopause when bone loss is most rapid. Epidemiologic studies
and the few prospective clinical trials of estrogen suggest that
ERT or HRT decreases the risk of osteoporotic fractures by 30 to
50%. Because other antiresorptive drugs may have an additive
effect when given with estrogen, combination therapy should be
considered in patients who have very low bone density, continue
to lose bone, or incur a fracture while taking ERT or HRT.
Bisphosphonates are potent antiresorptive drugs that directly
inhibit osteoclast activity. For women who cannot tolerate
estrogen or have contraindications (eg, preexisting breast
cancer, risk factors for breast cancer), bisphosphonates are
considered the next choice; these drugs increase bone mass and
decrease the risk of fractures, particularly in patients taking
glucocorticoids. Bisphosphonates, particularly alendronate, have
also decreased the incidence of vertebral and nonvertebral
fractures by >= 50% in large cohorts of postmenopausal women.

Alendronate is used to prevent (5 mg/day) and treat (10
mg/day) osteoporosis. Pamidronate is available IV for treatment
of hypercalcemia of malignancy and Paget's disease but has
been used in osteoporosis.
Selective estrogen receptor modulators (SERMs) have been
developed that are antiestrogenic and have antiresorptive effects
on bone.

Calcitonin has been used for many years in the prevention and
treatment of osteoporosis.

Other therapies: Anabolic therapies are under study; none is
approved for osteoporosis. Intermittent injections of parathyroid
hormone and fluoride stimulate bone formation and inhibit bone
resorption, but their safety and efficacy remain to be
established. Thiazides can decrease urinary calcium excretion
and slow bone loss. They may be particularly useful in patients
with hypercalciuria and osteoporosis (eg, those with idiopathic
hypercalciuria).
Management

Non-pharmacological Pharmacological
Non-pharmacological

1. Diet.
1000 mg Calcium daily intake for postmenopausal
women 24 % reduction in hip #.
5
1000 mg equivalent to 1 pint milk/50 g cheese/50
g sardines/1 pot of yogurt.
Avoid caffeinated products. Evidence inconclusive.

2. Regular exercise. Weight bearing exercise > 30
mins/day # rate.
4

3. Stop smoking. Pre-menopause leads to 25 %
# rate postmenopausal
4

4. alcohol consumption to < 21 units/wk
male, <14 units/wk women
4

Pharmaocological(NICE guidance)
3

1. osteoporosis, no # 2. osteoporosis,
already sustained #
Central DXA
Measures bone density at the hip and spine
DXA image of the hip
DXA image of the lumbar spine
Lateral Spine
Imaging with Fan-
Array
Dual Energy
X-ray
Absorptiometry
Vertebral Fracture
Assessment
Surgeon Generals
Report on
Bone Health and
Osteoporosis

Pyramid for Osteoporosis Prevention and Treatment
Pharmacotherapy
(antiresorptives and anabolics)
Address Secondary Factors
(drugs and diseases)
Lifestyle Changes
(nutrition, physical activity, and fall prevention)
What does this mean for your patients?
Leading the Effort to Help Prevent and
Treat Osteoporosis
US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. US Department of
Health and Human Services, Office of the Surgeon General; 2004.
Lifestyle Issues
Tobacco - eliminate it
Alcohol moderate it
Nutrition - adequate weight, protein--
magnesium, trace elements....multivite
Exercise strength, aerobic, flexibility,
balance
Fall prevention- home safety, shoes, walking
aids, glasses
Nutrition
Milk, Yogurt
Calcium, magnesium, potassium, phosphorus,
zinc, protein, vitamin A, vitamin D, vitamin
B12, riboflavin

Risk reduction for
Osteoporosis, hypertension, obesity, colon cancer, diabetes,
metabolic syndrome

Exercise
Walking reduces hip fracture risk
4 hours per week reduced hip fracture by 41% in a
study of 61,200 women
JAMA 2002

Activity of any type reduces fracture risk-
Balance, Strength, Flexibility, Aerobic
Hip Protectors
Calcium 1200 mg
Calcium has been singled out as a major health
concern today because it is critically important
to bone health and the average American
consumes levels of calcium that are far below
the amount recommended for optimal bone
health.

Surgeon Generals Report on Bone Health 2004
Calcium 1200 mg
Dietary
Fortified foods
Calcium citrate
Taken with or without food
Calcium carbonate
Taken with food
Divided doses
Vitamin D
Sufficiency > 32 ng/ml Comfort zone- 40s, 50s
Many wellness relationships
Insufficiency < 32 ng/ml
Disease states

New England Journal of Medicine July 19 2007
Medical Progress: Vitamin D Deficiency
M F Holick

800-1000 IU daily for patients 50 +

...although some elderly patients may require 2000 IU/day......

NOF Clinicians Guide 2008

Bisphosphonates Approved for Treating
Postmenopausal Osteoporosis
Fosamax Plus D
(alendronate sodium/
cholecalciferol) Tablets
and
Fosamax (alendronate sodium)
Tablets
INDICATION
Increases BMD
Reduces incidence of hip and spine
fractures
GENERIC Alendronate
Actonel and calcium the
other six days
(risedronate sodium
tablets/calcium 500mg )
and
Actonel (risedronate
sodium)
INDICATION
Increases BMD
Reduces incidence of vertebral
fracture and a composite end
point of nonvertebral fracture
Boniva
(ibandronate sodium) tablets

Boniva IV infusion

INDICATION
Increases BMD
fracture

Reclast IV 5 mg/year
DOSING 5 & 10 mg daily
Fosamax plus D
70 mg/2800 IU once weekly
Fosamax
35 mg once weekly or 5mg/day
70 mg once weekly or 10 mg/day
Fosamax Liquid
70 mg bottle once weekly
DOSING
Actonel 5 mg/day or
35 mg once weekly
Or with Calcium
75mg 2 days/month
150mgonce a month
ADMINISTRATION
Take at least 30 min before first
food of the day. Do not lie down
for at least 30 min after dosing.

DOSING
Boniva 2.5 mg/day or
150 mg once monthly

ADMINISTRATION
food of the day. Do not lie down for
at least 60 min after dosing.

Boniva 3 mg IV every 3 mos

Alendronic Acid Dose:
6

Men 10 mg daily
Women
i. 70 mg OW if postmenopausal,
ii. 10 mg daily if corticosteroid induced
osteoporosis not on HRT.

Strontium Ranelate
MOA: stimulates bone formation + reduces bone resorption.
6

Special instructions:
Avoid food 2 hrs before and after taking in particular calcium-
containing products

Side effects: severe allergic reactions such as drug rash with
eosinophilia and systemic symptoms (DRESS). Signs:
rash/fever/swollen glands/ WCC

Dose: 2 g OD.

Raloxifene
MOA: SERM, beneficial effects on bone, but
no effect on breast or endometrium.

CI: past VTE, endometrial carcinoma

Dose: 60 mg OD
Teriparatide
MOA: recombinant fragment of parathyroid
hormone. Increasing availability of Calcium.

Special instructions- only initiated by
specialists experienced in the treatment of
osteoporosis.

Dose: 20 mcg OD s/c
Denosumab
7
New NICE guidance
Tx option for the 1
0
prevention of osteoporotic # if the
following apply:

1. Postmenopausal women at ed risk of #
2. Unable to comply with special instructions for
administering alendronate/risedronate/etidronate
3. Intolerances or CI to the above
4. Can be used in pts who have a combination of T-score
+ age and no. of independent clinical risk factors for #
(see nxt box)
Vertebral Fracture Cascade
THE HUMAN COST
Downward Spiral
Other Connective
Tissue Diseases
Antiphospholipid Syndrome
Triad: Any TEST plus:
Thrombotic events
Spontaneous abortion(s)
Thrombocytopenia
Others: Migraine, Raynauds, Libman-
Sacks endocarditis, MR, Transverse
myelitis, neuropathy
Ab found in >30% SLE, other CTD
Correlates with IgG Ab and B
2

Glycoprotein I
Rx: Warfarin, heparin
PTT/LAC
RPR
Cardiolipin
3 Tests
Reiter's Syndrome
Arthritis that produces pain, swelling, redness and heat in the
joints. It can affect the spine and commonly involves the joints
of the spine and sacroiliac joints. It can also affect many other
parts of the body such as arms and legs. Main characteristic
features are inflammation of the joints, urinary tract, eyes,
and ulceration of skin and mouth.

The symptoms are fever, weight loss, skin rash, inflammation,
sores, and pain.
Reiter's Syndrome
Reiter's often begins following
inflammation of the intestinal or
urinary tract. It sets off a disease
process involving the joints, eyes,
urinary tract, and skin. Many
people have periodic attacks that
last from three to six months. Some
people have repeated attacks,
which are usually followed by
symptom-free periods.

Diagnosis is made through a
physical exam, skin lesions, and a
test for the HLA-B27 gene
Psoriatic Arthritis
Causes pain and swelling in some
joints and scaly skin patches on some
areas of the body.
The symptoms are:
About 95% of those with psoriatic arthritis
have swelling in joints outside the spine,
and more than 80% of people with
psoriatic arthritis have nail lesions. The
course of psoriatic arthritis varies, with
most doing reasonably well.
Silver or grey scaly spots on the scalp,
elbows, knees and/or lower end of the
spine.
Pitting of fingernails/toenails
Pain and swelling in one or more joints
Swelling of fingers/toes that gives them a
"sausage" appearance.
In early disease, pain occurs
only after joint use and is
relieved by rest

As the disease progresses, pain
occurs with minimal motion or
even at rest

Nocturnal pain is commonly
associated with severe disease
Treatment and Prognosis of
Meds
Early PT/exercises
Heat/cold therapy
Joint protection
Surgery

Osteoarthritis is a slowly progressive disease
The eventual outcome is complete destruction of the
joint, and ultimately surgical intervention is required
RHEUMATIC HEART
DISEASE IN CHILDREN
ACUTE RHEUMATIC FEVER
Autoimmune consequence of infection with Group A
streptococcal infection

Results in a generalised inflammatory response affecting
brains, joints, skin, subcutaneous tissues and the heart.

The clinical presentation can be vague and difficult to
diagnose.

Currently, the modified Duckett-Jones criteria form the
basis of the diagnosis of the condition.

RHEUMATIC HEART DISEASE
Rheumatic Heart Disease is the permanent
heart valve damage resulting from one or
more attacks of ARF.
It is thought that 40-60% of patients with ARF
will go on to developing RHD.
The commonest valves affecting are the mitral
and aortic, in that order. However all four
valves can be affected

Juvenile Idiopathic
Arthritis (JIA)
Juvenile
Idiopathic
Arthritis (JIA)
and Other
Rheumatic
Diseases in
Children
-
Etiology
Immune mediated disease
Abnormal immunoregulation
Abnormal cytokine production in the
inflammatory pathway (TNF, IL-6, IL-2R, IL-
1alpha)
Complex genetic predispositions
HLA associations
Environmental triggers
Infections
Trauma
Stress
Diagnostic Tests

There is no lab test that diagnoses
JIA
CBC
Rheumatoid factor
Antinuclear Antibody (ANA) with titer
ESR or CRP
Classification Criteria for JIA
Age at onset <16 years
Duration of Arthritis: 6 weeks
Arthritis in one or more joints defined as swelling
or effusion, or presence of two or more of the
following signs: (in 1 or more joints)
Limitation of ROM
Tenderness or pain on motion
Increased heat
Exclusion of other diseases

Chronic arthritis
in childhood: JIA
Its not a single disease, but a group of related,
genetically heterogeneous, phenotypically
diverse immunoinflammatory disorders
affecting joints and other structures, possibly
activated by contact with an external antigen
or antigens.
With onset of inflammation, the synovial lining thickens and secretes more fluid, which may remain in the joint
and cause swelling. The inflamed lining produces warmth, swelling, and pain.
As inflammation progresses, the synovial lining grows over the cartilage and starts to erode it. As inflammation
continues, changes include marked erosion of cartilage, cystic changes and thinning of the bone.
Polyarticular JIA - RF negative
Five or more joints in the
first 6 months of disease
Asymmetric joint
involvement
Large joints of knees,
wrists, elbows and ankles
often affected
Morning stiffness, joint
pain
Intermittent low-grade
fever
Polyarticular - RF positive
Arthritis affecting 5 or more joints in the first 6
months of disease.
Similar to adult RA
Females with onset in adolescence
Rheumatoid nodules
Early onset of erosive synovitis
Symmetric joint involvement
Small joints of hands or feet are affected
TMJ: micronathia
Cervical spine may be affected
Rheumatoid Nodules
Occur in 5-10% of children with
JIA
Most frequently on elbow
Pressure points, digital flexor
tendon sheaths, Achilles
tendons, bridge of nose in child
who wears glasses
Firm or hard, usually mobile,
nontender.
Solitary or multiple, may
change in size, may last months
to years.
JIA: Psoriatic Arthritis
Arthritis and psoriasis or
Arthritis with 2 of the following:
Dactylitis - sausage like swelling
of toe or finger
Nail pitting
Psoriasis in a first degree
relative (parents, siblings)
Slightly more females
Symmetrical involving large and
small joints
Medications
NSAIDs
DMARDs: Methotrexate,
Plaquenil, Sulfasalazine
Biologic response
modifiers
Glucocorticosteroids
Miscellaneous
Methotrexate
Standard dose: 10-15 mg/m2 or 0.3-0.6
mg/kg/week, subQ
Improvement seen in 6-8 weeks, but may take
up to 6 months.
Labs every 6 weeks: CBC, CMP
No alcohol
Used for treatment of uveitis (4-6 months to
determine efficacy)
Glucocorticosteroids
IV Solumedrol and daily oral Prednisone

systemic flares ~ pericarditis or persistent Sx
temporary measure until DMARD is effective

Joint injections - usually under sedation
Triamcinolone hexacetonide (Aristaspan)
long acting steroid
Works best with large joints
Of,of ......GATA
Bucuresti

REUMATOLOGIE

NOUTATI IN TRATAMENTUL BOLILOR REUMATICE

Anti-Resorptives
(Anti-Catabolics)
Bisphosphonates

Estrogens
SERMs
Raloxifene (Evista)
Calcitonin
(Miacalcin, Fortical, Calcimar)

Anti-Resorptives
(Anti-Catabolics)
Bisphosphonates

Estrogens
SERMs
Raloxifene (Evista)
Calcitonin
(Miacalcin, Fortical, Calcimar)

Bisphosphonates Approved for Treating
Postmenopausal Osteoporosis
Fosamax Plus D
(alendronate sodium/
cholecalciferol) Tablets
and
Fosamax (alendronate sodium)
Tablets
INDICATION
Increases BMD
Reduces incidence of hip and
spine fractures
GENERIC Alendronate
Actonel and calcium the
other six days
(risedronate sodium
tablets/calcium 500mg )
and
Actonel (risedronate
sodium)
INDICATION
Increases BMD
fracture and a composite end
point of nonvertebral fracture
Boniva
(ibandronate sodium) tablets

Boniva IV infusion

INDICATION
Increases BMD
fracture

Reclast IV 5 mg/year
DOSING 5 & 10 mg daily
Fosamax plus D
Fosamax
35 mg once weekly or 5mg/day
70 mg once weekly or 10 mg/day
Fosamax Liquid
70 mg bottle once weekly
DOSING
Actonel 5 mg/day or
35 mg once weekly
Or with Calcium
75mg 2 days/month
150mgonce a month
ADMINISTRATION
food of the day. Do not lie down
for at least 30 min after dosing.

DOSING
Boniva 2.5 mg/day or
150 mg once monthly

ADMINISTRATION
food of the day. Do not lie down for
at least 60 min after dosing.

Boniva 3 mg IV every 3 mos

Fosamax
(alendronate)
Cuts fracture risk by ~50%

Formulations:
5mg, 10mg, 35mg, 70mg
70mg + 2800IU D, 70mg + 5600IU D
70mg Liquid
GENERIC alendronate 70mg weekly
Actonel
(risedronate)
Cuts fracture risk ~50%

Formulations:
5mg, 35mg, 35mg + 6 day calcium packet
75mg two consecutive days monthly
150mg once monthly
Boniva
(ibandronate)
Cuts fracture risk ~50%

Formulations:
2.5mg, 150mg PO monthly

IV 3mg q 3 months
Zoledronate (Reclast)
5 mg IV annually

Will this change the way we view
pharmacological treatment of
osteoporosis? It has.
5 mg IV annually

Given within 90 days of Hip Fracture with a D3 load,
and FU Calcium and D
Increase BMD FN and TH

Reduction
Spine & non spine fractures 35%
Mortality 28%

Lyles NEJM 2007 357: 1799-1809
5 mg IV annually

Approved for Use in Men
Approved for GIO 2009
Approved for Prevention 2009
(2 year dosing regimen)
Bisphosphonates
Adverse events
GI (same as placebo in studies)
Flu-like Acute Phase Reaction
Bone pain
Hypocalcemia
Iritis/Uveitis
ONJ
Unusual subtrochanteric fractures

Comparative Risks
Data so far

Subtrochanteric fractures comprise 2-4% of all Hip
Fractures (fairly uncommon)

Unusual or atypical Subtroch femur fractures
Bisphosphonate associated fractures comprise 1/3 of those-
criteria are:
Thigh pain prodrome, pseudo-fracture appearance, lateral
beaking, transverse fracture pattern
Trabecular Bone Showed No Qualitative or
Quantitative Abnormalities in FLEX*
Alendronate/Placebo Group:
Average bone volume fraction,
16.5%
Alendronate/Alendronate Group: Average
bone volume fraction,
16.6%

* On-edge view is depicted.
1. Recker R et al. J Bone Miner Res. 2004;19(suppl 1):S45.
2. Data available on request from Merck & Co., Inc. Please specify 20650700(1)FOS.

Current Thought
Long term continuation: > 5 years
+ Reduction in clinical vertebral fracture with
long-term ALN (10 years)
Suggests most benefit from continuing ALN in those at high risk
of new vertebral fracture Others might be
discontinued
No clinical evidence for compromise in bone quality with
long-term treatment (any bisphosphonates)
Little guidance for long term continuation of bisphosphonates
other than ALN
(6 year trial of ZOL comingstudy end 12/09)
Black 2010
Current Thought
Continuing ALN for 10 years instead of stopping after 5
years
Reduces NVF risk in women even without prevalent
vertebral fracture, whose FN T-scores,
achieved after 5 years of ALN, are < or = -2.5
But does not reduce risk of NVF in women whose T-
scores are > -2.
Schwartz JBMR 5-2010
Current Thought

5 year plan

10 year plan
Anabolic Therapy
Action on the Osteoblast

rather than the

Osteoclast

Teriparitide (PTH 1-34)
The only anabolic agent for osteoporosis
Acts on the osteoblast
Given SubQ daily
Approved November 2002
Indications- severe osteoporosis, GIO, men
Given for 12 - 24 months
Followed with an antiresorptive agent
Teriparatide
Adverse events
Osteosarcoma in rats
Hypercalcemia 11% vs 1%
Dizziness 2.6% vs 1.4%
Leg cramps 2.6% vs 1.3%
New and Emerging Treatments
Antiresorptive (anti-catabolic)
Denosumab (Prolia)
Odanacatib
Lasofoxifene
Bazedoxifene
CE/bazedoxifene
New delivery systems -
oral salmon calcitonin

Osteo-anabolic (bone-forming)
Sclerostin inhibitor
Variations of PTH
Endogenous PTH
stimulation - calcium
sensing receptor antagonist
(calcilytic)
New delivery systems
transdermal PTH
Strontium ranelate Combinations
of antiresorptive and anabolic
Denosumab (Prolia)
(Anti-resorptive agent)
Approved June 1, 2010
Made by Amgen

A fully human monoclonal antibody that binds
with high affinity to, and inhibits the activity
of, human RANK ligand, a key mediator of
osteoclast activity

RANKL is Implicated in Bone Loss Across a Broad
Range of Conditions
Postmenopausal osteoporosis
Male osteoporosis
Disuse osteoporosis
Transplantation osteoporosis
Inflammatory arthritis
Periprosthetic osteolysis
Hyperparathyroidism
Cancer-induced bone loss
Bone metastases, multiple myeloma
Treatment-induced bone loss
Glucocorticoids, aromatase inhibitors, androgen deprivation therapy
RANKL Stimulates Bone Resorption
Growth Factors
Hormones
Cytokines
RANK
RANKL
Activated
Osteoclast
CFU-M
Pre-Fusion
Osteoclast
Multinucleated
Osteoclast
RANK Ligand Is Essential for Osteoclast Formation, Function, and Survival
Bone
CFU-M = colony
forming unit
macrophage
Adapted from Boyle WJ, et al. Nature. 2003;423:337-342.
Osteoblast
Lineage
Denosumab Mechanism of Action
Growth Factors
Hormones
Cytokines
Bone
CFU-M = colony
forming unit
macrophage
Osteoblast
Lineage
Osteoclast
CFU-M
Pre-Fusion
Osteoclast
Multinucleated
Osteoclast
RANK
RANKL
OPG
Dmab
Dmab-FREEDOM Results
68% decrease in vertebral fractures
2.3% vs 7.2%, P<0.0001
40% decrease in hip fractures
0.7% vs. 1.2%, P=0.036
20% decrease in non-vertebral fractures
6.5% vs. 8.0%, P=0.011
Dmab increased BMD and reduced BTMs compared to
placebo
AEs and SAEs generally similar to placebo
No increased risk of cancer, infection, CV disease, delayed fracture
healing, hypocalcemia, no ONJ
Increased risk of cellulitis, eczema, flatulence
Decreased risk of falls, concussion
Cummings SR et al. N Engl J Med. 2009;361:1-10.
Choosing Therapy
Deciding who to treat
Utility of DXA and VFA
Using NOF 2008 & FRAX to guide clinical decisions

Deciding how to treat
Non-pharmacologic therapy
Pharmacologic therapy
Initial choice of therapy- Anticatabolic or Anabolic agent
Prevention vs Treatment Dosing
Sequential therapy- Forteo
Repeat therapy- Forteo
Multiple T cell Subsets Contribute to the Development of Arthritis
adapted from McInnes and Schett, Nat. Rev. Immunol., 7:429-442, 2007
CD4
CD28
Key Factors that Regulate Osteoclast Differentiation
in Arthritis
Nature Reviews Immunology, 2007
Th17 Cells Contribute to Cartilage Distruction
in Additional Ways
Progressive Chronic Inflammation Can Lead to Joint Destruction
Early Arthritis - soft tissue swelling,
especially around the PIP joints
Chronic inflammation
in the joint leads to
bone destruction
evident as erosions
Prolonged severe
chronic arthritis
leads to deformity and
disability.
What is the Immune Response Directed Against?
Very Diverse Autoantigens
Lyme Disease:
Residual Organisms
Cross-reactive antigens

Rheumatoid Arthritis:
Type II collagen
IgG (rheumatoid factor)
Citrullinated proteins (arginine residues modified)

Systemic Lupus Erythematosus (intra- and extra-cellular antigens):
Nuclear antigens:
Ribonuclear proteins
Histones
dsDNA
Leukocyte cell surface antigens
Cardiolipin

Rheumatoid Factors: An Auto-antibody to Self IgG Fc
Homogeneous
ANA

Nucleolar
ANA
Speckled
ANA

Centriolar
ANA
Multiple Nuclear Antigens Can be Detected by Autoantibodies
in Sera of Patients with Rheumatic Diseases
Why does tolerance fail?

Why do people develop auto-immune
rheumatologic diseases?
Factors that Predispo se an Individual
to Rheumatologic Diseases

I. Susceptibili ty Genes

A. MHC class I (i.e., HLA-B27 in
spond yloarthropathies)

B. MHC class II (i. e. HLA-DR4 in RA)

C. Complement d eficienc y states (i. e., C2 or C4
deficiency in SLE)

D. Fc Receptor Polymorphisms (i. e., FcR
deficiency in SLE)

E. PTPN22, a tyrosine phosphatase, polymorphism
associated with rheumatoi d arth ritis, SLE, others

F. Gende r (female:m ale cases of SLE ar e 9:1)

G. Others (48 susceptib ilit y loci for SLE in the
genome)

Genetic Basis of Rheumatic Diseases:
Genotype contributes to rheumatic disease susceptibility
________ Twin Studies____________
Monozygotic Dizygotic Genetic Component
Disease Concordance (%) Concordance (%) Explained by HLA (%)

Rheumatoid Arthritis 15-34 0-6 35

SLE 25-57 0-3

Ankylosing Spondylitis 50-75 13-18 37
______________________________________________________________________________
Most often rheumatic diseases are polygenic. A certain
genotype predisposes an individual to a disease, but does
not make disease development a certainty.
Genome Wide Scan of SNPs Associated with RA
Plenge et al. NEJM. 357:1199 (2007)
A common polymorphism in PTPN22 confers susceptibility to
multiple autoimmune diseases
- RA, Lupus, T1 diabetes, Hashimotos Thyroiditis

Whole genome scan for RA
PTPN22 is #2 hit
Odds ratio < 2
II. Environmental Factors

A. Viral infect ions (hepati tis B, hepatitis C, others)

B. Bacterial infecti ons (Shigella, Salmonella,
gp A strep., etc.)

C. Drugs (procainamide, dilantin, others)

D. Toxins (heavy metals, others)

E. UV-light (i.e., in SLE)

III. Status of the Immune System

A. Relative state of activation

B. Relative balance of Th1 and Th2

C. History of previous respo nses

IV. Status of Targ et Organ/Tissue

A. Visibi lity of autoantigen (privileged sites,
intra- vs extra-cellular, etc)

B. Expression level of autoantigen

C. Expression level of MHC

D. Costimulatory molecules

E. Ongoing inflamma tion
Multiple Factors Contribute to the Development of Arthritis
Clinical Features

Acute Arthritis
Rapid onset (hours or days)
Severe symptoms
Mediated by components of innate immune response,
especially neutrophils (proteases, leukotrienes, prostaglandins, etc.)
Can result in rapid joint destruction
Can also evolve into chronic disease
Examples: Gout and Infectious Arthritis

Chronic Arthritis
More gradual onset (days to weeks)
Symptoms are more moderate, AM stiffness is a prominent symptom
Mediated by the adaptive immune response, especially T cells
and macrophages - a Th1 disease
Cytokines and chronic inflammation lead to joint remodeling and
destruction via erosions
Examples: Rheumatoid Arthritis, Ankylosing Spondylitis, SLE,
Lyme Disease

Pattern of Joint Involvement is Distinct in Different Diseases

Monoarticular vs Polyarticular
Mono Poly
Gout RA
Infection SLE
Reactive

Joint distribution
PIPs and MCPs: RA, SLE
DIPs: Osteoarthritis, Psoriatic
MTP: Gout

Symmetrical vs Asymmetrical
Symmetrical: RA, SLE
Asymmetrical: Psoriatic, Reactive

Rheumatic Disease Are Systemic Inflammatory Diseases with
an Underlying Immune or Inflammatory Pathogenesis
Disease Organ System Involvement

Rheumatoid Arthritis Joints (arthritis)
Vessels (vasculitis)
Eyes (scleritis and episcleritis)
Hematologic (anemia, thrombocytosis)
Pulmonary (plueritis, alveolitis, etc,)

Systemic Lupus Erythematosus (SLE) Joints (arthritis)
Skin (photosensitive rash)
Serosa (pericardium & pleura)
Hematology (anemia, thrombocytopenia)
Kidneys (glomerulonephritis)
Lungs (interstitial disease, alveolitis, etc.)
CNS (cognitive dysfunction, seizures, etc.)

Lyme Disease Joints (arthritis)
Skin (Erythema chronicum migrans)
Heart (carditis)
CNS (meningo-encephalitis)

Rheumatoid Arthritis is Systemic
Inflammatory Disease
SLE is a Systemic Inflammatory Disease
Therapeutic Strategies
Reagents that blunt inflammation but dont have effects on disease progression:
Aspirin
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Non-selective and selective COX-2 antagonists
Steroids (prednisone)

Disease Modifying Anti-Rheumatic Drugs (DMARDs):
Broad Acting:
Methotrexate
Hydroxychloroquin
Azathoprine
Cyclophosphamide
Cyclosporin
More selective biologics:
TNF antagonists
IL-6R antagonists
IL-1R antagonists
anti-B cell (CD20) therapy
costimulatory inhibitors (CTLA4-Ig)
Intravenous Immunoglobulin (iv Ig)

Choy, E. H.S. et al. N Engl J Med 2001;344:907-916
Methods of Blocking the Activity of an Inflammatory Cytokine
Blocking CD28-dependent Costimulation
Abatacept is a fusion of the extracellular domain of CTLA-4 (similar to CD28 but with higher affinity for CD80
and CD86) with the Fc fragment of IgG1 (for effector function and to prolong half-life)
From: Moreland
http://www.medscape.com/viewprogram/3415_pnt
Biological Therapeutics
Targets, Rationale, Status
Update in Rheumatology

Wilmer L. Sibbitt, Jr., M.D.
1

1
Departments of Internal Medicine, Rheumatology and Neurology
University of New Mexico Health Sciences Center , Albuquerque, NM, USA

Educational Objectives:

1. To be aware of advances in diagnosis of
rheumatic diseases

2. To understand the application of new
antirheumatic therapies
Joint Swelling
What is the Cause?
Major Rheumatic Diseases
Osteoarthritis
Systemic Lupus
erythematosus
Systemic Sclerosis
Spondyloarthropathies
Poly-Dermatomyositis
Crystal - Induced
Arthritis
Septic Arthritis
Vasculitis
Joint Swelling - Synovial Effusion
Arthrocentesis and Injection therapy
Mark Anatomy with Pen and Choose Approach
Anteriolateral
Inferiopatellar
Approach
Tibial
Plateau
Patellar
Tendon
Patella
Lateral
Suprapatellar
Bursa
Antisepsis with Chlorhexidine
US-Image
Guidance

Portable US Unit
with Multiple
Imaging and
Doppler
Capabilities
US - IA Injection
with Assistant
Ultrasound-Directed Procedures
US - IA Injection
with One-hand
Ultrasound Guidance for IA Injections
Sibbitt WL Jr et al J Rheumatol. 2009 Sep;36(9):1892-902
Osteoarthritis: A Progressive Disease
Updated Therapy for Osteoarthritis
Glucosamine or Glucosamine/Chondroitin
supplements
Reduce injury to joint (weight loss, treat
gout, etc).
Acetaminophen and analgesics
Conventional or COX-2 Inhibitor NSAIDS
IA injections with corticosteroids
IA injections with hyaluronic acid
Reconstructive surgery
American College of Rheumatology Subcommittee on Osteoarthritis
Guidelines. Recommendations for the Medical Management of Osteoarthrits of
the Hip and Knee, Arthritis & Rheumatism. 2000:43;1905-1915
1st-Low dose corticosteroids - short/long term
1st -Methotrexate - long term
2nd - Leflunomide - long term
2nd - Anti-TNF Agents (anti-Tumor Necrosis Factor)
- best overall therapy
3rd - Kineret (anakinra) - IL-1 receptor
3rd - Orencia (abatacept)- anti-T cell agent
3rd - Rituxan (Rituximab) anti-B cell therapy
1st-3rd - Corticosteroid joint injections
4th - Reconstructive surgery
Reference: American College of Rheumatology 2008 Recommendations for the Use of Nonbiologic and
Biologic Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis Arthritis & Rheumatism. Vol. 59,
No. 6, June 15, 2008, pp 762-784
Methotrexate
Obtain PPD, Chest X-ray, renal and hepatic tests,
and exclude HCV before starting
Good long-term efficacy and tolerability
Slows radiographic measured erosions
Hi-risk in elderly and renal impaired patients
Chemical monitoring indicated
Hepatic biopsy rarely indicated
Be aware of pulmonary toxicity in first 4 months
of therapy
Anti-TNF Drugs
Enbrel
- entanerocept - SC - 50 mg/wk
Humira
- adalimumab - SC - 40 mg/q 2wks

Remicade
-infliximab - IV - 3-10mg/kg/4-8 wks

Cimzia
- certolizumab - SC - 400 mg/4 wks

Simponi
- golimumab - SC - 50-100 mg/4 weeks

Anti-TNF Drugs
Months
TNF-MTX
TNF
MTX
Placebo
Orencia (abatacept)
anti-T cell agent
Fully human soluble immunoglobulin fusion
protein
Selective Co-stimulation Modulator
Interferes with CD80/86-CD28 interaction.
30 min IV infusions at 0, 2, and then q 4 weeks.
< 60 kg 500 mg, 60-100 kg 750 mg and
weighing >100 kg 1000 mg.
50.4 % response (ACR) rate at 6 months
(19.5% placebo)
Infections, headache, flu-like symptoms,
infusion reactions, nausea.
Orencia (abatacept)
anti-T cell agent
Rituxan (Rituximab)
anti-B cell agent
depletes CD20+ B-cells
methylprednisolone 100 mg IV, then
two-1000 mg IV infusions at 0 and
2 weeks.
51 % response rate at 6
months (14% placebo)
Infections, flu-like symptoms,
infusion reactions, severe
mucocutaneous reactions.
Warning with Biologic Anti-Rheumatic agents!
Active infection - TB, HCV, HCB should be excluded.
Biologic agents should not be given with any active
infection.
If PPD +, must receive prophylactic therapy
Patients should receive non-live vaccines
Vaccinate for pneumococcus and influenza.
Infections should be promptly treated and agent
withheld at least temporarily
Herpes Zoster (shingles) should be recognized and
treated promptly.
Be aware of increased incidence of lymphoma.
Chronic or Tophaceous Gout
Acute Gout
Diagnostic Tests for Gout
Serum uric acid x several times
Athrocentesis for crystal examination
Exclusion of RA, SLE, infection, CPPD,
Reiters syndrome
Hand and foot radiographs
CBC, Cr, uric acid, Ca, Electrolytes
Hepatic enzymes, UA
24 hr urine for creatinine and uric acid
Hyperuricemia Syndromes
Stage 1 -Asymptomatic hyperuricemia (uric
acid < 7.0 mg/dl)
Stage 2 - Acute gouty arthritis (acute gout)
Late Stage 2 - Intercritical gout (frequently
occuring acute gout)
Stage 3 - Tophaceous or chronic gout
Uric acid nephrolithiasis
Acute uric acid nephropathy
Chronic sodium urate nephropathy or
interstitial nephritis
Annual Gout Prevalence Among All Enrollees by Age
Group 1990-1999
J Rheumatol Aug 2004
Therapy for Gout
Acute: NSAIDS, Prednisone, IA Corticosteroids
Prophylaxis: Colchicine .5-.6 mg qd-bid
Chronic: Allopurinol 100-900 mg qd to keep uric acid below 6
mg/dl,
Febuxostat 40 to 80mg qd
Urocosuric agents less preferable.
Do not use high dose colchicine - toxic!
Do not use IV colchicine - may be fatal!
Avoid NSAIDs with renal insufficiency

Updated Therapy for Acute Gout
1) High Dose Oral NSAIDS (if no history of PUD, hemorrhagic
diathesis, anticoagulants, ASA sensitivity or renal
insufficiency)
2) NO High Dose Oral Colchicine (toxic)
3) NO Intravenous Colchine (toxic and sometime fatal)
4) Short term high dose oral corticosteroids
5) Intraarticular injected corticosteroids
5) Continue Allopurinol, Febuxostat or uricosuric agents
through attack.
Updated Therapy for Chronic or
Tophaceous Gout
1) Life-long treatment for tophaceous or frequent gout, erosions on radiographs, extreme
hyeruricemia (uric acid > 8.6 mg/dl), nephrolithiasis, or osteoarthritis in affected joints.
2) If normal renal function, start prophylactic colchicine 0.6 mg bid, and allopurinol at 100-
300 mg qd, increase up to 600 to 900 mg qd based on uric acid
3) For renal impairment (Cr >2 mg/dl or GFR< 50ml/min), start cochicine at 0.6 mg qd and
allopurinol 100 mg qd, but increase allopurinol based on serum acid level not GFR; if
nephrologists do not permit allopurinol then febuxostat 40 mg per day.
4) No high dose or IV colchicine; discontinue after 6 months,
5) Avoid or limit daily NSAIDS unless no contraindications
6) Do not stop allopurinol, febuxostat, or uricosuric agents during acute gouty attack.
7) Goal is to radically reduce serum uric acid (4.0-5.9 mg/dl)
Reference: Quality of care indicators for gout management. Arthritis Rheum 2004;50:937-43
Febuxostat - Uloric
A nonpurine, selective inhibitor of xanthine oxidase
FDA approved for treatment of gout
Current data support
Potent inhibition with significant urate reduction
Ability to administer in renal insufficiency
1
and mild or moderate hepatic insufficiency
with no dosage adjustments
2
Safe, effective and well tolerated in limited data of allopurinol intolerant patients
3
N
N
N
H
N
OH
Allopurinol
1. Swan et al. Arthritis Rheum. 2003;48(9):S529.
2. Khosravan et al. Arthritis Rheum. 2004;50(9):S806.
3. Becker et al. Arthritis Rheum. 2004;50(9):S803.
Febuxostat
O
NC
N
CO
2
H
S
CH
3
CH
3
H
3
C

Febuxostat - Uloric
Elimination both hepatic and renal.
Can use in subjects hypersensitive to allopurinol.
Dosing: Febuxostat 40mg to 80 mg by mouth per day
For renal insufficiency start 40 mg po qd
Laboratory testing: 2-4 weeks Uric acid, CBC, hepatic enzymes,
Cr
Most common side effects: nausea (1.3%), arthralgias (1.1%),
gout flare, rash (1.6%)
Do not use with or adjust dosage with drugs metabolized by
xanthine oxidase - theophylline, mercaptopurine, and
azathioprine

Rheumatoid Arthritis: Modern Management of an
Ancient Disease

Dr Chandini Rao
Consultant Rheumatologist

RHEUMATOLOGY IN THE
21
st
CENTURY
548
History of Rheumatoid Arthritis (RA)
123 AD first text describes symptoms very
similar to RA

1800 first recognised description of RA by
French physician Dr A J Landr-Beauvais
(1772-1840)

1859 name rheumatoid arthritis" itself was
coined by British Dr A B Garrod.
549
What is it?
Chronic, progressive, autoimmune
disease
Causes inflammation in joints
(especially hands, wrists, feet)
Systemic condition

550
What is inflammation?
Normal body defence mechanism
Increased blood flow
Blood cells produce chemical
messengers to continue the process
Heat, swelling, redness, pain, loss of
function
551
553
554
555
What causes RA?
Genetics
Environment

556
Genetics
1st degree relative: 2-7 fold risk
Identical twin: 16% chance of RA
Need an environmental trigger as well
557
Environment
Geography
Hormones
Infection
Smoking
Diet
558
Symptoms
Joint pain
Joint swelling
Morning stiffness
Fatigue
Weight loss
Flu-like symptoms

559
What else does RA do?
Eyes: dryness, inflammation
Lungs: fluid, inflammation, nodules
Skin: nodules, ulcers
Heart: fluid, inflammation, ischaemic
heart disease
Blood: anaemia, low counts
560
How is RA treated?
General Principles:
Patient education/self-management
Multi-professional team care
Medication
Surgery

561
Symptomatic Treatments
Education/support
Rest/relaxation
Joint protection
Physiotherapy
Painkillers
Anti-inflammatory drugs
Steroids
Joint injections
Pain Management Clinics
562
Reduction of Joint Damage
Disease-modifying Anti-Rheumatic
Drugs (DMARDS)

Methotrexate
Sulfasalazine
Leflunomide
Hydroxychloroquine
Azathioprine
Ciclosporin
Gold
Penicillamine

Biologic drugs

Anti-TNF therapy:
Infliximab
Etanercept
Adalimumab
Certolizumab
Golimumab
Rituximab
Abatacept
Tocilizumab

563
Goals of Therapy
To relieve pain, stiffness, swelling,
fatigue
To prevent joint damage/disability
To improve quality of life
? To achieve disease remission
564
Principles of Treatment
Early diagnosis
Early initiation of treatment
Regular assessment (Disease Activity
Scores)
Treat to Target
Annual review
565
Famous people with RA
Dorothy Hodgkin: Nobel prize winning scientist,
developed severe RA at age 28. Developed X-ray
crystallography, discovered the structure of insulin and
enabled discovery of the genetic code.

Christiaan Barnard: performed first heart transplant in
1967, 11 years after developing RA. Wrote a book on
living with arthritis

Kathleen Turner: Hollywood actress

Bob Mortimer: British comedian

566
Pierre-Auguste Renior
(1841-1919)
French, impressionist
1892 RA 51 yrs

567
568
569
570
571
Early RA
572
ADVANCED RA.
573
Psoriatic Arthritis
574
The next Members health seminar will
take place on:-

Thursday, September 22nd 2011
12 -1 pm in the Lecture Theatre,
Education Centre, BVH
The topic is:
Bereavement across Lancashire and South
Cumbria.

Rheumatic Fever
Normal Heart Anatomy
Rheumatic Fever (RF)
Definition:
Rheumatic fever (RF) is an autoimmune
disease affecting the heart and extracardiac
sites (joints, brain, skin and others)

The incidence of RF has been lowered in the
developed countries but is still high in poor
communities
The disease affects children and young adults
(5-15years)
The disease follows upper respiratory
infection (tonsillitis) with Group A Beta
hemolytic streptococci
Theories of Pathogenesis:

Toxic products of streptococci
Immunologic cross-reactivity between
Streptococcal substances and heart muscle (heart
reactive antibodies)
Sensitized T-lymphocytes may lead to cardiac
injury

JONES' CRITERIA FOR DIAGNOSIS OF RF:
Major Manifestations
Carditis (friction rub, murmur,
cardiomegaly, CHF)
Arthritis (migratory
polyarthritis, swollen, red,
tender)
Chorea
Erythema marginatum

Minor Manifestations
Clinical
Fever
Arthralgia
History of rheumatic fever or
rheumatic heart disease
Laboratory
Acute phase reactants (ESR,
C-reactive protein,
leukocytosis)
Prolonged P-R interval on
ECG

PATHOLOGY OF RHEUMATIC FEVER
Cardiac Disease (Rheumatic heart disease)
Extra-Cardiac Disease
RHEUMATIC HEART DISEASE
Rheumatic heart disease: all the heart layers
are affected (pancarditis)
1. Rheumatic myocarditis
2. Rheumatic pericarditis
3. Rheumatic endocarditis

1- Rheumatic myocarditis:
Acute phase: it is characterized by the development of
pathognomonic lesions called Aschoffs Bodies within the
myocardium.

Gross features:
Aschoff bodies are multiple tiny nodules (1-2 mm in
diameter)

Microscopic features:
Aschoff body is a lesion composed of:
Fibrinoid necrosis ( destroyed fragmented collagen)
Surrounded by lymphocytes and histiocytes &
Aschoff cells (large mononuclear or multinuclear macrophages)

Aschoffs body
Blood vessel
fibrinoid degeneration
Aschoff cells
Chronic phase:
Over years or decades the Aschoff bodies
undergo fibrous scarring
2- Rheumatic Pericarditis:
Acute phase: Aschoff bodies are formed
accompanied by serofibrinous inflammation.

Chronic phase: Fibrosis and adhesions may occur
between the visceral and the parietal layers of the
pericardium
3- Rheumatic Endocarditis:
It affects both mural and valvular endocardium
1. Mural Endocardium:
i- Acute phase: Aschoff bodies develop in the
endocardium
ii- Chronic phase: healing results in a white patch
Valvular Endocardium

Vegetations (thrombi) develop at the lines of
contact of the cusps causing friction of the
swollen cusps.

Rheumatic Mitral Valve
Small vegetations are
formed at injured parts
CHRONIC RHEUMATIC VALVULAR DISEASE
Mitral & Aortic Valves Pathology:
Thickening of valve leaflet, especially along the lines
of closure
Fusion of commissures
Result is mitral or aortic stenosis, insufficiency, or
both

Rheumatic Mitral Stenosis
Thick valve leaflet
Fusion of commisures
EXTRACARDIAC LESIONS OF RHEUMATIC FEVER
Joints: Rheumatic arthritis affect the large joints in a fleeting way i.e
joint inflammation is followed by joint resolution, then another joint
become inflamed followed by resolution and so on. The affected joint is
painful, tender, hot & swollen.

Brain: Rheumatic chorea (rapid involuntary purposeless movements); it
is due to inflammation of the basal ganglia. The condition is reversible

Skin: Rheumatic subcutaneous nodules occur over bony prominences
and their structure is similar to the Aschoff bodies.

Rheumatic arteritis: affecting the coronaries, renal, mesenteric and
cerebral arteries

Pleurisy and peritonitis: serofibrinous type
PERICARDIAL DISEASES

I. PERICARDITIS

Inflammation of the pericardium
Causes
MI, Staphylococcus, tumor, TB, uremia

II. PERICARDIAL EFFUSION
Serous fluid in pericardial sac
Usual cause: Chronic Heart Failure

III. HEMOPERICARDIUM
Myocardial rupture from MI
Trauma
Bleeding from infection, tumor, etc.
Haemorrhage from aorta

Hemopericardium
Hemopericardium

Presented by:
Praharsha R. Menon
PGY 2
03/18/2010

Q: What do comedienne Lucille Ball, French
painter Pierre-Auguste Renoir, Hollywood
actress Kathleen Turner and heart transplant
surgeon Dr. Christiaan Barnard have in
common?

A: Rheumatoid Arthritis
Key Features
Symmetric, inflammatory polyarthritis
Autoimmune
Females > Males
Symptoms > 6 wks
Morning stiffness > 1 hr
> 3 joints involved
Spares:
Thoracolumbar spine
DIP of fingers
www.cks.nhs.uk/.../rheumatoid_arthritis_arc
Nodules: S/C or periosteal, at pressure points
Rheumatoid factor :
Ab : recognizes Fc portion of IgG
+: implies c/c inflammation
70 % + at onset, 85% + in first 2 yrs
Associated with more severe disease,
extra-articular manifestations,
mortality
Rheumatoid Nodule
Stage I:
Acute: synovial thickening; confined to joint capsule
Stage II:
Persistent inflammation c/c pain, joint damage
Stage III:
Inflammation and damage limiting joint function
Stage IV:
Permanent joint damage and deformity disability

Extra-articular features
General
fever, lymphadenopathy, weight loss, fatigue
Dermatologic
palmar erythema, nodules, vasculitis
Ocular
episcleritis/scleritis, scleromalacia perforans, choroid
and retinal nodules
Cardiac
pericarditis, myocarditis, coronary vasculitis, nodules
on valves

Neuromuscular
entrapment neuropathy, peripheral neuropathy,
mononeuritis multiplex
Hematologic
Feltys syndrome, large granular lymphocyte syndrome,
lymphomas
Pulmonary
pleuritis, nodules, interstitial lung disease, bronchiolitis
obliterans, arteritis, effusions
Others
Sjogrens syndrome, amyloidosis

Diagnosis
Score >/= 6 : diagnosis
Joint Involvement
Serology
Duration of synovitis
Acute phase reactants
MITCHEL L. ZOLER; FEBRUARY 1 5 , 2 0 1 0 FAMILY PRACTICE NEWS
Joint Involvement
1 medium-large joint (0 points)
2-10 medium-large joints (1 point)
1-3 small joints (2 points)
4-10 small joints (3 points)
More than 10 small joints (5 points)
Serology
RF neg, Anti CCP neg (0 points)
RF +/ Anti CCP + at low titer (2 points)
RF +/ Anti CCP + at high titer (3 points)
Low titer: > upper lmt. of normal, upto 3x
upper lmt of normal
High titer: > 3 x upper lmt. of normal
Duration of synovitis
< 6 weeks: 0 points
>/= 6 weeks: 1 point

Acute phase reactants:
CRP and ESR normal : 0 points
Abnormal CRP or abnormal ESR : 1 point

Clinical course
Type 1 = Self-limited: 5%
to 20%

Type 2 = Minimally
progressive:5% to 20%

Type 3 = Progressive:
60% to 90%

Bloodwork
CBC: AOCD
Thrombocytosis
Leukopenia in Feltys syndrome
ESR
CRP
RF
Other: based on Differential diagnosis

Radiologic progression
Differential Diagnosis
Spondyloarthropathies
CTDs
Gout
CPPD
Viral infections
Fibromyalgia
Lyme disease
Rheumatic fever
Treatment guidelines
Confirm the diagnosis
Determine where the patient stands in the
spectrum of disease
When damage begins early, start aggressive
treatment early
Use the safest treatment plan that matches the
aggressiveness of the disease
Monitor treatment for adverse effects
Monitor disease activity, revise Rx as needed

Medications:
NSAIDs
Steroids
DMARDs:
Biologic: anti- TNF, Abatacept, Etanercept,
Rituximab, Infliximab, Adalimumab
Non- biologic: Methotrexate, Leflunamide,
Sulfasalazine, Hydroxychloroquine, Minocycline,
Gold
Baseline evaluation
MTX, Lef, Min, SSZ, HCQ, all biologic agents:
CBC, Liver transaminases, Crn
In addition: Ophthal. Exam for HCQ; Hep B and C testing for Lef,
MTX
Monitoring:

Therap. agents <3 months 36 months >6 months
HCQ None after
baseline
None None
Leflunomide 24 weeks 812 weeks 12 weeks
Methotrexate 24 weeks 812 weeks 12 weeks
Minocycline None after
baseline
None None
Sulfasalazine 24 weeks 812 weeks 12 weeks
Summary: Evidence- based rating of
recommendations
Patients with rheumatoid arthritis should be treated
ASAP with DMARDs to control symptoms and delay
disease progression. A
Patients with persistent inflammatory joint disease (> 6-
8 weeks) already receiving analgesics or NSAIDs should
be considered for rheumatology referral, preferably
within 12 weeks. C
Combination therapy may be more effective than
treatment with one drug alone. A
Exercise is beneficial for aerobic capacity and muscle
strength with no detrimental effects on disease activity
or pain levels. C

Rindfleisch J.A.: American Family Physician; Sep 15, 2005
What tests should be ordered?
A 15 year old girl with multiple joint pains and
joint swelling

A 8 yo boy with persistent fevers, intermittent
rashes, and joint pain

Juvenile Idiopathic Arthritis
CBC-D
ESR
ANA
If polyarticular course, add RF
If older onset with sacroiliac tenderness and
tendon insertion site tenderness, add HLA-B27
If systemic course, add LFTs and coags
(PT/PTT/d-dimers/fibrinogen)

A 13 year old Hispanic girl with a facial rash,
joint pain, mouth sores, fatigue, and blood in
her urine

Systemic Lupus Erythematosus
CBC-D
ESR
ANA
dsDNA
C3/C4 levels
Urinalysis and Urine protein/creatinine ratio
Antiphospholipid Antibodies (Anti-cardiolipin
ab, PTT, DRVVT, and LAC, B2glycoprotein)

A 6 year old boy with muscle weakness, leg
pains, and rash over his eyelids and on his
elbows
Dermatomyositis
CBC-D
ESR
ANA
CPK
Aldolase
LDH
AST/ALT

A 10 year old boy with difficulty swallowing,
facial rash, joint pain, and shortness of breath,
muscle pain

Mixed Connective Tissue Disease
CBC-D
ESR
ANA
ENA (anti-RNP and anti-Sm)
Consider Pulmonary Function Tests, ECHO,
Swallowing studies

A 13 year old girl with recurrent sinusitis, rash,
cough, joint pain, and hematuria
Vasculitis
(Wegeners Granulomatosis)
BUN/Cre
ANCA
ESR
CBC-D
Urinalysis, Uprot/cr
vWAg
(PFTs, Sinus and Chest CT)

A 17 year old woman with tightening of her
skin, tapering of her fingertips, and cold blue
hands and feet
Scleroderma
ANA
Anti-Scl 70 antibody
Anti-centromere antibody
Antiphospholipid antibody

Tumors of Bone
Patrick Henderson, M-IV
USCSOM
August 28, 2007
Bone Tumors
Prof. Hussien Gadalla
General considerations
Primary bone tumors are much less than
secondary tumors.
All age groups affected, but some tumors
occur in certain age
Almost every bone can be affected, but some
tumors prefer certain location
Most of the tumors give osteolytic lesion in X-
ray, but few are osteoblastic
Age of Tumors
20>..osteoid osteoma, osteoblastoma,
osteogenic Sarcoma, Ewings.

20- 40Giant cell tumors, Secondary
Osteogenic Chondrosarcoma, Lymphoma, Mets.

60Mets, Myeloma, Chondrosarcoma, MFH,
Fibrosarcoma.
Site or location of Tumors
Radiographic Features of the Various
Tumors
Benign: well circumscribed, no reaction and
sclerotic border.

Malignant: ++++reaction, large,
permeative, destructive and moth eaten.

Conditions/Mets: more than one bone,
symmetry.
Malignant
tumor
Benign
tumor
Classification of primary bone tumors
A. Bone-Forming Tumors
BENIGN
Osteoma:
Osteoid osteoma:
Osteoblastoma:
Malignant:
Primary osteosarcoma
Secondary osteosarcoma

Classification of primary bone tumors
B. Cartilage-Forming Tumors
BENIGN :
Osteochondroma
Chondroma

MALIGNANT :
Chondrosarcoma

C. Miscellaneous Tumors
Giant-cell tumor (usually benign)
Ewing tumor (malignant)

D. Tumor-like lesions
Fibrous Cortical Defect (benign)
Fibrous Dysplasia (benign)

Bone-Forming Tumors:

Osteoma:
Age: 40-50 ys.
Site: on or inside the skull, paranasal sinuses and
facial bones
Exophytic growth: Round-to-oval sessile Project
from subperiosteal or endosteal surfaces
Usually single
Multiple lesions are feature of Garder ssndrome.
Usually slow- growing benign tumors
Presentation: sinus obstruction, disfigurement and
pressure on brain.
Osteoid Osteoma &Osteoblastoma
Both are benign bone tumors with similar
histologic features
Grossly both tumors round to oval,
hemorrhagic and gritty
Differ in:
Size
Sites of origin
Symptoms
Behavior

Osteoid Osteoma Osteoblastoma
Age 10-20 years 10-20 years
Sex 2:1 males 2:1 males
Site Femoral neck Spine

Pain Mod.-severe Worse
at night , Aspirin
response 90%
dull aching pain
Worse at night,
Aspirin relief,<50%
Nidus less than 2.0 cm 2.0 -10.0 cm

Recurrence No 10%

Osteosarcoma
Most common primary malignant tumor of bone
Age: 10-20 years:
75% in patients below 20 years of age (primary type)
25 % old age (secondary to Paget disease)
Site: Metaphyses of long bones of limbs (60% occur around the
knee )
M : F ratio = 1.6 : 1

Major sites
of
Osteosarcoma
Risk factors
Paget disease of bone
Ionizing radiation
Fibrous dysplasia
Chronic osteomyelitis
Bone infarcts
Mutation of TP53 gene (retionblastoma gene).
Osteosarcoma
Distal femoral osteosarcoma with prominent bone formation
extending into the soft tissues. The periosteum, which has been
lifted, has laid down a proximal triangular shell of reactive bone
known as a Codman triangle (arrow).
Clinical features
Presenting symptoms:
Pain
Swelling
Pathological fracture
Marked increase in the serum alkaline
phosphatase.
Early hematogenous spread to the lungs,
liver and brain.

MALIGNANT TUMOURS OF BONE
Classification of malignant tumors of bone:
1. Osteosarcoma (Osteogenic sarcoma)
2. Chondrosarcoma
3. Osteoclastoma (Giant cell tumor )
4. Ewing sarcoma
Osteosarcoma
(Osteogenic sarcoma)
Most common primary malignant tumor of
bone

Clinically:
Males> females
Most occur in teenagers (age 10-25 years)
Localized pain and swelling
Classic X-ray findings:
1. Codman's triangle (periosteal elevation)
2. Sunburst pattern
3. Bone destruction

Codman's triangle
Osteosarcoma
Osteosarcoma
Pathology:
Often involves the metaphysis of long bones
Usually around the knee (distal femur and
proximal tibia)
Large firm white tan mass with necrosis and
haemorrhage

Osteosarcoma
Osteosarcoma
Secondary osteosarcoma:
Occurs in old people
Associated with Pagets disease or chronic
osteomyelitis
Highly aggressive
Chondrosarcoma
Definition:
Malignant tumor of chondroblasts

Etiology:
The tumor may arise de novo (primary) or
secondary to preexisting enchondroma, exostosis
(osteochondromas) or Pagets disease
Clinically:
Male> females
Age: 30-60 years
Enlarged mass with pain and swelling
Typically involves the pelvic bones, spine and
shoulder girdle
Chondrosarcoma
Chondrosarcoma
Giant cell tumor
(Osteoclastoma)
Uncommon malignant neoplasm containing
mult-inucleated giant cells admixed with
stromal cells

It is a locally malignant bone tumor with a
high rate of recurrence
Clinically:
Females>males
Age: 20-50 years
Bulky mass with pain and fractures

X-ray:
Expanding lytic lesion surrounded by a thin rim of
bone
It may have a soap-bubble appearance
Osteoclastoma
Soap bubble appearance
Pathology:
Often involves the epiphysis of long bones
Usually around the knee
Red brown mass with cystic degeneration

Osteoclastoma
Osteoclastoma
Osteoclasts-like giant cells
Ewing sarcoma
Malignant neoplasm of undifferentiated cells arising
within the bone marrow cavity

Clinical features:
Males>females
Most occur in teenagers (5-20)
Presented with pain, swelling and tenderness

X-ray:
Concentric, onion-skin layering of new periosteal bone
Ewing sarcoma
Pathology:
Often affects the diaphysis of long bones
Most common sites are the femur, pelvis and tibia
White tan mass with necrosis and hemorrhage

Ewing sarcoma
687
T-Cell Activation
T-cell activation requires 2 signals:
1st signal: The antigen presented by the
MHC is recognized by the T-cell receptor
2nd signal: Co-stimulatory molecules CD80
and CD86 on APCs bind to CD28, an auto-
regulatory protein, on the T-cell surface
T-cells have an intrinsic mechanism to
terminate T-cell activation, which
regulates immune activation
Osteoarthritis


Summary
Bisphosphonates remain the most
potent antiresorptive agents available
Recent analysis of the risks and
benefits of bisphosphonate therapy
have started to clarify how long they
can be used
Adequate vitamin D and calcium
supplementation should be instituted

LEClinical Manifestations
Renal involvement
Pleural effusions
Pericarditis
Raynauds phenomenon
Neurologic manifestation
Serositis

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Universitatea Titu Maiorescu

- adalimumab - SC - 40 mg/q 2wks

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