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Bone and joint diseases
December 12, 2017
Bone properties
 Bones
 stiff
 do not bend when loaded.
 flexible - absorb the energy
imposed by loading as
potential energy by elastic
then plastic deformation.
 Structural failure may occur
if bones deform too little or
too much.
 High remodeling reduces the
mineral content of bone,
resulting in loss of stiffness.
Bone properties
 Age- and menopause-related
abnormalities in bone remodeling
produce loss of material and structural
properties.
 Sex hormone deficiency
 increases the volume of bone
resorbed
 reduces the volume of bone formed.
 The contributions made by differences in
material composition, tissue mineral content,
collagen type and cross-linking) structure (bone
size, cortical thickness and porosity, trabecular
number, thickness, connectivity), and other
factors (microdamage burden, osteocyte
density) to sex and racial differences in bone
fragility remain poorly defined.
Skeletal fragility
Skeletal fragility can result from:
 failure to produce a skeleton of
optimal mass and strength during
growth;
 excessive bone resorption resulting
in decreased bone mass and
microarchitectural deterioration of the
skeleton;
 and an inadequate formation
response to increased resorption
during bone remodeling.
Bone remodeling
 Osteoclast activation
 Resorbtion phase- due to osteoclast activationshort
period
 Reverse phase- bone surface is covered by
mononuclear cell
 Formation phase- osteoblast production in
bone matrix - long.
Bone cells
Osteoblasts
the surface of the rising / remodeling bone,
less well within the relatively passive adult.
synthesize and store the bone matrix,
mineralize it, gradually convert to osteocytes.
the surface binds alkaline phosphatase,
mineralization matrix.
Osteoclasts
at sites of active erosion on the surface of the
bone, in so-called resorptive wells.
many lysosomes with high acid phosphatase
activity.
phagocytes collagen and other organic
components of the matrix.
Osteocytes
the main component of the adult bone,
scattered in the lakes, interconnecting the
protuberances create a complex cellular
network.
their average life is estimated at 25 years,
death resolves resorption.
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Copyright ©2005 AmericanSocietyfor Clinical Investigation
Raisz, L. G. J. Clin. Invest. 2005;115:3318-3325
Regulation of osteoclast formation and
activity
Osteoclasts activation
 Regulation of osteoclast formation and
activity.
 contact between cells of the osteoblast and
osteoclast lineages.
 to stimulate differentiation and proliferation of
hematopoietic progenitors, which then express
RANK as preosteoclasts.
 Osteoclast differentiation and activity are
stimulated by RANK/RANKL interaction, and
 this interaction can be blocked by soluble OPG.
Ligand for receptor activator nuclear factor- kappa B ligand
(RANKL) a osteoprotegrin (OPG) as final effector cytokines in
malignant sceletal diseases (to the previous picture).
 1) Interaction RANKL with RANK supports
differentiation and activation ofi osteoclasts
 2) Activated osteoclasts cause humoral
hyperkalcemia in malignant tumors, osteolytic
metastases, pathological fractures ind in painrelated
malignancies.
 3) OPG functions as receptor neutralizing
RANKL which obstuct its ligation with RANK.
 4) many growth factors, cytokines, hormons
converge at the level of RANKL and OPG and
regulate differenciation and activation of
osteoclasts. Il-1 and TNF support production of
RANKL and OPG, while PTH, PTHrP and
glucocorticoids increase production of RANKL,
but dicrease OPG production
 5) to some extent, IL-1 and TNF are able to
modulate differentiation and activation of
osteoclasts independently on RANKL and
RANK.
OPG/RANK/RANKL as a common effector in bone immune
system and a vascular system ( to the previous figure)
 OPG, RANK and RANKL are selectively produced by many
cell types in diferent tissue: lymphocytes, osteoblasts and
endothelial cells.
 RANKL is functioning as a survival factor for dendritic cells
and as a osteoclastogenic factor after RANK ligation.
 OPG inhibits osteolysis and blocks RANKL/RANK interaction.
 OPG/RANKL/RANK triad is considered a
osteoimmunomodulating complex.
Osteoclasts activation
 Under pathologic
conditions,
inflammatory and
malignant cells can
increase osteoclastogenesis
by
producing soluble or
membrane-bound MCSF
and RANKL as
well as PTH-related
protein (PTHrP),
cytokines, and
prostaglandins.
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Parathyroid Hormone Relation Peptide (PTHrP)
 PTHrP was discoverde as mediator of syndrome "humoral
hypercalcemia of malignancy" (HHM).
 During the syndrome inn different type of cancer (in absebce of
metastases) similar compounds to PTH are produceds which is
related to:
 Hypercalcemia
 Hypophosphatemia
 Increased cAMP exctretion by urine
 The effects are similar to those caused by PTH; no PTH levels
are detected. Genetic families of PTH and PTHrP: PTHrP, PTH and TIP39
are probably members of the same fgenetic family. Their
receptors PTH1R and PTH2R are 7 transmembrane G
protein-coupled receptors.
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Production of PTHrP regulated by growth factor (GF) in tumor states. Tumor cells are
able to be stimulated at a distance (outside the bone) by autocrine growth factors to
an increased production of PTHrP. It reaches via circulation the bone tissue and
supports bone resorption. Metastatic tumor cells in the bone are able to secrete PTHrP
supporting bone resorption and paracrine growth factors which further support PTHrP
production.
Gene Mutation Disease
RANK
18 bp duplication Familial expansile osteolysis
27 bp duplication Early onset Paget’s disease
15 bp duplication
Expansile skeletal
hyperphosphatasia
RANKL
Deletion of amino acids 145-177
Autosomal recessive
osteopetrosis
A single nucleotide change (596T-A) in exon 8 of
both alleles
Autosomal recessive
osteopetrosis
Deletion of two nucleotides (828_829delCG)
Autosomal recessive
osteopetrosis
OPG Deletion making OPG inactive Juvenile Paget’s disease
20 bp deletion resulting in premature termination of
OPG translation
Juvenile Paget’s disease
Cytokines, prostaglandins
 There is evidence that polymorphisms of IL-1, IL-
6, TNF- , and their receptors can influence bone
mass in humans.
 Prostaglandins have both stimulatory and
inhibitory actions; the predominant effect of
PGE2, which is the major prostaglandin produced
by bone cells, is to stimulate both resorption and
formation.
 Prostaglandins, particularly PGE2, are produced by
bone cells largely through the action of inducible
cyclooxygenase 2 (COX2).
 COX2 is induced by most of the factors that
stimulate bone resorption and thus may enhance
the response to these agents. Treatment with COX
inhibitors blunts the response to impact loading and
fluid shear stress, indicating that prostaglandins
play an important role in the response on
mechanical forces, and this may be enhanced by
estrogen. In epidemiologic studies, small increases
in BMD and decreases in fracture risk have been
reported in individuals using NSAIDS.
Cytokines, prostaglandins, NO, and
leukotrienes
 NO is produced by bone cells and is a cofactor for
the anabolic response to mechanical loading.
However, unlike prostaglandins, NO may inhibit
bone resorption, perhaps by increasing OPG
production.
 Leukotrienes, the products of lipoxygenase, can
affect bone by stimulating resorption and
inhibiting formation.
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Estrogen influence on bone state
 Estrogen is critical for
 epiphyseal closure in puberty in both sexes
and
 regulates bone turnover in men as well as
women.
 Estrogen has a greater effect than androgen in
inhibiting bone resorption in men, although
androgen may still play a role.
 Estrogen may also be important in the
acquisition of peak bone mass in men.
 Osteoporosis in older men is more closely
associated with low estrogen than with low
androgen levels.
Central role of estrogen deficiency - today
 An increase in bone resorption, and not impaired bone
formation, appears to be the driving force for bone loss
in the setting of estrogen deficiency.
 The rapid and continuous bone loss that occurs for
several years after the menopause indicate an impaired
bone formation response, since in younger individuals
going through the pubertal growth spurt, even faster
rates of bone resorption can be associated with an
increase in bone mass.
 However, the increased bone formation that normally
occurs in response to mechanical loading is diminished
in estrogen deficiency, suggesting estrogen is both anticatabolic
and anabolic.
Copyright ©2005 AmericanSocietyfor Clinical Investigation
Raisz, L. G. J. Clin. Invest. 2005;115:3318-3325
Remodelling of bones. Estrogen action
places (i)
Collagen abnormalities
 A polymorphism of the first intron of the gene
coding for the type I collagen 1 chain and
increased levels of homocysteine can influence
fracture risk independent of BMD (bone mass
density).
 This may be due to differences in helix formation or
cross-linking of collagen, challenging the concept that
mineral and matrix composition are normal in
osteoporosis and that only structural abnormalities
account for skeletal fragility.
Calcium
Calcium, vitamin D, and parathyroid
hormone
 The active 1,25 dihydroxy vitamin
D (calcitriol),
 optimal intestinal absorption of
calcium and phosphorus,
 exerts a tonic inhibitory effect
on parathyroid hormone (PTH)
synthesis,
 dual pathways that can lead to
secondary hyper-
parathyroidism.
 Vitamin D deficiency and
secondary hyperparathyroidism
can contribute to
 accelerated bone loss and
 increasing fragility, but also to
 neuromuscular impairment that
can increase the risk of falls.
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Vitamin D
 Sunscreens, especially those with SPF ratings greater
than 8, effectively block synthesis of vitamin D in the
skin.
 Vitamin D toxicity: Excessive exposure to sunlight
does not lead to overproduction of vitamin D. Vitamin
D toxicity is inevitably the result of overdosing on
vitamin D supplements. Ingestion of milligram
quantities of vitamin D over periods of weeks of
months can be severely toxic to humans and animals.
Regulation of gene expresssion by VDR Vitamin D - consequences
 Deficit and insufficincy of vitamin D = global healthy problem.
 High risk for acute and chronic disease, as
 Infection diseases
 Autoimmune diseases
 DM type I and II
 High risk of atherosclerosis
 Some tumor types (colorectal carcinoma, breast and prostate cancer, ovarial
cancer)
 Cognitive dysfunction
 Infertility
 Gravidity and around delivery complications
Pludowski P et al. Vitamin D effects on musculoskeletal health, immunity,
autoimmunity, cardiovascular disease, cancer, fertility, pregnancy,
dementia and mortality—A review of recent evidence, Autoimmunity
Reviews, Volume 12, Issue 10, August 2013, Pages 976-989
Calcitonin
 Calcitonin is a hormone known to participate in calcium and
phosphorus metabolism. Its main role is to increase calcium
deposition in bones.
 In mammals, the major source of calcitonin is from the
parafollicular or C cells in the thyroid gland, but it is also
synthesized in a wide variety of other tissues, including the lung
and intestinal tract.
 Calcitonin is a 32 amino acid peptide cleaved from a larger
prohormone. It contains a single disulfide bond, which causes the
amino terminus to assume the shape of a ring.
 Alternative splicing of the calcitonin pre-mRNA can yield a mRNA
encoding calcitonin gene-related peptide; that peptide appears to
function in the nervous and vascular systems. The calcitonin
receptor has been cloned and shown to be a member of the seventransmembrane,
G protein-coupled receptor family.
Calcitonin
 The most prominent factor controlling calcitonin
secretion is the extracellular concentration of
ionized calcium.
 Elevated blood calcium levels strongly stimulate
calcitonin secretion, and secretion is suppressed when
calcium concentration falls below normal.
 A number of other hormones have been shown to
stimulate calcitonin release in certain situations, and
nervous controls also have been demonstrated.
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o cofactor for γ-carboxylase, enzyme which catalyses conversion of specific
residuals of glutamic acid to Gla residuals
o γ-carboxylation of proteins of bone matrix which contain Gla as MGP (=
matrix Gla protein) a osteokalcin.
o Uncompleted γ-carboxylation of osteocalcin and MGP during vitamin K
decrease lead to osteoporosis and high risk of fractures.
o stimulates synthesis of osteoblastic markers and bone deposition.
o decreases bone reabsorbtion by inhibition of osteclasts formation and by
decrease of their resorbtion activity.
o Vitamin K2 treatment induces osteoclast apoptosis, but inhibits
osteoblasts apoptosis which is leading to increased bone formation.
o Vitamin K2 supports osteocalcin expression ( increases its mRNA) which
can be further modulated by 1, 25-(OH)2 vitamin D3.
Vitamin K and bones
Vitamin K2 is
transcription regulator
od specific bone genes,
functioning using SXR
which will lead to
increase of osteoblastic
markers expression.
SXR originally identifies
as xenobiotic sensor…
Local and systemic growth factors
 Remodeling imbalance, characterized by an
impaired bone formation response to increased
activation of bone remodeling, is an essential
component of the pathogenesis of osteoporosis.
This may be due, in part, to an age-related
decrease in the capacity of osteoblasts to
replicate and differentiate. However, it seems
likely that specific defects in the production or
activity of local and systemic growth factors will
also contribute to impaired bone formation.
Metabolic bone diseases
Osteoporosis
 (estrogen deficiency, glucocorticoids increase, vitamin
K2 deficiency?)
Osteodystrophy
 (primary and secondary hyperparathyreoidism)
Ostemalacia/ rickets
 vitamin D defficiency)
Metabolic bone diseases
 Osteoporosis remains the most common metabolic abnormality
of bone. It has been described as “a silent epidemic” affecting
one in two women and one in five men, older than 50 years of
age, during their lifetime.
 It is now defined as a systemic skeletal disease characterized by
low bone mass and micro-architectural deterioration of bone
resulting in fractures with little or no trauma.
Osteoporosis
 The bone mass of an individual in later life is a
result of the peak bone mass accrued during
intrauterine life, childhood, and puberty, as well as
the subsequent rate of bone loss.
 Although genetic factors strongly contribute to peak
bone mass, environmental factors in intrauterine
life, childhood, and adolescence modulate the
genetically determined pattern of skeletal growth.
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Osteoporosis
 is a skeletal disease characterised by low bone
mass and microarchitectural deterioration with a
resulting increase in bone fragility and hence
susceptibility to fracture.
 Caucasin population: about 50% of women and
20% of men older than 50 years will have a fragility
fracture in their remaining lifetime.
Etiopathogenesis of osteoporosis
 complex interactions among local and systemic regulators of
bone cell function.
 The heterogeneity of osteoporosis may be due to
 differences in the production of systemic and local regulators,
 changes in receptors,
 signal transduction mechanisms,
 nuclear transcription factors, and
 enzymes that produce or inactivate local regulators.
 Since the first human osteoporosis study indicated an association
among bone mass, fragility, and polymorphisms in the vitamin D
receptor (VDR) gene, more than 30 candidate genes have been
reported that might influence skeletal mass and fragility.
 Since osteoporosis is a complex, polygenic disorder, the
contributions of specific gene polymorphisms are likely to be
relatively small, but may still be clinically important.
Osteoporosis - causes
 Glucocorticoids excess
 Estrogene deficiency
 Vitamin K2 deficiency?
Osteoporosis induced by cortisol
 Cortisol modifies
proliferative and
metabolic activities
of bone cells
 Cortisol inhibits
osteoblastogenesis
 Reduces half-life
time of osteoblasts
which is leading to
decreased bone
formation
Common adverse effects of glucocorticoid therapyglucocorticoid-induced
osteoporosis
 Glucocorticoid-induced osteoporosis is the most common type
of iatrogenic osteoporosis and a frequent cause of secondary
osteoporosis.
 An estimated 50% of patients taking glucocorticoids for longer
than 6 months will develop secondary osteoporosis.
 The absolute risk for glucocorticoid-induced osteoporosis is
higher in patients aged 65 years or older given their baseline
age-related fracture risk, although the relative risk of fracture
related to glucocorticoid use may be even higher in patients
under 65.
Cortisol
generally
antagonizes
insulin …
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Osteomalacia and rickets
 Classically, the deficiency of vitamin D,
essential for the absorption of calcium, has
been the major cause of rickets in the child
and osteomalacia in the adult
 resulting in absence or delay in the
mineralization of growth cartilage or newly
formed bone collagen.
Osteomalacia and rickets
 A consequence of a low serum phosphate
and normal serum calcium.
 Two such conditions are x-linked
hypophosphatemic rickets/osteomalacia
and oncogenic osteomalacia.
 When present, the signs of rickets and
osteomalacia in the low serum phosphate
states are indistinguishable from the classic
hypocalcemic states.
X-linked hypophosphatemic osteomalacia
 The condition is
characterized by low
tubular reabsorption
of phosphate in the
absence of
secondary
hyperparathyroidism.
 X-linked
hypophosphatemia
occurs in about 1 in
25,000 and is
considered the most
common form of
genetically induced
rickets.
Oncogenic osteomalacia
 Oncogenic osteomalacia is a
paraneoplastic syndrome in which a bone
or soft tissue tumor or tumor-like lesion
induces hypophosphatemia and low
vitamin D levels that reverse when the
inciting lesion is resected.
Oncogenic osteomalacia
 Phosphotonin
 a humoral factor,
 has been identified in clinical and experimental studies as
being responsible for the serum biochemical changes.
 causes hyperphosphaturia by inhibiting the reabsorption of
phosphate by the proximal renal tubules.
 Fibroblast growth factor 23, phosphate-regulating gene with
homologies to endopeptides located on the ‘x’ chromosome
(PHEX) and matrix extracellular phosphoglycoprotein (MEPE)
are candidates proposed for the production of phosphatonin
and the altered pathophysiology in oncogenic osteomalacia.
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Articular diseases
 irreversible destruction of the
cartilage, tendon, and bone
that comprise synovial joints
 rheumatoid arthritis (RA) and
 osteoarthritis (OA).
 While cartilage is made up of
proteoglycans and type II
collagen, tendon and bone
are composed primarily of
type I collagen.
Rheumatoid Arthritis
 The prevalence of rheumatoid arthritis in most Caucasian
populations approaches 1% among adults 18 and over
and increases with age, approaching 2% and 5% in men
and women, respectively, by age 65
 The incidence also increases with age, peaking between
the 4th and 6th decades
 Both prevalence and incidence are 2-3 times greater in
women than in men
 Monozygotic twins 13.5% vs dizygotic twins 3.5%
“One must from time to time attempt things that are
beyond one’s capacity.”
—Pierre-Auguste Renoir
Rheumatoid Arthritis
 Rheumatoid arthritis is
an autoimmune disease
affecting the joints,
tendons, and bones,
resulting in inflammation
and destruction of these
tissues.
 The term ‘arthritis’ is used to
denote clinically apparent soft
tissue swelling or fluid (not
bony overgrowth alone).
Rheumatoid Arthritis
 Description
 Morning stiffness
 Arthritis of 3 or more
joints
 Arthritis of hand joints
 Symmetric arthritis
 Rheumatoid nodules
 Serum rheumatoid factor
 Radiographic changes
 having rheumatoid
arthritis – positive 4 of 7
criteria, with criteria 1-4
present for at least 6
weeks
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Functional Presentation and
Disability of RA
 In the initial stages of each joint involvement,
there is warmth, pain, and redness, with
corresponding decrease of range of motion of
the affected joint
 Progression of the disease results in reducible
and later fixed deformities
 Muscle weakness and atrophy develop early in
the course of the disease in many people
Rheumatoid Arthritis
Pathogenesis of RA
 complex interaction between
genetic and environmental factors
and
 the repeated activation of innate
and adaptative immunite system
 evolves into the breakdown of
immune tolerance, aberrant
autoantigen presentation and
antigen-specific T and B cells
activation.
 Genetic factors have an important role in
the susceptibility to rheumatoid arthritis
 HLA-DRB
First step – joint disease?
 Although the synovium is the principal site of
pathology in the established phase of disease, it may
not be the site where the disease is initiated.
 Systemic immune abnormalities in individuals without
joint symptoms, and a lack of immune infiltrates in the
synovium during the earliest phase before clinical signs
and symptoms of arthritis, point to other tissues being
important in the initiation of adaptive immune
reactions.
 Important tissues for research include bone marrow,
lymph nodes, the gut, periodontal tissue, the lung and
the neuroendocrine system.
RA without clinical arthritis
 An initial phase, characterised by systemic autoimmunity
without synovial inflammation, may be followed by a shorter
phase during which asymptomatic synovitis is present.
RA progression
 events culminate in synovial inflammation, hyperplasia
and bone destruction leading to joint swelling and
deformity and to systemic inflammation.
Clinical Presentation of RA
Early RA Intermediate RA
Severe RA
Latinis KM, et al. The Washington ManualTM Rheumatology
Subspecialty Consult. Philadelphia, Pa: Lippincott Williams &
Wilkins; 2004.
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RA progression
Early Pannus
Granulation,
inflammation
at synovial
membrane,
invades joint,
softens and
destroys
cartilage
Mod advanced Pannus
joint cartilage disappears,
underlying bone destroyed,
joint surfaces collapse
Fibrous Ankylosis
Fibrous connective tissue
replaces pannus; loss of joint otion
Bony Ankylosis
Eventual tissue and joint
calcification
RA progression
Subcutaneous nodules
(disappear and appear
without warning)
Diagnostic Tools
in Rheumatoid Arthritis
Rheumatoid factor
Anti-CCP antibodies
Plain X-ray
MRI
Ultrasound
Rheumatoid Factor
 Antibody directed against the Fc portion of IgG
 Present in approximately 80% of RA patients
 Sensitivity for RA is ~80%
 Specificity is 85-95%
 May be involved in disease pathogenesis
 Higher levels tend to be associated with poorer prognosis
 Found in other conditions, especially Hepatitis C
Anti-Cyclic Citrullinated Peptide
(CCP) Antibodies in RA
 Anti-citrulline Abs produced in
RA synovium
 Early RA Diagnosis
 sensitivity 48%; specificity
96%
 seen in 2% of pts with other
autoimmune diseases and
infections (vs. 14% for RF)
 less than 1% of healthy
controls
 Predicts erosive disease PPV -
63% and NPV - 90%
 Present years before the onset
of symptoms. 34% of blood
samples obtained 2.5 yr before
onset of symptoms (vs. 1.8% of
controls)
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Plain X-ray
Magnetic Resonance Imaging as a
Diagnostic Tool
McQueen FM et al. Ann Rheum Dis. 1999;58:156-163.
McQueen FM et al. Ann Rheum Dis. 1998;57:350-356.
14
45
0
10
20
30
40
50
X-ray MRI
Erosions Detected:
X-rays vs MRI (%)
Ultrasound as a Diagnostic Tool
Keen et al. Rheum Dis Clinic
N Am 31 (2005) 699-714
Features Related to Poor Outcomes
 Extra-articular disease
 High rheumatoid factor titer, positive anti-CCP antibody
 Poor functional status
 Involvement of multiple joints
 Radiographic erosions
 Sustained elevation of acute-phase reactants (eg, ESR)
 Low socioeconomic status/educational level
 Increased genetic risk of developing RA plus smoking
Anaya JM, et al. Ann Rheum Dis. 1994;53:782-783. Pincus T, et al. Balliere’s Clin Rheumatol.
1992;6:161-191. Furst DE. Rheum Dis Clin North Am. 1994;20:309-319. Padyukov L, et al. Arthritis
Rheum. 2004;50:3085-3092.
Complications of Rheumatoid
Arthritis
Complications:
 Carpal tunnel
syndrome, Baker’s
cyst, vasculitis,
subcutaneous
nodules, Sjögren’s
syndrome,
peripheral
neuropathy, cardiac
and pulmonary
involvement,
Felty’s syndrome,
and anemia
Rheumatoid arthritis: episcleritis
Copyright © 1972-2004 American College of
Rheumatology Slide Collection. All rights
reserved.
16.3.2018
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Treatment before the
BIOLOGICS
NSAIDs for stiffness
Corticosteroids for inflammation
and to suppress the autoimmunity
Disease Modifying Anti rheumatic
Drugs (DMARDs)
 Drug of choice -Methotrexate 7.5-
25mg weekly
But also Cyclosporine, Azathioprine,
cyclophosphamide
Monoclonal antibodies and RA
 Tumor Necrosis (alpha) Inhibitors 5 FDA approved
 Infliximab ( Remicaid ) an infusion
 Etanercept ( Enbrel) against soluble TNF receptors
 Adalimunab (Humira) against soluble and
membrane bound TNF receptors
 Certolizumab (Cimza) pegylated
 Golimumab (Simponi)
 Rituximab (rituxan) anti CD20 B cells
 Abatacept anti Costimulation blocking CD80/86
CD28
 Anakinra (Kineret) anti IL 1 receptor LOW EFFECT
 Tocilizumab (Actemra) anti IL 6
RA Therapies: The Next Generation
Biosimilars
Anti-IL-6 receptor
Sarilumab
Anti-IL-17A
Secukinumab
Anti-IL-20
Anti-CD22
Epratuzamab
Chemokine inhibitor: CCX354-L2
PDE4 inhibitor: aprimilast
Seronegative
Spondyloarthropathy
 Consist of a group of related
disorders that include Reiter's
syndrome, ankylosing spondylitis,
psoriatic arthritis, and arthritis in
association with inflammatory bowel
disease
 Occurs commonly among young
men, with a mean incidence
between ages 25 and 34
 The prevalence is about 1%
 The male-to-female ratio approaches
4 to 1 among adult Caucasians
 Genetic factors play an important
role in the susceptibility to each
disease
Seronegative
Spondyloarthropathy
 The spondyloarthropathies share certain common
features, including the absence of serum rheumatoid
factor, an oligoarthritis commonly involving large joints
in the lower extremities, frequent involvement of the
axial skeleton, familial clustering, and linkage to HLA-
B27
 These disorders are characterized by inflammation at
sites of attachment of ligament, tendon, fascia, or joint
capsule to bone (enthesopathy)
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Sacroiliitis
 Sacroiliitis is an inflammation
of the sacroiliac joint.
 Symptoms usually include a
fever and reduced range of
motion.
 Picture of 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
Ankylosing Spondylitis
 Chronic disease that
primarily affects the
spine and may lead to
stiffness of the back.
 The joints and
ligaments become
inflamed. The joints
and bones may fuse.
 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: X-rays, and
blood tests for 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
 Silver or grey scaly spots on the
scalp, elbows, knees and/or
lower end of the spine.
 Pain and swelling in one or
more joints
 Swelling of fingers/toes that
gives them a "sausage"
appearance.
Degenerative Joint Disease
(Osteoarthritis)
 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
one’s 40s
 Prevalence increases with
age and the disease
becomes almost universal in
individuals aged 65 and older
 Primarily affects weightbearing
joints such as the
knees, hips, and
lumbrosacral spine
Degenerative Joint Disease
 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
Diseases of Muscles
Myopathies: disorders of muscle
fibres
Dystrophy: a genetic myopathy.
Neurogenic: interference with nerve
supply.
Bilateral & symmetrical: myopathy
Asymmetric: neurogenic.
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Classification
Inherited Acquired
• Muscular dystrophies Endocrinopathies
• Myotonic dystrophy Drug induced
• Congenital myopathis Idiopathic
inflammatory
myopathy
• Metabolic myopathies Metabolic myopathy
• Channelopathies Myasthenia Gravis
/LEMS
Muscular dystrophy
 Muscular dystrophy is a heterogeneous group of
inherited disorders recognized by progressive
degenerative muscle weakness and loss of
muscle tissue (started in childhood).
 Affect muscles strength and action.
 Generalized or localized.
 Skeletal muscle and other organs may involve
 Limitation: Difficulties with walking or Maintaining
posture, Muscle spasms. Neurological, Behavioral, Cardiac, or
other Functional limitations.
Muscular Dystrophy
 Causes
 Inheritance
 Dominant genes
 Recessive gene
Depends on the age when symptoms appear, and
the types of symptoms that develop.
 It is estimated that between 50,000 -250,000 are
affected annually. 1 per 3500 live male births
1- X-Linked Muscular Dystrophy (Duchenne
Muscular Dystrophy- DMS)
2- Becker Muscular Dystrophy- BMS
3- Myotonic Dystrophy.
4- Other Muscular Dystrophies:
Less common, share many features with DMS, BMS,
affect certain muscle groups (Fascioscapulohumeral
muscular dystrophy; autosomal
dominant\Oculopharyngeal muscular dystrophy;
autosomal dominant, Congenital muscular
dystrophies; autosomal recessive etc..).
DMD, BMD
 1- Caused by abnormalities in DMD, a gene that is located in the
Xp21 region It encodes a 427-kD protein named
dystrophin.
 2- The genetic abnormalities are deletions with point
mutations accounting for the rest.
 Approximately two thirds of the cases are familial, and the
remainder represent new mutations.
 Dystrophin is a cytoplasmic protein located adjacent to the
sarcolemmal membrane in myocytes, it concentrated at the
plasma membrane over Z-bands, where it forms a strong
mechanical link to cytoplasmic actin.
 dystrophin and the dystrophin-associated protein complex
form an interface between the intracellular contractile apparatus
and the extracellular connective tissue matrix  transferring the
force of contraction to connective tissue.
 The absence of dystrophin myocyte degeneration
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16
Myotonic dystrophy
 1- Inherited as an autosomal
dominant trait a\w a CTG
trinucleotide repeat expansion on
chromosome 19q13.2–
q13.3affect the mRNA for the
dystrophia myotonia protein
kinase (DMPK) sustained
involuntary contraction of a group
of muscles & stiffness.
DMD, BMD and others
Type Onset Age
(years)
Clinical Features Other organ systems
involved
Duchenne Before 5 1.Progressive
weakness of girdle
muscles.
2.unable to walk after
age 12
3.progressive
kyphoscoliosis
4.Respiratory failure in
2dor 3d decade.
Cardiomyopathy
Mental impairment
Becker
5-25yr
early childhood
to adult
1.Progressive
weakness of girdle
muscles
2. able to walk after
age 15.
1.3. respiratory failure
may develop by 4th
grade
Cardiomyopathy
Emery-Dreifuss Childhood to adult Elbow contractures,
humeral and perineal
weakness
Cardiomyopathy
Limb-Girdle early childhood to
adult
Slow progressive
weakness of shoulder and
hip girdle muscles
Cardiomyopathy
Distribution of onset of muscle
weakness
A. Typical proximal (limb-girdle)
distribution of a myopathic disorder
(DMD)
B. More distal (glove and stocking)
distribution of a neurogenic disorder (SMA)
C. FSH –own distribution
D. SP - own distribution
Myastenia Gravis - MG
 is a muscle disease caused by immune-mediated loss
of acetylcholine receptor.
 Prevalence: of about 30 in 100,000 persons.
 Age: < 40 yrs of life.
 Sex: commonly affect female> male, in older equally.
 Evidence based nearly all cases: decrease in the
number of muscle acetylcholine receptors (AChRs),
and circulating antibodies to the AChR are present in
nearly all cases.
 Risk- thymic abnormalities are common in these
patients
MG - autoimmunity
 Autoantibodies against the AChR lead to loss of
functional AChRs at the neuromuscular junction by:
 (1) Fixing complement and causing direct injury to the
postsynaptic membrane.
 (2) Increasing the internalization and degradation of
the receptors.
 (3) Inhibiting binding of acetylcholine.
 Outcomes:
 A) Electrophysiologic studies are notable for
diminished.
 B) Sensory as well as autonomic functions are not
affected
Thank you for your attention