Connective Tissue Diseases

Emmanuel C. Perez, M.D., MPH, FPCP, FPRA

Connective Tissue Diseases

Systemic lupus Erythematosus

Rheumatoid Arthritis
Polymyositis / Dermatomyositis
Systemic Sclerosis
Sjogrens Syndrome
Mixed Connective Tissue Disease

Polymyositis /
Dermatomyositis

Polymyositis /
Dermatomyositis
Inflammatory disease of striated
skeletal muscle, some times with
characteristic skin rash
Occurs between the 4th to 6th decade of
life with a female preponderance

Classification of Myositis

Dermatomyositis
Polymyositis
Myositis associated with CTD
Myositis associated with malignancy
Inclusion body myositis
Myositis due to infectious agents
Drug- and Toxin-induced myositis

Pathogenesis
Abberations in the immune system that gives
rise to an increased susceptibility to infectious
agents (viruses an toxoplasma gondii), and to
modifications of cellular immunity that lead to
the development of mononuclear cells
capable of injuring muscle
Complement may play a role in tissue injury
in dermatomyositis

Histopathology
Inflammatory cellular infiltrate with
associated degeneration and necrosis of
muscle fibers
Regeneration of fibers and perivascular
inflammatory infiltrate leading to interstitial
fibrosis later on
Calcinosis maybe seen especially in the
childhood form

Histopathology
Infiltrates in PM and IBM contain mainly C8+
T-lymphocytes and macrophages, while B
cells are more common in DM
Vasculopathy maybe seen in the small
arteries of the muscle, skin and the
gastrointestinal tract
Eosinophilic inclusions in the sarcoplasm an
nucleus maybe seen in inclusion body
myositis

Diagnostic Criteria for PM/ DM

Symmetric proximal muscle weakness

(with

or without dysphagia or respiratory muscle involvement)

Elevation of serum muscle enzymes

(creatine

kinase, aldolase, LHD, AST)

Typical EMG triad

Short-duration, small-amplitude, polyphasic motor unit

potentials
Pseudomyotonic high-frequency pattern
Spontaneous fibrillation and (+) sharp waves (saw tooth
pattern) in resting muscle

Typical histology in muscle specimens

Characteristic skin rash of dermatomyositis

Skin Rashes of Dermatomyositis

Lilac discoloration of the upper eyelids
with periorbital edema (Heliotrope rash)
Erythematous or atrophic scaling,
patchy or linear rash involving the
extensor surfaces of the joints (Gottrons
rash), face, neck and back (Shawl sign),
or the chest in a V-shaped pattern (Vneck sign)
Erythematous scaling (Gottrons
papules) over the MCP an PIP joints

Clinical Features of IMD

Features

DM

PM

Myositis
w/ CTD

Rash

90%

(-)

20%

Proximal weakness

50% - 60% 95%, with

myalgia

40%

Arthralgia, Raynauds
phenomenon, Dysphagia

10% - 25% 10% - 15%

50%

Interstitial pneumonitis,
cariomyopathy, heart
blocks

rare

rare

Other Myositis
Myositis associated with malignancy
DM higher association with malignancy; elderly PM-DM
patients 4x likely to have cancer
Myositis precedes malignancy by an average of 1 to 2
years (70%) but in some it follows it (30%)

Inclusion body Myositis

Common in elderly males

Insidious onset with slight elevation of muscle enzymes
Neuropathic features maybe observed
Poor response to therapy

Other Myositis
Infectious myositis
Viral (influenza, coxsackie, HIV), Bacterial
(Staphylococcus, TB), Parasitic (Trichinella)
Toxoplasmosis, Lyme disease

Drug- or Toxin-induced Myositis

HMG coA reductase inhibitors (statins), Gemfibrozil

PTU
Penicillamine, Azathioprine, Zidovudine
Alcohol, Coccaine

Other Myopathy Syndromes

Muscle
Enzymes

Muscle bx
inflammation

Corticosteroids

Normal

none

Hypothyroidism

none

Polymyositis

++

Statin-induced

Arthritis and Allied Conditions 2000

Laboratory Exams
CBC, ESR
Muscle enzymes
Creatine kinase, aldolase, AST, LDH

Serum myoglobin
(+) ANAs, (+) anti-tRNA ( associated with
pulmonary disease)

EMG studies
Muscle biopsy

Differential Diagnosis

Hypothyroid myopathy
Myasthenia Gravis
Muscular Dystrophies
Polymyalgia Rheumatica
Fibromyalgia

Alcohol abuse
Trichinosis
Electrolyte disturbance
Metabolic disorers

Treatment
Corticosteroids
Prednisone 40 to 60 mg daily
IV pulse methylprednisolone
Indicators of clinical response:
muscle strength improvement
normalization of muscle enzymes

Cytotoxic drugs
Methotrexate
Azathioprine

Treatment
Rehabilitation therapy
Other therapies
Cyclosporine
Cyclophosphamide
IV gamma globulin

Prognosis
75% respond to steroid therapy,
especially if treated early
Myositis with malignancy has worst
prognosis, with poor response to steroid
therapy
Usual cause of death is sepsis

Systemic Sclerosis

Scleroderma
generalized disorder of the interstitial
connective tissues and vasculature with
distinct abnormalities of three systems:
* immune and autoimmune
* vascular and microvascular
* mesenchymal extracellular matrix

that lead to exuberant FIBROSIS

Criteria for Classification of

Scleroderma
Major criterion
proximal scleroderma

Minor criteria
sclerodactyly
digital pitting scars or loss of substance from the
finger pad
bibasilar pulmonary fibrosis
*at least one major or two minor criteria must be present
Arthritis Rheum 23:581-590,1980

Classification
Diffuse cutaneous scleroderma
(systemic sclerosis)
Limited cutaneous scleroderma

Diffuse Cutaneous Scleroderma

proximal skin thickening involving the
face/neck, trunk, and symmetrically the
fingers, hands, arms, and legs
rapid onset of disease following Raynauds
phenomenon
significant visceral disease: lung, heart, GI, or
kidney
association with antinucleolar antibodies and
absence of anticentromere antibody
overall poor prognosis: survival 40-60% at 10
years

Limited Cutaneous Scleroderma

skin thickness limited to symmetrical change of
fingers, distal arms, legs, and face/neck
progression of disease after onset of Raynauds
phenomenon
late visceral disease with prominent hypertension
and digital amputation
CREST syndrome
association with anticentromere antibody
relatively good prognosis: survival >70% at 10
years

CREST Syndrome
Raynauds
phenomenon

Esophageal
dysmotility

Calcinosis
Sclerodactyly

Telangiectasia

Possible causes of Scleroderma

Genetic factors
Infectious agents
viral, e.g. CMV
molecular mimicry

Non-infectious
environmental factors

silica dust
petroleum-based solvents
vinyl chloride
contaminated rapeseed oil
L-tryptophan

Drugs
bleomycin
pentazocin
cocaine

Microchimerism
no. of immunologic
stem cell of fetal origin in
women with scleroderma

Pathogenesis
pathologic hallmark: progressive
fibrosis of the skin and various internal
organs (lungs, heart, GIT)
disruption of the normal architecture of
the affected organs leading to their
dysfunction and failure
up-regulation of collagen gene
expression in SSc fibroblasts

Immunopathogenesis
SUSCEPTIBLE HOST
Exogenous triggers

B-cell activation
Autoantibodies, Ig

T-CELL ACTIVATION

Activation of nonspecific
inflammatory cells

Inflammatory infiltrates
Soluble mediators, cytotoxicity

FIBROBLASTS

ENDOTHELIAL CELLS
Activation, injury

FIBROSIS

ISCHEMIC VASCULOPATHY

Antinuclear antibodies in Scleroderma

Diffuse cutaneous SSc
Limited cutaneous SSc
Anti-DNA topoisomerase l
Pulmonary fibrosis
Peripheral vasculopathy

Anticentromere
calcinosis
telangiectasias
Pulmonary fibrosis

NONE

Anti-RNA polymerase l, ll , lll

Scleroderma kidney
Pulmonary fibrosis

SKIN THICKNESS

MAXIMUM

Autoantibodies
anti-topoisomerase-I (Scl-70)
specific
diffuse scleroderma
interstitial lung fibrosis
protection from isolated pulmonary
hypertension
digital pitting scars and maximum skin
thickness score
lcSSc: more frequent and more severe
joint, skin, and lung involvement

Autoantibodies
anti-RNA polymerase I, III
diffuse scleroderma
more often male and older at onset
higher frequency of renal and cardiac
disease

anti-U3RNP (fibrillarin)
non-specific
poor outcome in black male patients with
dcSSc and visceral involvement

Autoantibodies
anticentromere antibodies
limited scleroderma
increased esophageal disease
possible increased isolated pulmonary
hypertension
protection from pulmonary fibrosis and
renal disease

PM-Scl
scleroderma-polymyositis overlap syndrome

Genetic marker
HLA-DR52a
interstitial lung fibrosis

Scleroderma Facies
- face is stretched, and
mask-like or
expressionless
- pinched nose
- thin lips with
diminished oral
aperture
- radial fissuring around
the mouth
- mouse-like face

Cutaneous manifestations
Skin involvement
inflammatory
edematous phase
puffiness, swelling,
skin flexibility

indurative phase
skin thickening, puffy
fingers, loss of normal
body creases and skin
appendages

atrophic phase

Cutaneous manifestations
Raynauds phenomenon
- closure of digital arteries in
response to cold
- 3 color phases:
whiteness or pallor due to
vasoconstriction
cyanosis due to stasis and
removal of oxygen from the
blood
redness due to vasodilatation
and reactive hyperemia

Cutaneous manifestations

periungal telangiectasia

abnormal nail-fold
capillary patterns

Cutaneous manifestations
ulcerations
telangiectasias
calcinosis cutis (9%)
calcium hydroxyapatite deposits

pigmentary abnormalities
salt and pepper pattern

Muscle Abnormalities

non-specific
muscle enzymes: normal to >100X
EMG abnormalities
skeletal muscle involvement ~ risk for
significant myocardial dysfunction

Gastrointestinal Manifestations
Esophagus
abnormal motility
gastroesophageal reflux
Barretts esophagus
adenocarcinoma
infectious esophagitis
pill-induced esophagitis
Stomach
gastroparesis
telangiectasias
Small intestine
pseudo-obstruction
bacterial overgrowth
telangiectasias
pneumatosis cystoides intestinalis
small bowel diverticula

Colon
wide-mouth diverticula
colonic inertia
fecal/barium impaction
megacolon
perforation
telangiectasias
Anorectum
impaired internal sphincter
relaxation
anal sphincter resting pressure
rectal compliance
rectal prolapse
Hepatic
primary biliary cirrhosis
drug-induced hepatitis

Pulmonary Manifestations
Interstitial inflammation
and fibrosis
Pulmonary vascular
disease
Bronchiolectasis (cysts)
Spontaneous
pneumothorax
Pleural disease

Aspiration pneumonia
Calcinosis
Malignancy
Pneumoconiosis
(silica)
Diffuse alveolar
hemorrhage

Interstitial Lung Fibrosis

Major Pulmonary Manifestations

Clinical Features

Pulmonary
Hypertension

Interstitial
Pulmonary Fibrosis

Clinical subset

lcSSc

lcSSc or dcSSc

Symptoms

dyspnea, syncope

dyspnea, cough

Signs

loud P2

crackles, digital
pitting

PFT

isolated DLCO

FVC, FEV1,
DLCO, FEV1/FVC,
TLC

ANA associations

(+) ACA, but not

predictive

(+) Scl-70

5-year survival

<10% from diagnosis

~45% from initial

PFTs

Cardiac Involvement
myocardial fibrosis
hallmark of cardiac involvement
patchy
systolic and/or diastolic dysfunction

myositis
myocardial infarction
conduction abnormalities and arrhythmias
pericardial disease
valvular disease

Scleroderma Renal Crisis

new onset of accelerated arterial
hypertension and/or rapidly progressive
oliguric renal failure during the course of
systemic sclerosis
primary process: endothelial cell injury
in 10% of all patients --at greatest risk are
those with diffuse scleroderma (20-25%)
75% occur within 4 years from first
symptom

Nervous System Involvement

Central nervous system
modification of EEG
activity
psychiatric
symptomatology
bulbar palsy
Peripheral nervous system
optic neuritis
trigeminal neuropathy
bulbar palsy
7th, 8th, 9th,12th cranial
nerve neuropathy

Autonomic nervous system

sympathetic dysfunction
parasympathetic
dysfunction
gastrointestinal dysfunction

Management Strategies
Vascular therapy
Immunomodulation
Antifibrotic drugs

Raynauds phenomenon
Non-pharmacologic therapy
stop smoking, avoidance of aggravating
drugs (e.g. blockers)
central and peripheral warmth (body
warmers, muffs, gloves, etc.)
even, ambient temperature
physical exercises (whirling of the arms,
biofeedback techniques)

Raynauds phenomenon
Pharmacologic therapy
Calcium channel blockers
long acting nifedipine, nicardipine

Alpha blockers
prazosin

ACE inhibitors
Agents which affect serotonin
5-hydroxytryptamine, ketanserin, SSRIs (fluoxetine)

Topical therapy
transdermal nitroglycerin patches, topical
nitroglycerin

Raynauds phenomenon
parenteral vasodilators
carbo-prostacyclin (Iloprost)
Wigley FM et al., Ann Intern Med 1994; 120:199
greater reduction in the no. of weekly attacks (39 vs. 22% with
placebo)
greater mean reduction in the global Raynaud severity score
15% more patients showed healing of at least 50% of digital
cutaneous lesions
Stratton R et al., J Clin Invest 2001 Jul; 108 (2): 241-50
reduction in skin tightness

PGE1(Alprostadil)
Bartolone S et al., Minerva Cardioangiol 1999 May; 47(5):137-43

evening primrose oil (concentrated linoleic

and gamolenic acids)

Raynauds phenomenon
Surgical procedures
lumbar sympathectomy
radical arteriolysis (digital sympathectomy)
debridement, digital amputation

Immunomodulation
Cyclophosphamide
uncertain
primary role in combination with
corticosteroids for patients with fibrosing
alveolitis who do not yet have advanced
fibrosis

Corticosteroids
restricted to patients with myositis, active
fibrosing alveolitis, symptomatic serositis,
the early edematous phase of the skin
disease, and refractory arthritis and
tenosynovitis

Immunomodulation
Cyclosporine
suppresses CMI and reduces collagen
synthesis
diminished skin thickening but no change in
cardiac or pulmonary disease
nephrotoxic

Methotrexate
improved skin scores and sense of well being
of greater benefit in localized scleroderma
(immunohistochemical parameters)
Seyger MM et al., J Pathol 2001
Apr; 193(4):511-16

Antifibrotic Therapy
D-penicillamine
affects collagen biosynthesis and the immune
system
improved cumulative five year survival (80%)
and a lower rate of new visceral involvement
73 patients on D-penicillamine vs. 45 patients on placebo
Steen VD et al., Ann Intern Med 1982; 97:652

75% improvement in skin sclerosis in 69 patients treated

with penicillamine for 6 months
Jimenez SA, et al., J Rheumatol 1991; 18:1496

Antifibrotic Therapy
Interferons
inhibit collagen synthesis
interferon more potent than interferon

Colchicine
inhibits collagen production by disrupting
microtubule formation in fibroblast
cytoskeleton

Other agents
antithymocyte and antilymphocyte globulin
improvement of autoimmune hemolytic
anemia, glomerulonephritis, lung fibrosis, skin
and joint involvements
in cases of severe autoimmune diseases
unresponsive to regular immunosuppressive
treatment
Scand J Rheumatol 1993; 22(6):261-6

plasmapheresis

Other agents
extracorporeal photopheresis
effective treatment modality in severe
scleroderma particularly when started early,
with stabilization of the disease course and
partial remission of the cutaneous findings,
whereas visceral involvement may rarely
improve
Krasagakis K et al., Dermatology 1998

196(3):309-15

allogeneic bone marrow transplantation

J Rheumatol Suppl 1997 May; 48:72-8

Other agents
PUVA photochemotherapy
for localized scleroderma
Aragane Y et al., J Cutan Med Surg 2001
Mar-Apr; 5(2):135-9

antithymocyte globulin + mycophenolate

mofetil
for recent onset diffuse scleroderma
Stratton RJ et al., Rheumatology (Oxford) 2001
Jan;40(1): 84-8

New Potential Therapies

Immune
Rapamycin
blocks cytokine action in T-cell activation/proliferation

Mycophenolate mofetil
inhibits lymphocyte proliferation

Stem cell therapy

Oral tolerance
induces regulatory suppression of specific immune
response through oral administration of small
amounts of antigen

New Potential Therapies

Antifibrotic
anticentromere antibodies
block mediators of fibroblast activation

enzyme antagonists
lysyl and prolyl hydroxylase inhibitors

pretranslational inhibition

Organ-based Therapy:
Skin Disease
Pruritus
antihistamines
lubricating creams

Calcinosis

surgical removal
antibiotics if infected
probenecid, colchicine, warfarin (not proven)
diltiazem

Organ-based Therapy:
Musculoskeletal Symptoms
Arthritis
acetaminophen,
NSAIDs
low dose steroids

Myopathy
muscle strengthening exercises + NSAIDs

physical therapy to limit contractures

Organ-based Therapy:
Renal Disease
ACE inhibitors
mainstay of treatment
increased anti-hypertensive efficacy
associated with improved survival
better preservation of renal function
greater incidence of renal functional recovery
Steen VD et al., Arthritis Rheum 1998; 41:1613

Organ-based Therapy:
Renal Disease
Calcium channel blockers
added if response to ACE inhibitor is inadequate

Intravenous prostacyclin
at the onset
anecdotal reports
help in the microvascular lesion

Fish oils
theoretically beneficial hemodynamic and antiplatelet
properties
efficacy unproven

Organ-based Therapy:
Pulmonary Disease
No evidence of lung disease
Reevaluate patient every 6 months to permit early
diagnosis since >70% of patients eventually develop
lung disease
Symptoms (e.g. dyspnea)
Pulmonary function tests including DLco

Fibrosing Alveolitis and

Interstitial Lung Disease
Ground glass opacification on HRCT
immediate therapy indicated since this pattern almost
always responds with an improvement in lung function
and/or the appearance on CT scan
Low dose prednisolone (20 mg every other day) plus
oral cyclophosphamide for 3 months, then reevaluate
Cyclophosphamide monthly IV infusion plus prednisone
20-30 mg/day continued for at least 6 months
May substitute azathioprine for cyclophosphamide

Fibrosing Alveolitis and

Interstitial Lung Disease
Predominantly reticular
pattern on HRCT
Fast clearance of isotope on
DTPA scanning: treat as
ground glass group
Normal DTPA clearance:
monitor without specific
therapy

Pulmonary Vascular Disease and

Pulmonary Hypertension
Nifedipine
no definitive studies which show an improvement in survival

Chronic anticoagulation with warfarin

still unproven but may show similar benefit to those with primary
pulmonary hypertension (INR 2.0)

Misoprostol
based on hypothesis that it improves functional capacity and
survival

Prostacyclin analogs
pulmonary arterial pressure and improved exercise tolerance

Endothelin receptor antagonist (Bosentan)

Organ-based Therapy:
Cardiac Disease
pericarditis
pericardial
effusion
myocardial fibrosis

NSAIDs, corticosteroids
pericardiocentesis,
pericardiotomy
none

myocarditis

corticosteroids

arrhythmias

often no treatment
required

Organ-based Therapy:
Gastrointestinal Disease
GERD
prokinetic drugs, omeprazole, surgery

Intestinal pseudoobstruction
prokinetic drugs and dietary modification for the
early phase
rotating antibiotics for bacterial overgrowth

Malnutrition
parenteral nutrition

Summary
Progressive fibrosis of the skin and various
internal organs is the pathologic hallmark of
scleroderma.
Excessive collagen deposition in affected tissues
is responsible for most of its clinical
manifestations.
While supportive therapy is mandated,
pharmacologic manipulation of the multiple steps
involved in the complex pathway leading to
exaggerated fibrogenesis offers a potentially
successful approach to treatment.

Sjogrens Syndrome
Chronic inflammatory disease
associated with lymphocyte infiltration
of exocrine glands
Classification
Primary
Secondary (with associated connective
tissue disease)

Sjogrens Syndrome
Defined as the presence of two of the
following findings:
Keratoconjuctivitis sicca (dry eyes)
Xerostomia (dry mouth)
Any of CTD syndromes

Sjogrens Syndrome
More common among middle aged
women 40 years and above (90%)
Sex ratio 9:1
Immunogenetic studies demostrate
HLA-B8, DR3 and DRw52
Some may subsequently develop
malignant B-cell lymphoma

Associated Diseases with

Sjogrens Syndrome
Autoimmune disorders
Rheumatoid arthritis
(30-55%)
SLE (5-10%)
Scleroderma (5-8%)
Polymyositis (2-4%)
Mixed Connective
Tissue Disease
Juvenile Rheumatoid
Arthritis

Other autoimmune
diseases
Hashimotos thyroiditis
Chronic active hepatitis

Lymphoproliferative
malignancies (leukemia)
Sarcoidosis
Lymphosarcoma
Dysproteinemias

Pathogenesis of
Sjogrens Syndrome
Characterized by lymphocytic (T-helper
/inducer) infiltation of exocrine glands
and B-lymphocyte hyperreactivity.
Autoantibodies directed to
immunoglobulins (rheumatoid factor)
and nuclear/ cytoplasmic antigens
(Ro/SS-A, La/ SS-B)

Antibody Associations in
Sjogrens Syndrome

Earlier disease onset

Longer disease duration
Salivary gland enlargement
Severe lymphocytic infiltration of minor
salivary glands
Extraglandular manifestations:
lymphadenopathy
purpura
vasculitis

Clinical Manifestations of
Sjogrens Syndrome
Xerostomia with dry, erythematous, sticky oral
mucosa
Decreased lacrimal and salivary gland functions

Dysphagia with burning sensation in the mouth

Inability to speak continously
Increased dental caries
Parotid gland enlargement
Dry eyes with sandy or gritty sensation leading to eye
irritation, redness, itching and corneal ulcerations

Extraglandular Manifestations
in Sjogrens Syndrome

Arthralgias/ Non-erosive arthritis

Raynauds phenomenon
Lymphadenopathy
Lung, Kidney, and liver involvement
Vasculitis
Lymphoma
Splenomegaly
Peripheral neuropathy
Myositis

Treatment
Symptomatic relief and limit damage of
xerostomia and KCS
Fluid replacement: i.e. artificial tears
Avoidance of the following medications:
Diuretics
Anti-hypertensives
Antidepressants

Other medications:
Pilocarpine, bromhexine
Hyroxychloroquine
steroids

THANK YOU
for your kind attention