DIFFUSE CONNECTIVE TISSUE

DISEASES
4th year, General Medicine, 2014

DIFFUSE CONNECTIVE TISSUE
DISEASES

1. SYSTEMIC LUPUS ERYTHEMATOSUS : SLE

2. SCLERODERMA ( scleroderma : Scl)

3. POLIMYOSITIS (PM)
4.
4. DERMATOMYOSITIS (DM)

5. RHEUMATOID ARTHRITIS (RA)

6. SJGREN SYNDROME :
1. 6.1 primary
2. 6.2. secondary : usually associated with each of the five
connective tissue diseases/ collagen diseases
DIFFUSE CONNECTIVE TISSUE
DISEASES


OVERLAP SYNDROME :
collagen disease with an intricate
simptomatology (RA, SS, SLE)
present in 25% cases of the patients


Systemic Sclerosis

Systemic sclerosis (SSc) is a chronic,
multisystem disease of unknown etiology
characterized by autoimmunity and
inflammation, functional and structural
abnormalities in small blood vessels, and
progressive fibrosis of the skin and
visceral organs
Scleroderma is usually divided into two
main forms, and then further subdivided
Morphea : leg
Linear scleroderma: thigh and leg
EPIDEMIOLOGY
Systemic sclerosis, an acquired, sporadic disease
with worldwide distribution, affects all races.

Estimates of its incidence in the United States
range from 9 to 19 cases per million per year.

Prevalence rate estimates range from 28 to 253
cases per million.

SSc is more common in females, with women-to-
men ratios of 3 to 5 : 1.
ETIOLOGY
GENETIC FACTORS

Some SSc patients (1.6%) have a fi rst-degree
relative with the disease [relative risk (RR) =
13], indicating an important genetic contribution
to disease susceptibility.

Genetic investigations in SSc havefocused on
polymorphisms of candidate genes, particularly
those involved in regulation of immunity and
inflammation, vascular function, and connective
tissue homeostasis.
ETIOLOGY
ENVIRONMENTAL FACTORS

The relatively low rates of twin concordance for SSc suggest the
importance of environmental factors in disease susceptibility.

Among environmental factors, infectious agents (particularly
viruses), exposure to environmental and occupational toxins
(silica, polyvinyl chloride, aromatic hydrocarbons) and drugs
(bleomycin, pentazocine, cocaine, and appetite suppressants -
derivatives of fenfluramine) have been suspected of playing a role
in the etiology of SSc.

The occurrence of SSc in some women with silicone breast
implants raised concern regarding a possible association, but
careful epidemiologic investigations found no evidence of
increased risk of SSc
PATHOLOGY

An integrated view of the pathogenesis of
SSc must incorporate :

the development of vasculopathy,
activation of the cellular and humoral immune
responses,
progressive fibrosis (fibroblast activation) of
multiple organs
PATHOLOGY

Autoimmunity, altered endothelial cell
function, and vascular reactivity may
be the earliest manifestations of SSc,
leading to Raynauds phenomenon
years before other disease features
are present. Complex interplay among
these processes initiates, amplifies, and
sustains aberrant tissue repair and
fibrosis.
Scleroderma: Raynauds phenomenon, blanching of hands
PATHOLOGY
The distinguishing pathological hallmark of SSc is
an obliterative vasculopathy of small arteries
and arterioles, combined vascular and interstitial
fibrosis in target organs.

The organs most prominently affected by
obliterative vasculopathy are the heart, lungs,
kidneys, and intestinal tract.
Fibrosis is prominent in the skin, lungs,
gastrointestinal tract, heart, tendon sheath,
perifascicular tissue surrounding skeletal
muscle, and in some endocrine organs, such as
the thyroid gland.


Clinical Features
Raynauds Phenomenon


Reversible vasospasm of digital vessels
Occurs in more than 90% of people with SSc.
Associated with color changes of the skin of the digits.
Attacks triggered by cold temperature or emotional
stress.
Tissue damage
May be seen in patients with chronic or severe
Raynauds resulting in :
tissue fibrosis of the fingers (sclerodactyly),
loss of tissue from the digital pads (digital pitting),
digital ulceration,and on occasions, ischemic demarcation
and the need for digital surgery or amputation.
Scleroderma: Raynauds phenomenon, blanching of hands
Scleroderma: Raynauds phenomenon, cyanosis
of the hands
A, B) Digital ulcers and digital gangrene are
caused by severe degrees of ischemia.
Digital ulcers are caused by severe
degrees of ischemia
Digital gangrene are caused by severe
degrees of ischemia

Clinical Features
Skin

The hallmark feature of SSc is thickened skin

Early changes
In the earliest stage of disease, the skin appears mildly
inflamed with nonpitting edema and, in some cases, erythema,
and pruritus.
Over time, collagen deposition leads to thickening of the
dermis, with gradual damage to the normal skin and its
appendages. The patient notices tightening of the skin and
decreased flexibility.

Late changes
As SSc progresses into the fibrotic stage, the skin becomes
more thickened, and severe drying of the surface often leads
to pruritus. The skin then becomes atrophic and thinned, with
tethering secondary to the binding of fibrotic tissue to
underlying structures.
Scleroderma: edematous changes, hands
Scleroderma: skin induration, hands
Scleroderma: acrosclerosis and terminal digit
resorption
Metacarpophalangeal ulcers are due to poor perfusion in areas
of stretched skin or in areas of repeated minor trauma.

Clinical Features
Skin

Skin manifestations also include
hyper- and/or hypopigmentation,
telangiectasias, calcinosis, dermal
ulcers, digital tip pitting scars, and
digital tip gangrene
Scleroderma: Mauskopf, facial changes
Telangiectasias most commonly occur over the fi ngers, palms,
dorsum of the hands, and face.
Scleroderma: Mauskopf, facial changes
CREST syndrome: calcinosis cutis, fingers
Calcinosis can occur in the hands as well as in the forearms,
elbows, knees, and legs.
Metacarpophalangeal ulcers are due to poor perfusion in areas
of stretched skin or in areas of repeated minor trauma.
Digital gangrene are caused by severe
degrees of ischemia
Clinical Features
gastrointestinal manifestations

Next to skin involvement, the GI system is most commonly
affected
Gastrointestinal symptoms are related to dysmotility
which, in turn, is related to smooth muscle atrophy and
fibrosis

Mouth A small oral aperture, dry mucosal membranes, and
periodontal disease (Sjogrens syndrome) can lead to problems
with chewing foods, loss of teeth, and poor nutrition.

Upper esophagus Dysphagia and heartburn are the most
common gastrointestinal symptoms found in SSc.

Lower esophagus Esophageal disease is associated with
esophageal reflux (GERD), esophagitis, and delayed emptying of
the stomach, leading to early satiety, bloating, nausea, and
vomiting.

Scleroderma: abnormal motility, esophagus
(radiograph)
Isenberg DA, Renton P, Imaging in Rheumatology, 2003
Clinical Features
gastrointestinal manifestations

Small intestine Dysmotility of the small intestine may be
asymptomatic, or it can cause severe distension, abdominal pain,
and vomiting. Mild abdominal distension, crampy abdominal pain,
diarrhea, weight loss, and malnutrition also can be
consequencesof malabsorption caused by bacterial overgrowth in
stagnant intestinal fluids.


Large intestine As a consequence of muscular atrophy of the
large bowel wall, asymptomatic wide-mouth diverticula unique to
SSc commonly are found in the transverse and descending colon.


Primary biliary cirrhosis (PBC) occurs in a small proportion of
patients but at a rate that is greater than expected in the general
population
Scleroderma: wide-mouthed diverticula, colon
(radiograph)
Clinical Features
Musculoskeletal
Characteristics of musculoskeletal involvement include (1) :

Joint contractures (due to involvement of overlying skin) and
restricts motion
The hands, wrists, and elbows are the most commonly affected
joints
Range of motion may also be reduced at the shoulders, hips,
knees, and ankles
Tendon friction rubs
the most commonly affected tendon sheaths are those of the ankle
dorsifl exors, the fi nger extensors, and the knee extensors
Myopathy, myositis :
mild proximal muscle weakness;
normal or slight elevations of creatine phosphokinase (CPK);
poor response to corticosteroids
the dominant musculoskeletal problem in late SScis muscle
atrophy and weakness
Clinical Features
Musculoskeletal

Characteristics of musculoskeletal
involvement include (2) :

Bone resorption
Osteolysis or bone resorption of the digital tufts, seen
in 40% to 80% of patients, is believed to be on the
basis of chronic ischemia
Synovitis :
the arthritis of SSc is nonerosive
Compression neuropathies :
The most common compression neuropathy in SSc is
carpal tunnel syndrome
PULMONARY AND PULMONARY
VASCULAR DISEASE

Pulmonary disease is now the leading cause of
death in SSc

Patients with dcSSc are at higher risk of
developing significant lung fi brosis compared to
those with lcSSc

Early lung disease is frequently asymptomatic
dry cough, dyspnea on exertiona are later symptoms

PULMONARY AND PULMONARY
VASCULAR DISEASE

Pulmonary function test that show a restrictive
pattern is the most sensitive test for pulmonary
parenchymal disease
decreases in the vital capacity, lung volumes, and/or
diffusing capacity for carbon monoxide (DLCO) are
indicative of restrictive changes.

An isolated decrease in DLCO may also indicate
pulmonary hypertension.

Computed tomography (CT) scans of the lung are
more sensitive than radiographs for the detection
of early fibrotic changes
PULMONARY AND PULMONARY
VASCULAR DISEASE

The prevalence of PAH in the SSc patient population when
measured by right heart catheterization is 8% to 12%

The prevalence of PAH by echocardiogram alone is more than
double and emphasizes the point that right heart catheterization
is necessary to confirm the diagnosis

Pulmonary hypertension can occur on the basis of two main
pathologic processes:
(1) those primarily involving destruction or obliteration of lung
vasculature, such as pulmonary fibrosis, recurrent thromboembolic
disease, or scleroderma vasculopathy;
(2) those associated with decreased cardiac output, for example,
diastolic dysfunction, congestive heart failure, or valvular disease.

Pulmonary arterial hypertension (PAH) is a term used to describe
the first group of conditions
RENAL DISEASE AND
SCLERODERMA RENAL CRISIS

Scleroderma renal crisis (SRC) was the most common
cause of death in SSc prior to the introduction of
angiotensin -converting enzyme (ACE) inhibitors

SRC still occurs, typically in the setting of early diffuse
disease (<4 years from onset).

In SRC, malignant hypertension can occur suddenly in
individuals with previously normal blood pressure values.

Factors predictive of SRC include diffuse skin disease, rapid
progression of skin involvement, disease duration <4 years,
anti-RNA polymerase III antibody, new anemia, new
cardiac events, and antecedent high dose corticosteroid
usage.
Laboratory Features

Routine studies Routine chemistries and
complete blood count should be obtained at
baseline and at follow-up as necessary

Antinuclear antibodies Positive in most
patients, typically in a speckled pattern. Specific
antinuclear antibodies (anticentromere,
antitopoisomerase anti Scl 70 -, and RNA
polymerase, etc.) may be seen in subsets of SSc
patients and help to predict the risk of future
organ involvement and course.
Diagnosis
KEY CLINICAL FEATURES OF
SYSTEMIC SCLEROSIS
Diffuse cutaneous
systemic sclerosis (dcSSc)

Proximal skin thickening
involving the trunk, upper
arms and thighs, in addition to
symmetrical involvement of
the fi ngers, hands, arms, and
face/neck
Rapid onset of disease
following the appearance of
Raynauds phenomenon
Significant visceral disease:
lungs, heart, gastrointestinal,
and/ or kidneys
Absence of anticentromere
antibodies
Variable disease course but
overall poor prognosis, with
survival 40% to 60% at 10
years
Limited cutaneous
systemic sclerosis (lcSSc)
Symmetrical skin thickening limited
to the areas below the elbows and
knees and involving the face/neck
Progression of disease typically
months or years after the onset of
Raynauds phenomenon
Later and less severe development
of visceral disease
Late development of pulmonary
arterial hypertension
Association with anticentromere
antibodies
Relatively good prognosis with
survival >70% at 10 years

Overlap syndromes
Diffuse or limited systemic sclerosis with
typical features of one or more of the other
defi ned connective tissue diseases
Mixed connective tissue disease: features
of systemic lupus erythematosus,
systemic sclerosis, and polymyositis in
the presence of anti-U1 RNP antibodies
Treatment
Scleroderma: pulmonary fibrosis (radiograph)
Isenberg DA, Renton P, Imaging in Rheumatology, 2003

FIBROZA PULMONARA >>>>>>>>>>>>>>>>>>>>>>>
Isenberg DA, Renton P, Imaging in Rheumatology, 2003
Scleroderma: acrolysis (radiographs)
Scleroderma: calcinosis and acrolysis (radiograph)
Idiopathic Inflammatory
Myopathies

Idiopathic inflammatory myopathies (IIM) is a
heterogeneous group of disorders characterized
by chronic inflammation of striated muscle and
skin.

Painless proximal muscle weakness with or
without rash is the hallmark feature

Increased serum muscle enzymes, muscle
biopsy, electromyography (EMG), and magnetic
resonance imaging (MRI) can assist in the
diagnosis.
Idiopathic Inflammatory
Myopathies
Idiopathic Inflammatory Myopathies
Epidemiology

The idiopathic inflammatory myopathies are relatively rare
diseases:
estimates of prevalence range from 0.5 to 9.3 cases per
million

The age at onset of the idiopathic inflammatory myopathies
has a bimodal distribution, with peaks between ages 10 and
15 years in children and between 45 and 60 years in adults.

Both myositis associated with malignancy and IBM are
more common after the age of 50 years.

Female predominance is especially great between the ages
of 15 and 44 years, in myositis associated with other
collagen-vascular diseases, and in blacks
Idiopathic Inflammatory Myopathies
Pathogenesis

Etiology is still unclear but selected
environmental exposures in genetically
predisposed hosts have been found

Genetic Factors
Polymorphic alleles in the major histocompatibility locus
(MHC) are the major immunogenetic risk and protective
factors identified for the IIM
Environmental Factors
The infectious agents : Group A streptococcus and
influenza have the strongest evidence of association with
onset of juvenile IIM and toxoplasmosis with adult DM from
case-controlled epidemiologic studies
Noninfectious agents : ultraviolet light, physical exertion,
psychological stress, medications, and vaccines, collagen
implants
Idiopathic Inflammatory Myopathies
Clinical Features

The dominant clinical feature of the idiopathic
inflammatory myopathies is symmetric proximal
muscle weakness

The weakness initially affects the muscles of the
shoulder and pelvic girdle

Weakness of neck muscles, particularly the flexors,
occurs in about half the patients

Pharyngeal muscle weakness may cause dysphonia and
difficulty in swallowing
Idiopathic Inflammatory Myopathies
Clinical Features

PM is a systemic disease, and patients may develop morning
stiffness, fatigue, anorexia, weight loss, and fever.
If weight loss persists or is severe, an associated malignancy should be
considered

Arthralgias are not uncommon, but frank synovitis is less usual

Pulmonary and cardiac manifestations may occur at any time
during the course of the disease
Interstitial pneumonitis may cause dyspnea, a nonproductive cough,
hypoxemia, and fatal respiratory failure
Cardiac involvement is usually absent or is restricted to
electrocardiographic abnormalities.
However, heart block, supraventricular arrhythmia, or cardiomyopathy may
develop, causing syncope, palpitations, or congestive heart failure
Idiopathic Inflammatory Myopathies
Clinical Features
Skin

The clinical features of DM include all those
described for PM plus cutaneous manifestations

The skin rash of dermatomyositis may precede, develop
simultaneously with, or follow symptoms of myopathy

Gottrons papules
Mechanics hands
Photosensitivity with
Rash on the face or anterior chest, termed the V sign
Raynauds phenomenon.
Papule Gottron


Malignancy and Myositis
Recent reports strongly support an increased risk
of cancer in patients with polymyositis and an
even greater risk with dermatomyositis.

The overall risk of cancer is greatest in the fi rst
3 years after the diagnosis of myositis, but an
increased risk of malignancy persists through all
years of follow-up, emphasizing the importance
of continued surveillance.

The strongest associations are with ovarian, lung,
pancreatic, stomach, and colorectal cancer and
with non-Hodgkins lymphoma.
INVESTIGATIONS
Serum Muscle Enzymes
Enzymes that leak into the serum from injured skeletal
muscle include the CK, aldolase, AST, ALT, and LDH

Electromyography
Electromyography is a sensitive but nonspecific method
of evaluating muscle for evidence of infl ammationEMG,
about half show the classic fi ndings of inflammation of
fibrillation potentials, complex repetitive discharges,
positive sharp waves, and complex motor unit potentials
of low amplitude and short duration

Muscle Biopsy
Muscle histology remains the gold standard for
confirming the diagnosis of an IIM
INVESTIGATIONS
MRI is noninvasive and can be used to
visualize large areas of muscle
HRCT (high resolution CT) and chest
radiographs
Pulmonary function testing

Serum Autoantibodies
ANA
AntiJo 1 antibodies are directed against
histidyl-tRNA synthetase
Pharmacologic Therapy
Corticosteroids :

Start : 60 mg/day of prednisone
after normalization of the serum CK (often within 13
months), the prednisone can be consolidated to a once-
daily dose and tapered by approximately 20% to 25% of
the existing dose every 3 to 4 weeks to a daily morning
dose of 5 to 10 mg.
this dose should be maintained for several months
depending on the clinical course, but patients often
flare, necessitating an increase of CS to a previously
effective (but not necessarily initial) dose.

Pharmacologic Therapy
Other Immunosuppressive Agents
Methotrexate or azathioprine are often
the first IS, steroid-sparing agents
chosen and their combination has
proven efficacious in refractory myositis

Extramuscular Manifestations