connective tissue diseases dr. müge bıçakçıgil kalaycı rheumatology department of yeditepe...
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CONNECTIVE
TISSUE DISEASES
Dr. Müge Bıçakçıgil kalaycı
Rheumatology department of Yeditepe University Medical Faculty
Indroduction collagen vascular
diseases,autoimmune diseases
difficult to diagnose– nonspecific symptoms– tend to overlap
Common features:
1. Host and genetic predisposition – familial occurrence, female preponderance
2. Overlapping clinical features
3. Blood vessel as important target organ – vasculitis, vasculopathy
4. Immunologic correlates – circulating Ig, immune complexes
The Immune System:
- designed to protect the host from invading pathogens
(non-self or foreign pathogens) and to eliminate
disease.
- Lymphocytes: play a key role, has receptors to
monitor these antigens
- exquisitely responsive to invading pathogens
while
retaining the capacity to recognize self antigens
Autoimmunity
- arises when the body mounts an immune response against itself due to failure to distinguish self tissues and cells from foreign (non-self) antigens.
- Primary mechanisms involved in pathogenesis is unclear
Autoimmune diseases
Characterized by production of:
a) autoantibodies that react with host tissue
b) Immune effector T cells that are autoreactive to endogenous self-peptides
Tissue Injury
common histiologic feature– inflammatory damage CT and blood vessels– fibrinoid material deposition
Major groups of connective tissuedisease
• Systemic lupus erythematosus (SLE)• Antiphospholipid syndrome (primary or
secondary)• Systemic sclerosis (scleroderma)• Polymyositis and dermatomyositis• Sjögren's syndrome (primary and
secondary)• Miscellaneous (Mixed CTD,
undifferentiated CTD)
Systemic Lupus Erythematosus
(SLE)
Systemic Lupus Erythematosus(SLE)
Chronic multisystemic disease of autoimmune origin
Characterized by flare-ups and remissions
Characteristically affects skin and joints, although any system can be involved
- prototype autoimmune disease
- unknown etiology
- production of Ab to components of the cell nucleus
Systemic Lupus Erythematosus (SLE)
Predominantly occurs in womens
F/M : 9/1 Prevalence -1/1000 to 1/10.000
Onset is usually after puberty (20s-30s)
More commonin African Americans than whites
Clinical Features
Constitutional symptoms:
Fatique, fever, malaise, weigth loss
Low grade fever-active SLE
Rarely 39.5 C-(possible infection)
Muco-cutaneous
Skin Rashes (55-90%)Photosensitivity to sunlight
Malar rash-’butterfly rash’ fixed erythema, edema in sun-exposed areas(nose and cheeks)sparing the nasolabial fold
Discoid rash- erythematous patches with kerototic scaling
Maculopapular eruptions- face,V-of the neck,forearms
Photosensitivity
Butterfly facial rash
Systemic lupus erythematosus: butterfly rash
Raynaud’s phenomenon(20-60%) Peripheral extremity changes induced
by cold and may be complicated by digital ulcers
Livedoreticularis
Bullous and blistering lesions
Cutaneous vasculitis
Nailfold capillary changes
Alopecia
Ulcers in nose and mouth (20-50%)
Raynaud’sphenomenon
Livedo reticularis
Alopeciadiffuse or patchy
Mucosal ulcers
Sicca symptoms- secondary Sjogren’s syndrome
Vasculitis
Systemic lupus erythematosus: hands, interarticular dermatitis
Musculoskelatal
Jaccoud arthropathy is the term for the nonerosive hand deformities This may mimic rheumatoid arthritis (RA) ulnar deviation and phalangeal subluxations.
Small-joint arthritis of the hands and wrists is most frequent
Myositis rarely occurs and is more commonly related to overlap syndromes or corticosteroid-induced myopathy.
Synovitis and Jaccoud’s arthropathy
Renal involvement
The kidney is the most commonly involved visceral organ in SLE.
Glomerular disease usually develops within the first few years after onset.
Acute nephritic disease may manifest as hypertension and hematuria.
Nephrotic syndrome may cause edema, weight gain, or hyperlipidemia.
Acute or chronic renal failure may cause symptoms related to uremia and fluid overload.
consider biopsy if:Proteinuria > 0.5 g/24 hoursred or white cells in urinecasts creatinine clearance reduced
(<80ml/min)
Neuropsychiatric Headache is the most common neurological
symptom
Mood disorders-anxiety and depression
Cognitive disorders
Psychosis, Delirium
Seizures
Stroke and transient ischemic attack (TIA) may be related to vasculitis.
Aseptic meningitis may occur.
Cardiac
Pericarditis that manifests as chest pain is the most common cardiac manifestation of SLE and may occur with or without a detectable pericardial effusion.
Libman-Sacks endocarditis is noninfectious but may manifest with symptoms similar to those of infectious endocarditis.
Myocarditis may occur in SLE with heart failure symptomatology.
Pericarditis commonest
Cardiac manifestations
Pulmonary features pneumonitis/fibrosis or haemorrhage
pleurisy commonestconsider also PEand infection
pulmonary hypertension
Hematologic abnormalities
oleucopenia,
olymphopenia,
oAnemia (hemolytic anemia)
othrombocytopenia
Diagnosis
Diagnosis based on the clinical findings and laboratory evidence.
Screening laboratory studies to diagnose possible SLE should include:
CBC count with differential- help to screen for leucopenia, lymphopenia, anemia, and thrombocytopenia
serum creatinine
urinalysis with microscopy/ urine protein proteinuria ,hematuria, casts, or pyuria.
ANA
inflammatory markers.
Complement levels: C3 and C4 levels are often depressed in patients with active SLE
ANA
Antinuclear antibody is an autoantibody against a part of the nucleus
Frequent ANA patterns Speckled Homogeneous /
Diffuse Nucleolar Rim / Peripheral Centromere
In patients with high clinical suspicion or high ANA titers, additional testing is indicated.
Antinuclear antibodies (ANAs) - Higher titers generally more specific (>1:160)
This may include anti–double-stranded DNA (dsDNA)antibodies, complement, and ANA subtypes such as anti-Smith (Sm) antibodies
, SSA, SSB, and ribonucleoprotein (RNP)
The following are autoantibody tests used in SLE diagnosis:
ANA - Screening test; sensitivity 95%; not diagnostic without clinical features
Anti-dsDNA - High specificity; sensitivity only 70%; level variable based on disease activity
Anti-Sm - Most specific antibody for SLE; only 30-40% sensitivity
Anti-SSA (Ro) or Anti-SSB (La) - Present in 15% of patients with SLE and Sekonder Sjögren syndrome; associated with neonatal lupus
Anti-RNP - may indicate mixed connective tissue disease with overlap SLE, scleroderma, and myositis
antiphospholipid antibodies (anticardiolipin immunoglobulin G [ACA IgG] or immunoglobulin M [ACA IgM] or lupus anticoagulant)
biologic false-positive serologic test results for syphilis
Anti-histone - Drug-induced lupus (DIL) ANA antibodies often this type (eg, with procainamide or hydralazine; minocycline)
Classification criteria for diagnosis of SLE (>4 of 11)
Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Renal disorder
proteinuria > 0.5g cells &/or casts
Neurological disorder seizure or psychosis
Haematologic disorder haemolytic anaemia leukopenia,
lymphopenia thrombocytopenia
Immunological disorder anti-DNA, anti-Sm anti-cardiolipin
ANA positivity
Treatment Guided by the individual patient's
manifestations.
avoid sun exposure
Fever, rash, musculoskeletal, and serositis manifestations - hydroxychloroquine and NSAIDS. Low-to-moderate–dose steroids are necessary for acute flares.
CNS involvement and renal disease- high-dose steroids and other immunosuppression agents such as cyclophosphamide, azathioprine, or mycophenolate.
Traditionally, class IV diffuse proliferative lupus nephritis has been treated with aggressive cyclophosphamide induction therapy.
Antiphospholipid antibody syndrome
Antiphospholipid antibody syndrome
Recurrent venous thrombosis deep vein thrombosis pulmonary embolus
Recurrent arterial thrombosis myocardial infarction stroke (cerebro-vascular accident)
Recurrent miscarriages
Antiphospholipid antibody syndrome (APS)
Half are associated with SLE Occurs in 10-20% of SLE patients often livedo reticularis, low platelets
Antiphospholipid antibody syndrome (APS)
Positive tests may include Lupus anticoagulant (false prolongation
of PTT) Anticardiolipin antibody (aCL) or other
antiphospholipid antibodies False positive VDRL Anti beta 2 glikoprotein Igm, Ig g
APS
Treatment varies on symptoms and signs
ASA or LMW heparin in pregnancy Warfarin if DVT ASA and possibly warfarin if CVA
Sjögren’s Syndrome
Sjögren’s syndrome
A slowly progressive inflammatory disease affecting primarily the exocrine glands- especially the salivary and lacrimal glands
İnfiltration of Lymphocyte, plasma cells, and macrophages into target tissues.
Autoantibodies-Anti SS-A (Ro) and anti SS-B (La)
HLA –DR3 and HLA DR4-development and the severity
Enviromental factors (eg; viral or retroviral infections)
Hormonal factors
Female gender ( %90 )
30-40 years
Primary or secondary (Rheumatoid arthritis, Systemic lupus erythematosus, Scleroderma)
The decrease in exocrine gland secretions seen in SS results in dryness that can affect every mucocutaneous surface of the body
The Sicca Complex
Xerostomia- xerophthalmia
Clinical Features
Oral: Burning and dryness of oral mucosal
surfaces Difficult to chew or swallow Atrophy of lingual papillae fissures of tongue and lips Oral candidiasis
Bilateral parotid and submandibular gland enlargement, pain , and tenderness
Bacterial infections of the major salivary glands
Ocular: Gritty or sandy discomfort and the
sensation of a foreign body in the eye
Photophobia
Ocular infections
Cutaneous
Dry skin with chronic scaling and pruritus
Leucocytoclastic vasculitis –petechiae or palpable purpura
Nasal Decreased smell and attenuation in
the ability to taste food Dryness of sinus-acute or chronic
sinusitis
Vaginal Pain, pruritus dyspareunia and
recurrent vaginal candidiasis dysuria
Musculoskelatal
İnflammatory,symmetric,nonerosive,arthralgic syndrome that affects small proksimal joints
Fibromyalgia
Proksimal muscle weakness
Pulmonary
Tracheobronchial dryness –chronic dry cough
The lymphocytic infiltration of tracheobronchial tree-signs and symptoms of acute and chronic obstructive pulmonary disease
Restrictive lung disease-infiltration of the pulmonary interstitium
Lymphocytic interstitial pneumonitis
Fibrosing alveolitis, pulmonary vasculitis
Pleuritis
Rare but potentially fatal complication
Gastrointestinal
Upper esophageal dysphagia
Reflux esophagitis
Acute and chronic pancreatitis
Chronic active hepatitis and primary biliary cirrhosis
Chronic atrophic gastritis
Pernicious anemia
Lymphocytic colitis and mal absorbtions
Renal
Chronic lymphocytic interstitial nephritis –common extraglandular complication
Decreased urinary concentrating ability, glycosuria, potassium wasting
Renal tubular asidosis (hypercalciuria and nephrolithiasis)
Membranous glomerulonephritis
(immune complex accumulation)
Diagnosis
Laboratory Findings: Autoantibodies develop in most
patients RF (90%)
ANA(80%-usually speckled pattern)
SS-A(Ro) (%60), SS-B(La) (%30)
Polyclonal hypergammaglobulinemia
ESR elevated
Anemia, leucopenia, thrombocytopenia, elevated circulating immune complexes
cryoglobulinemia
Diagnosis
Characteristic autoantibodies - Ro, La
Salivary flow (<1,5 mL in 15 minutes)
Salivary gland Sintigraphy-decreased uptake and release of 99m Tc-pertechnetate
schirmer’s test-<5 mm –positive
Rose bengal staining-detects damage to the conjunctival epithelium
-red spot areas1+(sparsely scattered)2+(densely scattered)3+ (coursely) in 3 different areas of the eye
Total of three areas are added(>4 is abnormal)
Minor salivary gland biopsy Single most specific and sensitive
test
Biopsi graded according to their focus scores
The number of foci of 50 or more mononuclear per 4mm2 of salivary gland tissue
Revised International Classification Criteria for Sjögren syndrome
I-Ocular symptomsII-Oral symptomsIII-Ocular signs(schirmer test,Rose Bengal
score)IV-HistopathologyV- Salivary gland
involvement(sialometri,salivary scintigraphy
VI-autoantibodies 4 of 6 criteria-IV or VI positive3 of 4 objective criteria
Treatment
symptomatic• oral fluid intake• saliva substitutes• artificial tears
avoid• decongestants• antihistamines• diuretics• anticholinergic
Treatment
Parasympathomimetic agents pilocarpine , cevimeline
clotrimazole/nystatin
close dental care
ArthritisNSAIDsHydroxychloroquine
Interstitial lung disease, renal disase, or vasculitis- High dose glucocorticoids or cytotoxic therapy (azathioprine,methotrexate,mycophenolate mofetil, cyclosporine, cyclophosphamid)
surveillance for malignancy
Systemic sclerosis / scleroderma
Systemic sclerosis / scleroderma
Pathophysiology Auto-immune disease
Unknown aetiology
Generalised disorder of CT affecting skin (scleroderma) and internal organs
Characterised by fibrotic arteriosclerosis of peripheral and visceral vasculature
Extracellular matrix accumulation (collagen) in skin and viscera
Associated with specific auto-antibodies
Epidemiology Rare 3-5 x more common in women Presents in middle age (30-50 yrs)
Systemic sclerosis / scleroderma
Signs and symptoms
Skin on hands/feet/face affected Sclerodactyly
edema fingers and hands
Sclerodactyly
Scleroderma: acrosclerosis
skin thickeningCharacteristic appearance
Beaked noseFixed expressionRadial furrowing of lipsLimitation of mouth
movements-decreased mouth opening
Accompanying telangiectasia, calcinosis, Raynaud’s
Clinical Features
Calcinosis Digital Ulceration
visceral manifestations
GI tract, lung, kidneys
arthralgias and muscle weakness often
dysphagia
• 80% distal 2/3pathology• decrease/absentparistalsis, dilation,hiatal hernia
widespread skin thickening are at the greatest risk of visceral involvement, which may include the heart, lungs, kidneys or gastrointestinal system
Raynaud’s phenomenon is almost always apparent at presentation in patients with the CREST syndrome and in about 70% of patients with diffuse disease.
SclerodermaCREST
Systemic sclerosis (scleroderma)
Diagnosis Clinical
Specific auto-antibodies
positive ANA with a nucleolar pattern
Anti-centromere antibodies are found in 50 to 95% of patients with CREST syndrome, but only in about 10% of patients with diffuse scleroderma and visceral disease.
Scl-70 and PM-Scl. Scl-70 (DNA topoisomerase I).
Antibodies to Scl-70 are detected in some patients with diffuse scleroderma.
Antibodies to PM-Scl are seen in some patients with “sclerodermatomyositis,” an overlap of inflammatory myositis and scleroderma.
ESR, anemia, hypergammaglobulinemia, RF
Organ specific investigations
A chest x-ray pulmonary function tests
fibrosing alveolitis- interstitial fibrosis -diffuse skin involvement
isolated pulmonary hypertension-CREST syndrome.
A barium swallow - esophageal dysmotility, reflux or esophageal stricture.
Nailfold capillary microscopy
Treatment– symptomatic• calcium channel blockers in Raynaud’s• H2 blockers for reflux• NSAIDS and steroids for arthralgias and myalgias• hand rehabPulmonary involvement- pulse
cyclophosphamid
POLYMYOSİTİS &
DERMATOMYOSİTİS
– group of disorders– proximal muscle weakness– nonsuppurative inflammation skeletal Muscle
• prevalence 5 cases/mil/year• 2 to 1 F>M• 40-60 yrs• pediatric variant 5-15-yrs
Myositis can be associated with malignancy
Polymyositis begins insidiously over 3-6 months
Pelvic and shoulder musculature are most affected.
Esophagial dysfunction or cricopharyngeal obstruction cause dysphagia.
Myalgias, artralgias are common but severe muscle tenderness and sinovitis are unusual
Raynoud phenomenon
Periorbital edema
Pulmonary and cardiac manifestations may precede the onset of muscle weakness
Supraventricular arrhytmia, cardiomyopathy and congestive heart failure
İnterstitial fibrosis or interstitial pneumonitis
Clinical classification of the inflamatory myopathies Polymyositis Dermatomyositis Juvenile dermatomyositis myositis associated with neoplasia myositis associated with collagen
vascular disease Inclusion body myositis
Vasculitis
Ectopic calcification ( sc. tissue,muscle)
Vasculitis cause gastrointestinal ulcerations, hemorrhage or perforation
Dermatomyositis sine myositis
Dermatomyositis sine myositis
Biopsi confirmed classical cutaneous findings of dermatomyositis
Motor function, muscle enzyme, EMGs are normal
İncreased prevalence of neoplasia
Diagnosis
Laboratory findings
Elevated creatine kinase (CK) CK levels correlates with disease activity
Aldolase, aspartate aminotransferase (AST)
Alanine aminotransferase (ALT) LDH
ESR- 50%-N
ANA-50%
Most myositis specific autoantibodies are directed against amino acyl-t RNA synthetase activities (anti Jo-1)
Anti –Mi-2- directed against helicase activities
Anti SRP- signal recognition particle