CONNECTIVE TISSUE DISEASES Dr. Müge Bıçakçıgil kalaycı Rheumatology department of Yeditepe University Medical Faculty.

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