Connective Tissue Diseases: An overview

The Connective Tissue Diseases

A group of overlapping auto-immune diseases Abnormalities of acquired (& sometimes innate) immune system present,with anti-nuclear antibodies, causing tissue damage Multiple organs involved but connective tissues usually affected Both genetic and environmental components to aetiology of CTDs

Systemic Lupus Erythematosis

The prototypic connective tissue disease, with excess antibody formation and immune complex deposition in tissues Complex Genetic Disease Complement deficiencies may alter immune complex handling Genetic variation (e.g. in Fc receptors) influences antibody binding and pathologic effects

SLE: rash, face and neck

SLE: bullous lesions, palate

SLE: photosensitivity, face and neck

SLE: inter-articular dermatitis, hands

SLE: digital gangrene, hands, vasculitis/microantiopathy

SLE: Libman-Sacks endocarditis

SLE: red blood cell cast, urine

SLE: glomerulonephritis, focal

(photomicrograph)

Systemic lupus erythematosus: IgG deposition, glomerulus (photmicrograph)

Systemic lupus erythematosus: brain (MRI)

Anti- Cemtromere pattern

Anti-Nuclear Antibodies (ANA or ANF)

+ indirect immunoflourescence test showing presence of antibodies to some component of the cell nuclei A typical feature of most CTDs

ANF- Nucleolar Pattern

ANF- Speckled pattern

If ANA Positive

Check ENA Ro/La Sjogrens Syndrome, Ro Neonatal lupus/congenital heart block. Crosses Placenta! Sm Renal disease Scl70 Systemic sclerosis Anti centromere CREST syndrome

Diagnosis of SLE

ANA Positive (high titre more likely to be significant) ENA DsDNA Complement levels

Clinical Features including urinalysis and BP

SLE: the diagnostic dilemma

SLE can affect multiple organ systems producing different clinical presentations Presents to multiple specalists: Dermatologist (rash), rheumatologist (arthritis), haematologist (haemolitic anaemia etc), neprhologist (nephritis) etc Diagnosis depends on recognising typical multisystem involvement, and identifying autoantibodies The screening test for SLE is the Anti-Nuclear factor ANF (positive in 98%)

Systemic lupus erythematosus: ACR classification criteria

Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis

Renal disorder Neurological disorder Hematological disorder Immunologic disorder Antinuclear antibody

Systemic lupus erythematosus: 1982 classification criteria definitions

Malar

rash rash

Fixed erythema, sparing the nasolabial folds

Discoid

Raised patches, adherent keratotic scaling, follicular plugging; may cause scarring Photosensitivity Skin rash from sunlight Oral/nasopharyngeal Usually painless ulcers Arthritis Nonerosive, inflammatory Serositis Pleuritis or pericarditis

Systemic lupus erythematosus: 1982 classification criteria definitions, contd

Renal

Persistent proteinuria or cellular casts Glomerulonephritis etc Neurologic disorder Seizures or psychosis, stroke-like syndromes etc. Haematologic Hemolytic anemia, leukopenia lymphopenia or thrombocytopenia Immunologic disorder Antibodies to dsDNA or Sm or positive antiphospholipid antibodies ( incl., lupus anticoagulant, or falsepositive serologic test for syphilis) Antinuclear antibody test Positive

disorder

SLE : Renal disease

Glomerulonephritis (gn) is a typical presentation of SLE and usually associated with anti-bodies to dsDNA Kidneys may be normal, or only show immune deposits on EM or immunofluorescence Mesangial gn, or focal or diffuse proliferative gn or diffuse membranous gn all seen May present with nephritic or nephrotic syndromes or just with biochemical abnormalities early on.

Autoantibody-disease associations: SLE and druginduced lupus

Antigen dsDNA ssDNA Histone Sm

SLE 40% 70% 70% 30% 30% 10% 35% 15%

Drug-Induced LE No 75%-80% >95% No No

antigen RNP RNP

Nuclear

Ribosomal SS-A/Ro SS-B/La

No No

Treatment of SLE

Treatment of SLE involves suppressing inflammation & the abberent immune response

Anti-malarials (hydroxy-chloroquine) work well for skin and joint diseaseand modulate disease. Glucocorticoids (GCs) are needed for all severe manifestations of SLE, in high doses for nephritis or CNS involvement Immunosuppressants such as azathiaprine or mycophenylate mofetyl, cycophosphamide are used for additional benefit and to spare GC. Renal and CNS disease Rituximab and anti-Blyss

Scleroderma

A generalised autoimmune disorder of connective tissue affecting skin & internal organs Characterised by fibrotic angiopathy of peripheral and visceral vasculature Accumulation of extracellular matrix & collagen in skin and viscera Associated with typical autoantibodies, esp anticentromere, anti-SCL-70 Several subsets with different clinical features

Scleroderma: Clinical features

Peak onset age 30-50 yrs: Female:male = 4:1

Raynauds phenomenon; esp adult onset Scleroderma: tightening & thickening of skin
Involvement of internal organs, GI tract, lungs, heart, kidneys causes most morbidity & mortality Risk of internal organ involvement strongly correlates with extent of skin disease

Scleroderma: Raynauds phenomenon, blanching of hands

Scleroderma: sclerodactyly & poor hand function

Scleroderma: acrosclerosis and terminal digit resorption, poor hand function

CREST syndrome: calcinosis cutis, fingers

Scleroderma: Mauskopf, Pinched facial features, tight skin microstomia

Scleroderma: facial changes Telangiectasia

CREST Syndrome: Clinical features

Limited cutaneous scleroderma: sclerodactyly of hands feet, face affected but no proximal or trunk involvement Esophageal dysmotility & heartburn Calcinosis & Reynauds & telangiectasia Anti-centromere antibodies typical Pulmonary hypertension a late complication Tends to progress slowly over decades

Scleroderma: Systemic Sclerosis 1

Proximal arms and trunk skin involved More rapid progression & worse prognosis Tight skin causes hand dysfunction etc., GI involvement leads to dysmotility, heartburn, malabsorption, bacterial overgrowth Progressive fibrotic intersitial lung disease

Scleroderma: Systemic Sclerosis - 2

Scleroderma renal crisis is: Renal vascular disease leads to severe ischaemia of kidneys, activation of the renin-angiotensin system and severe (malignant) hypertension with renal failure etc. Pathology shows onionskin intimal thickening of arteriololes Treatment is aggressive use of ACE inhibitors which corrects the pathophysiology

Extensive early skin disease in scleroderma

Scleroderma: kidney (arteriograms) showing loss of arterioles (on Rt) leading to renal ischaemia

Scleroderma: abnormal motility, esophagus (radiograph)

Watermelon stomach

Treatment Of Scleroderma

No specific treatment ACE inhibitors (decrease renal disease mortality by 50%) PPI:Reflux Calcium chanel inhibitors: raynauds Anti TGF beta (disapointing results) Stem cell/ Bone marrow transplant

Idiopathic inflammatory myopathies (IIMs)

A group of systemic autoimmune diseases with myositis as a major feature Frequently myositis associated autoantibodies are present and they can determine clinical features

Types of myositis

Dermatomyositis Polymyositis Myositis associated w other connective tissue diseases Myositis associated w malignancy Inclusion body myositis Others

Myositis-specific antibodies
ANTIBODY Anti-tRNA synthetases (Jo-1) DISEASE ASSOCIATION Dermatomyositis, interstitial lung disease, mechanics hands African-American women, poor prognosis Older women, shawl sign, good prognosis Polymyositis/scleroderm a overlap PREVALENCE 20%

Anti-SRP (signal recognition protein) Anti-Mi-2 PM/SCL

Rare

5% Rare

Dermatomyositis: facial rash heliotrope rash on eyelids: rash is photosensitive

Dermatomyositis: rash, chest

Copyright 1972-2004 American College of Rheumatology Slide Collection. All rights reserved.

Dermatomyositis with Gottrens papules, rash on hands, erythema around nailbeds

Diagnosis of IIM

Presence of proximal muscle weakness on manual muscle testing and examination Raised muscle enzymes (CPK, LDH,AST, Aldolase) indicating muscle damage Evidence on EMG of typical myopathic findings Positive muscle biopsy showing evidence of inflammatory myopathy Positive ANF or other myositis specific antibodies

Dermatomyositis: acute myositis (photomicrograph)

Copyright 1972-2004 American College of Rheumatology Slide Collection. All rights reserved.

Other myositis

15-30% of older patients (> 50yrs) with DM have an associated cancer, as do a small number with polymyositis Inclusion body myositis is a slowly progressive myositis of older men (> women) w proximal and distal weakness, poor response to treatment. Pathology shows typical inclusion bodies on EM Statin induced myositis

Treatment Polymyositis

Inflammatory polymyositis: Corticosteroids. May use Methtrexate/ Azathioprine as steroid sparing agents Statin induced: Stop statin Inclusion Body myositis: no therapy

Sjogrens Syndrome

Immune mediated inflammation of salivary glands with Sicca is typical of this CTD B-Cell hyperactivity is also seen with hypergammaglobulinaemia + ANF with anti Ro or anti-La antibodies May co-exist with RA or SLE etc. Rare features include vasculitis and CNS disease, and B-Cell lymphoma

Sjogrens syndrome

Parotid and salivary gland enlargement, & inflammation Sicca syndrome, dry eyes and mouth + Schirmers test Keratoconjunctivitis sicca

Mixed Connective Tissue Disease

Overlap SLE/Scleroderma/ RA/Polymyositis Very High Titre ANA. (eg 1:2500) RNP Positive Usually milder disease than SLE or Scleroderma