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Connective Tissue Diseases. Adam Wray, D.O. September 7, 2004. ANA Assay. Classic ANA immunofluorescence is still considered first line screening test for AI-CTD Historically, rodent cells rather than human cells were used as the substrate

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Connective Tissue Diseases

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connective tissue diseases

Connective Tissue Diseases

Adam Wray, D.O.

September 7, 2004

ana assay
ANA Assay
  • Classic ANA immunofluorescence is still considered first line screening test for AI-CTD
  • Historically, rodent cells rather than human cells were used as the substrate
  • Rodent cell nuclei lack some autoantigens present in human cell nuclei (Ro antigen)
  • 1-2% of SLE patients are ANA (-) using human tumor cell line base substrate (Hep-2)
  • Hence, “ANA negative SLE” a historical phenomenon
  • Titer of <1:160 using human tumor cell line substrate has little clinical utility
drug induced ana sle
Drug Induced ANA/SLE
  • Procainamide
  • Hydralazine
  • Isoniazid
  • Chlorpromazine
  • Phenytoin
  • Methyldopa
  • Minocycline
lupus erythematosus
Lupus Erythematosus
  • Chronic Cutaneous LE
    • DLE
    • Verrucous LE
    • Lichen Planus-LE overlap.
    • Chiblain LE
    • Lupus Panniculitis (LE profundus)
      • With DLE
      • With Systemic LE
discoid le
Discoid LE
  • Young adults. F:M=2:1
  • Cat’s Tongue (Langue au chat) = carpet tacks
  • Lesions heal centrally first with atrophy, scarring, and dyspigmentation
  • Up to 24% will have mucosal involvement.
  • 95% of cases confined to the skin at the onset and will remain so.
discoid le11
Discoid LE
  • Unusual for lesions below neck without lesions above the neck
  • Spontaneous involution with scarring is common
  • Progression to SLE is rare and may be identified by abnormal labs.
    • ANA – elevated
    • Leukopenia, hematuria, or albuminuria
  • Thinned epidermis
  • Loss of normal rete ridges
  • Follicular plugging
  • Hydropic changes of basal layer
  • Lymphocytic perivascular infiltrate
  • Increase interstitial mucin depositon
  • Pilosebaceous atrophy discriminates from SCLE
  • DIF is positive more than 75% of cases with Igs located at DEJ
  • Topical steroid, high potency with occlusion if needed.
  • Intralesional Injection with Kenalog
  • Antimalarials: safest and most beneficial system therapy.
    • Plaquenil for 3 months, if no response switch to Aralen.
    • If response is still incomplete, add Quinacrine, since this won’t increase retinal toxicity
verrucous le
Verrucous LE
  • AKA hypertrophic LE
  • Resembling KA or hypertrophic LP
  • Treatment with TAC or Intralesional
  • Also can be treated with Accutane or Plaquenil.
verrucous le16
2% of patients with chronic cutaneous LE

Histo: epidermis is papillomatous, hyperplastic, and surmounted by hyperkeratotic scale

Verrucous LE
le lp overlap syndrome
LE-LP Overlap syndrome
  • Large atrophic hypopigmented bluish-red patches and plaques.
  • Fine telangiectasia and scale usually present
  • Response to treatment is poor
  • Dapsone or Accutane maybe effective
chilblain le
Chilblain LE
  • AKA lupus pernio
  • Chronic, unrelenting form of LE with fingertips, rims of ear, calves and heels in women.
  • Chilblain lesions are due to cold
  • Usual LE treatment
le panniculitis
LE Panniculitis
  • AKA LE Profundus
  • Deep subcutaneous nodules 1-4cm
  • Head, face, and upper arms
  • Woman age 20-45
  • Histology shows lymphocytic panniculitis, hyaline degeneration of the fat, hyaline papillary bodies. Over lying epidermis shows hydropic changes and follicular plugging
  • Treatment with Antimalarials.
  • Subacute cutaneous LE
    • Papulosquamous
    • Annular
    • Syndromes commonly exhibiting similar morphology
      • Neonatal LE
      • Complement deficiency syndromes
  • Typically photosensitive
  • Lesions confined to sun-exposed skin
  • Regular association with anti-Ro antibody (SS-A)
  • Psoriasiform, polycyclic annular lesions
  • Shawl distribution: V neck, upper outer and inner arms.
  • ¾ of the patients have arthralgia
  • 20% have leukopenia
  • 80% have positive ANA
  • Associated with HLA-DR3-Positive.
drugs triggering anti ro antibodies and thus lesions of scle





Lesions may or may not clear once the medication is discontinued.

Drugs triggering anti-Ro antibodies and thus lesions of SCLE
neonatal le
Neonatal LE
  • Annular scaling erythematous macules and plaques
  • Appear on head and extremities
  • First few months of life in babies born to mothers with LE, RA, or other connective tissue disease
  • Resolve spontaneously by 6 month of age
  • HALF of the patients have associated congenital heart block, usually 3rd degree
neonatal le32
Neonatal LE
  • Lesions histologically identical to SCLE
  • Almost 100% have anti-Ro antibodies
  • Unlike adult SCLE, lesions have predilection for the face, especially periorbital region
  • Lesions typically resolve without scarring
  • Other internal findings
    • Hepatobiliary disease
    • Thrombocytopenia
acute cutaneous le
Acute Cutaneous LE
  • Characteristic butterfly facial erythema
  • May last from days to several weeks
  • Bullous lesion occur as single or grouped vesicle or bullae
  • Subepidermal bulla containing neutrophils.
  • HLA-DR2 positive
  • Minute telangiectasias appear in time on the face or elsewhere and commonly appear about the nail folds.
  • Rowell Syndrome: EM-like lesion dominant in LE
systemic le
Systemic LE
  • Young to middle age women
  • Skin involvement occur 80% of the case
  • American Rheumatism Association has 11 criteria
  • If 4 or more of the criteria are satisfied, the patient is said to have SLE
ara sle criteria
ARA SLE criteria
  • Malar Erythema
  • Discoid Lupus
  • Photosensitivity
  • Oral Ulcers
  • Arthritis
  • Serositis
  • Nephritis
  • Hematologic
  • CNS Changes
  • Immunologic disorder
  • ANA
systemic manifestation
Systemic Manifestation.
  • Arthralgia is the earliest abnormality.
  • 95% of SLE patient will have arthralgia.
  • Avascular necrosis of femoral head.
  • Thrombosis in vessels secondaary to presence of lupus anticoagulant.
  • Renal involvement in nephritic or nephrotic type.
  • Mycocarditis, cardiomegly, EKG changes.
systemic manifestation43
Systemic Manifestation.
  • CNS involvement
  • Idiopathic thrombocytopenic purpura.
  • Sjogren’s syndrome
  • Mixed with dermatomyositis
treatment of sle
Treatment of SLE
  • Treatment depending on the organ system(s) involved.
  • Skin, musculoskeletal, and serositis-type manifestations generally respond to treatment with hydroxychloroquine and nonsteroidal anti-inflammatory medications.
  • Porphyria cutaneous tarda may co-exist with LE, in this case, Plaquenil is TOXIC!!!
  • More serious organ involvement, such as CNS involvement or renal disease, often necessitates immunosuppression with high-dose steroids and cyclophosphamide.
  • Stop smoking!
  • Poikiloderma
  • Gratton's sign - flat-topped violaceous papules
  • Heliotrope - reddish -purple flush around the eyes
  • Over knuckle streak erythema
  • Shawl pattern
  • Bimodal distribution
  • Calcinosis Cutis may occur in over half of the children with DM
  • Associated with Malignancy in 10-50% of adults
  • Symmetrical muscle weakness
  • assoc c malignant neoplasm when over 40
  • periungual telangiectasia
  • Prednisone 1mg/kg with slow taper
  • Sunscreen, antimalarial
  • Mechanics hand: hyperkeratosis, fissuring, scaling involvement in the palm of the hand.
muscle involvement
Muscle involvement
  • Symmetrical muscle weakness
  • Unable to raise arms to comb their hair
  • Cardiac involvement with cardiac failure in terminal phase
  • Amyopathic dermatomyositis or dermatomyositis sine myositis: DM without muscle changes
childhood dm
Brunsting type

Slow course

Progressive weakness


Steroid responsiveness

Banker type

Vasculitis of muscles and GI tract

Rapid onset

Severe weakness

Steroid unresponsiveness

Childhood DM
  • characterized by symmetric thickening, tightening, and induration of the skin of the fingers and the skin
  • These changes may affect the entire extremity, face, neck, and trunk (thorax and abdomen).
  • Occurs in localized and systemic forms
localized morphea
Localized Morphea
  • Smooth, hard, somewhat depressed, yellowish white, or ivory-colored lesions.
  • Common on the trunk
  • Margins surrounded by light violaceous zone or by telangiectasias.
  • Resemble pigskin (prominent follicular orifices)
  • Slowly involute over a 3-5 year period.
generalized morphea
Generalized Morphea
  • Widespread hard indurated plaques.
  • No systemic involvement
  • Patient appear young because of the firmness of the skin.
  • Resolution less likely than the localized version.
atrophoderma of pasani and pierini
Atrophoderma of Pasani and Pierini
  • Reduction of thickness of dermal connective tissue
  • Upperback and lumbar sacral area
  • Benign course, usually resolve after few months or few years.
  • No effect treatment
  • Variant of morphea.
linear scleroderma
Linear Scleroderma
  • Linear lesions extend to length of arms or leg
  • Begin first decade of life
  • May also occur parasagitally down the forehead, known as en coup de sabre
  • Parry-Romberg syndrome: progressive facial hemiatrophy, epilepsy, exophalmos, and alopecia, maybe a form of linear scleroderma.
crest syndrome
CREST Syndrome
  • AKA Thibierge-Weissenbach Syndrome.
  • Systemic sclerosis may be limited to the hands, and is called acroslerosis.
  • Not as severe as PSS
  • ANA shows anticentromere antibody, and is highly specific.
  • Most favorable diagnosis
progressive systemic sclerosis
Progressive Systemic Sclerosis
  • Raynaud’s is the first manifestation of PSS most of the time and is eventually nearly always present
  • Round fingerpad sign: loose the normal peaked contour and appear round from the side.
  • Pterygium inversum unguis: distal part of nailbed remains adherent to ventral surface of nail plate. Seen also in LE
progressive systemic sclerosis77
Progressive Systemic Sclerosis
  • 75% have dilated nail fold capillary loops
  • Esophageal involvement in 90% of patients
  • Pulmonary fibrosis
  • Cardiac involvement
  • Articular pain, swelling, polyarthritis.
  • Skin involvement after 1 year of diagnosis:
  • Group I – sclerodactyly alone – 71% 10 year survival rate
  • Group II - Skin stiffness above metacarpal-phalangeal joints but not involving trunk – 58% survival rate.
  • Group III – truncal involvement – 21% survival.
lab finding
LAB Finding
  • Topoisomerase I (formerly Scl–70) is present in 20-30% of patients with diffuse disease (absent in limited disease) and has an increased association with pulmonary fibrosis
  • Anticentromere antibodies are present in about 60-90% of patients with limited disease and 10-15% with diffuse disease.
  • Increased collagen bundle and thickness of the dermis
  • Pilosebaceous units are absent. Eccrine glands and ducts are compressed by collagen.
  • Eccrine glands present at the mid dermis rather than at the junction of dermis/subQ fat.
  • Symptomatic tx
  • Treatment aimed at minimizing complications
  • Regular massage, warmth, and protection from trauma
  • No smoking
eosinophilic fasciitis
Eosinophilic Fasciitis
  • Patient engaging in strenuous muscular effort few days or week before acute onset of weakness. Follow by severe induration of the skin and subQ tissue of forearms and legs.
  • Coarse peau d’orange appearance.
  • Groove sign: depression follows the course of underlying vessels when arms are held laterally. Represents line of demarcation between muscle groups
  • Excellent response to corticosteroid.

Comparison of deep morphea and eosinophilic fasciitis. A Note the ‘pseudo-cellulite’ appearance of the involved skin of the thigh in deep morphea. B In eosinophilic fasciitis, the level of fibrosis is also deep.

  • Patchy lymphocytic and plasma cell infilrate in the fascia and subfacial muscle and great thickening, 10-50 times normal of the fascia.
mixed connective tissue disease
Mixed Connective Tissue Disease
  • Mixed features of scleroderma, SLE, and dermatomyositis
  • IgG deposition in speckled (particulate) pattern in epidermal nuclei of normal skin on DIF is a distinctive finding in MCTD
  • Treatment with daily dose of prednisone 1mg/kg shows good improvement.
  • Most patients have anti-U1RNP antibodies
sjogren s syndrome
Sjogren’s Syndrome
  • AKA Sicca syndrome
  • Triad of keratoconjunctivitis sicca, xerostomia, and rheumatoid arthritis.
  • RF is usually positive
  • Elevated C-reactive Protein, IgG, IgA, and IgM
  • 80% has anti-Ro/SSA antibody.
  • >50% have anti-La/SSB antobodies
  • Only symptomatic treatment available.
  • Labial salivary gland biopsy most definitive test
schirmer test
Assesses lacrimal gland function

Whatman paper wick folded over eyelid for 5 minutes

<5mm tear film migration = lacrimal gland dysfunction

Schirmer test
rheumatoid nodules
Rheumatoid Nodules
  • 20-30% of RA patients
  • Subcutaneous nodules
  • Found anywhere on the body
  • Histologically shows dense foci of fibrinoid necrosis surrounded by histiocytes in palisaded arrangement.
relapsing polychondritis
Relapsing Polychondritis
  • Intermittent episodes of inflammation of the articular and nonarticular cartilage eventuating in chondrolysis.
  • MAGIC syndrome = Behcet’s + Relapsing Polychondritis (Mouth And Genital ulcers with Inflamed Cartilage)
  • Treatment with Dapsone for few weeks, then maintenance for 4-6 asymptomatic months.