Connective Tissue Diseases

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Connective Tissue Diseases

• Adam Wray, D.O.
• September 7, 2004

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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 lt1160 using human tumor cell line
  substrate has little clinical utility

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ANA Immunofluorescence Patterns
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Drug Induced ANA/SLE

• Procainamide
• Hydralazine
• Isoniazid
• Chlorpromazine
• Phenytoin
• Methyldopa
• Minocycline

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Lupus Erythematosus

• Chronic Cutaneous LE
• DLE
• Verrucous LE
• Lichen Planus-LE overlap.
• Chiblain LE
• Lupus Panniculitis (LE profundus)
• With DLE
• With Systemic LE

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Discoid LE

• Young adults. FM21
• Cats 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.

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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

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Histology

• 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

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Treatment

• SUNSCREEN!!!!
• 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 wont increase retinal toxicity

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Verrucous LE

• AKA hypertrophic LE
• Resembling KA or hypertrophic LP
• Treatment with TAC or Intralesional
• Also can be treated with Accutane or Plaquenil.

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Verrucous LE

• 2 of patients with chronic cutaneous LE
• Histo epidermis is papillomatous, hyperplastic,
  and surmounted by hyperkeratotic scale

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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

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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

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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.

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SCLE

• Subacute cutaneous LE
• Papulosquamous
• Annular
• Syndromes commonly exhibiting similar morphology
• Neonatal LE
• Complement deficiency syndromes

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SCLE

• Typically photosensitive
• Lesions confined to sun-exposed skin
• Regular association with anti-Ro antibody (SS-A)

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SCLE

• 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.

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Drugs triggering anti-Ro antibodies and thus
lesions of SCLE

• HCTZ
• NSAIDS
• Diltiazem
• Griseofulvin
• Terbinafine
• Lesions may or may not clear once the medication
  is discontinued.

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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

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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

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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

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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

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ARA SLE criteria

• Malar Erythema
• Discoid Lupus
• Photosensitivity
• Oral Ulcers
• Arthritis
• Serositis
• Nephritis
• Hematologic
• CNS Changes
• Immunologic disorder
• ANA

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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.

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Systemic Manifestation.

• CNS involvement
• Idiopathic thrombocytopenic purpura.
• Sjogrens syndrome
• Mixed with dermatomyositis

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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!

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Dermatomyositis

• 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

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Dermatomyositis

• 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.

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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

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Childhood DM

• Brunsting type
• Slow course
• Progressive weakness
• Calcinosis
• Steroid responsiveness

• Banker type
• Vasculitis of muscles and GI tract
• Rapid onset
• Severe weakness
• Steroid unresponsiveness

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Scleroderma

• 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

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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.

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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.

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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.

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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.

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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

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Progressive Systemic Sclerosis

• Raynauds 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

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Progressive Systemic Sclerosis

• 75 have dilated nail fold capillary loops
• Esophageal involvement in 90 of patients
• Pulmonary fibrosis
• Cardiac involvement
• Articular pain, swelling, polyarthritis.

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Prognosis

• 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.

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LAB Finding

• Topoisomerase I (formerly Scl70) 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.

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Histology

• 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.

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Treatment

• Symptomatic tx
• Treatment aimed at minimizing complications
• Regular massage, warmth, and protection from
  trauma
• No smoking

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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 dorange 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.

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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.
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Histology

• Patchy lymphocytic and plasma cell infilrate in
  the fascia and subfacial muscle and great
  thickening, 10-50 times normal of the fascia.

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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

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Sjogrens 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.
• gt50 have anti-La/SSB antobodies
• Only symptomatic treatment available.
• Labial salivary gland biopsy most definitive test

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Schirmer test

• Assesses lacrimal gland function
• Whatman paper wick folded over eyelid for 5
  minutes
• lt5mm tear film migration lacrimal gland
  dysfunction

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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.

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Relapsing Polychondritis

• Intermittent episodes of inflammation of the
  articular and nonarticular cartilage eventuating
  in chondrolysis.
• MAGIC syndrome Behcets Relapsing
  Polychondritis (Mouth And Genital ulcers with
  Inflamed Cartilage)
• Treatment with Dapsone for few weeks, then
  maintenance for 4-6 asymptomatic months.

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