Connective Tissue Diseases Adam Wray, D.O. September 7, 2004.

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 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

ANA Immunofluorescence Patterns

Drug Induced ANA/SLE

Procainamide Hydralazine Isoniazid Chlorpromazine Phenytoin Methyldopa Minocycline

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

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 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

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

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 won’t increase retinal toxicity

Verrucous LE

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

Plaquenil.

Verrucous LE

2% of patients with chronic cutaneous LE

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

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

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

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.

SCLE

Subacute cutaneous LE– Papulosquamous– Annular– Syndromes commonly exhibiting similar

morphology• Neonatal LE

• Complement deficiency syndromes

SCLE

Typically photosensitive

Lesions confined to sun-exposed skin

Regular association with anti-Ro antibody (SS-A)

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.

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.

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 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 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

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

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 Manifestation.

CNS involvement Idiopathic thrombocytopenic purpura. Sjogren’s syndrome Mixed with dermatomyositis

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!

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

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.

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

– Calcinosis

– Steroid responsiveness

Banker type– Vasculitis of muscles

and GI tract

– Rapid onset

– Severe weakness

– Steroid unresponsiveness

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

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

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

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 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

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

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 Sclerosis

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

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.

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.

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.

Treatment

Symptomatic tx Treatment aimed at minimizing

complications Regular massage, warmth, and protection

from trauma No smoking

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.

Histology

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 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

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

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

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.