14 Connective Tissue Disorders
SYSTEMIC SCLEROSIS
It is characterized by cutaneous and internal organ fibrosis. Raynaud’s phenomenon is the earliest feature and may precede the onset of disease by months or years. The heart, lungs, gastrointestinal, kidney and other organs may be involved.
Pathogenesis
Exact cause of systemic sclerosis is unknown.
Important steps in its pathogenesis include:
• Excessive synthesis of collagen and matrix macromolecules.
• Endothelial cell injury.
• Dysregulation of the immune system.
Classification
• Diffuse disease: Characterized by extensive proximal and truncal skin induration.
• Limited disease: Induration is confined to hands, forearm, face, and legs. Its variant is called CREST syndrome (Thibierge-Weissenbach syndrome) (Calcinosis, Raynaud’s phenomenon, Esophageal dys-function, Sclerodactyly and Telangiectasia).
American Rheumatism Association Criteria Major
• Scleroderma proximal to the digits, affecting limbs, face, neck and trunk.
Minor
• Sclerodactyly (Fig. 14.10).
• Digital pitted scarring (Fig. 14.11).
• Bilateral basal pulmonary fibrosis.
One major criterion or two or more minor criteria suggest the diagnosis of systemic sclerosis.
Note: These criteria have 97% sensitivity and 98%
specificity.
Fig. 14.10: Progressive systemic sclerosis—
sclerodactyly with calcification over the inter-phalangeal joints of fingers
Cutaneous Manifestations
Three phases of dermal involvement can be distinguished:
1. Edematous phase (stiff, puffy, fingers) 2. Indurative phase (hard, tight, hide bound) 3. Atrophic phase (softened skin, burnt out).
Hands and Feet
• Early: Raynaud’s phenomenon.
• Swollen or tumid fingers and hands.
• “Round finger pad sign”-fingers lose their normal peaked contour but rather appear as rounded hemisphere when viewed from the side.
• Painful ulcerations at fingertips (Rat bite ulcer) with pitted scars.
• Late: sclerodactyly (induration of skin over the fingers) with tapering of fingers (Figs 14.10 and 14.11).
• Skin is tightly bound down.
• Leathery crepitations over joints and flexion contractures.
• “Heuck-Gottron sign”- loss of cuticle with telangiectases.
• Bony resorption.
• Atrophy of the pulp of the fingers.
• Gangrene of the fingers.
• Pigmentation.
• Calcinosis.
Face
• Periorbital edema is the early manifestation
• Late manifestations include: Mask like facies (difficulty in eversion of lower eyelids), thinning of lips, microstomia, radial perioral furrowing, small sharp nose (Fig. 14.12), telangiectasia (mat-like) and diffuse hyperpigmentation.
• Forehead is smooth and shiny, and skin is bound down and hard.
• There is reduced wrinkling on the forehead and mandibular atrophy.
Trunk
• Early: tense, stiff and waxy appearing skin that cannot be pinched and folded.
• Late: impairment of respiratory movement of chest wall and of joint mobility.
• “Neck sign”-ridging and tightening of the neck on extension due to sclerosis.
Fig. 14.11: Progressive systemic sclerosis—finger tip pits due to scarring
Fig. 14.12: Progressive systemic sclerosis—mask like facies, thinning of lips and small sharp nose
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Other Changes
“Salt and pepper” pigmentation (Fig. 14.13), gangrene of fingers, mat like telangiectasia, leg ulcers and livedo reticularis.
Organ Involvement in PSS
• Esophageal fibrosis, pulmonary interstitial fibrosis, myocardial fibrosis, small intestinal fibrosis, large intestinal fibrosis, renal involvement, skeletal muscle atrophy and thyroid fibrosis.
• Others are bone, eye, CNS, teeth, tendons.
Investigations
• Routine tests such as complete hemogram, liver function tests, sedimentation rate, C-reactive protein.
• Skin biopsy- Dermal sclerosis typically results in rectangular punch biopsy specimen. As the dermis replaces the subcutaneous tissue, eccrine glands appear to be in the mid portion of the thickened dermis. The subcutaneous fat is quantitatively reduced and adventitial fat is lost. On DIF testing of skin the nucleolus may be stained in the keratinocytes if antinucleolar circulating antibodies are present and a “pepper dot” epidermal nuclear
pattern may be seen in CREST patients who have anticentromere antibodies in their serum.
• Nail fold capillary microscopy.
• ANA (+ve in more than 90%), Ab-SSA, SSB, Sm, nRNP, Scl-70 (specific for diffuse systemic sclerosis), anticentromere antibody (specific for CREST syndrome).
• Rheumatoid factor positive in 30%
• Organ workup: urine analysis, barium swallow, esophageal manometry, barium enema, chest x-ray and pulmonary function test.
Differential Diagnosis
1. Generalized morphea (Raynaud’s phenomenon is rare, systemic involvement is unusual, no atrophic stage, no facial telangiectasia or perioral furrowing, skin of trunk and limbs are equally involved) 2. Pseudosclerodermas (Specific features of each
should be looked for)
3. Occupational and iatrogenic scleroderma (History of specific exposure should arouse the suspicion).
4. Other collagen vascular disorders- mixed collagen vascular disorders, overlap syndromes
5. Graft versus host disease
Prognosis and Cause of Death
• Course of the disease is variable. Death occurs from intercurrent infection, respiratory failure, cardiac failure, renal failure, sometimes, malignant hypertension and perforation of the gastrointestinal tract.
Other Conditions Where Sclerodermoid Changes are Seen
Phenylketonuria, progeria, Rothmund-Thomson syndrome, Werner’s syndrome, porphyria cutanea tarda, primary systemic amyloidosis, Hashimoto’s disease, carcinoid syndrome, Fig. 14.13: Progressive systemic sclerosis—“salt and
pepper pigmentation”—depigmentation with speckled hyperpigmented macules over the front of the chest
childhood diabetes mellitus and drugs (bleomycin, pentazocine, carbidopa, and 5-hydroxytryptophan).
Treatment
There is no specific treatment and no therapy is known to alter the course of a disease. Treatment is primarily directed towards complications.
Pharmacological agents used for systemic sclerosis can be grouped into various categories.
• Collagen modulators: D-penicillamine (125 mg alternate days, 750-1500 mg per day), relaxins, and interferons.
• Vasoactive agents: Captopril, nifedipine and pentoxifylline.
• Immunosuppressive agents: Systemic corti-costeroids (prednisolone 0.5 mg mg per kg body weight daily), azathioprine (1-2 mg mg per kg body weight daily), cyclophosphamide (2 mg per kg body weight daily), cyclosporine (3-5 mg per kg body weight daily) and methotrexate (20-30 mg weekly).
For internal organ involvement— Angiotensin converting enzyme inhibitors are treatment of choice for renal hypertension, proton pump inhibitors (omeprazole 20-40 mg daily) indicated for esophageal dysfunction and for pulmonary hypertension intravenous prostacyclin; inter-stitial lung disease may respond best to cyclophosphamide. Physical therapy can help avoid contractures and retain function.
DERMATOMYOSITIS
It is a systemic, inflammatory disease involving primarily skin and muscles. Symmetric, proximal muscle weakness occurs especially in the hips, thigh, and upper arm. Patients with only muscular symptoms and signs but no cutaneous findings are said to have polymyositis. These can be associated with malignancies especially in adulthood – carcinoma of lung, breast, female genital tract, stomach, kidney and testes.
Cutaneous Manifestations of Dermatomyositis
Pathognomonic
• Gottron’s papules: Violaceous, flat topped papules on interphalangeal joints and knuckles. Similar lesions may occur over other bony prominences such as knees, elbows and medial malleoli.
• Gottron’s sign: Symmetric macular violaceous erythema with or without edema over the above mentioned sites.
Characteristic
• Periorbital violaceous erythema with associated edema of eyelids and periorbital tissue (heliotrope rash) (Fig. 14.14).
• Periungual telangiectasia with associated dystrophic cuticles.
• Macular violaceous erythema overlying the dorsal hands, extensor forearms and arms, deltoids, posterior shoulders, nape of neck, V area of neck, upper chest and forehead.
“Shawl sign”-erythema and scale (with or without poikiloderma) over the shoulder regions.
• Mechanic’s hands: Bilaterally symmetrical confluent hyperkeratosis distributed along the
Fig. 14.14: Dermatomyositis—“Heliotrope rash”—
periorbital violaceous erythema with associated edema of eyelids
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ulnar aspects of the thumbs and radial aspects of the index and middle fingers with occasional extension to the palmar surface.
Compatible
• Poikiloderma atrophicans vasculare
• Calcinosis cutis.
Systemic features include arthritis (25%), oral ulcers (20%), calcinosis (distinctive feature of juvenile dermatomyositis), pulmonary fibrosis (20%), gastrointestinal ulcerations and hemorrhages, occasionally myocarditis or myopathy.
Investigations
• Skin biopsy, muscle biopsy, muscle enzymes, electromyography, ANA, Ab-SSA, SSB, Sm, nRNP, Jo-1and PM-1.
Diagnostic Criteria
1. Progressive symmetric proximal muscle weakness.
2. Elevated muscle enzyme levels.
3. Abnormal electromyogram.
4. Abnormal muscle biopsy.
5. Characteristic cutaneous manifestations.
Definite: 5 plus three other criteria.
Probable: 5 plus two other criteria.
Differential Diagnosis
Includes other myopathies (inclusion body myositis, muscular dystrophy, neuromuscular atrophy, myasthenia gravis, thyrotoxic myopathy, Cushing’s disease, sarcoidosis, alcoholism), drugs (lipid lowering agents, hydroxyurea, NSAIDs), overlap syndromes, vasculitis, polymyalgia rheumatica and trichinosis.
Treatment
• Skin disease: Topical steroids, hydroxy-chloroquine.
• Muscle disease: Systemic corticosteroids are first line therapy. Second line agents are
methotrexate (5-15 mg weekly) and azathioprine (1-3 mg per kg body weight daily).
• Intravenous immunoglobulins are indicated for resistant cases, children with vasculitic component and those with steroid induced diabetes mellitus.
• Bed rest during flares, physical therapy when stable.
• Appropriate treatment of underlying malignancy where it is associated.