Section 17. Autoimmune Connective Tissue Diseases

Juvenile rheumatoid arthritis (JRA) is a generalized systemic disease of unknown etiology characterized by a transient macular, papular, or urticarial rash and ensuing fever, lymphadenopathy, hepatosplenomegaly (HSM), anemia, and arthralgia.

Insight

There are four classical evanescent eruptions: (1) urticaria, (2) erythema marginatum (of acute rheumatic fever), (3) the rash of Still disease, and (4) serum sickness.

Classification

JRA has three major types:

1. 1. Systemic onset (20%): Still’s disease, fevers, rash, lymphadenopathy (LAD), HSM, serositis, polyarthritis

   2. Polyarticular (20%): >five joints, hands, feet > knees/wrists/ankles

   3. Oligo-/Pauciarticular (60%): < four joints, knees > ankles

Synonyms Still’s disease, juvenile idiopathic arthritis, juvenile chronic arthritis.

Epidemiology

Age Peaks: 2 to 4 years, adolescence.

Gender Systemic JRA: M = F. Others: F > M, 2:1.

Prevalence 1/1000.

Genetics Polymorphisms for the genes encoding tumor necrosis factor-α (TNF-α), migratory inhibitory factor, interleukin-6 (IL-6), and tapasin (endoplasmic reticulum component involved in antigen presentation).

Etiology Unknown.

Pathophysiology

Cytokines TNF-α, migratory inhibitory factor, and IL-6 parallel the fever spikes, but the pathogenesis of JRA is still not understood. JRA tends to be precipitated by emotional, infectious, or surgical stress.

History

The onset of JRA may be sudden or insidious, depending on the age of the patient (the younger the patient, the more severe the systemic manifestations). Cutaneous eruptions occur in 90% of patients and may be the initial presentation. The rash of JRA is evanescent and can be macular or urticarial. Systemically, there may be associated fever, adenopathy, splenomegaly, anemia, and arthralgias.

Physical Examination

Skin Findings

Type Macules, papules, urticarial plaques (Fig. 17-1).

Size 2–6 mm to 8–9 cm.

Color Salmon pink to red, with a zone of pallor (Fig. 17-2).

Distribution Areas of trauma/heat: axilla, waist, olecranon process/ulnar forearm, dorsal hands, knees, ears, scapula, sacrum, buttocks, and heels.

Other Palms and soles: thenar and hypothenar eminences may be erythematous. Periungual telangiectases (5% of patients). Spindling fingers (50%, spindle-shaped deformity of fingers because proximal interphalangeal involvement > distal interphalangeal involvement).

General Findings

Fever >38.9°C

LAD, HSM

Musculoskeletal Arthralgias/arthritis: single joint (knees > ankles/hips > hands), symmetric polyarthritis joints, motion limitation (knees: 90%, fingers: 75%, wrists/ankles: 66%).

Serositis Pericarditis, pleuritis, or peritonitis.

Other Myocarditis, uveitis, CNS involvement.

Differential Diagnosis

The diagnosis of JRA is made based on clinical characteristics and history of arthritis lasting for more than 6 weeks, with appropriate studies to exclude other causes such as other autoimmune diseases, other causes of periodic fever, urticaria, rheumatic fever, hypersensitivity reactions, granuloma annulare, sarcoid, and other granulomatous diseases.

Laboratory Examinations

Dermatopathology Edematous collagen fibers, perivascular infiltrate with neutrophils, plasma cells, and histiocytes.

Hematology Leukocytosis, anemia, + rheumatoid factor (80%), elevated erythrocyte sedimentation rate (ESR), hypoalbuminemia, hyperglobulinemia.

Radiology Joint destruction in late disease.

Course and Prognosis

The course and prognosis of JRA are variable. The younger the age of onset, the more prominent the systemic manifestations. The rash typically precedes the systemic symptoms by up to 3 years. The disease may end after a few months and never recur, or it may recur after months or years of remission. The disease typically improves by puberty and 85% of patients achieve remission. Only 10% have residual severe crippling arthritis.

Management

For active disease, symptoms can be relieved with aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) (indomethacin, Naprosyn), hydrochloroquine, and systemic steroids. Anti-TNF drugs (infliximab, etanercept) have been used, but are less helpful in systemic-onset JRA. For severe cases that are resistant to other therapies, have crippling deformities, iridocyclitis, or vasculitis, systemic corticosteroids, methotrexate, azathioprine, leflunomide, mycophenolate mofetil, chlorambucil, thalidomide, intravenous immunoglobulin, cyclophosphamide, IL-1/IL-6 receptor antagonists (anakinra, tocilizumab) have been used. For structural correction of severe deformities, surgery is a last resort.

Acute cutaneous lupus erythematosus (ACLE) is the most common cutaneous presentation associated with systemic lupus erythematosus (SLE) (Table 17-1). SLE is a serious multisystem disease involving connective tissue and blood vessels; the clinical manifestations include fever (90%); skin lesions (85%); arthritis; and renal, cardiac, and pulmonary disease.

Epidemiology

Age 25% younger than 20 years, peaks: 11 to 13 years, 30 to 40 years.

Gender Prepubertal: M = F; adults: F > M, 6:1.

Incidence Prepubertal: rare; adults: 4 in 1000.

Race African American > Asian, Latin American, Caucasian.

Genetics Family history (<5%) suggests a hereditary component.

Pathophysiology

SLE is antibody-mediated, and the trigger for autoantibody production may be multifactorial (genetics, viral or bacterial infection, host tissue response/susceptibility). The production of autoantibodies generates the membrane-attack complex and results in host tissue injury that is nonorgan specific, and may differ from person to person.

History

Up to 80% of patients with SLE have ACLE (malar rash, discoid lesions, photosensitivity, or atrophy), and in 25% of patients, the skin is the first presenting symptom.

Physical Examination

Skin Findings

Type Macules, scale, erosions, atrophic plaques.

Color Pink, red, hypo- or hyperpigmentation.

Shape Round or oval.

Distribution Localized “butterfly” rash on face in light-exposed areas (Fig 17-3), forearms, dorsa of hands.

Hair Patchy or diffuse alopecia.

Mucous Membrane Ulcers, purpuric necrotic lesions on palate (80%), buccal mucosa, or gums (Fig. 17-4).

Other Periungual telangiectases and palmar erythema are also seen.

General Findings

Lymphadenopathy (LAD) 50%.

Musculoskeletal Arthralgia or arthritis (15%).

Renal Proteinuria, cellular casts (50%).

Cardiac Pericarditis (20%).

Pulmonary Pleuritis, pneumonitis (20%).

Gastrointestinal Arteritis, peritonitis, hepatomegaly (30%), splenomegaly (20%).

Neurologic Peripheral neuropathy (14%), CNS disease (10%), seizures, or psychosis (14%).

Hematologic Anemia, leukopenia, lymphopenia, thrombocytopenia, elevated ESR.

Laboratory Examinations

Dermatopathology Epidermal atrophy, liquefaction degeneration of the dermoepidermal junction, edema of the dermis, dermal inflammatory infiltrate (lymphocytes), and fibrinoid degeneration of the connective tissue and walls of the blood vessels.

Other Organs Fibrinoid degeneration of connective tissue and walls of the blood vessels associated with an inflammatory infiltrate of plasma cells and lymphocytes.

Immunofluorescence The lupus band test (direct immunofluorescence) demonstrates IgG, IgM, and C1q granular/globular in a band-like pattern along the dermoepidermal junction. This is positive in lesional skin (90%), sun-exposed areas (80%), and non-sun-exposed areas (50%).

Serologic Antinuclear antibody (ANA) test positive (>95%), peripheral pattern of nuclear fluorescence and anti-double-stranded DNA antibodies are highly correlated with ACLE.

Differential Diagnosis

ACLE can be confused with sunburn, rosacea, drug-induced photosensitivity, eczema, or seborrheic dermatitis. The diagnosis of SLE can be made if four of the following criteria are present:

1. 1. Malar rash (butterfly appearance)

   2. Discoid rash

   3. Photosensitivity

   4. Oral ulcers

   5. Arthritis

   6. Serositis (pleuritis or pericarditis)

   7. Renal complications (proteinuria or cellular casts)

   8. Neurologic disorder (seizures or psychosis)

   9. Hematologic disorder (anemia, leukopenia, thrombocytopenia)

   10. Immunologic disorder (+LE prep, anti-DNA, anti-Sm, false +FPR)

   11. ANA (90% of patients have a titer of ≥ 1:32)

Course and Prognosis

SLE is a lifelong controllable disease with a survival rate of >90%. Mortality is secondary to renal failure, CNS lupus, cardiac failure, or infection.

Management

ACLE responds best to sun protection and sun avoidance. Topical management includes short courses of high-potency topical or intralesional steroids, calcineurin inhibitors (tacrolimus or picrolimus), and retinoids. SLE responds to NSAIDs and salicylates for mild disease (arthritis). More severe disease responds to antimalarials (hydrochloroquine, chloroquine, quinacrine). The indications for systemic steroids (prednisone, methylprednisolone) include CNS involvement, renal involvement, severely ill patients without CNS involvement, and hemolytic crisis. Antimalarial-resistant disease may require azathioprine, cyclophosphamide, retinoids, thalidomide, dapsone, clofazimine, sulfasalazine, or immune response modifiers (rituximab).

Discoid lupus erythematosus (DLE) is a form of chronic cutaneous lupus erythematosus (LE) most commonly seen by dermatologists, but is rarely associated with SLE (Table 17-1).

Insight

Discoid lupus frequently involves the conchal bowl of the ear; lesions present there are highly suggestive of discoid lupus.

Epidemiology

Age All ages, peak: 20 to 40 years.

Gender F > M, 3:1.

Prevalence 85% of chronic LE.

Race African American > Asian, Latin American, Caucasian.

Pathophysiology

DLE is antibody-mediated, and the trigger for autoantibody production may be multifactorial (genetics, infection, UV radiation, smoking).

History

Discoid lesions are chronic and recurrent, most commonly seen in photodistributed areas, but can be widespread on the body. The lesions spread centrifugally and may merge. Resolution of the active lesion results in atrophy and scarring leading to permanent disfigurement.

Physical Examination

Skin Findings

Type Papules, plaques, scale, crust, scars (Fig. 17-5).

Color Pink, red, hypo- or hyperpigmentation.

Shape Round or oval.

Palpation Indurated, atrophic.

Distribution Face, scalp, ears > generalized, forearms.

Hair Follicular plugging, patchy or diffuse scarring alopecia (Fig. 17-6).

Mucous Membrane Discoid lesions on lips, nasal mucosa, conjunctivae, genitalia.

General Findings

Musculoskeletal Arthralgia or arthritis.

Laboratory Examinations

Dermatopathology Hyperkeratosis, atrophy of the epidermis, vacuolar changes in the basal layer, thickening of the basement membrane, follicular plugging, pigment incontinence, a perivascular lymphocytic infiltrate, and increased mucin in the dermis.

Immunofluorescence The lupus band test (direct immunofluorescence) is positive in 90% of DLE patients.

Serologic ANA-positive (20%), SS-A (anti-Ro) autoantibodies (3%), anti-dsDNA or nDNA or anti-Sm antibodies (<5%) usually indicate SLE.

Other Cytopenia, elevated ESR, positive rheumatoid factor, decreased complement levels, proteinuria.

Differential Diagnosis

DLE can be confused with prurigo nodularis, psoriasis, drug-induced photosensitivity, lichenplanis, granuloma annulare, rosacea, sarcoid, eczema, or seborrheic dermatitis.

Course and Prognosis

Typically, DLE is limited to the skin and there is no systemic involvement. However, a discoid rash is one of the eleven major criteria for SLE and 5% of patients with generalized DLE will get SLE. Rarely, squamous cell carcinomas can develop in chronic lesions of DLE.

Management

DLE management is targeted at controlling lesions and minimizing scarring. DLE responds best to sun protection, sun avoidance, and smoking cessation. Topical management includes short courses of high-potency topical or intralesional steroids, calcineurin inhibitors (tacrolimus or picrolimus), and retinoids. More severe disease responds to antimalarials (hydrocholorquine, chloroquine, quinacrine). Antimalarial-resistant disease may require methotrexate, mycophenolate mofetil, azathioprine, thalidomide, or efalizumab. Scarring can be cosmetically covered with make-up or wigs.

Dermatomyositis (DM) is a systemic disease characterized by violaceous (heliotrope), inflammatory changes of the eyelids and periorbital area; erythema of the face, neck, and upper trunk; and flat-topped violaceous papules over the knuckles associated systemically with polymyositis.

Clinical Spectrum Ranges from DM with only cutaneous inflammation (DM sine myositis, or amyopathic DM) to polymyositis with only muscle inflammation (hypomyopathic myositis)

Synonyms Idiopathic inflammatory dermatomyopathies.

Epidemiology

Age 25% of patients are children: peak 10 to 15 years. Adults: peak 45 to 47 years, 20% have an associated malignancy.

Gender Children: F > M, 2:1. Adults: F > M, 5:1.

Incidence 7/million.

Etiology Immune-mediated with triggers such as infection, drug, or malignancy (in adults).

Genetics Increased frequency of HLA-B8/HLA-DR3 in children and HLA-B14 in adults suggests a genetic predisposition exists.

Pathophysiology

DM is an immune-mediated process triggered by external factors (infection, drug, malignancy) in genetically predisposed individuals. Systemically, acute and chronic inflammation of striated muscle accompanied by segmental necrosis of myofibers results in progressive muscle weakness.

History

In juvenile DM, frequently, there is a history of a preceding viral illness followed by fever, muscle weakness, fatigue, and rash. Unlike adult DM, juvenile DM has a decreased rate of malignancies and the mortality is low.

Physical Examination

Skin Findings

Type Macules, scale, papules (Gottron’s), atrophy, ulcers, scars.

Color Reddish-purple heliotrope. Poikiloderma (hypo- and hyperpigmentation, telangiectasia, and atrophy).

Distribution Photodistributed: eyes, malar area (Fig. 17-7), extensor surfaces, neck, upper chest, and nape of neck.

Hands Gottron’s papules—dorsa of knuckles (sparing interarticular areas, Fig. 17-8).

Nailfolds Periungual telangiectasia, “ragged” cuticles.

Mucous Membranes Vivid red hue on gum line, ulceration, white plaques on tongue and mucosa.

Other Calcinosis cutis.

General Findings

Musculoskeletal Proximal/Limb girdle muscle weakness > facial/bulbar, pharyngeal, esophageal muscle weakness. Muscle tenderness and atrophy.

Pulmonary (30%) Interstitial fibrosis, acute respiratory disease syndrome.

Cardiac Rhythm disturbances, conduction defects.

Differential Diagnosis

The differential diagnosis for DM includes LE, mixed connective tissue disease (MCTD), psoriasis, allergic contact dermatitis, photodrug eruption, eczema, steroid myopathy, trichinosis, and toxoplasmosis.

The diagnostic criteria for DM are a characteristic rash and two of the following:

1. 1. Proximal muscle weakness

   2. Elevated serum “muscle enzyme” levels

   3. Diagnostic muscle biopsy

   4. Characteristic electromyographic changes

Laboratory Examinations

Dermatopathology Flattening of epidermis, hydropic degeneration of basal cell layer, edema of upper dermis, scattered inflammatory infiltrate, PAS-positive fibrinoid deposits at dermoepidermal junction and around upper dermal capillaries, and an accumulation of acid mucopolysaccharides in dermis.

Muscle Biopsy Muscle biopsy of deltoid, supraspinatus, gluteus, quadriceps will show segmental necrosis within muscle fibers with loss of cross-striations; waxy/coagulative type of eosinophilic staining; ± regenerating fibers; inflammatory cells, histiocytes, macrophages, lymphocytes, plasma cells. Vasculitis may also be seen.

Chemistry Elevated creatine phosphokinase most specific for muscle disease; also aldolase, glutamic oxaloacetic transaminase, lactic dehydrogenase.

Urine Elevated 24-hour creatinine excretion (>200 mg/24 hours).

Electromyogram Increased irritability on insertion of electrodes, spontaneous fibrillations, pseudomyotonic discharges, positive sharp waves; excludes neuromyopathy. With evidence of denervation, suspect coexisting tumor.

Electrocardiogram Myocarditis; atrial, ventricular irritability, atrioventricular block.

X-ray of Chest ± Interstitial fibrosis.

Course and Prognosis

Dermatitis and polymyositis usually are detected at the same time; however, skin or muscle involvement can occur initially, followed at some time by the other. Juvenile DM, unlike adult DM, is rarely associated with Raynaud’s phenomenon, malignancies, or mortality. In children, 33% of patients will have spontaneous remission in 1 to 2 years, 33% of patients will have 1 to 2 relapses, and 33% of patients will have persistent symptoms >2 years.

Management

DM management includes sun protection and sun avoidance. Cutaneous lesions can be treated with topical steroids or calcineurin inhibitors. Systemic disease responds to NSAIDs, salicylates, systemic corticosteroids (prednisone or methylprednisolone). In severe cases, immunosuppressive drugs (azathioprine, methotrexate, cyclosporine) may be necessary. For refractory disease, possible therapies include plasmapheresis, hydroxychloroquine, systemic retinoids, mycophenolate mofetil, dapsone, thalidomide, intravenous immunoglobulin, chlorambucil, systemic tacrolimus, sirolimus, infliximab, or rituximab.

In the acute stages, children may need hospitalization to monitor for palatorespiratory muscle involvement with myositis. In such cases, adequate respiration and prevention of aspiration is needed.

Morphea is a localized cutaneous sclerosis characterized by early violaceous-colored plaques later evolving to ivory-colored sclerotic areas, which may be solitary, linear, or generalized.

Insight

An important, though much less-frequent, presentation of morphea is bruise-like patches; the patients are often evaluated for bleeding disorders before they are referred to dermatology.

Synonyms Circumscribed scleroderma, linear scleroderma, scleroderma en coup de sabre.

Epidemiology

Age 20% onset before 18 years. Average age onset: 7 years.

Incidence 27/million

Gender F > M, 2:1

Etiology Unknown. Lichen sclerosis may be somehow related.

Pathophysiology

The pathogenesis of morphea is unknown. The primary event might be a local trigger occurring within the skin, which leads to focal, asymmetric inflammation and sclerosis of the skin. One trigger is thought to be infection related from Borrelia in Western Europe.

History

The onset of morphea is insidious with erythematous violaceous plaques that slowly evolve into firm, waxy, ivory-colored, or postinflammatory hyperpigmented sclerotic areas.

Physical Examination

Skin Findings

Type Plaques, scar.

Size 2 to 15 cm.

Color Red, purplish, ivory; hyperpigmented (Fig. 17-9).

Shape Round or oval.

Palpation Indurated, hard. May be hypoesthetic.

Arrangement Usually multiple, bilateral, asymmetric.

Distribution Trunk, breasts, abdomen, limbs, face, genitalia > axillae, perineum, areola.

Hair Follicles obliterated, scarring alopecia.

Nails Nail dystrophy.

General Findings

Musculoskeletal (11%) Flexion contractures, underlying muscle, fascia, bone involvement.

Other Coup de sabre, linear morphea on forehead. Parry–Romberg syndrome: hemiatrophy of face (Fig. 17-10). Both can have neurologic (4%) and/or ocular (2%) complications.

Differential Diagnosis

The differential diagnosis for morphea includes progressive systemic sclerosis, lichen sclerosis et atrophicus, eosinophilic fasciitis, eosinophilia–myalgia syndrome associated with L-tryptophan ingestion, and acrodermatitis chronica atrophicans.

Laboratory Examinations

Dermatopathology Swelling and degeneration of homogenous, eosinophilic collagen fibrils, mild perivascular, and dermal–subcutis infiltrate; dermal appendages progressively disappear.

Serology ANA-positive, increased antibodies to ssDNA, topoisomerase IIa, phospholipid, fibrillin 1, and histones.

Course and Prognosis

Morphea lesions in children tend to progress from 3 to 5 years, and then stop. In <10% of patients, the scarring can lead to contractures, handicaps, or growth retardation.

Management

For morphea, physical therapy is warranted for lesions overlying joints, which may impede mobility. Topical and intralesional steroids are of limited use. Topical calcipotriol has been tried with mixed results. Severe cases may respond to psoralen ultraviolet A, UV A1 (UVA1), systemic steroids, methotrexate, antimalarials, phenytoin, penicillamine, Salazopyrin, cyclosporine, colchicine, or systemic calcipotriol.

Systemic sclerosis (SCc) is a rare, severe autoimmune disorder characterized by sclerotic changes of the skin and internal organs.

Classification

1. 1. Limited SCc is characterized by fibrotic changes of the fingers, hands, and face. Includes CREST (Calcinosis cutis, Raynaud’s, Esophageal dysfunction, Sclerodactyly, Telangiectasia) syndrome.

   2. Diffuse SCc: Fibrotic changes of the fingers, hands, arms, trunk, face, and lower extremities.

Synonyms Progressive systemic sclerosis, systemic scleroderma.

Epidemiology

Age All ages. Peak: 30 to 50 years.

Gender F > M, 4:1.

Incidence 20/million.

Race Black > white.

Genetics A 15-fold increase in first-degree relatives.

Pathophysiology

The pathogenesis of SCc is unknown. The primary event might be autoimmune endothelial cell injury in blood vessels. Early in the course of the disease, target organ edema occurs followed by fibrosis; the cutaneous capillaries are reduced in number and the remaining vessels dilate and proliferate, becoming visible telangiectasias. Fibrosis is also present because of overproduction of collagen by fibroblasts.

History

Raynaud’s phenomenon with pain/tingling of the fingertips/toes is usually the first sign of SCc. Patients with SCc have a characteristic tightening of the facial features producing a pinched-nose, pursed-lip appearance (Fig. 17-11). Systemic involvement leads to migratory polyarthritis, heartburn, dysphagia, constipation, diarrhea, abdominal bloating, malabsorption, weight loss, exertional dyspnea, and dry cough.

Physical Examination

Skin Findings

Type Macules, edematous plaques, ulcerations.

Color Triphasic: pallor, cyanosis, rubor. Hypo-hyperpigmentation.

Fingers Sclerodactyly, flexion contractures (Fig. 17-12), bony resorption, periungual telangiectasia, cutaneous calcifications (Fig. 17-13).

Face Masklike, thinning of lips, small mouth, radial perioral furrowing, small sharp nose.

Palpation Indurated, stiff, smooth, hardened, bound down. Leathery crepitation over joints.

Distribution Fingers, hands, upper extremities, trunk, face, lower extremities.

Hair Thinning/complete loss of hair on distal extremities. Loss of sweat glands with anhidrosis.

Nails Nails grow clawlike over shortened distal phalanges..

Other Mat-like telangiectasia on face, neck, upper trunk, hands, lips, oral mucous membranes, gastrointestinal (GI) tract.

Mucous Membranes Sclerosis of sublingual ligament, induration of gums, tongue.

General Findings

Lung Interstitial lung disease, pulmonary fibrosis, pulmonary artery hypertension.

Cardiac Congestive heart failure.

Renal Hypertensive renal disease.

Gastrointestinal Esophageal reflux, dysphagia, constipation, diarrhea, malabsorption.

Musculoskeletal Carpal tunnel syndrome. Muscle weakness.

Differential Diagnosis

Other sclerotic entities that need to be considered in the differential diagnosis of SCc include scleredema, scleromyxedema, MCTD, eosinophilic fasciitis, LE, DM, morphea, chronic graft-versus-host disease, lichen sclerosis et atrophicus, polyvinyl chloride exposure, and adverse drug reaction (pentazocine, bleomycin).

Laboratory Examinations

Dermatopathology A mild cellular infiltrate around dermal blood vessels, eccrine coils, subcutaneous tissue, effacement of the rete ridges; paucity of blood vessels, thickening and hyalinization of vessel walls, narrowing of lumen; atrophied dermal appendages; calcium deposits; and compact, homogenized collagen.

Serology ANA-positive, nucleolar, discrete speckled pattern. Diffuse SCc: anti-topoisomerase I (Scl 70), anti-RNA-polymerase I and III, anti-fibrillarin. Limited SCc: anticentromere antibodies.

Course and Prognosis

The course for diffuse SCc is characterized by slow, relentless progression of skin and/or visceral sclerosis; 80% of patients die within 10 years after the onset of symptoms. With angiotensin-converting enzyme inhibitors for the management of renal crisis, the leading cause of death in SCc is cardiac and pulmonary dysfunction. Spontaneous remissions do occur. CREST syndrome progresses more slowly and has a more favorable prognosis.

Management

The treatment of SCc is primarily focused on internal organ disease. For polyarthritis, salicylates and NSAIDs are helpful. For Raynaud’s phenomenon, calcium channel blockers (nifedipine), angiotensin II receptor blockers (losartan), intravenous prostaglandin E1 (alprostadil) can improve circulation. For renal disease, angiotensin-converting enzyme inhibitors have been life-saving. For GI involvement, small frequent meals, head elevation in bed, antacids, and prokinetic agents can help. For pulmonary disease, cyclophosphamide, mycophenolate mofetil, azathioprine, chlorambucil, 5-fluorouracil, cyclosporine, systemic steroids, prostacyclin analogues (epoprostenol, treprostinil), and endothelin receptor antagonists (sildenafil, sitaxsentan) have been used.

Cutaneous SCc can be managed with avoidance of vasospastic agents (cold, stress, fatigue, smoking), minimizing trauma. For cutaneous ulcers, occlusive wet dressings, enzyme debriding agents (collagenase), and topical growth factors (PDGF) can be helpful. For severe cases, systemic therapeutic modalities, such as, minocycline, methotrexate, corticosteroids, extracorporeal photophoresis, calcipotriol, D-penicillamine, colchicine, and potassium P-aminobenzoate, psoralen ultraviolet A, and UVA1 have been tried with varied results.

MCTD is a rare, autoimmune disease characterized by U1RNP-positive antibodies, Raynaud’s phenomenon, dactylitis, low-grade fever, and arthritis.

Synonyms Undifferentiated connective tissue disease, Sharp’s syndrome.

Epidemiology

Age All ages. Peak: 20 to 30 years.

Gender F > M, 16:1.

Incidence Least common autoimmune connective tissue disease.

Genetics HLA-DR4 and HLA-DR2.

Pathophysiology

The exact pathogenesis of MCTD is unknown, but involves the production of autoantibodies against U1RNP more than in patients with lupus, scleroderma, or DM.

History

Raynaud’s phenomenon with pain/tingling of the fingertips and dactylitis (sausage digits) are usually the first clinical sign of MCTD. The hands and fingers become tight and may ulcerate with, or without, calcinosis cutis. Sclerodermoid or poikilodermatous areas of the upper trunk and proximal extremities may evolve.

Physical Examination

Skin Findings

Type Macules, plaques, ulcerations.

Color Red, purple; hypo- or hyperpigmented.

Distribution Fingers (dactylitis, bony resorption, periungual telangiectasia, cutaneous calcifications; Fig. 17-14), hands > upper extremities, upper trunk. Acute flares: malar face (Fig. 17-15).

General Findings

Musculoskeletal (85%) Polyarthritis.

Gastrointestinal (75%) Esophageal dysmotility, reflux esophagitis, dysphagia.

Pulmonary Pulmonary hypertension.

Differential Diagnosis

Other sclerotic entities that need to be considered in the differential diagnosis of MCTD include scleroderma, LE, DM, overlap syndromes, morphea, chronic graft-versus-host disease, and lichen sclerosis et atrophicus.

Laboratory Examinations

Dermatopathology Vasculopathy or small and medium blood vessels, interface dermatitis, dermal fibrosis.

Serology ANA-positive, high titers of U1RNP antibodies.

Course and Prognosis

The course for MCTD is characterized by slow, relentless progression of skin and pulmonary disease. Over time, some MCTD patients may develop classic systemic LE or scleroderma. A common complication from the arthritis in MCTD is Jaccoud’s arthropathy from periarticular disease and ligament laxity. The major cause of death in patients with MCTD results from pulmonary hypertension.

Management

The treatment of MCTD is primarily focused on targeted organ involvement. For polyarthritis, salicylates and NSAIDs are helpful. For Raynaud’s phenomenon, calcium channel blockers (nifedipine) can improve circulation. For GI involvement, small frequent meals, head elevation in bed, antacids, and prokinetic agents can help. For pulmonary disease, cyclophosphamide, mycophenolate mofetil, azathioprine, methotrexate, cyclosporine, plasmapheresis, and autologous peripheral stem cell transplantation have been used.