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COLLAGEN VASCULAR DISEASES
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COLLAGEN VASCULAR DISEASES Jeffrey P. Callen, MD
Collagen vascular diseases are multisystem disorders that frequently affect the skin5 At times, cutaneous disease is the initial manifestation. This article focuses on lupus erythematosus (LE), dermatomyositis, and sclerodermoid syndromes. LUPUS ERYTHEMATOSUS
LE is a multisystem disorder with a spectrum from a relatively benign, self-limited cutaneous eruption to a severe, often fatal, systemic disease.23The American College of Rheumatology (ACR) has developed a set of criteria that could be used for the classification of systemic lupus erythematosus (SLE)?5When a patient has four or more of the criteria either concurrently or serially during any period of observation, the patient can be classified as having SLE. In the 1940s and 1950s, dermatologists first recognized that most of their patients with chronic, scarring, discoid LE lesions had few, if any, systemic findings, whereas those with photosensitivity or malar erythema (or both) frequently had systemic disease. They also recognized a subset with transient skin lesions that did not result in scarring or atrophy; these patients had systemic disease, but their prognosis was not as poor as that of unselected patients with SLE. Various names have been applied to this subset, but that coined by Sontheimer and Gilliam, subacute cutaneous LE, is the best accepted. The classification of cutaneous subsets was stressed by Gilliam and S~ntheimer,’~ who proposed that patients be classified by the type of skin disease present into two groups:
From the Department of Medicine, Division of Dermatology, University of Louisville, Louisville, Kentucky
MEDICAL CLINICS OF NORTH AMERICA VOLUME 82 * NUMBER 6 NOVEMBER 1998
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(1)those that are histopathologically LE specific or (2) those that are not histopathologically specific (Table 1). Chronic cutaneous LE can be manifested by several clinical variations. The most common manifestation is the discoid LE 1esi0n.~These patients may be subclassified as having localized discoid LE, when lesions are on the head and neck only, or widespread discoid LE, when lesions are on other body surfaces as well as the head and neck. Other, less common forms of chronic cutaneous LE include hypertrophic or verrucous (wartlike) lesions, lesions on the palms or soles, oral discoid LE, and lupus panniculitis (lupus profundus). The discoid LE lesion is characterized by erythema; telangiectasia; adherent scale, varying from fine to thick; follicular plugging; dyspigmentation; and atrophy and scarring (Fig. 1). The lesions are usually
Table 1. CLASSIFICATION OF MUCOCUTANEOUS LESIONS IN LUPUS ERYTHEMATOSUS I. LE-specific histopathology A. Chronic cutaneous LE 1. Discoid LE (widespread vs localized) 2. HyperIrophic/verrucous LE 3. Palmar/plantar LE 4. Oral discoid 5. LE panniculitis B. SCLE 1. PMLE-like lesions 2. Annular lesions a. Oriental SCLE (annular erythema of 1" SS) 3. Papulosquamous lesions (? photosensitive psoriasis) 4. Neonatal LE 5. C2-deficient LE-like syndrome 6. Drug-induced SCLE C. ACLE 1. Malar erythema 2. Photosensitivity dermatitis 3. Generalized erythema II. LE-nonspecific histopathology A. Vasculopathy 1. Urticaria 2. Vasculitis 3. Livedo reticularis/leg ulcerations B. Mucosal lesions C. Nonscarring alopecia D. Bullous LElEBA E. Associated mucocutaneous problems 1. Mucinous infiltrations 2. Porphyrias 3. Lichen planus 4. Psoriasis 5. Sjogren's syndrome 6. Squamous cell carcinomas LE = Lupus erythematosus; SCLE cutaneous lupus erythematosus; 1" SS bullosa acquisita.
= =
subacute cutaneous lupus erythematosus; ACLE = acute primary Sjogren's syndrome; and EBA = epidermolysis
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Figure 1. Discoid lupus erythernatosus. This woman demonstrates multiple features of discoid lupus erythematosus, including follicular plugging, scarring, atrophy, and dyspigmentation.
sharply demarcated and can be round, thus giving rise to the term discoid (or disclike). The presence of scarring or atrophy is the characteristic that separates these lesions from those of subacute cutaneous LE. The differential diagnosis most often includes papulosquamous diseases, such as psoriasis, lichen planus, secondary syphilis, superficial fungal infection, polymorphous light eruption, and sarcoidosis. Histopathologic examination is usually helpful in confirming a diagnosis, and only rarely is immunofluorescence microscopy necessary. Hypertrophic or verrucous LE is a unique clinical subset in which an unusual lesion occurs.3o The thick, adherent scale is replaced by massive hyperkeratosis (Fig. 2). These lesions must be differentiated from warts or squamous cell carcinomas. Patients with hypertrophic LE usually manifest typical discoid LE lesions elsewhere. These patients tend to have chronic disease, with few systemic symptoms or laboratory abnormalities. A small group of patients (about 5% to 10%) also have systemic disease. Some patients progress from pure cutaneous disease into this subset, and the features predictive of this are widespread discoid LE, the presence of clinically appreciable periungual telangiectasias, a persistently elevated sedimentation rate, leukopenia, and positive tests for antinuclear antibodies (ANAs). These patients generally have a more benign prognosis than unselected patients with SLE. Subacute cutaneous LE is a skin lesion that has all the features of discoid LE without the scarring or atrophy.13 Patients with subacute cutaneous LE lesions as their major cutaneous manifestation have been
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Figure 2. Hypertrophic (verrucous) lupus erythematosus. These wart-like lesions were present in a patient with typical discoid lupus erythematosus elsewhere.
classified as having a subset called subacute cutaneous LE. A patient in the subacute cutaneous LE subset can also have scarring lesions of discoid LE or can have lesions generally associated with SLE, such as a malar rash or vasculitic lesions. Many subacute cutaneous LE patients (about 50%) fulfill four or more of the ACR criteria for SLE; thus, some authorities have not recognized these patients as forming a distinct subset. Subacute cutaneous LE skin lesions are of at least two types: annular or papulosquamous. Annular subacute cutaneous LE lesions are characterized by erythematous rings with central clearing (Fig. 3). There is often a slight trailing scale. The annular lesions of subacute cutaneous LE must be differentiated from figurate erythemas, such as erythema annulare centrifugum, or from dermatophyte infection. Papulosquamous subacute cutaneous LE lesions are characterized by plaques and papules with scale (Fig. 4).These lesions must be differentiated from psoriasis and lichen planus. In both forms of subacute cutaneous LE, the lesions often begin as erythematous papules or plaques in a photosensitive distribution. Subacute cutaneous LE may be associated with Sjogren’s
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Figure 3. This erythematous annular lesion lacks scarring or atrophy, yet represents a histologically specific pattern of lupus erythematosus.
syndrome, idiopathic thrombocytopenic purpura, cutaneous vasculitis, or deficiency of the second component of complement (C2d). Subacute cutaneous LE may be induced by a variety of drugs, most notably hydrochlorothiazide and calcium channel blockers.*OThe anti-Ro (SS-A) antibody is frequently positive in patients with subacute cutaneous LE; however, its presence is not diagnostic of subacute cutaneous LE, and its absence does not exclude the diagnosis.
Figure 4. Subacute cutaneous lupus erythematosus, papulosquamous varient. This patient developed an exquisitely photosensitive eruption with minimal sun exposure.
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Malar erythema is the classic butterfly rash from which the name lupus erythematosus (wolflike redness) was coined (Fig. 5). This rash is exacerbated by sun exposure or exposure to artificial light sources. Patients with a butterfly rash usually have active systemic disease. Livedo reticularis or pyoderma gangrenosum-like leg ulcerations may occur in patients with antiphospholipid antibodies (anticardiolipin and lupus anticoag~lant).~~ Many of these patients have LE, but some have primary antiphospholipid antibody syndrome. These patients are characterized by arterial occlusions, which can result in transient ischemic attacks, cerebrovascular accidents, and recurrent fetal loss; by venous occlusive disease, which can be manifest as thrombophlebitis, renal or hepatic vein occlusion, or pulmonary embolism; by thrombocytopenia; and by cardiac valvular vegetations and dysfunction.22 Laboratory Abnormalities in Patients with Cutaneous Lupus Erythematosus
The antinuclear antibody (ANA) is a system that represents many antibodies to multiple s u b ~ t r a t e s The . ~ ~ frequency of a positive ANA correlates with the substrate used. The reported pattern of the ANA may also correlate with specific antibodies; however, except when interpreted by experts, the ANA pattern should not be considered to be
Figure 5. Systemic lupus erythematosus. This young woman has a typical butterfly eruption of systemic lupus erythematosus.
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specific. Antinative (double-stranded) DNA is quite specific for SLE and correlates with active disease, in particular, renal disease. Anti-Ro (SSA) was initially described in ANA-negative LE and Sjogren’s syndrome. It is also present in mothers of neonates with cutaneous LE or congenital heart block and subacute cutaneous LE patients, particularly those patients with vasculitis, C2 deficiency, or drug-induced variants. Therapy should not be based solely on these laboratory abnormalities. Cutaneous immunofluorescence was applied as a diagnostic and prognostic tool that led to a better understanding of LE. Lesional immunofluorescence may be helpful when the clinical and histopathologic diagnosis is in question. Normal facial skin, however, can demonstrate 10% to 20% false-positive rea~ti0ns.l~ The use of noninvolved, nonexposed skin in the lupus band test is believed to correlate with active renal disease. Refined antibody testing has reduced the need for immunofluorescence testing.
Therapy of Cutaneous Lupus Erythematosus Before therapy is begun, it is necessary to evaluate the patient thoroughly to note the extent of disease and to be able to reassure the patient of the benignity of the process. Table 2 lists the tests that should be ordered. Table 3 lists the therapeutic options available? Photosensitivity is a major factor in all types of cutaneous LE. Almost all subacute cutaneous LE patients are photosensitive, and about 60% to 75% of SLE patients demonstrate photosensitivity. This reaction is induced by UVB light, but in some individuals UVA light (320 to 360
Table 2. EVALUATION OF THE PATIENT WITH CUTANEOUS LUPUS ERYTHEMATOSUS Standard Testing Careful history and physical examination Skin biopsy for routine histology Complete blood count with differential and platelet count Serum multiphasic analysis Antinuclear antibody Serologic tests Anti-nDNA Anti-RNP (U1 RNP) Anti-Ro (SS-A) Erythrocyte sedimentation rate Urinalysis Optional Tests Serum protein electrophoresis Circulating immune complexes lmmunofluorescence skin biopsy Antiphospholipid antibodies Total hemolytic complement (if abnormal, C3, C2, C4 levels) Creatinine clearance
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Table 3. THERAPEUTIC AGENTS USEFUL FOR CUTANEOUS LUPUS ERYTHEMATOSUS Standard Therapy Sunscreens Topical corticosteroids lntralesional corticosteroids (avoid atrophy) Antimalarials Hydroxychloroquine: potential ocular toxicity Chloroquine: potential ocular toxicity Alternatives Dapsone (best for bullous LE, vasculitis) Auranofin (oral gold) 13-cis-retinoic acid (Accutane) Clofazimine Low-dose cytotoxic agents: azathioprine or methotrexate Systemic corticosteroids (poorly effective for chronic lesions) Interferon (recombinant a-interferon) LE = Lupus erythematosus.
run) can be involved as well." Therefore the most important therapeutic manipulation is the use of sunscreens and sun avoidance. Broad-spectrum sunscreeDs with a sun protective factor (SPF) of at least 15 should be used every day. Topical corticosteroids should be prescribed in conjunction with other agents. The specific agent used is chosen based on the clinical lesion and area of the body that is affected. The prescribing physician must keep in mind that these agents can produce atrophy, which is also a sign of the disease. Lesions that do not respond to topical agents can be injected intralesionally with a corticosteroid such as triamcinolone acetonide (3 to 4 mg/mL). Antimalarials form a mainstay of systemic therapy of cutaneous LE. The mechanism of action of these agents is unknown, but it may relate to photoprotection or to immunomodulation. The agents available include hydroxychloroquine hydrochloride and chloroquine phosphate. Chloroquine and hydroxychloroquine may be associated with a retinopathy. Hydroxychloroquine is given by mouth in a dose of 200 to 400 mg/d. DERMATOMYOSITIS
Dermatomyositis is a condition that combines an inflammatory myopathy with characteristic cutaneous disease. This disorder is closely related to polymyositis, which has a similar inflammatory myopathy as is found in dermatomyositis but occurs in the absence of the characteristic cutaneous findings.36These disorders are of unknown cause, but immune-mediated muscle damage is believed to be important as a pathogenic mechanism. Dermatomyositis appears to be characterized by an increased frequency of internal malignancy, whereas the association with malignancy in patients with polymyositis is probably coin~idental.~~
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Both disorders have associated morbidity and possible mortality; therefore a prompt, aggressive approach to therapy is indicated. Bohan and Peter1 suggested the use of five criteria to define the entities of polymyositis and dermatomyositis and suggested a classification system. The criteria include (1) proximal symmetric muscle weakness that progresses over a period of weeks to months, (2) elevated serum levels of muscle-derived enzymes, (3) abnormal electromyogram, (4) abnormal muscle biopsy, and (5) the presence of cutaneous disease compatible with dermatomyositis. The following system of classification has been useful in differentiating groups of patients: (1) dermatomyositis, (2) polymyositis, (3) myositis with malignancy, (4) childhood myositis, (5) overlap syndromes with other collagen vascular disease and myositis, (6) inclusion body myositis, and (7) dermatomyositis-sinemyositis (amyopathic dermatomyositis). Clinical Manifestations The characteristic and possibly pathognomonic cutaneous features of dermatomyositis are the heliotrope rash and Gottron’s papules. Several other cutaneous features that occur in patients who have dermatomyositis are characteristic of the disease despite not being pathognomonic and include malar erythema, poikiloderma in a photosensitive distribution, a violaceous erythema on the extensor surfaces, and periungual and cuticular changes. The heliotrope rash consists of a dark lilac ‘discoloration or a violaceous-to-dusky erythematous rash with or without edema in a symmetric distribution involving periorbital skin (Fig. 6). Gottron’s papules are found over bony prominences, particularly over the metacarpopha-
Figure 6. Dermatomyositis. This young woman developed inflammatory myopathy in conjunction with a typical heliotrope eruption around the eyelids and typical lesions elsewhere on her body.
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Figure 7. Gottron's papules. Typical erythematous to violaceous lesions over the bony prominences on the extensor surfaces of the hands.
langeal joints, the proximal interphalangeal joints, or the distal interphalangeal joints (Fig. 7). They may also be found over bony prominences, such as the elbows, knees, and feet. Nailfold changes consist of periunp a l telangiectasias and a characteristic cuticular change with hypertrophy of the cuticle and small, hemorrhagic infarcts within this hypertrophic area (Fig. 8). Poikiloderma can occur within Gottron's papules or can occur on exposed skin, such as the extensor surfaces of the arm or V of the neck (Fig. 9). Kasteler and Callen*"have described patients with scalp involvement characterized by a scaly erythema, diffuse alopecia, and intense pruritus (Fig. 10). These patients are often misdiagnosed as seborrheic dermatitis or psoriasis.
Figure 8. Cuticular hypertrophy, splinter hemorrhages, and periungual telangiectasias are present in this patient with dermatomyositis.
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Figure 9. Poikilodermatous eruption in the photosensitive distribution is present in this woman with dermatomyositis.
Dermatomyositis-sink-myositis(amyopathic dermatomyositis) is diagnosed when typical cutaneous disease is present without clinical weakness and normal serum muscle enzyme levels.*4,33 A small subset of patients never develop myositis despite having prominent cutaneous changes. These patients are often misdiagnosed as lupus erythematosus. Further, there exists a larger group in whom the myositis resolves with therapy, and the skin disease becomes the most important feature of the
Figure 10. Scalp involvement in a patient with dermatomyositis.
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disease. Lastly, there have been several reports of a dermatomyositis-like eruption occurring in patients taking long-term hydroxyurea therapy for chronic myelogenous leukemia, essential thrombocythemia, or polycythemia rubra Vera. Clinical and laboratory abnormalities suggestive of muscle disease are characteristic features of dermatomyositis and polymyositis. Even in patients who initially have only skin disease, myositis most often follows at some point in time. The myopathy affects mainly the proximal muscle groups of the shoulder and pelvic girdles and is usually symmetric. Initial complaints include weakness, fatigue, an inability to climb stairs, an inability to raise the arms for actions such as hair grooming or shaving, an inability to rise from a squatting or sitting position, or a combination of these features. The progression of disease is variable but usually occurs over a period of weeks to months. An inability to swallow and symptoms of aspiration may reflect the involvement of striated muscle of the pharynx or upper esophagus. Dysphagia often signifies a rapidly progressive course and may be associated with a poor prognosis. The laboratory abnormalities include elevations of muscle-derived enzymes, disturbances of electrical action, and histopathologic changes. The enzymes that are commonly elevated are creatine kinase, aldolase, lactic dehydrogenase, and serum transaminases. Creatine kinase determination seems to be the most available test and correlates well with the activity of the muscle disease. On occasion, patients may have normal muscle enzymes, and in these individuals the measurement of creatine excretion in the urine may be reflective of active muscle disease. Electromyography characteristically shows sharp or positive waves, insertional irritability fibrillation, and short polyphasic motor units. Innervation remains intact; thus there is a lack of neuropathic changes. Muscle biopsy shows typical features, including type I1 fiber atrophy, necrosis, regeneration, a centralization of the nuclei, and a lymphocytic .~ testing that infiltrate in a perifascicular or perivascular r e g i ~ n Other may be used includes various imaging techniques; in particular, magnetic resonance imaging has been useful in diagnosis and follow-up of patients with dermatomyositis. Magnetic resonance imaging may also aid in the selection of a site for muscle biopsy. Dermatomyositis and polymyositis are multisystem disorders. This is reflected by the high frequency of other clinical features in patients with these diseases.2Arthralgias, arthritis, or both may be present in up to one fourth of the patients with inflammatory myopathy. Esophageal disease as manifested by dysphagia is estimated to be present in 15% to 50% of patients with inflammatory myopathy. The dysphagia can be of two types: proximal dysphagia or distal dysphagia. Pulmonary disease occurs in dermatomyositis and polymyositis in approximately 15% to 30% of patients. Cardiac disease may also occur in patients with polymyositis, as manifested by myocarditis or pericarditis. Calcinosis of the skin or muscle is unusual in adults but may occur in up to 40% of children with dermatomyositis.
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Myositis and Malignancy
The issue of the relationship of dermatomyositis and polymyositis to malignancy remains controversial. The frequency of malignancy in dermatomyositis varies from 5% to 60% in various studies. This variation is probably related to differing methodology. In 1992, Siguregeirsson et alZ7documented the increased frequency of malignancy in dermatomyositis over the general population in a well-controlled study. Their patients with polymyositis had a slight increase in cancer frequency, which could be explained by a more aggressive cancer search. Although malignancies may occur before the onset of myositis, concurrently with myositis, or after the onset of dermatomyositis, it appears from a Danish study that the frequency of malignancy returns to that of the general populaIn addition, the myositis tion 3 years after the diagnosis of myo~itis.~ may follow the course of the malignancy (a paraneoplastic course) or may follow its own course independent of the treatment of the malignancy. Siguregeirsson et alZ7also suggested that ovarian cancer might be overrepresented. Other investigators have also reported an overrepresen37 tation of ovarian cancer in dermatomyositis patients.8* Evaluation
The diagnosis of myositis is one of exclusion (Table 4). A complete history should be obtained, with particular attention to drugs or toxins that may be involved." A history of previous malignancies; previous travel; changes in the diet; and any symptoms of associated phenomena, such as dysphagia or dyspnea or arthritis, should be included. A thorough review of systems is necessary. An evaluation of patients with dermatomyositis for malignancy should be directed by the history, physical examination, and laboratory findings as well as the patient's age and sex. Course and Therapy
Several general measures are helpful in treating patients with dermatomyositis and polymyositis. Bed rest is often valuable in the individual with progressive weakness; however, this must be combined with an aggressive but passive range-of-motion exercise program to prevent contractures. Nutrition is important because of a negative nitrogen balance that exists in inflammatory myopathy. This is particularly important in children. Patients who have evidence of dysphagia should have the head of their bed elevated and should avoid eating meals before retiring. The mainstay of therapy for dermatomyositis is the use of systemic corticosteroids. Traditionally, prednisone is given in a dose of 0.5 to 1 mg/kg/d as the initial therapy. Approximately 25% to 30% of patients with dermatomyositis or polymyositis do not respond to systemic corti-
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Table 4. EVALUATION OF THE PATIENT WITH MYOSlTlS Careful history Previous malignancy Associated symptoms History of toxins, infections, travel, drug intake, bovine collagen implants, or breast augmentation surgery Complete physical examination Dermatologic evaluation Female: pelvic and breast examinations Male: rectal examination Evaluation of muscle disease Creatine kinase (CK or CPK), aldolase, urinary creatine EMG (if creatine kinase is normal) Muscle biopsy (if creatine kinase and EMG are abnormal) Skin disease evaluation Biopsy Differential Routine laboratory studies Complete blood count, serum multiphasic analysis, urinalysis Chest x-ray Thyroid function Stool Hematest Electrocardiogram Female: Papanicolaou smear, mammography Pulmonary function tests Esophageal studies Manometry or cineradiography Optional Holter monitor Echocardiogram Autoantibody studies: Jo-1, PM, Ku, Mi-2 Viral serologies Further testing based on abnormalities discovered in above tests CK = Creatine kinase; CPK
=
creatine phosphokinase; EMG = electromyogram.
costeroids or develop significant steroid-related side effects. In these patients, immunosuppressive agents (methotrexate, azathioprine, cyclophosphamide, chlorambucil, or cyclosporine) may be an effective means of inducing or maintaining a remission.**The most recent therapeutic manuever for immunosuppressive-resistant dermatomyositis is the use of intravenous immunoglobulin. Dalakas et all2demonstrated that the myopathy as well as the cutaneous disease improved. Therapy of cutaneous disease in patients with dermatomyositis is often difficult because even though the myositis may respond to treatment with corticosteroids or immunosuppressives, the cutaneous lesions often persist. Although cutaneous disease may be of minor importance in patients with serious fulminant myositis, in many patients cutaneous disease becomes the most important aspect of their disorder. Most patients with cutaneous lesions are photosensitive; thus, as in patients with LE, the daily use of a sunscreen with an SPF of at least 15 is recommended. Some may require a broader-spectrum sunscreen. Hydroxy-
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chloroquine in dosages of 200 to 400 mg/d is effective in approximately 80% of patients treated, as a means of partially controlling their cutaneous disease and allowing a decrease in the corticosteroid dosage.38The use of low-dose methotrexate has been effective in many of the author’s patients.*l The prognosis of dermatomyositis and polymyositis varies greatly, depending on the series of patients studied. Factors that affect the prognosis include the patient’s age, the type and severity of myositis, the presence of dysphagia, the presence of an associated malignancy, and the response to corticosteroid therapy. That therapy alters prognosis seems to be well established by retrospective reports on the benefits of corticosteroids and immunosuppressives.
SCLERODERMA
Scleroderma is a term used to describe a specific clinical disease spectrum represented by cutaneous or multisystem involvement (or both). In addition, several disorders are associated with sclerodermoid changes (Table 5). Scleroderma is a disorder of unknown cause and
Table 5. SCLERODERMA AND SOME SCLERODERMOID CONDITIONS Localized scleroderma Morphea (dermal, subcutaneous, and pansclerotic variants) Linear scleroderma Generalized morphea Systemic sclerosis (scleroderma) Limited (acrosclerosis, CREST variant) Diffuse Overlap with another collagen vascular disease (LE or DM) Mixed connective tissue disease Idiopathic syndromes possibly related to scleroderma Eosinophilic fasciitis Eosinophilia myalgia syndrome Mucinoses Scleredema Scleromyxedema (lichen myxedematosus or papular mucinosis) Chemical or drug-induced sclerosis Polyvinyl chloride Silicone (breast implants, injectable)/? collagen injections Bleomycin Spanish rapeseed oil Metabolic Porphyria cutanea tarda Carcinoid syndrome Immunologic Chronic graft-versus-host disease Vibratory injury ~
~_______
LE = Lupus erythematosus; DM, = dermatomyositis.
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pathogenesis. There are two major categories: localized scleroderma and systemic sclerosis. Localized Scleroderma
Localized scleroderma refers to primary involvement of the skin, with minimal, if any, systemic features."j Only rarely have patients with localized scleroderma developed systemic sclerosis. Three major types of localized scleroderma exist: morphea, generalized morphea, and linear scleroderma. Morphea is represented by indurated dermal or subcutaneous plaques (Fig. 11).The disease is most common in young women. Morphea sometimes overlaps or coexists with another cutaneous condition known as lichen sclerosus et atrophicus. In contrast, a small number of patients develop numerous and larger lesions that coalesce (Fig. 12). These individuals are said to have generalized morphea. Patients with morphea usually have a benign course, characterized by softening of lesions with time. An observation that administration of high-dose UVA1 phototherapy is effective in treating lesions32has been followed by the observation that this therapy induces the production of interstitial collagenase by fibroblasts in the lesions of morphea.18Another potential therapy that has been studied in a open trial is the administration of oral 1,25-hydroxyvitamin D3.I9 Linear scleroderma is most often a single sclerotic linear lesion. This variant is also more common in young women. The disease frequently occurs on the extremities or the forehead (Fig. 13).When on the forehead, the term e n coup de sabre has been applied. When the disease crosses a joint, limitation of motion is possible as well as decreased growth. In addition, facial disfigurement can occur. Linear scleroderma also appears to soften over time, but treatment with physical therapy to reduce the likelihood of permanent contracture is indicated.
Figure 11. Morphea. A single plaque of indurated skin on the back of this adolescent.
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Figure 12. Generalized rnorphea. Coalescent plaques of induration on the trunk. (Courtesy of Dr. Kenneth E. Greer, Charlottesville, VA.)
Raynaud’s Phenomenon and Raynaud’s Disease Raynaud’s phenomenon is a triphasic color reaction induced by cold or emotional distress and involves the digits.6The initial pallor is followed by cyanosis, then a reactive hyperemia. In addition to the
Figure 13. En coup de sabre-linear
scleroderrna involving the facial skin.
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Figure 14. Pitting of the fingertips is the result of ischemia from severe Raynaud’s phenomenon.
color changes, either numbness or pain may occur. Rewarming not only relieves the color changes, but also relieves the symptoms. As the disorder progresses, repeated ischemic episodes can result in small pitted areas on the distal digits (Fig. 14), ulcerations, or gangrene. The process is termed Xaynaud’s disease when there is no identifiable cause. There are frequent reports, however, of patients with long-standing Raynaud’s disease who later develop SLE or systemic sclerosis. The diseases that need to be considered in a patient with Raynaud’s phenomenon are listed in Table 6. Management of Raynaud’s phenomenon is directed at prevention, removal of exacerbating factors, and vasodilation. Patients may wear gloves and avoid situations that are known to precipitate an episode, such as cold exposure. The use of tobacco (smoking or chewing) should be stopped. Drugs that cause vasoconstriction should be avoided. Drugs that allow for vasodilation are often helpful in reducing the severity or
Table 6. CONDITIONS ASSOCIATED WITH RAYNAUD’S PHENOMENON Collagen Vascular Diseases Scleroderma Lupus erythematosus Rheumatoid arthritis Dermatomyositis Vasculitis (polyarteritis nodosa) Mixed connective tissue disease Hematologic disorders Cryoglobulinemia (particularly type I) Cryofibrinogenemia Cold agglutinin Macroglobulinemia Hyperglobulinemic purpura Polycythemia Thrombocythemia
Arterial disease Thromboangiitis obliterans Atherosclerosis Embolic disease Drugs Ergots p-blockers Bleomycin Caffeine Nicotine Neurovascular compression Thoracic outlet syndrome Carpal tunnel syndrome Vibratory injury Malignancy
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number of episodes that the patient may have. Agents such as topical nitroglycerin, calcium channel blockers (nifedipine, diltiazem), and prostacyclin analogues (iloprost) have been demonstrated to be useful in many patients. Systemic Sclerosis (Progressive Systemic Sclerosis)
Systemic sclerosis is characterized by both cutaneous and internal organ fibrosis. Almost all patients have Raynaud’s phenomenon, which is a common presenting manifestation. Systemic sclerosis is much more frequent in women. The pathogenesis of systemic sclerosis is not known, but theories involve a dysregulation of collagen synthesis, endothelial cell injury, and abnormal immunity. Patients with systemic sclerosis may be subclassified as having diffuse disease or limited disease. In the limited form, the primary involvement is on acral skin (hands, forearms, legs, and face), whereas in the diffuse form there is extensive sclerosis of the proximal portions of the extremities as well as the truncal skin. In general, the prognosis is poorer in patients with diffuse disease. Sclerodactyly is a hallmark of the disease in both forms. In addition, abnormal pigmentation is a common finding. Telangiectasia and nail fold capillary abnormalities are also common. The term CREST syndrome has been developed to denote a subset of patients with systemic sclerosis and refers to calcinosis, Xaynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia. These patients tend to possess anticentromere antibodies and often have a slowly progressive course.31Pulmonary hypertension also is more common in this group of patients. Systemic disease is a common feature of systemic sclerosis. Pulmonary function is frequently decreased. Esophageal dysmotility and gastrointestinal dysmotility are common. Renal dysfunction is uncommon, but when present it can result in a life-threatening situation. Patients with diffuse disease frequently possess antitopoisomerase I antibodies. There is no cure for scleroderma; therefore treatment is directed at symptomatic relief.26Therapy for Raynaud’s phenomenon was discussed earlier. Prevention of aspiration pneumonitis in patients with esophageal disease is indicated. The use of D-penicillamine is often considered, but the results of long-term studies are controversial. Eosinophilic Fasciitis and Eosinophilia Myalgia Syndrome
Eosinophilic fasciitis is characterized by the sudden onset of progressive induration of the skin. Patients often report that the disease followed an unusual amount of exertion. The patients do not have Raynaud’s phenomenon, sclerodactyly or autoantibodies, but frequently have hyperglobulinemia and eosinophilia. Histologically, they have a
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fasciitis. Patients may respond to therapy with prednisone or methotrexate. A syndrome characterized by eosinophilia, myalgia, cutaneous sclerosis, neuropathy, and pulmonary dysfunction developed in patients taking contaminated L-tryptophan. Some of the features closely mimic eosinophilic fasciitis, but the patients often fail to respond to therapy and may experience progressive debilitation or even death.34 References 1. Bohan A, Peter JB: Polymyositis and dermatomyositis. N Engl J Med 292344-347,1975 2. Bohan A, Peter JB, Bowman RL, et a1 A computer-assisted analysis of 153 patients with polymyositis and dermatomyositis. Medicine 56955, 1977 3. Callen JP: Management of antimalarial-refractory cutaneous lupus erythematosus. LUPUS 6203-208, 1997 4. Callen JP: Chronic cutaneous LE. Arch Dermatol 118:412416, 1982 5. Callen JP, Tuffanelli DL, Provost TT: Collagen-vascular disease: An update. J Am Acad Dermatol 28:477-484, 1993 6. Campbell PM, Leroy EC: Raynaud phenomenon. Semin Arthritis Rheum 16:92-103, 1986 7. Campellone JV, Lacomis D, Giulani MJ, et a1 Percutaneous needle muscle biopsy in the evaluation of patients with suspected inflammatory myopathy. Arthritis Rheum 40~1886-1891,1997 8. Cherin P, Piette JC, Herson S, et a1 Dermatomyositis and ovarian cancer: A report of 7 cases and literature review. J Rheumatol201897-1899, 1993 9. Chow W-H, Gridley G, Mellemkjaer L, et a1 Cancer risk following polymyositis and dermatomyositis: A nationwide cohort study in Denmark. Cancer Causes Control 6:9-13, 1995 10. Crowson AN, Magro CM: Subacute cutaneous lupus erythematosus arising in the setting of calcium channel blocker therapy. Hum Pathol 28:67-73, 1997 11. Cukier J, Beauchamp RA, Spindler JS, et a1 Association between bovine collagen implants and a dermatomyositis or polymyositis-like syndrome. Ann Intern Med 118920-928, 1993 12. Dalakas MC, Illa I, Dambrosia JM, et a1 A controlled trial of high-dose intravenous immune globulin infusions as a treatment for dermatomyositis. N Engl J Med 329:19932000, 1993 13. David-Bajar KM: Subacute cutaneous lupus erythematosus. J Invest Dermatol 1OO:ZS8S, 1993 14. Euwer RL, Sontheimer R D Amyopathic dermatomyositis (dermatomyositis sine myositis). J Am Acad Dermatol 24:959-966, 1991 15. Fabr6 VC, Lear S, Reichlin M, et a1 Twenty percent of biopsy specimens from sunexposed skin of normal young adults demonstrate positive immunofluorescence. Arch Dermatol 1271006-1011, 1991 16. Falanga V Localized scleroderma. Med Clin North Am 731143-1156, 1989 17. Gilliam JN, Sontheimer R D Distinctive cutaneous subsets in the spectrum of lupus erythematosus. J Am Acad Dermatol4471475, 1981 18. Gruss C, Reed JA, Altmeyer P, et al: Induction of interstitial collagenase (MMP-1) by UVA-1 phototherapy in morphea fibroblasts. Lancet 3501295-1296, 1997 19. Humbert P, Delaporte E, Dupond JL, et a1 Treatment of localized scleroderma with oral 1,25-dihydroxyvitamin D3. Eur J Dermatol 421-23, 1994 20. Kasteler JS, Callen JP: Scalp involvement in dermatomyositis: Often overlooked or misdiagnosed. JAMA 2721939-1941, 1994 21. Kasteler JS, Callen JP: Low-dose methotrexate administered weekly is an effective corticosteroid-sparing agent for the treatment of the cutaneous manifestations of dermatomyositis. J Am Acad Dermatol 36:67-71, 1997
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22. Krnic-Barrie S, O’Connor CR, Looney SW, et al: A retrospective review of 61 patients with antiphospholipid syndrome. Arch Intern Med 1572102-2108, 1997 23. Lee LA, David KM: Cutaneous lupus erythematosus. Curr Probl Dermatol 1:161-200, 1989 24. Lehmann P, Holzle E, Kind P, et al: Experimental reproduction of skin lesions in lupus erythematosus by UVA and UVB radiation. J Am Acad Dermatol 22181-187, 1990 25. Petri M: Antiphospholipid antibodies: Lupus anticoagulant and anticardiolipin antibody. Curr Probl Dermatol4:171-201, 1992 26. Siebold JR, Furst DE, Clements PJ: Why everything (or nothing) seems to work in the treatment of scleroderma. J Rheumatol 19:673-676, 1992 27. Siguregeirsson 8, Lindelof 8, Edhag 0, et al: Risk of cancer in patients with dermatomyositis or polymyositis. N Engl J Med 326:363-367, 1992 28. Sinoway P, Callen JP: Chlorambucil: An effective corticosteroid sparing agent for patients with recalcitrant dermatomyositis. Arthritis Rheum 36:319-324, 1993 29. Sontheimer RD, McCauliffe DP, Zappi E, et al: Antinuclear antibodies: Clinical correlations and biologic significance. Adv Dermatol 73-53, 1991 30. Spann CR, Callen JP, Klein JB, et al: Clinical, serologic and immunogenetic studies in patients with chronic cutaneous (discoid) lupus erythematosus who have verrucous and/or hypertrophic skin lesions. J Rheumatol 15:256-261, 1988 31. Steen VD, Ziegler GL, Rodnan GP, et al: Clinical and laboratory associations of anticentromere antibody in patients with progressive systemic sclerosis. Arthritis Rheum 27125-131, 1984 32. Stege H, Berneburg M, Humke S, et al: High-dose UVA-1 radiation therapy for localized scleroderma. J Am Acad Dermatol 36:938-944, 1997 33. Stonecipher MR, Jorizzo JL, White WL, et al: Cutaneous changes of dermatomyositis in patients with normal muscle enzymes: Dermatomyositis sine myositis? J Am Acad Dermatol28:951-956, 1993 34. Swygert LA, Back EE, Auerbach SE, et al: Eosinophilia-myalgia syndrome: Mortality data from the US national surveillance system. J Rheumatol 20:1711-1717, 1993 35. Tan EM, Cohen AS, Fries JF, et al: The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271-1277, 1982 36. Targoff IN: Dermatomyositis and polymyositis. Curr Probl Dermatol 3:131-180, 1991 37. Whitmore SE, Anhalt GJ, Provost TT, et al: Serum CA-125 screening for ovarian cancer in patients with dermatomyositis. Gynecol Oncol 65241-244, 1997 38. Woo TY, Callen JP, Voorhees JV, et al: Cutaneous lesions of dermatomyositis are improved by hydroxychloroquine. J Am Acad Dermatol 10592-600, 1984
Address reprint requests to Jeffrey P. Callen, MD Department of Medicine Division of Dermatology University of Louisville 310 East Broadway Louisville, KY 40202 e-mail: jefca8aol.com
0025-7125/98 $8.00
+ .OO
COLLAGEN VASCULAR DISEASES Jeffrey P. Callen, MD
Collagen vascular diseases are multisystem disorders that frequently affect the skin5 At times, cutaneous disease is the initial manifestation. This article focuses on lupus erythematosus (LE), dermatomyositis, and sclerodermoid syndromes. LUPUS ERYTHEMATOSUS
LE is a multisystem disorder with a spectrum from a relatively benign, self-limited cutaneous eruption to a severe, often fatal, systemic disease.23The American College of Rheumatology (ACR) has developed a set of criteria that could be used for the classification of systemic lupus erythematosus (SLE)?5When a patient has four or more of the criteria either concurrently or serially during any period of observation, the patient can be classified as having SLE. In the 1940s and 1950s, dermatologists first recognized that most of their patients with chronic, scarring, discoid LE lesions had few, if any, systemic findings, whereas those with photosensitivity or malar erythema (or both) frequently had systemic disease. They also recognized a subset with transient skin lesions that did not result in scarring or atrophy; these patients had systemic disease, but their prognosis was not as poor as that of unselected patients with SLE. Various names have been applied to this subset, but that coined by Sontheimer and Gilliam, subacute cutaneous LE, is the best accepted. The classification of cutaneous subsets was stressed by Gilliam and S~ntheimer,’~ who proposed that patients be classified by the type of skin disease present into two groups:
From the Department of Medicine, Division of Dermatology, University of Louisville, Louisville, Kentucky
MEDICAL CLINICS OF NORTH AMERICA VOLUME 82 * NUMBER 6 NOVEMBER 1998
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(1)those that are histopathologically LE specific or (2) those that are not histopathologically specific (Table 1). Chronic cutaneous LE can be manifested by several clinical variations. The most common manifestation is the discoid LE 1esi0n.~These patients may be subclassified as having localized discoid LE, when lesions are on the head and neck only, or widespread discoid LE, when lesions are on other body surfaces as well as the head and neck. Other, less common forms of chronic cutaneous LE include hypertrophic or verrucous (wartlike) lesions, lesions on the palms or soles, oral discoid LE, and lupus panniculitis (lupus profundus). The discoid LE lesion is characterized by erythema; telangiectasia; adherent scale, varying from fine to thick; follicular plugging; dyspigmentation; and atrophy and scarring (Fig. 1). The lesions are usually
Table 1. CLASSIFICATION OF MUCOCUTANEOUS LESIONS IN LUPUS ERYTHEMATOSUS I. LE-specific histopathology A. Chronic cutaneous LE 1. Discoid LE (widespread vs localized) 2. HyperIrophic/verrucous LE 3. Palmar/plantar LE 4. Oral discoid 5. LE panniculitis B. SCLE 1. PMLE-like lesions 2. Annular lesions a. Oriental SCLE (annular erythema of 1" SS) 3. Papulosquamous lesions (? photosensitive psoriasis) 4. Neonatal LE 5. C2-deficient LE-like syndrome 6. Drug-induced SCLE C. ACLE 1. Malar erythema 2. Photosensitivity dermatitis 3. Generalized erythema II. LE-nonspecific histopathology A. Vasculopathy 1. Urticaria 2. Vasculitis 3. Livedo reticularis/leg ulcerations B. Mucosal lesions C. Nonscarring alopecia D. Bullous LElEBA E. Associated mucocutaneous problems 1. Mucinous infiltrations 2. Porphyrias 3. Lichen planus 4. Psoriasis 5. Sjogren's syndrome 6. Squamous cell carcinomas LE = Lupus erythematosus; SCLE cutaneous lupus erythematosus; 1" SS bullosa acquisita.
= =
subacute cutaneous lupus erythematosus; ACLE = acute primary Sjogren's syndrome; and EBA = epidermolysis
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Figure 1. Discoid lupus erythernatosus. This woman demonstrates multiple features of discoid lupus erythematosus, including follicular plugging, scarring, atrophy, and dyspigmentation.
sharply demarcated and can be round, thus giving rise to the term discoid (or disclike). The presence of scarring or atrophy is the characteristic that separates these lesions from those of subacute cutaneous LE. The differential diagnosis most often includes papulosquamous diseases, such as psoriasis, lichen planus, secondary syphilis, superficial fungal infection, polymorphous light eruption, and sarcoidosis. Histopathologic examination is usually helpful in confirming a diagnosis, and only rarely is immunofluorescence microscopy necessary. Hypertrophic or verrucous LE is a unique clinical subset in which an unusual lesion occurs.3o The thick, adherent scale is replaced by massive hyperkeratosis (Fig. 2). These lesions must be differentiated from warts or squamous cell carcinomas. Patients with hypertrophic LE usually manifest typical discoid LE lesions elsewhere. These patients tend to have chronic disease, with few systemic symptoms or laboratory abnormalities. A small group of patients (about 5% to 10%) also have systemic disease. Some patients progress from pure cutaneous disease into this subset, and the features predictive of this are widespread discoid LE, the presence of clinically appreciable periungual telangiectasias, a persistently elevated sedimentation rate, leukopenia, and positive tests for antinuclear antibodies (ANAs). These patients generally have a more benign prognosis than unselected patients with SLE. Subacute cutaneous LE is a skin lesion that has all the features of discoid LE without the scarring or atrophy.13 Patients with subacute cutaneous LE lesions as their major cutaneous manifestation have been
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Figure 2. Hypertrophic (verrucous) lupus erythematosus. These wart-like lesions were present in a patient with typical discoid lupus erythematosus elsewhere.
classified as having a subset called subacute cutaneous LE. A patient in the subacute cutaneous LE subset can also have scarring lesions of discoid LE or can have lesions generally associated with SLE, such as a malar rash or vasculitic lesions. Many subacute cutaneous LE patients (about 50%) fulfill four or more of the ACR criteria for SLE; thus, some authorities have not recognized these patients as forming a distinct subset. Subacute cutaneous LE skin lesions are of at least two types: annular or papulosquamous. Annular subacute cutaneous LE lesions are characterized by erythematous rings with central clearing (Fig. 3). There is often a slight trailing scale. The annular lesions of subacute cutaneous LE must be differentiated from figurate erythemas, such as erythema annulare centrifugum, or from dermatophyte infection. Papulosquamous subacute cutaneous LE lesions are characterized by plaques and papules with scale (Fig. 4).These lesions must be differentiated from psoriasis and lichen planus. In both forms of subacute cutaneous LE, the lesions often begin as erythematous papules or plaques in a photosensitive distribution. Subacute cutaneous LE may be associated with Sjogren’s
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Figure 3. This erythematous annular lesion lacks scarring or atrophy, yet represents a histologically specific pattern of lupus erythematosus.
syndrome, idiopathic thrombocytopenic purpura, cutaneous vasculitis, or deficiency of the second component of complement (C2d). Subacute cutaneous LE may be induced by a variety of drugs, most notably hydrochlorothiazide and calcium channel blockers.*OThe anti-Ro (SS-A) antibody is frequently positive in patients with subacute cutaneous LE; however, its presence is not diagnostic of subacute cutaneous LE, and its absence does not exclude the diagnosis.
Figure 4. Subacute cutaneous lupus erythematosus, papulosquamous varient. This patient developed an exquisitely photosensitive eruption with minimal sun exposure.
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Malar erythema is the classic butterfly rash from which the name lupus erythematosus (wolflike redness) was coined (Fig. 5). This rash is exacerbated by sun exposure or exposure to artificial light sources. Patients with a butterfly rash usually have active systemic disease. Livedo reticularis or pyoderma gangrenosum-like leg ulcerations may occur in patients with antiphospholipid antibodies (anticardiolipin and lupus anticoag~lant).~~ Many of these patients have LE, but some have primary antiphospholipid antibody syndrome. These patients are characterized by arterial occlusions, which can result in transient ischemic attacks, cerebrovascular accidents, and recurrent fetal loss; by venous occlusive disease, which can be manifest as thrombophlebitis, renal or hepatic vein occlusion, or pulmonary embolism; by thrombocytopenia; and by cardiac valvular vegetations and dysfunction.22 Laboratory Abnormalities in Patients with Cutaneous Lupus Erythematosus
The antinuclear antibody (ANA) is a system that represents many antibodies to multiple s u b ~ t r a t e s The . ~ ~ frequency of a positive ANA correlates with the substrate used. The reported pattern of the ANA may also correlate with specific antibodies; however, except when interpreted by experts, the ANA pattern should not be considered to be
Figure 5. Systemic lupus erythematosus. This young woman has a typical butterfly eruption of systemic lupus erythematosus.
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specific. Antinative (double-stranded) DNA is quite specific for SLE and correlates with active disease, in particular, renal disease. Anti-Ro (SSA) was initially described in ANA-negative LE and Sjogren’s syndrome. It is also present in mothers of neonates with cutaneous LE or congenital heart block and subacute cutaneous LE patients, particularly those patients with vasculitis, C2 deficiency, or drug-induced variants. Therapy should not be based solely on these laboratory abnormalities. Cutaneous immunofluorescence was applied as a diagnostic and prognostic tool that led to a better understanding of LE. Lesional immunofluorescence may be helpful when the clinical and histopathologic diagnosis is in question. Normal facial skin, however, can demonstrate 10% to 20% false-positive rea~ti0ns.l~ The use of noninvolved, nonexposed skin in the lupus band test is believed to correlate with active renal disease. Refined antibody testing has reduced the need for immunofluorescence testing.
Therapy of Cutaneous Lupus Erythematosus Before therapy is begun, it is necessary to evaluate the patient thoroughly to note the extent of disease and to be able to reassure the patient of the benignity of the process. Table 2 lists the tests that should be ordered. Table 3 lists the therapeutic options available? Photosensitivity is a major factor in all types of cutaneous LE. Almost all subacute cutaneous LE patients are photosensitive, and about 60% to 75% of SLE patients demonstrate photosensitivity. This reaction is induced by UVB light, but in some individuals UVA light (320 to 360
Table 2. EVALUATION OF THE PATIENT WITH CUTANEOUS LUPUS ERYTHEMATOSUS Standard Testing Careful history and physical examination Skin biopsy for routine histology Complete blood count with differential and platelet count Serum multiphasic analysis Antinuclear antibody Serologic tests Anti-nDNA Anti-RNP (U1 RNP) Anti-Ro (SS-A) Erythrocyte sedimentation rate Urinalysis Optional Tests Serum protein electrophoresis Circulating immune complexes lmmunofluorescence skin biopsy Antiphospholipid antibodies Total hemolytic complement (if abnormal, C3, C2, C4 levels) Creatinine clearance
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Table 3. THERAPEUTIC AGENTS USEFUL FOR CUTANEOUS LUPUS ERYTHEMATOSUS Standard Therapy Sunscreens Topical corticosteroids lntralesional corticosteroids (avoid atrophy) Antimalarials Hydroxychloroquine: potential ocular toxicity Chloroquine: potential ocular toxicity Alternatives Dapsone (best for bullous LE, vasculitis) Auranofin (oral gold) 13-cis-retinoic acid (Accutane) Clofazimine Low-dose cytotoxic agents: azathioprine or methotrexate Systemic corticosteroids (poorly effective for chronic lesions) Interferon (recombinant a-interferon) LE = Lupus erythematosus.
run) can be involved as well." Therefore the most important therapeutic manipulation is the use of sunscreens and sun avoidance. Broad-spectrum sunscreeDs with a sun protective factor (SPF) of at least 15 should be used every day. Topical corticosteroids should be prescribed in conjunction with other agents. The specific agent used is chosen based on the clinical lesion and area of the body that is affected. The prescribing physician must keep in mind that these agents can produce atrophy, which is also a sign of the disease. Lesions that do not respond to topical agents can be injected intralesionally with a corticosteroid such as triamcinolone acetonide (3 to 4 mg/mL). Antimalarials form a mainstay of systemic therapy of cutaneous LE. The mechanism of action of these agents is unknown, but it may relate to photoprotection or to immunomodulation. The agents available include hydroxychloroquine hydrochloride and chloroquine phosphate. Chloroquine and hydroxychloroquine may be associated with a retinopathy. Hydroxychloroquine is given by mouth in a dose of 200 to 400 mg/d. DERMATOMYOSITIS
Dermatomyositis is a condition that combines an inflammatory myopathy with characteristic cutaneous disease. This disorder is closely related to polymyositis, which has a similar inflammatory myopathy as is found in dermatomyositis but occurs in the absence of the characteristic cutaneous findings.36These disorders are of unknown cause, but immune-mediated muscle damage is believed to be important as a pathogenic mechanism. Dermatomyositis appears to be characterized by an increased frequency of internal malignancy, whereas the association with malignancy in patients with polymyositis is probably coin~idental.~~
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Both disorders have associated morbidity and possible mortality; therefore a prompt, aggressive approach to therapy is indicated. Bohan and Peter1 suggested the use of five criteria to define the entities of polymyositis and dermatomyositis and suggested a classification system. The criteria include (1) proximal symmetric muscle weakness that progresses over a period of weeks to months, (2) elevated serum levels of muscle-derived enzymes, (3) abnormal electromyogram, (4) abnormal muscle biopsy, and (5) the presence of cutaneous disease compatible with dermatomyositis. The following system of classification has been useful in differentiating groups of patients: (1) dermatomyositis, (2) polymyositis, (3) myositis with malignancy, (4) childhood myositis, (5) overlap syndromes with other collagen vascular disease and myositis, (6) inclusion body myositis, and (7) dermatomyositis-sinemyositis (amyopathic dermatomyositis). Clinical Manifestations The characteristic and possibly pathognomonic cutaneous features of dermatomyositis are the heliotrope rash and Gottron’s papules. Several other cutaneous features that occur in patients who have dermatomyositis are characteristic of the disease despite not being pathognomonic and include malar erythema, poikiloderma in a photosensitive distribution, a violaceous erythema on the extensor surfaces, and periungual and cuticular changes. The heliotrope rash consists of a dark lilac ‘discoloration or a violaceous-to-dusky erythematous rash with or without edema in a symmetric distribution involving periorbital skin (Fig. 6). Gottron’s papules are found over bony prominences, particularly over the metacarpopha-
Figure 6. Dermatomyositis. This young woman developed inflammatory myopathy in conjunction with a typical heliotrope eruption around the eyelids and typical lesions elsewhere on her body.
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Figure 7. Gottron's papules. Typical erythematous to violaceous lesions over the bony prominences on the extensor surfaces of the hands.
langeal joints, the proximal interphalangeal joints, or the distal interphalangeal joints (Fig. 7). They may also be found over bony prominences, such as the elbows, knees, and feet. Nailfold changes consist of periunp a l telangiectasias and a characteristic cuticular change with hypertrophy of the cuticle and small, hemorrhagic infarcts within this hypertrophic area (Fig. 8). Poikiloderma can occur within Gottron's papules or can occur on exposed skin, such as the extensor surfaces of the arm or V of the neck (Fig. 9). Kasteler and Callen*"have described patients with scalp involvement characterized by a scaly erythema, diffuse alopecia, and intense pruritus (Fig. 10). These patients are often misdiagnosed as seborrheic dermatitis or psoriasis.
Figure 8. Cuticular hypertrophy, splinter hemorrhages, and periungual telangiectasias are present in this patient with dermatomyositis.
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Figure 9. Poikilodermatous eruption in the photosensitive distribution is present in this woman with dermatomyositis.
Dermatomyositis-sink-myositis(amyopathic dermatomyositis) is diagnosed when typical cutaneous disease is present without clinical weakness and normal serum muscle enzyme levels.*4,33 A small subset of patients never develop myositis despite having prominent cutaneous changes. These patients are often misdiagnosed as lupus erythematosus. Further, there exists a larger group in whom the myositis resolves with therapy, and the skin disease becomes the most important feature of the
Figure 10. Scalp involvement in a patient with dermatomyositis.
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disease. Lastly, there have been several reports of a dermatomyositis-like eruption occurring in patients taking long-term hydroxyurea therapy for chronic myelogenous leukemia, essential thrombocythemia, or polycythemia rubra Vera. Clinical and laboratory abnormalities suggestive of muscle disease are characteristic features of dermatomyositis and polymyositis. Even in patients who initially have only skin disease, myositis most often follows at some point in time. The myopathy affects mainly the proximal muscle groups of the shoulder and pelvic girdles and is usually symmetric. Initial complaints include weakness, fatigue, an inability to climb stairs, an inability to raise the arms for actions such as hair grooming or shaving, an inability to rise from a squatting or sitting position, or a combination of these features. The progression of disease is variable but usually occurs over a period of weeks to months. An inability to swallow and symptoms of aspiration may reflect the involvement of striated muscle of the pharynx or upper esophagus. Dysphagia often signifies a rapidly progressive course and may be associated with a poor prognosis. The laboratory abnormalities include elevations of muscle-derived enzymes, disturbances of electrical action, and histopathologic changes. The enzymes that are commonly elevated are creatine kinase, aldolase, lactic dehydrogenase, and serum transaminases. Creatine kinase determination seems to be the most available test and correlates well with the activity of the muscle disease. On occasion, patients may have normal muscle enzymes, and in these individuals the measurement of creatine excretion in the urine may be reflective of active muscle disease. Electromyography characteristically shows sharp or positive waves, insertional irritability fibrillation, and short polyphasic motor units. Innervation remains intact; thus there is a lack of neuropathic changes. Muscle biopsy shows typical features, including type I1 fiber atrophy, necrosis, regeneration, a centralization of the nuclei, and a lymphocytic .~ testing that infiltrate in a perifascicular or perivascular r e g i ~ n Other may be used includes various imaging techniques; in particular, magnetic resonance imaging has been useful in diagnosis and follow-up of patients with dermatomyositis. Magnetic resonance imaging may also aid in the selection of a site for muscle biopsy. Dermatomyositis and polymyositis are multisystem disorders. This is reflected by the high frequency of other clinical features in patients with these diseases.2Arthralgias, arthritis, or both may be present in up to one fourth of the patients with inflammatory myopathy. Esophageal disease as manifested by dysphagia is estimated to be present in 15% to 50% of patients with inflammatory myopathy. The dysphagia can be of two types: proximal dysphagia or distal dysphagia. Pulmonary disease occurs in dermatomyositis and polymyositis in approximately 15% to 30% of patients. Cardiac disease may also occur in patients with polymyositis, as manifested by myocarditis or pericarditis. Calcinosis of the skin or muscle is unusual in adults but may occur in up to 40% of children with dermatomyositis.
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Myositis and Malignancy
The issue of the relationship of dermatomyositis and polymyositis to malignancy remains controversial. The frequency of malignancy in dermatomyositis varies from 5% to 60% in various studies. This variation is probably related to differing methodology. In 1992, Siguregeirsson et alZ7documented the increased frequency of malignancy in dermatomyositis over the general population in a well-controlled study. Their patients with polymyositis had a slight increase in cancer frequency, which could be explained by a more aggressive cancer search. Although malignancies may occur before the onset of myositis, concurrently with myositis, or after the onset of dermatomyositis, it appears from a Danish study that the frequency of malignancy returns to that of the general populaIn addition, the myositis tion 3 years after the diagnosis of myo~itis.~ may follow the course of the malignancy (a paraneoplastic course) or may follow its own course independent of the treatment of the malignancy. Siguregeirsson et alZ7also suggested that ovarian cancer might be overrepresented. Other investigators have also reported an overrepresen37 tation of ovarian cancer in dermatomyositis patients.8* Evaluation
The diagnosis of myositis is one of exclusion (Table 4). A complete history should be obtained, with particular attention to drugs or toxins that may be involved." A history of previous malignancies; previous travel; changes in the diet; and any symptoms of associated phenomena, such as dysphagia or dyspnea or arthritis, should be included. A thorough review of systems is necessary. An evaluation of patients with dermatomyositis for malignancy should be directed by the history, physical examination, and laboratory findings as well as the patient's age and sex. Course and Therapy
Several general measures are helpful in treating patients with dermatomyositis and polymyositis. Bed rest is often valuable in the individual with progressive weakness; however, this must be combined with an aggressive but passive range-of-motion exercise program to prevent contractures. Nutrition is important because of a negative nitrogen balance that exists in inflammatory myopathy. This is particularly important in children. Patients who have evidence of dysphagia should have the head of their bed elevated and should avoid eating meals before retiring. The mainstay of therapy for dermatomyositis is the use of systemic corticosteroids. Traditionally, prednisone is given in a dose of 0.5 to 1 mg/kg/d as the initial therapy. Approximately 25% to 30% of patients with dermatomyositis or polymyositis do not respond to systemic corti-
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Table 4. EVALUATION OF THE PATIENT WITH MYOSlTlS Careful history Previous malignancy Associated symptoms History of toxins, infections, travel, drug intake, bovine collagen implants, or breast augmentation surgery Complete physical examination Dermatologic evaluation Female: pelvic and breast examinations Male: rectal examination Evaluation of muscle disease Creatine kinase (CK or CPK), aldolase, urinary creatine EMG (if creatine kinase is normal) Muscle biopsy (if creatine kinase and EMG are abnormal) Skin disease evaluation Biopsy Differential Routine laboratory studies Complete blood count, serum multiphasic analysis, urinalysis Chest x-ray Thyroid function Stool Hematest Electrocardiogram Female: Papanicolaou smear, mammography Pulmonary function tests Esophageal studies Manometry or cineradiography Optional Holter monitor Echocardiogram Autoantibody studies: Jo-1, PM, Ku, Mi-2 Viral serologies Further testing based on abnormalities discovered in above tests CK = Creatine kinase; CPK
=
creatine phosphokinase; EMG = electromyogram.
costeroids or develop significant steroid-related side effects. In these patients, immunosuppressive agents (methotrexate, azathioprine, cyclophosphamide, chlorambucil, or cyclosporine) may be an effective means of inducing or maintaining a remission.**The most recent therapeutic manuever for immunosuppressive-resistant dermatomyositis is the use of intravenous immunoglobulin. Dalakas et all2demonstrated that the myopathy as well as the cutaneous disease improved. Therapy of cutaneous disease in patients with dermatomyositis is often difficult because even though the myositis may respond to treatment with corticosteroids or immunosuppressives, the cutaneous lesions often persist. Although cutaneous disease may be of minor importance in patients with serious fulminant myositis, in many patients cutaneous disease becomes the most important aspect of their disorder. Most patients with cutaneous lesions are photosensitive; thus, as in patients with LE, the daily use of a sunscreen with an SPF of at least 15 is recommended. Some may require a broader-spectrum sunscreen. Hydroxy-
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chloroquine in dosages of 200 to 400 mg/d is effective in approximately 80% of patients treated, as a means of partially controlling their cutaneous disease and allowing a decrease in the corticosteroid dosage.38The use of low-dose methotrexate has been effective in many of the author’s patients.*l The prognosis of dermatomyositis and polymyositis varies greatly, depending on the series of patients studied. Factors that affect the prognosis include the patient’s age, the type and severity of myositis, the presence of dysphagia, the presence of an associated malignancy, and the response to corticosteroid therapy. That therapy alters prognosis seems to be well established by retrospective reports on the benefits of corticosteroids and immunosuppressives.
SCLERODERMA
Scleroderma is a term used to describe a specific clinical disease spectrum represented by cutaneous or multisystem involvement (or both). In addition, several disorders are associated with sclerodermoid changes (Table 5). Scleroderma is a disorder of unknown cause and
Table 5. SCLERODERMA AND SOME SCLERODERMOID CONDITIONS Localized scleroderma Morphea (dermal, subcutaneous, and pansclerotic variants) Linear scleroderma Generalized morphea Systemic sclerosis (scleroderma) Limited (acrosclerosis, CREST variant) Diffuse Overlap with another collagen vascular disease (LE or DM) Mixed connective tissue disease Idiopathic syndromes possibly related to scleroderma Eosinophilic fasciitis Eosinophilia myalgia syndrome Mucinoses Scleredema Scleromyxedema (lichen myxedematosus or papular mucinosis) Chemical or drug-induced sclerosis Polyvinyl chloride Silicone (breast implants, injectable)/? collagen injections Bleomycin Spanish rapeseed oil Metabolic Porphyria cutanea tarda Carcinoid syndrome Immunologic Chronic graft-versus-host disease Vibratory injury ~
~_______
LE = Lupus erythematosus; DM, = dermatomyositis.
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pathogenesis. There are two major categories: localized scleroderma and systemic sclerosis. Localized Scleroderma
Localized scleroderma refers to primary involvement of the skin, with minimal, if any, systemic features."j Only rarely have patients with localized scleroderma developed systemic sclerosis. Three major types of localized scleroderma exist: morphea, generalized morphea, and linear scleroderma. Morphea is represented by indurated dermal or subcutaneous plaques (Fig. 11).The disease is most common in young women. Morphea sometimes overlaps or coexists with another cutaneous condition known as lichen sclerosus et atrophicus. In contrast, a small number of patients develop numerous and larger lesions that coalesce (Fig. 12). These individuals are said to have generalized morphea. Patients with morphea usually have a benign course, characterized by softening of lesions with time. An observation that administration of high-dose UVA1 phototherapy is effective in treating lesions32has been followed by the observation that this therapy induces the production of interstitial collagenase by fibroblasts in the lesions of morphea.18Another potential therapy that has been studied in a open trial is the administration of oral 1,25-hydroxyvitamin D3.I9 Linear scleroderma is most often a single sclerotic linear lesion. This variant is also more common in young women. The disease frequently occurs on the extremities or the forehead (Fig. 13).When on the forehead, the term e n coup de sabre has been applied. When the disease crosses a joint, limitation of motion is possible as well as decreased growth. In addition, facial disfigurement can occur. Linear scleroderma also appears to soften over time, but treatment with physical therapy to reduce the likelihood of permanent contracture is indicated.
Figure 11. Morphea. A single plaque of indurated skin on the back of this adolescent.
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Figure 12. Generalized rnorphea. Coalescent plaques of induration on the trunk. (Courtesy of Dr. Kenneth E. Greer, Charlottesville, VA.)
Raynaud’s Phenomenon and Raynaud’s Disease Raynaud’s phenomenon is a triphasic color reaction induced by cold or emotional distress and involves the digits.6The initial pallor is followed by cyanosis, then a reactive hyperemia. In addition to the
Figure 13. En coup de sabre-linear
scleroderrna involving the facial skin.
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Figure 14. Pitting of the fingertips is the result of ischemia from severe Raynaud’s phenomenon.
color changes, either numbness or pain may occur. Rewarming not only relieves the color changes, but also relieves the symptoms. As the disorder progresses, repeated ischemic episodes can result in small pitted areas on the distal digits (Fig. 14), ulcerations, or gangrene. The process is termed Xaynaud’s disease when there is no identifiable cause. There are frequent reports, however, of patients with long-standing Raynaud’s disease who later develop SLE or systemic sclerosis. The diseases that need to be considered in a patient with Raynaud’s phenomenon are listed in Table 6. Management of Raynaud’s phenomenon is directed at prevention, removal of exacerbating factors, and vasodilation. Patients may wear gloves and avoid situations that are known to precipitate an episode, such as cold exposure. The use of tobacco (smoking or chewing) should be stopped. Drugs that cause vasoconstriction should be avoided. Drugs that allow for vasodilation are often helpful in reducing the severity or
Table 6. CONDITIONS ASSOCIATED WITH RAYNAUD’S PHENOMENON Collagen Vascular Diseases Scleroderma Lupus erythematosus Rheumatoid arthritis Dermatomyositis Vasculitis (polyarteritis nodosa) Mixed connective tissue disease Hematologic disorders Cryoglobulinemia (particularly type I) Cryofibrinogenemia Cold agglutinin Macroglobulinemia Hyperglobulinemic purpura Polycythemia Thrombocythemia
Arterial disease Thromboangiitis obliterans Atherosclerosis Embolic disease Drugs Ergots p-blockers Bleomycin Caffeine Nicotine Neurovascular compression Thoracic outlet syndrome Carpal tunnel syndrome Vibratory injury Malignancy
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number of episodes that the patient may have. Agents such as topical nitroglycerin, calcium channel blockers (nifedipine, diltiazem), and prostacyclin analogues (iloprost) have been demonstrated to be useful in many patients. Systemic Sclerosis (Progressive Systemic Sclerosis)
Systemic sclerosis is characterized by both cutaneous and internal organ fibrosis. Almost all patients have Raynaud’s phenomenon, which is a common presenting manifestation. Systemic sclerosis is much more frequent in women. The pathogenesis of systemic sclerosis is not known, but theories involve a dysregulation of collagen synthesis, endothelial cell injury, and abnormal immunity. Patients with systemic sclerosis may be subclassified as having diffuse disease or limited disease. In the limited form, the primary involvement is on acral skin (hands, forearms, legs, and face), whereas in the diffuse form there is extensive sclerosis of the proximal portions of the extremities as well as the truncal skin. In general, the prognosis is poorer in patients with diffuse disease. Sclerodactyly is a hallmark of the disease in both forms. In addition, abnormal pigmentation is a common finding. Telangiectasia and nail fold capillary abnormalities are also common. The term CREST syndrome has been developed to denote a subset of patients with systemic sclerosis and refers to calcinosis, Xaynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia. These patients tend to possess anticentromere antibodies and often have a slowly progressive course.31Pulmonary hypertension also is more common in this group of patients. Systemic disease is a common feature of systemic sclerosis. Pulmonary function is frequently decreased. Esophageal dysmotility and gastrointestinal dysmotility are common. Renal dysfunction is uncommon, but when present it can result in a life-threatening situation. Patients with diffuse disease frequently possess antitopoisomerase I antibodies. There is no cure for scleroderma; therefore treatment is directed at symptomatic relief.26Therapy for Raynaud’s phenomenon was discussed earlier. Prevention of aspiration pneumonitis in patients with esophageal disease is indicated. The use of D-penicillamine is often considered, but the results of long-term studies are controversial. Eosinophilic Fasciitis and Eosinophilia Myalgia Syndrome
Eosinophilic fasciitis is characterized by the sudden onset of progressive induration of the skin. Patients often report that the disease followed an unusual amount of exertion. The patients do not have Raynaud’s phenomenon, sclerodactyly or autoantibodies, but frequently have hyperglobulinemia and eosinophilia. Histologically, they have a
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fasciitis. Patients may respond to therapy with prednisone or methotrexate. A syndrome characterized by eosinophilia, myalgia, cutaneous sclerosis, neuropathy, and pulmonary dysfunction developed in patients taking contaminated L-tryptophan. Some of the features closely mimic eosinophilic fasciitis, but the patients often fail to respond to therapy and may experience progressive debilitation or even death.34 References 1. Bohan A, Peter JB: Polymyositis and dermatomyositis. N Engl J Med 292344-347,1975 2. Bohan A, Peter JB, Bowman RL, et a1 A computer-assisted analysis of 153 patients with polymyositis and dermatomyositis. Medicine 56955, 1977 3. Callen JP: Management of antimalarial-refractory cutaneous lupus erythematosus. LUPUS 6203-208, 1997 4. Callen JP: Chronic cutaneous LE. Arch Dermatol 118:412416, 1982 5. Callen JP, Tuffanelli DL, Provost TT: Collagen-vascular disease: An update. J Am Acad Dermatol 28:477-484, 1993 6. Campbell PM, Leroy EC: Raynaud phenomenon. Semin Arthritis Rheum 16:92-103, 1986 7. Campellone JV, Lacomis D, Giulani MJ, et a1 Percutaneous needle muscle biopsy in the evaluation of patients with suspected inflammatory myopathy. Arthritis Rheum 40~1886-1891,1997 8. Cherin P, Piette JC, Herson S, et a1 Dermatomyositis and ovarian cancer: A report of 7 cases and literature review. J Rheumatol201897-1899, 1993 9. Chow W-H, Gridley G, Mellemkjaer L, et a1 Cancer risk following polymyositis and dermatomyositis: A nationwide cohort study in Denmark. Cancer Causes Control 6:9-13, 1995 10. Crowson AN, Magro CM: Subacute cutaneous lupus erythematosus arising in the setting of calcium channel blocker therapy. Hum Pathol 28:67-73, 1997 11. Cukier J, Beauchamp RA, Spindler JS, et a1 Association between bovine collagen implants and a dermatomyositis or polymyositis-like syndrome. Ann Intern Med 118920-928, 1993 12. Dalakas MC, Illa I, Dambrosia JM, et a1 A controlled trial of high-dose intravenous immune globulin infusions as a treatment for dermatomyositis. N Engl J Med 329:19932000, 1993 13. David-Bajar KM: Subacute cutaneous lupus erythematosus. J Invest Dermatol 1OO:ZS8S, 1993 14. Euwer RL, Sontheimer R D Amyopathic dermatomyositis (dermatomyositis sine myositis). J Am Acad Dermatol 24:959-966, 1991 15. Fabr6 VC, Lear S, Reichlin M, et a1 Twenty percent of biopsy specimens from sunexposed skin of normal young adults demonstrate positive immunofluorescence. Arch Dermatol 1271006-1011, 1991 16. Falanga V Localized scleroderma. Med Clin North Am 731143-1156, 1989 17. Gilliam JN, Sontheimer R D Distinctive cutaneous subsets in the spectrum of lupus erythematosus. J Am Acad Dermatol4471475, 1981 18. Gruss C, Reed JA, Altmeyer P, et al: Induction of interstitial collagenase (MMP-1) by UVA-1 phototherapy in morphea fibroblasts. Lancet 3501295-1296, 1997 19. Humbert P, Delaporte E, Dupond JL, et a1 Treatment of localized scleroderma with oral 1,25-dihydroxyvitamin D3. Eur J Dermatol 421-23, 1994 20. Kasteler JS, Callen JP: Scalp involvement in dermatomyositis: Often overlooked or misdiagnosed. JAMA 2721939-1941, 1994 21. Kasteler JS, Callen JP: Low-dose methotrexate administered weekly is an effective corticosteroid-sparing agent for the treatment of the cutaneous manifestations of dermatomyositis. J Am Acad Dermatol 36:67-71, 1997
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22. Krnic-Barrie S, O’Connor CR, Looney SW, et al: A retrospective review of 61 patients with antiphospholipid syndrome. Arch Intern Med 1572102-2108, 1997 23. Lee LA, David KM: Cutaneous lupus erythematosus. Curr Probl Dermatol 1:161-200, 1989 24. Lehmann P, Holzle E, Kind P, et al: Experimental reproduction of skin lesions in lupus erythematosus by UVA and UVB radiation. J Am Acad Dermatol 22181-187, 1990 25. Petri M: Antiphospholipid antibodies: Lupus anticoagulant and anticardiolipin antibody. Curr Probl Dermatol4:171-201, 1992 26. Siebold JR, Furst DE, Clements PJ: Why everything (or nothing) seems to work in the treatment of scleroderma. J Rheumatol 19:673-676, 1992 27. Siguregeirsson 8, Lindelof 8, Edhag 0, et al: Risk of cancer in patients with dermatomyositis or polymyositis. N Engl J Med 326:363-367, 1992 28. Sinoway P, Callen JP: Chlorambucil: An effective corticosteroid sparing agent for patients with recalcitrant dermatomyositis. Arthritis Rheum 36:319-324, 1993 29. Sontheimer RD, McCauliffe DP, Zappi E, et al: Antinuclear antibodies: Clinical correlations and biologic significance. Adv Dermatol 73-53, 1991 30. Spann CR, Callen JP, Klein JB, et al: Clinical, serologic and immunogenetic studies in patients with chronic cutaneous (discoid) lupus erythematosus who have verrucous and/or hypertrophic skin lesions. J Rheumatol 15:256-261, 1988 31. Steen VD, Ziegler GL, Rodnan GP, et al: Clinical and laboratory associations of anticentromere antibody in patients with progressive systemic sclerosis. Arthritis Rheum 27125-131, 1984 32. Stege H, Berneburg M, Humke S, et al: High-dose UVA-1 radiation therapy for localized scleroderma. J Am Acad Dermatol 36:938-944, 1997 33. Stonecipher MR, Jorizzo JL, White WL, et al: Cutaneous changes of dermatomyositis in patients with normal muscle enzymes: Dermatomyositis sine myositis? J Am Acad Dermatol28:951-956, 1993 34. Swygert LA, Back EE, Auerbach SE, et al: Eosinophilia-myalgia syndrome: Mortality data from the US national surveillance system. J Rheumatol 20:1711-1717, 1993 35. Tan EM, Cohen AS, Fries JF, et al: The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271-1277, 1982 36. Targoff IN: Dermatomyositis and polymyositis. Curr Probl Dermatol 3:131-180, 1991 37. Whitmore SE, Anhalt GJ, Provost TT, et al: Serum CA-125 screening for ovarian cancer in patients with dermatomyositis. Gynecol Oncol 65241-244, 1997 38. Woo TY, Callen JP, Voorhees JV, et al: Cutaneous lesions of dermatomyositis are improved by hydroxychloroquine. J Am Acad Dermatol 10592-600, 1984
Address reprint requests to Jeffrey P. Callen, MD Department of Medicine Division of Dermatology University of Louisville 310 East Broadway Louisville, KY 40202 e-mail: jefca8aol.com