Acute cutaneous lupus erythematosus=الذئبة الحمامية الجلدية الحادة |
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Acute cutaneous lupus erythematosus
Lupus erythematosus is a heterogeneous connective-tissue disease associated with polyclonal B-cell activation and is believed to result from the interplay of genetic, environmental, and hormonal factors. The spectrum of disease involvement can vary from limited cutaneous involvement to devastating systemic disease.
From a dermatologic standpoint, the type of skin involvement can prove to be a good barometer of the pattern of underlying systemic activity. Lupus erythematosus–specific skin diseases are recognized in 3 categories, including (1) acute cutaneous lupus erythematosus (ACLE), (2) subacute cutaneous lupus erythematosus (SCLE), and (3) chronic cutaneous lupus erythematosus (CCLE). Clinical characteristics of each group are unique, although histopathologically, only subtle differences are identified. The focus of this article is acute cutaneous lupus erythematosus.
Acute cutaneous lupus erythematosus refers to a typical malar eruption in a butterfly pattern localized to the central portion of the face and/or a more generalized maculopapular eruption representing a photosensitive dermatitis. Acute cutaneous lupus erythematosus has a strong association with the systemic disease for which patients present to rheumatologists and internists.
Pathophysiology
The etiology of lupus erythematosus is believed to be multifactorial, involving genetic, environmental, and hormonal factors. An association with human leukocyte antigen DR2 and human leukocyte antigen DR3 has been identified. Concordance in monozygotic twins and familial associations support a genetic basis in acute cutaneous lupus erythematosus.
More than 25 genes have been identified as contributing to the mechanisms that predispose patients to lupus. They include alleles in the major histocompatibility complex region (multiple genes): IRF5, ITGAM, STAT4, BLK, BANK1, PDCD1, PTPN22, TNFSF4, TNFA1P3, SPP1, some fc gene receptors, and deficiency in several complement components, including C1qC4+C2. In patients who are predisposed genetically, exposure to natural ultraviolet radiation is a frequent precipitating factor for lupus erythematosus.1,2
Certain viruses (eg, Epstein-Barr virus, cytomegalovirus, HIV) have been implicated in precipitating or exacerbating lupus erythematosus.
Chemicals such as L-canavanine, which is present in alfalfa sprouts, have been known to induce systemic lupus erythematosus (SLE)–like illness. Drugs implicated in inducing a lupus erythematosus–like illness (eg, procainamide, isoniazid, hydralazine) are uncommonly associated with cutaneous manifestations.
Immunopathology
Data concerning direct immunofluorescence in acute cutaneous lupus erythematosus are sparse. In one study, the results of 5 (100%) of 5 skin biopsy specimens were reported as positive for the lupus band test. The lupus band test refers to the presence of immunoglobulins and C3 complement components along the dermoepidermal junction. All 3 immunoglobulin classes (immunoglobulin G [IgG], immunoglobulin M [IgM], immunoglobulin A [IgA]) and a variety of complement components have been identified at the dermoepidermal junction. Research has shown that 60% of patients with a malar eruption of lupus erythematosus have positive lupus band test results. In nonlesional skin, positive lupus band test results correlate strongly with an aggressive course of systemic disease.3
History
The most common presentation of acute cutaneous lupus erythematosus is a red macular eruption involving the malar area. The forehead, periorbital area, and neck also may be involved, representing a photodistribution. Occasionally, unilateral involvement may occur, as shown below
Less commonly, acute cutaneous lupus erythematosus presents as a generalized photosensitive eruption, while more rarely, patients present with widespread blistering simulating toxic epidermal necrolysis (TEN). TEN is believed to be a phototoxic reaction
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Acute cutaneous lupus erythematosus can be transient, lasting for several days to weeks. Lesions wax and wane with sun exposure over a period of several hours; however, some patients experience prolonged disease activity. Resolution of lesions may result in postinflammatory hyperpigmentation, especially in patients with darkly pigmented skin. Usually, the lesions are nonscarring.
Patients with acute cutaneous lupus erythematosus frequently experience superficial ulceration of the oral and nasal mucosae. These lesions may produce extreme discomfort in some patients, although the lesions may be entirely painless in others. The posterior surface of the hard palate is the site affected most frequently; however, the gingival, buccal, and lingual mucosae also may be involved.
Note that acute cutaneous lupus erythematosus may coexist with other lupus erythematosus–specific skin diseases. Localized acute cutaneous lupus erythematosus lesions have been observed in 20% of subacute cutaneous lupus erythematosus patients; however, occurrence of acute cutaneous lupus erythematosus with chronic cutaneous lupus erythematosus is unusual.
Physical
- Primary lesions include the following:
- Confluent erythema and edema
- Erythematous macules and papules that eventually become confluent
- Bullous lesions resembling TEN
- Morbilliform macules and papules in a generalized photo-distributed pattern
- Distribution of lesions
- Malar eminence (representing the wings of the butterfly) and the nasal bridge (representing the body of the butterfly) typically are involved. Other sites of involvement include the forehead, periorbital area, and sides of the neck. Occasionally, a generalized photo-induced eruption may occur.
- Associated findings include superficial ulceration primarily involving the posterior surface of the hard palate. Occasionally, buccal and gingival mucosae and the tongue may be involved.
Causes
In patients who are disposed genetically to developing systemic lupus erythematosus, the disease can be triggered by viruses (eg, EBV) and exposure to ultraviolet light. Medications typically do not induce acute cutaneous lupus erythematosus in patients with drug-induced lupus erythematosus
Laboratory Studies
- Since acute cutaneous lupus erythematosus (ACLE) and systemic lupus erythematosus (SLE) are associated closely, it is safe to assume that the laboratory findings in systemic lupus erythematosus closely mirror the findings in acute cutaneous lupus erythematosus.
- Antinuclear antibody (ANA) assay: ANA results invariably are positive in patients with systemic lupus erythematosus and, therefore, in patients with acute cutaneous lupus erythematosus. The peripheral rim pattern is associated most strongly with lupus erythematosus, although other patterns commonly are present. ANA results are less likely to be positive in dermatomyositis, which mimics lupus erythematosus both clinically and histologically.
- Anti–double-stranded DNA antibody (anti-dsDNA) assay: Anti-dsDNA is specific for systemic lupus erythematosus and is present in 60-80% of patients with acute cutaneous lupus erythematosus, often in high titers.
- Complement: Complement levels usually are depressed in patients with acute cutaneous lupus erythematosus.
- Anti-Sm antibody assay: Anti-Sm antibody has a strong specificity for systemic lupus erythematosus; therefore, perform this assay to exclude underlying systemic involvement. This is particularly relevant in patients in whom anti-dsDNA results are negative.
- Low-specificity tests
- U1 ribonucleoprotein antibody assay: Results are positive in mixed connective-tissue disease, which sometimes manifests as a malar eruption.
- CBC count: Anemia, leukopenia, and/or thrombocytopenia may be seen in patients with acute cutaneous lupus erythematosus who have systemic involvement.
- Erythrocyte sedimentation rate: Although a nonspecific marker, marked elevations in levels indicate possible systemic involvement.
- Urinalysis: Proteinuria, hematuria, and urine casts are indicative of underlying nephritis.
- Creatinine and BUN levels: Elevation indicates renal compromise.
Procedures
- Skin biopsy: Diagnosis is supported by histopathologic examination of the skin. Further substantiation is obtained by performing immunofluorescence examination of skin lesions.
Histologic Findings
The most striking change in acute cutaneous lupus erythematosus is the presence of edema involving upper dermis and focal liquefactive degeneration of the basal cell layer. Cellular dermal infiltrate is sparse and consists of lymphocytes. In extreme cases, dissolution of the basal layer occurs secondary to extensive vacuolization, forming a subepidermal bulla
Medical Care
- Systemic corticosteroids (prednisone 0.5-1 mg/kg/d) usually are the mainstay of therapy for systemic disease. Skin changes tend to respond in tandem with the systemic response to treatment. A rheumatologist usually undertakes systemic treatment. When administering systemic corticosteroids, address adverse effects such as diabetes mellitus, hypertension, osteonecrosis, the stigmata of Cushing syndrome, and the risk of osteoporosis.
- Perform a baseline bone densitometry scan, and if normal, repeat the scan at 6 months.
- Ideally, perform 24-hour urine collection to check calcium levels, since steroids enhance renal excretion of calcium, thereby increasing the patient's susceptibility to developing renal stones. If the results are normal, administer cholecalciferol (400-800 IU/d) and calcium (1500 mg/d).
- If evidence of hypercalciuria is present, administer thiazide diuretics until levels return to normal.
- If osteoporosis is present, refer the patient to an osteoporosis specialist for consideration of treatment with bisphosphonates.
- Additional immunosuppressive agents, such as azathioprine (0.5-3 mg/kg/d), cyclophosphamide (1-5 mg/kg/d, typically 50-200 mg/d), and thalidomide (100-200 mg/d), are used as adjuvant therapy to treat systemic disease because of steroid-sparing effects.
- Hydroxychloroquine also has been shown to have steroid-sparing effects and is administered as first-line therapy to most patients with systemic disease. The effects of hydroxychloroquine on skin lesions are especially beneficial.
- Intravenous IgG (IVIG; 0.5-1 g/kg/d for 4 d) has become important in controlling recalcitrant disease.5
- Mycophenolate mofetil has shown poor results in disease refractory to multiple treatment modalities.6
- One case reports describes the effectiveness of plasmapheresis for refractory toxic epidermal necrolysis (TEN)–like acute cutaneous lupus erythematosus.7
Consultations
- Refer patients with clinical and serologic evidence of lupus erythematosus to a rheumatologist for further treatment.
- Refer patients with red blood cell casts, significant proteinuria (>0.5 g/mL/24h), and a diastolic blood pressure of more than 90 mm Hg to a nephrologist.
Diet
Dietary restrictions may be necessary in the presence of renal compromise.
Activity
Advise patients to avoid activities involving excessive exposure to the sun.
Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Belimumab is investigational. It is a neutralizing B-lymphocyte stimulator monoclonal antibody that inhibits the biologic activity of the soluble form of essential B cells. Belimumab is currently undergoing phase III clinical trials for the potential treatment of systemic lupus erythematosus (SLE). Doses used in the phase II trials were randomized to 1, 4, or 10 mg/kg intravenously on days 1, 14, and 28, and then every 28 days for 76 weeks. The treatment significantly improved the SLE disease activity index (SLEDAI) scores in seropositive patients (ANA ≥1:80 or anti-dsDNA >30 IU) and physicians global assessment score.8
Epratuzumab is investigational. It is a humanized anti-CD22 monoclonal antibody that partially depletes B cells. Treatment is shown to decrease disease activity but not autoantibody levels in patients with moderately active systemic lupus erythematosus. In an open-label, single-case study of 14 patients with systemic lupus erythematosus, patients received intravenous epratuzumab at 360 mg/m2 every 2 weeks for 4 doses, with analgesic/antihistamine premedication prior to each dose. Total British Isle Lupus Assessment Group (BILAG) scores were decreased by greater than or equal to 50% in all 14 patients at 6 weeks.
Corticosteroids
Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
Prednisone (Sterapred)
Glucocorticoid (adrenocortical steroid) absorbed easily into GI tract. Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production.
Adult
0.5-1 mg/kg/d PO prn for short periods
Pediatric
Administer as in adults
Ketoconazole, erythromycin, clarithromycin, estrogens, birth control pills increase levels; aminoglutethimide, phenytoin, phenobarbital, rifampin, cholestyramine, and ephedrine decrease levels Levels of potassium-depleting diuretics (potentiates potassium loss and digitalis toxicity) and cyclosporine may increase; levels of isoniazid, insulin (resistance is induced), and salicylates may decrease Monitor anticoagulant therapy and theophylline levels
Absolute: Systemic fungal infection; herpes simplex keratitis; hypersensitivity (usually with corticotropin, occasionally with IV preparations) Relative: Hypertension; active TB ; congestive heart failure; prior psychosis; positive IPPD test result; glaucoma; severe depression; diabetes mellitus; active peptic ulcer disease; cataracts; osteoporosis; recent bowel anastomosis; pregnancy.
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur. Use lower dose in hypothyroidism, liver disease, and obesity (conditions decrease cortisol-binding globulin and increase free fraction of steroid); pregnancy, hyperthyroidism, and concurrent estrogen therapy may increase cortisol-binding globulin level
Immunosuppressives
Used for immunosuppression and, ultimately, for disease control.
Azathioprine (Imuran)
Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity. For dermatomyositis/polymyositis, respiratory and muscular symptoms respond but skin lesion response has not been consistent. Slow acting with therapeutic effect not seen for 6-8 wk. Metabolites accumulate slowly, and maximal immunosuppression not reached until 8-12 wk. Available as 25-, 50-, 75-, and 100-mg tab or 100-mg vial.
Adult
1 mg/kg/d qd or bid (empiric) or by TPMT level (see Precautions); increase dose by 0.5 mg/kg/d after 6-8 wk prn; increase q4wk, not to exceed 2 mg/kg/d for most dermatologic purposes
Pediatric
Initial: 2-5 mg/kg/d PO/IV Maintenance: 1-2 mg/kg/d PO/IV
Allopurinol increases risk of pancytopenia; captopril/ACE inhibitors may increase risk of anemia and leukopenia; increased dose of warfarin may be necessary; may need increased dose of pancuronium for adequate paralysis; live-virus vaccines, co-trimoxazole (increased risk of hematologic toxicity); rifampicin (transplants possibly rejected); clozapine (increased risk of agranulocytosis)
Absolute: Documented hypersensitivity, pregnancy or attempting pregnancy, and clinically significant active infection Relative: Concurrent use of allopurinol; prior treatment with alkylating agents (cyclophosphamide, chlorambucil, melphalan, others) (high risk of neoplasia) Pediatric: Safety and efficacy in not established
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
TPMT testing not entirely reliable; it involves testing TPMT activity in RBCs, which correlates with systemic TPMT activity; functional enzyme test shown to have variability between test sites, and kits may contain varying amounts of enzyme inhibitor; starting at low doses, monitoring for pancytopenia, and then increasing dose is alternative; if clinical response is not good, patient may be a homozygote for high activity and may need an increased dose Possible increased risk of lymphoproliferative disorders with long-term therapy; increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur Dosing by TPMT TPMT <5 U: No treatment with azathioprine TPMT 5-13.7 U: Up to 0.5 mg/kg/d TPMT 13.7- 19 U: Up to 1.5 mg/kg/d TPMT >19 U: Up to 2.5 mg/kg/d
Cyclophosphamide (Cytoxan, Neosar)
Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.
Adult
500-750 mg/m2 IV qmo
Pediatric
Administer as in adults
Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
Documented hypersensitivity; severely depressed bone marrow function
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis
Thalidomide (Thalomid)
Immunomodulatory agent that may suppress excessive production of tumor necrosis factor-alpha and may down-regulate selected cell-surface adhesion molecules involved in leukocyte migration. In patients <50 kg (110 lb), start at low end of dose regimen.
Adult
100-300 mg/d PO qd with water, preferably hs and at least 1 h pc
Pediatric
Not established
May increase sedation of alcohol, barbiturates, chlorpromazine, and reserpine; women must use 2 additional methods of contraception or abstain from intercourse because of teratogenic effects
Documented hypersensitivity
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Perform pregnancy test within 24-h period prior to initiating therapy (weekly during first month, followed by monthly tests in women with regular menstrual cycles or q2wk with irregular menstrual cycles); bradycardia may occur; use protective measures (eg, sunscreens, protective clothing) against exposure to sunlight or UV light (eg, tanning beds); prescribing physician must register with STEPS provider registry established by manufacturer
Hydroxychloroquine (Plaquenil)
Inhibits chemotaxis of eosinophils, locomotion of neutrophils, and impairs complement-dependent antigen-antibody reactions. Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate.
Adult
310 mg PO qd or bid for several wk depending on response; 155-310 mg/d for prolonged maintenance therapy
Pediatric
3-5 mg base/kg/d PO qd or divided bid; not to exceed 7 mg/kg/d
Serum levels increase with cimetidine; magnesium trisilicate may decrease absorption; may increase digoxin levels; do not give with chloroquine due to increased retinal toxicity
Absolute: Hypersensitivity, retinopathy from any cause Relative: Pregnancy/lactation; retinal/visual-field change; severe blood dyscrasias; psoriasis; G-6-PD deficiency; significant hepatic dysfunction; myasthenia gravis; significant neurologic disease; long-term therapy in children
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; not recommended for long-term use in children; perform periodic (6 mo) ophthalmologic examinations; test periodically for muscle weakness
Immune globulin IV (Sandoglobulin, Gammagard, Gamimune, Gammar-P)
Neutralize circulating myelin antibodies through anti-idiotypic antibodies; down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; promotes remyelination; may increase CSF IgG (10%).
Adult
2g/kg IV over 10-12 h Gammagard S/D: 1 g/kg as single dose or 400 mg/kg for 4 consecutive days beginning within 7 d of fever onset; administration concomitantly with appropriate aspirin therapy (80-100 mg/kg/d divided qid) recommended
Pediatric
Not established
Antibodies in globulin preparation may interfere with response to live viral vaccines (eg, MMR); defer using live viral vaccines until approximately 11 mo after immunoglobulin administration; no known drug interactions
No absolute contraindication other than documented hypersensitivity; patients who are IgA deficient should receive IVIG preparations with no IgA; anti-IgE/IgG antibodies, severe thrombocytopenia, or coagulation disorders Gammagard S/D contains only trace amounts of IgA and is not indicated in patients with selective IgA deficiency in whom the IgA deficiency is the only abnormality of concern and it should be given with caution to patients with antibodies to IgA or IgA deficiencies that are a component of an underlying primary immunodeficiency disease for which IVIG therapy is indicated; in such instances, a risk of anaphylaxis may exist despite the fact that Gammagard S/D contains only trace amounts of IgA
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Check serum IgA level before IVIG (use an IgA-depleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-30 d postinfusion); increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease; laboratory result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia
Monoclonal Antibody
Rituximab (Rituxan)
Murine/human chimeric anti-CD20 monoclonal antibody. CD20 is expressed early in pre-B cell development. Binding induces complement-dependent B-cell cytotoxicity along with antibody-dependent cellular toxicity.
Adult
375 mg/m2 qwk for 4 wk (usual dose); no standardized regimen established; early open-label phase I/II study showed varying doses, from 1 infusion of 100 mg/m2 to 4 weekly infusions of 375 mg/m2, without cyclophosphamide bolus or glucocorticoid treatment, significantly reduced Systemic Lupus Activity Measure score over 1 y in 65% of patients
Pediatric
Not established
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