eMedicine Specialties > Dermatology > Bullous Diseases
Pemphigus, Paraneoplastic: Treatment & Medication
Updated: Nov 6, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
Treatment
Medical Care
Response to treatment paraneoplastic pemphigus is generally poor, especially for mucosal lesions. Initial care is aimed at treating superinfection, if present. Warm compresses, nonadherent wound dressings, and topical antibiotic ointment are helpful. Potent immunosuppressive agents are required to decrease blistering, but they are often ineffective. High-dose corticosteroids are first-line therapy for paraneoplastic pemphigus,9 followed by steroid-sparing agents such as azathioprine, cyclosporine, and mycophenolate mofetil. In general, the skin lesions of paraneoplastic pemphigus are more responsive to therapy than mucosal lesions.
Other therapeutic options for paraneoplastic pemphigus include plasmapheresis, immunophoresis, intravenous gammaglobulin,31 and stem cell ablation therapy with high-dose cyclophosphamide8 without stem cell rescue. Rituximab has been tried in several patients with mixed results.32,33 A review described the use of rituximab in paraneoplastic pemphigus. Treating the underlying malignancy may control autoantibody production, and intravenous gammaglobulin (IVIG) at the time of surgery may help prevent the development of bronchiolitis obliterans.
Surgical Care
For solid neoplasms, curative resection should be attempted when appropriate, but this does not halt disease progression. If surgery results in decreased autoantibody production, the paraneoplastic pemphigus may improve. IVIG before, during, and after the surgery may block autoantibody released from the tumor.
Consultations
Respiratory therapy may be beneficial when pulmonary involvement from paraneoplastic pemphigus causes respiratory insufficiency. Consultations from a pulmonary medicine specialist, an ophthalmologist, a gastroenterologist, and an otolaryngologist should be obtained when appropriate.
Medication
The medications used to treat paraneoplastic pemphigus are potent immunosuppressive agents with numerous adverse effects. All patients taking these medications require periodic monitoring of laboratory values.
Immunosuppressives
These agents diminish the production of autoantibodies and decrease resultant blistering and erosions.
Prednisone (Deltasone, Orasone, Sterapred)
Affects all organ systems. On a cellular level, affects cell activation, replication, differentiation, and mobility. Net result is inhibition of immediate and delayed hypersensitivity. Suppression of antibody production requires higher doses than suppression of monocyte function.
Adult
1-2 mg/kg/d PO; alternatively, 0.5-2 mg/kg/d PO; taper as condition improves; single morning dose is safer for long-term use, but divided doses have more anti-inflammatory effect
Pediatric
4-5 mg/m2/d PO; alternatively, 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk as symptoms resolve
Ketoconazole, erythromycin, clarithromycin, estrogens, and birth control pills may increase levels; aminoglutethimide, phenytoin, phenobarbital, rifampin, cholestyramine, and ephedrine may decrease levels
Levels of potassium-depleting diuretics (potentiate potassium loss and digitalis toxicity) and cyclosporine may increase; isoniazid, insulin (resistance is induced), and salicylate levels may decrease
Monitor anticoagulant therapy and theophylline levels
Absolute: Systemic fungal infection; herpes simplex keratitis; hypersensitivity (usually with corticotropin; occasionally with intravenous preparations)
Relative: hypertension; active tuberculosis, CHF; prior psychosis; positive intermediate purified protein derivative 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
Use lower dose in hypothyroidism, liver disease, and obesity (cortisol-binding globulin levels decreased, and free fraction of steroid increased); pregnancy, hyperthyroidism, and concurrent estrogen therapy may increase cortisol-binding globulin levels
Patients requiring long-term glucocorticoid use should have measurements of baseline weight and blood pressure, placement of a purified protein derivative test, ocular examination, and, when appropriate, stool ova and parasite examination for Strongyloides organisms; consider measurements of bone density for patients at risk for osteoporosis; patients receiving glucocorticoids for long periods may require acutely increased dosages during periods of major stress; abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use
Azathioprine (Imuran)
Often used in conjunction with prednisone for dermatologic purposes as a steroid-sparing agent. Purine analog with cytotoxic properties. Prodrug metabolized to 6-mercaptopurine. Inhibits RNA and DNA synthesis.
Adult
1-3 mg/kg/d PO; clinical efficacy takes several wk; alternatively, 1 mg/kg/d PO for 6-8 wk; increase by 0.5 mg/kg q4wk until response or dose reaches 2.5 mg/kg/d
May be best to base dose on TPMT level.
Pediatric
Initial dose: 2-5 mg/kg/d PO/IV
Maintenance dose: 1-2 mg/kg/d PO/IV
Allopurinol increases risk of pancytopenia; captopril/ACE inhibitors may increase risk of anemia and leukopenia; increase in warfarin dose may be necessary; increased dose of pancuronium may be needed 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; clinically significant active infection
Relative: Concurrent use of allopurinol; prior treatment with alkylating agents (eg, cyclophosphamide, chlorambucil, melphalan) because of high risk of neoplasia; pediatric patients (safety and efficacy in pediatric population not established)
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Previous treatment with alkylating agents as part of chemotherapeutic regimen increases risk of secondary malignancy; low levels of TPMT, which metabolizes azathioprine, increase risk for toxicity; initial baseline and weekly blood cell counts and kidney and liver function tests required; rarely causes a hypersensitivity syndrome, which manifests as fever, malaise, constitutional symptoms, and hepatitis; patients receiving azathioprine are susceptible to infection even with normal WBC counts
Cyclosporine (Sandimmune, Neoral)
Demonstrated to be helpful in a variety of skin disorders. Potent immunosuppressive agent most often used in organ transplantation. Diminishes production of autoantibodies and decreases resultant blistering and erosions. Acts by inhibiting T lymphocytes and lymphokine production.
Adult
1-4 mg/kg/d IV divided bid; alternatively, 2-5 mg/kg/d PO in divided doses
Pediatric
Administer as in adults
Erythromycin, clarithromycin, azithromycin, norfloxacin ciprofloxacin, cephalosporins, doxycycline, ketoconazole, itraconazole, fluconazole, ritonavir, indinavir, saquinavir, nelfinavir, diltiazem, verapamil, nicardipine, cimetidine, methylprednisolone, dexamethasone, thiazides, furosemide, allopurinol, bromocriptine, danazol, amphotericin B, metoclopramide, oral contraceptive pills, warfarin, and grapefruit juice may increase levels
Rifampin, rifabutin, nafcillin, carbamazepine, phenobarbital, phenytoin, valproate, octreotide, and ticlopidine may decrease levels
Tobramycin, gentamicin, ketoconazole, azapropazone, trimethoprim/sulfamethoxazole, vancomycin, sulindac, amphotericin B, indomethacin, naproxen, cimetidine, ranitidine, diclofenac, tacrolimus, and melphalan may potentiate renal toxicity
Decreases renal clearance may lead to digitalis toxicity with coadministration of digoxin or myositis with coadministration of lovastatin; decreased renal clearance may lead to convulsions with coadministration of methylprednisolone or prednisolone; coadministration with ACE inhibitors, potassium supplements, or potassium-sparing diuretics increases risk of hyperkalemia
Absolute: Significantly decreased renal function; uncontrolled hypertension; documented hypersensitivity; clinically cured or persistent malignancy (except nonmelanoma skin cancer)
Relative: Age <18 y or >64 y (transplant recipients as young as 1 y have been treated with no unusual effects; however, safety in patients <18 y not established); controlled hypertension; planning to receive a live attenuated vaccine; active infection or evidence of immunodeficiency; concurrent phototherapy, coal tar, methotrexate, or other immunosuppressive agents; pregnancy or breastfeeding; unreliable patient; severe hepatic dysfunction
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
Frequent laboratory monitoring is essential, especially when dose is changed or other medications are started; decrease dose for any relevant clinical or laboratory abnormalities; monitoring blood concentration is sometimes helpful; nephrotoxic and hepatotoxic; causes hypertension and predisposes patients to secondary malignancy
Cyclophosphamide (Cytoxan, Neosar)
Recent reports suggest that cyclophosphamide in combination with systemic steroids is a useful regimen for paraneoplastic pemphigus. Has been used to ablate bone marrow, followed by stem cell rescue (peripheral blood stem cell transplantation). Chemically related to nitrogen mustards. As an alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. Many PO/IV regimens exist, depending on disease being treated and status of patient.
Adult
Ablative dose of 50 mg/kg IV qd for 4 d has been used; pulses of 500 mg IV qd for 3 d and 150 mg qd, in conjunction with 100 mg of PO prednisolone or dexamethasone; alternatively, 2.5-3 mg/kg/d PO qid
Pediatric
Not established
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
Secondary malignancies develop; can cause sterility, amenorrhea, hemorrhagic cystitis, and immune suppression; regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis
Immunomodulatory agents
IVIG is being increasingly used in high doses to treat many dermatologic inflammatory and autoimmune diseases, including autoimmune bullous disorders and dermatomyositis. However, few controlled trials exist, and it is costly and time consuming to administer. IVIG has been used as monotherapy and as adjunctive therapy.
Immune globulins intravenous (Gammagard, Gamimune, Sandoglobulin)
Prepared from pooled plasma of 10,000-20,000 donors. Has many mechanisms of action, which are mediated by the Fc portion of IgG or the antigen-binding and variable regions of the F (ab') 2 portion. Has been used for dermatomyositis, pemphigus foliaceus, pemphigus vulgaris, epidermolysis bullosa acquisita, bullous pemphigoid, and herpes gestationis. High dose is needed for treatment of inflammatory and autoimmune disorders in comparison to replacement therapy for patients with deficiency.
Adult
2 g/kg IV over 2-5 d monthly
Pediatric
Administer as in adults
Increases toxicity of live virus vaccine (MMR); do not administer within 3 mo of vaccine
Documented hypersensitivity; IgA deficiency; anti-IgE/IgG antibodies
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 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, patients with diabetes, patients with volume depletion, and those with 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
More on Pemphigus, Paraneoplastic |
| Overview: Pemphigus, Paraneoplastic |
| Differential Diagnoses & Workup: Pemphigus, Paraneoplastic |
 Treatment & Medication: Pemphigus, Paraneoplastic |
| Follow-up: Pemphigus, Paraneoplastic |
| References |
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Further Reading
Keywords
paraneoplastic pemphigus, PNP, pemphigus
