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eMedicine Journal
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Pediatrics
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Rheumatology
Vasculitis and Thrombophlebitis Synonyms, Key Words, and Related Terms: vasculitis, superficial venous thrombosis, Henoch-Schönlein purpura, Kawasaki disease, infantile polyarteritis nodosa, polyarteritis nodosa, Takayasu's arteritis, Takayasu arteritis, temporal arteritis, Wegener granulomatosis, Wegener’s granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, essential cryoglobulinemic vasculitis, cutaneous leukocytoclastic vasculitis |
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Author Information | Introduction | Clinical | Differentials | Workup | Treatment | Medication | Follow-up | Miscellaneous | Test Questions | Pictures | Bibliography
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 | AUTHOR INFORMATION | Section 1 of 12    |
Authored by Christine Hom, MD, Assistant Professor, Department of Pediatrics, Division of Pediatric Rheumatology, New York Medical College
Christine Hom, MD, is a member of the following medical societies: American College of Rheumatology, American Medical Association, and Arthritis Foundation
Edited by Barry L Myones, MD, Director of Research, Pediatric Rheumatology Center, Texas Children's Hospital at Houston; Associate Professor, Departments of Pediatrics & Immunology, Pediatric Rheumatology Section, Baylor College of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Thomas JA Lehman, MD, Clinical Professor of Pediatrics, Weill-Cornell University; Chief, Department of Pediatrics, Division of Pediatric Rheumatology, Hospital for Special Surgery; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; and Barry L Myones, MD, Director of Research, Pediatric Rheumatology Center, Texas Children's Hospital at Houston; Associate Professor, Departments of Pediatrics & Immunology, Pediatric Rheumatology Section, Baylor College of Medicine
| Author's Email: | Christine Hom, MD |  |
|---|---|---|
| Editor's Email: | Barry L Myones, MD |
eMedicine Journal, March 30 2006, VOLUME 7,
Number 3
| INTRODUCTION | Section 2 of 12  |
Background: Vasculitis is a descriptive term associated with a heterogeneous group of diseases that results in inflammation of blood vessels. Arteries and veins of any size in any organ may be affected, leading to ischemic damage to organs. The pattern of vessel involvement is highly variable, leading to innumerable clinical presentations. The most common vasculitides of childhood are Henoch-Schönlein purpura and Kawasaki disease. See articles on Kawasaki Disease, Infantile Polyarteritis Nodosa, Polyarteritis Nodosa, and Takayasu Arteritis.
For the clinician, diagnosing the cause of vasculitis is a difficult task that involves distinguishing disease entities with possibly overlapping clinical presentations. Classification criteria have been established for a number of distinct clinical syndromes, but these are less useful in making a diagnosis in patients who do not meet all the criteria of any one disease. While groups of patients with unifying features can be identified, a patient with vasculitis often presents initially with nonspecific constitutional findings. Diagnosis may not be made until more specific organ involvement occurs. Making a diagnosis in a patient with vasculitis is an evolving process because later organ system involvement may suggest revision of the initial diagnosis. Diagnosis must be flexible, following the course of the illness over time.
Primary systemic vasculitis is relatively rare, so the physician must eliminate other known causes of vasculitis, including infection, malignancy, collagen vascular disease, hypocomplementemic urticarial vasculitis, drug hypersensitivity, inflammatory bowel disease, and sarcoidosis. Many other infectious and inflammatory conditions mimic the signs and symptoms of vasculitis and must be ruled out.
Consider vasculitis in patients with constitutional symptoms in conjunction with multisystem disease, palpable purpura, unexplained neurologic symptoms, decreased pulses, bruits, or elevated inflammatory indices. Conversely, physical findings may be scant, without explanation for the presenting symptoms. A high index of suspicion may lead to early and aggressive treatment, with better outcomes for previously fatal diseases.
Various classification schemes for vasculitis have been proposed, most recently by an international consensus conference in Chapel Hill, North Carolina in 1994. This classification is as follows:
A practical, more comprehensive classification was proposed by Lie in 1994:
Primary vasculitides
Secondary vasculitides
Pathophysiology: Because the vasculitides comprise a group of different diseases, no single disease process explains the common final pathway of vessel wall inflammation. Immune complex disease, antibody-dependent cellular cytotoxicity (ADCC), endothelial activation, and coagulopathy have been invoked in models of inflammatory disease of the vasculature.
In immune complex disease, small (19S) immune complexes reach the vessel wall through increased vascular permeability and are deposited in the wall where Fc portions of immunoglobulin G (IgG) and immunoglobulin M (IgM) activate complement and initiate T- and B-cell responses with cytokine activation and recruitment of neutrophils. Levels of interferon-alpha and interleukin-2 (IL-2) are highly elevated in patients with polyarteritis nodosa. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta are moderately elevated in polyarteritis nodosa.
In antibody-mediated disease, endothelial cell cytolysis follows binding of specific antibodies to granulocytic cells with subsequent activation of natural killer cells. B cells may also play a role; patients with Wegener granulomatosis had increased levels of B-cell activating factor of the TNF family (BAFF); levels decreased with treatment to control levels. B-cell targeted therapies have been used anecdotally in treatment of Wegener granulomatosis; an NIH funded randomized controlled trial of rituximab (anti-CD20) is in progress.
Antineutrophil cytoplasmic antibodies (ANCAs) have been implicated as pathogenic in Wegener granulomatosis, MPA, and polyarteritis nodosa. These antibodies, directed against proteins in the cytoplasm, were first described in 1985. In vitro, ANCAs activate neutrophils with up-regulation of adhesion molecules. The activated neutrophils adhere to endothelium and stimulate lysis of endothelial cells in the presence of TNF-alpha. Activated neutrophils express membrane-bound proteinase 3 (PR3; normally a cytosolic protein), the target antigen of cytoplasmic pattern ANCA (c-ANCA). Perinuclear ANCAs (p-ANCAs) are directed against myeloperoxidase, as well as other antigens, including elastase and lactoferrin. ANCAs identify a subset of small-vessel vasculitis with pulmonary and renal disease with poorer prognosis; rapidly rising ANCA titers have been associated with disease flare. ANCAs bind to membrane PR3 and trigger degranulation of neutrophils, endothelial cell injury, and necrotizing vasculitis with granuloma formation.
Antiendothelial cell antibodies (AECAs) are found in primary vasculitis, as well as in infection-related vasculitis, so they are not helpful in differentiating primary vasculitis. In vitro, these antibodies demonstrate complement-dependent cytotoxicity against endothelial cells. The antibodies may play a role in vascular damage as an end pathway in multiple vasculitis syndromes. Bound to endothelial cells, AECAs may also potentiate injury by neutrophils via Fc receptor binding on neutrophils.
The endothelium plays an active role in physiologic function, controlling vascular permeability and cell-adhesion molecules. In addition, the endothelium secretes a large range of proinflammatory cytokines, including prostaglandins, nitric oxide, adenosine nucleotides, and platelet-activating factor, in response to cellular injury. Endothelium can also be stimulated to express major histocompatibility complex II (MHC II) molecules and can present antigen to T cells with subsequent proliferation of T-cell populations.
Superantigen-mediated activation of B-cell subsets has been proposed as a mechanism for Kawasaki disease. The seasonal pattern of Kawasaki disease suggests an infectious etiology; a vigorous IgA response in the respiratory tract and medium vessels of patients with Kawasaki disease suggests a respiratory pathogen. Parvovirus B19, Chlamydia pneumoniae, Epstein-Barr virus, and toxin-producing staphylococcal or streptococcal infections have been proposed as putative etiologic agents but have not been substantiated. Most recently, a New Haven coronavirus has been associated with Kawasaki disease (8/11 vs 1/22 controls positive for PCR), but only 1/48 patients with Kawasaki disease tested positive for the coronavirus on nasopharyngeal swab in a subsequent series.
In thrombophlebitis, a complex interaction of endothelial activation, thrombogenic nidus, and hypercoagulability leads to thrombosis and vessel inflammation.
Frequency:
In the United Kingdom, the annual incidence of MPA is 3.6 cases per million population; incidence of polyarteritis nodosa is 2.4 cases per million population. The combined annual incidence of MPA and polyarteritis nodosa in Kuwait is reported as 45 cases per million population.
Mortality/Morbidity: Morbidity and mortality of these syndromes is highly variable, from the self-limited course of uncomplicated Henoch-Schönlein purpura to fulminant Wegener granulomatosis. Overall, morbidity and mortality are determined by the extent of end-organ renal, pulmonary, cardiac, or CNS disease and ischemic disease caused by thrombosis. Children with renal and pulmonary involvement have a poorer outcome.
Aggressive early treatment is essential in a number of vasculitis syndromes. Untreated, Wegener granulomatosis carries a 100% mortality rate with a mean survival time of 5 months. Treatment of Wegener granulomatosis has resulted in an 87% remission rate, but with a 53% relapse rate. In a 1998 series by Valentini, renal failure occurred in only one seventh (14%) of pediatric patients treated with cyclophosphamide and corticosteroids for ANCA-positive glomerulonephritis. In patients with polyarteritis nodosa, the mortality rate at 5 years decreased from 85% to 20% with cytotoxic and glucocorticoid therapy. Most deaths due to uncontrolled vasculitis occur in the first 6 months. Additional morbidity and, ultimately, mortality occurs because of cytotoxic and immunosuppressive therapies used to control the disease.
In contrast, cutaneous polyarteritis nodosa is a relapsing and often painful disease limited to the skin with nodules or ulceration, and prognosis is excellent.
Patients with vasculitis secondary to hepatitis B become chronic viral carriers, and many progress to hepatic cirrhosis and esophageal varices.
Venous thrombophlebitis may lead to chronic vasculopathy, known as postphlebitic syndrome, with venous insufficiency, swelling, pain, and ulceration.
Race: The vasculitides are observed in people of all races and ethnicities, but they are not equally distributed. Children of Japanese descent have a higher incidence of Kawasaki disease. Young women of Japanese and Indian descent are affected more often with Takayasu arteritis. Non-Hispanic whites living in Turkey and other areas of the Middle East have an increased incidence of Behçet disease.
Sex:
Age:
| CLINICAL | Section 3 of 12 |
History: Obtain a comprehensive history and full review of systems in all patients in whom vasculitis is suspected. The complete clinical picture often suggests the diagnosis. History should address any medications or herbal remedies, recent or recurrent upper respiratory illness, rashes, skin ulcerations, constitutional symptoms, and central and peripheral neurologic symptoms. Also seek other conditions, such as asthma, anemia, malignancy, and inflammatory bowel disease. Family history may help to identify patients with coagulopathy, antiphospholipid antibody syndrome, or other autoimmune diseases.
Classification criteria for vasculitis have been established by the American College of Rheumatology. These clinical guidelines are not meant for diagnostic purposes but are used to define uniform and distinct patient groups for definition and analysis of study populations for clinical research studies and treatment protocols.
Clinical information for several vasculitides is provided below:
Physical: A careful complete examination is required when a vasculitis is suspected.
Causes:
| DIFFERENTIALS | Section 4 of 12 |
Anti-GBM Antibody Disease
Antiphospholipid Antibody Syndrome
Behcet Syndrome
Coronary Artery Anomalies
Endocarditis, Bacterial
Endocarditis, Fungal
Goodpasture Syndrome
Hematuria
Hepatitis B
Hepatitis C
Infantile Polyarteritis Nodosa
Kawasaki Disease
Mixed Connective Tissue Disease
Polyarteritis Nodosa
Proteinuria
Sarcoidosis
Sjogren Syndrome
Systemic Lupus Erythematosus
Takayasu Arteritis
Thrombasthenia
Thromboembolism
Weber-Christian Disease
Wegener Granulomatosis
Other Problems to be Considered:
Atrial myxoma
Atrial thrombus
Churg-Strauss disease
Cogan syndrome
Erythema nodosum
Henoch-Schönlein purpura
Lemierre syndrome
Mucha-Habermann syndrome
MPA
Panniculitis
Rheumatoid vasculitis
Thrombophlebitis
Glomerulonephritis
| WORKUP | Section 5 of 12 |
Lab Studies:
Imaging Studies:
Other Tests:
Procedures:
| TREATMENT | Section 6 of 12 |
Medical Care:
Surgical Care: For patients with thrombophlebitis, removal of any local intravascular instrumentation is recommended. Placement of Greenfield filters is not recommended for patients with hypercoagulability.
Consultations:
Diet: Prescribe a low-sodium diet if the patient is hypertensive.
Activity: Activity may be performed as tolerated. Patients taking anticoagulants should not participate in contact sports.
| MEDICATION | Section 7 of 12 |
Immunosuppression is achieved using corticosteroids and, for patients with renal or CNS involvement, with cyclophosphamide as induction therapy. Monthly pulse doses of cyclophosphamide are associated with a higher incidence of relapse. Following induction, azathioprine or methotrexate has been used as maintenance to reduce toxicity from cyclophosphamide. Anecdotally, TNF-alpha blockade with etanercept or infliximab may be used; reports on use of rituximab (anti-CD20) have begun to appear. With the heterogeneity of vasculitis syndromes, response to a given agent may be variable. TNF blockade has been helpful in Takayasu arteritis but has not been useful in Wegener granulomatosis. IVIG and antiplatelet doses of aspirin are standard of care for Kawasaki disease.
Drug Category: Corticosteroids -- Potent immunosuppressive activity with rapid onset of action.
| Drug Name | Prednisone (Deltasone, Sterapred) -- Used to control acute symptoms and laboratory evidence of inflammation. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production. |
|---|---|
| Adult Dose | 5-60 mg/d PO qd or divided bid to normalize symptoms and laboratory parameters; taper possible by 2 wk in some entities, as symptoms resolve |
| Pediatric Dose | 1-2 mg/kg/d PO to control acute symptoms and laboratory evidence of inflammation; after achievement of control, attempts may be made to taper within 4 wk in some entities (varies) |
| Contraindications | Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI bleeding or ulceration |
| Interactions | Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Cushingoid side effects, including hypertension, hirsutism, moon facies, and striae; adrenal suppression, osteoporosis, pseudotumor cerebri, and increased appetite |
| Drug Name | Cyclophosphamide (Cytoxan) -- Used as first-line therapy for severe systemic vasculitides such as Wegener granulomatosis and for steroid-refractory disease. 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 Dose | 1-2 mg/kg PO qd 0.5-1 g/m2 IV pulse every mo |
| Pediatric Dose | Administer as in adults; has also been used at the lower dosage q2-3wk |
| Contraindications | Documented hypersensitivity; severely depressed bone marrow function |
| Interactions | 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; watch for additive effects with other drugs inducing leukopenia |
| Pregnancy | D - Unsafe in pregnancy |
| Precautions | Hemorrhagic cystitis, syndrome of inappropriate antidiuretic hormone secretion, and hypertension; ovarian failure increases with age (>50% in patients >35 y) as does male sterility; neutropenia; nadir may occur between 7-14 d after IV dose |
| Drug Name | 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. |
|---|---|
| Adult Dose | 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; not to exceed 100-150 mg/d PO |
| Pediatric Dose | Initial dose: 2-5 mg/kg/d PO/IV Maintenance dose: 1-2 mg/kg/d PO/IV; not to exceed 100-150 mg/d PO |
| Contraindications | Documented hypersensitivity; low levels of serum thiopurine methyl transferase (TPMT) |
| Interactions | Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine |
| Pregnancy | D - Unsafe in pregnancy |
| Precautions | Leukopenia; increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur; check TPMT level prior to therapy and monitor liver, renal, and hematologic function; pancreatitis rarely associated |
| Drug Name | Heparin -- Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse but is able to inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous fibrinolysis. Provide as continuous heparin infusion to maintain aPTT at 1.5 times the control. |
|---|---|
| Adult Dose | Initial dose: 40-170 U/kg IV Maintenance infusion: 18 U/kg/h IV Alternatively, 50 U/kg/h IV initially, followed by continuous infusion of 15-25 U/kg/h and increase dose by 5 U/kg/h q4h prn using aPTT results |
| Pediatric Dose | Initial dose: 50-100 U/kg IV Maintenance infusion: 15-25 U/kg/h IV; increase dose by 2-4 U/kg/h q6-8h prn using aPTT results |
| Contraindications | Documented hypersensitivity; subacute bacterial endocarditis; active bleeding; history of heparin-induced thrombocytopenia; severe thrombocytopenia; intracranial hemorrhage |
| Interactions | Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, ASA, dextran, dipyridamole, and hydroxychloroquine may increase heparin toxicity |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Heparin-induced thrombocytopenia may occur within hours of starting or restarting heparin therapy; in neonates, preservative-free heparin is recommended to avoid possible toxicity (gasping syndrome) by benzyl alcohol, which is used as preservative; use caution in severe hypotension and shock; monitor for bleeding in peptic ulcer disease, menstruation, increased capillary permeability, and when administering IM injections |
| Drug Name | Enoxaparin (Lovenox) -- Low molecular weight heparin. Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse but is able to inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous fibrinolysis. Advantages include intermittent dosing and decreased requirement for monitoring. Heparin anti–factor Xa levels may be obtained if needed to establish adequate dosing. |
|---|---|
| Adult Dose | 1 mg/kg SC bid |
| Pediatric Dose | 0.5-1 mg/kg SC bid |
| Contraindications | Documented hypersensitivity; subacute bacterial endocarditis; active bleeding; history of heparin-induced thrombocytopenia; severe thrombocytopenia; intracranial hemorrhage |
| Interactions | Platelet inhibitors or PO anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Possible accelerated osteoporosis with long-term use; risk of heparin-induced thrombocytopenia |
| Drug Name | Warfarin (Coumadin, Coumarin) -- Interferes with hepatic synthesis of vitamin K–dependent coagulation factors. |
|---|---|
| Adult Dose | 5-10 mg PO qd; titrate after 2-5 d to maintain INR at 2.5-3.5 following a thrombotic episode; 2-10 mg/d usual dose |
| Pediatric Dose | 0.05-0.34 mg/kg/d PO |
| Contraindications | Documented hypersensitivity; severe liver or renal disease; active bleeding; peptic ulcer disease; malignant hypertension; pregnancy |
| Interactions | Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, PO contraceptives, and sucralfate; medications that may increase anticoagulant effects of warfarin include PO antibiotics, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfonamides, gemfibrozil, acetaminophen, and sulindac |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | Response to PO anticoagulants may be markedly decreased in biliary obstruction because of reduced vitamin K absorption and may be decreased in hepatitis and cirrhosis because of decreased production of vitamin K–dependent clotting factors; do not switch brands once desired therapeutic range is achieved; discontinue use at least 3 d prior to invasive surgical procedure and check PT/INR |
| Drug Name | Immune globulin, intravenous (Sandoglobulin, Gamimune, Gammar-P) -- Multiple mechanisms. May absorb superantigens or toxins in Kawasaki disease. May saturate available Fc receptors. May block cytokines, cytokine receptors, or both. May absorb complement activation products. May down-regulate immunoglobulin synthesis. Blocks Fc receptors on macrophages. Suppresses inducer T and B cells and augments suppressor T cells. Blocks complement cascade. May increase CSF IgG (10%). |
|---|---|
| Adult Dose | 2 g/kg IV over 2-5 d |
| Pediatric Dose | 2 g/kg IV infusion over 6-10 h for Kawasaki disease |
| Contraindications | Documented hypersensitivity; IgA deficiency; IgE/IgG anti-IgA antibodies |
| Interactions | Increases toxicity of live virus vaccine (MMR); do not administer within 3 mo of vaccine |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Premedication with acetaminophen and diphenhydramine to be considered; possible reduction of adverse effects of flushing, fever, hypotension, and aseptic meningitis |
| Drug Name | Trimethoprim-sulfamethoxazole (Bactrim, Septra) -- As Pneumocystis carinii prophylaxis. This drug may delay flare in patients with Wegener granulomatosis. Dihydrofolate reductase inhibitor in combination with sulfonamide. |
|---|---|
| Adult Dose | 1 DS tab (160 mg TMP/800 mg SMZ) PO 3 times/wk |
| Pediatric Dose | <2 months: Contraindicated >2 months: 10 mg/kg/d, based on TMP, PO 3 times/wk; not to exceed 320 mg TMP |
| Contraindications | Documented hypersensitivity; megaloblastic anemia due to folate deficiency; porphyria; age <2 mo |
| Interactions | May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly patients; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Do not use during last trimester of pregnancy because of potential toxicity to newborn (eg, jaundice, hemolytic anemia, kernicterus) Dosage adjustments (adult adjustments) CrCl (mL/min) 80-50: Recommended IV dose q18h CrCl 50-10: Recommended IV dose q24h CrCl <10: Not recommended HD: 4-5 mg/kg after HD During peritoneal dialysis: 0.16-0.8 g q48h Discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBCs frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, give 5-15 mg/d leucovorin); caution in folate deficiency (eg, chronic alcoholics, elderly persons, those receiving anticonvulsant therapy, those with malabsorption syndrome); hemolysis may occur in G-6-PD deficient individuals; AIDS patients may not tolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); give fluids to prevent crystalluria and stone formation; may cause Stevens-Johnson syndrome, toxic epidermal necrolysis, agranulocytosis, and aplastic anemia |
| Drug Name | Methotrexate (Rheumatrex, Folex) -- Antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA synthesis and cell reproduction. Effects may also be mediated by adenosine via the inhibition of aminoimidazole carboxamide ribonucleotide (AICAR) transformylase, leading to increased release of adenosine. Adjust dose gradually to attain satisfactory response. |
|---|---|
| Adult Dose | 0.3 mg/kg/wk PO/IM; not to exceed 20 mg/dose |
| Pediatric Dose | 0.3 mg/kg/wk PO/SC, titrate upwards to 1 mg/kg/wk; not to exceed 30 mg/dose (although higher doses up to 50 mg have been used over shorter treatment periods); alternatively, standard range is 10-20 mg/m2/wk |
| Contraindications | Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency |
| Interactions | PO aminoglycosides may decrease absorption and blood levels of concurrent PO methotrexate (MTX); charcoal lowers MTX levels; coadministration with etretinate may increase hepatotoxicity of MTX; folic acid or its derivatives contained in some vitamins may decrease response to MTX; indomethacin and phenylbutazone can increase MTX plasma levels; may decrease phenytoin serum levels; probenecid, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, may increase effects and toxicity of MTX; may increase plasma levels of thiopurines |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | Monitor CBCs monthly and liver and renal function q1-3mo during therapy (monitor more frequently during initial dosing, dose adjustments, or when risk of elevated MTX levels, eg, dehydration); MTX has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if significant drop in blood counts occurs; aspirin, NSAIDs, or low-dose steroids may be administered concomitantly with MTX (possibility of increased toxicity with NSAIDs, including salicylates, has not been tested) |
| FOLLOW-UP | Section 8 of 12 |
Further Outpatient Care:
In/Out Patient Meds:
Transfer:
Deterrence/Prevention:
Complications:
Prognosis:
Patient Education:
| MISCELLANEOUS | Section 9 of 12 |
Medical/Legal Pitfalls:
Special Concerns:
| TEST QUESTIONS | Section 10 of 12 |
CME Question 1: A 2-year-old girl presents with a 5-day history of fever, conjunctivitis, swollen hands and feet, and morbilliform rash. She is irritable and has poor oral intake. Her lips are swollen and injected. Cervical adenopathy is present. Which of the following treatments is indicated for this child?
A: Intravenous antibiotics
B: Acetaminophen and oral rehydration
C: Intravenous gamma globulin, 2 g/kg
D: Baby aspirin, 5 mg/kg qd
E: Intravenous acyclovir
The correct answer is C: This patient’s clinical presentation is most consistent with Kawasaki disease. Fever and irritability are very typical. While bacterial or viral meningitis may be considered, signs and symptoms of classic Kawasaki disease should be sought in patients with protracted high fever and irritability. Additionally, swollen hands and feet and injected lips would not usually be observed in meningitis. The treatment of choice is intravenous gamma globulin, 2 g/kg, and aspirin, 3-5 mg/kg. Low-dose aspirin is continued in the subacute and convalescent phase.
CME Question 2: A 6-year-old boy presents because this morning he developed cramping abdominal pain and has vomited twice. His mother carries him into the office; on physical examination, the dorsa of his feet are swollen and bluish. Pulses and capillary refill are normal. Blood pressure is elevated. He is noted to have purpura on the face. Stool guaiac is positive. Two weeks ago, he had an upper respiratory tract infection along with fever, myalgias, headaches, and malaise, which lasted 3-4 days. What is the most likely diagnosis?
A: Systemic-onset juvenile rheumatoid arthritis
B: Viral syndrome
C: Polyarteritis nodosa
D: Wegener granulomatosis
E: Henoch-Schönlein purpura
The correct answer is E: Patients with Henoch-Schönlein purpura may not present with palpable purpura. Swelling of the dorsa of the feet and painful periarthritis without frank joint effusion are characteristic. Nephritis at presentation is associated with a worse prognosis. Purpura and petechiae usually occur below the waist but are found on the face in 10% of cases.
Pearl Question 1 (T/F): Vasculitis in childhood is most commonly due to Henoch-Schönlein purpura or polyarteritis nodosa.
The correct answer is False: Henoch-Schönlein purpura and Kawasaki disease are the two most common systemic vasculitides of childhood. Polyarteritis nodosa is rare in childhood and is associated with renal, nerve, and skin involvement. As compared with adults, the prognosis in childhood is excellent. A cutaneous polyarteritis is more commonly observed, and it does not carry the grave prognosis associated with adult disease.
Pearl Question 2 (T/F): Perinuclear antineutrophil cytoplasmic antibody (p-ANCA) or antimyeloperoxidase antibody is a useful marker for Wegener granulomatosis.
The correct answer is False: Cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) is associated with Wegener granulomatosis, and it is found in up to 80% of cases. p-ANCA is more typical in microscopic polyangiitis.
Pearl Question 3 (T/F): In a 17-year-old patient with fever, high erythrocyte sedimentation rate, decreased radial pulse, and hypertension, biopsy of the radial vessel would be diagnostic.
The correct answer is False: Vasculitis most commonly occurs in focal segmental lesions, and healthy tissue may be immediately adjacent to severe stenoses. Yield from vascular biopsies is increased with larger tissue specimens. In polyarteritis nodosa, up to 30-50% of blind muscle biopsies may reveal arteritis. A single biopsy procedure followed by angiography is calculated to have 85% sensitivity and 96% specificity.
Pearl Question 4 (T/F): Patients with antiphospholipid antibody syndrome have neurologic findings.
The correct answer is True: Patients with antiphospholipid antibody syndrome may present with chorea, migraine headaches, transverse myelitis, or stroke.
| PICTURES | Section 11 of 12 |
| Caption: Picture 1. Vasculitis and thrombophlebitis. Vasculitis in childhood. | |
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| BIBLIOGRAPHY | Section 12 of 12 |
| NOTE: |
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| Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The authors, editors, and publisher of this journal have used their best efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and human error is always possible, the authors, editors, and publisher or any other party involved with the publication of this article do not warrant the information in this article is accurate or complete, nor are they responsible for omissions or errors in the article or for the results of using this information. The reader should confirm the information in this article from other sources prior to use. In particular, all drug doses, indications, and contraindications should be confirmed in the package insert. FULL DISCLAIMER |
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Author Information | Introduction | Clinical | Differentials | Workup | Treatment | Medication | Follow-up | Miscellaneous | Test Questions | Pictures | Bibliography
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