Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Dermatologic Therapy, Vol. 23, 2010, 320–327 Printed in the United States · All rights reserved © 2010 Wiley Periodicals, Inc. DERMATOLOGIC THERAPY ISSN 1396-0296 Erythema nodosum and erythema induratum (nodular vasculitis): diagnosis and management dth_1332 320..327 Heidi Gilchrist & James W. Patterson Department of Pathology, University of Virginia Health System, Charlottesville, Virginia ABSTRACT: Erythema nodosum is the most common type of panniculitis; it may be due to a variety of underlying infectious or otherwise antigenic stimuli. The pathogenesis remains to be elucidated, but both neutrophilic inflammation and granulomatous inflammation are implicated. Beyond treating underlying triggers, therapeutic options consist mainly of nonsteroidal anti-inflammatory drugs, symptomatic care, potassium iodide, and colchicine. Erythema induratum (nodular vasculitis) is a related but distinctly different clinicopathologic reaction pattern of the subcutaneous fat. It is classically caused by an antigenic stimulus from Mycobacterium tuberculosis but may be associated with several other underlying disorders. After appropriate antimicrobial treatment in tuberculous cases, therapy for erythema induratum is similar to options for erythema nodosum. KEYWORDS: erythema induratum, erythema nodosum, management, nodular vasculitis, treatment Introduction EN Erythema nodosum (EN) and erythema induratum (EI; nodular vasculitis) are classic forms of panniculitis, and both may represent manifestations of various disease processes. Classification of the clinicopathologic reaction pattern and identification of underlying infection or other disorders may be an exacting task, as the subcutaneous adipose tissue displays a limited variety of responses to inflammatory stimuli, and there may be some overlap in clinical presentation and in histological features on biopsy. After treatment of any identified potential etiologies, therapeutic options are similar for both forms of panniculitis. Diagnosis Address correspondence and reprint requests to: Heidi Gilchrist, MD, Department of Pathology, UVA Health System, Box 800214, 1215 Lee Street, Hospital Expansion, 3rd Floor, Charlottesville, VA 22908, or email: [email protected]. 320 EN is the most common form of panniculitis. It classically presents as tender, warm, erythematous subcutaneous nodules on the bilateral pretibial areas. Although it can occur in both sexes and at any age, it has a predilection for young women, particularly during the second through the fourth decades of life. In a study of 129 patients, the mean age was 31 years, but ages ranged from 9 to 70 years with 10 patients younger than 15 years (1). The female to male ratio has been reported as 4–5 : 1 (2). EN has also been reported to occur in anatomic locations other than the shins, especially on the thighs and extensor forearms (1). Rarely, the head, neck, or trunk may be involved (3). Ulceration or suppuration of lesions of EN is exceedingly rare, although it has been reported in a case associated with Crohn’s disease (4). More Erythema nodosum and erythema induratum usually, individual nodules last approximately 2 weeks and then slowly involute without scarring. New crops of lesions can continue to arise for as long as 6 weeks. Occasionally, if subcutaneous hemorrhage has occurred, the lesions of EN resolve with a bruise-like hyperpigmentation and are then sometimes termed erythema contusiforme. There are also chronic variants of EN; lesions are more likely to be unilateral and migratory, or undergo centrifugal spread with central clearing. These variants are known as erythema nodosum migrans or subacute nodular migratory panniculitis (5). EN is often accompanied by systemic symptoms including fever, malaise, arthritis, and arthralgias. These symptoms can comprise a prodrome as early as 1–3 weeks before the lesions appear (4). Arthralgias and rheumatoid factor-negative arthritis have been reported to persist for up to 2 years after the resolution of EN lesions. Abnormal laboratory studies can include leukocytosis greater than 10,000 per mm3 and elevated erythrocyte sedimentation rate and C-reactive protein levels (6). Pathophysiology A word about the pathogenesis of EN is required in order to logically discuss the therapeutic options. EN is generally regarded as a type IV delayed hypersensitivity response to a variety of antigens, although this is likely an oversimplification (7). This nonspecific subcutaneous reaction pattern is commonly idiopathic; a trigger is not identified in one third to one half of cases (2,8,9). Table 1 lists common and uncommon known causes of EN (1,6,10–12). The most common infectious cause and the most common cause in children is streptococcal upper respiratory infections (Lancefield Group A, Streptococcus pyogenes), accounting for 28–44% of cases (1,13). In some instances, EN denotes a favorable prognosis for the underlying condition, predicting a lower likelihood of disseminated disease in coccidioidomycosis (14) and a less protracted disease course with spontaneous resolution of sarcoidosis (1). Given the broad variety of possible triggers for EN, a thorough history and physical examination are essential to narrowing the list of possible etiologies. Depending on the patient’s signs and symptoms, a reasonable laboratory and radiologic workup might include antistreptolysin O or antiDNase B levels, a chest X-ray, stool cultures, a tuberculin skin test, and a urine pregnancy test. In the absence of specific symptoms or positive findings, further studies are probably not cost– effective (1). Skin biopsy may be of great benefit in diagnosing clinically atypical cases of EN. As for all panniculitides, a deep incisional biopsy with a generous sample of the subcutaneous fat gives the greatest chance of a definitive diagnosis. Histopathologically, EN is the prototypical septal panniculitis. Neutrophils frequently predominate in Table 1. Etiologies of erythema nodosum Common causes Uncommon causes Infectious agents Lancefield Group A Streptococcus Coccidioides immitis Gastroenteritis due to Yersinia, Salmonella, and Campylobacter Chlamydia pneumoniae Chlamydia trachomatis Mycoplasma pneumoniae Mycobacterium tuberculosis Brucella melitensis Hepatitis B (infection or vaccine) Epstein–Barr virus Medications Estrogens/oral contraceptive pills Sulfonamides Penicillins Halogens (bromides, iodides) Cabergoline Underlying disease processes Crohn’s disease Sarcoidosis (Lofgren’s syndrome) Ulcerative colitis Behçet’s disease Sweet’s syndrome Hormonal states Malignancy Pregnancy Acute myelogenous leukemia Hodgkin’s disease Carcinoid tumor Pancreatic carcinoma 321 Gilchrist & Patterson early lesions, and increased circulating neutrophils in the peripheral blood may promote production of reactive oxygen intermediates and resulting tissue damage (15,16). Indeed, many of the therapeutic options discussed below may be effective through their actions on neutrophils. There is also growing evidence for the role of other inflammatory cells and biochemical mediators (15–17). Both early and late lesions of EN can show granulomatous features, ranging from Miescher’s microgranulomas accompanying the early acute inflammation to widened, fibrotic subcutaneous septa with multinucleate giant cells in late lesions. Granulomatous diseases have been closely linked to deregulated tumor necrosis factor (TNF)-alpha production, and a strong correlation between a TNF-alpha gene promoter polymorphism and sarcoidosis-associated EN has been described (18). This postulates a role for therapies that inhibit TNF-alpha as well as for other treatments that are antigranulomatous. Therapeutic options The primary treatment for EN is to remove the underlying trigger, if possible. Potential causative drugs should be discontinued based on risk– benefit assessment and consultation with the prescribing physician. Underlying infections or malignancies should receive appropriate treatment. Beyond these steps, the mainstay of treatment is symptomatic, as most cases are self-limited and will resolve spontaneously. Patients should be cautioned that up to 2 months may elapse before they stop developing new lesions. Recurrences occur in 33–41% of cases and are more likely if the etiology is unknown (6,19). Nonsteroidal anti-inflammatory drugs. The firstline therapy is nonsteroidal anti-inflammatory drugs (NSAIDs), including salicylic acid derivatives (20). Of note, NSAIDs should be avoided in patients with acute and chronic renal disease as these medications cause renal artery constriction and a decrease in renal perfusion. NSAIDs also increase the risk of gastrointestinal bleeding in patients on hemodialysis (21). In addition, NSAIDs should be used with caution in patients with cardiovascular disease, as they have been reported to be associated with an increased incidence of both nonfatal and fatal myocardial infarctions and strokes (22). Further caution should be exercised in patients with known gastritis or esophagitis because NSAIDs can aggravate these conditions; addition of a proton pump inhibitor at standard doses may allow these patients to tolerate the therapy. Finally, NSAID use is contraindicated after the fifth month of gestation because of the risk of premature closure or constriction of the ductus arteriosus, persistent fetal pulmonary hypertension, intracranial hemorrhage, and fetal renal toxicity (23). In the absence of the above contraindications, most healthy adults with EN can be treated with NSAIDs at standard doses (see Table 2) with good success. Based on anecdotal experience, the present authors usually begin therapy with indomethacin and use ibuprofen and naproxen as second-line agents, but individual patients may respond differently, and the clinician should be comfortable prescribing a variety of NSAIDs as monotherapy. Rest, elevation, and compression. Bed rest and regular elevation of the legs are highly recommended adjuvant treatments. Some of the pain of Table 2. Adult dosing of oral nonsteroidal anti-inflammatory drugs for the treatment of erythema nodosuma Drug Dose Frequency (hours) Daily maximum dose (mg) Aspirin Celecoxib Diclofenac Ibuprofen Indomethacin 325–650 mg 100–200 mg 50–75 mg 200–800 mg 25–75 mg q4 q12 q12 q6–8 q8–12 4000 400 150 3200 150 Ketoprofen Naproxen Salsalate Sulindac 25–75 mg 250–500 mg 1–1.5 g 150–200 mg q6–8 q8–12 q8–12 q12 300 1000 3000 400 a Physician’s Desk Reference, 63rd edition, 2009. LFTs, liver function tests; q, every. 322 Comments May aggravate asthma Contraindicated with sulfonamide allergy Check LFTs at baseline and periodically May aggravate depression or psychiatric disturbances Rare pancreatitis and potentially fatal hypersensitivity syndrome Erythema nodosum and erythema induratum EN is likely caused by the pressure of edema on surrounding tissues. In the present authors’ experience, raising the legs above the level of the heart for at least 30 minutes twice daily can mitigate the discomfort. It should be emphasized that placing the legs high enough to maximize venous return (i.e., ankles above the chest) is essential. The patient should be instructed to lie supine on the floor or a piece of furniture, and place the legs in a vertical position on an adjoining wall. Gentle flexion and extension of the ankles while in this position can create a muscular pumping action, further encouraging lymphatic and venous drainage. In addition, gradient support stockings or pressure bandages can help to decrease edema and discomfort while the patient is active. The present authors instruct the patient to purchase knee-high hosiery with a 15–20 mmHg pressure gradient. Longer and tighter hose may be difficult to don and uncomfortable to wear, decreasing patient compliance. Potassium iodide. Potassium iodide (KI) is a timehonored therapy in the arsenal of the dermatologist. First discovered in the 19th century as a treatment for thyroid disease, today, it is used to treat a variety of dermatologic conditions, including EN and nodular vasculitis (24). The mechanism of action of KI is not entirely known, but there is evidence that it inhibits neutrophil chemotaxis (25) as well as significantly suppresses neutrophils’ ability to generate toxic oxygen intermediates (26). Also, given the reported successes of KI used to treat Wegener’s granulomatosis (27), disseminated granuloma annulare (28,29), and lymphocutaneous sporotrichosis (30,31), an antigranulomatous effect can also be postulated, although the basic science of such a potential mechanism remains to be elucidated. Practically, KI is administered as a saturated solution of KI (SSKI), which, in the United States Pharmacopeia generic formulation, contains 1000 mg/mL. Available from Upsher-Smith Laboratories, Inc. of Minneapolis, Minnesota, the solution is supplied in 30 and 237-mL bottles with calibrated droppers (10 drops delivers 0.3 mL or 300 mg) (32). A common starting dose for adults is 300 mg three times daily, with weekly titration up to 500 mg three times daily if needed. Improvement may be seen after 2 weeks (33,34). Nausea, dysgeusia, bitter eructation, excessive salivation, and gastrointestinal irritation are common. To mitigate these side effects, the clinician can opt to start at a lower dose: 100–150 mg three times daily with upward titration as tolerated. The taste of SSKI can be made more tolerable to the patient by diluting it with water, milk, or juice. In the present authors’ experience, the sweetness and acidity of orange juice or cola has shown the best results with rendering the solution palatable and increasing patient compliance. The manufacturer advises that SSKI should be stored at a controlled temperature, tightly closed, and protected from light. When exposed to cold temperatures, the solution may crystallize, but warming and shaking should dissolve the crystals. The solution should be discarded if the color changes to brownishyellow (32). In addition to the common, unpleasant, minor side effects described above, KI can also cause more rare but serious adverse effects. The Wolff– Chaikoff effect occurs when the thyroid gland stops producing thyroid hormone in the presence of excess levels of iodine. Healthy patients with intact thyroid autoregulatory mechanisms are generally not affected; however, patients with Hashimoto’s disease, patients with a history of Graves’ disease previously treated with surgery or radioactive iodide, and patients receiving certain medications (i.e., lithium, amiodarone, sulfonamides, phenazone) can be at risk for hypothyroidism and goiter (24). Dermatologists who prescribe SSKI should obtain a thorough history regarding preexisting thyroid disease and current medications. If SSKI therapy extends beyond 1 month, screening thyroid-stimulating hormone level is recommended (24). If iodide-induced hypothyroidism is detected, KI should be discontinued, and thyroid hormone levels are expected to return to normal within 1 month (35). Additional rare but serious adverse effects of KI include potentially fatal pulmonary edema with associated cardiac failure (36) and, after prolonged use, potassium toxicity with symptoms of confusion, hand numbness, generalized weakness, and cardiac arrhythmias. Patients receiving potassium-sparing diuretics or angiotensinconverting enzyme inhibitors, or who have chronic renal disease are at most risk for potassium toxicity (37). Table 3 lists other side effects of KI (24). Colchicine. Colchicine has proved to be useful in the treatment of EN, particularly for lesions that occur in the setting of Behçet’s disease (15). Reported successful doses are between 1 and 2 mg per day, divided into twice daily dosing. For unclear reasons, women are more likely to respond to colchicine than men (38). 323 Gilchrist & Patterson Table 3. Potential side effects of potassium iodide administration Well known Rare reports Acneiform eruptions Dermatitis herpetiformis, exacerbations Gastrointestinal effects (see text) Hypothyroidism Angioedema Bullous pemphigoid Cardiac irritability Hyperthyroidism Iododerma Lymphadenopathy Metabolic acidosis Myalgias Periarteritis nodosa Potassium toxicity Pulmonary edema Pustular psoriasis Urticaria Vasculitis (granulomatous) A plant-derived alkaloid, colchicine’s antiinflammatory activity is thought to partly derive from its ability to arrest microtubule polymerization, resulting in impaired neutrophil chemotaxis (39). There is also new evidence that colchicine suppresses inflammasome-driven caspase-1 activation, blocks adhesion of neutrophils to endothelium by decreasing expression of L-selectin, and inhibits neutrophilic production of superoxide anions (40). Common side effects of colchicine are gastrointestinal (diarrhea, abdominal pain) and can be ameliorated by starting with a once daily low dose (e.g., 0.6 mg daily) and increasing to twice daily dosing as the patient builds gastrointestinal tolerance. Bone marrow suppression with pancytopenia is a rare, dose-dependent side effect of colchicine, occurring 3–5 days after a high dose (mainly reported with accidental colchicine poisoning in children). Granulocyte colonystimulating factor can be administered if necessary, but the bone marrow usually recovers 7–10 days after discontinuation of colchicine (41). Other therapeutic options. EN associated with inflammatory bowel disease, particularly cases in which skin lesions parallel intestinal inflammation in severity, may respond to infliximab (42,43). However, EN has also paradoxically been reported to occur in patients treated with infliximab with resolution of the lesions upon discontinuation of the medication (44,45). Other therapeutic agents reported useful in the treatment of EN include hydroxychloroquine (particularly for chronic EN) (46,47), cyclosporin 324 A, thalidomide, and systemic corticosteroids (7). As with the use of any immunosuppressive medications, an underlying infectious cause of the EN should be ruled out before therapy is instituted. EI/nodular vasculitis Diagnosis The term “erythema induratum” was coined by Bazin in 1855, who described deep violaceous nodules on the posterior lower legs of young women. He classified it as an “erythematous benign scrofulid,” presumed to be of tuberculous origin because of its coexistence with pulmonary tuberculosis. In the early 20th century, there were reports of a similar clinicopathologic entity that did not seem to be associated with tuberculous disease, and the terminology “erythema induratum of Whitfield” arose to describe these nontuberculous cases. In 1945, Montgomery et al. introduced the concept of “nodular vasculitis” as a new category for the presumably noninfectious variant of EI (48). Today, most authors continue to use these terms interchangeably, and for simplicity, the present authors choose to use the term EI to refer to a distinct clinical and histological reaction pattern regardless of etiology. EI presents clinically as recurrent crops of tender, violaceous nodules and plaques on the posterior lower legs. Lesions have also been reported on the feet, thighs, buttocks, and forearms (48). The nodules tend to evolve over several weeks, often developing focal ulceration and drainage. The areas heal with scarring and postinflammatory hyperpigmentation. The age of the patients in one review ranged from 13 to 66 years (mean 37 years) (49). Although EI can occur in men, there is an overwhelming female predominance. Histopathological examination most commonly shows diffuse septolobular panniculitis with primary neutrophilic vasculitis of nearby vessels. The classic vessel involved is a large muscular artery, but a systematic microscopic review of 101 biopsy specimens by Segura et al. showed the most common pattern to be vasculitis involving the small venules of the fat lobule (47% of cases) (50). When the vasculitis is less prominent, serial sections may be required to identify it. There are varying degrees of acute and chronic inflammation, coagulative and caseation-like necrosis, and poorly developed granulomas. The Erythema nodosum and erythema induratum simultaneous presence of both primary vasculitis and granulomas suggests a role for both type III and type IV hypersensitivities in the pathogenesis of EI (51). Pathogenesis As previously noted, EI was historically causally associated with tuberculosis because of frequent co-occurrence of the two diseases, although no mycobacterial organisms were ever identified on histopathological examination. With the invention of the polymerase chain reaction technique in 1984, detection of minute quantities of antigen became possible. Beginning in the early 1990s with the development of specific primers able to distinguish Mycobacterium tuberculosis DNA from that of other species, there were several reports of detection of such material in lesions classified as EI or nodular vasculitis (52–55). However, EI has also been associated with both infectious nontuberculous and noninfectious disorders. Infectious nontuberculous cases have been associated with Nocardia, Pseudomonas, and Fusarium (56). One case has also been described in conjunction with “red fingers syndrome” (chronic, painless erythematous macules and patches on the distal fingers and toes associated with cryoglobulins and/or a vasculopathy) in a patient with chronic hepatitis C (57). There may also be an association with hepatitis B virus (50). Noninfectious associations may include previous episodes of superficial thrombophlebitis of the lower legs, hypothyroidism, chronic lymphocytic leukemia, rheumatoid arthritis, and Crohn’s disease (50). Finally, nodular vasculitis has been reported in association with treatment with propylthiouracil, with rapid resolution after the medication was discontinued (58). As noted above, the vasculitic pathology of EI suggests a type III hypersensitivity reaction or immune complex-mediated vasculitis (51). Others have suggested that the reaction pattern more likely represents a type IV hypersensitivity reaction or a specific T lymphocyte-mediated response to an antigenic stimulus (mycobacterial or other) (59). Indeed, patients with tuberculosis-associated EI can have an exaggerated response to intradermal purified protein derivative (PPD)-simulating cellulitis because of the extensive release of cytokines and chemokines by activated T lymphocytes (60). Commercially available interferon-gamma release assays specific to M. tuberculosis antigens (QuantiFERON®-TB Gold test, Cellestis, Carnegie, VIC, Australia, and T-SPOT.TB®, Oxford Immuno- tech, Abingdon, UK) further demonstrate the release of high levels of interferon-gamma by activated T cells in patients with EI. Such laboratory tests may be valuable in avoiding uncomfortable exaggerated hypersensitivities to intradermal PPD testing when screening for M. tuberculosis infection in patients with EI (61). Therapeutic options Treatment of EI should target the underlying cause, if possible. All patients with suspected EI should receive a Mantoux skin test, an intradermal PPD application, or an interferon-gamma release assay as described above. Patients with positive tests should receive a full 9-month course of triple-agent antituberculous therapy under the care of an infectious disease specialist (62). Appropriate antimicrobial therapy should be provided for any other underlying infections, potentially associated systemic conditions should be treated, and any suspected medications should be discontinued if feasible. KI has also been reported as an effective treatment for EI (63,64). Further therapies are similar to the treatment of EN as described above: NSAIDs, rest, elevation, compression, and, possibly (in severe cases and once underlying infection has been ruled out) systemic corticosteroids may all be helpful. There are also isolated case reports of successful treatment of EI with mycophenolate mofetil (65) and oral gold (66). Conclusion Although they share some similar clinical and histological features, EN and EI are distinctive pathologic entities that can be due to a variety of causes. Treatment, especially for the chronic variants, may be challenging for the clinician. The mainstays of therapy include addressing any underlying disease, prescribing anti-inflammatory medications, and educating the patient about symptomatic adjuvant care. In recalcitrant cases, a variety of immunosuppressive drugs have been tried with isolated reports of successful treatment. References 1. Cribier B, Caille A, Heid E, Grosshans E. Erythema nodosum and associated diseases. A study of 129 cases. Int J Dermatol 1998: 37: 667–672. 2. Garcia-Porrua C, González-Gay MA, Vázquez-Caruncho M, et al. Erythema nodosum: etiologic and predictive factors 325 Gilchrist & Patterson 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. in a defined population. Arthritis Rheum 2000: 43: 584– 592. White WL, Hitchcock MG. Diagnosis: erythema nodosum or not? Semin Cutan Med Surg 1999: 18: 47–55. Requena L, Sanchez Yus E. Erythema nodosum. Semin Cutan Med Surg 2007: 26: 114–125. Bafverstedt B. Erythema nodosum migrans. Acta Derm Venereol 1954: 34: 181–193. Mert A, Ozaras R, Tabak F, Pekmezci S, Demirkesen C, Ozturk R. Erythema nodosum: an experience of 10 years. Scand J Infect Dis 2004: 36: 424–427. Requena L, Sanchez Yus E. Panniculitis. Part I. Mostly septal panniculitis. J Am Acad Dermatol 2001: 45: 163–183. Gordon H. Erythema nodosum: a review of one hundred and fifteen cases. Br J Dermatol 1961: 73: 393–409. Forstrom L, Winkelman RK. Acute panniculitis: a clinical and histological study of 34 cases. Arch Dermatol 1977: 183: 909–917. Kakourou T, Drosatou P, Psychou F, Aroni K, Nicolaidou P. Erythema nodosum in children: a prospective study. J Am Acad Dermatol 2001: 44: 17–21. Lin JT, Chen PM, Huang DF, Kwang WK, Lo K, Wang WS. Erythema nodosum associated with carcinoid tumour. Clin Exp Dermatol 2004: 29: 426–427. Durden FM, Variyam E, Chren MM. Fat necrosis with features of erythema nodosum in a patient with metastatic pancreatic carcinoma. Int J Dermatol 1996: 35: 39–41. Schwartz RA, Nervi SJ. Erythema nodosum: a sign of systemic disease. Am Fam Physician 2007: 75: 695–700. Arsura EL, Kilgore WB, Ratnayake SN. Erythema nodosum in pregnant patients with coccidioidomycosis. Clin Infect Dis 1998: 27: 1201–1203. Senturk T, Aydintug O, Kuzu I, et al. Adhesion molecule expression in erythema nodosum-like lesions in Behcet’s disease. A histopathological and immunohistochemical study. Rheumatol Int 1998: 18: 51–57. Kunz M, Beutel S, Brocker E. Leukocyte activation in erythema nodosum. Clin Exp Dermatol 1999: 24: 396– 401. Llorente L, Richaud-Patin Y, Alvarado C, et al. Elevated Th1 cytokine mRNA in skin biopsies and peripheral circulation in patients with erythema nodosum. Eur Cytokine Netw 1997: 8: 67–71. Labunski S, Posern G, Ludwig S, Kundt G, Brocker EB, Kunz M. Tumor necrosis factor-alpha promoter polymorphism in erythema nodosum. Acta Derm Venereol 2001: 81: 18–21. Mert A, Kumbasar H, Ozaras R, et al. Erythema nodosum: an evaluation of 100 cases. Clin Exp Rhematol 2007: 25: 563–570. Tremaine WJ. Treatment of erythema nodosum, aphthous stomatitis, and pyoderma gangrenosum in patients with IBD. Inflamm Bowel Dis 1998: 4: 68–69, 73. Jankovic SM, Aleksic J, Rakovic S, et al. Nonsteroidal antiinflammatory drugs and risk of gastrointestinal bleeding among patients on hemodialysis. J Nephrol 2009: 22: 502– 507. Baron JA, Sandler RS, Bresalier RS, et al. Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial. Lancet 2008: 372: 1756–1764. Damase-Michel C, Christaud J, Berrebi A, Lacroix I, Montastruc JL. What do pregnant women know about nonsteroidal anti-inflammatory drugs? Pharmacoepidemiol Drug Saf 2009: 18: 1034–1038. Sterling JB, Heymann WR. Potassium iodide in dermatology: a 19th century drug for the 21st century – uses, phar- 326 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. macology, adverse affects, and contraindications. J Am Acad Dermatol 2000: 43: 691–697. Honma K, Saga K, Onodera H, Takahashi M. Potassium iodide inhibits neutrophil chemotaxis. Acta Derm Venereol 1990: 70: 247–249. Miyachi Y, Niwa Y. Effects of potassium iodide, colchicines, and dapsone on the generation of polymorphonuclear leukocyte-derived oxygen intermediates. Br J Dermatol 1982: 107: 209–214. Torinuki W. Wegener’s granulomatosis successfully treated with prednisolone and potassium iodide. J Dermatol 1994: 21: 693–695. Giessel M, Graves K, Kalivas J. Treatment of disseminated granuloma annulare with potassium iodide. Arch Dermatol 1979: 115: 639–640. Caserio RJ, Eaglstein WH, Allen CM. Treatment of granuloma annulare with potassium iodide. J Am Acad Dermatol 1984: 10: 294–295. Mercurio MG, Elewski BE. Therapy for sporotrichosis. Semin Dermatol 1993: 12: 285–289. Cabezas C, Bustamante B, Holgado W, Begue R. Treatment of cutaneous sporotrichosis with once daily dose of potassium iodide. Pediatr Infect Dis 1996: 15: 352–354. http://www.upsher-smith.com/PDFs/SSKI_PI.pdf. Horio T, Imamura S, Danno K, et al. Potassium iodide in the treatment of erythema nodosum and nodular vasculitis. Arch Dermatol 1981: 117: 29–31. Cohen PR, Holder WR, Rapini RP. Concurrent Sweet’s syndrome and erythema nodosum: a report, world literature review and mechanism of pathogenesis. J Rheumatol 1992: 19: 814–820. Jubiz W, Carlile S, Lagerquist LD. Serum thyrotropin and thyroid hormone levels in humans receiving chronic potassium iodide. J Clin Endocrinol Metab 1997: 44: 379–382. Haung TY, Peterson GH. Pulmonary edema and iododerma induced by potassium iodide in the treatment of asthma. Ann Allergy 1981: 46: 264–266. Delk C, Holstege CP, Brady WJ. Electrocardiographic abnormalities associated with poisoning. Am J Emerg Med 2007: 25: 672–687. Yurdakul S, Mat C, Tuzun Y, et al. A double-blind trial of colchicines in Behcet’s syndrome. Arthritis Rheum 2001: 44: 2686–2692. Molad Y. Update on colchicines and its mechanism of action. Curr Rheumatol Rep 2002: 4: 252–256. Nuki G. Colchicine: its mechanism of action and efficacy in crystal-induced inflammation. Curr Rheumatol Rep 2008: 10: 218–227. Harris R, Marx G, Gillett M, Kark A, Arunanthy S. Colchicine-induced bone marrow suppression: treatment with granulocyte colony-stimulating factor. J Emerg Med 2000: 18: 435–440. Siemanowski B, Regueiro M. Efficacy of infliximab for extraintestinal manifestations of inflammatory bowel disease. Curr Treat Options Gastroenterol 2007: 10: 178– 184. Clayton TH, Walker BP, Stables GI. Treatment of chronic erythema nodosum with infliximab. Clin Exp Dermatol 2006: 31: 823–824. Rosen T, Martinelli P. Erythema nodosum associated with infliximab therapy. Dermatol Online J 2008: 14: 3. Delle Sedie A, Bazzichi L, Bombardieri S, Riente L. Psoriasis, erythema nodosum, and nummular eczema onset in an ankylosing spondylitis patient treated with infliximab. Scand J Rhematol 2007: 36: 403–404. Erythema nodosum and erythema induratum 46. Alloway JA, Franks LK. Hydroxychloroquine in the treatment of chronic erythema nodosum. Br J Dermatol 1995: 132: 661–662. 47. Jarrett P, Goodfield MJ. Hydroxychloroquine and chronic erythema nodosum. Br J Dermatol 1996: 134: 373. 48. Cribier E, Grosshans E. Bazin’s erythema induratum: obsolete concept and terminology. Ann Dermatol Venereol 1990: 117: 937–943. 49. Cho KH, Lee DY, Kim CW. Erythema induratum of Bazin. Int J Dermatol 1996: 35: 802–808. 50. Segura S, Pujol RM, Trindade F, et al. Vasculitis in erythema induratum of Bazin: a histopathologic study of 101 biopsy specimens from 86 patients. J Am Acad Dermatol 2008: 59: 839–851. 51. Schneider JW, Jordaan HF. The histopathologic spectrum of erythema induratum of Bazin. Am J Dermatopathol 1997: 19: 323–333. 52. Degitz K, Messer G, Schirren H, et al. Successful treatment of erythema induratum of Bazin following rapid detection of mycobacterial DNA by polymerase chain reaction [letter]. Arch Dermatol 1993: 129: 1619–1620. 53. Schneider JW, Jordaan HF, Geiger DH, et al. Erythema induratum of Bazin. A clinicopathologic study of 20 cases and detection of Mycobacterium tuberculosis DNA in skin lesions by polymerase chain reaction. Am J Dermatopathol 1995: 17: 350–356. 54. Chuang YH, Kuo TT, Wang CM, et al. Simultaneous occurrence of papulonecrotic tuberculid and erythema induratum and the identification of Mycobacterium tuberculosis DNA by polymerase chain reaction. Br J Dermatol 1997: 137: 276–281. 55. Baselga E, Margall N, Barnadas MA, et al. Detection of Mycobacterium tuberculosis DNA in lobular granulomatous panniculitis (erythema induratum-nodular vasculitis). Arch Dermatol 1997: 133: 457–462. 56. Patterson JW, Brown PC, Broecker AH. Infection-induced panniculitis. J Cutan Pathol 1989: 16: 183–193. 57. Gimenez-Garcia R, Sanchez-Ramon S, Sanchez-Antolin G. Red fingers syndrome in recurrent panniculitis in a patient with chronic hepatitis C. J Eur Acad Dermatol Venereol 2003: 17: 692–694. 58. Wolf D, Ben-Yehuda A, Okon E, et al. Nodular vasculitis associated with propylthiouracil therapy. Cutis 1992: 49: 253–255. 59. Ollert MW, Thomas P, Korting HC. Erythema induratum of Bazin. Evidence of T-lymphocyte hyperresponsiveness to purified protein derivative of tuberculin: report of two cases and treatment. Arch Dermatol 1993: 129: 469–473. 60. Lighter J, Tse TB, Li Y, et al. Erythema induratum of Bazin in a child: evidence for a cell-mediated hyper-response to Mycobacterium tuberculosis. Pediatr Infect Dis J 2009: 28: 326–328. 61. Angus J, Roberts C, Kulkarni K. Usefulness of the QuantiFERON test in the confirmation of latent tuberculosis in association with erythema induratum. Br J Dermatol 2007: 157: 1293–1294. 62. Requena L, Sanchez Yus E. Panniculitis. Part II. Mostly lobular panniculitis. J Am Acad Dermatol 2001: 45: 325– 361. 63. Schulz EJ, Whiting DA. Treatment of erythema nodosum and nodular vasculitis with potassium iodide. Br J Dermatol 1976: 94: 75–78. 64. Hoti H, Imamura S, Danno K, et al. Potassium iodide in the treatment of erythema nodosum and nodular vasculitis. Arch Dermatol 1981: 117: 29–31. 65. Taverna JA, Radfar A, Pentland A, et al. Case reports: nodular vasculitis responsive to mycophenolate mofetil. J Drugs Dermatol 2006: 5: 992–993. 66. Shaffer N, Kerdel FA. Nodular vasculitis (erythema induratum): treatment with auranofin. J Am Acad Dermatol 1991: 25: 426–429. 327