1. Department of Dermatology, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain; and 2. Department of Dermatology, Hospital General Universitario, Universidad de Valencia, Valencia, Spain.
Erythema nodosum is the most frequent clinico-pathological variant of the panniculitides. The disorder is a cutaneous reaction consisting of inflammatory, tender, nodular lesions, usually located on the anterior aspects of the lower extremities. The process may be associated with a wide variety of diseases, being infections, sarcoidosis, rheumatologic diseases, inflammatory bowel diseases, medications, autoimmune disorders, pregnancy, and malignancies the most common associated conditions. The typical eruption consists of a sudden onset of symmetrical, tender, erythematous, warm nodules and raised plaques usually located on the shins, ankles and knees. Often the lesions are bilaterally distributed. At first, the nodules show a bright red color, but within a few days they become livid red or purplish, and finally they exhibit a yellow or greenish appearance taking on the look of a deep bruise. Ulceration is never seen and the nodules heal without atrophy or scarring. Some clinical variants of erythema nodosum have been described under different names, including erythema nodosum migrans, subacute nodular migratory panniculitis, and chronic erythema nodosum, but probably they are just clinical variants which may all be included within the spectrum of erythema nodosum. Histopathologically, erythema nodosum is the stereotypical example of a mostly septal panniculitis with no vasculitis. The septa of subcutaneous fat are always thickened and variously infiltrated by inflammatory cells that extend to the periseptal areas of the fat lobules. The composition of the inflammatory infiltrate in the septa varies with age of the lesion. In early lesions edema, hemorrhage, and neutrophils are responsible for the septal thickening, whereas fibrosis, periseptal granulation tissue, lymphocytes, and multinucleated giant cells are the main findings in late stage lesions of erythema nodosum. A histopathologic hallmark of erythema nodosum is the presence of the so-called Miescher's radial granulomas, which consist of small, well-defined nodular aggregations of small histiocytes arranged radially around a central cleft of variable shape. Treatment of erythema nodosum should be directed to the underlying associated condition, if identified. Usually, nodules of erythema nodosum regress spontaneously within a few weeks, and bed rest is often sufficient treatment. Aspirin, nonsteroidal anti-inflammatory drugs, such as oxyphenbutazone, indomethacin or naproxen, and potassium iodide may be helpful drugs to enhance analgesia and resolution. Systemic corticosteroids are rarely indicated in erythema nodosum and before these drugs are administered an underlying infection should be ruled out.
Erythema nodosum is the most frequent clinico-pathological variant of the septal panniculitides. The disorder usually exhibits an acute onset and is clinically characterized by the eruption of erythematous tender nodules and plaques located predominantly over the extensor aspects of the lower extremities. The lesions show spontaneous regression, without ulceration, scarring, or atrophy, and recurrent episodes are uncommon. Erythema nodosum is a cutaneous reactive process that may be triggered by a wide variety of possible stimuli. Infectious diseases, sarcoidosis, rheumatologic diseases, inflammatory bowel diseases, medication reactions, autoinmune disorders, pregnancy, and malignancies the most common associated conditions.
Erythema nodosum was originally described in 1798 by the English dermatologist, Willan, in his classic monograph on erythemas, and this author emphasized the higher frequency of the process in women.The disorder was further delineated by Wilson in 1842, who considered erythema nodosum to be a part of erythema multiforme because he had observed urticaria, figurate erythema, purpura, and the nodose lesions to overlap. Later, Hebra, in 1860, expanded the clinical characteristics of the process and described the color changes in the evolution of the lesions, proposing the term dermatitis contusiformis to name the disorder.
This process can occur at any age, but most cases appear between the second and fourth decades of the life, with the peak of incidence being between 20 and 30 years of age, due to the high incidence of sarcoidosis at this age. Several studies have demonstrated that erythema nodosum occurs three to six times more frequently in women than in men, however, the sex incidence before puberty is approximately equal.[5, 6] In general, erythema nodosum is seen in younger patients than erythema induratum of Bazin. Racial and geographic differences of incidence vary throughout the world, also depending on the prevalence of diseases that are etiologic factors. Prevalence of erythema nodosum in a semirural area of England over a 2-year period gave a figure of 2.4 per 1000 population per year. Prevalence varies also according to the type of the patients attended to in a clinic: the average hospital incidence was about 0.5 percnet of new cases seen in Departments of Dermatology in England and about 0.38 percent of all patients seen in a Department of Internal Medicine in Spain. In a recent study, the average annual incidence rate of biopsy proven erythema nodosum in a hospital of the northwestern Spain for the population 14 years and older was 52 cases per million of persons, although certainly this rate underestimated the authentic incidence of the disease because only included cases confirmed by biopsy. Most cases of erythema nodosum occur within the first half of the year, probably due to the more frequent incidence of streptococcal infections in this period of the year, and there is no difference in distribution between urban and rural areas.[8, 10] Familial cases are usually due to an infectious etiology.
The typical eruption is quite characteristic and consists of a sudden onset of symmetrical, tender, erythematous, warm nodules and raised plaques usually located on the shins, ankles and knees. The nodules, which range from 1 to 5 cm or more in diameter, are usually bilaterally distributed (Figures 1-3). Nodules may become confluent resulting in erythematous plaques (Figure 4). In rare instances, more extensive lesions may appear, involving the thighs, extensor aspects of the arms, neck, and even the face. At first, the nodules show a bright red color and are raised slightly above the skin. Within a few days, they become flat, with a livid red or purplish color (Figures 5-7). Finally, they exhibit a yellow or greenish appearance often taking on the look of a deep bruise ("erythema contusiformis"). This contusiform color evolution is quite characteristic of erythema nodosum and allows a specific diagnosis in late stage lesions. Ulceration is never seen in erythema nodosum and the nodules heal without atrophy or scarring. Usually acute bouts of erythema nodosum are associated with a fever of 38-39 C°, fatigue, malaise, arthralgia, headache, abdominal pain, vomiting, cough, or diarrhea. Episcleral lesions and phlyctenular conjunctivitis may also accompany the cutaneous lesions. Less frequent clinical manifestations associated with erythema nodosum are lymphadenopathy, hepatomegaly, splenomegaly and pleuritis. The eruption generally lasts 3-6 weeks, but persistence beyond this time is not unusual. Recurrences are exceptional.
Erythema nodosum in children has a much shorter duration than in adults, arthralgias are seen in a minority of the patients and fever is an accompaying manifestation in fewer than half of the cases.[12, 13, 14]
Some clinical variants of erythema nodosum have been described under different names. These variants include erythema nodosum migrans,[15, 16, 17, 18] subacute nodular migratory panniculitis of Vilanova and PiÒol,[19, 20] and chronic erythema nodosum. Erythema nodosum migrans was reported by Bafverstedt in 1954 as an entity clinically different from classic erythema nodosum, but with identical histopathologic findings. The lesions were unilateral and only one or few lesions were present. They consisted of erythematous plaques that extended peripherally and healed at the center and were preferentially located on the lateral rather the anterior side of the leg. The progressing border is brightly erythematous, whereas the resolving center has a yellowish hue (Figure 8). The lesions are painless or less tender than those of classic erythema nodosum. In 1973 Hannuksela reported on 438 patients with subcutaneous nodules on the lower extremities, of these 56 had features that were interpreted as erythema nodosum migrans. Similar cases appeared in the literature shortly after.[17, 18] The term subacute nodular migratory panniculitis was coined by Vilanova and Piñol in 1956 for a variant of septal panniculitis which they considered to be clinical and histopathologically different from erythema nodosum. This opinion was supported by Perry and Winkelmann in 1964. Fine and Meltzer favored the name chronic erythema nodosum as the best denomination for lesions previously described as erythema nodosum migrans or subacute nodular migratory panniculitis. However, more recently, some authors still believe that erythema nodosum migrans and chronic erythema nodosum are two different clinico-pathological entities. These authors studied 58 examples of granulomatous septal panniculitis, and 36 cases were considered to be chronic erythema nodosum, whereas 14 cases were interpreted as erythema nodosum migrans. The basis of their classification was mostly clinical, they analyzed features such as: duration, morphology, number, location, symmetry, pattern of extension, and associated systemic manifestations. Histopathologically, lesions of erythema nodosum migrans showed marked thickening of the septa of subcutaneous fat, with an abundant number of granulomas containing frequent multinucleated giant cells, granulation tissue and conspicuous proliferations of capillaries at the separation between septa and fat lobules. In lesions of erythema nodosum migrans there was no evidence of phlebitis. In contrast, lesions interpreted as chronic erythema nodosum showed a lesser degree of thickening of the septa and less inflammatory infiltrate, but phlebitis and extravasated erythrocytes were prominent and characteristic findings. In our opinion, these histopathologic differences do not separate erythema nodosum migrans from chronic erythema nodosum, and they are probably expressions of the different stage of evolution of lesions rather than two different entities. At the present moment, most authors believe that erythema nodosum migrans, subacute nodular migratory panniculitis, and chronic erythema nodosum are clinical variants which may all be included within the spectrum of erythema nodosum.
A rare variant of erythema nodosum in children and young adults is characterized by lesions only involving the palms or soles (Figure 9), and often the process is unilateral.[23, 24, 25, 26] These children developed painful erythematous nodules usually after physical activity. Histopathologic features of these lesions of unilateral palmar or plantar erythema nodosum are similar to those of classical erythema nodosum.
Erythema nodosum may be associated with a wide variety of disease processes and its observation must always be followed by a search for underlying etiology. A review of the literature reveals that the list of etiologic factors which can lead to erythema nodosum is long and varied, including infections, drugs, malignant diseases, and a wide group of miscellaneous conditions (Table 1).[8, 27-121] Although there are considerable geographic variations related to endemic infections, in our country streptococcal infections are the most frequent etiologic factor for erythema nodosum in children, whereas other infectious processes, drugs, sarcoidosis, autoimmune disorders and inflammatory diseases of the bowel are the most commonly associated disorders in adults.
The relationship between a previous episode of upper respiratory infection by group A β-hemolytic streptococcus and erythema nodosum is well-known, especially in children and young adults. Usually, the cutaneous lesions appear two or three weeks after the throat infection and they are accompanied by an elevation of the antistreptolysin-O (ASO) titre. An intradernal positive test to streptococcal antigens is often seen in patients with erythema nodosum secondary to streptococcal infections, although when the cutaneous nodules develop the cultures of routine throat swabs usually do not detect microorganisms.[10, 46]
Tuberculosis is now an uncommon etiologic factor for erythema nodosum in our country and other areas of southern Europe.[10, 11, 122] These cases are seen only in children and the cutaneous lesions usually indicate a primary pulmonary infection, being concomitant with the conversion of the tuberculin test.
Drugs are frequently implicated as the cause of erythema nodosum. Sulphonamides, bromides, and oral contraceptive pills have been long recognized as the most common medications responsible for acute bouts of erythema nodosum, but the list of possibilities is very large (Table 1). In recent years, the amount of hormones in contraceptive pills has been lowered markedly, and thus erythema nodosum secondary to this medication is now rare. In those cases in which the patient develops erythema nodosum after having taken an antibiotic for an infectious disease, it is difficult to discern whether the cutaneous reaction is due to the antiobiotic or the infectious agent.
Sarcoidosis constitutes one of the most common etiologic factors in adult patients with secondary erythema nodosum in our country. In some countries, specially in northern Europe, erythema nodosum and bilateral hilar adenopathy are frequently seen as early manifestations of sarcoidosis (Lofgren's syndrome). However, erythema nodosum and bilateral hilar adenopathy are not exclusively seen with sarcoidosis and they have also been associated with lymphoma, tuberculosis, streptococcal infections, coccidioidomycosis, and histoplasmosis. Furthermore, a recent prospective study in France demonstrated that a significant percentage of patients presented with Lofgren's syndrome as the first manifestation of acute infection due to Chlamydia pneumoniae.
In adults, erythema nodosum associated with enteropathies often correlates with a flare-up of the disease, although the cutaneous eruption may preceed the clinical appearance of the inflammatory bowel disease. Ulcerative colitis is more frequently associated with erythema nodosum than Crohn's disease.[103,120]
Many patients with Behçet disease develop lesions that clinically resemble those of erythema nodosum. Histopathologic studies, however, have demonstrated that a significant proportion of these patients with Behçet syndrome and erythema nodosum-like lesions showed a mostly lobular panniculitis with the frequent finding of leukocytoclastic or lymphocytic vasculitis.[126, 127] In other words, some patients with Behçet disease show a panniculitis different from that of erythema nodosum.
The simultaneous occurrence of Sweet syndrome and erythema nodosum have been considered a rare association.[117, 128, 129, 130, 131, 132, 133] In 1992, Cohen et al. reviewed the world literature and found 8 biopsy-proven cases, none of which was associated with an underlying malignant neoplasm. In 1993, Wilkinson et al. described two additional cases, one occurred in association with sarcoidosis and the other one appeared after an upper respiratory tract infection. In 1995 Ben-Noun also reported a case that occurred after a streptococcal pharyngitis. In 1995 Suzuki et al. described a patient with acute myelogenous leukemia in whom Sweet syndrome also developed. There was rapid improvement of the cutaneous lesions after treatment with prednisolone, but one year later, erythema nodosum reappeared. In 1999, Watz et al. reported two patients with simultaneous occurrence of Sweet syndrome and erythema nodosum, one patient with acute myelogenous leukemia and the other patient with Crohn's disease. However, recently Ginarte and Toribio commented that the association between Sweet syndrome and erythema nodosum is not as rare as the review of the published case reports seems to indicate, since this carries an important bias. These authors reviewed several series of patients with Sweet syndrome and found that 15-30 percent of patients with Sweet syndrome showed biopsy-proved erythema nodosum.[134, 135, 136, 137, 138] Based on these data, Ginarte and Toribio concluded that the simultaneous occurrence of these two reactive processes is a frequent feature that may be due to a common underlying mechanism of pathogenesis (streptococcal upper respiratory tract infection or inflammatory bowel disease) and they respond to the same treatment (corticosteroids, potassium iodide), also supporting a close relationship between them.
Despite thorough clinical and laboratory investigations, the etiology of erythema nodosum remained uncertain in a significant percentage of cases, ranging from 37-60% of cases in all reported series.[6, 10, 11, 60, 122, 139, 140]
Erythema nodosum is considered to be a hypersensitivity response to a wide variety of inciting factors. The variability of possible antigenic stimuli that can induce erythema nodosum indicates that this disorder is a cutaneous reactive process and that the skin has limited responses to different provoking agents. Erythema nodosum probably results from the formation of immune complexes and their deposition in and around venules of the connective tissue septa of the subcutaneous fat. Circulating immunocomplexes and complement activation have been recorded in patients with erythema nodosum.[141, 142, 143] Histopathologic features in fully developed lesions also suggest a delayed hypersensitivity mechanism and direct immunofluorescence studies have shown deposits of immunoglobulins in the blood vessel walls of the septa of subcutaneous fat.[144, 145] However, other authors failed to demonstrate circulating immunocomplexes in patients with erythema nodosum, and a type IV delayed hypersensitivity reaction may also play an important role in the pathogenesis of the disorder.
Early lesions of erythema nodosum are histopathologically characterized by a neutrophilic inflammatory infiltrate involving the septa of the subcutaneous tissue. Recent investigations have demonstrated that patients suffering from erythema nodosum had a fourfold higher percentage of reactive oxygen intermediates (ROI) produced by activated neutrophils in their peripheral blood compared with healthy volunteers. Furthermore, the percentage of ROI-producing cells in patients with erythema nodosum correlated with the clinical severity. These data support that ROI might play a role in the pathogenesis of erythema nodosum. ROI might exert their effects by oxidative tissue damage and by promoting tissue inflammation.
Patients with erythema nodosum associated with sarcoidosis produce an uncommon tumor necrosis factor,TNF-α II. These patients showed a nucleotide exchange, (G-A) at position -308 in the human TNF-α gene promoter, whereas patients with erythema nodosum without underlying sarcoidosis displayed a similar allele frequency compared with controls. These results support the notion that erythema nodosum in association with sarcoidosis might be pathogenetically linked to altered TNF-α production due to a genetic promoter polymorphism. In contrast, other authors have found that the proinflammatory cytokine pattern showed increased interleukin-6 serum concentrations both in infectious and non infectious disease-related erythema nodosum, whereas a minor involvement of TNF was found in these patients.
The reason the anterior aspects of the legs are so susceptible for the development of lesions of erythema nodosum is unknown. Some authors have proposed that there is no other site on the skin surface where the combination of a relatively sparse arterial supply is associated with a venous system subject to gravitational effects and cooling and a lymphatic system which is hardly rich enough to meet the requirements of any increase in fluid load and which has no mechanical stimulus. The skin of the shins has no underlying muscle pump and receives little in the way of massage. All these local anatomic factors would favor the location of the lesions of erythema nodosum on the shins.
Since the list of possible etiologic factors in erythema nodosum is extensive, a rational, cost-effective diagnostic approach in patients with erythema nodosum is desirable. A complete clinical history should be elicited in all patients, with reference of previous diseases, medications, foreign travel, pets and hobbies, as well as familial cases.
Initial evaluation should include complete blood count, determination of the sedimentation rate, antistreptolysin-O (ASO) titer, urinalysis, throat culture, intradermal tuberculin test and chest roentgenogram. The white blood count is normal or only slightly raised, but the erythrocyte sedimentation rate is often very high, returning to normal when the eruption fades. In children, the elevation of the erythrocyte sedimentation rate correlates significantly with the number of cutaneous lesions. The rheumatoid factor is usually negative but there is a temporary rise in the α2-globulin. A high antistreptolysin titre is seen in those cases of erythema nodosum associated with a streptococcal throat infection. Usually, a significant change, at least 30%, in (ASO) titer in two consecutive determinations performed in a 2-4 week interval indicates recent streptococcal infection. When the etiology is doubtful, a sample of blood should be serologically investigated for those bacterial, virological, fungal or protozooal infections more prevalent in that area.
In those cases suspected of being tuberculous, an intradermal tuberculin test should be performed, but the results must be interpreted in the context of the tuberculous prevalence in the studied area. In Spain, a significant percentage of healthy adults show positive results for the tuberculin test. In sarcoidosis, there is a decrease in the degree of reactivity of previously positive patients. The Kvein test is now less used because of fears of AIDS transmission.
A chest X-ray should be performed in all patients with erythema nodosum to rule out pulmonary diseases as the cause of the cutaneous reactive process. Radiologically demonstrable bilateral hilar lymphadenopathy with febrile illness and erythema nodosum with no evidence of tuberculosis characterize Lofgren's syndrome, which in most cases represents an acute variant of pulmonary sarcoidosis with a benign course. This syndrome is more frequent in females, especially during pregnancy and the puerperium.
Histopathologically, erythema nodosum is the stereotypical example of a mostly septal panniculitis with no vasculitis. The septa of subcutaneous fat are always thickened and variously infiltrated by inflammatory cells that extend to the periseptal areas of the fat lobules. Usually, a superficial and deep perivascular inflammatory infiltrate predominantly composed of lymphocytes is also seen in the overlying dermis. This dermal inflammation along with vasodilatation probably accounts for the erythematous appearance of early lesions, whereas the changes in the subcutis are responsible for the nodularity of the lesions on palpation.
The composition of the inflammatory infiltrate in the septa varies with the age of the lesion. In early lesions, edema, hemorrhage, and neutrophils (Figure 10) are responsible for the septal thickening, whereas fibrosis, periseptal granulation tissue, lymphocytes, and multinucleated giant cells are the main findings in late stage lesions of erythema nodosum. In rare instances eosinophils are the predominant inflammatory cells in early lesions of erythema nodosum. Sometimes, in these early lesions the inflammatory cell infiltrate may be more apparent in the fat lobules than in the septa, because inflammatory cells extend into the periphery of the fat lobules between individual fat cells in a lace-like fashion, and the process appears as a predominantly lobular panniculitis. However, in contrast with authentic lobular panniculitis, necrosis of the adipocytes is not prominent. A histopathologic hallmark of erythema nodosum is the presence of the so-called Miescher's radial granulomas, that consist of small, well-defined nodular aggregations of small histiocytes around a central stellate or banana shaped cleft (Figure 11).[150, 151, 152] The nature of the central cleft is unknown and although some authors have considered them as lymphatic spaces, our immunohistochemical and ultrastructural studies of cases of Miescher's radial granulomas have failed to demonstrate endothelial or other cellular lining of these clefts. In early lesions, Miescher's radial granulomas appear scattered in the septa and surrounded by neutrophils. In older nodules of erythema nodosum, histiocytes coalesce to form multinucleated giant cells, many of which still retain in their cytoplasm a stellate central cleft reminiscent of those centers of Miescher's radial granuloma (Figures 12-14). Sometimes Miescher's radial granulomas are conspicuous in the septa, but occasionally serial sections may be necessary to identify them. In our view, these Miescher's radial granulomas are present in all stages of the evolution of erythema nodosum lesions and they should be searched for in order to make a specific diagnosis. However, in our experience, Miescher's radial granulomas are specific for erythema nodosum, other authors believe that similar granulomas may be present in lesions of Sweet syndrome, erythema induratum of Bazin, Behçet disease, and necrobiosis lipoidica. Another histopathologic characteristic of erythema nodosum is the absence of vasculitis, although in rare instances a necrotizing small vessel vasculitis with fibrinoid necrosis of the vessel walls has been described in the septa. Histopathologic study of a series of 79 cases of erythema nodosum, demonstrated that authentic leukocytoclastic vasculitis is usually absent, and only 18 of 79 specimens disclosed slight nonspecific changes in some isolated veins and venules, whereas many other vessels were intact in the middle of the inflammatory nodule. In contrast with these findings, ultrastructural studies in erythema nodosum have described damage to endothelial cells of the small vessels of the septa of subcutaneous fat with some extension of inflammatory cells into the vessel walls.[154, 155]
In late stage lesions of erythema nodosum, the inflammatory infiltrate in the septa is sparse, and there are markedly widened septa with granulation tissue at the interface between connective tissue septa and fat lobules. (Figure 15) As erythema nodosum evolves, the septa become fibrotic and replaced by granulomas, and the fat lobules become progressively replaced and effaced by widening septa, which can even completely obliterate the lobules. In these late lesions it may be difficult to establish whether the lesion is a mostly septal or mostly lobular panniculitis, because the entire subcutaneous tissue is effaced by a fibrotic and granulomatous process. With time, despite the striking fibrosis, the lesions resolve without atrophy or scarring of the involved septa.
Lipomembranous or membranocystic panniculitis is a histopathologic pattern that has been described in residual lesions of different types of panniculitis, including erythema nodosum. It consists of cystic spaces in the fat lobule that result from necrosis of the adipocytes. The cystic spaces are lined with a homogeneous eosinophilic membrane with convoluted projections into the cystic cavity. These intracystic papillary projections stain brightly with periodic acid-Schiff and Sudan black and are resistant to diastase. In our opinion, lipomembranous or membranocystic panniculitis is a histopathologic pattern that may been seen in residual lesions of different types of panniculitis and is not a specific variant of panniculitis.
Histopathologic study of lesions of erythema nodosum in patients with systemic or discoid lupus erythematosus demonstrated, in addition to septal thickening with foci of foreign body giant cell collection accompanied by areas of hemorrhage, varying degrees of hyalin necrosis of fat lobules, as well as thickening, hyalinization, and fibrin deposition in and around the walls of small septal blood vessels. These features probably reflect the underlying connective tissue disease with a superimposed picture of typical erythema nodosum and may be a helpful clue to the clinical background of a connective tissue disorder.
Erythema induratum of Bazin is the main differential diagnosis for erythema nodosum. The clinical picture or erythema nodosum differs from erythema induratum of Bazin in showing lesions usually located on the shins that regress in a few weeks with no tendency for necrosis and scarring. In contrast, typical lesions of erythema induratum of Bazin appear on the posterior aspects of the legs of adult women with erythrocyanotic circulation, are more persistent, often ulcerate (Figure 16), and regress leaving an atrophic scar. In atypical cases, the differential diagnosis between these two entities may be solved by histopathological examination, because erythema nodosum is a mostly septal panniculitis, whereas erythema induratum of Bazin is a predominantly lobular panniculitis (Figure 17). For this differential diagnosis, biopsy specimens taken by scalpel excision are preferable to punch biopsies, and when available, early lesions from as proximal a site as possible should be selected. Table 2 summarizes the main clinical and histopathological differences between erythema nodosum and erythema induratum of Bazin.
Cutaneous lesions of superficial thrombophlebitis may show a clinical appearance similar to that of erythema nodosum. However, the lesions are usually located on the sides of the lower legs and consist of hard, irregular and fibrotic cords or plaques rather than erythematous nodules (Figure 18). A biopsy of these lesions demonstrates that the affected vein appears with luminal thrombosis and with inflammatory infiltrate within its wall (Figure 19). In contrast to erythema nodosum, and despite the intense damage of the involved vein with dense inflammatory infiltrate, lesions of superficial thrombophlebitis show little or no inflammatory infiltrate in the connective tissue of the septa and the adjacent fat lobule, and the process is more vasculitic than panniculitic.
Cutaneous polyarteritis nodosa can also present as bilateral tender erythematous nodules on the lower legs. However, the involved area usually shows livedo reticularis; the nodules are preferentially located on the calves and often ulcerate (Figure 20). Histopathologically, lesions of cutaneous polyarteritis nodosa show vasculitis involving medium sized arteries and arterioles at the septa of the subcutaneous tissue. The involved vessels appear with a thickened wall, and characteristically, the tunica intima of the involved artery exhibits an eosinophilic ring of fibrinoid necrosis, giving a targetlike appearance to the vessels (Figure 21). As in superficial thrombophlebitis, cutaneous polyarteritis nodosa is a vasculitic process with little or no inflammatory involvement of the adjacent septa and lobules of the subcutaneous tissue.
Because fully developed lesions of erythema nodosum are histopathologically characterized by a granulomatous component, subcutaneous sarcoidosis (Figure 22) should also considered. However, in subcutaneous sarcoidosis granulomatous involvement predominates in the fat lobules rather than in the septa (Figure 23), and the septa do no exhibit the fibrosis and the thickening usually seen in fully developed lesions of erythema nodosum.
Erythema nodosum leprosum is an inadequate term to describe an immune-complex vasculitic process involving the dermis of patients with lepromatous leprosy. The term is misleading because it may easily be confused with authentic erythema nodosum. In most cases the process develops when therapy results in massive death of lepra bacilli and the lesions present not only as nodules, but also as necrotic, pustular or hemorrhagic lesions. The face, which is rarely involved in authentic erythema nodosum, is a frequent location for lesions of erythema nodosum leprosum . In doubtful cases a biopsy should easily distinguish between the two. Erythema nodosum leprosum is a process involving the dermis, and when it extends to the subcutaneous fat, the small blood vessels of the fat lobule are severely damaged and appear with fibrinoid necrosis of their wall and luminal thrombi. Special stains demonstrate numerous dead and degenerated acid-fast bacilli. In contrast, biopsies of erythema nodosum show a mostly septal panniculitis without vasculitis.
Plantar erythema nodosum should be differentiated from the so-called traumatic plantar urticaria, which consists of tender erythematous nodules which develop on the soles of children after physical activity. Some authors believe that plantar erythema nodosum and traumatic plantar urticaria in children are the same entity rather than two different processes, although the lesions reported as traumatic plantar urticaria regressed in a few hours or days. Furthermore, histopathologic study demonstrated a perivascular inflammatory infiltrate of neutrophils and lymphocytes in the papillary and reticular dermis. However, the biopsies of those cases reported as traumatic plantar urticaria contained no subcutaneous fat at all, and therefore a diagnosis of plantar erythema nodosum could be not definitely ruled out.[161, 162] Palmoplantar erythema nodosum in children should be also differentiated from idiopathic palmoplantar neutrophilic eccrine hidradenitis, which is also clinically characterized by painful erythematous nodules involving the palms and soles of children that appear after physical activity.[163, 164, 165, 166, 167, 168, 169, 170] However, the histopathologic differential diagnosis between idiopathic palmoplantar neutrophilic hidradenitis and erythema nodosum is straightforward, because in the former the neutrophilic infiltrate is surrounding and within the eccrine coils of the deeper dermis, whereas in early erythema nodosum, neutrophils of the inflammatory infiltrate are interstitially arranged between collagen bundles of the septa of the subcutaneous tissue.
Cutaneous B-cell lymphoma may present with erythematous tender nodules on the lower extremities mimicking erythema nodosum clinically (Figure 24).[171, 172] However histopathologic study reveals atypical lymphocytes, with hyperchromatic nuclei and mitotic figures involving both the septa and the fat lobule (Figure 25) or within the lumina of the blood vessels of the subcutaneous fat in cases of intravascular B-cell subcutaneous lymphoma.[171, 172]
Most cases of erythema nodosum regress spontaneously in 3-4 weeks. More severe cases require about 6 weeks to resolve. Relapses are exceptional, but they are more common in patients with idiopathic erythema nodosum and erythema nodosum associated with nonstreptococcal or streptococcal upper respiratory tract infections.  In elderly patients, especially those with severe venous insufficiency and gravitational edema of the lower extremities, the acute episode of erythema nodosum may be followed by a persistent erythematous swelling of the ankles (Figure 26).
Complications of erythema nodosum are uncommon. One patient developed retrobulbar optic nerve neuritis during the acute episode of erythema nodosum, and another patient with chronic hepatitis C had erythema nodosum with concomitant erythema multiforme and lichen planus that coincided with the reactivation of viral replication.[173, 174]
Treatment of erythema nodosum should be directed to the underlying associated condition, if identified. Usually, nodules of erythema nodosum regress spontaneously within a few weeks, and bed rest is often sufficient treatment. Aspirin and nonsteroidal anti-inflammatory drugs such as oxyphenbutazone, in a dosage of 400 mg per day, indomethacin, in a dosage of 100 to 150 mg per day, or naproxen, in a dosage of 500 mg per day, may be helpful to enhance analgesia and resolution.[175, 176, 177] If the lesions persist longer, potassium iodide in a dosage of 400 to 900 mg daily or a saturated solution of potassium iodide, 2 to 10 drops in water or orange juice three times per day, has been reported to be useful.[178, 179, 180] The mechanism of action of potassium iodide in erythema nodosum is unknown, but a theoretical mechanism involves its stimulation of heparin release from mast cells. Heparin acts to suppress delayed hypersensitivity reactions. The reported response in some patients with erythema nodosum lesions to heparinoid ointment under occlusion supports this proposed mechanism of action. On the other hand, potassium iodide also inhibits neutrophil chemotaxis. Potassium iodide is contraindicated during pregnancy, because it can produce a goiter in the fetus. Severe hypothyroidism secondary to exogenous intake of iodide has been also described in patients with erythema nodosum treated with potassium iodide.
Systemic corticosteroids are rarely indicated in erythema nodosum and before these drugs are administered an underlying infection should be ruled out. When administered, prednisone in a dosage of 40 mg per day has been followed by resolution of the nodules in few days. Intralesional injection of triancinolone acetonide, in a dosage of 5 mg/ml, into the center of the nodules may cause them to resolve.
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