Erythema nodosum

Background

This is a septal panniculitis which presents with painful, erythematous nodules usually 1-5 cm in diameter. They are usually located on the anterior lower legs, arms, soles, and trunk. The lesions may be associated with fever, malaise, and arthralgia. Resolution after 2-6 weeks is the usual course. There are numerous associations but in 1/3 of cases, no association can be found.

OUTLINE

Disease Associations

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Differential Diagnosis

Prognosis

Treatment

Commonly Used Terms

Internet Links

DISEASE ASSOCIATIONS CHARACTERIZATION

ANTIPHOSPHOLIPID ANTIBODIES

Erythema nodosum associated with antiphospholipid antibodies: a report of three cases.

Nekhlyudov L, Gradzka M, Conti-Kelly AM, Greco TP.

Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
Lupus 2000;9(8):641-5 Abstract quote
Erythema nodosum is a dermatologic condition characterized by painful, erythematous nodules on the anterior surfaces of the lower extremities. Its association with a variety of conditions has been previously described.

We present three cases of erythema nodosum in patients with elevated anticardiolipin antibodies. In one patient, a temporal relationship was seen in the simultaneous detection of antibodies and skin lesions.

We propose an association between erythema nodosum and the antiphospholipid antibody syndrome (APS).

DRUGS
Sulfonamides
Penicillin
Minocycline
Salicylates
Iodides
Gold salts
Oral contraceptives

ECHINACEA

Recurrent erythema nodosum associated with echinacea herbal therapy
J Am Acad Dermatol 2001;44:298-9

A case report

INFECTIONS Tularemia
Streptococcal infections
Campylobacter
Salmonella
Histoplasma
Yersinia

SARCOIDOSIS

Papular sarcoidosis of the knees: a clue for the diagnosis of erythema nodosum-associated sarcoidosis.

Marcoval J, Moreno A, Mana J.

Department of Dermatology, Pathology, Hospital de Bellvitge, University of Barcelona, Spain.
J Am Acad Dermatol. 2003 Jul;49(1):75-8. Abstract quote
BACKGROUND: In recent years we have systematically explored the skin whenever sarcoidosis was suggested and we have observed with increasing frequency the presence of granulomatous cutaneous lesions of sarcoidosis involving the knees.

OBJECTIVE: We sought to evaluate the specific cutaneous lesions of sarcoidosis involving the knees.

METHODS: A total of 18 patients with biopsy-proven specific cutaneous sarcoidosis predominantly involving the knees were included in the study. Biopsy specimens were evaluated under polarized light.

RESULTS: Of these cases, 4 corresponded to scar-sarcoidosis, 1 to plaque-type sarcoidosis, and 13 were an admixture of papules and minute scars frequently associated with erythema nodosum (papular sarcoidosis of the knees). Foreign particles were observed in 10 of 13 patients with papular sarcoidosis.

CONCLUSION: Papular sarcoidosis of the knees can be considered a frequent form of cutaneous sarcoidosis, mainly observed in acute forms of the disease, and frequently associated with erythema nodosum.

Sarcoid and erythema nodosum arthropathies.

Pettersson T.

Department of Medicine, Helsinki University Central Hospital, HUCH, FIN-00029, Finland.

Baillieres Best Pract Res Clin Rheumatol 2000 Sep;14(3):461-76 Abstract quote
Sarcoidosis is a systemic granulomatous disease of unknown origin, characterized in affected organs by an accumulation of activated T lymphocytes and macrophages. Musculoskeletal manifestations of sarcoidosis include acute and chronic arthritis and muscular and osseous sarcoidosis.

In certain populations, acute sarcoidosis often presents with constitutional symptoms, polyarthritis and erythema nodosum (Lofgren's syndrome). Erythema nodosum, often with joint symptoms, also occurs in association with several other conditions including infections, medications and other underlying diseases.

The diagnosis of sarcoidosis should be based on a tissue biopsy, but a patient with typical Lofgren's syndrome may not require biopsy proof. Among the long list of biochemical markers that have been suggested as aids for diagnosis and monitoring of sarcoidosis, calcium in serum and urine and angiotensin-converting enzyme in serum are well-established clinical tools. Serum angiotensin-converting enzyme can be used for monitoring disease activity in the individual patient, but because of lack of sensitivity and specificity its diagnostic value is rather low.

Non-steroidal anti-inflammatory agents usually effectively alleviate acute sarcoid arthritis and joint symptoms associated with erythema nodosum. In severe acute arthritis and in chronic arthritis, corticosteroids may be required to control the symptoms. In patients requiring persistent corticosteroid therapy, antimalarial agents and methotrexate constitute therapeutic alternatives.

SWEET'S SYNDROME

Sweet's syndrome evolved from recurrent erythema nodosum in a patient with myelodysplastic syndrome.

Nishie W, Kimura T, Kanagawa M.

Department of Dermatology, Kin-I-kyo Central Hospital, Sapporo, Japan.

J Dermatol 2002 Feb;29(2):91-5 Abstract quote
A 63-year-old man had painful nodules on his lower legs. Microscopic examination showed septal and lobular panniculitis composed of lympho-histiocytic infiltrates.
Based on the clinical and histopathological findings, the diagnosis of erythema nodosum (EN) was made. Nonsteroidal anti-inflammatory drugs were temporarily effective, but the eruptions had repeated to the present, and 16 months later, myelodysplastic syndrome (MDS) was diagnosed. Then, 6 months later, he developed a high fever and edematous fresh red-colored nodules on his neck, arm and upper trunk.

Histopathologically, a diffuse, dense, dermal infiltrate of neutrophils was seen, and Sweet's syndrome (SS) was diagnosed. SS is known to develop in patients with MDS, and EN is one of the dermatoses that occur in conjunction with hematoproliferative disorders. Furthermore, SS evolving from recurrent EN and the simultaneous occurrence of SS and EN have been reported in some patients.
In our case, we suggest that some mediators such as cytokines associated with MDS might have first induced EN, and then, as the MDS developed, they were replaced by others that caused SS.

SYSTEMIC DISEASES Sarcoidosis
Sweet's syndrome
Behcet's disease
Inflammatory bowel disease
Carcinomas
Leukemia
Lymphoma

GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION

GENERAL

Erythema nodosum.

Requena L, Requena C.

Department of Dermatology, Fundacion Jimenez Diaz, Universidad Autonoma, Madrid, Spain.

Dermatol Online J 2002 Jun;8(1):4 Abstract quote
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: prospective study of 32 cases.

Fernandes NC, Maceira J, Muniz Mde M.

Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Hospital Universitario Clementino Fraga Filho, Brasil.

Rev Inst Med Trop Sao Paulo 1994 Nov-Dec;36(6):507-13 Abstract quote
The results of 32 cases studied lead us to the conclusion that erythema nodosum's investigation routine is very important, once in our retrospective study, the percentage of cases of unknown etiology was 69.4%, and in this prospective study it is 21.8%.

In 10 cases (31.2%), more than one causing agent was suspected. Infections (bacterial, helminthic, fungal, by protozoa) were diagnosed in 26 cases, streptococcal infection having predominated (12 cases). Drugs-dipirone, aspirin, anovulatory--were suspected as causing agents in 13 cases.

The association of erythema nodosum and histoplasmosis capsulata is described for the first time in Brazil.

We consider erythema nodosum to be a complex syndrome which should be regarded as a manifestation of underlying diseases. The fact that all 32 subjects were women, 26 of them during menacme, suggests that particular hormonal media may favor the action of various processes (infections and drugs), precipitating erythema nodosum's clinical picture.

VARIANTS

PEDIATRIC
J Am Acad Dermatol 2001;44:17-21

35 children
27/35 (77%) secondary to infection
Beta hemolytic Streptococcus 17
Mycoplasma pneumoniae 3
Yersinia enterocolitica 1
Pseudomonas 1
M. Tb 2
Crohn's 2
Hodgkin's disease 1
Unknown 8

Mean duration of 11.5 days
Recurrences in 2

Erythema nodosum in children: a study of 27 patients.

Labbe L, Perel Y, Maleville J, Taieb A.

Pediatric Dermatology Unit, Hopital Pellegrin Enfants, Bordeaux, France.
Pediatr Dermatol 1996 Nov-Dec;13(6):447-50 Abstract quote
Erythema nodosum (EN) seems to occur in children more rarely than in adults. It still remains the most frequent acute panniculitis, for which the diagnosis is almost always clinical.

In a retrospective study of 27 pediatric patients, we have attempted to clarify the clinical spectrum and prognosis of this disease and discuss the differential diagnosis of nodular eruptions on the lower limbs of children. In almost half the patients of our series, the cause of EN remained undetermined. Streptococcal infections (usually of the pharynx) were the most common cause of EN in children (22% of patients in our series), followed by Yersinia infection in about 15% of patients. Tuberculosis, an important cause in the past, was never found, but must always be excluded.

A benign course was noted in all patients. Erythema nodosum is easily recognized clinically, but other subcutaneous lesions, especially nodular vasculitis and Schonlein-Henoch purpura, have to be excluded by pathologic study, in cases of atypical presentation or long duration.

HISTOLOGICAL TYPES CHARACTERIZATION

GENERAL
The septal panniculitis can be discerned by low power magnification under the microscope
Lymphocytes mixed with giant cells, histiocytes, and eosinophils.

Miescher's radial granulomas may be present but true tuberculoid type granulomas are uncommon.

Early lesions may contain neutrophils.
Endothelial swelling of the septal vessels is common but a true vasculitis is rare.

Histopathologic spectrum of erythema nodosum.

Thurber S, Kohler S.

Department of Dermatology, Stanford University, Stanford, CA, USA.

J Cutan Pathol. 2006 Jan;33(1):18-26. Abstract quote

Erythema nodosum (EN) is the most common panniculitis and histologically represents the prototype of a septal panniculitis. However, the histologic findings can be quite variable.

We describe four patients with EN who each underwent two consecutive biopsies. In each case, the first biopsy showed histopathologic features that fall outside the usual spectrum of disease. Two cases showed predominantly neutrophilic infiltrates with focal suppuration as well as vasculitis of medium-sized arteries. The areas of suppuration were more extensive in the first case prompting special stains for microorganisms that were all negative. The third case demonstrated a lobular panniculitis with a predominantly lymphohistiocytic infiltrate. Special stains were negative in this case as well. The fourth case revealed vasculitis of a medium sized artery, small vessel vasculitis, and a mixed septal and lobular panniculitis with a polyclonal population of atypical lymphocytes. In all patients, the clinical course and the subsequent biopsy were classic for EN.

We conclude that lobular neutrophilic panniculitis with suppuration, small vessel vasculitis, and even medium vessel arteritis may rarely occur in EN. There are few clues in these unusual cases that allow for a specific diagnosis from the start, and often, a second biopsy is required.

Miescher's radial granuloma. A characteristic marker of erythema nodosum.

Sanchez Yus E, Sanz Vico MD, de Diego V.

Departamento de Dermatologia, Hopsital Universitaro San Carlos, Facultad de Medicina, Universidad Complutense, Madrid, Spain.

Am J Dermatopathol 1989 Oct;11(5):434-42 Abstract quote
Miescher, in 1947 and 1951, described peculiar radial nodules in erythema nodosum (EN).

They consisted of relatively small histiocytes, radially placed around a central cleft. In early lesions, these nodules occurred in association with edema and infiltration of polymorphonuclear leukocytes; later, giant cells originated from the outer borders of the granuloma. Miescher's radial granulomas (MRGs) are mainly located in the interlobular septa and in the deeper layers of the cutis. Although Miescher considered this structure as being specific for EN, it has largely been ignored in the subsequent literature.

We have studied 79 biopsy specimens of EN and 182 biopsy specimens of other types of panniculitis. Sixty (76%) of the 79 biopsy specimens of EN disclosed some MRG whereas none was found in the other types of panniculitis. MRG is a characteristic and easily recognizable structure, even at low magnification, and appears to be a useful marker of EN.

A detailed study has also been made of the histologic features of EN. Its variations, as well as those of MRG, are related to the chronology of the nodule.

VARIANTS

CHRONIC MIGRATORY FORM OF VILANOVA Rare

Septal granulomatous panniculitis: comparison of the pathology of erythema nodosum migrans (migratory panniculitis) and chronic erythema nodosum.

de Almeida Prestes C, Winkelmann RK, Su WP.

Department of Dermatology, Mayo Clinic, Rochester, MN 55905.
J Am Acad Dermatol 1990 Mar;22(3):477-83 Abstract quote
Fifty-eight cases of septal granulomatous panniculitis were reviewed; 14 cases were diagnosed as erythema nodosum migrans (migratory panniculitis) and 36 as chronic erythema nodosum on the basis of clinical and histopathologic features.

Erythema nodosum migrans was characterized by markedly thickened and fibrotic septae, marked capillary proliferation (like granulation tissue), and massive granulomatous reaction (with giant cells) along the borders of the widened septa. Hemorrhage was rare, and phlebitis was not seen. Chronic erythema nodosum showed mild septal change, little fibrosis, and lymphohistiocytic perivascular inflammation with only focal granulomatous formation. Phlebitis and hemorrhage were common. The condition termed erythema nodosum migrans has many of the same clinical features as chronic erythema nodosum, and we think this term is preferable to migratory panniculitis.

We believe that there are sufficient clinical and histopathologic features to justify considering erythema nodosum migrans as a unique clinicopathologic entity.

FAT NECROSIS

Nodular cystic fat necrosis in a patient with erythema nodosum.

Ahn SK, Lee BJ, Lee SH, Lee WS.

Department of Dermatology, Younsei Wonju College of Medicine, Wonju, Korea.
Clin Exp Dermatol 1995 May;20(3):263-5 Abstract quote
Nodular cystic fat necrosis shows a distinctive spectrum of clinical and histological features. Most of the lesions are mobile subcutaneous nodules in regions vulnerable to trauma, such as the elbows, knees, and shins. There have been no reports of an association with other conditions.

The histology is characterized by encapsulated fat necrosis in which multiple, non-viable adipocytes are surrounded by condensed fibrous tissue.

We report a case of early stage nodular cystic fat necrosis associated with erythema nodosum.

DIFFERENTIAL DIAGNOSIS CHARACTERIZATION

BEHCET DISEASE

NODULAR VASCULITIS

Erythema nodosum versus nodular vasculitis.

Sanz Vico MD, De Diego V, Sanchez Yus E.

Department of Dermatology, Hospital Universitario San Carlos, Facultad de Medicina, Universidad Complutense, Madrid, Spain.

Int J Dermatol 1993 Feb;32(2):108-12 Abstract quote
BACKGROUND. Erythema nodosum (EN) is usually considered to be a septal panniculitis, and nodular vasculitis (NV) a lobular panniculitis. We tested the usefulness of this histologic classification in clarifying a frequent clinical dilemma: EN versus NV.

METHODS. Over 3 years 109 patients with panniculitis were included in this study. After a history and a physical examination, a clinical diagnosis was made according to well-established criteria.

RESULTS. From the study of 88 patients, we concluded that in the clinically typical cases, the clinico-pathologic agreement was 93% and 94% for EN and NV respectively, whereas it diminished to 79%, 72%, and 67% in the cases clinically diagnosed as EN migrans, atypical EN, and atypical NV, respectively. Moreover, septal and lobular panniculitis were always two clear-cut, different, opposite patterns of hypodermal inflammation to these conditions.

CONCLUSIONS. In the absence of a known pathogenetic mechanism, the histopathology remains the most objective discriminating marker between EN and NV, mainly in the clinically atypical and doubtful cases.

WHIPPLE'S DISEASE

Erythema nodosum-like lesions in treated Whipple's disease: signs of immune reconstitution inflammatory syndrome.

Schaller J, Carlson JA.

Department of Dermatohistology, Catholic Clinics, Duisburg, Germany.

J Am Acad Dermatol. 2009 Feb;60(2):277-88. Abstract quote

Treatment of systemic infections due to mycobacteria and HIV infection can lead to paradoxical worsening, the immune reconstitution inflammatory syndrome, in a minority of patients.

Herein we describe a patient with Whipple's disease, a chronic systemic inflammatory disease caused by Tropheryma whipplei, who developed cutaneous and later ocular disease after initiation of antibiotic therapy. A 42-year-old man with a 12-year history of arthralgias presented with deteriorating health, including weight loss, diarrhea, fever, and acral hyperkeratosis. Whipple's disease was suspected and subsequently confirmed by finding periodic acid-Schiff (PAS)-positive foamy macrophages and T whipplei DNA by polymerase chain reaction (PCR) assays in duodenal biopsy specimens. After 5 weeks of antibiotic treatment with ceftriaxone, erythema nodosum (EN)-like lesions developed on the legs and trunk. Notably, lesional and nonlesional skin harbored intracellular and extracellular degenerated bacteria that were associated with a neutrophilic and granulomatous inflammatory response in lesional skin. Continued antibiotic therapy was associated with recurring EN-like skin nodules, orbital swelling, and facial herpes simplex virus 1 infection. Corticosteroid therapy controlled the duration and severity of the EN-like nodules and orbital swelling.

Apart from cutaneous hyperpigmentation, skin disease in Whipple's disease is infrequent and can be categorized as disorders due to malnutrition from malabsorption or so-called reversal reactions consisting of reactive erythemas, and neutrophilic and granulomatous responses to T whipplei, the latter of which can represent an immune reconstitution inflammatory reaction after initiation of antibiotic therapy. Finally, based on the presence of T whipplei in normal skin, skin biopsy may serve as another site for diagnostic testing in patients suspected of having Whipple's disease.

TREATMENT CHARACTERIZATION

POTASSIUM IODIDE

Potassium iodide in the treatment of erythema nodosum and nodular vasculitis.

Horio T, Imamura S, Danno K, Ofuji S.
Arch Dermatol 1981 Jan;117(1):29-31 Abstract quote
Twenty-nine patients with erythema nodosum, nodular vasculitis, or erythema nodosum-like lesions associated with Behcet's syndrome were treated with potassium iodide.

Administration of the drug for systemic effect showed a substantial effect in 11 of 15 patients with erythema nodosum, seven of ten with nodular vasculitis, and one of four with leg lesions of Behcet's syndrome. Relief of subjective symptoms, including tenderness, joint pain, and fever, occurred within 24 hours. Substantial improvement in the eruption occurred within a few days, and the lesions disappeared completely ten to 14 days after therapy was initiated. The patients to whom the medication was administered shortly after the initial onset of erythema nodosum seemed to respond most satisfactorily.

The effect of the drug was marked in the patients with positive C-reactive protein reactions, joint pains, and/or fever. Possible mechanisms by which potassium iodide exerts its effect are discussed.

Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fifth Edition. Mosby Elesevier 2008

Commonly Used Terms

Miescher's radial granulomas-Spindled to oval histiocytes arranged around a minute slit.

Panniculitis

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DISEASE ASSOCIATIONS	CHARACTERIZATION
ANTIPHOSPHOLIPID ANTIBODIES
Erythema nodosum associated with antiphospholipid antibodies: a report of three cases. Nekhlyudov L, Gradzka M, Conti-Kelly AM, Greco TP. Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.	Lupus 2000;9(8):641-5 Abstract quote Erythema nodosum is a dermatologic condition characterized by painful, erythematous nodules on the anterior surfaces of the lower extremities. Its association with a variety of conditions has been previously described. We present three cases of erythema nodosum in patients with elevated anticardiolipin antibodies. In one patient, a temporal relationship was seen in the simultaneous detection of antibodies and skin lesions. We propose an association between erythema nodosum and the antiphospholipid antibody syndrome (APS).
DRUGS	Sulfonamides Penicillin Minocycline Salicylates Iodides Gold salts Oral contraceptives
ECHINACEA
Recurrent erythema nodosum associated with echinacea herbal therapy	J Am Acad Dermatol 2001;44:298-9 A case report
INFECTIONS	Tularemia Streptococcal infections Campylobacter Salmonella Histoplasma Yersinia
SARCOIDOSIS
Papular sarcoidosis of the knees: a clue for the diagnosis of erythema nodosum-associated sarcoidosis. Marcoval J, Moreno A, Mana J. Department of Dermatology, Pathology, Hospital de Bellvitge, University of Barcelona, Spain.	J Am Acad Dermatol. 2003 Jul;49(1):75-8. Abstract quote BACKGROUND: In recent years we have systematically explored the skin whenever sarcoidosis was suggested and we have observed with increasing frequency the presence of granulomatous cutaneous lesions of sarcoidosis involving the knees. OBJECTIVE: We sought to evaluate the specific cutaneous lesions of sarcoidosis involving the knees. METHODS: A total of 18 patients with biopsy-proven specific cutaneous sarcoidosis predominantly involving the knees were included in the study. Biopsy specimens were evaluated under polarized light. RESULTS: Of these cases, 4 corresponded to scar-sarcoidosis, 1 to plaque-type sarcoidosis, and 13 were an admixture of papules and minute scars frequently associated with erythema nodosum (papular sarcoidosis of the knees). Foreign particles were observed in 10 of 13 patients with papular sarcoidosis. CONCLUSION: Papular sarcoidosis of the knees can be considered a frequent form of cutaneous sarcoidosis, mainly observed in acute forms of the disease, and frequently associated with erythema nodosum.
Sarcoid and erythema nodosum arthropathies. Pettersson T. Department of Medicine, Helsinki University Central Hospital, HUCH, FIN-00029, Finland.	Baillieres Best Pract Res Clin Rheumatol 2000 Sep;14(3):461-76 Abstract quote Sarcoidosis is a systemic granulomatous disease of unknown origin, characterized in affected organs by an accumulation of activated T lymphocytes and macrophages. Musculoskeletal manifestations of sarcoidosis include acute and chronic arthritis and muscular and osseous sarcoidosis. In certain populations, acute sarcoidosis often presents with constitutional symptoms, polyarthritis and erythema nodosum (Lofgren's syndrome). Erythema nodosum, often with joint symptoms, also occurs in association with several other conditions including infections, medications and other underlying diseases. The diagnosis of sarcoidosis should be based on a tissue biopsy, but a patient with typical Lofgren's syndrome may not require biopsy proof. Among the long list of biochemical markers that have been suggested as aids for diagnosis and monitoring of sarcoidosis, calcium in serum and urine and angiotensin-converting enzyme in serum are well-established clinical tools. Serum angiotensin-converting enzyme can be used for monitoring disease activity in the individual patient, but because of lack of sensitivity and specificity its diagnostic value is rather low. Non-steroidal anti-inflammatory agents usually effectively alleviate acute sarcoid arthritis and joint symptoms associated with erythema nodosum. In severe acute arthritis and in chronic arthritis, corticosteroids may be required to control the symptoms. In patients requiring persistent corticosteroid therapy, antimalarial agents and methotrexate constitute therapeutic alternatives.
SWEET'S SYNDROME
Sweet's syndrome evolved from recurrent erythema nodosum in a patient with myelodysplastic syndrome. Nishie W, Kimura T, Kanagawa M. Department of Dermatology, Kin-I-kyo Central Hospital, Sapporo, Japan.	J Dermatol 2002 Feb;29(2):91-5 Abstract quote A 63-year-old man had painful nodules on his lower legs. Microscopic examination showed septal and lobular panniculitis composed of lympho-histiocytic infiltrates. Based on the clinical and histopathological findings, the diagnosis of erythema nodosum (EN) was made. Nonsteroidal anti-inflammatory drugs were temporarily effective, but the eruptions had repeated to the present, and 16 months later, myelodysplastic syndrome (MDS) was diagnosed. Then, 6 months later, he developed a high fever and edematous fresh red-colored nodules on his neck, arm and upper trunk. Histopathologically, a diffuse, dense, dermal infiltrate of neutrophils was seen, and Sweet's syndrome (SS) was diagnosed. SS is known to develop in patients with MDS, and EN is one of the dermatoses that occur in conjunction with hematoproliferative disorders. Furthermore, SS evolving from recurrent EN and the simultaneous occurrence of SS and EN have been reported in some patients. In our case, we suggest that some mediators such as cytokines associated with MDS might have first induced EN, and then, as the MDS developed, they were replaced by others that caused SS.
SYSTEMIC DISEASES	Sarcoidosis Sweet's syndrome Behcet's disease Inflammatory bowel disease Carcinomas Leukemia Lymphoma

GROSS APPEARANCE/CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
Erythema nodosum. Requena L, Requena C. Department of Dermatology, Fundacion Jimenez Diaz, Universidad Autonoma, Madrid, Spain.	Dermatol Online J 2002 Jun;8(1):4 Abstract quote 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: prospective study of 32 cases. Fernandes NC, Maceira J, Muniz Mde M. Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Hospital Universitario Clementino Fraga Filho, Brasil.	Rev Inst Med Trop Sao Paulo 1994 Nov-Dec;36(6):507-13 Abstract quote The results of 32 cases studied lead us to the conclusion that erythema nodosum's investigation routine is very important, once in our retrospective study, the percentage of cases of unknown etiology was 69.4%, and in this prospective study it is 21.8%. In 10 cases (31.2%), more than one causing agent was suspected. Infections (bacterial, helminthic, fungal, by protozoa) were diagnosed in 26 cases, streptococcal infection having predominated (12 cases). Drugs-dipirone, aspirin, anovulatory--were suspected as causing agents in 13 cases. The association of erythema nodosum and histoplasmosis capsulata is described for the first time in Brazil. We consider erythema nodosum to be a complex syndrome which should be regarded as a manifestation of underlying diseases. The fact that all 32 subjects were women, 26 of them during menacme, suggests that particular hormonal media may favor the action of various processes (infections and drugs), precipitating erythema nodosum's clinical picture.
VARIANTS
PEDIATRIC	J Am Acad Dermatol 2001;44:17-21 35 children 27/35 (77%) secondary to infection Beta hemolytic Streptococcus 17 Mycoplasma pneumoniae 3 Yersinia enterocolitica 1 Pseudomonas 1 M. Tb 2 Crohn's 2 Hodgkin's disease 1 Unknown 8 Mean duration of 11.5 days Recurrences in 2
Erythema nodosum in children: a study of 27 patients. Labbe L, Perel Y, Maleville J, Taieb A. Pediatric Dermatology Unit, Hopital Pellegrin Enfants, Bordeaux, France.	Pediatr Dermatol 1996 Nov-Dec;13(6):447-50 Abstract quote Erythema nodosum (EN) seems to occur in children more rarely than in adults. It still remains the most frequent acute panniculitis, for which the diagnosis is almost always clinical. In a retrospective study of 27 pediatric patients, we have attempted to clarify the clinical spectrum and prognosis of this disease and discuss the differential diagnosis of nodular eruptions on the lower limbs of children. In almost half the patients of our series, the cause of EN remained undetermined. Streptococcal infections (usually of the pharynx) were the most common cause of EN in children (22% of patients in our series), followed by Yersinia infection in about 15% of patients. Tuberculosis, an important cause in the past, was never found, but must always be excluded. A benign course was noted in all patients. Erythema nodosum is easily recognized clinically, but other subcutaneous lesions, especially nodular vasculitis and Schonlein-Henoch purpura, have to be excluded by pathologic study, in cases of atypical presentation or long duration.

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Gross Appearance and Clinical Variants
Histopathological Features and Variants
Differential Diagnosis
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DIFFERENTIAL DIAGNOSIS	CHARACTERIZATION
BEHCET DISEASE
NODULAR VASCULITIS
Erythema nodosum versus nodular vasculitis. Sanz Vico MD, De Diego V, Sanchez Yus E. Department of Dermatology, Hospital Universitario San Carlos, Facultad de Medicina, Universidad Complutense, Madrid, Spain.	Int J Dermatol 1993 Feb;32(2):108-12 Abstract quote BACKGROUND. Erythema nodosum (EN) is usually considered to be a septal panniculitis, and nodular vasculitis (NV) a lobular panniculitis. We tested the usefulness of this histologic classification in clarifying a frequent clinical dilemma: EN versus NV. METHODS. Over 3 years 109 patients with panniculitis were included in this study. After a history and a physical examination, a clinical diagnosis was made according to well-established criteria. RESULTS. From the study of 88 patients, we concluded that in the clinically typical cases, the clinico-pathologic agreement was 93% and 94% for EN and NV respectively, whereas it diminished to 79%, 72%, and 67% in the cases clinically diagnosed as EN migrans, atypical EN, and atypical NV, respectively. Moreover, septal and lobular panniculitis were always two clear-cut, different, opposite patterns of hypodermal inflammation to these conditions. CONCLUSIONS. In the absence of a known pathogenetic mechanism, the histopathology remains the most objective discriminating marker between EN and NV, mainly in the clinically atypical and doubtful cases.
WHIPPLE'S DISEASE
Erythema nodosum-like lesions in treated Whipple's disease: signs of immune reconstitution inflammatory syndrome. Schaller J, Carlson JA. Department of Dermatohistology, Catholic Clinics, Duisburg, Germany.	J Am Acad Dermatol. 2009 Feb;60(2):277-88. Abstract quote Treatment of systemic infections due to mycobacteria and HIV infection can lead to paradoxical worsening, the immune reconstitution inflammatory syndrome, in a minority of patients. Herein we describe a patient with Whipple's disease, a chronic systemic inflammatory disease caused by Tropheryma whipplei, who developed cutaneous and later ocular disease after initiation of antibiotic therapy. A 42-year-old man with a 12-year history of arthralgias presented with deteriorating health, including weight loss, diarrhea, fever, and acral hyperkeratosis. Whipple's disease was suspected and subsequently confirmed by finding periodic acid-Schiff (PAS)-positive foamy macrophages and T whipplei DNA by polymerase chain reaction (PCR) assays in duodenal biopsy specimens. After 5 weeks of antibiotic treatment with ceftriaxone, erythema nodosum (EN)-like lesions developed on the legs and trunk. Notably, lesional and nonlesional skin harbored intracellular and extracellular degenerated bacteria that were associated with a neutrophilic and granulomatous inflammatory response in lesional skin. Continued antibiotic therapy was associated with recurring EN-like skin nodules, orbital swelling, and facial herpes simplex virus 1 infection. Corticosteroid therapy controlled the duration and severity of the EN-like nodules and orbital swelling. Apart from cutaneous hyperpigmentation, skin disease in Whipple's disease is infrequent and can be categorized as disorders due to malnutrition from malabsorption or so-called reversal reactions consisting of reactive erythemas, and neutrophilic and granulomatous responses to T whipplei, the latter of which can represent an immune reconstitution inflammatory reaction after initiation of antibiotic therapy. Finally, based on the presence of T whipplei in normal skin, skin biopsy may serve as another site for diagnostic testing in patients suspected of having Whipple's disease.