Erythema nodosum (EN) is a common acute nodular septal panniculitis, characterized by the sudden onset of erythematous, firm, solid, deep nodules or plaques that are painful on palpation and mainly localized on extensor surfaces of the legs. These nodules are characterized by a typical histological appearance regardless of the etiology, marked by acute inflammation of the dermo-hypodermic junction and interlobular septa of the hypodermic fat, evolving without necrosis or sequelae.[1][2][3]
Erythema nodosum is an acute, or recurrent hypersensitivity reaction to a variety of antigens with a clear female predominance that may be associated with several different stimuli or pathological conditions.
Erythema nodosum can occur due to a vast number of underlying causes including but not limited to idiopathic, infectious, and a variety of noninfectious causes as outlined below.[4][5][6][7]
Idiopathic: No obvious etiology have been found in about 30% to 50% of published cases
Infections
Bacterial
Viral
Fungal
Parasitic
Noninfectious Causes
Drugs
Malignancy
Inflammatory Bowel Disease
Miscellaneous
Some pregnant patients may develop erythema nodosum during the second trimester. In addition, recurrence of the disorder may also occur with future pregnancies.
EN is the most common clinical form of the acute nodular hypodermis. It occurs more often in women between 25 and 40 years, but it can be observed at any age. Compared to men, women are affected three to six times more. It is rare without sex predominance in the pediatric population. Of worldwide ubiquitous distribution, there is, however, an ethnic and geographical difference in the incidences explained by the variation of triggering etiological factors. Familial cases have been reported and are usually caused by an infectious etiology.
EN is the result of a nonspecific cutaneous reaction to various antigens. The mechanism involved would be immunologically mediated. Numerous direct and indirect evidence supports the notion of type IV delayed hypersensitivity response to many antigens. It is postulated that the pathogenesis may be due to deposition of immune complex in the venules of subcutaneous fat, production of oxygen free radicals, TNF-alpha and granuloma formation. However, this hypothesis is not accepted by all authors.
Skin biopsy is not usually needed in the typical forms as a diagnosis can be reached from a detailed history and physical examination. Usual features suggestive EN include acute onset tender nodules on typical locations(most commonly on shins).
Skin biopsy is useless in typical forms. It is indicated in cases of unusual topography, the persistence of nodules several weeks, fistulization or atrophic scarring, and/or livedoid disposition of nodules. It highlights the involvement of interlobular septa by a lymphohistiocytic inflammatory infiltrate, sparing fat lobules and vessels. This aspect is invariable, whatever the etiology.
EN is characterized in a rather stereotyped way, whatever its cause, by the following evolutionary aspects:
Prodromal Phase
Stade Phase
Regressive Phase
EN never involves necrosis, ulceration, or scarring. It often evolves in several outbreaks, favored by orthostatism, and spreading out, at worst, over 4 to 8 weeks. The succession of outbreaks confers on the eruption of a polymorphic appearance with knots of different ages, featuring the various shades of local biligenia.
Besides the skin lesion, more than 50% of patients will also complain of joint and muscle pain. Sometimes joint swelling and morning stiffness may be present. The swelling may resolve in a few days but the pain may last for a few months. There is usually no joint destruction and the synovial fluid is sterile.
The positive diagnosis of EN is primarily clinical. However, a thorough anamnesis (looking for tuberculous contagion, fever, bloody diarrhea, abdominal pain, respiratory problems, dysphagia, etc.) should be conducted as well as a complete clinical examination, always looking for associated signs.
In typical cases, a complementary investigation for positive diagnostic is not necessary. Nevertheless, it finds its place in the etiological diagnosis. Taking into account the above, the etiological assessment of an EN should include examinations according to the clinical orientation:
Extended rest is desirable and may require work stoppage. Analgesics are prescribed on request. Venous compression reduces the pain felt in orthostatism. Steroidal anti-inflammatory drugs, colchicine (1 to 2 mg/day), maybe prescribed until symptoms improve. Etiologic treatment is essential in some cases, and antibiotic therapy is needed in case of streptococcal infection or anti-tuberculosis treatment. In the case of Löfgren syndrome, pulmonary radiographic monitoring is recommended, because if mediastinal adenopathies disappear in a few months in most patients, sarcoidosis may persist in 10% of cases.[8][9]
The prognosis for patients with EN is good but there is a small risk of recurrence. The skin lesions often take months to resolve but there is usually no scarring or pigmentation change.
EN is a noisy but benign syndrome, with a spontaneously favorable course, which is related to an underlying condition that needs to be diagnosed by clinical examination and some complementary oriented tests. In addition to symptomatic treatment, that of the underlying condition may be necessary.
EN is often encountered by primary care providers and nurse practitioners. While the diagnosis is clinical in most cases, sometimes a biopsy may be required to rule out another disorder. Healthcare workers should seek a consult with a dermatologist if there is any doubt about the diagnosis. For the most part, the treatment is conservative with rest. Primary care clinicians should not initiate any type of medical therapy if the diagnosis is uncertain. In addition, since the diagnosis is clinical, the patient should not be subjected to unnecessary procedures. The type of laboratory workup depends on the suspected cause. While EN may be painful, it is a benign disorder that usually remits spontaneously. If the primary disorder is not managed, EN may persist for months or even years. The pharmacist should ensure that the patient is on no medication that causes EN. If the female is on an oral contraceptive, then an alternative form of contraception should be recommended. The primary care clinicians should communicate with the dermatologist to ensure that the patient is receiving the optimal level of care. (Level V)
[1] | Roth N,Biedermann L,Fournier N,Butter M,Vavricka SR,Navarini AA,Rogler G,Scharl M, Occurrence of skin manifestations in patients of the Swiss Inflammatory Bowel Disease Cohort Study. PloS one. 2019; [PubMed PMID: 30682031] |
[2] | Morgado F,Batista M,Coutinho I,Cardoso JC,Tellechea Ó, Erythema nodosum and sarcoid granulomas - letting the cat out of the bag. Dermatology online journal. 2018 Dec 15; [PubMed PMID: 30677793] |
[3] | Choi ME,Lee KH,Won CH,Chang SE,Lee MW,Choi JH,Lee WJ, A case of erythema nodosum-like panniculitis induced by nivolumab in a patient with oesophageal cancer. The Australasian journal of dermatology. 2019 Jan 17; [PubMed PMID: 30656640] |
[4] | Fujikawa T,Senoo A, Recurrent Erythema Nodosum as a Warning of Tuberculous Lymphadenitis. Mayo Clinic proceedings. 2019 Jan; [PubMed PMID: 30611448] |
[5] | Algahtani H,Shirah B,Marghalani S,Algarni A, Erythema nodosum in a patient with multiple sclerosis on dimethyl fumarate. Multiple sclerosis and related disorders. 2018 Dec 25; [PubMed PMID: 30597324] |
[6] | Porges T,Shafat T,Sagy I,Zeller L,Bartal C,Khutarniuk T,Jotkowitz A,Barski L, Clinical, Epidemiological, and Etiological Changes in Erythema Nodosum. The Israel Medical Association journal : IMAJ. 2018 Dec; [PubMed PMID: 30550008] |
[7] | Hanami Y,Mori T,Kikuchi N,Yamamoto T, Association of pyoderma gangrenosum, erythema nodosum and aseptic liver abscess without significant underlying disease. Clinical and experimental dermatology. 2018 Nov 20; [PubMed PMID: 30460715] |
[8] | Leung AKC,Leong KF,Lam JM, Erythema nodosum. World journal of pediatrics : WJP. 2018 Dec; [PubMed PMID: 30269303] |
[9] | Laroche A,Alarcon Chinchilla E,Bourgeault E,Doré MA, Erythema Nodosum as the Initial Presentation of Nivolumab-Induced Sarcoidosis-Like Reaction. Journal of cutaneous medicine and surgery. 2018 Nov/Dec; [PubMed PMID: 29772919] |