Painful Protuberances

This week in Morning Report, we discussed the case of a gentleman who presented with a several-day history of tender, erythematous, bumpy rash on his lower extremities. He visited a few Emergency Rooms and clinics where he was treated with several courses of antibiotics for presumed cellulitis, but with no improvement of his symptoms.

By the time our astute residents saw him, the ‘rash’ was on bilateral extremities, tender to palpation, erythematous, and nodular in appearance. On history, we discovered that he had a prodromal illness of sore throat, fevers, myalgias, and fatigue. Taken together, this presentation sounds pretty convincing for…erythema nodosum.

I think of erythema nodosum as a ‘canary in the coalmine’ sign because it is seen in such a wide range of multi-system pathologies. While over 50% of erythema nodosum is idiopathic and self-limiting, the rest of the time it can be a harbinger of many disease states and thus deserves a thoughtful and directed workup.

Let’s review our key learning points from this case!

1. What is Erythema Nodosum?

Erythema Nodosum (EN) is a form of panniculitis, i.e. an inflammation of subcutaneous fat with sparing of the epidermis and dermis (that’s why EN classically heals without scarring). Under the microscope, you will see inflamed septae in adipose tissue, with occasional characteristic Miescher’s granulomas.

The classic appearance of EN – tender, erythematous subcutaneous nodules. Remember that in darker skin tones, EN can look less erythematous and more like hyperpigmentation. Image from Wikimedia Commons, used with attribution.
Erythema nodosum in darker skin tones may not look erythematous, but rather like hyperpigmentation. Adapted from Annals of Nigerian Medicine 2011:5(2).

There is some evidence that EN actually represents a delayed hypersensitivity reaction (i.e., Type IV reaction) to various presenting antigens. If your patient has lesions that are ulcerating, blistering, hemorrhagic, or purpuric, revisit the diagnosis — remember to keep a broad differential in mnd including cellulitis, vasculitis, pyoderma gangrenosum, tick-borne lesions, or sequelae of VTE.

2. How does EN generally present?

Erythema nodosum generally affects females > males (~6:1 ratio) of ages 20-50. The lesions may wax and wane over time, and are tender when active inflammation is present. Many patients will have prodromal constitutional symptoms of fevers, malaise, weight loss, arthralgias/myalgias approximately 1-3 weeks before the lesions themselves appear.

It is important to do a thoughtful history and physical in patients, looking for signs/symptoms of other EN triggers. From head to toe, we might look for the following findings (Why? Challenge yourself to name the disease associations!):

  • uveitis, iritis, ‘candle wax drippings’ on fundoscopy
  • oral ulcers
  • parotid swelling or tenderness
  • lymph node enlargement
  • active joint effusions
  • splenomegaly

3. What are causes of Erythema Nodosum?

I can’t memorize lists for the life of me, so my approach to any problem is to understand the pathology, then think about all the systems that might be affected. If we think of EN as a Type IV hypersensitivity reaction, we can then think of all the different ‘triggering antigens’ that might cause this reaction. We discussed a huge spectrum of diagnoses, categorized into the following broad buckets:

4. What tests should you perform?

Generally, routine bloods, ESR/CRP, strep pharyngitis testing (Rapid Antigen / PCR), chest x-ray, latent TB testing (TBST/IGRA), +/- Beta-HCG are your highest-yield initial investigations. Further investigations will of course be guided by your history and physical.

Biopsies for EN are generally not needed up front, unless the diagnosis is in question or the clinical course unremitting.

5. Treatment of Erythema Nodosum

  • The main principle of EN treatment is to treat the underlying cause
  • Non-pharmacological measures such as avoiding skin irritants, rest, ice, etc. may be helpful
  • NSAIDs are the mainstay of pharmacological treatment (primarily aimed at reducing inflammation in subcutaneous adipose tissue)
  • Potassium iodide drops or tablets are also used in treatment, although the mechanism of action is poorly understood
  • Finally, immunosuppression including glucocorticoids, hydroxychloroquine, etc. can be used for recurring or refractory cases of EN. A comprehensive investigation into secondary causes of EN must be performed (including referrals to appropriate specialists!) before starting these, as injudicious use of immunosuppressants can certainly cause more harm than benefit.

I hope you found this helpful! As always, please send any questions and comments to Thank you to our AACU resident for presenting this case, and to all our trainees for participating in an excellent discussion!

Note: These recaps are based on real-life cases presented during weekly Morning Report; however, no real patient information/investigations/images/identifying details are presented. Any clinical information presented has been modified and completely de-identified for privacy.

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