LAUSR

Dear Editor Inhibitory immune checkpoints on T lymphocytes prevent chronic activation of the immune system, which is critical for immune homeostasis. Many cancer cells upregulate these checkpoints to evade the anti-tumor immune response. Immune Checkpoint Inhibitors (ICIs) are increasingly used to target said pathway and treat advanced malignancies. ICIs are monoclonal antibodies that target cytotoxic T-lymphocyteassociated protein-4 (ipilimumab), program cell death protein-1 receptor (nivolumab, pembrolizumab), or program cell death ligand-1 (atezolizumab, durvalumab). By targeting these inhibitory receptors, ICIs can overcome tumor immune subversion and halt disease progression. However, by blocking inhibitory receptors with ICIs, T lymphocytes activate, in turn potentially targeting self-antigens causing a variety of immune-related adverse events (irAEs). The most common irAEs are cutaneous, typically presenting as a maculopapular rash, pruritus, or lichenoid, psoriasiform, and eczematous dermatoses. Herein, we present a rare case of ICIinduced erythema nodosum (EN) and review the prior reported cases. A 69-year-old female with stage IV poorly differentiated non-small cell lung cancer, hypothyroidism, osteoarthritis, hyperlipidemia, gastroesophageal reflux disease (GERD), and depression presented to the clinic with a two-month history of a painful rash on her bilateral lower extremities. The rash developed 9 weeks after the initiation of pembrolizumab, pemetrexed, and carboplatin infusions for the treatment of her lung cancer. Prior to presentation to our clinic, her oncologist initially prescribed clobetasol 0.05% cream and oral antihistamines, with minimal disease improvement. One week later, an oral methylprednisolone taper pack was started, resulting in moderate improvement. Of note, the patient denied recent sore throat, travel, a prior history of a similar rash, other new medications, or a history of inflammatory bowel disease. Upon examination, erythematous, indurated, and tender nodules were noted on the pretibial legs bilaterally (Figure 1A,B). A punch biopsy from the upper left shin revealed a widened septal panniculitis extending to the surrounding lobules (Figure 1C,D). Septal granulomas were present. The findings, while non-specific, were compatible with our clinical impression of erythema nodosum. Naproxen 250 mg twice daily was started with significant improvement of the rash after 2 weeks. Unfortunately, she was unable to tolerate this treatment due to her GERD. The patient is currently receiving pembrolizumab and pemetrexed infusions every 3 weeks and is using clobetasol 0.05% cream twice daily with improvement in the rash and pain to a tolerable level. Erythema nodosum is the most common type of panniculitis. The exact pathogenesis is unknown, but it appears to be due to a delayed hypersensitivity reaction. Approximately 55% of cases are idiopathic, while the most common associations include: infections such as streptococcal upper respiratory infections, sarcoidosis, autoimmune conditions, inflammatory bowel disease, oral contraceptives, and pregnancy. ICIs have also been associated with EN. Onset of symptoms for the most commonly reported cutaneous irAEs range from 3 to 12 weeks after starting immunotherapy. ICIinduced EN appears to have a more delayed onset, ranging from 4 to 40 weeks. Due to the delayed reaction, the association may be challenging to recognize. In fact, few prior cases reported suspicion of cancer progression to cutaneous metastases. Thus, it is crucial to be aware of this association to avoid confusion. Most patients with ICI-induced-EN appeared to have mild to moderate symptoms, but treatment is often needed to continue ICI therapy comfortably. Non-steroidal anti-inflammatories were effective in reducing the rash and pain in 3/9 cases. Topical and oral steroids have also been used successfully. Lastly, discontinuation of the ICI typically leads to resolution of the EN. We report this case and review prior reported cases in the literature to bring awareness to this potential irAE. Recognition and adequate treatment of ICI-induced-EN is necessary for the continuation of these life-saving therapies.