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Year : 2020  |  Volume : 3  |  Issue : 4  |  Page : 814-816

Skin rash: Disease or drug?


Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Submission02-Nov-2020
Date of Decision08-Dec-2020
Date of Acceptance09-Dec-2020
Date of Web Publication25-Dec-2020

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, HBB - 11th Floor, Tata Memorial Hospital, Dr. Ernst Borges Road, Parel, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_347_20

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How to cite this article:
Kumar S, Noronha V, Patil VM, Joshi A, Menon N, Prabhash K. Skin rash: Disease or drug?. Cancer Res Stat Treat 2020;3:814-6

How to cite this URL:
Kumar S, Noronha V, Patil VM, Joshi A, Menon N, Prabhash K. Skin rash: Disease or drug?. Cancer Res Stat Treat [serial online] 2020 [cited 2021 Oct 22];3:814-6. Available from: https://www.crstonline.com/text.asp?2020/3/4/814/305010




  Case Vignette Top


A 63-year-old man was diagnosed with metastatic malignant mesothelioma of the lung. He initially received palliative chemotherapy with pemetrexed/carboplatin/bevacizumab for five cycles until January 2019. On progression, he received second-line chemotherapy with gemcitabine/vinorelbine for two cycles until March 2019. His disease progressed, and subsequently he presented at our institute for further management. A review of his histopathology blocks confirmed mesothelioma, adenomatoid pattern. He was started on third-line palliative systemic therapy with nivolumab 3 mg/kg once every 2 weeks. He achieved a partial response after 4 cycles, and the response was sustained for 12 cycles of nivolumab until October 2019. A next-generation sequencing panel for solid tumors was performed for mutation analysis, but no actionable mutations were detected. After the 18th cycle of nivolumab, he presented with hyperpigmented skin rashes on his wrist, forearms, and on the lower limb that extended up to the middle of his thigh [Figure 1]. What is the diagnosis, and what should be done next? Once you have finalized your answer, turn to pg. 815 to read on.
Figure 1: An hyperpigmented skin rash on the bilateral lower limbs

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  Workup and Clinical Course Top


A dermatology consultation was taken for the patient. A diagnosis of Grade-3 vasculitic skin rash was made as the patient had significant symptoms of pruritus associated with the rash. The rash was Grade 3 as per the Common Terminology Criteria for Adverse Events (CTCAE) v4.03 (Grade 3 is characterized by macules/papules that cover more than 30% of the body surface area, with or without symptoms, limiting the self-care activities of daily living).[1]

The patient was treated with steroids, initially with methylprednisolone 1 mg/kg intravenous (IV) and then continued as oral steroids for 2 weeks. A skin biopsy was deferred as the patient responded well to steroids with resolution of the skin rash within 10 days of starting methylprednisolone [Figure 2]. A subsequent computed tomography scan revealed progressive disease. As the patient had progressive worsening of the symptoms, he was planned for best supportive care and palliative care only.
Figure 2: Resolving skin rash after initiation of intravenous steroids

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  Discussion Top


Immune-related skin toxicity is one of the most commonly seen adverse events in patients who are treated with programmed cell death protein 1 (PD-1) monoclonal antibodies. These adverse events are seen in up to ~34% of the patients treated with nivolumab/pembrolizumab, and usually develop early during the course of therapy.[2] Dual PD-1/programmed death-ligand 1 blockade (nivolumab + ipilimumab) leads to earlier and more severe immune adverse events compared to single-agent PD-1 therapy. In a study of patients with metastatic melanoma, the median time to develop Grade 3–4 treatment-related skin adverse events was 5.6 weeks for nivolumab + ipilimumab and 19.4 weeks for nivolumab alone.[3] The most common skin toxicity is a rash or pruritus. Vitiligo is seen more commonly in patients with melanoma, and it has been observed that this correlates with a good clinical response to anti-PD-1 therapy in this patient subgroup.[4] An unusual feature of the case presented here is that the patient developed skin toxicity after receiving nivolumab therapy for 9 months. However, delayed immune-related adverse events are known to occur even up to 1 year after the discontinuation of treatment.[5]

Skin rashes are reported in ~15% of the patients receiving anti-PD-1 therapy, with Grade 3/4 rashes occurring rarely (<3% of the cases).[6] When a patient first presents with a skin rash while on anti-PD-1 therapy, it is a prerequisite to first rule out other causes such as:

  1. Other drug-related skin toxicities: Drug rash can be caused by medications such as allopurinol, betalactam antibiotics, sulfonamides, angiotensin-converting enzyme inhibitors, and hypoglycemics. This rash is usually maculopapular,[7] and has a temporal relationship with the causative drug. The rash usually occurs within 1–4 weeks of taking the drug
  2. Infective etiology (bacterial/viral/fungal): In patients with infective rashes, the presence of other clinical signs of infection will usually point toward the diagnosis toward the diagnosis. In cases in which the diagnosis is in doubt, a skin biopsy should be performed
  3. Metastatic skin lesions: Metastatic skin rashes may occur in malignancies such as melanoma and breast cancer. Skin biopsy should be used to confirm the diagnosis
  4. Paraneoplastic skin lesions: These may occur in patients with dermatomyositis or erythema gyratum repens. Patients with dermatomyositis present with proximal muscle weakness, with classic heliotrope rash and Gottron papules (flat-topped, erythematous papules found over bony prominences, particularly the metacarpophalangeal joints). Erythema gyratum repens skin rash has a classical “wood-grain” appearance, and often precedes the detection of a malignancy.


The case described above did not have any history of drug intake preceding the onset of skin rash and did not have any other clinical signs of infection. A diagnosis of immunotherapy-related skin rash was thus made and was confirmed ex juvantibus once it responded rapidly to corticosteroid therapy.

It is important to document the severity of the skin rash by a careful physical examination of the entire body, including the mucosal areas, and this should be graded as per the CTCAE.[1] A dermatology referral and skin biopsy should be sought for any rash that has a severity of more than Grade 2.

For a Grade-1 skin rash, treatment with anti-PD-1 agents can be continued. The patient can be given symptomatic treatment with topical emollients, topical application of mild steroids (hydrocortisone 2.5%), and oral antihistamines for pruritus. If the patient develops a Grade-2 skin rash, treatment can be continued with close monitoring on a weekly basis for any worsening of the skin rash. If the rash does not resolve, treatment should be interrupted until the severity reduces to Grade 1. Symptomatic treatment can be given as for Grade-1 toxicity. In the event of a Grade-3 skin rash, treatment with checkpoint inhibitors should be stopped immediately. High-strength topical steroids (e.g., betamethasone 0.05%) with systemic corticosteroids such as prednisolone or methylprednisolone at 0.5–1 mg/kg should be started immediately, with further modifications on a case-to-case basis. The steroids should be weaned off over a period of 2–4 weeks. Checkpoint inhibitor therapy may be resumed once the severity reduces to Grade 1. In the rare event of a Grade-4 skin rash (associated with epidermal detachment, e.g., Stevens–Johnson syndrome, toxic epidermal necrolysis, and bullous dermatitis), treatment with anti-PD-1 agents should be permanently discontinued, and patients should be admitted immediately to the intensive care unit and treated under the supervision of a dermatologist. The treatment consists of methylprednisolone 1–2 mg/kg IV and should be tapered when the rash heals[8],[9] [Figure 3].
Figure 3: Skin toxicity management flowchart. IV: Intravenous, ICU: Intensive care unit

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  Conclusion Top


Immune-related skin toxicity is a common adverse event seen in patients receiving checkpoint inhibitors. After ruling out other causes of skin rashes, the toxicity should be graded and managed appropriately as per guidelines. In the rare event of a severe toxicity, checkpoint inhibitor therapy should be permanently discontinued.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his names and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Common Terminology Criteria for Adverse Events (CTCAE) | Protocol Development | CTEP. Available from: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. [Last acce?ssed on 2020 Aug 16].  Back to cited text no. 1
    
2.
Belum VR, Benhuri B, Postow MA, Hellmann MD, Lesokhin AM, Segal NH, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer 2016;60:12-25.  Back to cited text no. 2
    
3.
D'Angelo SP, Larkin J, Sosman JA, Lebbé C, Brady B, Neyns B, et al. Efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma: A pooled analysis. J Clin Oncol 2017;35:226-35.  Back to cited text no. 3
    
4.
Hua C, Boussemart L, Mateus C, Routier E, Boutros C, Cazenave H, et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol 2016;152:45-51.  Back to cited text no. 4
    
5.
Kanjanapan Y, Day D, Butler MO, Wang L, Joshua AM, Hogg D, et al. Delayed immune-related adverse events in assessment for dose-limiting toxicity in early phase immunotherapy trials. Eur J Cancer 2019;107:1-7.  Back to cited text no. 5
    
6.
Boutros C, Tarhini A, Routier E, Lambotte O, Ladurie FL, Carbonnel F, et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol 2016;13:473-86.  Back to cited text no. 6
    
7.
Bigby M. Rates of cutaneous reactions to drugs. Arch Dermatol 2001;137:765-70.  Back to cited text no. 7
    
8.
Menon N, Mailankody S. Immunotherapy protocols in lung cancer. Cancer Res Stat Treat 2018;1:139-62.  Back to cited text no. 8
  [Full text]  
9.
Haanen JB, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol 2017;28:iv119-42.  Back to cited text no. 9
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

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