Small vessel vasculitis and dry gangrene secondary to combined CTLA-4 and PD-1 blockade in malignant mesothelioma

Our plain-English summary of Small vessel vasculitis and dry gangrene secondary to combined CTLA-4 and PD-1 blockade in malignant mesothelioma, by J. Kefas, C. Harwood, M.J. Lewis, et al (BMC Rheumatology, 2022).

The study

• Authors: J. Kefas, C. Harwood, M.J. Lewis, P. Szlosarek
• Journal: BMC Rheumatology
• Published: 2022;6(1):10
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour with an overall poor prognosis. In October 2020, first line treatment with the PD-1 antagonist nivolumab and the CTLA-4 antagonist ipilimumab for unresectable disease was FDA approved-the first approved treatment regime since 2004. Interim analyses from the phase 3 CHECKMATE-743 study shows improvements in overall survival. Skin-related toxicities are the most commonly reported any-grade treatment-related adverse event from combined nivolumab and ipilimumab therapy.

Case Presentation: Here we report a case of a 35-year-old white male who developed digital ischaemia secondary to small vessel vasculitis after receiving PD-1 and CTLA-4 blockade therapy for MPM. His progressive ischaemia became gangrenous, and he required multi-speciality input and treatment with prednisolone, prostacyclin, mycophenolate mofetil and hydroxychloroquine.

Conclusions: Our case highlights the importance of early detection, intervention, and a multispecialty approach to managing such complications in order to minimise the associated morbidity and mortality.

© 2022. The Author(s).

In plain English

This article is a case report about one patient. The authors described a 35-year-old white man who presented in April 2018 with left-sided biphasic malignant pleural mesothelioma. The article states he had no evidence of asbestos exposure and no BAP1 inherited cancer syndrome. After surgery, radiotherapy, chemotherapy and other trials, he received combined immunotherapy with ipilimumab (a CTLA-4 blocker) and pembrolizumab (a PD-1 blocker) in 2020. Within four weeks he noticed mottled (livedoid) skin changes in his left hand. These later spread to all four limbs, with purpura on his left big toe. Blood tests were positive for antinuclear antibodies. The authors judged this consistent with immunotherapy-induced small vessel vasculitis with digital ischaemia. Because he declined a skin biopsy, cholesterol embolism could not be ruled out. Steroids improved his condition, but dry gangrene of the left big toe could not be reversed. The gangrene later spread to all five toes when steroids were reduced. Further treatment stabilised the vasculitis. He then had COVID-19 pneumonia and died of a secondary bacterial pneumonia in October 2020. The authors concluded that early detection, intervention and a multi-speciality approach are important for such complications.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: case report (one patient)
• Who was studied: One 35-year-old white man who presented in April 2018 with a large, symptomatic pleural effusion caused by left-sided biphasic malignant pleural mesothelioma. The authors are affiliated with London hospitals, but the case text does not state where the patient lived or was treated.
• Exposure: The exposure studied was immunotherapy, not asbestos. The patient received combined ipilimumab (1 mg/kg every 6 weeks) and pembrolizumab (2 mg/kg every 3 weeks) for 6 weeks in 2020. He had earlier been in a randomised trial of nivolumab or placebo. The article reports no evidence of asbestos exposure.
• Main results:
  • Within four weeks of starting combined immunotherapy, the patient noticed livedoid skin changes in his left hand. By May 2020 these were spread symmetrically across all four limbs, with purpura on the left big toe (hallux).
  • Blood tests were positive for speckled antinuclear antibody (titre 1/640). They were also positive for extractable nuclear antigens (Ro 60 positive, La weakly positive). Tests for rheumatoid factor, anticardiolipin antibodies, cryoglobulins, HIV, ANCA and double-stranded DNA were negative. Complement levels were normal.
  • The authors judged the presentation consistent with immunotherapy-induced ANA-positive small vessel vasculitis with digital ischaemia.
  • Intravenous methylprednisolone followed by oral steroids improved his condition, but the dry gangrene in the left big toe could not be reversed.
  • When prednisolone was reduced to 30 mg daily in August 2020, the gangrene spread to all 5 toes of the left foot. He was then treated with methylprednisolone, prostacyclin, prednisolone, mycophenolate mofetil and hydroxychloroquine, and the vasculitis stabilised.
  • Two weeks after the vasculitis stabilised, he was hospitalised with COVID-19 pneumonia. He was later readmitted with secondary bacterial pneumonia and died in October 2020.
• The authors' conclusion: The authors concluded that prompt recognition and a multi-speciality collaborative approach are essential to minimise the illness and deaths linked to such complications. They also said larger studies are needed to find the cause of immunotherapy-related small vessel vasculitis and the best treatment.
• Limitations the authors state:
  • The patient declined a skin biopsy, so the authors could not exclude cholesterol embolism as an alternative diagnosis.

Topics

Medical terms in this study, explained in our Lexicon: CTLA-4, Mesothelioma, Pleural Mesothelioma, Prognosis, Nivolumab (Opdivo), Ipilimumab (Yervoy), Unresectable, Overall Survival.

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