Rapid granulomatosis with polyangiitis induced by immune checkpoint inhibition

Rheumatology key message Check point inhibition induced granulomatosis with polyangiitis in an anti-neutrophil cytoplasmic antibody positive melanoma patient. Sir, there is a rise in the use of immune-potentiating drugs in oncology. The immune checkpoint modulators ipilimumab [an anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibody], and nivolumab and pembrolizumab [anti-programmed cell death 1 (PD1) antibodies] have demonstrated survival benefit in metastatic melanoma. Potential drawbacks of anti-CTLA4 and anti-PD1 are their immune-potentiating side effects. CTLA4, a key negative regulator of T cell activation, binds to CD80/CD86 on the surface of antigen-presenting cells (APCs). This interaction dampens the costimulatory second signal of T cell activation mediated via interaction between CD80/CD86 on APCs and CD28 on T cells. Thus, by blocking the action of CTLA4, ipilimumab promotes stimulation and potentiation of T cell activation. Also, PD1 belongs to the CD28/CTLA4 family of negative regulators of T cell activation, which serves to protect against autoimmune diseases [1]. However, cancer cells can co-opt the PD1 pathway to escape immune surveillance. Therefore, blockade of either the CTLA4 or the PD1 pathway has become an attractive target in cancer therapy.' We treated a 56-year-old woman with metastatic melanoma successfully with four courses of 3 mg/kg ipilimumab. During ipilimumab treatment she reported mild arthralgias. Unfortunately, 6 months later she had progressive melanoma, and treatment with 850 mg/m2 dacarbazine every 3 weeks was initiated. The disease progressed further after two courses and dacarbazine was discontinued. At that time, pembrolizumab became available in the setting of a Named Patient Program. She was included after giving informed consent. One week after her first infusion of 2 mg/kg pembrolizumab, she had high-grade fever without signs of infection. She developed purpura on her feet and arthritis in her hands, elbows and ankles. A chest X-ray revealed stable pulmonary nodular lesions (Fig. 1A) and her urine sediment was normal. She was diagnosed as having serum sickness based on the presence of arthritis, high-grade fever and cutaneous vasculitis and was treated with 40 mg prednisone once daily. Under this regimen she developed progressive dyspnoea, and a repeated chest X-ray 1 week later showed diffuse infiltrates (Fig. 1B). Complement C3 and C4 levels were normal and her skin biopsy showed vasculitis without immunoglobulin or complement deposition. Repeated urinalysis showed a massive number of dysmorphic erythrocytes and proteinuria. She tested positive for PR3-ANCA. In retrospect, a spare serum sample revealed there was already a low titer shortly before the start of pembrolizumab. Oral CYC, 150 mg once daily, and pulse methyl prednisone induced rapid resolution of symptoms (Fig. 1C). Progression and resolution of bilateral pulmonary lesions (A) Bilateral pulmonary lesions in a patient with progressive metastatic melanoma. (B) Progression of the pulmonary lesions after initiation of pembrolizumab. (C) Improvement after 3 weeks of high-dose steroids and CYC. This is the first report of the development of granulomatosis with polyangiitis (GPA) after sequential immune checkpoint inhibition with ipilimumab and pembrolizumab, as well as the first report of vasculitis observed after pembrolizumab treatment. It is intriguing that this life-threatening condition suddenly arose shortly after a single dose of pembrolizumab. In retrospect, the pre-existing pulmonary nodular anomalies might have been subclinical GPA. Interestingly, aberrant expression of PD1 on Th cells in GPA is reported to be of importance in the pathophysiology of GPA [2]. Genome-wide association studies have revealed an associated between GPA and polymorphic variants in the genes encoding PR3 and its main inhibitor α1 antitrypsin [3]. However, polymorphisms in PDCD1 (the gene encoding PD1) and the CLTA4 gene are reported to play a role in patients with GPA [4]. After ipilimumab treatment, several forms of vasculitis, including large-vessel vasculitis have been reported [5–7]. The patient in the present case developed arthralgias during ipilimumab treatment, which in retrospect might be considered to be symptoms preceding GPA. Abatacept, a functional counterpart of ipilimumab, is composed of a modified Fc-region of IgG1 and the ligand-binding domain of CTLA4, which leads to CD80/86 inhibition on APCs. Of interest is an open-label trial in 20 GPA patients treated with abatacept that reported disease improvement in 18 patients (90%) [8]. Based on our findings, one could hypothesize that ipilimumab induced PR3-ANCA production, which set the stage for the development of GPA that was rapidly unleashed by pembrolizumab treatment. Together with existing data on PD1 polymorphism in GPA and on aberrant expression of PD1 on Th cells in GPA, this report highlights the important role of PD1 in the development of GPA. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: G.A.P. Hospers participates in advisory boards of Bristol-Myers Squibb and Merck Sharp Dohme with financial support for the institution. All other authors have declared no conflicts of interest.