Blank, C.U.

Hak, A.E.

Hilhorst, M.

Klarenbeek, P.L.

Reijers, I.L.M.

Tan, M.

Leiden University Scholary Publications

1031Clinical and Experimental Rheumatology 2020Letters to the EditorsAcrocyanosis after neoadjuvant ipilimumab plus nivolumab: a case report Sirs,The introduction of immunotherapy has marked the beginning of a new era in can-cer treatment resulting in a long-term ben-efit in several cancer types including mela-noma (1). Checkpoint inhibitors targeting the cytotoxic T-lymphocyte-associated pro-tein 4 (CTLA-4) or programmed cell death 1 (ligand) [PD-(L)1] have become standard of care for late stage disease. A wide variety of immune-related adverse events (irAE) has been described (2). Here we report a patient who presented with acrocyanosis after treatment with immune checkpoint inhibition (ICI).In December 2018, a 55-year-old woman was diagnosed with stage III melanoma with an inguinal lymph node metastasis originat-ing from a primary melanoma on her right calf. She had no medical history of car-diovascular or autoimmune diseases. At the Netherlands Cancer Institute she received two cycles neoadjuvant ipilimumab 1mg/kg (CTLA-4 antibody) and nivolumab 3 mg/kg (PD-1 antibody) in the setting of a clinical study [NCT02977052], followed by excision of the lymph node metastasis after 6 weeks. She achieved complete pathologi-cal remission. Two months after the last ICI infusion she developed paresthesia in her right index finger. Within 10 days the symp-toms gradually increased with episodes of blue discoloration resembling the Raynaud phenomenon to persisting acrocyanosis in both hands (Fig. 1A). On suspicion of an irAE, treatment with 1 mg/kg prednisolone and 30 mg nifedipine was initiated. A skin biopsy of her right index finger showed no abnormalities. Her symptoms worsened and prednisolone treatment was intensified to 2 mg/kg. The patient was referred to the Vasculitis Expertise Center of the Amsterdam Uni-versity Medical Centre one week later. By then, additional splinter bleeds at the nail-folds were present. Laboratory assessment showed no abnormalities (Table I). Cardiac embolisms were excluded and Doppler ultrasound showed normal signals in both arms and hands (not shown). The nifedipine dose was raised to 30 mg twice daily. Due to side effects and a lack of clinical response, the corticosteroid dosage was tapered to 30mg per day. Unfortunately, the pain in the fingers progressed and the treating oncologist started mycophenolate mofetil (MMF) and aspirin. Ten days later, tacroli-mus 5 mg twice daily was added. The biop-sied skin area and another papercut wound showed necrotic tissue (Fig. 1B). To avoid further ischaemia the patient was admitted for intravenous iloprost while continuing the immunosuppression. During 5 subse-quent days of iloprost infusions the wounds showed slow recovery. Three weeks later the symptoms had strongly improved. Nail-fold capillaroscopy at that time showed no abnormalities (not shown). During the two months thereafter the immunosuppressive drugs were tapered while nifedipine treat-ment was continued. The acrocyanosis and wounds disappeared whereas a mild pain in her fingers lasted for 16 weeks longer be-fore disappearing completely. Up until now, this patient is free of recurrence from her melanoma.Fig. 1. A: Start of acrocyanosis 8 weeks after the last infusion of checkpoint inhibitors. B: Development of ischaemic areas on the right hand after skin biopsy (index finger) and a paper cut (ring finger). C: Resolution of acrocyanosis after treatment and development of vitiligo 6 months after the last infusion with checkpoint inhibitors. Table I. Lab results at the time of presentation.Variable  Value ReferenceSedimentation rate 2 0–30 mm/UC-reactive protein 0.7 0–5 mg/LHaemoglobin 9.0 7.5–10 mmol/LThrombocytes 392 150–400 10E9/LLeukocytes 12.3 (H) 4.0–10.5 10E9/L   Eosinophils 0.00 0–0.5 10E9/L   Basophils 0.01 0–0.2 10E9/L   Neutrophils 11.54 (H) 1.8–7.2 10E9/L   Lymphocytes 0.47 (L) 1.5–4.0 10E9/L   Monocytes 0.12 0.1–1.0 10E9/L   Immature granulocytes 0.15 (H) <0.06 10E9/LPotassium 4.5 3.5–4.5 mmol/LCalcium 2.32 2.2–2.6 mmol/LAlbumin 44 35–50 g/LCreatinine 77 65–95 µmol/LeGFR 75 >60 mL/min/1.73m²Urea 7.3 (H) 2.1–7.1 mmol/LBilirubin 8 0–17 µmol/LAlk.fosf. 79 40–120 U/L 37°CGamma-GT 19 0–40 U/L 37°CASAT 19 0–40 U/L 37°CALAT 21 0–34 U/L 37°CLDH 251 (H) 0–247 U/L 37°CFerritin 88 20–250 µg/LFolic acid 15.5 5.2–34.8 nmol/LCryoglobulins Negative 0–0.1 g/LVitamin B12 708 (H) 150–700 pmol/LAnti-nuclear antibodies Negative  Negative Scleroderma immunoblot Negative* NegativeAnti-β2-glycoprotein Negative NegativeAnti-phospholipids Negative NegativeComplement C3 0.95 0.9–1.8 g/LComplement C4 0.23 0.1–0.4 g/LTSH 0.16 (L) 0.5–5 mE/LFree T4 18.3 12.0–22.0 pmol/LTPO antibodies <30 0–60 kU/L*Scleroderma immunoblot included antibodies against Scl-70, centromere (A and B), RNA polymerase III (11 and 155 kD), fibrillarin, NOR90, Th/To, PM-Scl100, PM-Scl75, Ku, PDGFR and Ro-52. 1032 Clinical and Experimental Rheumatology 2020Letters to the EditorsThe development of acrocyanosis and/or digital ischaemia in the setting of ICI is de-scribed before but seems rare (3-8). The ae-tiology remains unclear because most cases – including ours – showed no biochemical markers of inflammation, nor histological signs of immune cell tissue infiltration and/or damage. This contradicts the majority of systemic autoimmune diseases where usu-ally inflammation can be found and/or au-toantibodies are present. Acral ischaemia has previously been de-scribed as a paraneoplastic phenomenon (9) but since our patient achieved complete re-sponse and is still relapse-free, it is unlikely that the observed symptoms are a result of a paraneoplastic syndrome. The optimal treatment for ICI-induced acro-cyanosis/digital ischaemia remains unclear. Results from treatment with prostacyclin analogues or calcium channel blockers are controversial (4, 5). High-dose (methyl)prednisolone might be considered, however several cases report no efficacy (4, 5). Simi-lar to our case, addition of MMF to pred-nisolone and iloprost treatment resulted in complete resolution of symptoms in another case. Thus, aggressive immune suppression combined with atrial vasodilation and plate-let aggregation inhibition might be a prom-ising therapy option for steroid-refractory acrocyanosis.   In summary, acrocyanosis as an ICI in-duced irAE is a rare but serious complica-tion, which seems to require more intense therapy than other irAEs (10). It should be managed multidisciplinary to avoid digital necrosis and amputation. Ethics approvalThe patient gave written informed consent for the anonymous publication of her case, including photographs of her hands. I.L.M. REIJERS1,2 * M. HILHORST3,4 *M. TAN4P.L. KLARENBEEK3A.E. HAK3 C.U. BLANK1,2*These authors contributed equally.1Department of Medical Oncology,2Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam; 3Department of Rheumatology and Clinical Immunology, 4Department of Internal Medicine, Amsterdam UMC, the Netherlands.Please address correspondence to: Christian U. Blank,  Department of Medical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands. E-mail: c.blank@nki.nlCompeting interests: none declared.© Copyright CliniCal and ExpErimEntal rhEumatology 2020.References  1. HEIGENER DF, RECK M: Giant steps and stumbling blocks. Nat Rev Clin Oncol 2017; 15: 71.  2. POSTOW MA, SIDLOW R, HELLMANN MD: Immune-related adverse events associated with im-mune checkpoint blockade. New Engl J Med 2018; 378: 158-68.  3. KHADDOUR K, SINGH V, SHAYUK M: Acral vas-cular necrosis associated with immune-check point inhibitors: case report with literature review. BMC Cancer 2019; 19: 449.  4. GAMBICHLER T, STRUTZMANN S, TANNAPFEL A, SUSOK L: Paraneoplastic acral vascular syn-drome in a patient with metastatic melanoma under immune checkpoint blockade. BMC Cancer 2017; 17: 327.  5. PADDA A, SCHIOPU E, SOVICH J, MA V, ALVA A, FECHER L: Ipilimumab induced digital vasculitis. J Immunother Cancer 2018; 6: 12.  6. THOREAU B, GOUAILLIER-VULCAIN F, MACHET L et al.: Acute lower limb ischaemia and diabetes in a patient treated with anti-PD1 monoclonal anti-body for metastatic melanoma. Acta Derm Venereol 2017; 97: 408-9.  7. LE BUREL S, CHAMPIAT S, ROUTIER E et al.: Onset of connective tissue disease following anti-PD1/PD-L1 cancer immunotherapy. Ann Rheum Dis 2018; 77: 468.  8. FRANCO F, MÉNDEZ M, GUTIERREZ L, SANZ J, CALVO V, PROVENCIO M: Nivolumab-associated digital small-vessel vasculitis in a patient with an advanced renal cell carcinoma. Immunotherapy 2019; 11: 379-84.  9. RODRIGUES T, BARCELOS A: Digital ischemia as a paraneoplastic phenomenon. Acta Reumatol Port 2016; 41: 378-79.10. HAANEN JBAG, CARBONNEL F, ROBERT C et al.: Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018; 29 (Sup-pl. 4): iv264-iv6.

Acrocyanosis after neoadjuvant ipilimumab plus nivolumab: a case report

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Acrocyanosis after neoadjuvant ipilimumab plus nivolumab: a case report

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