Dermatological complications of therapy with biologics in inflammatory autoimmune diseases.

BACKGROUND AND OBJECTIVE: Cutaneous adverse events (CAEs) occur in up to 10 % of patients with immune-mediated inflammatory disease (IMID) treated with antitumor necrosis factor (TNF)α agents. The aim of this clinical study was to track and observe the course of CAEs in all biologic therapies. PATIENTS AND METHODS: The population for this study consisted of patients with CAEs under biologic therapy who were examined by experienced board-certified dermatologists in the outpatient department of the University Hospital Essen, Department of Dermatology. RESULTS: Altogether 39 patients with a total of 45 CAEs were included in this study. In 60 % of the cases a form of paradoxical psoriasis was diagnosed. Two thirds (66.6 %) of the patients with CAEs were diagnosed with an underlying inflammatory bowel disease (IBD). TNFα antagonists were the triggering agents in about 95 % of the cases. Changes in biological therapy were required in nearly half of the cases (46.2 %). Almost 90 % of the patients had either a complete (42.1 %) or a partial response (47 %). CONCLUSIONS: Management of CEAs under biological therapy can be challenging in clinical practice. Case discussions between gastroenterologists, rheumatologists and dermatologists should be undertaken to best manage patients with CAEs and avoid unnecessary changes of therapy.

[Vogt-Koyanagi-Harada-like uveitis under immune checkpoint inhibitor treatment for metastasized malignant melanoma]. / Vogt-Koyanagi-Harada-artige Uveitis unter Immun-Checkpoint-Inhibitor-Therapie beim metastasierten malignen Melanom.

This article presents the case of a 68-year-old female patient who reported bilateral progressive visual loss over 4 weeks. The patient had a known metastatic malignant cutaneous melanoma, which was treated with the immune checkpoint inhibitors nivolumab and ipilimumab. The ophthalmological examination revealed a bilateral anterior chamber flare with endothelial precipitates as well as choroidal folds, an orange-red discoloration of the retina and a serous retinal/choroidal detachment in the left eye. In the course of time the patient developed poliosis and vitiligo. Systemic and local steroid treatment resulted in a distinct improvement of the findings. An intravitreal triamcinolone injection led to complete regression of the progressive macular edema. In rare cases immune checkpoint inhibitors can cause Vogt-Koyanagi-Harada-like uveitis. As ocular inflammation can be well controlled by local and systemic steroids, checkpoint inhibitor treatment should be continued in cases with good treatment response whenever possible. Interdisciplinary cooperation with close controls is absolutely necessary in these cases.

Cytomegalovirus reactivation in patients with refractory checkpoint inhibitor-induced colitis.

OBJECTIVES: Immune checkpoint inhibitors can cause severe immune-related adverse events, with immune-related diarrhea and colitis (irColitis) being among the most frequent ones. While the majority of patients with irColitis respond well to corticosteroid treatment ± other immunomodulatory drugs such as infliximab, some patients do not show resolution of their symptoms. In the present study, we analysed the frequency of therapy-refractory irColitis, the underlying cause, and useful diagnostic approaches. METHODS: Between 2006 and 2016, 370 patients with metastatic malignant melanoma were treated with checkpoint inhibitors at the Department of Dermatology at the University Hospital Essen. All patients were identified for whom diarrhea and/or colitis was documented in the digital patient records. Patients who did not respond to standard immunosuppressive therapy within 2 weeks were classified as refractory. Demographic and clinical data of all patients were collected. RESULTS: We identified 41 patients with irColitis, the majority occurring during treatment with ipilimumab. Amongst these, 5 (12.2%) were refractory to standard immunomodulatory treatment with corticosteroids and infliximab. Therapy-refractory cases tended to show more severe inflammation in colonic biopsies (p = 0.04). In all therapy-refractory cases cytomegalovirus (CMV) was detectable. CMV-DNA in colonic biopsies and in plasma was significantly more often detectable in therapy-refractory cases (in colonic biopsies p = 0.005, in plasma: p = 0.002). Presence of serum CMV IgM and positive immunohistochemical stainings of colon biopsies for CMV were also associated with refractory colitis (p=0.021; p = 0.053). CONCLUSIONS: This report on CMV reactivation during management of checkpoint inhibitor-induced colitis emphasises the need for repetitive diagnostic measures in treatment-refractory irColitis.

Checkpoint inhibitors in chronic kidney failure and an organ transplant recipient.

BACKGROUND: Immune-checkpoint inhibitors have been approved for the treatment of metastatic melanoma based on several phase III trials. Patients after organ transplantation and patients with impaired renal function were excluded from these studies. Recently, allograft rejections were reported in organ transplant recipients receiving PD-1 blocking antibodies. PATIENTS AND FINDINGS: Four patients with metastatic melanoma and impaired kidney function (baseline serum creatinine 1.79-2.59 mg/dl) were treated with immune-checkpoint blockers, of which one was a kidney-transplant recipient receiving immunosuppressive therapy with tacrolimus and prednisolone. The patient was initially treated with the anti-CTLA-4 antibody ipilimumab after detailed explanation of the potential risk of allograft rejection. Upon disease progression, therapy was switched to the anti-PD-1 antibody nivolumab. The other three patients were treated with nivolumab or pembrolizumab, two of them after previous therapy with ipilimumab. RESULTS: The patients received a median of six doses (range 3-21) of anti-PD-1 antibodies and 3-4 doses of ipilimumab. Kidney function tests remained stable throughout the course of checkpoint blockade. In the kidney transplant recipient, neither ipilimumab nor nivolumab led to an allograft rejection. Responses to anti-PD-1 treatment were divergent with two patients showing disease progression, one achieving a mixed response and one experiencing a complete response. CONCLUSION: These cases show that checkpoint inhibitors can be a safe therapeutic option in patients with impaired kidney function. Furthermore, we report the first organ transplant patient with malignant melanoma who received ipilimumab followed by nivolumab without experiencing a kidney allograft rejection.