Case of the Month

• 01/2021 Nodular malignant melanoma left knee
  • 06/2022: lymph node metastasis left inguinal, complete resection
  • pT2aN1bM0, IIIB (AJCC 2017)

• 07/2022 Adjuvant immunotherapy with pembrolizumab

After 2 doses of adjuvant immunotherapy with the immune checkpoint inhibitor pembrolizumab, the patient presented with bilateral hearing loss. Furthermore, they developed dyspnea and leg edema. Troponin and nt-pro-BNP were slightly elevated. The D-dimer was slightly elevated and the ECG showed an S1Q3 type, thus we ruled out a pulmonary artery embolism using CT angiography. Echocardiography showed preserved systolic function and diastolic dysfunction (HFpEF, heart failure with preserved ejection fraction). A cardiac catheter examination could rule out a stenosis requiring intervention.

A cardiac MRI showed focal transmural late gadolinium enhancement (LGE) of the basal inferior wall. Since, in addition to inflammatory changes, cardiac metastases were also part of the differential diagnosis, a PET-CT was performed for further clarification. Finally, we agreed on ICI-myocarditis as the most likely cause. A myocardial biopsy was not performed due to the difficult localization.

We initiated systemic therapy with prednisolone with an initial dose of 1000 mg, which was reduced to 1 mg/kg after 5 days and then tapered. A weight reduction of 4 kg could be achieved through a negative fluid balance. A follow-up cardiac MRI is planned.

The immunotherapy was permanently discontinued.

Myocarditis is a rare side effect of immunotherapy (incidence ca. 1%) with a very high mortality (50%), therefore cardiac biomarkers should be regularly monitored during immunotherapy. Before starting therapy, a baseline ECG and troponin determination should be performed. Biomarker abnormalities or clinical symptoms should be followed by cardiac evaluation. Troponin and ECG taken together are abnormal in 50-90% of cases of ICI-myocarditis, cardiac MRI shows changes in 25-50% of cases. Echocardiography is often unremarkable. A cardiac catheter examination should be performed once to rule out coronary artery disease; myocardial biopsy is gold standard. Immunotherapy should be interrupted or discontinued and systemic corticosteroid therapy (1-2 mg/kg or even 1g/day) initiated. In therapy-refractory cases, mycophenolate mofetil (MMF), infliximab or anti-thymocyte-globuline (ATG) have been suggested as second-line therapies (ASCO-Guidelines, Schneider BJ, J Clin Oncol, 2021). Case reports reported on the successful use of abatacept and alemtuzumab as second-line therapies for ICI-myocarditis (Salem JE, N Engl J Med, 2019; Esfahani K, N Engl J Med, 2019).

Myocarditis is a rare side effect of immune checkpoint inhibitors with extremely high mortality, therefore monitoring of cardiac biomarkers and good side effect management is crucial.

• 1978 uveal melanoma right eye, HLA-A*02 negative, IV (AJCC 2017)
• 04/2021 cutaneous melanoma, IA (AJCC 2017)
  • 09/2021: subcutaneous melanoma metastasis
  • 11/2021: liver melanoma metastasis, BRAF wild type
    • Both metastases probably associated with uveal melanoma (histologically)

• 01/2022 – 02/2022 Combined immunotherapy with ipilimumab 3 mg/kg + nivolumab 1 mg/kg (3 doses)

After 3 doses of combined immunotherapy with the immune checkpoint inhibitors (ICI) ipilimumab and nivolumab, the patient presented with a burning sensation and swelling in the left eye. The ophthalmological emergency service suspected conjunctivitis, so corticoid-containing eye drops and eye ointment were used, but the swelling continued to increase. An ophthalmological examination revealed impaired ocular motility, so a cerebral MRI was performed, which revealed inflammatory changes (swelling, edema and contrast uptake) in the left lateral rectus muscle and an exophthalmos. An ipilimumab/nivolumab-induced myositis of the lateral rectus muscle was diagnosed. The creatine kinase (CK) was in the normal range.

We initiated a systemic therapy with prednisolone with an initial dose of 2 mg/kg, which was soon reduced to 1 mg/kg and then tapered off. Just two days after the start of the prednisolone treatment, the swelling had completely subsided; ocular motility also returned to normal over time. After tapering off the prednisolone to 10 mg, irColitis developed, which had to be treated with infliximab due to a steroid-refractory course.

Up to now, staging has shown stable disease, therefore immunotherapy was not reinduced due to the potential exacerbation of the steroid-refractory colitis. If necessary, reinduction should be carefully evaluated.

Myositis is a rare side effect of immunotherapy, occurring in <1% of patients and potentially fatal. An overlap with myocarditis and mysthenia gravis-like symptoms has been described. Diagnostic clues are provided by symptoms (muscle weakness, myalgia), increased CK, a myopathic pattern on electromyography, contrast uptake on MRI, and inflammatory or necrotic changes on muscle biopsy. Antibodies are mostly negative. Usually, immunotherapy should be interrupted or discontinued and systemic corticosteroid therapy (1-2 mg/kg) initiated. If therapy is refractory, plasmapheresis or IVIG, infliximab, MMF, MTX, or azathioprine can be initiated (Moreira et al., Eur J Cancer, 2019; Moslehi et al., Lancet, 2018; Kostine et al., Ann Rheum Dis, 2021).

Interestingly, in contrast to our case, three published cases of ocular myositis showed CK elevation (between 1844 and 7765 U/L), possibly due to involvement of other muscles. The 3 cases were treated with corticosteroids; in 1/3 of the cases the anti-PM-Scl 75 antibodies and anti-SRP antibodies were positive and plasmapheresis was also performed. In all three cases, the symptoms improved or resolved (Garibaldi et al., Neuromuscular Disorders, 2020; Kamo et al., BMC Neurology, 2019).

In the differential diagnosis, ocular irAE (e.g. conjunctivitis, secleritis or unveitis) also had to be considered initially. Ocular irAE occur in approximately 1% of patients receiving ICI therapy and non-muscular ocular irAE can often be treated topically, so interruption of ICI therapy may not be required.

Ocular myositis is a rare side effect of immune checkpoint inhibitors that physicians should be aware of and that requires ICI therapy interruption and systemic corticosteroids.

• 03/2021 amelanotic melanoma, BRAF wild type
  • 09/2021: Lung metastasis, complete resection
  • pT4bN0M1c, IV (AJCC 2017)

• 10/2021 – 11/2021 Immunotherapy with nivolumab 240 mg every 2 weeks (adjuvant)
• 02/2022 – 03/2022 Immunotherapy with nivolumab 240 mg every 2 weeks (adjuvant)
• 04/2022 – 05/2022 Immunotherapy with nivolumab 240 mg every 2 weeks (adjuvant)

After 1 month of adjuvant therapy with nivolumab, the patient presented with fever, myalgia without CK elevation, arthralgia and elevated inflammatory parameters. Due to a suspected systemic inflammatory reaction, most likely due to the immunotherapy, the nivolumab therapy was paused and the patient received methylprednisolone 1 mg/kg bw with subsequent taper. Shortly after resuming immunotherapy, the patient presented again with elevated inflammatory parameters, a hyperinflammatory syndrome was suspected, but the patient also described stabbing pains in his left eyebrow and ear. Nivolumab was re-initiated again, and shortly thereafter the patient complained of recurrent amaurosis fugax in the right eye. Duplex sonography showed the typical findings of a giant cell arteritis of the temporal artery. We initiated a therapy with prednisolone 1 mg/kg bw.

In summary, the patient showed laboratory signs of inflammation, fever, myalgia and arthralgia, temporal headaches and recurrent amaurosis fugax. In retrospect, the initial myalgia may be interpreted as a sign of polymyalgia rheumatica, and the stabbing pain in eyebrow and ear as a sign of arteritis temporalis.

We initiated therapy with prednisolone 1 mg/kg bw. The additional administration of tocilizumab is planned. To date, the patient has shown no recurrence of the melanoma.

A continuation of immunotherapy may be discussed after a detailed benefit-risk assessment but is currently not planned.

Giant cell arteritis (GCA) is an inflammatory autoimmune disease of large blood vessels; histology shows a granulomatous inflammatory reaction with fused macrophages (“giant cells”). Symptoms are variable and include e.g. headache, difficulty opening the mouth, flu-like symptoms, double vision and amaurosis fugax, fever, weight loss, and polymyalgia. GCA is frequently associated with polymyalgia rheumatica and has an approximately 20% risk of blindness.

GCA is a rare side effect of immunotherapy. An analysis of VigiBase revealed 18 cases of temporal GCA, 55% of the cases occurred after anti-CTLA4 therapy and one third of the cases were accompanied by visual impairment or blindness (Salem et al, Lancet Oncol., 2018). Two case reports described GCA under anti-PD1 therapy (Narala et al., Am J Ophthalmol Case Rep., 2020; Betrains et al., J Clin Rheumatol., 2021); in both cases, immunotherapy was discontinued and the patients treated with steroids. Therapy of ICI-induced GCA may also include methotrexate or tocilizumab (Heinzerling et al., Dtsch Arztebl., 2019). Evidence supports an important role of PD-1 and CTLA-4 pathways in the pathophysiology of vasculitis (Zhang et al., Proc Natl Acad Sci, 2017).

Giant cell arteritis is a rare side effect of immune checkpoint inhibitors that physicians should be aware of. In the case of typical systemic symptoms, headaches or vision disturbances, a low-threshold GCA clarification should be carried out.

• 01/2021 non-small-cell lung cancer (adenocarcinoma)
  • Initial stage: cT2N0cM0, IIB, PD-L1 expression 10%

• 01/2021 – 03/2021 Radiochemotherapy with cisplatin, vinorelbine and radiation 66,6 Gy
  • Partial response
• 05/2021 - 02/2022 Immunotherapy with durvalumab 10 mg/kg bw every 2 weeks (19 doses)
  • Partial response

After 9 months (and 19 doses) of immunotherapy with the anti-PD1 antibody durvalumab 10 mg/kg bw every 2 weeks, the patient developed a “rash”. Initially, the immunotherapy was discontinued and the patient treated with topical steroids and systemic prednisolone 60 mg p.o. for 10 days, which led to an initial improvement of the skin condition. While tapering the steroids, there was another exacerbation and 150 mg prednisolone i.v. were administered. Since there was no improvement under this therapy, the patient was referred to the department of Dermatology.

The patient presented with erythema and erythematous plaques covering approximately 18% of the body surface area, predominantly on the distal extremities. There was also lamellar desquamation and blistering, particularly on the hands. Histology showed vesicular detachment at the level of the basement membrane zone, a perivascular lymphocytic infiltrate, single-cell apoptosis and single eosinophils. The fluorescence pattern was non-specific. In summary, the findings corresponded to an erythema multiforme (EM)-like drug reaction.

The dose of corticosteroids was increased to 250 mg prednisolone i.v. for 3 days and then reduced to 80 mg p.o. The steroids were then tapered very slowly, but had to be increased again twice. In parallel, topical therapy with mometason cream was carried out. Due to the steroid-refractory or steroid-dependent course, secondline immunosuppression (therapy with intravenous immunoglobulins (IVIG) as well as extracorporal photophereses) was discussed.

Four months after the onset of the erythema multiforme, currently, a cortisone dose of 30 mg is required. Secondline immunosuppression was not started and the checkpoint inhibitor therapy was not yet re-initiated.

Cutaneous side effects are observed in 46-62% of patients on checkpoint inhibitor therapy and occur after a median of 2-3 weeks, but also up to two years after the start of immunotherapy. Rash, pruritus, and vitiligo-like lesions are the most common; lichenoid reactions, blistering reactions, psoriasis, and sarcoid-like lesions are less common. In 90% of cases, cutaneous irAE are mild and can be treated with topical therapy. Serious and potentially fatal cutaneous adverse events include DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms), Stevens-Johnsons Syndrome, toxic epidermal necrolysis, bullous skin lesions, and dermatitis herpetiformis (Heinzerling et. al, Dtsch Arztebl, 2019; Belum et. al., Eur J Cancer, 2016). The literature on erythema multiforme under immunotherapy is limited to individual case reports. Cases have been reported with ipilimumab, nivolumab and pembrolizumab. Treatment was mostly with systemic steroids, in one case also with IVIG. EM often led to discontinuation of immunotherapy (Zimmer, L et al, J Transl. Med, 2015; Jour et. al., J Cutan Pathol., 2016; Sundaresan et. al., Dermatol Online J., 2017; Utsunomiya et. al., Case Rep Dermatol., 2018; Yano et. al., Trends in Immunotherapy, 2021; Hashimoto et al, J Clin Med., 2021; Ambur et. al., Cureus, 2021).

Cutaneous irAEs are often mild but can be severe, requiring discontinuation of immunotherapy and initiation of systemic therapy. Dermatologists should be involved in managing cutaneous side effects, since specific skin findings may require varying treatments.