Case of the Month

65-year-old male patient with Pembrolizumab-induced Lichen planus

Medical history

Metastatic non-small cell lung cancer (NSCLC), stage IV M1C (UICC):

Spleen, kidney, and bone metastases

Initial diagnosis: April 24

Oncological Therapy

04/2024: Initial diagnosis of metastatic NSCLC

04/2024: Cerebral radiation therapy

05/2024: Initiation of combined immunochemotherapy with 6 cycles of pemetrexed, carboplatin, and 200 mg pembrolizumab

Since August 2024: 200 mg pembrolizumab qw3, NSCLC in partial response

Immune-related adverse event

Since December 2024, the patient has reported severe pruritus (VAS 8/10) along with the appearance of multiple erythematous papules. Treatment with topical and oral steroids, including 20 mg of prednisolone prescribed by the oncologist and general practitioner, was initiated but proved ineffective.

How we proceeded

In February 2025, the patient presented to the dermatology department. At that time, oral prednisolone was gradually tapered, and a skin biopsy confirmed the diagnosis of lichen planus. Following this, treatment with acitretin 20 mg (administered as 0-0-2 from February 28 to May 9, 2025) and UVB 311 nm phototherapy (from March 3 to April 14, 2025) was initiated. However, this resulted in only partial improvement, and the condition worsened after discontinuation of the light therapy.

Given the severity of the condition (CTCAE Grade 3 lichen planus) and the insufficient response to UVB 311, steroid and acitretin therapy, methotrexate treatment was started after a multidisciplinary discussion in out ToxBoard. Subcutaneous methotrexate at a dose of 15 mg once weekly was initiated on May 14, 2025. Folic acid supplementation was also started, and topical steroid therapy was continued.

Could we continue the therapy?

Treatment with pembrolizumab was continued.

Background

Despite the clinically significant therapeutic successes, treatment with PD-1 inhibitors such as pembrolizumab is associated with a number of immune-mediated side effects that can affect almost any organ system. The skin is particularly frequently affected. Dermatological side effects range from mild manifestations such as pruritus and maculopapular exanthema to autoimmune phenomena such as vitiligo, psoriasis-like changes to severe immune-mediated diseases (1). According to the European S1 guidelines, first-line treatments for lichen planus include the administration of topical or systemic corticosteroids, as well as therapy with acitretin. Second-line options comprise broadband or narrowband UVB phototherapy, a combination of UVB with acitretin, or the topical application of calcineurin inhibitors (2). In cases refractory to these measures, third-line therapies may be considered. These include methotrexate (15–20 mg per week for 4 to 15 weeks), azathioprine (administered orally at 50 mg twice daily or 1–2 mg/kg/day for a duration of 3 to 7 months), cyclophosphamide (50–100 mg/day for 3 to 6 months) as well as extracorporeal photopheresis (2). The literature suggests that methotrexate demonstrates high efficacy and a favorable safety profile, particularly in cases of extensive cutaneous lichen planus, making it a viable alternative to corticosteroids (3). The patient should be clearly informed about the potential risk of worsening the underlying oncological disease with methotrexate therapy. Therefore, a strict and well-considered indication is essential in such cases. An increasing number of reports in the literature have identified extracorporeal photopheresis (ECP) as a promising treatment option for steroid-refractory immune-related adverse events, including lichen planus. This is particularly relevant given the immunopathogenic nature of lichen planus, which involves T-cell mediated inflammation. In cases where conventional immunosuppressive therapies fail, ECP offers an immunomodulatory approach that may help restore immune tolerance without the broad immunosuppression associated with systemic steroids. Therefore, ECP should be considered a viable therapeutic option in the management of steroid-refractory lichen planus (4, 5).

Our conclusion

Immune response lichen planus often responds poorly to acitretin. In patients with non-small cell lung cancer, phototherapy with 311nm UVB has been shown to provide good relief, but it is indicated with caution in skin tumors. Patients should be advised of the slow onset of action of methotrexate therapy and treated symptomatically for pruritus. ECP is recommended in cases of severe pruritus (VAS 8/10), otherwise sufficient improvement should not be achieved.

References

1. Sibaud V. Dermatologic Reactions to Immune Checkpoint Inhibitors : Skin Toxicities and Immunotherapy. Am J Clin Dermatol. 2018;19(3):345-61.

2. Ioannides D, Vakirlis E, Kemeny L, Marinovic B, Massone C, Murphy R, et al. European S1 guidelines on the management of lichen planus: a cooperation of the European Dermatology Forum with the European Academy of Dermatology and Venereology. J Eur Acad Dermatol Venereol. 2020;34(7):1403-14.

3. Khurana A, Sharath S, Sardana K. Efficacy And Safety Of Low-Dose Methotrexate In Generalized And Recalcitrant Lichen Planus: A Retrospective Study At A Tertiary Care Center. Dermatol Pract Concept. 2024;14(4).

4. Ruf T, Rahimi F, Anz D, Tufman A, Salzer S, Zierold S, et al. Extracorporeal Photopheresis as a Treatment Option for Immune-Related Adverse Events: Two Case Reports and a Prospective Study. J Immunother. 2024;47(6):227-31.

5. Birckel E, Lipsker D, Cribier B. [Efficacy of photopheresis in the treatment of erosive lichen planus: A retrospective study]. Ann Dermatol Venereol. 2020;147(2):86-92.

71-year-old male patient with Ipilimumab/Nivolumab-induced Triple M syndrome (Myasthenia gravis, Myositis, Myocarditis)

Medical history

Metastatic cutaneous melanoma, stage III (pT4b N2b M0, AJCC 2017) BRAF V600 mutated; unresectable Metastases cervical lymph nodes

Oncological Therapy

11/2024: Primary excision

11/2024 CT: Pathologically enlarged lymph nodes on the left cervical side, as well as on the left axillary side.

12/2024 MRI: No evidence of intracranial metastases

01/2024: Puncture of cervical lymph node, left side: Detection of non-resectable lymph node metastasis of a malignant melanoma

01/2025: 2 cycles Ipilimumab+Nivolumab

Immune-related adverse event

Approximately 1.5 weeks following the initial administration of Ipilimumab and Nivolumab, the patient experienced escalating leg pain, progressive dyspnea, and diplopia, prompting presentation to the emergency department.

How we proceeded

The patient presented with markedly elevated troponin, creatine kinase (CK), and myoglobin levels, coupled with severely reduced left ventricular function. Immediate coronary angiography was performed, which excluded obstructive coronary artery disease. Intravenous methylprednisolone (1 g daily) was initiated. Concurrent pneumonia prompted the initiation of antibiotic therapy. Subsequently, while CK and myoglobin levels decreased, the patient developed increasing adynamia and progressive muscle weakness. Incipient respiratory insufficiency necessitated the initiation of non-invasive ventilation. Following interdisciplinary consultation (ToxBoard), a checkpoint inhibitor-induced 3-M syndrome (myasthenia gravis, myositis, and myocarditis) was suspected. Electromyography (EMG) and nerve conduction studies supported a T-cell mediated myasthenic syndrome. Immunosuppression was augmented with tocilizumab and intravenous immunoglobulins (IVIG). This treatment resulted in continuous improvement in both the patient's clinical condition and laboratory markers of myositis. During the treatment course, the patient experienced two episodes of pulseless ventricular tachycardia, each requiring approximately two minutes of resuscitation. Concurrently, increasing respiratory exhaustion despite non-invasive ventilation led to endotracheal intubation and invasive mechanical ventilation. Following further ToxBoard consultation, immunosuppression was expanded to include the Janus Kinase (JAK) inhibitor ruxolitinib. Furthermore, a temporary pacemaker was implemented for atrial overdrive pacing, and continuous renal replacement therapy (CRRT) was initiated for progressive renal insufficiency. Subsequently, the patient's cardiorespiratory status improved, allowing for extubation and weaning from catecholamine support. The patient is currently experiencing vancomycin-resistant Enterococcus (VRE) bacteremia and remains in the intensive care unit.

Could we continue the therapy?

Due to the patient's ongoing adverse event at the time of reporting, and their continued need for intensive care, continuation of the therapy is contraindicated. Current staging demonstrates a stable, partially regressive lesion profile, with no evidence of new metastatic disease.

Background

Triple M Overlap Syndrome, a rare but serious complication of immune checkpoint inhibitor (ICI) therapy, involves the simultaneous occurrence of myocarditis, myositis, and myasthenia gravis (MG). Patients typically manifest with weakness in the eyes, face, throat, or throughout the body, along with shortness of breath and chest pain.  In suspected immune-mediated Triple M Syndrome, diagnostic evaluation should include echocardiography, serological assessment of troponin, creatine kinase, aldolase, erythrocyte sedimentation rate, C-reactive protein, and autoantibodies, imaging studies, cardiac catheterization, electromyography/nerve conduction studies, and biopsies [1].   Autoantibody positivity is less frequent in ICI-induced MG compared to other forms of MG [2].   Management of Triple M Syndrome typically involves discontinuing immune checkpoint inhibitor (ICI) therapy, admitting the patient to an intensive care unit, and initiating systemic corticosteroids as the primary treatment [1].  Effective management and improved clinical outcomes require multidisciplinary collaboration. For instance, interdisciplinary case discussions within a ToxBoard framework are crucial. In this particular ToxBoard case, therapy escalations beyond high-dose steroid therapy were considered, including IVIG, tocilizumab (anti-interleukin 6 antibody), and JAK inhibitors. Given that Triple M syndrome is not primarily antibody-mediated, plasmapheresis is not the first-line treatment. The syndrome is T-cell mediated; therefore, mycophenolate mofetil or Anti-thymocyte globulin (ATG) may be administered to induce T-cell suppression; alternatively, cyclosporine can be utilized to achieve maximal T-cell suppression [3].  However, the limited nature of tumor response must always be considered.

Our conclusion

Immune-mediated adverse events, such as Triple M syndrome, represent a critical and potentially fatal complication of immunotherapy, necessitating prompt intervention, including intensive care management and collaborative interdisciplinary strategies.

References

[1] Baptista C., Margarido I., Bizarro R., Branco FP., Faria A. (2025). Triple M Overlap Syndrome: Myocarditis, Myositis and Myasthenia Gravis After a Single Administration of Pembrolizumab. Cureus, 17(1), e76834. https://doi.org/10.7759/cureus.76834

[2] Adeoye FW., Jaffar N., Surandran S., Begum G., Islam MR. (2024). Durvalumab-Induced Triple-M Syndrome. European journal of case reports in internal medicine, 11(8), 004729. https://doi.org/10.12890/2024_004729

[3] Kerbauy MN., Rocha FA., Arcuri LJ., Cunegundes PS., Kerbauy LN., Machado CM., Ribeiro AAF., Banerjee PP., Marti LC., Hamerschlak N. (2024). Immune reconstitution dynamics after unrelated allogeneic transplantation with post-transplant cyclophosphamide compared to classical immunosuppression with anti-thymocyte globulin: a prospective cohort study. Haematologica, https://doi.org/10.3324/haematol.2024.285921

60-year-old male patient with Nivolumab-induced polyarthritis and suspected necrotizing fasciitis

Medical history

Metastatic cutaneous melanoma, stage IV, M1d (AJCC 2017), BRAF V660K/V600R/V600M mutated; metastases in the brain, right parotid, lymph nodes and soft tissue

ECOG 0

Oncological Therapy

2006 Resection and lymph node resection

05/2019 Right parotid metastasis (right neck dissection)

07/2019-07/2020 Pembrolizumab adjuvant

08/2021 Recurrence (lymph node and soft tissue metastases)

08/2021-11/2021 Ipilimumab/nivolumab

11/2021-03/2022 Nivolumab, discontinuation due to recurrence (soft tissue metastasis)

05/2022-08/2023 Dabrafenib/trametinib

02/2023-08/2023 Stable disease

08/2023 Brain metastasis right temporal

09/2023-10/2023 Two cycles dacarbazine (DTIC)

10/2023 Reinduction of immunotherapy with ipilimumab/nivolumab as well as stereotactic irradiation of single cerebral metastases

12/2023 Diarrhea (approx. 10 stools/day), ICI-induced, improvement after a short prednisolone course with 1 mg/kg body weight

01/2024-04/2024 Nivolumab 240mg every 2 weeks

05/2024 Double dose of nivolumab (480mg every 4 weeks)

Immune-related adverse event

Approximately 1.5 weeks after receiving the double dose of nivolumab, the patient developed intermittent large joint pain (shoulders, knees, hips) and severe swelling and overheating of the right knee joint and the adjacent dorsal lower leg. Low dose cortisone (20 mg prednisolone/day) only led to a temporary, slight improvement in symptoms. He was admitted to a regional hospital. CT showed multiple air pockets on the medial head of the gastrocnemius muscle and several knee punctures excluded infectious cause. Due to the detected intraarticular air, severe pain in the right calf, swelling and overheating of the area around the right knee and reduced general condition, necrotizing fasciitis was suspected, so soft tissue surgery was performed on the right lower leg. The surgeons found an old hematoma, secretion, glassy disintegration of the m. sartorius, m. soleus and the m. gastrocnemius fascia, and an initial muscular disintegration of the medial m. gastrocnemius head. Histologically, there was no evidence of malignancy and there was no proof of streptococcus pyogenes or other bacteria. After the surgery, the patient was monitored in the intensive care unit and received clindamycin and piperacillin/tazobactam i.v. because the inflammatory parameters were elevated.

How we proceeded

After discharge the patient presented to our oncology outpatient clinic in a wheel chair with severe pain of the knee joints, weakness and pain in the muscles, especially the shoulders and the right calf. Joints were swollen with minimal effusions. Upon induction of prednisolone (1mg/kg body weight) the pain stopped within one day and the patient could get up from the wheel chair again. The initial radiological findings were re-evaluated and synovitis was diagnosed, without evidence of necrotizing fasciitis. The effusion in the knee showed 6,200 leukocytes/µl and an aviscous consistency, without crystals or bacteria. In summary, the patient suffered from myositis and polyarthritis induced by the checkpoint inhibitor therapy and subsequently an iatrogenic infection in the area of ​​the arthroscopic joint puncture. Prednisolone/d was tapered and methotrexate 15mg/week s.c. initiated. If this therapy does not significantly improve symptoms or the glucocorticoids cannot be tapered off, therapy with tocilizumb will be considered.

Could we continue the therapy?

Since the patient is still suffering from the adverse event at the time of reporting and currently receives prednisolone in combination with methotrexate, the immune checkpoint inhibitor therapy is currently paused. Depending on the clinical findings, however, reinduction will be discussed later due to the advanced tumor state of the melanoma.

Background

Rheumatic and musculoskeletal immune related adverse events (irAEs) are observed in about 10% of patients receiving immune checkpoint inhibitors (ICIs) [1]. Musculoskeletal irAEs show a large clinical spectrum [2], are often steroid-refractory [3] and frequently persist after cessation of ICI therapy [4]. Myositis is important to monitor since it can occur concomitantly with cardiomyositis[2].

In case of steroid-refractory rheumatic irAE several conventional synthetic disease-modifying antirheumatic drugs (csDMARD) have been used and so far, no specific drug has proven superiority. Methotrexate was the most frequently drug prescribed, followed by hydroxychloroquine then sulfasalazine, either as monotherapy or in combination [1]. No safety issues were described regarding long-term use of methotrexate associated with ICI in a few patients, with a median follow-up of over 1 year [5]. However, it takes around 4-8 weeks for the full effect to occur, so patients often have to continue taking a steroid in a tapering dosage during this period [1].

In severe rheumatic and systemic irAE or with insufficient response to csDMARD, biological disease-modifying antirheumatic drugs (bDMARD) may be considered, with TNF or IL-6 inhibitors being the preferred options for inflammatory arthritis[6]. However, prolonged use of TNF inhibitors can induce widespread, significant immunosuppression, which can negatively impact the antitumor efficacy of ICI therapy [7]. The anti-interleukin (IL)-6 receptor antibody, tocilizumab, is approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. It is reported to drastically improve symptoms for patients with severe ICI-induced polyarthritis [7].

The decision to reinduce the ICI-therapy should be based on the severity of musculoskeletal irAE, the extent of required immunosuppressive regimen and response of the irAE, the tumor dynamics, as well as therapy alternatives[1]. A pre-existing autoimmune rheumatic and/or systemic disease should not preclude the use of cancer immunotherapy. Baseline immunosuppressive regimen should be kept at the lowest dose possible (for glucocorticoids, below 10 mg prednisone per day) [1].

Our conclusion

This patient was thought to have a severe infection leading to necrotizing fasciitis, whereas his muskuloskeletal irAE quickly improved upon initiation of corticosteroids. Great care is needed before initiating immunosuppression in suspected infection. Thus, clarifying the genesis between an infectious and an autoimmune cause of the symptoms during ICI therapy is essential.

References

1.            Kostine, M., et al., EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors. Ann Rheum Dis, 2021. 80(1): p. 36-48.

2.            Moreira, A., et al., Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors. Eur J Cancer, 2019. 106: p. 12-23.

3.            Tomsitz, D., et al., Steroid-Refractory Immune-Related Adverse Events Induced by Checkpoint Inhibitors. Cancers (Basel), 2023. 15(9).

4.            Schulz, T.U., et al., Persistent immune-related adverse events after cessation of checkpoint inhibitor therapy: Prevalence and impact on patients' health-related quality of life. Eur J Cancer, 2022. 176: p. 88-99.

5.            Leipe, J., et al., Characteristics and treatment of new-onset arthritis after checkpoint inhibitor therapy. RMD Open, 2018. 4(2): p. e000714.

6.            Grumme, L. and H. Schulze-Koops, [Rheumatological side effects of checkpoint inhibitors and their treatment]. Z Rheumatol, 2023. 82(3): p. 187-194.

7.            Kim, S.T., et al., Successful treatment of arthritis induced by checkpoint inhibitors with tocilizumab: a case series. Ann Rheum Dis, 2017. 76(12): p. 2061-2064.

44-year old female patient with pembrolizumab-induced polyserositis

Medical history

10/21 superficial spreading melanoma (Breslow thickness: 1.5mm), localization: upper back

Axillary Sentinel Lymph Node Biopsy left (1/1) and right (0/1), pT2a N1a M0, St. IIIB (AJCC 2017)

BRAF V600E

Oncological Therapy

12/2021 – 09/2022 – adjuvant therapy with pembrolizumab (12 cycles) 

Immune-related adverse event

11 months after initiation of immunotherapy with pembrolizumab, the patient presented with pleural effusion and ascites. First, steroid therapy was initiated. During steroid tapering, the patient developed recurrent chylous pleural effusion and ascites. Steroid therapy was re-initiated but without success. Spironolactone, antibiotics, and a fat-free diet were initiated. Steroid therapy was stopped. Subsequently, the patient presented with severe dyspnea and fever due to recurrent chylous pleural effusion and ascites. Repeatedly pleural effusions and ascites were drained yielding up to 5 liter of fluids with no evidence for malignant cells. Staging and assessment of the tumor marker S100 revealed no progression of disease. The young patient had to quit work and has been in and out of hospitals for 5 months. She also appeared cachectic upon our first consultation.

How we proceeded

Since symptoms were steroid-refractory upon relapsing symptoms during steroid taper and the second increase of steroids we initiated systemic therapy intravenous immunoglobulins (IVIG).  After 4 cycles, we started parallel treatment with Extracorporeal Photopheresis (ECP). Lymphangiography was planned to rule out lymphatic fistulae. The patients` condition has significantly improved upon start of IVIG in combination with ECP. She currently reports no dyspnea, with less ascites.  She adheres to a low-fat, high-protein diet. ECP and IVIG therapies are ongoing.

Therapy with ruxolitinib could be considered in the future. Follow-up nutritional and metabolic consultations are scheduled to evaluate the further approach regarding the fat-free diet.

Could we continue the immunotherapy?

The checkpoint inhibitor therapy was permanently discontinued.

Background

The patient presents with a complex case of checkpoint-inhibitor induced polyserositis with recurrent chylous pleural effusions and ascites induced by adjuvant anti-PD1 therapy. The treatment approach has involved a combination of immunomodulatory and nutritional interventions in addition to repeated drainage of the effusions.

IrSerositis is a rare side effect of immunotherapy and can induce potentially life-threatening side effects with cardiac and pulmonary affection (Zierold et al., 2022). Knowledge about this immune-related adverse event is scarce. It can manifest acutely or progress slowly, occurring between 7 days and up to 72 or even 200 weeks after initiation of immunotherapy (Zierold et al., 2022). Concurrent malignant infiltrates are possible, emphasizing the importance of histopathological analysis (presence of lymphocytes, absence of malignant cells) (Zierold et al., 2022). Treatment of irSerositis can be challenging. High-dose steroid therapy could be a viable primary treatment option. Nevertheless, frequent pleural or ascites drainages are often required. For steroid-refractory immune-related adverse events (irAEs), a second-line therapy may be initiated (e.g., Infliximab, Ruxolitinib). Once, spontaneous resolution was reported (Kolla et Patel, 2016). Tumor outcomes during treatment of irSerositis vary (Zierold et al., 2022).

Our conclusion

Polyserositis is a very rare side effect of immune checkpoint inhibitors. Prompt diagnosis with exclusion of malignant cause and treatment are essential. The patient's positive response to the current treatment regimen with IVIG and ECP is encouraging.

Participate

  • Document cases of rare, complex, severe and therapy-refractory side effects induced by immunotherapy
  • Join our team of experts for analysis of irAE
  • Initiate or contribute to research projects with regard to irAE