Cytokine release syndrome triggered by programmed death 1 blockade (sintilimab) therapy in a psoriasis patient: A case report

Abstract

BACKGROUND

In recent years, immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy across diverse malignancies. Notably, in patients with advanced gastric cancer, the use of programmed death 1 (PD-1) blockade has significantly prolonged overall survival, marking a pivotal advancement comparable to the impact of Herceptin over the past two decades. While the therapeutic benefits of ICIs are evident, the increasing use of immunotherapy has led to an increase in immune-related adverse events.

CASE SUMMARY

This article presents the case of a patient with advanced gastric cancer and chronic plaque psoriasis. Following sintilimab therapy, the patient developed severe rashes accompanied by cytokine release syndrome (CRS). Fortunately, effective management was achieved through the administration of glucocorticoid, tocilizumab, and acitretin, which resulted in favorable outcomes.

CONCLUSION

Glucocorticoid and tocilizumab therapy was effective in managing CRS after PD-1 blockade therapy for gastric cancer in a patient with chronic plaque psoriasis.

Key Words: Cytokine release syndrome, Programmed death 1 blockade, Sintilimab, Psoriasis, Gastric cancer, Case report

Core Tip: The increasing use of immunotherapy has led to an increase in immune-related adverse events. This article presents the case of a patient with advanced gastric cancer and chronic plaque psoriasis. Following sintilimab therapy, the patient developed severe rashes accompanied by cytokine release syndrome. Fortunately, effective management was achieved through the administration of glucocorticoids, tocilizumab, and acitretin, which resulted in favorable treatment outcomes.

INTRODUCTION

Gastric cancer, a prevalent and heterogeneous malignancy, ranks fifth globally in incidence and fourth in China. Unfortunately, the majority of patients with gastric cancer are diagnosed at stage IV due to low early detection rates, thereby missing the window for initial surgery[1,2]. Limited effective chemotherapy options result in a short overall survival. The advent of immune checkpoint inhibitors (ICIs), such as programmed death 1 (PD-1) inhibitors, has highlighted the significant survival extension that can be achieved through PD-1 blockade in gastric cancer, as demonstrated in trials such as CheckMate-649 and Orient-16 (NCT03745170)[3]. This increased survival has propelled the combination of chemotherapy and PD-1 blockade to the forefront as a first-line treatment for advanced gastric cancer.

However, the widespread use of ICIs has led to a surge in diverse immune-related adverse events (irAEs). While most grade ≤ 2 irAEs can be managed with standard symptomatic treatment, a subset of irAEs, specifically grade ≥ 3 irAEs or life-threatening side effects, require precise and timely intervention[4]. Psoriasis, an immune-mediated disease, involves a delicate balance between autoimmunity and autoinflammation. ICIs have the potential to disrupt this balance, leading to exacerbations of psoriasis and other dermatological issues[5]. This article describes an elderly male who experienced severe skin toxicity and cytokine release syndrome (CRS) after receiving only one dose of sintilimab.

CASE PRESENTATION

Chief complaints

Fever with rash for 11 d.

History of present illness

A 75-year-old male patient had been recently diagnosed with advanced gastric cancer (stage T4NxM1 (IVB)). After the first cycle of treatment with oxaliplatin, capecitabine and sintilimab, he developed a low-grade exacerbated rash accompanied by fever, with a body temperature less than 38 °C. His daily life was not significantly affected. The patient came to our hospital for further treatment.

History of past illness

The patient had a medical history of infantile paralysis, hypertension, diabetes mellitus, and plaque psoriasis spanning several years.

Personal and family history

The patient denied any family history of malignancy.

Physical examination

The patient's vital signs were as follows: body temperature, 38.7 °C; pulse oximetry, 92%; reported shortness of breath; and blood pressure and heart rate within normal ranges. The rash significantly worsened but without skin ulceration (Figure 1A).

Figure 1 Clinical images show exacerbations of psoriasis after immune therapy. A: With low-level exacerbated psoriatic lesions; B, D, E, and F: Cytokine release syndrome and flare of psoriasis along with skin damage in the forehead, face, antebrachium, hand and dorsum, etc.; C: Posttreatment.

Laboratory examinations

The patient’s C-reactive protein level was 232.94 mg/L (reference: 0-7 mg/L), while his leukocyte and neutrophil counts remained within the normal ranges.

FINAL DIAGNOSIS

The final diagnosis of was CRS, hypertension, diabetes mellitus, infantile paralysis, and plaque psoriasis.

TREATMENT

After admission to the hospital, immediate low-flow oxygen inhalation was initiated to address hypoxia, and antipyretic analgesics were administered to reduce body temperature. Although there was no evidence of infection, antibiotics were prescribed to mitigate any fatal complications that might develop.

While the patient's polypnea resolved, the fever recurred, with the body temperature increasing to 41 °C. His blood pressure decreased to 88/55 mmHg, and the rash intensified, resulting in skin damage on the forehead, face, antebrachium, hand, and dorsum, among other areas (Figure 1B, D, E, and F). Considering capillary leakage syndrome (CLS) of the right crus, hypotension, hypoproteinemia, and elevated levels of multiple inflammatory markers and erythrocyte sedimentation rate (Table 1), CRS was deemed likely. The patient was administered high-dose methylprednisolone at 2 mg/kg/d; however, for personal reasons, he declined the interleukin-6 inhibitor tocilizumab. Despite the oral administration of celecoxib or tramadol as the patient's temperature normalized, skin swelling and arthralgia persisted. Two days later, the patient consented to tocilizumab at 8 mg/kg, leading to a gradual improvement in symptoms. A second dose was administered three days after the initial dose. The dosage of methylprednisolone was systematically reduced over 7 d, and acitretin was introduced concurrently. The acitretin dose was decreased at a rate of 25% every 3-5 d based on the patient's response, and oral prednisolone was initiated when the acitretin dose fell below 40 mg/d.

Table 1 Patient abnormal laboratory values and reference value results.

Laboratory test	Value at presentation	Reference value
Interleukin-2	0.97 pg/mL	≤ 9.80 pg/mL
Interleukin-4	1.98 pg/mL	≤ 3.00 pg/mL
Interleukin-6	631.25 pg/mL	≤ 16.60 pg/mL
Interleukin-10	12.93 pg/mL	≤ 4.90 pg/mL
TFN-α	2.36 pg/mL	≤ 5.20 pg/mL
Interferon-γ	66.89 pg/mL	≤ 17.3 pg/mL
CRP	232.94 mg/L	≤ 7 mg/L
Procalcitonin	0.25 ng/mL	≤ 0.5 ng/mL
ESR	60 mm/h	≤ 15 mm/h
APTT	49.4 s	26.0-40.0 s
INR	1.62	1.0-1.27
Fibrinogen1	6.73	2.0-4.0
Albumin	23.5 g/L	30-40 g/L
Rheumatoid factor	6.25 IU/mL	≤ 30 IU/mL
SARS-Co RNA	Negative	Negative
Influenza virus-A RNA	Negative	Negative
Influenza virus-B RNA	Negative	Negative
EB-Ab. IgM	Negative	Negative

¹With Clauss method.

TFN: Tumor necrosis factor; INR: International normalized ratio of prothrombin time; APTT: Activated partial thromboplastin time; EB-Ab: Epstein-Barr virus antibody; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate.

OUTCOME AND FOLLOW-UP

Over 4 wk, the patient's CLS, diffuse rash, and arthralgia ameliorated, leading to hospital discharge without recurrence or worsening of psoriasis symptoms (Figure 1C). A low maintenance dose of prednisolone (6 mg/d) was continued for an additional 2 wk during the follow-up period.

DISCUSSION

Studies indicate a pivotal role for Th1 and Th17 cells in the pathogenesis of psoriasis. By blocking the PD-1 pathway, PD-1 inhibitors may inadvertently increase the activity of Th1 and Th17 cells, leading to the onset, recurrence, or exacerbation of psoriasis[6,7]. Clinical investigations have established psoriasis as a significant risk factor for the accelerated development of psoriatic rash compared to patients without a prior history. A retrospective analysis by Halle et al[8] revealed a 57% incidence of relapsed or worsened psoriasis in cancer patients after ICI treatment, with an average onset time of 44 d. For many psoriasis patients, local or systemic treatments are effective, but discontinuation or suspension of drug therapy based on individual response is necessary for some patients. Additional options include oral administration of glucocorticoids or tretinoin in cases where external treatments prove ineffective.

CRS is clinically characterized by a spectrum of inflammatory symptoms and signs. Severe CRS is more commonly associated with CAR-T-cell therapy, while CRS occurring after PD-1 inhibitor therapy is relatively rare. The notable cases reported by Rotz et al[9] and Hu et al[10] involved alveolar soft part sarcoma and pulmonary fibrosis, respectively, with complicating CRS following nivolumab and sintilimab treatments. Distinguishing and diagnosing CRS after PD-1 treatment is challenging due to the variety of clinical manifestations. The patient whose case we present exhibited the recurrence and exacerbation of rash as the initial manifestation, followed by acute high fever, hypoxia, and severe skin lesions. The disease progressed rapidly, becoming life-threatening and leading to a grade 3 CRS according to the Common Terminology Criteria for Adverse Events grading system[11]. Treatment involving methylprednisolone and tocilizumab proved effective, aligning with the literature on CRS after ICI treatment[12]. Moreover, emerging evidence suggests that tocilizumab has potential for alleviating cancer-related cachexia and demonstrated latent effects in preclinical tumor models. Consequently, certain medical centers are exploring PD-1 plus tocilizumab therapy in patients at high risk of irAEs[13,14]. However, further analysis and discussion of the therapeutic efficacy are needed given the current insufficient clinical evidence.

Patients with psoriasis encounter a common challenge - the potential for psoriasis exacerbation upon discontinuation of glucocorticoid treatment for CRS. Our experience suggests the efficacy of a gradual reduction in the glucocorticoid dose over 1 wk when systemic symptoms are effectively controlled. Moreover, conventional methods such as acitretin, vitamin D3 derivatives, or ultraviolet irradiation can complement psoriasis treatment. It is advisable to continue medication for more than 2-3 wk when tapering to low doses of glucocorticoids rather than abruptly stopping the drug.

CONCLUSION

In summary, the use of immunotherapy in psoriasis patients is on the rise with the increasing prevalence of immunotherapy. It is crucial to be vigilant about the side effects of immunotherapy to promptly identify and manage serious complications. Our case underscores the therapeutic efficacy of glucocorticoids and tocilizumab in managing CRS after PD-1 blockade therapy for gastric cancer in a patient with chronic plaque psoriasis.