Is there evidence to support the use of infliximab in immune mediated pneumonitis?

Is there evidence to support the use of infliximab in immune mediated pneumonitis?

Comment by InpharmD Researcher

As the majority of literature is limited to case reports, optimal care for steroid-resistant, immune-mediated pneumonitis is unknown. Current guidelines suggest initiating infliximab 5 mg/kg for patients who are not demonstrating improvement with corticosteroids after 48 hours. However, a single case study reported success with early initiation after 24 hours (see table 2). Another case report found an improvement after initiating infliximab on day 17 (see table 3). Additionally, a small retrospective study of 12 patients speculates intravenous immunoglobulin alone or with infliximab may improve survival compared to infliximab alone (see table 1).

Background

Per the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines, immunosuppressive treatment should be started immediately In the case of documented or high suspicion of immune-related pneumonitis. For grade 3 or 4 pneumonitis, they recommend discontinuing immune checkpoint inhibitor treatment, covering with an empiric antibiotic, and initiating methylprednisolone or prednisolone at 2 to 4 mg/kg/day. If there is no improvement after 48 hours, they recommend adding infliximab 5 mg/kg. Mycophenolate mofetil may be considered in cases of concurrent hepatotoxicity. [1], [2]

An 2020 article discusses the management for immune-related pneumonitis, while briefly mentioning the use of infliximab. Corticosteroids are typically the first recommended treatment option for pneumonitis grade 2 or higher. In refractory cases, non-corticosteroid therapies, including infliximab, have seen success mainly in anecdotal case reports. [3]

A case series assessed the clinical course of 3 pneumonitis patients who received infliximab 5 mg/kg IV along with methylprednisolone IV. Two of the patients experienced clinical and radiographic improvement but one patient was admitted to hospice and died. One patient who survived observed no recurrent pneumonitis for 26 months while the other was referred to palliative care. [4]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Is there evidence to support the use of infliximab in immune mediated pneumonitis?

Level of evidence

D - Case reports or unreliable data Read more→

Please see Tables 1-3 for your response.

Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes
Design	Retrospective study (N= 12)
Objective	To provide a comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis at a single, high-volume academic institution.
Study Groups	Intravenous immunoglobulin (n= 7) Infliximab (n= 2) Combination (n= 3)
Inclusion Criteria	Confirmed ICI-pneumonitis
Exclusion Criteria	Confirmed alternative diagnosis which includes cancer progression, radiation pneumonitis, or lung infection
Methods	Patients with confirmed ICI-pneumonitis (clinical or radiographic lung inflammation either during or after anti-PD-(L)1 therapy) were analyzed. From the included patients, those identified with steroid-refractory ICI-pneumonitis (failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids to up to 14 days of use) were included in the result analysis. Three types of treatment used in refractory cases were identified: intravenous immunoglobulin, infliximab, and a combination of the two. Patients who received infliximab were given one dose of 5 mg/kg.
Duration	Data collection period: January 2011 to January 2020
Outcome Measures	Clinical improvement in steroid-refractory ICI-pneumonitis defined as reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis
Baseline Characteristics		Intravenous immunoglobulin (n= 7)	Infliximab (n= 2)	Combination (n= 3)
	Age at ICI-pneumonitis diagnosis, years	66	66	68
	Female	43%	100%	33%
	White	86%	100%	100%
	Smoking status Never Current/former	43% 57%	0 100%	0 100%
	Tumor history Lung carcinoma Non-small cell lung carcinoma Small cell lung carcinoma Oropharyngeal squamous cell carcinoma Renal cell carcinoma Pancreatic adenocarcinoma	71% 80% 20% 0 0 0	100% 100% 0 0 0 0	67% 100% 0 33% 0 0
	Initial cancer stage II III IV	14% 43% 43%	50% 0 50%	33% 0 67%
Results	Endpoint	Intravenous immunoglobulin (n= 7)	Infliximab (n= 2)	Combination (n= 3)
	Clinical improvement Died due to steroid-refractory ICI-pneumonitis or infectious complications	2 (29%) 3 (43%)	0 2 (100%)	0 3 (100%)
	Hospital length of stay, days	21 (6-48)	13.5 (13-14)	20 (8-31)
	Intubation due to steroid-refractory ICI-pneumonitis	1 (14%)	1 (50%)	1 (33%)
Adverse Events	N/A
Study Author Conclusions	Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
InpharmD Researcher Critique	The study is limited by the retrospective design and small patient population; the results must be verified in prospective clinical trials. Improvement in steroid-refractory ICI-pneumonitis was not confirmed via imaging (typically confirmed by symptom improvements).

References:
[1] Balaji A, Hsu M, Lin CT, et al. Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes. J Immunother Cancer. 2021;9(1):e001731. doi:10.1136/jitc-2020-001731

Early infliximab in life-threatening immune-mediated pneumonitis
Design	Case Study
Case presentation	A 47-year-old male being treated with combination immune checkpoint inhibition (Ipilumumab and Nivolumab) for metastatic melanoma presented as an emergency with rapidly progressive dyspnea. This was associated with a dry cough and generalized myalgia. No fevers and no other significant symptoms. He had completed two cycles of combination immune checkpoint inhibitor (ICI) therapy and had noted a significant decrease in his primary neck lesion. Clinical diagnosis was life-threatening immune-mediated granulomatous pneumonitis. The patient was initially treated with intravenous methylprednisolone (2mg/kg), high flow oxygen through a nasal high flow circuit, chest physiotherapy, and intravenous antibiotics (amoxicillin/clavulanic acid). Given the severity of the presentation, a decision was made to treat with intravenous Infliximab (5mg/kg) after 24 h of treatment alongside methylprednisolone. The patient made positive progress including oxygen requirements reduced corresponding with significant symptomatic improvement. He completed 3 days of intravenous methylprednisolone and was converted to oral prednisolone (1mg/kg) and mycophenolate mofetil. His infection screen including beta-glucan was negative. A repeat chest X-ray 1-week post-admission showed significant radiological improvement mirroring his clinical progress.
Study Author Conclusions	Immune-mediated pneumonitis is a challenging presentation because of the broad spectrum of radiological manifestations and the range of differential diagnoses including infection, progressive malignant lung disease, and concomitantly given medications causing lung disease. Patients with non-small cell lung carcinoma and renal cell carcinoma treated with ICI therapy are more likely to develop pneumonitis than patients with melanoma. This may relate to an increased susceptibility due to higher levels of underlying lung disease or greater tobacco exposure but further research is required to identify patients at higher risk of immune-mediated pneumonitis. Severe immune-mediated pneumonitis is associated with significant mortality. The European Society for Medical Oncology guidelines advocate the use of immunosuppressive agents, such as Infliximab or Cyclophosphamide, if there is no clinical improvement or deterioration after 48 h of treatment with IV methylprednisolone. There are no randomized trials comparing the timing of emergency treatment with immunosuppressive agents in patients with severe immune-mediated toxicities. Patients with life-threatening immune-mediated pneumonitis may benefit from earlier emergency initiation of immunosuppressive agents, such as in this case, and this requires further study.

References:
[1] Cooksley T, Marshall W, Gupta A. Early infliximab in life-threatening immune-mediated pneumonitis. QJM. 2019;112(12):929-930. doi:10.1093/qjmed/hcz224

Rapid temporal improvement of pembrolizumab-induced pneumonitis using the anti-TNF-α antibody infliximab
Design	Case report
Case presentation	A 67-year-old man with a 45-pack-year history of tobacco use presented with a massive left pleural effusion. He had undergone sigmoidectomy for colon cancer at the age of 37, and had had transient thyrotoxicosis at the age of 55. A chest computed tomography (CT) scan revealed a mass in the left upper lobe with left pleural effusion, enlarged mediastinal and contralateral hilar lymph nodes and intrapulmonary metastatic nodules in the right lung. The patient was diagnosed with immune-mediated pneumonitis, and administration of a high-dose intravenous corticosteroid (125 mg methylprednisolone) with a broad spectrum antibiotic for possible bacterial infection was initiated. On day 15, however, the patient was transferred to the intensive care unit with worsening hypoxia requiring mechanical ventilation. As pneumonitis was refractory to corticosteroid treatment (250 mg methylprednisolone on days 15-17), we administered 5 mg/kg infliximab on day 17. Infliximab rapidly improved respiratory status, and the PaO2/FiO2 ratio increased from 91 mmHg (day 16) to 169 mmHg (day 21). Although the consolidation in the right lower lobe did not improve, the resolution of the ground-glass opacities in the right upper and middle lobes was observed on day 23. The IV methylprednisolone dose was gradually tapered from 125 mg on days 18-20, to 60 mg on days 21-27, and 50 mg on day 28 and thereafter. On day 31, however, the patient’s respiratory status deteriorated again and he died on day 34. Autopsy revealed organizing phase diffuse alveolar damage in the right lower lobe with extensive collapse of alveolar spaces. No infectious etiology was identified, and the tumor in the left lung showed no pathological response to pembrolizumab.
Study Author Conclusions	In the current case, the pembrolizumab-induced pneumonitis with AIP/ARDS pattern on CT did not respond to corticosteroid treatment, but respiratory status improved one week after administration of infliximab. To our knowledge, the present case is the first report of immune-mediated pneumonitis that demonstrated transient improvement and reexacerbation two weeks after infliximab therapy. Considering that infliximab has a half-life of 7-12 days, elimination of infliximab might have led to reexacerbation of the pneumonitis in the current patient. In conclusion, infliximab induced rapid improvement of immune-mediated pneumonitis that lasted for two weeks. Repeated administration of infliximab for a certain period may be beneficial in the treatment of immune-mediated pneumonitis. The present case highlights the need for further research on the choice and optimal dose and duration of immunosuppressants in the treatment of severe immune-mediated pneumonitis.

References:
[1] Sawai Y, Katsuya Y, Shinozaki-Ushiku A, et al. Rapid temporal improvement of pembrolizumab-induced pneumonitis using the anti-TNF-α antibody infliximab. Drug Discov Ther. 2019;13(3):164-167. doi:10.5582/ddt.2019.01032