A better understanding of immune-related adverse events is essential for the early detection and appropriate management of these phenomena. We conducted an observational study of cases recorded at ...the French reference center for hypereosinophilic syndromes and in the French national pharmacovigilance database. Thirty-seven reports of eosinophilia induced by treatment with immune checkpoint inhibitors (ICIs) were included. The median range time to the absolute eosinophil count (AEC) peak was 15 4─139 weeks. The median AEC was 2.7 0.8─90.9 G/L. Eosinophil-related manifestations were reported in 21 of the 37 cases (57%). If administered, corticosteroids were always effective (n = 10 out of 10). Partial or complete remission of eosinophilia was obtained in some patients not treated with corticosteroids, after discontinuation (n = 12) or with continuation (n = 4) of the ICI. The AEC should be monitored in ICI-treated patients. If required by oncologic indications, continuation of ICI may be an option in asymptomatic hypereosinophilic patients, and in corticosteroid responders.
Beyond the production of autoantibodies, B-cells are thought to play a role in systemic sclerosis (SSc) by secreting proinflammatory/profibrotic cytokines. B-cells are a heterogeneous population with ...different subsets distinguished by their phenotypes and cytokine production. Data about B-cell subsets, cytokine production and intracellular pathways leading to this production are scarce in SSc. The aim of our study was to describe B-cell homeostasis, activation, proliferation, cytokine production in B-cells and serum and B-cell intracellular signaling pathways in SSc. We hypothezided that B-cell homeostasis and cytokine production were altered in SSc and could be explained by serum cytokine as well as by intracellular signaling pathway abnormalities.
Forty SSc patients and 20 healthy controls (HC) were prospectively included. B-cell subsets were determined by flow cytometry using CD19, CD21, CD24, CD38, CD27, IgM and IgD. CD25, CD80, CD95, HLA-DR were used to assess B-cell activation. Intracellular production of IL-10 and IL-6 were assessed by flow cytometry after TLR9 and CD40 stimulation. IL-6, IL-10, Ki67, Bcl2 mRNA were quantified in B-cells. Cytokine production was also assessed in sera and supernatants of B-cell culture, using a multiplex approach. Signaling pathways were studied through phosphorylation of mTOR, ERK, STAT3, STAT5 using a flow cytometry approach.
We found that SSc patients exhibited an altered peripheral blood B-cell subset distribution, with decreased memory B-cells but increased proportion of naive and CD21LoCD38Lo B-cell subsets. We observed an increased expression of activation markers (CD80, CD95, HLA-DR) on some B-cell subsets, mainly the memory B-cells. Secretion of IL-6, BAFF and CXCL13 were increased in SSc sera. There was no correlation between the peripheral blood B-cell subsets and the serum concentrations of these cytokines. After stimulation, we observed a lower proportion of IL-10 and IL-6 producing B–cells in SSc. Finally, we observed a significant decrease of mTOR phosphorylation in SSc patient B-cells.
In conclusion, we observed an altered B-cell homeostasis in SSc patients compared to HC. Memory B-cells were both decreased and activated in patients. IL-10 producing B-cells were decreased in SSc. This decrease was associated with an alteration of mTOR phosphorylation in B-cells. Conversely, there was no correlation between serum cytokine profile and B-cell homeostasis alterations.
•In systemic sclerosis, memory B-cells are decreased but markedly activated.•There is a decrease in regulatory IL-10 producing B-cells in patients.•This decrease is associated with an alteration of mTOR phosphorylation in B-cells.•IL-6, BAFF and CXCL-13 are increased in patients sera.•However, they are not correlated with the altered B-cell subset distribution.
IntroductionAdministration of immune checkpoint inhibitors (ICIs) induces different patterns of response, including the classical complete or partial response and disease progression and new patterns ...such as hyperprogressionand pseudoprogression. Pseudoprogression is defined as an increase in tumor size followed by a response to treatment, resulting from an exacerbated immune cell infiltration in the tumor bed, including CD103+ and CD8+ cells Citation1. Pseudoprogression is a rare phenomenon, with a rate not exceeding 10% in patients treated with ICI Citation2. In everyday practice, the misclassification of pseudoprogression as disease progression remains a concern. According to iRECIST guidelines, confirmation of the progression with later imaging is mandatory to make sure that the 'unconfirmed' progression is 'disease progression' and not 'pseudoprogression' Citation3. Hodi et al. Citation4 described that pseudoprogression occurs more often at the beginning of ICI treatment. Here, we report two cases of dramatic pseudoprogression occurring 36 and 10 months after the initiation of ICI.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
ABSTRACT
Background
Cancer-associated thrombotic microangiopathy (TMA) is a rare disease, with a poor prognosis. The classical treatment is urgent chemotherapy. Few data are available on the efficacy ...of plasma exchange (PE) and eculizumab in these patients.
Methods
Cases of cancer-related TMA treated between January 2008 and December 2019 in 12 French treatment centres were retrospectively analysed, excluding cases associated with chemotherapy and stem cell transplantation. Patients were divided into four groups depending on the treatment received: none, PE therapy alone, chemotherapy, with or without PE therapy, or eculizumab, with or without chemotherapy and PE therapy.
Results
The data of 59 patients with cancer-associated TMA were analysed. Twenty of these cases were related to a cancer recurrence. The cancer was metastatic in 90% of cases (53/59). Bone marrow invasion was observed in 20/41 biopsies. Some laboratory results, including disseminated intravascular coagulation high ferritin and C-reactive protein, were suggestive of cancer. None of the 16 patients whose alternative complement pathway was assessed had abnormal levels of protein expression or activity. The median survival time was 27 days. Chemotherapy was significantly associated with improved survival, with a 30-day survival rate of 85% (17/20) among patients who received PE and chemotherapy, versus 20% (3/15) among patients who received PE alone. Patients treated with eculizumab in addition to chemotherapy and PE therapy did not have longer overall survival or higher haematological remission rates than those treated with chemotherapy and PE therapy alone. Renal remission rates were non-significantly higher, and times to remission non-significantly shorter, in the eculizumab group.
Conclusions
Nephrologists and oncologists should make themselves aware of cancer diagnoses in patients with TMA and bone marrow biopsies should be performed systematically in these cases. All 59 patients had poor survival outcomes, but patients treated with urgent initiation of chemotherapy survived significantly longer than those who were not.
Graphical Abstract
Graphical Abstract
Abstract
Background and Aims
Thrombotic microangiopathy (TMA) are a heterogeneous group of diseases characterized by mechanical hemolytic anemia, peripheral thrombocytopenia, and organ failure of ...variable severity. In patients with cancer, TMAs are frequently induced by antineoplastic drugs but may be related to the malignant disease itself. Small series have reported poor prognosis. Only chemotherapy succeeded in lengthening life expectancy, even if few reports have described efficacy of therapeutic plasma exchange (TPE) or Eculizumab. Complement regulation was not studied in these publications, as the pathophysiology was rarely explored. In this study, we investigated retrospectively 59 cases of cancer-associated TMAs, to describe characteristics at diagnosis and efficacy of treatment.
Method
We conducted a retrospective multicentric observational study including all patients with a diagnosis of cancer-associated TMA, hospitalized in nephrological intensive care units (members of the French Intensive Care Network), between 2008 and 2019. We excluded patients receiving chemotherapy known to cause TMAs. We analyzed clinical and biological characteristics at diagnosis. We reported complement analysis when available. We defined four distinct treatment groups: No treatment (N), Plasmapheresis (P), Chemotherapy with or without chemotherapy (C+P), Eculizumab with or without Chemotherapy or Plasmapheresis (E+C+P). Renal remission and global survival were compared according to treatment group.
Results
We included 59 patients admitted to intensive care units for cancer-associated TMA. Twenty patients had a past history of cancer. Fifty percent was female, and mean age was 62.8 years. The primary cancer was breast (23.7%), lung (18.6%), stomach (10.2%), and prostate (10.2%). Adenocarcinoma was the most frequent histologic subtype (47.5%). The cancer was metastatic in almost cases (89.8%). At presentation, TMA manifestations were pulmonary (57.6%), neurologic (49.2%), bone pain (30.5%), and disseminated intravascular coagulopathy (DIVC) (55.9%). Forty-one patients had a bone marrow aspiration and/or biopsy. Among them, medullar metastases were found in 20 patients (48.7%). We observed low C3 in 14.7% of cases suggesting an activation of the alternative pathway. No genetic analysis was performed. Only one patient had an undetectable ADAMTS13 <5% without inhibitory ADAMTS13 antibodies. Renal failure was seen in 28 patients whom 63.7% had severe grade 3 acute kidney injury. Renal biopsy was performed in 6 patients with severe arteriolar TMA lesions. Seventeen patients had no treatment (N), fifteen patients were treated with TPE (P), twenty patients received chemotherapy with TPE (C+P), and seven patients received Eculizumab with TPE (E). Hematological and renal remission was not significantly different between treatment groups (p=0.74 and p=0.10 respectively). Mortality was high, 52.5% at one month, 90% after one year of follow-up. The median duration of survival was 27 days 8.5;95.5 in patients who received treatment. Survival was improved in (C+P) and (E+C+P) groups, significantly (p<0.0001).
Conclusion
We report the largest series of cancer-associated TMAS since the advent of Eculizumab for the treatment of HUS. Typical presentation included old age, bone pain, dyspnea, and DIVC. These symptoms, when associated with TMA, should therefore suggest a diagnosis of cancer. Bone marrow aspiration or biopsy led to diagnosis of cancer in half of cases, and should be systematically performed to rapidly confirm diagnosis. The overall prognosis remained dramatically poor, with a mortality rate of 90% in the first year. Chemotherapy is probably the most efficient therapy to delay the death. C3 serum level was decreased in only 7 patients, suggesting that the pathophysiology of cancer-associated TMA is not linked to complement activation. As a result, neither TPE nor Eculizumab improved survival rate.
Cancer patients with pre-existing autoimmune disease, such as systemic sclerosis (SSc), are excluded from clinical trials, so the data on tolerability and efficacy of immune checkpoint inhibitors in ...these patients are limited. This study investigated the tolerability and efficacy of anti–programmed death ligand 1 (PD (L)1) immunotherapies in patients with pre-existing SSc.
Scleronco-01 was a multicentre, nationwide, open-label, phase IV observational study, from 2019 to 2021.
Seventeen SSc patients receiving treatment for lung carcinoma (n = 13, 77%), head and neck cancer (n = 2, 12%), melanoma (n = 1, 6%), and colorectal carcinoma (n = 1, 6%) were included. The median (interquartile range) patient age was 60 (34–82) years. Fifteen (88%) patients received anti-PD1 (nivolumab and pembrolizumab) and two (12%) anti-PD-L1 (durvalumab). The median follow-up duration was 12 (range, 2–38) months. Four patients (24%) experienced flare-up of SSc symptoms. Ten patients (59%) developed an immune-related adverse event (grade I–II in 11 patients 65%, grade III–IV in one 6%) without grade V. The overall response rate was 41% (7/17 patients). The median overall survival was 15.8 (95% confidence interval: 7.3 to not reached) months.
Anti-PD1 or PD-L1 immunotherapies are suitable options for cancer patients with pre-existing SSc. Longer follow-up periods are required for long-term safety analyses.
•Immune checkpoint inhibitors can generate immune-related adverse events (irAEs).•IrAEs are more frequent in patients with pre-existing autoimmune diseases (AIDs).•Systemic Sclerosis (SSc) is an AID associated with cancer.•Anti-PD(L)1 immunotherapies are an acceptable anti-cancer treatment for SSc patients.
The aims of our study were to describe the evolution of interstitial lung disease (ILD) extent on HRCT scan in systemic sclerosis (SSc), to identify baseline prognostic factors associated with ILD ...evolution and to assess whether the evolution of pulmonary function tests (PFTs) correlated with this evolution.
58 SSc with ILD (SSc-ILD) patients were included. All HRCT scans and PFTs available were collected. We modelized PFTs and HRCT scans evolution using linear mixed model with random effect.
Patients underwent a median number of 3 HRCT scans (total n = 203) and 5 PFTs (total n = 329), during a mean follow-up of 5.3 ± 4.9 years. Mean SSc duration was 2.5 ± 3.1 years at the diagnosis of ILD. Mean baseline ILD extent was 32.3 ± 28.7%. We found a significant mean progression of ILD extent on serial HRCT scans of 0.92 ± 0.36% per year (p = 0.018). Male sex, diffuse cutaneous SSc (dcSSc), presence of anti-topoisomerase 1 antibodies, a higher DLCO, limited ILD and a low coarseness score at baseline in bivariate analysis, and presence of antitopoisomerase 1 antibodies and a coarseness score of 0 in multivariate analysis, were associated with faster progression of ILD extent over time There was a significant correlation between the progression of ILD extent and the decline of DLCO but only a trend for FVC. ILD extent at baseline and during follow-up was associated with survival.
Male sex, dcSSc, anti-topoisomerase 1 antibodies and a less severe ILD at baseline were associated with a faster progression of ILD over time. Evolution of DLCO significantly correlated with change in ILD extent on HRCT scan. Our study helps defining the profile of patients at risk of experiencing a progression of ILD on HRCT scans.
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