Haemophagocytic Lymphohistiocytosis Following the anti-PD-1 Nivolumab in a Patient with Gastric Cancer and Ankylosing Spondylitis.

Background: Autoimmune diseases are not contraindications for immune checkpoint inhibitors (ICI) therapy in patients with cancer. However, immune-related adverse events (irAEs) are frequently observed in patients receiving ICIs including dermatitis, thyroiditis, colitis, and pneumonitis. Thrombocytopenic purpura, aplasia, and haemophagocytic lymphohistiocytosis (HLH) are rarely observed during ICIs. Case description: We report the case of a male patient with pre-existing untreated HLA B27 and ankylosing spondylitis with gastric cancer and liver metastases. The 79-year-old man was treated with anti-HER2 trastuzumab and anti-PD-1 nivolumab. Seventeen days after the seventh cycle of treatment, he presented at the emergency department with acute fever, confusion, and hypotension. Laboratory results showed pancytopenia, and elevation of ferritin and triglyceride. No infections were detected. Although not seen in a bone marrow biopsy, clinical presentation, and absence of infection, together with an H-score of 263, indicated HLH. The patient was treated with dexamethasone for four days and discharged on a tapering dose of steroids. At the two-month follow-up, clinical presentation was normal and blood test almost normalised. At 8 months, no liver metastases were observed. Conclusions: In a patient with a pre-existing autoimmune condition, immunotherapy led to the development of HLH, which was controlled by glucocorticoid. Absence of the feature of haemophagocytosis in the bone marrow biopsy did not exclude the diagnosis, as HLH can occur in the spleen or in the liver. Glucocorticoid therapy did not prevent the anti-cancer effect of ICIs, and liver metastases disappeared 8 months post-HLH. This case warrants further research on the interplay between autoimmunity and ICI response, as well as ICI-induced irAEs. LEARNING POINTS: Haemophagocytic lymphohistiocytosis (HLH) post seventh cycle of trastuzumab (anti-HER2) and nivolumab (anti-PD-1) was controlled with glucocorticoid.Breach of tolerance was due to immunotherapy-induced HLH in a patient with pre-existing autoimmune condition (HLA B27- positive ankylosing spondylitis).There was a complete disappearance of liver metastases 8 months post-HLH.

Extranodal NK/T cell lymphoma and lymphomatoid granulomatosis in a patient with chronic lymphocytic leukaemia: Case report for a new perspective on Richter syndrome.

RATIONALE: Richter syndrome (RS) defines the transformation of chronic lymphocytic leukemia (CLL) into a more aggressive lymphoma. Although the term RS is most often reserved for transformation of CLL into diffuse large B-cell lymphoma (DLBCL), and less frequently Hodgkin lymphoma , the list of cases with more variable presentations in the literature is growing. PATIENT CONCERNS: A 71-year-old Caucasian man initially consulted an otolaryngologist for a 1-year history of nasal congestion. DIAGNOSES: The asynchronous occurrence of 2 rare angiocentric Epstein-Barr virus (EBV)-related lymphoproliferative disorders in a patient with CLL, specifically clonally related lymphomatoid granulomatosis (LYG), and an extranodal NK/T-cell lymphoma, nasal type, are described herein. INTERVENTIONS: Radiation therapy and a regimen of cis-platinum were administered for the NK/T cell lymphoma, and ibrutinib for LYG. OUTCOMES: The patient remains in complete clinical remission 8 years after the diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma and recurrent extranodal NK/T cell lymphoma, and 2 years after the diagnosis of clonally related LYG. LESSONS: Although the precise pathogenesis of RS remains incompletely understood, various molecular alterations, in particular long-term immunosuppression, may lead to RS, similar to the causal link existing between non-Hodgkin lymphomas and HIV infection, and post-transplantation lymphoproliferative disorders. EBV infection is linked to the pathogenesis of several types of lymphomas and found in a subset of patients with RS; immunosuppression, in the context of CLL or other pathological conditions or pharmacological agents, can disrupt the fine balance between virus and the host immune system, and result in EBV-driven lymphoproliferations of B-, T-, or NK-cell origin. The findings of our literature review thus suggest that such non-diffuse large B-cell lymphoma , non-Hodgkin lymphoma CLL transformations, may be considered as rare variants of RS.

Naive CD4 T-cell activation identifies MS patients having rapid transition to progressive MS.

OBJECTIVE: Our objective was to determine whether altered naive CD4 T-cell biology contributes to development of disease progression in secondary progressive multiple sclerosis (SPMS). METHODS: We compared the naive CD4 T-cell gene expression profiles of 19 patients with SPMS and 14 healthy controls (HCs) using a whole-genome microarray approach. We analyzed surface protein expression of critical genes by flow cytometry after T-cell receptor (TCR) stimulation of naive CD4 T cells isolated from HCs and patients with SPMS. RESULTS: Hierarchical clustering segregated patients with SPMS into 2 subgroups: SP-1, which had a short duration of relapsing-remitting multiple sclerosis (MS), and SP-2, which had a long duration of relapsing-remitting MS. SP-1 patients upregulated numerous immune genes, including genes within TCR and toll-like receptor (TLR) signaling pathways. SP-2 patients showed immune gene downregulation in comparison with HCs. We identified an SP-1-specific transcriptional signature of 3 genes (TLR4, TLR2, and chemokine receptor 1), and these genes had higher surface protein expression in SP-1 than in SP-2. After TCR stimulation for 48 hours, only SP-1 showed a progressive linear increase in TLR2 and TLR4 protein expression. CONCLUSIONS: Differences in naive CD4 T-cell biology, notably of TCR and TLR signaling pathways, identified patients with MS with more rapid conversion to secondary progression, a critical determinant of long-term disability in MS.

Castleman's Disease: a rare finding in a pediatric neck.

Castleman's Disease is a rare lymphoproliferative disorder. In the literature, only 29 cases, associated with the neck presentation in children, have been reported. This is another case report regarding a 5-year old child who presented with a persistent cervical lymphadenopathy. Final pathology, after undergoing exploratory neck dissection and surgical excision, revealed Castleman's Disease. This report, augmented with a literature review of all the 29 cases, compares the clinical course of this patient with the other cases. In conclusion, although Castleman's Disease carries a favorable prognosis in children, surgical excision is recommended to confirm the diagnosis and to rule out other causes.

Multiple sclerosis: a disorder of altered T-cell homeostasis.

Uncertainty exists as to whether similar or different mechanisms contribute to the pathogenesis of different subtypes of multiple sclerosis (MS). Detailed analysis of naive T cell homeostasis shows that patients with relapsing-remitting MS (RRMS) and with primary progressive MS (PPMS) have early-onset thymic involution that causes reduced thymic output. The reduced thymic output leads to secondary peripheral homeostatic alterations in naïve CD4 T-cells, which closely mimic T-cell alterations observed in an experimental animal model of diabetes mellitus. Homeostatic T-cell receptor (TCR) signalling and proliferation of naïve T cells are induced by self-peptides. Consequently, the findings of increased TCR signalling of naïve CD4 T-cells, without increased proliferation, in PPMS, and the increased homeostatic proliferation of naïve CD4 T-cells in RRMS favour the development of autoimmunity. Thus, it seems highly likely that peripheral T-cell alterations secondary to a thymic abnormality contribute to the pathogenesis of both MS subtypes.

Reduced thymic output and peripheral naïve CD4 T-cell alterations in primary progressive multiple sclerosis (PPMS).

We compared naïve CD4 and CD8 T-cell homeostasis in primary progressive multiple sclerosis (PPMS), relapsing-remitting MS (RRMS) and controls. Quantitation of signal joint T-cell receptor (TCR) excision circles (sjTRECs) and quantitative estimates of daily thymic export confirm our previous report of reduced thymic output in RRMS and demonstrate reduced thymic output in PPMS. In PPMS, the decreasing % CD31+ naïve CD4 T-cells but constant sjTRECs and constant naïve CD4 T-cell numbers with age, together with increased Bcl-2 expression suggest increased TCR signaling with increased naïve T-cell survival. We conclude PPMS patients have peripheral immune alterations related to reduced thymic output.

Reconstitution of circulating lymphocyte counts in FTY720-treated MS patients.

FTY720 (Fingolimod) reduces multiple sclerosis disease activity by inducing lymphopenia and inhibiting lymphocyte re-entry from lymph nodes. Peripheral lymphocyte reconstitution following drug discontinuation has been considered relatively rapid (2-4 weeks), based on short-term studies. We investigated the kinetics of lymphocyte reconstitution in MS patients in open label extension phases of FTY720 clinical trials who discontinued therapy after prolonged use (>1-5 years), and examined histological features of a mediastinal lymph node obtained from a lymphopenic FTY720 patient. Although three patients showed reconstitution of peripheral lymphocytes within the predicted timeline, two patients continued to be lymphopenic 9 and 34 months after therapy cessation. Lymph nodes from the latter patient showed preserved architecture. Notwithstanding preserved lymph node integrity, time for lymphocyte reconstitution after prolonged FTY720 therapy can be significantly greater than predicted by shorter-term studies. This is relevant for clinical decisions regarding management of patients using this therapy and for introducing alternate therapies.

Thymic involution and proliferative T-cell responses in multiple sclerosis.

We investigated naïve CD4 T-cell homeostasis in relapsing-remitting multiple sclerosis (RRMS). Quantification of signal joint T-cell receptor excision circles in FACS-isolated CD31hi cells, which correspond closely to CD4 recent thymic emigrants (RTEs), indicates that young patients have reduced generation of CD4 RTEs compared to age-matched controls. In RRMS, compared to controls, CXCR4 analyses indicate age-associated thymic output of progressively immature CD4 RTEs, and Ki-67 data demonstrate altered T-cell proliferative responses that fail to maintain naïve CD4 T-cell numbers with age. Thus, RRMS patients have early thymic involution with compensatory homeostatic peripheral T-cell proliferative responses that may predispose patients to autoreactivity.

Clinical multiple sclerosis occurs at one end of a spectrum of CNS pathology: a modified threshold liability model leads to new ways of thinking about the cause of clinical multiple sclerosis.

Multiple sclerosis (MS) is a complex trait, the causes of which are elusive. A threshold liability model influences thinking about the causes of this disorder. According to this model, a population has a normal distribution of genetic liability to MS. In addition, a threshold exists, so that MS begins when an individual's liability exceeds the MS threshold; environmental and other causative factors may increase or decrease an individual's MS liability. It is argued here, however, that this model is misleading, as it is based on the incorrect assumption that MS is a disorder that one either has or does not have. This paper hypothesizes, instead, that patients with a diagnosis of MS share identical CNS pathology, termed MS pathology, with some individuals who have a diagnosis of possible MS and with some apparently healthy individuals, who may never have a diagnosis of MS. In order to accommodate this hypothesis, the current threshold liability model is modified as follows. (1) In addition to a normal distribution of MS liability within a population, a spectrum of MS pathology occurs in some who have a high MS liability. (2) A clinical MS threshold exists at a point on this liability distribution, where the burden and distribution of MS pathology permits a diagnosis of clinical MS. (3) Additional thresholds exist that correspond to a lower MS liability and a lesser burden of MS pathology than occur at the clinical MS threshold. This modified threshold model leads to the postulate that causes act at various time points to increase MS liability and induce MS pathology. The accumulation of MS pathology sometimes leads to a diagnosis of clinical MS. One implication of this model is that the MS pathology in clinical MS and in some with possible MS differs only in the extent but not in the type of CNS injury. Thus, it may be possible to obtain insight into the causative environmental factors that increase MS liability and induce MS pathology by focusing on patients who have clinical MS; some environmental factors that induce new lesions in patients with clinical MS may be identical to those that induce MS pathology in genetically susceptible individuals who do not have clinical MS. Identification of these causative factors has importance, as specific treatment may prevent the accumulation of MS pathology that leads to the significant CNS damage associated with clinical MS.

The initiation of multiple sclerosis: a new infectious hypothesis.

Both genetic and environmental factors cause multiple sclerosis (MS). Few genes have been identified, however, and environmental factors remain elusive. Some postulate an infectious cause, but no pathogens are reproducibly demonstrable in CNS lesions. I postulate that the CNS is not the infectious target in MS, but propose a two-hit infectious hypothesis focusing on nai;ve CD4 T-cells that initiate demyelination: (1) Various common viruses infect the thymus during childhood (first hit) and enhance nai;ve CD4 T-cell reactivity to CNS autoantigens; (2) Heterogeneous pathogens fully activate these T-cells during adulthood (second hit) to initiate myelin injury. The novel concept of thymic infection provides insight into the nature of some susceptibility genes, helps explain the high discordance rates in genetically susceptible individuals, and suggests it is futile to search for pathogens in MS lesions. Pathogen heterogeneity, i.e., the lack of a single infectious cause, implies there can be no simple therapies to prevent or treat MS.