Anti-interferon Gamma Research Articles

A homogeneous bioluminescent inhibition immunoassay to detect anti-interferon gamma antibodies.

Adult-onset immunodeficiency with antibodies to interferon-γ (AOID with AIGA), is a rare, acquired immunodeficiency causing susceptibility to disseminated non-tuberculous mycobacteria and other intracellular opportunistic infections. The diagnosis depends on demonstrating the presence of endogenous anti-interferon-γ antibodies (AIGA) that suppress Th1 cell mediated immunity. Bioluminescent immunoassays are a newly emerging immunoassay format which utilise the action of bioluminescent enzymes on a substrate for specific analyte detection. In-short, detecting antibodies are conjugated with a bioluminescent enzyme. The detecting antibodies bind the analyte of interest and produce light (luminescence) after addition of a substrate. The purpose of this study was to evaluate two newly developed bioluminescent immunoassays using Lumit® (Promega) technology as a diagnostic test for AOID with AIGA. Specific aims included the clinical validation of a new inhibition bioluminescent immunoassay technique to detect AIGA which block detection of interferon-γ (IFN-γ) in-vitro and correlation of inhibition bioluminescent immunoassay results with AOID with AIGA disease status. Two bioluminescent inhibition immunoassays were developed. One which adapted an existing kit from Promega (Lumit® Human IFN-γ Immunoassay) and one which was developed in-house. 87 healthy controls and 48 patients with previously diagnosed AOID with AIGA were recruited and tested using these two methods. Results showed both bioluminescent inhibition immunoassays were able to clearly discriminate between AOID with AIGA patients and healthy controls. The mean inhibition percentage between patient groups correlated with disease activity. Both assays appeared to be more sensitive when compared to the existing inhibition ELISA.

Prognostic value of anti-IFI16 autoantibodies in pulmonary arterial hypertension and mortality in patients with systemic sclerosis

ObjectivesTo determine the diagnostic value of anti-interferon gamma inducible protein 16 (IFI16) autoantibodies in systemic sclerosis (SSc) patients negative for all tested SSc-specific autoantibodies (SSc-seronegative patients) and to evaluate the clinical significance of these autoantibodies, whether isolated or in the presence of anti-centromere autoantibodies (ACA). MethodsOverall, 58 SSc-seronegative and 66 ACA-positive patients were included in the study. All patients were tested for anti-IFI16 autoantibodies by an in-house direct ELISA. Associations between clinical parameters and anti-IFI16 autoantibodies were analysed. ResultsOverall, 17.2% of SSc-seronegative and 39.4% of ACA-positive patients were positive for anti-IFI16 autoantibodies. Anti-IFI16 autoantibodies were found only in patients within the limited cutaneous SSc (lcSSc) subset. A positive association between anti-IFI16 positivity and isolated pulmonary arterial hypertension (PAH) was found (odds ratio [OR]=5.07; p=0.014) even after adjusting for ACA status (OR=4.99; p=0.019). Anti-IFI16-positive patients were found to have poorer overall survival than negative patients (p=0.032). Cumulative survival rates at 10, 20 and 30 years were 96.9%, 92.5% and 68.7% for anti-IFI16-positive patients vs. 98.8%, 97.0% and 90.3% for anti-IFI16-negative-patients, respectively. Anti-IFI16-positive patients also had worse overall survival than anti-IFI16-negative patients after adjusting for ACA status in the multivariate Cox analysis (hazard ratio [HR]=3.21; p=0.043). ConclusionAnti-IFI16 autoantibodies were associated with isolated PAH and poorer overall survival. Anti-IFI16 autoantibodies could be used as a supplementary marker of lcSSc in SSc-seronegative patients and for identifying ACA-positive patients with worse clinical outcome.

A bioluminescent homogeneous immunoassay to detect anti-interferon gamma antibodies

A bioluminescent homogeneous immunoassay to detect anti-interferon gamma antibodies

Macrophage activation syndrome with acute hepatitis in a patient with adult-onset immunodeficiency with anti-interferon gamma antibodies: a case report

BackgroundMacrophage activation syndrome is a rare disorder leading to unregulated immune activity manifesting with nonspecific constitutional symptoms, laboratory abnormalities, and multiorgan involvement. We report the case of a patient who presented with acute hepatitis secondary to macrophage activation syndrome diagnosed by liver biopsy and successfully treated with intravenous immune globulin, anakinra, and rituximab.Case presentationA 42-year-old Laotian woman with adult-onset immunodeficiency with anti-interferon gamma antibodies presented with a fever, headache, generalized myalgia, dark urine, and reduced appetite in the setting of family members at home with similar symptoms. Her laboratory workup was notable for evidence of acute hepatitis without acute liver failure. After an unrevealing comprehensive infectious and noninvasive rheumatologic workup was completed, a liver biopsy was performed ultimately revealing the diagnosis of macrophage activation syndrome. She was successfully treated with intravenous immune globulin, anakinra, and rituximab.ConclusionThis case highlights the importance of maintaining macrophage activation syndrome on the differential of a patient with acute hepatitis of unknown etiology in the correct clinical context and the value of a liver biopsy in making a diagnosis when noninvasive testing is unrevealing.

Emapalumab, a Fully Human Anti-Interferon Gamma Monoclonal Antibody, in Pediatric Patients with Primary Hemophagocytic Lymphohistiocytosis: Long-Term Follow-up of a Phase 2/3 Study

Background: Primary hemophagocytic lymphohistiocytosis (pHLH) is a rare, life-threatening genetically heterogeneous, autosomal recessive disorder, characterized by immune dysregulation and hyperinflammation. Acute treatment of pHLH has traditionally involved immunochemotherapy with glucocorticoids and etoposide to suppress hyperinflammation and facilitate the patient undergoing allogeneic hematopoietic stem cell transplantation (HSCT), the only potentially curative therapy. Emapalumab, a fully human immunoglobulin G1 anti-interferon-γ (IFNγ) monoclonal antibody, binds free and receptor-bound IFNγ, neutralizing its biologic activity. Emapalumab has demonstrated efficacy in patients with pHLH and has a favorable safety profile with no increase in the risk of adverse events (AEs), including infections, with increasing drug exposure prior to patients undergoing HSCT. Objective: To monitor the long-term safety and efficacy of emapalumab in patients with pHLH, including the period after undergoing HSCT. Methods: Long-term follow-up study (NCT02069899) of patients with pHLH who had received ≥1 dose of emapalumab in a multicenter, single-arm, open-label phase 2/3 clinical trial who were followed for 1 year after HSCT or last administration of emapalumab in the parent study (NCT01818492). Patients received emapalumab for 4 to 8 weeks in the parent study, which included a 4-week short-term follow-up period, during which patients could have undergone HSCT. Treatment with emapalumab could continue according to the parent study protocol during follow-up, if a favorable benefit/risk assessment was established. Any concomitant treatment ongoing at the time of study entry was continued as considered necessary by the investigators. Endpoints included safety, 1-year survival, and HSCT outcomes. Results: Overall, 37/45 patients who participated in the phase 2/3 study entered long-term follow-up, with 24 patients (64.9%) completing the study; 13 patients (35.1%) withdrew from the study, most commonly because of AEs (6 patients [46.2%]) and withdrawal of informed consent (2 patients [15.4%]). All patients had ≥1 concomitant medications including systemic corticosteroids and ≥1 systemic antimicrobial. Emapalumab treatment continued during long-term follow-up for 22 patients (59.5%). All patients experienced at least one AE during follow-up ( Table), most commonly infections or infestations (27 patients [73.0%] reported an infection AE). Most AEs were mild or moderate in intensity. Four patients (10.8%) had study drug-related AEs. Overall, 56.8% of patients experienced at least one severe AE. 28 patients (75.7%) experienced at least 1 serious AE (SAE), but only 1 patient (2.7%) had a treatment-related SAE (Coombs positive hemolytic anemia). Infusion-related reactions of rash were observed in 2 patients (5.4%), but these reactions were temporary and resolved without treatment. No patients experienced AEs leading to study drug discontinuation. Nine patients died during the study (4 prior to HSCT conditioning and 5 during the post-conditioning period). No study drug-related deaths were reported. 28 (75.7%) patients were alive at last observation or 1 year after last emapalumab dose and 33 (89.2%) survived to undergo HSCT or until 1 year after last emapalumab dose (whichever came first). 29 patients (78.4%) underwent HSCT, including 18 during long-term follow-up. 24 of the 29 (82.8%) patients who underwent HSCT were alive at last observation or 1 year after last emapalumab dose. Sustained engraftment was achieved in 23 patients (79.3%; 95% confidence interval, 61.6-90.2%). During the follow-up period, 6 patients (20.7%; 95% confidence interval [CI], 9.8-38.4%) experienced primary or secondary graft failure after undergoing HSCT and 7 patients (24.1%; 95% CI, 1.2-42.1%) had acute or chronic graft-versus-host disease. At the 12-months post-transplant visit, 25/26 (96.2%) patients maintained a complete response, while 1 (3.8%) patient was reported to have maintained a partial response. No pHLH reactivation was reported during the study. Conclusions: The long-term outcomes for patients with pHLH treated with emapalumab are consistent with observations made during a phase 2/3 study. A favorable safety profile was maintained, and a high proportion of patients received HSCT and achieved long-term survival.

Prevalence and clinical manifestations of cutaneous findings in patients with adult-onset immunodeficiency due to anti-interferon gamma autoantibodies: an eight-year retrospective study.

Cutaneous findings in adult-onset immunodeficiency due to anti-interferon gamma autoantibodies (anti-IFN-γ autoAbs) are common. Currently, data on this topic are scarce. We retrospectively reviewed medical records of 202 skin episodes from 77 patients diagnosed with adult-onset immunodeficiency due to anti-IFN-γ autoAbs. The exclusion of drug eruptions left 180 episodes from 74 patients for further analysis. Reactive dermatosis was diagnosed in 66.1%, followed by disseminated skin infection (18.3%) and local skin infection (15.6%). Neutrophilic dermatosis (ND) tended to appear on the upper part of bodies, while leg lesions were common in the non-ND. Disseminated infection occurred more frequently with ND. Mycobacterium abscessus was the most common pathogen of concomitant infection. Remission was achieved in 21.6% and was significantly associated with females. Reactive dermatosis was the most common skin manifestation. ND was found in the upper part of bodies and associated with disseminated infection. Drug-free remission was scarcely achieved.

P090 Protocol for the two-cohort, open-label, single-arm EMERALD study of emapalumab, an anti-interferon gamma monoclonal antibody, in patients with macrophage activation syndrome in rheumatic diseases

Abstract Background/Aims Macrophage activation syndrome (MAS), a form of secondary haemophagocytic lymphohistiocytosis, is a severe, life-threatening complication of rheumatic diseases such as Still’s disease (systemic juvenile idiopathic arthritis or adult-onset Still’s disease) and systemic lupus erythematosus (SLE). Interferon gamma has been implicated in the underlying pathology of both conditions. Standard first-line treatment for MAS is high-dose glucocorticoids (GCs); however, additional treatments are used without a standardised approach in patients who are treatment-refractory. When 9 patients with an inadequate response to high-dose GCs were administered emapalumab in a pilot study (NCT03311854), interferon gamma was rapidly neutralised and MAS was controlled. Emapalumab also had a favourable safety profile. A new study (EMERALD) is currently enrolling patients with MAS in Still’s disease and SLE to further evaluate the efficacy and safety of emapalumab. Methods The open-label, single arm, multicentre, phase 2/3 interventional EMERALD study (NCT05001737) is enrolling paediatric and adult subjects with MAS and an inadequate response to high-dose GCs into two cohorts: MAS in Still’s disease (n = 25) and MAS in SLE (n = 16). Each cohort is a single-arm study comprising two phases: an optional run-in phase and an interventional phase. Key eligibility criteria vary by cohort and phase (Table). During the run-in phase, patients are treated with high-dose GCs and followed until MAS remission or inadequate response, or for a maximum of 12 weeks. Patients enrolled in the interventional phase are treated with intravenous emapalumab (initial dose 6 mg/kg, subsequent doses 3 mg/kg) for 4 weeks or until protocol-defined complete response (CR), then followed up for 1 year. Results The primary endpoint of the study is protocol-defined CR at Week 8 after first emapalumab administration. Secondary efficacy endpoints include GC tapering, survival, time to first CR, overall response (CR and partial response), time to first overall response, MAS recurrence, pharmacokinetic/pharmacodynamic profile of emapalumab and patient-reported outcomes. Safety endpoints include assessments of adverse events, abnormal laboratory parameters and anti-drug antibodies. Conclusion The ongoing EMERALD study is designed to address the unmet need for new efficacious and safe therapies for the treatment of MAS. Disclosure P. Brogan: Consultancies; P.B. has acted as a consultant for Sobi, Novartis, Roche and UCB. A. Grom: Consultancies; A.G. has acted as a consultant for Novartis, AB2 Bio, Novimmune and Sobi. R. Kanceva: Corporate appointments; R.K. is an employee of Sobi. F. De Benedetti: Consultancies; F.D.B. has acted as a consultant for AbbVie, Sobi, Pfizer, Roche, Sanofi, Novartis and Novimmune. Grants/research support; F.D.B has received research grants from AbbVie, Sobi, Pfizer, Roche, Sanofi, Novartis and Novimmune.

Distinct Lymphocyte Immunophenotyping and Quantitative Anti-Interferon Gamma Autoantibodies in Taiwanese HIV-Negative Patients with Non-Tuberculous Mycobacterial Infections.

The presence of anti-interferon-γ autoantibodies (AutoAbs-IFN-γ) is not rare in patients suffering from persistent non-tuberculous mycobacterial (NTM) infections that are characteristic of adult-onset immunodeficiency syndrome. The immune disturbances in this distinct disorder remain to be elucidated. Patients with NTM infections but without effective response over 3months' treatment were referred to our institute to quantify their level of AutoAbs-IFN-γ after excluding defective IL12/23-IFN-γ circuit and reactive oxygen species production. The AutoAbs-IFN-γ and percentage of lymphocyte subpopulations most relevant to T and B cell pools were assessed and compared with age-matched healthy controls. A total of 31 patients were enrolled during the 15-year study period (2008-2022), 20 patients with > 50% suppression of IFN-γ detection at 1:100 serum dilution were classified into the Auto-NTM group. The remaining 11 with negligible suppression were assigned to the No Auto-NTM group. Mycobacterium chimaera-intracellulare group (MAC), M. kansasii, and M. abscessus were the most common pathogens. Pneumonia (19 vs 7), lymphadenitis (11 vs 5), Salmonellasepsis (6 vs 2), osteomyelitis (5 vs 1), and cutaneous herpes zoster (4 vs 4) were the main manifestations in both the Auto-NTM and No Auto-NTM groups who had similar onset-age (55.3 vs 53.6years; p = 0.73) and follow-up duration (71.9 vs 54.6months;p = 0.45). The Auto-NTM group had significantly higher transitional (IgM + + CD38 + +), CD19 + CD21-low, and plasmablast (IgM-CD38 + +) in the B cell pool, with higher effector memory (CD4 + /CD8 + CD45RO + CCR7 -), senescent CD8 + CD57 + , and Th17 cells, but lower naïve (CD4 + /CD8 + CD45RO - CCR7 +) and Treg cells in the T cell pool when compared to the No Auto-NTM and healthy groups. NTM patients with/without AutoAbs-IFN-γ had lower Th1-like Tfh (CD4 + CXCR5 + CXCR3 + CCR6 -) cells. All Auto-NTM patients still had non-remitted mycobacterial infections and higher AutoAbs-IFN-γ despite anti-CD20 therapy in 3 patients. In patients with suspected adult-onset immunodeficiency syndrome, two thirds (20/31) were recognized as having significantly inhibitory AutoAbs-IFN-γ with higher antibody-enhancing transitional, CD19 + CD21-low and plasmablast B cells; as well as higher effector memory, senescent CD8 + CD57 + and Th17 cells, but lower naïve T and Treg cells in contrast to those with negligible AutoAbs-IFN-γ. Such immunophenotyping disturbances might correlate with the presence of AutoAbs-IFN-γ. However, the mutual mechanisms need to be further clarified.

Development of an immunochromatographic strip test for rapid detection of a potent neutralizing anti-interferon gamma antibody in adult-onset immunodeficiency.

Adult-onset immunodeficiency (AOID) is associated with the presence of anti-interferon gamma autoantibodies (anti-IFN-γ autoAbs), which neutralizes IFN-γ signaling and leads to susceptibility to intracellular opportunistic infections. However, measuring neutralizing autoAbs is not practical for general clinical laboratories. This study aims to develop a competitive immunochromatographic (IC) strip test for detecting autoAbs that recognize the same epitope as a potent neutralizing antibody. The competitive IC strip test detecting autoAbs that recognize the same epitope as mouse anti-IFN-γ monoclonal antibody, clone B27 (B27 mAb) was fabricated and used to determine B27 epitope recognizing autoAb (B27 AAb) in AOID plasma. The competitive ELISA was used as a comparative method. AR patients. The efficacy of the IC strip test was compared with competitive ELISA and found a percent positive agreement of 91.30%, a percent negative agreement of 79.31%, and a percent overall agreement of 84.62%. The results from the competitive IC strip test were consistent with those from competitive ELISA, indicating that the generated IC strip could detect B27 AAb in AOID plasma.

B DISCERNING: ROLE OF RITUXIMAB IN INTERFERON GAMMA AUTOANTIBODY DISEASE

<h3>Introduction</h3> Adult-onset immunodeficiency with anti-interferon gamma autoantibodies can lead to disseminated infections by opportunistic pathogens. This case describes interferon gamma autoantibodies responsible for treatment resistant disseminated mycobacterium avium (MAC) infection. <h3>Case Description</h3> A 52 year-old man originally from Laos was seen as an outpatient consult for concern for immunodeficiency. He originally presented with weight loss and fatigue, and CT chest showed a spiculated mass with lymphadenopathy. Lymph node biopsy demonstrated MAC, and PET scan suggested multi-organ disease. He failed to improve on standard antimicrobial therapy, requiring prolonged hospitalization. Family history was significant for parental consanguinity and a sister with severe MAC infection. Our differential diagnosis included Mendelian susceptibility to mycobacterial disease (MSMD) and acquired interferon-gamma autoantibodies. Genetic testing with the Invitae Primary Immunodeficiency panel was unrevealing, and testing for clinically significant interferon gamma autoantibodies was positive. Due to further clinical deterioration, treatment with rituximab was initiated. His symptoms improved after four weekly infusions with complete depletion of B cells. Despite clinical improvement, he was re-admitted for AKI and hypercalcemia resistant to standard management. His hypercalcemia was ultimately attributed to immune reconstitution inflammatory syndrome (IRIS) due to granulomatous MAC formations. <h3>Discussion</h3> Severe MAC infections are rare and should bring to mind both Mendelian susceptibility to mycobacterial disease and acquired autoantibodies directed against interferon gamma. Rituximab therapy should be considered for patients with auto-antibodies who do not respond to antimicrobial therapy. A potential consequence of such therapy is hypercalcemia secondary to immune reconstitution inflammatory syndrome.

Determination of a distinguished interferon gamma epitope recognized by monoclonal antibody relating to autoantibody associated immunodeficiency

Anti-interferon gamma autoantibodies (anti-IFN-γ autoAbs) neutralize the IFN-γ-mediated functions, contributing to immunodeficiency. A particular autoAb in patient serum had been previously demonstrated to recognize the same determinant on IFN-γ as the neutralizing anti-IFN-γ monoclonal antibody clone B27 (B27 mAb). This study explored the epitope recognized by B27 mAb. The specific peptide sequence recognized by B27 mAb, TDFLRMMLQEER, was retrieved from a phage display random peptide library. Sequence alignment and homology modeling demonstrated that the queried phage peptide sequence and structure were similar to amino acids at position 27–40 (TLFLGILKNWKEES) of the human IFN-γ. This determinant resides in the contact surface of IFN-γ and interferon gamma receptor 1. To elucidate the crucial amino acids, mutations were introduced by substituting T27 and T27F29L30 with alanine or deleting the amino acid residues T27–L33. The binding of B27 mAb to IFN-γ T27A using western blotting was lesser than that to wild-type. The interaction with triple mutant and T27–L33 deletion mutant using western blotting and sandwich ELISA was abolished. The finding demonstrated that T27, F29, and L30 are critical residues in the B27 antigenic determinant. Identification of the functional domain of IFN-γ decrypted the relevance of neutralizing autoAb in adult-onset immunodeficiency.

Listeriosis in a Metropolitan Hospital: Is Targeted Therapy a Risk Factor for Infection?

Targeted therapies are widely used for treatment of autoimmune diseases as well as solid organ and hematological malignancies. Various opportunistic infections have been described in patients on targeted therapies. Although case reports or a few case series of listeriosis have been reported to be associated with targeted therapy, most of the cases were related to anti-tumor necrosis factor-α monoclonal antibody. In this study, we describe the epidemiological and clinical profiles of listeriosis in a tertiary hospital in Shenzhen, a Southern Chinese metropolitan city in China. During the 9-year-and-6-month study period, a total of five cases of listeriosis were recorded and all of them had Listeria monocytogenes bacteremia. All five patients had predisposing factors, including corticosteroid (n = 3), targeted therapy (n = 2), pregnancy (n = 2) and anti-interferon gamma autoantibody (n = 1). The two patients who had targeted therapy during their course of cancer treatment received inhibitors of the epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) pathway. The first one was a 52-year-old woman with metastatic adenocarcinoma of the lung. She was given gefitinib (EGFR tyrosine kinase inhibitor), osimertinib (third-generation EGFR tyrosine kinase inhibitor) and afatinib (tyrosine kinase inhibitor that can bind to EGFR, HER2 and HER4). The second one was a 40-year-old woman with carcinoma of the breast with brain metastasis. She was given trastuzumab (anti-HER2 monoclonal antibody) and lapatinib (dual tyrosine kinase inhibitor of the EGFR/HER2 pathway). These two patients represent the second and third reports of listeria infections associated with EGFR/HER2 pathway inhibitors in the literature. Targeted therapy is an important predisposing factor for listeriosis. Listeria infection is an important differential diagnosis in patients on targeted therapy who present with sepsis and/or central nervous system infection, and the use of antibiotic regimens that cover listeria is crucial for empirical treatment. Avoidance of high-risk food items in these patients is important for the prevention of listeriosis.

Systemic Juvenile Idiopathic Arthritis/Pediatric Still's Disease, a Syndrome but Several Clinical Forms: Recent Therapeutic Approaches.

Background: Systemic Juvenile Idiopathic Arthritis (SJIA)/Pediatric Still’s disease is associated with different phenotypes and outcomes from currently available treatments. Methods: A review of opinion, based on personal experience in a reference pediatric rheumatology center and key publications, to explore the most important questions regarding disease heterogeneity and treatment approaches. Results: A few situations deserve particular attention: 1/patients with recent-onset SJIA who may benefit from a treat-to-target approach with a key place for interleukin (IL)-1 inhibition; 2/SJIA patients refractory to Il-1 and IL-6 antagonists in whom several options may be discussed, including thalidomide or allogeneic hematopoietic stem cell transplantation; 3/SJIA patients with macrophage activation syndrome who may benefit from both well-used classical treatment and innovative approaches, such as anti-interferon gamma therapy or Janus Kinase (JAK) inhibitors; 4/SJIA with severe lung involvement, 5/SJIA patients who achieve complete remission on treatment, with some recent evidence that treatment may be reduced in intensity but not so easily withdrawn. Conclusions: a case-by-case discussion with expert teams is recommended in this heterogeneous, often difficult-to-treat population of patients.

Next-Generation Sequencing-Based Diagnosis of Bacteremic Listeria monocytogenes Meningitis in a Patient with Anti-Interferon Gamma

Abstract Although various opportunistic infections have been described in patients with anti-interferon gamma autoantibodies, so far there is no Listeria monocytogenes infection reported to be associated with this primary immunodeficiency. Here, we describe the first case of bacteremic L. monocytogenes meningitis in a 59-year-old Chinese man with anti-interferon gamma autoantibodies, who presented with acute onset of fever and severe headache. Blood culture was positive but culture of the cerebrospinal fluid was negative, although it showed features suggestive of partially treated bacterial meningitis. The presence of L. monocytogenes in the cerebrospinal fluid was confirmed by next-generation sequencing. Avoidance of high-risk food items in these patients is important for the prevention of listeriosis. The use of antibiotic regimens that cover Listeria is crucial for empirical treatment, particularly if such patients develop acute or subacute meningitis. Next-generation sequencing is becoming an important diagnostic modality for culture-negative infections.

Trials in Progress: A Two-Cohort, Open-Label, Single-Arm Study of Emapalumab, an Anti-Interferon Gamma (IFNγ) Monoclonal Antibody, in Patients with Macrophage Activation Syndrome (MAS) in Rheumatic Diseases

▪Introduction: MAS is a severe, life-threatening complication of rheumatic diseases such as Still's disease and systemic lupus erythematosus (SLE). MAS is a form of secondary hemophagocytic lymphohistiocytosis, characterized by a hyperinflammatory state caused by immune cell dysregulation which can lead to multiorgan damage. Sustained activation and expansion of T lymphocytes and macrophages stimulates the hypersecretion of proinflammatory cytokines such as IFNγ.The mainstay of treatment for MAS is high doses of glucocorticoids (GCs); however, they do not always provide adequate control in all patients. Additional treatments are used without a standardized approach; however, morbidity and mortality remain high. Preliminary data from a pilot study including 9 patients with inadequate response to high-dose intravenous GCs (NCT03311854) showed that emapalumab, a fully human anti-IFNγ monoclonal antibody, led to rapid neutralization of IFNγ and was efficacious in controlling MAS with a favorable safety profile [De Benedetti et al. Annals Rheumatic Dis 2020;79(Suppl. 1):194]. A study to further evaluate the efficacy and safety of emapalumab in patients with MAS in Still's disease and SLE is enrolling patients.Objective: To describe the design and objectives of a Phase 2/3 study aiming to confirm the efficacy and safety of emapalumab in the treatment of MAS in rheumatic disease.Study Design and Methods: This open-label, single arm, multicenter, interventional study (Figure 1) is enrolling pediatric and adult subjects into two cohorts 1) MAS in Still's disease (systemic juvenile idiopathic arthritis and adult onset Still's disease; n=25) and 2) MAS in SLE (n=16). Eligible patients must present with an inadequate response to high doses of GCs. Each cohort is a single-arm study composed of two phases: an optional run-in phase and an interventional phase. Key eligibility criteria vary by cohort and phase (Table 1). During the run-in phase, patients are treated with GCs according to the investigators' clinical practice and followed until MAS remission or inadequate response, or for a maximum of 12 weeks. Patients with an inadequate response to GCs (and potentially to other therapies) enroll in the interventional phase to be treated with intravenous emapalumab (initial dose 6mg/kg, subsequent doses 3mg/kg) for 4 weeks or until a complete response (CR) is achieved, and are followed off-drug for 1 year.Based on the assumptions of a successful treatment with GCs (null hypothesis) of up to 40% for cohort 1 (i.e. CR rate of 40%) and 30% for cohort 2 (i.e. CR rate of 30%), if the truth is 70% complete responders (for both cohorts), then a total of 25 and 16 patients, respectively, is required to demonstrate a statistically significant proportion of CR with a power of 80% using a one-sided exact binomial test at a significance level of 2.5%. The study design for cohort 1 is a group sequential design, including an interim analysis assessing efficacy with an adjusted type 1 error after 16 patients have reached Week 8 after the first dose of emapalumab.The primary endpoint of the study is CR (response criteria defined in Table 2) at Week 8 after first emapalumab administration. Secondary efficacy endpoints include GC tapering, survival, time to first CR, overall response (CR and partial response), time to first overall response, MAS recurrence, PK/PD profile of emapalumab, and patient-reported outcomes. Safety endpoints include assessments of adverse events, abnormal laboratory parameters, and anti-drug antibodies.Summary: This ongoing trial is designed to address the unmet need for new efficacious and safe therapies for the treatment of MAS. [Display omitted] DisclosuresGrom: AB2 Bio: Consultancy; Novartis: Consultancy. Bachir: Sobi: Current Employment. Asnaghi: Sobi: Current Employment. De Benedetti: Novimmune: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sobi: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. OffLabel Disclosure:Emapalumab-lzsg is an IFN-gamma blocking antibody indicated for the treatment of adult and pediatric (newborn and older) patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent, or progressive disease or intolerance with conventional HLH therapy.

Lymphadenopathy Associated With Neutralizing Anti-interferon-gamma Autoantibodies Could Have Monoclonal T-cell Proliferation Indistinguishable From Malignant Lymphoma and Treatable by Antibiotics: A Clinicopathologic Study.

Early recognition of adult-onset immunodeficiency associated with neutralizing anti-interferon gamma autoantibodies (anti-IFNγ Abs) remains difficult, and misdiagnoses have been reported. Although febrile lymphadenopathy is among the most common initial manifestations of this disorder, no comprehensive clinicopathologic analysis of lymphadenopathy in patients with anti-IFNγ Abs has been reported. Here, we describe 26 lymph node biopsy specimens from 16 patients. All patients exhibited concurrent disseminated nontuberculous mycobacterial infections, and 31% received a tentative diagnosis of lymphoma at initial presentation. We found 3 distinct histomorphologic patterns: well-formed granuloma (46%), suppurative inflammation or loose histiocytic aggregates (31%), and lymphoproliferative disorder (LPD, 23%). The latter shared some of the features of malignant T-cell lymphoma, IgG4-related disease, and multicentric Castleman disease. Half of the specimens with LPD had monoclonal T cells, and 33.3% were indistinguishable from angioimmunoblastic T-cell lymphoma as per current diagnostic criteria. All lymphadenopathy with LPD features regressed with antibiotics without administration of cytotoxic chemotherapy or immunotherapy. The median follow-up time was 4.3 years. Our study highlights the substantial challenge of distinguishing between lymphoma and other benign lymphadenopathy in the setting of neutralizing anti-IFNγ Abs. Increased vigilance and multidisciplinary discussion among clinicians and pathologists are required to achieve the most appropriate diagnosis and management.

Population Pharmacokinetic Analysis of Emapalumab, a Fully Human, Anti-Interferon Gamma Monoclonal Antibody, in Children with Primary Hemophagocytic Lymphohistiocytosis

Introduction: Primary hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome characterized by pathologic immune activation and hyperinflammation. It typically manifests during infancy and is invariably fatal if untreated. Interferon gamma (IFNy) is considered a key contributor to the hyperinflammation of HLH. Thus, neutralization of IFNy could help control the disease until haematopoietic stem cell transplantation, the only curative treatment. Emapalumab, a fully human, anti-IFNy monoclonal antibody, binds to and neutralizes IFNy. Emapalumab is the first and only approved (FDA) treatment for primary HLH. It is indicated for the treatment of adult and pediatric patients with HLH with refractory, recurrent, or progressive disease, or intolerance to conventional HLH therapy. Objective: To develop a population pharmacokinetic (PK) model to describe the PK profile of emapalumab. Methods: PK data were obtained from patients with primary HLH administered emapalumab intravenously during an open-label, single-group, phase 2/3 clinical trial (NCT01818492) and as part of a compassionate use program. A population PK analysis was performed using nonlinear mixed effects modeling (NONMEM® version 7.3.0). Predictive performance of the model was assessed using a visual predictive check. Results: The PK of emapalumab was adequately described by a two-compartment model. All model parameters were estimated with good precision. Central and peripheral volumes of distribution were 0.059 and 0.079 L/kg, respectively. Exploratory graphical analysis showed that (i) IFNy production varied significantly between and within patients as a function of time; (ii) the higher the IFNy production, the faster the elimination of emapalumab due to target-mediated drug disposition; and (iii) the higher the IFNy production, the higher the dose of emapalumab required to reach the neutralizing concentration of IFNy (evidenced by a higher target-mediated clearance of emapalumab). Of the parameters examined, only body weight and total IFNy (free and bound) levels were found to significantly influence the PK of emapalumab. The allometric exponents of body weight for the volume of distribution and clearance were 1 (fixed) and 0.886 (95% confidence interval 0.68, 1.09), respectively. These values support the bodyweight-based dosing of emapalumab (i.e. mg/kg). At values of total IFNy from 103 to 106 pg/mL, the total clearance (linear + target mediated) of emapalumab ranged from 0.0012 to 0.0140 L/h for a bodyweight of 5 kg, with corresponding terminal half-lives from 17.5 to 2.3 days. This wide variance in clearances and half-lives partly explains the emapalumab dose adaptations that are required for treating primary HLH patients. Conclusion: The population PK model reliably predicted serum concentrations of emapalumab in patients with primary HLH. The central and peripheral volumes of distribution were low, clearance was slow, and the terminal half-life long. The expected dynamic of the biology of IFNy was confirmed and included in the population PK model. Simulations using this model supported the proposed dosing scheme of emapalumab in patients with primary HLH. Disclosures Laveille: Sobi: Consultancy. Jacqmin:Sobi: Consultancy. de Min:Sobi: Consultancy.

1355. Efficacy and Tolerability of Linezolid Adjunctive Treatment for Nontuberculous Mycobacterial Infection in Patients with Acquired Anti-Interferon-Gamma Autoantibody

BackgroundDespite a long duration of combined oral antimycobacterial drugs, relapse/ reinfection of nontuberculous mycobacteria (NTM) is common among patients with anti-interferon gamma autoantibodies (anti-IFN-γ auto-Abs).MethodsWe reported here, an interim analysis of the prospective study of 25 patients with anti-IFN-γ auto-Abs, who received oral linezolid (LZD) adjunctive treatment for their NTM infections, at Siriraj Hospital, Bangkok, Thailand, between December 2017 and April 2019.Results8 patients (32%) were male, with a median age of 52.5 years. NTM identified among them included Mycobacterium abscessus (n = 19), M. avium complex (MAC) (n = 2), M. fortuitum (n = 2), M. kansasii (n = 1), and both M. abscessus and MAC (n = 1). The median duration of follow-up was 11 months (range 1.6–15 months). LZD 600 mg/day was given until clinical remission, then reduced to 300 mg/day for a total duration of at least 9 months. Other patient’s managements, including choice and duration of other antimycobacterial therapy were determined by the attending physician. Clinical remission was achieved, and LZD was discontinued at 9 months in 10 patients. NTM infection remained active and LZD was continued to 12 months in 4 patients. Two patients only completed 6 months of LZD. Culture proven relapse of M. abscessus occurred in 3 patients during LZD treatment, and 1 patient developed M. haemophilum infection after discontinuation of all drugs for 3 months. One patient was retreated with intravenous antimycobacterial drugs based on clinical suspicious of relapse NTM infection. LZD-related serious adverse events leading to discontinue of LZD occurred in 5 patients; severe myelosuppression (n = 1), peripheral neuropathy (n = 2), exfoliative dermatitis (n = 1), and idiopathic increased intracranial pressure (n = 1). Anemia occurred in 3 patients during the 600 mg LZD once-daily treatment period. No patient developed anemia after LZD was adjusted to 300 mg twice daily. The rate of peripheral neuropathy was similar throughout the study period.ConclusionLZD might reduce the rate of relapsed/ reinfection of NTM infection in these patients. LZD 300 mg twice daily was less toxicity and more tolerable than 600 mg once daily. Long-term study with this modified regimen is now on-going.Disclosures All authors: No reported disclosures.

Orphan designation: Recombinant human anti-interferon gamma monoclonal antibody (emapalumab), Treatment of haemophagocytic lymphohistiocytosis

Orphan designation: Recombinant human anti-interferon gamma monoclonal antibody (emapalumab), Treatment of haemophagocytic lymphohistiocytosis

Pathogenicity of Mycolicibacterium phlei, a non-pathogenic nontuberculous mycobacterium in an immunocompetent host carrying anti-interferon gamma autoantibodies: a case report

BackgroundMycolicibacterium phlei (M. phlei) is known to be a non-pathogenic nontuberculous mycobacterium (NTM) which rarely causes diseases in humans. A disseminated NTM infection is mostly caused by the Mycobacterium avium complex (MAC) and is known to develop in immunocompromised hosts, like those with acquired immune deficiency syndrome (AIDS). Here, we report a case of disseminated M. phlei infection in an immunocompetent host carrying anti-interferon gamma (IFN-γ) autoantibodies.Case presentationWe detected M. phlei in multiple organs of an elderly woman with no significant medical history except positivity for anti-IFN-γ autoantibodies. She tested negative for human immunodeficiency virus (HIV)-1, 2/ Human T-cell leukemia virus type 1 (HTLV-1) antibody. High-resolution computed tomography (HRCT) of the chest demonstrated a nodule in the left S1 + 2 segment, interlobular septal thickening, multi lymphadenopathy, and osteolysis. A maximum intensity projection image following fluorodeoxyglucose-positron emission tomography (FDG-PET) revealed multifocal hypermetabolic lesions in the nodule and all the swollen lymph nodes seen in HRCT. FDG also accumulated in multiple bones. Advanced primary lung cancer was suspected, and biopsies of each lesion were performed. The pathology revealed caseating granuloma, positive for acid-fast bacteria, and DNA sequencing of the acid-fast bacteria confirmed the organism to be M. phlei. The patient also tested positive for anti-IFN-γ autoantibodies. Based on these findings, she was diagnosed with disseminated M. phlei infection, with anti-IFN-γ autoantibodies.ConclusionsThough known to be non-pathogenic, we show that M. phlei can be pathogenic like the MAC in immunocompetent individuals carrying anti-IFN-γ autoantibodies.