Bortezomib treatment for refractory nontuberculous mycobacterial infection in the setting of interferon gamma autoantibodies

Rocco, Joseph M; Rosen, Lindsey B.; Hong, Gloria; Treat, Jennifer; Kreuzburg, Samantha; Holland, Steven M.; Zerbe, Christa S.

doi:10.1016/j.jtauto.2021.100102

Cited by 8 publications

(6 citation statements)

References 15 publications

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“…One patient used RTX before the diagnosis of AOID due to suspected IgG4RD [ 17 ], and another patient used RTX due to the diagnosis of diffuse large B cell lymphoma after 2 years [ 18 ]. The commonly used protocols were 375 mg/m 2 weekly to monthly [ 19 – 21 ] or 1 g monthly [ 22 – 24 ]. The median treatment times for the patients with RTX and without RTX were 22 months (1.5 ~ 156 months) and 16 months (0.5 ~ 92 months), respectively.…”

Section: Resultsmentioning

confidence: 99%

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Characteristics and Outcomes of Anti-interferon Gamma Antibody-Associated Adult Onset Immunodeficiency

et al. 2023

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Purpose Anti-interferon gamma antibody (AIGA) is a rare cause of adult onset immunodeficiency, leading to severe disseminated opportunistic infections with varying outcomes. We aimed to summarize the disease characteristics and to explore factors associated with disease outcome. Methods A systematic literature review of AIGA associated disease was conducted. Serum-positive cases with detailed clinical presentations, treatment protocols, and outcomes were included. The patients were categorized into controlled and uncontrolled groups based on their documented clinical outcome. Factors associated with disease outcome were analyzed with logistic regression models. Results A total of 195 AIGA patients were retrospectively analyzed, with 119(61.0%) having controlled disease and 76 (39.0%) having uncontrolled disease. The median time to diagnosis and disease course were 12 months and 28 months, respectively. A total of 358 pathogens have been reported with nontubercular mycobacterium (NTM) and Talaromyces marneffei as the most common pathogens. The recurrence rate was as high as 56.0%. The effective rates of antibiotics alone, antibiotics with rituximab, and antibiotics with cyclophosphamide were 40.5%, 73.5%, and 75%, respectively. In the multivariate logistic analysis, skin involvement, NTM infection, and recurrent infections remained significantly associated with disease control, with ORs of 3.25 (95% CI 1.187 ~ 8.909, P value = 0.022), 4.74 (95% CI 1.300 ~ 17.30, P value = 0.018), and 0.22 (95% CI 0.086 ~ 0.551, P value = 0.001), respectively. The patients with disease control had significant AIGA titer reduction. Conclusions AIGA could cause severe opportunistic infections with unsatisfactory control, particularly in patients with recurrent infections. Efforts should be made to closely monitor the disease and regulate the immune system.

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Section: Resultsmentioning

confidence: 99%

“…Four patients had only partial remission [ 14 , 21 , 25 ], and another three patients had progressive infection even after RTX treatment [ 21 , 26 ]. Two patients failed RTX but achieved disease control with bortezomib [ 22 ] or daratumumab [ 27 ].…”

Section: Resultsmentioning

confidence: 99%

Characteristics and Outcomes of Anti-interferon Gamma Antibody-Associated Adult Onset Immunodeficiency

et al. 2023

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“…Therefore, combining BTZ with an immunosuppressive agent that targets plasma cell precursors, such as rituximab, is likely necessary to prevent the generation of new plasma cells. A previously published case study reported successful reduction of anti-IFN-γ-auto-Abs and improved IFN-γ-induced STAT-1 phosphorylation after BTZ administration in patients with refractory infections after rituximab treatment, which resulted in a better clinical and radiological outcome [ 34 ]. In addition, daratumumab, which is a novel anti-CD38 monoclonal antibody, was also reported to decrease anti-IFN-γ-auto-Abs after rituximab combined with BTZ [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Bortezomib for Treating Anti-Interferon-Gamma Autoantibody-Associated Adult-Onset Immunodeficiency Syndrome

Angkasekwinai,

Suputtamongkol,

Tantibhedhyangkul

et al. 2023

Clinical Infectious Diseases

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Background There is currently no effective treatment for adult-onset immunodeficiency (AOID) syndrome with anti-interferon-gamma autoantibodies (anti-IFN-γ-auto-Abs). The purpose of this study is to investigate the effectiveness of bortezomib (BTZ) for decreasing anti-IFN-γ-auto-Abs.‏ Methods A pre-and post-intervention study was conducted during February 2017-June 2019 at Siriraj Hospital (Bangkok, Thailand).‏ Five patients were invited to receive once weekly BTZ (1.‏3 mg/m2 body surface area) subcutaneously for 8 weeks followed by oral cyclophosphamide (1 mg/kg/day) for 4 months.‏ The primary outcomes were the difference in antibody level at 8 and 48 weeks compared to baseline, and the incidence of serious adverse events (AEs).‏ The secondary outcome was the occurrence of opportunistic infections (OIs) throughout 72 weeks after starting BTZ.‏ Results The median patient age was 46 years (range: 34-53).‏ All patients had 3-5 OIs prior to enrollment.‏ All patients were receiving antimycobacterial agents for treatment of nontuberculous mycobacterial infection at enrollment.‏ There was no significant difference in the mean optical density of auto-Abs at 8 weeks (3.‏73 ± 0.‏72) or 48 weeks (3.‏74 ± 0.‏53) compared to baseline (3.‏84 ± 0.‏49) (p = 0.‏336 and p = 0.‏555, respectively).‏ However, after serum dilution, the antibody titer non-significantly decreased during 8-16 weeks after BTZ initiation (p = 0.‏345).‏ Ten OIs were observed during 24-72 weeks after BTZ initiation, and Mycobacterium abscessus was the most prevalent pathogen.‏ Conclusions Treatment with BTZ followed by cyclophosphamide yielded no significant decrease in antibody titer levels, and ten OIs were observed during 24-72 weeks of BTZ.‏ No serious AEs were observed.‏ Combining rituximab with BTZ is likely necessary to prevent generation of new autoantibody-producing plasma cells.‏

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“…In clinical practice, healthcare providers should consider turning to immunosuppressive drugs with other targets rather than extending the use of rituximab and cyclophosphamide. Recent case reports have identified other immunotherapies, such as daratumumab (a monoclonal antibody targeting CD38) ( 24 ), bortezomib (a proteosome inhibitor) ( 23 ), and adalimumab (a tumor necrosis factor inhibitor) ( 31 ), which can improve the prognosis of patients with a poor response to treatment with rituximab and cyclophosphamide.…”

Section: Discussionmentioning

confidence: 99%

Pathogen spectrum and immunotherapy in patients with anti-IFN-γ autoantibodies: A multicenter retrospective study and systematic review

Qiu

Fang

et al. 2022

Front. Immunol.

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BackgroundAnti-interferon-γ autoantibody (AIGA) positivity is an emerging immunodeficiency syndrome closely associated with intracellular infection in individuals without human immunodeficiency virus (HIV). However, the information on epidemiology, pathogen spectrum, and immunotherapy among these patients lack a systematic description of large data.MethodsThis systematic literature review and multicenter retrospective study aimed to describe the pathogen spectrum and review treatment strategies among patients with AIGA positivity.ResultsWe included 810 HIV-negative patients with AIGA positivity infected with one or more intracellular pathogens. Excluding four teenagers, all the patients were adults. The most common pathogen was nontuberculous mycobacteria (NTM) (676/810, 83.5%). A total of 765 NTM isolates were identified in 676 patients with NTM, including 342 (44.7%) rapid-grower mycobacteria, 273 (35.7%) slow-grower mycobacteria, and 150 (19.6%) unidentified NTM subtype. Even with long-term and intensive antimicrobial treatments, 42.6% of patients with AIGA positivity had recurrence and/or persistent infection. Sixty-seven patients underwent immunoregulatory or immunosuppressive therapy, and most (60) achieved remission. The most common treatment strategy was rituximab (27/67, 40.3%) and cyclophosphamide (22/67, 32.8%), followed by cyclophosphamide combined with glucocorticoids (8/67, 11.9%).ConclusionsIntracellular pathogen was the most common infection in patients with AIGA positivity. The predominant infection phenotypes were NTM, varicella-zoster virus, Talaromyces marneffei, and Salmonella spp., with or without other opportunistic infections. AIGA immunotherapy, including rituximab or cyclophosphamide, has yielded good preliminary results in some cases.

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Bortezomib treatment for refractory nontuberculous mycobacterial infection in the setting of interferon gamma autoantibodies

Cited by 8 publications

References 15 publications

Characteristics and Outcomes of Anti-interferon Gamma Antibody-Associated Adult Onset Immunodeficiency

Characteristics and Outcomes of Anti-interferon Gamma Antibody-Associated Adult Onset Immunodeficiency

Efficacy of Bortezomib for Treating Anti-Interferon-Gamma Autoantibody-Associated Adult-Onset Immunodeficiency Syndrome

Pathogen spectrum and immunotherapy in patients with anti-IFN-γ autoantibodies: A multicenter retrospective study and systematic review

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