scholarly journals Reintroduction of immunosuppressive medications in pediatric rheumatology patients with histoplasmosis: a case series

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Rachel A. Brown ◽  
Fatima Barbar-Smiley ◽  
Cagri Yildirim-Toruner ◽  
Monica I. Ardura ◽  
Stacy P. Ardoin ◽  
...  
Keyword(s):  
Rheumatic Disease ◽  
Lupus Erythematosus ◽  
Histoplasma Capsulatum ◽  
Case Series ◽  
Organ Damage ◽  
Necrosis Factor Alpha ◽  
Pulmonary Histoplasmosis ◽  
Immunosuppressive Medications ◽  
Biologic Dmard ◽  
Factor Alpha

Abstract Background Children with rheumatic diseases (cRD) receiving immunosuppressive medications (IM) are at a higher risk for acquiring potentially lethal pathogens, including Histoplasma capsulatum (histoplasmosis), a fungal infection that can lead to prolonged hospitalization, organ damage, and death. Withholding IM during serious infections is recommended yet poses risk of rheumatic disease flares. Conversely, reinitiating IM increases risk for infection recurrence. Tumor necrosis factor alpha inhibitor (TNFai) biologic therapy carries the highest risk for histoplasmosis infection after epidemiological exposure, so other IM are preferred during active histoplasmosis infection. There is limited guidance as to when and how IM can be reinitiated in cRD with histoplasmosis. This case series chronicles resumption of IM, including non-TNFai biologics, disease-modifying anti-rheumatic drugs (DMARDs), and corticosteroids, following histoplasmosis among cRD. Case presentation We examine clinical characteristics and outcomes of 9 patients with disseminated or pulmonary histoplasmosis and underlying rheumatic disease [juvenile idiopathic arthritis (JIA), childhood-onset systemic lupus erythematosus (cSLE), and mixed connective tissue disease (MCTD)] after reintroduction of IM. All DMARDs and biologics were halted at histoplasmosis diagnosis, except hydroxychloroquine (HCQ), and patients began antifungals. Following IM discontinuation, all patients required systemic or intra-articular steroids during histoplasmosis treatment, with 4/9 showing Cushingoid features. Four patients began new IM regimens [2 abatacept (ABA), 1 HCQ, and 1 methotrexate (MTX)] while still positive for histoplasmosis, with 3/4 (ABA, MTX, HCQ) later clearing their histoplasmosis and 1 (ABA) showing decreasing antigenemia. Collectively, 8/9 patients initiated or continued DMARDs and/or non-TNFai biologic use (5 ABA, 1 tocilizumab, 1 ustekinumab, 3 MTX, 4 HCQ, 1 leflunomide). No fatalities, exacerbations, or recurrences of histoplasmosis occurred during follow-up (median 33 months). Conclusions In our cohort of cRD, histoplasmosis course following reintroduction of non-TNFai IM was favorable, but additional studies are needed to evaluate optimal IM management during acute histoplasmosis and recovery. In this case series, non-TNFai biologic, DMARD, and steroid treatments did not appear to cause histoplasmosis recurrence. Adverse events from corticosteroid use were common. Further research is needed to implement guidelines for optimal use of non-TNFai (like ABA), DMARDs, and corticosteroids in cRD following histoplasmosis presentation.

scholarly journals Reintroduction of Immunosuppressive Medications in Pediatric Rheumatology Patients With Histoplasmosis: A Case Series

2021 ◽  
Author(s):  
Rachel Brown ◽  
Fatima Barbar-Smiley ◽  
Cagri Yildirim-Toruner ◽  
Monica I. Ardura ◽  
Stacy P. Ardoin ◽  
...  
Keyword(s):  
Rheumatic Disease ◽  
Lupus Erythematosus ◽  
Histoplasma Capsulatum ◽  
Case Series ◽  
Organ Damage ◽  
Necrosis Factor Alpha ◽  
Pulmonary Histoplasmosis ◽  
Immunosuppressive Medications ◽  
Biologic Dmard ◽  
Factor Alpha

Abstract Background: Children with rheumatic diseases (cRD) receiving immunosuppressive medications (IM) are at a higher risk for acquiring potentially lethal pathogens, including Histoplasma capsulatum (histoplasmosis), a fungal infection that can lead to prolonged hospitalization, organ damage, and death. Withholding IM during serious infections is recommended yet poses risk of rheumatic disease flares. Conversely, reinitiating IM increases risk for infection recurrence. Tumor necrosis factor alpha inhibitor (TNFai) biologic therapy carries the highest risk for histoplasmosis infection after epidemiological exposure, so other IM are preferred during active histoplasmosis infection. There is limited guidance as to when and how IM can be reinitiated in cRD with histoplasmosis. This case series chronicles resumption of IM, including non-TNFai biologics, disease-modifying anti-rheumatic drugs (DMARDs), and corticosteroids, following histoplasmosis among cRD.Case Presentation: We examine clinical characteristics and outcomes of 9 patients with disseminated or pulmonary histoplasmosis and underlying rheumatic disease [juvenile idiopathic arthritis (JIA), childhood-onset systemic lupus erythematosus (cSLE), and mixed connective tissue disease (MCTD)] after reintroduction of IM. All DMARDs and biologics were halted at histoplasmosis diagnosis, except hydroxychloroquine (HCQ), and patients began antifungals. Following IM discontinuation, all patients required systemic or intra-articular steroids during histoplasmosis treatment, with 4/9 showing Cushingoid features. Four patients began new IM regimens [2 abatacept (ABA), 1 HCQ, and 1 methotrexate (MTX)] while still positive for histoplasmosis, with 3/4 (ABA, MTX, HCQ) later clearing their histoplasmosis and 1 (ABA) showing decreasing antigenemia. Collectively, 8/9 patients initiated or continued DMARDs and/or non-TNFai biologic use (5 ABA, 1 tocilizumab, 1 ustekinumab, 3 MTX, 4 HCQ, 1 leflunomide). No fatalities, exacerbations, or recurrences of histoplasmosis occurred during follow-up (median 33 months).Conclusions: In our cohort of cRD, histoplasmosis course following reintroduction of non-TNFai IM was favorable, but additional studies are needed to evaluate optimal IM management during acute histoplasmosis and recovery. In this case series, non-TNFai biologic, DMARD, and steroid treatments did not appear to cause histoplasmosis recurrence. Adverse events from corticosteroid use were common. Further research is needed to implement guidelines for optimal use of non-TNFai (like ABA), DMARDs, and corticosteroids in cRD following histoplasmosis presentation.

scholarly journals Blockade of Endogenous Leukotrienes Exacerbates Pulmonary Histoplasmosis

2004 ◽  
Vol 72 (3) ◽  
pp. 1637-1644 ◽  
Author(s):  
Alexandra I. Medeiros ◽  
Anderson Sá-Nunes ◽  
Edson G. Soares ◽  
Camila M. Peres ◽  
Célio L. Silva ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Histoplasma Capsulatum ◽  
Interleukin 1 ◽  
Lung Parenchyma ◽  
Synthesis Inhibitor ◽  
Necrosis Factor Alpha ◽  
Pulmonary Histoplasmosis ◽  
Cytokine Levels ◽  
New Strategy ◽  
Factor Alpha

ABSTRACT Leukotrienes are classical mediators of inflammatory response. New aspects of leukotriene function have recently been described. We examine here the previously unreported role that leukotrienes play in the regulation of cytokines in a murine model of histoplasmosis. We demonstrate that administration of MK 886, a leukotriene synthesis inhibitor, caused Histoplasma capsulatum-infected mice to die by the day 15 of infection, whereas the correlating death rate in untreated infected mice was 0%. Treating infected animals with MK 886 inhibited leukotriene synthesis but increased leukocyte recruitment to the lungs. Subsequent to this phenomenon, levels of tumor necrosis factor alpha, interleukin-1 (IL-1), IL-6, and KC chemoattractant cytokines and fungi in the lung parenchyma increased, as did inflammatory response. In contrast, IL-2, IL-5, IL-12, and gamma interferon cytokine levels actually decreased. Thus, murine response to pulmonary histoplasmosis may be leukotriene modulated. This finding may enable us to alter the course of the immune response and inflammation caused by histoplasmosis. The data from the present study suggest an important new strategy for immunologic or drug intervention in human patients.

scholarly journals POS0204 AUTOANTIBODIES AND SYSTEMIC LUPUS ERYTHEMATOSUS INDUCED BY ANTI-TUMOUR NECROSIS FACTOR ALPHA THERAPY IN RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 318.1-318
Author(s):  
D. Santos Oliveira ◽  
A. Martins ◽  
F. R. Martins ◽  
F. Oliveira Pinheiro ◽  
M. Rato ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Disease Duration ◽  
Seroconversion Rate ◽  
Necrosis Factor Alpha ◽  
Malar Rash ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor ◽  
Over Time

Background:Anti-tumour necrosis factor alpha (anti-TNF-α) therapy is commonly used to treat inflammatory conditions such as rheumatoid arthritis (RA). Autoantibodies namely antinuclear antibodies (ANA) induced by these treatments are well established. However, anti-TNF-α-induced systemic lupus erythematosus (SLE) is rarely described and its incidence is yet unknown.Objectives:This study aimed to determine the prevalence of ANA seroconversion and to characterize the development of SLE induced by anti-TNF-α therapy in patients with RA over time.Methods:An observational retrospective cohort study was conducted with at least one year of follow-up. Patients with diagnosis of RA, according to American College of Rheumatology criteria (ACR), and registered on Rheumatic Diseases Portuguese Register (Reuma.pt) who started their first anti-TNFα between 2003 and 2019 were included. Patients with positive ANA (titer ≥100) and/or positive double-strand DNA (dsDNA) antibodies and/or with a diagnosis of SLE at their first visit were excluded. Demographic, clinical and laboratory data were obtained by consulting Reuma.pt. As there are no recognized criteria for drug-induced SLE, the diagnosis of SLE induced by anti-TNF-α was considered if there is a temporal relationship between clinical manifestations and anti-TNF-α-therapy, the presence of at least 1 serologic ACR criteria (ANA or anti-dsDNA) and at least 1 nonserologic ACR criteria (arthritis, serositis, hematologic disorder or malar rash) [1]. Continuous variables are presented with mean, standard deviation, median, quartile 1 and quartile 3. Categorical variables are presented with absolute and relative frequencies.Results:A total of 211 patients (mean age of 49.9±10.9 years old; 84.4% female) were included with a median follow-up time of 6 [3-14] years. We found a seroconversion rate for ANA of 75.4% (n=159) with median treatment duration of 31 [8.5-70.5] months. The most common titre was 1/100 with diffuse and speckled patterns. ANA seroconversion was higher for etanercept (47.8%, n=76) than with adalimumab (23.9%, n=38), infliximab (13.8%, n=22), golimumab (12.6%, n=20) or certolizumab (1.9%, n=3). SLE induced by anti-TNF-α occurred in two patients (0.9%) with erosive and seropositive (rheumatoid factor and anti-citrullinated protein antibodies) RA previously treated with two conventional synthetic disease-modifying antirheumatic drugs, including methotrexate. The first patient, a female with 66 years old and 17 years of disease duration, developed SLE after 16 months of infliximab, with constitutional symptoms, abrupt worsening of polyarthritis, ANA titer of 1/320 diffuse pattern and positive dsDNA (248 UI/mL) antibodies. The second patient, a woman with 43 years old and 11 years of disease duration, developed SLE after 41 months of adalimumab with malar rash and ANA titer of 1/320 diffuse pattern, positive dsDNA (285 UI/mL), positive anti-histone antibodies and hypocomplementemia. In these two cases, anti-TNF-α therapy was stopped and recovery was spontaneous without treatment. The first patient switched to adalimumab and the second switched to golimumab without recurrence of SLE for more than ten years.Conclusion:We found a high rate of ANA seroconversion induced by anti-TNFα therapy in patients with RA. However, similar to previous literature, only 0.9% of patients developed SLE with mild manifestations without major organ involvement. Although the drug with the highest ANA seroconversion rate was etanercept, those responsible for induced SLE were infliximab and adalimumab. Patients improved after discontinuation of therapy and tolerated an alternative anti-TNF-α drug without recurrence of induced SLE over time. Therefore, ANA and SLE induced by anti-TNF-α should be considered and reported in the follow-up of RA patients. Further research is needed to explore the impact of this adverse event on the outcomes of treatment over time.References:[1]Hochberg MC. Arthritis Rheum. 1997;40(9):1725.Disclosure of Interests:None declared

scholarly journals Increased Frequency of the Uncommon Allele of a Tumour Necrosis Factor Alpha Gene Polymorphism in Rheumatoid Arthritis and Systemic Lupus Erythematosus

1994 ◽  
Vol 12 (2) ◽  
pp. 127-133 ◽  
Author(s):  
Victor A. Danis ◽  
Michelle Millington ◽  
Valentine Hyland ◽  
Ron Lawford ◽  
Qirong Huang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Systemic Lupus Erythematosus ◽  
Tumour Necrosis Factor ◽  
Lupus Erythematosus ◽  
Tumour Necrosis ◽  
Tumour Necrosis Factor Alpha ◽  
Systemic Lupus ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Necrosis Factor

The frequency of the uncommon allele (TNF2) of a polymorphism in the promoter region of the tumour necrosis factor alpha (TN Fα) gene in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) was found to be 3 times that of the normal anglo-saxon population. In SLE patients, this allele was strongly associated with HLA-DR3 expression and was also more frequent in patients who did not have malar rash. Functional studies of normal monocyte cytokine production in vitro showed that this genotype was associated with increased IL-1α protein production but there were no differences in the production of TNFα protein.

Malignancy

2013 ◽  
pp. 172-176
Author(s):  
Jennifer Hamilton ◽  
Clive Kelly
Keyword(s):  
Rheumatic Disease ◽  
Evidence Base ◽  
Necrosis Factor Alpha ◽  
Relative Risks ◽  
Underlying Malignancy ◽  
Clinical Presentations ◽  
Increased Risk ◽  
Risk Of Malignancy ◽  
Musculoskeletal Manifestations ◽  
Factor Alpha

This chapter addresses the links between malignancy and rheumatic disease. It begins with a summary of rheumatological conditions associated with an increased risk of malignancy, and describes and discusses specific neoplasms associated with each rheumatic disorder. The present knowledge base is summarized in tabular form, describing the relative risks of different malignancies for each relevant rheumatic disease. The diseases featured include rheumatoid arthritis, primary Sjögren’s syndrome, scleroderma, dermatomyositis and systemic lupus. The next section reviews the drugs used in present rheumatological practice known to be associated with malignancy, describing the specific established risks linked to each of the following agents: azathioprine, cyclophosphamide, ciclosporin, anti-tumour necrosis factor alpha (TNFα‎‎) agents, and mycophenolate mofetil. The evidence base and strength of these associations are summarized. Finally we describe the musculoskeletal manifestations that arise as a consequence of underlying malignancy, considering bone pain, polymyalgia, arthropathy, and vasculitis as clinical presentations or complications of underlying neoplasia. This section also includes descriptions of less common rheumatic disorders that may also be associated with cancer, including erythema nodosum, Sweet’s syndrome, and pyoderma gangrenosum.

Tumor necrosis factor-alpha single nucleotide polymorphisms in juvenile systemic lupus erythematosus

2015 ◽  
Vol 76 (8) ◽  
pp. 533-536 ◽  
Author(s):  
Fatemeh Tahghighi ◽  
Vahid Ziaee ◽  
Mohammad Hassan Moradinejad ◽  
Arezou Rezaei ◽  
Sara Harsini ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Tumor Necrosis ◽  
Nucleotide Polymorphisms ◽  
Systemic Lupus ◽  
Juvenile Systemic Lupus Erythematosus ◽  
Necrosis Factor Alpha ◽  
Single Nucleotide ◽  
Factor Alpha ◽  
Necrosis Factor

scholarly journals Infliximab alleviates the mortality, mesenteric hypoperfusion, aortic dysfunction, and multiple organ damage in septic rats

2017 ◽  
Vol 95 (7) ◽  
pp. 866-872 ◽  
Author(s):  
Erdem Kamil Ozer ◽  
Mustafa Tugrul Goktas ◽  
Ibrahim Kilinc ◽  
Aysun Toker ◽  
Hulagu Bariskaner ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Organ Damage ◽  
Multiple Organ ◽  
Protective Effects ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Mesenteric Perfusion ◽  
Necrosis Factor

Tumor necrosis factor-alpha (TNF-α) is a pivotal mediator that triggers inflammatory process, oxidative stress, and multiple organ injury in sepsis. We investigated the effects of infliximab on survival, mesenteric artery blood flow (MBF), vascular reactivity, and oxidative and inflammatory injuries in cecal ligation and puncture (CLP)-induced sepsis. Wistar rats were divided into Sham, CLP, Sham+infliximab, and CLP+infliximab subgroups. Twenty-four hours before the operations, rats were injected intraperitoneally with infliximab (7 mg/kg) or vehicle (saline; 1 mL/kg). Twenty hours after the operations, MBF and phenylephrine responses of isolated aortic rings were measured. Tissue damages were examined biochemically and histopathologically. Furthermore, survival rates were monitored throughout 96 h. Infliximab improved survival, mesenteric perfusion, and aortic function after CLP. Increases of serum AST, ALT, LDH, BUN, Cr, and inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6) induced by CLP were blocked by infliximab. Infliximab prevented malondialdehyde elevations in septic liver, lung, spleen, and kidney tissues, as well as glutathione reductions in septic liver, spleen, and kidney tissues. Protective effects of infliximab on multiple organ damage were also observed histopathologically. Infliximab showed protective effects in sepsis due to its improvement effects on mesenteric perfusion, aortic function, and its anti-inflammatory and antioxidative effects.

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