POS1153 EFFECTIVENESS OF SCREENING IN PATIENTS WITH RHEUMATIC DISEASE ON BIOLOGICAL THERAPY AND RISK OF ACTIVE TUBERCULOSIS

Background:Treatment with biologic therapy has been associated with a high risk of reactivation of latent tuberculosis (TB). Preventive strategies for tuberculosis remain a crucial step before initiating biologics in rheumatic disease.Treatment with biological therapy has been associated with high risk of reactivation of latent tuberculosis (TB). Prevention strategies remain a crucial step before initiating biologics.Objectives:We aimed to assess the effectiveness of TB screening before the initiation of biologics and the risk of occurrence of active TB among patients with rheumatic diseases on biologic therapies.The study aimed to access the effectiveness of TB screening recommendations before the initiation of biological therapy and identify the incidence of active TB among these patients.Methods:We performed a hospital-based retrospective cohort study among rheumatic disease patients on biological therapy in two centers in Jeddah between January 2005 to December 2019. Medical files were retrospectively reviewed for demographics data, baseline screening for TB, use of prophylaxis, information on DMARDs and biological therapies, and outcomes results were collected.Results:A total of 365 patients were included over a period of 14 years. Two hundred ninety-two (80%) had Rheumatoid arthritis (RA),13% psoriatic arthritis (PSA), 9% spondyloarthritis (SPA), 2% SLE, and 4% others. The mean age was 47.54 (±14.2), 311 (85%) were females with a mean duration of disease 8.45 years (± 6.58). Hundred forty-nine (42.3%) were on steroids. Anti TNFs were prescribed in 213 (58.4%) patients, Non Anti-TNFs 124 (36.6%) patients, and Jak inhibitors 18 (5%) patients.TB screening was done to all patients except 3 patients (data missing) before commencing biologics. Forty-four (12.1%) patients had latent TB at baseline and all received chemoprophylaxis with isoniazid before starting biologics. Four patients with active TB were identified (one with Behcet’s disease and three with RA). One patient had a reactivation of latent TB and 3 patients developed de novo TB. Three out of four had an infection in the first 6 months of treatment (one on infliximab and two on rituximab) and one case after 1 year of stopping adalimumab. Two cases had pulmonary TB and two others with extrapulmonary TB (pericarditis and brain abscess each). All four patients with active TB were treated with standard anti TB medications. Three had complete resolution of their TB and one died.Conclusion:Baseline screening has been effectively carried out in our cohort as per recommendations. Physician should be vigilant not only for reactivation of latent TB but occurrence of de novo TB in patients on biological therapy.References:[1]Gardam, M. A. et al. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet. Infect. Dis.3, 148-155, doi:10.1016/s1473-3099(03)00545-0 (2003).[2]Winthrop, K. L., Yamashita, S., Beekmann, S. E. & Polgreen, P. M. Mycobacterial and other serious infections in patients receiving anti-tumor necrosis factor and other newly approved biologic therapies: case finding through the Emerging Infections Network. Clin. Infect. Dis.46, 1738-1740, doi:10.1086/587989 (2008).[3]Cantini, F., Niccoli, L. & Goletti, D. Tuberculosis risk in patients treated with non-anti-tumor necrosis factor-α (TNF-α) targeted biologics and recently licensed TNF-α inhibitors: data from clinical trials and national registries. J. Rheumatol. Suppl.91, 56-64, doi:10.3899/jrheum.140103 (2014).Acknowledgements:We would acknowledge Dr. Noran Alhashmi, Dr. Roaa Jodah, and Dr. Lamis Ramadan for their assistance in data collection.Disclosure of Interests:None declared.

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Challenges in Diagnosing Latent Tuberculosis Infection in Patients Treated with Tumor Necrosis Factor Antagonists

The Journal of Rheumatology ◽

10.3899/jrheum.100623 ◽

2011 ◽

Vol 38 (7) ◽

pp. 1234-1243 ◽

Cited By ~ 34

Author(s):

EDWARD C. KEYSTONE ◽

KIM A. PAPP ◽

WENDY WOBESER

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Latent Tuberculosis Infection ◽

Inflammatory Diseases ◽

Diagnostic Testing ◽

False Negative ◽

Latent Tuberculosis ◽

Tuberculosis Infection ◽

Tnf Α ◽

Necrosis Factor

Reactivation of latent tuberculosis infection (LTBI) is well recognized as an adverse event associated with anti-tumor necrosis factor-α (anti-TNF-α) therapy. The strengths and weaknesses of current techniques for detecting LTBI in patients with chronic inflammatory diseases such as rheumatoid arthritis (RA) and psoriasis have not been fully examined. T cell hyporesponsiveness due to immunosuppression caused by illness or drugs, referred to as anergy, may produce false-negative tuberculin skin test (TST) and interferon-γ release assay (IGRA) results. The literature suggests that anergy may influence screening performance of TST and IGRA tests in candidates for anti-TNF-α therapy. Conversely, the potential for false-positive TST and IGRA results must be considered, as treatment for LTBI may be associated with significant morbidity. This review examines the reliability issues related to LTBI diagnostic testing and provides practical direction to help prevent LTBI reactivation and facilitate successful anti-TNF-α treatment.

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Lactoferrin: influences on Langerhans cells, epidermal cytokines, and cutaneous inflammation

Biochemistry and Cell Biology ◽

10.1139/o01-227 ◽

2002 ◽

Vol 80 (1) ◽

pp. 103-107 ◽

Cited By ~ 33

Author(s):

I Kimber ◽

M Cumberbatch ◽

R J Dearman ◽

D R Headon ◽

M Bhushan ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Langerhans Cells ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

De Novo ◽

Intradermal Injection ◽

Interleukin 1Β ◽

Tnf Α ◽

Factor Α ◽

Necrosis Factor

It has been suggested previously that, in addition to other biological roles, lactoferrin (LF) may display anti-inflammatory properties secondary to the regulation of cytokine expression. To explore this concept further, we have here examined in human volunteers the influence of recombinant homologous LF on the migration of epidermal Langerhans cells (LC), a process that is known to be dependent upon the local availability of certain proinflammatory cytokines including tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). In common with previous studies in mice, it was found that topical administration of LF prior to exposure at the same site to the contact sensitizer diphenylcyclopropenone resulted in a significant reduction of allergen-induced LC migration from the epidermis (measured as a function of the frequency of CD1a+ or HLA-DR+ LC found in epidermal sheets prepared from punch biopsies of the treated skin sites). However, under the same conditions of exposure, LF was unable to influence migration of LC induced by the intradermal administration of TNF-α data consistent with the hypothesis that one action of LF in the skin is to regulate the local production of this cytokine. Further support for this hypothesis was derived from experiments conducted with IL-1β. This cytokine is also able to induce the mobilization of LC following intradermal injection, although in this case, migration is known to be dependent upon the de novo production of TNF-α. We observed that prior exposure to LF resulted in a substantial inhibition of IL-1β-induced LC migration, data again consistent with the regulation of TNF-α production by LF. Collectively, these results support the view that LF is able to influence cutaneous immune and inflammatory processes secondary to regulation of the production of TNF-α and possibly other cytokines.Key words: lactoferrin, Langerhans cells, tumor necrosis factor α, interleukin 1β.

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Preventing Tuberculosis Flare in Patients with Inflammatory Rheumatic Diseases Receiving Tumor Necrosis Factor-α Inhibitors in India — An Audit Report

The Journal of Rheumatology ◽

10.3899/jrheum.081042 ◽

2009 ◽

Vol 36 (7) ◽

pp. 1414-1420 ◽

Cited By ~ 29

Author(s):

ANAND N. MALAVIYA ◽

SANJIV KAPOOR ◽

SHRIRAM GARG ◽

ROOPA RAWAT ◽

SUBRAMANIAN SHANKAR ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Screening Strategy ◽

Screening Tests ◽

Inflammatory Rheumatic Diseases ◽

Tnf Α ◽

Latent Tb ◽

Factor Α ◽

Necrosis Factor

Objective.To test the efficacies of a strategy for preventing tuberculosis (TB) in Indian patients with inflammatory rheumatic diseases (IRD) treated with tumor necrosis factor-α (TNF-α) inhibitor.Methods.The screening strategy included tuberculosis skin test (TST), QuantiFERON-TB Gold (QTG) test, standard chest radiograph, and contrast enhanced-computerized tomography of the chest (CT).Results.Among 53 patients screened, 17 (32%) had ≥ 1 test positive, with 5 (9.4%) patients having TB infection (clinical, CT, biopsy). The remaining 12 patients showed latent TB; 1 additional patient with negative screening tests was diagnosed with latent TB retrospectively for he developed TB disease within a few weeks of receiving infliximab. The remaining 35 patients tested negative with all tests. The combination of 4 screening tests gave a sensitivity of 0.83, specificity of 0.74, positive predictive value (PPV) 0.29, and negative predictive value (NPV) 0.97. Only 22 patients could afford treatment with TNF-α inhibitors; 19 of them were negative in the screening tests. Three patients who were positive on TST and/or QTG received prophylactic treatment with TNF-α inhibitor. Since implementation of the screening strategy, only 1 of 22 (4.5%) patients given TNF-α inhibitor developed probable TB disease.Conclusion.With the use of these 4 TB screening tests in India, where TB is highly prevalent, TB could be excluded with a high degree of certainty (NPV 0.97). However, as even this combination of tests has only moderate sensitivity and specificity and poor PPV for detecting TB, vigilance may be advisable even if only one of the tests is positive.

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Peritoneal Tuberculosis during Infliximab Treatment in a Patient with Ulcerative Colitis Despite a Negative Quantiferon Test

Pathogens ◽

10.3390/pathogens10050535 ◽

2021 ◽

Vol 10 (5) ◽

pp. 535

Author(s):

Anna Colombo ◽

Mauro Giuffrè ◽

Lory Saveria Crocè ◽

Sergio Venturini ◽

Renato Sablich

Keyword(s):

Ulcerative Colitis ◽

Latent Tuberculosis ◽

Infliximab Treatment ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Current Controversy ◽

Latent Tb ◽

Factor Alpha ◽

Necrosis Factor ◽

Quantiferon Test

Infliximab is an IgG1 antitumor necrosis factor monoclonal antibody that is commonly used to treat inflammatory bowel disease (IBD) and other autoimmune disorders. However, it is known to increase the risk of reactivation of latent tuberculosis (LTBI) due to its capability to disrupt TB granulomas. We describe a case of extrapulmonary TB in a patient with ulcerative colitis who was treated with Infliximab after a negative Quantiferon Test. In addition, we report briefly on the current controversy about the appropriateness, interval, and methods for the repeated screening of latent TB in IBD patients that are treated with antitumor necrosis factor alpha (TNF-α) antibodies.

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Active Tuberculosis Risk With Tumor Necrosis Factor Inhibitors After Treating Latent Tuberculosis

JCR Journal of Clinical Rheumatology ◽

10.1097/rhu.0000000000000074 ◽

2014 ◽

Vol 20 (2) ◽

pp. 68-73 ◽

Cited By ~ 8

Author(s):

Minkyung Kwon ◽

Mindong Sung ◽

Yong-Jin Kwon ◽

Young Goo Song ◽

Sang-Won Lee ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Latent Tuberculosis ◽

Active Tuberculosis ◽

Tumor Necrosis Factor Inhibitors ◽

Necrosis Factor ◽

Tuberculosis Risk

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Effects of Tumor Necrosis Factor Alpha on Host Immune Response in Chronic Persistent Tuberculosis: Possible Role for Limiting Pathology

Infection and Immunity ◽

10.1128/iai.69.3.1847-1855.2001 ◽

2001 ◽

Vol 69 (3) ◽

pp. 1847-1855 ◽

Cited By ~ 336

Author(s):

Vellore P. Mohan ◽

Charles A. Scanga ◽

Keming Yu ◽

Holly M. Scott ◽

Kathryn E. Tanaka ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Essential Role ◽

Low Dose ◽

Latent Tuberculosis ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha ◽

Dose Model ◽

Necrosis Factor

ABSTRACT Reactivation of latent tuberculosis contributes significantly to the incidence of disease caused by Mycobacterium tuberculosis. The mechanisms involved in the containment of latent tuberculosis are poorly understood. Using the low-dose model of persistent murine tuberculosis in conjunction with MP6-XT22, a monoclonal antibody that functionally neutralizes tumor necrosis factor alpha (TNF-α), we examined the effects of TNF-α on the immunological response of the host in both persistent and reactivated tuberculous infections. The results confirm an essential role for TNF-α in the containment of persistent tuberculosis. TNF-α neutralization resulted in fatal reactivation of persistent tuberculosis characterized by a moderately increased tissue bacillary burden and severe pulmonic histopathological deterioration that was associated with changes indicative of squamous metaplasia and fluid accumulation in the alveolar space. Analysis of pulmonic gene and protein expression of mice in the low-dose model revealed that nitric oxide synthase was attenuated during MP6-XT22-induced reactivation, but was not totally suppressed. Interleukin-12p40 and gamma interferon gene expression in TNF-α-neutralized mice was similar to that in control mice. In contrast, interleukin-10 expression was augmented in the TNF-α-neutralized mice. In summary, results of this study suggest that TNF-α plays an essential role in preventing reactivation of persistent tuberculosis, modulates the pulmonic expression of specific immunologic factors, and limits the pathological response of the host.

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Stimulus-dependent Synergism of the Antiapoptotic Tumor Necrosis Factor Receptor–associated Factor 2 (TRAF2) and Nuclear Factor κB Pathways

Journal of Experimental Medicine ◽

10.1084/jem.188.7.1381 ◽

1998 ◽

Vol 188 (7) ◽

pp. 1381-1384 ◽

Cited By ~ 37

Author(s):

Soo Young Lee ◽

David R. Kaufman ◽

Ana L. Mora ◽

Angela Santana ◽

Mark Boothby ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

De Novo ◽

Dominant Negative ◽

Nuclear Factor ◽

Associated Factor ◽

Tnf Α ◽

Wide Range ◽

Induced Apoptosis ◽

Necrosis Factor

Tumor necrosis factor (TNF) signaling leads to pleiotropic responses in a wide range of cell types, in part by activating antiapoptotic and proapoptotic signaling pathways. Thus, although TNF can cause apoptosis and may prove useful in the treatment of malignancies, most cells are resistant to TNF-induced cell death unless de novo protein synthesis is inhibited. Previous studies suggested that TNF activation of the nuclear factor (NF)-κB transcription factor family antagonizes the proapoptotic signals initiated by TNF-α. TNF receptor–associated factor (TRAF)2 has also been shown to mediate crucial antiapoptotic signals during TNF stimulation, yet is not essential in activation of NF-κB under physiologic conditions, thus raising questions about the relationship between these antiapoptotic pathways. We report here that inhibition of TRAF2 and NF-κB function in primary cells, by coexpression of a constitutive repressor of multiple NF-κB/Rel proteins (IκBα.DN) and a dominant negative form of TRAF2 (TRAF2.DN), synergistically enhanced TNF-induced apoptosis. The effects were stimulus dependent, such that neither inhibitory molecule affected Fas- and daunorubicin-induced apoptosis to the same degree as TNF-induced death. These findings indicate that the NF-κB and TRAF2 pathways activate independent antiapoptotic mechanisms which act in concert to suppress the proapoptotic signals induced by TNF-α.

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AB1282-HPR CONCORDANCE BETWEEN TUBERCULIN TEST AND INTERFERON-GAMMA RELEASE ASSAY IN THE SCREENING OF LATENT TUBERCULOSIS INFECTION IN PATIENTS WHO ARE GOING TO INITIATE A TNF INHIBITOR

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3395 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1931.2-1932

Author(s):

M. D. M. Cutillas Perez ◽

C. Marin Silvente ◽

E. Saiz ◽

M. F. Pina

Keyword(s):

Risk Factor ◽

Tumor Necrosis Factor ◽

Interferon Gamma ◽

Tumor Necrosis ◽

Latent Tuberculosis Infection ◽

Latent Tuberculosis ◽

Tuberculin Test ◽

Biological Drugs ◽

Necrosis Factor ◽

Tuberculosis Risk

Background:The drugs that inhibit tumor necrosis factor (anti-TNF) alpha can reactivate a latent tuberculosis infection (ILTB) so requiring a rigorous screening before its onset. The tuberculin test (PT) has a high false negative rate in patients with immunomediated rheumatic diseases (IMID) and false positive in patients vaccinated with Bacillus Calmette Guérin (BCG). The neu methods of interferon gamma release (IGRA) seem to solve this problem, but its use is not standardized.Objectives:Establish the degree of concordance in the diagnosis of ILTB between PT and IGRA in patients who are going to star an anti-TNF drug, in general, and in different situation like taking corticosteroids, being treated with disease modifying drugs, have been vaccinated with BCG or have risk factor for ILTB.Methods:From May 2016 to November 2019, 195 patients with IMID who underwent ITLB screening prior to the initiation of an anti-TNF drug were included in this study. The concordance between PT and IGRA was calculated using the cohen’s kappa index, for the general sample first and then for subgroups. An analysis of the factor that influence the result of PT and IGRA has also been carried out.Results:The prevalence of ILTB was 26.7%. Of the total positive PT and Booster (n=50), QTF-G-IT was positive only in 15 patients (30%). The agreement between PT and QTF-G-IT was 0.33 (p<0.05). In the subproups, a moderate agreement was found in patients who did not take corticosteroids (k=0.45, p<0,05) and greater than the global one in those who had risk factor for ITLB (k=0.37, p<0.05).Conclusion:In our study the agreement between PT and QT-G-IT is low in general, being somewhat higher in unvaccinated patients and with a high probability for ILTB. Taking this result into account due to the low concordance, the ideal ILTB screening strategy in patients who are going to start a anti-TNF would consist of performing both tests.References:[1]Goletti D, Petrone L, Ippolito G, Niccoli L, Cantini F, Goletti D, et al. Expert Review of Anti-infective Therapy Preventive therapy for tuberculosis in rheumatological patients undergoing therapy with biological drugs with biological drugs. Expert Rev Anti Infect Ther. 2018;16(6):501-12.[2]Ortiz AM, González-álvaro I, Laffón A. Mecanism os de acción de fármacos modificadores de la evolución de la artritis reumatoide. 2001;420-7.[3]Algood HMS, Lin PL, Flynn JL. Tumor necrosis factor and chemokine interactions in the formation and maintenance of granulomas in tuberculosis. Clin Infect Dis. agosto de 2005;41 Suppl 3:S189-93.[4]Bopst M, Garcia I, Guler R, Olleros ML, Rulicke T, Muller M, et al. Differential effects of TNF and LTalpha in the host defense against M. bovis BCG. Eur J Immunol. junio de 2001;31(6):1935-43.[5]Winthrop KL, Novosad SA, Baddley JW, Calabrese L, Chiller T, Polgreen P, et al. Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance. Ann Rheum Dis. diciembre de 2015;74(12):2107-16.[6]Randhawa PS. Lymphocyte subsets in granulomas of human tuberculosis: an in situ immunofluorescence study using monoclonal antibodies. Pathology. julio de 1990;22(3):153-5.[7]Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, et al. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis. marzo de 2003;3(3):148-55.[8]Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med. octubre de 2001;345(15):1098-104.[9]Gomez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum. agosto de 2003;48(8):2122-7.Disclosure of Interests:None declared

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