Risk of Reactivation of Latent Tuberculosis in Psoriasis Patients on Biologic Therapies: A Retrospective Cohort from a Tertiary Care Centre in Northern Italy.

Psoriatic patients with latent tuberculosis infection and properly treated active tuberculosis need careful management when prescribing modern biological drugs. Although data and guidelines regarding tumour necrosis factor-α inhibitors advise caution and initiation of prophylactic therapy in patients with latent tuberculosis infection, the same indications do not seem to find equal force for interleukin (IL)-23 and IL-17 inhibitors. In order to evaluate the risk of reactivation in patients with latent tuberculosis infection or properly treated active tuberculosis, an observational retrospective study was conducted on the population referred to our centre at Dermatologic Clinic of University of Turin, Italy. In the last 10 years at the clinic 19 psoriatic patients were found to be at risk of tuberculosis reactivation: 10 patients were QuantiFERON- TB-positive at baseline, 2 became positive during treatment, 6 reported prior tuberculous infection, and 1 was QuantiFERON-TB-negative at baseline and developed disseminated tuberculosis during treatment with anti-tumour necrosis factor-α. Overall, 10.5% of this group of patients developed active tuberculosis; however, stratifying by biologic therapy, zero cases were observed among patients treated with anti-IL-17, -23, or -12/23 over a relatively long follow-up (48.1 months) A review of the available literature following our experience confirms the increased risk of tuberculosis reactivation with tumour necrosis factor-α inhibitors. Concerning anti-IL-23 and IL-17 drugs, available data showed high safety in patients at risk of tuberculosis reactivation. Screening of patients who should be taking IL-17 and IL-23 inhibitors is recommended for public health purposes. In case of a positive result with these therapies, consulting with an infectious diseases specialist is suggested in order to weigh up the risks and benefits of prophylactic treatment.

Comparison of developing tuberculosis following tumor necrosis factor inhibition and interleukin-6 inhibition in patients with rheumatoid arthritis: a nationwide observational study in South Korea, 2013-2018.

BACKGROUND: Tumor necrosis factor (TNF) inhibitors increase the risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA). This study compared the incidence of TB after treatment with TNF inhibitors and tocilizumab in patients with RA, separately in those who were treated for latent tuberculosis infection (LTBI) and those without evidence of LTBI. METHODS: This study included patients with RA who initiated TNF inhibitors and tocilizumab between December 2013 and August 2018. Patient data were collected from the nationwide database of the Health Insurance Review and Assessment service in South Korea. The incidence of TB was compared among different biologic drugs in patients with or without LTBI treatment. RESULTS: Of 4736 patients, 1168 were treated for LTBI and 48 developed TB (554.9 per 100,000 person-years). When compared based on etanercept, infliximab showed a higher risk of TB (adjusted incidence rate ratio 2.71, 95% confidence interval 1.05-7.01), especially in patients without evidence of LTBI. Other TNF inhibitors and tocilizumab showed a comparable incidence of TB, regardless of treatment for LTBI. There was no significant difference in TB incidence after biologic therapy between patients with and without LTBI treatment (627.9/100,000 vs. 529.5/100,000 person-years). In patients treated for LTBI, no differential risk of TB was observed among biologic drugs. CONCLUSIONS: The incidence of TB was not significantly different among biologic drugs in the current era, except for infliximab in patients who were not treated for LTBI. Treatment of LTBI might alleviate the drug-specific risk of TB in patients with RA.

The risk of tuberculosis infection in 410 Saudipatients receiving adalimumab therapy.

BACKGROUND: Adalimumab is a fully humanized monoclonal antibody inhibitor of tumor necrosis factor-a used to treat various autoimmune disorders. Adalimumab poses a risk for tuberculosis (TB) infection, especially in countries where TB is endemic. OBJECTIVE: Determine the rate of TB infection after adalimumab therapy in Saudi Arabia. DESIGN: Medical record review. SETTINGS: Tertiary care center in Riyadh. PATIENTS AND METHODS: Demographic and clinical data were retrieved from the electronic healthcare records of all patients who received adalimumab treatment from 2015 to 2019. MAIN OUTCOME MEASURES: Occurrence of TB after adalimumab therapy. SAMPLE SIZE: 410 patients (median ([QR] age, 37 [28], range 4-81 years), 40% males RESULTS: Rheumatoid arthritis was the most frequent indication (n=153, 37%). The patients were followed for a mean of 36 (8.9) months. No case of TB infection or reactivation was observed. An inter-feron-gamma release assay (IGRA) was requested in 353/391 (90.3%) patients, prior to initiating therapy. The IGRA was positive in 26 cases (6.6%). The IGRA-positive patients received isoniazid prophylactically. Bacterial infectious complications of adalimumab therapy occurred in 12 (2.9%) patients. Urinary tract infection was the most frequent complication (culture requested in 48 patients, positive in 8). CONCLUSION: Adalimumab treatment was not associated with a risk of TB disease or TB reactivation in our cohort over the follow-up observation period. No TB reactivation occurred with adalimumab therapy when TB prophylaxis was used. The positive IGRA rate in patients on adalimumab treatment was low (7%). LIMITATIONS: Single center and one geographical area in Saudi Arabia. CONFLICT OF INTEREST: None.

Indoor Air Pollution and Susceptibility to Tuberculosis Infection in Urban Vietnamese Children.

Rationale: The Southeast Asian tuberculosis burden is high, and it remains unclear if urban indoor air pollution in this setting is exacerbating the epidemic. Objectives: To determine the associations of latent tuberculosis with common urban indoor air pollution sources (secondhand smoke, indoor motorcycle emissions, and cooking) in Southeast Asia. Methods: We enrolled child household contacts of patients with microbiologically confirmed active tuberculosis in Vietnam, from July 2017 to December 2019. We tested children for latent tuberculosis and evaluated air pollution exposures with questionnaires and personal aerosol sampling. We tested hypotheses using generalized estimating equations. Measurements and Main Results: We enrolled 72 patients with tuberculosis (27% with cavitary disease) and 109 of their child household contacts. Latent tuberculosis was diagnosed in 58 (53%) household contacts at baseline visit. Children experienced a 2.56-fold increased odds of latent tuberculosis for each additional household member who smoked (95% confidence interval, 1.27-5.16). Odds were highest among children exposed to indoor smokers and children <5 years old exposed to household smokers. Each residential floor above street-level pollution decreased the odds of latent tuberculosis by 36% (adjusted odds ratio, 0.64; 95% confidence interval, 0.42-0.96). Motorcycles parked inside children's homes and cooking with liquid petroleum gas compared with electricity increased the odds of latent tuberculosis, whereas kitchen ventilation decreased the effect, but these findings were not statistically significant. Conclusions: Common urban indoor air pollution sources were associated with increased odds of latent tuberculosis infection in child household contacts of patients with active tuberculosis.

Risk of tuberculosis reactivation with interleukin (IL)-17 and IL-23 inhibitors in psoriasis - time for a paradigm change.

Tuberculosis is an infectious disease with a major global impact, ranked in the top 10 mortality causes worldwide. In an immunocompetent individual, the host defence mechanisms control Mycobacterium tuberculosis infection and induce the latent form of the disease. However, in the presence of diseases or therapies, which exert an immunosuppressive effect, latent tuberculosis can be re-activated. Psoriasis is an immune-mediated, inflammatory disease, and its treatment has rapidly evolved over the last few years. It has long been recognized that the tumour necrosis factor (TNF)-α inhibitors are associated with increased risk of reactivation of latent tuberculosis infection. Thus, international guidelines have been suggesting tuberculosis screening before starting the treatment with all biological agents since then. In addition, the institution of chemoprophylaxis in the presence of latent tuberculosis and the annual screening for tuberculosis thereafter have also been indicated. However, anti-tuberculosis treatments can have significant side-effects and there are currently several contraindications to their use. The risk benefit of starting anti-tuberculous treatment should be carefully weighed up. The emergence of new biological drugs for the treatment of psoriasis, such as interleukin (IL)-17 and IL-23 inhibitors, has reignited the subject of tuberculosis reactivation as it is possible that IL-17 and 23 blockade do not carry the same risk of TB reactivation as TNF-α inhibitors. Although preclinical studies have shown that cytokines IL-17 and IL-23 have a possible role against infection with M. tuberculosis, data from clinical trials and post-marketing surveillance with drugs that inhibit these cytokines appear to suggest that they are not crucial to this response. In this article, we review the available data on tuberculosis reactivation after the treatment of psoriasis with IL-17 and IL-23 inhibitors, and its possible impact on the way we currently manage latent tuberculosis infection before or after starting treatment with these new drugs.

[Anti-PD1 immunotherapy followed by tuberculosis infection or reactivation]. / Tuberculose pulmonaire sous traitement par immunothérapie type anti-PD1.

INTRODUCTION: Immunotherapy is now a standard of care in oncology. There is a need to improve our knowledge about immune-related adverse events, especially infectious diseases. CASE REPORT: We describe the case of a 49-year old male who received anti-PD1 therapy, to treat metastatic melanoma with pulmonary metastasis. After 3 cycles of nivolumab, computed tomography scanning showed a decrease of the pulmonary metastasis in the upper left lobe, but revealed new pulmonary lesions such as tree-in-bud and a lung cavity in the same lobe. This was diagnosed as pulmonary tuberculosis with no antibiotic resistance identified. The patient continued the immunotherapy and was initiated onto a standard anti-tuberculosis therapy. In the absence of an initial positive IFN-γ release assay (Quantiferon) test, but as there might have been a history of primary infection during childhood, a reactivation of tuberculosis was considered to be likely. CONCLUSIONS: This is the ninth case of tuberculosis infection under immunotherapy and it underlines the need to consider infection risks in patients undergoing immunotherapy. An INF-γ release assay screening test should be considered an essential part of the pre-treatment work-up.

Screening for acquired latent tuberculosis in rheumatoid arthritis patients on tumor necrosis factor inhibition therapy in Southern California.

BACKGROUND: There are no studies assessing the development of latent tuberculosis infection (LTBI) in patients on tumor necrosis factor inhibitors (TNFα-I) in high TB prevalence areas of the USA. Our objective was to assess the rate of LTBI development in rheumatoid arthritis (RA) patients on TNFα-I therapies in San Bernardino and Riverside Counties of California, high TB prevalence areas in the US. METHODS: Data were extracted from the electronic health record for 217 adult RA patients across three health centers from January 2010 to January 2017 who have had at least 1 year of TNFα-I use and negative initial QuantiFERON Gold status. Demographics, TNFα-I type, duration of use, TB risk factors, QuantiFERON results, rates of re-screening, TB test seroconversion, and its association with drug use and other factors were assessed. RESULTS: Of the 217 patients, 115 (53%) received baseline and annual screening for LTBI. LTBI was diagnosed in 9.4% (10) of patients. Four patients were on infliximab, three on golimumab, two on adalimumab, and one on etanercept. Hispanic patients tended to have a greater than 200% increase in odds of seroconversion compared to non-Hispanic patients. Infliximab and golimumab were associated with a 92% and 400% increase in odds of seroconversion, respectively. CONCLUSION: The LTBI developed in 9.4% of the patients. This is higher than what is reported for previous US studies. Screening for LTBI in the US should take into consideration TB prevalence, ethnicity, drug type, and duration of use. For our local population and similar populations, annual screening should be practiced. Key Points • Although patients on TNFα inhibitor (TNFα-I) therapy are at high risk of latent tuberculosis infection (LTBI), few studies report the rate of LTBI in patients living in high prevalence areas of the US. • The rate of LTBI was 9.4% in patients on TNFα-I therapy in Southern California. The risk of seroconversion was higher in patients of Hispanic ethnicity and also higher for those on infliximab and golimumab compared to those on other TNFα-I therapies. • Screening guidelines for LTBI screening on TNFα-I should consider local TB prevalence, drugs used, duration of use and ethnicity for cost efficient, and optimal healthcare.

Risk of tuberculosis reactivation during interleukin-17 inhibitor therapy for psoriasis: a systematic review.

Immunosuppressive therapies, effective in treating inflammatory disorders such as psoriasis, increase the risk of serious infections, such as tuberculosis (TB). For example, tumour necrosis factor (TNF)-alpha inhibitors significantly increase the risk of TB reactivation in patients with latent TB infection (LTBI), which has led clinicians to routinely test for TB prior to initiation of these medications. This protocol has since extended to other, newer immunomodulatory therapies for psoriasis, such as interleukin (IL)-17 inhibitors, including secukinumab, ixekizumab and brodalumab. We conducted a systematic review to examine whether there is any evidence that IL-17 inhibitor therapy for psoriasis increases the risk of TB reactivation. Using PubMed and EMBASE, our literature search resulted in 139 total articles. After manually reviewing each article for the discussion of IL-17 inhibitors for psoriasis, with data originating from clinical trials, and assessment for incidence of TB reactivation, 23 articles met the full inclusion criteria for our review. Overall, we found no cases of TB reactivation in patients treated with IL-17 inhibitors for psoriasis. This suggests that IL-17 inhibitors may be safely used in psoriasis patients with LTBI who receive appropriate LTBI treatment. However, long-term real-world studies are warranted to further evaluate this risk.

Tuberculosis in biologic users for rheumatic diseases: results from the South African Biologics Registry (SABIO).

OBJECTIVES: To evaluate the rate of tuberculosis (TB) in biologic users for rheumatic diseases in South Africa, the effectiveness of our latent TB infection (LTBI) programme, risk factors and outcome. METHODS: TB cases were collected from the South African Biologics Registry (SABIO), rheumatologists and pharmaceutical companies. Demographics, LTBI screening and treatment, biological and disease modifying antirheumatic drug (DMARD) therapies, TB diagnosis and outcomes were recorded. RESULTS: 96 TB cases were collected from 1999 to June 2017: rheumatoid arthritis 55, ankylosing spondylitis 27, psoriatic arthritis 4, and juvenile inflammatory arthritis 10. The TB rate was 1240/100 000 person years for biologic users (n=96) versus the biologic naive cohort of 0/100 000 years with an incidence rate difference of 0.0124 (p<0.0001). 60/96 had pulmonary and 36/96 had extra-pulmonary TB. Reactivation TB occurred in 45/96 cases. TB occurred in all biologics licenced in South Africa, the majority in monoclonal inhibitors (1683/100 000 person years) compared with etanercept (861/100 000 person years) and non-tumour necrosis factor (TNF) inhibitors (681/100 000 person years). The incidence rate ratio for monoclonal inhibitors compared with etanercept was 1.96 (p=0.005) and 2.47 (p=0.002) compared with non-TNF inhibitors with no significant difference between non-TNF inhibitors and etanercept (p=0.336). From those (12.9%) who screened LTBI positive, 14 developed TB, while the majority (77) screened LTBI negative. Black race, male sex, younger age and residence in the Western Cape were statistical risk factors. Two drug resistant TB cases and six deaths occurred. CONCLUSION: Reactivation and new onset TB is a significant risk for all biologics users in SA. Screening for LTBI is an imperative preventative strategy.

High risk of activation of latent tuberculosis infection in rheumatic disease patients.

Objective: To evaluate the risk of activation of latent tuberculosis infection (LTBI) in Chinese patients with rheumatic diseases who have received glucocorticoid treatment.Methods: We conducted a 2-year study, enrolling 1788 patients with rheumatic diseases who were treated with glucocorticoid for at least 4 weeks at the Department of Immunology and Rheumatology, First Affiliated Hospital of Nanchang University. Interferon-release assays (IGRA) were performed with patient blood samples obtained at baseline. Patient data, including age, gender, body mass index (BMI), duration and dosage of glucocorticoid and disease-modifying antirheumatic drug (immunosuppressant) treatment and comorbidities (malignancies, diabetes, chronic renal failure, silicosis) were collected. Patients were followed for 2 years to detect the emergence of active tuberculosis (TB).Results: 21.8% (349/1600) of the patients tested positive in IGRA, indicating LTBI. 2-year follow-up showed that 18 (5.16%) patients with positive IGRA but only 4 (0.35%) patients with negative IGRA developed active TB (p < .05). SLE patients had the highest activation rate of 2.22 per 100 total recruitment cases/year. Univariate and multivariate analysis showed that low BMI(<18.5), administration of high dose glucocorticoids (>15 mg daily), and comorbidities that included interstitial lung disease and malignant cancers were significantly associated with LTBI activation.Conclusion: Our results suggest that screening and preventive therapy of LTBI may be advisable for Chinese rheumatic disease and particularly SLE patients undergoing glucocorticoid therapy with dosage above 15 mg prednisone equivalent daily for more than 4 weeks.

Outcomes of Treatment for Latent Tuberculosis Infection in Patients With Inflammatory Bowel Disease Receiving Biologic Therapy.

Background: Treatment for latent tuberculosis infection (LTBI) is of particular concern in patients with inflammatory bowel disease (IBD) initiating biologic therapies to prevent tuberculosis (TB) reactivation. This study aimed to evaluate the effectiveness of LTBI treatment in IBD patients receiving biologic therapy. Methods: There was a retrospective review of all IBD patients diagnosed with LTBI following a tuberculin skin test (TST) and/or interferon gamma release assay (IGRA) and who received biologic therapy between 2002 and 2016. The primary outcome was tuberculosis reactivation after completion of LTBI treatment. Results: Three-hundred twenty-nine IBD patients were identified, and 35 (27 Crohn's disease; 8 ulcerative colitis) met the study inclusion criteria. The mean age was 38.3 years, and 68.6% were male. The most common LTBI treatment regimen was isoniazid (INH) for 9 months (74%). Biologic therapies used were infliximab (40%), adalimumab (29%), vedolizumab (20%), and certolizumab pegol (11%). Combination therapy with an immunomodulator was administered in 57% of cases. The median time from initiation of LTBI treatment to biologics was 43 days. The mean duration of follow-up was 2.9 years. The estimated median annual risk of TB reactivation without treatment was 0.52% by a prediction formula. Only 1 patient taking adalimumab monotherapy developed reactivation of TB several years after completing 6 months of isoniazid therapy. The estimated TB reactivation rate was 0.98 cases per 100 patient-years of follow-up in our cohort. Conclusions: Treatment for LTBI in patients with IBD treated with biologics is effective but does not eliminate the risk of reactivation. 10.1093/ibd/izy133_video1izy133.video15776720675001.

Tuberculosis and interleukin blocking monoclonal antibodies: Is there risk?

Several new monoclonal antibodies that interfere with interleukin (IL) cascades have come to market in recent years. They follow a generation of drugs that block tumor necrosis factor (TNF). It has been well established that TNF is important in the containment of Mycobacterium tuberculosis (Mtb) and that blocking this cytokine increases the risk of tuberculosis (TB) infection. Thus, judicious screening for Mtb of patients taking TNF blocking drugs has been the standard of care. It remains unclear if the newer monoclonal, interleukin blocking drugs, which affect IL-12, IL-23, and IL-17 pathways are associated with risk of Mtb reactivation. Herein we discuss what is known about the immunologic response to Mtb and discuss the data that is currently available for the new interleukin monoclonal antibody blocking medications regarding the risk of latent TB reactivation or active TB infection.

Desarrollo de infección tuberculosa latente y efectos adversos de la isoniazida durante tratamiento con biológico por enfermedad de Crohn / Development of latent tuberculosis and adverse effects with isoniazid during biologist therapy´s in Crohn´s disease / Desenvolvimento de tuberculose latente durante e efeitos adversos da isoniazida o tratamento com biológicos para a doença de Crohn

Los fármacos anti factor de necrosis tumoral alfa (TNF-α) bloquean una de las citoquinas implicadas en la patogénesis de la Enfermedad Inflamatoria intestinal (EII). Su uso se relaciona con aumento de tuberculosis (TB), por lo que el despistaje previo es obligatorio. En la infección tuberculosa latente (ITBL) se utiliza isoniazida como quimioprofilaxis, fármaco que no se encuentra libre de reacciones adversas. Se presenta y discute el caso de una paciente con reacción adversa en piel secundaria al uso de isoniazida.

Anti-tumor necrosis factor alfa drugs are responsible for blocking one of the cytoquines implicated on inflammatory bowel disease pathogenesis. Its use has been linked to an increase in tuberculosis cases which is why screening before starting treatment is mandatory. Latent tuberculosis is treated with isoniazid as chemoprophylaxis although its use may provoke adverse effects. A case is presented of a patient with skin adverse reaction due to the use of isoniazid.

Os medicamentos anti factor de necrose tumoral alfa (TNF-α ) bloqueiam uma das citocinas envolvidas na patogénese da doença inflamatória intestinal (DII). A sua utilização está associada com um aumento da tuberculose (TB), de modo que a despistagem anterior dessa doença é necessária. Na TB latente, frequentemente se utiliza a isoniazida é usado como quimioprofilaxia, uma droga que não está livre de reações adversas. Apresentamos e discutimos o caso de uma paciente com reação adversa na pele secundária ao uso da isoniazida.

Unaffected reaction level in tuberculin skin test by long-term therapy with tumor necrosis factor inhibitors for rheumatoid arthritis.

AIM: The tuberculin skin test (TST) is used to diagnose tuberculosis; however, the influence of tumor necrosis factor (TNF) inhibitors on the test is unclear. This study investigated whether therapy with TNF inhibitors suppresses the TST reaction due to immunosuppression or whether the TST reaction increases due to reactivation of latent Mycobacterium tuberculosis infection. METHOD: Ninety-one patients with rheumatoid arthritis receiving TNF inhibitors (40 using infliximab and 51 using etanercept) were studied. The TST was performed before starting TNF inhibitors (T1) and more than 1 year after starting them (T2). RESULTS: At T1, the reaction was negative in 45 patients, weakly positive in 21 patients, moderately positive in 18 patients and strongly positive in seven patients, while the numbers at T2 were 44, 20, 16 and 11, respectively. There were no significant differences of the TST reaction between T1 and T2 in all patients (P = 0.657), patients using infliximab (P = 0.462) or patients using etanercept (P = 1.00). No patients with a strongly positive TST reaction at T1 became negative at T2. However, two patients who were negative at T1 became strongly positive at T2. Although they had no signs of M. tuberculosis infection, isoniazid prophylaxis was given. CONCLUSION: The TST reaction was not suppressed after more than 1 year of therapy with TNF inhibitors. Patients in whom the TST reaction changes from negative to strongly positive may need appropriate prophylaxis.

Tuberculosis Screening and Reactivation Among a National Cohort of Patients with Inflammatory Bowel Disease Treated with Tumor Necrosis Factor Alpha Antagonists.

BACKGROUND: Tumor necrosis factor antagonists (anti-TNFs) are effective in treating inflammatory bowel disease (IBD) but may cause reactivation of tuberculosis (TB). TB screening rates and related outcomes are not well described among patients with IBD. This study aims to evaluate the prevalence and determinants of TB screening before anti-TNF initiation and related outcomes among patients with IBD. METHODS: We identified patients with IBD with filled prescriptions for anti-TNFs using the National Veterans Affairs administrative data sets. Determinants of TB screening were identified by univariate and multivariate analyses. Patients with TB reactivation were identified by ICD9 codes or prescriptions for isoniazid, and confirmed by chart review. RESULTS: A total of 3357 patients with IBD were identified with filled anti-TNF prescriptions. Approximately 72% to 86% of patients received TB screening. In multivariate analyses, patients in rural areas were less likely to be screened for TB compared with those in urban areas (odds ratio 0.72, 95% confidence ratio 0.54-0.95). Patients who received care at academically affiliated facilities were more likely to have received screening for TB (odds ratio 1.49, 95% confidence ratio 1.31-1.95). In 7210 patient-years of follow-up on anti-TNF, TB reactivation was confirmed in 2 patients, both of whom had a history and treatment of latent TB before anti-TNF initiation. CONCLUSIONS: TB screening before anti-TNF is estimated to be between 72% and 86%. Receipt of care at urban, academic-affiliated, high-volume IBD facilities is associated with higher rates of screening. Reactivation of TB in a highly screened cohort is estimated to be 2.8 per 10,000 patient-years.