The introduction of biological agents, especially the tumor necrosis factor inhibitors (anti-TNF), for the treatment of rheumatic diseases increased the risk of developing tuberculosis (TB). Screening for latent TB infection (LTBI) is strongly recommended before starting therapy with anti-TNF agents. The objective of this study was to identify the prevalence of LTBI and TB among patients with rheumatic diseases on anti-TNF agents. This is a cross-sectional study. The electronic medical records of all adult patients (≥18 years old) undergoing anti-TNF treatment were reviewed. Every patient underwent tuberculin skin test (TST) before starting anti-TNF treatment. In total, 176 patients were included; the mean age was 51.9 ± 12.4 years, 34.7% were males, and 90.9% were white. The underlying diseases were rheumatoid arthritis (RA) in 50.6% (N = 89), ankylosing spondylitis (AS) in 27.8% (N = 49), and psoriatic arthritis (PsA) in 17.6% (N = 31). The prevalence of positive TST was 29.5%. Household contact with TB was significantly associated with a positive TST (p = 0.020). RA patients had lower TST reactions than AS patients (p = 0.022). There were six cases of TB (3.4%) diagnosed during anti-TNF therapy. We demonstrated a high prevalence of positive TST (29.5%) among patients with rheumatic diseases in a region with high TB prevalence. Our data corroborates the ACR's recommendation that patients who live in high TB incidence settings should be tested annually for LTBI.

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.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.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.Reactivation and new onset TB is a significant risk for all biologics users in SA. Screening for LTBI is an imperative preventative strategy.© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

To test the validity of an augmented tuberculosis skin test (a-TST) combined with Quantiferon TB-gold (QFTG) test for the screening of latent tuberculosis infection (LTBI) in patients with rheumatoid arthritis (RA) being considered for treatment with biologic disease-modifying anti-rheumatic drugs or targeted synthetic disease-modifying anti-rheumatic drugs.Standard TST using 1 tuberculin unit (TU) of purified protein derivative (PPD, RT23 strain) was carried out. If the positivity was less as compared to the general population, then a-TST using 10 TU PPD was employed. Simultaneously, QFTG test was also performed.Using standard TST, 6/44 (13.6%), patients were positive compared to the reported figures of ~ 40% of the general population; 38 of the remaining TST-negative patients were then given an a-TST with 10 TU PPD; eight of them dropped out. Of the remaining 30 patients, eight (26.6%) were positive. Another 70 patients tested directly with a-TST; 22 (31.4%) were found positive. Thus, of a total of 100 patients tested with a-TST, 30 (30%) were positive. In 54 a-TST negative patients, QFTG was done; seven (13%) were positive. Thus, in combined a-TST with QFTG, 43% of the RA patients were found positive, suggestive of the presence of LTBI.Combined a-TST with QFTG testing gave 43% positivity among RA patients, which is close to the reported ~ 40% Mantoux positivity in the general population. Therefore, this method for the screening of LTBI in Indian patients with RA being considered for tumor necrosis factor alpha treatment could be satisfactory for offsetting TB flare. It may apply to other high-burden TB countries around the world.© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

There is paucity of data on tuberculosis in Indian patients with systemic lupus erythematosus (SLE). We retrospectively studied clinical features and outcome of tuberculosis in SLE.Medical records of patients who developed tuberculosis simultaneous or after the diagnosis of SLE were retrospectively reviewed. All patients fulfilled 1997 ACR and/or SLICC 2012 classification criteria for SLE. A diagnosis of tuberculosis required bacteriological, histopathological or CT/MRI suggestive of tuberculosis and initiation of four drug antituberculous therapy. Baseline parameters were compared with the rest of cohort to identify predictors of tuberculosis.In our cohort of 1335 SLE patients, 48 (3.6%) developed tuberculosis. Incidence of tuberculosis was calculated to be 733 per 100,000 patient years and occurred after a mean disease duration of 3.0 ± 4.1 years. Extrapulmonary tuberculosis (n = 37) was commoner than pulmonary tuberculosis (n =11). Most common radiological pattern in pulmonary tuberculosis was miliary and musculoskeletal TB was most common extrapulmonary TB. A microbiological diagnosis was obtained in 52.1% patients. Male gender was associated with higher risk of tuberculosis [OR 3.30 (1.55-7.05)]. Mortality was 14.5% and all patients who died had either disseminated (n = 5) or central nervous system (CNS) tuberculosis (n = 2).Incidence of tuberculosis in SLE is higher than general population and is associated with different phenotype and higher mortality. Male gender was associated with increased risk of tuberculosis in SLE.

To investigate the prevalence and spectrum of comorbidities in South Africans with systemic lupus erythematosus (SLE).A nested case-control study of a known alive group (AG) and deceased group (DG) of 200 and 40 patients, respectively, matched for age and sex, attending a tertiary Lupus Clinic. Comorbidities that were documented included, but not restricted to, those listed in the Charlson comorbidity index (CCI). Lupus disease severity was assessed using the lupus severity index (LSI).Patients were mainly black female (94%), and the median age (IQR) and median disease duration (IQR) were 33 (25-42) and 6 (3-11) years, respectively. Overall, 191 (79.5%) patients experienced ≥ 1 comorbidities. The median (IQR) LSI and CCI scores were significantly higher in the DG than the AG (8.5 (6.7-9.1) vs 6.3 (5.2-8.3), p < 0.001 and 1 (1-3) vs 0 (0-2), p = 0.002, respectively). The commonest comorbidities were hypertension (42%), serious infections (36.6%) and tuberculosis (TB) (18.8%), the latter two being significantly more common in the DG (OR = 7.34, p < 0.0001 and OR = 3.40, p = 0.001, respectively). Of the CCI comorbidities, congestive cardiac failure (OR = 10.39, p = 0.0003), cerebrovascular disease (OR = 7.29, p = 0.01) and chronic kidney disease (OR = 3.08, p = 0.02) were more common in the DG. Both serious infections and TB were independent predictors of death.In this study of predominantly black South African SLE patients, comorbidities were common, with serious infections and TB amongst the commonest comorbidities. Unlike in industrialised Caucasian populations, cardiovascular comorbidities were rare in spite of a high prevalence of HPT.

Infections are one of the most common causes of morbidity and mortality in patients with systemic lupus erythematosus (SLE). SLE patients have a higher risk of tuberculosis (TB) infection due to impaired immune defence.To investigate the demographics, clinical characteristics and outcomes of patients with SLE and concomitant TB.Medical records of SLE patients with TB who were admitted to Peking Union Medical College (PUMC) Hospital in 1983-2019 were retrospectively reviewed. Age- and sex-matched SLE inpatients without TB were randomly selected as controls. Clinical and laboratory features and treatment were analysed and compared, and subjects were followed up to assess their outcome.Of the 10 469 SLE inpatients, 249 (2.4%) were diagnosed with TB. Compared with controls, SLE/TB + patients exhibited higher frequency of prior haematologic, mucocutaneous and musculoskeletal system involvement, and prior treatment with potent glucocorticoid/immunosuppressive agents (GC/ISA). Arthritis and alopecia, positive T-SPOT.TB test and lymphocytopenia were more common in SLE/TB + patients. SLE/TB + patients with lupus before TB (SLE → TB) had higher risk of miliary TB (22.8%) and intracranial TB (16.5%) than SLE/TB + patients with lupus after TB (TB → SLE). SLE/TB + patients exhibited shorter long-term survival than SLE/TB- patients; those with poorer in-hospital outcomes had more severe lymphocytopenia and had received less treatment with ISAs.Systemic lupus erythematosus patients treated vigorously with GC/ISA should be alerted of increased risk of TB infection, especially miliary and intracranial TB. Positive T-SPOT.TB and lymphocytopenia served as discriminatory variables between SLE/TB + and SLE/TB- patients. Lymphocytopenia was associated with poorer outcomes in SLE/TB + patients.© 2020 The Association for the Publication of the Journal of Internal Medicine.

Treatment with tumour necrosis factor antagonists (anti-TNF) has been recognized as a risk factor for tuberculosis (TB) reactivation. Our aim was to evaluate risk of TB reactivation in rheumatologic and non-rheumatologic diseases treated with the same anti-TNF agents with and without concomitant therapies.We searched for randomized controlled trials (RCTs) evaluating infliximab, adalimumab, and certolizumab in both rheumatologic and non-rheumatologic diseases until 2012. Results were calculated as pooled rates and/or pooled odd ratios (OR).Overall, 40 RCTs with a total of 14,683 patients (anti-TNF: 10,010; placebo: 4673) were included. TB reactivation was 0.26% (26/10,010) in the anti-TNF group and 0% (0/4673) in the control group, corresponding to an OR of 24.8 (95% CI 2.4-133). TB risk was higher when anti-TNF agents were combined with methotrexate or azathioprine as compared with either controls (24/4241 versus 0/4673; OR 54; 95% CI 5.3-88) or anti-TNF monotherapy (24/4241 versus 2/5769; OR 13.3; 95% CI 3.7-100). When anti-TNF was used as monotherapy, TB risk tended to be higher than placebo (2/5769 versus 0/4673; OR 4; 95% CI 0.2-15.7).TB risk with anti-TNF agents appeared to be increased when these agents were used in combination with methotrexate or azathioprine as compared with monotherapy regimen. TB risk seemed to be higher than placebo, even when monotherapy is prescribed.

Latent tuberculosis infection (LTBI) accounts for almost a quarter of the world population, and, in 5-10% of the subjects with impaired immune-response against M. tuberculosis growth, it may progress to active tuberculosis (TB). In this review, we focus on the need to propose a screening for LTBI including preventive therapy offer in rheumatic patients undergoing therapy with biological drugs. Areas covered: We report on evidence that biologics are associated with an increased risk of active TB reactivation. This effect seems to be mainly limited to treatment with anti-tumor necrosis factor (TNF) agents, while non-anti-TNF-targeted biologics are not likely associated to any increased risk. We introduce the concept that the patients' coexisting host-related risk factors, such as comorbidities, are crucial to identify those at higher risk to reactivate TB. We report that preventive TB therapy is well tolerated in patients treated with biological drugs. Expert commentary: Availability of non-anti-TNF targeted biologics, that are not associated with an increased risk of TB reactivation, offers a great opportunity to tailor a therapeutic intervention at low/absent TB risk. After proper LTBI screening investigations, preventive TB therapy has been demonstrated to be effective and well-tolerated to reduce the risk of TB reactivation in rheumatic patients requiring biological drugs.

To assess the risk of adverse events (AEs) in patients with RA treated with tocilizumab, an IL-6 receptor antibody, in published randomized controlled trials (RCTs).A systematic literature search was conducted using the Cochrane library, PUBMED and EMBASE for all RCTs (of the use of tocilizumab for RA) until September 2009. Fixed effect meta-analyses were conducted to compare the incidence of AEs after treatment with tocilizumab 8 and 4 mg/kg in combination with MTX, and 8 mg/kg tocilizumab monotherapy, with controls. Pooled summary odds ratios (ORs) were calculated using the Mantel-Haenszel method.Six trials were analysed (four trials included 8 mg/kg tocilizumab and MTX combination therapy, three of which also assessed the 4 mg/kg dose). Three studies assessed tocilizumab monotherapy at 8 mg/kg. Pooled ORs revealed statistical significance for an increased risk of AEs in the 8 mg/kg combination group compared with controls (OR = 1.53; 95% CI 1.26, 1.86). The risk of infection was significantly higher in the 8 mg/kg combination group compared with controls (OR = 1.30; 95% CI 1.07, 1.58). No increased incidence of malignancy, tuberculosis reactivation or hepatitis was seen.Tocilizumab in combination with MTX as a treatment for RA is associated with a small but significantly increased risk of AEs, which is comparable with that of other biologics. Vigilance for untoward effects is, therefore, imperative in any patient treated with these immuno-suppressive agents.

Central nervous system (CNS) tuberculosis (TB) is a rare but catastrophic event in patients with systemic lupus erythematosus (SLE). Here we report a case of cerebral TB in a patient with lupus myocarditis and nephritis, following cyclophosphamide immunosuppression. To our knowledge this is the first reported case of cerebral TB in SLE in a non-endemic country. A 31-year-old female with SLE and a history of regular travel to Kenya presented to our centre with clinical features of acute heart failure. She was diagnosed with severe lupus myocarditis, and a renal biopsy also confirmed lupus nephritis. Prior to admission, she had also had a cough, fever and weight loss and was under investigation for suspected TB infection. She was treated with ivabradine, beta-blockers and diuretics together with methylprednisolone and cyclophosphamide immunosuppression. Subsequent sputum cultures confirmed TB and she was commenced on triple therapy. Despite this, she developed confusion, dizziness, blurred vision and fluctuating consciousness. Magnetic resonance imaging (MRI) and lumbar puncture revealed CNS TB infection resulting in meningitis. This was later complicated by obstructive hydrocephalus due to TB abscesses. A ventriculoperitoneal (VP) shunt was inserted and TB medications were given intravenously (IV) with dexamethasone. Following a prolonged hospital admission, the patient eventually recovered and rituximab treatment was used to control her SLE. TB infection has been associated with SLE flares. It is likely in this case that TB exacerbated a lupus flare and subsequent immunosuppression resulted in mycobacterial dissemination to the CNS. Systemic and CNS features of TB and SLE are difficult to distinguish and their contemporaneous management represents a diagnostic and therapeutic challenge.

The purpose of this study was to investigate the incidence, risk factors, and treatment outcome of tuberculosis (TB) in solid organ transplant (SOT) recipients treated with rifampicin.The incidence density of TB was calculated by a retrospective cohort study. Risk factors for TB were analyzed by a nested case-control study. Treatment outcome and effects of anti-TB drugs on immunosuppressants and allograft were compared between patients whose initial 2-month intensive regimen included rifampicin and those whose intensive regimen did not.Among the 2144 SOT recipients over 16 years, 40 cases of TB were found (1.7%). The incidence density was 372 cases per 10(5) patient years (95% confidence interval [CI], 270-503), which was 4 times higher than for the general Korean population (90 cases per 10(5) person years). The median time to the development of TB was 234 days (range, 33-3940 days). The use of tacrolimus (odds ratio [OR] 4.90; 95% CI, 1.74-13.80; P = 0.003) and cytomegalovirus (CMV) infection within the prior 3 months (OR 4.62; 95% CI, 1.44-14.87; P = 0.01) were found to be risk factors for TB. Patients whose intensive regimen included rifampicin were more likely to have an increased dose of calcineurin inhibitors than patients whose intensive regimen did not include rifampicin (13/15 [86.7%] vs. 3/14 [21.4%], P = 0.001). Graft rejection and mortality did not differ between the 2 groups.Use of tacrolimus and CMV infection were major risk factors for TB in SOT recipients. The graft outcome and mortality did not differ whether rifampicin was used or not during the first 2-month intensive phase.© 2012 John Wiley & Sons A/S.

The accurate diagnosis of latent tuberculosis infection (LTBI) is an important component of any tuberculosis control programme and depends largely on tuberculin skin testing. The appropriate interpretation of skin test results requires knowledge of the possible confounding factors such as previous BCG vaccination. Uncertainty about the effect of BCG vaccination on tuberculin skin testing and the strength with which recommendations are made to individual patients regarding treatment of LTBI have identified a need to analyse the available data on the effect of BCG on skin testing. A meta-analysis of the evidence for the effect of BCG vaccination on tuberculin skin testing in subjects without active tuberculosis was therefore performed.Medline was searched for English language articles published from 1966 to 1999 using the key words "BCG vaccine", "tuberculin test/PPD", and "skin testing". Bibliographies of relevant articles were reviewed for additional studies that may have been missed in the Medline search. Articles were considered for inclusion in the meta-analysis if they had recorded tuberculin skin test results in subjects who had received BCG vaccination more than 5 years previously and had a concurrent control group. Only prospective studies were considered. The geographical location, number of participants, type of BCG vaccine used, type of tuberculin skin test performed, and the results of the tuberculin skin test were extracted.The abstracts and titles of 980 articles were identified, 370 full text articles were reviewed, and 26 articles were included in the final analysis. Patients who had received BCG vaccination were more likely to have a positive skin test (5 TU PPD: relative risk (RR) 2.12 (95% confidence interval (CI)1.50 to 3.00); 2 TU RT23: 2.65 [corrected] (95% CI 1.83 to 3.85). The effect of BCG vaccination on PPD skin test results was less after 15 years. Positive skin tests with indurations of >15 mm are more likely to be the result of tuberculous infection than of BCG vaccination.In subjects without active tuberculosis, immunisation with BCG significantly increases the likelihood of a positive tuberculin skin test. The interpretation of the skin test therefore needs to be made in the individual clinical context and with evaluation of other risk factors for infection. The size of the induration should also be considered when making recommendations for treatment of latent infection.

Seven tuberculosis (TB) clinics in South Africa.As both purified protein derivative (PPD) and a -specific skin test (C-Tb) contain region of difference 1 (RD1) antigens, we conducted a study to evaluate whether there was any interaction between the two during concomitant and separate administration in patients with newly diagnosed culture-positive TB.Adult patients with active TB ( = 456, 20% human immunodeficiency virus infected) were randomised to receive only C-Tb, only PPD, or concomitant injection of both C-Tb and PPD using the Mantoux technique. Indurations were read after 48-72 h. QuantiFERON-TB Gold In-Tube (QFT) was performed in tandem.Of the 456 study participants, 154 simultaneously received both C-Tb and PPD, 153 only C-Tb and 149 only PPD. There was no effect of concomitant injection of PPD on the mean C-Tb induration (19 mm, 95%CI 17-22 vs. 18 mm, 95%CI 16-21; = 0.91). In patients with active TB, C-Tb sensitivity (78%) was similar to PPD (81%) and QFT (84%; excluding 82/429 [19%] indeterminate results). All tests showed reduced sensitivity in participants with CD4 <100 cells/μl.In patients with active TB, there was no interaction between C-Tb and PPD during concomitant injection of both agents. Sensitivities were similar for PPD and C-Tb.

Immunological testing for tuberculosis has been one of the most rapidly developing areas in the last decade. A new-generation immunological skin test, Diaskintest (DST), has been developed in the Russian Federation and successfully implemented into clinical practice since 2009. This article presents the results of a meta-analysis of publications reporting data on the use of the recombinant tuberculosis allergen DST (n = 121) from 2009 to 2019 included in Russian and international databases. The analysis included a total of 61 papers consistent with the study design, which cumulatively presented the results of 3,777,083 patients tested with DST (83.0%). The obtained data showed that the overall diagnostic sensitivity of the test in this population, regardless of age, was 86.0%, with 98.0% negative results. It was found that the intensity of the immune response of tuberculosis patients to specific ESAT-6 and CFP-10 antigens of DST may depend on the biological properties of the pathogen characteristic to various Mycobacterium tuberculosis genotypes, tuberculosis severity, and the presence of concomitant diseases. These factors are more prevalent in the adult population. In children, however, the test sensitivity reaches 100%. The proportion of positive DST results in HIV-positive patients tested for tuberculosis was 60.0%. The analysis showed that the accuracy (overall validity) of DST was 95.1% in the total studied population (95% confidence interval [CI]: 95.06-95.1) and 92.4% in HIV-positive patients (95% CI: 91.9-92.7).

Identifying latently infected individuals is crucial for the elimination of tuberculosis (TB). We evaluated for the first time the performance of a new type of interferon-γ release assay, QuantiFERON-TB Plus (QFT-Plus), which includes an additional antigen tube (TB2), stimulating both CD4 and CD8 T-cells in contacts of TB patients.Contacts were screened for latent TB infection by tuberculin skin test, QFT-Plus and QuantiFERON-TB Gold in Tube (QFT-GIT).In 119 TB contacts, the overall agreement between QFT-Plus and QFT-GIT was high, with a Cohen's κ of 0.8. Discordant results were found in 12 subjects with negative QFT-GIT and positive QFT-Plus results. In analyses of markers of TB exposure and test results, the average time spent with the index case was the strongest risk factor for positivity in each of these tests. The difference in interferon-γ production between the two antigen tubes (TB2-TB1) was used as an estimate of CD8 stimulation provided by the TB2. TB2-TB1 values >0.6 IU·mL were significantly associated with proximity to the index case and European origin.QFT-Plus has a stronger association with surrogate measures of TB exposure than QFT-GIT in adults screened for latent TB infection. Interferon-γ response in the new antigen tube used an indirect estimate of specific CD8 response correlates with increased Mycobacterium tuberculosis exposure, suggesting a possible role in identifying individuals with recent infection.Copyright ©ERS 2016.

Three months of a once-weekly combination of rifapentine and isoniazid for treatment of latent tuberculosis infection is safe and effective for persons 12 years or older. Published data for children are limited.To compare treatment safety and assess noninferiority treatment effectiveness of combination therapy with rifapentine and isoniazid vs 9 months of isoniazid treatment for latent tuberculosis infection in children.A pediatric cohort nested within a randomized, open-label clinical trial conducted from June 11, 2001, through December 17, 2010, with follow-up through September 5, 2013, in 29 study sites in the United States, Canada, Brazil, Hong Kong (China), and Spain. Participants were children (aged 2-17 years) who were eligible for treatment of latent tuberculosis infection.Twelve once-weekly doses of the combination drugs, given with supervision by a health care professional, for 3 months vs 270 daily doses of isoniazid, without supervision by a health care professional, for 9 months.We compared rates of treatment discontinuation because of adverse events (AEs), toxicity grades 1 to 4, and deaths from any cause. The equivalence margin for the comparison of AE-related discontinuation rates was 5%. Tuberculosis disease diagnosed within 33 months of enrollment was the main end point for testing effectiveness. The noninferiority margin was 0.75%.Of 1058 children enrolled, 905 were eligible for evaluation of effectiveness. Of 471 in the combination-therapy group, 415 (88.1%) completed treatment vs 351 of 434 (80.9%) in the isoniazid-only group (P = .003). The 95% CI for the difference in rates of discontinuation attributed to an AE was -2.6 to 0.1, which was within the equivalence range. In the safety population, 3 of 539 participants (0.6%) who took the combination drugs had a grade 3 AE vs 1 of 493 (0.2%) who received isoniazid only. Neither arm had any hepatotoxicity, grade 4 AEs, or treatment-attributed death. None of the 471 in the combination-therapy group developed tuberculosis vs 3 of 434 (cumulative rate, 0.74%) in the isoniazid-only group, for a difference of -0.74% and an upper bound of the 95% CI of the difference of +0.32%, which met the noninferiority criterion.Treatment with the combination of rifapentine and isoniazid was as effective as isoniazid-only treatment for the prevention of tuberculosis in children aged 2 to 17 years. The combination-therapy group had a higher treatment completion rate than did the isoniazid-only group and was safe.clinicaltrials.gov Identifier: NCT00023452.