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Mediterr J Rheumatol 2021;32(4):290-315
Tuberculosis in Children with Rheumatic Diseases on Biologic Disease-Modifying Anti-Rheumatic Drugs: A Narrative Review
Authors Information

1. Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India

2. Department of Medicine, Government Medical College, Kasaragod, India

3. Arthritis and Rheumatology Clinic, Delhi, India

4. University of Florence, School of Health Science, Rheumatology Unit, Meyer Children's University Hospital, Florence, Italy

5. Department of Paediatric Rheumatology, Amrita Institute of Medical Sciences, Kochi, India

6. Bristol Royal Hospital for Children & University of Bristol, United Kingdom

7. Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

C Kavadichanda, MB Adarsh, L Gupta 

Abstract

Chronic rheumatic diseases entail the use of biologics in children. Immunosuppressive effects of drug therapy put children at risk of various infections including tuberculosis (TB). Even though TB is a major concern among individuals on biological DMARDs, the incidence and distribution among children on these drugs is not known. Hence, we performed a literature search to ascertain the prevalence of tuberculosis amongst children with rheumatic disorders treated with biological agents. Articles available on MEDLINE and SCOPUS published on or after January 1, 2010 to 1 October 2019 were reviewed and collated. We found that published data on TB infections in children with rheumatic disorders on biologics is scant even from regions with highest TB burden. Tuberculosis was reported on occasion (0-5 cases per country) in the developed world with most reports being from Turkey. While most of the retrospective studies suggest that TB risk is minimal in the paediatric rheumatology patients, prospective studies suffer from a short observation period. Most registries focus on response to therapy rather than complications. In this review we have then discussed about the variation in screening strategies for latent TB and the role of bacille Calmette-Guerin (BCG) vaccination. Based on the dearth of data and inconsistency in data collection, we propose a way forward in the form of establishing well-designed long-term prospective national registries from countries with high background prevalence of TB with focus not only on treatment efficacy but also on adverse events and infections.


Article Submitted: 19 Jun 2021; Revised Form: 17 Aug 2021; Article Accepted: 15 Sep 2021; Available Online: 27 Dec 2021

https://doi.org/10.31138/mjr.32.4.290

This work is licensed under a Creative Commons Attribution 4.0 International License. 

©Kavadichanda C, Adarsh MB, Ajmani S, Maccora I, Balan S, Ramanan AV, Agarwal V, Gupta L.

Full Text

INTRODUCTION

Despite the advent of glucocorticoids and immunosuppressive therapies, chronic rheumatic diseases of childhood such as Juvenile Idiopathic Arthritis (JIA), Systemic Lupus Erythematosus (SLE), Idiopathic Inflammatory Myositis (IIM), Auto-inflammatory Syndromes (AIS)and Paediatric Vasculitis (PV) result in significant morbidity, and, at times, even mortality.1–3 In the developing world, infections are the leading contributors to such morbidity. Tuberculosis (TB) is one such infection, which remains a particular challenge in these parts of the world.4 The emergence of drug-resistant tubercular strains and polypharmacy, in the setting of chronic illnesses further compounds the problem.5

Recent estimates suggest the prevalence of TB in India to be 3.2 cases per thousand population.4 The presence of rheumatic disorders (RDs) entails treatment with glucocorticoids and immunosuppressive drugs for prolonged periods, more so in cases of lupus, vasculitis and myositis. Some patients with JIA, lupus, vasculitis, and, rarely, IIM, also have underlying antibody deficiencies or complement pathway defects, further increasing their infection risk. Over the past years, there have been efforts towards decreasing usage of glucocorticoids in rheumatic disorders and advocating rational use of immunosuppressive agents. In addition to this, public health initiatives have attempted to address the issues of adequate treatment of TB.2 The changing dynamics of therapeutic practices could have a bearing on the prevalence of TB in these diseases, and also influence the ways this problem can be addressed. Thus, it is important to understand the prevalence, risk factors, and outcomes of TB infection among children with RDs on biologics. In this review, we have performed a literature search on the prevalence, screening strategies, and global reporting patterns of TB across various studies among children with RDs on biological DMARDs. We have then summarised the available literature and discussed the possibilities that could explain our findings. Finally, we have suggested the way ahead to obtain more robust information from underrepresented countries.

 

REVIEW STRATEGY

The search strategy for writing review articles as proposed by Gasparyan et al. was followed.6 Articles available on MEDLINE and Scopus, published on or after January 1, 2010, until October 1, 2010 were reviewed using search words “juvenile” and “dermatomyositis” and “biologics” (n=71); “paediatric” AND “Lupus” AND “biologics” (n=81); “paediatrics” AND “Vasculitis” AND “Biologics” (n=55).

In addition, for the literature review on registry data in paediatric rheumatology, Scopus searches were conducted combining “registry” with each of the following: “paediatric” AND “Lupus” (n=100), “juvenile” and “myositis” (n=40); “juvenile” and “arthritis” (n=368); biologics” AND “Rheumatology” (n=359) and “Autoinflammatory” AND “syndromes” (n=50).

Also, select review articles on the subject were cross-referenced to obtain additional references. Figure 1 summarises the search results.


Figure 1. Number of articles obtained after searching through MEDLINE and Scopus.
 


Articles with data on outcomes in children of treatment with biologics were included. Review articles, systematic reviews, case reports, and articles without data in children, and those in languages other than English, and where full-text was not available were excluded. Congress abstracts did not feature in the searches. Studies which had TB where there was no clear separation between those receiving bDMARDS vs those on csDMARDs were excluded. Serious infections were defined as per the publishing author’s definitions. The Zotero software, an open-source tool, was used for references management and citations.

 

SELECTION OF ARTICLES

Screening by title

The Scopus searches were imported into Zotero, and articles were first screened by title by one author, and those without relevance, systematic reviews, meta-analysis, narratives, and in languages other than English were removed (Figure 1). The exact process of data extraction is elaborated in the supplementary material.

 

Juvenile Idiopathic Arthritis and Tuberculosis

Juvenile idiopathic arthritis is a chronic rheumatic disorder consisting of polyarticular (rheumatoid factor positive and negative), oligoarticular, systemic-onset JIA, enthesitis-related-arthritis, psoriatic and undifferentiated subtypes. The occurrence of infections is known and associated with poor outcomes.7 Tuberculosis is a chronic infection that can result in significant morbidity and mortality in children with JIA.8

Data in JIA consists of mixed cohorts of various subtypes of arthritis. Interestingly, most series report no occurrence of Tuberculosis (Tables 1, 2 and 3). Tuberculosis has been reported in four prospective studies, involving 2 each from Turkey and Portugal, and 1 each from Brazil and a multicentre trial. The follow-up duration in these studies ranged over 1-5 years. Of the various biologic registries screened, the only two cases of Tuberculosis reported are from Turkey. This is in contrast to minimal or no reports of Tuberculosis from UK, most European countries (France, Germany, Italy, and Greece) and Canada. The general prevalence of tuberculosis in Turkey is26/100,000 (2005). Brazil has one of the highest TB burdens with over 70,000 incident cases per year (Figure 2D). Portugal has the highest TB prevalence in Western Europe at 23 per 10,000 population, which resonates with the 2 cases reported of two studies in 232 patients.9

Interestingly, a study from India which has one of the highest background prevalence of Tuberculosis in the world, reported no Tuberculosis though the follow-up duration was 11 months. Plotting data available from various studies in paediatric rheumatology on a world map reveals the distribution is primarily limited to regions with low TB prevalence (Figure 2A). There is sizeable risk of confirmation biases regarding the safety of biologics resulting from absence of data from high TB incident parts of the world (Figure 2C).


Table 1. Data of tuberculosis in retrospective studies of patients with Juvenile arthritis on biologics.
 



Table 2. Data of tuberculosis in prospective studies of patients with juvenile arthritis on biologics.
 



Table 3. Data from studies on cohorts/registries of children with Juvenile arthritis on biologics.
 



Figure 2. Global distribution of cases. A. Data available on children with paediatric rheumatic disorders on biologics. B. Number of tuberculosis cases reported from studies summarised in Figure 2A. C. Number of incident tuberculosis cases worldwide*. D. Global incidence of tuberculosis per 10000 people#.
 


On the contrary, in adults, there are reports of greater tuberculosis on anti-TNFs, with the risk being highest with IFX(cumulative incidence 0.5% within the first 500 days of registration) as compared with ETA (0.2%).10,11 It is worthwhile considering if BCG vaccination practices in children could explain differences between children and adults. Usage of biologics also induces an immunosuppressant state, and there is known risk of higher extra-pulmonary forms of TB in such a setting.12 Diagnosing these could be a challenge, particularly so in the absence of a robust biomarker for extrapulmonary forms of tuberculosis.13

 

Juvenile Lupus and Tuberculosis

Data on tuberculosis in paediatric lupus is scant, being limited to 7 retrospective and 2 prospective studies (Supplementary Table S1). While most described the use of Rituximab, one prospective study on Belimumab featured 39 cases over 6 months of follow-up. The maximum duration of follow-up was 3 years and the largest series of 104 was from the United States in 2015. Whilst none of the series reported any tuberculosis, the largest series had overall 22 infections, of which 20 were major infections. Of note, most patients were on concomitant immunosuppressants or steroids during the study period.

However, literature is replete with case reports of tuberculosis in lupus.14 We have previously found TB in 6% of children with LN.5 Thus, poor tuberculosis reporting could be from use of biologics in patients with less severe disease (minor organ manifestations), early mortality or underreporting. Previously use of high-dose cyclophosphamide (CYC) has been identified as a risk factor for infections in lupus.(15)The risk of infections could possibly be lower with biologics such as belimumab and RTX but this needs to be confirmed in larger studies.(16)

Juvenile inflammatory myositis and tuberculosis

Out of the various studies on inflammatory myositis, none looked at data on Tuberculosis specifically (Supplementary Table S2) suggesting dire need to collect information relevant to this in future studies. On the other hand, we have 4 papers previously describing high prevalence of tuberculosis in myositis, suggesting the need for careful assessment of this aspect in prospective cohorts with longer term follow-up.17-20 We have described TB in 17.1% children from India with myositis (n=35, unpublished data). Unfortunately, biologics use is limited in this part of the world due to insurance policies and consequent financial constraints further leading to dearth of data.

Juvenile Vasculitis and Tuberculosis

Data on paediatric vasculitis is scant, being limited to 5 retrospective series, most being on Behcet’s disease, Takayasu’s arteritis, and Polyarteritis nodosa from Turkey, UK and Canada, overall reporting 35 cases (Supplementary Table S3). No serious infections were reported over the longest study period of 2.1 years.

Autoinflammatory syndromes and Tuberculosis

Although there is emerging data from registries including the Eurofever registry on various auto-inflammatory syndromes, most focus on treatment regimens and response to therapy with dearth of data on infections. In the limited studies available (Supplementary Table 4), no Tuberculosis was reported.21-23

Choice of biologics and risk of TB in children

Children with rheumatic disorders might be predisposed to Tuberculosis due to the intrinsic mechanism of action of biologics, anti-TNFs in particular, as they target TNF-α, the key cytokine for the Th1 axis. Experience from the biologic usage in adult rheumatic diseases has shown higher chances of TB reactivation with anti TNF agents. We identified 37 episodes of TB in 34 patients out of the 14,218 patients treated with anti TNF agents. In the non-TNF biologic group, a single case of TB has been reported with tocilizumab (OR-6.92 95% CI 0.95,50.56) (Table 4). Anti-TNF therapy may not be a cause for TB reactivation among children with autoimmune diseases on biological agents. The role of TNF in controlling TB infection is reflected by the mice models deficient in TNF. These rodents are unable to control M. tuberculosis infection and form granulomas in their lungs.24 TNF-a is required in the protective immune response against M.tuberculosis (MTB) in mice.25 TNF is an important signal for macrophage activation, in conjunction with IFN-g. This cytokine has a key role in the immune responses to MTB, because it is involved in multiple processes, such as macrophage activation and cell recruitment to the sites of infection (natural killer cells, granulocytes, fibroblasts, and T cells), which either leads to granuloma formation or kills the pathogen. Furthermore, it activates CD8+ T cell that could directly kill the bacteria, TNF-α additionally activates CD8+ cytotoxic T cells (CTLs) that may be important because these cells release granulysin and directly kill intracellular bacteria. TNF-α also promotes the maturation of monocytes to dendritic cells (DCs) and/or macrophages, inducing the antigen presentation of intracellular mycobacteria. TNF-α produced in a local infection site allows macrophages, natural killer (NK) cells and γδ T cells gather at the infection site and bring their activation.26 The activated CTL cells have the ability to produce perforin protein and TNF-α by itself, which guide TB-infected monocytes to apoptosis, which involves intracellular living TB bacilli, and to induce the autophagy of infected cells via activated.24

The other possibility is an increased risk due to the presence of an autoimmune disease. The risk of infections seems to be increased in rheumatic diseases not only from the drugs used, but also the presence of T lymphocytes dysfunction and cytokine imbalance. Azfar et al. have shown that lupus patients have suppressed reactive oxygen species and tumour necrosis factor-alpha activity in human monocytes in response to mycobacterium TB.27 Previously, the risk of TB has been shown to be increased in children with JIA independent of the use of anti-TNFs.28,29 However, in this study, the risk of TB was equal to the general population for children who either received anti-TNFs, or non TNF biological agents. This in sharp contrast to numerous other reports of TB in adults, suggesting that anti-TNFs might be safer in children than reported adults. Though this could also be attributed to smaller numbers in subgroup analysis, and remains to be confirmed.

Presence of other infections can be risk factors for subsequent infections, though there is limited data from the current searches to substantiate that. One of the children who had CMV infection also had TB. In addition, primary immunodeficiencies such as X-linked agammaglobulinemia can mimic JIA and put the children at risk for infections.30,31

 

Causes for low TB in children in current data set

Low numbers due to studies in regions with low incidence of TB

The number of studies from the various countries along with the reported number of TB cases, are plotted on a world map (Figure 2A,B). This pictorial view of the geographic distribution of the data obtained shows the stark distinction where most of the studies are concentrated in the affluent European and North American countries. Understandably, the reports of TB (Figure 2B) available are also from these countries. It is evident that the countries with the highest burden of TB (Figure 2C) have hardly any data on the biological use in children with RDs. Our literature search has brought out the inequalities in data availability across the world, and this has resulted in the probable assumption of low risk of TB among children with RDs on bDMARDs. Although the data review here suggested limited cases of TB on biologics, closer examination of the worldwide prevalence of TB makes paucity of data to be a possibility. The data from the PharmaChild registry had 17 episodes of TB in 14 children receiving biologicals for JIA.32 All the cases were reported from children on TNF inhibitors. TB was most reported from Asian patients - 52%, followed by 37% among the European patients, and 11% in the children treated at the centres in the USA. Since the registry covered 32 countries across the globe, the data seem to point at the fact that the low incidence of TB in other studies seen in Figure 2, is due to a concentration of studies from countries which are not endemic to TB.33 Studies from areas with moderate TB burden like Turkey and Brazil did report tuberculosis (Figure 2).

 

Low number of TB cases as consequence of the methodologies used to collect data

Moreover, the low reporting of adverse events could be relevant to the kind of data collected. Many articles in paediatric rheumatology focus on response to therapy. Thus, data recording of infections takes a backseat. Two cases of tuberculosis were reported in a single study from Turkey, with the use of etanercept and adalimumab, which focused on collecting infection related data (Table 4). The total numbers of infections reported were also remarkably higher in this study, suggesting possible geographic influence as well as methods/intent of data collection. Both developed TB despite a negative latent TB infection (LTBI) screen. Recently, a survey was conducted amongst physicians treating children with rheumatic disorders in India, that suggested a high incidence of TB, more so while the children were on biologics than after they were stopped.34 Thus, it seems here that what we see in Turkey is just the tip of the iceberg, and the problem might be much severe in areas of TB endemicity. In the current era of biosimilars, data from post marketing surveillance records in the developed world can be mined to gain insight into TB incidence rates.35


Table 4. Summary of available data that could be analysed for tuberculosis incidence in paediatric rheumatology with various biologics.
 


Varied screening strategies before administering biologics

On a different note, low number of TB cases could also be due to varied TB and LTBI screening strategies before using bDMARDs. However, the recent survey from Indian rheumatologists suggests screening is universally practiced, though there is no consensus on the optimum method of screening.34 Thus, a closer look into the prevalent practices and cost-benefit ratios of the strategy used for screening might be insightful in the future. Recently, Hassanzadeh et al. established that blanket screening for TB using the TB Spot assay increased the risk of polypharmacy, adverse drug effects and increased cost manifold.36 A recent systematic review confirmed the lack of consensus in screening strategies for TB in the immunosuppressed in guidelines across countries.37 Thus, region-specific data needs to be gathered before implementing screening strategies in rheumatology as the risk and cost efficacy ratios might differ significantly according to TB incidence rates.37

 

Shorter follow-up duration in children

Moreover, studies can be marred by short follow-up period, as post-marketing surveillance offers best insight into rare adverse effects.35 Thus, registries are likely to provide a better overview. The PharmaChild registry which involved 32 countries across the globe reported 24 cases (17 on biological DMARDS) of tuberculosis in children with JIA.38 Similar compilations are particularly needed from parts the world with high background prevalence of tuberculosis. The short window of childhood might limit study periods as children move on to adulthood, as compared with studies in adults, which are likely to have longer follow-up periods.

 

TB risk in children in comparison with adults

TB screening practices could vary in children, as can be the threshold to prescribe biologics. Varied Tuberculosis incidence in different regions call for region specific guidelines in screening keeping the risk benefit ratio in mind. Lack of clarity in current guidelines is likely to accentuate the problem.

 

BCG vaccination

Difference in TB occurrence in children as compared with adults on anti-TNFs could also be a function of prevalent vaccination practices. Infant BCG vaccination has shown high efficacy of 70%-80% against childhood TB, especially meningeal and disseminated forms.39 Sara Suliman et al have shown that BCG re-vaccination in adults with LTBI induces long-lived BCG-reactive NK cell responses.40 This was in contrast to the limited cytokine change by Isoniazid preventive therapy, which was administered in 33 patients (39 in control group). Recently Katelaris et al. found that LTBI prevalence was lower amongst contacts of TB patients even 20 years after the initial vaccination, though vaccine efficacy declined as a function of time since vaccination.41 In light of waning vaccine efficacy in adulthood, BCG re-vaccination could possibly reduce TB incident rates while on bDMARDs.

 

CONCLUSION

To conclude, there is dearth of data on incident TB rates in children with rheumatic disorders with exposure to bDMARDs from TB endemic countries. There is a felt need for regional registries to understand the prevalence, patterns, and prevalent screening practices to chalk out cost effective approaches with the intent to prevent long term debility.

 

AUTHOR CONTRIBUTION

All authors were involved in ideation and manuscript preparation.

 

ACKNOWLEDGEMENTS

The authors thank Dr Durga P Misra for conducting Scopus searches for the review.

 

CONFLICT OF INTEREST

The authors declare no conflict of interest.


Supplementary Table 1. Data of tuberculosis in paediatric lupus and myositis on biologics.
 



Supplementary Table 2. Data of tuberculosis in paediatric vasculitis on biologics.
 



Supplementary Table 3. Data from paediatric biologic registries.
 



Supplementary Table 4. Prevalence of tuberculosis in paediatric autoinflammatory diseases.
 

References
  1. Hiraki LT, Feldman CH, Marty FM, Winkelmayer WC, Guan H, Costenbader KH. Serious Infection Rates Among Children With Systemic Lupus Erythematosus Enrolled in Medicaid. Arthritis Care Res 2017 Nov;69(11):1620-6.
  2. Muhammed H, Gupta L, Zanwar AA, Misra DP, Lawrence A, Agarwal V, et al. Infections Are Leading Cause of In-Hospital Mortality in Indian Patients with Inflammatory Myopathy. J Clin Rheumatol 2019 Dec;
  3. Al-Mayouf SM, Fallatah R, Al-Twajery M, Alayed T, Alsonbul A. Outcome of children with systemic rheumatic diseases admitted to pediatric intensive care unit: An experience of a tertiary hospital. Int J Pediatr Adolesc Med 2019 Dec;6(4):142-5.
  4. TB India Report 2018: Ministry of Health and Family Welfare [Internet]. [cited 2020 Mar 27]. Available from: https://tbcindia.gov.in/showfile.php?lid=3314
  5. Gupta L, Srivastava P, Agarwal V, Aggarwal A, Able L, Misra R, et al. High incidence of Tuberculosis in SLE patients [Internet]. Conference Abstract APLAR 2015 [cited 2020 Mar 27]. Available from: https://www.researchgate.net/publication/284448018_High_incidence_of_Tuberculosis_in_SLE_patients#fullTextFileContent
  6. Gasparyan AY, Ayvazyan L, Blackmore H, Kitas GD. Writing a narrative biomedical review: considerations for authors, peer reviewers, and editors. Rheumatol Int 2011 Nov 29;31(11):1409-17.
  7. Moorthy LN, Peterson MG, Hassett AL, Lehman TJ. Burden of childhood-onset arthritis. Pediatr Rheumatol 2010 Dec 8;8(1):20-1.
  8. Hsin Y-C, Zhuang L-Z, Yeh K-W, Chang C-W, Horng J-T, Huang J-L. Risk of Tuberculosis in Children with Juvenile Idiopathic Arthritis: A Nationwide Population-Based Study in Taiwan. Doherty TM, editor. PLOS ONE 2015 Jun 5;10(6):e0128768.
  9. Tuberculosis surveillance and monitoring in Europe 2016 [Internet]. [cited 2020 Mar 27]. Available from: http://www.euro.who.int/__data/assets/pdf_file/0019/310087/TB-surveillance-report-2016-Portugal.pdf?ua=1
  10. Sartori NS, Picon P, Papke A, Neyeloff JL, da Silva Chakr RM. A population-based study of tuberculosis incidence among rheumatic disease patients under anti-TNF treatment. Abu-Shakra M, editor. PLOS One. 2019 Dec 2;14(12):e0224963.
  11. Dixon WG, Hyrich KL, Watson KD, Lunt M, Galloway J, Ustianowski A, et al. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis 2010 Mar;69(3):522-8.
  12. Machuca I, Vidal E, de la Torre-Cisneros J, Rivero-Román A. Tuberculosis en pacientes inmunodeprimidos. Enfermedades Infecc Microbiol Clínica 2018 Jun;36(6):366-74.
  13. Lee JY. Diagnosis and Treatment of Extrapulmonary Tuberculosis. Tuberc Respir Dis 2015;78(2):47.
  14. Lao M, Chen D, Wu X, Chen H, Qiu Q, Yang X, et al. Active tuberculosis in patients with systemic lupus erythematosus from Southern China: a retrospective study. Clin Rheumatol 2019 Feb 23;38(2):535-43.
  15. Danza A, Ruiz-Irastorza G. Infection risk in systemic lupus erythematosus patients: susceptibility factors and preventive strategies. Lupus 2013 Oct 4;22(12):1286-94.
  16. Pehlivan Y, Kisacik B, Bosnak VK, Onat AM. Rituximab seems to be a safer alternative in patients with active rheumatoid arthritis with tuberculosis. Case Rep 2013 Jan 21;bcr2012006585–bcr2012006585.
  17. Marie I, Hachulla E, Chérin P, Hellot M-F, Herson S, Levesque H, et al. Opportunistic infections in polymyositis and dermatomyositis. Arthritis Care Res 2005 Apr 15;53(2):155-65.
  18. Airio A, Kauppi M, Kautiainen H, Hakala M, Kinnula V. High association of mycobacterial infections with polymyositis in a non-endemic country for tuberculosis. Ann Rheum Dis 2007 Oct 1;66(10):1404-5.
  19. Chen I-J, Tsai W-P, Wu Y-JJ, Luo S-F, Ho H-H, Liou L-B, et al. Infections in polymyositis and dermatomyositis: analysis of 192 cases. Rheumatology 2010 Dec 1;49(12):2429-37.
  20. Hernández-Cruz B, Sifuentes-Osornio J, Ponce-de-León Rosales S, Ponce-de-León Garduño A, Díaz-Jouanen E. Mycobacterium tuberculosis infection in patients with systemic rheumatic diseases. A case-series. Clin Exp Rheumatol 1999;17(3):289-96.
  21. Gattorno M, Hofer M, Federici S, Vanoni F, Bovis F, Aksentijevich I, et al. Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis 2019 Aug;78(8):1025-32.
  22. Levy R, Gérard L, Kuemmerle-Deschner J, Lachmann HJ, Koné-Paut I, Cantarini L, et al. Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry. Ann Rheum Dis 2015 Nov;74(11):2043-9.
  23. Ozen S, Demirkaya E, Amaryan G, Koné-Paut I, Polat A, Woo P, et al. Results from a multicentre international registry of familial Mediterranean fever: impact of environment on the expression of a monogenic disease in children. Ann Rheum Dis 2014 Apr;73(4):662-7.
  24. Lin PL, Plessner HL, Voitenok NN, Flynn JL. Tumor Necrosis Factor and Tuberculosis. J Investig Dermatol Symp Proc 2007 May;12(1):22-5.
  25. Flynn JL, Goldstein MM, Chan J, Triebold KJ, Pfeffer K, Lowenstein CJ, et al. Tumor necrosis factor-α is required in the protective immune response against mycobacterium tuberculosis in mice. Immunity 1995 Jun;2(6):561-72.
  26. Sia JK, Rengarajan J. Immunology of Mycobacterium tuberculosis Infections. Microbiol Spectr 2019 Jul 5;7(4).
  27. Azfar SF, Islam N. Suppression of Mycobacterium Tuberculosis Induced Reactive Oxygen Species andTumor Necrosis Factor-Alpha Activity in Human Monocytes of Systemic LupusErythematosus Patients by Reduced Glutathione. Oman Med J 2012 Jan 16;27(1):11-9.
  28. Yasui K. Immunity against Mycobacterium tuberculosis and the risk of biologic anti-TNF-α reagents. Pediatr Rheumatol 2014 Dec 2;12(1):45.
  29. Hsin Y-C, Zhuang L-Z, Yeh K-W, Chang C-W, Horng J-T, Huang J-L. Risk of Tuberculosis in Children with Juvenile Idiopathic Arthritis: A Nationwide Population-Based Study in Taiwan. Doherty TM, editor. PLOS One 2015 Jun 5;10(6):e0128768.
  30. Zhu Z, Kang Y, Lin Z, Huang Y, Lv H, Li Y. X-linked agammaglobulinemia combined with juvenile idiopathic arthritis and invasive Klebsiella pneumoniae polyarticular septic arthritis. Clin Rheumatol 2015 Feb 25;34(2):397-401.
  31. GARRED P, RICHTER C, ANDERSEN ÅB, MADSEN HO, MTONI I, SVEJGAARD A, et al. Mannan‐Binding Lectin in the Sub‐Saharan HIV and Tuberculosis Epidemics. Scand J Immunol 1997 Aug 3;46(2):204-8.
  32. Swart J, Giancane G, Horneff G, Magnusson B, Hofer M, Alexeeva Е, et al. Pharmacovigilance in juvenile idiopathic arthritis patients treated with biologic or synthetic drugs: combined data of more than 15,000 patients from Pharmachild and national registries. Arthritis Res Ther 2018 Dec 27;20(1):285.
  33. Swart J, Giancane G, Horneff G, Magnusson B, Hofer M, Alexeeva Е, et al. Pharmacovigilance in juvenile idiopathic arthritis patients treated with biologic or synthetic drugs: combined data of more than 15,000 patients from Pharmachild and national registries. Arthritis Res Ther 2018 Dec 27;20(1):285.
  34. Kavadichanda C, Gupta L, Balan S. Survey on Tuberculosis in children on biologics for rheumatic illnesses. Indian J Rheumatol 2020;15(2):130-3.
  35. Koike T, Harigai M, Ishiguro N, Inokuma S, Takei S, Takeuchi T, et al. Safety and effectiveness of adalimumab in Japanese rheumatoid arthritis patients: postmarketing surveillance report of the first 3,000 patients. Mod Rheumatol 2012 Aug 13;22(4):498-508.
  36. Hassanzadeh R, France J, Bawa S. Targeted Screening for Latent TB Infection prior to Biologic Therapy to Improve Patient Safety and Reduce Costs: A Prospective Observational Study. ISRN Infect Dis 2014;2014:1-6.
  37. Hasan T, Au E, Chen S, Tong A, Wong G. Screening and prevention for latent tuberculosis in immunosuppressed patients at risk for tuberculosis: a systematic review of clinical practice guidelines. BMJ Open 2018 Sep 12;8(9):e022445.
  38. Swart J, Giancane G, Horneff G, Magnusson B, Hofer M, Alexeeva Е, et al. Pharmacovigilance in juvenile idiopathic arthritis patients treated with biologic or synthetic drugs: combined data of more than 15,000 patients from Pharmachild and national registries. Arthritis Res Ther 2018 Dec 27;20(1):285.
  39. Trunz BB, Fine P, Dye C. Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness. The Lancet 2006 Apr;367(9517):1173-80.
  40. Suliman S, Geldenhuys H, Johnson JL, Hughes JE, Smit E, Murphy M, et al. Bacillus Calmette–Guérin (BCG) Revaccination of Adults with Latent Mycobacterium tuberculosis Infection Induces Long-Lived BCG-Reactive NK Cell Responses. J Immunol 2016 Aug 15;197(4):1100-10.
  41. Katelaris AL, Jackson C, Southern J, Gupta RK, Drobniewski F, Lalvani A, et al. Effectiveness of BCG Vaccination Against Mycobacterium tuberculosis Infection in Adults: A Cross-sectional Analysis of a UK-Based Cohort. J Infect Dis 2020 Jan 1;221(1):146-55.
  42. Bracaglia C, Buonuomo PS, Tozzi AE, Pardeo M, Nicolai R, Campana A, et al. Safety and Efficacy of Etanercept in a Cohort of Patients with Juvenile Idiopathic Arthritis Under 4 Years of Age. J Rheumatol 2012 Jun 15;39(6):1287-90.
  43. Favalli EG, Pontikaki I, Becciolini A, Biggioggero M, Ughi N, Romano M, et al. Real-life 10-year retention rate of first-line anti-TNF drugs for inflammatory arthritides in adult- and juvenile-onset populations: similarities and differences. Clin Rheumatol 2017 Aug 8;36(8):1747-55.
  44. Ayaz NA, Demirkaya E, Bilginer Y, Özçelik U, Çobanoğlu N, Kiper N, et al. Preventing tuberculosis in children receiving anti-tnf treatment. Clin Rheumatol 2010 Apr 19;29(4):389-92.
  45. Hugle B, Burgos-Vargas R, Inman RD, O’Shea F, Laxer RM, Stimec J, et al. Long-term outcome of anti-tumor necrosis factor alpha blockade in the treatment of juvenile spondyloarthritis. Clin Exp Rheumatol 32(3):424-31.
  46. Brunelli JB, Bonfiglioli KR, Silva CA, Kozu KT, Goldenstein-Schainberg C, Bonfa E, et al. Latent tuberculosis infection screening in juvenile idiopathic arthritis patients preceding anti-TNF therapy in a tuberculosis high-risk country. Rev Bras Reumatol Engl Ed 2017 Sep;57(5):392-6.
  47. Kilic O, Kasapcopur O, Camcioglu Y, Cokugras H, Arisoy N, Akcakaya N. Is it safe to use anti-TNF-α agents for tuberculosis in children suffering with chronic rheumatic disease? Rheumatol Int 2012 Sep 26;32(9):2675-9.
  48. Zuber Z, Rutkowska-Sak L, Postępski J, Dobrzyniecka B, Opoka-Winiarska V, Kobusińska K, et al. Etanercept treatment in juvenile idiopathic arthritis: The Polish registry. Med Sci Monit 2011;17(12):SR35-42.
  49. Verazza S, Davì S, Consolaro A, Bovis F, Insalaco A, Magni-Manzoni S, et al. Disease status, reasons for discontinuation and adverse events in 1038 Italian children with juvenile idiopathic arthritis treated with etanercept. Pediatr Rheumatol 2016 Dec 20;14(1):68.
  50. Isha Saini, Lesa Dawman NG and *SK K. Biologicals in Juvenile Idiopathic Arthritis. Indian Pediatr 2016;(53):260-1.
  51. Atikan BY, Cavusoglu C, Dortkardesler M, Sozeri B. Assessment of tuberculosis infection during treatment with biologic agents in a BCG-vaccinated pediatric population. Clin Rheumatol 2016 Feb 18;35(2):427-31.
  52. Aygun D, Sahin S, Adrovic A, Barut K, Cokugras H, Camcıoglu Y, et al. The frequency of infections in patients with juvenile idiopathic arthritis on biologic agents: 1-year prospective study. Clin Rheumatol 2019 Apr 17;38(4):1025-30.
  53. Mourão AF, Santos MJ, Melo Gomes JA, Martins FM, Mendonça SC, Oliveira Ramos F, et al. Effectiveness and long-term retention of anti-tumour necrosis factor treatment in juvenile and adult patients with juvenile idiopathic arthritis: data from Reuma.pt. Rheumatology 2016 Apr;55(4):697-703.
  54. Horneff G, Foeldvari I, Minden K, Trauzeddel R, Kümmerle-Deschner JB, Tenbrock K, et al. Efficacy and Safety of Etanercept in Patients With the Enthesitis-Related Arthritis Category of Juvenile Idiopathic Arthritis: Results From a Phase III Randomized, Double-Blind Study. Arthritis Rheumatol 2015 May;67(8):2240-9.
  55. Giannini EH, Ilowite NT, Lovell DJ, Wallace CA, Rabinovich CE, Reiff A, et al. Long-term safety and effectiveness of etanercept in children with selected categories of juvenile idiopathic arthritis. Arthritis Rheum 2009 Sep;60(9):2794-804.
  56. Prince FHM, Twilt M, Cate R ten, van Rossum MAJ, Armbrust W, Hoppenreijs EPAH, et al. Long-term follow-up on effectiveness and safety of etanercept in juvenile idiopathic arthritis: the Dutch national register. Ann Rheum Dis 2009 May;68(5):635-41.
  57. Ruperto N, Lovell DJ, Quartier P, Paz E, Rubio-Pérez N, Silva CA, et al. Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis. Arthritis Rheum 2010 Feb 26;62(6):1792-802.
  58. Constantin T, Foeldvari I, Vojinovic J, Horneff G, Burgos-Vargas R, Nikishina I, et al. Two-year Efficacy and Safety of Etanercept in Pediatric Patients with Extended Oligoarthritis, Enthesitis-related Arthritis, or Psoriatic Arthritis. J Rheumatol 2016 Apr;43(4):816-24.
  59. Imagawa T, Yokota S, Mori M, Miyamae T, Takei S, Imanaka H, et al. Safety and efficacy of tocilizumab, an anti-IL-6-receptor monoclonal antibody, in patients with polyarticular-course juvenile idiopathic arthritis. Mod Rheumatol 2012 Feb 12;22(1):109-15.
  60. Brunelli JB, Schmidt AR, Sallum AME, Goldenstein-Schainberg C, Bonfá E, Silva CA, et al. High rate of serious infection in juvenile idiopathic arthritis patients under biologic therapy in a real-life setting. Mod Rheumatol 2018 Mar 4;28(2):264-70.
  61. Tarkiainen M, Tynjälä P, Vähäsalo P, Lahdenne P. Occurrence of adverse events in patients with JIA receiving biologic agents: long-term follow-up in a real-life setting. Rheumatology 2015 Jul;54(7):1170-6.
  62. Kingsbury DJ, Bader-Meunier B, Patel G, Arora V, Kalabic J, Kupper H. Safety, effectiveness, and pharmacokinetics of adalimumab in children with polyarticular juvenile idiopathic arthritis aged 2 to 4 years. Clin Rheumatol 2014 Oct 2;33(10):1433-41.
  63. Imagawa T, Takei S, Umebayashi H, Yamaguchi K, Itoh Y, Kawai T, et al. Efficacy, pharmacokinetics, and safety of adalimumab in pediatric patients with juvenile idiopathic arthritis in Japan. Clin Rheumatol 2012 Dec 2;31(12):1713-21.
  64. Lovell DJ, Reiff A, Ilowite NT, Wallace CA, Chon Y, Lin S-L, et al. Safety and efficacy of up to eight years of continuous etanercept therapy in patients with juvenile rheumatoid arthritis. Arthritis Rheum 2008 May;58(5):1496-504.
  65. Lovell DJ, Ruperto N, Goodman S, Reiff A, Jung L, Jarosova K, et al. Adalimumab with or without Methotrexate in Juvenile Rheumatoid Arthritis. N Engl J Med 2008 Aug 21;359(8):810-20.
  66. Ruperto N, Lovell DJ, Cuttica R, Wilkinson N, Woo P, Espada G, et al. A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum 2007 Sep;56(9):3096-106.
  67. Klein A, Becker I, Minden K, Foeldvari I, Haas J, Horneff G. Adalimumab versus adalimumab and methotrexate for the treatment of juvenile idiopathic arthritis: long-term data from the German BIKER registry. Scand J Rheumatol 2019 Mar 4;48(2):95-104.
  68. Southwood TR, Foster HE, Davidson JE, Hyrich KL, Cotter CB, Wedderburn LR, et al. Duration of etanercept treatment and reasons for discontinuation in a cohort of juvenile idiopathic arthritis patients. Rheumatology 2011 Jan 1;50(1):189-95.
  69. Schmeling H, Minden K, Foeldvari I, Ganser G, Hospach T, Horneff G. Efficacy and Safety of Adalimumab as the First and Second Biologic Agent in Juvenile Idiopathic Arthritis: The German Biologics JIA Registry. Arthritis Rheumatol 2014 Sep;66(9):2580-9.
  70. Horneff G, Schulz AC, Klotsche J, Hospach A, Minden K, Foeldvari I, et al. Experience with etanercept, tocilizumab and interleukin-1 inhibitors in systemic onset juvenile idiopathic arthritis patients from the BIKER registry. Arthritis Res Ther 2017 Dec 22;19(1):256.
  71. Sevcic K, Orban I, Brodszky V, Bazso A, Balogh Z, Poor G, et al. Experiences with tumour necrosis factor- inhibitors in patients with juvenile idiopathic arthritis: Hungarian data from the National Institute of Rheumatology and Physiotherapy Registry. Rheumatology 2011 Jul 1;50(7):1337-40.
  72. Otten MH, Prince FHM, Twilt M, ten Cate R, Armbrust W, Hoppenreijs EPAH, et al. Tumor Necrosis Factor-blocking Agents for Children with Enthesitis-related Arthritis — Data from the Dutch Arthritis and Biologicals in Children Register, 1999–2010. J Rheumatol 2011 Oct;38(10):2258-63.
  73. Kearsley-Fleet L, Sampath S, McCann LJ, Baildam E, Beresford MW, Davies R, et al. Use and effectiveness of rituximab in children and young people with juvenile idiopathic arthritis in a cohort study in the United Kingdom. Rheumatology 2019 Feb 1;58(2):331-5.
  74. Trachana M, Koutsonikoli A, Farmaki E, Printza N, Tzimouli V, Papachristou F. Safety and efficacy of Rituximab in refractory pediatric systemic lupus erythematosus nephritis: a single-center experience of Northern Greece. Rheumatol Int 2013 Mar 19;33(3):809-13.
  75. AlE’ed A, AlSonbul A, Al-Mayouf SM. Safety and efficacy of combined cyclophosphamide and rituximab treatment in recalcitrant childhood lupus. Rheumatol Int 2014 Apr 12;34(4):529-33.
  76. Dale RC, Brilot F, Duffy L V., Twilt M, Waldman AT, Narula S, et al. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology 2014 Jul 8;83(2):142-50.
  77. Olfat M, Silverman ED, Levy DM. Rituximab therapy has a rapid and durable response for refractory cytopenia in childhood-onset systemic lupus erythematosus. Lupus 2015 Aug 24;24(9):966-72.
  78. Reis J, Aguiar F, Brito I. Anti CD20 (Rituximab) therapy in refractory pediatric rheumatic diseases. Acta Reumatol Port 41(1):45-55.
  79. Tambralli A, Beukelman T, Cron RQ, Stoll ML. Safety and Efficacy of Rituximab in Childhood-onset Systemic Lupus Erythematosus and Other Rheumatic Diseases. J Rheumatol 2015 Mar;42(3):541-6.
  80. Watson L, Beresford MW, Maynes C, Pilkington C, Marks SD, Glackin Y, et al. The indications, efficacy and adverse events of rituximab in a large cohort of patients with juvenile-onset SLE. Lupus 2015 Jan 12;24(1):10-7.
  81. Hui-Yuen JS, Reddy A, Taylor J, Li X, Eichenfield AH, Bermudez LM, et al. Safety and Efficacy of Belimumab to Treat Systemic Lupus Erythematosus in Academic Clinical Practices. J Rheumatol 2015 Dec;42(12):2288-95.
  82. Lehman TJ, Singh C, Ramanathan A, Alperin R, Adams A, Barinstein L, et al. Prolonged improvement of childhood onset systemic lupus erythematosus following systematic administration of rituximab and cyclophosphamide. Pediatr Rheumatol 2014 Dec 14;12(1):3.
  83. Oddis C V., Reed AM, Aggarwal R, Rider LG, Ascherman DP, Levesque MC, et al. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: A randomized, placebo-phase trial. Arthritis Rheum 2013 Feb;65(2):314-24.
  84. Eleftheriou D, Dillon MJ, Tullus K, Marks SD, Pilkington CA, Roebuck DJ, et al. Systemic Polyarteritis Nodosa in the Young: A Single-Center Experience Over Thirty-Two Years. Arthritis Rheum 2013 Sep;65(9):2476-85.
  85. Eleftheriou D, Varnier G, Dolezalova P, McMahon A-M, Al-Obaidi M, Brogan PA. Takayasu arteritis in childhood: retrospective experience from a tertiary referral centre in the United Kingdom. Arthritis Res Ther 2015 Dec 25;17(1):36.
  86. Aeschlimann FA, Eng SWM, Sheikh S, Laxer RM, Hebert D, Noone D, et al. Childhood Takayasu arteritis: disease course and response to therapy. Arthritis Res Ther 2017 Dec 22;19(1):255.
  87. Sahin S, Hopurcuoglu D, Bektas S, Belhan E, Adrovic A, Barut K, et al. Childhood-onset Takayasu arteritis: A 15-year experience from a tertiary referral center. Int J Rheum Dis 2019 Jan;22(1):132-9.
  88. Poddighe D, Mukusheva Z, Dauyey K, Assylbekova M. Adalimumab in the treatment of pediatric Behçet’s disease: case-based review. Rheumatol Int 2019 Jun 11;39(6):1107-12.
  89. Markomichelakis NN, Aissopou EK, Maselos S, Tugal-Tutkun I, Sfikakis PP. Biologic Treatment Options for Retinal Neovascularization in Behçet’s Disease. Ocul Immunol Inflamm 2019 Jan 2;27(1):51-7.
  90. Acar M, Sütçü M, Aktürk H, Hançerli-Torun S, Erol OB, Salman N, et al. Tuberculosis screening in pediatric patients receiving tnf-alpha inhibitor therapy. Turk J Pediatr 2017;59(5):503.
  91. Suwannamalai P, Authavekiat P, Udomsubpayakul U, Janavitayanujit S. The infectious profiles of anti-tumor necrosis factor agents in a Thai population: a retrospective study a the university-based hospital. Int J Rheum Dis 2009 Jul;12(2):118-24.
  92. Stoll ML, Grubbs JA, Beukelman T, Mannion ML, Jester TW, Cron RQ, et al. Risk of tuberculosis among Alabama children and adolescents treated with tumor necrosis factor inhibitors: a retrospective study. Pediatr Rheumatol 2017 Dec 9;15(1):79.
  93. Calzada-Hernández J, Anton-López J, Bou-Torrent R, Iglesias-Jiménez E, Ricart-Campos S, Martín de Carpi J, et al. Tuberculosis in pediatric patients treated with anti-TNFα drugs: a cohort study. Pediatr Rheumatol 2015 Dec 3;13(1):54.
  94. Galeotti C, Meinzer U, Quartier P, Rossi-Semerano L, Bader-Meunier B, Pillet P, et al. Efficacy of interleukin-1-targeting drugs in mevalonate kinase deficiency. Rheumatology 2012 Oct 1;51(10):1855-9.
  95. Neven B, Marvillet I, Terrada C, Ferster A, Boddaert N, Couloignier V, et al. Long-term efficacy of the interleukin-1 receptor antagonist anakinra in ten patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheum 2010 Jan;62(1):258-67.
  96. Lepore L, Paloni G, Caorsi R, Alessio M, Rigante D, Ruperto N, et al. Follow-Up and Quality of Life of Patients with Cryopyrin-Associated Periodic Syndromes Treated with Anakinra. J Pediatr. 2010 Aug;157(2):310-15.e1.
  97. Arostegui JI, Anton J, Calvo I, Robles A, Iglesias E, López-Montesinos B, et al. Open-Label, Phase II Study to Assess the Efficacy and Safety of Canakinumab Treatment in Active Hyperimmunoglobulinemia D With Periodic Fever Syndrome. Arthritis Rheumatol 2017 Aug;69(8):1679-88.
  98. Hawkins PN, Lachmann HJ, Aganna E, McDermott MF. Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum 2004 Feb;50(2):607-12.
  99. De Benedetti F, Gattorno M, Anton J, Ben-Chetrit E, Frenkel J, Hoffman HM, et al. Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes. N Engl J Med 2018 May 17;378(20):1908-19.
  100. Kuemmerle-Deschner JB, Hachulla E, Cartwright R, Hawkins PN, Tran TA, Bader-Meunier B, et al. Two-year results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes. Ann Rheum Dis 2011 Dec 1;70(12):2095-102.
  101. Kuemmerle-Deschner JB, Tyrrell PN, Koetter I, Wittkowski H, Bialkowski A, Tzaribachev N, et al. Efficacy and safety of anakinra therapy in pediatric and adult patients with the autoinflammatory Muckle-Wells syndrome. Arthritis Rheum 2011 Mar;63(3):840-9.
  102. Sibley CH, Plass N, Snow J, Wiggs EA, Brewer CC, King KA, et al. Sustained response and prevention of damage progression in patients with neonatal-onset multisystem inflammatory disease treated with anakinra: A cohort study to determine three- and five-year outcomes. Arthritis Rheum 2012 Jul;64(7):2375-86.