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1©Kavadichanda C, Adarsh MB, Ajmani S, Maccora I, Balan S, Ramanan AV, Agarwal V, Gupta L.
This work is licensed under a Creative Commons Attribution 4.0 International L
NARRATIVE REVEW
Tuberculosis in Children with Rheumatic Diseases on Biologic Disease-Modifying Anti-Rheumatic Drugs: A Narrative Review
Chengappa Kavadichanda1 , MB Adarsh2 , Sajal Ajmani3, Maria Maccora4, Balan Ss, Ramanan AV6, Vikas Agarwal7, Latika Gupta7
department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India, 2Department of Medicine, Government Medical College, Kasaragod, India, 3Arthritis and Rheumatology Clinic, Delhi, 4University of Florence, School of Health Science, Rheumatology Unit, Meyer Children's University Hospital, Florence, Italy, 5Department of Paediatric Rheumatology, Amrita Institute of Medical Sciences, Kochi, India, 6Bristol Royal Hospital for Children & University of Bristol, United Kingdom, 7Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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.
Mediterr J Rheumatol 2021;32(4):290-315 https://doi.org/10.31138/mjr.32.4.290
Article Submitted: 19 Jun 2021; Revised Form: 17 Aug 2021; Article Accepted: 15 Sep 2021; Available Online: 27 Dec 2021
Corresponding Author:
Dr. Latika Gupta Assistant Professor, Department of Clinical Immunology Sanjay Gandhi Postgraduate Institute of Medical Sciences Lucknow 226014, India Tel.: +91-522-2495182 E-mail: drlatikagupta@gmail.com
Keywords: tuberculosis, biologics, rheumatology, paediatrics
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 con-
290 Cite this article as: Kavadichanda C, Adarsh MB, Ajmani S, Maccora I, Balan S, Ramanan AV, Agarwal V, Gupta L. Tuberculosis in Children with Rheumatic Diseases on Biologic Disease-Modifying Anti-Rheumatic Drugs: A Narrative Review. Mediterr J Rheumatol 2021;32(4):290-315.
tributors 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.
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.
Search strategy
MEDLINE and Scopus
Published on or after January 1,2010
Literature review on data in various paediatric rheumatic diseases
tuberculosis" AND "juvenile" AND "arthritis14
"juvenile" AND "dermatomyositis" AND "biologies"
paediatric" AND "lupus" AND "biologics
'•paediatrics" AND "vasculitis'' AND "biologies"
—» Literature review on registry data in paediatric rheumatology
"registry" AND 'Juvenile" and "arthritis n=368
"paediatric" AN 0 " I upus" n-100
"juvenile" and "myositis" n=40
"Autoinflammatory" AND "syndromes" n=50
"biologics" AND "rheumatology" n=3S9
'Select review articles on the subject were also cross'referenced to obtain additional references
1 Studies which had TB where in: thele was no dear separetjon between those receiving bOMARDi vs Lhose on isDMAFtDs hanE been excluded * Serious infections were defined as per the authors definitions
Figure 1. Number of articles obtained after searching through MEDLINE and Scopus.
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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-anal-ysis, 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 biolog-ics resulting from absence of data from high TB incident parts of the world (Figure 2 C). 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
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*.
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-a, 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-y. 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-a additionally activates CD8+ cytotoxic T cells (CTLs) that may be important because these cells release gran-ulysin and directly kill intracellular bacteria. TNF-a also promotes the maturation of monocytes to dendritic cells (DCs) and/or macrophages, inducing the antigen presentation of intracellular mycobacteria. TNF-a produced in a local infection site allows macrophages, natural killer (NK) cells and y6 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-a 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 lympho-
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cytes 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 bio-logics, 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
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 Glasgow, an area of low TB prevalence and high BCG vaccination. Chest radiograph and clinical interview were used to identify risk factors for LTBI. The annual risk of TB was calculated using tables from BTS recommendations and then compared to the risk of drug-induced hepatitis. All patients were given a T-SPOT according to current local policy. Indeterminate T-SPOTs were recorded and repeated. Results . For 130 patients, a total of 160 tests were required resulting in a cost of £ 24,000. 99 (76% 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.
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SUPPLEMENTARY TABLES Details of 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).
Screening by abstract
The list of articles remaining after the initial screen was passed on to another author, to screen the individual abstracts for relevance, type of study and study population (children or adults). During the article screening, the initial rounds of elimination by screening titles and abstracts was done by one author each and subsequent rounds by two different authors.
Screening by reading full-text
The full text of articles obtained after two rounds of exclusions was then accessed. Those deemed irrelevant at this stage or where full-text was not available on the internet were then excluded. Similar screening strategy as delineated above was followed. The approach was mostly inclusive. Randomised placebo-controlled studies or any other controlled trials, retrospective case series, published data from registries, correspondence with data from more than 3 patients were included for data synthesis. Case reports, systematic reviews and metanalysis were excluded. Predesigned data extraction form (DEF), Table 1 was used to record data from the articles obtained after the above three stages of screening. The DEF was devised by two rheumatologists individually who then discussed and merged the variables suggested by each.
Differences were resolved by consensus between two rheumatologists. DOI numbers, year and author names were recorded to avoid duplication of studies. TB was defined as in the individual studies.
Further, the number of studies from the various countries was tabulated and the number of participants, as well as TB cases, reported recorded for each. These were plotted on a world map (Figures 1A,B) to get a pictorial view of the geographic distribution of the data obtained. Multicentre studies were excluded from the above figure as attributions to individual countries were not possible. Tables 1, 2 and 3 summarise data on tuberculosis in different paediatric rheumatic diseases, while Table 4 summarises data obtained from various registries. Furthermore, the quality of evidence of each study was recorded and summarised as a Table 2, disease wise, to understand the weightage that can be accorded to each of these.
Table 1. Data of tuberculosis in retrospective studies of patients with Juvenile arthritis on biologies.
Retrospective
Country Italy Taiwan Italy Turkey Canada
Year 2012 2015 2017 2010 2015
Author Bracaglia42 Hsin29 Favalli43 Ayaz44 Hugle45with a median follow-up period of 7.2 years. Prospective data was collected according to a standardized protocol. Outcomes examined were TEC, TAJC, markers of inflammation (ESR, CRP
Tuberculosis-No of patients 0 1 0 0 0
Type of article/ paper Retrospective analysis of a cohort Nested case control analysis of Taiwan National Health Insurance Research Database Data extracted from local registry looking at the causes for anti TNF withdrawal Retrospective chart review Retrospective chart review
Type of JIA N=25 N=111 N=360 N=36 N=16
PA-RF+ 3(12) NA 31 6 (16.7) 0
PA-RF- 1(4) NA 75 0 0
OA 3 (12) NA 101 0 0
OA Extended 9(36) NA 70 3 (8.3) 0
ERA 0 NA 26 12 (33.3) 16
SJIA 8(32) NA 48 14 (38.9) 0
PsA 1(4) NA 9 1 (2.8) 0
Undiff 0 NA 0 0 0
Duration of follow-up (Median) 10 months (2-41) 3.49 ± 1.79 years (Mean) 10 years 36 months (range 4-216 months) 7.2 years (4.5 - 12.1) 117.1 patient-years
N total whose complete data is available 25 111 354 36 16
Drug ETN 25 Anti TNF (Mainly ETN)-111 IFX-89 ETN-205 ADA-66 ETN-36 IFX, ADA and ETN combinations-16 IFX alone 8 ETN alone 5 ETN followed by ADA 1 IFX followed by ADA 1 IFX followed by ETN, then by ADA 1
Biologic Doses received ETN0.8-1 mg/kg once weekly Anti TNF (No data on individual drugs) NA NA NA
Duration of biologic treatment 23 months (mean) Max 8 years NA 11.5 months (348 months) NA
Concomitant drugs MTX 24 (96%) CYS 3 (1.6%) MTX (number NA) NA NA NA
Steroids 10 952.6%) NA NA NA NA
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Brazil Turkey Poland Italy India Turkey
2017 2011 2011 2016 2016 2016
Brunelli46 Kilic47 Zuber48 Verazza49 Saini50 B A Atikan51
0 0 1 1 0 0
Retrospective cohort that included JIA patients eligible to anti-TNF therapy Retrospective chart review Polish registry data collected between January 2003 and March 2010 Retrospective Multicentre Italian Paediatric Rheumatology Study Group led chart-based review Research letter Retrospective chart review of patients who were given biologicals and had received BCG vaccines
N =69 N=132 N=188 N=1038 N=10 N=71
9 (13) 73, (50.7) 13 (7) 50 (4.8) 3 18
22 (32) 79 (42) 329 (31.7)
0 22, (15.3) 27 (14) 139 (13.4) 0 5
12 (17) 30 (16) 325 (31.3) 0
6 (9) 14, (9.7) 1 (0.5) 48 (4.6) 0 20
19 (28) 19, (13.2) 28 (15) 106 (10.2) 7 23
1 (1) 4,(2.8) 2(1) 34 (3.3) 0 5
0 0 8 (4) 7 (0.7) 0 0
2.9 years(0.3-24.6) 5.86 ± 3.77 years Mean ±SD 52 (41.7) months Range- 2-183 months 2.1 (0.6-5.5)years 11 (range 4-41) months 3 years
69 132 39 NA 10 NA
ADA-12 ETN-35 ETN switched to^ ADA 17 ADA^ETN2 ETN ^ IFX 1 IFX ^ ETN ^ ADA 1 ETN ^ ADA ^ IFX 1 ETN 115 IFX 17 ETN + IFX 6 IFX + ADA 4 ETN + ADA 2, ETN-188 ETN-1038 ETN-5 TCZ-5 ABA-1 (switched from TCZ) ETN-41 ADA-21 CANA-5 TCZ-4
NA NA NA NA NA NA
ADA-21.4 (2.3-73.5) ETN-25.6 (0.5-95) IFX-1.9 (0.03-8.5) NA 393 patient-years 2.1 (0.6-5.5) 11 (range 4-41) months 3 years
MTX-60 (87) Dose 25 (5-50) LEF- 23 (33) CYS-13(19) NA 37(95) Mtx749 (72.2) NA NA
31 (45) NA 35(92) 267 (25.7) NA NA
ADA: Adalimumab; ETN: Etanercept; IFX: Inflixim; ABA: Abatacept; CER: Certolizumab; GOL: Golimumab; JIA: Juvenile idiopathic arthritis; AZA: Azathioprine; MTX: Methotrexate; CYS: Cyclosporine; LEF: Leflunomide; SSZ: Sulfasalazine; CAN: Canakinumab; RTX: Rituximab; ANK: Anakinra; TCZ: Tocilizumab; JIA: Juvenile idiopathic arthritis; PA: Polyarticular; SJIA: Systemic onset juvenile idiopathic arthritis; ERA: Enthesitis related arthritis; OA: oligoarticular; Undiff: Undifferentiated.
Table 2. Data of tuberculosis in prospective studies of patients with juvenile arthritis on biologies.
Prospective
Country Turkey Portugal Germany USA and Canada The Netherlands Multicentre-Europe, Latin America and USA Multicenter- 19 countries Japan
Year 2018 2016 2015 2009 2009 2010 2015 2011
Author Aygun52 Mourao53 Horneff54 Giannini55 Prince56 Ruperto57 Constantin58 Imagawa59
Tuberculosis-No of patients 2 (1-ETN) (1-ADA) 2 1- ADA 1-ETN (Skin test conversion) 0 0 0 (But 1 had TB after switching to IFX- Reported as a case report) 0 0 0
Type of article/ paper Single centre cohort From Reuma.pt. database Phase III Randomise Double-Blind Study Phase IV, open-label, multicenter registry Multi-centre (Dutch national registry) Long-term, open-label extension phase of a double-blind, random-ised, controlled withdrawal trial Phase IIIb, open label, multicentre study Open-labelled multicentre study
Type of JIA N =307 N=227 N=41 N=397 N=146 N=186 N=127 N=19
PA-RF+ 18 (5.9) 36 (17.5) 0 351 11 (8) 38 (20%) 0 9
PA-RF- 85 (27.7) 48 (23.3) 0 0 55 (38) 84 (44) 0 8
OA 100 (32.6) 20 (9.7) 0 0 0 0 0 0
OA Extended 33 (16) 0 Included as PA 28 (19) 27 (14%) 60(47.2) 2
ERA/SpA 42 (13.6) 31 (15.1) 20 0 5 (3) 0 38(29.9) 0
SJIA 52 (16.9) 28 (13.6) 0 45 39 (27) 37 (20%) 0 0
PsA 10 (3.3) 10 (4.8) 0 0 8 (5) 0 29(174) 0
Undiff 0 21 (9.8) 0 1 0 0 0 0
Duration of JIA before biologics (Median, IQR) NA 13.7 (10.1) years 2.4 ± (2.1) years 58.1±44.5 ETN 40.7±41.7 ETN+MTX 4.1 years 1,069 days (range 168-1,457 days) NA 4.7 yrs (1-17)
Duration of follow-up (Median) 12 months At least 12 months 48 weeks 36 months (41% completed 36 months) 2.5 years per patient, (range 0.3 to 7.3 years) 589 days 96-weeks 48 weeks* all except 2
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Brazil Finland USA and EU Japan Multicentre Multicentre Germany Multicentre - North America, South America and Europe
2017 2015 2014 2012 2008 2008 2015
Brunelli60 Maarit Tarkiainen61 Kingsbury62 Imagawa63 Lovell64 Lovell65 Gerd Horneff54 Ruperto N66
1- With TCZ 0 1 case of MAC with ADA 0 0 0 0 0 1 Lung infiltrate with negative sputum AFB
Longitudinal data of patients with JIA receiving at least 8 weeks of biological agent documented between August 2004 to March 2016 Observational multicentre study multicentre, open-label, phase 3b single-arm, open-label, multicentre study Multicentre open label extension trial* Not classified as per modified ILAR Randomised, double-blind, stratified, placebo-controlled, multicentre, medication-withdrawal study with a 16-week open-label lead-in phase, a 32-week double-blind withdrawal phase, and an open-label extension phase. Phase III Randomised, Double-Blind Study Randomised, Placebo-Controlled, Double blind Trial
N=107 N=348 N =32 N =25 N=58 n=171 N=20 N=117
52(48.6) 16 (4.6%) 1(3.1) 17(68) 5 40(23.4) 0 117
175 (50.3%) 20(62.5) 8(32) 0 131(76.6) 0 0
19(17.8) 30 (8.6%) 0 0 34 0 0 0
65 (18.7%) 8(25) 0 0 0 0 0
7 (6.5) 22 (6.3%) 0 0 0 0 20 0
28 (26.2) 19 (5.5%) 2(6.3) 0 19 0 0 0
1(0.9) 0 0 0 0 0 0 0
0 1(0.3%) 1(3.1) 0 0 0 0 0
Median 4.8 years (0.1-21) NA 12.3 (9.3) mean months 4.7 (3.72) mean years 8 years 4.0±3.7 3.6±4.0 Years in ADA+MTX and ADA arms 2.4 ± (2.1) years NA
median 3.0 years (0.15-11.5) 50.5 months (range 1.0154.7) Max-120 weeks 60 weeks 58 48 weeks 48 weeks 52 weeks
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Table 2. Data of tuberculosis in prospective studies of patients with juvenile arthritis on biologies. (continued)
Prospective
Exposure in patient years NA 706.92 patient-years 35.6 patient year NA 436.1 patient years NA NA NA
N total whose complete data is available 307 227 38 397 146 153 109 17
Drug ETN 189 ADA 60 ANK 22 CAN 12 IFX 11 TCZ 13 ETN 157 ADA 29 ABA 8 TCZ 2 ANK 11 IFX 19 RTX 1 ETN 41 ETN-397 ETX only 103 ETN+ MTX -294 ETN-146 ABA-186 ETN-127 TCZ-19
Biologic Doses received NA NA ETN treatment (0.8 mg/kg BW, maximum dose 50 mg/week) ETN 0.8 mg/kg/ week, maximum dose 50 mg 0.8 mg/kg once weekly 10mg/kg ABA q4W ETN 0.8 mg/ kg once weekly (QW; max dose, 50 mg) for up to 96 weeks 8 mg/kg TCZ every 4 weeks.
Duration of biologic treatment 42.11 ± 35.78 months (range 2-380 months) 4.5 (3.1) Years 48 weeks NA 1.7 years (range 0.1 to 6.8 years) NA 96 weeks 48 weeks
Concomitant drugs NA MTX- 170 patients SSZ 16 SSZ was allowed MTX 294 Dose-12.6 ±5.3 (ETN) 16.9± 5.9(MTX+ETN) MTX-113 (77) MTX in 74% 57 (30%) Prior biologies NA MTX 100%
Steroids (%) NA NA No NA 90 (62) NA
Other NA NA NA NA NA
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398.3 patient-years (py): 179.1py for ETA, 92.5py for ADA, 21.7py for IFX, 77.8py for ABA and 27.2py for TCZ 710 py-ETN, 591PY-IFX, 188 PY-ADA, 8 PY-RTX, 5.3 PY-ANK, 6.4 PY-ABA, 6.4 PY- TCZ and 1.0 PY- GLM 45.1 PY NA NA NA 29.9 patient year NA
107 348 26 25 9 128 19 117
ETN ADA ABA TCZ IFX ETN 213 IFX214 ADA94 RTX9 ANK-8 ABA-6 TCZ 4 GLM3 ADA31 ADA25 ETN58 ADA171 ETN 20 IFX-117
NA NA 24 mg/m2 (maximum=20 mg/ dose) every other week up to 120 weeks 20 mg for patients weighing <30 kg, and 40 mg for patients weighing >30 kg) eow ETN 0.8 mg/kg/ week fixed dose based on body weight (20 mg for patients weighing <30 kg, and 40 mg for patients weighing >30 kg) eow NA 6mg/kg and 3mg/ kg standard protocol
Median 3.0 years (0.15-11.5 NA 515 (245) days 24 weeks 318 PY 48 weeks 48 weeks 52 weeks and 38 weeks
NA NA MTX 27 (84.4) MTX-20(80) (100) MTX-85(49.7) NA Mtxupto 15mg/m2
NA NA 20(62.5) NA 22 (38%) NA NA NA
NA NA NA NA NA NA NA
Table 3. Data from studies on cohorts/registries of children with Juvenile arthritis on biologies.
Country Germany UK Multicenter member centres 32 countries Germany
Year 2019 2011 2018 2014
Author A Klein67 Southwood68 J Swart32 Schmeling69
Registry Name BIKER Biologics and New Drugs Registry (BNDR) PharmaChild German Biologics JIA Registry
Tuberculosis-No of patients 0 0 24 over all 14 on biologies Total 17 Tb in 14 patients on biologicals 0
Type of article/ paper long-term data from the German BIKER registry Prospectively collected Data Combined data form PharmaChild registry along with German and Swedish registries The registry is a longitudinal multicentre observational study that has been maintained since 2000
Biological agent ADA 584 ETN-483 ETN-3600 ADA-1778 IFX- 705 CER- 33 GOL- 161 TCZ-633 ABA- 420 RTX 103 ANK- 339 CAN- 145 ADA-289
Rheumatological condition JIA N=584 JIA N=483 JIA N= 8274 JIA N=289
PA-RF+ 34 (5.8) 48 (9) 322 (3.9) 17 (6.2)
PA-RF- 203 (34.7) 157 (33) 2183 (26.4) 101 (34.9)
OA 42 11 (2) 2011 (24.3) 28 (9.6)
OA Extended 0 79 (16) 1060 (12.8) 68 (23.5)
ERA 98 38 (8) 924 (11.2) 39 (13.5)
SJIA 0 77 (16) 911 (11) 8(2.7)
PsA 49 30 (6) 285 (3.4) 14 (4.8)
Undiff 11 36 (7) 578 (7.0) 14 (4.8)
Unclassified 0 7 (1) 0 0
Duration of follow- NA NA NA NA
up (Median)
Follow-up in patient years 1082 patient-years (PY) 941 patient-years of follow-up 435.7 patient-years
N total whose complete data is available 584 483 5173 289
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Germany Hungary The Netherlands UK
2017 2011 2011 2019
Horneff70 Sevcic71 Otten72 Fleet73
BIKER Germany National Institute of Rheumatology and Physiotherapy Registry: Hungary Dutch Arthritis and Biologicals in Children Register Biologics for Children with Rheumatic Diseases (BCRD) study
0 0 0 0
Cohort of Systemic JIA Cohort Cohort of children receiving Tumour Necrosis Factor-blocking Agents for in JIA-ERA -collected between 1999-2010 Cohort
ETN-143 TCZ-71 IL-1 Inhib-60 ETN-72 ETN 20 ADA-2(1 switched) IFX-2 (1 switched) RTX- 41
JIA-N=245 JIA-N=72 JIA-N=22 JIA-N=41
0 6(8) 0 13 (33)
0 36(50) 0 14 (35)
0 0 0 2 (5)
0 20(28) 0 9 (23)
0 3(4) 22 0
245 6(8) 0 1 (3)
0 1(2) 0 1 (3)
0 0 0 0
0 0 0 0
NA 12 months 14-28 months 177 days (IQR 109-398)
ETN-n = 143; 355.8PY TCZ-n = 72; 111.6PY n = 60; 116.8PY NA 38.7 patient years 51 person-years
245 22 38
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Treatment duration and drugs 15.1 ± 12.8 months ADA 15.2 ± 13.3 months ADA+ MTX NA ETN- 719 (300-1338) days ADA- 442 (174-927) days IFX- 425 (160-951) days TCZ-351 (126-742) days ABA- 342 (156-715) days ANK- 299 (94-837) days GOL- 270 (106-623) days CAN-351 (133-1032) days RTX-42 (24-87) days CER-166 (106-309) days 1.2 years (IQR 0.58-1.88) in Biologics naive groups and 1.13 years (IQR 0.61-1.94) in previous biologic usage group
Concomitant drugs MTX in 356 patients NA NA MTX- 171 (59.2) LEF-13 (4.5) SSZ- 6 (2.1)
Steroids NA NA NA 102 (35.3)
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ETN-n = 143; 355.8PY TCZ-n = 72; 111.6PY n = 60; 116.8PY ETN 0.4 mg/kg body weight twice weekly or ADA 40 mg every 2 weeks 12 months NA 51 person-years
MTX-185 NA MTX-17(77) SSZ-2 (9) NA
176 NA 3 (14) NA
Table 4. Summary of available data that could be analysed for tuberculosis incidence in paediatric rheumatology with various biologics.
Drug/disease JIA Lupus Myositis Autoinflammatory syndromes Vasculitis
Infliximab 783(A) 547(B) 0 0 10(C)9(B)
Adalimumab 2925 (A) 489(B) 0 0 1(B)11(C)
Etanercept 6974 (A) 2019(B) 0 0 1(C)
Certolizumab 70 (A)0(B) 0 0 0
Golimumab 385 (A) 3(B) 0 0 0
Rituximab 210 (A) 51(B) 75(B) 48(E) 185(C) 3(C)
Belimumab 0(A) 0(B) 39(B) 0 0
Anakinra 810 (A) 63(B) 0 0 29(A) 27(B)1(D) 0
Canakinumab 241 (A) 0 0 4(A)109(E) 0
Tocilizumab 998 (A) 0 0 2(B) 9(C)
Abatacept 521 (A) 0 0 0
Combination of anti TNFs 3(A) 0 0 0
A: Registry data; B: Cohort; C: Case series; D: Anecdotal reports; E. Trials.
Supplementary Table 1. Data of tuberculosis in paediatric lupus and myositis on biologies.
Retrospective
Drug RTX RTX RTX+CYC RTX RTX
Country Greece Greece Saudi-Arabia Australia, CaNAda CaNAda
Year 2011 2011 2013 2014 2015
Author Maria TrachaNA71 Maria TrachaNA71 Ashwaq72 Dale73 M Olfat74
Tuberculosis- No of patients 0 0 0 0 0
Type of article/ paper Case series Case series Case series Case series Case series
N with complete data 4 4 16 18 24
Disease classification SLE-LN SLE-LN SLE NPSLE Hematologic SLE
Duration of follow-up (Median, IQR, years) 1.33 1.33 3.2 2.5 3.6 (1.9-5.7)
Total no of infection events 0 0 2 NA 1
Major/ serious Infections-Number of events 0 0 2 NA 1
Opportunistic infections 0 0 NA NA NA
Minor Infections- Number of events 0 0 NA NA NA
Death 0 0 0
Biologic Doses received 375/m2, 4 doses 375/m2, 4 doses 375mg/m2, 2 doses NA 375/m2, 4 doses
Duration of biologic treatment One cycle One cycle One cycle for 12, 2 cycle for 2,4 cycles for 2. Each 6 months apart NA NA
Concomitant drugs MMF (all) MMF (all) CYC, HCQ NA MMF (5), CYC (1)
Steroids Yes (all) Yes (all) NA Yes (all) Yes, in 17
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Prospective
RTX RTX RTX Belimumab RTX RTX
Portugal USA UK USA USA Multicenter
2016 2015 2015 2015 2014 2013
Reis754 with JSLE and 1 with extended oligoarticular JIA, received 10 cycles of RTX (23 infusions Tambrelli76 Watson77 Hui yen78 Lehman79 Oddis80
0 0 0 0 0 0
Case series Case series Cohort Cohort (adult and paediatric) Cohort randomized, placebo-phase controlled trial
5 104 63 39 12 48
SLE, JIA 50 SLE + 54 other AIRD SLE SLE SLE-LN JDM
2 2.2 NA 0.5 5 44 weeks
2 22 2 NA 2 NA*
2 20 2 7 2 NA*
1 (Cryptococcosis) 0 1 CMV NA NA NA*
NA 2 NA NA NA NA*
0 1 ILD 0 0 0
750 mg, 2 doses 750 mg/ m2 (maximum 1 g), administered 2 weeks apart NA 750 mg/m2 administered twice 2 weeks apart 750mg/m2, 2 doses at 0,6,18 months 575 mg/m2 if BSA<1.5 m2 and 750 mg/m2 if BSA>1.5m2
NA Median 2 (1-11) courses NA 104 courses 18 months NA
MMF (4) MMF, CYC, HCQ MMF, CYC, AZA (24) MMF (49%), HCQ (92%), AZA (23%) CYC NA
Yes (all) Yes, in all Yes, in 93% Yes, in 82% Yes, in all Yes, in all
RTX: Rituximab; CYC: Cyclophosphamide; USA: United States of America; UK: United Kingdom; SLE: Systemic lupus erythematosus; NPSLE: neuropsychiatric systemic lupus erythematosus; JIA: Juvenile idiopathic arthritis; LN: Lupus nephritis; AIIRD: Autoimmune inflammatory rheumatic diseases; IQR: Interquartile range; NA: Not available; CMV; Cytomegalovirus; ILD: Interstitial lung diseases; MMF: Mycophenolate mofetil; HCQ: hydroxychloroquine; AZA: Azathioprine; JDM: Juvenile dermatomyositis; BSA: Body surface area. *cannot differentiate between data from adult and juvenile DM
Supplementary Table 2. Data of tuberculosis in paediatric vasculitis on biologies.
Retrospective Prospective
Drug IFX 5 ETN 1 RTX 3 IFX 3 ADA 2 TCZ 3 IFX 9 ADA 1 TCZ 2 TCZ 6 ADA-9 IFX 1
Country UK UK Canada Turkey Kazakhstan Turkey
Year 2013 2015 2017 2018 2019 2017
Author Despina Eleftheriou81 Despina Eleftheriou82 Florence A. Aeschlimann83 SezginSahin84 Dimitri Poddighe85 Nikos N. Markomichelakis86
Tuberculosis-No of patients 0 0 0 0 0 0
Type of article/ paper Single centre Single tertiary referral centre Single-centre cohort Review of hospital records Case-based review Case series (adults and juvenile)
N with complete data 9 6 10 NA 9 1 (rest were adults)
Disease Polyarteritis nodosa Takayasu arteritis Takayasu arteritis Takayasu arteritis Bechet's Diseases Behcet's Disease
Duration of follow-up (Median, years) 3 (2.1-5) NA 2.1 (IQR1.2-5.5) NA 0.25-2 1
Total no of infection events NA NA 0 NA NA NA
Major/ serious Infections-No of events NA NA 0 NA NA NA
Opportunistic infections NA NA NA NA NA NA
Minor Infections- No of events NA NA NA NA NA NA
Tuberculosis- No of patients NA NA 0 NA 0 0
Duration of biologic treatment (months) NA NA Variable, 3-20 NA 3-24 3-24
Concomitant drugs NA NA MTX (3), AZA (1) NA MMF (1), AZA (1) AZA
Steroids Yes, all NA Yes, in 3 NA NA Yes
IFX: Infliximab; ETN: Etanercept; RTX: Rituximab; ADA- Adalimumab; TCZ: Tocilizumab; UK: United Kingdom; USA: United States of America; IQR: Interquartile range; NA: Not available.
Country Turkey Thailand Alabama, USA Spain
Year 2017 2009 2017 2015
Author Acar87 SuwanNAlai88 Stoll M89 Hernández90
Tuberculosis- No of patients 1 (JIA) on ADA 0 1 (IBD) on ADA 0
Type of article/ paper Retrospective analysis Retrospective analysis of data from single centre Retrospective analysis Cohort observational study
Total number N=73 N=5 N=1033 n=214
Type of AIIRD
JIA 16 (21.9) 3 613 163 (73.6)
SLE 0 0 13 0
Vasculitis (Including BD) 3 (4.1) 0 5 0
SSc/MCTD 0 0 0 0
Sarcoidosis 3 (4.1) 0 17 0
IIM 0 1 3 0
PSS 0 0 7 0
Uveitis 39 (53.4) 0 31 8 (3.7)
IBD 8 (11) 0 265 46 (20.8)
Autoinflammatory 0 1 11 3 (1.5)
Others 4(5.5) 0 35 0
Duration of follow-up (Median) 18 (6-60) months NA 1564 person-years 641 patients-year, Median- IQR 2.3 years (1.4-4.3).
N total whose complete data is available 73 5 1033 214
Total no of infection events NA NA NA NA
Major/ serious Infections- No of events NA NA NA NA
Opportunistic infections NA NA NA NA
Minor Infections- No of events NA NA NA NA
Drug ADA-39 ETN-22 IFX-12 ETN-3 IFX-2 IFX-527 ADA-469 ETN-324 CER-9 GOL-6 ETN-51.7% ADA (31.0 %) IFX-17.3%
Biologic Doses received NA NA NA NA
Duration of biologic treatment NA NA IFX- 840.6 ADA- 495.3 ETN-194.6 CER-2.0 GOL-1.5 Patient years ETN 1.9 [1.8-3.7]; ADA 1.8 [1.2-2.6]; and IFX 2.1 [1.4-3.3] patient years
Concomitant drugs MTX-37 (50.7) CYS-13 (17.8) AZA-9 (12.3) NA NA NA
Steroids 45 (61.6) NA NA NA
Other NA NA NA NA
Supplementary Table 4. Prevalence of tuberculosis in paediatric autoinflammatory diseases.
Retrospective Prospective
Country France France Italy USA
Year 2012 2009 2010 2017
Author Galeotti91 Neven92 Lepore93 Arostegui94
Tuberculosis- No of patients 0 0 0 0
Type of article/ paper E-mail survey among the members of the French Paediatric Society for Paediatric Rheumatology (SOFREMIP) -Registry based Data from medical records of NOMID/CINCA syndrome patients from 2 centres Registry based Open label Phase II
N with complete data 6 8 17
Disease classification MKD n=6 NOMID/CINCA n=8 CINCA/MWS-n=17 HIDS n-6
Duration of follow-up (Median, IQR, years) 11-21 months 26-42 months 37.5 months (range, 12 to 54 months) Max-24 months
Total no of infection events 2 0 NA NA
Major/ serious Infections-Number of events 1 0 NA NA
Opportunistic infections 0 0 0 0
Minor Infections-Number of events 1 0 NA NA
Death 0 0 0 0
Drug CAN-4 ANK- 4 ANK-8 ANK-17 CAN-6
Biologic Doses received ANK-1 to 5mg/kg/day CAN-2 to 7 mg/kg every 8 weeks ANK- 3-10 mg/kf/day ANK-starting dosage of 1 mg/ kg/d (maximum, 100 mg) 300 mg (or4 mg/ kg for patients weighing<40 kg)
Duration of biologic treatment 15 (4-72) months 26-42 months NA NA
Concomitant drugs NA NA NA NA
Steroids 1 NA NA NA
MKD: Mevalonate kinase deficiency; NOMID: Neonatal-onset multisystem inflammatory disease; CINCA: Chronic infantile neurologic, cutaneous, articular syndrome; MWS: Mückle Wells Syndrome; crFMF: Colchicine resistant familial Mediterranean fever; TRAPS: Tumor necrosis factor associated periodic fever; FCAS: familial cold autoinflammatory syndrome; HIDS: Hyperimmunoglobulinemia D with Periodic Fever Syndrome; RTX: Rituximab; CYC: Cyclophosphamide; USA: United States of America; UK: United Kingdom; SLE: Systemic lupus erythematosus; NPSLE: neuropsychiatric systemic lupus erythematosus; JIA: Juvenile idiopathic arthritis;
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UK Multicenter Canada, USA, Germany, Ireland, Spain, Turkey, Switzerland, Russia, Japan Multicenter Germany USA
2004 2018 2011 2011 2012
Hawkins95 Benedetti96 Kuemmerle-Deschner97 Kuemmerle-Deschner98 Sibley99
0 0 0 0 0
Prospective follow-up Randomised controlled trial followed by an open label follow-up open-label, phase III study conducted at 33 centres Single centre observational study Cohort-5 year follow-up
1 53 46 5 20
MWS-n=1 crFMF-n-14 MKD-n=28 TRAPS—n=14 FCAS-5 MWS-23 NOMID-18 MWS-5 NOMID-22
3 months 16 weeks 290 days (29-625 days) 11 months (range 5-14 months) Max -5 years 148.1 patient-year
0 NA NA 5 NA
0 8 cr-FMF-3/100 PY MKD-7/100 PY TRAPS-0/100 PY NA 0 3
0 0 0 0 0
0 NA NA 5 NA
0 0 0 0 0
ANK-1 CAN-56 CAN-47 ANK-5 ANK-22
ANK-100 mg once daily CAN-150 mg, or 2 mg per kilogram of body weight for patients weighing <40 kg every week 150 mg or 2 mg/kg (<40 kg) every 8 weeks for up to 2 years 1-2 mg/kg in patients weighing <40 kg and 100 mg for patients weighing >40 kg started at 1 mg/kg by daily subcutaneous injection. Stepwise dose increases of 0.5-1 mg/kg per injection were made as frequently as every 2 weeks to achieve laboratory and organ inflammation remission
3 months Exposure in PY crFMF- 45.6 MKD- 51.0 TRAPS-39.2 290 days (29-625 days) At least 2 weeks 60 months
NA Colchicine (100%) NA NA NA
NA NA NA NA NA
LN: Lupus nephritis; AIIRD: Autoimmune inflammatory rheumatic diseases; IQR: Interquartile range; NA: Not available; CMV: Cytomegalovirus; ILD: Interstitial lung diseases; MMF: Mycophenolate mofetil; HCQ: hydroxychloroquine; AZA: Azathioprine.
