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 Table of Contents  
BRIEF REPORT
Year : 2020  |  Volume : 15  |  Issue : 2  |  Page : 130-133

Tuberculosis is a significant problem in children on biologics for rheumatic illnesses: Results from a survey conducted among practicing rheumatologists in India


1 Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
2 Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
3 Department of Rheumatology, Amrita Vishwa Vidyapeetham, School of Medicine, Kochi, Kerala, India

Date of Web Publication29-May-2020

Correspondence Address:
Dr. Latika Gupta
Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injr.injr_191_19

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  Abstract 


Background: India is endemic for tuberculosis (TB) and the use of immunosuppressants is likely to accentuate the problem. Whilst steroids and conventional disease modifying anti-rheumatic drugs (DMARDs) are believed to increase the risk for tuberculosis, certain biologics such as B cell depleting agents and Interleukin-17 inhibitors are not perceived in the same light. Thus, an attempt was made to capture physicians' perspectives and patterns of biologic DMARDs use in paediatric rheumatology as well as their experience with the occurrence of Tuberculosis in children with rheumatic and musculoskeletal diseases (RMD).
Methods: An electronic survey developed on an online cloud-based website (Survey Monkey®) was served to physicians practicing rheumatology in India. Eligible participants (physicians practicing rheumatology) had a week to voluntarily complete the three-minute long questionnaire. While factual set explored observations, opinion set of questions graded perspectives using the Likert scale. Descriptive statistics and figures were obtained from surveymonkey.com.
Results: Of the 52 respondents, most of whom were practicing rheumatologists (86.5%), 23 (44.2%) recalled the occurrence of TB after starting biologics. Of these, 13 (25%) encountered this situation in more than one patient. Extra-pulmonary forms of TB were more common (26 of 42, 61.9%), though TB was reported more often while the patient was on biologics than after discontinuing them (n=20 versus 8). Screening strategies varied, with Mantoux, interferon gamma release assay and chest radiographs being used together by most (21, 40%) physicians. Nineteen (52.8%) believed that TB in this setting required longer therapy while 7 (20%) thought adverse drug effects were seen often. Equal number of respondents thought that TB induced diosease flares.
Conclusion: TB occurs often in children with RMDs treated with bDMARDs in India. Extra-pulmonary forms are more common and consensus on screening strategies poor. Amongst physicians, there is a perceived risk of prolonged anti-tubercular therapy and adverse drug effects though not of disease flares induced by TB.

Keywords: Biological factors, India, pediatric, rheumatology, tuberculosis


How to cite this article:
Kavadichanda G C, Gupta L, Balan S. Tuberculosis is a significant problem in children on biologics for rheumatic illnesses: Results from a survey conducted among practicing rheumatologists in India. Indian J Rheumatol 2020;15:130-3

How to cite this URL:
Kavadichanda G C, Gupta L, Balan S. Tuberculosis is a significant problem in children on biologics for rheumatic illnesses: Results from a survey conducted among practicing rheumatologists in India. Indian J Rheumatol [serial online] 2020 [cited 2020 Oct 30];15:130-3. Available from: https://www.indianjrheumatol.com/text.asp?2020/15/2/130/282825




  Introduction Top


India is endemic for tuberculosis (TB), and the use of immunosuppressants is likely to accentuate the problem. High prevalence of TB has previously been reported in juvenile lupus in Indian patients.[1] However, the risk attributability to various drugs used in rheumatology is unclear.

While steroids and anti-tumour necrosis factors (TNFs) are thought to increase the risk for TB, certain other biologics such as rituximab, abatacept, and interleukin-17 inhibitors are not perceived in the same light. Guidelines have mandated screening and timely exclusion of patients with latent TB before embarking on these therapies. While it seems plausible that the use of these drugs might incur a reduced risk of TB by their steroid-sparing effect, this could be a result of meticulous screening as well.

Thus, an attempt was made to capture physicians' perspectives and patterns of biologic disease-modifying antirheumatic drug (bDMARDs) use in pediatric rheumatology as well as their experience with the occurrence of TB in children with rheumatic and musculoskeletal diseases (RMDs).


  Methodology Top


Design of the questionnaire

An electronic open survey was developed on an online cloud-based website (Survey Monkey®). Questions were designed to explore prevalence practices, experiences, and beliefs of physicians treating rheumatic disorders toward the use of biologics for treating children with rheumatic disorders in India.

Overall, the questionnaire featured 19 questions, most of which were multichoice. The questions were divided into factual and opinion set. A Likert scale was used to rate responses in the opinion set. For most questions, the respondents had to choose one out of five responses. While five questions were population characteristic identifiers, the rest sought understanding of the patterns of biologic use and the observations pertaining to that. The average survey time was 3 min. The respondents could not change or review the answers after submission. Of the 19 questions, all were mandatory apart from identifier (name). The final questionnaire is presented as [Supplementary Table 1]. IP checks were done to avoid duplicated responses from a single respondent. All questions that were mandatory (apart from the last one name of respondent) were analyzed. Two rheumatology consultants reviewed the questions and confirmed them to be representative of the content validity of the survey.[Table 1]
Table 1: Respondent characteristics

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Physician selection

The questionnaire was served to adult and pediatric rheumatologists treating children with RMDs. The survey was circulated over email and WhatsApp® groups of adult and pediatric rheumatology societies of India in the 2nd week of December 2019 [Figure 1]. Eligible participants (physicians practicing rheumatology) had a week to voluntarily complete the questionnaire. Consent was implied if the participants responded, and no incentives were offered for survey completion. We adhered to the Checklist for Reporting Results of Internet E-surveys to report the data.[2] The data were collected, and descriptive statistics were obtained from surveymonkey.com.
Figure 1: Flowchart of methods including survey dissemination

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  Results Top


Characteristics of survey respondents and experience in prescribing biologic disease-modifying antirheumatic drugs

The survey was completed by 52 physicians experienced in treating rheumatic diseases [Table 1]. Majority (45/52) of the respondents were rheumatologists, four were internists, and three were pediatricians. Forty-four participants had experience in treating children with RMDs. Most of them (45/52) had at least 3 years of experience, of which 16 had over 10 years of experience in treating childhood RMDs. All but three had ever-prescribed bDMARD for children with RMD, of which 18 had treated at least twenty children with biologics. Juvenile idiopathic arthritis was the most common indication for prescribing bDMARDs followed, on occasion, by lupus and vasculitis.

Number and site of tuberculosis cases recalled

While most respondents felt that the use of biologics increased the risk of TB [Figure 2]a, 23 of 52 (44.2%) could recall the occurrence of TB after starting biologics. Of these, 13 (25%) encountered this situation in more than one patient. Extrapulmonary forms of TB were fairly common and were seen in 26 of 42 (61.9%) patients [Figure 2]b. TB was reported more often while the patient was on biologics than after discontinuing them [Figure 2]c and [Figure 2]d.
Figure 2: Overview of incidence, site, and outcome of tuberculosis among children on biologics. (a) Biologic use in children is associated with increased risk of tuberculosis, (b) Sites of tuberculosis, (c) How often did the patients develop tuberculosis while on biologics? (d) How often did they develop tuberculosis after stopping biologics? (e) These patients with tuberculosis required prolonged course of antitubercular drugs, (f) Tuberculosis led to mortality

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Perceptions about course, treatment, and mortality

Majority (52.8%) of the physicians felt that a prolonged course of antitubercular drugs (ATT) is needed in children contracting TB after the use of bDMARDs [Supplementary Table 2]. An equal number of respondents felt that TB may or may not alter the RMD disease activity. Most physicians felt that there were no drug interactions or a higher incidence of adverse events with ATT. TB contributed to mortality according to ten participants [Figure 2]e and [Figure 2]f.{Table 2}



Screening strategies for latent tuberculosis

All the physicians reported screening for latent tuberculosis (LTB) prior to starting bDMARDs. The most common screening strategy was a combination of tuberculin skin test (TST), interferon gamma release assay, and chest radiograph in 21 (40.4%) followed by radiograph with TST (14, 21.9%) as the second most common practice [Supplementary Table 2].

Suggestions to reduce risk and burden

Thirty respondents felt that rigorous screening for latent TB should be employed prior to starting bDMARDs. Others felt that the indication for the use of biologics should be more stringent in children, while few others believed that closer follow-up be mandated once they are on bDMARDs [Supplementary Table 2].


  Discussion Top


Although India is known to be a high incidence region for TB at 199/100,000 population (10% of which are children),[3] there is a dearth of data on the occurrence of infections in children on bDMARDs for RMDs. We found that physicians believe there is heightened risk for TB, and it contributes to prolonged therapy and, at times, mortality.

Extrapulmonary TB was more common among children on bDMARDs. This distribution seems to be an exaggeration of the natural form of TB in children where extrapulmonary TB is more common than in the adults.[4] A partially matured immune system further suppressed by chronic diseases and immunosuppressive agents may be a reason for this. Further studies quantifying the bacillary burden and immunophenotyping of the immune cells are required to establish the above hypothesis.

Anti-TNF inhibitors have consistently showed a higher predisposition to TB reactivation in comparison to other bDMARDS.[4],[5] Although we did not collect information on the type of biologic used, infliximab can cause intense immunosuppression in the first few months, with peak occurrence of TB reported at 5.5 months as compared with 13 months with adalimumab in adults.[6] It seems plausible that devising region-specific protocols, where loading dose is obviated, might reduce the risk of TB in this part of the world.[7] The fact that TB developed even after the stoppage of bDMARDs in a handful limits attributability though it substantiates the need for cautious follow-up even after the biologics are stopped.

Disease occurrence and phenotype could differ in children from that in adults due to varied physiology, lesser comorbidities, and hesitation on part of the physician to prescribe polypharmacy in children. Glaring growth stunting can be a deterrent for excessive use of glucocorticoids in the long term. Children are likely to be screened for LTB aggressively. One more important factor is the Bacillus Calmette–Guérin vaccination in children covered under the universal immunization program. The vaccine has shown to protect children from both pulmonary and extrapulmonary TB at least up to the age of 10 years.[8]

The only study on the use of prophylaxis in 97 adults with lupus reported a remarkable decline in TB from 11.6% to 2% over a 2-year observation period in Mumbai, India.[9] Another article confirmed that in patients who seroconvert for TST while on biologics, TB could be prevented with isoniazid prophylaxis.[10] However, the risk of polypharmacy and increased pill burden assumes greater importance in children, thus more data are needed to substantiate this as a long-term goal.

Caution is advised in interpreting the data from a nonpiloted survey served across groups, which had a significant overlap in participants due to the possibility of clustered responses from geographically similar areas as well as recall bias. As response to the survey was on a volunteer basis, the possibility of selection bias exists. Nevertheless, the findings here raise concern and call for structured data collection throughout the country, which is best achieved through the formulation of a nation-wide biologic registry to gather data on prevalent infections in this part of the world.


  Conclusion Top


TB occurs often in children with RMDs treated with bDMARDs in India. Extrapulmonary forms are more common, and consensus on screening strategies is poor. Among physicians, there is a perceived risk of prolonged antitubercular therapy and adverse drug effects though not of disease flares induced by TB.

Acknowledgments

The authors thank all respondents for taking this survey.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Key results

Biologic use in children with rheumatic disorders was found to be associated with the occurrence of TB by 41.1% (23/51) of rheumatologists. 13/23 (56.5%) encountered TB more than once.

Extrapulmonary forms are as common (61.9%) as pulmonary TB.

40.4% of rheumatologists use triple screening before administering biologics.

57.7% of respondents felt that screening strategies can be improved to reduce risk further.



 
  References Top

1.
Gupta L, Srivastava P, Agarwal V, Lawrence A, Misra R, Aggarwal A. High incidence of tuberculosis in SLE patients: APL15-0273. Int J Rheum Dis 2015;18:124-5.  Back to cited text no. 1
    
2.
Eysenbach G. Improving the quality of Web surveys: The checklist for reporting results of internet e-surveys (CHERRIES). J Med Internet Res 2004;6:e34.  Back to cited text no. 2
    
3.
TB Statistics India – Latest 2018 Figures. TBFacts. Available from: https://tbfacts.org/tb-statistics-india/. [Last accessed on 2019 Dec 16].  Back to cited text no. 3
    
4.
Datta M, Swaminathan S. Global aspects of tuberculosis in children. Paediatr Respir Rev 2001;2:91-6.  Back to cited text no. 4
    
5.
Ranza R, de la Vega MC, Laurindo IM, Gómez MG, Titton DC, Kakehasi AM, et al. Changing rate of serious infections in biologic-exposed rheumatoid arthritis patients. Data from South American registries BIOBADABRASIL and BIOBADASAR. Clin Rheumatol 2019;38:2129-39.  Back to cited text no. 5
    
6.
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;69:522-8.  Back to cited text no. 6
    
7.
Chaturvedi V, Singal V, Marwaha V, Pispati PK, K. Rao UR, Joshi VR, et al. No case of tuberculosis with low dose infliximab without loading schedule in ankylosing spondylitis: A one year open label study of toxicity and efficacy in 108 patients abstract no 15. Abstract Book APLAR. Jeju, Korea: Asia Pacific League of Associations for Rheumatology Congress; 2004. p. 14.  Back to cited text no. 7
    
8.
Abubakar I, Pimpin L, Ariti C, Beynon R, Mangtani P, Sterne JA, et al. Systematic review and meta-analysis of the current evidence on the duration of protection by bacillus Calmette-Guérin vaccination against tuberculosis. Health Technol Assess 2013;17:1-372, v-vi.  Back to cited text no. 8
    
9.
Gaitonde S, Pathan E, Sule A, Mittal G, Joshi VR. Efficacy of isoniazid prophylaxis in patients with systemic lupus erythematosus receiving long term steroid treatment. Ann Rheum Dis 2002;61:251-3.  Back to cited text no. 9
    
10.
He D, Bai F, Zhang S, Jiang T, Shen J, Zhu Q, et al. High incidence of tuberculosis infection in rheumatic diseases and impact for chemoprophylactic prevention of tuberculosis activation during biologics therapy. Clin Vaccine Immunol 2013;20:842-7.  Back to cited text no. 10
    


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