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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 11  |  Issue : 2  |  Page : 175-182

Active tuberculosis infection in moroccan patients with rheumatic diseases under biologic therapy: A multicenter national study


1 Department of Rheumatology B, El Ayachi Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
2 Department of Rheumatology, Faculty of Medicine, Benha University, Banha, Egypt
3 Department of Rheumatology B, El Ayachi Hospital, Faculty of Medicine and Pharmacy, Mohammed V University; Laboratory of Physiology, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
4 Department of Rheumatology A, El Ayachi Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
5 Department of Rheumatology, Mohammed V Military Hospital, Rabat, Morocco
6 Department of Rheumatology, CHU Ibn Rochd, Casablanca, Morocco
7 Department of Rheumatology, CHU Hassan II, Fez, Morocco
8 Department of Rheumatology, Moulay Ismail Military Hospital, Meknes, Morocco
9 Department of Rheumatology, Avicenne Military Hospital, Marrakech, Morocco
10 Department of Rheumatology, CHU, Oujda, Morocco
11 Department of Rheumatology, First Medical and Surgical Center, Agadir, Morocco
12 Department of Rheumatology, Arrazi Hospital, CHU Mohammed VI, Marrakech, Morocco
13 Department of Rheumatology, CHU, Tangier, Morocco
14 Department of Public Health Laboratory, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco

Date of Submission21-Aug-2020
Date of Decision27-Mar-2022
Date of Acceptance27-Apr-2022
Date of Web Publication14-Jun-2022
Date of Print Publicaton14-Jun-2022

Correspondence Address:
Ilham Aachari
Department of Rheumatology B, El Ayachi Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Impasse Souissi, Rabat 10100
Morocco
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmy.ijmy_153_20

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  Abstract 


Background: The aim of this study was to evaluate the prevalence of active tuberculosis (TB) infection in Moroccan patients with rheumatic diseases under biologic therapy, and to describe the demographic characteristics of these patients as well as to explore potential risk factors. Methods: This 14-year nationally representative multicenter study enrolled Moroccan patients with rheumatic diseases who had been treated with biologic therapy. Patient medical records were reviewed retrospectively for demographic characteristics, underlying rheumatic diseases, associated comorbidities, and TB-related data. Results: In total, 1407 eligible patients were studied, detailed records were obtained for only 130 patients; 33 cases with active TB were identified at an estimated prevalence rate of 2.3%. The mean age was 42.9 ± 12 years and 75.8% were males. Ankylosing spondylitis accounted for 84.8% of active TB cases, and the majority of the cases (31/33) occurred among antitumor necrosis factor-alpha (TNF-α) users. A total of 8 out of 33 patients were positive at initial latent TB infection (LTBI) screening by tuberculin skin test and/or interferon-gamma release assay. Consumption of unpasteurized dairy products (odds ratio [OR], 34.841; 95% confidence interval [CI], 3.1–389.7; P = 0.04), diabetes (OR, 38.468; 95% CI, 1.6–878.3; P = 0,022), smoking (OR, 3.941; 95% CI, 1–159.9; P = 0.047), and long biologic therapy duration (OR, 1.991; 95% CI, 1.4–16.3; P = 0.001) were identified as risk factors for developing active TB. Conclusion: Moroccan patients with rheumatic diseases under anti-TNF-α agents are at an increased TB risk, especially when risk factors are present. Strict initial screening and regular monitoring of LTBI is recommended for patients living in high TB prevalence areas.

Keywords: Biological therapies, disease-modifying antirheumatic drugs, infections and arthritis, rheumatoid arthritis, spondylarthropathies


How to cite this article:
Aachari I, Tahiri L, Elolemy G, Taik FZ, Afilal S, Fellous S, Berkchi JM, Rkain H, Bahiri R, Majjad A, Achemlal L, Ousehal S, Nassar K, Mkinsi O, Mahha FZ, El Aissaoui A, Chaoui I, Harzy T, Youssoufi T, Hassikou H, Kherrab A, Niamane R, Eddarami J, Ichchou L, Ghozlani I, El Bouchti I, Abourazzak FZ, Razine R, Allali F. Active tuberculosis infection in moroccan patients with rheumatic diseases under biologic therapy: A multicenter national study. Int J Mycobacteriol 2022;11:175-82

How to cite this URL:
Aachari I, Tahiri L, Elolemy G, Taik FZ, Afilal S, Fellous S, Berkchi JM, Rkain H, Bahiri R, Majjad A, Achemlal L, Ousehal S, Nassar K, Mkinsi O, Mahha FZ, El Aissaoui A, Chaoui I, Harzy T, Youssoufi T, Hassikou H, Kherrab A, Niamane R, Eddarami J, Ichchou L, Ghozlani I, El Bouchti I, Abourazzak FZ, Razine R, Allali F. Active tuberculosis infection in moroccan patients with rheumatic diseases under biologic therapy: A multicenter national study. Int J Mycobacteriol [serial online] 2022 [cited 2022 Jul 6];11:175-82. Available from: https://www.ijmyco.org/text.asp?2022/11/2/175/347511




  Introduction Top


Tuberculosis (TB) is a major health problem worldwide, occurring mainly in low-income countries and classified as one of the first ten causes of mortality.[1] Latent TB infection (LTBI) is the reservoir of the TB epidemic.[2] It is estimated that up to a third of the world's population is infected with Mycobacterium tuberculosis (Mtb) with approximately 5%–10% lifetime risk of progressing to active TB in immune-competent hosts.[3],[4]

Over the last 20 years, biological disease-modifying antirheumatic drugs (DMARDs, herein referred to as biologic therapy) have guaranteed significant gains in the treatment of different rheumatic diseases. Several agents targeting different levels of immune response are currently available in practice, including interleukin-6 (IL) inhibitor, anti-IL-1, anti-IL-12/23, anti-CD20, anti-CD28, and antitumor necrosis factor-alpha (anti-TNF-α) agents.[5] TB reactivation in patients with LTBI has been reported for anti-TNF-α and to a lesser extent for nonanti-TNF-α agents.[6],[7] Cytokine TNF-α plays a vital role in the host defense mechanism against Mtb and in the formation of granuloma that hinders the spread of infection.[8]

Several registers worldwide[9],[10] have recorded an increased incidence of TB in patients with rheumatoid arthritis (RA) under TNF-α inhibitors. The risk is further increased if anti-TNF-α agent is combined with immune modulator.[11] Over half of the cases were extrapulmonary disease that mostly occurred in endemic areas.[4] Therefore, screening for LTBI before initiating anti-TNF-α therapy is mandated by current guidelines.[12],[13] Precise documentation of exposure, chest X-ray (CXR), and use of tuberculin skin test (TST) and/or interferon-gamma release assays (IGRAs) are all required for screening.[14]

Morocco is ranked as one of the heavily burdened TB countries. In 2017, 30,897 new cases were notified in Morocco, and the estimated incidence was 99 new cases/100,000 population. This public endemic problem justifies the settlement of the National TB Control Program established by the Ministry of Health in Morocco.[15]

The objective of this study was to determine the prevalence of active TB infection in Moroccan patients with rheumatic diseases under biologic therapy. An additional objective was to describe the demographic characteristics of these patients and to explore the potential risk factors.


  Subjects and Methods Top


This is a 14-year (from June 2005 to April 2019) controlled study with retrospective data collection based on computerized database and medical records of patients with rheumatic diseases followed at Rheumatology Departments of different Moroccan University Hospitals. We conducted a case–control study in order to identify risk factors that may contribute to active TB in patients receiving biologic agents by comparing subjects who have that condition with controls (patients with rheumatic diseases under biological therapy who did not develop active TB).

Type of sampling and reasons for selection

All patients having rheumatic diseases who received biological therapy (Anti TNF and non Anti TNF) and followed up from June 2005 to April 2019 at our Outpatient Department were included.

All subjects were regularly followed in the rheumatology outpatient clinic of a tertiary university hospital at 3 month intervals, with the possibility of unscheduled visits when necessary. All records of the patients have been stored in the archives of the nine rheumatology departments that participated in the study, via traditional archiving (non-electronic platforms). There was no change in the methods for saving and recovering data during the period included in the study. All cases of active tuberculosis infection have been notified and listed in the archives, and only 33 cases of active TB have been notified in the period of the study. Detailed information concerning the demographic characteristics of the patients (age, sex, marital status, educational level, residence (urban or rural)) were recorded. Besides, other data were collected regarding history of smoking, consumption of unpasteurized dairy products, associated co-morbidities and underlying rheumatic disease characteristics (disease duration, concomitant /previous biologic therapy and its duration, conventional synthetic Disease Modifying Anti Rheumatic Drug (csDMARDs), and steroid therapy). Data on HIV and other immunosuppressive diseases were sought but were not available. Furthermore, TB disease related data (past history of TB, contact with active TB patients during the past two years, site and form of TB, TST and IGRA results, and LTBI prophylaxis) were recorded.

All patients met the following inclusion criteria: (1) 18 years or older, (2) diagnosed with rheumatic diseases, and (3) treated with biologic therapy. Exclusion criteria were being younger than 18 years old and the existence of a history of other immunosuppressive disease, HIV infection or a history of cancer.

The diagnosis of LTBI is based on demonstration of a specific immune response against Mtb, with or without live bacteria, in absence of clinical or radiological evidence of active TB. The patients were screened for LTBI by TST and IGRA (QuantiFERON-TB Gold [QFT-G]). TST was performed by intradermal injection of 0.1 ml of purified protein derivative on the volar side of the forearm according to the Mantoux method. The diameter of skin induration was recorded in millimeters 48–72 h after initial inoculation and the result was considered positive if skin induration was was ≥5 mm24. In Moroccan institutions, QFT-G is the IGRA test available. Assay was performed and interpreted according to instructions of the manufacturer. A positive TST and/or IGRA was an indication for initiation of TB prophylaxis.

Active TB was defined as having active symptoms consistent with TB and confirmed by positive microbiological evidence of TB (positive acid-fast bacilli smear, TB culture, or polymerase chain reaction). All patients with lesions on CXR did chest computed tomography (CT) scan to rule out underlying pathology. Patients, who developed active TB during the period following initiation of biologic therapy and up to 12 months after the last dose were considered new TB cases associated with the use of biologics.

Detailed information concerning the demographic characteristics of the patients (age, sex, marital status, residence, level of education), history of smoking and consumption of unpasteurized dairy products, associated comorbidities, underlying rheumatic disease characteristics (disease duration, concomitant/previous biologic therapy and its duration, conventional synthetic DMARDs [csDMARDs], and steroid therapy) and TB disease-related data (past history of TB, contact with active TB patients, site and form of TB, TST and IGRA results, and isoniazid prophylaxis) were recorded.

The study was conducted in compliance with the Helsinki Declaration and approved by ethical committee at each of the collaborating institutions (El Ayachi Hospital, Mohammed V University, Mohammed V Military Hospital, CHU Ibn Rochd, CHU Hassan II, Moulay Ismail Military Hospital, Avicenne Military Hospital,CHU Oujda, 1st Medical Surgical Center, Agadir, CHU Mohammed VI, CHU Tangier and Benha University, Egypt). All participants (whose data were included in this study) were contacted by phone and invited to come to the rheumatology department in their city, where they were informed of the purpose and progress of the study, and then they were invited to read and sign a written consent for their information to be used. Informed consent was obtained from all subjects or, if subjects are illiterates, from a parent and/or a legal guardian. All personal data were anonymized prior to data analysis.

Statistical analysis

The statistical analysis was calculated using SPSS (Statistical Package for Social Sciences, IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp). Quantitative variables data are presented as mean, standard, median, and minimum-maximum deviation. For qualitative variables, data are expressed in numbers and percentages. Intra-group comparisons were made using the Mann–Whitney test or Student's t-test for quantitative variables and the Chi-square test for qualitative variables using Fisher's exact test correction if indicated. Univariate and multivariate logistic regression analyses were conducted to identify factors associated with the risk of development of active TB in the study population. All independent variables with P ≤ 0.3 in the univariate analysis were taken into account in the multivariate logistic regression analysis. P < 0.05 was considered statistically significant.


  Results Top


During the study period, 1407 eligible patients who received biological therapy were included in the study to assess the prevalence of active TB infection. Of these, 33 patients had active TB, and the estimated overall prevalence rate was 2.3% (33/1407). Due to the retrospective aspect of the study, data of the rest 1277 patients were missing and therefore those patients were excluded. Only detailed records were obtained for 130 patients (including those who developed active TB). Among the 130 patients, 33 cases of TB were compared to 97 controls (patients under biological therapy who did not develop active TB infection) in order to describe the demographic characteristics and identify potential risk factors.

The selection of the study population is shown in [Figure 1].
Figure 1: Study population selection

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Characteristics of active tuberculosis patients

Twenty-five (75.8%) patients were males, the mean age was 42.9 ± 12 years, and 61% (n = 20) of them were married. All patients were Moroccans, most of whom lived in urban areas (n = 30, 91%), and illiterates accounted for a large proportion (n = 10, 30.3%). 30.3% (n = 10) of the patients consumed unpasteurized dairy products and 27.3% (n = 9) were active smokers. Associated comorbidities were diabetes mellitus (DM) (n = 5, 15.2%), end-stage renal disease (ESRD) (n = 3, 9.1%), and Crohn's disease (n = 2, 6.1%).

The underlying rheumatic diseases were mainly ankylosing spondylitis (AS) (n = 28, 84.8%) and to lesser extent RA (n = 5, 15.2%). csDMARDs were used in 33.3% of the patients (n = 11) and steroids were used in 21.2% of the patients (n = 7). Thirty-one patients developed active TB related to treatment with TNF-α inhibitors: adalimumab (ADA; n = 13), infliximab (IFX; n = 12), etanercept (ETN; n = 5), and golimumab (n = 1), while only two patients received nonanti-TNF biologics: tocilizumab (TCZ) and rituximab (RTX). Some of our patients received multiple biological agents before developing active TB infection. Among these patients, ten had biologic switching; eight patients had a single switch while two patients had double switches due to loss of adequate response.

All the patients who developed active TB had undergone screening for LTBI before initiating biologic therapy. Eighteen patients (55%) were initially screened using TST, five were tested positively, IGRA was performed for only two of them, and the results proved positive. The remaining 15 patients (45%) were initially screened with IGRA, and the result was positive in only three patients [Figure 2]. CXRs were obtained for all patients, abnormal signs were detected in only one (AS) patient with positive IGRA test (TST was not done), and subsequently, a CT scan showed a noninfected bronchiectasis. Two patients (6.1%) had past history of TB prior to biologic therapy (one of them was on ETN, and the other was on IFX) and only one patient (3%) reported a recent contact. A total of 8 out of 33 patients positive for LTBI were given TB prophylaxis prior to initiation of biologic therapy based on isoniazid (INH) plus rifampicin for 3 months in three patients and INH monotherapy for 6 months in two patients. Regarding the remaining three patients, there was no confirmed data on the preventive regimen used. However, all patients who were diagnosed with LTBI completed TB prophylaxis. The rest 25 patients did not have LTBI and therefore the TB prophylaxis was not needed.
Figure 2: Screening for latent tuberculosis infection before initiating biologic therapy

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The median interval between initiation of biologic therapy and development of active TB was 9 months. Among patients with active TB, 18 patients (54.5%) had extrapulmonary TB, including lymph nodes (4/18): multifocal (4/18), peritoneal (3/18), vertebral (2/18), miliary (2/18), pleural (1/18), intestinal (1/18), and anal (1/18). Antituberculous therapy was given in all cases. The treatment outcome was favorable in 81.8% of the cases (n = 27), relapse occurred in one case, immune reconstitution syndrome in one case, and hepatotoxicity in one case. Two patients are still under anti-TB therapy without any reported complications and one patient died.

[Table 1] shows the comparison between patients with active TB and controls. Although a significantly higher proportion of active TB was observed in AS (P = 0.003) patients, no significant association was found with regard to disease duration (P = 0.656) or therapeutic agents (P > 0.05). Moreover, none of the used different biologic therapies were significantly associated with active TB (P > 0.05). Smoking (P = 0.017), diabetes (P = 0.025), and hemodialysis (P = 0.015) were significantly higher in active TB patients compared to the non-TB group. There were no statistically significant differences in age, sex, marital status, residence, and level of education between patients of both the groups (TB and non-TB). However, the comparison of the median duration of exposure to biological agents in the active TB group and the control group showed a statistically significant difference between the two groups (P = 0.002). In addition, comparison between patients with pulmonary and extrapulmonary TB showed no significant difference in demographic characteristics [Table 2].
Table 1: Comparison between the characteristics of tuberculosis and nontuberculosis patients

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Table 2: Comparison between patients with pulmonary and extrapulmonary tuberculosis

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As summarized in [Table 3], consumption of unpasteurized dairy products (odds ratio [OR], 34.841; 95% confidence interval [CI], 3.1–389.7; P = 0,04), diabetes (OR, 38.468; 95% CI, 1.6–878.3; P = 0.022), smoking (OR, 3.941; 95% CI, 1–159.9; P = 0.047), and prolonged duration of biologic therapy (OR, 1.991; 95% CI, 1.4–16.3; P = 0.001) were significant risk factors for developing active TB in patients with rheumatic diseases under biologic therapy. Meanwhile, an association was observed between anti-TNF-α therapy and the development of active TB in univariate regression analysis (P = 0.07), however, this association was not statistically significant in multivariate regression analysis.
Table 3: Risk factors by univariate and multivariate logistic regression

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Re-initiation of biologic therapy after completing TB treatment was considered in 17 patients (51.5%) within an average of 16 ± 2 months from onset of TB. The same biologic agent was restarted in eight patients (47%), while switching to another biologic was considered in nine patients (53%).


  Discussion Top


TB is endemic in Morocco; its prevalence according to the Ministry of Public Health is 1% for new cases. A new case of TB is defined as a patient who has never been treated for TB or who has taken TB medication for less than a month. This study was conducted nationwide to determine the prevalence and risk factors of active TB infection in Moroccan patients with rheumatic diseases under biologic therapy, and to describe the sociodemographic characteristics of these patients. The estimated overall prevalence rate of TB in the present study population (2.3%) was more than twice the rate reported in our national general population. An elevated risk of TB has been previously reported among patients with different rheumatic diseases.[16],[17] Chen et al.[18] have found a higher prevalence of active TB (3.9%) among RA patients receiving anti-TNF-α therapy. Furthermore, the number of RA patients among all TB patients was almost three times the prevalence of RA among the Japanese population with an increased risk of severe TB disease.[19] However, the overall estimated incidence of TB in patients with rheumatic diseases under anti-TNF-α therapy varies by disease, population, and the anti-TNF drug used.[17] The exact causes of increased susceptibility to TB in rheumatic patients are not clear, but the compromised immune system associated with the disease, immunosuppressive drugs, and associated comorbidities are possible factors.[20]

In this study, AS patients accounted for the majority of the patients with active TB disease (84.8%), all of whom were receiving anti-TNF-α therapy. Moreover, 31 out of 33 patients with active TB were on anti-TNF-α therapy. The risk of TB in TNF blocker-naive AS cohort was reported 4.3 times higher than that in the general Korean population, especially among young adults, and this risk was not increased by the use of anti-TNF-α therapy.[21] However, in a previous study conducted in Sweden,[22] biologic-naive AS and other spondyloarthritis (SpA) patients were not at a higher risk of developing active TB disease compared to the non-AS/SpA comparators, but they had a high risk when treated with anti-TNF-α drugs. The exact mechanisms that increase the risk of TB infection in patients with biologic-naive AS are still unclear, however, unspecified subclinical pulmonary involvement (presented as apical fibrosis, interstitial lung disease, bronchiectasis, or emphysema) occurs frequently in AS, especially at the early stage of the disease.[23]

Recently, new-targeted therapies have been developed, working on cells or cytokines that are barely or not involved in the immune response against Mtb. In the present study, two patients (out of 33 patients) with active TB received nonanti-TNF drugs (TCZ and RTX). Our data support the reassuring results related to the risk of TB reactivation associated with the use of TCZ, RTX, and abatacept (ABA) in RA patients. These reassuring data are consistent with the mechanism of action of these drugs which does not affect tuberculous granuloma.[24]

The development of active disease from LTBI in patients receiving anti-TNF-α drugs is a significant issue that requires further assessment of the performance of screening tests. Among patients with active TB, baseline LTBI was positive in 8/33 (24.25%), five patients (15.15% of active TB patients) tested positive with TST, and three patients (9.09% of active TB patients) tested positive with IGRA. The higher positive rate of TST in our patients, compared to positive IGRA, does not infer a lower specificity of IGRA in LTBI screening where confirmatory IGRA was performed for only two patients and proved positive. This may be explained by the fact that TST measures responses of effector and memory T-cells while IGRA often measures the response of effector T-cell. Since only circulating effector memory T-cells have enough time to produce interferon after a 24-h incubation in IGRA, whereas central memory T-cells first began producing interferon after a longer (72 h in TST) incubation period.[25] In addition, data showed that QFT-G performed well in screening of low-prevalence populations, but suboptimal performance was reported in healthy people who had a high risk of TB exposure.[26] In the absence of gold standards for defining LTBI, the real sensitivity and specificity of TST and IGRA cannot be measured. TST can detect past infection with Mtb or other mycobacteria and Bacillus CalmetteGuérin (BCG) vaccination and therefore can produce many false-positive results.[27] On the contrary, IGRA tests are more specific as they are not affected by previous BCG vaccination or infection with other nontuberculous mycobacterial species (except Mycobacterium szulgai, Mycobacterium kansasii, and Mycobacterium marinum).[28] False-negative results can occur with both tests as consequences of T-cell anergy, which may occur in patients receiving glucocorticoids and immunosuppressive therapy.[27],[29]

Different biologic drugs do not have a similar potential in reactivating LTBI. In the present study, all LTBI patients who developed an active disease were receiving anti-TNF-α drugs (three patients on ADA, three patients on IFX, and two patients on ETN). Our results were supported by the findings of previous studies indicating that TNF antagonists pose the greatest danger of LTBI reactivation. However, monoclonal antibodies (ADA and IFX) have been found to be more related to LTBI reactivation than soluble TNF-α receptor fusion protein,[9],[10],[30],[31],[32],[33],[34] and this could be explained by the weaker binding of ETN to membrane TNF receptor on activated T-cells.[35],[36] Moreover, it has been shown that the risk of TST conversion increased significantly during 3 years of anti-TNF-α therapy[37] and the conversion in interferon-gamma values higher than 4.00 IU/mL was associated with more than 40 times the risk of developing TB in the next 6–24 months.[38]

The median interval between initiation of biologic therapy and development of active TB in our patients was 9 months. A biphasic emergence of active TB disease in RA patients (after 3 and 20–24 months of long-term anti-TNF-α therapy) has been reported.[18] In line with the results of previous studies reporting a more prevalent extrapulmonary TB in RA patients receiving anti-TNF-α therapy,[18] 18 (54.5%) of 33 patients had extrapulmonary involvement, and most of them were on TNF blockers (17/18). In a Brazilian study, anti-TNF-α therapy was reported as a major risk factor for extrapulmonary and disseminated TB forms among patients with RA.[39] Reactivation of past infection, rather than new primary infection, has been suggested as a possible major cause of the high prevalence of extrapulmonary TB.[21]

Consumption of unpasteurized dairy products, diabetes, smoking, and prolonged duration of biologic therapy were all identified as risk factors for developing active TB in our patients. In addition, ESRD was significantly higher in patients with active TB. Globally, human immunodeficiency virus infection is the main risk factor for TB. Other risk factors include smoking, silicosis, cancer, DM, ESRD, overcrowding, and malnutrition. Smoking cigarettes can damage the lungs and suppress adaptive immune responses that affect a patient's response to TB treatment.[39] In systemic lupus erythematosus patients, the cumulative dose of prednisolone and nephritis were reported as independent risk factors for the development of TB.[21] Furthermore, we could not find any association between the type of biologics and the development of active TB. As in previous studies, we did not notice any association between the use of csDMARDs and the development of TB.[21] Although corticosteroids are believed to be a major risk factor for TB infection, we have been unable to find any role for them in our patients.

The demographic characteristics of the patients and their behavior, including their behavior toward therapy, seem to play a significant role in the incidence of TB. To the best of our knowledge, this is the first study to explore the sociodemographic characteristics of patients with rheumatic diseases who developed active TB under biologic therapy. There were no statistically significant differences in age, sex, marital status, residence, and level of education between patients of both the groups (TB and non-TB). In addition, univariate logistic analysis showed no significant difference in demographic characteristics between patients with pulmonary and extrapulmonary TB. Higher infection rates and relapse of TB have been reported in urban areas than rural areas, due to increased possibility of transmission of airborne pathogens in urban dwellers. In addition, unemployment, low levels of education, living in an unhealthy environment, and overcrowding could be possible reasons of prevalent TB in the lower class. Failure to determine any specific sociodemographic characteristics in our patients can be related to the lower number of TB cases associated with limited statistical accuracy.

In addition to a few TB cases, there are some limitations in our study. The retrospective nature of the study is considered a methodological limitation with difficulty to make comparisons between patients with and without active TB because of missing recorded data and the small number of TB patients (33 cases). Some important sociodemographic characteristics have not been recorded, for example, the income or the average daily earnings of the patients that can reflect the economic risk factor. The incidence rate could not be measured as we had difficulty in identifying new cases annually. Multiple testing is considered another limitation to our study as well as the wide range of 95% CI for each risk factor that we found which lowers the precision of estimation. Furthermore, the type of the study as a multicenter study carries some limitations concerning the heterogeneity in clinical practice among centers, however, careful systematic reviewing of patients' files and detailed database by trained researchers minimizes the risk of bias.


  Conclusion Top


The risk of TB in Moroccan patients with rheumatic diseases receiving biologic therapy was more than double the reported rate in the general Moroccan population. The majority of the active TB cases occurred under anti-TNF-α therapy, and risk factors included prolonged biologic therapy duration, smoking, DM, and consumption of unpasteurized dairy products.

Our study showed that despite initial LTBI screening, a high prevalence of active TB infection was noted in patients with rheumatic diseases under biological therapy. In light of these findings, more intensive screening strategies for these patients should be adopted, using not only TST and IGRA but also symptom questioning, physical examination as well as regular surveillance of LTBI.

Limitation of the study

There are some limitations in our study. The retrospective nature of the study is considered a methodological limitation with difficulty to make comparisons between patients with and without active TB because of missing recorded data and the small number of TB patients (33 cases). Some important socio-demographic characteristics have not been recorded, for example the income or the average daily earnings of the patients that can reflect the economic risk factor. The incidence rate could not be measured as we had difficulty in identifying new cases annually. Multiple testing is considered as another limitation to our study as well as the wide range of 95% CI for each risk factor that we found which lowers the precision of estimation. Also, the type of the study as a multicenter study carries some limitations concerning the heterogeneity in clinical practice among centers, however, careful systematic reviewing of patients' files and a detailed database by trained researchers minimizes the risk of bias.

Ethical clearance

The study was conducted in compliance with the Helsinki Declaration and approved by ethical committee at each of the collaborating institutions (El Ayachi Hospital, Mohammed V University, Mohammed V Military Hospital, CHU Ibn Rochd, CHU Hassan II, Moulay Ismail Military Hospital, Avicenne Military Hospital,CHU Oujda, 1st Medical Surgical Center, Agadir, CHU Mohammed VI, CHU Tangier and Benha University, Egypt).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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