Screening of Latent Tuberculous Infection (LTBI) before Starting Anti-Tumor Necrosis Factor Therapy in Patients with Psoriasis: A Primer for Clinical Dermatologist.

Anti-tumor necrosis agents are being increasingly used in the management of moderate to severe psoriasis. Therapy with antitumor necrosis factor alpha (TNF-α) agents is being fraught with reactivation of latent tuberculosis infection (LTBI). This paper addresses the intricate relation between LTBI and anti-TNF-α agents and provides working guidelines for screening of LTBI and its management before prescribing anti-TNF-α therapy in patients with psoriasis. Copyright:

Introduction

The incidence of tuberculosis (TB) was around 10 (8.9–11.0) million globally in 2019.[1] In 2019, the largest number of new TB cases occurred in the World Health Organization (WHO) South-East Asian region, with 44% of new cases, followed by the WHO African region, with 25% of new cases and the WHO Western Pacific with 18%. The 30 high TB burden countries accounted for 87% of all estimated incident cases worldwide. The eight countries that stood out as having the largest number of incident cases (two-third of total incidence in the world) in 2019 were India, Indonesia, China, Philippines, Pakistan, Nigeria, Bangladesh, and South Africa (in descending order). Around 24.04 lakhs patients of TB have been notified in the year 2020.[2] Approximately 1.2 million people who were HIV-negative died of TB in 2019 and an additional 0.20 million HIV-positive people died of TB. It is one of the top 10 causes of death worldwide and caused more deaths than HIV/AIDS in 2019.[1]

According to WHO Strategic and Technical Advisory Group for TB (STAG-TB), amongst all high burden country list (HBC) India has been included in the list of high-TB-burden countries, high TB/HIV-burden countries, and high-MDRTB-burden countries. Approximately 40% of Indians are latently infected with TB.[34]

Pathogenesis of tuberculous infection

Mycobacterium tuberculosis/Tubercle bacilli are carried in airborne particles, called droplet nuclei, of 1–5 m in diameter size generated from the person having active respiratory TB (lung or laryngeal). After inhalation of the droplet nuclei containing M. tuberculosis, the infectious bacilli traverse the mouth or nasal passages, upper respiratory tract, and bronchi to reach the alveoli of the lungs.

Within 2–8 weeks, macrophages ingest and surround the tubercle bacilli. The cells form a barrier shell, called a granuloma, that keeps the bacilli contained, leading to establishment of latent tuberculosis infection (LTBI).

Persons with LTBI have M. tuberculosis in their bodies, but do not have TB disease and cannot spread the infection to another susceptible host. However, in some infected individuals, the tubercle bacilli overcome the cellular immune system and multiply, resulting in progression from LTBI to TB. The progression from LTBI to TB may occur at any time, hence, detection of LTBI is of utmost important in cases where chance of iatrogenic immunosuppression persists. Currently, LTBI can be screened by using either tuberculin skin test (TST) or an interferon-gamma release assay (IGRA). It usually takes about 2–8 weeks interval for the body's immune system to be able to react to tuberculin and for the infection to be detected by the TST or IGRA. Within weeks after infection, the immune system is usually able to halt the multiplication of the tubercle bacilli, preventing further progression.

Psoriasis, antitumor necrosis factor therapy, and latent tuberculous infection

The incidence of psoriasis is 0.5%–3% of the world's population. The pathogenesis of psoriasis is multifactorial and is considered to be result of combination of genetic susceptibility, immune dysregulation, and environmental factors.[5] Key cytokines involved in the pathogenesis of psoriasis are tumor necrosis factor alpha (TNF-α) and interleukins (IL-12, IL-17, IL-22, and IL-23).[6] Due to advances in the understanding of the immuno-pathogenesis of psoriasis, more specific/targeted drugs are being used for the treatment of the same. In the last three decades, biologics have revolutionized the treatment of psoriasis and various classes of biologics are currently approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). These include TNFα inhibitors (etanercept, infliximab, adalimumab and certolizumab); IL-17 inhibitors (secukinumab, ixekizumab, brodalumab); Il-12/23 inhibitor (ustekinumab) and Il-23 inhibitors (guselkumab, risankizumab and tildrakizumab)

However; various studies suggests that anti-TNF-α therapy is associated with up to 25 times risk of activation of LTBI, depending on the clinical setting and the anti- TNF agent used.[789101112] Risk of TB infection reactivation caused by the monoclonal antibody is generally higher than that of the receptor antibody.[12]

Therefore, it is logical that psoriatic patients who will be receiving anti-TNF-α therapy should be proactively screened for LTBI and if found to be positive, prophylaxis with anti-TB treatment should be instituted prior to initiation of biological treatment.

In this review, authors have attempted to discuss various aspects of LTBI screening, active TB infection and treatment regimens for LTBI.

Latent tuberculous infection: Who needs investigation?

LTBI is defined as a state of persistent immune response to prior-acquired M. tuberculosis antigens without evidence of clinically manifest active TB. The lifetime risk of reactivation of TB in person with documented LTBI is 5%–10%, with risk being maximum in first 5 years of acquiring infection.[13] Risk of reactivation depends on immunological status of the host. Testing for LTBI should be performed only in individuals who have high risk of reactivation of TB and those who will benefit from treatment. These high-risk groups as per current WHO guidelines are (i) People living with HIV (ii) Children less than 5 years who are close contact of people with TB (iii) Patients initiating anti-TNF-α treatment (iv) Patient receiving dialysis (v) patient preparing for organ or hematologic transplantation (vi) Patients with silicosis.[14]

Testing for LTBI should be performed only after clinical evaluation has ruled out active TB.

Screening for latent tuberculous infection

TST and IGRAs are being currently done for diagnosis of LTBI. The diagnosis of LTBI is traditionally based on TST positivity in the absence of active TB.[15] However; TST has a low sensitivity and specificity in patients with atypical mycobacterial infection and Bacillus Calmette-Guérin (BCG) vaccination and hence less useful in our country, where BCG vaccination is universal and atypical mycobacterial infections are common. The IGRAs have been introduced to compensate for the drawback of TST in detecting LTBI.[416171819]

National Psoriasis Foundation (NPF) guidelines advise screening for active TB and LTBI using clinical history, radiograph of chest, and TST.[20] Centre for disease control (CDC) also recommends chest radiography to rule out active TB in patient with positive Mantoux test and patient with abnormal radiograph chest finding should undergo diagnostic sputum evaluation.[21] All patients with psoriasis who are considered as a potential candidate for receiving anti-TNF-α therapy should also receive HIV testing.

Tuberculin skin test

TST is one of the widely used investigations for diagnosis of TB since nineteenth century. Targeted tuberculin testing for LTBI has been considered as strategic component of TB control by The Centers for Disease Control and Prevention (CDC, Atlanta, USA) which specifically identifies persons at high risk for developing TB and would benefit by treatment of LTBI, if detected.

Tuberculin skin test administration

TST is commonly done by intradermal injection, called the Mantoux technique after Charles Mantoux, who described the technique in the early part of the twentieth century. A standardized product called PPD-S (purified protein derivative-standardized) prepared from M. tuberculosis is used for the purpose. There are various types of PPD of non-tuberculous (i.e. atypical) mycobacterium like PPD-A (M. avium); PPD-G (Gause strain of scotochromogen); PPD-B (non-photochromogen Battey bacilli); PPD-F (rapid grower M. fortuitum) and PPD-Y (yellow photochromogen M. kanasasii).

TST is performed by injecting 0.1 mL of tuberculin PPD intradermally into the inner surface of the forearm using tuberculin syringe, with the needle bevel facing upward. The injection should produce a pale elevation of the skin (a wheal) 6 to 10 mm in diameter when placed correctly. Subcutaneous administration will result in rapid “washout” from the area without time for the development of a reaction, whereas very superficial placement will result into leakage of reagent through the skin. Hence, a highly trained laboratory professional should be delegated the task of TST administration. If the injection is unsuccessful and not able to raise a desired wheal, it may be repeated immediately, usually on the other forearm.

Reading of tuberculin skin test

The reaction should be read between 48 and 72 h after administration.

The reaction is measured in millimeters of the induration (palpable, raised, hardened area or swelling) across the forearm (perpendicular to the long axis). The induration not the erythema measurement is done in the test [Tables 1 and 2].[18]

Table 1

Interpretation of Tuberculin skin Test

An induration of 5 or more millimeters is considered positive in	An induration of 10 or more millimeters is considered positive in	An induration of 15 or more millimeters is considered positive in
HIV-infected persons	Recent immigrants (<5 years) from high-prevalence countries	Any person, including persons with no known risk factors for TB. However, targeted skin testing programs should only be conducted among high-risk groups
A recent contact of a person with TB disease
Persons with fibrotic changes on chest radiograph consistent with prior TB	Injection drug users Residents and employees of high-risk congregate settings
Patients with organ transplants	Mycobacteriology laboratory personnel
Persons who are immunosuppressed for other reasons (e.g., taking the equivalent of >15 mg/day of prednisone for 1 month or longer, taking TNF-a antagonists)	Persons with clinical conditions that place them at high risk
	Children <4 years of age
	Infants, children, and adolescents exposed to adults in high-risk categories

Table 2

Causative factors for False-positive reactions and False-Negative reactions

False-Positive Reactions	False-Negative Reactions
Infection with non-tuberculosis mycobacteria	Cutaneous anergy (anergy is the inability to react to skin tests because of a weakened immune system)
Previous BCG vaccination	Recent TB infection (within 8-10 weeks of exposure)
Incorrect method of TST administration	Very old TB infection (many years)
Incorrect interpretation of reaction	Very young age (less than 6 months old)
Incorrect bottle of antigen used	Recent live-virus vaccination (e.g., measles and smallpox)
	Overwhelming TB disease
	Some viral illnesses (e.g., measles and chicken pox)
	Incorrect method of TST administration
	Incorrect interpretation of reaction

The physician should particularly stress on measurements of indurated area rather than accepting the reading as 'positive or 'negative' as this will allow any future comparisons.

Interpretation of TST

Skin test interpretation depends on two factors:

Measurement in millimeters of the induration

Person's risk of being infected with TB and of progression to disease if infected

Boosted reaction

The ability to react to tuberculin may decrease over time in some persons infected with M. tuberculosis leading to a false-negative reaction. In such cases, two-step testing is done where second TST is given after an initial negative test. The initial TST may stimulate the immune system, causing a positive or boosted reaction to subsequent tests. The second boosted reading is the correct one––that is, the result that should be used for decision-making or future comparison. Boosting is maximal if the second test is placed between 1 and 5 weeks after the initial test, and it may continue to be observed for up to 2 years.

Mantoux conversion

Change of Mantoux reactivity within a 2-year period with the following criteria: conversion is defined as a change (within a 2-year period) of Mantoux reactivity that meets either of the following criteria.[22]

a change from a negative to a positive reaction

an increase of ≥10 mm.

Conversion has been associated with an annual incidence of TB disease of 4% in adolescents or 6% in contacts of smear-positive cases.

Conversion is the development of new or enhanced hypersensitivity due to infection with tuberculous or non-tuberculous mycobacteria; including BCG vaccination which is opposite of boosting occurs due to recall of the hypersensitivity response in the absence of new Infection.

Therefore, when testing TB contacts for conversion, the second tuberculin test is done 8 weeks after the date of last contact with the source case.

Bacillus Calmette-Guérin vaccine and the Mantoux test

According to the US recommendation, TST is not contraindicated for BCG-vaccinated persons and also prior BCG vaccination should not influence the interpretation of the test.

A diagnosis of latent TB infection (LTBI) and treatment for the same is considered for any BCG-vaccinated person whose skin test is 10 mm or greater, under any of the following circumstances.

History of contact with another person with infectious TB

Was born or has lived in a high TB prevalence country

Continuous exposure to populations where TB prevalence is high

Disadvantages of TST

Poor inter-reader reliability

False-positives/specificity (Non tuberculous mycobacterial infection or prior BCG vaccination)

Poor positive predictive value in low prevalence region

Interferon gamma release assay

Background of interferon gamma release assay

Various subsets of immune cells (e.g. macrophages, T lymphocytes) are involved in the immune response directed against the bacilli after being infected with M. tuberculosis. These cells do not fully eradicate the bacilli, but rather contain the infection.[2324] Macrophages have an important role in the first line of defense against the infection by ingesting and subsequently killing the organisms. However, M. tuberculosis bacilli escape the immune system and have the ability to persist within macrophages, thereby averting the attack by these host cells.[2526] The cytokine interferon-gamma (IFN-γ) plays an important role in the elimination of M. tuberculosis by activating the production of reactive oxygen and nitrogen intermediates in macrophages, which cause destruction of bacterial pathogens. CD4 T-cells recognizing M. tuberculosis antigens produce IFN-γ causing activation of M. tuberculosis-infected macrophages and kill the bacilli and control their growth.[2728]

IGRAs are blood-based tests assessing the presence of effector and memory immune responses directed against the M. tuberculosis antigens. They predominantly measure the presence of M. tuberculosis-specific effector memory T-cells, the presence of which is considered indicative of previous in-vivo exposure to the bacilli. These tests measure the presence of an adaptive immune response to M. tuberculosis antigens, and are thus an indirect measure of M. tuberculosis exposure.[29]

Types of interferon gamma release assay

Two IGRAs that have been approved by the U.S. Food and Drug Administration (FDA) [Table 3]-

Table 3

Difference between QFT-GIT and T-SPOT

	QFT-GIT	T-SPOT
Initial process	Process whole blood within 16 h	Process peripheral blood mononuclear cells (PBMCs) within 8 h, or if T-Cell Xtend is used, within 30 h
M. tuberculosis antigen	Single mixture of synthetic peptides representing ESAT-6, CFP-10 & TB7.7.	Separate mixtures of synthetic peptides representing ESAT-6 & CFP-10
Measurement	IFN-g concentration	Number of IFN-g producing cells (spots)
Possible results	Positive, negative, indeterminate	Positive, negative, indeterminate, borderline

QuantiFERON®-TB Gold In-Tube test (QFT-GIT);

T-SPOT®.TB test (T-Spot)

QFT-GIT:

IGRAs are performed on fresh blood specimens. The QFT-GIT is performed by drawing 1 mL of blood into one of each of the three manufacturer-precoated, heparinized tubes. The tubes are then incubated for 16 to 24 h at 37°C within 16 h of blood collection. The plasma is harvested after centrifugation and used to assess the concentration of IFN-γ by ELISA test. Results are interpreted according to the manufacturer's recommendations.[30]

T-SPOT:

8 mL of blood are required and the assay is performed within 8 h of blood collection (using, for example, heparinized tubes). Alternatively, the manufacturer also provides a reagent (T-Cell Xtend) which extends processing time to 32 h after blood collection. The T-cell-containing peripheral blood mononuclear cell (PBMC) fraction is separated from whole blood and distributed to the microtiter plate wells (2,50,000 cells/well) provided in the T-SPOT-TB assay kit. Following 16–20 h (at 37°C with 5% CO2) incubation, the number of IFN-γ-secreting T-cells (represented as spot-forming units) can be detected by ELISPOT assay. Results are interpreted according to the manufacturer's recommendations.[31]

Benefits of interferon gamma release assay

Single visit

Not affected by prior BCG vaccination status

Not dependent on observer (erythema or induration unlike TST)

Can be used for follow-up as does not result in boosted reaction unlike TST

Disadvantages of interferon gamma release assay

Cost: It is an expensive test, as compared to TST. Hence WHO guidelines suggest that IGRA should not replace TST in low and middle income countries for detection of LTBI.

False positive and poor positive predictive value in low prevalence region

Blood samples must be processed within 8–30 h after collection, whereas white blood cells are still viable

Errors in collecting or transporting blood specimens or in running and interpreting the assay can decrease the accuracy of IGRAs.

Which test to use and how to use?

First step in screening for LTBI is to rule out active TB by history, clinical examination and if required necessary investigation (chest radiograph and sputum examination for acid fast bacilli). All potential candidates should be asked about symptoms of active pulmonary TB (cough, hemoptysis, fever, night sweats, weight loss, chest pain and shortness of breath) and history of TB in family and close contacts. Test for LTBI should be administered only when active TB is reasonably ruled out as it can lead to development of resistance apart from inadequate treatment of active TB.

WHO guidelines suggest use of either TST or IGRA (not both) for detection of LTBI. We propose following steps for detection of LTBI based on relevant literature and cost effectiveness in our scenario. IGRAs should not replace TST in resource poor settings.

TST should be used as a first test for detection of LTBI.

IGRA should be done

When results from TST are indeterminate

When TST is positive and to increase the acceptability of treatment

To follow up patient who are on biological therapy, when TST is of limited value

In case, a patient is positive for TST or IGRA, chest X-ray should be done and any abnormality should prompt evaluation for treatment of active TB. A computed tomography scan can be ordered if chest X-ray reveals any tuberculous foci.

Treatment of latent tuberculous infection

Treatment options available for treatment of LTBI as per WHO guidelines are as follows:

Regimen Dose

6 months of isoniazid (INH) monotherapy Children: 10 mg/kg/day

Adults: 5 mg/kg/day (Max: 300 mg)

9 months of INH monotherapy [32] -do-

3–4 months of rifampicin monotherapy Children: 10 mg/kg/day

Adults: 10 mg/kg/day (Max: 600 mg)

3 months regimen of weekly rifapentine and INH Rifapentine:

10.0–14.0 kg: 300 mg

14.1–25.0 kg: 450 mg

25.1–32.0 kg: 600 mg

32.1–49.9 kg: 750 mg

(Max dose: 900 mg)

3–4 months rifampicin and isoniazid Doses mentioned above

Pyrazinamide containing regimens are not used for treatment of LTBI because of unacceptable hepatotoxicity.

There are not enough studies to support or refute superiority of one regimen over another for treatment of LTBI. However, longer treatment has higher risk of hepatotoxicity and compliance issues. Hence, 3 months of rifampicin and isoniazid regimen is probably safer as compared to 6–9 months of isoniazid monotherapy.

American thoracic society and CDC guidelines suggest use of 9 months daily INH for treatment of LTBI as first line therapy.[33]

WHO and National Institute of Health, United Kingdom recommends 6 months INH as acceptable treatment for LTBI.

Adverse event monitoring: During treatment adverse event monitoring for rash, hepatotoxicity, peripheral neuropathy is very important. INH therapy should be supplemented with pyridoxine (vitamin B6) to prevent peripheral neuropathy

Risk of drug resistance: With use of monotherapy for prolonged duration, there is a possible concern for development of resistance. Systematic review of current available literature suggests that use of isoniazid monotherapy or isoniazid + rifampicin for treatment of LTBI does not lead to increase in resistance.[3435]

Treatment of LTBI prevents up to 60%–70% patients from developing active TB; however, a patient may develop active TB despite prophylaxis especially with TNF inhibitors and patient should be followed up regularly.[36]

Conclusion

Anti-TNF-α therapy has already surpassed the conventional line of treatment for moderate to severe psoriasis in most of the developed countries of the world and soon will be an affordable therapeutic option in Indian subcontinent. TB being an endemic health concern in Indian subcontinent and further reactivation by use of anti-TNF-α agents warrants that existence of region specific guidelines for screening psoriatic patients which are potential candidates for receiving anti-TNF-α agents.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.