Conversion Rate of Tuberculosis Screening Tests among Dermatology Patients Treated with Tumor Necrosis Factor Inhibitors.

Background: The use of tumor necrosis factor-α inhibitors (TNFi) has been associated with an increased risk latent tuberculosis (TB) reactivation. The role of TB screening assays in monitoring patients during TNFi therapy remains uncertain. Spontaneous conversions and reversions have been described. Aims: This study aims to determine the conversion and reversion rate of TB screening tests among dermatology patients receiving TNFi in a country with moderate TB incidence. Subjects and
Methods: A retrospective single-center study conducted on all patients in whom treatment with TNFi was initiated in our dermatology clinic in a tertiary university hospital, Riyadh, Saudi Arabia, until September 2018. Data were collected from the hospital electronic patient information system.
Results: One hundred and eighteen patients were included. Majority (79.9%) of patients used adalimumab. Psoriasis was the most common indication (90%). Among patients with negative baseline TB screening who had been retested during TNFi therapy (n = 65; 55%), conversion to positive was observed in nine patients (13.8%) with a mean duration of exposure of 39.7 months, whereas among patients with positive TB testing result (n = 18), 10 (55.5%) reverted to negative. Conclusions: This study emphasizes the need for prospective large-scale multispecialty studies assessing the significance of TB retesting, which should be considered when designing rescreening protocols. Copyright:

Introduction

Tumor necrosis factor-α (TNFα) is an important cytokine in preventing reactivation of latent tuberculosis (TB) infection (LTBI). The use of tumor necrosis factor-α inhibitors (TNFi) has been associated with an increased risk of active TB.[1] LTBI can be demonstrated by tuberculin skin test (TST) and/or interferon-gamma release assays (IGRAs), which include QuantiFERON-TB Gold in tube (QFT-GIT) and T-SPOT.TB.[2] IGRAs are more specific than TST as their results are not influenced by previous bacillus Calmette–Guerin vaccination.[3] The value of IGRAs for baseline screening has been recognized; however, their role in monitoring patients during TNFi therapy remains uncertain.[4] There is increasing concern regarding the significance of these TB screening assay conversions during retesting. Conflicting guidelines exist regarding the frequency of TB retesting in patients undergoing TNFi therapy. The National Psoriasis Foundation recommends annual TB screening in all patients,[5] whereas the American College of Rheumatology recommends annual screening in only patients with risk factors for TB.[6] Few studies examined the performance of these assays as monitoring tools for TB during biologic therapy among dermatology patients.[78910] This study aims to determine the conversion rate of TB screening tests among dermatology patients receiving TNFi agents with negative baseline screening results at our institution, in addition to determine the reversion rate among those with positive TB testing result, and the prevalence of TB infection in dermatology patients before and after initiation of TNFi.

Subjects and Methods

We conducted a single-center retrospective study from October 2018 to March 2019 in all patients to whom treatment with TNFi was initiated until September 2018 in dermatology outpatient clinics of King Khalid University Hospital, a tertiary hospital in Riyadh, Saudi Arabia. The data were collected from the hospital electronic patient information system. We included patients who were naïve to TNFα blockers before their first visit to our clinics and those with a total duration of TNFi use of 30 days or longer. Patients with missing data and patients who were on TNFi for nondermatological conditions were excluded. Data items recorded included patients' demographic data, indication of treatment, type of TNFi used, duration of treatment, type of TB screening test used, results of TB screening tests before and after initiation of TNFi, and LTBI treatment provided, and for those who converted from negative to positive, we recorded duration of exposure to TNFα blockers. Diagnosis of LTBI by infectious diseases or pulmonology specialists was made based on positive QFT and/or TST result and negative chest X-ray. Conversion was defined as a negative TB testing at baseline and a positive IGRA at follow-up, and reversion was defined as a positive TB testing at baseline or follow-up and negative IGRA upon further retesting.

This study was approved by the Institutional Review Board of College of Medicine, King Saud University, Riyadh. The ethics committee approval, it was obtained in October 2018. Data were collected, stored, managed, and coded in a spreadsheet using Excel 2010 software. Data were analyzed using SPSS version 21.0 (IBM Inc., Chicago, IL, USA). Descriptive analysis was done, where categorical variables were presented in the form of frequencies and percentages and continuous variables in the form of means. Chi-square test was used to compare categorical data. For comparing continuous data, Student's t-test was used for variables with normal distribution. A P value <0.05 was considered significant.

Results

Patients' demographic and clinical characteristics

A total of 118 patients were included in the study with a mean age of 34.66 (minimum 8, maximum 71) years. Table 1 demonstrates patients' demographic and clinical characteristics. Adalimumab (n = 94; 79.9%) was the most common TNFi used, followed by etanercept (n = 18; 15.3%), and only one patient was on infliximab (n = 0.8%). Five patients (4.2%) were on etanercept and then switched to adalimumab. The most common indication for starting TNFi was psoriasis (n = 106; 89.9%), followed by hidradenitis supprativa (n = 11; 9.3%), and one patient dissecting cellulitis (0.8%).

Table 1

Demographic and clinical characteristics of the patients

Demographic variable	Patients (n=118)
Age (years), mean (range)	34.66 (8-77)
Gender, n (%)
Male	56 (47.5%)
Female	62 (52.5%)
Underlying disease, n (%)
Psoriasis	106 (89.8%)
Hidradenitis suppurativa	11 (9.3%)
Dissecting cellulitis	1 (0.8%)
TNF inhibitor, n (%)
Adalimumab	94 (79.7%)
Etanercept	18 (15.3%)
Adalimumab-Etanercept	5 (4.2%)
Infliximab	1 (0.8%)
Mean duration of TNF inhibitor exposure	32 months

Baseline TB screening tests

TB screening tests prior to TNFi initiation were conducted in 96 (81.4%) patients; the majority (n = 83; 86.45%) had a negative testing result, with a minority of positive (n = 9; 9.37%) and indeterminate results (n = 4; 4.16%). TST alone was used as an initial screening test in 33 patients (34.3%), both TST and IGRAs in 12 patients (12.5%), and IGRA alone in 51 patients (53.12%). Those with a positive baseline TB testing (n = 9) were subsequently diagnosed with LTBI by infectious diseases or pulmonology specialists. Therefore, the prevalence of LTBI before starting TNFi in our study was 9.37%. No patients with active TB were detected prior to initiation of treatment. Eight patients received isoniazid for 9 months, and one received isoniazid and rifampicin for 3 months, which were completed 1 month before initiating TNFi therapy.

Follow-up TB tests

Seventy-eight patients (66%) underwent retesting of TB after initiation of TNFi, all of which using IGRA. The mean duration between TB testing was 21 months. Among those with a positive baseline TB testing (n = 9), three patients remained positive (33.3%), four patients reverted to negative (44.4%), one patient reverted to indeterminate (1.01%), and one did not undergo further retesting (1.01%). Those with a negative baseline (n = 83; 70.3%) had been retested (n = 65; 78.3%); conversion to positive was observed in nine patients (13.8%) during TNFi therapy. Mean duration of exposure to TNFi prior to positive conversion was found to be 39.7 months. Four patients were on etanercept, four on adalimumab, and only one patient switched from etanercept to adalimumab. Six of them reverted back to negative, and three of them did not undergo further retesting. LTBI was diagnosed by infectious diseases or pulmonology specialists in all nine patients. All patients received isoniazid prophylaxis for 9 months except for one due to pregnancy-related concern. None of the patients developed active TB during TNFi therapy. Among those with a positive TB testing result whether at baseline or follow-up (n = 18), reversion rate to negative was found to be 55.5% (n = 10). Table 2 demonstrates patient characteristics with positive conversion during TNFi therapy. None of the characteristics described were found to have statistically significant associations when compared with those who did not convert (P < 0.05). All of those with an indeterminate baseline (n = 4) reverted to negative upon retesting. Figure 1 demonstrates the distribution of baseline TB screening testing results prior to initiation of TNFi therapy and follow-up retesting results after initiation of TNFi treatment.

Table 2

Characteristics of patients with positive conversion during TNFi therapy (n=9)

Characteristics	Convertors (n=9)
Age (mean)	40 years
Gender, n (%)
Male	2 (22.2%)
Female	7 (77.8%)
Underlying disease, n (%)
Psoriasis	9 (100%)
Hidradenitis suppurativa	0 (0%)
Dissecting cellulitis	0 (0%)
TNF inhibitor, n (%)
Adalimumab	4 (44.4%)
Etanercept	4 (44.4%)
Etanercept/Adalimumab	1 (11.1%)
Infliximab	0 (0.8%)
Mean duration of exposure	39.7 months

Figure 1

Flow-chart distribution of baseline tuberculosis (TB) screening testing results prior to initiation of TNF inhibitor therapy and follow-up retesting results after initiation of TNF inhibitors treatment

Discussion

TNFi are used commonly in dermatology practice, especially among psoriatic patients.[11] Increased risk of infections such as TB is a well-known risk.[1] Few studies examined the performance of these assays as monitoring tools for TB during biologic therapy among dermatology patients.[78910] In addition, no previous studies addressing the rate of conversion and/or reversion of TB screening tests were conducted in Saudi Arabia, a country with moderate TB incidence (TB case rate of 10 per 100,000 population) according to the World Health Organization reports in 2017.[12] The conversion rate in our study was 13.8%, which is similar to the results of other studies addressing the performance of IGRAs among psoriasis patients on TNFi in intermediate TB burden countries such as Taiwan 14.3%.[7] In comparison to the United States (a low-burden TB country), two separate studies were conducted among psoriasis patients on TNFi both reporting similar results with only 0.4%[8] and 0.5%[13] conversion rates from negative to positive QFT during TNFi therapy. The authors of these studies argue that serial TB testing in low-risk TB countries in patients on TNFi with no known risk factors is unnecessary. However, in another Italian cohort also, a low-risk TB country of 50 patients with psoriasis on TNF blockers, 10% converted to positive.[10] Our study also reported an overall reversion rate of 55.5% among those tested with positive TB screening result whether prior to or during TNFi therapy. In a meta-analysis that evaluated TB testing reversion among individuals with or without prophylactic treatment,[14] findings of the included studies were found to be heterogeneous. Summarized QFT reversion rate was found to be 24.9% in participants completed preventive therapy and 25.3% among those without preventive treatment, respectively. The authors suggest that the reversion of TB infection testing might not be a reliable tool for monitoring LTBI treatment efficacy and they did not support to use serial QFT test for prophylactic treatment efficacy evaluation.

Our study is limited by its retrospective design, also that it included patients from a single center and a single specialty.

In conclusion, due to a considerable conversion rate of 13.8% among our study population which was consistent with results of other studies conducted in intermediate TB burden countries, annual TB screening testing is recommended particularly in such countries. This study also emphasizes the need for prospective multispecialty large-scale studies assessing the clinical utility and cost-effectiveness of repeat LTBI testing in long-term screening of psoriatic patients on TNFi therapy, which should be considered when designing rescreening strategies that can be based on a country's TB burden.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.