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Tuberculin test conversion in patients with chronic inflammatory arthritis receiving biological therapy.

Introduction

Chronic inflammatory arthritis is a disabling condition that reguires early and appropriate treatment. The introduction of biological therapies has improved the treatment of this disease. These medications have an acceptable safety profile, although increasing the risk of opportunistic infections (1, 2). Tumor necrosis alpha (TNF-[alpha]) inhibitors (TNFi) were the first ones to be introduced and presently are used most frequently. TNF-[alpha] plays a key role in the formation and maintenance of granulomas responsible for containing intracellular pathogens, such as Mycobacterium Tuberculosis (MT). A fourfold increased risk of tuberculosis (TB) has been reported in patients under anti-TNF treatment (3, 4). Argentina is a country with an averageTB incidence. In 2011, a total of 10,618 cases were reported to the National Program (incidence rate, 26/100,000), and 640 people died from TB during 2010 (5).

The Mantoux test or TST was developed in the XIX century and is still in use. It is the only widely available method to detect latent TB. Despite of its long history, some aspects of its interpretation are still controversial (7, 8). The cutoff value to determine infection depends on the epidemiology of the region and the patient type. In our country, theTB Argentine Consensus that took place in 2009 determined a cut/off value for the general population of [greater than or equal to]10 mm and [greater than or equal to]5 mm (9) for immunocompromized patients and high-risk contacts.

TST evaluates delayed hypersensitivity (mediated by T lymphocytes) to MT proteins. The reaction occurs in case of the exposure to bacillary proteins, the BCG vaccination, or mycobacterial infection. A negative test means that there is no hypersensitivity, and it is commonly interpreted as the absence of previous contact. However, two situations may occur:

People may lose responsiveness in time. This may be seen in elderly patients, infected or vaccinated after the age of 15 and who had no posterior infection (10).

The absence of reaction was described in patients with autoimmune diseases with compromised Th1 response (11).

Other situations unrelated to the patient's responsiveness in which the TST response can be modified also exist. These include differences in the administration of the derivative and/or mode of reading or "booster" phenomenon. A TST conversion represents latent or recent infection.

The purpose of our study was to evaluate the freguency of a TST conversion in patients with autoimmune arthropathies receiving biological therapy. Furthermore, we aimed to investigate the association between the TST shift and an active MT infection and to explore other variables that could affect the TST conversion.

Methods

A multicenter, observational study including patients with chronic inflammatory arthritis was performed. Three rheumatologic centers participated, two from the Autonomous City of Buenos Aires (Instituto de Rehabilitacion Psicofisica and Hospital de Agudos General Enrigue Tornu) and one from La Plata City (Hospital San Martin de La Plata). Outpatients with rheumatoid arthritis (RA) according to the ACR 1987 (12) and ACR/EULAR 2010 (13) criteria; juvenile idiopathic arthritis (JIA) according to the ILAR criteria (14); spondylarthritis (SpA) by the ASAS axial criteria (15) or peripheric SpA criteria (16); and psoriatic arthritis (PsA) according to the CASPAR criteria (17) were included into the study. Patients receiving biological therapy with TNF inhibitors (TNFi) (etanercept, adalimumab, infliximab, certolizumab, golimumab), interleukin 6 (IL-6) inhibitor (tocilizumab), or inhibitor of the T-lymphocyte CTLA4 co stimulatory signal (abatacept) were included. All the patients had to have a previous negative TST test ([less than or equal to]5 mm) prior to the beginning of the first biological treatment. Subseguently, a second TST test was performed in all patients within a time interval between 2 and 22 months from the first one, and without there being any change in the biological agent. This time interval was established to avoid the"booster" phenomenon and the loss of the antigenic stimuli (6-8). The TST test consisted of injecting 0.1 mL of TST (eguivalent to 2 tuberculin units), followed by a 48-72-hour papule measurement by trained blind readers. Positivity was defined as a variation in the diameter of the papule greater than 5 mm compared to the first TST test (9).

Patients with a history of active or latent TB, or patients who had two TST tests performed outside the established interval time, and patients with acute or chronic infections that could interfere with the result were excluded from the study. All patients provided written consent to participate in the study. Sociodemographic data (age, sex, type of residency and education) were collected. Certain pathological conditions associated with an increased risk of contracting TB were especially collected, including the following:

Overcrowding, which according to the World Health Organization (WHO) means three or more people per bedroom.

Low weight, which according to the WHO means protein caloric deficiency that results in a body mass index (BMI) <18.5.

Alcoholism, which according to the WHO means daily alcohol intake greater than 20-40 grams in women and 40-60 grams in men (18).

Poverty, which according to the National Institute of Statistics and Census in Argentina (19) means monthly income less than $1500 (Argentinean pesos) for a family with three children (August, 2013), and this date coincided with our study.

Variables related to the disease such as its duration, comorbidities, and treatments received were investigated by direct interview with the patient and from medical records. High steroid use was considered as prednisone or eguivalent [greater than or equal to]10 mg/day or three or more injectable corticosteroids in 1 year. The type and dose of disease-modifying anti-rheumatic drug (DMARD) and biologic treatment were noted.

Disease activity was assessed using RAPID 3 (20) and DAS28 (21) for RA and PsA, while BAS-DAI (22) was used for patients with axial SpA (axSpA). Functional capacity was evaluated by means of HAQ (23) and BASFI (14).

Statistical analysis

Descriptive statistics were performed to calculate the means, standard deviations, medians, interquartile ranges (IQR), frequencies, and percentages. Continuous data were analyzed using the T-test or Mann-Whitney U test, and categorical data were analyzed with Chi2 and Fisher's exact test. A multiple logistic regression analysis was performed using the presence of a TST conversion as the dependent variable to detect variables associated with the conversion. A p-value less than 0.05 was considered to be statistically significant.

Results

Eighty-five patients were included into the study, 63 (74.1%) with RA, 14 (16.5%) with PsA, 4 (4.7%) with JIA, and 4 (4.7%) with axSpA. Sixty-seven patients were female (78.8%). Most patients lived in urban areas (98.8%), and only one patient lived in a rural zone. Patients had a median age of 52 years (IQR 46-60), median disease duration of 11.5 years (IQR 4.8-16), and a median schooling length of 12 years (IQR 7-14). Eleven patients lived under overcrowding conditions (12.9%), and seven below the poverty line. Fourteen patients (16.5%) had TB risk factors, some of them more than one associated factor (17 factors in 14 patients): 9 (10.6%) had type 2 diabetes, 1 (1.2%) alcoholism, 2 (2.4%) had contact with TB patients, and 5 (5.9%) presented a TB history with complete treatment. Seventy-eight patients (91.8%) received concomitant biologic therapy with classic DMARDs, and 42 (49.4%) received steroids of whom 16 were under high doses ([greater than or equal to]10mg/day) (Table 1).

A tuberculin skin test conversion was seen in 8 (9.4%) patients, being more frequent in men than in women (62.5% vs 37.5%; p=0.009) and in those with longer disease duration (mean 226[+ or -]109 months vs mean 130[+ or -]105 months [p=0.017]). These associations remained significant after adjusting for age. No association was found between the TST conversion and disease activity (DAS28, RAPID3, BASDAI), disability (HAQ-A, BASFI), comorbidities, or other sociodemographic variables.

Patients with the TST conversion were further evaluated by the Infectology or Pneumonology Departments and received prophylactic isoniazid at a dose of 300 mg/day. After a median follow-up period of 14.8 months, only one patient developed active pulmonary TB. This patient suffered from type 2 diabetes, had a history of treated TB in the past, and received high-dose corticosteroid therapy, which could explain other possible risk factors (Table 2).

Discussion

Given the known increased risk of TB in patients treated with biological therapies, the present study investigated the frequency of tuberculin conversion in patients with chronic inflammatory diseases receiving biologics (17). Several European registries have reported an increased frequency of TB in patients with RA under biologic treatment (4, 24). This incidence was highest among those patients who did not perform an adequate screening for latent TB, and extrapulmonary forms are the most frequently observed (23).

A Korean study revealed that 28 out of 86 RA patients with biologic treatment had a TST conversion, encouraging annual monitoring of patients with a negative TST receiving biologics (25). Similar results were observed in Italy, where the conversion frequency was 13.6%, and no patients developed active TB (26). In our study, we observed a TST conversion in 9.4% of the studied population, more frequently among men and in those with longer disease duration. Only one patient developed active TB, although it is noteworthy that all patients with positive conversion received prophylaxis for latent TB with isoniazid.

There are reports of a greater frequency of anergy to TST in patients with chronic arthritis. In Turkey, JIA patients had more frequently a negative TST when compared to the healthy population (24% vs 6.6%) (11). Similar data were described in Peru, where 70% of RA patients had TST anergy in contrast to 26% of the general population (7).

Some limitations to our study include the lack of QuantiFERON test given its high cost. However, although some studies have shown greater sensitivity of this method compared to TST, the difference was not significant in a recent study (27). Second, all patients with a TST conversion received isoniazid, not knowing what would had happened if these patients did not receive the recommended prophylaxis. The national vaccination calendar in Argentina includes a mandatory dose of BCG vaccine to all newborns, before leaving the hospital where they were born. Since 2007, there is no longer a need for a second dose that took place at age 6, before entering primary school. For this reason, all our patients had received BCG, and its effect on TST results could not be evaluated. Finally, the study design does not clarify whether a TST test is really necessary after the initiation of a biologic therapy or whether prophylactic treatment should be given in case of a conversion.

In conclusion, in our cohort, a TST conversion in patients with chronic inflammatory diseases was low, and only one patient developed active TB. Further studies are reguired to establish the benefit-to-risk ratio of subseguent TST monitoring during biologic treatment and the conseguent need to conduct a prophylactic treatment.

Ethics Committee Approval: Ethics committee approval was received for this study from the Ethics Committee of Instituto de Rehabilitacion Psicofisica (Approval Date: June 3, 2015).

Informed Consent: Written informed consent was obtained from subjects who participated in this study.

Peer-review: Externally peer-reviewed

Author Contributions: Concept - G.C.; Design - M.C., E.E.S., O.L.C., MAC; Supervision - M.C., O.L.C., M.A.C., E.E.S.; Data Collection and/or Processing - E.E.S., O.L.C., M.A.C., A.G., A.I.M., C.G., O.R., E.G.C.; Analysis and/or Interpretation - O.L.C., M.A.C., E.G.C., E.E.S., C.G.; Literature Search - O.L.C., M.A.C., E.G.C., E.E.S.; Writing Manuscript - E.E.S., O.L.C., M.A.C., A.G., A.I.M., C.G., O.R., E.G.C.; Critical Reviews - E.E.S., O.L.C., MAC, A.I.M., C.G., O.R., E.G.C.

Conflict of Interest: The authors have no conflict of interest to declare.

Financial Disclosure: The authors declared that this study has received no financial support.

References

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(5.) 1980-2009-Instituto Nacional de Enfermedades Respiratorias E. Coni. PRO. TB.Doc.Tec. No. 16/09.

(6.) Ahmed AR, Blose DA. Delayed-type hypersensitivity skin testing. A review. Arch Dermatol 1983; 119:934-45. [CrossRef]

(7.) Ponce de Leon D, Acevedo-Vasguez E, Sanchez-Torres A, Cucho M, Alfaro J, Perich R, et al. Attenuated response to purified protein derivative in patients with rheumatoid arthritis: study in a population with a high prevalence of tuberculosis Ann Rheum Dis 2005; 64: 1360-1. [CrossRef]

(8.) Menzies D. Interpretation of repeated tuberculin tests boosting, conversion, and reversion. Am J Respir Crit Care Med 1999; 159: 15-21. [CrossRef]

(9.) Abbate E, Ballester D, Barrera L, Brian MC, Echazarreta A, Gaitan C, et al. Consenso Argentino de Tuberculosis. Rev Arg Med Resp 2009; 9:61-9.

(10.) Wang L, Tunner M, Elwood RA. Meta-analysys of the effect of bacilli Calmette Guerin vaccination on tuberculin test measurements. Torax 2002; 57:804-9.

(11.) Kiray E, Kasapcopur O, Bas V, Kamburoglu-Goksel A, Midilli K, Arisoy N, et al. Purified Protein Derivative Response in Juvenile Idiopathic Arthritis. J Rheumatol 2009; 36: 2029-32. [CrossRef]

(12.) Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315-24. [CrossRef]

(13.) Funovits J, Aletaha D, Bykerk V, Combe B, Dougados M, Emery P et al. The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: methodological report phase I. Ann Rheum Dis 2010; 69: 1589-95. [CrossRef]

(14.) Petty RE, Southwood TR, Manners P, Baum J, Glass D, Goldenberg J, et al, International League of Associations for Rheumatology Classification of Juvenile Idiopathic Arthritis: Second Revision, Edmonton, 2001. J Rheumatol 2004;31:390-2.

(15.) Rudwaleit M, van der Heijde D, Landewe R, Listing J, Akkoc N, Brandt J, et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondy-loarthritis (part II): validation and final selection. Ann Rheum Dis 2009; 68: 777-83. [CrossRef]

(16.) Rudwaleit M, van der Heijde D, Landewe R, Akkoc N, Brandt J, Chou C, et al. The Assessment of SpondyloArthritis international Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general. Ann Rheum Dis 2011; 70:25-31. [CrossRef]

(17.) Taylor TST, Gladman D, Helliwell P Marchesoni A, Mease P Mielants TST, et al. Classification criteria for psoriatic arthritis. Development of new criteria from a large international study. Arthritis Rheum 2006; 54:2665-73. [CrossRef]

(18.) Anderson P Gual A, Colon J. Alcohol TST atencion primaria de la salud: informaciones clinicas basicas para la identification TST el manejo de riesgos TST problemas. Washington, D.C.: OPS, [c]2008.

(19.) Informe costo de canasta basica Septiembre del 2013, INDEC (Instituto Nacional De Estadisticas TST Censos).

(20.) Maldonado Ficco TST, Perez Alamino R, Schneeberger EE, Maldonado Cocco JA, Citera G. Validation del cuestionario RAPID3 en una cohorte de pacientes con artritis reumatoidea temprana TST establecida, TST su correlation con otros indices de actividad. Rev Argent Reumatol 2011;22:31-9.

(21.) Prevoo MLL, van't Hof MA, Kuper TST, et al. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38:44-8. [CrossRef]

(22.) Citera G, Maldonado Cocco JA, Moroldo M, Burgos-Vargas R, Anaya J, Lopez I, et al. Validation de la version en espanol de los cuestionarios de capacidad funcional BASFI TST actividad de la enfermedad BASDAI en pacientes con Espondilitis Anguilosante en cuatro paises latinoamericanos. Rev Arg Reumatol 1999; 10(Supl 1): 25.

(23.) Citera G, Arriola MS, Maldonado Cocco JA, Rosemffet MG, Sanchez MM, Goni MA, et al. Validation and cross cultural adaptation of an argentine Spanish version of the health assessment guestionnaire disability index. J Clin Rheum 2004; 10:110-5. [CrossRef]

(24.) Dixon WG, Watson K, Lunt M, Hyrich L, Silman AJ, Symmons DP, et al. Rates of Serious Infection, Including Site-Specific and Bacterial Intracellular Infection, in Rheumatoid Arthritis Patients Receiving Anti-Tumor Necrosis Factor Therapy. Arthritis Rheum 2006; 54: 2368-76. [CrossRef]

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Osvaldo Luis Cerda (1), Maria de los Angeles Correa (1), Amelia Granel (2), Ana Ines Marcos (2), Claudia Giraldo (3), Oscar Rillo (3), Emilce Edith Schneeberger (1), Gustavo Citera (1)

ORCID IDs of the authors:

O.L.C. 0000-0002-1 137-1945;

M.A.C.C. 0000-0002-8885-390X;

A.G. 0000-0002-6287-1827;

A.I.M. 0000-0003-4846-0236;

C.G. 0000-0003-2345-4374;

O.R. 0000-0003-0469-7813;

E.E.S. 0000-0001-7671-5748;

G.C. 0000-0002-3724-1874

(1) Instituto de Rehabilitation Psicofisica, Buenos Aires, Argentina

(2) Hospital San Roque de Gonnet, La Plata, Argentina

(3) Hospital General de Agudos Dr, Ignacio Pirovano, Buenos Aires Argentina

Address for Correspondence:

Gustavo Citera, Instituto de Rehabilitation Psicofisica, Buenos Aires, Argentina

E-mail; gustavocitera@gmail.com

Submitted: 22 June 2018

Accepted: 15 September 2018

Available Online Date: 6 November 2018

DOI:10.5152/eurjrheum.2018.18096
Table 1. Sociodemographic, clinical, and therapeutic characteristics

Variable                               n=85

Male sex n (%)                         18 (21.2)
Disease:
  Rheumatoid arthritis n (%)           63 (74.1)
  Psoriatic arthritis n (%)            14 (16.5)
  Juvenile idiopathic arthritis n (%)   4 (4.7)
  Ankylosing spondylitis n (%)          4 (4.7)
Poverty n (%)                           7 (8.2)
Overcrowding n (%)                     11 (12.9)
Occupation
  Housewife n (%)                      26 (30.6)
  Professional n (%)                   13 (15.3)
  Retired n (%)                        11 (12.9)
  Administrative n (%)                 10 (11)
  Trader n (%)                          8 (9.4)
  Construction worker n (%)             3 (3.5)
  Health professional n (%)             2 (2.4)
  Student n (%)                         1 (1.2)
  Unemployed n (%)                     10 (11.8)
R isk factor (in 14 patients)          14 (16.5)
  Type 2 diabetes n (%)                 9 (10.6)
  Alcoholism n (%)                      1 (1.2)
  History of TBC with complete          5 (5.9)
  treatment n (%)
  Contact with TB n (%)                 2 (2.4)
Concomitant DMARD treatment
  Methotrexate n (%)                   72 (84.7)
  Leflunomide n (%)                    18 (21.2)
  Hydroxycloroquine n (%)               6 (7.1)
  Sulfazalasin n (%)                    1 (1.2)
Biologic treatment
  Etanercept n (%)                     27 (31.8)
  Adalimumab n (%)                     18 (21.2)
  Infliximab n (%)                     15 (17.6)
  Certolizumab n (%)                    1 (1.2)
  Golimumab n (%)                       3 (3.5)
  Abatacept n (%)                       8 (9.4)
  Tocilizumab n (%)                    13 (15.3)
Steroid therapy n (%)                  42 (49.4)
  Prednisone >10 mg/day n (%)          16 (18.8)

TB: tuberculosis, DMARD: disease-modifying anti-rheumatic drug

Table 2. Characteristics of the eight patients with TST conversion

Patient  Disease  Sex  Occupation           Poverty  Overcrowding  DBT

1        PsA      M    Professional         No       No            No
2        RA       F    Housewife            No       No            No
3        RA       F    Unemployed           No       No            No
4        PsA      M    Trader               No       Yes           No
5        RA       F    Trader               No       No            No
6        RA       M    Trader               No       No            No
7        RA       M    Construction worker  No       No            Yes
8        PsA      M    Trader               No       No            No

                           Use of       Type of
         TB       Steroid  Concomitant  bDMARD       Time of
Patient  history  use      cDMARD       Used         Chest X-Ray

1        No       No       No           Adalimumab   Normal
2        No       No       Yes          etanercept   Normal
3        No       No       Yes          etanercept   Normal
4        No       No       Yes          adalimumab   Normal
5        No       Yes      Yes          etanercept   Normal
6        No       No       No           tocilizumab  Normal
7        Yes      Yes      Yes          adalimumab   Abnormal
8        Yes      No       Yes          etanercept   Normal

         TST         Isoniazid
Patient  Conversion  Treatment     Active TB

1        22 months   Yes           No
2        8 months    Yes           No
3        12 months   Yes           No
4        7 months    Yes           No
5        9 meses     Yes           No
6        17 meses    Yes           No
7        20 meses    TB treatment  Yes
8        8 meses     Yes           No

DBT: diabetes, TB: tuberculosis, DMARD: disease-modifying anti-
rheumatic drug, RA: rheumatoid arthritis, PsA: psoriatic arthritis, SD:
standard deviation, Steroid use: prednisone >10 mg/day
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Title Annotation:Original Article
Author:Cerda, Osvaldo Luis; Correa, Maria De Los Angeles; Granel, Amelia; Marcos, Ana Ines; Giraldo, Claudi
Publication:European Journal of Rheumatology
Article Type:Report
Date:Mar 1, 2019
Words:3475
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