CASE

●
●The male patient at the age of 47 had a history of ankylosing spondylitis since 1983. He
has been on immunosuppressive treatment for twenty years. Since analgesic anti-inflammatory
drugs and glucocorticoids did not resolve the symptoms, it was decided on September 2012 that
TNFα antagonist monoclonal antibody should be initiated and various anti-TNF treatments
(adalimumab, etanercept and infliximab) had been prescribed. Patient was evaluated for
tuberculosis (TB) by TB Mendel-Mantoux skin test before immunosuppression treatment and
when Tuberculin Skin Test (TST) result was found to be 6 mm, it was recommended that patient
should use prophylactic Isoniazid 300 mg/day for 9 months. At first month control visit, no side
effects of Isoniazid were observed.
●After one month, patients discontinued Isoniazid as it induced his appetite too much and
did not share this information with his physician. In 2013 March, he referred again with the
complaints of cough, loss of weight and fatigue, which continued for a month without resolution.
On chest X-ray which yielded mild diffuse interstitial infiltrates and chest computed tomography
showed significant bilateral lung tissue opacities and pericardial effusion and sputum smear
examination, the patient was diagnosed with smear positive pulmonary TB. Following the
collection of multiple additional samples for microbiological investigations, a calculated anti-
tuberculosis quadruple treatment was immediately initiated with rifampicin, isoniazid, ethambutol
and pyrazinamide. Of those, citrate blood sample, TB PCR from sputum and staining for acid-
fast bacilli from bronchoalveolar lavage as well as lung biopsy were negative. Drug susceptibility
testing yielded that the patient’s microbic agent was sensitive to all TB drugs. After four drug
treatment for two months, it was decided to maintain Isoniazid and rifampicin treatment until the
completion of immunosuppressive treatment.

SIGNS AND SYMPTOMS

Opportunistic infections are associated with significant mortality and morbidity in

individuals with a compromised immune system. The risk factors for opportunistic infections
include congenital immunodeficiency, HIV infection, chronic diseases such as diabetes mellitus
and emphysema, malnutrition, older age and use of immunosuppressive medications such as
immunomodulators (methotrexate, thiopurines) corticosteroids and anti-TNFα therapy.

Patients presented with the classic but non-specific symptoms such as cough, fever, and
weight loss should be considered at risk for tuberculosis. Accordingly, previous chest X-rays
had been normal in our patient at admission to the primary care hospital. However, the
subsequent chest X-rays upon admission to our hospital were suggestive for miliary TB as
diffuse infiltrates evolved over the course of the disease.

Furthermore, the use of thioprine, 6-mercaptopurine (6-MP)) corticosteroids, and anti-

TNFα agents were associated with an increased risk. Combination of these agents increased
the risk manifold. The reactivation risk of latent TB is significantly associated with receiving
TNFα inhibitors, with a 5-fold higher risk of reactivation in the first 52 weeks after initiation of
therapy in the patients receiving TNFα inhibitors. This may be the reason for TNFα to be
essential for granuloma formation that is responsible for sequestration of mycobacteria. Thus,
inhibition of TNFα may cause reactivation of latent infection.

MEDICINE TAKEN

Adalimumab
Is an immunosuppressant that is indicated for patients with ankylosing spondylitis. It binds
with specificity to tumor necrosis factor-alpha (TNF-alpha) 2, 3 and inhibits its interaction with
the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis
factor expressing cells in vitro when in the presence of complement.
Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is
a naturally occurring cytokine that plays a role in normal inflammatory and immune responses.
Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic
arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic
inflammation and the joint destruction that are major complications of these diseases.
Furthermore, it alters biological responses that are induced/regulated by TNF, including
changes in the levels of adhesion molecules responsible for leukocyte migration during
inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M

Etanercept
Is also used to improve psoriatic arthritis and ankylosing spondylitis. Etanercept binds
specifically to tumor necrosis factor (TNF) and thereby modulates biological processes that are
induced or regulated by TNF. Such processes or molecules affected include the level of
adhesion molecules expressed, as well as serum levels of cytokines and matrix
metalloproteinase-3, also known as stromelysin.
***TNF is a naturally occurring cytokine that is involved in normal inflammatory and
immune responses.

Infliximab
Is a tumor necrosis factor (TNF-alpha or TNF-α) blocker and a chimeric monoclonal IgG1
antibody composed of human constant (75%) and murine variable (25%) regions. Infliximab
disrupts the activation of pro-inflammatory cascade signalling. Infliximab has shown to reduce
infiltration of inflammatory cells into sites of inflammation. It also attenuates the expression of
molecules mediating cellular adhesion {including E-selectin, intercellular adhesion molecule-1
(ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)}, chemoattraction {[IL-8 and
monocyte chemotactic protein (MCP-1)} and tissue degradation {matrix metalloproteinase
(MMP) 1 and 3}.

Isoniazid
Is an anti-TB agent indicated for the treatment of all forms of tuberculosis in which
organisms are susceptible. Isoniazid inhibits the synthesis of mycolic acids in susceptible
bacteria which results in loss of acid-fastness and disruption of bacterial cell wall. At therapeutic
levels, it is bactericidal against actively growing intracellular and extracellular Mycobacterium
tuberculosis organisms.
Rifampin (Rifampicin)
It is a first-line drug for treating TB, Is used with other anti tuberculosis to treat
pulmonary TB. Rifampicin works by killing the bacteria that are causing the infection. It does this
by targeting and inactivating a bacterial enzyme called RNA-polymerase. The bacteria use
RNA-polymerase to make essential proteins and to copy their own genetic information (DNA).
Without this enzyme the bacteria cannot reproduce and they die. It inhibits DNA-dependent
RNA polymerase, which impairs RNA synthesis; bactericidal.

BIBLIOGRAPHY
Adalimumab. (2005). Retrieved July 17, 2019, from
https://www.drugbank.ca/drugs/DB00051
Etanercept. (2005). Retrieved July 17, 2019, from
https://www.drugbank.ca/drugs/DB00005
Infliximab. (2005). Retrieved July 17, 2019, from https://www.drugbank.ca/drugs/DB00065
Isoniazid. (n.d.). Retrieved July 17, 2019, from
http://www.mims.com/philippines/drug/info/isoniazid?mtype=generic
Murray S, Mendel C, Spigelman M: TB Alliance regimen development for multidrug-
resistant tuberculosis. Int J Tuberc Lung Dis. 2016;20(12):38–41. 10.5588/ijtld.16.0069
[PubMed] [CrossRef] [Google Scholar]
Onal CO, Kibaroglu E (2014) Pulmonary Tuberculosis Caused By Immunosuppressive
Treatment. J Clin Case Rep 4: 383. doi:
10.4172/2165-7920.1000383