Neurotuberculosis in a Patient with Ulcerative Colitis Using Long-Term Adalimumab: A Rare Case

Background

Tuberculosis (TB) is considered a worldwide public health problem and is a disease with high incidence and prevalence worldwide. It is estimated that one-third of the world’s population has latent TB, and approximately 10 million people had TB in 2019, including 32% of women over 15 years of age [1].

The 2 main forms of inflammatory bowel disease (IBD) are Crohn disease and ulcerative colitis (UC); these immune-mediated conditions are characterized by chronic inflammation, with periods of remission and exacerbation. UC affects the mucosa and submucosa of the colorectal segment and, in more severe cases, causes bleeding and ulcers [2]. There is no clinical intervention that can cure the disease. Adequate treatment for UC is still quite limited, and constant searches for new forms of treatment are currently underway. In the past 2 decades, the management of UC has evolved, especially due to the increasing use of biological agents worldwide. However, the use of biological products such as infliximab and adalimumab, which both neutralize tumor necrosis factor alpha (TNF-α) and have immunomodulatory and immunosuppressive actions, increases the risk of serious and/or opportunistic infections, such as TB [3]. There is a high prevalence of tuberculosis in emerging countries, and the use of anti-TNF in patients with UC increases the risk of atypical reactivation of its latent form or primary infections.

In this article, we aimed to report a case of neurotuberculosis (NTB) in a female patient with UC 4 years after the start of therapy with adalimumab and to discuss the clinical aspects, diagnosis, management, and prognosis.

Case Report

This case report describes a 34-year-old female patient who had severe pancolitis UC (Figure 1) since the age of 20 years. UC was diagnosed during an emergency hospitalization in which the patient presented with bloody diarrhea with mucous that occurred at a frequency of 10 episodes a day, and the diarrhea was associated with painful abdominal cramps. The patient also felt urgent evacuation that had been gradually worsening for more than 5 months; in addition, the patient had changes in her inflammatory markers, with an increased C-reactive protein level and iron deficiency anemia. A colonos-copy was performed at that time, which showed severe pancolitis, characterized by hyperemia, continuous edema from the rectum to the cecum, erosions and ulcerations throughout the colon and rectum, and friability of the mucosa. Initially, for the rescue of severe acute colitis, the patient received intravenous corticosteroids on admission, but there was no response. Then, after carrying out all the screening tests that are recommended for starting biological therapy, including a Mantoux test, which was negative, infliximab was started with a good response. The patient was discharged with maintenance infliximab in combination with azathioprine, which she took for 2 years. The patient required drug optimization due to non-healing of the mucosa but had a loss of secondary response, and the patient’s drug therapy was changed to monotherapy adalimumab, which she had been taking for the past 4 years.

In a routine consultation at an IBD outpatient clinic of a reference hospital in Brazil, she reported continuous and progressive holocranial headaches in the last 20 days, which were associated with daily afternoon fevers of 38 and night sweating. She denied any other symptoms. She denied exposure to TB or familiarity with TB.

Her laboratory tests showed no evidence of anemia, changes in leukocytes, or changes in C-reactive protein. Colonoscopy with biopsies for cytomegalovirus testing and testing for other infections were also performed, and no abnormalities were noted. The analysis of cerebrospinal fluid showed protein, 32 mg/dL; glucose, 59 mg/dL; lactate, 13.8 mg/dL; leukocytes, 1/mm3; red blood cells, 0; and adenosine deaminase, 0.01 u/L. The patient had negative Chinese ink, fungal culture, ELISA cysticercosis, toxoplasmosis immunofluorescence, cytomegalovirus, VDRL, and HTLV I and II tests.

On cerebral magnetic resonance imaging, small enhancing cortical lesions in the left frontal lobe and 2 other larger lesions in the left temporal lobe and right frontal lobe were found and were suggestive of tuberculomas, the larger measuring approximately 10 mm (Figure 2). The diagnostic hypothesis of NTB was raised, and treatment was started.

Sustained deep remission was maintained with adalimumab for 4 years. Annually, she was screened for latent TB with chest X-rays and a Mantoux tuberculin skin test, and the TB test results were always negative.

The initial management consisted of the suspension of immunosuppressive therapy and treatment with rifampicin, isoniazid, ethambutol, pyrazinamide, and prednisone. At the time of this report, 12 months after the diagnosis, the patient showed clinical and neurological improvement and was clinically asymptomatic, with no changes in her laboratory tests and without neurological sequelae. Her disease was maintained with prednisone, as indicated by the neurologist. A new colonoscopy was scheduled to define her maintenance drug treatment.

Discussion

TNF-α is a pro-inflammatory cytokine that acts in the formation and maintenance of granulomas in response to intracellular organisms and has an important role in the pathogenesis of chronic inflammatory diseases and other immune-mediated diseases, whether in the activation, differentiation, and recruitment of different immune cells [4]. With the emergence of immunobiological antibodies to TNF-α, the reality in the management of IBD, whether UC or Crohn disease, with moderate to severe disease has changed. These agents are able to delay the natural course of the disease, decrease the number of surgeries, and improve the quality of life of patients [5].

Anti-TNFs critically alter the regulation of inflammatory processes and apoptosis pathways and the activation, recruitment, and differentiation of cells, reducing tissue damage. There is no doubt about the benefit of using anti-TNFs in patients with UC. However, in addition to their limited effectiveness, these drugs are not entirely harmless and have relevant adverse effects, such as the development of severe infections [6]. In this context, when neutralizing TNF-α, there is an immunomodulatory and immunosuppressive action, as TNF-α interferes with the granulomatous immune response [7], increasing the risk of serious and/or opportunistic infections, among which TB is one of the most frequent [8].

After starting anti-TNF therapy, the risk of developing TB increases by 1.6 to 25 times [6–9]. In TB-endemic countries, the risk of developing active TB in patients using anti-TNF is 10%. There is evidence that this occurs, on average, 12 weeks after starting treatment [7]. In addition, anti-TNF therapy increases not only the risk of developing active TB [10] but also the reactivation of TB, leading to the development of more serious complications, dissemination to extrapulmonary sites, and worse outcomes [11]. The high risk for the development of TB may be related to the reduction in CD8+ cells responsible for the antimicrobial activity against Mycobacterium tuberculosis [12].

The extrapulmonary involvement of TB affects approximately 15% of patients. The involvement of the central nervous system is considered one of the most serious extrapulmonary disorders of TB [1]. NTB is the most severe form of TB [13] and is responsible for 1% to 5% of the cases of extrapulmonary involvement [1,14,15]. TB in the central nervous system is usually due to the spread of pulmonary infection, rarely occurs in isolation, and usually occurs with the presence of tuberculomas [16], as reported in this case. When it occurs, association with lung disease is more common (approximately 59% of cases). A delayed diagnosis can lead to worse outcomes, with high morbidity and mortality [17].

Isolated NTB without other manifestations is a rare form of infection in patients with IBD taking anti-TNF. As seen in our case report, a patient with UC developed isolated disease. The diagnosis of this condition is based on the presence of suspicious symptoms and the biochemical analysis of the cerebro-spinal fluid, and the diagnosis is confirmed by the detection of tuberculosis bacillus in the cerebrospinal fluid.

In patients taking anti-TNF medications and with the use of new technologies, the understanding of the pathogenesis of the development of latent TB to active disease and the discovery of new biomarkers are necessary [18]. The tuberculin skin test has high sensitivity, and in a recent study, it minimized false-negative results in the identification of patients with TB when compared with the interferon-γ release assay (IGRA) [19].

In immunosuppressed patients, especially patients on anti-TNF or steroids and patients with HIV or TB, screening tests may not identify latent infections. That is, patients with IBD taking anti-TNF medications have an increased risk for false negativity on the tuberculin skin test and IGRA [20].

We understand that the diagnosis of NTB would be facilitated by the identification of M. tuberculosis by direct methods, which did not occur in this case. However, even in the absence of circumstantial evidence of tuberculosis, as mentioned above, the hospital’s Neurology team, together with the Infectiology and Gastroenterology Departments, evaluated the case and performed the treatment. The patient’s history of taking adalimumab, the history of residing in an endemic area of tuberculosis, the changes found in the resonance images, and the patient’s clinical manifestations all guided the decision for a more objective conduct, since the other examinations performed were negative for other pathologies. Our diagnosis was confirmed retrospectively based on the response to anti-TB drug therapy.

Physicians and health personnel that treat patients with IBD should continue to actively and routinely search for latent TB through periodic reevaluations with targeted consultation and should note classic TB symptoms, such as cough, fever, weight loss, night sweating, performance laboratory tests, chest X-ray, and tomography, even when patients have taken the medication for a long period, since there is no single criterion standard test for detecting the disease [21].

Early recognition with the correct diagnosis, suspension of anti-TNF drugs, and early treatment are fundamental steps for therapeutic success, and these could avoid disease aggravation and reduce sequelae, neurological complications, and mortality.

Conclusions

The reported case is important because it was a patient with isolated TB in the central nervous system without pulmonary involvement, and the patient had underlying UC and took adalimumab. Even in patients undergoing anti-TNF-α therapy for a long time, the possibility of TB should always be considered in the presence of a fever of unknown origin.