Disseminated tuberculosis associated with fingolimod treatment in a patient with multiple sclerosis

Abstract

Fingolimod is a sphingosine-1-phosphate receptor modulator approved as a disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (MS). A woman in her 30s was treated with fingolimod for relapsing-remitting MS. After 7 years of treatment, she presented with non-productive cough, night sweats, breathlessness and unintentional weight loss. She had a negative interferon-gamma release assay (IGRA). A high-resolution CT thorax showed innumerable miliary opacities in both lungs. Bronchoalveolar lavage was positive for Mycobacterium tuberculosis complex PCR. An MRI head showed multiple small punctate contrast-enhancing lesions most typical for tuberculomas. We describe the first reported case of disseminated tuberculosis (TB) associated with fingolimod treatment. Patients who are receiving DMT must be closely observed for the development of opportunistic infections, and IGRA results should be interpreted with caution. Screening for latent TB prior to commencing fingolimod should be considered on an individual basis. The management of TB in MS patients on DMT requires an interdisciplinary approach.

Background

Fingolimod has been approved by the National Institute for Health and Care Excellence (NICE) since 2012 as an oral disease-modifying therapy (DMT) for highly active relapsing-remitting multiple sclerosis (MS). It is a sphingosine-1-phosphate (S1P) receptor modulator that, by binding to S1P receptors on lymphocytes, prevents egression of lymphocytes from lymph nodes. As a result, lymphocytes that autoreact to myelin causing demyelination in MS are unable to enter the peripheral circulation or cross the blood-brain barrier. When fingolimod treatment is discontinued, there is a recognised risk of rebound with MS relapse as the lymphocytes re-enter the circulation.

Fingolimod is associated with a significantly increased risk of infection, particularly lower respiratory tract infection and herpes virus infection.¹ Tuberculosis (TB) during fingolimod therapy had been reported in two cases previously.^{2 3} Although screening for latent TB should be considered in high-risk patients,⁴ routine screening is not advised by NICE or by the manufacturers of fingolimod.^{5 6}

Case presentation

A woman in her 30s was diagnosed with relapsing-remitting MS in 2007 and was treated with interferon beta-1a as a DMT. In 2013, she had a further relapse indicating that she had highly active relapsing-remitting MS, and interferon beta-1a was escalated to fingolimod. The patient was a non-smoker, lifelong resident of the UK, of mixed Indian and British ethnicity and worked as a speech and language therapist.

In 2013, prior to commencing fingolimod, a chest X-ray to screen for infection was normal. In 2015, the initial report of a routine brain MRI scan for MS monitoring raised concern for new demyelinating lesions. As escalation of DMT may have been required, an interferon-gamma release assay (IGRA) test was done and the result was negative. On neuroradiology review of the MRI, there were no new demyelinating lesions; therefore, escalation of DMT was not required. The patient continued on fingolimod with no relapses and stable brain MRI.

In 2020, after 7 years of treatment with fingolimod, the patient presented to the respiratory clinic with a non-productive cough, night sweats, fatigue, breathlessness and unintentional weight loss. There were no new neurological symptoms.

Investigations

Initial blood tests showed lymphopenia (0.22×10⁹/L), present since 2013, elevated inflammatory markers (erythrocyte sedimentation rate mm/hour and C-reactive protein 45 mg/L) and negative HIV antibody/antigen. No growth resulted from standard sputum culture. A chest X-ray showed multiple, bilateral small nodules with coalescence in the upper zones. High-resolution CT thorax confirmed the presence of a ‘miliary’ pattern of innumerable tiny, non-cavitary nodules, distributed randomly, with a peripheral tree-in-bud pattern in the upper lobes and a single calcified nodule in the right upper lobe (figure 1). A bronchoscopy was performed, and an automated liquid culture of lavage fluid from the left upper lobe identified a presumptive Mycobacterium. Mycobacterium tuberculosis complex PCR was positive, and the whole genome sequencing confirmed Mycobacterium tuberculosis, fully sensitive to first-line antituberculosis drugs.

Figure 1.

Coronal section of high-resolution CT thorax showing innumerable miliary opacities in both lungs and peripheral tree-in-bud changes more noticeable in the upper lobes.

A brain MRI to assess MS lesion load incidentally showed multiple small punctate contrast-enhancing lesions distributed throughout the cortex, deep white matter and pituitary (figure 2). A neuroradiological opinion was that the MRI changes were most typical for tuberculomas, although other inflammatory causes of immune-reconstitution inflammatory syndrome and progressive multifocal leukoencephalopathy were considered possible. A lumbar puncture to investigate for inflammatory causes showed normal cerebrospinal fluid (CSF) constituents with white cell count of 1×10⁶/L, total protein 0.41 g/L and glucose 3.4 mmol/L (serum glucose 5.0 mmol/L). No acid-fast bacilli were seen in the CSF, and culture was negative for mycobacteria.

Figure 2.

(A)Brain MRI May 2019, non-contrast coronal d inversion recovery (FLAIR) sequence showing periventricular demyelination. (B and C) Brain MRI September 2020, non-contrast coronal FLAIR sequence and axial T2 sequence showing new lesions. (D) Brain MRI October 2020, post-contrast axial T1 sequence showing new lesions to have punctate contrast enhancement.

Treatment

The patient was diagnosed with disseminated TB. Standard UK antituberculous therapy of rifampicin, isoniazid (with pyridoxine), pyrazinamide and ethambutol was started and fingolimod was discontinued. Due to the persistence of lymphopenia and concerns over the impact of ongoing immunosuppression, the drug-intensive phase 4 of treatment was extended from 2 to 4 months, with a total of 12 months of antituberculous chemotherapy given. An alternative DMT was required. After the patient’s lymphocyte count had recovered, ocrelizumab treatment was commenced.

Outcome

A brain MRI repeated after a 1-month interval showed improvement, with decreased enhancement of the tuberculomas and no new lesions. The patient has completed 12 months of TB treatment, has returned to work and has had a symptomatic and radiological recovery. MS disease control has remained stable on ocrelizumab therapy.

Discussion

TB behaves differently depending on the host’s immune response. In the immunocompetent patient, infection with TB prompts a T cell response with CD4 T cells playing a central role in granuloma formation to contain the bacteria.⁷ In the immunosuppressed patient, where this response is impaired, the bacteria is able to spread haematogenously leading to disseminated TB.

Fingolimod sequesters lymphocytes in the lymph nodes, with a preferential retention of CD4 over CD8 T cells. This results in both a reduction in the overall number of circulating lymphocytes and a reversal of the normal CD4 and CD8 ratio. Additionally, when T cells are exposed to fingolimod, there is a reduced production of cytokines such as tumour necrosis factor-alpha and interferon-gamma, which play a critical role in the immune response to TB.⁸

Our patient presented with a miliary pattern of pulmonary TB and cerebral tuberculomas, suggesting haematogenous spread. Although other inflammatory causes of the brain lesions were considered, the normal CSF results supported a diagnosis of cerebral tuberculomas. Considering the presentation of disseminated TB and the mechanism of action of fingolimod, the outcome of an interspecialty discussion between respiratory, infectious diseases and neurology was that fingolimod therapy was likely causative.

TB during fingolimod therapy had been reported in two cases previously.^{2 3} Both patients were successfully treated with antituberculosis therapy. One of the patients was diagnosed with tuberculous meningitis and fingolimod was discontinued. There is no further description of the other case, and there are no reported cases of disseminated TB associated with fingolimod therapy.

Our patient had not been screened for latent TB prior to commencing fingolimod; however, she had a normal chest X-ray prior to fingolimod treatment and a negative IGRA during fingolimod treatment. For individuals who are immunosuppressed or on DMTs that affect lymphocytes, the results of IGRA should be interpreted with caution. The IGRA test relies on the production of interferon-gamma by lymphocytes in response to TB; however, if this immune response is impaired, there is a higher risk of an indeterminate or false negative result. Clinicians should be aware that a negative IGRA taken while the patient is receiving immunosuppression does not exclude latent TB, and a detailed assessment of TB risk (including exposure history, population prevalence and imaging) may be warranted.^{9 10}

The management of our patient required an interdisciplinary approach to balance adequately treating TB infection while minimising the risks of MS relapse and drug toxicity. The TB multidisciplinary team, alongside the patient’s preferences, informed the decision to extend the four-drug treatment in the context of persistent lymphopenia.

It was agreed that an alternative MS DMT should be commenced after the patient’s lymphocyte count had recovered. The MS multidisciplinary team suggested ocrelizumab as it is an anti-CD20 monoclonal antibody that principally depletes B cells and has relatively little effect on T cells. Furthermore, the anti-CD20 therapies are not associated with an increased risk of TB.¹¹

The use of immunomodulatory therapies is expanding, and this case highlights the importance of understanding their mechanisms of action and potential complications. In such cases, an interdisciplinary approach is essential to ensure optimum management of both the pre-existing condition and the treatment complication.

Learning points.

• Opportunistic infections, such as tuberculosis (TB), are a potential complication of fingolimod treatment.

• Patients who are receiving a disease-modifying therapy (DMT) must be closely observed for the development of complications or opportunistic infections.

• Screening and rescreening for latent TB prior to commencing fingolimod should be considered on an individual basis.

• The results of interferon-gamma release assay should be interpreted with caution for patients who are immunosuppressed or on DMT.

• The management of TB in patients on DMT for multiple sclerosis requires an individualised and interdisciplinary approach with the involvement of neurology, respiratory and infectious disease specialists.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).