Original Article

Risk of tuberculosis reactivation with rituximab therapy

Amjad Alkadi, Najla Alduaiji, ABSTRACT
Ali Alrehaily
Background: Tuberculosis (TB) is one of the worlds deadliest diseases, and one-third
Department of Medicine, King Faisal Specialist
Hospital and Research Center, Riyadh, Kingdom
of the worlds population is infected with it. The link between antitumor necrosis factor
of Saudi Arabia therapy and reactivation of latent TB is well recognized. However, only limited studies
have evaluated the risk of TB with rituximab, a B-cell-targeting therapeutic agent
Address for correspondence: used recently for rheumatological diseases, primarily rheumatoid arthritis. Moreover,
Amjad Alkadi, Department of Medicine,
King Faisal Specialist Hospital and Research
no studies have assessed this risk in TB endemic regions with a high incidence and
Center, Riyadh, Kingdom of Saudi Arabia. prevalence of TB (e.g., Saudi Arabia).
E-mail: Amjad.alqadi@hotmail.com
Objective: To examine the risk of acquiring TB or activating latent TB in adult patients
with rheumatological disease who received rituximab therapy.
Methodology: Retrospective cohort study included 60 patients at King Faisal Specialist
Hospital and Research Centre, Saudi Arabia, between October 1, 2010, and March
31, 2011.
Result: Six patients (10%) were subsequently excluded because of the treatment
for latent TB (5 patients) or prior treatment for TB (1 patient). The follow-up period
was 6 months for 53 patients (98.15%) and 3 months for 1 patient (1.85%). During
follow-up, none of the patients received the purified protein derivative skin test while
radiological studies were performed for 30 patients (55.55%). 53 patients (98.15%)
had no symptoms suggestive of TB upon follow-up, and no patient experienced a TB
flare-up.
Conclusion: Rituximab can be considered a first line of therapy for the management
of rheumatological diseases in the presence of the risk of TB reactivation, especially
in endemic areas with a high prevalence and incidence of TB.
WEBSITE: ijhs.org.sa
ISSN: 1658-3639 Keywords: Rheumatoid arthritis, rituximab, systemic lupus erythematosus,
PUBLISHER: Qassim University tuberculosis

Introduction occurs in the tissue but may not be as dramatic. Moreover,

rituximab does not eliminate long-lived plasma cells, the
Tuberculosis (TB) is one of the most deadly diseases major source of protective antibodies.4 Rituximab was the
worldwide, and one-third of the worlds population is infected first B-cell-targeting therapeutic agent approved for the use in
with it. In 2014, nearly 9.6 people became sick with TB, and humans4 and was first approved for the treatment of lymphoma
about 1.5 million TB-related deaths occurred worldwide.1 In based on studies in oncology and hematology and has been
2014, Saudi Arabia had a population of 30,770,375.2 The total more recently approved for the use in rheumatology. 4,5 In
number of cases of TB was 3248 according to a report from the particular, a 2-year, multicenter, randomized, double-blind,
World Health Organization in 2014. Moreover, the incidence placebo-controlled, Phase III trial of rituximab therapy showed
of TB was 12/100,000, and the prevalence was 16/100,000 of that patients with an inadequate response to antitumor necrosis
the Saudi population.3 factor (anti-TNF) had significant and clinically meaningful
improvements in rheumatoid arthritis (RA) activity.6
Rituximab is a chimeric monoclonal antibody (human constant
regions and mouse variable regions) that recognizes human The link between anti-TNF therapy and reactivation of latent
CD20, a cell surface glycoprotein expressed on B-cells from TB is well recognized. Patients receiving anti-TNF therapy
early in development in the bone marrow until terminal are more likely to present with disseminated infection,
differentiation into plasma cells. After a single course of which carries considerable mortality.7-9 Although no studies
rituximab, the peripheral blood routinely remains depleted have reported increased TB or opportunistic infections
of B-cells for 6-12 months. In addition, depletion of B-cells with rituximab in clinical trials,10 the American College of

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 Alkadi, et al.: Risk of Tuberculosis Reactivation with Rituximab Therapy
Rheumatology in 2008 recommended screening patients for TB Ethical considerations
before rituximab therapy.11 On the other hand, an international
expert committee concluded that there is no evidence indicating The study was performed after being approved by the Office of
the necessity to screen patients systematically for TB before Research Affairs, the Research Advisory Council, KFSH and
12
using rituximab in those with RA. Furthermore, the safety RC. Since the present study was a retrospective observational
and efficacy of rituximab was demonstrated in case reports of chart review study, no patient consent was required.
RA patients who had developed TB while under treatment with
anti-TNF or who had a history of the treatment for pulmonary Statistical analysis
13-15
TB. In addition, a case report of active TB and RA was Data were entered in the form of a code (to protect patient
treated with anti-TB and rituximab a week later with recovery confidentiality) into a Microsoft Office Excel 2007 spreadsheet
of TB and remission of RA.15 and subsequently analyzed by a statistician at the statistical
department of KFSH and RC.
However, because these previous studies did not directly
address this issue or were limited in scope, additional studies
would be beneficial in confirming the safety of rituximab Results
in the presence of a risk for TB, particularly in TB endemic
regions with a high incidence and prevalence of this disease. A total of 60 adult patients with rheumatological disease
Hence, the study aim was to evaluate the risk of acquiring received rituximab therapy. 6 patients (10%) were subsequently
TB or reactivation latent TB in patients with rheumatological excluded from the study because they were being treated for
disease who received rituximab therapy in endemic area such latent TB (5 patients) or had been recently treated for TB
as Saudi Arabia. (1 patient). Therefore, 54 patients were included in the study.

Methods The mean age (standard deviation) of the patients (46 females,
8 males) was 37.2 (14.5) years (range, 14-65 years). The
Patient population common rheumatological disease was RA (24 patients
[44.44%]), followed by systemic lupus erythematosus (11
Candidates for this study consisted of adult patients (14 years patients [20.37%]). Among the remaining patients
or older according to hospital policy) with rheumatological (35.19%), 5 patients had dermatomyositis; 5, overlap
diseases who received rituximab at King Faisal Specialist syndrome; 3, juvenile idiopathic arthritis; 2, polymyositis;
Hospital and Research Centre (KFSH and RC) between 2, Wegeners granulomatosis; 1, mixed connective tissue
October 1, 2010, and March 31, 2011. Patients were included disease; and 1, scleroderma (Table 1). Rituximab was given
regardless of whether or not they underwent a TB screen as per the RA protocol to 45 patients (83.33%); the lymphoma
(e.g. tuberculin skin test and chest X-ray) before rituximab protocol was applied to 8 patients (14.81%) while 1 patient
therapy, whereas patients who had received treatment for TB received a different regimen.
were excluded from the study.
Table 1: Baseline characteristics and diagnosis

Study design Baseline Number (%)

Characteristics

The study design was a retrospective cohort design. We as Saudi Arabia and (2) to establish a relationship between the
collected the following information from the patients charts dose of rituximab and the risk of TB, if any.
and the patients electronic information system: Demographic
data (gender and age); primary diagnosis; rituximab regimen,
which was either a RA protocol (1000 mg on days 1 and 15)
or a lymphoma protocol (375 mg/m2 once weekly as a course
of 4 intravenous infusions on days 1, 8, 15, and 22); and the
tuberculin skin test and a radiological study before rituximab
therapy. Patients were followed up to 6 months for symptoms
suggestive of TB and tuberculin skin test and radiological
study if any.

Study endpoints
The study endpoints were (1) to determine the risk of acquiring
TB or reactivation latent TB in patients with rheumatological
disease who received rituximab therapy in endemic area such

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 Alkadi, et al.: Risk of Tuberculosis Reactivation with Rituximab Therapy
Age (mean, yearsSD) 37.214.5
Gender
Male 8 14.81
Female 46 85.19
Diagnosis
RA 24 44.44
SLE 11 20.37
Others 19 35.19
Dermatomyositis 5
Overlap syndrome 5
JIA 3
Polymyositis 2
WG 2
MCTD 1
Scleroderma 1

WG: Wegeners granulomatosis, MCTD: Mixed connective tissue disease

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 Alkadi, et al.: Risk of Tuberculosis Reactivation with Rituximab Therapy
Before rituximab therapy, the purified protein derivative (TNF-) targeted biologics and recently licensed TNF-
(PPD) skin test was performed for 11 patients (20.37%), and inhibitors which was done through review of data from clinical
the results were negative. However, the majority of patients, trials and national registries. The study was retrospective and
43 (79.63%), did not receive the PPD skin test. its conclusion is similar to ours indicating safety of rituximab.17

Radiological examinations before rituximab therapy were On the other hand, a case report was published about
performed for 38 patients (70.37%). Of these patients, occurrence of knee TB after rituximab therapy in patient
37 (68.52%) had normal results or no findings suggestive of with RA and therefore they suggested TB screening before
TB while 1 patient (1.85%) had findings suggestive of TB in rituximab therapy.18 However, that patient had two pulses
the form of bronchiectatic changes and pleural thickening. of glucocorticoid which by itself contribute to the risk of
However, 16 patients (29.63%) did not have any radiological reactivation of TB and thus limited any conclusion from this
study. case.

The patients were followed for an adequate period; 53 patients Limitations of the Study and
(98.15%) were followed for 6 months while 1 patient (1.85%) Recommendations for Future Research
was followed for 3 months. During the follow-up, none of the
patients received the PPD skin test while radiological studies The study was retrospective in nature, and thus, we had
were conducted for 30 patients (55.55%). Of these 30 patients, incomplete TB screening before rituximab therapy and
29 (53.7%) showed normal results or findings not suggestive incomplete follow-up investigations. In addition, the sample
of TB while 1 patient had a suspicious finding in the form of size was small, and one patient had short follow-up only
several nodules in the right and left upper lobes on top of the 3 months after therapy which is still shorter duration than the
bronchiectatic changes. Furthermore, 53 patients (98.15%) duration of action of rituximab which is 6 months. Therefore,
had no symptoms suggestive of TB upon follow-up. However, future studies should be conducted prospectively with a larger
the 1 patient who had findings suggestive of TB before and size group to confirm the above findings and to make sure of
after the therapy developed respiratory and constitutional adequate follow-up duration.
symptoms. The patient was investigated, and TB was ruled
out. Furthermore, the patient responded well to antibiotics and Acknowledgments
was diagnosed with bronchiectasis exacerbation secondary to
bacterial infection. Thus, no patient was found to have a TB This work was supported by King Faisal Specialist Hospital
flare-up after rituximab therapy. and Research Center, Riyadh, Saudi Arabia.

Discussion and Conclusion References

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