Rituximab Use and the Increased Risk of Reactivation of Latent Tuberculosis?

Tuberculosis (TB) is one of the world’s deadliest diseases, and one-third of the world’s population is infected with it. The link between anti-tumor necrosis factor (TNF-α) therapy and reactivation of latent TB is well recognized. The association of TB infections with the use of rituximab (RTX) is not well understood. Only limited studies have evaluated the risk of TB with RTX. The low or absent risk of latent TB reactivation associated with RTX use has been widely accepted worldwide. The use of RTX is associated with some side effects such as cytopenia and increased risk of infections such as John Cunningham virus reactivation leading to multifocal leukoencephalopathy. The role of RTX as an immunosuppressant has been established. RTX being an immunosuppressant can be considered to be related to infections such as TB. However, its association with TB in endemic countries such as India is yet to be understood. This is the case history of a 47-year-old female with recurrent digital ulcers and Raynaud’s phenomenon being diagnosed with a case of systemic sclerosis (SSc) in 2008 (Scl 70 antibody positive). She was put on hydroxychloroquine and oral corticosteroids. She also gave a history of infertility and took treatment for the same. She delivered twin children 11 years back (2012) through in vitro fertilization. She discontinued the treatment for almost 10 years when her scleroderma progressed to multiple digital ulcers and fingertip resorption. At the same period, she also noticed progressive breathlessness. She consulted another doctor who advised RTX 500 mg in 2 doses at 1-month interval. After 5 months of RTX therapy, the patient developed an intermittent cough, low-grade fever, and loss of appetite. She also developed blackish discoloration and swelling of the left 2nd toe [Figure 1]. The patient had skin tightening, fish mouth appearance, and salt and pepper pigmentation of the skin. There was resorption of fingertips and nails. The left 2nd toe was gangrenous [Figure 1]. On auscultation, bilateral medium-pitched crackles were heard in the lung bases. Her chest X-ray showed bilateral reticulonodular shadow and left upper zone infiltrates with cavitation [Figure 2]. Computed tomography of the thorax was taken which showed reticular shadows, traction bronchiectasis, and ground-glass shadows on both sides, more in the lower lobes [Figure 3]. The left upper lobe showed cavitating consolidation [Figure 2b]. The patient underwent bronchoscopy and bronchoalveolar lavage fluid showed Mycobacterium tuberculosis sensitive to rifampicin. The patient was initiated on Category-1 anti-TB treatment.Figure 1:: Physical findings suggestive of scleroderma. Hypopigmented skin lesions over the dorsum of the hand, (a) X-ray of hands showing calcinosis cutis and resorption of phalanx of left little finger, (b) bluish discoloration due to gangrene (c) and bone resorption of the toes (d)Figure 2:: X-ray chest posterioanterior view showing consolidation (yellow arrow) left upper zone (a)and high-resolution computed tomography of the thorax showing cavitating consolidation (Black arrow) left upper lobe (b)Figure 3:: High-resolution computed tomography axial cuts through lower lobes (a and b) showing bilateral symmetrical reticulonodular shadows, ground-glass shadows, and traction bronchiectasis (Black arrows)RTX is an anti-CD20 monoclonal antibody, which controls inflammation by targeting peripheral B-cells. RTX has been used successfully in various autoimmune diseases during the last few years. The exact mechanism of action of RTX is not completely understood. RTX may have a favorable effect on SSc. RTX targets B-cells that is present in skin biopsies of patients with scleroderma[1] and is the source of autoantibodies, which may contribute to the pathogenesis.[2] It is also proved that RTX indirectly affects other immune cells such as T-cells,[3,4] which have been implicated in the pathogenesis of SSc.[5,6] Two recent uncontrolled studies have explored the potential clinical efficacy of a single cycle of RTX in SSc. In the study by Smith et al.,[7] clinical and histological improvement of skin fibrosis was observed at 24 weeks following RTX treatment, and in the study by Lafyatis et al.,[8] a significant reduction of the myofibroblast score in skin biopsies of RTX-treated patients was reported. These reports suggest that RTX may favorably affect skin fibrosis in SSc. The American College of Rheumatology in 2008 recommended screening patients for TB before RTX therapy.[9] On the other hand, an international expert committee concluded that there is no evidence indicating the necessity to screen patients systematically for TB before using RTX in those with rheumatoid arthritis (RA).[10] A study by Alkadi et al. assessed the risk of TB reactivation with RTX and found no TB flare-ups following the therapy. They concluded that the results of their study supported the conclusion of the aforementioned international expert committee that there is no necessity to screen patients for TB before the use of RTX therapy.[11] TB of the knee joint was reported after RTX therapy in a patient with RA and the authors suggested TB screening before RTX therapy.[12] A nationwide retrospective cohort study from Taiwan, a high TB-risk country, reported two cases of active TB in 763 patients with RA treated with RTX.[13] These two patients had a history of previous anti-TNF treatment, and active TB occurred after 8 and 10 years of RTX therapy. No cases of active TB were observed in 1303 RA patients included in the French AIR registry who had received at least 2 RTX courses,[14] in 370 patients with different autoimmune diseases in the GRAID registry from Germany,[15] in 234 in Greece,[16] whereas one TB case was recorded in 2484 RTX-exposed RA patients in the German GERINIS registry.[17] The low or absent risk of TB reactivation associated with RTX administration has been confirmed by two other studies on 56 RA patients at high-TB risk[18] and on patients previously treated for active TB.[14] Only sporadic cases of active TB, not exceeding the frequency of the disease in the general population, were reported in RTX-exposed patients with RA. In conclusion, in patients with rheumatic diseases receiving RTX, the TB risk is negligible, and according to the RTX Consensus Expert Committee,[10] the screening procedures for latent TB infection before starting RTX therapy seem unnecessary. It is a fact that patients with autoimmune disorders are on different immunosuppressants for a prolonged period, sometimes getting multiple such drugs at one time, making it difficult to prove a causal relationship to a single drug. Reported sporadic cases from various regions may suggest that RTX induces immunosuppression to induce TB reactivation, even though the incidence is very low compared with TNF-α inhibitors. Better surveillance of patients taking treatment with RTX for a longer period may throw light on this issue. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.