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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 1  |  Page : 66-70

Safety of rituximab on testicles, a double-blindedcontrolled trial in mice


Department of Medicine, Division of Rheumatology, College of Medicine, King Saud University, Riyadh, Saudi Arabia

Date of Submission01-Sep-2019
Date of Decision27-Sep-2019
Date of Acceptance16-Oct-2019
Date of Web Publication06-Jan-2020

Correspondence Address:
Sultan Mogren Al-Mogairen
Department of Medicine, Division of Rheumatology, College of Medicine, King Saud University, P. O. Box 2925, Riyadh - 11461
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JNSM.JNSM_38_19

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  Abstract 


Objectives: Rituximab (RTX) is a biologic agent used for rheumatic and autoimmune disorders. RTX is a drug indicated for the treatment of patients with refractory rheumatoid arthritis patients who have not responded to nonbiological therapy and one or more anti-tumor necrosis factor-α drugs. The purpose of this trial was to investigate the RTX effects on testes in BALB/c mice by histology. Materials and Methods: A total of 20 mice were divided into two groups. Ten mice were subjected to weekly subcutaneous (SC) injection of RTX (0.31 mg/25 g body weight, in a final volume of 0.03 ml normal saline [NS] solution) for only the first 4 weeks. For the control group, ten mice were subjected to weekly SC injection of 0.03 ml NS solution. At the 10th week after first SC injection, mice were sacrificed, and histological analysis of tests was performed. Results: One out of ten mice died in the RTX-tested group; meanwhile, the remaining mice and the NS-tested group mice showed no abnormal histological findings. Conclusion: This is the first experimental animal trial which demonstrated that RTX treatment may not elicit testicular toxicity.

Keywords: Histology, rheumatoid arthritis, rituximab, safety, testes


How to cite this article:
Al-Mogairen SM. Safety of rituximab on testicles, a double-blindedcontrolled trial in mice. J Nat Sci Med 2020;3:66-70

How to cite this URL:
Al-Mogairen SM. Safety of rituximab on testicles, a double-blindedcontrolled trial in mice. J Nat Sci Med [serial online] 2020 [cited 2020 Jan 21];3:66-70. Available from: http://www.jnsmonline.org/text.asp?2020/3/1/66/275172




  Introduction Top


The biological agents recommended in the management of rheumatic and autoimmune diseases include abatacept, rituximab (RTX), and tocilizumab. RTX also indicated for lymphoproliferative disorder.[1],[2] The peak incidence rate of non-Hodgkin's lymphoma (NHL) at the age of 75 years or older. In contrast, the peak incidence rate of rheumatoid arthritis (RA) between 40 and 70 years of age with higher survival rate at the 5 years of follow-up. Therefore, several studies have been conducted in pregnant women with rheumatic and autoimmune diseases, particularly RA.[3],[4] One of the major studies was related to pregnancy outcomes after maternal exposure to RTX, which reported 90 live births after maternal exposure and 68 (76%) full-term deliveries. Indications for RTX among exposed mothers include RA (29 pregnancies), NHL (24 pregnancies), systemic lupus erythematosus (11 pregnancies), autoimmune hematological diseases (17 pregnancies), multiple sclerosis (three pregnancies), and Castleman disease, mixed connective tissue disease, and renal transplantation (one pregnancy each).[5] The combination of RTX with methotrexate (MTX) was approved for the treatment of RA in patients resistant to initial therapy with disease-modifying anti-rheumatic drugs (DMARDs), including MTX and one or more anti-tumor necrosis factor (TNF) biological drugs. Several randomized clinical trials have demonstrated the efficacy and safety of RTX for the treatment of RA patients.[6],[7],[8],[9],[10]

RTX is known chimeric monoclonal immunoglobulin antibody that binds CD20 antigen on the surface of B cells.[7],[11],[12],[13],[14],[15],[16],[17] Due to its biological nature, RTX may induce hypersensitivity reactions, mainly in the first doses.[8],[9],[18],[19] A wide range of hypersensitivity side effects was reported, including urticaria, angioedema, fever, rigors, pruritus, nausea, vomiting, headache, dyspnea, rhinitis, bronchospasm, flushing, and hypotension. Other severe side effects are cardiac arrhythmias, renal toxicity, tumor lysis syndrome, progressive multifocal leukoencephalopathy, fulminant hepatitis B reactivation, and bowel perforation or obstruction.[8]

Acquired gonadal dysfunction can be ascribed for both genders to drugs, radiation, infection, injury, poisons, and autoimmune diseases. However, drug treatment constitutes the most important factor for testicular dysfunction in patients with rheumatic illnesses.[20],[21],[22],[23]

No human or animal studies have been reported to date about the direct effect of RTX on the testicles.[24] Therefore, the objective of the current study was to evaluate the safety of RTX through histological examination of mouse testicles.


  Materials and Methods Top


Male BALB/c mice weighing 23–27 g and of 12–14 weeks of age were obtained from the college of Pharmacy at King Saud University. This pilot study was approved by the Research Ethics Committee at the Faculty of Medicine, with approval number (E-14-1300). These experiments were performed in accordance with ethical principles. All mice received humane care.

Mice were housed in a standard ventilated room inside polycarbonate plastic cages, which were secured with a stainless steel cover, and the room was located in the laboratory animal house at the Faculty of Medicine. The mice were exposed to artificial light (12:12-h light: dark cycle) and observed for 3 weeks before exposure to subcutaneous (SC) injections. All mice were healthy and active.

As we did not have sufficient data to assess the risk rate of testicular toxicity owing to RTX administration, we utilized the “resource equation” approach to determine the adequate and minimum number of mice required for the study. According to this calculation, the least calculated number of mice was 4, and the maximum was 7; hence, ten mice in each group were enough to meet the objectives.[25]

In addition since the proper dose of RTX for mouse studies was not found in the literature, we extrapolated this based on recommended dosages reported for humans. Bredemeier et al. used low dose (500 mg) versus high dose (1000 mg) of RTX infusion for treatment of RA.[7] Thus, corresponding to an average SC dose of RTX 750 mg for an adult of 60 kg, a dose of 0.31 mg for a mouse with an average weight of 25 g was used.

Mice were divided into two groups of ten mice each. One group received weekly SC injections of RTX (0.31 mg/25 g body weight, in final volume of 0.03 ml with normal saline [NS]) for only the first 4 weeks. The second group was administered with weekly SC injections of 0.03 ml NS till the end of the experiment. Our study is a portion of a multi-arm study using MTX and four biological agents including etanercept; therefore, we utilized week by week NS SC injection for this common control NS-tested group. The trial was double blinded to the laboratory assistant and the histopathologist.

At the 10th week, mice were sacrificed by applying pressure to the neck and dislocating cervical spine. The testicular samples were harvested, bisected, and fixed in 10% buffered formalin solution for 24 h. Testicular tissues were collected in previously coded tubes and sent to the pathologist for examination without disclosing the treatment and group assignment of each mouse sample or the outcomes of the study. After hematoxylin and eosin staining, the tissues were studied under the light microscope.

Statistical analysis

Statistical differences between the RTX-tested and NS-control groups were calculated utilizing Fisher's exact test. Differences were considered statistically significant at P < 0.05.


  Results Top


Regarding RTX-tested group, one of ten mice died during the final 3 weeks of the study. No clinical signs of illness were observed before death. No deaths were notified in the NS control group.

Histological findings are shown for the NS-control [Table 1] and the RTX-treated groups [Table 1]. The sample was recorded as negative for testicular changes if no abnormal histological findings were noted [Figure 1]. Otherwise, they were considered positive. Furthermore, no significant changes in testicular morphology between mice treated with RTX [Table 1] and [Figure 2] or those which received NS solution were observed [Table 1] and [Figure 1].
Table 1: Histological findings of the rituximab-tested and the control normal saline-tested groups

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{Table 1}
Figure 1: Control testicle showed tubules with normal spermatogonia, spermatocytes, and mature sperms. The interstitium revealed normal Leydig cells (H and E staining, ×300)

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Figure 2: Rituximab-tested testicle showed normal spermatogonia, spermatocytes, and mature sperms. The interstitium revealed normal Leydig cells (H and E staining, ×300)

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  Discussion Top


RTX is an approved biologic agent for induction of remission in patients with juvenile idiopathic arthritis, RA, granulomatosis with polyangiitis, and microscopic polyangiitis.[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39]

RTX is generally well tolerated, independently of the time or course of the treatment. A long-term study for the use of RTX over 9½ years did not detect increased safety risk or side effects. Despite the recommended dosage of RA being used, the death rate in the current study was 10% of RTX-tested group. Meanwhile, no mortality was reported in the control group. Autopsy was not performed, as there was no obvious signs of illness prior to death were noted, and housing conditions and feeding were the same for both groups; and therefore, we assume that cardiovascular attack was likely the cause of the death of the RTX-treated mouse. There was no evidence to suggest an increased incidence of myocardial infarction related to RTX treatment. Furthermore, mortality rates in human studies were in agreement with the existing data and the expected rates obtained in an age- and sex-matched US population.[10] However, patients with uncontrolled cardiac illness are ruled out from major clinical trials of RA because of concerns about potential cardiac complications associated with infusion reactions. On the contrary, mice might react to experimental interventions in ways different from humans.[40],[41]

DMARDs safety data on the male genital organs have been limited.[24]

MTX administration was related to the development of teratogenicity in pregnant women taking MTX. On the contrary, an observational cohort study did not confirm the fetal risk after paternal treatment with MTX; therefore, no recommendations are currently available regarding halting MTX treatment for male patients before conception.[42]

Cyclophosphamide is a chemotherapy drug used in female and male rheumatic patients. However, this alkylating agent might lead to organ toxicity, including in the testicles, in both humans and animals; hence, increasing the risk of male infertility.[20] Histological changes due to toxicity include germinal cells degeneration and necrosis, atrophy of seminiferous tubules, and widening of  Sertoli cells More Details with vacuolization in interstitial tissues.[43]

Some observational studies have demonstrated that treatment with anti-TNF drugs including infliximab, etanercept, and adalimumab did not increase the risk of male infertility, as these anti-TNF drugs apparently did not produce abnormalities with regard to the quantity and quality of sperms.[20],[24],[27],[28],[29],[30],[31],[32],[33],[34],[35]

No clinical trials or animal studies investigating the direct effect of RTX on the testicles have been reported.[24]

Drug toxicity might be on target or mechanism-based toxicity (e.g., anti-CD20). Other mechanisms might be due to off-target toxicity through binding to an alternate target of the affected gonad or hypersensitivity such as RTX-induced allergic granulomatous hepatitis reported recently from our multi-arm trial. Testicular toxicity by histology might mirror or reflect the functional ability of the testicles by impairing of spermatogenesis.[44],[45],[46]

A lack of significant changes in testicular histology in the RTX-treated mouse group indicates that RTX was likely not a toxic drug to the testicles of BALB/c mice. However, notably, detection of testicular side effects of drugs in mice in real time presents a challenge since there is a latency period of a few weeks between the time of seminiferous tubule injury and the time that semen examination reveals the injury.[20],[23],[47],[48],[49],[50],[51],[52] Nevertheless, early onset of drug-induced gonadal toxicity might become evident within days to a few weeks of the insult.[53],[54],[55],[56]


  Conclusion Top


To our knowledge, this is the first mouse study to demonstrate by histological analysis, the absence of testicular toxicity post SC injections of RTX, which might indicate that this drug is safe with regard to male fertility. However, to confirm these results, further investigations should include semen analysis and measurements of serum testosterone and gonadotropin concentrations.

Acknowledgments

The author is grateful to the College of Medicine Research Centre, Deanship of Scientific Research, King Saud University, Riyadh, and Saudi Arabia, for their support and to the pharmacists Mr. Wajed Ali Khan, Mr. Mohammed Ali Khan, and Mr. Nazeeh Al Saeed. The author would like to thank Dr. Najma Khalil and Dr. Abdullah Al Kahil for collecting data and to the Research Ethics Committee at the College of Medicine for the approval of our animal study.

Financial support and sponsorship

The author would like to thank the Deanship of Scientific Research at King Saud University, for the research group fund number RGP-126. They had no role in the design of the trial, collection, interpretation, and analysis of data.

Conflicts of interest

There are no conflicts of interest.



 
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