Cytomegalovirus infection in patients with rheumatic disorders under rituximab treatment: a scoping review

Abstract

Background

Cytomegalovirus (CMV), a DNA virus known for asymptomatic infections in immunocompetent individuals, can lead to fatal complications in the setting of immunosuppression. Rituximab (RTX) is an anti-CD20 monoclonal antibody with immunosuppressive properties, used as a first-line treatment choice for various rheumatic disorders. Although multiple reviews have analyzed the effects of RTX on CMV infection incidence in the population with a history of transplantation and malignancies, limited data are available on CMV incidence in those with rheumatic disorders under RTX treatment.

Methods

In August 2025, a thorough search in PubMed, EMBASE, Web of Science, MEDLINE (Ovid), and Scopus was conducted according to the framework proposed by Arksey and O’Malley, and the PRISMA-ScR guidelines were employed for reporting and structuring the research question (Population: individuals with rheumatic disorders, Concept: association between RTX administration and CMV infection, Context: RTX exposure) Tricco (Ann Intern Med 169(7):467-73, 2018). Original English studies on human subjects with rheumatic disorders infected with CMV infection or disease were included. The RTX dosage range was defined as low (doses < 500 mg per infusion), moderate (doses ranging from 500 to 1000 mg per infusion), and high (doses ≥ 1000 mg per infusion). Following abstract and full-text screening, relevant data were compiled into an Excel spreadsheet.

Results

A total of 13 studies, involving 459 patients, were recorded, among which 23 (5.01%) CMV infectious episodes were identified, most commonly reported as reactivation (39.13%, n = 9). The majority of CMV episodes occurred in individuals with anti-neutrophil cytoplasmic antibody-associated vasculitis and dermatomyositis, accounting for six cases. Six (2.57%), 10 (83.33%), and one (1.31%) infectious episode were reported among those with a history of low-, moderate-, and high-dose infusions, respectively. One fatal episode of CMV pneumonia occurred in a female patient diagnosed with MPA who was previously treated with four low-dose infusions of RTX.

Conclusion

This review’s findings illustrated a 5% prevalence of CMV infection following RTX infusion in patients with rheumatic disorders. Accurately estimating the infection burden of this population requires more extensive and precise studies.

Introduction

Human cytomegalovirus (CMV) is a double-stranded deoxyribonucleic acid (DNA) virus genus that belongs to a highly contagious viral family known as Herpesviridae and mainly causes asymptomatic infections [1]. Although not usually fatal, in the presence of immunosuppression, drastic complications, sometimes as severe as end-organ dysfunction and death, can occur [2, 3], with those of non-Caucasian ethnicity and lower socioeconomic status at higher risk [4], as studies report higher percentages of CMV infection, almost as high as 90% in developing countries compared to the 60% frequency rates in developed nations [5]. Additionally, CMV is an immunomodulator, facilitating other opportunistic infections [6–8]. Although similar, CMV infection and disease are different terms, as CMV infection refers to “virus isolation or detection of viral proteins or nucleic acids in bodily fluids or tissue specimens,” which can sometimes be asymptomatic [9]. However, active CMV disease is defined as the presence of clinical illness and signs and symptoms indicative of infection, often accompanied by tissue involvement [9].

Rituximab (RTX) is an anti-cluster of differentiation 20 (anti-CD20) chimeric monoclonal antibody that induces apoptosis and hypogammaglobulinemia induction, resulting in immunosuppression, and is frequently employed in the treatment of rheumatic disorders, such as rheumatoid arthritis (RA), microscopic polyangiitis (MPA), and granulomatosis with polyangiitis (GPA), as well as immune-mediated malignancies (CD20-positive B-cell Non-Hodgkin’s Lymphoma and chronic lymphocytic leukemia) [1, 10–12]. Furthermore, it has shown effectiveness in patients diagnosed with refractory systemic lupus erythematosus (SLE), acknowledged by the European Alliance of Associations for Rheumatology in 2023, which identified RTX as a promising therapeutic option for this patient population [13]. There are conflicting opinions on the risk of infection incidence following RTX administration, with some studies implicating RTX, while others report no increased risk [14–20]. Likewise, various studies have examined the CMV infection incidence following RTX use, and reports range from no mortality and morbidity to fatality in some individuals [21–23].

Although multiple systematic reviews have analyzed the effects of RTX therapy on CMV infection in patients with a history of transplantation and hematologic malignancies, data on CMV prevalence and outcome among rheumatic disease patients remain limited [24–26]. Given the ambiguity of this subject, a comprehensive review is necessary. Thus, we propose a scoping review to systematically map the existing literature on the association between RTX and CMV infection and disease in patients with rheumatic disorders and highlight research gaps.

Methodology

Design

A scoping review framework developed by Arksey and O’Malley was followed in this paper [27]. Based on this framework, our scoping review was divided into five segments: First, we defined our research question, structured using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) (Population: adult individuals with rheumatic disorders, Concept: association between RTX administration and CMV infection, Context: RTX exposure) [28]. Then, we identified the related studies via a thorough search in PubMed, EMBASE, Web of Science, MEDLINE (Ovid), and Scopus. Thirdly, eligible studies were selected, and data were gathered (original English studies conducted on CMV-infected patients with a previous history of RTX administration); finally, the results were synthesized and reported (see results).

Data sources and search strategy

A systematic search was performed in online databases from inception until August 2025, encompassing PubMed, EMBASE, Web of Science, MEDLINE (Ovid), and Scopus. The search utilized the following terms: “Cytomegalovirus,” “CMV,” “Cytomegalovirus infection,” “Rituximab,” “Mabthera,” “IDEC C2B8 Antibody,” “Rituxan,” “Ruxience,” “Truxima,” “Riabni,” and “DB00073.” Subsequently, forward and backward citation searching (snowballing) of reference lists and citing articles for all included studies was performed to identify further eligible studies.

Inclusion and exclusion criteria

Studies were included if they encompassed the following criteria: Original English-language, peer-reviewed studies conducted in adults (≥ 18 years old) diagnosed with rheumatic disorders who have received at least one RTX infusion, and in which CMV infection or CMV disease is diagnosed or CMV infection status is reported (e.g., CMV serology, CMV DNA, or tissue evidence), with or without clinical symptoms, and provided information on the RTX dosage administered. Furthermore, studies were also eligible if the overall RTX dosage administered to the total study population was reported, even when the precise RTX dosage specific to CMV-positive patients was not separately specified.

In vitro or in vivo studies, letters to editors, editorials, commentaries, review articles, unpublished studies or preprints, study protocols, studies in pediatric populations, studies lacking clear RTX dosage and an exact number of CMV cases, CMV infection type, and CMV incidence among RTX recipients, as well as studies conducted in populations with no history of rheumatic disorders and those who had received RTX as a treatment for COVID-19 or malignancies, including lymphoma and leukemia, and candidates for transplantation surgeries or CMV reactivation post-hematopoietic stem cell transplantation (HSCT) were excluded. Scoping reviews are designed to answer broader questions than systematic reviews. As a result, the qualities of the studies were not assessed. The scoping review checklist, as provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-ScR), was used to standardize and enhance the study [28].

Screening and eligibility

Two independent reviewers used the Rayyan screening tool to assess titles and abstracts for initial eligibility. Full texts of the included studies were then obtained and thoroughly reviewed by two reviewers. In cases of disagreement, a meeting was held to discuss the results until a consensus was reached.

Data extraction

Collected data included authors’ names, publication year, country, study type, total population, gender distribution within the study, mean total age of participants, population of the intervention group (RTX receivers), RTX dosage, co-administered drugs (other than RTX), organ-specified CMV infection type, population of CMV-positive cases, CMV prophylaxis, and infection’s outcome if provided. The collected data were then compiled into an Excel sheet based on recommendations from Arksey and O’Malley [27]. RTX doses were classified into three categories based on the dosing range specified in the product’s package information and the doses frequently employed for immune-related conditions: (1) low dose: doses < 500 mg per infusion; (2) moderate dose: doses between 500 and 1000 mg per infusion; and (3) high dose: doses ≥ 1000 mg per infusion [29–32].

CMV reactivation was characterized by the replication of latent CMV in a previously seropositive individual, determined through the detection of CMV DNA or antigen in blood or tissues via molecular methods as opposed to primary CMV infection, which is the first time a person is ever infected with the virus [9]. Furthermore, CMV viremia was defined as the identification of the virus or CMV DNA in blood samples by culture techniques or molecular testing [9].

Results

Search results

Our initial search yielded 8066 articles, and 2302 following backward and forward citation tracking, which were then reduced to 293 after abstract screening (Fig. 1). Following full-text screening, 13 articles met the inclusion criteria and were of sufficient evidence level. We recorded three cross-sectional studies, four cohort studies, four case reports, one randomized controlled trial (RCT), one case series study, and 459 patients. Additionally, patients were diagnosed with either of the disorders: dermatomyositis (DM), anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Sjögren’s syndrome (SS), RA, and systemic sclerosis. The frequencies of the rheumatic disorders are illustrated in Table 1, and a summary of their characteristics is provided in Table 2.

Fig. 1.

The PRISMA flowchart of the study

Table 1.

Distribution of the disorders’ frequencies

Disorder	N (%), total number of patients = 459
AAV*	296 (64.48)
Sjögren’s syndrome	78 (16.99)
DM*	33 (7.18)
systemic sclerosis	51 (11.11)
RA*	1 (0.21)

^* AAV: ANCA-associated vasculitis, RA: rheumatoid arthritis, DM: dermatomyositis

Table 2.

The characteristics of studies included in the review

Author (year), country, Study design	Rheumatic disease type, total study population	RTX*-receivers population (%)	Male population (%), total mean age	RTX dosage	Other drugs	CMV* infected 1. Population 2. type, 3. treatment, 4. infection outcome
Harada (2023), Japan, Retrospective cross sectional [33], Case 1	AAV*, 35	4 (11.42)	0, 89	500 mg	PDN*, MPSL*	1. Four (11.42) 2. Viremia 3. PDN dose reduction 4. Survival
Harada (2023), Japan, Retrospective cross sectional [33], Case 2	AAV, 35	4 (11.42)	100, 55	700 mg	PDN, MPSL, CYC*	1. Four (11.42) 2. Viremia, 3. PDN dose reduction 4. Survival
Harada (2023), Japan, Retrospective cross sectional [33], Case 3	AAV, 35	4 (11.42)	100, 85	500 mg	PDN, MPSL	1. Four (11.42) 2. Viremia 3. observation 4. Survival
Harada (2023), Japan, Retrospective cross sectional [33], Case 4	AAV, 35	4 (11.42)	100, 64	200 mg	PDN, MPSL	1. Four (11.42) 2. Viremia 3. PDN dose reduction 4. Survival
Ohta (2023), Case report [34]	AAV, 1	1 (100)	100, 87	Three infusions of 500 mg	PDN	1. One (100) 2. Viremia 3. Oral VGCV 4. Survival
Nagasaka (2023), japan, cohort [35]	AAV, 79	75 (94.93)	30.7, 73	1. Four weekly infusions of 375 mg/m2 in 40, for two weeks in 18, for one week in 7 2. Two doses of 1000 mg in three 3. Other regimens in 7	PDN, MPSL and CYC for remission group, TMP-SMX*	1. One (1.26) 2. Viremia (1) 3. NA 4. Deterioration of vasculitis
Holle (2012), Germany, Cross sectional [36]	GPA*, 59	59 (100)	59.3, 54	Four weekly injections of 375 mg/m2, all patients received at least one cycle; 12 received 12 cycles; three received 4 cycles	PDN, CYY, MTX, TNF-α* antagonists	1. One (1.69) 2. Reactivation 3. NA 4. NA
Calich (2014), France, Cohort [37]	GPA, 66	66 (100)	48.5, 50	1. Four weekly infusions of 375 mg/m2 in 61 2. Two infusions of 1000 mg in 5	MPSL	1. One (1.51) 2. Reactivation 3. NA 4. NA
Hsieh (2023), Taiwan, Retrospective cohort [38]	MPA*/GPA, 53 (GPA = 18, MPA = 35)	53 (100)	37.7, GPA:50, MPA:57	Four weekly infusions of 375mg/m2 or fortnightly at 1000 mg twice	CYC, PE*	1. Three (5.66) 2. Retinitis (1, GPA), pneumonitis and viremia (2, MPA) 3. NA 4. NA
Huang (2019), France, Case report [39]	GPA, 1	1 (100%)	100, 65	Four weekly RTX infusions 375 mg/m2	CYC, CS*, AZA*, PRED*	1. One (100) 2. Vestibular gingival ulcers 3. GCV* 4. Survival
Nagafuchi (2014), Japan , case series, Case #4 [40]	MPA, 1	1 (14.2)	0, 70	Four weekly infusions of 375 mg/m2	PDN	1. One (100) 2. Pneumonia 3. NA 4. Death
Tse (2014), USA, Case report [41]	MPA, 1	1 (100%)	0, 64	Four weekly infusions of 375 mg/m2	Vancomycin, Meropenem, PRED, CYC, AZA, G-CSF*, IVIG	1. One (100) 2. Reactivation 3. IV* GCV and then oral VGCV 4. Survival
Shirai (2023), Japan, Retrospective cross sectional [42]	Anti-MDA5 positive DM, 33	8 (24.24)	17.6 in 2014–2018 and 18.8 in 2019–2021, 50.4 in 2014–2018 and 53.8 in 2019 and 2021	500 mg weekly infusions	MPSL, dexamethasone palmitate CYC, tacrolimus, tofacitinib, PE	1. Six (18.18) 2. Reactivation 3. GCV 4. Survival
Daoussis (2017), Greece, RCT [43]	systemic sclerosis-associated ILD*, 51	33 (64.7)	Male population of the Intervention group = 47.67, Male population of the control group = 83.82, Mean age of the Intervention group = 54.3, Mean age of the control group = 52.11	Four weekly infusions of 375 mg/m2 (two or more cycles were given and each cycle was repeated every 6 months)	MTX*, HCQ*, MMF	1. One (1.96) 2. Pneumonia 3. NA 4. NA
Gottenberg (2013), France, Cohort [44]	Primary SS*, 78	78 (100)	14.1, 59.8	1. Two weekly infusions of 1000 mg in 67 2. Four weekly infusions of 375 mg/m2 in 11	CS, HCQ, MTX, AZA, PE, MMF, IVIG, LEF*	1. One (1.28) 2. Pneumonia 3. NA 4. Survival
Vallet (2011), France, Case report [45]	RA*, 1	1 (100%)	0, 66	Two weekly infusions of 1000 mg (each cycle repeated once)	MTX, adalimumab, etanrecept, IVIG	1. One (100) 2. Colitis 3. GCV, VGCV 4. Survival

^*NA: not applicable, AAV: ANCA-associated vasculitis, ILD: interstitial lung disease, RA: rheumatoid arthritis, RTX: rituximab, CMV: cytomegalovirus, PDN; prednisolone, PRED: prednisone, MPSL: methylprednisolone, CYC: cyclophosphamide, TMP-SMX: trimethoprim/sulfamethoxazole, MTX: methotrexate, HCQ: hydroxychloroquine, TNF-α: tumor necrosis factor alpha, IV: intravenous, PE: plasma exchange, CS: corticosteroid, CYA: cyclosporine A, G-CSF: granulocyte colony-stimulating factor, AZA: azathioprine, GCV: ganciclovir, VGCV: valganciclovir, LEF: leflunomide, IVIG: intravenous immunoglobulin, CP: clobetasol propionate, MMF: mycophenolate mofetil

Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV)

In this scoping review, 296 (64.48%) cases were diagnosed with AAV across nine studies, including three cohorts [35, 37, 38], two observational studies [33, 36], one case series [40], and three case reports [34, 39, 41], and in total, we identified 115 cases of AAV without subtype classification (38.85%) [33–35], 144 cases of GPA (48.64%) [36, 37, 39], and 37 individuals diagnosed with MPA (12.50%) [38, 40, 41]. 69.56% (n = 80) of those diagnosed with uncategorized AAV received RTX as induction therapy, and the majority of them received low-dose RTX infusions (82.50%, n = 66) [35]. Three (3.75%) and four (5%) patients received high and moderate doses, respectively [33–35]. In Nagasaka’s study, seven received other regimens as induction therapy [35].

Low-dose RTX infusions were the most commonly reported dosage among individuals diagnosed with GPA (84.02%, n = 121), followed by high-dose infusions administered to five (3.47%) individuals [36, 37, 39]. Two (5.40%) patients with MPA received low-dose RTX infusions [40, 41]. One observational study did not specify the number of cycles. However, 53 participants diagnosed with MPA or GPA received low- or high-dose weekly RTX infusions [38].

Regarding CMV infection, a total of 14 episodes were recorded: viremia in seven (six with AAV and one with MPA) (50%) [33–35, 38], reactivation in three (two with GPAs and one with MPA) (21.42%) [36, 37, 41], retinitis in one (GPA) (7.14%) [38], pneumonia in two (all with MPA) (14.28%) [38, 40], and CMV-induced ulcer in one (GPA) (7.14%) [39]. In total, six infectious episodes occurred in individuals with uncategorized AAV [33–35], four among those with GPA [36–39], and four in individuals with MPA [38, 40, 41].

Three studies failed to provide the CMV infection outcome [36–38]. Among the six remaining articles, one patient diagnosed with MPA and CMV pneumonia who previously received low-dose RTX infusions did not survive [40].

Dermatomyositis

One cross-sectional study reported the incidence of CMV infection among 33 (7.18%) individuals diagnosed with dermatomyositis, of whom 8 (24.24%) patients received moderate-dose RTX [42]. Among the individuals that received RTX, CMV reactivation was detected in six (75%) individuals who were successfully treated with ganciclovir (GCV) [42].

Sjögren’s syndrome (SS)

This review identified a cohort study on individuals with SS (78 patients, 16.99%) [44]. Sixty-seven (85.89%) individuals received high-dose infusions, and 11 (14.10%) received low-dose infusions, with one case of CMV pneumonia identified six months following the 5th RTX cycle [44].

Rheumatoid arthritis (RA)

We identified one (0.21%) individual with RA, reported in a case report, who received two weekly high-dose infusions, was diagnosed with CMV colitis, and was treated with GCV and valganciclovir (VGCV) [45].

Systemic sclerosis

Our search yielded only one study on systemic sclerosis-associated interstitial lung disease individuals (n = 51, 11.11%), of whom 33 (64.7%) were treated with low-dose infusions. After RTX infusions, one patient was diagnosed with CMV pneumonia, for whom treatment choice and outcome are unavailable [43].

RTX dosage

381 (83%) received RTX remission induction therapy, ranging from low- to high-dose infusions (100 mg to 1000 mg infusions per dose). Adequate data on RTX dosage categorization were available for 321 (84.25%) individuals. Weekly high-dose infusions were administered to 76 (23.67%) [35, 37, 44, 45]. Moreover, 233 (72.58%) and 12 (3.73%) received low and moderate-dose infusions, respectively [33–37, 39–44]. In two studies, RTX dosages were reported for the total population but were not separately detailed for CMV-positive patients [35, 38].

CMV incidence

In total, 23 (5.01%) episodes were recorded, with CMV reactivation being the most commonly reported (39.13%, n = 9). CMV viremia was the second most commonly reported infection, accounting for 30.43% (n = 7), followed by pneumonia (17.39%, n = 4), retinitis (4.34%, n = 1), colitis (4.34%, n = 1), and gingival ulcer (4.34%, n = 1) (Table 3).

Table 3.

Distribution of CMV infection, RTX dosage, and rheumatic disorders

Rheumatic disorder, n	CMV infection type, n Total episodes: 23	RTX dose, n
Uncategorized ANCA*, 115	Viremia, 6	Low, 1
		Moderate, 4
		Low or High, 1
GPA*, 144	Reactivation, 2	Low, 1
		Low or High, 1
	Retinitis, 1	Low or High, 1
	Gingival ulcer, 1	Low, 1
MPA*, 37	Viremia, 1	Low or High, 1
	Reactivation, 1	Low, 1
	Pneumonia, 2	Low, 1
		Low or High, 1
DM*, 33	Reactivation, 6	Moderate, 6
systemic sclerosis, 51	Pneumonia, 1	Low, 1
Sjögren’s syndrome, 78	Pneumonia, 1	Low or High, 1
RA*, 1	Colitis, 1	High, 1

^*AAV: ANCA-associated vasculitis, RA: rheumatoid arthritis, DM: dermatomyositis

Evidence on dose-specified CMV episodes was available for 17 individuals. Among individuals who received low-dose infusions (n = 233, 61.15%), six (2.57%) CMV-positive patients were identified, of whom two (33.33%) had reactivations, two (33.33%) had pneumonias, one (16.66%) had viremia, and one (16.66%) had CMV-induced gingivitis ulcers [33, 35–37, 39–41, 43, 44]. In the 12 (3.14%) individuals with a past drug history of moderate-dose RTX infusions, 10 (83.33%) episodes, including six (60%) reactivations and four (40%) viremias, were recorded [33, 34, 42]. Of the 76 individuals (19.94%) who received high-dose infusions, we identified one patient (1.31%) with colitis [45].

Mortality

CMV infectious episode outcome was discussed for 17 (73.91%) individuals, of whom one (5.88%) infectious episode led to death, who was a female patient diagnosed with MPA and had previously received four infusions of 375 mg/m² RTX at weekly intervals and was later diagnosed with CMV pneumonia [40]. The infection outcome was not provided for six individuals (26.08%) [36–38, 43].

Discussion

CMV is an opportunistic pathogen that poses complications in immunosuppressed individuals, such as patients with rheumatic diseases undergoing RTX treatment, and while CMV complications have been thoroughly investigated in individuals with hematologic malignancies and transplant recipients, the evidence concerning RTX-treated individuals with rheumatic disorders is still insufficient [46–48]. This scoping review aimed to provide an overview of CMV incidence following RTX use in patients with rheumatic disorders and to identify the existing gap for future research, and our findings demonstrated a 5.01% pooled prevalence of CMV infection following RTX administration in rheumatic disease patients, with the majority diagnosed with CMV reactivation, followed by viremia. Notably, a larger proportion of individuals with CMV infection were among those who received moderate doses of RTX, suggesting a possible dose-dependent susceptibility, underscoring the need for vigilance in monitoring CMV infection in rheumatology patients receiving moderate RTX dosages, particularly given the immunosuppressive effects of RTX [49, 50].

While CMV infection rates are well-studied in transplant recipients and hematologic malignancy patients treated with RTX, ranging from 5% to 15%, rheumatic disease populations have not been well characterized [51–56]. Although CMV incidence rates in adults with hematologic malignancies undergoing hematopoietic stem cell transplantation receiving RTX vary widely, several cohorts have reported CMV infection incidence rates as high as 18% in such patients [19, 57–59]. Such an effect may be attributed to the late-onset neutropenia, hypogammaglobulinemia, persistent B-cell depletion, and cytokine release syndrome following RTX administration [12, 50, 60–62]. Similarly, CMV infection incidence following RTX administration has been reported in individuals with autoimmune disorders [12, 63, 64]. One recent observational study focused on the incidence of infections following high-dose (1000 mg) RTX infusions and reported two cases diagnosed with CMV infection (0.28%) in patients with rheumatic and musculoskeletal diseases, which is lower than the rates reported in this review [64]. One RCT reported 63% higher odds of developing CMV infection 12 months post RTX administration, with CMV cases accounting for 4.77% of their RTX recipients, further supported by findings of a systematic review [65, 66]. Comparably, one study reported significantly higher cumulative dosages of RTX within their CMV-positive population with rheumatic disorders, corroborated by the findings of a case report, which reported a fatal case of CMV reactivation following RTX administration, indicating the potential clinical severity of CMV post-RTX in rheumatic diseases, necessitating increased clinical awareness and infection risk stratification based on RTX dose and rheumatic diagnosis [22, 63].

While CMV mortality rates following RTX administration in individuals with hematologic malignancies and transplantations are not well-determined, studies have reported increased mortality rates following RTX administration due to viral infections [48, 67, 68]. The present review indicated a 5.88% mortality rate following RTX administration in a patient diagnosed with MPA, previously treated with four weekly low-dose RTX infusions [40]. Such a finding may be attributed to the number of cycles received by the patient, as doses of 375 mg/m² are routinely prescribed four times weekly, compared to two times weekly in those receiving 1000 mg infusions, possibly leading to prolonged hypogammaglobulinemia due to the repeated RTX infusions, suggesting that treatment cycles and schedules may affect infection risk via immune dysfunction [40, 56, 69, 70]. Furthermore, studies have demonstrated that regardless of RTX, CMV-positive patients with autoimmune disorders, including rheumatic diseases, are at a threefold higher mortality risk, suggesting that these individuals inherently possess an increased mortality risk compared to controls [71, 72].

Previous studies report that individuals treated with lower RTX doses may have a lower probability of developing infections, and the probability of developing infectious episodes may increase linearly with RTX dosages, although one study reported that the cumulative incidence of infections was similar for low and moderate doses [73, 74]. Furthermore, one study evaluated the differences between low-dose and ultra-low RTX infusions and reported a lower incidence of infection following an ultra-low-dose infusion. Despite this finding, treatment with higher RTX doses led to lower infection rates during a more extended follow-up period [47]. Additionally, although none of the participants were diagnosed with CMV infection, one study reported no significant differences regarding infection incidence between individuals who received RTX doses of 1000 mg or higher and those who received lower doses of RTX [75]. In this review, 83.33% of individuals with a history of moderate-dose infusions were at CMV risk compared to 2.75% and 1.31% for individuals with low- and high-dose infusions, respectively. Furthermore, the association between CMV incidence and RTX administration remains unclear, as individuals with rheumatic disorders are commonly treated with various immunosuppressive agents in addition to RTX, heightening their risk of developing fatal and serious infectious episodes, necessitating the need for further studies to clarify the association between CMV incidence and RTX infusion dosage [19, 22]. This evidence underscored the need for prospective studies stratifying patients by disease subtype (e.g., RA, AAV) and RTX dosing regimens (low, moderate, high; frequency and total cumulative dose) to elucidate dose-response relationships with CMV risk, in addition to accounting for concomitant immunosuppressive therapies to isolate the specific effect of RTX on CMV infection susceptibility.

This scoping review suggests that routine CMV screening and monitoring might be contemplated for rheumatic patients undergoing moderate or multiple doses of RTX, due to the immunosuppressive effects that elevate CMV risk. Furthermore, future research should prioritize prospective studies that stratify CMV incidence by rheumatic disease and RTX dosing, as well as evaluate the necessity for CMV prophylaxis in patients receiving moderate or multiple infusions.

Our review was limited because the reviewed studies were not primarily focused on CMV infection, and this complication was reported as a secondary finding in the included studies. Secondly, the information available on this infection was insufficient and sometimes imprecise. To our knowledge, this is the first review to evaluate the CMV infection incidence rate following RTX administration in patients diagnosed with rheumatic disorders. Our findings depicted limited evidence on this subject and the need to evaluate the dose-dependent susceptibility to CMV infection following RTX administration in these individuals.

Conclusion

The findings of this review illustrated that CMV infection may represent a clinically relevant complication in patients with rheumatic disorders treated with RTX, particularly those receiving moderate doses of RTX infusions. While a range of syndromes was observed, reactivation appeared to be the most frequently reported, and in order to better understand the implications of CMV infection in this population, future studies with larger cohorts and refined methodologies are warranted, with particular attention to infectious complications in those with rheumatic disorders treated with RTX.

Abbreviations

CMV

Cytomegalovirus

RTX

Rituximab

DNA

Deoxyribonucleic acid

Anti-CD20

Anti-cluster of differentiation 20

MPA

Microscopic polyangiitis

GPA

Granulomatosis with polyangiitis

RA

Rheumatoid arthritis

HSCT

Hematopoietic stem-cell transplantation

PRISMA-ScR

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

AAV

ANCA associated vasculitis

GCV

Ganciclovir

IV

Intravenous

VGCV

Valganciclovir

ILD

Interstitial lung disease

Author contributions

ER: Conceptualization, Data curation, Methodology, Project administration, Writing original draft, Review and Editing. KF: Data curation, Investigation, Writing–original draft, Review and Editing. HV: Formal Analysis, Validation, Visualization, Writing–original draft. FG and MF: Data curation, Writing original draft. AA, AR, HK: Review and Editing. MS: Conceptualization, Project administration, Supervision, Writing original draft, Review and editing.

Funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Data availability

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.