[Academic Presentation] Recent Advances in the Study of Lymphopenia in Systemic Lupus Erythematosus

Article reprinted from: Chinese Medical Abstracts – Dermatology, Issue 2, 2017.

Authors: Shi Yinjuan, Liu Lu, Lin Yan, Cui Yong

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory connective tissue disease that predominantly affects young women. It can involve multiple organs throughout the body, with common manifestations including damage to the skin, kidneys, hematologic system, lungs, nervous system, heart and brain, and musculoskeletal system. Its clinical presentation is complex and highly variable, with a prolonged course characterized by alternating periods of activity and remission. Laboratory findings frequently reveal abnormalities in hematologic parameters; among these, lymphopenia is one of the most common clinical features of SLE and serves as one of the criteria for diagnosing hematologic involvement in SLE.

1. Overview of Lymphocytopenia in SLE

According to the SLE scoring criteria established by the American College of Rheumatology (ACR) and the Systemic Lupus International Collaborating Clinics (SLICC), a peripheral lymphocyte count of less than 1.5 × 10^9/L, occurring on at least two occasions, is defined as lymphocytopenia. The prevalence of lymphocytopenia among patients with SLE ranges from 20% to 93%, with rates of 24% to 59% in pediatric patients and 62% at initial diagnosis in adults; over the course of disease progression, the cumulative incidence exceeds 90%. Lymphocyte levels exhibit dynamic fluctuations throughout the course of SLE, and their response to treatment remains difficult to predict. Among laboratory findings in SLE, hematologic abnormalities are the most common. Aleem et al. examined hematologic abnormalities in 624 SLE patients—90.7% female, with a mean age of 34.3 ± 11.9 years—and found that lymphocytopenia was the second most frequent abnormality, occurring in 40.3% of cases, surpassed only by anemia, which was observed in 63%. Among leukopenias, lymphocytopenia was the most prevalent, followed by neutropenia, which occurred in 30.0% of patients. Notably, many SLE patients continue to exhibit persistent hematologic abnormalities despite ongoing therapy, even years after treatment initiation; anemia is the most challenging to resolve, with leukopenia presenting a secondary challenge.

2 Mechanisms of Lymphocytopenia in SLE

The mechanisms underlying lymphopenia in SLE remain unclear, though reports suggest that the production of antilymphocyte antibodies (ALA) is one of the key pathogenic factors. Li C et al. studied 130 Chinese patients with SLE—93.8% female, with a mean age of 33.3 ± 12.4 years—and found that more than half of those with lymphopenia tested positive for ALA; furthermore, among ALA‑positive patients, 90.9% exhibited lymphopenia. Multivariate analysis revealed an independent association between ALA and lymphopenia. Possible mechanisms by which ALA induces lymphopenia include: (1) depletion of circulating T lymphocytes; and (2) direct cytotoxic effects on lymphocytes via complement‑mediated lysis, antibody‑dependent cell‑mediated cytotoxicity, opsonization of cell surface antigens, and modulation of immune cell functions, ultimately triggering apoptosis. In addition, recent studies have increasingly highlighted the role of intrinsic lymphocyte apoptosis in the pathogenesis of lymphopenia in SLE. Dhir et al., using flow cytometry on peripheral blood mononuclear cells (PBMCs), demonstrated that a decline in the percentage of T cells was inversely correlated with the level of T‑cell apoptosis, suggesting a causal relationship. These findings indicate that, regardless of whether lymphopenia is present, lymphocyte counts—particularly the proportion of T cells within PBMCs—are closely linked to the physiological or pathological status of lymphocytes themselves, including apoptotic processes. Lymphopenia may thus be associated with increased susceptibility to T‑cell apoptosis. Rastin et al. examined 35 patients (23 females, 12 males) and 20 controls (10 females, 10 males). They observed significantly higher levels of T‑cell apoptosis in female patients compared with males. Semi‑quantitative RT‑PCR analysis further revealed that, following estradiol exposure, the expression of Caspase‑8 in the estradiol‑treated group was threefold higher than in the non‑exposed control group (1.34 ± 0.19 vs. 0.45 ± 0.09), whereas in males it increased only twofold (1.7 ± 0.27 vs. 0.96 ± 0.23). However, absolute levels of Caspase‑8 and FasL were higher in male patients than in females. Cell‑induced apoptosis is generally thought to proceed via both intrinsic and extrinsic pathways. The death receptor Fas, its ligand FasL, and Caspase‑8 are critical components of the extrinsic apoptotic signaling cascade, while the anti‑apoptotic protein Bcl‑2 plays a pivotal role in the intrinsic pathway. Studies have shown that FasL and Caspase‑8 expression are markedly elevated in SLE patients. In patients with SLE‑associated lymphopenia, the precise interplay among different T‑cell subsets remains incompletely understood. Gómez‑Martín D. et al. conducted separate analyses of 84 SLE patients and healthy controls, finding that patients with lymphopenia exhibited consistently lower absolute counts of CD4+CD25high Treg cells and CD4+CD69+ T cells compared with those without lymphopenia, along with higher disease activity scores. Patients with lymphopenia also faced a heightened risk of Treg cell depletion. Among these patients, those treated with azathioprine showed distinct patterns compared with active disease states: they displayed reduced absolute counts of CD4+CD69+ T cells and CD4+IL‑17+ T cells, accompanied by diminished immunological tolerance mediated by Treg cells. Functional studies further indicated that effector T cells in SLE patients undergo excessive proliferation and develop resistance to their own Treg‑mediated immune tolerance, thereby disrupting overall immune homeostasis.

3 Correlation between lymphocytopenia and concurrent infections

In patients with SLE, lymphopenia may be asymptomatic, may be associated with infection, or may indicate disease activity. However, whether lymphopenia increases the risk of infection remains controversial. Some in vitro studies suggest that lymphopenia is linked to dysregulated immune responses, yet the direct association between lymphocyte depletion and the risk of infection has not been established. Merayo-Chalico et al. examined 167 SLE patients—89 with infection and 78 without—and found that lymphopenia, corticosteroid therapy, and low C3 levels were independent risk factors for severe infections in SLE. Moreover, lymphopenia at disease onset or during the course of SLE was identified as a risk factor for severe infections. In contrast, many reports have highlighted an association primarily with opportunistic infections. Additionally, this study did not find a link between immunosuppressive agents (prednisone, azathioprine, mycophenolate mofetil, clofazimine) and lymphopenia, whereas clinical observations often associate lymphopenia with such therapies. Nearly half (49.4%) of patients with severe infections developed infections of the genitourinary system or skin and soft tissues. Among SLE patients who developed infections—including bacteremia, central nervous system involvement, and disseminated infections—the mortality rate was correspondingly elevated (approximately 20%), suggesting that patients with lymphopenia are at heightened risk of fatal infections. The causative pathogens were predominantly single bacterial species, with over 5% being high-risk, life‑threatening organisms such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Candida glabrata; mycobacteria were also frequently encountered.

4 The correlation between lymphocyte reduction and neuropsychiatric lupus.

The extent of neuropsychiatric involvement in patients with systemic lupus erythematosus (SLE) remains incompletely defined, and studies reporting the incidence of various neuropsychiatric manifestations yield inconsistent findings. Neuropsychiatric SLE (NP‑SLE) currently lacks a universally accepted diagnostic criterion; definitive diagnosis is often challenging until overt clinical features of lupus—particularly prominent neuropsychiatric symptoms such as altered consciousness or seizures—are evident. Yu et al. conducted a retrospective case‑analysis of 186 pediatric SLE patients and found that at initial presentation, lymphopenia (lymphocyte count <1500/mm³) was significantly associated with oral ulcers, leukopenia, anti‑dsDNA antibodies, and decreased C4 levels. During disease flares, lymphopenia correlated with anti‑dsDNA titers, high‑dose methylprednisolone pulse therapy, disease activity, and organ‑system damage. Multivariate regression analysis further demonstrated that severe lymphopenia served as an independent risk factor for neuropsychiatric SLE, whereas it acted as a protective factor against lupus nephritis (LN). Chiba, Sommerlad, and others have reported three cases of SLE initially presenting with neuropsychiatric symptoms, suggesting that lymphopenia may facilitate early diagnosis of NP‑SLE. All patients presented primarily with typical psychiatric symptoms—including depressive states, auditory hallucinations, and perceptual distortions—with two additionally having a history of facial erythema. Laboratory evaluations consistently revealed lymphopenia without other abnormalities. Clinically, monotherapy with antipsychotics proved poorly effective, whereas combination therapy with corticosteroids and immunosuppressants such as cyclophosphamide resulted in meaningful symptom relief. These observations underscore the importance of establishing an independent diagnosis of NP‑SLE in cases characterized by psychiatric symptoms, cognitive impairment, or seizures. Assessment of past medical history and relevant laboratory tests can provide critical diagnostic clues, warranting referral to specialized care.

5 Targeted therapies that modulate lymphocyte function

There is currently no targeted therapy for lymphopenia in patients with systemic lupus erythematosus (SLE). Following treatment for lupus flares, markers of disease activity typically improve, and lymphocyte counts tend to rise. As B cells play a central role in the pathogenesis of SLE, much research has focused on B‑cell–directed interventions. B‑cell depletion therapy (BCDT), unlike conventional non‑specific immunosuppression, exerts its effects by selectively and specifically eliminating B cells through biologic targeting. Rituximab (RTX, MabThera), the most widely studied BCDT agent to date, is a chimeric human–mouse monoclonal antibody against CD20. It binds specifically to the CD20 antigen on the surface of B cells and induces their elimination via complement‑dependent or antibody‑dependent cytotoxic mechanisms and apoptosis, thereby reducing the production of autoantibodies and pro‑inflammatory cytokines and achieving immunosuppressive effects. Both open-label studies and clinical applications have demonstrated favorable outcomes with rituximab. However, two large‑scale, randomized controlled trials focusing on extra‑renal SLE and lupus nephritis did not yield consistent findings. Compared with the clinical use of rituximab, these trials highlight numerous unresolved questions in clinical practice. Therefore, it is essential not only to evaluate the therapeutic value of BCDT in large patient cohorts but also to accurately assess the true efficacy of investigational agents, with the aim of designing more robust trial protocols for the clinical management of SLE.

Li et al. studied 35 patients with SLE complicated by refractory cytopenias who underwent mesenchymal stem cell transplantation (MSCT). One week after treatment, the circulating Th17 cell count decreased; this percentage continued to decline at 1 month, 3 months, and 6 months. By the 12‑month follow-up, Th17 levels had returned to near‑normal values, accompanied by a reduction in lupus disease activity scores and improvements in hematologic parameters. Concurrently, Treg cell (regulatory T cell) levels showed a gradual increase and recovery at 1 week, 1 month, and 12 months post‑treatment. These findings suggest that the restoration of a dynamic balance between Tregs and Th17 cells in circulation following MSCT may underlie the improvement in hematologic outcomes. In vitro experiments further confirmed that MSCs can upregulate the proportion of CD4+CD25+Foxp3+ T cells while downregulating the proportion of CD3+CD8−IL‑17A+ T cells. Among the 35 SLE patients with refractory cytopenias treated with MSCT, the majority required progressively lower doses of corticosteroids and immunosuppressants to maintain disease stability; more than one year of follow-up revealed that these patients remained in remission. However, whether the observed increases in Treg cells and decreases in Th17 cells following MSCT represent a direct effect of MSCT or an additive effect of MSCT combined with immunosuppressive therapy remains to be elucidated in future studies.

6 Conclusion

Lymphocytopenia is one of the common hematologic abnormalities in patients with systemic lupus erythematosus (SLE), and both the presence and severity of lymphocytopenia correlate with disease activity. Patients with severe lymphocytopenia are at increased risk of opportunistic infections, particularly those receiving immunosuppressive therapy, necessitating prophylactic interventions. SLE is a complex, chronic condition characterized by a prolonged course and variable clinical manifestations. Although conventional therapies have demonstrated reliable efficacy, their adverse effects significantly compromise patients’ quality of life and prognosis. Consequently, an ideal treatment strategy should halt disease progression, minimize organ damage, and improve patients’ quality of life. Currently, biologic targeted therapies have garnered considerable attention; however, only a limited number of clinical trials have been successful, with the efficacy of B‑cell–targeted therapies having been substantiated in numerous studies.

Note: This article is intended for academic exchange only and may not be used for commercial purposes. Copyright belongs to the original author; if any infringement occurs, please contact us immediately, and we will address it promptly.