Current and Future Challenges of Hypogammaglobulinemia in Autoimmune Rheumatic Disease Patients Receiving B‐Cell Therapies

B cell targeted therapies (BCTT) are recognized to be effective in a range of autoimmune rheumatic diseases (AIRD), including systemic lupus erythematosus (SLE) and anti-neutrophil cytoplasmic antibody associated vasculitis (AAV). BCTT include B-cell depleting therapies (BCDT), for example, rituximab, and those interfering with B-cell activation, for example, belimumab [1]. Despite early smaller studies of short duration indicating otherwise, it is now well recognized that hypogammaglobulinemia is an important side effect, particularly for BCDT. Indeed, physicians looking after AIRD have been ahead of the game recognizing this important side effect. In the June issue of this journal, Tsao et al. published recommendations from the Taiwanese College of Rheumatology for secondary hypogammaglobulinemia in patients with systemic AIRD [2]. Globally, these are only the second published BCTT-related hypogammaglobulinemia recommendations specific to AIRD, though there are sections within other society recommendations, for example, American College of Rheumatology (ACR) and American Academy of Asthma, Allergy and Immunology (AAAAI) applicable to BCTT and hypogammaglobulinemia [3, 4]. Key points from these recommendations are summarized in Table 1. Baseline IgG levels before commencing BCTT. Before and/or 4–6 months after each BCTT infusion. IgRT trial for IgG levels listed below and history of infection. If no history, shared decision making to consider trial. Isolated IgG < 1.5 g/L without history of infection warrants IgRT trial. Assessment every 6–12 months, including infection history and IgG. Consider pausing IgRT if immunosuppression stopped (9–12 months after BCTT discontinued). Reevaluate IgG and immune function 3–4 months after pausing IgRT. Patients with GPA/MPA and receiving remission maintenance therapy with rituximab. Conditional recommendation of IgRT if HG, e.g., < 3.0 g/L, and recurrent severe infections. Also consider for HG without infections but with impaired vaccine responses. Baseline IgG levels pre-BCTT. Follow up monitoring 3–6 months after BCTT infusions; interval shorter if risk factors or prior low IgG. Discontinue IgRT if no infections for 3–6 months AND IgG level returned to normal. Reassess infection risk and IgG level 3–4 months after IgRT discontinuation. Monitor IgG periodically. Mechanistically it was considered that BCDT would have limited effects on serum immunoglobulins, as CD20 is expressed on B-cells but not on plasmablasts or plasma cells, which are responsible for antibody production. However, the effects of prolonged/pronounced B-cell depletion by these agents appear to impact the natural process of B-cell differentiation which normally results in replenishment of plasma cells [1]. Hypogammaglobulinemia can vary in its severity, in terms of the absolute IgG level, the duration of hypogammaglobulinemia (i.e., transient or persistent), and its clinical relevance—i.e. association with increased risk of infection. Undiagnosed hypogammaglobulinemia places AIRD patients at unnecessary risk of infection, with consequent increased morbidity and mortality. Studies have identified a number of risk factors for post-BCTT hypogammaglobulinemia, including baseline IgG level, cumulative rituximab dose, use of certain concomitant or prior immunosuppressive agents, for example, cyclophosphamide, and nature of underlying AIRD [5-7]. Prior to commencing BCTT, it would be useful for physicians to consider such factors in order to stratify the risk of the patient developing hypogammaglobulinemia. While recognition of BCTT-related hypogammaglobulinemia may have improved over the past few years, monitoring of immunoglobulins both at baseline, during BCTT, and following completion of BCTT can still be improved further [8]. Tsao et al. recommend baseline IgG testing pre-BCTT, and then at 3–6 month intervals following commencement. The concept of baseline and follow-up IgG measurements is supported by Wijetilleka et al., and by several society recommendations; the recommended timing of testing quoted in these articles varies slightly, but the principle remains the same [4, 5]. In the pediatric setting, the concept of inborn errors of immunity (IEI) characterized by immune dysregulation is emerging, so-called primary immune dysregulation disorders. The development of post-BCTT hypogammaglobulinemia may be related to an underlying IEI, giving rise to early onset autoimmunity as well as hypogammaglobulinemia [9]. This is especially true in patients presenting with autoimmune cytopenia [10]. Hence in pediatric-onset autoimmune patients, it is especially important that the baseline IgG is checked, as this may already be low in IEI patients. Measurement of immunoglobulins assesses the quantity of the humoral immune response. The use of specific antibody measurements (e.g., to pneumococcus, tetanus) and, if necessary, vaccine challenges represents a measure of the quality of the humoral response [5]. Specific antibody testing is utilized to stratify risk in patients with post-BCTT HG in the ACR AAV and AAAAI secondary immunodeficiency guidance [3, 4]. Although, Tsao et al. do not refer to the usage of this testing, this may also be considered a more pragmatic approach, as BCTT is known to affect post-vaccine antibody responses for many months [4]. Hence, such measurements may be of limited value in this patient group. While much of the published data concerns rituximab, we need to consider the potential impact of rituximab biosimilars, newer anti-CD20 agents, and novel BCTT's. For example, while obinutuzumab is claimed to induce more potent B-cell depletion, could this therapeutic effect be associated with an increased risk of hypogammaglobulinemia? CAR-T cells targeting B cells have been reported to be effective in patients with refractory SLE. This category of BCTT appears to carry a very high risk of hypogammaglobulinemia, especially in children, and this may need to be specifically addressed in future recommendations [11]. Furthermore, the risk of more complex regimens involving multiple agents such as combining BCDT with belimumab, or BCDT with plasma cell therapies also needs to be considered. Indeed, the risk of hypogammaglobulinemia with the latter combination is likely to be higher. Further assessment regarding the risks and effects of hypogammaglobulinemia needs to be included in future clinical trial design of BCTT. Registry data of AIRD and AAV where BCTT are utilized should include data on immunoglobulin measurements. Interestingly, there appears to be a difference in risk of post-BCTT hypogammaglobulinemia between different AIRD. For example, the risk in SLE and AAV appears to be higher than in rheumatoid arthritis [7]. The reasons behind this need to be further evaluated, but may include factors related to the disease pathogenesis itself, cumulative BCTT dose, as well as other immunosuppressive and corticosteroid use. The use of immunoglobulin replacement (IgRT) in post-BCTT hypogammaglobulinemia in AIRD is an important management option, but it is important to emphasize that only a minority of patients require IgRT. Roberts et al. reported that IgRT was required in 4.2% of their cohort of 243 rituximab-treated AIRD and systemic vasculitis patients [12]. In a later study from the same center focusing only on the subgroup with hypogammaglobulinemia, Tieu et al. noted that 29/142 (20%) hypogammaglobulinemic patients required IgRT [13]. What has not yet been well established are the specific criteria for introducing IgRT. Tsao et al. propose a range of thresholds for intervention with IgRT dependent on IgG level and infection history/risk of infection. An important concept in these recommendations, also present in the ACR AAV guideline, is the proposed use of IgRT in patients with IgG < 300 mg/dL even in the absence of history of infections [2, 3]. This pragmatic approach recognizes that these patients are at high risk of infection, especially with ongoing BCTT/other immunosuppression, and the danger in delaying IgRT while waiting for infections to occur. Ideally, the applicability of recommendations should be universal, but clearly there may be limitations dependent on the specific healthcare system. For example, Tsao et al. do not discuss the use of subcutaneous immunoglobulin (SCIg) and instead focus only on intravenous immunoglobulin (IVIg) as this is the only administration route available in their healthcare system. SCIg is an excellent alternative, where available, with reduced adverse effects, lower IgG fluctuations, and improved patient convenience [14]. The choice of course has major implications for the patient, who is then committed to either attending the hospital for IVIg infusions or self-infusing with SCIg at home; though the route will be periodically assessed at clinical reviews. The decision also has significant health economic issues, such that we may need to consider the cost of medium or long-term IgRT as part of the overall cost of BCTT. In some healthcare systems, access to any form of IgRT may not be possible or affordable, and alternatives which are less than ideal such as antibiotic prophylaxis might have to be considered. The use of IgRT is not open-ended, and Tsao et al. astutely comment on the criteria for discontinuation of IgRT and the criteria for restarting IgRT should infections recur. Regional disparities mean that some healthcare systems may not have the capabilities or infrastructure to implement regular IgG monitoring or administer IgRT equitably upon recognition of its clinical need. Commercial considerations by pharmaceutical companies may also influence the availability of different IgRT products across the region. Adaptation of guidelines is essential to develop national policies that reflect local realities and health financing systems, particularly in resource-constrained environments. The issue of post-BCTT hypogammaglobulinemia in AIRD and considering whether to start, continue, or stop IgRT highlights the importance of close working relationships between Rheumatologists, Clinical Immunologists, and Laboratory Immunology. The challenge of post-BCTT hypogammaglobulinemia will only increase with the plethora of novel BCTT being trialed for patients with AIRD. Mohammed Yousuf Karim: conceptualization, writing – conceptualization, writing – original draft. Khadija Karim: writing – editing and revising, manuscript preparation. Professor Karim has undertaken consulting and speaker duties for Takeda Ltd., and speaking duties for CSL Behring Ltd. The data that support the findings of this study are available from the corresponding author upon reasonable request.