Immunoglobulin abnormalities are frequent and diverse in patients with lupus nephritis. The most frequent finding is of elevated immunoglobulin levels, consistent with the generalised increased immune activity found in SLE. Such a pattern is also well recognised in Sjogren’s syndrome. Although non-specific, the finding of polyclonal hypergammaglobulinemia can be a further laboratory clue for connective tissue disease in undiagnosed patients.
Neither selective IgA nor IgM deficiency are usually associated with recurrent infections, and do not typically require intervention with IGRT. Selective IgA deficiency is defined as IgA < 0.07 g/L, with normal IgG and IgM levels [11]. This is different to partial IgA deficiency where the IgA level is below the lower limit of the reference range, but still detectable. In selective IgA deficiency, it is important to be aware of the very small risk of reaction to transfusions and immunoglobulin infusions (due to contamination with small amounts of IgA which these patients recognize as foreign). Patients with partial IgA deficiency do not have this risk, as they are tolerant to IgA. Selective IgA deficiency is known to be associated with SLE: Cassidy et al. reported prevalence of 2.6% in their cohort including 152 adults, defining IgA deficiency as < 0.01 g/L [12], while we found a 2.4% prevalence. Selective IgA deficiency is also common in the general population (1 in 223 to 1 in 1000), though the vast majority of patients with selective IgA deficiency do not have problems with infections [11].
Selective IgM deficiency has not traditionally been thought to be a major risk factor for recurrent infection, though there is more recognition recently as an immunodeficiency disorder [13]. It may be associated with more severe or long-standing SLE, and could relate to long-term corticosteroid or immunosuppressive therapy [8, 14]. We found 4/83 (4.8%) patients with both low IgM and IgG, and the risk of infection in these patients is considered to be more strongly linked to the low IgG, though some studies show that low IgM in association with low IgG can be associated with increased risk of infection-related chronic lung disease/bronchiectasis [15]. The Urowitz group in Canada showed showed consistent association between low immunoglobulin level and clinically significant infection in SLE. They reported that low IgG and IgM levels increased the risk of severe infection [16].
Although we found low IgG levels in 8.4% of our cohort, most patients in this group did not report increased infections. Common variable immunodeficiency has been associated with SLE, but is still very rare [6]. Low IgG may be reversible in some patients with immunosuppressive drug-related reduction, including non-biologic medications such as corticosteroids (17). Low IgG (though not usually IgA or IgM) can be found in severe cases of nephrotic syndrome with marked proteinuria. Smilek et al. reported hypogammaglobulinemia in 16/102 (15.7%) patients prior to initiation of induction therapy for lupus nephritis in the Abatcept and Cyclophosphamide Combination Efficacy and Safety Study (ACCESS). Serum IgG levels inversely correlated with urinary protein-creatinine ratio (7). We have reported a patient with severe SLE-related nephrotic syndrome, with IgG falling to a nadir of 1.7 g/L while urine protein excretion was 11.95 g/24 h. This improved to 4.9 g/L as the urine protein lessened to 1.19 g/24 h with treatment over a 6-month period [8].
It is most important to consider infection history, as this is the key factor in decision-making regarding immunoglobulin replacement. Monitoring of immunoglobulin levels at 6–12 monthly intervals may be appropriate. Such monitoring over time can help to distinguish between patients developing minor, transient, hypogammaglobulinemia without infections, and those less commonly, who develop a sustained reduction and clinically significant picture [2, 9, 17]. Although most hypogammaglobulinemic patients are asymptomatic, it is noteworthy that hypogammaglobulinemia has been associated with an increased infection risk in patients with AIRD in multiple studies [13]. There is data from AAV, RA, and SLE, as above [1, 16].
It is also noteworthy that low baseline IgG is a risk factor for clinically significant hypogammaglobulinemia in AIRD patients treated with BCTT [18]. During rituximab treatment, baseline IgG level at the start of maintenance therapy was the only factor associated with future development of ‘significant’ hypogammaglobulinemia, defined as IgG < 4 g/L [19]. Significant hypogammaglobulinemia only developed if baseline maintenance IgG was in the lowest quartile (4.08–5.59 g/L). Hence, the importance of measurement of immunoglobulins prior to commencing BCTT is emphasized.
Measurement of specific anti-microbial antibodies (pneumococcus, tetanus, haemophilus) is used to assess functional antibody deficiency and when appropriate, response to test vaccination is used as a diagnostic tool in patients with low specific antibody results. In patients with persistent hypogammaglobulinemia, and/or recurrent infections, and/or impaired response to test vaccination (functional antibody deficiency), early referral to Clinical Immunology is recommended [17]. We do not have data on specific antibody measurements in our cohort, as these tests were not routinely requested. When indicated, assessment of suitability for IGRT is often undertaken by Clinical Immunology, according to a recent multidisciplinary taskforce [17], due to their IGRT experience, in contrast to high dose immunomodulatory immunoglobulin [20]. The use of IGRT has been effective in management of a selected group of AIRD patients with secondary hypogammaglobulinemia [1, 2, 21]. The UK group utilized a replacement dose of 0.4 g/kg/month, the recommended dose as per the Department of Health guidelines [21, 22]. Both intravenous and subcutaneous routes are effective and safe for immunoglobulin replacement [20].
For patients with extremely low IgG levels (below 1–2 g/L), and evidence of functional antibody deficiency, IGRT can be considered even in the absence of recurrent infection, because of the major future risk of infection.
We acknowledge the limitations of this concise report, as we are not able to access and provide detailed individual clinical information regarding treatment schedules, disease activity, renal biopsy findings, and white cell count results. This further data would have undoubtedly provided additional useful background and context for the reader.
