Lupus and IgA nephropathy: coexistence or coincident?

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease, with approximately 50% of patients developing renal involvement during the disease course. Lupus nephritis (LN) can be categorized into six subtypes: minimal mesangial (class I), mesangial proliferative (class II), focal proliferative (class III), diffuse proliferative (class IV), membranous nephropathy (class V) and advanced sclerosing (class VI). Typical LN is characterized by a “full house” pattern under immunofluorescent microscopy, with positive staining for IgG, IgA, IgM, C3 and C1q [1]. In addition to these subtypes, non-lupus nephropathies in SLE patients have rarely been reported. One such nephropathy is IgA nephropathy (IgAN), which is the most common primary glomerulonephritis worldwide [2].

The co-occurrence of IgAN with other autoimmune diseases is not very common; however, some studies have suggested that it may be particularly associated with diseases such as SLE, rheumatoid arthritis, inflammatory bowel disease, celiac disease and ankylosing spondylitis. Although the coexistence of IgAN in SLE is rare and underexplored, it has important implications for treatment and prognosis [3].

In this study, we reviewed the literature regarding SLE patients with IgAN. We also evaluated similar patients from our clinic and described their clinical features. Furthermore, we compared these patients with the LN cohort from our clinic and the primary IgAN cohort from the literature. Our aim was to evaluate the clinical features and outcomes of SLE patients with IgAN, comparing them with those of primary IgAN and SLE patients with LN.

To date, as many as 16 cases of SLE-IgAN have been reported [7‐16]. Additionally, we present clinical features of two patients from our clinic and compare all these cases with the LN cohort from our clinic and one of the primary IgAN cohorts in the literature. The rate of end-stage renal disease in the group of SLE and IgAN was 11.1% and the mortality rate was 5.6%. In the LN cohort of 47 patients, the progression rate to end-stage renal failure was found to be 10.6% and the mortality rate was 10.6%.

The SLE is a chronic autoimmune disease, with approximately 50% of patients experiencing renal involvement during the disease course. While LN is a well-recognized manifestation, the existence of non-LN in SLE patients, such as IgA nephropathy, has been rarely reported. Hence, conducting a kidney biopsy in patients with renal abnormalities is crucial for an accurate diagnosis and treatment guidance [2]. Lupus nephritis is characterized by the accumulation of polyclonal immunoglobulins, predominantly of the IgG isotype and complement fractions (C1q, C3, C4) on the capillary basal membrane [1]. Conversely, in IgAN the IgA staining pattern should predominantly involve the mesangium, with or without additional staining of the capillary loops. While IgG and IgM may also be detected, their intensity should not surpass that of IgA, except in the case of IgM, which may be more prominent in sclerotic regions [17]. In the literature, some cases of atypical LN with mainly IgA deposition have been described. Although the coexistence of SLE and IgAN is not fully elucidated, it has been hypothesized that predominant mesangial IgA deposition may represent a distinct subtype of SLE nephritis; however, the absence of IgG and complement factors of the classical pathway (C1q and C4) does not align with typical LN [7, 11, 12].

The SLE predominantly affects women of childbearing age, with a female to male ratio of 9:1; however, male gender is associated with poorer renal outcomes. Lupus nephritis typically develops within 5 years of SLE diagnosis [18]. In contrast, IgAN primarily affects males during the second and third decades of life. In our study, the majority of SLE patients with IgAN were female, while there were more male patients in the primary IgAN group. The median age of patients with SLE and IgAN was 41.6 years, whereas the median age of patients in the primary IgAN cohort was 44 years. In the LN cohort, the median age of patients was 30 years. Similar to our study, Hongyan et al. described the clinical characteristics of a total of 5 SLE patients (2 males, 3 females) with predominant IgA deposition. They found some differences compared to primary IgAN, such as older age than primary IgAN, with an average of 42.2 ± 13.59 years [12].

The classical clinical presentation of LN typically includes persistent proteinuria, defined by the American College of Rheumatology classification criteria as 0.5 g per 24 h or a dipstick score of greater than 3+, or the presence of cellular casts or active urinary sediment. Elevated serum creatinine levels may also be indicative [1]. In contrast, primary IgAN is characterized by episodic gross hematuria or persistent microscopic hematuria, with concurrent proteinuria not always present. Approximately 40% of patients progress to end-stage renal disease, and serum complement levels are typically normal [17]. In our study, the vast majority of SLE patients with IgAN presented with varying levels of proteinuria and microscopic hematuria at initial presentation. Of the cases four presented with nephrotic range proteinuria, while two patients presented with acute kidney injury. Despite treatment, renal function continued to deteriorate in these cases, ultimately leading to end-stage renal disease.

In SLE patients, high titers of anti-dsDNA antibodies, often in conjunction with decreased levels of complement proteins C3 and C4, are typically associated with disease flare, particularly renal involvement. Conversely, serum complement levels are expected to be normal in cases of primary IgAN [19]. In our study, approximately half of the SLE with IgAN patients exhibited elevated anti-dsDNA antibodies and decreased complement levels, underscoring the importance of renal biopsy and the likelihood of non-LN in the context of serologically or clinically active lupus. In this context, low complement levels may reflect extrarenal lupus activity [11, 13].

The differentiation between lupus nephritis and IgAN is crucial due to differences in therapeutic management and prognostic outcomes. Treatment for LN typically involves immunosuppressive therapy tailored to the histopathological class of the disease, with antimalarial drugs recommended for all patients unless contraindicated [18]. In recent KDIGO (Kidney Disease Improving Global Outcomes) guidelines for IgAN (public review draft), the initial therapeutic strategy predominantly emphasizes the management of blood pressure and the reduction of proteinuria through the utilization of renin-angiotensin-aldosterone system (RAAS) inhibitors, as well as dual endothelin-angiotensin receptor antagonism (DEARA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i), either as monotherapy or in combination. Notably, targeted-release budesonide (nefecon) is the only agent shown to reduce levels of pathogenic IgA and IgA immune complexes, and a 9-month course is recommended for patients at risk of progressive renal function decline. Systemic glucocorticoids are generally used sparingly in IgAN; however, if nefecon is unavailable, patients at higher risk of progressive renal deterioration may benefit from a short duration, reduced dose glucocorticoid regimen, alongside antimicrobial prophylaxis and guided by a thorough toxicity risk assessment [20].

In this study, the vast majority of SLE with IgAN patients showed renal function improvement after treatment with glucocorticoids, with or without immunosuppressive drugs. Hongyan et al. also demonstrated the beneficial effect of glucocorticoids and immunosuppressive treatment on SLE with IgAN [12]; however, a 19-year-old female patient diagnosed with cerebral lupus died due to an unknown systemic infection [7]. Another patient, a 72-year-old man presenting with acute progressive glomerulonephritis, received high-dose pulse glucocorticoid therapy and cyclophosphamide pulse treatment but failed to recover renal function, necessitating continued hemodialysis [15]. Similarly, Patel et al. reported on a 74-year-old woman with known SLE and chronic kidney disease attributed to diabetes mellitus and hypertension, who presented with acute kidney injury. Renal biopsy findings revealed IgAN with crescent formation. Despite treatment with pulse methylprednisolone and plasmapheresis, the renal function did not recover, leading to initiation of hemodialysis [14]. These cases underline that when IgAN is complicated by acute glomerulonephritis and crescent formation, patients may exhibit poor renal outcomes despite glucocorticoid and immunosuppressive drug therapy.

Lupus nephritis stands as a significant contributor to morbidity and mortality in SLE, with approximately 10% of cases progressing to end-stage renal disease [1]. In the literature, the reported mortality rate for proliferative LN (classes III, IV, or III/IV + V) is 5–25% and the progression rate to kidney failure is 10–30% [21]. In our LN cohort of 47 patients, the progression rate to end-stage renal failure was found to be 10.6% and the mortality rate was 10.6%. In SLE with IgAN group, the progression rate to kidney failure was found to be 11.1% and the mortality rate was 5.6%. On the other hand, in the primary IgAN group, 34% of 215 patients progressed to end-stage kidney disease, with a reported mortality rate of 20%, primarily due to cardiovascular diseases [6]. These findings may suggest that SLE with IgAN may exhibit slightly better renal outcomes compared to primary IgAN.

The main limitation of our study is that the data were compiled from case reports and case-based reviews in the literature, highlighting the need for long-term follow-up data on these cases; however, our study stands out as a more comprehensive comparison of the clinical characteristics of patients with SLE and IgAN with the primary IgAN population.

The reason why certain SLE patients are more susceptible to developing IgAN remains unclear. The shared genetic and environmental backgrounds of SLE and IgAN support our hypothesis that these two diseases may coexist due to similar immunological mechanisms.

In summary, SLE with IgAN exhibits some distinct clinical characteristics from primary IgAN. As evidenced by the follow-up of reported cases in the literature, SLE with mainly IgA deposition may present a more indolent course compared with primary IgAN; however, when IgAN is complicated by acute glomerulonephritis and crescent formation, such patients may demonstrate poor renal outcomes despite treatment with glucocorticoids and immunosuppressive drugs. Hence, it is imperative to perform a kidney biopsy in lupus patients with renal abnormalities, as the diagnosis may not always be LN and it should be kept in mind that IgAN may also coexist in lupus patients. An accurate diagnosis is crucial for guiding appropriate therapeutic regimens.

Nevertheless, more data are needed on clinical features, treatment approaches, and prognostic outcomes in patients with SLE and IgAN. Therefore, prospective and comparative studies with larger patient populations should be conducted in the future.