Systemic Lupus Erythematosus and Albumin-Globulin Index, a specific finding in lupus flares?
Introduction: Systemic lupus erythematosus (SLE) is the model of autoimmune disease. Several types of immunoglobulins are involved in the development of the disease, mainly IgG, IgM and IgA.
Objective: To describe the potential use of the albumin/globulin ratio as an indicator of activity in SLE.
Development: fifty per cent of patients with SLE exhibit hypoalbuminemia with hypergammaglobulinemia in the disease activity periods. Hypoalbuminemia is mainly related to the presence of lupus nephritis. The half of patients with lupus nephritis develop proteinuria with values of nephrotic syndrome. The proteinuria equals or partially reverses the albumin/globulin ratio. The inverted albumin/globulin ratio is insufficient to establish the presence of lupus activity. Other clinical entities producing polyclonal hypergammaglobulinaemia should be excluded. The SLE activity criteria increase the sensitivity of the inverted albumin/globulin ratio.
Conclusions: the interpretation of the albumin/globulin ratio requires the activity estimation by differents clinical criteria (SLICC, SLEDAI, BILAG, etc.). The inverted albumin/globulin ratio can not be interpreted as a stand-alone indicator of disease activity in every SLE patients
Keywords: Lupus Erythematosus, Systemic; Autoimmunity; Globulins; Immunoglobulins; Serum Albumin; Lupus Nephritis.
Systemic lupus erythematosus (SLE) is an autoimmune disease, first reported in the Middle Ages. Its name is attributed to Dr Rogerius, who first used it to refer to the malar erythema typical of the disease. The discovery in 1948 by haematologist Malcolm Hargraves of lupus erythematosus cells or “LE cells” was a milestone in the understanding of the pathophysiology and specific laboratory findings. (1) Still, despite technological advances, the cause of SLE remains an enigma and involves a wide variety of autoimmune immunoglobulins (Ig).
Globulins are quantified by electrophoresis of proteins (EP) and consist of α-1 and α-2 globulins, β globulins and gamma globulins or Ig. Up to five classes of Ig (IgG, IgA, IgM, IgD and IgE) and 18 subtypes are described according to the order of the chain in their composition. (2)
Several laboratory markers have been validated to estimate the presence of lupus flares or remission periods. The main targets of these markers are specific autoimmune Ig, which increases the sensitivity in contrast to a global globulin measurement. The total Ig value is subject to established variations due to several factors, among them chronic infections causing hypergammaglobulinemia. This article aims to describe the utility of the albumin/globulin ratio as an indicator of activity in SLE.
About 50% of SLE patients presented with hypoalbuminemia and hypergammaglobulinemia, which is a causative factor for the inversion of the albumin/globulin ratio. Hypergammaglobulinemia is a polyclonal type, with a predominance of IgG and IgM (Figs. 1 and 2). (2)
Sakthiswary and D’Cruz(3) demonstrated in a meta-analysis of 216 SLE patients that the use of intravenous Ig concentrates (IgEV) significantly reduced the values of SLEDAI, SLAM and LAI activity indices (p=0.002; CI=95%). The mechanism of action of IgEV in SLE is not entirely clear. It is postulated that the Fc portion of IgEVs bind to macrophage Fc receptors and inhibit the binding of the patient’s own autoimmune Ig, and positively affect the clinical course. (3) This IgEV status suggests that elevation of autoimmune Ig in SLE triggers a positivity in activity indices. Elevation of a specific type of autoimmune Ig alters the overall burden and causes hypergammaglobulinemia.
Fig. 1 - Schematic representation of the normal electrophoretic proteinogram in healthy patients.
Fig. 2 - Schematic representation of polyclonal hypergammaglobulinemia in patients with SLE.
The antinuclear antibodies (ANA) in SLE are autoimmune Ig classified according to the structures they affect. These structures include the nucleosome, non-histone DNA-associated proteins, non-histone RNA-associated proteins or extractable nucleus antigens (ENA), the nucleolus and cytoplasmic antigens. The International Consensus of ANA Patterns (ICAP) conducted in 2016 defined 28 variants. The variants can range from anti-cell (AC-1) to AC-28 and are further grouped into nuclear, cytoplasmic, or mitotic patterns. (4)
Other types of autoimmune Ig associated with SLE and also related to ANA patterns, with an increase in periods of activity, are anti-double-stranded DNA (anti-DNA) antibodies (60-83%),(4,5) anti-P ribosomal antibodies (12-16%), rheumatoid factor (15-25 %), ENA antibodies (anti-Ro or SSA [25-50 %], anti-La or SSB [10-20 %], anti-Sm [5-30 %] and anti-RNP [25-50 %]), and to a lesser extent antiphospholipid antibodies (aPL). (4) Polyclonal hypergammaglobulinemia is related to the diversity of autoimmune Ig classes and subtypes. Specific epitopes of autoimmune Ig tend to form circulating immune complexes and cause renal organ damage.
Hypoalbuminemia is linked to the presence of lupus nephritis, which ranges from 40-70% of all SLE patients. Ding et al. found that an increase in urine albumin concentration of 7.53 µg/mL had a 67 % sensitivity and 82 % specificity for the detection of severe renal injury. (6) Blanco-Mesa et al. estimated that 24-hour proteinuria increased with a longer disease progression and decreased glomerular filtration rate. (7) Faria-Miguel et al. reported that 24-hour proteinuria was higher in children diagnosed with early-onset lupus nephritis (p<0.001; 95 % CI), who had an increased SLICC activity index (p=0.004; 95 % CI).(8)
Glomerular proteinuria is the result of increased permeability of the capillary wall of the glomerulus. This type of proteinuria can be selective or non-selective with loss of IgG, IgA and IgM. The positivity of anti-IgM antiserum indicates the outflow of high molecular weight molecules through the glomerulus. (9) This outflow is more evident in advanced stages of lupus nephritis with glomerulosclerosis. Proteinuria in advanced stages is similar to that of nephrotic syndrome and is estimated to be present in 50% of patients with lupus nephritis. (10) In these cases more albumin than globulins are lost due to their low molecular weight, which directly affects the value of the albumin/globulin ratio and causes its partial or total inversion.
Clinical entities with the capacity to elevate the gamma-band of the EP in its polyclonal form include, in addition to SLE, a large number of infectious diseases and immune processes following infections, rheumatoid arthritis, liver cirrhosis, polyarteritis nodosa, scleroderma, among others(2).
The finding of an inverted albumin/globulin ratio is insufficient to affirm the presence of lupus activity. It is necessary to link the inverted albumin/globulin ratio with a clinical and laboratory evaluation depending on the various criteria or indexes to determine disease activity (BILAG, ECLAM, SLAM, SLICC, SLEDAI, LAI and SLAQ).(11,12) Clinical entities modifying the gamma band in its polyclonal form should also be excluded.
The impossibility of excluding these entities makes it necessary to perform a complete immunologic profile to quantify an increase in the various types of autoantibodies indicative of activity. The detection of antibodies is essential in these cases because the inversion of the albumin/globulin ratio is a non-specific acute phase reactant with little utility in isolation.
Although there are many factors capable of modifying the albumin/globulin ratio, this could be a useful laboratory test to determine activity in SLE. The interpretation of the test must include the estimation of activity by the most commonly used clinical criteria (SLICC, SLEDAI, BILAG, among others). Further research is needed to evaluate the sensitivity and specificity of this finding as an indicator of activity in patients with SLE.
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