Activation of the classical pathway complement system has long been implicated in stimulating immune complex mediated tissue destruction in systemic lupus erythematosus (SLE). C3 and C4 complement levels are utilized as part of SLE diagnosis and monitoring criteria. Recently, cell bound complement activation products (CBCAPs) have shown increased sensitivity in diagnosing and monitoring lupus activity, compared to traditional markers. CBCAPs are increasingly utilized in rheumatology practice as additional serological markers in evaluating SLE patients. We report a case of a patient diagnosed with SLE that had chronically low C3 and C4, along with negative CBCAPs. We surmise that the patient has an inherited complement deficiency as the etiology of her SLE and that CBCAPs could be used to predict such deficiency.
The pathogenesis of systemic lupus erythematosus (SLE) has long been ascribed to the presence of immune complexes, prompting complement pathway activation and complement consumption. As such, serum complement (i.e., C3 and C4) measurements have been utilized as part of the Systemic Lupus International Collaborating Clinics (SLICC) criteria in diagnosing and monitoring SLE. However, several factors have emerged as evidence of the inadequate utility of serum C3 and C4 in monitoring SLE activity. First, there is a wide range of serum C3 and C4 levels that overlap between healthy individuals and those with SLE. Second, the consumption of C3 and C4 during activation may be counteracted by increased synthesis of complement during active inflammation. Thirdly, hereditary deficiencies in complement such as C4 may result in persistently low complement levels reflective of decreased synthesis rather than increased consumption [
Over the last decade, measurements of cell bound complement activation products (CBCAPs) have played an increasingly prominent role in aiding in the diagnosis of SLE as well as monitoring disease activity. This is borne out of the rationale that as complement activation occurs during lupus flares, complement is consumed thus lowering its level. Activation derived complement products are then generated at a rate proportional to the degree of disease activity [
A 25-year-old African American woman initially presented to the hospital in 2014 with anosmia, blurry vision, and arthralgias. Subsequent serological evaluation led to a diagnosis of SLE (Table
July 09, 2014.
ANA | Result | Reference ranges |
---|---|---|
Immunofluorescence (IIF) | 1 : 5120 (positive)/homogeneous | Negative (<1 : 80); positive (≥1 : 80) |
| ||
Analyte | Result | Reference ranges |
| ||
Anti-dsDNA (ELISA) | 581 IU/mL (positive, confirmed by | ≤301 (negative); > 301 (positive) |
Anti-Smith (ELISA) | 46 U/mL (positive) | <5 (negative); 5–10 (equivocal); > 10 (positive) |
EC4d (FACS) | 6 Net MFI (negative) | ≤12 (negative); > 12–75 (positive); > 75 (strong |
BC4d (FACS) | 34 Net MFI (negative) | ≤48 (negative); > 48–200 (positive); > 200 (Strong Positive) |
Anti-U1RNP IgG | 13 U/ml (positive) | <5 negative; 5–10 equivocal; > 10 positive |
Anti-RNP70 IgG | 1 U/ml (negative) | <7 negative; 7–10 equivocal; > 10 positive |
Anti-SS-A/Ro IgG | 182 U/ml (positive) | <7 negative; 7–10 equivocal; > 10 positive |
Anti-SS-B/La IgG | >320 U/ml (positive) | <7 negative; 7–10 equivocal; > 10 positive |
Anti-C1q IgG | 144 U/ml (positive) | <20 units (negative); ≥ 20 units (positive) |
C3 | 53 mg/dl | 90–180 mg/dl |
C4 | 3 mg/dl | 16–47 mg/dl |
April 1, 2015.
ANA | Result | Reference ranges |
---|---|---|
Immunofluorescence (IIF) | 1 : 1280 (positive)/homogeneous | Negative (<1 : 80); positive (≥1 : 80) |
| ||
Analyte | Result | Reference ranges |
| ||
Anti-dsDNA (ELISA) | 867 IU/mL (positive, confirmed by | ≤301 (negative); > 301 (positive) |
Anti-Smith (ELISA) | 46 U/mL (positive) | <5 (negative); 5–10 (equivocal); > 10 (positive) |
EC4d (FACS) | 6 Net MFI (negative) | ≤12 (negative); > 12–75 (positive); > 75 (strong positive) |
BC4d (FACS) | 43 Net MFI (negative) | ≤48 (negative); > 48–200 (positive); > 200 (strong positive) |
Anti-U1RNP IgG | 14 U/ml (positive) | <5 (negative); 5–10 (equivocal); > 10 (positive) |
Anti-RNP70 IgG | 2 U/ml (negative) | <7 (negative); 7–10 (equivocal); > 10 (positive) |
Anti-SS-A/Ro IgG | >240 U/ml (positive) | <7 (negative); 7–10 (equivocal); > 10 (positive) |
Anti-SS-B/La lgg | >320 U/ml (positive) | <7 (negative); 7–10 (equivocal); > 10 (positive) |
C3 | 69 mg/dl | 90–180 mg/dl |
C4 | 3 mg/dl | 16–47 mg/dl |
ELISA: enzyme-linked immunosorbent assay. FACS: fluorescence-activated cell sorting.
Deficiencies of early complement components are strongly associated with SLE or lupus like disease. This is hypothesized to occur for several reasons. Functionally, complement identifies, opsonizes, and disposes apoptotic cells and immune complexes formed between antibodies and foreign or self-antigens. The inability to clear these apoptotic cells can cause them to be a source of autoantigens and thereby drive autoantibody production [
Complement deficiency in humans can be inherited or acquired. Acquired complement deficiencies are quite common and can occur as a result of decreased synthesis, increased protein loss, or increased consumption. The liver produces several complement components, and low complements can be seen in individuals with advanced liver failure. Increased protein loss associated with nephritic syndrome or protein losing enteropathy can result in complement deficiencies [
This interesting case raises the possibility of our patient having an inherited complement deficiency as the etiology of her SLE. It also provides an explanation for her bacteremia and recurrent sinusitis. The rationale for this observation is that the patient has had continuously low levels of serum complement. Initially, it was thought that the low complement levels were due to consumption from active SLE. However, the patient’s sera C3 and C4 have been low even when her SLE was inactive. In addition, the patient’s measured CBCAPs were negative even when measured during an active lupus flare. An inherited complement deficiency can explain her chronically low complement levels and absent CH50 level. Her measured CBCAPs are most likely negative because there is not enough complement activation to produce a measurable quantity of complement split products. In addition, as observed by Calano et al., erythrocytes have a lifespan of 120 days and may bind and accumulate C4d throughout that period. Thus, EC4d levels would likely reflect the collective result of complement activation and SLE disease activity over a 120 day period [
Our observation is limited by certain considerations. First, a full evaluation of complement deficiency has not been done in this patient. Evaluating inherited complement deficiencies and analyzing complement GCN are complicated and not feasible in an outpatient clinical rheumatology practice. Another consideration is that the patient has an acquired complement deficiency rather than an inherited complement deficiency. Autoantibodies binding to complement proteins could lead to a state of an acquired deficiency and contribute to SLE pathogenesis similar to the way genetic deficiencies do [
CBCAPs have emerged as highly sensitive SLE indicators and are now routinely being measured in clinical practice along with traditional serological markers in diagnosing and assessing SLE activity. Further study is needed, but we believe that CBCAPs may play a novel role in predicting an inherited complement deficiency. We recommend clinicians consider this possibility when evaluating SLE patients with chronically low complement levels and negative CBCAPs.
The authors declare that there is no conflict of interests regarding the publication of this paper.