Acquired disorders of the complement system

INTRODUCTION — Deficiencies in complement proteins may be inherited or acquired (secondary). Secondary causes of complement deficiency will be presented in this topic review. Inherited disorders of the complement system, as well as a description of the complement pathways and the clinical evaluation of complement, are presented separately. (See "Inherited disorders of the complement system" and "Complement pathways" and "Overview and clinical assessment of the complement system".)

OVERVIEW — Acquired deficiencies in complement proteins are more common than inherited complement disorders. Reductions in complement secondary to acquired disease processes are usually only partial and affect several complement components at once. As an example, approximately 50 percent of patients with systemic lupus erythematosus (SLE) will have reductions in C4 and C3, reflecting classical pathway activation.

These acquired complement deficiencies are most commonly encountered in diseases featuring autoantibodies. In many diseases, such as milder forms of SLE, augmented hepatic synthesis of components may be sufficient to maintain the levels in the normal range. The management of most disorders of the complement system featuring excessive activation focuses on the treatment of the underlying disorders.

Challenges in interpretation — One problem clinicians may encounter when managing disorders featuring acquired deficiencies of complement components is that the predisease levels of proteins, such as C3, are rarely known. For example, the "normal" laboratory range of C3 in the population is from 80 to 160 mg/dL. A 17-year-old female with new-onset SLE may present with a C3 value of 92 mg/dL. Although this is considered in the "normal range," if her post-treatment C3 value rises to 125 mg/dL in six weeks, then her predisease value was at least this or higher. Even at 125 mg/dL, a C3 turnover study or assessment of complement split products might show mildly accelerated consumption. Measuring C4, which commonly parallels changes in C3 levels, is more complicated because of C4 copy number, which is discussed elsewhere. Thus, complement levels need to be interpreted in the context of the clinical setting. (See "Inherited disorders of the complement system", section on 'C4 deficiency'.)

MECHANISMS OF ACQUIRED COMPLEMENT DISORDERS — Acquired deficiencies in complement proteins may result from several mechanisms:

●Accelerated consumption by immune complexes (common)

●Reduced hepatic synthesis (uncommon)

●Loss of complement components in the urine (rare)

●Somatic mutation in a complement gene (rare)

INCREASED CONSUMPTION BY IMMUNE COMPLEXES — Most diseases in which complement activation is sufficient to reduce plasma levels are characterized by the presence of immune complexes. The disease that best illustrates this point is SLE.

Typical pattern of complement abnormalities — The most common pattern of complement protein deficiencies in disorders involving increased consumption by immune complexes is a low C4, a low C3, and low total hemolytic complement (THC; also referred to as CH50).In a large Japanese series of patients with low C4, C3, and CH50, SLE accounted for approximately two-thirds of the cases, while other vasculitic syndromes accounted for approximately 20 percent, as shown in the table (table 1) [1]. By requiring both a low C4 and C3, the authors selected for patients with classical pathway activation.

By comparison, activation by the lectin pathway is insufficient to substantially decrease C3 and C4 in blood. Alternative pathway activation usually resulting in the pattern of normal C4 and a low C3, which is uncommonly encountered, include glomerulonephritis, partial lipodystrophy, acute rheumatic fever, and some forms of vasculitis (mediated by immune complexes).

Systemic lupus erythematosus — Low C4 and C3 (C2 would also be reduced but is usually not measured) occur in about 50 percent of patients with SLE, reflecting activation of the classical complement pathway by immune complexes. Accelerated consumption outstrips synthesis and is the cause of hypocomplementemia in about 90 percent of such cases, while the remaining 10 percent also show signs of reduced hepatic synthesis. The mechanism for the latter is unknown.

The usual pattern of complement activation in SLE involves the classical pathway, leading to low C3 and C4, while factor B of the alternative pathway is normal. However, a small percentage of patients (approximately 3 to 5 percent) demonstrate predominant alternative pathway activation, as evidenced by normal C4 but low C3 and factor B. In this situation, the autoantibodies are often subclasses that do not activate the classical pathway directly but coat the surface of the antigen, providing a surface for alternative pathway proteins to be protected from regulators [2]. (See 'IgG4–positive multiorgan lymphoproliferative syndrome' below.)

Immune complex deposition has been documented in the pathogenesis of tissue damage in most organs afflicted in SLE, particularly the skin, kidneys, joints, and serosal surfaces. Low complement values tend to correlate with more severe SLE, especially with renal disease, and with antibodies to double-stranded DNA. A return to normal levels with treatment is a good prognostic sign. If a patient with SLE presents with low C4 and C3 levels that improve with treatment in parallel with other parameters, then C4 and C3 may become a valuable biomarker of disease activity. (See "Lupus nephritis: Diagnosis and classification".)

Patients with SLE may be susceptible to infection with encapsulated bacteria because of immunosuppressive medications, functional asplenia, and/or hypocomplementemia, although the relative contribution of hypocomplementemia is unclear [3-6]. Vaccination and prophylaxis of SLE patients against infection are discussed separately. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults".)

A developing area of research involves the measurement of complement fragment deposition (such as C3d and C4d) on peripheral blood cells (ie, red blood cells, platelets, and lymphocytes) as a biomarker of lupus disease activity, analogous to the use of HbA1c in diabetes mellitus [7-9]. Similarly, blood levels of the activation fragments or split products, such as C3a, C5a, Bb, soluble C5b-C9, and others, are being investigated. While becoming more available commercially, neither cell-based nor plasma "split products" of complement activation are routinely utilized by most experienced lupus clinicians. Possible reasons for this include cost, relative unavailability of the tests, and difficulty or lack of experience in interpreting these results. In addition, no convincing data demonstrate that these tests offer a distinct advantage in the evaluation of C4 and C3 antigenic levels for most patients.

One marker of disease activity in immune complex-mediated syndromes is an acquired reduction in the levels of complement receptor 1 (CR1, also known as CD35 and the C3b receptor) on erythrocytes. As is the case for split products, there are multiple issues relative to assessing and interpreting CR1 levels on cells [10-12].

Antiphospholipid syndrome — Hypocomplementemia can be observed in patients with antiphospholipid syndrome (APS), analogous to what is seen in SLE [13,14]. APS and hypocomplementemia are discussed in more detail separately. (See "Clinical manifestations of antiphospholipid syndrome", section on 'Hypocomplementemia'.)

Cryoglobulinemia — Cryoglobulins are serum proteins that precipitate at subphysiologic temperatures. Mixed cryoglobulins commonly consist of immune complexes that contain immunoglobulins, antigen, rheumatoid factor, and complement components (particularly fragments of C3 and C4). Cryoglobulinemia may be either essential (no underlying identifiable disease process) or secondary (in association with another disease). Chronic hepatitis B and C account for most all of the formerly idiopathic cases of mixed cryoglobulinemia. Monoclonal paraproteins that precipitate in the cold may also activate complement [15]. Although rare, an association of mixed cryoglobulinemia with certain malignancies has been described [16]. (See "Overview of cryoglobulins and cryoglobulinemia".)

The usual complement profile in the setting of essential or secondary cryoglobulinemia is that of classical pathway activation. The complement profile shows decreased levels of C4 and C2 with normal or slightly lowered C3. C3 levels are usually only modestly altered because it is harder to form C3 convertases on a soluble or precipitated immune complex than on a cell membrane.

In rheumatic disorders, the presence of cryoglobulins is usually associated with more severe disease. As an example, in SLE, there is a correlation of mixed cryoglobulins with renal involvement, vasculitic manifestations, and hypocomplementemia.

Vasculitic syndromes — Systemic vasculitides are characterized by inflammation of the arterial and/or venous walls leading to stenosis or thrombosis. Many vasculitic syndromes are caused by immune complexes [17]. In these disorders, classical pathway activation by immune complexes initiates inflammatory processes and tissue destruction, primarily affecting blood vessels. Complement activation is usually not as marked as in SLE, although up to 50 percent of patients with polyarteritis may have decreased serum complement levels. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults".)

As in SLE, complement values can be helpful in assessing the clinical course, especially the response to therapy. (See "Overview of and approach to the vasculitides in adults" and "Clinical manifestations and diagnosis of rheumatoid vasculitis".)

Hypocomplementemic urticarial vasculitis — In hypocomplementemic urticarial vasculitis, classical pathway activation by immune complexes initiates inflammatory processes and tissue destruction, primarily affecting blood vessels. Complement activation is usually not as marked as in SLE. As in SLE, complement values can be helpful in assessing the clinical course, especially the response to therapy. (See "Overview of and approach to the vasculitides in adults".)

Anti-neutrophil cytoplasmic antibody-associated vasculitis — In anti-neutrophil cytoplasmic antibody-associated vasculitis (ANCA-AAV), plasma levels of C3a, C5a, soluble C5b-9 and Bb can be elevated in active stages of disease compared with remission [18-20]. In addition, lower serum C3 levels at diagnosis were associated with poorer patient and renal outcomes in one study [21]. Note that avacopan, an orally administered antagonist to C5a, has been approved to treat ANCA-AAV. (See "Pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis", section on 'Pathogenic role of ANCA'.)

Renal diseases — Many nephritides result from an inflammatory reaction within the kidney glomerulus that features leukocyte infiltration and cellular proliferation. Antibodies in the kidney may result from local immune complex formation or originate in the circulation as immune complexes that then lodge in the glomerulus. In either instance, the result can be activation of the complement system, with recruitment of inflammatory cells and subsequent tissue damage [22].

The complement system is involved in multiple renal diseases, including acute poststreptococcal nephritis, immunoglobulin A (IgA) nephropathy, membranous nephropathy, complement-mediated thrombotic microangiopathy (hemolytic uremic syndrome), types I and II membranoproliferative glomerulonephritis, SLE nephritis, tubulointerstitial nephritis, and Goodpasture's disease. Immunohistochemical analyses for complement-activated fragments in renal biopsy specimens are often helpful in establishing that complement activation is occurring. In these renal diseases, neither serum hypocomplementemia nor the quantity of C3 fragments deposited is as dramatic as in SLE. (See "Mechanisms of immune injury of the glomerulus" and "IgA nephropathy: Clinical features and diagnosis" and "Membranous nephropathy: Pathogenesis and etiology" and "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis" and "Complement-mediated hemolytic uremic syndrome in children", section on 'Complement antibodies' and "Inherited disorders of the complement system".)

C3 nephritic factor — Secondary C3 deficiency may arise when an autoantibody stabilizes the alternative pathway C3 convertase, increasing the half-life of the convertase and causing excessive C3 activation. The autoantibody against the alternative pathway convertase is called C3 nephritic factor. The typical complement profile is a normal C4 with a low C3, factor B, and alternative pathway AH50, indicating alternative pathway activation [23]. (See "Complement pathways" and "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis".)

Patients with C3 nephritic factor typically present in childhood with membranoproliferative glomerulonephritis that may be accompanied by partial lipodystrophy as well as frequent infections with encapsulated bacteria [24]. Nephritic factor levels do not correlate predictably with disease activity, and progressive renal damage can occur in patients who are persistently normocomplementemic. The clinical features of glomerulonephritis associated with C3 nephritic factor are reviewed separately. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis".)

Dense deposit disease — Dense deposit disease (DDD) is a rare but devastating glomerular illness that primarily affects children. Dysregulation of the alternative pathway of complement has been associated with pathology [25]. Most patients with DDD present with hypocomplementemia that persists throughout the course of disease. C3 and factor B levels are low, while C4 is normal. More than 80 percent of patients demonstrate a C3 nephritic factor. Genetic analyses have identified mutations in complement regulatory proteins (factors H and I) in these patients. (See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis".)

C3 glomerulopathy — The role of the complement system in renal disease has become better elucidated. However, the nomenclature is in transition. The term "C3 glomerulopathy" (C3G) defines a glomerular pathologic entity that is composed almost solely of C3 and no or trace levels of immunoglobulin. It consists of DDD and C3 glomerulonephritis (C3GN). C3G usually manifests with a membranoproliferative glomerulonephritis [26,27]. (See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis".)

C4 nephritic factor — C4 nephritic factor is an autoantibody that reacts with an epitope expressed on C4 within the classical pathway C3 convertase (C4b2a). It leads to deficiency of C3 that is consumed by the stabilized classical pathway C3 convertase. Thus, the patient may present with recurrent bacterial infections secondary to the low C3 [28]. The C4 nephritic factor also has been found in a few patients with poststreptococcal glomerulonephritis and SLE, although its role in pathogenesis has not been defined [28-30].

Autoimmune hemolytic anemia — In cold agglutinin disease, immunoglobulin M (IgM) autoantibodies react with red blood cell antigens at reduced body temperatures, such as in the extremities. The antibodies activate the classical pathway, leading to the deposition of large quantities of C4, C3, and C5b-9. The red blood cell may be either phagocytosed or lysed. Cold agglutinins are associated with lymphoid malignancy (chronic cold agglutinin syndrome) or arise transiently following viral and mycoplasma infections. In approximately 20 percent of immunoglobulin G (IgG)-mediated (warm antibody-mediated) hemolytic anemias, complement fixation also occurs and tends to correlate with more severe disease. (See "Cold agglutinin disease", section on 'Pathogenesis'.)

IgG4–positive multiorgan lymphoproliferative syndrome — This syndrome features immunoglobulin G₄ (IgG₄) that reacts with antigens on a variety of tissues, including the pancreas (autoimmune pancreatitis) and salivary glands in Mikulicz's disease [31-33]. A variety of other idiopathic inflammatory conditions, including sclerosing cholangitis, autoimmune hypophysitis, retroperitoneal and mediastinal fibrosis, interstitial nephritis, and others, have also been associated with these autoantibodies. A hallmark pathologically is IgG₄-positive plasma cell infiltration. The antibodies are not directly activating like those of IgG subclasses 1 and 3 but rather provide an altered surface on which the alternative pathway can be engaged. (See "Clinical manifestations and diagnosis of IgG4-related disease".)

Neuromyelitis optica spectrum disorders — NMOSD represent autoimmune inflammatory diseases of the central nervous system. In many cases, antibodies against the water channel protein, AQP4, lead to antibody-associated complement activation with concomitant pathology [34]. Eculizumab has been approved for treatment of AQP4-positive NMOSD [34]. (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis" and "Neuromyelitis optica spectrum disorder (NMOSD): Treatment and prognosis".)

Myasthenia gravis — In myasthenia gravis (MG), many patients exhibit autoantibodies against the acetylcholine receptor (AChR), which drive complement activation and lead to disease pathology [35,36]. Eculizumab has also been approved for treatment of adult patients with generalized MG who are AChR positive [35,36]. Other complement inhibitors are in clinical trials. (See "Chronic immunotherapy for myasthenia gravis".)

Viral infections — Hepatitis B and C infections are associated with immune complex formation secondary to the release of antigen from the infected liver. These immune complexes often manifest as cryoglobulins. Also, other viral infections, such as parvovirus and flavivirus infections featuring large antigenic loads, can develop a transient hypocomplementemia as the antibodies combine with viral antigen [37]. Thus, these forms of hepatitis represent an example of a chronic serum sickness-like reaction (antigen binding by an immune host making antibody, leading to complement activation). (See "Virology, epidemiology, and pathogenesis of parvovirus B19 infection".)

Acquired C1 inhibitor deficiency — A deficiency of C1 inhibitor (C1-INH) causes the autosomal dominant disorder hereditary angioedema (HAE). C1-INH deficiency also can be acquired. Acquired C1-INH deficiency has mostly been reported in patients with B cell lymphoproliferative disorders who present with new-onset swelling of the skin [38], abdominal viscera, and/or larynx. More than one mechanism has been implicated in the complement abnormalities seen in acquired C1-INH deficiency. Most patients demonstrate an autoantibody to the C1-INH that blocks its function or causes its premature removal. Others feature a monoclonal autoantibody on the B cell surface that activates C1 and consumes the C1-INH.

Acquired C1-INH deficiency should be considered in patients with angioedema in which complement studies show low C4, low C1q, low or normal C1-INH antigenic levels, and reduced C1-INH function. Serum protein electrophoresis should be considered in acquired C1-INH deficiency as basic testing for lymphoproliferative disease. C1q levels are normal in the hereditary form, and this test is important in distinguishing the two disorders. Otherwise, complement profiles are similar in hereditary and acquired C1-INH deficiency. (See "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis" and "Acquired C1 inhibitor deficiency: Management and prognosis".)

REDUCED HEPATIC SYNTHESIS — The liver is the synthetic site of most complement components and inhibitors, and reduced hepatic synthesis may lead to hypocomplementemia in various types of advanced liver disease (table 1). As an example, low C3 and C4 levels may be seen in severe alcoholic liver disease. C3 and C4 are easily measured, but most other components would be decreased as well. CH50 and AH50 would also likely be impaired. However, because complement abnormalities are only detectable with severe liver disease, the coagulation system provides a more clinically useful measurement of hepatic synthetic function. (See "Clinical use of coagulation tests" and "Tests of the liver's biosynthetic capacity (eg, albumin, coagulation factors, prothrombin time)", section on 'Coagulation factors'.)

As noted above, some patients with systemic lupus erythematosus (SLE) demonstrate decreased hepatic synthesis of complement components. (See 'Systemic lupus erythematosus' above.)

LOSS OF COMPLEMENT COMPONENTS IN THE URINE — In severe forms of nephrotic syndrome, several complement components can be lost in the urine, although factor D is the only component that can be lost in substantial amounts. Factor D has a molecular weight of 25,000 daltons and is the smallest component of the alternative pathway. Its loss would be detected as a decrease in the alternative pathway AH50 titer. No clinical consequences have been reported in association with this laboratory observation.

SOMATIC MUTATION OF A COMPLEMENT GENE — Many proteins are tethered to cells by a glycophosphatidylinositol (GPI or "greasy foot") anchor. An acquired mutation in bone marrow stem cells of an enzyme on the X chromosome required to produce this anchor causes a deficiency of the GPI-linked complement regulatory proteins DAF (CD55) and CD59 on blood cells. The normal function of these proteins is the inhibition of complement activation by disassociating C3 convertases (DAF) and by blocking binding of C8 and C9 to the assembling membrane attack complex (MAC) (CD59). (See "Regulators and receptors of the complement system".)

Deficiency of DAF and CD59 predisposes cells to lysis, especially red blood cells (RBCs). The disease process is known as paroxysmal nocturnal hemoglobinuria (PNH). Hemolytic anemia, mediated by the unchecked complement system, is the most prominent clinical manifestation. Complement levels are normal in most patients with PNH, but, in very severe disease, alternative pathway components (C3, factor B) may be low. (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria" and "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria" and "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria".)

SUMMARY

●Acquired complement deficiencies are more common than inherited – Acquired complement deficiencies are more likely to explain abnormal laboratory findings. (See 'Overview' above.)

●Mechanisms – The mechanisms responsible for acquired complement deficiencies are accelerated consumption by immune complexes (common), reduced hepatic synthesis (uncommon), and loss of complement components in the urine (rare). (See 'Mechanisms of acquired complement disorders' above.)

•Increased consumption of complement by immune complexes – The most prevalent mechanism of secondary hypocomplementemia is increased consumption by immune complexes. The disease that best illustrates this process is systemic lupus erythematosus (SLE). The usual pattern of complement activation in such disorders involves activation of the classical pathway, leading to low C3 and C4, while factor B of the alternative pathway is normal. (See 'Increased consumption by immune complexes' above.)

•Reduced hepatic synthesis – This uncommon cause of hypocomplementemia is seen in various types of advanced liver disease, because the liver is the synthetic site of most complement components and inhibitors. However, liver disease must be severe before there is a detectable decrease in plasma levels. (See 'Reduced hepatic synthesis' above.)

•Loss in the urine – A rare cause of secondary hypocomplementemia is loss of complement proteins in the urine. Factor D can be reduced in severe nephrotic syndrome, although this laboratory finding is of uncertain clinical significance. (See 'Loss of complement components in the urine' above.)