Complement deficiencies

Introduction

Complement proteins play direct key roles in host microbial defense. They complement the actions of specific antibodies and aid the processing and removal of immune complexes. [1] [2] The complement system is pro-inflammatory, and multiple complex control factors are necessary to ensure that potential tissue damage is limited or minimised. Disease states occur with deficiencies in complement proteins (which can cause increased risk of invasive bacterial infections, and may be associated with autoimmune disease), or defects of factors controlling, focussing, and limiting complement activation. Complement deficiencies can be inherited or acquired (secondary to a complement-consuming disease state).

Physiology of healthy states

Complement proteins are present in blood plasma in an inactive form. Collectively, there are more than 50 complement proteins, including complement regulatory factors (many of which are cell surface restricted) and individual components of the cascade system. Complement proteins are manufactured in the liver and form part of the acute phase response. Most are proteases, which, on activation, cleave the next complement protein in the cascade sequence. The sequence of amplification steps shows similarities to the blood coagulation cascade.

The complement cascade can be activated by either of 2 main routes: the classical pathway (CP), or the more primitive alternative pathway (AP). The CP complements (improves) specific antibody responses, whereas the AP is part of the innate (non-antigen-specific) immune system and is important in antibody-independent defense against bacterial infection. The AP contributes comparatively little to adaptive, antigen-specific responses. [1] [2] [3] The numbers and names of complement system components and factors are typically based on their dates of discovery, which explains why the cascade is not arranged in a logical numerical order. Newer components (generally linked with the AP) are called factors (e.g., complement factor B).

Summary of the complement cascade system, outlining classical pathway and alternative pathway activationUnsworth DJ. Complement deficiency and disease. J Clin Path. 2008;61:1013-1017; used with author's permission

The main method of CP activation is by antibody (immunoglobulin) mechanisms. The Fc (fragment crystallisable) tail regions of normal IgM and IgG antibodies (not IgA) activate the CP when the antibodies become structurally altered (e.g., when bound to a specific antigen within an immune complex or within a cryoglobulin). There are 3 types of cryoglobulin: type I (composed exclusively of a monoclonal immunoglobulin component); type II (composed of monoclonal IgM rheumatoid factor complexed with polyclonal immunoglobulin); and type III (composed entirely of polyclonal immunoglobulin). Cryoglobulins can be triggered by infection, autoimmunity, or underlying malignancy (lymphoma). Malignancy is more likely with types I and II.

The CP is activated when the first CP component, C1q, binds to the Fc region. In the absence of antibodies, bacteria bound to C-reactive protein (CRP) can also bind to C1q and activate the CP. Another non-immunoglobulin molecule that can activate the CP is mannose-binding lectin (MBL). MBL is an acute phase reactant with structural similarities to C1q. Independent of C1q, it can activate the CP by binding to carbohydrate residues on bacteria or other structures.

In contrast to the CP, the AP is activated mainly by non-antibody (non-immunoglobulin) mechanisms. It involves proteins including properdin and factor B. The AP is constantly ticking over in the background. In healthy states this activity is self-limited; however, AP responses are amplified in the presence of, for example, bacteria.

Once the CP or AP is activated, enzyme complexes (C3 convertases) are generated that cleave C3 into 2 fragments (C3a and C3b). C3a is the smaller fragment, and, like C4a and C5a, which are generated later, is a pro-inflammatory signalling molecule (anaphylotoxin). Anaphylotoxins are chemo-attractants, they recruit inflammatory cells and activate mast cells or other targets. Generation of C3b, the larger fragment of C3, is the key step of complement activation. C3b receptors on phagocytic cells and on erythrocytes participate in phagocytic removal. Potentially pathological immune complexes (containing antibody complexed with viral, bacterial, or autoantigens) bind complement protein, generating C3b. This opsonises (flags) such immune complexes for selective waste disposal by phagocytic cells expressing C3b receptors. Cell surface-bound C3b can also trigger the terminal complement cascade (TCC). TCC activation requires factors C5, C6, C7, C8, and C9, and it generates a lipophilic membrane attack complex (MAC). MAC is capable of causing target cell death by cell membrane lysis. A variety of control factors (some expressed membrane proteins) prevent MAC formation, which prevents unintentional host cell MAC-mediated cell death.

The complement system is pro-inflammatory, and multiple complex control factors are necessary to ensure that potential tissue damage is limited or minimised.

• C3 convertases are inherently unstable, with low half-lives; this helps limit and control complement activation.

• Excess MAC-mediated complement lysis is avoided using the following normal cell membrane control proteins: decay accelerating factor (DAF), CD59 (protectin), and C8 binding protein.

• Factor H, factor I, and C1-inhibitor are other key components involved in regulation and inhibition of the complement system. [4]

Inherited complement deficiencies

Hereditary angio-oedema (HAE)

• There are 2 autosomal dominant forms of HAE C1-inhibitor deficiency: 80% occur due to inadequate C1-inhibitor production (type I) and 20% occur due to production of dysfunctional C1-inhibitor (type II).

• Both forms typically show reduced C4 as a secondary consequence of poorly controlled classical pathway (CP) activity.

• C1-inhibitor functional tests are abnormal in both types, but in type II biochemical levels of C1-inhibitor are normal.

• C1-inhibitor deficiency (HAE and non-HAE) is very unlikely if C4 values are normal between attacks; normal C4 during an attack excludes the diagnosis of C1-inhibitor deficiency.

• Kinins generated secondary to complement activation play a role in vascular leakage contributing to angio-oedema development.

C1q, C2, C4 deficiency

• Pre-existing complement deficiency or malfunction of CP components including C1q, C4, C2, C3, or complement receptors (including C3b receptor) can predispose to SLE.

• Genetic complement deficiency in SLE cannot be reversed.

Factor H deficiency

• Factor H plays a role in disrupting C3 convertases; therefore, deficiency causes on-going C3 depletion and increased risk of bacterial infection.

• Causes nephritis.

Factor I deficiency

• Factor I plays a role in disrupting C3 convertases; therefore, deficiency causes ongoing C3 depletion and increased risk of bacterial infection.

• Causes nephritis.

Factor B deficiency

• Causes secondary C3 deficiency.

Properdin deficiency

• X-linked.

• Deficiency in properdin is specifically linked to increased neisserial (meningococcal/gonococcal) susceptibility.

C5, C6, C7, C8, or C9 deficiency

• Causes membrane attack complex (MAC) deficiency.

• Deficiency of MAC components (C5-9) is specifically linked to increased neisserial (meningococcal/gonococcal) susceptibility.

Mannose-binding lectin (MBL) deficiency

• Theoretically, can also be linked to recurrent infection.

• However, MBL is deficient in up to 5% of the healthy population with little apparent adverse effect in the majority.

Acquired complement deficiencies

Systemic lupus erythematosus (SLE)

• Can cause C3 and C4 consumption.

• Classical pathway (CP) complement abnormalities can suggest the possibility of SLE (and perhaps rule out drug-induced lupus); however, complement deficiency is neither necessary nor sufficient to confirm diagnosis.

• Complement deficiency due to SLE may be reversible with immunosuppression; however, genetic complement deficiency in SLE cannot be treated.

• Monitoring biochemical levels of C3 and C4 can be helpful in selected SLE patients: for example, when SLE causes glomerulonephritis, clinical improvement is often accompanied by restoration of normal C3 and C4 levels. [5]

• Monitoring C3 and C4 can also alert to possible relapse as immunosuppressive treatments are withdrawn.

Non-HAE C1-inhibitor deficiency (late onset/acquired)

• C1-inhibitor may be excessively consumed, typically because of a clonal B lymphocyte proliferation (B-cell lymphoma).

• C1-inhibitor may also be consumed as part of massive immune complex type disease such as urticarial vasculitis.

• May also be caused by autoantibodies that block or interfere with otherwise normal C1-inhibitor function.

• Distinguished from HAE by late adult onset, non-familial, and with reduced levels of C1q. [6]

• When C1-inhibitor is absent of dysfunctional, complement pathway factors, including C4, are consumed excessively. Hence, routine measurements of C4 can simply address whether HAE or another cause of C1-inhibitor deficiency or malfunction is likely.

• C1-inhibitor deficiency (HAE and non-HAE) is very unlikely if C4 values are normal between attacks; normal C4 during an attack excludes the diagnosis of C1-inhibitor deficiency.

Cryoglobulinaemia

• Can occur due to haematological malignancy.

• Many (but not all) cryoglobulinaemias cause reduced complement C4.

• Normal C3 and C4 levels do not exclude cryoglobulinaemia.

Partial lipodystrophy

• Adipocytes can produce C3, properdin, and factor B, and trigger foci of alternative pathway (AP) complement activation.

• Associated with nephritic factor (IgG): IgG nephritic factor can activate complement and lyse adipocytes in vitro by stabilising the AP C3 convertase.

Atypical haemolytic-uraemic syndromes (HUS)

• Associated with factor H and I deficiencies, which may cause nephritis.

Glomerulonephritis

• There are multiple causes of glomerulonephritis.

• Often, immunologic mechanisms are involved, and some of these arise because of complement deficiencies.

• Acute nephritis with associated streptococcal infection, in the Western world, typically presents in children following massive AP activation; it is believed that antibody responses are limited early in infection.

Nephritic factor autoimmune conditions

• Includes autoimmune diseases such as membranoproliferative glomerulonephritis.

• Nephritic factor (IgG) is a generated autoantibody that is specific for the AP.

• It stabilises AP C3 convertase, increasing its half-life, which causes complement activity to be poorly controlled, and C3 to be over-consumed.

• Secondary C3 depletion may (rarely) lead to increased vulnerability to infection, but in the majority of cases infection risk is not increased.

• An analogous autoantibody, specific for CP C3 convertase, has been described; this causes a similar syndrome to membranoproliferative glomerulonephritis.

Paroxysmal nocturnal haemoglobulinuria (PNH)

• PNH is a rare, acquired condition typically presenting in adults (women more than men) with the triad of haemolysis, thrombosis, and pancytopenia.

• Somatic mutation of haemopoietic stem cells generates defective erythrocytes, platelets, and lymphocytes; defective erythrocytes show increased susceptibility to membrane attack complex (MAC)-mediated complement lysis.

• Arises due to poor expression of normal cell membrane control proteins: decay accelerating factor (DAF), CD59 (protectin), and C8 binding protein; this allows uncontrolled MAC formation with cell lysis.

Age-related macular degeneration (AMD)

• Some very common diseases such as AMD are associated with polymorphisms of particular complement system genes. With AMD, the association is with several components of the alternative complement system; however, routine measurements of C3 and C4 in serum are rarely abnormal. The association suggests an auto-inflammatory mechanism. [7]

Epidemiology

• Although bacterial infections are common in clinical practice, an underlying, predisposing complement deficiency is rarely the cause (about <5 cases per million per year).

• Hereditary angio-oedema (HAE) is very rare, with an incidence of about 2 cases per million of the total population per year. Prevalence is estimated as 1 in 50,000. [8] For every new case of HAE that presents to a general hospital clinic, there will be about 1000 other cases of angio-oedema (often accompanied by urticaria) with no complement system abnormalities. The cause of angio-oedema is far more likely to be allergic (type 1 hypersensitivity), drug-related (e.g., use of non-steroidal anti-inflammatory drugs [NSAIDs] or angiotensin-converting enzyme [ACE] inhibitors), or idiopathic than to be HAE.

• Non-HAE C1-inhibitor deficiency is as rare as HAE.

• About 30% of SLE patients have a pre-existing complement deficiency. [1] [2] [3]

• Complement deficiency or acquired complement consumption may be a feature of glomerulonephritis. Primary deficiencies causing nephritis (e.g., factor H/I deficiency) do occur but are very rare (estimated <1 case per million per year).

• Paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic-uraemic syndrome (HUS) are also very rare conditions. PNH occurs in women more than men.

Clinical presentation

Patients may present with a cause of complement consumption (e.g., SLE, vasculitis, other autoimmune diseases, paroxysmal nocturnal haemoglobinuria [PNH], atypical haemolytic-uraemic syndrome [HUS], iron deficiency anaemia, aplastic anaemia, leukaemia, cryoglobulinaemia), or with a complication of 'inherited' complement deficiency (e.g., angio-oedema, SLE, glomerulonephritis, partial lipodystrophy, recurrent bacterial infections).

• Presenting infections can include: recurrent pyogenic infections (e.g., deep abscess, osteomyelitis, pneumonia); bacteraemia; recurrent meningococcal infection; and disseminated gonococcal infection. Neisserial bacteria (meningococcal and gonococcal) are particularly sensitive to complement-mediated attack.

• Some specific clinical presentations raise the possibility of complement deficiency. These include: >1 episode of invasive meningococcal infection; infection with some of the more rare meningococcal serotypes; [3] disseminated gonococcal infection; and multiple episodes of bacterial infection. Complement deficiency in association with increased risk of meningococcal disease requires meningococcal vaccination and consideration of lifelong antibiotics. [9]

• Patients with hereditary angio-oedema (HAE) may present with non-pruritic, recurrent, angio-oedematous swellings; common sites include the lips, tongue, eyelids, larynx, and GI tract. They do not have associated urticaria. Swellings can be initiated by infection (or other routine triggers of the classical complement pathway). Without preventive treatment, the occurrence of attacks may vary from being weekly to <1 per year.

• Patients with late adult-onset angio-oedema that is non-familial may have non-HAE (autoimmune) C1-inhibitor deficiency. Low levels of C1q support this diagnosis. [6]

• Common presentations of SLE are UV light-sensitive rashes, arthritis, autoimmune cytopenias, renal failure (glomerulonephritis), and neurological disorders.

• Clinical presentation of cryoglobulinaemia varies according to cause, but common features include peripheral (lower limb) vasculitic rashes, arthritis, Raynaud's phenomenon, and glomerulonephritis.

• Glomerulonephritis has a range of possible clinical presentations. In developed countries, acute nephritis with associated streptococcal infection typically presents in children with haematuria.

• Partial lipodystrophy is usually proximal, around the face and upper body.

Typical clinical presentations for various complement defectsCreated by BMJ Evidence Centre, based on contribution from D.J. Unsworth, PhD, FRCP

Past medical history may reveal a cause or complication of complement deficiency. The most common cause of acquired complement deficiency is SLE. However, few SLE patients show a pattern of recurrent bacterial infection, and, where they do, causes are multifactorial and include a direct link to use of powerful immunosuppressive agents in treatment.

Taking an appropriate family history is also very important.

• With the exception of properdin deficiency, which presents in males and is cross-linked, these deficiencies are mostly autosomal recessive. They are, therefore, more likely in cultures where first-degree relatives intermarry.

• HAE may be familial (autosomal dominant). Some, but not all, cases present with a clear family history. However, some familial cases may not have symptoms despite having the same genetic defect as their relatives.

• Patients with atypical HUS may have a positive family history for atypical HUS.

Diagnostic tests

Tests for possible complement deficiency should be performed on patients who present with disease conditions suggesting possible underlying deficiency, including patients with:

• Rheumatological disease (e.g., SLE and other autoimmune connective tissue diseases)

• Renal disease (e.g., acute nephritis)

• Infectious disease (e.g., atypical or recurrent bacterial infection, such as cases with the rarer meningoccal serotypes and cases with recurrent meningococcal sepsis)

• Partial lipodystrophy

• Cryoglobulinaemia

• Family history of complement deficiency.

The clinical presentation can give a clue to the underlying complement defect and guide which blood tests should be undertaken.

• A second episode of meningococcal disease and gonococcal arthritis may indicate properdin or membrane attack complex (MAC) deficiency and require a fresh serum sample for AP50 and CH50.

• Recurrent pyogenic infections (abscesses, osteomyelitis, pneumonias) may indicate C3 or mannan-binding lectin (MBL) deficiency and require a serum sample for routine C3, C4, and MBL levels.

• C1-inhibitor deficiency may be indicated by recurrent angio-oedema without urticaria and late-onset angio-oedema with history of lymphoma/autoimmune disease. The former requires a fresh serum sample for C1-inhibitor tests and the latter a serum sample for C1q and routine C1-inhibitor tests.

• Membranoproliferative glomerulonephritis and partial lipodystrophy may indicate C3 deficiency due to nephritic factor, and require a fresh serum sample for AP50 and CH50.

• Classical pathway factor (C1q, C4, C2) deficiency may be indicated with any autoimmune condition and should initially be tested for with routine serum C3 and C4 levels.

Blood tests to request for various clinical presentationsCreated by BMJ Evidence Centre, based on contribution from D.J. Unsworth, PhD, FRCP

Routine FBC and CRP tests in patients with acute infection (neisserial/meningococcal/gonococcal) will show elevated WBC and CRP levels. Routine microbiology cultures may demonstrate serogroup W135, X, Y, or Z, which will confirm the presence of the more rare meningococcal serotypes.

Blood testing for complement deficiencies include standard testing (C3, C4) and functional testing (C1-inhibitor, CH50, AP50).

• Fresh serum is mandatory for CH50 and AP50 in order to exclude decay artifact.

• Serum for C1-inhibitor function tests can be fresh or frozen.

• Normal C3 is required for AP50 and CH50 tests to work.

• CH50 and AP50 function tests artificially measure target cell (erythrocyte) lysis in test tubes. The tests are dependent on full assembly of MAC complexes (C5 to C9) to cause target cell haemolysis.

• CH50 function tests require the functioning of components C1 to C9.

• AP50 function tests require the functioning of all AP components (C3 and factors C5 to C9).

Standard blood testing for complement deficiency (C1-inhibitor, C3, C4) is widely available, and can be performed on routine serum samples. Quantitative C1-inhibitor, C3, and C4 levels often allow for more detailed diagnostic deductions. When routine screening tests show normal quantities of C3 and C4, a complement-mediated pathology is unlikely, although not impossible.

• Normal C3 and reduced C4 levels point to classical pathway defects such as C1-inhibitor deficiency, C2 deficiency, C4 deficiency, SLE, and many cases of cryoglobulinaemia.

• Reduced C3 and C4 levels point to a severe classical pathway defect such as SLE with nephritis.

• Reduced C3 and normal C4 levels point to alternative pathway defects such as factor H and I deficiencies, glomerulonephritis, and membranoproliferative glomerulonephritis.

• Reduced C1-inhibitor levels with reduced C4 levels point to a C1-inhibitor defect such as type I hereditary angio-oedema (HAE), whilst normal C1-inhibitor levels with reduced C4 levels point to a C1-inhibitor defect such as type II (HAE).

Expected results for standard complement blood testsCreated by BMJ Evidence Centre, based on contribution from D.J. Unsworth, PhD, FRCP

Functional testing (C1-inhibitor enzyme function, CH50, AP50) is logistically difficult, principally due to the absolute necessity for very fresh serum (reaching the lab within 2 hours of sampling, or frozen down and dispatched on dry ice), and is reserved for particular situations, including investigation of possible rare complement deficiency states. These functional tests are not suitable for serial/repeat testing with the aim of disease monitoring as sample decay causes errors and misleading results.

• Reduced AP50 and normal CH50 levels point to alternative pathway defects, while normal AP50 and reduced CH50 levels point to a pre-C3 classical pathway defect such as C1q, C4, or C2 deficiency.

• Reduced AP50 and CH50 levels point to either membrane attack complex (MAC) component defects leading to recurrent meningococcal infection and disseminated gonococcal infection or C3 deficiency leading to deep abscess formation, osteomyelitis, pneumonia, and bacteraemia.

• Normal AP50 and CH50 levels with recurrent meningococcal infection may point to a defect in properdin.

• Reduced C1-inhibitor function assay points to a C1-inhibitor defect such a HAE (types I and II).

Expected results for functional blood testsCreated by BMJ Evidence Centre, based on contribution from D.J. Unsworth, PhD, FRCP

Abnormal initial AP50 and CH50 screens support the need for further studies. For example, definitive diagnosis of a specific complement factor deficiency (e.g., C6 deficiency in a family with recurrent meningococcal disease) requires specialist tests to prove deficiency. Specialist tests may include using monoclonal antibody reagents to confirm the absence of individual complement proteins.

Other tests

• Paroxysmal nocturnal haemoglobinuria (PNH), atypical haemolytic-uraemic syndrome (HUS), and other clinical states associated with complement control factor defects are diagnosed by demonstrating poor erythrocyte expression of factors or components that are otherwise normally expressed (e.g., factor H, factor I, decay accelerating factor [DAF], CD59, C8). In some cases (e.g., PNH) this testing helps confirm disease state; in other cases (e.g., HUS), the diagnosis may already be clear but this testing helps define the cause.

• With the exception of recurrent neisserial infections, patients with recurrent unexplained pyogenic bacterial infections should also be checked for other immune deficiencies including immunoglobulin deficiency, which is more prevalent than complement deficiency.

• In SLE, identifying underlying complement deficiency is largely only of academic interest in many cases; complement tests do not make a diagnosis of SLE. Usually, improvement or classical pathway factor recovery during immunosuppressive treatment clarifies the issue. Otherwise, complex genetic testing is required to prove suspected complement deficiency. However, these genetic tests are not widely available, and are mainly reserved for research. SLE can be tested for, using diagnostic autoantibody tests.

• Normal C3 and C4 levels do not exclude cryoglobulinaemia. Serum cryoglobulin levels are tested when clinical suspicion of diseases associated with reduced complement C4 is high (e.g., vasculitic rash, particularly affecting the colder extremities; arthritis; or acute renal failure). The definitive diagnostic test involves obtaining fresh clotted blood, collected in a prewarmed (37°C [98.6°F]) thermos flask. Serum is then rapidly separated to reduce the risk of cryoglobulin being concealed within clotted blood.

• Diagnosis of glomerulonephritis will depend on a range of blood and other tests, which may include renal biopsy. Local detection of pathological complement fragments in renal biopsy material (in immunohistological stains for C1q, C3, C3b, C3d, or others) may help with diagnosis.

• Diagnosis of nephritic factor autoimmune conditions depends on the demonstration of serum (containing IgG autoantibody) causing similarly reduced C3 activation when mixed with normal serum control.

Management: prophylaxis, treatment, monitoring

Theoretically, deficient complement proteins could be replaced, using FFP (fresh frozen plasma) from blood donors, for example. Practically, however, the half-life of infused complement proteins is too short, and the proteins may be pro-inflammatory, so this approach is generally not recommended. Despite these issues, FFP has been used with positive effect in some patients (e.g., patients with atypical haemolytic-uraemic syndrome [HUS]). [10]

Basic generic clinical management steps include:

• Screening relatives for occult complement deficiency

• Encouraging and optimising immunisation programmes (seeking to boost protective antibody levels where possible) [11]

• Considering prescription of preventive daily (lifelong) antibiotics (similar to antibiotic prophylaxis post-splenectomy).

C1-inhibitor deficiency (hereditary angio-oedema [HAE]/acquired)

• Treatment includes prevention and treatment of acute attacks. [8]

• Anabolic steroids may act by increasing gene expression in heterozygotes (prevention only). C1-inhibitor and C4 levels increase with treatment. Clinically, patients report fewer attacks when compliant with this treatment.[B Evidence] Compliance may be poor, however, especially in female patients, because adverse effects include weight gain, masculinisation, and the possibility of abnormal liver function tests. Androgens are contraindicated in women with breast cancer and pregnant women, and should not be used during the pre-conception period if pregnancy is planned. Oestrogen-based contraceptives should also be avoided in these patients. [12]

• C1-inhibitor can be purified from blood donor plasma and used as a fast-acting intravenous infusion (for prevention and acute treatment).[B Evidence] However, these treatments are expensive, and blood-derived concentrates carry risks of bloodborne virus transmission. New recombinant forms are undergoing trials and will potentially reduce this risk. Conestat alfa is available in Europe, but is not yet available in the US. [13] This is the treatment of choice in pregnant women; [14] however, there is no data on the recombinant formulation in pregnancy. Plasma-derived C1-inhibitor should be made available for labour and delivery. [12]

• Antifibrinolytic agents such as tranexamic acid (for prevention and acute treatment) can help by reducing consumption of C1-inhibitor by the blood coagulation cascade.[C Evidence] These agents are contraindicated in patients with increased risk of thrombosis. They can be considered in pregnant women if C1-inhibitors are not available. [12]

• Inhibitors of bradykinin (e.g., icatibant) have recently been introduced and are available for subcutaneous injection (acute treatment); however, caution is still needed in pregnancy as experience in this patient group is limited. [15] [16] [B Evidence] It is important to note that C1-inhibitor therapy is still regarded as the gold standard treatment, especially for life-threatening attacks, until further data to support the use of bradykinin inhibitors are available.

• Recombinant plasma kallikrein inhibitors (e.g., ecallantide) have recently been introduced and are available for subcutaneous injection (acute treatment). [17] [15] [B Evidence]

• Treatments for acquired C1-inhibitor deficiency depend on the underlying primary cause. Generally, treatment of the underlying condition corrects the defect. The above treatments can be used in parallel where appropriate.

• Successful treatment leads to restoration of C4 levels whatever the cause of the C1-inhibitor deficiency. Serial measurements of C1-inhibitor are therefore used to monitor treatment.

• High-risk situations (e.g., peri-operative period, labour and delivery, dental procedures) should be identified and short-term prophylaxis put in place before any procedure is carried out. [14]

• Self-administration of C1-inhibitor at home when prodromal symptoms occur may decrease morbidity and mortality associated with HAE. [18]

SLE

• Genetic complement deficiency in SLE cannot be treated.

• Acquired complement deficiency in SLE may be managed with immunosuppressive agents to treat the inflammatory or vasculitic complications of pathological immune complexes.

• Monitoring biochemical levels of C3 and C4 can be helpful in certain patients. [5] For example, when SLE causes glomerulonephritis, clinical improvement is often accompanied by restoration of normal C3 and C4 levels. Conversely, monitoring C3 and C4 can provide an alert to possible relapse as immunosuppressive treatments are withdrawn.

• Newer immunosuppressive drugs that show promise in the treatment of SLE include designer biologicals (synthetic/engineered) that are either directed against B lymphocytes, [19] or are designed to prevent complement activation.

Cryoglobulinaemia

• Treatment of severe disease is dependent on the primary cause (e.g., lymphoma).

• Serial C4 measurements can be used to monitor treatment. [20]

Glomerulonephritis

• Treatment depends on the primary cause.

• In cases of post-streptococcal nephritis, low C3 levels should return to normal over a matter of months as infection is cleared with antibiotic therapy. C3 recovery in these situations excludes genetic deficiency.

Nephritic factor autoimmune conditions

• In the majority of cases, infection risk (secondary to C3 depletion) is not increased, and there is no agreed consensus on whether antibiotic prophylaxis is worthwhile.

• Membranoproliferative glomerulonephritis may require kidney transplantation, although disease can recur post-transplantation.

Dense deposit disease

• Seen in renal biopsy specimens using electron microscopy. Caused by local in vivo complement deposition due either to nephritic factor or defective regulation of the alternative pathway (factor H-related or other), and is associated with markedly reduced serum C3 level.

• Therapeutic monoclonal antibody against C5a (e.g., eculizumab) can be used to treat these patients and may prove useful in preventing recurrent disease in renal allografts. [21]

Paroxysmal nocturnal haemoglobulinuria (PNH)

• Synthetic (humanised) monoclonal antibodies designed to block uncontrolled activity of the terminal (lytic) complement pathway have recently been used in PNH. Eculizumab, which binds to complement C5, has been shown to prevent haemolysis in PNH. [22]

Nephritis related to dense deposit disease

• Eculizumab has been successfully used in renal failure patients with renal complement deposition, for example, in atypical haemolytic uremic syndrome secondary to genetic deficiency of Factor H (or other control factors in the alternative pathway). [23]