Conditions for which IVIg has an emerging therapeutic role

Replacement therapy for life-threatening infection due to hypogammaglobulinaemia related to other diseases or medical therapy.

Note: The following secondary causes of hypogammaglobulinaemia are considered elsewhere:

1. Acquired hypogammaglobulinaemia secondary to haematological malignancies or stem cell transplantation (see page 48)
2. HIV in children (see page 185)
3. Solid organ transplantation (see page 208)

Recurrent and/or severe bacterial infections may arise from hypogammaglobulinaemia of diverse causes. Hypogammaglobulinaemia may arise from protein losing states, malnutrition and medical immunosuppression. In most cases, successful management of the underlying condition will reverse the immunodeficiency, restoring immunocompetence. In some cases, recurrent or severe infection may arise from secondary immunodeficiency where the underlying cause cannot be reversed, or where there are unwanted effects of removing or reducing immunosuppressive therapy. New immunosuppressive regimens such as monoclonal B-cell depletion with Rituximab or similar agents do not generally induce hypogammaglobulinaemia at standard doses.

However, repeated cycles of B-cell depletion in combination with other agents used to treat life-threatening immune-mediated diseases may increase rates of infection related to hypogammaglobulinaemia.

Hypogammaglobulinaemia secondary to underlying disease or medical therapy (including haemopoietic stem cell transplantation [HCST]) with all the following:

1. Serum IgG less than the lower limit of the reference range on two separate occasions;

AND

2. Underlying cause of hypogammaglobulinaemia cannot be reversed or reversal is contraindicated;

AND

3. At least one of the following:
   1. One invasive or life-threatening bacterial infection (e.g. pneumonia, meningitis, sepsis) in the previous year; or
   2. Clinically active bronchiectasis confirmed by radiology.

Reversible underlying cause of hypogammaglobulinaemia.

The following conditions should not be approved under this indication:

1. Acquired hypogammaglobulinaemia secondary to haematological malignancies or stem cell transplantation (see page 48);
2. HIV in children (see page 185); or
3. Transplantation related immunomodulation (solid organ transplantation; see page 208).

Six-monthly review to assess clinical benefit.

Cessation of IVIg should be considered, at least after each 12 months of therapy, extended as required to enable cessation of therapy in September/October, with repeat clinical and/or immunological evaluation before re-commencement of therapy.

Written confirmation from the treating physician that:

• an annual review has been undertaken;
• the patient had demonstrated clinical benefit;
• a trial period of cessation of IVIg for the purpose of immunological evaluation is medically contraindicated on safety grounds.

In principle, IVIg should be continued or renewed only if there is a demonstrated clinical benefit.

Maintenance dose: 0.4 g/kg every four weeks, modified to achieve IgG trough level of at least the lower limit of the age-specific serum IgG reference range.

Loading dose: One additional dose of 0.4 g/kg in the first month of therapy is permitted if the serum IgG level is markedly reduced.

Chronic suppurative lung disease: Dosing to achieve IgG trough level of up to 9 g/L is permitted if chronic suppurative lung disease is not adequately controlled at an IgG trough level at the lower limit of the age- specific serum IgG reference range.

Subcutaneous administration of immunoglobulins is a suitable alternative to IVIg in this disease.

Dosing above 1 g/kg per day is contraindicated for some IVIg products.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

The term ‘specific antibody deficiency’ describes failure of specific antibody response to an antigen challenge, and is most often used in the more restrictive sense of applying to polysaccharide antibody responses only.

Patients who have normal total IgG levels but impaired production of specific antibodies, including those with isolated deficient responses to numerous polysaccharide antigens after vaccination, can present a diagnostic challenge. IgG replacement therapy should be provided when there is well-documented severe polysaccharide non-responsiveness and evidence of recurrent infections with a documented requirement for antibiotic therapy and ongoing recurrent infections despite antibiotic prophylaxis (Orange et al 2006).

It is now generally agreed that IgG subclass level estimation in serum is relatively poorly predictive of infectious risk and is of limited value in the definition of those patients most likely to benefit from IVIg therapy.

Further research investigating clinical and laboratory features of this disorder is required.

To access IVIg for a period of 12 months, the following qualifying criteria must be met:

1. A clinical immunologist must be consulted to confirm the diagnosis;

AND

2. Frequent bacterial infections despite oral antibiotic therapy consistent with best practice recommendations;

AND

3. Documented failure of serum antibody response to unconjugated pneumococcal or protein vaccine challenge.

1. Isolated IgG subclass deficiency in the absence of evidence of specific antibody deficiency.
2. Low total IgG. This should be considered under primary or secondary immunodeficiency.

Natural history of specific antibody deficiency remains poorly defined, although antibody production will improve for many patients over time, particularly children.

To be eligible to receive IVIg for a further 12 months, the following is required:

Written confirmation from the treating clinical immunologist that:

• an annual review has been undertaken;
• the patient had demonstrated clinical benefit;
• a trial period of cessation of IVIg for the purpose of immunological evaluation is medically contraindicated on safety grounds.

Cessation of IVIg should be considered, at least after each 12 months of therapy extended as required to enable cessation of therapy in September/October.

This should particularly be considered in patients who do not have suppurative lung disease or bronchiectasis. An immunoglobulin washout period of four to six months is necessary to enable an accurate assessment. Prophylactic antibiotics may be considered to cover the period of IVIg cessation.

Patients may qualify for further IVIg therapy:

• under other immunodeficiency criteria (e.g. common variable immunodeficiency [CVID]) depending on the results of subsequent immune evaluation; or
• rarely under specific antibody deficiency following re-emergence of severe significant infection requiring hospitalisation.

In principle, IVIg should only be continued or renewed if there is a demonstrated clinical benefit.

Note that re-vaccination with pneumococcal polysaccharide vaccine is not recommended because of safety concerns, and the potential for specific hyporesponsiveness induced by repeated vaccination (O’Brien et al 2007).

1. New patients

IVIg is not funded for new patients diagnosed with IgG subclass deficiency.

2. Patients who were receiving IVIg for IgG subclass deficiency before initial publication of the Criteria (December 2007)

• Without clinically active bronchiectasis or suppurative lung disease:

These patients should have ceased IVIg and had their immunological status re-evaluated. Patients with a confirmed IgG deficiency have become eligible under another indication (e.g. primary immunodeficiency with antibody deficiency). Patients without a confirmed IgG deficiency have ceased IVIg therapy.

• With clinically active bronchiectasis or suppurative lung disease over the previous 12 months: To be eligible to receive IVIg for a further 12 months, the following is required:

1. Written confirmation from the treating clinical immunologist that :

• an annual review has been undertaken;
• the patient has demonstrated clinical benefit; and
• a trial period of cessation of IVIg for the purpose of immunological evaluation is medically contraindicated on safety grounds.

AND

2. Written confirmation by a second physician that cessation of IVIg for the purpose of immunological evaluation is medically contraindicated on safety grounds.

Cessation of IVIg should be considered, at least after each 12 months of therapy extended as required to enable cessation of therapy in September/October.

NOTE: The above criteria for initial and ongoing access to IVIg funded by all governments under the National Blood Arrangements will be reviewed in light of emerging evidence at the next review of the Criteria.

Maintenance dose: 0.4 g/kg every 4 weeks.

Loading dose: not approved.

Subcutaneous administration of immunoglobulins (SCIg) is a suitable alternative to IVIg in this setting.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

1. ADEM unresponsive to steroid therapy or where steroids are contraindicated (e.g. suspicion of CNS infection).
2. Recurrent or multiphasic ADEM unresponsive to steroid therapy or where steroid therapy has become intolerable or is contraindicated.

ADEM is a monophasic inflammatory condition of the central nervous system that usually presents in children and young adults. It typically occurs following a viral prodrome with multifocal neurological disturbance and altered conscious state. ADEM usually follows a monophasic course, but patients may experience recurrence of the initial symptom complex (recurrent ADEM) or a second episode of ADEM (multiphasic ADEM). The majority make a full recovery.

ADEM is thought to have an autoimmune basis. Pathologic similarities to experimental allergic encephalomyelitis (EAE), an animal model of inflammatory demyelination, support this theory. It is postulated that a common antigen shared by an infectious agent and a myelin epitope results in an autoimmune response.

Patients show multiple demyelinating lesions on magnetic resonance imaging (MRI) in the deep and subcortical white matter. The differential diagnosis includes other inflammatory demyelinating disorders, such as multiple sclerosis, optic neuritis and transverse myelitis.

High-dose corticosteroids are first-line treatment of ADEM. IVIg has been used for patients who fail to respond to steroid therapy or in patients where steroids are contraindicated. Most patients with ADEM recover completely over a period of six weeks from onset.

There is no biological marker for ADEM. Diagnosis is by clinical recognition of the multifocal neurological disturbance and altered conscious state, with the typical MRI findings of demyelination.

1. ADEM unresponsive to steroid therapy or where steroids are contraindicated (e.g. suspicion of CNS infection).

Note: Assessment by a neurologist is recommended, but not mandatory.

OR

2. Recurrent or multiphasic ADEM unresponsive to steroid therapy, or where steroid therapy has become intolerable or is contraindicated, with assessment by a neurologist mandatory.

Objective evidence of improvement in relapse rate in comparison to pre-treatment levels.

Six-monthly review by a neurologist is required for recurrent or multiphasic ADEM.

Induction: 2 g/kg in 2 to 5 divided doses.

Maintenance dose: For recurrent or multiphasic
ADEM only: 0.4–2 g/kg, 4–6 weekly.

Aim for the minimum dose to maintain optimal functional status and prevent relapses.

In recurrent or multiphasic ADEM, assessment by a neurologist is mandatory.

Dosing above 1 g/kg per day is contraindicated for some IVIg products.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

ANCA associated systemic necrotising vasculitides are life-threatening immune-mediated inflammatory diseases comprising one of four clinical syndromes:

1. Wegener granulomatosis;
2. microscopic polyangiitis;
3. Churg–Strauss syndrome; and
4. ANCA (PR3 or MPO)-positive idiopathic rapidly progressive glomerulonephritis.

In these cases the ANCA specificity is directed against the neutrophil cytoplasmic antigens PR3 and MPO. ANCA that lack MPO or PR3 specificity tend to be non-specific. Biopsy of affected tissue is required to establish the diagnosis.

Standard combinations of corticosteroids and cytotoxic immunosuppression are generally effective at controlling disease, but relapses are common. IVIg has a limited role as one of several therapeutic options in relapsing disease.

MPO or PR3 ANCA-positive systemic necrotising vasculitis with both of the following:

1. Current (or within the previous six months) standard cytotoxic immunosuppressive ANCA-vasculitis regimens;

AND

2. Persisent active disease.

• Six-month review assessing evidence of clinical benefit.
• Reduction in the Birmingham vasculitis activity score of more than 50% after three months.
• Erythrocyte sedimentation rate and C-reactive protein concentration.
• ANCA titre.

2 g/kg in single or divided doses.

Dosing above 1 g/kg per day is contraindicated for some IVIg products.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

AIHA is a rare but serious autoimmune disease in which an individual’s antibodies recognise antigens on their own red blood cells. AIHA presents as an acute or chronic anaemia characterised by the occurrence of biochemical parameters of red cell destruction associated with a positive direct antiglobulin test indicating the presence of antibodies and/or complement on the red cell surface. It may be secondary to a number of underlying disorders or drugs.

Investigations

A full blood count will confirm the presence of anaemia. A peripheral blood smear may reveal evidence of spherocytes along with polychromasia due to reticulocytosis. A direct antiglobulin test is usually positive, the serum lactate dehydrogenase is raised, and there is a reduction in serum haptoglobin.

Prognosis

The prognosis of AIHA is good in most cases although severe refractory AIHA can cause cardio-respiratory problems because of severe anaemia, especially in adults.

Standard therapy

Corticosteroid administration is the cornerstone of therapy. For those with relapsing disease, splenectomy and immunosuppression are second line treatments while anti-CD20 antibodies have shown promise in individual cases of refractory disease.

1. Symptomatic or severe AIHA (Hb <60 g/L, except patients with co-morbidities) refractory to conventional therapy with corticosteroids;

OR

2. As a temporising measure before splenectomy;

OR

3. As initial and maintenance therapy in AIHA in patients unsuitable for splenectomy or immunosuppression.

• Resolution of haemolytic anaemia (rising haemoglobin concentrations, falling bilirubin and LDH).
• Clinical improvement in symptoms and signs.

Up to 2 g/kg as a single or divided dose.

Dosing above 1 g/kg per day is contraindicated for some IVIg products.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

BP is a rare disease of elderly people characterised by tense blisters and vesicles with a prominent inflammatory component. The cause is unknown. Lesions result from a failure of basal keratinocytes to adhere to the epidermal basement membrane.

The course of BP is characterised by exacerbations and remissions. Pruritis is a common feature and an increase in pruritis may herald an exacerbation.

In most patients, BP is not a life-threatening disease. The side effects of systemic immunosuppressive therapy need to be managed. In most patients, the disease spontaneously clears within six years and all medication can be stopped. In a small group, the disease recurs after treatment is stopped. Skin infection is the most common complication.

A submission by the Australasian College of Dermatologists recommends IVIg use in BP only in severe cases where improvement with conventional therapy is not readily achieved.

Moderate to severe disease diagnosed by a dermatologist

AND

1. Corticosteroids or immunosuppressive agents are contraindicated;

OR

2. Condition is unresponsive to corticosteroids and immunosuppressive agents;

OR

3. Presenting with severe side effects of therapy.

• Response demonstrated at review at six months. Improvement to be demonstrated for continuation of supply.
• Reduction in recurrence of disease or relapse.
• Ability to reduce dose or discontinue other therapies.
• Improved quality of life.
• Resolution of blisters and healing of affected skin.
• Resolution of pruritis.

Efficacy demonstrated with doses of at least 2 g/kg per monthly treatment cycle.

Dosing above 1 g/kg per day is contraindicated for some IVIg products.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

CP or MMP is a rare, acquired subepithelial blistering disease characterised by erosive lesions of mucous membranes and skin. Serious complications may occur due to erosions and scarring. Hoarseness, pain, tissue loss and even upper airway destruction can occur with nasopharyngeal or laryngeal involvement, and oesophageal and urogenital lesions may lead to stenosis or strictures. CP is usually a chronic, progressive disorder.

The aim of long-term treatment is cessation of the self-destructive autoimmune process. Failure to do so results in invariable progression of the disease, culminating in progressive scarring. Permanent remission is usually possible if the disease is diagnosed early and treated sufficiently for one to five years.

For the 70% of patients who have eye involvement, the disease progresses to conjunctival scarring and shrinkage, but may take 10–20 years to reach the end stage of bilateral blindness.

Prolonged clinical remission and reduction in side effects was demonstrated in one small case series (15 cases) of patients with CP/MMP unresponsive to systemic corticosteroids and immuno-suppressive agents or presenting with multiple side effects of therapy (Biotext 2004).

A small non-randomised, non-blinded trial (16 patients) showed significant improvement in the mean time for clinical control, recurrence, disease progression and drug-related side effects among patients receiving IVIg compared to conventional immunosuppressive therapy (Frommer and Madronio 2006).

The (2003) consensus statement from the Harvard Medical School Department of Dermatology identified a study of 10 MMP patients who had progressive ocular involvement and did not respond to corticosteroids or immunosuppressants. IVIg administration as monotherapy arrested the progression and vision was maintained after IVIg was discontinued. The authors cited two other studies of oral pemphigoid in 15 and 7 patients respectively who could not be treated with dapsone; IVIg was compared to immunosuppressants. IVIg led to early and long-term remission and no disease progression.

Moderate to severe disease diagnosed by a dermatologist;

AND

1. Corticosteroids or immunosuppressive agents are contraindicated;

OR

2. Condition is unresponsive to corticosteroids and immunosuppressive agents;

OR

3. Presenting with severe side effects of therapy.

• Response demonstrated at review at six months. Improvement to be demonstrated for continuation of supply.
• Disease recurrence or relapse and duration of clinical remission.
• Ability to reduce dose or discontinue other therapies.
• Resolution of conjunctival inflammation.
• Reduction of drug-related side effects.

Efficacy demonstrated with doses of at least 2 g/kg per monthly treatment cycle.

Dosing above 1 g/kg per day is contraindicated for some IVIg products.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

Evans syndrome is a rare but serious autoimmune disease defined by the simultaneous or sequential occurrence of AIHA and immune thrombocytopenia purpura (ITP) without underlying aetiology. As such, it is a diagnosis of exclusion and other disorders, such as collagen vascular diseases, especially systemic lupus erythematosus (SLE) and scleroderma should be ruled out.

The 2005 review by Norton and Roberts provided perspective on diagnosis, clinical features and management.

A 2005 review on the management of Evans syndrome, based on Massachusetts Hospital data and a literature review, showed a transient response in all patients unless IVIg was given every three weeks (Norton and Roberts 2006). The review concluded that the data supported a role for IVIg in first-line therapy. It was not clear whether it was important for steroids to be given at the same time, although this is common practice. A total dose of 2 g/kg in divided doses appeared to be sufficient.

The review also stated that there might be a role for IVIg in preference to steroids in the acute setting in very young children.

1. Refractory to conventional therapy with corticosteroids;

OR

2. Where corticosteroids are contraindicated;

OR

3. As a temporising measure before splenectomy.

• Maintenance therapy rarely required.
• Resolution of haemolytic anaemia.
• Improvement in platelet count.
• Clinical improvement in symptoms and signs.

Up to 2 g/kg in divided dose.

Dosing above 1 g/kg per day is contraindicated for some IVIg products.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

FMAIT/NAIT develops because of maternal sensitisation to foetal platelets that possess a paternally inherited antigen. In Caucasians, the antigen is human platelet antigen (HPA) 1a in 80% of cases and HPA-5b in 15%, but other antigens are also implicated. The mother’s antibodies cross the placenta and coat the baby’s platelets, with accelerated platelet clearance leading to thrombocytopenia. This may result in serious and potentially life-threatening bleeding in the foetus or neonate. Pathogenesis is analogous to that of haemolytic disease of the newborn due to red cell antigen-antibody incompatibility.

The aim of management of the thrombocytopenic foetus or neonate is to increase the platelet count.

If foetal blood sampling reveals thrombocytopenia, IVIg may be administered weekly to the mother, with or without steroids, until delivery. Recent studies using IVIg weekly from around 20 weeks gestation, without foetal blood sampling, have shown reduced foetal and neonatal morbidity. This approach may be used for current pregnancies where the condition in a previous pregnancy was not associated with a foetal death or severe haemorrhage. Testing on maternal blood for foetal DNA or early genetic testing of the foetus (for platelet genotype) may predict the need to use IVIg.

Management of this condition is a specialised area and may include administration of HPA-compatible intrauterine and/or neonatal platelet transfusions. Further information regarding specialised platelet support is available from the Blood Service. Random (non-HPA-matched) platelets may be of benefit in the neonatal setting when matched platelets are not available (Kiefel 2006).

Clinical suspicion of FMAIT in antenatal or neonatal setting based on clinical and laboratory features, including:

1. Thrombocytopenia or spontaneous haemorrhage in the foetus;

OR

2. Thrombocytopenia with or without haemorrhage in the neonate;

OR

3. Unexplained foetal death in a previous pregnancy and the presence of maternal platelet-specific alloantibodies that are known or suspected to cause this condition (most commonly HPA-1a or HPA-5b).

• Foetal or neonatal morbidity and mortality in the context of maternal alloantibodies.
• Occurrence and severity of thrombocytopenia in the neonate.
• Maternal HPA-1a antibody level (if assay is available). Note that the strength/titre of maternal antibody level, even if available, is not proven clinically relevant and not able to be compared readily between laboratories at this time.

Maternal dose: 1 g/kg weekly throughout pregnancy, with starting time tailored to individual risk profile and history if relevant. Other doses and schedules have been used and some studies have used IVIg in conjunction with steroids.

Treatment of the neonate: 1 g/kg. Occasionally more than one dose is required if thrombocytopenia persists.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

Bone marrow diagnosis or other biopsy evidence of haemophagocytosis in the characteristic clinical setting.

Note: Since other therapies (cytotoxic agents) have major potential side effects, optimal therapy is not yet defined.

Amelioration of cytopenia(s), hepato/splenomegaly and lymphadenopathy if present.

Survival or death.

2 g/kg is the most widely published dose.

Emmenegger et al (2001) reported that better outcomes were associated with early administration of IVIg in their small case series (10 patients).

Dosing above 1 g/kg per day is contraindicated for some IVIg products.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

ITP is a reduction in platelet count (thrombocytopenia) resulting from shortened platelet survival due to anti-platelet antibodies. When counts are very low (<30x10⁹/L) bleeding into the skin (purpura) and mucous membranes can occur. Bone marrow morphology is normal. In some cases, there is additional impairment of platelet function related to antibody binding to glycoproteins on the platelet surface. ITP is divided into chronic and acute forms. In children, the acute form is the most common. The disease tends to present abruptly with dramatic evidence of bleeding into the skin (petechiae and purpura) and mucous membranes (gum bleeding, nose bleeds, blood blisters).

Occurrence

Girls and boys are affected equally. In 75% of patients, the episode follows vaccination or a viral infection such as varicella or infectious mononucleosis.

Prognosis

At least 80–90% of children will have spontaneous remission of their disease within 6–12 months. In 5–10% of cases, the disease may become chronic (lasting >6 months). Morbidity and mortality from acute ITP is very low.

Category 1 classification in the Biotext (2004) review was based on four low–moderate quality RCTs.

The Frommer and Madronio (2006) review identified a good-quality systematic review/meta-analysis of RCTs to support the Category 1 classification.

Note: While the effectiveness of IVIg is not disputed, clinical experts advise that most children with ITP do not require IVIg therapy; indeed, no treatment at all is required for many children. Corticosteroids are the alternative therapy to IVIg.

Acute ITP

1. Life-threatening bleeding due to thrombocytopenia;

OR

2. Thrombocytopenia with platelet count <30x10⁹/L and moderate to severe mucosal and/or cutaneous bleeding.

Chronic ITP

1. Life-threatening bleeding due to thrombocytopenia;

OR

2. In responsive patients for treatment of thrombocytopenia (<30x10⁹/L) with moderate to severe bleeding symptoms where other therapeutic options have failed or are contraindicated;

OR

3. In responsive patients given before surgery to elevate the platelet count to haemostatically safe levels.

1. Platelet count >30x10⁹/L.
2. Absence of significant bleeding.

• Platelet count at 48 hours.
• Control or resolution of bleeding.
• Duration of effect.
• Progression to chronic ITP.

Acute ITP

Life-threatening bleeding: up to 2 g/kg total dose, generally given as 2 doses of 1 g/kg.

Other indications: 0.5 g/kg given as a single dose, repeated at 24–48 hours if the response is inadequate. A higher total dose of 2 g/kg may be required in 5–10% of cases.

Duration of response to initial dose is typically two to four weeks. A repeat dose may be considered if recurrent symptomatic thrombocytopenia occurs.

Chronic ITP

Life-threatening bleeding: up to 2 g/kg total dose, generally given as 2 doses of 1 g/kg.

Other indications: 0.5 to 1 g/kg at intervals generally > three weekly.

Dosing above 1 g/kg per day is contraindicated for some IVIg products.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

IgM paraproteinaemic neuropathy is a slowly progressive, predominantly sensory neuropathy that may eventually produce disabling motor symptoms. The condition is associated with IgM paraprotein, which is a monoclonal antibody to myelin associated glycoprotein (MAG).

IgM paraproteinaemic neuropathy is the most common subgroup of the monoclonal gammopathy of undetermined significance (MGUS) group.

It is distinguishable from chronic inflammatory demyelinating polyneuropathy (CIDP) by:

• the presence of tremor;
• a greater severity of sensory loss, with ataxia and relatively mild or no weakness;
• damage tends to be permanent and the degree of improvement in IgM paraproteinaemic neuropathy is much smaller than the improvement observed in CIDP patients.

Nerve conduction studies usually show uniform symmetrical conduction slowing with prolonged distal latencies and distal attenuation (distal index is prolonged).

Test for antibodies to neural antigens (MAG or other neural antigens) may be helpful.

The Biotext (2004) review included three low quality studies (one RCT, one case-control and one case- series) with 20 patients. No benefit from treatment with IVIg was demonstrated in the case-control study (Biotext 2004).

The Frommer and Madronio (2006) found a Cochrane systematic review of five medium-quality RCTs with 97 patients of any age with a diagnosis of MGUS. There was inadequate evidence of efficacy of IVIg in anti-myelin-associated glycoprotein paraprotein peripheral neuropathies.

Diagnosis by a neurologist of IgM paraproteinaemic neuropathy with:

1. Functional impairment of activities of daily living;

AND

2. Other therapies have failed or are contraindicated or undesirable.

IVIg should be used for three to six months (three to six courses) before determining whether the patient has responded. If there is no benefit after three to six courses, IVIg therapy should be abandoned.

Review

Regular review by neurologist is required; frequency as determined by clinical status of patient.

For stable patients on maintenance treatment review by a neurologist is required at least annually.

Effectiveness

Clinical documentation of effectiveness is necessary for continuation of IVIg therapy.

Effectiveness can be demonstrated by objective findings of either:

1. Improvement in functional scores (activities of daily living — ADLs) or quantitative muscle scores, or Medical Research Council (MRC) muscle assessment or neuropathy score; or
2. Stabilisation of disease as defined by stable functional scores (ADLs) or quantitative muscle scores, or MRC muscle assessment or neuropathy score after previous evidence of deterioration in one of these scores.

Induction: 2 g/kg in 2 to 5 divided doses.

Maintenance: 0.4–1 g/kg, 2 to 6 weekly.

Maintenance treatment only with clear, objective improvement.

Aim for minimum dose to maintain optimal functional status.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

Pre-transplantation

Patients in whom an antibody or antibodies prevent transplantation (donor specific anti-human leukocyte antigen (HLA) antibody/ies or anti-blood group antibody).

Post-transplantation

To treat steroid-resistant acute rejection which may be cellular or antibody mediated.

For prevention and/or treatment of rejection where other therapies are contraindicated or pose a threat to the graft or patient.

Transplant rejection occurs when a recipient’s immune system attacks a transplanted organ or tissue. Despite the use of immunosuppressants, one or more episodes of rejection can occur after transplantation. Both cellular and humoral (antibody-mediated) effector mechanisms can play a role.

The presence and pattern of rejection need to be established by biopsy. Laboratory tests to assess the presence and strength of antibodies to the donor antigens can provide additional useful information. Clinical assessment, blood tests, ultrasound and nuclear imaging are used primarily to exclude other causes of organ dysfunction.

Acute cellular rejection occurs in 15–30% of renal transplants and is responsive to steroids in more than 90% of cases. When rejection is steroid resistant, IVIg is a safer therapy than anti-T cell antibody therapy with equal efficacy.

Antibody mediated rejection (AbMR) occurs in 5–10% of renal transplants that have been performed with a compatible cross match. Before the use of IVIg and plasma exchange, AbMR failed to respond adequately to therapy in most cases. Additionally, complications from therapy were severe and sometimes fatal. AbMR responds to IVIg with or without plasma exchange in more than 85% of patients.

An RCT enrolling adult patients with end stage renal disease (ESRD) who were highly sensitised to HLA antigens found that IVIg was better than placebo in reducing anti-HLA antibody levels in highly sensitised patients with ESRD (followed for two years after transplant), and that transplant rates were improved with IVIg therapy (Jordan et al 2004).

Multiple case series have been reported in the literature, indicating efficacy in (acute) antibody mediated rejection, and recommended by a consensus conference (Takemoto et al 2004).

Jordan et al (1998) combined data from seven renal transplant recipients and three heart transplant recipients with steroid-resistant combined antibody-mediated and cellular rejection. All patients in this series were successfully treated with high-dose IVIg.

A small RCT of transplanted patients with a five-year follow-up period showed that IVIg was as effective as OKT3 monoclonal antibodies in the treatment of steroid resistant rejection (survival rate at two years was 80% in both groups) but IVIg generated fewer side effects (Casadei et al 2001).

Pre-transplantation

Patients in whom an antibody or antibodies prevent transplantation (donor-specific anti-HLA antibody/ies or anti-blood group antibody).

Post-transplantation

1. Biopsy proven cellular rejection unresponsive to steroids with clinical evidence of graft dysfunction;

OR

2. Acute antibody mediated rejection with clinical evidence of graft dysfunction;

OR

3. As treatment or prophylaxis for rejection where conventional immunosuppressive therapy is contraindicated, for example:

• in a patient with life-threatening infection in whom conventional immunosuppression will place the patient at even greater risk;
• when the transplant is at risk (e.g. due to BK virus infection).

• Allograft organ function tests.
• Biopsy response.
• Laboratory monitoring of anti-HLA antibody and/or anti-blood group antibody responses.
• Duration of graft and patient survival.
• Reversal of clinical graft dysfunction.

IVIg with plasma exchange: 0.1 to 0.5 g/kg post exchange.

IVIg alone: 2 g/kg to a maximum of 140 g as a single dose, or 2 to 3.5 g/kg in a divided dose.

When IVIg is used alone, further doses may be warranted two to four weeks after initial therapy depending on clinical response and/or biopsy findings.

Dosing above 1 g/kg per day is contraindicated for some IVIg products.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

Short-term therapy in patients with clinically definite relapsing remitting MS in the following circumstances:

• Pregnancy and the immediate post-partum period when other immunomodulation is contraindicated;
• Young patients with severe relapsing remitting disease in whom other therapies have failed;
• Severe relapse with no response to high-dose methylprednisolone.

MS is a chronic disorder of the central nervous system (CNS) characterised by a triad of inflammation, demyelination and gliosis. Lesions of MS, known as plaques, are typically disseminated in time and location throughout the brain and spinal cord.

Four clinical types of MS have been described: relapsing/remitting MS (RRMS), primary progressive MS (PPMS), secondary progressive MS (SPMS), and progressive/relapsing MS (PRMS).

Diagnosis requires two or more episodes of symptoms and two or more signs that reflect pathology in anatomically non-contiguous white matter tracts of the CNS. Symptoms must last >24 hours and occur as separate episodes at least one month apart. At least one of the two signs must be present on neurological examination, while the other may be detected by paraclinical tests such as intrathecal IgG (oligoclonal bands and visual evoked potentials).

The Biotext (2004) literature review included one systematic review, six RCTs, three case-control studies and one case-series with a total sample size of 849. The quality of the included studies varied widely. The systematic review found some benefit. No benefit was found in two of the RCTs (IVIg did not appear to reverse established muscle weakness), and significant benefit was reported in two RCTs. The other two RCTs were identified by Biotext from the Cochrane register of trials, but no further information about the studies was obtained.

The review by Frommer and Madronio (2006) included eight high-quality RCTs and one medium-quality double-blinded controlled trial with a total of 708 patients. These studies suggested that the occurrence of relapse may be reduced by IVIg at three years, but conclusive evidence in relation to the use of IVIg in reducing relapse rates and severity of relapse in established disease could not be demonstrated. IVIg treatment for the first year from onset of the first neurological event significantly lowered the incidence of second attacks and reduced disease activity as measured by MRI.

IVIg administered in monthly pulses for up to two years appeared to reduce annual exacerbation rates in patients with RRMS and SPMS, but its effect on long-term disability was unclear.

Clinically definite RRMS as defined by McDonald et al (2001) criteria and confirmed by a neurologist with one of the following indications:

1. Pregnancy and immediate post partum period when other immunomodulation is contraindicated;

OR

2. Young patients with severe relapsing remitting disease in whom other therapies have failed;

OR

3. Severe relapse with no response to high-dose methylprednisolone.

Application for IVIg use for these indications will be considered on a case-by-case basis and may be reviewed by an expert neurologist in MS in each state

Note: There are numerous immunomodulatory therapies available for multiple sclerosis. IVIg is not available for routine ongoing treatment for patients with MS.

1. Primary progressive MS.
2. Progressive phase of MS without relapses.

• Six-monthly review by a neurologist is required.
• Objective evidence of improvement in relapse rate in comparison to pre-treatment levels.
• Other measures that may be useful include: - expanded disability status scale;

- MS functional scores;

- other functional measures.

Induction: 1–2 g/kg in 2 to 5 divided doses.

Maintenance dose for indications 1 and 2 above:

0.4–1 g/kg, 4 to 6 weekly.

Aim for minimum dose to maintain optimal functional status.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

Diagnosis of OMA by a neurologist:

1. In children;

OR

1. As second-line treatment following the use of adrenocorticotrophic hormone or corticosteroids.

2. Note: Given the rarity of OMA and its devastating effects, IVIg should be used where it is considered appropriate by a neurologist.

Review

Regular review by neurologist is required; frequency as determined by clinical status of patient.

For stable patients on maintenance treatment, review by a neurologist is required at least annually.

Effectiveness

Objective indicators of relief of symptoms of OMA and improvement or stabilisation of scores of ADLs.

Induction: 1–2 g/kg in 2 to 5 divided doses.

Maintenance: 0.4–1 g/kg, 4 to 6 weekly.

Aim for the minimum dose to maintain optimal functional status.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

PF is a rare autoimmune blistering skin disease characterised by loss of cohesion of cells (acantholysis) in the superficial (subcorneal) layers of the epidermis. The lesions are generally well demarcated and do not coalesce to form large eroded areas (as seen in pemphigus vulgaris). It is mediated by an autoantibody that targets desmoglein 1, a cell-to-cell protein molecule that binds the desmosomes of neighbouring keratinocytes in the epidermis.

The disease has a long-term course with patients maintaining satisfactory health. Spontaneous remissions occasionally occur.

Severe widespread PF, defined as disease involving 30% or more of body surface area, diagnosed by a dermatologist;

AND

1. Corticosteroids or immunosuppressive agents are contraindicated;

OR

2. Condition is unresponsive to corticosteroids and immunosuppressive agents;

OR

3. Presenting with severe side effects of therapy.

• Response demonstrated at review at six months. Improvement to be demonstrated for continuation of supply.
• Clinical progression: Treatment is stopped when patients are clinically free from disease and have a negative finding on direct immunofluorescence.
• Autoantibody titres reflect the response to systemic therapy.

Efficacy demonstrated with doses of at least 2 g/kg per monthly treatment cycle.

Dosing above 1 g/kg per day is contraindicated for some IVIg products.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

PV is a rare but potentially fatal condition accounting for approximately 70% of pemphigus cases. While the cause is unknown, an immuno-genetic predisposition is well established. PV may also be drug-induced. Drugs reported to be most significantly associated with PV include penicillamine, captopril and other thiol-containing compounds. Rifampicin and emotional stress have recently been reported as triggers for PV.

The oral cavity is almost always affected and erosions can be scattered and extensive, with subsequent dysphagia. Blistering and erosions secondary to the rupture of blisters may be painful and limit the patient’s daily activities.

Pemphigus may occur in patients with other autoimmune diseases, particularly myasthenia gravis and thymoma.

Prognosis

The severity and natural history of PV are variable. Before the advent of steroids, most patients with PV died. Treatment with systemic steroids has reduced the mortality rate to 5–15%. Most deaths occur during the first few years of disease and if the patient survives five years, the prognosis is good. Early disease is easier to control than widespread disease and mortality may be higher if therapy is delayed. Morbidity and mortality are related to the extent of disease, the maximum dose of corticosteroid required to induce remission, and the presence of other diseases.

Moderate to severe disease diagnosed by a dermatologist;

AND

1. Corticosteroids or immunosuppressive agents are contraindicated;

OR

2. Condition is unresponsive to corticosteroids and immunosuppressive agents;

OR

3. Presenting with severe side effects of therapy.

• Response demonstrated at review at six months. Improvement to be demonstrated for continuation of supply.
• Titres of serum antibodies against keratinocytes.
• Whether systemic corticosteroids can be gradually discontinued.
• Total dose and duration of corticosteroid therapy, and number of relapses before and after the initiation of IVIg therapy.

Efficacy demonstrated with doses of at least 2 g/kg per monthly treatment cycle.

Dosing above 1 g/kg per day is contraindicated for some IVIg products.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

PTP is caused by antibodies to platelet-specific antigens, usually anti-HPA1a. PTP may result in profound thrombocytopenia with associated life- threatening bleeding. While the platelet count typically recovers spontaneously, this can take several weeks or more.

Specialised investigations (antibody screening, patient/donor genotyping) and antigen-matched platelet and/or red cell transfusion support may be required — contact the Blood Service for more information.

Clinical diagnosis/suspicion of PTP with thrombocytopenia associated with life-threatening bleeding.

Note: Laboratory confirmation is desirable where possible in the time frame (usually an urgent, life-threatening clinical situation).

• Platelet counts in the days and weeks following IVIg.
• Resolution of bleeding.

1 g/kg as a total dose, repeated if necessary

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

TEN is a rare, life-threatening hypersensitivity reaction to certain medications, such as sulphonamides, antibiotics, non-steroidal anti-inflammatory drugs and anti-convulsants. Drug-induced epidermal apoptosis has been proposed as possible pathogenesis. Stevens–Johnson syndrome (SJS) is a less extensive manifestation of the same phenomenon.

TEN and SJS are characterised by severe bullous reaction with extensive destruction of the epidermis, and morphologically by ongoing apoptotic keratinocyte cell death that results in the separation of the epidermis from the dermis.

The term SJS is now used to describe patients with blistering and skin detachment involving a total body surface area of <10%. SJS/TEN describes patients with 10–30% detachment, and TEN describes patients with >30% skin detachment.

The Biotext (2004) review identified one small cohort study (20 patients) without a control group, which found that there appeared to be no significant effect and that death rate seems to be higher than previously reported.

The Frommer and Madronio (2006) review found one small randomised study (four patients) with a control group of two patients (supportive care only). This study found that there was some improvement in epithelialisation and prominent difference in CD95 receptor between treated patients and controls. However, neither IVIg nor its comparison group could completely stop the TEN process.

TEN or SJS/TEN overlap with all the following:

1. Diagnosis by a dermatologist;

AND

2. Body surface area (erythema and/or erosions) of 10% or more;

AND

3. Evidence of rapid evolution.

Notes:

• IVIg should be initiated as early as possible, preferably within 24 hours of diagnosis.
• Urgent skin biopsy should be performed for confirmation but should not delay IVIg therapy if indicated.
• The Adverse Drug Reactions Advisory Committee should be notified of the inciting medication.

2 g/kg, preferably as a single dose, or divided over three consecutive days.

Dosing above 1 g/kg per day is contraindicated for some IVIg products.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

Streptococcal TSS: In view of the high mortality risk, IVIg is indicated for early use in both adults and children.

Staphylococcal TSS: IVIg is indicated where rapid improvement is not obtained with fluid resuscitation and inotropes.

In both conditions IVIg is used in addition to surgical intervention, antibiotic therapy and supportive measures.

TSS is a life-threatening illness characterised by hypotension and multi-organ failure. It may be caused by Staphylococcus aureus (rarely isolated) or Streptococcus pyogenes that produce and release superantigenic exotoxins. The exotoxins activate T-cells on a large scale resulting in a massive release of inflammatory cytokines.

Streptococcal TSS is defined by:

I Group A Streptococci (S. pyogenes) isolated from:

• (IA) a normally sterile site (e.g. blood, cerebrospinal fluid, pleural or peritoneal fluid, tissue biopsy, surgical wound); or
• (IB) a non-sterile site (e.g. throat, sputum, vagina, superficial skin lesion).

IIA. Hypotension: systolic blood pressure = 90 mmHg in adults or in the 5th percentile for age in children; and

IIB. Two or more of the following:

1. Renal impairment: serum creatinine for adults at least twice the upper limit of normal for age; in patients with existing renal disease, elevation over baseline by a factor of at least 2;
2. Coagulopathy: platelet count of ≤100x10⁹/L or disseminated intravascular coagulation, defined by prolonged clotting times, low fibrinogen level, and the presence of fibrin degradation products;
3. Liver involvement: alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin level at least twice the upper limit of normal for age; in patients with existing liver disease, elevation over baseline by a factor of 2;
4. Adult respiratory distress syndrome, defined by acute onset of diffuse pulmonary infiltrates and hypoxaemia in the absence of cardiac failure; or evidence of diffuse capillary leak manifested by acute onset or generalised oedema; or pleural or peritoneal effusions with hypoalbuminaemia;
5. Generalised erythematous macular rash that may desquamate;
6. Soft tissue necrosis, including necrotising fasciitis or myositis; or gangrene.

A definite case is an illness fulfilling criteria IA and II (A and B).

A probable case is an illness fulfilling criteria IB and II (A and B) where no other aetiology is identified.

(Working Group on Severe Streptococcal Infections 1993).

Staphylococcal TSS is defined by:

1. Fever: temperature ≥38.9°C;
2. Hypotension: systolic blood pressure ≤90 mmHg in adults or in the 5th percentile for age in children;
3. Diffuse macular rash with subsequent desquamation one to two weeks after onset (including palms and soles);
4. Multisystem involvement (three or more of the following):

1. Hepatic: bilirubin or aminotransferase ≥2 times normal;
2. Haematologic: platelet count ≤100x10⁹/L;
3. Renal: blood urea nitrogen or serum creatinine level ≥2 times normal;
4. Mucous membranes: vaginal, oropharyngeal or conjunctival hyperaemia;
5. Gastrointestinal: vomiting or diarrhoea at onset of illness;
6. Muscular: severe myalgia or serum creatine phosphokinase level ≥2 times upper limit;
7. Central nervous system: disorientation or alteration in consciousness without focal neurological signs and in the absence of fever or hypotension.

A confirmed case is a case with all of the manifestations described above. However, in severe cases death may occur before desquamation develops.

A probable case is an illness with all but any one of the manifestations described above (Wharton et al 1990).

Prognosis

Streptococcal TSS has a mortality rate of 30–80% in adults and 5–10% in children, with most deaths secondary to shock and respiratory failure.

Staphylococcal TSS can also be fatal but mostly has a better prognosis.

Streptococcal TSS: A small case series (Norrby-Teglund et al 2005), a cohort study (Kaul et al 1999) and an RCT, which was terminated prematurely (Darenberg et al 2003), suggested that IVIg improves outcomes.

Staphylococcal TSS: In vitro and animal studies suggested that IVIg is effective in neutralising staphylococcal superantigens. Anecdotal reports refer to the clinical effectiveness of IVIg in staphylococcal TSS.

1. Diagnosis of streptococcal or staphylococcal TSS in accordance with criteria listed above, preferably with isolation of organism;

AND

2. Failure to achieve rapid improvement with fluid resuscitation, inotropes, surgery, antibiotic therapy and other supportive measures.

2 g/kg as a single dose.

Schrage et al (2006) reported differences between various preparations of IVIg and their ability to neutralise streptococcal superantigens. They commented that ‘the variations between IVIg preparations from different manufacturers are most likely caused by the different geographical regions from which the plasma samples were collected and might reflect differences in ... group A streptococcal ... exposure.’ The clinical significance of these findings is not yet known.

Darenberg et al (2004) suggested that higher doses of IVIg might be required for staphylococcal TSS than streptococcal TSS, based on in vitro neutralisation of superantigens.

Dosing above 1 g/kg per day is contraindicated for some IVIg products.

Refer to the current product information sheet for further information.

The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.