Conditions: H-I

HDN arises from foetomaternal antigen incompatibility and can result in clinically significant foetal/neonatal haemolysis, severe anaemia and hyperbilirubinaemia.

Although prophylaxis programs have reduced the frequency of rhesus (Rh) D HDN, antibodies to RhD remain the most common cause in Australia. Antibodies to other antigens in the Rh system (e.g. Rhc, E), ABO and other antigens (e.g. K) may also cause disease ranging from mild to life-threatening.

IVIg may be used in selected cases in consultation with experts in foetomaternal medicine and transfusion medicine.

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.

Small case studies only - Insufficient data (Category 4a)

IVIg may be considered in the management or prevention of severe haemolytic transfusion reaction not responding to other interventions (e.g. corticosteroids).

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.

Small case studies only - Insufficient data (Category 4a)

Management of severe haemophagocytic syndrome not responding to other treatments.

Haemophagocytic syndrome is characterised by fever, splenomegaly, jaundice, rash and the pathologic finding of haemophagocytosis (phagocytosis by macrophages of erythrocytes, leukocytes, platelets and their precursors) in bone marrow and other tissues with peripheral blood cytopenias. Haemophagocytic syndrome has been associated with a wide range of infectious, autoimmune, malignant and other disorders (modified from Fisman 2000). Mortality is high.

Small case studies only - Insufficient data (Category 4a)

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.

IVIg is not supported as a first-line treatment, because preferable alternative treatments are available.

IVIg may be considered in exceptional circumstances where there is progressive neurologic decline despite appropriate steroid therapy.

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.

Small case studies only - Insufficient data (Category 4a)

The need for IVIg in paediatric HIV has been substantially reduced with the advent of highly active antiretroviral therapy (HAART). A trial of therapy may however be considered in children with significant recurrent bacterial infections despite HAART.

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.

Evidence of probable benefit (Category 2a)

1. Refractory acute ITP on the recommendation of a clinical haematologist

Patients with severe thrombocytopenia (platelets <30×10⁹/L) who have not responded to corticosteroid therapy.

2. ITP with life-threatening haemorrhage or the potential for life-threatening haemorrhage

Patients with severe thrombocytopenia (<30×10⁹/L) with clinical evidence of a haemostatic defect (e.g. mucous membrane haemorrhage) or active bleeding.

3. ITP in pregnancy

1. Platelets <30×10⁹/L
2. Impending delivery

4. Specific circumstances

1. Planned surgery
2. Other concurrent risk factors for bleeding (e.g. concurrent anti-coagulant therapy)
3. Severe ITP (platelets <30×10⁹/L) where corticosteroids and immunosuppression are contraindicated
4. Chronic ITP under the guidance of a clinical haematologist, as adjunctive therapy or where other therapies have failed or are not appropriate

5. HIV–associated ITP

Patients with severe ITP associated with HIV infection.

Evidence of probable benefit (Category 2a)

ITP is a reduction in platelet count (thrombocytopenia) resulting from shortened platelet survival due to anti-platelet antibodies. When counts are very low (<30×10⁹/L), bleeding into the skin (purpura) and mucous membranes can occur. Bone marrow platelet production (megakaryopoiesis) is morphologically 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. It is a common finding in patients with HIV, and while it may be found at any stage of the infection, its prevalence increases as HIV disease advances.

Around 80% of adults with ITP have the chronic form of disease. The highest incidence of chronic ITP is in women aged 15–50 years, although some reports suggest increasing incidence with age.

Chronic ITP may relapse and remit spontaneously and the course may be difficult to predict. If the platelet count can be maintained at a level that prevents spontaneous bleeding or bruising, the outlook is good.

1. Refractory acute ITP:

1. Patients qualify for initial IVIg therapy when conventional doses of corticosteroids (0.5-2.0 mg/kg prednisolone, or equivalent) have failed to improve the platelet count or stop bleeding within a clinically appropriate time frame, as assessed by a clinical haematologist. The objective of therapy is to induce a prompt increase in the platelet count (to >30×10⁹/L) while other therapies are introduced.

2. Patients qualify for continuing doses when splenectomy has failed or is contraindicated AND where therapy with at least one second-line agent has been unsuccessful in maintaining a platelet count >30×10⁹/L.

   With ongoing therapy, IVIg may be administered to achieve a platelet count >30×10⁹/L. Further doses may be administered in responsive patients for up to 6 months (thereafter see Chronic refractory ITP). The frequency and dose should be titrated to maintain a platelet count of at least 30×10⁹/L. The objective of therapy is to maintain a safe platelet count while other therapeutic options are explored.

2. ITP with life-threatening haemorrhage or the potential for life-threatening haemorrhage:

IVIg therapy may be given when conventional doses of corticosteroids have failed or in conjunction with steroids when a rapid response is required.

3. ITP in pregnancy:

1. Platelets <30×10⁹/L: IVIg therapy may be used to avoid corticosteroids, immunosuppressive agents and splenectomy. Further doses titrated to maintain a platelet count >30×10⁹/L may be administered every three to four weeks throughout the pregnancy.
2. Impending delivery: IVIg therapy may be used to achieve a platelet count considered safe for delivery (80–100×10⁹/L).

4. Specific circumstances:

1. Planned surgery: IVIg may be used to achieve a platelet count considered safe for surgery. The safe threshold will vary with the nature of the surgery (Recommended platelet counts for patients without concurrent risks of bleeding: minor dental work >30×10⁹/L, minor surgery >50×10⁹/L, major surgery >80×10⁹/L, major neurosurgery >100×10⁹/L.
2. Severe ITP: IVIg may be used where corticosteroids and immunosuppression are contraindicated.
3. Chronic refractory ITP unresponsive to all other available therapies: These patients may be considered for long- term maintenance therapy with IVIg, subject to regular review by a haematologist.

5. HIV-associated ITP:

1. Failure of antiretroviral therapy with platelet count <30×10⁹/L;

OR

2. Life-threatening haemorrhage secondary to thrombocytopenia.

• In chronic refractory ITP, six-month review assessing evidence of clinical benefit
• Resolution of bleeding
• Increment in platelet count.

Initial therapy: 1–2 g/kg as a single or divided dose.

Ongoing therapy: When indicated, 1–2 g/kg in single or divided dose at 4 to 6 weekly intervals titrated to symptoms and platelet count.

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.

Clear evidence of benefit (Category 1)

ITP is a reduction in platelet count (thrombocytopenia) resulting from shortened platelet survival due to anti-platelet antibodies. When counts are very low (<30×10⁹/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.

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 thrombocytopenial

OR

2. Thrombocytopenia with platelet count <30×10⁹/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 (<30×10⁹/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 >30×10⁹/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.

Patients with IgM paraproteinaemic neuropathy with functional impairment in whom other therapies have failed or are contraindicated or undesirable.

Conflicting evidence of benefit (Category 2c)

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.

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 2–5 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.

1. Patients with polymyositis (PM) or dermatomyositis (DM) with significant muscle weakness unresponsive to corticosteroids and other immunosuppressive agents.
2. Patients with inclusion body myositis (IBM) who have dysphagia affecting function.
3. Patients with rapidly progressive IBM.

Evidence of probable benefit (Category 2a)

The inflammatory myopathies are a group of three discrete disorders of skeletal muscle: DM, PM and IBM.

These disorders are acquired and have in common the occurrence of significant muscle weakness and the presence of an inflammatory response within the muscle.

The diagnosis of DM, PM or IBM is usually made by neurologists or rheumatologists, and relies on the combination of careful clinical evaluation, an elevated creatine kinase level, electromyography and muscle biopsy.

Diagnosis made by a neurologist, rheumatologist or immunologist of:

1. Patients with PM or DM who have significant muscle weakness or dysphagia and have not responded to corticosteroids and other immunosuppressive agents;

OR

2. Patients with IBM who have dysphagia affecting function;

OR

3. Patients with rapidly progressive IBM.

Expert consensus does not recommend IVIg to treat the limb weakness of IBM.

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 a neurologist, rheumatologist, or clinical immunologist is required; frequency as determined by clinical status of patient.

For stable patients on maintenance treatment, review by a specialist 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 (ADLs) or quantitative muscle scores or MRC muscle assessment;

OR

2. Stabilisation of disease as defined by stable functional scores (ADLs) or quantitative muscle scores or MRC muscle assessment 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, 4–6 weekly.

Aim for the minimum dose to maintain optimal functional status.

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.