Conditions for which IVIg has an established therapeutic role

Prevention of recurrent bacterial infections due to antibody failure associated with haematological malignancies.

Prevention of recurrent bacterial infections in patients undergoing HSCT for haematological malignancies.

One small crossover study of 12 patients with CLL or NHL reported that the number of serious bacterial infections was significantly decreased (p = 0.001) in the months in which patients received IgG every three weeks for one year. Serious bacterial infections showed a trend to be associated with an IgG level <6.4 g/L.

Three randomised controlled trials (RCTs) and one crossover trial of low–moderate quality reported a reduction in infection rates in CLL patients with hypogammaglobulinaemia after three to four-weekly administration of IVIg for one year.

One placebo-controlled RCT of monthly IVIg given to 82 MM patients for one year (with 22 withdrawing due to reaction) concluded that IVIg protects against life-threatening infections and significantly reduces risk of recurrent infections. The greatest benefit was seen in individuals who had a poor response to pneumococcal vaccine. A small prospective RCT with 30 multiple myeloma patients reported a possible decrease in symptoms of chronic bronchitis.

A recent systematic review and meta-analysis of patients undergoing HSCT [60 trials (>4000 patients)] reported an increased risk of veno-occlusive disease with no survival benefit particularly in studies conducted since 2000. The authors concluded that routine prophylaxis with IVIg is not supported, but suggest that its use may be considered in lymphoproliferative disorder patients with hypogammaglobulinaemia and recurrent infections, for reduction of clinically documented infections.

Diagnosis of acquired hypogammaglobulinaemia secondary to haematological malignancies or stem cell transplantation with:

• Recurrent or severe bacterial infection(s) and evidence of hypogammaglobulinaemia (excluding paraprotein);

OR

• Hypogammaglobulinaemia with IgG <4 g/L (excluding paraprotein).

Note: For data tracking purposes, the type of malignancy being treated should be recorded with each request for IVIg.

The following conditions should not be approved under this indication:

1. HIV in children (see page 185);
2. Transplantation-related immunomodulation (solid organ transplantation; (see page 208);
3. Secondary hypogammaglobulinaemia (including iatrogenic immunodeficiency (see page 106).

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 an 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 <4 g/L.

Subcutaneous administration of immunoglobulin can be considered as an alternative to IVIg. A suggested dose is 0.1 g/kg lean body mass every week modified to achieve an IgG trough level of at least the lower limit of the age-specific serum IgG reference range.

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.

PID comprise a group of more than 120 separate conditions. Many of these are manifest by failure of protective antibody production. Key diagnoses include common variable immunodeficiency (CVID), severe combined immunodeficiencies, transient hypogammaglobulinaemia of infancy, Wiskott Aldrich syndrome and X-linked agammaglobulinaemia. In certain conditions, such as Wiskott Aldrich syndrome, antibody failure may not be manifest as hypogammaglobulinaemia but functional antibody responses will be impaired.

Some PID does not involve antibody failure, such as chronic granulomatous disease and deficiencies of complement components. In these cases, antibody replacement therapy is not justified.

The following conditions should not be approved under this indication:

1. Miscellaneous hypogammaglobulinaemia (see Secondary hypogammaglobulinaemia, page 106)
2. Specific antibody deficiency (see page 110)
3. IgG subclass deficiency (not funded; see page 112).

Review criteria for primary immunodeficiency diseases with antibody deficiency are not mandated.

Nevertheless, the following may be of value to the clinician:

• frequency of clinical episodes of infection
• trough levels; and
• renal function.

Maintenance dose: 0.4 g/kg every four weeks, modifying dose and schedule 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.

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.

CIDP is an acquired sensorimotor polyneuropathy characterised by a progressive or relapsing/ remitting course with evidence of demyelination on electrophysiological or pathological studies and response to immunomodulating therapies.

There is no specific diagnostic test, but characteristic clinical and laboratory findings help distinguish this disorder from other immune mediated neuropathic syndromes. Serum protein electrophoresis with immunofixation may be indicated to search for monoclonal gammopathy and associated conditions.

The Biotext (2004) review found one Cochrane review of six RCTs with a total sample size of 170. The quality of the studies was low–moderate, found IVIg improved disability in the short-term, and had comparable results to treatment with plasma exchange or prednisolone.

The Frommer and Madronino (2006) review found one low-quality RCT with a total sample size of 20, which demonstrated that more patients responded to immunoadsorption than IVIg, although the baseline disease duration was higher in the IVIg group. Differences were not significant.

1. Diagnosis of CIDP verified by a neurologist; AND
2. Significant functional impairment of activities of daily living (ADL).

IVIg should be used for three to six months (three to six courses) before determining whether the patient has responded. Most individuals will respond within three months unless there is significant axonal degeneration whereby a six-month course will be necessary.

If there is no benefit after three to six courses, IVIg therapy should be abandoned.

Review

Regular review by a 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, 2–6 weekly.

The amount per dose should be titrated to the individual’s response.

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.

GBS is the commonest cause of acute flaccid paralysis in the West. The syndrome typically presents with rapidly progressive, relatively symmetrical ascending limb weakness consistent with a polyradiculoneuropathy and often with associated cranial nerve involvement.

Motor signs and symptoms usually predominate over sensory signs and symptoms. Loss of tendon reflexes occurs in most cases. Major complications include respiratory failure and autonomic dysfunction.

The disease is monophasic, reaching its nadir usually within two weeks, although arbitrary definition accepts a limit of four weeks. A plateau phase of variable duration follows the nadir before gradual recovery. Although recovery is generally good or complete in the majority of patients, persistent disability has been reported to occur in about 20% and death in 4 to 15% of patients.

IVIg has been shown to have the same efficacy as plasma exchange. The choice is based on availability, practicality, convenience, cost, and ease or safety of administration (Asia–Pacific IVIg Advisory Group).

Investigations

There is no biological marker for GBS. It is diagnosed by clinical recognition of rapidly evolving paralysis with areflexia. Investigations include the following:

• Cerebrospinal fluid (CSF) protein elevation, although the level may be normal in the first two weeks of illness. The CSF white cell count may rise transiently, but a sustained pleocytosis suggests an alternative diagnosis or association with an underlying illness (e.g. HIV).
• Electrophysiological studies may show changes after the first or second week of the illness, including conduction block, conduction slowing or abnormalities in F waves.

One systematic review of nine RCTs of moderate quality found IVIg hastened recovery in adults with GBS to the same degree as plasma exchange (Biotext 2004).

One low-quality RCT with a small sample size (n=21), in which the randomisation of patients to the IVIg treatment group was skewed, was identified. Children who received IVIg treatment showed earlier signs of improvement, and disability scores were lower at four weeks than the placebo group (Frommer and Madronio 2006).

Patients with GBS (or variant) with significant disability and disease progression.

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

Primary outcome measures: improvement in disability grade four weeks after treatment:

1. healthy
2. minor symptoms or signs of neuropathy but capable of manual work
3. able to walk without support of a stick but incapable of manual work
4. able to walk with a stick, appliance or support
5. confined to bed or chair bound
6. requiring assisted ventilation
7. dead

Secondary outcome measures:

1. time until recovery of unaided walking
2. time until recovery of walking with aid
3. time until discontinuation of ventilation (for those ventilated)
4. death or disability (inability to walk without aid after 12 months)
5. treatment-related fluctuation

2 g/kg in 2 to 5 divided doses.

Approximately 10% of patients relapse, which may require a second treatment with IVIg. A second dose of IVIg must only be on the advice of and after assessment by a neurologist.

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. Refractory acute ITP on the recommendation of a clinical haematologist

Patients with severe thrombocytopenia (platelets <30x10⁹/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 (<30x10⁹/L) with clinical evidence of a haemostatic defect (e.g. mucous membrane haemorrhage) or active bleeding.

3. ITP in pregnancy

a. Platelets <30x10⁹/L

b. Impending delivery

4. Specific circumstances

a. Planned surgery

b. Other concurrent risk factors for bleeding (e.g. concurrent anti-coagulant therapy)

c. Severe ITP (platelets <30x10⁹/L) where corticosteroids and immunosuppression are contraindicated

d. 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.

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 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.

Five small prospective studies, including three randomised studies, demonstrated equivalent efficacy of IVIg in comparison to prednisone 1 mg/kg/ day and high-dose dexamethasone regimen. Overall, the studies found a dose response with more rapid increment in platelet counts at scheduling ≥0.8 g/kg on day one compared with 0.4 g/kg/day for three days.

A small controlled study (10 patients in each arm) of HIV-positive patients with severe thrombocytopenia reported possible benefit for the restoration and maintenance of platelet count for the duration of the haemorrhagic disorder (Biotext 2004).

An international consensus statement from January 2010 (Provan et al 2010) reported on new data and provided consensus-based recommendations relating to diagnosis and treatment of ITP in adults, in children, and during pregnancy. This statement concluded that few RCTs have been conducted and that multi-centre, prospective RCTs are required.

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 >30x10⁹/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 >30x10⁹/L.

With ongoing therapy, IVIg may be administered to achieve a platelet count >30x10⁹/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 30x10⁹/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 <30x10⁹/L: IVIg therapy may be used to avoid corticosteroids, immunosuppressive agents and splenectomy. Further doses titrated to maintain a platelet count >30x10⁹/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 (80–100x10⁹/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 >30x10⁹/L, minor surgery >50x10⁹/L, major surgery >80x10⁹/L, major neurosurgery >100x10⁹/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 <30x10⁹/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.

1. Patients with PM or DM with significant muscle weakness unresponsive to corticosteroids and other immunosuppressive agents.
2. Patients with IBM who have dysphagia affecting function.
3. Patients with rapidly progressive IBM.

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.

PM: The Biotext (2004) review included one prospective case-series study of 35 adults with chronic refractory polymyositis. IVIg may be of benefit in these patients, improve mean muscle power and allow reduction in dose of corticosteroid. Further research is needed.

DM: The Biotext (2004) review included one double-blind, placebo-controlled trial considered of low quality of 15 patients with biopsy-confirmed, treatment-resistant dermatomyositis. IVIg treatment combined with prednisone led to significant improvement in muscle strength and neuromuscular symptoms of patients in the intervention group (n=8).

IBM: The Biotext (2004) review included three small controlled studies, two of which had a crossover design. A total sample of 77 patients diagnosed with IBM was followed for between 4 and 12 months. The three studies showed possible slight benefit in reducing endomysial inflammation, disease progression and severity of IBM. Further research is needed.

One submission reported the effectiveness of IVIg therapy for PM and DM as add-on therapy for patients who have not responded to steroids and immunosuppression (NSW IVIg User Group). A further submission confirms a role for IVIg as add-on maintenance therapy in some patients resulting in an increased chance of complete remission and reduction in corticosteroid dose. A third submission suggests that IVIg can be tried as add-on treatment for patients with PM or DM who have not responded adequately to corticosteroids and second-line immunosuppressive agents (Asia–Pacific IVIg Advisory Board 2004).

Weak evidence suggests that it may benefit patients with dysphagia associated with IBM (Asia–Pacific IVIg Advisory Board 2004).

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.

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 activities of daily living (ADL) or quantitative muscle scores or Medical Research Council (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.

Kawasaki disease is an acute, febrile, multi-system disease of children and young infants often involving the coronary arteries. Coronary artery aneurysms may occur from the second week of illness during the convalescent stage.

The cause of the condition is unknown but there is evidence that the characteristic vasculitis results from an immune reaction characterised by T-cell and macrophage activation to an unknown antigen, secretion of cytokines, polyclonal B-cell hyperactivity, and the formation of autoantibodies to endothelial cells and smooth muscle cells. It is likely that in genetically susceptible individuals, one or more uncharacterised common infectious agents, possibly with super-antigen activity, may trigger the disease.

Diagnosis

A diagnosis of Kawasaki disease is generally made if fever of four or more days’ duration is associated with at least four of the following changes, which often appear sequentially:

• bilateral (non-purulent) conjunctival injection;
• changes of the mucous membranes of the upper respiratory tract and oropharynx, including diffuse redness of pharyngeal mucosa, dry fissured lips, red fissured lips, and/or ‘strawberry tongue’;
• changes of the extremities, including peripheral erythema, peripheral oedema, and subsequent periungual or more generalised desquamation;
• polymorphous rash;
• cervical lymphadenopathy.

A diagnosis of Kawasaki disease may be made if fever and fewer than four of the changes listed above are present where there is strong clinical suspicion of Kawasaki disease (refer to Newburger 2004). Between 10% and 20% of cases, particularly in younger infants, present with fever and fewer than four of the listed criteria. Expert advice should be sought.

Data support the use of IVIg while there is ongoing inflammation (usually taken as ongoing fever or raised acute inflammatory markers). Prognosis is worse if IVIg is used 10 days post-onset, but should be used at any time if there is evidence of inflammation. Up to 15% of patients do not respond to initial IVIg therapy. Consensus is for re-treatment with 2 g/kg of IVIg before considering steroids.

2 g/kg in a single dose over 10–12 hours unless cardiac function necessitates the administration of a prolonged or divided treatment dose, usually once only.

Re-treatment with 2 g/kg in a single dose may be given when there is ongoing inflammation.

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.

LEMS is a disorder of neuromuscular transmission first recognised clinically in association with lung cancer and subsequently in cases in which no neoplasm was detected.

Patients with LEMS have a presynaptic neuromuscular junction defect. The clinical picture is characterised by proximal muscle weakness with augmentation of strength after exercise, mild oculomotor signs, depressed deep tendon reflexes and autonomic dysfunction (dry mouth, constipation, erectile failure).

In the Biotext (2004) review, one systematic review (containing one RCT with 9 patients) and one case series of 7 patients with a crossover design were included. IVIg appeared to provide some benefit to patients with LEMS. However, both studies only included a small number of patients.

Expert consensus states that IVIg produces temporary improvement in patients with LEMS. It therefore has a role as second line therapy (Asia–Pacific IVIg Advisory Board 2004).

One submission to the National Blood Authority reported on a randomised controlled trial that showed significant improvement in strength associated with a decline in the level of pathogenic antibodies (NSW IVIg User Group).

1. Mandatory assessment by a neurologist;

AND

2. Severely affected nonparaneoplastic LEMS patients in whom other therapy (e.g. with 3,4-diaminopyridine) has failed.

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. Initial review three to six monthly.

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 (ADL) or quantitative muscle scores or Medical Research Council (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, 2–6 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.

MMN is a relatively rare disorder characterised by slowly progressive, asymmetric, predominately distal limb weakness without sensory impairment. Weakness often begins in the arms and the combination of weakness, wasting, cramps and fasciculations may suggest a diagnosis of motor neuron disease. However, clinical examination may demonstrate that the pattern of weakness follows the distribution of individual nerves rather than a spinal segmental pattern.

Investigations will typically show conduction block on nerve conduction studies. IgM anti-GM-1 antibodies have been reported in a large number of patients with MMN and provide confirmatory evidence but are not essential for the diagnosis.

The Biotext (2004) review found six low-quality case studies or crossover RCTs with a total sample size of 68 patients. A possible benefit of IVIg treatment in these patients was observed, although five studies were not controlled.

The Frommer and Madronio (2006) review found one high-quality systematic review (a Cochrane review) of four crossover RCTs with 34 patients. Evidence for improvement in muscle strength with IVIg and limited evidence of a reduction in disability after IVIg administration.

Consensus statements assert that IVIg is the only safe treatment demonstrated to work in patients with MMN. It is recommended in those who have significant disability. Dose and monitoring is similar to chronic inflammatory demyelinating polyneuropathy. IVIg therapy is usually long term, but the minimum effective dose for each patient should be sought.

Plasma exchange and steroids appear to cause a worsening in the condition of patients with MMN with conduction block. Regular maintenance doses of IVIg are needed.

The National Guideline Clearinghouse recommends the use of IVIg in the treatment of patients with progressive, symptomatic MMN that has been diagnosed using electrophysiology, ruling out other possible conditions that may not respond to IVIg treatment.

• Presence of upper motor neuron signs.
• Significant sensory impairment without an adequate alternative explanation.

IVIg should be used for three to six months (three to six courses) before determining whether the patient has responded. Most individuals will respond within three months unless there is significant axonal degeneration whereby a six-month course will be necessary. 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: 0.4–2 g/kg, 2–6 weekly. The amount per dose should be titrated to the individual’s response.

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.

1. As an alternative treatment to plasma exchange in acute exacerbation (myasthenic crisis) or before surgery and/or thymectomy.
2. As maintenance therapy for moderate to severe MG when other treatments have been ineffective or caused intolerable side effects.

MG is an autoimmune disease associated with the presence of antibodies to acetylcholine receptors (AChR) or to muscle-specific tyrosine kinase (MuSK) at the neuromuscular junction. Some patients with myasthenia gravis are antibody negative.

Clinical features are characterised by fluctuating weakness and fatigability of voluntary muscles, namely levator palpebrae, extraocular, bulbar, limb and respiratory muscles. Patients usually present with unilateral or bilateral drooping of eyelid (ptosis), double vision (diplopia), difficulty in swallowing (dysphagia) and proximal muscle weakness. Weakness of respiratory muscles can result in respiratory failure in severe cases or in acute severe exacerbations (myasthenic crisis).

Diagnosis is suspected based on the clinical picture described above, without loss of reflexes or impairment of sensation. Repetitive nerve stimulation typically shows a decreasing response at 2–3 Hz, which repairs after brief exercise (exercise facilitation). Edrophonium can be used for confirmation. Other useful investigations include serum anti-AChR or MuSK antibody titre, or SFEMG (single-fibre electromyography).

A Cochrane review of four RCTs (a total of 147 children and adult patients) found benefit but no significant difference between IVIg and plasma exchange, and no significant difference between IVIg and methylprednisolone. One of the four studies found no benefit of IVIg (i.e. no significant difference between IVIg and placebo). The individual trials were of poor design and some had small numbers of participants, so more research is needed (Biotext 2004).

Anecdotal evidence of efficacy has come from clinicians. There is insufficient placebo-controlled evidence for IVIg use as a steroid-sparing agent or before thymectomy in stable MG, although multiple case reports suggest benefit in this context.

The Asia–Pacific Advisory Group (2004) supports the use of IVIg over a single day for the treatment of myasthenia gravis exacerbations, in myasthenic crisis, or in patients with severe weakness poorly controlled with other agents. It does not support the use of IVIg for maintenance in stable moderate or severe MG unless other therapies have failed and IVIg has shown benefit.

Effectiveness of IVIg is equivalent to steroids and plasma exchange but IVIg may be easier to administer than plasma exchange and avoids the side effects of steroids.

Mandatory diagnosis and assessment by a neurologist;

AND

1. As an alternative treatment to plasma exchange in acute exacerbation (myasthenic crisis) or before surgery and/or thymectomy;

OR

1. As maintenance therapy for moderate to severe MG when other treatments have been ineffective or caused intolerable side effects.

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. Initial review three to six monthly.

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 improvement in fatigability and weakness.

Various scores can be used, including:

• forward arm abduction time (up to a full five minutes);
• Quantitative Myasthenia gravis score (Duke);
• respiratory function (e.g. forced vital capacity); quantitative dynamometry of proximal limb muscles;
• variation of a myasthenic muscular score (MSS).

Maintenance: 0.4–1 g/kg, 4–6 weekly.

Induction or before surgery, or during myasthenic crisis: 1–2 g/kg in 2 to 5 divided doses.

Aim for minimum dose to maintain optimal functional status.

Note: smaller dosage may be of greater efficacy.

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.

NH manifests in the foetus and newborn and is characterised by abnormal accumulation of iron in the liver and extra-hepatic tissues. Affected neonates present with fulminant liver failure, usually in the context of a history of prematurity, intrauterine growth retardation and oligohydramnios. NH differs from most other causes of neonatal liver disease, other than congenital infections, in that the condition begins in utero and fulminant liver disease is manifested in the first few days of life. The aetiology and pathogenesis remains uncertain. The NH phenotype may be the outcome of numerous disease processes. There is also evidence, however, that NH is an alloimmune disorder. First, there is an approximate 80% likelihood of NH once a woman has an affected baby. Second, mothers can have affected babies with different fathers. It has not been described that fathers can have affected half-siblings with different mothers.

Symptoms and signs

Affected neonates present with signs of liver failure, including extreme cholestasis, hypoalbuminaemia, coagulopathy, ascites and hypoglycaemia.

Diagnosis of neonatal haemochromatosis is made after other causes of neonatal liver failure have been ruled out.

In addition to extensive iron deposition (siderosis), liver biopsy would show cirrhosis with diffuse fibrosis, bile duct proliferation, and giant cells. Siderosis is also present in other tissues and viscera (e.g. epithelial tissues and the heart) but not in reticuloendothelial cells.

Occurrence

NH is a rare disease but the rate of recurrence after the index case in a sibship is up to 80%.

Prognosis

About 20% survival with medical treatment.

• Occurrence of NH, or evidence of liver disease (serum ferritin and a-fetoprotein levels, coagulopathy) in the offspring of women who have previously given birth to an NH-affected neonate.
• Requirement for liver transplantation in these neonates.
• Survival and development of infants following maternal IVIg therapy during pregnancy.

1 g/kg body weight weekly from the 18th week until the end of gestation.

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 stiff person syndrome present with symptoms related to muscular rigidity and superimposed episodic spasms. The rigidity insidiously spreads involving axial muscles, primarily abdominal and thoracolumbar, as well as proximal limb muscles. Typically, co-contraction of truncal agonist and antagonistic muscles leads to a board-like appearance with hyperlordosis. Less frequently, respiratory muscle involvement leads to breathing difficulty and facial muscle involvement to a mask-like face.

Investigations that may be useful for diagnosis include auto-antibodies to GAD-65 or GAD-67, electromyography recordings from stiff muscles that may show continuous discharges of motor unit, and cerebrospinal fluid oligoclonal bands.

The Biotext (2004) review included one randomised, double blind, placebo-controlled trial with a crossover design of 16 patients with stiff person syndrome and anti-GAD-65 antibodies. A significant treatment effect with IVIg was seen, resulting in patients’ decreased stiffness and heightened sensitivity scores.

According to expert consensus, considering the disabling progressive course of stiff person syndrome, IVIg should be offered as the first-line treatment. Although periodic infusions would be required in the majority, further studies are needed to determine optimal dosage and duration (Asia–Pacific Advisory Board 2004).

Review

Regular review by a 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 stiffness, including:

• improvement or stabilisation of activities of daily living scores;
• other specialised scoring systems, such as distribution-of-stiffness index and heightened sensitivity scale.

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

Maintenance: 1–2 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.