Conditions: C-G

IVIg may be appropriate therapy for catastrophic antiphospholipid syndrome, a term that describes the accelerated form of antiphospholipid syndrome characterised by widespread small vessel thrombosis leading to multiorgan failure. It is not indicated for the treatment of antiphospholipid syndrome in other cases. Please see Antiphospholipid syndrome (non‐obstetric) (page 14) and Recurrent foetal loss (with or without antiphospholipid syndrome) (page 14).

Qualifying criteria for IVIg therapy

A patient will qualify for IVIg when all the following criteria are met:

1. Evidence of rapidly evolving thrombosis involving two or more organs;
2. Unequivocal laboratory evidence of antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin antibodies and/or beta 2 glycoprotein I antibodies); and
3. Other causes of thrombotic microangiopathy are considered less likely.

Confirmation by histopathology of thrombotic small vessel occlusion in at least one organ or tissue is desirable but should not delay IVIg therapy if indicated.

A single treatment is usually sufficient, based on a dose of 2 g/kg divided over 2–5 days. The potential pro-thrombotic effect of IVIg should be considered in this indication.

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)

First-line treatment for CIDP with treatment initiated when progression is rapid, or walking is compromised, or there is significant functional impairment.

Clear evidence of benefit (Category 1)

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.

1. Diagnosis of CIDP verified by a neurologist;

AND

2. Significant functional impairment of activities of daily living.

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 (MCC) 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.

Cicatricial pemphigoid resistant to glucocorticoid and immunosuppressive therapy.

Evidence of probable benefit (Category 2a)

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.

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.

Management of these rare and severe bleeding disorders should be undertaken only by or in consultation with haemophilia treatment centres. When indicated, IVIg only forms part of the management of these complex patients, with additional haemostatic support required.

IVIg may be considered in the following circumstances:

1. Inhibitors to factor VIII (FVIII) in haemophilia A and inhibitors to factor IX (FIX) in haemophilia B, especially in cases where there has been failure of immune tolerisation and poor response to recombinant factor VIIa or factor eight inhibitor bypassing activity (FEIBA) — only as part of the Bonn–Malmö protocol for immune tolerance induction.
2. Autoimmune acquired von Willebrand syndrome — correction of FVIII and von Willebrand factor levels for the management of bleeding and before invasive procedures, except cases associated with IgM paraprotein where response is unlikely. Use is indicated in failure to respond to chemotherapy/ immunosuppressants or where there is insufficient time for chemotherapy/immunosuppressants to be given. Initial therapy either 0.4 g/kg for 5 days or 1 g/kg for 2 days. Continued therapy 1 g/kg once every 3–4 weeks.
3. Acquired haemophilia A for:
   1. Support of correction of FVIII level for the management of bleeding, and before invasive procedures in individuals in whom steroid or immunosuppressive therapy is contraindicated or has failed to eradicate the inhibitor (2 g/kg over 2–5 days); or
   2. Support of correction of FVIII level following failure of first line therapies (steroids and immunosuppressants) and poor response to recombinant factor VIIa or FEIBA when used as part of the Bonn–Malmö protocol.
4. Other acquired (autoimmune) coagulation inhibitors (e.g. acquired Factor V inhibitors) to correct factor level for the management of bleeding and before invasive procedures in cases where other therapeutic approaches have failed or are contraindicated (2 g/kg over 2 to 5 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.

Evidence of probable benefit (Category 2a)

Devic disease is an idiopathic inflammatory demyelinating disorder of the central nervous system characterised by recurrent bouts of optic neuritis and myelitis. It is distinct from multiple sclerosis and evidence of B-cell autoimmunity has been found. A circulatory antibody to aquaporin-4 is found in many patients providing further evidence of B-cell autoimmunity in its pathogenesis and suggestive of a role for IVIg therapy. Single case reports of various therapies, including IVIg, have shown variable benefit in this otherwise devastating disorder.

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 exceptional circumstances for intractable pain or progressive muscle weakness in patients in whom steroids are ineffective or cannot be tolerated. This condition is monophasic and usually self- limiting. A single treatment may be sufficient, although monthly infusions for up to six months may be required for recurrent pain.

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 should be considered for severe cases refractory to conventional immunosuppressive 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)

• Landau–Kleffner syndrome
• Lennox–Gastaut syndrome

IVIg should be considered in childhood cases only after failure of all conventional therapies and full assessment by a paediatric 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.

Evidence of probable benefit (Category 2a)

To reduce platelet destruction and improve haemolysis in patients no responding to corticosteroid therapy.

Small case studies only; insufficient data (Category 4a).

Evans syndrome is a rare but serious autoimmune disease defined by the simultaneous or sequential occurrence of autoimmune haemolytic anaemia (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.

1. Refractory to conventional therapy with corticosteroids;

OR

2. Where corticosteroids are contraindicated;

OR

3. As a temporising measure before splenectomy.

Patients in whom a trial of corticosteroids has not been undertaken (providing corticosteroids are not contra- indicated and can be tolerated at the required doses).

• 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.

Prevention or treatment of foetal or neonatal thrombocytopenia or haemorrhage.

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

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.

IVIg may be indicated in select cases. Tagami et al, Endocrinology 43:6, 689-99 have shown that IVIg is effective in this condition. Other studies have shown IVIg to be as effective as corticosteroids with fewer side effects. May be indicated where steroids have failed or are contraindicated.

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)

Clear evidence of benefit (Category 1)

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.

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:

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