Prescribing intravenous immunoglobulin: summary of Department of Health guidelines
BMJ 2008; 337 doi: https://doi.org/10.1136/bmj.a1831 (Published 20 October 2008) Cite this as: BMJ 2008;337:a1831
- Drew Provan, consultant haematologist1,
- Helen M Chapel, consultant immunologist2,
- W A Carrock Sewell, consultant immunologist and visiting professor of immunology3,
- Denise O’Shaughnessy, senior medical adviser4
- on behalf of the UK Immunoglobulin Expert Working Group
- 1Department of Haematology, Barts and the London NHS Trust, The Royal London Hospital, London E1 2ES
- 2Nuffield Department of Medicine, University of Oxford, and Oxford Radcliffe Hospitals NHS Trust, Oxford OX3 9DU
- 3Scunthorpe General Hospital, North Lincolnshire and Goole NHS Trust, North Lincolnshire DN15 7BH
- 4Blood Policy Unit, Department of Health, London SE1 6LH
- Correspondence to: D Provan a.provan{at}virgin.net
- Accepted 9 August 2008
Why read this summary?
Therapeutic immunoglobulin, a preparation of normal human polyclonal immunoglobulin G derived from pooled human plasma, has become an important treatment option in a range of medical conditions beyond its use in immune deficiencies, particularly autoimmune and acute inflammatory diseases.1 For some time, concern has been expressed over the availability of immunoglobulin. Severe global supply shortages began in the late 1990s, when demand exceeded supply by up to 30%,2 and production problems specific to the United Kingdom have curtailed supply. This supply shortage has been compounded by increasing use in established indications3 and widespread off-label prescribing.4 To ensure that supply is maintained, even in times of acute shortage, for the patients considered to be the highest priority because of a risk to life without treatment, potential prescribers of immunoglobulin need help in identifying treatment indications for which its use is appropriate. This article summarises the most recent Department of Health guidelines on prescribing intravenous immunoglobulin, published in May 2008.5
Recommendations
Recommendations are based on systematic review of evidence based guidelines and Cochrane reviews, supplemented by expert opinion. The level of evidence for each indication is indicated as Ia, Ib, IIa, IIb, III, or IV; the grade of recommendation is given as A, B, C, or D. Our approach was adapted from the system used by the Agency for Healthcare Policy and Research (US Department of Health and Human Services).6
Recommendations are colour coded to reflect treatment prioritisation. Red indicates conditions for which treatment is considered the highest priority because of a risk to life without treatment, and blue indicates conditions for which, although the evidence base is reasonable, the priority is moderate because other treatments are available (see figure⇓). Box 1 lists those conditions for which the evidence base is weak (these are known as grey conditions). For all blue and grey conditions, immunoglobulin treatment should be considered on a case by case basis, prioritised against other competing demands for immunoglobulin, especially in times of shortage. Definitions of short and long term treatment are given in box 2. For potential alternative treatments, see the full guidance.5 Indications with evidence that immunoglobulin treatment may not be appropriate are listed in box 3.
Summary of recommendations for treatment with intravenous immunoglobulin in diseases for which the treatment prioritisation is high (red) or moderate (blue). The appropriateness of immunoglobulin treatment is denoted as yes (appropriate in all cases if the physician wants to prescribe it), selected (appropriate in only selected cases and in these, only if the physician wants to prescribe it); and no (not appropriate). See box 1 for those diseases for which the prioritisation is low because the evidence base is weak
Box 1 Conditions for which the treatment priority is low because the evidence base for treatment with intravenous immunoglobulin is weak
In many cases the evidence base is weak because the disease is rare. Rare diseases not listed below should be considered to be grey conditions, and immunoglobulin treatment should be considered on a case by case basis, prioritised against other competing demands.
Immunology
Secondary antibody deficiencies
Haematology
Acquired red cell aplasia not caused by parvovirus B19
Acquired von Willebrand’s disease
Aplastic anaemia or pancytopenia
Autoimmune neutropenia
Haemolytic uraemic syndrome
Post-exposure prophylaxis for viral infection if intramuscular injection is contraindicated or if hyperimmune immunoglobulins are not available
Post-transfusion hyperhaemolysis (usually in patients with sickle cell disease)
Systemic lupus erythematosus with secondary immunocytopenia
Haemato-oncology
Graft versus host disease after allogeneic bone marrow transplant or haematopoietic stem cell transplant
Infection after allogeneic bone marrow transplant or haematopoietic stem cell transplant
Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS)
Neurology
Acute disseminated encephalomyelitis
Acute idiopathic dysautonomia
Autoimmune diabetic proximal neuropathy
Bickerstaff’s brain stem encephalitis
Central nervous system vasculitis
Cerebral infarction with antiphospholipid antibodies
Intractable childhood epilepsy
Neuromyotonia
Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS)
Paraneoplastic disorders
Polymyositis
Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS)
Potassium channel antibody associated, non-neoplastic limbic encephalitis
Vasculitic neuropathy
Dermatology
Atopic dermatitis or eczema
Pyoderma gangrenosum
Urticaria
Paediatrics
Intractable childhood epilepsy
Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS)
Paediatric rheumatology
Juvenile systemic lupus erythematosus
Other systemic vasculitides
Systemic juvenile idiopathic arthritis
Adult rheumatology
Catastrophic antiphospholipid syndrome
Polymyositis
Systemic lupus erythematosus
Systemic lupus erythematosus with secondary immunocytopenia
Systemic vasculitides and antineutrophil cytoplasmic antibody disorders
Transplantation
Acute antibody mediated rejection after solid organ transplantation
Box 2 Definition of short and long term treatment
Short term treatment
This is defined as treatment in serious or potentially life threatening conditions and/or treatment that consists of a single course of treatment, which may comprise more than one dose, up to a maximum of three doses. A single dose is defined as the appropriate dosage (usually in g/kg) for the disease indication, which may be fractionated and delivered over one to five days.
Long term treatment
Long term treatment comprises one or more courses of immunoglobulin where further courses may be anticipated from the diagnosis before the start of treatment or be decided on after response to a single trial of the treatment.
Box 3 Indications for which immunoglobulin is not recommended,* by specialty
Immunology
Immunodeficiency secondary to paediatric HIV infection
Haemato-oncology
Autologous bone marrow transplant
Neurology
Adrenoleukodystrophy, Alzheimer’s disease, amyotrophic lateral sclerosis, autism, chronic fatigue syndrome, critical illness neuropathy, inclusion body myositis, multiple sclerosis
Rheumatology
Inclusion body myositis, rheumatoid arthritis
Infectious diseases
Neonatal sepsis (prevention or treatment), sepsis in the intensive care unit not related to specific toxins or Clostridium difficile
Other specialties
Asthma, autoimmune uveitis, Graves’ ophthalmopathy, failure of in vitro fertilisation, recurrent spontaneous pregnancy loss
*Described as “black” indications in the Demand Management Plan for Immunoglobulin Use7
Overcoming barriers
The biggest challenge is to change established prescribing patterns and encourage acceptance of the guideline recommendations. To engage prescribers in the guideline development process, the Department of Health launched a formal stakeholder review process involving royal colleges, medical societies, patient groups, and manufacturers of immunoglobulin. The review resulted in substantial changes to the guidelines and improvements in the terminology used in the recommendations.
The guidelines were formulated as part of a larger national demand management programme for immunoglobulin, sponsored by the Department of Health. This included a demand management plan for immunoglobulin use,7 which recommends that trusts or strategic health authorities establish a local immunoglobulin assessment panel to approve and monitor the local prescribing of immunoglobulin, and also a national immunoglobulin database. The database will monitor immunoglobulin use to allow accurate forecasting, facilitate appropriate demand management, and provide a more accurate picture of prescribing by indication at national and local level.
Further information on the guidance
Background
Global restrictions on the availability of immunoglobulin and problems specific to the United Kingdom have curtailed supply. These problems include the need for BPL, the major UK supplier of immunoglobulin, to source plasma from the United States because of the risk of variant Creutzfeldt-Jakob disease in the UK; the closure of a UK manufacturer (Scottish National Blood Transfusion Service); and acute shortages caused by unexpected withdrawals of batches of immunoglobulin for safety reasons.8
In 2006 the Department of Health appointed an immunoglobulin Expert Working Group to formulate the national demand management programme for immunoglobulin, with the objective of ensuring availability of immunoglobulin for all essential infusions, regardless of geographical location.8 As part of the programme, the Department of Health published the first edition of Clinical Guidelines for Immunoglobulin Use.9 The second edition was published in May 2008.5
To ensure availability of immunoglobulin for those most in need, the second edition now classifies immunoglobulin treatment indications according to the evidence base and treatment priority. The guidelines are not as prescriptive for indications for which there is little evidence of immunoglobulin efficacy (grey indications—cited in box 1 in this summary) as they are for indications for which there is evidence suggesting that immunoglobulin treatment is inappropriate (see box 3). The guideline recommends that prescribing of immunoglobulin by general practitioners ceases.
Methods
The Expert Working Group has a membership that includes specialist clinical users of therapeutic immunoglobulin, clinical and procurement pharmacists, and members of the Department of Health.5 The Guideline Development Group, which included experts from the four principal medical specialties that commonly prescribe immunoglobulin (immunology, neurology, haematology, and haemato-oncology),5 conducted a systematic literature review for high quality, single specialty, and single disease guidelines that provide recommendations based on systematic reviews of the literature, published evidence based guidelines for immunoglobulin, and relevant Cochrane reviews. These were supplemented by expert opinion.
This approach to guideline development is not as rigorous as undertaking an independent, systematic assessment of the clinical evidence base. The Guideline Development Group assessed the quality of included studies and offered a grade of evidence for each indication, based on an adaption of the system used by the Agency for Healthcare Policy and Research at the US Department of Health and Human Services.6 The guideline was opened to external review by registered stakeholders. The development group assessed the stakeholders’ comments, reanalysed the data, and, if appropriate, modified the guideline. The outcomes of the 2008 stakeholder review is available online (www.ivig.nhs.uk).
The guideline will be updated again in 2009, followed by biennial review. Information about the progress of the update and associated activities that form the broader national demand management programme for immunoglobulin can be found at the immunoglobulin website (www.ivig.nhs.uk).
Future research
Areas in which additional research is needed include the following:
Optimal dosing of immunoglobulin in primary immunodeficiency disorders
Optimal dosing of immunoglobulin and relative efficacy of rituximab in autoimmune haemolytic anaemia
Possible role of immunoglobulin in neonatal sepsis
Guillain-Barré syndrome: effectiveness and cost effectiveness of additional doses of immunoglobulin; efficacy in mild (ambulant) disease
Chronic inflammatory demyelinating polyradiculoneuropathy: efficacy and cost effectiveness of combination therapy with immunosuppressants; relative efficacy of subcutaneous immunoglobulin in patients who are dependent on immunoglobulin
Multifocal motor neuropathy: relative efficacy of rituximab; relative efficacy of immunosuppressants; relative efficacy of subcutaneous immunoglobulin in patients who are dependent on immunoglobulin
Efficacy of immunoglobulin in rare autoantibody mediated diseases—such as stiff person syndrome, limbic encephalitis
Efficacy of immunoglobulin for autoimmune diabetic proximal neuropathy; potassium channel antibody associated, non-neoplastic limbic encephalitis; Rasmussen syndrome
Efficacy of immunoglobulin as a steroid sparing agent in pemphigoid and epidermolysis bullosa acquisita; predictive factors for response to immunoglobulin in pemphigoid
Relative efficacy of rituximab in bullous skin diseases
Dermatomyositis: predictive factors for response to immunoglobulin
Role of immunoglobulin in severe sepsis in the general intensive care unit
Use of immunoglobulin in the management of severe C difficile colitis
Low versus high dose immunoglobulin in antibody incompatible transplantation
Notes
Cite this as: BMJ 2008;337:a1831
Footnotes
This is one of a series of BMJ summaries of new guidelines, which are based on the best available evidence; they highlight important recommendations for clinical practice, especially where uncertainty or controversy exists.
The authors acknowledge the contribution of Deloitte in coordinating the development process.
Contributors: DP and DO’S drafted the paper, with editorial help from Aidan McManus and Lucy Hyatt (MMRx Consulting). All authors contributed to its revision and the final draft. DP chaired the guideline development group, HMC chaired the demand management plan group, and WACS chaired the database development group.
Funding: The guidelines were commissioned and funded by the Department of Health.
Competing interests: All authors were members of the Department of Health’s IVIg Expert Working Group: guideline development group (DP, DO’S), demand management plan group (HMC, DO’S), and database development group (WACS, DO’S).
Provenance and peer reviewed: Not commissioned; not externally peer reviewed.