Oxford Handbook of Clinical Immunology and Allergy (3 edn)
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Introduction
The aim of this chapter is to give an overview of the very complex but exciting area of immunotherapy. Despite great advances in the basic science, the results of clinical immunotherapy have not been as good as had been hoped. Nonetheless, the advances in basic immunology continue to provide new avenues to explore.
Major mechanisms of immunomodulation
Immunization:
active
passive.
Replacement therapy:
immunoglobulin (IM, SC, IV)
C1-esterase inhibitor
α1-antitrypsin
plasma.
Immune stimulants:
drugs
cytokines.
Immune suppressants:
drugs
monoclonal antibodies
cytokines and antagonists
IVIg
antibody removal (plasmapheresis).
Desensitization:
bees and wasps
other allergens.
Anti-inflammatory agents:
NSAIDs
anti-cytokines (anti-TNF) IL-1ra
anti-complement mAbs
anti-endotoxin mAb
anti-T cell/anti-B cell mAbs.
Adoptive immunotherapy:
bone marrow transplantation
stem cell transplantation
?thymic transplants.
Passive immunization
Protection is provided by transfer of specific high-titre antibody from donor to recipient. The effect is transient (maximum protection 6 months). Protection is immediate (unlike active immunization).
Problems
Risk of transmission of viruses.
Serum sickness (including demyelination), acute reactions.
Development of antibodies against infused antibodies reduces effectiveness.
Identification of suitable donors (Lassa fever, rabies).
Types
Pooled specific human immunoglobulin.
Animal sera (antitoxins, antivenins).
?Monoclonal antibodies (anti-endotoxin).
Uses
Hepatitis A prophylaxis (but new vaccine provides active immunization and longer prophylaxis).
Hepatitis B (for needlestick injuries), tetanus, rabies, Lassa fever.
Botulism, VZV (especially during pregnancy and in the immunocompromised), diphtheria, snake bites (post-exposure).
Rhesus incompatibility (post-delivery anti-D).
Active immunization
The purposes of active immunization are as follows.
To stimulate the production of protective antibody (opsonization, complement fixation, enhanced phagocytosis, blocking uptake (virus neutralization)).
To stimulate antigen-specific T cells: whether these are Th1 or Th2 cells depends on the type of pathogen and the optimal protective response.
To produce long-lasting immunological memory (T and B cells).
Mediated by the retention of antigen on follicular dendritic cells in lymph nodes, leading to a long-term depot.
Hence antibody levels often persist years after the primary course of immunizations has been completed, rather than decaying to zero.
To produce ‘herd immunity’: the generation of a sufficiently large pool of immune individuals reduces the opportunity for wild-type disease to spread, increasing the effectiveness of the immunization programme:
immunization rates>75% are required to achieve this.
Active immunization can use:
purified component, e.g. toxin (inactivated = toxoid)
subcomponent
live attenuated pathogen (e.g. BCG, polio).
Active immunizationcan be combined with passive immunization (although this may reduce the development of long-term immunological memory).
This approach is used for tetanus and rabies as a strategy for treatment post-exposure.
Toxoid/subcomponent vaccines
Immune response frequently requires augmentation with adjuvants.
May be side effects from adjuvants.
No risk that disease will be produced.
Inactivation may damage key epitopes and reduce protection.
Safe to use in the immunocompromised but responses (and protection) unpredictable.
Attenuated vaccines
Usually more immunogenic and do not require adjuvants.
Risk of reversion to wild type (e.g. polio).
Side effects from culture contaminants (demyelination from duck embryo rabies).
May produce mild form of disease (measles, mumps).
Contraindicated in immunosuppressed (paralytic polio in antibody deficiency).
Unexpected viral contaminants (SV40, polio; hepatitis B, yellow fever).
General problems of active immunization
Active immunization has a number of problems, including the following.
Allergy to any component (e.g. residual egg protein, often in viral vaccines from the growth media).
Reduced/absent responses in immunocompromised (including splenectomy).
Delay in achieving protection (primary and secondary immune responses require multiple injection schedules).
Preferred route of administration (site of IM; SC, ID):
route of administration may determine the type of immune response
route to be relevant for the route of infection of the pathogen (e.g. need for mucosal immunity to enteric organisms).
Storage: most live vaccines require refrigerated storage to maintain potency; this may be a problem, especially in tropical countries.
Age at which a vaccine is administered may alter the response, e.g. responses to polysaccharide antigens are poor in:
children under the age of 24 months
the elderly.
Maternal antibody, passive immunization, concomitant medical illness, and associated drug therapy may reduce the response.
Ideally, responses should be checked serologically in patients where there may be a poor response.
Serological unresponsiveness does not preclude good T-cell immunity (hepatitis B).
Anti-self-immune response to immunization (e.g. autoimmunity after meningococcus group B polysaccharide administration).
Multiple immunogenic strains of target organism (e.g. Meningococcus, Pneumococcus).
Additional stimulation of the immune system
Poorly immunogenic antigens can be used if combined with agents that non-specifically increase immune responses (‘adjuvants’). Adjuvants mimic PAMPs (pathogen association molecular patterns), increase the innate immune response via TLR, and augment the activity of dendritic cells macrophages and lymphocytes.
Adjuvants.
‘Depot’ of antigen (alum-precipitated; oil), squalene
Non-specific stimulation (Freund’s adjuvant, MDP). Freund’s adjuvant is too potent to be used in humans! However, it has been safely used in microlitre quantities.
Polymerization (liposomes, ISCOMs—Quil A).
dsDNA and ssDNA (which encourage endocytosis).
unmethylated CpG dinucleotides.
expression in vectors (e.g. use of vaccinia, chimeric viruses, BCG, Salmonella).
Virosomes (membrane-bound haemagglutinin and neuraminidase from influenza virus)—facilitates uptake into antigen-presenting cells.
Use of immunogenic carrier proteins conjugated to primary antigen:
tetanus toxoid
diphtheria toxoid.
Modern approaches to vaccine development
Development of more potent but safer vaccines is always the goal.
Molecular techniques have been used to modify pathogens by site-specific mutation, reducing pathogenicity, or inserting the gene into a carrier (vaccinia, Salmonella).
Development of the host response to the carrier organisms means that it can only be used once.
Molecular techniques allow the safe synthesis of bulk quantities of antigen (e.g. hepatitis B surface antigen).
Recombinant technique needs to be selected carefully to ensure appropriate post-translational glycosylation of the antigen.
Recombinant organisms can also be used to target antigens to particular cells. For example:
Salmonella is rapidly taken up by macrophages
inserted gene products will also be directed straight to antigen-presenting cells.
Conjugation of poorly immunogenic antigens (such as polysaccharides) to immunogenic proteins (tetanus, diphtheria toxoids).
Humoral immune response to the polysaccharide switches from IgG2 to IgG1 and IgG3.
Specific peptides are being used experimentally to try to stimulate specific T-cell responses.
Epitope mapping of antigens to determine the T- and B-cell epitopes is required.
Direct injection into muscle of nucleic acid (RNA, DNA) coding for specific genes, coupled to gold microsphere carriers or in plasmids, generates an immune response.
Nucleic acid is not degraded but is taken up into myocytes and specific protein production can be detected for several months thereafter, leading to an excellent depot preparation.
Concern over risk of bystander attack by the immune system on myocytes containing the injected DNA.
Generation of effective response
To generate an effective immune response, both host and pathogen factors need to be taken into account. Factors encouraging the development of an effective vaccine involve both infectious agent factors and host factors.
Infectious agent factors.
One or a small number of serotypes; little or no antigenic drift.
Pathogen is only moderately or poorly infectious.
Antigens for B- and T-cell epitopes are readily available.
The immune response can be induced readily at the site of natural infection.
Wild-type infection is known to produce protective immunity.
Availability of animal models to test vaccine strategies.
Host factors.
Humoral and cellular immunity is readily induced.
MHC background of population is favourable to a high response.
Proposed antigens induce appropriate Th1 or Th2 response.
Factors in the infectious agent that mitigate against an appropriate immunization response and therefore prevent the development of good vaccines include the following.
Marked antigenic variation/drift; many serotypes causing disease. This limits the ability to generate an effective vaccine (e.g. pneumococcal disease).
Potential for change in host range of the pathogen (e.g. change in cell tropism of viruses such as HIV).
Infection may be transmitted by infected cells that are not recognized by the immune system even after immunization.
Integration of viral DNA into the host genome (latency).
Natural infection does not induce protective immunity.
Pathogen uses ‘escape’ mechanisms:
resistant external coats (e.g. mycobacteria)
poorly immunogenic capsular polysaccharides
antigenic variation in response to host immune recognition (e.g. influenza virus, malaria)
camouflage with host proteins (e.g. CMV and β2-microglobulin)
production of proteins similar to host proteins (e.g. enterobacteria) may give rise to autoimmunity
extracellular enzyme production to interfere with host defence (staphylococcal protein A)
production of molecules that disrupt immune responses (e.g. superantigens).
Pathogen-induced immunosuppression (HIV).
Failure to form appropriate response (e.g. complement-fixing antibodies).
No suitable animal model.
Host factors that mitigate against an appropriate immunization response and therefore prevent the development of good vaccines include the following.
Immune response is inappropriate, e.g. antibody when cellular response is required (e.g. leishmaniasis).
Immune response enhances infection, e.g. antibody formation may enhance infection through increased uptake into macrophages (yellow fever, ?HIV).
Cells of immune system are target of infection.
‘Wrong’ MHC background predisposes to low response or autoimmunity.
The ultimate goal of any immunization programme is the eradication of the disease. This requires that:
the infection is limited only to humans
there is no animal or environmental reservoir
absence of any subclinical or carrier state in humans
a high level of herd immunity can be established to prevent person-to-person spread:
this requires considerable infrastructural support to ensure that all at-risk populations are targeted for immunization
this has only been achieved for smallpox
however, herd immunity for smallpox has waned as immunization programmes have stopped; bioterrorism with smallpox is a significant threat.
‘Replacement’ therapy
This is used for treatment of primary and some secondary immune deficiencies (see Table 16.1).
| Type of deficiency | Replacement therapy |
|---|---|
Antibody deficiency | Immunoglobulin (IV, SC) |
α1-antitrypsin deficiency | α1-antitrypsin |
MBL deficiency | MBL (experimental—value uncertain) |
Complement deficiency | C1-esterase inhibitor |
Fresh frozen plasma (virally inactivated)? | |
Cellular immune deficiency | Bone marrow transplantation (stem cell transplant) |
Cord blood transplant | |
Thymic transplant | |
Combined immune deficiency (SCID) | Bone marrow transplantation (stem cell transplant) |
Cord blood transplant | |
Thymic transplant | |
Gene therapy (ADA) | |
Red cells (ADA) | |
PEGylated-ADA | |
Immunoglobulin (IV, SC) | |
Cytokines (IL-2, γ-IFN) | |
Phagocytic defects | Bone marrow transplantation (stem cell transplant) |
Cord blood transplant | |
Granulocyte transfusions | |
Cytokines (G-CSF, GM-CSF, IL-3) |
| Type of deficiency | Replacement therapy |
|---|---|
Antibody deficiency | Immunoglobulin (IV, SC) |
α1-antitrypsin deficiency | α1-antitrypsin |
MBL deficiency | MBL (experimental—value uncertain) |
Complement deficiency | C1-esterase inhibitor |
Fresh frozen plasma (virally inactivated)? | |
Cellular immune deficiency | Bone marrow transplantation (stem cell transplant) |
Cord blood transplant | |
Thymic transplant | |
Combined immune deficiency (SCID) | Bone marrow transplantation (stem cell transplant) |
Cord blood transplant | |
Thymic transplant | |
Gene therapy (ADA) | |
Red cells (ADA) | |
PEGylated-ADA | |
Immunoglobulin (IV, SC) | |
Cytokines (IL-2, γ-IFN) | |
Phagocytic defects | Bone marrow transplantation (stem cell transplant) |
Cord blood transplant | |
Granulocyte transfusions | |
Cytokines (G-CSF, GM-CSF, IL-3) |
Intravenous immunoglobulin (IVIg) for replacement therapy 1
Manufacture and specification
IVIg is a blood product prepared by cold ethanol precipitation of pooled plasma.
Donors are screened for transmissible infections (HIV, HCV, HBV).
UK plasma is not currently used (risk of prion disease); no test currently available to identify prion disease in donors.
Donated plasma is usually quarantined until donor next donates (avoids undetected infection at time of first donation).
Donor pool usually >1000 donors to ensure broad spectrum of antibody specificities.
Subsequent purification steps vary between different manufacturers but all are based on the original Cohn fractionation process.
The IgA content is variable.
Significant levels of IgA may be important when treating IgA-deficient patients, who may recognize the infused IgA as foreign and respond to it, leading to anaphylactoid responses on subsequent exposure.
It is uncertain how much of a problem this is, and there is no standardized method for detecting clinically significant anti-IgA antibodies.
All current UK products have low/undetectable IgA.
Product must have low levels of pre-kallikrein activator, Ig fragments, and aggregates as these three can cause adverse events on infusion.
Variations of IgG subclasses do not seem to make significant differences to the effectiveness as replacement therapy.
Comparing the presence of functional antibodies in individual products is difficult as there are no internationally standardized assays, but IVIg must have intact opsonic and complement-fixing function.
All licensed products must have at least two validated antiviral steps:
cold ethanol precipitation
pH4/pepsin
solvent/detergent treatment
pasteurization
nanofiltration.
Model viruses are used to demonstrate that the process is effective
No product should be viewed as virally ‘safe’.
Full counselling about risks and benefits must be given to patient, with written information, and this must be recorded in the medical notes.
Written consent must be obtained prior to therapy and retained in the medical notes.
A pre-treatment serum sample should be stored, to facilitate ‘look-back’ exercises if required
Liquid preparations are now preferred for ease of administration.
Most manufacturers are moving to 10% solutions, with more rapid infusion times. 20% solutions of SCIg are now available; standard SCIg is 16%.
IVIg/SCIg is stabilized with sugars (e.g. maltose) or proline.
Uses
IVIg (or SCIg—see ‘Intramuscular and subcutaneous immunoglobins for replacement therapy’, p.396) is mandatory for replacement in:
the major antibody deficiencies (XLA, CVID)
combined immunodeficiencies (pre- and immediately post-BMT).
IVIg is also recommended in patients with secondary hypogammaglobulinaemia, such as CLL and myeloma, post-chemotherapy etc. (see Chapter 2).
The role of IVIg in IgG subclass and specific antibody deficiency is less secure, and regular prophylactic antibiotics might be tried first, with IVIg reserved for continuing infection despite therapy (assess risk–benefit).
Where there is doubt, a 1-year trial is reasonable, with monitoring of clinical effectiveness through the use of symptom diaries.
To ensure a realistic trial, adequate dosing and frequency of infusions must be undertaken to ensure that benefit will be obvious.
Dose regime
Treatment should provide 0.2–0.6g/kg/month given every 2–3 weeks for primary antibody deficiency, or as an adjunct in combined immunodeficiency.
Older patients with CLL may manage on monthly infusions.
Most patients on monthly schedules become non-specifically unwell or develop breakthrough infections after 2–3 weeks.
Under these circumstances the interval should be shortened.
Rare hypercatabolic patients, or those with urinary or gastrointestinal loss, may require weekly infusions of large doses to maintain levels.
Adjust dose according to the trough IgG level, aiming to achieve a trough IgG level within the normal range (6–16g/L).
Aim for higher trough in patients with established bronchiectasis or chronic sinusitis (target trough 9g/L), as this will reduce lung damage.
Breakthrough infections are an indication to reassess interval and target trough level.
IVIg for replacement therapy 2: adverse reactions and risks of infection
Adverse reactions
Most adverse reactions are determined by the speed of infusion and the presence of underlying infection.
Untreated patients receiving their first infusions are at most risk.
Reactions are typical immune complex reactions:
headache
myalgia
arthralgia
fever
bronchospasm
hypotension
collapse
chest pain.
Pre-treatment of the patient with antibiotics for 1 week prior to the first infusion reduces antigenic load and reaction risk.
Hydrocortisone (100–200mg IV) and an oral antihistamine (cetirizine, fexofenadine) given before the infusion are also of benefit.
The first infusion should be given at no more than two-thirds of the manufacturer’s recommended rate.
Start slowly and increase rate in steps every 15 minutes.
Similar precautions may be required before the second infusion.
Reactions may occur in established recipients if:
there is intercurrent infection
there is a batch or product change.
Other adverse events include:
urticaria
eczematous reactions
delayed headache and fatigue (responds to antihistamines!)
medical problems from transferred antibodies (e.g. ANCA—uveitis).
Aseptic meningitis—usually seen with hdIVIg, but occasionally with replacement doses.
Products should only be changed for clinical not financial reasons.
Severe anaphylactoid reactions have been reported after switching products.
IVIg products are not interchangeable.
Risk of infection
Infection remains a major concern:
hepatitis B is no longer an issue
there have been a significant number of outbreaks of hepatitis C
other hepatitis viruses (HGV) may cause problems
no risk of HIV transmission, as the process rapidly destroys the virus
safety in respect of prion disease is not known, but risk will be cumulative with continuing exposure
Antiviral steps reduce but do not eliminate risk.
Batch exposure needs to be kept to a minimum.
Batch records must be kept to facilitate tracing recipients.
IVIg for replacement therapy 3: monitoring and home therapy
Monitoring
Check HCV PCR and baseline LFTs pre-treatment.
Store pre-treatment serum long-term.
Monitor trough IgG levels on all patients regularly (alternate infusions).
Monitor liver function (alternate infusions, minimum every 3–4 months)—transmissible hepatitis.
Repeat HCV PCR if any unexplained change in LFTs.
Monitor CRP—evidence of infection control.
▶ Record batch numbers of all IVIg administered.
Use symptom diaries in appropriate patients to monitor infective symptoms, antibiotic use, and time off work/school.
In the event of a significant adverse reaction:
immediate blood sampling for evidence of elevated mast-cell tryptase, complement activation (C3, C4)
send sample for anti-IgA antibodies (if IgA deficient)
screen for infection (CRP, cultures).
Rare antibody-deficient patients seem to react persistently to IVIgs; changing to a different product may sometimes assist. Occasionally continued prophylactic antihistamines, paracetamol, or even steroids may be required before each infusion to ensure compliance with therapy.
Home therapy
For patients with primary immunodeficiencies, home treatment is a well-established alternative to hospital therapy.
Criteria for entry to home therapy programmes are laid down in approved guidelines (see Table 16.2).
Specific centres in the UK are recognized as being able to provide appropriate training.
Patients should not be sent home on IVIg without formal training and certification by an approved centre.
The centres will also arrange for long-term support, with trained home therapy nurses and support from community pharmacy suppliers.
UK Primary Immunodeficiency Network (www.ukpin.org.uk) can provide details of approved centres in the UK. The International Patient Organization for Primary Immunodeficiencies (IPOPI) can provide details of overseas contacts.
Home therapy is not available in all countries for legal and/or financial reasons.
| Criteria for home therapy | Comments |
|---|---|
4–6 months hospital therapy | Must be reaction-free |
Must have good venous access (IVIg) | Consider SCIg if venous access poor |
Patient must be motivated | |
Patient must have a trainable long-term partner | Infusions must never be given alone |
Patient must have access to telephone at site where infusions will be given | To call for assistance if problems |
GP must be supportive | Rare for GP to be called |
Patient must accept regular follow-up at Training Centre | Annual supervised infusions are advisable |
Patient must agree to keep infusion logs with batch records | Essential for dealing with batch recalls, look-back exercises |
Patient and partner must complete training programme, with written assessment | Training manual must be provided |
| Criteria for home therapy | Comments |
|---|---|
4–6 months hospital therapy | Must be reaction-free |
Must have good venous access (IVIg) | Consider SCIg if venous access poor |
Patient must be motivated | |
Patient must have a trainable long-term partner | Infusions must never be given alone |
Patient must have access to telephone at site where infusions will be given | To call for assistance if problems |
GP must be supportive | Rare for GP to be called |
Patient must accept regular follow-up at Training Centre | Annual supervised infusions are advisable |
Patient must agree to keep infusion logs with batch records | Essential for dealing with batch recalls, look-back exercises |
Patient and partner must complete training programme, with written assessment | Training manual must be provided |
Intramuscular and subcutaneous immunoglobulins for replacement therapy
Intramuscular immunoglobulin (IMIg)
There is no role for IMIg in replacement therapy. Administered doses are too low to be effective in preventing infection. However, occasional older patients prefer the convenience of a weekly injection at their GP’s surgery to hospital-based infusions. IMIg has been associated with an adverse reaction rate of 20%.
Subcutaneous immunoglobulin (SCIg)
For those with poor venous access, high-dose SCIg replacement is at least equivalent to IVIg in terms of maintaining adequate trough IgG levels and preventing infection.
16% solution of immunoglobulin is used; 20% solution now also available.
Specific licensed SCIg preparations are now available from several manufacturers.
It is administered via a syringe driver in a weekly dose of 100mg/kg at multiple sites.
One or two infusion pumps may be used, depending on type and availability.
Rate is usually set to the maximum; some pumps use restrictors on the giving sets.
Usual maximum tolerated dose is 10mL per site; products with enzymes to aid dispersal are being developed and may allow larger doses to be given at single sites.
Tolerability is reasonable, with local irritation being the only significant side effect.
Home therapy can be undertaken (for guidance, see ‘IVIg for replacement therapy 3’, p.395).
Regular trips to hospital or GP will be required for trough IgG and LFT and CRP monitoring.
Trough levels tend to run approximately 1g/L higher than the same dose given as IVIg on a 2–3-weekly cycle.
Syringe drivers must be checked at least annually by a qualified medical electronics technician.
C1-esterase inhibitor for replacement therapy
Deficiency of C1-esterase inhibitor causes episodic angioedema, which may be fatal if it involves the upper airway (see Chapter 1).
Purified C1 inhibitor is available in the UK as Berinert®, Cinryze®, and Ruconest®.
These are blood-derived products and carry the same risks as IVIg with respect to tranmissible infections.
Products undergo viral inactivation steps (steam treatment).
Patients should have samples checked for LFTs and HCV status prior to each course of treatment.
Appropriate consent should be obtained if possible.
Batch numbers must be recorded.
Indications for treatment include:
attacks above the shoulders
surgical prophylaxis (including major dental work).
Weekly administration has been used in pregnancy where there are frequent severe attacks.
It is less effective against bowel oedema, but if pain is severe one dose should be given.
Attacks involving the bowel should be treated with fluids, analgesics, and NSAIDs.
Surgery should be avoided unless there is good evidence for pathology unrelated to HAE.
Dose is 500–1500U (1–3 ampoules) administered as a slow bolus IV.
Manufacturer’s information and guidelines suggest that the higher dose is required, but this is not always true.
Levels of C1-esterase inhibitor level in the serum should rise to >50% for several days.
Same dose is used for prophylaxis.
When used as treatment, it will prevent attacks progressing, but will not lead to a dramatic resolution of symptoms. Accordingly, laryngeal oedema may require other measures, such as tracheostomy, as urgent procedures.
Recombinant C1-esterase inhibitor, produced in rabbit milk (Rhucin®), is now available; known allergy to rabbits precludes treatment because of a risk of anaphylaxis. Recipients must be screened annually for the development of anti-rabbit IgE antibodies. It has a short half-life compared with Berinert® and therefore is only suitable for acute treatment.
Purified-blood-derived nanofiltered C1 esterase inhibitor, Cinryze®, is also now licensed, As it is blood derived, unlike Rhucin®, normal precautions relating to the use of blood products should be observed, as for Berinert®.
Plasma can be used if the purified concentrate is unavailable, but is less effective and may even increase the oedema by providing fresh substrate for the complement and kinin cascades.
Pooled virally inactivated fresh frozen plasma is now available, and may carry a reduced risk of infection, although this is debated.
On the whole, plasma should be avoided unless there is no alternative in the emergency situation.
Other immunotherapies for hereditary angioedema (HAE)
Other therapies for the acute treatment of HAE, which avoid the use of blood-derived and recombinant C1 esterase inhibitor, are now available.
Icatibant (Firazyr®) is a bradykinin B2 receptor blocking drug, which is effective at reducing the symptoms of acute attacks of HAE.
It is administered as a subcutaneous injection of 30mg (repeated once if necessary after 6 hours).
It is now licensed for self-administration at home in the UK, and there is a home support programme in place.
It has a short half-life and therefore is not suitable for prophylaxis for surgery.
Injections can be painful and may limit uptake.
Ecallantide (Dy88) is an inhibitor of plasma kallikrein and is licensed in the USA but not Europe for treatment of acute attacks.
The main concern is the risk of anaphylaxis from the drug (not good in patients with angioedema!!).
α1-Antitrypsin (α1-AT) for replacement therapy
α1-AT deficiency leads to progressive emphysema and liver disease. Purified α1-AT is now available on a named-patient basis. Trials have not been that encouraging, but this is because late-stage patients with established disease have been involved. No good prophylactic trials have been undertaken in asymptomatic patients, so it is not yet known how effective the drug is in preventing complications. Supplementation may also be useful during acute infections when high local levels of trypsin are released by activated neutrophils. Infusions need to be given at least weekly to maintain enzyme activity.
Mannan binding lectin (MBL) for replacement therapy
Trials of MBL replacement therapy in deficient patients have not shown any significant clinical benefit.
Immune stimulation
Specific immunostimulation
Non-specific immunostimulation
A number of agents which act as non-specific immune stimulators and have significant clinical benefit are now available.
Specialist literature should be consulted for current dose regimes.
BCG
Direct stimulant of immune system; activates macrophages.
Only found to be of value in bladder cancer.
As it is a live agent, it should not be administered to those with concomitant immunosuppression (lymphoid malignancy, drug-induced).
Derivative of cell wall muramyl dipeptide (MDP) licensed in Japan to enhance bone marrow recovery after chemotherapy.
Other bacterial products (extracts of Corynebacterium) are under investigation as immunostimulants.
Cimetidine
Known to have immunoregulatory properties, not related to anti-H2 activity, as actions do not appear to be shared with other anti-H2 drugs such as ranitidine.
Thought to reduce T-suppressor activity.
Has been used with success in the hyper-IgE syndrome to reduce IgE and in CVID to increase IgG production.
Glatiramer (copaxone)
An immunostimulatory drug, comprising synthetic peptides, which is administered by injection.
Used in the treatment of relapsing and remitting multiple sclerosis.
Side effects include chest pain, allergic reactions, and lymphadenopathy.
G-CSF/GM-CSF
Act on bone marrow precursors to increase production of mature neutrophils.
Used as adjuncts to chemotherapy to prevent or reduce neutropenic sepsis.
Used to mobilize stem cells for apheresis.
Used to treat congenital neutrophil disorders: Kostman’s syndrome, cyclic neutropenia, idiopathic neutropenia.
PEGylated form of G-CSF available to increase duration of action.
May increase the risk of myeloid malignancy.
Do not use in Kostman’s syndrome where there are cytogenetic abnormalities, as risk of malignant transformation is increased.
Bone pain may be a side effect.
Interleukin-2 (Aldesleukin)
Licensed for use in metastatic renal cell carcinoma.
Can produce tumour shrinkage, but no increase in survival.
IV administration is associated with a severe capillary leak syndrome.
Rarely used.
α-interferon
Main use now is in treatment of hepatitis C, in combination with ribavirin.
PEGylated interferon is available to increase duration of action.
Also valuable in carcinoid tumours, hairy cell leukaemia and lymphomas, myeloma, melanoma, and hepatitis B.
Side effects can be severe and include severe flu-like symptoms and a severe depressive state (suicide may be provoked). Patients with a history of depression should not receive α-IFN.
Dose is determined by the condition treated.
β-interferon
Used in the treatment of relapsing and remitting multiple sclerosis (although support from NICE has been equivocal at best).
Side effects similar to those of α-interferon but may also cause humoral immune abnormalities. Monitoring of serum immunoglobulins pre- and post-treatment is recommended.
γ-interferon (Immukin®)
γ-IFN-1b is used as adjunctive therapy in patients with chronic granulomatous disease for prevention and treatment of infections.
It can also be used to increase response rate to HBV vaccination in poor responders.
Side effects include severe flu-like symptoms.
Dose is usually 50–100μg/m2 three times a week.
Levamisole
Originally introduced as an anti-parasitic drug.
Found to increase circulating T cells, activate macrophages, and enhance DTH reactions.
Used in RhA and as an adjuvant in colonic cancer (FDA approved).
May cause agranulocytosis (in HLA B27+ patients).
Immunosuppressive/immunomodulatory drugs: corticosteroids
These drugs are based on endogenous products of the adrenal cortex and form the mainstay of immunosuppressive therapy; synthetic compounds are more potent. Natural steroids are highly plasma bound (corticosteroid-binding globulin, albumin). Actions of corticosteroids are manifold.
Actions
Transiently increased neutrophils (decreased margination and release of mature neutrophils from marrow).
Decreased phagocytosis and release of enzymes (lysosomal stabilization).
Marked monocytopenia and reduced monokine (IL-1) production.
Alteration of cellular gene expression (high-affinity cytoplasmic receptor translocated to nucleus) via nFκB inhibition through increased cytoplasmic concentrations of IκBa.
Release of lipomodulin (inhibits phospholipase A2 with reduction of arachidonic acid metabolites).
Lymphopenia due to sequestration in lymphoid tissue and interference with recirculation (CD4+ T cells > CD8+ T cells > B cells) and lymphocytotoxic effects (high doses).
Decreased T-cell proliferative responses (inhibit entry into G1 phase).
Reduced serum IgG and IgA.
No effect on NK or antibody-dependent cell-mediated cytotoxicity (ADCC) activity.
Side effects
Carbohydrate metabolism: poor cellular glucose uptake, increased hepatic gluconeogenesis, and glycogen deposition.
Increased lipolysis and free fatty acid (FFA); increased selective fat deposition.
Inhibit protein synthesis and enhance protein catabolism.
Increase glomerular filtration rate (GFR) and sodium retention; decrease calcium absorption, inhibit osteoblasts.
Clinical side effects are multitudinous:
diabetes
hyperlipidaemia
obesity
poor wound healing
growth arrest (children)
myopathy
hypertension
purpura and skin thinning
cataracts
glaucoma
peptic ulcer
allergy (synthetic steroids)
avascular necrosis
psychiatric complications
thrush.
Patients on medium- to long-term treatment require regular checks of blood pressure, blood sugar, and bone mineral density.
Prophylactic therapy against bone loss is highly desirable, especially in females and all older patients.
Optimal therapy is yet to be determined but includes hormone replacement therapy (HRT), if not contraindicated by underlying disease, vitamin D and calcium, or oral bisphosphonate.
Doses of over 20mg/day for long periods may increase the risk of opportunist infection with Pneumocystis carinii; therefore consideration should be given to the use of low-dose co-trimoxazole.
Uses
Autoimmune diseases (e.g. SLE, vasculitis, rheumatoid arthritis).
Polymyalgia rheumatica, giant-cell arthritis.
Allergic diseases (asthma, hay fever).
Inflammatory diseases (Crohn’s disease).
Malignant disease (lymphoma).
Allograft rejection.
Other immunological diseases (ITP, glomerulonephritis).
Dosage regimes
Variable according to the disease being treated, and up-to-date literature should always be consulted.
Prednisolone is the stock drug. Other steroids have little advantage but the British National Formulary has equivalency tables.
Enteric-coated tablets are kinder to patients, but may lead to erratic absorption.
If plain steroids are used, gastroprotection with either an H2-antagonist or a proton pump inhibitor is most effective in preventing ulceration.
Low-dose steroids for RhA (prednisolone 7.5mg/day) have been used. Most patients are now on methotrexate or anti-TNF agents.
Higher doses (up to 30mg/day) are required for SLE (larger doses for cerebral lupus).
Life-threatening immunological disease requires much higher doses: 1–2mg/kg orally or IV.
Various pulsed regimes using IV methylprednisolone have been advocated, especially in acute vasculitis. The evidence is split over their effectiveness: 10mg/kg is advocated, pulsed at varying intervals, often in combination with IV cytotoxics.
Topical steroids with limited absorption are invaluable in controlling local allergic symptoms (asthma, hay fever).
Where patients who have been on long-term steroids are being tapered, they will remain adrenally suppressed for up to 6 months after cessation of therapy and therefore should have steroid cover for illnesses, operations, etc. Patients should carry warning cards.
Immunosuppressive/immunomodulatory cytotoxic drugs: azathioprine
Azathioprine is converted in vivo to 6-mercaptopurine and acts to inhibit the synthesis of inosinic acid (precursor of purines), thus inhibiting DNA synthesis and reducing cell replication.
Actions
Preferentially inhibits T-cell activation rather than B-cell activation.
Reduces the circulation of large ‘activated’ lymphocytes, but has little effect on small resting lymphocytes.
Long-term use causes significant lymphopenia (T and B cells).
Hypogammaglobulinaemia, due to inhibition of B-cell proliferation (less or no effect on T-cell proliferation).
Suppression of monokine production.
Side effects
Causes profound bone marrow suppression. This is related to deficiency alleles of the enzyme thiopurine methyltransferase (TPMT) involved in its metabolism.
Screening for enzyme levels is widely available.
Toxic hepatitis (?related to TPMT deficiency).
Opportunist infections (including HSV, papillomaviruses).
mnosuppressive/immunomodulatory cytotoxic drugs
Gastric upset (probably unrelated to TPMT deficiency).
Teratogenicity.
?Malignancy (lymphoma).
PUO syndrome (hypersensitivity).
Uses
Autoimmune diseases (SLE, rheumatoid arthritis, vasculitis, liver disease, myasthenia, inflammatory bowel disease).
As a steroid-sparing agent.
Dosage
In view of the potential for severe/fatal side effects, azathioprine must be introduced carefully.
Initial dose should not exceed 1mg/kg and the patient should receive weekly FBCs with a differential white count for the first month of therapy.
If there is any drop in platelets or white cells, it is unsafe to continue with therapy.
Deficiency alleles for TPMT are present in 1 in 300 of the population; pre-treatment screening is helpful.
If it is tolerated, the dose can be increased to 2.5mg/kg (or in special circumstances to 4mg/kg).
The need for continuing therapy needs to be reviewed regularly.
Hypogammaglobulinaemia may be severe and require replacement therapy, although recovery may eventually occur over several years.
Liver function tests must also be monitored.
Allopurinol is contraindicated with azathioprine as it interferes with elimination and raises blood levels.
Immunosuppressive/immunomodulatory cytotoxic drugs: cyclophosphamide and chlorambucil (alkylating agents)
These drugs bind to and cross-link DNA, and possibly also RNA, thus interfering with DNA replication and transcription. Effects depend on the phase of the cell cycle during exposure and the competence of the DNA repair mechanisms.
Actions
Dose-dependent lymphopenia (T (CD8 > CD4) and B cells).
Reduced B-cell proliferation and antibody synthesis (reduced IgG and IgM).
Lesser effect on T cells (CD8 >> CD4, which may actually enhance T-cell responsiveness under certain circumstances).
Side effects
Bone marrow depression.
Alopecia.
Haemorrhagic cystitis (caused by acrolein)—ensure good hydration and use mesna for doses >200mg/kg. May be less risk with pulsed IV therapy.
Sterility (males and females—offer males sperm banking, warn all patients of reproductive age, and record in notes).
Secondary lymphoid neoplasms (especially NHL (11-fold increase), bladder tumours (10% long-term), skin tumours (fivefold increase), and acute myeloblastic leukaemia).
Opportunist infections (use co-trimoxazole and antifungal prophylaxis).
Nausea and vomiting (high dose).
Major uses
Vasculitis, especially Wegener’s granulomatosis, PAN, MPA, CSS.
SLE and RhA.
Glomerulonephritis (including Goodpasture’s syndrome).
Dosage
There is considerable debate over the optimal regimes for use of cyclophosphamide.
Continuous low-dose oral cyclophosphamide (2–4mg/kg/day).
Intravenous pulse therapy (10mg/kg/pulse or 0.75–1g/m2 body surface area; intervals determined by protocol and blood counts).
Long-term side effects may be higher with continuous oral therapy, but this may reflect the higher total dose, and lower doses may be effective.
In life-threatening conditions, high-dose IV pulses, with IV steroids, will have a faster effect (remember mesna cover and IV fluids).
Chlorambucil is used orally in doses of 0.03–0.06mg/kg/day and is less toxic to the bladder than cyclophosphamide, but is probably equally toxic to bone marrow in therapeutic doses.
Dosages of both drugs will require adjustment in renal impairment. Regular blood counts are required, according to current local protocols.
Immunosuppressive/immunomodulatory cytotoxic drugs: methotrexate (MTX)
Methotrexate is a competitive inhibitor of the enzyme dihydrofolate reductase and impairs synthesis of tetrahydrofolate from folic acid (required as cofactor for thymidine synthesis). Therefore it interferes with DNA synthesis. It is also thought to interfere with other intracellular enzymes. As an immunosuppressive agent it is used in low weekly doses (much lower than the doses used as an anti-neoplastic agent). Low-dose MTX probable inhibits the enzyme 5-amino-imidazole-4-carboxamide ribonucleotide (AICAR) transformylase, leading to the accumulation of AICAR and increased adenosine.
Actions
Variable effects on lymphocyte numbers in peripheral blood.
Possible inhibition of monokine production.
Inhibition of lipo-oxygenase pathway.
Reduction in antibody synthesis.
Converted to methotrexate polyglutamates, which persist long term intracellularly and are potent inhibitors of AICAR tranformylase and dihydrofolate reductase.
Side effects
Mucositis, nausea, and vomiting.
Bone marrow suppression (megaloblastic—may be reversed by folinic acid rescue); may be worse if other anti-folate drugs are co-administered (e.g. sulfasalazine, co-trimoxazole).
Hepatic fibrosis (dose-related).
Pneumonitis (5% of patients), a hypersensitivity reaction.
Sterility.
Uses
RhA; psoriatic arthropathy.
Polymyositis/dermatomyositis.
GvHD in BMT.
Adjunctive therapy with infliximab (see ‘Immunosuppressive/immunomodulatory biologicals: anti-TNF agents’, p.416).
Dosage
The drug is given weekly either orally or IM.
Initial dose is 7.5mg (adult), increased stepwise depending upon side effects and clinical benefit to a maximum of 20–30mg/week.
Dose may need reducing in renal impairment.
Care needs to be taken with co-administration of other drugs.
Folinic acid may reduce risk of bone marrow toxicity and mucositis (given 24–36 hours later). Folic acid will not be effective as MTX inhibits its conversion to the active form.
The most frequent cause of side effects, including death, is the inadvertent daily administration of the drug—always check carefully. Do not rely on pharmacy systems to spot errors.
Baseline tests should include FBC, LFTs, CXR, and lung function.
Monitor weekly (initially) pre-dose FBCs and regular LFTs.
If abnormal LFTs are noted, the drug dose should be reduced or the drug stopped.
It is thought that the risks of monitoring for liver disease by biopsy outweigh any benefit.
Development of pneumonitis is an absolute indication for withdrawing the drug; high-dose steroids may be required.
Immunosuppressive/immunomodulatory cytotoxic drugs: 2-chlorodeoxyadenosine (2CDA, cladribine) and fludarabine
Mode of action is by inhibition of adenosine deaminase, i.e. effectively producing ADA-deficient severe combined immunodeficiency.
Primary use is in the treatment of haematological malignancy (B-cell tumours) but, with careful use, they have the potential to be potent immunosuppressive agents.
Both produce a profound and long-lasting B-cell and CD4+ T-cell lymphopenia.
Prophylactic antibiotics (co-trimoxazole) and antifungals are advisable.
Long-term monitoring of lymphocyte surface markers and serum immunoglobulins is advisable after treatment.
Immunosuppressive/immunomodulatory drugs: ciclosporin (CyA)/tacrolimus (FK506)/sirolimus (rapamycin)
These three agents are macrolide antibiotics derived from fungi. They act specifically on T-helper cells, but leave other cell types unaffected. Target cells are inhibited but not killed (therefore effects are fully reversible on cessation of treatment).
Modes of action
Ciclosporin (CyA) interacts with cyclophilin, a 17kDa protein (peptidyl-prolyl cis–trans isomerase), and tacrolimus interacts with FK-BP12, a 12kDa protein similar to cyclophilin.
The complex prevents calcineurin, a calcium- and calmodulin-dependent protein, from dephosphorylating the nuclear factor of activated T cells (NF-AT), reducing transcription of the IL-2 gene.
Immunosuppressive activity is not directly related to this activity.
CyA and tacrolimus inhibit IL-2 and IL-2Ra gene expression and prevent T-cell activation (cells arrested at G0/G1).
Sirolimus has no effect on IL-2 production; it binds FK-BP, but the complex does not inhibit calcineurin. It appears to block calcium-independent signalling (via CD28) and inhibits mTOR.
May interfere with macrophage function (lymphokine release and receptor synthesis).
CyA interferes with B-cell proliferation and antibody production.
Side effects
Hypertension.
Hirsutism.
Nephrotoxicity.
Hepatotoxicity.
Lymphomas (NHL—85% EBV+).
Opportunist infections (CMV, papillomaviruses, HHV-8).
Neurotoxicity.
Multiple drug interactions (CyA and tacrolimus induce cytochrome P450(IIEI)).
Diabetes (inhibition of insulin release).
Headache.
Uses
Combination therapy for allografts.
RhA, SLE.
Autoimmune diseases (uveitis, Behçet’s syndrome, inflammatory bowel disease).
Dosage
CyA and tacrolimus are available orally and intravenously.
Dosage for CyA depends on the circumstances, but 10–15mg/kg/day may be required for allograft rejection, while 5mg/kg may suffice for autoimmune disease.
Tacrolimus dosage is 0.1–0.3mg/kg/day for allograft rejection. Experience of this drug is less in autoimmune disease, but doses up to 0.1mg/kg/day in divided doses appear to be effective.
Monitoring of drug levels is desirable for both drugs; this can prevent toxicity and monitor compliance.
Sirolimus dosage is 6mg as a stat dose followed by 2mg daily, with drug monitoring and appropriate dosage changes, in allografts. Dosages for use in autoimmune disease are not defined.
Because it operates on different activation pathways it may make a useful combination treatment.
Creatinine and electrolytes, liver function, and blood pressure should be monitored regularly.
Now that generic versions are available it is essential that the brand is specified, especially in the transplant setting, as the bioavailability of the different products is NOT the same. Transplanted organs have been lost because of inadvertent product switches.
Immunosuppressive/immunomodulatory drugs: mycophenolate mofetil (MMF)
Mycophenolate mofetil (MMF; CellCept®)
This drug is a prodrug of mycophenolic acid. Its actions are similar to those of azathioprine and it can be used as a replacement. It is usually well tolerated. Mycophenolic acid (Myfortic®) can be used as an alternative and may be tolerated where MMF is not.
Actions
Blocks inosine monophosphate dehydrogenase and synthesis of guanine, but has no effect on salvage pathway.
It acts predominantly on lymphocytes to prevent proliferation, but has little effect on non-lymphoid cells.
Side effects
Lymphopenia.
Opportunist infections (CMV, HSV), PML.
Lymphoma.
Hepatotoxicity, pancreatitis.
Electrolyte disturbance (hyperkalaemia, hypomagnesemia, hypocalcaemia).
Breathing problems and pleural effusions; pulmonary fibrosis.
Uses
Prophylaxis of allograft rejection
Autoimmune disease: SLE nephritis, uveitis.
Dosage
Dosage is 1g twice daily, increased to maximum of 1.5g twice daily.
It is also available for intravenous infusion.
Myfortic® is given in a dose of 720mg twice daily (equivalent to MMF 1g twice daily).
FBC and LFTs should be monitored regularly.
Immunosuppressive/immunomodulatory drugs: leflunomide
After oral administration leflunomide is converted to an active metabolite that inhibits dihydro-orotate dehydrogenase (involved in pyrimidine synthesis and required by T cells).
T-cell proliferation is blocked.
Used in RhA: as effective as methotrexate.
Onset of action is slow (4–6 weeks).
Side effects include severe hepatotoxicity and Stevens–Johnson syndrome.
Drug can be ‘washed-out’ with colestyramine or activated charcoal (binds it in the gut).
It is teratogenic: effective contraception is required.
Dose is 100mg daily for 3 days, and then 10–20mg daily.
Monitoring with regular FBC and LFTs mandatory.
Immunosuppressive/immunomodulatory drugs: d-penicillamine and gold
d-penicillamine
This enigmatic drug comes and goes in terms of its utility as an immunomodulator.
Precise immunological actions are not known.
It decreases antibody production.
It inhibits T-cell proliferation, possibly through enhanced hydrogen peroxide production or sulphydrylation of the surface receptors of the lymphocytes.
Neutrophil chemotaxis and oxidative function are impaired.
Macrophage antigen-presenting function and monokine production are reduced.
Also believed to inhibit collagen synthesis; hence its use in scleroderma.
Very slow in its onset of action.
Main side effects include a range of autoimmune diseases, including myasthenia gravis, renal disease (nephrotic), SLE, polymyositis, and Goodpasture’s syndrome.
Mainly used in RhA and scleroderma, but has fallen out of favour because of side effects.
Dosage is 250mg daily increased to 1g daily.
Regular monitoring (every 1–2 weeks initially) of renal function, urinalysis, and FBC required.
Penicillin-allergic patients may be at increased risk of reacting to penicillamine.
Gold
Gold may be given either as IM injections or orally. Evidence suggests that parenteral therapy is more effective.
Concentrated selectively in macrophages and reduces monokine production (IL-1). Hence it also reduces T- and B-cell responses.
Impairs endothelial expression of adhesion molecules and hence reduces cellular traffic to sites of inflammation.
Profile of side effects is similar to that of penicillamine, and the onset of action is also slow.
It is used only in RhA—now mainly replaced by anti-TNF agents and methotrexate.
Dosage depends on the route, and expert advice on current regimes should be sought from a clinician experienced in its use.
Immunosuppressive/immunomodulatory drugs: hydroxychloroquine/mepacrine
Antimalarials have a particular role to play in the management of joint and skin complaints in connective tissue diseases.
Effective in relieving the fatigue experienced in association with connective tissue diseases such as SLE and Sjögren’s syndrome.
Mode of clinical action is uncertain.
Interfere with the production of cytokines and reduction of production of granulocyte lysosomal enzymes. Drug accumulates in lysosomes.
Decrease chemotaxis, phagocytosis, and superoxide production in neutrophils
Inhibit TLR9 and reduce antigen presentation by dendritic cells to T cells.
Anti-platelet action demonstrated: may be valuable in anti-phospholipid syndrome.
Onset of action is slow.
Well-tolerated with few side effects.
Haemolysis may occur in G6PD-deficient patients.
Retinal toxicity may be a problem with hydroxychloroquine, and is definitely a problem with chloroquine (no longer used in rheumatic disease).
Evidence that there is a significant risk of ocular toxicity from normal doses of hydroxychloroquine is minimal. Cumulative dose >1000g is associated with risk.
Annual follow-up by optometrist recommended
Near vision should be recorded with test type before starting treatment, and at 6–12-month intervals thereafter.
Loss of colour discrimination may be an early sign.
Hydroxychloroquine may cause nausea and vomiting which can be severe and usually occurs during the initiation phase.
Haemolysis may occur in G6PD-deficient individuals—this affects children more than adults.
Mepacrine stains the skin yellow.
Preferred antimalarial is hydroxychloroquine.
Starting dose for hydroxychloroquine is 400mg/day (adult), reducing to maintenance of 200mg/day. Alternatively the maximum daily dose is calculated as 6.5mg/kg lean body mass.
Mepacrine is an unlicensed drug in the context of autoimmune disease, and the dose is 50–100mg/day.
Immunosuppressive/immunomodulatory drugs: thalidomide and analogues/pentoxifylline
Thalidomide is an interesting drug which reduces the severity of conversion reactions due to treatment of lepromatous leprosy.
Mechanisms of action include:
potent inhibition of TNFα production by monocytes, as a result of interference with gene transcription
decrease in the expression of adhesion molecules
reduction of circulating CD4+ T cells/immunomodulatory drugs
inhibition of γ-interferon production by T cells, as a result of preferential stimulation of Th2 cells
inhibition of angiogenesis
inhibition of IL-6 production
activation of apoptotic pathways via caspase 8.
Side effects include its well-documented teratogenicity, neuropathy, and drowsiness (which may limit dose).
It is used in the management of ulceration in Behçet’s syndrome and in reducing the severity of GvHD.
It is used with benefit in multiple myeloma, with dexamethasone.
Dosage is 100mg/day, reducing to 50mg on alternate days.
It is an unlicensed drug in the UK and is only available from the manufacturer if the patient is enrolled in a monitoring programme.
Nerve conduction studies should be carried out as a baseline pre-treatment, and at intervals on treatment.
Women of child-bearing age must be formally counselled over the risks and agree to take appropriate contraceptive measures. This must be recorded in the notes.
Lenalidomide (Revlimid®) is a derivative of thalidomide, introduced for treatment of multiple myeloma and myelodysplastic syndromes. It has direct anti-tumour effects (apotosis)—inhibition of the microenvironment via anti-angiogenic and anti-osteoclastic activity.
Pomalidomide is another derivative of thalidomide undergoing clinical trials.
Pentoxifylline was originally introduced for peripheral vascular disease. It has similar but weaker actions to thalidomide in inhibiting TNFα production. Clinical benefit may be difficult to discern, but it is non-toxic.
Immunosuppressive/immunomodulatory drugs: sulfasalazine and colchicine
Sulphasalazine
Sulphasalazine was originally introduced as an antibiotic.
It comprises sulphapyridine coupled to 5-aminosalicylic acid via a diazo bond that can be split by enteric bacteria.
Its precise mode of action as an immunomodulatory agent is uncertain.
It has minor immunosuppressive activities, mainly localized to the gut, but little effect on peripheral blood lymphocyte numbers or function.
It is used predominantly in inflammatory bowel disease, rheumatoid arthritis, and seronegative arthritides in doses of 500–2000mg/day in divided doses.
It has a significant array of side effects including male infertility (azoospermia), macrocytic anaemia, rash, Stevens–Johnson syndrome, and secondary hypogammaglobulinaemia.
Regular monitoring of FBC is required.
Colchicine
Colchicine is a useful anti-inflammatory.
Its precise immunological role is uncertain, but it inhibits microtubule assembly and therefore inhibits mitosis.
Concentrated in neutrophils and inhibits chemotactic activity, thus reducing the accumulation of non-specific inflammatory cells.
Valuable in Behçet’s syndrome and familial Mediterranean fever; may be helpful in other autoinflammatory diseases.
Value is limited by side effects at therapeutic doses (diarrhoea and gastrointestinal discomfort).
Usual dose is up to 0.5mg four times daily, if tolerated.
Grapefruit juice may increase toxicity.
Immunosuppressive/immunomodulatory drugs: dapsone
Used to treat dermatitis herpetiformis, urticarial vasculitis, and IgA dermatoses.
Inhibits β-integrin-mediated neutrophil adherence to endothelium by binding to intracellular G-protein.
Inhibits myeloperoxidase.
Main side effect is haemolysis, which is marked in G6PD-deficient patients.
Always check G6PD status prior to use and monitor FBC for signs of haemolysis (reduced haptoglobins are a sensitive indicator of haemolysis).
Dose is usually 1–2mg/kg/day.
Immunosuppressive/immunomodulatory drugs: JAK3 inhibitors/tyrosine kinase inhibitors
Used to treat cancers and leukaemias, but also valuable for other conditions such as hypereosinophilia.
Imatinib (Glivec®) is the prototype and is active against the active form of the oncogene Abl, a tyrosine kinase.
Tofacitinib is specific JAK3 inhibitor which is being tested in rheumatoid arthritis and psoriasis.
Immunosuppressive/immunomodulatory drugs: bortezomib
Bortezomib (Velcade®) is used to treat myeloma.
It inhibits the catalytic site of the 26S proteasome, which may allow apoptosis of the malignant myeloma cells.
It increases the risk of shingles, and prophylactic aciclovir is advisable.
It also causes neuropathy and myelosuppression.
Immunosuppressive/immunomodulatory biologicals: high-dose IVIg
High-dose IVIg is widely used as an immunomodulatory agent in autoimmune diseases. Unfortunately, many of the uses have not been well supported by proper double-blind placebo-controlled trials and, in view of the potential risks of infection (increased in response to volume exposure in these groups (see ‘IVIg for replacement therapy 2’, p.392)), this cannot be condoned. The precise mechanisms of action clinically are uncertain, although many mechanisms have been postulated.
Actions
Fc-receptor blockade of phagocytic cells.
Inhibition of cytokine production.
Inactivation of pathogenic autoantibodies (anti-idiotypes).
Inhibition of autoantibody production by B cells.
Decreased T-cell proliferation.
Actions of soluble cytokines, cytokine receptors, and antagonists present in IVIg.
Inhibitory actions of stabilizing sugars.
Side effects
Aseptic meningitis (elevated lymphocytes and protein in CSF) ?secondary to sugars.
Renal failure (secondary to osmotic load from sugars).
Massive intravascular haemolysis (secondary to IgG isoagglutinins).
Hyperviscosity (CVAs, MI).
Immune complex reactions in patients with high-titre rheumatoid factors, cryoglobulins (types II and III), or other immune complex disease (e.g. SLE).
Anaphylactoid reactions (IgA deficiency, infected).
Main uses
Replacement therapy for primary and secondary immunodeficiencies (see ‘IVIg for replacement therapy 1’, p.392).
Autoimmune cytopenias (ITP, AIHA).
Vasculitis: Kawasaki syndrome, Wegener’s granulomatosis.
Neurological diseases (acute Guillain–Barré, CIDP, pure motor neuropathy, myasthenia gravis, LEMS, MS).
Factor VIII and factor IX inhibitors.
Anti-phospholipid antibodies in pregnancy.
Autoimmune skin disease (pemphigus, pemphigoid, epidermolysis bullosa acquisita).
Eczema.
Polymyositis, dermatomyositis.
Dosage
Dosage regimes range from 0.4g/kg/day for 5 days, through 1g/day for 2 days, to 2g/kg/day as a single dose.
Minimal evidence is available to distinguish between the schedules.
Fewer doses may be required for ITP.
My own practice is to start all high-dose regimes on the 5-day schedule to assess tolerability, and then increase to 1 g/kg/day for 2 days subsequently.
In adults and children, risks of renal impairment and aseptic meningitis are highest with the ultra-rapid infusion schedule of 2g/kg/day, and I avoid this if possible.
Rapid infusions should be avoided in all elderly patients because of the risks of hyperviscosity.
Pre-treatment IgA deficiency and high-titre rheumatoid factors should be excluded, and renal function assessed.
Pre-treatment FBC, LFTs, and hepatitis serology (HBV, HCV) should also be measured.
IgA-deficient patients require special care, and should be on products low in IgA.
If there is renal impairment to start with, creatinine should be measured daily. If there is a rise of 10% or more, then therapy should be discontinued.
FBC should be repeated during the course to ensure that haemolysis does not take place (haptoglobin is a sensitive indicator of intravascular haemolysis).
Infusion rates should follow manufacturers’ guidelines.
There must be no switching of products.
▶ Batch numbers must be recorded.
Immunosuppressive/immunomodulatory biologicals: polyclonal antibodies, high-dose anti-D immunoglobulin, and blood transfusion effect
Polyclonal antibodies
Xenogeneic antisera raised by the immunization of animals with purified human T cells or thymocytes (rabbit anti-thymocyte globulin (ATG) and rabbit anti-lymphocyte globulin (ALG)) are potent immunosuppressive agents.
They cause a profound lymphopenia.
They are difficult to standardize and have significant batch-to-batch variation.
They also contain cross-reactive antibodies that react with other cells types, including platelets.
Utility is limited by the development of a host-anti-rabbit response, which both neutralizes the xeno-antiserum and gives rise to a serum sickness reaction.
Actions
Complement-mediated lymphocyte destruction.
Cause marked but variable lymphopenia.
Reduced T-cell function.
Uses
Acute graft rejection or GvHD.
Diamond–Blackfan syndrome.
Dosage
Dosage depends on batch but is usually within the range 5–30mg/kg/day.
The effect can be monitored by absolute lymphocyte counts or flow cytometric analysis of peripheral blood lymphocytes.
High-dose anti-D immunoglobulin
High-dose anti-D immunoglobulin can be used to control autoimmune haemolytic anaemia in rhesus D+ patients.
Mechanism of action is unclear.
Blood transfusion effect
In renal allografts it has been well documented that both donor and random blood transfusions reduce the risks of graft rejection.
The immunological mechanism is uncertain.
Immunosuppressive/immunomodulatory biologicals: anti-TNF agents
Since the second edition of this book there has been an explosion of monoclonal antibodies, now mainly chimeric or humanized molecules, and these are replacing murine monoclonal antibodies which have a high rate of induction of anti-mouse antibodies which abolish the effectiveness.
Infliximab (Remicade®)
Chimeric monoclonal antibody to TNFα.
Licensed for use in Crohn’s disease, rheumatoid arthritis, ankylosing spondylitis, psoriasis, juvenile arthritis.
Major hazard of use is significant increase in tuberculosis.
Screening for TB prior to administration is advised.
Use of Quantiferon Gold may be valuable in establishing previous tuberculous infection.
Development of PUO, cough, and weight loss should trigger search for TB.
Induces development of anti-nuclear antibodies.
Must be used in combination with MTX to prevent the development of anti-chimera antibodies.
Dose 3mg/kg as IV infusion, repeated at 2 weeks, 6 weeks, and then 8-week intervals.
Cessation of therapy in Crohn’s disease may lead to loss of effect when re-introduced.
Adalimumab (Humira®)
Another monoclonal antibody to TNFα.
Side effects, dosing, and indications are similar to those for infliximab.
Co-therapy with MTX is recommended.
Dose is 40mg on alternate weeks subcutaneously.
Golimumab (Simponi®)
Another monoclonal antibody to TNFα recently licensed for use in rheumatoid arthritis.
Certolizumab (Cimzia®)
Another monoclonal antibody to TNFα.
Pegylated Fab′ fragment of humanized anti-TNF MAb.
Marketed for use in Crohn’s disease.
Etanercept (Enbrel®)
Etanercept is a soluble fusion protein of the ligand-binding portion of the type 2 TNF receptor (p75) coupled to the Fc portion of human IgG1.
It binds both TNFα and TNFβ.
It is synergistic with MTX.
It is licensed for use in RhA, psoriatic arthritis, and juvenile arthritis.
It may be of value in Behçet’s disease and uveitis.
Demyelination has been reported; risk of immunosuppression is significant.
Dose is 25–50mg twice weekly by subcutaneous injection for 12 weeks, reducing to 25mg twice weekly with a maximum duration of therapy of 24 weeks.
If there is no response by 12 weeks, it should be discontinued.
Immunosuppressive/immunomodulatory biologicals: other cytokines
Ustekinumab (Stelara®)
Human monoclonal antibody directed against IL-12 and IL-23.
Approved for treatment of psoriasis and possibly useful in psoriatic arthropathy.
Associated with possible increased infection risk (TB) and increased cancer risk.
Allergic reactions reported.
Anakinra (Kineret®)
A recombinant version of the naturally occurring IL-1 receptor antagonist.
Blocks the action of IL-1.
Has been used in RhA, but evidence of benefit is not compelling and NICE no longer recommends it.
Causes neutropenia and headache.
Dose is 100mg daily subcutaneously.
Canakinumab (Ilaris®)
Rilonacept (IL-1-Trap, Arcalyst®)
Dimeric fusion protein comprising extracellular domain of IL1R and Fc of human IgG1; binds and neutralizes IL-1.
Tocilizumab (Actemra®)
Humanized monoclonal antibody against IL-6 receptor.
Mainly developed and now approved for use in RhA, but likely to be effective in a range of antibody-mediated diseases, including myeloma, Castleman’s syndrome.
Administered monthly in a dose of 8mg/kg by IV infusion.
Immunosuppressive/immunomodulatory biologicals: anti-T-cell agents
Since the first edition of this book there has been an explosion of monoclonal antibodies,
OKT3 (muromonab-CD3®)
Murine antibody against T-cell CD3 ε-chain.
Used to treat allograft rejection.
Associated with high incidence of the development of HAMA (human anti-mouse antibodies) which reduce its effect and cause a serum sickness reaction.
Now withdrawn. A humanized variant is in development; other anti-CD3 antibodies are available.
Otelixizumab (TRX4)
Chimeric humanized against T-cell CD3 ε-chain.
In trials for type I diabetes.
Ruplizumab (Antova®)
Anti-CD154 (gp39, CD40 ligand) blocks the binding of CD154 on activated but not resting T cells with CD40 on B cells and APCs.
Of possible benefit in SLE and nephritis
Complications have included thrombosis and thrombocytopenia.
Zanolimumab (HuMax-CD4®)
Anti-CD4 humanized monoclonal antibody
Of possible benefit in RhA, psoriasis, and T-cell lymphomas.
Immunosuppressive/immunomodulatory biologicals: Anti-CD25 agents
These are now being introduced to prevent graft rejection in solid organ transplantation.
Basiliximab (Simulect®)
A humanized monoclonal IgG1antibody that binds to the α-chain of the high-affinity IL-2 receptor (CD25) and prevents T-cell proliferation.
Used in the prophylaxis of acute organ rejection in renal allografts in combinations with ciclosporin and corticosteroids.
Main side effect is severe hypersensitivity.
Dose is 20mg 2 hours before transplant and 20mg 4 days after surgery.
Daclizumab (Zenapax®)
A humanized monoclonal antibody that binds to the γ-chain of the IL-2 receptor and prevents T-cell proliferation.
Used in the prophylaxis of acute organ rejection in renal allografts in combinations with ciclosporin and corticosteroids.
Has been shown to benefit birdshot chorioretinopathy and multiple sclerosis.
Main side effect is severe hypersensitivity.
Dose is 1mg/kg by IV infusion in the 24 hours pre-transplant, which is continued daily for 14 days.
Immunosuppressive/immunomodulatory biologicals: anti-co-stimulatory agents
Abatacept (Orencia®)
A fusion protein of CTLA-4 and immunoglobulin that binds to B7. Inhibits co-stimulation of T cells.
Approved for use in rheumatoid arthritis and is being tested in inflammatory bowel disease, lupus nephritis, and type 1 diabetes.
Belatacept (Nulojix®)
A fusion protein of CTLA-4 and immunoglobulin that binds to B7. Inhibits co-stimulation of T cells.
It differs from abacept by only two amino acids.
It is being studied in renal transplantation
It appears to increase the risk of post-transplant lymphoproliferative disease
Ipilimumab (Yervoy®)
A human monoclonal antibody against CTLA-4.
Being trialled for melanoma (approved by FDA), small cell lung cancer, and prostate cancer.
TGN1412
Humanized antibody against CD28.
Caused a severe cytokine release syndrome in first human trial in normal volunteers (approved by MHRA) which was not predicted by prior studies.
Predicted that administration may have caused long-term immune damage.
Company became insolvent as a result of the adverse publicity.
Immunosuppressive/immunomodulatory biologicals: anti-B-cell agents
Alemtuzumab (MabCampath®)
Humanized anti-CD52 monoclonal (Campath®).
Lytic antibody: targets predominantly B cells.
Used in B-cell lymphomas and B-lymphoproliferative disease (EBV+) in the immunosuppressed.
Causes tumour lysis and cytokine release syndrome (capillary leak), as for rituximab.
Rituximab (MabThera®)
A humanized anti-CD20 monoclonal antibody. CD20 is strongly expressed on normal and malignant B cells.
Licensed for use in non-Hodgkin’s B-cell lymphomas.
Can cause massive tumour lysis syndrome, with cytokine release (antibody-complement mediated lysis) and capillary leak syndrome 1–2 hours after infusion.
Fever and chills, nausea and vomiting, and hypersensitivity reactions are common.
Analgesic, corticosteroid, and antihistamine should be administered before treatment.
Full resuscitation facilities should be available.
Synergistic with chemotherapy.
Likely to be valuable in the treatment of autoimmune diseases where autoantibody plays a significant role (autoimmune haemolytic anaemia, ITP).
Also shows promise as adjunctive therapy in SLE and other antibody-mediated autoimmune diseases.
Side effects include severe and prolonged hypogammaglobulinaemia due to destruction of normal B cells.
Ofatumumab (Humax-CD20, Arzerra®)
A humanized anti-CD20 monoclonal antibody
Recognises different epitopes to rituximab.
Licensed for the treatment of resistant CLL but has also shown promise in lymphoma, rheumatoid arthritis, and multiple sclerosis.
Administration can be complicated by a cytokine-release syndrome, and pre-medication with analgesics, antihistamines, and corticosteroids is recommended.
Belimumab (LymphoStat-B, Benlysta®)
A human monoclonal antibody against B-lymphocyte stimulator (BLyS, also known as BAFF (B-cell activation factor of TNF family)).
Approved for use in SLE in North America and Europe, although not trialled in severe SLE. Cost likely to be about £35 000 per annum per patient.
Side effects include nausea, diarrhoea, and allergic reactions. Increased risk of infections noted in clinical trials (avoid live vaccines during treatment).
Immunosuppressive/immunomodulatory biologicals: anti-allergic agents
Two drugs have so far been shown to be useful (mepolizumab and omalizumab). Other approaches against IL-4, IL9, IL-13, and TNFA are being explored in clinical trials.
Mepolizumab (Bosatria®)
A humanized monoclonal antibody against IL-5.
Shown to be useful in treatment of eosinophilic conditions including asthma and possibly F1P1L1/PDGFRA negative hyper-eosinophilic syndromes.
Omalizumab (Xolair®)
A humanized monoclonal antibody against the IgE Fc region that prevents binding to the high-affinity IgE receptor (FceR1).
FceR1 is downregulated on basophils and this provides a useful flow cytometric test for efficacy.
Now validated as a treatment for moderate to severe asthma.
In the UK, severity is marked by repeated attendance at hospital, penalizing those who have severe disease but self-manage at home.
Local PCT approval for treatment is variable, giving rise to postcode prescribing.
It is being investigated as adjunctive therapy to desensitizing immunotherapy.
Dose is determined by serum total IgE, meaning that those with very high IgE levels cannot be treated.
It is administered subcutaneously every 2–4 weeks.
Anaphylaxis to treatment has been reported.
Immunosuppressive/immunomodulatory biologicals: anti-integrin agents
A number of agents have been produced against integrins. Those against CD11/CD18 have all been disappointing and have been associated with severe side effects. Efalizumab (anti-CD11a) was introduced for psoriasis, but its licence has been withdrawn in the USA because of concerns over the risk of progressive multifocal leukoencephalopathy(PML).
Natalizumab (Tysabri®)
A humanized monoclonal antibody against A4-integrin.
Thought to work by preventing inflammatory cell migration, particularly through the blood–brain barrier.
Used for treatment of MS and Crohn’s disease.
Associated with PML and was temporarily withdrawn from the market. Cases of PML may be linked to combined therapy with other agents.
Immunosuppressive/immunomodulatory biologicals: miscellaneous
Gemtuzumab (Mylotarg®)
A monoclonal antibody against the CD33 antigen expressed on myeloid leukaemic blasts and normal myeloid cells.
Used to treat AML in first relapse.
Trastuzumab
A humanized antibody against the epidermal growth factor receptor Her-2.
Blocks and downregulates the receptor.
Valuable in the treatment of metastatic breast cancer where the tumour overexpresses Her-2.
Her-2 is also expressed on other tumours.
Abciximab (ReoPro®)
Monoclonal antibody binding to platelet glycoprotein IIb/IIIa receptors.
Used once only as an adjunct to heparin and aspirin in high-risk patients undergoing percutaneous transluminal coronary artery interventions to prevent thrombotic complications.
Digoxin-specific antibody (Digibind®)
Fab′ fragments of antibody against digoxin.
Used to treat digoxin poisoning by binding to the drug.
Bevacizumab (Avastin®)
Humanized monoclonal antibody that inhibits vascular endothelial growth factor A (VGEF-A).
Approved to treat a variety of cancers especially with metastases, although effects may be small.
Also used to treat macular degeneration.
Eculizumab (Soliris®)
Monoclonal humanized antibody binding to complement C5 and preventing its activation by C5 convertase, thus preventing the generation of the terminal lytic sequence.
Licensed for the treatment of paroxysmal nocturnal haemoglobinuria (in the UK, cases must be referred to supra-regional specialist service).
Undergoing investigation as a drug for treatment of acute complement-mediated graft rejection.
Increases risk of meningococcal disease (as expected from primary complement deficiency). Patients should be immunized with quadrivalent conjugated meningococcal vaccine at least 2 weeks prior to receiving drug. This will not provide protection against group B meningococci.
Total lymphoid irradiation (TLI)
TLI is an experimental immunosuppressive therapy, having been used previously for the treatment of lymphoid malignancies.
Produces profound impairment of T-cell numbers and function, although there is a small population of radio-resistant small lymphocytes.
A more modern variant is to use UV-sensitizing agents (psoralens) and then irradiate leucocytes in an extracorporeal circulation (photopheresis).
TLI may be of benefit in intractable RhA, multiple sclerosis, and severe SLE.
Side effects
Severe leucopenia.
Thrombocytopenia.
Opportunist infections.
Lymphoma (NHL).
Photopheresis
Extracorporeal phototherapy, using sensitizing agents, is used for the treatment of graft-versus-host disease, inflammatory bowel syndrome.
8-methoxypsoralen, which binds to lymphocyte DNA when activated, is used as the sensitizer.
Thoracic duct drainage
Has been used in the past for treatment of severe RhA.
Causes a severe and long-lasting immunosuppression.
Similar effects are seen from accidental thoracic duct damage in oesophageal and cardiac surgery, where a chylous effusion is allowed to drain unchecked.
A profound and persistent lymphopenia of both T and B cells is caused.
Recovery of immune function may occur over a long period.
Prophylaxis against Pneumocystis carinii pneumonia and fungal infections will be required if the drainage is accidental.
Plasmapheresis
Plasmapheresis is the removal of plasma constituents using automated cell separators. The plasma components are removed by either centrifugation or membrane filtration.
Erythrocytes and other cellular components are re-infused and the removed plasma replaced with either FFP or FFP + IVIg to maintain circulating volume.
About 50% of the plasma is removed each time.
A therapeutic course is usually 3–5 daily treatments.
The amount of antibody removed depends on volume of distribution.
90% of IgM but only 20% of IgG is removed each time as only 40% of the IgG is within the vascular space.
Plasmapheresis also has the advantage of removing immune complexes and small mediators (toxins, anaphylotoxins, cytokines etc.), in addition to the antibodies.
Plasmapheresis is only suitable for urgent therapy, as antibody levels return rapidly and frequently overshoot to higher levels after plasmapheresis is discontinued.
It is important to commence conventional immunosuppression at the same time.
Side effects
Leakage/air embolism.
Anticoagulation (citrate toxicity)/thrombocytopenia.
Reactions to replacement fluids.
Uses
Hyperviscosity (Waldenström’s macroglobulinaemia, IgA myeloma).
Goodpasture’s syndrome/Wegener’s granulomatosis.
Cryoglobulinaemia.
Myasthenia gravis.
Guillain–Barré syndrome (but IVIg is as good).
It has been tried in other autoimmune diseases (RhA, factor VIII antibodies, MS, lupus nephritis) with variable anecdotal success.
A limiting factor in its use is access to appropriate equipment.
Immunoadsorption
Selective removal of autoantibodies has been attempted using an extracorporeal circuit including a column of inert beads coated with protein A or protein G for specific adsorption of IgG.
This treatment is experimental and it is not widely used in clinical practice.
Allergy interventions: drugs
Treatment for allergic disease is divided into three major target areas: mast cells, released mediators, and the specific immune response. Treatment can be topical or systemic: topical is preferred if this is effective. The underlying chronic inflammatory component, especially of asthma, always needs to be addressed rather than just using symptomatic agents. Corticosteroids and antihistamines are more effective as prophylactic agents, taken before allergen exposure.
Mast-cell active drugs
Corticosteroids (interfere with synthesis of leukotrienes).
Mast-cell stabilization: cromoglicate/nedocromil/ketotifen (prevent allergen-triggered calcium flux and hence prevent degranulation).
Released mediators
β-agonists (smooth muscle relaxation, ?some anti-inflammatory effect (salmeterol)).
Antihistamines: use long-acting high-potency non-sedating drugs without cardiotoxicity (loratadine, desloratadine, levocetirizine, cetirizine, fexofenadine).
Corticosteroids.
Anti-PAF drugs (clinical results disappointing).
Leukotriene (LTD4) antagonists: montelukast, zafirlukast (useful adjunctive treatment in asthma).
5-lipoxygenase inhibitor: zileuton (asthma).
Kinin antagonists: icatibant (anti-bradykinin B2 receptor antagonist), WIN64338, FR173657 (orally active B2 antagonist).
Specific IgE
Desensitization.
Peptide therapy (experimental).
Anti-FcRε therapy (experimental).
Omalizumab, anti-IgE (see p.422).
Allergy interventions: desensitization (immunotherapy)
Mechanism of benefit
Mechanism of desensitization is uncertain: specific IgE may rise in early stages of treatment, and then fall.
The role of ‘blocking antibodies’ (IgG4) is unknown.
One hypothesis suggests that sequential exposure gradually switches the CD4+ T-cell response from Th2 to Th1, reducing IgE production and the levels of the pro-allergic cytokines IL-4 and IL-5.
Indications
Desensitization should be considered for patients with:
anaphylaxis to insect venoms
rhinoconjunctivitis not controlled with maximal medical therapy, used correctly, and including repeated courses of oral steroids
asthma may be amenable to treatment but carries high risks
anaphylaxis to venoms.
In the UK, most vaccines are available only on a named-patient basis.
Exclusions
Current UK guidelines suggest that desensitization is inappropriate for those with the following:
multiple allergies
severe asthma (FEV1 <75% predicted)—seasonal wheeze only induced by pollen is not a contraindication to desensitization out of the pollen season
heart disease
hypertension requiring β-blockade (difficult to resuscitate in emergencies!)
use of ACE inhibitors (increased risk of angioedema, local and systemic)
during pregnancy
excess alcohol consumption (increased risk of side effects).
Age >50 years is associated with poor responses (exception is venom immunotherapy).
Schedules
Traditional desensitization is done with weekly injections of increasing doses of aqueous allergen until maintenance doses are reached at 14–18 weeks.
Once on maintenance doses, intervals between injections are spaced out to 4–6 weeks for 3 years.
Short course (4 or 6 injections over the winter) of adsorbed allergens (Pollinex® and Pollinex Quattro®) are as effective for pollen allergies. Course is repeated annually for 3 years.
Allergens available in the UK include the following.
Venoms: bee, wasp, bumblebee (for market gardeners who use bumblebees for pollination!).
Pollens: grass, birch pollen, ragweed (USA mainly).
Animals: cat (potent allergen associated with high incidence of side effects), horse, dog (but this is not as effective as the others).
House dust mite.
Highly purified allergens should always be used: whole-insect extracts or multiple allergen combinations are not recommended in the UK.
All except Pollinex® are unlicensed at present and therefore are administered on a named-patient basis:
formal written consent is required.
Precise protocol and total duration of therapy varies depending on the allergen.
All require long-term commitment from patients.
Schedules are onerous and the leeway for changes to accommodate holidays is minimal.
Patients must not undertake vigorous exercise after injections (increased risk of side effects).
Injections should not be given if patient is unwell.
Pre-treatment with antihistamines reduces risk of local reactions.
Peak flow should be monitored before and 30 minutes after injection.
All patients must stay for at least 1 hour post-injection (no exceptions).
Rush and ultra-rush schedules have been devised for venom allergy, but are rarely required in practice and significantly increase the risks of reactions.
Desensitization must be carried out in hospital, and staff must be conversant with emergency management of anaphylaxis and cardiac arrest procedures.
Side effects
Main side effects are pain and swelling at site of injections (pre-treat with antihistamine and supply oral steroid).
Systemic reactions may occur (cough is often the first sign): treat as for any acute allergic reaction.
Risk of reactions is increased:
during the up-dosing period (aqueous allergens)
in patients treated with cat allergen
if patient has intercurrent infection (defer injection)
if patient is extremely anxious (use sedation if necessary)
if patient is exposed to allergen naturally during the up-dosing period;
if patient is drinking excess alcohol
if patient is started on an ACE inhibitor.
Sublingual therapy
Sublingual desensitization is widely practised in Europe but its use is limited in the UK.
Allergen drops or tablets are placed under the tongue on a daily basis.
Local tingling and minor swelling may occur.
Experience from Europe suggests that this is safe and effective, and can be administered at home.
Grazax®, a sublingual tablet for grass pollen allergy, is licensed in the UK, but treatment should be initiated and supervised by a trained allergist/immunologist. Shellfish allergy is a contraindication due to the nature of the coating on the tablet.
3 years treatment is still required.
First dose of sublingual treatment should be administered in hospital. Thereafter, self-treatment at home is appropriate.
Adoptive immunotherapy
Stem cell transplantation
See Chapter 15.
Interleukin-2 and LAK therapy
LAK therapy (lymphokine-activated killer cells) has been proposed as a treatment for malignant disease.
Peripheral blood lymphocytes are harvested and then stimulated in vitro with high-dose IL-2 and re-infused into the patient with additional IL-2.
Side effects are severe and tumoricidal activity is limited.
A better approach may be to expand tumour-invading lymphocytes (TIL).
The therapy is moderately toxic in therapeutic doses (fluid retention, capillary leak syndrome).
There is some evidence of benefit in melanoma and renal cell carcinoma (salvage therapy).
