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Home , Transplant rejection

Experimental and clinical pharmacology Immunosuppressants – clinical applications

Paul Trevillian, Senior Staff Nephrologist and Transplant Physician, Department of , John Hunter Hospital, Newcastle, New South Wales

Summary daily for 1–3 days) they are directly lymphocytotoxic. In smaller Immunosuppressants are used to control severe doses, they are immunosuppressive and anti-inflammatory by limiting production. The required dose and duration of manifestations of allergic, autoimmune and treatment therefore tends to be disease specific. transplant-related diseases. Some drugs have Some diseases, for example , respond to a short course a diffuse effect on the while which can be abruptly stopped, but most rheumatic diseases others have specific targets. Drugs with diffuse require the dose to be very slowly tapered over months, effects are more likely to cause damaging adverse especially when single figure milligram doses of prednisone effects, but the effectiveness of the more specific are reached. Abrupt cessation runs the risk not only of relapse drugs may be reduced if their action can be of disease, but also hypoadrenocorticism. (Adrenal suppression bypassed by alternative metabolic pathways. can be confirmed by a one-hour synthetic ACTH stimulation test if there is clinical concern.) In the withdrawal phase, non-specific Treatment protocols therefore frequently use polyarthralgias and myalgias are common, but generally drug combinations to minimise adverse effects respond to a small dose increment followed by a renewed, and to prevent resistance to treatment. Although slower taper. protocols are essential to allow scientific Second-line drugs, usually antiproliferative drugs such as evaluation, the clinician must be prepared to tailor , mycophenolate or methotrexate, may have a treatment based on the ongoing assessment of steroid-sparing effect in the maintenance phase of treatment. drug effects, disease activity and the robustness However, they also have their own toxicities. of the individual patient. Patients prescribed should be told to expect the common early adverse effects, such as sweatiness, hoarse Key words: inhibitors, corticosteroids, transplantation. voice, loss of diurnal sleep patterns, and appetite stimulation. (Aust Prescr 2006;29:102–8) Rarely, more serious acute psychiatric disturbances are seen such as agitation, aggression or psychosis. Long-term, and less Introduction reversible, adverse effects include Cushingoid appearance, Many of the currently available immunosuppressants were proximal myopathy, hypertension, hyperlipidaemia, diabetes, developed for use in oncology or transplantation. As this cataract formation, peptic ulceration, osteopenia and aseptic treatment is potentially life-saving desperate measures can necrosis of bone. be justified. However, there are now over 80 autoimmune diseases and several common allergic conditions in which Small molecules (Table 1) immunosuppressants could play a role although they may not The small molecule immunosuppressants include calcineurin be life-saving. inhibitors, such as cyclosporin, and antiproliferative drugs, such Some immunosuppressants act through immunodepletion as . of effector cells, while others are predominantly immunomodulatory, affecting the activity of cells, usually Calcineurin inhibitors through cytokine inhibition. Immunosuppressants can be Since the 1980s, calcineurin inhibitors have been the main categorised as , small molecules or proteins.1 contributors to the success of solid transplantation, especially kidneys. By blocking interleukin-2 synthesis, they Glucocorticoids prevent activation of T- and are therefore useful in Corticosteroids are the mainstay of most immunosuppressive disorders of cell-mediated immunity. Calcineurin inhibitors have regimens in both the induction and maintenance phases. In high a proven role in the prevention of acute cellular rejection of intravenous pulse doses (methylprednisolone 250–1000 mg transplanted organs, in psoriasis and in nephrotic syndrome.

102 | VOLUME 29 | NUMBER 4 | AUGUST 2006 Table 1 Small molecule immunosuppressant drugs in current use

Class of drug Generic name Potential clinical uses Drug monitoring Main adverse effects

Immunophilin-binding drugs

Calcineurin cyclosporin organ transplants, TDM(C0 or C2), creatinine, nephrotoxicity, inhibitors nephrotic syndrome, potassium, magnesium, hypertension, tremor, psoriasis, atopic glucose, lipids hirsutism, gum eczema, rheumatoid hypertrophy, diabetes, arthritis haemolytic uraemic syndrome

organ transplants TDM(C0), creatinine, as for cyclosporin but potassium, magnesium, more tremor, diabetes, glucose, lipids less hypertension and fewer cosmetic effects

Mammalian sirolimus organ transplants TDM(C0), lipids, FBC, UA delayed wound target of healing, mouth ulcers, rapamycin acne, pancytopenia, (mTOR) hyperlipidaemia, inhibitors interstitial pneumonitis, peripheral oedema, Inhibitors of nucleotide synthesis Purine mycophenolate organ transplants, TDM not widely used, FBC diarrhoea, dyspepsia, synthesis mofetil vasculitides, SLE neutropenia, anaemia, inhibitors viral infections

Purine azathioprine organ transplants, FBC, LFTs neutropenia, analogue , macrocytosis, liver SLE, inflammatory dysfunction, skin cancers, bowel disease interaction with allopurinol Pyrimidine leflunomide rheumatoid arthritis, FBC, LFTs diarrhoea, nausea, rash, synthesis organ transplants alopecia, hepatitis, inhibitor pancytopenia

Antimetabolites Dihydrofolate methotrexate rheumatoid arthritis FBC, LFTs anaemia, neutropenia, reductase (may be used in parallel nausea, hepatitis, inhibitor with TNF inhibitors or pulmonary leflunomide), psoriasis, psoriatic arthritis, inflammatory bowel disease

Alkylating drugs Prodrug of systemic vasculitides, FBC, MSU, UA neutropenia, anaemia, phosphoramide especially Wegener's alopecia, haemorrhagic mustard granulomatosis, cystitis, sepsis, infertility, SLE, membranous bladder cancer glomerulonephritis

TDM therapeutic drug monitoring TNF tumour necrosis factor

C0 = trough concentration MSU midstream urine for microscopy and culture

C2 = concentration 2 hours after a dose FBC full blood count UA urinalysis SLE systemic erythematosus LFTs liver function tests

| VOLUME 29 | NUMBER 4 | AUGUST 2006 103 They have been used in many other autoimmune conditions erythematosus.5 Monthly intravenous pulses are as effective but have a diminishing role in rheumatoid arthritis. While they as daily oral use in systemic lupus erythematosus, but allow a are good at maintaining autoimmune diseases in remission, reduced total dosage. Cyclophosphamide is also used to induce withdrawal often leads to relapse. sustained remission in relapsing nephrotic syndrome. Marrow In solid , combinations of calcineurin suppression with neutropenia is common after six weeks of inhibitors, mycophenolate mofetil and prednisone give better treatment and continuing more than six months runs the risk of results than monotherapy. Ironically, calcineurin inhibitors are gonadal suppression and infertility in both sexes. nephrotoxic and may contribute to long-term renal failure, both Methotrexate in transplanted organs and normal kidneys. They also aggravate This antimetabolite is used in some autoimmune diseases hypertension and hyperlipidaemia thereby inducing an including psoriasis, psoriatic arthritis, rheumatoid arthritis and unfavourable cardiovascular profile. There is also an increased Crohn's disease. As a disease-modifying antirheumatic drug, its risk of diabetes. use in combination with tumour necrosis factor inhibitors (such Mycophenolate mofetil as infliximab or etanercept) or leflunomide has been shown to markedly improve symptoms in rheumatoid arthritis.6 Since it was introduced into Australia in 1996 mycophenolate mofetil has largely replaced azathioprine in organ transplantation. Proteins (Table 2) One advantage over azathioprine is that allopurinol can be used Polyclonal antilymphocyte (antithymocyte) have been for gout prophylaxis without the need to reduce the dose of used in Australia since the 1960s. More recently, hybridoma mycophenolate. Possibly because of its anti- properties2 technology has produced a plethora of monoclonal antibodies mycophenolate seems particularly effective in severe forms of against molecules expressed by human immune effector cells. systemic lupus erythematosus. It is also gaining favour as a steroid-sparing drug in the maintenance phase of a number of T- depleting antibodies such as muromonab-CD3 have been widely used to prevent or treat acute rejection of immune disorders, particularly the vasculitides.3 organ transplants. The main drawback is a 'cytokine storm' The main adverse effects are haematological and reaction to the first dose, which can cause life-threatening gastrointestinal. On higher doses a third of patients will develop pulmonary oedema. diarrhoea. An enteric-coated formulation of mycophenolate has and are monoclonal antibodies against been developed to try and reduce gastrointestinal adverse effects. the interleukin-2 (CD25). They are used as induction Therapeutic drug monitoring is available but not widely used. drugs in transplantation as they significantly reduce the acute Sirolimus and everolimus rejection rate, with little or no increase in morbidity. They are not yet significantly used in autoimmune diseases. These potent antiproliferative drugs have gained acceptance in renal transplantation as a strategy to minimise the use of The anti-B cell (anti-CD20), , is licensed for calcineurin inhibitors in low immunological risk patients.4 use against B-cell lymphomata, but there are now published They have a decreased likelihood of causing hypertension and anecdotal reports of its effectiveness in 29 different autoimmune 7 glucose intolerance. Although these drugs are associated with diseases. Randomised controlled trials are proceeding in less nephrotoxicity than calcineurin antagonists, they potentiate systemic lupus erythematosus, rheumatoid arthritis, the renal toxicity of cyclosporin and regular monitoring of dermatomyositis, antineutrophil cytoplasmic antibody (ANCA)- renal function is recommended. Sirolimus and everolimus are positive vasculitis and in renal transplantation of highly generally avoided perioperatively because they can severely sensitised recipients. delay wound healing. They are potent inhibitors of intimal A new , alemtuzumab, is directed against hyperplasia in arteries, and sirolimus-eluting intra-arterial stents a surface molecule (CD54), which is widely distributed on are now used to reduce re-stenosis rates. However, they can lymphocytes, and dendritic cells, thereby causing increase serum cholesterol and lipids. The balance of the harm severe and long-lasting depletion of these cell lines. As a result, and benefit of continued treatment should be re-evaluated the risk of serious infection is increased. The use of this antibody in patients who develop severe refractory hyperlipidaemia. is cautiously making the transition from immunoprophylaxis in Therapeutic drug monitoring is essential because of the risk of transplant recipients to a wider use in immune diseases.8 toxicity such as anaemia, leucopenia and thrombocytopenia. Two monoclonal antibodies against tumour necrosis factor, infliximab and adalimumab, and etanercept which prevents Cyclophosphamide tumour necrosis factor binding to its receptor, are licensed Cyclophosphamide is a cytotoxic drug. It is the drug of choice for use in rheumatoid arthritis. They are also being used in for Wegener's granulomatosis, but is also used in other ankylosing spondylitis, psoriatic arthritis and inflammatory vasculitides such as microscopic polyangiitis and systemic lupus bowel disease.9 Infusion reactions are common.

104 | VOLUME 29 | NUMBER 4 | AUGUST 2006 Table 2

Protein-based immunosuppressant drugs in current use

Drug Potential clinical uses Adverse effects

Lymphocyte depleting antibodies Polyclonal antithymocyte prevention and treatment of allograft cytokine-release syndrome (fever, chills, globulin rejection hypotension), thrombocytopenia, leucopenia, treatment of moderate to severe aplastic anaemia Muromonab-CD3 prevention and treatment of allograft severe cytokine-release syndrome, rejection in transplant patients pulmonary oedema, acute renal failure, gut upset, neurological disturbances Alemtuzumab treatment of B-cell chronic lymphocytic mild cytokine-release syndrome, leukaemia, immunoprophylaxis for renal neutropenia, anaemia, pancytopenia, transplants, GVHD, , immune thrombocytopenia, thyroid disease rheumatoid arthritis

Rituximab treatment of B-cell non-Hodgkin's lymphoma infusion reactions, reactions antibody-mediated transplant rejection, SLE, (uncommon) vasculitis

Non-depleting antibodies and fusion proteins Basiliximab prevention of allograft rejection in transplant hypersensitivity reactions (uncommon) Daclizumab patients

Belatacept (LEA29Y) prevention and treatment of allograft clinical trials still in progress rejection in transplant patients

Tumour necrosis factor inhibitors Etanercept rheumatoid arthritis, ankylosing spondylitis, injection site and infusion reactions, heart psoriatic arthritis failure, opportunistic infections including fungi and tuberculosis, lymphoproliferative Infliximab rheumatoid arthritis, ankylosing spondylitis, disease, demyelinating disease – reactivation Adalimumab psoriatic arthritis, Crohn's disease of multiple sclerosis, SLE-like illness

Pooled immunoglobulin Intravenous immunoglobulin Kawasaki disease, CIDP, multiple sclerosis, rash, headache, abdominal pain, haemolysis Guillain-Barré, ITP, bone marrow transplants, (especially in patients with blood groups A, myeloma, chronic lymphocytic leukaemia AB), thromboses, liver dysfunction, aseptic with hypogammaglobulinaemia, transplant meningitis, acute renal failure rejection

GVHD versus host disease SLE systemic lupus erythematosus CIDP chronic inflammatory demyelinating polyneuropathy ITP idiopathic thrombocytopenic purpura

Pooled intravenous immunoglobulin was introduced to provides passive immunity means that it is regarded as having restore immunocompetence to patients with congenital a low risk of infectious complications compared to other acquired immune deficiency syndrome. Paradoxically, the immunosuppressants. Consequently, it has been used in many discovery of its ability to inhibit the production and binding conditions without good supportive evidence of efficacy, so the of auto- and allo-antibodies means that it is now more widely Australian National Blood Authority guidelines now restrict its used as an immunomodulatory drug in the treatment of use.11 Nevertheless, it is likely that immunoglobulin use will debilitating autoimmune diseases and antibody-mediated continue to rise as knowledge about its mechanisms of action allograft rejection.10 The fact that immunoglobulin also accumulates.

| VOLUME 29 | NUMBER 4 | AUGUST 2006 105 Using immunosuppressants – strategies and – is the affected organ beyond recovery protocols – the likelihood of relapse Treatment protocols are designed to: – the ability to monitor disease parameters long term (a) remove/suppress the predominant immune effectors and/or ■ Is this patient likely to withstand the treatment I will (b) resolve acute recommend (host fitness parameters)? Consider: – age (older patients are easier to immunosuppress but (c) prevent relapse. have a greater risk of infection) To achieve (a) and (b), high doses are often used initially – sepsis risk ('induction phase'). To achieve (c), lower doses of safer drugs are – cancer risk often chosen for the longer term ('maintenance phase'). – cardiovascular/diabetes risk Withdrawal of therapy is usually only considered after achieving – presence of comorbidities clinical and laboratory evidence of sustained remission. Drugs are withdrawn gradually, one at a time and in the case of – patient compliance and availability for follow-up. corticosteroids only after a long taper. In choosing the dose and duration of immunosuppressive treatments, one must always weigh disease activity versus host Empiricism vs controlled trials fitness. For example, an elderly patient with perinuclear-ANCA Many protocols have evolved empirically from an positive microscopic polyangiitis, confined to the kidneys, with understanding of the putative immune mechanisms operating crescents in 10% of glomeruli, will not need as aggressive an in a particular disease. Sometimes the protocols were derived approach as the same disease in a young patient, with 80% from what had been seen to work in conditions with apparently crescents, lung haemorrhage and mononeuritis multiplex. similar immunopathology. Randomised controlled trials of immunosuppressive protocols are available in the more Managing and monitoring patients taking common conditions such as rheumatoid arthritis or organ immunosuppressants transplantation, but as new drugs emerge, the combinations Patients need to be under constant surveillance, usually by a for comparison become bewildering. Today's 'gold standard' partnership between the specialist and the general practitioner. treatment can be very quickly outdated, perhaps even before Frequency of visits depends on perceived level of risk, but it has been optimised. Tailoring of to the typical parameters to monitor are summarised in Table 3. individual is desirable, but this approach makes protocol Patients may need prophylaxis against the adverse effects of comparisons difficult. their treatment (Table 4). Similarly, the disease being treated may be so pleomorphic Therapeutic drug monitoring is available now for a number that finding like populations to compare in trials becomes of drugs, for example cyclosporin, tacrolimus, sirolimus and very difficult. For example, lupus nephritis has five distinct mycophenolate. This allows for 'concentration-controlled' histological subtypes, each with their own prognosis. regimens. Some common drugs, for example corticosteroids, still have no good measure of individual bioavailability. Choosing immunosuppressive regimens Infection risk In order to make sound judgements when choosing a treatment protocol the clinician has to consider the clinical trial evidence increases susceptibility to infections and then decide: which can become life-threatening in a matter of hours. At first, common bacterial infections of wounds, chest or urine ■ Is the aim to pre-empt an anticipated immune response predominate, but after 1–2 months of therapy opportunistic (for example, after organ transplantation) or to suppress an infections emerge, particularly herpes viruses, pneumocystis established immune-mediated inflammation (for example, pneumonia, fungi and atypical mycobacteria. acute glomerulonephritis)? Vaccinations against influenza (injected) and pneumococcus are ■ In the case of an immune disease, how much recommended in chronically immunosuppressed patients.12 immunosuppression will be required and for how long (that They are safe and reasonably effective when given in the is, an assessment of disease activity)? Consider: stable maintenance phase. In general, live attenuated virus – the natural history of the untreated disease vaccines, such as varicella or measles, should not be given to – is the disease multiphasic (for example, polyarteritis immunosuppressed patients (or to close family contacts). nodosa) or 'single shot' (for example, microscopic polyangiitis) Cancer risk – the extent and severity of the disease in this particular In patients taking immunosuppressants, early cancers are often patient viral induced. They include lymphoproliferative disorders and

106 | VOLUME 29 | NUMBER 4 | AUGUST 2006 Table 3 Table 4 Routine monitoring of patients taking immunosuppressant Common prophylactic treatments for patients taking drugs immunosuppressant drugs

Monitoring of Acute phase reactants (e.g. C-reactive Infection 'Heavy' immunosuppression may immune system protein, erythrocyte sedimentation prophylaxis warrant prophylaxis for rate) cytomegalovirus (valganciclovir), Disease-specific auto-antibodies Pneumocystis jiroveci pneumonia (e.g. antineutrophil cytoplasmic (cotrimoxazole) and candidiasis antibody, anti-double-stranded DNA (oral nystatin) antibody) Influenza and pneumococcal Immunoglobulin and complement vaccines concentrations Anticoagulation Immune diseases are frequently Organ function and associated with thrombophilia and lymphocyte counts, requiring antiplatelet drugs or and T-cell subsets warfarin

Monitoring of Haemoglobin, platelets, lipids, blood Cardiovascular/ Corticosteroids, calcineurin inhibitors adverse effects glucose diabetes risk and mammalian target of Blood pressure rapamycin inhibitors all have adverse cardiovascular risk profiles. Skin cancer surveillance, rectal 'Statins' and antidiabetic drugs are examination, pap smear and possibly often indicated. prostate specific Bone densitometry Bone preservation May require calcium, vitamin D and bisphosphonate supplements Cataract screening Ulcer prophylaxis Consider H antagonist or proton Therapeutic drug Meeting therapeutic targets (where 2 pump inhibitor especially with monitoring known) steroid use Defines poor absorption Helps assess compliance References 1. Halloran PF. Immunosuppressive drugs for cervical cancer. In the long term, nearly all common cancers transplantation. N Engl J Med 2004;351:2715-29. are increased, but particularly skin cancers. After 20 years 2. Edwards JC, Cambridge G. Prospects for B-cell-targeted of immunoprophylaxis following renal transplant, 80% of therapy in . Rheumatology (Oxford) Australian patients will have developed skin cancer. 2005;44:151-6. 3. Appel GB, Radhakrishnan J, Ginzler EM. Use of Conclusion mycophenolate mofetil in autoimmune and renal diseases. Transplantation 2005;80:S265-71. Advances in our understanding of the immune aetiology 4. Mulay AV, Hussain N, Fergusson D, Knoll GA. Calcineurin of many debilitating diseases have resulted in wider use of inhibitor withdrawal from sirolimus-based therapy in kidney immunosuppressant drugs in common clinical practice. The transplantation: a systematic review of randomized trials. last two decades have seen the development of several useful Am J Transplant 2005;5:1748-56. small molecule drugs but also a profusion of monoclonal 5. Buhaescu I, Covic A, Levy J. Systemic vasculitis: still a antibodies targeting the immune system. Increasingly, primary challenging disease. Am J Kidney Dis 2005;46:173-85. care physicians are involved in the supervision of patients taking 6. Doan T, Massarotti E. Rheumatoid arthritis: an overview of new these drugs. This task has been made easier and safer by the and emerging therapies. J Clin Pharmacol 2005;45:751-62. establishment of therapeutic targets for drug monitoring and 7. Eisenberg R. Update on rituximab. Ann Rheum Dis 2005;64 Suppl 4:iv55-7. the obligatory use of prophylactic drugs to prevent common 8. Reiff A. A review of Campath in autoimmune disease: adverse effects. Good clinical judgement, supported by biologic therapy in the gray zone between laboratory investigations, is needed to differentiate the patients immunosuppression and immunoablation. Hematology who are over-immunosuppressed (and therefore at risk of 2005;10:79-93. infections and cancer) from those experiencing relapse of their 9. Nash PT, Florin TH. Tumour necrosis factor inhibitors. Med J underlying disease. Aust 2005;183:205-8.

| VOLUME 29 | NUMBER 4 | AUGUST 2006 107 10. Jordan SC, Vo AA, Tyan D, Nast CC, Toyoda M. Current approaches to treatment of antibody-mediated rejection. Self-test questions Pediatr Transplant 2005;9:408-15. The following statements are either true or false 11. Australian Health Ministers' Advisory Council. Review of (answers on page 115) the use and supply of intravenous immunoglobulins in Australia. Canberra: Blood and Blood Products Committee; 5. The risk of cervical cancer is increased in women taking 2000. http://www.nba.gov.au/PDF/ivig.pdf [cited 2006 Jul 4] immunosuppressant drugs. 12. Guidelines for vaccination of solid organ transplant 6. Calcineurin inhibitors increase the risk of cardiovascular candidates and recipients. Am J Transplant 2004;4 Suppl disease. 10:160-3.

Conflict of interest: none declared

Dental notes Prepared by Dr M McCullough of the Australian be inserted in the already anaesthetised buccal papilla and Dental Association gently forwarded until the solution can be deposited into the palatal tissues. Care should be taken regarding dosage and Painful paediatric procedures (see page 94) toxic concentrations and practitioners should be aware of the Dental procedures can be one of a child's most uncomfortable signs of toxicity. Occasionally, referral to a specialist paediatric experiences if not handled correctly. They can have adverse dentist and the use of sedation or general anaesthesia for psychological effects for the remainder of the child's life with lengthy and involved procedures may be the best approach regard to both future dental experiences, and how they relate to for the long-term psychological well-being and positive health other healthcare professionals. Dentists need to be acutely aware behaviour of the child. of a child's feelings of vulnerability and fear of the unknown when coming to the dentist for the first time. Ideally the dentist Xerostomia: a common adverse effect of drugs should follow guidelines such as the standards of care of the and radiation (see page 97) Australasian Academy of Paediatric Dentistry. Xerostomia (dry mouth) is a relatively common condition and Children should be introduced to the dental surgery in a non- is due to salivary dysfunction. It has multiple causes, including threatening manner, ideally when only an examination is developmental, inflammatory and neoplastic disorders. necessary. However, on occasion a child requires treatment after Common causes are anxiety, an adverse effect of drugs, and they have been in pain for some time, and the expectation of radiotherapy in the head and neck region. A decrease in the treatment is overlayed by previous experience or embellished quantity or quality of saliva has a profound effect on the oral accounts of the experiences of their friends, siblings and most environment. This results in extensive and recurrent smooth importantly the attitudes portrayed by adults, particularly their surface dental decay, increased periodontal disease, significant parents. The concerns and procedures outlined in the medical worsening of any underlying mucosal disease and an increased article (page 94) are generally applicable to dental practice. likelihood of oral candidosis and difficulty with the retention Establishing rapport with the child and communicating at the of dentures. Ideally, before patients start taking drugs that can appropriate developmental level leads to the use of behaviour cause xerostomia or undergoing radiotherapy in the head management techniques such as 'tell, show, do', distraction and and neck region, they should have a detailed dental check-up systematic desensitisation which should result in an atraumatic followed by treatment of any active disease. Topical agents dental visit for the child. can be very useful in reducing decalcification and promoting Local anaesthesia has, in the past, been considered by some mineralisation of teeth. Dentists can advise patients on methods practitioners to be unnecessary for deciduous teeth; however for the care of their teeth as well as methods to diminish the it should be stressed that if a procedure is predicted to be feeling of oral dryness that so profoundly affects patients' painful anaethesia should be provided. Topical anaesthesia quality of life. Patients with xerostomia must have regular dental should be used, with the material localised onto dry mucosa reviews and excellent oral hygiene as the removal of any teeth for 60 seconds, minimising the amount that the child may taste may result in them being unable to cope with dentures. Patients by using the end of a cotton roll. Local anaesthesia should be with Sjogren's syndrome also require long-term follow-up as introduced through tight mucosa for inferior alveolar blocks they have a significantly higher incidence of lymphoma in their and buccal infiltrations. For palatal tissues, the needle can salivary glands.

108 | VOLUME 29 | NUMBER 4 | AUGUST 2006