Drugs that act on the immune system: immunosuppressive and immunostimulatory drugs

Freya A. Goumas, Felix Braun, Dieter C. Broering, and Matthias Behrend

38

Drugs that act on the immune system: immunosuppressive and immunostimulatory drugs

Ciclosporin

(SED-15, 743; SEDA-29, 426; SEDA-30, 452; SEDA-31, 619)

Cardiovascular Hypertension is a wellknown adverse effect of calcineurin inhibitor therapy. The mechanisms have not been elucidated and are still controversial. In a patient undergoing hemodialysis, cardio­ thoracic bioimpedance showed evidence of raised systemic vascular resistance with nor­ mal blood volume (1A). She stopped taking ciclosporin and her blood pressure fell. Ciclosporin was restarted in a dosage of 25 mg/day and her systemic vascular resis­ tance was 1275 dyne/s5. When the dosage was increased to 100 mg/day, her blood pressure rose to 200/80 mmHg and her sys­ temic vascular resistance to 1874 dyne/s5, with normal cardiac output and a low-normal intrathoracic fluid volume.

Nervous system Ciclosporin can cause pseudotumor cerebri (2A). • A 15-year-old girl with hypodiploid acute lym­ phoblastic leukemia took methotrexate and ciclosporin 1.5 mg/kg after bone marrow

Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32038-1 � 2010 Elsevier B.V. All rights reserved.

transplantation and 30 days later developed a continuous frontal headache with bilateral papilledema. Her blood ciclosporin concentra­ tion was 85 µg/l. A CT scan showed mild pro­ minence of the lateral and third ventricles with no intracranial masses or obstructing lesions. The cerebrospinal fluid (CSF) was normal. Ciclosporin was withdrawn and replaced by tacrolimus. After a few days her headache resolved and fundoscopy showed less disc edema. • A 12-year-old boy with myelodysplastic syndrome took methotrexate and ciclosporin 1.5 mg/kg after stem cell transplantation and the blood ciclosporin concentration was kept at 150–200 µg/l. After 45 days he developed persistent unexplained nausea and vomiting with no headache, unresponsiveness to antiemetics and bilateral papilledema. A CT scan showed no evidence of intracranial masses and the CSF was normal. He was given acetazola­ mide and ciclosporin was replaced by myco­ phenolate mofetil. His symptoms resolved after a short course of methylprednisolone and the papilledema improved.

In 20–40% of liver transplant recipients taking calcineurin inhibitors, central nervous system toxicity presents a wide spectrum of mild to severe neurological and psychiatric disorders, for which intravenous lipid may be beneficial. Of 45 Japanese patients who received living-donor transplants, 10 devel­ oped neurological complications, such as changes in mental status, confusion, seizures, altered level of consciousness, neuralgia, headache, and tremor; 3 were taking ciclosporin and 7 tacrolimus (3c). If the

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blood–brain barrier is impaired, unbound calcineurin inhibitors might be able to enter the brain more readily. Based on this hypothesis, five patients (two of whom were taking ciclosporin and three tacrolimus) received an intravenous lipid supplement of 20% soybean oil 0.1–0.2 ml/kg/hour for 2–3 days, after which, and without a change in the dosage of the calcineurin inhibitor, their neurological symptoms improved remarkably. Metabolism In an international multicenter study of the incidence of diabetes mellitus after renal transplantation, the primary safety end point was a composite of new-onset diabetes or impaired fasting glucose within the first 6 months (4C). The primary efficacy end point was a composite of biopsy-proven acute rejection, graft loss or death at 6 months after transplantation. The patients were randomized to ciclosporin microemul­ sion (n = 336) or tacrolimus (n = 346) with mycophenolic acid, a glucocorticoid and basiliximab. Diabetes susceptibility factors, glucocorticoid doses and demographics were similar between the groups. There was new-onset diabetes or impaired fasting glucose at 6 months in 26% of those who were given ciclosporin and 34% of those who were given tacrolimus. The primary efficacy end points occurred in 13% of those who were given ciclosporin and 9.8% of those who were given tacrolimus. Mean glomerular filtration rate (GFR), mean serum creatinine and mean blood pressure were similar in the two groups at 6 months, but median total cholesterol, LDL cholesterol and triglycerides were significantly higher at 6 months with ciclosporin. The possible adverse effects of ciclosporin (mean dose 233 mg/day) on first- and second-phase insulin secretion have been investigated using a 3-hour hyperglycemic glucose clamp technique in nine non-diabetic patients on hemodialysis, seven men and two women, mean age 61 years, before and after 2 weeks of treatment with ciclosporin (5c). The average fasting concentration of C-peptide rose significantly from 1.65 to

1.93 nmol/l after 2 weeks of treatment with ciclosporin. First-phase insulin secretion did not change significantly, but second-phase secretion was significantly inhibited by ciclosporin and second-phase C-peptide secretion also fell in eight patients. Mouth Ciclosporin can cause oral nongingival inflammatory fibrovascular hyper­ plasia (6A). • A 14-year-old boy had a hemopoietic cell transplantation for acute lymphocytic leuke­ mia and was given ciclosporin. He had exophy­ tic, polypoid, multinodular masses on the tongue, measuring 2
1 and 0.5
0.5 cm. • An 8-year-old boy had a hemopoietic cell transplantation for acute leukemia followed by ciclosporin therapy. He later developed a 2
1 cm, ulcerated, slightly tender, exophytic, polypoid, multinodular mass on the right side of the tongue. • A 3-year-old boy had a hemopoietic cell transplantation for purine nucleoside phos­ phorylase deficiency and was later given first ciclosporin and then tacrolimus for graft­ versus-host disease involving the buccal mucosa and the tongue. He subsequently developed two polypoid, multinodular masses on the right and left dorsum and lateral bor­ ders of the tongue. • A 58-year-old woman underwent right lung transplantation for severe chronic obstructive pulmonary disease followed by immunosup­ pression with tacrolimus and prednisone. She later developed two linear, exophytic, slightly tender, sessile, polypoid soft-tissue masses in her lip.

In all cases the lesions were excised and histology showed granulation and fibrous tissue with collagenization and edema, overlying ulceration, and acute and chronic inflammation. Urinary tract Treatment with calcineurin inhibitors is often associated with chronic renal insufficiency and conversion to myco­ phenolate may improve renal function (7c). In a single-center study, 49 patients who underwent liver transplantation between 1986 and 2002 were given a combination of calcineurin inhibitors and glucocorti­ coids; azathioprine was used as adjuvant therapy in 71%, but was withdrawn before the introduction of mycophenolate, starting at 500 mg bd during the first week,

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Chapter 38

followed by an increase every week up to 1 g bd. The daily dose of calcineurin inhibi­ tor was reduced by 10–20% stepwise every 4 weeks after the optimal dose of mycophe­ nolate was reached; the calcineurin inhibi­ tors were withdrawn if possible within 6 months. Mean creatinine clearance was 43 ml/minute when mycophenolate was introduced and in 45 patients it was less than 60 ml/minute. Of 39 patients who responded to a reduced dose of calcineurin inhibitor, 18 recovered completely and 21 had partial recovery of renal function; 10 were non-responders; 14 patients in whom the calcineurin inhibitor was completely withdrawn at 1 year after mycophenolate introduction tended to have a higher increase in creatinine clearance (22 ml/min­ ute). Patients with alcoholic cirrhosis had the worst deterioration in renal function and a smaller improvement after dosage reduction. In one patient, mycophenolate was withdrawn because of severe diarrhea. In 32 patients other adverse effects were easily controlled with symptomatic treat­ ment or a reduction in dosage. In 40 patients with renal dysfunction (creatinine clearance 40–80 ml/minute) who randomized to continue calcineurin inhibi­ tor therapy or switch to sirolimus, renal function improved in the latter within 3 months (75 versus 56 ml/minute) (8C). At 12 months this difference persisted (72 ver­ sus 58 ml/minute) but was not significant. Two patients developed steroid-sensitive rejection, one in each arm. Other adverse effects were mild, and included mouth sores (25%), hyperlipidemia requiring treatment (15%), and pruritus (5%). Infection risk Fungal infection Fungal infections are common in organ transplant recipients. In a prospective, multicenter, international study of the variables that affect the risk of dissemination and out­ comes, 111 transplant recipients with Cryp­ tococcus neoformans infection were studied (9C). Cryptococcus neoformans infection was defined as follows: positive cultures in specimens, including blood cultures; or histopathological or cytopathological exam­ ination of specimens from needle aspiration

707

or biopsies showing encapsulated yeast cells; or positive cryptococcal antigen in the blood or CSF in a patient with a compatible clin­ ical presentation. Cryptococcosis occurred a median of 21 months after transplantation; 54% of the patients had pulmonary infec­ tions, 52% had nervous system infections, and 8.1% had skin, soft-tissue, or osteoarti­ cular infections. There was disseminated cryptococcosis in 61%, and in 32% the infection was limited to the lungs. Patients who were taking ciclosporin or tacrolimus were significantly less likely to have nervous system infections and were more likely to have cryptococcosis limited to the lungs. There were nervous system infections in 50% of the patients who took ciclosporin, 47% of those taking tacrolimus, and 80% of those taking azathioprine or mycophenolate mofetil. The risk of disseminated infection was significantly higher after liver transplan­ tation. The mortality rate at 90 days was 14%. The mortality rate was 20% in patients taking ciclosporin, 7.9% in those taking tacrolimus, and 40% in those taking azathioprine or mycophenolate mofetil. The mortality rate was significantly higher in patients with abnormal mental status, renal insufficiency at baseline, fungemia, and dis­ seminated infection, and was lower in patients taking a calcineurin inhibitor. Tumorigenicity In a single-center study, 10 patients who developed de novo neoplasms or had a recurrence of hepatocellular carci­ noma were switched from ciclosporin or tacrolimus to everolimus (10c). The median time from transplantation to diagnosis of the neoplasm was 38 (range 82–142) months. The median time from diagnosis to the start of everolimus therapy was 4 (range 2–32) months. Target everolimus trough concen­ trations were 3–8 ng/ml. At the end of fol­ low-up, seven patients were alive; five were in complete remission, and two had tumor stability without significant growth or distant metastases. Three patients died, one because of disease progression and the other two because of hepatic lymphoma and laryngeal cancer. Median survival from tumor diagno­ sis was 21 (range 7.5–41) months. In the control group of 14 patients, who took

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ciclosporin, prednisone, and azathioprine or mycophenolate mofetil, median survival was 5.3 (range 0–70) months. The probability of survival was significantly greater with everolimus. Drug–drug interactions Antiepileptic drugs In a 14-year-old girl levetiracetam did not affect the ciclosporin plasma concentra­ tion, but oxcarbazepine reduced it from 170 ng/l to 70 ng/l, despite an increase in ciclosporin dosage from 310 to 600 mg/ day (11A). When levetiracetam was used in stead of oxcarbazepine 750mg bd, the dose of ciclosporin was reduced to 340 mg/day, with satisfactory plasma concentrations. Itraconazole Co-medication with itra­ conazole causes a flattening of the ciclos­ porin blood concentration profile in lung transplant recipients (12c). The pharmaco­ kinetic profiles before and after itracona­ zole 200–400 mg/day in 13 lung transplant recipients were comparable. Food–drug interactions Tangerine juice did not alter the AUC0!12 h of whole-blood ciclosporin in children with renal transplants (13C). Management of adverse effects In patients taking ciclosporin there are increased con­ centrations of specific cytokines, particu­ larly transforming growth factor (TGF)­ beta, in hyperplastic gingival tissue, suggest­ ing that this growth factor plays a role in accumulation of extracellular matrix. Roxithromycin inhibits the production of TGF-beta by inflammatory cells and may reduce ciclosporin-induced gingival over­ growth (14c).

Everolimus (SDA-RAD) (SED-15, 1306; SEDA-29, 433; SEDA-30, 453; SEDA-31, 622) Respiratory There have been several reports of bronchiolitis obliterans organizing

pneumonia in patients taking everolimus (15A, 16A). • A 56-year-old woman took ciclosporin, azathioprine, and a glucocorticoid after renal transplantation. After excision of a lip malig­ nancy she was given everolimus instead, and 2 months later developed a cough, dyspnea, and a low-grade fever. A chest X-ray showed a lesion at the base of the left lung compati­ ble with pneumonitis. Bronchoscopy showed bronchiolitis obliterans organizing pneumo­ nia, which responded to a corticosteroid within 3 days. • A 45-year-old man took ciclosporin, azathio­ prine, and prednisone after heart transplanta­ tion, but developed worsening renal function and was given everolimus instead of ciclos­ porin; 4 months later he developed a fever, dry cough, dyspnea, and pleuritic chest pain. A chest X-ray and CT scan showed bilateral lesions predominantly in the superior lobes and on the left side. Bronchoscopy and alveo­ lar lavage showed no evidence of infection and he was given ciclosporin again. A transbron­ chial biopsy showed intra-alveolar fibrinous exudates with fibroblastic foci and scanty lym­ phoid interstitial infiltration. After withdrawal of everolimus he improved and the CT scan became normal. • A 66-year-old man took ciclosporin and azathioprine after heart transplantation but converted to everolimus because of progres­ sive renal dysfunction and 2 months later developed a fever, dry cough and pleuritic chest pain. A chest X-ray showed basal lesions on the right side. Transbronchial biopsy showed intra-alveolar fibrinous exudates with fibroblastic foci in the alveolar and bronchial lumens and a scanty lymphoid interstitial infil­ trate. Everolimus was withdrawn and ciclo­ sporin restarted. He improved rapidly and became asymptomatic within 6 months.

Infection risk In a short-term study in eight kidney transplant recipients who were switched from a calcineurin inhibitor to everolimus, renal biopsies were per­ formed in six and showed chronic allograft nephropathy grades 1A–2. In six cases the calcineurin inhibitor was withdrawn and in two the dosage was reduced by 30% (17c). Everolimus was started on the day after; the initial dose was 0.75 mg bd. Three patients had infections (pneumonia, ocular viral infection, and herpes zoster), which responded to antibiotics and everolimus dosage reduction.

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Leflunomide

(SED-15, 2015; SEDA-29, 435; SEDA-30, 454; SEDA-31, 625)

Observational studies BK virus, which is closely related to the JC virus, is the most frequent polyomavirus. It was first isolated in 1971 from the urine of a kidney transplant patient. Polyomavirus-associated nephropa­ thy affects 1–10% of kidney transplant reci­ pients, and there is graft failure/loss in about 90%. Treatment with leflunomide, besides reducing immunosuppression, improves graft function in such cases. In a single-center study, leflunomide was used to treat poly­ omavirus-associated nephropathy in 11 of 346 kidney transplant recipients (18c). The initial dose was 100 mg/day for 5 days, fol­ lowed by 40 mg/day, maintaining serum con­ centrations at 40–80 mg/l. The median follow-up time was 16 months, after which median serum creatinine concentration was 150 (90–378) µmol/l versus 189 (92–265) µmol/l at baseline and estimated creatinine clearance was 45 (19–95) versus 36 ml/min­ ute. There were no significant increases in liver enzymes. Platelet counts were reduced below 100
109/l in only three patients and there were no bleeding events. Four patients developed fungal pneumonia 2 weeks after leflunomide treatment, and were successfully treated with voriconazole. Respiratory In a prospective study of 136 patients with active rheumatoid or psoriatic arthritis taking leflunomide 20 mg/ day, 5 developed cavitating pneumonia after the start of leflunomide treatment (19c). Of 1010 patients who took leflunomide for rheumatoid arthritis for at least 1 month, 10 developed interstitial lung dis­ ease; the risk was greater in those with pre­ existing lung diseases (20c). Pulmonary nodulosis has been associated with leflunomide (21A). Thoracoscopic biopsy showed fibrinoid necrosis with palli­ sading macrophages and a few giant cells, suggestive of a rheumatoid nodule; Ziehl– Nielsen staining for mycobacteria was nega­ tive. Leflunomide was withdrawn and the pulmonary nodules regressed within 6 months.

709

Nervous system In 32 patients with rheu­ matoid arthritis taking leflunomide or other disease-modifying antirheumatic drugs, leflu­ nomide was associated with an apparent increase in the symptoms of peripheral neuropathy after 6 months; however, the symptoms did not correlate with neuro­ physiological studies (22c). In 16 patients with rheumatoid arthritis taking leflunomide and 16 who were taking disease-modifying antirheumatic drugs, 54% of the former and 8% of the controls had increased neuropathy symptom scores 6 months into the study (23c). However, there was no significant difference between the two groups in upper and lower limb sensory and motor amplitudes. One developed both clinical and neurophysiological evidence of a peripheral neuropathy 5 months into the study and improved after withdrawal of leflunomide. Acid base balance Renal tubular acidosis has been associated with leflunomide (24A). • A 35-year-old woman with seronegative arthritis developed renal tubular acidosis after taking leflunomide 20 mg/day for 9 months; she had a metabolic acidosis with a normal anion gap; the urine pH was 6.9. Leflu­ nomide was withdrawn and she was given colestyramine to accelerate the clearance of leflunomide. The serum bicarbonate normal­ ized within 3 weeks and was still normal 8 months later.

Hematologic Reports of suspected adverse reactions associated with the use of leflunomide have been evaluated in Australia (25c). Pancytopenia was defined by the following diagnostic criteria: severe anemia (hemoglobin concentration below 10 g/dl), neutropenia (polymorphonuclear leukocyte count below 1.5
109/l), and thrombocytopenia (platelet count below 100
109/l). There were 11 cases from January 2000 to September 2002 that met these criteria. Three had fatal outcomes, in two cases due to sepsis. Five patients had recovered at the time of reporting and three had not. Nine were also taking methotrexate; of these, six had been taking doses of 7.5–20 mg/week when they started taking leflunomide. The other three

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patients had taken leflunomide and devel­ oped pancytopenia after methotrexate was taken in addition. In two cases, when methotrexate was added, pancytopenia occurred after 19 and 32 weeks of combina­ tion therapy.

RNA synthesis. Unlike other cell types that can recycle nucleotides via the salvage pathway, B and T lymphocytes depend on de novo synthesis and the action of myco­ phenolate is therefore directed against this specific cell group.

Skin Leflunomide-induced subacute cuta­ neous lupus erythematosus with erythema multiforme-like lesions (26A), leflunomide­ induced skin necrosis (27A) and progressive generalized blistering and a widespread pru­ nosus skin rash (28A) have been described.

Observational studies In a retrospective analysis 70 patients were identified who had received mycophenolate for inflamma­ tory bowel disease; 19 had ulcerative colitis and 51 had Crohn’s disease (31c). There were 40 women and 30 men; the mean age was 42 years. The average dose was 1.5 g/day. The mean duration of therapy was 3.9 months. Adverse effects were attrib­ uted to mycophenolate in 19 patients, 2 of whom continued taking it; one had a rash that resolved and the other had deranged liver function tests, which resolved after withdrawal of mycophenolate; on restarting treatment, the liver function tests remained normal. The other patients had to stop taking mycophenolate because of severe adverse effects, such as non-specific malaise, beha­ vioral changes (including depression), joint pains, rashes, pancreatitis, diarrhea, abnor­ mal liver function tests, and alopecia. Of six patients with myositis refractory to conventional immunosuppressive therapy, two had dermatomyositis, three had poly­ myositis, and one fulfilled the clinical cri­ teria for SLE and developed myositis (32c). They took mycophenolate for a mean of 22 months in a mean dosage of 1.6 g/day þ prednisolone. Two patients developed mild adverse effects, nausea and headaches, which did not require the with­ drawal of mycophenolate. In a retrospective analysis of the use of mycophenolate in uveitis in 17 children (10 boys, 7 girls, aged 2–13 years), there was a steroid-sparing effect in 88% (33c). There were mild adverse effects, such as headache, rash, or gastrointestinal discom­ fort, in seven patients, and withdrawal was required in one child. In a single-center study of mycopheno­ late in moderate to severe atopic dermatitis in 20 patients aged 54–79 years, all of whom had failed or developed dependence on systemic corticosteroids, and had failed

Infection risk Cytomegalovirus antigen­ emia rapidly increased following lefluno­ mide administration in a 46-year-old man with a diffuse large B-cell lymphoma, wor­ sening renal function and incompletely con­ trolled multidrug-resistant cytomegalovirus infection after an autologous stem cell transplantation (29A). Teratogenicity Congenital malformations have been described after maternal expo­ sure to leflunomide during the first tri­ mester of pregnancy (30A). • A 43-year-old woman with rheumatoid arthri­ tis became pregnant while taking leflunomide, which was withdrawn after 16 weeks of gesta­ tion. She gave birth 9 weeks prematurely to a boy who was blind in the right eye and had cerebral palsy with left-sided spasticity.

Leflunomide reversibly binds dihydro­ orotate dehydrogenase, the rate-limiting mitochondrial enzyme in the synthesis of pyrimidine ribonucleotide uridine mono­ phosphate. This leads to reduced DNA synthesis, inhibiting T cell clonal expansion.

Mycophenolate mofetil

(SED-15, 2402; SEDA-29, 445; SEDA-30, 455; SEDA-31, 627) Mycophenolate acid is a non-competitive, reversible inhibitor of inositol monophos­ phate dehydrogenase, an enzyme required for de novo guanosine nucleotide biosynth­ esis, and it subsequently affects DNA and

Drugs that act on the immune system

Chapter 38

or experienced adverse effects from other systemic therapies and/or phototherapy, mycophenolate produced improvement in 18 cases (34c). One patient withdrew at 4 weeks because of persistent severe pruritus. Another improved, but mycophenolate was withdrawn because of nausea; however, the patient later responded to and tolerated a second course. There were few adverse effects, the commonest ones being nausea, constipation, diarrhea, stomach pains, fati­ gue, anorexia, and headache. Four patients developed herpes zoster at 8–56 weeks after the start of mycophenolate therapy, and all responded promptly to standard antiviral therapy. In one patient, the white blood cell count fell but normalized on a lower dose. In a retrospective analysis of the use of mycophenolate in 14 children with atopic dermatitis (9 boys, 5 girls) aged 2–16 years, all of whom had failed to respond to con­ ventional topical treatment and/or oral glucocorticoids and ciclosporin, 4 responded completely, 4 had an excellent response, 5 had a good response and 1 had an inade­ quate response (35c). Two patients devel­ oped mild gastrointestinal upsets during the first week of treatment. One patient had a history of recurrent simplex viral infections and two requiring systemic antimicrobial therapy for episodes of extensive impetigi­ nization and folliculitis and recurrent sta­ phylococcal furunculosis. Metabolism Immunosuppressive drug ther­ apy causes hyperlipidemia. During com­ bined therapy for 12 months with a glucocorticoid þ mycophenolate or azathio­ prine, there were no significant differences between the groups in total cholesterol, high-density lipoprotein (HDL), LDL or very-low-density lipoprotein (VLDL) (36c). Mouth Mycophenolate can cause mouth ulcers (37A). • A 60-year-old woman with liver cirrhosis, taking ciclosporin and methylprednisolone, started taking mycophenolate when she had an acute episode of rejection and 5 days later developed ulcers on her tongue and hard palate. She was given aciclovir and

711 mycophenolate was withdrawn; 5 days later, the ulcers disappeared. • A 31-year-old woman who regularly took paracetamol and piroxicam olamine for polyarthralgia developed subacute liver failure and hepatic encephalopathy and underwent liver transplantation. Her immunosuppression con­ sisted of ciclosporin and methylprednisolone. One week later she developed biliary stenosis from choledochal kinking and required retro­ grade cholangiopancreatography and stent instillation. She was then given mycophenolate and developed oral ulcers. The mycophenolate was withdrawn and 1 week later the ulcers had completely disappeared.

Gastrointestinal Mycophenolate in induc­ tion and maintenance therapy of severe lupus nephritis has been compared with cyclophosphamide and azathioprine in a meta-analysis of randomized controlled trials (38M). Compared with cyclophospha­ mide, mycophenolate significantly reduced the risk of infection but there was no differ­ ence in the risk of end-stage renal disease. Mycophenolate increased the risk of gastro­ intestinal symptoms, but the results were not statistically significant. Compared with azathioprine, mycophenolate did not reduce the incidence of death, end-stage renal dis­ ease, relapse or doubling of serum creati­ nine. Gastrointestinal symptoms such as diarrhoea or nausea and vomiting occurred more often with mycophenolate than azathioprine. Teratogenicity Experimental studies and clinical observations have shown terato­ genic effects after in utero exposure to mycophenolate (39A). • A 25-year-old Spanish woman underwent renal transplantation. She took tacrolimus 12 mg/day and mycophenolate 500 mg/day and 2 years later became pregnant. Myco­ phenolate was discontinued at 10 weeks of gestation. At 20 weeks ultrasonography showed fetal cleft lip and palate. Amniocentesis was performed and a normal female karyotype was diagnosed. At 41 weeks a girl was delivered with bilateral upper cleft lip and complete cleft palate, bilateral microtia, hypertelorism, micro­ gnathia and mild left ptosis. A CT scan of the temporal bone showed bilateral absence of the external ear canals and small tympanic cavities. A CT scan of the brain and cerebellum was normal. At the age of 9 months the girl needed

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hearing aids, but her physical and neuro­ development were normal for her age.

Pimecrolimus (SED-15, 2833; SEDA-29, 449;SEDA-30, 456; SEDA-31, 628) Skin Pimecrolimus ointment can cause allergic contact dermatitis (40A). • A 9-year-old boy with atopic dermatitis devel­ oped allergic contact dermatitis after using tacrolimus ointment 0.1% for 8 months. A provocative test in the preauricular area resulted in a few isolated papules and a double-blind, vehicle-controlled test on the arms resulted in non-confluent erythematous papules on the side treated with pimecrolimus.

Sirolimus (rapamycin) (SED-15, 3148; SEDA-29, 449; SEDA-30, 457; SEDA-31, 628) Observational studies In a single-center study of drug-eluting stents in 64 patients, sirolimus-eluting stents were used in 57 and paclitaxel-eluting stents in 7 (41c). There was procedural success in 63 patients. One 87-year-old patient died in hospital due to papillary muscle rupture and refractory heart failure. There were no 30-day cases of stent thrombosis, re-infarction or target vessel re-intervention. During follow-up, one patient died in a rehabilitation facility 52 days after intervention due to nosoco­ mial pneumonia and sepsis. There were no late cases of stent thrombosis, re-infarction, or target vessel re-intervention. Systematic reviews Sirolimus-eluting stents and bare-metal stents have been compared in a meta-analysis of 14 trials in 4958 patients (42M). There was no significant effect on overall long-term survival and sur­ vival free from myocardial infarction. Siro­ limus-eluting stents were associated with a sustained reduction in the need for re-inter­ vention but with an overall risk of stent thrombosis that was at least as high as that seen with bare-metal stents.

Respiratory Sirolimus can cause alveolar hemorrhage (43A). • A 55-year-old man, who had undergone heart transplantation 8 years before for ischemic cardiomyopathy, and who was taking ciclo­ sporin and mycophenolate, was given siro­ limus. After 2 months he developed an intermittent low-grade fever with occasional spikes to 39°C, accompanied by chills, for about 4 weeks; he also had shortness of breath, a dry cough, a few episodes of diar­ rhea, weight loss of about 9 kg and worsen­ ing fatigue. There were bilateral basal coarse crackles in the lungs. The oxygen saturation was 93%, the PaO2 7.9 kPa, PaCO2 3.5 kPa, pH 7.48 and hemoglobin 8.4 g/dl. The serum creatinine rose from 159 to 283 µmol/l on day 4. A chest X-ray showed bilateral interstitial infiltrates, predominantly in the lower lobe, and a CT scan showed ground-glass parench­ ymal opacities. Opportunistic pulmonary infections were ruled out by serological tests and blood cultures. Bronchoscopy showed diffuse bloody secretions and bronchoalveo­ lar lavage showed diffuse alveolar hemor­ rhage; there were no malignant cells or organisms. Sirolimus was withdrawn and he was given prednisone 40 mg bd. He improved and 6 days later was asymptomatic.

Sirolimus can cause interstitial pneumonitis (44A–46A). • A 61-year-old man took azathioprine and methylprednisolone after kidney transplanta­ tion for chronic glomerulonephritis but later developed allograft nephropathy and multiple precancerous skin lesions. Azathioprine was withdrawn and sirolimus 2 mg/day introduced. After 1 month the dose was increased to 3 mg/ day and 2 weeks later he developed a fever and dyspnea on exertion and at rest. A CT scan showed bilateral interstitial infiltrates in the lower lobes. Sirolimus was withdrawn and he recovered rapidly. • A 67-year-old man took ciclosporin, myco­ phenolate, and methylprednisolone after renal transplantation for secondary focal seg­ mental glomerulosclerosis. After 2 years he was switched to sirolimus 4 mg/day þ methyl­ prednisolone because of a skin tumor and 2 weeks later developed stomatitis, progressive shortness of breath on exertion, and a non-pro­ ductive cough. A chest X-ray showed bilateral lower lobe infiltrates and a CT scan showed extensive interstitial changes. Transbronchial biopsy showed lymphocytic alveolitis with no evidence of infection. Sirolimus was withdrawn and methylprednisolone given. His symptoms improved immediately.

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• A 62-year-old man took ciclosporin þ methyl­ prednisolone after renal transplantation but developed borderline rejection and calcineurin inhibitor toxicity. His immunosuppression was switched to sirolimus 2 mg/day þ methylpred­ nisolone and 2 weeks later he developed shortness of breath on exertion, subfebrile temperatures, a non-productive cough, weight loss and fatigue. A chest X-ray and CT scan showed bilateral interstitial infiltrates in both lower lobes. Sirolimus was withdrawn and methylprednisolone given; he recovered immediately. • A 42-year-old woman was given thymoglobulin, high-dose methylprednisolone, tacrolimus, and mycophenolate for acute vascular rejection after kidney transplantation for systemic lupus erythematosus. Later, mycophenolate was switched to sirolimus 2–3 mg/day and she was subsequently given diltiazem 270 mg/day. After 3 weeks she developed leg edema and progressive dyspnea on exertion and at rest. The sirolimus trough concentration was 21 µg/l. Despite withdrawal of diltiazem and normaliza­ tion of sirolimus concentrations, the symptoms did not resolve. An X-ray and a CT scan showed interstitial pneumonitis. Sirolimus was with­ drawn and the dose of methylprednisolone was increased. Her symptoms improved and the infil­ trates vanished. • A 62-year-old man was given ciclosporin and glucocorticoids after liver transplantation for alcoholic liver cirrhosis but developed progres­ sive graft dysfunction. Ciclosporin was switched to tacrolimus þ mycophenolate. Later, siro­ limus 3 mg/day was introduced and tacrolimus withdrawn because of worsening renal func­ tion. Despite progressive dosage reduction the sirolimus concentration remained high (at around 20 µg/l) and after 3 months he devel­ oped progressive dyspnea, a low-grade fever, chills, a dry cough, and fatigue. He improved slightly with antibiotic therapy but relapsed 1 week later. Withdrawal of sirolimus led to rapid clinical improvement. • A 1-year-old girl was given tacrolimus, pred­ nisolone and mycophenolate after heart transplantation but developed intractable diarrhea. The dosage of mycophenolate was reduced and subsequently replaced by siro­ limus 1 mg/m2. After 3 days she developed dyspnea, hypoxemia and respiratory acidosis. A chest X-ray showed bilateral infiltrates. The sirolimus trough concentration was 23 µg/l. Despite broad-spectrum antimicrobial drug therapy, intubation and mechanical ventilation were required. Echocardiography showed nor­ mal allograft function and microbiological stu­ dies were all negative. After withdrawal of sirolimus and intravenous administration of hydrocortisone, there was pronounced clinical improvement.

713

All these patients were given a loading dose at the start of therapy and/or had an increase in the dose of sirolimus or trough con­ centration before the onset of symptoms. Additional potential susceptibility factors included allograft dysfunction and male sex. Metabolism The effects of sirolimus and everolimus on serum triglycerides have been analysed retrospectively in 55 heart transplant patients (47c). In 28 patients taking sirolimus, median triglyceride con­ centrations increased significantly by up to 65% and were clearly above the upper limit of the reference range. Total cholesterol concentrations increased by 25%. The use of statins increased significantly from 48% at baseline to 93% at 12 months. LDL con­ centrations were higher in those taking sirolimus. Sirolimus inhibits the growth of tumor cell lines in vitro and in vivo. In 25 patients who were converted from a calcineurin inhi­ bitor-based immunosuppressive regimen to sirolimus (concentrations over 6 µg/l) after detection of a tumor (11 lymphomas, 10 skin cancers, 1 thyroid, 1 lung, 1 native kid­ ney, and 1 laryngeal carcinoma), serum cho­ lesterol rose significantly from 4.58 mmol/l at baseline to 5.60 mmol/l after 1 year; LDL rose from 2.65 to 3.30 mmol/l at 1 year and triglycerides from 1.66 to 2.05 mmol/l at 3 months; creatinine clearance increased from 60 to 66 ml/minute at 1 year (48c). Urinary tract Sirolimus can cause protein­ uria. In a single-center study in 78 patients (43 men, 35 women; mean age 37 years) after transplantation, 63 were converted from calcineurin inhibitors þ mycopheno­ late þ glucocorticoids to sirolimus; 16 devel­ oped proteinuria (49c). In addition, 2 of 15 patients who had received sirolimus de novo developed proteinuria. The protei­ nuria occurred at a mean of 11 months after the start of sirolimus therapy. The mean value was 2.6 g/day. In 5 patients it reached nephritic levels, and there was edema in 13. In five patients an angiotensinconverting enzyme (ACE) inhibitor or

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angiotensin II receptor antagonist was used. Sirolimus was withdrawn in six patients. At the time of proteinuria, sirolimus trough concentrations were 4.4–15.3 µg/l, but there was no correlation between proteinuria and trough concentrations. Withdrawal of siro­ limus was associated with resolution. Fertility Oligospermia has been attributed to sirolimus (50A). • A 26-year-old man was given sirolimus, tacro­ limus, and a glucocorticoid after heart–lung transplantation for severe pulmonary hyper­ tension. The glucocorticoid was withdrawn after 6 months. About 3 years later he devel­ oped a benign Leydig-cell tumor of the left testicle with widespread testicular atrophy and severely reduced spermatogenesis. Siroli­ mus was withdrawn and replaced by mycophe­ nolate and 1 year later spermatogenesis had improved.

Tacrolimus

(SED-15, 3279;

SEDA-29, 453; SEDA-30, 458; SEDA-31,

630)

Observational studies Tacrolimus prolongs graft survival and may be considered after high-risk keratoplasty. In a comparison of the effect of systemic tacrolimus on the survival of corneal grafts, high-risk patients (n = 47) were defined as having at least two quadrants of stromal vascularization and/or a history of previous graft failure (51c). Oral tacrolimus was begun at a dose of 2 mg/day on the day of surgery and was adjusted to achieve a whole blood tacrolimus trough concentration of 1–12 µg/l. The mean dosage was 2.5 mg/day. All the patients also used topical steroids. Tacrolimus was continued for 18 months postoperatively or until the sutures were removed; in patients who had episodes of rejection it was contin­ ued for 1 year after the last episode. Four patients stopped taking tacrolimus because of adverse effects and were excluded from the analysis; four died at various stages of follow-up. In the 43 patients who were analysed, the graft was clear in 28 at the time of the last follow-up or death. Eight patients had episodes of rejection while taking

tacrolimus, of whom three had multiple epi­ sodes that were controlled by intravenous steroids. Five had irreversible rejection resulting in graft failure. Four had episodes of rejection after discontinuing tacrolimus. Graft failure occurred in one patient because of rejection and in nine because of non-immune causes, including raised intra­ ocular pressure, stem cell failure, and bac­ terial keratitis. In 30 of 39 patients who were included in the 2-year survival analy­ sis, eligible grafts were clear at 2 years; 6 failed grafts were not related to rejection and 3 were due to rejection. Increased blood pressure attributed to tacrolimus was con­ trolled with low-dose ACE inhibitors. Other adverse effects were headaches, malaise (n = 4), paresthesia (n = 3), and insomnia, pancreatitis, folliculitis, diabetes, lymphopenia, and a reversible increase in serum creatinine (1 each). Nervous system Tacrolimus can cause sei­ zures. In a single-center study of 132 liver transplant patients, 12 had tacrolimus-related seizures during the early postoperative per­ iod (52c). In 5 patients with posterior leukoencephalopathy syndrome, MRI scans showed the characteristic findings of hyperintensity of the white matter on T2 weighted images; there were no abnormalities in the other 7 patients. Ciclosporin was substituted in 11 patients and sirolimus in 1, and all received antiepileptic drug therapy. After 3 months the MRI findings resolved. Antiepileptic drug therapy was withheld in 5 patients at an average follow-up of 20 months. Tacrolimus can cause cerebellar ataxia (53A). • A 58-year-old woman took tacrolimus þ prednisone after living-donor liver transplan­ tation for hepatic cirrhosis. After 7 days she developed slurred speech, an intention tremor and a swaying gait. Tacrolimus was withdrawn and she was given ciclosporin instead. An MRI scan showed no abnormal intensities. The dose of ciclosporin was reduced from 200 to 100 mg/day and mycophenolate 1 g/day was added. Her blood ciclosporin concentration fell below the usual target range. The next day, the cerebellar ataxia improved and she was able to walk for at least 20 minutes.

Drugs that act on the immune system

Chapter 38

Tacrolimus can cause cerebellar atrophy (54A). • A 31-year-old man developed cerebellar ataxia 9 years after heart transplantation while taking tacrolimus þ mycophenolate. An MRI scan showed dilated sulci in the cerebellar region and an atrophic cerebellum. Tacrolimus was switched to sirolimus and although the symptoms improved they did not resolve com­ pletely. He also had hyperthyroidism and underwent thyroidectomy.

Chronic sensorimotor polyneuropathy may be an adverse effect of tacrolimus (55A). • A 44-year-old woman took tacrolimus 3 mg bd after living-donor kidney transplantation for focal glomerular sclerosis. After 10 months she complained of ‘twitching’ of the right side of the face followed by that of the left side, associated with facial numbness. She had difficulty in chewing and drinking through a straw and complained of gait imbalance. There was bilateral, symmetrical, moderately severe peripheral facial weakness, and severe weakness of bilateral intrinsic hand muscles, hip flexors, hamstrings, extensor hallucis longus, and extensor digitorum brevis muscles. The serum tacrolimus concentration was 9.3 µg/l. Electromyography and nerve conduc­ tion studies showed typical findings of a demyelinating motor neuropathy involving limb and cranial nerves. She was given intra­ venous immunoglobulin for 5 days, and 3 months later her symptoms had completely resolved. • A 53-year-old man took tacrolimus 7 mg bd (trough concentration 7.3 µg/l) after a cada­ veric kidney transplant for hypertensive end-stage renal disease. Immediately post­ operatively he complained numbness of the medial three fingers of the right hand and 5 days later developed stiffness and pain in that region. Cranial nerve examination was normal but he had severe weakness of toe dorsiflexion bilaterally. Vibration sensation was reduced at both ankles and in the med­ ial three fingers of the right hand. Gait and coordination were unremarkable. The ankle jerks were absent bilaterally. Nerve conduc­ tion studies showed diffuse low-amplitude­ evoked responses in both arms and absent motor-evoked response in the legs, suggestive of diffuse, predominantly axonal neuropathy, except for partial conduction block in the left ulnar nerve. The dose of tacrolimus was reduced to 2 mg bd and 6 weeks later his sen­ sory symptoms resolved and the neurological examination returned to normal.

Tacrolimus binds to plasma proteins and accumulates in erythrocytes. In an unusual

715

case, a woman with a trough tacrolimus concentration of 75 µg/l developed tacroli­ mus toxicity, with disorientation in space, time and person, somnolence and dys­ arthria; she recovered when her serum concentration fell to 75 µg/l after a gastro­ intestinal hemorrhage (56A).

Tumorigenicity A kidney transplant recipient with unrecognized Muir–Torre syndrome used a tacrolimus-based mainte­ nance regimen and developed 33 sebaceous gland tumors over 2 years (57A). • A 51-year-old man underwent renal transplan­ tation and was given tacrolimus. At 39 years of age, he had had a sigmoid cancer treated by resection and 5 years later a transitional cell carcinoma of the renal pelvis treated by nephrectomy, after which his renal function deteriorated and hemodialysis was eventually necessary. Five months after transplantation he developed a rapid eruption of wart-like lesions on his face and chest wall, and during the next 2 years numerous lesions were removed. There was one sebaceous carcinoma, one basal cell carcinoma, one kerato­ acanthoma, and several sebaceous adenomas. Altogether he developed 33 sebaceous neo­ plasms and was found to have six adenomatous polyps in the colon. Muir–Torre syndrome was confirmed by genetic analysis. Therapy was switched to sirolimus, and during the next 5 weeks he developed no new sebaceous adeno­ mata. Owing to persistent severe weakness, muscle cramps and impaired concentration, he was switched back to tacrolimus and within 2 months developed numerous new sebaceous lesions. Sirolimus was again used and no new skin lesions occurred.

Muir–Torre syndrome is a rare autosomal dominant condition in which multiple pri­ mary tumors and sebaceous gland tumors co-occur. This report suggests that the risk of the latter may be enhanced by tacrolimus. Drug route of administration Topical application Tacrolimus ointment applied to the external auditory canal is being used in the treatment of chronic non-infectious external otitis refractory to other therapy. In an evaluation of tacrolimus for this indication in 53 patients (92 ears; 27 men and 26 women, aged 5–83 years), an ear wick containing Protopic 0.1% was inserted

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into the external auditory canal every sec­ ond or third day and continued until the symptoms resolved (58c). In the short term (days 9–12), there was improvement in 45 patients (77 ears). There were mild adverse effects, including a feeling of heat, occa­ sional skin burning or stinging, and tempora­ rily increased pruritus. There was bacterial superinfection in two cases, treated suc­ cessfully with local antibiotics. During longterm treatment (10–22 months), the number of episodes was reduced and only 15 patients complained of recurrence. There was com­ plete healing in 24 patients at the end of follow-up. In an open study in 466 children, aged 2–15 years, a thin coat of tacrolimus oint­ ment was applied twice daily to affected areas during episodes of active atopic der­ matitis (59c). Initially 0.03% tacrolimus ointment was used either for 2 weeks or until the lesions cleared, whichever was first. Then 0.1% ointment was used. There were 138 withdrawals during the study (30%), about half being for admin­ istrative reasons; 38 (8.2%) were because of lack of efficacy and 16 (3.4%) because of an adverse effect. The most common adverse effects were pruritus and a burning sensation in the skin. There was no increase in the incidence of viral infections. Topical tacrolimus is an alternative treatment for lichen sclerosus, a chronic relapsing disease. In 11 patients, all of whom had been unresponsive or poorly responsive to super-potent topical cortico­ steroids, tacrolimus 0.1% ointment was applied twice daily for 6 weeks and then tapered over a further 6 weeks (60c). The adverse effects were pruritus and burning, but these effects were always mild and transient and disappeared after a few applications. Drug–drug interactions Cinacalcet Co­ administration of tacrolimus 2 mg bd with cinacalcet 30 mg/day caused a fall in tacro­ limus concentrations from 4–8 µg/l to 2.6 µg/ l after 1 week (61A). The dosage of tacro­ limus was adjusted and after 19 days cina­ calcet was withdrawn, after which the tacrolimus concentration rose. During the

interaction renal function worsened and did not recover. Cinacalcet is mostly meta­ bolized by CYP3A4, CYP2D6, and CYP1A2 and it inhibits CYP2D6; tacrolimus is meta­ bolized by CYP3A4. Both are also highly protein-bound, and displacement of tacro­ limus by cinacalcet may have contributed to this interaction.

Temsirolimus Temsirolimus is a specific inhibitor of rapa­ mycin (mTOR) kinase, a component of intracellular signaling pathways involved in the growth and proliferation of cells and the response of such cells to hypoxic stress. Compared with the interferons, temsirolimus improves overall survival among patients with metastatic renal cell carcinoma and a poor prognosis. Observational studies The effect of temsiro­ limus on survival in renal cell carcinoma has been studied in a multicenter phase III trial in 626 patients (62c). The patients had advanced renal cell carcinoma, stage IV or recurrent disease, and a Karnofsky index  60, and had not received previous systemic therapy. They were divided into three groups, who were given interferon alfa-2a 3 million units three times a week (to a maximum of 18 million units if tolerated) (n = 207), temsiro­ limus 25 mg/week as a 30-minute intra­ venous infusion (n = 209) or the combination (n = 210) (temsirolimus 15 mg/week and interferon 3–6 million units three times a week). Treatment was continued as long as there was no disease progression, sympto­ matic deterioration or intolerable adverse events. Those who received temsirolimus alone had longer overall survival and progression-free survival times than those who received interferon alone (respective median overall survival times 10.9 and 7.3 months) The most common adverse effects of temsiro­ limus were rash, peripheral edema, hyper­ glycemia, and hyperlipidemia. Weakness was more common with interferon. Temsirolimus was associated with fewer serious adverse effects than interferon.

Drugs that act on the immune system

Chapter 38

THIOPURINES Liver Treatment with thiopurines can cause three types of hepatotoxicity: hypersensitivity, idiosyncratic cholestatic reactions, and endothelial cell injury (which can cause raised portal pressure, veno-occlusive disease or peliosis hepatis) (63M).

Azathioprine

(SED-15, 377; SEDA-29, 424; SEDA-30, 459; SEDA-31, 635) Cardiovascular Azathioprine has been associated with atrial fibrillation (64A).

• A 52-year-old man with steroid-dependent ulcerative colitis relapsed and was given azathioprine, which was withdrawn some months later because of episodes of lipo­ thymia, with bouts of palpitation, nausea, and vomiting. During an exacerbation 2 years later he was given azathioprine 50 mg and 2 hours later developed nausea, vomiting, and general malaise. He had an irregular heart beat, and an electrocardiogram showed atrial fibrillation with a ventricular rate of 120/minute. Azathioprine was withdrawn and propafenone given. Repeated electrocar­ diography showed sinus rhythm and there were no further episodes of atrial fibrillation.

Respiratory Bronchiolitis obliterans and non-infective pneumonia have been attribu­ ted to azathioprine (65A) • For a 71-year-old man with Crohn’s colitis, in whom prednisone 20 mg/day and mesalazine had been incompletely effective, the mesala­ zine was withdrawn and azathioprine 100 mg/ day was started. After 2 weeks he developed a fever, worsening diarrhea and abdominal pain. Intravenous glucocorticoids and then intravenous infliximab and ciclosporin were ineffective. He then developed shortness of breath and a non-productive cough, and required oxygen. There was a leukocytosis (> 20
109/l) and a CT scan showed ground glass opacities predominantly in the upper lobes of the lungs bilaterally. A biopsy sug­ gested bronchiolitis obliterans. Azathioprine was withdrawn and within 3 days the white cell count normalized and his clinical status improved. • A 43-year-old woman taking prednisone for ulcerative colitis was given azathioprine 100 mg/day for 3 weeks. She developed increasing cough and shortness of breath, and

717 continued to deteriorate despite oral anti­ biotics. She was cyanotic and hypoxic, and required intubation and ventilation. A CT scan showed a right middle lobe pneumonia with bibasal consolidation. Microbiology was negative. Azathioprine was withdrawn and she was given intravenous hydrocortisone. She improved and was weaned off the ventila­ tor 5 days later. Her respiratory function normalized.

Liver Azathioprine can cause nodular regenerative hyperplasia, a rare hepatic lesion defined by diffuse nodularity of the hepatic parenchyma, without annular fibro­ sis, with alternating areas of atrophy and hyperplasia. In a multicenter study of patients taking azathioprine between 1994 and 2005, 37 cases were identified (66c). The median dose of azathioprine was 2 mg/ kg/day. The median time to diagnosis was 48 months after the start of therapy. Portal hypertension was the presenting feature in 31 patients with complications in 14, includ­ ing 9 with acute variceal bleeding and 5 with ascites; 15 underwent primary or secondary treatment for portal hypertension, including beta-blockers and nitrates (n = 11), endo­ scopic therapy (n = 9), embolization (n = 2), and transjugular intrahepatic portosystemic shunting (n = 2). One patient underwent liver transplantation for hepatic encephalo­ pathy following TIPS insertion. There were no deaths or cases of hepatocellular carcinoma. Skin Acute generalized exanthematous pustulosis has been associated with azathioprine (67A). • A 54-year-old woman with diabetes was given prednisolone and azathioprine 50 mg/day for pemphigus foliaceus and after 20 days devel­ oped disabling arthralgia, a fever (40.7°C), hypotension (85/45 mmHg), and a generalized, non-follicular pustular eruption with back­ ground erythema over 24 hours. Initially she was treated for septic shock with intravenous fluids and cefuroxime. However, later her symptoms were thought to be consistent with hypersensitivity to azathioprine, which was withdrawn. She improved over the next 48 hours and the pustular eruption and systemic symptoms resolved, with mild desquamation. Patch and prick tests with azathioprine were negative.

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Susceptibility factors Genetic Homo­ zygous polymorphisms associated with absence of thiopurine methyltransferase (TPMT) can cause life-threatening azathiopr­ ine-induced myelotoxicity (68A).

pelvis and the mid and lower poles, with infil­ tration into surrounding structures. A large renal tumor engulfing the hilar vessels and infiltrating the duodenum and the inferior caval vein was excised. It was a well-differentiated squamous cell carcinoma. Postoperatively, azathioprine was withdrawn, and 1 year later the patient was asymptomatic.

• An 85-year-old man with idiopathic pulmonary fibrosis was given azathioprine 100 mg/day and prednisone 40 mg/day and after 6 weeks devel­ oped fatigue, increasing dyspnea and respira­ tory failure and required ventilation. There was leukopenia (0.4
109/l), anemia (hemo­ globin 65 g/l), and thrombocytopenia (17
109/l). Fibre-optic bronchoscopy showed diffuse bleeding and cultures of the bronchoal­ veolar lavage fluid grew Staphylococcus aureus. He was homozygous for the TPMT*3A muta­ tion and was therefore likely to have little or no TPMT activity. He died with respiratory failure.

Teratogenicity The effects of azathioprine have been studied in pregnancy in 419 women, 189 taking azathioprine and 230 controls (70c). Azathioprine 50–100 mg/day was associated with lower birth weight (2995 versus 3252 g) and gestational age (37.8 versus 39.1 weeks) and more cases of prematurity (21% versus 5.2%).

Tumorigenicity Long-term use of azathioprine can cause squamous cell carci­ noma of the kidney (69A).

6-Thioguanine

• A 43-year-old man took azathioprine for more than 2 years for a demyelinating neuropathy and developed vague right-sided abdominal pain with no urinary or bowel symptoms. Ultrasonography, unremarkable 2 years before, showed a large right renal mass and a CT scan showed a large contrast-enhancing mass in the right kidney involving the renal

Treatment with 6-thioguanine can cause hepatic nodular regenerative hyperplasia in patients with inflammatory bowel dis­ ease, resulting in an increased hepatic venous pressure gradient and clinically sig­ nificant portal hypertension (71c).

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7. Creput C, Blandin F, Deroure B, Roche B, Saliba F, Charpentier B, Samuel D, Durr­ bach A. Long-term effects of calcineurin inhibitor conversion to mycophenolate mofe­ til on renal function after liver transplanta­ tion. Liver Transpl 2007;13(7):1004–10. 8. Shenoy S, Hardinger KL, Crippin J, Desai N, Korenblat K, Lisker-Melman M, Lowell JA, Chapman W. Sirolimus conversion in liver transplant recipients with renal dysfunction: a prospective, randomized, single-center trial. Transplantation 2007;83(10):1389–92. 9. Singh N, Alexander BD, Lortholary O, Dromer F, Gupta KL, John GT, Del Busto R, Klintmalm GB, Somani J, Lyon GM, Pursell K, Stosor V, Munoz P, Limaye AP, Kalil AC, Pruett TL, Garcia-Diaz J, Humar A, Hous­ ton S, House AA, Wray D, Orloff S, Dowdy LA, Fisher RA, Hitman J, Wagener MM, Husain S. Cryptococcus neoformans in organ transplant recipients: impact of calci­ neurin-inhibitor agents on mortality. J Infect Dis 2007;195(5):756–64. 10. Gomez-Camarero J, Salcedo M, Rincon D, Lo IO, Ripoll C, Hernando A, Sanz C, Clem­ ente G, Banares R. Use of everolimus as a rescue immunosuppressive therapy in liver transplant patients with neoplasms. Trans­ plantation 2007;84(6):786–91. 11. Franzoni E, Sarajlija J, Garone C, Malaspina E, Marchiani V. No kinetic interaction between levetiracetam and cyclosporine: a case report. J Child Neurol 2007;22(4):440–2. 12. Irani S, Fattinger K, Schmid-Mahler C, Achermann E, Speich R, Boehler A. Blood concentration curve of cyclosporine: impact of itraconazole in lung transplant recipients. Transplantation 2007;83(8):1130–3. 13. Sorkhi H, Moghadamnia AA, Oaliaee F, Pouramir M, Firoozjahi AR, Pasha AA, Goodarzi MR. Effect of tangerine juice on cyclosporine levels in renal transplant chil­ dren. Pediatr Nephrol 2008;23(3):499–501. 14. Condé SA, Aarestrup FM, Vieira BJ, Bastos MG. Roxithromycin reduces cyclosporine­ induced gingival hyperplasia in renal trans­ plant patients. Transplant Proc 2008;40(5): 1435–8. 15. Carreno CA, Gadea M. Case report of a kidney transplant recipient converted to everolimus due to malignancy: resolution of bronchiolitis obliterans organizing

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