Rescue therapy with mycophenolate mofetil in refractory uveitis

RESEARCH LETTERS

women came from the local ward, local or neighbouring district cord-blood thyrotropin and urinary iodine indicated moderate and mild iodine deficiency,1 which suggests that the neonates were still at risk of brain damage. Although almost all salt tested was iodised, use of non-iodised salt by pregnant women from beyond the study area cannot be excluded. Those women are, however, not likely to be among the poorest people since they could pay transport and hospital fees. Findings could be explained by insufficient time since the introduction of iodised salt, or that iodine concentrations in household salt, which are sufficient for schoolchildren, are inadequate for other vulnerable groups. We recognise the need to minimise the risk of iodineinduced hyperthyroidism5 and we urge countries to carefully monitor iodine concentrations in local salt types at production, retail, and household levels. Before salt iodation is lowered, however, assessment of iodine status in vulnerable groups other than schoolchildren, such as pregnant women and neonates, is critical. We thank Godwin Ndossi for his support, the local population, hospital staff, and the Ilembula mission. Financial support was provided by Sida and the Swedish Mission Council. 1

2

3

4

5

WHO. Indicators for assessing iodine deficiency disorders and their control through salt iodation. WHO/UNICEF/ICCIDD, 1994. WHO/NUT/94.6 Todd C, Allain T, Gomo Z, Hasler J, Ndiweni M, Oken E. Increase in thyrotoxicosis associated with iodine supplements in Zimbabwe. Lancet 1995; 346: 1563–64. Bourdoux P, Ermans A, Mukalay wa Mukalay A, Filetti S, Vigneri R. Iodine-induced thyrotoxicosis in Kivu, Zaire. Lancet 1996; 347: 552–53. WHO. Recommended iodine levels in salt and guidelines for monitoring their adequacy and effectiveness. WHO/UNICEF/ICCIDD, 1996: WHO/NUT/96, 13. Delange F. Risks and benefits of iodine supplementation. Lancet 1998; 351: 923–24.

Unit for International Child Health, University Hospital, Uppsala University, Sweden; and Tanzania Food and Nutrition Centre (TFNC), Dar es Salaam, Tanzania (V Assey)

Rescue therapy with mycophenolate mofetil in refractory uveitis Dara J Kilmartin, John V Forrester, Andrew D Dick

Uveitis is a major cause of visual impairment in the working population, with an important socioeconomic impact.1 Despite the advent of cyclosporin and tacrolimus for T-cell mediated uveitis, resistance, toxicity (especially nephrotoxicity), and intolerance restrict effective therapy. Mycophenolic acid (MMF) has a selective antiproliferative effect on lymphocytes, is effective in the prevention of allograft rejection and treatment of autoimmune disease,2 and inhibits uveitis in animal models.3 The clinical role of MMF in refractory uveitis is unknown. With informed consent, we did a small open-label nonrandomised study of MMF as rescue therapy in patients who

had refractory uveitis with previous cyclosporin resistance or toxicity. MMF was started at 2 g daily, alone or in combination with previous therapy of corticosteroids, cyclosporin, or tacrolimus. Azathioprine was discontinued. We assessed clinical efficacy by visual acuity, binocular indirect ophthalmoscopy score (a clinical assessment of intraocular inflammation by a measure of vitreal haze),4 and fundoscopy. Binocular indirect ophthalmoscopy scores and visual acuity are not strictly independent outcome measures. However, vitreal haze/binocular indirect ophthalmoscopy score can improve with immunotherapy without improvement in visual acuity, and visual acuity can improve in the absence of vitreal haze. Nine patients (15 eyes) were recruited with a mean age of 39·5 years (SD 13·7) and previous uveitis duration of 5·7 years (5·3). MMF indications were cyclosporin adverse effects (six patients, two of whom also had tacrolimus intolerance) and cyclosporin resistance (three patients). Previous nephrotoxicity induced by cyclosporin was present in five patients. MMF therapy was maintained for 25·2 weeks (8·6). Patients were treated with MMF alone (one patient) or in combination with corticosteroids (three patients), cyclosporin (three patients), and combined corticosteroids and cyclosporin (two patients). Mean doses were 10·4 mg/day (5·3) for corticosteroids and 3·2 mg/kg (1·2) cyclosporin daily. For visual acuity and binocular indirect ophthalmoscopy score, eight eyes improved (肁2 Snellen lines or 肁1 binocular indirect ophthalmoscopy score), five eyes remained unchanged and two eyes worsened (because of aggressive retinal vasculitis). Mean visual acuity improved from 6/23 to 6/17 (Snellen equivalent by conversion from log minimum angle of resolution) and binocular indirect ophthalmoscopy score improved (p=0·03, Mann-Whitney U test) from 1·3 (0·3) to 0·6 (0·2) from baseline to the last MMF dose. The main reasons for improvement were decrease in vitreal haze and macular oedema. Therapeutic failure occurred in two patients, in one because of MMF intolerance (nausea, headaches, and myalgia) and MMF was withdrawn after 15 weeks of therapy, and in one patient with bilateral uncontrolled disease. Otherwise, adverse effects were mild and common (four patients myalgia, two fatigue, two headaches, two nausea, two acne), with no adverse effects in three patients. There were no major adverse effects. Current immunosuppressive therapy in aggressive refractory uveitis is aimed at preserving vision. We have previously reported visual deterioration in 42% of patients with refractory uveitis on triple therapy of corticosteroids, cyclosporin, and azathioprine,5 compared with visual deterioration in 13% in this study. Our data suggest that MMF is effective in maintaining vision and may improve visual acuity despite chronic disease. Mycophenolate mofetil was provided by Roche Ltd. 1 2 3

Suttorp-Schultern MSA, Rothova A. The possible impact of uveitis in blindness: a literature survey. Br J Ophthalmol 1996; 80: 844–49. Lipsky JJ. Mycophenolate mofetil. Lancet 1996; 348: 1357–59. Chanaud NP III, Vistica BP, Eugui E, Nussenblatt RB, Allison AC,

Case

Diagnosis

Previous systemic therapy

MMF indication

Clinical status

Stable follow-up (weeks)*

1 2 3 4 5 6 7 8 9

Idiopathic JCA Multifocal choroiditis Serpiginous choroditis Retinal vasculitis Pars planitis Sarcoidosis Idiopathic Behçet’s disease

CST, Cs CST, Cs CST, Ca CST, Cs, Aza, tacrolimus CST, Cs, Aza CST, Cs CST, Cs CST, Cs, Aza CST, Cs, Aza, tacrolimus

Cs intolerance Cs failure Cs toxicity/failure Cs toxicity/failure; tacrolimus intolerance Cs intolerance Cs intolerance Cs toxicity/failure Cs toxicity/failure Cs toxocity/failure;x tacrolimus intolerance

Improved but MMF intolerance Improved Improved Improved Worsened Improved Improved Improved Improved

15 35 36 30 27 27 21 26 10

JCA=juvenile chronic arthritis; CST=corticosteroids; Cs=cyclosporin; Aza-azathioprine. *No inflammatory recurrence during this time period.

Treatment outcomes

THE LANCET • Vol 352 • July 4, 1998

35

RESEARCH LETTERS

4 5

Gery I. Inhibition of experimental autoimmune uveoretinitis by mycophenolate mofetil, an inhibitor of purine metabolism. Exp Eye Res 1995; 61: 429–34. BenEzra D, Forrester JV, Nussenblatt RB, Tabbara K, Timonen P. Uveitis scoring system. Berlin: Springer-Verlag, 1992: 1–9. Dick AD, Azim M, Forrester JV. Immunosuppressive therapy for chronic uveitis: optimising therapy with steroids and cyclosporin A. Br J Ophthalmol 1997; 81: 1107–02.

compounds must also be carefully monitored to prevent rare but potential disastrous results. 1

2

Department of Ophthalmology, University of Aberdeen Medical School, Foresterhill, Aberdeen AB25 2ZD, UK (A D Dick) 3

Subarachnoid haemorrhage associated with Ginkgo biloba Salvador Vale

A 61-year-old man presented in September, 1997, with a 5-day history of headache, back pain, nausea, and sleepiness. He had been previously in excellent health and enjoyed outdoor exercise. On examination no physical abnormalities were found, including his neurological status. Blood pressure was 135/85 mm Hg. He had a normal blood count and mildly increased bleeding time (6 min, normal 1–3). Serum urea, nitrogen, creatinine, bilirubin, and hepatic enzymes were normal, as were prothrombin and partial thromboplastin times. A computed tomographic cranial scan obtained without the administration of contrast material was also normal. A lumbar puncture yielded 6 mL of slightly xanthochromic fluid without gross blood. Microscopical examination revealed 6 cells per ␮L of which five were red cells and one was white. Glucose was 3·7 mmol/L protein 240 mg/L. A subarachnoid haemorrhage was diagnosed. Detailed questioning revealed that he had been taking Ginkgo biloba 40 mg tablets, three or four times a day, for more than 6 months before the beginning of his symptoms. The patient recovered uneventfully. He was advised to stop the extract and in January, 1998, he was doing well. His bleeding time is now 3 min and he has refused further medical investigations. Ginkgo biloba extract is an over-the-counter herbal medication, which is marketed as a supplement to improve mental alertness (the reason our patient was taking it). However, the extract is a potent inhibitor of plateletactivating factor1 and long-term use has been associated with increased bleeding time, spontaneous haemorrhage, and subdural haematomas.2 It has been shown that hypertension, diabetes mellitus, anticoagulant treatment, and the amount of alcohol taken within the preceding week are associated with intracerebral haemorrhage, whereas cigarette smoking and platelet-antiaggregating agents increase the risk for subarachnoid haemorrhage.3 Alcohol potentiates aspirininduced prolongation of bleeding time. Other potential risk factors for haemorrhagic stroke include thrombolytic therapy and use of amphetamines or cocaine. In our case, the only risk factor found was the mildly increased bleeding time. It is not proven that the subarachnoid haemorrhage was caused by the Gingko biloba, but the absence of other risk factors, the temporal association of the increased bleeding time with the haemorrhagic stroke, and the antiplatelet aggregation profile of the extract, are suggestive of a pathogenic connection. I am concerned about recent reports (for example, ref 4) that show moderate improvement in cognition in some patients with Alzheimer’s disease taking the Ginkgo biloba extract, because they may promote increased drug use in patients with more risk factors for intracranial haemorrhage (systemic arterial hypertension, diabetes, amyloid senile plaques, &c). Although we frequently use plateletantiaggregating agents in these patients, their doses and sideeffects are carefully monitored. I suggest that doses of herbal

36

4

Chung KF, Dent G, McCusker M, Guinot, Page CP, Barnes PJ. Effect of a ginkolide mixture (BN 52063) in antagonising skin and platelet responses to platelet activating factor in man. Lancet 1987; i: 248–51. Rowin J, Lewis SL. Spontaneous bilateral subdural hematomas associated with chronic Ginkgo biloba ingestion. Neurology 1996; 46: 1775–76. Juvela S. Prevalence of risk factors in spontaneous intracerebral hemorrhage and aneurismal subarachnoid hemorrhage. Arch Neurol 1996; 53: 734–40. Le Bars PL, Katz MM, Berman N, et al. A placebo-controlled, double-blind, randomised trial of an extract of Ginkgo biloba for dementia. JAMA 1997; 278: 1327–32.

Unidad de Investigaciones Clínicas, Junta de Asistencia Privada, Regina 7, CP 06080, México D F, México

Oestrogen-receptor status in management of breast cancer in UK B J Mander, K Heal, A D Porushotham, G C Wishart

In patients with breast cancer, oestrogen receptor (ER) status is recognised as a powerful predictor of response to endocrine therapy in both advanced disease1 and in the adjuvant setting.2 A study3 has shown that the availability of ER status strongly influences recommendations for adjuvant systemic therapy, including the selection of appropriate clinical trials for individual patients in keeping with a move towards more individualised treatment of women with breast cancer. 4 We aimed to assess the importance, use, and availability of this prognostic marker in breast cancer units in the UK. A postal questionnaire was sent to the lead clinicians of all 236 breast-cancer units listed in the Macmillan Directory of Breast Cancer Services in the UK (1996). Addressees were asked about their opinion of the importance of measurement of ER status in the management of their patients with primary invasive breast cancer. In addition, they were asked about the availability, use, technique of measurement, and threshold for positivity of the technique. Questionnaires were returned from 169 (71%) units treating over 23 900 new cases of breast cancer annually and the results are presented in the table. Of these, 87·5% stated assessment of ER status was important in the management of their patients. In all, 84% of units had access to the facility although this was available on-site in only 60%. ER status was not assessed on any primary tumours in 16% of units, whereas 38% determined it on all. The remaining 46% used a selective policy, which in the majority involved measurement in premenopausal or high grade node-negative tumours. Most centres measure ER status by an immunohistochemical technique. Threshold for positivity was determined by percentage of cells staining positive in 41%, although the absolute cut-off for positivity varied widely. A scoring technique combining percentage of cells staining positive with intensity of staining was adopted in 34%. The remainder deferred the decision to their pathologist, or did not respond. ER status is widely perceived to be important. Our study has shown, however, that 12·5% of breast-cancer units do not believe ER status to be important in the management of primary breast cancer, and, furthermore, it is not measured in at least 16% of breast cancers in the UK. There is also little consensus regarding the threshold for ER positivity. Although most units who measure ER status use an inexpensive immunohistochemical technique, 40% of responders do not have this facility available on-site. The establishment of breast-cancer units in the UK,

THE LANCET • Vol 352 • July 4, 1998