Alternatives to Allopurinol Hyper-Responsiveness to EBV In

Ann Rheum Dis: first published as 10.1136/ard.46.6.493-b on 1 June 1987. Downloaded from Correspondence 493 2 Ropes M W. Bennett G A. Cobb S. Jacox R. Jessar R A. 6 Auscher C. Pasquier C. Mercier N. Delbarre F. Oxidation of Revision of diagnostic criteria for rheumatoid arthritis. Bull pyrazolo (3.4-d) pyrimidine in a xanthinuric man. Isr J Med Sci Rheu,n Dis 1958: 9: 175-6. 1973: 9: 3. 3 Nepom G T. Seyftied C E. Holbeck S L. Wilske K R. 7 Elion G B. Benezra F M. Caneilas 1. Carrington L 0. Hitchings Nepom B S. Identification of HLA-DwI4 genes in DR4+ G H. Effects of xanthine oxidase inhibitors on purine meta- rheumatoid arthritis. Lancet 1986: ii: 1(0)2-5. bolism. Isr J Clzetn 1968; 6: 787-96. 8 Rundles R W. Metz E N. Silberman H R. Allopurinol in the treatment of gout. Aiiii ltiter,i Med 1966: 64: 229-58. 9 Delbarre F. Amor B. Auscher C. De Gery A. Treatment of gout with allopurinol: a studv of 1t)6 cases. Ann,l Rheutn Dis Alternatives to allopurinol 1966: 25: 627-33. 10 Rundles R W. Metabolic effects of allopurinol and In their letter to the Annals Kelsey et al state that alloxanthine. Atiti Rheu,n Dis 1966: 25: 615-2). SIR, 11 Lockard 0 Jr, Harmon C. Nolph K. Irvin W. Allergic reaction there is 'no available alternative to allopurinol with its to allopurinol with cross-reactiyity to oxypurinol. Ann Intern unique mode of action'.' There are at least two alter- Med 1976; 85: 333-5. natives2; tisopurine (IH-pyrazolo[3,4-d]pyrimidine-4- thiol (CSH4N4S)) and oxypurinol (lH-pyrazolo[3,4-d] pyrimidine-4.6-diol(C,H4N402)). Neither are available in the United Kingdom. In the treatment of gout, tisopurine has been shown to reduce effectively both the plasma and urinary uric acid Hyper-responsiveness to EBV levels of hyperexcretors, but plasma levels only of normal in ankylosing spondylitis excretors. These effects were shown without a concom- itant increase in urinary hypoxanthine and xanthine excretion.-" Tisopurine is only one tenth as active as SIR. Recently, Drs Robinson and Panayi reported a allopurinol (1H-pyrazolo[3,4-dlpyrimidin-4-ol(C,H4N40)) deficient control of in vitro Epstein-Barr virus (EBV) as a xanthine oxidase inhibitor in vitro.7 and is ineffective infection in patients with ankylosing spondylitis (AS).' in lowering uric acid levels in gout associated with a partial Under blind study control, using peripheral blood mono- deficiency of the enzyme hypoxanthine guanine phos- nuclear cells from B27+ spondylitic patients, we have copyright. phoribosyl transferase.3 5 Therefore, tisopurine reduces observed a similar hyper-responsiveness to EBV. Cultures uric acid concentrations by interfering with the early stages were set up in quadruplicate in 96-well, flat bottomed of its synthesis, thus avoiding increased blood concen- microtitre plates. Virus supernatant, obtained from a 10 trations of hypoxanthine and xanthine. There is no day culture of B95-8 marmoset cells, was titrated and evidence that there is a cross reactivity between tisopurine mononuclear cells were added to each well to give a final and allopurinol. The dose range is from 200 to 400 mg concentration of 5 x 105 cells/ml. Fig. 1 shows the daily. minimum virus concentration required to immortalise the Oxypurinol is the active metabolite of allopurinol in blood B cells of patients with either clinically active AS or vivo. Its half life is about eightfold longer than that of rheumatoid arthritis (RA). In these experiments, cells http://ard.bmj.com/ allopurinol.' Allopurinol is the more effective adminis- from 90% (9 of 10) of the spondylitic patients and 69% (11 tered orally in view of the relatively poor absorption of of 16) of the rheumatoid patients formed permanent cell oxypurinol from the gastrointestinal tract.' Although lines and the range of minimum concentrations was several patients with a history of untoward reactions to similar; the results are based on six week cultures. allopurinol have received oxypurinol without cross reac- Since we have shown previously an increased respon- tivity,"' others do cross react, and in some the reaction siveness to EBV of rheumatoid blood B cells2 we extended may have an immunological basis." the experiments further to evaluate the role of the spondylitic B cell in this observed hyper-responsiveness. on September 24, 2021 by guest. Protected Rheumatology Department, A S M JAWAD Non-T cells, negatively selected using 2-aminoethyliso- The London Hospital thiouronium bromide hydrobromide (AET) treated sheep erythrocytes, were infected with EBV supernatant at a References dilution of 1/10. Work from our laboratory has previously 1 Kelsey S M, Struthers G R, Beswick T. Blake D R. Desensitisa- shown this dose to be effective in the measurement of tion to allopurinol. Ann Rheum Dis 1987; 46: 84. hyper-responsiveness in RA.- Infected and uninfected cells 2 Reynolds J E F (ed). Martindale: The extra pharmacopoeia. were set up in 24-well, flat bottomed plates at a concentra- 28th ed. London: The Pharmaceutical Press. 1982: 419-22. tion of 5 x 10" cells/ml. The results of six week cultures are 3 Delbarre F. Auseher C, De Gery A. Brouilhet H. Olivier J L. shown in Table 1. In this study no healthy individuals were Le traitment de la dyspurinic goutteuse par la mercapto- used and the number of rheumatoid patients was small. pyrazolo-pyrimidine (MPP: thiopurinol). Presse Med 1968: 49: The results for the rheumatoid patients, however, were in 2329-32. agreement with our previous data from a larger study.- 4 Serre H. Simon L. Claustre J. Inhibitors of uric acid synthesis in the treatment of gout: a report of 126 cases. Semin Hop (Paris) There, we reported that no B cells from healthy controls 1970: 46: 3295-301. spontaneously grew into cell lines as compared with 22% 5 Grahame R. Simmonds H A. Cadenhead A. Dean B M. of the B cell samples from rheumatoid patients and only Metabolic studies of thiopurinol in man and pig. Isr J Med Sci 40% of infected healthy B cells were maintained in culture 1973; 9: 17. for six weeks; some of the 'normal' controls carried the Ann Rheum Dis: first published as 10.1136/ard.46.6.493-b on 1 June 1987. Downloaded from 494 Correspondence B27 antigen. All superinfected rheumatoid B cells formed Taking the results of our two studies together. we permanent cell lines. In this studv B cells from approx- conclude that patients with AS. like those with RA. showia imately 800% of the spondvlitic patients were activelv B cell defect. Whether this implies similar disease mechan- dividing after six weeks in culture and B cells from two of isms. as suggested by Dr Robinson. requires further studx these patients spontaneouslv transformed into cell lines. since AS. unlike RA. is predominantly HLA class I associated and in our studies reported here. with respect to hyper-responsiveness to EBV. the patients with AS formed a separate group. intermediate between rheumra- RI *,,*°. toid and healthv. Bone and Joint Reseairch Unit. V151ENNE R WINROW' The London Hospital J DAVID PERRY'" Medical College and 3Rheumatology Department. The London Hospital. 21 London El 2AD References 4t I Robinson S. Panasvi G S. Deficicnt control of in vitro Epstein-Barr sirus infcction in paticnts with ankslosing spond- litis. Annii Rheumn DiN 1986: 45: 974-7. 2 Sticrlc H E. Brown K A. Pcrrv J D. Holborow E J. Incrcascd 8 rcsponsivcncss of rhcumaitoid B lsmphocvtcs to stimulation hy Epstcin-Barr sirus. Rhletomtol Iti 1983: 3: 7-1 1. 'D 16' The costoclavicular syndrome copyright. 32. SIR. De Silva has described costoclavicular svndrome (a variant of thoracic outlet svndrome) due to traction from brassieres in large breasted women.' Dr De Silva's claim > 64' that this is a hitherto undescribed cause of the condition' is w not true. In 1972 Kave reported sensory and motor changes in the upper extremities of women with macro- 128' mastia. which he felt to be 'a variant of the svndrome of thoracic outlet compression'.' In 1979 McGough. Pearce. and Byrne describing thcir non-operative treatment ofhttp://ard.bmj.com/ thoracic outlet syndrome wrote 'Large-breasted women >128 were urged to be fitted with an underwire support brassiere, so that the weight of the breast would bc supported around the thorax rather than over the shoulder.' RA AS We are also concerned bv De Silva's contention that Fig. 1 The minimum EBV concentration necessarY to normal blood tests and v- ravs are sufficient investihations initiate cell line formation by peripheral blood to rule out other conditions. In our experience the most on September 24, 2021 by guest. Protected mononuclear cells from rheumatoid or spondylitic patients common cause of upper extremity pain is carpal tunnel is shown. Cultures were set lip in quadruplicate and R syndrome. Thoracic outlet svndrome was diagnosed much denotes cultures where two or more wells showed regression more frequently in the first half of this century than it is and no cell lines were formed. The results at six weeks now. and it is becoming apparent that many of these earlier are shown. patients actually had carpal tunnel syndrome.4 All patients suspected of thoracic outlet syndromes should undergo electrodiagnostic studies to rule out carpal tunnel Table 1 Results ofsix week cultures using a limiting viral syndrome. dose (1/10 dilution) Division of Rehabilitation Medicine. KENNETH C WRIGHT No celllitiesltotal No ("4 Mononuiclear cell of of patients University of Pittsburgh. JOHN J NICHOl S Population7 RA Pittsburgh. PA 15213. A.S USA Unfractionated 1/15 (7) 1/5 (2() Unfractionatcd + EBV 6/15 (40)) 4/5 (8() References Non-T 2/14 (14) 2/5 (4() Anin + EBV 11/14(79) 5/5 (1()) I Dc Silva M.

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