798 Annals ofthe Rheumatic Diseases 1990; 49: 798-800 Ann Rheum Dis: first published as 10.1136/ard.49.10.798 on 1 October 1990. Downloaded from Thrombocytopenia due to aurothioglucose, sulphasalazine, and

M J Wijnands, W A Allebes, A M Th Boerbooms, L B van de Putte, P L van Riel

Abstract was resumed, now in the usual dose of A 56 year old woman with 50 mg. After a single intramuscular injection developed relapsing thrombocytopenia during severe thrombocytopenia with a platelet count successive treatments with aurothioglucose, of 5x109/l occurred. Physical examination sulphasalazine, and hydroxychloroquine. The yielded normal results, in particular, no signs of presence of IgM or IgG antibodies or immune bleeding or enlargement of the spleen were complexes reactive with autologous platelets found. All drug treatment, including parenteral could not be shown. Relapsing thrombo- gold, naproxen, and paracetamol, except cytopenia may indicate a genetically deter- temazepam, was discontinued. Treatment con- mined HLA-DR3 and B8 aberrant immuno- sisted of an infusion of 6 units of thrombocyte logical response to stimuli such as certain concentrate and prednisone 40 mg daily. The second line drugs. patient's previous drugs, except aurothioglucose, were subsequently reinstated. A fast recovery of the platelet count occurred (figure) and the Treatment with second line antirheumatic prednisone was tapered off. After discontinu- drugs often produces side effects. In this report ation of the corticosteroids a flare-up of the we describe an exceptional patient with rheuma- disease occurred and sulphasalazine was pre- toid arthritis who developed isolated thrombo- scribed. The patient responded very well to cytopenia during successive treatments with this, but again the platelet count dropped to aurothioglucose, sulphasalazine, and hydroxy- 35 x 109 platelets/I. Physical examination showed . Although thrombocytopenia is a no signs of bleeding, but there was a slight common side effect of parenteral gold, it is very erythema on the back and mild arthritis of some rare during treatment with sulphasalazine and finger joints and the right knee. Laboratory has only once been reported to be caused by tests showed an ESR of 57 mm in the first hour; hydroxychloroquine. a haemoglobin concentration of 119 g/l; a white cell count of 5 2x 109/1, with a normal differen- tial; a C3 of 1726 mg/I; C4 of 275 mg/I; Clq http://ard.bmj.com/ Case report binding assay of 5%; circulating immune com- A 56 year old woman had had seropositive plexes containing IgM and small amounts of rheumatoid arthritis since January 1986. Initial IgG. Immune complexes containing IgA were treatment consisted of non-steroidal anti- not found; IgM was 109 g/l; IgG was 11-3 g/l; inflammatory drugs. Because of persistent and IgA was slightly increased to 2-63 g/l. Bone disease activity, parenteral gold (aurothioglucose marrow examination showed megakaryocytosis on September 29, 2021 by guest. Protected copyright. 50 mg weekly) was added. After five months and no signs of increased intramedullary activity this effective treatment had to be discontinued of the mononuclear phagocyte system. Sulpha- because ofdermatitis and proteinuria. Parenteral salazine was stopped and spontaneous recovery gold treatment was reinstated after one year in a of the thrombocyte count was noticed. The very low dose (5 mg monthly). During the four patient sustained another flare-up of the disease months that this low dose treatment was given, and hydroxychloroquine treatment was started. the patient reported neither improvement nor After two and a half months the thrombocyte side effects. count fell again to 70x 109 platelets/I. The In August 1988 the patient visited our hospital thrombocyte count rose to nearly normal values for the first time. Physical examination showed within two weeks of discontinuing the active polyarthritis of the hands, wrists, elbows, hydroxychloroquine. Low dose corticosteroids University Hospital and forefeet. Laboratory investigations showed were given because ofpersistent disease activity. Nijmegen, P0 Box 9101, an increased erythrocyte sedimentation rate Since then the patient has had a normal 6500 B Nijmegen, a count. The Netherlands, (ESR) of 89 mm in the first hour; haemoglobin thrombocyte Department of concentration of 98 g/l; a white cell count of Serum samples obtained in October, Rheumatology 5 7x109/l with a normal differential; a platelet November, and twice in February were frac- M J Wijnands count of 85 x 109/1; no antinuclear antibodies. A tionated by isokinetic sucrose gradient centri- A M Th Boerbooms et L B van de Putte Rose-Waaler test gave a result of 320 IU, and fugation as described by Faaber al.' Undiluted P L van Riel the latex reaction was 50 IU. There was no serum fractions were tested for IgM and IgG Department of proteinuria. HLA typing was done and showed reactivity in an enzyme linked immunosorbent Transplantation Serology the presence of HLA-B8 and HLA-DR3 anti- assay (ELISA) as described by Sintnicolaas et W A Allebes gens. Because of the thrombocytopenia the al.2 The reactivity of the patient's serum frac- Correspondence to: count was after a few it tions with autologous platelets indicates that no Dr Wijnands platelet repeated days; then amounted to 150x 109/1. A month later the IgG or IgM autoreactive platelet antibodies Accepted for publication 20 November 1989 platelet count was 186x 109/1 and parenteral were present. The reactivity patterns of patient Thrombocytopenia due to aurothioglucose, sulphasalazine, and hydroxychloroquine 799

Platelbeucocyte count (xI09/l) Haemoglobin (gA) than 1/10) as an explanation, for the signals of unfractionated sera did not exceed the signals of Ann Rheum Dis: first published as 10.1136/ard.49.10.798 on 1 October 1990. Downloaded from 1 the fractionated sera (data not shown). 100 The alloreactivity found in the serum sample taken in November can most likely be explained 80 as being due to a secondary response provoked 6 by the transfusion, because the patient had been pregnant in the past. 40 To our knowledge, an isolated thrombo- cytopenia resulting from treatment with sulpha- 20 salazine has not been described either in 0 patients with inflammatory bowel disease, or in g) rheumatoid arthritis. Only cases of thrombo- cytopenia associated with concomitant leuco- penia, 718 hypogammaglobulinaemia,'9 and erythroid aplasia20 have been reported. Antimalarial drugs such as quinine and June July quinidine are notorious for inducing thrombo- 1988 1989 cytopenia. Chloroquine has also been reported Haematological indices and treatment over time in patient described. to possess such properties.2' Although hydroxy- chloroquine is regularly prescribed for patients with rheumatoid arthritis, and in large quan- tities, occurrence of thrombocytopenia induced and control sera were identical. No auto- or by this drug has been reported only once.22 alloreactive IgM or IgG immunle complexes It is not known whether previous thrombo- were present, which could be concluded from cytopenia during chrysotherapy increases the the data obtained with the 'pellett or bottom' risk of recurrence of a fall in platelet count fractions in the ELISA. IgG allorceactivity was during subsequent treatment with sulphasalazine clearly shown in the serum sample obtained in or hydroxychloroquine, as has been suggested November four weeks after the p]latelet trans- by Bliddal et al.23 24 The relapsing thrombo- fusion. The serum sample obtained four months cytopenia, however, may indicate a genetically later showed hardly any IgG alloreactivity. determined HLA-DR3 and B8 aberrant immunological response to stimuli such as certain second line drugs. Discussion Thrombocytopenia as a result of dniug treatment We are indebted to the Dutch League against Rheumatism for is a rather common feature, occurrring in 1-3% financial support and to Dr P Faaber for the fractionation of the gold.3 Two sera and for providing helpful discussion. of patients treated with parenteral http://ard.bmj.com/ different types of thrombocytopeniia have been distinguished46: the 'toxic' type aund the more I Faaber P, Van de Broek M F, Rijke G P M, Capel P J A, common 'immune ' mediated' type. With respect antibodiesBerden J HtoM.RAJIDirectcells.bindingScandofJmonomericImmunol anti-DNA1985; 22: to the latter, a strong correlatio)n with the 539-48. presence of the HLA-B8 and HL)A-DR3 anti- 2 SintnicolaasBolhuis R K,L H.VanA demicroplateSteuyt KELISAJ B, Vanfor thePuttendetectionW L ofJ, gens has been found."' platelet allo-antibodies: comparison with the platelet

The fact that we not i on September 29, 2021 by guest. Protected copyright. could show the presence 3 GerberiimmunofluorescenceR C, Paulus H E.test.GoldBrJtherapy.HaematolClin Rheum1987; 66:Dis363-7.1975; of autoreactive antibodies or immunte complexes 1: 307-8. in even A, Dawood F, Sturrock R D, the patient reported, not n the serum 4 MadhokDick HR,M.PullarChrysotherapyT, Capell H and thrombocytopenia. Ann sample obtained during severe tI irombocyto- Rheum Dis 1985; 44: 589-91. not mean 5 Adachi J D, Bensen W G, Kassam Y, et al. Gold induced penia, does necessarily 1 that auto- thrombocytopenia: 12 cases and a review of the literature. reactive antibodies or immune comlplexes could Semin Arthritis Rheum 1987; 16: 287-93. not have been responsible for the severe 67 CoblynKay A GJL.S,MyelotoxicityWeinblatt M,ofHoldsworthgold. BrMedJD, 1976;Glassi:G.1266-8.Gold- thrombocytopenia. In retrospect, tlhe thrombo- induced thrombocytopenia. Ann Intern Med 1981; 95: noted in our at 178-81. cytopenia patient the initial visit 8 Armstrong R D, Faith A, Panayi G S, Batchelor J R. Gold- might have been caused by the lo' w dose gold induced thrombocytopenia: detection of anti-platelet anti- before referral to our given hospit;al. In about 9 Speerstrabody. ClinF, ReekersRheumatolP, Van1983;de2:Putte183-8.L B A, Vandenbroucke 30% of patients with drug induce*d A*thrombo-thrombo- J P. HLA associations in aurothioglucose- and D-penicil- antibodies reactive with autologous lamine-induced haematotoxic reactions in rheumatoid cytopenia arthritis. Tissue Antigens 1985; 26: 35-40. thrombocytes'2 cannot be found in in vitro 10 Adachi J D, Bensen W G, Singal D P, Powers P J. Gold tests. Sometimes the binding of aintibodies or induced thrombocytopenia: platelet associated IgG and HLA typing in three patients. J 1984; 11: immune complexes to platelets can be observed 355-7. Rheumatol when the r its W G, Moore N, Tugwell P, D'Souza M, Singal D P. only suspected drug-oi one of 1I1 BensenHLA antigens and toxic reactions to metabolites-is added.1316 We se:reened the in patients with rheumatoid arthritis. J Rheumatol 1984; sera without tive explan- 12 11: 358-61. additions. An alternai 12 Von dem Borne A E G Kr, Pegels J G, Van der Stadt R J, Van ation for why autoreactivity was nlot detected der Plas-van Dalen C M, Helmerhorst F M. Thrombo- may be that autoreactive antibodies have cytopenia associated with gold therapy: a drug-induced might autoimmune disease? BrJI Haematol 1986; 63: 509-16. been of low titres, adsorbed to the p]latelets, and 13 Kelton J G, Meltzer D, Moore J, et al. Drug-induced cleared from the blood. Because of the thrombocytopenia is associated with increased binding of high IgG to platelets both in vivo and in vitro. Blood 1981; 58: sensitivity of the ELISA we rejcect lack of 524-9. as an we als 14 Hamilton H E, Sheets R F. Sulfisoxazole-induced sensitivity explanation; ;o reject the cytopenic purpura. Immunologic mechanism asthrombo-cause. dilution introduced by the fractioination (less JAMA 1978; 239: 2586-7. 800 Wijnands, Allebes, Boerbooms, van de Putte, van Riel

15 Eisner E V, Shahidi N T. Immune thrombocytopenia due to aplasia after administration. Arch Intern Med a 1980; 140: 1122. drug metabolite. N Englj Med 1972; 287: 376-81. Ann Rheum Dis: first published as 10.1136/ard.49.10.798 on 1 October 1990. Downloaded from 16 Kosty M P, Hench P K, Tani P, McMillan R. Thrombo- 21 Rollo I M. Antiprotozoal drugs. In: Dukes M N G, ed. cytopenia associated with auranofm therapy: evidence for Meyler's side effects of drugs. Vol 8. Amsterdam: Excerpta a gold-dependent immunologic mechanism. Am J Hematol Medica, 1975: 659-67. 1989; 30: 236-9. 22 Bunch T W, O'Duffy D, Tompkins R B, O'Fallon W M. 17 Rave 0. Blutbildverianderungen unter Sulphasalazintherapie Controlled trial ofhydroxychloroquine and D- bei rheumatoider Arthritis. Z Rheumatol 1987; 46: 86-91. singly and in combination in the treatment of rheumatoid 18 Tunn E J, Farr M, Scott D G I, Symmons D P M, Bacon arthritis. Arthritis Rheun 1984; 27: 267-76. P A. Sulphasalazine and Felty's syndrome. Haematological 23 Bliddal H, Eiberg B, Helin P. Gold-induced leucopenia may problems. BrJ9 Rhemnatol 1986; 25 (suppl 2): 48. predict a similar adverse reaction to sulphasalazine. Lancet 19 Farr M, Tunn E, Bacon P A, Smith D H. Hypogamma- 1987; i: 390. globulinaemia and thrombocytopenia associated with 24 Bliddal H, Eiberg B, Heln P, Svejgaard A. HLA types in sulphasalazine therapy in rheumatoid arthritis. Ann Rheum patients with rheumatoid arthritis developing leucopenia Dis 1985; 44: 723-6. after both gold and sulphasalazine treatment. Ann Rheum 20 Davies G E, Palek J. Selective erythroid and megakaryocytic Dis 1989; 48: 539-41. http://ard.bmj.com/ on September 29, 2021 by guest. Protected copyright.