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Home , Aspartate transaminase

Ann Rheum Dis: first published as 10.1136/ard.44.11.798 on 1 November 1985. Downloaded from

Annals of the Rheumatic Diseases, 1985; 44, 798-800

Case report

Raised and aspartate levels in two rheumatoid patients treated with sulphasalazine

M FARR, D P M SYMMONS, AND P A BACON From the Department ofRheumatology, University of Birmingham, Birmingham B15 2TJ

SUMMARY is a rare complication of sulphasalazine therapy in ulcerative colitis. This report describes two rheumatoid patients in whom raised serum levels of occurred soon after starting sulphasalazine treatment for their arthritis. In both cases the serum levels returned to normal after stopping the drug. Drug-induced hepatotoxicity should be considered in patients with rheumatoid arthritis (RA) who develop raised serum levels of liver enzymes while taking sulphasalazine. by copyright. Key words: rheumatoid arthritis, raised liver enzyme levels.

Sulphasalazine (SASP) is a well established drug in been taking piroxicam for four months before the treatment of inflammatory bowel disease. Dur- starting SASP and this was continued unchanged. ing the last 10 years it has also been found to be an Five days after commencing SASP (500 mg daily) effective second-line drug in rheumatoid arthritis. l-5 she developed epigastric pain, nausea, flatulence, It has recently been described as a safe alternative to and vomiting. This rapidly settled when the drug gold therapy, with a much lower incidence of was stopped. She was advised to modify the drughttp://ard.bmj.com/ toxicity. Several adverse reactions have been regimen by taking it on alternate days. However, associated with sulphasalazine and are almost al- she failed to do this and reverted to the daily dose of ways reversible with discontinuation of the drug.7 500 mg. After a further five days the same symptoms Hepatotoxicity has not previously been described in recurred. She stopped the SASP but continued RA patients receiving SASP. This report describes piroxicam. When her condition was reviewed a hepatotoxicity, as indicated by raised serum alkaline month after commencing sulphasalazine her gas- phosphatase and aspartate transaminase levels, in trointestinal problems had completely subsided, on September 25, 2021 by guest. Protected two patients with RA treated with sulphasalazine. general clinical examination was normal, and her arthritis had improved. Serial blood tests are shown Case reports in Table 1. Alkaline phosphatase had risen from 327 to > 2000 U/l and aspartate transaminase from 14 to CASE 1 130 U/l since starting SASP. Electrophoresis of A 72-year-old lady with a three-year history of alkaline phosphatase isoenzymes showed the rise to seropositive erosive rheumatoid arthritis was started be due to the liver isoenzyme only. B on enteric-coated sulphasalazine because she had surface antigen (HBsAg) was negative by radioim- persistent active arthritis. She had not previously munoassay. The rise in liver enzymes was not received a second-line agent or . She had associated with , fever, or any other abnor- mal signs or symptoms, and at this stage she felt well and her arthritis had improved. During the next Accepted for publication 18 April 1985. Correspondence to Dr Margaret Farr, Department of month her serum alkaline phosphatase level fell to Rheumatology, Medical School, Birmingham B15 2TJ. 723 U/l and aspartate to 18 U/l. After 3½/2 798 Ann Rheum Dis: first published as 10.1136/ard.44.11.798 on 1 November 1985. Downloaded from

Raised serum alkalinie phosphatase and aspartate transaminase levels 799 Table 1 Serium levels in patientts I atiln 2 oj (lkalinie p)lo.splialase asparttlte tratnsaminase, hiliruibin, and haemoglobin (Hb) atnd the erYthrocYte sedinrienttatiotn rate (ESR) dulrinig tre(atmtienit ivith sulphasalakzine (SASP) SASP Alka/lifi AspI)((rtate Biliri bin HI) ESR (veeks) (Ing) (UIh)phaase tR(L' b111 e (timol I) (g, dtb /sttinllz) (U,'I) (LI' l}

5(0(0 327 14 5 11 2 79 > 2(XN) 13(0 12 12.3 47 75 723 18 5 12'7 586 14 x84 13 6 10(4 9(0 Paticnt 2 51)0 352 2(1) 9 10-3 33 1(O(M( 646 23 6 9.6 43 3 745 43 6 10(-1 36 4 19 7 488 23 9 10-6 325 Norm,al riangc 7(1-30(0 5 3(1 26 115-14-5 ((-2(1

months the alkaline phosphatase had fallen to 384 Discussion U/i and aspartate transferase to 13 U/I; she re-

mained well. Hepatotoxicity associated with sulphasalazine when by copyright. used to treat ulcerative colitis has been reported CASE 2 infrequently. The Committee on Safety of Medi- A 71-year-old lady with a 10-year history of sero- cines has received 323 adverse reaction reports due positive erosive rheumatoid arthritis was started on to SASP therapy in inflammatory bowel disease sulphasalazine to control her active joint disease. since 1964, only 11 of which involved liver disorders. Previously she had received gold in 1977 and 1981 Hepatotoxicity has not been previously reported but had developed a rash on both occasions. She had with SASP used in the treatment of rheumatoid not received any other second-line antirheumatic arthritis. It has, however, been associated with other drugs and was currently taking naproxen 50() mg second-line antirheumatic drugs, e.g., penicil- twice daily, indomethacin suppository 100 mg at lamine8 and gold.9 http://ard.bmj.com/ night, and temazepam 10 mg at night. Her general Abnormalities of liver enzymes have been re- health was good. ported in active rheumatoid disease. Kendall et al. in Two days after starting enteric-coated sulphasala- 1970") found that alkaline phosphatase was raised in zine at a dose of 500 mg daily her alkaline 26% of rheumatoid patients and that it was also phosphatase st'arted to rise (Table 1). In line with higher in more active disease. Aspartate transami- our routine clinical practice the dose of sulphasala- nase has also been reported to be raised in some RA

zine was increased to 1000 mg daily, one week after patients." Although both the patients in this report on September 25, 2021 by guest. Protected therapy was started. The alkaline phosphatase had active rheumatoid disease, with liver enzymes in continued to rise until the drug was stopped one the upper part of the normal range before treat- week later and then fell again over the next two ment, there is no doubt that the enzyme levels weeks. Electrophoresis of the isoenzymes of alka- markedly increased after SASP therapy and fell line phosphatase showed the rise to be due to the again when the drug was withdrawn. The rise was liver isoenzyme only. The patient remained well not associated with an exacerbation of their arthri- during this time and did not have any jaundice, tis. The rise in liver enzymes occurred within a fever, or hepatomegaly, though she did have an month of starting SASP in both cases. This pattern asymptomatic urinary tract infec- is consistent with reports of hepatic complications tion. An ultrasound of the liver and gall bladder due to SASP treatment in ulcerative colitis which showed no abnormality. None of her other medica- usually occur within 14 days of starting tions were changed immediately before the rise in treatment.'2 13 There have, however, been isolated alkaline phosphatase and only the sulphasalazine reports of late onset hepatotoxicity associated with was stopped. this drug.'4 The rise in liver enzyme levels in our Ann Rheum Dis: first published as 10.1136/ard.44.11.798 on 1 November 1985. Downloaded from

800 Farr, Symmons, Bacon patients was detected early and fell again after 4 Pullar T, Hunter J A. Capell H A. Sulphasalazine in rheuma- withdrawal of the drug. but hepatotoxicity may toid arthritis: a double blind comparison of sulphasalatzinc with placeho and sodium aurothiomalatc. Br Metd J 1983: 287: progress to acute focal hepatocellular necrosis' or 1102-4. chronic granulomatous hepatitis. 16 The nausea, 5 Farr M. Tunn E. Crockson A P. Bacon P A. The long tcrnm vomiting, flatulence, and abdominal pain experi- effects of sulphasalazine in the trcatment of rheumiatoid arthritis enced by patient 1 are well recognised early side and a comparative studv with penicillaminc. C/in Rlwientiol effects of SASP due to the sulphonamide compo- 1984: 3: 473-82. 6 Bax D E. Amos R S. Sulphasalazine: a sate, cffcctivc aicnt for nent and may not be directly associated with the rise prolonged control of rheumatoid arthritis. A comparison with in liver enzymes. sodium aurothiomalatc. Aniii Rheuin Dis 1985:, 44: 194-9. The mechanism of SASP associated reactions in 7 Pullar T. Capell H A. Sulphasalazine: a 'ness antirheufmuatic drug. Br J Rheum 1984. 13: 26-34. these two patients is probably due to a hypersensi- 8 Rosenbaum J. Katz W A. Schumachcr 1 R. ficpatotoxicity tivity reaction resulting from the sulphapyridine associatcd with use of D-penicillamine in rheumattoid arthritis. moiety of SASP.'2 6 and it may progress to Anti Rheum Dis 198ff: 39: 152-4. cholestatic jaundice and hepatic injury. Thus early 9 Keen W F. Anastassiades T P. Long tcrm chrysothcrapy. Incidence of toxicity and cfficacy during sequential timc hepatotoxicity should be added to the list of possible periods. Arthritis Rlhletn 1979; 22: 495-50)1. complications of SASP thlerapy in RA. It is impor- 1() Kendaill M J. Cockel R. Bccker J. Hawkins C F. RIiscd scrum tant to monitor liver function to detect and reverse alkaline phosphatase in rheumatoid diseasc. 4ntn Rheioi D)is this adverse reaction promptly. 197t): 29: 537-40). 11 Wilding. P, Kcndall M J. Ilolder R. Grimes J A. Farr M. The We airc grateful to Dr Lindia Blcc1cv and Miss R Laswrcncc foi- their influence of drugs and disease activity on hiochemical and help. MF receives financial support l'f-omii the Arthritis and hacmatological data in rhcumatoid arthritis. (lin (Chin A ti Rheumatism Council foi- Rcsearch. 1975; 64: 185-94. 12 Losck J D, Werlin S L. Sulphasalazine hcpatotoxicits Alt oJIN Child 1981: 135: 1)70-2. References 13 Sotolongo R P, Necpe L 1. Rudzki C. et ul. livperscnsitivitv reaction to sulphasalazine with scvere hepatotoxicitv. Gastroen-

1 MeConkey B, Amos R S, Durham S. Forstcr P J G. Hubball S. by copyright. Walsh L. Sulphasalazine in rheumatoid arthritis. Br MedJ 1980; terologs' 1978: 7: 95-9. 280: 442-4. 14 Lennard T W J. Farndon J R. Sulphasalazinc hcpattotoxicitv 2 Bird H A, Dixon J S, Pickup M E A. A hiochemical assessment after 15 years' successful trcatment in ulcerativc colitis. Br Med of sulphasalazine in rheumatoid arthritis. J Rheumatol 1982; 9: J 1983: 287: 96. 36-46. 15 Dujovne C A, Chait C H-, Zimmerman 1 I 1. Sulphonamide 3 Neumann V C, Grindulis K A. Huhall S. McConkev B, Wright hepatic injury. N Enigl J Med 1967; 277: 785-8. V. Comparison between penicillamine and sulphasalazine in 16 Espiritu C R, Kim T S. Levine R A. Granulomatous hcpatitis rheumatoid arthritis: Leeds-Birmingham Trial. Br Med J 1983; associated with sulphadimethioxine hypersensitivity. JA MA 287: 1099-102. 1967; 202: 985-8. http://ard.bmj.com/ on September 25, 2021 by guest. Protected Clinical vignette

Knee pain

Otherwise inexplicable knee pain is often associated with exquisite tenderness over the lower pole of the medial ligament and responds well to regular knee-bend exercises of the pre-ski variety. If the feet are flat, intrinsic foot exercises should be practised as well. MARY CORBEIT

(Readers are invited to submit brief accounts of new or little known physical signs in rheumatic diseases-Editor.)