Scandinavian Journal of Rheumatology
ISSN: 0300-9742 (Print) 1502-7732 (Online) Journal homepage: http://www.tandfonline.com/loi/irhe20
Influence of Acetylator Status on Sulphasalazine Efficacy and Toxicity in Patients with Rheumatoid Arthrftis G. D. Kitas, M. Farr, L. Waterhouse & P. A. Bacon To cite this article: G. D. Kitas, M. Farr, L. Waterhouse & P. A. Bacon (1992) Influence of Acetylator Status on Sulphasalazine Efficacy and Toxicity in Patients with Rheumatoid Arthrftis, Scandinavian Journal of Rheumatology, 21:5, 220-225, DOI: 10.3109/03009749209099228 To link to this article: http://dx.doi.org/10.3109/03009749209099228
Published online: 12 Jul 2009.
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Date: 17 April 2016, At: 22:38
Influence of Acetylator Status on Sulphasalazine Efficacy and Toxicity in Patients with Rheumatoid Arthrftis G. D. Kitas, M. Farr, L. Waterhouse and P. A. Bacon Department of Rheumatology, University of Birmingham, Birmingham, U.K.
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Kitas GD, Farr M, Waterhouse L, Bacon PA. Influence of Acetylator Status on Sulphasalazine Efficacy and Toxicity in Patients with Rheumatoid Arthritis. Scand J Rheumatol 1992; 21: 220-225. The influence of acetylator status on the therapeutic efficacy and the toxicity of sulphasalazine (SASP) was assessed in 106 patients with rheumatoid arthritis (RA). Changes of indices of disease activity after 6 months, and progression of erosions after 2 years of SASP treatment were similar in fast and slow acetylators. Incidence and nature of withdrawals and side-effects, and requirement for intra-articular steroid injections or combination therapy due to poor response to SASP were almost identical in the two groups. A significant increase of the hepatic enzyme aspartate transaminasc was noted mainly in slow acetylators, but was not associated with clinical disease. These results suggest that acetylator status does not relate significantly to either the efficacy or the toxicity of SASP in RA. It is possible that hepatic metabolism is affected by SASP, particularly in slow acetylators, but this does not lead to clinically identifiable problems.
Key Words: Sulphasalazine, Rheumatoid Arthritis, Acetylator Status
SASP is now considered an established second line agent for the treatment of R A (1-5). Its efficacy and toxicity vary considerably between identically treated patients (6-14). This may reflect differences in the metabolism of the drug between individuals. SASP consists of 5-aminosalicylic acid (5-ASA) linked by an azo-bond to the sulphonamide sulphapyridine (SP). Approximately 30% of the drug is absorbed from the upper gastrointestinal tract and a small proportion of this is excreted unchanged in the urine. The remainder is excreted unchanged in the bile, and together with the nonabsorbed portion, reaches the distal small intestine and colon (15). There, the azo-bond is reduced by bacterial action, and SASP is split into its constituent components. 5-ASA remains largely in the colon and is recovered unchanged in the faeces. In contrast, SP is almost totally absorbed from the colon, partially metabolised, and excreted in the urine as the free sulphonamide and its metabolites. SP is metabolised predominantly in the liver by acetylation and to a much lesser extend glucuronidation and hydroxylation. Individuals differ markedly in the rate at which drugs are acetylated, and there is a bimodal distri-
G. D. Kitas, Department of Rheumatology. The Medical School, University of Birmingham, Vincent Drive, Birmingham B15 2'IT Received 12 February 1992 Accepted 25 June 1992
bution of the general population into fast and slow acetylators (approximately 40% and 60% respectively in the U. K.). The rate of acetylation is under genetic control: rapid acetylation is an autosoma1 dominant trait. In addition to SP and other sulphonamides, many other drugs undergo acetylation including hydralazine, isoniazide, dapsone, procainamide, phenelzine, and nitrazepam. Acetylator phenotype appears to play an important role in the therapeutic effect, and even more the toxicity of many of these drugs (16). The mechanism of action of SASP is unknown. Distribution studies indicate that the parent drug SASP may act as a vehicle to deliver its (active) metabolites to distal disease sites (15). Studies in inflammatory bowel disease (IBD) suggest that 5ASA is the active moiety, whereas SP may be responsible for most of the toxicity of SASP (15, 17). Healthy volunteers and patients with IBD who are slow acetylators have higher serum levels and longer half life of total SP, and also greater incidence of side-effects than fast acetylators; no apparent association between acetylator phenotype and therapeutic response to SASP has been noted in these patients (18-20). In contrast, it has been suggested that in RA, SP is the active moiety (21, 22): it is therefore possible, that in this disease, acetylator phenotype may affect both therapeutic response and adverse reactions to SASP. To the best of our knowledge, this question has been addressed to date only by three studies (2325); these were differently designed and reached apparently conflicting conclusions.
Sulphasalnzine acetylation in RA In the present study, we investigated whether acetylator phenotype has a bearing on the control of disease activity and severity and also on the toxicity of SASP, in a group of carefully characterised patients with RA. We also addressed some relevant methodological issues which may be of importance to the interpretation of results obtained in the previous studies.
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Materials and methods Assessment of acetylator status:
Acetylator status was assessed in patients already receiving SASP orally. Random urine samples were collected and assayed using a colorimetric method for free and acetylated SP. The percent acetylated SP was then determined by the method of Schroder (26) using the formula: Urine acetylated SP Urine total (acetylated
+ free) SP
x 100
The possibility of diurnal variation was assessed in 8 patients with RA receiving lg SASP twice daily, by measuring acetylation rate using urine samples collected at 0, 1, 3, 6, 9 and 12 hours after taking their morning SASP tablets. No significant diurnal variation was found in any of the individuals studied (mean coefficient of variation 8.8%). The accuracy and reproducibility of the method was assessed by providing the laboratory with 10 identically handled aliquots of the same urine sample from 8 patients receiving SASP, in a blind manner. Acetylation rate was then measured in these samples in two consecutive assays. Subsequent analysis of the results indicated that the method had a coefficient of variation of 5.6% (data not shown). This suggested that a single cutoff point (55% according to the laboratory) could not be used to differentiate fast from slow acetylators. According to these results, individuals with acetylation rate of > 60% were allocated confidently in the fast acetylator group, while individuals with acetylation rate of < 50% were allocated in the slow acetylator group. Patients with equivocal acetylation rates (50%-60%) were not included in the subsequent analysis. Patients
One hundrend and six individuals were randomly selected from a large pool of patients (> 500) attending the research outpatient clinics of the Rheumatism Research Wing, University of Birmingham. They all fulfilled the 1958 A R A criteria (27) for definite or classical RA. SASP (Salazopy-
rin E N tabs) was introduced to all patients at an initial dose of 0.5 g/day. This was increased by weekly increments of 0. 5 glday up to a total of 2 g/day, or a smaller dose, if toxicity was encountered. The standard dose of 2 glday was further increased in some patients who could tolerate it, if no therapeutic benefit was apparent by 3 months of treatment. Age, sex, disease duration and seropositivity for rheumatoid factor (SCAT titre) were rccorded for each of the patients studied. Disease activity just before and 6 months after initiation of treatment with SASP was assessed in all 106 patients by the erythrocyte sedimentation rate (ESR), as well as duration of early morning stiffness (EMS), grip strength (GS), a visual analogue scale for pain (VAS) and a total articular index (TAI) (4) performed by a single metrologist. Disease severity was assessed by the radiological progression of erosions (Larsen score of hands and wrists) between the time of initiation of SASP therapy and two years after continuous treatment exclusively with SASP. This was performed on 62 of the 106 patients, who had complete sets of X rays of the hands and wrists, and were still on SASP treatment alone after 2 years. Liver function was assessed at time 0 and 6 months of SASP treatment by measuring the enzymes alkaline phosphatase (ALP) and serum aspartate transaminase (AST), using routine laboratory methods. Reasons and timing of withdrawal from the study, nature and timing of side-effects, administration of intra-articular steroid injections during the 6 months of study and requirement for additional treatment with second line agents were also recorded for each patient. Statistical analysis
This was performed using non-parametric tests (Mann-Whitney U test). Results were expressed as median and range. The x2 test was used for frequency distribution analysis of the results between the fast and slow acetylator groups. Results
Of the 106 patients studied, 37 (35%) were definitely fast acetylators, 54 (51%) were slow acetylators and 15 (14%) could not be included confidently in either group. An attempt was made to analyse the entire patient group as a continuous variable, according to percent acetylated SP, but this did not correlate significantly with any of the indices of disease activity or severity, or their changes during the observation periods (data not 221
G. D. Kitas et al. Table I: Characteristics of RA patients on initiation of SASP treatment.
(n=37)
Slow acetylators (n=54)
Significance (Mann-Whitney or X2)
Age (years) Sex (fema1e:male) Disease duration (years) Rheumatoid factor (t : -1
53.0 (18.0- 73.0) 25: 12 9.0 (1.0- 28.0) 27:ll
51.0 (25.0- 69.0) 36: 19 7.5 (2.0- 24.0) 37:17
SASP dose (absolute glday) SASP dose (mg/kg body weight)
2.0 (1.0- 3.0) 29.6 (11.2- 56.5)
2.0 (1.0- 3.0) 31.2 (14.5- 52.6)
Erythrocyte sedimentation rate (mm/h) Total articular index Early morning stiffness (min) Grip strength Visual analog scale (pain)
51.0 (7.0-135.0) 30.0 (9.0- 71.0) 60.0 (0.0-840.0) 227.0 (90.0-600.0) 48.0 (0.0- 88.0)
45.0 (1.C-120.0) 33.5 (8.0- 70.0) 60.0 (0.0-840.0) 204.0 (30.0-600.0) 46.5 (0.0-100.0)
NS NS NS NS NS NS NS
Alkaline phosphatase (UIL) Aspartate transaminase (U/L)
231.0 (130.0-768.0) 16.0 (8.0-31.0)
235.5 (103.C-457.0) 18.0 (10.0- 42.0)
NS NS
(n=38) (6.0- 65.0)
NS
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Fast acetylators
(n=24) Larsen score (hands t wrists)
40.0
(4.0-91.0)
36.5
NS NS
NS NS
Demographic, clinical and laboratory characteristics of patients with rheumatoid artritis (RA) with definitely fast or slow acetylator phenotype on initiation of treatment with sulphasalazine (GASP).The clinical assessment of all patients was performed by a single observer (L.W.). Values shown are median and range. Statistical analysis was performed by the Mann-Whitney U test for all parameters with the exception of the frequency distribution of sex and presence of rheumatoid factor for which the two groups were compared by X2 test. NS = not significant (p>0.05). Normal ranges: alkaline phosphatase: 70-300 UIL; aspartate transaminase: 5-30 UIL.
shown). Subsequent analysis was therefore performed comparatively only in the definite fast and slow acetylator groups. The fast and slow acetylator groups were not significantly different (by Mann-Whitney or x2 tests) for age, sex, disease duration, seropositivity and dose of SASP (absolute and in mg/kg of body weight) used for treatment. The two groups were also not significantly different for disease activity and severity as assessed by the various indices, or the levels of liver enzymes on initiation of treatment (Table I). At 6 months of treatment, slow acetylators showed significantly lower ESR than fast acetylators (p = 0.0389, Mann-Whitney). Differences in the clinical indices of disease activity (MS, VAS, GS, TAI) between the two groups were not significant (p > 0.05) (Table 11). The change (delta) of each of the indices of disease activity between month 0 and 6 was calculated on an individual patient basis, and the two groups were again compared: with the exception of ESR which showed significantly greater reduction in the slow than in the fast acetylator group (p = 0.0416, Mann-Whitney), changes in the other indices of activity were not different between the two groups (p > 0.05) (Table 11). Two slow and one fast acetylator required administration of intra-articular steroid injections due to poor response to treatment. Ten fast (27%) and seven (12%) slow acetylators were judged to require additional treatment with a sec222
ond disease modifying anti-rheumatic drug (not significant by x’). Radiological progression of erosions between initiation and 2 years of continuous SASP treatment was assessed in 62 of the 106 patients studied. Thirty eight of these patients (60%) were slow acetylators and 24 (40%) were fast. The two groups did not differ significantly either at initiation of treatment (Table I) or 2 years later (Table 11): overall progression (increase in Larsen score) occured in both groups and was of almost identical magnitude (Table 11). Seventeen fast (72%) and 26 (68%) slow acetylators showed a marked progression (increase in Larsen score > 5 ) , while the remaining in each group showed minimal progression ( < 5); these differences were not significant by x2 test. Only 1 patient (a slow acetylator) showed an improvement in the Larsen score. Minor change occured in the liver enzyme ALP between 0 and 6 months of treatment, and this was comparable between the fast and slow acetylator groups (Table 11). However, the levels of AST at 6 months of treatment were significantly higher in the slow than in the fast acetylator group (p = 0.00756 by Mann-Whitney). This was partly because the elevation of AST in slow acetylators was greater than in fast (p = 0.0291 by Mann-Whitney), but mainly because it occured in significantly more slow acetylators (68%) than fast acetylators (31%) (p < 0.001 by x’). Four fast (9%) and 5 slow acetylators (9%) were withdrawn from the study within the 6 month study
Sulphasalazine acetylation in RA Table II: Changes in clinical, laboratory and radiological parameters after SASP therapy.
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Fast acetylators (n=37) (2.0- 110.0) (22.0- t88.0)
Slow acetylators (n=54) 21.0 -25.0
(1.0- 85.0) -40.0- t68.0)
Significance (Mann-Whitney)
ESR dESR
35.0 -14.0
p = 0.0389 p = 0.0416
EMS dEMS
5.0 (0.0- 720.0) -55.0 (-840.0- t45.0)
15.0 (0.0- 720.0) -30.0 (-720.0-t420.0)
NS NS
GS dCiS
268.0 (91.0- 600.0) i25.5 (- 117,C-t 233.0)
277.0 (98.0- 600.0) t73.0 1-131.0t289.0)
NS NS
VAS dVAS
27.0 (00- 78.0) -17.0 (-66.0- t52.0)
17.0 (0.0- 79.0) -26.0 (-86.0- t70.0)
NS NS
TAI dTAl
16.0 (5.0- 50.0) -8.5 (-32.0- t9.0)
16.5 -10.0
(0.0- 53.0) (-35.0 t7.0)
NS NS
ALP dALP
223.0 (107.0- 435.0) -25.0 (-333.0- t52.0)
232.0 (130.0- 397.0) -19.0 (-160.0- t94.0)
NS
AST dAST
15.0 (11.0- 34.0) t1.0 (-22.0- t14.0)
26.0 (12.0- 78.0) t6.5 (-10.0- t65.0)
p = 0.00756 p = 0.0291
LS dLS
(n=24) 56.5 (6.0- 107.0) t8.0 (0.C-t25.0)
(n=38) 51.0 (11.0- 64.0) t7.0 (-12.0- t26.0)
NS NS
NS
ESR (ertyhrocyte sedimentation rate); EMS (early morning stiffness); GS (grip strength); VAS (visual analog scale for pain); TAI (total articular index); LS (Larsen score of hands and wrists); ALP (alkaline phosphatase); AST (aspartate transaminase); d (delta = change of each parameter after SASP treatment compared with initiation of therapy); SASP (sulphasalatine); NS (not significant: p>0.05). Values shown are median and range. Statistical analysis was performed using the Mann-Whitney U test. All parameters shown were assessed at 6 months of therapy with SASP, apart from the Larsen score, which was assessed at 2 years of therapy with SASP as the only disease modifying drug. Changes (delta) of each of the parameters shown were calculated on an individual patient basis.
period. Reasons for withdrawal were of the same nature and equally distributed between the two groups: 1 patient in each group was withdrawn due to inefficacy, and the remaining patients due to side effects. Side effects occured in a quarter (25%) of the patients in each group (9 fast and 14 slow acetylators). They were of similar nature and severity, and in most cases occured within the first 3 months of treatment (details shown in Table 111). Discussion
Metabolic differences between individual patients may result in variations of the efficacy and toxicity of a certain drug in a certain disease. Previous studies have addressed this in patients with RA treated with SASP. Pullar et al in 1985 (23) studied retrospectively 54 RA patients treated with a standard dose of SASP (3 g/day) for 6 months and prospectively 60 patients with pre-determined acetylator status treated with a high dose (the fast acetylators) or a low dose of SASP (the slow acetylators): they concluded that acetylator status had a remote bearing on the efficacy of SASP, but appeared to be important in determining the incidence of gastrointestinal side-effects (nausea and vomiting). In contrast, Bax et al (24) compared two groups of patients pre-selected for very good
or no therapeutic response to SASP: they found a trend for slow acetylators to occur more frequently in the good responder group, but did not comment on the incidence and nature of side effects. Carroll in 1983 (25) found that fast acetylators tended to have a better response than their slow counterparts, suggesting that an acetylation product of the parent compound, probably acetyl-SP, may be the active moiety. None of these studies investigated a possible influence of acetylator status on the longterm control of disease severity, as assessed by the radiological progression of erosions. The present study addressed the effect of acetylator status on the efficacy of SASP, both in terms of disease activity and severity, and on the nature and incidence of side-effects, in 106 patients with RA. These were treated with 1.5-3 glday of SASP, depending on their tolerance of the drug and their overall response to it as assessed by the physician, but irrespective of their acetylator status. The latter was assessed once patients were established on a standard SASP dose. Population and disease characteristics of the fast and slow acetylators in this study were not different on initiation of treatment. It is therefore unlikely that acetylator status (and its genetic linkages) play a role in the natural history of RA. Fast and slow acetylators did not appear to have differential tolerance to, or therapeutic dose require-
G. D. Kitas et a/. Table 111: Side effect incidence and profile. Side Effect
Slow acetylators (n=54)
Fast acetylators
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(=37) Total:
9 (24.3%)
Gastrointestinal: (nausea, vomiting, flatulence, abdominal discomfort, heartburn)
7 (18.9%)
14 (25.9%) 11 (20.3%)
Central nervous system: (dizziness, tiredness, headaches)
2 (5.4%)
3 (5.6%)
Cardiovascular: (tachycardia, palpitations)
0 (O.O%,)
1
Haematological: leucopenia macrocytosis
1 1
2 (3.7%) 2 (3.7%)
Mucocutaneous: rashes
1
(2.7%) (2.7%) (2.7%)
Raised liver enzymes: alkaline phosphatase aspartate transaminase
1 1
(2.7%) (2.7%)
2 (3.7%) 5 (9.2%)
ment of SASP, both on an absolute and a per kg of body weight basis. The short term (6 month) efficacy of SASP in controlling the inflammatory activity of RA was not significantly different between the two groups. Only the ESR showed a slightly greater reduction in the slow than in the fast acetylator group but this may be due to a type I1 statistical error and is therefore of debatable significance. In addition to this, there were no significant differences between the slow and fast acetylator groups with regard to the long-term control of disease severity, as assessed by the radiological progression of erosions. These findings are more in concordance with those of Pullar et al (23) than with those of Carroll (25) or Bax et al (24). In contrast to one of the previous studies (23), which found a higher frequency of nausea and vomiting in the slow acetylators, our results indicate that there is no significant difference in the frequency and nature of side effects between fast and slow acetylators. The most likely explanation for this is a difference in the patients studied, since the way the drug was introduced to patients in both studies was very similar. An additional explanation may be the fact that we tend to maintain our patients on a smaller (tolerable) dose of SASP for some time, if such side effects occur; we find that subsequent increase of the dose to therapeutic levels at a later stage is in many cases well tolerated. Slow acetylators in the present study showed a higher frequency of increase, and a higher increase of the hepatic enzyme AST after treatment with SASP. The significance of this on a population basis is debatable. Firstly, only 6 (of the 106) patients ( 5 slow and l fast acetylator) showed levels 224
1
(1.8%)
(1.9%)
of AST above the normal range during therapy with SASP, and this was not marked or sustained, despite continuation of treatment; in the rest of the cases AST was increased after 6 months of treatment with SASP, but was still within the normal range. Secondly, in no case was this accompanied by clinical symptoms and signs. However, usually early, but also late onset hepatotoxicity with marked elevation of liver enzymes has been reported in a few cases of both IBD and R A treated with SASP (15, 29, 30). This reinforces the notion that liver function should be carefully monitored in patients treated with SASP. In summary, acetylator status appears to be of minimal, if any, significance in predicting short and long term efficacy or the nature and severity of toxicity of sulphasalazine in rheumatoid arthritis. Acknowledgements
We would like to thank Pharmacia for financial support and Dr. Paul Emery for his helpful advice. References 1. McConkey B , Amos RS, Butler EP, Crockson RA, Crockson AP, Walsh L. Sulphasalazine in rheumatoid arthritis. Br. Med. J. 1980; 280: 4 4 2 4 . 2. Neumann VC, Grindulis KA, Hubball S, McConkey B, Wright V. Comparison between penicillamine and sulphasalazine in rheumatoid arthritis. Leeds-Birmingham trial. Br. Med. J . 1983; 227: 109!+102. 3. Pullar T, Hunter JA, Capell HA. Sulphasalazine in rheumatoid arthritis: a double-blind comparison of sulphasalazine with placebo and sodium aurothiomalate. Br. Med. J . 1983: 287: 1102-4
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Sulphasalazine acetylation in RA 4. Farr M. Tunn EJ, Crockson AP, Bacon PA. The long term effects of sulphasalazine in the treatment of rheumatoid arthritis and a comparative study with penicillamine. Clin. Rheumatol. 1984; 3: 473-82 5. Bax DE, Amos R. S. Sulphasalazine: a safe, effective agent for prolonged control of rheumatoid arthritis. A comparison with aurothiomalate. Ann. Rheum. Dis. 1985; 44: 194-9. 6. Grindulis KA, McConkey B. The outcome of attempts to continue treatment with gold, penicillamine, sulphasalazine or dapsone for 2 years in rheumatoid arthritis. Ann. Rheum. Dis. 1984; 43: 398401. 7. Pullar T, Hunter JA, Capell HA. Effect of sulphasalazine on the radiological progression of rheumatoid arthritis. Ann. Rheum. Dis. 1987; 46: 398-402. 8. Farr M, Kitas GD, Bacon PA. Assessing the outcome of sulphasalazine therapy in rheumatoid arthritis. Br. J. Rheumatol. 1987; 26: 3. 9. Situnayake D, Grindulis KA, McConkey B. Long term treatment of rheumatoid arthritis with sulphasalazine, gold or penicillamine. A comparison using life table methods. Ann. Rheum. Dis. 1987; 461: 177-83. 10. Farr M, Waterhouse L, Bacon PA. 5-year outcome of rheumatoid patients treated with sulphasalazine (SASP). Br. J. Rheumatol. 1989; 28: 2. 11. Pullar T, Hunter JA, Capell HA. Toxicity of sulphasalazine in patients with rheumatoid arthritis. Br. J. Rheumatol. 1985; 24: 214. 12. Farr M, Scott DGI, Bacon PA. Side effect profile of 200 patients with inflammatory arthritis treated with sulphasalazine. Drugs 1986; 32 (suppl. 1): 49-53. 13. Amos RS, Pullar T , Bax DE, Situnayake D, Capell HA, McConkey B. Sulphasalazine for rheumatoid arthritis. Toxicity in 774 patients monitored for 1 to 11 years. Br. Med. J. 1986; 293: 420-3. 14. Donovan S, Hawley S , MacCarthy J, Scott DL. Tolerability of enteric-coated sulphasalazine in rheumatoid arthritis: results of a co-operating clinics study. Br. J. Rheumatol. 1990; 29: 2 0 1 4 . 15. Peppercorn MA. Sulphasalazine: Pharmacology, clinical use. toxicity and related new drug development. Ann. Intern Med. 1984; 3: 377-86. 16. Lunde PKM, Frislid K, Hansteen V. Disease and acetylator polymorphism. In: Gibaldi M. , Prescott L. eds. Handbook of clinical pharmacokinetics. Australia; Adis Health Science Press. 1983.
17. Azad Khan AK, Piris J, Truelove SC. An experiment to determine the active therapeutic moiety of sulphasalazine. Lancet 1977; 289: 2-5. 18. Azad Khan AK, Truelove SC. Optimum dose of sulphasalazine for maintenance treatment in ulcerative colitis. Gut 1980; 21: 232-41. 19. Das KM, Eastwood MA, McManus JPA, Sirius W. Adverse reactions during salicyllazosulphapyridine therapy and the relation with drug metabolism and acetylator phenotype. N. Engl. J. Med. 1973; 289: 491-5. 20. Das KM, Eastwood MA. Acetylation polymorphism of sulphapyridine in patients with ulcerative colitis and Crohn’s disease. Clin. Pharmacol. Ther. 1975; 18: 514-20. 21. Pullar T, Hunter JA, Capell HA. Which component of sulphasalazine is active in rheumatoid arthritis? Br. Med. J. 1985; 290: 1535-8. 22. Farr M, Broderick A, Bacon PA. Plasma and synovial fluid concentration of sulphasalazine and 2 of its metabolites in rheumatoid arthritis. Rheumatol. Int. 1985; 5: 247-5 1 . 23. Pullar T , Hunter JA, Capell HA. Effect of acetylator phenotype on efficacy and toxicity of sulphasalazine in rheumatoid arthritis. Ann. Rheum. Dis. 1985; 44: 831-7. 24. Bax DE, Greaves MS, Amos RS. Sulphasalazine for rheumatoid arthritis: relationship between dose, acetylator phenotype and response to treatment. Br. J. Rheumatol. 1986; 25: 282-4. 25. Carrol G. A comparative study of sulphasalazine and penicillamine in rheumatoid arthritis. Aust. N Z J. Med. 1983; 13: 212-6. 26. Schroder H. Simplified method for determining acetylator phenotype. Br. Med. J. 1972; 30: 506-7. 27. Ropes MW. Diagnostic criteria for rheumatoid arthritis: 1958 revision. Ann. Rheum. Dis. 1959; 18: 49-54. 28. Pullar T , Hunter JA, Capell HA. Sulphasalazine in the treatment of rheumatoid arthritis: relationship of dose and serum levels in efficacy. Br. J. Rheumatol. 1985; 24: 269-76. 29. Farr M, Symmons DPM, Bacon PA. Raised serum alkaline phosphatase and aspartatc transaminase levels in 2 rheumatoid patients treated with sulphasalazine. Ann. Rheum. Dis. 1985; 44: 798-800. 30. Losec JD, Werlin SI. Sulphasalazine hepatotoxicity. Ann. J. Dis. Med. 1981; 135: 1070-2.
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ISSN: 0300-9742 (Print) 1502-7732 (Online) Journal homepage: http://www.tandfonline.com/loi/irhe20
Influence of Acetylator Status on Sulphasalazine Efficacy and Toxicity in Patients with Rheumatoid Arthrftis G. D. Kitas, M. Farr, L. Waterhouse & P. A. Bacon To cite this article: G. D. Kitas, M. Farr, L. Waterhouse & P. A. Bacon (1992) Influence of Acetylator Status on Sulphasalazine Efficacy and Toxicity in Patients with Rheumatoid Arthrftis, Scandinavian Journal of Rheumatology, 21:5, 220-225, DOI: 10.3109/03009749209099228 To link to this article: http://dx.doi.org/10.3109/03009749209099228
Published online: 12 Jul 2009.
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Date: 17 April 2016, At: 22:38
Influence of Acetylator Status on Sulphasalazine Efficacy and Toxicity in Patients with Rheumatoid Arthrftis G. D. Kitas, M. Farr, L. Waterhouse and P. A. Bacon Department of Rheumatology, University of Birmingham, Birmingham, U.K.
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Kitas GD, Farr M, Waterhouse L, Bacon PA. Influence of Acetylator Status on Sulphasalazine Efficacy and Toxicity in Patients with Rheumatoid Arthritis. Scand J Rheumatol 1992; 21: 220-225. The influence of acetylator status on the therapeutic efficacy and the toxicity of sulphasalazine (SASP) was assessed in 106 patients with rheumatoid arthritis (RA). Changes of indices of disease activity after 6 months, and progression of erosions after 2 years of SASP treatment were similar in fast and slow acetylators. Incidence and nature of withdrawals and side-effects, and requirement for intra-articular steroid injections or combination therapy due to poor response to SASP were almost identical in the two groups. A significant increase of the hepatic enzyme aspartate transaminasc was noted mainly in slow acetylators, but was not associated with clinical disease. These results suggest that acetylator status does not relate significantly to either the efficacy or the toxicity of SASP in RA. It is possible that hepatic metabolism is affected by SASP, particularly in slow acetylators, but this does not lead to clinically identifiable problems.
Key Words: Sulphasalazine, Rheumatoid Arthritis, Acetylator Status
SASP is now considered an established second line agent for the treatment of R A (1-5). Its efficacy and toxicity vary considerably between identically treated patients (6-14). This may reflect differences in the metabolism of the drug between individuals. SASP consists of 5-aminosalicylic acid (5-ASA) linked by an azo-bond to the sulphonamide sulphapyridine (SP). Approximately 30% of the drug is absorbed from the upper gastrointestinal tract and a small proportion of this is excreted unchanged in the urine. The remainder is excreted unchanged in the bile, and together with the nonabsorbed portion, reaches the distal small intestine and colon (15). There, the azo-bond is reduced by bacterial action, and SASP is split into its constituent components. 5-ASA remains largely in the colon and is recovered unchanged in the faeces. In contrast, SP is almost totally absorbed from the colon, partially metabolised, and excreted in the urine as the free sulphonamide and its metabolites. SP is metabolised predominantly in the liver by acetylation and to a much lesser extend glucuronidation and hydroxylation. Individuals differ markedly in the rate at which drugs are acetylated, and there is a bimodal distri-
G. D. Kitas, Department of Rheumatology. The Medical School, University of Birmingham, Vincent Drive, Birmingham B15 2'IT Received 12 February 1992 Accepted 25 June 1992
bution of the general population into fast and slow acetylators (approximately 40% and 60% respectively in the U. K.). The rate of acetylation is under genetic control: rapid acetylation is an autosoma1 dominant trait. In addition to SP and other sulphonamides, many other drugs undergo acetylation including hydralazine, isoniazide, dapsone, procainamide, phenelzine, and nitrazepam. Acetylator phenotype appears to play an important role in the therapeutic effect, and even more the toxicity of many of these drugs (16). The mechanism of action of SASP is unknown. Distribution studies indicate that the parent drug SASP may act as a vehicle to deliver its (active) metabolites to distal disease sites (15). Studies in inflammatory bowel disease (IBD) suggest that 5ASA is the active moiety, whereas SP may be responsible for most of the toxicity of SASP (15, 17). Healthy volunteers and patients with IBD who are slow acetylators have higher serum levels and longer half life of total SP, and also greater incidence of side-effects than fast acetylators; no apparent association between acetylator phenotype and therapeutic response to SASP has been noted in these patients (18-20). In contrast, it has been suggested that in RA, SP is the active moiety (21, 22): it is therefore possible, that in this disease, acetylator phenotype may affect both therapeutic response and adverse reactions to SASP. To the best of our knowledge, this question has been addressed to date only by three studies (2325); these were differently designed and reached apparently conflicting conclusions.
Sulphasalnzine acetylation in RA In the present study, we investigated whether acetylator phenotype has a bearing on the control of disease activity and severity and also on the toxicity of SASP, in a group of carefully characterised patients with RA. We also addressed some relevant methodological issues which may be of importance to the interpretation of results obtained in the previous studies.
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Materials and methods Assessment of acetylator status:
Acetylator status was assessed in patients already receiving SASP orally. Random urine samples were collected and assayed using a colorimetric method for free and acetylated SP. The percent acetylated SP was then determined by the method of Schroder (26) using the formula: Urine acetylated SP Urine total (acetylated
+ free) SP
x 100
The possibility of diurnal variation was assessed in 8 patients with RA receiving lg SASP twice daily, by measuring acetylation rate using urine samples collected at 0, 1, 3, 6, 9 and 12 hours after taking their morning SASP tablets. No significant diurnal variation was found in any of the individuals studied (mean coefficient of variation 8.8%). The accuracy and reproducibility of the method was assessed by providing the laboratory with 10 identically handled aliquots of the same urine sample from 8 patients receiving SASP, in a blind manner. Acetylation rate was then measured in these samples in two consecutive assays. Subsequent analysis of the results indicated that the method had a coefficient of variation of 5.6% (data not shown). This suggested that a single cutoff point (55% according to the laboratory) could not be used to differentiate fast from slow acetylators. According to these results, individuals with acetylation rate of > 60% were allocated confidently in the fast acetylator group, while individuals with acetylation rate of < 50% were allocated in the slow acetylator group. Patients with equivocal acetylation rates (50%-60%) were not included in the subsequent analysis. Patients
One hundrend and six individuals were randomly selected from a large pool of patients (> 500) attending the research outpatient clinics of the Rheumatism Research Wing, University of Birmingham. They all fulfilled the 1958 A R A criteria (27) for definite or classical RA. SASP (Salazopy-
rin E N tabs) was introduced to all patients at an initial dose of 0.5 g/day. This was increased by weekly increments of 0. 5 glday up to a total of 2 g/day, or a smaller dose, if toxicity was encountered. The standard dose of 2 glday was further increased in some patients who could tolerate it, if no therapeutic benefit was apparent by 3 months of treatment. Age, sex, disease duration and seropositivity for rheumatoid factor (SCAT titre) were rccorded for each of the patients studied. Disease activity just before and 6 months after initiation of treatment with SASP was assessed in all 106 patients by the erythrocyte sedimentation rate (ESR), as well as duration of early morning stiffness (EMS), grip strength (GS), a visual analogue scale for pain (VAS) and a total articular index (TAI) (4) performed by a single metrologist. Disease severity was assessed by the radiological progression of erosions (Larsen score of hands and wrists) between the time of initiation of SASP therapy and two years after continuous treatment exclusively with SASP. This was performed on 62 of the 106 patients, who had complete sets of X rays of the hands and wrists, and were still on SASP treatment alone after 2 years. Liver function was assessed at time 0 and 6 months of SASP treatment by measuring the enzymes alkaline phosphatase (ALP) and serum aspartate transaminase (AST), using routine laboratory methods. Reasons and timing of withdrawal from the study, nature and timing of side-effects, administration of intra-articular steroid injections during the 6 months of study and requirement for additional treatment with second line agents were also recorded for each patient. Statistical analysis
This was performed using non-parametric tests (Mann-Whitney U test). Results were expressed as median and range. The x2 test was used for frequency distribution analysis of the results between the fast and slow acetylator groups. Results
Of the 106 patients studied, 37 (35%) were definitely fast acetylators, 54 (51%) were slow acetylators and 15 (14%) could not be included confidently in either group. An attempt was made to analyse the entire patient group as a continuous variable, according to percent acetylated SP, but this did not correlate significantly with any of the indices of disease activity or severity, or their changes during the observation periods (data not 221
G. D. Kitas et al. Table I: Characteristics of RA patients on initiation of SASP treatment.
(n=37)
Slow acetylators (n=54)
Significance (Mann-Whitney or X2)
Age (years) Sex (fema1e:male) Disease duration (years) Rheumatoid factor (t : -1
53.0 (18.0- 73.0) 25: 12 9.0 (1.0- 28.0) 27:ll
51.0 (25.0- 69.0) 36: 19 7.5 (2.0- 24.0) 37:17
SASP dose (absolute glday) SASP dose (mg/kg body weight)
2.0 (1.0- 3.0) 29.6 (11.2- 56.5)
2.0 (1.0- 3.0) 31.2 (14.5- 52.6)
Erythrocyte sedimentation rate (mm/h) Total articular index Early morning stiffness (min) Grip strength Visual analog scale (pain)
51.0 (7.0-135.0) 30.0 (9.0- 71.0) 60.0 (0.0-840.0) 227.0 (90.0-600.0) 48.0 (0.0- 88.0)
45.0 (1.C-120.0) 33.5 (8.0- 70.0) 60.0 (0.0-840.0) 204.0 (30.0-600.0) 46.5 (0.0-100.0)
NS NS NS NS NS NS NS
Alkaline phosphatase (UIL) Aspartate transaminase (U/L)
231.0 (130.0-768.0) 16.0 (8.0-31.0)
235.5 (103.C-457.0) 18.0 (10.0- 42.0)
NS NS
(n=38) (6.0- 65.0)
NS
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Fast acetylators
(n=24) Larsen score (hands t wrists)
40.0
(4.0-91.0)
36.5
NS NS
NS NS
Demographic, clinical and laboratory characteristics of patients with rheumatoid artritis (RA) with definitely fast or slow acetylator phenotype on initiation of treatment with sulphasalazine (GASP).The clinical assessment of all patients was performed by a single observer (L.W.). Values shown are median and range. Statistical analysis was performed by the Mann-Whitney U test for all parameters with the exception of the frequency distribution of sex and presence of rheumatoid factor for which the two groups were compared by X2 test. NS = not significant (p>0.05). Normal ranges: alkaline phosphatase: 70-300 UIL; aspartate transaminase: 5-30 UIL.
shown). Subsequent analysis was therefore performed comparatively only in the definite fast and slow acetylator groups. The fast and slow acetylator groups were not significantly different (by Mann-Whitney or x2 tests) for age, sex, disease duration, seropositivity and dose of SASP (absolute and in mg/kg of body weight) used for treatment. The two groups were also not significantly different for disease activity and severity as assessed by the various indices, or the levels of liver enzymes on initiation of treatment (Table I). At 6 months of treatment, slow acetylators showed significantly lower ESR than fast acetylators (p = 0.0389, Mann-Whitney). Differences in the clinical indices of disease activity (MS, VAS, GS, TAI) between the two groups were not significant (p > 0.05) (Table 11). The change (delta) of each of the indices of disease activity between month 0 and 6 was calculated on an individual patient basis, and the two groups were again compared: with the exception of ESR which showed significantly greater reduction in the slow than in the fast acetylator group (p = 0.0416, Mann-Whitney), changes in the other indices of activity were not different between the two groups (p > 0.05) (Table 11). Two slow and one fast acetylator required administration of intra-articular steroid injections due to poor response to treatment. Ten fast (27%) and seven (12%) slow acetylators were judged to require additional treatment with a sec222
ond disease modifying anti-rheumatic drug (not significant by x’). Radiological progression of erosions between initiation and 2 years of continuous SASP treatment was assessed in 62 of the 106 patients studied. Thirty eight of these patients (60%) were slow acetylators and 24 (40%) were fast. The two groups did not differ significantly either at initiation of treatment (Table I) or 2 years later (Table 11): overall progression (increase in Larsen score) occured in both groups and was of almost identical magnitude (Table 11). Seventeen fast (72%) and 26 (68%) slow acetylators showed a marked progression (increase in Larsen score > 5 ) , while the remaining in each group showed minimal progression ( < 5); these differences were not significant by x2 test. Only 1 patient (a slow acetylator) showed an improvement in the Larsen score. Minor change occured in the liver enzyme ALP between 0 and 6 months of treatment, and this was comparable between the fast and slow acetylator groups (Table 11). However, the levels of AST at 6 months of treatment were significantly higher in the slow than in the fast acetylator group (p = 0.00756 by Mann-Whitney). This was partly because the elevation of AST in slow acetylators was greater than in fast (p = 0.0291 by Mann-Whitney), but mainly because it occured in significantly more slow acetylators (68%) than fast acetylators (31%) (p < 0.001 by x’). Four fast (9%) and 5 slow acetylators (9%) were withdrawn from the study within the 6 month study
Sulphasalazine acetylation in RA Table II: Changes in clinical, laboratory and radiological parameters after SASP therapy.
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Fast acetylators (n=37) (2.0- 110.0) (22.0- t88.0)
Slow acetylators (n=54) 21.0 -25.0
(1.0- 85.0) -40.0- t68.0)
Significance (Mann-Whitney)
ESR dESR
35.0 -14.0
p = 0.0389 p = 0.0416
EMS dEMS
5.0 (0.0- 720.0) -55.0 (-840.0- t45.0)
15.0 (0.0- 720.0) -30.0 (-720.0-t420.0)
NS NS
GS dCiS
268.0 (91.0- 600.0) i25.5 (- 117,C-t 233.0)
277.0 (98.0- 600.0) t73.0 1-131.0t289.0)
NS NS
VAS dVAS
27.0 (00- 78.0) -17.0 (-66.0- t52.0)
17.0 (0.0- 79.0) -26.0 (-86.0- t70.0)
NS NS
TAI dTAl
16.0 (5.0- 50.0) -8.5 (-32.0- t9.0)
16.5 -10.0
(0.0- 53.0) (-35.0 t7.0)
NS NS
ALP dALP
223.0 (107.0- 435.0) -25.0 (-333.0- t52.0)
232.0 (130.0- 397.0) -19.0 (-160.0- t94.0)
NS
AST dAST
15.0 (11.0- 34.0) t1.0 (-22.0- t14.0)
26.0 (12.0- 78.0) t6.5 (-10.0- t65.0)
p = 0.00756 p = 0.0291
LS dLS
(n=24) 56.5 (6.0- 107.0) t8.0 (0.C-t25.0)
(n=38) 51.0 (11.0- 64.0) t7.0 (-12.0- t26.0)
NS NS
NS
ESR (ertyhrocyte sedimentation rate); EMS (early morning stiffness); GS (grip strength); VAS (visual analog scale for pain); TAI (total articular index); LS (Larsen score of hands and wrists); ALP (alkaline phosphatase); AST (aspartate transaminase); d (delta = change of each parameter after SASP treatment compared with initiation of therapy); SASP (sulphasalatine); NS (not significant: p>0.05). Values shown are median and range. Statistical analysis was performed using the Mann-Whitney U test. All parameters shown were assessed at 6 months of therapy with SASP, apart from the Larsen score, which was assessed at 2 years of therapy with SASP as the only disease modifying drug. Changes (delta) of each of the parameters shown were calculated on an individual patient basis.
period. Reasons for withdrawal were of the same nature and equally distributed between the two groups: 1 patient in each group was withdrawn due to inefficacy, and the remaining patients due to side effects. Side effects occured in a quarter (25%) of the patients in each group (9 fast and 14 slow acetylators). They were of similar nature and severity, and in most cases occured within the first 3 months of treatment (details shown in Table 111). Discussion
Metabolic differences between individual patients may result in variations of the efficacy and toxicity of a certain drug in a certain disease. Previous studies have addressed this in patients with RA treated with SASP. Pullar et al in 1985 (23) studied retrospectively 54 RA patients treated with a standard dose of SASP (3 g/day) for 6 months and prospectively 60 patients with pre-determined acetylator status treated with a high dose (the fast acetylators) or a low dose of SASP (the slow acetylators): they concluded that acetylator status had a remote bearing on the efficacy of SASP, but appeared to be important in determining the incidence of gastrointestinal side-effects (nausea and vomiting). In contrast, Bax et al (24) compared two groups of patients pre-selected for very good
or no therapeutic response to SASP: they found a trend for slow acetylators to occur more frequently in the good responder group, but did not comment on the incidence and nature of side effects. Carroll in 1983 (25) found that fast acetylators tended to have a better response than their slow counterparts, suggesting that an acetylation product of the parent compound, probably acetyl-SP, may be the active moiety. None of these studies investigated a possible influence of acetylator status on the longterm control of disease severity, as assessed by the radiological progression of erosions. The present study addressed the effect of acetylator status on the efficacy of SASP, both in terms of disease activity and severity, and on the nature and incidence of side-effects, in 106 patients with RA. These were treated with 1.5-3 glday of SASP, depending on their tolerance of the drug and their overall response to it as assessed by the physician, but irrespective of their acetylator status. The latter was assessed once patients were established on a standard SASP dose. Population and disease characteristics of the fast and slow acetylators in this study were not different on initiation of treatment. It is therefore unlikely that acetylator status (and its genetic linkages) play a role in the natural history of RA. Fast and slow acetylators did not appear to have differential tolerance to, or therapeutic dose require-
G. D. Kitas et a/. Table 111: Side effect incidence and profile. Side Effect
Slow acetylators (n=54)
Fast acetylators
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(=37) Total:
9 (24.3%)
Gastrointestinal: (nausea, vomiting, flatulence, abdominal discomfort, heartburn)
7 (18.9%)
14 (25.9%) 11 (20.3%)
Central nervous system: (dizziness, tiredness, headaches)
2 (5.4%)
3 (5.6%)
Cardiovascular: (tachycardia, palpitations)
0 (O.O%,)
1
Haematological: leucopenia macrocytosis
1 1
2 (3.7%) 2 (3.7%)
Mucocutaneous: rashes
1
(2.7%) (2.7%) (2.7%)
Raised liver enzymes: alkaline phosphatase aspartate transaminase
1 1
(2.7%) (2.7%)
2 (3.7%) 5 (9.2%)
ment of SASP, both on an absolute and a per kg of body weight basis. The short term (6 month) efficacy of SASP in controlling the inflammatory activity of RA was not significantly different between the two groups. Only the ESR showed a slightly greater reduction in the slow than in the fast acetylator group but this may be due to a type I1 statistical error and is therefore of debatable significance. In addition to this, there were no significant differences between the slow and fast acetylator groups with regard to the long-term control of disease severity, as assessed by the radiological progression of erosions. These findings are more in concordance with those of Pullar et al (23) than with those of Carroll (25) or Bax et al (24). In contrast to one of the previous studies (23), which found a higher frequency of nausea and vomiting in the slow acetylators, our results indicate that there is no significant difference in the frequency and nature of side effects between fast and slow acetylators. The most likely explanation for this is a difference in the patients studied, since the way the drug was introduced to patients in both studies was very similar. An additional explanation may be the fact that we tend to maintain our patients on a smaller (tolerable) dose of SASP for some time, if such side effects occur; we find that subsequent increase of the dose to therapeutic levels at a later stage is in many cases well tolerated. Slow acetylators in the present study showed a higher frequency of increase, and a higher increase of the hepatic enzyme AST after treatment with SASP. The significance of this on a population basis is debatable. Firstly, only 6 (of the 106) patients ( 5 slow and l fast acetylator) showed levels 224
1
(1.8%)
(1.9%)
of AST above the normal range during therapy with SASP, and this was not marked or sustained, despite continuation of treatment; in the rest of the cases AST was increased after 6 months of treatment with SASP, but was still within the normal range. Secondly, in no case was this accompanied by clinical symptoms and signs. However, usually early, but also late onset hepatotoxicity with marked elevation of liver enzymes has been reported in a few cases of both IBD and R A treated with SASP (15, 29, 30). This reinforces the notion that liver function should be carefully monitored in patients treated with SASP. In summary, acetylator status appears to be of minimal, if any, significance in predicting short and long term efficacy or the nature and severity of toxicity of sulphasalazine in rheumatoid arthritis. Acknowledgements
We would like to thank Pharmacia for financial support and Dr. Paul Emery for his helpful advice. References 1. McConkey B , Amos RS, Butler EP, Crockson RA, Crockson AP, Walsh L. Sulphasalazine in rheumatoid arthritis. Br. Med. J. 1980; 280: 4 4 2 4 . 2. Neumann VC, Grindulis KA, Hubball S, McConkey B, Wright V. Comparison between penicillamine and sulphasalazine in rheumatoid arthritis. Leeds-Birmingham trial. Br. Med. J . 1983; 227: 109!+102. 3. Pullar T, Hunter JA, Capell HA. Sulphasalazine in rheumatoid arthritis: a double-blind comparison of sulphasalazine with placebo and sodium aurothiomalate. Br. Med. J . 1983: 287: 1102-4
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