British Journal of Rheumatology 1990;29:280-283
A MULTICENTRE DOUBLE-BLIND COMPARISON OF AURANOFIN, INTRAMUSCULAR GOLD THIOMALATE AND PLACEBO IN PATIENTS WITH PSORIATIC ARTHRITIS BY J. PALIT1, J. HILL3, H. A. CAPELL2, J. CAREY2, S. O'N. DAUNT4, M. I. D. CAWLEY4, H. A. BIRD3 AND G. NUKI1 'Rheumatic Diseases Unit, Northern General Hospital, Edinburgh EH5 2DQ;2Centre for Rheumatic Diseases, Royal Infirmary, Glasgow G4 OSF; 3Clinical Pharmacology Unit, Royal Bath Hospital, Harrogate HG1 2PS; 4Rheumatology Unit, Southampton General Hospital, Southampton SO9 4XY
KEY WORDS: Second-line treatment,
Oral gold, Toxicity, Effectiveness.
malate after informed consent had been obtained. Intramuscular gold was administered as sodium aurothiomalate 50 mg i.m. weekly after a test dose of 10 mg provided that routine urinalysis was clear, and a full blood count, including platelets, was satisfactory before each injection. The dose of auranofin, or identical placebo tablets, was increased by 1 mg per day at each monthly assessment if there had been no symptomatic improvement. In those patients showing no improvement after 4 months the code was broken. Patients who were receiving placebo were switched to treatment with auranofin and treatment was discontinued in those who had already received oral gold. Assessments were undertaken by a single observer in each centre who was unaware which treatment regimen was being administered. Assessments were undertaken before starting therapy and then at 2 weeks, 4 weeks, 8 weeks, 12 weeks and 24 weeks. The assessments undertaken on each occasion and later subjected to statistical analysis (Wilcoxon matched pairs signed rank test) were the Ritchie articular index [13], a visual analogue pain score [14], grip strength [15] and the Westergren erythrocyte sedimentation rate (ESR). Laboratory tests undertaken at each assessment included a full blood count, a plasma biochemical profile (electrolytes, urea, creatinine, urate and standard liver function tests) and a routine chemical urinalysis.
INTRAMUSCULAR gold salts have been used as suppressive antirheumatic drugs for the treatment of rheumatoid arthritis (RA) for more than 50 years [1]. In the last decade an oral gold compound, auranofin, has been developed [2] which has been shown to produce a second-line effect in patients with RA and which is associated with fewer adverse effects [3—6]. Second-line suppressive antirheumatic drug therapy is less often needed in patients with psoriatic arthritis but there have been reports that intramuscular gold compounds can be helpful in this condition [7-9]. More recently, small uncontrolled studies have suggested that auranofin may also be effective in patients with psoriatic arthropathy [10, 11]. A recent double-blind study comparing auranofin with placebo suggested that the therapeutic advantage of auranofin was modest in psoriatic arthritis [12]. This paper reports the results of the first placebocontrolled, prospective, multicentre comparison of the safety and efficacy of auranofin and i.m. gold in the treatment of patients with uncomplicated psoriatic arthritis.
METHODS Eighty-two patients (27 from Edinburgh, 25 from Glasgow, 12 from Leeds and 18 from Southampton) with active symptomatic psoriatic arthritis of at least 1 year's duration were studied. Patients who had previously received gold or other suppressive antirheumatic drug therapy were not included, but all patients continued to receive non-steroidal analgesic antiinflammatory drugs in unchanged dosage throughout the course of the trial. None of the patients received oral or intra-articular steroids during the period of study. Patients were randomly allocated to receive auranofin 3 mg b.d., identical placebo tablets or i.m. gold thio-
TABLE I DETAILS OF PATIENTS IN EACH TREATMENT GROUP
Placebo («=26)
Submitted 11 May; revised version accepted 9 November 1989. Correspondence to Dr H. Capell, Centre for Rheumatic Diseases, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF. 280
Auranofin I.m. gold («=29) (" = 27)
Mean age (years)
45
46
47
Male Female Duration of psoriasis (mean years) Duration of arthritis (mean years)
15
13
11
16
12 15
16
14
21
8
6
7
Downloaded from http://rheumatology.oxfordjournals.org/ at University of New South Wales on July 16, 2015
SUMMARY The efficacy and safety of the oral gold compound auranofin and intramuscular gold thiomalate have been compared in a placebo-controlled, double-blind, four-centre trial in 82 patients with psoriatic arthritis requiring remittive drug therapy. There were statistically significant falls in Ritchie articular index, visual analogue pain score and ESR at 12 and 24 weeks following i.m. gold but no significant changes in the auranofin group. Intramuscular gold was safe and more effective than auranofin as a second-line, suppressive antirheumatic agent for patients with psoriatic arthritis when followed for 6 months.
281
PALIT ETAL.: AURANOFIN AND GOLD THIOMALATE IN PSORIATIC ARTHRITIS
trial; 14 on placebo, 20on auranofin and 17 on i.m. gold completed 24 weeks. At 12 weeks and 24 weeks there were statistically significant falls in pain score, articular index and ESR in the patients receiving i.m. gold. There were no statistically significant changes in the auranofin group at 12 or 24 weeks, but the placebo group did show some improvement in pain score and articular index at 24 weeks.
TABLE II ADVERSE REACTIONS LEADING TO WITHDRAWAL IN THE FIRST 24 WEEKS OF THERAPY
Placebo
6
1
1 1
I(wk3)*
—
—
I(wk4)t
— 12 —
1 2 3
1 — — 1
12
9
10
— —
DISCUSSION In a prospective comparative trial of i.m. gold, oral gold and placebo in psoriatic arthritis, only i.m. gold thiomalate was associated with early and consistent improvement in pain, tenderness and ESR. This confirms previous uncontrolled and retrospective studies which have suggested that i.m. gold can be effective in psoriatic arthritis [1,3], but fails to confirm the results of early uncontrolled studies which suggested that the new oral gold compound auranofin was also effective in this disease [9,10]. A type I error cannot, however, be excluded. In a larger study of 238 patients with psoriatic arthritis entered into a double-blind trial comparing auranofin and placebo, auranofin was found to be statistically superior to placebo treatment only in the physicians' global assessment and functional scores. There was no statistically significant improvement in any of the other disease parameters. The authors of that study concluded that the use of auranofin in the treatment of psoriatic arthritis is safe but its therapeutic advantage over treatment with non-steroidal anti-inflammatory drugs alone is modest [12]. Previous studies have emphasized that treatment of psoriatic arthritis with i.m. gold is not associated with exacerbation of psoriasis [7,8]. This has been confirmed in this study, but neither form of gold therapy was associated with any remission of cutaneous psoriasis. In the study referred to above, psoriasis worsened in six auranofin-treated patients and three placebotreated patients which might be expected by chance in such a large study group. Mucocutaneous side-effects are, however, common with i.m. gold, even in patients with R A and it should be noted that the commonest causes of withdrawal from
tOne patient on i.m. gold showed persistent IgA deficiency and was withdrawn. *One patient on auranofin developed agranulocytosis within 3 weeks of therapy. She had been started on fenbufen just prior to entry to the trial and did have evidence of eosinophilia (eosinophil count = 1.3xl09/l) before commencement of auranofin therapy. She recovered completely after withdrawal of both drugs and rechallenge to find out which of these two was responsible for the agranulocytosis was not considered justifiable.
RESULTS Analysis of results for 3 and 6 months are presented. Details of age, sex and duration of disease of the 82 patients entering the study are shown in Table I according to allocation to treatment with oral gold (29), i.m. gold (27) and placebo (26). The treatment groups were comparable in respect to these parameters. Twenty (69%) of the patients on auranofin, 17 (63%) of the patients on i.m. gold and 14 (54%) of the placebotreated patients completed 6 months of the study. The reasons for discontinuing therapy in patients from each group between 0 and 48 weeks are shown in Table II. There were no other significant changes in the biochemical profiles. The results of pain scores, grip strength, Ritchie articular indices and ESR are shown in Table III and Table IV for 12 and 24 weeks of therapy. Initial values were comparable (Kruskal-Wallis test). Twenty-four patients from the placebo group, 24 from the auranofin and21ofthei.m.goldgroupscompletedl2weeksofthe
TABLE III RESULTS OF ASSESSMENTS AFTER 12 WEEKS
Placebo ("=24) Week Pain score (cm) Median Range Grip strength (mmHg) Median Range Ritchie index Median Range ESR (mm/h) Median Range
0
Auranofin («=20)
P
12
0
12
I.m. gold ("=21)
P 0
12
P
4.3
4.4
1.1-9.9
0.9-9.2
NS
4.4 1.0-9.5
3.9 0.9-8.4
NS
4.9 0.5-9.9
2.5 0.3-9.8
0.0111
181
189 41-300
NS
179 86-300
167 68-300
NS
180 51-300
202 48-300
NS
9 1-30
NS
12 1-30
13 2-30
NS
14
9.0 0-24
0.004
18 3-110
NS NS
24 1-70
19 2-48
NS
16 2-77
0.039
50-300 10
0-27 17
3-86
1-58 32
1-110
Downloaded from http://rheumatology.oxfordjournals.org/ at University of New South Wales on July 16, 2015
Rash Mouth ulcer Proteinuria Haematological Immunological Systemic glandular fever like illness Diarrhoea Ineffectiveness Defaulted Total
Auranofin l.m. gold
BRITISH JOURNAL OF RHEUMATOLOGY VOL. XXIX NO. 4
282
TABLE IV RESULTS OFASSESSMENTS AFTER 24 WEEKS
Placebo («=14) 0
24
4.3 1.1-9.9
2.0 0.3-6.9
123 90-300
24
NS
4.9 0.5-9.9
2.7 0.3-6.3
0.009
181 54-300
NS
161 51-300
192 67-300
NS
13 1-30
13 0-24
NS
14 1-58
9.0 0-17
0.001
24 1-70
16 2-46
NS
32 1-110
15 3-78
0.036
24
0.019
4.7 1.0-9.5
4.2 1.3-9.2
192 64-300
NS
173 86-300
11 0-27
9 0-26
0.041
17 3-86
18 6-75
NS
ACKNOWLEDGEMENTS
Financial support for this study was provided by Smith, Kline and French. This manuscript was typed by Mrs L. Leckenby. REFERENCES
1. Nuki G, Gumpel JM, eds. Myocrisin: 50years experience. London: MCI Symposium, 1985 ;II: 1-142. 2. WalzDI,diMartinoMJ,ChakrinLW.SuttonBM,Misher A. Anti-arthritic properties and unique pharmacological profile o f a petenttat^hfysotherapeutic agent, SK&F D-31962. J Pharmacol Exp Ther 1976;197:142-50.
P
0
0
this treatment in our study of psoriatic patients were rash (19%) and mouth ulcers (9.5%). One patient was withdrawn because of IgA deficiency, a rare but well documented side-effect of gold therapy [16]. Diarrhoea is frequently quoted as a common and troublesome side-effect of auranofin in R A patients [17,18]. In the present study of psoriatic arthritic patients only one out of 23 patients had to be withdrawn because of this complication. One patient developed agranulocytosis. Although the bone marrow examination and sequence of clinical events strongly suggested that this was drug induced, it is difficult to be certain whether auranofin or fenbufen, which had recently been introduced, was responsible. A recent review [19] of world-wide safety experience with auranofin in 4000 patients suggested that anaemia (0.8%), leucopenia (0.6%) and thrombocytopenia (0.7%) are rare adverse reactions to this oral gold compound. Twelve out of 20patients on placebo discontinued the treatment before 6 months due to ineffectiveness. Not surprisingly the patients who remained on placebo until 24 weeks had milder disease than the group as a whole. In conclusion the present study confirms that i.m. gold is an effective remittive agent in patients with psoriatic arthritis over 6 months and suggests that it may be more effective than auranofin in these circumstances. Larger and longer studies will need to be undertaken to ascertain whether auranofin has any useful remittive effect in patients with psoriatic arthritis and whether any form of gold therapy slows the progression of joint damage in this disease.
I.m. gold ("=17)
P
3. Lewis D, Capell H. Is auranofin preferable to gold sodium thiomalate in the management of rheumatoid arthritis? In: Capell HA, Cole DS, Manghani KK, Morris RW, eds. Auranofin. Amsterdam: Excerpta Medica, 1983; 147-55. 4. Dequeker J, Francx L, Deckers Y. Comparison of oral gold (auranofin) and injectable gold (gold sodium thiopropanol sulphate) treatment in patients with rheumatoid arthritis: a single blind study. In: Capell HA, Cole DS, Manghani KK, Morris RW, eds. Auranofin. Amsterdam: Excerpta Medica, 1983: 156-64. 5. Schattenkirchner M, Kaik B, Mullerfassbender H, et al. Auranofin and sodium aurothiomalate in the treatment of rheumatoid arthritis: a double blind comparative multicentre study. J Rheumatol 1982;9 (S8):184. 6. BlodgettRCJr,HeuerMA,PietruskoRG. Auranofin: a unique oral chrysotherapeutic agent. Semin Arthritis Rheum 1984;13:255-73. 7. Wright V. Psoriatic arthritis: a comparative study of rheumatoid arthritis and arthritis associated with psoriasis. Ann Rheum Dis 1961;20:123. 8. Dorwart BB, Gall EP, Schumacher RH, Krauser RE. Chrysotherapy in psoriatic arthritis: efficacy and toxicity compared to rheumatoid arthritis. Arthritis Rheum 1978;21:513-15. 9. Richter MB, Kinsella P, Corbet M. Gold in psoriatic arthropathy. Ann Rheum Dis 1980;39:279-80. 10. Dequeker J, Verdickt W, Gevers G, Vanschonbroek K. Long term experience with oral gold in rheumatoid arthritis and psoriatic arthritis. Clin Rheumatol 1984;3:67-74. 11. Tumiati B, Baricchi R, Bellelli A. Psoriatic arthritis. Long term treatment with auranofin. Clin Rheumatol 1986;5:124-5. 12. CaretteS,CalinA,McCaffertyJP,WallinBA,andThe Auranofin Cooperating Group. A double-blind placebo-controlled study of auranofin in patients with psoriatic arthritis. Arthritis Rheum 1989;32:158-65. 13. Ritchie DM, Boyle JA, Mclnnes JM, et al. Clinical studies with an articular index for the assessment of joint tenderness in patients with rheumatic arthritis. Q J Med 1968,37:393-406. 14. Scott JT, Huskisson EC. Graphic representation of pain. Pain 1976:2:175-84. 15. Lee P, Baxter A, Dick WC. An assessment for grip strength measurement in rheumatoid arthritis. ScandJ Rheumatol 1974;3:17-23. 16. Stanworth DR, Johns P, Williamson N, Shadforth M,
Downloaded from http://rheumatology.oxfordjournals.org/ at University of New South Wales on July 16, 2015
Week Pain score (cm) Median Range Grip strength (mmHg) Median Range Ritchie index Median Range ESR (mm/h) Median Range
Auranofin (n=20)
P
PALIT ETAL.:
AURANOFIN AND GOLD THIOMALATE IN PSORIATIC ARTHRITIS
Felix-Davies D, Thompson R. Drug induced IgA deficiency in rheumatoid arthritis. Lancet 1977;i:1001. 17. BandillaK, Gross D, Gross W,etal. Oral gold therapy with auranofin (SK & F 39162). A multicentre open study in patients with rheumatoid arthritis. J Rheumatol 1982;9(Suppl 8): 154-9.
283
18. Katz WA, Alexander S, Bland JW, etal. The efficacy and safety of auranofin compared to placebo in rheumatoid arthritis. J Rheumatol 1982;9(Suppl 8):173-8. 19. Heuer MA, Peitrusko RG, Morris RW, Scheffier BJ. An analysis of worldwide safety experience with auranofin. J Rheumatol 1985 ;12:695-9.
CLINICAL CONUNDRUM
THE prevalence of the gonococcal arthritis-dermatitis syndrome or disseminated gonococcal infection (DGI) appears to vary geographically. Most DGI cases reported in English language medical journals have originated from either the United States or Scandinavia; the frequency of this syndrome appears to be less common in the United Kingdom and there have been relatively few reports of DGI from Africa or other parts of the developing world. What are the reasons for the apparent geographic variation of this relatively rare complication of a common disease (uncomplicated gonorrhoea)? There is a substantial body of data to support the thesis that biological characteristics of gonococcal strains modify the likelihood that gonorrhoea patients will develop DGI. Early studies of DGI epidemiology conducted in Seattle, Washington, demonstrated that Neisseria gonorrhoeae isolates from DGI patients could be differentiated from most gonococci isolated from patients with uncomplicated genital infections by their resistance to complement mediated bactericidal activity of normal human sera. The same investigators also found that most DGI isolates were also unusually sensitive to in vitro killing by penicillin G. Subsequent studies demonstrated that, in Seattle, where much of the early study of DGI patients and gonococcal isolates from them were performed, serum resistance and penicillin sensitivity were phenotypic correlates associated with gonococcal strains characterized by nutritional requirements (auxotrophy) for arginine, hypoxanthine, and uracil (AHU" strains). AHU" auxotrophy, however, was subsequently shown not to be a universal characteristic of gonococcal isolates from DGI patients. While DGI isolates from Seattle and Denver were found to be predominantly AHU" strains (76% and 85%, respectively), in Boston and Atlanta AHU" gonococci comprised only 58% and 34% of isolates respectively from DGI patients. More recently, epidemiological studies using gonococcal protein 1 serotyping have further clarified the dominant association of protein 1 type on DGI prevalence. Protein 1, the predominant gonococcal outer membrane protein by weight, can be divided into two mutually exclusive species, protein 1-A and protein 1-B, which in turn can be further subdivided using panels of protein 1-A or 1-B specific monoclonal antibodies. Most AHU" gonococci belong to protein 1-A serogroups and, in cities where gonococci isolated from DGI patients are not AHU" strains, most isolates from DGI patients are none the less protein 1-A strains. In the studies of DGI isolates from Seattle, Denver, Boston, and Atlanta mentioned above, whereas the prevalence of AHU" auxotrophy varied from 34 to 85% among isolates from DGI patients, a stronger association with protein 1-A serogroups was noted, with 82-86% of the same isolates belonging to protein 1-A serovars. As observed for AHU" auxotrophy, the association of serum
resistance has also been demonstrated to be more strongly associated with protein 1-A serogroups than AHU" auxotrophy. Additional observations suggest that gonococci vary from region to region with respect to the prevalence of protein 1-A serotypes and that this variation affects the prevalence of DGI. In the multicentre studies mentioned above, only 13-57% of isolates from patients with uncomplicated gonorrhoea in the same communities belonged to protein 1-A serogroups (as opposed to 82-86% of DGI isolates). In addition, protein 1-A containing gonococcal serovars appear to be less common in the UK than in the areas of the US from which DGI has been commonly reported. Finally, still another Seattle study reported that between the mid-1970s and early 1980s the frequency of DGI had declined substantially, paralleling a community-wide decline in the prevalence of protein 1-A containing gonococci from 54% to 24% of all isolates. Thus in summary, the apparent differences in the DGI prevalence currently appear to correlate most closely with geographic variation in the prevalence of gonococci containing protein 1-A serovars. Whether the association of DGI with protein 1-A containing gonococci is directly related to characteristics of protein 1-A or is related to other, associated but not causal factors, remains to be proven. E. W. HOOK
Division of Infectious Diseases, Johns Hopkins Hospital, Blalock 1111, Baltimore, MD 21205, USA
FURTHER READING
1. Sandstrom EG, Knapp JS, Reller LB, Thompson SE, Hook EW III, Holmes KK. Serogroupingof Neisseria gonorrhoeae: correlation of serogroup with disseminated gonococcal infection. Sexually Transmitted Diseases 1984;ll:77-80. 2. Knapp JS, Thornsberry C, Schoolnik GA, Wiesner PJ, Holmes KK. Cooperative Study Group. Phenotypic and epidemiologic correlates of auxotype in Neisseria gonorrhoeae. J Infect Dis 1978;132:160-5. 3. O'Brien JP, Goldberg DL, Rice PA. Disseminated gonococcal infection: a prospective anlysis of 49 patients and a review of pathophysiology and immune mechanisms. Medicine 1983;62:395-^06. 4. Cannon JG, Buchanan TM, Sparling PF. Confirmation of association of protein 1 serotype of Neisseria gonorrhoeae with ability to cause disseminated infection. Infect Immun 1983;40:816-19. 5. Rompalo AM, Hook EW III, Roberts PL, Ramsey PG, Handsfield HH, Holmes KK. The acute arthritis-dermatology syndrome. The changing importance of Neisseria gonorrhoeae and Neisseria meningitidis. Arch Intern Med 1987;147:281-3. 6. IsonCA,GedneyJ,EasmonCSF. Chromosomal resistance of gonococci to antibiotics. Genitourin Med 1987;63:239-43.
Downloaded from http://rheumatology.oxfordjournals.org/ at University of New South Wales on July 16, 2015
Discussion about septic arthritis with American colleagues leads inescapably to the conclusion that gonococcal arthritis is much more common in the USA than in the UK. Is it the strain of organism, differences in lifestyles or what?
A MULTICENTRE DOUBLE-BLIND COMPARISON OF AURANOFIN, INTRAMUSCULAR GOLD THIOMALATE AND PLACEBO IN PATIENTS WITH PSORIATIC ARTHRITIS BY J. PALIT1, J. HILL3, H. A. CAPELL2, J. CAREY2, S. O'N. DAUNT4, M. I. D. CAWLEY4, H. A. BIRD3 AND G. NUKI1 'Rheumatic Diseases Unit, Northern General Hospital, Edinburgh EH5 2DQ;2Centre for Rheumatic Diseases, Royal Infirmary, Glasgow G4 OSF; 3Clinical Pharmacology Unit, Royal Bath Hospital, Harrogate HG1 2PS; 4Rheumatology Unit, Southampton General Hospital, Southampton SO9 4XY
KEY WORDS: Second-line treatment,
Oral gold, Toxicity, Effectiveness.
malate after informed consent had been obtained. Intramuscular gold was administered as sodium aurothiomalate 50 mg i.m. weekly after a test dose of 10 mg provided that routine urinalysis was clear, and a full blood count, including platelets, was satisfactory before each injection. The dose of auranofin, or identical placebo tablets, was increased by 1 mg per day at each monthly assessment if there had been no symptomatic improvement. In those patients showing no improvement after 4 months the code was broken. Patients who were receiving placebo were switched to treatment with auranofin and treatment was discontinued in those who had already received oral gold. Assessments were undertaken by a single observer in each centre who was unaware which treatment regimen was being administered. Assessments were undertaken before starting therapy and then at 2 weeks, 4 weeks, 8 weeks, 12 weeks and 24 weeks. The assessments undertaken on each occasion and later subjected to statistical analysis (Wilcoxon matched pairs signed rank test) were the Ritchie articular index [13], a visual analogue pain score [14], grip strength [15] and the Westergren erythrocyte sedimentation rate (ESR). Laboratory tests undertaken at each assessment included a full blood count, a plasma biochemical profile (electrolytes, urea, creatinine, urate and standard liver function tests) and a routine chemical urinalysis.
INTRAMUSCULAR gold salts have been used as suppressive antirheumatic drugs for the treatment of rheumatoid arthritis (RA) for more than 50 years [1]. In the last decade an oral gold compound, auranofin, has been developed [2] which has been shown to produce a second-line effect in patients with RA and which is associated with fewer adverse effects [3—6]. Second-line suppressive antirheumatic drug therapy is less often needed in patients with psoriatic arthritis but there have been reports that intramuscular gold compounds can be helpful in this condition [7-9]. More recently, small uncontrolled studies have suggested that auranofin may also be effective in patients with psoriatic arthropathy [10, 11]. A recent double-blind study comparing auranofin with placebo suggested that the therapeutic advantage of auranofin was modest in psoriatic arthritis [12]. This paper reports the results of the first placebocontrolled, prospective, multicentre comparison of the safety and efficacy of auranofin and i.m. gold in the treatment of patients with uncomplicated psoriatic arthritis.
METHODS Eighty-two patients (27 from Edinburgh, 25 from Glasgow, 12 from Leeds and 18 from Southampton) with active symptomatic psoriatic arthritis of at least 1 year's duration were studied. Patients who had previously received gold or other suppressive antirheumatic drug therapy were not included, but all patients continued to receive non-steroidal analgesic antiinflammatory drugs in unchanged dosage throughout the course of the trial. None of the patients received oral or intra-articular steroids during the period of study. Patients were randomly allocated to receive auranofin 3 mg b.d., identical placebo tablets or i.m. gold thio-
TABLE I DETAILS OF PATIENTS IN EACH TREATMENT GROUP
Placebo («=26)
Submitted 11 May; revised version accepted 9 November 1989. Correspondence to Dr H. Capell, Centre for Rheumatic Diseases, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF. 280
Auranofin I.m. gold («=29) (" = 27)
Mean age (years)
45
46
47
Male Female Duration of psoriasis (mean years) Duration of arthritis (mean years)
15
13
11
16
12 15
16
14
21
8
6
7
Downloaded from http://rheumatology.oxfordjournals.org/ at University of New South Wales on July 16, 2015
SUMMARY The efficacy and safety of the oral gold compound auranofin and intramuscular gold thiomalate have been compared in a placebo-controlled, double-blind, four-centre trial in 82 patients with psoriatic arthritis requiring remittive drug therapy. There were statistically significant falls in Ritchie articular index, visual analogue pain score and ESR at 12 and 24 weeks following i.m. gold but no significant changes in the auranofin group. Intramuscular gold was safe and more effective than auranofin as a second-line, suppressive antirheumatic agent for patients with psoriatic arthritis when followed for 6 months.
281
PALIT ETAL.: AURANOFIN AND GOLD THIOMALATE IN PSORIATIC ARTHRITIS
trial; 14 on placebo, 20on auranofin and 17 on i.m. gold completed 24 weeks. At 12 weeks and 24 weeks there were statistically significant falls in pain score, articular index and ESR in the patients receiving i.m. gold. There were no statistically significant changes in the auranofin group at 12 or 24 weeks, but the placebo group did show some improvement in pain score and articular index at 24 weeks.
TABLE II ADVERSE REACTIONS LEADING TO WITHDRAWAL IN THE FIRST 24 WEEKS OF THERAPY
Placebo
6
1
1 1
I(wk3)*
—
—
I(wk4)t
— 12 —
1 2 3
1 — — 1
12
9
10
— —
DISCUSSION In a prospective comparative trial of i.m. gold, oral gold and placebo in psoriatic arthritis, only i.m. gold thiomalate was associated with early and consistent improvement in pain, tenderness and ESR. This confirms previous uncontrolled and retrospective studies which have suggested that i.m. gold can be effective in psoriatic arthritis [1,3], but fails to confirm the results of early uncontrolled studies which suggested that the new oral gold compound auranofin was also effective in this disease [9,10]. A type I error cannot, however, be excluded. In a larger study of 238 patients with psoriatic arthritis entered into a double-blind trial comparing auranofin and placebo, auranofin was found to be statistically superior to placebo treatment only in the physicians' global assessment and functional scores. There was no statistically significant improvement in any of the other disease parameters. The authors of that study concluded that the use of auranofin in the treatment of psoriatic arthritis is safe but its therapeutic advantage over treatment with non-steroidal anti-inflammatory drugs alone is modest [12]. Previous studies have emphasized that treatment of psoriatic arthritis with i.m. gold is not associated with exacerbation of psoriasis [7,8]. This has been confirmed in this study, but neither form of gold therapy was associated with any remission of cutaneous psoriasis. In the study referred to above, psoriasis worsened in six auranofin-treated patients and three placebotreated patients which might be expected by chance in such a large study group. Mucocutaneous side-effects are, however, common with i.m. gold, even in patients with R A and it should be noted that the commonest causes of withdrawal from
tOne patient on i.m. gold showed persistent IgA deficiency and was withdrawn. *One patient on auranofin developed agranulocytosis within 3 weeks of therapy. She had been started on fenbufen just prior to entry to the trial and did have evidence of eosinophilia (eosinophil count = 1.3xl09/l) before commencement of auranofin therapy. She recovered completely after withdrawal of both drugs and rechallenge to find out which of these two was responsible for the agranulocytosis was not considered justifiable.
RESULTS Analysis of results for 3 and 6 months are presented. Details of age, sex and duration of disease of the 82 patients entering the study are shown in Table I according to allocation to treatment with oral gold (29), i.m. gold (27) and placebo (26). The treatment groups were comparable in respect to these parameters. Twenty (69%) of the patients on auranofin, 17 (63%) of the patients on i.m. gold and 14 (54%) of the placebotreated patients completed 6 months of the study. The reasons for discontinuing therapy in patients from each group between 0 and 48 weeks are shown in Table II. There were no other significant changes in the biochemical profiles. The results of pain scores, grip strength, Ritchie articular indices and ESR are shown in Table III and Table IV for 12 and 24 weeks of therapy. Initial values were comparable (Kruskal-Wallis test). Twenty-four patients from the placebo group, 24 from the auranofin and21ofthei.m.goldgroupscompletedl2weeksofthe
TABLE III RESULTS OF ASSESSMENTS AFTER 12 WEEKS
Placebo ("=24) Week Pain score (cm) Median Range Grip strength (mmHg) Median Range Ritchie index Median Range ESR (mm/h) Median Range
0
Auranofin («=20)
P
12
0
12
I.m. gold ("=21)
P 0
12
P
4.3
4.4
1.1-9.9
0.9-9.2
NS
4.4 1.0-9.5
3.9 0.9-8.4
NS
4.9 0.5-9.9
2.5 0.3-9.8
0.0111
181
189 41-300
NS
179 86-300
167 68-300
NS
180 51-300
202 48-300
NS
9 1-30
NS
12 1-30
13 2-30
NS
14
9.0 0-24
0.004
18 3-110
NS NS
24 1-70
19 2-48
NS
16 2-77
0.039
50-300 10
0-27 17
3-86
1-58 32
1-110
Downloaded from http://rheumatology.oxfordjournals.org/ at University of New South Wales on July 16, 2015
Rash Mouth ulcer Proteinuria Haematological Immunological Systemic glandular fever like illness Diarrhoea Ineffectiveness Defaulted Total
Auranofin l.m. gold
BRITISH JOURNAL OF RHEUMATOLOGY VOL. XXIX NO. 4
282
TABLE IV RESULTS OFASSESSMENTS AFTER 24 WEEKS
Placebo («=14) 0
24
4.3 1.1-9.9
2.0 0.3-6.9
123 90-300
24
NS
4.9 0.5-9.9
2.7 0.3-6.3
0.009
181 54-300
NS
161 51-300
192 67-300
NS
13 1-30
13 0-24
NS
14 1-58
9.0 0-17
0.001
24 1-70
16 2-46
NS
32 1-110
15 3-78
0.036
24
0.019
4.7 1.0-9.5
4.2 1.3-9.2
192 64-300
NS
173 86-300
11 0-27
9 0-26
0.041
17 3-86
18 6-75
NS
ACKNOWLEDGEMENTS
Financial support for this study was provided by Smith, Kline and French. This manuscript was typed by Mrs L. Leckenby. REFERENCES
1. Nuki G, Gumpel JM, eds. Myocrisin: 50years experience. London: MCI Symposium, 1985 ;II: 1-142. 2. WalzDI,diMartinoMJ,ChakrinLW.SuttonBM,Misher A. Anti-arthritic properties and unique pharmacological profile o f a petenttat^hfysotherapeutic agent, SK&F D-31962. J Pharmacol Exp Ther 1976;197:142-50.
P
0
0
this treatment in our study of psoriatic patients were rash (19%) and mouth ulcers (9.5%). One patient was withdrawn because of IgA deficiency, a rare but well documented side-effect of gold therapy [16]. Diarrhoea is frequently quoted as a common and troublesome side-effect of auranofin in R A patients [17,18]. In the present study of psoriatic arthritic patients only one out of 23 patients had to be withdrawn because of this complication. One patient developed agranulocytosis. Although the bone marrow examination and sequence of clinical events strongly suggested that this was drug induced, it is difficult to be certain whether auranofin or fenbufen, which had recently been introduced, was responsible. A recent review [19] of world-wide safety experience with auranofin in 4000 patients suggested that anaemia (0.8%), leucopenia (0.6%) and thrombocytopenia (0.7%) are rare adverse reactions to this oral gold compound. Twelve out of 20patients on placebo discontinued the treatment before 6 months due to ineffectiveness. Not surprisingly the patients who remained on placebo until 24 weeks had milder disease than the group as a whole. In conclusion the present study confirms that i.m. gold is an effective remittive agent in patients with psoriatic arthritis over 6 months and suggests that it may be more effective than auranofin in these circumstances. Larger and longer studies will need to be undertaken to ascertain whether auranofin has any useful remittive effect in patients with psoriatic arthritis and whether any form of gold therapy slows the progression of joint damage in this disease.
I.m. gold ("=17)
P
3. Lewis D, Capell H. Is auranofin preferable to gold sodium thiomalate in the management of rheumatoid arthritis? In: Capell HA, Cole DS, Manghani KK, Morris RW, eds. Auranofin. Amsterdam: Excerpta Medica, 1983; 147-55. 4. Dequeker J, Francx L, Deckers Y. Comparison of oral gold (auranofin) and injectable gold (gold sodium thiopropanol sulphate) treatment in patients with rheumatoid arthritis: a single blind study. In: Capell HA, Cole DS, Manghani KK, Morris RW, eds. Auranofin. Amsterdam: Excerpta Medica, 1983: 156-64. 5. Schattenkirchner M, Kaik B, Mullerfassbender H, et al. Auranofin and sodium aurothiomalate in the treatment of rheumatoid arthritis: a double blind comparative multicentre study. J Rheumatol 1982;9 (S8):184. 6. BlodgettRCJr,HeuerMA,PietruskoRG. Auranofin: a unique oral chrysotherapeutic agent. Semin Arthritis Rheum 1984;13:255-73. 7. Wright V. Psoriatic arthritis: a comparative study of rheumatoid arthritis and arthritis associated with psoriasis. Ann Rheum Dis 1961;20:123. 8. Dorwart BB, Gall EP, Schumacher RH, Krauser RE. Chrysotherapy in psoriatic arthritis: efficacy and toxicity compared to rheumatoid arthritis. Arthritis Rheum 1978;21:513-15. 9. Richter MB, Kinsella P, Corbet M. Gold in psoriatic arthropathy. Ann Rheum Dis 1980;39:279-80. 10. Dequeker J, Verdickt W, Gevers G, Vanschonbroek K. Long term experience with oral gold in rheumatoid arthritis and psoriatic arthritis. Clin Rheumatol 1984;3:67-74. 11. Tumiati B, Baricchi R, Bellelli A. Psoriatic arthritis. Long term treatment with auranofin. Clin Rheumatol 1986;5:124-5. 12. CaretteS,CalinA,McCaffertyJP,WallinBA,andThe Auranofin Cooperating Group. A double-blind placebo-controlled study of auranofin in patients with psoriatic arthritis. Arthritis Rheum 1989;32:158-65. 13. Ritchie DM, Boyle JA, Mclnnes JM, et al. Clinical studies with an articular index for the assessment of joint tenderness in patients with rheumatic arthritis. Q J Med 1968,37:393-406. 14. Scott JT, Huskisson EC. Graphic representation of pain. Pain 1976:2:175-84. 15. Lee P, Baxter A, Dick WC. An assessment for grip strength measurement in rheumatoid arthritis. ScandJ Rheumatol 1974;3:17-23. 16. Stanworth DR, Johns P, Williamson N, Shadforth M,
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Week Pain score (cm) Median Range Grip strength (mmHg) Median Range Ritchie index Median Range ESR (mm/h) Median Range
Auranofin (n=20)
P
PALIT ETAL.:
AURANOFIN AND GOLD THIOMALATE IN PSORIATIC ARTHRITIS
Felix-Davies D, Thompson R. Drug induced IgA deficiency in rheumatoid arthritis. Lancet 1977;i:1001. 17. BandillaK, Gross D, Gross W,etal. Oral gold therapy with auranofin (SK & F 39162). A multicentre open study in patients with rheumatoid arthritis. J Rheumatol 1982;9(Suppl 8): 154-9.
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18. Katz WA, Alexander S, Bland JW, etal. The efficacy and safety of auranofin compared to placebo in rheumatoid arthritis. J Rheumatol 1982;9(Suppl 8):173-8. 19. Heuer MA, Peitrusko RG, Morris RW, Scheffier BJ. An analysis of worldwide safety experience with auranofin. J Rheumatol 1985 ;12:695-9.
CLINICAL CONUNDRUM
THE prevalence of the gonococcal arthritis-dermatitis syndrome or disseminated gonococcal infection (DGI) appears to vary geographically. Most DGI cases reported in English language medical journals have originated from either the United States or Scandinavia; the frequency of this syndrome appears to be less common in the United Kingdom and there have been relatively few reports of DGI from Africa or other parts of the developing world. What are the reasons for the apparent geographic variation of this relatively rare complication of a common disease (uncomplicated gonorrhoea)? There is a substantial body of data to support the thesis that biological characteristics of gonococcal strains modify the likelihood that gonorrhoea patients will develop DGI. Early studies of DGI epidemiology conducted in Seattle, Washington, demonstrated that Neisseria gonorrhoeae isolates from DGI patients could be differentiated from most gonococci isolated from patients with uncomplicated genital infections by their resistance to complement mediated bactericidal activity of normal human sera. The same investigators also found that most DGI isolates were also unusually sensitive to in vitro killing by penicillin G. Subsequent studies demonstrated that, in Seattle, where much of the early study of DGI patients and gonococcal isolates from them were performed, serum resistance and penicillin sensitivity were phenotypic correlates associated with gonococcal strains characterized by nutritional requirements (auxotrophy) for arginine, hypoxanthine, and uracil (AHU" strains). AHU" auxotrophy, however, was subsequently shown not to be a universal characteristic of gonococcal isolates from DGI patients. While DGI isolates from Seattle and Denver were found to be predominantly AHU" strains (76% and 85%, respectively), in Boston and Atlanta AHU" gonococci comprised only 58% and 34% of isolates respectively from DGI patients. More recently, epidemiological studies using gonococcal protein 1 serotyping have further clarified the dominant association of protein 1 type on DGI prevalence. Protein 1, the predominant gonococcal outer membrane protein by weight, can be divided into two mutually exclusive species, protein 1-A and protein 1-B, which in turn can be further subdivided using panels of protein 1-A or 1-B specific monoclonal antibodies. Most AHU" gonococci belong to protein 1-A serogroups and, in cities where gonococci isolated from DGI patients are not AHU" strains, most isolates from DGI patients are none the less protein 1-A strains. In the studies of DGI isolates from Seattle, Denver, Boston, and Atlanta mentioned above, whereas the prevalence of AHU" auxotrophy varied from 34 to 85% among isolates from DGI patients, a stronger association with protein 1-A serogroups was noted, with 82-86% of the same isolates belonging to protein 1-A serovars. As observed for AHU" auxotrophy, the association of serum
resistance has also been demonstrated to be more strongly associated with protein 1-A serogroups than AHU" auxotrophy. Additional observations suggest that gonococci vary from region to region with respect to the prevalence of protein 1-A serotypes and that this variation affects the prevalence of DGI. In the multicentre studies mentioned above, only 13-57% of isolates from patients with uncomplicated gonorrhoea in the same communities belonged to protein 1-A serogroups (as opposed to 82-86% of DGI isolates). In addition, protein 1-A containing gonococcal serovars appear to be less common in the UK than in the areas of the US from which DGI has been commonly reported. Finally, still another Seattle study reported that between the mid-1970s and early 1980s the frequency of DGI had declined substantially, paralleling a community-wide decline in the prevalence of protein 1-A containing gonococci from 54% to 24% of all isolates. Thus in summary, the apparent differences in the DGI prevalence currently appear to correlate most closely with geographic variation in the prevalence of gonococci containing protein 1-A serovars. Whether the association of DGI with protein 1-A containing gonococci is directly related to characteristics of protein 1-A or is related to other, associated but not causal factors, remains to be proven. E. W. HOOK
Division of Infectious Diseases, Johns Hopkins Hospital, Blalock 1111, Baltimore, MD 21205, USA
FURTHER READING
1. Sandstrom EG, Knapp JS, Reller LB, Thompson SE, Hook EW III, Holmes KK. Serogroupingof Neisseria gonorrhoeae: correlation of serogroup with disseminated gonococcal infection. Sexually Transmitted Diseases 1984;ll:77-80. 2. Knapp JS, Thornsberry C, Schoolnik GA, Wiesner PJ, Holmes KK. Cooperative Study Group. Phenotypic and epidemiologic correlates of auxotype in Neisseria gonorrhoeae. J Infect Dis 1978;132:160-5. 3. O'Brien JP, Goldberg DL, Rice PA. Disseminated gonococcal infection: a prospective anlysis of 49 patients and a review of pathophysiology and immune mechanisms. Medicine 1983;62:395-^06. 4. Cannon JG, Buchanan TM, Sparling PF. Confirmation of association of protein 1 serotype of Neisseria gonorrhoeae with ability to cause disseminated infection. Infect Immun 1983;40:816-19. 5. Rompalo AM, Hook EW III, Roberts PL, Ramsey PG, Handsfield HH, Holmes KK. The acute arthritis-dermatology syndrome. The changing importance of Neisseria gonorrhoeae and Neisseria meningitidis. Arch Intern Med 1987;147:281-3. 6. IsonCA,GedneyJ,EasmonCSF. Chromosomal resistance of gonococci to antibiotics. Genitourin Med 1987;63:239-43.
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Discussion about septic arthritis with American colleagues leads inescapably to the conclusion that gonococcal arthritis is much more common in the USA than in the UK. Is it the strain of organism, differences in lifestyles or what?
