British Journal of Rheumatology 1992;31:461^63
PHTHALYLSULPHATHIAZOLE IN RHEUMATOID ARTHRITIS BY C. ASTBURY, J. HILL AND H. A. BIRD Clinical Pharmacology Unit (Rheumatism Research), Royal Bath Hospital, Cornwall Road, Harrogate, North Yorkshire HG1 2PS
SUMMARY Sixteen patients with active rheumatoid arthritis were treated with phthalylsulphathiazole (4 g/day) over a period of 24 weeks. Although there was some statistically significant improvement in plasma viscosity, IgM, pain score, morning stiffness and summated change score, this was either intermittent or not maintained. Five patients withdrew from the trial before completion, four (25%) with non-serious adverse reactions and one patient from lack of efficacy; only one patient elected to remain on the drug beyond the 24-week period. Low free and total sulphathiazole serum concentrations were found, confirming that most of the drug remained within the gut. This investigation suggests, certainly at the dose used, that phthalylsulphathiazole does not have the properties of a second-line agent. Higher doses of the drug will not be ethically feasible. Sulphonamides, Second-line agent. Rheumatoid arthritis.
the re-introduction of sulphasalazine to treat rheumatoid arthritis (RA) over a decade ago, its mode of action has not been confirmed. The discovery that sulphapyridine, the sulphonamide component, also displays antirheumatoid activity in its own right [1, 2] suggests that an antibacterial action cannot be ruled out despite earlier reports [3]. Studies with other antibacterial agents have produced conflicting results [4-7]. We have previously shown cotrimoxazole (sulphamethoxazole-trimethoprim) to be ineffective and postulated that if sulphapyridine was effective in treating RA because of its antibacterial properties then its site of action might be the gastrointestinal tract [6]. It appears that patients with RA have an increased faecal carriage of Clostridium perfringens [8] which is reduced during treatment with sulphasalazine [9]. Since all sulphonamides have essentially the same antibacterial properties but display different kinetic properties, we have investigated the use of a 'non-absorbable' sulphonamide, phthalylsulphathiazole (PST) in the treatment of active rheumatoid arthritis. This agent has, in the past, been employed to sterilize the bowel prior to surgery and in the 1940s, prior to the introduction of sulphasalazine, was investigated for the treatment of inflammatory bowel disease [10, 11]. SINCE
METHODS Sixteen patients with active classical, definite or probable RA (ARA criteria) were treated with 4 g/day PST for a period of 24 weeks. No patients had received a second-line agent for a minimum of 8 weeks before the study. Back-up analgesics and non-steroidal antiinflammatory drug therapy were permitted; oral steroids were also allowed providing the dosage remained constant throughout the study period. Patients were excluded from the trial if they had a history of sulphonamide intolerance or had had previous bowel sur-
gery. All patients had active disease as defined by plasma viscosity >1.72 cP or C-reactive protein >0.05 mg/dl, plus any two of the following criteria: (1) swelling of more than three joints; (2) tenderness of more than six joints; (3) morning stiffness lasting over 45 min; (4) Ritchie articular index >20. Biochemical and clinical assessments of disease activity [12] were carried out at 4-weekly intervals over the study period. At each of these clinic visits patients were also asked if they had experienced any sideeffects to the treatment since their previous visit. All patients were offered the chance to continue treatment beyond the 24 weeks if they wished to do so. Free and total sulphathiazole (sulphathiazole plus acetylsulphathiazole plus phthalylsulphathiazole) concentrations in serum were determined spectrophotometrically using a modification of the Bratton Marshall technique [13]. Changes in disease activity during the study were determined by the Wilcoxon matched-pairs, signedranks test, though any patients withdrawing from the study before week 8 were excluded. Concomitant changes in mean serial biochemical and clinical assessments were determined by Pearson correlations. A similar type of assessment had previously been carried out for sulphasalazine [14, 15] and sulphapyridine [2]. RESULTS Transient improvement in some assessments of disease activity (plasma viscosity, IgM, summated change score, morning stiffness and pain score) were observed but these were not maintained through to the end of the study (Table I). The Pearson correlation matrix showed few correlations (Table II), the only statistically significant correlations occurred between pain score with haemoglobin, plasma viscosity and IgM and summated change score with IgM. No serious toxicity was found with the drug; however, five patients (31%) withdrew from the study
Submitted 22 April; revised version accepted 1 August 1991. Correspondence to Dr C. Astbury.
© 1992 British Society for Rheumatology
0263-7103/92/070461 + 03 $03.00/0 461
Downloaded from http://rheumatology.oxfordjournals.org/ at Harvard University on July 16, 2015
KEY WORDS:
BRITISH JOURNAL OF RHEUMATOLOGY VOL. XXXI NO. 7
462
TABLE I MEDIAN CHANGES (RANGE) IN DISEASE ACTIVITY DURING TREATMENT WITH PHTHALYLSULPHATHIAZOLE (4 G/DAY); WILCOXON MATCHEDPAIRS SLGNED-RANKS TEST Week no
Assessment — [normal range] n
4
8
12
16
20
24
12
12
12
12
12
12
11
12.8 (10.6-15.8) 1.81 (1.73-2.12)
12.7 (9.5-15.0) 1.84 (1.62-2.25) 8.9 (7.7-13.0) 1.90 (0.05-7.39) 18 (5-65) 1.20 (0.51-2.63) 2.57 (1.65-4.66) 11.7 (7.2-19.4) 340 (265-595)
12.6 (10.0-15.8) 1.82 (1.64-2.07) 8.1 (6.0-13.1)
12.8 (10.2-14.6) 1.78"* (1.67-2.15) 7.9 (6.9-14.3) 1.31 (0.00-3.86) 18 (5-59) 1.15 (0.47-1.86) 2.22 (1.53-1.62) 12.3 (6.3-18.3) 383 (290-610) 1.16 (0.84-1.76) 18 (0-45) 88 (0-600)
12.4 (9.9-16.1) 1.83* (1.64-2.08) 8.6 (6.8-21.8) 1.93 (0.00-4.93) 16 (4-55) 1.08** (0.48-1.79) 2.16 (1.47-6.59) 11.9 (6.3-18.0) 355 (275-580) 1.31 (0.80-2.03) 15 (1-41) 54*** (0-240) 101.2 (97.3-113.9) 95.5 (49.0-205) 2.5** (0-1)
12.5t
12.9 (10.4-16.9) 1.81 (1.67-1.97) 8.9 (7.9-13.9)
8.7 (7.5-13.2)
1.26 (0.05-4.09) 21 (5-40) 1.22 (0.53-2.40) 2.57 (1.54-4.82) 11.9 (7.4-18.9)
IgA (g/1) [0.80-4.00] IgG (g/1) [5.3-16.5] SH (|AM) [450-600] HIST (mg/dl) [1.45-1.60] AI
330 (280-520)
1.22 (0.66-1.53) 22 (11-15) 68 (0-403) 100
EMS (min) SCS GRIP (mm.Hg) Pain
89.5 (49.0-160) 3 (3-1)
1.07t (0.81-1.24) 13 (2-37) 77 (0-240) 100 (97.7-107.9) 91.8 (39.5-151) 3
1.00 (0.00-3.82)
17 (5-62) 1.22 (0.46-2.30) 2.41 (1.35-4.62) 13.1 (6.3-18.9) 368 (275-540) 1.13 (0.87-1.50) 16 (5-37) 66 (0-240) 100.1 (97.8-111.3) 84.3 (40.0-170) 3 (1-4)
100.8*
(98.6-116.7) 82.0 (60.5-119) 2.5*** (1-3)
(10.1-15.9) 1.82** (1.65-1.99) 8.1 (6.5-13.4) 1.69 (0.00-4.54) 13 (9-62) 1.06*** (0.53-1.86) 2.30 (1.52-1.46) 11.7 (6.3-19.4) 370 (235-575)
1.15 (0.70-2.01) 17 (2-38) 62 (0-600) 101.1 (96.5-123.6) 94.0 (40.0-191) -y***
(1-3)
1.25 (0.00-2.50)
15 (7-50) 1 15 (0.53-1.78)
2.20 (1.48-4.82) 11.0 (7.0-17.3)
360 (185-500) 1.37 (0.81-1.99) 16 (0-44) 34*** (0-201) 101.1 (96.5-128.4) 82.5 (39.0-191) 3* (1-1)
Improvement: *P
PHTHALYLSULPHATHIAZOLE IN RHEUMATOID ARTHRITIS BY C. ASTBURY, J. HILL AND H. A. BIRD Clinical Pharmacology Unit (Rheumatism Research), Royal Bath Hospital, Cornwall Road, Harrogate, North Yorkshire HG1 2PS
SUMMARY Sixteen patients with active rheumatoid arthritis were treated with phthalylsulphathiazole (4 g/day) over a period of 24 weeks. Although there was some statistically significant improvement in plasma viscosity, IgM, pain score, morning stiffness and summated change score, this was either intermittent or not maintained. Five patients withdrew from the trial before completion, four (25%) with non-serious adverse reactions and one patient from lack of efficacy; only one patient elected to remain on the drug beyond the 24-week period. Low free and total sulphathiazole serum concentrations were found, confirming that most of the drug remained within the gut. This investigation suggests, certainly at the dose used, that phthalylsulphathiazole does not have the properties of a second-line agent. Higher doses of the drug will not be ethically feasible. Sulphonamides, Second-line agent. Rheumatoid arthritis.
the re-introduction of sulphasalazine to treat rheumatoid arthritis (RA) over a decade ago, its mode of action has not been confirmed. The discovery that sulphapyridine, the sulphonamide component, also displays antirheumatoid activity in its own right [1, 2] suggests that an antibacterial action cannot be ruled out despite earlier reports [3]. Studies with other antibacterial agents have produced conflicting results [4-7]. We have previously shown cotrimoxazole (sulphamethoxazole-trimethoprim) to be ineffective and postulated that if sulphapyridine was effective in treating RA because of its antibacterial properties then its site of action might be the gastrointestinal tract [6]. It appears that patients with RA have an increased faecal carriage of Clostridium perfringens [8] which is reduced during treatment with sulphasalazine [9]. Since all sulphonamides have essentially the same antibacterial properties but display different kinetic properties, we have investigated the use of a 'non-absorbable' sulphonamide, phthalylsulphathiazole (PST) in the treatment of active rheumatoid arthritis. This agent has, in the past, been employed to sterilize the bowel prior to surgery and in the 1940s, prior to the introduction of sulphasalazine, was investigated for the treatment of inflammatory bowel disease [10, 11]. SINCE
METHODS Sixteen patients with active classical, definite or probable RA (ARA criteria) were treated with 4 g/day PST for a period of 24 weeks. No patients had received a second-line agent for a minimum of 8 weeks before the study. Back-up analgesics and non-steroidal antiinflammatory drug therapy were permitted; oral steroids were also allowed providing the dosage remained constant throughout the study period. Patients were excluded from the trial if they had a history of sulphonamide intolerance or had had previous bowel sur-
gery. All patients had active disease as defined by plasma viscosity >1.72 cP or C-reactive protein >0.05 mg/dl, plus any two of the following criteria: (1) swelling of more than three joints; (2) tenderness of more than six joints; (3) morning stiffness lasting over 45 min; (4) Ritchie articular index >20. Biochemical and clinical assessments of disease activity [12] were carried out at 4-weekly intervals over the study period. At each of these clinic visits patients were also asked if they had experienced any sideeffects to the treatment since their previous visit. All patients were offered the chance to continue treatment beyond the 24 weeks if they wished to do so. Free and total sulphathiazole (sulphathiazole plus acetylsulphathiazole plus phthalylsulphathiazole) concentrations in serum were determined spectrophotometrically using a modification of the Bratton Marshall technique [13]. Changes in disease activity during the study were determined by the Wilcoxon matched-pairs, signedranks test, though any patients withdrawing from the study before week 8 were excluded. Concomitant changes in mean serial biochemical and clinical assessments were determined by Pearson correlations. A similar type of assessment had previously been carried out for sulphasalazine [14, 15] and sulphapyridine [2]. RESULTS Transient improvement in some assessments of disease activity (plasma viscosity, IgM, summated change score, morning stiffness and pain score) were observed but these were not maintained through to the end of the study (Table I). The Pearson correlation matrix showed few correlations (Table II), the only statistically significant correlations occurred between pain score with haemoglobin, plasma viscosity and IgM and summated change score with IgM. No serious toxicity was found with the drug; however, five patients (31%) withdrew from the study
Submitted 22 April; revised version accepted 1 August 1991. Correspondence to Dr C. Astbury.
© 1992 British Society for Rheumatology
0263-7103/92/070461 + 03 $03.00/0 461
Downloaded from http://rheumatology.oxfordjournals.org/ at Harvard University on July 16, 2015
KEY WORDS:
BRITISH JOURNAL OF RHEUMATOLOGY VOL. XXXI NO. 7
462
TABLE I MEDIAN CHANGES (RANGE) IN DISEASE ACTIVITY DURING TREATMENT WITH PHTHALYLSULPHATHIAZOLE (4 G/DAY); WILCOXON MATCHEDPAIRS SLGNED-RANKS TEST Week no
Assessment — [normal range] n
4
8
12
16
20
24
12
12
12
12
12
12
11
12.8 (10.6-15.8) 1.81 (1.73-2.12)
12.7 (9.5-15.0) 1.84 (1.62-2.25) 8.9 (7.7-13.0) 1.90 (0.05-7.39) 18 (5-65) 1.20 (0.51-2.63) 2.57 (1.65-4.66) 11.7 (7.2-19.4) 340 (265-595)
12.6 (10.0-15.8) 1.82 (1.64-2.07) 8.1 (6.0-13.1)
12.8 (10.2-14.6) 1.78"* (1.67-2.15) 7.9 (6.9-14.3) 1.31 (0.00-3.86) 18 (5-59) 1.15 (0.47-1.86) 2.22 (1.53-1.62) 12.3 (6.3-18.3) 383 (290-610) 1.16 (0.84-1.76) 18 (0-45) 88 (0-600)
12.4 (9.9-16.1) 1.83* (1.64-2.08) 8.6 (6.8-21.8) 1.93 (0.00-4.93) 16 (4-55) 1.08** (0.48-1.79) 2.16 (1.47-6.59) 11.9 (6.3-18.0) 355 (275-580) 1.31 (0.80-2.03) 15 (1-41) 54*** (0-240) 101.2 (97.3-113.9) 95.5 (49.0-205) 2.5** (0-1)
12.5t
12.9 (10.4-16.9) 1.81 (1.67-1.97) 8.9 (7.9-13.9)
8.7 (7.5-13.2)
1.26 (0.05-4.09) 21 (5-40) 1.22 (0.53-2.40) 2.57 (1.54-4.82) 11.9 (7.4-18.9)
IgA (g/1) [0.80-4.00] IgG (g/1) [5.3-16.5] SH (|AM) [450-600] HIST (mg/dl) [1.45-1.60] AI
330 (280-520)
1.22 (0.66-1.53) 22 (11-15) 68 (0-403) 100
EMS (min) SCS GRIP (mm.Hg) Pain
89.5 (49.0-160) 3 (3-1)
1.07t (0.81-1.24) 13 (2-37) 77 (0-240) 100 (97.7-107.9) 91.8 (39.5-151) 3
1.00 (0.00-3.82)
17 (5-62) 1.22 (0.46-2.30) 2.41 (1.35-4.62) 13.1 (6.3-18.9) 368 (275-540) 1.13 (0.87-1.50) 16 (5-37) 66 (0-240) 100.1 (97.8-111.3) 84.3 (40.0-170) 3 (1-4)
100.8*
(98.6-116.7) 82.0 (60.5-119) 2.5*** (1-3)
(10.1-15.9) 1.82** (1.65-1.99) 8.1 (6.5-13.4) 1.69 (0.00-4.54) 13 (9-62) 1.06*** (0.53-1.86) 2.30 (1.52-1.46) 11.7 (6.3-19.4) 370 (235-575)
1.15 (0.70-2.01) 17 (2-38) 62 (0-600) 101.1 (96.5-123.6) 94.0 (40.0-191) -y***
(1-3)
1.25 (0.00-2.50)
15 (7-50) 1 15 (0.53-1.78)
2.20 (1.48-4.82) 11.0 (7.0-17.3)
360 (185-500) 1.37 (0.81-1.99) 16 (0-44) 34*** (0-201) 101.1 (96.5-128.4) 82.5 (39.0-191) 3* (1-1)
Improvement: *P
