N . D.Peters et al.
Intravenous Methylprednisolone Pulse Therapy in Ankylosing Spondylitis N. D. Peters' and L. Ejstrup2 Department of Rheumatology, 'Hjorring and *Skive Hospitals, Denmark
Scand J Rheumatol Downloaded from informahealthcare.com by University of Sydney on 01/01/15 For personal use only.
Peters ND, Ejstrup L. Intravenous Methylprednisolone Pulse Therapy in Ankylosing Spondylitis. Comparison of 1000 mg and 375 mg Methylprednisolone given intravenously on three consecutive days. Scand J Rheumatol. 1992; 21: 134-38 The aim of this double-blind study was to compare the effect of high-dose (1000 mg) and low-dose (375 mg) methylprednisolone pulse therapy administered intravenously once daily for three consecutive days, in active ankylosing spondylitis. Seventeen patients with active ankylosing spondylitis were randomly allocated to high-dose (8 patients) or low-dose (9 patients) regimen. Although there was no placebo group in this study, it is our impression that in patients with active ankylosing spondylitis, both high-dose (1000 mg) and low-dose (375 mg) methylprednisolone pulse therapy given on three consecutive days, is effective as regards pain relief and improvement in spinal mobility. There were no statistically significant differences between the two groups, though there was a trend towards the high dose yielding a greater and longer lasting improvement. No serious adverse reactions were observed.
Key words: intravenous methylprednisolone pulse therapy, active ankylosing spondylitis
Ankylosing spondylitis is an inflammatory disease of unknown aetiology. The treatment is symptomatic and consists in analgetics, anti-inflammatory drugs, and exercise therapy. Remission-inducing substances like gold salts, penicillamine, and antimalarials have no effect (1). Opinions differ as to whether sulphasalazine, given at the early stages of the disease, can influence the course (2). Oral corticosteroids at conventional doses have also been disappointing, their effect being far less dramatic than in several other rheumatic diseases (1). In 1981, Mintz et al. (3) were the first to report on the efficacy of methylprednisolone pulse therapy in ankylosing spondylitis. In an open study they demonstrated a dramatic effect of three pulse treatments with 1000 mg methylprednisolone intravenously, the effect on spinal mobility and on pain lasting for more than 10 months. Subsequently, a beneficial effect of methylprednisolone pulse therapy in active ankylosing spondylitis has been reported in two open studies (4, 5). The number of patients, however, was low in all three studies. There are no randomized, placebo-controlled double-blind studies, probably because of blinding
N. Daugaard Peters, Department of Rheumatology, Hjarring Sygehus, DK-9800 Hjorring, Denmark
Received 27 May 1991 Accepted 14 January 1992
134
problems, patients receiving intravenous treatment with steroids developing flushing. More serious and even fatal adverse reactions have been reported following intravenous methylprednisolone to other types of patients (6). No serious adverse reactions to this treatment have been reported in ankylosing spondylitis. The aim of this study was to compare the efficacy of 1000 mg (high dose) and 375 mg (low dose) intravenous methylprednisolone once daily for three consecutive days in patients with active ankylosing spondylitis. Patients and Methods
Seventeen patients with active ankylosing spondylitis participated in the study. Informed consent was obtained from all the patients and the study was approved by the local ethical committees. All patients fulfilled the New York diagnostic criteria for established ankylosing spondylitis (1). During one month, all the patients had experienced insufficient effect of non-steroidal anti-inflammatory drugs (NSAID) on pain and stiffness, despite treatment at maximum doses combined with exercise therapy in hot pools. None of the patients had received pulse methylprednisolone within the last 12 months or systemic or local treatment with steroids within the last 3 months. None had received remission-inducing drugs within the last 6 months. Furthermore, patients with total ankylosis in the cervical, thoracic or lumbar spine owing to ankylosing syndesmophytes were excluded. The usual contra-indica-
Intravenous Methylprednisolone Pulse Therapy Table I. Clinical data of patients. 375 mg
Scand J Rheumatol Downloaded from informahealthcare.com by University of Sydney on 01/01/15 For personal use only.
Number of patients Median age (range) (years) Sex (MIFI Median disease duration (years) Eye involvement Peripheral joint involvement HLA-B27 positive/negative Median ESR (range) (mmlh)
9 39 (2!Xl! 112 7 (1-22) 3 4 811 37 (12-65)
1000 mg
a 41 (31-55) 612 10.5 (1-20) 2 1 6/2 19 18-45)
tions to steroid treatment were observed. The patients were well instructed in exercise therapy in the hot pool and continued this therapy without any changes. Demographic data is given in Table I and 11. The study was carried out as a group-comparative randomized double-blind study using the double-dummy technique. The medication employed was from Upjohn. Methylprednisolone, 1000 or 375 mg, was dissolved in 50 ml isotonic saline and administered intravenously over 30 minutes between 8.00 and 9.00 a.m. on three consecutive days. The patient's degree of pain was measured on a visual analogue scale (VAS) as the average pain during the preceding 24 hours. Furthermore, NSAID and analgetics were discontinued on day 0 and the time for their reinstitution was recorded. The following clinical variables were determined on day 0, 3, 30, 60, 90, 120, 150, and 180: chinmanubrium distance, thorax excursion, finger-tofloor distance, Schober's test on the lumbar spine, and morning stiffness.
Table 11. Baseline mean values and range for the efficacy- data. Variabel
Low-Dose
High-Dose
Finger-to-floor distance
31.17 (14.0-38.0) 57.78 (21.0-83.0) 78.751 (60-1 20) 2.28 (1.0-4.0) 5.38' (3.0-9.5) 11.61 (11.0-14.0) 3.24 (1.6-6.7)
36.25 (15.0-55.0) 51.50 (29.1)-78.0) 66.25 (20-120) 2.91 (1.0-5.0) 3.753 (1.5-6.0) 11.68 (10.5-13.5) 2.44 (10.5-1 3.5)
Mean Range VAS-score (mm) Mean Range Morning stiffness ( m i d Mean Range Thorax excursion (cm) Mean Range Chin-manubrium distance (cm) Mean Range Schober's test (cm) Mean Range IgA (gll) Mean Range
'One patient omitted because of morningstiffness = 0 min 'One patient omitted because chin-manubrium distance = 0.0 cm 3Tw0 patients omitted because chin-manubrium distance = 0.0 cm
The clinical examination was performed between 8.00 and 9.00 a.m. and after the examination, the patients had their usual exercise therapy. Laboratory tests on day 0, 3, 30, 90 and 180 comprised: ECG, ESR, haemoglobin, differential count, white blood count, IgA, IgM, IgG, carbamide, creatinine, sodium, potassium, and blood glucose. Furthermore, tissue-typing was performed (HLA-B27 positive or HLA-B27 negative). Statistical analysis
All effect variables were analysed using the same method, mean and median curves of the course were drawn, and for each time (day) of measurement, a comparison between the two groups was made using the Mann-Whitney test (one-sided). The difference between the two groups as to the mean values for day 60 to day 180 was compared using the t-test (one-sided). A regression analysis was performed in the one case (VAS) where the rise from day 3 onwards could be considered linear from all patients. The level of significance chosen was 5%. Results
As seen in Fig. l A , there was a fall in the finger-tofloor distance from day 0 to 3, indicating the beneficial effect of methylprednisolone pulse therapy. The values remained at a fairly constant level during the whole study period. When the values are baseline-corrected, the high-dose group had the greatest improvement. The difference, however, is not statistically significant, nor is there any significant day-to-day difference. Fig. 1B shows that the lumbar mobility improved in both groups without any difference between groups. The improvement was maintained during the whole study period. The pain score measured on VAS improved in the beginning, and most markedly so in the highdose patients (Fig. 1C). However, no statistically significant differences were found. After day 3, the pain score increased linearly. The regression line for each group shows that the low-dose group reaches its pretreatment value after 253 days, whereas it takes 347 days in the case of the high-dose group. The difference between groups was not significant. Fig. 1D shows the course of morning stiffness. Both groups obtained a marked improvement on day 3. The improvement is greatest in the low-dose group, but then the effect diminishes rather quickly and the pretreatment value is reached on approximately day 160. In the high-dose group, 135
N . D. Peters et al. UORN*(G
snmss
YY L M L OAT W I W . P0.M
0
I)
w
m
mn um s t y 1 w
1)
-. a
1"
Fig. 1. The clinical effect of low-dose (375 mg) and highdose (loo0 mg) intravenous methylprednisolone administered on day 0, 1 and 2. (Average = Mean).
1m
(U'IYYI
Scand J Rheumatol Downloaded from informahealthcare.com by University of Sydney on 01/01/15 For personal use only.
FIG. 10
twill al
w s u u uruoouc sw
ULEYL M Y W-IM r R l P
mn y.l STYI w
nc.
-a
(UIYWT
1c
the improvement attenuates but slowly and the pretreatment vaiue is not reached until day 180. There were no significant differences between the groups. Thorax excursions improved markedly on day 3 in both groups, with attenuation of the effect after approximately 160 days (Fig. 1E). On day 150, the improvement in the high-dose group was significantly greater (p < 0.05), irrespective of whether the observations were baseline-corrected or not. Fig. 1F shows the chin-manubrium distance during the study period. There was an improvement on day 3 which remained rather constant during the whole period. The values are at the same level in the two groups, but when baselinecorrected, the 136
greatest effect is obtained in the low-dose group. There was, however, no significant difference between groups. Re-institution of treatment with analgetid NSAID was necessary at median 8 days (0-61) after the end of pulse methylprednisolone in the low-dose group against median 25 days (7-180) in the high-dose group, which is not statistically significant. Table I11 lists the adverse reactions recorded, divided into those occurring in immediate relation to the infusion days (day 0-4)and late reactions (day 5-180). Almost all the patients, both in the low- and in the high-dose group, experienced flushing. Furthermore, there were statements of
Intravenous Methylprednisolone Pulse Therapy Table 111. Adverse reactions following pulse methylprednisolone. Number of patients Day 0-4
Scand J Rheumatol Downloaded from informahealthcare.com by University of Sydney on 01/01/15 For personal use only.
flushing Dizziness Bitter taste Insomnia Palpitation irritability Increase in weight Dry mouth Sexual dysfunction
Day 5 1 8 0
375mg
1OOOmg
375mg
9 1
8 2 1 1 1
1 (day 5)
1 1 1
1000 rng
1
1
mild dizziness, sleep disturbances, irritability, small increase in weight, and dry mouth; one patient stated impotence. On the second infusion day one patient in the high-dose group had tachycardia for 5 minutes, and one patient in the iow-dose group had symptoms of tachycardia for 30 minutes on day 5. ECG immediately after the end of the attacks was normal. The laboratory tests showed unchanged values during the study period, with the exception of a fall in ESR and in IgA. There were no significant differences between groups. Discussion
Oral administration of 1000 mg of prednisolone has been found just as effective as 1000 mg intravenous methylprednisolone (7) in the treatment of rheumatoid arthritis, but the efficacy of oral steroids has not been studied in ankylosing spondylitis. A comparison of 40 mg, 500 mg and 1000 mg intravenous methylprednisolone in the treatment of active rheumatoid arthritis showed that a longterm effect, i.e. more than three weeks, is obtained only with a dose of 1000 mg (8). In an open study, Mintz et al. (3) administered 1000 mg of methylprednisolone intravenously on three consecutive days and reported a dramatic effect on spinal mobility and pain in patients with active ankylosing spondylitis. Fewer infusions gave poorer results and more than three infusions yielded no further improvement (3). Methylprednisolone pulse therapy has not been extensively used, possibly owing to reports on serious adverse reactions in the form of cardiac arrhythmias, cardiac arrest, and convulsions when given to patients with other inflammatory connective tissue disorders (9). These reactions may pos-
sibly be explained by the pharmacological effect of methylprednisolone which involves a rapid exchange of electrolytes across the cell membranes ( 6 )* No serious adverse reactions have ever been demonstrated in relation to pulse methylprednisolone to patients with ankylosing spondylitis. In the present study, 375 mg was chosen as the lowest dose, since at this dose all patients develop flushing. In this way we obtained blinding of both observer and patient. Fig. 1 shows an immediate and long-lasting effect on pain, morning stiffness, and spinal mobility. However, we could demonstrate no statistically significant differences between groups, though there was a trend towards a more marked and longer effect in the high-dose group. When evaluated by time of re-institution of analgetic and anti-inflammatory treatment, the effect was maintained longer in the high-dose patients. Thus, patients in this group managed without medication for 25 days (7-180) against 8 days (0-61) in the low-dose group. The failure of obtaining a significantly higher effect in the high-dose group could possibly be explained by differences in the inflammatory activity as evaluated by the levels of ESR and IgA. Another possible explanation is a statistical Type 2 error owing to the low number of patients. A further 13 patients (total 30 patients) could have reduced Type 2 error to a value < 0.05. In agreement with reported findings, no serious adverse reactions were observed in the present study, neither in direct relation to the infusions nor occurring as late reactions. No differences between the low- and high-dose group were found as to the occurrence of adverse reactions. One patient in either group had a short attack of tachycardia. Unfortunately, however, ECG was not performed during the attacks. The blood pressures were normal during the attacks, and so were the ECGs immediately after the end of the attacks. Whether this can be considered an adverse reaction to the treatment is uncertain, since it is wellknown that patients with ankylosing spondylitis may have intermittent atrial tachycardia and A-V block (10).
Conclusion Intravenous methylprednisolone has an acute pain-relieving effect in patients with ankylosing spondylitis in whom analgetics and anti-inflammatory drugs are insufficient. Furthermore, it has a good and long-lasting effect on spinal mobility. 137
N . D. Peters
et
al.
Despite the small number of patients, the study seems to suggest that poorer results are obtained with the low than with the high dose. No serious adverse reactions were demonstrated in this study. References
Scand J Rheumatol Downloaded from informahealthcare.com by University of Sydney on 01/01/15 For personal use only.
Bluestone R. Ankylosing spondylitis. In: McCarthy DJ, ed. Arthritis and allied conditions. Lea & Fibiger, 1985: 819. McConkey B. Sulphasalazine and ankylosing spondylitis. Br J Rheumatol 1990; 29: 2-5. Mintz G, Enriquez RD, Mercado U, Robles J, Jeminez FJ, Gutierrez G . Intravenous methylprednisolone pulse therapy in severe ankylosing spondylitis. Arthritis Rheum 1981; 24: 734-6. Ejstrup L, Daugaard Peters N. Intravenous methylprednisolone pulse therapy in ankylosing spondylitis. Dan Med Bull 1985; 32: 231-3.
138
5. Richter MB, Woo P, Panayi GS. Pulse methylprednisolone therapy in ankylosing spondylitis. Arthritis Rheum 1982; 25 (Suppl): 13. 6. Tubiana M, Seine P, Balafrej M. High dose intravenous corticosteroid therapy. Eular Bull 1985; 2: 52-5. 7. Needs C, Smith M, Boutagy J, et al. Comparison of methylprednisolone (1 g IV) with prednisolone (1 g orally) in rheumatoid arthritis. J Rheumatol 1988; 15: 224-8. 8. Shipley ME, Bacon PA, Berry H , et al. Pulsed methylprednisolone in active early rheumatoid disease: a doseranging study. Br J Rheumatol 1988; 27: 2 1 1 4 . 9. Smith MD, Ahern MJ, Roberts-Thomson PJ. Pulse methylprednisolone therapy in rheumatoid arthritis: unproved therapy, unjustified therapy, or effective adjunctive treatment ? Ann Rheum Dis 1990; 49: 265-7. 10. Thomsen NH, H ~ r s l e vPetersen K, Beyer JM. Ambulatory 24-hour continuous electrocardiographic monitoring in 54 patients with ankylosing spondylitis. Eur Heart J 1986; 7: 240-6.
Intravenous Methylprednisolone Pulse Therapy in Ankylosing Spondylitis N. D. Peters' and L. Ejstrup2 Department of Rheumatology, 'Hjorring and *Skive Hospitals, Denmark
Scand J Rheumatol Downloaded from informahealthcare.com by University of Sydney on 01/01/15 For personal use only.
Peters ND, Ejstrup L. Intravenous Methylprednisolone Pulse Therapy in Ankylosing Spondylitis. Comparison of 1000 mg and 375 mg Methylprednisolone given intravenously on three consecutive days. Scand J Rheumatol. 1992; 21: 134-38 The aim of this double-blind study was to compare the effect of high-dose (1000 mg) and low-dose (375 mg) methylprednisolone pulse therapy administered intravenously once daily for three consecutive days, in active ankylosing spondylitis. Seventeen patients with active ankylosing spondylitis were randomly allocated to high-dose (8 patients) or low-dose (9 patients) regimen. Although there was no placebo group in this study, it is our impression that in patients with active ankylosing spondylitis, both high-dose (1000 mg) and low-dose (375 mg) methylprednisolone pulse therapy given on three consecutive days, is effective as regards pain relief and improvement in spinal mobility. There were no statistically significant differences between the two groups, though there was a trend towards the high dose yielding a greater and longer lasting improvement. No serious adverse reactions were observed.
Key words: intravenous methylprednisolone pulse therapy, active ankylosing spondylitis
Ankylosing spondylitis is an inflammatory disease of unknown aetiology. The treatment is symptomatic and consists in analgetics, anti-inflammatory drugs, and exercise therapy. Remission-inducing substances like gold salts, penicillamine, and antimalarials have no effect (1). Opinions differ as to whether sulphasalazine, given at the early stages of the disease, can influence the course (2). Oral corticosteroids at conventional doses have also been disappointing, their effect being far less dramatic than in several other rheumatic diseases (1). In 1981, Mintz et al. (3) were the first to report on the efficacy of methylprednisolone pulse therapy in ankylosing spondylitis. In an open study they demonstrated a dramatic effect of three pulse treatments with 1000 mg methylprednisolone intravenously, the effect on spinal mobility and on pain lasting for more than 10 months. Subsequently, a beneficial effect of methylprednisolone pulse therapy in active ankylosing spondylitis has been reported in two open studies (4, 5). The number of patients, however, was low in all three studies. There are no randomized, placebo-controlled double-blind studies, probably because of blinding
N. Daugaard Peters, Department of Rheumatology, Hjarring Sygehus, DK-9800 Hjorring, Denmark
Received 27 May 1991 Accepted 14 January 1992
134
problems, patients receiving intravenous treatment with steroids developing flushing. More serious and even fatal adverse reactions have been reported following intravenous methylprednisolone to other types of patients (6). No serious adverse reactions to this treatment have been reported in ankylosing spondylitis. The aim of this study was to compare the efficacy of 1000 mg (high dose) and 375 mg (low dose) intravenous methylprednisolone once daily for three consecutive days in patients with active ankylosing spondylitis. Patients and Methods
Seventeen patients with active ankylosing spondylitis participated in the study. Informed consent was obtained from all the patients and the study was approved by the local ethical committees. All patients fulfilled the New York diagnostic criteria for established ankylosing spondylitis (1). During one month, all the patients had experienced insufficient effect of non-steroidal anti-inflammatory drugs (NSAID) on pain and stiffness, despite treatment at maximum doses combined with exercise therapy in hot pools. None of the patients had received pulse methylprednisolone within the last 12 months or systemic or local treatment with steroids within the last 3 months. None had received remission-inducing drugs within the last 6 months. Furthermore, patients with total ankylosis in the cervical, thoracic or lumbar spine owing to ankylosing syndesmophytes were excluded. The usual contra-indica-
Intravenous Methylprednisolone Pulse Therapy Table I. Clinical data of patients. 375 mg
Scand J Rheumatol Downloaded from informahealthcare.com by University of Sydney on 01/01/15 For personal use only.
Number of patients Median age (range) (years) Sex (MIFI Median disease duration (years) Eye involvement Peripheral joint involvement HLA-B27 positive/negative Median ESR (range) (mmlh)
9 39 (2!Xl! 112 7 (1-22) 3 4 811 37 (12-65)
1000 mg
a 41 (31-55) 612 10.5 (1-20) 2 1 6/2 19 18-45)
tions to steroid treatment were observed. The patients were well instructed in exercise therapy in the hot pool and continued this therapy without any changes. Demographic data is given in Table I and 11. The study was carried out as a group-comparative randomized double-blind study using the double-dummy technique. The medication employed was from Upjohn. Methylprednisolone, 1000 or 375 mg, was dissolved in 50 ml isotonic saline and administered intravenously over 30 minutes between 8.00 and 9.00 a.m. on three consecutive days. The patient's degree of pain was measured on a visual analogue scale (VAS) as the average pain during the preceding 24 hours. Furthermore, NSAID and analgetics were discontinued on day 0 and the time for their reinstitution was recorded. The following clinical variables were determined on day 0, 3, 30, 60, 90, 120, 150, and 180: chinmanubrium distance, thorax excursion, finger-tofloor distance, Schober's test on the lumbar spine, and morning stiffness.
Table 11. Baseline mean values and range for the efficacy- data. Variabel
Low-Dose
High-Dose
Finger-to-floor distance
31.17 (14.0-38.0) 57.78 (21.0-83.0) 78.751 (60-1 20) 2.28 (1.0-4.0) 5.38' (3.0-9.5) 11.61 (11.0-14.0) 3.24 (1.6-6.7)
36.25 (15.0-55.0) 51.50 (29.1)-78.0) 66.25 (20-120) 2.91 (1.0-5.0) 3.753 (1.5-6.0) 11.68 (10.5-13.5) 2.44 (10.5-1 3.5)
Mean Range VAS-score (mm) Mean Range Morning stiffness ( m i d Mean Range Thorax excursion (cm) Mean Range Chin-manubrium distance (cm) Mean Range Schober's test (cm) Mean Range IgA (gll) Mean Range
'One patient omitted because of morningstiffness = 0 min 'One patient omitted because chin-manubrium distance = 0.0 cm 3Tw0 patients omitted because chin-manubrium distance = 0.0 cm
The clinical examination was performed between 8.00 and 9.00 a.m. and after the examination, the patients had their usual exercise therapy. Laboratory tests on day 0, 3, 30, 90 and 180 comprised: ECG, ESR, haemoglobin, differential count, white blood count, IgA, IgM, IgG, carbamide, creatinine, sodium, potassium, and blood glucose. Furthermore, tissue-typing was performed (HLA-B27 positive or HLA-B27 negative). Statistical analysis
All effect variables were analysed using the same method, mean and median curves of the course were drawn, and for each time (day) of measurement, a comparison between the two groups was made using the Mann-Whitney test (one-sided). The difference between the two groups as to the mean values for day 60 to day 180 was compared using the t-test (one-sided). A regression analysis was performed in the one case (VAS) where the rise from day 3 onwards could be considered linear from all patients. The level of significance chosen was 5%. Results
As seen in Fig. l A , there was a fall in the finger-tofloor distance from day 0 to 3, indicating the beneficial effect of methylprednisolone pulse therapy. The values remained at a fairly constant level during the whole study period. When the values are baseline-corrected, the high-dose group had the greatest improvement. The difference, however, is not statistically significant, nor is there any significant day-to-day difference. Fig. 1B shows that the lumbar mobility improved in both groups without any difference between groups. The improvement was maintained during the whole study period. The pain score measured on VAS improved in the beginning, and most markedly so in the highdose patients (Fig. 1C). However, no statistically significant differences were found. After day 3, the pain score increased linearly. The regression line for each group shows that the low-dose group reaches its pretreatment value after 253 days, whereas it takes 347 days in the case of the high-dose group. The difference between groups was not significant. Fig. 1D shows the course of morning stiffness. Both groups obtained a marked improvement on day 3. The improvement is greatest in the low-dose group, but then the effect diminishes rather quickly and the pretreatment value is reached on approximately day 160. In the high-dose group, 135
N . D. Peters et al. UORN*(G
snmss
YY L M L OAT W I W . P0.M
0
I)
w
m
mn um s t y 1 w
1)
-. a
1"
Fig. 1. The clinical effect of low-dose (375 mg) and highdose (loo0 mg) intravenous methylprednisolone administered on day 0, 1 and 2. (Average = Mean).
1m
(U'IYYI
Scand J Rheumatol Downloaded from informahealthcare.com by University of Sydney on 01/01/15 For personal use only.
FIG. 10
twill al
w s u u uruoouc sw
ULEYL M Y W-IM r R l P
mn y.l STYI w
nc.
-a
(UIYWT
1c
the improvement attenuates but slowly and the pretreatment vaiue is not reached until day 180. There were no significant differences between the groups. Thorax excursions improved markedly on day 3 in both groups, with attenuation of the effect after approximately 160 days (Fig. 1E). On day 150, the improvement in the high-dose group was significantly greater (p < 0.05), irrespective of whether the observations were baseline-corrected or not. Fig. 1F shows the chin-manubrium distance during the study period. There was an improvement on day 3 which remained rather constant during the whole period. The values are at the same level in the two groups, but when baselinecorrected, the 136
greatest effect is obtained in the low-dose group. There was, however, no significant difference between groups. Re-institution of treatment with analgetid NSAID was necessary at median 8 days (0-61) after the end of pulse methylprednisolone in the low-dose group against median 25 days (7-180) in the high-dose group, which is not statistically significant. Table I11 lists the adverse reactions recorded, divided into those occurring in immediate relation to the infusion days (day 0-4)and late reactions (day 5-180). Almost all the patients, both in the low- and in the high-dose group, experienced flushing. Furthermore, there were statements of
Intravenous Methylprednisolone Pulse Therapy Table 111. Adverse reactions following pulse methylprednisolone. Number of patients Day 0-4
Scand J Rheumatol Downloaded from informahealthcare.com by University of Sydney on 01/01/15 For personal use only.
flushing Dizziness Bitter taste Insomnia Palpitation irritability Increase in weight Dry mouth Sexual dysfunction
Day 5 1 8 0
375mg
1OOOmg
375mg
9 1
8 2 1 1 1
1 (day 5)
1 1 1
1000 rng
1
1
mild dizziness, sleep disturbances, irritability, small increase in weight, and dry mouth; one patient stated impotence. On the second infusion day one patient in the high-dose group had tachycardia for 5 minutes, and one patient in the iow-dose group had symptoms of tachycardia for 30 minutes on day 5. ECG immediately after the end of the attacks was normal. The laboratory tests showed unchanged values during the study period, with the exception of a fall in ESR and in IgA. There were no significant differences between groups. Discussion
Oral administration of 1000 mg of prednisolone has been found just as effective as 1000 mg intravenous methylprednisolone (7) in the treatment of rheumatoid arthritis, but the efficacy of oral steroids has not been studied in ankylosing spondylitis. A comparison of 40 mg, 500 mg and 1000 mg intravenous methylprednisolone in the treatment of active rheumatoid arthritis showed that a longterm effect, i.e. more than three weeks, is obtained only with a dose of 1000 mg (8). In an open study, Mintz et al. (3) administered 1000 mg of methylprednisolone intravenously on three consecutive days and reported a dramatic effect on spinal mobility and pain in patients with active ankylosing spondylitis. Fewer infusions gave poorer results and more than three infusions yielded no further improvement (3). Methylprednisolone pulse therapy has not been extensively used, possibly owing to reports on serious adverse reactions in the form of cardiac arrhythmias, cardiac arrest, and convulsions when given to patients with other inflammatory connective tissue disorders (9). These reactions may pos-
sibly be explained by the pharmacological effect of methylprednisolone which involves a rapid exchange of electrolytes across the cell membranes ( 6 )* No serious adverse reactions have ever been demonstrated in relation to pulse methylprednisolone to patients with ankylosing spondylitis. In the present study, 375 mg was chosen as the lowest dose, since at this dose all patients develop flushing. In this way we obtained blinding of both observer and patient. Fig. 1 shows an immediate and long-lasting effect on pain, morning stiffness, and spinal mobility. However, we could demonstrate no statistically significant differences between groups, though there was a trend towards a more marked and longer effect in the high-dose group. When evaluated by time of re-institution of analgetic and anti-inflammatory treatment, the effect was maintained longer in the high-dose patients. Thus, patients in this group managed without medication for 25 days (7-180) against 8 days (0-61) in the low-dose group. The failure of obtaining a significantly higher effect in the high-dose group could possibly be explained by differences in the inflammatory activity as evaluated by the levels of ESR and IgA. Another possible explanation is a statistical Type 2 error owing to the low number of patients. A further 13 patients (total 30 patients) could have reduced Type 2 error to a value < 0.05. In agreement with reported findings, no serious adverse reactions were observed in the present study, neither in direct relation to the infusions nor occurring as late reactions. No differences between the low- and high-dose group were found as to the occurrence of adverse reactions. One patient in either group had a short attack of tachycardia. Unfortunately, however, ECG was not performed during the attacks. The blood pressures were normal during the attacks, and so were the ECGs immediately after the end of the attacks. Whether this can be considered an adverse reaction to the treatment is uncertain, since it is wellknown that patients with ankylosing spondylitis may have intermittent atrial tachycardia and A-V block (10).
Conclusion Intravenous methylprednisolone has an acute pain-relieving effect in patients with ankylosing spondylitis in whom analgetics and anti-inflammatory drugs are insufficient. Furthermore, it has a good and long-lasting effect on spinal mobility. 137
N . D. Peters
et
al.
Despite the small number of patients, the study seems to suggest that poorer results are obtained with the low than with the high dose. No serious adverse reactions were demonstrated in this study. References
Scand J Rheumatol Downloaded from informahealthcare.com by University of Sydney on 01/01/15 For personal use only.
Bluestone R. Ankylosing spondylitis. In: McCarthy DJ, ed. Arthritis and allied conditions. Lea & Fibiger, 1985: 819. McConkey B. Sulphasalazine and ankylosing spondylitis. Br J Rheumatol 1990; 29: 2-5. Mintz G, Enriquez RD, Mercado U, Robles J, Jeminez FJ, Gutierrez G . Intravenous methylprednisolone pulse therapy in severe ankylosing spondylitis. Arthritis Rheum 1981; 24: 734-6. Ejstrup L, Daugaard Peters N. Intravenous methylprednisolone pulse therapy in ankylosing spondylitis. Dan Med Bull 1985; 32: 231-3.
138
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