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Tetracycline in the treatment of rheumatoid arthritis. A double blind controlled study

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Tetracycline in the Treatment of Rheumatoid Arthritis
A Double Blind Controlled Study
Martha Skinner, Edgar S. Cathcart, John A. Mills and Robert S. Pinals
Mycoplasmas have been implicated as etiologic agents in rheumatoid arthritis
and it has been suggested that tetracycline, which inhibits the growth of these
organisms, is beneficial in the treatment of this disease. To test this hypothesis,
27 patients with classical or definite rheumatoid arthritis were selected from
three university hospital arthritis clinics and assigned at random to treatment
for one year with either tetracycline 250 mg/day or a placebo. The results
demonstrated no significant benefit from tetracycline therapy.
In 1948 it was first suggested that pleuropneumonia-like organisms might be pathogenic for synovial tissues as well as the
genitourinary tract (1). Later, Bartholomew (2) isolated these organisms, now
known as Mycoplasmas from rheumatoid
synovial fluid in tissue cultures. In 1966,
others showed cell-free rheumatoid synovia1 fluid had a cytopathogenic effect when
inoculated into spnovial cells in tissue culture suggesting the presence of a microbiologic agent (3). More .recently Williams et
al (4) demonstrated inhibition of leukocyte migration by M ycoplasma fermentans in 29 of 43 patients with rheumatoid
arthritis.
Following the discovery that MycoplasFrom the Boston University Medical Services,
Boston City Hospital and the Evans Department
of Clinical Research, University Hospital, Boston
University Medical Center, Boston, Mass., Tufts
Medical Service, Lemuel Shattuck Hospital, Tufts
University School of Medicine, Boston, Mass., Departmen t of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Mass.,
and from the Department of Public Health, Commonweal th of Massachusetts.
Supported in part by grants from the National
Institute of Arthritis and Metabolic Diseases, AM05285-10 and USPHS Grants AM 5067 and AM 3564
ma were sensitive to broad spectrum antibiotics, patients with arthritis and positive
cultures from the genitourinary tract were
treated accordingly. I n particular, patients
with rheumatoid arthritis were said to improve markedly after long term treatment
with tetracycline (5,6,7). It has even been
reported that a gorilla afflicted with a
rheumatoid arthritis-like syndrome apparently due to a strain of Mycoplasma recovered when treated with tetracycline (8).
Because of the possible significance of
these findings, a double blind controlled
study was carried out. Patients were treated
with either low dose tetracycline or placebo
for a one year period and their subsequent
disease assessed according to a number of
parameters. The results are presented below.
MATERIALS AND METHODS
Design of Trial
Thirty patielits with definite d classical rheumatoid arthritis according to the American Rheumatism Association criteria (9) were selected and
and from the Massachusetts Chapter of the Arthritis
Foundation and the Arthritis Foundation.
Arthritis and Rheumatism, Vol. 14, No. 6 (November-December 1971)
727
SKINNER ET A 1
randomly assigned a number corresponding to a
supply of capsules' which were to be taken, one per
day for 52 weeks. Fourteen patients in the placebo
group and 13 patients in the tetracycline group
completed the study. Of these, 17 were from the
Boston City Hospital, four were from the Lemuel
Shattuck Hospital and six were from the Massachusetts General Hospital. Table 1 compares the
clinical and laboratory data in the two treatment
groups. None of the patients had received gold,
antimalarials, indomethacin, phenylbutazone or immunosuppressive drugs within four months of the
study. Three patients, all falling by chance in the
tetracycline group, were receiving corticosteroids (5
and 7.5 mg prednisone and 375 mg dexamethasone
per day respectively) . This was continued throughout the study. All patients were continued on their
previous dose of salicylates which ranged from 3.0
to 6.0 glday.
Each patient was evaluated initially and after two
weeks at which time the medication was begun.
Followup visits during treatment were at weeks
four, 10, 18, 30 and 42 and 54. The patients were
seen again at week 60, six weeks after the trial
medication had been stopped to determine whether
discontinuing the trial medication would result in
an exacerbation.
Evaluations were made according to the recommendations of the Cooperating Clinics Committee
of the American Rheumatism Association (10). On
each visit, the same physician determined grip
strength; the number of warm, tender and swollen
*Identical capsules containing either tetracycline,
250 mg, or a placebo were prepared by Lederle
Laboratories, Pearl River, NY.
Table 1. Comparison of the Clinical Data in
the Two Treatment Groups
Parameter
Total no. of patients
Male
Female
Median age (yr)
Median duration of RA (yr)
Functional class*
Positive rheumatoid factor
Rheumatoid nodules
Anemia (Hct < 36)
* Steinbrocker criteria (13)
728
Tetracycline
Placebo
13
(5)
(8)
55
5
2
11
5
1
14
(1)
(13)
52
9.5
1.9
12
9
5
joints: the number of seconds required to walk a
distance of 50 feet and the duration of subjective
morning stiffness. In addition. ring size of each
finger, using standard jewelers rings, was determined. Range of motion of each joint was evaluated
at Week 2 and 54.
Laboratory studies performed on each visit included Westergren sedimentation rate, hematocrit,
white #bloodcell count and urinalysis. Initially and
at Week 10 and 42, blood urea nitrogen, transaminase, and alkaline phosphatase were obtained. The
latex fixation test for rheumatoid factor was done
initially and at Week 54. X-rays of the hands,
knees, feet, hips and neck were taken on the first
and last visits.
Statistical Analysis
The findings were evaluated before the double
blind code was broken. Mean values of the first two
examinations at Week 0 and 2 prior to the start of
treatment were used as a baseline. A comparison
was made between this and the mean values of the
examinations at Week 42 and 54, which were
during and at the end of the course of treatment.
The data were analyzed by comparing the mean
values for each parameter measured, before and
after treatment, in each treatment group and
between the two groups using a Student's t test.
The data were also analyzed by determining the
number of patients improved, the same or worse in
all parameters measured. Arbitrary standards were
chosen and applied to both groups. For grip
strength and walking time, a 20% change was
considered significant and rated (+) if )better or
(-)
if worse. Less than a 20% change was
considered not significant and rated (0). Ring sizes
were analyzed by adding the sum of sizes recorded
on all 10 fingers. An increase (-) or decrease (+)
by six sizes or more was considered significant. T h e
number of swollen or tender joints were calculated
independently. For these parameters, an increase
(-)
or decrease (+) of 20% or more in the
number and also of at least six joints was considered significant. The sedimentation rate was rated
increased (-) or decreased (+) according to a
change of ZOO/, and at least 10 mm/hr. Morning
stiffness differed significantly if by at least 60
minutes from the initial value.
The range of motion was scored as follows. The
total number of degrees of all motions in each
natural plane about each joint were added together, Small joints, for example, the metacarpophalangeal joints of one hand, were regarded as a single
Arthritis and Rheumatism, Vol. 14, No. 6 (November-December 1971)
TETRACYCLINE IN RA
group and considered equivalent to one large joint.
Thus, an arithmetic sum was obtained both before
and after treatment for each of 21 joints or joint
groups, that is, 10 joints on each side plus the neck.
Each joint or group was awarded a (+I) for a 10%
gain and a (+2) for a 20% or more gain in
motion. Corresponding negative values were awarded for loss of motion. The sum of the awarded
pluses and minuses was tabulated. If this sum
amounted to five or more the change in range of
motion was considered significant.
RESULTS
Three patients dropped out of the study.
One patient on tetracycline was dropped at
Week 40 when it was discovered he was
unreliable and had been taking the medicine only sporadically. One patient 6n placebo stopped the capsules at Week 12 because of insomnia, heartburn and diarrhea.
Another patient on placebo stopped after
32 weeks because of progressive arthritis
and lack of benefit from the trial drug. She
had not been taking the medication regularly, was depressed and was consuming
large quantities OI alcohol. Using the above
criteria, there had been no objective
change in her arthritis during the period of
treatment.
Three patients who completed the study
complained of side effects attributed to the
trial medication. One patient on tetracycline had epigastric pain, anorexia and
weight loss. An upper gastrointestinal
series was negative. This patient was also
taking prednisone 7.5 mg/day. One patient
on placebo developed a rash just before the
end of the study. Another patient on placebo complained of diarrhea.
When analyzing the results by comparing
the mean values for each parameter measured (Table 2), ring size and the total
number of swollen joints showed minor
improvement in each group, but there was
no significant difference between the two
treatment groups. Morning stiffness showed
a mean increase of 66 minutes i n the tetracycline group and was significantly worse
both when compared to initial values
and to the placebo group. This -value
reflected an increased morning stiffness in 9
of 13 patients, 7 of these for one hour or
more. Significant changes were not noted
with respect to grip strength, number of
tender joints, duration of walking time and
sedimentation rate. It was of interest that
the tetracycline group had an increase in
weight throughout the year totaling 45 lb,
whereas the placebo group had an overall
weight loss of 14.5 lb.
Assessments for each parameter measured in both study groups were also analyzed (Table 3). T h e results for each
parameter were examined for the number
improved, the same or worse. There was a
striking worsening in range of motion for
both. I n fact, nine of the 13 patients in the
tetracycline group lost motion although the
amount was significant by our arbitrary
criteria in only five patients. I n the placebo
group, 11 of the 12 patients examined lost
motion, with the amount considered significant in five patients.
No patient in either group achieved
complete clinical remission or demonstrated a remarkable degree of improvement. I n
one patient in the tetracycline group who
had suffered from chronic bronchitis, respiratory symptoms disappeared during the
treatment period. She has since remained
on tetracycline 250 mglday and been free of
bronchitis. A patient in the placebo group
had a n exacerbation of rheumatoid symptoms after discontinuing the trial medication.
Rheumatoid factor titers, by the latex
fixation test, were determined before and
after treatment i n 12 patients in the tetracycline group. They were unchanged in
nine (2 1 tube dilution) and greater in
three patients (+2 or more tube dilutions).
Arthritis and Rheumatism, Vol. 14, No. 6 (November-December 1971)
729
SKINNER ET A 1
Table 2.
Mean Values for First Two Visits (Before) Compared to Last Two Visits (After) of
Various Parameters in Both Treatment Groups
Parameter
Grip strength (mm Hg)
Before
After
Difference (before-after)
Difference (drug-placebo)
Ring size (10 fingers)
Before
After
Difference (before-after)
Difference (drug-placebo)
Morning stiffness (min)
Before
After
Difference (before-after)
Difference (drug-placebo)
Tender joints (total)
Before
After
Difference (before-after)
Difference (drug-placebo)
Swollen joints (total)
Before
After
Difference (before-after)
D ifference (drug-placebo)
Walking time (sec/50 feet)
Before
After
Difference (before-after)
Difference (drug-placebo)
Sedimentation rate (mm/hr)
Before
After
Difference (before-after)
Difference (drug-placebo)
Tetracycline
Placebo
143.9
142.9
123.0
124.9
None
None
None
99.3
93.5
86.0
82.4
Improved (P < .01)
121.9
187.5
Worse (P
135.7
128.3
< .02)
None
P <.02
21.6
18.2
16.1
15.2
None
None
None
13.5
8.4
Improved (P
12.2
10.1
Improved (P <.lo)
< .05)
None
12.8
13.3
12.4
13.0
None
None
None
38.4
36.8
52.9
54.7
None
None
None
In the placebo group rheumatoid factor
was measured before and after treatment in
all 14 cases. It was lower in two patients,
the same in 1 1 and greater in one.
Satisfactory radiographs of joints at beginning and end of the treatment period
were available in only 12 patients. They
were read by one person (ESC) without
730
Improved (P < .01)
None
knowledge of the names or dates of the
films. I n the tetracycline group, one patient
was classified as worse, with a definite increase in bone erosions and four as
unchanged. In the placebo group, three
patients were worse and four were considered to be unchanged.
Three patients in the tetracycline group
Arthritis and Rheumatism, Vol. 14, No. 6 (November-December 1971)
TETRACYCLINE IN RA
Table 3.
Comparison of the Parameters Measured in the Two Treatment Groups
Tetracycl ine
Parameter
Grip strength
Ring size*
Morning stiffness
No. of tender joints
No. of swollen joints
Walking time
Sedimentation rate
Range of motiont
Placebo
Improved
Same
Worse
2
5
0
3
4
3
1
10
1
1
6
5
9
9
1
8
8
1
0
2
10
7
2
5
Improved
Same
Worse
12
9
10
6
11
10
10
6
* Ring size done on 12 of 13 patients, tetracycline group.
t
Range of motion done on 12 of 14 patients, placebo group.
had knee joint aspirations during the treatment period. At the end of the study the
synovial fluid and serum which had been
drawn simultaneously were assayed for tetracycline HCl, at the Lederle Laboratories. T h e synovial fluids all contained
56-78y0 of the serum values (Table 4).
T h e synovial fluid analysis showed all to be
inflammatory in nature, with fair mucin
and 11,950-18,150 WBC, 75-89y0 of which
were polymorphonuclear leukocytes.
DISCUSSION
T h e results of the present study fail to
support the view that tetracycline-sensitive
organisms play an active role in longstanding rheumatoid arthritis. T h e possibility
that such organisms are in some way
Table 4.
Tetracycline (pg/ml) Levels in Patients
with Rheumatoid Arthritis*
Case No.
Synov ia I
fluid
Serum
Percent
of serum
1
2
3
1.52
0.19
0.42
1.94
0.34
0.57
7a
56
74
*Assays performed by the B cereus agar diffusion method. Lederle Laboratories
related to the initiation of rheumatoid arthritis can not be excluded. Although none
of the study patients received more than
250 mg tetracycline/day, it should be emphasized that favorable results were obtained in previous therapeutic trials when
even smaller dosages of the same antibiotic
were used. Furthermore, it should be pointed out that this antibiotic is bacteriocidal
for Mycoplasma pneumoniae in concentrations as low as 0.39 g / m l (11). It is noteworthy that this level was exceeded in two
of the three random synovial fluids tested
in this study.
No side effects due to the trial medication were encountered. T h e weight gain in
the tetracycline group, although not significant, is of interest in view of the fact that
this antibiotic is reported to have a growthstimulating effect in animals (12).
There were no instances of remissions or
remarkable improvements in either group
of patients, nor were there any exacerbations when the drug was stopped. Patients in the tetracycline and placebo
groups were similar in age, functional class
and presence of rheumatoid factor. T h e
tetracycline group, however, was slightly
favored in that it contained a patient pop-
Arthritis and Rheumatism, Vol. 14, No. 6 (November-December 1971)
731
SKINNER ET A 1
ulation with more males, shorter duration
of disease, fewer patients with nodules a n d
a lesser n u m b e r of patients with mild anemia. Although all of the patients receiving
small doses of corticosteroids fell, by
chance, into the tetracycline group, their
results did not differ from the group as a
whole. The only significant change i n any
measurement between t h e tetracycline and
the placebo groups was in duration of
morning stiffness, a n d this was i n favor of
the placebo group. I t is noteworthy that
both groups showed a tendency to lose
joint motion during the period of observation, perhaps reflecting the trend of rheumatoid arthritis patients to lose motion
with time. I n conclusion, therefore, this
study demonstrated no significant benefit
from long term tetracycline therapy in patients with classic and definite rheumatoid
arthritis.
ACKNOWLEDGMENTS
We are grateful to Miss June Sutcliffe for help
with the clinical evaluations and to Dr. Hugo
Muench for biostatistical assistance. This study was
supported in part by a grant from the Lederle
Laboratories.
4.
5.
6.
7.
8.
9.
10.
REFERENCES
Dienes L, Ropes MW, Smith WE, et al:
T h e role of pleurbpneumonia-like organisms in genitourinary and joint diseases.
New Eng J Med 238:509-515, 563-567, 1948
Bartholomew LE: Isolation and characterization of Mycoplasma (PPLO) from patients with rheumatoid arthritis, systemic
lupus erythematosus and Reiter's syndrome.
Arthritis Rheum 8:376-388, 1965
Gordon DA, Franklin AE, Mustard JF:
Cellular damage and platelet- aggregation
associated with tissue cultures 'inoculated
732
11.
12.
13.
with rheumatoid arthritis synovial fluid.
Arthritis Rheum 9:508, 1966
Williams MH, Brostoff I, Roitt IM: Positive role of Mycoplasma fermentans in
pathogenesis of rheumatoid arthritis. Lancet 2277-280, 1970
Brown T McP: Discussion: PPLO and their
possible relation to articular disease. American Rheumatism Association Rheumatic
Diseases, Philadelphia, Saunders, 1952, p
40 1
Brown T McP, Bush SW and Felts WR:
Rheumatoid diseases and gout, Long-term
Illness: Management of the Chronically I11
Patient. Edited by MG Wohl. Philadelphia,
WB Saunders, 1959, pp 93-125
Sanchez I: Tetracycline treatment in rheumatoid arthritis and other rheumaitc diseases. Brasil Med 82:22-31, 1968
Brown T McP, Clark HW, Bailey JS, et al:
A mechanistic approach to treatment of
rheumatoid type arthritis naturally occurring in a gorilla. Trans h e r Clin Climat
Ass (in press)
Ropes MW, Bennett GA, Cobb S, et al:
1958 Revision of diagnostic criteria for
rheumatoid arthritis. Bull Rheum Dis 9:
175-176, 1958
The Cooperating Clinics Committee of the
American Rheumatism Association: A seven
day variability study of 499 patients with
peripheral rheumatoid arthritis. Arthritis
Rheum 8:302-335, 1965
Crawford YE: Mycoplasma of human derivation, A Microbial Enigma Mycoplasma
and Bacterial L-forms. Edited by YE Crawford, PF Smith, C Panos, et al. Cleveland,
World, 1967, p 64
Lepper MH: Metabolic effects of tetracyclines. Ann Intern Med 58:553-556, 1963
Steinbrocker 0, Traeger CH and Batterman RC: Therapeutic criteria in rheumatoid arthritis. JAMA 140:659-662, 1949
Arthritis and Rheumatism, Vol. 14, No. 6 (November-December 1971)
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