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

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 pleu- ropneumonia-like organisms might be path- ogenic for synovial tissues as well as the genitourinary tract (1). Later, Bartholo- mew (2) isolated these organisms, now known as Mycoplasmas from rheumatoid synovial fluid in tissue cultures. In 1966, others showed cell-free rheumatoid synovi- a1 fluid had a cytopathogenic effect when inoculated into spnovial cells in tissue cul- ture suggesting the presence of a microbio- logic agent (3). More .recently Williams et al (4) demonstrated inhibition of leu- kocyte migration by M ycoplasma fermentans in 29 of 43 patients with rheumatoid arthritis.

Following the discovery that Mycoplas-

From 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., De- partmen t of Medicine, Massachusetts General Hos- pital and Harvard Medical School, Boston, Mass., and from the Department of Public Health, Com- monweal th of Massachusetts.

Supported in part by grants from the National Institute of Arthritis and Metabolic Diseases, AM- 05285-10 and USPHS Grants AM 5067 and AM 3564

ma were sensitive to broad spectrum antibi- otics, patients with arthritis and positive cultures from the genitourinary tract were treated accordingly. In particular, patients with rheumatoid arthritis were said to im- prove 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 appar- ently due to a strain of Mycoplasma recov- ered 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 be- low.

MATERIALS AND METHODS

Design of Trial Thirty patielits with definite d classical rheuma-

toid arthritis according to the American Rheuma- tism 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

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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 Massachu- setts 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 im- munosuppressive 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 recom- mendations 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

Tetra- Parameter cycline Placebo

Total no. of patients Male Female

Median age (yr) Median duration of RA (yr) Functional class* Positive rheumatoid factor Rheumatoid nodules Anemia (Hct < 36)

13 (5) (8) 55 5 2

11 5 1

14 (1)

52 (13)

9.5 1 .9

12 9 5

* Steinbrocker criteria (13)

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 in- cluded Westergren sedimentation rate, hematocrit, white #blood cell count and urinalysis. Initially and at Week 10 and 42, blood urea nitrogen, transami- nase, 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. The 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 togeth- er, Small joints, for example, the metacarpophalan- geal joints of one hand, were regarded as a single

728 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 regu- larly, 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 in 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). The 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. In 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. In 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. In one patient in the tetracycline group who had suffered from chronic bronchitis, respi- ratory 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 an exacerbation of rheumatoid symptoms after discontinuing the trial medication.

Rheumatoid factor titers, by the latex fixation test, were determined before and after treatment in 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).


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Table 2. Mean Values for First Two Visits (Before) Compared to Last Two Visits (After) of Various Parameters in Both Treatment Groups

Parameter Tetracycline Placebo

Grip strength (mm Hg) Before After Difference (before-after) Difference (drug-placebo)

Before After Difference (before-after) Difference (drug-placebo)



Before After Difference (before-after) D ifference (drug-placebo)

Walking t ime (sec/50 feet) Before After Difference (before-after) Difference (drug-placebo)

Sedimentation rate (mm/hr) Before After Difference (before-after) Difference (drug-placebo)

Ring size (10 fingers)

Morning stiffness (min)

Tender joints (total)

Swollen joints (total)

143.9 142.9 None

None

99.3 93.5

Improved (P < .01) None

121.9 187.5

Worse (P < .02)

21.6 18.2

None

P <.02

None

13.5 8 .4

Improved (P < .05) None

12.8 13.0

None None

38.4 36.8

None None

123.0 124.9 None

86.0 82.4

Improved (P < .01)

135.7 128.3 None

16.1 15.2

None

12.2 10.1

Improved (P <. lo)

13.3 12.4

None

52.9 54.7

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 be- ginning and end of the treatment period were available in only 12 patients. They were read by one person (ESC) without

knowledge of the names or dates of the films. In 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


TETRACYCLINE IN RA

Table 3. Comparison of the Parameters Measured in the Two Treatment Groups

Tetracycl ine Placebo

Parameter Improved Same Worse Improved Same Worse

Grip strength 2 10 1 Ring size* 5 6 1

No. of tender joints 3 9 1 No. of swollen joints 4 9 0 Walking time 3 8 2 Sedimentation rate 1 10 2 Range of motiont 1 7 5

Morning stiffness 0 5 8

* 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 Laborato- ries. T h e synovial fluids all contained 56-78y0 of the serum values (Table 4). The 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 The results of the present study fail to

support the view that tetracycline-sensitive organisms play an active role in longstand- ing rheumatoid arthritis. The possibility that such organisms are in some way

Table 4. Tetracycline (pg/ml) Levels in Patients with Rheumatoid Arthritis*

Syn ov ia I Percent Case No. fluid Serum of serum

1 1.52 1.94 7a 2 0.19 0.34 56 3 0.42 0.57 74

*Assays performed by the B cereus agar dif- fusion method. Lederle Laboratories

12 9 10 6 11 10 10 6

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 em- phasized that favorable results were obtained in previous therapeutic trials when even smaller dosages of the same antibiotic were used. Furthermore, it should be point- ed out that this antibiotic is bacteriocidal for Mycoplasma pneumoniae in concentra- tions 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. The 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 growth- stimulating effect in animals (12).

There were no instances of remissions or remarkable improvements in either group of patients, nor were there any exacer- bations when the drug was stopped. Pa- tients 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-


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ulation with more males, shorter duration of disease, fewer patients with nodules and a lesser number 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 in any measurement between the tetracycline and the placebo groups was in duration of morning stiffness, a n d this was in favor of the placebo group. I t is noteworthy that both groups showed a tendency to lose joint motion during the period of observa- tion, perhaps reflecting the trend of rheumatoid arthritis patients to lose motion with time. In 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.

REFERENCES Dienes L, Ropes MW, Smith WE, et al: The role of pleurbpneumonia-like organisms in genitourinary and joint diseases. New Eng J Med 238:509-515, 563-567, 1948 Bartholomew LE: Isolation and character- ization 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

with rheumatoid arthritis synovial fluid. Arthritis Rheum 9:508, 1966

4. Williams MH, Brostoff I, Roitt IM: Posi- tive role of Mycoplasma fermentans in pathogenesis of rheumatoid arthritis. Lan- cet 2277-280, 1970

5. Brown T McP: Discussion: PPLO and their possible relation to articular disease. Amer- ican Rheumatism Association Rheumatic Diseases, Philadelphia, Saunders, 1952, p 40 1

6. 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

7. Sanchez I: Tetracycline treatment in rheumatoid arthritis and other rheumaitc diseases. Brasil Med 82:22-31, 1968

8. Brown T McP, Clark HW, Bailey JS, et al: A mechanistic approach to treatment of rheumatoid type arthritis naturally occur- ring in a gorilla. Trans h e r Clin Climat Ass (in press)

9. Ropes MW, Bennett GA, Cobb S, et al: 1958 Revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis 9: 175-176, 1958

10. 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

11. Crawford YE: Mycoplasma of human deri- vation, A Microbial Enigma Mycoplasma and Bacterial L-forms. Edited by YE Craw- ford, PF Smith, C Panos, et al. Cleveland, World, 1967, p 64

12. Lepper MH: Metabolic effects of tetra- cyclines. Ann Intern Med 58:553-556, 1963

13. Steinbrocker 0, Traeger CH and Batter- man RC: Therapeutic criteria in rheumatoid arthritis. JAMA 140:659-662, 1949


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