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The problem of therapeutic evaluation in Rheumatoid Arthritis.

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The Problem of Therapeutic Evaluation in
Rheumatoid Arthritis
By STANLEY
L. WALLACE
AND CHARLES
RACAN
The difficulties encountered in the eval- Le difficultates incontrate in le evaluuation of therapy for rheumatoid ar- tation de therapias pro arthritis rheumathritis are reviewed. The authors stress toide es delineate. Le autores sublinea
the necessity for controlled studies, blind le necessitate de studios a controlo, de
comparisons of untested agents, appro- comparationes “occultate” de Dove
priate methods for measurement of thera- agentes, de appropriate methodos pro
peutic response and statistical evaluation le mesuration del responsa therapeutic,
e del evalutation statistic del resultatos.
of results.
T
HE EVALUATION of therapeutic agents in rheumatoid arthritis is diffi-
cult, the literature being replete with claims and counterclaims of the
efficacy of many agents. So complex is this situation, as a matter of fact, that
it is unusual to find a disease in which only one agent-the salicylates-has
received universal acceptance even though that agent despite its obvious
advantages of safety and availability is definitely wanting in effectiveness in
many instances. This is in direct contrast to such other fields of medicine
as the infectious diseases, hematology and cardiology, where there are many
widely accepted therapeutic agents.
With such difficulties, the evaluation of therapy in rheumatoid arthritis must
include a clearcut distinction between symptom alleviation and effects on
the course of the disease. Thus a potent analgesic such as morphine which
will relieve symptoms is rarely advocated as a therapeutic remedy in rheumatoid arthritis. Attention must also be paid to the distinction between acute
and long-lasting benefits. There is no cavil with the observation that suppression of almost all the manifestations of the disease may be accomplished
by the administration of steroids, but this benefit may be short-lived. In a
recent study,l even after as brief a period as one year, the results of steroid
therapy were in no way better than those with salicylates, although the initial
improvement with the latter agent was less. The duration of beneficial effects
is of paramount importance in evaluation of therapy.
In the older literature, most agents used in the therapy of rheumatoid
arthritis were described as beneficial in about two-thirds of patients. In recent
years accurate methods have been evolved for the evaluation of therapeutic
agents in disease. These methods have been applied to rheumatoid arthritis
in comparing cortisone to aspirin in patients with early‘ and late2 disease,
and to an evaluation of chloraquin;3 however, they have not as yet been
applied to the evaluation of gold therapy in this disease.q
From the Department of Medicine, Cokcmbfa University College of Physiciuns and Surgeons, and the Edmard Daniels Fnulkner Arthritis Clinic oj the Presbyterian Hospitul, h’ew
York, N.Y.
S. L. W. is a trainee of the Notionul Institute of Arthritis and Metabolic Diseases.
20
THERAPEUTIC EVALUATION IN RHEUMATOID ARTHRITIS
21
Theoretically, the controlled clinical trial of therapeutic agents should be
the only appropriate way of assessing the value of these agents in rheumatoid
arthritis. The concept of the controlled clinical trial includes, however, a
large number of variables that need to be considered separately. It is the
purpose of this paper to discuss the various aspects of the clinical trial with
particular reference to rheumatoid arthritis.
The clinical evaluation of drugs can be divided into three phases: l., selection and characterization of patients to be treated; 2., technics for carrying
out the study; and 3., methods of measuring the results of therapy.
SELECTION AND CHARACTERIZATION OF P A m V T S
To study the effect of a drug, it is necessary first to define the disease under
treatment. In many studies in the literature, no criteria for selection of patients are listed. These omissions emphasize the need for more specific and
generally accepted standards for the diagnosis of rheumatoid arthritis.
Recently a committee of the American Rheumatism Association has listed
diagnostic criteria for definite, probable, and possible rheumatoid arthritis.”
These criteria are inescapably arbitrary. The presence of symmetric polyarthritis with the usually associated symptoms persisting for six weeks, and
not caused by another specific disease process, would be enough to classify
a given patient as definitely having rheumatoid arthritis. There are some who
feel that these criteria are not sufficiently restrictive, and that it would be
better to limit the diagnosis to patients with arthritis and nodules, positive
agglutination tests, or widespread connective tissue lesions.
The criteria of the American Rheumatism Association committee are useful
in setting forth minimum standards for selection of patients in the study of
therapeutic agents in rheumatoid arthritis. However, further delimitation
and characterization of the patient population to be studied is desirable. The
age and sex of the patient, duration of the disease prior to therapy, and results of serologic testing must be known. The presence or absence of nodules
should be noted. As approximate measures of the severity of the arthritis, the
classifications of progression (table 1) and of functional capacity (table 2)
of the American Rheumatism Associationa are of value.
Finally, some method of quantitation of the activity of idammation in
the disease before therapy is needed. Lansbury‘ has reported a method for
measuring rheumatoid activity, using a combination of three objective indexes (sedimentation rate, hemoglobin and the patient’s ability to compress
an inflated blood pressure cuff) and three subjective indices (pain on motion, morning stiffness, and fatiguability). The latter symptoms are quantitated by determining the number of aspirin tablets taken daily by the patient for pain, the duration of morning stihess, and the number of hours
of physical activity before fatigue occurs. However, such manifestations are
subject to marked variation unrelated to the state of rheumatoid activity.
The numbers determined by application of this method are interpolated in
a standard table (table 3) and “percentages” calculated, which are averaged
to give an index of rheumatoid activity. Joint inflammation is not measured
directly in any of the indexes. Lansbury’s results, despite obvious sources of
22
STANLEY L. WALLACE AND CHARLES RACAN
TABLE1.-Classification
Stage
I
Roentgenologic
Signs
Muscle
Atrophy
0
osteoporosis;
sometimes no
destructive
changes.
of Rheumatoid Progression
Extra-articular
Lesions
(Nodules.
tenovaginitis)
Joint Deformity
Ankylosis
0
0
0
osteoporosis;
slight cartilage
or subchondral
bone destruction
may be present.
adjacent
may be
present
0
0
111
Osteoporosis;
cartilage
destruction;
bone
destruction.
extensive
may be
present
subluxation
ulnar deviation,
and/or
hyperextension
0
IV
same as I11 with
bony ankylosis.
extensive
may be
present
same as I11
I1
.-
fibrous or
bony ankylosis
(Reprinted from Steinbrocker, O., Tracger, C . H. and Batterman, R. C.: Therapeutic
criteria in rhedmatoid arthritis. J.A.M.A. 140:659, 1949. )
TABLE2.-Classificution of Functiorml Capacity
-
Class
I
~
_
_
Complete
Ability to carry on all usual duties without handicaps
I1
Adequate for nomial activities
Despite handicap of discomfort or limited motion at
one or more ioints
111
Limited
Only to little or none of the duties of usual occupation
or self care
IV
Incapacitated largely or wholely
Bedridden or confined to wheelchair; little or no
self care.
(Reprinted from Steinbrocker, O., Traeger, C. H. and Batterman, R. C.: Therapeutic
criteria in rheumatoid arthritis. J.A.M.A. 140359, 1949.)
error, indicate a satisfactory correlation with clinical impressions of rheumatoid activity.
We have recently begun to employ a modification of Lansbury’s method
(table 4), which is simpler and less time consuming to use and so far, in a
limited number of patients, has also been satisfactory in quantitating rheumatoid activity. This method also uses six manifestations of active inflammation in rheumatoid arthritis, substituting the presence and spread of joint
inflammation (not deformity) in the patient for his ability to compress an
inflated blood pressure cuff. Since weakness and fatigue are so extremely
23
THERAPEUTIC EVALUATION IN RHEUMATOID ARTHRITIS
Morning
Stiffness
5
10
16
20
30
45
Hrs.
1.0
1.5
2.0
2.6
3.0
3.6
4.0
4.6
5.0
5.5
6.0
6.6
7.0
7.6
8.0
..
..
..
..
..
..
..
..
..
2
5
7
9
14
21
29
43
67
71
86
100
114
129
148
161
171
186
200
214
229
..
..
..
..
..
..
..
..
..
Fatigue
Afkr
8.0
7.5
7.0
6.5
6.0
5.5
6.0
4.6
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
..
..
..
..
..
..
..
..
..
..
..
..
..
..
Aspirin
D8Y
Tabe. %
%
0
14
29
43
61
71
86
100
114
129
143
167
171
186
200
214
229
..
..
..
..
..
..
..
..
..
..
..
..
..
..
TABLE3.-Thc I,unsbuy Systemic Zndex
0
1
2
3
4
5
6
I
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
..
..
..
..
..
280
210
260
250
240
230
220
210
200
190
180
170
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
..
..
..
0
..
0
6
12
19
25
31
37
44
50
56
0
0
0
0
0
81
87
6
12
19
26
31
37
44
50
66
62
94
100
106
112
119
125
131
137
144
160
166
162
169
176
69
76
81
87
94
100
106
112
119
125
131
137
144
160
62
69
76
..
ESR
Anemia
-
0
12
25
37
50
62
75
87
100
112
125
137
150
162
175
in7
200
212
925
237
260
262
276
287
300
812
..
..
..
6-min.
Cutler
Grip
Weakness
mm. M%
F%
..
..
ow.
M%
13.4
13.2
13.0
12.8
12.6
12.4
12.2
12.0
11.8
11.6
11.4
11.2
11.0
10.8
10.6
10.4
10.2
10.0
9.8
9.6
9.4
9.2
9.0
8.8
8.6
8.4
8.2
8.0
0
7
15
22
0
0
0
30
0
31
44
52
60
0
..
..
..
0
89
0
9
19
29
33
48
67
96
67
104
111
116
126
133
141
148
166
163
170
185
193
200
76
86
95
106
114
124
133
143
153
162
111
181
190
200
..
..
..
..
61
74
81
178
1.0
1.6
2.0
2.6
3.0
3.5
4.0
4.5
5.0
6.5
..
..
6.0
6.5
1.0
7.6
8.0
8.6
9.0
9.5
10.0
10.6
11.0
11.5
12.0
12.5
13.0
13.5
14.0
14.5
16.0
15.6
16.0
WesterSed.Rate
0
10
20
30
40
50
60
70
80
90
100
110
120
130
140
160
160
170
180
190
200
210
220
230
240
260
260
210
280
290
300
10
15
20
26
30
35
40
46
60
66
60
0
8
17
26
as
110
116
120
126
130
136
140
146
160
42
60
68
67
76
83
92
100
108
117
126
la8
142
160
158
167
176
183
192
200
208
217
226
233
..
..
66
70
75
80
86
90
96
100
106
..
..
The percentile equivalenta are given in the nearest whole numbers and the scales are arranged b~
taking the average value for each item as 100 with 0 as normal. The Westergren ESR scale b based
on data furnished by Drs. Ziff, Duff and Galindez. The scale for hemoglobin valuea wan established
by taking extreme values ( 0 and 200%) and arranging the scale to agree.
(Reprinted from Iansbury, J. : Quantitation of the activity of rheumatoid arthritis. 5. A method for
summation of the systemic indices of rheumatoid activity. Am. J. Med. Sc. 4S2:300, 1956.)
subjective, the examiner's impression as to their presence and severity is used
rather than an attempt to measure them. These evidences of rheumatoid
activity are divided only into four degrees of severity-severe, moderate,
mild, or not present-are given point values and are added to give an index
of activity.
These two methods, like others suggested for summating rheumatoid activity, are entirely empirical. Extensive experience is necessary before either or
both can be shown to have intrinsic value and before they can be used in
the characterization of patients with rheumatoid arthritis and in the evaluation of therapy.
TECHNICS
FOR CARRYING
OUT THE STUDY
The generally accepted methods8J'Jofor studying the effects of new drugs
include:
less than
30 minutes
30 minutes or
more; less
than 3 hours
3 hours or
more
MILD ( 1 )
MODE RATE
(2)
SEVERE
(3)
pronounced
moderate
!.light
none
Fatigue &
Weakness
more than 8 ASA
tablets with
poor relief
8 ASA tablets
or more with
good relief
less than 8
ASA tablets with
good relief
none
Joint Pain
persistent joint
swelling, redness,
heat; many joints
involved
persistent joint
swelling, redness,
heat; few joints
involved
transient joint
heat, redness
and 'or swelling
_
_
I
_
Il(;Ilc
Acute Joint
Manifestations
Add total points: 1 for each in the mild category, 2 for moderate, and 3 for severe.
none
Morning
Stiffness
NONE ( 0 )
Activity
TAFILE4.-A Simplified Systemic Index
over SO inin. hr.
31-50 mm.,hr.
1.5-30 nim. 'hr.
nornial
Sedimentation
Rate
(Westergren)
below 9.5 Gni.
95-11 Gm.
11-12.5 Gni.
nornial
Hemoglobin
THERhpEUTIC EVALUATION IN RHEUMATOID ARTHRITIS
25
1. Prospective rather than retrospective study.
2. Randomization of patient assignment to the various therapeutic groups,
so that these groups may be comparable in all respects. In some studies, subgroups are set up prior to the allocation of patients to therapy to ensure the
strict equivalence of all groups.
3. Double or triple blind testing to eliminate observer error of assessment.
In such testing, neither the patient nor the observer is aware of the material
used. The agent to be assessed, a placebo, and preferably a standard of
reference (an agent with known therapeutic activity) should be used. All
agents should be used in all patients, and the drug and placebo should be
administered to the various patients in random order.
4. Statistical evaluation of results.
Not all these standard technics are feasible in the study of drugs in rheumatoid arthritis. The long-term administration of placebos known to be
ineffective in this disease cannot be justified ethically. This leaves only a
comparison between the drug to be studied and a drug whose effectiveness
is known.
Another cause of difEculties in the assessment of drugs is the variability
of the natural history of both untreated and conservatively treated rheumatoid arthritis. Approximately one-quarter of patients with this disease follow
an intermittent course with spontaneous remissions alternating with periods
of active arthritis." In two large s e r i e ~ ' ~
about
, ~ ~ 50 per cent of conservatively
treated patients with rheumatoid arthritis showed improvement on 9 to 11
year average follow-ups. Any drug studied, in order to be assessed properly,
would need to be administered over a long period of time. It would be dif6cult to evaluate in the same patient the effects both of the drug under study
and of the standard of reference.
In addition, the variability of the disease makes it difficult to set up a
therapeutic study with treatment groups that are comparable in all respects.
To ensure equivalence, subgroups would have to be created to include such
variables as age, sex, duration of disease prior to therapy, presence or absence
of nodules, results of serologic testing, classifications of progression and
inflammatory activity of the disease and functional capacity of the patient. If
such subgroupings were not made prior to therapy, then the patients treated
with the unknown agent and those treated with the standard of reference
would have to be shown to be similar in these respects. A large number of
patients with rheumatoid arthritis, necessarily from many clinics, would be
required in order to obtain information of possible statistical significance.
The subgroupings would need to be done at each center. Even then, the
likelihood of multiple observer bias and error in a multicenter study is present.
The question has been raised of the need for blind comparison of the agent
whose therapeutic effecbveness is known and the one with unknown activity.
Lasagna9 and Hilllo maintain that with rigid safeguards it is possible to obtain significant information from studies not using the double blind technic.
In such studies there must be complete reliance on objective criteria in the
measurement of results. Unless strictly objective standards are used, a thera-
26
STANLEY L. WALLACE AND CHARLES RAGAN
peutic evaluation not using the double blind technic may suffer from marked
observer error.
In many studies in the past, no control group has been employed, but
attempts have been made to compare the results of therapy in one group of
patients with results from an untreated or differently treated group from the
literature or from the earlier files of the same institution. This comparison is
usually statistically invalid because comparability of the treated and supposed
control groups cannot be established.
METHODSOF MEASURING
RESULTS
The point in time at which appropriate measurements should be made
must be determined before the results of therapy can be evaluated. Ideally,
only end results should be considered, but in a disease as chronic and as
capricious as rheumatoid arthritis, this is not practicable. The arbitrary
selection of one, two or three year end points, however, may give too little
consideration to the natural variability of the disease.
Many ways of measuring the results of therapy in rheumatoid arthritis have
been used. Changes in individual objective phenomena (sedimentation rate,
hemoglobin, joint tenderness, joint range of motion, strength of grip, time to
climb stairs or tie knots) and subjective phenomena (morning stiffness, pain,
fatiguability ) have been measured. Sociologic changes as in employment
status have been considered.
The American Rheumatism AssociationGhas established a classification of
response to therapy that unfortunately suffers from the fact that it considers
simultaneously changes in inflammation and in permanent joint deformity.
These need not parallel one another. A modification of this classification
based on new data is now in process.
Three separate major responses to therapy should be recorded; these are
changes in the degree of progression of the rheumatoid arthritis (table l), in
functional capacity (table 2 ) and in activity of inflammation (tables 3 and 4),
if this last index proves reliable with further experience. It must be noted,
however, that the measurement of these changes involves in large part the
consideration of subjective rather than objective phenomena. This becomes
an obstacle to the proper interpretation of results in a drug evaluation not
done by the double blind technic.
In addition to the changes in progression, functional capacity and activity
of inflammation, note should be made of changes in the individual objective
findings listed above. Changes in x-ray findings need to be considered separately. In order to remove the possibility of bias, the x-rays should be read
by radiologists not acquainted with the findings in the patient or his therapy.10
The importance of serial joint x-rays in the evaluation of treatment, and the
possibility of radiologic evidence of progression of rheumatoid arthritis in
the face of clinical quiescence, has been emphasized.14
Data resulting from the study would then be analyzed statistically, and
the significance, if any, determined of possible differences between the results
THERAPEUTIC EVALUATION IN RHEUMATOID ARTHRITIS
27
of therapy in the groups treated with the known agent and with the unknown.
CONCLUSIONS
The difficulties in the controlled clinical evaluation of therapeutic agents
in rheumatoid arthritis have been considered. It is not likely that an ideal,
controlled study can be designed at this time. Nevertheless, valuable information may be obtained from studies embodying the following principles:
( 1.)complete comparability of therapeutic groups; (2.) blind comparison of
the untested agent with a standard of reference; (3.) appropriate methods of
measuring response to therapy; and (4.)statistical evaluation of results.
If the comparison of the two drugs is not blind, then it is necessary that
the methods of measuring results be completely objective. In essence, this
approximates the procedures used by the Medical Research Council-Nuffield
Foundation' and Empire Rheumatism Council2 studies in Great Britain in
comparing the effects of aspirin and cortisone in rheumatoid arthritis.
Even with a well set up study, the variability and chronicity of rheumatoid
arthritis and the doubt as to the proper end pciint at which to make measurements make it uncertain that the resulting information would be valid. Whether
the information obtained warrants the enormous expenditure in time, facilities,
and personnel implicit in such a study is also questionable. There is, however,
no easier way to obtain information which may be of value.
REFERENCES
1. Joint Committee of the Medical Research Council and the Nuffield Foundation: A comparison of cortisone
and aspirin in the treatment of early
cases of rheumatoid arthritis. British
Med. J. 1~1223,1954.
2. Empire Rheumatism Council: Multicentre controlled trial comparing
cortisone acetate and acetylsalicylic
acid in the long-term treatment of
rheumatoid arthritis. Annals Rheum.
Dis. 14~353,1955.
3. Cohen, A. S. and Calkins, E.: A controlled study of chloroquine as an
antirheumatic agent, presented at the
Ninth International Congress on Rheumatic Diseases, Toronto, Canada, June
26, 1957.
4. Freyberg, R. H.: The place of gold
compounds in the treatment of rheumatoid arthritis. J. Chronic Dis.
5723, 1957.
5. Ropes, M. W.,Bennett, G. A., Cobb,
S., Jacox, R. and Jessar, R. A.: Pro-
posed diagnostic criteria for rheumatoid arthritis. J. Chronic Dis. 5330,
1957.
0. Steinbrocker, O., Traeger, C. H. and
Batterman, R. C.: Therapeutic criteria
in rheumatoid arthritis. J.A.M.A.
140~659,1949.
7. Lansbury, J.: Quantitation of the activity of rheumatoid arthritis. 5. A
method for summation of the systemic
indices of rheumatoid activity. Am.
J. bled. Sc. 232~300,1956.
8. Beecher, H. K.: Experimental pharmacology and measurement of the subjective response. Science 116~167,
1952.
9. Lasagna, L.: The controlled clinical
trial: Theory and practice. J. Chronic
Dis. 1~353,1955.
10. Hill, A. B.: The clinical trial. New England J. Med. 247~113,1952.
11. Reynolds, W.A. and Short, C. L.: The
clinical manifestations of rheumatoid
28
STANLEY
arthritis. Med. Clinics N. A. March
1955, p. 365.
12. Ragan, C.: The general management of
rheumatoid arthritis. J.A.M.A. 141:
124, 1949.
13. Short, C. L.and Bauer, W.: The course
of rheumatoid arthritis in patients re-
L. WALLACE AND CHARLES RAGAN
ceiving simple medical and orthopeJ. Med.
dic measures. New England
238:142, 1948.
14. Bollet, A. J. and Bunim, J. J.: The importance of serial x-rays in the evaluation of treatment of rheumatoid arthritis. Med. Clinics N. A. March,
1955, p. 439.
Stanley L. W a h c e , M.D., Trainee, National Institute of Arthritis and Metabolic Diseases; Clinical Instructor, Department of Medicine, State University of New York College of
Medicine at Brooklyn.
Charles Ragan, M.D.,Associate Professor of Clinical Medicine, Columbia University College of Physicians and Surgeons; Associate Attending Physician, Presbyterian Hospital,
New York, N.Y.
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