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The early history of antirheumatic drugs.

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The Early History of Antirheumatic Drugs
Gerald
P. Rodnan and Thomas G. Benedek
The account which follows deals with
the early development of a number of
drugs and treatments which have been
widely employed as therapy for patients
with rheumatic diseases. We shall not be
concerned with medicaments of recent origin, but shall concentrate instead on the
history of certain more venerable remedies
in order to trace the transition from herbal
to pharmacopeia. It should be emphasized,
however, that drug therapy has been but
one avenue of relief for the rheumatic patient, for since ancient times a variety of
other types of treatment have been utilized
(1) Among these were magical and religious cures, many forms of counter-irritation (including cautery, acupuncture and
moxibustion) , as well as blood-letting and
galvanism. Some of these practices have
continued to be applied in their original
forms to the present day, while others, upon
refinement, have served as the foundation
for various methods of physical therapy.
It is of interest to note that the experts of
yesteryear, being less inhibited by scientifically controlled studies, provided a far
greater choice of remedies than that offered
.
From the Department of Medicine, University of
Pittsburgh, and the Pittsburgh Veterans Administration Hospital, Pittsburgh, Pa.
Supported in part by Graduate Training Grant
2A-5031 in Arthritis and Rheumatism.
GERALD
P. RODNAN,
MD: Professor of Medicine.
Department of Medicine, University of Pittsburgh,
Pittsburgh, Pa 15215. THOMAS
G. BENEDEK,
MD:
Assistant Professor of Medicine, University of Pittsburgh.
Reprint requests should be addressed to Dr.
Rodnan.
Submitted for publication Nov 23, 1969; accepted,
Dec 23. 1969.
Arthffs and Rheumatism, Vol. 13, No. 2 (March-April. i970)
by present day authorities. Indeed, in consulting early treatises on rheumatism and
gout one finds a veritable cornucopia of
cures, one more exotic than the next, and
each highly extolled (2). In these times, there
was little appreciation of the importance of
psychophysiologic factors in determining
the response of the patient with a chronic
disease to the ministrations of an enthusiastic therapist. However, there were a few
refreshing exceptions to the rule. For instance, in 1726, Blackmore, commenting on
the cure of scrofula by the “king’s touch,”
was bold enough to suggest that the efficacy
of this procedure was a result of the “wonderful Power of Imagination” ( 3 ) .
CO LCHICINE
Colchicine is an alkaloid of complex ring
structure which is obtained from the seeds
and corms of Colchicum autumnale, a lilaceous bulb popularly known as “autumn
crocus” or “wild” or “meadow saffron.”
The term “colchicum” is taken from the
ancient district of Colchis, which was located on the eastern shore of the Black Sea
and served as the original source of this or
a closely related species of the plant. The
earliest history of colchicine is confused due
to the existence of several terms for botanicals which may or may not have been
identical to C auturnnale, eg, hermodactyl,
surinjan and ephemeron. This difficulty is
evident in De Materia Medica, the herbal
of Dioscorides (first century AD) (4), and
has been well reviewed by Sharp (5) and
Hartung (6).
145
RODNAN S BENEDEK
T h e introduction of colchicine as an
antirheumatic agent has generally been
credited to Alexander of Tralles (sixth
century AD), who recommended hermodactyl (finger of Hermes or Mercury) as
a cathartic in the treatment of podagra
(7). Alexander made no claim to originality
in this connection: of the 11 prescriptions
containing hermodactyl which he presented,
he acknowledged 3 to have been obtained
from other physicians. T h e use of hermodactyl was supported by the influential
Paulus Aeginata (seventh century), as well
as by later Arabian authorities, who described the properties of colchicine. Concerning the cure of arthritis due to a “sanguineous humour,” Paulus wrote:
round, broad above, and narrow beneath, white &
sweete, covered with many coates or felmes, having
by one side right in the middle as it were a clift or
parting, whcrcas the stalke bearing the flower
groweth. The roote being dried beconimeth blacke.
Hermodactill hath great broad leaves like the
Lillie, three or four comming foorth of one root,
amongst which groweth the stalk about the height
of a foote, bearing triangled huskes like to the
Marsh flague or false Acorns, but alway smaller, the
which being ripe d o open themselves into three
partes: within that is inclosed a rounde seede,
blacke and hard. T h e flowers grow u p after the
leaves and stalke are perished, upon short stems or
stalkes. like the floures of Saffron, The roote is
Dodoens notes that “the pleasant flowers
come ioorth of the ground’ in September.
He also asserts that there are two kinds of
Hermodactill: the one known as Agrestis
bulbus in Latin, T u e chien or Mort chiens
in French, Zeitlosen and Wisen Zeitlosen in
“high Almaigne,” and Hermodactilen in
the “base Almaigne of the Herborists”; the
other, found in shops, is called Hermodactilus. T h e former, he considered “corrupt
and venomous, therefore not used in medicine,” while the latter “driveth foortli by
siege slimie flaume, drawing the same from
far parts, and is very good to be used
against the gout, the Sciatica, and all
paines in the ioints.” T h e treatment is not
without danger, however, since it “stirreth
u p tossings, wamblings, windinesse, and
vomiting, and subverteth and overturneth
the stomacke.” T h e antidote is to be found
in the combination of the Hermodactill
with “either Ginger, long Pepper, Anise
seed, or Cumin, and a little Mastick.” Oddly enough, Dodoens provides an illustration
of the baneful variety of Hermodactill
(which “inflameth the stomacke, and hurtetli the inward parts, so that i n fine it
causeth bloudy excrements, and within the
space of one day, death”), but not of the
therapeutically useful plant. He also fails
to indicate how the unwary can distinguish
one from the other.
Ascribing the benefits of colchicum to
the evacuation of noxious matter fitted
well into the humoral theory which so long
prevailed. I n seventeenth century medical
texts, extracts of the plant are listed as
constituents of numerous cathartics and
146
Arthritis and Rheumatism, Vol. 13, No. 2 (MarchApril 1970)
Some, in the paroxysms of all arthritic diseases,
have recourse to purging with hermodactylus; but
it is to be remarked that the hermodactylus is bad
for the stomach, producing nausea and anorexia,
and ought, therefore, to be used only in the case of
those who are pressed by urgent business; for it
removes rheumatism speedily, and after two days at
most, so that they are enabled to resume their
accustomed employment (8)
.
Accounts and illustrations of C autumnale, together with comments concerning its
medical uses are to be found in many
herbals. We have selected the works of
Mathiolus (9) (Fig 1) and Dodoens (10) as
representative of this literature. T h e latter
begins his account of “hermodactill or Mede
Saffron,” with the following description:
Fig 1. Illustration of colchicum taken from herbal of Mathiolus (1500-1577) (9). Description of this plant begins,
“Meadow saffron or eightbloom is the colchicum, which gets its name from the place Colchis. It is also called Ephemerum lethale and vulgo Bulbus agrestis. The apothecaries use the root for Hermodactyl, and make the pills called
Hermodactyls from it, and other purging medicine, which they give to the gouty arthritics, not without great error and
detriment to the patients. For these meadow saffrons are injurious and poisonous when used internally.” Mathiolus
expressed doubt concerning the identity of meadow saffron to the hermodactyl recommended by the ancients for treatment of gout.
ROD”
& BENEDEK
diet drinks.” However, some authorities,
The discovery of this remedy, dated by
such as Thomas Sydenham (1624-1689), the above, took place in 1770. Eau mtdieschewed the use of colchicum (hermodac- cinale was said to be capable of completely
tyl) , warning that overvigorous purgation purifying the blood, thus relieving obstrucmight only serve to stir u p the very hu- tions and congestions. It was particularly
mours which the physician was attempting recommended for gout, sciatica, scrofula,
to calm (1 1) . Because of these objections skin eruptions, and “generally all those
and concern about toxicity, this agent lost maladies resulting from a corruption of the
favor. Hermodactyl appears as one of 13 blood or humours, above all when these
ingredients of a purge mentioned in the have not become too chronic and when
first Pharmacopoea Londinensis (1618) nature is still strong enough to act con(12), but is absent in this formulary after jointly with the remedy.” The bulk of
1639 and did not regain official sanction dHusson’s book consists of correspondence
until 1788, when we find the following between the irregular practitioner-discoverpreparation:
er and a number of physicians and pharmacists, and of numerous letters from the
Oxymel of Meadow-Saffron
proverbial grateful patients who testified
Take of the fresh root of Meadow-saffron,
to the miraculous powers of Eau me‘dicinale
cut into thin slices, one ounce by weight.
in the relief of gouty paroxysms. It is clear,
Distilled vinegar one pint.
however, that d’Husson regarded his remeClarified Honey two pounds.
Macerate the root of Meadow-saffron, with the dy as a panacea.
vinegar, i n a glass vessel, with a gentle heat, for
In 1810, Dr. E. G. Jones recounted the
forty-eight hours. Strain the liquor, pressed out history of a patient “whose sufferings in
strongly from the root, and add the honey. Lastly, gout have scarcely ever been exceeded, and
boil the mixture, frequently stirring it with a
which, beginning at an early period of his
wooden spoon, to the thickness of a syrup (13).
life, had nearly deprived him of the use of
I n 1763 Baron von Storck recommended his limbs” (16). During the summer of
this prescription of L de Colchico not for 1808, this gentleman, then residing in Enggout, but for dropsy and a number of other land, sustained a severe seizure of gout and
determined to try Eau me‘dicinale:
nonrheumatic complaints (14) .
Ultimate recognition of the competency As the pain and other symptoms portended a severe
of colchicine centers about a fascinating fit, he ventured to take the full dose. It produced
concoction known as Eau mtdicinale. In a all the good effects that could be hoped for; a
volume published in 1783, the composition speedy cessation of pain, and the entire removal of
of this nostrum, which was originally the paroxysm, within forty-eight hours. T h e success
was obtained without any further disturbance than
prepared by a former French army officer a considerable nausea, which came on in about
Nicholas dHusson, is described as follows:
seven hours after the medicine was taken, and
lasted, gradually decreasing, two days (16).
The Eau tne‘dicinale is the extract of a botanical the
properties of which have been ignored by the
ancients as well as by modern authorities. This
discovery was made 13 years ago: since that time
experience has continued to prove its efficacy and
utility (15).
Similar benefits were afterwards obtained
by a number of “persons of considerable
rank and consequence,” and the fame of
the remedy quickly spread among the Eng-
148
Arthritis and Rheumatism, Vol. 13, No. 2 (March-April 1970)
EARLY HISTORY OF ANTIRHEUMATIC DRUGS
lish. I n 1811, Ring noted that “the Eau
Medicinale swallows up all other remedies
for the gout, as the rod of Aaron swallowed
up the rods of the magicians”* (17).
There was a lively controversy concerning the composition of this cure. It was
variously conjectured to be a tincture of:
gratiola, white hellebore (combined with
Sydenham’s laudanum) , fox glove, wild
cucumber, rhododendron, tobacco and
other plants both common and rare (18).
Ring made note of the account of hermodactyl by Alexander of Tralles and commented, prophetically, that “the bad
effects, as well as the good effects of this
medicine, were in some degree similar to
those produced by the celebrated nostrum
now in vogue, the Eau Medicinale” (17) .
Finally, in 1814 we find the announcement that Mr. John Want, Surgeon to the
Northern Dispensary of London? has determined the chief ingredient of Eau mkdicinale to be none other than the hermodactyl or root of the meadow saffron, C autumnale:
Journal goes on to record that Want had
used this preparation in “at least FORTY
cases, followed by results of the most satisfying nature . . .” Dr. Thomas Sutton’s
rejoinder that Want had done little more
than resurrect an abandoned purgative and
had failed to establish its identity with the
French medicine (ZO), evoked a riposte
from the offended surgeon:
The assertion that all purgatives will cure gout, is
so obviously unsupported by common experience,
that our readers will scarcely require its refutation:
and it only remains for me to show, that the
curative powers of the colchicum autumnale are
quite unconnected with its purgative operation.
Upon this I may observe, that in many cases it
removes the paroxysm of gout without any sensible
operation of any kind. This fact is very notorious. If
Dr. S. requires the proof of it, I may instance
(among many others) the case of the illustrious
President of the Royal Society, [Sir Joseph Banks]
long known to have been a martyr to the disease
(21) *
The author of this unsigned communication in the London Medical and Physical
I n describing his discovery, Want indicated that he was led to the choice of
colchicum by his study oE the writings of
Alexander of Tralles, and he claimed that
the identity of tincture of colchicum and
Eau mtdicinale were established by the
testimony of patients who had taken both
medicines. A letter published in the London Medical and Physical Journal, and
hitherto neglected, casts strong doubt upon
the ingenuousness of Mr. Want’s. explanation. This communication, addressed to Dr.
Sutton and signed “An occasional Visitor
of the Society,” reads, in part, as follows:
*Numbers 17: 6-8.
+We have been able to learn very little about
Want, despite extensive search. He was admitted
a Member of the Royal College of Surgeons of England in 1809, and his name last appears in the lists
of the College in 1821. (Personal communication
from W. R. LeFanu, Librarian of the Royal College
of Surgeons of England, June 7, 1967.)
On perusing Mr. Want’s answer to your remarks
upon the preparation of a medicine which he
conceives to be the true eau medicinale, he says, he
is perfectly convinced, from the united testimony of
several distinguished literary characters, that the
two compositions are identically the same. Mr.
Want needed not their testimony, if he had ac-
Arthritis and Rheumatism, Vol. 13, No. 2 (March-April 1970)
149
He directed a tincture to be made by infusing for
two or three days, a quantity of the fresh-sliced
root of Colchicum autumnale, in proof spirits of
wine, in the proportion of four ounces of the
Mr. W. purchased
former to eight of the latter
the root a t Butler’s, in Convent Garden, but it may
be procured at all the physical herb shops, and
under the vulgar name of meadow saflron may be
found in every part of England (19).
...
RODNAN 81 BENEDEK
knowledged the having obtained a specimen of thc
plant from which the French remedy was prepared
it having been given him by the housekeeper of
the preparer or vender of that medicine, during his
attendance upon her. This, I think, is conclusive, as
to the identity of the two remedies (22).
.. .
In a footnote to this embarrassing
document, the editor (perhaps Mr. Want,
who served in this post for a period) noted
that “The answer to Dr. S. and his anonymous informant is in the hands of the
printer; but it has been thought adviseable
to defer it, on account of the pressure of
matter more interesting to the proEession
than controversial squabbles.” If this “answer’’ dicl in fact appear, it has eluded
discovery.
I n the first edition (1816) of a text
which was destined to exert great influence, Scudamore (who later claimed that
he was the first to have prescribed C nutzimnale under that name) included mention of an acetic acid extract of colchicum
in a purge (23). Scudamore was confused
about the identity of hermodactyl. He dismissed Eau me‘dicinale (which he had attempted to analyze) as a “baneful nostrum” of uncertain composition, whose advocates were “lovers of quackery, or impatient of the rules of regular treatment”
(23). He considered Eau me‘dicinale to be
“the fruitful source of many cases of chronic gout; by enfeebling the nervous system;
and occasioning, along with irregular pain
and obscure inflammation, a degree of
despondency and languor never before experienced” (23). He also held it responsible for retrocedent gout, by virtue of its
interference with external (articular)
symptoms of the gout which led to a
dangerous retreat of the inflammation into
one or another internal organs, including
the stomach, heart or brain (23) .
150
Eau me‘dicinale quickly lost groud after
Want’s “discovery,” being replaced in p o p
ular favor by one or another of the extracts
of colchicum, which soon came to be regarded as a sovereign remedy for the gout.
This drug was endorsed by no less’noble a
personage than the Prince Regent (later
King George IV) . Sir Astley Cooper, who
attended the royal victim, noted that:
He [George IV] was a good judge of the medicine
which would best suit him. He bore enormous
doses of opiates-one hundred drops of laudanum,
for instance, In bleeding, also, I have known from
twenty to twenty-five ounces taken from him several times. . . He suffered much from rheumatism
and gout, but the colchicum relieved him.
One
morning [in 18171 when he had rheumatism in his
hip, and there was a doubt about the propriety of
giving colchicum, he said, ‘Gentlemen, I have borne
your half-measures long enough to please you-now
t will please myself, and take colchicum,’ which he
dicl, and was soon relieved (24).
.
...
I t is more than likely that Louis XVIII
of France, George’s friend and fellow goutsufferer, also modified his original preference for the Eau me‘dicinale (Fig 2 ) . T h e
Reverend Sydney Smith, the celebrated wit,
yet another martyr to “that toe-consuming
tyrant,” also became an ardent advocate of
colchicum:
On observing some of the autumn crocus in
flower he [Sydney Smith] stopped: ‘There!’ he
said, ‘who would guess the virtue of that little
plant?’ But I find the power of colchicum so great,
that if I feel a little gout coming on, I go into the
garden, and hold out my toe to that plant, and it
gets well directly. I never do more without orders
from head-quarters. Oh1 when I have the gout, I
feel as if I was walking on my eycballs (25)
.
T h e introduction of colchicum into the
United States is well reviewed by Wallace
(26), who notes that Clark, a medical stu-
Arthritis and Rheumatism, Vol. 13, No. 2 (March-April 1970)
Fig 2. Detail from engraving entitled Preparing for War [with Napoleon], by George Cruikshank, published by M. Jones, London, June 1, 1815. Napoleon had
escaped from Elba and landed in France on March 1. Less than 3 weeks after the appearance of this cartoon, he met decisive defeat at Waterloo (June 18). The portly
gentleman on the throne is George, Prince Regent of England, (later George IV) giving orders for “a brilliant Fete” which will include “lacivious Mistresses & Bachanalian orgies-to it Pel1 Mell-my soul is eager for the fierce encounter.” Astride the clubfooted horse (laleyrand)
sits Louis XVlll of France, who had fled to Ghent
upon Napoleon’s return. He speaks: “Well-we’re Tally for the Feild rsicl tomorrow! but don’t forget the Eau Medicinal & the Fleecy hosiery-alass these gouty
limbs are but ill adapted to jack boots & spurs, I think I had better fight my battles over a cool bottle with my friend George.”
RODWAW 81 BEWEDEK
dent, published extracts OE a dissertation
on Eau mtdicinale and colchicum in 1818
(27). He concluded, as had Want, that the
two substances had similar effects, and
referred to the benefits of colchicum in
gout obtained by his preceptor, Dr. John
Syng Dorsey. PellCtier and Caventou isolated the active principle from the colchicum corm in 1820 (28). Geiger (1833)
determined this to be an alkaloid and proposed the name colchicine (29). T h e first
official Pharmacopeia of the United States,
1820, contained directions for preparation
of the wine and syrup of colchicum (30),
and, in both the fourth edition of the
American New Dispensatoiy (182 1) (31)
and the third edition of the Dispensatory
of the United States of America (1839)
(32) the drug is highly recommended for
the treatment of gout.
SALICYLATES
The remote history of salicin, the natural glycoside from which salicylic acid may
be extracted, is obscure. It occurs in various plants, but in greatest concentration in
the bark of the willow (Salix) and the
poplar. Dioscorides seems to have been
familiar with its analgesic quality, for he
wrote in his herbal: “The leaves [of the
willow] being beaten small and dranck
with a little pepper and wine doe help such
as are troubled with the Iliaca Passio [colic]
The decoction of ye leaves and
barck is an excellent fomentation for ye
Gout.. (33).
Among several virtues of the willow
listed by Dodoens, we find the following
reference to its antirheumatic properties:
“The leaves and rinds of Withy boiled in
wine, do appease the paine of the sinuwes,
and do restore againe their strength, if they
...
.
152
be nourished with the fomentation of natural heat thereof (34).
Various preparations of willow bark
have been used as folk remedies in many
parts of the world. This fact is nicely substantiated in a letter from a physician in
rural South Africa to the editor of Lancet
in 1876. He described the case of a woman
who was
..
. in the cruel bonds of as fierce an attack of
rheumatic fever as I ever saw . I prescribed the
usual alkaline mixture, with calomel and Dover’s
powder a t bedtime, and rode away. Some two
months after, my former patient entered my surgery, looking remarkably well, and I very naturally
congratulated myself and her that she had recovered so completely. 1 was quite taken aback when
she bluntly told me that my physic hadn’t helped
her a bit. On inquiring what had helped her, she
said that the old Hottentot shepherd had made her
a decoction of the shoots of the willows which grow
on the banks of the river, and after taking this for a
(35).
few days she began to get better.
. .
..
Interest in salicin developed slowly, and
for well over a century its use remained
intertwined with that of Peruvian bark-ie,
quinine. In 1763 The Reverend Mr. Stone
wrote to the Royal Society about his discovery of the effects of white willow bark:
About six years ago I accidentally tested it and
was surprised a t its extraordinary bitterness: which
immediately raised me a suspicion of its having the
properties of the Peruvian bark. As this tree
delights in a moist or wet soil, where agues chiefly
abound, the general maxim, that many natural
maladies carry their cures along with them, or that
remedies lie not far from their causes, was so very
apposite to this particular case, that I could not
help applying it (36).
He dried the bark, pounded it into powder, and administered it, usually in a dose
of 40 gr every 4 hr. “It hath been given I
believe to fifty persons, and never failed in
Arthritis and Rheumatism, Vol. 13, No. 2 (March-April 1970)
EARLY HISTORY OF ANTIRHEUMATIC DRUGS
the cure, except in a few autumnal and
quartan agues with which the patients had
been long and severely afflicted
H. Leroux, a French pharmacist, isolated salicin in a pure state in 1829. Shortly
thereafter R. Piria, an Italian chemist,
prepared salicylic acid from this glycoside.
J. Pagenstecher, a Swiss pharmacist, extracted salicylaldehyde by distilling the
flowers of Spirea ulmaria, a shrub of the
rose family. He conveyed this information
to K. J. Lowig, a German chemist, who in
1835 obtained salicylic acid by oxidation of
the distilled aldehyde. Because of its vegetable source he called the acid “spirsaure.”
Acetyl salicylic acid was first synthesized by
C. Gerhardt, a French chemist, in 1853, but
it was many years before its pharmacologic
qualities were recognized (37).
Salicin enjoyed scattered use from about
1830, largely as a substitute for quinine
(38). I n 1874 two German chemists, H.
Kolbe and E. Lautemann, devised a practical method for the commercial production
of salicylic acid. This coincided with the
clinical study of salicin by T. J. MacLagan
of Edinburgh (39), and in the following
three years salicin, salicylic acid, and sodium
salicylate rapidly came into widespread
use.
MacLagan claimed that his use of salicin in the teatment of “acute rheumatism”
(rheumatic fever) was “no haphazard experiment, but had a fair foundation in
reason and analogy.” The analogy, however, resembled that employed by The Reverend Stone, to wit: rheumatic fever and
malaria both have a “miasmatic origin.”
Since quinine comes from regions in which
malaria is prevalent, a cure for rheumatic
fevef might be found in a miasmatic region
in which this disease is prevalent* The
willow seemed to fit these specifications,
and a preparation of it was available. “SaIicin has long enjoyed a reputation for tonic
and febrifuge properties, and was at one
time a good deal used as a substitute for
quinine. It has of late years, however, gone
very much out of use, and now does not
even find a place in the British Pharmacopeia” (39). Although MacLagan and a
few others defended the superiority of salicin, especially its greater palatability, it was
rapidly replaced by the far cheaper synthetic salicylic acid.#
Four months before the appearance of
MacLagan’s first publication extolling the
virtues of salicin, L. Riess from Berlin
reported his observations on the antipyretic
properties of salicylic acid in a group of
over 400 patients, mainly cases of typhoid
fever. Describing his first use of sodium
salicylate, he wrote:
Arthritis and Rheumatism, Vol. 13, No. 2 (March-April 1970)
153
...”
1
”
Y
The ingestion of salicylic acid as such is not at all
pleasant, whether it is administered suspended in
an aqueous vehicle, or in an alcoholic solution
Therefore, based on the supposition that salicylic acid enters the blood as sodium salt, I soon tried
the administration of sodium salicylate, and found
the effect of this almost identical with that of the
free acid.
Since the ingestion of this medicine in
an aqueous solution is in most cases not disagreeable I continued to use it
usually in the formula:
5.0
Salicylic acid
Sodium phosphate
10.0
Aqua dest
50.0
in most cases doses of 5 ccm. are best (41).
...
...
...
.. .
Soon after, Riess, who employed sodium
salicylate (42), and Stricker, who used salicylic acid (43) independently reported on
the analgesic effect of these drugs, mainly
in the treatment of acute rheumatic fever.
Stricker expressed doubt about the value of
salicylic acid in rheumatoid arthritis and
*Wholesale prices in London, Jan 1877: quinine
11 shillings/oz; sa~icy~ic
acid 1 shilling/oz; sodium
salicylate 1 shilling 3 pence/oz (40).
RODNAN & BENEDEK
found it ineffective in gonorrheal arthritis.
Riess and Stricker were chiefly responsible for the introduction of salicylate therapy in Germany, and T. J. MacLagan and
W. H. Broadbent in England. I n France,
this distinction belonged to Germain See,
who confirmed the value of this medication
in treating rheumatic fever, and appears to
have been the first to note its efficacy in the
treatment of rheumatoid arthritis (44) :
In the case of the common chronic rheumatism, the
trials which I have instituted are most gratifying;
the painful attacks abate as quickly as in acute
rheumatism. In addition the joint swelling diminishes considerably, and motion is improved, even
after years of pain, stiffness and immobility,
provided that the bony involvement is not too
advanced (12 studies of chronic rheumatism cured
or improved).
SCe was even more favorably impressed by
the response of gout to salicylate:
But it is in acute and chronic gout that the
results are the most remarkable: in my initial
experience I was struck by the promptness with
which the most painful acute paroxysms were
checked; in the space of 2 to 3 days the pain, joint
swelling, redness and tenderness all disappeared.
Chronic gout also yields to the application of
salicylates. With the continued use of this treatment, in only moderate doses, the patients are
protected from acute attacks.
Of additional interest, the chronic periarticular
swelling quickly disappears, the articular tophi
diminish and cease to be inflamed; in a word the
cure can be complete.
..
SCe prescribed large amounts of sodium
salicylate (8-10 g/day) ,and he encountered
the resultant symptoms of salicylism. These
diminished when the dose was reduced to 4
or 5 glday.
His report evoked the following editorial
in the British Medical Journal:
As soon as his report that was read before the
Academy of Medicine was published, he was literally assailed by .rheumatic and gouty patients, who
154
came from all parts of the country to consult him.
M. Ske has made a good thing of it; for I am told
that a gouty old gentleman, who was one of the first
to apply to him for advice, had to put down ZOO0
francs, or f80, for the consultation. As may be
imagined, the phnrnzaciens are also making a good
harvest, and they offer the new remedy to the
public in every variety of form as a panacea for the
affections for which they are and are not indicated;
but an unwitting public, easily gulled, soon find to
their cost that not only they have not been cured,
but, terrified by some of the disagreeable symptoms
produced by the medicine, give it up without
allowing it a fair trial, and thus throw discredit on
a remedy which, if properly an1 intelligently employed, may be looked upon almost as a specific
failures are
treatment of gout and rheumatism
owing most probably to the timidity with which
certain practitioners have prescribed it; for, to be
effective, it must be administered in sufficiently
large doses: four to six grammes (60 to 90 grains) a
day of salicylic acid, or eight to ten grammes (120
to 150 grains) of the salicylate of soda. He gives a
(45).
decided preference to the latter
.. .
...
A monograph by Campbell (1879), entitled The Salicylic Treatment of Gout,
Rheumatic Gout, Neuralgia and Diabetes,
was the first English report of the use of
salicylate to’treat diseases other than rheumatic fever (46). I n respect to the first three
conditions cited i n the title, the author
quoted enthusiastically from See. He advocated the use of lithium salicylate, which
he believed caused fewer side effects than
the sodium salt. Nevertheless, the advisability of salicylate therapy was accepted far
more slowly for gout than for other diseases.
Authorities such as Duckworth (1889)
(47) and Minkowski (1903) (48) continued to oppose its use in this condition.
I n the 1870s the concept that pyrexia
was a disease in itself, rather than a symp
tom, was only beginning to be discredited,
and the study of fever was receiving
renewed interest due to the introduction of
practical
clinical thermometry.
The
Arthritis and Rheumatism, Vol. 13, No. 2 (March-April 1970)
EARLY HISTORY OF ANTIRHEUMATIC DRUGS
fledgling pharmaceutical industry, having thrown Onto the markct almost every day, and one
produced the first drug
was both an needs a marvelous memory if one wants to remember all of the new names. ,Many pop up, are praised
proceed- and recommended by a few authors, and especially
effective antipyretic and
ed to search for more and better
bv the manufacturers, and after a short time one
quinine still being the standard of compari- hears no more of them.
When nearly a year ago, I received from Friedrich
son. It seems peculiar now, in view of the
frequency of gastric intolerance to sodium Bayer & Co. in Elberfeld a new salicylate preparasalicylate, that few attempts were made to tion to try out, I therefore approached its use with
a not inconsiderable skepticism. T h e new medicafind other salicylate compounds for inter- tion, named aspirin . . .
nal use, and that the value of acetyl salicylic acid as a pharmaceutical was discovered Witthauer concluded:
only fortuitously. T h e circumstances of this
Due to my favorable experiences the manufacturhappenstance are revealed in a letter to er, after long hesitation, has decided to introduce
the author of a book on the history of aspirin forthwith. I only hope that the difficult
chemical engineering, the substance of production method will not result in too high a
price, so that this medication, which I consider
which he included in a footnote:
valuable, can come into general use (50).
According to a personal communication from
Felix Hofmann (I.C. Farbenfabriken of BayerElberfeld) to the author, the fortuitous cause for
the introduction of acetyl salicylic acid was the
request by his arthritic father for salicylic acid in a
form which would not induce vomiting, because
after prolonged use he could no longer tolerate it.
Thereupon, F. H. searched through neglected
preparations of salicylate derivates which had been
synthesized for other purposes long ago and had
them tested. Thus acetyl salicylic acid, aspirin,* was
chanced upon (49).
Unfortunately, we have no information
about the tests which led Hofmann, who
was a chemist, to try this particular preparation. Nevertheless in 1898, the company
was sufficiently impressed to consign samples of it to various physicians. The first of
these to publish his findings was Witthauer, who administered a dose of 1 g
mixed with powdered sugar and a teaspoon
of water 4 or 5 timeslday. Most of the 50
patients had rheumatic fever, gout and
pleurisy. His article begins:
T h e first American study of aspirin, by
Floeckinger, also yielded favorable results
(51) . Initially, this investigator administered the drug in an alcoholic solution, and
when gastric irritation occurred, he concluded that this was due not to the aspirin
but to its vehicle. Subsequently, he “administered aspirin in wafers in 15 grain doses”
without side effects, and “in all cases of
acute and chronic muscular rheumatism the
remedy proved extremely serviceable
.”
Five years later, Burnet reported on 200
patients he had treated with aspirin, summarizing the status of its usefulness as rheumatologic therapy: “The treatment of rheumatism is now universally standardized,
salicin, or some other of the salicyl compounds, as they are termed, being employed in every case” (52).
..
The Effect of Salicylate on Uric Acid
Excretion
Nowadays a certain amount of courage is required to recommend a new medicine. They are
In his reports in 1877, See noted that the
daily administration of 8-10 g sodium
*The term “aspirin” was derived as follows: A salicylate to patients with gravel led to a
(acetyl) + SPIR (Spirea, from which Spirdure or
salicylic acid was prepared by Lowig) + I N (suffix). marked increase in uric acid excretion,
Arthritis and Rheumatism, Vol. 13, No. 2 (March-April 1970)
155
RODNAN 81 BWEDEK
*For more than 40 years, uric acid was measured
by various modifications of a gravimetric technic
introduced by Salkowski in 1871. which depended
on the precipitation of silver urate (54,55). This
method gave acceptably reproducible results with
urine and the quantities reported are of the proper
order of magnitude. However, it did not detect any
urate in the blood of normal individuals and yielded variable results in patients who could be expected to be hyperuricemic (56). These technics
were replaced in 1913 by the colorimetric procedures of Folin and Denis, which were based on the
chromogenic reaction between uric acid and phosphotungstic acid (57,58). These latter were less
specific, but far more sensitive and easier to perform
than the gravimetric methods.
the paradoxical effect of small doses of
salicylate on urate excretion was reported
in 1900 by Goodbody (61), who equivocated, however, by stating that “ . . . the
slight decrease, noticed during A’s second
period, when a small quantity of sodium
salicylate was taken, might either be due to
the normal fluctuations tending that way,
or that a small quantity of sodium salicylate
has no action in increased uric acid output.” The subject, who had a “tendency
to gravel,” was maintained on a constant
diet and fluid intake. T h e mean uric acid
excretion during the 4 days he took 1.0
g/day sodium salicylate was 10% less than
that of the preceding 6-day control period.
Subsequently, he was given 2.0 g/day for 9
days, and his mean excretion was then 377,
greater than it had been during the control
period.
Ulrici (1901) (62), in experiments on
himself, observed that a mean dose of 4
g/day sodium salicylate for 3 days resulted
in seven times as great an increase in
urinary urate as in total nitrogen excretion. He concluded that increased catabolism could not explain the uricosuric effect,
and that “one must assume in addition also
a very specific effect of salicylic acid on the
factors which determine the magnitude of
urate excretion.” Nevertheless, he did not
discuss the role of the kidneys in uricosuria.
T h e first investigator who attempted to
explain uricosuria on a renal basis was
Denis (1915) (63). With his recently developed analytic method, he showed that
the administration of 7 g/day sodium salicylate not only caused urinary uric acid
concentration to increase, but blood urate
content to diminish. Although the concept
of renal clearance had not yet been developed, Denis concluded that “. . the
increased output of uric acid following
salicylate medication is clearly due to a
156
Arthritis and Rheumatism, Vol. 13, No. 2 (March-April i970)
which was not simply related to diuresis.
“Sometimes one can detect as much as 11/*
to 3 grams of uric acid per liter of urine.
Furthermore, salicylic acid, by being partially transformed in the body to salicyluric
acid, provides another advantage . . .”
-
(53)
See cited no details of his studies, and his
report led to a controversy concerning the
uricosuric properties of salicylates, which
took decades to resolve. This dispute resulted from a lack of recognition of the
relationship between salicylate dosage and
urate excretion, as well as from deficiencies
in analytical technic.+ T h e first report pertaining to See’s observations about the uricosuric properties of salicylate contradicted
his conclusions. Marrot (1879) (59) noted
a transient diuretic effect and reduced excretion of uric acid in patients with rheumatic fever who were given 2.4-4.0 g/day
sodium salicylate. I n patients with rheumatoid arthritis, no effect of salicylate on
urate excretion was found. A year later,
Lecorche and Talamon confirmed Ste’s
finding (60). Administering 2-8 g/day sodium salicylate to patients with rheumatic
fever, these authors observed that the uricosuric effect was greatest on the first day,
when urate excretion doubled, and then
diminished rapidly.
T h e first experimental demonstration of
.
EARLY HISTORY OF AMTIRHEUMATIC DRUGS
rine (42 articles) and kairin (34 articles)
(68) . Chemical investigations soon demonstrated that antipyrine did not contain the
quinoline nucleus, but rather a pyrazolone
and a benzene ring. The search continuedNONSALICYLATE ANALGESICS
for febrifuges rather than analgesics, but
Subsequent pharmacetical investigations from then on investigators concentrated on
of antipyretic drugs were carried out more phenolic and pyrazolone compounds.
T h e analgesic effect of antipyrine was
systematically than those which had dealt
with salicylates. Although these investiga- soon recognized. Since it and the previously
tions also began with quinine, they were cited drugs were being introduced primaribased, at least, on fragmentary chemical ly for treatment of fevers, the best opportuinformation, rather than obscure analogy. nity to observe their analgesic properties
Quinoline had been synthesized in 1879 by was afforded by a febrile, painful disease.
Wilhelm Koenigs and was found to be a Most of the initial observations, therefore,
weak antipyretic, similar to quinine. An- pertained to cases of acute rheumatic fever.
other German chemist, Otto Fischer, erro- For instance, Guttman (69) wrote in 1885:
neously assumed that a portion of the Among the acute diseases I would like to mention
quinine molecule was a hydrated quino- acute rheumatic fever, in which quite apart from its
line, and that derivatives of quinoline antipyretic action, antipyrine exerts a favorable
could be synthesized which would not only effect. In one case, 24 hours after a 5 gr. dose of
be more powerful antipyretics, but also antipyrine the pain had entirely disappeared from
all affected joints and active movement of these was
cheaper than quinine. Accordingly, he syn- reestablished. According to some of my experiences
thesized a substance called “kairin” (1882) , this medication also seems worth trying in chronic
which was the first synthetic alkaloid and articular rheumatism.
the first antipyretic agent produced ac- Davis (1887) (70), in the first American
cording to a pharmacologic plan. Kairin clinical article on antipyrine, reviewed the
and thallin, the latter produced by Skraup, extensive physiologic studies that already
were the most extensively used of the severhad been performed, as well as his own
al quinoline derivatives synthesized be- experience and concluded:
tween 1882 and 1885. Both suppressed fever very effectively, but they caused severe It is as efficacious as the salicylate of soda, producchills and sometimes shock, and hence, ing similar therapeutic results, and is less nauseous
than the latter, and does not produce headache or
were soon abandoned (64-66).
ringing of the ears. Besides reducing, by its antipyIn 1884, Ludwig Knorr synthesized an- retic properties, the fever, and also the pain, which
other substance, which he also believed to many antipyretics relieve, it reduces the pain by
be a quinoline, and called it “dimethyl- acting directly upon the nervous system.
oxychinizin” (67). It was introduced into
The p-aminophenols, a new class of anclinical practice the same year under the tipyretics which also proved to be analname antipyrine, and its acceptance proba- gesics, were next introduced. The first of
bly was more responsible for the disappear- these was acetanilide (Antifebrin) which
ance of the aformentioned quinolines than became available in 1886. I n the initial
was salicylate. I n the Index Medicus for report we find: “In a case of acute rheumat1884 and 1885, the two most frequently ic fever Antifebrin effected prompt dimincited nonsalicylate antipyretics were antipy- ution of the severe joint pain and the
lowered threshold value of the kidney, not
only for uric acid, but in all probability for
other waste products as well.”
Mhritis and Rheumatism, Vol. 13, No. 2 (March-April 1970)
157
RODNAN & BENEDEK
fever” (71). I n the following year acetophenetidin (phenacetin), which is p-ethoxyacetanilide, was introduced (72). Both of
these drugs gained rapid acceptance, thereby stimulating a methodical investigation
of substituted p-aminophenols in the hope
of obtaining even more potent agents of, at
least, similar safety (73). Among those
tested was p-hydroxyacetanilide (acetaminophen), but it was discarded because
..
it elicits the same side effects as p-aminophenol, even though more weakly, so that
its medical use, despite prompt antipyretic
and analgesic action, also does not recommend itself” (74). T h e conclusion of this
investigation was that no single drug comparable to phenacetin could be found.
However, two agents which were combinations of p-aminophenol and urethane, were
deemed significantly superior in part:
“Neurodln” (acetyl-p-oxyphenylurethane)
being a more effective analgesic and “Thermodin” (acetyl-p-ethoxyphenylurethane) an
antipyretic. Neither of these drugs became
popular. Acetaminophen remained in discard until it was reinvestigated in 1948 (75,
76); and it has been in clinical use since
about 1956 (77).
Aminopyrine (Pyramidon), which is dimethylaminoantipyrine, was introduced in
1896 (78). I t came to be considered more
effective than its parent compound both as
an antipyretic and an analgesic, gradually
replacing the latter in practice. For 40
years, aminopyrine remained one of the
major analgesics, especially in Europe. I n
the treatment of rheumatic diseases, it was
advocated particularly for acute rheumatic
fever. After 1934, its general use declined
because of its increasing incrimination in
the production of agranulocytosis (79) .
Aminopyrine is quite insoluble. In order
to develop a parenteral preparation, an
agent which would increase its solubility
was sought. This investigation led to the
synthesis of another pyrazolone compound,
which was marketed in 1949 in a 1:l mixture with aminopyrine under the name
Irgapyrine (80). Because of favorable reports of the antirheumatic efficacy of this
preparation, the new drug was introduced
by itself in 1952 under the name phenylbutazone. This compound and bwo of its
metabolites (sulfinpyrazone, introduced in
1957, and oxyphenbutazone, introduced in
1958) are the only pyrazolone derivatives
now iv general clinical use. Sulfinpyrazone,
which is more rapidly excreted than the
other two drugs, is not an analgesic and is
employed because of its potent uricosuric
effect. I t appears to lack the toxic potentialities of the parent compound, the most
important of which are the partial or total
depression of hemopoeisis (81).
158
Arthritis and Rheumatism, Vol. 13.. No,2 (March-April 1970)
‘ I .
GOLD SALTS
The introduction of gold compounds
into the rheumatologic pharmacopeia was
a result of a sequence of singularly unscientific hypotheses, and an explanation of the
beneficial effects of these substances in the
treatment of rheumatoid arthritis remains
obscure. T h e story begins with a lecture by
Robert Koch at an international medical
congress in 1890, wherein he recounted
some of his investigations of the tubercle
bacillus, which he had discovered, in 1882
(82)
-
During the course of time I have tested a very
large number of substances for their effect on pure
cultures of tubercle bacilli, and it has been found
that not a few substances are capable, even in very
especially
low dosage, to inhibit their growth
noteworthy were the gold cyanide compounds,
because they were far more effective than any other
substances; they inhibit the growth of tubercle
bacilli even in a dilution of 1 to 2 million.
However, all of these substances were completely
ineffective when they were tried in tuberculous
animals.
...
EARLY HISTORY OF ANTIRHEUMATIC DRUGS
Koch did not state why he chose this reported on his use of aurothioglucose
particular salt of gold, or whether he con- (Solganal*) to treat 39 patients with bacsidered the possibility that the effect might terial endocarditis and various, poorly
have been due to the cyanide radicle. No defined diseases, which in most cases a p
further reports appeared until 1913, when pear to have been rheumatic fever. Land6
Bruck and Gliick (83) reported on the was particularly impressed by the relief of
response of lupus vulgaris, and Junker joint pain which was achieved, and he
(84) on that of pulmonary tuberculosis to concluded that
. . one may say that a
the intravenous administration of potassi- trial of Solganal is worthwhile in chronicalum auricyanide. The former authors had ly febrile cases of painful arthritis resistant
determined before their clinical trial that to the usual treatment.”
injection of 15 mg/kg/day of this comLand6’s report was followed by the piopound was lethal to: rabbits, but that 1 neering clinical studies of J. Forestier, who
mg/kg/day for 15 days was well tolerated. in 1928 began to use gold-thiopropanol
Thereupon, they established a clinical dos- sodium sulfonate (Allochrysine) in the
age of 20-50 mg every 2-3 days for adults treatment of rheumatoid arthritis (87). Reand 5-30 mg for children. I n the same year, viewing his experience with over 550 cases
Feldt published studies of the same com- in 1935, he expressed this rationale:
pound as well as studies of a complex If gold salts are active in a chronic disease like
of cantharidin-ethylenediamine-aurocyanide human tuberculosis, why should they not be active
(Aurocantan) in guinea pigs and rabbits in another chronic disease in which an important
(85). He concluded that it was the gold infectious factor seems to be present? If our hyrather than the cyanide that affected the pothesis were true, it should soon be demonstrable
microorganisms in the concentrations used. that gold salts are active in true rheumatoid
arthritis and in all forms of infective arthritis . . .
Furthermore, contrary to Koch, Feldt ob- (88)
served beneficial effects and continued to
Gold therapy was introduced in the
search for more effective antituberculous
United
States with extraordinary hesitancy
gold compounds. The first clinical applica(89).
Most
of the initial reports were
tion of any of these (gold sodium thiosulof
rheumatoid
arthritis, osteoarthritis, as
fate, Sanochrysine) was reported in 1924 by
well
as
infectious
arthritis; and various gold
H. Mollgaard, a Danish veterinarian who
compounds
were
administered in varying
was studying bovine tuberculosis. I n the
schedules,
either
intramuscularly or innext 5 years, the Acta Tuberculosea Scandtravenously.
Forestier
(90) reported benefiinavica alone carried 32 reports on chrysocial
results
in
42%
of
36 patients with
therapy. These confirmed the beneficial
ankylosing
spondylitis.
However,
despite
effect of several gold compounds in the
the
lack
of
any
systematic
clinical
evaluatreatment of tuberculosis.
tion, the impression was generally accepted
The first attempt to use a gold comthat gold therapy is less effective and more
pound in the treatment of a nontubercudangerous in the treatment of ankylosing
lous disease was reported by Land6 in 1927
spondylitis than in rheumatoid arthritis.
(86). His hypothesis was: gold has a nonAfter a decade of conflicting clinical respecific antiseptic effect; the main problem
ports about the value of chrysotherapy in
was to discover a compound which would
treating rheumatoid arthritis, Sir Stanley
be sufficiently well tolerated. Thus, without
presenting any laboratory investigations, he
+&hering Corp, Bloomfield, NJ.
‘ I .
Arthritis and Rheumatism, Vol. 13, No. 2 (March-April 1970)
159
ROD“
Davidson of the Empire Rheumatism Council began in 1938 to plan a multicenter study
of this question in which the double-blind
technic was to be employed (91) . This project, however, was deferred because of the
war, and Fraser (92) in Glasgow became the
first to conduct such a trial (1944). I n this
study, 1 group of subjects received 13 weekly injections of sodium aurothiomalate
(Myochrisin+) or a total dose of 1 g, while
a control group received injections of the
vehicle. Clinical improvement was observed in 82% of the 57 treated and in 45y0
of the 46 control subjects.
T w o attempts to assess chrysotherapy objectively preceded Fraser’s trial. T h e first
investigation, in which both the course of
treatment and the diagnostic and therapeutic criteria were standardized, was published by Snyder in 1939 (93). This study
revealed some improvement i n 48% of 50
patients with rheumatoid arthritis, in 45y0
of 20 patients with osteoarthritis, and in
26y0 of 30 patients with “mixed arthritis.”
I n the following year, Ellman (94) reported a more elaborate investigation. T h e
subjects were 90 patients with rheumatoid
arthritis who were assigned to 3 groups
after being matched according to age and
duration o€ disease. Group 1 received
0.2-0.3 g/week aurothioglucose intramuscularly; Group 2 received 0.1 g/week;
Group 3 received only the vehicle. Two
equal courses interrupted by a 6 week
pause, were administered in 9 months. Although the greatest improvement occurred
in patients in Group 1, they also suffered
the most toxic effects. T h e results are obscured somewhat by the observation that 23
of the 30 control subjects also improved.
I n 1957, the Empire Rheumatism Council initiated its multicenter study which was
unique because the subjects were assessed
not only at the completion of the course of
+Merck Sharp & Dohme, West Point, Pa.
160
& BENEDEK
treatment, but also a t 18 and 30 months
thereafter (95). Ninety treatment and 95
control subjects began the investigation; 77
of the former and 82 of the latter were
available for the final evaluation. A total
dose of 1.0 g sodium aurothiomalate
(Myochrisin) was given in 20 weekly injections to patients in the treatment group,
while a dose of 0.01 mg was administered to
the control group. Neither the physicians
nor the subjects knew which preparation
was being employed. Significant clinical
improvement by all criteria, except radiographic appearance, was observed more
frequently among the treated patients.
This improvement tended to disappear during the final year of the evaluation. T h e
data, nevertheless, supported the impressions of many clinicians that chrysotherapy
is efficacious in many patients with rheumatoid arthritis, and if improvement occurs,
it tends to persist for a year or more after
therapy is concluded.
X-RAY THERAPY
T h e first application of roentgen rays for
diagnostic purposes by Jastrowitz in 1896
(96) was followed rapidly by attempts to
employ x-ray therapeutically. It is startling
now to read in an article of 1896 that “The
tubes which we use for these treatments
have a radiation of medium strength; for
economy we generally take those tubes
which no longer are satisfactory for photography” (97). There was uncertainty about
whether the same rays that produced photographs also exerted an influence on tissues,
or whether the latter effect was due merely
to the heat that was generated. I n this early
period, treatment with x-radiation was directed chiefly towards lupus vulgaris or
tuberculous adenitis. As early as 1897, however, an article appeared “On the cure of
articular rheumatism in children with
roentgen rays” (98) . This study pertained
Arthritis and Rheumatism, Vol. 13, No. 2 (March-April 1970)
EARLY HISTORY OF ANTIRHEUMATIC DRUGS
to 4 girls, one of whom had recurrent rheumatic fever, and 3 who may have had
rheumatoid arthritis. All were said to have
been relieved of pain, and contractures of
the knees improved in one.
I n 1905, Moser reported his experience
in the treatment of gout and rheumatoid
arthritis and concluded “Roentgen irradiation [is] a most effective treatment . . .
Roentgen irradiation should be considered
not only as an analgesic, but rather that it
affects the basic abnormality in both diseases . . .” (99). Nevertheless, x-ray therapy
of arthritis only became popular after 1925,
receiving particular impetus from the publications of Kahlmeter (100). Earlier reports are almost impossible to evaluate or
compare because of inadequate diagnostic
information and lack of technical data
about the quantity of radiation. The prevailing impression appears to have been that
acutely inflamed joints, particularly infected joints, were more likely to benefit from
irradiation than joints which were the seat
of some chronic process. Judging from the
numbers of publications, the use of radiation therapy for rheumatic diseases was
accepted only belatedly in the United
States, since virtually all descriptions before 1933 came from Europe, chiefly from
Germany and Sweden.
Most radiologists agreed that the antiphlogistic effect of x-ray therapy was exerted by an unknown and nonspecific
mechanism. The popularity of irradiation
decreased, in part, because of the introduction oE effective chemotherapy. Garland
(1935), for instance, treated 80 joints in 30
patients with gonorrheal arthritis achieving a “cure” in 30 and “improvement” in
45 joints (101). He had less success, with
other types of arthritis. Even if his report
and corroborating ones were correct, the
subsequent introduction of sulfanilamide
(1938), as well as other drugs specifically
Arthritis and Rheumatism, Vol. 13, No. 2 (March-April 1970)
effective against the gonococcus eliminated
the need for x-ray therapy.
Improvements in the technic of x-ray
therapy coincided with the introduction of
other new therapeutic modalities such as
gold. It is likely that the application of
chrysotherapy in the late 1930s had as
much or more to do with the decline of
x-ray therapy in the treatment of rheumatoid arthritis than any consensus about its
ineffectiveness in treating the disease.
Reports of a few cases of ankylosing
spondylitis were included in earlier publications about roentgen therapy oE arthritides; however, Kemen (1936) was the first
to report results in a sizeable group of
patients. He observed improvement in 87%
of 77 patients (102). The first extensive
American experience was published by
Smyth in 1941 confirming the previously
reported generally favorable results (103) .
Soon, agreement was reached that x-ray
therapy was the treatment of choice for
ankylosing spondylitis. Then, in 1948, Graham reported the occurrence oE leukemia
in 2 patients who had received x-irradiation (104). Between 1955 and 1960,
additional reports came from Holland, England, Canada, and the United States. All
of them confirmed the increased incidence
of leukemia, particularly of the myelogenous type in patients who had received x-ray
therapy for ankylosing spondylitis (105) .
This virtually ended the use of x-ray therapy for systemic rheumatic diseases.
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