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Drug s like penicillamine and gold have a distinctive action in rheum atoid arthritis. It
may be called 'specific' to distinguish it from the non- specific or symptomatic action
of anti-inflammatory drugs. Drugs of thi s type act slowly, benefit extra-articular
features of the disease as weil as the joints, reduce ESR and rheumatoid factor titre
and may slow the progression of X-ray changes and alter the outcome of the disease.
Their action is to some extent disease-dependant. Th e first choice of drug s of this
type is now penicillamine. It compares favourably with other drugs ofthe same type
including gold, azathioprine and levami sole. Great care and some ski11 are required
compound which was safe enough to be recommended for widespread use would take
over the role of'first line treatment ofrheumatoid arthritis.
which includes penicillamine. In occasional patients, thes e drugs induce aremission;
in man y the y provide suppression of the disease to a greater extent than can be
achieved with non -steroidal anti-inflammatory drugs. In a few the y do nothing. All
have adverse effects which relegate them to a secondary role in the management
programme. All demand skilIed and careful supervision.
Th e indications for treatment with penicillamine-like drugs are summarised in
Table I. The commonest type of pat ient is one who has failed to achieve adequate
control of symptoms with anti-inflammatory drugs. The disease is somewhat
unpredictable in the first few months and thi s decision should therefore.be delayed.
Patients who present with the most acute symptoms have the best prognosis and it is
changes have developed if the patient's full potential for recovery is to be achieved. It
is important to look out for the pat ient whose disea se is progressing. There ma y be
THERAPY FOR RHEUMATOID ARTHRITIS 299
clinical or radiological indications of this, the development of deformities or new
erosions for example. lt would be nice to predict which patients will develop these
problems but it is difficult, The prognosis in rheumatoid arthritis is a little worse in
young patients and in those who are strongly seropositive. Two minor indications for
penicillamine-like drugs are troublesorne extra-articular features like nodules and
Table 1 Indications for penicillarnine-Iikedrugs in rheumatoid arthritis
Persistentlyactive diseaseafter six months treatment with optimal anti-inflammatory
Progressive diseaseeither with developingdeformities, restriction ofjoint motion or new
Excessive requirement of corticosteroids.
Troublesome extra-articular features.
Drugs ofthis type have distinctive properties (Table 2). They act slowly, taking 4-6
months to reach a plateau. They improve extra-articular features of the disease as
erosions. This is the only available evidence that they can alter the outcome of the
disease. Future studies should concentrate more on this important aspect.
Table 2 Characteristics of'penicillarnine-likedrugs
Effects on extra-articular featuresofthe disease.
Reduction in ESR and rheumatoid factorand immunoglobulins.
Slowingof radiologicalchanges.
There is no agreement on the name of this dass of compounds. A selection of
drugs which have the same action are effective in a number of other conditions.
Drugs of other types may act slowly and last for a long time. Remissions are unusual
and modification of the disease is poorly documented. Basic has inappropriate
chemical connotations. At the present time, these drugs can be regarded as the second
line but this may change. Perhaps it is best to use the pharmacological principle of
calling drugs after a member oftheir dass - these are penicillamine-like,
Table 3 Names for penicillamine-likedrugs
Drugs which have penicillamine-like actions, some or all ofthose listed in Table 2,
ideal. lt is therefore worth looking at some of the newer and less weil studied
compounds for possible future advances.
Table 4 Drugs with penicillamine-like activity in rheumatoid arthritis
Gold salts: Sodium aurothiomalate.
Chloroquine and hydroxychloroquine.
Alclofenac, fenclofenac and clozic.
Auranofm is a new gold salt which ditTers from the others in that it can be given
orally. lt ditTers in several other aspects. Unlike most compounds in this dass, it is
weakly active in some animal models of inflammation such as adjuvant arthritis
(Waltz, di Martino, Chakrin, Sutton & Misher, 1976). However the dose required is
much higher than the human dose. In animals and probably also in man, the levels of
gold in serum and tissues is less than with injectable salts which might be associated
with less toxicity. There is good evidence that it is the gold rather than other parts of
the molecule which exert the action at least in animal models. The compound
certainly seems to be less toxic in man than traditional gold compounds. lt causes
diarrhoea and occasional rashes but no blood dyscrasias have yet been reported and
withdrawal rates have been lower than those expected from injected salts (Weisman
& Hanifm, 1979). It appears to have similar actions but formal comparisons with
other compounds ofthis dass have not yet been reported.
Thiol compounds other than penicillamine have received attention and several
it very similar to penicillamine. lt was a useful alternative for some patients and this
emphasises the need for choice. The more compounds are available, the more
patients will fmd one which controls their arthritis without intolerable side etTects.
This study also examined the mode of action of these compounds by trying to fmd
mechanism of action. Propertiesnot held in common like the ability to chelate
copper or atTect collagen are therefore unlikely to be important. The only common
property of these two compounds was their abil ity to enhance the secondary lesions
of adjuvant arthritis, evidence for enhancement ofa cell-mediated immune response.
This can also be demonstrated with levamisole and supports the view that these
compounds are 'immuno-modulatory'. Amor, Mery & de Gery (1980) studied
tiopronine and found it also similar to penicillamine and with similar side etTects.
The compound is 2-mercapto propionyl glycine. Perhaps the best tolerated ofthese
thiol compounds is the disulphide of 5-thiopyridoxine, pyritinol. lt is
available in some parts ofEurope as a cerebral stimulant but Camus, Crouzet, Prier
& Bergerin (1978) found it to have penicillamine-like actions in rheumatoid arthritis,
THERAPY FOR RHEUMATom ARTHRITIS 301
though weaker than penicillamine itself. lt certainly has less side effects, though those
reported have the flavour of penicillamine, for example they include pemphigus
(Ciratte, Duterque, Blanchet, Belaich, Lazarovici, Morel, Foix & Fischesser, 1978).
McConkey, Davies, Crockson, Crockson, Butler & Constable (1976) used dapsone
in rheumatoid arthritis reporting a slow action with reduction in ESR and acute
phase proteins but not rheumatoid factor. McConkey, Amos, Durham, Forster,
Hubball & Walsh (1980) tried sulphasalazine and obtained similar results.
Argument continues to rage over whether anti-flammatory drugs can also have a
penicillamine-like effect. It was first suggested with alclofenac, confirmed by one
group and refuted by another. It has since been suggested with fenclofenac, and
might be relevant to the activity of a new compound, clozic. lt is also possible that
anti-inflammatory drugs like benoxaprofen which act on lipoxygenase rather than
cyclo-oxygenase and on mononuclear cell functions might show this type of action.
With all these compounds, definite , confirrned and accepted evidence is not yet
Pharmaeokinetics andmode of action
The pharmacokinetics ofthese compounds appear to bear little relation to their effect
in rheumatoid arthritis. Levamisole, for example, is given weekly though it has a
short plasma half-life of about 4 h. It is clearly not the presence of the compound
in plasma that matters. The mode of action of these compounds remains obscure
though an 'irnmuno-modulatory' effect would explain everything while saying
Penicillamine is now the first choice of compound from this group. Its properties are
now weil documented (Huskisson, 1976) and there is considerable agreement about
how it should be used . It compares favourably with other well-studied compounds of
this type . The optimal dosage ofpenicillamine is 250mg twice daily, though it is clear
that there is variation in the requirements ofdifferent patients and a flexible regime is
better than a fixed dose (Blake, Bucknall & Bacon, 1980). Some patients require only
250mg daily and this should be the starting dose . Some patients require up to Ig
daily. An essential part of the success of penicillamine therapy is the supervision of
patients and management of complications. lt is a tragedy if treatment is interrupted
by a complication which could have been overcome in some other way. Some ofthe
side effects of penicillamine resolve even if treatment is continued and often at the
same rate as if it had been stopped. These include loss of taste and proteinuria.
Provided that the latter is not excessive and that there is no deterioration of renal
function , it should not interfere with treatment. Some side effects require that
treatment be stopped and restarted at a lower dose . These include the early rashes
and thrombocytopenia. Some side effects are dangerous and not compatible with
further treatment. They include aplastic anaemia and rare but serious complications
like myasthenia gravis. Despite all these problems, it should be possible to maintain
about 75% of patients treated with penicillamine for at least 2 years when side effects
Gold salts have one advantage over penicillamine, a lower overall incidence ofside
effects (Huskisson, Gibson, Balme , Berry, Burry, Grahame, Hart & Wojtulewski,
1974). They have several disadvantages. Those side effects wh ich occur are more
likely to lead to withdrawal of treatment and long-term therapy is the aim of such
drugs. More important, penicillamine is superior to gold in slowing the progression
of radiological c ha nges (G ibso n, Husk isson , Wojtul ewsk i, Scott. Balme, Burry,
Az a thio prine and penicill amin e ha ve been found to be si m ila r in effectiveness a nd
in overa ll tox icit y (Berry, Lyanage, Durance, Barnes, Berger & Evans, 1976).
Immunosuppressive drugs must be used with caution, es pe cia lly in yo ung patients
because o f the slig htly increa sed risk o f ma lignancy (K inl en , Shiel & Doll, 1979) .
They ne vertheless provide a useful alternative especiall y fo r th e patient who fails to
C hlo roq ui ne is si mi la r to go ld and therefore probabl y pen icill amin e, but ha s no
effect on radiological progression , a se rio us disadvantage. The eye cha nges ha ve been
exagge rated and can be avoide d by ca utio us do sage so that th e drug is another
alternative for the difficult patien t.
The pl ace of levamisole ha s now been cla rified by comparati ve stud ies and
different dosage regimes (Husk isson & Adams, 1980) . A single weekl y dose ofl50mg
appears to be the minimum required to ach ieve an optimal effect though it ma y be
with weekly therapy. One complication is more common with intermittent than
continuous therapy. Patients have weekl y 'reactions', characterised by fever, malaise
a nd various other symptorns. Nevertheless levamisole is a nother useful alternative to
The ideal compound of thi s type has not yet been found . The sea rch co ntinues.
Meantim e penicillamine offers the po ssibility of controlling a substa ntia l proportion
of patients with persistent or progre ssive rheumatoid arthritis and there are a number
of alternat ives for the intolerant or unresponsive patient.
Amor, B., Mery, C. & de Gery, A. (1980). La tiopronine, nouvel anti-rhumatismal a action lente
dans la polyarthrite rhumatoide. Revue de Rhumatisme, 47, 157-162.
Berry, H., Lyanage, S. P., Durance, R. A., Barnes, C. G., Berger, L. A. & Evans, S. (1976).
Azath ioprine and pen icillam ine in treatment of rheumatoid arthritis: a controlled trial.
Blake, D. R., Bucknall, R. C. & Bacon, P. A. (1 980). D-penicillamin e in rheumatoid arthritis
(fixed versus variable regimes). Future trends in infla mmation, in press.
rhumatoides traite es par la pyrithioine avec un recul de un an. Revue de Rhumatisme. 45,
Ciratte, J., Duterque, M., Blanchet , P., Belaich , S., Lazarovici, c., Morel, P., Foix, C. &
Fischesser, D. (1978). Deux cas de pemphigus superficial par le pyritinol. Ann. Dermatl.
Venerol(Paris) , 105, 573-577.
Gibson, T. J., Huskisson, E. c., Wojtulewski, J. A., Scott, P. J., Balme, H. W., Burry, H. c.,
Grahame, R. & Hart, F. D. (1976). Evidence that D-penicillamine alters the course of
rheumatoid arthritis. Rheumatology and Rehabilitation. 15,211-215.
Huskisson , E. C. (19 76). Penicillamine and the rheumatologist: a review. Pharmatherapeutica,
Huskisson, E. C. & Adam s, J. G. (1980). An overview ofthe current status oflevamisole in the
treatment ofrheumatic diseases. Drugs, 19, 100-104.
Huskisson, E. c.,Gibson, T.J., Balme, H. W., Berry, H., Burry, H. c.,Grahame, R., Hart , F. D.
& Wojtulewski, J. A. (19 74). Trial comparing D-penicill amin e and gold in rheum ato id
arthritis. Annals Rheum. Dis.. 33, 532-535.
Huskisson, E. C; Jaffe, I. A., Scott, J. & Dieppe, P. A. (1980). 5-thiopyridoxine in rheumatoid
arthritis: clinical and experimental studies: Arth. Rh eumat.. 23, 106-110.
Kinlen, L. J., Shiel, A. G. R. & Doll, R. (1979). Collaborative United Kingdom - Australasian
study of cancer in patients treated with immunosuppressive drugs. Brit. med. J.. 2,
THERAPY FOR RHEUMATOm ARTHRITIS 303
McConkey, B., Arno s, R. S., Durharn. S., Forster, P. J. G., Huball. S. & Walsh, L. (1980).
Sulphasalazine in rheumatoid arthritis. Brit. med. 1., 1,442-444.
McConkey, B., Davies, P., Crockson, R. A., Cro ckson , A. P., Butler, M. & Constable, T. J.
(1976). Dapsone in rheumatoid arthritis. Rh eumatology and Rehabilitation, 15,230-234.
agent : SK&F D-39162 . J. Pharmac. exp. Ther.. 197,142-152 .
Weisman. M. H. & Hannifm, D. M. (1979). Management ofrheumatoid arthritis with oral gold.
Arthritis and Rheumatism Branch,
National Institutes 01Arthritis. Metabolism and Digestive Diseases,
National Institutes ofHealth ,
Bethesda. Ma ryland 20205. USA
Altering immunity by pharmacological or mechanical mean s has pro vided at once
the most powerful and most hazardous ways of treating rheumatoid arthritis. The
drugs include corticostero ids, particularl y as a high-dose pulse, the cytotoxic drugs,
particularly the alk ylating agent s and ant i-metabolites, and the imidazol e family of
nucleic acid pathways so as to affect differentially sub-classes of lymphocytes, seems
likely to pro vide dru gs in this category in the near futur e. The mechanical mean s of
altering immunity include direct remo val of lyrnph by thoracic duct drainage,
apheresis ofplasma, oflymphocytes, ofmonocytes, or various combinations thereof,
and Iymph node irradiation. They are all based on the reasonable view that
disordered immunity is important in the pathogenesis of rheumatoid arthritis. They
do not require that disordered immunity is the root cause of arthritis. Ingeneral , they
resemble gold and penicillamine in being slow to take effect and slow to wear off, and
are distinctly more powerful than non-steroidal anti-inflammatory drugs which
inhibit prostagiandin synthetase. Although they all affect immunity, it is not certain
what aspect of their act ion makes them work, just as it is possible that gold and
penicillamine work through some ofthe immunological actions ascribed to them.
The evidence for disordered immunity in rheumatoid arthritis is roughly as
folIows. The disease is primarily an inflammation of the joints in which the
synovium is expanded by an infiltrate of cells - Iymphocytes, plasma cells, and a
connective tissue called pannus. An IgM or sometimes IgG ant ibod y, rheumatoid
factor , which reacts with immunoglobulin is often but not alwa ys synthesized by the
syno vial infiltrate , and is found in both serum and synovial fluid. Serum levels of
a2-globulin are elevated , and the immunoglobulins may or may not be elevated.
Complement is low in the synovial fluid but not the serum. Immune complexes may
or may not be present in abnormal amounts. Levels of various subpopulations of
Iymphocytes are high, low, or normal, depending on by whom or how they are
mea sured. Cellular immune functions are similarly variable, but generally depress
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