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IMMUNOREACTIVE METHODS AND RH EUMATOID ARTHRITIS 305

With this melange of findings, it is by no means c1ear what needs damping or

stoking. Since most ofthese modes oftherapy themselves may have both stimulatory

and depressive influences on the immune system, depending on what is measured,

there is no certainty how they exert their beneficial effects.

Corticosteroids

The early use of corticosteroids in rheumatoid arthritis revealed a profound and

rapid benefit from what would now be considered moderate to large daily oral doses,

a rapid offset of action, and virtually a physical addiction to continuous therapy

(Polley & Slocurnb, 1976). Incidentally, the withdrawal syndrome of this addiction

will appear in the form of a rheumatic syndrome when corticosteroids are stopped,

even in those who have no underlying connective tissue disease . More recently, low

daily doses have been used with great benefit and little risk in rheumatoid arthritis.

But very recently there has been a search, stimulated by attempts to repel impending

renal transplant rejection, to find, in very large intravenous doses of corticosteroids,

pharmacological effects on immunity beyond those known . Corticosteroids, in

single, moderate, oral doses cause an acute, transient neutrophilia due to increased

marrow release and decreased egress from the circulation because of decreased

endothelial adherence; a Iymphopenia, mainly ofT cells, due to altered recirculation

patterns, not lysis; a monocytopenia and decreased accumulation of monocytes at

sites ofinflammation, and a minor fall in gamma globulin several days later which is

due to transiently depressed synthesis (parillo & Fauci, 1979; Butler & Rossen, 1973).

Humoral immune responses are unchanged, but the ability to sensitize with

dinitrochlorobenzene and for Iymphocytes to transform to phytohaemaglutinin are

reduced, evidence of depressed cellular immunity. All ofthese effects are short-lived,

none lasting more than about 48 h even when doses are repeated several days in a

row. Large intravenous pulses cause similar effects (Webei, Ritts, Taswell, Donadio

& Woods , 1974).

These observations do not prepare one for the longer lasting effects of an

intravenous pulse sometimes seen in patients with rheumatoid arthritis. In the two

good published studies - one uncontrolled (Fan, Yu , Clements, Fowlston, Eisman &

Bluestone, 1978) and one a double-blind trial comparing 1000 mg daily for three days

with 10 mg daily for three days (Gottlieb, Riskin, Vidal , Hyer & McKinney, 1980)-

most of the patients rapidly developed a sense of well-being and the virtual

disappearence of morning stiffness. The number of swollen and tender joints

decreased, with maximum beneficial effects occurring on about day four. By a week,

benefit was still evident, by four weeks it had disappeared in about halfthe patients,

but as long as four months later a few patients still showed some improvement.

Although the effects of doses, repeated at monthly or longer intervals, are just being

studied critically (Liebling, Lieb, McLaughlin, Blocka, Furst, Nyman & Paulus,

1980), one might predict that although benefits may still occur, side effects, which

have been notably absent in the small experience so far, will accumulate (Garrett &

Paulus, 1980). Only an immediate, bitter taste in the mouth appears c1early

connected to the regimen used now.

Cytotoxic drugs

Although it was quickly forgotten when corticosteroids became available, the earliest

use of cytotoxic and related drugs in 1950 showed real promise. Both nitrogen

mustard (Jimenez Diaz, Lopez Garcia, Mercante & Perianes, 1951) and aminopterin

were used (Gubner, August & Ginsberg, 1951). In the past 15 years , several other

drugs have been used with more or less success and toxicity.

306 P. H. PLOTZ

Cyclophosphamide has been the most effective of them, and probably the single

most effective agent ever used in severe rheumatoid arthritis, save aspirin and

corticosteroids (Cooperating Clinics Committee, 1970; Townes, Sowa & Shulman,

1976). It has demonstrated a greater effect, with more apparent complete or nearcomplete rernissions, than any other drug . The appearance of new bony erosions is

inhibited. Although there is some uncertainty about the lowest effective daily oral

dose, a dose below 100 mg daily added to a small dose ofsteroids is of'benefit (Smyth,

Bartholomew, Mills, Steigerwald, Strong & Recart, 1975).

The toxicity of cyclophosphamide is likewise great. Beyond the immediate hair

loss and marrow suppression which reflect the expected effects, infertility due to

gonadal atrophy in both men and women must be considered an almost universal

side effect, bladder toxicity in the form of haemorrhagic cystitis and fibrosis is

comrnon, and carcinogenesis, particularly ofthe bladder and lymphoid and myeloid

tissues, may occur even after the drug has been stopped (Cascatio & Scott, 1979;

Plotz, Klippel, Decker, Grauman, Wolff, Brown & Rutt, 1979). Such hazards should

lead to this drug being reserved for patients who have failed or are intolerant to any

other therapy. In an attempt to find a safer way ofusing cyclophosphamide, a doubleblind trial is underway, using intravenous monthly pulses , a mode of administration

which permits the elimination of most of the presumed uroepithelial toxic

metabolites in a dilute form .

The c1osely-related chlorambucil has been widely used in France, appears effective

(de Seze & Kahn, 1974), and is relatively easy to give, but it has roughly the same

toxicities as cyclophosphamide (Kahn, Arlet, Bloch-Michel, Caroit, Chaouat &

Renier, 1979) and thus there seems to be no great future for it.

Azathioprine, though probably not as potent as the alkylating agents, is much

easier to use (Urowitz, Hunter, Bookrnan, Gordon, Smythe & Ogryzlo, 1974), being

in fact easier to use than D-penicillamine. Carcinogenesis is well-documented but not

common. The use ofazathioprine is spreading in the United States, but it will not be

the miracle cure.

The only drug in this family without c1ear evidence of carcinogenicity is

methotrexate. It is also without proven benefit in controlled trials in rheumatoid

arthritis, though there is evidence of efficacy in psoriatic arthritis. Presently used

intermittent regimens minimize liver toxicity, but the drug should not be used if

alcoholism or liver disease is present. This drug deserves further trials.

Other drugs

All of the cytotoxic drugs - cyclophospharnide, chlorambucil, azathioprine, and

methotrexate - have widespread effects on immunity and inflammation which are by

and large suppressive, particularly to the cellular side of immunity, but is that what is

wanted?

The drug, levamisole, was used in rheumatoid arthritis and many other diseases

because it was found to enhance some immune responses in animals. The drug is

moderately helpful in rheumatoid arthritis (Multicentre Study Group, 1978). Except

for skin rash and a flu-like illness, it is easy to use on a weekly schedule. A profound

and potentially fatal neutropenia occurs as an idiosyncratic reaction in up to a few

percent of rheumatoid patients. It is alleged that checking the white blood cell count

the day after each weekly dose, and stopping the drug ifsignificant leucopenia occurs,

allays this hazard. There also may be, as with gold and D-penicillamine, a c1ustering

oftoxicity in patients of certain HLA types . It is doubtful that the benefits ofthis drug

have much, or anything, to do with its effects in 'normalizing' immunity, but since all

the successful drugs in use to treat rheumatoid arthritis were first used for a reason

now known to be fallacious, we should not mind if the reason is wrong . This drug

is not approved for use in arthritis in the United States and is not widely used.

IMMUNOREACTIVE METHODS AND RHEUMATOID ARTHRITIS 307

The discovery that certain nucleotide enzyme deficiencies are responsible for

immune deficiency diseases has led to the development of drugs which, by blocking

such enzymes specifically, can block the function of some Iymphocyte subsets

specifically. This approach seems likely to lead not only to new therapies in

connective tissue and other immunological diseases, but also to new insights into

their pathogenesis. None of these drugs has yet, to present knowledge, been tried in

human disease.

Mechanical immunosuppression

It has been said that ifthe invention ofthe locomotive and the automobile had been

reversed, tracks and trains might now be worshipped instead of highways and cars .

Similarly if their invention had been reversed, blunt methods Iike thoracic duct

drainage, apheresis, and Iymph node irradiation might now be discarded for the ease

of a daily pill like cyclophosphamide. Instead, the use of these non-specific

mechanical ways to treat rheumatoid arthritis is only now being explored.

Thoraeie duct drainage has been tried only as far as is known, by the clinics in Los

Angeles and Kyoto (Paulus, Machleder, Levine, Yu & MacDonald, 1977; Ueo,

Tanaka, Torninaga, Ogawa & Sukurami, 1979). The small experience in Los Angeles

- nine successful cannulations in twelve patients with severe disease -Ied to improvement in painful joints, morning stiffness, grip strength, ring size, and nodules within a

week. The procedure was continued for three to fifteen weeks, allowing the removal

of up to 1012 cells, mainly Iymphocytes. The Iymphoplasma was returned to the

patient intravenously. The original disease activity recurred in two to twelve weeks

after drainage was stopped. Reinfusion with live but not dead cells caused an

exacerbation. Sedimentation rate and rheumatoid factor changed irregularly or not at

all, and changes in immunoglobulins were minor. Some cellular responses were

depressed, but several measures of inflammation were normal. The procedure is

cumbersome and already obsolete.

Plasmapheresis, to remove antibodies, particularly rheumatoid factor and the

magical and perhaps mythical immune complexes responsible for the disease, and

Iymphapheresis, to remove the cells which made them or are stimulated by them,

are the modish way of treating immunological diseases. Among the several dozen

diseases submitted to plasmapheresis, myasthenia gravis , Goodpasture's syndrome,

and rapidly progressive glomerulonephritis seem almost surely to be responsive.

Only rheumatoid arthritis has yet shown promise with Iymphapheresis.

The story ofthe use ofthese methods in rheumatoid arthritis is a cautionary tale .

The uncontrolled, but promising experience from the Cedars-Sinai Hospital in Los

Angeles resembled the experience with thoracic duct drainage, with improvement

after a week or so in several of the standard measures of disease activity (Wallace,

Goldfinger, Gratti, Lowe, Fan, Bluestone & Klinenberg, 1979). Most benefit was seen

ifboth Iymphocytes and plasma were removed and one ofthe long-acting drugs was

given concommitantly. Clinical improvement lasted from two weeks to as long as

eight months and long outlasted the changes in immunoglobulins, sedimentation

rate, complernent, and immune complexes. In a controlled, open trial of

plasmapheresis in rheumatoid arthritis, the procedure was performed on half of a

group of patients, all of whom were put to rest in the hospital and given optimal

physical therapy without a slow acting agent (Rothwell, Gordon, Davis, Dasgupta,

Johny, Russell & Percy, 1980). Those who had 4-5 Iitres of plasma removed weekly

showed no more improvement than the control patients. It is rumoured that plasmapheresis is increasingly available, at least in the United States, even in store-front

clinics, suggesting the ease with which it can be done, but several deaths have

occurred. The studies published so far are not the last word on the subject and do not

give rise to great hopes.

308 P. H. PLOTZ

Lymphapheresis has been most carefully studied in the Arthritis and

Rheumatism Branch at the National Institutes of Health. The first experience with

four patients treated on an open basis was highly promising (Karsh, Wright, Klippei ,

Decker, Deisseroth & Flye, 1979). A controlled, double-blind trial (Karsh, Klippel,

Plotz, Wright, Flye & Decker, 1980) was then initiated. Patients with scvere disease

were all subjccted to a twice- or thrice- weekly procedure in which whole blood was

separated on a cell separator centrifuge. "T reated' pat ients had the main band of

lighter cells , mostly Iymphocytes and rnonocytes, and the plasma in which thcy

tra velled, about 400 ml , removed. 'Control' patients had all the cells returned to

them, but a fraction ofplasma near the cells and equal in volume to 'treated' plasma

removed. Twelvc patients were subjected to between 13-16 procedures over live

wecks. Lymphocytcs, especially T cells , were reduced, particularly in the early

weeks. Clinical improvement in this group of quite severely involved patients was

variable, but overall , those whose cells were removed responded substantially better

than the controls with a couple ofexception s. Improvement was early, within the first

couple of weeks , and resembled the improvement described with the other

mechanical techniques. Benefit was sustained for four or more months after lymphapheresis was stopped. Several patients had profound improvement, but those with

extensive anatomicaI changes certainly did not achieve long-term improvement.

Changes in the schedule ofthe procedure and its use as an adjunct to other therapy

will almost surcl y improve the outcome, but it is hard to believe that thi s method will

be more than a station on the way to depress immune function specifically, The

apheresis methods are relatively easy and relatively free, so far, of major and minor

side effects.