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The treatment of rheumatoid arthritis and necrotizing vasculitis with penicillamine.

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CURRENT COMMENT
The Treatment of Rheumatoid Arthritis and Necrotizing
Vasculitis with Penicillamine
Israeli A. Jaffe
l’he use of penicillamine in the treatment of patients with rheumatoid arthritis
followed observations of the effect of prolonged administration of the drug o n rheumatoid factor (RF) in vivo. A gradual fall
in serum levels of RF persisted for many
months after the drug was discontinued in
contrast to the prompt return to control
values when a comparable decrease i n titer
was produced by plasmapheresis (1). This
finding indicated that penicillamine-induced serologic changes were not due
simply to intravascular depolyinerization of
y h l rheumatoid factor, but that there was
a more fnndamental eRect on either the
disease process, the immune response, or
both-probably on a cellular level. 4 s the
driig was given to more patients, the same
pattern of titer change was observed repeatedly, and was often associated with
clinical improvement and a return to normal values for laboratory parameters of
disease activity (2). These clinical and
laliora tory observations have now been
confirmed by others. Zuckner et a1 reported
a marked fall in latex-fixation titer (LFT)
in all of their penicillamine treated rheumatoid patients, two-thirds of whom were
improved clinically (3). Payne antl Cahill
found good to excellent clinical improvement in all patients who were treated with
penicillamine for 3 months o r longer. Clinical improvement was accompanied by a
decrease in erythrocyte sedimentation rate
(ESR) , LFT, and serum glycoprotein and
an increase in hemoglobin antl heniatocrit
(4) . Whether the clinical benefit produced
Ily the drug is of a sufficient magnitude to
withstand the rigors of a controlled trial
will be determined.
Clinical and Laboratory Observations
From the S c w York Medical College, New York.
KY.
Supported by the Health Research Council of
the City of S e w York (HRU 1097), the Arthritis
Foundation, the National Institute of Arthritis
and Metabolic Diseases (.4M 11586 and TI A l l
5.582) and the US Army Medical Research antl
Development Coininand (DA-49-193MD-244.5).
ISRAEIJ.4. JAFFE, MI): Director, Rheumatic Disease Service, S e w York Medical College, 1249 Fifth
Ave, S e w York, NY 10029.
Reprint requests should he addressed t o Dr.
Jaffe.
Submitted for publication March 18. 1970; accepted May 10, 1970.
436
Sixty coitrses * of penicillamine have
been administered to 49 patients with rheuniatoid arthritis during the past 8 years.
T h e basis for clinical evaluation has been
detailed study of these patients, most of
whom were seropositive antl fulfilled criteria for .mstained disease cictivity (5). Each
patient served as his own control. Some of
the patients who have been under continuous observation for 5-7 years, gradiiallv
relapsed after the drug was withdrawn but
responded favorably after penicillamine
tlierapy was reinstituted; both events occurred after variable latent periods. T h e
*A course of penicillamine is defined as treatment for a minimum of 12 months at the maintenance dosage level.
Arthritis and Rheumatism, Vol. 13, No. 4 (July-August 1970)
PENlClLlAhllNE FOR RA AND VASCULITIS
results may be briefly summarized as follows: Approxiniately 80‘;” of these courses
ok treatment resulted in a SOY& or greater
degree of improvement as evidenced by a
reduction in subjective and objective signs
of active disease, a sustained fall of 50% or
more in the ESR and a drop in LFT
usually to a level of 1:80-1:160, regardless
oE pretreatment values (6). Clinical iniprovement generally commenced 12-16
weeks after treatment was initiated. Diminishing duration of morning stiffness and
loss of afternoon fatigue were frequently
the earliest subjective responses. Objective
changes as evidenced by a decrease in synovial swelling, joint tenderness, and size of
rheuniatoid nodules, as well as an increase
in range of motion, usually were not observed until at least 6 months of treatment
had elapsed. At approximately this time, a
reduction in ESR and LFT and a n increase in hemoglobin commenced. Analgesic requirements were then gradually
lessened and corticosteroids, when part of
the pretreatment regimen, were slowly tapered in all instances, although a period of
1 year or longer of penicillamine therapy
was often required to achieve complete
withdrawal. I n general, patients who responded earliest experienced the highest
grade of remission. While some patients
sustained a fall in R F without clinical
improvement (usually those with faradvanced, destructive disease) , no patient
who failed to show a fall in R F experienced a favorable clinical result. After penicillamine was discontinued, improvement
persisted for 4-6 months or longer in most
oE the patients.
Studies with penicillamine in necrotizing
vasculitis have been most encouraging. T h e
3 patients studied in this clinic all sustained a remission of this syndrome under
penicillamine therapy. T h e first patient to
be treated (7),relapsed and died of mesenteric arteritis and intestinal gangrene 6
months after the drug was discontinued.
T h e second patient continues in remission
as he enters his sixth year of uninterrupted treatment (8). I n July 1968, there
was slight but definite rise in his serum
RF by quantitative precipitin test. Coincident with this laboratory finding, his personal physician independently reported the
development of a small, new area of tissue
breakdown on the previously healed amputation stump (Fig 1). Penicillamine dosage
was increased, RF fell to its previous value,
and the lesion promptly healed. T h e third
patient is still under observation, since the
drug has only recently been discontinued.
T h e author is aware of 2 rheumatoid patients with vasculitis in Great Britain who
have shown a similar favorable clinical
response to penicillamine, associated with a
marked decrease in Rose-Waaler titers.
Five successfully treated patients were reported by French investigators, but chlorambucil was given with the penicillamine,
making therapeutic evaluation impossible
(9) .
Method of Administration, Side Effects
and Toxicity
T h e major limiting factor in the extension of these studies with penicillamine to
larger numbers of patients with rheumatoid arthritis has been the side effects attendant upon chronic administration of the
drug (2). T h e most useful advance in this
regard has been the development, in this
clinic, of the graduated dosage regimen
(Table 1).
Penicillamine treatment is initiated with
a single dose of 250 mg/day. This is then
slowly increased by 250 mg/day, every 14
days, with each succeeding dosage incre-
Mhritis and Rheumatism, Vol. 13, No. 4 (July-August 1970)
437
JAFFE
Fig 1. Area of necrosis in healed
amputation stump of penicillamine
treated patient with necrotizing vasculitis. Development followed reduction in penicillamine dosage and
was associated with rise in RF titer.
An increase in amount of penicillamine administered resulted in healing
of lesion and fall in titer to level
which had been previously achieved
prior to dose reduction.
ment made only as the patient’s tolerance
permits (6). T h e penicillamine is always
administered postprandially, in divided
doses, and pyridoxine supplements (10)
are not given routinely unless the patient is
nutritionally depleted or higher than usual
maintenance levels are employed. A maintenance dose of 1.5 g/day, which has been
found optimum for most patients, is generally achieved within 12-14 weeks. I n some
patients, adequate suppression of disease
activity can be obtained with a dose of 1.0
g/day while in others, 2.0 g/day may be
required. Any change in the maintenance
dosage will usually not be reflected clinically until 6-8 weeks have elapsed. If there has
been no indication of favorable change
either clinically or in laboratory values for
disease activity after 6 months of therapy at
the maintenance level, it may be assumed
that the patient will not respond to penicil438
lamine and the drug should be discontinued.
As has been the case with L-dopa, the
gradual introduction of penicillamine significantly improved its clinical tolerance
(1 1) . T h e side effects of nausea, vomiting,
pruritus, skin rash and drug fever, often
associated with eosinophilia, had heretofore been responsible for discontinuing
penicillamine in approximately half of the
treated patients. Since the graduated dosage regimen was adopted, the incidence of
these side effects has dropped to 20%, and
they are often readily controlled by delaying the next increment in dosage or by
temporarily adding a n antihistamine to the
regimen. While leukopenia still develops
occasionally, i t tends to be transient and is
usually not of sufficient magnitude to warrant cessation of therapy. It is essential,
however, that white blood cell counts be
Arthritis and Rheumatism, Vol. 13, No. 4 (July-August 1970)
PENlClLLAMlNE FOR RA AND VASCULITIS
Table 1. Graduated Dosage Regimen* for Penicillamine Therapy in Rheumatoid Arthritis
Weeks of medication
Time
0-2
2-4
4-6
~
Breakfast
Lunch
Midafternoon
Dinner
Bedtime
CuSO4t
-
250 m g
~
250 mg
250 mg
CUSOl
-
250 mg
CUSOI
250 m g
250 mg
-
-
6-8
-
250 mg
250mg
-
CuSOa
250mg
250 mg
8-10
10-12
250 mg
250mg
500 mg
-
500 mg
~~
cus4
250mg
500 mg
-
cuso,
500 m g
* If side effects supervene, treatment is either discontinued or held at a given level until patient’s
tolerance permits a further increase in dosage. Should it become necessary to interrupt therapy, reinstituting the drug after 6-8 weeks is often successful, provided treatment is again begun with 250 mg
and increased as outlined.
t When copper sulfate is included in regimen, it is given as 5 ml of a 0.1% solution in fruit juice immediately before dinner and spaced at least 1% hr from nearest penicillamine dosage.
pertormed twice monthly for at least the
first 6 months, with attention given to the
adequacy of platelets as seen in the
peripheral smear.
T h e two major side effects which do not
appear to have been favorably influenced
by the graduated dosage program are a n
alteration in the sense of taste (hypogeusia) (12) and nephropathy (13). Alteration or diminution in taste perception,
which may progress to a total loss of the
ability to taste, is encountered in approximately 1 out of 5 patients. Hypogeusia
always cleared within 8-12 weeks following
its onset, even when the drug was not
discontinued, hence it is not considered an
absolute contraindication to further treatment. T h e cause of the abnormality in
taste may depend upon copper depletion,
the SH radical, o r both (14) .
Nephropathy is certainly the most serious toxicity of penicillamine and it generally occurs after 1 year of treatment. It is
manifest first as proteinuria which, if
sufficiently severe, may result in develop
ment of the nephrotic syndrome (15). T h e
mechanism appears to he that of a n im-
mune-complex nephritis, with the deposition of y globulin and complement on
the glomerular basement membrane and
subepithelial deposits in the glomerulus by
electron microscopy (13, 16). T h e nephropathy has been reversible in these patients
after stopping the penicillamine, although
u p to 12 months may elapse before the
proteinuria completely disappears. A urinalysis must be performed bimonthly and
discontinuance of therapy is mandatory in
all patients developing persistent proteinuria of 2+. I n 3 patients with this complication, retreatment with penicillamine 9-12
months after the drug was stopped was not
associated with recurrence of the toxicity;
however, retreatment earlier resulted in a
prompt increase in urinary protein excretion.
Both hypogeusia and nephropathy a p
pear to occur in far greater incidence in
patients with presumably normal copper
metabolism ie, rheumatoid arthritis and
cystinuria, than in patients with Wilson’s
disease (17). T h e explanation for this has
not been elucidated but it may, in some
manner, be related to a protective effect of
Arthritis and Rheumatism, Vol. 13, No. 4 (July-August 1970)
439
JAFFE
increased copper stores. T h e possible value
of prophylactic administration of copper
sulfate (5 ml of a 0.1% solution/day) on
the incidence and severity of nephropathy
and hypogeusia is currently under study,
however, data is insufficient to permit a
conclusion.
Mechanism of Action of Penicillamine
T h e prolonged administration of penicillamine to patients with rheumatoid arthritis not only reduces yM rheumatoid factor, as determined serologically, but other
classes of immunoglobulins as well ( 7 ) .
In a recent report of a patient with yG711 cryoglobulinemia, a marked decrease
in ,A, yG, and y M immunoglobulins
under penicillamine therapy was elegantly
demonstrated (18). Zuckner et al, in their
series of penicillamine-treated rheumatoid
patients, failed to find consistent changes in
immunoglobulin levels measured by immunodiffusion despite marked reductions in
LFT; this may be explained by the lower
dosage of penicillamine which they employed (3). Payne and Cahill, using a dose
of 1.5 g/day, noted a decrease in 7s y
globulin as measured in the ultracentrifuge
and a reduction in total y globulin by
electrophoresis (4). A portion of an ultracentrifugal analysis of the serum proteins of a penicillamine-responsive rheumatoid arthritis patient whose L F T fell from
1:2,560 to 1:160 after 8 months of treatment is shown in Fig 2. Note the fall in the
intermediate y globulin complexes and
the 7s globulin, both of which are sulfhydry1 resistant in vitro.
Two hypotheses are suggested to explain
the fall in R F and decrease in immunoglobulin levels with prolonged penicilla-
Fig 2. Ultracentrifugal analysis
of serum proteins in penicillamineresponsive rheumatoid patient before and after 8 months of treatment. Sedimentation is at 52,640
rpm, 1-r, at W, 80' and 96'.
Serum in both determinations was
diluted 1:2 with saline. Note fall
in the 7s y globulin and intermediate y globulin complexes,
which was associated with a
marked decrease in LF titer.
Arthritis and Rheumatism, Vol. 13, No. 4 (July-Auptt 1970)
PENICILLAMINE FOR RA AND VASCULITIS
mine therapy. The first relates to a possible reduction persistecl in a manner analogous
effect of the drug upon a presumed anti- to that observed with the KF after the drug
genic stimulus, while the second considers was discontinued.
Patients with Wilson's disease and cystinsuppression of the immune response.
If penicillamine were effective against an uria, many of whom have been under conas-yet-unidentified infective agent (19) in tinuous treatment with penicillamine for
rheumatoid arthritis, then the fall in titer periods of 5-10 years, have not experienced
would be analogous to that found in an increased susceptibility to bacterial, visubacute bacterial endocarditis, where the ral or opportunistic infections (27). This
anti-y globulin factors gradually disappear absence of immune-incompetence during
after appropriate, specific chemotherapy penicillamine therapy must relate, in part,
has been instituted (20) . Alternatively, to the nature of the leukopenia produced
penicillamine-induced alterations of 7s y by the drug. T h e leukopenias observed
globulin (or its complexes), with decreased with penicillamine represent drug idiorynantigenicity, might also be responsible for crasy rather than pharmacologically inthe serologic changes. Although there is at duced cytotoxicity, since they occur infrepresent no experimental evidence to sup- quently and are independent of dosage.
port either of these contentions, they merit Thus, if penicillamine is an immunosuppressant, it differs from other compounds
further consideration.
of this type-the purine analogs, alkylating
An immunosuppressive effect of penicilagents and folic acid antagonists, which act
lamine has been demonstrated in some
by a nonspecific cytostatic or cytocidal
laboratory models. In rabbits, using P1
mechanism (28) , reflected in dose-related
HSA, there was a significant delay in the
reductions in peripheral WBC counts.
onset of the primary immune response
Certain of the known pharmacologic
in all penicillamine-treated animals, with
no demonstrable antibody formation in properties of penicillamine-ie, pyridoxine
two-thirds (2 1) . Hubner and Gengozian antagonism (10, 29) , dermolathyrism (30,
found a depression in total antibody pro- 31), and alterations in trace metal metaboduction, 7s and 19S, in penicillamine- lism (32), profoundly alter cellular functreated mice given S typhosu antigen (22). tion and might relate to the fundamental
In contrast to these findings, however, the action of the drug in rheumatoid disease.
formation of an RF-like substance in rabbits after the intravenous administration of
E cola' (23), was not influenced by penicillamine (24). Furthermore, there was no
impairment in lymphocyte transformation
in cells obtained from patients with rheumatoid arthritis during penicillamine therapy (3). Although these experimental
findings are somewhat at variance, penicillamine treatment of patients with cryoglobulinemia (18, 25) and autoimmune hemolytic anemia (26) resulted i n a marked
reduction in serum antibody levels. This
CONCLUSION
There is no well delineated biochemical
lesion in rheumatoid arthritis analogous to
the depletion of cerebral dopamine in
Parkinson's disease (1 1) . Perhaps the only
reasonably consistent biochemical marker
in most rheumatoid patients is that found
in the serologic reactions and immunoglobulin aberrations. It is suggested that a
chemotherapeutic agent which consistently
offers objective evidence of activity in at
Arthritis and Rheumatism, Vol. 13, No. 4 (July-August 1970)
4441
JAFFE
6. Jafte 1A: Penicillamine in rheumatoid disease with particular reference to rheumatoid factor. Postgrad Med J (London)
44:suppl 34-40, 1968
7. Jaffe 1A: Kheumatoid arthritis with arteritis-Report of a case treated with penicillamine. An11 Intern Ned 61:556562, 1964
8. J a f e IA, Smith KW: Kheumatoid vasculitis
-Keport
of a second case treated with
penicillamine. Arthritis Rheuni 1 1585-592,
1968
least this one inajor parameter, merits further consideration. Patients with sustained
rheumatoid disease who are candidates for
treatment with gold salts, antimalarials,
corticosteroids, or antimetabolites, meet the
criteria for a therapeutic trial with penicillaniine on a n investigative basis. Further
confirmation of efficacy would provide impetus to studies of molecular modifications,
with a view toward improving the therapeutic ratio a n d better understanding the
mechanism of action of the drug.
9.
ACKNOWLEDGMENTS
The author wishes to express his gratitude to
Professor Henry Kunkel, Kockefeller University,
NY, for his continued guidance throughout the
performance of these studies. Dr. Robert Winchester, Rockefeller University, performed the
ultracentrifugal analysis shown in Fig 2. T h e
laboratory studies would not have been possible
without the technical assistance of Mrs. Parvin
Merryman, his. I’enicillamine used in these
studies was generously provided by Dr. Elmer
Alpert, Merck Sharp & Dohme Research Laboratories, West Point, Pa.
10.
1I.
12.
13.
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443
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