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N-[4-hydroxyphenyl] retinamide in rheumatoid arthritisA pilot study.

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ARTHRITIS ti RHEUMATISM
Vol. 39, No. 6, June 1996. pp 1021-1026
‘0 1996, American College of Rheumatology
1021
N-[4-HYDROXYPHENYL] RETINAMIDE IN
RHEUMATOID ARTHRITIS
A Pilot Study
ELLEN M. GRAVALLESE, MALCOLM L. HANDEL, JONATHAN COBLYN, RONALD J. ANDERSON,
RICHARD I. SPERLING, ELIZABETH W. KARLSON, AGNES MAIER, ERIC M. RUDERMAN,
FRANCA FORMELLI, and MICHAEL E. WEINBLA’IT
Objective. To evaluate the efficacy and tolerability
of N - [4 hydroxyphenyl] retinamide (CHPR), a synthetic
retinoid, in the treatment of rheumatoid arthritis (RA).
Methods. An uncontrolled, open clinical trial with
synovial biopsy pre- and postmedication to evaluate the
clinical effects of 4-HPR as well as its effects on metalloproteinase gene expression.
Results. Twelve patients with severe, longstanding
RA were enrolled in this study. Six patients withdrew
before study completion, 2 because of drug toxicity, 2
because of a flare of RA, and 2 because of intercurrent
medical problems. No patient met predetermined Paulus criteria for treatment response, and there was no
improvement in the laboratory parameters, except for a
modest decrease in C-reactive protein. No decrease in
messenger RNA for the metalloproteinases collagenase
Supported by the R. W. Johnson Pharmaceutical Research
Institute. Dr. Gravallese’s work was supported by an Arthritis Investigator Award from the Arthritis Foundation. Dr. Handel’s work was
supported by a Neil Hamilton Fairly Fellowship from the National
Health and Medical Research Council, Australia. Dr. Ruderman’s
work was supported by NIH grants AI-07306 and AR-07530. Dr.
Sperling’s work was supported by NIH grant AR-01885.
Ellen M. Gravallese, MD, Malcolm L. Handel. PhD, FRACP
(current address: St. Vincent’s Hospital, Darlinghurst, Australia), Eric
M. Ruderman. MD (current address: Rush University, Chicago,
Illinois): Harvard School of Public Health and Brigham and Women’s
Hospital, Boston, Massachusetts; Jonathan Coblyn. MD, Ronald J.
Anderson, MD, Richard I. Sperling, MD, Elizabeth W. Karlson, MD,
Agnes Maier, BA, Michael E. Weinblatt, MD: Brigham and Women’s
Hospital, Boston, Massachusetts; Franca Formelli, PhD: Istituto Nazionale Tumori. Milan, Italy.
Address reprint requests to Ellen M. Gravallese, MD, Division of Rheumatology/Immunology, Brigham and Women’s Hospital,
75 Francis Street, Boston, MA 02115.
Submitted for publication September 15, 1995; accepted in
revised form January 8, 1996.
and stromelysin was seen in the 2 patients in whom
paired synovial biopsies were obtained.
Conclusiotr. No beneficial clinical effect was observed with the retinoid 4 - W R in the treatment of severe,
longstanding RA at the 300 mg/day dosage studied. The
use of higher dosages is precluded by the observed toxicities. The effect of this drug in patients with early or mild
disease was not studied. Although this particular retinoid
was not effective in this pilot study, the use of other
retinoids in RA should still be considered.
N-[4-hydroxyphenyl] retinamide (4-HPR) is a
synthetic analog of vitamin A with multiple biological
effects in common with other retinoids. 4-HPR has been
shown to inhibit the proliferation of certain epithelial
malignancies, including human breast cancer and bladder cancer cells (1,2), as well as to inhibit mammary
tumorigenesis in mice in vivo (3). A potential role for
retinoids in the treatment of rheumatoid arthritis (RA)
has been proposed (4) and is supported by preclinical
studies in 2 animal models of arthritis. A dosedependent suppression of the chronic phase of streptococcal cell wall (SCW)-induced arthritis was noted in
LEW/N rats treated with 4-HPR beginning on day 0 or
day 11 after disease initiation (5). The abnormal growth
characteristics of synoviocytes derived from rats with
SCW-induced arthritis were found to be inhibited in
vitro by all-trans-retinoic acid ( 6 ) . In addition, treatment
of rats that had either developing or established adjuvant arthritis with 13-cis-retinoic acid led to a significant
decrease in joint inflammation (7).
Clinical trials employing retinoids in the treatment of patients with arthritis have also provided encouraging results. Trials with etretinate in the treatment
of psoriatic arthritis (8,9) have demonstrated a statisti-
GRAVALLESE ET AL
1022
cally significant improvement in articular indices, as well
as a decrease in the erythrocyte sedimentation rate
(ESR) and in C-reactive protein (CRP) levels. In o n e
trial of Reiter’s syndrome, etretinate treatment led to
some global improvement in joint symptoms (10). However, only a modest clinical response was noted in an
open trial of etretinate treatment of RA (11).
I n cell culture experiments, favorable effects of
retinoids on the production of the metalloproteinases
collagenase (MMP-1) and stromelysin (MMP-3) have
been demonstrated (12-14). These metalloproteinases
a r e enzymes that have been implicated in the mediation
of joint destruction in RA because of their potential to
degrade components of the extracellular connective
tissue and cartilage matrix. In vitro studies of synovial
fibroblasts have demonstrated that retinoids inhibit the
transcription of the collagenase gene (15,16). Inhibition
of stromelysin gene expression in transformed rat fibroblast cells by retinoic acid has also been shown (14). In
addition, in preclinical animal models of arthritis, a
decrease in collagenase activity has been demonstrated
after treatment with retinoids (5,7).
T h e present uncontrolled, open study was undertaken to determine whether 4-HPR demonstrated any
efficacy in patients with active RA, to evaluate the
tolerance to the drug in this patient population, and to
determine the effects of treatment with 4-HPR in vivo on
synovial collagenase and stromelysin messenger RNA
(mRNA) expression.
PATIENTS AND METHODS
Patient selection. Twelve patients with active RA
enrolled in this study. All patients met the American College
of Rheumatology (formerly, the American Rheumatism Association) criteria for RA (17). Entry criteria for this study
included failure to respond to nonsteroidal antiinflammatory
drugs (NSAIDs) and at least 1 second-line agent. All patients
must have been taking a stable dose of NSAIDs for at least 1
month. Low-dose prednisone ( 5 5 mdday) at stable doses for
at least 1 month was also allowed.
Women of childbearing potential were required to be
surgically sterile to be eligible for this study. Patients with a
history of serious concomitant illnesses: elevated fasting triglyceride levels 2600 rnddl, fasting cholesterol levels 2300
mg/dl, retinal disease, or patients taking 210,000 IU/day of
vitamin A were excluded. Patients must have discontinued
second-line therapy for at least 2 months prior to study
initiation, or for methotrexate, 1 month before study initiation.
The protocol was approved by the Institutional Review
Board of Brigham and Women‘s Hospital, and each patient
gave written informed consent prior to study entry. In patients
with knee synovitis, permission for sampling of synovial tissue
by a percutaneous needle biopsy was also requested. This
protocol was filed with the United States Food and Drug
Administration under a personal Investigational New Drug
(IND #39,008).
Study design. This was a 24-week, open pilot study.
After an initial screening visit (week -l), patients were
evaluated at baseline (week 0), week 2, and week 4, and every
4 weeks thereafter. Vital signs and standard clinical disease
variables for RA were determined at each visit. Capsule counts
at each visit were used as a measure of drug compliance.
During the 24-week study, patients were seen at the same time
of day by the same investigator.
Patients received 4-HPR (RW Johnson Pharmaceutical Research Institute, Spring House, PA) at a dosage of 300
mg/day. Patients were instructed to take 3 capsules of 4-HPR
(100 mg/capsule) once daily with the largest meal of the day.
To reduce the potential for ocular toxicity, patients were
instructed not to take 4-HPR for 3 days following each monthly
visit; this served as a 3-day drug holiday (18,19). Patients were
allowed to continue medications for coexisting medical conditions and remained on NSAID and low-dose prednisone
regimens. Doses of NSAIDs and prednisone were required to
remain constant during the trial, and intraarticular steroids
were not allowed during the study. Acetaminophen was allowed for pain control.
Individual patient response was determined by using
the Paulus criteria for response (20). By this definition, patients must have achieved improvement in 4 of 6 disease
variables defined as: a 20% improvement in morning stiffness,
20% improvement in the ESR, 20% improvement in the joint
tenderness index, 20% improvement in the joint swelling index,
and a 2-grade improvement in patient global assessment or an
improvement from “mild” to “none,” and a 2-grade improvement in physician global assessment or an improvement from
“mild” to “none.” In this study, our definition of a beneficial
response required that at least 3 patients meet the Paulus
criteria for response. No successes constituted a negative
result.
Laboratory assessments. A complete blood cell count
(CBC), blood chemistry profile, urinalysis, and ESR were
obtained at each visit. At baseline and at study completion,
levels of rheumatoid factor, fasting triglycerides, fasting total
and high-density lipoprotein (HDL) cholesterol, total IgG and
IgM, and CRP were obtained. An electrocardiogram was also
obtained at baseline and at study completion. Radiographs of
the hands were taken at baseline, in case a longer clinical trial
was performed.
In consenting patients with knee synovitis (n = S), a
percutaneous synovial biopsy with a 14-gauge Parker-Pearson
needle was performed on the more clinically active knee prior
to drug initiation. Approximately 5-8 samples from each
patient were obtained from the suprapatellar pouch. A repeat
biopsy was performed on the same knee at 24 weeks or in the
event of withdrawal from the study, at the patient’s final visit.
Measurements of 4-HPR and its metabolite N-[Cmethoxyphenyl]
retinamide (4-MPR) in synovial fluid were performed by
high-performance liquid chromatography as previously described (19).
In situ hybridization. Tissue fragments obtained by
synovial biopsy were immediately fixed in 4% paraformaldehyde at 4”C, dehydrated in 30% sucrose at 4”C, and embedded
in OCT compound (Miles, Elkhart, IN). Tissue sections were
1023
A SYNTHETIC RETINOID IN RA
stained with hematoxylin and eosin to evaluate for adequate
synovial sampling. Samples were stored at -80°C until paired
biopsies could be evaluated by i n situ hybridization. Two
patients had analyzable tissue on both the pretreatment and
posttreatment biopsies.
Collagenase, stromelysin, and control gene (Pl) sense
and antisense "S-labeled RNA probes were generated as
previously described (21). A 589-basepair Xba IIHind 111
fragment of the stromelysin complementary DNA (cDNA)? a
400-bp Xba IIEco RI fragment of the collagenase cDNA, and
a 210-bp fragment of the ribosomal P protein P1 cDNA, a gene
encoding a human ribosomal P protein (22),were subcloned
into pKS Bluescript (Stratagene, La Jolla, CA). The cDNA
subclones were linearized and incubated with T7 or T3 RNA
polymerase to generate sense and antisense probes. Collagenase and stromelysin cDNA were both gifts of Dr. Constance
Brinckerhoff (Dartmouth Medical School, Hanover, NH). The
P1 cDNA was the gift of Dr. Benjamin Rich (Harvard Medical
School, Boston, MA).
Synovial tissue sections (6 pm or 8 pm) from the
pretreatment and posttreatment biopsies were placed on polyL-lysine- coated slides and processed simultaneously utilizing
identical solutions, probe preparations, and hybridization conditions. Prehybridization steps were as previously described
(21), including digestion with proteinase K (1 pg/ml) at 37°C
for 20 minutes and treatment with 0.25% acetic anhydride in
100 mM triethanolamine for 10 minutes. All slides were
hybridized at 45°C overnight under previously described conditions, using "S-labeled RNA probes ( 5 X 10' counts per
minuteIlS-pI volume of hybridization mix added to each slide).
Washes, dehydration, and autoradiography were as previously
described (23), and slides were stored at 4°C in light-proof
containers. An initial short exposure of pre- and posttreatment
slides was performed, and the final exposure time was chosen
to optimize grain density for image analysis. Sections for image
analysis were lightly counterstained with methyl green for cell
counting.
Image analysis was performed using the Imexec program (Image Analysis Laboratory, New England Medical
Center, Boston, MA) on a VAXserver 3900 (Digital Equipment, Maynard, MA). Images were captured and digitized with
an SCSI Monochrome Frame Grabber (Analogic, Peabody,
MA), a Zeiss Universal microscope, and a CCD array camera
(model 3710D2; CID Technologies, Liverpool, NY). Images
were selected by identifying the synovial lining layer. then
capturing every third (4OX) field. Each slide contained at least
3 to >8 biopsy fragments, from which 7-15 images (mean 11
images) were analyzed for each probe.
For each captured image, the total synovial lining area,
area of synovial lining covered by grains, and number of
counterstained nuclei in the lining were measured. Cells within
the synovial lining were counted manually. Gray scale thresholding was used to determine grain area. Thresholds were
allowed to vary from image to image in order to correct for
slight differences in tissue density and counterstaining. To
compare pretreatment and postreatment biopsy samples, images were obtained and images were digitized in the same
session for each probe, without altering gain and light settings.
The mean hybridization ratio for all images from a given slide
was calculated, and the differences between hybridization on
pretreatment and posttreatment biopsy samples were com-
pared. The P1 probe WIS used to test for equivalence of mRNA
preservation in both pretreatment and posttreatment samples.
Sense probes showed minimal hybridization, and demonstrated the specificity of the stromelysin, collagenase, and PI
probes.
RESULTS
Twelve patients with RA enrolled in this study.
Their mean age was 59 ('-2.7) years; mean disease
duration was 15 ('-4.5) years. All 12 patients had
received at least 3 previous second-line therapies, and 11
of the 12 had received methotrexate. Seven of the 12
patients were also receiving low-dose prednisone ( 5 5
mglday). Capsule counts indicated a high degree of
compliance with this study regimen.
Six patients withdrew before study completion.
Two withdrew because of a flare of RA, 2 because of
intercurrent medical problems, and 2 because of drug
toxicity. T h e toxicities observed in this study a r e similar
to those previously reported with retinoid therapy.
T h e r e were no unusual adverse events, and all toxic
effects resolved with drug discontinuation. Three patients reported decreased night vision, which reversed
with discontinuation of the drug. Two of these patients
withdrew because of this toxic effect, 1 at week 8 and 1
at week 1. In the patient who withdrew at week 8, visual
symptoms improved during the drug holiday but returned again with drug reintroduction. Gastrointestinal
abnormalities were reported by 3 patients. O n e patient
developed nausea. Two patients developed gastrointestinal bleeding: 1 patient withdrew at week 8 because of
presumed NSAID-related peptic ulcer disease, and 1
withdrew at week 18 because of rectal bleeding from a
benign colonic adenoma, which was resected. Two patients reported dizziness during the study.
D u e to patient withdrawals, a n intent-to-treat
analysis was performed. N o patient met the Paulus
criteria for response. There was n o evidence of improvement in standard parameters of arthritis activity a t the
patients' final visit compared with their baseline visit
(Table 1). A modest decrease in the C R P level (P =
0.049) but not the ESR was observed. T h e r e was no
change in the CBC, blood chemistries, or fundoscopic
examination findings during the study.
Concentrations of 4-HPR and its metabolite
4-MPR were measured in synovial fluid from 1 patient
prior to initiation of 4-HPR and after 8 weeks of
therapy. Levels for 4-HPR and 4-MPR were not detectable in the pretreatment sample, but in t h e posttreat-
GRAVALLESE ET AL
1024
Table 1. Clinical disease variables at baseline and after treatment
with N-[4-hydroyphenyl] retinamide
Joint count
Pain (maximum 68)
Swelling (maximum 66)
Global assessment
(maximum 4)
Physician
Patient
Erythrocyte sedimentation rate
(mmihour)
C-reactive protein (mg/dl)
Baseline
(mean ? SEM)
Final visit
(mean ? SEM)
26.5 i 3.7
18.7 i 2.3
24.5 -t 4.9
19.8 ? 3.2
2.8 5 0.3
2.9 ? 0.3
68.9 ? 8.1
2.8 i 0.3
2.7 i 0.3
61.5 i 7.7
6.2 -t 1.1
4.1 i 0.8
ment sample, 4-HPR was 50 nglml and 4-MPR was 264
nglml.
Eight patients underwent pretreatment synovial
biopsy; 3 of these 8 patients withdrew from the study and
did not undergo posttreatment biopsy. Of the remaining
5 patients, only 2 had analyzable tissue with synovial
lining on both the pre- and posttreatment biopsies.
These 2 patients had their final biopsies at week 8 and
week 16, due to premature termination of the study for
visual impairment and flare of arthritis, respectively.
Quantitative in situ hybridization was performed on
tissues obtained by needle biopsy pre- and posttreatment
in these 2 cases. Biopsies were evaluated for the expression of mRNA for the metalloproteinases collagenase
and stromelysin, and for the control gene P1. Mean
hybridization ratios for all images for a given gene
product were calculated and compared in pre- and
posttreatment samples. No decrease in mRNA for the
metalloproteinases was detected after treatment with
4-HPR in the 2 cases analyzed (Table 2).
DISCUSSION
In this pilot study of 12 patients with longstanding
RA, no clinical effect was observed with the retinoid
4-HPR. No patient met predetermined criteria for response, and 2 patients withdrew because of a flare of
RA. In addition, no improvement in laboratory parameters was noted, except for a modest decrease in the
CRP without a concomitant decrease in the ESR. The
absence of patient response in this model suggests that,
at this dosage, 4-HPR has no significant efficacy in
patients with longstanding, active RA.
The dosage of 4-HPR used in this study was 300
mglday, which is higher than the 200 mglday dosage used
in breast cancer prophylaxis studies (24). Although drug
levels were not measured in plasma, one can infer, based
on the observed toxicity profile in this study, i.e., decreased nocturnal visual acuity, that drug levels were
sufficient to achieve a biological effect. In fact, 3 of 12
patients (25%) developed visual impairment, which reversed with drug discontinuation, thus preventing the
use of higher drug doses. In addition, the drug and one
of its metabolites (4-MPR) were measurable in the
synovial fluid in the 1 patient studied. Side effects that
may occur with 4-HPR in addition to reversible night
blindness include skin dryness, elevation in liver enzyme
levels, elevation in cholesterol and triglyceride levels,
joint pain, myalgias, headache, fatigue, and teratogenesis. These additional side effects did not occur in patients
in this study.
Whether this drug would be efficacious in patients with earlier or milder RA was not tested. The
patients enrolled in this study had severe, longstanding
RA with a mean disease duration of 15 (k4.5) years, and
all 12 patients had received at least 3 previous secondline therapies, including methotrexate in 11 of them. In
this patient population, established high levels of proinflammatory mediators may override any therapeutic
effects of 4-HPR. This is suggested by results in animal
models in which a clinical response and a decrease in
collagenase activity was noted when 4-HPR was given at
the time of initiation of arthritis or 11 days into the
course. A less dramatic effect was noted when the drug
was administered to animals with more established
disease (5). In one preclinical trial of retinoid treatment
of collagen-induced arthritis, a significant exacerbation
of arthritis was noted after treatment with both 4-HPR
and 13-cis-retinoic acid (25). This suggests that other
pathogenic mechanisms which may be disease-model
Table 2. Quantitation of messenger RNA for metalloproteinases
and control gene by in situ hybridization in synovial biopsies obtained
from 2 patients before and after treatment with N-[4-hydroyphenyl]
retinamide (4-HPR)*
Patient,
probe
Patient 1
Stromelysin
Collagenase
P1
Patient 2
Stromelysin
Collagenase
P1
Before
4-HPR
After
4-HPR
308 i 80
303 t 55
184 t 11
489 i 65
639 I 3 8
169 2 27
755 i 90
525 i 53
797 i 68
1014 i 91
1353 i 114
546 i 38
* For each image of synovial lining, the area (in pixels) covered by
grains was divided by the number of nuclei (see Patients and Methods).
Values are the mean ? SEM for all images analysed for a given probe
within each biopsy. Patient 1 was treated with 4-HPR for 16 weeks and
patient 2 for 8 weeks.
1025
A SYNTHETIC RETINOID IN RA
specific can predominate over the protective effects of
retinoids. Other reported effects of retinoids which could
be detrimental in RA include an increase in natural killer
cell activity (26) and a possible enhanced production of
interleukin-1 (27).
It has been demonstrated that retinoids decrease
collagenase activity in cultured synovial fibroblasts in
vitro (12,15) and in preclinical animal models of arthritis
(5,7). No decrease in collagenase or stromelysin mRNA
expression was observed in the two patients in this study
in whom paired synovial biopsies were obtained. Induction of collagenase and stromelysin gene expression has
been shown to be mediated at least in part by the
activator protein-1 (AP-1) sequence in the promoter
regions of these genes, to which the transcription factors
jun and fos bind (13,28). The effect of retinoids on
metalloproteinase gene expression is thought to be
accomplished by the retinoid-receptor complex blocking
activation of the metalloproteinase promoters through
the AP-1 site (14,16).
The retinoids and their metabolites act through
binding to 2 classes of receptor, the retinoic acid receptors a, p, and y (RARs) (29) and the retinoid X
receptors (RXRs) (30.31). Binding of retinoids to these
receptors requires specific receptor-ligand combinations, and different receptor-ligand complexes can exert
different effects on gene transcription. For this reason, it
is premature to conclude that all retinoids would be
ineffective in the treatment of RA; it is possible that
other retinoids would be effective due to differences in
receptor binding profiles in vivo. The specific receptors
present in RA synovial lining cells and the balance
between various RARs and AP-1 components in these
cells may also affect the clinical outcome. In addition,
patients with early RA may have a more favorable
response to retinoids. Finally, the concentration of
4-HPR in the joint in this study may have been suboptimal, since it has been reported that low concentrations of all-trans-retinoic acid (110p7M)stimulate collagenase production in human fibroblasts in vitro (32). In
conclusion, 4-HPR was not clinically effective in this
pilot study of patients with severe, longstanding RA.
However, the use of other retinoids should still be
considered.
ACKNOWLEDGMENTS
We are grateful to Drs. Constance Brinckerhoff,
Michael Sporn, Esther Rose, and Fredrick Minn for their
interest and support of this project. We also wish to thank the
staff of the Brigharn and Women’s Hospital Arthritis Center
and the Investigational Drug Service for their assistance with
the study.
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