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Treatment of psoriatic arthritis with oral 125-dihydroxyvitamin D3a pilot study.

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1723
BRIEF REPORT
TREATMENT OF PSORIATIC ARTHRITIS WITH ORAL
1,25-DIHYDROXYVITAMIN D,: A PILOT STUDY
DAVID HUCKINS, DAVID T. FELSON, and MICHAEL HOLICK
We conducted a 6-month open-label trial in
which 10 patients with active psoriatic arthritis received
2 p g of oral 1,25-dihydroxyvitamin D3 daily. Statistically significant improvement was noted in the tender
joint count and physician global impression. Of these 10
patients, 4 had substantial ( 2 5 0 % ) improvement, and 3
had moderate ( 2 2 5 % ) improvement in the tender joint
count. Two patients were unable to receive therapeutic
doses because of hypercalciuria. High-dose vitamin D
may be a useful therapeutic agent for psoriatic arthritis.
The principal therapies used in psoriatic arthritis are nonsteroidal antiinflammatory drugs (NSAIDs),
prednisone, and, in some cases, antimalarial agents,
gold salts, and methotrexate (1). All therapies have
potential toxicity, and psoriatic arthritis is often difficult to treat effectively (I). Recently, Smith et al (2)
and others (3,4) reported the use of oral 1,25-dihydroxyvitamin D3 [l ,25(OH),D3] in patients with psoriasis; up to 70% of the patients achieved significant
improvement in their skin lesions. Based on this
experience, we began a therapeutic trial of oral
1,25(OH),D3 in patients with psoriatic arthritis to see if
there was a beneficial effect on their arthritis, and, if
From the Boston University Arthritis Center and the Departments of Medicine, Boston City Hospital and University Hospital, Boston, Massachusetts.
Supported by NIH Multipurpose Arthritis Center grant
AR-20613.
David Huckins. MD: Arthritis Fellow; David T. Felson,
MD, MPH: Associate Professor of Medicine; Michael Holick, PhD,
MD: Professor of Medicine.
Address reprint requests to David T. Felson, MD, MPH.
Arthritis Center, A-203, Boston University School of Medicine, 80
East Concord Street, Boston, MA 021 18.
Submitted for publication January 17, 1990; accepted in
revised form May 7, 1990.
Arthritis and Rheumatism, Vol. 33, No. 11 (November 1990)
so, was there any correlation between improvement in
the skin lesions and improvement in the arthritis.
PATIENTS AND METHODS
Patient selection criteria. Patients 18-70 years of
age with active psoriatic arthritis were eligible for this
study. They were recruited from the clinic populations
of the Boston University Hospitals (University Hospital, Boston City Hospital, and Boston VA Medical
Center) or were referred by rheumatologists in private
practice. In the absence of diagnostic criteria for
psoriatic arthritis, criteria for inclusion in this study
required that patients have classic psoriatic skin lesions, the absence of both serum rheumatoid factor
and subcutaneous nodules, and 3 or more of the
following: tenderness or pain on motion in at least 1
joint or periarticular area, swelling of at least 1 joint or
periarticular area, sausage digits, morning stiffness, or
typical radiographic findings of psoriatic arthritis
(distal interphalangeal erosions and expansion of the
terminal phalanx, terminal phalanx osteolysis, sacroiliitis, erosive oligoarticular arthritis, or spinal syndesmophytes). Patients were also required to have had no
change in second-line therapy within 3 months of entry
into the study and to be classified as functional class
1-111 (5).
To be eligible for this study, patients had to
have active disease, as defined by the presence of 2 or
more tender joints (or periarticular areas) and 1 or
more of the following: minimum of 45 minutes of
morning stiffness, erythrocyte sedimentation rate
(ESR) 228 mm/hour, or inflammatory joint fluid without evidence of crystals or infection. Patients were
excluded if they had hypercalcemia, hypercalciuria, or
BRIEF REPORTS
1724
a history of nephrolithiasis, or were pregnant, anticipated becoming pregnant, or were nursing mothers.
Study design. This was a 6-month open-labeled
trial using oral 1 ,25(OH),D3 (Rocaltrol; provided by
Hoffman-LaRoche, Nutley, NJ), beginning with a dosage of 0.5 pglday. The dosage was increased by 0.25
&day every 2 weeks, to a maximum dosage of 2.0
pg/day. The 1 ,25(OH),D3 was administered at bedtime
because of a lower incidence of hypercalciuria and
hypercalcemia than when administered during the day
(2); this is presumably because there is less dietary
calcium available in the gut for absorption at night
when the serum level of 1,25(OH),D3 reaches its peak.
In addition, exogenous vitamin D inhibits endogenous
synthesis of 1,25(OH),D3 and increases its catabolism.
If serum or 24-hour urine calcium levels became
elevated, then the dosage of 1,25(OH)2D3was reduced
to the previous dosage at which serum and urine
calcium levels had been normal, and patients were
instructed to refrain from consuming dairy products.
Blood tests were then repeated 2 weeks later, and, if
the results were normal, the stepwise increase in
dosage was continued.
Evaluation. Patients were evaluated twice before treatment, at a 2-week interval, to establish a
disease activity baseline for later comparison. At each
visit, patients were questioned regarding the duration
of morning stiffness, overall activity of arthritis (graded from 0 to lo), and any change in their dosage of
steroids or NSAIDs. While we required that the second-line drug regimen remain stable, patients were
allowed to change their dosage of NSAIDs or steroids
during the trial, and this was followed as an indicator
of arthritis activity. We chose outcome measures
according to the recent recommendations of Anderson
et al(6). Once a month, the patients were evaluated for
joint tenderness in 66 diarthrodial joints and for tenderness in periarticular areas, as an indicator of enthesopathy. The “tender joint count” was the sum of all
tender joints and periarticular areas, with 1 = tender,
0 = nontender. Grip strength was also measured using
a mercury column sphygmomanometer. Also at each
visit, the examining physician scored the patient’s
global arthritis activity on a numerical scale from 0 to
10. Finally, at each visit, the patient completed the
Arthritis Impact Measurement Scales (AIMS) questionnaire (7). Evaluations for all examinations were
performed by the same observer (DH) in the same
manner.
In order to correlate changes in skin rash with
changes in arthritis activity, photographs of the rash
Table 1. Characteristics of 10 psoriatic arthritis patients who
received 1,25-dihydroxyvitaminD, therapy*
Mean age, years (range)
Mean disease duration, years (range)
Psoriasis
Arthritis
Functional class
I
I1
Ill
Sex
Female
Male
Concurrent therapy
NSAlDs
Methotrexate
Prednisone
Gold
* NSAIDs
=
47.3 (34-63)
19.8 (340)
13.6 (2-25)
2
6
2
nonsteroidal antiinflammatory drugs.
were taken at each visit. The final photographs at the
end of the trial were compared with the baseline
photographs and graded as - 1 = worsening rash, 0 =
no change, 1 = mild improvement, 2 = moderate
improvement, and 3 = marked improvement. Photographic evaluation was performed without knowledge
of the arthritis response.
Laboratory studies. At the initial visit, blood
was drawn for antinuclear antibody, rheumatoid factor, ESR, phosphate, calcium, blood urea nitrogen,
creatinine, albumin, total protein, 25(OH)D3, and
1 ,25(OH)2D3 levels. A 24-hour urine collection was
obtained for measurement of calcium and creatinine.
Blood was drawn every 2 weeks for calcium, phosphate, creatinine, and 1,25(OH),D3 levels, along with
a 24-hour urine calcium measurement. The ESR was
checked once a month, at the time of each arthritis
examination.
Statistical analysis. For each outcome measure,
the average of the values for the first 2 visits was used
as the baseline value. This was compared with the
value from the last visit for each outcome measure,
and the difference was calculated.
The statistical significance for each outcome
measure was then determined using a paired t-test.
Statistical significance was defined as a I0.05, by
2-tailed test. Individual outcome measures for each
patient were also classified as showing substantial
improvement (250%) or moderate improvement
(r25%), based on the criteria described by Bombardier et al (8).
BRIEF REPORTS
RESULTS
Patient characteristics. Ten patients met inclusion criteria and entered the trial (see Table I). There
were 8 men and 2 women. The mean age was 47.3
years, the mean duration of psoriasis was 19.8 years,
and the mean duration of arthritis was 13.6 years. The
use of arthritis medication was frequent, but all patients had active ongoing arthritis, with a mean baseline tender joint count of 15.8 (range 5.5-39.5). All
patients had swollen joints.
Six patients completed 6 months of therapy.
One of these patients developed transient hypercalcemia and hypercalciuria, which responded immediately
to a temporary reduction in the dosage of 1,25(OH),D,. Of the 4 patients not completing 6 months, 1
was withdrawn because of a protocol violation after 4
months (her methotrexate dosage was temporarily
reduced because of oral ulcers); she had responded to
therapy and continued to receive vitamin D treatment.
Another patient completed 5 months of therapy and
then was lost to followup; he had also responded to
therapy, with 250% improvement in the tender joint
count. Two other patients dropped out of the study
because of hypercalciuria, which made them unable to
take the maximum dosage of 1,25(OH)$,. There was
no change in renal function nor any nephrolithiasis in
any patient during the study.
The results of therapy for all patients who
entered the study, regardless of whether they completed the trial (intent-to-treat analysis), and for those
patients who completed the 6 months of therapy are
shown in Table 2. There was improvement in all
measures of arthritis activity, although changes in
many measures did not reach statistical significance.
For the intent-to-treat analysis, there was significant
improvement in the tender joint count ( P < 0.01) and
physician global assessment (P < 0.05). For other
measures, (the ESR and pain and physical activity as
determined by the AIMS), patients sustained improvemen1 that nearly reached significance (0.05 < P <
0.10). Five patients had substantial improvement and 2
had moderate improvement in physician global assessment; 4 patients had substantial improvement and 3
had moderate improvement in tender joint count.
Of the 9 patients whose skin lesions were
evaluated, 4 had marked improvement, as determined
by a decrease in the scaling and thickness of the
plaques. Of these 4 patients, 2 had substantial improvement in the tender joint count, 1 had moderate
improvement, and I had no improvement. Two pa-
1725
Table 2. Results of 1,25-dihydroxyvitamin D, therapy in patients
with psoriatic arthritis*
Mean Mean
initial end
Change
score score (mean 2 SEM)t
I
Intent-to-treat analysis
(n
= 10)
5.52 4.35 -1.18 f 1.04
Patient global assessment
(0-10 scale)
AIMS pain (0-10 scale)
7.48 5.89 -1.52 f 0.78
AIMS physical activity
6.00 4.55 - 1.33 f 0.65
(0-10 scale)
4.45 2.80 -1.65 t 0.55
Physician global
assessment (0-10 scale)
15.75 9.70 -6.05 2 1.47
Tender joint count
154.55 165.49 10.94 2 13.60
Grip strength (mm Hg)
Erythrocyte sedimentation 23.00 13.60 -9.80 f 14.47
rate ( m d h o u r )
Patients completing
6 months (n = 6)
5.21 4.00 -1.21 2 1.18
Patient global assessment
(0-10 scale)
7.58 6.16 -1.22 2 0.98
AIMS pain (0-10 scale)
5.50 4.33 -1.16 f 0.83
AIMS physical activity
(0-10 scale)
Physician global
4.43 2.50 - 1.75 t 0.59
assessment (0-10 scale)
17.92 11.83 -6.08 2 2.22
Tender joint count
145.54 167.33 21.79 f 21.09
Grip strength (mm Hg)
Erythrocyte sedimentation 24.17 14.00 -10.16 2 3.48
rate (mm/hour)
1.13
1.95$
2.05$
3.025
4.1~1
0.80
2.14$
1.02
1.35
1.39
2.985
2.750
1.03
2.920
* One patient included in the intent-to-treat analysis was not included in the measurement of pain and physical activity from the
Arthritis Impact Measurement Scale (AIMS).
t Values are in the direction of improvement.
$ 0.05 < P < 0.10.
0 P < 0.05.
!I P < 0.01.
tients actually had worsening of their psoriasis during
the trial; one of these patients had moderate improvement in the tender joint count, the other had no
change. The only patient taking prednisone had decreased the dosage from 7.5 mg/day to 5 mg/day during
the study, while noting substantial improvement. Two
patients reduced the dosage of their NSAID by 50%
during the study, while 1 patient, who left the study
after 4 months because of hypercalciuria and inefficacy, increased his NSAID dosage.
Figure I shows the mean tender joint count,
mean physician global assessment, and mean doses of
1,25(OH),D3 at each visit for the 6 patients who
completed the entire 6-month study. It often took 2-3
months for improvement to occur, and improvement
never occurred at a dosage less than 1.5 &day.
1726
BRIEF REPORTS
Mean 20
Tender 19 Joint
18
Count l 7 -
- 10
-
-9
"
(d
-
-
- 8
16
15 14 -
13
12
11
- 5
-
10
g+-----x
71
-1
- 4
-
8
4 -
,
3 2 -
Mean
RccaItrOl 0 9
- 1
-
A
1 -
1
I
I
DISCUSSION
This open-label trial of oral 1,25(OH),D3 in 10
patients with active psoriatic arthritis showed a statistically significant improvement in both the physician
global assessment and tender joint count. In addition,
the decrease in ESR levels and the improvement in the
AIMS pain and physical activity scores approached
statistical significance (0.05 < P < 0.10). Among those
patients completing the trial, the ESR, physician
global assessment, and joint count values all improved
significantly. The improvement in the activity of the
skin lesions was variable and was not clearly related to
an improvement in arthritis. Of the 10 patients enrolled
in the trial, 5 elected to continue therapy with oral
1,25(OH),D3 after the trial was completed.
Vitamin D may have immunoregulatory effects
that ameliorate inflammatory arthritis. 1,25(OH),D,
has been shown to potentiate the inhibitory effect of
cyclosporin A on helper T cells from patients with
rheumatoid arthritis (9), to inhibit T lymphocyte mitogenesis (lo), and to have varying effects on lymphokine production (1 1,12). Another such possibility is
that there is a common cellular mechanism that leads
both to the proliferation of skin cells and to synovial
inflammation and proliferation. I ,25(0H),D3. inhibits
proliferation and induces terminal differentiation in
epidermal cells from psoriatic patients (13), and it may
have similar direct effects on synovial cells.
Mean
Physician
Global
- 2 Assessment
- 3
I
I
I
I
n
-0
Also, 1,25(OH),D, may be effective in alleviating the psoriasis that causes the active arthritis. If this
were the case, one would expect parallel changes in
the arthritis and the skin lesions. In this study, all
patients who had significant clearing of skin lesions
either had improvement or no change in their arthritis,
but the patients with no improvement or worsening of
their skin lesions had variable responses in their
arthritis. With this small sample size of 10 patients,
we cannot clearly define any relationship between
changes in arthritis activity and skin disease.
One of the principal drawbacks of this study is
its open-label design. This raises the possibility of
observer bias and cannot take into account the placebo
effect. The long lag period prior to response and
response only at high dosages makes the placebo effect
an unlikely explanation for the findings. Another limitation of the study is that the number of patients is
small. However, the finding of statistically significant
improvement in the tender joint count and physician
global impression, despite the sample numbers, makes
these findings more impressive.
A third problem is that patients were allowed to
adjust their dosages of prednisone and NSAIDs during
the trial. However, most patients who did so decreased
the dosage, which would indicate improvement.
In summary, this small, open-label trial suggests a possible beneficial effect of oral 1,25(OH),D3 in
BRIEF REPORTS
patients with psoriatic arthritis. Lf this beneficial effect
is confirmed in future controlled trials, then 1,25(OH),D, offers an attractive alternative therapy f o r
psoriatic arthritis, since its only known side effects are
hypercalcemia and hypercalciuria, which can be monitored easily and can respond quickly to a reduction in
dosage. Monitoring of 24-hour urinary calcium levels
every 2 weeks is necessary until a stable dosage is
reached, but after that time, the frequency of this
measurement can be reduced.
Acknowledgments. We thank Drs. Caryn Libbey,
Burton Sack, Stuart Schneller, Robert Meenan, and Jeffrey
Wohkethan. and Diane Jovce. RN.
1727
7.
8.
9.
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