close

Вход

Забыли?

вход по аккаунту

?

Treatment of psoriatic arthritis with extracorporeal photochemotherapy and conventional psoralenultraviolet A irradiation.

код для вставкиСкачать
ARTHRITIS & RHEUMATISM
Vol. 39, No. 9, September 1996, pp 1519-1523
0 1996, American College of Rheurnatology
1519
TREATMENT OF PSORIATIC ARTHRITIS WITH
EXTRACORPOREAL PHOTOCHEMOTHERAPY AND
CONVENTIONAL PSORALEN-ULTRAVIOLET A IRRADIATION
CARIN VAHLQUIST, MARWNE LARSSON, JAN ERNERUDH, GOSTA BERLIN,
THOMAS SKOGH, and ANDERS VAHLQUIST
Objective. To study the use of combined photopheresis and psoralen-ultraviolet A irradiation (PUVA)
in the treatment of psoriatic arthritis.
Methods. Eight patients with psoriasis and seronegative arthritis received photopheresis for 12 weeks,
followed by photopheresis plus PUVA for another 12
weeks. Clinical and laboratory examinations were performed every 3 months for up to 1 year after therapy.
Results. Four patients experienced a marked improvement of joint symptoms that lasted for 212
months post-therapy (74%decrease in the Ritchie articular index; P < 0.01). Prior to therapy, these patients
had a higher CD4CD8 ratio than the poor responders.
Only minor laboratory changes occurred.
Concluswn. A more extensive trial of photopheresis plus PUVA in psoriatic arthritis is warranted.
Photochemotherapy has been viewed with increasing interest as a means of selectively and efficiently
destroying cells or tissues that exhibit undesired growth
or disturbed differentiation. Light activation of certain
compounds, such as psoralen, causes a crosslinking of
DNA, as well as many nongenomic effects that either
modify or kill the cells (for review, see ref. 1). In
dermatologic praxis, oral or topical psoralen combined
Presented in part at the Tenth Congress of the European
Society for Haemopheresis, Vienna, Austria, September 1995, and at
the Annual Meeting of the European Society for Dermatological
Research, Vienna, Austria, September 1995.
Supported by grants from the Swedish Psoriasis Association
and the County Council of Ostergotland.
Carin Vahlquist, MD, PhD, Marianne Larsson, MD, Jan
Ernerudh, MD, PhD, Gosta Berlin, MD, PhD, Thomas Skogh, MD,
PhD, Anders Vahlquist, MD, PhD: University Hospital, Linkoping,
Sweden.
Address reprint requests to Carin Vahlquist, MD, PhD,
Department of Dermatology, University Hospital, S-58185 Linkoping,
Sweden.
Submitted for publication October 2, 1995; accepted in revised form April 15, 1996.
with ultraviolet A (320-390 nm) irradiation (PUVA) has
long been used for the treatment of severe psoriasis,
eczema, and to a lesser extent, cutaneous T cell lymphoma. Extracorporeal photochemotherapy (photopheresis) was originally developed to achieve a more
potent effect on blood cells, especially the malignant
lymphocytes associated with T cell leukemia (SCzary
syndrome) (1).
Photopheresis has recently been used also in
diverse autoimmune disorders (2). The photopheresis
procedure consists of oral administration of psoralen
followed by exposure of the patient’s leukocytes (enriched by leukapheresis) to UVA irradiation in a specially designed device. All blood products are then
returned to the circulation. Photopheresis can selectively
modulate abnormal T cell clones and possibly cause the
systemic release of cytokines, which in turn can exert
immunomodulatory effects (2). It is known that manipulated autoreactive T cells have a vaccination-like effect
when injected into experimental animals, and this phenomenon may possibly be an explanation of the systemic
effects of photochemotherapy (3).
Disturbed T cell function and possibly autoimmunity are considered to be important factors in the
pathogenesis of psoriasis (4), and may also explain the
high frequency of arthritis in this common skin disorder.
Patients with severe psoriatic arthritis often require
immunosuppressive therapy (corticosteroids, methotrexate, sulfasalazine, retinoids, cyclosporin A), which have
potentially severe side effects; yet the beneficial effects of
this therapy are often meager.
Photopheresis has been tried previously in the
treatment of psoriatic arthritis ($6) and rheumatoid
arthritis (7), but only a few patients have been included
in the studies and the results have been equivocal. We
performed a more detailed study on a larger group of
patients with psoriatic arthritis, adding the potentially
VAHLQUIST ET AL
1520
Table 1. Clinical characteristics of the patients*
Patient
Agehex
38/F
52lM
39/F
53/M
4O/M
44F
38M
44/M
~~
Years of
arthritis
6
7
15
9
13
6
10
15
RAI
Years of
psoriasis
PASI
score
24
23
29
24
32
24
21
17
23
7
27
13
15
6
10
25
4
3
4
17
22
46
13
31
Response to
MTX
None
-
-
None
-
Adv. eff.
Good$
Gold
HCQ
Adv. eff.
ssz
Adv. eff.
Adv. eff.
None
-
None
-
Nonet
None
-
Ongoing therapy at
start of trial
-
Pred. 2.5 mg, NSAID
NSAID
NSAID
NSAID
NSAID
Acetaminophen
Acetaminophen
-
ASA
~
* RAI = Ritchie articular index; PASI = Psoriasis Area Severity Index; MTX = methotrexate; HCQ = hydroxychloroquine; SSZ = sulfasalazine;
Adv. eff. = adverse effects; Pred. = prednisone; NSAID = nonsteroidal antiinflammatory drug; ASA = acetylsalicylic acid.
t Initially good effect, but became resistant to the therapy after several years.
Later stopped MTX because of desire to become pregnant.
*
synergistic effect of conventional PUVA therapy to
photopheresis monotherapy.
PATIENTS AND METHODS
Patients with chronic, seronegative polyarthritis and
psoriatic skin lesions, who had had a poor response to previous
therapy, were eligible for the study. Eight patients attending
the rheumatology clinic at our institution were enrolled, after
giving informed consent (Table 1). None of the patients had
severe functional disability. The skin symptoms were mild to
moderate and were mainly located on the extremities. None of
the patients had been treated with PUVA previously. No
treatment with slow-acting antirheumatic drugs was allowed
for 3 months prior to initiation of the study treatment or during
the study. None of the patients had a significant worsening or
improvement of arthritic symptoms during the 3-month prestudy period. Patients were allowed to continue receiving mild
antiinflammatory/analgesic therapy (mainly nonsteroidal antiinflammatory drugs) throughout the study. Patient 1continued
to take low-dose oral steroids that she had been taking for
several years, until the twelfth week of the study, when the drug
was withdrawn in association with hand surgery. Topical
treatment consisting of emollients and corticosteroid creams
was unrestricted during the study. Sunscreens were recommended during treatment days.
Study design. The study was approved by the Local
Ethical Committee and the Medical Products Agency of
Sweden. The trial was performed between January 1993 and
May 1995, as an open study. Photopheresis was given initially
as monotherapy for 12 weeks, then combined with PUVA for
12 weeks in patients with insufficient response, and patients
were followed up for 1year after discontinuation of the study
therapy (Figure 1).The patients were examined clinically and
by means of laboratory investigations (see below) on the day
before the fist administration of photopheresis, after 6, 12,
and 24 weeks of treatment, and 3, 6, and 12 months after
discontinuation of therapy.
Photopheresis and PUVA. The photopheresis equipment consisted of a UVAR instrument (Therakos, West
Chester, PA) which was used as previously described (8).
Briefly, after oral intake of 8-methoxypsoralen @-MOP; Puvamet; Tika, Lund, Sweden), 240 ml of buEy coat and 200 ml
of plasma were removed by a discontinuous apheresis procedure and diluted with 200 ml of saline. The cell solution was
passed through a disposable transparent plastic channel, exposed for 90 minutes to UVA light (2 J/cm2), and returned to
the patient’s circulation.
Photopheresis was initially administered on 2 consecutive days (double treatment) and repeated after 2,4,8, and 12
weeks. In the second part of the study (weeks 13-24), photopheresis was administered once every month. During this
period PUVA treatment was added, initially twice per week for
6 weeks, then once weekly. The same oral dose of 8-MOP (see
below) was given 1-2 hours before PUVA or photopheresis.
Whole-body UVA irradiation, beginning with 0.5 J/cm2 and
increasing in a stepwise manner to a maximum of 3.5 J/cm2,
was given in a P W A 6001 Cabin (Waldmann, Schwenningen,
Austria).
Because of the well-known variability of psoralen
bioavailability, the plasma concentration profile 1-4 hours
after administration of a standard oral dose of 0.6 m a g of
8-MOP was assessed in each patient before the treatment was
started. The individual dosage was adjusted so as to attain a
peak plasma concentration of >lo0 ng/ml, determined by a
standard high-pressure liquid chromatography technique (9).
I
ov
12v
:
/
24w
3
6
l2mo.
mtt-
%irrpy
Figure 1. Flow chart of the treatment and evaluation protocol. Photopheresis was also administered after 2 weeks (not shown). PUVA =
psoralen-ultraviolet A irradiation; w = week; mo. = month.
PHOTOPHERESIS IN PSORIATIC ARTHRITIS
1521
Table 2. Clinical and laboratory variables in relation to therapy”
~
~
~
~
Treatment period
Skin involvement, PAS1
No. of swollen joints
RAI
Health Assessment Questionnaire
Well-being, 0-10-point VAS
ESR, mmhour
WBC, 10gfliter
Platelets, 1o9/liter
CRP, mg/liter
Haptoglobin, gmfliter
IL-6, ngliter
sIL-~R,unitdm1
HLA-DR+ T cells, as % of CD3+ cells
~
Followup period
Pretreatment
12 weeks
24 weeks
3 months
6 months
12 months
18 -t 15
17 -t 14
24.3 -t 4.6
1.0 2 0.5
5.9 5 1.0
17 -t 9
7.5 -t 1.6
266 ? 66
14 2 6
2.4 2 0.8
40 2 26
558 -t 227
2.4 -t 1.6
13 2 15
1129
15.1 t 6.5$
0.9 2 0.3
3.8 2 1.8$
18 2 13
6.1 2 1.3t
229 2 67
13 2 5
2.3 2 0.8
48 2 47
557 2 266
1.8 2 0.8
5 t 5t
8 Z 5T
11.5 t 5.7$
0.9 2 0.4
3.5 t 1.1*
13 2 8
6.2 2 1.5
236 -C 57
13 t 8
2.1 t 0.7
37 2 35
474 2 185
3.9 2 l.lt
ND
10 t 7
13.0 2 5.8$
1.0 t 0.4
4.6 2 2.4
15 2 9
6.6 2 1.5
244 t 50
12 5 5
2.1 2 0.8
29 2 15
524 2 222
3.8 2 1.9
ND
11?9
12.3 t 8.2$
1.0 t 0.3
5.1 2 2.3
22 2 12
7.1 2 1.0
265 t 82
15 2 6
2.2 2 0.7
32 2 19
554 t 224
3.8 t 2.3
625
12 2 14
11.8 2 7.5$
1.0 t 0.4
4.2 t 2.lt
12 t 10
6.2 t 1.4
242 t 46
12 2 5
1.6 2 0.7
ND
ND
ND
* Values are the mean 2 SD. ND = not determined; VAS = visual analog scale; ESR = erythrocyte sedimentation rate; WBC = white blood cells;
CFW = C-reactive protein; IL-6 = interleukin-6; sIL-2R = soluble interleukin-2 receptor. See Table 1 for other definitions.
t P < 0.05 versus pretreatment.
$ P < 0.01 versus pretreatment.
The 8-MOP concentration was also determined repeatedly in
the leukocyte suspension obtained during photopheresis.
Clinical assessments. In the rheumatologic examinations, the following variables were assessed: Ritchie articular
index (RAI) (53-joint score plus distal interphalangeal finger
joints) (lo), number of swollen joints (62-joint score), duration
of morning stiffness, and grip strength (Grippit; AB Detector;
Gothenburg, Sweden). The Health Assessment Questionnaire
(HAQ) as described by Fries et al (11) was administered. In
addition, the patient’s assessment of well-being was recorded
on a visual analog scale, where 0 represented optimal wellbeing and 10 the worst possible condition.
The skin symptoms were assessed using the Psoriasis
Area Severity Index (PASI) (12). The PASI adds the scores for
erythema, scaling, infiltration, hyperkeratosis, and pustules
(0 = no symptoms, 4 = very severe symptoms) in different
regions (trunk, extremities, head, etc.) and multiplies the sums
by the corresponding scores for the extent of the lesions in
these regions (0 = no psoriasis, 5 = 71-90% involvement)
(maximum possible score 600).
Laboratory investigations. Routine blood and urine
tests were performed at each visit. Lymphocyte populations
were determined by two-color flow cytometry (EPICS Profile
11; Coulter Electronics, Hialeah, FL). Fluorochromeconjugated monoclonal antibodies were incubated with
EDTA-treated peripheral blood. The samples were then
treated automatically by the Q-prep method (Coulter), including hemolysis of the red blood cells. The following fluorescein
isothiocyanate isomer I (F1TC)- or phycoerythrin (RD1)conjugated monoclonal antibodies were used: anti-CD2 (T11RDl), anti-CD3 (m-FITC), anti-CD4 (TCFITC), antLCD8
(T8-FITC), anti-CD45RA (2H4-RD1), anti-S6FI (S6FI-RDl),
anti-CD26 (TA1-RDl), and anti-HLA-DR (13-RD1).
The occurrence of antinuclear antibodies ( M A ) was
determined by immunofluorescenceusing HEp-2 cells (Immunoconcepts, Sacramento, CA) and indirect immunofluorescence
microscopy essentially as described elsewhere (13). Rheumatoid factor (FW)was determined by nephelometry. Plasma
interleukin-6 (IL-6) and soluble IL-2 receptor (sIL-2R) levels
were assessed by enzyme-linked immunosorbent assay as described by Goldman et al (14).
Statistical analysis. Data analysis and graphic presentations were done using CA-Cricket Graph I11 (Computer
Associates International, Islandia, NY).Statistical evaluations
were performed using StatView (Abacus Concepts, Berkeley,
CA). When the Mann-Whitney U test was used, P values less
than 0.05 were considered significant.
RESULTS
Clinical outcome. All 8 patients completed the
study, with only minor modifications of the protocol.
Two patients (patients 1 and 2) had to stop PUVA
therapy after 6 weeks and 8 weeks, respectively, due to
abnormal light sensitivity during summertime. One patient developed a drug eruption while taking enalapril
(for hypertension), and another experienced nausea and
dizziness when taking the psoralen tablets. No other
adverse effects were reported.
Table 2 shows that, whereas the skin lesions
improved especially during the second treatment period,
most of the rheumatologic measures already showed
improvement during the first 12 weeks, when photopheresis was given as the only treatment, and remained
improved throughout the study. The Fries index (HAQ)
was low from the beginning (no patients were severely
disabled) and did not change significantly during the
study.
In the global assessment after 24 weeks, particularly good results were obtained in 4 patients. Figure 2a
shows that the mean RAI in this group of “responders”
decreased after only 6 weeks, whereas the “nonre-
VAHLQUIST ET AL
1522
h
0
0
0
Patlent No.
‘....V
t3
I
v
12
24
3
6
It
10
0
0
I
0
2
0
3
A
4
w
5
*
6
V
l
v
8
..........
responder (mean)
nonrespondcr(mean)
0
12
‘4
Treatment
period (wks)
.%
h
I’
Follow-up period
(months)
Figure 2. Individual values for the Ritchie articular index (a) and the patient’s assessment of
well-being, on a visual analog scale (VAS) (b), before and after treatment. Solid symbols indicate
responders (6-weeks values are also included for this group). See text for definition of responders.
sponders” showed only a minor decrease in the RAI.
The difference between the groups was statistically significant (P < 0.05) as late as 12 months post-therapy.
Figure 2b shows that pronounced differences were also
seen in the patients’ own scoring of well-being. Similar
differences were noted in other parameters of joint
involvement, i.e., grip strength and duration of morning
stiffness (data not shown).
The use of analgesic and antiintlammatory therapy did not change in either of the groups. A few weeks
before the last evaluation, patient 8 underwent a short
course of systemic corticosteroid treatment for an allergic drug eruption.
Laboratory outcomes. The plasma psoralen concentration showed considerable variation between subjects. However, only small dosage adjustments had to be
made (0.4-0.8 mgikg) to attain therapeutic levels (see
Patients and Methods). The 8-MOP concentration in the
buf€y coat exposed to UVA during photopheresis was
102 2 53 ng/ml (mean I+_ SD), considered to be an
adequate level.
Only minor changes were seen in the general
1523
PHOTOPHERESIS IN PSORIATIC ARTHRITIS
laboratory parameters (Table 2). Mean a,-antitrypsin
and orosomucoid levels varied inconsistently between
1.1 and 1.4 gmjiter, and the mean &-microglobulin level
was constant at 1.6 mg/liter (data not shown). The
plasma IL-6 level was increased above the normal range
( 4 0 ng/liter) in all patients before the start of therapy,
whereas sIL-2R levels were within the normal range
(<1,000 units/ml). RF and ANA were persistently negative in all patients. No significant differences in laboratory variables were seen between the responders and
nonresponders (data not shown).
The lymphocyte profiles showed no significant
changes during the course of the study or between the
groups. Table 2 shows that the proportion of activated
HLA-DR positive T cells (expressed as the percent of
CD3+ cells; normal <5.1%) increased slightly at the
end of treatment and remained at this level during the
followup period. The pretreatment CD4:CDS ratios
were higher in responders as compared with nonresponders (mean -+ SD 2.4 ? 1.4 in responders and 1.2 5
0.1 in nonresponders; P = 0.02 [normal <2.4]). The
individual CD4:CDS ratios were virtually constant during and after the treatment period.
DISCUSSION
The results of this open study indicate that a
subpopulation of patients (4 of 8) with severe psoriatic
arthritis respond very well to photopheresis plus PUVA
therapy and that this effect may persist for more than a
year after therapy. Presently, we cannot predict which
patients will respond. The CD4CD8 ratio was higher in
all responders than in all nonresponders, but this finding
needs to be confirmed in a larger series of patients. Also,
a clear-cut clinical response within the first 3 months of
therapy seems to predict a favorable prognosis.
The reason for the better effects in our study as
compared with previous studies of photopheresis in
smaller numbers of patients with psoriatic arthritis (5,6)
might be a more favorable selection of patients or the
fact that we used a combination of photopheresis and
PUVA. PUVA is probably a worthwhile addition, because photopheresis per se has little effect on the skin
manifestations of psoriasis (ref. 15 and present report),
and skin inflammation may possibly trigger the extracutaneous manifestations of the disease. Another argument for combined treatment is the possibility of reducing the number of expensive photopheresis sessions. Our
study did not show any major laboratory changes that
could explain the mechanism of action of photopheresis
in psoriatic arthritis. There was a trend toward increased
T cell activity (increased proportion of HLA-DRexpressing T cells) during and after treatment, but this
finding must be interpreted with caution because of the
small number of observations and the fact that multiple
statistical analyses were performed. By and large, photopheresis seems to be a “silent” therapy in the sense
that laboratory changes are minor and adverse effects
rare. It is possible, though, that photopheresis exerts a
vaccination-like effect against pathologic T cell clones, as
originally proposed by Edelson et a1 (l),which does not
clearly show up in the immunologic tests used in the
present study.
REFERENCES
1. Edelson R, Heald P, Perez M, Rook A Photopheresis update.
Prog Dermatol 25:l-6, 1991
2. Rook A, Cohen J, Lessin S, Vowels B Therapeutic applicationsof
photopheresis. Dermatol Clin 11:339-347, 1993
3. Panayi G Phototherapy-T-cell vaccination by another name?
Clin Exp Immunol 95363-365, 1994
4. Valdimarsson H, Baker B, Jonsdottir I, Powles A, Fry L: Psoriasis:
a T-cell-mediated autoimmune disease induced by streptococcal
superantigens? Immunol Today 16:145-149,1995
5. Wilfert H, Honingsmann H, Steiner G, Smolen J, Wolff K
Treatment of psoriatic arthritis by extracorporeal photochemotherapy. Br J Dermatol 122:225-232, 1990
6. DeMisa R, h a n a J, Harto A, Boixeda P, Moreno R, Ledo A
Psoriathic arthritis one year of treatment with extracorporeal
photochemotherapy. J Am Acad Dermatol301037-1038, 1994
7. Malawista S, Trock DH, Edelson R L Treatment of rheumatoid
arthritis by extracorporeal photochemotherapy: a pilot study.
Arthritis Rheum 34:646-654, 1991
8. Edelson R, Berger C, Gasparro F, Jegasothy B, Heald P, Wintroub
B: Treatment of cutaneous T-cell lymphoma by extracorporeal
photochemotherapy: preliminary results. N Engl J Med 316:297303, 1987
9. Puglisi C, deSilva A, Meyer J: Determination of 8-methoxypsoralen, a photoactive compound, in blood by high pressure liquid
chromatography. Anal Lett 1039-50, 1977
10. Ritchie DM, Boyle JA, McInnes JM, Jasani MK, Dalakos TG,
Grieveson P, Buchanan WW: Clinical studies with an articular
index for the assessment of joint tenderness in patients with
rheumatoid arthritis. QJM 37:393-406, 1968
11. Fries J, Spitz P, Young D: The dimensions of health outcomes: the
Health Assessment Questionnaire disability and pain scales. J
Rheumatol 9:789-793, 1982
12. Fredriksson T Oral treatment of psoriasis and pustulosis palmoplantaris with Ro 10-9359. Dermatology 157 (suppl 1):13-18,1978
13. Vrethem M, Skogh T, Berlin G, Ernerudh J: Autoantibodies
versus clinical symptoms in blood donors. J Rheumatol 19:19191921, 1992
14. Goldman B, Oh S, Davis B, Kadin M, Poiesz B, Koh H: Serum
soluble interleukin 2 receptor levels in erythrodermic cutaneous
T-cell lymphoma correlate with response to photopheresis-based
treatment. Arch Dermatol 1291116-1170, 1993
15. Vonderheid EC, Kang C-A, Kadin M, Bigler R, Griffin TD,
Rogers TJ: Extracorporeal photopheresis in psoriasis vulgaris
clinical and immunologic observations. J Am Acad Dermatol
23:703-712, 1990
Документ
Категория
Без категории
Просмотров
3
Размер файла
460 Кб
Теги
treatment, arthritis, psoriatic, psoralenultraviolet, irradiation, convention, photochemotherapy, extracorporeal
1/--страниц
Пожаловаться на содержимое документа