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Efficacy of tumor necrosis factor ╨Ю┬▒ blockade for enthesitis in spondylarthropathyComment on the article by Marzo-Ortega et al.

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ARTHRITIS & RHEUMATISM
Vol. 46, No. 12, December 2002, pp 3390–3398
© 2002, American College of Rheumatology
LETTERS
Wait times for new patients to see rheumatologists are lengthy,
ranging from 4 to 24 weeks in both community practices and
academic medical centers. This is unacceptable, particularly in
light of our new understanding of the disease progression of
our core diseases, including rheumatoid arthritis. Delay in
treatment of even several months may be deleterious to
patients with rheumatoid arthritis (Pincus T, Gibofsky A,
Weinblatt ME. Urgent care and tight control of rheumatoid
arthritis as in diabetes and hypertension: better treatments but
a shortage of rheumatologists. Arthritis Rheum 2002;47:851–
4). With the crisis in the number of practicing rheumatologists,
we need to develop better systems to reduce the wait times for
patients with systemic rheumatic disease. It is unacceptable for
patients with rheumatoid arthritis to wait months for a newpatient appointment. We need to triage and manage patients
better so that patients with systemic rheumatic diseases can be
seen in a more timely manner.
I am delighted that my address generated such lively
discussion, having received many calls, letters, and e-mails,
particularly regarding my comments about ethics, industry
relations, and the work force situation. This crisis in work force
must be addressed, because without a sufficient number of
rheumatologists to care for all of our patients, rationing of
visits for those with nonsystemic rheumatic illnesses (including
fibromyalgia) may be required to adequately care for those
with systemic rheumatic disease.
DOI 10.1002/art.10569
The value of rheumatologists to patients with
fibromyalgia: comment on the presidential address by
Weinblatt
To the Editor:
Although I reviewed the American College of Rheumatology presidential address (Weinblatt ME. ACR presidential address: the best of times, the worst of times, rheumatology
2001. Arthritis Rheum 2002;46:567–73) with great interest as
soon as it arrived, I regret that its Tale of Two Cities metaphor
inspired not only juxtaposition, but also a conflicting emotional
response quite separate from its intended message.
Although the address triumphantly chronicled many
accomplishments and described our new challenges, I felt
belittled by the comments regarding fibromyalgia. Rheumatologists have a proud tradition of walking where others fear to
tread. Our participation in investigating the enigmas of breast
implants, Lyme disease, tryptophan, and myriad other puzzles
only hastened the eventual understanding of these problems.
Who is better qualified than rheumatologists to finally unravel
the daunting mystery of fibromyalgia? I believe that Dr.
Weinblatt may be inaccurate when he suggests that rheumatologists provide “little value” to patients with fibromyalgia.
The comments regarding Mary Betty Stevens personified my hopes and aspirations as well. While each specialty
seems to be trying to discard their most emotionally challenging disorders to primary care physicians and psychiatrists, I
doubt that those inspiring pioneers ever took the easy road by
“restricting followup visits.” We will overcome this daunting
adversary called fibromyalgia. And, as with previous challenges, we will eventually be just as proud of that effort and
determination.
We are all committed to caring for patients with
inflammatory diseases, but our past success should inspire us
to conquer all of our challenges, not just to enjoy the fruits of
our recent advances for a portion of our patients.
Michael E. Weinblatt, MD
Brigham and Women’s Hospital
and Harvard Medical School
Boston, MA
DOI 10.1002/art.10562
Increased osteoprotegerin and decreased pyridinoline
levels in patients with ankylosing spondylitis:
comment on the article by Gratacós et al
Andrew J. Holman, MD
Seattle, WA
To the Editor:
As previously reported in Arthritis & Rheumatism,
measurement of bone mass in patients with ankylosing spondylitis (AS), shows conflicting results (1). The same appears to
occur in the evaluation of biochemical markers of bone
metabolism in AS (2).
We reasoned that some of these discrepant results
observed in the various studies using urinary markers of bone
resorption were attributable to the fact that the markers are
expressed in relation to the amount of creatinine excreted, and
that considerable variation could be expected due to the fact
that various degrees of immobilization related to the ankylosis
could lead to distinct levels of creatinine in the urine, altering
the amount of pyridinoline present. To bypass these limitations, we assessed serum (rather than urine) pyridinoline
values, using the novel serum osteoprotegerin (OPG) assay in
a select population of patients with AS.
DOI 10.1002/art.10572
Reply
To the Editor:
I thank Dr. Holman for his comments regarding my
presidential address. I had hoped that my comments would
generate lively discussion (“as a soon to be past president, I
now welcome controversy!”). I certainly appreciate his comments regarding the issue of our specialty and fibromyalgia. In
fact, many of our colleagues, including Drs. Bennett, Goldenberg, Smythe, and others, have made extraordinary contributions to this field. Our specialty and our patients are indebted
to those investigators in the area of fibromyalgia. However, as
I noted in my address, the issue now really is access to care.
3390
LETTERS
3391
Table 1. Clinical characteristics of 25 patients with ankylosing
spondylitis*
Age, mean ⫾ SD years
Disease duration, mean ⫾ SD years
Male/female, no.
Peripheral arthritis plus spinal involvement, no.
Spinal involvement only, no.
BASFI score, mean ⫾ SD (0–10)
BASDAI score, mean ⫾ SD (0–10)
38.5 ⫾ 9.0
13.5 ⫾ 7.6
23/2
23
2
5.5 ⫾ 1.9
4.7 ⫾ 2.1
* BASFI ⫽ Bath Ankylosing Spondylitis Function Index (see ref. 9);
BASDAI ⫽ Bath Ankylosing Spondylitis Disease Activity Index (see
ref. 8).
OPG is a naturally occurring cytokine that is a member
of the family of tumor necrosis factor receptors and as such
plays a critical role in the regulation of bone resorption. It has
been shown that OPG acts as an inhibitor of osteoclastogenesis
and increases bone density (4,5).
We studied 25 patients (23 men and 2 women) with
AS, selected from among those attending the outpatient
rheumatology clinic of the Hospital Central Santa Casa de São
Paulo. The mean age of the patients was 37.0 years, and the
mean duration of disease was 13 years (range 1–26 years). All
patients fulfilled the New York revised criteria for AS (6).
Twenty-three patients had both spinal and peripheral involvement (Table 1). The control group included 40 healthy ageand sex-matched individuals with a mean ⫾ SD age of 44 ⫾ 3
years.
We used the CrossLaps (Osteometer, Copenhagen,
Denmark) carboxy-pyridinoline serum assay, performed according to the instructions. The intraassay coefficients of
variation were 6.0 and 6.2, respectively; these values were
obtained internally using a large group of patients (7). Direct
quantitative determination of OPG in serum was performed by
a standard 96-well enzyme-linked immunosorbent assay format (Immunodiagnostic, Bensheim, Germany). Disease activity was measured according to published criteria (8,9). Data
were usually reported as the mean ⫾ SEM, with correlations
by Spearman’s coefficient test. P values less than 0.05 were
considered statistically significant.
The results observed are shown in Table 2. The serum
pyridinoline values of AS patients were significantly reduced
compared with those of normal controls, and serum OPG
levels were significantly increased in AS patients compared
Table 2. Biochemical bone markers in patients and controls*
Study group
Marker
Serum pyridinoline, pmoles/
liter
Serum osteoprotegerin, pg/ml
* Values are the mean ⫾ SD.
Ankylosing
spondylitis
Control
P
1,255 ⫾ 983
2,176 ⫾ 252
⬍0.01
138 ⫾ 25
62 ⫾ 43
⬍0.01
with controls. There was a significant negative correlation
between serum pyridinoline and OPG levels (r ⫽ 0.78).
Our study shows that in patients with AS, serum
pyridinoline levels are reduced at the same time that OPG
levels are increased. The lower levels observed in patients with
AS suggest that osteoclastic activity is reduced in AS, pointing
to the possibility that we may be dealing with low bone
remodeling in such patients.
This is the first study of its kind to assess OPG levels in
patients with AS. Two pitfalls of our investigation are the fact
that OPG is synthesized by various skeletal and extraskeletal
tissues and cell types and regulation of this synthesis is
dependent on a variety of hormones and cytokines, and the
fact that circulating OPG levels may only partially reflect the
bone/bone marrow microenvironment. However, these pitfalls
are present in all studies of bone biology using serum markers.
Taking in consideration that OPG may soon be used for the
therapy of bone diseases, our results may also have future
clinical aplications.
Ricardo Prado Golmia, MD
Branca Dias Batista Sousa, MD
Morton Aaron Scheinberg, MD, PhD, FACP
Center for Clinical Immunology and LID Laboratory
São Paulo, Brazil
1. Gratacós J, Collado A, Pons F, Osaba M, Sanmartı́ R, Roqué M, et
al. Significant loss of bone mass in patients with early, active
ankylosing spondylitis: a followup study. Arthritis Rheum 1999;42:
2319–24.
2. Bronson WD, Walker SE, Hillman LS, Keisler D, Hoyt T, Allen
SH. Bone mineral density and biochemical markers of bone metabolism in ankylosing spondylitis. J Rheumatol 1998;25:929–35.
3. Beck-Jensen JE, Kollerup G, Sorensen HA, Pors Nielsen S, Sorensen OH. A single measurement of biochemical markers of bone
turnover has limited utility in the individual person. Scand J Clin
Lab Invest 1997;57:351–9.
4. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy
R, et al. Osteoprotegerin: a novel secreted protein involved in the
regulation of bone density. Cell 1997;89:309–19.
5. Hofbauer LC, Khosla S, Dunstan CR, Lacey D, Boyle WJ, Riggs BI.
The roles of osteoprotegerin and osteoprotegerin ligand in the
paracrine regulation of bone resorption. J Bone Miner Res 2000;
15:2–12.
6. Moll JM, Wright V. New York clinical criteria for ankylosing
spondylitis: a statistical evaluation. Ann Rheum Dis 1973;32:
354–63.
7. Christgau S, Rosenquist C, Alexandersen P, Bjarnason NH, Ravn P,
Fledelius C, et al. Clinical evaluation of the Serum CrossLaps One
Step ELISA, a new assay measuring the serum concentration of
bone-derived degradation products of type I collagen C-telopeptides. Clin Chem 1998;44:2290–300.
8. Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P,
Calin A. A new approach to defining disease status in ankylosing
spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index.
J Rheumatol 1994;21:2286–91.
9. Calin A, Garrett S, Whitelock H, Kennedy LG, O’Hea J, Mallorie
P, et al. A new approach to defining functional ability in ankylosing
spondylitis: the development of the Bath Ankylosing Spondylitis
Functional Index. J Rheumatol 1994;21:2281–5.
3392
LETTERS
DOI 10.1002/art.10571
Reply
To the Editor:
We read with interest the letter by Golmia et al
concerning the controversial topic of the physiopathologic
mechanism responsible for the loss of bone mass observed in
patients with AS. In our opinion, the bone mass loss in AS
patients is not controversial. In this respect, sufficient data
have been published in the literature to support the loss of
bone mass in early stages of the disease, with no clear
relationship with vertebral stiffness and limitation (1,2). Moreover, this bone mass loss recently has been shown to be
associated with inflammatory activity of AS, as demonstrated
in our study (2) and later confirmed by other investigators (3).
However, and in agreement with Golmia et al, the precise
mechanism by which distinct factors, particularly inflammatory
activity, play a role in bone remodeling remains controversial
(4–8).
Using novel laboratory tests (serum pyridinoline and
OPG determinations), Golmia et al observed reduced osteoclastic activity, which raises the possibility of low bone
remodeling in these patients. The majority of previously
reported studies, however, support increased bone resorption
in AS patients (4–6). Furthermore, given the association
between the bone mass loss and the inflammatory activity of
AS and the well-known effects on bone exerted by proinflammatory cytokines (interleukin-6, tumor necrosis factor ␣)
(9–10) in this process (11–12), increased bone resorption
would appear to be a more logical mechanism to account for
the demineralization. Moreover, the study by Golmia et al
lacks the assessment of other classic bone remodeling biochemical markers (e.g., bone-specific alkaline phosphatase,
osteocalcin, urine pyridinium cross-links), and, consequently,
their possible correlation with the biochemical bone markers
reported by the authors. In our opinion, this is of importance,
bearing in mind that the definitive validation of serum pyridinoline and OPG determinations in clinical practice is still
pending.
Although all these observations do not invalidate the
interesting results reported by Golmia et al, they do require
that these data be regarded with caution. Furthermore, they
underline the enormous difficulty encountered in assessing the
physiopathologic mechanism implicated in the bone mass loss
in patients with AS when this mechanism is evaluated far away
from the site of bone mass loss, using only a few biochemical
bone markers. In this regard, the complex network of relationships between cells involved in bone remodeling and the
inflammatory process driven by several local factors (cytokines,
etc.) point to the need for local tissue studies to gain further
insight into this topic.
Jordi Gratacós, MD
Raimon Sanmarti, MD
University Hospital of Parc Tauli
Barcelona, Spain
1. Will R, Palmer R, Bhalla AK, Calin A. Osteoporosis in early
ankylosing spondylitis: a primary pathological event? Lancet 1989;
2:1483–5.
2. Gratacós J, Collado A, Pons F, Osaba M, Sanmartı́ R, Roqué M,
et al. Significant loss of bone mass in patients with early, active
ankylosing spondylitis: a followup study. Arthritis Rheum 1999;42:
2319–24.
3. Dos Santos FP, Constantin A, Laroche M, Destombes F, Bernard
J, Mazieres B, et al. Whole body and regional bone mineral density
in ankylosing spondylitis. J Rheumatol 2001;28:547–9.
4. Acebes C, de la Piedra C, Traba ML, Seibel MJ, Garcia Martin C,
Armas J, et al. Biochemical markers of bone remodeling and bone
sialoprotein in ankylosing spondylitis. Clin Chim Acta 1999;289:
99–110.
5. Macdonald AG, Birkinshaw G, Durham B, Bucknall RC, Fraser
WD. Biochemical markers of bone turnover in seronegative
spondyloarthropathy: relationship to disease activity. Br J Rheumatol 1997;36:50–3.
6. Toussirot E, Ricard-Blum S, Dumoulin G, Cedoz JP, Wendling D.
Relationship between urinary pyridinium cross-links, disease activity and disease subsets of ankylosing spondylitis. Rheumatology
(Oxford) 1999;38:21–7.
7. Mitra D, Elvins DM, Collins AJ. Biochemical markers of bone
metabolism in mild ankylosing spondylitis and their relationship
with bone mineral density and vertebral fractures. J Rheumatol
1999;26:2201–4.
8. Speden DJ, Calin AI, Ring FJ, Bhalla AK. Bone mineral density,
calcaneal ultrasound, and bone turnover markers in women with
ankylosing spondylitis. J Rheumatol 2002;29:516–21.
9. Macdonald BR, Gowen M. Cytokines and bone. Br J Rheumatol
1992;31:149–55.
10. Manolagas SC, Jilka RL. Bone marrow, cytokines, and bone
remodeling: emerging insights into the pathophysiology of osteoporosis. N Engl J Med 1995;332:305–11.
11. Gratacós J, Collado A, Filella X, Sanmartı́ R, Cañete J, Llena J, et
al. Serum cytokines (IL-6, TNF-␣, IL-1␤ and IFN-␥) in ankylosing
spondylitis: a close correlation between serum IL-6 and disease
activity and severity. Br J Rheumatol 1994;33:927–31.
12. Braun J, Bollow M, Neure L, Seipelt E, Seyrekbasan F, Herbest H,
et al. Use of inmunohistologic and in situ hybridization techniques
in the examination of sacroiliac joint biopsy specimens from
patients with ankylosing spondylitis. Arthritis Rheum 1995;38:
499–505.
DOI 10.1002/art.10565
Increased cutaneous reactions to hydroxychloroquine
(Plaquenil) possibly associated with formulation
change: comment on the letter by Alarcón
To the Editor:
We read with interest Alarcón’s case report of retinopathy in a patient receiving hydroxychloroquine (HCQ) (1). We
have not seen any patients with HCQ retinal toxicity in our
large clinic cohort. However, over the last year we have noticed
a marked increase in the number of cutaneous reactions
occurring in patients who are taking HCQ.
Antimalarials are generally well tolerated when compared with other disease-modifying drugs (2). In terms of
cutaneous reactions, antimalarials can induce urticaria, pruritus, alopecia, hair bleaching, dry skin, pigment changes, rashes,
flares of psoriasis and exfoliating lesions, as well as a Stevens–
Johnson-like syndrome (3–10). Most patients continue HCQ
therapy in the long term, but ⬃3% discontinue HCQ because
of adverse cutaneous reactions. We now report a marked
increase in the number of cutaneous reactions to HCQ over
the last year, which apparently coincided with a change in
formulation by the manufacturer.
44
60
44
36
54
56
49
49
1
2
3
4
5
6
7
8
9
10
11
Probable SLE
Discoid lupus
Discoid lupus
SLE
SLE, DLE
Lupus-like
syndrome
SLE, cryoglobulinemia
SLE
SLE, APS
SLE, APS
SLE, DLE
Diagnosis
Asthma, hypertension
–
Hyperlipidemia
Multinodular goiter,
TIA
–
TIA, depression
Breast cancer
Epilepsy, peripheral
neuropathy
Trigeminal neuropathy
Cecum cancer
Endometriosis
Other main diseases
Yes
No
No
Yes
No
Yes
Yes
No
No
No
Yes
Sjögren’s
syndrome
Morphine, fluoxetine,
carbamazepine,
tramadol,
amitriptyline
No
No
No
No
Penicillin
No
Co-trimoxazole
Penicillin
No
No
Drugs
No
No
No
Alcohol
No
No
No
No
No
No
No
Food
Allergies
No
No
No
Metal clips,
elastoplast,
perfume
No
No
Nickel, cobalt
No
No
No
No
Other
No
No
No
No
No
No
No
No
No
No
No
Family
history
No
No
No
No
No
No
No
No
No
MI, CVA
CVA
Other family
history
* The study period for patient 1 was October 1999 to October 2000; the study period for all other patients was October 2000 to October 2001. SLE ⫽ systemic lupus erythematosus;
APS ⫽ antiphospholipid syndrome; TIA ⫽ transient ischemic attack; MI ⫽ myocardial infarction; CVA ⫽ cerebrovascular accident; DLE ⫽ discoid lupus erythematosus.
33
62
56
Patient
Clinical characteristics of 11 female patients with cutaneous reactions to hydroxychloroquine*
Age, years,
at time of
reaction
Table 1.
LETTERS
3393
3/20/01
7/14/01
3/7/01
7/13/01
3/29/01
10/15/97
10/8/00
1/98
7/31/00
3/15/01
1
2
3
4
5
6
7
8
9
10
11
8/4/01
11/15/00
10/27/00
10/00
11/28/00
4/7/01
6/8/01
3/19/01
7/14/01
3/24/01
10/18/99
9
30
19
20
20
23
23
12
1
4
–
2
6
3.8
4
4
5
5
2
5
1
–
Total grams
of new
formulation
taken
No
Yes
No
Yes
Yes
No
No
No
No
Yes
No
HCQ
continued
after
reaction
Severe irritating,
widespread rash
Mild rash
Facial rash
Rash and nausea
Rash on arms
Rash on arms
Rash on face, trunk,
arms, and legs
Neck, chest, and leg
rash, vomiting
Blisters, irritation
and swollen hands
Widespread rash
Hyperpigmentation
Type of reaction
Warfarin, HRT, naproxen,
ranitidine, steroid
Aspirin, rofecoxib,
tamoxifen
Steroid cream, enalapril,
aspirin
Aspirin, lisinopril,
ibuprofen
Steroid cream,
depomedrone
Rofecoxib, lanzoprazole
Aspirin, praxiline
Aspirin
–
Clomipramine, Dermovate
Pravastatin
Concomittant medications
Pos
Pos
Neg
Neg
Pos
Neg
Pos
Pos
Pos
Pos
Neg
ANA
Neg
Neg
Neg
Ro (⫹)
Neg
Neg
Neg
Neg
Neg
Neg
Neg
ENA
1.17
0.52
1.26
0.99
0.78
1.00
0.94
1.5
0.65
0.95
1.11
C3,
gm/
liter
0.24
0.16
0.26
0.16
0.12
0.55
0.26
0.34
0.06
0.17
0.17
C4,
gm/
liter
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
DNA
* The study period for patient 1 was October 1999 to October 2000; the study period for all other patients was October 2000 to October 2001. Patient 1 received the orange
formulation of HCQ; all other patients received the white formulation. ANA ⫽ antinuclear antibody; ENA ⫽ extractable nuclear antigen; HRT ⫽ hormone replacement therapy.
1/28/98
Patient
Date of
event
No. of days
taking new
formulation
until event
Associations between formulation change of hydroxychloroquine (HCQ) and cutaneous reactions in 11 female patients*
Date
HCQ
started
Table 2.
3394
LETTERS
LETTERS
We audited our records for HCQ reactions for 1 year
prior to October 2000, when the formulation of HCQ was
changed, and compared these data with the incidence of
adverse cutaneous reactions associated with HCQ from October 2000 until October 2001. The information sources used
included our patient database as well as clinical records and
pharmacy records. All patients who experienced cutaneous
reactions were interviewed. The chi-square test, with Yates’
correction for small numbers, was used to assess the difference
in the incidence of HCQ reactions between the 2 periods of
study. P values less than 0.05 were considered significant.
During the year from October 1999 to October 2000,
only 1 patient had a possible HCQ-related skin reaction, out of
a total of 149 new prescriptions for HCQ (0.07%). During the
year from October 2000 to October 2001, we observed 10
patients with a cutaneous reaction associated with HCQ
therapy, out of a total of 137 new prescriptions for HCQ
(7.3%). This difference was significant (␹2 ⫽ 8.5, P ⬍ 0.01).
The clinical characteristics of these patients are shown in Table
1. The most common diagnosis was systemic lupus erythematosus (SLE), although HCQ was also prescribed for other
diseases (Sjögren’s syndrome, discoid lupus). The median age
of the patients was 49.4 years (range 33–62 years), and they
had been taking the old and new formulations of HCQ for a
median of 255 and 15.3 days, respectively. For patient 1, the
cumulative dose of the old formulation was 51 gm. For the
other 10 patients, the median cumulative dose of the new
formulation was 3.78 gm. Three patients had experienced
previous allergic reactions to penicillin or cotrimoxazole, and 1
patient had previous allergic reactions to multiple drugs (morphine, fluoxetine, carbamazepine, tramadol, and amitryptiline)
(Table 1).
In all 10 patients observed between October 2000 and
October 2001, HCQ hypersensitivity was manifest as an acute
skin reaction. The time range between commencement of the
new formulation of HCQ and the appearance of a rash was
1–30 days (most reactions occurred in the first 1–2 weeks).
Generally, the rash was mild and disappeared 1–3 weeks after
the drug was stopped. Concomitant medications used by the
patients are shown in Table 2.
The skin lesions included rashes, blisters, irritation,
and burning and swelling mainly over the face, arms, hands,
chest and/or legs. Two patients also experienced nausea and/or
vomiting. In 8 patients, the cutaneous reaction resolved after
discontinuing HCQ. Four patients (patients 2, 7, 9, and 10)
cautiously restarted HCQ in spite of the skin reactions, because it had controlled their symptoms, and none experienced
any further reactions. Patient 2 stopped taking HCQ after 4
days of nausea, diarrhea, and vomiting then restarted it,
without further complications. All of the other patients
stopped taking HCQ completely, because the adverse effects
were extensive.
From October 1999 until October 2000, only 1 patient
had a skin reaction while receiving the previous orange-coated
formulation. In this patient, the reaction consisted of hyperpigmentation of the skin 20 months after starting the old
formulation of HCQ and was, therefore, not a true allergic
reaction. Between October 2000 and October 2001, 10 patients
apparently developed true cutaneous reactions to the new
white formulation of HCQ, and this was not related to any
increase in the number of new prescriptions for HCQ. We have
informed the Committee on Safety of Medicines for the
United Kingdom of these reactions via the yellow card system.
Cutaneous reactions to HCQ are uncommon; ⬃3% of
3395
patients experience an allergic skin reaction. In the literature,
there are several case reports of severe cutaneous reactions
following HCQ administration. For example, a woman with
seronegative polyarthritis developed an acute generalized exanthematous pustulosis, a typical skin reaction to drugs (8),
and another developed a widespread rash after receiving
puvatherapy and HCQ (9). In other patients, HCQ induced
pustular psoriasis or a bullous rash (6,10).
Our data show that there has been no increase in the
rate of new prescriptions for HCQ in our connective tissue
disease clinics. However, over the 2 years of study, we observed
a 100-fold increase, from 0.07% to 7.3%, in the frequency of
cutaneous adverse effects associated with new HCQ prescriptions. In our experience over the last 20 years, the prevalence
of cutaneous reactions to HCQ has been consistent with that in
the published literature (⬃3% or less). In October 2000, the
formulation of HCQ was changed by the manufacturer, with
the removal of a coloring agent (sunshine yellow E110). The
tablets changed in color from orange to white. The marked
increase in skin reactions that we have observed is thus rather
unexpected, given that coloring agents are often associated
with allergies. Indeed, our data have shown that the incidence
of drug and other allergies is high in patients with SLE (11).
The prevalence of penicillin allergy in the general population is
also high. However, there did not appear to be cross-reactivity
between HCQ and penicillin allergies in our patients.
To date, unpublished data from the manufacturers of
HCQ have not demonstrated any increase in skin reactions in
other countries where this new formulation has been used.
Thus, the reasons for this sudden increase remain unclear.
However, rheumatologists and patients should be aware of the
apparently increased risk of skin reactions associated with the
new formulation of HCQ.
M. Salido, MD, PhD
Rayne Institute, St. Thomas’ Hospital
London, UK
and Hospital Clinico San Carlos
Madrid, Spain
B. Joven, MD, PhD
Rayne Institute, St. Thomas’ Hospital
London, UK
and Hospital 12 de Octubre
Madrid, Spain
D. P. D’Cruz, MD, FRCP
M. A. Khamashta, MD, PhD, MRCP
G. R. V. Hughes, MD, FRCP
Rayne Institute, St. Thomas’ Hospital
London, UK
1. Alarcón GS. How frequently and how soon should we screen our
patients for the presence of antimalarial retinopathy? [letter].
Arthritis Rheum 2002;46:561.
2. D’Cruz DP. Antimalarial therapy: a panacea for mild lupus?
Lupus 2001;10:148–151.
3. Meier H, Elsner P, Wuthrich B. [Occupationally-induced contact
dermatitis and bronchial asthma in an unusual delayed reaction to
hydroxychloroquine]. Hautarzt 1999;50:665–9.
4. Holme SA, Holmes SC. Hydroxychloroquine-induced pruritus.
Acta Derm Venereol 1999;79:333.
5. Jimenez-Alonso J, Tercedor J, Jaimez L, Garcia-Lora E. Antima-
3396
6.
7.
8.
9.
10.
11.
larial drug-induced aquagenic-type pruritus in patients with lupus.
Arthritis Rheum 1998;41:744–5.
Vine JE, Hymes SR, Warner NB, Cohen PR. Pustular psoriasis
induced by hydroxychloroquine: a case report and review of the
literature. J Dermatol 1996;23:357–61.
Sibilia J, Cribier B, Javier RM, Pflumio F, Kuntz JL. Recurrent
psoriatic onychoperiostitis induced by hydroxychloroquine. Rev
Rhum Engl Ed 1995;62:795–7.
Assier-Bonnet H, Saada V, Bernier M, Clerici T, Saiag P. Acute
generalized exanthematous pustulosis induced by hydroxychloroquine. Dermatology 1996;193:70–1.
Bonnetblanc JM, Combeau A, Dang PM. [Hydroxychloroquinepuvatherapy photoinduced acute generalized exanthematous pustulosis]. Ann Dermatol Venereol 1995;122:604–5.
Kutz DC, Bridges AJ. Bullous rash and brown urine in a systemic
lupus erythematosus patient treated with hydroxychloroquine.
Arthritis Rheum. 1995;38:440–3.
Sequeira JF, Cesic D, Keser G, Bukelica M, Karanagnostis S,
Khamashta MA, et al. Allergic disorders in systemic lupus erythematosus. Lupus 1993;2:187–91.
DOI 10.1002/art.10596
Efficacy of tumor necrosis factor ␣ blockade for
enthesitis in spondylarthropathy: comment on the
article by Marzo-Ortega et al
To the Editor:
We read with great interest the article by MarzoOrtega and coworkers on the efficacy of etanercept in the
treatment of the entheseal pathology in resistant spondylarthropathy (SpA) (1). Using magnetic resonance imaging (MRI),
the authors demonstrated that tumor necrosis factor ␣ (TNF␣)
blockade can induce marked improvement or regression of
enthesitis and associated osteitis in both the axial skeleton and
the peripheral skeleton. The following case presentation confirms their observations.
The patient is a 34-year-old man with HLA–B27–
positive juvenile-onset undifferentiated SpA lacking axial involvement. In 1996, he had a severe, disabling, nonsteroidal
antiinflammatory drug (NSAID)–resistant flare of the disease
in his left knee and in the insertions of the Achilles tendon and
plantar fascia (both sites), which was treated with sulfasalazine
at a dosage of 3 gm/day. After 6 months of therapy, the daily
dosage was reduced to 2 gm/day, and after 12 months sulfasalazine was discontinued. The disease remained in remission until
August 2000, when the patient experienced severe pain in his
right hip that was resistant to indomethacin at a dosage of 150
mg/day. Physical examinations performed on several occasions
in the following months showed severe tenderness and limitation of motion of the right hip. There was also slight tenderness
in the left hip.
On October 14, 2000, radiographs of the pelvis were
normal, and laboratory evaluation showed a normal erythrocyte sedimentation rate and a C-reactive protein (CRP) value
of 17.6 mg/liter (normal ⬍5). MRI showed an increased signal
on short tau inversion recovery images in both hips, extending
from the right femoral head to the intertrochanteric region,
caused by bone marrow edema (Figure 1A).
Because of the severity of the clinical situation and the
MRI findings, we decided to treat the patient with infliximab,
after obtaining his informed consent. He received the drug at
LETTERS
a dose of 5 mg/kg by intravenous infusion at 0, 2, and 6 weeks.
He was evaluated at baseline, on days 3, 7, and 14, and then
every 2 weeks. The day after the first infusion, the hip pain
improved, and after 1 week the daily dose of indomethacin was
reduced to 100 mg. On the day of the second infusion, CRP
was normal, and hip pain was less severe. The dosage of
indomethacin was reduced to 50 mg/day. On the day of the
third infusion, the pain had disappeared, and indomethacin
was discontinued. A repeat MRI, performed 8 weeks after the
first examination and the beginning of infliximab therapy,
showed a dramatic improvement of bone edema at the right
hip and regression on the left side (Figure 1B). On T1weighted images, with fat saturation obtained after the administration of intravenous gadolinium, there was low enhancement in the right femoral head and no enhancement in the left.
To date, the disease has remained in remission, and the patient
has taken no medication. A third MRI performed at month 6
was normal.
Both main biologic agents blocking TNF␣, the chimeric monoclonal IgG1 antibody infliximab and the 75-kd
IgG1 fusion protein etanercept, have been proven effective in
both ankylosing spondylitis (2,3) and psoriatic arthritis (3–6).
Both agents can ameliorate the enthesitis-related bone edema
that is visible on MRI (1,7). Unresponsiveness of undifferentiated SpA to sulfasalazine is another possible indication for
TNF␣ blockade therapy (8). We decided to use infliximab to
treat our patient with undifferentiated SpA, because of the
severity of hip pain and the impressive MRI findings showing
enthesitis and osteitis involving the femoral head and neck.
The appearance of enthesitis and osteitis on MRI was similar
to that of idiopathic transient osteoporosis of the hip from
which our case can be differentiated, especially based on the
absence of localized osteoporosis on radiographs (9).
As suggested by Marzo-Ortega et al, bone edema
caused by enthesitis and osteitis is the forerunner of severe
destruction and new bone formation in SpA (1). The authors
also suggested that by suppressing the diffuse osseous pathology, TNF␣ blockade may prevent destructive arthritis. In our
case, infliximab may have prevented destructive hip arthritis.
Future studies on a large number of similar cases will resolve
this question.
Ignazio Olivieri, MD
Angela Padula, MD
San Carlo Hospital of Potenza
and Madonna delle Grazie Hospital
Potenza and Matera, Italy
Enrico Scarano, MD
San Carlo Hospital of Potenza
Potenza, Italy
1. Marzo-Ortega H, McGonagle D, O’Connor P, Emery P. Efficacy of
etanercept in the treatment of the entheseal pathology in resistant
spondylarthropathy: a clinical and magnetic resonance imaging
study. Arthritis Rheum 2001;44:2112–7.
2. Brandt J, Haibel H, Cornely D, Golder W, Gonzalez J, Redding J,
et al. Successful treatment of active ankylosing spondylitis with
anti–tumor necrosis factor ␣ monoclonal antibody infliximab. Arthritis Rheum 2000;43:1346–52.
3. Van den Bosch F, Kruithof E, Baeten D, De Keyser F, Mielants H,
Veys EM. Effects of a loading dose regimen of three infusions of
chimeric monoclonal antibody to tumor necrosis factor alpha
(infliximab) in spondyloarthropathy: an open pilot study. Ann
Rheum Dis 2000;59:428–33.
LETTERS
3397
Figure 1. Magnetic resonance imaging (MRI) of the hips. A, Short tau inversion recovery image showing increased signal extending from the right
femoral head to the intertrochanteric region due to bone marrow edema. B, Repeat MRI, performed 8 weeks after the first examination and the
beginning of infliximab therapy, showing dramatic improvement of bone edema at the right hip and regression at the left side.
3398
LETTERS
4. Antoni C, Dechant C, Ogilvie A, Kalden-Nemeth D, Kalden JR,
Manger B. Successful treatment of psoriatic arthritis with infliximab
in a MRI controlled study. J Rheumatol 2000;27 Suppl 59:24.
5. Braun J, de Keyser F, Brandt J, Mielants H, Sieper J, Veys E. New
treatment options in spondyloarthropathies: increasing evidence for
significant efficacy of anti-tumor necrosis factor therapy. Curr Opin
Rheumatol 2001;13:245–9.
6. Mease PJ, Goffe BS, Metz J, Vanderstoep A. Etanercept in the
treatment of psoriatic arthritis and psoriasis: a randomised trial.
Lancet 2000;356:385–90.
7. Stone M, Salonen D, Lax M, Payne U, Lapp V, Inman R. Clinical
and imaging correlates of response to treatment with infliximab in
patients with ankylosing spondylitis. J Rheumatol 2001;28:1605–14.
8. Brandt J, Haibel H, Reddig J, Sieper J, Braun J. Successful short
term treatment of severe undifferentiated spondyloarthropathy
with the anti-tumor necrosis factor-alpha monoclonal antibody
infliximab. J Rheumatol 2002;29:118–22.
9. Major NM, Helms CA. Idiopathic transient osteoporosis of the hip.
Arthritis Rheum 1997;40:1178–9.
DOI 10.1002/art.10597
Reply
To the Editor:
We are very pleased that our original observation that
TNF␣ blockade can induce marked improvement/regression of
enthesitis and osteitis in SpA has been confirmed by Olivieri
and colleagues.
They describe a case in which a dramatic response,
with rapid and sustained improvement, was achieved after 3
infusions of infliximab in a patient with undifferentiated SpA.
Recent double-blind studies have confirmed the efficacy of the
TNF blocking agents infliximab (1,2) and etanercept (3) in the
treatment of the different subtypes of SpA. Likewise, the
experience reported by Olivieri et al confirms our own (4),
showing the efficacy of these drugs in the treatment of
enthesitis, the characteristic pathologic manifestation of these
diseases.
These are, however, early days in our experience with
these drugs. Importantly, Olivieri and colleagues raise the
question of long-term benefit. Although ⬎300 patients with
SpA have been reported in trials worldwide, general experience is still short-lived. This is clearly an issue that will
determine the cost-effectiveness of this therapy. Studies are
already in place to answer this question.
Helena Marzo-Ortega, MD
Dennis McGonagle, MD
Paul Emery, MD
University of Leeds
Leeds, UK
1. Van den Bosch F, Kruithof E, Baeten D, Herssens A, de Keyser F,
Mielants H, et al. Randomized double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor ␣ (infliximab)
versus placebo in active spondylarthropathy. Arthritis Rheum 2002;
46:744–65.
2. Braun J, Brandt J, Listing J, Zink A, Alten R, Golder W, et al.
Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002;359:1187–93.
3. Gorman JD, Sack KE, Davis JC Jr. Treatment of ankylosing
spondylitis by inhibition of tumor necrosis factor alpha. N Engl
J Med 2002;346:1349–56.
4. Marzo-Ortega H, McGonagle D, O’Connor P, Emery P. Efficacy of
etanercept in the treatment of the entheseal pathology in resistant
spondylarthropathy: a clinical and magnetic resonance study. Arthritis Rheum 2001;44:2112–7.
Erratum
In the article by Aganna et al published in the September 2002 issue of Arthritis & Rheumatism (pp
2445–2452), the name of the eighth author, Alison Bybee, PhD (Royal Free Medical School, London, UK) was
inadvertently omitted.
We regret the error.
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