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Emerging clinical spectrum of tumor necrosis factor receptorassociated periodic syndromeComment on the articles by Hull et al and Dod┬й et al.

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ARTHRITIS & RHEUMATISM
Vol. 48, No. 6, June 2003, pp 1764–1770
© 2003, American College of Rheumatology
LETTERS
treatment. This should include examination of the retina
through a dilated pupil and testing of central visual field
sensitivity by either a self-testing grid chart (Amsler grid) or an
automated field tester (Humphrey 10-2 testing). If the patient
is in the low-risk category and these examination results are
normal, the AAO recommendation is that no further special
ophthalmologic testing is needed for the next 5 years.
In the US, HCQ is used more than CQ, and it is
available only in a 200-mg tablet. Maintenance treatment with
200 mg of HCQ daily will be relatively safe for virtually all but
the lowest-body-weight patients, but 400 mg daily puts patients
who weigh ⬍135 pounds into the higher-risk category. However, adjustment of HCQ dosage is easy to achieve because the
duration of action is so prolonged that daily dosage levels can
be calculated on a weekly basis (for example, taking 2 tablets
one day, and 1 the next).
For patients in the higher-risk category, which includes
anyone using these drugs regularly for ⬎5 years, annual eye
examinations are recommended. Although the incidence of
toxicity remains relatively low with long-term use, it becomes
more difficult to predict who may or may not be at risk, and the
consequence of missing the early signs of retinopathy can be
permanent vision loss. The screening procedure should include
retinal examination and Amsler grid or Humphrey field testing. Should any hint of toxicity appear, more elaborate tests
can be performed, such as multifocal electroretinography,
which objectively measures the electrical responses from the
central retina.
If toxicity is suspected or documented, the drug should
ideally be stopped. This is not always an easy decision,
however, especially if the impression of toxicity is early or
tenuous, or if the treatment has been very effective in controlling a severe or unstable rheumatic condition. The medical
physician and the patient should be informed about the
ophthalmologic findings and the risks, so a cooperative decision can be made about whether to halt the drug or to
cautiously continue it with close monitoring of vision function
and with an acceptance that some vision could be lost.
It is hoped that these new recommendations will clarify
the rationale for HCQ and CQ screening and will also make it
easier during the initial years of treatment, when the risk of
retinopathy is low.
DOI 10.1002/art.10980
New American Academy of Ophthalmology
recommendations on screening for hydroxychloroquine
retinopathy
To the Editor:
Chloroquine (CQ) and hydroxychloroquine (HCQ)
are used widely in the treatment of rheumatic disease, and they
have the potential to cause serious retinal toxicity when high
doses have been taken over a long period of time. What type
and what frequency of screening should be performed to
recognize toxicity as early as possible? A few authors have
proposed that screening is not required, given the relative
rarity of toxic retinopathy, but this seems unwise since the
result can be blindness. The Physicians’ Desk Reference recommends quarterly examinations (Physicians’ desk reference.
57th ed. Montvale [NJ]: Thomson PDR; 2003), but this is too
frequent relative to the speed of clinical changes and does not
seem cost-effective relative to the low incidence. The American Academy of Ophthalmology (AAO) recently assembled a
task force to examine the available evidence on these drugs
and to develop screening recommendations that would be in
accordance with both modern knowledge and the economic
realities of practice (Marmor MF, Carr RE, Easterbrook M,
Farjo AA, Mieler WF, for the American Academy of Ophthalmology. Recommendations on screening for chloroquine and
hydroxychloroquine retinopathy. Ophthalmology 2002;109:
1377–82).
The mechanism of CQ and HCQ toxicity is not well
understood, and it is unknown whether the primary damage is
upon the retinal photoreceptors or the melanotic retinal
pigment epithelium (RPE) layer that lies just behind the
retina. The typical clinical finding of early retinopathy is
paracentral depigmentation surrounding the center of vision,
called “bull’s-eye maculopathy.” Sometimes a loss of visual
sensitivity can be discerned even before fundus changes are
visible, by careful testing of paracentral vision. If drug usage
continues, toxicity will eventually result in widespread retinal
and RPE atrophy. The only known treatment is cessation of
the medication, but unfortunately the retinopathy will often
progress for some time even after it is stopped. Thus, early
recognition is the best defense against serious vision loss.
While the retinopathy is potentially serious and permanent, the incidence of toxicity in clinical practice is very
small. Studies of several large series of patients with rheumatic
disease have demonstrated little or no toxicity among thousands of subjects. The vast majority of reports of toxicity have
occurred in individuals taking ⬎6.5 mg/kg/day of HCQ or 3
mg/kg/day of CQ, for ⬎5 years.
The AAO committee recommended that patients
treated with CQ or HCQ take maintenance dosages below
these levels, if at all possible. Patients taking the drugs can be
divided into 2 groups: low-risk patients, who receive these
lower dosages and have used the drug for ⬍5 years, and
higher-risk patients, who have used the drug for longer periods, who are taking larger dosages, or who have other risk
factors such as high body fat level, concomitant kidney or liver
disease, concomitant retinal disease, or older age (⬎60 years).
All individuals starting these drugs should have a complete
baseline ophthalmologic examination within the first year of
Michael F. Marmor, MD
Stanford University Medical Center
Stanford, CA
DOI 10.1002/art.11019
Report of an additional case of anti–tumor necrosis
factor therapy and Listeria monocytogenes infection:
comment on the letter by Glück et al
To the Editor:
Glück and colleagues recently reported 2 interesting
cases of Listeria monocytogenes infection possibly associated
with infliximab therapy (1). Only 4 cases of Listeria meningitis
1764
LETTERS
have been reported in the literature, 2 of which occurred in
patients with Crohn’s disease (2,3). We now report an additional case.
The patient, a 57-year-old white man with an 8-year
history of psoriatic arthritis, developed Listeria meningitis after
receiving a sixth infusion of infliximab. His medical conditions
included coronary artery disease, atrial fibrillation, arterial
hypertension, and latent nonactive chronic infection with the
hepatitis C virus. He was being treated with oral methotrexate
(15 mg/week), prednisone (10 mg/day), and indomethacin,
with good tolerance but only a partial response to the arthritis
symptoms. Therefore, we initiated infliximab therapy at 3
mg/kg, with infusions given at 0, 2, and 6 weeks, and then every
8 weeks.
One month after the sixth infusion of infliximab, the
patient suddenly developed headache and disorientation. He
was admitted to the emergency department with a 12-hour
history of vomiting, fever (up to 39°C), and bradypsychia
without meningeal signs. A cerebral computed tomography
scan did not show any abnormalities. The patient underwent
lumbar puncture, and the results were consistent with acute
meningitis. Broad-spectrum antibiotic therapy that included
ampicillin was started, and the patient was admitted immediately to the critical care unit. On the second day, the presence
of L monocytogenes in the cerebrospinal fluid culture was
confirmed. The patient made excellent progress with appropriate treatment and was discharged without neurologic sequelae after 1 month.
To our knowledge, in addition to the 2 patients with
RA who were recently described by Glück et al (1), only 2
other cases of Listeria infection related to infliximab therapy
in patients with Crohn’s disease have been reported (2,3).
This is the first reported case of Listeria meningitis in a
patient with psoriatic arthritis that is closely related to
infliximab therapy.
Moreover, according to the Web site of the US
Food and Drug Administration (FDA) (Accessed Oct. 12,
2002. URL: www.fda.gov.ohrms/dockets/ac/01/briefing/
3379b2_01_3-CBER.tables.pdf), a total of 11 cases of L
monocytogenes infection occurring after infliximab infusions
have been reported; we have not found these cases published elsewhere. Unfortunately, 4 of these 11 patients died
of Listeria sepsis. Life-threatening listeriosis may be a real
complication of immunotherapy using tumor necrosis factor
(TNF) blockers, and this type of infectious disease could be
more frequent than we expect. TNF␣ is truly involved in the
murine defense against L monocytogenes (4), and TNFblocking therapy might enhance the susceptibility of the
central nervous system to infection with this agent. However, the specific mechanism by which TNF␣ and other
cytokines exert their effect against Listeria infection remains
unclear.
In conclusion, we must be aware of both the crucial
role that TNF plays against serious pathogens and the possibility of Listeria meningitis in a patient treated with infliximab
in whom an infectious neurologic disorder develops. In fact,
after reviewing the FDA data, we believe that this, in addition
to tuberculosis, could be a frequent infliximab-related opportunistic infection.
1765
Angel Garcia Aparicio, MD
Santiago Muñoz-Fernández, MD, PhD
Gema Bonilla, MD
Ambrosio Miralles, MD
Victor Cerdeño, MD
Emilio Martı́n-Mola, MD, PhD
Hospital Universitario La Paz
and Universidad Autónoma de Madrid
Madrid, Spain
1. Glück T, Linde H-J, Schölmerich J, Müller-Ladner U, Fiehn C,
Bohland P. Anti–tumor necrosis factor therapy and Listeria monocytogenes infection: report of two cases [letter]. Arthritis Rheum
2002;46:2255–7.
2. Morelli J, Wilson FA. Does administration of infliximab increase
susceptibility to listeriosis? Am J Gastroenterol 2000;95:841–2.
3. Kamath BM, Mamula P, Baldassano RN, Markowitz JE. Listeria
meningitis after treatment with infliximab. J Pediatr Gastroenterol
Nutr 2002;34:410–2.
4. Kato K, Nakane A, Minagawa T, Kasai N, Yamamoto K, Sato N, et
al. Human tumor necrosis factor increases the resistance against
Listeria infection in mice. Med Microbiol Immunol (Berl) 1989;178:
337–46.
DOI 10.1002/art.11145
Reply
To the Editor:
We appreciate the comments by Aparicio et al describing details of another case of listeriosis associated with infliximab therapy. Indeed, a number of cases of Listeria infection in
patients receiving TNF-blocking agents (with considerable
mortality) have been reported to the FDA. The use of
anti-TNF drugs clearly offers new treatment options for patients with aggressive rheumatic disease, and the spectrum of
diseases for which TNF inhibitors are beneficial (e.g., psoriatic
arthritis and the spondylarthropathies) is currently expanding.
However, as rheumatology specialists, it is our duty to carefully
select candidates for anti-TNF therapy and to monitor those
patients more closely (compared with patients receiving standard immunosuppressive treatment), in order to protect them
from potentially lethal infections associated with such therapy.
Considering all aspects of therapy as well as the
currently available data, at present the following recommendations concerning the risk for Listeria infection during antiTNF therapy can be given: 1) Consumption of Camembert or
similar cheeses, which are often contaminated by Listeria,
should be discouraged in patients receiving anti-TNF treatment. 2) Use of trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia prophylaxis, as suggested by Kremer
(Kremer JM. Reply to Anti–tumor necrosis factor therapy and
Listeria monocytogenes infection: report of two cases [letter].
Arthritis Rheum 2002;46:2257), will most likely protect against
listeriosis (and other bacterial infections) as well as but may
not be tolerated by all patients and is also associated with other
problems and side effects related to long-term antibiotic
prophylaxis. 3) Even subtle signs of meningitis or other central
nervous system abnormalities in such patients should initiate a
1766
LETTERS
thorough clinical workup. Empiric coverage of Listeria in the
initial antibiotic regimen is mandatory (e.g., by adding ampicillin). 4) The risks for infectious complications seem to be
greater for infliximab than for etanercept (FDA: Safety update
on TNF␣ antagonists: infliximab and etanercept. Accessed
Jan. 27, 2003. URL: www.fda.gov).
Mycobacteria and Listeria have now been recognized
as problematic pathogens for patients with a compromised
Th1-type immune response due to therapy with anti-TNF
agents, as nicely underlined by the case report by Aparicio et
al. However, other infectious agents (e.g., Leishmania or
invasive fungal pathogens) may also cause severe disease under
such conditions.
In summary, a patient in whom signs of infectious
disease develop during anti-TNF therapy must receive a rapid
and careful evaluation, with a high suspicion for atypical
pathogens. We may see infectious complications more often in
the future.
Thomas Glück, MD
U. Müller-Ladner, MD
University of Regensburg
Regensburg, Germany
DOI 10.1002/art.11018
Pseudoscleroderma associated with transforming
growth factor ␤1–producing advanced gastric
carcinoma: comment on the article by Varga
To the Editor:
We read with interest the review article by Varga (1),
in which modulation of transforming growth factor ␤ (TGF␤)–
mediated profibrotic action by the Smad protein family was
discussed. In systemic sclerosis (SSc), inflammatory cells infiltrating lesional tissues secrete TGF␤, which also stimulates
connective tissue growth factor (CTGF) secretion in lesional
fibroblasts (1). TGF␤, however, is also secreted from other
cells, such as tumor cells. In particular, expression of TGF␤1 is
detected in 22.8–35.9% of patients with gastric carcinoma
(2,3). Here we discuss a patient in whom severe proximal
scleroderma, esophageal dysmotility, and bibasilar pulmonary
fibrosis developed along with development of TGF␤1–
producing gastric carcinoma.
In December 2000, an 83-year-old Japanese man noticed sclerotic skin changes in his neck and upper/lower
extremities and visited the dermatology clinic of Keio University Hospital. A skin biopsy specimen obtained from his right
thigh showed hyperproliferation of swollen, homogeneous
collagen fibers. The histologic skin changes were identical to
those of SSc but not of scleredema. He did not present with
Raynaud’s phenomenon, sclerodactyly, digital pitting scar, or
telangiectasia. Because the sclerotic skin changes subsequently
spread to his upper chest, abdomen, back, and buttocks, he was
admitted to the rheumatology section in our hospital. His total
skin thickness score (TSS) (4) was 66 (based on a possible total
score of 104). A blood test revealed no evidence of diabetes
mellitus. Serum antinuclear antibodies and rheumatoid factor
were not detected, but a slight increase in the white blood cell
count (10,000/mm3), the erythrocyte sedimentation rate (18
mm/hour), the C-reactive protein level (0.5 mg/dl), and the
IgG level (2,290 mg/dl) was observed. Serum levels of
interleukin-6 (IL-6) (5.41 pg/ml; normal ⬍4.62) and plasma
TGF␤1 (2.15 ng/ml; normal ⬍1.80) as determined by enzymelinked immunosorbent assay were also elevated. Gastrointestinal examination detected severe esophageal dysmotility and
gastric carcinoma. An endoscopic biopsy of the gastric carcinomatous lesion showed poorly differentiated adenocarcinoma. A full-body computed tomography scan indicated bibasilar pulmonary fibrosis but no evidence of lung or
abdominal metastasis. Two months after total gastrectomy, the
patient’s esophageal dysmotility and pulmonary fibrosis had
not changed, but his TSS improved to 29. The serum level of
IL-6 was normalized (1.30 pg/ml), and plasma TGF␤1 in
post-tumor resection was decreased (1.88 ng/ml).
Reverse transcriptase–polymerase chain reaction (RTPCR) analysis of samples from the resected stomach was
performed (5). Total RNA from specimens obtained from both
carcinomatous and normal sites (Figure 1A) was isolated by
guadidinium thiocyanate–phenol–chlorform extraction. Complementary DNA (cDNA) amplification for ␤-actin (541 bp)
was performed for 30 cycles, with an annealing temperature of
58°C. Amplification of cDNA for TGF␤1 (247 bp) was performed for 35 cycles, with an annealing temperature of 65°C.
Primer sequences for ␤-actin and TGF␤1, respectively, were as
follows: forward 5⬘-GTG-GGG-CGC-CCC-AGG-CAC-CA3⬘, reverse 5⬘-CTC-CTT-AAT-GTC-ACG-CAC-GAT-TTC3⬘; forward 5⬘-AAG-TGG-ATC-CAC-GAG-CCC-AA-3⬘, reverse 5⬘-GCT-GCA-CTT-GCA-GGA-GCG-CA-3⬘. Aliquots
of the PCR products (7.5 ␮l) were separated and visualized
with ethidium bromide staining after electrophoresis on a 1.5%
agarose gel in Tris–acetate–EDTA buffer at 100V for 20
minutes (Figure 1B). TGF␤1 messenger RNA (mRNA) was
detected in the carcinomatous site but not in the normal gastric
site.
Sclerotic skin diseases resembling SSc and occurring in
patients with malignant tumors or other diseases are sometimes referred to as pseudoscleroderma or pseudosclerosis
(6,7). Because the distribution of skin sclerosis in our patient
was different from that of SSc, he was diagnosed as having
pseudoscleroderma associated with an advanced gastric carcinoma. Querfeld et al described a patient with pseudoscleroderma associated with lung cancer, in whom expression of
collagen ␣1 and CTGF mRNA were markedly increased in
fibroblasts scattered throughout the dermis (7). Although
acrosclerosis and nailfold changes were observed in that patient, TGF␤1 expression in the lesional skin was not detected,
and which tissue secreted collagen ␣1– or CTGF-stimulating
factors such as TGF␤ was not determined. The patient described by Querfeld et al had high titers of antinuclear
antibodies and IgM anticardiolipin antibodies but not
scleroderma-specific autoantibodies. Our experience together
with that of Querfeld et al suggests that certain tumor cells
secrete soluble factors that induce SSc-mimicking skin changes
and organ involvement.
In our patient, removal of TGF␤1-producing tumor
cells resulted in the amelioration of sclerotic skin changes. This
is the first report of pseudoscleroderma associated with
LETTERS
1767
Takao Fujii, MD, PhD
Tsuneyo Mimori, MD, PhD
Kyoto University Graduate School of Medicine
Kyoto, Japan
Noriko Kimura, MD
Shinji Satoh, MD
Michito Hirakata, MD, PhD
Keio University School of Medicine
Tokyo, Japan
1. Varga J. Scleroderma and Smads: dysfunctional Smad family dynamics culminating in fibrosis. Arthritis Rheum 2002;46:1703–13.
2. Saito H, Tsujitani S, Oka S, Kondo A, Ikeguchi M, Maeta M, et al.
The expression of transforming growth factor-␤1 is significantly
correlated with the expression of vascular endothelial growth factor
and poor prognosis of patients with advanced gastric carcinoma.
Cancer 1999;86:1455–62.
3. Maehara Y, Kakeji Y, Kabashima A, Emi Y, Watanabe A, Akazawa
K, et al. Role of transforming growth factor-␤1 in invasion and
metastasis in gastric carcinoma. J Clin Oncol 1999;17:607–14.
4. Steen VD, Medsger TA Jr, Rodnan GP. D-penicillamine therapy in
progressive systemic sclerosis (scleroderma): a retrospective study.
Ann Intern Med 1982;97:652–9.
5. Nakamura M, Katano M, Kuwahara A, Fujimoto K, Miyazaki K,
Morisaki T, et al. Transforming growth factor ␤1 (TGF-␤1) is a
preoperative prognostic indicator in advanced gastric carcinoma.
Br J Cancer 1998;78:1373–8.
6. Gray RG, Gottlieb NL. Pseudoscleroderma in hypertrophic osteoarthropathy. JAMA 1981;246:2062–3.
7. Querfeld C, Sollberg S, Haerkamp C, Eckes B, Krieg T. Pseudoscleroderma associated with lung cancer: correlation of collagen
type I and connective tissue growth factor gene expression. Br J
Dermatol 2000;142:1228–33.
DOI 10.1002/art.11146
Reply
Figure 1. A. Normal (1) and carcinomatous (2) sites in the resected
stomach. B, Reverse transcription–polymerase chain reaction analysis.
Transforming growth factor ␤1 (TGF␤1) was detected (247 bp) in the
sample obtained from the carcinomatous site but not in that obtained
from the normal site. ␤-actin (541 bp) was amplified in both samples.
TGF␤1-secreting gastric carcinoma. Further study of the abnormal up-regulation of TGF␤1 (including the latent form of
TGF␤1) in malignant tumors is needed to clarify this association.
To the Editor:
The report by Fujii et al describes an elderly man with
pseudoscleroderma who was found to have adenocarcinoma of
the stomach. The diagnosis of pseudoscleroderma was based
on the atypical distribution of skin changes (involving the neck,
trunk, and extremities, but sparing the fingers), histopathologic
findings in the skin, and the absence of Raynaud’s phenomenon or serologic features of SSc. Following gastrectomy, the
extent of skin involvement decreased by half, and serum TGF␤
levels declined from 2.15 ng/ml to 1.88 ng/ml. Because TGF␤
mRNA was detected by RT-PCR in the resected gastric tissue,
the authors propose the intriguing hypothesis that tumorderived TGF␤1 may have contributed to the development of
widespread skin fibrosis in this patient, and that clinical
improvement was attributable to a decline in TGF␤1 secretion.
A previous report described concurrent pseudoscleroderma
and lung cancer (1), but the tumor was not examined for TGF␤
secretion, and Gruber et al reported a case of SSc associated
with TGF␤-secreting adenocarcinoma of the lung (2).
TGF␤ is preeminent among the multiple cytokines and
growth factors implicated in the pathogenesis of fibrosis. In
cancer, TGF␤ has 2 paradoxical roles: as a tumor suppressor in
the early stages but as a tumor promoter in later stages (3).
Could tumors that secrete TGF␤ induce pseudoscleroderma
1768
LETTERS
and similar disorders? Despite the fact that 20% of gastric
adenocarcinomas and other tumors have been shown to produce TGF␤ (4), their association with scleroderma-like conditions appears to be rare. Thus, the literature does not support
an association between TGF␤-producing tumors and scleroderma, although it is possible that in some cancer patients the
skin changes are overlooked. In addition to pseudoscleroderma, palmar fasciitis has been described as a paraneoplastic
complication (5). It is intriguing to speculate that tissue fibrosis
in some patients with malignancies may be attributable to
TGF␤ production by tumors.
In summary, a causal relationship between pseudoscleroderma and TGF␤1 production by adenocarcinomas is proposed but remains unproven. It is tempting to consider that
TGF␤ secreted by certain tumors may induce scleroderma or
related fibrotic disorders in some individuals. An important
lesson is that patients who present with atypical features of
scleroderma merit careful screening and continued monitoring
for cancer.
John Varga, MD
University of Illinois at Chicago
1. Querfeld C, Sollberg S, Huerkamp C, Eckes B, Krieg T. Pseudoscleroderma associated with lung cancer: correlation of collagen
type I and connective tissue growth factor gene expression. Br J
Dermatol 2000;142:1228–33.
2. Gruber BL, Miller F, Kaufman LD. Simultaneous onset of systemic
sclerosis (scleroderma) and lung cancer: a case report and histologic
analysis of fibrogenic peptides. Am J Med 1992;92:705–8.
3. Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor
suppression and cancer progression. Nat Genet 2001;29:117–29.
4. Saito H, Tsujitani S, Oka S, Kondo A, Ikeguchi M, Maeta M, et al.
The expression of transforming growth factor-beta1 is significantly
correlated with the expression of vascular endothelial growth factor
and poor prognosis of patients with advanced gastric carcinoma.
Cancer 1999;86:1455–62.
5. Medsger TA, Dixon JA, Garwood VF. Palmar fasciitis and polyarthritis associated with ovarian carcinoma. Ann Intern Med 1982;96:
424–31.
DOI 10.1002/art.10981
Emerging clinical spectrum of tumor necrosis factor
receptor–associated periodic syndrome: comment on
the articles by Hull et al and Dodé et al
To the Editor:
We read with interest the recent reports by Hull et al
(1) and Dodé et al (2). We herein describe a family with the
R92Q TNFRSF1A mutation, thereby widening the debate
initiated by Hull and colleagues regarding the pathologic cause
of myalgia in tumor necrosis factor receptor–associated periodic syndrome (TRAPS). Our report also demonstrates a wide
spectrum of inflammation manifestations compatible with the
proposed enlarging clinical spectrum of TRAPS reported by
Dodé et al. However, we suggest the need to clarify diagnostic
criteria for TRAPS, particularly in patients with lowpenetrance TNFRSF1A mutations.
The patient, a 37-year-old man (index case), presented
with a 15-year history of inflammation symptoms of unknown
Figure 1. Lymphocytic vasculitis of muscle with the TNFRSF1A mutation.
cause. At age 22 years he developed bilateral synovitis of the
knees. Seven years later, he developed recurrent abdominal
pain, testicular pain, breathlessness, myalgia, and fevers, followed by an erythematous rash. Analysis of the TNFRSF1A
gene revealed the R92Q mutation, confirming the diagnosis of
TRAPS. Muscle biopsy revealed thickening of small blood
vessel walls only, without evidence of myositis or fasciitis.
Corticosteroid treatment was ineffective, although twiceweekly administration of subcutaneous etanercept improved
the patient’s recorded symptoms.
The patient’s 64-year-old father, who also had the
R92Q TNFRSF1A mutation, was subsequently evaluated. He
reported a 16-year history of increasingly severe but constant
lower limb muscle cramps and pain, but no history of recurrent
fever. Clinical examination revealed tense hard quadriceps
muscles and difficulty with hand grip and walking. A complete
blood cell count, the erythrocyte sedimentation rate, the
C-reactive protein level, serologic evaluation of autoimmunity,
and levels of antineutrophil cytoplasmic antibody, immunoglobulins (including IgD), and creatine kinase were normal.
Electromyographic studies and magnetic resonance imaging
(MRI) of the quadriceps were also normal, but muscle biopsy
revealed lymphocytic vasculitis (Figure 1). A dramatic clinical
response was achieved with intravenous methylprednisolone,
but symptoms were unresponsive to both intravenous cyclophosphamide and etanercept. Repeat muscle biopsy revealed
foci of interstitial lymphocytes, one of which was centered
around a blood vessel. Subsequent treatment with infliximab
was unsuccessful, although oral etoposide produced symptom
relief and improved the patient’s mobility.
The sister of the index case patient was a 36-year-old
female with the R92Q TNFRSF1A mutation; she had no
history of recurrent fever. At age 14 years, she developed
bilateral tenosynovitis of the tibialis anterior that responded to
tendon release but was followed by tenosynovitis of the
extensor tendons in the foot. By age 17 years, she had
developed intermittent cramps in her toes and arthralgia in her
LETTERS
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fingers and wrists, which has persisted. The acute-phase response, serologic evaluation of autoimmunity, and rheumatoid
factor were negative during episodes of tenosynovitis.
Two additional family members with the R92Q
TNFRSF1A mutation included a healthy 62-year-old man who
had calf pain and cramps on most days, and a healthy
39-year-old man with a history of childhood inguinal hernia
repair (a feature previously described in some families with
TRAPS). Three family members were negative for TNFRSF1A
mutations and had no history of inflammatory disease. The 3
subjects with the R92Q TNFRSFA1 mutation and symptoms of
inflammation also reported intervertebral disc prolapse requiring surgery before age 40 years, which was not apparent in the
R92Q-negative patients.
We agree with Hull et al that myalgia represents a
common finding in TRAPS, but its etiology may be variable.
We previously described myalgia in a man with C33Y TRAPS
(3). In that patient, muscle biopsy revealed thick-walled small
vessels with a focus of interstitial edema only, while MRI of the
forearm demonstrated edema in the deep musculature and
overlying skin. Dodé et al previously suggested myositis as the
cause of myalgia in C30S TRAPS, and we now broaden the
spectrum of muscle involvement in patients with TNFRSF1A
mutations with our description of lymphocytic vasculitis in
muscle. Of particular note, MRI scanning was normal in our
subject, despite the fact that he was symptomatic.
The index case patient in this family has a typical
history of TRAPS, illustrated by recurrent fever, myalgia,
abdominal pain, and breathlessness. The 2 other subjects with
inflammation symptoms, however, have histories that are
atypical of TRAPS (e.g., absence of fever and, for the patient
with lymphocytic vasculitis, a lack of periodicity and late onset
of symptoms). Although both subjects had the R92Q
TNFRSF1A mutation and no other cause of their symptoms
was apparent, we suggest that the diagnosis of TRAPS could
be inappropriate for these subjects. We suggest that Dodé and
colleagues should exercise the same caution when enlarging
the clinical spectrum of TRAPS (i.e., diagnosing TRAPS based
on late-onset pericarditis in patients with low- or variablepenetrance mutations, including R92Q and P46L).
The diagnosis of TRAPS is currently based on clinical
features associated with TNFRSF1A mutations. Other laboratory indicators, e.g., reduced circulating soluble TNFRSF1A
receptor levels and reduced in vitro cleavage of TNFRSF1A
from the cell surface, are variable and in isolation are not
indicative of TRAPS. We propose that the presence of lowpenetrance mutations (e.g., R92Q) in 1% of the normal
population (4) requires that the clinical and laboratory diagnostic criteria for TRAPS be refined. This family study, the
increased incidence of R92Q in early arthritis, and our finding
of 1 of 21 patients with systemic vasculitis (predominantly
Wegener’s granulomatosis) having the R92Q mutation suggests that R92Q TNFRSF1A predisposes to a wide spectrum of
inflammatory disease as a whole, and represents a lowpenetrance mutation for TRAPS.
E. Drewe, MBBS
P. C. Lanyon, MBBS, DM
R. J. Powell, MBBS, DM
Queens Medical Center
Nottingham, UK
1. Hull KM, Wong K, Wood GM, Chu W-S, Kastner DL. Monocytic fasciitis: A newly recognized clinical feature of tumor
necrosis factor receptor dysfunction. Arthritis Rheum 2002;46:
2189–94.
2. Dodé C, André M, Bienvenu T, Hausfater P, Pecheux C, Bienvenu
J, et al. The enlarging clinical, genetic, and population spectrum of
tumor necrosis factor receptor–associated periodic syndrome. Arthritis Rheum 2002;46:2181–8.
3. McDermott EM, Smillie DM, Powell RJ. Clinical spectrum of
familial Hibernian fever: a 14-year follow-up study of the index case
and extended family. Mayo Clin Proc 1997;72:806–17.
4. Aksentijevich I, Galon J, Soares M, Mansfield E, Hull K, Oh HH,
et al. The tumour-necrosis-factor receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral origins, genotypephenotype studies, and evidence for further genetic heterogeneity
of periodic fevers. Am J Hum Genet 2001;69:301–4.
DOI 10.1002/art.11147
Reply
To the Editor:
We thank Drewe et al for their interest in our recent
article demonstrating monocytic fasciitis as the etiology of
myalgia in a patient with TRAPS and in which we proposed
that this mechanism might explain the myalgia observed in a
subset of patients with this disorder. Although we agree that
our findings do not account for every case of myalgia in
TRAPS, we do feel strongly that the monocytic fasciitis
reported accounts for the well-described migratory myalgia
and rash associated with this disease. We are aware of the
possibility of lymphocytic vasculitis in TRAPS, because we
coauthored with Drewe and colleagues (1) a description of this
finding in 2 patients with persistent nonmigrating myalgia.
It is interesting that the authors describe finding the
R92Q mutation in 1 of 21 patients with Wegener’s granulomatosis, because this further supports our hypothesis suggesting a
role for this mutation in a broader spectrum of inflammatory
diseases (2). In that publication, which originally described the
R92Q mutation, we identified 7 of 135 patients (5%) who were
referred to our institution with early synovitis as harboring the
R92Q mutation, compared with 1% of normal controls. We
are currently conducting a larger study screening a cohort of
patients with rheumatoid arthritis (RA) to further test this
hypothesis.
At the present time, we believe that it would be
premature to establish clinical criteria for TRAPS, because the
genetic lesion has been recognized for only 4 years, and thus
the spectrum of clinical manifestations is still subject to a
broadening base of clinical experience. What exactly constitutes a symptom related specifically to TNF receptor mutations
is uncertain, but as the number of mutations responsible for
TRAPS continues to expand at a rapid pace (⬎24 total
mutations over the past 4 years), the number of associated
clinical findings is increasing. The diversity of symptoms that
we have observed since originally describing the disorder in
1999 (3) has been clearly illustrated in both our recent clinical
description of patients with the R92Q mutation (1) and by
1770
LETTERS
Dodé et al (4). Thus, limiting the diagnosis of TRAPS to
mutation-positive individuals with a combination of selected
signs/symptoms may be short-sighted at this juncture.
Moreover, as medical science prefers to classify diseases based upon known underlying etiologies, the boundaries
for defining what constitutes the clinical syndrome of TRAPS
may expand. For example, when a patient meets the clinical
criteria for RA but harbors a TNFRSF1A mutation, do they
have RA or TRAPS? Prior to the recognition of Lyme disease
as a consequence of Borrelia burgdorferi infection, some of the
patients with Lyme arthritis would have met criteria for RA,
yet we would not today use that latter diagnosis for such
individuals. Similarly, there may be a preference for the
diagnosis of TRAPS, which implies an underlying genetic
mechanism, in patients with manifestations of other idiopathic
rheumatic disorders who have TNFRSF1A mutations.
We suggest that at this early stage of our understanding of the pathophysiologic consequences of TNF receptor
mutations, their role in more genetically complex diseases, and
the degree of genetic and environmental modifiers affecting
the phenotypic expression, that we remain open regarding the
symptoms related to TRAPS.
Keith M. Hull, MD, PhD
Daniel L. Kastner, MD, PhD
National Institute of Arthritis and Musculoskeletal
and Skin Diseases
National Institutes of Health
Bethesda, MD
1. Hull KM, Drewe E, Aksentijevich I, Singh HK, Wong K, McDermott EM, et al. The TNF receptor-associated periodic syndrome
(TRAPS): emerging concepts of an autoinflammatory disorder.
Medicine 2002;81:349–68.
2. Aksentijevich I, Galon J, Soares M, Mansfield E, Hull K, Oh HH,
et al. The tumor-necrosis-factor receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral origins, genotypephenotype studies, and evidence for further genetic heterogeneity
of periodic fevers. Am J Hum Genet 2001;69:301–14.
3. McDermott MF, Aksentijevich I, Galon J, McDermott EM,
Ogunkolade BW, Centola M, et al. Germline mutations in the
extracellular domains of the 55 kDa TNF receptor, TNFR1, define
a family of dominantly inherited autoinflammatory syndromes. Cell
1999;97:133–40.
4. Dodé C, Papo T, Fieschi C, Pêcheux C, Dion E, Picard F, et al. A
novel missense mutation (C30S) in the gene encoding tumor
necrosis factor receptor 1 linked to autosomal-dominant recurrent
fever with localized myositis in a French family. Arthritis Rheum
2000;43:1535–42.
DOI 10.1002/art.11148
Clinical Images: Tumoral calcinosis associated with sarcoidosis
The patient was diagnosed as having sarcoidosis in 1995 at the age of 78 years, when she presented with pulmonary infiltrates,
bilateral ankle arthritis, hepatitis, and bilateral parotid swelling. A biopsy of the right parotid gland revealed chronic granulomatous
sialadenitis consistent with sarcoidosis. In 1996, she began to experience the rapid development of large, multilobulated calcific
masses in the subcutaneous tissue and muscles surrounding her right hip, neck, and anterior chest wall. During the next 3 years, the
calcification spread to both hips, thighs, elbows, hands, and the right knee. The radiographs shown here demonstrate the rapid
increase in calcification of the left thigh from April 1998 (A) to December 1998 (B). The patient’s clinical history and radiographic
findings are consistent with tumoral calcinosis, which has been reported in rare cases to be associated with sarcoidosis.
John D. Carter, MD
Elizabeth Warner, MD
University of South Florida
Tampa, FL
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