Letters to the Editor
Treatment of acquired haemophilia A requires urgent
control of bleeding and inhibitor eradication by immunosuppression, mainly steroid based, alone or combined
with CYC. Rituximab, a monoclonal anti-CD20 antibody,
has been used in mono- and combination therapy to treat
acquired haemophilia A. Complete remission (CR) rates of
61–90% [6–8] were described when used combined with
other immunosuppressives. Time to remission is longer in
rituximab- compared with CYC-based regimens, with a
median time to undetectable factor VIII inhibitor level of 64
days, but with fewer relapses (3%), resulting in more durable CR rates [8]. In this case, occurring under steroid
maintenance therapy and with a history of previous CYC
use, we chose rituximab to avoid toxicity. Due to the lack
of controlled data, the scientific community is still divided
about the position of rituximab in first- or second-line
therapy when treating acquired haemophilia A.
Rheumatology key message
.
Acquired haemophilia warrants consideration in
autoimmune-prone patients, with severe immune
dysregulation after autologous haematopoietic stem
cell transplantation.
Disclosure statement: The authors have declared no
conflicts of interest.
Ellen De Langhe1, Jan Lenaerts1, Daan Dierickx2,
Peter Hendrickx3, Geert M. Verleden4,
Wim A. Wuyts4, Kathelijne Peerlinck5 and
Rene Westhovens1
1
Department of Rheumatology, 2Department of Hematology,
Dokterspraktijk De Brug, Mol, 4Department of Respiratory
Medicine and 5Department of Vascular Medicine and
Hemostasis, University Hospitals Leuven, Leuven, Belgium.
Accepted 8 August 2014
Correspondence to: Ellen De Langhe, Department
of Rheumatology, University Hospitals Leuven,
Herestraat 49, 3000 Leuven, Belgium.
E-mail: [email protected]
3
References
1 Shetty S, Bhave M, Ghosh K. Acquired hemophilia A:
diagnosis, aetiology, clinical spectrum and treatment
options. Autoimmun Rev 2011;10:311–6.
2 van Laar JM, Farge D, Sont JK et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse
cyclophosphamide in diffuse cutaneous systemic sclerosis. a randomized clinical trial. JAMA 2014;311:2490–8.
3 Beyne-Rauzy O, Fortenfant F, Adoue D. Acquired
haemophilia and PM-Scl antibodies. Rheumatology 2000;
39:927–8.
4 Loh Y, Oyama Y, Statkute L et al. Development of a
secondary autoimmune disorder after hematopoietic stem
cell transplantation for autoimmune diseases: role of conditioning regimen used. Blood 2007;109:2643–548.
www.rheumatology.oxfordjournals.org
5 Daikeler T, Labopin M, Di Gioia M et al. Secondary
autoimmune diseases occurring after HSCT for an
autoimmune disease: a retrospective study of the EBMT
Autoimmune Disease Working Party. Blood 2011;118:
1693–8.
6 Stasi R, Brunetti M, Stipa E et al. Selective B-cell depletion
with rituximab for the treatment of patients with acquired
hemophilia. Blood 2004;103:4424–8.
7 Franchini M, Veneri D, Lippi G et al. The efficacy of rituximab in the treatment of inhibitor-associated hemostatic
disorders. Thromb Haemost 2006;96:119–25.
8 Collins P, Baudo F, Knoebl P et al. Immunosuppression for
acquired hemophilia A: results from the European
Acquired Haemophilia Registry (EACH2). Blood 2012;120:
47–55.
Rheumatology 2015;54:197–199
doi:10.1093/rheumatology/keu419
Advance Access publication 22 October 2014
Childhood-onset PsA in Down syndrome with
psoriasis susceptibility variant CARD14 rs11652075
SIR, Down syndrome (DS), which results from trisomy of
chromosome 21, is the most common autosomal chromosomal disorder [Online Mendelian Inheritance in Man
(OMIM): 190685]. Some cases of childhood-onset PsA in
DS patients have been reported [1]. Moreover, arthritis is
more common in children with DS [2]. However, the genetic risk factors for PsA concomitant with DS have not
been adequately examined. Herein we describe a case
of DS accompanied by PsA in a boy who was homozygous for the psoriasis susceptibility variant rs11652075 of
CARD14.
The 15-year-old Japanese boy in this case study had
been followed up by our clinic for 10 years (Fig. 1a and b).
He was diagnosed with DS shortly after birth based on the
presence of an extra chromosome 21 in karyotype analysis.
At 2 years of age he showed scaly erythematous plaques on
the trunk and extremities. He was diagnosed as having
psoriasis vulgaris and was treated with steroid and vitamin
D ointments at another hospital. At 10 years of age he had
arthralgia of the bilateral fingers and dislocation of the right
thumb (Fig. 1c and d). He tested negative for RF and CCP
antibody. Hence he was diagnosed as having PsA. He was
initially treated with MTX 7.5 mg/kg/week and thereafter
received infliximab. His PsA has been well controlled for 4
years with 3 mg/kg infliximab every 8 weeks. His parents do
not have psoriasis or arthritis, however, his maternal
grandfather’s brother had psoriasis vulgaris.
The ethics committee of the Nagoya University Graduate
School of Medicine approved the present genetic analysis,
which was conducted according to the Declaration of
Helsinki. The participants gave written informed consent.
Because the CARD14 mutation sometimes causes inherited
or childhood-onset psoriasis, a direct sequencing analysis of
the entire coding region of CARD14 and exon–intron boundaries was conducted [3, 4]. The analysis revealed that the
patient and his parents were homozygous for rs11652075
197
Letters to the Editor
FIG. 1 Skin manifestations and arthritis in the patient
(a) A flat nasal bridge, thick lips and thickened scaly erythema were observed on the face. (b) A scaly erythematous
plaque was present on the left leg. (c) X-ray indicated dislocation of the IP joint of the right thumb. (d) Affected joints are
indicated as red circles.
(c.2458C>T; p.Arg820Trp), psoriasis susceptibility 2
(PSORS2), which is a psoriasis susceptibility variant [3].
HLA-Cw*0602 (PSORS1) is among the main genetic factors
associated with a predisposition for psoriasis. We analysed
HLA-C in the participants using Micro SSPTM HLA typing
trays (One Lambda, Canoga Park, CA, USA) [4]. The patient
and his mother had compound heterozygous HLA-Cw*01
and HLA-Cw*07 mutations and his father was homozygous
for HLA-Cw*01. None of the individuals had HLA-Cw*0602.
DS is sometimes accompanied by psoriasis [5].
Moreover, DS is often associated with seborrhoeic
198
dermatitis, which may occasionally predispose patients
to psoriasis [5]. Patients with DS have immunological
defects, including reduced numbers of circulating
regulatory T cells [6]. CARD14 rs11652075 is a genetic
risk factor for psoriasis. CARD14 encodes caspase
recruitment domain 14, which activates nuclear factor
kappa-light-chain-enhancer of activated B cells in keratinocytes [3]. We conclude that a combination of immunological defects due to trisomy 21 and homozygous
CARD14 rs11652075 contributed to the pathogenesis of
childhood-onset PsA in this patient since the parents
www.rheumatology.oxfordjournals.org
Letters to the Editor
without chromosome abnormality did not develop psoriasis or arthritis even though they were homozygous for
CARD14 rs11652075. However, the combination of
trisomy and the variant might be coincidental and therefore unrelated to PsA in the patient. In conclusion, to our
knowledge this case is the first to suggest that a
combination of chromosome 21 trisomy and psoriasis
susceptibility variant CARD14 rs11652075 can lead to
childhood-onset PsA.
pustular psoriasis with psoriasis vulgaris in the Japanese
cohort. J Invest Dermatol 2014;134:1755–7.
5 Madan V, Williams J, Lear JT. Dermatological manifestations of Down’s syndrome. Clin Exp Dermatol 2006;31:
623–9.
6 Broers CJ, Gemke RJ, Weijerman ME et al. Frequency of
lower respiratory tract infections in relation to adaptive
immunity in children with Down syndrome compared to
their healthy siblings. Acta Paediatr 2012;101:862–7.
Rheumatology key message
.
A combination of Down syndrome and CARD14
rs11652075 can lead to childhood-onset PsA.
Acknowledgements
The authors thank Haruka Ozeki, Yuka Terashita and
Akemi Tanaka for their technical help in analysing variants
of CARD14 and HLA-C. This study was supported in part
by a Grant-in-Aid for Challenging Exploratory Research
(26670526; to K.S.) and a Grant-in-Aid for Scientific
Research (A) (23249058; to M.A.), both from the Ministry
of Education, Culture, Sports, Science and Technology of
Japan, and by a grant for Research on Measures for
Intractable Diseases (to M.M.) from the Ministry of
Health, Labor and Welfare of Japan.
Funding: None.
Disclosure statement: The authors have declared no
conflicts of interest.
Kazumitsu Sugiura1, Toshiyuki Kitoh2,
Daisuke Watanabe3, Masahiko Muto4 and
Masashi Akiyama1
1
Department of Dermatology, Nagoya University Graduate
School of Medicine, Nagoya, 2Department of Pediatrics,
3
Department of Dermatology, Aichi Medical University,
Nagakute and 4Department of Dermatology, Yamaguchi
University Graduate School of Medicine, Ube, Japan.
Correspondence to: Kazumitsu Sugiura, Department of
Dermatology, Nagoya University Graduate School of
Medicine, 65 Tsurumai-cho, Showa-ku Nagoya 466-8550,
Japan. E-mail: [email protected]
References
1 Tudor RB. Letter: psoriatic arthritis in a child with Down’s
syndrome. Arthritis Rheum 1976;19:651.
2 Padmakumar B, Evans Jones LG, Sills JA. Is arthritis more
common in children with Down syndrome? Rheumatology
2002;41:1191–3.
3 Sugiura K. The genetic background of generalized pustular psoriasis: IL36RN mutations and CARD14 gain-offunction variants. J Dermatol Sci 2014;74:187–92.
4 Sugiura K, Muto M, Akiyama M. CARD14 c.526G>C
(p.Asp176His) is a significant risk factor for generalized
www.rheumatology.oxfordjournals.org
Rheumatology 2015;54:199–200
doi:10.1093/rheumatology/keu397
Advance Access publication 6 October 2014
Salivary gland ultrasound to diagnose Sjögren’s
syndrome: a claim to standardize the procedure
SIR, We read with great interest the recent study by Takagi
et al. [1], which reports on the clinical usefulness of major
salivary gland ultrasound (SGUS) to classify SS patients.
This study shows that SGUS could replace any item of the
ACR classification criteria without modifying their concordance with American–European Consensus Group
(AECG) classification criteria.
Using a different study design with physician diagnosis
as a gold standard, we have shown that the adjunction of
SGUS as an independent item improves the diagnostic
performance of both AECG and ACR classification criteria
[2, 3]. Despite notable differences in our results, mainly on
the concordance between AECG and ACR criteria [4], the
global conclusion of these studies is the same: SGUS
should be included in future classification criteria.
However, as highlighted recently by Goules and
Tzioufas [5], further steps in the validation of this test
have to be overcome before its definitive inclusion in
new classification criteria for primary SS. First, all recent
studies published on the topic have shown good performance of SGUS in diagnosing SS, but each team uses a
different definition of a pathological procedure [6–8]. The
main abnormal SGUS feature related to SS diagnosis
seems to be parenchyma heterogeneity, due to the occurrence of a hypoechogenic area resembling fluid cysts
(even if no data exist on the histological significance of
these sonographic findings). However, several other
items are optionally included in the different proposed
sonographic scores, such as gland size, hyperechogenic
bands, precision of the borders, intraglandular calcification, parenchyma inflammation assessed by power
Doppler or vascular abnormalities assessed by colour
Doppler. The relative diagnostic value of these items has
to be determined in order to develop a consensual scoring
system that could be used by all physicians.
Second, US may be more examiner dependent than
other imaging procedures. Scarce data exist on the
intra- and interobserver reproducibility of SGUS. In the
current context of the wide diffusion of US among
rheumatologists, specific formations will have to be developed to ensure the accuracy of the procedure performed in clinical practice. The stability of SGUS
199