ARTICLE
Auteur(s) : Paolo
Amerio1, Carmela Innocente1, Claudio
Feliciani2, Domenico Angelucci3, Domenico
Gambi4, Antonio Tulli1
1Dermatology Dept., University G. D’Annunzio, Chieti,
Italy
2Dermatology Dept., Catholic University of The S. Heart,
A. Gemelli Hospital, Rome, Italy
3Service of Pathology, ASL Chieti-Ortona, Chieti,
Italy
4Neurology Dept., University G. D’Annunzio, Chieti,
Italy
accepté le 16 Janvier 2006
Lupus is a systemic autoimmune illness of unknown etiology. Many
drugs can induce clinical symptoms similar to those present in
lupus erythematosus in which case a diagnosis of “drug-induced
lupus erythematosus (DILE)” is made [1]. There are no pathognomonic
symptoms for DILE, any clinical manifestation that may occur in
idiopathic lupus erythematosus can be present in DILE. Similarly to
idiopathic lupus, DILE can be divided into systemic (SLE), subacute
(SCLE) and cutaneous chronic lupus (CCLE) [2]. The diagnosis of
DILE could be suspected when the disease is characterized by: 1) a
close time relationship with the intake of a drug reported to
induce lupus, 2) a negative clinical history for autoimmune
disease, 3) resistance to therapy and 4) the presence of
antihistone antibodies [3]. Currently, the exact time gap between
the intake of the drug and the appearance of the clinical symptoms
is unknown, but many authors suggest a period ranging from 3 weeks
to 2 years [4], even if some cases have been reported after longer
periods [5].Carbamazepine (CBZ) is a drug commonly used in the
treatment of seizure disorders, chronic pain syndromes, trigeminal
neuralgia, and psychiatric illnesses. CBZ side effects usually are
limited to drowsiness, ataxia, nausea and vomiting. However, it can
also induce severe reactions such as Stevens-Johnson syndrome [6]
or SLE [7], while purely cutaneous lupus reactions are very rare.
In the literature the time of onset of DILE by CBZ is reported to
be very variable [4, 5]. We describe a case of CBZ-induced SCLE
presenting after 5 years of CBZ treatment.
Case report
A 77-year-old woman presented to our clinic with a two-year history
of erythematous-desquamative lesions on the trunk and upper arms.
The lesions initially appeared on the hands and subsequently spread
to the back. She referred a 7-year history of CBZ (400 mg/die)
treatment for an accidental cranial trauma and denied any other
medication. The patient had been treated, soon after the onset of
the lesions, with hydroxychloroquine (200 mg/day), with only a
minor improvement; this poor response prompted the patient to
discontinue the drug after 8 months. On clinical examination she
presented small, erythematous-desquamative lesions located on the
dorsal aspect of both hands and on the chest, while erythematous
polycyclic lesions with a hyperkeratotic border were present on the
back (figure 1).
The patient also complained of myalgic pain and generalized
weakness.
Complete blood count, renal and hepatic function tests were
within normal limits except for γ-GT (116 U/L, n.v. 15-73 U/L), the
erythrocyte sedimentation rate was 35 mm/h (n.v.
1-12 mm/h), the antinuclear antibodies (ANA), anti-Sm and
anti-SmRNP antibodies were positive a titre of 1:80, 38.0 UI (n.v.:
0-25.0) and 49.0 UI (n.v.: 0-25.0), respectively. All other
autoantibodies (SSA/ro, SSB/La, Scl-70, Jo-1, double stranded DNA,
c-ANCA and p-ANCA) were negative. Antihistone antibodies titre was
306 UI, this value was higher than a determination (102 UI) made 2
years previously in another hospital. CBZ level was 8.9 mcg/ml,
well inside the therapeutic range (4 to 12 mcg/ml). A biopsy
performed during our hospital admission revealed an orthokeratotic
hyperkeratosis, slight acanthosis and increased thickness of basal
membrane. Superficial dermis showed only slight perivascular
inflammation. Direct immunofluorescence of lesional skin showed IgG
granular deposition at the basement membrane. The patient did not
fulfil the ARA criteria for the diagnosis of SLE and a diagnosis of
subacute cutaneous lupus erythematosus (SCLE) was made.
After a normal EEG the neurologist consultant agreed to slowly
taper the CBZ considering that the patient had not reported
epileptic episodes for 5 years after the initial crisis. The drug
was gradually reduced from 400 mg/die to 100/die in 2 months and
then definitely discontinued.
The patient experienced some flare ups of the cutaneous
presentation during the first month of tapering. However, within a
few weeks after CBZ discontinuation all skin lesions greatly
improved (figure
2). After 3 months of follow-up ANA were still present at a
titre of 1:80, anti histone antibodies were negative. Anti-Sm
antibodies were also negative at 5 month follow-up.
Discussion
SCLE is a disease characterized by non scarring papulosquamous or
annular skin lesions that usually appear on the neck, upper trunk,
extensor aspects of the shoulders, forearms and dorsum of the
hands. The majority (> 70%) of patients with SCLE are anti
Ro-SSA antibody positive, and around 10% of patients present other
autoantibodies such as Sm, dsDNA, and U1RNP [8]. The
pathogenesis of SCLE is still not clear but it seems that patients
with this disease have an increased frequency of a particular
polymorphism (-308A) in the promoter region of tumor necrosis
factor-α (TNF-α). Subjects homozygous for the -308A TNF-α allele
appear to be more susceptible to environmental factors such as UV
radiation, viral infections and chemical or drug exposure that
leads finally to an alteration in the cellular apoptosis mechanism
and thus to SCLE development [9].
Among the numerous drugs which have been reported to induce
SCLE, the most frequently involved are: diuretics, calcium channel
blockers, ACE inhibitors, antimicrobials, non steroidal
anti-inflammatory drugs, interferons and anticonvulsivants [9, 10].
CBZ-induced lupus is an uncommon disease, in a review in 1991
eighty cases were reported from 1963 to 1990 [5] and ten additional
cases have been described in literature from 1991 till today.
Almost all the reports described systemic lupus reactions. One
recent report, however, described a case of Ro/SSA-positive
cutaneous lupus erythematosus induced by CBZ [11]. Ro/SSA-positive
cutaneous lupus erythematosus is a new entity that better
characterises drug-induced cutaneous lesions similar to subacute
lupus erythematosus without any systemic symptom.
Our patient presented cutaneous lesions characteristic in
appearance and distribution, for SCLE, but we could not classify
this case as a Ro/SSA-positive cutaneous lupus erythematosus
because of the peculiar antibody pattern associated. In our patient
Ro-SSA and La-SSB were negative all through the disease history,
while she presented positivity for anti-Sm and for antihistone
antibodies at a high titre. Ro-SSA antibodies support the diagnosis
of SCLE but, according to the original definition, their presence
is not needed to make the diagnosis [12]. Anti-Sm Antibodies are
highly specific to the diagnosis of SLE, but their presence has
also been reported in almost 10% of SCLE patients [13]. Antihistone
antibodies are specific for drug-induced SLE and were present at
high titre in our patient. Interestingly, the antihistone antibody
titre and, to a lesser extent, anti-Sm antibody titre decreased in
our patient, in correlation with the resolution of the clinical
picture.
Although our patient presented striking SCLE-like cutaneous
lesions without the typical serological pattern for SCLE, we think
that the most probable diagnosis is that of drug-induced SCLE.
However, we cannot exclude a drug-induced cutaneous exacerbation of
a pre-existing oligo-symptomatic SLE, that she did not report in
the anamnesis and that did not satisfy the ARA criteria. In either
case, the particularity of this case report lies in the close
relationship between modification of both cutaneous lesions and
antihistone antibodies titre and CBZ discontinuation. The induction
of the cutaneous lesions by CBZ is very rare. Unfortunately, we
were not able to perform a test to genotype the TNF-α promoter
region.
Although the relationship between the clinical manifestation and
the intake of the drug was clear-cut in our patient, the clinical
symptoms only presented 5 years after the beginning of CBZ therapy.
So we can hypothesise that other environmental factors [14]
together with CBZ may have triggered the cutaneous lesions in a
genetically predisposed individual. The cutaneous lesions were,
then, maintained by the drug until it was discontinued.
We present this case for the unusual clinical association
between SCLE and CBZ intake and to underline that the temporal
relationship between initial drug intake and onset of lupus
symptoms may vary greatly.
References
1 Yung LR, Richardson BC. Drug-induced lupus. Rheum Dis
Clin North Am 1994; 20: 61-6.
2 Antonov D, Kazandjieva J, Wetugov D,
Gospodinov D, Tsankov N. Drug induced lupus
erythematosus. Clin Dermatol 2004; 22: 157-60.
3 Egner W. The use of laboratory tests in the diagnosis of
SLE. J Clin Pathol 2000; 53: 424-43.
4 Atzeni F, Marrazza MG, Sarzi-Puttini P,
Carrabba M. Drug-induced lupus erythematosus. Reumatismo 2003;
55: 147-54.
5 Toepfer M, Sitter T, Lochmuller H,
Pongratz D, Muller-Felber W. Drug-induced systemic lupus
erythematosus after 8 years of treatment with carbamazepine. Eur J
Clin Pharmacol 1998; 54: 93-4.
6 Feliciani C, Verzotti A, Coscione G,
Toto P, Morelli F, Di Benedetto A, Saladini C,
Chiarelli F, Tulli A. Skin reaction due to antiepileptic
drugs: several case report with long term follow up. Int J
Immunopath Pharmacol 2003; 16: 89-93.
7 Jain KK. Systemic lupus erythematosus (SLE)-like
syndromes associated with carbamazepine therapy. Drug Saf 1991; 6:
350-60.
8 Sontheimer RD. Subacute cutaneous lupus erythematosus:
25-year evolution of a prototypic subset (subphenotype) of lupus
erythematosus defined by characteristic cutaneous, pathological,
immunological, and genetic findings. Autoimmun Rev 2005; 4:
253-63.
9 Werth VP, Zhang W, Dortzbach K,
Sullivan K. Association of a promoter polymorphism to tumor
necrosis factor alpha with subacute cutaneous lupus erythematosus
and distinct photoregulation of transcription. J Invest Dermatol
2000; 115: 726-30.
10 Marzano AV, Borghi A, Mercogliano M,
Facchetti M, Caputo R. Nitrendipine-induced subacute
lupus erythematosus. Eur J Dermatol 2003; 13: 213-6.
11 Capponi A, De Simone C, Guerriero C,
Rotoli M, Bartoloni C. Ro/SSA-positive cutaneous lupus
erythematosus induced by carbamazepine. Arch Dermatol 2005; 141:
103-4.
12 Sontheimer RD, Thomas JR, Gilliam JN. Subacute
cutaneous lupus erythematosus. A cutaneous marker for a distinct
lupus erythematosus subset. Arch Dermatol 1979; 115: 1409-15.
13 Sontheimer RD. Subacute cutaneous lupus erythematosus: a
decade’s perspective. Med Clin North Am 1989; 73: 1073-90.
14 Shapiro M, Sosis AC, Junkin-Hopkins JM,
Werth VP. Lupus erythematosus induced by medications,
ultraviolet radiation, and other exogenous agents: a review with
special focus on the development of subacute cutaneous lupus
erythematosus in a genetically predisposed individual. Int J
Dermatol 2004; 43: 87-94.
|
Version imprimable
Version PDF
