Disseminated Therapy-Refractory Erythema Elevatum Diutinum with Paraproteinemia Treated with Intravenous Immunoglobulins: A Case Report and Review of Literature
K
Sawallich*, Z Leitz, P von den Driesch
Center for Dermatology, Klinikum Stuttgart,
Stuttgart, Germany
*Corresponding
author: K Sawallich, Center for Dermatology, Klinikum Stuttgart,
Priessnitzweg 24, 70374 Stuttgart, Germany. Tel: +4977127851811; Email:
k.sawallich@klinikum-stuttgart.de
Received
Date: 3 July, 2017; Accepted
Date: 20 July, 2017; Published Date:
27 July, 2017
Citation: Sawallich K, Leitz Z, Driesch PV (2017) Disseminated
Therapy-Refractory Erythema Elevatum Diutinum with Paraproteinemia Treated with
Intravenous Immunoglobulins: A Case Report and Review of Literature. Clin Exp
Dermatol Ther: CEDT-131. DOI: 10.29011/2575-8268/100031
Background: Erythema Elevatum Diutinum (EED) is a chronic form
of leukocytoclastic vasculitis. A variety of underlying systemic diseases can
be associated.
Methods: We report a rare case of widespread EED in association
with paraproteinemia. A review of the available literature was performed.
Therapy options are discussed.
Results: Biopsy revealed leukocytoclastic vasculitis. The
patient with therapy-resistant EED was treated with dapsone, topical and
systemic corticosteroids as well as intravenous immunoglobulins. Using this
combined therapy, the patient experienced improvement of skin lesions and
complete resolution of the pruritus. The systemic treatment was well tolerated.
Conclusion: Our patient demonstrates how far beyond the usual
predilections sites an EED may occur. The underlying paraproteinemia maybe an
underlying explanation for the severity seen in this case. The results of the
combined treatment were nevertheless promising.
1. Introduction
Erythema Elevatum Diutinum (EED) is a rare
chronic vasculitis that effects young and middle-aged adults between the ages
of 30 and 60 years and consists of papules, plaques or nodules. Common
locations are the extensor surfaces of extremities [1,2]. The standard therapy
consists of dapsone as the mainstay of treatment [3-6]. Furthermore, topical or
systemic corticosteroids are reported to be effective [4,7]. Other options are
nicotinamid or antibiotics such as clarithromycin, erythromycin or penicillin
in combination with dapsone [8-9]. We report on the successful treatment of EED
with intravenous immunoglobulins in combination with dapsone and systemic
corticosteroids which previously had failed to control the disease as
individual therapies. We provide a short review of the current literature on
the known role of underlying systemic diseases and dapsone as the treatment of
choice for EED. Additionally, we highlight the role of intravenous
immunoglobulins used in combination with dapsone.
2. Case
A 74-year old female patient was referred to
our department with erythematous plaques and nodules which occurred on the
extensor surfaces of feet, knees, elbows and fingers as well as erythematous
macules on the trunk and extremities for at least 2 years (Figure 1 a/b/c/d).
The patient reported that the skin lesions initially appeared on her feet. Past
medical history included breast cancer (high grade ductal carcinoma-in-situ),
intraductal papillarymucin neoplasia of the pancreas and recurrent pneumonia.
A skin biopsy revealed a sub epidermal pustular
bulla, chronic leukocytoclastic vasculitis, vascular wall necrosis and
erythrocyte extravasates (Figure 2 a/b/c). Lymphocytes and eosinophils were
present. Serological tests showed pathological serum immunofixation
electrophoresis with IgA- and IgM-heavy-chains as well as free kappa and lambda
light chains.
In 2009 the patient commenced a therapy with
dapsone (100 mg/day) and systemic prednisolone from the initial dose of 60 mg/
day in addition to topical corticosteroids. She continued a therapy with
dapsone (50 mg/day) and dose reduction of prednisolone 4 mg every week. Under
this therapy regime, she achieved only a partial remission of the skin lesions
and pruritus remained unresolved.
In 2015 the patient presented with a severe
relapse of the EED despite continuous treatment. We initiated therapy with oral
Nicotinamid, 200 mg 1/day, for 3 months as well as intra-lesional
corticosteroid injections (triamcinolone acetonide, 10 mg) and cryotherapy
every two weeks.
No positive effects were seen after three
months, hence treatment with intravenous immunoglobulins (1 mg/kg bodyweight/
day i.v.) over 6 days every 8 weeks was introduced. The patient received three
treatment cycles which were well tolerated. No obvious side-effects could be
noted. All lesions softened and flattened and the pruritus resolved. Response
to this treatment was highly encouraging.
Peripheral blood cell counts showed abnormal
results at the beginning of treatment (Hb 11,9 g/dl) (normal 12,0-16,0 g/dl).
After combined treatment with dapsone and intravenous immunoglobulins Hb and
Hkt showed normal results (Hb 13,9 g/dl (normal 12,0-16,0 g/dl) and Hkt 43,7 %
(Norm 35-45 %)). Platelet count was 422 T/µl (Normal 150-350 T/µl) before
combined therapy and 370 T/µl (normal 150-350 T/µl) after combined therapy. The
White Blood Cell (WBC) was 3,69 T/µl (normal 4,00-10,00 T/µl) at the beginning
and increased to 8,93 T/µl (normal 4,00-10,00 T/ µl) after the combined
therapy.
Prior to treatment with dapsone there was
abnormal value in the serum chemistry including CRP. CRP reduced from 1,2 to
0,4 mg/dl (normal <0,5 mg/dl) after combined therapy with intravenous
immunoglobulins. Creatinine and liver enzymes were within normal ranges before
and after therapy (creatinine 0,8 mg/dl (normal 0,5-0,9 mg/dl), AST (GOT) 22
U/l (normal < 31 U/l),ALT (GPT) 21 U/l (<34 U/l), GGT 17 U/l (normal <
38 U/l).
Values of serum IgA, IgM showed improvement
after therapy. Before therapy serum electrophoresis was pathological. Serum
immunfixation revealed (IgA- and IgM-heavy-chains as well as free kappa and
lambda light chains). After combined therapy serum electrophoresis did not show
any pathological values.
3. Discussion
and Review of Literature
EED is a chronic skin disorder characterized by
plaques and nodules, distributed symmetrically on the extensor surfaces
[1-2,4,10]. Similar to our case report EED is most frequently found on acral
and periarticular skin (Figure 1 a/b). EED belongs to a group of diseases which
are called reactive neutrophilic dermatoses [11].
Associated conditions are autoimmune disorders
such as chronic bowel disease [12], rheumatoid arthritis [13], SLE, Sjögren and
Sarcoidosis. Reactive neutrophilic dermatoses may also occur in association
with autoinflammatory syndromes. Examples of disorders that have been linked to
reactive neutrophilic dermatoses in the literature include infections [6] (e.g.
streptococcal [14], yersiniosal, mycoplasmic, cysticercosis, ureaplasmic),
hematological diseases (e.g. leukemia, lymphoma [15], paraproteinemia [16,17]),
pregnancy, solid malignant tumours and rarely drugs.
To our knowledge, this case seems to be the
first case of EED, which shows such widespread lesions especially on the
extremities. Our case demonstrates, how far beyond the usual predilections
sites an EED may occur. The literature review revealed some cases of erythema
elevatum diutinum associated with paraproteinemia [16,17]. We believe that this
chronic association with IgA paraproteinemia has led to the severe extent of
the disease in our case.
EED exhibits histopathologic leukocytoclastic
vasculitis [10] as also seen in our case. Therapeutically, dapsone is
considered to be first choice for EED in the literature [3-6] and was partially
successful in our case but could not control the severe relapse after several
years of treatment. Neither did nicotinamid or antibiotics in combination with
dapsone [8-9]. We decided to use intravenous immunoglobulins additionally,
which produced the best therapy effect in our patient. Our literature search
revealed another case report which highlighted the dramatic effect of IVIG in
cutaneous leukocytoclastic vasculitis [18].
Intravenous
Immunoglobulin (IVIG) is standard first-line therapy for Kawasaki Disease (KD)
which is a medium-size-artery vasculitis [19]. Recently, a European S1
consensus guideline encouraged the use of intravenous immunoglobulin for second
line use of cutaneous vasculitis [20]. In conclusion, we believe that dapsone
remains the treatment of choice for EED however, in therapy-resistant cases new
therapy options should be considered. The use of intravenous immunoglobulins
presents as an option for severe therapy resistant forms of the disease.
Randomized studies regarding this, however, would be of great interest and are
necessary to underline the possible therapeutical effect.
Figure
1:Clinical
presentation of the patient before systemic therapy with topical and systemic
steroid and intravenous immunoglobulin. Lesions are present on hand and feet. (a) Plaques on the extensor surfaces of
the hands and fingers. (b) Large
plaques and fibrosing nodules, distributed symmetricallyon the extensor surfaces of feet. (c)Erythematous
macules on the trunk. (d)
Erythematous macules and nodules on the extremities.
Figure
2: (a)
A skin biopsy revealed a sub epidermal pustular bulla and chronic
leukocytoclastic vasculitis.(b)
Chronic leukocytoclastic vasculitis, vascular wall necrosis and erythrocyte
extravasates. Lymphocytes and eosinophils were present.(c)Scattered eosinophils in the mixed perivascular cellular
infiltrate.
- High WA, Hoang MP, Stevens K, Cockerell CJ (2003) Late-stage nodular erythema elevatum diutinum. J Am Acad Dermatol49: 764-767.
- Yiannias JA, el-Azhary RA, Gibson LE (1992) Erythema elevatum diutinum: a clinical and histopathologic study of 13 patients. J Am Acad Dermatol26: 38-44.
- Grabbe J, Haas N, Möller A, Henz BM (2000) Erythema elevatum diutinum-evidence for disease-dependent leucocyte alterations and response to dapsone. Br J Dermatol 143: 415-420.
- Momen SE, Jorizzo J, Al-Niaimi F (2014) Erythema elevatum diutinum: a review of presentation and treatment. J Eur Acad Dermatol Venereol 28: 1594-1602.
- Dronda F, González-López A, Lecona M, Barros C (1996)Erythema elevatum diutinum in human immunodeficiency virus-infected patients-report of a case and review of the literature. ClinExpDermatol 21: 222-225.
- Rover PA, Bittencourt C, Discacciati MP, Zaniboni MC, Arruda LH, et al. (2005) Erythema elevatum diutinum as a first clinical manifestation for diagnosing HIV infection: case history. Sao Paulo Med J 123: 201-203.
- Gibson
LE, el-Azhary RA (2000)Erythema elevatum diutinum. Clin Dermatol 18: 295-299.
- Muratori S, Carrera C, Gorani A Alessi E (1999) Erythema elevatum diutinum and HIV infection: a report of five cases. Br J Dermatol 141: 335-338.
- Pérez-Bernal A, Moreno-Giménez JC, Sotillo-Gago I, Camacho-Martínez F(1983) Erythema elevatum et diutinum treated with nicotinamide and tetracyclines. Med CutanIbero Lat Am 11: 51-53.
- Ziemer M, Koehler MJ, Weyer W (2011) Erythema elevatum diutinum- a chronic leucocytoclastic vasculitis microscopically indistinguishable from granuloma faciale? J Cutan Pathol 38: 876-883.
- Wallach D (2005) Neutrophilic dermatoses.Rev Med Interne26: 41-53.
- Walker KD, Badame AJ (1990) Erythema elevatum diutinum in a patient with Crohn's disease. J Am AcadDermatol 22: 948-952.
- Nakajima H, Ikeda M, Yamamoto Y, Kodama H (1999) Erythema elevatum diutinum complicated by rheumatoid arthritis. J Dermatol 26: 452-456.
- Cream JJ, Levene GM, Calnan CD (1971) Erythema elevatum diutinum: an unusual reaction to streptococcal antigen and response to dapsone. Br J Dermatol 84: 393-399.
- Futei Y, Konohana I (2000) A case of erythema elevatum diutinum associated with B-cell lymphoma: a rare distribution involving palms, soles and nails. Br J Dermatol142:116-119.
- Chow RK, Benny WB, Coupe RL, Dodd WA, Ongley RC (1996) Erythema elevatum diutinum associated with IgA paraproteinemia successfully controlled with intermittent plasma exchange. Arch Dermatol 132:1360-1364.
- Thomas CL, Folkes L, Akhras V (2015) A case of mistaken identity: unilateral erythema elevatum diutinum associated with IgA paraproteinaemia. ClinExpDermatol40: 761-764.
- Ong CS, Benson EM (2000) Successful treatment of chronic leucocytoclastic vasculitis and persistent ulceration with intravenous immunoglobulin. Br J Dermatol143: 447-449.
- Shulman ST (2017) Intravenous Immunoglobulin for the Treatment of Kawasaki Disease. Pediatr Ann 46: 25-28.
- Enk A, Hadaschik E, Eming R, Fierlbeck G, French L, et al. (2017) Europäische Leitlinien (S1) fürdie Anwendung von hochdosierten intravenösen Immunglobulinen in der Dermatologie.J Dtsch Dermatol Ges15: 227-238.