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Erythema nodosum in children: a prospective study.

BACKGROUND: The studies of series of children with erythema nodosum (EN) are limited and mostly retrospective. OBJECTIVE: We evaluated the epidemiology, etiology, clinical manifestations, course, and prognosis of EN in children. METHODS: Thirty-five children with EN (17 boys, 18 girls; mean age, 8.79 years) have been studied. Four excluded children proved, on biopsy, to have leukocytoclastic vasculitis (n = 3) or eosinophilic cellulitis (n = 1). RESULTS: In 27 of the 35 children (77%), the etiology of EN was established by laboratory investigations. In 25 children the causative factor of EN was an infectious agent (including beta-hemolytic streptococcus [n = 17], and Mycobacterium tuberculosis [n = 2]), whereas in 2 patients, EN was associated with Crohn's disease in one and Hodgkin's disease in the other. In 8 of the 35 children (23%) the etiology of EN remained undetermined. The mean duration of the rash was 11.5 days. Recurrences were noted in only 2 children (1 episode in 1 child and 3 episodes in the other). CONCLUSION: Currently the most common provoking agent of EN in children in Greece is beta-hemolytic streptococcus. However, Mycobacterium tuberculosis should still be considered as a cause of the disorder. Also, the course of EN is benign and recurrences are exceptional.

Adolescent↗

Recurrent erythema nodosum associated with Echinacea herbal therapy.

We report a case of recurrent erythema nodosum that is temporally and perhaps causally associated with use of echinacea herbal therapy. The genus Echinacea is traditionally used as an immunostimulant in the prophylaxis and treatment of upper respiratory tract infections. In vitro and in vivo studies of echinacea administration in animal and human-derived models suggest a definite stimulatory effect on the cellular immune system, although the clinical impact of echinacea is still unknown. The public's increasing use of alternative and complementary therapies necessitates that dermatologists be familiar with the cutaneous adverse effects of these agents.

Adult↗

Erythromelalgia precipitated by acral erythema in the setting of thrombocytopenia.

Erythromelalgia is a rare syndrome that is characterized by episodic attacks of burning pain in the distal extremities, which last from minutes to days and are precipitated by exercise, warmth, or limb dependency. There is a primary or idiopathic form and a secondary form that occur with myeloproliferative or other diseases. All previous reports about erythromelalgia that is the result of a myeloproliferative process have documented associated thrombocytosis. We describe a 40-year-old woman with myelodysplastic syndrome who experienced erythromelalgia in the setting of acral erythema and thrombocytopenia, first induced by chemotherapy and recurring after a radiation- and chemotherapy-based myeloablative regimen that was administered before a T-cell-depleted allogeneic bone marrow transplantation.

Adult↗

Necrolytic migratory erythema as the only presenting sign of a glucagonoma.

We describe a 39-year-old man with a 3-year history of a recalcitrant psoriasiform eruption that was accentuated in the intertriginous areas. Hsitopathology was consistent with psoriasis. A glucagon level was 744 pg/mL with the upper limit of normal being 130 pg/mL. Computed tomographic scan of the abdomen revealed a 5-cm mass in the tail of the pancreas. The tumor was removed and found to be a glucagonoma (pancreatic islet tumor). The clinical eruption resolved promptly with surgical excision. Neither the clinical eruption nor the tumor has recurred for 6 months. The course of disease confirms the diagnosis of necrolytic migratory erythema associated with a glucagonoma.

Adult↗

Late-stage nodular erythema elevatum diutinum.

Erythema elevatum diutinum (EED) is a rare chronic vasculitic process of unknown etiology that presents as bilateral, symmetrical, periarticular, red-brown papules and plaques, often over dorsa of joints. Early histologic changes are characterized by leukocytoclastic vasculitis. With chronicity, the lesions develop dense neutrophilic infiltrate and fibrosis. We describe an unusual case of late-stage nodular EED present for 35 years in a seronegative 75-year-old man. Asymptomatic papules and plaques measuring from 0.7 to 9.0 cm were seen over the interphalangeal joints, elbows, knees, and ankles. The histologic findings were characterized by predominant concentric fibrosis that formed well-circumscribed dermal and subcutaneous nodules. Awareness of this unusual presentation of EED helps to avoid misdiagnosis as cutaneous neoplasms.

Aged↗

Erythema nodosum: an experience of 10 years.

In this study, we investigated clinical features, aetiology, prospective follow-up results and also factors favouring secondary erythema nodosum (EN) in patients with EN. A total of 50 patients (mean age 38 y) with a diagnosis of EN between 1993 and 2002 in our clinic were included in the study prospectively. A biopsy was performed in 30 of the patients. Patients were considered to have secondary EN when an underlying condition was found, and to have primary (or idiopathic) EN when no such condition was found. For the diagnosis of the underlying diseases, diagnostic criteria and/or diagnostic methods were used. Categorical variables were compared by using chi2 test. The majority of the patients were female (6F/1M) and 54% of cases had a determined aetiology. The foremost aetiology was primary tuberculosis (18%) followed in decreasing order by a poststreptococcal (16%), sarcoidosis (12%), inflammatory bowel diseases (IBD) (4%), Behçet's disease (2%), and pregnancy (2%). All the patients were followed for a mean duration of 7 y. The nodosities relapsed every y in 74% of idiopathic EN patients but in only 1 (Behçet's disease) of the secondary ones. Factors favouring secondary EN were as follows: prolonged fever, cough, sore throat, not relapsing EN, abnormal chest X-ray, leukocytosis, an erythrocyte sedimentation rate of higher than 50 mm/h and a CRP value of higher than 6 times the upper limit of normal. All the patients had bed rest and the majority was given naproxen. The outcomes were usually favourable within 7 d. The patients with an underlying disease were given specific treatment. EN has been associated with numerous diseases. In order to reduce cost and duration of diagnosis, every centre should determine its own most frequent aetiological factors. Factors favouring secondary EN should also be determined. Our study revealed primary tuberculosis, streptococcal pharyngitis, sarcoidosis, IBD, and Behçet's syndrome as the main aetiologies of EN.

Adolescent↗

Prolonged treatment with recombinant interferon gamma induces erythema nodosum leprosum in lepromatous leprosy patients.

10 patients with borderline and lepromatous leprosy were selected for a prolonged trial with recombinant interferon gamma (rIFN-gamma). Patients received 30 micrograms intradermally for six injections over a 9-d period, and then either 100 micrograms intradermally every 1 mo for 10 mo or every 2 wk for 5 mo (total, 1.2 mg). Erythema nodosum leprosum (ENL) was induced in 60% of the patients within 6-7 mo, as compared with an incidence of 15% per year with multiple drug therapy alone. The mean whole-body reduction in bacterial index over the first 6 mo was 0.9 log units. Cutaneous induration at the intradermal injection sites of greater than or equal to 15 mm predicted the development of a subsequent reactional state. Monocytes obtained from patients receiving the lymphokine demonstrated an increased respiratory burst and a 2.5-5.1-fold increase in tumor necrosis factor alpha (TNF-alpha) secretion in response to agonists. Patients in ENL had an even higher release of TNF-alpha from monocytes as well as high levels of TNF-alpha in the plasma (mean, 2,000 pg/ml). Thalidomide therapy was required to treat the systemic manifestations of ENL. Control of toxic symptoms with thalidomide was associated with a 50-80% reduction in agonist-stimulated monocyte TNF-alpha secretion. IFN-gamma enhanced the monocyte release of TNF-alpha by 3-7.5-fold (agonist dependent) when added to patient's cells in vitro, and this could be suppressed by the in vitro addition of 10 micrograms/ml of thalidomide.

Erythema Nodosum↗

Autoantibodies to desmoplakin I and II in patients with erythema multiforme.

Erythema multiforme (EM) represents a syndrome of chronic recurrent inflammatory skin disease. Depending on the severity and extent of skin and mucosal involvement, it is defined either as EM minor or EM major. In this study we demonstrate the presence of autoantibodies (aAbs) against desmoplakin I and II, two major proteins of the desmosomal plaque, in six of six patients with the severe variant of EM, EM major. Light microscopic studies of lesional skin and mucous membranes localized in vivo bound immunoglobulin G (IgG) in a dotted desmosomal pattern along the cytoplasmic membranes of keratinocytes. By immunoelectronmicroscopy, in vivo bound IgG was confined to the desmosomal plaques. These findings were confirmed by indirect immunolocalization studies that demonstrated the presence of IgG aAbs in the serum of patients during active disease. These aAbs did not only bind to desmosomal plaques of epithelial cells where they colocalized with defined murine monoclonal antibodies directed against desmoplakin I and II, but also labeled the intercalated discs of myocardial cells. Biochemical characterization of circulating IgG aAbs revealed desmoplakin I and II as actual target autoantigens. By passive transfer of serum into newborn mice, in vivo binding of serum aAbs to keratinocytes was shown. The findings presented in this study imply a humoral immune response in certain patients with EM major and indicate a potential pathogenetic role of aAbs against desmoplakin I and II in this disease.

Animals↗

Selective up-regulation of matrix metalloproteinase-9 expression in human erythema migrans skin lesions of acute lyme disease.

Despite the absence of enzymes that digest extracellular matrix, Borrelia burgdorferi spreads in the skin to form erythema migrans (EM) lesions and then disseminates to other organs. We studied the induction by bacteria of host matrix metalloproteinases (MMPs) in EM skin lesions of patients with acute Lyme disease. In blister fluid from the EM lesions, the expression of MMP-9 was selectively increased by 1900%+/-1037%, compared with blister fluid from the surrounding normal-appearing skin. The expression of all other MMP messenger RNAs was similar in the EM lesions and normal-appearing skin. Selective up-regulation of MMP-9 in the EM lesions was found. Fibroblasts and, to a lesser degree, mononuclear cells were the sources of local MMP-9 production. These results demonstrate specific up-regulation of MMP-9 in the EM skin lesions of patients with acute Lyme disease. Bacterial induction of host proteases may play a role in the dissemination of B. burgdorferi.

Acute Disease↗

Microbiologic evaluation of patients from Missouri with erythema migrans.

BACKGROUND: Borrelia lonestari infects Amblyomma americanum, the tick species that is the most common cause of tick bites in southeast and south-central United States, and this spirochete has been detected in an erythema migrans (EM)-like skin rash in 1 patient. Therefore, B. lonestari is considered to be a leading candidate for the etiologic agent of EM in this region. METHODS: Skin biopsy specimens obtained from patients from the Cape Girardeau area of Missouri who had EM-like lesions were cultured in Barbour-Stoenner-Kelly medium and evaluated by polymerase chain reaction (PCR) targeting multiple genes. Serum specimens were tested by enzyme-linked immunosorbent assay for antibodies against sonicated whole-cell Borrelia burgdorferi. Results were compared with those obtained over the same period for patients from New York State who had EM. RESULTS: B. lonestari was not detected by PCR in any of 31 skin biopsy specimens collected from 30 Missouri patients. None of 19 cultures of Missouri skin samples that were suitable for evaluation were positive for B. burgdorferi, compared with 89 (63%) of 142 cultures of samples collected from New York State patients (P<.001). None of the 25 evaluable Missouri patients were seropositive for antibodies against B. burgdorferi, compared with 107 (75%) of 143 New York State patients (P<.001). CONCLUSIONS: Neither B. lonestari nor B. burgdorferi is likely to be the cause of EM-like skin lesions in patients from the Cape Girardeau area of Missouri. The etiology of this condition remains unknown.

Borrelia↗

Milkers' nodules complicated by erythema multiforme and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation for multiple myeloma.

We describe a case of cow-transmitted parapoxvirus infection--also known as milkers' nodules--after a hematopoietic stem cell transplantation for multiple myeloma. The infection was complicated by erythema multiforme and acute exacerbation of graft-versus-host disease. Parapoxvirus was confirmed by electron microscopy. The natural history of milker's nodules in immunocompetent hosts is described and compared to that in our immunocompromised patient.

Adult↗

Recurrent erythema in patients with long-term parvovirus B19 infection.

We describe 3 patients with long-term parvovirus B19 infection (defined as detectable parvovirus B19 DNA load for >6 months after the onset of symptoms), which we monitored by serial testing for parvovirus B19 load and the presence of parvovirus B19-specific antibodies in blood. The patients showed recurrent erythema at intervals of several months.

Adult↗

Prospective clinical evaluation of patients from Missouri and New York with erythema migrans-like skin lesions.

BACKGROUND: The most common and most recognizable feature of Borrelia burgdorferi infection (Lyme disease) is the skin lesion erythema migrans (EM). An illness associated with an EM-like skin lesion, but which is not caused by B. burgdorferi, occurs in many southern states in the United States (southern tick-associated rash illness [STARI], also known as Masters disease). METHODS: Clinical features of 21 cases of EM-like skin lesions in 21 patients from Missouri were compared in a prospective study with those of 101 cases in 97 patients with EM-like skin lesions from New York. RESULTS: Among Missouri cases, the peak incidence of EM-like skin lesions occurred earlier in the year than it did among New York cases (P<.001). Case patients from Missouri were more likely to recall a tick bite than were case patients from New York (85.7% and 19.8%, respectively; P<.001), and the time period from tick bite to onset of the skin lesion was shorter among Missouri case patients (6.1+/-4.2 days and 10.4+/-6.1 days, respectively; P=.011). Missouri case patients were less likely to be symptomatic than were New York case patients (19.0% and 76.2%, respectively; P<.001), and Missouri case patients were less likely to have multiple skin lesions (4.8% and 26.7%, respectively; P=.042). EM-like lesions in Missouri cases were smaller in size than those in New York cases (8.3+/-2.2 cm and 16.4+/-11.5 cm, respectively; P<.001), more circular in shape (P=.004), and more likely to have central clearing (76.2% and 21.6%, respectively; P<.001). After antibiotic treatment, Missouri case patients recovered more rapidly than did New York case patients (P=.037). CONCLUSION: Cases of EM-like skin lesion in patients from Missouri and New York have distinct clinical presentations.

Adult↗

Effective treatment of erythema nodosum leprosum with thalidomide is associated with immune stimulation.

The immunomodulatory drug thalidomide is the treatment of choice for erythema nodosum leprosum (ENL), an inflammatory cutaneous and systemic complication of multibacillary leprosy. To elucidate the mechanism of action of thalidomide in this syndrome, we prospectively investigated 20 patients with ENL who were treated with thalidomide for 21 days. All patients responded to treatment, with the majority of them having complete resolution of cutaneous lesions within 7 days. This response was associated with a marked but transient increase in ex vivo mitogen-induced expression of interleukin (IL)-2 and interferon- gamma by CD4(+) and CD8(+) T cells that was observed on treatment day 7, but these returned to pretreatment levels by day 21. Plasma tumor necrosis factor- alpha levels were not high at baseline, and they increased modestly during treatment. Plasma levels of IL-12 increased steadily during thalidomide treatment. Hence, the therapeutic effect of thalidomide in ENL appears to be associated with transient immune stimulation, which suggests that the drug may promote an active immunoregulatory response.

Adolescent↗

Erythema migrans in solid-organ transplant recipients.

Six adult solid-organ transplant recipients who had chronic drug-induced immunosuppression and who presented with solitary erythema migrans were treated with antibiotics administered at the same dosage and for the same duration used for the treatment of early, localized Lyme borreliosis in immunocompetent patients. The patients had a smooth course of illness and a favorable outcome but did not develop a measurable borrelial serum antibody response.

Anti-Bacterial Agents↗

Differential expression of Borrelia burgdorferi genes during erythema migrans and Lyme arthritis.

Borrelia burgdorferi, the agent of Lyme disease, selectively expresses genes in the arthropod vector and mammalian host. Specific B. burgdorferi gene expression during human infection was examined in tissue specimens, using RNA-polymerase chain reaction, from 3 patients with Lyme disease. ospA was investigated because OspA is down-regulated by B. burgdorferi in ticks during engorgement and is a vaccine candidate in phase III clinical trials. p35 and p37 were also assessed because these genes are induced by spirochetes during murine Lyme borreliosis and play roles in protective immunity. p35 and p37 mRNA were detected in erythema migrans biopsy specimens from 2 patients and in the synovium of 1 patient with Lyme arthritis. ospA mRNA was not identified in any of these tissues. These data show that ospA is repressed while p35 and p37 are induced in human infection; these results are the first direct demonstration of differential B. burgdorferi gene expression during Lyme disease.

Adolescent↗

Erythema migrans: a chronicle.

Arvid Afzelius first described and named erythema migrans (EM), a clinical entity that he assumed to be caused by an agent transmitted by the bite of a tick (Ixodes reduvius). Certain neurologic, cutaneous, and other syndromes observed in Europe were recognized in the 1920s and 1930s to be disabling sequelae of EM. In the 1940s and 1950s the effectiveness of penicillin as therapy for EM was demonstrated. In 1968 the first patient with EM and neurologic sequelae in North America benefited from treatment with penicillin. In 1975, an epidemic arthropathy appeared in the area of Lyme, Connecticut. Despite resemblance to EM (the initial appearance of cutaneous lesions), the complex was called Lyme disease because of the occurrence of cardiac, neurologic, and arthritic sequelae. The vector of Lyme disease, Ixodes dammini--a tick that harbors agents that cause Lyme disease and babesiosis--was identified and characterized in 1979. The spirochete that causes Lyme disease was designated Borrelia burgdorferi. The North American and European species of spirochete and the clinical syndromes to which they are related are described.

Babesiosis↗