Hobart W. Walling

Cutaneous Lupus Erythematosus Issues in Diagnosis and Treatment

Cutaneous lupus erythematosus (LE) may present in a variety of clinical forms. Three recognized subtypes of cutaneous LE are acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE), and chronic cutaneous LE (CCLE). ACLE may be localized (most often as a malar or ‘butterfly’ rash) or generalized. Multisystem involvement as a component of systemic LE (SLE) is common, with prominent musculoskeletal symptoms. SCLE is highly photosensitive, with predominant distribution on the upper back, shoulders, neck, and anterior chest. SCLE is frequently associated with positive anti-Ro antibodies and may be induced by a variety of medications. Classic discoid LE is the most common form of CCLE, with indurated scaly plaques on the scalp, face, and ears, with characteristic scarring and pigmentary change. Less common forms of CCLE include hyperkeratotic LE, lupus tumidus, lupus profundus, and chilblain lupus. Common cutaneous disease associated with, but not specific for, LE includes vasculitis, livedo reticularis, alopecia, digital manifestations such as periungual telangiectasia and Raynaud phenomenon, photosensitivity, and bullous lesions. The clinical presentation of each of these forms, their diagnosis, and the inter-relationships between cutaneous LE and SLE are discussed. Common systemic findings in SLE are reviewed, as are diagnostic strategies, including histopathology, immunopathology, serology, and other laboratory findings.Treatments for cutaneous LE initially include preventive (e.g. photoprotective) strategies and topical therapies (corticosteroids and topical calcineurin inhibitors). For skin disease not controlled with these interventions, oral antimalarial agents (most commonly hydroxychloroquine) are often beneficial. Additional systemic therapies may be subdivided into conventional treatments (including corticosteroids, methotrexate, thalidomide, retinoids, dapsone, and azathioprine) and newer immunomodulatory therapies (including efalizumab, anti-tumor necrosis factor agents, intravenous immunoglobulin, and rituximab). We review evidence for the use of these medications in the treatment of cutaneous LE.

Collagenase-3 Binds to a Specific Receptor and Requires the Low Density Lipoprotein Receptor-related Protein for Internalization

We have previously identified a specific receptor for collagenase-3 that mediates the binding, internalization, and degradation of this ligand in UMR 106-01 rat osteoblastic osteosarcoma cells. In the present study, we show that collagenase-3 binding is calcium-dependent and occurs in a variety of cell types, including osteoblastic and fibroblastic cells. We also present evidence supporting a two-step mechanism of collagenase-3 binding and internalization involving both a specific collagenase-3 receptor and the low density lipoprotein receptor-related protein. Ligand blot analysis shows that 125I-collagenase-3 binds specifically to two proteins (∼170 kDa and ∼600 kDa) present in UMR 106-01 cells. Western blotting identified the 600-kDa protein as the low density lipoprotein receptor-related protein. Our data suggest that the 170-kDa protein is a specific collagenase-3 receptor. Low density lipoprotein receptor-related protein-null mouse embryo fibroblasts bind but fail to internalize collagenase-3, whereas UMR 106-01 and wild-type mouse embryo fibroblasts bind and internalize collagenase-3. Internalization, but not binding, is inhibited by the 39-kDa receptor-associated protein. We conclude that the internalization of collagenase-3 requires the participation of the low density lipoprotein receptor-related protein and propose a model in which the cell surface interaction of this ligand requires a sequential contribution from two receptors, with the collagenase-3 receptor acting as a high affinity primary binding site and the low density lipoprotein receptor-related protein mediating internalization.

Tanning bed exposure increases the risk of malignant melanoma.

Background  Epidemiologic studies have associated tanning bed exposure and cutaneous melanoma. The relationship between the extent of tanning bed exposure and the risk of melanoma has not been elucidated in detail.

Treatment Options for Hyperhidrosis

Hyperhidrosis is a disorder of excessive sweating beyond what is expected for thermoregulatory needs and environmental conditions. Primary hyperhidrosis has an estimated prevalence of nearly 3% and is associated with significant medical and psychosocial consequences. Most cases of hyperhidrosis involve areas of high eccrine density, particularly the axillae, palms, and soles, and less often the craniofacial area. Multiple therapies are available for the treatment of hyperhidrosis. Options include topical medications (most commonly aluminum chloride), iontophoresis, botulinum toxin injections, systemic medications (including glycopyrrolate and clonidine), and surgery (most commonly endoscopic thoracic sympathectomy [ETS]). The purpose of this article is to comprehensively review the literature on the subject, with a focus on new and emerging treatment options. Updated therapeutic algorithms are proposed for each commonly affected anatomic site, with practical procedural guidelines.For axillary and palmoplantar hyperhidrosis, topical treatment is recommended as first-line treatment. For axillary hyperhidrosis, botulinum toxin injections are recommended as second-line treatment, oral medications as third-line treatment, local surgery as fourth-line treatment, and ETS as fifth-line treatment. For palmar and plantar hyperhidrosis, we consider a trial of oral medications (glycopyrrolate 1–2mg once or twice daily preferred to clonidine 0.1 mg twice daily) as second-line therapy due to the low cost, convenience, and emerging literature supporting their excellent safety and reasonable efficacy. Iontophoresis is considered third-line therapy for palmoplantar hyperhidrosis; efficacy is high although so are the initial levels of cost and inconvenience. Botulinum toxin injections are considered fourth-line treatment for palmoplantar hyperhidrosis; efficacy is high though the treatment remains expensive, must be repeated every 3–6 months, and is associated with pain and/or anesthesia-related complications. ETS is a fifth-line option for palmar hyperhidrosis but is not recommended for plantar hyperhidrosis due to anatomic risks. For craniofacial hyperhidrosis, oral medications (either glycopyrrolate or clonidine) are considered first-line therapy. Topical medications or botulinum toxin injections may be useful in some cases and ETS is an option for severe craniofacial hyperhidrosis.

Primary hyperhidrosis increases the risk of cutaneous infection: A case-control study of 387 patients

BACKGROUND Although primary hyperhidrosis (PHH) has been frequently associated with diminished quality of life, the medical consequences of the condition are less well studied. OBJECTIVE The objective was to study the clinical presentation of PHH and to determine its relationship to cutaneous infection. METHODS A retrospective case-control study of patients encountered between 1993 and 2005 with the International Classification of Diseases, Ninth Revision diagnosis code for hyperhidrosis (HH) and meeting criteria for PHH was conducted. RESULTS Of 387 patients with PHH included, 59% were female and 41% were male; mean age was 27.3 years (range 2-72). Sites of HH included soles (50.1%), palms (45.2%), and axillae (43.4%). Distributional patterns of HH were isolated axillary (27.6%), palmoplantar (24.3%), isolated plantar (15%), axillary/palmoplantar (5.7%), isolated palmar (5.7%), and craniofacial (5.2%). Axillary HH was more common in female patients (P = .004). The mean age of onset (18.6 +/- 12.3 years) indicated a mean duration of untreated symptoms of 8.9 years. Age at onset for palmoplantar HH (11.5 +/- 8 years) was significantly younger than for axillary HH (20.0 +/- 8.3 years; P < .0001), whereas onset of craniofacial HH (25.4 +/- 13.7 years) was older (P < .001). Exacerbating factors included stress/emotion/anxiety (56.7%) and heat/humidity (22%). The overall risk of any cutaneous infection was significantly (P < .0001) increased in HH compared with controls (odds ratio [OR] 3.2; 95% confidence interval [CI] 2.2-4.6). Site-specific risks of fungal infection (OR 5.0; 95% CI 2.6-9.8; P < .0001), bacterial infection (OR 2.6; 95% CI 1.2-5.7; P = .017), and viral infection (OR 1.9; 95% CI 1.2-3.0; P = .011) were all increased. Risks of pitted keratolysis (OR 15.4; 95% CI 2.0-117; P = .0003), dermatophytosis (OR 9.8; 95% CI 3.4-27.8; P < .0001), and verruca plantaris/vulgaris (OR 2.1; 95% CI 1.3-3.6; P = .0077) were particularly increased. Association with atopic/eczematous dermatitis (OR 2.9; 95% CI 1.5-55; P = .019) was observed. LIMITATIONS Retrospective design and single-institution study are limitations. CONCLUSIONS Patients with HH are at high risk of secondary infection. Management of HH may have a secondary benefit of decreasing this risk.

Molecular aspects of Huntington's disease

Huntingtons disease (HD) is a progressive neurodegenerative disease striking principally medium spiny GABAergic neurons of the caudate nucleus of the basal ganglia. It affects about one in 10,000 individuals and is transmitted in an autosomal dominant fashion. The molecular basis of the disease is expansion of the trinucleotide CAG in the first exon of a gene on chromosome four. The CAG repeats are translated to polyglutamine repeats in the expressed protein, huntingtin. The normal function of huntingtin remains incompletely characterized, but based upon recently defined protein‐protein interactions, it appears to be associated with the cytoskeleton and required for neurogenesis. Huntingtin has been demonstrated to interact with such proteins as HAP1, HIP1, microtubules, GADPH, calmodulin, and an ubiquitin‐conjugating enzyme. Polyglutamine expansion alters many of these interactions and leads to huntingtin aggregation and the formation of neuronal nuclear inclusions, ultimately culminating in cell death. In this review, we discuss the molecular aspects of HD, including the present understanding of huntingtin‐protein interactions, studies with transgenic mice, and postulated mechanisms of huntingtin aggregation. J. Neurosci. Res. 54:301–308, 1998.

Bowen's Disease: A Four-Year Retrospective Review of Epidemiology and Treatment at a University Center

BACKGROUND Cutaneous squamous cell carcinoma (SCC) in situ (Bowens disease; BD) is a common intraepidermal malignancy. The aim of this study was to characterize the demographics, distribution, treatment, and recurrence risk of BD in a university population. METHODS A retrospective survey of histologically confirmed BD diagnosed between January 1999 and January 2003. RESULTS A total of 299 patients (193 men, 106 women) with 406 cases of BD were identified. The most common sites were the upper extremities (27%), ears (15%), and cheeks (11%). Men were significantly more likely to have SCC in situ on the scalp, ear, and anterior trunk, while the cheek, nose, and lower legs were significantly more common sites among women (p<.05). An office-based procedural treatment was performed in 92% of cases. Elliptical excision was the most common treatment modality (27%) followed by Mohs micrographic surgery (MMS; 20%) and then shave excision (19%). Histologic recurrence was seen in 15 of 406 cases (4%), one of which recurred as invasive SCC. Cryotherapy was associated with the highest recurrence rate (5-year recurrence of 13.4%), followed by topical 5-fluorouracil (9%) and shave excision (9%). Curettage and fulguration (6.5%), MMS (6.3%), and elliptical excision (5.5%) had lower 5-year recurrence rates. LIMITATIONS Our experience at a single institution in the midwestern United States may not be reflective of a wider population. CONCLUSION The most common locations for BD were in areas with high sun exposure. Multiple treatment options are available and recurrence is uncommon. Margin control surgery should be considered for tumors in high-risk areas.

Clinical differentiation of primary from secondary hyperhidrosis

BACKGROUND Hyperhidrosis (HH) is excessive sweating that may be primary (idiopathic) or secondary to medication or disease. Clinical features supporting primary or secondary etiology have not been well documented. OBJECTIVE To identify clinical and demographic features predictive of a diagnosis of primary versus secondary HH. METHODS A retrospective chart review was conducted over a 13-year period (1993-2005) of all patients (children and adults) seen at a university-based outpatient dermatology department with an International Classification of Diseases, 9th revision diagnosis code for HH (N = 415). RESULTS Three hundred eighty-seven patients (93.3%) had primary HH (PHH); 28 patients (6.7%) had secondary HH (SHH). SHH patients were older (39.0 ± 18.6 years vs 27.3 ± 12.3 years) with more frequent onset at age older than 25 years (55% for SHH vs12.1% for PHH; odds ratio [OR] 8.7; 95% confidence interval [CI] 3.5-21.4; P < .00001 for each). SHH was more often unilateral/asymmetric (OR: 51; 95% CI: 12.6-208), generalized (vs focal; OR: 18; 95% CI: 7.3-47.6), and present nocturnally (OR: 23.2; 95% CI: 4.3-126; P < .00001 for each). Of SHH cases, endocrine disease accounted for 57% (including diabetes mellitus [11], hyperthyroidism [4], and hyperpituitarism [1]). Neurologic disease accounted for 32% (including peripheral nerve injury [3], Parkinsons disease [2], reflex sympathetic dystrophy [2], spinal injury [1] and Arnold-Chiari malformation [1]). Malignancy (pheochromocytoma), respiratory disease, and psychiatric disease were each represented once. Compared to other secondary causes, asymmetric HH favored neurologic disease (OR: 63; 95% CI: 4.9-810); P = .0002). LIMITATIONS Results were obtained from a single, university-based population. CONCLUSIONS On the basis of these data, the diagnostic criteria for PHH were assessed statistically. Criteria include: excessive sweating of 6 months or more in duration, with 4 or more of the following: primarily involving eccrine-dense (axillae/palms/soles/craniofacial) sites; bilateral and symmetric; absent nocturnally; episodes at least weekly; onset at 25 years of age or younger; positive family history; and impairing daily activities. These criteria discriminate well between PHH and SHH (sensitivity: 0.99; specificity: 0.82; positive predictive value: 0.99; negative predictive value: 0.852) and may facilitate optimal clinical management.

Update on the management of chronic eczema: new approaches and emerging treatment options

Atopic dermatitis (AD) is a common disease with worldwide prevalence, affecting up to 20% of children and 3% of adults. Recent evidence regarding pathogenesis has implicated epidermal barrier defects deriving from filagrin mutations with resulting secondary inflammation. In this report, the authors comprehensively review the literature on atopic dermatitis therapy, including topical and systemic options. Most cases of AD will benefit from emollients to enhance the barrier function of skin. Topical corticosteroids are first-line therapy for most cases of AD. Topical calcineurin inhibitors (tacrolimus ointment, pimecrolimus cream) are considered second line therapy. Several novel barrier-enhancing prescription creams are also available. Moderate to severe cases inadequately controlled with topical therapy may require phototherapy or systemic therapy. The most commonly employed phototherapy modalites are narrow-band UVB, broadband UVB, and UVA1. Traditional systemic therapies include short-term corticosteroids, cyclosporine (considered to be the gold standard), methotrexate, azathioprine, mycophenolate mofetil, and most recently leflunamide. Biologic therapies include recombinant monoclonal antibodies acting on the immunoglobulin E / interleukin-5 pathway (omalizumab, mepolizumab), acting as tumor necrosis factor-α inhibitors (infliximab, etanercept, adalimumab), and acting as T-cell (alefacept) and B-cell (rituxumab) inhibitors, as well as interferon γ and intravenous immunoglobulin. Efficacy, safety, and tolerability are reviewed for each medication.

Systemic therapy for primary hyperhidrosis: A retrospective study of 59 patients treated with glycopyrrolate or clonidine

BACKGROUND Data regarding systemic medications in the management of hyperhidrosis (HH) are limited. OBJECTIVE The goal of this study was to provide evidence for the safety and efficacy of systemic medications for primary HH. METHODS A retrospective chart review was conducted of patients seen at an academic dermatology department prescribed systemic medications for primary HH. RESULTS A total of 71 patients were prescribed systemic agents. Twelve patients (17%) were lost to follow-up and were excluded from further analysis. A total of 59 patients with at least 2 months of follow-up data (mean age 28.9 ± 12.0 years; 37 women, 22 men; mean follow-up 19.5 months) were included in the analysis. Palmoplantar and/or axillary HH was most common (42/59; 71%); followed by generalized (9/59; 15%) and craniofacial (8/59; 14%) HH. Glycopyrrolate (generally 1-2 mg once or twice daily) was prescribed to 45 patients, with response rate of 67% (30/45). Fifteen treatment failures included 6 nonresponders and 9 with adverse effects, including xerostomia and gastrointestinal disturbance. Clonidine (0.1 mg twice daily) was prescribed to 13 patients, with a response rate of 46% (6/13). Seven treatment failures included 3 nonresponders and 4 with adverse effects, all relating to decreased blood pressure. One patient responded to oxybutynin at 5 mg twice daily. There were no significant differences in efficacy (P = .21; odds ratios 0.43, 95% confidence interval 0.12-1.5) or adverse effects (P = .46; odds ratios 1.78, 95% confidence interval 0.44-7.1) in comparing glycopyrrolate versus clonidine. LIMITATIONS This was a retrospective study from a single, university-based population. CONCLUSION Systemic therapy with glycopyrrolate or clonidine can be effective for HH. Nearly two-thirds responded to therapy, and less than a quarter had treatment-limiting adverse effects, all of which were self-limited and nonserious.