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.

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Cutaneous lupus erythematosus: issues in diagnosis and treatment.

Chemotherapeutic agents are a widely used treatment modality. Side effects range from common to unusual and may be confused with other cutaneous sequelae of oncologic treatment. The goal of this communication is to elaborate on previous descriptions of the cutaneous manifestations of chemotherapeutic treatment and to discuss more recent findings. (J Am Acad Dermatol 1999;40:367-98.) Learning objective: At the conclusion of this learning activity, participants should be able to generate a differential diagnosis of possible etiologies for varying patterns of cutaneous involvement in patients receiving chemotherapy and identify the various cutaneous side effects of chemotherapeutic treatment. In addition, they should be able to distinguish life-threatening side effects that require immediate management from more benign manifestations of chemotherapeutic treatment.

Mucocutaneous reactions to chemotherapy

Recent advancements and developments in molecular biotechnology have allowed more precise reclassification of many microorganisms. With the use of these new taxonomy tools, several organisms previously thought to belong to other genera have been recently described as bartonellae. Of the 11 organisms now described as Bartonella spp., only four have been shown to be pathogenic for humans. Table 1 lists the four Bartonella human pathogens along with the their known epidemiology and the scope and range of disease associated with each. All are now considered to be bacteria and can be grown on blood-enriched agar although primary isolation in some may best be achieved in cell tissue culture. B. bacilliformis infection is limited to certain geographic regions in South America where the only human reservoir and the sandfly vector(s) that spreads the disease reside together. Specific antibiotic treatment is dramatically effective in treating the highly fatal, acute intraerythrocytic hemolytic form of the disease, but their effectiveness in treating the vascular proliferative forms (verruga peruana) or the chronic asymptomatic, bacteremic, carrier state of the disease has not been effective. This disease should remain confined to its present endemic geographic areas in South American unless asymptomatic bacteremic persons from these areas migrate to areas where sandflies and humans exist that are capable of establishing this infection in new endemic areas. B. quintana and B. henselae cause a wide range of clinical diseases in humans, the type and extent of which varies significantly with the immune status of the host. In immunocompetent hosts the pathologic response is granulomatous, suppurative, extracellular and intracellular, generally self-limited and usually unresponsive to antibiotic treatment, even to those drugs to which the organism is shown to be sensitive in vitro. In contrast, in immunocompromised hosts the pathologic response is vasculoproliferative, organisms may be seen intracellularly but they are often seen in abundance in extracellular clumps and infection is usually progressive and fatal unless treated. In these patients clinical response to treatment with drugs that are effective in vitro against these organisms has usually been dramatic. Of these agents those that penetrate cells and are found in high concentrations intracellularly, such as erythromycin, clarithromycin, azithromycin, rifampin, doxycycline and gentamicin, appear to be most effective. These agents not only appear to provide the most dramatic treatment response in patients with BA, BP and PRFB and other manifestations of B. henselae (and B. quintana as well) in immunocompromised persons, they appear to be the most promising agents for treatment of persons with both typical and atypical CSD. Further studies will be necessary to more clearly elucidated the mechanisms responsible for the diverse clinical presentations of infection with these organisms in human hosts relative to their immune status. In addition clarification of the epidemiology of B. elizabethae infections in humans may be helpful in understanding the nature of infection with Bartonella organisms.

The expanding spectrum of Bartonella infections : II. Cat scratch disease.

Bartonella quintana and Bartonella henselae are fastidious gram-negative bacteria responsible for bacillary angiomatosis, trench fever, cat scratch disease, and endocarditis. During a 5-year period, we received 2,043 samples for culture of Bartonella sp. We found Bartonella sp. to be the etiologic agent in 38 cases of endocarditis, 78 cases of cat scratch disease, 16 cases of bacteremia in homeless people, and 7 cases of bacillary angiomatosis. We correlated the results of positive cultures with the clinical form of the disease, type of sample, culture procedure, PCR-based genomic detection, and antibody determination. Seventy-two isolates of B. quintana and nine isolates of B. henselae from 43 patients were obtained. Sixty-three of the B. quintana isolates and two of the B. henselae isolates, obtained from patients with no prior antibiotic therapy, were stably subcultured. The sensitivity of culture was low when compared with that of PCR-based detection methods in valves of patients with endocarditis (44 and 81%, respectively), skin biopsy samples of patients with bacillary angiomatosis (43 and 100%, respectively), and lymph nodes of cat scratch disease (13 and 30%, respectively). Serological diagnosis was also more sensitive in cases of endocarditis (97%) and cat scratch disease (90%). Among endocarditis patients, the sensitivity of the shell vial culture assay was 28% when inoculated with blood samples and 44% when inoculated with valvular biopsy samples, and the sensitivity of both was significantly higher than that of culture on agar (5% for blood [P = 0.045] and 4% for valve biopsy samples [P < 0.0005]). The most efficient culture procedure was the subculture of blood culture broth into shell vials (sensitivity, 71%). For patients with endocarditis, previous antibiotic therapy significantly affected results of blood culture; no patient who had been administered antibiotics yielded a positive blood culture, whereas 80% of patients with no previous antibiotic therapy yielded positive blood cultures (P = 0.0006). Previous antibiotic therapy did not, however, prevent isolation of Bartonella sp. from cardiac valves but did prevent the establishment of strains, as none of the 15 isolates from treated patients could be successfully subcultured. For the diagnosis of B. quintana bacteremia in homeless people, the efficiency of systematic subculture of blood culture broth onto agar was higher than that of direct blood plating (respective sensitivities, 98 and 10% [P < 10−7]). Nevertheless, both procedures are complementary, since when used together their sensitivity reached 100%. All homeless people with positive blood cultures had negative serology. The isolation rate of B. henselae from PCR-positive lymph nodes, in patients with cat scratch disease, was significantly lower than that from valves of endocarditis patients and skin biopsy samples from bacillary angiomatosis patients (13 and 33%, respectively [P = 0.084]). In cases of bacillary angiomatosis for which an agent was identified to species level, the isolation rate of B. henselae was lower than the isolation rate of B. quintana (28 and 64%, respectively [P = 0.003]). If culture is to be considered an efficient tool for the diagnosis of several Bartonella-related diseases, methodologies need to be improved, notably for the recovery of B. henselae from lymph nodes of patients with cat scratch disease.

Culture of Bartonella quintana and Bartonella henselae from human samples: a 5-year experience (1993 to 1998).

The classification and diagnosis of cutaneous lupus erythematosus.

Clinical and histopathologic features and immunologic variables in patients with severe chilblains. A study of the relationship to lupus erythematosus.

Background Although mild early cutaneous transient reactions to vaccinations are common, late-onset chronic lesions have been scarcely reported. We report herein a series of 9 patients presenting with cutaneous and subcutaneous pseudolymphoma. Observations Nine patients presenting with late-onset, chronic skin lesions occurring at the site of antihepatitis B (8 cases) and antihepatitis A (one case) vaccination were reported. Histopathologic and immunohistochemic studies, and molecular analysis of clonality of skin biopsy specimens, were performed. Furthermore, the presence of vaccine products was investigated in skin lesions by using histochemical, microanalytic, and electronic microscopy techniques. Results Histopathologic studies showed dermal and hypodermal lymphocytic follicular infiltrates with germinal center formation. The center of follicles was mostly composed of B cells without atypia, whereas CD4+ T cells were predominant at the periphery. Molecular analysis of clonality revealed a polyclonal pattern of B-cell and T-cell subsets. Aluminium deposits were evidenced in all cases by using histochemical staining in all cases, and by microanalysis and ultrastructural studies in one case. Associated manifestations were vitiligo (one case) and chronic fatigue with myalgia (two cases). Conclusion Cutaneous lymphoid hyperplasia is a potential adverse effect of vaccinations including aluminium hydroxide as an adjuvant. Further prospective studies are warranted to evaluate the incidence of this complication in the immunized population.

Vaccination-induced cutaneous pseudolymphoma.

Background and Design: Noninfectious cutaneous neutrophilic lesions can occur during granulocytopenia, but their mechanism remains unknown. We undertook a retrospective study of the neutrophilic dermatoses that developed during granulocytopenia induced by chemotherapy for acute myelogenous leukemia. Results: Seven men and one woman were included (2.6% of treated cases of acute myelogenous leukemia); half had acute myelogenous leukemia subtypes 4 and 5. The male-to-female ratio was 7:1. Neutrophilic eccrine hidradenitis was diagnosed in five cases, Sweet's syndrome in two cases, and difficult-to-classify neutrophilic dermatoses in one case. Cutaneous lesions appeared 12.5 days after the start of chemotherapy, and the mean leukocyte count was 0.426× 109/L. Three patients needed corticosteroids systemically. Conclusion: Neutrophilic dermatoses during chemotherapy-induced granulocytopenia seem to occur more frequently in men with acute myelogenous leukemia subtypes 4 and 5. (Arch Dermatol. 1995;131:1141-1145)

Neutrophilic dermatoses during granulocytopenia.

Background Incidental finding of vascular invasion has been described in some benign granular cell tumours. Malignancy in granular cell tumours is excessively rare and its assessment relies on necrosis and cytological criteria. Aims To assess histopathological invasive features, particularly vascular invasion, in a large series of granular cell tumours of the skin. Methods 119 granular cell tumours of the skin were collected in 114 patients between 2001 and 2011. Histopathological and epidemiological data were collected. Five step sections and one orcein staining were performed in all cases. Results Mean age of the patients was 43.7±18 years. Granular cell tumours were multiple in 7% of patients. They were classified as benign in 111 cases, and atypical in eight cases. No malignant granular cell tumour was present. Tumours had 1.48±1.3 cm mean diameter, showed peripheral invasive growth pattern in 71% of cases, had a mean depth of 8.8±4.7 mm, and reached the subcutis in 66% of cases. Infiltration of arrector pili muscle occurred in 23% (95% CI 16% to 32%), and perineural spread in 66% (95% CI 56% to 74%) of cases. Vascular invasion occurred in 23% (95% CI 16% to 32%) of cases, with subendothelial layers infiltration or vascular obliteration. No intraluminal embolus was found. No association was found between vascular invasion and clinical outcome. Conclusions Histopathological features of local invasion are frequent in otherwise benign granular cell tumours. Vascular invasion consists of an infiltration of the subendothelial layers, without intraluminal cells, and may not be considered as a marker of adverse prognosis.

https://jcp.bmj.com/content/jclinpath/67/1/19.full.pdf

Vascular invasion and other invasive features in granular cell tumours of the skin: a multicentre study of 119 cases.

Reactive angioendotheliomatosis (RAE) is a rare benign cutaneous vascular proliferation characterized by intravascular hyperplasia of endothelial cells and tuft-like proliferation of vessels. A 75-year-old man had erythematous and violaceous macules, some stellate and others arranged in a livedoid pattern, evolving toward necrosis with central areas having an atrophie blanche appearance spread on the trunk, inguinal folds, and right thigh. He was on hemodialysis and had a benign monoclonal gammopathy. Cutaneous biopsy revealed RAE characterized by the proliferation of epithelioid and spindle-shaped cells in superficial and middermis lining vascular channels, arranged in clusters, and sometimes displaying an intravascular growth pattern. These cells stained for CD31, CD34, and actin. Interestingly, prominent amyloid deposits were found in the wall of some vessels in deep dermis often causing obstruction of their lumina. The cause of RAE is unknown, but it can be associated with infections, antiphospholipid syndrome, dysglobulinemia, cryoproteinemia, and lower extremities arteritis, and it may occur near arteriovenous fistula;. In this patient, we believe that RAE was caused by obliteration of dermal vessels by amyloid deposits. Indeed, it is thought that RAE could be caused by ischemia secondary to vascular obstruction. This is the first reported patient with RAE associated with amyloid deposits.

L Pinquier

Papers

Clinical and histopathologic features and immunologic variables in patients with severe chilblains. A study of the relationship to lupus erythematosus.

Vaccination-induced cutaneous pseudolymphoma.

Neutrophilic dermatoses during granulocytopenia.

Vascular invasion and other invasive features in granular cell tumours of the skin: a multicentre study of 119 cases.

Reactive angioendotheliomatosis secondary to dermal amyloid angiopathy.