Dermatology position paper on the revision of the 1982 ACR criteria for systemic lupus erythematosus.

The 1982 ACR classification criteria have become de facto diagnostic criteria for systemic lupus erythematosus (SLE), but a review of the criteria is necessary to include recent diagnostic tests. The criteria were not developed with the help of dermatologists, and assign too much weight to the skin as one expression of a multiorgan disease. Consequently, patients with skin diseases are classified as SLE based mostly on skin symptoms. We discuss specific problems with each dermatologic criterion, but changes must await a new study. We suggest the following guidelines for such a study, aimed at revision of the criteria. 1) The SLE patient group should be recruited in part by dermatologists. 2) The study should evaluate an appropriate international ethnic/racial mix, including late onset SLE as well as pediatric patients. 3) All patients should have current laboratory and clinical evaluations, as suggested in the paper, to assure the criteria can be up-to-date. This includes anti-SS-A and anti-SS-B antibodies and skin biopsies for suspected cutaneous lupus erythematosus except for nonscarring alopecia and oral ulcers. 4) The study should be based on a series of transparent power calculations. 5) The control groups should represent relevant differential diagnoses in numbers large enough to assess diagnostic problems that might be specific to these differential diagnoses. In order to demonstrate specificity of the criteria with a 95% confidence interval between 90 and 100%, each control group of the above should have at least 73 patients.

The cutaneous microcirculation.

The cutaneous microcirculation is organized as two horizontal plexuses. One is situated 1-1.5 mm below the skin surface and the other is at the dermal-subcutaneous junction. Ascending arterioles and descending venules are paired as they connect the two plexuses. From the upper layer, arterial capillaries rise to form the dermal papillary loops that represent the nutritive component of the skin circulation. There are sphincter-like smooth muscle cells at the point where the ascending arterioles divide to form the arteriolar component of the upper horizontal plexus. At the dermal-subcutaneous junction, there are collecting veins with two cusped valves that are oriented to prevent the retrograde flow of blood. Laser Doppler flowmetry has demonstrated vasomotion of red cell flux localized to the sites of ascending arterioles. The simultaneous recording by laser Doppler flowmetry of red cell flux and the concentration of moving red blood cells from individual sites allows one to construct topographic maps of these two values. These two maps, based on initial studies using correlative skin biopsies, can define 1 mm3 volumes of skin that are predominantly arteriolar in composition, venular in composition, or essentially devoid of all microvascular elements. The electron and light microscopic features that define the microvascular segments, when coupled with that ability of laser Doppler flowmetry to define the predominant microvascular segments under the probe, allow one to study both the mechanisms of normal physiologic states and the pathogenetic mechanisms underlying pathologic skin disorders in which the microvasculature plays a predominant role.

The cutaneous microcirculation: ultrastructure and microanatomical organization.

The cutaneous microcirculation is organized as two horizontal plexuses. One is situated 1-1.5 mm below the skin surface, and the other is at the dermal-subcutaneous junction. Ascending arterioles and descending venules are paired as they connect the two plexuses. From the upper layer, arterial capillaries arise to form the dermal papillary loops that represent the nutritive component of the skin circulation. There are sphincter-like smooth muscle cells at the point where the ascending arterioles divide to form the arteriolar component of the upper horizontal plexus. At the dermal subcutaneous junction, there are collecting veins with 2-cusped valves that are oriented to prevent the retrograde flow of blood. Laser Doppler flowmetry (LDF) has demonstrated vasomotion of red cell flux localized to the sites of ascending arterioles. The simultaneous recording by LDF of red cell flux and the concentration of moving red blood cells from individual sites allows one to construct by computer topographic maps of these two valves. The two maps, based on initial studies using correlative skin biopsy specimens, can define 1-mm3 volumes of skin that are predominantly arteriolar in composition, predominantly venular in composition, or essentially devoid of all microvascular elements. The electron and light microscopic features that define the microvascular segments, when coupled with the ability of LDF to define the predominant microvascular segments under the probe, will allow one to study both the mechanisms of normal physiological states and the pathogenetic mechanisms underlying pathological skin disorders in which the microvasculature plays a predominant role.

Total skin electron beam therapy followed by adjuvant psoralen/ultraviolet-A light in the management of patients with T1 and T2 cutaneous T-cell lymphoma (mycosis fungoides).

PURPOSE: Patients with mycosis fungoides [cutaneous T-cell lymphoma (CTCL)] may benefit from adjuvant therapy after completing total skin electron beam therapy (TSEBT). We report the results for T1/T2 CTCL patients treated with adjuvant oral psoralen plus ultraviolet light (PUVA) with respect to overall survival (OS), disease-free survival (DFS), salvage of recurrence, and toxicity. METHODS AND MATERIALS: Between 1974 and 1993, TSEBT was administered to a total of 213 patients with CTCL. Records were reviewed retrospectively, and a total of 114 patients were identified as having T1 or T2 disease. Radiotherapy was provided via a 6-MeV linac to a total of 36 Gy, 1 Gy/day, 4 days/week, for 9 weeks. Beginning in 1988, patients were offered adjuvant PUVA within 2 months of completing TSEBT. This was started at 0.5-2 J/m2, 1-2 treatments/week, with a taper over 3-6 months. Therapy then continued once per month. There were 39 T1 and 75 T2 patients. Six T1 (15%) and eight T2 (11%) patients were treated with adjuvant PUVA. A further 49% of the 114 patients received adjuvant systemic therapy, 3% received spot external beam, 4% received adjuvant ECP, 2% received topical nitrogen mustard, 22% received a combination of therapies exclusive of PUVA, and 9% received no adjuvant therapy. Patients were balanced in all subgroups based on pre-TSEBT therapy. The median age of the cohort was 58 (range 20-88), with a median follow-up time of 62 months (range 3-179). RESULTS: Within 1 month after completing of TSEBT, 97% of T1, and 87% of T2 patients had achieved a complete remission. Stratified by adjuvant therapy, none of six T1 and one of eight T2 patients who received adjuvant PUVA failed within the first 3 years after completion of TSEBT. A total of 43% of the T1 and T2 patients receiving other or no adjuvant treatment failed within the same time course. The 5-year OS for the entire cohort was 85%. Those who received PUVA had a 5-year OS of 100% versus a 5-year OS for the non-PUVA group of 82% (p < 0.10). The 5-year DFS for the entire cohort was 53%. Those who received PUVA had a 5-year DFS of 85% versus a 5-year DFS for the non-PUVA group of 50% (p < 0.02). By T stage, those with T1 receiving PUVA exhibited no relapses, whereas those with T1 not treated with PUVA had a crude relapse rate of 36%. Median DFS was not reached at 103 months for the T1 adjuvant PUVA patients versus 66 months for the non-PUVA patients (p < 0.01). For those with T2, crude relapse rates were 25% and 55%, respectively, with DFS of 60 (median DFS not reached) and 20 months (p < 0.03). The 5-year DFS for patients salvaged with PUVA was 50%. Toxicity of adjuvant and salvage PUVA therapy was acceptable, with only two patients requiring a reduction in PUVA dosage. CONCLUSION: PUVA can maintain remissions in patients with CTCL after TSEBT. There is a significant benefit in DFS but no statistically significant improvement in OS. Prospective, randomized data are needed to confirm these results. PUVA is also effective as a salvage therapy after TSEBT in early-stage patients with recurrence, with acceptable toxicity.

A patient with cutaneous T-cell lymphoma and dermatomyositis.

Dermatomyositis in adults has been associated with a variety of internal malignancies. We present a case of a patient with dermatomyositis and cutaneous T-cell lymphoma.

Additional courses of total skin electron beam therapy in the treatment of patients with recurrent cutaneous T-cell lymphoma.

BACKGROUND: Recurrent cutaneous T-cell lymphoma (CTCL) is managed with a variety of modalities. Repeat treatment with additional courses of total skin electron beam therapy (TSEBT) has not been formally evaluated. OBJECTIVE: Our purpose was to evaluate the efficacy and toxicity of additional TSEBT for recurrent CTCL. METHODS: A total of 14 patients were treated with TSEBT and received at least two courses, with five of those patients receiving a third course. Patients were offered additional TSEBT if they suffered recurrence despite other therapy if the extent of the recurrence precluded localized radiation. The median follow-up was 36 months. RESULTS: The median dose for the entire group was 57 Gy. Thirteen patients (93%) achieved a complete response (CR) after the initial course. After the second course, 12 patients (86%) had a CR; of the five patients who underwent a third course, three (60%) achieved a CR. The median disease-free interval after the first course of therapy for those with a CR was 20 months and 11.5 months after the second course. Median survival after the second course was 15 months. All patients had xerosis, pruritus, desquamation, mild erythema, epilation, and anhidrosis of the skin. CONCLUSION: Patients with recurrent CTCL recalcitrant to other forms of therapy or too diffuse for treatment with localized radiation fields are candidates for additional TSEBT. This therapy is effective and well tolerated with an acceptable risk profile.

The Golgi association of endothelial nitric oxide synthase is necessary for the efficient synthesis of nitric oxide.

The particulate enzyme, endothelial nitric oxide synthase (eNOS), produces nitric oxide to maintain normal vasodilator tone in blood vessels. In this study, we demonstrate that eNOS is a Golgi-associated protein in cultured endothelial cells and intact blood vessels. Using a heterologous expression system in HEK 293 cells, we show that wild-type myristoylated and palmitoylated eNOS, but not mutant, non-acylated eNOS targets to the Golgi. More importantly, HEK 293 cells expressing wild-type eNOS release substantially more NO than cells expressing the mutant, non-acylated enzyme. Thus, eNOS is a novel Golgi-associated protein, and Golgi compartmentalization is necessary for the enzyme to respond to intracellular signals and produce NO.

Systemic chemotherapy and extracorporeal photochemotherapy for T3 and T4 cutaneous T-cell lymphoma patients who have achieved a complete response to total skin electron beam therapy.

PURPOSE: To evaluate the impact of systemic adjuvant therapies on relapse-free (RFS) and overall survival (OS) of cutaneous T-cell lymphoma (CTCL) patients treated with total skin electron beam therapy (TSEBT). METHODS AND MATERIALS: Between 1974 and 1990, TSEBT (36 Gy at 1 Gy/day; 9 weeks; 6 MeV electrons) was administered with curative intent to a total of 163 CTCL (mycosis fungoides) patients using six fields supplemented by orthovoltage boosts (120 kvp, 1 Gy x 20) to the perineum, soles of feet, and apical scalp (120 kvp, 2 Gy x 3). In this group, all patients who achieved a clinical complete response or a good partial response were offered one of two competing regimens of either adjuvant doxorubicin/cyclophosphamide or adjuvant extracorporeal photochemotherapy (ECP). RESULTS: When the results for the group who achieved a complete response (CR) to TSEBT were analyzed, OS for T1 and T2 patients was excellent (85-90% at 5-10 years) and not improved by either adjuvant regimen. However, T3 and T4 patients who received either adjuvant doxorubicin/cyclophosphamide (75% at 3 years) or adjuvant ECP (100% at 3 years) had better overall survival than those who received neither adjuvant regimen (approximately 50% at 5 years). The difference between the OS curves for those who received ECP vs. those who received no adjuvant therapy approached statistical significance (p < 0.06), while a significant survival benefit from the addition of chemotherapy for TSEBT complete responders was not observed. Neither adjuvant therapy provided benefit with respect to relapse free survival after TSEBT. CONCLUSIONS: These results suggest that an adjuvant nontoxic regimen of extracorporeal photochemotherapy may prolong survival in advanced stage CTCL patients who have achieved a complete remission after TSEBT. The combination of doxorubicin/cyclophosphamide had no significant impact on overall survival in those patients who achieved CR to TSEBT, and neither adjuvant therapy had an impact on relapse free survival for all T-stages. Such results are the basis for the current development of a prospective, randomized trial studying the impact of ECP after TSEBT in patients with advanced stage CTCL.

Hypopigmented variant of mycosis fungoides: demography, histopathology, and treatment of seven cases.

BACKGROUND: Hypopigmented macules have been described infrequently as a presenting form of mycosis fungoides (MF). OBJECTIVE: This study was designed to clarify general characteristics of a hypopigmented MF variant. METHODS: Seven new cases were investigated with the use of descriptive epidemiology techniques. Demographic parameters, histopathology, and treatment outcomes were analyzed. These data were combined with those from prior reports to develop a broad composite view of this disease process. RESULTS: The median ages in our series were 36 years for disease onset and 39 years at biopsy diagnosis. All patients had brown or black skin. Histologic findings consistently showed a lack of epidermal atrophy and moderate to profound exocytosis. Treatment with PUVA induced rapid and complete repigmentation in six of seven patients. CONCLUSION: On the basis of our experience and a literature review, the hypopigmented variant of MF occurs in a younger population than typical forms of the disease and affects persons with dark skin almost exclusively. Microscopic features include lack of epidermal atrophy and moderate to extreme epidermotropism of infiltrating mononuclear cells. The treatment of choice appears to be PUVA.

Malignant melanoma and other second cutaneous malignancies in cutaneous T-cell lymphoma. The influence of additional therapy after total skin electron beam radiation.

BACKGROUND: Previous large studies have shown that patients with cutaneous T-cell lymphoma are at increased risk for basal cell carcinoma and squamous cell carcinoma, and anecdotal case reports have suggested an association with malignant melanoma. It has been postulated that the exposure of cutaneous structures to potentially carcinogenic therapies, such as ionizing radiation or alkylating agents, might be causally associated with the development of these second cutaneous malignancies, but, to date, no study has directly addressed this issue. The purpose of this study was to evaluate the occurrence of second cutaneous malignancies in a group of patients with cutaneous T-cell lymphoma treated with total skin electron beam therapy and to examine the additional effects of oral psoralen with UV-A phototherapy, topical mechlorethamine hydrochloride therapy, and further radiation therapy. One hundred sixty-four patients with cutaneous T-cell lymphoma who had received total skin electron beam therapy between 1974 and 1990 were identified, and information was abstracted from their records. RESULTS: Six patients developed malignant melanoma 12 to 95 months after total skin electron beam therapy. Of the six patients, three had received oral psoralen with UV-A as additional therapy and two had received topical mechlorethamine. None had received additional radiation therapy. Twenty-four patients developed more than 37 basal cell carcinomas and 34 squamous cell carcinomas from 11 months to more than 10 years after total skin electron beam therapy. Of the 24 patients, 15 had received oral psoralen with UV-A and 12 had received mechlorethamine as additional therapy. Additional radiation therapy had been administered to nine patients. During a median follow-up of 6 years, no patients died of any second cutaneous malignancy. CONCLUSION: We found a high rate of both melanoma and nonmelanoma skin cancer. The additional use of mechlorethamine or oral psoralen plus UV-A, but not radiation, was significantly associated with the development of basal cell carcinoma and squamous cell carcinoma, but not malignant melanoma.

Inducibility and expression of microvascular endothelial adhesion molecules in lesional, perilesional, and uninvolved skin of psoriatic patients.

Previous studies have demonstrated 1) that patterns of inducible endothelial cell expression of endothelial leukocyte adhesion molecule-1 (ELAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in response to cytokines varies both with anatomic position within the dermal microvasculature and with the presence of perivascular inflammatory infiltrates, and 2) that the anatomic architecture of the dermal superficial plexus (SVP) is altered in inflamed lesional but not in univolved skin of psoriatic patients. The present study was designed to evaluate the pattern of cytokine inducibility of ELAM-1 and VCAM-1 in altered dermal microvessels of psoriatic patients. At the light microscope level, preculture biopsies of uninvolved and perilesional skin were indistinguishable by morphology and ELAM-1 and VCAM-1 expression were virtually absent. In contrast, biopsied lesional skin showed elongated capillary loops and increased numbers of T cells compared to uninvolved and perilesional skin. The dermal microvasculature of the SVP of lesional skin contained ELAM-1+ in 29.4% of vessels and VCAM-1+ endothelial cells in 8.7% of vessels. After 24 h of organ culture in medium supplemented with tumor necrosis factor and interleukin-4, ELAM-1+ endothelial cells in the SVP were increased significantly in uninvolved (from mean 0.5% to 27% of vessels), perilesional (from mean 5.5% to 41.8% of vessels), and lesional skin (from mean 29.4% to 45.7% of vessels). VCAM-1 was not inducible on SVP endothelial cells in uninvolved skin but VCAM-1+ endothelial cells were increased significantly in perilesional (from mean 0.7% to 23.7% of vessels) and lesional skin (from mean 8.7% to 41.4% of vessels). In uninvolved and perilesional skin ELAM-1 and VCAM-1 were confined to endothelial cells below the rete. In contrast, endothelial cells of the intrapapillary part of the capillary loop of lesional skin became cytokine responsive, in that ELAM-1 and VCAM-1 could be induced at this site. By immunoelectron microscopy, expression was most intense on the luminal surface of venular endothelial cells and at the interendothelial junctions. In conclusion, we have presented evidence that the cytokine responsiveness of microvascular endothelial cells is altered in psoriasis in a pattern that may explain both the circumscribed nature and the epidermal involvement of the psoriatic plaque.

Peripheral assessment of phenylephrine-induced vasoconstriction by laser Doppler flowmetry and its potential relevance to homeostatic mechanisms.

BACKGROUND: Cutaneous laser Doppler flowmetry enables monitoring of changes in skin perfusion by quantifying the phase shift of laser light induced by moving red blood cells under a fiberoptic probe. It thus can identify the presence of and response to a vasoconstrictive stimulus. However, aspects of the technique must be defined before it can be used with maximum effectiveness. We evaluated the responses of two different laser Doppler outputs, the concentration of moving blood cells (CMBC) and red cell flux (CMBC times cell velocity), and the responses at two sites of probe application, the finger and forearm, during systemic infusions of phenylephrine. METHODS AND RESULTS: Eight healthy volunteers were monitored with a brachial blood pressure cuff, ECG, and laser Doppler flowmeter probes applied to the palmar surface of the fourth finger and volar forearm of the arm opposite the pressure cuff. After baseline readings were obtained, the subjects received three 10-minute intravenous infusions of phenylephrine at rates of 0.4, 0.8, and 1.6 micrograms.kg-1.min-1. The two parameters, flux and CMBC, trended similarly. Flux and CMBC at the finger declined significantly in response to each infusion (P < .05 using repeated-measures ANOVA with Duncan's multiple range test). In contrast, flux and CMBC of the forearm had highly variable responses, with an overall increase during each infusion (P < .05 for % delta of forearm versus % delta of finger readings during the 0.4 microgram.kg-1.min-1 infusion). Heart rate declined significantly during each infusion, consistent with a baroreceptor-mediated response, even though systolic and diastolic blood pressures each increased by less than 2 mm Hg during the 0.4 microgram.kg-1.min-1 infusion. CONCLUSIONS: As expected, laser Doppler readings at the finger decreased during infusion of an alpha 1-agonist. Although, like the digital vessels, forearm vessels have the potential to constrict, the increases in forearm readings suggest that these vessels are highly susceptible to homeostatic responses. The increase in CMBC (a parameter that is sensitive primarily to local changes in vascular caliber) suggested vasodilation of the underlying vessels. The forearm vasodilation and the concomitant decline in heart rate most likely represented vagally mediated baroreceptor activity, which was altered even though blood pressure changed minimally during the 0.4 microgram.kg-1.min-1 infusion. Thus, integrated assessment of skin perfusion at the finger and forearm may provide valuable information about the direct and indirect effects of a vasoactive stimulus. The present application of laser Doppler flowmetry suggests activation of vasodilatory reflexes despite minimal changes in blood pressure.

Spatial heterogeneity in normal skin perfusion recorded with laser Doppler imaging and flowmetry.

Spatial and temporal variations in forearm skin perfusion captured by laser Doppler perfusion imaging (LDI) have been compared with topographic maps recorded by laser Doppler flowmetry. In order to determine the shortest LDI sampling time required at each measurement site, with an adequate signal-to-noise ratio and with the ability to display the heterogeneity in skin perfusion, the noise-limited resolution of the LDI system as well as various sampling times were tested. The noise-limited resolution for medium and high light intensities were less than 0.5% (temporal) and 0.3% (spatial) of full scale. A sampling time of 1 sec was selected and image presentation was made by performing bilinear interpolation between perfusion values. The same area (10 x 10 mm) was mapped with LDI and topographic mapping at seven different sites. In addition, a larger area covering the surrounding skin was recorded with LDI. The small area recordings with LDI and topographic mapping could be identified in the larger LDI image. High-and low-perfusion spots coincided between the two systems. Temporal variations were studied by repeated LDI recordings of the same areas as above. Small spots were selected in the areas and plotted versus time. Without provocation, the total perfusion changes at each spot showed large variations, but the relative perfusion levels between neighboring spots persisted. Provocation with heat increased the perfusion in all spots.

Impact of non-CTCL dermatologic diagnoses and adjuvant therapies on cutaneous T-cell lymphoma patients treated with total skin electron beam radiation therapy.

PURPOSE: To evaluate the impact of pre-cutaneous T-cell lymphoma dermatologic diagnoses and adjuvant therapies on the relapse-free and overall survivals of patients treated with total skin electron beam therapy. METHODS AND MATERIALS: Between 1974 and 1990, 164 patients were evaluated by members of Yale University School of Medicine departments of Dermatology and Therapeutic Radiology and treated with total skin electron beam therapy to a total dose of 3600 cGy. Patients who achieved a clinical complete response were offered doxorubicin/cyclophosphamide chemotherapy, extracorporeal photopheresis, or no systemic adjuvant therapy. The effects of TNM stage, antecedent non-T-cell lymphoma dermatologic diagnoses, and systemic adjuvant therapies were analyzed for their impact on relapse-free and overall survival. RESULTS: In this cohort of patients, an antecedent dermatologic diagnosis of follicular mucinosis or lymphomatoid papulosis was significantly associated with a shorter relapse-free survival for T1 and T2 patients, while antecedent "non-specific" dermatitides were associated with a somewhat better relapse-free survival. When the impact of systemic adjuvant therapies was analyzed, neither systemic doxorubicin/cyclophosphamide chemotherapy nor systemic extracorporeal photopheresis were found to delay cutaneous relapse. CONCLUSION: Our results suggest that antecedent follicular mucinosis and lymphomatoid papulosis may be associated with short relapse-free survival in T1 and T2 patients treated with total skin electron beam therapy. They also imply that neither adjuvant chemotherapy nor extracorporeal photopheresis delay cutaneous relapse after total skin electron beam therapy.