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ObjectivesAssess the efficacy and safety of tocilizumab in patients with systemic sclerosis (SSc) in a phase II study.MethodsPatients with SSc were treated for 48 weeks in an open-label extension phase of the faSScinate study with weekly 162 mg subcutaneous tocilizumab. Exploratory end points included modified Rodnan Skin Score (mRSS) and per cent predicted forced vital capacity (%pFVC) through week 96.ResultsOverall, 24/44 (55%) placebo-tocilizumab and 27/43 (63%) continuous-tocilizumab patients completed week 96. Observed mean (SD (95% CI)) change from baseline in mRSS was –3.1 (6.3 (–5.4 to –0.9)) for placebo and –5.6 (9.1 (–8.9 to–2.4)) for tocilizumab at week 48 and –9.4 (5.6 (–8.9 to –2.4)) for placebo-tocilizumab and –9.1 (8.7 (–12.5 to –5.6)) for continuous-tocilizumab at week 96. Of patients who completed week 96, any decline in %pFVC was observed for 10/24 (42% (95% CI 22% to 63%)) placebo-tocilizumab and 12/26 (46% (95% CI 27% to 67%)) continuous-tocilizumab patients in the open-label period; no patients had >10% absolute decline in %pFVC. Serious infection rates/100 patient-years (95% CI) were 10.9 (3.0 to 27.9) with placebo and 34.8 (18.0 to 60.8) with tocilizumab during the double-blind period by week 48 and 19.6 (7.2 to 42.7) with placebo-tocilizumab and 0.0 (0.0 to 12.2) with continuous-tocilizumab during the open-label period.ConclusionsSkin score improvement and FVC stabilisation in the double-blind period were observed in placebo-treated patients who transitioned to tocilizumab and were maintained in the open-label period. Safety data indicated increased serious infections in patients with SSc but no new safety signals with tocilizumab.Trial registration numberNCT01532869; Results.

Objective.Vasculopathy is a key factor in the pathophysiology of systemic sclerosis (SSc) and the main cause for Raynaud phenomenon (RP), digital ulcers (DU), and/or pulmonary arterial hypertension (PAH). It is so far unknown how patients with SSc are treated with vasoactive agents in daily practice. To determine to which extent patients with SSc were treated with different vasoactive agents, we used data from the German Network for Systemic Scleroderma registry.Methods.The data of 3248 patients with SSc were analyzed.Results.Patients were treated with vasoactive drugs in 61.1% of cases (1984/3248). Of these, 47.6% received calcium channel inhibitors, followed by 34.2% treated with angiotensin-converting enzyme (ACE) inhibitors, 21.1% treated with intravenous (IV) prostanoids, 10.1% with pentoxifylline, 8.8% with angiotensin 1 receptor antagonists (AT1RA), 8.7% with endothelin 1 receptor antagonists (ET1RA), 4.1% with phosphodiesterase type 5 (PDE5) inhibitors, and 5.3% with others. Patients with RP received vasoactive therapy in 63.3% of cases, with DU in 70.1%, and with PAH in 78.2% of cases. Logistic regression analysis revealed that patients with PAH were significantly more often treated with PDE5 inhibitors and ET1RA, and those with DU with ET1RA and IV prostanoids. In addition, 41.8% of patients were treated with ACE inhibitors and/or AT1RA. Patients registered after 2009 received significantly more often ET1RA, AT1RA, and IV prostanoids compared with patients registered prior to 2005.Conclusion.These data clearly indicate that many patients with SSc do not yet receive sufficient vasoactive therapy. Further, in recent years, a marked change of treatment regimens can be observed.

Introduction Complete lymph node dissection (CLND) after a positive sentinel node (SN) biopsy provides important prognostic information in melanoma patients but has been questioned for therapeutic use recently. We explored whether quantification of the tumour spread to SNs may replace histopathology of non-sentinel nodes (NSNs) for staging purposes. Patients and methods We quantified melanoma spread in SNs and NSNs in 128 patients undergoing CLND for a positive SN. In addition to routine histopathology, one-half of each of all 1496 SNs and NSNs was disaggregated into a single cell suspension and stained immunocytochemically to determine the number of melanoma cells per 106 lymph node cells, i.e. the disseminated cancer cell density (DCCD). Results We uncovered melanoma spread to NSNs in the majority of patients; however, the tumour load and the proportion of positive nodes were significantly lower in NSNs than in SNs. The relation between SN and NSN spread could be described by a mathematical function with DCCDNSN = DCCDSNc/101−c (c = 0.69; 95% confidence interval [CI]: 0.62–0.76). At a median follow-up of 67 months, multivariable Cox regression analyses revealed that DCCDSN (p = 0.02; HR 1.34, 95% CI: 1.05–1.71) and the total number of pathologically positive nodes (p = 0.02; HR 1.53, 95% CI: 1.07–2.22) were significant risk factors after controlling for age, gender, thickness of melanoma and ulceration status. A prognostic model based on DCCDSN and melanoma thickness predicted outcome as accurately as a model including pathological information of both SNs and NSNs. Conclusion The assessment of DCCDSN renders CLND for staging purposes unnecessary.

OBJECTIVES: Patient acceptable symptom state (PASS) as an absolute state of well-being has shown promise as an outcome measure in many rheumatologic conditions. We aimed to assess whether PASS may be effective in active diffuse cutaneous SSc differentiating active from placebo. METHODS: Data from the phase 2 Safety and Efficacy of Subcutaneous Tocilizumab in Adults with Systemic Sclerosis (faSScinate) trial were used, which compared tocilizumab (TCZ) vs placebo over 48 weeks followed by an open-label TCZ period to 96 weeks. Three different types of PASS questions were evaluated at weeks 8, 24, 48 and 96, including if a current state would be acceptable over time as a yes vs no response and Likert scales about how acceptable a current state is if remaining over time. Additional outcomes assessed included modified Rodnan skin score, HAQ disability index (HAQ-DI), physician and patient global assessments on a visual analogue scale, CRP and ESR. RESULTS: The placebo group consisted of 44 patients and the TCZ group had 43 patients. At baseline, 33% achieved a PASS for all three PASS questions, with the proportion increasing to 69, 71 and 78%, respectively, at 96 weeks. Changes in PASS scores showed a moderately negative correlation with HAQ-DI and patient and physician global assessments visual analogue scales, which indicates expected improvements as PASS improved. The PASS question, 'Considering all of the ways your scleroderma has affected you, how acceptable would you rate your level of symptoms?' showed significant correlations with patient-reported outcomes and differentiating placebo vs TCZ at 48 weeks (P = 0.023). Conclusion: PASS may be used as a patient-centred outcome in SSc, especially as a 7-point Likert scale. Further validation is required to determine the utility as an outcome measure in trials and clinical practice.

Background: Systemic sclerosis (SSc)-overlap syndromes are a very heterogeneous and remarkable subgroup of SSc-patients, who present at least two connective tissue diseases (CTD) at the same time, usually with a specific autoantibody status. Objectives: To determine whether patients, classified as overlap syndromes, show a disease course different from patients with limited SSc (lcSSc) or diffuse cutaneous SSc (dcSSc). Methods: The data of 3240 prospectively included patients, registered in the database of the German Network for Systemic Scleroderma and followed between 2003 and 2013, were analysed. Results: Among 3240 registered patients, 10% were diagnosed as SSc-overlap syndrome. Of these, 82.5% were female. SSc-overlap patients had a mean age of 48±1.2 years and carried significantly more often ‘other antibodies’ (68.0%; p

The exact prevalence of psoriatic arthritis (PsA) among patients with psoriasis is still not conclusive. Data in the literature vary between 5.8 and 30 %. Objective of this study was to gain more information on the prevalence of PsA among patients with psoriasis in Germany. Between 09/2010 and 05/2011, consecutive patients from dermatological private practices and a university hospital with psoriasis were asked to fill out the validated German Psoriatic Arthritis Diagnostic (GEPARD) Questionnaire. Patients who answered ≥4 questions with "yes" were invited to come for a rheumatological check up. Those patients who refused a rheumatological examination were counted as "absence of PsA". Laboratory tests for inflammatory markers as well as the severity of skin manifestations were assessed. The diagnosis of PsA was made according to the CASPAR criteria, and imaging was performed in addition. A total of 404 questionnaires were evaluated; 50.5 % answered ≥4 questions positively; 19.3 % had a history of PsA confirmed by a rheumatologist; and in 10.9 %, PsA or spondyloarthritis was newly diagnosed during the present study. This leads to an overall prevalence of PsA in patients with psoriasis of 30.2 %. The frequency of psoriatic arthritis in the present study is higher than expected from previous studies in Germany. The prevalence is consistent with findings of a large observational survey from Scandinavia. Using the CASPAR criteria and imaging in all patients, certainty of the diagnosis is very high. The GEPARD Questionnaire is a helpful tool to identify people at risk for psoriatic arthritis.

Pyoderma gangrenosum (PG) is a severe ulcerative skin disease. Despite systemic immunosuppressive therapy, PG ulcers often progress and can develop into life-threatening conditions. In this case series, we treated 6 patients suffering from recalcitrant PG with topical coagulation factor XIII, which has been shown to exert beneficial effects on tissue regeneration and wound healing. All 6 patients showed a positive response to treatment with a marked reduction in wound size that was maintained during a 3-month follow-up period. The treatment was well tolerated with no remarkable adverse effects or complications. Topical factor XIII has potential in combination with standard immunosuppressive therapy for the treatment of PG.

The purpose of this study was to assess the impact of enteric-coated mycophenolate sodium (EC-MPS) on skin and pulmonary manifestations of patients with progressive systemic sclerosis (Ssc). A prospective, open-label single-centre trial with EC-MPS 2 × 720 mg/day over 12 months and a long-term follow-up of 50 months were conducted. Modified Rodnan skin score (mRSS) was used to assess the skin and pulmonary function tests to assess the pulmonary involvement. In order to quantify the extent of alveolitis/fibrosis via densitometry, the high attenuation value, median lung density and percentiles of lung tissue densities were obtained by high-resolution computed tomography. Eleven patients were included. Three patients had to stop medication before month 6 (2× side effects, 1× progression). For the remaining eight patients, the median mRSS was non-significantly reduced from 13.5 at baseline to 11 at month 12. According to the CT histography, median lung density and high attenuation values remained stable. However, the course of percentiles -200 to -300 and particularly -300 to -400 Hounsfield units slightly increased in seven of eight patients after 12 months, suggesting worsening of pulmonary involvement. Accordingly, median diffusing capacity for carbon monoxide showed a tendency to decline (75.1 % vs. 70.2) while forced vital capacity non-significantly improved (78.0 vs. 85.5 %) during the study. Four patients are still on EC-MPS without clinical signs of progression after 50 months follow-up. EC-MPS showed non-significant improvement of the skin. Pulmonary fibrosis remained stable with only a slight tendency towards progression which might be ascribed to the medication as well as the natural course of the disease. CT histography appears to be a sensitive method for the detection of progression of pulmonary fibrosis and therefore should be considered for further studies in Ssc.

Summary Background Systemic sclerosis is a rare disabling autoimmune disease with few treatment options. The efficacy and safety of tocilizumab, an interleukin 6 receptor-α inhibitor, was assessed in the faSScinate phase 2 trial in patients with systemic sclerosis. Methods We did this double-blind, placebo-controlled study at 35 hospitals in Canada, France, Germany, the UK, and the USA. We enrolled adults with progressive systemic sclerosis of 5 or fewer years' duration from first non-Raynaud's sign or symptom. Patients were randomly assigned (1:1) to weekly subcutaneous tocilizumab 162 mg or placebo. The primary endpoint was the difference in mean change from baseline in modified Rodnan skin score at 24 weeks. This study is registered with ClinicalTrials.gov, number NCT01532869. Findings We enrolled 87 patients: 43 assigned to tocilizumab and 44 assigned to placebo. The least squares mean change in modified Rodnan skin score at 24 weeks was −3·92 in the tocilizumab group and −1·22 in the placebo group (difference −2·70, 95% CI −5·85 to 0·45; p=0·0915). The least squares mean change at 48 weeks was −6·33 in the tocilizumab group and −2·77 in the placebo group (treatment difference −3·55, 95% CI −7·23 to 0·12; p=0·0579). In one of several exploratory analyses, fewer patients in the tocilizumab group than in the placebo group had a decline in percent predicted forced vital capacity at 48 weeks (p=0·0373). However, we detected no significant difference in disability, fatigue, itching, or patient or clinician global disease severity. 42 (98%) of 43 patients in the tocilizumab group versus 40 (91%) of 44 in the placebo group had adverse events. 14 (33%) versus 15 (34%) had serious adverse events. Serious infections were more common in the tocilizumab group (seven [16%] of 43 patients) than in the placebo group (two [5%] of 44). One patient died in relation to tocilizumab treatment. Interpretation Tocilizumab was not associated with a significant reduction in skin thickening. However, the difference was greater in the tocilizumab group than in the placebo group and we found some evidence of less decline in forced vital capacity. The efficacy and safety of tocilizumab should be investigated in a phase 3 trial before definitive conclusions can be made about its risks and benefits. Funding F Hoffmann-La Roche, Genentech.

To explore the role of whole-body magnetic resonance imaging (MRI) in detecting musculoskeletal involvement in patients with systemic scleroderma and musculoskeletal symptoms. Eighteen consecutive patients (8 men, 10 women) with systemic scleroderma (median age 46 years) presenting with musculoskeletal complaints underwent whole-body MRI at 1.5 T. Images were evaluated for abnormal signal intensity and/or thickening of subcutaneous fatty tissue septa, muscular fasciae, intramuscular perifascial septa, muscle signal intensity and articular or tendon sheath synovial abnormalities on STIR and post-gadolinium scans. Additionally, C-reactive protein, creatinine kinase and the modified Rodnan skin score were determined. MRI indicated evidence of fasciitis, articular synovial inflammation, and subcutaneous thickening in 16 (89 %) patients. MRI findings were compatible with myopathy or myositis in 14 (78 %) patients, tenosynovitis in 11 (61 %) patients and enthesitis in 10 (56 %) patients. Typically, these manifestations were distributed symmetrically and mostly generalised. We only found few correlations with modified Rodnan skin score, C-reactive protein and creatinine kinase. In patients with systemic scleroderma experiencing musculoskeletal symptoms, whole-body MRI is able to detect involvement of muscles, fasciae, joints and entheses more confidently compared with clinical and laboratory parameters. • Whole-body MRI reliably detects musculoskeletal involvement in patients with systemic scleroderma. • Abnormal MRI findings are frequently seen in patients with symptomatic systemic scleroderma. • Musculoskeletal MRI findings correlate only in part with the clinical score and laboratory biomarkers. • Early detection of musculoskeletal abnormalities by MRI may improve the staging.

Objective To describe the long-term effects of infertility on life and partnership satisfaction. Design Longitudinal cohort study. Setting A university outpatient andrology and gynecology infertility clinic. Patient(s) 275 men and 272 women treated for infertility between August 2000 and December 2001. Intervention(s) None. Main Outcome Measure(s) The Life Satisfaction Questionnaire (FLZ), the Partnership Questionnaire (PFB), and sociodemographic items at baseline (T1) and 5 years later (T2). Result(s) Compared with a representative sample, our male and female participants had higher Finance and Partnership scores and lower Health scores on the FLZ at T1. They also had markedly higher PFB scores, with the exception of Conflict Behavior. After 5 years (T2), 101 men and 113 women rated the Partnership and Sexuality FLZ subscales as well as all the PFB subscales statistically significantly lower than at baseline. Only the women rated the Self-esteem FLZ subscale lower than at baseline (T1). Participants who became parents had lower Leisure and Partnership FLZ subscale scores, and fathers had lower Finance FLZ subscale scores. Conclusion(s) Satisfaction declined over 5 years for both men and women, but only in the partnership-related domains. Women were more affected than men. The success of infertility treatment had only a minor influence on a couple's future satisfaction.

Summary Metastases from uveal melanoma are often confined to the liver. Palliative hepatic chemoembolization has been considered to be a reasonable treatment approach. We enrolled 14 patients with hepatic metastases from uveal melanoma into a pilot trial of transarterial chemoembolization (TACE). All patients received additional systemic immuno-chemotherapy or best supportive care. In 31 procedures 100 mg/m 2 of cisplatine was continuously infused by means of a power injector preceding embolization by manual injection of polyvinyl alcohol particles. In three procedures cisplatine was replaced by 200 mg/m 2 carboplatine because of increased serum creatinine levels. Tumor response was evaluated using RECIST criteria. Fourteen patients received 34 TACE's (mean: 2.4 treatments). Eight patients (57%) achieved partial response (PR), four patients (29%) had stable disease and two patients (14%) tumor progression. Median time to progression was 8.5 months (5–35 months). Median survival after first TACE was 14.5 months in responders compared to 10 months in non-responders ( p = 0.18, not significant) and 11.5 months (3–69 months) in all patients. In seven patients with metastases occupying less than 25% of liver volume median survival was 17 months compared to 11 months in seven patients with tumor involvement of more than 25% (p = 0.02) with partial response rate of 86% and 29%, respectively. TACE of liver metastases from uveal melanoma is well tolerated and may prolong survival in patients with limited tumor extension.

Acta Ophthalmol. 2011: 89: 17–24 Abstract. Purpose: To evaluate whether tumour therapy for malignant uveal melanoma leads to a shedding of melanoma cells into the systemic circulation. Methods: Ninety-four peripheral blood samples from 81 patients with malignant uveal melanoma were collected before and after different tumour therapies and the number of circulating melanoma cells (CMCs) was investigated (seven patients with enucleation, 49 patients with stereotactic radiotherapy, 19 patients with endoresection of the tumour, 15 patients with ruthenium-brachytherapy and four patients with transpupillary thermotherapy). A cellular approach was used to detect CMCs through an immunocytological assay with tumour cell enrichment by immunomagnetic cell sorting. The number of CMCs was analysed further according to specific patient characteristics, tumour parameters and the development of metastasis. Results: There was no significant difference between the number of CMCs before and after the different therapies (p = 0.78). There was also no significant association between established prognostic parameters of primary uveal melanoma and the detection of CMCs (all p >0.05). The number of CMCs was not related to the development of metastasis in a short median follow-up time of 16 months (p > 0.05). Conclusion: No changes in CMC values were observed before and after different tumour therapies. In the majority of cases therapy does not lead to a shedding of detectable melanoma cells into the systemic circulation.

Purpose: In patients with uveal melanoma, tumor cell dissemination and subsequent formation of metastases are confined mainly to the hematogenous route. Here, we sought to isolate circulating melanoma cells in peripheral blood of patients with primary uveal melanoma and clinically localized disease. Experimental Design: Blood samples from 52 patients with clinically localized uveal melanoma and from 20 control individuals were prospectively collected before therapy of the primary tumor. Tumor cells expressing the melanoma-associated chondroitin sulfate proteoglycan were enriched by immunomagnetic cell sorting and visualized by immunocytologic staining. Results were compared with clinical data at presentation. Results: In 10 of 52 patients [19%; 95% confidence interval (95% CI), 10-33%], between 1 and 5 circulating melanoma cells were detected in 50 mL peripheral blood. No melanoma-associated chondroitin sulfate proteoglycan–positive cells were detected in any of the 20 controls examined. The presence of tumor cells in peripheral blood was associated with ciliary body invasion [odds ratio (OR), 20.0; 95% CI, 3.0-131.7], advanced local tumor stage (OR, 6.7; 95% CI, 1.8-25.4), and anterior tumor localization (OR, 4.0; 95% CI, 1.2-12.7), all established factors for uveal melanoma progression. Conclusions: Immunomagnetic enrichment enables detection of intact melanoma cells in peripheral blood of patients with clinically localized ocular disease. Visualization and capturing of these cells provide a unique tool for characterizing potentially metastasizing tumor cells from a primary melanoma at an early stage of the disease.

To describe musculocutaneous MR-findings responsible for disability in chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT).Between June 2005 and February 2008, we performed whole-body musculoskeletal magnetic resonance imaging (MRI; n = 12) or regional MRI (n = 4) in 16 consecutive patients presenting with disabling sclerodermatous cGVHD (e.g., skin edema, fixed deep dermal sclerosis, joint contractures, painful muscular contractures, or myalgia).In all patients, MRI showed musculocutaneous abnormalities reflecting different degrees of inflammation and collagen tissue involvement of the skin (n = 10), subcutaneous fat tissue (n = 13), muscle fasciae (n = 16), subfascial muscular septae (n = 6), or findings compatible with myositis (n = 3). The most frequently involved muscle fasciae comprised those of the vastus lateralis muscle (n = 12), biceps femoris muscle (n = 11), gastrocnemius medialis muscle (n = 8), serratus anterior muscle, and latissimus dorsi muscle (each, n = 5). Increased signal of involved tissues on STIR-images and fat-saturated postgadolinium T1-weighted images represented the most frequent MR-signal abnormalities.MR imaging of musculocutaneous cGVHD allows accurate evaluation including assessment of deep tissue infiltration and assists in the differential diagnosis.

Objective. Systemic sclerosis (SSc) is a rare, heterogeneous disease, which affects different organs and therefore requires interdisciplinary diagnostic and therapeutic management. To improve the detection and follow-up of patients presenting with different disease manifestations, an interdisciplinary registry was founded with contributions from different subspecialties involved in the care of patients with SSc. Methods. A questionnaire was developed to collect a core set of clinical data to determine the current disease status. Patients were grouped into five descriptive disease subsets, i.e. lcSSc, dcSSc, SSc sine scleroderma, overlap-syndrome and UCTD with scleroderma features. Results. Of the 1483 patients, 45.5% of patients had lcSSc and 32.7% dcSSc. Overlap syndrome was diagnosed in 10.9% of patients, while 8.8% had an undifferentiated form. SSc sine scleroderma was present in 1.5% of patients. Organ involvement was markedly different between subsets; pulmonary fibrosis for instance was significantly more frequent in dcSSc (56.1%) than in overlap syndrome (30.6%) or lcSSc (20.8%). Pulmonary hypertension was more common in dcSSc (18.5%) compared with lcSSc (14.9%), overlap syndrome (8.2%) and undifferentiated disease (4.1%). Musculoskeletal involvement was typical for overlap syndromes (67.6%). A family history of rheumatic disease was reported in 17.2% of patients and was associated with early disease onset (P < 0.005). Conclusion. In this nationwide register, a descriptive classification of patients with disease manifestations characteristic of SSc in five groups allows to include a broader spectrum of patients with features of SSc.

OBJECTIVE. Our objective was to describe the spectrum of MRI features in patients with deep and generalized morphea.CONCLUSION. Imaging features of morphea are not specific and usually overlap with those of other disorders involving the skin, fascia, and musculature, such as some types of fasciitis, myositis, and so forth. Nevertheless, the imaging features of morphea reflect pathomorphologic changes of this rare disorder and enable a complete assessment of the disease extent, including depth of infiltration and disease activity.

BACKGROUND Interferons have been reported to significantly contribute to tumor suppression via both induction of p53 gene expression and inhibition of angiogenesis. OBJECTIVE The assessment of treatment toxicity and antitumoral effectiveness of continuous IV administration of interferon-beta based on an overall evaluation of laboratory, radiographic, and clinical parameters observed during the trial. METHODS The authors treated patients with advanced malignant melanoma with continuous IV infusions of 1 x 10(6) IU interferon-beta daily ( approximately 0.6 x 10(6) IU interferon-beta/m2 daily). RESULTS Continuous IV administration of interferon-beta had no significant effect on overall patient outcome. Interferon side effects were not a reason for treatment discontinuation in any of the patients observed during this trial. CONCLUSIONS Continuous IV interferon-beta had no significant effect on overall patient outcome in a group of patients with advanced malignant melanoma. To our knowledge, this is the first report on the continuous IV administration of interferon-beta in patients with advanced malignant melanoma.

The aim of this study was to evaluate the incidence of neurological manifestations of Behcet's disease (BD) in patients on cyclosporin A (CSA) compared with those on other medications. The records of 117 patients with BD who visited our hospital between 1990 and 2003 were reviewed with respect to symptoms and medication. All episodes of constant therapy prior to central nervous system (CNS) involvement were counted, and then the associations were analysed by the exact Fisher-Freeman-Halton test and adjusted for multiple tests by the Bonferroni-Holm method. We observed ten new cases of CNS manifestations in our patients with BD being regularly seen and treated in our tertiary care centre. The overall prevalence of neuro-BD in our patient group was 8.5%. In a retrospective analysis, the incidence of new-onset neurological disease (neuro-BD) in all patients with BD who regularly visited our hospital was significantly higher in patients on CSA than in those on other medications (6 of 21 vs 0 of 175 episodes, P

Mycophenolate mofetil (MMF) is an immunosuppressive agent that has been shown to be effective in transplant patients. Some case reports and pilot studies have suggested efficacy against systemic lupus erythematosus (LE), particularly in the case of lupus nephritis. Reports on MMF treatment of skin manifestations of LE are still anecdotal. We report two cases with extensive skin lesions owing to subacute cutaneous LE (SCLE). Both patients had been treated with azathioprine and antimalarials without effect. Finally both patients were given highly dosed glucocorticosteroids, which were also ineffective but led to vertebral fractures because of long-term steroid treatment in one patient and steroid-induced psychosis in the other. MMF 2 g daily caused the skin manifestations to disappear within a few weeks in both patients. One patient was followed up for more than 24 months, and showed good toleration of MMF treatment. The skin remained stable over this period when at least 1 g MMF per day was administered. In conclusion, MMF appears to be an attractive treatment option in skin manifestations of SCLE, and seems to be beneficial for patients with steroid-refractory lesions that are also resistant to treatment with immunosuppressants or antimalarials. The observations suggest that further evaluation of this route in randomized controlled trials is warranted.

SummaryBackground Primary cutaneous γ/δ T-cell lymphoma (PCGD-TCL) is aggressive and has a poor prognosis. In contrast, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) of the α/β T-cell receptor phenotype is known to follow an indolent course and have a more favourable prognosis. In the past, PCGD-TCL and SPTCL were often considered to be a manifestation of the same disease, and aggressive systemic polychemotherapy has commonly been the first-line therapy for both. Given the understanding that SPTCL is a separate and less aggressive entity, clinical data exclusively evaluating the efficacy of conservative treatment in SPTCL are needed. Objectives To assess the overall clinical response to systemic corticosteroids in the treatment of SPTCL. Methods This was a retrospective cross-sectional study based on a patient data repository from two tertiary care university hospitals in Zurich (Switzerland) and Tubingen (Germany). The repository spanned 13 years. Results In four of the five patients (80%) with SPTCL, treatment with systemic corticosteroids induced a complete remission. Conclusions Systemic corticosteroids may be an excellent first-line single-agent therapy for SPTCL.

The extent and consequences of professional delay in diagnosis were analysed in 83 patients with palmoplantar and subungual melanomas treated from January 1986 to March 1997 in our department. Seventeen (52%) out of 33 subungual melanomas and 10 (20%) out of 50 palmoplantar melanomas were clinically misdiagnosed by physicians. Three palmoplantar melanomas (6%) were initially misinterpreted by pathologists. In 23 of the 27 cases (85%) the clinical misdiagnosis was made by non-dermatologists. Misdiagnosis caused a median delay of 12 months in the diagnosis of palmoplantar melanomas and 18 months in the diagnosis of subungual melanomas. Delay in diagnosis was associated with increased tumour thickness, more advanced stage at time of melanoma diagnosis and a lower estimated 5-year survival rate (15.4% versus 68.9% for palmoplantar; 68.5% versus 90.9% for subungual). Acral melanomas are frequently misdiagnosed due to their less common locations and because plantar and subungual melanomas often do not fit the 'changing mole' pattern. To Improve the patient's prognosis it is necessary to increase the physicians' skill in the diagnosis of acral melanomas. Histological examination should always be performed in acral lesions that do not heal.

An 80-year-old woman was referred to our hospital with a spontaneously appearing bullous dermatosis limited to the soles of both feet, causing an intense pruritus. She also suffered from Parkinson's disease and depression, and had been treated with levodopa, benserazide, and mirtazapine for several years. On clinical examination, we found several tense and hemorrhagic bullae, with a diameter of up to 3 cm, at both plantar sites and multiple, confluent, dyshidrotic vesicles ( Figs 1 and 2). The rest of the skin, including the mucous membranes and palms, was normal. The first clinical diagnosis was podopompholyx, but histopathologic findings and direct immunofluorescence revealed a diagnosis of bullous pemphigoid, showing subepidermal blisters (Fig. 3) and linear deposits of C3 and immunoglobulin G (IgG). Indirect immunofluorescence was positive, the IgG autoantibodies bound to the epidermal site of salt-split skin, and circulating antibodies against bullous pemphigoid antigens 1 and 2 were found. Because of this typical clinical picture, a diagnosis of dyshidrotic pemphigoid, a localized form of bullous pemphigoid, was made. Under systemic treatment with prednisolone, 40 mg/day, the skin healed completely within 2 weeks. Descriptions of dyshidrotic pemphigoid limited to the soles of both feet are very rare, and the clinical findings might easily lead to a misdiagnosis of podopompholyx.

Daptomycin has proven efficacy in patients with Gram-positive complicated skin and soft tissue infections (cSSTIs), including those caused by Staphylococcus aureus, regardless of methicillin susceptibility. This study was undertaken to evaluate the efficacy and safety of daptomycin in elderly patients. This was an open-label, multicentre, randomized phase IIIb study conducted in hospitalized patients Patients aged ≥65 years with a diagnosis of Gram-positive cSSTIs with or without bacteraemia were included. In addition, infections were required to be of sufficient severity to require inpatient hospitalization and treatment with parenteral antibiotics for at least 96 h. The main exclusion criterion was the presence of a non-complicated SSTI that could heal by itself or be cured by surgical removal of the site of infection. Patients were randomized (2:1) to intravenous daptomycin or pooled intravenous standard therapies (semi-synthetic penicillin or vancomycin, referred to as the ‘comparator’). Duration of treatment was between 5 and 14 days for cSSTIs without bacteraemia and between 10 and 28 days for cSSTIs with bacteraemia. The primary objective was descriptive comparison of clinical success in clinically evaluable patients at test of cure, 7–14 days post treatment. Secondary objectives were microbiological outcome, duration of treatment and safety. In total, 120 patients were randomized (81 to daptomycin; 39 to the comparator) and 102 patients completed the study. Baseline characteristics were similar between the two groups. Common infections included cellulitis, ulcers and abscesses; six patients had bacteraemia [five documented (daptomycin, n = 3; comparator, n = 2); and one suspected (daptomycin, n = 1)]. Test-of-cure clinical success rates were numerically higher for daptomycin than for the comparator [89.0 % (65/73) vs. 83.3 % (25/30); odds ratio 1.65 (95 % confidence interval 0.49–5.54)]. For patients with S. aureus infections, cure rates were 89.7 % (35/39) versus 69.2 % (9/13), respectively; percentage points difference, 20.5 (95 % confidence interval −12.2 to 50.9)]. Rates of adverse events (AEs) and serious AEs were similar in both treatment arms; however, discontinuation rates for AEs/serious AEs were lower for daptomycin than for the comparator (3.8 % vs. 10.0 %). Three serious AEs were considered to be related to the study drug: one case each of pancytopenia (semi-synthetic penicillin), renal failure (vancomycin) and asymptomatic increase in creatine phosphokinase concentrations (daptomycin). In elderly patients, for whom data were previously limited, the efficacy and safety of daptomycin have been confirmed, including for infections caused by S. aureus, regardless of methicillin susceptibility.

The purpose of this article is to explore the role of MRI in monitoring musculoskeletal involvement in patients with morphea who are undergoing treatment with methotrexate and prednisolone.Twenty-two consecutive patients (six men and 16 women; median age, 52 years) with systemic scleroderma and deep morphea prospectively underwent whole-body MRI twice, before treatment (time 1) and during follow-up after 6-12 months (time 2). Images were evaluated for abnormal signal intensity or thickening of sub-cutaneous fatty tissue septa, muscular fasciae, intramuscular perifascial septa, muscle signal intensity, and articular or tendon sheath synovial abnormalities on STIR and gadolinium-enhanced scans. For clinical assessment, the localized scleroderma (morphea) severity index and a 0-6 pain score were applied.From a clinical point of view, none of our patients had progression of the disease, 12 patients were responders (defined as an improvement of localized scleroderma severity index and pain score ≥ 50%), and 10 patients had stable disease. Among responders, the number of patients with subcutaneous septal thickening (time 1, n = 9; time 2, n = 2), fascial enhancement (time 1, n = 8; time 2, n = 3), and articular synovitis (time 1, n = 5; time 2, n = 1) decreased more than in the stable disease group (subcutaneous septal thickening: time 1, n = 9; time 2, n = 8; fascial enhancement: time 1, n = 5; time 2, n = 5; articular synovitis: time 1, n = 8; time 2, n = 6). Subcutaneous thickening, fascial thickening, and fascial enhancement were scored significantly lower at follow-up MRI in responders.MRI findings were sensitive to changes in musculoskeletal manifestations in patients with deep morphea undergoing systemic treatment with methotrexate and prednisolone. Thus, MRI can be recommended as an additional tool for response monitoring.

The pharmacodynamics and biologic activities of recombinant human interferon-beta (rHuIFN-beta) derived from chinese hamster ovary (CHO) cells were examined during long-term therapy in 7 melanoma patients. The CHO-derived rHuIFN-beta was given s.c. in a dose of 3 x 10(6) U three times per week for 24 weeks. Serum levels of IFN could not be detected before and 48 h after the s.c. injections. 2'-5'-Oligoadenylate synthetase (2-5 OAS), beta 2-microglobulin, and neopterin levels increased significantly 48 h after application, with a maximum after 96 h. Subsequently, the values decreased and remained only slightly elevated during the long-term therapy. Natural killer (NK) cell activity increased in the first 96 h significantly and fell below pretreatment values after 4 weeks. The decrease of biologic response could not be attributed to the occurrence of anti-IFN-beta antibodies because only 2 of the 7 patients developed neutralizing antibodies after 16 and 24 weeks of treatment, respectively. This trial confirms the biologic potency of CHO-derived rHuIFN-beta. However, the selected parameters demonstrate that immunostimulation is only possible over a short treatment period.

The effect of 13-cis-retinoic acid and highly purified human leukocyte interferon alpha (Alphaferon) therapy for metastatic melanoma was studied. A group of 17 patients with disseminated malignant melanoma were treated over a 6-month period. They received 60 mg 13-cis-retinoic acid/day continuously and ten cycles of interferon alpha (IFN alpha). IFN was administered by subcutaneous injection, at a daily dose of 6 x 10(6) IU Alphaferon. The 5-day treatment period was followed by an IFN-free interval of 2 weeks. We were able to observe an overall response rate of 30% with 12% complete responses (2 out of 17 patients). Sites of response included the skin, lung, liver and lymph nodes. All responses have now lasted over 6 months. Therapy was generally well tolerated and could be performed on an outpatient basis. Side-effects of this combination therapy did not exceed the established side-effects of the two substances. We also studied 2'-5'-oligoadenylate synthetase, beta 2-microglobulin and neopterin levels during the whole treatment course. All patients were within the normal range before treatment and a sharp rise occurred during each IFN cycle. The maximum being observed 24 h after the third injection. This indicates a high biological activity of IFN alpha administered cyclically during the whole treatment course. This finding also corresponds well with the absence of neutralizing antibodies before and after the whole treatment period.

To describe musculoskeletal manifestations seen at magnetic resonance (MR) imaging in patients with localized scleroderma (LS) and to examine the relationship of MR findings to clinical subtypes and clinically suspected musculoskeletal features.Institutional review board approval was obtained. Forty-three patients (30 female, 13 male; mean age, 42 years) with LS underwent MR imaging with a 1.5-T MR imager between November 2005 and June 2010. Findings were classified into clinical subtypes according to recently published consensus criteria. Images were evaluated for morphologic changes and signal abnormalities of subcutaneous fat septa, muscle fasciae, intramuscular septa, joint and/or tendon sheath synovia, entheses, and bone marrow. Clinically suspicious features of musculoskeletal manifestations-such as articular or periarticular pain, joint contractures, swelling, and increased warmth of the joints or extremities-were recorded.Musculoskeletal involvement was detected with MR imaging in 32 (74%) of 43 patients. It was detected with MR imaging in 26 (96%) of 27 patients in whom it was clinically suspected and in six (38%) of 16 patients in whom it was not clinically suspected. We found fascial thickening (26 [60%] of 43 patients), increased fascial enhancement (23 [53%] of 43 patients), articular synovitis (17 [40%] of 43 patients), tenosynovitis (nine [21%] of 43 patients), perifascial enhancement (seven [16%] of 43 patients), myositis (six [14%] of 43 patients), enthesitis (three [7%] of 43 patients), bone marrow involvement (two [5%] of 43 patients), and subcutaneous septal thickening (28 [65%] of 43 patients). The highest prevalence of musculoskeletal involvement was seen in patients with pansclerotic morphea.MR imaging reveals musculoskeletal involvement in patients with localized scleroderma.

Aleukemic leukemia cutis is a rare condition characterized by the infiltration of the skin by leukemic cells before their appearance in the peripheral blood or bone marrow. We report here a 62-year-old seemingly healthy patient who presented with disseminated erythematous maculae. A skin biopsy showed leukemia cutis of monocytic type. No involvement of bone marrow or peripheral blood was found. The patient developed acute monocytic leukemia 7 months later. We present this case to illustrate how leukemia cutis can masquerade as a clinically benign-appearing cutaneous eruption without leukemic changes in blood or bone marrow. To confirm the diagnosis of aleukemic leukemia cutis, immunohistochemistry of the skin lesions as well as a complete staging procedure is necessary.

Diagnosis: infestation with Sarcoptes scabiei variant bovis. Sarcoptes scabiei var. bovis was isolated from skin scraping samples obtained from the cows (figure 1). In addition, multiple eggs and scybala were found on direct microscopy. Antiscabious treatment of the animals was performed. The pruritus of both patients spontaneously resolved within 3 days after treatment of the animals. The rash disappeared within 1 week. Infestation with Sarcoptes scabiei var. bovis (cattle itch mite) can produce a pruritic rash in humans (figure 2), which generally manifests 24-96 h after contact with the affected animal (figure 3) and is also known as "dairyman's itch" [1]. Typical lesions are papules and papulovesicles with central excoriation. The rash is not restricted to spots of direct contact with the affected animal. Man is an inadequate host. Persistent lesions result from reinfestation [2]. In our case, other members of the family were not affected, because they were not directly involved in the care of the cows.

Purpose To demonstrate the feasibility of whole-body magnetization transfer (MT) contrast imaging. Materials and Methods Whole-body MT imaging was performed on eight healthy volunteers and five patients (mean age = 40.5 ± 17.8 years) with diagnoses of dermatomyositis (N = 1), B-symptoms with suspicion of paraneoplastic disease (N = 1), metastatic malignant melanoma (N = 1), and multiple sclerosis (MS) (N = 2). Measurements were carried out on a 1.5-Tesla whole-body MR scanner capable of parallel signal reception. A three-dimensional (3D) gradient-echo sequence (TR = 17 msec, TE = 4.8 msec, flip angle = 10°) was applied in combination with a Gaussian off-resonance MT preparation pulse acting at an off-resonance of 1.500 Hz with a 500° effective flip angle. Whole-body images were constructed from five different body regions. Results In all subjects, whole-body MT contrast images were obtained within less than 20 minutes of measuring time. The images showed sufficient diagnostic image quality to assess the patients' pathologies. The MT ratios (MTRs, in percent units) for the volunteers were as follows: white matter (WM) 51.1 ± 1.0, gray matter (GM) 42.2 ± 1.3, skeletal muscle (mean value of four muscle groups) 50.3 ± 2.1, liver 39.4 ± 3.2, spleen 31.8 ± 2.6, renal cortex 30.4 ± 1.9, and renal medulla 25.6 ± 1.3. The MTRs for the pathologies were as follows: skeletal muscle in dermatomyositis ∼30, metastases in malignant melanoma 30.7–36.0, uterus myoma 49.3, and MS lesions 30–40. Conclusion Our preliminary data indicate that MT contrast in whole-body MRI is feasible, and may be useful for rapid whole-body assessment of diseases that exhibit high contrast in MT imaging, such as MS and muscular disorders. J. Magn. Reson. Imaging 2006. © 2006 Wiley-Liss, Inc.

Background: Localized scleroderma is characterized by circumscribed fibrotic plaques and may progress to widespread skin involvement and fibrosis. Interferon gamma (IFN-γ) has been shown to be a potent inhibitor of collagen synthesis and of the migration and proliferation of dermal fibroblasts. Objective: Our purpose was to determine whether IFN-γ is effective in the treatment of localized scleroderma. Methods: A double-blind, randomized, placebo-controlled, multicenter study was conducted. Twenty-four patients with progressive lesions received 100 μg of IFN-γ or placebo subcutaneously on 5 consecutive days for 2 weeks followed by 100 μg of IFN-γ or placebo once weekly for 4 weeks. Thereafter patients were observed for 18 weeks. To determine whether improvement could be related to an altered level of collagen messenger RNA (mRNA), biopsy specimens were taken from uninvolved and involved skin before and after therapy. Results: The patients treated with IFN-γ or placebo showed no significant difference in size or fibrosis of lesions or collagen type I mRNA synthesis. However, a reduction in the number of new lesions was observed in the IFN-γ-treated group. The biopsy specimens obtained from involved skin showed a moderate increase of type I collagen and a significant decrease in the small proteoglycan decorin mRNA levels. Conclusion: The results indicate that IFN-γ is ineffective in the treatment of localized scleroderma, but may inhibit the development of new lesions.

A 46-year-old woman presented with a two year history of pruritic erythematous plaques with blisters, as well as oral erosions. Even though the cutaneous lesions fit best with dermatitis herpetiformis, bullous pemphigoid or pemphigoid gestationis, the histologic examination revealed eosinophilic spongiosis, most compatible with some form of pemphigus. The identification of intercellular IgG deposition on direct immunofluorescence and circulating IgG pemphigus antibodies on indirect immunofluorescence microscopy led to diagnosis of pemphigus herpetiformis. This rare form of pemphigus does not often involve the oral mucosa. In our patient, the explanation is that she had antibodies against desmoglein 3 but not desmoglein 1. Treatment with prednisolone and azathioprine caused rapid and complete healing.

A 69-year-old woman presented to our clinic as an emergency with erythematous, well-circumscribed plaques, which were partly vesicular, on her extremities and in her armpits, and additionally hemorrhagic blisters on both her palms and her fingers (Fig. 1a), which had developed 2 days after the first appearance of the skin lesions. The rapid onset of the lesions (within a few hours) and the pain associated with them were extremely troublesome to the patient. On admission she complained of fever, tiredness and being easily fatigued. Because of a urinary tract infection 1 month prior to admission, trospiumchloride was given. On clinical examination, body temperature was found to be above 38 °C and infraclavicular lymph nodes were enlarged but not tender. Normal or negative laboratory tests included blood counts, liver and kidney parameters, electrolytes and infection screen. Laboratory examination demonstrated minor leukocytosis and absolute neutrophilia (white blood cell count 10 440 cells/μL, neutrophils 8030 cells/μL). X-ray screening, abdominal ultrasound and laboratory investigations were all normal. There was no response to antibiotics when erythromycine was given. However, there was a good response to systemic corticosteroids. The patient was treated with a low dosage of prednisolone, beginning at 50 mg/day, which was then tapered off. Skin lesions resolved within 7 days. Histology from a lesion on the patient's left forearm showed a dense interstitial inflammatory infiltration consisting predominantly of neutrophilic granulocytes from the subepidermal layer to the middle of the reticular dermis. Inflammatory cells penetrated into both blood vessels and vessel walls; vasculitis was not prominent. In the lower dermis, perivascular infiltrations of lymphomononuclear cells were found. In addition, intraepidermally multiple partly confluent vesicles, with inclusions of neutrophilic granulocytes, were found, confirming the diagnosis of this rare variant of an acute febrile neutrophilic dermatosis (Fig. 1 b).

A pemphigus vulgaris (PV) patient with a 14-year history of severe and painful blistering of skin and mucous membranes as well as side effects from corticosteroids and concomitant immunosuppressive drug treatment was managed successfully by protein A immunoadsorption (IA). After 19 sessions of protein A IA, the patient showed remission of PV and healing of mucocutaneous lesions and the skin. The level of the pathogenic autoantibodies to the adhesion proteins desmoglein 1 (Dsg-1) and desmoglein 3 (Dsg-3) measured by ELISA and immunofluorescence microscopy revealed a significant removal of autoantibodies after each IA therapy. There was a weak rebound of anti-Dsg-1 and anti-Dsg-3 antibodies between IA sessions but an overall decrease over the period of IA therapy. This case demonstrates the effective use of protein A IA as an adjuvant and corticosteroid-sparing therapy in severe pemphigus refractory to standard immunosuppressive therapy and underscores the need for careful monitoring of autoantibodies.

Purpose: Improved detection of early-disseminated melanoma cells may eventually translate into more effective patient care. We present a novel strategy for detection of melanoma cells in sentinel lymph nodes and confirm their malignant descent by genomic characterization. Experimental Design: In sentinel lymph nodes from 358 melanoma patients, we prospectively compared the rates of tumor cell detection between immunocytochemistry using HMB45 and Melan A antibodies on disaggregated lymph node samples and standard histopathology (H&E staining and immunostaining on tissue sections). Immunocytochemical melanoma cell detection was controlled by testing lymph node samples from 59 nonmelanoma patients and by isolation and comparative genomic analysis of 30 antigen-positive cells. Results: Of the 358 patients, 43 (12%) were positive by standard histopathology, whereas HMB45 immunocytochemistry detected 159 of 358 (44%) positive patients. None of the control samples reacted with the HMB45 antibody. Reexamination of samples that were classified as negative by histopathology revealed that extensive serial sectioning would be necessary to achieve sensitivity similar to HMB45 immunocytochemistry. Interestingly, both the number of immunocytochemically positive samples and the number of positive cells in the sentinel node correlated with the thickness of the primary tumor (r = 0.34; P = 0.001 and P < 0.0001, respectively). Twenty-four of 30 isolated immunocytochemically positive cells (80%) displayed chromosomal aberrations, some of which were isolated from histopathologically negative nodes. Conclusion: Immunocytochemical detection of melanoma cells in sentinel lymph nodes is superior to standard histopathology. It remains to be determined whether the detection and genomic characterization of isolated melanoma cells in sentinel lymph nodes will provide relevant prognostic information.

Epithelioid hemangioendothelioma is an uncommon malignant vascular tumor usually involving soft tissue and, in rare cases, the skin. Histologically and biologically it is considered to be a borderline neoplasm between an angiolymphoid hyperplasia with eosinophilia and an epithelioid angiosarcoma. Here we describe an 11-year-old girl with a 1-year history of an isolated, spontaneously appearing, painful ulceration on the instep of the right foot. The histopathologic examination of a wedge biopsy specimen revealed epithelioid eosinophilic cells with intracytoplasmic vacuoles containing erythrocytes. Immunohistochemical staining was positive for the endothelial markers CD31, CD34, and factor VIII. On the basis of these findings the diagnosis of epithelioid hemangioendothelioma was made. Two weeks after complete excision of the tumor, a lymph node metastasis in the right groin was excised. Because of another inoperable lymph node metastasis on the proximal right femur, polychemotherapy was started. As our case report shows, in the event of a nonhealing cutaneous ulceration the possibility of a malignant tumor such as epithelioid hemangioendothelioma should be considered, even in children. (J Am Acad Dermatol 2003;49:113-6.)

Although effective conventional therapies are available to treat basal cell carcinoma (BCC), undesirable side effects, including scarring, and in some cases permanent damage, often occur in problematic areas of the body, especially around the eyes, mouth, and cartilage of the nose and ears. In previous studies, intratumoural injection of recombinant interferon beta-1a (rIFN-beta-1a) has been shown to result in complete remission (CR) in 47% to 86% of patients with BETACC. The primary objective of the study was to determine the response rate to rIFN-beta-1a, in a larger BETACC patient population. Secondary objectives included evaluating the effect of tumour type/size on response as well as residues, cosmetic results, and relapse rate after CR. The safety profile of intratumoural rIFN-beta-1a in BETACC patients was also evaluated. This was an open-label, multicentre study involving 139 patients with BETACC (diameter between 5.0 and 20 mm). Intratumoural injections of rIFN-beta-1a (1.0 x 106 IU) were administered three times a week for 3 weeks. The response was determined 16 weeks after start of treatment and the status of patients was followed for up to 5 years. At 16 weeks, the response rate to intratumoural rIFN-beta-1a was 66.9% (95% CI, range 58.2-74.8%). There was no significant difference between the response rates for patients with solid or other BETACC tumour types. Similarly, tumour size did not significantly affect the response rate. The cosmetic result of treatment was rated as good or very good in 83% of responders. The relapse rate after CR was 4.5% (median follow-up 2 years). All patients showed local inflammatory reactions, which were generally considered to be the adverse drug reactions (ADRs). Systemic ADRs mostly consisted of flu-like symptoms and occurred in 32/139 patients. No ADRs were considered to be the serious. These results show that intratumoural injections of rIFN-beta-1a are effective in the treatment of BETACC in the majority of patients. In addition, rIFN-beta-1a is safe and generally well tolerated. rIFN-beta-1a represents an effective alternative treatment for BETACC.

Background: Bee and wasp venom extracts contain potent allergens capable of inducing severe clinical reactions. To analyze immediate-type hypersensitivity to defined hymenoptera venom components, a recently developed in vitro test was applied that is based on the upregulation of CD203c expression on basophils. Methods: CD203c expression on blood basophils of 9 healthy donors and 39 patients allergic to bee and/or wasp venom was analyzed by flow cytometry before and after activation with the purified bee venom allergens phospholipase A2 (Api m 1), hyaluronidase (Api m 2) and melittin (Api m 4), or the purified wasp venom allergens phospholipase A1 (Ves v 1), hyaluronidase (Ves v 2) and the recombinant antigen 5 (Ves v 5). Venom-induced CD203c upregulation on basophils was compared with skin tests and assessment of specific IgE. Basophils of nonresponders were preincubated with 10 ng/ml interleukin-3 (IL-3) prior to allergen stimulation. Results: CD203c upregulation on basophils was induced by defined hymenoptera venom components in 35/39 patients with a diagnosed allergy to wasp and/or bee venom. Twenty-seven of the 34 tested patients with wasp allergy showed CD203c upregulation in response to Ves v 5, 26 of these patients also reacted with Ves v 2 and 17 with Ves v 1. Nine of 13 patients with bee allergy reacted with Api m 1, 13 individuals with Api m 2 and none of these patients with the minor allergen Api m 4. A diagnosed wasp allergy could also be confirmed in the prestimulated basophils (IL-3) of 2 nonresponder individuals who failed to upregulate CD203c in response to IgE receptor cross-linking prior to culture with IL-3. Conclusions: Flow-cytometric determination of CD203c upregulation on basophils activated by molecularly defined allergens is a powerful method to identify the precise allergen reactivity in sensitized individuals.

We describe a 69-year-old patient with long-standing mixed connective tissue disease who suffered from severe skin eruptions that did not respond to various immunosuppressive regimens. Therapy with high-dose intravenous immunoglobulin was successful in controlling the patient's disease without major side effects. We think that this regimen—although expensive—might be an interesting therapeutic option in selected patients with mixed connective tissue disease that is refractory to other treatment modalities. (J Am Acad Dermatol 2002;46:123-7.)

Objective: To increase the awareness of bovine serum albumin (BSA) sensitivity as a potentially lethal complication during ET. Design: Case report. Setting: Routine ET in university hospital. Patient(s): A 26-year-old woman who was undergoing her first ET. Intervention(s): ET with BSA containing standard fluid medium. Main Outcome Measure(s): Specific immunoglobulin (Ig) E antibodies and skin tests. Result(s): The patient demonstrated increased levels of specific IgE antibodies to BSA and a clearly positive scratch test for BSA. Conclusion(s): Anaphylactic reactions to BSA can occur during ET. The risk can be reduced substantially if a detailed medical history is obtained.

Objective: To confirm significant improvement of the skin score in systemic sclerosis by treatment with interferon gamma in a larger group of patients and to investigate on a molecular level the influence of interferon gamma on collagen type I messenger RNA expression. Design: Open, noncontrolled multicenter study. Setting: Five outpatient clinics specializing in the care of systemic scleroderma. Patients: Thirty-two patients suffering from the diffuse or limited form of systemic sclerosis and progressive disease were recruited; 20 patients finished the study. Intervention: Each patient received interferon gamma, 50 μg subcutaneously 3 times a week for 1 year. Main Outcome Measure: Skin score, collagen type I messenger RNA in skin biopsy specimens. Results: The patients who completed the study showed an unchanged median skin score after 1 year of therapy. In addition, similar collagen type I messenger RNA levels were detected in skin biopsy specimens taken from involved skin before and after therapy in these patients. Conclusions: Treatment of systemic scleroderma with interferon gamma is associated with stabilization of the skin score and lack of worsening of visceral involvement. Arch Dermatol. 1997;133:609-613

Disialoganglioside antigens GD2 and GD3 are expressed on most melanoma cells. On melanoma surrounding T-cells in immunohistological sections, disialogangliosides can also be found, as well as in a small % of T-lymphocytes in peripheral blood from healthy persons. In order to find out if there is a difference in ganglioside expression on peripheral T-lymphocytes between melanoma patients and healthy persons, we examined the expression of CD3 as T-lymphocytic antigen and GD2 or GD3 antigens, respectively, by flow cytometry. We used peripheral mononuclear blood cells of 12 patients with advanced disseminated malignant melanoma and of 12 healthy control donors. For immunostaining, murine monoclonal antibodies Leu-4, 14G2a and MB3.6 were used, recognizing CD3, GD2 and GD3. GD2 expression was found on only a low proportion of T-lymphocytes in patients and healthy persons (pat.: mean = 1.2% +/- 0.7%, co.: mean = 0.4% +/- 0.4%). Disialoganglioside antigen GD3, however, could be demonstrated on an average of 8.4% +/- 4.6% of patients' and on 4.0% +/- 2.1% of healthy persons' T-cells. There is a statistically significant difference (P < 0.01) between the data of patients' and control group. We conclude that there is a correlation between advanced malignant melanoma and expression of GD3 antigen on patients' peripheral T-lymphocytes. The immunological relevance of our findings is discussed.

Background and Design: A retrospective study involving 20 patients with melanoma with clinically suspicious lymph nodes was conducted to compare the diagnostic validity of fludeoxyglucose F 18 positron emission tomography (PET) and real-time ultrasonography in lymph node metastases of malignant mela Results: A total of 83 lymph nodes were assessed with ultrasonography and PET. Imaging results were confirmed by histologic studies or close follow-up ultrasonographic examinations. Positron emission tomography revealed a sensitivity of 74% and a specificity of 93%. Both investigative methods show comparative sensitivity and specificity. Conclusions: Ultrasonography is much easier to perform, less time-consuming, and less expensive than PET and it is nonhazardous; therefore, it is ideal for follow-up procedures. Since in routine staging procedures, only sites of expected lymph node involvement are examined, there is a risk of metastases being missed in cases of atypical drainage patterns. Fludeoxyglucose F 18 PET can image proliferating tumors in multiple organ systems and lymph node sites in one session, making it suitable for screening in primary staging procedures and for monitoring response to therapy. Since it is based on metabolic changes, there is good differentiation between scar and tumor tissue. Major disadvantages are restricted access to investigation centers, high imaging costs, and limited anatomical location of metastatic lesions. We conclude that PET does not offer significant advantages in the diagnosis of lymph node metastases compared with ultrasonography. (Arch Dermatol. 1995;131:1394-1398)

The interferon-inducible enzyme, 2'-5'-oligoadenylate synthetase, was estimated in healthy donors and in patients before and after subcutaneous application of recombinant interferon beta and gamma. Tests were carried out with lysates of peripheral blood mononuclear cells, using an established radioenzymatic assay, and in serum samples, using a new radioimmunoassay. Both test systems substantially yielded the same results: after a single injection of interferon beta (1-5 x 10(6) IU), 2'-5'-oligoadenylate synthetase increased in a dose-dependent manner reaching maximal catalytic concentrations in most patients after 24-48 hours (leukocytes) and 48-72 hours (serum). In contrast, interferon gamma (2-4 x 10(6) IU) caused only a small induction of 2'-5'-oligoadenylate synthetase. However, daily application of interferon gamma for 7 days led to a distinct time-dependent increase of 2'-5'-oligoadenylate synthetase activity concentration during this observation period. Characteristically, even during daily application, the 2'-5'-oligoadenylate synthetase activity concentration dropped just 48-72 hours after the first injection of interferon beta. The determination of 2'-5'-oligoadenylate synthetase proved to be useful for optimizing and monitoring subcutaneous therapy with interferon. The new radioimmunoassay which allows the determination of this enzyme in serum is superior to other methods used in the past.

A 56-year-old woman with an 8-year history of CREST syndrome, a variant of scleroderma, presented with increasing calcium deposits that were causing inflammation and swelling of the index finger of her left hand (Figure 1), as well as Raynaud phenomenon, telangiectasia, and mild sclerosis of her fingers. She had intense pain and extreme morbidity and was severely handicapped in her office job. A barium swallow test revealed moderate esophageal dysmotility, and a computed tomographic scan demonstrated mild pulmonary fibrosis. Spirometry revealed normal values, particularly for carbon monoxide diffusing capacity and inspiratory vital capacity. There was no evidence of pulmonary hypertension, cardiac or renal manifestations, or systemic metabolic abnormalities in calcium regulation. Serologic tests were positive for antinuclear antibodies and anti–Scl-70 antibodies. Long-term treatment with D-penicillamine (30 weeks), warfarin sodium (13 weeks), and extracorporeal shock wave lithotripsy did not result in any improvement in the cutaneous calcifications or inflammation. The plastic surgeons refused to consider a surgical approach because of the risk of protracted and complicated wound healing.