Rudolf Stadler

A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of pemphigus.

OBJECTIVE To investigate the safety and efficacy of oral methylprednisolone combined with azathioprine sodium or mycophenolate mofetil for the treatment of pemphigus. DESIGN A prospective, multicenter, randomized, nonblinded clinical trial to compare 2 parallel groups of patients with pemphigus (pemphigus vulgaris and pemphigus foliaceus) treated with oral methylprednisolone plus azathioprine or oral methylprednisolone plus mycophenolate mofetil. Settings Thirteen departments of dermatology in Germany. Patients We included patients with pemphigus vulgaris (n = 33) or pemphigus foliaceus (n = 7) evidenced by clinical lesions suggestive of pemphigus, intraepidermal blistering on histological analysis of skin biopsy specimens, intercellular deposition of IgG within the epidermis, and immunoblot analysis findings for antidesmoglein 3 and/or antidesmoglein 1 autoantibodies. MAIN OUTCOME MEASURES The cumulative total methylprednisolone doses and rate of remission. Secondary outcome measures were safety profiles and duration of remission. RESULTS In 13 (72%) of 18 patients with pemphigus receiving oral methylprednisolone and azathioprine, complete remission was achieved after a mean +/- SD of 74 +/- 127 days compared with 20 (95%) of 21 patients receiving oral methylprednisolone and mycophenolate mofetil in whom complete remission occurred after a mean +/- SD of 91 +/- 113 days. The total median cumulative methylprednisolone dose used was 8916 mg (SD, +/-29 844 mg) in the azathioprine group compared with 9334 mg (SD, +/-13 280 mg) in the mycophenolate group. In 6 (33%) of 18 patients treated with azathioprine, grade 3 or 4 adverse effects were documented in contrast to 4 (19%) of 21 patients who received mycophenolate mofetil. Conclusion Mycophenolate mofetil and azathioprine demonstrate similar efficacy, corticosteroid-sparing effects, and safety profiles as adjuvants during treatment of pemphigus vulgaris and pemphigus foliaceus.

Primary cutaneous melanoma. Prognostic classification of anatomic location

Background. Anatomic location has been identified by several investigators as a significant prognostic factor for patients with primary cutaneous melanoma (CM). However, the best determination of higher and lower risk sites is still controversial, and the biologic significance of tumor site in the course of primary CM is unknown. The aim of the present study was to identify higher and lower risk sites based on multivariate analysis.

Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial

BACKGROUND Complete lymph node dissection is recommended in patients with positive sentinel lymph node biopsy results. To date, the effect of complete lymph node dissection on prognosis is controversial. In the DeCOG-SLT trial, we assessed whether complete lymph node dissection resulted in increased survival compared with observation. METHODS In this multicentre, randomised, phase 3 trial, we enrolled patients with cutaneous melanoma of the torso, arms, or legs from 41 German skin cancer centres. Patients with positive sentinel lymph node biopsy results were eligible. Patients were randomly assigned (1:1) to undergo complete lymph node dissection or observation with permuted blocks of variable size and stratified by primary tumour thickness, ulceration of primary tumour, and intended adjuvant interferon therapy. Treatment assignment was not masked. The primary endpoint was distant metastasis-free survival and analysed by intention to treat. All patients in the intention-to-treat population of the complete lymph node dissection group were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02434107. Follow-up is ongoing, but the trial no longer recruiting patients. FINDINGS Between Jan 1, 2006, and Dec 1, 2014, 5547 patients were screened with sentinel lymph node biopsy and 1269 (23%) patients were positive for micrometastasis. Of these, 483 (39%) agreed to randomisation into the clinical trial; due to difficulties enrolling and a low event rate the trial closed early on Dec 1, 2014. 241 patients were randomly assigned to the observation group and 242 to the complete lymph node dissection group. Ten patients did not meet the inclusion criteria, so 233 patients were analysed in the observation group and 240 patients were analysed in the complete lymph node dissection group, as the intention-to-treat population. 311 (66%) patients (158 in the observation group and 153 in the dissection group) had sentinel lymph node metastases of 1 mm or less. Median follow-up was 35 months (IQR 20-54). Distant metastasis-free survival at 3 years was 77·0% (90% CI 71·9-82·1; 55 events) in the observation group and 74·9% (69·5-80·3; 54 events) in the complete lymph node dissection group. In the complete lymph node dissection group, grade 3 and 4 events occurred in 15 patients (6%) and 19 patients (8%) patients, respectively. Adverse events included lymph oedema (grade 3 in seven patients, grade 4 in 13 patients), lymph fistula (grade 3 in one patient, grade 4 in two patients), seroma (grade 3 in three patients, no grade 4), infection (grade 3 in three patients, no grade 4), and delayed wound healing (grade 3 in one patient, grade 4 in four patients); no serious adverse events were reported. INTERPRETATION Although we did not achieve the required number of events, leading to the trial being underpowered, our results showed no difference in survival in patients treated with complete lymph node dissection compared with observation only. Consequently, complete lymph node dissection should not be recommended in patients with melanoma with lymph node micrometastases of at least a diameter of 1 mm or smaller. FUNDING German Cancer Aid.

Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID)

IntroductionEvidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkins lymphoma in a real-life clinical setting.MethodsPatients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators.ResultsA total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physicians visual analogue scale; mean improvement from baseline of 12.1 mm).ConclusionsData from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.

Adjuvant low-dose interferon α2a with or without dacarbazine compared with surgery alone: a prospective-randomized phase III DeCOG trial in melanoma patients with regional lymph node metastasis

BACKGROUND More than half of patients with melanoma that has spread to regional lymph nodes develop recurrent disease within the first 3 years after surgery. The aim of the study was to improve disease-free survival (DFS) and overall survival (OS) with interferon (IFN) alpha2a with or without dacarbazine (DTIC) compared with observation alone. PATIENTS AND METHODS A total of 444 patients from 42 centers of the German Dermatologic Cooperative Oncology Group who had received a complete lymph node dissection for pathologically proven regional node involvement were randomized to receive either 3 MU s.c. of IFNalpha2a three times a week for 2 years (Arm A) or combined treatment with same doses of IFNalpha2a plus DTIC 850 mg/m(2) every 4-8 weeks for 2 years (Arm B) or to observation alone (Arm C). Treatment was discontinued at first sign of relapse. RESULTS A total of 441 patients were eligible for intention-to-treat analysis. Kaplan-Meier 4-year OS rate of those who had received IFNalpha2a was 59%. For those with surgery alone, survival was 42% (A versus C, P = 0.0045). No improvement of survival was found for the combined treatment Arm B with 45% survival rate (B versus C, P = 0.76). Similarly, DFS rates showed significant benefit for Arm A, and not for Arm B. Multivariate Cox model confirmed that Arm A has an impact on OS (P = 0.005) but not Arm B (P = 0.34). CONCLUSIONS 3 MU interferon alpha2a given s.c. three times a week for 2 years significantly improved OS and DFS in patients with melanoma that had spread to the regional lymph nodes. Interestingly, the addition of DTIC reversed the beneficial effect of adjuvant interferon alpha2a therapy.

Markers and Relative Risk in a German Population for Developing Malignant Melanoma

ABSTRACT: The relationship between cutaneous malignant melanoma (MM) and possible risk factors was assessed in a case‐controlled study. Two hundred patients and 200 non‐melanoma controls of German origin matched for age and sex were interviewed and examined for pigmented moles and pigmentation characteristics. In patients with MM significantly more melanocytic nevi ≥ 2 mm (MCN) were found (mean, 53 MCN) compared to control cases (mean, 18 MCN). For persons with >60 MCN the relative risk (RR) for developing MM increased 15 times compared to ≤ MCN. Additional independent markers for an increased risk were presence of atypical MCN (RR = 7 vs. none) found in 45% of patients and in 5% of the control group, moderate to large numbers of actinic lentigines (RR = 6.2 vs. none), and lack of tanning as well as a tendency to sunburn (skin type I; RR = 2.2 vs. skin type IV) No significant correlation was found between the relative risk for MM and hair color, eye color, duration of free time sun exposure and number of sunburns. Individuals with permanent outdoor profession and sun exposure, however, showed a clearly increased relative risk for developing MM.

Cost-of-illness of chronic leg ulcers in Germany

Chronic wounds are important because of their frequency, their chronicity and high costs of treatment. However, there are few primary data on the cost‐of‐illness in Germany. The aim was to determine the cost‐of‐illness of venous leg ulcers (VLU) in Germany. Prospective cost‐of‐illness study was performed in 23 specialised wound centres throughout Germany. Direct, medical, non medical and indirect costs to the patient, statutory health insurers and society were documented. Thereover, health‐related quality of life (QoL) was recorded as intangible costs using the Freiburg quality of life assessment for wounds (FLQA‐w, Augustin). A total of 218 patients (62.1% female) were recruited consecutively. Mean age was 69.8 ± 12.0 years. The mean total cost of the ulcer per year and patient was €9569, [€8658.10 (92%) direct and €911.20 (8%) indirect costs]. Of the direct costs, €7630.70 was accounted for by the statutory health insurance and €1027.40 by the patient. Major cost factors were inpatient costs, outpatient care and non drug treatments. QoL was strikingly reduced in most patients. In Germany, VLU are associated with high direct and indirect costs. As a consequence, there is a need for early and qualified disease management. Deeper‐going cost‐of‐illness‐studies and cost‐benefit analyses are necessary if management of chronic wounds is to be improved.

Epidemiologic evidence for the role of melanocytic nevi as risk markers and direct precursors of cutaneous malignant melanoma: Results of a case control study in melanoma patients and nonmelanoma control subjects

BACKGROUND Melanocytic nevi (MN) are markers of melanoma risk, but their potential role as precursors of cutaneous malignant melanoma (CMM) is still controversial. OBJECTIVE The overall and site-specific relative risk (RR) of developing CMM was evaluated according to site-specific MN counts. METHODS MN prevalence by anatomic site and by age was compared in 200 CMM patients and in 200 nonmelanoma control subjects; RRs were calculated. RESULTS In CMM patients both MN and CMM were mainly found on the legs in women and on the posterior trunk in men, whereas in the control subjects most MN were found on the arms. MN counts on the trunk in men and on the legs in women were best predictors of the overall CMM risk (RR: 33-fold and 15-fold, respectively, for greater than 20 vs up to 4 MN). For both genders combined, the RR for CMM developing on the trunk and legs (predominant CMM locations) was best predicted by MN counts in the respective body region (RR: 24-fold and 27-fold, respectively). MN prevalence peaked in the fourth to fifth decade of life and most CMM were diagnosed during the fifth and sixth decades. CONCLUSION The site-specificity of melanoma risk found for high MN counts on the trunk and the legs and the close similarities in age distribution suggest that the role of MN as direct precursors of CMM has been underestimated and exceeds the number of histologically evident MN associated with CMM.

Frequency of disease-associated and other nuclear autoantibodies in patients of the German network for systemic scleroderma: correlation with characteristic clinical features

IntroductionIn the present study, we analysed in detail nuclear autoantibodies and their associations in systemic sclerosis (SSc) patients included in the German Network for Systemic Scleroderma Registry.MethodsSera of 863 patients were analysed according to a standardised protocol including immunofluorescence, immunoprecipitation, line immunoassay and immunodiffusion.ResultsAntinuclear antibodies (ANA) were detected in 94.2% of patients. In 81.6%, at least one of the autoantibodies highly associated with SSc or with overlap syndromes with scleroderma features was detected, that is, anti-centromere (35.9%) or anti-topoisomerase I (30.1%), followed in markedly lower frequency by antibodies to PM-Scl (4.9%), U1-ribonucleoprotein (U1-RNP) (4.8%), RNA polymerases (RNAPs) (3.8%), fibrillarin (1.4%), Ku (1.2%), aminoacyl-transfer RNA synthetases (0.5%), To (0.2%) and U11-RNP (0.1%). We found that the simultaneous presence of SSc-associated autoantibodies was rare (1.6%). Furthermore, additional autoantibodies were detected in 55.4% of the patients with SSc, of which anti-Ro/anti-La, anti-mitochondrial and anti-p25/p23 antibodies were most frequent. The coexistence of SSc-associated and other autoantibodies was common (43% of patients). SSc-associated autoantibodies disclosed characteristic associations with clinical features of patients, some of which were previously not acknowledged.ConclusionsThis study shows that five autoantigens (that is, centromere, topoisomerase I, PM-Scl, U1-RNP and RNAP) detected more than 95% of the known SSc-associated antibody responses in ANA-positive SSc patients and characterise around 79% of all SSc patients in a central European cohort. These data confirm and extend previous data underlining the central role of the determination of ANAs in defining the diagnosis, subset allocation and prognosis of SSc patients.

Guidelines on the use of extracorporeal photopheresis

After the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T‐cell lymphoma was published in 1983 with its subsequent recognition by the FDA for its refractory forms, the technology has shown significant promise in the treatment of other severe and refractory conditions in a multi‐disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease.