Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a forty-eight-week randomized, double-blind, placebo-controlled, parallel-group phase III trial.

OBJECTIVE: To evaluate the efficacy and safety of treatment with ocrelizumab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and an inadequate response to MTX. METHODS: STAGE was a phase III randomized, double-blind, parallel-group international study to evaluate the safety and efficacy of ocrelizumab compared with placebo in patients with active RA continuing MTX treatment. Patients receiving stable doses of MTX were randomized to receive 2 infusions of placebo (n = 320), ocrelizumab 200 mg (n = 343), or ocrelizumab 500 mg (n = 343) on days 1 and 15 as well as weeks 24 and 26. Coprimary end points were the proportion of patients with an American College of Rheumatology 20% improvement criteria (ACR20) response at weeks 24 and 48. Secondary end points included the change from baseline in the modified Sharp/van der Heijde score (SHS) and the ACR50/70 responses. RESULTS: The ACR20 response rates were 35.7% in the placebo group, 56.9% in the ocrelizumab 200 mg group, and 54.5% in the ocrelizumab 500 mg group at 24 weeks, and 27.6%, 58.3%, and 62.1%, respectively, at 48 weeks (P < 0.0001 versus placebo for each dose at both time points). At week 48, both of the ocrelizumab doses improved the ACR50 and ACR70 response rates 3-fold as compared with placebo and showed a statistically significant (P < 0.0001) reduction in joint damage progression relative to placebo (mean change in SHS reduced by 85% and 100% for the 200-mg and 500-mg doses, respectively). Rates of serious infection were comparable in the placebo (3.48 per 100 patient-years) and ocrelizumab 200 mg (3.54 per 100 patient-years) groups but were elevated in the ocrelizumab 500 mg group (8.66 per 100 patient-years). CONCLUSION: With both ocrelizumab doses, the primary end point was met, and the signs and symptoms of RA were significantly improved at weeks 24 and 48. Ocrelizumab also significantly inhibited the progression of joint damage. A higher rate of serious infections was observed with 500 mg of ocrelizumab as compared with ocrelizumab 200 mg or placebo.

Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to at least one tumor necrosis factor inhibitor: results of a forty-eight­week randomized, double-blind, placebo-controlled, parallel-group phase III trial.

OBJECTIVE: To evaluate the safety and efficacy of ocrelizumab plus methotrexate (MTX) or leflunomide (LEF) in patients with active rheumatoid arthritis (RA) and an inadequate response to tumor necrosis factor α inhibitors. METHODS: This was a multicenter randomized, double-blind, placebo-controlled, parallel-group study that continued over 48 weeks. Patients receiving stable doses of MTX or LEF were randomized to receive 2 infusions of placebo (n = 277), ocrelizumab 200 mg (n = 278), or ocrelizumab 500 mg (n = 285) on days 1 and 15 as well as at weeks 24 and 26. Coprimary end points were the proportion of patients with response according to the American College of Rheumatology 20% improvement criteria (ACR20) at weeks 24 and 48. Secondary end points included the change from baseline in the modified Sharp/van der Heijde score (SHS) and the ACR50/70 responses. RESULTS: ACR20 responses were 22.0% in the placebo group, 42.2% in the ocrelizumab 200 mg group, and 47.9% in the ocrelizumab 500 mg group at 24 weeks and 19.5%, 48.7%, and 50.7%, respectively, at 48 weeks (P < 0.0001 versus placebo for each comparison at each time point). At 48 weeks, patients receiving both doses of ocrelizumab showed significantly improved ACR50 and ACR70 responses of ~3-fold versus placebo. Only those in the ocrelizumab 500 mg group showed statistically significant (P = 0.0017) inhibition of joint damage progression (mean change in the SHS) relative to placebo (61% inhibition) at 48 weeks. Overall adverse events and infections during the 48 weeks of study were comparable in all treatment groups. Serious infections were observed more frequently in patients taking ocrelizumab (5.1% and 4.3%) than in those taking placebo (2.5%). CONCLUSION: Patients in both of the ocrelizumab groups met the clinical primary efficacy end points. Inhibition of change in the SHS was statistically significant at 48 weeks for those in the ocrelizumab 500 mg group. The rate of serious infections in this trial was higher for both ocrelizumab doses as compared with placebo.

Role of self-major histocompatibility complex/peptide ligands in selection and maintenance of a diverse T cell repertoire.

Positive selection has long been thought to be a devise for producing a repertoire of T cells that can efficiently recognize foreign peptides in the context of self-major histocompatibility complex (MHC) molecules. However, in the light of recent evidence that long-term survival of mature T cells requires continuous contact with self-MHC molecules, the possibility for an additional role for positive selection has emerged: to generate a repertoire of T cells that can be maintained in the periphery through contact with self-MHC/peptide ligands. In support of this idea, our recent work suggests that positive selection is highly peptide specific and, more important, that mature T cells require extrathymic contact with the same MHC/peptide ligands that initially induced positive selection in the thymus in order for prolonged survival and to undergo homeostatic proliferation in response to T cell deficiency.

Reliability of reverse transcription-polymerase chain reaction (RT-PCR)-based assays for the detection of circulating tumour cells: a quality-assurance initiative of the EORTC Melanoma Cooperative Group.

Reverse transcription-polymerase chain reaction (RT-PCR)-based assays detecting occult neoplastic cells are increasingly being used for the study of tumour dissemination and minimal residual disease. However, different methods are employed by various research groups and the results are heterogenous. We prospectively assessed the results from nine laboratories performing tyrosinase RT-PCR assays for the detection of melanoma cells on a series of blind samples. After complete analysis, the results were compared for sensitivity and specificity. All laboratories reported correct results for cDNA standards. Five laboratories attained acceptable specificity and a sensitivity detecting 10 cells in 10 ml of whole blood. Four laboratories had unacceptable specificity and/or sensitivity. This blind study highlights the difficulty of RT-PCR data interpretation and the need for quality assurance between laboratories. Measures to increase the reliability of RT-PCR assays are proposed, which have to be prospectively evaluated in future studies.

The effect of glucose and insulin on vagally induced gastrin, bombesin-like immunoreactivity and somatostatin secretion from the perfused rat stomach.

Previous studies in the isolated perfused rat stomach have shown that elevated glucose and insulin concentrations modulate BLI and somatostatin release during arterially administered peptidergic stimuli. In the present study the effect of elevated levels of glucose or insulin was examined on vagally induced changes of gastrin, somatostatin and BLI secretion. The lumen of the stomach was perfused with saline pH 7 or pH 2. Vagal stimulation (5 Hz, 1 msec, 10V) increased gastrin and BLI secretion and inhibited somatostatin release. The increase of the perfusate glucose concentration from 100 mg/dl to 150 or 300 mg/dl or the addition of insulin (100 microU/ml) augmented vagally stimulated gastrin release at luminal pH 7 but not pH2. Vagally induced inhibition of somatostatin was attenuated by both concentrations of glucose at either luminal pH while insulin had no effect. BLI secretion was affected neither by elevated glucose nor by insulin. On the other hand, the noncholinergic component of vagally induced BLI secretion in the presence of atropine was augmented by insulin. These data demonstrate that glucose and insulin can modulate vagally activated gastric neuroendocrine functions which could be of relevance during the ingestion of carbohydrate containing meals.

Preoperative characterization of pigmented skin lesions by epiluminescence microscopy and high-frequency ultrasound.

BACKGROUND AND DESIGN: Previous studies have referred to the value of epiluminescence microscopy in the differential diagnosis of pigmented skin lesions and to the possibility of preoperative tumor thickness measurement in malignant melanoma by high-frequency ultrasound. Both noninvasive methods have been combined in this study. The question of improved diagnostic accuracy was discussed. Previously proposed epiluminescence microscopic characteristics of 508 melanocytic lesions and sonographic characteristics of 792 skin tumors were investigated for their sensitivity and specificity. The tumor thickness of 108 malignant melanomas was measured sonographically. RESULTS: Black dots, irregular pigment network, and grayish-blue areas have been shown to be the most sensitive characteristics, whereas pseudopods, grayish-blue areas, and a whitish veil have been shown to be the most specific epiluminescence microscopic features for malignant melanoma. Sonography alone cannot reliably distinguish between different skin tumors. Preoperatively, the tumor thickness of 85% of the melanomas was assessed correctly concerning the pT stage. CONCLUSIONS: A 20-MHz ultrasound, in addition to epiluminescence microscopy, may improve the diagnostic accuracy by delivering information about depth and topographic location of skin tumors, but cannot give highly specific information about tissue dignity. It is a reliable tool for tumor thickness measurement for surgical planning.

Elevated serum levels of interleukin-10 in patients with metastatic malignant melanoma.

Interleukin-10 (IL-10), originally described as a product of TH2 cell clones, has been recognized as a potential immunosuppressive cytokine. To investigate the relevance of IL-10 in melanoma patients in vivo, we studied IL-10 serum levels in 104 untreated patients in different stages of the disease; 20 healthy subjects and 22 patients with inflammatory dermatoses served as controls. Serum levels were measured by ELISA. Only one of 31 patients with stage I melanoma (3%) and one of 16 stage II patients (6%) showed detectable IL-10 levels. Interestingly, six of 17 patients with lymph node metastases (stage III, 35%) and 29 of 40 patients with widespread disease (stage IV, 73%) revealed IL-10 levels of 15-480 pg/ml. No healthy person and only one control patient had a detectable IL-10 serum level. The data suggest that IL-10 in melanoma patients may contribute to down-modulation of anti-tumour responses in vivo.

Expression of CD30 on T helper cells in the inflammatory infiltrate of acute atopic dermatitis but not of allergic contact dermatitis.

The CD30 molecule has been proposed as a marker for a subset of CD4+CD45RO+ (memory) T cells with potent B cell helper activity producing IL-5 and IFN-gamma and as a specific marker for Th2 cells. Recently, an association has been demonstrated between elevated serum levels of soluble CD30, which is shed by CD30+ cells in vitro and in vivo, and atopic dermatitis but not respiratory atopic disorders or allergic contact dermatitis. We studied the expression of CD30 in the inflammatory infiltrate of atopic dermatitis compared with that of allergic contact dermatitis, with special regard to skin disease activity (acute vs subacute/ chronic). Biopsies were obtained from 16 patients suffering from atopic dermatitis (acute n = 6, subacute/ chronic n = 10), from 7 patients with acute allergic contact dermatitis and from 5 positive patch-test reactions. Paraffin-embedded as well as snap-frozen material was stained with anti-CD30 and anti-CD45RO mAbs according to standard procedures. Double-staining procedures for CD30CD3, CD30CD4, CD30CD45RO and CD30CD68 were also performed. Abundant CD45RO+ cells were detected both in atopic dermatitis and in allergic contact dermatitis lesions. We found scattered CD30+ cells in only one of six formalin-fixed paraffin-embedded acute atopic dermatitis biopsies, but in all of the respective snap-frozen specimens, possibly because CD30 expression on atopic dermatitis infiltrating cells is weak and sensitive to formalin fixation and paraffin embedding. CD30CD3 and CD30CD4 double staining identified CD30+ cells to be helper T lymphocytes. No significant CD30 expression (either in paraffin-embedded or in frozen material) could be found in subacute/chronic atopic dermatitis lesions or in any of the specimens of allergic contact dermatitis. The results suggest a specific regulatory function of CD30+ T cells in acute atopic dermatitis. With respect to the view that CD30 is a marker for Th2 cells, our observations confirm previous findings that Th2 cells predominate in the infiltrate particularly of acute atopic dermatitis. CD30 expression in acute atopic dermatitis but not in acute allergic contact dermatitis might be helpful in the histological differentiation of these disorders and in the further characterization of atopy patch testing.

Differential expression of transforming growth factor beta 1 and interleukin 10 in progressing and regressing areas of primary melanoma.

The coexistence of tumor specific immunity with a progressing tumor remains a major paradox of tumor immunology. This enigma is most evident in partially regressing melanomas, where efficient eradication of tumor cells is closely linked to uncontrolled tumor growth. Mechanisms involved in this differential susceptibility of tumor cells to the host immune response may include altered production of immunosuppressive cytokines, i.e., transforming growth factor (TGF) beta or interleukin (IL) 10. Since only limited amounts of tissue samples are available from primary tumors, a semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) was established which allowed to estimate the amount of cytokine mRNA expressed in a small number of melanoma cells segregated by indirect immunomagnetic isolation. Thereby, we determined the expression of TGF-beta 1 and IL-10 mRNA in melanoma cells obtained from regressing and progressing areas of 9 primary tumors. TGF-beta 1 mRNA could be detected in all undiluted samples from progressing areas and in 7 samples from regression zones. Titration of the sample revealed that in 6 cases TGF-beta 1 mRNA could be detected at a significant higher titer in progressing than in regressing areas. IL-10 mRNA was present in 8 samples obtained from progressing and in 7 samples from regressing tumor areas. In 6 tumors IL-10 mRNA was detectable at a higher titer in the progression zones. Specificity of the PCR amplification was confirmed with a series of restriction enzyme digestions of the resulting PCR product. Based on these findings the hypothesis that immunosuppressive cytokines, such as TGF-beta 1 or IL-10, represent important factors for the melanoma cells to escape immune surveillance is supported.

[Behavior therapy self control in chronic compulsive organismic defective habit development]. / Verhaltenstherapeutische Selbstkontrolle bei chronifiziert-zwanghaften organismischen Fehlgewöhnungen.

Patients with chronic compulsive organismic mishabituations, which are rather difficult to treat, can be helped by self-control methods of behavioural therapy combined with suggestive measures. The author currently regards this therapeutic approach to be superior to aversion therapy, which was occasionally used for such cases in the past. The contribution presents a scheme of therapy which can be generalized and is based on the work of Meichenbaum and Leonhard. The scheme consists of two parts containing four phases each. The actual approach and the modification necessary to tailor it to the individual case is explained by means of an example involving the treatment of psychogenic polydipsia.

[Apparative aversive therapy in combination with verbal suggestions in special obsessional syndromes (initial investigation)]. / Apparative Aversionstherapie in Kombination mit Verbalsuggestionen bei besonderen Zwangssyndromen (Erkundungsuntersuchung).

The author restricts the use of aversion therapy by means of deliberate production of pain to obsessional, especially therapy-resistant disturbances of a permanent nature, with consideration being, of course, given to ethical factors. Experiences worthy of generalization are derived from methodically varied courses of treatment, bringing out suggestive moments subliminally involved in any therapeutical situation and also specifically used by the therapist. In addition, the author emphasizes the need for simultaneously developing, besides aversion therapy, positive attitudes and behavior patterns.

[Evaluation of the efficacy of concomitant special psychotherapeutic methods by patients in an internal medicine clinic]. / Zur Beurteilung der Wirksamkeit begleitender spezieller Psychotherapiemethoden durch Patienten einer internistischen Klinik.

Patients of a medical clinic whose complaints are diagnosed above all as functional are suitably at once also treated by the clinical psychologists. For this purpose the authors created an effective combination of methods. It consists of a group and individual therapy and contains rational and emotional, in addition suggestive and behaviour-therapeutic elements which for each patient are united to an individual concept. For the purpose of the control of efficiency in a particular examination was inquired how the various methods have become effective in the individual patients and which were used preferably, respectively. The inquiry is performed at the earliest half a year after the discharge. Out of 149 answers the most important results are represented and conclusions for practice are derived.

[Psychodiagnostic characteristics of patients with functional cardiovascular disorders]. / Psychodiagnostische Besonderheiten bei Patienten mit funktionellen Herz-Kreislauf-Störungen.

As a contribution to the early recognition in 368 patients with functional disturbances of heart and circulation is examined, whether there are relations between distinguishable groups of complaint syndromes and different degree of neurotisation . Apart from this the characteristics of the symptoms for the adequate complaint syndromes found in the individual diagnosis are summarized to rank series, in which cases different distributions of frequency reveal. Certain parallels to similar investigations of other authors are discussed and conclusions for prophylactic and therapeutic measures are derived.

[Concept of the management of sex deviation (methodology and current results)]. / Ein Behandlungskonzept für sexuelle Deviationen (Methodik und bisherige Ergebnisse).

The problem of bettering sexually deviant persons who have already incurred several penalties is of major importance in social as well as forensic respects. Since the departure from accepted sexual norms is believed by scientists to be due not only to an abnormal disposition, but to distinctive traits acquired at a very early age as well, attempts at treatment with suitable means should not at once be regarded as useless. The authors present a concept that integratevely combines suggestive and behavior-therapeutical methods, that is standardized to a certain extent, and that has yielded encouraging results in addition to being anything but time-consuming. This paper is aimed at colleagues interested in trying to help perfect this concept.

[Videomicroscopy in differential diagnosis of skin tumors and secondary prevention of malignant melanoma]. / Videomikroskopie in der Differentialdiagnose von Hauttumoren und der sekundären Prävention des malignen Melanoms.

During a 12-month period, 824 pigmented skin lesions were examined, and the clinical, videomicroscopic and histological diagnoses were compared. Patients with skin lesions that were difficult to assess were recruited from the outpatient clinic of the department of dermatology within the Technical University of Munich. The study reveals that videomicroscopy as a variation of epiluminescence microscopy much improves diagnostic accuracy, especially of early malignant melanoma, but also with regard to the differentiation between melanocytic and non-melanocytic lesions, is achieved. Furthermore, patients with a high relative risk of developing malignant melanoma, such as patients with multiple naevi, can be scheduled for thorough microscopical controls. The possibility of uncomplicated photographic documentation of a large number of naevi after excision of the suspicious lesions allows valuable periodic follow-ups with macroscopical and microscopical comparison.

[Congenital poikiloderma of the verrucous type in Thomson syndrome with associated myopathy]. / Kongenitale Poikilodermie vom Typus verrucosus des Thomson-Syndroms mit assoziierter Myopathie.

This report deals with a 15-year-old girl suffering from the verrucous type of Thomson's syndrome. Initial poikilodermatous skin changes developed on both cheeks at the age of 3 months. Subsequently, rapid generalization of typical skin findings was observed. The clinical heterogenity of this syndrome is discussed with reference to the existing literature and the present case. Up to now, very few comparable cases of associated neurological symptoms have been described.

Elevated serum levels of soluble CD30 are associated with atopic dermatitis, but not with respiratory atopic disorders and allergic contact dermatitis.

Type 2 helper T-cell immune responses can be demonstrated in the human atopic disorders atopic dermatitis and allergic asthma/rhinoconjunctivitis. The CD30 (Ki-1) antigen, originally described on Hodgkin and Reed-Sternberg cells, has recently been proposed as a marker of T cells with potent B-cell helper activity producing IL-5 and gamma-IFN, as well as on CD4+ and CD8+ T cells with a Th2 cytokine profile. As a soluble form of CD30 (sCD30) is released by CD30+ cells in vivo, we studied its clinical significance in atopic disorders compared with allergic contact dermatitis and healthy controls. Elevated sCD 30 levels were associated with atopic dermatitis (P < 0.0001), but not with respiratory atopic disorders or allergic contact dermatitis. sCD30 levels in patients with atopic-dermatitis were independent of serum IgE. The particular occurrence of serum sCD30 in patients with atopic dermatitis indicates a special regulatory function of CD30+ cells in this disease.

Autologous regulation of naive T cell homeostasis within the T cell compartment.

Naive T cells undergo spontaneous slow proliferation on adoptive transfer into syngeneic T cell (T)-deficient hosts. Recent work has shown that such "homeostatic" T cell proliferation is driven by MHC molecules loaded with self-peptides rather than foreign peptides. Because naive T cells in normal T-sufficient hosts remain in interphase despite continuous contact with self-MHC/peptide ligands, T cells apparently inhibit homeostatic proliferation of neighboring T cells. To address this, we have investigated the requirements necessary for "bystander" T cells to inhibit homeostatic proliferation of other T cells. Three key findings are reported. First, homeostatic proliferation of T cells only occurs in specific microenvironments, namely the T cell compartment of the secondary lymphoid tissues. Second, direct entry into T cell compartments is also required for bystander inhibition of homeostatic proliferation. Third, bystander inhibition is mediated largely by naive rather than activated/memory T cells and does not require proliferation or TCR ligation. These findings suggest that homeostasis of naive T cells is unlikely to be regulated through competition for systemic soluble factors or for specific stimulatory self-MHC/peptide ligands. Rather, the data favor mechanisms that involve competition for local non-MHC stimulatory factors or direct cell-to-cell interactions between the T cells themselves within the T cell compartment.