[Off-label biologic therapy of ANCA-associated and non-ANCA-associated small-vessel vasculitis : Efficacy and safety analysis of a national registry (GRAID2)]. / Off-label-Biologikatherapie von ANCA-assoziierten und nicht-ANCA-assoziierten Kleingefäßvaskulitiden : Wirksamkeits- und Sicherheitsanalyse eines nationalen Registers (GRAID2).

OBJECTIVE: To evaluate the clinical efficacy and safety of off-label biological therapies in patients with ANCA-associated vasculitis (AAV) and non-ANCA-associated small-vessel vasculitis (nAAV) in clinical practice. METHODS: The German Registry in Autoimmune Diseases 2 (GRAID2) is a national, retrospective, non-interventional, multicentre observational study (August 2006 until December 2013) on patients with autoimmune diseases refractory to standard immunosuppressive therapy treated with off-label biologicals. RESULTS: Data from 64 patients (20.6% of all GRAID2 patients) were collected: 54 patients (84.4%) had ANCA-associated vasculitis (AAV) and 10 patients (15.6%) had non-ANCA-associated small-vessel vasculitis (nAAV). Of the AAV patients, 96.3% were treated off-label with rituximab (RTX) and 3.7% with tumor necrosis factor alpha (TNFα)-inhibitors. Of patients with nAAV, 30% were treated with RTX, 60% with TNFα-inhibitors, and 10% with tocilizumab. The main reasons for off-label biological treatment in AAV patients were pulmonary, renal, or ear, nose, and throat involvement. These manifestations clearly improved in most patients after off-label biological therapy was initiated. Daily glucocorticoid dosage could be reduced. The off-label biological therapy was generally well tolerated. In AAV patients, 4.18 severe infections per 100 patient years were observed. There was one death in the nAAV group caused by fungal infection and ileus. A correlation between this fatality and RTX treatment was regarded as possible. CONCLUSION: Safety and efficacy of off-label RTX-treatment in AAV-patients could be assessed in the GRAID2 data. Results point to good efficacy and safety of RTX in this special patient cohort and support the approval of RTX for AAV induction therapy.

[Rituximab for treatment of Felty's syndrome]. / Rituximab zur Therapie des Felty-Syndroms.

Felty's syndrome is a rare variant of severe seropositive rheumatoid arthritis with neutropenia and splenomegaly. It is difficult to treat and associated with a poor prognosis due to the substantial risk of infections. This article presents the case of a patient with refractory disease who responded to rituximab with permanent normalization of neutrophil counts. Repeated infusions were necessary to induce and maintain remission.

[Interleukin-1-mediated diseases]. / Interleukin-1-vermittelte Erkrankungen.

Interleukin-1 (IL-1)-mediated diseases are caused by an inappropriately high production and release of IL-1 beta which results in a multitude of symptoms, e.g. arthritis, exanthema, conjunctivitis, serositis, fever and loss of hearing. If IL-1-mediated diseases remain unrecognized or are recognized and treated too late, long-term complications, such as amyloidosis may occur. In recent years the diagnostic and therapeutic options with respect to IL-1-mediated diseases have drastically improved. These diseases often manifesting in childhood can now be treated with monoclonal antibodies against IL-1 or with IL-1 receptor antagonists. Increased IL-1 secretion does not only play a role in relatively rare hereditary diseases, such as cryopyrin-associated periodic fever syndromes or familial Mediterranean fever but also in widespread diseases, such as gout or type 2 diabetes. This article will focus on pathogenic, diagnostic and therapeutic aspects of IL-1-mediated inflammatory diseases.

[B-cell-directed therapy in patients with connective tissue diseases]. / Anti-B-Zelltherapie bei Kollagenosen.

B cells are able to present antigen, secrete cytokines and differentiate into (auto)antibody secreting cells and are therefore considered as an important therapeutic target in patients with autoantibody-mediated autoimmune disease. Benefits and limitations of B-cell-directed therapies and unmet medical needs are discussed in this minireview. B cell targeting broadens our armamentarium available to treat SLE and other connective tissue diseases. But further research addressing unmet medical needs is required and refractory patients receiving B cell-directed off-label therapeutics should be enrolled in registries to collect information on the value and safety of these drugs in rare autoimmune diseases.

Current state of evidence on 'off-label' therapeutic options for systemic lupus erythematosus, including biological immunosuppressive agents, in Germany, Austria and Switzerland--a consensus report.

Systemic lupus erythematosus (SLE) can be a severe and potentially life-threatening disease that often represents a therapeutic challenge because of its heterogeneous organ manifestations. Only glucocorticoids, chloroquine and hydroxychloroquine, azathioprine, cyclophosphamide and very recently belimumab have been approved for SLE therapy in Germany, Austria and Switzerland. Dependence on glucocorticoids and resistance to the approved therapeutic agents, as well as substantial toxicity, are frequent. Therefore, treatment considerations will include 'off-label' use of medication approved for other indications. In this consensus approach, an effort has been undertaken to delineate the limits of the current evidence on therapeutic options for SLE organ disease, and to agree on common practice. This has been based on the best available evidence obtained by a rigorous literature review and the authors' own experience with available drugs derived under very similar health care conditions. Preparation of this consensus document included an initial meeting to agree upon the core agenda, a systematic literature review with subsequent formulation of a consensus and determination of the evidence level followed by collecting the level of agreement from the panel members. In addition to overarching principles, the panel have focused on the treatment of major SLE organ manifestations (lupus nephritis, arthritis, lung disease, neuropsychiatric and haematological manifestations, antiphospholipid syndrome and serositis). This consensus report is intended to support clinicians involved in the care of patients with difficult courses of SLE not responding to standard therapies by providing up-to-date information on the best available evidence.

[Patient/rheumatologist evaluation of infusion treatment for rheumatoid arthritis]. / Bewertung einer Infusionbehandlung der rheumatoiden Arthritis durch Patienten und Rheumatologen.

OBJECTIVES: The various biologic agents currently available for the treatment of RA can be administered subcutaneously (s.c.) or via intravenous (i.v.) infusion with variable intervals depending on the drug. This investigation aims to identify the preferences and concerns of affected patients and their physicians. METHODS: We conducted a survey of 102 patients with RA currently receiving Rituximab (RTX) therapy. They were asked about different aspects of their current and previous RA therapy, including overall satisfaction, tolerability, mode of drug administration, as well as duration and intervals. In addition, 17 rheumatologists were asked about different aspects of s.c. or i.v. drug administration, their preference and the suspected preference of their patients. RESULTS: The mean age of our patients was 59 ± 11.2 years. Patients had failed ≥2 DMARD therapies and ≥ 1 biologic treatment. The impact of RTX infusions on planning different activities including job, hobbies or travelling was considered as low or very low in 76% of the respondents. Interestingly, 63.4% of patients would prefer an infusion every 6-9 months as RA therapy, whereas 21.5% would prefer tablets only; 12.9% of our patient cohort would prefer s.c. injections every second week, and only 2% would prefer an infusion every month. In all, 92% of patients questioned would choose RTX therapy again. In contrast, 88% of rheumatologists preferred s.c. injection and even 94% of them assumed that their patients would do so as well if they had the choice. The suggested reasons included greater flexibility, convenience and independence during s.c. therapy. CONCLUSION: Contrary to the assumption of rheumatologists, we have demonstrated a preference among RTX patients for i.v. drug administration every 6-9 months over other methods of administration.

HLA-DRhigh/CD27high plasmablasts indicate active disease in patients with systemic lupus erythematosus.

OBJECTIVES: Monitoring of peripheral B-cell subsets in patients with systemic lupus erythematosus (SLE) revealed an activity-related expansion of CD27(++)CD20(-)CD19(dim) Ig-secreting cells. A similar subset has also been identified 6-8 days after tetanus/diphtheria vaccination in normal individuals and in patients with infectious disease. METHODS: This subset was analysed further focussing on the HLA-DR surface expression in a cohort of 25 patients with SLE. RESULTS: This study revealed that 86% (range 59-97%) of CD27(++)CD20(-)CD19(dim) cells express high levels of HLA-DR, are also expanded in the bone marrow, and represent plasmablasts enriched with anti-dsDNA secreting cells. The remaining CD27(++)CD20(-)CD19(dim) cells were HLA-DR(low) and represent mature plasma cells. Importantly, HLA-DR(high) plasmablasts showed a closer correlation with lupus activity and anti-dsDNA levels than the previously identified CD27(++)CD20(-)CD19(dim) cells. CONCLUSION: HLA-DR(high)CD27(++)CD20(-)CD19(dim) plasmablasts represent a more precise indicator of lupus activity and suggest that there is an overproduction or lack of negative selection of these cells in SLE.

Peripheral B cell abnormalities and disease activity in systemic lupus erythematosus.

Autoreactive B cells and plasma cells appear to be of central importance in the pathogenesis of systemic lupus erythematosus (SLE) characterized by a plethora of autoantibodies. Recent insights into abnormalities of B cell and plasma cell compartments in human SLE have identified a number of cellular disturbances within these compartments that in part correlate with the disease activity. This review discusses these findings and the potential underlying extrinsic and/or intrinsic influences apparently driving general B cell activation in this entity.

Wetting phenomena on micro-grooved aluminum surfaces and modeling of the critical droplet size.

The behavior of water droplets on aluminum surfaces with parallel grooves tens of microns in width and depth is considered, and a mechanistic model is developed for predicting the critical droplet size-droplets at incipient sliding due to gravity. The critical droplet size is nearly 50% smaller on micro-grooved surfaces than on the same surface without micro-grooves. The application of existing models fails to predict this behavior, and a new model based on empiricism is developed. The new model provides reasonable predictions of the critical droplet size for a given inclination angle, advancing contact angle, and maximum contact angle. When the grooves are aligned parallel to gravity, the maximum apparent contact angle does not occur at the advancing front but rather along the side of the droplet because of contact-line pinning. Droplets on these surfaces are elongated and possess a parallel-sided base contour shape. Novel data are provided for droplets in a Wenzel state, a Cassie-Baxter state, and combined state on micro-grooved surfaces, and the ability of the empirical model to handle these variations is explored. These findings may be important to a broad range of engineering applications.

Differential effects of epratuzumab on peripheral blood B cells of patients with systemic lupus erythematosus versus normal controls.

OBJECTIVE: B lymphocytes have been implicated in the pathogenesis of lupus and other autoimmune diseases, resulting in the introduction of B cell-directed therapies. Epratuzumab, a humanised anti-CD22 monoclonal antibody, is currently in clinical trials, although its effects on patients' B cells are not completely understood. METHODS: This study analysed the in vivo effect of epratuzumab on peripheral B cell subsets in 12 patients with systemic lupus erythematosus, and also addressed the in vitro effects of the drug by analysing anti-immunoglobulin-induced proliferation of isolated B cells obtained from the peripheral blood of 11 additional patients with lupus and seven normal subjects. RESULTS: Upon treatment, a pronounced reduction of CD27(-) B cells and CD22 surface expression on CD27(-) B cells was observed, suggesting that these cells, which mainly comprise naïve and transitional B cells, are preferentially targeted by epratuzumab in vivo. The results of in vitro studies indicate additional regulatory effects of the drug by reducing the enhanced activation and proliferation of anti-immunoglobulin-stimulated lupus B cells after co-incubation with CD40L or CpG. Epratuzumab inhibited the proliferation of B cells from patients with systemic lupus erythematosus but not normal B cells under all culture conditions. CONCLUSIONS: Epratuzumab preferentially modulates the exaggerated activation and proliferation of B cells from patients with lupus in contrast to normal subjects, thus suggesting that epratuzumab might offer a new therapeutic option for patients with systemic lupus erythematosus, as enhanced B cell activation is a hallmark of this disease.

Retention forces and contact angles for critical liquid drops on non-horizontal surfaces.

Retention forces and drop parameters are investigated for drops on the verge of sliding on vertical and inclined surfaces. Using earlier observations of drop geometry, the retentive-force factor relating surface-tension forces to contact-angle hysteresis is reliably determined. The retention force for a drop is found to be insignificantly affected by the aspect ratio of its contour. The maximum size of a drop is predicted with good accuracy, based on the two-circle method for approximating shapes of drops. The Bond number of a critical drop is found to be constant for a given surface and liquid. A general relation is proposed between the characteristic advancing and receding contact angles. The relation is supported by a large set of contact-angle data. In the absence of theta R data, the relation allows estimating the receding contact angle and the critical drop size, using only the advancing angle.

Dissemination of a Sjögren's syndrome-associated extranodal marginal-zone B cell lymphoma: circulating lymphoma cells and invariant mutation pattern of nodal Ig heavy- and light-chain variable-region gene rearrangements.

OBJECTIVE: Both the genesis and outgrowth of extranodal marginal-zone B cell lymphomas (MZLs) of the mucosa-associated lymphoid tissue (MALT) type are generally thought to represent antigen-driven processes. We undertook this study to analyze lymphoma progression and dissemination outside of the MALT-type lesions. METHODS: Histopathologic and Ig heavy- and light-chain variable-region gene (V(H/L)) analyses were performed in sequential tissue samples from a patient with primary Sjögren's syndrome (SS) with glandular (parotid) manifestations and subsequent nodal dissemination of a low-grade MZL. RESULTS: This MZL expressed a CD20+,CD27+,sIgM/kappa+,IgD-,CD5-,CD10-,Bcl-6-,CD23-,p53-,p21-,MDM2- phenotype and mutated V(H)1-69/D2-21/J(H)4alpha-V(kappa)A27/J(kappa)2 Ig rearrangements. Notably, circulating lymphoma cells from the parotid glands occurred transiently in the patient's blood, as detected by single-cell polymerase chain reaction. In addition, 2 minor B cell clones (clones 2 and 3, with V(H)3-07/D3-22/J(H)3b-V(lambda)3L/J(lambda)2/3 and V(H)3-64/D3-03/J(H)2-V(kappa)A19/J(kappa)2 rearrangements, respectively) were also detected in the parotid glands and blood, and 1 of these (clone 2) was also detected in the lymph nodes. Ig V(H/L) analyses revealed ongoing (antigen-driven) mutations of the glandular lymphoma rearrangements, but an invariant mutation pattern of their nodal counterparts. CONCLUSION: These data indicate coexpansion and transient (re)circulation of the lymphoma clone and 2 additional glandular B cell clones in a primary SS-associated extranodal MZL. Combined histologic and molecular features of the nodal lymphoma subclone reflect a process of "follicular colonization" that eventually froze the mutation machinery after accumulation of additional (antigen-driven) Ig V(H/L) mutations.

Liquid drops on vertical and inclined surfaces; I. An experimental study of drop geometry.

Experiments have been conducted to investigate the geometric parameters necessary to describe the shapes of liquid drops on vertical and inclined plane surfaces. Two liquids and eight surfaces have been used to study contact angles, contact lines, profiles, and volumes of drops of different sizes for a range of surface conditions. The results show the contact-angle variation along the circumference of a drop to be best fit by a third-degree polynomial in the azimuthal angle. This contact-angle function is expressed in terms of the maximum and minimum contact angles of the drop, which are determined for various conditions. The maximum contact angle, thetamax, is approximately equal to the advancing contact angle, thetaA, of the liquid on the surface. As the Bond number, Bo, increases from 0 to a maximum, the minimum contact angle, thetamin, decreases almost linearly from the advancing to the receding angle. A general relation is found between thetamin/thetaA and Bo for different liquid-surface combinations. The drop contour can be described by an ellipse, with the aspect ratio increasing with Bo. These experimental results are valuable in modeling drop shape, as presented in Part II of this work.

Liquid drops on vertical and inclined surfaces; II. A method for approximating drop shapes.

In this article, a new method is proposed to approximate the shapes of liquid drops on vertical and inclined surfaces. Based on observations from Part I, the profile of a drop at a given azimuthal angle is approximated by two circles sharing a common tangent at the maximum height. The drop volume is obtained by integrating all profiles over the circumference of the base. The volume is thus described as a function of the contact angles and the three-phase contact line. The new method accurately predicts the volumes of drops tested in Part I and independent measurements from the literature. Simplifying the drop shape to a spherical cap can lead to a 75% error in drop-volume prediction. The proposed method is used to study the effect of drop parameters on volume prediction. The two-circle geometry can also be used to measure contact angles from profile images.

Enhanced serum prolactin (PRL) in patients with systemic lupus erythematosus: PRL levels are related to the disease activity.

Recent accumulated evidence suggests that prolactin (PRL) is an important immunomodulator and plays a part in the pathogenesis of systemic lupus erythematosus (SLE). The current study assessed the frequency of hyperprolactinaemia in patients with SLE and its association with defined clinical manifestations or serological abnormalities. PRL levels were analysed in 60 patients with SLE including a follow-up of 20 patients, 18 patients with rheumatic autoimmune diseases other than SLE (AID) and in 47 normal healthy subjects (NHS) using ELISA. Clinical manifestations and disease activity (ECLAM) were recorded. Autoantibodies (anti-dsDNA, anti-CL) were determined by standard techniques. In all, 28.3% of the patients with SLE had raised serum PRL. Their PRL levels (17.4+/-15.1 ng/ml, P<0.0001) and those of patients with AID (13.1+/-10.3 ng/ml, P<0.001) were significantly higher compared to NHS (6.3+/-3.2 ng/ml). Anti-dsDNA (r(s) = 0.3, P = 0.04) and anti-CL antibody titres (IgG; r(s) = 0.3, P = 0.03) correlated with PRL level. Furthermore, elevated erytthrocyte sedimentation rate (ESR), anaemia, decrease in C3, fatigue, fever and renal involvement were associated with hyperprolactinaemia. These results were confirmed by follow-up examinations. Moderate hyperprolactinaemia is present in a subset of patients with SLE and serum PRL correlates with clinical and serological disease activity.

Prolactin enhances the in vitro production of IgG in peripheral blood mononuclear cells from patients with systemic lupus erythematosus but not from healthy controls.

OBJECTIVES: Recent evidence suggests that prolactin (PRL) plays a part in the pathogenesis of systemic lupus erythematosus (SLE). Because B cell hyperreactivity and autoantibodies are characteristic hallmarks of SLE, this study aimed at assessing the impact of this pituitary hormone on IgG production by stimulating peripheral blood mononuclear cells (PBMC) with PRL. METHODS: PBMC from 11 patients with SLE assessed by the ECLAM score and eight healthy controls were incubated with PRL and cultured for seven days. IgG production was measured by enzyme linked immunosorbent assay (ELISA). RESULTS: Spontaneous IgG production of SLE PBMC was significantly enhanced compared with that found in healthy controls. After PRL stimulation, the IgG concentrations of supernatants from SLE PBMC were significantly higher than those of unstimulated PBMC (median 394 ng/ml). Of note, the physiological concentration of PRL (20 ng/ml) induced IgG production more effectively (median 1139 ng/ml) than PRL at 100 ng/ml (median 1029 ng/ml). In contrast, preincubation with PRL did not stimulate IgG production in normal PBMC. A significant correlation between PRL induced IgG production and the disease activity (ECLAM) of the patients with SLE was seen. Moreover, the maximum amount of PRL induced IgG depended on the serum PRL concentrations of the patients with SLE. CONCLUSIONS: The results suggest that PBMC from patients with SLE have an extraordinarily high susceptibility to PRL, showing the most striking effect at a concentration usually found in vivo. This indicates a potential role for mild hyperprolactinaemia in the pathogenesis of SLE, influencing both IgG production and disease activity.

Enhanced mutational activity and disturbed selection of mutations in V(H) gene rearrangements in a patient with systemic lupus erythematosus.

To determine the impact of somatic hypermutation and selective influences on the V(H) gene repertoire in SLE, the mutational frequency and pattern of mutations in nonproductively and productively rearranged V(H) genes obtained from genomic DNA of individual CD19+ B cells were analyzed in a patient with SLE. The mutational frequencies of nonproductive (6.54 x 10(-2)) as well as of productive (4.38 x 10(-2)) V(H) rearrangements were significantly higher in the SLE patient than in normal controls (3.8 x 10(-2), p<0.001 and 3.3 x 10(-2); p<0.001, respectively). Analysis of nonproductive rearrangements documented only minor abnormalities of the targeting of the mutator in the SLE patient. The majority of "mutational hot spots", although different than in normals, appeared in the CDRs and an increased frequency of mutations in RGYW/WRCY sequences was observed. Moreover, no biases in base pair changes were found in the nonproductive repertoire. In contrast, there was a selection against A and T mutations and towards G mutations within the productive repertoire. Importantly, there were no significant differences in the R/S ratios of mutations within the FRs between the nonproductive and productive repertoire consistent with abnormalities in elimination of B cells expressing V(H) genes with these mutations. The result of this abnormality was a significantly higher R/S ratio of the V(H)genes in the productive repertoire of the SLE patient compared to normals (p<0.05). These data indicate that the mutational machinery was markedly enhanced in this SLE patient but exhibited nearly normal targeting, whereas selective influences were abnormal. These findings suggest that both enhanced mutational activity and disturbances in selection may have played a role in the emergence of autoreactivity in this SLE patient.

Postpartum depression in the breastfeeding mother.

This article reviews the literature discussing postpartum depression and lactation, noting that most studies are plagued by definitional problems relating to feeding group purity and lack of clarity regarding the definition of depression. The implications for nurses when they are asked to care for a breastfeeding mother with postpartum depression are identified and discussed, with special attention paid to the importance of maintaining and/or supporting the maternal role. Decision-making relating to interruption or continuation of breastfeeding as a result of psychotropic drug therapy is discussed.