Successful long-term systemic sclerosis treatment by high-frequent low-dose B cell-depleting therapy.

OBJECTIVES: Systemic sclerosis (SSc) is a multiorgan disease with a 10-year mortality rate of up to 50 %. B cell-depleting therapy with rituximab (RTX) appears effective in SSc treatment, but data from randomized controlled trials (RCTs) are lacking, and the frequency and dosage of RTX in SSc have no consensus. We aimed to evaluate the long-term efficacy and safety of quarterly RTX administration in SSc. METHODS: This study retrospectively analyzed 40 patients with SSC treated with RTX twice within 14 days every 3 months from 2010 to 2020. The patients fulfilled the LeRoy and the American College of Rheumatology/European League Against Rheumatism Criteria for SSc. Modified Rodnan skin score (mRSS), lung function test results, and serum immunoglobulin (IgG, IgA, and IgM) concentrations were analyzed. RESULTS: A total of 40 patients with SSc received RTX over a median time of 3.9 years (range: 1-10 years). The median mRSS (baseline: 19, 24 months: 16, p < 0.001) demonstrated a significant improvement, and the predicted forced vital capacity was stable. No new or unexpected safety signals, especially regarding treatment-related infectious adverse events, were observed. Immunoglobulin concentrations were within normal range, and specific antibodies to pneumococcal polysaccharides were preserved despite long-term B cell-depleting therapy. None of the patients died during the observation period of up to 10 years. CONCLUSION: SSc was effectively and safely treated with low-dose RTX quarterly. RCTs are warranted to validate the advantage of continuous B cell depletion by quarterly low-dose RTX administration compared to other treatment intervals.

[Common German language nomenclature for systemic sclerosis]. / Gemeinsame deutschsprachige Nomenklatur für die systemische Sklerose.

Large data bases and the projects arising from them have led to a much improved understanding of systemic sclerosis over the last decade. Serology has developed further so that more autoantibodies are available for routine testing. Capillary microscopy has become standard and relevant progress has also been made in therapy. Many diagnostic terms found in medical documentation do not adequately reflect this progress. The nomenclature is inconsistent and, therefore, confusing. The international classification of diseases (ICD) nomenclature is, from our point of view, also in need of improvement. This article aims to reestablish a common German language standard for systemic sclerosis, which reflects current knowledge and is suitable for implementation in the clinical routine.

Ultrasound screening for interstitial lung disease in rheumatoid arthritis.

OBJECTIVES: As interstitial lung disease (ILD) in rheumatoid arthritis (RA) patients is associated with increased mortality due to loss of diffusion capacity and pulmonary hypertension, regular screening for structural abnormalities of the lung is advised. In addition to standard radiological examination with computed x-ray tomography, ultrasound of the lung could allow non-invasive and radiation-free structural monitoring of the lung. The objective of this study was to test the frequency of abnormalities in lung sonography in patients with RA who did not have clinical signs or symptoms of lung disease. METHODS: In a prospective study of 64 consecutive patients with rheumatoid arthritis and 40 healthy volunteers, we screened the pleura and the pulmonary parenchyma for sonographic abnormalities. All RA patients underwent high resolution computer tomography of the lung. RESULTS: 28% of RA patients showed pleural nodules or B-line phenomena. In these patients, CT scans showed signs of incipient interstitial lung disease. Lung sonography showed sporadic abnormalities in 7% of the healthy controls. CONCLUSIONS: Transthoracic ultrasound of the lung is an inexpensive and safe tool to screen patients with RA for incipient pulmonary structural changes.

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.

The kappa-deleting element. Germline and rearranged, duplicated and dispersed forms.

Human light chain genes are used in a kappa before lambda order. Accompanying this hierarchy is the rearrangement of a kappa-deleting element (Kde) which eliminates the kappa locus before lambda gene rearrangement. In approximately 60% of rearrangements the Kde recombines at a conserved heptamer within the J kappa-C kappa intron. We demonstrated that aberrant V/J rearrangements possessing apparent "N" nucleotides existed 5' to the J kappa-Kde rearrangements. This suggests that the Kde may selectively eliminate nonfunctional V/J alleles. A kappa-producing cell that displayed the unusual finding of lambda gene rearrangement demonstrated a rearranged Kde. This rearrangement was a V kappa/Kde recombination and the heptamer-11 bp spacer-nonamer flanking the V kappa is the target site of the Kde 40% of the time. The mouse possesses a counterpart to the Kde (recombining sequence [RS]) and the highly conserved regions surround the heptamer-spacer-nonamer signals. No complete protein product was predicted from the germline Kde near its break-point and no consistent fusion product was predicted from either the V/Kde or V/J-Kde rearrangements. A distal portion of the Kde is duplicated and is present at 2q11 as well as 2p11. The evolutionary conservation of the kappa-elimination event, the duplication and maintenance of the Kde indicates that it has a function. A portion of the Kde may still prove to encode a trans-acting factor that directly affects lambda rearrangement. A certain role for the Kde is its site-specific rearrangement, which destroys ineffective kappa genes and sets the stage for lambda gene utilization.

Hepatotoxicity of antibacterials: Pathomechanisms and clinical.

Drug-induced hepatotoxicity is a frequent cause of liver disease and acute liver failure, particularly in patients treated with multiple drugs. Several antibacterial drugs have the potential to cause severe liver injury and failure. This article aims to increase the awareness and understanding of drug induced liver injury (DILI) due to antibacterial drugs. It reviews the pattern of antibacterial DILI and provides details on molecular mechanisms and toxicogenomics, as well as clinical data based on epidemiology studies. Certain antibacterial drugs are more frequently linked to hepatotoxicity than others. Therefore, the hepatotoxic potential of tetracyclines,sulfonamides, tuberculostatic agents, macrolides, quinolones,and beta-lactams are discussed in more detail. Efforts to improve the early detection of DILI and the acquisition of high-quality epidemiological data are pivotal for increased patient safety.

Superior specificity of anti-citrullinated peptide antibodies in patients with chronic lymphocytic leukemia and arthritis.

OBJECTIVES: Sera from patients with lymphoid neoplasias contain rheumatoid factors (RF) so often that RF are of limited use for diagnosing arthritis in lymphoma patients. Antibodies against citrullinated peptides (ACPA) might be helpful in distinguishing between true RA and rheumatoid factor-positive conditions with arthritis. We compared the specificity of RF and of ACPA for the diagnosis of RA in patients with B-cell chronic lymphocytic leukemia (CLL). METHODS: One hundred and seven patients with CLL without any clinical signs of arthritis and five patients with RA and concomitant CLL were included in the investigation. Serum samples were tested for RF-isotypes IgM, IgG and IgA. ACPA were determined with an ELISA that detects anti-cyclic citrullinated peptide (aCCP) antibodies. RESULTS: RF well beyond the cut-off levels were detected in 50% of the CLL patients without RA. The isotype distribution was 41% IgM-RF, 20% IgG-RF and 3% IgA-RF. None of the 107 CLL patients without arthritis had Accp antibodies. Within the whole cohort of CLL patients the specificity for the diagnosis of RA was 100% for aCCP antibodies and 59% for IgM-RF. CONCLUSIONS: Only aCCP antibodies but not IgM-, IgG- or IgA-RF are useful for the diagnosis of RA in patients with CLL.

[Immunomodulatory therapy improves quality of life with rheumatoid arthritis]. / Die immunmodulierende Therapie verbessert die Lebensqualität bei rheumatoider Arthritis.

Pain, fatigue as well as functional and social impairments reduce the health-related quality of life in rheumatoid arthritis patients. Using numeric evaluations and qualitative questionnaires, it could be shown in both controlled drugs trials and in practice registries that modern drug therapy achieves an improvement in terms of quality of life (as well as in other patient-related treatment results). However, the improvements often do not achieve even the average quality-of-life levels seen in healthy people.

Recruitment of Mycobacterium tuberculosis specific CD4+ T cells to the site of infection for diagnosis of active tuberculosis.

UNLABELLED: Accurate and early diagnosis of active tuberculosis (TB) is problematic as current diagnostic methods show low sensitivity (acid-fast bacilli smears), are time-consuming (culture of biological samples) or show variable results [Mycobacterium tuberculosis (MTB)-specific PCR]. OBJECTIVES: In the course of infection, MTB-specific T cells clonally expand at the site of infection and may thus be used as diagnostic marker for active disease. DESIGN: In this cohort study, the frequency of MTB-specific, interferon (IFN)-gamma expressing CD4(+) T cells obtained from peripheral blood and the site of disease in 25 patients with suspected TB was assessed (n = 11, bronchoalveolar lavage; n = 7, pleural fluid; n = 1, ascites; n = 1, joint fluid; n = 5, cerebrospinal fluid). RESULTS: Amongst 15 patients who showed proven active TB infection, a striking increase of MTB-specific T cells was detected at the site of infection compared with peripheral blood (median increase: 28.5-fold, range: 7.25-531 fold; median of IFN-gamma-producing CD4(+) T cells from blood: 0.02%, range: 0-0.52%; median of IFN-gamma-producing CD4(+) T cells from the site of infection: 1.81%, range: 0.29-6.55%, P < 0.001). MAIN OUTCOME MEASURE: Recruitment of MTB-specific T cells to the site of infection yielded a sensitivity of 100% and specificity of 90%, irrespective of the compartment affected. CONCLUSIONS: The accumulation of MTB-specific T cells at the site of infection may prove as useful diagnostic marker for an accurate and rapid diagnosis of active TB.

IL10R1 loss-of-function alleles in rheumatoid arthritis and systemic lupus erythematosus.

OBJECTIVE: IL-10 is a pleiotropic cytokine involved in the regulation of innate and cell-mediated immunity and a key mediator within the disturbed SLE immune system. IL-10 binds to IL10R1, which is expressed on a variety of immune cells and activates the JAK-STAT pathway. Two (out of several known) genetic IL10R1 variants may alter IL-10 binding or signal transduction. Here we investigate the differential activity of these IL10R1 variants and their possible association with RA or SLE susceptibility. METHODS: IL10R1-wt, IL10R1-S138G, IL10R1-G330R, or IL10R1- S138G +G330R were cloned into pIRESpuro3 and transfected into HeLa cells. Single cell clones were tested for IL-10-induced SOCS3- and SLAM gene expression by real-time PCR. DNA from 182 RA patients, 222 SLE patients, and 250 healthy controls was genotyped by allele-specific PCR. RESULTS: A biphasic increase of SOCS3 mRNA was observed that peaked at 15 minutes and 4 hours after IL-10 stimulation. The presence of IL10R1 S138G and G330R showed a weaker induction of both SOCS3 and SLAM upon stimulation with IL-10. In RA a homozygous G330R genotype was more commonly present than in controls (15.4% vs. 7.6%; p<0.05). In SLE the G330R allele frequency was also increased (36.3% vs. 30.0%; p<0.05) without showing a gene-dose relationship at the genotype level. CONCLUSIONS: Based on these results, both variants of the IL10R1 gene are loss-of-function alleles. IL10R1 G330R may possibly contribute to RA or SLE disease susceptibility in Caucasian populations.

Aymptomatic CMV viremia is associated with increased levels of serum amyloid A in patients with advanced HIV-infection.

OBJECTIVE: We evaluated assays for the measurement of acute phase protein levels in plasma for their usefulness to identify sensitively an inflammatory response to active cytomegalovirus CMV infection in HIV-infected patients. METHODS: Plasma samples were collected from 28 CMV-seropositive patients with advanced HIV-infection (CD4-cell count <200/microl) before commencement of antiretroviral therapy. Sensitivity, specificity, and area under receiver operating characteristic curve for the selected acute phase protein assays (haptoglobin, fibronectin, high-sensitivity C-reactive protein (hs-CRP), human interleukin-6, serum amyloid A (SAA), and human lipopolysacharide binding protein) were compared with results of a CMV-specific PCR assay. RESULTS: CMV viremia was detectable in 8/28 patients. Levels of SAA correlated well with those of hs-CRP (r' = 0.439, P = 0.019 (Spearman rank correlation)). Levels of SAA >3 mg/L discriminated with 100% sensitivity and 40% specificity between HIV-infected patients with and without active CMV infection. Sensitivity of fibronectin was 100% and specificity 15% at a threshold-value corresponding with the lower limit of normal values as defined by the manufacturer of the assay (>29 mg/dL). Levels of the other acute phase proteins evaluated did not correlate with detection of CMV-DNA in plasma. CONCLUSION: Increased levels of SAA indicate sensitively an inflammatory response to active CMV infection. Use of a CMV-specific virological assay is required to confirm the specificity of a high SAA-level but may be limited to samples with high SAA-levels. Hence, screening for increased levels of SAA in patients with advanced HIV-infection may allow early identification of active CMV infection.

Expression of Bcl-2 and Bcl-2-Ig fusion transcripts in normal and neoplastic cells.

We examined the expression of the Bcl-2 gene at chromosome segment 18q21, that is translocated into the Ig heavy chain gene locus in t(14;18) bearing lymphomas. Bcl-2, while B cell associated, is expressed in a variety of hematopoietic lineages including T cells. Bcl-2 mRNA levels are high during pre-B cell development, the time at which the t(14;18) translocation occurs, but are down regulated with maturation. Like certain other oncogenes, Bcl-2 is quiescent in resting B cells but up-regulated with B cell activation. Mature B cell lymphomas with a t(14;18) have log-folds more mRNA than matched counterparts without the translocation. A sensitive S1 protection assay revealed that all transcripts in t(14;18) B cells were Bcl-2-Ig fusion mRNAs and originated from the translocated allele. Thus, there is a marked deregulation of Bcl-2 when it is introduced into the Ig locus in t(14;18) lymphomas.

Deficiency of the autologous mixed lymphocyte reaction in patients with classic hemophilia treated with commercial factor VIII concentrate. Correlation with T cell subset distribution, antibodies to lymphadenopathy-associated or human T lymphotropic virus, and analysis of the cellular basis of the deficiency.

14 patients with hemophilia were studied for the distribution of T cell subsets, the presence of antibody to lymphadenopathy-associated or human T lymphotropic virus type III (LAV/HTLV-III), and their responsiveness in autologous mixed lymphocyte reactions. In addition, mitogen and alloantigen responsiveness and Interleukin-2 production were investigated. Seven patients were found to have low Leu 3a/Leu 2a (T4/T8) ratios; eight patients had antibody to LAV/HTLV-III; and an additional patient had acquired immunodeficiency syndrome. Responsiveness to mitogens and alloantigens as well as Interleukin-2 production were comparable with those of healthy individuals. However, patients with low ratio, many of whom had antibodies to LAV/HTLV-III, had a highly deficient autologous mixed lymphocyte reaction. This reduced response of T cells to autologous non-T cells could not be corrected by elimination of Leu 2a/T8 cells, which indicated that there was a preferential loss of the Leu 3a cell subset(s) which responded to autologous non-T cells. Thus, these patients have a deficiency of intercellular communication within their immune system.

Changing pattern of candidaemia 2001-2006 and use of antifungal therapy at the University Hospital of Vienna, Austria.

A retrospective survey of candidaemia between 2001 and 2006 was performed at the University Hospital of Vienna, a 2200-bed centre with large organ transplantation and haematology-oncology units. The incidence rate of Candida spp. in blood cultures increased from 0.27 cases/1000 admissions in 2001 to 0.77 cases/1000 admissions in 2006 (p <0.005). The incidence of candidaemia caused by Candida albicans and by non-albicans Candida spp. both increased during this period; although there was a trend towards an increased incidence (37%) of non-albicans Candida spp., particularly Candida glabrata, in surgical wards, C. albicans remained the predominant pathogen (63%). In the haematology-oncology unit, C. albicans remained the leading pathogen (23/29 isolates, 79%), followed by Candida tropicalis and C. glabrata (2/29, 7% each), Candida sake and Candida lusitaniae (1/29, 3% each). The overall survival rate was 43.8%, ranging from 32.8% in 2004 to 63.6% in 2002. In total, 108 (33.2%) patients died within 4 weeks of the first isolation of Candida spp. from blood; 58 (54%) of these patients died within the first 7 days, and a further 34 patients died within the next 3 months. Fluconazole was used extensively (24 701.5 defined daily doses), followed by amphotericin B (8981.4 defined daily doses), during 2005. The consumption of antifungal agents increased continuously (p <0.05) because of increased use of voriconazole and caspofungin. Although the numbers of susceptible patients remained unchanged, the net increase in the number of cases of candidaemia warrants a re-evaluation of the risk-factors and the use of improved diagnostic procedures for invasive fungal infections.

Effects of tigecycline, linezolid and vancomycin on biofilms of viridans streptococci isolates from patients with endocarditis.

BACKGROUND: Endocarditis, and prosthetic valve endocarditis in particular, is a serious disease with high morbidity and mortality. We investigate the effects of tigecycline, linezolid and vancomycin on biofilms of viridans group streptococci (VGS) isolated from patients with definite native or prosthetic valve endocarditis. METHODS AND RESULTS: Ten of 20 VGS blood stream isolates from patients with endocarditis formed biofilms in the microtiter plate biofilm model. The minimal inhibitory concentrations (MIC) for tigecycline, linezolid and vancomycin were determined using the microdilution broth method. Biofilms were grown for 24 hours and were incubated with tigecycline, linezolid and vancomycin at increasing concentrations from 1-128x MIC of the isolate being tested. Biofilm thickness was quantified by measuring the optical density (OD) after dyeing it with crystal violet. The incubation of the biofilms with tigecycline, linezolid or vancomycin resulted in a significant reduction of OD compared to the control biofilm without antibiotic (p<0.05). The optical density ratio (Odr) decreased significantly at 2x MIC for tigecycline, and at 8x MIC for linezolid and vancomycin (p<0.05). Although biofilms persisted even at the highest antibiotic concentrations of 128x MIC, bacterial growth was eradicated starting at concentrations of 16x MIC for vancomycin and of 32x MIC for linezolid, but not for tigecycline, up to a concentration of 128x MIC. CONCLUSIONS: In the present study on viridans streptococci isolated from patients with endocarditis, tigecycline and linezolid reduced the density of the biofilms as effectively as vancomycin. However, linezolid and vancomycin were bactericidal at higher concentrations. Linezolid and vancomycin at very high doses may be useful in the treatment of biofilm-associated diseases caused by VGS infections.

Intravenous fosfomycin-back to the future. Systematic review and meta-analysis of the clinical literature.

OBJECTIVES: We conducted a systematic review and meta-analysis to summarize the clinical evidence and usage patterns of intravenous fosfomycin from its development to the present time. METHODS: PubMed, the Cochrane Library and local journals were searched for relevant studies reporting aggregated data of intravenous fosfomycin use in adults and children, with no restrictions regarding study design. Single case reports were excluded. Data were systematically abstracted for all included studies. Clinical and microbiological efficacy from randomized controlled and comparative observational studies were synthesized using meta-analysis to calculate pooled effect sizes. RESULTS: In all, 128 studies on intravenous fosfomycin in 5527 patients were evaluated. Fosfomycin was predominantly used for sepsis/bacteraemia, urinary tract, respiratory tract, bone and joint, and central nervous system infections. No difference in clinical (OR 1.44, 95% CI 0.96-2.15) or microbiological (OR 1.28, 95% CI 0.82-2.01) efficacy between fosfomycin and other antibiotics was observed in comparative trials. The pooled estimate for resistance development during fosfomycin monotherapy was 3.4% (95% CI 1.8%-5.1%). Fosfomycin showed a favourable safety profile, with generally mild adverse events not requiring discontinuation of treatment. Included studies explored intravenous fosfomycin as an anti-staphylococcal agent in monotherapy and combination therapy, whereas studies from 1990 focused on combination therapy (fosfoymcin + ß-lactams or aminoglycosides) for challenging infections frequently caused by multidrug-resistant organisms. CONCLUSION: Intravenous fosfomycin can play a vital role in the antibiotic armamentarium, given its long history of effective and safe use. However, well-designed randomized controlled trials are still desired.