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Summary Background Patients with inflammatory diseases, such as rheumatoid arthritis, often receive glucocorticoids, but long-term use can produce adverse effects. Evidence from randomised controlled trials to guide tapering of oral glucocorticoids is scarce. We investigated a scheme for tapering oral glucocorticoids compared with continuing low-dose oral glucocorticoids in patients with rheumatoid arthritis. Methods The Steroid EliMination In Rheumatoid Arthritis (SEMIRA) trial was a double-blind, multicentre, two parallel-arm, randomised controlled trial done at 39 centres from six countries (France, Germany, Italy, Russia, Serbia, and Tunisia). Adult patients with rheumatoid arthritis receiving tocilizumab and glucocorticoids 5–15 mg per day for 24 weeks or more were eligible for inclusion if they had received prednisone 5 mg per day for 4 weeks or more and had stable low disease activaity, confirmed by a Disease Activity Score for 28 joints–erythrocyte sedimentation rate (DAS28-ESR) of 3·2 or less 4–6 weeks before and on the day of randomisation. Patients were randomly assigned 1:1 to either continue masked prednisone 5 mg per day for 24 weeks or to taper masked prednisone reaching 0 mg per day at week 16. All patients received tocilizumab (162 mg subcutaneously every week or 8 mg/kg intravenously every 4 weeks) with or without csDMARDs maintained at stable doses during the entire 24-week study. The primary outcome was the difference in mean DAS28-ESR change from baseline to week 24, with a difference of more than 0·6 defined as clinically relevant between the continued-prednisone group and the tapered-prednisone group. The trial is registered with ClinicalTrials.gov , NCT02573012 . Findings Between Oct 21, 2015, and June 9, 2017, 421 patients were screened and 259 (200 [77%] women and 59 [23%] men) were recruited onto the trial. In all 128 patients assigned to the continued-prednisone regimen, disease activity control was superior to that in all 131 patients assigned to the tapered-prednisone regimen; the estimated mean change in DAS28-ESR from baseline to week 24 was 0·54 (95% CI 0·35–0·73) with tapered prednisone and −0·08 (–0·27 to 0·12) with continued prednisone (difference 0·61 [0·35–0·88]; p Interpretation In patients who achieved low disease activity with tocilizumab and at least 24 weeks of glucocorticoid treatment, continuing glucocorticoids at 5 mg per day for 24 weeks provided safe and better disease control than tapering glucocorticoids, although two-thirds of patients were able to safely taper their glucocorticoid dose. Funding F Hoffmann-La Roche.

Establishing a diagnosis in cases of fever of unknown origin (FUO) in immunocompromised patients can be difficult. In 25-35% infectious diseases are the underlying cause. This article reports the case of a 74-year-old woman with a 5-month history of fever. Through open biopsy of the femoral shaft and microbiological analysis, a diagnosis of neoehrlichiosis could be established. After initiation of treatment with doxycycline, the symptoms quickly resolved resulting in a complete recovery.Fieber unklarer Genese („fever of unknown origin“ [FUO]) kann insbesondere bei immunsupprimierten Patienten eine Vielzahl an Ursachen haben. In ca. 25–35 % der Fälle liegt dabei eine infektiöse Ursache zugrunde. Die Diagnosestellung ist häufig erschwert und wird mit zeitlicher Latenz gestellt. Wir schildern den Fall einer 74-jährigen Patientin mit einem seit 5 Monate bestehenden FUO, bei der mittels offener Femurbiopsie und mikrobiologischer Untersuchung die Diagnose einer Neoehrlichiose gestellt werden konnte. Nach Einleitung einer Therapie mit Doxycyclin kam es zu einer raschen und kompletten Besserung der Beschwerden.

Prior to surgical interventions physicians and patients with inflammatory rheumatic diseases remain concerned about interrupting or continuing anti-inflammatory medication. For this reason, the German Society for Rheumatology has updated its recommendations from 2014.After a systematic literature search including publications up to 31 August 2021, the recommendations on the use of of glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologics (bDMARDs) were revised and recommendations on newer drugs and targeted synthetic (ts)DMARDs were added.The glucocorticoid dose should be reduced to as low as possible 2-3 months before elective surgery (in any case10 mg/day) but should be kept stable 1-2 weeks before and on the day of surgery. In many cases csDMARDs can be continued, exceptions being a reduction of high methotrexate doses to ≤15 mg/week and wash-out of leflunomide if there is a high risk of infection. Azathioprine, mycophenolate and ciclosporin should be paused 1-2 days prior to surgery. Under bDMARDs surgery can be scheduled for the end of each treatment interval. For major interventions Janus kinase (JAK) inhibitors should be paused for 3-4 days. Apremilast can be continued. If interruption is necessary, treatment should be restarted as soon as possible for all substances, depending on wound healing.Whether bDMARDs increase the perioperative risk of infection and the benefits and risks of discontinuation remain unclear based on the currently available evidence. To minimize the risk of a disease relapse under longer treatment pauses, in the updated recommendations the perioperative interruption of bDMARDs was reduced from at least two half-lives to one treatment interval.HINTERGRUND: Vor operativen Eingriffen stellt sich Ärzten und Patienten mit entzündlich rheumatischen Erkrankungen weiterhin die Frage nach einer Unterbrechung oder Fortsetzung der entzündungshemmenden Medikation. Die Deutsche Gesellschaft für Rheumatologie hat hierfür ihre Empfehlungen von 2014 aktualisiert.Nach einer systematischen Literaturrecherche mit Einschluss von Publikationen bis zum 31.08.2021 wurden die Empfehlungen zum Umgang mit Glukokortikoiden, konventionell synthetischen „disease-modifying antirheumatic drugs“ (csDMARDs) und Biologika (bDMARDs) überarbeitet und Empfehlungen zu neueren Substanzen und „targeted synthetic (ts) DMARDs“ ergänzt.Die Glukokortikoiddosis sollte 2 bis 3 Monate vor elektiven Eingriffen so niedrig wie möglich reduziert (in jedem Fall10 mg/Tag), 1 bis 2 Wochen vor und am Operationstag jedoch stabil gehalten werden. csDMARDs können in vielen Fällen fortgeführt werden, Ausnahmen sind eine Reduktion hoher Methotrexat-Dosierungen auf ≤15 mg/Woche und Auswaschen des Leflunomid bei hohem Infektionsrisiko. Azathioprin, Mycophenolat und Ciclosporin sollten 1 bis 2 Tage vor der Operation pausiert werden. Unter bDMARDs können Operationen zum Ende des jeweiligen Therapieintervalls geplant werden. Januskinase(JAK)-Inhibitoren sollten bei größeren Eingriffen für 3 bis 4 Tage pausiert werden. Apremilast kann fortgeführt werden. Bei notwendiger Unterbrechung gilt für alle Substanzen, die Therapie in Abhängigkeit der Wundheilung baldmöglichst wieder zu beginnen.Ob bDMARDs das Infektionsrisiko perioperativ erhöhen und welche Rolle die Absetzzeit dabei spielt, bleibt bei gegenwärtiger Evidenz noch unklar. Um das Risiko eines Krankheitsschubs unter längerer Therapiepause zu minimieren, wurde in den aktualisierten Empfehlungen die perioperative Pausierung von bDMARDs von mindestens 2 Halbwertszeiten auf ein Therapieintervall reduziert.

Prior to surgical interventions physicians and patients with inflammatory rheumatic diseases remain concerned about interrupting or continuing anti-inflammatory medication. For this reason, the German Society for Rheumatology has updated its recommendations from 2014.After a systematic literature search including publications up to 31 August 2021, the recommendations on the use of of glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologics (bDMARDs) were revised and recommendations on newer drugs and targeted synthetic (ts)DMARDs were added.The glucocorticoid dose should be reduced to as low as possible 2-3 months before elective surgery (in any case10 mg/day) but should be kept stable 1-2 weeks before and on the day of surgery. In many cases csDMARDs can be continued, exceptions being a reduction of high methotrexate doses to ≤15 mg/week and wash-out of leflunomide if there is a high risk of infection. Azathioprine, mycophenolate and ciclosporin should be paused 1-2 days prior to surgery. Under bDMARDs surgery can be scheduled for the end of each treatment interval. For major interventions Janus kinase (JAK) inhibitors should be paused for 3-4 days. Apremilast can be continued. If interruption is necessary, treatment should be restarted as soon as possible for all substances, depending on wound healing.Whether bDMARDs increase the perioperative risk of infection and the benefits and risks of discontinuation remain unclear based on the currently available evidence. To minimize the risk of a disease relapse under longer treatment pauses, in the updated recommendations the perioperative interruption of bDMARDs was reduced from at least two half-lives to one treatment interval.HINTERGRUND: Vor operativen Eingriffen stellt sich Ärzten und Patienten mit entzündlich rheumatischen Erkrankungen weiterhin die Frage nach einer Unterbrechung oder Fortsetzung der entzündungshemmenden Medikation. Die Deutsche Gesellschaft für Rheumatologie hat hierfür ihre Empfehlungen von 2014 aktualisiert.Nach einer systematischen Literaturrecherche mit Einschluss von Publikationen bis zum 31.08.2021 wurden die Empfehlungen zum Umgang mit Glukokortikoiden, konventionell synthetischen „disease-modifying antirheumatic drugs“ (csDMARDs) und Biologika (bDMARDs) überarbeitet und Empfehlungen zu neueren Substanzen und „targeted synthetic (ts) DMARDs“ ergänzt.Die Glukokortikoiddosis sollte 2 bis 3 Monate vor elektiven Eingriffen so niedrig wie möglich reduziert (in jedem Fall10 mg/Tag), 1 bis 2 Wochen vor und am Operationstag jedoch stabil gehalten werden. csDMARDs können in vielen Fällen fortgeführt werden, Ausnahmen sind eine Reduktion hoher Methotrexat-Dosierungen auf ≤15 mg/Woche und Auswaschen des Leflunomid bei hohem Infektionsrisiko. Azathioprin, Mycophenolat und Ciclosporin sollten 1 bis 2 Tage vor der Operation pausiert werden. Unter bDMARDs können Operationen zum Ende des jeweiligen Therapieintervalls geplant werden. Januskinase(JAK)-Inhibitoren sollten bei größeren Eingriffen für 3 bis 4 Tage pausiert werden. Apremilast kann fortgeführt werden. Bei notwendiger Unterbrechung gilt für alle Substanzen, die Therapie in Abhängigkeit der Wundheilung baldmöglichst wieder zu beginnen.Ob bDMARDs das Infektionsrisiko perioperativ erhöhen und welche Rolle die Absetzzeit dabei spielt, bleibt bei gegenwärtiger Evidenz noch unklar. Um das Risiko eines Krankheitsschubs unter längerer Therapiepause zu minimieren, wurde in den aktualisierten Empfehlungen die perioperative Pausierung von bDMARDs von mindestens 2 Halbwertszeiten auf ein Therapieintervall reduziert.

The current outbreak of the SARS-CoV-2 infection provides countless unprecedented challenges—also with regard to the management of patients with inflammatory rheumatic disease. In an attempt to provide guidance, the German Society of Rheumatology instructed its commission for pharmacotherapy (Kommission Pharmakotherapie) to develop up-to-date recommendations for the management of patients with inflammatory rheumatic diseases during the Covid-19 pandemic. As to date there are little, if any, evidence-based data to scientifically justify guidance, the present preliminary recommendations are based on an expert consensus by 17 experienced rheumatologists in Germany, taking into account analogies to the procedures for other, longer known viral infections, theoretical considerations and already known facts about the SARS-CoV-2 infection. A deviation from these recommendations may be useful in each individual case. The recommendations will be updated frequently (www.dgrh.de). Every physician should also be aware of novel developments while the infection proceeds. 1.1. Patients with inflammatory rheumatic diseases may have an increased risk of infection (box 1). Whether this also applies to SARS-CoV-2 infections is not known. It is also not known whether Covid-19 is more severe in patients with inflammatory rheumatic …

ZUSAMMENFASSUNG: Am 21.12.2020 hat die EMA mit der mRNA-Vakzine BNT162b2 der Firmen BioNTech/Pfizer (Comirnaty®, BioNTech, Mainz, Deutschland; Pfizer, New York City, NY, USA) den ersten Impfstoff gegen SARS-CoV‑2 in der Europäischen Union zugelassen, am 06.01.2021 folgte bereits der zweite (Moderna®, Moderna, Cambridge, MA, USA). Viele weitere Zulassungen werden in Kürze folgen. Mit der Verfügbarkeit der Impfung sind bei Patienten/-innen genau wie bei Ärzten/-innen viele Fragen aufgekommen, die in diesem Hot-Topic-Artikel so aktuell wie möglich adressiert werden sollen. ABSTRACT: On 21 December 2020 the European Medicines Agency (EMA) approved the mRNA vaccine BNT162b2 (Comirnaty®, BioNTech, Mainz, Germany; Pfizer, New York City, NY, USA) as the first vaccine against SARS-CoV‑2 in the European Union and the second vaccine (Moderna®, Moderna, Cambridge, MA, USA) followed on 6 January 2021. Many more approvals will follow within a short period of time. With the availability of the vaccination many questions have arisen for patients as well as for physicians, which are addressed as up to date as possible in this hot topic article.

Cryoglobulinemia often occurs secondary to an underlying monoclonal gammopathy (MG). MG is a common finding in the elderly population with a prevalence of 5% in persons aged 70 years and older and can range from asymptomatic monoclonal gammopathy of unknown significance (MGUS) to symptomatic multiple myeloma (MM) for which treatment is clearly indicated. However, rare forms of MG lead to clinical symptoms and are summarized as monoclonal gammopathy of clinical significance (MGCS). Here, no clear treatment recommendations exist, treatment ranges from symptomatic treatment of paraneoplasia to causal treatment of the underlying plasma cell clone. Here, we report an exemplary case of a 74-year-old female with MG and cryoglobulinemic vasculopathy seriously affecting skin and peripheral nervous system accompanied by severe pain. First- and second-line treatments with conventional immunosuppressive agents and B cell depleting therapy did not lead to sustained remission. After identifying MG as the potential underlying cause MGCS was considered. As symptoms were markedly affecting quality of life, myeloma-derived treatment with anti-CD38 antibody daratumumab, lenalidomide and dexamethasone was initiated and subsequently clinical symptoms and laboratory cryoglobulinemia resolved. In conclusion, this case report shows for the first time that daratumumab-based treatment of MGCS can be effective and is well-tolerated.

Journal der Deutschen Dermatologischen Gesellschaft : JDDG = Journal of the German Society of Dermatology 19(9), 1371-1395 (2021). doi:10.1111/ddg.14491, Published by Wiley-Blackwell, Berlin

Background Vasculitides comprise a group of rare diseases which affect less than 5 in 10.000 individuals. Most types of vasculitis can become organ- and life-threatening and are characterized by chronicity, high morbidity and relapses, altogether resulting in significant morbidity and mortality. Previous studies have been either monocentric or mainly retrospective – studies with a prospective design mostly consisted of rather small cohorts of 100 to 200 patients. The aim of the Joint Vasculitis Registry in German-speaking countries (GeVas) is to record all patients who have been recently diagnosed with vasculitis or who have changed their treatment due to a relapse (inception cohort). In GeVas, data are collected prospectively in a multicenter design in Germany, Austria and Switzerland. By this approach, courses of vasculitis and their outcomes can be monitored over an extended period. Methods GeVas is a prospective, web-based, multicenter, clinician-driven registry for the documentation of organ manifestations, damage, long-term progress and other outcomes of various types of vasculitis. The registry started recruiting in June 2019. As of October 2020, 14 centers have been initiated and started recruiting patients in Germany. Involvement of sites in Austria and the German-speaking counties of Switzerland is scheduled in the near future. Discussion In June 2019, we successfully established a prospective multicenter vasculitis registry being the first of its kind in German-speaking countries. The participating centers are currently recruiting, and systematic analysis of long-term vasculitis outcomes is expected in the ensuing period. Trial registration German Clinical Trials Register (Deutsches Register Klinischer Studien): DRKS00011866. Registered 10 May 2019.

A few days after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was declared a pandemic, the German Society for Rheumatology (DGRh) compiled the first group of recommendations for the care of patients with inflammatory rheumatic diseases in light of SARS-CoV-2/coronavirus disease 2019 (COVID-19). These first recommendations were based on an expert consensus and were largely non-evidence-based. Now that the first scientific data from registries, cross-sectional studies, case reports and case series are available, the DGRh has developed a timely update. This update is based on a literature search of publications available through 15 June 2020 and addresses preventive measures (such as hygiene measures or vaccinations) and the use of immunomodulatory/immunosuppressive drugs. Driven by the commitment to let patients benefit from these new evidence-based recommendations as quickly as possible, the DGRh published the update in German on its homepage and in the Zeitschrift für Rheumatologie immediately after completion. Here we report the key recommendations to make them available to the international community, provide the scientific methodology used to develop the recommendations, give additional thoughts and advice for the management of patients with rheumatic diseases during the COVID-19 pandemic and discuss our recommendations in the context of other international recommendations.

A few days after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was declared a pandemic, the German Society for Rheumatology (DGRh) compiled the first group of recommendations for the care of patients with inflammatory rheumatic diseases in light of SARS-CoV-2/coronavirus disease 2019 (COVID-19). These first recommendations were based on an expert consensus and were largely non-evidence-based. Now that the first scientific data from registries, cross-sectional studies, case reports and case series are available, the DGRh has developed a timely update. This update is based on a literature search of publications available through 15 June 2020 and addresses preventive measures (such as hygiene measures or vaccinations) and the use of immunomodulatory/immunosuppressive drugs. Driven by the commitment to let patients benefit from these new evidence-based recommendations as quickly as possible, the DGRh published the update in German on its homepage and in the Zeitschrift für Rheumatologie immediately after completion. Here we report the key recommendations to make them available to the international community, provide the scientific methodology used to develop the recommendations, give additional thoughts and advice for the management of patients with rheumatic diseases during the COVID-19 pandemic and discuss our recommendations in the context of other international recommendations.

In oncology clinical trials, crossover is used frequently but may lead to uncertainties regarding treatment effects.To investigate the handling of evidence from crossover trials by the European Medicines Agency (EMA) and the German Federal Joint Committee (G-BA).For oncology medicines with early benefit assessments before January 2015, presence of crossover, clinical data, EMA requests for additional data, and G-BA benefit ratings/evidence levels were analyzed from manufacturers' dossiers, G-BA appraisals, European Public Assessment Reports, and original publications.Eleven of 21 benefit assessments included crossover trials. Significant intergroup differences (P 0.05) in overall survival (OS) were noted in 7 of 11 trials with and 7 of 10 without crossover. For 6 of 11 medicines with crossover, these were demonstrated before crossover. Treatment effects generally worsened with increasing proportions of crossover. The EMA requested additional data more frequently if crossover was performed, particularly if no OS data were available before crossover. The G-BA granted a considerable benefit to 73% of medicines with crossover and 40% of those without. Evidence levels were intermediate for 50% and 75%, respectively. None of the medicines received the highest evidence level.In G-BA appraisals, oncology medicines with crossover received better additional benefit ratings, but were assigned lower evidence levels, than those without. The five medicines with crossover after progression were assigned lower evidence levels than the six medicines with crossover after demonstration of superior OS, indicating that the way in which crossover is implemented may be one factor influencing the assignment of evidence levels by the G-BA.

To evaluate early and late responses in biological-naïve patients with rheumatoid arthritis (RA) initiating tocilizumab and early tocilizumab non-responders who switched to rituximab.In this open-label, non-randomised phase 3 study, RA patients with inadequate response to conventional synthetic DMARDs received tocilizumab 8 mg/kg intravenously at study begin and weeks 4, 8 and 12. After evaluation at week 16, early responders (Disease Activity Score based on 28 joints-erythrocyte sedimentation rate [DAS28-ESR]2.6) completed the study; partial responders (DAS28-ESR decrease1.2 or DAS28-ESR ≥2.6-≤3.2) were to continue tocilizumab through week 28; non-responders (DAS28-ESR decrease ≤1.2) switched to rituximab (1000 mg, weeks 16 and 18) with safety follow-up through week 66.Of 519 patients, 222 (42.8%) achieved early DAS28-ESR remission at week 16; 240 patients continued treatment, 213 (41.0%) received tocilizumab, and 27 (5.2%) switched to rituximab. At week 32 DAS28-ESR remission was achieved by 117/213 patients (54.9%) who continued tocilizumab and 4/27 patients (14.8%) who switched to rituximab; good EULAR response was achieved by 66.7% and 25.9% and CDAI remission by 19.2% and 14.8% of patients, respectively. Serious adverse events occurred through week 32 in 45/490 patients (9.2%) who received tocilizumab (serious infections, 2.7%) and through week 66 in 8/27 patients (29.6%) who switched to rituximab.Early response to tocilizumab was observed in 42.8% of patients. Half of early partial responders benefitted from continuing tocilizumab. Switching non-responders to rituximab seems feasible. No new safety signals were observed in patients treated with tocilizumab or switched to rituximab.

Circulating anti-neutrophilic cytoplasmic autoantibodies targeting proteinase 3 (PR3-ANCA) are a diagnostic and pathogenic hallmark of granulomatosis with polyangiitis (GPA). It is, however, incompletely understood if inflamed tissue supports presence or emergence of PR3-ANCA

Opportunistic infections are a major concern in renal and transplant medicine. We present the case of a renal transplant recipient with a generalised Mycobacterium haemophilum infection after an increase in immunosuppressive therapy and treatment with a tumour necrosis factor-α (TNF-α) inhibitor. Infection involved skin and soft tissue, joints and bones, as well as the renal transplant with an interstitial nephritis. Rapid diagnosis using PCR and DNA sequencing allowed early appropriate treatment. Triple antibiotic therapy and reduction in immunosuppression resulted in a slow but sustained recovery. Immunosuppression causes severe opportunistic infections. TNF-α inhibitors are very effective and well tolerated but have an increased susceptibility to infections with mycobacteria. Mycobacterial infections represent a significant clinical risk to transplant recipients because of their aggressive clinical course and the need for complex toxic antibiotic treatments. In these patients, M. haemophilum is a cause of skin infections.

PurposeTo determine the sensitivity to change of the US7 score among RA patients under various therapies and to analyze the effect of each therapeutic option over 1 year. To estimate predictors for development of destructive bone changes.MethodsMusculoskeletal ultrasound (US7 score), DAS28, CRP and ESR were performed in 432 RA patients at baseline and after 3, 6 and 12 months. The cohort was divided into four sub-groups: first-line DMARDs (Group 1; 27.3%), therapy switch: DMARDs to second DMARDs (Group 2; 25.0%), first-line biologic after DMARDs therapy (Group 3; 35.4%) and therapy change from biologic to second biologic (Group 4; 12.3%).ResultsThe US7 synovitis and tenosynovitis sum scores in grey-scale (GSUS) and power Doppler ultrasound (PDUS) as well as ESR, CRP decreased significantly (pConclusionsThe comparable developments of the US7 score with clinical and laboratory data illustrates its potential to reflect therapeutic response. Therefore, the novel US7 score is sensitive to change. Patients who switched from one biologic to another exhibited a significant decline in erosions after 12 months, while the erosions scores in the other groups were stable.

Background Remission is the established goal in rheumatoid arthritis (RA) treatment. Although originally defined by a disease activity score in 28 joints (DAS28)

In implant-associated posttraumatic osteomyelitis, a massive infiltration of leukocytes into the infected site is seen. As described previously, the most infiltrated cells were highly activated polymorphonuclear neutrophils. In addition, a considerable T-cell infiltrate was noted. Whereas our previous work was mainly concerned with the phenotypical and functional characterization of the polymorphonuclear neutrophils, we now analyzed T lymphocytes of 32 patients with implant-associated posttraumatic osteomyelitis. We found evidence for an expansion of CD8 T cells in the peripheral blood of the patients and for an infiltration of these cells into the infected site. Further analysis of the surface-receptor pattern by three-color cytofluorometry revealed that the majority of these cells belonged to the cytotoxic-effector phenotype. Of note is that cytotoxic T cells are generally associated with virus infection. Thus, the detection of those cells in patients with bacterial infection was rather unexpected and points to a novel, not yet appreciated, role of CD8 T cells also in the defense of bacterial infections.

SummaryPersistent, localized Staphylococcus aureus infections, refractory to antibiotic treatment, can result in massive tissue destruction and surgical intervention is often the only therapeutic option. In that context, we investigated patients with S. aureus-induced infection at various sites, apparent as either olecranon bursitis, empyema of the knee joint or soft tissue abscess formation. As expected, a prominent leucocyte infiltrate was found, consisting predominantly of polymorphonuclear neutrophils (PMN) (up to 75%) and to a lesser extent of T lymphocytes and natural killer (NK) cells. In line with their bactericidal capacity, PMN expressed the high-affinity receptor for IgG, CD64 and the lipopolysaccharide (LPS) receptor CD14; moreover, the oxygen radical production in response to the bacterial peptide f-MLP was enhanced, while chemotactic activity was greatly reduced. The more intriguing finding, however, was that a portion of PMN had acquired major histocompatibility complex (MHC) class II antigens and CD83, indicative of a transdifferentiation of PMN to cells with dendritic-like characteristics. Of note is that a similar transdifferentiation can be induced in PMN in vitro, e.g. by gamma interferon or by tumour necrosis factor alpha. Co-cultivation of transdifferentiated PMN with autologous T lymphocytes resulted in prominent T cell proliferation, provided that S. aureus enterotoxin A was added. Taken together, persistent S. aureus infection induces PMN to acquire characteristics of dendritic cells, which in turn might promote the local immune response.

Joint involvement occurs in most patients with systemic lupus erythematosus (SLE), and severe lupus arthritis is often refractory to conventional treatments. Anakinra is used in the treatment of rheumatoid arthritis, but its therapeutic potential has not been proved in patients with SLE.To determine the safety/tolerability and efficacy of anakinra in patients with SLE with leading joint involvement.In patients with SLE with active polyarthritis and no other uncontrolled systemic/organ manifestations, 100 mg/day anakinra was self administered subcutaneously for 3 months. Disease activity was assessed by VAS, number of swollen/tender joints, ECLAM score, and serological and immunological measures.Four patients with SLE were studied; anakinra was safe in all four patients and no drug related serious adverse events occurred. A subjective benefit was seen in all patients and a trend towards better activity measures after 4 weeks. After an initial response, one patient left the study because of an arthritic flare after 6 weeks.In this study anakinra was apparently safe and well tolerated and led to clinical and serological improvement. Anakinra might be an interesting alternative in individual patients with lupus arthritis not responding to conventional treatments.

Polymorphonuclear neutrophils (PMNs) produce an abundance of bactericidal and cytotoxic molecules consistent with their role as first-line defense against bacterial infection. PMNs, however, also cause efficient cellular cytotoxicity when targeted through Fc receptors to appropriate antibody-coated target cells. Although this so-called antibody-dependent cellular cytotoxicity (ADCC) was described many years ago, the mechanism of killing is still elusive. We now have found that PMNs contain perforin and granzyme B, the 2 molecules known as the cytotoxic entity of natural killer cells and of cytotoxic T lymphocytes as well. Lysates of PMNs were lytic for chicken erythrocytes in a time-, temperature-, and Ca2+-dependent manner. Moreover, apoptosis of Jurkat cells was induced, consistent with the observation that the PMN lysates contain enzymatically active granzyme B. Taken together, our data provide evidence for the presence of perforin and granzyme B within the cytotoxic arsenal of PMNs. (Blood. 2004;103:1099-1104)

Shortening of telomeres: Evidence for replicative senescence of T cells derived from patients with Wegener's granulomatosis. Background Replicative senescence describes the fact that somatic cells undergo a finite and predictable number of cell divisions before entering an irreversible state of growth arrest. Progressive shortening of the telomeres, a consequence of cell division, is a reliable indicator of replicative senescence. Method We analyzed telomere length of DNA derived from T cells of patients suffering from Wegener's granulomatosis by Sourthern blotting. Moreover, expression of CD28, another marker for replicative senescence, was tested by cytofluorometry. Results In patients with disease for more than 5 years, short telomeres were detected in addition to telomeres of normal length, indicating replicative senescence of discrete T-cell clones. Reduced expression of CD28 was noted, particularly on CD8-positive T cells, derived from patients with disease for more than 5 years and short telomeres. Conclusion Our data provide evidence that a portion of T cells had undergone replicative senescence, which in turn indicates clonal expansion of T cells as consequence of activation.

SUMMARY Polymophonuclear cells (PMN) of healthy donors do not express major histocompatibility complex (MHC) class II antigens or the T-cell costimulatory molecules CD80 or CD86. Expression of these receptors, however, is seen in patients with chronic inflammatory diseases. We now report that, by culturing PMN of healthy donors with autologous serum, interferon-c (IFN-c) and granulocyte‐ macrophage colony-stimulating factor (GM-CSF), de novo synthesis of MHC class II, CD80 and CD86 could be induced. MHC class II-positive PMN acquired the capacity to present staphylococcus enterotoxin to peripheral T cells, apparent as induction of interleukin-2 (IL-2) synthesis and proliferation of the T cells. Moreover, the PMN also processed tetanus toxoid (TT) and induced proliferation of TT-specific T cells in a MHC class II-restricted manner. Taken together, these data indicate that PMN can be activated to function as accessory cells for T-cell activation.

Polymorphonuclear neutrophils (PMN) are considered to be short-lived, terminally differentiated cells undergoing spontaneous apoptosis if not appropriately stimulated. In patients with systemic infections and inflammatory disease, however, PMN have an extended life span and acquire new surface receptors and functions. Expression of CD64, the high-affinity receptor for immunoglobulin, has been found, and functionally active elastase and surface-associated fibronectin as well. The latter is of particular interest since fibronectin is known as a multifunctional, multimodal extracellular matrix protein, participating in cell adherence, cell signaling, and cell cycle control. To study the surface-associated fibronectin further, PMN of healthy donors were cultivated to induce de novo synthesis of fibronectin. PMN produced fibronectin, which remained associated with the cell surface, where it was partially cleaved. PMN derived fibronectin exhibited a rare splice pattern: predominantly fibronectin containing the extradomain B (EDB) was generated, but evidently no IIICS domain; the latter is known as a receptor for beta1 integrins. How the presence of EDB affects the properties of fibronectin is not yet understood. Studies with recombinant EDB have failed to show a membrane-binding site or a direct participation of EDB in the adhesion process. The function of PMN-associated fibronectin is still under investigation. The rapid cleavage by surface-associated proteases suggests that fibronectin acts as a tightly regulated adhesion protein, and probably also as a precursor molecule for fibronectin-derived biologically active mediators.

Rheumatoid arthritis (RA) affects 1% of the adult population and is a chronic disease lasting for many decades. RA often results, despite therapy, in progressive joint destruction, deformity and disability, causing a major economic loss for the patients and the society. Most common the onset of the disease is between the 4th and 5th decade: RA affects 3 times more women than men. Both, the diagnostic as well as the therapeutic opportunities, have greatly improved over the last years. Nevertheless, there are still deficiencies in the care of patients with early RA (ERA). Consequently, the "German Society for Rheumatology" has set up recommendations for "The management of early RA", which are introduced in this article.

Recombinant human granulocyte colony-stimulating factor (rhuG-CSF) is frequently given to patients with leukopenia or neutropenia caused by various underlying diseases. The treatment with rhuG-CSF is apparently safe, although cutaneous vasculitis and flares in patients with autoimmune diseases are described. We describe 2 patients with histologically proven antineutrophil cytoplasmic antibody-associated systemic vasculitis with disease flares after administration of rhuG-CSF, given to improve collection of stem cells prior to autologous stem cell transplantation.

The interaction of CD95 with its ligand CD95L is important for negative selection of B cells during the germinal center (GC) reaction. Recently, mutations conferring resistance to CD95-induced apoptosis have been described for human GC B cells. Hence, as has been demonstrated for CD95-deficient mice, also GC-derived autoreactive B cells carrying somatic CD95 gene mutations may potentially service negative selection and participate in the development of autoimmune diseases. Here, single plasmablasts (PB) which are implicated in the production of autoantibodies in systemic lupus erythematosus (SLE) patients as well as ten human B cell lines producing autoantibodies were analyzed for destructive somatic CD95 gene mutations. However, inactivating CD95 gene mutations were very rare in PB and not detected in the cell lines. Sequence analysis of V gene rearrangements amplified from single PB confirmed that the cells are (post) GC B cells and additionally demonstrated massive clonal expansion of these cells in two of four SLE patients. We conclude that CD95 gene mutations play little if any role in the generation of the pool of PB in SLE patients and that mutations in the CD95 gene are rare among autoantibody-producing B cells in SLE and rheumatoid arthritis.

Summary Upon cultivation with interferon-γ (IFN-γ) and granulocyte/macrophage-colony stimulating factor (GM-CSF) polymorphonuclear neutrophils (PMN) acquire characteristics of dendritic cells, including expression of major histocompatibility complex (MHC) class II antigens, of the co-stimulatory antigens CD80, CD86 and of CD83, the latter considered to be specific for dendritic cells. Dendritic-like PMN were also able to present to T cells antigens in a MHC class II-restricted manner. To assess whether dendritic-like PMN are also generated in vivo, cells of patients with acute bacterial infections and of patients with chronic inflammatory diseases (primary vasculitis) were tested. During acute infection up to 80% of PMN acquired CD83, but remained negative for MHC class II, CD80 or CD86. PMN of patients with primary vasculitis expressed MHC class II antigens, CD80 and CD86, but not CD83, indicating that up-regulation of MHC class II and of CD83 are not necessarily linked to each other. Indeed, parallel studies with PMN of healthy donors showed that while IFN-γ and granulocyte/macrophage colony stimulating factor (GM-CSF) induced both, MHC class II and CD83, tumour necrosis factor (TNF)-α selectively induced de novo synthesis of CD83. The function of CD83 on PMN is still elusive. A participation in the MHC class II-restricted antigen presentation could be ruled out, consistent with the segregation of MHC class II and CD83 expression. Regardless, however, of its function, CD83 expression could serve as a marker to differentiate between acute and chronic inflammation.

Acquired hemophilia A (AHA) and acquired von Willebrand Syndrome (AVWS) are both rare bleeding disorders that can be associated with lymphoproliferative or autoimmune diseases. AHA is uniformly caused by inhibitory autoantibodies against coagulation factor VIII (FVIII), while the pathophysiology of AVWS comprises several distinct mechanisms, including reduced synthesis, accelerated clearance, or increased proteolysis. In this regard, autoantibodies to von Willebrand factor (VWF) have been described in patients with systemic lupus erythematosus (SLE) or monoclonal gammopathy. Here, we report the case of a 71-year-old patient with a recent onset of spontaneous mucocutaneous and soft-tissue bleeding due to severely decreased FVIII and VWF. While there was no evidence for monoclonal gammopathy, specific IgG antibodies against both FVIII and VWF were detected. Furthermore, VWF multimer analysis revealed the presence of ultralarge plasma multimers and absence of the typical multimeric triplet structure, a finding consistent with decreased proteolytic processing of massively released, but rapidly cleared VWF. Both FVIII and VWF readily responded to immunosuppressive therapy with prednisolone. Interestingly, clinical and laboratory findings established the diagnosis of “late-onset SLE” in our patient. Thus, about 45 years after the first description of AVWS in a 12-year-old boy with SLE, we present another unusual case of concomitant autoimmune-mediated AHA and AVWS in an elderly SLE patient, which, to the best of our knowledge, has not been reported so far.

Polymorphonuclear neutrophils in Wegener's granulomatosis acquire characteristics of antigen presenting cells. Background Constitutive expression of major histocompatibility complex (MHC) class II antigens and of the co-stimulatory receptors CD80 and CD86 is restricted to professional antigen presenting cells. Polymorphonuclear neutrophils (PMN) of healthy donors are negative for those antigens. Our recent study, however, found that PMN of patients with active Wegener's granulomatosis acquired MHC class II antigens. Methods To continue and extend the previous study results, PMN and monocytes of 60 patients with Wegener's granulomatosis, 24 patients with microscopic polyangiitis (MPA), 20 patients with acute bacterial infection, and 53 healthy donors were analyzed for the expression of MHC class II antigens as well as of CD80 and CD86. Moreover, induction on PMN of MHC class II expression was studied, as was antigen presentation as a possible functional consequence. Results PMN of patients with acute, active Wegener's granulomatosis expressed MHC class II antigens, CD80 and CD86; on monocytes up-regulation of MHC class II was seen. In contrast, PMN of patients with inactive disease, or with relapse, patients with microscopic polyangiitis or with bacterial infections expressed neither MHC class II, nor CD80 or CD86. PMN of healthy donors acquired these antigens when cultured in the presence of T cells or T cell-derived cytokines. The PMN were then able to present to T cell antigens in a MHC-class II restricted manner. Conclusion During active disease, the PMN of patients with Wegener's granulomatosis acquire characteristics of antigen presenting cells, whereas the PMN of patients with MPA or bacterial infection do not. The finding reflects differences in the pattern of the respective inflammatory response and suggests new effector functions of PMN. Moreover, MHC class II expression on PMN could serve as a novel marker for active Wegener's granulomatosis.

Helicobacter pylori induces cell death by apoptosis. However, the apoptosis-inducing factor is still unknown. The virulence factor vacuolating cytotoxin A (VacA) is a potential candidate, and thus its role in apoptosis induction was investigated in the human gastric epithelial cell line AGS. The supernatant from the vacA wild-type strain P12 was able to induce apoptotic cell death, whereas the supernatant from its isogenic mutant strain P14 could not. That VacA was indeed the apoptosis-inducing factor was demonstrated further by substantial reduction of apoptosis upon treatment of AGS cells with a supernatant specifically depleted of native VacA. Furthermore, a recombinant VacA produced in Escherichia coli was also able to induce apoptosis in AGS cells but failed to induce cellular vacuolation. These findings demonstrate that the vacuolating cytototoxin of H. pylori is a bacterial factor capable of inducing apoptosis in gastric epithelial cells.

Polymorphonuclear neutrophils (PMN) are in the first line of defense against bacterial infections. They are considered to be end-differentiated cells undergoing constitutive apoptosis within hours after release from the bone marrow. During pathological events, however, their life span is extended in conjunction with morphological and functional alterations indicative of a transdifferentiation of mature PMN. To further characterize differentiated PMN, the alterations seen in vivo were reproduced by cultivating PMN of healthy donors with either gamma-interferon, granulocyte/macrophage colony stimulating factor, or a combination thereof. Thus cultivated cells escaped from apoptosis, and protein synthesis was induced, notably of the major histocompatibility complex (MHC) class II antigens, CD80 and CD86. Moreover, CD83, thought to be specific for dendritic cells was synthesized, while typical markers of PMN, including CD66b, CD11a/CD11b/CD11c, CD15, CD18 were preserved. A profound alteration of both cellular morphology and of function was seen: the cultivated PMN lost their chemotactic activity but had acquired the ability to present to T-cells a peptide antigen in a MHC class II restricted manner. The data lead to the conclusion that mature PMN can differentiate further to cells with characteristics of DCs, thereby connecting PMN to the specific T-cell response.