[Experiences and results from Rheuma-VOR]. / Erfahrungen und Ergebnisse aus Rheuma-VOR.

Rheumatoid arthritis, psoriatic arthritis and axial spondylarthritis are the most common chronic autoimmune rheumatic diseases. For all three diseases an early diagnosis and initiation of treatment is crucial. The proof of concept network study "Rheuma-VOR" is a further developed version of the predecessor project ADAPTHERA and was extended to several federal states. The aim of this prospective study is to improve the early diagnosis of rheumatoid arthritis, psoriatic arthritis and axial spondylarthritis and thus positively impact the quality of care for patients with the help of multidisciplinary coordinating centers. To date 3710 disease-specific questionnaires from patients with the suspected diagnosis of rheumatoid arthritis, psoriatic arthritis or axial spondylarthritis from 1298 different primary care providers were registered in the multidisciplinary coordination centers. A total of 1958 appointments were made with 1 of the 53 participating rheumatology specialists. In 876 patients, 1 of the 3 rheumatic diseases was diagnosed in an early stage. The waiting period was on average 42.5 days depending on the federal state, which is well below the nationwide average. It should also be noted that the coordinated cooperation and risk stratification of the Rheuma-VOR coordination centers relieved the capacity of rheumatology specialists by 1281 appointments (34.5%). In addition, the 2­week Rheuma Bus Tour and the accompanying initiatives in Rhineland-Palatinate (Rheuma-VOR screening app and the triage consultation) are showing first promising positive results.

Effect of oral exposure to artificially weathered Deepwater Horizon crude oil on blood chemistries, hepatic antioxidant enzyme activities, organ weights and histopathology in western sandpipers (Calidris mauri).

Shorebirds were among birds exposed to Mississippi Canyon 252 (MC252) crude oil during the 2010 Deep Water Horizon (DWH) oil spill in the Gulf of Mexico. The western sandpiper (Calidris mauri) was chosen as one of four species for initial oral dosing studies conducted under Phase 2 of the avian toxicity studies for the DWH Natural Resource Damage Assessment (NRDA). Thirty western sandpipers were assigned to one of three treatment groups, 10 birds per group. The control group was sham gavaged and the treatment groups were gavaged with 1 or 5mL oil kg bw-1 daily for 20 days. Periodic blood samples for hemoglobin measurements were collected during the trial. A final blood sample used to determine hemoglobin concentration in addition to complete blood counts, plasma clinical chemistries, haptoglobin concentration and plasma electrophoresis was collected when birds were euthanized and necropsied on day 21. Tissues were removed, weighed and processed for subsequent histopathological evaluation. There were numerical decreases in hemoglobin concentrations in oil-dosed birds over the 21-day trial, but values were not significantly different compared to controls on day 21. There were no significant differences between controls and oiled birds in complete blood counts, plasma chemistries, haptoglobin concentration, and plasma electrophoresis endpoints. Of the hepatic oxidative stress endpoints assessed, the total antioxidant capacity assessment (Trolox equivalents) for the control group was lower compared to the 1mL oil kg bw-1 group. Absolute liver weights in the 5mL oil kg bw-1 group were significantly greater compared to controls. While not conclusive, the numerical decrease in hemoglobin concentration and significant increase in absolute liver weight are consistent with exposure to oil. Histological changes in the adrenal gland could be considered a non-specific indicator of stress resulting from exposure to oil. It is possible that the quantity of oil absorbed was not sufficient to induce clearly evident hemolytic anemia or that the western sandpiper is relatively insensitive to ingested oil.

[Hepatitis A immunity in refugees in Germany during the current exodus]. / Hohe Hepatitis-A-Immunitätsrate bei Flüchtlingen in Deutschland.

BACKGROUND: Germany is facing a huge humanitarian challenge with rapidly rising numbers of refugees entering the country. Data on hepatitis A seroprevalence and infection in refugees and asylum seekers in Europe during the current refugee exodus is scarce. OBJECTIVES: To assess hepatitis A (HAV) seroprevalence and immunity in refugees arriving in northern Germany in 2015. MATERIALS AND METHODS: A cross-sectional study of 235 refugees seeking shelter in reception centers in Northern Germany in August 2015 was performed, as acute Hepatitis A had been detected in one refugee in this camp. In order to analyze acute HAV infection and overall immunity, serological screening for HAV antibodies (combined IgG and IgM) was performed. The immunity threshold was defined as <20 IU/l. In all positive screening results, separate IgM testing was performed to detect acute infections. RESULTS: Males accounted for 84.3 % of HAV screened refugees and the mean age of refugees was 29.1 ± 11.2 years. Children and adolescents below the age of 18 years made up 8.8 % of the migrants. Overall HAV immunity within the cohort was 90 %, and a mild age-dependent increase in HAV immunity was observed, with 81.1 % immunity in children <18 years and a 100 % seropositivity in subjects >50 years. One 20-year-old female refugee had positive IgM results with high HAV antibodies, most likely due to subacute HAV infection. CONCLUSIONS: This comparably high rate of HAV protected refugees in our cohort supports the notion that the probability of large HAV outbreaks in current German refugee centers is low. However, depending on their current living situation, HAV vaccination should be considered for each refugee child, and healthcare providers and personnel working in refugee centers should be vaccinated against HAV.

Autoantibodies binding to ubiquitin-fold modifier-conjugating enzyme 1 (Ufc1) and pleckstrin homology domain containing, family G (with RhoGef domain) member 2 (Plekhg2) are associated with mycobacterial infections.

OBJECTIVES: The diagnosis of extrapulmonary tuberculous infections and nontuberculous mycobacterial (NTM) infections is difficult because the symptoms are nonspecific and suitable specimens for bacterial culture are often not available. Recent publications reported the existence of autoantibodies in tuberculous infections. We screened for specific autoantibodies in mycobacterial infections. METHODS: We screened four in 29 patients with active mycobacterial infections and different controls using protein array technology. We could identify autoantibodies against ubiquitin-fold modifier-conjugating enzyme 1 (Ufc1) and pleckstrin homology domain containing, family G (with RhoGef domain) member 2 (Plekhg2) in all four patients. Subsequently, we designed enzyme-linked immunosorbent assays (ELISAs) for the detection of autoantibodies binding to Ufc1 and Plekhg2. RESULTS: Autoantibodies binding to Ufc1 and Plekhg2 were found in 19 of 29 patients (66%) with active mycobacterial infections. In comparison, we found these autoantibodies in one of 31 patients (3%) with successfully treated mycobacterial infections, in three of 40 (8%) HIV-infected patients not receiving combination antiretorviral therapy (cART) and in six of 134 (5%) blood donors. Interestingly, six of eight (75%) patients with HIV-associated B-cell non-Hodgkin lymphoma (B-NHL) at the onset of disease had autoantibodies against Ufc1 and Plekhg2, but none of nine (0%) patients after treatment of HIV-associated B-NHL, none of seven patients with non-HIV-associated B-NHL and 11 of 115 (10%) patients with other malignant diseases had autoantibodies against both proteins. CONCLUSIONS: In view of the high frequency of these autoantibodies, we postulate that they might be of potential use for additional diagnostics for mycobacterial infections, and further studies may shed light on the pathomechanisms of these two autoantibodies.

7th International Immunoglobulin Conference: Immunodeficiencies.

Most primary immunodeficiency disorders (PID) are the result of single gene defects. Based on this fact, more than 240 different entities have been identified. Those PIDs with predominant antibody deficiency are treated with immunoglobulin (Ig) replacement therapy. This review focuses on the diagnosis, clinical characteristics and treatment of patients suffering from PID, or secondary immunodeficiency disorders (SID) caused, for instance, by irradiation, immunosuppressive drugs or thymectomy. Common variable immunodeficiency (CVID) is the most commonly diagnosed and least understood form of PID, with a heterogeneous range of symptoms and genotypes, requiring individualized treatment plans. This includes adjusting the dose and treatment interval, administrating Ig by intravenous or subcutaneous injection by either pump or push, and finally deciding which treatment options are best for a given patient. Ig therapy can also be used to treat immunodeficiencies resulting from lymphoproliferative and autoimmune diseases or immunosuppression following organ transplantation; however, there is an urgent need for research in this field. Accurate and early diagnosis of PID is important to ensure that optimal treatment is started early to maintain the patient's health. Detailed patient registries have been established to increase awareness of PID, as well as provide a valuable resource for further research.

Large vessel vasculitis and spondyloarthritis: coincidence or associated diseases?

INTRODUCTION: Although cardiac complications have been reported in established spondyloarthritis (SpA), little is known about peripheral axial SpA in large vessel vasculitis (LVV). The aim of this study was to assess the prevalence of SpA in patients with newly diagnosed LVV. METHOD: Retrospective single-centre analysis of all newly diagnosed LVV patients was performed between January 2011 and December 2012. Vasculitides were confirmed on thoracic magnetic resonance imaging (MRI) or 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). Patients completed a standardized questionnaire incorporating the Berlin criteria to assess inflammatory back pain. Existing scans were reassessed for sacroiliitis and ferritin antibodies measured in all patients. RESULTS: Fifteen patients exhibiting new LVV were identified. Diagnosis was confirmed using MRI in nine patients and FDG-PET/CT in six. Six patients (40%) fulfilled American College of Rheumatology (ACR) criteria for giant cell arteritis (GCA) and polymyalgia rheumatica (PMR), and nine PMR only. Four patients fulfilled the Berlin criteria for inflammatory back pain, with three demonstrating sacroiliitis on imaging. All remaining patients demonstrated no sacroiliitis. One further patient with LVV lacking features of inflammatory back pain had known psoriatic arthritis (PsA). Patients with coexisting SpA were younger (mean age 57 years vs. 66 years) and had higher C-reactive protein (CRP) levels (200 mg/L vs. 85 mg/L) at presentation. Four SpA patients and seven out of nine patients with isolated LVV had ferritin antibodies. CONCLUSIONS: We have demonstrated a higher than anticipated prevalence of SpA in LVV, given the reported 0.5-1% prevalence in the general population. Coexisting SpA should be considered in LVV patients exhibiting inflammatory back pain despite steroid initiation. Ferritin antibodies demonstrated a similarly high prevalence in aortitis and SpA as reported previously in untreated GCA and PMR.

Elevated CD57 and CD95 expressions are associated with lower numbers of CD4⁺ recent thymic emigrants in HIV-1 infected immune responders following antiretroviral treatment.

The goal of this study was to understand how immune reconstitution through ART in HIV-1 infected patients affects CD4(+) recent thymic emigrants (identified as CD31(+) naïve T cells). We performed FACS analysis of CD4(+) CD31(+) naïve T cells from PBMCs in a cross-sectional age-matched cohort, including 25 healthy controls (HC), 18 untreated HIV-1 infected viremic progressors (VP), 10 untreated HIV-1 infected viral controllers (VC), and 24 HIV-1 infected immune responders (IR) following ART. Our data reveal that 37.5% of IR failed to restore their CD4(+) CD31(+) naïve T cell counts. In addition, significantly higher expressions of Ki67, CD57, and CD95 were observed in CD4(+) CD31(+) naïve T cells of both VP and IR comparing to HC and VC. The significantly elevated CD57 and CD95 expressions are observed in IR with low CD4(+) CD31(+) naïve T cell counts. Therefore, our data indicate an incomplete immune reconstitution of CD4(+) CD31(+) naïve T cells in more than one third of IR, which is associated with HIV-1 driven immunological phenotypic alterations.

Impact of GB virus C viraemia on clinical outcome in HIV-1-infected patients: a 20-year follow-up study.

OBJECTIVES: The impact of coexisting GB virus C (GBV-C) infection on the clinical course of HIV infection remains controversial. Early data from HIV-1 infected patients attending the Hannover Medical School in 2001 suggested prognostic benefit in GBV-C viraemic patients. The aim of this study was to evaluate patterns in long-term mortality and morbidity outcomes in this cohort. The impact of the introduction of antiretroviral therapy (ART) on the perceived benefits of GBV-C viraemia was subsequently investigated. METHODS: A retrospective follow-up analysis of data in this cohort was performed. GBV-C status (GBV-C RNA positive, antibodies against GBV-C envelope protein E2 or no evidence of GBV-C exposure) had been determined at enrolment, with several markers of HIV disease progression (such as viral load and CD4 cell count) being collated from 1993/1994, 2000 and 2012. These eras were chosen to reflect variations in treatment strategies within the cohort. In addition, mortality and HIV-related morbidity data were collated for all patients. RESULTS: Complete data were available for 156 of 197 patients (79%). In highly active antiretroviral therapy (HAART)-naïve patients, GBV-C RNA positivity conferred significant improvements in the course of HIV infection and mortality as well as lower rates of HIV-related diseases. E2 positivity alone conferred no significant advantage. With the advent of HAART, however, the benefits GBV-C RNA positivity disappeared. CONCLUSIONS: Although GBV-C coinfection appears to inherently improve morbidity and mortality in HIV-infected patients, modern HAART has eradicated these advantages. Evidence of synergy between GBV-C status and HAART response exists, with further studies examining the role of GBV-C in existing treatment de-escalation strategies being required.

Epitope mapping of antibodies against ferritin heavy chain in giant cell arteritis and polymyalgia rheumatica.

OBJECTIVES: In a previous study we found an association between antibodies against the human ferritin heavy chain (HFC) protein and giant cell arteritis (GCA) and/or polymyalgia rheumatica (PMR), especially in GCA/PMR patients prior to glucocorticoid treatment. Antibodies against the N-terminal part of ferritin were present in 92% of untreated patients, 69% of patients with disease flare, and 13% of patients in remission. These antibodies appeared to be markers for the early detection of a disease complex usually diagnosed with considerable delay. Our aim in this study was to optimize the diagnostic test by epitope mapping of antibodies against HFC using peptide antigens in enzyme-linked immunosorbent assays (ELISAs). METHOD: We evaluated serum samples from a selected group of GCA/PMR patients in whom the sensitivity of antibodies against the N-terminal ferritin peptide was only 35%. Patients with late-onset rheumatoid arthritis (LORA), patients with fever, patients with granulomatosis with polyangiitis (GPA), patients without any autoimmune disease at age > 65 years, and blood donors served as controls. RESULTS: By combining different ELISAs we were able to increase the frequency of human ferritin peptide antibodies in GCA/PMR (p < 0.0001) without significantly altering the false-positive rate (FPR) of the diagnostic test. The frequency of antibodies against human ferritin peptide increased from 53% to 74% in GCA/PMR patients with disease flare, from 29% to 40% in GCA/PMR patients in partial remission, and from 8% to 45% in GCA/PMR patients in complete remission. CONCLUSIONS: The potential diagnostic test for GCA/PMR can be improved by combining three human ferritin peptide antibodies.

Outcomes of splenectomy in patients with common variable immunodeficiency (CVID): a survey of 45 patients.

Splenectomy has been used in patients with common variable immunodeficiency disorders (CVID), mainly in the context of refractory autoimmune cytopenia and suspected lymphoma, but there are understandable concerns about the potential of compounding an existing immunodeficiency. With increasing use of rituximab as an alternative treatment for refractory autoimmune cytopenia, the role of splenectomy in CVID needs to be re-examined. This retrospective study provides the largest cohesive data set to date describing the outcome of splenectomy in 45 CVID patients in the past 40 years. Splenectomy proved to be an effective long-term treatment in 75% of CVID patients with autoimmune cytopenia, even in some cases when rituximab had failed. Splenectomy does not worsen mortality in CVID and adequate immunoglobulin replacement therapy appears to play a protective role in overwhelming post-splenectomy infections. Future trials comparing the effectiveness and safety of rituximab and splenectomy are needed to provide clearer guidance on the second-line management of autoimmune cytopenia in CVID.

[Adult onset Still's disease, fever, diagnosis and therapy]. / Adulter Morbus Still, Fieber, Diagnose und Therapie.

Adult onset Still's disease (AOSD) with an incidence of 1-3 cases per 1 million belongs to the most difficult diagnosis of febrile diseases. The lack of biomarkers and its similarity to infectious and malignant and rheumatic diseases lead to a prolongation of its diagnosis. The following report focuses on providing an overview of the current knowledge of relevant symptoms and laboratory parameters for the diagnosis of AOSD and new treatment possibilities.

Association of ferritin autoantibodies with giant cell arteritis/polymyalgia rheumatica.

OBJECTIVES: Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are relatively common inflammatory disorders. Establishing the diagnosis however may be difficult, since so far no specific biomarkers of the disorders are available. METHODS: As a screening procedure, the authors used protein arrays for the detection of new autoantigens in GCA and PMR. The results of the protein array were confirmed by different ELISAs detecting IgG antibodies against the human ferritin heavy chain, N-terminal 27 amino acids of the human ferritin heavy chain or the homologous peptide of Staphylococcus epidermidis. Sera of patients with only GCA (n=64), only PMR (n=47) and both PMR and GCA (n=31) were used. RESULTS: In the ELISA using the human ferritin peptide, the sensitivity of IgG antibodies against ferritin was 92% in 36 GCA and/or PMR patients before initiation of treatment, 22/32 (69%) in patients with disease flares and 64/117 (55%) in the total cohort including treated and inactive patients. In controls, the false positive rate was 11/38 (29%) in systemic lupus erythematosus, 1/36 (3%) in rheumatoid arthritis, 0/31 (0%) in late onset rheumatoid arthritis, 3/46 (6.5%) in B-non-Hodgkin's lymphoma and 1/100 (1%) in blood donors. In the ELISA using the ferritin peptide of S epidermidis, 89% of 27 patients with untreated GCA and PMR were positive. CONCLUSION: Antibodies against the ferritin peptide were present in up to 92% of untreated, active GCA and PMR patients. They can be useful as a diagnostic marker of PMR and GCA.

Impaired CD4+ cell recovery during antiretroviral therapy in patients with HIV resistance mutations.

Antiretroviral therapy is limited by the development of human immunodeficiency virus (HIV) resistance mutations. Although resistance testing is recommended during therapy failure, little is known about the optimal time points for testing or its impact on treatment. In this study, we investigated HIV polymorphisms and mutations and assessed their influence on the outcome of highly active antiretroviral therapy (HAART). We focused on viral load and CD4+ cell counts as the most important parameters for therapy response. Resistance mutations were present in 19% of all patients prior to antiretroviral treatment. Mutations causing direct antiretroviral drug resistance were observed in 10%. Analyzing therapy response, we found a significant correlation between resistance mutations and impaired CD4+ cell recovery six months after the initiation of antiretroviral treatment. Lower CD4+ cell counts were also observed in a subgroup of patients infected with a virus presenting mutations that directly lowered drug susceptibility.

[University contribution to implementation of the treat-to-target concept in rheumatology]. / Universitärer Beitrag zur Implementierung des Treat-To-Target-Konzepts in der Rheumatologie.

Following similar examples for diabetes mellitus and hypertension an attempt was made to establish a treat-to-target (T2T) program for rheumatic diseases in order to improve the course of the disease. Nevertheless, it is a factum that rheumatology, a recognized discipline in internal medicine, was not represented in university clinics corresponding to its scientific, clinical and socioeconomic importance. On the question how rheumatology in university clinics can contribute to the implementation of a T2T program, several aspects have to be considered. These include improvement in training and further education, establishment of clinical scientific core topics, formulation of guidelines, initiation of controlled studies, establishment of long-term cohorts and the incorporation of pathogenetic and therapeutic information in international networks and national symposia.

A fatal case of AIDS-defining meningoencephalitis by C. neoformans, sensitive to antifungal therapy.

Cryptococcus neoformans is the most common cause of life threatening meningoencephalitis in HIV-infected patients. Diagnosis is based on tests for cryptoccocal antigen in serum and cerebrospinal fluid, and on culture of the organism. We present a case of AIDS-related cryptococcal meningoencephalitis unresponsive to antifungal combination therapy, despite of evidence of fungal susceptibility in vitro. Significant decreases in cryptococcal antigen titers in serum and cerebrospinal fluid did not correlate with progress in disease and fatal outcome.

[HIV-therapy-associated immune reconstitution syndrome presenting as immunogenic hyperthyroidism]. / Immunogene Hyperthyreose als Immunrekonstitutionssyndrom unter HIV-Therapie.

HISTORY AND CLINICAL FINDINGS: A 51-year-old man infected with HIV-1 presented with weight loss, weakness, fever, agitation, tachycardia and tremor first occurring three year after initiation of antiretroviral therapy. INVESTIGATIONS: The electrocardiogram showed atrial fibrillation. Laboratory findings revealed hyperthyroidism with fully suppressed thyroid stimulating hormone (TSH). Antibodies against thyroid globulin and TSH-receptor were markedly increased. Both alpha-fodrin antibodies and antinuclear antibodies were abnormal. Retrospective analysis revealed an association of hyperthyroidism and the presence of autoantibodies with a sudden immune reconstitution under HIV-therapy. DIAGNOSIS, TREATMENT AND COURSE: An immune reconstitution inflammatory syndrome (IRIS) presenting as Graves's disease was diagnosed and treated with radioiodide. The patient recovered to clinical euthyroidism while antiretroviral treatment remained unchanged. CONCLUSION: IRIS against infectious or self-antigens during HIV treatment results from local or systemic inflammatory imbalances. IRIS with autoimmune manifestations may occur even years after initiation of an effective antiretroviral therapy.

[Reactivation of tuberculosis with Mycobacterium bovis infection of the oral mucosa during immunosuppression]. / Tuberkulosereaktivierung mit Mycobacterium-bovis-Infektion der Mundschleimhaut unter Immunsuppression.

HISTORY: A 70-year-old woman who had for five years been treated with tumour necrosis factor (TNF)-a-inhibitors for rheumatoid arthritis was admitted because of treatment-refractory oral ulcerations and persisting considerable soft-tissue swelling over the left maxilla. INVESTIGATIONS AND DIAGNOSIS: Multiple mucosal biopsies from the left maxillary sinus revealed necrotizing granulomatous inflammation suspicious of mycobacterial infection. This was subsequently confirmed in concurrent microbiological cultures and ultimately identified as Mycobacterium bovis. This species of the mycobacterium tuberculosis complex has in recent times rarely been seen in clinical practice in Germany. On further questioning the patient reported that she had been treated for "lung disease" as a schoolgirl. TREATMENT AND COURSE: The patient was isolated and quadruple therapy with isoniazide (INH), rifampin (RMP), ethambutol (EMB) and pyrazinamide (PZA) was initiated. Rapid improvement of her condition occurred within two weeks. When microbiological sub-typing using 16s-RNA sequencing had confirmed M. bovis, PZA was replaced by moxifloxacin. CONCLUSION: When investigating the cause of treatment-refractory infections and ulcerations, particularly among immunosuppressed patients, consideration should always be given to mycobacterial infections. Detailed and targeted history-taking is vital.

[Eosinophilic fasciitis and asplenia]. / Eosinophile Fasziitis und Asplenie.

Eosinophilic fasciitis (Shulman syndrome) is a chronic inflammation primarily of the septums and fascia, and is characterized by the infiltration of eosinophils with additional similarities to systemic sclerosis. Several diseases have been described in association with eosinophilic fasciitis. Among these are aplastic anaemia, haemolytic anaemia, thrombocytopenia, lymphoproliferative disorders, thyroiditis, pulmonary fibrosis, Sjögren's syndrome, Raynaud's phenomenon, myositis, medium vessel vasculitis, pericarditis, colitis and glomerulonephritis. To date, no association with congenital asplenia has been described. We report the case of a woman with eosinophilic fasciitis and congenital asplenia and discuss the possible causes and potential consequences.