[Delegation of medical duties to qualified rheumatology assistants : Effect on depression and anxiety in patients with rheumatoid arthritis]. / Delegation ärztlicher Leistungen an rheumatologische Fachassistenten : Effekte auf Depression und Angst bei Patienten mit rheumatoider Arthritis.

BACKGROUND: At least 1 comorbidity occurs in 80% of patients with rheumatoid arthritis (RA). In addition to cardiovascular comorbidities psychological comorbid conditions are common. The prevalence of depression and anxiety is higher in patients than in the general population. Screening for comorbidities is crucial. A shortage of outpatient specialist care barely allows resources for this. The implementation of team-based care holds the potential to improve the standard of care while simultaneously working against the shortage of care. OBJECTIVE: The aim of the study was to examine the effects of care on the course of depression and anxiety in patients with seropositive RA and active disease. MATERIAL AND METHODS: A multicenter pragmatic randomized controlled trial was conducted over the course of 1 year with 224 patients. After baseline, five more visits followed. In the intervention group (IG), three were initially carried out by qualified rheumatological assistants. Depression, anxiety and patient satisfaction with outpatient care were looked at in detail. RESULTS: In the IG the anxiety symptoms significantly improved over 12 months (p = 0.036). The proportions of patients with anxiety also significantly changed in the IG (p < 0.001), while there was no change in the control group between baseline and month 12. The values of the depression scale did not differ significantly (p = 0.866). In terms of the information dimension of the satisfaction questionnaire, patients in the IG felt significantly better informed after 6 months (p = 0.013) and 12 months (p = 0.003). CONCLUSION: A positive effect of team-based care on the course of depression and anxiety in patients with seropositive RA and active disease could be shown.

Increased CD56(bright) NK cells in HIV-HCV co-infection and HCV mono-infection are associated with distinctive alterations of their phenotype.

BACKGROUND: HIV-HCV co-infection is associated with accelerated progression to hepatic fibrosis, cirrhosis and hepatocellular carcinoma than HCV mono-infection. The contribution of innate immunity during HIV-HCV co-infection has been a relatively under-investigated area. Natural killer (NK) cells are pivotal sentinels of innate immunity against viruses and tumour cells. In this study we evaluated the effect of HIV-HCV co-infection on peripheral blood NK cell subsets with emphasis on the phenotype of CD56(bright) NK cells. METHODS: Sixty patients were included in the study; HIV mono-infected (n = 12), HCV mono-infected (n = 15), HCV-HIV co-infected (n = 21) and healthy controls (n = 16). PBMCs were isolated and immunophenotyping of NK cells was performed by flowcytometry. RESULTS: We observed an expansion of CD56(bright) NK cell subset in HIV-HCV co-infection as compared to healthy controls and HIV mono-infected group. All the infected groups had an upregulated expression of the activating receptor NKG2D on CD56(bright) NK cells in comparison to healthy controls while not differing amongst themselves. The expression of NKp46 in HIV-HCV co-infected group was significantly upregulated as compared to both HIV as well as HCV mono-infections while NKp30 expression in the HIV-HCV co-infected group significantly differed as compared to HIV mono-infection. The CD56(bright) NK cell subset was activated in HIV-HCV co-infection as assessed by the expression of CD69 as compared to healthy controls but was significantly downregulated in comparison to HIV mono-infection. CD95 expression on CD56(bright) NK cells followed the same pattern where there was an increased expression of CD95 in HIV mono-infection and HIV-HCV co-infection as compared to healthy controls. In contrast to CD69 expression, CD95 expression in HCV mono-infection was decreased when compared to HIV mono-infection and HIV-HCV co-infection. Finally, expression of CXCR3 on CD56(bright) NK cells was increased in HIV-HCV co-infection in comparison to HIV mono-infection while remaining similar to HCV mono-infection. CONCLUSION: Thus, HIV-HCV co-infection is able to modulate the phenotype of CD56(bright) NK cell subset in a unique way such that NKp46 and CXCR3 expressions are distinct for co-infection while both mono-infections have an additive effect on CD56(bright), CD69 with CD95 expressions. HCV mono-infection has a dominant effect on NKp30 expression while NKG2D and CD127 expressions remained same in all the groups.

Natural killer cell heterogeneity: cellular dysfunction and significance in HIV-1 immuno-pathogenesis.

Natural killer (NK) cells are innate immune effectors that provide first line of defence against viruses. Human NK cells are heterogeneous in nature, and their functions rely on a dynamic balance between germ-line-encoded activating and inhibitory receptors. HIV-1 infection results in altered NK cell receptor repertoire and impaired effector functions including the ability to lyse virus-infected cells and secretion of antiviral cytokine IFN-γ. Over the last decade, additional NK cell subset-specific molecules have been identified, leading to emergence of a more complex cellular diversity than previously thought. Herein, we discuss NK cell subset redistribution, altered receptor repertoire and influence of interaction of polymorphic leucocyte antigen (HLA) and killer cell immunoglobulin-like receptors (KIR) on HIV-1 disease progression.

FcγRIII (CD16)-mediated ADCC by NK cells is regulated by monocytes and FcγRII (CD32).

Monocytes are known to engage in reciprocal crosstalk with NK cells but their influence on NK-cell-associated antibody-dependent cellular cytotoxicity (ADCC) is not well understood. We demonstrate that in humans FcγRIII (CD16)-dependent ADCC by NK cells is considerably enhanced by monocytes, and that this effect is regulated by FcγRII (CD32) crosslinking in healthy individuals. It is known that during HIV-1 infection, NK cells are known to express low levels of CD16 and exhibit reduced ADCC. We show that immune regulation of CD16-mediated NK-cell cytotoxicity by monocytes through CD32 engagement is substantially disturbed in chronic progressive HIV-1 infection. Expression of activating isoform of CD32 represented a compensatory mechanism for reduced expression of CD16 on NK cells during HIV-1 infection. As a result, the regulation of NK-cell-associated ADCC by monocytes is skewed and eventually constitutes a novel factor that contributes to HIV-1-associated immune deficiency, dysregulation and pathogenesis. Our data therefore provide evidence, for the first time, that in humans monocytes act as a rheostat for FcγRIII-mediated NK-cell functions maintaining a well-balanced immune response.

High frequencies of polyfunctional CD8+ NK cells in chronic HIV-1 infection are associated with slower disease progression.

UNLABELLED: Natural killer (NK) cells are effector and regulatory innate immune cells and play a critical role in the first line of defense against various viral infections. Although previous reports have indicated the vital contributions of NK cells to HIV-1 immune control, nongenetic NK cell parameters directly associated with slower disease progression have not been defined yet. In a longitudinal, retrospective study of 117 untreated HIV-infected subjects, we show that higher frequencies as well as the absolute numbers of CD8(+) CD3(-) lymphocytes are linked to delayed HIV-1 disease progression. We show that the majority of these cells are well-described blood NK cells. In a subsequent cross-sectional study, we demonstrate a significant loss of CD8(+) NK cells in untreated HIV-infected individuals, which correlated with HIV loads and inversely correlated with CD4(+) T cell counts. CD8(+) NK cells had modestly higher frequencies of CD57-expressing cells than CD8(-) cells, but CD8(+) and CD8(-) NK cells showed no differences in the expression of a number of activating and inhibiting NK cell receptors. However, CD8(+) NK cells exhibited a more functional profile, as detected by cytokine production and degranulation. IMPORTANCE: We demonstrate that the frequency of highly functional CD8(+) NK cells is inversely associated with HIV-related disease markers and linked with delayed disease progression. These results thus indicate that CD8(+) NK cells represent a novel NK cell-derived, innate immune correlate with an improved clinical outcome in HIV infection.

Selective expansion of pro-inflammatory chemokine CCL2-loaded CD14+CD16+ monocytes subset in HIV-infected therapy naïve individuals.

We have previously demonstrated the critical role of C-C chemokine CCL2 in HIV-1 pathogenesis, and circulating monocytes as the major source of CCL2. Since the functional aspect of monocyte subsets in context to CCL2 production is unclear, we investigated the frequency and production of CCL2 by circulating monocyte subsets in a cohort of HIV- therapy naïve patients. A cohort of HIV-infected therapy naïve patients (n=9) and healthy controls (n=6) were recruited for this study. To examine monocyte subset frequency and CCL2 production, we performed surface and intra-cellular staining of freshly isolated peripheral blood mononuclear cells (PBMC) and subjected to flow cytometry. A preferential expansion of CD14(+)CD16(+) monocyte subset, coupled with increased intracellular production of CCL2 was observed in HIV-1 patients compared to healthy controls. Interestingly this phenotype was mostly restricted to CD14(+)CD16(+) monocyte subsets. This study identifies pro-inflammatory CCL2 producing CD14(+)CD16(+) monocyte subset that expands selectively in HIV-1 infection and could potentially participate in causing immuno-pathology.

Dominant clonotypes within HIV-specific T cell responses are programmed death-1high and CD127low and display reduced variant cross-reactivity.

HIV epitope-specific T cell responses are often comprised of clonotypic expansions with distinct functional properties. In HIV(+) individuals, we measured programmed death-1 (PD-1) and IL-7Rα expression, MHC class I tetramer binding, cytokine production, and proliferation profiles of dominant and subdominant TCR clonotypes to evaluate the relationship between the composition of the HIV-specific T cell repertoire and clonotypic phenotype and function. Dominant clonotypes are characterized by higher PD-1 expression and lower C127 expression compared with subdominant clonotypes, and TCR avidity positively correlates with PD-1 expression. At low peptide concentrations, dominant clonotypes fail to survive in culture. In response to stimulation with peptides representing variant epitopes, subdominant clonotypes produce higher relative levels of cytokines and display greater capacity for cross-recognition compared with dominant clonotypes. These data indicate that dominant clonotypes within HIV-specific T cell responses display a phenotype consistent with ongoing exposure to cognate viral epitopes and suggest that cross-reactive, subdominant clonotypes may retain greater capacity to suppress replication of viral variants as well as to survive in the absence of strong antigenic signaling.

Work participation in patients with axial spondyloarthritis: high prevalence of negative workplace experiences and long-term work impairment.

INTRODUCTION: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that typically affects people in their second and third decades of life, which are important years for establishing a professional career. We aim to study outcomes of work participation (WP) and their associations with demographic and clinical confounders, in addition to prevalence of negative workplace experiences in axSpA. METHODS: In total, 770 patients with axSpA participated in the multicentre, observational ATTENTUS-axSpA survey in Germany. Demographic information, clinical parameters and patient-related outcomes (including disease activity and function) with a focus on WP were prospectively recorded. RESULTS: A high prevalence of negative workplace experiences was reported among the 770 patients analysed. Overall, 23.4% of patients were not employed and 6.5% received disability pensions. Current work cessation was prevalent in 120 patients, and 28 of those were out of work for 10 years or longer. Of the 590 currently employed patients, 31.9% reported absenteeism and 35.9% reported presenteeism for >1 month within the past year. Multivariate logistic regression identified low disease activity (Bath Ankylosing Spondylitis Disease Activity Index), better physical function (Bath Ankylosing Spondylitis Functional Index) and better global functioning (Assessment of SpondylAarthritis International Society-Health Index) as the main predictors for unimpaired WP (n=242). Importantly, biological treatment, disease duration, age, sex, education level and body mass index were not reliable predictors. DISCUSSION: Despite improvements in pharmacological treatment options, we still observed substantially impaired WP in patients with axSpA. These data emphasise the high unmet need for targeted strategies to provide improved medical and social care.

CCL2: a potential prognostic marker and target of anti-inflammatory strategy in HIV/AIDS pathogenesis.

Chemokines are critical components of the immune system that participate in immune homeostasis and alterations in chemokine balance can result in severe inflammatory and autoimmune diseases. The role of chemokines and their receptors in viral infections including HIV-1 was predicted from the early studies of HIV-1 co-receptor CCR5 and its ligands and a divergent role of C-C chemokines in HIV-1 pathogenesis has been established. For example, CCL3 (MIP-1α), CCL4 (MIP-1ß) and CCL5 (RANTES) have been shown to possess antiviral effects by binding to the HIV-1 co-receptor CCR5, whereas CCL2, a pro-inflammatory chemokine, supports HIV-1 replication despite being a member of same chemokine family. Furthermore, the well-established role of CCL2 in driving the Th2 immune response supports its potential role in HIV-1/AIDS. Recent reports suggest multiple pathways of CCL2 affect HIV-1 infection. In this review, we provide a comprehensive overview of the role and potential mechanisms of the HIV-1-CCL2 interplay in driving virus-induced immuno-pathology, suggesting that CCL2 could be an anti-inflammatory target in the treatment of HIV-1 infection.

Comprehensive analysis of frequency and phenotype of T regulatory cells in HIV infection: CD39 expression of FoxP3+ T regulatory cells correlates with progressive disease.

There are conflicting data about the frequency and role of regulatory T cells (Tregs) during the course of HIV infection. Peripheral blood of a large cohort of HIV-infected patients (n = 131) at different stages of disease, including 15 long-term nonprogressors and 21 elite controllers, was analyzed to determine the frequency and phenotype of Tregs, defined as CD4(+), CD25(high), CD127(low), FoxP3(high) cells. A significantly increased relative frequency of Tregs within the CD4(+) compartment of HIV(+) patients compared to that of healthy controls (P < 0.0001) was observed. Additionally, the relative frequency of Tregs directly correlated with HIV viral load and inversely with CD4(+) counts. However, the absolute Treg number was reduced in HIV-infected patients versus healthy controls (P < 0.0001), with the exception of elite controllers (P > 0.05). The loss of absolute Treg numbers coincided with rising markers of immune activation (P < 0.0006). The initiation of antiviral therapy significantly increased absolute Treg numbers (P < 0.0031). We find that the expression of CD39, a newly defined ectonucleotidase with immunomodulatory functions on Tregs, correlated with progressive HIV disease, HIV viral load, and immune activation. Of note, when tested in peripheral blood mononuclear cells of healthy volunteers, the in vitro capacity to suppress T-cell proliferation was limited to CD4(+), CD25(high), CD39(+) T cells. Interestingly, Tregs of elite controllers exhibited not only the highest expression of CCR5, CTLA-4, and ICOS but also the lowest level of CD39. The data presented here reconcile the seemingly contradictory results of previous studies looking at Tregs in HIV and highlight the complexity of Treg-mediated immunoregulation during human viral infections.

Clonal expansion and TCR-independent differentiation shape the HIV-specific CD8+ effector-memory T-cell repertoire in vivo.

Flexibility of the HIV-specific T-cell receptor repertoire is a hallmark of HIV-1 infection. Altered differentiation of HIV-specific CD45RO(+)/CCR7(-) (TemRO) CD8(+) effector-memory T cells into CD45RA(+)/CCR7(-) (TemRA) CD8(+) effector-memory T cells as well as increased expression of the senescence marker CD57 has been frequently observed HIV-1 infection, but the structural relationship between clonal expansion and T-cell differentiation has not been defined. In this study, we demonstrate that HIV-specific clonotypes have differing degrees of TemRA differentiation but always maintain a significant proportion of TemRO-phenotype cells. These data indicate that structural constraints of the TCR/peptide major histocompatibility complex interaction play a central role in the TemRA differentiation of HIV-specific CD8(+) T cells in chronic HIV-1 infection. Clonotypes with a predominantly TemRA phenotype had a substantial fraction of cells without expression of CD57; and in contrast to the high clonotypic variability of TemRA differentiation, expression of CD57 was highly correlated among T-cell clonotypes within epitope-specific responses, indicating TCR-independent expression of CD57 in vivo. Our data highlight the importance of the structural composition of the TCR repertoire for the effector-memory differentiation of the immune response in chronic viral infections and suggest that TCR-dependent and -independent homeostasis shapes the pathogen-specific effector-memory repertoire in vivo.

HIV infection is associated with a preferential decline in less-differentiated CD56dim CD16+ NK cells.

HIV-1 infection is characterized by loss of CD56(dim) CD16(+) NK cells and increased terminal differentiation on various lymphocyte subsets. We identified a decrease of CD57(-) and CD57(dim) cells but not of CD57(bright) cells on CD56(dim) CD16(+) NK cells in chronic HIV infection. Increasing CD57 expression was strongly associated with increasing frequencies of killer immunoglobulin-like receptors (KIRs) and granzyme B-expressing cells but decreasing percentages of cells expressing CD27(+), HLA-DR(+), Ki-67(+), and CD107a. Our data indicate that HIV leads to a decline of less-differentiated cells and suggest that CD57 is a useful marker for terminal differentiation on NK cells.

Effect of nurse-led care on outcomes in patients with ACPA/RF-positive rheumatoid arthritis with active disease undergoing treat-to-target: a multicentre randomised controlled trial.

OBJECTIVE: To determine the non-inferiority of nurse-led care (NLC) in patients with anticitrullinated protein antibody (ACPA)-positive and/or rheumatoid factor (RF)-positive rheumatoid arthritis (RA) with active disease who are starting disease-modifying antirheumatic drug therapy, following treat-to-target (T2T) recommendations. METHODS: A multicentre, pragmatic randomised controlled trial was conducted to assess clinical effectiveness, anxiety, depression and patient satisfaction following a non-inferiority design. The participants were 224 adults with ACPA/RF-positive RA who were randomly assigned to either NLC or rheumatologist-led care (RLC). The primary outcome was the Disease Activity Score in 28 Joints measured with C reactive protein (DAS28-CRP) assessed at baseline and after 3, 6, 9 and 12 months. A DAS28-CRP difference of 0.6 was set as the non-inferiority margin. Mean differences between the groups were assessed following per-protocol and intention-to-treat strategies. RESULTS: Demographic data and baseline characteristics of patients in the NLC group (n=111) were comparable to those of patients in the RLC group (n=113). The improvement in disease activity (change in DAS28-CRP, primary outcome) over the course of 12 months was significant in both groups (p<0.001). No significant differences were observed between the NLC and RLC groups (p=0.317). Non-inferiority of NLC was shown for the primary outcome and all secondary outcomes. CONCLUSION: This study supported the non-inferiority of NLC in managing T2T and follow-up care of patients with RA with moderate to high disease activity and poor prognostic factors in addition to RLC. TRIAL REGISTRATION NUMBER: DRKS00013055.

Limited T cell receptor diversity of HCV-specific T cell responses is associated with CTL escape.

Escape mutations are believed to be important contributors to immune evasion by rapidly evolving viruses such as hepatitis C virus (HCV). We show that the majority of HCV-specific cytotoxic T lymphocyte (CTL) responses directed against viral epitopes that escaped immune recognition in HCV-infected chimpanzees displayed a reduced CDR3 amino acid diversity when compared with responses in which no CTL epitope variation was detected during chronic infection or with those associated with protective immunity. Decreased T cell receptor (TCR) CDR3 amino acid diversity in chronic infection could be detected long before the appearance of viral escape mutations in the plasma. In both chronic and resolved infection, identical T cell receptor clonotypes were present in liver and peripheral blood. These findings provide a deeper understanding of the evolution of CTL epitope variations in chronic viral infections and highlight the importance of the generation and maintenance of a diverse TCR repertoire directed against individual epitopes.

Despite biased TRBV gene usage against a dominant HLA B57-restricted epitope, TCR diversity can provide recognition of circulating epitope variants.

The role of epitope-specific TCR repertoire diversity in the control of HIV-1 viremia is unknown. Further analysis at the clonotype level is important for understanding the structural aspects of the HIV-1 specific repertoire that directly relate to CTL function and ability to suppress viral replication. In this study, we performed in-depth analysis of T cell clonotypes directed against a dominantly recognized HLA B57-restricted epitope (KAFSPEVIPMF; KF11) and identified common usage of the TCR beta-chain TRBV7 in eight of nine HLA B57 subjects examined, regardless of HLA B57 subtype. Despite this convergent TCR gene usage, structural and functional assays demonstrated no substantial difference in functional or structural avidity between TRBV7 and non-TRBV7 clonotypes and this epitopic peptide. In a subject where TRBV7-usage did not confer cross-reactivity against the dominant autologous sequence variant, another circulating TCR clonotype was able to preferentially recognize the variant peptide. These data demonstrate that despite selective recruitment of TCR for a conserved epitope over the course of chronic HIV-1 infection, TCR repertoire diversity may benefit the host through the ability to recognize circulating epitope variants.

Kinetic analysis by real-time PCR of hepatitis C virus (HCV)-specific T cells in peripheral blood and liver after challenge with HCV.

Intrahepatic virus-specific CD8(+) T cells are thought to be important for the control of hepatitis C virus (HCV) infection, yet the precise kinetics for the expansion of epitope-specific T cells over the course of infection are difficult to determine with currently available methods. We used a real-time PCR assay to measure the frequency of clonotypic HCV-specific CD8(+) T cells in peripheral blood and snap-frozen liver biopsy specimens of two chimpanzees (Pan troglodytes) with previously resolved HCV infection who were rechallenged with HCV. In response to rechallenge, the magnitude of each clonotypic response was 10-fold higher in the liver than in the blood, and the peak clonotype frequency was concurrent with the peak viral load. The higher frequency of HCV-specific clonotypes in the liver than in peripheral blood was maintained for at least 3 months after the clearance of viremia. After antibody-mediated CD8(+) T-cell depletion and another viral challenge, the rebound of these clonotypes was seen prior to an appreciable reconstitution of CD8(+) T-cell values and, again, at higher frequencies in the liver than in peripheral blood. These data demonstrate the importance of intrahepatic virus-specific CD8(+) T cells for the clearance of infection and the rapid kinetics of expansion after virus challenge.

Sensitivity and Specificity of Autoantibodies Against CD74 in Nonradiographic Axial Spondyloarthritis.

OBJECTIVE: Autoantibodies against CD74 (anti-CD74) are associated with ankylosing spondylitis (AS). The present multicenter study, the International Spondyloarthritis Autoantibody (InterSpA) trial, was undertaken to compare the sensitivity and specificity of anti-CD74 and HLA-B27 in identifying patients with nonradiographic axial spondyloarthritis (axSpA). METHODS: Patients ages 18-45 years with inflammatory back pain of ≤2 years' duration and a clinical suspicion of axSpA were recruited. HLA-B27 genotyping and magnetic resonance imaging of sacroiliac joints were performed in all patients. One hundred forty-nine patients with chronic inflammatory back pain (IBP) not caused by axSpA served as controls, and additional controls included 50 AS patients and 100 blood donors whose specimens were analyzed. RESULTS: One hundred patients with inflammatory back pain received a diagnosis of nonradiographic axSpA from the investigators and fulfilled the Assessment of SpondyloArthritis international Society (ASAS) criteria. The mean age was 29 years, and the mean symptom duration was 12.5 months. The sensitivity of IgA anti-CD74 and IgG anti-CD74 for identifying the 100 axSpA patients was 47% and 17%, respectively. The specificity of both IgA anti-CD74 and IgG anti-CD74 was 95.3%. The sensitivity of HLA-B27 was 81%. The positive likelihood ratios were 10.0 (IgA anti-CD74), 3.6 (IgG anti-CD74), and 8.1 (HLA-B27). Assuming a 5% pretest probability of axSpA in chronic back pain patients, the posttest probability, after consideration of the respective positive test results, was 33.3% for IgA anti-CD74, 15.3% for IgG anti-CD74, and 28.8% for HLA-B27. A combination of IgA anti-CD74 and HLA-B27 results in a posttest probability of 80.2%. CONCLUSION: IgA anti-CD74 may be a useful tool for identifying axSpA. The diagnostic value of the test in daily practice requires further confirmation.