Monocyte Scintigraphy in Rheumatoid Arthritis: The Dynamics of Monocyte Migration in Immune-Mediated Inflammatory Disease

Background: Macrophages are principal drivers of synovial inflammation in rheumatoid arthritis (RA), a prototype immune-mediated inflammatory disease. Conceivably, synovial macrophages are continuously replaced by circulating monocytes in RA. Animal studies from the 1960s suggested that macrophage replacement by monocytes is a slow process in chronic inflammatory lesions. Translation of these data into the human condition has been hampered by the lack of available techniques to analyze monocyte migration in man. Methods/Principal Findings: We developed a technique that enabled us to analyze the migration of labelled autologous monocytes in RA patients using single photon emission computer tomography (SPECT). We isolated CD14+ monocytes by CliniMACS in 8 patients and labeled these with technetium-99m (99m-Tc-HMPAO). Monocytes were re-infused into the same patient. Using SPECT we calculated that a very small but specific fraction of 3.4x10(-3) (0.95-5.1x10(-3)) % of re-infused monocytes migrated to the inflamed joints, being detectable within one hour after re-infusion. Conclusions/Significance: The results indicate monocytes migrate continuously into the inflamed synovial tissue of RA patients, but at a slow macrophage-replacement rate. This suggests that the rapid decrease in synovial macrophages that occurs after antirheumatic treatment might rather be explained by an alteration in macrophage retention than in monocyte influx and that RA might be particularly sensitive to treatments targeting inflammatory cell retention

Advances in rheumatology: new targeted therapeutics

Treatment of inflammatory arthritides - including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis - has seen much progress in recent years, partially due to increased understanding of the pathogenesis of these diseases at the cellular and molecular levels. These conditions share some common mechanisms. Biologic therapies have provided a clear advance in the treatment of rheumatological conditions. Currently available TNF-targeting biologic agents that are licensed for at east one of the above-named diseases are etanercept, infliximab, adalimumab, golimumab, and certolizumab. Biologic agents with a different mechanism of action have also been approved in rheumatoid arthritis (rituximab, abatacept, and tocilizumab). Although these biologic agents are highly effective, there is a need for improved management strategies. There is also a need for education of family physicians and other healthcare professionals in the identification of early symptoms of inflammatory arthritides and the importance of early referral to rheumatologists for diagnosis and treatment. Also, researchers are developing molecules - for example, the Janus kinase inhibitor CP-690550 (tofacitinib) and the spleen tyrosine kinase inhibitor R788 (fostamatinib) - to target other aspects of the inflammatory cascade. Initial trial results with new agents are promising, and, in time, head-to-head trials will establish the best treatment options for patients. The key challenge is identifying how best to integrate these new, advanced therapies into daily practice

Drug-microbiota interactions and treatment response: Relevance to rheumatoid arthritis

Knowledge about associations between changes in the structure and/or function of intestinal microbes (the microbiota) and the pathogenesis of various diseases is expanding. However, interactions between the intestinal microbiota and different pharmaceuticals and the impact of these on responses to treatment are less well studied. Several mechanisms are known by which drug-microbiota interactions can influence drug bioavailability, efficacy, and/or toxicity. This includes direct activation or inactivation of drugs by microbial enzymes which can enhance or reduce drug effectiveness. The extensive metabolic capabilities of the intestinal microbiota make it a hotspot for drug modification. However, drugs can also influence the microbiota profoundly and change the outcome of interactions with the host. Additionally, individual microbiota signatures are unique, leading to substantial variation in host responses to particular drugs. In this review, we describe several known and emerging examples of how drug-microbiota interactions influence the responses of patients to treatment for various diseases, including inflammatory bowel disease, type 2 diabetes and cancer. Focussing on rheumatoid arthritis (RA), a chronic inflammatory disease of the joints which has been linked with microbial dysbiosis, we propose mechanisms by which the intestinal microbiota may affect responses to treatment with methotrexate which are highly variable. Furthering our knowledge of this subject will eventually lead to the adoption of new treatment strategies incorporating microbiota signatures to predict or improve treatment outcomes

Synovial macrophages as a biomarker of response to therapeutic intervention in rheumatoid arthritis: Standardization and consistency across centers

Successive studies from one academic center (Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands) have consistently suggested that synovial tissue expression of sublining macrophages may be a biomarker of clinical response to therapeutic intervention in rheumatoid arthritis (RA) clinical trials. A proof-of-concept, randomized clinical trial was completed at a second academic center (St. Vincent's University Hospital, Dublin, Ireland), and the relationship between the change in disease activity and the change in sublining macrophages in distinct treatment cohorts was determined. The preliminary findings were not conclusive, but appeared to support a role for sublining CD68+ macrophages as a biomarker of clinical response to therapeutic intervention in cohorts of patients with RA

Increased cortisol relative to adrenocorticotropic hormone predicts improvement during anti-tumor necrosis factor therapy in rheumatoid arthritis.

Objective. Some patients with chronic inflammatory diseases such as rheumatoid arthritis (RA) improve rapidly from anti-tumor necrosis factor (anti-TNF) therapy. No sensitive markers are available that might predict outcome of anti-TNF therapy. We undertook this study to investigate the predictive value of hypothalamic-pituitary-adrenal (HPA) axis hormones for clinical improvement during anti-TNF therapy. Methods. An observational study in 23 RA patients was followed by a validation study in 38 RA patients. The patients receiving anti-TNF antibodies had no glucocorticoid treatment, and we measured baseline serum levels of adrenocorticotropic hormone (ACTH) and cortisol. Improvement during anti-TNF antibody treatment was judged by the Disease Activity Score in 28 joints (DAS28), and serum levels of cortisol were measured at followup. Results. The observational study demonstrated that improvement in the DAS28 correlated negatively with baseline serum levels of cortisol (R = -0.520, P = 0.011) and the cortisol:ACTH ratio (R = -0.700, P = 0.0002). In the longitudinal part of the study at followup, those patients with good improvement and initially low serum levels of cortisol demonstrated an increase of serum cortisol, in contrast to patients with little or no improvement. Findings in the observational study were supported by those in the validation study in a group of RA patients with less inflammation (correlation of improvement in the DAS28 with cortisol:ACTH ratio: R = -0.320, P = 0.025). Conclusion. This is the first study in a human chronic inflammatory disease to demonstrate that inflammation-induced TNF interferes with HPA axis integrity, which is linked to the disease outcome. These findings position the HPA axis centrally in the vicious circle of perpetuation of chronic inflammation

Elinsiirron saaneen nuoren siirtyminen lasten ja nuorten hoitotyöstä aikuisten terveyspalveluiden käyttäjäksi

Opinnäytetyömme tarkoituksena on kuvata saumaton, hoitoon sitoutumista tukeva hoitopolku nuoren elinsiirtopotilaan siirtyessä lasten ja nuorten hoitotyöstä aikuisten terveyspalvelujen käyttäjäksi. Työmme on osa lasten ja nuorten hoitotyön osaamisen tulevaisuuden hanketta. Hankkeen tarkoituksena on uusien toimintakäytäntöjen luominen, verkostomaisen työskentelyn vahvistaminen, sekä saumattomien hoitopolkujen kehittäminen. Hankkeessa yhteistyökumppaneina ovat HYKS Naisten- ja lastentautien tulosyksikkö, Metropolia ammattikorkeakoulun Hoitotyön koulutusohjelma ja Tampereen yliopiston Hoitotieteen laitos. Työssämme keskitymme potilaan siirtymävaiheen solmukohtiin, kuvaamme nykyisen hoitopolun ja pyrimme löytämään näkökulmia sekä toimintamalleja, jotka antaisivat nuorelle, hänen perheelleen sekä hoitoyksikölle valmiuksia siirtymisprosessin vaiheisiin. Työssämme keskitymme nuorten kehittymishaasteisiin ja pyrimme kartoittamaan nuorten hoitomyönteisyyttä ja vastaanottavaisuutta edistäviä keinoja ja välineitä. Opinnäytetyömme aihe on uusi hoitotieteellisen tutkimuksen kohde ja löytämämme materiaali on luonteeltaan täsmällistä, tuoretta ja vastaa hyvin työmme edistymisen vaateisiin. Käytimme työssämme kvantitatiivista tutkimusmenetelmää. Tutkimustyön tarve sekä prosessin kehittäminen potilaan tarpeita vastaavaksi tällä hoitotyön saralla on erittäin tärkeää. Kansainvälisesti siirtymisessä koetaan haastavimmaksi prosessin alkamisen äkillisyys, riittämätön tiedonkulku lasten ja aikuisten puolen välillä ja tätä kautta hoidon jatkuvuuden kankeus. Toisin sanoen siirtymiseen valmistavien toimintojen aikaistaminen, kirjallinen informaatio ja sujuvampi yhteistyö palveluiden tarjoajien välillä, ovat suurimmat kehittymishaasteet

Why CCR2 and CCR5 Blockade Failed and Why CCR1 Blockade Might Still Be Effective in the Treatment of Rheumatoid Arthritis

BACKGROUND: The aim of this study was to provide more insight into the question as to why blockade of CCR1, CCR2, and CCR5 may have failed in clinical trials in rheumatoid arthritis (RA) patients, using an in vitro monocyte migration system model. METHODOLOGY/PRINCIPAL FINDINGS: Monocytes from healthy donors (HD; n = 8) or from RA patients (for CCR2 and CCR5 antibody n = 8; for CCR1 blockade n = 13) were isolated from peripheral blood and pre-incubated with different concentrations of either anti-CCR1, anti-CCR2, or anti-CCR5 blocking antibodies (or medium or isotype controls). In addition, a small molecule CCR1 antagonist (BX471) was tested. Chemotaxis was induced by CCL2/MCP-1 (CCR2 ligand), CCL5/RANTES (CCR1 and CCR5 ligand), or by a mix of 5 RA synovial fluids (SFs), and cellular responses compared to chemotaxis in the presence of medium alone. Anti-CCR2 antibody treatment blocked CCL2/MCP-1-induced chemotaxis of both HD and RA monocytes compared to isotype control. Similarly, anti-CCR5 antibody treatment blocked CCL5/RANTES-induced chemotaxis of RA monocytes. While neither CCR2 nor CCR5 blocking antibodies were able to inhibit SF-induced monocyte chemotaxis, even when both receptors were blocked simultaneously, both anti-CCR1 antibodies and the CCR1 antagonist were able to inhibit SF-induced monocyte chemotaxis. CONCLUSIONS/SIGNIFICANCE: The RA synovial compartment contains several ligands for CCR1, CCR2, and CCR5 as well as other chemokines and receptors involved in monocyte recruitment to the site of inflammation. The results suggest that CCR2 and CCR5 are not critical for the migration of monocytes towards the synovial compartment in RA. In contrast, blockade of CCR1 may be effective. Conceivably, CCR1 blockade failed in clinical trials, not because CCR1 is not a good target, but because very high levels of receptor occupancy at all times may be needed to inhibit monocyte migration in vivo