news & views glycosylation prevents the spread of viruses.10 the antibacterial and antifungal effects of antimalarial agents appear to be linked to interference with antigen presentation, which is mediated by pH-dependent iron deprivation and by increasing the phagolysosomal pH; this ultimately leads to reduced immune system activation and inhibits the growth of intracellular organisms.10 moreover, the basic intracellular pH induced by anti malarial agents could have antiviral effects and result in the blockade of hydrolases and posttranslational modifications, including inhibition of glycosylation of newly synthesized proteins. notably, glycosylation inhibition might lead to interactions of chloroquine with sugar-modifying enzymes or glycosyltransferases and could account for effects on a number of processes that are sialic-acid dependent, including intracellular as well as extracellular functions (for example, binding to surface receptors). a third and rather appealing concept hypothesizes that interference with innate immune activation, that is, by blocking toll-like receptor (tlr) 3, tlr7 and tlr9, could be responsible for a number of effects of antimalarial agents. thus, antimalarial agents can interfere with intracellular recognition of nucleic-acid-binding by tlr7 and tlr9, which are harbored in intracellular compartments and block the activation of interferon in sle. since tlr recognition is also involved in protection against infection, a tempting idea is that antimalarial agents lead to prominent tlr inhibition by changing the intracellular pH. Despite reports of the valuable clinical effects of antimalarial agents in sle, we still need additional confirmation from clinical studies as well as more-detailed basic studies to decipher their mechanisms of action. since only about 40–50% of patients with sle are treated with antimalarial agents, the available data on these drugs demand reconsideration of their pleiotropic effects in sle patients where not contraindicated. ultimately, a better understanding of the individual effects of antimalarial agents could pave the way for innovative drugs that combine immunomodulatory and anti-infective potency, or that even provide new etiopathogenic insights into sle. Department of Medicine, Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin and Deutsches Rheumaforschungszentrum, Charitéplatz 01, 10098 Berlin, Germany.
[email protected] doi:10.1038/nrrheum.2009.235
nature reviews | rheumatology
Competing interests The author declares no competing interests. 1.
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James, J. A. et al. Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus. Lupus 16, 401–409 (2007). Kaiser, R., Cleveland, C. & Criswell, L. A. Risk and protective factors for thrombosis in systemic lupus erythematosus: results from a large, multi‑ethnic cohort. Ann. Rheum. Dis. 68, 238–241 (2009). Ruiz‑irastorza, G. et al. effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus. Lupus 15, 577–583 (2006). siso, A. et al. Previous antimalarial therapy in patients diagnosed with lupus nephiritis: influence on outcomes and survival. Lupus 17, 281–288 (2008). Tsakonas, e. et al. A long‑term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. The Canadian Hydroxychloroquine study Group. Lupus 7, 80–85 (1998).
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Pons‑estel, G. J. et al. Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXv, data from a multiethnic Us cohort. Arthritis Rheum. 61, 830–839 (2009). 7. Ruiz‑irastorza, G., egurbide, M. v., Olivares, n., Martinez‑Berriotxoa, A. & Aguirre, C. vitamin D deficiency in systemic lupus erythematosus: prevalence, predictors and clinical consequences. Rheumatology (Oxford) 47, 920–923 (2008). 8. Bultink, i. e. M. et al. Deficiency of functional mannose‑binding lectin is not associated with infections in patients with systemic lupus erythematosus. Arthritis Res. Ther. 8, R183 (2006). 9. smitten, A. L. et al. The risk of hospitalized infection in patients with rheumatoid arthritis. J. Rheumatol. 35, 387–393 (2008). 10. Rolain, J. M., Colson, P. & Raoult, D. Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century. Int. J. Antimicrob. Agents 30, 297–308 (2007).
psyChology
Emotional disclosure in RA: does it work? Joan L. Duda and Jet J. C. S. Veldhuijzen van Zanten
what is the psychological and clinical effectiveness of a home-based emotional disclosure intervention? results from a randomized, controlled trial of such an intervention in patients with rheumatoid arthritis could have implications for the future of therapeutic research and clinical practice. the capacity to regulate emotions is predictive of perceived health in patients with rheumatoid arthritis (ra).1 negative emotions, in particular stress, tend to exacerbate disease symptoms in this population. emotional disclosure is an intervention centered on the promotion of emotion regulation and of confronting negative emotional experiences.2 Purposeful writing or talking about emotional topics is thought to lead to a more adaptive cognitive restructuring of the traumatic event or events in question. via such disclosure, the individual is expected to formulate a more coherent and meaningful sense of the stressful circumstances.3 Particularly within laboratory studies, support has been garnered for the effects of emotional disclosure on reductions in stress and on improvements in positive psychological outcomes, in both patient and control populations. Beyond these psychological effects, emotional disclosure is assumed to lead to physiological benefits and, specifically, is thought to have a role in enhancing immune function.
with the aim of testing this type of inter vention in a ‘real-world setting’, van middendorp et al.4 adapted an emotional disclosure protocol for implementation in the homes of patients with ra. oral disclosure was requested across four, short (15 minute) weekly sessions. the effects of the emotional disclosure intervention were compared with a time-management treatment, in which patients were asked to provide oral descriptions of recent and upcoming activities. assessments were taken at baseline, and at 1 week and 3 months postintervention. the primary outcome measure was psychological well-being, which was operationalized with respect to cheerful versus depressed mood, assessed by use of the impact of rheumatic Diseases on General Health and lifestyle questionnaire. no differential effect in the primary outcome measure emerged, and the two groups did not vary with respect to clinical outcomes. However, differences between the groups were observed over time with respect to indicators of physiological functioning, including urinary cortisol levels volume 6 | JanuarY 2010 | 11
news & views and markers of inflammation (interleukin [il]-6, interferon [iFn]-γ), as well an antiinflammatory assessment (il-10). notably, however, the effect sizes were small. the two groups differed significantly in 24-h levels of urinary cortisol, which were decreased in the intervention group and increased in the control group at 1 week. although urinary cortisol levels provide an indication of daily cortisol release, they do not offer information about the diurnal pattern of cortisol release, in particular the cortisol awakening response, which has been associated with health outcomes. an abnormal diurnal cortisol profile has been implicated in several diseases, such as severe depression and ra.5,6 in patients with ra, the daily pattern of cortisol release is thought to contribute to variations in disease activity and/or severity.6 in explicating changes observed in cortisol secretion, an additional consideration could be the determination of correlations between levels of cortisol and inflammatory molecules. the use of this approach in the study by van middendorp et al. 4 would have enabled more-careful speculation about the possible underlying physiological mechanisms involved in the observed changes in cortisol levels.
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Negative emotions, in particular stress, tend to exacerbate disease symptoms
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although the emotional disclosure intervention had an effect on physiological measures, it might seem surprising that no effect was observed on psychological mood. However, this finding is in agreement with a previous study that examined the effects of emotional disclosure on wound healing, where an immune response was found in the absence of a psychological effect of the intervention.7 in that study, weinman et al. argued that the null finding could have resulted from the lack of sensitivity of the psychological assessments employed. Contemporary work in the field of psychology suggests that the determination of psychological well-being entails going beyond a determination of whether someone is in a positive mood, or not in a bad mood (reflecting a ‘hedonic’ conception of well-being). in the work of Diener and colleagues,8 for example, emphasis is placed on the assessment of subjective wellbeing (swB), which captures individuals’ evaluations of their own lives. such swB judgments contain a cognitive dimension (for example, ratings of life satisfaction), as well 12 | JANUARY 2010 | volUme 6
as an emotional component (for example, experiencing positive affect most of the time, and reports of infrequent negative affect). in addition, researchers have called for the consideration of eudaimonic conceptions of well-being, which include determinations of optimal functioning (such as subjective vitality), personal growth and meaningful engagement in life activities. Past studies have indicated that eudaimonic measures of well-being are more closely linked to assessments of disease biomarkers than hedonic measures of well-being.9 more work is necessary to explore the impact of emotional disclosure interventions on such multifaceted determinations of swB and functioning. additionally, how these psychological factors interact both with physiological assessments and, in the case of a patient population, with a reduction in disease activity need to be evaluated. van middendorp and colleagues4 suggest that the observed increases in il-6 and iFn-γ levels in the time-management group were reflective of worse disease control in these patients compared with those who participated in the emotional disclosure intervention. this conclusion, however, is not reflected in the clinical assessments of disease activity: the average erythrocyte sedimentation rate, a clinical measure of inflammation, was unchanged in both groups and did not differ between the groups. the investigators propose that the observed increases in il-6 and iFn-γ levels in the time-management group occurred as a result of stress induced by talking repeatedly about their daily activities. indeed, both acute and chronic stress can cause an inflammatory response. However, the notion that four brief sessions can result in increased levels of inflammation 3 months later is not justified. Furthermore, if this time-management intervention led to increased stress levels, questions should be raised about the appropriateness of the control intervention. van middendorp and colleagues were appropriately conservative in suggesting that their findings do not call for widespread application of the intervention they used in patients with ra. the researchers duly noted that the patients included in this study had relatively positive physical function, as determined by baseline measures of inflammatory activity, joint tenderness and joint swelling, as well as emotional health. the extent to which these patients could improve, therefore, was limited. of importance, 43% of the patients initially contacted refused to be involved in the study owing to the perceived burden
of their participation (23%), or concerns about talking about their emotions relating to a meaningful life event (20%). Clearly, the experimental research in question indicates that the appeal and benefit of emotional disclosure is not shared by everyone, a stipulation that is consistent with the literature on these types of intervention.10 nonetheless, the careful work of van middendorp et al. 4 holds promise as a psychological intervention for patients with ra, at least for those who are experiencing emotional upheaval and would like to talk (or write) about it. this premise, however, needs to be further tested. in subsequent research, eudaimonic assessments of psychological outcomes could move us beyond short-term measures of mood states. School of Sport and Exercise Sciences, University of Birmingham, Birmingham B15 2TT, UK (J. L. Duda, J. J. C. S. Veldhuijzen van Zanten). Correspondence to: J. L. Duda
[email protected] doi:10.1038/nrrheum.2009.254 Competing interests The authors declare no competing interests. 1.
van Middendorp, H., Geenen, R., sorbi, M. J., van Doornen, L. J. & Bijlsma, J. w. emotion regulation predicts change of perceived health in patients with rheumatoid arthritis. Ann. Rheum. Dis. 64, 1071–1074 (2005). 2. Pennebaker, J. w. in The (Non)expression of Emotions in Health and Disease (eds vingerhoets, A., van Bussel, F. & Boelhouwer, J.) 267–278 (Tilburg University Press, 1997). 3. Graybeal, A., sexton, J. D. & Pennebaker, J. w. The role of story‑making in disclosure writing: the psychometrics of narrative. Psychol. Health 17, 571–581 (2002). 4. van Middendorp, H., Geenen, R., sorbi, M. J., van Doornen, L. J. & Bijlsma, J. w. Health and physiological effects of an emotional disclosure intervention adapted for application at home: a randomized clinical trial in rheumatoid arthritis. Psychother. Psychosom. 78, 145–151 (2009). 5. Hsiao, F.‑H. et al. The self‑perceived symptom distress and health‑related conditions associated with morning to evening diurnal cortisol patterns in outpatients with major depressive disorder. Psychoneuroendocrinology doi:10.1016/j.psyneuen.2009.08.019. 6. Cutolo, M. et al. Altered circadian rhythms in rheumatoid arthritis patients play a role in the disease’s symptoms. Autoimmun. Rev. 4, 497–502 (2005). 7. weinman, J., ebrecht, M., scott, s., walburn, J. & Dyson, M. enhanced wound healing after emotional disclosure intervention. Br. J. Health Psychol. 13, 95–102 (2008). 8. Diener, e., Lucas, R. & scollon, C. n. Beyond the hedonic treadmill: revising the adaptation theory of well‑being. Am. Psychol. 61, 305–314 (2006). 9. Ryff, C. D., singer, B. H. & Dienberg Love, G. Positive health: connecting well‑being with biology. Philos. Trans. R. Soc. Lond. B Biol. Sci. 359, 1383–1394 (2004). 10. Frattaroli, J. experimental disclosure and its moderators: a meta‑analysis. Psychol. Bull. 132, 823–865 (2006).
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