HAQ-DI Scores Research Articles

Comparison of physical function in early rheumatoid arthritis patients treated with biologics for 1year who achieved clinical remission or low disease activity.

This study aimed to evaluate whether targeting clinical remission is appropriate for suppressing physical dysfunction in patients with early rheumatoid arthritis (RA). Subjects were all 75 early RA patients (within 2years of onset) who were continuously treated with biologics for 12months at our hospital. We evaluated the Simplified Disease Activity Index (SDAI) and Disability Index of the Health Assessment Questionnaire (HAQ-DI) at 3, 6, and 12months from the initiation of biologics therapy. Rates of functional remission (HAQ-DI≤0.5) at 12months in the clinical remission (SDAI≤3.3) group and the low disease activity [LDA (3.3<SDAI≤11)] group were 97 and 86%, respectively. Multivariate logistic regression analysis revealed that duration of disease and SDAI at 6months were significantly associated with the achievement of functional remission at 12months. The best cut-off value of SDAI at 6months for predicting functional remission at 12months was 15.7 by receiver operating characteristic curve analysis. HAQ-DI scores in the LDA group were significantly higher than those in the clinical remission group at 6 and 12months. The mean HAQ-DI score at 12months in the clinical remission group improved significantly relative to the mean HAQ-DI score at 6months in the LDA group. Our findings highlight the importance of achieving LDA at least by 6months after initiating biologics therapy, and achieving clinical remission as soon as possible, in order to minimize physical dysfunction in patients with early RA.

Twenty-Year Outcome and Association Between Early Treatment and Mortality and Disability in an Inception Cohort of Patients With Rheumatoid Arthritis: Results From the Norfolk Arthritis Register.

ObjectiveTo describe the outcome in patients with rheumatoid arthritis (RA) over 20 years from symptom onset, and to assess the association between early treatment (with disease‐modifying antirheumatic drugs/steroids) and mortality and disability during follow‐up.MethodsPatients recruited to the Norfolk Arthritis Register (NOAR) between 1990 and 1994 who met the 2010 American College of Rheumatology/European League Against Rheumatism RA criteria at baseline were included in this analysis. Demographic and clinical variables were collected at baseline and at years 1–3, 5, 7, 10, 15, and 20. Disease activity (swollen joint count [SJC]/tender joint count [TJC]), disability (Health Assessment Questionnaire disability index [HAQ DI]), and mortality over 20 years were determined. Associations between treatment group (early treatment [ET], treatment ≤6 months after symptom onset; late treatment [LT], treatment >6 months after symptom onset; never treatment [NT], no treatment) and mortality and disability were assessed using weighted pooled logistic regression and weighted multilevel mixed‐effects linear regression, respectively. Inverse weights were used to account for confounding by indication and censoring.ResultsThis study included 602 patients with RA (median age 56 years [interquartile range 44–68 years]; 65.9% women). The median SJCs and TJCs were low during the follow‐up period (1–3 swollen joints and 3–6 tender joints). The median HAQ DI score increased after year 1 but remained at low/moderate levels (median 1.25 after year 10). The risk of mortality was reduced in the ET and LT groups compared with that in the NT group. The ET group and the NT group had comparable HAQ DI scores during the follow‐up period (β = 0.03, 95% confidence interval [95% CI] −0.06, 0.12), while the HAQ DI score was increased in the LT group (for LT versus NT, β = 0.10 [95% CI 0.02, 0.17]).ConclusionThe results of this study indicate the importance of early treatment with regard to the long‐term outcomes in patients with RA.

Independent Association of Severity of Muscle Weakness With Disability as Measured by the Health Assessment Questionnaire Disability Index in Scleroderma.

To determine whether the presence and degree of muscle weakness in scleroderma is associated with disability. The study included a cohort of 1,718 scleroderma patients who had available data on muscle strength and disability. The primary independent variable was muscle weakness as defined by the maximum Medsger muscle severity score and the outcome was disability as measured by the last recorded Health Assessment Questionnaire disability index (HAQ DI) score. Univariate regression analyses were performed to assess the association of HAQ DI scores with the Medsger muscle severity score and other scleroderma characteristics. A multivariate regression analysis was performed to determine whether an association existed between the degree of muscle weakness and disability, while controlling for confounders. In 1,718 patients with scleroderma, 22.8% (392 of 1,718) had muscle weakness, as defined by a Medsger muscle severity score of ≥1. This subset was more likely than those without weakness to have diffuse cutaneous scleroderma (55.6% versus 35.1%; P < 0.0001), higher modified Rodnan skin thickness scores (mean ± SD 16.3 ± 13.7 versus 10.3 ± 10.6; P < 0.00001), shorter disease duration (mean ± SD 5.21 ± 6.75 versus 6.22 ± 7.67 years; P = 0.02), synovitis (17.7% versus 11.4%; P = 0.001), forced vital capacity <70% (46.2% versus 30.6%; P = 0.0001), and higher creatine kinase values (mean ± SD 441 ± 1,211 versus 151 ± 255; P = 0.00001). Both univariate and multivariate analyses revealed that for every unit of increase in the Medsger muscle severity score, there was a clinically significant (minimum clinically important difference ± 0.14) increase in the mean HAQ DI score at last followup visit. The presence of muscle weakness associates with several features of worse disease burden and independently associates with disability as measured by the HAQ DI.

Modeling of the clinical and economic impact of a risk-sharing agreement supporting a treat-to-target strategy in the management of patients with rheumatoid arthritis in France

Objectives: To evaluate the cost-effectiveness of a Treat-to-Target strategy with certolizumab pegol in patients with rheumatoid arthritis in the context of a pay-for-performance agreement in which medication costs are refunded in case of discontinuation during the first 3 months of treatment.Methods: The Treat-to-Target strategy consisted of a systematic switch to second-line tumor necrosis factor (TNF)α inhibitor in case of an unmet ACR50 response at 3 months compared to current routine clinical practice. A reference cohort treated first-line with certolizumab pegol according to current practice without systematic switching was considered as the comparator. A decision-tree model was constructed to estimate clinical outcome (health assessment questionnaire-disability index or HAQ-DI score), time spent in ACR50 response (ACR 50), and direct costs of treatment over a 2-year period. HAQ scores were derived from American College of Rheumatology 50 (ACR50) responses. All TNFα inhibitors were assumed to have equivalent efficacy and tolerability. Costs were estimated at 2013 French retail prices (date of the pay-for-performance agreement).Results: The mean duration of an ACR50 response was 1.23 years in the Treat-to-Target strategy certolizumab pegol cohort vs 0.98 years in the reference cohort, resulting in a mean gain in HAQ at 24 months of 0.117. The Treat-to-Target strategy with a mix of TNFα inhibitors as second-line therapy was more expensive than the reference strategy in absolute terms, but this difference was entirely offset by the pay-for-performance agreement. The Treat-to-Target strategy was, thus, cost-neutral over a 2-year period after the payback of CZP cost for patients not achieving the target at 3 months.Conclusions: In the context of a pay-for-performance agreement, the management of patients with rheumatoid arthritis using a Treat-to-Target strategy with certolizumab pegol in first line is dominant compared to standard use of this drug in the French setting in 2013.

Relationship between clinical and patient-reported outcomes in a phase 3 trial of tofacitinib or MTX in MTX-naïve patients with rheumatoid arthritis

ObjectiveTo compare the relationship between clinical measures and patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) treated with tofacitinib or methotrexate (MTX).MethodsIn a phase 3 randomised controlled trial, patients...

Complex rehabilitation and the clinical condition of working rheumatoid arthritis patients: does cryotherapy always overtop traditional rehabilitation?

Aim: Rehabilitation slows the progress of rheumatoid arthritis (RA) and prevents progression of disability. This study aimed to compare the impact of two rehabilitation programmes on pain, disease activity, locomotor function, global health and work ability forecast in RA patients. Materials and methods: Sixty-four employed women aged 24–65 years participated in the study. All patients underwent individual and instrumental kinesiotherapy. Thirty-two patients underwent cryogenic chamber therapy and local cryotherapy as well as non-weight-bearing, instrumental and individual kinesiotherapy. The remaining 32 patients received traditional rehabilitation in the form of electromagnetic and instrumental therapy, individual and pool-based non-weight-bearing kinesiotherapy. Rehabilitation lasted 3 weeks. Patients were examined three times: prior to rehabilitation, after 3 weeks of therapy and 3 months after completion of rehabilitation. The following study instruments were used: to assess disease activity: DAS-28; functional impairment: HAQ-DI; pain severity: VAS; patients’ overall well-being: a scale from 0 to 100 (Global Health Index); and patients’ own prognosis of fitness for work: the 6th question from Work Ability Index (WAI). Statistical analysis of data was performed using the STATISTICA 8.0 package. Mixed-design two-way analysis of variance was used for hypothesis testing. Results: All patients improved after rehabilitation. The group of patients those who underwent cryotherapy had improved DAS-28, HAQ-DI, VAS and global health scores immediately following the 3-week rehabilitation programme (p < 0.001, p = 0.001, p = 0.007 and p < 0.001, respectively), as well as at the 3-month follow-up (p < 0.001, p < 0.001, p = 0.009 and p < 0.001, respectively). Rehabilitation using cryotherapy resulted in greater improvement in disease activity DAS-28 [F(2,105) = 5.700; p = 0.007; η2 = 0.084] and HAQ-DI locomotor function scores [F(2,109) = 6.771; p = 0.003; η2 = 0.098] compared to traditional rehabilitation. The impact of both forms of rehabilitation on patients’ own prognosis of work ability in the next 2 years was not significant. Results of patients who underwent traditional approach showed decreased disease activity following the initial 3-week period; however, this improvement did not sustain to the end of follow-up, 3 months later. Conclusions: Complex rehabilitation in RA has a positive effect on patients’ clinical condition. The rehabilitation programme that includes cryotherapy overtops traditional rehabilitation, particularly as regards improvement in locomotor function, disease activity and sustaining willingness to continue working and exerts long-lasting effect.Implications for RehabilitationRehabilitation using cryotherapy is more effective in improving locomotor function, decreasing disease activity and sustaining willingness to continue working compared to traditional rehabilitation.Rehabilitation using cryotherapy significantly reduces the intensity of pain experienced by patients with RA, and this positive effect is maintained at 3 months post-rehabilitation.Complex rehabilitation, particularly treatment using cryotherapy, improves patients’ subjective assessment of their overall well-being and perception of their disease.Complex rehabilitation in rheumatoid arthritis has a positive effect on patients’ clinical condition.

Effect of rehabilitation in systemic sclerosis

Physical therapy could be of interest to reduce disability of systemic sclerosis (SSc) patients. To develop a physical therapy program for SSc and compare its efficacy with that of usual care. 12-month, parallel-group randomized controlled trial involving a modified Zelen design conducted between September 2005 and October 2011. Randomization was computer-generated with allocation concealment by fax to a central coordinating office. Investigators were not blinded, but participants in the control group were blinded to study hypothesis. Four tertiary-care hospitals. Patients were enrolled if they had a SSc diagnosis, a disability rating ≥ 0.5 on the Health Assessment Questionnaire Disability Index (HAQ-DI) or complaints of decreased mouth opening or limited range of motion of at least one joint. The experimental intervention was a 1-month personalized supervised physical therapy program provided by specifically trained care providers followed by home sessions. The comparator was usual care. The primary outcome was the HAQ-DI score at 12 months. In the intention-to-treat analysis, as compared with the usual care group ( n = 108), patients in the physical therapy group ( n = 110) showed reduced disability at 1 month (HAQ-DI between-group difference (0.14; 95% confidence interval [CI] –0.24 to –0.03; P = 0.01), at 6 months the HAQDI scores between-group difference was –0.12; 95% CI, –0.23 to 0.01; P = 0.054. There was no statistically significant difference at 12 months (between-group difference at 12 months, –0.01; 95% CI –0.15 to 0.13; P = 0.86). There was a statistically significant difference for hand mobility and function, and pain, at 1 month but no difference at 12 months. Microstomia was lower in the physical therapy group at 1, 6 and 12 months (between-group difference at 12 months, 1.62; 95% CI 0.32 to 2.93; P = 0.01). No differences in adverse effects were observed between the two treatment groups. A 1-month personalized supervised physical therapy program followed by home exercise sessions had short-term benefits for patients with SSc but did not reduce disability at 12 months. The program had long-term benefits for microstomia. NCT00318188 .

Calidad de vida relacionada con la salud en pacientes con artritis reumatoide de Medellín-Colombia, 2014

BackgroundRheumatoid arthritis affects the health related quality of life (HRQOL); the HRQOL complements clinical evaluation and is explained by multiple clinical and sociodemographic factors. ObjectiveTo evaluate the impact of rheumatoid arthritis on HRQOL and identify its main associated factors in a population of Medellín. Materials and methodsCross-sectional study all patients with rheumatoid arthritis of an institution of Medellín. A survey with demographic, socioeconomic and clinical variables, the Health Asssesment Questionaire Disability Index and International Physical Activity Questionnaires were applied. HRQOL was assessed with the Medical Outcome Study Short Form 36 (MOSSF-36). Analyses were based on frequencies, summary measures, U Mann Whitney test and Kruskal Wallis, Spearman correlations and multiple linear regression model in SPSS 21.0. Results112 patients were included with a mean age of 53±12years, 63.4% sedentary, the average years of diagnosis of the disease was 10.6±6.5years, 75% with any comorbidity; the mean HAQ-DI score was 0.84±.57. The dimension most affected in the HRQOL was physical performance with 35.3points and lower was social function with 67.7points. The functionality and physical activity, overweight, years of diagnosis, sex, age, and socioeconomic status were established as the main associated factors with HRQOL. ConclusionRheumatoid arthritis negatively impacts HRQOL. The identification of associated factors with HRQOL allows the implementation of interventions to improve the quality of life of these patients, while allowing focus the attention and monitoring in high risk groups such as sedentary and overweight or obese patients.

Tight control of rheumatoid arthritis in a resource-constrained setting: a randomized controlled study comparing the clinical disease activity index and simplified disease activity index.

The aim of this study was to explore the clinical utility of the clinical disease activity index (CDAI). We compared the disease control with protocolized treatment adjustment following a tight control strategy utilizing either the simplified disease activity index (SDAI) or the CDAI. In a prospective 12 month study, DMARD-naive RA patients were randomized to either a CDAI or SDAI arm and were treated with traditional DMARDs, increased on a monthly basis according to a predefined protocol to achieve low disease activity. Of 102 patients (84 females, 96 Black Africans), the mean symptom duration was 3.0 years (s.d. 3.8) and the mean 28-joint DAS (DAS28) at baseline was 6.2 (s.d. 1.2). By 12 months, the proportion of patients in the CDAI and SDAI groups achieving low disease activity (30% and 32%) and remission (33 and 34%) were similar. There were no significant differences in the mean DAS28 or its components or in HAQ Disability Index or health-related quality of life scores. Baseline predictors of low disease activity at 12 months were shorter symptom duration (P = 0.03) and lower HAQ-DI score (P = 0.04). Given that the CDAI performed as well as the SDAI, and considering the cost savings and convenience because no acute phase reactant test is necessary, we suggest the CDAI may be an appropriate tool for monthly disease activity monitoring as part of a tight control strategy in developing countries.

The clinical burden of generalized osteoarthritis represented by self-reported health-related quality of life and activity limitations: a cross-sectional study.

The involvement of multiple joints is common in osteoarthritis (OA), often referred to as generalized osteoarthritis (GOA). However, since research and practice mainly focus on a specific OA localization, the health status of patients with GOA is largely unknown. Therefore, we aimed to describe the clinical burden of GOA in terms of self-reported health-related quality of life (HRQoL) and activity limitations. In this cross-sectional study, individuals clinically diagnosed with GOA and referred to multidisciplinary treatment, completed questionnaires on socio-demographics, joint involvement, HRQoL (SF-36) and activity limitations (HAQ-DI). SF-36 physical (PCS) and mental component summary scores (MCS) were calculated using norm-based data. The patient's specific most important activity limitations were linked to the International Classification of Functioning, Disability and Health. A total of 147 patients participated [85 % female; mean (SD) age 60 (8) years]. The majority (93 %) had symptomatic OA in both the upper and lower extremities. Predominant joints with symptomatic OA were the hands (85 %) and knees (82 %). Mean (SD) SF-36 PCS and MCS scores were 37 (7) and 48 (10), respectively, showing a broad impact of GOA on the physical component of health. The mean (SD) HAQ-DI score was 1.27 (0.50) indicating moderate to severe functional limitations. Activities concerning mobility and domestic life were considered most important activity limitations, especially walking. The results show a high clinical burden of GOA in terms of HRQoL and activity limitations. This study points to the need of developing non-pharmacological interventions for patients with GOA that should target on improving the physical component of health and mobility limitations.

SAT0226 Tocilizumab (TCZ) as Combination Therapy and as Monotherapy VS Methotrexate (MTX) in MTX-Naive Patients with Early Rheumatoid Arthritis: Patient-Reported Outcomes (PROS) from A Randomized, Placebo-Controlled Trial

BackgroundTreatment with TCZ in combination with MTX or as monotherapy in MTX-naive patients (pts) with early RA previously demonstrated improvements in signs and symptoms and in inhibition of structural joint...

THU0156 Impact of Golimumab on Physical Function and Employability of Patients with Rheumatoid Arthritis: 5-Year Data from 3 Phase III Clinical Trials

ObjectivesTo assess the impact of golimumab (GLM) on physical function and employability in patients with rheumatoid arthritis (RA) with various prior treatment histories, after 5 years of therapy.MethodsThe efficacy and...

FRI0266 Health-Related Quality of Life of Patients with Rheumatoid Arthritis Achieving DAS28 Remission, Improvement in Physical Function and NO Radiographic Progression after Treatment with Intravenous Golimumab

ObjectivesTo evaluate “comprehensive remission” in patients with rheumatoid arthritis (RA) treated with intravenously administered golimumab (GLM) and the association with normalized health related quality of life (HRQOL).MethodsGO-FURTHER was a multicenter,...

THU0114 Efficacy and Safety of Spironolactone in the Treatment of Rheumatoid Arthritis and Ankylosing Spondylitis

BackgroundSynthetic disease-modifying antirheumatic drugs (DMARDs) though effective have limitations often requiring use of expensive parenteral biologic DMARDs in Rheumatoid Arthritis (RA) and Ankylosing Spondylitis (AS). Hence there is a need...

AB0244 Radiographic Evaluation of Large Joint Damage in Patients with Rheumatoid Arthritis Using ARASHI Scoring Method

BackgroundStructural impairment of large joints in patients with rheumatoid arthritis (RA) is strongly associated with functional disabilities. Although evaluation methods of large joint damage were limited, the ARASHI study group...

AB0220 Disability and Health-Related Quality of Life of Filipino Patients with Rheumatoid Arthritis

BackgroundRheumatoid arthritis is associated with physical disability as the disease progresses. Disability, in turn, exerts a significant impact on general health satisfaction and mortality of the RA patient. High disease...

IL-6 inhibition improves nitric oxide in rheumatoid arthritis

Aim To investigate the serum nitrite levels in patients with active rheumatoid arthritis (RA) after treatment with tocilizumab, an IL-6 antagonist, and to correlate between inflammatory disease activity measures and endothelial dysfunction. Materials and methods Eleven anti-IL-6-naive RA patients with high disease activity (DAS28 &gt;5.1) were investigated. Inflammatory disease activity (DAS28 and HAQ-DI scores, ESR and CRP), serum nitrite concentration and flow mediated dilation (FMD) of the brachial artery were measured before and after 12 weeks of therapy with tocilizumab 8mg/kg intravenous infusion every 4 weeks. Serum nitrite levels and FMD were also estimated in 10 age- and sex- matched healthy controls. Results Serum nitrite levels in RA patients at baseline were significantly higher when compared to healthy volunteers (P &lt;0.01). Level of serum nitrite significantly decreased (P &lt;0.001), inflammatory disease activity measures and FMD significantly improved (P &lt;0.001) after treatment. There was a significant correlation of serum nitrite with FMD, CRP, and DAS 28 both at baseline (P &lt;0.05) and after 12 weeks therapy (P &lt;0.05). Conclusion Nitrite production is enhanced to a greater extent in patients with RA compared to controls. Reduction in nitrite level after treatment is associated with the improvement in disease activity and endothelial dysfunction. Serum nitrite level may serve as a good predictor of both inflammatory disease activity and response to therapy in RA.

Rituximabe para o tratamento da artrite reumatoide: Revisão sistemática

IntroductionRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic joint inflammation that often leads to significant disability. Several effective anti–TNF agents have been used, but some patients have shown an inadequate response. Rituximab is a therapeutic monoclonal antibody indicated in such cases. MethodsWe conducted a systematic review to access efficacy and safety of rituximab in patients with active RA which have or have not been treated with anti–TNF agents before, and to relate outcome with RF and anti–CCP serology. We searched major electronics databases, grey literature and searched for references manually. We used Review Manager®5.1 for meta–analysis. ResultsWe included six RCTs comparing rituximab 1000mg with placebo. Methotrexate was used by both groups. Treatment with rituximab was more effective in naïve and in anti–TNF treatment failure patients ACR20/50/70 and EULAR response. We observed lower changes in Total Genant–modified Sharp score, erosion score and joint narrowing scores in the rituximab group, and SF–36, FACIT–T and HAQ–DI scores were also better in this group. There were no differences between groups regarding safety outcomes, with exception of acute injection reactions, which were more common on rituximab group. More RF/anti–CCP seropositive patients achieved ACR20 than RF/anti–CP negative patients in rituximab group. ConclusionAvailable data support the use of rituximab for the treatment of RA, as it is an effective and safe option for naïve and anti–TNF treatment failure patients. RF and anti–CCP seam to influence treatment results, but this inference needs further research.

Rituximab for rheumatoid arthrits treatment: a systematic review

IntroductionRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic joint inflammation that often leads to significant disability. Several effective anti-TNF agents have been used, but some patients have shown an inadequate response. Rituximab is a therapeutic monoclonal antibody indicated in such cases. MethodsWe conducted a systematic review to access efficacy and safety of rituximab in patients with active RA which have or have not been treated with anti-TNF agents before, and to relate outcome with RF and anti-CCP serology. We searched major electronics databases, grey literature and searched for references manually. We used Review Manager®5.1 for meta-analysis. ResultsWe included six RCTs comparing rituximab 1000mg with placebo. Methotrexate was used by both groups. Treatment with rituximab was more effective in naïve and in anti-TNF treatment failure patients - ACR20/50/70 and EULAR response. We observed lower changes in Total Genant-modified Sharp score, erosion score and joint narrowing scores in the rituximab group, and SF-36, FACIT-T and HAQ-DI scores were also better in this group. There were no differences between groups regarding safety outcomes, with exception of acute injection reactions, which were more common on rituximab group. More RF/anti-CCP seropositive patients achieved ACR20 than RF/anti-CP negative patients in rituximab group. ConclusionAvailable data support the use of rituximab for the treatment of RA, as it is an effective and safe option for naïve and anti-TNF treatment failure patients. RF and anti-CCP seam to influence treatment results, but this inference needs further research.

Anti-cyclic citrullinated peptide (anti-CCP) and anti-mutated citrullinated vimentin (anti-MCV) relation with extra-articular manifestations in rheumatoid arthritis.

We evaluated the association between anti-cyclic citrullinated peptide antibodies (anti-CCP) and anti-mutated citrullinated vimentin antibodies (anti-MCV) with the presence of extra-articular (ExRA) manifestations in 225 patients with rheumatoid arthritis (RA). Ninety-five patients had ExRA and 130 had no ExRA. There was no association of anti-CCP and anti-MCV levels with the presence of ExRA as total group (P = 0.40 and P = 0.91, resp.). Making an analysis of individual manifestations, rheumatoid nodules were associated with positivity for rheumatoid factor (RF); (P = 0.01), anti-CCP (P = 0.048), and anti-MCV (P = 0.02). Instead, RF, anti-CCP, or anti-MCV were not associated with SS, chronic anemia, or peripheral neuropathy. Levels of anti-CCP correlated with the score of the Health Assessment Questionnaire-Disability Index (HAQ-Di) (r = 0.154, P = 0.03), erythrocyte sedimentation rate (ESR); (r = 0.155, P = 0.03), and RF (P = 0.254, P < 0.001), whereas anti-MCV titres only correlated with RF (r = 0.169, P = 0.02). On adjusted analysis, ExRA was associated with longer age (P = 0.015), longer disease duration (P = 0.007), higher DAS-28 score (P = 0.002), and higher HAQ-DI score (P = 0.007), but serum levels of anti-CCP and anti-MCV were not associated. These findings show the need to strengthen the evaluation of the pathogenic mechanisms implied in each specific ExRA manifestation.