Abstract Objective The aim of this study was to assess the relationship between self-reported non-adherence, non-trough drug levels, immunogenicity and conventional synthetic DMARD (csDMARD) co-therapy in TNF inhibitor (TNF-i) drug response in PsA. Methods Serum samples and adherence questionnaires were collected at baseline, 3, 6 and 12 months for PsA patients prescribed TNF-i. Non-trough adalimumab (ADL) and etanercept (ETN) drug levels were measured at 3 and 6 months using commercially available ELISAs. Clinical response was assessed using PsA response criteria (PsARC) and change in 28-joint DAS (ΔDAS28) between baseline and 3, 6 and 12 months. Results In 244 PsA patients (52.5% ADL and 47.5% ETN), self-reported non-adherence was associated with PsARC non-response over 12 months using generalized estimating equation (GEE) modelling (P = 0.037). However, there was no significant difference between non-trough ADL or ETN drug levels based on self-reported non-adherence. Higher ETN levels at 3 months were associated with PsARC response at 3 (P = 0.015), 6 (P = 0.037) and 12 months (P = 0.015) and over 12 months using GEE modelling (P = 0.026). Increased ADL drug levels at 3 months were associated with greater ΔDAS28 at 3 months (P = 0.019). ADL anti-drug antibody-positive status was significantly associated with lower 3- and 6-month ADL levels (P < 0.001) and ΔDAS28 and PsARC response at 3, 6 and 12 months. Meanwhile, MTX co-therapy was associated with a reduction in immunogenicity at 3 and 6 months (P = 0.008 and P = 0.024). Conclusion Although both were associated with reduced response, the objectively measured non-trough drug levels showed more significant associations with drug response than self-reported non-adherence measures.
Background: Missing data in clinical epidemiological researches violate the intention to treat principle, reduce statistical power and can induce bias if they are related to patient’s response to treatment. In multiple imputation (MI), covariates are included in the imputation equation to predict the values of missing data. Objectives: To find the best approach to estimate and impute the missing values in Kuwait Registry for Rheumatic Diseases (KRRD) patients data. Methods: A number of methods were implemented for dealing with missing data. These included Multivariate imputation by chained equations (MICE), K-Nearest Neighbors (KNN), Bayesian Principal Component Analysis (BPCA), EM with Bootstrapping (Amelia II), Sequential Random Forest (MissForest) and mean imputation. Choosing the best imputation method was judged by the minimum scores of Root Mean Square Error (RMSE), Mean Absolute Error (MAE) and Kolmogorov–Smirnov D test statistic (KS) between the imputed datapoints and the original datapoints that were subsequently sat to missing. Results: A total of 1,685 rheumatoid arthritis (RA) patients and 10,613 hospital visits were included in the registry. Among them, we found a number of variables that had missing values exceeding 5% of the total values. These included duration of RA (13.0%), smoking history (26.3%), rheumatoid factor (7.93%), anti-citrullinated peptide antibodies (20.5%), anti-nuclear antibodies (20.4%), sicca symptoms (19.2%), family history of a rheumatic disease (28.5%), steroid therapy (5.94%), ESR (5.16%), CRP (22.9%) and SDAI (38.0%), The results showed that among the methods used, MissForest gave the highest level of accuracy to estimate the missing values. It had the least imputation errors for both continuous and categorical variables at each frequency of missingness and it had the smallest prediction differences when the models used imputed laboratory values. In both data sets, MICE had the second least imputation errors and prediction differences, followed by KNN and mean imputation. Conclusion: MissForest is a highly accurate method of imputation for missing data in KRRD and outperforms other common imputation techniques in terms of imputation error and maintenance of predictive ability with imputed values in clinical predictive models. This approach can be used in registries to improve the accuracy of data, including the ones for rheumatoid arthritis patients. References: [1]Junninen, H.; Niska, H.; Tuppurainen, K.; Ruuskanen, J.; Kolehmainen, M. Methods for imputation of missing values in air quality data sets. Atmospheric Environment 2004 , 38 , 2895–2907. [2]Norazian, M.N.; Shukri, Y.A.; Azam, R.N.; Al Bakri, A.M.M. Estimation of missing values in air pollution data using single imputation techniques. ScienceAsia 2008 , 34 , 341–345. [3]Plaia, A.; Bondi, A. Single imputation method of missing values in environmental pollution data sets. Atmospheric Environment 2006 , 40 , 7316–7330. [4]Kabir, G.; Tesfamariam, S.; Hemsing, J.; Sadiq, R. Handling incomplete and missing data in water network database using imputation methods. Sustainable and Resilient Infrastructure 2019 , pp. 1–13. [5]Di Zio, M.; Guarnera, U.; Luzi, O. Imputation through finite Gaussian mixture models. Computational Statistics & Data Analysis 2007 , 51 , 5305–5316. Disclosure of Interests: None declared
Antisynthetase syndrome (ASS) is an idiopathic inflammatory myopathy characterised by the presence of anti-Jo-1 antibodies. Patients usually present with myositis, interstitial lung diseases, and arthritis. Corticosteroid therapy is the first line treatment. With regard to immunosuppressive use, no consensus has been reached. Rituximab has been reported to be successful in treatment of refractory ASS in small case series
Objectives
We report our experience of using rituximab in refractory ASS by describing the outcome and follow up of 3 cases
Methods
The case notes of 3 patients (2 males and 1 female; ages: 50, 42, and 54 years), diagnosed with ASS based on positive anti-Jo1 antibodies and muscle biopsy, were analyzed retrospectively. Treatment with several conventional therapeutic agents was tried sequentially over a mean period of 10 months without sustained remission (see Figs. 1, 2 and 3). In view of the refractory nature of their disease, a decision to commence rituximab was made (1000 mg IV, twice, with a 2-week interval). The available follow up periods for the 3 patients are 36 months in 2 patients, and 67 months in 1 patient. Response to treatment was assessed by improvement in muscle weakness & creatinine kinase (CK) levels
Results
Response to treatment was observed after a period of 4-5 months following treatment with rituximab. This manifested as improvement in symptoms (muscle weakness, joint pain and shortness of breath), & CK levels (see Figs. 1, 2, and 3). In the first patient (Fig. 1) the improvement following the initial treatment with rituximab was sustained for almost 3 years before he required retreatment with rituximab for relapses (relapsed 4 times afterwards over a period of 32 months, with an average of 11 months between relapses). Retreatment with rituximab in the second patient (Fig. 2) who relapsed at 8 and 18 months following the initial treatment resulted in remission 4-5 months later, and eventually he came off immunosupressive therapy. Retreatment with rituximab in the third patient (Fig. 3) who relapsed at 9 months following initial treatment resulted in remission 4-5 months later. She remained well and continued to receive rituximab prophylactically 6-monthly. The 3 patients have been successfully weaned off the higher dose of prednisolone they used to be on prior to treatment with rituximab; the first patient is currently maintained on prednisolone alone (10 mg daily); the second patient was weaned off prednisolone successfully and is currently on no treatment; while the third is maintained on prednisolone 5 mg daily plus methotrexate 25 mg weekly
Conclusions
This small retrospective case series indicates a beneficial effect of rituximab in ASS refractory to conventional treatment, in keeping with other case series1,2. However the response to treatment may take several months. The relapses at an average of 10 months following initial treatment with rituximab coincide with the timing of repopulation. The optimal timing of retreatment and whether prophylactic retreatment with rituximab at time of repopulation should be considered, remain to be defined.
References
Martha Sem et al. Rituximab treatment of the anti-synthetase syndrome - a retrospective case series. Rheumatology (2009) 48 (8): 968-971. Elien A. M. Mahler et al. Rituximab treatment in patients with refractory inflammatory myopathies. Rheumatology (2011) doi: 10.1093/rheumatology/ker088
Background: Smoking has been proposed to be associated with the development of anti-citrullinated peptide antibodies (ACPA) in rheumatoid arthritis (RA) patients. Objectives: To study the relationship between smoking and ACPA as well as smoking and RF in patients with RA in Kuwait Registry for Rheumatic Diseases (KRRD). Methods: Data on RA patients were extracted from KRRD from four major hospitals from February 2013 through December 2019. As females rarely smoke in Kuwait with a smoking prevalence of 3% in female RA patients in KRRD, females were excluded from the study population to reach the minimum statistical percentage needed to perform chi square test and assess the association between smoking and other variables. Statistical tests were applied where appropriate. Logistic regression was conducted to adjust for possible confounders including age, disease duration, comorbidities, family history of a rheumatic disease, ANA, treatment agents and disease activity and quality of life assessment tools. Results: A total of 863 RA male patients were studied with a mean age of 53.9±12.5 years and a mean disease duration 7.3±5.5 years. 652 (75.6%) had positive RF and 624 (72.3%) had positive ACPA. 431 (50%) had at least one comorbidity. 640 (74.2%) were on conventional disease modifying agents (cDMARD’s) and 223 (25.8%) were on biologic therapy. 183 (21.2%) were smokers. After adjustment of other factors, logistic regression showed that smokers were significantly different than non-smokers in terms of a positive ACPA (β=-1.051, p <0.001, odds=4.019) and a positive RF (β=-0.804, p =0.019, odds=2.517). Conclusion: Smokers have a higher risk of expressing a positive RF and a positive ACPA in a male population. Smoking should be considered as a possible risk factor for RA and efforts should be done to educate the population to cease smoking to possibly lower that risk. References: [1]Benowitz, N.L., 2009. Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics. Annual review of pharmacology and toxicology, 49, pp.57-71. [2]Firestein, G.S., 2003. Evolving concepts of rheumatoid arthritis. Nature, 423(6937), p.356. [3]Heliövaara, M., Aho, K., Aromaa, A., Knekt, P. and Reunanen, A., 1993. Smoking and risk of rheumatoid arthritis. The Journal of rheumatology, 20(11), pp.1830-1835. [4]Hoy, K. W., 2009. Quantitative Research in Education: A Primer. SAGE. pp. 69-86. [5]Kerlan-Candon, S., Combe, B., Vincent, R., Clot, J., Pinet, V. and Eliaou, J.F., 2001. HLA-DRB1 gene transcripts in rheumatoid arthritis. Clinical & Experimental Immunology, 124(1), pp.142-149. [6]Kuada, J., 2012. Research Methodology: A Project Guide for University Students. Samfundslitteratur. pp. 45-56. [7]Kumar, R., 2010. Research Methodology: A Step-by-Step Guide for Beginners. SAGE. pp. 148-159. [8]Masdottir, B., Jonsson, T., Manfreðsdóttir, V., Víkingsson, A., Brekkan, Á. and Valdimarsson, H., 2000. Smoking, rheumatoid factor isotypes and severity of rheumatoid arthritis. Rheumatology, 39(11), pp.1202-1205. [9]Neuman, W., 2009. Understanding research. Boston: Pearson. pp. 230- 255. Disclosure of Interests: None declared
An association between serum uric acid (UA) and disease activity in rheumatoid arthritis (RA) patients has not been well studied.
Objectives
We describe RA patients with high and normal UA and study its association with RA activity.
Methods
Adult RA patients from The Kuwait Registry for Rheumatic Diseases (KRRD) who satisfied the ACR classification criteria for RA from four major hospitals were studied from February 2013 through April 2017. Patients with recorded UA were identified. Visits with documented UA levels were included. UA of ≥357 µmol/L (6 mg/dL) was considered high. Statistical correlations were made.
Results
A total of 564 RA patients with 2710 hospital visits and available UA were identified, 353 (62.6%) females. Mean age 50.8±11.5 years and disease duration 10.5±2.9 years. Mean DAS28 was 2.9±1.2 and mean HAQ-DI 0.77±0.67. Rheumatoid factor (RF) was positive in 431/564 (76.4%) and anti-cyclic citrullinated peptide antibodies (ACPA) in 374/564 (66.3%). Mean UA was 271±78 µmol/L with 12.7% readings being high. There were more males among patients with high UA than with normal UA(56% vs 36%,p<00.1) with no difference in age. UA was negatively correlated with DAS28(p<0.001), CDAI(p<0.001), SDAI(p=0.038), ESR(p=0.034), VAS pain(p=0.049), morning stiffness(p=0.033), patient's global assessment(p=0.006), physician's global assessment(p=0.033), number of tender joints(p<0.001) and number of swollen joints(p<0.001). There was no significant correlation with RF, ACPA or HAQ. The use of steroid, synthetic and biologic antirheumatic drugs, either individually or as a class, was similar among patients with high and normal UA.
Conclusions
RA patients with a higher UA had a lower disease activity despite using similar antirheumatic drugs. Reasons behind such association need to be further studied.
Up to 40% of psoriatic arthritis (PsA) patients experience first-line Tumour Necrosis Factor inhibitors (TNF-i) failure. Lower serum drug levels (SDL) have been associated with lower response in autoimmune conditions. This study aimed to: (i) establish the relationship between adalimumab (ADL) and etanercept (ETN) SDL and 3-month response; and (ii) identify optimal non-trough SDL thresholds in PsA.PsA patients commencing ADL or ETN were recruited to the UK observational study OUTPASS. Patients were seen pre-TNF-i and at 3 months when response was measured, and non-trough serum samples collected. Response was defined according to the PsARC or EULAR criteria. Descriptive statistics and concentration-effect curves established differences in SDL based on response. Receiver operating characteristics and regression identified optimal SDL thresholds.PsA ETN (n = 97) PsARC and EULAR good responders had significantly higher 3-month SDL compared with non-responders (p= 0.006 and p= 0.020 respectively). Non-trough 3-month ETN SDL discriminated PsARC responders from non-responders (AUC = 0.70), with a threshold of 1.8 µg/ml being 63% specific and 69% sensitive. EULAR good and non-/moderate responders were discriminated with an AUC of 0.65 with a threshold of 2.0 µg/ml being 57% specific and 69% sensitive. ADL prescribed (n = 104) EULAR good responders had significantly higher 3-month SDL (p= 0.049). Non-trough 3-month ADL SDL discriminated EULAR good and non-/moderate responders (AUC = 0.63) with a threshold of 3.6 µg/ml being 48% specific and 81% sensitive.Higher 3-month SDL were detected in responders. Interventions to optimise SDL may improve treatment response earlier. This study suggests 3-month SDL thresholds which may be useful in clinical practice to optimise treatment response.
OBJECTIVE: To assess the diagnostic accuracy of raised serum uric acid level in females with pre-eclampsia, in predicting low birth weight. SUBJESTS & METHODS: Cross sectional study carried out at Gynecology Department, FGSH Poly Clinic, Islamabad & duration of study was 6 months from July 21, 2021 to Jan 20, 2022. A total of 225 Preeclampsia pregnant female were clinically examined and included in the study. Blood sample were collected for serum uric acid and followed till the birth of the baby. RESULTS: The study included age ranged from 18 up to 40 years. Average age was 28.69years +5.01SD. Sensitivity & specificity of uric acid level in Serum in diagnosis of low birth weight are 85.71% and 81.42% respectively while it has positive predictive & negative predictive value of 51.43% & 96.13% respectively. Diagnostic accuracy of uric acid level in serum was 82.22%. CONCLUSION: Uric acid level in serum is of great diagnostic and prognostic importance in women with pre-eclampsia & helps in predicting low birth weight.
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