Browsing by Subject "rheumatoid arthritis"

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  • Kelkka, Tiina; Savola, Paula; Bhattacharya, Dipabarna; Huuhtanen, Jani; Lönnberg, Tapio; Kankainen, Matti; Paalanen, Kirsi; Tyster, Mikko; Lepistö, Maija; Ellonen, Pekka; Smolander, Johannes; Eldfors, Samuli; Yadav, Bhagwan; Khan, Sofia; Koivuniemi, Riitta; Sjöwall, Christopher; Elo, Laura L.; Lahdesmaki, Harri; Maeda, Yuka; Nishikawa, Hiroyashi; Leirisalo-Repo, Marjatta; Sokka-Isler, Tuulikki; Mustjoki, Satu (2020)
    Rheumatoid arthritis (RA) is a complex autoimmune disease targeting synovial joints. Traditionally, RA is divided into seropositive (SP) and seronegative (SN) disease forms, the latter consisting of an array of unrelated diseases with joint involvement. Recently, we described a severe form of SN-RA that associates with characteristic joint destruction. Here, we sought biological characteristics to differentiate this rare but aggressive anti-citrullinated peptide antibody-negative destructive RA (CND-RA) from early seropositive (SP-RA) and seronegative rheumatoid arthritis (SN-RA). We also aimed to study cytotoxic CD8+ lymphocytes in autoimmune arthritis. CND-RA, SP-RA and SN-RA were compared to healthy controls to reveal differences in T-cell receptor beta (TCR beta) repertoire, cytokine levels and autoantibody repertoires. Whole-exome sequencing (WES) followed by single-cell RNA-sequencing (sc-RNA-seq) was performed to study somatic mutations in a clonally expanded CD8+ lymphocyte population in an index patient. A unique TCR beta signature was detected in CND-RA patients. In addition, CND-RA patients expressed higher levels of the bone destruction-associated TNFSF14 cytokine. Blood IgG repertoire from CND-RA patients recognized fewer endogenous proteins than SP-RA patients' repertoires. Using WES, we detected a stable mutation profile in the clonally expanded CD8+ T-cell population characterized by cytotoxic gene expression signature discovered by sc-RNA-sequencing. Our results identify CND-RA as an independent RA subset and reveal a CND-RA specific TCR signature in the CD8+ lymphocytes. Improved classification of seronegative RA patients underlines the heterogeneity of RA and also, facilitates development of improved therapeutic options for the treatment resistant patients.
  • Vilén, Mikael (Helsingfors universitet, 2017)
    Monissa sairauksissa suoliston seinässä voidaan havaita tulehdus, läpäisevyyden kasvu ja mikrobiston muutoksia verrattuna terveisiin verrokkeihin. Tästä syystä suoliston mikrobiston muokkaamisella ja anti-inflammatorisilla bakteerilajeilla on potentiaalia kyseisten sairauksien hoidossa sekä preventiossa. Tulehduksen hoidossa tehokkaaksi menetelmäksi on osoittautunut mm. ulosteensiirrot, mutta sen anti-inflammatorisesta vasteesta vastaavat mekanismit ovat vielä osittain epäselviä. Tämän tutkielman kirjallisuuskatsauksessa tarkasteltiin suoliston mikrobiston ja läpäisevyyden häiriöiden vaikutuksia terveyteen ja erityisesti nivelreumaan. Nivelreumapotilailla on tyypillisesti kohonnut suoliston läpäisevyys, mutta sen merkitys sairauden etenemisessä ja patogeneesissä on vielä tuntematon. Suoliston mikrobiston häiriöt ja läpäisevyyden muutokset saattavat aiheuttaa immuunireaktion, joka voi johtaa nivelen rakenteisiin kohdistuvan autoimmuniteetin puhkeamiseen. Kokeellisessa osiossa tutkittiin suolistosta eristettyjen potentiaalisesti anti-inflammatoristen Propioni acnes –bakteerin ja toistaiseksi tuntemattoman linjan (27cc1) bakteerin vaikutuksia suoliston läpäisevyyteen. Koe suoritettiin Caco2-enterosyyttisolulinjalla ja sen muodostaman epiteelin läpäisevyyttä arvioitiin TER (transepithelial electrical resistance) -mittauksilla. Valituilla bakteereilla ei havaittu kokeissa merkittävää vaikutusta epiteelin läpäisevyyteen in vitro.
  • Joensuu, Jaana (Helsingfors universitet, 2013)
    Rheumatoid arthritis (RA) is a chronic autoimmune disease with prevalence of 0.8% among Finnish adult population. Consequent medical treatment, joint replacement surgery and productivity losses lead to significant expenses for society. While biological treatments for RA are costly, they can improve patients' quality of life and work participation. Economic evaluations provide information on the benefits and costs of these expensive treatments to aid optimal utilization of limited healthcare resources. This master`s thesis comprises the description of the Finnish Current Care Guidelines for RA, the cost of biological treatments and the principles of economic evaluations and health technology assessment. A systematic literature review was performed to identify existing studies examining the cost-effectiveness of biological treatments for RA. Of the 4890 references found with the literature search, 38 original studies and 9 previous systematic reviews were included in the current systematic literature review. Details of the methods as well as information on treatments, costs, benefits and incremental cost-effectiveness were extracted. Quality of the original studies was evaluated using quality assessment tools. Ninety percent (34/38) of the original studies used cost-utility modeling approach. Quality of life estimates were derived from RA specific health assessment questionnaire in a majority of the studies. Based on the current systematic literature review, the evidence on the cost-effectiveness of biological treatments is inconsistent. The incremental cost-effectiveness of the tumor necrosis factor (TNF) blockers was 13 500-772 000 €/ quality adjusted life year (QALY) in comparison to conventional disease modifying anti rheumatic drugs (DMARD) among patients without previous treatment with DMARDs. Several studies reported incremental cost-effectiveness ratios over 100 000 €/QALY in this population. Among patients with insufficient response to DMARDs, TNF blockers provided incremental cost-effectiveness ratios between 6 700 and 317 000 €/QALY. In most studies Rituximab was found to be a cost-effective alternative in contrast to other treatments among patients with insufficient response to TNF blockers. Biological treatments are not cost-effective among patients naïve to conventional DMARDs. Meanwhile, in patients with previous DMARD failure TNF-blockers might be cost-effective. The evidence on the cost effectiveness of biological treatments supports Finnish Current Care Guidelines. The quality assessment of the included studies revealed several sources of bias, consequently reducing the validity of the studies. Only a few of the conference abstracts in current subject has been published later as an article indicating existence of reporting bias. This study has several strengths. First, a comprehensive literature search was performed. Second, the quality of included studies was carefully evaluated. Finally, the methods and reporting are transparent. Weakness of the current study is one person extracting data and assessing the quality of the studies, which may reduce the reliability of this study. This systematic literature review is a basis for future studies examining cost-effectiveness of biological treatments in Finnish healthcare system.
  • Schrama, Johannes Cornelis; Fenstad, Anne M; Dale, Håvard; Havelin, Leif; Hallan, Geir; Overgaard, Soren; Pedersen, Alma B; Kärrholm, Johan; Garellick, Göran; Pulkkinen, Pekka; Eskelinen, Antti; Mäkelä, Keijo; Engesaeter, Lars B; Fevang, Bjorg-Tilde (2015)
    Background and purpose - Medical treatment of rheumatoid arthritis (RA) has changed dramatically over the last 15 years, including immune modulation. We investigated the risk of revision for infection after primary total hip replacement (THR) in patients with rheumatoid arthritis over a 16-year period, and compared it with that in THR patients with osteoarthritis (OA). Patients and methods - We identified 13,384 THRs in RA patients and 377,287 THRs in OA patients from 1995 through 2010 in a dataset from the Nordic Arthroplasty Register Association (NARA). Kaplan-Meier survival curves, with revision for infection as the endpoint, were constructed. Cox regression analyses were performed to calculate the relative risk (RR) of revision for infection adjusted for age, sex, fixation technique, and year of primary surgery. Results - RA patients had a 1.3 times (95% CI 1.0-1.6) higher risk of revision for infection. After 2001, this risk increased more for RA patients than for OA patients. During the first 3 months and from 8 years postoperatively, the risk of revision for infection was higher in RA patients with THRs fixated with antibiotic-loaded cement than in corresponding OA patients. Interpretation - We found a slightly higher overall risk of revision for infection in RA patients than in OA patients, but this difference was only present after 2001. In THRs with antibiotic-loaded cement, the risk of very early and late infections leading to revision was higher in RA patients than in OA patients.
  • Aaltonen, Kalle (Helsingfors universitet, 2010)
    Rheumatoid arthritis is an inflammatory autoimmune disease with prevalence of 0,8 per cent of Finnish people. Rheumatoid arthritis may lead to immobility and premature death. Treatment of Rheumatoid Arthritis includes disease modifying anti-rheumatic drugs and surgery. TNF-blockers are efficacious new drugs, which halt the progression of joint destruction caused by inflammation. The first TNF-blocker to receive permission of the national agency for medicines was Infliximab in 1999. Since then Infliximab has been followed by Etanercept, Adalimumab, Golimumab and Certolizumab. TNF-blockers have been found to be more efficacious than placebo in both clinical trials and register studies. In addition they are considered to be safe enough for clinical use despite the increased risk for tuberculosis and certain cancers. The number of patients annually treated with TNF-blockers in Finland increased threefold between 2004 and 2008. In 2008 the medication costs per patient were 11 669€ for Etanercept and 13 074€ for adalimumab. Systematic literature review is a study, which searches, identifies and combines individual studies. Usually Systematic reviews include a meta-analysis, which uses statistical methods to combine the results of the studies. Meta-analysis aims for increasing power and generalisibility of the studies and reducing the potential bias in individual studies. In order not to introduce bias by itself the systematic review must be done following the methods approved by the scientific community. In addition the process must be documented in detail. Following a predefined search strategy the systematic literature search found 5308 references. After a process involving the evaluation of the patients, intervention, control, outcomes, study design and the risk of bias 27 studies were selected to be included in the systematic review and meta-analysis. Of the included studies, nine had adalimumab, six had etanercept, five had infliximab, four had golimumab and three certolizumab as intervention. TNF-blocker was used either alone or in combination with methotrexate whereas control was either placebo or methotrexate. Altogether, there were 11 533 patients in the intervention group and 9027 in the control group. The results of the meta-analysis indicate reveal that the patients treated with TNF-blockers are twice as likely to reach a 20 % increase on ACR criteria compared to control patients. The likelihood to reach improvements of 50 and 70 % was 3 and 3.5 times higher, respectively. There were no statistically significant differences in efficacy between individual TNFblockers. Increasing the dosage of a TNF-blocker did not increase efficacy. However, combination of TNF-blocker and methotrexate was superior to monotreatment of TNF-blocker without increasing the likelihood of discontinuation of treatment. There were no statistically significant differences between the efficacy of TNF-blocker monotherapy and methotrexate. Adalimumab, infliximab and certolizumab lead more often to treatment discontinuation compared to etanercept and golimumab, which do not differ from control. This systematic review probably found all studies that investigated the efficacy of TNF-blockers in a randomized controlled trial. Study selection and evaluation were based on widely accepted methods. This study has two weaknesses. Firstly, literature search and study selection and evaluation were done only by a single researcher. Secondly, unpublished studies and study results were not actively obtained outside electronic databases.
  • FinnGen Rheumatology Clinical Expe; Palomaki, Antti; Palotie, Aarno; Koskela, Jukka; Eklund, Kari K.; Pirinen, Matti; Ripatti, Samuli; Laitinen, Tarja; Mars, Nina (2021)
    Objectives To estimate lifetime risk of developing rheumatoid arthritis-associated interstitial lung disease (RA-ILD) with respect to the strongest known risk factor for pulmonary fibrosis, a MUC5B promoter variant. Methods FinnGen is a collection of epidemiological cohorts and hospital biobank samples, integrating genetic data with up to 50 years of follow-up within nationwide registries in Finland. Patients with RA and ILD were identified from the Finnish national hospital discharge, medication reimbursement and cause-of-death registries. We estimated lifetime risks of ILD by age 80 with respect to the common variant rs35705950, a MUC5B promoter variant. Results Out of 293 972 individuals, 1965 (0.7%) developed ILD by age 80. Among all individuals in the dataset, MUC5B increased the risk of ILD with a HR of 2.44 (95% CI: 2.22 to 2.68). Out of 6869 patients diagnosed with RA, 247 (3.6%) developed ILD. In patients with RA, MUC5B was a strong risk factor of ILD with a HR similar to the full dataset (HR: 2.27, 95% CI: 1.75 to 2.95). In patients with RA, lifetime risks of ILD were 16.8% (95% CI: 13.1% to 20.2%) for MUC5B carriers and 6.1% (95% CI: 5.0% to 7.2%) for MUC5B non-carriers. The difference between risks started to emerge at age 65, with a higher risk among men. Conclusion Our findings provide estimates of lifetime risk of RA-ILD based on MUC5B mutation carrier status, demonstrating the potential of genomics for risk stratification of RA-ILD.
  • Malmberg, Markus; Palomäki, Antti; Sipilä, Jussi O. T.; Rautava, Päivi; Gunn, Jarmo; Kytö, Ville (2021)
    Background: Patients with rheumatoid arthritis (RA) have increased risk of developing cardiovascular disease and events. Little is, however, known about the influence of RA to the outcomes after surgical aortic valve replacement (SAVR). Methods: In a retrospective, nationwide, multicenter cohort study, RA patients (n = 109) were compared to patients without RA (n = 1090) treated with isolated SAVR for aortic valve stenosis. Propensity score-matching adjustment for baseline features was used to study the outcome differences in a median follow-up of 5.6 years. Results: Patients with RA had higher all-cause mortality (HR 1.76; CI 1.21-2.57; p = 0.003), higher incidence of major adverse cardiovascular events (HR 1.63; CI 1.06-2.49; p = 0.025), and they needed more often coronary artery revascularization for coronary artery disease (HR 3.96; CI 1.21-12.90; p = 0.027) in long-term follow-up after SAVR. As well, cardiovascular mortality rate was higher in patients with RA (35.7% vs. 23.4%, p = 0.023). There was no difference in 30-day mortality (2.8% vs. 1.8%, p = 0.518) or in the need for aortic valve reoperations (3.7% vs. 4.0%, p = 0.532). Conclusions: Patients with rheumatoid arthritis had impaired long-term results and increased cardiovascular mortality after SAVR for aortic valve stenosis. Special attention is needed to improve outcomes of aortic valve stenosis patients with RA after SAVR.
  • Kampman, Johanna (Helsingfors universitet, 2016)
    Rheumatoid arthritis (RA) is a chronic autoimmune disease with prevalence around 0.8 % in Finland. Joint inflammation causes pain, tenderness and swelling in joint as well as loss of functional and work capacity. Patients need healthcare resources and medical treatments cause substantial costs to patient and society. Severity of RA can be measured by Disease Activity Score (DAS28) and Health Assessment Questionnaire (HAQ). Previous studies suggest these measures are related to higher direct and indirect cost. The aims of this study are to determine cost of RA in Finland and analyse cost by disease activity and functional disability. Literature review was performed by using some methods from systematic reviews to identify previous studies examining cost of RA by DAS28 and HAQ scores. Secondly in this master thesis was made a quantitative cost analysis which study population was identified from the National register for Biologics in Finland (ROB-FIN) and patient records of the Central Finland Central Hospital. The cost data for direct and productivity costs was received from Finnish national registries. Costs were determined from the followed six months after patients' (N=2285) first routine outpatient visit to specialized healthcare. Distribution of costs was examined by DAS28 and HAQ score based classification. Additionally cost related to RA was determined separately between biologic and non-biologic drug users. Total average costs of the study population were 11 720 € biannually. Direct costs, productivity costs and total costs were higher for patients with higher DAS28 and HAQ scores. Increase in average total costs between best and worst DAS28 and HAQ classifications were 7817 -15 838 € and 8545 - 16 718 €, respectively. In the cost categories changes in both directions were detected between different DAS28 and HAQ score classifications. Drug costs comprised largest part of direct costs (56 %). RA related average total costs increased from best to worst DAS28 and HAQ class for both biologic and non-biologic drug users (p<0,01). Similar study based real life register data is not previous made in Finland. Studies in other countries can`t be directly adapted to Finnish healthcare system, treatment traditions and productivity costs. This study provides information for real-life cots of RA and how they are related to disease activity and functional disability. This information can be used in modelling of cost-effectiveness.
  • Lehmonen, Lauri; Vuorinen, Aino-Maija; Koivuniemi, Riitta; Leirisalo-Repo, Marjatta; Holmström, Miia Maria; Kivistö, Sari; Kaasalainen, Touko (2018)
    RATIONALE AND OBJECTIVES: To evaluate the effects of 1 year of medical treatment on myocardial function in active rheumatoid arthritis (RA). MATERIALS AND METHODS: Thirty-nine female patients with RA without any known cardiovascular disease underwent a cardiovascular magnetic resonance (CMR) examination before and after 1 year of antirheumatic treatment. The population comprised untreated active early RA (ERA) and chronic RA patients, who were grouped accordingly. The CMR protocol included volumetric determinations, late gadolinium enhancement imaging, myocardial tagging, and native T1 mapping. DAS28-CRP disease activity scores were calculated before and after the treatment. RESULTS: Results are reported as median (quartile 1-quartile 3). Time to peak diastolic filling rate improved in ERA (495 [443-561] ms vs 441 [340-518] ms, P = .018). Peak diastolic mean mid short-axis circumferential strain rate of all six segments was improved (82 [74-91] %/s vs 91 [77-100] %/s, P = .05), particularly in the anterior segment (82 [63-98] %/s vs 86 [77-109] %/s, P = .013). DAS28-CRP decreased in ERA (3.8 [3.2-4.1] vs 1.6 [1.4-2.2], P < .001). In chronic RA, no statistically significant improvement was detected. CONCLUSIONS: Early treatment of active RA is important, as myocardial function detected with CMR tagging improved in ERA in parallel with decreasing inflammatory activity.
  • Hammer, Hilde Berner; Hansen, Inger Marie Jensen; Järvinen, Pentti; Leirisalo-Repo, Marjatta; Ziegelasch, Michael; Agular, Birte; Terslev, Lene (2021)
    Objectives. Given that subjective variables might reduce remission by composite DAS (CDAS), the main objectives were to explore whether RA patients with mainly tender vs mainly swollen joints had differences in patient-reported outcome measures (PROMs), clinical or US assessments or in achieving remission defined by CDAS or US. Methods. In a Nordic multicentre study, RA patients initiating tocilizumab were assessed by PROMs, clinical, laboratory and US assessments (36 joints and 4 tendons) at baseline, 4, 12 and 24 weeks. Remission was defined according to clinical disease activity index (CDAI)/Boolean or no Doppler activity present. Tender-swollen joint differences (TSJDs) were calculated. Statistics exploring changes over time/differences between groups included Wilcoxon, Mann-Whitney, Kruskal-Wallis and Spearman tests. Results. One hundred and ten patients were included [mean (S.D.) age 55.6 (12.1) years, RA duration 8.7 (9.5) years]. All PROMs, clinical, laboratory and US scores decreased during follow-up (P < 0.001). During follow-up, tender joint counts were correlated primarily with PROMs [r = 0.24-0.56 (P < 0.05-0.001)] and swollen joint counts with US synovitis scores [r = 0.33-0.72 (P < 0.05-0.001)]. At 24 weeks, patients with TSJD > 0 had higher PROMs and CDAI (P < 0.05-0.001) but lower US synovitis scores (P < 0.05). Remission by CDAI/Boolean was seen in 26-34% and by Doppler 53%, but only 2-3% of patients with TSJD > 0 achieved CDAI/Boolean remission. Conclusion. Patients with more tender than swollen joints scored higher on subjective assessments but had less US synovitis. They seldom achieved CDAS remission despite many being in Doppler remission. If patients with predominantly tender joints do not reach CDAS remission, objective assessments of inflammation should be performed.
  • Mustonen, Anne-Mari; Käkelä, Reijo; Joukainen, Antti; Lehenkari, Petri; Jaroma, Antti; Kaariainen, Tommi; Kroger, Heikki; Paakkonen, Tommi; Sihvo, Sanna Pauliina; Nieminen, Petteri (2021)
    Simple Summary Anomalies of fatty acid metabolism characterize osteoarthritis and rheumatoid arthritis in the knee joint. No previous study has investigated the synovial fluid fatty acid manifestations in these aging-related inflammatory diseases in the shoulder. The present experiment compared the fatty acid alterations between the shoulder and knee joints in trauma controls and in patients with end-stage osteoarthritis or end-stage rheumatoid arthritis. The fatty acid signatures in the synovial fluid of trauma controls were mostly uniform in both anatomical locations. Shoulders with rheumatoid arthritis were characterized by elevated percentages of arachidonic acid and docosahexaenoic acid and with reduced proportions of oleic acid. The fatty acid profiles of knees with osteoarthritis or rheumatoid arthritis were relatively uniform and displayed lower proportions of linoleic acid, docosahexaenoic acid and total n-6 polyunsaturated fatty acids. The results indicate location- and disease-dependent differences in the synovial fluid fatty acid composition. These alterations may affect joint lubrication, synovial inflammation and pannus formation as well as cartilage and bone degradation and contribute to the pathogeneses of inflammatory joint diseases. Anomalies of fatty acid (FA) metabolism characterize osteoarthritis (OA) and rheumatoid arthritis (RA) in the knee joint. No previous study has investigated the synovial fluid (SF) FA manifestations in these aging-related inflammatory diseases in the shoulder. The present experiment compared the FA alterations between the shoulder and knee joints in patients with end-stage OA or end-stage RA. SF samples were collected during glenohumeral or knee joint surgery from trauma controls and from OA and RA patients (n = 42). The FA composition of SF total lipids was analyzed by gas chromatography with flame ionization and mass spectrometric detection and compared across cohorts. The FA signatures of trauma controls were mostly uniform in both anatomical locations. RA shoulders were characterized by elevated percentages of 20:4n-6 and 22:6n-3 and with reduced proportions of 18:1n-9. The FA profiles of OA and RA knees were relatively uniform and displayed lower proportions of 18:2n-6, 22:6n-3 and total n-6 polyunsaturated FAs (PUFAs). The results indicate location- and disease-dependent differences in the SF FA composition. These alterations in FA profiles and their potential implications for the production of PUFA-derived lipid mediators may affect joint lubrication, synovial inflammation and pannus formation as well as cartilage and bone degradation and contribute to the pathogeneses of inflammatory joint diseases.
  • Palmroth, Maaria; Kuuliala, Krista; Peltomaa, Ritva; Virtanen, Anniina; Kuuliala, Antti; Kurttila, Antti; Kinnunen, Anna; Leirisalo-Repo, Marjatta; Silvennoinen, Olli; Isomäki, Pia (2021)
    Objective Current knowledge on the actions of tofacitinib on cytokine signaling pathways in rheumatoid arthritis (RA) is based on in vitro studies. Our study is the first to examine the effects of tofacitinib treatment on Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathways in vivo in patients with RA. Methods Sixteen patients with active RA, despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), received tofacitinib 5 mg twice daily for three months. Levels of constitutive and cytokine-induced phosphorylated STATs in peripheral blood monocytes, T cells and B cells were measured by flow cytometry at baseline and three-month visits. mRNA expression of JAKs, STATs and suppressors of cytokine signaling (SOCS) were measured from peripheral blood mononuclear cells (PBMCs) by quantitative PCR. Association of baseline signaling profile with treatment response was also investigated. Results Tofacitinib, in csDMARDs background, decreased median disease activity score (DAS28) from 4.4 to 2.6 (p < 0.001). Tofacitinib treatment significantly decreased cytokine-induced phosphorylation of all JAK-STAT pathways studied. However, the magnitude of the inhibitory effect depended on the cytokine and cell type studied, varying from 10% to 73% inhibition following 3-month treatment with tofacitinib. In general, strongest inhibition by tofacitinib was observed with STAT phosphorylations induced by cytokines signaling through the common-gamma-chain cytokine receptor in T cells, while lowest inhibition was demonstrated for IL-10 -induced STAT3 phosphorylation in monocytes. Constitutive STAT1, STAT3, STAT4 and STAT5 phosphorylation in monocytes and/or T cells was also downregulated by tofacitinib. Tofacitinib treatment downregulated the expression of several JAK-STAT pathway components in PBMCs, SOCSs showing the strongest downregulation. Baseline STAT phosphorylation levels in T cells and monocytes and SOCS3 expression in PBMCs correlated with treatment response. Conclusions Tofacitinib suppresses multiple JAK-STAT pathways in cytokine and cell population specific manner in RA patients in vivo. Besides directly inhibiting JAK activation, tofacitinib downregulates the expression of JAK-STAT pathway components. This may modulate the effects of tofacitinib on JAK-STAT pathway activation in vivo and explain some of the differential findings between the current study and previous in vitro studies. Finally, baseline immunological markers associate with the treatment response to tofacitinib.