Tofacitinib treatment modulates the levels of several inflammation-related plasma proteins in rheumatoid arthritis and baseline levels of soluble biomarkers associate with the treatment response.

The data on the effects of tofacitinib on soluble proteins in patients with rheumatoid arthritis (RA) is currently very limited. We analyzed how tofacitinib treatment and thus inhibition of the Janus kinase-signal transducer and activation of transcription pathway affects the in vivo levels of inflammation-related plasma proteins in RA patients. In this study, 16 patients with active RA [28-joint disease activity score (DAS28) >3.2] despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) started tofacitinib treatment 5 mg twice daily. Levels of 92 inflammation-related plasma proteins were determined by proximity extension assay at baseline and at 3 months. Tofacitinib treatment for 3 months, in csDMARD background, decreased the mean DAS28 from 4.4 to 2.6 (P < 0.001). Marked (>20%) and statistically significant (P < 0.05) changes were found in the levels of 21 proteins, 18 of which decreased and 3 increased. Of these proteins, 17 are directly involved in inflammatory responses or in the cellular response to cytokines. The highest (>50%) decrease was observed for interleukin-6 (IL-6), C-X-C motif chemokine ligand 1, matrix metalloproteinase-1, and AXIN1. Higher baseline levels of IL-6 and lower levels of C-C motif chemokine 11 and Delta and Notch-like epidermal growth factor-related receptors were associated with DAS28 improvement. Our results indicate that tofacitinib downregulates several proinflammatory plasma proteins that may contribute to the clinical efficacy of tofacitinib. In addition, soluble biomarkers may predict the treatment response to tofacitinib.

Short interruptions of TNF-inhibitor treatment can be associated with treatment failure in patients with immune-mediated diseases.

INTRODUCTION: The prevalence of immune-mediated diseases has increased in the past decades and despite the use of biological treatments all patients do not achieve remission. The aim of this study was to characterise the reasons for short interruptions during treatment with two commonly used TNF-inhibitors infliximab and adalimumab and to analyse the possible effects of the interruptions on immunisation and switching the treatment. MATERIAL AND METHODS: This case-control study was based on retrospective analyses of patient records and a questionnaire survey to clinicians. A total of 370 patients (194 immunised cases and 172 non-immunised controls, 4 excluded) were enrolled from eight hospitals around Finland. Eleven different diagnoses were represented, and the largest patient groups were those with inflammatory bowel or rheumatic diseases. RESULTS: Treatment interruptions were associated with immunisation in patients using infliximab (p < .001) or adalimumab (p < .000001). Patients with treatment interruptions were more likely to have been treated with more than one biological agent compared to those without treatment interruptions. This was particularly prominent among patients with a rheumatic disease (p < .00001). The most frequent reason for a treatment interruption among the cases was an infection, whereas among the control patients it was remission. The median length of one interruption was one month (interquartile range 1-3 months). CONCLUSION: Our results suggest that the interruptions of the treatment with TNF-inhibitors expose patients to immunisation and increase the need for drug switching. These findings stress the importance of careful judgement of the need for a short interruption in the biological treatment in clinical work, especially during non-severe infections.

The activity of JAK-STAT pathways in rheumatoid arthritis: constitutive activation of STAT3 correlates with interleukin 6 levels.

OBJECTIVE: Many cytokines involved in RA activate the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways. Therapeutic drugs that inhibit these pathways are being developed for RA. To investigate disease-related alterations in the activity of JAK-STAT pathways in RA, we studied the expression and activation of STAT1 and STAT3 in unstimulated and cytokine-stimulated cells and determined the levels of circulating cytokines. METHODS: The expression of STAT1 and STAT3 mRNA in peripheral blood (PB) and SF T cells and monocytes was studied in RA patients and healthy volunteers by RT-PCR. Basal and cytokine (IFN-γ, IL-6, IL-10)-induced STAT phosphorylation was analysed in PB T cells and monocytes using multicolour flow cytometric analysis. RESULTS: STAT3 mRNA levels were up-regulated in both PB and SF T cells and monocytes from RA patients. STAT1 expression was elevated in SF monocytes. The levels of phospho-STAT3 in resting PB T cells and monocytes were significantly higher in patients with RA than in healthy volunteers. IL-6 levels were elevated in RA plasma and correlated with the level of STAT3 phosphorylation in CD4(+) T cells and monocytes. IL-6-mediated STAT3 activation was deregulated in T cells from RA patients. IL-6-induced phosphorylation of STAT3 was decreased in CD4(+) T cells from patients with high plasma IL-6 levels and constitutive STAT3 phosphorylation. CONCLUSION: The results suggest that IL-6 induces hyperactivation of STAT3 in circulating immune cells in active RA, and this subsequently desensitizes the IL-6 response in T cells.

Disease activity of idiopathic juvenile arthritis continues through adolescence despite the use of biologic therapies.

OBJECTIVES: To investigate the use of DMARDs and biologic treatments and disease activity in patients with JIA referred to the adult rheumatology clinic and to provide further information regarding the need for long-term rheumatologic care. METHODS: We studied the data of 154 patients retrospectively from hospital records if they met the following criteria: diagnosis of JIA and at least one visit to the adult rheumatologic unit. Previous and current antirheumatic treatment, duration of biologic therapy and disease activity were recorded. RESULTS: At the end of patient follow-up, the median age of the eligible patients was 19 years (range 16-24 years) and the disease duration was 8 years (range 0-20 years). Twenty-nine per cent of the patients were still on biologic therapies. The total median duration of treatment with at least one biologic agent was 4.2 years, and 44% of treatment durations lasted >5 years. Some disease activity was present in the last year in 58% of patients. Activity in the temporomandibular joint was detected in 14% and uveitis in 8%. Thirteen per cent did not need further specialist care and in 14% all antirheumatic medication could be tapered off. CONCLUSION: Almost one-third of adolescents and young adults with JIA who needed specialist care were on biologics. The need for treatment in many cases is long term (>5 years). Most patients (58%) still showed evidence of mild disease activity. Adolescents and young adults with JIA are a distinct patient group in adult health care and a specialized multidisciplinary approach to treatment is needed.

[Imaging of inflammatory back pain]. / Tulehduksellisen selkäkivun kuvantamis- diagnostiikka.

We recommend magnetic resonance imaging of the sacroiliac joints as the first line imaging method in suspected inflammatory back disorder. Plain X-ray can be taken from those over 35 years of age. A nonconclusive finding in plain X-ray should be verified by MR imaging. For the present, diagnostic criteria for spondylarthritis do not take into account spinal changes. Typical spinal findings can, however, be helpful in making treatment decisions. In case the spinal region MR imaging should be utilized if possible, because radiography is particularly insensitive for thoracic spine. After a confirmed diagnosis, the inflammatory nature of the condition can usually be assessed clinically.