Rheumatoid arthritis

Rheumatoid arthritis is a chronic inflammatory joint disease, which can cause cartilage and bone damage as well as disability. Early diagnosis is key to optimal therapeutic success, particularly in patients with well-characterised risk factors for poor outcomes such as high disease activity, presence of autoantibodies, and early joint damage. Treatment algorithms involve measuring disease activity with composite indices, applying a treatment-to-target strategy, and use of conventional, biological, and newz non-biological disease-modifying antirheumatic drugs. After the treatment target of stringent remission (or at least low disease activity) is maintained, dose reduction should be attempted. Although the prospects for most patients are now favourable, many still do not respond to current therapies. Accordingly, new therapies are urgently required. In this Seminar, we describe current insights into genetics and aetiology, pathophysiology, epidemiology, assessment, therapeutic agents, and treatment strategies together with unmet needs of patients with rheumatoid arthritis

Soluble urokinase plasminogen activator receptor (suPAR) in the assessment of inflammatory activity of rheumatoid arthritis patients in remission.

Abstract Background: Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker increasingly used for the assessment of systemic inflammation. We aimed to evaluate suPAR for the assessment of inflammatory activity in rheumatoid arthritis (RA) patients in remission. Methods: In our cross-sectional study we measured plasma suPAR and C-reactive protein (CRP) levels as well as erythrocyte sedimentation rate (ESR) in 120 RA patients at various stages of disease activity and 29 healthy age-matched controls. Results: suPAR, CRP and ESR values were higher in RA patients compared to healthy individuals. When suPAR levels were analyzed according to DAS28 scores of RA patients, suPAR level in the subgroup with DAS282.6, but still higher than in controls [4.45 (3.33-5.56) ng/mL vs. 3.66 (3.10-4.67) ng/mL vs. 2.80 (2.06-3.42) ng/mL, p<0.0001, median (interquartile range)]. In contrast, CRP and ESR values were comparable in the subgroup with DAS28</=2.6 and in healthy individuals. We further analyzed the correlation between the number of tender and/or swollen joints and suPAR levels in RA patients in remission. suPAR values were significantly higher in patients with four tender and/or swollen joints than in patients with 2-3 or 0-1 tender and/or swollen joints. Conclusions: While CRP and ESR values indicate remission of the chronic inflammatory process in RA, suPAR values are still elevated compared to healthy individuals. suPAR might be particularly valuable in the recognition of inflammatory activity in patients who are in remission according to DAS28 scores but have symptoms of tender and/or swollen joints

IL-6 Mediated Transcriptional Programming of Naïve CD4+ T Cells in Early Rheumatoid Arthritis Drives Dysregulated Effector Function.

Objective: We have previously shown that increased circulating interleukin-6 (IL-6) results in enhanced CD4+ T cell signaling via signal transduction and activator of transcription-3 (STAT3) in early rheumatoid arthritis (RA). We tested the hypothesis that transcriptional "imprinting" of T-cells by this mechanism skews downstream effector responses, reinforcing immune dysregulation at a critical, but targetable, disease phase. Methods: We modeled naïve CD4+ T cell exposure to pathophysiological concentrations of IL-6 in vitro, assessing the dynamic transcriptional and functional consequences for downstream effector cells utilizing microarray and flow cytometry. Fresh blood from treatment-naïve early arthritis patients was phenotyped in parallel for comparison. Results: T cell sensitivity to IL-6 was most marked in the naïve subset, and related to gp130 rather than IL-6R expression. Exposure of healthy naïve CD4+ T cells to IL-6 induced the same STAT3 target genes as previously seen to discriminate RA patients from disease controls. After TCR stimulation IL-6 pre-exposed cells exhibited enhanced proliferative capacity, activation, and a propensity toward Th1 differentiation, compared to non-exposed cells. An entirely analogous phenotype was observed in early RA compared to control CD4+ T cells. Conclusions: Sustained IL-6 exposure at a critical point in the natural history of RA "primes" the adaptive immune system to respond aberrantly to TCR stimulation, potentiating disease induction with implications for the optimal timing of targeted therapy

Mavrilimumab, a fully human granulocyte-macrophage colony-stimulating factor receptor α monoclonal antibody: long-term safety and efficacy in patients with rheumatoid arthritis

Objective: Mavrilimumab, a human monoclonal antibody, targets granulocyte-macrophage colony-stimulating factor receptor alpha. We report mavrilimumab long-term safety and efficacy in rheumatoid arthritis patients in two phase IIb studies (1071, 1107) and open-label extension (OLE; NCT01712399). Methods: In 1071, patients with disease-modifying antirheumatic drug (DMARD)-inadequate responses received mavrilimumab 30, 100, 150 mg, or placebo every other week (eow), plus methotrexate. In 1107, patients with anti-tumor necrosis factor agent- and/or DMARD-inadequate responses received mavrilimumab 100 mg eow or golimumab 50 mg every 4 weeks, plus methotrexate. Patients entering the OLE received mavrilimumab 100 mg eow plus methotrexate. Mavrilimumab long-term safety and efficacy were assessed. Results: In total, 442 patients received mavrilimumab (14/245 patients from 1071, 9/70 from 1107, 52/397 from OLE discontinued mavrilimumab treatment throughout the studies). The cumulative safety exposure was 899 patient-years (PY); the median duration of mavrilimumab treatment was 2.5 (range 0.1–3.3) years. Most common treatment-emergent adverse events were nasopharyngitis (n=69, 7.68/100 PY), bronchitis (n=51, 5.68/100 PY). At Weeks 74/104: 3.5%/6.2% patients showed reduction in forced expiratory volume in 1 second; 2.9%/3.4% patients showed reduction in forced vital capacity, respectively (&gt;20% reduction from baseline to &lt;80% predicted). Most pulmonary changes were transient and only infrequently associated with adverse events. Mavrilimumab 100 mg eow demonstrated sustained efficacy; 65.0% and 40.6% patients achieved Disease Activity Score 28–C-reactive protein &lt;3.2 and &lt;2.6, respectively at Week 122. Conclusion: Mavrilimumab long-term treatment maintained response and was well-tolerated with no TEAE incidence increase. Safety data were comparable with both phase IIb qualifying studies

An overview of psoriatic arthritis – epidemiology, clinical features, pathophysiology and novel treatment targets

Psoriatic arthritis is a chronic inflammatory joint disease occurring in a subgroup of patients suffering from psoriasis. This article gives an overview of the complexity of psoriatic arthritis, looking at several aspects of this heterogeneous disease, such as epidemiology, important clinical features and comorbidities as well as current concepts of the pathophysiology and subsequent insights in novel treatment targets.(VLID)348921

The safety and immunogenicity of live Zoster Vaccination in patients with rheumatoid arthritis before starting Tofacitinib: a randomized phase II trial

Objective Patients with rheumatoid arthritis (RA) are at increased risk of herpes zoster, and vaccination is recommended for patients ages 50 years and older, prior to starting treatment with biologic agents or tofacitinib. Tofacitinib is an oral JAK inhibitor for the treatment of RA. We evaluated its effect on the immune response and safety of live zoster vaccine (LZV). Methods In this phase II, 14-week, placebo-controlled trial, patients ages 50 years and older who had active RA and were receiving background methotrexate were given LZV and randomized to receive tofacitinib 5 mg twice daily or placebo 2–3 weeks postvaccination. We measured humoral responses (varicella zoster virus [VZV]–specific IgG level as determined by glycoprotein enzyme-linked immunosorbent assay) and cell-mediated responses (VZV-specific T cell enumeration, as determined by enzyme-linked immunospot assay) at baseline and 2 weeks, 6 weeks, and 14 weeks postvaccination. End points included the geometric mean fold rise (GMFR) in VZV-specific IgG levels (primary end point) and T cells (number of spot-forming cells/106 peripheral blood mononuclear cells) at 6 weeks postvaccination. Results One hundred twelve patients were randomized to receive tofacitinib (n = 55) or placebo (n = 57). Six weeks postvaccination, the GMFR in VZV-specific IgG levels was 2.11 in the tofacitinib group and 1.74 in the placebo group, and the VZV-specific T cell GMFR was similar in the tofacitinib group and the placebo group (1.50 and 1.29, respectively). Serious adverse events occurred in 3 patients in the tofacitinib group (5.5%) and 0 patients (0.0%) in the placebo group. One patient, who lacked preexisting VZV immunity, developed cutaneous vaccine dissemination 2 days after starting tofacitinib (16 days postvaccination). This resolved after tofacitinib was discontinued and the patient received antiviral treatment. Conclusion Patients who began treatment with tofacitinib 2–3 weeks after receiving LZV had VZV-specific humoral and cell-mediated immune responses to LZV similar to those in placebo-treated patients. Vaccination appeared to be safe in all of the patients except 1 patient who lacked preexisting VZV immunity

Secukinumab Provides Significant and Sustained Inhibition of Joint Structural Damage in a Phase III Study of Active Psoriatic Arthritis

In this phase III, double-blind, placebo-controlled study, 606 patients with psoriatic arthritis were randomised to intravenous (IV) secukinumab 10 mg/kg (weeks 0, 2, 4) followed by subcutaneous secukinumab 150 mg (IV→150 mg) or 75 mg (IV→75 mg), or placebo. Patients were stratified by prior anti-TNF (tumour necrosis factor) exposure (71% anti-TNF-naïve). At week 16, placebo-treated patients who had ≥20% reduction in tender and swollen joint count (responders) remained on placebo until week 24; non-responders were re-randomised to secukinumab 150 or 75 mg. The van der Heijde modified total Sharp score (mTSS) was determined at baseline, week 16/24 and week 52.In the overall population, radiographic progression was inhibited through 52 weeks; efficacy was demonstrated for both erosion and joint space narrowing scores and in patients who switched from placebo to secukinumab at week 24. Subgroup analyses showed secukinumab reduced progression at week 24, regardless of prior anti-TNF use; mean change from baseline to week 24 in mTSS in the secukinumab pooled and placebo groups was 0.05 and 0.57, respectively for anti-TNF-naïve patients and 0.16 and 0.58, respectively in anti-TNF-IR patients. Anti-TNF-naïve patients showed negligible progression through week 52. Inhibition of structural damage was observed through week 52, irrespective of concomitant methotrexate use. A high proportion of patients showed no progression (≤0.5) with secukinumab from baseline to week 24 (IV→150 mg, 82.3%; IV→75 mg, 92.3%) and from week 24 to week 52 (IV→150 mg, 85.7%; IV→75 mg, 85.8%).Secukinumab inhibited radiographic progression in patients with active psoriatic arthritis through 52 weeks of therapy

Value of self-performed joint counts in rheumatoid arthritis patients near remission

INTRODUCTION: To determine the validity and reliability of patients' self-performed joint counts compared to joint counts by professional assessors in rheumatoid arthritis (RA) patients in different disease activity states. METHODS: In patients with established RA we determined the inter-rater reliability of joint counts performed by an independent evaluator and the patient using intraclass correlation (ICC), and agreement on activity in individual joints by kappa statistics. We also performed longitudinal analyses to assess consistency of assessments over time. Finally, we investigated the concordance of joint counts of different assessors in patients with different levels of disease activity. RESULTS: The reliability of patient self-performed joint counts was high when compared to independent objective assessment (ICC; 95%confidence interval (CI)) for the assessment of swelling (0.32; 0.15 to 0.46) and tenderness (0.75; 0.66 to 0.81), with higher agreement for larger joints (kappa: 0.57 and 0.45, respectively) compared to smaller joints (metacarpo-phalangeal joint (MCPs): 0.31 and 0.45; and proximal interphalangeal joint (PIPs): 0.22 and 0.47, for swelling and tenderness, respectively). Patients in remission according to the Simplified Disease Activity Index (SDAI ≤ 3.3) showed better concordance of the joint counts (swollen joint count (SJC) ties 25/37, tender joint count (TJC) ties 26/37) compared to moderate/high disease activity states (SDAI > 11; MDA/HDA: SJC ties 9/72, TJC ties 21/72). Positive and negative predictive values regarding the presence of SDAI remission were reasonably good (0.86 and 0.95, respectively). A separate training session for patients did not improve the reliability of joint assessment. The results were consistent in the longitudinal analyses. CONCLUSIONS: Self-performed joint counts are particularly useful for monitoring in patients having attained remission, as these patients seem able to detect state of remission

Anticarbamylated protein antibodies are associated with long-term disability and increased disease activity in patients with early inflammatory arthritis:Results from the Norfolk Arthritis Register

Objectives: Anticarbamylated protein (anti-CarP) antibodies are a novel family of autoantibodies recently identified in patients with inflammatory arthritis. The aim of this study was to investigate their association with long-term outcomes of disability and disease activity over 20 years’ follow-up in a cohort of patients with inflammatory polyarthritis (IP).  Methods: Norfolk Arthritis Register recruited adults with recent-onset swelling of ≥2 joints for ≥4 weeks from 1990 to 2009. At baseline, Health Assessment Questionnaire (HAQ) and 28 joint disease activity scores (DAS28) were obtained, and C reactive protein, rheumatoid factor (RF), anticitrullinated protein antibodies (ACPA) and anti-CarP antibodies were measured. Further HAQ scores and DAS28 were obtained at regular intervals over 20 years. Generalised estimating equations were used to test the association between anti-CarP antibody status and longitudinal HAQ and DAS28 scores; adjusting for age, gender, smoking status, year of inclusion and ACPA status. Analyses were repeated in subgroups stratified by ACPA status. The relative association of RF, ACPA and anti-CarP antibodies with HAQ and DAS28 scores was investigated using a random effects model.  Results: 1995 patients were included; 1310 (66%) were female. Anti-CarP antibodies were significantly associated with more disability and higher disease activity, HAQ multivariate β-coefficient (95% CI) 0.12 (0.02 to 0.21), and these associations remained significant in the ACPA-negative subgroups. The associations of RF, ACPA and anti-CarP antibodies were found to be additive in the random effects model.  Conclusions: Anti-CarP antibodies are associated with increased disability and higher disease activity in patients with IP. Our results suggest that measurement of anti-CarP antibodies may be useful in identifying ACPA-negative patients with worse long-term outcomes. Further, anti-CarP antibody status provided additional information about RF and ACPA

Interpretation of DAS28 and its components in the assessment of inflammatory and non-inflammatory aspects of rheumatoid arthritis

Background: DAS28 is interpreted as the inflammatory disease activity of RA. Non-inflammatory pain mechanisms can confound assessment. We aimed to examine the use of DAS28 components or DAS28-derived measures that have been published as indices of non-inflammatory pain mechanisms, to inform interpretation of disease activity. Methods: Data were used from multiple observational epidemiology studies of people with RA. Statistical characteristics of DAS28 components and derived indices were assessed using baseline and follow up data from British Society for Rheumatology Biologics Registry participants [1] commencing anti-TNF therapy (n = 10813), or [2] changing between non-biologic DMARDs (n=2992), [3] Early Rheumatoid Arthritis Network participants (n=813), and [4] participants in a cross-sectional study exploring fibromyalgia and pain thresholds (n=45). Repeatability was tested in 34 patients with active RA. Derived indices were the proportion of DAS28 attributable to patient-reported components (DAS28-P), tender-swollen difference and tender:swollen ratio. Pressure pain detection threshold (PPT) was used as an index of pain sensitisation. Results: DAS28, tender joint count, visual analogue scale, DAS28-P, tender-swollen difference and tender:swollen ratio were more strongly associated with pain, PPT and fibromyalgia status than were swollen joint count or erythrocyte sedimentation rate. DAS28-P, tender-swollen difference and tender:swollen ratio better predicted pain over 1 year than did DAS28 or its individual components. Conclusions: DAS28 is strongly associated both with inflammation and with patient-reported outcomes. DAS28-derived indices such as tender-swollen difference are associated with non-inflammatory pain mechanisms, can predict future pain and should inform how DAS28 is interpreted as an index of inflammatory disease activity in RA