Structural and Functional Changes of the Invariant NKT Clonal Repertoire in Early Rheumatoid Arthritis.

Invariant NKT cells (iNKT) are potent immunoregulatory T cells that recognize CD1d via a semi-invariant TCR (iNKT-TCR). Despite the knowledge of a defective iNKT pool in several autoimmune conditions, including rheumatoid arthritis (RA), a clear understanding of the intrinsic mechanisms, including qualitative and structural changes of the human iNKT repertoire at the earlier stages of autoimmune disease, is lacking. In this study, we compared the structure and function of the iNKT repertoire in early RA patients with age- and gender-matched controls. We analyzed the phenotype and function of the ex vivo iNKT repertoire as well as CD1d Ag presentation, combined with analyses of a large panel of ex vivo sorted iNKT clones. We show that circulating iNKTs were reduced in early RA, and their frequency was inversely correlated to disease activity score 28. Proliferative iNKT responses were defective in early RA, independent of CD1d function. Functional iNKT alterations were associated with a skewed iNKT-TCR repertoire with a selective reduction of high-affinity iNKT clones in early RA. Furthermore, high-affinity iNKTs in early RA exhibited an altered functional Th profile with Th1- or Th2-like phenotype, in treatment-naive and treated patients, respectively, compared with Th0-like Th profiles exhibited by high-affinity iNKTs in controls. To our knowledge, this is the first study to provide a mechanism for the intrinsic qualitative defects of the circulating iNKT clonal repertoire in early RA, demonstrating defects of iNKTs bearing high-affinity TCRs. These defects may contribute to immune dysregulation, and our findings could be exploited for future therapeutic intervention.

SYNDROME DES ANTIPHOSPHOLIPIES. À PROPOS DE 30 CAS.

OBJECTIVES: To analyze clinical and immuno- logic manifestations of Lebanese patients with the antiphos- pholipid syndrome (APS). PATIENTS AND METHODS: Our study was retrospective and was done on hospitalized patients be- tween 2001 and 2013. All these patients fulfilled the interna- tional criteria for diagnosis (Sydney criteria). RESULTS: Of the 30 patients selected, we noticed a female predominance (sex ratio: 2.75). The age at diagnosis ranged between 9 and 72 years with a mean age of 43 - 17 years. "Primary" APS was present in 70% of patients; APS was associated with systemic lupus erythematosus (SLE) in 23% of patients, with a mixed connective tissue disease in 3% and systemic vasculitis in 3%. A catastrophic APS occurred in 3 cases (10%). The most com- mon presenting manifestations were deep venous thrombosis (53%), pulmonary embolism (33%) and stroke (13%). Eleven patients (37%) had venous thrombosis, 7 (23%) had arterial thrombosis alone and 7 (23%) both arterial and venous throm- bosis. Deep venous thrombosis occurred mostly in the lower limbs (70%) whereas arterial thrombosis occurred in cerebral arteries in 50% of cases. The most common fetal complica- tions were early fetal loss (62.5%). Anticardiolipin antibodies were the most frequently identified antibodies (83%), followed by anti-p2GPI (70%) and anticoagulant lupus (11%). An effec- tive anticoagulation by anti-vitamin K was performed in 29 pa- tients. Corticosteroids were prescribed in 13 cases and were associated to immunosuppressant drugs in 6 cases of second- ary APS and the 3 catastrophic APS. The patients with cat- astrophic APS received also intravenous immunoglobulin. Response to treatment was favorable in 86% of patients with a mean follow up of 6 4 years. We deplored 4 deaths, 2 with- in the catastrophic APS. CONCLUSION: The APS does not seem to have particular features in Lebanon. The primary form seems to be the most common. It is important to diagnose this syn- drome earlier before the onset of serious complications.

Rheumatoid Arthritis: The Impact of Mental Health on Disease: A Narrative Review.

Over 60% of rheumatoid arthritis (RA) patients achieve a good response after 12 months of treatment when following the European league against rheumatism (EULAR) guidelines for treatment. However, almost half of patients still suffer from moderate to severe disease activity despite this. In addition, mental health problems may remain despite reduced measures of inflammation systemically and within joints. Depression is two times more common in RA patients than in the general population, and intriguingly a bi-directional relationship with RA has been shown in cross-sectional studies. Chronic inflammation impairs the physiological responses to stress including effective coping behaviours, resulting in depression, which leads to a worse long-term outcome in RA. In RA patients, the pain score is not always solely related to inflammatory arthritis and immunological disease activity by Bak et al. (Patient Prefer Adherence 13:223-231, [1]). Non-inflammatory pain secondary to anxiety, depression, sleep disturbance and the psychosocial situation needs to be considered whilst fibromyalgia, mechanical pain and neuropathic pain can also contribute to overall pain scores by Chancay et al. (Women's Midlife Health 5:3, [2]). Hence, the UK National Institute for Health and Care Excellence (NICE) guideline for the management of RA included psychological interventions for fatigue, low mood and social well-being (NICE NG100, 2018) [3], and the NICE clinical guidelines (CG91) [4] suggest managing mental health and depression in chronic medical conditions to improve treatment outcomes. This is a narrative review of the impact of mental health on RA disease activity in terms of patient-reported outcomes (PROs).

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory condition that affects 1% of the global population. RA can cause inflammation and damage to the joints. It can also present with extra-articular manifestations, affecting other major organs in the body. RA patients are more prone to have anxiety, depression and cognitive impairment compared to the general healthy population. Those mental health conditions contribute to less responsiveness to treatment and higher disease activity in RA mainly due to fatigue and bodily pain. Medications used in RA can improve anxiety and depression to a certain extent but not completely. Therefore, it is important to determine the most appropriate tool to monitor mental health well-being and quality of life (QoL) of RA patients in rheumatology outpatient clinics to optimise the care of the RA patients.

Rheumatoid arthritis in the elderly: Characteristics and treatment considerations.

The elderly rheumatoid arthritis (RA) population consists of both elderly-onset RA that manifests after the age of 60 and individuals diagnosed with RA early in life who age naturally to become members of this group. The elderly RA population is expanding due to both increased life expectancy and an increased incidence of elderly onset RA. Elderly onset RA seems to have a characteristic clinical pattern and perhaps biological profile different to that of early onset RA. The management of RA in elderly patients can be challenging, as robust treat-to-target approaches must be balanced against the adverse events due to increased comorbidities in old age. This produces a tendency to prefer less aggressive treatment in elderly RA patients in clinical practice. Despite the concerns about adverse events, there is limited evidence on the best way to approach RA in this population, as elderly patients are often not well presented in the clinical trials. Herein, we review the literature to assess the efficacy and safety of RA therapies in this age group. We then suggest a tailored approach that can be adopted in clinical practice, based on the disease severity and risk profiles of elderly RA patients.

Upadacitinib for the treatment of rheumatoid arthritis.

Introduction: Tofacitinib and baricitinib have recently been approved as second-line treatments for Rheumatoid arthritis (RA) though their maximum expected efficacy may be limited by dose-related toxicities. Upadacitinib selectively inhibits Janus Kinase 1 (JAK1) which could potentially reduce JAK2 and JAK3-related side effects. Areas covered: In this paper, we review a newly developed oral selective JAK inhibitor, upadacitinib for the treatment of RA. The doses of upadacitinib extended-release 15 and 30 mg daily selected in phase III RA studies have shown a near-maximum efficacy in phase II studies. Upadacitinib inhibited radiographic progression and displayed rapid and sustained clinical and functional efficacy in RA when in combination with methotrexate (MTX), upadacitinib was superior to placebo in MTX-Inadequate Responders (IRs) and biologic disease modifying antirheumatic drugs-IRs while as monotherapy, it was superior to MTX in MTX-IRs and MTX-naïve patients. Upadacitinib was superior to adalimumab using ACR70, reduction of pain-VAS and improvement of HAQ-DI. The comparison with abatacept is still ongoing. Expert commentary: Upadacitinib has displayed a rapid and favorable efficacy profile in RA but despite being a selective JAK1 inhibitor appears to have a similar safety profile to less-selective Jakinibs. Longer term safety data are awaited.