Defective STAT5 Activation and Aberrant Expression of BCL6 in Naive CD4 T Cells Enhances Follicular Th Cell-like Differentiation in Patients with Granulomatosis with Polyangiitis.

Granulomatosis with polyangiitis (GPA) is a potentially fatal small vessel vasculitis of unknown etiology, characterized by anti-neutrophil cytoplasmic autoantibodies, chronic inflammation, and granulomatous tissue damage. T cell dysregulation, comprising decreased regulatory T cell function and increased circulating effector memory follicular Th cells (TFH), is strongly associated with disease pathogenesis, but the mechanisms driving these observations are unknown. We undertook transcriptomic and functional analysis of naive CD4 T cells from patients with GPA to identify underlying functional defects that could manifest in the pathogenic profiles observed in GPA. Gene expression studies revealed a dysregulation of the IL-2 receptor ß/JAK-STAT signaling pathway and higher expression of BCL6 and BCL6-regulated genes in GPA naive CD4 T cells. IL-2-induced STAT5 activation in GPA naive CD4 T cells was decreased, whereas STAT3 activation by IL-6 and IL-2 was unperturbed. Consistently, BCL6 expression was sustained following T cell activation of GPA naive CD4 T cells and in vitro TFH differentiation of these cells resulted in significant increases in the production TFH-related cytokines IL-21 and IL-6. Thus, naive CD4 T cells are dysregulated in patients with GPA, resulting from an imbalance in signaling equilibrium and transcriptional changes that drives the skewed pathogenic CD4 effector immune response in GPA.

Physician-patient interaction and medication adherence in lupus nephritis.

OBJECTIVE: The quality of physician-patient interaction can have a significant impact on medication adherence. Little is known about this relationship in patients with lupus nephritis. METHODS: A cross-sectional, quantitative study. Data collected included demographics, current medication, systemic lupus erythematosus disease activity index, medication adherence, beliefs about medicines, shared decision-making, patient-doctor depth of relationship, patient-doctor quality of relationship, interpersonal trust in a physician and illness perceptions. RESULTS: Ninety-eight patients with lupus nephritis completed the questionnaires. Logistic regression indicated that medication adherence was significantly predicted by (a) interpersonal trust in a physician (B = 0.85, Wald 3.94, 95% confidence interval (CI) 1.01, 5.44; P = 0.05); (b) timeline cyclical (B = -0.89, Wald 4.95, 95% CI 0.19, 0.90; P < 0.05) and beliefs about the necessity of medicines (B = 0.75, Wald 4.14, 95% CI 1.03, 4.38; P < 0.05). Mediation analysis showed that beliefs about the necessity of medicines significantly mediated the relationship between trust and medication adherence when adjusted for age (B = 0.48, 95% CI 0.06, 1.08; P < 0.01). A further mediation analysis showed that patient-doctor depth of relationship (B = 0.05, 95% CI 0.01, 0.09; P < 0.001), shared decision-making (B = 0.07, 95% CI 0.01, 0.13; P < 0.001) and patient-doctor quality of relationship (B = 0.08, 95% CI 0.01, 0.16; P < 0.001) significantly mediated the relationship between illness coherence and interpersonal trust in a physician. CONCLUSION: The findings highlighted two key elements: (a) the importance of trust in relation to medication adherence; and (b) a good understanding of patients' illness is linked to a better relationship with their doctor and greater participation in shared decision-making which is associated with increased trust. Tailored psycho-educational interventions could contribute to improving the patient-doctor relationship quality, trust and increased shared decision-making, which, in turn, might improve medication adherence in patients with lupus nephritis.

Fatigue in adults with primary antiphospholipid syndrome: findings from a mixed-methods study.

OBJECTIVE: This study aimed to explore the experience and impact of fatigue in adults with primary antiphospholipid syndrome (pAPS). METHODS: This sequential, explanatory mixed-methods study enrolled adults with a six-month or more history of pAPS. Consenting participants completed the Functional Assessment of Chronic Illness Therapy-Fatigue subscale (FS), Multi-Dimensional Perceived Social Support Scale, Patient Health Questionnaire (PHQ9), Pittsburgh Sleep Quality Index (PSQI), International Physical Activity Questionnaire (IPAQMETS). Relationships between FS and other variables were explored with multiple linear regression. Interviews were conducted with a subgroup of participants, and the data were analysed thematically. RESULTS: A total of 103 participants were recruited (Mage = 50.3 years; standard deviation = 10.1 years; 18 males). Of these, 62% reported severe fatigue. Greater fatigue was associated with lower mood, physical inactivity, poorer sleep quality and lower perceived social support. The best-fit model explained 56% of the variance in FS (adjusted R2 = 0.560, F(3, 74) = 33.65, p > 0.001) and included PHQ9 and IPAQMETS as significant predictors, and PSQI as a non-significant predictor. Twenty participants completed interviews. Three key themes were identified: characteristics of fatigue, impact on life and coping strategies. CONCLUSION: Fatigue was a common symptom of pAPS and challenging to manage. Other factors, particularly mood and physical activity, influenced fatigue. Evidence-based self-management interventions are needed.

Pregnancy outcome in patients with systemic vasculitis: a single-centre matched case-control study.

OBJECTIVE: To study the outcome of pregnancy in patients with systemic vasculitis (SV) compared with age-, BMI- and ethnicity-matched healthy pregnant controls. METHODS: Fifty-one pregnancies in 29 SV patients were retrospectively studied. There were nine patients with granulomatosis with polyangiitis (GPA), three with eosinophilic GPA, seven with Takayasu's arteritis, two with ANCA-positive vasculitis with renal involvement, two with Behçet's disease, three with urticarial vasculitis, one with primary cerebral vasculitis, one with relapsing polychondritis and one with IgA vasculitis. BVAS and the vasculitis damage index were evaluated retrospectively. Sixty-two healthy women with 156 pregnancies matched in a 2:1 ratio for age, BMI and ethnicity formed the control group. RESULTS: Median gestational age at delivery was lower in the SV group: 36 weeks and 2 days (34-42) vs controls 40 (37-42) weeks (P < 0.03). Median birth weight in the SV group was 3.0 kg (2.0-5.2), whereas that of the controls was 3.5 (2.28-4.32) kg (P = 0.004). The median customized birth weight centile was 38.6 in the SV group and 37.2 in the control group. In the SV group, 9 patients had 13 miscarriages, 3 had pre-eclampsia, and 2 had an intrauterine death. In the control group, 20 patients had 27 miscarriages, 1 had pre-eclamptic toxaemia, and 1 had an antepartum haemorrhage. Eight patients with SV flared during pregnancy and 11 flared after delivery. CONCLUSION: Patients with SV had a lower median gestational age, but customized birth weights were similar to those of healthy women. Women with SV may flare during pregnancy and the post-partum period and may experience significant pregnancy morbidity.

The HAVEN study-hydroxychloroquine in ANCA vasculitis evaluation-a multicentre, randomised, double-blind, placebo-controlled trial: study protocol and statistical analysis plan.

BACKGROUND: Patients with non-severe ANCA-associated vasculitis (AAV) are often prescribed immunosuppressive medications that are associated with severe side effects and a reduced quality of life. There is an unmet need for safer effective treatments for these patients. Hydroxychloroquine is being explored due to its effect in similar autoimmune conditions such as systemic lupus erythematosus. METHODS: Double-blind, placebo-controlled multicentre trial recruiting 76 patients across 20 sites. Participants will be randomised 1:1 to hydroxychloroquine or placebo in addition to standard of care immunosuppressive therapies over the course of 52 weeks. A phase II selection design will be used to determine hdroxychloroquine's efficacy, using prednisolone dosage and Birmingham Vasculitis Activity Score as a measure of disease activity. Secondary outcomes will explore other elements of AAV progression, including disease flares and time to remission. DISCUSSION: This trial aims to explore Hydroxychloroquine as a treatment for patients with AAV. If effective, the need for immunosuppressive treatments such as prednisolone could be reduced. Hydroxychloroquine is safer, cheaper and has fewer adverse effects than conventional immunosuppressive treatments. This could improve patient outcomes while saving money for the NHS. TRIAL REGISTRATION: ISRCTN: ISRCTN79334891. Registered 07 June 2021. EudraCT: 2018-001268-40. Registered 13 September 2019. CLINICALTRIALS: gov: NCT04316494. Registered 20 March 2020.