Meningococcal arthritis and myopericarditis: a case report.

BACKGROUND: We report the first adult case of Neisseria meningitidis W-135 presenting with meningococcal arthritis and myopericarditis concomitantly, without other classical features of meningococcal disease. CASE PRESENTATION: A 67-year-old Caucasian man presented with acute-onset polyarthralgia, myalgia, and fever. On examination he had polyarticular synovitis. An electrocardiogram (ECG) demonstrated ST-elevation in leads I, II, III, aVF, and V2-V6 without reciprocal depression, and a high-sensitivity troponin level was significantly elevated. Cardiac magnetic resonance (CMR) imaging on day five of admission demonstrated patchy pericardial enhancement. Neisseria meningitidis W-135 was isolated from both synovial fluid and blood cultures. The clinical outcome was favourable with intravenous ceftriaxone and myopericarditis treatment (colchicine and ibuprofen). CONCLUSIONS: We conclude that this is a rare case of disseminated Neisseria meningitidis W-135 presenting with acute polyarticular septic arthritis and myopericarditis, without other classical features of systemic meningococcal disease. The earlier described entity of primary meningococcal arthritis (PMA) can present in patients with meningococcal bacteraemia, and may not be distinct from disseminated meningococcal disease, but rather an atypical presentation of this.

Hormone replacement therapy (conjugated oestrogens plus bazedoxifene) for post-menopausal women with symptomatic hand osteoarthritis: primary report from the HOPE-e randomised, placebo-controlled, feasibility study.

Background: Symptomatic hand osteoarthritis is more common in women than in men, and its incidence increases around the age of menopause, implicating oestrogen deficiency. No randomised controlled trials of hormone replacement therapy (HRT) have been done in people with hand osteoarthritis. We aimed to determine the feasibility and acceptability of a form of HRT (conjugated oestrogens plus bazedoxifene) in post-menopausal women with painful hand osteoarthritis. Methods: The HOPE-e feasibility study was a randomised, double-blind, placebo-controlled trial, for which we recruited women aged 40-65 years, for whom 1-10 years had passed after their final menstrual period, with definite hand osteoarthritis and at least two painful hand joints. Participants were recruited across three primary or secondary care sites and from the community and were randomly assigned (1:1) to receive conjugated oestrogens plus bazedoxifene or placebo, orally once every day for 24 weeks, before weaning for 4 weeks until the end of the study. The primary feasibility outcomes were rates of identification, recruitment, randomisation, retention, and compliance of eligible participants, and the likelihood of unmasking. The secondary objective was to generate proof-of-concept quantitative and qualitative data on the acceptability of proposed clinical outcomes for a full trial and adverse events. We used an intention-to-treat analysis, and criteria for progression to a full trial were pre-defined as recruitment of at least 30 participants across all sites in 18 months; a dropout rate of less than or equal to 30% of randomised individuals; and acceptability to the majority of participants, including acceptable rates of adverse events. Due to the COVID-19 pandemic, the recruitment window was reduced to 12-15 months. A proportionately reduced minimum sample size of 22 was judged to be sufficient to test feasibility. This trial was registered at ISRCTN, ISRCTN12196200. Findings: From May 9, 2019 to Dec 31, 2020, 434 enquiries or referrals were received. We did 96 telephone pre-screens; of the 35 eligible participants, seven were excluded as ineligible at the telephone or face-to-face screening and 28 (80% [95% CI 63-92]) were randomly assigned. Of the 406 who were not randomly assigned, 250 (62%) were ineligible (with contraindicated medications accounting for 50 [20%] of these), 101 (25%) did not respond to further enquiries, and 55 (14%) chose not to proceed (with the most common reason being not wanting to take a hormone-based drug). All 28 randomised participants completed all follow-up assessments with high compliance and outcome measure completeness. All three adverse event-related treatment withdrawals were in the placebo group. No serious adverse events were reported. Participants and investigators were successfully masked (participant Bang's blinding index placebo group 0·50 [95% CI 0·25-0·75]). The trial met the prespecified criteria for progression to a full trial. Interpretation: This first-ever feasibility study of a randomised controlled trial of HRT for post-menopausal women with painful hand osteoarthritis met its progression criteria, although it was not powered to detect a clinical effect. This outcome indicates that a full trial of an HRT in this population is feasible and acceptable and identifies potential refinements with regard to the design of such a trial. Funding: Research for Patient Benefit programme, National Institute for Health Research.

Hand Osteoarthritis: investigating Pain Effects of estrogen-containing therapy (HOPE-e): a protocol for a feasibility randomised placebo-controlled trial.

BACKGROUND: Hand osteoarthritis (OA) is a common condition, causing pain, stiffness and reduced quality of life. Incidence is higher amongst women, particularly around the age of the menopause. Whilst the relationship between sex hormones and OA has been studied in vitro, in epidemiological studies and in clinical trials of hormone replacement therapy (HRT), this study is the first to investigate the effect of estrogen-containing therapy on hand pain in post-menopausal women with symptomatic hand OA in a randomised study design. METHODS: This is a feasibility study of a double-blinded placebo-controlled intervention with 1:1 randomisation to either a combination of conjugated estrogens 0.45 mg and bazedoxifene acetate 20 mg (Duavive) or placebo. The target population is post-menopausal women with symptomatic hand OA, aiming to recruit 60-90 study participants. The primary objective is to assess the feasibility of a future fully powered randomised controlled trial (RCT). Participants will take the study medication for 24 weeks and be followed up for 28 weeks after randomisation. The primary outcomes used to determine feasibility are eligible participant identification rates and routes; recruitment, randomisation and retention rates of eligible participants; study medication compliance; and the likelihood of unintentional unblinding. Secondary outcomes include measures of hand pain, function, appearance and menopausal symptoms. An end of study questionnaire and focus groups will help to refine the final protocol for a full study. DISCUSSION: Identifying new treatments for symptomatic hand OA is a recognised research priority. The study will help us to understand whether there are sufficient interested and eligible individuals in this target population who would consider HRT for their hand symptoms. It will provide proof-of-concept RCT data on the effects of HRT on hand pain and other clinically relevant outcomes in this population. The study will gain valuable information on the feasibility of a full RCT and how best to run this. The findings will be published in a peer-reviewed journal and presented at a relevant conference. TRIAL REGISTRATION: ISRCTN12196200 registered on 15 January 2019.

Vascular abnormalities, paraoxonase activity, and dysfunctional HDL in primary antiphospholipid syndrome.

CONTEXT: Accelerated atherosclerosis has been described in antiphospholipid syndrome, but the vascular abnormalities and the underlying mechanisms remain unclear. OBJECTIVES: To compare vascular structure and function in patients with positive antiphospholipid antibodies (aPL) with controls and to assess their relationship with paraoxonase activity. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study of 77 women with positive antiphospholipid antibodies from a lupus outpatient clinic in London, England (90% of the eligible population) and 77 controls matched on frequency basis for age and cardiovascular risk factors between June 2006 and April 2009. Carotid intima media thickness (CIMT), flow-mediated dilatation, pulse wave velocity, and paraoxonase activity were measured in all patients. Anti-inflammatory and antioxidant properties of high-density lipoprotein (HDL) were examined. MAIN OUTCOME MEASURES: CIMT, pulse wave velocity, flow-mediated dilatation, and paraoxonase. RESULTS: Women with aPL had greater CIMT and pulse wave velocity compared with controls (mean [SD], 0.75 [0.16] vs 0.64 [0.09] mm; 95% confidence interval [CI], -0.14 to -0.06; P < .001; and 9.2 [1.6] vs 8.5 [1.8] m/s; 95% CI, -1.14 to -0.06; P = .04) and lower flow-mediated dilatation (6.2% [4.1%] vs 9.6% [4.2%]; 95% CI, 2.02%-4.69%; P < .001). Paraoxonase activity was lower in women with aPL vs controls (median [interquartile range], 91.2 [64.3-105.1] vs 103.0 [80.5-111.5] micromol p-nitrophenol/L/serum/min; 95% CI, 0.004-0.007; P = .005) and was inversely associated with CIMT and pulse wave velocity in women with aPL (standardized beta coefficient = -0.4 and -0.3, respectively; P < .05 for both), but not in the control group. High-density lipoprotein from women with aPL inhibited endothelial nitric oxide production in human aortic endothelial cells, in contrast with controls. The beneficial effects of HDL from women with aPL on vascular cell adhesion molecule 1 expression, superoxide production, and monocyte adhesion following activation of human aortic endothelial cells were largely blunted. CONCLUSIONS: Compared with controls, women with aPL had greater functional and structural arterial abnormalities, which were associated with lower activity of paraoxonase. In patients with aPL, HDL reduced nitric oxide bioavailability and had impaired anti-inflammatory and antioxidant properties.

Primary antiphospholipid syndrome: a distinct entity?

Although antiphospholipid syndrome (APS) was first fully described in the context of connective tissue diseases such as systemic lupus erythematosus (SLE), it was soon recognised that the condition can exist on its own. APS appears to represent a clinical spectrum, both in terms of APS features and the presence of other autoimmune conditions. The clinical and serological characteristics of "primary" APS (PAPS) are similar to those of secondary APS, although the clinical features are more commonly recognised in the presence of another autoimmune or inflammatory condition. Furthermore, patients with PAPS may subsequently develop SLE. It is important to identify PAPS, since it is likely to be a contributing factor for a significant proportion of patients with a variety of vascular, neurological and other conditions. It may emerge as more common than secondary APS.

Tocilizumab in refractory rheumatoid arthritis: long-term efficacy, safety, and tolerability beyond 2 years.

OBJECTIVES: To evaluate the long-term efficacy and safety of tocilizumab (TCZ) in clinical patients with rheumatoid arthritis (RA) refractory to synthetic disease-modifying antirheumatic drugs, anti-tumor necrosis factor agents, and B-cell depletion therapy with rituximab (RTX). METHODS: We conducted a single-center retrospective study of 22 patients with RA treated with TCZ. We collected data including demographics and medication histories. We recorded clinical parameters including tender joint counts and swollen joint counts, and laboratory parameters including inflammatory makers and lipid profiles over regular intervals of TCZ treatment. RESULTS: In all, 22 patients with RA were included, 20 of whom were female. The median age at the first dose of TCZ was 62 years (range: 35-75 years). The mean duration of the disease from diagnosis with RA to May 2015 was 15.7 years (range: 6-30 years). A total of 15 out of 22 patients remained on TCZ at the end of the study, and in all, there was an improvement in markers of disease activity following initiating TCZ. The effect was sustained for a mean of 35 months (SD±15.5 months, range: 9-72 months). Of the 17 patients who failed to respond to RTX previously, 12 patients remained on TCZ. In all, eight out of 22 patients developed adverse events, five of whom discontinued TCZ. In contrast to previously documented short-term data, TCZ did not result in a statistically significant (P<0.05) long-term deterioration in lipid profile for any of the lipid parameters measured in our cohort (mean ± SD at initiation of TCZ to most recent follow-up: total cholesterol 5.25±1.05 to 5.28±0.77 mmol/L, high-density lipoprotein 1.72±0.54 to 1.67±0.43 mmol/L, low-density lipoprotein 3.05±0.98 to 2.98±0.81 mmol/L, and cholesterol to high-density lipoprotein ratio 3.41±1.23 to 3.40±1.22). CONCLUSION: The efficacy of TCZ in patients with RA refractory to disease-modifying drugs, including anti-tumor necrosis factor blockade and RTX, is sustained over 3 years. TCZ confers a good safety profile in the long term even in patients who previously developed adverse events to other rheumatic drugs. In the long run, there is no statistically significant deterioration in lipid profile during treatment with TCZ.

Systemic inflammatory response syndrome in a patient diagnosed with high grade inflammatory triple negative breast cancer: a case report of a potentially rare paraneoplastic syndrome.

BACKGROUND: Inflammatory breast cancer is a complex pathological entity associated with poor outcomes. This loco-regional disease is characterised by a rapid clinical course in the presence breast erythema and infiltration of dermal lymphatics by tumours cells. Herein we describe a case of inflammatory breast cancer with a rare presentation and disease course defined by a profound systemic inflammatory response in the absence of an infective cause. CASE PRESENTATION: The patient presented with pyrexia and malaise following a recent tissue diagnosis of inflammatory breast cancer. At the time of admission the patient demonstrated clinical features of the systemic inflammatory response syndrome (SIRS) in the presence of a negative septic screen. Her condition deteriorated despite systemic broad spectrum intravenous antibiotics and she underwent surgical debulking of a 180 × 135 × 100 mm (821 g) primary tumour composed of oedematous, friable and haemorrhagic tissue (pT4,N1a,M0; oestrogen/progesterone/HER-2 receptor negative). Following surgery, the clinical picture dramatically improved with cessation of SIRS and normalisation of inflammatory markers. After 4 weeks the patient required readmission to hospital due to recurrent SIRS and negative septic screen. The patient received treatment with systemic chemotherapy showing transient clinical improvement and suppression of SIRS. Despite on going chemotherapy, systemic antibiotics and a trial of steroid therapy the patient died 5 months after her initial presentation to hospital. At the time of death she demonstrated persistent SIRS with elevated inflammatory markers. CONCLUSION: This is the first case report of inflammatory breath cancer associated with SIRS in the absence of clinically confirmed infection. Important learning points highlighted by this case are: (a) recognition of the diagnostic and therapeutic uncertainties that still exist in the context of inflammatory breast cancer; (b) appreciation of the potential paraneoplastic systemic inflammatory manifestations of this disease, and finally; (c) the importance a multidisciplinary and multimodal approach to treatment.

Randomised double-blind trial of combination antibiotic therapy in rheumatoid arthritis.

Objective. A combination of intravenous clindamycin and oral tetracycline has been used for many years as a treatment for active rheumatoid arthritis (RA), despite the absence of good evidence for its efficacy. A single-blind pilot study of this therapy suggested that a double-blind placebo-controlled trial was warranted. Methods. Patients with active RA were randomised in a 2 : 1 ratio to receive active treatment or placebo for 25 weeks. The active treatment consisted of intravenous clindamycin in a reducing regime, and oral tetracycline twice daily three times a week. 50 patients were to be recruited. The primary outcome measure was the proportion of patients achieving an ACR20 response. Results. An interim statistical analysis was performed after 20 patients had completed the study. Two patients in the active group achieved an ACR20 response, with none in the placebo group (NS). There was a better ESR20 response in the placebo group (P = .02). There were no other significant differences between the groups. The results indicated that it was unlikely that a significant difference in ACR20 response would emerge if the remaining 30 patients were recruited. The trial was therefore halted. Conclusion. This antibiotic regime is unlikely to be a valuable therapy for active rheumatoid arthritis.

Familial clustering of non-nuclear autoantibodies and C3 and C4 complement components in systemic lupus erythematosus.

OBJECTIVE: To determine whether key features of systemic lupus erythematosus (SLE), namely, production of non-nuclear antibodies (anti-C1q and anticardiolipin antibodies [aCL]) and depletion of complement components C3 and C4, aggregate in families. In addition, we examined relationships between anti-C1q and C3 and C4 levels. METHODS: The study cohort comprised 1,037 predominantly white (82%) nuclear families in which at least 1 member had SLE. Associations of antibody measurements between probands and their unaffected siblings were examined using parametric and nonparametric analyses, along with associations between unaffected siblings and their parents. The heritability of anti-C1q, C3, and C4 was estimated, and interdependencies between these factors were examined in a regression model accounting for the family structure of the data set. RESULTS: We demonstrated associations between siblings for anti-C1q (odds ratio [OR] 3.74, 95% confidence interval [95% CI] 2.65, 5.28) and IgG and IgM aCL (OR 4.08, 95% CI 1.83, 5.13 and OR 2.06, 95% CI 1.46, 2.91, respectively) and, for anti-C1q, association between unaffected parents and their unaffected offspring (OR 4.34, 95% CI 2.16, 8.72). We also demonstrated significant heritability of anti-C1q, C3, and C4 (approximately 45%). Anti-C1q was negatively associated with C3 and C4 in SLE probands but not in their healthy relatives. CONCLUSION: Non-nuclear antibodies and C3 and C4 cluster within the families of SLE probands, suggesting that specific autoantibody formation is partly genetically determined, even if the total genetic effect in unaffected relatives is insufficient to cause disease. Anti-C1q antibodies accelerate C3 and C4 depletion in patients with SLE but have no effect in the absence of disease.

Single-blind randomized trial of combination antibiotic therapy in rheumatoid arthritis.

OBJECTIVE: To determine the potential clinical efficacy of combination antibiotic therapy in treating rheumatoid arthritis (RA). METHODS: Twenty-one patients with active RA despite second-line treatment were randomized to receive either combination antibiotic therapy (treatment group, n = 11) or no additional therapy (control group, n = 10). Antibiotic therapy was given for 12 months and comprised oral tetracycline 250 mg twice daily, 3 times per week, and intravenous clindamycin infused on 5 consecutive days (300, 300, 600, 600, and 900 mg) followed by weekly infusions of 900 mg for 3 weeks and then fortnightly infusions for the remainder of the 12 months. The primary outcome measure was the American College of Rheumatology 20% (ACR20) response at the end of the initial treatment period of 12 months. RESULTS: Five patients in the treatment group (45%) achieved an ACR20 response at 1 year compared to none in the control group (p = 0.04). Eight patients in the treatment group and 1 in the control group had a greater than 20% improvement in tender joint count (p = 0.008). There were also significant differences between the groups in physician and patient global assessments. Nine patients in the treatment group completed the 6 months' followup; of these, 3 sustained the ACR20 response. CONCLUSION: Combined antibiotic therapy with intravenous clindamycin and oral tetracycline may be useful in the management of active RA. A double-blind, placebo-controlled trial of therapy is justified.