Eleana Ntatsaki

Epidemiology of ANCA-associated Vasculitis

The epidemiology of the antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV), comprising Wegeners granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome, poses considerable challenges to epidemiologists. These challenges include the difficulty of defining a case with a lack of clear distinction between the different disorders, case capture, and case ascertainment. The AAV are rare and therefore a large population is required to determine the incidence and prevalence, and this poses questions of feasibility. Despite these difficulties a considerable body of data on the epidemiology of the AAV has been built in the past 20 years with an interesting age, geographic, and ethnic tropism gradually being revealed. Most of the data come from White populations of European descent, and the overall annual incidence is estimated at approximately 10-20/million with a peak age of onset in those aged 65 to 74 years.

Systemic rheumatoid vasculitis in the era of modern immunosuppressive therapy

OBJECTIVES Systemic rheumatoid vasculitis (SRV) is a rare but potentially serious systemic disease manifestation of rheumatoid arthritis (RA) characterized by the development of necrotizing vasculitis. The incidence of SRV appears to be decreasing possibly reflecting progress in RA treatment. The aims of this study were to review the clinical manifestations of SRV in a stable well-defined population during 2001-10 and to compare with our previous cohort (1988-2000) and also a cohort from 1975 to 1981. METHODS Using Norfolk Vasculitis Register, a prospective register of patients with systemic vasculitis since 1988, all patients with a diagnosis of SRV from 1 January 2001 until 31 December 2010 were identified. SRV was defined according to the Scott and Bacon criteria (1984). Clinical features were obtained by retrospective case note review. RESULTS Eighteen patients with SRV were identified (10 male), median age at diagnosis was 72 years and average disease duration 15.6 years. The average annual incidence for 2001-10 was 3.9 per million. One-year mortality was 12% and 5-year mortality 60%. The clinical manifestations were similar apart from systemic and cutaneous features which were more common in the earlier cohorts. CONCLUSION The incidence of SRV has declined significantly in the last 40 years; but the clinical manifestations remain similar. Systemic symptoms, and cutaneous manifestations such as infarcts and nodules, are slightly less common in the recent cohort. Despite modern immunosuppressive therapy the prognosis remains poor.

Management of Polymyalgia Rheumatica

New guidelines are a step forward, but many unanswered questions remain

Risk factors for renal disease in systemic lupus erythematosus and their clinical implications

Lupus nephritis is one of the most common severe manifestations of systemic lupus erythematosus and is associated with significant morbidity and mortality. Genetic, ethnic and hormonal factors may influence the presence and severity of renal involvement and therefore affect the outcome and overall prognosis of patients. In this review, we will discuss the association of known lupus risk factors in developing renal disease and explore the recent literature to identify potential risk factors and their clinical implications in terms of diagnostic vigilance, management and prognosis.

The safety of pharmacological treatment options for lupus nephritis

ABSTRACT Introduction: The management of lupus nephritis (LN) has changed significantly over the last 10 years due to emerging evidence from large randomised clinical trials that produced good quality data and guided the formulation of two key concepts: the induction of remission and the maintenance phase of immunosuppressive therapy. Areas covered: Optimizing cyclophosphamide and glucocorticoid regimens and the introduction of mycophenolate mofetil for proliferative and membranous LN has been pivotal. Nevertheless, concerns remain about treatment toxicity especially long term glucocorticoid use and exposure to cumulative cyclophosphamide doses. Here we discuss the conventional and newer pharmacological options for managing LN focusing on drug safety and toxicity issues. Expert opinion: The need for effective and less toxic treatments led to the development of the role of targeted biologic therapies in LN. However, evidence from the initial randomized controlled trials has been disappointing, although this reflects inadequate trial design rather than true lack of efficacy.

Osteoprotegerin and Myocardial Fibrosis in Patients with Aortic Stenosis

Left ventricular myocardial fibrosis in patients with aortic stenosis (AS) confers worse prognosis. Plasma osteoprotegerin (OPG), a cytokine from the TNF receptor family, correlates with the degree of valve calcification in AS, reflecting the activity of the tissue RANKL/RANK/OPG (receptor activator of nuclear factor κΒ ligand/RANK/osteoprotegerin) axis, and is associated with poorer outcomes in AS. Its association with myocardial fibrosis is unknown. We hypothesised that OPG levels would reflect the extent of myocardial fibrosis in AS. We included 110 consecutive patients with AS who had undergone late-gadolinium contrast enhanced cardiovascular magnetic resonance (LGE-CMR). Patients were characterised according to pattern of fibrosis (no fibrosis, midwall fibrosis, or chronic myocardial infarction fibrosis). Serum OPG was measured with ELISA and compared between groups defined by valve stenosis severity. Some 36 patients had no fibrosis, 38 had midwall fibrosis, and 36 had chronic infarction. Patients with midwall fibrosis did not have higher levels of OPG compared to those without fibrosis (6.78 vs. 5.25 pmol/L, p = 0.12). There was no difference between those with midwall or chronic myocardial infarction fibrosis (6.78 vs. 6.97 pmol/L, p = 0.27). However, OPG levels in patients with chronic myocardial infarction fibrosis were significantly higher than those without fibrosis (p = 0.005).

Refractory rheumatoid vasculitis—a therapeutic dilemma

The case presented by Kumar et al. [1] reminds us of one of the most severe but now rare extra-articular manifestations of rheumatoid arthritis (RA); rheumatoid vasculitis (RV). RV is now a rare condition, with an annual incidence of 3.4/million, and it is now much less common than the anti-neutrophil cytoplasmic antibody (ANCA) vasculitides (AAV) [2]. The incidence has decreased substantially since early methotrexate treatment for RA become common during the 1990s. This reduction has paralleled the general decline in frequency of extra-articular RA, hospital admission rates and need for cervical spine surgery [3–6]. The risk factors for development of RV have long been recognized as male gender, smoking, long standing RA and strong positivity for rheumatoid factor. Recently Makol and colleagues observed in a case control study that the use of hydroxychloroquine and low-dose aspirin reduced the risk of RV [7]. This observation lends support to the idea that because hydroxychloroquine improves lipid profiles that it should be more widely used as a component of combination therapy regimens for RA [8]. The mortality remains high with up to 20% 1-year mortality, again worse than for the AAV [2]. The case highlights the empirical nature of treatment for RV. The traditional approach, which was tried by Kumar et al., is intravenous cyclophosphamide following the approach pioneered by Scott and Bacon in the 1980s [9]. Unfortunately, cyclophosphamide failed to halt disease progression and the patient was given intravenous immunoglobulin followed by rituximab. There has been increasing interest in the use of rituximab to treat RV. This approach has been derived from the experience of the use of rituximab in the AAV. Two seminal trials published in 2010 (RAVE and RITUXVAS) showed that rituximab was not inferior to intravenous cyclophosphamide for remission induction especially in relapsing patients [10, 11]. Given that rituximab is effective in uncomplicated RA, it seems logical to extend its use to this situation. In the French Autoimmunity and Rituximab (AIR) registry, there were 17 cases of RV treated with rituximab [12]. Thirteen patients were treated with the conventional RA dose of 1 gm given twice at a 2-week interval, and the remaining four patients received either 0.5 gm or 0.75 g at 2 weeks apart or four infusions of 0.75 g and 1 gm on four occasions at 1-week intervals. Sixteen patients received concomitant glucocorticoids. Remission was achieved in 6 months in 12 patients and 4 had a partial response and 1 had died. At 1 year, 14/17 patients (82%) were in complete remission as defined by a Birmingham Vasculitis Activity Score of 0 combined with an absence of clinical symptoms and signs of disease. Mean prednisolone dosage was reduced from 19.2 to 9.7mg/day, and at 12 months 14 patients (82%) were in sustained remission. Three patients had severe infections. Whether maintenance therapy required is unknown, the current vogue in AAV is to treat at regular intervals (4–6 months) with of a dose 500–1000mg for up to 2 years [13, 14]. Again this is a logical approach in RV. The present rarity of RV makes it unlikely that the use of rituximab to treat RV will ever be subjected to a randomized controlled trial. Modern treatment of RA with treat to target approaches has led to a reduction in this once feared complication of RA, and twenty-first century rheumatologists are now longer confronted with its consequences. But as this case report reminds us RV has not yet completely disappeared and it still carries significant mortality.