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Background The acute and long-term effects of severe acute respiratory syndrome coronavirus 2 infection in individuals with GN are still unclear. To address this relevant issue, we created the International Registry of COVID-19 infection in GN.Methods We collected serial information on kidney-related and -unrelated outcomes from 125 GN patients (63 hospitalized and 62 outpatients) and 83 non-GN hospitalized patients with coronavirus disease 2019 (COVID-19) and a median follow-up period of 6.4 (interquartile range 2.3–9.6) months after diagnosis. We used logistic regression for the analyses of clinical outcomes and linear mixed models for the longitudinal analyses of eGFR. All multiple regression models were adjusted for age, sex, ethnicity, and renin-angiotensin-aldosterone system inhibitor use.Results After adjustment for pre-COVID-19 eGFR and other confounders, mortality and AKI did not differ between GN patients and controls (adjusted odds ratio for AKI=1.28; 95% confidence interval [CI], 0.46 to 3.60; P=0.64). The main predictor of AKI was pre-COVID-19 eGFR (adjusted odds ratio per 1 SD unit decrease in eGFR=3.04; 95% CI, 1.76 to 5.28; PConclusions Pre-COVID-19 eGFR is the main risk factor for AKI regardless of GN diagnosis. However, GN patients are at higher risk of impaired eGFR recovery after COVID-19-associated AKI. These patients (especially those with high baseline proteinuria or a diagnosis of focal segmental glomerulosclerosis or minimal change disease) should be closely monitored not only during the acute phases of COVID-19 but also after its resolution.

The effects of SARS-CoV-2 infection on individuals with immune-mediated glomerulonephritis, who are often undergoing immunosuppressive treatments, are unknown. Therefore, we created the International Registry of COVID infection in glomerulonephritis (IRoc-GN) and identified 40 patients with glomerulonephritis and COVID-19 followed in centers in North America and Europe. Detailed information on glomerulonephritis diagnosis, kidney parameters, and baseline immunosuppression prior to infection were recorded, as well as clinical presentation, laboratory values, treatment, complications, and outcomes of COVID-19. This cohort was compared to 80 COVID-positive control cases from the general population without glomerulonephritis matched for the time of infection. The majority (70%) of the patients with glomerulonephritis and all the controls were hospitalized. Patients with glomerulonephritis had significantly higher mortality (15% vs. 5%, respectively) and acute kidney injury (39% vs. 14%) than controls, while the need for kidney replacement therapy was not statistically different between the two groups. Receiving immunosuppression or renin-angiotensin-aldosterone system inhibitors at presentation did not increase the risk of death or acute kidney injury in the glomerulonephritis cohort. In the cohort with glomerulonephritis, lower serum albumin at presentation and shorter duration of glomerular disease were associated with greater risk of acute kidney injury and need for kidney replacement therapy. No differences in outcomes occurred between patients with primary glomerulonephritis versus glomerulonephritis associated with a systemic autoimmune disease (lupus or vasculitis). Thus, due to the higher mortality and risk of acute kidney injury than in the general population without glomerulonephritis, patients with glomerulonephritis and COVID-19 should be carefully monitored, especially when they present with low serum albumin levels., Graphical abstract

Background Immune complexes within glomerular capillary walls cause crescentic GN (CrGN). Monocytes and macrophages are important in mediating CrGN, but little work has been done to phenotype the subpopulations involved and determine their respective contributions to glomerular inflammation. Methods Live glomerular imaging using confocal microscopy monitored intravascular monocyte subset behavior during nephrotoxic nephritis (NTN) in a novel WKY-hCD68-GFP monocyte/macrophage reporter rat strain. Flow cytometry and qPCR further analyzed ex vivo the glomerular leukocyte infiltrate during NTN. Results Non-classical monocytes surveyed the glomerular endothelium via lymphocyte function-associated antigen 1 (LFA-1) in the steady state. During NTN, non-classical monocytes were recruited first, but subsequent recruitment and retention of classical monocytes was associated with glomerular damage. Monocytes recruited to the glomerular vasculature did not undergo transendothelial migration. This finding suggests that inflammation in immune complex-mediated CrGN is predominantly intravascular, driven by dynamic interactions between intravascular blood monocytes and the endothelium. Glomerular endothelium and non-classical monocytes overexpressed a distinct chemokine axis, which may orchestrate inflammatory myeloid cell recruitment and expression of damage mediators. Reduced classical monocyte recruitment in Lewis rats during NTN confirmed a role for CD16 in mediating glomerular damage. Conclusions Monocyte subsets with distinct phenotypes and effector functions may be important in driving inflammation in experimental CrGN resulting from immune complexes formed within the glomerular capillary wall. LFA-1-dependent endothelial surveillance by non-classical monocytes may detect immune complexes through CD16, orchestrating the inflammatory response through intravascular retention of classical monocytes, which results in glomerular damage and proteinuria.

P2RX7, an ionotropic receptor for extracellular ATP, is expressed on immune cells, including macrophages, monocytes and dendritic cells and is up-regulated on non-immune cells following injury. P2RX7 plays a role in many biological processes, including production of pro-inflammatory cytokines such as IL-1β via the canonical inflammasome pathway. P2RX7 has been shown to be important in inflammation and fibrosis and may also play a role in autoimmunity. We have developed and phenotyped a novel P2RX7 knock-out (KO) inbred rat strain and taking advantage of the human-resembling unique histopathological features of rat models of glomerulonephritis, we induced three models of disease: nephrotoxic nephritis, experimental autoimmune glomerulonephritis, and experimental autoimmune vasculitis. We found that deletion of P2RX7 does not protect rats from models of experimental glomerulonephritis or the development of autoimmunity. Notably, treatment with A-438079, a P2RX7 antagonist, was equally protective in WKY WT and P2RX7 KO rats, revealing its 'off-target' properties. We identify a novel ATP/P2RX7/K+ efflux-independent and caspase-1/8-dependent pathway for production of IL-1β in rat dendritic cells, which was absent in macrophages. Taken together, these results comprehensively establish that inflammation and autoimmunity in glomerulonephritis is independent of P2RX7 and reveals the off-target properties of drugs previously known as selective P2RX7 antagonists. Rat mononuclear phagocytes may be able to utilise an 'alternative inflammasome' pathway to produce IL-1β independently of P2RX7, which may account for the susceptibility of P2RX7 KO rats to inflammation and autoimmunity in glomerulonephritis. This article is protected by copyright. All rights reserved.

PURPOSE OF REVIEW: Managing patients with glomerular disease during the COVID-19 pandemic has been challenging, as the infection risk associated with immunosuppression must be balanced against the need to control severe glomerular disease that can lead to kidney failure. This review provides an overview of COVID-19 and the effectiveness of SARS-CoV-2 vaccination in patients with glomerular disease. RECENT FINDINGS: Registry data, although biased towards outcomes of hospitalized patients, suggest that the mortality from COVID-19 is higher in patients with glomerular disease than in the general population. Glucocorticoid use prior to SARS-CoV-2 infection is associated with adverse outcomes from COVID-19. Rituximab significantly attenuates serological responses to both natural infection and vaccination against SARS-CoV-2, although it is not clear whether this leads to adverse outcomes. Case reports of disease flares occurring after vaccination have been reported, but causality in any of these cases has yet to be proven and the absolute risk remains very small. SUMMARY: Patients with glomerular disease represent an at-risk group for severe COVID-19 disease and vaccination is key to reducing this risk. As immunosuppressed patients demonstrate an attenuated response to vaccination, the efficacy of a third primary dose followed by a subsequent booster is being investigated.

Antibody mediated rejection is a major cause of renal allograft loss. Circulating preformed donor specific antibodies (DSA) can result as a consequence of blood transfusion, pregnancy or prior transplantation. Current treatment strategies are limited due to partial or transient efficacy, adverse side-effects or patient unsuitability. Previous in vivo studies exploring autoimmune diseases have shown that spleen tyrosine kinase (SYK) signalling is involved in the development of pathogenic autoantibody. The role of SYK in allogenic antibody production is unknown, and we investigated this in a rodent model of sensitization, established by the transfusion of F344 whole blood into LEW rats. Two-week treatment of sensitized rats with selective SYK inhibitor fostamatinib strongly blocked circulating DSA production without affecting overall total immunoglobulin levels, and inhibition was sustained up to 5 weeks post-completion of the treatment regimen. Fostamatinib treatment did not affect mature B cell subset or plasma cell levels, which remained similar between non-treated controls, vehicle treated and fostamatinib treated animals. Our data indicate fostamatinib may provide an alternative therapeutic option for patients who are at risk of sensitization following blood transfusion while awaiting renal transplant.

Experimental autoimmune vasculitis (EAV) is a model of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) induced by immunisation of susceptible rat strains with myeloperoxidase (MPO). Animals develop circulating MPO-ANCA, pulmonary haemorrhage, and glomerulonephritis, although renal injury is mild and recovers spontaneously without treatment. In this study we aimed to augment the severity of glomerulonephritis. Following induction of EAV on day 0, a sub-nephritogenic dose of nephrotoxic serum (NTS) containing heterologous antibodies to glomerular basement membrane was administered on day 14. This resulted in a significant increase in disease severity at day 28 compared to MPO immunisation alone - with more urinary abnormalities, infiltrating glomerular leucocytes, and crescent formation that progressed to glomerular and tubulointerstitial scarring by day 56, recapitulating important features of human disease. Importantly, the glomerulonephritis remained pauci-immune, and was strictly dependent on the presence of autoimmunity to MPO, as there was no evidence of renal disease following administration of sub-nephritogenic NTS alone or after immunisation with a control protein in place of MPO. Detailed phenotyping of glomerular leucocytes identified an early infiltrate of non-classical monocytes following NTS administration that, in the presence of autoimmunity to MPO, may initiate the subsequent influx of classical monocytes which augment glomerular injury. We also showed that this model can be used to test novel therapeutics by using a small molecule kinase inhibitor (fostamatinib) that rapidly attenuated both glomerular and pulmonary injury over a 4-day treatment period. We believe that this enhanced model of MPO-AAV will prove useful for the study of glomerular leucocyte behaviour and novel therapeutics in AAV in the future. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Summary Interleukin (IL)-6 is an emerging therapeutic target in myocardial infarction (MI). IL-6 has 2 distinct signaling pathways: trans-signaling, which mediates inflammation, and classic signaling, which also has anti-inflammatory effects. The novel recombinant fusion protein sgp130Fc achieves exclusive trans-signaling blockade, whereas anti–IL-6 antibodies (Abs) result in panantagonism. In a rat model of reperfused MI, sgp130Fc, but not anti–IL-6-Ab, attenuated neutrophil and macrophage infiltration into the myocardium, reduced infarct size, and preserved cardiac function 28 days after MI. These data demonstrate the efficacy of exclusive IL-6 trans-signaling blockade and support further investigation of sgp130Fc as a potential novel therapy in MI.

Class IV-S lupus nephritis is often associated with more necrosis and fewer subendothelial immune deposits compared to class IV-G lupus nephritis, suggestive of necrotising glomerular inflammation found in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. ANCAs are present in a significant proportion of patients with lupus nephritis. Here we determine whether ANCAs are associated with distinct clinical and histopathologic features of lupus nephritis. Thirty-two ANCA-positive biopsies were compared to 222 ANCA-negative biopsies from patients with lupus nephritis. The majority (82%) of ANCA-positive patients had antimyeloperoxidase antibodies. Class IV-S lupus nephritis and glomerular necrosis were significantly more common (36% vs. 16% and 35% vs. 15%, respectively) and isolated Class V lupus nephritis significantly less common (10% vs. 29%) in the ANCA-positive group. ANCA-positive patients had significantly higher dsDNA titers (335u/ml vs. 52u/ml), significantly lower serum C4 concentrations (0.125g/L vs. 0.15g/L) and significantly higher serum creatinine (130μmol/L vs. 84μmol/L) at the time of biopsy. Hence ANCAs appear to influence the histological pattern of lupus nephritis and are associated with worse baseline renal function and more active lupus serology. There was no significant difference in outcome between groups when matched for severity of disease and treatment using propensity scoring. Thus, further studies are needed to examine whether ANCAs in patients with lupus nephritis have a pathogenic role and whether they are associated with worse renal outcomes or are simply a marker of more severe disease.

Background Tacrolimus (TAC) is effective in treating membranous nephropathy (MN); however relapses are frequent after treatment cessation. We conducted a randomised controlled trial to examine whether the addition of mycophenolate mofetil (MMF) to TAC would reduce relapse rate. Methods Forty patients with biopsy proven idiopathic MN and nephrotic syndrome were randomly assigned to receive either TAC monotherapy (n = 20) or TAC combined with MMF (n = 20) for 12 months. When patients had been in remission for 1 year on treatment the MMF was stopped and the TAC gradually withdrawn in both groups over 6 months. Patients also received supportive treatment with angiotensin blockade, statins, diuretics and anticoagulation as needed. Primary endpoint was relapse rate following treatment withdrawal. Secondary outcomes were remission rate, time to remission and change in renal function. Results 16/20 (80%) of patients in the TAC group achieved remission compared to 19/20 (95%) in the TAC/MMF group (p = 0.34). The median time to remission in the TAC group was 54 weeks compared to 40 weeks in the TAC/MMF group (p = 0.46). There was no difference in the relapse rate between the groups: 8/16 (50%) patients in the TAC group relapsed compared to 8/19 (42%) in the TAC/MMF group (p = 0.7). The addition of MMF to TAC did not adversely affect the safety of the treatment. Conclusions Addition of MMF to TAC does not alter the relapse rate of nephrotic syndrome in patients with MN. Trial registration This trial is registered with EudraCTN2008–001009-41. Trial registration date 2008-10-08.

Background Lupus nephritis (LN) remains a major cause of morbidity in systemic lupus erythematosus. Worldwide, at 5 years about 19% (Class IV) and 4% (class V) of patients with LN develop end-stage renal disease (ESRD), depending upon the disease severity, ancestral and socio-economic factors as well as response to initial treatment. ESRD is an unusual direct cause of death in this disease but is associated with premature mortality. Objectives The aim of this study was to retrospectively review our large cohort of LN patients, predominantly treated with MMF and rituximab based steroid sparing regimens, who required renal biopsy for new presentation between 2010 and 2017 to analyse the factors associated with the development of ESRD. Methods We identified 176 patients with LN from a renal biopsy database, at our tertiary Lupus Centre presenting between 01/2010 and 09/2017. The 21 patients (11%) who progressed to ESRD were included, and using propensity score matching, were matched for age, gender and ethnicity with 63 patients who did not develop ESRD. Patients who required dialysis at presentation were excluded. Results Baseline characteristics were similar with regard to gender, age and ethnicity between both groups. Mean follow-up was 4±17 years overall (2.1±1.4 years in the ESRD group and 3.8±1.5 years in the non-ESRD group, p=0.0002). The ESRD group had significantly higher serum creatinine at baseline (184.2±143.6 vs 89.0±48.0, p=0.031) and and at 12 m (256.2 vs 79.5, p=0.001) and significantly lower baseline eGFR (44.6 vs 68.1, p=0.003) and eGFR at 12 m (27 vs 73.1, p=0.001). The absence of remission at 1 year was also associated with a higher risk of ESRD (71.7% vs 9.5%, p=0.001), as well as the presence of positive MPO-ANCA (p=0.040), the ANCA titre (p=0.031) and persistent low levels of complement (50% vs 21.5%, p=0.035). Using multivariable regression analysis, independent factors predictive of ESRD were baseline serum creatinine and no response to treatment at 12 months. There was no significant difference in outcome between groups regarding the type of induction treatment. Conclusions The rates of ESRD in our LN cohort are comparable with the published literature despite. In our patient population with high use of rituximab and low steroids, the features that predict poor long term outcome are baseline serum creatinine and the failure to attain a remission at 1 year. These data highlight the importance of a) early diagnosis of lupus nephritis and b) defining the features which determine non response at 1 year and being able to identify earlier what would be the right treatment regimen for each individual patient. References [1] Hanly JG, et al. Rheumatology (Oxford)2016; 55: 252–262. [2] Korbet SM, et al. Am J Kidney Dis2000; 35: 904–914. [3] Tektonidou MG,et al. Arthritis Rheumatol. 2016; 68(6):1432–4. [4] Ortega LM, et al. Lupus. 2010;19(5):557. Disclosure of Interest None declared

OBJECTIVES Rituximab is effective in inducing remission in ANCA-associated vasculitis (AAV), with randomized evidence to support its use as four infusions of 375 mg/m(2) (the conventional lymphoma dosing schedule). As B cell depletion (BCD) appears to occur very rapidly after the first dose, we questioned the need for repeat dosing and adopted a standard single-dose protocol of 375 mg/m(2) to treat active AAV. METHODS All consecutive cases with newly diagnosed or relapsing AAV for whom conventional immunosuppression was contraindicated or ineffective were enrolled. All were rituximab naive. Circulating CD19(+) B cells and clinical and serological markers of disease activity were recorded at regular intervals. Complete remission (CR) was defined as the absence of clinical features of AAV with a prednisolone dose 500 μM). Eight (42%) were on additional immunosuppression at the time of rituximab treatment. Satisfactory BCD (

Objectives. To correlate the kinetics of B-cell repopulation with relapse after B-cell depletion therapy in SLE patients and address whether variation in relapse rate, B-cell numbers and phenotype are related to anti-dsDNA antibody levels. Methods. Sixty-one patients with refractory SLE were treated with a standard rituximab regimen. Clinical and serological measures of disease activity and B-cell numbers were assessed. B-cell phenotype was examined in a subgroup of patients by flow cytometry. Results. Disease relapse was substantially delayed beyond B-cell repopulation, and early relapse was associated with a faster rate of repopulation. At relapse, B-cell numbers were significantly lower than at baseline in patients with high anti-dsDNA antibody levels (>100 IU/ml) but not in patients with low anti-dsDNA antibody levels. Of the patients with high anti-dsDNA antibodies at baseline, levels fell significantly only in those patients who remained in remission after repopulation. Relapse with high anti-dsDNA antibody levels was associated with an increased percentage of IgD−CD27hi plasmablasts, whereas relapse with low anti-dsDNA antibody levels was accompanied by an increased percentage of IgD−CD27− B cells. Conclusion. Anti-dsDNA antibody levels distinguished two patient groups, which differ in their B-cell number and phenotype at relapse following rituximab, and suggest that different B-cell pathologies exist in SLE. The data imply that B-cell numbers should be kept very low for a sustained period in patients with high dsDNA binding, therefore justifying a more aggressive regimen.

Objective The Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) is a validated instrument for assessing organ damage in systemic lupus erythematosus (SLE). Trained physicians must complete it, thus limiting utility where this is impossible. Methods We developed and pilot tested a self-assessed organ damage instrument, the Lupus Damage Index Questionnaire (LDIQ), in 37 SLE subjects and 7 physicians. After refinement, 569 English-speaking SLE subjects and 14 rheumatologists from 11 international SLE clinics participated in validation. Subjects and physicians completed the instruments separately. We calculated sensitivity, specificity, Spearman's correlations, and agreement using the SDI as the gold standard. Six hundred five SLE participants in the community-based National Data Bank for Rheumatic Diseases (NDB) study completed the LDIQ and we assessed correlations with outcome and disability measures. Results The mean LDIQ score was 3.3 (range 0–16) and the mean SDI score was 1.5 (range 0–9). The LDIQ had a moderately high correlation with the SDI (Spearman's r = 0.50, P 80%, except for neuropathy. Sensitivities were variable and lowest for damage, with 85% for all but neuropathy, reduced renal function, deforming arthritis, and alopecia. In the NDB, the LDIQ correlated well with the comorbidity index (r = 0.45), the Short Form 36 physical component scale (r = 0.43), the Medical Research Council dyspnea scale (r = 0.40), disability (r = 0.37), and the Systemic Lupus Erythematosus Activity Questionnaire score (r = 0.37). Conclusion The metric properties of the LDIQ are good compared with the SDI. It has construct validity and correlations with health assessments similar to the SDI. The LDIQ should allow expansion of SLE research. Its ultimate value will be determined in longitudinal studies.

BACKGROUND The pathogenesis and natural history of HIV-associated immune complex kidney disease (HIVICK) is not well understood. Key questions remain unanswered, including the role of HIV infection and replication in disease development and the efficacy of antiretroviral therapy (ART) in the prevention and treatment of disease. METHODS In this multicentre study, we describe the renal pathology of HIVICK and compare the clinical characteristics of patients with HIVICK with those with IgA nephropathy and HIV-associated nephropathy (HIVAN). Poisson regression models were used to identify risk factors for each of these pathologies. RESULTS Between 1998 and 2012, 65 patients were diagnosed with HIVICK, 27 with IgA nephropathy and 70 with HIVAN. Black ethnicity and HIV RNA were associated with HIVICK, receipt of ART with IgA nephropathy and black ethnicity and CD4 cell count with HIVAN. HIVICK was associated with lower rates of progression to end-stage kidney disease compared with HIVAN and IgA nephropathy (P < 0.0001). Patients with HIVICK who initiated ART and achieved suppression of HIV RNA experienced improvements in estimated glomerular filtration rate and proteinuria. CONCLUSIONS These findings suggest a pathogenic role for HIV replication in the development of HIVICK and that ART may improve kidney function in patients who have detectable HIV RNA at the time of HIVICK diagnosis. Our data also suggest that IgA nephropathy should be viewed as a separate entity and not included in the HIVICK spectrum.

The vasculitides are inflammatory disorders of blood vessels that can be classified as primary or secondary and as localised or systemic. Localised vasculitis affects a single organ, such as the skin, whereas the systemic vasculitides affect multiple organ systems.

Background and aims: The aim of this study was to develop and evaluate the UK version of the Functional Assessment Measure (UK FIM+FAM). Design: Before and after evaluation of inter-rater reliability. Development: Ten ‘troublesome’ items in the original FIM+FAM were identified as being particularly difficult to score reliably. Revised decision trees were developed and tested for these items over a period of two years to produce the UK FIM+FAM. Evaluation: A multicentre study was undertaken to test agreement between raters for the UK FIM+FAM, in comparison with the original version, by assessing accuracy of scoring for standard vignettes. Methods: Baseline testing of the original FIM+FAM was undertaken at the start of the project in 1995. Thirty-seven rehabilitation professionals (11 teams) each rated the same three sets of vignettes – first individually and then as part of a multidisciplinary team. Accuracy was assessed in relation to the agreed ‘correct’ answers, both for individual and for team scores. Following development of the UK version, the same vignettes (with minimal adaptation to place them in context with the revised version) were rated by 28 individuals (nine teams). Results: Taking all 30 items together, the accuracy for scoring by individuals improved from 74.7% to 77.1% with the UK version, and team scores improved from 83.7% to 86.5%. When the 10 troublesome items were taken together, accuracy of individual raters improved from 69.5% to 74.6% with the UK version (p Conclusion: The UK FIM+FAM compares favourably with the original version for scoring accuracy and ease of use, and is now sufficiently well-developed for wider dissemination.

Antiphospholipid antibodies (aPL) cause vascular thrombosis and/or pregnancy morbidity in the antiphospholipid syndrome (APS) (1). These clinical manifestations are triggered by the interaction of pathogenic aPL with various target cells, including monocytes, endothelial cells, and trophoblast cells, leading to the recruitment of cell surface receptors and subsequent perturbation of intracellular signaling pathways (2). These pathogenic aPL are generally IgG type (3, 4) and target a variety of antigens, including negative phospholipid, phospholipid binding proteins (particularly β2-glycoprotein I [β2GPI] and prothrombin), as well as other factors related to hemostasis, such as thrombin, protein C, activated protein C, protein S, plasmin, plasminogen, and tissue-type plasminogen activator (tPA) (5–13). In contrast, nonpathogenic aPL (found in 2–5% of healthy adults who lack features of the APS [14]) mostly bind directly to phospholipid (15). Thrombin, activated protein C, plasmin, and tPA, as well as activated factor VIIa (FVIIa), FIXa, FXa, and FXIIa, belong to the trypsin-like serine protease family of enzymes and are involved in the tight regulation of hemostasis (16). In previous studies, sera from between 13% and 54% of patients with the APS have been found to bind various different serine proteases (5, 8, 13). Furthermore, a panel of human monoclonal aPL produced from hybridomas displayed cross-reactivity with serine protease, binding to thrombin, activated protein C, plasmin, tPA, FIXa, and FXa (6–8, 17, 18). Overall, these serine proteases share ∼50% amino acid sequence similarity in their enzymatic domains but have greater homology at their catalytic sites. Given that several human monoclonal aPL have been found to inhibit the inactivation of procoagulant serine proteases and functional activities of anticoagulant/fibrinolytic serine proteases (7, 8, 13, 19), it has been suggested that some aPL may recognize the catalytic domain of serine proteases, leading to dysregulation of hemostasis and vascular thrombosis in the APS. To explore the interaction of aPL with target antigens in promoting thrombus formation, we have been studying a panel of recombinant human monoclonal IgG aPL, which differ from one another at points in their sequence precisely engineered by us. Studying this panel of IgG molecules has allowed us to investigate correlations between their sequences, binding, and biologic properties (20–23). These human monoclonal IgG aPL were all based on the human monoclonal IgG aPL IS4 (derived from a patient with APS), which binds β2GPI (24) and thrombin (8) and is thrombogenic in mice (25). Previously, we found that alterations in the pattern of somatic mutations in both the VH and VL regions of IS4 determined its ability to bind antigens relevant in the pathogenesis of the APS and to promote murine thrombogenesis (20–23). Interestingly, the in vivo thrombogenic effects of these monoclonal antibodies (mAb) were most closely predicted by their ability to bind thrombin, rather than phospholipid or β2GPI. Furthermore, mAb binding to thrombin followed a different pattern compared to the pattern observed with mAb binding to its zymogen prothrombin (21). Therefore, in the current study we used the same panel of mAb to examine whether binding to other serine proteases also parallels thrombogenicity in the mouse model, and whether the difference between binding to prothrombin and binding to thrombin is also seen with other zymogen/enzyme pairs, i.e., FIX and FIXa, or protein C and activated protein C. To assess the relevance of our findings obtained using monoclonal IgG aPL to polyclonal aPL found in vivo, we then tested serum samples and purified IgG samples from APS patients, systemic lupus erythematosus (SLE) patients without APS (subclassified according to positivity or negativity for aPL), and healthy controls. We investigated whether samples from those groups differed in the nature and avidity of their binding to serine proteases and ability to alter the functional activity of serine proteases.

Since 2000, we have given B-cell depletion therapy (BCDT) with rituximab to 76 patients with active SLE refractory to standard immunosuppression. Twenty-four of these patients have now received repeated cycles of BCDT. The aims of the study were to: (i) assess the efficacy and safety of repeated cycles of BCDT in treating refractory SLE; and (ii) assess whether retreatment produced a more sustained clinical response.BCDT was administered using CYC 750 mg, methylprednisolone 125-250 mg and rituximab 1 g given intravenously on two occasions, 2 weeks apart. Patients were reviewed at 1-2 monthly intervals and disease activity assessed using the BILAG activity index and serological markers. Clinical response was categorized as complete or partial remission, or no response, based on the change in BILAG scores.Eighteen patients had sufficient data for detailed analysis. All were female; mean age 29.9 years; mean duration of follow-up 58.7 months. Two patients died during follow-up and there were two infusion reactions. Disease activity was significantly reduced after both cycles of BCDT at 6 months. More patients achieved disease remission after the second cycle (82 vs 61% first cycle), which was maintained in 65% at 12 months (vs 39% first cycle). The time to disease flare was significantly longer after the second cycle (P0.001) and 33% of our patients have still not flared to date following retreatment (mean follow-up 24.5 months).Repeated cycles of BCDT with rituximab are effective in treating refractory SLE and has a favourable safety profile. Retreatment may produce a more sustained clinical response.

Objective: To describe and compare current practice in diagnosis and treatment of depression following acquired brain injury in two countries (UK and the Netherlands) which have different sets of guidelines. Setting and design: A cross-sectional survey of reported practice among rehabilitation physician members of the British and Dutch specialist societies. Methods: A 12-item postal questionnaire was sent to 496 rehabilitation physicians with two reminders: N = 353 (71%) responded, 146 of whom did not manage people with acquired brain injury, leaving 207 questionnaires for analysis (Netherlands N = 121, UK N = 86). Descriptive summary statistics were compiled. Categorical and dichotomous data were compared between the groups using chi-squared tests. Results: Sixty-seven (78%) of British respondents served a predominantly younger adult (65 years) population, compared with only 27 (22%) of the Dutch, who mainly treated patients of all ages. In line with their respective guidelines, more British respondents reported that they screened all acquired brain injury patients for depression (68/86 (79%) British versus 71/121 (59%) Dutch, P < 0.01), and used formal measures (37/68 (54%) versus 14/69 (20%), P < 0.001). They also took a more active role in treatment of depression: only 1 (1%) never used antidepressants, compared with 22 (18%) of Dutch respondents (P < 0.001). On the other hand, where antidepressants were prescribed, the Dutch respondents were more likely than the British to follow-up their patients (93/98 (95%) versus 67/84 (80%), P < 0.01). Conclusions: The survey demonstrates a broadly similar approach, but highlights some significant variance in practice between the two countries which may stem from differences in population and service provision as well as their respective guidelines.

It is well established that L-NAME, a generic NOS inhibitor, stimulates neurogenesis in the dentate gyrus of the adult rat and corticosterone reduces it. These experiments explore the interaction between L-NAME and corticosterone. L-NAME (50 mg/kg), as expected, increased proliferation, but also lowered plasma corticosterone levels. However, the stimulating action of L-NAME depends on the presence of rhythmic changes in plasma corticosterone, as it is abolished in rats treated with a subcutaneous implant of corticosterone, which flattens the diurnal rhythm. Adrenalectomized rats implanted with corticosterone also failed to respond to L-NAME. Giving them a single daily injection of corticosterone (2 mg/kg) in an attempt to replicate the diurnal rhythm restored the sensitivity of the progenitor cells to L-NAME. The mechanism for this result remains to be investigated. Excess corticosterone given by daily injection (40/mg/kg) reduced proliferation but did not alter the response to L-NAME, even though this occurred from a lower baseline. nNOS was demonstrable only in the inner (proliferative) layer of the dentate gyrus in control rats, and did not alter following excess corticosterone treatment. iNOS was detectable at low levels in control rats, but was increased markedly following corticosterone. eNOS was evident throughout the dentate gyrus, and also increased after corticosterone (particularly in the hilus). Aminoguanidine (100 mg/kg/day; an iNOS antagonist) significantly increased proliferation in corticosterone-treated rats (40 mg/kg/day) but not in controls without additional corticosterone, confirming that iNOS plays a role in corticosterone-regulated neurogenesis. Corticosterone may thus act on progenitor cells in part at least through increased nitric oxide (NO) formation. The effects of reduced NO on neurogenesis may rely on a dual mechanism: corresponding reductions in plasma corticosterone and increased induction of iNOS (and/or eNOS) within the dentate gyrus. The possibility that NO acts downstream of glucocorticoids in the dentate gyrus is suggested.

Objective: To ascertain which standardized instruments are currently most commonly used as outcome measures for rehabilitation in routine clinical practice in the UK. Design: The study used a postal questionnaire which was sent out to members of two major societies of rehabilitation professionals in the UK. Results: Of 182 rehabilitation centres represented by respondents, 140 (77%) collected at least one standardized measure and 42 did not. Principal reasons for not recording measures were lack of time and not knowing what to collect. As had been anticipated, a very wide range of different measures were used by different centres, however some clear favourites emerged including the 10 m Walk, the Motricity Index and the Nine-hole Peg Test. One hundred and twenty-three centres used one or more global disability measure of which the commonest were the Barthel Index or one of its modifications and the Functional Independence Measure (FIM) and/or Functional Assessment Method (FAM). Among units that used handicap or extended activities of daily living (EADL) scales, the Nottingham EADL, the London Handicap Scale and the General Health Questionnaire (GHQ-22 or 12) were most popular. Outside neurorehabilitation, the Harold Wood/Stanmore mobility grades were used by 10/18 amputee rehabilitation centres and the Health Assessment Questionnaire (HAQ) was used by 15/48 units providing musculoskeletal rehabilitation. Conclusions: It is clear that no one measure is suitable in all settings and services, but the most popular measures from this survey may reasonably form the basis for a 'basket of recommended instruments' that may help to guide units wishing to collect outcome data but not knowing which to choose.