Ravindra Rajakariar

Hematopoietic prostaglandin D2 synthase controls the onset and resolution of acute inflammation through PGD2 and 15-deoxyΔ12–14 PGJ2

Hematopoietic prostaglandin D2 synthase (hPGD2S) metabolizes cyclooxygenase (COX)-derived PGH2 to PGD2 and 15-deoxyΔ12–14 PGJ2 (15d-PGJ2). Unlike COX, the role of hPGD2S in host defense is ambiguous. PGD2 can be either pro- or antiinflammatory depending on disease etiology, whereas the existence of 15d-PGJ2 and its relevance to pathophysiology remain controversial. Herein, studies on hPGD2S KO mice reveal that 15d-PGJ2 is synthesized in a self-resolving peritonitis, detected by using liquid chromatography–tandem MS. Together with PGD2 working on its DP1 receptor, 15d-PGJ2 controls the balance of pro- vs. antiinflammatory cytokines that regulate leukocyte influx and monocyte-derived macrophage efflux from the inflamed peritoneal cavity to draining lymph nodes leading to resolution. Specifically, inflammation in hPGD2S KOs is more severe during the onset phase arising from a substantial cytokine imbalance resulting in enhanced polymorphonuclear leukocyte and monocyte trafficking. Moreover, resolution is impaired, characterized by macrophage and surprisingly lymphocyte accumulation. Data from this work place hPGD2S at the center of controlling the onset and the resolution of acute inflammation where it acts as a crucial checkpoint controller of cytokine/chemokine synthesis as well as leukocyte influx and efflux. Here, we provide definitive proof that 15d-PGJ2 is synthesized during mammalian inflammatory responses, and we highlight DP1 receptor activation as a potential antiinflammatory strategy.

Novel biphasic role for lymphocytes revealed during resolving inflammation

Acute inflammation is traditionally described as the influx of polymorphonuclear leukocytes (PMNs) followed by monocyte-derived macrophages, leading to resolution. This is a classic view, and despite subpopulations of lymphocytes possessing innate immune-regulatory properties, seldom is their role in acute inflammation and its resolution discussed. To redress this we show, using lymphocyte-deficient RAG1−/− mice, that peritoneal T/B lymphocytes control PMN trafficking by regulating cytokine synthesis. Once inflammation ensues in normal mice, lymphocytes disappear in response to DP1 receptor activation by prostaglandin D2. However, upon resolution, lymphocytes repopulate the cavity comprising B1, natural killer (NK), γ/δ T, CD4+/CD25+, and B2 cells. Repopulating lymphocytes are dispensable for resolution, as inflammation in RAG1−/− and wild-type mice resolve uniformly. However, repopulating lymphocytes are critical for modulating responses to superinfection. Thus, in chronic granulomatous disease using gp91phox−/− mice, not only is resolution delayed compared with wild-type, but there is a failure of lymphocyte re-appearance predisposing to exaggerated immune responses upon secondary challenge that is rescued by resolution-phase lymphocytes. In conclusion, as lymphocyte repopulation is also evident in human peritonitis, we hereby describe a transition in T/B cells from acute inflammation to resolution, with a central role in modulating the severity of early onset and orchestrating responses to secondary infection.

High pre-transplant soluble CD30 levels are predictive of the grade of rejection.

In renal transplantation, serum soluble CD30 (sCD30) levels in graft recipients are associated with increased rejection and graft loss. We investigated whether pre‐transplant sCD30 concentrations are predictive of the grade of rejection. Pre‐transplant sera of 51 patients with tubulointerstitial rejection (TIR), 16 patients with vascular rejection (VR) and an age‐matched control group of 41 patients with no rejection (NR) were analyzed for sCD30. The transplant biopsies were immunostained for C4d. The median sCD30 level was significantly elevated in the group with VR (248 Units (U)/mL, range: 92–802) when compared with TIR (103 U/mL, range: 36–309, p < 0.001) and NR (179 U/mL, range: 70–343, p < 0.03). Moreover, patients with TIR had significantly lower sCD30 levels compared to NR. Based on C4d staining, a TH2 driven process, the median sCD30 levels were significantly raised in C4d+ patients compared with C4d− group (177 U/mL vs. 120 U/mL, p < 0.05). sCD30 levels measured at time of transplantation correlate with the grade of rejection. High pre‐transplant levels are associated with antibody‐mediated rejection which carries a poorer prognosis. sCD30 could be another tool to assess immunological risk prior to transplantation and enable a patient centered approach to immunosuppression.

Post Transplant T‐Cell Lymphoma: A Case Series of Four Patients from a Single Unit and Review of the Literature

Post‐transplant lymphoproliferative disorders (PTLDs) occur in approximately 1% of renal graft recipients. Of these, up to 15 percent are of the T‐cell type. In this study, we present four cases of T‐cell lymphoma from our renal transplant population, each of whom presented with non‐specific symptoms, pancytopenia and/or liver dysfunction, with no obvious lymphadenopathy. They were all diagnosed with rare subsets of T‐cell PTLD that included hepato‐splenic T‐cell lymphoma and anaplastic large cell lymphoma (ALCL). At the time of presentation, the patients were too ill for treatment to be initiated and succumbed to their illness. Increased awareness of this condition may allow for earlier diagnosis and improve its prognosis.

Nonresolving Inflammation in gp91phox−/− Mice, a Model of Human Chronic Granulomatous Disease, Has Lower Adenosine and Cyclic Adenosine 5′-Monophosphate

In chronic granulomatous disease (CGD), there is failure to generate reactive oxygen metabolites, resulting in recurrent infections and persistent inflammatory events. Because responses to sterile stimuli in murine models of CGD also result in nonresolving inflammation, we investigated whether defects in endogenous counterregulatory mechanisms and/or proresolution pathways contribute to the etiology of CGD. To this end, we conducted a series of experiments finding, in the first instance that adenosine and cAMP, which dampen innate immune-mediated responses, show a biphasic profile in resolving peritonitis; peaking at onset, waning as inflammation progresses, and rising again at resolution. We also found elevations in adenosine and cAMP in resolving human peritonitis. In gp91phox−/− mice, an experimental model of CGD, levels of adenosine and cAMP were significantly lower at onset and again at resolution. Corroborating the finding of others, we show that adenosine, signaling through its A2A receptor and therefore elevating cAMP, is not only anti-inflammatory, but, importantly, it does not impair proresolution pathways, properties typical of nonsteroidal anti-inflammatory drugs. Conversely, antagonizing the A2A receptor worsens acute inflammation and prolongs resolution. Taking this further, activating the A2A receptor in gp91phox−/− mice was dramatically anti-inflammatory regardless of the phase the inflammatory response A2A agonists were administered, i.e., onset or resolution, demonstrating wide and robust pharmacological flexibility that is unlikely to subvert proresolution pathways. Therefore, we describe the biphasic profile of adenosine and cAMP throughout the time course of acute inflammation that is dysregulated in CGD.

Utility of a repeat renal biopsy in lupus nephritis: a single centre experience

Background The role of repeat renal biopsy in lupus nephritis (LN) to guide treatment or predict prognosis has been controversial. We assessed glomerular and tubulointerstitial histological characteristics of serial renal biopsies, correlations with clinical variables and the impact on subsequent management. Methods Out of a large single-centre cohort of 270 biopsy-proven LN patients, 66 (24%) had serial biopsies. LN classes based on glomerular pathology were defined according to the International Society of Nephrology/Renal Pathology Society 2003 classification, while tubulointerstitial pathologies were evaluated using the revised Austins semi-quantitative scoring system. Results LN class transitions from proliferative (III and IV) to non-proliferative classes (II and V) were uncommon (n = 4, 7.7%), while non-proliferatives frequently switched to proliferative classes (n = 12, 63.2%) and were more likely to receive increased immunosuppression (P = 0.040). Biochemical or serological variables could not predict these histopathological transitions. Tubulointerstitial score (mean ± standard deviation) progressed from 2.69 ± 2.03 on reference to 3.78 ± 2.03 on repeat biopsy (P = 0.001). Serum creatinine levels correlated with the degree of tubular atrophy on both reference (r = 0.33, P = 0.048) and repeat biopsy (r = 0.56, P < 0.001), and with interstitial scarring (r = 0.60, P < 0.001) on repeat biopsy. Greater interstitial inflammation on reference biopsy was associated with advanced interstitial scarring on repeat biopsies (r = 0.385, P = 0.009). Conclusions Repeat renal biopsy is an important tool to guide management, in particular in those with initial class II or V who flare. Although class transitions cannot be predicted by clinical parameters, serum creatinine level correlates with the degree of tubulointerstitial damage.

PS8:159 Moving with the times: social media use amongst lupus patients

Background Over the last decade the rise in social media use has been almost exponential. There are numerous online platforms where patients can interact for support and information gathering. A study presented at the ACR in 2013 showed lupus patients were willing to participate in Facebook chats for the purposes of disease education.1 We sought to discover current usage of social media amongst an ethnically mixed population attending an inner city tertiary lupus centre. Methods Questionnaires were distributed to consecutive patients attending the Barts Lupus Centre from October 2016 to February 2017. 17 questions asked about patient demographics and patients use of online information and support services, particularly social media platforms, with regards to lupus. Results 84 completed questionnaires were returned. 83% respondents were female. There were 28 South Asians, 26 Whites and 24 Blacks, 2 of other ethnic groups and 2 of mixed race. 64% (n=54) of patients accessed online lupus information and support sites. 45% percent (n=38) of patients reported using social media sites (26% South Asians, 34% Blacks and 34% Whites). Of those using social media 22% (n=8) patients used these tools daily and 30% (n=11) reported weekly use. Facebook (n=20), blogs (n=9), youtube (n=9), and Instagram (n=7) were cited as the most frequently used applications. Most patients (n=30) sought information on the disease, 17 (45%) wanted to find out about new treatments for lupus, 16 (42%) sought new ways to self-manage their disease, 14 (37%) sought interactions with other patients, and 10 (26%) were seeking support online. Patients most commonly wanted information on skin and joint complaints and family planning. 66% (n=56) thought their rheumatology team should have an online social media application to communicate with their patients. Conclusions A significant proportion of our lupus patients (45%) use social media to access information and support for their disease. Facebook, blogs, Instagram and Youtube are commonly used. Social media applications can provide physicians with a tool to interact with lupus patients to improve accessibility to health care and better health outcomes. Reference . Spring NH. 2013ACR/ARHP Annual Meeting, abstract 990.

PS2:43 Is lupus more prevalent in world’s most stressed countries?

Background A number of studies have implicated psychological stress as a trigger for autoimmune diseases. In a questionnaire study involving 120 lupus patients emotional stress was selected in over 75% cases as a trigger for their disease.1 The role of stress as a trigger in lupus however is controversial. Here we study whether there is an association between the prevalence of lupus in various countries and their reported stress measures. Methods We undertook a literature review of the reported prevalence of lupus in various countries across the world. We then recorded the reported stress index in those countries from Bloomberg’s study,2 which utilised seven equally weighted variables: homicide rates, GDP per capita income inequality, corruption perception, unemployment, urban air pollution and life expectancy to rank 74 countries according to stress levels. Pearsons correlation was used to measure association between national stress indices and lupus prevalence Results Results are presented in graph 1. Prevalence data was only available in the literature for limited countries. Of the countries studied no correlation was found between national stress indices and lupus prevalence (r=−0.028, p-value 0.449). Conclusion We found no association between a country’s prevalence of lupus and the measured stressfulness of its living environment.Abstract PS2:43 Figure 1 References . Stojanovich L. Stress as a trigger of autoimmune disease. Abstracts book: 5th International Congress on Autoimmunity, Sorrento, Italy, vol. 355. Autoimmun Rev; 2006. . World Health Organisation. United Nations Office on Drugs and Crime, International Monetary Fund, Central Intelligence Agency World Factbook, Transparency InternationalMay 2013.

Leptospirosis presenting as haemolytic uraemic syndrome: a case report

BackgroundLeptospirosis is a rare infectious disease especially in Western Countries. Renal involvement is a recognised complication of leptospirosis but leptospirosis-associated haemolytic uraemic syndrome is extremely rare and to our knowledge has only been reported once, in 1985.Case presentationA 29-year-old male was transferred to our Renal Unit with fevers, myalgia and diarrhoeal illness. Laboratory investigations revealed an acute kidney injury, acute liver injury, significantly raised lactate dehydrogenase with marked anaemia, thrombocytopenia and schistocytes on a blood film. A diagnosis of haemolytic uraemic syndrome was made. Surprisingly, the stool culture was negative which led to a suspicion of leptospirosis as one of the differential diagnoses. This was subsequently confirmed by enzyme-linked immunosorbent assay and microscopic agglutination test. He received plasma exchange and antibiotics and made a complete recovery on discharge.ConclusionLeptospirosis presenting as haemolytic uraemic syndrome is rare but should be considered in the differential diagnosis especially in the presence of significant liver injury, as current evidence suggests that the disease is re-emerging.

Systematic review and the external validity of randomized controlled trials in lupus nephritis

Introduction Randomized controlled trials (RCTs) are considered the gold standard for assessing treatment efficacy. However, sampling bias can affect the generalization of results to routine clinical practice. Here we assessed whether patients with lupus nephritis (LN) seen in routine clinical practice would have satisfied entry criteria to the major published RCTs in LN. Methods A systematic literature search from January 1974 to May 2015 was carried out, identifying all RCTs investigating LN induction treatment. Patients diagnosed with proliferative or membranous LN between 1995 and 2013 were identified from the Barts Lupus Centre database; baseline characteristics were compared with each RCT’s entry criteria to assess hypothetical inclusion or exclusion. Results Of 363 articles, 33 RCTs met inclusion criteria. Of 137 patients newly diagnosed with LN (111 with proliferative/mixed proliferative and 26 with pure membranous LN), 32% would have been excluded from RCT entry (range 8%–73%). The main reasons for exclusion would have been too severe disease, too mild disease, or prior immunosuppressant use, which were exclusion criteria in 26, 20, and 22 RCTs, respectively. A total of 27 patients with LN (20%) were re-biopsied due to flare; 68% of these would have been ineligible to enter RCTs. Conclusion Published RCTs do not truly reflect the heterogeneity of patients with LN in routine practice at our lupus center. The external validity of RCTs could be improved by including more representative patient cohorts. RCTs should be used as a guide but consideration should be given to similarities between individual patients and the characteristics of the trial cohorts before treatment decisions being made.