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The Systemic Lupus International Collaborating Clinics (SLICC), American College of Rheumatology (ACR), and the Lupus Foundation of America are developing a revised systemic lupus erythematosus (SLE) damage index (the SLICC/ACR Damage Index [SDI]). Shifts in the concept of damage in SLE have occurred with new insights into disease manifestations, diagnostics, and therapy. We evaluated contemporary constructs in SLE damage to inform development of the revised SDI.We conducted a 3-part qualitative study of international SLE experts. Facilitated small groups evaluated the construct underlying the concept of damage in SLE. A consensus meeting using nominal group technique was conducted to achieve agreement on aspects of the conceptual framework and scope of the revised damage index. The framework was finally reviewed and agreed upon by the entire group.Fifty participants from 13 countries were included. The 8 thematic clusters underlying the construct of SLE damage were purpose, items, weighting, reversibility, impact, time frame, attribution, and perspective. The revised SDI will be a discriminative index to measure morbidity in SLE, independent of activity or impact on the patient, and should be related to mortality. The SDI is primarily intended for research purposes and should take a life-course approach. Damage can occur before a diagnosis of SLE but should be attributable to SLE. Damage to an organ is irreversible, but the functional consequences on that organ may improve over time through physiological adaptation or treatment.We identified shifts in the paradigm of SLE damage and developed a unifying conceptual framework. These data form the groundwork for the next phases of SDI development.

Background/Aims Gangrene is a well-recognised complication of diabetes, peripheral arterial disease, frostbite and meningococcal disease amongst other conditions but is rare in patients with systemic lupus erythematosus [SLE]. Most reports describe individual patients and the prevalence in cohorts is very scarce. In 2008, our group reported five patients who had developed digital gangrene and two patients with “near gangrene”. We reviewed all the SLE patients seen in our lupus clinic between January 1978 and June 2022.The main goal was to address the prevalence and identify the possible trigger factors, aiming to find common clinical and serological features. We have also reviewed the acute and long-term management of gangrene in these patients as well as their long-term outcome. Methods We reviewed 820 patients with SLE attending the SLE Clinic in our UK tertiary referral center, followed up over 44 years, assessing demographics, clinical and serological features, treatment in the acute phase, outcome and long-term management. Results Eight out of 820 patients (0.97%) have developed gangrene. The age of onset of disease ranged from 12 to 26 years (mean 17.5 years, SD 4.609). The first episode of gangrene ranged from between presentation to 27 years after SLE onset, with a mean duration of SLE at the onset of the gangrene of 15.5 years (SD 11.711). All had active SLE at the time of critical peripheral ischaemia and anti-phospholipid (PL) antibodies were present in five out of the eight reported patients. The acute treatment was intravenous (IV) iloprost infusions with antiphospholipid-positive patients being anti-coagulated, most staying on long term anticoagulation therapy. The possible identified triggers (such as infection and cancer) were treated accordingly. Two patients did not respond to the initial treatment and needed further immunosuppression. All of these patients suffered digit loss. Conclusion Gangrene is a rare complication of SLE in patients with active disease but potentially able to cause severe damage. Anti-phospholipid antibodies are overrepresented in these patients but infection and cancer are other possible contributors. Anticoagulation therapy, steroids and iloprost are the first line therapy but in non-responders further immunosuppression may be needed to stop the evolution of gangrene. Disclosure J. Rua: None. D. Isenberg: Honoraria; Servier, Anges, Astrazeneca, UCB, Eli Lilly.

ObjectivesTo evaluate systemic lupus erythematosus (SLE) flares following hydroxychloroquine (HCQ) reduction or discontinuation versus HCQ maintenance.MethodsWe analysed prospective data from the Systemic Lupus International Collaborating Clinics (SLICC) cohort, enrolled from 33 sites within 15 months of SLE diagnosis and followed annually (1999–2019). We evaluated person-time contributed while on the initial HCQ dose (‘maintenance’), comparing this with person-time contributed after a first dose reduction, and after a first HCQ discontinuation. We estimated time to first flare, defined as either subsequent need for therapy augmentation, increase of ≥4 points in the SLE Disease Activity Index-2000, or hospitalisation for SLE. We estimated adjusted HRs (aHRs) with 95% CIs associated with reducing/discontinuing HCQ (vs maintenance). We also conducted separate multivariable hazard regressions in each HCQ subcohort to identify factors associated with flare.ResultsWe studied 1460 (90% female) patients initiating HCQ. aHRs for first SLE flare were 1.20 (95% CI 1.04 to 1.38) and 1.56 (95% CI 1.31 to 1.86) for the HCQ reduction and discontinuation groups, respectively, versus HCQ maintenance. Patients with low educational level were at particular risk of flaring after HCQ discontinuation (aHR 1.43, 95% CI 1.09 to 1.87). Prednisone use at time-zero was associated with over 1.5-fold increase in flare risk in all HCQ subcohorts.ConclusionsSLE flare risk was higher after HCQ taper/discontinuation versus HCQ maintenance. Decisions to maintain, reduce or stop HCQ may affect specific subgroups differently, including those on prednisone and/or with low education. Further study of special groups (eg, seniors) may be helpful.

Objectives This review addresses the question of what happens long-term to those systemic lupus erythematosus (SLE) patients who develop gangrene. It also seeks to find common clinical and serological features, risk factors and triggers and how best to manage this challenging complication. Methods We reviewed 850 patients with SLE attending a UK tertiary referral center, followed up over 44 years, assessing their demographics, clinical and serological features, treatment in the acute phase, their long-term outcome and long-term management. Results Ten out of 850 patients (1.2%) developed gangrene; the mean age of onset was 17 years (range 12–26 years) Eight out of 10 patients had a single episode of gangrene. One of the other two was not willing to have anticoagulation. The first episode of gangrene ranged from presentation to 32 years after SLE onset, mean duration of SLE at the onset of the gangrene was 18.5 years SD 11.5 years. Anti-phospholipid (PL) antibodies were over-represented in the patients with gangrene. All had active SLE at the time the gangrene developed. All patients were treated with intravenous (IV) iloprost infusions, and the antiphospholipid-antibody positive patients were anti-coagulated, most staying on long term anticoagulation. Underlying possible triggers were treated appropriately. Two patients who did not respond to the initial treatment needed further immunosuppression. All patients suffered digit loss. Conclusion Although rare, gangrene is a sinister, potentially late developing complication of SLE, it rarely recurs. It is associated with anti-phospholipid antibodies, active disease, and other possible triggers such as infection and cancer. Anticoagulation therapy, steroids and iloprost, and further immunosuppression may be needed to stop the evolution of gangrene.

BACKGROUND AND AIMS Atacicept is a dual BLyS/APRIL inhibitor. APRIL-SLE was a double-blind, placebo-controlled phase 2 study, which randomized moderate-to-severe systemic lupus erythematosus (SLE) patients to atacicept 75 mg, atacicept 150 mg or placebo. The primary endpoint was the proportion of subjects who experienced a new flare during the 52-week treatment period. In total, 111 patients in the placebo group, 112 patients in the atacicept 75 mg group and 62 patients in the atacicept 150 mg group completed 52 weeks of treatment. Patients with severe renal disease were excluded, while patients with proteinuria and mild–moderate chronic kidney disease, as assessed by KDIGO criteria, were eligible. The effect of atacicept on measures of renal function in these patients has not previously been reported. METHOD The study excluded moderate to severe glomerulonephritis, as defined by either of the following: urinary protein/creatinine ratio > 1 mg/mg and/or hematuria or a significant renal impairment as defined by glomerular filtration rate (GFR) < 50 mL/min/1.73 m2. Urine protein/creatinine ratio (UPCR) and GFR were measured at baseline, week 2, and then every 4 weeks until week 52. RESULTS In the APRIL-SLE study, the analysis for GFR and UPCR are of all patients (62–111 per group) with up to 15% of patients having a history of SLE-related renal disease. GFR time course showed stability for the atacicept groups compared to a 4.3% decline in the placebo group at week 52 from baseline (figure and table). Furthermore, reductions in UPCR from baseline at week 52 were observed in the atacicept groups compared to an increase in the placebo group. CONCLUSION In this phase 2 APRIL-SLE study, analysis of renal data suggests potential for improved renal function with atacicept treatment in SLE renal disease.

Background/Aims A major limitation of biologic therapy is formation of anti-drug antibodies (ADA). We previously demonstrated that ADA to rituximab are more prevalent in patients undergoing treatment for systemic lupus erythematosus (SLE) than rheumatoid arthritis and vasculitis, and predict subsequent infusion reactions. However, little is known regarding the long-term dynamics of ADA to rituximab. In this study we evaluated the longitudinal impact of ADA positivity in terms of drug kinetics, treatment response and neutralising capacity in SLE. Methods Patients with SLE undergoing treatment with rituximab were recruited to this study (n = 35). Serum samples were collected at the following intervals post-treatment; 1-3 months, 6 months, 12 months, 36 months (n = 114). Clinical and laboratory data was collected pre-treatment and at each time point. ADA were detected using an electrochemiluminescent immunoassay. Serum rituximab levels were measured via ELISA. A complement dependent cytotoxic assay was used to determine neutralising capability of ADA in a subgroup of positive samples (n = 38). Results ADA were found to be persistently positive over the 36-month follow-up period in 64.3% of patients. There was no significant difference in baseline disease activity (BILAG / SLEDAI-2K) between those who were subsequently ADA positive vs negative. ADA positive patients were younger at diagnosis compared with ADA negative (mean 22.50 ± 9.10 vs 37.29 ± 11.31 years, p = 0.002). Multivariate logistic regression found older age at diagnosis was associated with reduced incidence of persistent ADA with a 22% decrease in risk for each addition year after diagnosis (p = 0.03). ADA positive patients had a significantly lower C3 level at baseline (mean 0.61 ± 0.23 vs 0.87 ± 0.30, p = 0.026), which remained lower at each subsequent time point post-treatment up to 12 months. ADA titres peaked earlier and remained higher in those who had been treated with rituximab previously compared with those who were rituximab naive (median 132 AU/ml vs 7 AU/ml at 1-3 months). At 6 months post-treatment, patients with detectable ADA had a significantly lower circulating drug level than ADA negative (p = 0.0018). In terms of clinical response, ADA positive patients had an initial significant improvement in disease activity (SLEDAI-2K) by 3 months (p < 0.001). However, response was not maintained at 12 months. In comparison, ADA-negative patients showed a significant improvement in SLEDAI-2K at 6 months and this was maintained across the 36-month follow-up period. BILAG defined relapse within 12 months of treatment was only seen in ADA positive patients. Finally, all ADA positive samples were found to neutralise rituximab in vitro. Conclusion ADA to rituximab were common and persisted over the 36 month period of this study. ADA associated with earlier drug elimination, increased relapse rates and demonstrated neutralising capacity suggesting that ADA could be a significant limitation to sustained response to treatment. Disclosure C. Wincup: Grants/research support; Lupus UK, Versus Arthritis, British Society for Rheumatology. N. Dunn: None. C. Ruetsch-Chelli: None. A. Manouchehrinia: None. N. Kharlamova: None. M. Naja: None. B. Seitz-Polski: None. D. Isenberg: None. A. Fogdell-Hahn: None. C. Ciurtin: None. E. Jury: None.

It has become clear that rituximab treatment is useful for both B-cell malignancies and autoimmune rheumatic diseases. However this treatment is associated with an increased risk of an allergic reaction. We have reviewed the frequency with which these reactions occur in these different conditions. They appear to be less frequent when rituximab is used to treat rheumatoid arthritis and systemic lupus perhaps because concomitant steroids are invariably given to these patients with the rituximab which is not necessarily the case with the treatment of B-cell malignancies.

Objectives: This study aimed to demonstrate how to estimate the value of health gain after patients with a multisystem disease achieve a condition-specific composite response endpoint. Methods: Data from patients treated in routine practice with an exemplar multisystem disease (systemic lupus erythematosus) were extracted from a national register (British Isles Lupus Assessment Group Biologics Register). Two bespoke composite response endpoints (Major Clinical Response and Improvement) were developed in advance of this study. Difference-in-differences regression compared health utility values (3-level version of EQ-5D; UK tariff) over 6 months for responders and nonresponders. Bootstrapped regression estimated the incremental quality-adjusted life-years (QALYs), probability of QALY gain after achieving the response criteria, and population monetary benefit of response. Results: Within the sample (n = 171), 18.2% achieved Major Clinical Response and 49.1% achieved Improvement at 6 months. Incremental health utility values were 0.0923 for Major Clinical Response and 0.0454 for Improvement. Expected incremental QALY gain at 6 months was 0.020 for Major Clinical Response and 0.012 for Improvement. Probability of QALY gain after achieving the response criteria was 77.6% for Major Clinical Response and 72.7% for Improvement. Population monetary benefit of response was £1 106 458 for Major Clinical Response and £649 134 for Improvement. Conclusions: Bespoke composite response endpoints are becoming more common to measure treatment response for multisystem diseases in trials and observational studies. Health technology assessment agencies face a growing challenge to establish whether these endpoints correspond with improved health gain. Health utility values can generate this evidence to enhance the usefulness of composite response endpoints for health technology assessment, decision making, and economic evaluation.

Objectives To investigate predictors of sustained complete remission (CR) for 3 and 5 years, minimum. Methods Retrospective observational study from January 1978 to December 2019, including systemic lupus erythmatosus (SLE) patients who attended the Lupus Clinic in a tertiary hospital, for at least 3 years. We used the BILAG score and serological profile to classify patients into CR, serologically active clinically quiescent (SACQ) and serological remission (SR). Multivariable Cox regression analysis was performed to investigate predictors of CR and Kaplan–Meier curves were obtained. Results We included 564 patients; 15% achieved CR, 7% SACQ and 15% SR. Some 63% attained no remission. In the CR group, 73% sustained the remission for 5 years or more. Patients who did not reach any kind of sustained remission died significantly earlier (P 32 years) [HR 1.92 (1.24–2.97); P = 0.003]; absence of renal involvement [HR 2.55 (1.39–4.67); P = 0.002]; and of antiphospholipid syndrome (APS) [HR 4.92 (1.55–15.59); P = 0.007]. Conclusion Patients not achieving any kind of sustained remission have a higher risk of early mortality. White ethnicity, older age at diagnosis, absence of renal involvement and of APS were significantly associated with CR. Predictors for sustained CR do not change whether a 3-year or 5-year period is applied.

ObjectiveTo evaluate hydroxychloroquine (HCQ)-related retinal toxicity in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort.MethodsData were collected at annual study visits between 1999 and 2019. We followed patients with incident SLE from first visit on HCQ (time zero) up to time of retinal toxicity (outcome), death, loss-to-follow-up or end of study. Potential retinal toxicity was identified from SLICC Damage Index scores; cases were confirmed with chart review. Using cumulative HCQ duration as the time axis, we constructed univariate Cox regression models to assess if covariates (ie, HCQ daily dose/kg, sex, race/ethnicity, age at SLE onset, education, body mass index, renal damage, chloroquine use) were associated with HCQ-related retinal toxicity.ResultsWe studied 1460 patients (89% female, 52% white). Retinal toxicity was confirmed in 11 patients (incidence 1.0 per 1000 person-years, 0.8% overall). Average cumulative time on HCQ in those with retinal toxicity was 7.4 (SD 3.2) years; the first case was detected 4 years after HCQ initiation. Risk of retinal toxicity was numerically higher in older patients at SLE diagnosis (univariate HR 1.05, 95% CI 1.01 to 1.09).ConclusionsThis is the first assessment of HCQ and retinal disease in incident SLE. We did not see any cases of retinopathy within the first 4 years of HCQ. Cumulative HCQ may be associated with increased risk. Ophthalmology monitoring (and formal assessment of cases of potential toxicity, by a retinal specialist) remains important, especially in patients on HCQ for 10+ years, those needing higher doses and those of older age at SLE diagnosis.

Background Central nervous system (CNS) involvement accounts for over 90% of neuropsychiatric (NP) events compared to involvement of the peripheral nervous system (PNS) which accounts for most of the other events. Although there is a large body of work on CNS disease in SLE patients, involvement of the PNS is less well established. Objectives In a multi-ethnic/racial, prospective SLE inception cohort, to determine the clinical characteristics, associations and outcomes in different types of peripheral nervous system (PNS) disease. Methods Patients were evaluated annually for 19 NP events including seven types of PNS disease. Standardized case definitions and attribution models for each type of PNS event were used. SLE disease activity (SLEDAI-2K), organ damage (SLICC/ACR damage index), autoantibodies, patient (SF-36) and physician (Likert score) assessment of outcome were measured. Time to event and linear regressions were used as appropriate. Results Of 1,827 SLE patients, 88.8% were female, 48.8% Caucasian. The mean±SD age was 35.1±13.3 years, disease duration at enrollment 5.6±4.2 months and follow-up 7.6±4.6 years. There were 161 PNS events in 139/1,827 (7.6%) patients. The predominant events were peripheral neuropathy [66/161 (41.0%)], mononeuropathy [44/161 (27.3%)] and cranial neuropathy [39/161 (24.2%)] and the majority were attributed to SLE. Multivariate Cox regressions suggested longer time to resolution in patients with prior history of neuropathy, older age at SLE diagnosis, higher SLEDAI-2K scores, and for peripheral neuropathy versus other neuropathies. Neuropathy was associated with significantly lower SF-36 physical and mental component summary scores versus patients without NP events. By physician assessment, the majority of neuropathies resolved or improved over time and this was associated with improvements in SF-36 summary scores for peripheral neuropathy and mononeuropathy. Conclusion PNS disease is an important component of total NPSLE and has a significant negative impact on health related quality of life. The outcome is favourable for most patients, but several factors associated with longer time to resolution were identified. Disclosure of Interests John Hanly Consultant for: Eli Lilly Canada, Qiuju Li: None declared, Li Su: None declared, Murray B Urowitz Grant/research support from: GSK, Consultant for: BMS, Celgene, GSK, Lilly, UCB, Caroline Gordon Grant/research support from: Sandwell and West Birmingham Hospitals NHS Trust have received funding from UCB to support research work done by my research group that was unrelated to any pharmaceutical product or clinical trial., Consultant for: I have provided consultancy advice and taken part in scientific advisory boards on the design and analysis of clinical trials and the management of lupus for GSK, EMD Serono and UCB. I have taken part in adjudication and safety monitoring committees for BMS., Speakers bureau: I have been paid by UCB for speaking at meetings., Sang-Cheol Bae: None declared, Juanita Romero-Diaz: None declared, Jorge Sanchez-Guerrero: None declared, Sasha Bernatsky: None declared, Ann E Clarke: None declared, Daniel J Wallace: None declared, David Isenberg: None declared, Anisur Rahman: None declared, Joan T Merrill Grant/research support from: Genentech, UCB, GSK, EMD Serono, Pfizer, Celgene, Exagen, Bristol Myers Squibb, Medimmune/Astra Zeneca, Lilly, Amgen, Xencor, Neovacs, Consultant for: Genentech, UCB, GSK, EMD Serono, Pfizer, RemeGen, Celgene, Exagen, Bristol Myers Squibb, Medimmune/Astra Zeneca, Lilly, Immupharma, Amgen, Janssen, Sanofi, Neovacs, Anthera, Speakers bureau: UCB, GSK, EMD Serono, Bristol Myers Squibb, Medimmune/Astra Zeneca, Janssen, Paul Fortin: None declared, Dafna D Gladman Grant/research support from: AbbVie, Amgen, Celgene, Lilly, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Amgen, BMS, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, and UCB, Ian N. Bruce Grant/research support from: Genzyme Sanofi, GlaxoSmithKline, Consultant for: AstraZeneca, Eli Lilly, GlaxoSmithKline, ILTOO Pharma, MedImmune, Merck Serono, Speakers bureau: GlaxoSmithKline, UCB Pharma, Michelle A Petri Shareholder of: Pfizer, Merck, Grant/research support from: AstraZeneca, Exagen, Consultant for: Eli Lilly, GSK, Merck EMD Serono, Janssen, Amgen, Novartis, Quintiles, Exagen, Inova Diagnostics, AstraZeneca, Blackrock, Glenmark, UCB, and the Annenberg Center for Health Sciences, Ellen M Ginzler: None declared, M.A. Dooley: None declared, Kristjan Steinsson: None declared, Rosalind Ramsey-Goldman: None declared, Asad A Zoma: None declared, Susan Manzi: None declared, Ola Nived: None declared, Andreas Jonsen: None declared, Munther Khamashta: None declared, Graciela S Alarcon: None declared, Ronald F van Vollenhoven: None declared, Elisabet Svenungsson: None declared, Cynthia Aranow: None declared, Meggan Mackay: None declared, Guillermo Ruiz-Irastorza: None declared, Manuel Ramos-Casals: None declared, S. Sam Lim: None declared, Murat Inanc: None declared, Kenneth C Kalunian: None declared, Soren Jacobsen: None declared, Christine Peschken Consultant for: AstraZeneca, Diane L Kamen: None declared, Anca Askanase: None declared, Chris Theriault: None declared, Vernon Farewell: None declared

Objectives To analyse how the age at diagnosis modifies the phenotype of primary Sjogren syndrome (SS) Methods The Big Data Sjogren Project was formed in 2014 to take a “high-definition” picture of the main features of primary SS at diagnosis by merging international SS databases. By January 2019, the database included 11,420 patients from 24 countries of the 5 continents. Results Women (52.7 vs 54.6 yrs in men, p Patients with positive immunological markers had a younger diagnostic age, except for cryoglobulins (p Patients without systemic activity (ESSDAI score = 0) were diagnosed at an older age (55.5 vs 52.1 yrs in those with systemic activity, p Conclusion Age at diagnosis plays a key role in the glandular and systemic phenotype expressed by primary SjS patients at the time of diagnosis. Disclosure of Interests: Soledad Retamozo: None declared, Nihan Acar-Denizli: None declared, Wan Fai Ng: None declared, Ildiko Fanny Horvath: None declared, Astrid Rasmussen: None declared, Raphaele Seror Grant/research support from: Pfizer, Consultant for: Bristol-Myers Squibb, Pfizer, Amgen, Eli Lilly, Roche, Celgene, GlaxoSmithKline, MedImmune, Xiaomei Li: None declared, Chiara Baldini: None declared, Jacques-Eric Gottenberg Grant/research support from: Bristol-Myers Squibb, Grant/research support from: Bristol-Myers Squibb, Consultant for: Bristol-Myers Squibb, Lilly, Pfizer, Sanofi-Genzyme, UCB Pharma, Consultant for: Bristol-Myers Squibb, Eli Lilly, UCB, Sanofi-Genzyme, Pfizer, Pulukool Sandhya: None declared, Luca Quartuccio: None declared, Roberta Priori: None declared, Gabriela Hernandez-Molina: None declared, Berkan Armagan: None declared, Aike A. Kruize: None declared, Seung-Ki Kwok: None declared, Marika Kvarnstrom: None declared, Sonja Praprotnik: None declared, Damien Sene: None declared, Elena Bartoloni Bocci: None declared, Roser Solans-Laque: None declared, Maureen Rischmueller Consultant for: Abbvie, Bristol-Meyer-Squibb, Celgene, Glaxo Smith Kline, Hospira, Janssen Cilag, MSD, Novartis, Pfizer, Roche, Sanofi, UCB, Thomas Mandl: None declared, Yasunori Suzuki: None declared, David Isenberg: None declared, Valeria Valim: None declared, Agata Sebastian: None declared, Gunnel Nordmark: None declared, Hendrika Bootsma: None declared, Hideki Nakamura: None declared, Roberto Giacomelli Grant/research support from: Pfizer, Actelion, Speakers bureau: Actelion, Bristol-Myers Squibb, Merck Sharp & Dohme, Abbvie, Pfizer, Sobi, Roche, Valerie Devauchelle-Pensec Grant/research support from: Roche-Chugai, Speakers bureau: MSD, BMS, UCB, Roche, Benedikt Hofauer Consultant for: Consultant for Galvani Bioelectronics for the area of sleep disorders., Michele Bombardieri Grant/research support from: Celgene, Consultant for: Medimmune, Virginia Fernandes Moca Trevisani: None declared, Daniel Hammenfors: None declared, Sandra Pasoto: None declared, Tamer A Gheita: None declared, Fabiola Atzeni: None declared, Jacques Morel: None declared, Cristina Vollenveider: None declared, Sandra Consani-Fernandez: None declared, Xavier Mariette Grant/research support from: Servier, Consultant for: AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Pfizer, UCB Pharma, Manuel Ramos-Casals: None declared, Pilar Brito-Zeron: None declared

In this chapter an overview is provided of the investigations used in patients with systemic lupus erythematosus (SLE); these establish the abnormalities that can be found in each organ/system. Lupus is a very heterogeneous condition, affecting virtually every organ/system. In consequence, numerous investigations and tests are used to help make the diagnosis and define the extent of the organ/system involvement. The chapter is divided into investigations of the effects of SLE on the following systems: haematological, immunological, biochemical, renal, cardiovascular, pulmonary, gastroenterological, neurological, dermatological, and musculoskeletal. These targeted organ/system-based investigations can then be used to assess ongoing disease activity or the consequence of damage caused by previously active disease.

This chapter looks at the various biologic or target therapies that have been trialled and tested in the last two decades. The treatment of systemic lupus erythematosus (SLE) has progressed over the last few years due to an increased understanding of its pathogenesis; beginning with rituximab, one of the first biologics to be used, the chapter covers therapies up to the present day. Each subsection highlights the relevant mechanism of action which has led to new treatment options: anti-CD20 and 22, anti-B cell activating factors, anti-interferon alpha and anti-T cell activation. A summarized table is available providing a concise summary of the latest biologic therapies in treating SLE. The role of biologic therapies as monotherapy is still being defined, and with time there will be further change in the treatments available and the approach to the treatment of SLE using biologic therapies.

Systemic lupus erythematosus is a complex multisystem autoimmune disorder with a heterogeneous presentation and clinical course. The pathogenesis is multifactorial with evidence of genetic susceptibility, environmental triggers, and aberrancy in both the innate and adaptive immune systems. Although significant therapeutic advances have been made in recent decades, there remains a significant increase in mortality, highlighting the need for further understanding of the underlying immune mechanisms.

Shields, Vanessa E & Nicholas D J Baldwin, eds, 2008. Beyond Settlement: Making Peace Last After Civil Conflict. Madison-Teaneck, NJ: Fairleigh Dickinson University Press. 413 pp. ISBN 9780838641835

Since the approval of the chimeric anti-CD20 antibody rituximab for the treatment of adults with severe-to-moderate rheumatoid arthritis after an inadequate response to TNF blockade, B-cell depletion therapy has been used for the treatment of a broad range of refractory autoimmune disorders. Based on current experiences and a literature search, a systematic review and evaluation of the current status of B-cell depletion therapy in autoimmune diseases other than rheumatoid arthritis, including rheumatic, nephrologic, dermatologic and neurologic autoimmune entities, was performed by an international group of experts based at several academic centres. Although important questions remain about the value and place of B-cell depletion in autoimmune diseases other than RA, preliminary data indicate the value of this therapeutic approach in otherwise refractory patients. However, given the lack of robust data from large randomised controlled trials, anti-CD20 therapy should be considered on an individual basis in otherwise refractory patients and its use based on a risk/benefit net calculation.

Double-blind controlled trials undertaken over the past two decades have established the short-term effectiveness and side-effect profile of biologic drugs for patients with rheumatoid arthritis and related diseases. However, the development of biologics registers to capture 'real-life experience' and explore long-term effectiveness and complications is equally important. In this chapter, we demonstrate how these registers have identified long-term joint benefits, a reduction in cardiovascular mortality, reassurance concerning fears about cancer development, and a balanced view of the risk of infection.

Systemic lupus erythematosus (SLE) is characterized by an unpredictable and fluctuating course. Although various methods have been developed to measure disease activity, there is still a lack of consensus about the optimal criteria for SLE remission. The principal aim of our study was to identify the number of lupus patients achieving a complete remission (implying that for 3 years there were no clinical or serologic features and no treatment with steroids and immunosuppressive drugs) in a single cohort of patients followed for a period of up to 32 years. In addition, we have identified patients in clinical but not serologic remission (known as serologically active, clinically quiescent disease [SACQ]) and vice versa. We were particularly interested to determine the factors associated with complete remission.Eligible patients were followed up in the University College Hospital Lupus cohort from January 1978 until December 2010 for a period of at least 3 years. Complete remission was defined as a period of at least 3 years with clinical inactivity (British Isles Lupus Assessment Group scores of C, D, or E only) and laboratory remission (no antibodies to double-stranded DNA and normal complement C3 levels), and being off-treatment with corticosteroids and immunosuppressants. Antimalarial and nonsteroidal antiinflammatory drugs were allowed.Of 624 lupus patients at our hospital, a total of 532 patients met the strict inclusion criteria for the study. Of these 532 patients, 77 patients (14.5%) achieved complete remission for at least 3 years, and 23 (4.3%) achieved complete remission for a minimum period of 10 years. Ten of these 77 patients were subsequently lost to followup, and, interestingly, flares occurred subsequently in 15 of the 67 remaining patients (22.4%). Three patients relapsed after the tenth year of remission. Forty-five patients (8.5%) fulfilled the requirement for SACQ, and 66 patients (12.4%) achieved only serologic remission.Our study indicated that 14.5% of lupus patients achieved a complete remission for 3 years. However, flares may continue to occur beyond 10 years of remission. Long-term followup of SLE is therefore mandatory.

Polyreactive autoantibodies able to bind double-stranded DNA are a characteristic of systemic lucus erytheamtosus. Here, David Isenberg and Yehuda Shoenfeld discuss the likelihood that DNA is the immunogen in this disorder, and review a number of cross-reactions that may underline the detection of the antibodies.

Introduction The aim of this study was to examine the prevalence and functional effects of antibodies directed against Factor (F)Xa and other serine proteases (SP) in patients with antiphospholipid syndrome (APS). Methods Serum from patients with APS (n = 59), systemic lupus erythematosus (SLE; n = 106), other autoimmune rheumatic disease (ARD; n = 63) and 40 healthy controls (HC) were tested for IgG activity against thrombin (Thr), FXa, FVIIa, phosphatidylserine (PS)/FXa and antithrombin (AT)-III by enzyme-linked immunosorbent assay (ELISA). Anti-FXa positive IgG were purified to measure their avidity by chaotropic ELISA and functional effects upon clotting time (FXa-ACT) and FXa enzymatic activity (± AT-III). Results Anti-FXa IgG were found in patients with SLE (49.1%) and APS (33.9%) (P

Introduction IgG anti-apolipoprotein A-1 (IgG anti-apoA-1) antibodies are present in patients with systemic lupus erythematosus (SLE) and may link inflammatory disease activity and the increased risk of developing atherosclerosis and cardiovascular disease (CVD) in these patients. We carried out a rigorous analysis of the associations between IgG anti-apoA-1 levels and disease activity, drug therapy, serology, damage, mortality and CVD events in a large British SLE cohort. Methods Serum IgG anti-apoA-1 levels were measured in 100 healthy controls to define a cut-off for positivity. In 499 patients with SLE we obtained the earliest stored serum sample from their disease course and measured IgG anti-apoA-1 level. We then examined associations between IgG anti-apoA-1 positivity in early disease and the development of damage, CVD or death over a mean follow-up period of 12.1 years in these patients. In a separate study, we measured IgG anti-apoA-1 levels in 397 samples taken longitudinally from 49 patients with SLE over a mean period of 89 months of fluctuating disease activity and carried out multi-variable analysis to examine the demographic, serological, disease activity and treatment factors associated with IgG anti-apoA-1 level over time. Results In the longitudinal study, IgG anti-apoA-1 levels were significantly higher in patients with persistently active disease, those on high dose corticosteroid and those not taking hydroxychloroquine. Of the 499 subjects who had early disease IgG anti-apoA-1 levels measured, 135 (27%) were positive. However, we found no convincing associations between early IgG anti-apoA-1 positivity and development of damage, mortality or CVD. Conclusions IgG anti-apoA-1 developed early in a quarter of our patients with SLE, but this had no major impact on subsequent clinical outcomes. However, levels of IgG anti-apoA-1 vary over time and are associated with disease activity, treatment with high dose corticosteroid and not taking hydroxychloroquine.

Patients with autoimmune rheumatic diseases are more susceptible to infectious complications during the course of their disease. The introduction of biologics has been a major achievement in treating these diseases, but an increased risk of infection associated with these therapies has become evident. Some infections can be prevented by vaccination and it is clearly worthwhile considering which immunisations would be sensible and practicable for these patients. To date no formal specific recommendations for patients on biologics have been published. A search was made of Medline (via PubMed) from 1970 to January 2014 to provide results. This review aims to provide a systematic analysis of the data about vaccines and biologics and considers recommendations for vaccination in adult patients with autoimmune rheumatic diseases treated with biologics.

During the past 16 years, members of the British Isles Lupus Assessment Group (BILAG) have met on a regular basis and have been instrumental in devising a comprehensive disease activity index and, in association with others in the international rheumatological community, devising and/or testing damage and patients self-assessment indices. The history of what the BILAG group has achieved is set out here and the latest attempts at computerisation and improvements in the Disease Activity Index itself are described.

Double-blind controlled trials undertaken over the past two decades have established the short-term effectiveness and side-effect profile of biologic drugs for patients with rheumatoid arthritis and related diseases. However, the development of biologics registers to capture ’real-life experience’ and explore long-term effectiveness and complications is equally important. In this chapter, we demonstrate how these registers have identified long-term joint benefits, a reduction in cardiovascular mortality, reassurance concerning fears about cancer development, and a balanced view of the risk of infection.

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease with varied presentation and a disease course characterized by remission and flares. Over the last 50 years the prognosis of SLE has improved considerably. The introductions of corticosteroids and later of cytotoxic drugs, dialysis, and renal transplantation were the major contributors to this improvement. Nevertheless, the treatment and general management of lupus continues to present a challenge. While lupus may, for some patients, represent a relatively mild set of problems, many others require large doses of immunosuppressive drugs, which carry long-term concerns about side effects. New immunotherapeutic drugs, with actions more closely targeted to the immune cells and molecules involved in the pathogenesis of SLE, are being introduced and the future looks promising. The role of early atherosclerosis and cardiovascular disease as a cause of death in patients with SLE is increasingly recognized and will present further challenges in the future.

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease with varied presentation and a disease course characterized by remission and flares. Over the last 50 years, the prognosis of SLE has improved considerably. The introductions of corticosteroids and later of cytotoxic drugs, dialysis, and renal transplantation were the major contributors to this improvement. Nevertheless, the treatment and general management of lupus continues to present a challenge. While lupus may, for some patients, represent a relatively mild set of problems, many others require large doses of immunosuppressive drugs, which carry long-term concerns about side effects. New immunotherapeutic drugs, with actions more closely targeted to the immune cells and molecules involved in the pathogenesis of SLE, are being introduced and the future looks promising. The role of early atherosclerosis and cardiovascular disease as a cause of death in patients with SLE is increasingly recognized and will present further challenges in the future.

To present a pooled analysis of the efficacy of rituximab from European cohorts diagnosed with biopsy-proven lupus nephropathy (LN) who were treated with rituximab.Consecutive patients with biopsy-proven LN treated with rituximab in European reference centers were included. Complete response (CR) was defined as normal serum creatinine with inactive urinary sediment and 24-hour urinary albumin0.5 g, and partial response (PR) as a50% improvement in all renal parameters that were abnormal at baseline, with no deterioration in any parameter.164 patients were included (145 women and 19 men, with a mean age of 32.3 years). Rituximab was administered in combination with corticosteroids (162 patients, 99%) and immunosuppressive agents in 124 (76%) patients (cyclophosphamide in 58 and mycophenolate in 55). At 6- and 12-months, respectively, response rates were 27% and 30% for CR, 40% and 37% for PR and 33% for no response. Significant improvement in 24-h proteinuria (4.41 g. baseline vs 1.31 g. post-therapy, p=0.006), serum albumin (28.55 g. baseline to 36.46 g. post-therapy, p0.001) and protein/creatinine ratio (from 421.94 g/mmol baseline to 234.98 post-therapy, p0.001) at 12 months was observed. A better response (CR+PR) was found in patients with type III LN in comparison with those with type IV and type V (p=0.007 and 0.03, respectively). Nephrotic syndrome and renal failure at the time of rituximab administration predicted a worse response (no achievement of CR at 12 months) (p0.001 and p=0.024, respectively).Rituximab is currently being used to treat refractory systemic autoimmune diseases. Rituximab may be an effective option for patients with lupus nephritis, especially those refractory to standard treatment or who experience a new flare after intensive immunosuppressive treatment.