8th ANNUAL MEETING OF THE LUPUS ACADEMY, Warsaw, Poland, September 6–8, 2019
Name: 8th ANNUAL MEETING OF THE LUPUS ACADEMY, Warsaw, Poland, September 6–8, 2019
Latest articles from this conference
Published: 5 September 2019
Plenary II: Novel Therapeutic Approaches to Improve Clinical Outcomes, Volume 6; doi:10.1136/lupus-2019-la.14
It is almost 20 years since B-cell depletion using rituximab [anti CD20] was introduced for the treatment of systemic lupus erythematosus (SLE).1 Despite the failure of two major clinical trials2 both the ACR and EULAR guidelines recommend rituximab for the treatment of lupus nephritis and NHS England permits its use more widely. Well over 50,000 SLE patients worldwide have been treated with rituximab and it seems to be very effective for many haematological, musculoskeletal, dermatological and renal aspects of lupus.3 Increased risk of infection and hypogammaglobinaemia remain concerns.4 Newer fully-humanized anti-CD20 monoclonal antibodies (e.g. ofatumumab) offer a way forward for those who become allergic to rituximab, which is 20% murine. Research indicates that there are at least two types of anti-CD20 antibodies. In contrast, anti-plasma cell therapies have been much less widely utilized. Some studies using bortezomib (anti-proteasome) have been reported5 and studies with experimental anti CD19 monoclonals are under way. Although significant reductions in autoantibodies (and immunoglobulins) and a rise in serum complement have been noted, precursor B-cells and T-cells largely remain unaffected resulting in a rapid re-population of short-lived plasma cells. This result suggests that this approach will need to be combined with other B-cell therapies. Learning objectives Describe the role anti–CD20 antibodies in the treatment of SLE Explain the benefits of rituximab and ofatumumab for patients with SLE Discuss utilization of proteasome inhibitors, such as bortezomib, for the treatment of SLE References Leandro MJ, Edwards JC, Cambridge G, et al. An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis & Rheumatism 2002;46(10):2673–77. Ramos L, Isenberg D. Rituximab: the Lupus Journey. Current Treatment Options in Rheumatology 2015;1(1):30–41. Murphy G, Isenberg DA. New therapies for systemic lupus erythematosus — past imperfect, future tense. Nature Reviews Rheumatology 2019;15(7):403–12. Hennessey A, Lukawska J, Cambridge G, et al. AB0443 Infusion reactions to rituximab in systemic lupus erythematosus: a retrospective analysis. Annals of the Rheumatic Diseases 2017;76(Suppl 2):1205–05. Alexander T, Cheng Q, Klotsche J, et al. Proteasome inhibition with bortezomib induces a therapeutically relevant depletion of plasma cells in SLE but does not target their precursors. European Journal of Immunology 2018;48(9):1573–79.
Workshop, Volume 6; doi:10.1136/lupus-2019-la.11
Case 1: 27-year-old female with a 5-year history of SLE Richard Furie A 27-year-old female with a 5-year history of systemic lupus erythematosus (SLE) was admitted to the hospital because of confusion and fever. Past manifestations of SLE included polyarthritis, rash, recurrent episodes of pericarditis, and anaemia (but no nephritis). A flare 2 months prior to admission, consisting of pericarditis, fever, hypocomplementaemia, and a 2-fold rise in anti-DNA antibodies, was successfully treated with prednisone 40 mg/day; prednisone was subsequently tapered. At the time of admission, medicines included hydroxychloroquine 400 mg/day, prednisone 15 mg/day, calcium, and a vitamin. The patient was given broad-spectrum antibiotics for the treatment of sepsis and/or bacterial meningitis. Methylprednisolone 60 mg/day was also administered. However, the patient’s mental status worsened, and she became comatose. All cultures were sterile. Her creatinine, which was 0.6 mg/dL at baseline, rose 3-fold. The impression was that of a flare of SLE complicated by anaemia, thrombocytopaenia, nephritis and CNS disease. ‘Pulse’ steroids were administered for 3 days without subsequent improvement. Intravenous gamma-globulin failed to improve the thrombocytopenia, and her creatinine continued to rise. Discussion points Diagnosis and treatment of thrombotic microangiopathy (TMA) Proposed modifications to the classification of lupus nephritis Learning objectives Describe the clinical presentation of TMA Discuss treatment options of TMA Review proposed modifications to the classification of lupus nephritis Case 2: 16-year-old male with active SLE, trace protein and hematuria Dimitrios Boumpas A 16-year-old male (60 kg) presents with active SLE (SLEDAI 10). He has active serology with low C3 and C4, anti-DNA is positive at low titer. Normal Cr, albumin and HCT. Urinalysis shows trace protein (300 mg/dL) with 510 RBCs in the urine. He was treated with hydroxychloroquine and prednisone 20 mg/day and was referred to you 4 weeks later. His SLEDAI is now 4 (rash, serology) and urinalysis shows trace protein and hematuria. Discussion points Identify patients at higher risk to develop nephritis and look for renal disease -especially when active- by urinalysis Do not underestimate hematuria-especially if active serology and extrarenal lupus. Best to do a biopsy irrespective of the presence or not of proteinuria Have a low threshold for renal biopsy. If you think about it, just do it (unless contraindicated) Look for crescents/fibrinoid necrosis and tubular atrophy and interstitial fibrosis in the biopsy report Stratify according to severity (histologic and clinical factors) and treat accordingly. For most patients mycophenolate mofetil (MMF) is the drug for initial choice based upon its lack of gonadal toxicity In patients with chronic disease and scaring in the kidney, or those with nephrotic range proteinuria, may need to wait longer for proteinuria to subside Proteinuria is a good prognostic factor (if below 0.7 mg/dl) irrespective of hematuria Hematuria/active urine sediment are reliable indicators for activity and flare but not for prognosis Case 3: 25-year-old woman with arthritis, photosensitive rashes, leukopenia and thrombocytopenia and positive lupus serologies A 25-year-old woman presents with arthritis, photosensitive rashes, leukopenia and thrombocytopenia and positive lupus serologies. Her proteinuria is 1.3 gm/day and she has hematuria, normal serum creatinine and albumin 3.2g/day. Renal biopsy showed focal proliferative lupus nephritis (Class IIIa with AI 7 and CI 0). She was treated with MMF and then with azathioprine because of contemplation of pregnancy reaching remission. Two years later she has nephrotic range proteinuria, increased creatinine to 1.4 mg/dl, and a biopsy consistent with pure membranous lupus nephropathy. No chronicity. Discussion points Membranous nephropathy has a more benign course. Histologic transition may be observed Patients with nephrotic range proteinuria and impaired renal function are at greater risk for end stage renal disease and require more aggressive therapy Anticoagulant treatment in cases of nephrotic syndrome with serum albumin
Roundtable: Treatment Challenges, Volume 6; doi:10.1136/lupus-2019-la.21
Compared to proliferative lupus nephritis (PLN), membranous lesions are less inflammatory, have a more benign course, require less aggressive therapy, and have better prognosis.1 The 2012 EULAR/EDTA recommendations for lupus nephritis2 were recently updated (Fanouriakis A, et al 2019 to be submitted). Goals of therapy Optimisation (preservation or improvement) of renal function with at least 25% reduction in proteinuria at 3 months, 50% at 6 months and a urine protein/creatinine ratio (UPCR) target below 0.5–0.7 mg/g by 12 months (complete renal response). Initial therapy Glucocorticoids and immunosuppression if UPCR exceeds 1 mg/g despite the optimal use of renin-angiotensin-aldosterone system blockers, or from the beginning when nephrotic-range proteinuria is present. In pure Class V nephritis, mycophenolate mofetil (MMF) (dose 2–3 g/day; or mycophenolic acid [MPA] at equivalent dose) in combination with pulses IV methylprednisolone (total dose 500–2500 mg) followed by oral prednisone (20 mg/day, tapered to ≤5 mg/day by 3 months) can be used as initial treatment based on better efficacy/toxicity ratio. Alternative options include high-dose IV cyclophosphamide (0.5–0.75 g/m2 monthly for 6 months), calcineurin inhibitors (ciclosporin, tacrolimus) or their combination with MMF/MPA, particularly in patients with severe nephrotic syndrome. Subsequent therapy MMF/MPA (dose: 1–2 g/day) – especially if it was used as initial treatment – or azathioprine (AZA); 2 mg/kg/day – preferred if pregnancy is contemplated – for at least 3 years, in combination with low-dose prednisone (2.5–5 mg/day) when needed. If sustained complete response, gradual drug withdrawal, glucocorticoids first, can then be attempted, with immunosuppressives following after 3–5 years in complete response. Continuation, switching or addition of calcineurin inhibitors can be considered in pure Class V nephritis at the lowest effective dose taking into consideration the possibility for nephrotoxicity. Refractory disease Treatment may be switched to one of the alternative initial therapies mentioned above or rituximab (1000 mg on days 0 and 14). In a recent randomised controlled trial of rituximab in idiopathic membranous nephropathy, rituximab was equal to cyclosporine in achieving remission at 12 months (60% vs 52%) but superior to cyclosporine in maintaining remission at 24 months (60% vs 20%).3 Adjunct therapy ACE-inhibitors or angiotensin receptor blockers for patients with UPCR >0.5 mg/g or hypertension. Antilipidemics and hydroxychloroquine at a dose not to exceed 5 mg/kg/day. Anticoagulant treatment in cases of nephrotic syndrome with serum albumin
Programme, Volume 6; doi:10.1136/lupus-2019-la.prog
Hot Topic Lecture, Volume 6; doi:10.1136/lupus-2019-la.7
Recently, recommendations for the management of antiphospholipid syndrome (APS) in adults were published by the European League Against Rheumatism based on evidence from a systematic literature review and expert opinion.1 The antiphospholipid antibody (aPL) type, the presence of multiple (double or triple) versus single aPL type, their titre (moderate-high titre versus low titre) and the persistence of aPL positivity in repeated measurements are defined as the ‘ aPL profile’. The aPL profile is an important factor determining the risk of thrombotic and obstetric events, and consequently the intensity of treatment. The presence of aPL in asymptomatic individuals or patients with systemic lupus erythematosus (SLE) does not confirm the diagnosis of APS but can be associated with increased risk of thrombosis or pregnancy morbidity, depending on aPL characteristics and coexistence of other risk factors.2 Low dose aspirin (LDA) is recommended for asymptomatic aPL carriers, patients with SLE without prior thrombotic or obstetric APS, and non-pregnant women with a history of obstetric APS only, all with high- risk aPL profile. Immunosuppressive drugs plus steroids do not protect against recurrent thrombosis in APS. Patients with APS and first unprovoked venous thrombosis should receive long-term treatment with vitamin k antagonists (VKA) with a target international normalized ratio (INR) of 2.0–3.0. In patients with APS, with first arterial thrombosis, treatment with VKA with INR 2.0–3.0 or 3.0–4.0 is recommended, considering the individual’s bleeding/thrombosis risk. In all cases treatment should be continued even if the patient becomes aPL negative. Direct oral anticoagulants (DOACs) could be considered in APS patients with venous thrombosis who are not able to achieve a target INR despite good adherence to VKA or those in whom VKA is contraindicated (e.g. allergy or intolerance to VKA).3 Rivaroxaban should not be used in patients with APS with triple aPL positivity.4 Based on the current evidence, the use of DOACs in patients with APS and arterial events is not recommended due to the high risk of recurrent thrombosis. For patients with recurrent arterial or venous thrombosis despite adequate treatment, addition of LDA, increase of INR target to 3.0–4.0 or switch to low molecular weight heparin may be considered. Other potential strategies for refractory APS cases include rituximab and hematopoietic stem cell transplantation. Thrombocytopenia is not rare in APS and is mostly mild, not requiring intervention. Bleeding is uncommon in these patients and it is important not to stop VKA therapy because low platelet counts do not protect against thrombosis. Careful monitoring is advocated for mild-moderate thrombocytopenia, and corticosteroids are recommended for severe cases. In women with prior obstetric APS, combination treatment with LDA and prophylactic dosage heparin during pregnancy is recommended. In patients with recurrent pregnancy complications, increased heparin to therapeutic dose, addition of hydroxychloroquine or addition of low dose prednisolone in the first trimester may be considered. Use of intravenous immunoglobulin might be considered in highly selected cases. Patients with APS still develop significant morbidity and mortality despite current treatment. It is imperative to increase the efforts in determining optimal prognostic markers and therapeutic measures to prevent these complications.5 Learning objectives Discuss data that support treatment decisions for APS References Tektonidou MG, Andreoli L, Limper M, et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Annals of the Rheumatic Diseases 2019:annrheumdis-2019–215213. Uthman I, Noureldine MHA, Ruiz-Irastorza G, et al. Management of antiphospholipid syndrome. Ann Rheum Dis 2019;78(2):155–61. Cohen H, Hunt BJ, Efthymiou M, et al. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. The Lancet Haematology 2016;3(9):e426–36. Pengo V, Denas G, Zoppellaro G, et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood 2018;132(13):1365–71. Cervera R, Serrano R, Pons-Estel GJ, et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis 2015;74(6):1011–8.
Keynote Lecture, Volume 6; doi:10.1136/lupus-2019-la.17
It is widely acknowledged that we need better biomarkers for management of patients with systemic lupus erythematosus (SLE). While many have been proposed, few new markers have yet made it into clinical practice due to lack of robust validation studies. Historically, antibody titres, complement proteins, immunoglobulin titres and acute phase markers are widely used in clinical practice, although the evidence base and utility of these is also limited. The need for better biomarkers was highlighted in the recent EULAR guidelines for the management of SLE and for treating to target and it is worth considering these guidelines for questions that biomarkers should answer, and appropriate endpoints for clinical validation.1 In the EULAR guidelines for management of SLE a research agenda emphasised the need to predict susceptibility to develop SLE, involvement of particular organ systems over others, and response to specific therapeutic agents over others.1 Several of the 2014 EULAR treat to target guidelines suggest the need for biomarkers too.2 For example: prevention of flares is an objective that would be easier to meet if these could be predicted. Glucocorticoid tapering or withdrawal is recommended, but this may be difficult if we cannot predict which patients would flare. Finally, these guidelines state that treatment should not be escalated based on solely on persistent serological activity, highlighting the weakness of routinely used biomarkers. In clinical validation studies, like outcome measures, biomarkers must be shown to demonstrate truth (e.g. they measure what they say they measure), discrimination (e.g. classifying patients correctly and predicting prognosis), and feasibility (e.g. use of standard samples types, transportation and reliable assays in clinically accredited laboratories). Additionally for biomarkers, there may be issues of pre-analytic validation. Some of the most promising biomarkers in the field of SLE measure type I interferon (IFN) activity. type I IFN (i.e. IFN alpha, beta, kappa, epsilon and omega) are known to be important in lupus based on genetic susceptibility data. They are difficult to measure directly in serum due to binding to the abundant IFNAR receptor, and non-circulating sources. Instead, most assays measure cellular responses. The best validated of these measure expression of a set of genes known to respond to Type I IFN – an ‘interferon signature’. Interferons are a complex system with many different ligands and responder cells. Recent data have shown that IFN stimulated genes cluster into subgroups with different clinical significance, rather than a single ‘interferon signature’. This may improve their clinical utility. Gene expression assays for interferon have helped to stratify therapies that target interferon, and other therapeutic targets. These assays also predict clinical flares, glucocorticoid use. More recently, it has been shown that interferon scores can predict onset of SLE.3 In this latter work, the separation of interferon-stimulated genes into subgroups was crucial. The measurement of IFN-I status using whole blood IFN stimulated gene (ISG) expression has two key weaknesses in interpreting pathogenic processes. First, changes in expression may reflect expansion or contraction of certain circulating leukocyte populations that differ in their level of ISG expression.4 This characteristically occurs in inflammatory diseases. In the case of SLE, lymphopenia is almost universally seen.4 So any difference in whole blood gene expression may not necessarily indicate a change in production or exposure to IFN-I. Second, analysing whole blood ISG expression does not allow detection of key pathogenic processes among the noise of other, less relevant, effects of IFN-I on biology. For example, B cells are a key mediator in SLE. In these respects, flow cytometric biomarkers, such as memory B cell tetherin, may be advantageous, as they indicate the response to interferon in a particular cell type. Another important area of biomarkers that also uses flow cytometry is monitoring of B cell numbers after rituximab therapy. It was initially thought that rituximab induced complete B cell depletion, which left the explanation for poor clinical responses unclear, and left no biomarker to guide retreatment decisions. These assumptions were reversed by assays optimised to reliably measure plasmablasts in a routine clinical context as well as other B cell subsets in lower numbers. Plasmablasts have low expression of CD20 and are not directly killed by rituximab. They have a short half-life in the circulation, so their continued presence in the absence of other B cell subsets after rituximab may indicate ongoing B cell activity in other tissues. Such ‘highly sensitive flow cytometry’ studies demonstrated first that B lineage cell depletion was often incomplete in non-responders, which has ultimately led to trials of more intensive B cell depletion therapies. Further, plasmablast repopulation has been shown to be a predictor of impending relapse after rituximab in several studies. Other biomarkers with evidence of clinical validation include cell-bound complement, which may offer advantages of soluble complement product assays, other gene expression signatures, such as plasmablast and neutrophil signatures, and serum proteins, some of which may reflect interferon status. The challenge in future years will be to harmonise measurement of these biologic parameters and implement into clinical practice. Learning objectives Describe the need for better biomarkers in SLE Explain how better understanding of IFN and SLE disease expression will improve patient outcomes Discuss the potential challenges of measuring biologic parameters in clinical practice References Fanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis...
Published: 5 September 2019
Plenary I: Lupus Manifestations and Comorbidities: How Have Our Strategies Improved?, Volume 6; doi:10.1136/lupus-2019-la.6
Patients with systemic lupus erythematosus (SLE) manifest increased frequency of several comorbidities, particularly cardiovascular diseases, infections, osteoporosis and fragility fractures, and also, malignant disorders such as lymphoma.1 Comorbid diseases may develop both early and later during the course of the disease due to complex interaction between lupus inflammation and administered treatments, especially glucocorticoids. Their prevention, early diagnosis and management is of great importance to ensure favourable long-term patient outcomes, as highlighted in the 2019 Update of the EULAR recommendations for the management of SLE.2 Despite extensive research, there is paucity of controlled studies to guide the treatment of comorbidities in SLE patients, and it remains elusive whether therapeutic goals (e.g. target levels of serum LDL-cholesterol) in SLE should be different than those in the general population. The increased cardiovascular disease (CVD) burden seen in SLE patients emphasizes the need for primary prevention strategies cardiovascular disease. This includes the use of validated CVD risk prediction tools (e.g. Framingham Risk Score, Systematic COronary Risk Evaluation (SCORE), QRISK2), which however tend to underestimate the actual risk in patients with SLE.3 The role and indications in clinical practice for non-invasive modalities for assessing subclinical atherosclerosis (e.g. coronary artery assessment, carotid intima media thickness) is less clear.4 General non-pharmacological interventions include smoking cessation, avoidance of sedentary lifestyle and maintenance of ideal body mass index. High blood pressure should be adequately controlled preferentially with renin-angiotensin-aldosterone axis blockade, and dyslipidemia be treated with statins. Aspirin may be considered in SLE patients with high-risk antiphospholipid antibodies profile and/or high estimated CVD risk after careful evaluation of the bleeding risk.5 At the chronic maintenance stage, the dose of glucocorticoids should be minimized to less than 7.5 mg/day of prednisone equivalent. Importantly, hydroxychloroquine should be considered – unless contraindicated – in all cases due to its putative atheroprotective role.6 Infections and sepsis represent another important comorbidity associated with increased risk for hospitalization and death in patients with SLE.7 Application of general preventative strategies such as hygiene measures and immunizations cannot be overemphasized.8 Modification of SLE-related risk factors such as reduction of exposure to glucocorticoids and avoidance of treatment-related leukopenia/neutropenia are important.9 High-intensity immunosuppressive (high-dose azathioprine, mycophenolate, cyclophosphamide) or biologic (rituximab) therapies have also been associated with increased risk for infections, especially when used in combination with moderate or high doses of glucocorticoids10 11. Pre-emptive use of antibiotics is not recommended, nevertheless a low index of suspicion to diagnose an infection – including possible Pneumocystis pneumonia12 – and commence antibiotics promptly is warranted in high-risk groups including elderly or neutropenic patients, those with comorbidities (e.g. diabetes) or who are receiving glucocorticoids. Osteoporosis and fragility fractures are potentially avoidable and readily treated comorbidities in patients with SLE.13 14 Factors impacting adversely on bone mass density, particularly chronic use of glucocorticoids, should be corrected.15 Osteoprotective and/or anti-osteoporotic interventions should be similar to those in the general population or patients with other chronic inflammatory disorders, yet caution is recommended in cases of kidney disease and reduced glomerular filtration rate. To this end, SLE patients should also be screened for vitamin D insufficiency, which should be corrected considering its presumed multifaceted effects on the disease.16 Learning objectives Describe primary prevention strategies for SLE comorbidities including cardiovascular disease, infection and osteoporosis Explain screening and treatment options for key comorbid diseases in patients with SLE References Gonzalez LA, Alarcon GS. The evolving concept of SLE comorbidities. Expert review of clinical immunology 2017;13(8):753–68. Fanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Annals of the rheumatic diseases2019;78(6):736–45. Hippisley-Cox J, Coupland C, Brindle P. Development and validation of QRISK3 risk prediction algorithms to estimate future risk of cardiovascular disease: prospective cohort study. BMJ2017;357:j 2099. Wu GC, Liu HR, Leng RX, et al. Subclinical atherosclerosis in patients with systemic lupus erythematosus: A systemic review and meta-analysis. Autoimmunity reviews 2016;15(1):22–37. Zheng SL, Roddick AJ. Association of Aspirin Use for Primary Prevention With Cardiovascular Events and Bleeding Events: A Systematic Review and Meta-analysis. JAMA 2019;321(3):277–87. Fasano S, Pierro L, Pantano I, et al. Longterm Hydroxychloroquine Therapy and Low-dose Aspirin May Have an Additive Effectiveness in the Primary Prevention of Cardiovascular Events in Patients with Systemic Lupus Erythematosus. The Journal of rheumatology 2017;44(7):1032–38. Tektonidou MG, Wang Z, Dasgupta A, et al. Burden of Serious Infections in Adults With Systemic Lupus Erythematosus: A National Population-Based Study, 1996–2011. Arthritis care & research 2015;67(8):1078–85. van Assen S, Agmon-Levin N, Elkayam O, et al. EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Annals of the rheumatic diseases 2011;70(3):414–22. Danza A, Ruiz-Irastorza G. Infection risk in systemic lupus erythematosus patients: susceptibility factors and preventive strategies. Lupus...
Roundtable: Treatment Challenges, Volume 6; doi:10.1136/lupus-2019-la.19
Twenty to thirty percent of patients with systemic lupus erythematosus (SLE) patients experience a disease flare each year. Official definitions are available: The most used are based on physician decisions to change treatment; if treatment is added or escalated, that defines flare. Much research has focused on detecting flares before symptoms occur. The most effective and available is a decline in serum complement levels (C3 or C4), which often precedes symptoms; a recent study showed falling complement has a positive predictive value of 0.74 (very good) and a negative predictive value of 0.90 (excellent).1 Other biomarkers include rising titers of anti-dsDNA, falling platelet counts and for nephritis increase in proteinuria and appearance of red blood cells in the urine. Other blood markers, less available but probably better, include increased proportions of activated monocytes and naïve B cells, increases in levels of serum cytokine/chemokines ICAM-1 and IP-10, and increased numbers of RBC, platelets or B cells binding the complement split product, C4d. Several urinary biomarkers are likely to predict flares of nephritis, including MCP, NGAL and TWEAK, but these are not consistent across studies. As soon as symptoms of flare begin, the patient saying s/he is flaring is the best sign and is usually accompanied by changes in the laboratory values associated with that individual, such as falling platelet, WBC or RBC counts, increase in proteinuria, rising erythrocyte sedimentation rate, etc. Prevention of flare is a major goal of therapy and the effective treatments that induce improvement also reduce flare rates, including hydroxychloroquine, glucocorticoids, cyclophosphamide, mycophenolate, azathioprine, belimumab, rituximab, and calcineurin inhibitors. The physician must also rule out other causes of the ‘flare’ that are NOT SLE. In my experience, fever in an SLE patient is more often a sign of infection than of lupus flare (presence of shaking chills and of very high levels of C-reactive protein are more likely in infection); the urinary tract is the most common source of infection, followed by upper respiratory tract infection and pneumonia, septicemia is also common.2 3 Appropriate cultures should be obtained before escalating immunosuppression. Risk of infection will be lower if the patient has received all appropriate immunisations and is taking preventive medications while immunosuppressed. Similarly, ischemia of heart, brain, gastrointestinal tract can result from clotting with or without vasculitis, and you may consider anticoagulation while evaluating for active SLE. Serositis can result from uremia. When the physician decides SLE is flaring there are several approaches that suppress flare; probably the quickest is to give an intramuscular dose of long-acting glucocorticoid, such as 40–80 mg of triamcinolone acetonide or 20–40 mg of methylprednisolone acetate, which usually suppresses flare and lasts 2–4 weeks. If flare recurs, increase the daily glucocorticoid dose (patients often do this themselves – before consulting the physician). If there is still disease activity and you cannot taper prednisolone/prednisone to less than 10 mg daily, increase immunosuppression, either by increasing dose of immunosuppressive being given (e.g. azathioprine) or adding a new immunosuppressive.4 During this time, consider whether the patient is compliant with the regimen you established prior to flare: Compliance (defined as taking the medication as directed 80% of the time) occurs in only 50–70% of SLE patients: Poor compliance is associated with young patients, those with poor social and economic support systems, less educated, and those with strong beliefs in adverse effects of Western medications and/or utility of other healing approaches.5 I may choose to use intravenous medications in situations such as these. Most SLE patient use complementary supplements: Those that should be discouraged include St John’s wort, which interferes with metabolism of many drugs. Vitamin D levels should be normalised. N-acetylcysteine, polyphenols, omega-3 fatty acids, fish oil and thundervine herb may all have benefits but have not reached general acceptance in the medical community. Since the number of SLE flares is strongly correlated with damage to many body systems, with poor quality of life, and with most of the causes of death of SLE patients, physicians and other caregivers are obligated to identify SLE flares early and suppress them. Learning objectives Differentiate between infection and flare in patients with SLE Describe key biomarkers associated with SLE flare Explain how best to differentiate infection from SLE flare References Parker B, Bruce I. Clinical markers, metrics, indices and clinical trials. Dubois’ Lupus Erythematosus and Related Syndromes. 9th edition, Wallace D and Hahn B eds: Elsevier, 2019. Ospina FE, Echeverri A, Zambrano D, et al. Distinguishing infections vs flares in patients with systemic lupus erythematosus. Rheumatology (Oxford, England) 2017;56(suppl_1):i46-i54. Fanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis 2019;78(6):736–45. Lu R, Guthridge JM, Chen H, et al. Immunologic findings precede rapid lupus flare after transient steroid therapy. Scientific reports 2019;9(1):8590–90. Costedoat-Chalumeau N, Houssiau F, Izmirly P, et al. A Prospective International Study on Adherence to Treatment in 305 Patients With Flaring SLE: Assessment by Drug Levels and Self-Administered Questionnaires. Clinical pharmacology and therapeutics 2018;103(6):1074–82.
Published: 5 September 2019
Debate: New developments in Basic Science and Clinical Research: Defining SLE, Volume 6; doi:10.1136/lupus-2019-la.2
Systemic lupus erythematosus (SLE) is a complex disease characterised by a wide range of clinical manifestations and autoantibodies and virtually any manifestation is considered to be possible in patients with SLE. Classically the disease has a relapsing remitting course and is characterised by damage accrual, increased morbidity and mortality, comorbidities. Early recognition of the disease could allow early intervention, prevent damage accrual and improve long term outcomes. However, the disease onset may be insidious, with clinically evident disease developing over years, and this can delay both the diagnosis and the classification of SLE; in addition some patients presenting with signs and symptoms of systemic autoimmune diseases will never develop SLE but will remain undifferentiated over time (UCTD, undifferentiated connective tissue diseases). Finally many different conditions may mimic SLE. Classification is required to include patients in clinical trials and these difficulties suggest the need for classification criteria able to classify early disease. The existing classification criteria (ACR and SLICC) appear to have a lower specificity in early disease, with an increase after 5 years of disease. New classification criteria for SLE have been developed to define a threshold above which experts could classify SLE for the purpose of research.1-4 Clinical and serological characteristics of early SLE patients compared with mimicking diseases, were identified to inform the development of these criteria with the specific aim to develop classification criteria able to capture patients in the early disease. Learning objectives Describe the variability of the clinical picture of SLE and describe the characteristics of early SLE Highlight the difficulties for early diagnosis of SLE Differentiate early SLE from mimicking conditions Discuss the development of the new EULAR/ACR criteria and their performance in early SLE References Johnson SR, Khanna D, Daikh D, et al. Use of Consensus Methodology to Determine Candidate Items for Systemic Lupus Erythematosus Classification Criteria. J Rheumatol 2019;46(7):721–26. Tedeschi SK, Johnson SR, Boumpas DT, et al. Multicriteria decision analysis process to develop new classification criteria for systemic lupus erythematosus. Ann Rheum Dis 2019;78(5):634–40. Mosca M, Costenbader KH, Johnson SR, et al. Brief Report: How Do Patients With Newly Diagnosed Systemic Lupus Erythematosus Present? A Multicenter Cohort of Early Systemic Lupus Erythematosus to Inform the Development of New Classification Criteria. Arthritis & rheumatology (Hoboken, NJ) 2019;71(1):91–98. Tedeschi SK, Johnson SR, Boumpas D, et al. Developing and Refining New Candidate Criteria for Systemic Lupus Erythematosus Classification: An International Collaboration. Arthritis care & research 2018;70(4):571–81.
Roundtable: Treatment Challenges, Volume 6; doi:10.1136/lupus-2019-la.20
Discoid lupus erythematosus (DLE) is the most common form of chronic cutaneous lupus erythematosus (CCLE) and occurs as localised form (ca. 80%) or disseminated/generalized form (ca. 20%). The localised form presents with lesions on the face and scalp, especially the cheeks, forehead, ears, nose, and upper lip, whereas the generalized form presents with lesions involving the upper part of the trunk and the extensor aspects of the extremities.1 The lesions of DLE consist of sharply-demarcated, coin-shaped (‘discoid’) indurated erythematous plaques with adherent follicular hyperkeratosis.2 During the course of the disease the lesions may expand at the periphery with an active erythematous border and hyperpigmentation, resulting in atrophy, scarring, telangiectasia and hypopigmentation in the center of the lesions. At the scalp, eyebrows and bearded regions of the face, DLE can progress to total, irreversible scarring alopecia. In the perioral region, the lesions can lead to characteristic pitted acneiform (‘vermicular’) scarring.3 Mucosal DLE presents with chronic buccal plaques, showing typical roundish lesions with peripheral white hyperkeratotic striae and central atrophy, erosion or ulceration. Exposure to the sun or irritating stimuli (‘Koebner phenomenon’), such as trauma, can provoke or exacerbate the disease.4 DLE lesions occur in approximately 15–25% of patients in the course of SLE, but more than 95% of patients with DLE lesions suffer from cutaneous disease only. First-line treatment options in DLE include topical corticosteroids or calcineurin inhibitors; in patients with disfiguring and widespread disease, systemic agents need to be applied.5 The first-line systemic treatment is antimalarials, but some patients are therapy-resistant and immunosuppressive agents, such as methotrexate or mycophenolate mofetil, are used as alternative therapeutic option. The monoclonal antibody belimumab, which is approved for SLE as an adjunct therapy for patients with autoantibody-positive disease who despite standard therapy show high disease activity, may be effective, but needs to be evaluated using validated skin scores. Learning objectives Describe the different types of skin manifestations in DLE Explain the preventive strategies for DLE including photoprotection Discuss the topical and systemic treatment options for DLE References Costner M, Sontheimer R, Provost T. Lupus erythematosus. In: Sontheimer R, Provost T, eds. Cutaneous manifestations of rheumatic diseases. Philadelphia: Williams & Wilkins, 2003. Kuhn A, Landmann A, Bonsmann G. Cutaneous lupus erythematosus. In: GC T, ed. Systemic Lupus Erythematosus. 1st ed. Amsterdam: Systemic Lupus Erythematosus, 2016:333–40. Chang YH, Wang SH, Chi CC. Discoid lupus erythematosus presenting as acneiform pitting scars. International journal of dermatology 2006;45(8):944–5. Ueki H. Koebner phenomenon in lupus erythematosus with special consideration of clinical findings. Autoimmun Rev 2005;4(4):219–23. Kuhn A, Aberer E, Bata-Csorgo Z, et al. S2k guideline for treatment of cutaneous lupus erythematosus - guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV). Journal of the European Academy of Dermatology and Venereology : JEADV 2017;31(3):389–404.