Systemic Lupus Erythematosus E-Book: A Companion to Rheumatology: Companion to Rheumatology 3r.e.

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Average age of diagnosis The presence of aCL-IgM antibodies was associated with non-thrombotic manifestations. There were no significant differences in the recurrence of thrombosis between primary APS or associated with another autoimmune disease, nor association with positivity of autoantibodies. Conclusions: APS generates an important morbidity in pediatrics and should be considered as a cause of thrombosis in children, even in the absence of other autoimmune diseases.

Therefore, validated criteria for pediatric patients that consider APS not necessarily as a thrombotic disease should be developed. Di Genaro 1,2 , E. Callegari 3 , R. Blas 4 , A. Munarriz 5 , R. Pardo-Hidalgo 6 , and H. Tamashiro 7. Objectives: In previous studies we have reported that synovial fluid SF of spondyloarthritis SpA patients induces interleukin IL -6 production in fibroblast-like synoviocytes FLS , and this cytokine modulates metalloproteinase-9 activity of these cells. However, the molecules of the SpA synovial microenvironment that trigger this pro-inflammatory circuit are unknown.

The proteomic analysis showed that the most abundant proteins of the SpA SF come from extracellular location and cytoplasm. Understanding the pathogenic mechanisms associated with the synovial microenvironment may contribute to suggest new therapeutic approaches for SpA. Kivitz 1 , P. Nash 2 , H. Tahir 3 , A. Everding 4 , P. Pellet 5 , A. Widmer 5 , L. Pricop 6 , K. The primary endpoint was ACR20 response at Wk Missing values were imputed as non-responders.

Results: Of randomized pts, PBO Significant improvements in the secondary endpoints were also observed at Wk 16 for SEC vs. The most common AEs up to Wk 16 were nasopharyngitis PBO, respectively. No deaths were reported. Conclusions: SEC mg administered with and without LD demonstrated significant and sustained improvements in the signs and symptoms of PsA. The safety profile was similar with and without LD, and consistent with previous reports.

Fuentes-Silva 1,2 , C. Acosta 2 , C. Elera-Fitzcarrald 3 , S. Pons-Estel 6 , and C. Drenkard 7. Objectives: Education is critical to support effective management in people with lupus. We described the educational needs of Latin-American patients with lupus and explored associations with sociodemographic characteristics. We used Chi-square test to examine associations between needs and sociodemographic characteristics.

Table 1 shows the frequency of N1 to N5. There were not significant associations between educational needs and sociodemographic factors age, gender, region, education, occupation, disease duration. Conclusions: There is consistency in the educational needs of Latin-American lupus patients across regions and sociodemographic groups suggesting that there is a substantial gap in the education of this population.

Gandino, M. Brom, S. Ruta, M. Scolnik, J. Zacariaz, J. Marin, J. Rosa, R. Garcia-Monaco, and E. Objectives: To date, the diagnosis of knee osteoarthritis OA is based on clinical examination and radiological features. Our objective was to evaluate the diagnostic test properties of ultrasound US for the detection of radiographic knee OA. Exclusion criteria were: Younger than 18 years of age, history of knee surgery or trauma, severe knee deformities and a corticosteroid injection within the preceding 2 months.

US examinations were performed by an experienced rheumatologist, blinded to clinical and radiological data, using a MyLab 70 machine Esaote provided with a multi-frequency linear transducer 4—13 MHz. Standardized scanning method was adopted in order to evaluate the following US abnormal findings: osteophytes protrusions at the joint margin seen in two planes and visualized as either proximal or distal to the joint and degenerative femoral hyaline cartilage involvement presence of at least two of the following: loss of sharpness of the cartilage margins, loss of homogeneity of the cartilage layer and cartilage thinning focal or extend to the entire cartilaginous layer.

Weight-bearing anteroposterior AP and lateral knee radiographs were read by an experienced rheumatologist, blinded to the clinical and US data, who determine the presence or absence of radiological degenerative changes and classified the severity of knee OA using Kellgren-Lawrence KL grading scale. Table 2 shows the diagnostic test properties of the US abnormal findings for the detection of knee OA using radiological data as reference method.

Conclusions: US demonstrate an excellent sensitivity with an adequate specificity for the detection of radiographic knee OA. US could be used in patients with knee pain when OA is suspected. Sieper 2 , P. Mease 3 , R. Inman 4 , X. Wang 5 , M. Pangan 5 , and J. Anderson 4. Objectives: It is not known whether TNF blockers can be stopped in non-radiographic nr-axSpA patients who are in remission. Secondary endpoints were also assessed up to wk 68 nonresponder imputation. A significantly greater proportion of patients treated with ADA vs.

Time to flare analysis showed significantly lower risk of flare for ADA vs. At wk 68, significantly greater proportions of ADA vs. Conclusion: In pts with nr-axSpA who achieved sustained remission with ADA, continued therapy was associated with significantly more patients maintaining remission and lower disease activity than treatment withdrawal.

These results support the continuation of ADA therapy after achievement of sustained remission. Safety findings were consistent with the established safety profile of ADA. Roth 1 , L. Barzola 2 , L. Campos 3 , C. Hernandez 4 , D. Petry 5 , L. Ventura 4 , and T. Cazenave 6. Background and Aims: Musculoskeletal ultrasound MSUS is increasingly being utilized in children but validation has been limited to synovitis so far. The enthesis is an equally important structure and pediatric specific definitions as well as reliable scoring systems are needed given the unique pediatric anatomy.

The aim of this study was to develop and assess reliability of B-Mode and Doppler definitions and scoring systems for the pediatric enthesis. This was done through a comprehensive literature review followed by a practical exercise and consensus process. Similarly, a Doppler scoring system was developed through both literature review and consensus process and subsequently validated by a practical exercise. A total of six children 3 healthy, 3 enthesitis related juvenile arthritis were scanned during this exercise by six rheumatologists each and all images were analyzed by all participants.

B-Mode assessments included thickness, hypoechogenicity, erosions, enthesophytes and bony irregularities and increased blood flow was assessed with Power Doppler. The following entheses were assessed: Quadriceps tendon into the patella, proximal and distal patella tendon and Achilles tendon. Agreement with the definitions was determined using definition as 4 or 5.

Presence of structural changes on B-Mode were scored dichotomously as present and absent and agreement between raters on the Doppler scores was determined using two-way single score intraclass correlation coefficients ICC. ICC for all Doppler images was 0. Conclusion: B-Mode and Doppler definitions for the healthy and pathologic entheses in children as well as a Doppler Scoring system were developed and validated through a consensus process.

The presence of structural changes was overall low and Doppler signals may be present in a relatively large proportion of healthy entheses as well. Future studies will address criteria to differentiate findings suggestive of pathology from physiologic findings. Cerda 1 , F. Schneeberger 1 , M. Correa 1 , M. Rosemffet 1 , E. Buschiazzo 2 , R. Papasidero 4 , B. Barrios 4 , Ficco H. Maldonado 5 , and G. Citera 1. Objectives: To evaluate the survival of the second biological disease modifying anti-rheumatic drug bDMARD , the causes of its discontinuation and the time that had elapsed between the discontinuation of the first bDMARD and the beginning of the second one.

Socio-demographic variables age, sex, employment status, marital status, health coverage, education, number of cohabitants , and clinical variables comorbidities, smoking status, date of symptoms onset, the time elapsed between the interruption of the first bDMARD and the beginning of the second bDMARD and the response to this second bDMARD were obtained. Cumulative survival was evaluated using Kaplan Meier curves and log rank test for comparisons.

Results: patients were included, with a median age of Thirty-eight patients The most frequent cause of treatment discontinuation was lack of efficacy. Feuchter 1 , L. Bejarano 1 , D. Wiluzanski 2 , C. Altieri 2 , E. Romero 2 , J. Mansur 3 , Y. Martelli 4 , and L. Humbert 4. Methods: We examined the data from patients with postmenopausal osteoporosis. Patients came from 3 osteoporosis care centers in Mexico, Uruguay and Argentina. The changes observed at 2 years were evaluated in terms of percent change in vBMD. Applying 3D modelling techniques, may allow us to obtain better results using DMAb in the subgroup of patients at high risk of fractures.

More studies are required to confirm these results. Ferreira 1 , V. Trindade 1 , G. Espada 2 , Z. Morel 3 , E. Silva 1. Conclusion: This first large web-based survey demonstrated an overall excellent access for diagnosis and therapy of cSLE by LAPR, probably related to their high rate of practicing at tertiary care places University Hospitals. Adherence to therapy, pregnancy and substance abuse were identified as major challenges in this population, particularly in larger centers.

Fornaro 1 , T. Cazenave 1 , M. Orozco 1 , M. Martire 1 , E. Reyes 1 , H. Schmulevich 1 , G. Citera 1 , and M. Rosemffet 1. In spite of this, it remains a neglected anatomical area since clinical implications of ankle involvement appear to be continuously underestimated. To define the relationship between these findings and clinical and physical therapy parameters. US examinations were performed by two experienced rheumatologists.

The most frequent US abnormality in these patients was tibialis posterior tenosynovitis followed by peroneus longus tenosynovitis. Conclusions: Achilles tendon involvement is rather frequent in RA patients. Cosatti 1 , S. Natalia Tamborenea 3 , M. Curti 5 , A. Cappuccio 6 , O. Rillo 7 , P. Imamura 8 , E. Schneeberger 9 , F. Ballent 10 , M. Cousseau 11 , J. Velasco Zamora 12 , V. Saurit 13 , S. Toloza 14 , M. Danielsen 15 , V. Bellomio 16 , C. Graf 17 , S. Paira 18 , J. Cavallasca 19 , B. Pons Estel 20 , J. Moreno 21 , M.

Alba 23 , M. Verando 24 , G. Tate 3 , E. Mysler 3 , J. Sarano 25 , E. Civit 26 , F. Larroude 6 , M. Conforti 30 , D. Sohn 31 , C. Helling 3 , S. Roverano 18 , S. Malm-Green 24 , D. Medina Bornachera 32 , A. Alvarez 32 , A. Eimon 1 , G. Mayer 34 , J. Marin 8 , C. Catoggio 1 , and C. Pisoni 1. All centers are from Argentina. Sociodemographic and disease related variables, SDI score and smoking status were collected. Results: Eighty-nine percent of the patients were women, median age was 38 IQR 30—46 years. The median disease duration was 9 years IQR 4— When the ACR criteria were compared between smokers and non-smokers only discoid lupus was significantly associated with smoking exposure.

Univariable analyses comparing demographical and clinical characteristics of both groups are depicted in Table 1. Bejarano 1 , A. Secco 1 , A. Mamani 1 , S. Papasidero 2 , J. Nitsche 3 , L. Encinas 4 , F. Caeiro 4 , C. Gobbi 5 , E. Albiero 5 , A. Gomez 6 , JC Barreira 6 , R. Aguila Maldonado 7 , M. Garcia 7 , M. A Gallardo 8 , E. Soriano 8 , L.

Raiti 9 , G. Salvatierra 10 , and A. Eimon Objectives: To describe the work productivity and activity impairment in adult patients diagnosed with pSS. To evaluate the potential association between activity impairment and clinical manifestations, depression and anxiety. To compare activity impairment according to educational level and site of care public or private centers as surrogates of socio-economic status.

Methods: We included patients with diagnosis of pSS according to the American-European criteria treated at 11 private and public Argentine rheumatologic centers between November and December All patients with another autoimmune rheumatic or chronic disease were excluded.

The WPAI questionnaire was used. Design: Observational, analytic, cross-sectional study. For the descriptive analysis, continuous variables were informed as means and SD. Categorical variables were reported in percentages. A multivariable linear regression model was performed, taking impaired activity due to health as the dependent variable, adjusted by potential confounders.

The performance of the model was evaluated assumptions, atypical observations, multicollinearity. Results: patients were included, The mean percentage of working time lost due to health was The mean impaired activity due to health was No statistically significant differences were found between patients with full or higher secondary education Arthritis, xerostomia and depression were significantly and independently associated with impaired activity due to health. Patients treated in public centers presented a greater impaired activity.

This could be an expression of the impact of the socio-economic status. Objectives: Achieving remission or low disease activity LDA are treatment goals in rheumatoid arthritis RA and identifying their predictors in early disease is relevant in our region. For these analyses, patients with complete clinical and laboratory assessments at the baseline, one- and two-year follow up visits were included.

Gender, age at diagnosis, socioeconomic status by the Graffar scale , ethnicity, rheumatoid factor RF positivity, disability measured with the HAQ-DI , DMARDs and corticosteroid use were examined as potential predictive factors of these outcomes. Results: Five hundred and twenty-six patients were included, Before the baseline visit, Remission was met by Our data suggest that an early diagnosis and a more aggressive treatment approach at disease onset is needed to prevent the deleterious effects of persistently active RA.

Objective: Psoriatic Arthritis PsA is a chronic, systemic inflammatory disease which primarily affects the peripheral joints, connective tissues, and the axial skeleton. This study assessed the cost-effectiveness of secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin IL A, versus currently prescribed biologics in patients with PsA from the Argentinean social security perspective.

Non-responders or patients discontinuing initial-line of biologic were allowed to switch to subsequent-line biologics. Sensitivity analyses and an alternative scenario with higher cost option from the private payer perspective were conducted to test the robustness of the results. Infliximab provided slightly higher QALYs 7. Deterministic sensitivity analyses indicated that the results were sensitive to variation in PsARC response rates, drug acquisition costs, change in HAQ, and utility values.

Probabilistic sensitivity analysis showed that both secukinumab mg and mg had maximum net monetary benefits values. Results based on cost inputs from the private payer perspective were similar. Spearman's rank correlation was used to assess the association between antibodies. No other association were found with other non-criteria APS features. A wider use of these 2 novel aPL in the future will bring us more information about their- clinical utility and potentially, differential management in APS patients.

Burmester 1 , O. FitzGerald 2 , K. Winthrop 3 , V. Azevedo 4 , W. Rigby 5 , K. Kanik 6 , C. Wang 6 , P.


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Biswas 7 , T. Jones 8 , S. Menon 6 , N. Palmetto 7 , and R. Rojo 6. Objective: To describe the safety profile of tofacitinib, an oral Janus kinase inhibitor under investigation for the treatment of psoriatic arthritis PsA , from integrated Phase P 3 and long-term extension LTE studies. Results: C1 included tofacitinib- and PBO-treated pts; C2a included tofacitinib-treated pts; and C3 included tofacitinib-treated pts exposure: PY.

Nasopharyngitis 5. Discontinuation due to AEs occurred in 11 4. HZ was reported in 16 pts 2. In C3, 2 deaths occurred 0.

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MACE were reported in 3 pts 0. Conclusions: In patients with active PsA, tofacitinib demonstrated a safety profile consistent with that seen with tofacitinib in rheumatoid arthritis; no new risks were identified. Longer-term follow-up and larger pt populations will provide further information on the safety profile of tofacitinib in pts with PsA. Sousa 1 , J. Paupitz 1 , N. Aikawa 1 , L.

Takayama 1 , V. Caparbo 1 , and R. Pereira 1. The aim of this study was to evaluate the risk factors for bone mass loss in patients with JoSLE examining clinical and laboratory data, besides bone microarchitecture parameters. All patients were evaluated at baseline and after 3.

Results: The mean age of the patients was Sixty-one percent of patients presented aBMD gain, Comparing the BL and the BG groups, there was a higher frequency of alcohol consumption In addition, a higher frequency of renal activity was observed when the BL and NC groups were examined together and compared to the BG group No significant differences were observed regarding other clinical, laboratorial and microarchitecture bone parameters and treatment.

Conclusions: This is the first longitudinal study in the literature that examines the risk factors for bone mass loss in JoSLE patients. The authors emphasize the importance of evaluating not only renal disease activity, but also lifestyle habits, mainly alcoholism and calcium intake in these young women. Furthermore, this study suggests that trabecular and cortical bone compartments were deteriorated in this disease and that low serum levels of P1NP may be a predictor of bone involvement in JoSLE.

Ugarte-Gil 1,2. Hospital Guillermo Almenara Irigoyen.

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Hospital Cayetano Heredia; 4 Facultad de Medicina. Results: Two hundred and forty patients were included. Their mean SD age at diagnosis was Disease duration was Disease activity as assessed by the patient, either by VAS [ Likewise, there was no correlation between either measure and the SDI.

In contrast, disease activity as assessed by the patient, regardless of the scale or time obtained, correlated with several components of the LupusQoL physical health, pain, planning, emotional health and fatigue. These data are shown in Table 1. Disease activity as perceived by patients correlates with how they perceive the disease is affecting them rather than with disease activity per se. Kvien 1 , A.

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Deodhar 2 , L. Gossec 3 , P. Conaghan 4 , V. Strand 5 , M. Williams 7 , B. Porter 8 , K. Gandhi 8 , and S. Jugl 9. Objectives: In patients pts with ankylosing spondylitis AS , fatigue is a common symptom negatively affecting health-related quality of life HRQoL and social functioning. Analyses were based on the full analysis set and subgroups stratified by prior TNF therapy. Correlations between BL characteristics and improvements in fatigue were investigated using a logistical regression model. Only data from the approved dose SEC mg are presented.

Rapid and sustained fatigue responses were also seen in subgroups stratified by prior TNF use. Correlational analyses based on pooled data from both trials did not identify any BL factors that consistently predicted improvement in fatigue response at Wks 16, 52, and Deshmukh, T. Seo, M. Grifman, C. Swearingen, Y.

Objectives: Osteoarthritis OA is characterized by pain, swelling, and reduced function in the knee joint. Upregulated Wnt signaling drives OA through synovial inflammation, increased subchondral bone, and thinning cartilage. SM, a small molecule Wnt pathway inhibitor that demonstrated chondrogenic and anti-inflammatory properties preclinically 1 , was further evaluated to determine its potential to reduce inflammation, protect cartilage, improve joint health and modify pain in OA. Pain was measured as paw withdrawal threshold using Von Frey apparatus and weight distribution using incapacitance meter and analyzed using generalized estimating equation regression.

Conclusion: In a rat MIA OA model, SM injection reduced inflammation, protease production, and pain, with improved cartilage and joint health, compared to vehicle. Previously demonstrated regenerative effects in nonclinical studies 1 , along with anti-inflammatory properties, show SM may improve symptoms and potentially provide disease modification in OA.

Clinical studies are ongoing. OAC Gobbi 1 , S. Fontana 1 , E. Albiero 1 , P. Alba 1 , and M. Yorio 1. Bone disorders related to SS have not been described accurately in the current literature. The bones were fixed in formalin buffer, decalcified with EDTA and processed for their inclusion in paraffin; cuts were oriented to eosin in order to perform the histological assessment. The histomorphometrically assessment of tibial metaphysis area and the length of trabecular bone were performed. Conclusion: These results, in addition to our previous research, confirms that there is a bone disorder in this experimental model of SS.

It is necessary to carry out immunostaining techniques of quality and activity of bone tissue, with the purpose of objectify the response in NOD mice with SS. Busamia 1 , C. Gobbi 1 , K. Rhys 1 , M. Mariani 2 , S. Fontana 2 , S. Marchegiani S 3 , M Belletti 3 , E. Only few data are found in the literature about bone diseases in SS. These animals were cared for under special conditions, free of specific pathogens.

Neonatal lupus. In Rheumatology, 3rd Ed. Indian J. Pediatrics, ; Hepatobiliary disease in neonatal lupus erythematosus: Prevelance and clinical characteristics in cases enrolled in a national registry. Pediatrics Vol. Long term follow-up of children with neonatal lupus and their affected siblings. Arthritis Rheum ; Validation of the Doppler PR interval in the fetus.

J Am Soc Echocardiogr ; April ;p3. Systemic Lupus Erythematosus in Clinical Practice ; The heart and skin of neonatal lupus: does maternal health matter? Am J Medicine ; Cutaneous manifestations of neonatal lupus: characteristics of mothers and children enrolled in a national registry. Autoimmune-associated congenital heart block: bringing bedside challenges to the bench. In Lupus: Cellular and Molecular Pathogenesis. Humana Press; Totowa, NJ. Pregnancy in women with Sjogren's syndrome: neonatal problems.

Oxford University Press, New York, , pp. Journal of the American College of Cardiology. Buyon, JP. April ; p3. FcgR allelic polymorphisms: a candidate fetal factor in the development of congenital heart block [abstract]. Maternal disorders: Medical. Systemic lupus erythematosus. Although MS was associated with slightly better efficacy, this may have been due to imbalance in factors affecting remission and relapse, despite randomization with minimization. This study did not support the use of MS as a better tolerated and efficacious alternative to MMF for routine use, but MS could be considered in patients with gastrointestinal side effects from MMF.

Ciclosporin and tacrolimus do not cause myelosuppression and have the ability to reduce moderate disease activity Tables 2 and 7.


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  • There is more evidence for ciclosporin in non-renal lupus, and it has been particularly helpful in the treatment of cytopenias, where there is likely to be difficulty distinguishing cytopenias due to lupus from cytopenias due to drugs such as AZA, MTX and MMF.

    Both ciclosporin and tacrolimus can be used at the lowest possible dose in women planning pregnancy, and in those who are pregnant or breast-feeding [ ]. Nevertheless, the open-label RCTs suggested that ciclosporin reduced disease activity as well as AZA did [ ] and better than CSs alone [ ], and that ciclosporin treatment was associated with significant CS-sparing properties in both RCTs, equivalent to that of AZA in one trial [ ] as reported previously by the cohort studies.

    In the first of two additional studies not mentioned in the systematic review, ciclosporin was shown to treat thrombocytopenia in six patients [ ], three of whom were able to stop CSs. In the second study [ ], a retrospective cohort study, ciclosporin was used to manage 40 refractory lupus patients, including 11 patients with neurological conditions and 7 with overlap syndromes, as well as 18 with LN.

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    The study showed reduction in disease activity and only mild transient adverse events not requiring discontinuation. In the open-label RCT [ ], there were no unexpected adverse events, and with appropriate monitoring of renal function and blood pressure, it was not discontinued due to adverse events or inefficacy more often than AZA. There are two reports of tacrolimus in non-renal lupus and they were included in the systematic review [ ]. The first was a small retrospective cohort study [ ] with 10 non-renal patients showing significant reductions in SLEDAI and prednisolone over 1 year on 1—3 mg daily.

    The systematic review [ ] and our search found little evidence for efficacy and safety of LEF in lupus patients, with only two small studies in the literature. It is not suitable for women considering pregnancy, and a cholestyramine washout is required if pregnancy is desired or occurs while it is being taken [ ]. There was a randomized, double-blind, placebo-controlled trial in moderate SLE patients, with only six patients in each group [ ]. Side effects included transiently abnormal alanine aminotransferase ALT , leucopenia and hypertension.

    Caution is advised about its use in those with pre-existing subacute cutaneous lupus, as this may worsen as observed in other non-lupus studies. The patients must be managed in conjunction with a specialist centre for lupus and be entered in to the BILAG Biologics Register for standardized reporting of outcome see Fig. This is essential for providing more open-label data in a prospective study with control patients treated with other immunosuppressive therapies, given the failure of the international double-blind, placebo-controlled lupus trials to meet their primary end points, as discussed below EXPLORER for active non-renal disease [ , ] and LUNAR for LN [ ].

    This policy was agreed as a result of the increasing published evidence supporting the efficacy of rituximab in refractory lupus patients, who are likely to differ from those recruited to trials where there was no requirement to have failed conventional therapy. Pregnancy should be avoided for at least 6 months after exposure to rituximab [ ]. The current evidence supporting the efficacy and safety of rituximab in non-renal lupus was most recently reported in a systematic review [ ] in by Cobo-Ibanez with a literature search up to June Evidence for a steroid-sparing effect was based on the 2 open-label trials and 10 of the cohort studies [ ].

    There were few significant adverse events in the RCT, 2 open-label studies and 20 cohort studies [ ]. Better clinical response after a second course was observed in 2 of the cohorts that studied retreatment [ ], and a further report supported this observation and that steroid reduction occurred after each of two courses of rituximab [ ]. The evidence for rituximab treating mucocutaneous involvement was deemed weak [ ], and this may be explained by a recent report [ ] specifically addressing 26 SLE patients with various subtypes of lupus rash, which observed that acute lupus rash responded whereas chronic cutaneous lupus such as discoid rash did not respond to rituximab and that new lesions with typical histology may appear despite confirmed B cell depletion.

    Rituximab treatment early in the course of lupus disease, followed by AZA, was tried by Ezeonyeji et al. Reduction in disease activity, a fall in anti-dsDNA antibodies and complement, and significant lower cumulative prednisolone at 6 months compared with controls was observed. There is also an open-label LN study suggesting that early rituximab with i. The BILAG index was used in patients treated with rituximab in 8 open-label studies 3 prospective, 4 retrospective and 1 small case—control [ ].

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    A significant reduction in anti-dsDNA antibodies was observed in 6 of the 8 studies and a significant rise in complement was observed in 5 of 6 studies. Various versions of the SLEDAI were used in patients treated with rituximab in 12 open-label studies: 5 prospective, 6 retrospective and 1 open-label randomized trial, only 1 of which also analysed BILAG response.

    Anti-dsDNA levels fell in 3 of 3 studies and complement rose in 2 of 3 studies [ ]. Publications from cohorts in Germany [ ], Italy [ ] and Japan [ ] have confirmed similar levels of efficacy with various disease activity measures and provided further safety data in another patients. Patients on MTX as the background immunosuppressant derived more benefit from rituximab in a post hoc analysis than those in the placebo group [ ], and in contrast to those on background AZA or MMF [ ]. However, two case series reports have suggested that repeat courses of rituximab may increase the risk of hypogammaglobulinaemia and infection [ , ].

    Progressive multifocal leukoencephalopathy PML has been reported in 17 SLE patients, of whom 5 had been treated with rituximab. It seems likely that immunosuppression, however it is achieved, is the key factor in the development of PML. Lupus patients may be at increased risk of developing PML compared with other rheumatic diseases [ ]. There is now considerable evidence for the ability of rituximab to reduce disease activity in refractory non-renal SLE of moderate and severe severity, albeit mostly from cohort studies.

    There have been relatively few concerns in the individual reports and systematic reviews about adverse events, including infections, in lupus patients on rituximab. There is increasing evidence that rituximab has steroid-sparing properties, but further evidence for its use early in the disease course is needed. There have been two large phase III RCTs [ , ] investigating the use of belimumab in moderate—severe seropositive lupus mostly musculoskeletal and cutaneous disease; as severe active renal and NPSLE disease were exclusions.

    A variety of secondary end points were met, and there were no significant differences in adverse events, leading to the drug being approved and licensed by the US Food and Drug Administration and the European Medicines Agency. Pregnancy should not occur while on belimumab, but first trimester exposure is unlikely to be harmful [ ]. The response rates at week 76 were a little lower in all groups.

    Safety data from the phase II trial and its open-label extension have not shown any significant concerns and continued benefit for up to 7 years [ , ]. The most common side effects have been upper respiratory tract and urinary tract infections, arthralgia, headaches, fatigue and nausea. Serious infusion reactions and infections have been rare [ , ]. There have been two case reports of progressive multifocal leukoencephalopathy [ , ], but there is no evidence that belimumab increases the risk more than other immunosuppressive regimens in SLE patients [ ].

    Further post hoc analyses [ , ] on the pooled datasets from BLISS 52 and BLISS 76 trials have demonstrated that belimumab therapy was associated with significantly more patients showing improvements than with placebo in the most commonly affected musculoskeletal and mucocutaneous systems, and more immunological abnormalities normalized than with placebo [ ].

    Improvement was reported less consistently in other systems that were less often affected [ ]. There was less worsening in haematological, immunological and renal parameters in those patients on belimumab than in those on placebo [ ], but as with improvement, effects were not always dose related. This is consistent with the low rate of serious infections in the long-term open-label study of belimumab [ , ].

    Belimumab was also shown to reduce severe flares and CS use and to improve health-related quality of life most in these more severe subgroups [ ]. These analyses contributed to the decision by the European Medicines Agency to limit the market authorization for belimumab Benlysta to add-on therapy in adult patients with active autoantibody-positive SLE with a high degree of disease activity e. Treatment with belimumab in addition to standard therapy in autoantibody-positive SLE patients was associated with some improvements in clinical, laboratory and patient-reported outcome measures compared with placebo in addition to standard therapy and had a low risk of serious side effects.

    Based on the results of the two RCTs and the post hoc analyses, belimumab is considered by NICE to be cost-effective in the UK only for patients who meet the specific criteria [ ] see summary above and Fig. The drug is being used in other countries, particularly in the USA, where the licence covers patients with moderate disease activity and only specifies that patients must have active, autoantibody-positive lupus and be receiving standard therapy such as CSs, antimalarials, immunosuppressives and NSAIDs [ ].

    Immunosuppressive regimens for severe active SLE involve i. Patients who have serious manifestations with organ- or life-threatening disease require treatment with intensive immunosuppression followed by a prolonged period of less aggressive maintenance therapy to prevent relapse summarized with suggested dosing regimens in Table 7. In some cases there may be a thrombotic component to the clinical features that requires anticoagulation, for example in patients with APS as well as lupus.

    There is most evidence for the management of LN, less for neuropsychiatric disease and very little for other organ-specific manifestations. The main recommendations and SOAs with them are shown in Table 3. Further details about these recommendations and the evidence for them have been published [ 24 ]. The evidence for use of belimumab and of the calcineurin inhibitors ciclosporin and tacrolimus, particularly for cytopenias due to lupus, has already been reviewed above.

    Suggested initial target dosing regimens and lower maintenance regimens to prevent flares once patients are stable are shown in Table 7. The emphasis in the last 10 years has been on finding steroid-sparing regimens to treat severe lupus, using other immunosuppressants in conjunction with CSs either orally, intravenously or both , to induce and maintain response with the least risk of adverse events, particularly infection.

    In general, there is an increasing tendency to use oral prednisolone at a dose of 0. MP pulses as an alternative to, or in addition to, high-dose oral prednisolone was first reported as a treatment for LN [ 24 , , ]. MP pulses were introduced for the management of non-renal lupus in the early s [ ]. An open-label cohort study [ ] and an open-label trial [ ] using i. MP pulses followed by alternate day oral CSs found that pulse therapy led to rapid improvement in clinical symptoms and anti-dsDNA and C3 levels, but that an alternate day oral regimen was associated with relapses.

    MP pulses resulted in faster and more complete improvement in the first 2 weeks in 12 patients with SLE, but there was no significant difference in efficacy or safety parameters at 4 weeks or 6 months compared with the placebo group; however, all patients received 40—60 mg of oral prednisolone daily [ ].

    A double-blind RCT [ ] comparing three daily i. MP pulses of either or mg in 21 patients with SLE causing fever, cardiorespiratory, renal or NP manifestations with individualized outcomes based on entry manifestations suggested no difference in efficacy between the regimens. A retrospective study compared low-dose i.

    This study suggested that the lower dose was sufficient and safer for controlling SLE flares than the high-dose regimen, which was associated with an increased number of infections [ ]. There is limited evidence for any particular CS regimen for specific manifestations of severe non-renal lupus.

    Overall the LOE for i. It is most often used in women planning pregnancy or pregnant, as it is much safer in pregnancy than CYC or MMF, which are contra-indicated in such situations [ ]. There was only one open-label controlled trial, with 24 patients with severe life-threatening multisystem manifestations of lupus [ ], which showed no definite benefit from the addition of AZA compared with 40—60 mg prednisone alone for 6 months, before tapering over the next 18 months, although there was some steroid-sparing benefits seen at 12 months.

    AZA has been used more often as maintenance therapy after a course of CYC for severe lupus, based on the evidence from studies undertaken in patients with LN [ 24 , 25 ]. There are no trials or controlled studies addressing AZA as a primary treatment for neuropsychiatric lupus or any other specific serious non-renal manifestations of lupus, but it has been used after CYC for the treatment and prevention of recurrence of lupus psychosis in 13 patients [ ]. CYC, although not licensed for lupus, has been used for the treatment of severe lupus, particularly LN and organ- or life-threatening non-renal disease, since the late s, with the first open-label trial in LN reported in [ ].

    Oral CYC is associated with an increased risk of bladder cancer and has been replaced by i. CYC pulses in the management of severe lupus. There is most experience with i. CYC is teratogenic and is contra-indicated in women trying to conceive, or who are pregnant or breast-feeding. It is gonadotoxic and can cause infertility, and men should not father children while on CYC [ ]. The first controlled trial comparing prednisone with CYC in LN, non-renal lupus and PM was reported in [ ], and a similar design was used to compare oral CYC and AZA in lupus not responsive to 15 mg prednisolone [ ], but numbers were small and the aim of matching individual patients and comparing their outcomes was unsuccessful.

    Since then, studies have used different trial designs and evidence supporting the use of various doses of oral and later i. The best-known regimens are based on the National Institutes for Health i. CYC protocol monthly i. CYC for 2 years [ ] and the Euro-Lupus protocol, which uses lower doses mg fixed dose i. CYC 2-weekly for a total of 6 doses, followed by oral AZA [ ] and appears to be as effective and safer for LN in Europe than high-dose regimens [ ].

    In recent years, the 3-monthly i. CYC pulses were the most widely used regimes for all but the mildest cases of acute proliferative glomerulonephritis until MMF was found to be comparable in efficacy and safer [ 24 , 25 ]. Treatment regimens tested in LN have often been applied to severe non-renal lupus disease as there are fewer non-renal studies and they include heterogeneous patient populations.

    A systematic review [ ] evaluated 29 studies, including 4 unblinded RCTs in which patients with non-renal lupus were treated with a variety of CYC regimens. There are more data on the efficacy and safety of using CYC to treat non-renal lupus than of any other drug treatment; however, there are fewer high-quality studies than for LN, and diverse end points have been used, making it hard to compare the studies. There was no difference in response between i. Some of the best evidence supports the use of pulse i.

    MQ055 Rheumatology Systemic Lupus Erythematosus

    CYC regimen over i. MP alone [ ]. That trial used more CSs than we would recommend now and was based on a previous retrospective cohort study that suggested that i. The RCT [ ] recruited 32 SLE patients with active severe NP manifestations without thrombosis such as seizures, optic neuritis, peripheral or cranial neuropathy, coma, brainstem disease or transverse myelitis that had developed within the previous 15 days. MP daily for 3 days.

    One group received further 1 g of i. MP daily for 3 days repeated monthly for 4 months then bimonthly for 6 months and finally 3 monthly for one year. The other group received i. CYC treatment was also associated with greater improvement in other lupus manifestations, a significant reduction in SLEDAI score at 6 and 12 months, greater reduction in prednisolone dosage and more patients completing the protocol compared with the MP group. There was no difference in adverse events, including infections and deaths.

    Recruitment to the study was stopped early due to the higher failure rate of the MP arm. Although the RCT is not of high quality [ ] due to the small number of patients studied, the heterogeneity of the NP events, the variable outcome measures used for their assessment, and potential confounding by variable oral CS dosing, it is clear that the i. Anti-psychotic agents were used in nine patients for a mean of 6 months. Evidence for CYC and other treatments in neuro-ophthalmic manifestations of lupus have been reviewed in a systematic review [ ], but the data on treatment is mostly based on case reports and small case series, for example cases with neuromyelitis optica treated with or without CYC [ ].

    In contrast to the studies assessing low-dose regimens, high-dose CYC has been studied as well in the hope of achieving better responses in severe lupus. A prospective RCT [ ] was designed to compare the efficacy and safety of a widely used standard i. CYC regimen monthly i. CYC for 2 years with this high-dose i. CYC regimen. Entry criteria included moderate-to-severe lupus with renal 22 patients , neurologic 14 patients or other organ system involvement 11 patients. There was no evidence that response differed between the regimens, but non-responders to monthly i.

    CYC could be rescued with high-dose i. There was no difference in serious adverse events, infections, premature ovarian failure or deaths between the two groups. Leuprolide a gonadotropin-releasing hormone analogue was not used to protect against ovarian failure [ ]. This should be considered with i. CYC moderate- and high-dose regimens [ ], as amenorrhoea and ovarian failure are dose- and age-related adverse events of CYC [ , ], but are rare with the European low-dose i. CYC regimen mg 2-weekly for 3 months only recommended for LN [ 24 ].

    The remaining data [ ] supporting the use of CYC for other serious non-renal manifestations of lupus are obtained predominantly from a variety of cohort studies, small case series and case reports, including 5 patients with systemic lupus vasculitis [ ], 11 patients with myocarditis [ ] and 5 patients with heart failure due to myocarditis [ ]. There is one open-label RCT comparing i. CYC with enalapril for 6 months in the treatment of pulmonary hypertension, which showed greater benefit from CYC but an increased risk of infection and gastrointestinal side effects [ ].

    There is considerable evidence supporting the use of i. There is no evidence that CYC prevents chronic damage, and all regimens are teratogenic, but there is less risk with the Euro-Lupus regimen of adverse events such gastrointestinal side effects, alopecia, infection, amenorrhoea and infertility due to ovarian failure than with higher dose regimens [ 12 , 16 , 24 , 25 , , ]. There is very little evidence for the use of MMF in NPSLE, but it is being used to reduce other types of moderate and severe non-renal lupus disease activity Table 7 , to prevent flare and for its steroid-sparing properties, as an alternative to CYC or AZA, especially in cases where inefficacy, drug intolerance and concerns about toxicity arose.

    It is not compatible with conception, pregnancy or breast-feeding [ ]. Clinical examples of severe lupus are shown in Table 7 , and the evidence for rituximab is summarized in Table 2. The systematic reviews by Duxbury et al. There are insufficient data to comment on other specific severe lupus manifestations at present, but rituximab is accepted as having steroid-sparing properties three open-label studies [ , , ].

    It can be used in pregnancy but does not prevent heart block or fetal loss and in patients with infection. It is rarely indicated as there is not much evidence for its use Table 2. Much of the initial data are from case reports or small case series reporting treatment of acute events in small numbers of patients [ — ]. There were insufficient data to assess response using other outcome measures, although serious adverse events were rare and mild [ ]. The observational studies often did not report concomitant medication and used a variety of outcome measures and treatment regimens, as discussed below.

    Another open-label study [ ] assessed 13 female SLE patients with a flare who received 0. Short-term benefit was seen irrespective of concomitant therapy. There were few side effects in this study, but renal patients were avoided because nephrotoxicity has been reported in other studies [ ]. Patients with thrombocytopenia, vasculitis and alopecia did not respond. Another group also found a disappointing response to IVIG in thrombocytopenia [ ] in a retrospective analysis of 59 patients with immune-mediated severe thrombocytopenia, 44 of whom had definite lupus.

    A transient response to IVIG was reported in three patients with haemolytic anaemia in another study [ ].


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    • The effect of high-dose IVIG 30 g of sulfonated IVIG on days 1—4 and 21—24 in 12 mild to moderate active lupus patients [ ] was only temporary in most patients. A retrospective chart review of 17 patients including 11 with SLE , with a mean follow-up of 30 months and long-term high-dose IVIG treatment monthly for 6 months then every 2—3 months [ ], found that there was a significant reduction in the SLEDAI score with significant steroid-sparing effects, and remission was achieved in 12 patients [ ]. A case—control study [ ] compared 12 pregnant SLE patients with a history of recurrent spontaneous abortions who were on high-dose IVIG 0.

      Such improvements were not seen in the control group, and there were three fetal losses due to spontaneous abortion in this group compared with none in the IVIG group. However, other studies have not confirmed that IVIG can prevent fetal loss [ ], and it is possible that NSAIDs contributed to fetal loss in the control group [ ]. CHB was detected at 19, 20 and 25 weeks in 3 babies at a stage when 20 mothers had completed the IVIG protocol before the trial was stopped. An additional child without CHB developed a transient rash consistent with neonatal lupus [ ].

      Another European prospective study showed similar results [ ]. This study was too recent to be included in the comprehensive review on the use of IVIG in rheumatic diseases [ ] that covered the case—control study in pregnancy by Perricone et al. IVIG, particularly the high-dose regimen, can have some beneficial effects in the short term on disease activity, but has to be continued with intermittent courses for sustained benefit to be seen and only then has steroid-sparing properties.

      It has a low rate of adverse events in non-renal patients, but can cause nephrotoxicity, especially with pre-existing renal disease. The evidence supporting its use is weak compared with that of other treatments that are cheaper and easier to administer, so it should be reserved for patients in whom other treatments are contra-indicated or have failed. Plasma exchange in SLE has been used in small numbers of patients with conflicting results since the late s. A systematic review was published while this paper was in preparation [ ].

      It is rarely indicated, because there is inadequate data to support its use except in thrombotic TTP Table 2. The evidence supporting treatment with plasma exchange, which is expensive and often difficult to organize, remains poor except for thrombotic TTP [ , ], the catastrophic variant of APS [ ] and refractory neuropsychiatric, haematological and renal lupus [ ]. Even for rapidly progressive glomerulonephritis, the evidence is limited [ ].

      There was less support for the use of plasma exchange in SLE after a trial comparing plasma exchange in combination with CYC and CSs with standard therapy revealed no benefit from the plasma exchange for 40 patients with severe LN [ ]. However, there has been concern that improvements seen in this and 2 other uncontrolled studies [ , ] with 23 patients may have been due to the concomitant immunosuppressants. It is notable that the Lupus Plasmapharesis Study Group never reported on the final disappointing results of a randomized international multicentre trial comparing their synchronized protocol [ ] with the administration of pulse CYC alone.

      The evidence for treating patients who have diffuse alveolar haemorrhage, thrombotic TTP or catastrophic APS with lupus is predominantly from case reports and small case series [ , , ]. Given the high mortality in TTP in general, but especially with lupus [ , ], it is essential that patients with TTP are referred early for plasma exchange and specialist care [ , ]. Further details about the experience with and potential use of plasma exchange and immunoadsorption in lupus and APS, including LN, are covered by the systematic review [ ].

      There remains a need for further research to better define the patients who are most likely to benefit from plasma exchange, but in general they are considered to be those who have TTP, severe refractory disease or contra-indications to conventional treatment such as pregnancy.

      Diagnosis and assessment of lupus can be difficult due to multisystem involvement and variable laboratory and serological test results. These guidelines will increase knowledge and raise the standard of care for patients with lupus. The evidence for the treatment options discussed in this guideline, which reflect current best practice, has increased considerably in the last 10 years, although there is still relatively little evidence from high-quality RCTs.

      There should be no barriers to implementation, apart from limitations on the funding for rituximab and belimumab discussed in the relevant sections. The guidelines will be widely presented at local, regional and national meetings for health professionals and patients, carers and supporters of relevant charities.

      Lupus patients should be referred to a physician with experience in managing lupus who can confirm the diagnosis, assess the level of disease activity and provide advice on treatment and monitoring of the disease, its complications and side effects of therapy. Managing immunosuppressive therapies and their potential toxicities in patients with lupus can be a considerable challenge due to the risk of infection, difficulties with attribution of cytopenias to lupus or cytotoxic drugs, and difficulties in distinguishing manifestations of lupus disease activity from damage and co-morbid conditions.

      Input from a multidisciplinary team including nurse specialists and physiotherapists is usually required, and management may involve a variety of specialists, including rheumatologists, nephrologists, dermatologists, haematologists, cardiologists, chest physicians, neurologists, obstetricians, podiatrists and occupational therapists working as part of collaborative clinical networks involving regional specialist centres, local hospitals and GPs.

      It is important to get patients to a low level of disease activity, if not remission, using HCQ, immunosuppressants and the least amount of CSs possible, in order to reduce cumulative damage from the disease and its treatment with CSs [ 71 ]. If drug treatment is not working within the expected time frame, it is important to consider adherence to treatment and adjusting the therapy to reduce the accumulation of chronic damage. Patients need personalized advice, written information and education about the disease and its drug treatment from members of the multidisciplinary team, including specialist nurses and an individual to contact in the event of new symptoms.

      Additional topics covered should include sun avoidance, adequate vitamin D intake, weight control, exercise, not smoking and other measures to reduce atherosclerotic risk factors, as well as cancer screening, contraception and pregnancy planning when the disease is under good control on appropriate treatment for conception.

      There is a need for more evidence to support decision-making in the management of lupus patients. The guideline development group identified certain priorities for research into lupus to help address this issue, and these are shown in Table 8. T able 8 Research priorities to improve the management of lupus patients. To assess compliance with these guidelines, an audit proforma is available on the British Society for Rheumatology website. Funding : No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in these guidelines.

      Disclosure statement : D. All other authors have declared no conflicts of interest. Supplementary data are available at Rheumatology Online. Sign In. Advanced Search. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents. Scope and purpose of the guideline. Rigor of development. The guideline. Recommendations for clinical and serological features prompting consideration of a diagnosis of SLE.

      Recommendations for the assessment of SLE patients. Recommendations for monitoring of SLE. Recommendations for the management of mild SLE. Recommendations for the management of moderate SLE. Recommendations for the management of severe SLE. Applicability and utility. Mechanism for audit of the guideline. Supplementary data. The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults Caroline Gordon. Oxford Academic.

      Google Scholar. Maame-Boatemaa Amissah-Arthur. Mary Gayed. Sue Brown. Ian N. Benjamin Empson. Bridget Griffiths. David Jayne. Department of Medicine, University of Cambridge,. Munther Khamashta. Liz Lightstone. Peter Norton. Yvonne Norton. Karen Schreiber. David Isenberg. Article history. Revision Received:. Cite Citation. Permissions Icon Permissions. T able 1.

      T able 2. T able 3. Renal biopsy is indispensable since, in most cases, clinical, serologic and laboratory tests cannot accurately predict renal biopsy findings. CYC or calcineurin inhibitors ciclosporin, tacrolimus or rituximab are recommended as alternative options or for non-responders. AZA use is associated with a higher flare risk. Gradual drug withdrawal, glucocorticoids first, can then be attempted. T able 4. T able 5. T able 6.