14 Can we withdraw immunosuppressants in remitted patients

Remission has recently emerged as a potential target in the management of systemic lupus erythematosus (SLE), indeed remission is not uncommon and is associated with improved prognosis.1 2 Nevertheless, the best management of remitted patients, especially those in stable remission, remains elusive. In particular, whether immunosuppressive therapy (IS) may be safely discontinued, without exposing remitted patients to a significant risk of flare, has not yet been clearly determined. Accordingly, available recommendations for the management of SLE underline the importance of progressive tapering of glucocorticoids (GCs) until withdrawal, but do not remark on the possibility of discontinuing IS in remitted patients. Moreover, the timing of IS discontinuation has not yet been established and in clinical practice it is quite common that remitted patients continue to receive the same treatment which led to remission, with the aim of preventing flares, for an indefinite period of time. It has been recently reported that ISs were safely withdrawn after remission achievement in more than 75% of patients with SLE in a cohort of 319 patients treated with IS for different manifestations, including lupus nephritis (LN) (47%), arthritis (15.7%), haematological abnormalities (5.3%), skin rash (6.3%), neuropsychiatric SLE (1.9%), vasculitis (1.3%), serositis (0.6%), and multi-organ involvement (21.9%).3 The independent predictors of a safe discontinuation were hydroxychloroquine (HCQ) maintenance therapy after IS discontinuation and a longer duration of remission at IS discontinuation. Notably, being on HCQ and in remission for at least two consecutive years reduced the risk of flare by 81% and being on HCQ and in remission for at least three consecutive years by 86%. These findings are in keeping with recent recommendations, as antimalarials have been regarded as standard of care in all SLE patients unless contraindicated, including patients with LN, where antimalarials are proposed as an additional therapy. Interestingly, in this study maintenance therapy with 5 mg/day prednisolone equivalent alone did not protect against flares, as patients with low-dose maintenance therapy experienced a similar flare-rate compared to patients who discontinued all treatment at the time of IS withdrawal. In LN, different studies found a variable flare rate after IS discontinuation due to achievement of stable remission, ranging from 15% to 38.7%. Antimalarial therapy and a longer duration of remission at IS discontinuation resulted predictive of flare-free remission in some but not all these studies. Notably, the protective role of HCQ therapeutic levels against LN flares has recently been reported.4 Indeed, among remitted patients, those with a subsequent renal flare during the follow-up had significantly lower HCQ levels compared with those in persistent remission. To date, different authors suggested a wide range of duration of IS maintenance therapy after remission achievement in LN, varying from 3 to 6.5 years. Based on available data, we can conclude that IS may be withdrawn in selected SLE patients, based on the characteristics of the individual patient, including their maintenance therapy and the duration of remission, which requires a personalised approach. In this regard, long-term therapy with antimalarials should be recommended in all SLE patients.5 Continuous surveillance should be planned during treatment tapering and after withdrawal, to ensure any early signs or symptoms of disease relapse are detected. Learning Objectives Explain why, although GCs should be de-escalated and withdrawn as early as possible in remitted patients, the timing of IS tapering until discontinuation in these patients is still an unresolved issue Describe the recent data suggesting that maintenance therapy with HCQ and a longer duration of remission at the time of IS withdrawal are protective against lupus flares Explain the importance of tight surveillance of lupus patients, during IS therapy tapering and after IS withdrawal in order to detect early signs or symptoms predictive of a disease relapse References Zen M, Iaccarino L, Gatto M, et al. Prolonged remission in Caucasian patients with SLE: prevalence and outcomes. Ann Rheum Dis 2015;74(12):2117–22. van Vollenhoven R, Voskuyl A, Bertsias G, et al. A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS). Ann Rheum Dis 2017;76(3):554–61. Zen M, Saccon F, Gatto M, et al. Prevalence and predictors of flare after immunosuppressant discontinuation in patients with systemic lupus erythematosus in remission. Rheumatology (Oxford) 2020;59(7):1591–98. Cunha C, Alexander S, Ashby D, et al. Hydroxycloroquine blood concentration in lupus nephritis: a determinant of disease outcome?Nephrol Dial Transplant 2018 Sep 1;33(9):1604–10. Gatto M, Zen M, Iaccarino L, Doria A. New therapeutic strategies in systemic lupus erythematosus management. Nat Rev Rheumatol 2019;15:30–48

173 Immunosuppressant discontinuation in systemic lupus erythematosus: prevalence, risk of subsequent flare and effect on damage accrual

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Derivation and validation of the SLE Disease Activity Score (SLE-DAS): a new SLE continuous measure with high sensitivity for changes in disease activity

Objectives To derive and validate a new disease activity measure for systemic lupus erythematosus (SLE), the SLE Disease Activity Score (SLE-DAS), with improved sensitivity to change as compared with SLE Disease Activity Index (SLEDAI), while maintaining high specificity and easiness of use. Methods We studied 520 patients with SLE from two tertiary care centres (derivation and validation cohorts). At each visit, disease activity was scored using the Physician Global Assessment (PGA) and SLEDAI 2000 (SLEDAI-2K). To construct the SLE-DAS, we applied multivariate linear regression analysis in the derivation cohort, with PGA as dependent variable. The formula was validated in a different cohort through the study of: (1) correlations between SLE-DAS, PGA and SLEDAI-2K; (2) performance of SLEDAI-2K and SLE-DAS in identifying a clinically meaningful change in disease activity (ΔPGA≥0.3); and (3) accuracy of SLEDAI-2K and SLE-DAS time-adjusted means in predicting damage accrual. Results The final SLE-DAS instrument included 17 items. SLE-DAS was highly correlated with PGA (r=0.875, p<0.0005) and SLEDAI-2K (r=0.943, p<0.0005) in the validation cohort. The optimal discriminative ΔSLE-DAS cut-off to detect a clinically meaningful change was 1.72. In the validation cohort, SLE-DAS showed a higher sensitivity than SLEDAI-2K (change ≥4) to detect a clinically meaningful improvement (89.5% vs 47.4%, p=0.008) or worsening (95.5% vs 59.1%, p=0.008), while maintaining similar specificities. SLE-DAS performed better in predicting damage accrual than SLEDAI-2K. Conclusion SLE-DAS has a good construct validity and has better performance than SLEDAI-2K in identifying clinically significant changes in disease activity and in predicting damage accrual.info:eu-repo/semantics/publishedVersio

A new shape for an old function: lasting effect of a physiologic surgical restoration of the left ventricle

BACKGROUND: Long-term morphofunctional outcome may vary widely in surgical anterior left ventricular wall restoration, suggesting variability in post-surgical remodeling similar to that observed following acute myocardial infarction. The aim of this pilot study was to demonstrate that surgical restoration obtained with a particular shape of endoventricular patch leads to steady morphofunctional ventricular improvement when geometry, volume and residual akinesia can be restored as normal as possible. METHODS: This study involved 12 consecutive patients with previous anterior myocardial infarction, dilated cardiomyopathy and no mitral procedures, who underwent left ventricular reconstruction and coronary revascularization between May 2002 and May 2003 using a small, narrow, oval patch aiming at a volume ≤ 45 mL/m(2 )with elliptical shape. Eleven geometric parameters were examined preoperatively and at least 3, 12 and 24 months after the operation by serial echocardiographic studies and evaluated by paired t test taking the time of surgery as a starting point for remodeling. RESULTS: All patients were in NYHA class 1 at follow-up. Patch geometry obtained a conical shape of the ventricle with new apex, physiologic rearrangement of functioning myocardial wall and small residual akinesia. Ventricular changes at the four time-points showed that all parameters improved significantly compared to preoperative values (end-diastolic volume = 184.2 ± 23.9 vs 139.9 ± 22.0, p = 0.001; vs 151.0 ± 33.8, p = 0.06; vs 144.9 ± 34.0, p = 0.38; end-systolic volume = 125.7 ± 20.6 vs 75.2 ± 14.1, p = 0.001; vs 82.1 ± 23.9, p = 0,18; vs 77.1 ± 19.4, p = 0.41) without further changes during follow-up except for wall motion score index (2.0 ± 0.2 to 1.7 ± 0.2, to 1.4 ± 0.2, to 1.3 ± 0.2) and percentage of akinesia (30.4 ± 7.5 to 29.3 ± 4.2, to 19.8 ± 11.6, to 14.5 ± 7.2) which slowly and significantly improved suggesting a positive post-surgery remodeling. CONCLUSION: Ventricular reconstruction caring of physiological shape, volume, revascularization and residual akinesia obtained a steady geometry. Positive remodeling and equalization of geometrical outcome may persistently prevent long-term redilation

Remissione, low disease activity e sospensione della terapia immunosoppressiva nel lupus eritematoso sistemico. Risultati dalla coorte prospettica di Padova.

Premesse. Remissione (Rem) e low disease activity (LDA) sono recentemente emersi come concetti chiave nella gestione dei paziente affetti da lupus eritematoso sistemico (LES). L’effetto di diverse durate di Rem e LDA su misure di outcome come il danno d’organo non è stato ancora valutato. Resta ancora da definire quale sia la gestione terapeutica dei pazienti in Rem, essendo dibattuto ancora il timing della riduzione, fino alla sospensione, della terapia. Scopi. Valutare prevalenza, durata e effetto sul danno della Rem e LDA e studiare la frequenza della sospensione della terapia immunosoppressiva (TI) e i predittori di riacutizzazione di malattia in una coorte di pazienti affetti da LES. Pazienti e metodi. Abbiamo identificato 2 coorti: 1) pazienti con diagnosi di LES nel 1990-2009 e visti dal 2009 al 2015 per la valutazione di Rem e LDA; 2) pazienti con diagnosi di LES nel 1990-2018, trattati con TI e attualmente in follow-up (ultima visita nel 2017-2018) per la valutazione della sospensione della TI. L’attività di malattia è stata valutata tramite “SLE Disease Activity Index (SLEDAI)-2K” e “physician global assessment” (PGA), le riacutizzazioni con “SELENA-SLEDAI flare index” e il danno con “SLICC/ACR Damage Index” (SDI). Abbiamo identificato 3 livelli di Rem: Rem completa, definita come assenza di attività di malattia in pazienti non trattati con cortisonici (PDN) e TI; Rem clinica senza cortisone, definita come assenza di attività clinica in pazienti non trattati con PDN; Rem clinica con cortisone, definita come assenza di attività clinica in pazienti trattati con PDN 1-5 mg/die. La LDA è stata definita secondo la definizione del “lupus low disease activity state” (LLDAS): SLEDAI–2K&#8804;4, PGA (0–3)&#8804;1, prednisone &#8804;7.5 mg/die e dose standard di TI. Abbiamo valutato 5 durate di Rem e LLDAS: 1, 2, 3, 4, 5 o più anni consecutivi. L’effetto di Rem e LLDAS sul danno è stato valutato tramite regressione logistica multivariata. La sospensione delle TI è stata definita come completa sospensione di qualsiasi TI; la causa della sospensione è stata classificata come remissione o scarsa compliance/intolleranza. I predittori di riacutizzazioni e di flare-free survival sono stati analizzati rispettivamente tramite regressione logistica multivariata e regressione di Cox. Risultati. Nella coorte per la valutazione di Rem e LLDAS sono stati inclusi 293 pazienti: 253 (86.3%) femmine, durata di malattia media±DS 11.1±7.8 anni. Tra i pazienti in Rem 1 (27, 9.2%), 2 (47, 16%), 3 (45, 13.4%), 4 (26, 8.8%) anni, il danno era simile indipendentemente dal livello di Rem, mentre tra i pazienti in Rem &#8805;5 anni (113, 38.6%) il danno era maggiore in quelli in Rem con cortisone (p<0.001). All’analisi multivariata, la Rem &#8805;2 anni era protettiva nei confronti del danno (OR 0.23, 95% IC 0.06–0.85). Una LLDAS di 1, 2, 3, 4, o &#8805;5 anni consecutivi era raggiunta da 33 (11.3%), 43 (14.7%), 39 (13.3%), 31 (10.6%), e 109 (37.2%) pazienti. I pazienti in Rem &#8805;2 anni avevano un rischio significativamente minore di nuovo danno (OR 0.16, 95% IC 0.06-0.42, p<0.001). Tra i 456 pazienti attualmente in follow-up, 319 (70%) erano stati trattati con TI. Di questi, 139 (43.5%) avevano sospeso la TI, 105 (75.5%) per Rem. 26/105 (24.7%) pazienti in Rem e 23/34 (67.6%) che avevano sospeso per intolleranza si sono riacutizzati nel follow-up (p<0.001). All’analisi multivariata la terapia con antimalarici dopo sospensione della TI era il più forte fattore protettivo nei confronti delle riacutizzazioni di malattia (OR 0.24, 95% IC 0.07-0.84, p=0.026). Conclusioni. Nella nostra coorte abbiamo osservato che Rem e LLDAS erano frequenti ed erano fattori protettivi indipendenti per lo sviluppo di danno d’organo. Un terzo dei pazienti trattati con TI la sospendeva durante il follow-up. La terapia con antimalarici riduceva significativamente il rischio di riacutizzazione dopo sospensione della TI​Background. Remission and low disease activity (LDA) have recently emerged as key concepts in the management of systemic lupus erythematosus (SLE). The effect of different durations of remission and LDA on SLE outcomes has never been evaluated. Unsolved issues concern the treatment of patients in remission, being the choice and timing of drug tapering until withdrawal still a matter of debate. Aims. To assess the prevalence, duration and predictive effect on damage of remission and LDA in a monocentric cohort of patients with SLE. In addition, to evaluate the rate of immunosuppressant (IS) withdrawal and predictors of subsequent flare and flare-free survival. Patients and methods. Two cohorts were identified: 1) patients diagnosed with SLE between 1990-2009 and seen from 2009 to 2015 for remission and LDA evaluation; 2) patients diagnosed with SLE between 1990-2018, treated with IS over the disease course and seen at least once in 2017 or 2018 for IS withdrawal evaluation. Disease activity was assessed by SLE Disease Activity Index (SLEDAI)-2K and physician global assessment (PGA), flare by SELENA-SLEDAI flare index, and damage by SLICC/ACR Damage Index (SDI). Three levels of remission were defined: complete remission, i.e. no disease activity in corticosteroid- and IS-free patients; clinical remission off-corticosteroids, i.e. serologic active clinical quiescent disease in corticosteroid-free patients; clinical remission on corticosteroids, i.e. clinical quiescent disease with or without serological abnormalities in patients taking prednisone 1-5 mg/day. LDA was defined according to the “lupus low disease activity state” (LLDAS) definition: SLEDAI–2K&#8804;4, no new disease activity, PGA (0–3)&#8804;1, prednisone &#8804;7.5 mg/day, and well-tolerated IS dosages. Five range of durations of remission and LLDAS were evaluated, i.e. lasting 1, 2, 3, 4, 5 or more consecutive years. The effect of remission and LLDAS on SDI was evaluated by multivariate logistic regression analysis. IS discontinuation was defined as complete withdrawal of any IS. Reasons for discontinuation were classified as remission or poor compliance/intolerance. Predictors of a subsequent flare and flare-free survival were analyzed by multivariate logistic regression and Cox regression analyses, respectively. Results. 293 patients were included in the cohort for remission and LLDAS evaluation: 253 (86.3%) female, mean±SD disease duration 11.1±7.8 years. Among patients achieving 1-year (27, 9.2%), 2-year (47, 16%), 3-year (45, 13.4%), 4-year (26, 8.8%) remission, damage was similar irrespective of the level of remission achieved, whereas among patients achieving &#8805;5-year remission (113, 38.6%) damage was higher in those in clinical remission on-corticosteroids (p<0.001). At multivariate analysis, &#8805;2 consecutive year remission was protective against damage [OR (95% CI) 0.228 (0.061–0.850)]. LLDAS lasting 1-, 2-, 3-, 4-, or &#8805;5-consecutive years was achieved by 33 (11.3%), 43 (14.7%), 39 (13.3%), 31 (10.6%), and 109 (37.2%) patients, respectively. Patients who spent at least 2 consecutive years in were significantly less likely to have an increase in SDI (Odds ratio 0.16, 95% CI 0.06 to 0.42, p<0.001). Among 456 patients seen at least once in 2017-2018, 319 were ever treated with IS (70%). 139 patients (43.5%) discontinued IS, 105 of them (75.5%) due to remission. Among patients who discontinued IS, 26/105 remitted (24.7%) and 23/34 unremitted patients (67.6%) experienced a flare (p<0.001). Maintenance therapy with antimalarials (OR 0.24, 95% CI 0.07-0.84, p=0.026) was the strongest protective factor against disease flares. Conclusions. Remission and LLDAS were frequently observed and were protective against damage progression over the follow-up. One third of our patients discontinued ISs during the follow-up. Antimalarial therapy was the strongest protective factor against flare after IS discontinuation

Remissione, low disease activity e sospensione della terapia immunosoppressiva nel lupus eritematoso sistemico. Risultati dalla coorte prospettica di Padova.

Premesse. Remissione (Rem) e low disease activity (LDA) sono recentemente emersi come concetti chiave nella gestione dei paziente affetti da lupus eritematoso sistemico (LES). L’effetto di diverse durate di Rem e LDA su misure di outcome come il danno d’organo non è stato ancora valutato. Resta ancora da definire quale sia la gestione terapeutica dei pazienti in Rem, essendo dibattuto ancora il timing della riduzione, fino alla sospensione, della terapia. Scopi. Valutare prevalenza, durata e effetto sul danno della Rem e LDA e studiare la frequenza della sospensione della terapia immunosoppressiva (TI) e i predittori di riacutizzazione di malattia in una coorte di pazienti affetti da LES. Pazienti e metodi. Abbiamo identificato 2 coorti: 1) pazienti con diagnosi di LES nel 1990-2009 e visti dal 2009 al 2015 per la valutazione di Rem e LDA; 2) pazienti con diagnosi di LES nel 1990-2018, trattati con TI e attualmente in follow-up (ultima visita nel 2017-2018) per la valutazione della sospensione della TI. L’attività di malattia è stata valutata tramite “SLE Disease Activity Index (SLEDAI)-2K” e “physician global assessment” (PGA), le riacutizzazioni con “SELENA-SLEDAI flare index” e il danno con “SLICC/ACR Damage Index” (SDI). Abbiamo identificato 3 livelli di Rem: Rem completa, definita come assenza di attività di malattia in pazienti non trattati con cortisonici (PDN) e TI; Rem clinica senza cortisone, definita come assenza di attività clinica in pazienti non trattati con PDN; Rem clinica con cortisone, definita come assenza di attività clinica in pazienti trattati con PDN 1-5 mg/die. La LDA è stata definita secondo la definizione del “lupus low disease activity state” (LLDAS): SLEDAI–2K&#8804;4, PGA (0–3)&#8804;1, prednisone &#8804;7.5 mg/die e dose standard di TI. Abbiamo valutato 5 durate di Rem e LLDAS: 1, 2, 3, 4, 5 o più anni consecutivi. L’effetto di Rem e LLDAS sul danno è stato valutato tramite regressione logistica multivariata. La sospensione delle TI è stata definita come completa sospensione di qualsiasi TI; la causa della sospensione è stata classificata come remissione o scarsa compliance/intolleranza. I predittori di riacutizzazioni e di flare-free survival sono stati analizzati rispettivamente tramite regressione logistica multivariata e regressione di Cox. Risultati. Nella coorte per la valutazione di Rem e LLDAS sono stati inclusi 293 pazienti: 253 (86.3%) femmine, durata di malattia media±DS 11.1±7.8 anni. Tra i pazienti in Rem 1 (27, 9.2%), 2 (47, 16%), 3 (45, 13.4%), 4 (26, 8.8%) anni, il danno era simile indipendentemente dal livello di Rem, mentre tra i pazienti in Rem &#8805;5 anni (113, 38.6%) il danno era maggiore in quelli in Rem con cortisone (p<0.001). All’analisi multivariata, la Rem &#8805;2 anni era protettiva nei confronti del danno (OR 0.23, 95% IC 0.06–0.85). Una LLDAS di 1, 2, 3, 4, o &#8805;5 anni consecutivi era raggiunta da 33 (11.3%), 43 (14.7%), 39 (13.3%), 31 (10.6%), e 109 (37.2%) pazienti. I pazienti in Rem &#8805;2 anni avevano un rischio significativamente minore di nuovo danno (OR 0.16, 95% IC 0.06-0.42, p<0.001). Tra i 456 pazienti attualmente in follow-up, 319 (70%) erano stati trattati con TI. Di questi, 139 (43.5%) avevano sospeso la TI, 105 (75.5%) per Rem. 26/105 (24.7%) pazienti in Rem e 23/34 (67.6%) che avevano sospeso per intolleranza si sono riacutizzati nel follow-up (p<0.001). All’analisi multivariata la terapia con antimalarici dopo sospensione della TI era il più forte fattore protettivo nei confronti delle riacutizzazioni di malattia (OR 0.24, 95% IC 0.07-0.84, p=0.026). Conclusioni. Nella nostra coorte abbiamo osservato che Rem e LLDAS erano frequenti ed erano fattori protettivi indipendenti per lo sviluppo di danno d’organo. Un terzo dei pazienti trattati con TI la sospendeva durante il follow-up. La terapia con antimalarici riduceva significativamente il rischio di riacutizzazione dopo sospensione della TI