A comprehensive review on adult onset Still's disease.

[Still's disease in the adult].

Adult-onset Still’s disease (AOSD) is rare inflammatory disease of unknown etiology that usually affects young adults. The more common clinical manifestations are spiking fevers, arthritis, evanescent rash, elevated liver enzymes, lymphadenopathy, hepatosplenomegaly, and serositis. The multi-visceral involvement of the disease and the different complications, such as macrophage activation syndrome, may strongly decrease the life expectancy of AOSD patients. This study aimed to identify the positive and negative features correlated with the outcome of patients. A retrospective analysis of AOSD patients prospectively admitted to three rheumatologic centers was performed to identify the clinical features present at the time of diagnosis and to predict the possible outcome. Furthermore, we investigated the as yet to be validated prognostic value of the systemic score previously proposed. One hundred consecutive AOSD patients were enrolled. The mean systemic score showed that the majority of patients had a multi-organ involvement. Sixteen patients showed different complications, mainly the macrophage activation syndrome. A strong increase of inflammatory markers was observed. All patients received steroids at different dosages, 55 patients in association with immunosuppressive drugs and 32 in association with biologic agents. Sixteen patients died during the follow-up. Regression analysis showed that the higher values of the systemic score and the presence of AOSD-related complications, assessed at the time of diagnosis, were significantly correlated with patient mortality. A prognostic impact of the systemic score of ≥ 7.0 was reported. Our study showed that a higher systemic score and the presence of AOSD-related complications at the time of diagnosis were significantly associated with mortality. Of note, a cut-off at 7.0 of the systemic score showed a strong prognostic impact in identifying patients at risk of AOSD-related death.

https://link.springer.com/content/pdf/10.1186%2Fs12916-016-0738-8.pdf

Adult-onset Still’s disease: evaluation of prognostic tools and validation of the systemic score by analysis of 100 cases from three centers

Monogenic autoinflammatory diseases (mAIDs) are inherited errors of innate immunity characterized by systemic inflammation recurring with variable frequency and involving the skin, serosal membranes, synovial membranes, joints, the gastrointestinal tube, and/or the central nervous system, with reactive amyloidosis as a potential severe long-term consequence. Although individually uncommon, all mAIDs set up an emerging chapter of internal medicine: recent findings have modified our knowledge regarding mAID pathophysiology and clarified that protean inflammatory symptoms can be variably associated with periodic fevers, depicting multiple specific conditions which usually start in childhood, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndrome, and mevalonate kinase deficiency. There are no evidence-based studies to establish which potential genotype analysis is the most appropriate in adult patients with clinical phenotypes suggestive of mAIDs. This review discusses genetic and clinical hints for an ideal diagnostic approach to mAIDs in adult patients, as their early identification is essential to prompt effective treatment and improve quality of life, and also highlights the most recent developments in the diagnostic work-up for the most frequent hereditary periodic febrile syndromes worldwide.

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Hints for genetic and clinical differentiation of adult-onset monogenic autoinflammatory diseases

Background: Interleukin (IL)-1 plays a crucial role in the pathogenesis of Adult onset Still’s disease (AOSD). Objectives: To evaluate the efficacy and safety of anakinra (ANA) and canakinumab (CAN) in a large group of AOSD patients. Methods: Data on clinical, serological features and concomitant treatments were retrospectively collected at baseline and after 3, 6, and 12 months from AOSD patients (Yamaguchi criteria) referred by 18 Italian centers. Pouchot’s score was used to evaluate disease severity. Results: One hundred forty patients were treated with ANA; 4 were subsequently switched to CAN after ANA failure. The systemic pattern of AOSD was identified in 104 (74.2%) of the ANA-treated and in 3 (75%) of the CAN-treated groups; the chronic-articular type of AOSD was identified in 48 (25.8%) of the ANA-treated and in 1 (25%) of the CAN-treated groups. Methotrexate (MTX) was the most frequent disease modifying anti-rheumatic drug (DMARD) used before beginning ANA or CAN [91/140 (75.8%), 2/4 (50%) respectively]. As a second-line biologic DMARD therapy in 29/140 (20.7%) of the patients, ANA was found effective in improving all clinical and serological manifestations (p<0.0001), and Pouchot’s score was found to be significantly reduced at all time points (p<0.0001). No differences in treatment response were identified in the ANA-group when the patients were stratified according to age, sex, disease pattern or mono/combination therapy profile. ANA primary and secondary inefficacy at the 12 month time point was 15/140 (10.7%) and 11/140 (7.8%), respectively. Adverse events (AEs) [mainly represented by in situ (28/47, 59.5%) or diffuse (12/47, 25.5%) skin reactions and infections (7/47, 14.8%)] were the main causes for discontinuation. Pouchot’s score and clinical and serological features were significantly ameliorated at all time points (p<0.0001) in the CAN-group, and no AEs were registered during CAN therapy. Treatment was suspended for loss of efficacy only in one case (1/4, 25%). Conclusions: This is the largest retrospective observational study evaluating the efficacy and safety of IL-1 inhibitors in AOSD patients. A good response was noted at 3 months after therapy onset in both the ANA- and CAN-groups. Skin reaction may nevertheless represent a non-negligible AE during ANA treatment.

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Response to Interleukin-1 Inhibitors in 140 Italian Patients with Adult-Onset Still's Disease: A Multicentre Retrospective Observational Study.

Adult-onset Still’s disease (AOSD) is a systemic inflammatory condition of unknown aetiology characterized by typical episodes of spiking fever, evanescent rash, arthralgia, leukocytosis and hyperferritinemia. Given the lack of data in Italian series, we promote a multicentric data collection to characterize the clinical phenotype of Italian patients with AOSD. Data from 245 subjects diagnosed with AOSD were collected by 15 centres between March and May 2013. The diagnosis was made following Yamaguchi’s criteria. Data regarding clinical manifestations, laboratory features, disease course and treatments were reported and compared with those presented in other published series of different ethnicity. The most frequent features were the following: arthritis (93 %), pyrexia (92.6 %), leukocytosis (89 %), negative ANA (90.4 %) and neutrophilia (82 %). As compared to other North American, North European, Middle Eastern and Far Eastern cohorts, Italian data show differences in clinical and laboratory findings. Regarding the treatments, in 21.9 % of cases, corticosteroids and traditional DMARDs have not been able to control the disease while biologics have been shown to be effective in 48 to 58 patients. This retrospective work summarizes the largest Italian multicentre series of AOSD patients and presents clinical and laboratory features that appear to be influenced by the ethnicity of the affected subjects.

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Adult-onset Still’s disease: an Italian multicentre retrospective observational study of manifestations and treatments in 245 patients

Background Thanks to biologic therapies, disease remission in Rheumatoid Arthritis (RA) patients is not a wishful thinking but an achievable goal. Nevertheless, some patients experienced treatment discontinuation after obtaining disease remission. EULAR recommendations suggest to suspend steroids as soon as possible1, but in real life-setting this point is not always hold in esteem. Objectives The objective of our study was to assess the impact of steroids on the long-term drug survival and the possible predictors of drug discontinuation in RA patients who achieved Simplified Disease Activity Index (SDAI) remission at 1-year upon treatment with a first biologic disease modified anti-rheumatic drug (bDMARD). Methods Data of RA patients naive to bDMARDs, registered in Biologic Apulian Registry (BIOPURE) between 1st January 2008 to 31st December 2017, were retrospectively analysed. Demographic and clinical data of all RA patients were acquired at the initiation of first bDMARDs (“screening-time”) and after 1-year follow-up (“baseline-time”). The inclusion criterion in this study was the achievement of SDAI remission (SDAI ≤ 3.3) at 1 year of treatment with a first bDMARD. At “baseline-time”, RA patients on SDAI remission were divided, according to steroid administration, into concomitant “steroid-no” and “steroid-yes” groups. Drug retention rate and mean survival time (MST) were estimated using Kaplan-Meier (K-M) life-table method. Estimated hazard ratios (HRs) of discontinuing bDMARD were assessed by performing a multivariate Cox-regression analysis with stepwise backward methods. Results 216 RA patients started their first bDMARDs between 1st January 2008 to 31st December 2017. Among these, 86 (39.8%) patients achieved SDAI remission at 1-year of whom 54 (62.8%) were steroid free while 32 (37.2%) were still intaking low-dose steroids (mean 3.8 mg/die; SD ±1.4). Considering patients who achieved SDAI remission at “baseline-time”, global drug retention was 81.4% [MST=88.5 (95% CI: 80-97) months], higher for “steroid-no” patients [90.7%, MST=98.2 (95% CI: 89-107) months] than “steroid-yes” ones [68.8%, MST=68.9 (95% CI: 57-81) months] (long rank 7.086, p=0.008) (Figure 1). This difference was also seen when drug discontinuation by ineffectiveness was calculated [96.1%, MST=103 (95%CI: 96-110) months vs 72.4%, MST= 70.6 (95%CI 57-84) months, long rank 10.101, p=0.001], but not by adverse events. Moreover, no steroid administration (HR = 0.31, 95% CI:0.10-0.93) and concomitant Methotrexate therapy (HR = 0.34, 95% CI:0.12-0.98) were independently associated with low risk of bDMARDs interruption after the achievement of SDAI remission. Conclusion This study provided evidence that, among RA patients who achieved SDAI remission, those who stopped steroids and continued combination therapy with MTX had a very long drug survival with just the first bDMARD in a real-life setting. These results can help rheumatologists to precociously select RA patients who might start a tapering or spacing strategy of biologic drug. Reference [1] Smolen JS, Landewe R, Bijlsma J, Burmester G. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017Jun;76(6):960-977. Disclosure of Interests Marco Fornaro: None declared, Fabio Cacciapaglia: None declared, Giuseppe Lopalco Speakers bureau: SOBI, BMS, vincenzo venerito: None declared, Sante Schiraldi: None declared, Daniela Renna: None declared, Gaetana Laselva: None declared, Crescenzio Scioscia Speakers bureau: Abbvie, Giovanni Lapadula: None declared, Florenzo Iannone Consultant for: F Iannone has received consultancy fees and/or speaker honoraria from Pfizer, AbbVie, MSD, BMS, Novartis, Lilly, UCB outside this work, Speakers bureau: F Iannone has received consultancy fees and/or speaker honoraria from Pfizer, AbbVie, MSD, BMS, Novartis, Lilly, UCB outside this work

https://ard.bmj.com/content/annrheumdis/78/Suppl_2/1579.1.full.pdf

Ab0245 predictors of biologic therapy discontinuation in rheumatoid arthritis patients after remission achievement: a monocentric observational study from biologic apulian registry (biopure)

Background Polymyositis (PM) and Dermatomyositis (DM) are systemic inflammatory diseases affecting skeletal muscles and other organs, particularly hypopharynx and the upper tract of the esophagus, resulting in motility disfunction. The current treatment for PM and DM consists of steroids and immunosuppressants, but esophageal involvement is often refractory to standard therapies. Objectives To assess the efficacy and safety of intravenous immunoglobulins (Ig-iv) as therapy of refractory dysphagia in patients affected by idiopathic inflammatory myopathies (IIM) who have received conventional treatments for at least three months. Methods We enrolled 11 patients (9 F), 4 with DM, 7 with PM according to Bohan and Peter criteria. At baseline, all patients had received prednisone (5-10 mg/day) associated to Methotrexate (15 mg/wk) or Azathioprine (100 mg/day) for at least 3 months, without improvement of dysphagia. All patients received Ig-iv at a standard dose (2 g/kg/day only for a day). In all patients at entry and after each infusion VES 1h, PCR, LDH, CK levels were measured and Manual Muscle Strength Test (MMT12 e MMT-tight) was made. Dysphagia assessment included: Eating Assessment Tool (EAT; positive for score ≥3), Three-oz Swallow Test (3oST) and fibrolaryngoscopy (FEES –pharyngeal muscle propulsion, stasis of liquid and solid bolus). For the statistical analysis we used Wilcoxon Rank test, Fisher Exact Test, Chi-square test. Results At entry, there was evidence of correlation between MMT-12 and MMT-tight (p=0,005); CK and LDH levels were increased and EAT score was ≥3 in all patients. After the Ig-iv therapy we observed a statistically significant decrease in LDH levels (p=0,024), mainly between T0 and T1 (p Conclusions According to literature, our findings indicate that Ig-iv therapy improves muscle weakness. Furthermore, a meaningful improvement of dysphagia also occurred, suggesting that Ig-iv may be considered an effective and safe treatment for refractory dysphagia in IIM patients. Further studies of larger cohort of patients are needed to confirm our results and evaluate the outcomes across time. References Marie I et al. Intravenous immunoglobulins for steroid-refractory esophageal involvement related to polymyositis and dermatomyositis: a series of 73 patients. Arthritis Care Res (Hoboken). 2010 Dec;62(12):1748-55. Dalakas MC. The role of high-dose immune globulin intravenous in the treatment of dermatomyositis. Int Immunopharmacol. 2006 Apr;6(4):550-6. Epub 2005 Dec 20. Belafsky PC et al. Validity and reliability of the Eating Assessment Tool (EAT-10). Ann Otol Rhinol Laryngol. 2008 Dec;117(12):919-24. Schindler A. et al. Reliability and validity of the Italian Eating Assessment Tool. Ann Otol Rhinol Laryngol. 2013 Nov; 122(11):717-24. Katz U et al. Safety of intravenous immunoglobulin (IVIG) therapy. Autoimmun Rev. 2007 Mar;6(4):257-9. Epub 2006 Aug 28. Disclosure of Interest None declared

https://ard.bmj.com/content/annrheumdis/74/Suppl_2/1137.1.full.pdf

G. Laselva

Papers

Adult-onset Still’s disease: an Italian multicentre retrospective observational study of manifestations and treatments in 245 patients

Ab0245 predictors of biologic therapy discontinuation in rheumatoid arthritis patients after remission achievement: a monocentric observational study from biologic apulian registry (biopure)

AB0714 Improvement of Refractory Dysphagia in Patients with Idiopathic Inflammatory Myopathies Receveing Immunoglobulin Intravenous Therapy