Pragmatic targets for moderate/severe SLE and their implications for clinical care and trial design: sustained DORIS or LLDAS for at least 6 months is sufficient while their attainment for at least 24 months ensures high specificity for damage-free progression.

OBJECTIVES: Treatment targets in systemic lupus erythematosus (SLE) have been validated in unselected-in terms of severity-cohorts, which limits their generalisability. We assessed remission (Definition of Remission in SLE (DORIS)) and Lupus Low Disease Activity State (LLDAS) in a historical cohort of 348 patients with active moderate-to-severe disease and median follow-up of 5 years. METHODS: Active SLE was defined as Physician Global Assessment ≥1.5 and/or SLE Disease Activity Index 2000 ≥6, requiring therapy intensification. DORIS/LLDAS, organ damage, flares and adverse events were monitored. Shared frailty survival, generalised linear models and K-means clustering were applied. RESULTS: Sustained DORIS and LLDAS for ≥6 months occurred in 41.1% and 80.4%, respectively, and resulted in reduced damage accrual (HR: 0.58; 95% CI 0.36 to 0.93 and 0.61; 0.43 to 0.86) and severe flares (HR: 0.14; 0.08 to 0.27 and 0.19; 0.13 to 0.27). LLDAS without DORIS was also protective (HR: 0.65; 0.43 to 0.98 for damage, 0.49; 0.36 to 0.67 for flares). Models fitting increasing duration of targets showed that DORIS ≥50% and LLDAS ≥60% of time, or alternatively, ≥24 and ≥36 months, achieved optimal balance between feasibility (20.2-41.7%) and specificity (73.3-86.1%) for damage-free outcome. These targets were linked to reduced serious adverse events (risk ratio (RR): 0.56-0.71), hospitalisation (RR: 0.70) and mortality (RR: 0.06-0.13). Patients with predominant arthritis and mucocutaneous disease experienced reduced DORIS/LLDAS, compared with counterparts with major organ involvement. Conventional drugs were more frequently used in the former group, whereas potent immunosuppressive/biological agents in the latter. CONCLUSIONS: In moderate-to-severe SLE, sustained DORIS/LLDAS for at least 6 months is sufficient, while attainment for at least 24 months ensures higher specificity for damage-free progression, thus facilitating treat-to-target strategies and clinical trials. Arthritis and skin disease represent unmet therapeutic needs that could benefit from novel biologics.

Anifrolumab for systemic lupus erythematosus with multi-refractory skin disease: A case series of 18 patients.

OBJECTIVE: Skin involvement is common in systemic lupus erythematosus (SLE), but may be resistant to conventional treatment. We sought to evaluate the efficacy of anifrolumab (ANI) in refractory cutaneous manifestations of SLE. METHODS: Case series of patients with refractory cutaneous SLE from three Rheumatology Departments in Greece. Outcome measures were improvement in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), physician global assessment (PGA) and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Clinically relevant improvement in skin was defined as decrease ≥50% (CLASI50) from baseline values. RESULTS: Eighteen patients received ANI; all had active skin involvement at baseline. Mean (SD) SLEDAI and PGA at ANI initiation were 7.4 (2.7) and 1.4 (0.5), respectively, with a mean prednisone dose 4.9 (4.5) mg/day. Mean CLASI (Activity/Damage) at baseline was 13.9 (9.7)/2.9 (4.6). Patients were refractory to a mean 6.3 (1.5) immunomodulatory agents (including hydroxychloroquine and glucocorticoids) before the initiation of ANI. After a mean 8.5 (4.6) months, 89% (n = 16/18) of patients demonstrated significant improvement in general lupus and cutaneous disease activity, and glucocorticoid tapering. Mean SLEDAI and mean CLASI at last visit were 3.4 (1.9) and 2.1 (2.4)/1.4 (2.2), respectively, and mean daily prednisone dose decreased to 2.4 (2.2). Of note, in this group of highly refractory patients CLASI50 was achieved in 16/18 (89%) patients. One patient discontinued ANI after 4 infusions due to a varicella-zoster virus infection and one patient, who initially responded to treatment with ANI, experienced a skin flare due to temporary discontinuation due to Covid 19 infection. DORIS remission and LLDAS were attained in two (11.1%) and eleven (61.1%) patients, respectively. CONCLUSION: Anifrolumab is highly effective in various skin manifestations of SLE, even after prior failure to multiple treatments.

Distinct long-term disease activity trajectories differentiate early on treatment with etanercept in both rheumatoid arthritis and spondylarthritis patients: a prospective cohort study.

To characterize disease activity trajectories and compare long-term drug retention between rheumatoid (RA) and spondylarthritis (SpA) patients initiating tumor necrosis factor inhibitor (TNFi) treatment (etanercept). Prospective observational study of RA, axial (AxSpA) and peripheral SpA (PerSpA) patients initiating etanercept during 2004-2020. Kaplan-Meier plots were used for drug retention comparisons and multivariable Cox regression models for predictors of discontinuation. Long-term disease activity trajectories were identified by latent class growth models using DAS28-ESR or ASDAS-CRP as outcome for RA and AxSpA respectively. We assessed 711 patients (450 RA, 178 AxSpA and 83 PerSpA) with a median (IQR) follow-up of 12 (5-32) months. At 5 years, 22%, 30% and 21% of RA, AxSpA and PerSpA patients, respectively, remained on therapy. Etanercept discontinuation was independent of the diagnosis and was predicted by gender and obesity in both RA and SpA groups. Four disease activity (DA) trajectories were identified from 6th month of treatment in both RA and AxSpA. RA patients in remission-low DA groups (33.7%) were younger, had shorter disease duration, fewer comorbidities and lower baseline disease activity compared to moderate (40.6%) & high DA (25.7%) groups. In AxSpA 74% were in inactive-low DA and they were more often males, non-obese and had lower number of comorbidities compared to higher ASDAS-CRP trajectories. In RA and AxSpA patients, disease activity trajectories revealed heterogeneity of TNFi treatment responses and prognosis. Male gender, lower baseline disease activity and fewer comorbidities, characterize a favourable outcome in terms of disease burden accrual and TNFi survival.

The effects of golimumab on patient centric outcomes amongst rheumatoid arthritis patients in Greece. The GO-Q study.

This study aimed at assessing the impact of golimumab on health-related quality of life (HRQoL) and other patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) in real-world settings. GO-Q was an observational, prospective, 12-month study, which recruited patients with moderate-to-severely active RA initiating golimumab treatment per label in rheumatology clinics and private practices. Primary endpoint was the change in PROs [EuroQol-5 Dimensions-3 Levels (EQ-5D-3L) questionnaire, Health Assessment Questionnaire Disease Index (HAQ-DI), and Work Productivity and Activity Index for RA (WPAI:RA)] after 12 months of treatment. Other endpoints included Disease Activity Score for 28 joints with erythrocyte sedimentation rate (DAS28-ESR), healthcare resource utilization, and golimumab adherence. Changes in continuous variables from baseline were evaluated with the paired t test. One hundred forty-five patients were recruited. The mean [standard deviation (SD)] EQ-5D-3L index increased significantly at 12 months versus baseline [from 0.427 (0.206) to 0.801 (0.229); p < 0.0001], with changes as early as 3 and 6 months (both p < 0.0001). Accordingly, there were statistically significant changes in all WPAI:RA domains from baseline to 3, 6, and 12 months (p < 0.0001). Patients' function improved gradually from the third month until the end of follow-up (p < 0.0001 for all time-points). Thirty (27.3%) and 60 (54.6%) patients achieved remission (DAS28-ESR < 2.6) and low disease activity (DAS28-ESR ≤ 3.2), respectively, at 12 months. Adherence rate to golimumab was high (mean [SD] 90.3% (7.5) at 12 months). In patients with moderate-to-severely active RA, golimumab significantly improved HRQoL, physical function, and work productivity and activity, with improvements in disease activity over 12 months in real-world settings.

Lupus or not? SLE Risk Probability Index (SLERPI): a simple, clinician-friendly machine learning-based model to assist the diagnosis of systemic lupus erythematosus.

OBJECTIVES: Diagnostic reasoning in systemic lupus erythematosus (SLE) is a complex process reflecting the probability of disease at a given timepoint against competing diagnoses. We applied machine learning in well-characterised patient data sets to develop an algorithm that can aid SLE diagnosis. METHODS: From a discovery cohort of randomly selected 802 adults with SLE or control rheumatologic diseases, clinically selected panels of deconvoluted classification criteria and non-criteria features were analysed. Feature selection and model construction were done with Random Forests and Least Absolute Shrinkage and Selection Operator-logistic regression (LASSO-LR). The best model in 10-fold cross-validation was tested in a validation cohort (512 SLE, 143 disease controls). RESULTS: A novel LASSO-LR model had the best performance and included 14 variably weighed features with thrombocytopenia/haemolytic anaemia, malar/maculopapular rash, proteinuria, low C3 and C4, antinuclear antibodies (ANA) and immunologic disorder being the strongest SLE predictors. Our model produced SLE risk probabilities (depending on the combination of features) correlating positively with disease severity and organ damage, and allowing the unbiased classification of a validation cohort into diagnostic certainty levels (unlikely, possible, likely, definitive SLE) based on the likelihood of SLE against other diagnoses. Operating the model as binary (lupus/not-lupus), we noted excellent accuracy (94.8%) for identifying SLE, and high sensitivity for early disease (93.8%), nephritis (97.9%), neuropsychiatric (91.8%) and severe lupus requiring immunosuppressives/biologics (96.4%). This was converted into a scoring system, whereby a score >7 has 94.2% accuracy. CONCLUSIONS: We have developed and validated an accurate, clinician-friendly algorithm based on classical disease features for early SLE diagnosis and treatment to improve patient outcomes.

Incidence, risk factors and validation of the RABBIT score for serious infections in a cohort of 1557 patients with rheumatoid arthritis.

OBJECTIVES: Predicting serious infections (SI) in patients with rheumatoid arthritis (RA) is crucial for the implementation of appropriate preventive measures. Here we aimed to identify risk factors for SI and to validate the RA Observation of Biologic Therapy (RABBIT) risk score in real-life settings. METHODS: A multi-centre, prospective, RA cohort study in Greece. Demographics, disease characteristics, treatments and comorbidities were documented at first evaluation and one year later. The incidence of SI was recorded and compared with the expected SI rate using the RABBIT risk score. RESULTS: A total of 1557 RA patients were included. During follow-up, 38 SI were recorded [incidence rate ratio (IRR): 2.3/100 patient-years]. Patients who developed SI had longer disease duration, higher HAQ at first evaluation and were more likely to have a history of previous SI, chronic lung disease, cardiovascular disease and chronic kidney disease. By multivariate analysis, longer disease duration (IRR: 1.05; 95% CI: 1.005, 1.1), history of previous SI (IRR: 4.15; 95% CI: 1.7, 10.1), diabetes (IRR: 2.55; 95% CI: 1.06, 6.14), chronic lung disease (IRR: 3.14; 95% CI: 1.35, 7.27) and daily prednisolone dose ≥10 mg (IRR: 4.77; 95% CI: 1.47, 15.5) were independent risk factors for SI. Using the RABBIT risk score in 1359 patients, the expected SI incidence rate was 1.71/100 patient-years, not different from the observed (1.91/100 patient-years; P = 0.97). CONCLUSION: In this large real-life, prospective study of RA patients, the incidence of SI was 2.3/100 patient-years. Longer disease duration, history of previous SI, comorbidities and high glucocorticoid dose were independently associated with SI. The RABBIT score accurately predicted SI in our cohort.

Screening for cognitive impairment in systemic lupus erythematosus: Application of the Montreal Cognitive Assessment (MoCA) in a Greek patient sample.

BACKGROUND: Cognitive impairment (CI) is one of the most frequent neuropsychiatric manifestations of systemic lupus erythematosus (SLE). Given that extensive neuropsychological testing is not always feasible in routine clinical practice, brief cognitive screening tools are desirable. The aim of this study was to evaluate the Montreal Cognitive Assessment (MoCA) as a screening tool for CI in SLE. METHODS: Consecutive SLE patients followed at a single centre were evaluated using MoCA and an extensive neuropsychological test battery (NPT), including the Digits Forward and Digits Backwards, Rey Auditory Verbal Learning Memory Test, Trail Making Test, Stroop Colour-Word Test, Semantic and Phonetic Verbal Fluency tests and a 25-problem version of the General Adult Mental Ability test. The criterion validity of MoCA was assessed through receiver operating characteristic (ROC) analyses using three different case definitions: i) against normative population data, ii) and iii) against average performance of a comparison group of rheumatoid arthritis (RA) patients, to adjust for possible confounding effects of chronic illness and inflammatory processes on cognitive performance. The effect of patient-related (age, years of education, anxiety, depression, fatigue and pain) and disease-related (activity, damage, age at diagnosis, disease duration, use of glucocorticoid, psychotropic and pain medication) parameters on the MoCA was examined. RESULTS: A total of 71 SLE patients were evaluated. MoCA significantly correlated with all NPT scores and was affected by education level (p < 0.001), but not by other demographic or clinical variables. The optimal cutoff for detecting CI, as defined on the basis of normative population data, was 23/30 points, demonstrating 73% sensitivity and 75% specificity. A cutoff of 22/30 points, using neuropsychological profiles of the RA group as inflammatory disease controls, exhibited higher sensitivity (100%, based on both definitions) and specificity (87% and 90%, depending on the definition). The standard cutoff of 26/30 points displayed excellent sensitivity (91-100%) with significant expenses in specificity (43-45%). CONCLUSION: The MoCA is an easily applied tool, which appears to be reliable for identifying CI in SLE patients. The standard cutoff score (26/30) ensures excellent sensitivity while lower cutoff scores (22-23/30) may, also, provide higher specificity.

Combined genetic and transcriptome analysis of patients with SLE: distinct, targetable signatures for susceptibility and severity.

OBJECTIVES: Systemic lupus erythematosus (SLE) diagnosis and treatment remain empirical and the molecular basis for its heterogeneity elusive. We explored the genomic basis for disease susceptibility and severity. METHODS: mRNA sequencing and genotyping in blood from 142 patients with SLE and 58 healthy volunteers. Abundances of cell types were assessed by CIBERSORT and cell-specific effects by interaction terms in linear models. Differentially expressed genes (DEGs) were used to train classifiers (linear discriminant analysis) of SLE versus healthy individuals in 80% of the dataset and were validated in the remaining 20% running 1000 iterations. Transcriptome/genotypes were integrated by expression-quantitative trail loci (eQTL) analysis; tissue-specific genetic causality was assessed by regulatory trait concordance (RTC). RESULTS: SLE has a 'susceptibility signature' present in patients in clinical remission, an 'activity signature' linked to genes that regulate immune cell metabolism, protein synthesis and proliferation, and a 'severity signature' best illustrated in active nephritis, enriched in druggable granulocyte and plasmablast/plasma-cell pathways. Patients with SLE have also perturbed mRNA splicing enriched in immune system and interferon signalling genes. A novel transcriptome index distinguished active versus inactive disease-but not low disease activity-and correlated with disease severity. DEGs discriminate SLE versus healthy individuals with median sensitivity 86% and specificity 92% suggesting a potential use in diagnostics. Combined eQTL analysis from the Genotype Tissue Expression (GTEx) project and SLE-associated genetic polymorphisms demonstrates that susceptibility variants may regulate gene expression in the blood but also in other tissues. CONCLUSION: Specific gene networks confer susceptibility to SLE, activity and severity, and may facilitate personalised care.

Liver safety of non-tumour necrosis factor inhibitors in rheumatic patients with past hepatitis B virus infection: an observational, controlled, long-term study.

OBJECTIVES: The risk of hepatitis B virus (HBV) reactivation with non-tumour necrosis factor inhibitor (non-TNFi) biologic agents in patients with rheumatic diseases and past HBV infection has not been definively elucidated. We assessed the comparative safety of non-TNFi and TNFi biologic agents in such patients in real-life clinical settings. METGODS: We carried out a retrospective cohort study from the Department of Rheumatology, University Hospital of Heraklion. Patients who received abatacept (ABA), tocilizumab (TCZ) or rituximab (RTX) during the period 2003-2016 and were HbsAg(-), anti-HBc(+), anti-HBs(±) at baseline, were monitored for HBV reactivation. Patients treated with TNFi agents during the same period were used as a control group. RESULTS: 101 cases of non-TNFi (39 ABA, 32 RTX and 30 TCZ) and 111 cases of TNFi treatment were identified. In non-TNFi, 76 cases (75.2%) were anti-HBc(+)/anti-HBs(+) and 25 (24.8%) were anti-HBc(+)/anti-HBs(-), as compared to 82 (73.9%) and 29 (26.1%) in TNFi-treated, respectively. After a median (IQR) observation of 24.0 (34.7) months, two cases (2.0%) of HBV reactivation were identified in the non-TNFi group; one with ABA, successfully treated with entecavir, and one fatal case with RTX and prior exposure to cyclophosphamide. No reactivation was observed in the TNFi group (p=0.226 vs. non-TNFi). Αnti-HBs titres were significantly reduced compared to baseline in the non-TNFi group [median (IQR) 203.9 (954.7) mIU/ml before treatment versus 144.9 (962.9) mIU/ml after treatment, p=0.03]. CONCLUSIONS: Two cases of HBV reactivation highlight the risk for this complication in patients with past HBV infection under biologic therapy.

In early arthritis patients, high HAQ at baseline and DAS28 at three months predict suboptimal outcomes at two years: a retrospective cohort study.

OBJECTIVES: Early arthritis clinics (EAC) aim to improve rheumatoid arthritis (RA) outcomes by tailoring treatment targeting to remission. Our aim was to analyse disease course and relevant predictors over 2 years in early arthritis; we also assessed the applicability of the "treat-to-target approach" in a real-life EAC. METHODS: Patients with early arthritis recruited at the EAC of the University Hospital of Heraklion were followed prospectively according to a follow-up protocol for two years, without implementing a pre-specified treatment protocol, to capture real-life practices. Early predictors of "suboptimal outcomes" (high disease activity or HAQ>1.0 at 2 years) and biologic DMARD (bDMARD) initiation were evaluated with multivariate logistic regression. Intensification of treatment at 3 and 6 months and subsequent long-term outcome were also assessed. RESULTS: 251 patients [RA (n=188), undifferentiated arthritis (n=63)] were included. Although both DAS28 and HAQ at 2 years improved significantly compared to baseline in RA patients [mean (SD) DAS28 and median (IQR) HAQ 3.70 (1.32) and 0.44 (0.75) at 2 years, p<0.001 for both compared to baseline], 43.7% still had moderate and 18.8% high disease activity. The most powerful predictor of suboptimal outcomes or bDMARD initiation in RA was high disease activity at three months (adjusted odds ratio 2.22 and 2.62, respectively). At three and six months 72.8% and 62.4% of patients with medium/high disease activity received treatment intensification, which resulted in significant decrease in disease activity at 2 years (p<0.001 for ΔDAS28). CONCLUSIONS: DAS28 at three months was the most powerful predictor of suboptimal disease outcome during a 2-year follow-up in early RA. Despite significant DAS reductions, more than 50% of patients have active disease at two years. Failure to fully implement the treat-to-target strategy in our cohort could account for the low remission rates.

Adaptation to inflammatory rheumatic disease: Do illness representations predict patients' physical functioning over time? A complex relationship.

Patients with an inflammatory rheumatic disease (IRD), are often faced with significant limitations in physical functioning. Illness representations are a key-factor of their illness-related experience. Our aim was to examine (a) whether illness representations can predict or only reflect IRD patients' physical functioning over time, and (b) the specific pathways through which representations and physical functioning at baseline are associated with representations and functioning at follow-up. Patients with rheumatoid arthritis (N = 54) or systemic lupus erythematosus (N = 58) participated in the two phases of the study, 1 year apart. According to the results, illness representations were rather predicted by physical functioning than the other way around. At the same time, illness representations at baseline and at follow-up seemed to form a chain that mediated the relation between physical functioning at baseline and 1 year later. These findings may help us better delineate the interplay between the ways patients understand their condition and adaptation to illness.

Differential Expression of miR-4520a Associated With Pyrin Mutations in Familial Mediterranean Fever (FMF).

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent, acute, and self-limiting attacks of fever. Mutations in MEFV gene encoding pyrin account for FMF, but the high number of heterozygote patients with typical symptoms of the disease has driven a number of alternative aetiopathogenic hypotheses. The MEFV gene was knocked down in human myelomonocytic cells that express endogenous pyrin to identify deregulated microRNAs (miRNAs). Microarray analyses revealed 29 significantly differentially expressed miRNAs implicated in pathways associated with cellular integrity and survival. Implementation of in silico gene network prediction algorithms and bioinformatics analyses showed that miR-4520a is predicted to target genes implicated in autophagy through regulation of RHEB/mTOR signaling. Differential expression levels of RHEB were confirmed by luciferase reporter gene assays providing further evidence that is directly targeted by miR-4520a. Although the relative expression levels of miR-4520a were variable among FMF patients, the statistical expression of miR-4520a was different between FMF mutation carriers and controls (P = 0.0061), indicating an association between miR-4520a expression and MEFV mutations. Comparison between FMF patients bearing the M694V mutation, associated with severe disease, and healthy controls showed a significant increase in miR-4520a expression levels (P = 0.00545). These data suggest that RHEB, the main activator of mTOR signaling, is a valid target of miR-4520a with the relative expression levels of the latter being significantly deregulated in FMF patients and highly dependent on the presence of pyrin mutations, especially of the M694V type. These results suggest a role of deregulated autophagy in the pathogenesis of FMF. J. Cell. Physiol. 232: 1326-1336, 2017. © 2016 Wiley Periodicals, Inc.

Epidemiology and burden of systemic lupus erythematosus in a Southern European population: data from the community-based lupus registry of Crete, Greece.

OBJECTIVES: Several population-based studies on systemic lupus erythematosus (SLE) have been reported, yet community-based, individual-case validated, comprehensive reports are missing. We studied the SLE epidemiology and burden on the island of Crete during 1999-2013. METHODS: Multisource case-finding included patients ≥15 years old. Cases were ascertained by the ACR 1997, SLICC 2012 criteria and rheumatologist diagnosis, and validated through synthesis of medical charts, administrative and patient-generated data. RESULTS: Overall age-adjusted/sex-adjusted incidence was 7.4 (95% CI 6.8 to 7.9) per 100 000 persons/year, with stabilising trends in women but increasing in men, and average (±SD) age of diagnosis at 43 (±15) years. Adjusted and crude prevalence (December 2013) was 123.4 (113.9 to 132.9) and 143 (133 to 154)/105 (165/105 in urban vs 123/105 in rural regions, p<0.001), respectively. Age-adjusted/sex-adjusted nephritis incidence was 0.6 (0.4 to 0.8) with stable trends, whereas that of neuropsychiatric SLE was 0.5 (0.4 to 0.7) per 100 000 persons/year and increasing. Although half of prevalent cases had mild manifestations, 30.5% developed organ damage after 7.2 (±6.6) years of disease duration, with the neuropsychiatric domain most frequently afflicted, and 4.4% of patients with nephritis developed end-stage renal disease. The ACR 1997 and SLICC 2012 classification criteria showed high concordance (87%), yet physician-based diagnosis occurred earlier than criteria-based in about 20% of cases. CONCLUSIONS: By the use of a comprehensive methodology, we describe the full spectrum of SLE from the community to tertiary care, with almost half of the cases having mild disease, yet with significant damage accrual. SLE is not rare, affects predominantly middle-aged women and is increasingly recognised in men. Neuropsychiatric disease is an emerging frontier in lupus prevention and care.

Patterns of comorbidities differentially affect long-term functional evolution and disease activity in patients with 'difficult to treat' rheumatoid arthritis.

BACKGROUND: Characterisation of the long-term outcome of patients with 'difficult to treat' (D2T) rheumatoid arthritis and factors contributing to its evolution are unknown. Herein, we explored the heterogeneity and contributing factors of D2T long-term outcome. METHODS: Patients included from a prospective single centre cohort study. The EULAR definition of D2T was applied. Longitudinal clustering of functional status (modified Health Assessment Questionnaire (mHAQ)) and disease activity (Disease Activity Score-28 (DAS28)) were assessed using latent-class trajectory analysis. Multiple linear mixed models were used to examine the impact of comorbidities and their clusters on the long-term outcome. RESULTS: 251 out of 1264 patients (19.9%) were identified as D2T. Younger age, fibromyalgia, osteoarthritis, DAS28-erythrocyte sedimentation rate (ESR) at first biological or targeted synthetic disease-modifying antirheumatic drug (b/ts-DMARD) initiation and failure to reduce DAS28-ESR scores within the first 6 months of b/ts-DMARD therapy were significant predictors of patients becoming D2T. Long-term follow-up (total of 5872 person-years) revealed four groups of functional status evolution: 18.2% had stable, mildly compromised mHAQ (mean 0.41), 39.9% had gradual improvement (1.21-0.87) and two groups had either slow deterioration or stable significant functional impairment (HAQ>1). Similarly, four distinct groups of disease activity evolution were identified. Among the different clusters of comorbidities assessed, presence of 'mental-health and pain-related illnesses' or 'metabolic diseases' had significant contribution to mHAQ worsening (p<0.0001 for both) and DAS28 evolution (p<0.0001 and p=0.018, respectively). CONCLUSION: D2T patients represent a heterogeneous group in terms of long-term disease course. Mental-health/pain-related illnesses as well as metabolic diseases contribute to long-term adverse outcomes and should be targeted in order to optimise the prognosis of this subset of rheumatoid arthritis.

Progressive Multifocal Leukoencephalopathy in Systemic Lupus Erythematosus: A Consequence of Patient-Intrinsic or -Extrinsic Factors?

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system (CNS) caused by reactivation of the polyomavirus JC (JCV) typically in immunocompromised individuals. The risk of PML among rheumatic diseases may be higher for systemic lupus erythematosus (SLE), without, however, a clear association with the type and intensity of background therapy. We present the development and outcome of PML in a 32-year-old female lupus patient under mild immunosuppressive treatment, yet with marked B-cell lymphopenia in the peripheral blood and bone marrow (<1% of total lymphocytes). Despite treatment with the immune checkpoint inhibitor pembrolizumab, the patient showed progressive neurological and brain imaging deterioration and eventually died 15 months after PML diagnosis. To unveil possible underlying genetic liabilities, whole exome sequencing was performed which identified deleterious variants in GATA2 and CDH7 genes, which both have been linked to defective T- and/or B-lymphocyte production. These findings reiterate the possible role of disease-/patient-intrinsic factors, rather than that of drug-induced immunosuppression, in driving immune dysregulation and susceptibility to PML in certain patients with SLE.

A Peripheral Blood Signature of Increased Th1 and Myeloid Cells Combined with Serum Inflammatory Mediators Is Associated with Response to Abatacept in Rheumatoid Arthritis Patients.

Abatacept (CTLA4-Ig)-a monoclonal antibody which restricts T cell activation-is an effective treatment for rheumatoid arthritis (RA). Nevertheless, only 50% of RA patients attain clinical responses, while predictors of response are rather limited. Herein, we aimed to investigate for early biomarkers of response to abatacept, based on a detailed immunological profiling of peripheral blood (PB) cells and serum proteins. We applied flow cytometry and proteomics analysis on PB immune cells and serum respectively, of RA patients starting abatacept as the first biologic agent. After 6 months of treatment, 34.5% of patients attained response. At baseline, Th1 and FoxP3+ T cell populations were positively correlated with tender joint counts (p-value = 0.047 and p-value = 0.022, respectively). Upon treatment, CTLA4-Ig effectively reduced the percentages of Th1 and Th17 only in responders (p-value = 0.0277 and p-value = 0.0042, respectively). Notably, baseline levels of Th1 and myeloid cell populations were significantly increased in PB of responders compared to non-responders (p-value = 0.009 and p-value = 0.03, respectively). Proteomics analysis revealed that several inflammatory mediators were present in serum of responders before therapy initiation and strikingly 10 amongst 303 serum proteins were associated with clinical responses. Finally, a composite index based on selected baseline cellular and proteomics' analysis could predict response to abatacept with a high sensitivity (90%) and specificity (88.24%).

Comorbidities Burden and Implementation of the Treat-to-Target Strategy in Predicting Real-World Patient Outcomes in Spondyloarthritides.

New biologic and small molecule targeted agents have expanded the armamentarium of Spondyloarthritides (SpA), allowing more therapeutic options for patients who do not respond to therapy. The implementation of the treat-to-target (T2T) strategy with close monitoring and frequent treatment adaptations targeting disease remission has been proposed as the means to prevent radiographic progression and long-term adverse outcomes. In this project we will employ the "University of Crete Rheumatology Clinic Registry" to prospectively study in real-world practice musculoskeletal and extraarticular disease activity, patient function, comorbidities, sociodemographics, imaging, compliance to therapy and other lifestyle factors in axial and peripheral SpA patients. The predictive value of these variables in long-term (2years) outcomes will be evaluated. We will also assess the implementation of the T2T approach as well as its impact on long-term patients' outcomes (quality of life, productivity, adverse events). The successful completion of this study could pave the way for improved and personalized therapy in patients with SpA.

Correction: Nikoloudaki et al. Persistence of Depression and Anxiety despite Short-Term Disease Activity Improvement in Patients with Systemic Lupus Erythematosus: A Single-Centre, Prospective Study. J. Clin. Med. 2022, 11, 4316.

There was an error in the original publication [...].

Persistence of Depression and Anxiety despite Short-Term Disease Activity Improvement in Patients with Systemic Lupus Erythematosus: A Single-Centre, Prospective Study.

Mental disorders such as anxiety and depression are prevalent in systemic lupus erythematosus (SLE) patients, yet their association with the underlying disease activity remains uncertain and has been mostly evaluated at a cross-sectional level. To examine longitudinal trends in anxiety, depression, and lupus activity, a prospective observational study was performed on 40 adult SLE outpatients with active disease (SLE Disease Activity Index [SLEDAI]-2K ≥ 3 [excluding serology]) who received standard-of-care. Anxiety and depression were determined at baseline and 6 months by the Hospital Anxiety and Depression Scale. Treatment adherence was assessed with the Morisky Medication Adherence Scale-4. Increased anxiety (median [interquartile range] HADS-A: 11.0 [7.8]) and depression (HADS-D: 8.0 [4.8]) were found at inclusion, which remained stable and non-improving during follow-up (difference: 0.0 [4.8] and −0.5 [4.0], respectively) despite reduced SLEDAI-2K by 2.0 (4.0) (p < 0.001). Among possible baseline predictors, paid employment­but not disease activity­correlated with reduced HADS-A and HADS-D with corresponding standardized beta-coefficients of −0.35 (p = 0.017) and −0.27 (p = 0.093). Higher anxiety and depression correlated with lower treatment adherence (p = 0.041 and p = 0.088, respectively). These results indicate a high-mental disease burden in active SLE that persists despite disease control and emphasize the need to consider socioeconomic factors as part of comprehensive patient assessment.