Anifrolumab In Refractory Systemic Lupus Erythematosus: A Real-Life, Multicenter Study.

OBJECTIVE: To report the real-world experience on the use of ANI in refractory SLE. METHODS: Multicenter retrospective study involving 9 Italian SLE referral centers participating in a compassionate use program for the use of ANI in active adult SLE patients in whom all the available treatment choices failed, were not tolerated or contraindicated.At baseline, at 1, 3, 6, 9 and 12 months of treatment, overall and organ specific disease activity, flares, daily glucocorticoid (GC) dose, and adverse events were recorded. RESULTS: A total of 26 patients were enrolled. At 4 weeks after starting ANI, a significant decrease in SLEDAI-2K (p=0.005), SLEDAS (p=0.005) and PGA (p=0.001) was recorded, and the same trend was maintained over time. A significant reduction in CLASI-activity (p<0.001) and in tender (p=0.026) and swollen (p=0.017) joint count was also recorded. At 3 months of follow-up, 33% of patients already achieved a remission state, while 46% were in LLDAS; at 6 months, 50% were in remission and 80% in LLDAS. A significant reduction in the mean GC daily dose was observed, starting from week 4 (p=0.04). A total of 4 disease flares according to the SELENA-SLEDAI Flare Index were recorded (three mild-moderate and one severe). Overall, 4 out of 20 patients with at least 24 weeks of follow-up (20%) were considered "non responders". CONCLUSION: This study provides a real-world experience on the use of ANI in refractory SLE patients, confirming its rapid effectiveness and an overall acceptable safety profile.

Clinical, histologic and prognostic features of clinically amyopathic dermatomyositis.

OBJECTIVES: To characterise clinical amyopathic dermatomyositis (CADM) from a clinical, histological, and prognostic perspective. METHODS: We retrospectively recorded data from our DM cohort. Patients were categorised into three groups: classic DM, hypomyopathic DM (HDM), characterised by normal muscle strength and evidence of muscle involvement in laboratory tests and/or instrumental examinations and CADM, featured by normal muscle strength and unremarkable findings in both laboratory tests and instrumental examinations. Available muscle biopsies from each group were also compared. RESULTS: Our cohort included 63 DM (69.2%), 12 HDM (13.2%) and 16 CADM (17.6%) patients. Compared to DM, CADM patients were younger at onset and diagnosis (45.5±17 vs. 57±18, and 46±17 vs. 58±18 years, respectively; p<0.05). They were more likely to test positive for anti-MDA5 (37.5% vs. 4.8%) and anti- TIF1-γ (31.3% vs. 6.3%), had a higher incidence of arthritis (37.5% vs. 12.6%) and interstitial lung disease (ILD) (43.8% vs. 15.9%) (all comparisons with p<0.05). Muscle biopsies were available for 44 DM, 7 CADM, and 11 HDM patients, revealing similar sarcolemma MHC-I expression rates. Five-year survival rates were comparable across groups (DM: 74.6%, CADM: 75%, HDM: 83.3%). Cox analysis indicated the main mortality predictors in overall cohort were ILD (HR: 3.57, CI: 1.11-11.5) and cancer (HR: 3.67, CI: 1.17-11.5), not CADM (HR: 1.46, CI: 0.33-6.68). CONCLUSIONS: CADM patients differ in disease onset, autoantibody profiles, joint and lung involvement. While laboratory and instrumental tests have not shown muscle involvement in CADM, many muscle biopsies have shown MHC-I overexpression.

Anti-SAE dermatomyositis: clinical and histologic characteristics from a monocentric Italian cohort.

OBJECTIVES: Multiple myositis-specific antibodies have been identified, each associated with different clinical subsets of dermatomyositis (DM). Anti-SAE associated DM is considered the least studied subset. Our study aimed to evaluate the clinical and histological characteristics of DM patients with anti-SAE antibodies. As reference, patients with anti-Mi2 antibodies associated DM, representing a well-characterised subset, were analysed. METHODS: We recorded data from our DM cohort in the INflammatory MYositis REgistry (INMYRE). Patients were divided into two groups: those positive for anti-SAE and those positive for anti-Mi2 antibodies. Clinical characteristics, including skin, muscle, and extra-muscular involvements, were recorded. Available muscle biopsies were compared between the two groups. RESULTS: Of 92 DM patients, 10 (10.9%) were positive for anti-SAE and 17 (18.5%) for anti-Mi2. Anti-SAE positive DM patients showed classic DM findings but were characterised by a higher prevalence of skin itching (60% vs. 11.8%, p<0.01), shawl sign (40% vs. 5.9%, p<0.05) and lung involvement (30% vs. 0%, p<0.05) compared to anti-Mi2 positive patients. Furthermore, anti-SAE positive DM patients showed lower creatine kinase levels than those with anti-Mi2 (median [IQR]: 101 [58-647] vs. 1984 [974-3717], p<0.05) and a lower percentage of muscle fibre degeneration and necrosis (1.5%±1.7 vs. 5.9%±3.2, p<0.05) in muscle biopsies. No other differences were observed. CONCLUSIONS: Anti-SAE DM represents a disease subset characterised by classic cutaneous involvement often associated with itching, less severe muscle involvement, but potential pulmonary involvement that should always be investigated in these patients.

Similarities and differences between younger and older disease onset patients with newly diagnosed systemic lupus erythematosus.

OBJECTIVES: Several studies show that age at onset has an impact on the clinical-serological presentation, comorbidities and disease course of patients with systemic lupus erythematosus (SLE). We evaluated whether, in patients with recent onset SLE, the age at onset correlates with clinical-serological manifestations and with comorbidities. METHODS: We analysed 171 patients with a SLE diagnosis obtained within 12 months of diagnosis enrolled in the Early Lupus project. Based on the age of onset of the first disease symptom, they were stratified into 2 groups: early onset (18-45 years) and late onset (>45 years). The analysis was replicated by stratifying patients based on age at diagnosis (fulfillment of ACR classification criteria). Each comparison was made at baseline and at 36 months of follow-up. RESULTS: Baseline: patients with late onset displayed comorbidities (hypertension, dyslipidemia and osteoporosis) more frequently than early onset group. 11.4% of late onset patients had a malignancy in medical history, not recorded in the early onset cohort. The two groups differed neither in organ involvement (domain BILAG) nor in disease activity (ECLAM). Patients with early onset showed a disease with signs of higher serologic activity (higher frequency of anti-dsDNA positivity and lower mean C3 and C4 levels) and had malar rash more frequently than the late onset group (36.2% vs. 18.2%, p=0.042). Similar results were obtained by stratifying patients by age of diagnosis (18-45 years and >45 years), except for the higher frequency of discoid rash in the group with age at diagnosis >45 years (18% vs. 6.6%, p=0.045). 36 months: the 2 groups of patients independently of the stratification applied did not differ in the accumulation of damage, but showed a different pattern of 8 organ involvement. Musculoskeletal involvement was more frequent both in the late onset group (18.6% vs. 7.3%, p=0.043) and in the group with age at diagnosis >45 years (20.4% vs. 5.9%, p=0.009) compared to their counterparts, while renal involvement was more frequent in the group with age at diagnosis 18-45 years (21.4% vs. 6.1%, p=0.03).A sub analysis at 36 months on patients without hypertension and osteoporosis at enrollment showed that patients with older age at onset had a higher frequency of these comorbidities, compared to their counterparts. CONCLUSIONS: In our cohort, younger disease SLE onset seems to correlate with a more active immunological profile, while late onset with a higher incidence of comorbidities.

Glucocorticoid tapering and associated outcome in patients with newly diagnosed systemic lupus erythematosus: the real-world GULP prospective observational study.

OBJECTIVE: A subanalysis of the multicentre Early Lupus inception cohort was performed to investigate the real-world Glucocorticoids (GCs) Use in newly diagnosed systemic lupus erythematosus (SLE) Patients (GULP). METHODS: Patients starting prednisone (PDN) ≥5 mg/day and concomitant hydroxychloroquine or immunosuppressant within 12 months of SLE classification were enrolled. Core set variables were recorded at baseline and every 6 months, including changes in PDN dose, European Consensus Lupus Activity Measurement (ECLAM) and Systemic Lupus International Collaborating Clinics damage index. Regression models analysed predictors of tapering PDN<5 mg/day at any time and outcomes associated with different patterns of GCs tapering. RESULTS: The GULP study included 127 patients with SLE; 73 (57.5%) tapered and maintained PDN <5 mg/day, and 17 (13.4%) discontinued PDN within a 2-year follow-up. Renal involvement (HR: 0.41; p=0.009) and lower C3 serum levels (HR: 1.04; p=0.025) predicted a lack of PDN tapering below 5 mg/day. High ECLAM scores were associated with a greater probability of increasing PDN dose (OR: 1.6; p=0.004), independently of daily intake. Disease relapse rate did not statistically differ (p=0.706) between patients tapering PDN <5 mg/day (42/99, 42.4%) and those tapering PDN without dropping below 5 mg/day (13/28, 46.4%). Every month on PDN <5 mg/day associated with lower damage accrual (IRR: 0.96; p=0.007), whereas never tapering PDN <5 mg/day associated with a higher risk of developing GC-related damage (OR 5.9; p=0.014). CONCLUSION: Tapering PDN <5 mg/day was achieved and maintained in half of newly diagnosed patients with SLE and may represent a good balance between the need to prevent damage accrual and the risk of disease relapse.

Validity of Machine Learning in Predicting Giant Cell Arteritis Flare After Glucocorticoids Tapering.

Background: Inferential statistical methods failed in identifying reliable biomarkers and risk factors for relapsing giant cell arteritis (GCA) after glucocorticoids (GCs) tapering. A ML approach allows to handle complex non-linear relationships between patient attributes that are hard to model with traditional statistical methods, merging them to output a forecast or a probability for a given outcome. Objective: The objective of the study was to assess whether ML algorithms can predict GCA relapse after GCs tapering. Methods: GCA patients who underwent GCs therapy and regular follow-up visits for at least 12 months, were retrospectively analyzed and used for implementing 3 ML algorithms, namely, Logistic Regression (LR), Decision Tree (DT), and Random Forest (RF). The outcome of interest was disease relapse within 3 months during GCs tapering. After a ML variable selection method, based on a XGBoost wrapper, an attribute core set was used to train and test each algorithm using 5-fold cross-validation. The performance of each algorithm in both phases was assessed in terms of accuracy and area under receiver operating characteristic curve (AUROC). Results: The dataset consisted of 107 GCA patients (73 women, 68.2%) with mean age ( ± SD) 74.1 ( ± 8.5) years at presentation. GCA flare occurred in 40/107 patients (37.4%) within 3 months after GCs tapering. As a result of ML wrapper, the attribute core set with the least number of variables used for algorithm training included presence/absence of diabetes mellitus and concomitant polymyalgia rheumatica as well as erythrocyte sedimentation rate level at GCs baseline. RF showed the best performance, being significantly superior to other algorithms in accuracy (RF 71.4% vs LR 70.4% vs DT 62.9%). Consistently, RF precision (72.1%) was significantly greater than those of LR (62.6%) and DT (50.8%). Conversely, LR was superior to RF and DT in recall (RF 60% vs LR 62.5% vs DT 47.5%). Moreover, RF AUROC (0.76) was more significant compared to LR (0.73) and DT (0.65). Conclusions: RF algorithm can predict GCA relapse after GCs tapering with sufficient accuracy. To date, this is one of the most accurate predictive modelings for such outcome. This ML method represents a reproducible tool, capable of supporting clinicians in GCA patient management.

Severe muscle damage with myofiber necrosis and macrophage infiltrates characterize anti-Mi2 positive dermatomyositis.

OBJECTIVE: The aim of our study was to investigate clinical and histopathological findings in adult DM patients positive for anti-Mi2 (anti-Mi2+) antibodies compared with DM patients negative for anti-Mi2 (anti-Mi2-). METHODS: Clinical data of adult DM patients, who fulfilled EULAR/ACR 2017 classification criteria, were gathered from electronic medical records of three tertiary Rheumatology Units. Histopathological study was carried out on 12 anti-Mi2+ and 14 anti-Mi2- muscle biopsies performed for diagnostic purpose. Nine biopsies from immune mediated necrotizing myopathy (IMNM) patients were used as control group. RESULTS: Twenty-two anti-Mi2+ DM [90.9% female, mean age 56.5 (15.7) years] were compared with 69 anti-Mi2- DM patients [71% female, mean age 52.4 (17) years]. Anti-Mi2+ patients presented higher levels of serum muscle enzymes than anti-Mi2- patients [median (IQR) creatine-kinase fold increment: 16 (7-37)vs 3.5 (1-9.9), P <0.001] before treatment initiation. Moreover, a trend towards less pulmonary involvement was detected in anti-Mi2+ DM (9.1% vs 30.4%, P =0.05), without any case of rapidly progressive interstitial lung disease. At muscle histology, anti-Mi2+ patients showed more necrotic/degenerative fibres than anti-Mi2- patients [mean 5.3% (5) vs 0.8% (1), P <0.01], but similar to IMNM [5.9% (6), P >0.05]. In addition, the endomysial macrophage score was similar between anti-Mi2+ and IMNM patients [mean 1.2 (0.9) vs 1.3 (0.5), P >0.05], whereas lower macrophage infiltration was found in anti-Mi2- DM [mean 0.4 (0.5), <0.01]. CONCLUSIONS: Anti-Mi2+ patients represent a specific DM subset with high muscle damage. Histological hallmarks were a higher prevalence of myofiber necrosis, endomysial involvement and macrophage infiltrates at muscle biopsy.

Risk factors of damage in early diagnosed systemic lupus erythematosus: results of the Italian multicentre Early Lupus Project inception cohort.

OBJECTIVE: To investigate risk factors for damage development in a prospective inception cohort of early diagnosed SLE patients. METHODS: The Early Lupus Project recruited an inception cohort of patients within 12 months of SLE classification (1997 ACR criteria). At enrolment and every 6 months thereafter, the SLICC/ACR Damage Index was recorded. The contribution of baseline and time-varying covariates to the development of damage, defined as any SLICC/ACR Damage Index increase from 0 to ≥1, was assessed using univariate analysis. Forward-backward Cox regression models were fitted with covariates with P < 0.05 to identify factors independently associated with the risk of damage development. RESULTS: Overall, 230 patients with a mean (s.d.) age of 36.5 (14.4) years were eligible for this study; the mean number of visits per patient was 5.3 (2.7). There were 51 (22.2%) patients with SLICC/ACR Damage Index ≥1 after 12 months, 59 (25.6%) after 24 months and 67 (29.1%) after 36 months. Dyslipidaemia [P = 0.001; hazard ratio (HR) 2.9; 95% CI 1.5, 5.6], older age (P = 0.001; HR 3.0; 95% CI 1.6, 5.5), number of organs/systems involved (P = 0.002; HR 1.4; 95% CI 1.1, 1.8) and cardiorespiratory involvement (P = 0.041; HR 1.9; 95% CI 1.0, 3.7) were independently associated with an increased risk of developing damage. Risk profiles for damage development differed for glucocorticoid-related and -unrelated damage. HCQ use (P = 0.005; HR 0.4; 95% CI 0.2, 0.8) reduced the risk of glucocorticoid-unrelated damage. CONCLUSION: We identified risk factors of damage development, but little effect of glucocorticoids, in this early SLE cohort. Addressing modifiable risk factors from the time of SLE diagnosis might improve patient outcomes.

Evaluation of differences in carotid intima-media thickness in patients affected by systemic rheumatic diseases.

The objective of this study is to investigate whether rheumatic autoimmune diseases, systemic sclerosis (SSc) in particular, are associated with increased carotid intima-media thickness (C-IMT). A total of 108 clinical outpatients (93 females), mean age 51 ± 14 years suffering from CTD were consecutively enrolled. Patients were subdivided into the following two groups: (1) Systemic Sclerosis (SSc, 60 patients); (2) non-Systemic Sclerosis (NoSSc, 48 patients). No randomization was managed. All patients underwent structured clinical interview, physical examination, laboratory evaluation and two-dimensional echo-color Doppler of the carotid arteries to measure C-IMT and atherosclerotic plaques. Framingham risk score was also calculated. We also enrolled 108 healthy controls (HC), matched by sex and age. The primary outcome was to stratify cardiovascular risk of CTD patients. There were no significant differences between SSc and NoSSc patients regarding any of the demographics and traditional cardiovascular risk factors. Mean C-IMT was not significantly different between the whole CTD patients (0.86 ± 0.13 mm) and HC (0.83 ± 0.13 mm). C-IMT was significantly higher in SSc than in NoSSc group (0.91 ± 0.1 mm vs 0.80 ± 0.14 mm, p < 0.001). Furthermore, C-IMT in SSc group was significantly higher than C-IMT in controls (0.91 ± 0.1 mm vs 0.83 ± 0.13 mm, p < 0.001). C-IMT did correlate neither with disease activity nor with drug intake. SSc patients had a significant increase in C-IMT as compared to NoSSc patients and healthy controls.

Bone and kidney toxicity induced by nucleotide analogues in patients affected by HBV-related chronic hepatitis: a longitudinal study.

OBJECTIVES: Nucleotide analogues may promote renal and bone toxicity. The aim of the present study was to evaluate markers of osteorenal toxicity in patients affected by hepatitis B virus-related chronic hepatitis treated with lamivudine plus adefovir who were switched to tenofovir. PATIENTS AND METHODS: We evaluated 60 consecutive patients at the time of the switch of treatment and after 1, 3, 6, 9 and 12 months. The mean baseline estimated glomerular filtration rate (eGFR) was 89.3 ± 19.0 mL/min/1.73 m(2). RESULTS: During the study period we observed a reduction in mean eGFR up to 6 months after switching to tenofovir, and this remained stable for the last two timepoints. At the end of study, the mean eGFR was 82.6 ± 21.5 mL/min/1.73 m(2), a reduction of 7.5%. The mean baseline proteinuria was 202.6 ± 237.6 mg/24 h. Microhaematuria was observed in 22.6% of patients and hypophosphataemia in 18.6%. After 1 month of tenofovir, we observed a worsening of serum phosphate and parathyroid hormone levels, haemoglobinuria and 24 h proteinuria. After 3 and 12 months of tenofovir, these data tended to recover to baseline levels. A total of 92.6% of patients at baseline had hypovitaminosis D. After supplementation with cholecalciferol, this percentage decreased significantly. We observed a reduced bone mineral density (BMD) in 52.7% of patients at baseline; this increased to 77.8% after 6 months of tenofovir, but at the last timepoint the percentage of patients with a reduced BMD had fallen to a level above the baseline. CONCLUSIONS: In conclusion, patients exposed to lamivudine plus adefovir showed relevant osteorenal damage. The switch to tenofovir provoked a slight reduction in eGFR that stabilized after 6 months. The reduced BMD at baseline did not worsen under tenofovir treatment.

Paradoxical mucocutaneous flare in a case of Behçet's disease treated with tocilizumab.

We report on a patient with a long-standing history of recurrent oral aphthosis and pseudofolliculitis, diagnosed with Behçet's disease (BD), previously treated with high-dose prednisone, colchicine, cyclosporine, cyclophosphamide and methotrexate, all of which were partially effective. Treatment with the chimeric mouse-human anti-tumour necrosis factor (TNF)-α monoclonal antibody infliximab brought about the resolution of mucocutaneous lesions for a period of 6 years. After an oral and articular BD relapse, the anti-interleukin-6 agent tocilizumab was started in association with high-dose prednisone. Unexpectedly, the patient experienced a paradoxical mucocutaneous flare following tocilizumab administration, which worsened after the second infusion. Tocilizumab was then discontinued, and total recovery was achieved after the patient was started on the fully human anti-TNF-α monoclonal antibody golimumab in association with colchicine and methylprednisolone.