Rheumatic immune-and nonimmune-related adverse events in phase 3 clinical trials assessing PD-(L)1 checkpoint inhibitors for lung cancer: A systematic review and meta-analysis.

OBJECTIVES: We aimed to analyze rheumatic immune-related (ir) and nonimmune-related adverse events (AEs) due to immune-checkpoint inhibitors (ICIs) targeting programmed cell death-1 or its ligand PD-(L)1 in lung cancer patients from the available literature. METHODS: We performed a systematic review and meta-analysis of phase III randomized clinical trials (RCTs) assessing PD-(L)1-ICIs in lung cancer patients, from inception until January 12th, 2021. We extracted data of each trial to estimate odds ratio (OR) for rheumatic ir or non-irAE as classified in RCTs safety data. Sensitivity analyses (by ICI, treatment group and histology) were performed. RESULTS: Eighteen RCTs met the inclusion criteria (n=12172 subjects). The OR [95%IC] for rheumatic irAE in ICIs versus controls (either placebo or chemotherapy) was 2.20 [0.85,5.72]. Among rheumatic non-irAEs, both overall and severe (grade≥3) back pain were significantly more frequent in ICIs versus controls, 2.01 [1.09;3.73] and 2.90 [1.18;7.08], respectively. The overall frequency of arthralgia was similar between ICIs and controls; by sensitivity analysis RCTs assessing ICIs in combination with chemotherapy showed a significant association with arthralgia (1.55 [1.15;2.10]). Similarly, the frequency of myalgia was significantly lower in RCTs assessing ICIs alone versus chemotherapy (OR 0.32 [0.24;0.42]). Muscular pain was not significantly increased with ICI. CONCLUSION: Rheumatic irAEs are not increased in RCTs assessing PD-(L)1 inhibitors, not reflecting the real-life incidence, therefore likely underreported or misclassified. Back pain is significantly associated with them regardless its severity, while arthralgia only when ICIs are added on conventional chemotherapy.

Long-term Outcome of Children Born to Women with Autoimmune Rheumatic Diseases: A Multicentre, Nationwide Study on 299 Randomly Selected Individuals.

The concern about the offspring's health is one of the reasons for a reduced family size of women with rheumatic diseases (RD). Increased risk of autoimmune diseases (AD) and neurodevelopmental disorders (ND) has been reported in children born to patients with RD. Within a nationwide survey about reproductive issues of women with RD, we aimed at exploring the long-term outcome of their children. By surveying 398 patients who received their diagnosis of RD during childbearing age (before the age of 45), information about the offspring were obtained from 230 women who declared to have had children. A total of 148 (64.3%) patients were affected by connective tissue diseases (CTD) and 82 (35.7%) by chronic arthritis. Data on 299 children (156 males, 52.1%; mean age at the time of interview 17.1 ± 9.7 years) were collected. Twelve children (4.0%), who were born to patients with CTD in 75% of the cases, were affected by AD (8 cases of celiac disease). Eleven children had a certified diagnosis of ND (3.6%; 6 cases of learning disabilities); 9 of them were born to mothers with CTD (5 after maternal diagnosis). No association was found between ND and prenatal exposure to either maternal autoantibodies or anti-rheumatic drugs. Absolute numbers of offspring affected by AD and ND were low in a multicentre cohort of Italian women with RD. This information can be helpful for the counselling about reproductive issues, as the health outcomes of the offspring might not be an issue which discourage women with RD from having children.

Anti-neutrophil cytoplasmic antibody specificity determines a different clinical subset in granulomatosis with polyangiitis.

OBJECTIVES: It has been suggested that anti-neutrophil cytoplasmic antibody (ANCA) specificity, rather than clinical diagnosis influences the phenotype and course of ANCA-associated vasculitis (AAV). However, preliminary evidence suggests that further combined levels of categorisation might be of clinical relevance. The aim of this study was to investigate differences in clinical presentation at disease onset and outcomes based on clinical diagnosis and ANCA specificity. METHODS: Newly diagnosed patients with GPA or MPA assessed in three referral centres between 2000 and 2016 were included. Patients were grouped as MPO-ANCA-positive granulomatosis with polyangiitis (MPO-GPA), PR3-ANCA-positive-GPA (PR3-GPA), and MPO-ANCA-positive microscopic polyangiitis (MPO-MPA). RESULTS: Of the 143 AAV patients included (female 52%), 87 were categorised as PR3-GPA, 23 as MPO-GPA, and 33 as MPO-MPA. Patients with MPO-GPA were significantly younger than MPA patients (age 49±15 versus 63±10; p<0.001). MPO-GPA had significantly more frequent subglottic stenosis compared to PR3-GPA. Ear, nose, throat involvement was significantly more frequent in both GPA groups compared to MPA. Type of pulmonary involvement differed between both GPA groups and MPA with diffuse pulmonary haemorrhage being significantly more frequent in the latter (7% in PR3-GPA, 0% in MPO-GPA, 27% in MPOMPA; p<0.001). Renal involvement was more frequent in MPO-MPA compared to both MPO-GPA and PR3-GPA (impaired renal function in 84%, 39%, and 36%, respectively; p<0.001). PR3-GPA relapsed significantly more than the other two groups. After adjusting for age, MPO-GPA was a significant risk factor for mortality [HR 4.44 (95%CI 1.46-13.52), p=0.009]. CONCLUSIONS: ANCA specificity identifies specific subsets of disease characterised by different clinical presentation and outcome within the clinical diagnosis of GPA.

Meta-analysis of immune-related adverse events in phase 3 clinical trials assessing immune checkpoint inhibitors for lung cancer.

INTRODUCTION: The introduction in clinical practice of the immune checkpoint inhibitors (ICIs) radically changed the treatment algorithm of lung cancers. To characterize the toxicity of ICIs (atezolizumab, durvalumab, nivolumab, pembrolizumab) is important for personalizing treatment. PATIENTS AND METHODS: We performed a systematic review and meta-analysis of phase III randomized controlled trials assessing ICIs, from inception until April 23rd, 2020. We extracted the data from the ICI arm of each trial for indirect comparisons to estimate relative risk for immune-related adverse events (irAEs), severe (grade ≥3) irAEs, drug discontinuation due to irAEs or toxic death. RESULTS: Sixteen trials included a total of 6226 subjects randomized to the experimental immunotherapy arm. Immunotherapy was administered in monotherapy (8 trials), in combination with chemotherapy (6 trials) or other ICI (2 trials). Any grade irAEs and severe irAEs for ICI were 37.1% and 18.5%, respectively. Discontinuations due to any grade irAEs and severe irAEs were 13.8% and 9.2%, respectively; toxic deaths were 2.9% in the immunotherapy arm. Pooled data on any, severe and organ-specific irAEs showed that immunotherapy has a significantly lower risk of irAEs compared to immuno-chemotherapy, especially when analysis was restricted to monoimmunotherapy, like drug discontinuation and toxic death (all p < 0.05). Detailed comparisons between different ICIs provided treatment-related risk profiles for organ-specific irAEs. CONCLUSIONS: Our findings contribute to clarifying frequency and features of immune-related toxicities between different ICIs in lung cancer patients, including any grade irAEs, severe irAEs, drug discontinuation and toxic deaths, and may be useful to inform the selection of treatment.

Personalized medicine in rheumatoid arthritis: How immunogenicity impacts use of TNF inhibitors.

Up to 40% of patients treated with tumor necrosis factor alpha inhibitors (TNFi) do not respond to therapy. Testing drug bioavailability and/or anti-drug antibody (ADAb) levels may justify dosage adjustment or switch to different drugs, enabling a personalized medicine approach. We report a multicenter cross-sectional study on different methods [ELISA and a cell based functional assay (reporter gene assay - RGA)] for drug/ADAb detection, and on the relationship between drug bioavailability and ADAb. 163 patients with rheumatoid arthritis (RA) treated with infliximab (IFX; n = 67), adalimumab (ADL; n = 49) or etanercept (ETA; n = 47) were tested for drug and ADAb levels. Furthermore, we report prospective data from additional 70 patients (59 RA and 11 juvenile idiopathic arthritis - JIA) tested for drug and ADAb levels at baseline (T0) and after 3 (T3) and 6 months (T6) of treatment with ADL or ETA only. IFX-treated patients were not included because of the increasing use of IFX biosimilars. Stringent inclusion criteria were used in order to avoid unwanted variables in both studies; none of the patients used TNFi before the study, and TNFi was used only in combination with methotrexate. Clinical response was defined according to EULAR response criteria. The two assays performed comparably in the comparison study. Accordingly, ELISA was selected for the prospective study because of its feasibility in the clinical setting. The cross-sectional study found ADAb in IFX and ADL treated groups only, that were associated with a decrease in pharmacological drug availability in the blood. Comparable results were found for the ADL-treated group in the prospective study which also showed a relationship between drug/ADAb levels and the loss of clinical response. Altogether our findings support drug and anti-drug Ab monitoring in the real-world clinical setting thus enabling individualized treatment and reducing disability in chronic inflammatory arthritis.

Disease and treatment-related morbidity in young and elderly patients with granulomatosis with polyangiitis and microscopic polyangiitis.

OBJECTIVE: Aging may be a risk factor for morbidity in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We compared the rate and better characterized the type of disease- and treatment-related complications affecting young and elderly patients with AAV. METHODS: All new cases of granulomatosis with polyangiitis or microscopic polyangiitis diagnosed in three referral centers between 2000-2016 were included. Patients were stratified by age into young or elderly (< or ≥65 years old, respectively). Data were collected from diagnosis until end of follow-up, with scheduled annual visits or additional visits in case of relapse or complication requiring hospitalization. RESULTS: Of 141 patients included, 42 were elderly and 99 were young at the time of AAV diagnosis. Median follow-up was 58.0 [25-75% IQR, 31.0-60.0] months in young and 48.0 [23.25-60.0] months in elderly patients (p>0.05). Overall, the elderly group was associated to higher damage accrual assessed by Vasculitis Damage Index during follow-up (ß=0.28, p<0.05). Sixty-three (44.7%) patients had acute kidney injury due to AAV-glomerulonephritis at diagnosis. In contrast to elderly, young patients showed significant improvement in renal function over time, particularly in the first 6 months while on induction treatment (ΔeGFR, median [25-75%IQR], 5.3 [0.4-14] versus 22.8 [5.9-52.1] ml/min/1.73m2, p=0.008), without significant changes after ANCA type stratification. Despite similar immunosuppressive therapy approaches and relapse rates, elderly patients had a higher rate of severe infections compared to younger patients (HR 2.1, 95% CIs: 1.1-4.4, p=0.043). CONCLUSIONS: Elderly patients with AAV had higher susceptibility to disease- and treatment-related morbidity than younger patients, particularly to renal and infective morbidity.

Alveolar haemorrhage in ANCA-associated vasculitis: Long-term outcome and mortality predictors.

INTRODUCTION: Alveolar haemorrhage (AH) is considered an important cause of morbidity and early mortality in anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV). OBJECTIVES: The aim of this study was to identify predictors of outcome in patients with AH-AAV and to evaluate outcome and causes of death in this subset. MATERIALS AND METHODS: A multicenter retrospective study was conducted in 29 Italian Centers. Clinicians were asked to recruit all patients diagnosed with AAV-associated AH during the last 10 years, from 2007 to 2016. Univariate and multivariable analysis were performed. RESULTS: One-hundred and six patients were included (median age at onset of 55 years [IQR 42-67]). The majority were ANCA-positive (PR3 57.1%, MPO 33.7%) and 72.6% had also renal involvement. At presentation, anaemia was shown in 97 (92.4%) patients, hemoptysis in 54 (51.9%), respiratory failure in 68 (66.7%), of whom 48 (70.6%), requiring respiratory support. At the end of the 37 months [IQR 13-77] follow-up, 19/106 (17.9%) patients were dead. The main causes of death were active disease and infections. By stepwise regression analysis, age >65 years (HR 3.66 [95% CI 1.4-9.51], p = 0.008) and the need for respiratory support (HR 4.58 [95% CI 1.51-13.87], p = 0.007) at AH onset were confirmed to be predictive of mortality. CONCLUSIONS: Predictors of outcome in AAV-AH were determined. Factors related to the patient's performance status and the severity of the lung involvement strongly influenced the outcome. Balancing harms and benefits for the individual patient in induction and maintenance treatment strategies is crucial.

Overall mortality in combined pulmonary fibrosis and emphysema related to systemic sclerosis.

Objectives: This multicentre study aimed to investigate the overall mortality of combined pulmonary fibrosis and emphysema (CPFE) in systemic sclerosis (SSc) and to compare CPFE-SSc characteristics with those of other SSc subtypes (with interstitial lung disease-ILD, emphysema or neither). Methods: Chest CTs, anamnestic data, immunological profile and pulmonary function tests of patients with SSc were retrospectively collected. Each chest CT underwent a semiquantitative assessment blindly performed by three radiologists. Patients were clustered in four groups: SSc-CPFE, SSc-ILD, SSc-emphysema and other-SSc (without ILD nor emphysema). The overall mortality of these groups was calculated by Kaplan-Meier method and compared with the stratified log-rank test; Kruskal-Wallis test, t-Student test and χ² test assessed the differences between groups. P<0.05 was considered statistically significant. Results: We enrolled 470 patients (1959 patient-year); 15.5 % (73/470) died during the follow-up. Compared with the SSc-ILD and other-SSc, in SSc-CPFE there was a higher prevalence of males, lower anticentromere antibodies prevalence and a more reduced pulmonary function (p<0.05). The Kaplan-Meier survival analysis demonstrates a significantly worse survival in patients with SSc-CPFE (HR vs SSc-ILD, vs SSc-emphysema and vs other-SSc, respectively 1.6 (CI 0.5 to 5.2), 1.6 (CI 0.7 to 3.8) and 2.8 (CI 1.2 to 6.6). Conclusions: CPFE increases the mortality risk in SSc along with a highly impaired lung function. These findings strengthen the importance to take into account emphysema in patients with SSc with ILD.

Aging in Primary Systemic Vasculitis: Implications for Diagnosis, Clinical Manifestations, and Management.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) usually affect adults and older populations. The well recognized clinical (i.e., granulomatosis with polyangiitis [GPA], microscopic polyangiitis, and eosinophilic GPA) and serological phenotypes (i.e., anti-MPO-ANCA, anti-PR3-ANCA and ANCA negative) within AAV differ substantially for clinical, demographic, and epidemiological features, including age at presentation. Whether and how aging could contribute to the clinical expression of these disease phenotypes is intriguing and still overlooked. In addition, despite being predominantly a disease of the elderly, most of the studies analyzing drug interventions and the clinical trials on AAV explicitly excluded older patients, limiting the understanding of the disease in this subset of patients. In elderly patients induced with cyclophosphamide, a lower dose of treatment for patients aged 60 years or older and with reduced renal function has been recommended. Giant cell arteritis (GCA) and Takayasu's arteritis (TAK) are two primary systemic vasculitides involving large vessels that differ in age at presentation, with GCA patients being at least 10 years older than TAK patients. Different treatment approaches are effective in these conditions. However, a few authors have suggested that they might be considered expressions of the same clinical syndrome, rather than two different diseases. Novel insights into the role of senescence-related immunological and vascular processes might help to interpret the link between these two conditions. Overall, the impact of aging on all these vasculitides is complex and not easy to analyze. So far, few studies focusing on this topic have been published. We reviewed data on the clinical presentation, epidemiology, therapy, and disease- and treatment-related complications in patients affected by these vasculitides, highlighting the differences in young versus elderly subjects.

"Disease knowledge index" and perspectives on reproductive issues: A nationwide study on 398 women with autoimmune rheumatic diseases.

OBJECTIVE: The reproductive choices of women affected by rheumatic diseases (RD) can be influenced by several factors, including the quality of physician-patient communication. We conducted a survey on reproductive issues aiming at exploring the unmet needs of women with RD during childbearing age. METHODS: We administered 65 multiple-choice and 12 open-answer questions about pregnancy counselling, contraception, use of drugs during pregnancy and other women reproductive issues to 477 consecutive women with RD aged 18-55 years followed-up in 24 rheumatology centres in Italy. Analysis was restricted to 398 patients who received their diagnosis of RD before the age of 45. According to the RD diagnosis, patients were subdivided into 2 groups: connective tissue diseases (n = 249) and chronic arthritis (n = 149). RESULTS: At the time of interview, women in both groups had a mean age of 40 years. Nearly one third of patients in each group declared not to have received any counselling about either pregnancy desire nor contraception. A smaller family size than desired was reported by nearly 37% of patients, because of concerns related to maternal disease in one fourth of the cases. A "Disease Knowledge Index" (DKI) was created to investigate the degree of patients' information about the implications of their RD on reproductive issues. Having received counselling was associated with higher DKI values and with a positive impact on family planning. CONCLUSION: Italian women of childbearing age affected by RD reported several unmet needs in their knowledge about reproductive issues. Strategies are needed to implement and facilitate physician-patient communication.

Immediate treatment with tumour necrosis factor inhibitors in synthetic disease-modifying anti-rheumatic drugs-naïve patients with rheumatoid arthritis: results of a modified Italian Expert Consensus.

Objective: To establish clinical consensus for the optimal placement of TNF inhibitor (TNFi) in DMARDs-naïve RA patients. Methods: The steering group was composed of 15 Italian rheumatologists expert in the field of RA, who proposed and selected by consensus the clinically relevant questions on the role of TNFi treatment in DMARDs-naïve RA patients. The question was rephrased according to the population, intervention, comparison and outcome statement. The available scientific evidence on this topic were collected by updating the systematic literature reviews used for the EULAR 2013 recommendations up to January 2016. The aspects evaluated in the studies concerned clinical efficacy, radiographic structural damage and safety. After the systematic literature review the expert panel formulated a consensus statement, and a modified Delphi panel evaluated the level of agreement between panellists (strength of recommendation). Results: From a total of 1080 records we have included 6 studies, 2 randomized clinical trials and 4 open-label extension trials. Evidence from publications generated three statements for the final consensus document. The systematic literature review and the consensus statements developed showed that, for patients with early RA and in the presence of a treat-to-target strategy, the immediate use of anti-TNFi compared with an early (within 12 weeks) step-up to anti-TNF therapy did not confer a significant advantage regarding clinical, functional and radiographic outcomes. Conclusion: The most appropriate placement of the TNFi therapy in the treatment algorithm of early RA still remains a challenging clinical question that needs to be further addressed.

Safety profile of the interleukin-1 inhibitors anakinra and canakinumab in real-life clinical practice: a nationwide multicenter retrospective observational study.

A few studies have reported the safety profile of interleukin (IL)-1 blockers from real life. The aim of this study is to describe anakinra (ANA) and canakinumab (CAN) safety profile in children and adults, based on data from a real-life setting. Demographic, clinical, and therapeutic data from patients treated with ANA and CAN were retrospectively collected and analyzed. Four hundred and seventy five patients were enrolled; ANA and CAN were prescribed in 421 and 105 treatment courses, respectively. During a mean follow-up of 24.39 ± 27.04 months, 89 adverse events (AE) were recorded; 13 (14.61%) were classified as serious AE (sAE). The overall estimated rate of AE and sAE was 8.4 per 100 patients/year. Safety concerns were more frequent among patients aged ≥ 65 years compared with patients < 16 years (p = 0.002). No differences were detected in the frequency of safety concerns between monotherapy and combination therapy with immunosuppressants (p = 0.055), but a significant difference was observed when injection site reactions were excluded from AE (p = 0.01). No differences were identified in relation to gender (p = 0.462), different lines of biologic therapy (p = 0.775), and different dosages (p = 0.70 ANA; p = 0.39 CAN). The overall drug retention rate was significantly different according to the occurrence of safety concerns (p value < 0.0001); distinguishing between ANA and CAN, significance was maintained only for ANA (p < 0.0001 ANA; p > 0.05 CAN). Treatment duration was the only variable associated with onset of AE (OR = 0.399 [C.I. 0.250-0.638], p = 0.0001). ANA and CAN have shown an excellent safety profile; the risk for AE and sAE tends to decrease over time from the start of IL-1 inhibition.

Is balneotherapy effective for fibromyalgia? Results from a 6-month double-blind randomized clinical trial.

The aim of this study was to assess the efficacy and tolerability of balneotherapy (BT) in patients with primary fibromyalgia syndrome (FS). In a prospective, randomized, controlled, double-blind trial with a 6-month follow-up, 100 FS patients were randomized to receive a cycle of BT with highly mineralized sulfate water (BT group) or with tap water (control group). Clinical assessments were performed at screening visit, at basal time, and after treatment (2 weeks, 3 and 6 months). The primary outcome measures were the change of global pain on the Visual Analogue Scale (VAS) and Fibromyalgia Impact Questionnaire total score (FIQ-Total) from baseline to 15 days. Secondary outcomes included Widespread Pain Index, Symptom Severity Scale Score, Short Form Health Survey, State-Trait Anxiety Inventory (STAI), and Center for Epidemiologic Studies Depression Scale. We performed an intent-to-treat analysis. The Kolmogorov-Smirnov test was applied to verify the normality distribution of all quantitative variables and the Student's t test to compare sample data. In the BT group, we observed a significant improvement of VAS and FIQ-Total at the end of the treatment that persisted until 6 months, while no significant differences were found in the control group. The differences between groups were significant for primary parameters at each time point. Similar results were obtained for the other secondary outcomes except for the STAI outcome. Adverse events were reported by 10 patients in the BT group and by 22 patients in the control group. Our results support the short- and long-term therapeutic efficacy of BT in FS. TRIAL REGISTRATION: NCT02548065.

Ear, nose and throat involvement in granulomatosis with polyangiitis: how it presents and how it determines disease severity and long-term outcomes.

Ear, nose and throat (ENT) manifestations in granulomatosis with polyangiitis (GPA) represent the most frequent symptoms at disease onset. The aim of the study was to analyse ENT involvement at diagnosis, as well as how it could influence relapse rate, mortality and disease severity. A retrospective non-controlled cohort study was performed including all consecutive diagnosed GPA from 1996 to 2016 in two rheumatology centres of Northern Italy, focusing particularly on ENT presenting signs and symptoms at baseline. Eighty-nine patients (48.3% females) with new onset GPA were evaluated. They were mostly Caucasian (97.7%), middle aged (mean 54.5 years) and more frequently anti-neutrophil cytoplasmic antibodies (ANCA) positive (78.6%) with PR3 specificity (81.4%). At diagnosis, ENT involvement was reported in 71.9% patients, second only to systemic symptoms. These patients were significantly younger at disease onset (0.013), with less frequent renal involvement (0.014) irrespectively to ANCA status, but with significantly higher Vasculitis Damage Index (VDI) (0.001). The most frequent ENT manifestation was sinonasal involvement (58.4%, 73% of which with nasal inflammation/chronic sinusitis and 48% with nasal crusting), while otologic involvement (mainly otitis media/otomastoiditis) was observed in 34.8%. ENT-GPA patients presented a higher survival rate at 5 years (98.1 vs 77.7%, 0.049), and ENT involvement resulted to be an independent predictor of better outcome (OR 0.37, 95% CI 0.2-0.8, 0.019). Our data confirms that ENT involvement is not only one of the key clinical features of GPA, but also could point out a milder GPA subset with lower renal involvement and lower mortality rate, irrespectively to ANCA status.

Timing of onset affects arthritis presentation pattern in antisyntethase syndrome.

OBJECTIVES: To evaluate if the timing of appearance with respect to disease onset may influence the arthritis presentation pattern in antisynthetase syndrome (ASSD). METHODS: The patients were selected from a retrospective large international cohort of ASSD patients regularly followed-up in centres referring to AENEAS collaborative group. Patients were eligible if they had an antisynthetase antibody testing positive in at least two determinations along with arthritis occurring either at ASSD onset (Group 1) or during the course of the disease (Group 2). RESULTS: 445 (70%; 334 females, 110 males, 1 transsexual) out of the 636 ASSD we collected had arthritis, in the majority of cases (367, 83%) from disease onset (Group 1). Patients belonging to Group 1 with respect to Group 2 had an arthritis more commonly polyarticular and symmetrical (p=0.015), IgM-Rheumatoid factor positive (p=0.035), erosions at hands and feet plain x-rays (p=0.036) and more commonly satisfying the 1987 revised classification criteria for rheumatoid arthritis (RA) (p=0.004). Features such as Raynaud's phenomenon, mechanic's hands and fever (e.g. accompanying findings) were more frequently reported in Group 2 (p=0.005). CONCLUSIONS: In ASSD, the timing of appearance with respect to disease onset influences arthritis characteristics. In particular, RA features are more common when arthritis occurs from ASSD onset, suggesting an overlap between RA and ASSD in these patients. When arthritis appears during the follow-up, it is very close to a connective tissue disease-related arthritis. Also, the different prevalence of accompanying features between these two groups is in line with this possibility.

EBV-induced lymphoproliferative disorders in rheumatic patients: A systematic review of the literature.

OBJECTIVES: Epstein-Barr virus (EBV) is involved in the pathogenesis of approximately 40% of lymphoproliferative disorders (LPDs) arising in patients receiving immunosuppressive treatment (IST) for rheumatic diseases, but data from large cohorts are still not available. We aimed to identify clinicopathological features, management and outcome of this condition. METHODS: We reviewed all published cases of EBV-encoded RNA (EBER)-positive LPDs and included in our analysis one unpublished patient diagnosed in our Hospital. We excluded those cases without an underling rheumatic condition, a specific IST or not reporting univocal data. RESULTS: In the cumulative cohort of 159 patients, most were affected by rheumatoid arthritis (83.0%) and treated with methotrexate (75.4%). 68.5% of LPDs developed between the age of 40 and 70 years, after 13.3±9.6 years from rheumatic disease onset and 58.7±47.0 months of IST. LPDs were mostly B-cell lineage derived (39.0%), Ann Arbor disease's stage I (38.3%) and presented with extra-nodal involvement in 63.1%, which was most frequently represented by central nervous system (17.6%). The most common approach was IST withdrawal (93.3%), variably associated with radiotherapy(RT)/chemotherapy(CT) in 38.3% of cases. Overall, 61.7% of patients achieved a complete remission (CR; 30.2±24.0 months). Among published cases of patients that only suspended IS as first line treatment approach, 67.2% achieved CR. No significant demographic, clinical and histological differences between patients who achieved CR and who did not, and between who achieved CR by IST withdrawal alone and who did not were observed (P>0.05 in all comparison). CONCLUSIONS: The current study reviews all the published evidences of EBV-induced LPDs in patients receiving IST treatment for rheumatic conditions.

Clinical follow-up predictors of disease pattern change in anti-Jo1 positive anti-synthetase syndrome: Results from a multicenter, international and retrospective study.

OBJECTIVE: Arthritis, myositis and interstitial lung disease (ILD) constitute the classic clinical triad of anti-synthetase syndrome (ASSD). These patients experience other accompanying features, such as Raynaud's phenomenon, fever or mechanic's hands. Most ASSD patients develop the complete triad during the follow-up. In the present study we aimed to determine whether the subsequent appearance of accompanying features may suggest the development of triad findings lacking at the onset in anti-Jo1 positive ASSD patients. METHODS: Anti-Jo1 positive patients presenting with incomplete ASSD (no >2 classic triad features) were assessed. Clinical characteristics and clusters of disease manifestations were retrospectively collected and analyzed in a large international multicenter cohort of ASSD patients. RESULTS: 165 patients (123 women) with incomplete ASSD were identified. Ninety-five patients (57.5%) developed new classic triad manifestations after 15months median (IQR 9-51) and 40 (24%) developed new accompanying features after 19months median (IQR 6-56) from disease onset. During the follow-up, the ex-novo occurrence of triad features was observed in 32 out of 40 patients (80%) with new accompanying findings and in 63 out of 125 patients (50.5%) without new accompanying findings (p=0.002). In patients with at least one new accompanying feature the odds ratio for the occurrence of new triad manifestations was 3.94 with respect to patients not developing ex-novo accompanying findings (95% CI 1.68-9.21, p=0.002). CONCLUSION: Anti-Jo1 ASSD patients with incomplete forms at disease onset are at high risk for the subsequent occurrence of lacking classic triad findings. Although all ASSD patients should be carefully assessed for the occurrence of new triad features, a closer follow-up should be considered in the subgroup of patients developing ex novo accompanying findings. These patients, indeed, have near four-fold increased risk for new classic triad manifestation occurrence with respect to patients not presenting ex novo accompanying findings.

Factors influencing the choice of first- and second-line biologic therapy for the treatment of rheumatoid arthritis: real-life data from the Italian LORHEN Registry.

According to international recommendations, the selection of the biologic disease modifying anti-rheumatic drug (bDMARD) for rheumatoid arthritis (RA) is mainly left to the clinician's preference. We analyzed the real-life factors influencing the first-line choice or the switching strategy, focusing on the prescription of abatacept (ABA) or tocilizumab (TCZ) compared to TNFα inhibitors (TNFi). Patients enrolled in the Lombardy Rheumatology Network (LORHEN) Registry after January 1, 2010, when all considered bDMARD agents were available, were included. The population was divided into "first-" and "second-line" bDMARD. We included 1910 patients (first line n = 1264, second line n = 646). Age was higher in ABA or TCZ vs TNFi treated patients (p < 0.0001). Positive latent tuberculosis screening was associated with first-line ABA (p = 0.002). Methotrexate (MTX) combination therapy was lower in the TCZ group (p = 0.02). The type (dyslipidemia, hypertension, pulmonary disease) and the number of comorbidities influenced the choice towards ABA (p = 0.01). Multinomial logistic regression demonstrated that a second-line treatment, higher age, dyslipidemia, pulmonary disease, other comorbidities, and extra-articular RA manifestations were associated with ABA compared to TNFi. TCZ was associated with a second-line treatment, higher age, and more severe disease activity. Stopping the first bDMARD due to adverse events (AE) influenced the choice towards ABA. In real life, higher age and comorbidities influence the choice towards ABA and TCZ compared to TNFi. ABA was preferred in case of suspension of previous treatments due to AE. After failing a first-line TNFi, swapping to a different mechanism of action is more common.