Practice pattern for the use of intravenous iloprost for the treatment of peripheral vasculopathy in systemic sclerosis: A case-control study from the Italian national multicenter "SPRING" (Systemic Sclerosis Progression InvestiGation) Registry.

Background: Intravenous iloprost has been widely used for the treatment of systemic sclerosis peripheral vasculopathy. No agreement has been found on the regimen and the dosage of intravenous iloprost in different scleroderma subset conditions. This study aimed to evaluate the modalities of intravenous iloprost administration within a large cohort of systemic sclerosis patients from the SPRING Registry and to identify any associated clinical-demographic, instrumental or therapeutic data. Patients and Methods: Data of systemic sclerosis patients treated with intravenous iloprost for at least 1 year (case group) were retrospectively analyzed, including different timing and duration of intravenous iloprost session, and compared with those of untreated patients (control group). Results: Out of 1895 analyzed patients, 937 (49%) received intravenous iloprost treatment, while 958 (51%) were assigned to the control group. Among cases, about 70% were treated every 4 weeks, 24% with an interval of more than 4 weeks, and only 6% of less than 4 weeks. Most patients receiving the treatment every 4 weeks, or less, underwent infusion cycle for 1 day only, while if it was scheduled with an interval of more than 4 weeks, a total number of 5 consecutive days of infusions was the preferred regimen. The comparison between the two groups revealed that patients treated with intravenous iloprost had a higher frequency of DUs (p < 0.001), pitting scars (p < 0.001), diffuse cutaneous involvement (p < 0.001), interstitial lung disease (p < 0.002), as well as higher rates of anti-topoisomerase I, "late" scleroderma pattern at nailfold videocapillaroscopy. These findings were confirmed by multivariate analysis. Conclusion: Our data provide a picture on the Italian use of intravenous iloprost among systemic sclerosis patients and showed that it was usually employed in patients with a more aggressive spectrum of the disease. The disparity of intravenous iloprost treatment strategies in the different centers suggests the need of a rational therapeutical approach based on the clinical characteristics of different patients' subsets.

Clinical and Serological Characteristics of a Monocentric Cohort of Patients Affected by Interstitial Pneumonia with Autoimmune Features (IPAF).

Introduction: Interstitial lung diseases (ILDs) are diseases characterised by excessive deposition of collagen matrices in the pulmonary interstitium. Some of them are considered idiopathic (idiopathic pulmonary fibrosis - IPF), others are related to known pathologies such as connective tissue diseases (CTDs-ILD). Patient affected by ILD and features referable to CTD, not satisfying CTD criteria, are called Interstitial pneumonia with autoimmune features (IPAF) patients. Objective: The aim of this report was to investigate clinical and serologic features of a monocentric cohort of patients with IPAF. Another objective was to describe the autoantibody profile, clinical features, High Resolution Computerised Tomography (HRCT) and Nailfold Video Capillaroscopy (NVC) patterns. Methods: 36 IPAF patients were consecutively enrolled. Clinical, serological, and morphological features were collected. Results: 36 consecutive IPAF patients were enrolled from January 2021 to January 2022. Raynaud's phenomenon was the most frequent symptom identified. We also described other signs and symptoms not included in IPAF criteria. 36,1% of patients demonstrated a Usual Interstitial Pneumonia (UIP) pattern by HRCT. Pulmonary arterial pressure estimation (PAPs) resulted elevated (≥ 25 mmHg) in 6 patients. Antinuclear antibodies (ANA) ≥ 1/80 was the most frequent autoantibody, followed by anti-Ro, in patients with UIP pattern and Non-Specific Interstitial Pneumonia (NSIP) pattern at HRCT. NVC highlighted non-specific microangiopathy as the most common pattern especially in UIP patients. Conclusions: This paper may contribute to stimulate the interest in better characterisation of clinical, serologic, and instrumental features for IPAF patients by redefining IPAF classification criteria in order to treat them as best as possible.

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.

Progression and prognosis of interstitial pneumonia with autoimmune features: a longitudinal, prospective, multi-centre study.

OBJECTIVES: To evaluate the rate of progression towards specific autoimmune diseases (SADs) of a prospective, multi-centre cohort of patients classifiable as interstitial pneumonia with autoimmune features (IPAF). METHODS: IPAF patients were enrolled based on specific research criteria, and jointly followed by rheumatologists and pulmonologists for at least one year with clinical check-ups, serological exams including autoimmunity, capillaroscopy and high-resolution computed tomography (HRCT). Diagnostic assessment was repeated at least once a year, or earlier when deemed useful. RESULTS: We enrolled 191 IPAF patients through 95 different combinations of IPAF criteria. Of these, 24.1% progressed towards SAD, mainly in connective tissue diseases but also in microscopic polyangiitis. The IPAF patients who progressed were younger than stable IPAF patients (63±10 years vs. 68±9 years, p=0.002) and had a longer follow-up (36.9±18.7 vs. 29.3±15.7 months, p=0.007), but similar severity. No parameters were associated with overall progression, but some parameters were associated with the development of specific diagnoses: Sjögren's syndrome with positivity for SSA (p=0.007, χ2 7.4); idiopathic inflammatory myopathy with mechanic's hands (p=<0.0001, χ2 12.6), organizing pneumonia pattern (p=0.01, χ2 6.1), positivity for anti-Pm/scl (p=0.04 χ2 4.1) and anti-MDA5 (p=0.04, χ2 4.2); systemic sclerosis with palmar telangiectasias (p=<0.0001 2 18.3), positivity for anti-Scl70 (p=<0.0001 χ2 12.5) and anti-PM/Scl (p=0.001 χ2 10.1). CONCLUSIONS: IPAF patients had a rate of progression towards SAD similar to that reported in previous studies on undifferentiated connective tissue diseases, thus including some patients in which lung involvement could represent the first or even the sole clinical manifestation of a SAD.

Geographical heterogeneity of clinical and serological phenotypes of systemic sclerosis observed at tertiary referral centres. The experience of the Italian SIR-SPRING registry and review of the world literature.

INTRODUCTION: Systemic sclerosis (SSc) is characterized by a complex etiopathogenesis encompassing both host genetic and environmental -infectious/toxic- factors responsible for altered fibrogenesis and diffuse microangiopathy. A wide spectrum of clinical phenotypes may be observed in patients' populations from different geographical areas. We investigated the prevalence of specific clinical and serological phenotypes in patients with definite SSc enrolled at tertiary referral centres in different Italian geographical macro-areas. The observed findings were compared with those reported in the world literature. MATERIALS AND METHODS: The clinical features of 1538 patients (161 M, 10.5%; mean age 59.8 ± 26.9 yrs.; mean disease duration 8.9 ± 7.7 yrs) with definite SSc recruited in 38 tertiary referral centres of the SPRING (Systemic sclerosis Progression INvestiGation Group) registry promoted by Italian Society of Rheumatology (SIR) were obtained and clustered according to Italian geographical macroareas. RESULTS: Patients living in Southern Italy were characterized by more severe clinical and/or serological SSc phenotypes compared to those in Northern and Central Italy; namely, they show increased percentages of diffuse cutaneous SSc, digital ulcers, sicca syndrome, muscle involvement, arthritis, cardiopulmonary symptoms, interstitial lung involvement at HRCT, as well increased prevalence of serum anti-Scl70 autoantibodies. In the same SSc population immunusppressive drugs were frequently employed. The review of the literature underlined the geographical heterogeneity of SSc phenotypes, even if the observed findings are scarcely comparable due to the variability of methodological approaches. CONCLUSION: The phenotypical differences among SSc patients' subgroups from Italian macro-areas might be correlated to genetic/environmental co-factors, and possibly to a not equally distributed national network of information and healthcare facilities.

Clinical spectrum time course in non-Asian patients positive for anti-MDA5 antibodies.

OBJECTIVES: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. METHODS: We conducted a multicentre, international, retrospective cohort study. RESULTS: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. CONCLUSIONS: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern.

Sex-related Differences in Systemic Sclerosis: A Multicenter Cross-sectional Study From the National Registry of the Italian Society for Rheumatology.

OBJECTIVE: There is still a great deal to learn about the influence of sex in systemic sclerosis (SSc). In this respect, national registries provide large and homogeneous patient cohorts for analytical studies. We therefore investigated a wide-ranging and well-characterized SSc series with the aim of identifying sex differences in disease expression, with a special focus on demographic, clinical, and serological characteristics. METHODS: A multicenter SSc cohort of 2281 patients, including 247 men, was recruited in the Italian Systemic sclerosis PRogression INvestiGation (SPRING) registry. Demographic data, disease manifestations, serological profile, and internal organ involvement were compared. RESULTS: The overall female/male ratio was 8.2:1. Female/male ratios for limited cutaneous SSc, diffuse cutaneous SSc, and SSc sine scleroderma subsets were 8.7:1, 4.9:1, and 10.7:1, respectively. A shorter time from onset of Raynaud phenomenon to SSc diagnosis, an increased prevalence of the diffuse cutaneous subset, renal crisis, and digital ulcers were found in males, whereas a significantly higher percentage of sicca syndrome, serum antinuclear antibodies, antiextractable nuclear antigens, anti-La/SSB, and anticentromere protein B was detected in the female group. Males exhibited lower left ventricular ejection fraction, as well as higher prevalence of conduction blocks, arrhythmias, ground glass, and honeycombing. Moreover, forced vital capacity and total lung capacity were medially lower in men than in women. Finally, males were more frequently treated with immunosuppressive drugs. CONCLUSION: Our study further supports the presence of several sex-related differences in patients with SSc. These differences were pronounced in the severity of cutaneous, peripheral vascular, and cardiopulmonary involvement for male patients, whereas an increased prevalence of sicca syndrome and a specific autoantibody profile characterized the female sex.

Low Preconception Complement Levels Are Associated with Adverse Pregnancy Outcomes in a Multicenter Study of 260 Pregnancies in 197 Women with Antiphospholipid Syndrome or Carriers of Antiphospholipid Antibodies.

Antiphospholipid antibodies (aPL) can induce fetal loss in experimental animal models. Human studies did find hypocomplementemia associated with pregnancy complications in patients with antiphospholipid syndrome (APS), but these results are not unanimously confirmed. To investigate if the detection of low C3/C4 could be considered a risk factor for adverse pregnancy outcomes (APO) in APS and aPL carriers' pregnancies we performed a multicenter study including 503 pregnancies from 11 Italian and 1 Russian centers. Data in women with APS and asymptomatic carriers with persistently positive aPL and preconception complement levels were available for 260 pregnancies. In pregnancies with low preconception C3/C4, a significantly higher prevalence of pregnancy losses was observed (p = 0.008). A subgroup analysis focusing on triple aPL-positive patients found that preconception low C3 and/or C4 levels were associated with an increased rate of pregnancy loss (p = 0.05). Our findings confirm that decreased complement levels before pregnancy are associated with increased risk of APO. This has been seen only in women with triple aPL positivity, indeed single or double positivity does not show this trend. Complement levels are cheap and easy to be measured therefore they could represent a useful aid to identify patients at increased risk of pregnancy loss.

Baseline characteristics of systemic lupus erythematosus patients included in the Lupus Italian Registry of the Italian Society for Rheumatology.

OBJECTIVE: To report baseline data of SLE patients enrolled in the Lupus Italian Registry (LIRE). METHODS: Patients affected by SLE aged ≥ 16 years were consecutively recruited in a multicenter prospective study comparing two cohorts: patients starting biologic immunosuppressants (BC) and patients starting non-biologic immunosuppresants (NBC). RESULTS: 308 patients were enrolled, 179 in NBC and 129 in BC. Mean age at disease onset and at diagnosis was significantly higher in NBC (p = 0.023, p = 0.045, respectively). Disease duration was longer in BC (p = 0.022). Patients in BC presented arthritis more frequently (p = 0.024), those in NBC nephropathy (p = 0.03). Quality of life was worse in BC (p = 0.031). Anti-dsDNA, low C3, were significantly more frequent in BC (p < 0.001, p = 0.009, respectively). Mycophenolate, methotrexate and azathioprine were the drugs more frequently prescribed in NBC, Belimumab and Rituximab in BC. CONCLUSION: The predominant organ involvement was different in the two cohorts: kidney involvement predominated in NBC, joint involvement in BC. Despite the younger age at disease onset, patients of the BC had a longer disease duration and more frequently had taken a cumulative prednisone dosage greater than 10 g. Even the pattern of clinical manifestations inducing to prescribe biological rather than conventional immunosuppressants was quite different.Keywords: Autoantibody(ies), autoimmune disease, belimumab, cohort studies, glucocorticoids, immunosuppressants, rituximab, systemic lupus erythematosus.

Antiphospholipid syndrome's genetic and epigenetic aspects.

Studies on last genetic and epigenetic predisposition to APS are summarized. It is well known that genetic predisposition is in HLA system (DR4 and DRw53) and that lupus anticoagulant (LA) and anticardiolipin antibodies (aCL) are both associated with the same HLA antigens. Other genes, outside the MHC, give their contribution to the development of this autoimmune syndrome, such as IRF5, STAT4 and those related to inherited thrombophilia - factor V Leiden and G20210A prothrombin polymorphisms. Finally, post-transcriptional modifications of anti-beta2GPI antibodies could be implicated too. The most important discovery of last years is that altered microRNAs' expression is linked to autoimmunity, thrombosis, early atherosclerosis, and oxidative stress in APS.

Nailfold Capillaroscopy Characteristics of Antisynthetase Syndrome and Possible Clinical Associations: Results of a Multicenter International Study.

OBJECTIVE: To describe nailfold videocapillaroscopy (NVC) features of patients with antisynthetase syndrome (AS) and to investigate possible correlations with clinical and serological features of the disease. METHODS: We retrospectively analyzed NVC images of 190 patients with AS [females/males 3.63, mean age 49.7 ± 12.8 yrs, median disease duration 53.7 mos (interquartile range 82), 133 anti-Jo1 and 57 non-anti-Jo1-positive patients]. For each patient, we examined number of capillaries, giant capillaries, microhemorrhages, avascular areas, ramified capillaries, and the presence of systemic sclerosis (SSc)-like pattern. Finally, we correlated NVC features with clinical and serological findings of patients with AS. Concomitantly, a historical cohort of 75 patients with antinuclear antibody-negative primary Raynaud phenomenon (RP) and longterm followup was used as a control group (female/male ratio 4.13/1, mean age 53.9 ± 17.6 yrs) for NVC measures. RESULTS: NVC abnormalities were observed in 62.1% of AS patients compared with 29.3% of primary RP group (p < 0.001). An SSc-like pattern was detected in 67 patients (35.3%) and it was associated with anti-Jo1 antibodies (p = 0.002) and also with a longer disease duration (p = 0.004). Interestingly, there was no significant correlation between the presence of SSc-like pattern and RP, and only 47% of patients with SSc-like pattern had RP. CONCLUSION: NVC abnormalities are commonly observed in AS, independently from the occurrence of RP. The presence of an SSc-like pattern could allow identification of a more defined AS subtype, and prospective studies could confirm the association with clinical and serological features of AS.

Disease activity assessment of rheumatic diseases during pregnancy: a comprehensive review of indices used in clinical studies.

Pregnancy requires a special management in women with inflammatory rheumatic diseases (RDs), with the aim of controlling maternal disease activity and avoiding fetal complications. Despite the heterogeneous course of RDs during pregnancy, their impact on pregnancy largely relates to the extent of active inflammation at the time of conception. Therefore, accurate evaluation of disease activity is crucial for the best management of pregnant patients. Nevertheless, there are limitations in using conventional measures of disease activity in pregnancy, as some items included in these instruments can be biased by symptoms or by physiological changes related to pregnancy and the pregnancy itself may influence laboratory parameters used to assess disease activity. This article aims to summarize the current literature about the available instruments to measure disease activity during pregnancy in RDs. Systemic lupus erythematosus is the only disease with instruments that have been modified to account for several adaptations which might interfere with the attribution of signs or symptoms to disease activity during pregnancy. No modified-pregnancy indices exist for women affected by other RDs, but standard indices have been applied to pregnant patients. The current body of knowledge shows that the physiologic changes that occur during pregnancy need to be either adapted from existing instruments or developed to improve the management of pregnant women with RDs. Standardized instruments to assess disease activity during pregnancy would be helpful not only for clinical practice but also for research purposes.

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.

Off-label use of rituximab for systemic lupus erythematosus in Europe.

OBJECTIVES: Rituximab (RTX) is a biological treatment used off-label in patients with systemic lupus erythematosus (SLE). This survey aimed to investigate the off-label use of RTX in Europe and compare the characteristics of patients receiving RTX with those receiving conventional therapy. METHODS: Data on patients with SLE receiving RTX were taken from the International Registry for Biologics in SLE retrospective registry and complemented with data on patients with SLE treated with conventional therapy. For nationwide estimates of RTX use in patients with SLE, investigators were asked to provide data through case report forms (CRFs). Countries for which no data were submitted through CRFs, published literature and/or personal communication were used, and for European countries where no data were available, estimates were made on the assumption of similarities with neighbouring countries. RESULTS: The estimated off-label use of RTX in Europe was 0.5%-1.5% of all patients with SLE. In comparison with patients with SLE on conventional therapy, patients treated with RTX had longer disease duration, higher disease activity and were more often treated with immunosuppressives. The most frequent organ manifestations for which either RTX or conventional therapy was initiated were lupus nephritis followed by musculoskeletal and haematological. The reason for treatment was, besides disease control, corticosteroid-sparing for patients treated with conventional therapy. CONCLUSIONS: RTX use for SLE in Europe is restrictive and appears to be used as a last resort in patients for whom other reasonable options have been exhausted.

The Importance of an Early Diagnosis in Systemic Lupus Erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease with a high degree of variability at onset, making it difficult to reach a correct and prompt diagnosis. OBJECTIVES: To present the difficulties faced by the clinician in making a SLE diagnosis, based on the characteristics at study entry of an Italian cohort of SLE patients with recent onset as compared to two similar cohorts. METHODS: Beginning on 1 January 2012 all patients with a diagnosis of SLE (1997 ACR criteria) and disease duration of less than 12 months were consecutively enrolled in a multicenter prospective study. Information on clinical and serological characteristics was collected at study entry and every 6 months thereafter. RESULTS: Our cohort consisted of 122 patients, of whom 103 were females. Among the manifestations included in the 1997 American College of Rheumatology (ACR) criteria, cutaneous, articular and hematologic symptoms were the most prevalent symptoms at study entry. CONCLUSIONS: Data from the literature confirm that the diagnosis of SLE is challenging, and that SLE is a severe disease even at onset when a prompt diagnosis is necessary for initiating the appropriate therapy.

Genetic aspects of the antiphospholipid syndrome: An update.

Studies on the immunogenetic predisposition to antiphospholipid syndrome (APS) and on other non-genetic and epigenetic factors are summarised and discussed. Family studies suggest a genetic predisposition to APS. It appears that this genetic predisposition is in part accounted for by the HLA system, the most consistent associations being those with DR4 and DRw53. Furthermore, it appears that lupus anticoagulant (LA) and anticardiolipin (aCL) antibodies are both associated with the same HLA antigens. Population studies suggest that HLA genes have a role in conferring susceptibility to develop primary APS, with some differences in different ethnic groups. Other genes, outside the MHC, give their contribution to the development of this autoimmune syndrome, such as IRF5, STAT4 and those related to inherited thrombophilia--factor V Leiden and G20210A prothrombin polymorphisms. Finally, post-transcriptional modifications of anti-beta2GPI antibodies could be implicated too.

Efficacy and safety of off-label use of rituximab in refractory lupus: data from the Italian Multicentre Registry.

OBJECTIVES: To evaluate the efficacy and safety of rituximab (RTX) in patients with systemic lupus erythematosus (SLE) refractory to standard therapy in the clinical practice setting. METHODS: 145 SLE patients (ACR criteria) were treated with RTX in 11 Italian Centres: 118 with two infusions (1 g), two weeks apart; 27 with 4 infusions (375 mg/m2), one week apart, followed in 10 cases by two further doses, after 1 and 2 months. Systemic complete response (CR) was defined as European Consensus Lupus Activity Measurement (ECLAM) score ≤1 and partial response (PR) as 1< ECLAM ≤3. Renal CR (RCR) and renal PR (RPR) were defined according to EULAR recommendations for management of lupus nephritis. RESULTS: Data from 134 (92.4%) patients were available. The mean±SD follow-up was 27.3±18.5 months. After the first course of RTX, CR or PR were observed in 85.8% and CR in 45.5% of cases; RCR or RPR in 94.1% and RCR in 30.9% of patients after 12-month follow-up. Disease flares occurred in 35.1% and renal flares in 31.2% of patients during observational period. Among patients retreated, CR or PR were observed in 84.4% and CR in 57.8% of cases. Adverse events, infections, and infusion reactions occurred after first RTX course in 23.8%, 16.4%, and 3.8% of patients and after retreatment in 33.3%, 22.2% and 11.1%, respectively. No severe infusion reactions or deaths occurred. CONCLUSIONS: Data from Italian multicentre RTX Registry confirmed the efficacy and safety of RTX in SLE patients refractory to standard treatment in clinical practice setting.

Clinical profile and direct medical cost of care of adults presenting with systemic lupus erythematosus in Italy.

OBJECTIVES: To determine the clinical profile and estimate the annual direct medical cost of care of adult patients with active, autoantibody positive systemic lupus erythematosus (SLE) in Italy. METHODS: A two-year, retrospective, multicentre, observational study was conducted from January to May 2011. Patients' characteristics, SLE disease activity and severity, rate of flares, healthcare consumption (e.g. medications, etc.) were evaluated. Medical costs were assessed from the Italian National Health Insurance perspective. RESULTS: Four centres enrolled 96 eligible patients, including 85.4% women. Patients were equally stratified per disease severity (severe SLE: 51%). The mean (SD) age was 42.9 (13.8) years. At baseline, SLE duration was 12.6 (7.2) years. The mean (SD) SELENA-SLEDAI score was higher in severe than in non-severe patients 9.2 (6.4) vs. 3.3 (3.1) (p<0.001). The mean (SD) SLICC/ACR index score was similar in the two subgroups: 0.4 (0.8) vs. 0.3 (0.8). Over the study period, severe patients experienced on average 0.73 (0.56) flares/year and non-severe patients 0.57 (0.63). The annual medical cost was 1.6 times higher in severe than in non-severe patients (€2,101 vs. €1,320; p=0.031). The cost of medications was also 2.5 times higher in severe patients (€1101 vs. €445, p=0.007). Low C3/C4 complement levels and each severe flare incremented the annual cost of €550 (p=0.011) and €465 (p=0.02), respectively. CONCLUSIONS: The medical cost of SLE in Italy is related to disease severity and flares. Medications identified as the main cost drivers, and low C3/C4 complement levels and severe flares as the main cost predictors, increased significantly the cost of SLE management.

Bone status of children born from mothers with autoimmune diseases treated during pregnancy with prednisone and/or low molecular weight heparin.

BACKGROUND: To evaluate bone status in children born from mothers followed for autoimmune diseases and treated during pregnancy with low molecular weight heparin (LMVH) and/or prednisone. FINDINGS: History, physical examination, laboratory tests and phalangeal ultrasonography were performed. Demographic, clinical, and laboratory data were entered into a customized database, and results were analyzed with SPSS software. In children whose mothers were treated with LMWH, we retrieved dried blood spots taken for newborn screening, and analyzed the presence of heparin with tandem mass spectrometry. We enrolled 27 females and 14 males born from 31 mothers with SLE or connective tissue diseases. These women were continuously treated during pregnancy with LMWH (n = 10), prednisone (n = 16), or both (n = 15). Bone ultrasound revealed low values (≤ 3 centile for age) in ten patients. In a multistep regression analysis, age at examination resulted the single predictor of low ultrasound values (p < 0.004). Tandem mass spectroscopy failed to determine traces of heparin in newborn blood. CONCLUSIONS: Children born from mothers with autoimmune diseases are at risk to develop reduced bone mass. The administration of LMWH and of prednisone seems to be safe with regard to children's bone health.

Primary anti-phospholipid syndrome: any role for serum complement levels in predicting pregnancy complications?

OBJECTIVE: To evaluate the association between serum complement levels (C3 and C4) and obstetric complications. METHODS: Fifty-seven pregnancies in primary APS (PAPS) patients were compared with 49 pregnancies in patients with UCTD and SS. A group of 175 healthy pregnant women were studied to calculate a normality range for C3 and C4 during pregnancy. Such a range was applied to define hypocomplementaemia in PAPS and UCTD/SS. RESULTS: Both groups of patients (PAPS and UCTD/SS) showed significantly lower levels of C3 and C4 in each trimester as compared with healthy women; conversely, no significant difference was found between PAPS and UCTD/SS. Comparing PAPS pregnancies with and without complications, no difference was found in the prevalence of low C3 or low C4. CONCLUSION: No association was found between hypocomplementaemia and obstetric complications in PAPS. However, both cases of pre-eclampsia were characterized by low C3 throughout pregnancy. There is evidence that the complement system is a contributor to the mechanisms of aPL-mediated damage, but its predictive role on the final pregnancy outcome does not seem to be of major impact.