The Retention Rate and Safety of JAK Inhibitors in Rheumatoid Arthritis: Real Word Data from a Monocentric Cohort.

Background/Objectives: To date, the literature concerning real-world data on the retention rate and safety of Janus kinase inhibitors (JAKis) is limited. To retrospectively evaluate the overall drug retention rate (DRR) of different JAKis in a monocentric cohort of patients with rheumatoid arthritis (RA). Methods: Patients diagnosed with RA and treated with JAKis who were evaluated at our outpatient clinic from March 2017 to December 2023 were included in the study. Demographic, clinical characteristics, and comorbidities were recorded. The DRR was evaluated as the time to drug discontinuation, and baseline predictors of drug discontinuation were investigated through Cox regression after adjusting for baseline confounders. Results: The global DRR for JAKis was 51.3%. The DRR was 37.5% for tofacitinib, 46.6% for baricitinib, 69.4% for upadacitinib, and 53.5% for filgotinib. Considering all JAKis, the only significant predictor of drug discontinuation was the use of JAKis as a first-line treatment (HR 95% CI [0.25 (0.13-0.46)]. When considering each JAKi individually, a longer disease duration predicted TOF discontinuation (HR95% CI [1.05 (1.01-1.09)], while seropositivity protected against TOF being withdrawn (HR95% CI [0.41 (0.17-0.97)]. No independent predictors emerged for other JAKis. Conclusions: the use of JAKis as a first-line treatment as well as disease duration and serology may impact the DRR of JAKis, which may inform tailored treatment strategies in clinical practice.

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.

New onset sarcoidosis following biologic treatment in patients with seronegative inflammatory arthritis: A case series and systematic literature review.

OBJECTIVE: To report cases of new onset sarcoidosis upon biologic (bDMARDs) treatment administration in patients with seronegative inflammatory arthritis in a real-life cohort, alongside a systematic literature review (SLR) on this topic. METHODS: We performed a retrospective analysis on clinical records of patients with seronegative arthritis followed up in a monocentric cohort who underwent bDMARDs treatment due to the underlying rheumatic disease and described any newly diagnosed sarcoidosis in this cohort. Only ascertained cases with available radiological and/or histological documentation were considered. A SLR on new-onset sarcoidosis in seronegative arthritis receiving bDMARDs was performed across MEDLINE (through PubMed), Scopus and Ovid (Cochrane, Embase) electronic databases using appropriate strings. RESULTS: In our cohort, 4 new-onset cases of sarcoidosis were reported among patients with seronegative inflammatory arthritis receiving biologics. Three out of 4 patients were receiving anti-tumor necrosis factor alpha (TNFα) while 1 patient was on secukinumab (anti-IL17A) prior to sarcoidosis onset. The SLR disclosed 46 new-onset sarcoidosis cases upon biological treatment for seronegative arthritis, of whom 43 occurred during treatment with anti-TNFα, while 3 during anti-IL-17A therapy. In our cohort as well as in the majority of cases reported in the SLR, sarcoidosis presented with lymph nodal and lung involvement and displayed a benign course with spontaneous resolution in about 1 fourth of the cases. CONCLUSION: The use of biologics may relate to the onset of sarcoidosis; hence, clinicians must remain aware of the potential occurrence or reactivation of sarcoidosis when starting biologic treatment in patients with inflammatory arthritis, performing adequate patient assessment and surveillance. Since TNFα inhibitors may represent a therapeutic option for sarcoidosis, further evaluation on larger cohorts is needed to investigate any causal link with the development of sarcoidosis.

Systemic sclerosis sine scleroderma: clinical and serological features and relationship with other cutaneous subsets in a large series of patients from the national registry 'SPRING' of the Italian Society for Rheumatology.

OBJECTIVE: To describe demographic, clinical and laboratory features of systemic sclerosis sine scleroderma (ssSSc) in a large multicentre systemic sclerosis (SSc) cohort. METHODS: Data involving 1808 SSc patients from Italian Systemic sclerosis PRogression INvestiGation registry were collected. The ssSSc was defined by the absence of any cutaneous sclerosis and/or puffy fingers. Clinical and serological features of ssSSc were compared with limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) subsets. RESULTS: Among patients with SSc, only 61 (3.4%) were classified as having ssSSc (F/M=19/1). Time from Raynaud's phenomenon (RP) onset to diagnosis was longer in ssSSc (3 years, IQR 1-16.5) than lcSSc (2 years, IQR 0-7), and dcSSc (1 year, IQR 0-3) (p<0.001). Clinical ssSSc phenotype was comparable to lcSSc, except for digital pitting scars (DPS) (19.7% vs 42%, p=0.01), but significantly milder than dcSSc, particularly for digital ulcers (DU) (6.6% vs 35.7%, p<0.001), oesophagus (46.2% vs 63.5%, p=0.009), lung (mean diffusion capacity for carbon monoxide 72.2±19.6 vs 62.4±22.8, p=0.009; mean forced vital capacity 105.6±21.7 vs 89.2±20.9, p<0.001) and major videocapillaroscopic alterations (late pattern 8.6% vs 47.6%, p<0.001). Moreover, in ssSSc the percentages of anticentromere and antitopoisomerase were comparable to lcSSc (40% and 18.3% vs 36.7% and 26.6%), but divergent respect to dcSSc (8.6% and 67.4%, p<0.001). CONCLUSION: The ssSSc is a quite rare disease variant characterised by clinico-serological features comparable to lcSSc, but significantly different from dcSSc. Overall, longer RP duration, low percentages of DPS and peripheral microvascular abnormalities, and increased anti-centromere seropositivity distinguish ssSSc. Further investigations based on national registries might provide useful insights on the actual relevance of the ssSSc within the scleroderma spectrum.

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.

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.

A 3-Year Observational Study of Patients with Progressive Systemic Sclerosis Treated with an Intensified B Lymphocyte Depletion Protocol: Clinical and Immunological Response.

BACKGROUND: B-cells have been suggested to play a role in the pathogenesis of systemic sclerosis (SSc), representing, therefore, a potential therapeutic target. OBJECTIVES: We aimed at investigating the 36-month outcomes of 20 SSc patients who underwent an intensified B-depletion therapy (IBCDT) scheme, including both Rituximab (RTX) and cyclophosphamide (CYC). METHODS: Data from 20 severe patients (18 females and 2 males, mean age 66.7 ± 11.0 years) with diffuse SSc (anti-topoisomerase I antibody in 95%) patients with multiorgan involvement including interstitial lung disease (ILD) treated with an IBCDT were prospectively collected. IBCDT comprehended: RTX 375 mg/m2 administered for four weekly doses (on days 1, 8, 15, and 22), followed by two additional doses after 30 and 60 days, in addition to two administrations of 10 mg/kg of intravenous CYC plus three methylprednisolone pulses (15 mg/kg) and subsequently followed by oral prednisone rapidly tapered to low minimum dosage of 5 mg daily. In addition, 10 patients with more severe functional respiratory impairment at baseline were also treated with RTX 500 mg every 4 months during the first year and two times a year during the second and the third year. RESULTS: After 36 months of follow-up, we recorded significant amelioration in N-terminal-pro-brain natriuretic peptide (NT-proBNP) levels (mean 385.4 ± 517 pg/mL at baseline to 279 ± 543 after 36 months). In addition, a significant radiological improvement of ILD in 20% of patients (4/20) and a radiological stabilization with no sign of progression of interstitial involvement in 13/20 (65%) were documented. A total of 3 out of 20 (15%) patients experienced a worsening of the ILD. No patient showed further decrease in functional respiratory parameters, including forced vital capacity, forced expiratory volume in one second, and mean values of diffusing capacity for carbon monoxide Moreover, no patient showed any change in the ejection fraction and pulmonary artery pressure when comparing values at baseline and after 24 and 36 months of observation. No severe infection, renal flare, RTX-related side effects were observed. No patient died. CONCLUSIONS: Our findings support that the IBCDT was well tolerated and might be a promising therapeutic option for the management of SSc, especially in those subjects with multiorgan involvement that includes ILD.

Longitudinal change during follow-up of systemic sclerosis: correlation between high-resolution computed tomography and pulmonary function tests.

The objective of this study was to determine the correlation between functional and radiological longitudinal change in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), and to test the OMERACT definition of clinically meaningful progression of pulmonary function tests (PFTs) for the prediction of ILD radiological evolution. We retrospectively retrieved high-resolution computed tomography (HRCT) studies and PFTs including DLco, both available at two time-points and performed within 6 months of each other, in SSc patients. A subset of patients was selected using a 12-24-month clinically oriented interval (n = 58). The extent of ILD at HRCT was scored according to a visual semi-quantitative method (SQCT). The correlation of absolute change (Δ) in the SQCT score with change in FVC and DLco was examined using Pearson's correlation coefficient. The concordance between the OMERACT criteria (≥ 10% FVC relative decline; or 5-10% FVC and ≥ 15% DLco relative decline) and SQCT categorical change (5% and 10%) was investigated. A total of 129 patients were enrolled. During 12-24-month follow-up, ΔSQCT was negatively correlated with ΔFVC (r = - 0.487, p = 0.0001) and ΔDLco (r = - 0.298, p = 0.023). Ten patients demonstrated CT progression ΔSQCT > 5%, among whom 5 with ΔSQCT > 10%. OMERACT criteria identified 25 patients with progressive SSc-ILD, of whom only 5 presented ΔSQCT > 5 and 3 presented ΔSQCT > 10%. In conclusion, change in radiological extent of SSc-ILD was correlated to functional decline in a limited time-frame. Repeated HRCT after 12-24 months may be useful for the longitudinal characterization of ILD evolution in patients with stable pulmonary function. Conversely, functional changes are suggestive of a concurrent radiological progression only after this interval. Key Points • In SSc patients, chest HRCT performed every 12-24 months can detect minimal but significant changes in ILD extent, even in subjects with stable pulmonary function. • PFT changes in 12-24 months are related to the radiological ILD progression. • OMERACT criteria might overlook patients with radiological progression. • Repeated chest HRCT may be useful for monitoring SSc-ILD when performed within 12 to 24 months from baseline in order to promptly detect progression and possibly impact on prognosis.

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.

Quantitative chest computed tomography is associated with two prediction models of mortality in interstitial lung disease related to systemic sclerosis.

Objective: In this multicentre study, we aimed to evaluate the capacity of a computer-assisted automated QCT method to identify patients with SSc-associated interstitial lung disease (SSc-ILD) with high mortality risk according to validated composite clinical indexes (ILD-Gender, Age, Physiology index and du Bois index). Methods: Chest CT, anamnestic data and pulmonary function tests of 146 patients with SSc were retrospectively collected, and the ILD-Gender, Age, Physiology score and DuBois index were calculated. Each chest CT underwent an operator-independent quantitative assessment performed with a free medical image viewer (Horos). The correlation between clinical prediction models and QCT parameters was tested. A value of P < 0.05 was considered statistically significant. Results: Most QCT parameters had a statistically different distribution in patients with diverging mortality risk according to both clinical prediction models (P < 0.01). The cut-offs of QCT parameters were calculated by receiver operating characteristic curve analysis, and most of them could discriminate patients with different mortality risk according to clinical prediction models. Conclusion: QCT assessment of SSc-ILD can discriminate between well-defined different mortality risk categories, supporting its prognostic value. These findings, together with the operator independence, strengthen the validity and clinical usefulness of QCT for assessment of SSc-ILD.

Operator-independent quantitative chest computed tomography versus standard assessment of interstitial lung disease related to systemic sclerosis: A multi-centric study.

PURPOSE: Interstitial lung disease (ILD) related to systemic sclerosis (SSc) is assessed with pulmonary functional tests (PFTs) and semi-quantitative scores based on extent of ILD detectable on chest computed tomography (CT). CT quantitative indexes (QCTIs) are promising tools to assess extent of ILD. This study's aim is to evaluate the validity of QCTI compared with that of chest CT standard evaluation and PFTs. Moreover, QCTI differences between patients' subgroups according to prognostic stratifications were investigated. METHODS: ILD-SSc of patients from six rheumatological clinics was routinely assessed with chest CT and PFTs. Patients were clustered according to prognosis based on functional and/or radiological examinations. Finally, chest CTs were processed with OsiriX in order to obtain QCTI. RESULTS: Two hundred fifty-seven SSc patients were enrolled. QCTI correlation between extent of ILD and PFTs range from - 0.60 to 0.58 and from - 0.54 to 0.52, respectively. The majority of QCTI have a different distribution in patients' subgroups based on prognosis. Most of QCTI discriminate patients with an ILD severity leading to a poor prognosis. CONCLUSIONS: QCTI assessment of ILD-SSc is comparable to the evaluation based on chest CT and/or PFTs. QCTI values corresponding to severe ILD were identified. QCTIs are excellent candidates for a new and more reliable SSc-ILD assessment.

The 158VV Fcgamma receptor 3A genotype is associated with response to rituximab in rheumatoid arthritis: results of an Italian multicentre study.

OBJECTIVE: The polymorphism 158V/F of Fc fragment of IgG (FCGR) type 3A may influence the response to rituximab (RTX) in rheumatoid arthritis (RA). We investigated the FCG3A polymorphism in a large cohort of RA patients treated with RTX, also by considering the possible loss of response from month +4 to +6 after RTX and the presence of established predictors of response. METHODS: The study analysed 212 RA patients. European League Against Rheumatism (EULAR) response was evaluated at months +4 and +6 after the first RTX infusion. The FCGR3A polymorphism was analysed by PCR followed by Sanger sequencing. RESULTS: The FCGR3A genotypes were associated with EULAR response (good or moderate) at month +6 (response in 34/38 (89.5%) VV vs 70/106 (66%) VF and in 51/77 (66.2%) FF patients; p=0.01), but not at month +4 (response in 32/37 (86.5%) VV vs 69/102 (67.6%) VF and 53/73 (72.6%) FF patients; p=0.09). Loss of response was observed only in VF and FF carriers ((VV vs VF vs FF: 0/37 (0%) vs 11/102 (10.8%) vs 12/73 (16.4%); p=0.02)). Probability of response at month +6 was very high when at least two of the three following items selected by multivariate analysis were present: positive rheumatoid factor and/or anticyclic citrullinated peptide antibodies, previous treatment with ≤ 1 anti-tumor necrosis factor (TNF) agent, and 158VV FCGR3A genotype (p<0.0001; OR 7.9, 95% CI 4.1 to 15.1). CONCLUSIONS: The 158VV FCGR3A genotype was associated with response to RTX in a large cohort of RA patients. Patient genotyping may be helpful to plan RTX treatment, and may be integrated with clinical predictors.

The TTTT B lymphocyte stimulator promoter haplotype is associated with good response to rituximab therapy in seropositive rheumatoid arthritis resistant to tumor necrosis factor blockers.

OBJECTIVE: To investigate the polymorphisms in the promoter region of the B lymphocyte stimulator (BLyS) gene as markers of response to rituximab (RTX) in rheumatoid arthritis (RA). METHODS: The study was first conducted in 152 Italian RA patients and then replicated in an additional 117 RA patients (73 Italian, 44 British). The European League Against Rheumatism response criteria were used to evaluate the response rate at months 4 and 6 after the first cycle of RTX, by means of the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate; patients were classified according to the best response shown between months 4 and 6. BLyS promoter polymorphisms were analyzed by polymerase chain reaction followed by the analysis of the restriction fragments, BLyS promoter haplotypes were analyzed using the expectation-maximization algorithm, and BLyS serum levels were analyzed using enzyme-linked immunosorbent assay. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CIs). RESULTS: The TTTT BLyS promoter haplotype appeared to be significantly associated with response to RTX only in the subset of seropositive patients (those positive for rheumatoid factor and/or anti-cyclic citrullinated peptide). The replication study confirmed that this association was limited to seropositive RA patients in whom treatment with anti-tumor necrosis factor (anti-TNF) agents had previously failed. In the whole series of seropositive patients in whom anti-TNF agents had previously failed, patients carrying the TTTT BLyS promoter haplotype were more prevalent in good responders (18 of 43 [41.9%]) than in moderate responders (20 of 83 [24.1%]) or in nonresponders (1 of 21 [4.8%]) (for good responders versus nonresponders, OR 14.4 [95% CI 1.77-117.39], P=0.0028). Furthermore, multivariate analysis selected the TTTT BLyS promoter haplotype as an independent marker of good response to RTX (for good responders versus nonresponders, OR 16.2 [95% CI 1.7-152.5], P=0.01; for good responders versus moderate responders and nonresponders combined, OR 3.1 [95% CI 1.2-7.8], P=0.02). The relationship between BLyS polymorphisms and BLyS serum levels remained unclear. CONCLUSION: BLyS promoter genotyping may be suitable for identifying seropositive RA patients who may have a good response to RTX after anti-TNF agents have failed.

The CC homozygosis of the -174G>C IL-6 polymorphism predicts a lower efficacy of rituximab therapy in rheumatoid arthritis.

Identification of genetic biomarkers of response to biologics in rheumatoid arthritis (RA) is a relevant issue. Being IL-6 a key cytokine for B cell survival, the interleukin-6 (IL-6) -174G>C and the IL-6 receptor (IL-6R) D358A gene polymorphisms were investigated in 158 RA patients treated with rituximab (RTX). One hundred and twenty-eight (81.0%) were RF positive and 126 (79.7%) were anti-CCP positive. Response to therapy was evaluated at the end of the sixth month after the first RTX infusion, by using both the EULAR and the ACR criteria. The possible relationship with IL-6 serum levels was also studied. By univariate analysis, lack of response by the EULAR criteria was more prevalent in RA patients with the IL-6 -174 CC genotypes (39.1%), than in the GC/GG patients (18.5%) (OR 2.83; 95%CI=1.10-7.27; p=0.031). A good response was noticed in only one patient (4.3%) with the IL-6 -174 CC genotype, while it was present in 24.4% of GG/GC cases (p=0.06). By stepwise multivariate analysis (including RA duration, baseline DAS28, baseline HAQ, RF status, anti-CCP status and IL-6 genotype as covariates), the IL-6 -174CC genotype was selected as an independent predictor of no response to RTX by both EULAR and ACR≥50 criteria, while the IL-6R polymorphism resulted as not associated. No definite association between gene polymorphisms and IL-6 serum levels was noticed. Present results suggest a possible role for IL-6 genotyping to better plan treatment with RTX in RA, and larger studies are worthwhile.

Iloprost modulates the immune response in systemic sclerosis.

BACKGROUND: Iloprost has been suggested to possess anti-inflammatory and immunomodulating actions and it is widely use as a vasodilatator in systemic sclerosis (SSc). In this study we evaluate the effect of iloprost on immune response in SSc patients. To this extend we enrolled 15 women affected by SSc and infused iloprost for 5 days. The effect of iloprost on T cells and monocytes was measured by flow cytometry, Real time PCR and measuring cytokines production in vivo and in vitro by ELISA. RESULTS: Our results demonstrate that Iloprost reduces T cell and TNF alpha production both in vivo and in vitro. It reduces T regulatory cells number, but increases their activity after immune stimulation. It increases serum IL-2 and this increase persists 28 days after the last infusion, also RANKL was increased both in vivo and in vitro. We observed no effect on IFN gamma production. CONCLUSIONS: These results suggest that iloprost has anti-inflammatory and immunomodulating effects, reducing TNF alpha production by T cells and the number of T regulatory cells and increasing IL-2 and RANKL.

Rheumatoid factor positivity rather than anti-CCP positivity, a lower disability and a lower number of anti-TNF agents failed are associated with response to rituximab in rheumatoid arthritis.

OBJECTIVES: We explored clinical factors associated with a major response to rituximab (RTX) (e.g. ACR >/=50, and European League against Rheumatism (EULAR) moderate to good response) in patients with active long-standing RA and inadequate response to anti-TNF agents or traditional DMARDs. METHODS: RTX was used in 110 RA patients in six different Italian centres. The mean disease activity score on 28 joints (DAS28) was 6.4 +/- 0.99 and the mean HAQ was 1.63 +/- 0.68 at baseline. Thirty-two patients (29.1%) underwent RTX after the failure of DMARD therapy, 37 (33.6%) had failed or were intolerant to at least two anti-TNF agents, and 41 (37.3%) had failed or were intolerant to one anti-TNF agent. Univariate and multivariate analyses were performed. RESULTS: The number of previous anti-TNF agents (P = 0.043), HAQ (P = 0.023), RF positivity (P < 0.0001) and anti-cyclic citrullinated peptide (anti-CCP) positivity (P = 0.003) were associated with ACR response >or=50 between month +4 and month +6 after starting RTX by univariate analysis. Multivariate analysis confirmed that a lower HAQ, a lower number of anti-TNF agents failed before RTX and RF positivity, but not anti-CCP positivity, were the selected variables associated with an ACR response >or=50, with an accuracy of 84% of the model. Only RF positivity correlated with EULAR moderate to good response both in the univariate and in the multivariate analysis, with an accuracy of 79% of the model. CONCLUSION: RF-positive rather than anti-CCP-positive RA patients with lower baseline disability and a lower number of previously failed TNF blockers may be the best candidates to RTX.

Long-term effects of rituximab in rheumatoid arthritis: clinical, biologic, and pharmacogenetic aspects.

Rituximab selectively targets the B-cell compartment, including rheumatoid factor-positive B cells. Short-term efficacy and safety of rituximab in rheumatoid arthritis (RA) has been established by multicenter randomized placebo-controlled studies. Results of long-term follow-up of the phase II/III clinical trials have confirmed the efficacy and safety of repeated courses of rituximab in the responders. However, mechanisms of action in humans, retreatment regimens, biologic effects on memory B cells and on immunoglobulin levels of prolonged exposure of the immune system to B-cell depletion over time, and pharmacogenetic aspects remain open and intriguing issues of rituximab therapy. Several studies are ongoing to clarify possible clinical and biologic predictors of response to rituximab in RA and in other autoimmune diseases where rituximab has been proven to be effective. Preliminary clinical and pharmacogenetic results of our cohort of RA patients managed with rituximab from the year 2000 are presented.