Tocilizumab Effects on Coagulation Factor XIII in Patients with Rheumatoid Arthritis

Introduction: Rheumatoid arthritis (RA) is a chronic systemic auto-immune disease associated with a prothrombotic state. Tocilizumab, an interleukin-6 receptor inhibitor, is highly effective in controlling disease activity and thrombotic risk. Factor XIII (FXIII), involved in thrombotic complications, has been reported to be reduced in RA patients during maintenance treatment with tocilizumab, but no data are available before and after the drug administration. Thus, we investigated the effects of tocilizumab on FXIII, thrombin generation and inflammation in patients with RA na\uefve for the drug. Methods: We studied 15 consecutive adult patients with RA at baseline and 4 weeks after the onset of parenteral administration of tocilizumab, measuring disease activity and plasma levels of C-reactive protein (CRP), FXIII, and prothrombin fragments F1+2 by immunoenzymatic methods. Fifteen healthy subjects, sex-and age-matched with patients, served as normal controls for laboratory measurements. Results: At baseline, patients with established RA had a median DAS28 of 4.8 (3.2\u20138.3) and, compared to healthy controls, had higher plasma levels of CRP (p < 0.0001), FXIII (p = 0.017) and F1+2 (p < 0.0001). Four weeks after starting treatment with tocilizumab, based on the EULAR response criteria, eight patients were classifiable as responders and seven as non-responders. In responders, we observed a statistically significant reduction not only of the values of DAS28 and CRP (p = 0.012 for both), ut also of plasma levels of FXIII (p = 0.05) and F1+2 (p = 0.025). In non-responders, all the studied parameters were unchanged. Conclusion: The decrease of FXIII and F1+2 levels after tocilizumab treatment observed only in those patients who responded to the drug indicates that the effect of tocilizumab on the prothrombotic state is linked to the control of inflammation and disease activity and not to a direct effect of the drug, thus contributing to the reduction of the cardiovascular risk

Effectiveness and safety of oxycodone/naloxone in the management of chronic pain in patients with systemic sclerosis with recurrent digital ulcers : Two case reports

Digital ulcers (DUs) are a severe and frequent clinical feature of patients with systemic sclerosis (SSc). The presence of DUs may cause severe pain and often lead to impairment of patient\u2019s functional activities and health-related quality of life. Moreover, poor patient cooperation during the wound care procedure due to pain may be associated with a negative outcome of DU healing. Therefore, pain management has a key role in patients with SSc. These two case reports describe the effectiveness and safety of oxycodone/naloxone in patients with SSc complicated by painful chronic DUs. Such a therapy has provided pain relief and consequently an increased compliance during redressing wounds

COVID-19 infection and rheumatoid arthritis: Faraway, so close!

The outbreak of the new coronavirus infections COVID-19 in December 2019 in China has quickly become a global health emergency. Given the lack of specific anti-viral therapies, the current management of severe acute respiratory syndrome coronaviruses (SARS-CoV-2) is mainly supportive, even though several compounds are now under investigation for the treatment of this life-threatening disease. COVID-19 pandemic is certainly conditioning the treatment strategy of a complex disorder as rheumatoid arthritis (RA), whose infectious risk is increased compared to the general population because of an overall impairment of immune system typical of autoimmune diseases combined with the iatrogenic effect generated by corticosteroids and immunosuppressive drugs. However, the increasing knowledge about the pathophysiology of SARS-CoV-2 infection is leading to consider some anti-rheumatic drugs as potential treatment options for the management of COVID-19. In this review we will critically analyse the evidences on either positive or negative effect of drugs commonly used to treat RA in this particular scenario, in order to optimize the current approach to RA patients

A systematic review of systemic sclerosis instruments for the eular outcome measures library : An evolutionary database of validated patient-reported instruments

Background: Over time, a patient-centered evaluation of health status has become more important for systemic sclerosis (SSc), both in research and clinical setting. Patient-reported outcomes (PROs) are being increasingly used to measure various domains of disease status relevant to patients and physicians. The EULAR Outcome Measures Library (OML) is a freely available website with structured access to a growing database of validated PROs [1], but currently there are no PROs available on SSc at the EULAR OML. Objectives: To provide a comprehensive review of validated SSc-specific PROs and to critically appraise their validity. Methods: A sensitive search was developed in Medline and Embase (08/2015) to identify all validation studies, cohort studies, reviews or metaanalyses in which the objective were the development or validation of PROs evaluating organ involvement, disease activity or damage in SSc. A reviewer screened title and abstracts, selected the studies, and collected data concerning validation using ad hoc forms based on the COSMIN checklist. Results: From 13,140 articles captured, 74 met the predefined criteria. After excluding an instrument for the unavailability of an English version, the selected studies provided information on 6 SSc-specific PROs: the Scleroderma Assessment Questionnaire (SAQ), the scleroderma functional score (FS), the Raynaud's condition score (RCS), the Mouth Handicap in SSc (MHISS), the University of California Los Angeles-Scleroderma Clinical Trial Consortium Gastro-Intestinal tract (UCLA-SCTC-GIT 2.0), and the Skin Self-Assessment. The table summarizes the instruments and their measurement properties: Table 1 SSc-specific PROs Domains No. of items and range Measurement properties Reliability IC/TR/ME Validity Responsiveness Interpretability SAQ Functional status (vascular, respiratory, GIT and musculoskeletal apparatus) Items: 23Range: 0\u20133 ICC 0.79\u20130.95 Total score higher in pts with systemic involvement Vascular z=0.92\u20132.97; Respiratory z=1.34\u20132.52; GIT z= 123.14\u20134.03; Musculoskeletal status z=0.68\u20133.16 \u2013 FS Functional ability (upper limbs & muscle weakness) Items: 11Range: 0\u201333 Intra-observkw 0.19\u20130.6inter-observkw0.69\u20130.94 HAQ-DI r=0.90Skin score r=0.11 FS correlates with HAQ-DI 0.59, & Hand HAQ-DI 0.58 \u2013 RCS Severity and impact of Raynaud's phenomenon Item: 1Range 0\u201310 ICC 0.70 Disease activity, Rp measures, digital ulcers, mood/tension 67% variance ES 0.6SRM 0.64 MID 14\u201315 points (0\u2013100 VAS)PASS 34 points MHISS Disability involving the mouth Items: 12Range: 0\u201348 ICC 0.96 HAQ r=0.33, CHFS r=0.37, mouth opening r= 120.34, MACTAR r=0.11, HADd r=0.26, HADa r=0.17 \u2013 \u2013 UCLA SCTC GIT 2.0 GIT symptoms severity Items: 34Range: 0\u20133 Cronbach's \u3b1>0.70, constipation (\u3b1=0.67)ICC 0.71 Total GIT score r=0.60; Upper GIT r=0.52; Lower GIT r=0.60 rho 0.05\u20130.48 MID/improvement: 0.07\u20130.36;MID/worsening: 0.06 120.21;Floor: noneCeiling: 4% Skin self-assessment Skin thickening Items: 17Range: 0\u201351 ICC 0.5\u20130.61 Skin score r=0.435 No changes 1 yr follow-up \u2013 dcSScFloor 15%Ceiling n.a. Conclusions: Six SSc-specific PROs have a minimum validation and will be included in the EULAR OML. In general, the level of validation attained could be improved. Further development in the area of disease-specific PROs in SSc is warranted. References: Castrej\uf3n I, Gossec L, Carmona L. Ann Rheum Dis. 2015;74(2):475\u2013

hla typing in systemic sclerosis

Objective: the aim of the study was to investigate the relationship between Systemic Sclerosis (SSc) and HLA antigens, and to correlate these antigens with the clinical manifestations of the disease. Materials and methods: 55 patients were stratified according a) to the cutaneous involvement b) to the positivity of Scl- 70 and anticentromere antibody and c) to the internal organ involvement, in particular we used HRCT to demonstrate lung fibrosis, echocardiography for the diagnosis of pulmonary hypertension, blood creatinine, urinalysis and arterial hypertension to demonstrate renal failure, and esophagus double-countrast barium swallow for the diagnosis of esophagopathy. The control group consisting of 2000 healthy Caucasian subjects was recruited from the same population. Results: the frequency of the antigens A23 (p=0.003, RR=3.69), B18 (p<0.0001, RR=3.57), and DR11 (p<0.0001, RR=6.18) was statistically increased in the patients population compared with the healthy controls. Although there is no any significant correlation between HLA antigens and different clinical subsets of scleroderma, antigens B18 and DR11 could be associated with more severe clinical features. Conclusions: the presence of a significant association between SSc and specific HLA antigens (A23, B18, and DR11) could link the HLA system with SSc

Anti-atherogenic modification of serum lipoprotein function in patients with rheumatoid arthritis after tocilizumab treatment, a pilot study

Lipid metabolism derangement contributes to increased cardiovascular risk in Rheumatoid Arthritis (RA). It is still debated whether and how tocilizumab, an interleukin-6 receptor inhibitor used in active RA, impacts cardiovascular risk. We studied the effect of tocilizumab on the regulation of macrophage cholesterol homeostasis, measuring patient serum ability to respectively load (cholesterol loading capacity, CLC) and discharge (cholesterol efflux capacity, CEC) cells with cholesterol. Patients with RA (n = 8) were studied before and after 4 and 12 weeks of tocilizumab treatment. CLC was measured by a fluorimetric assay of intracellular cholesterol content in human macrophages and CEC was measured for the three main pathways, mediated by the transporters Scavenger Receptor class B-type I (SR-BI), ATP binding cassette-G1 (ABCG1) and-A1 (ABCA1) in specific cell models. After 12 weeks of tocilizumab treatment, serum LDL cholesterol levels were increased, while CLC was reduced. HDL cholesterol levels were unchanged, but CEC was significantly ameliorated for the SR-BI and ABCG1 pathways with respect to baseline. Tocilizumab reduces LDL pro-atherogenic potential despite increasing their serum levels and increases HDL protective activity in RA. The data of our pilot study suggest that tocilizumab regulates lipoprotein function in selected patient populations and lay the groundwork for future larger studies

Translation and cross-cultural adaptation into italian of the self-administered FLARE-RA questionnaire for rheumatoid arthritis

The aim was to provide a translation into Italian with cross-cultural adaptation of the French FLARE-Rheumatoid Arthritis (RA) questionnaire, and to test its acceptability, feasibility, reliability and construct validity in a single-centre cohort study. The French version of the FLARE-RA questionnaire was cross-culturally adapted and translated into Italian following an established forward\u2013backward translation procedure, with independent translations and backtranslations. To validate the Italian version we tested the internal validity with Cronbach\u2019s alpha, test-retest reliability with the intraclass correlation coefficient, agreement between assessments with Bland-Altman plots and construct validity with Spearman\u2019s correlation coefficients. The questionnaire was tested on 283 consecutive RA outpatients (mean age 56.1\ub1}13.9 years, 226/283 females, median disease duration 12.6 years ranging from 0.2 to 70.6). For the global score (11 items) the Cronbach\u2019s alpha coefficient was 0.94. The intraclass correlation coefficient was 0.87 (95% CI, 0.76-0.96). The correlation of FLARE-RA global score was 0.59 (95% CI, 0.50-0.66) with the Disease Activity Score on 28 joints, 0.63 (95% CI, 0.55-0.71) with the Simplified Disease Activity Index, 0.77 (95% CI, 0.71-0.83) with the RA Impact of Disease and 0.67 (95% CI, 0.59-0.73) with the Health Assessment Questionnaire. The Italian version of the FLARE-RA is feasible, brief and easy to administer. The translated and cross-cultural adapted showed accordingly to be valid and reliable. This questionnaire has some practical advantages, such as clarity, comprehensiveness, simplicity, and a minimum filling time. The development of cross-cultural adapted questionnaires in different languages is of pivotal importance to obtain standardized and comparable data across countries

Health-related quality of life burden in scleroderma patients treated with two different intravenous iloprost regimens

Systemic sclerosis (SSc)-related Raynaud's phenomenon (RP) and digital ulcers (DU) can impair health-related quality of life (HRQoL). The aim of our study was to estimate HRQoL in SSc patients treated with two different intravenous (IV) iloprost (ILO) regimens and in patients not treated with IV ILO. 96 consecutive SSc patients were enrolled in a pragmatic, prospective and non-randomized study, and divided into 3 groups: not requiring therapy with IV ILO (N=52), IV ILO once monthly (N=24) or IV ILO for 5 consecutive days every 3 months (N=20). Patients were followed up for three months. We assessed HRQoL using the generic preference-based questionnaire EQ-5D-5L. We conducted multiple regression analyses to estimate, in each treatment group, the mean general health (GH) and the mean utility index of the EQ-5D-5L, adjusting for possible confounders. The mean adjusted utility index and GH score, after three months' follow-up, were not different in the three groups: IV ILO was able to make patients requiring IV ILO similar to those not requiring it. Moreover, there was no difference in this model between the two ILO regimens (1 day monthly vs 5 consecutive days every 3 months). The two different IV ILO regimens (the most appropriate regimen was decided according to patients' characteristics and needs) were able to stabilize HRQoL in RP secondary to SSc non-adequately controlled by oral therapy

Outcomes, rates, and risk factors of transition of Raynaud&apos;s phenomenon to a connective tissue disease: systematic review and meta-analysis

Background: A number of observational studies were carried out in patients with isolated Raynaud's phenomenon (RP) to investigate the predictors of transition to RP secondary to connective tissue diseases (CTDs). Data from a meta-analysis, including studies until June 1996, highlighted the potential role of nailfold capillaroscopy and/or antinuclear antibodies (ANAs) in predicting such transition [1]. Objectives: To provide an updated comprehensive review and meta-analysis on the rates and the role of predictors of transition to CTDs and systemic sclerosis (SSc) in patients with RP. Methods: A systematic search of observational studies was undertaken using Medline and Embase (07/1996 to 08/2014). From the list of records retrieved, studies were screened by titles/abstracts and the full papers were sought where abstracts were felt to be relevant. Cohort studies reporting incidence and risk factors of transition from primary RP (pRP) or suspected secondary RP (ssRP) to CTDs were selected and data collected in ad hoc forms. pRP was defined according to Leroy and Medsger criteria (no history or physical findings suggestive of a secondary cause, normal capillaroscopy, negative serologic findings); ssRP was defined in presence of positive ANAs and/or abnormal capillaroscopy (even in association with symptoms or physical findings suggestive of a secondary cause without fulfilling criteria for a definite CTD). Relative risk (RR) and 95% confidence interval (CI) were extracted or calculated to present the association between risk factors and transition to CTDs. Random effects model was used to pool the results. Results: From 2.221 articles captured, 36 met the predefined criteria, 29 were excluded on full text, and 7 selected studies provided information on transition from pRP and/or ssRP to secondary RP: 5 prospective and 2 retrospective cohort studies. Six studies included a total of 4051 patients with pRP with a cumulative mean follow-up of 20241 person-years (mean follow-up 4.9\ub12 years); a total of 1220 transitions to overt CTDs were recorded (pooled incidence rate 2.5/100 person-years of observation, range 0\u20137.7); among these, 321 transitions were to SSc (pooled incidence rate 1.58/100 person-years, range 0\u20132.8). Five studies included 657 patients with ssRP with a cumulative mean follow-up of 2377 person-years (mean follow-up 3.6\ub11.1 years); a total of 188 transitions to CTDs were recorded (pooled incidence rate 7.9/100 person-years, range 3.3\u201326) and 135 to SSc (pooled incidence rate 5.7/100 person-years, range 2.1\u201313). With respect to the patients with pRP, having ANA without capillary abnormalities provided a modest risk to develop SSc (pooled RR 2.8, CI 2.1\u20133.8), even weaker resulted the association between capillary abnormalities without ANA and the risk of SSc transition (RR 1.3, CI 0.7\u20132.4). On the other hand, the coexistence of ANA and abnormal capillaroscopy significantly increased the risk of transition to SSc (RR 8.1, CI 6.9\u20139.7). Conclusions: A low incidence rate of transition from pRP to overt CTDs was confirmed. In patients with ssRP, whilst accepting the influence of selection bias of different studies, there appears to be a strong risk of transition toward a CTD regarding the concomitant presence of ANAs and abnormal capillaroscopy. References: Spencer - Green G. Arch Intern Med. 1998;158(6):595 \u2013 600

Outcomes, rates and predictors of transition of isolated Raynaud&apos;s phenomenon : a systematic review and meta-analysis

QUESTIONS: Published studies lack clear indicators of risk and predictors of transition from Raynaud's phenomenon (Rp) to connective tissue diseases (CTDs). Therefore, we aimed to study the outcomes, rates and predictors of transition to CTDs in patients with Rp. METHODS: A sensitive search was developed in Medline and Embase. Observational studies reporting incidence and risk factors of transition from Rp to a CTD were analysed by two independent reviewers. The main outcome was the rate of transition to a CTD; the secondary outcome was the evaluation of predictors. RESULTS: Of 856 articles captured, 7 selected studies met the inclusion criteria. A total of 4051 patients with primary Rp (pRp) and 1220 transitions to overt CTDs were recorded. The mean incidence rate of transition from pRp to a CTD was 2.65/100 person-years (standard error [SE] 1.2, 95% confidence interval [CI] 0.44-5.73). A total of 657 patients with suspected secondary Rp (ssRp) had antinuclear antibodies (ANAs) and/or capillary abnormalities; 188 transitions to CTDs were recorded, the mean incidence rate of transition from ssRp to CTD was 11.01/100 person-years (SE 4.0, 95% CI 0.11-22.12), and 135 transitions to systemic sclerosis (SSc), giving a mean incidence rate of transition from ssRp to SSc of 5.7/100 person-years (SE 2.19, 95% CI 1.02-13.19). With respect to patients with pRp, having ANAs without capillary abnormalities was associated with a risk for developing a CTD (pooled relative risks [RR] 7.63, 95% CI 2.87-20.29), whereas capillary abnormalities without ANAs resulted in a weaker risk of CTD transition (RR 5.53, 95% CI 1.45-21.06). The coexistence of ANAs and abnormal capillaroscopy significantly increased the risk of transition to CTD (RR 16.96, 95% CI 6.61-43.55). CONCLUSIONS: A low incidence rate of transition from pRp to overt CTD was found. In spite of a possible study selection bias, ssRp appears to have a strong risk of transition to a CTD when there is concomitant presence of ANAs and abnormal capillaroscopy