Nicola Ughi

Vitamin D in systemic sclerosis

Sir, The recently published paper of Caramaschi et al. [1], who reported very low levels of vitamin D in systemic sclerosis (SSc), prompted us to report our data. We studied the serum levels of vitamin D in a cohort of 43 North Italian patients with SSc (age 61±14 years, 42 females, 29 with limited SSc, 11 with diffuse SSc, three with SSc sine scleroderma). Ninety-nine patients with osteoarthritis (OA) (age 65±10 years, 91 females) served as controls. None of the subjects received or was receiving vitamin D supplementation in the previous year. Vitamin D levels were classified as normal (≥30 ng/ ml), insufficient (<30, ≥10 ng/ml) and deficient (<10 ng/ ml) [2]. There were no differences in vitamin D levels between SSc (18.1±15.2 ng/ml, mean±SD) and OA (17.3±12.0 ng/ ml). Normal levels were observed in six SSc patients (14.0%) and in 12 (12.2%) OA patients. No differences were found between the two groups with respect to the prevalence of insufficient vitamin D levels, found in 51.2% of SSc patients and in 62.6% of OA patients (p=0.278), as well as prevalence of deficient vitamin D levels (34.8% vs. 25.2%, SSc vs. OA, p=0.334). Vitamin D levels were independent of the duration of SSc, the different types of SSc and the presence of anticentromere or antitopoisomerase I autoantibodies (data not shown). Our data confirm previous studies reporting low vitamin D levels in the majority of SSc patients [1, 3–6]. The prevalence of vitamin D deficiency or insufficiency found in our patients is very similar to that observed by Caramaschi et al. [1]. However, the low vitamin D levels we found do not seem to be related to the disease itself since no lower values were observed in SSc patients compared to OA patients. The major strength of our study is the comparison we have made between SSc patients with sexand age-matched controls. As far as we know, there is only one published paper that included a control group [7]; although the sample size in this study was small, based on our data, no differences were found between the groups. Because of the considerable variability in the reported vitamin D levels in SSc patients [1, 3–6], the high frequency of hypovitaminosis D in the general population [8], and the fact that our findings did not support a relationship between SSc and vitamin D levels, further studies are required to establish which non SSc-related factors, such as age, body mass index, and lifestyle, can be linked to the low vitamin D levels observed in SSc patients.

Mesenchymal stem cells : potential for therapy and treatment of chronic non-healing skin wounds

abstract Wound healing is a complex physiological process including overlapping phases (hemostatic/inflammatory, proliferating and remodeling phases). Every alteration in this mechanism might lead to pathological conditions of different medical relevance. Treatments for chronic non-healing wounds are expensive because reiterative treatments are needed. Regenerative medicine and in particular mesenchymal stem cells approach is emerging as new potential clinical application in wound healing. In the past decades, advance in the understanding of molecular mechanisms underlying wound healing process has led to extensive topical administration of growth factors as part of wound care. Currently, no definitive treatment is available and the research on optimal wound care depends upon the efficacy and cost-benefit of emerging therapies. Here we provide an overview on the novel approaches through stem cell therapy to improve cutaneous wound healing, with a focus on diabetic wounds and Systemic Sclerosis-associated ulcers, which are particularly challenging. Current and future treatment approaches are discussed with an emphasis on recent advances.

Cancer in Italian Patients with Systemic Sclerosis

The association between cancer and systemic sclerosis (SSc) is known, although the underlying mechanisms remain unclear and epidemiological data is conflicting. Since no data exist on cancer in Italian SSc, we examined the frequency and characteristics of cancer in an Italian cohort of SSc patients to examine whether clinical and/or laboratory SSc-specific features represent a risk for developing malignancies in these patients. A retrospective chart review was carried out of 112 Italian SSc patients of whom 109 were women 3 and were men, aged 63±13 years; 81 patients had limited SSc, 25 had diffuse SSc and 6 had sine scleroderma SSc. Fifteen cancers were found in 14 patients. The majority (60%) occurred after SSc onset (average 16 years), 40% occurred before the onset of SSc (average 14 years). The most frequent was breast cancer (prevalence: 4.5%, relative prevalence:33.3%), followed by uterine cancer and lymphomas (prevalence: 2.7%, relative prevalence: 20% each). Lung cancer was not observed. Cancers were unrelated with SSc type, autoantibodies, organ involvement and treatments. In conclusion, clinical features do not seem to be linked with the risk of developing cancer in SSc patients. Interestingly, and in contrast with published data, no lung cancer was present in our patients, although lung involvement was observed in the majority of them. This finding, consistent with a lower prevalence of lung cancer in the Italian female general population, and the absence of associations between SSc-specific features and cancer, suggests that genetic and environmental factors might play a pivotal role in cancer risk in these patients.

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’s 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.

Metastatic Melanoma in a Young Woman Treated with TNF-Alpha Inhibitor for Psoriatic Arthritis: A Case Report

INTRODUCTION The risk of cancer with the use of biologic agents in rheumatic diseases is still a matter of debate. Published data suggest that the extent of cancer risk might differ according to the type of cancer, and there is recent clinical evidence for a significant increased risk for skin cancer, including melanoma. In contrast with the extensive literature on cancer risk in rheumatoid arthritis, little has been reported on the development of malignancies in spondyloarthroparthies. CASE PRESENTATION We report the case of an otherwise healthy 31-year-old Italian woman with psoriasic arthritis who developed a melanoma of left third toe with metastatic involvement of regional lymphnodes after a 3-year treatment with the TNF-alpha inhibitor adalimumab. CONCLUSION This case illustrates the possibility of a causal relationship between TNF-alpha inhibitors and melanoma. We believe that vigilance should continue in patients treated with TNF-alpha blocking agents, until the question on the increased incidence of cancers, including skin cancers, associated with these drugs will be defined.

Role of Fetuin-A in Systemic Sclerosis-associated Calcinosis

To the Editor: Calcinosis, a soft-tissue calcification occurring in the setting of normal serum calcium and phosphate levels, has been observed in connective tissue diseases, including systemic sclerosis (SSc)1, more frequently in the limited form (lcSSc) and in patients who are anticentromere antibody (ACA)-positive1. Calcinosis may be exceedingly painful and cause major clinical problems, including ulceration, infection, and joint contractures1. Hypovascularity, hypoxia, and tissue damage seem to favor its development, with genetic factors also playing a role. No treatment exists so far, and even surgical removal is unsatisfactory, since recurrences are common1. Fetuin-A (α-2-Heremans-Schmid glycoprotein, AHSG) is a major inhibitor of systemic calcification, and low serum levels have been associated with vascular and soft-tissue calcifications2. Any situation that lowers serum fetuin-A, including inflammatory conditions, could increase the risk of calcification, because fetuin-A is a negative acute-phase protein. AHSG gene variations seem to influence fetuin-A serum concentration3. Forty-one consecutive Italian patients with SSc [40 women, age 63 ± 13 years, 16 diffuse SSc (dcSSc), 25 lcSSc] were … Address correspondence to Dr. L. Belloli, Via Manzoni 56, Rozzano 20089, Italy. E-mail: laurabelloli{at}tiscali.it

FRI0173 Role of Methotrexate as Combination Therapy with Adalimumab and Etanercept in Rheumatoid Arthritis: Retrospective Analysis from A Local Registry

Background The role of methotrexate (MTX) in association with TNF inhibitors (TNFi) for the treatment of rheumatoid arthritis (RA) is well defined, although the optimal MTX dose is still unclear. Recently the CONCERTO randomized controlled trial demonstrated efficacy and safety of ascending MTX doses in combination with adalimumab (ADA) for the treatment of MTX-naïve RA [1], but observational data from real-life registries are still lacking. Objectives The aim of our study is to retrospectively evaluate the effect of different MTX regimen as combination therapy with 1st line ADA and etanercept (ETN) on 6- and 12-month clinical response and safety profile in RA patients. Methods We selected all RA patients treated with ADA or ETN as 1st line biotherapy in our Rheumatology Department from January 2000 to October 2015. The analysis was performed only on subjects with at least 1-year follow-up and the study population was stratified according to concomitant MTX regimen in 3 subgroups: TNFi as monotherapy (group 1), TNFi in association with low MTX dose (≤10 mg/week, group 2), and TNFi combined with high MTX dose (≥12.5 mg/week, group 3). Six- and 12-month clinical response was evaluated as mean change from baseline of disease activity score 28 (DAS28) and as DAS28 remission/low disease activity (LDA) rates, comparing the 3 subgroups by Kruskal-Wallis and Dunn tests. Results The study population included 322 RA patients (265 [82.3%] female, mean age [± standard deviation] 55.4 [±12.8] years, disease duration 11.4 [±9.4] years, positive rheumatoid factor 248 [77%], mean baseline DAS28 5.39 [±1.18]) treated with ADA (n=166) or ETN (n=156). According to concomitant MTX regimen, 108 patients were assigned to subgroup 1, 110 to subgroup 2, and 104 to subgroup 3. No significant differences were found in baseline characteristics among the 3 subgroups. The mean change from baseline of DAS28 was significantly higher in subgroup 3 compared with subgroup 1 and 2 at both 6 (2.14, 1.2, and 1.44, respectively; p<0.0001) and 12 months (2.33, 1.26, and 1.46, respectively; p<0.0001). Similarly, in the subgroup 3 we found a significantly higher proportion of patients achieving 1-year remission (44.1, 23.1, and 24.1%, respectively; p<0.0001) or LDA (57.3, 31.7, and 36.1%, respectively; p<0.0001). Treatment withdrawals due to adverse events were significantly more frequent in both subgroup 1 and 2 compared with subgroup 3 (19.3, 16.5, and 9.2%, respectively; p=0.02). Conclusions Our retrospective analysis demonstrated that in a real life setting the 6- and 12-month clinical response of ADA and ETN was significantly improved by combination strategy only when MTX has been used at high doses (≥12.5 mg/week). Interestingly, increasing MTX dose was also associated with a more favorable safety profile. References Burmester GR, Kivitz AJ, Kupper H, et al. Efficacy and safety of ascending methotrexate dose in combination with adalimumab: the randomized CONCERTO trial. Ann Rheum Dis 2015;74(6):1037–44. Disclosure of Interest None declared

SAT0214 Reliability and Validity of the Italian Version of the Ucla-Scleroderma Clinical Trial Consortium-Gastrointestinal Tract Instrument in Patients with Systemic Sclerosis

Background Gastrointestinal tract (GIT) involvement is frequent (up to 90%) in patients with systemic sclerosis (SSc). The UCLA Scleroderma Clinical Trial Consortium GIT (UCLA-SCTC GIT) 2.0 is a validated instrument for measuring the presence, severity and impact of GI symptoms on the health-related quality of life (HRQOL). Objectives To test the acceptability, feasibility, reliability and validity of the Italian translated version of UCLA-SCTC GIT 2.0. Methods Translation was performed using the concept elaboration, two forward translations with reconciliation followed by two back translations with review. This was then reviewed by the developer (DK) and pilot tested in 5 patients, the transcript was reviewed and any inconsistencies reconciled. Acceptability and feasibility of the questionnaire were evaluated based on the comments of the patients. Internal consistency was evaluated by Cronbach’s alpha. External consistency was measured by comparing with the SF-36 and EQ-5D by Spearman’s rho rank correlation coefficient. We considered coefficients ≥0.30 as meaningful. Results 20 consecutive SSc patients (mean age 57,9) were recruited, 90% were female. Four patients had a diffuse cutaneous (dc)-SSc, 11 limited cutaneous (lc)-SSc and 5 had very early (ve)-Ssc based on EUSTAR classification [3]. 26,3% had isolated anti-nuclear antibody positivity, 31,6% had anti-centromere positivity and 42,1% had anti-topoisomerase positivity. Mean disease duration since the first non-Raynaud symptom was 12,6 years. The UCLA-SCTC GIT was well accepted by the patients and no additional comments were noted regarding the content of the instrument. Percentage of missing data in UCLA-SCTC GIT score was 3,4% vs. 16% for SF-36 which has a similar number of total items. Internal consistency was good (alpha>0,70) in all domains except for the Distention/Bloating domain (alpha=0,53). Mean total UCLA-SCTC GIT score was 0,37 (range 0-2,83) and the worse scores were observed for Reflux (0,40, range 0-3), Distention/bloating (0,86, range 0-3) and for Constipation (0,53, range 0-2,5). GIT total score, Diarrhea and Fecal soilage domains significantly correlated with disease duration (p<0,03; p<0,05 and p<0,05 respectively). UCLA-SCTC GIT Emotional Well-being was strongly correlated with the mental component summary of SF-36 (p<0,03) and with the EQ-5D Self-care domain (p<0,05). Reflux and Diarrhea domains correlated with the EQ-5D Usual Activities (p<0,02 and p<0,05) and Self-care domains (p<0,01 for both), thus reflecting the impact on everyday and self-care activities. Conclusions This is the first validation study of the Italian version of UCLA-SCTC GIT 2.0. Our data support its feasibility, reliability, and validity, in Italian SSc patients. Disclosure of Interest None Declared

Update on the epidemiology, risk factors, and disease outcomes of systemic sclerosis

Systemic sclerosis (SSc) is a chronic immune-mediated connective tissue disease with heterogeneous organ involvement. New classification criteria were developed allowing disease identification even before the onset of its hallmark, skin fibrosis. Incidence and prevalence vary among reports and are influenced by methodology. Despite earlier diagnosis, mortality of SSc is still considerable, mainly because of cardiopulmonary causes. Genetic predisposition is entangled and implies genes of the major histocompatibility complex and also other loci related to immune regulation. Known environmental risk factor is exposure to organic solvents and silica, but no single risk factor has emerged. Disease outcome measures including patient-reported outcomes have been proposed and validated, and their use is expected to contribute to measure treatment response in clinical trials. Because of the low frequencies and the high heterogeneity of the disease, large multicenter research collaborations are envisaged to achieve advancement in SSc management.

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

QUESTIONS Published studies lack clear indicators of risk and predictors of transition from Raynauds 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.