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Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and antithrombotic agents is associated with increased risks of both bleeding and thromboembolism. In this prospective intervention study, community pharmacists screened for NSAID-antithrombotic interactions and contacted the prescribing physician to discuss interaction management. We included 782 interactions; these were found in an older, polymedicated patient population (mean age: 68 y, median of 5 other drugs). Ibuprofen (in 43.0% of cases) and low-dose aspirin (78.8%) were the most frequently involved NSAID and antithrombotic, respectively. Anticoagulants were involved in 16.1% of interaction cases. For 61% of cases, the interacting drugs were prescribed by the same physician. The pharmacist-physician discussion about how to manage the interaction mostly resulted in no change of pharmacotherapy (60.7%); the most frequent reason given by physicians was that the NSAID was for short-term use only. In 39.3% of cases the discussion resulted in a pharmacotherapy change; replacing the NSAID by paracetamol was the most common change.

OBJECTIVES: Today, the contribution of myositis-specific autoantibodies (MSA) in the diagnostic workup of idiopathic inflammatory myopathies (IIM) is on the rise. The aim of this study was to document MSA frequency as detected by lineblot in a set of consecutive MSA requests and to correlate the results with clinical diagnosis, IIM subtype and indirect immunofluorescence (IIF) findings. Additionally, a comparison between two lineblots was performed. METHODS: A total of 118 consecutive samples of patients with suspicion of IIM were analysed on IIF and two lineblots. A total of 107 patients with autoimmune rheumatic diseases served as controls. RESULTS: MSA were detected in 55% of IIM patients (n=31) and 7.9% (n=12) of patients without clinical diagnosis of IIM or myositis overlap syndrome. All the IIM patients had a MSA-compatible clinical subtype. There was no to fair agreement between both lineblots for the individual antibodies, with most discrepancies observed for anti-TIF1γ (κ=-0.021), anti-SRP (κ=-0.006) and anti-SAE (κ=0.395). Differences between both assays were mostly observed in the non-IIM patients, also showing signi cantly lower blot signal intensities compared to IIM patients (p=0.0013). MSA in the non-IIM patients frequently showed an incompatible IIF pattern. CONCLUSIONS: Lineblot seems to be an interesting tool for MSA detection in a clinical context, allowing the identification of clinical subtypes. However, considerable caution must be exercised in interpreting the results in case of low positive MSA signal intensity, discordant lineblot results and/or an incompatible IIF pattern.

Objectives: The epidemiology of interstitial lung disease (ILD) in systemic sclerosis (SSc) in Belgium is unknown. In literature, its prevalence varies between 19% and 52% in limited/diffuse cutaneous SSc (LcSSc/ DcSSc). However, its prevalence in "early" SSc (pre-clinically overt SSc without [yet] skin involvement), nor its incidence rate in SSc (LcSSc/DcSSc/"early" SSc) has ever been described. Against this background, we aimed to determine the prevalence/incidence (rate) and progression of ILD in SSc. Methods: 12-year follow-up data of consecutive SSc patients, included in two Flemish cohorts (University Hospitals Ghent and Leuven), were retrospectively analysed. ILD was classified according to the simplified Goh algorithm. Progression of ILD was defined as a relative decline of FVC >10%, a combined relative decline of FVC 5-10% and DLCO >15%, or as an increase in HRCT extent. Results: 722 patients (60% LcSSc/ 20% DcSSc/ 20% "early" SSc, median (IQR) follow-up 39 [12-80] months) had baseline HRCT. 243 were rated to have ILD at baseline and 39 during follow-up (prevalence of 34%/ incidence rate of 20.3/1000PY, 95%CI:14.5-27.8). Amongst those with baseline ILD, 60% had lung functional progression at five years of follow-up. In the "early" SSc subgroup, eight patients were rated to have ILD at baseline and three during follow-up (prevalence of 6%/ incidence rate of 5.8/1000 PY, 95%CI:1.2-17.0). Conclusion: Both LcSSc and DcSSc patients should be monitored for ILD evolution. The low prevalence and incidence of ILD in the "early" SSc subgroup may instruct future decisions on the construction of uniform patient follow-up pathways in "early" SSc. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Introduction Early screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) improves outcome. Therefore, we evaluated the screening for PAH during the 10-year follow-up of an unselected prospective SSc cohort by calculating the prevalence and the incidence rate of PAH and we compared the screening before and after implementation of the 2009 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. Methods Data were evaluated from each SSc-specific visit of 362 consecutive SSc patients included in the SSc Cohort of the Ghent University between May 2006 and December 2015. Results Of the 362 included patients, 23.2% had limited SSc, 59.9% limited cutaneous SSc and 16.9% diffuse cutaneous SSc. At baseline, one patient was already on PAH-specific treatment and eight patients were diagnosed with PAH, implicating a baseline PAH prevalence of 2.5% (9/362). During follow-up (median of 18 months [interquartile range: 0-54 months]), nine patients were diagnosed with incidental PAH, resulting in an incidence rate of 9.3/1000 person-years, 95% confidence intervals (95% CI): 4.3-17.7. Before the ESC/ERS guidelines, five PAH patients, all already diagnosed with prevalent PAH, were included in the cohort. After 2009, 13 patients (4 prevalent cases) were diagnosed with PAH, making the yearly incidence around 1% (0.82%-2.00%). Conclusions During 10-year follow-up in a cohort of 362 unselected SSc patients, the cumulative prevalence of PAH is 5% (18/362) and the incidence rate 9.3/1000 person-years, 95% CI: 4.3-17.7. Before implementation of the 2009 ESC/ERS screening algorithm, there were no incident cases.

Background Systemic sclerosis (SSc) and primary biliary cholangitis (PBC) are autoimmune diseases that may occur concomitantly and are both strongly associated with disease-specific autoantibodies. This study investigated the prevalence and fine specificity of PBC-specific serology (PBC-Ab) and associations with the SSc-subtypes and SSc-specific antibodies as well as the association with cholestatic liver enzymes. Furthermore, three different techniques for the detection of PBC-Ab were compared. Methods Serum of 184 Belgian SSc patients with a known SSc-antibody profile, was analyzed for PBC-Ab (antimitochondrial antibodies [AMA], anti-Gp210, anti-Sp100 and anti-PML) using indirect immunofluorescence (IIF) analysis on human epithelioma-2000 (HEp-2000) cells (ANA-IIF, Immunoconcepts) and liver-kidney-stomach tissue sections (IIF-LKS) (Menarini), and a line immunoblot (LB) (EuroImmun). Alkaline phosphatase/γ-glutamyl transferase (ALP/GGT) were evaluated at time of first sampling (t0) and after 3 years of follow-up (t3). Results PBC-Ab were present in 13% of patients and significantly correlated with centromere antibodies (anti-CENP-B), but not correlated with the limited cutaneous SSc subgroup (lcSSc). The most frequent reactivities were AMA (11%, with 9% AMA-M2) and Sp-100 antibodies (5%), showing a major overlap. There was no relevant association between the presence of PBC-Ab and ALP or GGT elevation at t0 nor at t3. Detection of AMA with IIF-LKS is comparable to LB. ANA-IIF screening was less sensitive compared to LB. Conclusions A wide range of PBC-Ab is detectable in SSc in the absence of cholestatic liver enzyme elevations, even after 3 years of follow-up. However, as these antibodies may precede PBC-disease up to 10 years further prospective follow-up of our cohort will be necessary.

Capillary microscopy is a safe and non-invasive tool to evaluate the morphology of the microcirculation typically affected in SSc. Next to being paramount for the "(very) early" diagnosis of SSc eyes are also geared toward capillaroscopy with the aim to be able to use it as a biomarker, especially in the prediction of future occurrence of DU. The following review will explain what capillary microscopy is and will focus additionally on studies evaluating the association between capillaroscopy and DU.

Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by vasculopathy and progressive fibrosis of the skin and visceral organs (gastrointestinal tract, heart, kidneys and lungs). Although the prevalence is low, SSc is a disease with high morbidity and mortality. Since pulmonary arterial hypertension (PAH) associated with SSc (SSc-PAH) and clinically evident cardiac involvement is associated with increased mortality, the cardiac complications and PAH in SSc are reviewed. Both diffuse cutaneous (DcSSc) and limited cutaneous (LcSSc) subgroups are at risk for cardiac involvement and SSc-PAH. Cardiac involvement can be divided in pericardial involvement, myocardial involvement and rhythm disturbances and mostly occurs asymptomatically. However, when symptomatic, it is associated with a poor prognosis. Screening for asymptomatic cardiac involvement should be considered in SSc in order to initiate treatment in an early stage. However, there are no randomized controlled trials on treatment options for cardiac involvement in SSc. SSc-PAH is a devastating complication of SSc, which can develop early in DcSSc and LcSSc. Screening for PAH should be performed since screening leads to earlier diagnosis and earlier treatment is associated with a better prognosis. Today, screening is performed by clinical judgement and echocardiography. Recently the DETECT algorithm, a 2-step screening algorithm is proposed in a SSc-subgroup at increased risk for PAH, but further validation is needed. Despite current treatment options with prostacyclins, endothelin-1 receptor antagonists and phosphodiesterase type-5 inhibitors, mortality remains high. Several promising new treatment options for PAH are evaluated in phase II and III clinical trials.

Objectives A reliable tool to evaluate flow is paramount in systemic sclerosis (SSc). We describe herein on the one hand a systematic literature review on the reliability of laser speckle contrast analysis (LASCA) to measure the peripheral blood perfusion (PBP) in SSc and perform an additional pilot study, investigating the intra- and inter-rater reliability of LASCA. Methods A systematic search was performed in 3 electronic databases, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In the pilot study, 30 SSc patients and 30 healthy subjects (HS) underwent LASCA assessment. Intra-rater reliability was assessed by having a first anchor rater performing the measurements at 2 time-points and inter-rater reliability by having the anchor rater and a team of second raters performing the measurements in 15 SSc and 30 HS. The measurements were repeated with a second anchor rater in the other 15 SSc patients, as external validation. Results Only 1 of the 14 records of interest identified through the systematic search was included in the final analysis. In the additional pilot study: intra-class correlation coefficient (ICC) for intra-rater reliability of the first anchor rater was 0.95 in SSc and 0.93 in HS, the ICC for inter-rater reliability was 0.97 in SSc and 0.93 in HS. Intra- and inter-rater reliability of the second anchor rater was 0.78 and 0.87. Conclusions The identified literature regarding the reliability of LASCA measurements reports good to excellent inter-rater agreement. This very pilot study could confirm the reliability of LASCA measurements with good to excellent inter-rater agreement and found additionally good to excellent intra-rater reliability. Furthermore, similar results were found in the external validation.

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Nailfold capillaroscopy is an easy, non-invasive technique to assess microvascular involvement in rheumatic diseases. Multiple studies describe capillaroscopic changes in systemic lupus erythematosus (SLE), including a wide range of non-specific findings. On behalf of the European League Against Rheumatism (EULAR) study group on microcirculation in rheumatic diseases, a systematic review was done to obtain all original research studies (in English) in which SLE patients had capillaroscopy. Forty such studies are identified. This article firstly provides a resume of the results of these studies according to capillaroscopic parameters (density, dimensions, morphology, haemorrhages), semi-quantitative assessment and qualitative assessment of capillaroscopy in SLE patients. Secondly, the correlations between capillaroscopic parameters in SLE patients and clinical and laboratory parameters (including auto-immune parameters) are outlined. The following capillaroscopic parameters are found to be significantly more prevalent in SLE patients compared to healthy controls: tortuous capillaries, abnormal morphology and haemorrhages. Hairpin-shaped capillaries are significantly less prevalent than in healthy persons. The semi-quantitatively determined nailfold capillaroscopic score (NFC score) in SLE patients is also higher than in healthy controls. Several correlations between clinical and laboratory parameters and capillaroscopic parameters are identified in the review. Disease activity is correlated with NFC score in seven studies, with abnormal morphology (i.e. "meandering") in one study and with haemorrhages in one study. Frequent attacks of Raynaud's phenomenon (RP) and gangrene are significantly correlated with dilated capillaries. In two studies a possible correlation between anti-SSA antibodies and lower density of capillaries is withheld. About other immune parameters conflicting results are found. In one study a significant negative correlation is found between 24-hour proteinuria and abnormal morphology (i.e. "meandering"). For the first time, an overview of the nailfold capillaroscopic changes that have been described in SLE and their correlations with clinical and laboratory findings is given. Further large-scale research on the identification of capillaroscopic changes in SLE and their correlations with standardised clinical and laboratory parameters, is ongoing at the EULAR study group on microcirculation in rheumatic diseases.

Objective.Our study reports the results of the MIRA (MabThera In Rheumatoid Arthritis) registry, set up to collect data about clinical usage, patient profile, and retention of rituximab (RTX) treatment in daily clinical practice in Belgium.Methods.Patients with active rheumatoid arthritis (RA) who failed at least 1 anti-tumor necrosis factor (anti-TNF) treatment were included in our study between November 2006 and October 2011. At baseline, demographics, medication, disease history, disease activity, rheumatoid factor (RF), and anticyclic citrullinated peptide antibodies (anti-CCP) status were recorded. Evolution of the 28-joint Disease Activity Score (DAS28)-erythrocyte sedimentation rate, retreatments, and reasons for therapy stop were followed prospectively.Results.The MIRA registry included 649 patients, with mean disease duration of 12.8 ± 0.4 years and DAS28 values at inclusion of 5.85 ± 0.48. Patients received on average 2.82 ± 0.07 (range 1–9) RTX treatments, over a mean followup period of 93.1 ± 2.6 weeks. At database lock, 433 patients (66.7%) were still under RTX treatment, 182 (28.0%) had stopped treatment, and 34 (5.2%) were lost to followup. Ineffectiveness (n = 108, 59%) and safety concerns (n = 39, 22%) were the most frequent reasons for discontinuing RTX therapy. From 2006 to 2011, RTX practice patterns clearly evolved toward RTX being started in patients with a lower number of previously failed anti-TNF drugs and lower baseline DAS28 values. A lower number of previous anti-TNF drugs, and positivity for RF and anti-CCP, predicted more successful longterm treatment. RTX treatment provided adequate longterm disease control.Conclusion.In our daily practice study, RTX provided good longterm disease control and treatment retention in refractory patients with RA. Over the years, rheumatologists tended to start this treatment in patients with fewer previous anti-TNF treatments and lower disease activity.

Objective.Our study describes the 10-year followup data of the Belgian Expanded Access Program (EAP) for infliximab (IFX), which included patients with active rheumatoid arthritis who were refractory to methotrexate. The objectives of the study were to evaluate the continuation rate, reasons for discontinuation, and longterm disease control under IFX treatment, and to study baseline characteristics associated with longterm successful IFX therapy.Methods.Between February 2000 and September 2001, 511 patients were enrolled in the Belgian IFX EAP, and 507 effectively started IFX therapy. Previously reported data showed that 160 patients were still treated with IFX after 7 years of followup. We describe the therapy status, reasons for IFX discontinuation, and the level of disease activity of this subgroup after 10 years of followup. Baseline characteristics of the total EAP cohort were used to describe variables associated with longterm successful IFX treatment.Results.After 10 years of followup, 110 of the 507 patients (21.7%) were still receiving IFX treatment. In the 7-year to 10-year period, which is the focus of the current study, 16 patients were lost to followup and 34 patients discontinued IFX treatment, mainly because of loss of efficacy. Patients successfully treated with IFX for 10 years had lower baseline values for 28-joint Disease Activity Score (DAS28), patient pain scale, physician visual analog scale, and Health Assessment Questionnaire in comparison with the rest of the study cohort. The mean DAS28 level of the subgroup still taking IFX after 10 years was 2.55 ± 1.01.Conclusion.In the Belgian EAP, 21.7% of patients continued to receive maintenance IFX treatment after 10 years of followup. IFX provided good longterm disease control in these patients.

To the Editor: B cell depletion therapy using rituximab (RTX) has emerged as a promising therapy in systemic sclerosis (SSc). Our group reported a clinical benefit on skin thickening when RTX (2 × 1000 mg) in combination with methylprednisolone (100 mg) was administered at months 0 and 61. The rationale behind the use of B cell depletion in SSc treatment is based on the growing evidence that B cells play a role in the pathogenesis of the disease2,3. In addition, SSc-associated antinuclear antibody (ANA) are present in the majority of patients, but are generally accepted to be rather static markers, primarily important in diagnosis rather than in followup4. Moreover, conflicting results have been published5 on the change in disease-specific ANA titers in relation to clinical response in other connective diseases (e.g., systemic lupus erythematosus and rheumatoid arthritis) after RTX. To our knowledge, no studies in SSc are available documenting the longterm effect of RTX on these autoantibody levels. In this letter we report the 2-year serologic followup data (months 0, 3, 6, 12, 15, 18, and 24) on the same 8 patients with SSc with diffuse skin involvement (dcSSc) who were included in our initial RTX studies1,6. The idea was to evaluate the relationship between SSc-ANA level changes and clinical response. To document this latter relationship, we performed … Address correspondence to C. Bonroy, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital 2P8, De Pintelaan 185, B-9000, Ghent, Belgium. E-mail: carolien.bonroy{at}uzgent.be

Objective Transforming growth factor β superfamily members are involved in the pathogenesis of systemic sclerosis (SSc). Growth differentiation factor 15 (GDF-15) is a distant member of this family. We undertook this study to evaluate the role of GDF-15 in SSc pathogenesis. Methods A longitudinal prospective cohort of SSc patients was screened for serum GDF-15 levels using enzyme-linked immunosorbent assay, and associations with clinical data were analyzed. In vitro stimulation experiments were performed on lung fibroblasts. The role of GDF-15 in fibrosis development in vivo was evaluated in the bleomycin lung fibrosis model in GDF-15–deficient mice. Results GDF-15 was measured at baseline in serum samples from 119 SSc patients. An increase in GDF-15 levels was observed in patients classified as having no skin involvement, those with limited cutaneous SSc, and those with diffuse cutaneous SSc. Moreover, baseline serum GDF-15 levels correlated strongly with disease activity and extent of organ involvement, particularly clinical symptoms of lung fibrosis, including impact on lung function at prospective followup. This was mimicked in the bleomycin model of SSc, in which animals exposed to bleomycin had elevated expression levels of GDF-15 in lung tissue. Lung fibroblasts isolated from GDF-15–deficient mice showed reduced induction of interleukin-6 and CCL2 upon bleomycin stimulation. Surprisingly, no differences in fibrosis development were observed between wild-type and GDF-15–deficient animals. Conclusion An intriguing profile of serum GDF-15 levels was found in SSc patients. GDF-15 expression is induced during fibrosis development and markedly correlates with lung function impairment in this disease. The protein may participate in fibrosis initiation, but is not indispensable in the course of fibrosis development in vivo.

Objective.Assessment of associations of nailfold videocapillaroscopy (NVC) scleroderma (systemic sclerosis; SSc) (“early,” “active,” and “late”) with novel future severe clinical involvement in 2 independent cohorts.Methods.Sixty-six consecutive Belgian and 82 Italian patients with SSc underwent NVC at baseline. Images were blindly assessed and classified into normal, early, active, or late NVC pattern. Clinical evaluation was performed for 9 organ systems (general, peripheral vascular, skin, joint, muscle, gastrointestinal tract, lung, heart, and kidney) according to the Medsger disease severity scale (DSS) at baseline and in the future (18–24 months of followup). Severe clinical involvement was defined as category 2 to 4 per organ of the DSS. Logistic regression analysis (continuous NVC predictor variable) was performed.Results.The OR to develop novel future severe organ involvement was stronger according to more severe NVC patterns and similar in both cohorts. In simple logistic regression analysis the OR in the Belgian/Italian cohort was 2.16 (95% CI 1.19–4.47, p = 0.010)/2.33 (95% CI 1.36–4.22, p = 0.002) for the early NVC SSc pattern, 4.68/5.42 for the active pattern, and 10.14/12.63 for the late pattern versus the normal pattern. In multiple logistic regression analysis, adjusting for disease duration, subset, and vasoactive medication, the OR was 2.99 (95% CI 1.31–8.82, p = 0.007)/1.88 (95% CI 1.00–3.71, p = 0.050) for the early NVC SSc pattern, 8.93/3.54 for the active pattern, and 26.69/6.66 for the late pattern versus the normal pattern.Conclusion.Capillaroscopy may be predictive of novel future severe organ involvement in SSc, as attested by 2 independent cohorts.

The population of elderly individuals with rheumatoid arthritis (RA) is expanding, due mainly to increasing life expectancy. A variety of theories have been proposed to explain the ageing process, including accumulation of DNA damage and resultant changes in biological processes. Such changes can influence the development and/or course of disease. Furthermore, alterations in biological function determine the biological age-as opposed to chronological age-of an individual, which strongly influences their ability to cope with disease. Moreover, comorbidities are more frequent in elderly individuals. Together, these factors complicate treatment of disease and necessitate careful patient management. Indeed, although evidence from clinical trials suggests that DMARDs and biologic agents have good efficacy and are well tolerated in elderly patients with RA, such individuals are often undertreated and inadequately managed. Unfortunately, insufficient data are available for the development of evidence-based guidelines for this population, as elderly patients are often excluded from clinical trials owing to age restrictions or comorbidities. Thus, additional clinical studies in elderly patients are warranted, with treatment regimens tailored according to vitality or frailty parameters. This Review focuses on the pathophysiological aspects of ageing and their implications for the management of RA in elderly patients.

Following results in open-label studies of rituximab in patients with systemic sclerosis, a Belgian three-centre initiative was launched to explore safety and efficacy of rituximab in early, diffuse cutaneous systemic sclerosis (dcSSc).Open-label study of 17 patients with early dcSSc, treated with two courses of rituximab, at month 0 and 6. Clinical examination, lung function testing, echocardiography, disease activity score (DAS) and functional status were performed at baseline and over 24 months of follow-up.Modified Rodnan skin score (MRSS) changed significantly over time, with a mean of 25.5 (standard deviation [SD] 6.0) at baseline to 12.6 (SD 5.1) at month 24 (Mixed Model Analysis [MMA] p 0.0001), which is a decrease of 51% at month 24 vs. baseline. DAS showed significant decrease over the total study period, with a score of 4.1 (SD 1.7) at baseline to 1.5 (SD 1.8) at month 24 (MMA p 0.0001). Additionally, this was significant at all time points vs. baseline, both for MRSS and DAS. Internal organ status remained clinically stable throughout the study period. No statistically significant differences compared to baseline were found at the follow-up time points. Seven serious adverse events took place, all except for one, considered unrelated to study medication.This is the first multicentre Belgian collaboration investigating potential efficacy of rituximab in early dcSSc. Rituximab appears to be safe and tolerable and it may have beneficial effects on skin involvement, on overall disease activity and on stabilization of internal organ status in early dcSSc.

OBJECTIVES: In agreement with other autoimmune diseases, systemic sclerosis (SSc) is associated with a strong sex bias. However, unlike lupus, the effects of sex on disease phenotype and prognosis are poorly known. Therefore, we aimed to determine sex effects on outcomes. METHOD: We performed a prospective observational study using the latest 2013 data extract from the EULAR scleroderma trials and research (EUSTAR) cohort. We looked at (i) sex influence on disease characteristics at baseline and (ii) then focused on patients with at least 2 years of follow-up to estimate the effects of sex on disease progression and survival. RESULTS: 9182 patients with SSc were available (1321 men) for the baseline analyses. In multivariate analysis, male sex was independently associated with a higher risk of diffuse cutaneous subtype (OR: 1.68, (1.45 to 1.94); p

Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are the leading causes of death in systemic sclerosis (SSc) patients. Although the six-minute walk test (6MWT) is used for evaluating ILD and PAH in clinical practice, no data are available on six-minute walk distance (6MWD) and oxygen desaturation in SSc patients without ILD and PAH.Prospectively collected data of the 6MWTs at baseline and 6-month follow-up of 300 consecutive SSc patients, included in the Ghent University Hospital Systemic Sclerosis Unit between May 2006 and April 2015 were analysed.The mean 6MWD of 165 SSc patients without ILD and PAH who performed a 6MWT at baseline or at the 6-month visit was 484±93m. Patients in the diffuse cutaneous (DcSSc) subgroup (435±94m) walked less than in the limited (LSSc) subgroup (499±91m, p=0.04) and tended to walk less than in the limited cutaneous (LcSSc) subgroup (483±92m, p=0.15). In 115 SSc patients without ILD and PAH who walked at both moments, there was no significant difference between the 6MWDs (mean difference -7.60m 95%CI [-19.93m; 4.73m], p=0.23) and the oxygen desaturation was not statistically different in 102 of them (mean difference 0.41% 95%CI [-0.49%; 1.31%], p=0.37).In SSc without ILD and PAH, the 6MWD and oxygen desaturation is clinically stable over a 6 months period. The DcSSc subgroup walks less than the LSSc and the LcSSc subgroup.

Objective.To report baseline and followup data on the first 438 patients with systemic sclerosis (SSc) included in the Belgian Systemic Sclerosis Cohort.Methods.According to LeRoy and Medsger’s classification, 73 patients with limited SSc (lSSc), 279 with limited cutaneous SSc (lcSSc), and 86 with diffuse cutaneous SSc (dcSSc) were included. History was collected and clinical examination, blood tests, and paraclinical investigations were repeated. The Disease Activity Score (DAS) and Disease Severity Score (DSS) of several organ systems were computed. An organ system was considered to demonstrate SSc if the corresponding DSS was ≥ 1.Results.At baseline, patients with dcSSc had more general, joint/tendon, muscle, gastrointestinal, and kidney involvement. Mean DLCO was below normal in patients with lSSc, indicating unsuspected lung involvement. Patients with anti-Scl-70 had more vascular, skin, joint/tendon, and lung involvement. Patients with anti-RNA polymerase III had more skin and joint/tendon involvement compared to patients with anticentromere. Time to death was statistically shorter for patients with dcSSc. New-onset lung disease was the most common complication over time. No changes in DAS were observed. By contrast, the general and the skin DSS worsened in patients with lcSSc and lSSc, respectively. Fifteen percent of patients with lSSc shifted to lcSSc at Month 30, but neither serology nor capillaroscopy findings at baseline were helpful in identifying those at risk.Conclusion.Our data indicate that the DSS can be used to define organ involvement in SSc. Differences can be seen between subsets classified not only according to cutaneous subtypes but also to autoantibody profile.

Background and Aims: Inflammatory bowel disease (IBD) is a chronic disease affecting mainly young people in their reproductive years. IBD therefore has a major impact on patients' family planning decisions. Management of IBD in pregnancy requires a challenging balance between optimal disease control and drug safety considerations. This article aims to provide a framework for clinical decision making in IBD based on review of the literature on pregnancy-related topics. Methods: Medline searches with search terms 'IBD', 'Crohn's disease' or 'ulcerative colitis' in combination with keywords for the topics fertility, pregnancy, congenital abnormalities and drugs names of drugs used for treatment of IBD. Results: IBD patients have normal fertility, except for women after ileal pouch-anal anastomosis (IPAA) and men under sulfasalazine treatment. Achieving and maintaining disease remission is a key factor for successful pregnancy outcomes in this population, as active disease at conception carries an increased risk of preterm delivery and low birth weight. Clinicians should discuss the need for drug therapy to maintain remission with their patients in order to ensure therapy compliance. Most IBD drugs are compatible with pregnancy, except for methotrexate and thalidomide. If possible, anti-TNF therapy should be stopped by the end of the second trimester and the choice of delivery route should be discussed with the patient. Conclusions: Disease control prior to conception and throughout pregnancy is the cornerstone of successful pregnancy management in IBD patients. (c) 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

OBJECTIVE: The aim of the present study was to evaluate the association between illness perceptions and the ability to cope with physical and mental health problems in a large cohort of systemic sclerosis (SSc) patients. METHODS: This was a cross-sectional study in 217 systemic sclerosis patients from the Belgian Systemic Sclerosis Cohort. Illness perception and coping were measured by the Revised Illness Perception Questionnaire and a coping questionnaire - the Coping Orientation of Problem Experience inventory (COPE). Physical and mental health-related quality of life was measured by the 36-item short-form health survey (SF-36), as were disease activity and several severity parameters. The relationship between illness perceptions and the ability to cope with physical/mental health problems was examined using multiple linear regression analysis. RESULTS: According to LeRoy's classification, 49 patients had limited SSc (lSSc), 129 had limited cutaneous SSc (lcSSc) and 39 had diffuse cutaneous SSc (dcSSc). Median disease duration was five years and the modified Rodnan skin score was 4. Good physical health was significantly associated with the lcSSc subtype and low disease activity (p

To define the burden of hand radiological damage in systemic sclerosis (SSc) patients, compared with a control group.Both hands of 167 SSc patients and 168 hands (82 right and 86 left) of age- and gender-matched controls were imaged by conventional radiograph. Two musculoskeletal radiologists semiquantitatively scored the following lesions: tuft acro-osteolysis, tuft calcinosis, joint space narrowings, marginal erosions, surface erosions, collapse arthropathies, periarticular calcifications, and juxta-articular osteoporosis, at the following areas: tufts, distal interphalangeal, proximal interphalangeal, metacarpophalangeal, carpal, and first carpometacarpal joints. Clinical and functional characteristics of the 167 SSc patients were obtained from the Belgian Systemic Sclerosis Cohort database.Tuft acro-osteolysis and calcinosis were the most common findings observed in SSc patients and were almost absent in controls. SSc patients displaying tuft acro-osteolysis/calcinosis suffered from more severe disease. Arthropathies were infrequently detected and mainly consisted of a mixture of osteoarthritis-related changes (joint space narrowing and surface erosions)-also observed in controls-and of 2 types of rare SSc-associated arthropathies: a rheumatoid arthritis-like pattern, characterized by marginal erosions (n = 7 patients), and a collapse arthropathy (n = 6 patients), characterized by pressure erosions and joint subluxation.Although a rheumatoid arthritis-like or a collapse arthropathy can be observed in SSc patients, arthropathies are less common than previously reported.

Approximately one-third of rheumatoid arthritis (RA) patients are seronegative for the 2 serological RA markers, rheumatoid factor (RF) and antibodies against cyclic citrullinated peptides (ACCP). Moreover, the sensitivities of both markers are lower in the diagnostically important early disease phase. The aim of this study was to identify additional autoantibody markers for early RA and for RF-negative, ACCP-negative (seronegative) RA. We screened an RA synovium cDNA phage display library with autoantibodies in plasma from 10 early (symptoms of maximum 1 year) and 10 seronegative (RF-negative, ACCP-negative) RA patients with validation in 72 additional RA patients and 121 controls (38 healthy controls, 43 patients with other inflammatory rheumatic diseases, 20 osteoarthritis patients and 20 subjects with mechanical joint complaints). Fourteen novel autoantibodies were identified that showed a 54% sensitivity and 90% specificity for RA. For 11 of these autoantibodies, an exclusive presence was demonstrated in RA patients (100% specificity, 37% sensitivity) as compared to controls. All early RA patients were positive for at least one of the identified autoantibodies and antibody-positivity was associated with a shorter disease duration (P = 0.0087). 52% of RA patients who initially tested negative for RF and ACCP, tested positive for at least one of the 14 novel autoantibodies, resulting in a 19% increase in sensitivity compared to current serological testing. Moreover, 5 identified autoantibodies were detected more frequently in seronegative RA patients, indicating that these autoantibodies constitute novel candidate markers for this RA subtype. We demonstrated that the targets of 3 of these 5 autoantibodies had an increased expression in RA synovial tissue compared to control synovial tissue, pointing towards a biological rationale for these auto antibody targets in RA. In conclusion, we identified novel candidate autoantibody markers for RA that can be detected in early and seronegative RA patients indicating the potential added value for RA diagnostics.

Biologicals revolutionized the treatment of Rheumatoid Arthritis (RA). The targeted suppression of key inflammatory pathways involved in joint inflammation and destruction allows better disease control, which, however, comes at the price of an elevated infection risk due to relative immunosuppression. The disease-related infection risk and the infection risk associated with the use of TNF-α inhibitors (infliximab, adalimumab, etanercept, golimumab and certolizumab pegol), rituximab, abatacept and tocilizumab are discussed. Risk factors clinicians need to take into account when selecting the most appropriate biologic therapy for RA patients, as well as precautions and screening concerning a number of specific infections, such as tuberculosis, intracellular bacterial infections, reactivation of chronic viral infections and HIV are reviewed.

Patients with immune-mediated inflammatory diseases (IMID) such as RA, IBD or psoriasis, are at increased risk of infection, partially because of the disease itself, but mostly because of treatment with immunomodulatory or immunosuppressive drugs. In spite of their elevated risk for vaccine-preventable disease, vaccination coverage in IMID patients is surprisingly low. This review summarizes current literature data on vaccine safety and efficacy in IMID patients treated with immunosuppressive or immunomodulatory drugs and formulates best-practice recommendations on vaccination in this population. Especially in the current era of biological therapies, including TNF-blocking agents, special consideration should be given to vaccination strategies in IMID patients. Clinical evidence indicates that immunization of IMID patients does not increase clinical or laboratory parameters of disease activity. Live vaccines are contraindicated in immunocompromized individuals, but non-live vaccines can safely be given. Although the reduced quality of the immune response in patients under immunotherapy may have a negative impact on vaccination efficacy in this population, adequate humoral response to vaccination in IMID patients has been demonstrated for hepatitis B, influenza and pneumococcal vaccination. Vaccination status is best checked and updated before the start of immunomodulatory therapy: live vaccines are not contraindicated at that time and inactivated vaccines elicit an optimal immune response in immunocompetent individuals.

Pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) are the leading causes of death in systemic sclerosis (SSc). Although the six-minute walk test (6MWT) is generally used for evaluating PAH and ILD, utility in SSc is undetermined. This study evaluates the role of 6MWT in SSc by systematic review and meta-analysis.A systematic literature search on PubMed, Web of Science and Cochrane Library Online was performed using the medical subject heading search terms for "systemic sclerosis", "CREST" and "six minute walk test", "six minute walk distance (6MWD)", "(cardiopulmonary) exercise test", "treadmill test" or "step test".Meta-analysis of 43 included studies (3185 SSc-all patients) revealed that the mean 6MWD was comparable between the SSc-PAH and SSc-ILD-PH subgroups (288m [95% CI: 259-317m] vs 286m [95% CI: 259-314m], p=0.93). The pooled mean of 725 SSc-PAH patients was significantly lower than the pooled mean of 413 SSc-noPAH patients (430m [95% CI: 402-458m], p0.001). 95 SSc-ILD-PH patients walked significantly less than 328 SSc-ILD patients (388m [95% CI: 362-415m], p0.001) and significantly less than 86 SSc-noILD patients (420m [95% CI: 325-515m], p=0.008). 81-98% of the SSc-PAH/ILD/ILD-PH patients performed a 6MWT.During a 6MWT, SSc-PAH patients walk less than SSc-noPAH patients and SSc-ILD-PH patients walk less than SSc-ILD and SSc-noILD patients.

Reviewing disease activity indices (DAI) in systemic sclerosis (SSc) and reporting their validation status.Literature was systematically reviewed on studies documenting the development of DAI, assessing the validation status of DAI and studies using a DAI in their analysis. The qualitative and quantitative validation status of existing DAI was assessed based on OMERACT and on definitions of the American College of Rheumatology (ACR) committee on quality measures.Three DAI in SSc have been proposed in literature: the European Scleroderma Study Group (EScSG) activity index, the 12-point DAI and the Combined Response Index for Systemic Sclerosis (CRISS). The EScSG activity index is yet applied as an outcome measure in 48 different studies. The EScSG activity index and the CRISS are provisional partially validated DAI.Future studies are needed to fully validate the EScSG activity index and the CRISS and to assess the validation status of the 12-point DAI.

The European Scleroderma Study Group (EScSG) activity index meets nearly all the OMERACT-standards of truth, discrimination and feasibility. The sensitivity to change remains to be attested. This study assesses sensitivity to change of the EScSG activity index in patients with early and severe diffuse cutaneous Systemic Sclerosis (dcSSc) treated with rituximab.12-month follow-up (open-label study) of 14 consecutive patients with early dcSSc. Patients received an infusion of two times 1000 mg rituximab at month 0 and 6, together with 100 mg methylprednisolone. Clinical read outs (modified Rodnan skin score [mRSS], lung function and echocardiography) and EScSG activity index were performed at month 0, 3, 6 and 12. Mixed models analyses (MMA) were used to evaluate changes in parameters over time.There was a clinically significant change in skin score with a mean (SD) mRSS of 24.8 (4.44) at baseline and 10.4 (3.12) at month 12 (MMA p0.001). Also the EScSG activity index decreased significantly, with a mean (SD) of 4.3 (1.79) at baseline and 0.7 (0.83) at month 12 (MMA p0.001). The estimated mean change of the EScSG activity index was -3.6 (95%CI -4.9; -2.4) over 12 months. Indices of internal organ involvement remained stable throughout the study.A significant improvement of the EScSG activity index was observed, in line with the significant improvement of the mRSS and the stabilisation of internal organ involvement. To our knowledge, this is the first study to attest sensitivity to change of the EScSG activity index in the subset of 'early' dcSSc.ClinicalTrials.gov Registration, http://clinicaltrials.gov, number NCT00379431.

Purpose: Rubella virus (RV) has a central role in the etiopathogenesis of Fuchs’ uveitis syndrome (FUS). We aim to offer new insights by comprehensive analysis of recent laboratory and epidemiologic data.Methods: We conducted a literature search for laboratory data and papers on etiopathogenesis.Results: Aqueous humour samples of FUS patients show immunoreactivity to RV, in a specific and sensitive manner. Identification of RV genome confirm intraocular infection in a subset of FUS patients. Epidemiologic findings further support causality. The clinical spectrum of RV-associated uveitis is similar but not identical to FUS. FUS eyes exhibit a predominance of CD8 + T cells, high IFN-? and IL-10 levels.Conclusions: RV is the leading cause of FUS. Cytokine-based findings mirror a viral etiology and chronic low-grade inflammation. RV-associated FUS represents a common pathway of intraocular RV inoculation after congenital or acquired infection. Other causes, including HSV and CMV, may lead to FUS.

Objective: Qualitative capillaroscopy patterns in juvenile- and adult-onset systemic sclerosis (SSc) were studied in adulthood using data from the EULAR Scleroderma Trials and Research (EUSTAR) database. Methods: Data collected between June 2004 and April 2013 were examined with focus on capillaroscopy. In this retrospective exploratory study, series of patients with juvenile-onset SSc were matched with series of adult-onset SSc having the same gender and autoantibody profile. Results: 30 of 123 patients with juvenile-onset and 2108 of 7133 with adult-onset SSc had data on capillaroscopy. Juvenile-onset SSc showed scleroderma pattern more frequently than adult-onset SSc (93.3% and 88%). The OR was 2.44 and 95% Cl 0.57-10.41. An active scleroderma pattern was present in 58% of juvenile- and 61% of adult-onset SSc. The OR was 0.91 and 95% Cl 0.28-2.93. The late scleroderma pattern was present in 61% of juvenile- and 55.5% of adult-onset SSc. The OR was 1.06 and 95% Cl 0.34-3.56. Conclusion: This is the first exploratory study on the comparison of capillaroscopy between juvenile- and adult-onset SSc in adulthood. Juvenile-onset SSc had an increase prevalence of sderoderma pattern, but a similar distribution of the three patterns was suggested. Further studies are needed to define this issue. (C) 2015 Elsevier Inc. All rights reserved.

Objective To identify biomarkers for effective treatment in early-phase clinical trials of spondylarthritis (SpA), by analyzing which synovial features can be reliably identified in patients with SpA. Methods Synovial biopsies were performed at weeks 0 and 12 in 20 SpA patients treated with infliximab, 20 treated with etanercept, and 12 who were not treated. Primary clinical outcome measures were patient and physician global assessment of disease activity. Extensive histologic evaluation included assessment of lining layer hyperplasia, vascularity, markers of cellular infiltration, and metalloproteinases (MMPs) in the lining and sublining layers. Results Changes in levels of CD163 (resident tissue macrophages) in the lining, and CD163, MMP-3, and myeloid-related protein 14 (MRP-14; infiltrating myeloid cells) in the sublining correlated significantly with changes in the primary clinical outcomes. Comparison between responders (n = 35) and nonresponders (n = 17) showed differences in the degree of change in the levels of CD163 in the lining and CD163, MMP-3, and CD3 in the sublining, whereas trends in change in the levels of MRP-8 and MRP-14 in the lining and sublining were similar in the 2 groups. Accordingly, the highest differences in standardized response means (SRMs) between the 2 groups were found for CD163 in the lining, MMP-3, CD163, CD3, and MRP-8 in the sublining, and the level of polymorphonuclear cells (PMNs). When comparing treated and untreated patients, high differences in SRMs were again found for CD163 in the lining, MMP-3, CD163, and MRP-8 in the sublining, and PMNs. These parameters performed prognostically as well as the erythrocyte sedimentation rate and better than the C-reactive protein level. Class prediction analysis yielded a 90% correct prediction using 8 synovial parameters, as follows: lining and sublining CD163, MRP-8, and MRP-14, sublining MMP-3, and PMNs. In validation analyses with independent samples, effective treatment was correctly predicted in 24 of 30 SpA patients and in 2 of 2 placebo-treated patients. Conclusion Changes in synovial macrophage subsets, PMN levels, and MMP-3 expression reflect response to treatment in SpA. The ability of these parameters to correctly identify effective therapy makes them interesting biomarkers for use in early-phase clinical trials in SpA.

In this paper, the ample experimental, clinical, genetic, histopathologic, and immunologic evidence for an important role of the gut in the pathogenesis of spondylarthropathy (SpA) and for an overlap between SpA and Crohn's disease is reviewed. These data suggest that SpA and Crohn's disease should be scientifically and clinically considered as distinct phenotypes of common immune-mediated inflammatory disease pathways rather than as separate disease entities. Classification, diagnosis, and therapy based on pathophysiologic insights is likely to become superior to an approach based exclusively on signs and symptoms, as evidenced by the recent evolution in treatment of SpA by tumor necrosis factor-a blockade.

Objective To analyze the clinical and biologic correlates of autoantibody induction during longer-term tumor necrosis factor α (TNFα) blockade with either the monoclonal antibody infliximab or the soluble receptor etanercept. Methods Thirty-four patients with spondylarthropathy (SpA) and 59 patients with rheumatoid arthritis (RA) were treated with infliximab for 2 years. Additionally, 20 patients with SpA were treated with etanercept for 1 year. Sera were blindly analyzed for antinuclear antibodies (ANAs), anti–double-stranded DNA (anti-dsDNA) antibodies, anti–extractable nuclear antigen (anti-ENA) antibodies, and antihistone, antinucleosome, and anticardiolipin antibodies (aCL). The anti-dsDNA antibodies were isotyped. Results High numbers of infliximab-treated patients with SpA or RA had newly induced ANAs (61.8% and 40.7%, respectively) and anti-dsDNA antibodies (70.6% and 49.2%, respectively) after 1 year, but no further increase between year 1 and year 2 was observed. In contrast, induction of ANAs and anti-dsDNA antibodies was observed only occasionally in the etanercept-treated patients with SpA (10% of patients each). Isotyping revealed almost exclusively IgM or IgM/IgA anti-dsDNA antibodies, which disappeared upon interruption of treatment. Neither infliximab nor etanercept induced other lupus-related reactivities such as anti-ENA antibodies, antihistone antibodies, or antinucleosome antibodies, and no clinically relevant lupus-like symptoms were observed. Similarly, infliximab but not etanercept selectively increased IgM but not IgG aCL titers. Conclusion The prominent ANA and anti-dsDNA autoantibody response is not a pure class effect of TNFα blockers, is largely restricted to short-term IgM responses, and is not associated with other serologic or clinical signs of lupus. Similar findings with aCL suggest that modulation of humoral immunity may be a more general feature of infliximab treatment.

Objective To address the ongoing debate concerning the specificity of synovial citrullinated proteins for rheumatoid arthritis (RA) and to analyze their pathophysiologic relevance to the induction or perpetuation of the RA-specific anti–citrullinated protein antibodies (ACPAs). Methods Synovium of 19 RA patients and 19 non-RA controls was immunostained for the presence of citrullinated proteins with a mouse monoclonal antibody (F95), for the citrullinating enzyme peptidyl arginine deiminase type 2 (PAD-2), and for the free citrulline–producing enzyme inducible nitric oxide synthase (iNOS). Extending the RA cohort to 61 patients, the findings of anticitrulline staining in synovium were related to serum and synovial fluid ACPA levels, as measured by enzyme-linked immunosorbent assay. Results F95 staining indicated the presence of synovial intracellular citrullinated proteins in 53% of RA samples versus 5% of control samples, whereas extracellular staining was not RA specific. Immunoblotting and inhibition experiments confirmed that the antibody recognized citrullinated proteins but not free citrulline. Accordingly, iNOS was equally found in RA and control synovium and in intracellular citrullinated protein–positive and intracellular citrullinated protein–negative samples. In contrast, intracellular citrullinated proteins colocalized with PAD-2, which was found in 59% of RA samples versus 17% of control samples. Independent of local disease activity, the presence of the RA-specific synovial intracellular citrullinated proteins was associated with significantly higher systemic and local ACPA levels and with local ACPA production in the joint. Conclusion These data confirm the presence of RA-specific intracellular citrullinated proteins in synovium. The link with PAD-2 and local and systemic ACPA levels emphasizes their pathophysiologic relevance for RA-specific humoral autoimmunity.

Objective Since CD163+ macrophages are selectively increased in spondylarthropathy (SpA) synovitis, we investigated the role of CD163+ macrophages in synovial inflammation. Methods Synovial biopsy samples from 26 SpA and 23 rheumatoid arthritis (RA) patients were analyzed for macrophage and lymphocyte subsets. Synovial fluid (SF) samples were analyzed by Western blotting and enzyme-linked immunosorbent assay for soluble CD163 (sCD163) and by flow cytometry for lymphocyte activation. We also analyzed sCD163 in sera from 100 SpA patients, 23 RA patients, 20 healthy controls, and 20 SpA patients treated with infliximab. Polymorphism of haptoglobin (Hp), the CD163 ligand, was determined in 130 SpA and 23 RA patients. Results CD163+ macrophages, but not CD68+ macrophages, were significantly increased in SpA versus RA synovium and in HLA–B27+ versus HLA–B27− SpA. Despite similar lymphocyte numbers, activated lymphocytes (CD69+) were significantly decreased in SpA versus RA patients, with an inverse correlation between CD163 and CD69 levels. Local production of sCD163 was evidenced by a 5–7-fold higher level of sCD163 in SF than in serum and by the correlation with synovial lining CD163+ macrophages in SpA. SF sCD163 levels correlated directly with global inflammation but correlated inversely with CD69+ SF T lymphocytes in the synovium. In contrast, serum sCD163 levels were only moderately increased, did not correlate with SF sCD163 levels or parameters of inflammation, and were unaffected by infliximab therapy. The distribution of Hp polymorphism was not altered in SpA and was not related to CD163 expression. Conclusion Increased numbers of CD163+ macrophages in SpA synovium and local production of sCD163 are associated with global inflammation as well as impairment of T cell activation, suggesting a dual role for CD163+ macrophages in SpA synovitis.

Spondylarthropathies (SpA) present mainly with spondylitis, pauciarticular peripheral arthritis and enthesopathy. Ankylosing spondylitis (AS) is the prototype disease in this concept. Other entities include reactive arthritis, arthritis in patients with inflammatory bowel disease, some forms of psoriatic arthritis and undifferentiated SpA. NSAIDs are the classical cornerstone of medical therapy in patients with SpA. The effect of these drugs on disease progression, more specifically the ankylosis, is uncertain. Sulfasalazine can be combined with NSAIDs, particularly if peripheral arthritis symptoms persist. However, this combination therapy is not effective for the spondylitis symptoms. Indeed, AS is one of the rheumatic diseases for which no real disease-modifying antirheumatic treatment is available. Challenges in chronic autoimmune arthritis have changed dramatically, especially since biotechnological compounds became available. These compounds allow for a specific intervention in the immune cascade underlying the disease. Tumour necrosis factor (TNF)-alpha antagonists (monoclonal antibodies such as infliximab, or soluble receptors such as etanercept) are the first representative drugs in this category. Open-label studies have shown the efficacy of these new targeted drugs, which has been confirmed by controlled studies, at least in the short term. Improvements in several clinical parameters, function, quality of life, biological parameters, histopathological synovial characteristics and magnetic resonance imaging, have all been observed. As a result of these favourable results, anti-TNFalpha therapy has been approved for the treatment of AS and should be considered for patients with severe axial symptoms and elevated serological markers of inflammatory activity who have responded inadequately to conventional nonsteroidal therapy. There is evidence that this new therapeutic approach has a disease- and even structure-modifying effect in SpA. In this context, structure modification should not only be seen as inhibition of bone and cartilage destruction but more broadly as modulation of tissue histology. Some questions remain unanswered, such as the long-term efficacy and safety of anti-TNFalpha therapy, the extent of structural benefit and the cost effectiveness. However, despite these concerns, anti-TNFalpha therapy represents a major therapeutic advancement in the treatment of AS.

Objective To investigate the role of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in spondylarthropathy (SpA) synovitis. Methods Paired samples of synovial biopsy tissue as well as serum and synovial fluid (SF) from 41 patients with SpA and 20 patients with rheumatoid arthritis (RA) and serum samples from 20 healthy controls were analyzed by immunohistochemistry and enzyme-linked immunosorbent assay for the presence of MMPs 1, 2, 3, and 9 and TIMPs 1 and 2. In addition, sera from 16 patients with ankylosing spondylitis (AS) and peripheral synovitis and 17 patients with AS and exclusively axial involvement were analyzed. An additional cohort of SpA patients was analyzed at baseline and after 12 weeks of infliximab treatment. Results Staining for MMPs and TIMPs showed a cellular and interstitial pattern in the synovial lining and sublining layers that was similar between the RA and SpA patients. Involvement of MMPs and TIMPs in SpA synovitis was suggested by the correlation with cellular infiltration, vascularization, and cartilage degradation. Higher serum levels of MMPs 3 and 9 were revealed in SpA and RA patients as compared with healthy controls. Production of MMP-3, but not MMP-9, in the serum reflected the presence of peripheral synovitis, as indicated by 1) the correlation between serum levels, SF levels (which were 1,000-fold higher than the serum levels), and synovial expression of MMP-3, 2) the increased levels of MMP-3 in AS patients with peripheral disease and not exclusively axial involvement, and 3) the correlation of serum and SF MMP-3 with parameters of synovial, but not systemic, inflammation. The modulation of the MMP/TIMP system by tumor necrosis factor α (TNFα) blockade was confirmed by the down-regulation of all MMPs and TIMPs in the synovium and a pronounced and rapid decrease of serum MMP-3. Conclusion MMPs and TIMPs are highly expressed in SpA synovitis and mirror both the inflammatory and tissue-remodeling aspects of the local disease process. Serum MMP-3, originating from the inflamed joint, represents a valuable biomarker for peripheral synovitis. Modulation of the MMP/TIMP system by infliximab could contribute to the antiinflammatory and tissue-remodeling effects of TNFα blockade in SpA.

To the Editor: Systemic sclerosis (SSc) is a multisystemic autoimmune disease characterized by fibrosis of the skin and internal organs, generalized microvasculopathy, and antibody response against various cellular antigens. Severe organ involvement occurs early in the course of diffuse cutaneous SSc (dcSSc) and has a bad prognosis1. Survival of the first years of the disease is associated with improved outcome. Therapies that may help the patient overcome this early period seem warranted2. Rituximab (RTX) has been reported as optional therapy in SSc3,4,5. Our group reported stabilization of internal organ involvement during a 2-year followup in an open pilot study of a 2–treatment course (months 0 and 6) of RTX in patients with early dcSSc6,7. In our pilot studies, modified Rodnan skin score (mRSS) decreased significantly after RTX course. The percent of decrease in the open pilot studies was corroborated by a similar decrease in the percentage of collagen score in blindly assessed histopathological skin analyses. Because SSc is characterized by a pronounced microangiopathy over time … Address correspondence to Dr. V. Smith, Department of Rheumatology, Ghent University Hospital, Faculty of Medicine and Health Sciences, Department of Internal Medicine, Ghent University, De Pintelaan 185, B – 9000 Ghent, Belgium. E-mail: vanessa.smith{at}ugent.be

In systemic sclerosis (SSc), microvasculopathy is an important feature, resulting in digital ulcers in 30% of patients with SSc each year.1 ,2 Assessment of microvasculopathy in SSc is of clinical interest mostly for diagnostic and therapeutic purposes. Nailfold videocapillaroscopy has in recent years earned its place in SSc as it makes early diagnosis of SSc possible in a Raynaud's population by evaluating morphological capillary abnormalities.3–5 Within an SSc population however, there is need for a technique that can evaluate blood perfusion in a dynamic way, to evaluate evolution of disease and more importantly response to therapy. For the latter, there is no validated technique available so far. Laser speckle contrast analysis (LASCA) is a relatively new technique that measures peripheral blood perfusion (PBP) in real time over a large area, in a non-contact manner, and is less time-consuming; it is thus convenient to implement in daily practice. …