Guidelines for biomarkers in autoimmune rheumatic diseases - evidence based analysis.

Autoimmune rheumatic diseases are characterised by an abnormal immune system response, complement activation, cytokines dysregulation and inflammation. In last years, despite many progresses in managing these patients, it has been shown that clinical remission is reached in less than 50% of patients and a personalised and tailored therapeutic approach is still lacking resulting in a significant gap between guidelines and real-world practice. In this context, the need for biomarkers facilitating early diagnosis and profiling those individuals at the highest risk for a poor outcome has become of crucial interest. A biomarker generally refers to a measured characteristic which may be used as an indicator of some biological state or condition. Three different types of medical biomarkers has been suggested: i. mechanistic markers; ii. clinical disease markers; iii. therapeutic markers. A combination of biomarkers from these different groups could be used for an ideal more accurate diagnosis and treatment. However, although a growing body of evidence is focused on improving biomarkers, a significant amount of this information is not integrated on standard clinical care. The overarching aim of this work was to clarify the meaning of specific biomarkers during autoimmune diseases; their possible role in confirming diagnosis, predicting outcome and suggesting specific treatments.

Randomized controlled trials and real-world data: differences and similarities to untangle literature data.

Randomized controlled trials (RCTs) represent the gold-standard of medical evidence to assess the efficacy and safety of therapeutic interventions. However, the need to minimize bias and ensure the correct design to explore the study aims often affects the generalizability of results. As a consequence, the evidence derived from the most rigorous research strategy available is not always representative of the real-world settings for which this evidence is ultimately intended. Observational studies, in contrast, although affected by a number of potential confounders, can more effectively capture treatment characteristics and safety issues that had not been identified by previous RCTs, owing to the short duration of follow-up or highly selective inclusion criteria. The aim of this review is to provide a comparative summary of the main advantages and pitfalls of RCTs and real-world data, emphasizing the need for a constant integration of all available levels of evidence to provide the best care for patients.

20 years of experience with tumour necrosis factor inhibitors: what have we learned?

TNF inhibitors are biologic DMARDs approved for the treatment of active RA in mid-1990s. They still represent a valuable therapeutic option to control the activity, disability and radiographic progression of the disease. In the context of TNF inhibitors, there are currently several molecules and different administration routes that provide optimal treatment personalization, allowing us to respond to a patient's needs in the best possible way. The increasing use of TNF inhibitors has not only improved the management of RA, but it has also helped in our understanding of the pathogenetic mechanisms of the disease. This review focuses on the basis of this targeted therapy and on the knowledge gained from their use about therapeutic effects and adverse events. Effectiveness analysed from drug registries and safety issues are presented together with recent data on infections (in particular, Mycobacterium tuberculosis and hepatitis B), cancer (lymphoma, skin cancers) and cardiovascular risk.

Switch or swap strategy in rheumatoid arthritis patients failing TNF inhibitors? Results of a modified Italian Expert Consensus.

Objective: To establish evidence-based and experts' opinion filtered statements on the optimal treatment choice between cycling (switch) and changing mode of action strategies (swap) in RA patients failing TNF inhibitors (TNFis). Methods: The relevant question (switch vs swap) was rephrased into a research question according to the population, intervention, comparison and outcome (PICO) strategy, considering all the available scientific evidence published from the 2013 EULAR set of recommendations up to mid-January 2016. Final statements derived from the retrieved scientific evidence and experts' consensus, with eventual rephrasing through a Delphi method during a national consensus of Italian rheumatologists. Results: From a total of 365 records, 12 studies were finally included. The final statements argued that, until head-to-head comparison data are available, switch and swap can be still considered suitable strategies in RA patients failing first TNFi, even though some data seem to lend more support to a different mode of action-targeted strategy. Conclusion: After failure of first TNFi course, switch and swap can be currently considered as alternative suitable approaches in RA patients.

The profiling of axial spondyloarthritis patient candidate to a biologic therapy: Consensus from a Delphi-panel of Italian experts.

OBJECTIVE: The project aimed to collect expert consensus statements for the profiling of patients with axial spondyloarthritis (axSpA) candidate to biologic agents (bDMARDs) treatment, in order to better define the drivers for the best treatment choice. METHODS: The 6 more interesting topics about axSpA patient profiling were identified by the project steering committee and a panel of axSpA Italian experts. A systematic literature review (SLR) was performed for each of the selected topics according to the PICO format. Two rounds of a modified Delphi process were conducted. In the 1st round, the steering committee evaluated the results of the SLR in order to formulate statements for each topic. In the 2nd round, the experts panel discussed, rephrased when needed, and voted the level of agreement (on a 5-point Likert-type scale) for each statement. Consensus was defined as ≥66% agreement. RESULTS: The topics selected for the analysis were the differential efficacy of available bDMARDs on enthesitis/dactylitis, uveitis, radiographic progression and cardiovascular involvement, and the clinical response in non radiographic-axSpA and in patients receiving a second-line bDMARD. The Delphi rounds formulated 19 statements, all reaching the defined level of consensus in a second round including 25 rheumatologists highly skilled in the management of axSpA. CONCLUSION: Identified consensus statements can help clinicians to apply to routine-care settings the results from clinical studies and international recommendations, providing a guide for individualization of treatment strategy in axSpA patients.

Prevalence of Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease in a cohort of patients treated with TNF-alpha inhibitors.

BACKGROUND: Treat to target (T2T), aiming at inactive disease (ID), has become the recommended strategy for axial-SpA (ax-SpA). Using the Ankylosing Spondylitis Disease Activity Score (ASDAS), we assessed the prevalence of ID in ax-SpA patients treated with TNFα inhibitors (TNFi). METHODS: A multicentric, cross-sectional study was performed assessing disease activity status (BASDAI and ASDAS) of consecutive patients with ax-SpA on stable treatment with TNFi for at least six months. We analyzed differences with nonradiographic axSpA (nr-ax-SpA) and the influence of population characteristics and comorbidities in reaching ID. ID was defined as ASDAS-CRP <1.3. RESULTS: A total of 218 patients were enrolled, 165 with AS and 53 with nr-ax-SpA. ASDAS-CRP ID was reached by 89 (40.8%) patients, while 163 (74.8%) of patients achieved good disease control with BASDAI. There were no significant differences between the two diagnostic groups. Multivariate logistic regression demonstrated a negative correlation of concomitant fibromyalgia, higher BASMI and current NSAIDs with the chances of reaching ASDAS-CRP ID or BASDAI <4. CONCLUSION: T2T represents a new challenge in the management of ax-SpA, with recently introduced disease activity measures being significantly more stringent. The prevalence of ID was affected by concomitant fibromyalgia, decreased spine mobility and concomitant NSAIDs.

One year in review 2017: novelties in the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic disease characterised by inflammation of the synovial tissue in joints, which can lead to joint destruction. The primary goal of the treatment is to control pain and inflammation, reduce joint damage and disability, and maintain or improve physical function and quality of life. The present review is aimed at providing a critical analysis of the recent literature on the novelties in the treatment of RA, with a particular focus on the most relevant studies published over the last year.

Power Doppler ultrasonographic assessment of the joint-draining lymph node complex in rheumatoid arthritis: a prospective, proof-of-concept study on treatment with tumor necrosis factor inhibitors.

BACKGROUND: Emerging research on the mechanisms of disease chronicity in experimental arthritis has included a new focus on the draining lymph node (LN). Here, we combined clinical-serological analyses and power Doppler ultrasound (PDUS) imaging to delineate noninvasively the reciprocal relationship in vivo between the joint and the draining LN in patients with rheumatoid arthritis (RA). METHODS: Forty consecutive patients refractory to conventional synthetic disease-modifying anti-rheumatic drugs were examined through parallel PDUS of the hand-wrist joints and axillary LNs and compared with 20 healthy subjects. A semiquantitative score for LN gray-scale (GS) parameters (nodal hypertrophy and cortical structure) and LN PD signal was developed. A 6-month follow-up study with serial sonographic assessments was then performed on initiation of tumor necrosis factor (TNF) inhibitors. RESULTS: PDUS analysis of RA axillary LNs revealed the existence of marked inter-individual heterogeneity and of quantitative differences compared with healthy individuals in both GS and PD characteristics. RA LN changes were plastic, responsive to anti-TNF treatment, and displayed a degree of concordance with synovitis activity in peripheral joints. However, low LN PD signal at baseline despite active arthritis was strongly associated with a poor clinical response to TNF blockade. CONCLUSIONS: PDUS analysis of the draining LN in RA allows capture of measurable inter-individual differences and dynamic changes linked to the underlying pathologic process. LN and joint sonographic assessments are nonredundant approaches that may provide independent perspectives on peripheral disease and its evolution over time.

Methotrexate and Rheumatoid Arthritis: Current Evidence Regarding Subcutaneous Versus Oral Routes of Administration.

UNLABELLED: Methotrexate (MTX) is still considered the drug of choice in rheumatoid arthritis (RA) management. Comparing subcutaneous (MTX SC) and oral (MTX OR) routes of administration is important to optimize the everyday therapeutic strategy in the real-life setting. This review summarizes scientific evidence currently available on this topic. As shown by pharmacokinetic studies, at the same dose level, bioavailability of MTX SC is significantly higher and less variable than that of MTX OR. This difference is even more pronounced for medium-to-high dosages (i.e., >15 mg/week). With regard to clinical response (Disease Activity Score-28, American College of Rheumatology Criteria), randomized, double-blind studies and retrospective or longitudinal analyses in real-life settings showed that MTX SC is more effective than MTX OR. This is true both in MTX-naive patients with early RA, and in patients who switch from MTX OR to MTX SC due to previous treatment failure, lack of efficacy and/or adverse events. Finally, MTX SC has a better tolerability profile than MTX OR, with fewer gastroenterological side effects. Delaying the use of more expensive biological therapies by switching from MTX OR to MTX SC in non-responders might provide cost savings, with relevant implications in the management of patients with RA. FUNDING: Alfa Wassermann.

Low Risk of Hepatitis B Virus Reactivation in HBsAg-negative/Anti-HBc-positive Carriers Receiving Rituximab for Rheumatoid Arthritis: A Retrospective Multicenter Italian Study.

OBJECTIVE: Patients with resolved hepatitis B virus (HBV) infection, i.e., hepatitis B surface antigen (HBsAg)-negative/antihepatitis B core antigen (anti-HBc)-positive, undergoing rituximab (RTX)-based chemotherapy for hematological malignancies without anti-HBV prophylaxis are at risk of HBV reactivation, but the risk in such patients receiving RTX for rheumatological disorders is not clear. We evaluated this risk in HBsAg-negative/anti-HBc-positive patients with rheumatoid arthritis (RA) undergoing RTX without prophylaxis. METHODS: Thirty-three HBsAg-negative/anti-HBc-positive outpatients with RA with undetectable HBV DNA by sensitive PCR assay [73% women, median age 60 years, 85% with HBsAg antibodies (anti-HBs), 37% with antihepatitis B envelope antigen] received a median of 3 cycles of RTX (range 1-8) over 34 months (range 0-80) combined with disease-modifying antirheumatic drugs (DMARD) without prophylaxis. All underwent clinical and laboratory monitoring during and after RTX administration, including serum HBsAg and HBV DNA measurements every 6 months or whenever clinically indicated. RESULTS: None of the patients seroreverted to HBsAg during RTX treatment, but 6/28 (21%) showed a > 50% decrease in protective anti-HBs levels, including 2 who became anti-HBs-negative. One patient (3%) who became HBV DNA-positive (44 IU/ml) after 6 months of RTX treatment was effectively rescued with lamivudine before any hepatitis flare occurred. Among the 14 patients monitored for 18 months (range 0-70) after RTX discontinuation, no HBV reactivation was observed. CONCLUSION: The administration of RTX + DMARD in patients with RA with resolved HBV infection leads to a negligible risk of HBV reactivation, thus suggesting that serum HBsAg and/or HBV DNA monitoring but not universal anti-HBV prophylaxis is justified.

Risk of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing biologic treatment: Extending perspective from old to newer drugs.

Hepatitis B virus (HBV) reactivation in rheumatoid arthritis (RA) patients undergoing biological therapy is not infrequent. This condition can occur in patients with chronic hepatitis B as well as in patients with resolved HBV infection. Current recommendations are mainly focused on prevention and management strategies of viral reactivation under tumor necrosis factor-α inhibitors or chimeric monoclonal antibody rituximab. In recent years, growing data concerning HBV reactivation in RA patients treated with newer biological drugs like tocilizumab and abatacept have cumulated. In this review, epidemiology, pathogenesis and natural history of HBV infection have been revised first, mainly focusing on the role that specific therapeutic targets of current biotechnological drugs play in HBV pathobiology; finally we have summarized current evidences from scientific literature, including either observational studies and case reports as well, concerning HBV reactivation under different classes of biological drugs in RA patients. Taking all these evidences into account, some practical guidelines for screening, vaccination, prophylaxis and treatment of HBV reactivation have been proposed.

Oral low-dose glucocorticoids should be included in any recommendation for the use of non-biologic and biologic disease-modifying antirheumatic drugs in the treatment of rheumatoid arthritis.

At present, growing scientific evidence from the medical literature and expert opinion provides strong consideration for a mandatory role of glucocorticoids (GCs) in the management of rheumatoid arthritis (RA). Earlier application strategies were based on initial high doses, with subsequent tapering schedules, resulting in dose-related side effects. Recent low-dose GC schemes are more feasible in routine care, while providing evidence of clinical, functional and structural efficacy. Thus, initial low-dose GC 'bridging' treatment on a disease-modifying antirheumatic drug background should be included in any existing recommendations for RA management, as very recently advocated by the EULAR Task Force 2013 updated guidelines. Long-term low-dose therapy appears to provide acceptable safety, leading to long-standing slowing of structural damage, seen even after GC therapy withdrawal. Gaps in knowledge about the optimal method to taper and possibly discontinue GC treatment remain, and this topic should be addressed in clinical trials and observational studies. Recent efforts in GC medication have also included the introduction of a modified-release drug formulation capable of drug delivery consistent with chronobiological pathogenetic rhythms of disease, which has been quite efficacious in controlling the signs and symptoms related to pathways of circadian cytokines. Long-term data will further clarify the add-on benefits of such modified-release formulations.

The role of low-dose glucocorticoids for rheumatoid arthritis in the biologic era.

In rheumatoid arthritis (RA), low-dose glucocorticoid (GC) therapy has a well-established effect on disease activity. Particularly in early RA, robust evidence demonstrates that GC treatment in association with standard disease-modifying anti-rheumatic drugs (DMARDs) is effective in inducing high remission rates, earlier and more persistently. Despite international recommendations that discourage long-term concomitant GC use, the majority of the clinical trials and observational registries on biologic agents include a high proportion (up to 80%) of patients in treatment with GC. From an analysis of the literature, a substantial lack of reliable information about the efficacy of GC in association with biologic agents emerges; in particular, the role of GC co-therapy in sustaining remission after biological therapy discontinuation remains to be clarified. Given the increasing prevalence of patients in sustained remission, a rational discontinuation strategy should include low-dose GCs in the experimental design to elucidate their role in inducing and maintaining biologic-free remission, for efficacy, safety and pharmacoeconomic considerations.

Drug survival of the first course of anti-TNF agents in patients with rheumatoid arthritis and seronegative spondyloarthritis: analysis from the MonitorNet database.

OBJECTIVES: To compare drug survival of different anti-TNF drugs (infliximab, INF, etanercept, ETA, and adalimumab, ADA) in rheumatoid arthritis (RA) and spondyloarthritis (SpA) by analysing data collected from an Italian multicenter observational cohort study. METHODS: All patients with RA or SpA registered in the MonitorNet database who started their first course of anti-TNF therapy were included. Overall drug survival was measured, along with specific reasons of discontinuation (inefficacy or adverse events). A first set of analyses using RA as reference category assessed the relationship between diagnosis and drug survival. A second set of analyses stratified by diagnosis (RA and SpA) used INF as reference drug. Adjustment for confounders was performed. The results are presented as adjusted hazard ratios (adjHR) and 95% confidence intervals (95%CI). RESULTS: 2640 RA patients and 1220 SpA patients with a median follow-up of 17 months (IQR 7.2-33.4) were included in the analyses. Patients with a diagnosis of SpA showed a lower risk of drug discontinuation with an adjHR (95%CI) of 0.81 (0.73, 0.90). In SpA, the subset of patients with ankylosing spondylitis (AS) showed the best survival on treatment. In RA, both ETA and ADA showed a significantly lower probability of withdrawal when compared to INF [adjHR (95%CI) 0.46 (0.38, 0.56) and 0.68 (0.57, 0.81), respectively]. Similar results were found in SpA. CONCLUSIONS: Drug survival for SpA is longer than that in RA mainly due to the AS subgroup. In both RA and SpA, ETA and ADA showed a better retention on treatment when compared to INF.

Glucocorticoids in rheumatoid arthritis.

Interest in the numerous benefits of corticosteroid medication in the management of rheumatoid arthritis (RA) goes back to the mid-1950s, and has recently been renewed. The established evidence of their rapid symptomatic effects, along with the growing recognition of their long-lasting disease-modifying properties and preliminary data about their sub-clinical action, led us to reconsider the potential of corticosteroids in the treatment of RA, given their acceptable safety profile, especially when used at low dosages. Over time, several corticosteroid-based therapeutic approaches have been explored in order to optimize their clinical benefits, while limiting the adverse effects. Clinical data reported with initial high-dosage corticosteroid schedules with subsequent step-down schemes suggest clinical efficacy, but are not applicable to patient management in a real-life setting. Encouraging results on the clinical and sub-clinical effects of low dosages have led to a shift in usual daily practice. We present past and recent efforts to clarify the role of corticosteroids in the treatment of RA, focusing on the best approach in terms of dose and timing of corticosteroid administration. Additional information about different routes of administration, step-down schedules and adverse effects are also considered.

Low-dose oral prednisone improves clinical and ultrasonographic remission rates in early rheumatoid arthritis: results of a 12-month open-label randomised study.

INTRODUCTION: In early rheumatoid arthritis (RA), low-dose oral prednisone (PDN) co-medication yields better clinical results than monotherapy with disease-modifying anti-rheumatic drugs (DMARDs). In addition, ultrasonography (US) evaluation reveals rapid and significant effects of glucocorticosteroids on subclinical synovitis. No data currently exist that examine the clinical and US results offered by glucocorticoid co-medication over DMARD monotherapy in early RA patients. METHODS: Two hundred and twenty patients with early RA (< 1 year from clinical onset) were treated according to a low disease activity (LDA) targeted step-up protocol including methotrexate (MTX) and, in the active treatment arm, low-dose (6.25 mg/day) oral PDN over 12 months. Clinical disease activity measures were collected at baseline, 2, 4, 6, 9 and 12 months, and US examination of hands was performed at baseline, 6 and 12 months. Grey-scale and power Doppler (PD) synovitis were scored (0 to 3) for each joint. At 12 months, clinical remission according to the disease activity score among 28 joints was defined as the clinical outcome, and a total joint PD score of 0 (PD negativity) as the imaging outcome. RESULTS: Each group included 110 patients with comparable demographic, clinical, laboratory and US characteristics. At 12 months, the LDA rate was similar in the two groups, whilst the clinical remission rate (risk ratio = 1.61 (95% confidence interval = 1.08, 2.04)) and PD negativity rate (risk ratio = 1.31 (95% confidence interval = 1.04, 1.64)) were significantly higher in the MTX+PDN group. CONCLUSION: In early RA, despite a similar response rate in terms of LDA, low-dose oral PDN co-medication led to a higher proportion of clinical remission and PD negativity compared with MTX monotherapy, thus ensuring a better disease activity control. TRIAL REGISTRATION NUMBER: Current Controlled Trials ISRCTN2486111.

Serum levels of CXCL13 are associated with ultrasonographic synovitis and predict power Doppler persistence in early rheumatoid arthritis treated with non-biological disease-modifying anti-rheumatic drugs.

INTRODUCTION: Biological markers specifically reflecting pathological processes may add value in the assessment of inter-individual variations in the course of rheumatoid arthritis (RA). The current study was undertaken to investigate whether baseline serum levels of the chemokine CXCL13 might predict clinical and ultrasonographic (US) outcomes in patients with recent-onset RA. METHODS: The study included 161 early RA patients (disease duration < 12 months) treated according to a disease activity score (DAS) driven step-up protocol aiming at DAS < 2.4. Clinical disease activity measures were collected at baseline, 2, 4, 6, 9 and 12 months, and US examination of the hands was performed at baseline, 6 and 12 months. Grey-Scale (GS) and Power Doppler (PD) synovitis were scored (0 to 3), with overall scores as the sum of each joint score. CXCL13 levels were measured at baseline by enzyme-linked immunosorbent assay and evaluated in relation to the achievement of low disease activity (LDA, DAS < 2.4) and US residual inflammation (PD ≤ 1) at 12 months. RESULTS: Baseline levels of CXCL13 were significantly higher in RA compared to healthy controls (n = 19) (P = 0.03) and correlated with measures of synovitis, such as the swollen joint count (R 0.28, P < 0.001), the US-GS (R 0.27, P = 0.003) and US-PD (R 0.26, P = 0.005) score. Although CXCL13 did not predict the likelihood of achieving clinical LDA at 12 months within a structured treat-to-target protocol, elevated levels of CXCL13 were associated with more frequent increases of methotrexate dosage (P < 0.001). Using adjusted analyses, the highest levels of CXCL13 (> 100 pg/ml) were the only independent predictor of residual imaging inflammation (P = 0.005), irrespective of initial US-PD scores, disease activity status, acute phase reactants and autoantibodies. Among the patients in clinical LDA at 12 months, US-PD scores ≤ 1 were less frequently achieved in the high baseline CXCL13 (> 100 pg/ml) group, with an adjusted OR = 0.06 (95% CI 0.01 to 0.55, P = 0.01). CONCLUSIONS: CXCL13 emerges as a new biological marker in early RA, accurate in assessing the severity of synovitis and the persistence of US-PD activity over time in response to conventional treatments.

Recommendations for the use of biologic therapy from the Italian Society for Rheumatology: off-label use.

The advent of biological agents has provided further opportunities to treat resistant or relapsing rheumatic diseases, with robust data for rheumatoid arthritis and spondyloarthritis coming from randomised controlled trials. However there are data also on other rare inflammatory rheumatic diseases even if the evidence available may be heterogeneous and/or controversial. Another challenging scenario is represented by diseases that are not uncommon, but that may present with multiple manifestations and prove resistant to conventional therapies, thus requiring the use of biological agents. To assist physicians in making correct therapeutic choices in such cases, the Italian Society for Rheumatology (SIR) has developed specific recommendations for the use of biological agents in rare disease or for the off-label use of such agents in refractory inflammatory disorders.

Subclinical remodelling of draining lymph node structure in early and established rheumatoid arthritis assessed by power Doppler ultrasonography.

OBJECTIVE: To investigate the suitability of power Doppler ultrasonography (PD-US) for the assessment of lymph node (LN) status in RA, evaluating the existence of structural and dynamic modifications in well-characterized stages of the disease. METHODS: Ten patients with active disease and five patients in clinical remission underwent complete clinical and PD-US examination of hands, wrists, axillary and cervical LNs on the same day. Synovitis and PD were graded 0-3. LN assessment included maximum short axis, cortical hypertrophy (CH) and PD signal distribution. All patients with active disease were re-evaluated prospectively 3 months after initiation of therapy. RESULTS: PD-US signs of axillary LN remodelling were observed in 7 out of 10 patients with active disease despite the absence of clinical lymphoadenopathy. Subclinical alterations were detected in both early untreated RA and in established disease. Characteristic structural changes consisted of hypertrophy of the LN cortex and PD signal amplification in cortical and hilar regions. Cervical LNs in active disease and axillary LNs in clinical remission were unaffected. LN PD amplification returned to normal ranges in patients with baseline alterations re-evaluated 3 months after therapy with TNF-α blocking agents and/or MTX. CONCLUSION: Draining LNs in RA are subjected to subclinical intra-parenchymal changes and vascular flow modulation detectable by PD-US. Sonographic signs of LN involvement associate with disease activity and are reversible upon treatment. These data point at LN reactivity as a dynamic component of RA inflammatory cascade and an attractive platform to be explored in prognostic and response to therapy evaluations.