Andrea Becciolini

The 12-item Psoriatic Arthritis Impact of Disease Questionnaire: Construct Validity, Reliability, and Interpretability in a Clinical Setting

Objective. To study, in a real-life setting, the construct validity, the reliability, and the interpretability of the 12-item Psoriatic Arthritis Impact of Disease (PsAID-12) questionnaire in patients with psoriatic arthritis (PsA). Methods. In 144 consecutive patients with PsA (81 men and 63 women, mean age of 51.4 ± 12.8 yrs, and 77 receiving biologic treatment), the PsAID-12 and other patient-reported outcomes (PRO) were collected, such as the Dermatology Life Quality Index. Each patient underwent articular and skin assessment. Results. Construct validity: Factor analysis revealed a 2-factor result defined as the PsAID Symptom Score and the PsAID Skin Score. In determining convergent validity, significant correlations were found between the PsAID-12 and the clinical Disease Activity index for Psoriatic Arthritis (cDAPSA; ρ = 0.867, p < 0.0001). Multivariable analysis showed that the PsAID-12 is determined by the articular disease activity (cDAPSA, p < 0.0001), severity of psoriasis (PsO; physician’s global assessment, p < 0.0001), and the presence of a coexisting fibromyalgia (FM; p < 0.0001). Reliability: Cronbach’s alpha coefficient was 0.93 for the total PsAID-12. Interpretability: Applying the cDAPSA categorization of disease activity states, the PsAID-12 cutoff values resulted in 1.4 between remission and low disease activity (LDA), 4.1 between LDA and moderate disease activity (MDA), and 6.7 between MDA and high disease activity. Conclusion. The PsAID-12 is an excellent PRO to evaluate the effect of PsA. It should be carefully handled in patients with coexisting FM.

Second-line biologic therapy optimization in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis

OBJECTIVE The Italian board for the TAilored BIOlogic therapy (ITABIO) reviewed the most consistent literature to indicate the best strategy for the second-line biologic choice in patients with rheumatoid arthritis (RA), spondyloarthritis (SpA), and psoriatic arthritis (PsA). METHODS Systematic review of the literature to identify English-language articles on efficacy of second-line biologic choice in RA, PsA, and ankylosing spondylitis (AS). Data were extracted from available randomized, controlled trials, national biologic registries, national healthcare databases, post-marketing surveys, and open-label observational studies. RESULTS Some previously stated variables, including the patients׳ preference, the indication for anti-tumor necrosis factor (TNF) monotherapy in potential childbearing women, and the intravenous route with dose titration in obese subjects resulted valid for all the three rheumatic conditions. In RA, golimumab as second-line biologic has the highest level of evidence in anti-TNF failure. The switching strategy is preferable for responder patients who experience an adverse event, whereas serious or class-specific side effects should be managed by the choice of a differently targeted drug. Secondary inadequate response to etanercept (ETN) should be treated with a biologic agent other than anti-TNF. After two or more anti-TNF failures, the swapping to a different mode of action is recommended. Among non-anti-TNF targeted biologics, to date rituximab (RTX) and tocilizumab (TCZ) have the strongest evidence of efficacy in the treatment of anti-TNF failures. In PsA and AS patients failing the first anti-TNF, the switch strategy to a second is advisable, taking in account the evidence of adalimumab efficacy in patients with uveitis. The severity of psoriasis, of articular involvement, and the predominance of enthesitis and/or dactylitis may drive the choice toward ustekinumab or secukinumab in PsA, and the latter in AS. CONCLUSION Taking in account the paucity of controlled trials, second-line biologic therapy may be reasonably optimized in patients with RA, SpA, and PsA.

Intravenous neridronate in the treatment of acute painful knee osteoarthritis: a randomized controlled study

OBJECTIVE The aim of this randomized, double-blind, placebo-controlled study was to assess the efficacy of i.v. neridronate in controlling pain in patients with acute painful knee OA. METHODS Sixty-four patients with acute knee pain (<3 months duration) suffering from knee OA with an MRI showing bone marrow lesions (BMLs) were randomized to receive either neridronate 100 mg given four times over 10 days or placebo. After 50 days the patients underwent clinical assessment and a further MRI was performed. Primary outcome was pain changes measured by a visual analogue scale (VAS; range 0-100). Secondary endpoints were WOMAC pain score, McGill pain questionnaire and 36-Item Short Form Health Survey. BMLs were evaluated by whole-organ MRI score. RESULTS At the day of the last infusion the VAS decreased significantly more in the neridronate group [from 59.0 (s.d. 14.7) to 30.4 (s.d. 15.6); -48.4%; P < 0.001]. Fifty days later the VAS remained unchanged in the placebo group, while a further significant decrease was observed in the neridronate group [from 30.4 (s.d. 15.6) to 9.4 (s.d. 10.8); -69.1%; P < 0.001]. Significant improvements compared with the placebo group were found for most of the other indices of pain and quality of life. The BMLs score in the neridronate group showed significant decreases compared with basal values and those of the placebo-treated patients. Four months after the treatment, 72% of the placebo-treated patients resumed analgesic or anti-inflammatory drugs, but only 12.9% resumed treatment in the neridronate group. CONCLUSION In patients with acute painful knee OA, four infusions of neridronate are associated with a clinically relevant pain benefit. TRIAL REGISTRATION ClinicalTrials.gov (http://clinicaltrials.gov), NCT01803360.

Sonographic subclinical entheseal involvement in dialysis patients

Long-term dialysis treatment can be associated with several musculoskeletal complications. Entheseal involvement in dialysis patients remains rarely studied as its prevalence is underestimated due to its often asymptomatic presentation. The aims of the study were to determine the prevalence of subclinical enthesopathy in haemodialysis and peritoneal dialysis patients at the lower limb level, to investigate the inter-observer reliability of ultrasound assessment and to analyse the influence of biometric and biochemical parameters. Ultrasound examination was conducted at the entheses of the lower limbs level in 33 asymptomatic dialysis patients and 33 healthy adopting the Glasgow Ultrasound Enthesitis Scoring System (GUESS). The inter-observer reliability was calculated in 15 dialysis patients. Ultrasound found at least one sign of enthesopathy in 165 out of 330 (50%) entheses of dialysis patients. In healthy subjects, signs of enthesopathy were present in 54 out of 330 (16.3%) entheses (p < 0.0001). No power Doppler signal was detected in healthy controls, in contrast to four of 330 entheses of dialysis patients. No US signs of soft tissue amyloid deposits were found. The GUESS score was significantly higher in dialysis patients than in controls (p < 0.0001). There was no difference in terms of enthesopathy between haemodialysis and peritoneal dialysis. Dialysis duration resulted to be the most important predictor for enthesopathy (p = 0.0004), followed by patient age (p = 0.02) and body mass index (p = 0.035). Parathormone, calcium, phosphorus, C-reactive protein, cholesterol and triglycerides apparently did not play a relevant role in favour of enthesopathy. The inter-observer reliability showed an excellent agreement between sonographers with different degree of experience. Our results demonstrated a higher prevalence of subclinical enthesopathy in both haemodialysis and peritoneal dialysis patients than in healthy subjects. Follow-up will provide further information with respect to the predictive value of US findings for the development of symptomatic dialysis-related arthropathy.

Eight‐year retention rate of first‐line tumor necrosis factor inhibitors in spondyloarthritis: A multi‐center retrospective analysis

To evaluate the 8‐year survival of the first tumor necrosis factor inhibitor (TNFi) in patients with axial spondyloarthritis (SpA) or psoriatic arthritis (PsA), identify the predictive factors for withdrawal, and compare the discontinuation rates for infliximab, etanercept, and adalimumab.

Profile of sarilumab and its potential in the treatment of rheumatoid arthritis

In recent years the use of biotechnological agents has drastically revolutionized the therapeutic approach and the progression of rheumatoid arthritis (RA). In particular, interleukin-6 (IL-6) has been demonstrated as a pivotal cytokine in the pathogenesis of the disease by contributing to both the innate and the adaptive immune system perturbation, and to the production of acute-phase proteins involved in the systemic expression of the disorder. The first marketed IL-6 blocker was tocilizumab, a humanized anti-IL-6 receptor (anti-IL-6R) monoclonal antibody. The successful use of tocilizumab in RA has encouraged the development of other biologic agents specifically targeting the IL-6 pathway, either directed against IL-6 cytokine (sirukumab, olokizumab, and clazakizumab) or IL-6 receptor (sarilumab). One Phase II and six Phase III randomized controlled trials demonstrated a broad efficacy of sarilumab across all RA patient subtypes, ranging from methotrexate (MTX) to tumor necrosis factor inhibitor insufficient responders. In particular, sarilumab as monotherapy demonstrated a clear head-to-head superiority over adalimumab in MTX-intolerant subjects. In addition, compared with tocilizumab, sarilumab showed a similar safety profile with significantly higher affinity and longer half-life, responsible for a reduction of the frequency of administration (every other week instead weekly). All these aspects may be important in defining the strategy for positioning sarilumab in the treatment algorithm of RA. Indeed, observational data coming from post-marketing real-life studies may provide crucial additional information for better understanding the role of sarilumab in the management of the disease. This review summarizes both the biological role of IL-6 in RA and the clinical data available on sarilumab as an alternative therapeutic option in RA patients.

Interreader Reliability in Assessment of Nailfold Capillary Abnormalities by Beginners: Pilot Study of an Intensive Videocapillaroscopy Training Program

Objective. To test the learning curve of rheumatologists with different experience in videocapillaroscopy (VCP) attending an intensive training program focused on interpretation of the main capillary nailfold abnormalities, the scleroderma (systemic sclerosis, SSc) pattern, and the normal pattern, and to determine their interreader agreement with an experienced investigator. Methods. Five investigators (1 senior, 1 junior, and 3 beginners) participated in the exercise. The study was composed of 2 steps. First, an independent investigator selected representative VCP images of normal patterns and capillary abnormalities. The second step included the training program, which ran 4 hours per day for 7 days. The senior rheumatologist taught investigators to recognize and interpret the normal pattern, the capillary abnormalities, and the different types of SSc pattern. These abnormalities were considered: homogeneously enlarged capillaries, giant capillaries, irregularly enlarged capillaries, microhemorrhages, neoangiogenesis, avascular areas, and capillary density. Results. A total of 300 VCP images were read from all the investigators. Both κ values and overall agreement percentages of qualitative and quantitative assessments showed progressive improvement from poor to excellent from the beginning to the end of the exercise. The sensitivity and specificity of the participants in the assessment of SSc pattern at the last lecture session were high. Conclusion. Our pilot study suggests that after an intensive 1-week training program, novice investigators with little or no experience in VCP are able to interpret the main capillary abnormalities and SSc pattern and to achieve good interreader agreement rates.

Spotlight on mavrilimumab for the treatment of rheumatoid arthritis: evidence to date

The introduction of biological therapies into clinical practice has dramatically modified the natural history of chronic inflammatory diseases, such as rheumatoid arthritis (RA). RA is a systemic autoimmune disease that causes articular damage and has a great negative impact on patients’ quality of life. Despite the wide spectrum of available biological treatments, ~30% of RA patients are still unresponsive, resulting in high disability and increased morbidity and mortality. In the last few decades, the scientific knowledge on RA pathogenesis vastly improved, leading to the identification of new proinflammatory molecules as potential therapeutic targets. Several in vitro and in vivo studies showed that granulocyte-macrophage colony-stimulating factor (GM-CSF), known to be a hematopoietic factor, is also one of the proinflammatory cytokines involved in macrophage activation, crucial for the pathogenic network of RA. Mavrilimumab, a human monoclonal antibody targeting the subunit α of GM-CSF receptor, was recently developed as a competitive antagonist of GM-CSF pathway and successfully adopted in human trials for mild to moderate RA. Mavrilimumab phase I and phase II studies reported an overall good efficacy and safety profile of the drug, and these encouraging results promoted the initiation of worldwide phase III studies. In particular, 158-week results of phase II trials did not show long-term lung toxicity, addressing the major concern about this target of pulmonary alveolar proteinosis development. However, further clinical studies conducted in larger RA populations are needed to confirm these promising results. This review summarizes the biological role of GM-CSF in RA and the preclinical and clinical data on mavrilimumab and other monoclonal antibodies targeted on this pathway as an alternative therapeutic option in RA patients who are unresponsive to conventional biological drugs.

Structural integrity versus radiographic progression in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, progressive and inflammatory disease often leading to irreversible destruction of articular structures and consequent disability. The key steps of RA pathogenetic mechanisms are the break of immune tolerance and the production of autoantibodies, followed by systemic and local inflammation resulting in damage of both subchondral bone (erosion) and cartilage (joint space narrowing (JSN)). Evidences from clinical trials suggest that erosions and JSN are the result of inter-related but partly independent pathogenetic pathways, in both cases mediated by pro-inflammatory cytokines, even if a direct effect of cyclic citrullinated peptides (anticitrullinated protein antibodies, ACPAs) on bone damage had been postulated. As a consequence, the suppression of inflammation provided by synthetic and biological disease-modifying antirheumatic drugs results in a decreased progression of bone and cartilage damage, supporting the effectiveness of the treat-to-target strategy. Nevertheless, radiographic progression may also be detected in patients achieving a sustained clinical remission. Two main reasons for this apparent uncoupling between clinical synovitis and damage progression should be considered. First, in some cases, the use of composite indices to define remission may not be completely adequate to identify residual disease activity, requiring the concomitant introduction of more sensible tools such as imaging. Second, the direct effect of biological drugs on bone destruction inducers, such as pro-inflammatory cytokines, may explain the suppression of radiographic progression despite the persistence of clinical synovitis. In this review, we discuss the link between autoimmunity, inflammation, joint damage and disability, focusing on how radiographic progression may predict functional disability.

Is there a need for new thresholds to define remission and low disease activity by Disease Activity Score 28 calculated with C reactive protein? Real life data from a local registry

We read with great interest the recent article by Fleischmann et al which reports a post hoc analysis of five rheumatoid arthritis (RA) randomised clinical trials (RCTs) to evaluate the correlation between Disease Activity Score in 28 joints calculated by using erythrocyte sedimentation rate (DAS28-ESR) or C reactive protein (DAS28-CRP).1 Since its introduction,2 DAS28-CRP has been used to evaluate clinical response in RCTs and daily practice by applying the same DAS28-ESR thresholds to define remission and low disease activity (LDA). Consistently with some previous reports,3–5 Fleischmann et al demonstrated that DAS28-CRP underestimates disease activity when using the same remission and LDA cut-off points validated for DAS28-ESR (2.6 and 3.2, respectively).6 Based on these findings, the authors suggested new thresholds for DAS28-CRP (2.4 for remission and 2.9 …