Rossana Scrivo

Autoimmune aspects of cytokine and anticytokine therapies

Cytokines and anticytokines are used increasingly in the treatment of immune, autoimmune, inflammatory, infectious, and malignant disorders. Commonly used treatments include the anti-tumor necrosis factor agents interferon alpha, interferon beta, interferon gamma, and interleukin 2. Several autoimmune phenomena have been reported in patients treated with these substances. This review summarizes the published data on the autoimmune manifestations associated with cytokine and anticytokine therapies, as well as describes possible mechanisms of these phenomena.

Switching tumour necrosis factor α antagonists in patients with ankylosing spondylitis and psoriatic arthritis: an observational study over a 5-year period

Objective: To evaluate the clinical response after switching from one tumour necrosis factor (TNF)α antagonist to another in patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Methods: In this ongoing, longitudinal, observational study, data were prospectively collected on efficacy and safety since 2000 for patients starting biological treatments. The present analysis was restricted to patients with a diagnosis of spondyloarthropathy (SpA) who switched from one TNFα antagonist to another because of inadequate efficacy or adverse events. Results: In total, 589 anti-TNFα-naive patients were registered, of whom 165 had a diagnosis of SpA; 7 patients with AS and 15 with PsA received >1 TNFα antagonist. Two patients with PsA were treated with all the drugs. In all, 16 subjects switched from infliximab to etanercept, 7 from etanercept to adalimumab and 1 from etanercept to infliximab. Overall, a clinical response was seen in 75% of patients who changed from infliximab to etanercept, and in 57.1% who switched from etanercept to adalimumab. Conclusions: The findings of this study on a selected population of patients with SpA indicate that the failure of an initial TNFα antagonist does not preclude the response to another one. Further trials are needed to confirm this preliminary observation.

A patient-derived and patient-reported outcome measure for assessing psoriatic arthritis: elaboration and preliminary validation of the Psoriatic Arthritis Impact of Disease (PsAID) questionnaire, a 13-country EULAR initiative

Introduction The objective was to develop a questionnaire that can be used to calculate a score reflecting the impact of psoriatic arthritis (PsA) from the patients’ perspective: the PsA Impact of Disease (PsAID) questionnaire. Methods Twelve patient research partners identified important domains (areas of health); 139 patients prioritised them according to importance. Numeric rating scale (NRS) questions were developed, one for each domain. To combine the domains into a single score, relative weights were determined based on the relative importance given by 474 patients with PsA. An international cross-sectional and longitudinal validation study was performed in 13 countries to examine correlations of the PsAID score with other PsA or generic disease measures. Test–retest reliability and responsiveness (3 months after a treatment change) were examined in two subsets of patients. Results Two PsAID questionnaires were developed with both physical and psychological domains: one for clinical practice (12 domains of health) and one for clinical trials (nine domains). Pain, fatigue and skin problems had the highest relative importance. The PsAID scores correlated well with patient global assessment (N=474, Spearman r=0.82–0.84), reliability was high in stable patients (N=88, intraclass correlation coefficient=0.94–0.95), and sensitivity to change was also acceptable (N=71, standardised response mean=0.90–0.91). Conclusions A questionnaire to assess the impact of PsA on patients’ lives has been developed and validated. Two versions of the questionnaire are available, one for clinical practice (PsAID-12) and one for clinical trials (PsAID-9). The PsAID questionnaires should allow better assessment of the patients perspective in PsA. Further validation is needed.

Neurocognitive Dysfunction in Systemic Lupus Erythematosus: Association with Antiphospholipid Antibodies, Disease Activity and Chronic Damage

Introduction Systemic lupus erythematosus (SLE) is characterized by frequent neuropsychiatric involvement, which includes cognitive impairment (CI). We aimed at assessing CI in a cohort of Italian SLE patients by using a wide range of neurocognitive tests specifically designed to evaluate the fronto-subcortical dysfunction. Furthermore, we aimed at testing whether CI in SLE is associated with serum autoantibodies, disease activity and chronic damage. Methods Fifty-eight consecutive patients were enrolled. Study protocol included data collection, evaluation of serum levels of ANA, anti-dsDNA, anti-cardiolipin, anti-β2-glycoprotein I, anti-P ribosomal, anti-endothelial cell, and anti-Nedd5 antibodies. SLEDAI-2000 and SLICC were used to assess disease activity and chronic damage. Patients were administered a test battery specifically designed to detect fronto-subcortical dysfunction across five domains: memory, attention, abstract reasoning, executive function and visuospatial function. For each patient, the raw scores from each test were compared with published norms, then transformed into Z scores (deviation from normal mean), and finally summed in the Global Cognitive Dysfunction score (GCDs). Results Nineteen percent of patients had mild GCDs impairment (GCDs 2–3), 7% moderate (GCDs 4–5) and 5% severe (GCDs≥6). The visuospatial domain was the most compromised (MDZs = −0.89±1.23). Anti-cardiolipin IgM levels were associated with visuospatial domain impairment (r = 0.331, P = 0.005). SLEDAI correlated with GCDs, and attentional and executive domains; SLICC correlated with GCDs, and with visuospatial and attentional domains impairment. Conclusions Anti-phospholipids, disease activity, and chronic damage are associated with cognitive dysfunction in SLE. The use of a wide spectrum of tests allowed for a better selection of the relevant factors involved in SLE cognitive dysfunction, and standardized neuropsychological testing methods should be used for routine assessment of SLE patients.

Is the Nail Psoriasis Severity Index reliable in the assessment of nail psoriasis by rheumatologists

To determine the agreement and reliability of the Nail Psoriasis Severity Index (NAPSI) in the assessment of nail involvement in patients with psoriatic arthritis (PsA) when performed by rheumatologists with no experience in using this instrument.

Emerging role for NK cells in the pathogenesis of inflammatory arthropathies

Natural killer (NK) cells are large, granular lymphocytes devoted to the defense against microbial agents and cancer cells, traditionally recognized as an important arm of the innate immunity, even if more recent data underpin a role also in the responses of acquired immunity. Several studies have led to ascertain that NK cells are involved in the pathogenesis of many immune-mediated diseases, where they may exert both protective and pathogenic roles. In particular, the CD56(bright) NK cell subset, showing immunoregulatory properties, has been found to accumulate in tissue sites of inflammation, such as the skin lesions in psoriatic patients and the synovial membrane in rheumatoid arthritis (RA) patients. In this latter disease, while data on the number of NK cells are still controversial among the different studies, more consensuses exist on the impaired activity of these cells. In another group of inflammatory arthritides, the spondyloarthropathies (SpA), the presence of peculiar allotypes of the killer cell immunoglobulin-like receptors (KIR) superfamily, coding for molecules expressed on NK cells, seems to modulate the susceptibility to this group of diseases, especially ankylosing spondylitis and psoriatic arthritis. Interestingly, in vitro studies showed that NK cells of patients with inflammatory arthropathies might produce pro-inflammatory Th1 cytokines; furthermore, they are involved in bone damage, interact and activate different cell types such as monocytes, dendritic cells and resident fibroblast-like synoviocites cells, thus creating and/or maintaining the inflammatory response. Certainly, these features encourage more research on the role of NK cells in the pathogenesis of inflammatory arthropathies, which could be essential to define potential new therapeutic strategies.

Switching from infliximab or etanercept to adalimumab in resistant or intolerant patients with spondyloarthritis: a 4-year study

OBJECTIVE TNF-alpha antagonists, infliximab (INF), etanercept (ETA) and adalimumab (ADA), have been demonstrated to be effective in controlling symptoms in SpAs. The aim of this study was to investigate the possibility of using ADA as a second or third choice. METHODS A retrospective study was conducted in patients with SpA treated with TNF-alpha blockers who switched from INF or ETA to ADA, for inefficacy or adverse events. Kaplan-Meier survival curves were plotted to determine the rates of continuation of the first treatment (INF or ETA) as compared with the rates of continuation of the second or third treatment with ADA. RESULTS A total of 1619 patients with SpA were treated with INF (35.3%), ETA (43.7%) and ADA (20.9%). In this cohort, ADA was started in 38 (2.34%) patients as a second anti-TNF-alpha drug and in 9 (0.56%) as a third anti-TNF-alpha drug. In SpA patients who failed the first anti-TNF-alpha, for whatever reason, survival curves for ADA (as a second anti-TNF-alpha) were significantly better than survival curves for these same patients on their first anti-TNF-alpha (overall: P < 0.0001; INF: P < 0.0011; ETA: P < 0.02). CONCLUSION Our retrospective study, resulting from real-life experience, showed that SpA patients who fail to respond to a first agent, INF or ETA, respond to ADA as a second-line drug regardless of the reason for switching.

Metabolomics approach in allergic and rheumatic diseases.

Metabolomics is the analysis of the concentration profiles of low molecular weight compounds present in biological fluids. Metabolites are nonpeptide molecules representing the end products of cellular activity. Therefore, changes in metabolite concentrations reveal the range of biochemical effects induced by a disease or its therapeutic intervention. Metabolomics has recently become feasible with the accessibility of new technologies, including mass spectrometry and high-resolution proton nuclear magnetic resonance, and has already been applied to several disorders. Indeed, it has the advantage of being a nontargeted approach for identifying potential biomarkers, which means that it does not require a preliminary knowledge of the substances to be studied. In this review, we summarize the main studies in which metabolomic approach was used in some allergic (asthma, atopic dermatitis) and rheumatic diseases (rheumatoid arthritis, systemic lupus erythematosus) to explore the feasibility of this technique as a novel diagnostic tool in these complex disorders.

Biomarkers of Subclinical Atherosclerosis in Patients with Autoimmune Disorders

Atherosclerosis is accelerated in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). We investigated a possible association of oxidized low-density lipoproteins (ox-LDLs), nitric oxide (NO), 3-nitrotyrosine, vitamin A, vitamin E, and β-carotene serum levels with subclinical atherosclerosis in RA and PsA. By the use of ELISA, we observed higher ox-LDL levels in patients with intima-media thickness (IMT) > 1 than in patients with IMT ≤ 1 and a negative correlation between NO levels and IMT values. By the use of high-performance liquid chromatography, we determined higher levels of vitamin A in patients with PsA and IMT ≤ 1 than in controls and lower levels of β-carotene in patients with RA and PsA than in controls. β-carotene concentrations were negatively correlated to the duration of disease in RA. Our study confirms that ox-LDLs and NO may be markers of accelerated atherosclerosis in RA and PsA whereas vitamins seem to be associated only to the presence of the autoimmune disorders.

Mycobacterial Interferon-γ Release Variations During Longterm Treatment with Tumor Necrosis Factor Blockers: Lack of Correlation with Clinical Outcome

Objective. To assess the performance of serial QuantiFeron-TB Gold In-Tube (QFT-GIT) tests in patients with rheumatic diseases during longterm systemic treatment with biologic therapy, evaluating conversions and reversions in relation to the clinical outcome. Methods. We conducted a prospective study on patients awaiting biologic agents. At baseline, they had chest radiographs, QFT-GIT tests, and tuberculin skin tests (TST); QFT-GIT was repeated at 3, 6, 12, and 18 months after onset of biologic therapy. In patients with no evidence of latent tuberculosis infection (LTBI) at baseline, TST was repeated at 12 months of biologic treatment. Results. Among patients (n = 102; women 65.7%; median age 47 yrs, range 20–82), 14 (13.7%) were considered as having LTBI because of a minimum of 1 abnormal screening test. The agreement between QFT-GIT and TST was 88% (κ = 0.14). During biologic treatment, both patients with (n = 14) and those without (n = 88) evidence of LTBI at baseline showed conversions and reversions in QFT-GIT results at different timepoints. These fluctuations were not paralleled by significant clinical changes. The TST repeated at 12 months in patients with no evidence of LTBI at baseline continued to be negative. The median baseline interferon-γ (IFN-γ) concentration was not significantly different from that observed at each subsequent timepoint. Conclusion. Dynamic changes occur with serial IFN-γ release assay testing in patients treated with biologic therapy that do not correlate with clinical outcome. A careful and integrated evaluation of the patient, including clinical information, should guide the treatment decision. This study was underpowered for definite conclusions and further studies are needed to determine the significance of these findings.