Antonio Spadaro

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.

The psoriatic arthritis cost evaluation study: a cost-of-illness study on tumour necrosis factor inhibitors in psoriatic arthritis patients with inadequate response to conventional therapy

Objective. To evaluate costs, benefits and cost–effectiveness of anti-TNF agents in PsA patients with inadequate response to conventional treatment. Methods. A total of 107 patients, from nine Italian rheumatology centres, with different forms of PsA were given anti-TNF treatment, mainly etanercept (87%). Information on resource use, health-related quality of life, disease activity, function and laboratory values were collected at baseline and through out the 12 months of therapy. Cost (expressed in euro 2007) and utility (measured by EuroQol) before and after anti-TNF therapy initiation were compared in order to estimate the incremental cost per quality-adjusted life year (QALY) gained, and cost–effectiveness acceptability curve was calculated. Results. At the end of 12 months, there was a significant increase in direct cost due to an increase of drug cost caused by TNF inhibitors that was only partially offset by the decrease in indirect cost. In the last 6 months of therapy, the direct cost increased by €5052, the cost for the National Health System (NHS) by €5044 and the social cost by €4638. However, a gain of 0.12 QALY resulted in a cost per QALY gained of €40 876 for the NHS and of €37 591 for the society. The acceptability curve showed that there would be a 97% likelihood that anti-TNF therapy would be considered cost-effective at willingness-to-pay threshold of €60 000 per QALY gained. Conclusion. Cost–effectiveness ratios are within the commonly accepted willingness-to-pay threshold. These results need to be confirmed in larger samples of patients.

Anti-tumour necrosis factor (TNF) α treatment of rheumatoid arthritis (infliximab) selectively down regulates the production of interleukin (IL) 18 but not of IL12 and IL13

Objective: To measure interleukin (IL)18 serum concentrations in patients with rheumatoid arthritis (RA) undergoing infliximab treatment (tumour necrosis factor (TNF) α blockade) and to evaluate the concomitant modification of IL12 and IL13 serum concentrations, two cytokines belonging to the Th1 and Th2 profile respectively and biologically related to IL18. Methods: Ten patients with RA not responding to disease modifying antirheumatic drugs (DMARDs) received intravenous infliximab at a dose of 3 mg/kg at baseline and after two and six weeks. Serum samples were collected from all patients before each infusion and assayed for IL18, IL12, and IL13 by enzyme linked immunosorbent assay (ELISA); IL18 was also measured eight weeks after the last infusion. Results: Serum concentrations of IL18 in all patients were already markedly reduced from baseline after two weeks (p<0.005). Serum IL18 was also decreased in a stable manner after six (p<0.01) and 14 weeks (p<0.01) compared with baseline concentrations. No significant modifications were found in serum concentrations of IL12 and IL13 at any time point. Conclusion: There was a rapid and persistent decrease in serum concentrations of IL18 in all the patients studied. This result provides evidence of an in vivo regulation of IL18 by TNFα and suggests that anti-TNFα therapy is likely to interrupt the synergistic effect between these two cytokines.

Identification of the clinical features distinguishing psoriatic arthritis and fibromyalgia.

Objective. To identify the clinical features that can help to distinguish between psoriatic arthritis (PsA) and fibromyalgia (FM). Methods. Our cross-sectional study was carried out in 10 Italian rheumatology centers between January and September 2009, and enrolled all consecutive patients with PsA and FM who agreed to participate. Standard clinical and laboratory data for PsA and FM were collected from all patients. Records were made of somatic symptoms, response to nonsteroidal antiinflammatory drugs (NSAID), self-evaluated pain, general health, disability, and responses to the Fibromyalgia Impact Questionnaire. Data were statistically analyzed by univariate and multivariate analyses, and receiver-operating characteristic curves. The analysis concentrated on the clinical features shared by the 2 conditions. Results. Two hundred sixty-six patients with PsA (mean age 51.7 yrs; disease duration 10.2 yrs) and 120 patients with FM (mean age 50.2 yrs; disease duration 5.6 yrs) were evaluated. Univariate analysis showed that patients with FM had higher mean tender point and enthesitis scores, more somatic symptoms, and responded less to NSAID. Multivariate analysis showed that the presence of ≥ 6 FM-associated symptoms and ≥ 8 tender points was the best predictor of FM. Conclusion. The shared clinical features of PsA and FM that had the greatest discriminating power for FM were the number of FM-associated symptoms and tender point count.

Patient Global Assessment in Psoriatic Arthritis: A Multicenter GRAPPA and OMERACT Study

Objective. During OMERACT 8, delegates selected patient global assessment (PGA) of disease as a domain to be evaluated in randomized controlled trials in psoriatic arthritis (PsA). This study assessed the reliability of the PGA, measured by means of 0–100 mm visual analog scale (VAS), and the additional utility of separate VAS scales for joints (PJA) and skin (PSA). Methods. In total, 319 consecutive patients with PsA (186 men, 133 women, mean age 51 ± 13 yrs) were enrolled. PGA, PJA, and PSA were administered at enrolment (W0) and after 1 week (W1). Detailed clinical data, including ACR joint count, Psoriasis Area and Severity Index (PASI), and Hospital Anxiety and Depression Scale, were recorded. Results. Comparison of W0 and W1 scores showed no significant variations (intraclass correlation coefficients for PGA 0.87, PJA 0.86, PSA 0.78), demonstrating the reliability of the instrument. PGA scores were not influenced by patient anxiety or depression, but were dependent on PJA and PSA (p = 0.00001). PJA was dependent on the number of swollen and tender joints (p < 0.00001). PSA scores were influenced by the extent of skin psoriasis and by hand skin involvement (p = 0.00001). Joint and skin disease were found not to correlate in terms of disease activity as evidenced by the swollen joint count compared to PASI (r = 0.11) and by the PJA compared to PSA (r = 0.38). Conclusion. PGA assessed by means of VAS is a reliable tool related to joint and skin disease activity. Because joint and skin disease often diverge it is suggested that in some circumstances both PJA and PSA are also assessed.

The Immunology of Rheumatoid Arthritis

Abstract:  Rheumatoid arthritis (RA) is represents the most common chronic inflammatory joint disease and is still a major medical challenge because of unsolved issues related to the etiologic and pathogenetic questions. Intensive research has been conducted over the last years that focused on the inappropriate activation of the immune system: although T cells have long been deemed to play a central role in the origin and propagation of joint inflammation, data accumulated so far have widened this perspective recognizing the contribution of other cells, as well as the major histocompatibility complex class II proteins and a composite set of costimulatory signals responsible for the production of proinflammatory cytokines and other soluble mediators implicated in tissue destruction typical of the disease. This paper will provide an insight into the immune system in RA, dissecting cellular and humoral aspects both in serum and in synovium of patients.

Remission in ankylosing spondylitis treated with anti-TNF-α drugs: a national multicentre study

OBJECTIVE The primary objective of this retrospective study was to investigate the possibility of achieving partial remission (PR) in AS patients treated with anti-TNF-α antagonists, such as adalimumab (ADA), etanercept (ETA) and infliximab (INF), in a real clinical practice setting. Predictors of PR were also evaluated. METHODS A retrospective study was conducted in patients with AS treated with ADA, ETA and INF from 2000 to 2012. Kaplan-Meier survival curves were plotted to determine the rates of PR during the treatment with anti-TNF-α drugs. RESULTS A total of 283 patients with AS were treated with ADA (18.7%), ETA (26.8%) and INF (54.4%) as first anti-TNF-α drugs, with a PR rate of 57.6%. The probability of obtaining PR with ADA, ETA or INF was not significantly different among all anti-TNF-α patients. AS patients treated with a second anti-TNF-α drug had a PR rate of 40.5%, but after switching for lack of response, the probability of obtaining PR with a second anti-TNF-α drug was significantly lower from that of the first anti-TNF-α drug (P = 0.0039). The probability of obtaining PR in patients with enthesitis (P = 0.04) or psoriasis (P = 0.0016) or low levels of CRP (P = 0.0225) was significantly lower compared with that of patients without these manifestations at baseline. CONCLUSION Our real-life study on PR confirmed the effectiveness of ADA, ETA or INF as first or second anti-TNF-α drugs. The presence at baseline of enthesitis or psoriasis or low CRP values yielded a lower probability of obtaining PR.

Oxidative stress parameters in different systemic rheumatic diseases

The involvement of oxidative stress in the pathogenesis of rheumatic disorders, such as systemic sclerosis (SSc) and chronic polyarthritides, has been suggested yet not thoroughly verified experimentally. We analysed 4 plasmatic parameters of oxidative stress in patients with SSc (n = 17), psoriatic arthritis (PsA) (n = 10) and rheumatoid arthritis (RA) (n = 9) compared with healthy subjects (n = 22). The biomarkers were: total antioxidant capacity (TAC) measured by ferric reducing antioxidant power (FRAP) method, hydroperoxides determined by ferrous ion oxidation in presence of xylenol orange (FOX) method and sulfhydryl and carbonyl groups assessed by spectrophotometric assays. The results showed significantly increased hydroperoxides in SSc, PsA and RA (3.97 ± 2.25, 4.87 ± 2.18 and 5.13 ± 2.36 μmol L−1, respectively) compared with the control group, (2.31 ± 1.40 μmol L−1; P < 0.05). Sulfhydryls were significantly lower in SSc (0.466 ± 0.081 mmol L −1), PsA (0.477 ± 0.059 mmol L−1) and RA (0.439 ± 0.065 mmol L−1) compared with the control group) (0.547 ± 0.066 mmolL−1; P < 0.05). TAC in all three diseases showed no difference in comparison with controls. Carbonyls were significantly higher in RA than in the control group (32.1 ± 42 vs 2.21 ± 1.0 nmol (mg protein)−1; P < 0.05). The obtained data indicate augmented free radical‐mediated injury in these rheumatic diseases and suggest a role for the use of antioxidants in mediated prevention and treatment of these pathologies.

Nailfold capillaroscopy changes in systemic lupus erythematosus : correlations with disease activity and autoantibody profile

In systemic lupus erythematosus (SLE) nailfold capillaroscopy (NC) studies have described many different nonspecific patterns. We decided to evaluate NC changes in 44 SLE patients, comparing them with the main clinical, demographic and laboratory parameters, thus to define the real role for NC and its abnormalities in the management of this disease. Fifteen patients (34%) complained of Raynaud’s phenomenon; nine of them (20%) showed relevant capillaroscopic changes (capillaroscopic score >1). In details: three patients (6.8%) had loss of capillaries, while 18 (41%) had a capillary length variability, 16 (36.5%) showing shorter and two (4.5%) longer capillaries; tortuous, meandering, bizarre, ramified and/or bushy capillaries were found in 26 (59%), seven (16%), two (4.5%), three (7%) cases, respectively. An irregular distribution of the capillary array was present in six cases (14%) while microhaemorrhages were found in four cases (9%). 4 patients (9%) showed enlarged capillaries and changes of blood flow. A capillaroscopic score >1 was more frequently associated with higher ECLAM (P < 0.005) and SLEDAI (P < 0.01) activity scores, with the presence of anti-cardiolipin (P < 0.04) and anti-Sm (P < 0.04) antibodies, and also with the presence (P < 0.04) and higher titer (P < 0.001) of anti-dsDNA antibodies. No statistically significant correlation was found among the different capillaroscopy findings, age, disease duration, or treatment, nor with any clinical manifestation of the disease, such as cutaneous, renal or neurological. Our findings confirm the importance of the microvascular involvement in SLE. The NC abnormalities seem to be related to the disease activity and to the presence of many different antibodies, highly involved in the expression of SLE. NC proved to be an easy-to-perform noninvasive technique, able to achieve useful data to better evaluate such a pleomorphic disease as SLE.

Down-regulation of natural killer cells and of g/d T cells in systemic lupus erythematosus. Does it correlate to autoimmunity and to laboratory indices of disease activity?

A depletion of natural killer (NK) cells seems to play a role in the course of systemic lupus erythematosus (SLE) whereas the possible involvement in this disease of T cell receptor (TCR) g/d positive T cells is still debated. The aim of this study was to evaluate the peripheral blood mononuclear cells (PBMCs) that express NK surface markers CD16 and CD56 or g/d TCR antigen in 58 SLE patients, investigating the possible role of these cell subsets involved in non-MHC-restricted cytotoxicity and their relationship with the main clinical and laboratory parameters. SLE patients had, with respect to controls, considerably decreased values of NK cells (P < 0.0004 in percentage and P < 0.00004 as absolute number), of non-MHC-restricted T cytotoxic lymphocytes (P < 0.007 and P < 0.0015, respectively) and of T cells expressing g/d TCR (P < 0.02 and P < 0.004, respectively). The absolute numbers of these cell subsets positively correlated to each other (P < 0.009). g/d T cells inversely correlated with higher ESR values, both percentually (P < 0.006; r ‘ 70.367) and in absolute number (P < 0.009; r ‘ 70.350). Moreover, the percentage values of this cell subset inversely correlated with higher levels of CRP (P < 0.05; r ‘ 70.256) while SLE patients with anti-SSB/La antibodies had lower values of T lymphocytes bearing g/d TCR, both as percentage (P < 0.008) and as absolute number (P < 0.02). Our study indicates that non-MHC-restricted cytotoxicity, shared by NK, NK-like and g/d T cells, may be down-regulated in SLE patients, owing to a significant reduction of these PBMC subsets. These specific cell subset impairments seem to affect only some aspects of the disease, suggesting a weakening of the regulatory properties of these cells in the control of different immunological and inflammatory features of SLE, that could be of importance in its clinical expression.