Long-term costs and outcomes in psoriatic arthritis patients not responding to conventional therapy treated with tumour necrosis factor inhibitors: the extension of the Psoriatic Arthritis Cost Evaluation (PACE) study.

OBJECTIVES: Poor information on long-term outcomes and costs on tumour necrosis factor (TNF) inhibitors in psoriatic arthritis (PsA) are available. Our aim was to evaluate long-term costs and benefits of TNF- inhibitors in PsA patients with inadequate response to conventional treatment with traditional disease-modifying anti-rheumatic drugs (tDMARDs). METHODS: Fifty-five out of 107 enrolled patients included in the study at one year, completed the 5-year follow-up period. These patients were enrolled in 8 of 9 centres included in the study at one year. Patients aged older than 18 years, with different forms of PsA and failure or intolerance to tDMARDs therapy were treated with anti-TNF agents. Information on resource use, health-related quality of life (HRQoL), disease activity, function and laboratory values were collected at baseline and through the 5 years of therapy. Costs (expressed in Euro 2011) and utility (measured by EQ-5D instrument) before TNF inhibitor therapy and after 1 and 5 years were compared. RESULTS: The majority of patients (46 out of 55; 83.6%) had a predominant or exclusive peripheral arthritis and 16.4% had predominant or exclusive axial involvement. There was a statistically significant improvement of the most important clinical variables after 1 year of follow-up. These improvements were maintained also after 5 years. The direct costs increased by approximately €800 per patient-month after 1 year, the indirect costs decreased by €100 and the overall costs increased by more than €700 per patient-month due to the cost of TNF inhibitor therapy. Costs at 5 year were similar to the costs at 1 year. The HRQoL parameters showed the same trends of the clinical variables. EQ-5D VAS, EQ-5D utility and SF-36 PCS score showed a significant improvement after 1 year, maintained at 5 years. SF-36 MCS showed an improvement only at 5 years. CONCLUSIONS: The results of our study suggest that TNF blockers have long-term efficacy. The higher cost of TNF inhibitor therapy was balanced by a significant improvement of HRQoL, stable at 5 years of follow-up. Our results need to be confirmed in larger samples of patients.

The adherence to ASAS classification criteria and to ASAS recommendations for the use of anti-TNH-alpha agents in axial spondyloarthritis.

OBJECTIVES: To determine the adherence of practicing rheumatologists, before and after an educational project, to Assessment of SpondyloArthritis international Society (ASAS) classification criteria and to ASAS recommendations for the use of anti-tumor necrosis factor (TNF)-alpha agents in patients with axial spondyloarthritis (SpA). METHODS: The project involved 53 rheumatologists attending 2 educational meetings on an update of SpA. Each meeting included interactive sessions on 1) clinical cases, 2) clinimetric evaluation, including ASAS core set for daily practice and 3) imaging. Diagnostic and therapeutic approach of each participant was tested using short clinical cases, obtained from real-life rheumatology settings, at the beginning and at the end of this educational project. Each case for diagnostic (n=10) or therapeutic purpose (n=10) had 10 possible choices. Each participant gave a score from 0 (total disagreement) to 10 (total agreement) for each choice. RESULTS: At baseline, the rheumatologists had an excellent agreement with ASAS classification criteria for axial SpA and anti-TNF-alpha treatment according to ASAS recommendations with a further significant improvement after the educational programme. In axial SpA cases with acute anterior uveitis (AU) or Crohn's disease, anti-TNF-alpha treatment was indicated mainly as monoclonal anti-TNF antibody. In presence of elevated levels of CRP, anti-TNF option has been considered useful. CONCLUSIONS: Practicing rheumatologists had a satisfying adherence to ASAS classification criteria and to ASAS recommendations for the use of anti-TNF-alpha agents for patients with axial SpA. Extra-articular manifestations and other variables might play a role in the decision-process of the management of axial SpA.

Pharmacoeconomic burden in the treatment of psoriatic arthritis: from systematic reviews to real clinical practice studies.

The economic assessment of treatment options in a chronic and severe disease like Psoriatic Arthritis (PsA) is crucial to estimate the burden of costs. In particular, the impact of new costly medications such as biologic agents have been studied to figure this important aspect of a multifaceted disease. In a previous observational, longitudinal multicentre cost evaluation study, the results showed that biologic agents are cost-effective. This study was obtained from the real clinical practice and encompassed PsA patients refractory to traditional treatments. Similar data were also obtained from reviews analysis of Randomized Controlled Trials (RCTs). Recently, Cawson et al. performed a systematic review, network meta-analysis and economic evaluation of biological therapy for the management of active PsA. The review was conducted to identify relevant, recently published studies and the new trial data were synthesized, via a Bayesian network meta-analysis (NMA), to estimate the relative efficacy of the TNF-α inhibitors in terms of Psoriatic Arthritis Response Criteria (PsARC) response, Health Assessment Questionnaire (HAQ) scores and Psoriasis Area and Severity Index (PASI). In particular the analysis showed that, on average, etanercept was the most cost-effective treatment and, at the National Institute for Health and Care Excellence willingness-to-pay threshold of between £20,000 to £30,000, etanercept is the preferred option. This study, as a systematic review, has been focused on main RCTs on active PsA treated by biological DMARDs and limitations to this analysis arise from a paucity of data on long-term follow up, as well as radiological progression and long-term safety. These interesting results reflected the important role of biologic agents in the management of PsA, highlighting their efficacy and cost-effectiveness. However, there are some unmet needs for pharmacoeconomic considerations based on prospective and/or on real clinical practice studies, as well as considering all the intriguing aspects of this challenging disease.

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.

Unmet needs in outcome measures of Psoriatic Arthritis: focus on axial radiographic and nail involvement.

OBJECTIVES: This article reviews some unmet needs on the outcome measures in Psoriatic Arthritis (PsA). In particular, the radiological assessment of axial PsA and the assessment of nail involvement still remain problematic and this, in turn, could affect the best management. At present, the radiological assessment of spine has been evaluated by using scoring systems borrowed from Ankylosing Spondylitis (AS). In particular, the Bath Ankylosing Spondylitis Radiology Index (BASRI) and the modified Stoke Ankylosing Spondylitis Spine Score (m-SASSS) have been validated for the axial PsA and a new index for assessing the radiological axial involvement in PsA was also developed, called Psoriatic Arthritis Spondylitis Radiology Index (PASRI). Nail involvement has been evaluated by two different instruments: the Nail Psoriasis Severity Index (NAPSI) and its modified version (mNAPSI). Both are good instruments but only a few data are available on these instruments when adopted at a daily clinical practice level.

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 ß-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 ß-carotene in patients with RA and PsA than in controls. ß-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.

Etanercept in psoriatic arthritis.

In this update on etanercept (ETN) in psoriatic arthritis (PsA) we analyze this drug's mechanism of action, clinical efficacy/effectiveness, optimal dosage, disease-modifying antirheumatic drugs (DMARD) association, radiological progression, safety, switching aspects, and pharmacoeconomy. The efficacy/effectiveness of ETN in PsA has been demonstrated in randomized placebo-controlled trials as well as in observational studies representing routine clinical practice. At 1 and 2 years, ETN inhibited radiographic disease progression, assessed by the modified total Sharp score. ETN (generally at a dosage of 50 mg/weekly) can be used either in monotherapy or in combination with DMARD such as methotrexate. A systematic search of randomized, placebo-controlled trials of ETN to treat adults with plaque psoriasis or PsA suggests that the short-term risk/benefit ratio is favorable. Longterm studies, such as observational studies, confirmed this safety profile of ETN. A variable percentage of patients withdrew anti-tumor necrosis factor-α (TNF-α) inhibitor treatment owing to inefficacy or poor tolerability. Observational studies showed that in the case of treatment failure with 1 agent, switching to the other agent may also be useful in patients with PsA because of the different molecular structures and targets of available TNF-α blockers. The clinical effect of ETN is associated with favorable pharmacoeconomic considerations.

The radiological assessment of axial involvement in psoriatic arthritis.

This article summarizes the state of radiological assessment of axial involvement in psoriatic arthritis (PsA). The definition and measurement of axial disease in PsA remain problematic and this situation in turn could affect the choice of approach to evaluate radiological findings of the spine. At present, the radiological assessment has been evaluated by using scoring systems borrowed from ankylosing spondylitis (AS). In particular, the Bath AS Radiology Index (BASRI) and the modified Stoke AS Spine Score (m-SASSS) have been validated for axial PsA. A recent study showed that BASRI and m-SASSS were valid instruments; however, neither score encompassed all radiological features of PsA. Therefore, a new index for assessing radiological axial involvement in PsA was developed--the PsA Spondylitis Radiology Index (PASRI). This new index encompassed a greater range of the spinal radiological features of PsA, providing a greater score range, and it correlated well with anthropometric and patient-reported outcomes. Recently, a study assessed the sensitivity to change of BASRI, m-SASSS, and PASRI, and showed that these 3 instruments provided a moderate sensitivity to change but high specificity to detect the true changes.

Clinical and ultrasonography assessment of peripheral enthesitis in ankylosing spondylitis.

OBJECTIVE: The aim of this study was to compare clinical examination with power Doppler US (PDUS) in the detection of entheseal abnormalities in patients with AS. METHODS: Thirty-six AS patients underwent clinical and PDUS examination of the following bilateral entheseal sites: common extensor tendon at its insertion at the lateral humeral epicondyle; gluteus tendons at their insertion at the greater trochanter; quadriceps tendon at its insertion at the superior pole of the patella; patellar tendon at its proximal insertion at the inferior pole of the patella; patellar tendon at its distal insertion at the tibial tuberosity; Achilles tendon at its insertion at the calcaneus; and plantar aponeuroses at its insertion at the calcaneus. RESULTS: Clinical and PDUS examination revealed at least one abnormal enthesis in 23 (63.9%) and 35 (97.2%) AS patients, respectively. Furthermore, of 432 entheses examined in our 36 AS patients, 64 (14.8%) were considered abnormal by clinical examination and 192 (44.4%) by PDUS. US abnormalities most commonly found were enthesophytes (31.7%), calcifications (33.7%), thickening (29.8%) and hypoechogenicity (26.6%). We found erosions and PD signals in 9.7 and 6% of examined entheseal sites, respectively. The evidence of entheseal abnormalities by clinical examination has a poor likelihood ratio (LR) for the presence of US abnormalities with vascularization (LR = 1.61), without vascularization (LR = 1.24) or erosions (LR = 1.51) at all sites. CONCLUSIONS: PDUS permits detection of structural and inflammatory abnormalities of the enthesis in AS and may complement the physical examination in order to better evaluate enthesitis.

Rituximab infusion-related adverse event rates are lower in patients with systemic lupus erythematosus than in those with rheumatoid arthritis.

OBJECTIVES: Rituximab (RTX) is a therapeutic option for patients with SLE or RA. We conducted a prospective, longitudinal, observational study to compare rates of RTX-related adverse events (AEs) in these two patient groups. METHODS: RTX was used in 23 patients with SLE that was refractory to conventional therapy and in 31 patients with RA that had been unsuccessfully treated with TNF-α inhibitors. Infusion-related and infectious AE rates were calculated for each group. RESULTS: Seven (22.5%) RA patients experienced an infusion-related reaction. These AEs involved 7/91 (7.7%) infusions administered in the RA group. None of the 102 infusions administered to SLE patients was associated with infusion-related AEs (P = 0.038 vs RA group). The mean daily glucocorticoid dose administered during the week preceding RTX treatment in the SLE group was higher than that for the RA group [0.25 (0.2) vs 0.18 (0.14) mg/kg, P = not significant] and significantly higher than that received by the subgroup of the seven RA patients who experienced infusion-related AEs [0.10 (0.02) mg/kg; P = 0.0017]. Infectious AE rates were also lower (but not significantly so) in the SLE group (8.7 vs 12.9% in RA). CONCLUSIONS: Repeated cycles of RTX in combination with different immunosuppressants is a safe therapeutic option for SLE and RA patients. The lower incidence of infusion-related AEs in the SLE patients might reflect the higher dosage glucocorticoid therapy they received during the week before RTX infusion.

Etanercept in spondyloarthropathies. Part I: current evidence of efficacy.

Etanercept is a recombinant soluble tumour necrosis factor alpha receptor administered subcutaneously at the dose of 50 mg weekly (or 25 mg/twice weekly) for the treatment of the main chronic arthritides: rheumatoid arthritis and spondyloarthropathies. It shows high qualities in terms of efficacy and manageability. Favourable results were reported in all localisations of spondyloarthropathies: axial disease, peripheral arthritis, and enthesitis. In particular, several studies demonstrated its efficacy on the clinical and functional indicators of ankylosing spondylitis. Similar data were also reported for psoriatic arthritis in which, in addition, a significant reduction in the progression of erosive damages was widely described. Furthermore, although only a few studies are available, very interesting results have been obtained in patients suffering from undifferentiated spondyloarthropathies and severe enthesitis.

Etanercept in spondyloarthopathies. Part II: safety and pharmacoeconomic issues.

Etanercept (ETN) and other anti-TNF-α agents have revolutionised the management of spondyloarthropathies (SpA). With the increasingly widespread and prolonged use of these drugs an assessment of their long-term safety is extremely important. An additional concern regarding biological agents is their higher costs compared with conventional drugs. We examined safety data regarding ETN from clinical reports, clinical trials, review articles, databases and registries. In addition, evidence was reviewed about the cost effectiveness of ETN in the treatment of patients with SpA. Our review suggests that ETN is well tolerated as long-term, continuous treatment of SpA with a favourable risk-benefit ratio maintained from 4 to 5 years. Diversity in structure and mode of action could explain some differences in the safety profile of ETN with respect to the other anti-TNF agents. In particular, ETN is less immunogenic and is less likely to induce tuberculosis re-activation than the other TNF-α antagonists. Although ETN is considerably more expensive than conventional therapy, it reduces direct and indirect costs associated to SpA by improving disease activity and quality of life. Recent pharmacoeconomic studies have demonstrated its cost-effectiveness in the treatment of SpA.

The effectiveness of a biologic agent on axial manifestations of psoriatic arthritis. A twelve months observational study in a group of patients treated with etanercept.

OBJECTIVES: To investigate the effectiveness of etanercept on axial manifestations of a group of patients with established psoriatic arthritis (PsA). METHODS: This was a multicentre observational study. PsA was classified based on the CASPAR criteria. Inclusion criteria were refractory PsA with axial manifestations and suitability for anti TNF-α therapy. Effectiveness was defined according to the ASAS response criteria (BASDAI: 50% relative or absolute change of 20mm and expert opinion in favour of continuation), and on the improvements of BASFI, anthropometric measures, PASI, ESR and CRP at 12 months. PASI 50 and 75 were also assessed, as well as the ACR20 and ACR50 response criteria for patients with peripheral arthritis. Comparisons between baseline and after 12-month treatment were done using the Wilcoxon signed rank test for the end-points considered. RESULTS: The study included 32 patients (25/7 M/F; median age 51yrs; 25th-75th percentiles: 34.5-58.7; median disease duration 14.5 yrs; 25th-75th percentiles: 9.2-17.00). Effectiveness of etanercept was observed in 72% of patients for the BASDAI (p<0.001), in 68% for the BASFI (p<0.001), in 76% for ESR (p<0.001) and in 68% of patients for CRP (p<0.01). The PASI improved in 72% of patients treated (p<0.0001), while PASI 50 and PASI 75 was reached in 81% and 55% of patients, respectively. ACR 20 and 50 was reached in 78 and 56% of patients with peripheral involvement respectively. CONCLUSIONS: The present study has shown that etanercept is effective on axial manifestations of established PsA, confirming the positive effects of anti TNF-α therapy on clinical manifestations of the disease.

Recommendations for the use of biologic therapy in the treatment of psoriatic arthritis: update from the Italian Society for Rheumatology.

OBJECTIVES: To update the 2006 Italian Society for Rheumatology recommendations for the use of biologic (TNF-α blocking) agents in the treatment of psoriatic arthritis (PsA). METHODS: A panel of experts performed a literature search and identified the items that required updating on the basis of new published data. A draft of the updated recommendations was circulated to a group of Italian Rheumatologists with a specific expertise in PsA and in therapy with biologic agents, and their suggestions were incorporated in the final version. RESULTS: A consensus was achieved regarding the initiation and the monitoring of anti-TNF-α agents in PsA. Inclusion and exclusion criteria were defined and specific recommendations were made for patients with psoriatic peripheral synovitis, spondylitis, enthesitis, and dactylitis, respectively. We also specified criteria for assessment of response to treatment and for withholding and withdrawal of therapy. CONCLUSIONS: These recommendations may be used for guidance in deciding which patients with PsA should receive biologic therapy. Further updates of these recommendations may be published on the basis of the results of new clinical studies and of data from post-marketing surveillance.

Certolizumab: efficacy and safety profile of a novel pegylated TNF-alpha blocking agent.

The treatment of Rheumatoid Arthritis (RA) has changed since the introduction of biological agents. In particular, the anti Tumor Necrosis Factor (TNF)-alpha molecules have been the first group of drugs showing a good efficacy and safety profile. Among these, a new anti TNF-alpha antibody has been recently indicated for the treatment of RA: certolizumab pegol (CZP). In the main clinical trials this new pegylated anti TNF-alpha has shown to be efficacious on clinical, functional and prevention of structural damage in patients with active RA and with inadequate response to traditional disease modifying drugs, including methotrexate. Moreover CZP showed to be well tolerated and most adverse events occurred were mild or moderate. Therefore, results obtained showed that this new molecule can play a role in the treatment of RA.

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.

Monitoring biological therapies in psoriatic arthritis.

Longterm use of tumor necrosis factor-alpha (TNF-alpha) blocking agents requires ongoing monitoring to confirm efficacy and to avoid drug toxicity. Epidemiologic studies may offer important complementary information about risks and benefits of this class of drugs. The safety profile of biologic therapies includes a wide spectrum of adverse events, of which the most relevant are risk of infections, malignancy, and cardiovascular diseases. The lack of published recommendations on monitoring suggests that clinicians must evaluate the patient for the risk or presence of any adverse events by regular checkups, with careful assessments, for their early detection. The safety profile in regard to psoriatic arthritis is discussed.

Rehabilitation in psoriatic arthritis.

This article summarizes the state of the art of rehabilitation in psoriatic arthritis (PsA). Very little evidence was available to assess the efficacy of rehabilitation. Some data were borrowed from studies on ankylosing spondylitis. Covering certain aspects of the disease by the standard measure of functioning was difficult. However, rehabilitation was considered by the GRAPPA Group (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis), as part of treatment of axial PsA.

Specific oxidative stress parameters differently correlate with nailfold capillaroscopy changes and organ involvement in systemic sclerosis.

Oxidative stress is suggested to be involved in the pathogenesis of systemic sclerosis (SSc). The aim of the present study was to clarify such a hypothesis by determination of four different plasmatic parameters of oxidative stress, and to define its role in the microvascular damage, assessed by nailfold capillaroscopy (NC). Plasma samples of 18 patients with SSc were analyzed. The biomarkers measured were: total antioxidant capacity, hydroperoxides (ROOHs), and sulfhydryl (SH) and carbonyl (CO) groups. Each patient had a detailed clinical assessment and underwent an NC. The results showed significantly increased ROOHs in SSc patients compared to control group (5.02 +/- 0.24 vs 3.28 +/- 0.19 micromol/l; p < 0.05). Plasmatic levels of SH groups were significantly lower in SSc (0.466 +/- 0.08 mmol/l) compared to control group (0.542 +/- 0.04 mmol/l; p < 0.002). Plasma levels of ROOHs correlated with the capillaroscopy semiquantitative rating scale score (p < 0.05) and with the rating system for avascular areas (p < 0.03). The levels of CO groups inversely correlated with modified Rodnan's skin score (p < 0.039) and were lower in patients with pulmonary fibrosis (p < 0.045), while the levels of SH groups were lower in those presenting gastrointestinal involvement (p < 0.029). The obtained data indicate augmented free radical-mediated injury in SSc and also show correlations among oxidative abnormalities, some clinical findings, and signs of a more severe microvascular involvement. These results give more evidence to the connection between oxidative impairment and SSc.

The immunology of rheumatoid arthritis.

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.