M. Lorenzin

Influence of tumor necrosis factor α inhibitors on testicular function and semen in spondyloarthritis patients

OBJECTIVE To evaluate sperm parameters and sexual hormones in young males affected with spondyloarthritis (SpA) before and after 1 year of anti-tumor necrosis factor (TNF) α treatment. DESIGN Prospective case-control study. SETTING Rheumatology and human reproduction pathology units at a university hospital. PATIENTS Ten SpA outpatients attending the rheumatology clinic; 20 healthy control subjects attending the unit of human reproduction pathology within an infertility prevention program. INTERVENTIONS At baseline and after a 12-month treatment, disease activity was assessed and an andrologic evaluation made. MAIN OUTCOME MEASURE(S) Rheumatologists assessed anamnestic, clinical, functional, and biomarker data. Andrologists evaluated semen analysis, fluorescence in situ hybridization for chromosomes X, Y, 13, 18, and 21, FSH, LH, and T plasma levels, and testicular color Doppler ultrasound. RESULTS At baseline, SpA patients showed reduced sperm motility, higher plasma LH and FSH, and lower T levels compared with control subjects; a significant correlation between disease activity and sperm quality was found. After treatment, a statistically significant decrease in sperm aneuploidies and normal hormone levels were observed. CONCLUSIONS Although inflammation in SpA appears to be related to impaired testicular function, anti-TNF-α agents seem to be safe on testicular function and fertility.

Atherosclerosis progression in psoriatic arthritis patients despite the treatment with tumor necrosis factor-alpha blockers: A two-year prospective observational study

OBJECTIVE To evaluate the progression of subclinical atherosclerosis in Psoriatic Arthritis (PsA) patients treated with anti-tumor necrosis factor (TNF)-α agents. METHODS Thirty-two PsA patients classified according to the CASPAR criteria and attending the Rheumatology Unit of the University of Padua Medical Center were enrolled in a two-year prospective, observational study. In accordance with the ASAS/EULAR recommendations on the management of these patients, those studied were prescribed biological agents [etanercept (n=21), adalimumab (n=6), infliximab (n=5)]. Plasma lipids, inflammatory biomarkers, including C-reactive protein (CRP), interleukin-6 (IL-6), vessel endothelium growth factor (VEGF), osteoprotegerin (OPG), and TNF-α, as well as Disease Activity Score 28 calculated with CRP (DAS 28-CRP) were evaluated at baseline and after two years of treatment. Bilateral carotid B-mode ultrasound measurements [the mean-intima media thickness (mean-IMT), the mean maximum-IMT (M-Max)] of each carotid artery segment (common, bulb, and internal carotid artery) and the post-occlusion flow-mediated dilation (FMD) of the brachial artery were also assessed at baseline and after two years. RESULTS Despite an improvement in the DAS 28-CRP score (P<0.0005) and lower low-density lipoprotein cholesterol (P<0.013) and triglyceride (P<0.036) values, there was a significant progression in both the mean-IMT (P<0.0005) and M-Max (P<0.0005). Moreover, no recovery in FMD (P=ns) was observed after two years of anti TNF-α treatment. Serum TNF-α levels were increased (P=0.003) and OPG values were decreased (P=0.011) at the end of follow- up with respect to baseline values. CONCLUSIONS Despite improvement in clinical status, arterial remodelling was observed in the PsA patients who were treated with anti TNF-α agents for two years.

Serological markers of erosive hand osteoarthritis

This review focuses on biomarkers in erosive hand osteoarthritis (EHOA), a subset of hand osteoarthritis (HOA), that primarily affects interphalangeal joints and is characterized by abrupt onset, severe pain and functional impairment, as well as signs of inflammation, in particular stiffness, swelling, erythema, paraesthesiae, and worse outcome. Inflammatory features and radiographic erosions are the main diagnostic hallmarks of this particular disease subset. As in other fields of OA, EHOA biomarkers can be classified as dry and soluble. Soluble biomarkers which are found in serum, synovial fluid and urine can be specific indicators of joint inflammation and degradation. With regard to inflammatory markers, C-reactive protein and myeloperoxidase have been found to be increased in EHOA, with respect to non-erosive HOA. All these markers have, moreover, been found to be correlated with disease activity. Another interesting marker linked to inflammation is hyaluronic acid, considered to be a marker of synovitis, which is frequently found in EHOA. The most useful cartilage markers in both erosive and non-erosive HOA, seems to be collagen (Coll) 2-1, Coll 2-1NO(2) and Col2-3/4C(short). Immunogenetic markers were also determined and an association between EHOA and a single nucleotide polymorphism on the gene encoding interleukin-1β was found in HLA and there was an increased frequency of HLA-B44 and HLA-DRB1*07 in EHOA.

Anterior Chest Wall Involvement in Early Stages of Spondyloarthritis: Advanced Diagnostic Tools

Objective. Anterior chest wall (ACW) involvement is difficult to evaluate in patients with spondyloarthritis (SpA). Bone scan is sensitive to ACW involvement, while magnetic resonance imaging (MRI) detects early alterations in SpA. We compared the sensitivity and specificity of bone scans and MRI in assessing ACW in early SpA. Methods. Out of 110 patients with early SpA attending the Outpatient Rheumatology Unit Clinic of Padua University from January 2008 to December 2010, the 40 complaining of pain and/or tenderness [60% with psoriatic arthritis (PsA), 12.5% with ankylosing spondylitis, and 27.5% with undifferentiated SpA] underwent bone scans and MRI. Results. At clinical examination, sternocostoclavicular joints were involved in 87.5% on the right, 77.5% on the left, and 35% on the sternum. Bone scan was positive in 100% and MRI in 62.5% of these patients. Early MRI signs (bone edema, synovial hyperemia) were observed in 27.5%, swelling in 5%, capsular structure thickness in 37.5%, erosions in 15%, bone irregularities in 15%, osteoproductive processes in 12.5%, and osteophytes in 5%. A higher prevalence of Cw6, Cw7, B35, and B38 was found in 15%, 48%, 28%, and 12%, respectively, of the patients with PsA who had bone scans. Conclusion. Noted mainly in women, ACW involvement was frequent in early SpA. Both bone scans and MRI are useful in investigating ACW inflammation. Bone scans were found to have high sensitivity in revealing subclinical involvement, but a low specificity. MRI provides useful information for therapeutic decision making because it reveals the type and extent of the process. The significant associations of HLA-Cw6 and Cw7 with PsA could suggest that genetic factors influence ACW involvement.

Impact of hypertension on vascular remodeling in patients with psoriatic arthritis.

We studied the impact of hypertension along with traditional and new cardiovascular risk factors on the structural and functional properties of arteries in psoriatic arthritis (PsA) patients. We examined 42 PsA subjects (aged 51±9 years) stratified according to hypertensive status (19 normotensive, PsA-NT and 23 hypertensives, PsA-HT). Thirty-eight normotensive subjects (C-NT) and 23 hypertensives (C-HT) comparable by age and sex served as controls. Mean carotid intima-media thickness (mean-IMT) and mean of the maximum IMT (M-Max) were evaluated by ultrasound in carotid artery segment bilaterally. Post-occlusion flow-mediated dilation (FMD) of the brachial artery was evaluated by ultrasonography. These parameters were correlated with risk factors, markers of inflammation and disease activity. Values of mean-IMT were higher in both groups of PsA patients compared with C-NT (0.68 mm in PsA-NT and 0.75 mm in PsA-HT versus 0.61 mm in C-NT). PsA-HT displayed higher M-Max (0.95 mm) versus both C-HT (0.71 mm) and PsA-NT (0.79 mm). FMD was impaired in PsA subjects compared with C-NT (5.7% in PsA-NT and 6.0% PsA-HT versus 9.3% in C-NT), whereas there was no difference among PsA-HT, PsA-NT, and C-HT groups. Values of carotid IMT were directly related to tumor necrosis factor (TNF)-α, osteoprotegerin (OPG), blood pressure and lipid profile levels. FMD showed an inverse relationship with TNF-α and blood pressure, but no correlation with lipids. In conclusion, PsA per se implies a pro-atherogenic remodeling, which is enhanced by the hypertensive status. TNF-α and OPG may have an independent role in the development of such vascular damage.

Molecular mechanisms of pain in crystal-induced arthritis

Crystal-induced arthritis (CIA) is characterized by an intense inflammatory reaction triggered by the deposition of monosodium urate, calcium pyrophosphate, and basic calcium phosphate crystals in articular and periarticular tissues. Severe, acute pain constitutes the most important clinical symptom in patients affected by these diseases. Pain along with redness, warmness, swelling, and stiffness in the affected joint arises abruptly in gout and disappears when the acute phase of the attack resolves. While an acute joint attack caused by calcium pyrophosphate crystals can mimic a gout flare, basic calcium phosphate crystal arthritis gives rise to a series of clinical manifestations, the most severe of which are calcific periarthritis, mostly asymptomatic, and a highly destructive arthritis known as Milwaukee shoulder syndrome, which is characterized by painful articular attacks. Pain development in CIA is mediated by several inflammatory substances that are formed after cell injury by crystals. The most important of these molecules, which exert their effects through different receptor subtypes present in both peripheral sensory neurons and the spinal cord, are prostaglandins, bradykinin, cytokines (in particular, interleukin (IL)-1β), and substance P. The pharmacological treatment of pain in CIA is strictly associated with the treatment of acute phases and flares of the disease, during which crystals trigger the inflammatory response. According to international guidelines, colchicines, nonsteroidal anti-inflammatory drugs, and/or corticosteroids are first-line agents for the systemic treatment of acute CIA, while biologics, namely anti-IL-1β agents, should be used only in particularly refractory cases.

Infection relapse in spondyloarthritis treated with biological drugs: a single-centre study

There is evidence from randomized controlled trials (1) as well as from observational studies (2) that there are more infections in patients treated with anti-tumour necrosis factor (TNF)-α agents. We studied the frequency of infectious events (IEs) and infection relapse (IR) in 225 patients (70.6% males) with spondyloarthritis (SpA), 56.0% with psoriatic arthritis (PsA) and 44.0% with ankylosing spondylitis (AS) (age 49.4 11.3 years, disease duration 13.2 8.4 years), receiving anti-TNF-α treatment and attending the Rheumatology Outpatient Clinic of Padova University (2004–2010). They were classified as: patients who developed IEs, patients who did not (no-IE), and patients who presented with IR. χ and Fischer’s exact tests for non-continuous variables and the t-test for continuous variables were used for statistical analysis. The mean duration of therapy was 30.6 20.9 months; 39.4 19.0 months for infliximab (I), 33.4 26.7 months for etanercept (E), and 19.0 19.0 months for adalimumab (A). Of the total, 31.8% were treated with I, 38.2% with E, 29% with A, another 23.5% were also on concomitant disease-modifying antirheumatic drug (DMARD) therapy, and 1.7%were taking steroids (methylprednisolone 4 mg). The disease activity scores were 53.3 23.2 for the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and 3.5 1.3 for the 28-joint Disease Activity Score (DAS28) and 35% had comorbidities (Table 1). Forty-six IEs were recorded (the IE onset time was 25.5 18.3 months (Figure 1), the infection rate was 3.93 per 100 patientyears. Of the total, 13.3% developed IE and 86.7% did not. When the two groups were compared there were no significant differences in: age, sex, disease duration, therapy duration, anti-TNF-α agents, disease activity, comorbidities, and concomitant therapy. These results partially confirm data from a study by Galloway et al, who performed a prospective observational study and compared the risk of infections in rheumatoid arthritis (RA) patients taking anti-TNF-α agents and/or DMARDs (3). They reported that the risk of infection did not differ in the patients treated with different anti-TNF-α and there was no difference in the relative risk of infection in the older members of the population. Furthermore, they reported that the risk of IEs was higher during the first 6 months of treatment whereas in our observational study the mean IE onset time was 25.5 months. With regard to concomitant therapy, we did not find any significant difference between the patients treated with DMARDs/steroids and those who were not. In a retrospective study on the use of

Lengthening the time intervals between doses of biological agents in psoriatic arthritis patients: A single-center retrospective study.

Anti-tumor necrosis factor (TNF) alpha therapy has changed the course of psoriatic arthritis (PsA), but clinical experience about lengthening of time intervals between drug administrations is still limited. The aims of the study were to evaluate: (1) the long-term efficacy (over a 4-year period) of etanercept/adalimumab in a subset of PsA patients who did not require switches; and (2) the progressive lengthening of time intervals between treatments in patients who achieved minimal disease activity (MDA). PsA outpatients attending the Rheumatology Clinic-University of Padova who took a single anti-TNF agent (etanercept/adalimumab) for a 4-year period were studied. Therapy efficacy was assessed using clinical, biochemical, and disease activity (DA) indexes. The intervals between treatments were empirically and progressively lengthened after MDA was reached and maintained. One hundred and forty-one patients (mean age, 51.22 ± 12.34 years; mean disease duration, 12.1 ± 8.42 years) treated with etanercept/adalimumab (47.5% and 52.5%, respectively) were studied. DA indexes showed a marked, persistent improvement in all the patients throughout 4 years. The interval between injections could be extended in 46.1% of the patients (35% for adalimumab, 58% for etanercept) without provoking relapses. The mean therapy interval at the end of the study period was 3.12 weeks for adalimumab 40 mg (with respect to 2 weeks) and 2.75 weeks for etanercept 25 mg (with respect to 0.5 weeks). The new therapy timetable also led to cost savings. In conclusion, lengthening the time intervals between injections of anti-TNF agents in PsA patients who reach MDA is safe, effective, cost-effective, and facilitates patient compliance.

The controversial relationship between osteoarthritis and osteoporosis: an update on hand subtypes

To compare hand osteoarthritis (HOA) subtypes and to examine possible links with local bone mineral density (BMD).

FRI0319 Levels of IL-1β and MMP-3 are increased in the synovial fluid from knee osteoarthritis (OA) in patients with concomitant erosive hand OA

Background Erosive osteoarthritis of the hand (EHOA) is believed to be a subset of HOA targeting interphalangeal (IP) joints and characterised by an abrupt onset, marked pain and functional impairment, inflammatory symptoms and signs, and a worse outcome than non-erosive HOA. Despite these characteristic features, it is still unclear if erosions are found only in predisposed patients or are a consequence of an inflammatory phase occurring in any patient with HOA. Some studies suggest that patients with EHOA share HLA or non-HLA genetic predisposition, in particular associated with a genomic region containing the interleukin (IL)-1β 5810 single nucleotide polymorphism. This would support the hypothesis the IL-1 has a role in the pathogenesis of this severe phenotype of HOA. Objectives This study was designed to assess the hypothesis that patients with EHOA share a different phenotype from those with non-EHOA. Thus, we investigated if synovial fluid (SF) levels of proinflammatory interleukin (IL)s and metalloproteinase (MMP)-3 from patients with knee OA presenting a concomitant EHOA were different from those with non-EHOA. Methods In consecutive patients with knee effusions due to OA (ACR criteria), SF was aspirated and subsequently analysed for the presence of crystals and leukocyte (WBC) counts; the remaining SF was stored at -80°C. Patients with crystals of any type and with other concomitant known arthropathies were excluded from the study. Thus, a total of 100 patients were enrolled and underwent hand X-rays which were subsequently examined for the presence of subchondral erosions in the interphalangeal joints. In all SF from patients with erosions of the hand and in 20 consecutive patients without erosions, levels of IL-1β, IL-6, IL-8 and MMP-3 were determined. Statistical analysis was performed with the Mann- Whitney nonparametric test and the Spearman test for correlations. Results Sixteen out of 100 patients (16%, 11 females, mean age 61.69±7.14), with knee OA had at least one erosion according to X-rays. Serum MMP- 3 levels were higher in EHOA patients with respect to non-EHOA (15.63±3.46 ng/ml vs 10.81±1.71 ng/ml) and the MMP-3 levels were correlated with disease duration (p<0.05; r=0.38) only in the EHOA patients. Significant correlation was found in cytokine levels, particularly in IL-1β (p<0.0001; r=0.91), IL-6 (p<0.05; r=0.53), MMP-3 (p=0.0006; r=0.76) in EHOA patients Conclusions High levels of cytokines, only in Knee OA patients with EHOA, could suggest that this particular form of OA have a genetic predisposition for the disease and these patients may present a more severe form of general OA Disclosure of Interest None Declared