Augusta Ortolan

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 in psoriatic arthritis: promising tools

The aim of this study was to identify specific biomarkers that could be used to screen for psoriatic arthritis (PsA), as well as to assess disease activity and treatment outcome in affected patients. Forty-three outpatients considered eligible for anti-TNF-α treatment (etanercept 50 mg/week) were enrolled. Serum samples of vascular endothelial growth factor (VEGF), metalloproteinase-3 (MMP3), pentraxin 3 (PTX3), and high-sensitive C-reactive protein (hs-CRP) were collected at baseline (t0) and after 6 (t6), 12 (t12), and 24 months (t24) of treatment. Baseline values were compared with those of a group of healthy controls matched for age and sex. Disease activity scores and functional tests (DAS28, BASDAI, PASI, BASFI, HAQ, VAS pain, and VAS patient global disease activity) after treatment were found to be significantly different from baseline values. At baseline, MMP3, hs-CRP and VEGF values in the PsA-patients were found to be significantly higher with respect to levels in the controls. There were no differences in the PTX3 values. MMP3 was significantly lower at t6 (P < 0.0001), t12 (P < 0.0001) and t24 (P < 0.0001). hs-CRP and VEGF were significantly lower, respectively, at t12 (P < 0.01; P < 0.05) and t24 (P < 0.05; P < 0.01). PTX3 was significantly higher at t24 (P < 0.05). A correlation was found between MMP3 and hs-CRP (r = 0.45, P = 0.0005). MMP3, hs-CRP, and VEGF appear to be useful for the early detection of PsA and to monitor disease progression. The rise in PTX3 did not appear to be linked to the inflammatory state of the disease but might be an expression of the atherosclerotic process frequently observed in PsA.

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.

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.

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).

Spine and sacroiliac joints on magnetic resonance imaging in patients with early axial spondyloarthritis: prevalence of lesions and association with clinical and disease activity indices from the Italian group of the SPACE study

Our aim was to determine the prevalence of spine and sacroiliac joint (SIJ) lesions on magnetic resonance imaging (MRI) in patients with early axial spondyloarthritis (axSpA) and their correlation with disease activity indices. Sixty patients with low back pain (LBP) (≥3 months, ≤2 years, onset ≤45 years), attending the SpA-clinic of the Unità Operativa Complessa Reumatologia of Padova [SpondyloArthritis-Caught-Early (SPACE) study], were studied following a protocol including physical examination, questionnaires, laboratory tests, X-rays and spine and SIJ MRI. Positive spine and SIJ MRI and X-rays images were scored independently by 2 readers using the SPARCC method, modified Stoke ankylosing spondylitis spine score and New York criteria. The axial pain and localization of MRI-lesions were referred to 4 sites: cervical/thoracic/lumbar spine and SIJ. All patients were classified into three groups: patients with signs of radiographic sacroiliitis (r-axSpA), patients without signs of r-axSpA but with signs of sacroiliitis on MRI (nr-axSpA MRI SIJ+), patients without signs of sacroiliitis on MRI and X-rays (nr-axSpA MRI SIJ-). The median age at LBP onset was 29.05±8.38 years; 51.6% of patients showed bone marrow edema (BME) in spine-MRI and 56.7% of patients in SIJ-MRI. Signs of enthesitis were found in 55% of patients in the thoracic district. Of the 55% of patients with BME on spine-MRI, 15% presented presented a negative SIJMRI. There was a significant difference between these cohorts with regard to the prevalence of radiographic sacroiliitis, active sacroiliitis on MRI and SPARCC SIJ score. The site of pain correlated statistically with BME lesions in thoracic and buttock districts. Since positive spine-MRI images were observed in absence of sacroiliitis, we can hypothesize that this finding could have a diagnostic significance in axSpA suspected axSpA.

Pain and microcrystalline arthritis

Microcrystals are responsible for some of the most common and complex arthropathies which are often accompanied by intense, severe pain and inflammatory reactions. The main pathogens are crystals of monosodium urate (MSU), responsible for the gout, calcium pyrophosphate (CPP), which deposits also in various clinical forms of arthopathies, and basic calcium phosphate associated with osteoarthritis. In this context, the microcrystal arthritis is characterized by multiple, acute attacks followed by chronic pain, disability, impaired quality of life, and increased mortality. Given their chronic nature, they represent an ever more urgent public health problem. MSU and CPP crystals are also able to activate nociceptors. The pain in mycrocrystalline arthritis (MCA) is an expression of the inflammatory process. In the course of these diseases there is an abundant release of inflammatory molecules, including prostaglandins 2 and kinins. Interleukin-1 represents the most important cytokine released during the crystal-induced inflammatory process. Therefore, clinically, pain is the most important component of MCA, which lead to functional impairment and disability in a large proportion of the population. It is fundamental to diagnose these diseases as early as possible, and to this aim, to identify appropriate and specific targets for a timely therapeutic intervention.

Biomarkers, imaging and disease activity indices in patients with early axial spondyloarthritis: the Italian arm of the SpondyloArthritis-Caught-Early (SPACE) Study

The study aimed to evaluate biomarkers facilitating early diagnosis of axial spondyloarthritis (axSpA) and correlations between them and disease activity parameters and imaging indexes. Patients with low back pain (LBP) (≥3 months, ≤2 years, onset ≤45 years) participating in the Italian arm of the SpondyloArthritis-Caught-Early SPACE study underwent a physical examination, questionnaires, laboratory tests, X-rays and MRI of the spine and sacroiliac joints (SIJ). An expert rheumatologist formulated axSpA diagnosis in accordance with Assessment of SpondyloArthritis International Society (ASAS) criteria. Disease activity and physical functioning were assessed using imaging, clinical and serological indices. Spine and SIJ MRI and X-rays were scored independently by 2 readers using the SPARCC, mSASSS and NY-criteria. Patients were classified as: subjects with signs of radiographic sacroiliitis (r-axSpA), subjects with signs of sacroiliitis on SIJ-MRI but not on X-rays (nr-axSpA MRI SIJ+) or subjects with no signs of sacroiliitis on MRI/X-rays but with >2 SpA features and signs of bone oedema on MRI spine (nr-axSpA MRI SIJ-/undifferentiated SpA). Significant differences were found in the prevalence of radiographic sacroiliitis, active sacroiliitis on MRI and SPARCC SIJ scores. Biomarker levels were not significantly increased in any of the patient groups. The correlations between IL-17 and IL-23 and other indices were not significant; correlations were found between IL-22 and BASFI, BASG1, HAQ, VAS pain, between mSASSS and MMP3, and between the latter and hsCRP. Although not significantly higher in any of the three groups, IL-22, MMP3 and hsCRP values were correlated with some disease activity indexes and with mSASSS. Large observational studies are required to confirm these preliminary findings.