Non-Pharmacological Interventions for Treating Psoriatic Arthritis.

Background and Objective: In this review, we discuss evidence concerning the management of psoriatic arthritis (PsA) patients with non-pharmacological interventions and additionally develop physical training protocols that could be prescribed to these patients. Methods: We selected 110 articles, published on PubMed and Google Scholar databases from 1972 to date, investigating the effects of generic hygienic-dietary recommendations and training programs in PsA or psoriasis (PSO) individuals. Results: Although data in support are limited, aerobic, endurance, and strength exercises as well as complementary techniques may all be useful in preserving or improving residual functional capacity, joint flexibility, and muscle strength. Exercise may reduce systemic inflammation, pain, and fatigue and additionally control PsA comorbidities, like dysmetabolism or obesity. Conclusions: The polyhedral clinical expression of PsA underlines the need for a multidisciplinary approach combining the synergistic effects of pharmacological and non-pharmacological treatments. The latter range from preventive measures, like dietary modifications, weight loss, and cigarette smoking cessation, to personalized training protocols according to disease activity and phenotype, comorbidities, and individual tolerability. In these patients, we strongly encourage the regular practice of motor activity at progressively increasing intensity with combined supervised aerobic, strength, endurance, and stretching exercises.

Interaction between Long Noncoding RNAs and Syncytin-1/Syncytin-2 Genes and Transcripts: How Noncoding RNAs May Affect Pregnancy in Patients with Systemic Lupus Erythematosus.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) often suffer from obstetric complications not necessarily associated with the antiphospholipid syndrome. These events may potentially result from the reduced placental synthesis of the fusogenic proteins syncytin-1 and syncytin-2, observed in women with pregnancy-related disorders. SLE patients have an aberrant noncoding (nc)RNA signature that may in turn dysregulate the expression of syncytin-1 and syncytin-2 during placentation. The aim of this research is to computationally evaluate and characterize the interaction between syncytin-1 and syncytin-2 genes and human ncRNAs and to discuss the potential implications for SLE pregnancy adverse outcomes. METHODS: The FASTA sequences of the syncytin-1 and syncytin-2 genes were used as inputs to the Ensembl.org library to find any alignments with human ncRNA genes and their transcripts, which were characterized for their tissue expression, regulatory activity on adjacent genes, biological pathways, and potential association with human disease. RESULTS: BLASTN analysis revealed a total of 100 hits with human long ncRNAs (lncRNAs) for the syncytin-1 and syncytin-2 genes, with median alignment scores of 151 and 66.7, respectively. Only lncRNAs TP53TG1, TTTY14, and ENSG00000273328 were reported to be expressed in placental tissue. Dysregulated expression of lncRNAs TP53TG1, LINC01239, and LINC01320 found in this analysis has previously been described in SLE patients as well as in women with a high-risk pregnancy. In addition, some of the genes adjacent to lncRNAs aligned with syncytin-1 or syncytin-2 in a regulatory region might increase the risk of pregnancy complications or SLE. CONCLUSIONS: This is the first computational study showing alignments between syncytin-1 and syncytin-2 genes and human lncRNAs. Whether this mechanism affects syncytiotrophoblast morphogenesis in SLE females is unknown and requires further investigation.

Prevalence of hepatitis B virus infection and risk of reactivation in rheumatic population undergoing biological therapy.

OBJECTIVES: Hepatitis B (HBV) is a common comorbidity among rheumatic patients. The prevalence of HBV infection and the rate of reactivation remain unclear. The literature data suggested a higher risk in chronic than in past infection. Currently, the literature data are mostly focused on anti-TNF and rituximab. This retrospective observational study aimed to analyse the prevalence of HBV infection and the risk of viral reactivation in a population of rheumatic patients undergoing anti-TNF and non-anti-TNF agents. METHODS: We analysed 1216 rheumatic patients, treated with both csDMARDs and bDMARDs between 2006 and 2017. Serologic markers for HBV (HBsAg, anti-HBs, anti-HBc) were performed prior and during biologic treatment. Patients with chronic or resolved infection were monitored every 3 months. RESULTS: The prevalence of HBV in our cohort was 15.7% (chronic infection: 0.4%, resolved infection: 12.6%, anti-HBc positivity alone: 2.6%). 12 (6.2%) out of 191 HBV infected patients experienced a reactivation. All of them showed markers of past infection. One patient experienced HBV reactivation despite lamivudine. Only one patient experienced acute hepatitis, probably due to the interruption of immunosuppressors in anticipation of surgery, not preceded by any HBV prophylactic treatment. CONCLUSIONS: HBV reactivation is a rare event in patients treated with a bDMARD and it can also occur while taking lamivudine, not only in chronic carriers (as per the literature data) but also in inactive ones. Regular screening followed by prompt treatment can prevent symptoms or complications. Due to the risk of hepatitis following the immune reconstitution, an antiviral therapy should be considered in the case of sudden discontinuation of csDMARDs or bDMARD.

Efficacy and Safety of Biosimilar and Originator Etanercept in Rheumatoid Arthritis Patients: Real-Life Data.

BACKGROUND: There is a lack of real-life clinical data for biosimilar etanercept, an anti-TNF blocking fusion protein. We describe the comparable efficacy and safety of originator and biosimilar etanercept in rheumatoid arthritis (RA) patients in a real-life clinical setting. Our data confirm that a biosimilar etanercept can be safely used as first-line treatment as well as in patients switched from a previous originator compound. OBJECTIVES: To compare the efficacy and safety of originator and biosimilar etanercept in a cohort of RA patients attending two Italian hospitals. METHODS: The study involved 81 consecutive adult RA patients treated for at least 6 months with originator or biosimilar etanercept and considered their clinical and laboratory data, concomitant medications, and adverse events at baseline, and after 3 and 6 months of treatment. RESULTS: Group 1 included 51 patients taking originator etanercept; group 2 included 30 taking biosimilar etanercept, including 19 who had been switched from the reference product. Despite a significant baseline difference in clinical disease activity, one-way analysis of variance showed that the two groups were clinically comparable after 6 months of treatment, and the same was true when only those receiving etanercept as first-line biological treatment were considered. Nine patients discontinued the treatment due to inefficacy or adverse events, which were never serious and were only reported in group 1. CONCLUSIONS: The efficacy and safety profiles of originator and biosimilar etanercept are comparable in RA patients in a real-life clinical setting. Further studies are needed to confirm these preliminary findings.

Systemic sclerosis Progression INvestiGation (SPRING) Italian registry: demographic and clinico-serological features of the scleroderma spectrum.

OBJECTIVES: Systemic sclerosis (SSc) is a severe multiple-organ disease characterised by unpredictable clinical course, inadequate response to treatment, and poor prognosis. National SSc registries may provide large and representative patients cohorts required for descriptive and prognostic studies. Therefore, the Italian Society for Rheumatology promoted the registry SPRING (Systemic sclerosis Progression INvestiGation). METHODS: The SPRING is a multi-centre rheumatological cohort study encompassing the wide scleroderma spectrum, namely the primary Raynaud's phenomenon (pRP), suspected secondary RP, Very Early Diagnosis of Systemic Sclerosis (VEDOSS), and definite SSc. Here we describe the demographic and clinical characteristics of a population of 2,028 Italian patients at the initial phase of enrolment, mainly focusing on the cohort of 1,538 patients with definite SSc. RESULTS: Definite SSc showed a significantly higher prevalence of digital ulcers, capillaroscopic 'late' pattern, oesophageal and cardio-pulmonary involvement compared to VEDOSS, as expected on the basis of the followed classification criteria. The in-depth analysis of definite SSc revealed that male gender, diffuse cutaneous subset, and anti-Scl70 seropositivity were significantly associated with increased prevalence of the most harmful disease manifestations. Similarly, patients with very short RP duration (≤1 year) at SSc diagnosis showed a statistically increased prevalence of unfavourable clinico-serological features. CONCLUSIONS: Nationwide registries with suitable subsetting of patients and follow-up studies since the prodromal phase of the disease may give us valuable insights into the SSc natural history and main prognostic factors.

Calcium physiology, metabolism and supplementation: a glance at patients with ankylosing spondylitis.

The aim of this review is to describe the metabolism of calcium in ankylosing spondylitis compared to physiologic conditions, and to present the current evidence on the benefits and disadvantages of calcium supplementation in these patients. A narrative review of the literature was conducted using the PubMed database and a total of 65 articles were selected. Calcium is involved in many physiopathological processes, including inflammation, bone loss and bone formation, all of which occur in ankylosing spondylitis. Many ankylosing spondylitis patients suffer from concomitant osteopenia or osteoporosis, which represent indications for calcium supplementation. Conversely, there are still concerns about the use of calcium salts for the prevention of bone fragility in non-osteoporotic or non-osteopenic patients. In these cases, biologic agents may indirectly normalize calcium dysmetabolism by rebalancing the cytokine milieu, in turn associated with bone remodeling. Calcium supplements may be disadvantageous for entheseal calcifications, but so far there are no clear data confirming that such an association exists.

Psoriatic arthritis: From pathogenesis to pharmacologic management.

The pathogenesis of psoriatic arthritis (PSA) is still a matter of debate. A favourable genetic background is interwoven with environmental triggering factors in a complex network. Shared antigens and the recirculation of immune cells may account for the clinical manifestations, involving both cutaneous and articular sites. A favourable genetic background has been demonstrated in many genomic and proteomic studies, being associated to polymorphic variants of the genes coding for Major Histocompatibility Complex I and cytokine pathways. In genetic-predisposed individuals, triggering factors, like infections, dysbiosis or mechanic stress may promote the development of the disease. The subsequent activation of the innate and adaptive immune system, following the stimulation of Toll-like Receptors, culminates in the expansion of dendritic cells, macrophages, CD4+ and CD8+ T cells, neutrophils, monocytes, Natural Killer lymphocytes and other cells with the final inflammation and damage of skin, joint and enthesis. Particularly, the activation of CD4+ T helper 17 lymphocytes represents a crucial point in the pathogenesis of the disease. The participation of the visceral adipose tissue may amplify the inflammatory process by means of the synthesis of pro-inflammatory adipokines. Current therapeutic algorithms address the variety of clinical manifestations with a tailored strategy aiming to achieve the best control of the symptoms with minimal side effects. Conventional immunosuppressive drugs, biologic agents and synthetic small molecules offer different attack routes and may be chosen individually or in combination according to the phenotype of the disease.

Hyperbaric oxygen treatment of fibromyalgia: a prospective observational clinical study.

OBJECTIVES: Fibromyalgia (FM) is a syndrome of unknown aetiology that is characterised by widespread musculoskeletal pain, fatigue and disordered sleep, and often associated with neuropsychiatric and cognitive symptoms. Current treatment options are only partially effective, but hyperbaric oxygen therapy (HBOT) seems to be capable of relieving some of the symptoms. The aim of this study was to evaluate the efficacy and safety of HBOT after fewer sessions than generally used, chosen on the basis of pre-clinical and clinical data showing its rapid and sustained antinociceptive effect. METHODS: Patients with FM underwent HBOT (100% oxygen at 2.5 ata with air breaks) administered on three days per week for a total of twenty 90-minute sessions. Pain, fatigue, the quality of sleep, symptoms of anxiety and depression, and the patients' health-related quality of life were prospectively assessed before and after ten and twenty sessions. RESULTS: Twenty-eight of the 32 study patients completed the 20 HBOT sessions. Pain scores and the symptoms of anxiety (but not those of depression) significantly improved after both 10 and 20 sessions, whereas fatigue and FM symptom severity scores significantly improved only after 20 sessions. There was no significant change in the quality of sleep. The adverse effects were limited. CONCLUSIONS: These findings support the view that HBOT is an effective, rapid and safe means of treating various symptoms of FM.

One year in review 2019: fibromyalgia.

Fibromyalgia is characterised by chronic pain, fatigue and functional symptoms. Its aetiopathogenesis is still a matter of debate, but various pharmacological and non-pharmacological therapies are currently available for its treatment. We review the literature concerning the most recent findings related to the aetiopathogenesis, diagnosis, clinical aspects and treatment of FM published between January 2018 and January 2019.

Evaluation of salivary and plasma microRNA expression in patients with Sjögren's syndrome, and correlations with clinical and ultrasonographic outcomes.

OBJECTIVES: To correlate the expression of microRNAs (miRNAs) 146a/b, 16, the 17-92 cluster and 181a in salivary and plasma samples taken from primary Sjögren's syndrome (pSS) patients with clinical, laboratory and ultrasound findings. METHODS: Plasma and salivary samples were collected from 28 patients with pSS according to 2012 ACR and/or 2016 ACR/EULAR criteria (27 females, mean age 64.4±10.1 years, mean disease duration 10.7±6.9 years), and from 23 healthy subjects used as controls. The following patient data were recorded: ESSDAI and ESSPRI scores, anti-SSA and anti-SSB antibody status and laboratory data, Schirmer's test, ultrasound scores of the four major salivary glands according to Cornec et al., and concomitant treatments. The retro-transcribed and quantified miRNAs were: miR16-5p, miR17-5p, miR18a-5p, miR19a-5p, miR19b-1-5p, miR20a, miR92-5p, miR146a-5p, miR146b-5p, miR181a-5p. RESULTS: SS patients had higher expression of salivary miR146a than gender- and age-matched controls (p=0.01). Spearman's regression analysis revealed that salivary miR146b was significantly more expressed in the patients with worse ESSPRI scores (p=0.02), whereas salivary miR17 and 146b and plasma miR17 expression was lower in the patients with higher ultrasound scores (respectively p=0.01, p=0.01 and p=0.04). Salivary miR18a expression was significantly increased in the patients who were anti-La/SSB positive (p=0.04). Neither salivary nor plasma miRNAs correlated with disease duration or concomitant therapies. CONCLUSIONS: Our data show that salivary mi146a may represent a marker of the disease, and that the expression of salivary miR17, 18a and 146b may be altered in patients with pSS, and associated with worse ultrasound and ESSPRI scores and anti-La/SSB positivity.

Earthquake vulnerability of fibromyalgia patients: six-month follow-up after the catastrophic disasters in central Italy.

OBJECTIVES: To investigate the 6-month impact of the catastrophic earthquakes that struck central Italy in August and October 2016 on the health-related quality of life (HRQoL) of patients with fibromyalgia (FM). METHODS: We compared a cohort of 55 consecutive FM patients who had been exposed to an earthquake with a control group of 49 FM patients who had not been exposed to it. At each time-point (baseline, and after one, two, four and six months), the patients completed self-reported electronic versions of the revised Fibromyalgia Impact Questionnaire (FIQR) and the Fibromyalgia Activity Score (FAS) on a web platform. RESULTS: At baseline, there were no significant between-group differences in the total FIQR score or the scores of its three domains of function, overall impact and symptoms, and no significant differences in the total FAS score or the FAS fatigue, quality of sleep, and Self-Assessment Pain Scale (SAPS) scores. However, after six months of observation, the median total FIQR score was higher in the earthquake-exposed patients (241.00, 95% confidence interval [CI] 230.55-255.35) than in the unexposed patients (177.50, 95% CI 157.30-185.48; p<0.0001), and the same was true of the median total FAS score (26.86, 95% CI 25.78-28.18 vs. 22.76, 95% CI 20.92-24.34; p<0.0001). Moreover, there were also significant differences in all of the FIQR and FAS domain scores. CONCLUSIONS: A natural catastrophe such as an earthquake can have a significant impact on the major domains of pain, fatigue, sleep, and the overall quality of life of FM patients.

One year in review 2017: fibromyalgia.

Fibromyalgia (FM) is a complex syndrome characterised by chronic pain, fatigue and functional symptoms. Widespread pain is often its most typical feature, whereas other manifestations may be associated to various extents. Its aetiopathogenesis is still a matter of debate, but various pharmacological and non-pharmacological therapies are currently available for its treatment. We review the literature concerning the most recent findings relating to the aetiopathogenesis, assessment and treatment of FM published between January 2016 and January 2017.

Motor cortex tRNS improves pain, affective and cognitive impairment in patients with fibromyalgia: preliminary results of a randomised sham-controlled trial.

OBJECTIVES: Fibromyalgia (FM) is a clinical syndrome characterised by widespread musculoskeletal pain, chronic fatigue, cognitive deficits, and sleep and mood disorders. The effectiveness of most pharmacological treatments is limited, and there is a need for new, effective and well-tolerated therapies. It has recently been shown that transcranial direct-current stimulation (tDCS) of the motor cortex reduces pain, and that tDCS of the dorso-lateral prefrontal cortex (DLPFC) improves anxiety, depression and cognitive impairment in FM patients. The new technique of transcranial random noise stimulation (tRNS) using randomly changing alternating currents has very recently been shown to improve working memory and pain in limited series of patients with FM or neuropathic pain. The aim of this study was to investigate the clinical effects of primary motor cortex (M1) tRNS in FM patients. METHODS: Twenty female FM patients aged 26-67 years were randomised to undergo active (real) or placebo (sham) tRNS sessions on five days a week (Monday-Friday) for two weeks. Each patient was evaluated before and after treatment using a visual analogue scale (VAS), the Fibromyalgia Impact Questionnaire (FIQ), the Hospital Anxiety and Depression Scale (HADS), the Trail Making Test (TMT), the Rey Auditory Verbal Learning Test (RAVLT), the Forward and Backward Digit Span test, and the FAS verbal fluency test. RESULTS: In comparison with sham treatment, active tRNS of M1 induced a general improvement in the clinical picture of FM, with a significant reduction in pain, depression, anxiety and FIQ scores and a significant improvement in TMT (A), RAVLT and FAS scores. CONCLUSIONS: These findings suggest that tRNS of M1 can be very effective in relieving FM symptoms. Unlike motor cortex tDCS, it seems to counteract both pain and cognitive disturbances, possibly because the invoked mechanism of stochastic resonance synchronises neural firing and thus leads to more widespread and lasting effects.

The influence of fibromyalgia on achieving remission in patients with long-standing rheumatoid arthritis.

To investigate the influence of fibromyalgia (FM) on achieving remission defined on the basis of the Simplified Disease Activity Index (SDAI) remission criteria in patients with long-standing rheumatoid arthritis (RA). This observational longitudinal cohort consisted of long-standing RA patients being treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or biological DMARDs (bDMARDs). After 6 months of follow-up, the patients fulfilling or not fulfilling the remission criteria were identified and compared with each other in terms of the presence of FM, neuropathic pain, and other comorbidities. At the end of the 6-month observation period, 24 of the 117 patients (20.4%) met the SDAI remission criteria. Logistic regression analysis showed that the modified Rheumatic Disease Comorbidity Index (mRDCI) (p = 0.0001), the FM presence (p = 0.0001), and the 36-item short-form health survey Mental Component Summary (SF-36 MCS) Score (p = 0.0088) were the strongest predictors of not being in SDAI remission. None of the patients with concomitant FM (17.1%) achieved SDAI remission. In comparison with the non-FM patients, the patients with RA and FM patients had worse scores on the SF-36 MCS (p = 0.011), on the sleep Visual Analogue Scale (VAS) (p = 0.018), on the self-counts of tender joints (p = 0.039), and on the PainDetect Questionnaire (PDQ) (p = 0.001). To avoid over treatment, an assessment of FM should be considered in RA patients who do not fulfil the remission criteria.

Biomarkers in Rheumatoid Arthritis.

BACKGROUND: Biomarkers are important for guiding the clinical and therapeutic management of all phases of rheumatoid arthritis because they can help to predict disease development in subjects at risk, improve diagnosis by closing the serological gap, provide prognostic information that is useful for making therapeutic choices and assessing treatment responses and outcomes, and allow disease activity and progression to be monitored. Various biomarkers can be used to identify subjects susceptible to the disease and those with pre-clinical rheumatoid arthritis before the onset of symptoms such as rheumatoid factor and anti-citrullinated protein antibodies. They can be correlated with a risk of developing rheumatoid arthritis and can predict more bone erosions and severe disease progression. Biomarkers such as the erythrocyte sedimentation rate and C-reactive protein levels provide information about disease activity, while predictive biomarkers allow clinicians to assess the probability of a treatment response before starting a particular therapy particularly in the era of biological drugs. This move from traditional approaches to patient stratification and targeted treatment should greatly improve patient care and reduce medical costs.

The Immunogenicity of Branded and Biosimilar Infliximab in Rheumatoid Arthritis According to Th9-Related Responses.

Our objective was to evaluate the immunogenicity of branded and biosimilar infliximab by detecting changes in T-helper-9 (Th9) percentages induced by an in vitro stimulation test. METHODS: Peripheral blood mononuclear cells collected from 55 consecutive rheumatoid arthritis (RA) outpatients (15 drug free, 20 successfully treated with branded infliximab, 20 branded infliximab inadequate responders) and 10 healthy controls were cultured, with or without 50 µg/mL of infliximab originator (Remicade®) or 50 µg/mL of infliximab biosimilar (Remsima®) for 18 h. Th9 lymphocytes were identified by means of flow cytometry as PU.1 and IRF4-expressing, IL-9-secreting CD4⁺ T cells. Furthermore, the markers CCR7 and CD45RA were used to distinguish naïve from memory IL-9 producer cells. RESULTS: Under unstimulated conditions, the drug-free RA patients had the highest percentages of Th9 lymphocytes. Following stimulation with branded infliximab, the percentages of PU.1 and IRF4-expressing Th9 cells, CCR7⁺, CD45RA- (central memory) and CCR7-, CD45RA- (effector memory) cells significantly increased in the group of inadequate responders, but no significant variation was observed after exposure to the biosimilar of infliximab. CONCLUSIONS: Th9 cells seem to be involved in the immune response to the epitopes of branded, but not biosimilar, infliximab, and this may depend on the recall and stimulation of both central and effector memory cells.

Infections and Biological Therapy in Patients with Rheumatic Diseases.

Long-term extension studies and observational drug registers have revealed an increased risk of serious infections in patients treated with anti-tumor necrosis factor agents, particularly infliximab, etanercept and adalimumab. The same may be true for the newer biological drugs rituximab, tocilizumab and abatacept, although this has yet to be confirmed by long-term observational studies. We review the risk of tuberculosis, herpes zoster and other opportunistic infections, and the recommendations for screening for tuberculosis and hepatitis B and C infections in patients with rheumatoid arthritis, with the aim of informing patients and encouraging greater awareness among physicians.

Paradoxical Expansion of Th1 and Th17 Lymphocytes in Rheumatoid Arthritis Following Infliximab Treatment: a Possible Explanation for a Lack of Clinical Response.

PURPOSE: The immunogenicity of anti-TNF-α drugs may affect their safety and efficacy. Infliximab (IFX), a chimeric monoclonal antibody, induces antibody formation in up to 60% of cases. Some studies have suggested the involvement of a Th1 response to TNFα blockers following immunization, but the triggering of Th17 responses has never been reported. The aim of this study is to investigate whether the immunogenicity of IFX affects the Th1, Th17 and Treg compartments in rheumatoid arthritis (RA) patients failing IFX therapy, and verify whether this may be responsible for treatment failure. METHODS: The study involved 55 patients with RA (15 treatment-naïve patients; 20 IFX responders; 20 IFX non-responders) and 10 healthy controls. PBMCs were cultured in the presence/absence of IFX, and the variations in the percentage of Th1, Th17 and Treg lymphocytes following IFX treatment were analysed. RESULTS: IFX-specific Th1 and Th17 responses and an increase in IL-21 production were observed in patients failing IFX (p < 0.01, p < 0.05, and p < 0.01 respectively). In contrast, IFX incubation reduced significantly Th1 and Th17 responses and IL-21 production (p < 0.05) in successfully-treated subjects, but did not affect these responses in healthy controls or treatment-naïve patients. CONCLUSIONS: RA patients may have impaired peripheral tolerance, which could favour the development of an aberrant immunological response to biological drugs. The loss of therapeutic effectiveness of IFX and the onset of adverse events may be due to a paradoxical activation of Th17 or Th1 lymphocytes following sensitisation, thus worsening the patients' inflammatory status.

Algo-dysfunctional syndromes: a critical digest of the recent literature.

The etiopathogenesis of the algo-dysfunctional syndromes, which include chronic fatigue syndrome, fibromyalgia and irritable bowel syndrome, is still debated, but it is widely accepted that it is best described by a multifactorial model that include genes, environmental factors such as external infections, inflammation, dietary habits, impaired endogenous cortisol production, the aberrant activation of some areas of the central nervous system, and small peripheral nervous fibre damage. This complexity suggests that they should be managed by means of a multidisciplinary approach involving the use of both pharmacological and non-pharmacological treatments. The aim of this review is to discuss the most recent scientific acquisitions concerning these syndromes and their treatment.