Rheumatoid arthritis (RA) is a heterogeneous, prevalent, chronic autoimmune disease characterized by painful swollen joints and significant disabilities. Symptomatic relief can be achieved in up to ...50% of patients using biological agents that inhibit tumor necrosis factor (TNF) or other mechanisms of action, but there are no universally effective therapies. Recent advances in basic and preclinical science reveal that reflex neural circuits inhibit the production of cytokines and inflammation in animal models. One well-characterized cytokine-inhibiting mechanism, termed the “inflammatory reflex,” is dependent upon vagus nerve signals that inhibit cytokine production and attenuate experimental arthritis severity in mice and rats. It previously was unknown whether directly stimulating the inflammatory reflex in humans inhibits TNF production. Here we show that an implantable vagus nerve-stimulating device in epilepsy patients inhibits peripheral blood production of TNF, IL-1β, and IL-6. Vagus nerve stimulation (up to four times daily) in RA patients significantly inhibited TNF production for up to 84 d. Moreover, RA disease severity, as measured by standardized clinical composite scores, improved significantly. Together, these results establish that vagus nerve stimulation targeting the inflammatory reflex modulates TNF production and reduces inflammation in humans. These findings suggest that it is possible to use mechanism-based neuromodulating devices in the experimental therapy of RA and possibly other autoimmune and autoinflammatory diseases.
Fibrodyplasia ossificans progressiva (FOP) is a rare hereditary disease, which has a variable course characterized by occasional flare-ups of heterotopic ossification (HO) in soft tissues that are ...followed by swelling, stiffness, pain and warmth. Here, we report for the first time a case of a 45-year-old female patient with known FOP recovering from COVID-19 with disease progression potentially linked with the viral illness. In December 2020 the patient contracted a mild form of COVID-19 infection without need for hospital admission. Since January 2021, the patient felt unwell, with occasional abdominal pain which progressively intensified. In March 2021 she presented with new onset of HO, complaining of pain, swelling and thickening sensation in the lower abdomen and left part of the neck. Computerized tomography (CT) and cytokine analysis were performed. CT scan revealed new heterotopic bone formation in multiple soft tissue areas of the neck indicating clear radiological progression. Radiotherapy, which has proven to be an efficient tool to control HO in this patient, was not able to halt HO formation after COVID-19 infection. Cytokine analysis of a plasma sample obtained during a flare-up after COVID-19 infection showed a significantly elevated pro-inflammatory cytokines compared to a flare-up panel prior to infection. Of the 23 analyzed levels of cytokines, a staggering number of 21 were above normal levels. This case is the first confirmation of uncontrolled post-COVID-19 effects in a FOP patient, which manifested with flare-ups followed by progressive HO, possibly caused by a thus far, never described form of post-COVID syndrome.
Interleukin-6 receptor antagonist tocilizumab is a biologic drug used for treating patients with active rheumatoid arthritis (RA) who failed to respond to synthetic or other biologic ...disease-modifying antirheumatic drugs or where they were contraindicated. Interleukin-6 receptor blockade results in a decrease of disease activity but has some potential adverse effects, the most common being infections. We present a case of a 75-year-old female patient with long-lasting RA, several comorbidities and multiple prior therapies, who developed back pain and general malaise during tocilizumab intravenous treatment. The laboratory findings were typical of toxemia, and the imaging findings revealed large psoas muscle abscess. Surgical and antibiotic treatment was performed with a good outcome. To our knowledge, this has been the first case of a psoas abscess in a patient with RA treated with tocilizumab described in the literature so far. We also present a review of the literature regarding infection, and particularly abscess formation in patients treated with biological disease-modifying antirheumatic drugs, tocilizumab included.
Health spa tourism services are provided in special hospitals for medical rehabilitation and health resorts, and include controlled use of natural healing factors and physical therapy under medical ...supervision in order to improve and preserve health. Health tourism is a service industry and therefore labor-intensive industry in which human resources are one of the key factors of business success. The aim of this study was to analyze business performance of special hospitals for medical rehabilitation and health resorts in Croatia in relation to the structure of employees, specifically the number of physicians and total medical personnel, as well as the share of physicians and medical personnel in the total number of employees. The assumption was that those who employ more physicians and medical employees are more successful. The empirical research was conducted and the assumption was tested firstly by correlation analysis and afterwards by regression analysis. The total number of employees in the researched health resorts and special hospitals amounted to 2,863, of which the share of physicians specialists accounted for almost 7%, while the share of total medical staff was almost 53%. From the results of our research, it can be concluded that special hospitals for medical rehabilitation and health resorts, which employ more physicians and medical personnel, are achieving better financial business performance. Based on the results obtained, it is possible to provide guidance for further growth and development in the direction of basing the primary offer on medical-health offer, rather than on wellness offer, which is a strong trend in the world. These findings are important for planning the health and tourism policies in Croatia and similar countries.
Nonpharmacological interventions are one of the mainstreams of treatment for patients with spondyloarthritis (SpA). They include education, measures regarding joint protection, posture and rest, ...therapeutic exercise, physical therapy modalities, orthoses, and acupuncture. A key component in the rehabilitation of patients with SpA entities is therapeutic exercise, which can be performed as land-based or water-based. Positive effects of the exercises are manifested in reducing pain, maintaining mobility, improving posture, increasing aerobic capacity and improving quality of life. The best effects can be obtained when exercise is performed under the supervision of a physiotherapist at a health institution. The majority of studies on therapeutic exercise in SpA are related to ankylosing spondylitis (AS), while there is a paucity of studies devoted to other conditions. Although progress has been made in the quantity and quality of research on this topic, there are still issues regarding the quality of studies and considerable variability among them, which makes it difficult to compare different methods and harmonize and develop rehabilitation protocols according to evidence-based medicine.
Fibrodysplasia ossificans progressiva (FOP) is an extremely rare disease in which bone tissue forms in extraskeletal sites, which is known as heterotopic ossification (HO). Extracellular vesicles ...(EVs) are small phospholipid-enclosed particles released by various cells which have an emerging, but not completely understood role in various (patho)physiological processes. In order to further study the pathophysiology of FOP we conducted a small observational study comparing the proteomic profiles of EV cargo, derived from pooled plasma of four patient groups: FOP patient (N = 1) during active disease phase (flare-up), FOP patients during remission (N = 2), patients after long bone fracture (N = 20) and healthy controls (N = 10). After isolation of EVs – their protein cargo was determined using liquid chromatography / mass spectrometry, after which a functional gene enrichment analysis was performed. Our results show a sizeable difference of the proteomics profiles in which EVs from the bone fracture group show significant activity of integrin interactions, Wnt, VEGF, IGF-1 and PDGF pathways; conversely, FOP patients' EVs indicate that HO occurs via processes of innate immunity and the Ephrin B signaling pathway. We hypothesize that the Ephrin B signaling (expressed in EVs) contributes to HO by aiding in mesenchymal stem cell recruitment and osteogenic differentiation, as well as by contributing to the inflammatory response, including macrophage chemotaxis and activation. This is, to our knowledge, the first published analysis of EV protein cargo in FOP.
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•Proteomics-based analysis of extracellular vesicles’ protein cargo in FOP patients, bone fracture healing and controls.•Marked differences in signaling pathways expressed in extracellular vesicles in FOP vs. patients with bone fractures.•Ephrin B signaling pathway expressed in extracellular vesicles identified as a likely cogwheel in heterotopic ossification.
The aim was to assess the prevalence of chronic multimorbidity in patients with chronic low back pain or other chronic back disorders (BD). We analyzed data from the population-based cross-sectional ...European Health Interview Survey (EHIS) performed in the Republic of Croatia 2014-2015 by the Croatian Institute of Public Health. Outcome was the point-prevalence of chronic multimorbidity defined as having ≥2 chronic illnesses out of 14 contained in the EHIS questionnaire, after adjustment for ten sociodemographic, anthropometric and lifestyle confounders. Amoung fourteen targeted illnesses were asthma, allergies, hypertension, urinary incontinence, kidney diseases, coronary heart disease or angina pectoris, neck disorder, arthrosis, chronic obstructive pulmonary disease, diabetes mellitus, myocardial infarction, stroke, depression, and the common category "other". We analyzed data on 268 participants with BD and 511 without it. Participants with BD had a significantly higher relative risk of any chronic multimorbidity (RRadj=2.12; 95% CI 1.55, 2.99; p<0.001), as well as of non-musculoskeletal chronic multimorbidity (RRadj=2.29; 95% CI 1.70, 3.08; p=0.001) than participants without BD. All chronic comorbidities except for asthma and liver cirrhosis were significantly more prevalent in participants with BD than in participants without BD. In the population with BD, the participants with multimorbidity had three to four times higher odds for unfavorable self-reported health outcomes than the participants with no comorbid conditions, whereas the existence of only one comorbidity was not significantly associated with a worse outcome compared to the population with no comorbidities. In conclusion, the population suffering from BD has a higher prevalence of chronic multimorbidity than the population without BD and this multimorbidity is associated with unfavorable health outcomes.
The hypothesis of the study was that polymorphisms in promoter regions -238 and -308 of
TNF-α
could be associated with different clinical outcomes in inflammatory bowel diseases (IBD) and ...immune-mediated rheumatic diseases (IMRD). The aim was to examine the possible association of both polymorphisms with concentration of C-reactive protein (CRP) and fecal calprotectin (fCAL), onset of the remission and development of the ADA in patients on therapy with anti-TNF inhibitors. The prospective study was done in patients with IBD and IMRD on infliximab (IFX) or adalimumab (ADM). Patients were genotyped for
TNF-α
-238 and -308 polymorphisms. The concentration of CRP, fCAL, IFX or ADM and antibodies to drugs were measured according to manufacturer’s instructions and followed-up for 6 or 12 months. Out of all patients (
N
= 112), number of patients in remission did not differ according to genotypes (for IBD patients
P
= 0.509 vs 0.223; for IMRD patients
P
= 0.541 vs 0.132 for
TNF-α
-238 and -308, respectively). Initial CRP concentration was higher in IBD patients with
TNF-α
-308 GG than GA/AA genotypes in patients who failed to achieve remission 11.8 (4.4–39.6) vs 3.1 (1.5–6.5),
P
= 0.033. In IBD patients with remission, fCAL concentration after at least 6 months of therapy was higher in
TNF-α
-308 GG than in GA genotype 52 (25–552) vs 20 (20–20) µg/g,
P
= 0.041. Our results showed the association of
TNF-α
-308 GG genotype with a higher concentration of CRP and fecal calprotectin in patients with inflammatory bowel diseases on IFX or ADM therapy. Clinical remission and development of antibodies to anti-TNF drugs were not associated with
TNF-α
-238 and -308 polymorphisms.
Vitamin D is beneficial in patients with immune-mediated rheumatic diseases as it has been shown that it lowers the incidence risk and the level of inflammation. To examine the association between ...clinical outcomes and initial 25-hydroxyvitamin D 25(OH)D concentrations in patients with the immune-mediated rheumatic diseases treated with infliximab for 9 months. This study was performed in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) treated with infliximab for at least 38 weeks. Disease activity was assessed using Disease Activity Score (DAS28) for RA and PsA and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for AS, while the global assessment was performed using the Visual Analogue Scale (VAS). Patients were divided into 2 groups according to 25(OH)D concentration which was classified as deficient or non-deficient (below and above 50 nmol/L, respectively). Concentrations of infliximab (IFX) and C-reactive protein (CRP) were measured according to the manufacturer’s instructions.This study was performed in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) treated with infliximab for at least 38 weeks. Disease activity was assessed using Disease Activity Score (DAS28) for RA and PsA and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for AS, while the global assessment was performed using the Visual Analogue Scale (VAS). Patients were divided into 2 groups according to 25(OH)D concentration which was classified as deficient or non-deficient (below and above 50 nmol/L, respectively). Concentrations of infliximab (IFX) and C-reactive protein (CRP) were measured according to the manufacturer’s instructions. The study included 23 patients (14 with RA, 6 with AS and 3 with PsA), median age 54 years, 15 females. Vitamin D deficient and non-deficient groups had median initial concentrations of 38 and 61 nmol/L, respectively. DAS28 and pain on VAS calculated at the 2nd and 38th week showed a statistically significant decrease only in RA and PsA patients with vitamin D deficiency (
P
= 0.02 and 0.06, respectively). Lower initial concentration of 25(OH)D in patients treated with infliximab was associated with better improvement of clinical measures (DAS28 and VAS) of disease after 9 months of therapy.
The aim of the study was testing the hypothesis that body height has a moderating effect on the association of weight and chronic low back pain (LBP) induced disability, and that this moderating ...effect is different in women and men. We performed a nested cross-sectional analysis using data collected at baseline in a prospective cohort study conducted in 2008-2009 at a special hospital for medical rehabilitation in Croatia. The outcome was the Roland-Morris Disability Questionnaire (RMDQ) score. The independent variable was body weight. The focal moderators were body height and sex. The moderation analysis was adjusted for seven sociodemographic and clinical covariates. We analyzed data on 72 patients with a median (interquartile range) age of 50 (43-55) years, 36 (50%) of whom were women, treated for nonspecific, chronic LBP. The interaction of sex, body weight and height was a significant predictor of the RMDQ score after adjustments for all covariates (increase of R2=0.13; p=0.001; false discovery rate <5%). In both sexes, the correlation between body weight and the RMDQ score was significantly moderated by body height but in opposite ways. In conclusion, the effects of body weight on physical disability are moderated by body height, but this moderation effect differs between women and men.
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