Correlation between angiotensin-converting-enzyme 2 gene polymorphisms and systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) is a disease with cardiovascular impairment and polymorphisms of the gene coding of angiotensin-converting-enzyme 2 (ACE2) may account for its development. Three single nucleotide polymorphisms of ACE2 (C>G rs879922, G>A rs2285666 and A>G rs1978124) were found to increase the risk for development of arterial hypertension (AH) and cardiovascular (CVS) diseases in different ethnicities. We investigated associations of polymorphisms rs879922, rs2285666 and rs1978124 with the development of SSc. METHODS: Genomic DNA was isolated from whole blood. Restriction-fragment-length polymorphism was used for genotyping of rs1978124, while detection of rs879922 and rs2285666 was based on TaqMan SNP Genotyping Assay. Serum level of ACE2 was assayed with commercially available ELISA test. RESULTS: 81 SSc patients (60 women, 21 men) were enrolled. Allele C of rs879922 polymorphism was associated with significantly greater risk for development of AH (OR=2.5, p=0.018), but less frequent joint involvement. A strong tendency to earlier onset of Raynaud's phenomenon and SSc was seen in carriers of allele A of rs2285666 polymorphism. They had lower risk for development of any CVS disease (RR=0.4, p=0.051) and tendency to less frequent gastrointestinal involvement. Women with genotype AG of rs1978124 polymorphism had significantly more frequent digital tip ulcers and lower serum level of ACE2. CONCLUSIONS: Polymorphisms of ACE2 may account for the development of AH and CVS disorders in SSc patients. Strong tendencies to more frequent occurrence of disease specific characteristics distinct to macrovascular involvement will require further studies evaluating significance of ACE2 polymorphisms in SSc.

Respiratory involvement in antineutrophil cytoplasmic antibody-associated vasculitides: a retrospective study based on POLVAS registry.

OBJECTIVES: The study aimed to characterise the Polish population of (ANCA)-associated vasculitides (AAV) with respiratory involvement (RI), in comparison to the subgroup without lung manifestations and the other cohorts. METHODS: Retrospective analysis of the Polish population of AAV with RI was conducted, based on data from the POLVAS registry. Standard descriptive statistics, χ2 test, and Mann-Whitney U test were used to perform comparisons. RESULTS: Among 461 cases qualified to this study, there were 316 cases with RI (68.5%), 206 with granulomatosis with polyangiitis (GPA) (65.2%), 80 with eosinophilic granulomatosis with polyangiitis (EGPA) (25.3%) and 30 with microscopic polyangiitis (MPA) (9.5%). Proportion of RI in GPA, MPA, and EGPA accounted for 67.8%; 40.0%; 97.6%, respectively. The number of relapses was higher in the RI group (median 1.0 vs. 0.0; p=0.01). In the subgroup of combined GPA and MPA with RI, the trends toward higher proportion of deaths (11.7% vs. 5.7%; p=0.07), relapses requiring hospitalisation (52.2% vs. 42.4%, p=0.07) and relapses requiring admission to the intensive care unit (5.6% vs. 1.4%, p=0.09) were observed, median maximal concentration of CRP was higher (46 vs. 25 mg/l; p=0.01) and more aggressive treatment was administered. CONCLUSIONS: Prevalence of RI in the Polish population of AAV is similar to the values reported in the literature, however, the proportion observed in GPA is closer to those presented in Asian than Western European cohorts. RI seems to be associated with a more severe course of disease and its presence prompts more aggressive treatment.

Subphenotypes of ANCA-associated vasculitis identified by latent class analysis.

OBJECTIVES: ANCA-associated vasculitides (AAV) are a heterogeneous group of rare diseases with unknown aetiology and the clinical spectrum ranging from life-threatening systemic disease, through single organ involvement to minor isolated skin changes. Thus, there is an unmet need for phenotype identification, especially among patients with granulomatosis with polyangiitis (GPA). Patients with microscopic polyangiitis (MPA) seem to be clinically much more uniform. Recently, three subcategories of AAV have been proposed and described as non-severe AAV, severe PR3-AAV, and severe MPO-AAV. METHODS: In line with these attempts, we decided to use an unbiased approach offered by latent class analysis (LCA) to subcategorise GPA and MPA in a large cohort of Polish AAV patients included in a multicentre POLVAS registry. RESULTS: LCA of our AAV group identified a four-class model of AAV, including previously proposed three subphenotypes and revealing a fourth (previously not described) clinically relevant subphenotype. This new subphenotype includes only GPA patients, usually diagnosed at a younger age as compared to other groups, and characterised by multiorgan involvement, high relapse rate, relatively high risk of death, but no end-stage kidney disease. CONCLUSIONS: Based on multiple clinical and serological variables, LCA methodology identified 4-class model of AAV. This newly described fourth class of AAV may be of clinical relevance and may require prompt diagnosis and aggressive treatment due to the multiorgan involvement, high risk of relapse and marked mortality among these relatively young GPA subjects.

Clinical manifestations of Whipple's disease mimicking rheumatic disorders.

Whipple's disease is a rare, chronic, systemic disorder caused by Tropheryma whipplei infection. The most common symptoms are weight loss, arthralgia, diarrhea and abdominal pain. Other organ involvement can also occur in the patients. Joint manifestations may mimic rheumatoid arthritis or spondyloarthritis. Arthalgia, arthritis, spondylodiscitis, bursitis and/or tenosynovitis are seen in the majority of the patients. This explains why some of the symptoms are misdiagnosed as those of rheumatic diseases. Understanding of Whipple's disease is important for differential diagnostics of several rheumatic symptoms.

Osseous manifestations of sarcoidosis.

Sarcoidosis is a systemic multisystem inflammatory disease of unknown etiology. The disease is characterized by formation of non-caseating granulomas. The most common presentation is bilateral hilar lymphadenopathy and lung infiltration, but the disease is very heterogeneous, with an unpredictable clinical course. Musculoskeletal manifestations are common. Bone involvement is less frequent, and usually occurs in patients with chronic multisystem course of the disease. They are most commonly found in the phalanges of hands and feet, and are usually bilateral. The skull, long bones, ribs, pelvis, and axial skeleton may also be affected. Osseous involvement may be asymptomatic but in some cases can cause a severe disability. Imaging techniques are important for diagnosis. Radiological investigations revealed sclerotic or destructive lesions (involving also joints), cystic and punched out lesions and cortical abnormalities. Biopsy is required for differential diagnosis with respect to malignancy. Treatment is a part of systemic therapy and is not needed in all cases. Glucocorticoids and TNF-α antagonists are used for management.

Ocular manifestations in patients with systemic sclerosis.

Systemic sclerosis (SSc) is a rare, chronic autoimmune disease with unknown etiology. Its prominent features are fibrosis, vasculopathy and impaired immune response. Disease can also affect eyes leading to various findings in ophthalmological examination. The objective of this study was to determine the prevalence and type of ocular involvement in patients with SSc. A systematic literature review was conducted using electronic databases. A combination of following keywords was used: "systemic sclerosis" and ophthalmology-related search terms, including the keywords "eye", "ocular" and "ophthalmic". In conclusion, eyelid and conjunctival abnormalities and dry eye disease are among the most common ocular manifestations of SSc. Their diversity is connected to complexity of the disease.

Dercum's disease (adiposis dolorosa): a review of clinical presentation and management.

Dercum's disease (adiposis dolorosa) is a rare disease of unknown etiology characterized by painful subcutaneous adipose tissue deposits with various localization over the body. The deposits occur histologically as lipomas and are associated with overweight or obesity and a variety of psychiatric disturbances (anxiety, depression, sleep disturbances). Classification of Dercum's disease is related to size and location of adipose nodules (generalized diffuse, generalized nodular, localized nodular and juxta-articular forms). Diagnosis in based on clinical presentation and exclusion of a number of other disorders associated with lipomas. There is no generally accepted management of the patients. Liposuction or lidocaine application has been reported successful in some cases. Other therapeutic methods have been reported but their effectiveness is based on anecdotal descriptions only, and were not confirmed in clinical trials.

Serum angiostatin and endostatin levels in patients with granulomatosis with polyangiitis and immune complex small vessel vasculitis.

OBJECTIVES: Inflammation has been revealed to be associated with angiogenesis. Granulomatosis with polyangiitis (GPA) and immune complex small vessel vasculitis (ICSVV) are forms of systemic vasculitides of different pathogenesis. GPA is a necrotizing granulomatosis and ICSVV is associated with inflammation of postcapillary venules induced by deposits of immune complexes. The aim of the study was to determine serum levels of angiostatin and endostatin, natural angiogenesis inhibitors, in patients with GPA and ICSVV as well as healthy individuals. MATERIAL AND METHODS: Two groups of patients with GPA (20 patients) and ICSVV (20 patients) as well as 20 controls were investigated. All patients were investigated before initiation of immunosuppressive therapy or administration of corticosteroids. Angiostatin and endostatin levels were assayed with the ELISA method. RESULTS: Enhanced serum levels of angiostatin and endostatin were found in patients with GPA but not in those suffering from ICSVV. In patients with GPA increased levels of angiogenesis inhibitors correlated with the disease activity. A correlation between angiostatin and endostatin levels was observed in all groups of investigated individuals. CONCLUSIONS: It is suggested that formation of necrotizing granulation is associated with profound activation of angiogenesis and an increase in serum levels of inhibitors is a phenomenon occurring during blood vessel formation in the granulation tissue. The obtained results confirm involvement of angiogenesis in pathogenesis of at least some forms of vasculitides and suggest the need for continuation of investigations in this field.

Biosimilar switching - current state of knowledge.

Evidence from over 10 years of clinical experience demonstrates that biosimilar medicines approved in the European Union can be used for all their registered indications as safely as their originators and with no negative impact on therapeutic efficacy. The debate on the use of biosimilars in rheumatology focuses specifically on the safety of switching between biosimilars and reference products. Studies conducted to date, including randomised double-blind and open-label extension trials, have not demonstrated any significant differences in therapeutic efficacy or safety between patients switched from one medicine to another and those who were continued on a single medicine. According to the latest recommendations for the use of biosimilars in rheumatic diseases, developed by an international task force in 2017, there is no clinical evidence that a single switch from an originator to a biosimilar medicine is associated with any significant risk for patient safety or reduction in therapeutic efficacy.

Effect of adalimumab on the expression of genes encoding TNF-α signal paths in skin fibroblasts in vitro.

INTRODUCTION: Tumour necrosis factor (TNF-α) is one of the main cytokines participating in inflammation and immune response. Biological effects of the cytokine action, mediated by two receptors: TNFRSF1A and TNFRSF1B involve activation of many signal paths, thus change the transcription activity of many genes. The mechanism of action of an anti-TNF medicine consists in blocking TNF-α though preventing activation of signal paths. AIM: To single out mRNA and microRNA genes relating to TNF-α signal paths, the expression of which could indicate sensitivity of cells to the medicine in question. MATERIAL AND METHODS: The material used in the research consisted in the cell line of regular human skin fibroblasts NHDF (CC-2511 Lonza, Basel, Switzerland) exposed to adalimumab with a concentration of 8.00 µg/ml of the medium for 2, 8 and 24 h, compared with the control material, i.e. non-stimulated cells. Molecular analysis was performed using the oligonucleotide expressive micro-matrices technology HG-U133A, miRNA 2.0 Array micro-matrices and RTqPCR. RESULTS: mRNA: BIRC5, MAP3K4, ZFAND5, JUN differentiate cells exposed to the anti-TNF medicine, regardless of the time of cell/medicine incubation. TNF-α transcription activity is reduced during exposure of NHDF cells to adalimumab. miRNA regulating transcription activity of the said 4 mRNA and miRNA related to TNF-α and its receptors was also singled out. CONCLUSIONS: It was ascertained that adalimumab has therapeutic potential and affects genes engaged in signal paths activated by TNF-α. The results indicate the TNF-α usefulness as the molecular, supplementary marker in diagnostics and control of treatment effects.

Tofacitinib in the treatment of patients with rheumatoid arthritis: position statement of experts of the Polish Society for Rheumatology.

Tofacitinib is a newly approved small-molecule targeted synthetic disease-modifying antirheumatic drug. The drug was designed as a selective and specific inhibitor of pro-inflammatory receptor signalling. Tofacitinib inhibits the process of intracellular signalling from the receptor to the cellular nucleus and inhibits the inflammation process via a new pathway (inhibition of the Janus kinases), which is unavailable to biological medicines. Tofacitinib has been approved for use in the treatment of patients with moderate to severe active RA. The drug may be used in combination with methotrexate or another conventional synthetic disease-modifying antirheumatic drug or in monotherapy. The efficacy of tofacitinib has been confirmed in several clinical trials. The drug inhibits radiographic progression of the disease. The innovative mechanism of action of tofacitinib is a noteworthy feature because it offers hope of effective treatment for patients who fail to respond to other drugs. The presented article discusses the mechanism of action and the clinical application of tofacitinib. Tofacitinib represents a new group of disease-modifying antirheumatic drugs that can be placed on an equal footing with biological drugs already available.

Satisfaction and discontent of Polish patients with biological therapy of rheumatic diseases: results of a multi-center questionnaire study.

OBJECTIVES: Biologics are medications widely applied in the management of inflammatory rheumatic diseases. The drugs were found to be effective but their application is associated with some disadvantages. Medication with biologics is relatively expensive, and in Poland, it is carried out in specialized centers. The study was designed to evaluate various aspects of satisfaction and dissatisfaction of Polish patients treated with biologics. MATERIAL AND METHODS: An anonymous questionnaire was distributed in 23 Polish rheumatological centers involved in the treatment; 1212 returned questionnaires were used for analysis. Responses were received from 606 patients with rheumatoid arthritis, 427 with ankylosing spondylitis, 117 psoriatic arthritis, and 62 adult patients with juvenile idiopathic arthritis (in whom administration of the drugs had been introduced before they were 18 years old). The investigated group constituted about one-fifth of all rheumatic patients on biologics in Poland. RESULTS: A beneficial or very beneficial influence of the medication on the state of physical health was found mostly in patients with rheumatoid arthritis (51.3 and 30.5%) and ankylosing spondylitis (51.0 and 36.8%). Family life was improved by the treatment especially in patients with ankylosing spondylitis (40.7 and 35.6% beneficial and very beneficial, respectively), sleep quality and sexual life mostly in those with ankylosing spondylitis (beneficial/very beneficial influence 41.5/38.4, and 38.7/23.9, respectively). There was a rather small influence of biological treatment on the financial situation of the patients. In general, satisfaction with the treatment was evaluated as positive or very positive in 88% of all investigated patients.In a significant part of the patients, transportation to the medical center was considered as a disadvantage of the treatment. About one-third of the patients considered laboratory and imaging tests to be done before initiation of the medication as a difficulty, and for about 40% waiting time for qualification for the medication was a significant disadvantage. The route of drug administration was without importance for 4/5 of the patients. CONCLUSIONS: Summing up, the results were similar in the patients suffering from various diseases although those with psoriatic arthritis felt the highest satisfaction (possibly due to the positive aesthetic effect), and those with ankylosing spondylitis had significant improvement in sexual life (probably due to younger age). Relatively low satisfaction was found in patients with juvenile idiopathic arthritis. There was a small influence of medication on financial status of the patients. Application of biologics has few disadvantages and most of them are associated with the organization of health services (waiting time for the tests, transportation to the medical centers).

Sesquicentennial of the birth of Edmund Faustinus Biernacki, a discoverer of the erythrocyte sedimentation rate.

Edmund Faustinus Biernacki (1866-1911) was a Polish physician and philosopher of medicine. He described erythrocyte sedimentation, designed equipment to measure the erythrocyte sedimentation rate, and applied it to clinical practice. His contribution to the development of one of the most commonly used medical laboratory tests is forgotten, and the test is attributed to other scientists.

Coexistence of systemic sclerosis and sarcoidosis.

Coexistence of systemic sclerosis (SSc) and sarcoidosis (SA) is rarely reported; 21 cases only were reported in the English medical literature before 2011. It is suggested that low incidence of overlap syndrome of SSc with SA is resulted from different immune mechanisms involved in pathogenesis of the diseases. In SSc patients, a role of Th2 lymphocytes is suggested while in patients with SA such role is attributed to Th1 lymphocytes. The paper presents a 47-year-old woman suffering from SSc for over 6 years. CT scan of the lungs revealed the nodulus of the right lung and enlarged mediastinal lymphatic nodes. Pathologic evaluation of the nodulus provided basis for diagnosis of sarcoidosis. Diagnosis of SSc was based on clinical and capilaroscopic evaluation as well as detection of anti-topoisomerase I antibodies. In the course of the disease, fibrosis of the lung, pulmonary hypertension and cardiac abnormalities with rhythm disturbances were developed. Treatment included cyclophosphamide, mycophenolate mofetil, sildenafil, losartan. Stabilization of the general state of the patient was achieved.

Calprotectin in rheumatic diseases: a review.

Calprotectin also known as MRP8/14 or S100A8/A9 is a heterodimeric complex of two S100 calcium-binding proteins: myeloid-related protein 8 (MRP-8 or S100A8) and MRP-14 (or S100A9). At present, according to many authors, it is considered that calprotectin MRP8/14 is a potentially more sensitive biomarker of disease activity in rheumatoid disease than conventional inflammatory indices such as the erythrocyte sedimentation rate, C-reactive protein and others. A review of the literature on concentration of calprotectin in patients with some rheumatic diseases (rheumatoid arthritis, juvenile idiopathic arthritis, adult-onset Still's disease, systemic vasculitis, polymyalgia rheumatica, ankylosis spondylitis, systemic lupus erythematosus, and primary Sjögren's syndrome) is presented.

Mixed generalized/juxta-articular form of Dercum's disease.

Dercum's disease is a rare disorder with subcutaneous formation of fatty tissue (lipomas) with symptoms of pain, fatigue, stiffness, weakness and in some cases arthritis. The rarity of this disease causes that it is not taken into consideration in the rheumatological differential diagnosis, so this short report draws attention to this rare disease.

Medical terminology: Its size and typology.

Medical terminology is one of the largest specialized terminologies and is estimated to contain over 250,000 items. Classification of medical terminology into six categories is proposed. The categories are as the following: (A) medical terms that are a part of general basic lexicon of average native speaker (0.02-0.03 % of all terms), (B) specialized medical terms known by average physician (about 45 % of all terms), (C) highly-specialized terms of subspecialties (about 15 % of all terms) (D) medical terms that primarily belong to other terminologies (e.g. biological, chemical, physical, statistical) (about 20 % of all terms), (E) medical slang (0.04-0.05 % of all terms), and (F) pharmaceutical terminology (about 20 % of all terms).

[The heart and anticytokine therapy]. / Serce a leczenie antycytokinowe.

Treatment targeting TNF revolutionized management for rheumatoid arthritis patients offering attainment of clinical remission, preventing patients from disability and improving their quality of life. Anti-cytokine therapy, however may in some circumstance contribute to development of serious adverse effects, including congestive heart failure. The heart failure in patients treated with anti-TNF agents seems to be paradoxical as TNF plays an important pathogenetic role in both conditions. In congestive heart failure, TNF may act as a regulatory factor and may stabilize the heart function, so TNF blockade may result in progression of the heart failure. In this paper, the pathogenetic role of TNF has been discussed with the special emphasis to the role of cytokine in conditions of heart failure and systemic inflammation.