Angiotensin-converting enzyme 1 gene polymorphisms in patients with systemic sclerosis-associated interstitial lung disease: a single centre retrospective observational study.

Angiotensin-converting enzyme (ACE) 1 gene polymorphisms have been associated with vascular permeability, alveolar endothelial dysfunction and fibroblast proliferation and have been studied in pulmonary diseases such as COPD and idiopathic pulmonary fibrosis. Similar mechanisms of ACE 1 polymorphisms have been seen in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). We are presenting a retrospective observational study in patients with SSc-ILD and analysing the association of ACE 1 gene polymorphisms (DD, II and ID) with the features of SSc, changes in pulmonary function tests (PFTs) and lung HRCT over three different periods of time (at the time of the diagnosis, 5 and 10 years after the diagnosis). The aim of the study was to determine whether ACE 1 gene polymorphisms have an effect on the severity of SSc-ILD. We found no statistically significant differences in the development and severity of SSc-ILD and changes in PFTs between subgroups of ACE 1 gene polymorphism over the analysed periods (at the time of diagnosis HRCT changes p = 0.270, FEV1 p = 0.483, FVC p = 0.497, DLco p = 0.807, after 5 years HRCT changes p = 0.163, FEV1 p = 0.551, FVC p = 0.362, DLco p = 0.620 and 10 years of follow-up HRCT changes p = 0.853, FEV1 p = 0.589, FVC p = 0.328, DLco p = 0.992). However, patients with the ID genotype showed a significant reduction in FEV1 after 10 years of follow-up in comparison to baseline levels (91.0 (IR 80.0-105.0) at the time of diagnosis and 84.0 (IR 69.0-99.0) after 10 years, p = 0.014). Our study suggests that ACE 1 gene polymorphisms do not have a role in the severity of SSc-ILD. Further studies are needed to explain the exact role of ACE 1 gene polymorphisms in SSc-ILD and SSc in general.

Real world experience with nintedanib in connective tissue disease-related interstitial lung disease: a retrospective cohort study.

Various connective tissue diseases tend to affect specific organs, lungs being the organ with the most serious repercussions and consequences. The diagnosis of interstitial lung disease makes the treatment more difficult and worsens long-term prognosis and overall survival. Positive results from the registration studies of nintedanib led to approval of the drug for the treatment of idiopathic pulmonary fibrosis and chronic fibrosing interstitial lung diseases in connective tissue diseases. After registration, real-world data on the use of nintedanib are being collected in everyday clinical practise. The objective of the study was to collect and analyse real world experience gathered after the registration of nintedanib for the treatment of CTD-ILD and to show if the positive results collected from a homogeneous and "representative" study population can be applied to everyday clinical practice. We are presenting a retrospective observational case-series study of patients treated with nintedanib from the three largest Croatian centers specialised in the treatment of connective tissue diseases with interstitial lung diseases. Stabilisation or improved of lung function tests was reported in 68% of patients when changes in predicted FVC were observed and in 72% of patients when changes in DLco were analysed. Almost all of the reported patients (98%) were treated with nintedanib as an add-on drug to immunosuppressants. The most common side-effects were gastrointestinal symptoms and abnormal liver function tests in less extent. Our real-world data confirm the tolerability, efficacy and similar side-effects of nintedanib as reported in pivotal trials. Key Points • Interstitial lung disease is a common manifestation of several connective tissue diseases and its progressive fibrosing phenotype contributes to high mortality rate and many unmet needs regarding the treatment remain. • Registration studies of nintedanib obtained sufficient data and positive results to support approval of the drug. • Real-world evidence from our CTD-ILD centres confirm the clinical trial data regarding efficacy, tolerability and safety of nintedanib.

Delphi-Based Consensus on Interstitial Lung Disease Screening in Patients with Connective Tissue Diseases (Croatian National-Based Study).

The aim of this study was to develop a Croatian Delphi-based expert consensus for screening interstitial lung disease (ILD) associated with connective tissue disease (CTD). A systematic literature review was conducted on risk factors for the development of ILD, prevalence and incidence of ILD, diagnostic and screening methods for ILD, and prognosis of ILD in idiopathic inflammatory myopathy (IIM), mixed connective tissue disease (MCTD), primary Sjögren's syndrome (pSS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc) were performed. Based on the evidence found, experts developed questionnaires for screening and monitoring ILD in each CTD, which were provided via an online survey. Following the electronic survey, two screening algorithms were developed based on the consensus opinions. The detection strategy for ILD included high-resolution computed tomography (HRCT) in addition to pulmonary function testing for IIM, MCTD, and SSc. and pulmonary function testing for newly diagnosed pSS, RA and SLE. However, in patients with identified risk factors for ILD HRCT, these tests should also be performed. A screening strategy for early identification of patients with various CTD-ILD was first developed by a multidisciplinary team of rheumatologists, pulmonologists, and radiologists to identify early CTD patients at risk of ILD, a severe extra-articular manifestation of CTD.

Successful IL-17A inhibitor cycling in psoriatic arthritis patient: a case report and a literature review.

Psoriatic arthritis is an inflammatory arthritis with heterogeneous disease presentation. The most affected clinical domain of the disease determines the therapeutic approach. We report the case of a 34-year-old man with all six crucial domains of psoriatic arthritis (psoriasis, peripheral arthritis, axial skeletal manifestations, dactylitis, nail changes, and enthesitis) treated unsuccessfully with conventional synthetic DMARDs, NSAID's, and steroids as well as topical treatment and phototherapy. With golimumab as the first line of bDMARD partial remission was achieved. After 24 months the treatment was switched to secukinumab due to secondary inefficacy. The psoriasis and psoriatic arthritis relapsed after 21 months of treatment with secukinumab. The patient was cycled to ixekizumab with an excellent result. IL-17A inhibitor cycling may be a successful treatment option in some difficult to treat psoriatic arthritis patients.

Demyelinating disease (multiple sclerosis) in a patient with psoriatic arthritis treated with adalimumab: a case-based review.

Over the past two decades, tumor necrosis factor-α (TNF-α) inhibitors became one of the most important drugs in the treatment of patients with psoriatic arthritis. Unfortunately, some of the patients exhibit unwanted side effects of the treatment. We describe a patient with psoriasis, psoriatic arthritis and uveitis who was treated with adalimumab and after 4 months of the treatment developed clinical and neuroradiological signs of demyelinating disease of the central nervous system. She experienced no signs and symptoms of neurological disease prior to adalimumab administration. After a detailed neurological work-up she was diagnosed with relapsing-remitting type of multiple sclerosis and treated with oral and pulse glucocorticoids and later with dimethyl fumarate. Adalimumab was discontinued. The question remains was the demyelination induced by the TNF-α blockade or was it unmasked by the introduction of the cytokine blocking agent. In patients suffering from inflammatory arthritis, treating disease to target as well as a close follow-up and knowledge of potential side effects of treatment remains crucial in good clinical practice.

B regulatory cells and monocyte subpopulations in patients with chronic graft-vs-host disease.

AIM: To assess the correlations of B regulatory cells (Bregs) and monocyte subsets in peripheral blood with the National Institutes of Health (NIH)-consensus-defined clinical manifestations of chronic graft-vs-host disease (cGvHD), in an attempt to establish their role as cellular biomarkers. METHODS: This multidisciplinary prospective study enrolled adult cGVHD patients treated in the University Hospital Center Zagreb and University of Zagreb School of Medicine. Immunophenotypic subpopulations of CD24highCD38high Bregs (CD27-, CD27+, and total) and monocyte (classical, intermediate, and non-classical) counts were correlated with demographic, transplant, and cGVHD-related data. Bivariate correlation analysis was performed to evaluate the correlations between Bregs and monocytes subsets and cGVHD organ involvement, as well as cGVHD severity and immunosuppression intensity. RESULTS: Twenty-two adult patients (54.5% female) with cGVHD were enrolled. The median (range) age was 44.5 years (24-65). All patients were transplanted for hematologic malignancies and 40.9% had severe NIH cGVHD global score. The median time from cGVHD diagnosis to the analysis was 16.6 months (0-176). The organ most frequently affected with cGVHD were the eyes (68.2%), skin (45.5%), lungs (45.5%), and liver (40.9%). Lower total and CD27-Bregs counts were correlated with worse cGVHD severity, higher immunosuppression intensity, and lung cGVHD, in terms of cell count, but also with skin cGVHD, in terms of percentages. Patients with liver and joint/fascia cGVHD had a lower percentage of non-classical monocytes and patients with more severe global NIH score had a higher classical monocytes count. CONCLUSION: Different organs affected by cGVHD are differently associated with different subpopulations of Bregs and monocytes.

Misleading symptoms of hereditary angioedema type II mimicking familial mediterranean fever.

Hereditary angioedema (HAE) is a rare, debilitating and potentially life-threatening disease characterized by recurrent attacks of oedema. With the development of new therapies and better availability of diagnostic tools, important advances have been made. However, the disease still remains frequently misdiagnosed and inadequately treated. Familial Mediterranean fever (FMF) is an autoinflammatory syndrome comprised of serositis, fever, arthritis and skin involvement. Both diseases can cause severe abdominal pain resembling that of acute abdomen. We report a case of three family members that presented with various symptoms that could fit in a clinical picture of both diseases, only to confirm a diagnosis of HAE type II after a diagnostic delay of many years.

HEREDITARY ANGIOEDEMA DUE TO C1-INHIBITOR DEFICIENCY IN PEDIATRIC PATIENTS IN CROATIA - FIRST NATIONAL STUDY, DIAGNOSTIC AND PROPHYLACTIC CHALLENGES.

Hereditary angioedema (HAE) is a rare autosomal dominant disease with deficiency (type I) or dysfunction (type II) of C1 inhibitor, caused by mutations in the C1-INH gene, characterized by recurrent submucosal or subcutaneous edemas including skin swelling, abdominal pain and life-threatening episodes of upper airway obstruction. The aim of this study was to investigate healthcare experiences in children with HAE due to C1 inhibitor deficiency (C1-INH-HAE) in Croatia in order to estimate the number of affected children and to recommend management protocols for diagnosis, short-term prophylaxis and acute treatment. Patients were recruited during a 4-year period at five hospitals in Croatia. Complement testing was performed in patients with a positive family history. This pilot study revealed nine pediatric patients positive for C1-INH- HAE type I, aged 1-16 years, four of them asymptomatic. Before the age of one year, C1-INH levels may be lower than in adults; it is advisable to confirm C1-INH-HAE after the age of one year. Plasma-derived C1-INH is recommended as acute and short-term prophylactic treatment. Recombinant C1-INH and icatibant are licensed for the acute treatment of pediatric patients. In Croatia, HAE is still underdiagnosed in pediatric population.

Improvement of neurological and ocular symptoms of Behçet's disease after the introduction of infliximab.

Behçet's disease is a chronic inflammatory condition of unknown origin characterized by multiple organ involvement. The most common symptoms of Behçet's disease are recurrent oral and/or genital ulcerations in combination with symptoms affecting eyes, skin, central and peripheral nervous system, blood vessels and gastrointestinal tract. We present a 43-year-old female patient with the history of recurrent episodes of genital and oral ulcerations, elevated acute phase reactants and skin lesions. The diagnosis of Behçet's disease has been delayed (for more than 10 years) and reached only after she developed neurological and ocular symptoms. Treatment with glucocorticoids and azathioprine was partially successful. High doses of glucocorticoids were needed to control the disease and cyclosporine A was nephrotoxic. Remission was reached after the introduction of infliximab (plus methotrexate) and glucocorticoids were stopped. In the recent years, infliximab has been accepted as a standard therapy for refractory cases of Behçet's disease (neurological, ocular or gastrointestinal). Our patient presented with refractory ocular and neurological symptoms and infliximab was effective for both manifestations. Long-term side-effects of glucocorticoids and other immunosuppressants can be avoided with TNF-α blockade. We emphasize the importance of a timely and accurate diagnosis and significance of excluding more common diseases in a work-up algorithm.

Improvement of overlapping hidradenitis suppurativa and ankylosing spondylitis after the introduction of adalimumab.

Hidradenitis suppurativa is a chronic inflammatory disorder characterized by occlusion of the follicular pilosebaceous units of the skin. The treatment options are sometimes very limited and unpleasant odor and abundant drainage complicate the disease. Ankylosing spondylitis is a form of seronegative spondyloarthritis with predominantly axial but also peripheral joint involvement. Both of the conditions lower the patient's quality of life and affect everyday activities. We describe a 39-year-old male patient with both diseases treated with different medications with only a modest result. After the initiation of a tumor necrosis factor α (TNF-α) inhibitor (adalimumab) the patient experienced first the musculoskeletal and later on the skin improvement. The introduction of TNF-α inhibitors should be considered early in the treatment of overlapping hidradenitis suppurativa and the spondyloarthritis spectrum of conditions. Available medical data confirm the positive results and beneficial effect on disease course, activity and, most importantly, quality of life.

Different Therapeutic Paths (Colchicine vs. Anakinra) in Two Patients With Schnitzler's Syndrome.

Schnitzler's syndrome is a rare autoinflammatory syndrome with unidentified mechanism of disease and etiology with unknown definitive treatment algorithm. The two obligatory criteria for the diagnosis of Schnitzler's syndrome include chronic urticarial rash and monoclonal gammopathy (immunoglobulin M or immunoglobulin G). In this article, we describe two patients with different courses of disease with different average lengths of time between initial symptoms and the final diagnosis (6 months to 8 years). Exclusion of more common conditions is needed to ensure the correct diagnosis. Treatment strategy depends on the patient's constitutional symptoms (fever, malaise, generalized myalgia, and arthralgias) and laboratory tests of inflammation. Treatment includes usage of conventional drugs and cytokine blockade (interleukin-1 and interleukin-6). Further studies are needed to determine the precise mechanism of disease and the appropriate targeted therapy.

[RETROSPECTIVE DATA ANALYSIS OF THE PATIENTS WITH INFLAMMATORY JOINT DISEASES TREATED WITH GOLIMUMAB IN CROATIA]. / RETROSPEKTIVNA ANALIZA PODATAKA BOLESNIKA OBOLJELIH OD UPALNIH REUMATSKIH BOLESTI U HRVATSKOJ LIJECENIH GOLIMUMABOM.

Golimumab is a human monoclonal antibody which inhibits tumor necrosis factor-alpha (TNF-α) and is approved for the treatment of inflammatory arthritides (rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis) when the conventional non-pharmacological and pharmacological therapies fail to cause remission or low disease activity. In this retrospective study there were included patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis who were treated in Croatia with golimumab, from June 2011 to June 2013. included and these retrospective data are compared with similar data from clinical trials and other available databases. Standard variables of disease activity and functional ability were observed. Results demonstrated significant efficacy of golimumab regarding lowring the disease activity and imrpving functional ability in pateints with these inflammatory rherumatic disease. In conclusion, in this retrospective study during two years treatment golimumab showed efficacy in decreasing disease activity and imrpove functional ability in patiemts with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.

[Capillaroscopy in rheumatological practice--one center experience]. / Kapilaroskopija u reumatoloskoj praksi--iskustvo jednog centra.

Capillaroscopy is a method for evaluating morphological characteristics of nailfold capillaries. The simplicity, noninvasiveness and easiness-to-perform make the method accessible in everyday rheumatological practice. Raynaud's phenomenon is the main indication for performing capillaroscopy (differentiating between primary and secondary Raynaud's phenomenon) and diagnosing early stages of systemic sclerosis. According to some authors capillaroscopy should be included in the work-up algorithm for patients with puffy fingers and Raynaud's phenomenon. Other autoimmune conditions (systemic lupus erythematosus, polymyositis/dermatomyositis, mixed connective tissue disease, antiphospholipid syndrome and other diseases which affect microvasculature - diabetes mellitus, thromboangiitis obliterans) can have some abnormalities of the capillaroscopic pattern. We present the results of the capillaroscopies performed in our center during the period of one year.

Eosinophilia-myalgia syndrome induced by excessive L-tryptophan intake from cashew nuts.

Eosinophilia is characterized by more than 0.5 × 109 eosinophils per liter in the full blood count. A wide range of conditions, from asthma to parasitic infections, autoimmune diseases, and certain forms of cancer, have been known to trigger abnormally high amount of eosinophils. It is essential to reach the correct diagnosis and treat the underlying disease aggresively. Definition of the eosinophilia-myalgia syndrome was offered in 1980s by Centers for Disease Control and Prevention for surveillance purposes, and criteria were revised in 2001, with high specificity. We report a case of 59-year old female who started a special weight-reducing diet regimen that included excessive cashew nut ingestion. Several months after she has presented with periferal blood eosinophilia and constitutional symptoms. Detailed work-up has not found elements for haematological, systemic autoimmune, neoplastic or infectious disease. She was diagnosed with eosinophilia-myalgia syndrome due to extreme L-tryptophan intake, a compound found in the cashew nut's oil. She responded well to cashew nut withdrawal and steroid therapy. In the follow-up period she remained stable with normal eosinophil count and there was not a need for any specific therapy.

Fever of unknown origin: large vessel vasculitis diagnosed by PET/CT.

PET/CT is starting to play an important role in evaluating fever of unknown origin (FUO), due to its ability to localize and delineate areas of high metabolic activity, such as neoplastic proliferation and inflammation, including vasculitis. We present a case of giant cell arteritis (GCA) in a 72-year-old female patient admitted to our department with a 4-month history of FUO, weight loss and fatigue, without specific symptoms or signs. Laboratory investigations suggested acute phase response, with a pronounced erythrocyte sedimentation rate, high CRP level and microcytic anemia. A thorough diagnostic evaluation was performed to exclude an unknown primary tumor, which was initially suspected due to a positive family history of cancer. Surprisingly, PET/CT revealed large vessel vasculitis affecting the ascending, descending and abdominal aorta, as well as subclavian, proximal brachial and carotid arteries bilaterally. Biopsy of the superficial temporal artery confirmed the diagnosis of GCA. Treatment with methylprednisolone and azathioprine led to resolution of clinical symptoms and normalization of laboratory parameters. In addition to the use of PET/CT in the evaluation of FUO, its value as a method complementary to temporal artery biopsy is also discussed.

[Rare myositides and myopathies]. / Rijetki miozitisi i miopatije.

Inflammatory myopathies comprise dermatomyositis, polymyositis, inclusion body myositis, secondary myopathies associated with connective tissue diseases, malignancies, sarcoidosis and Behçet's disease. In the article the inclusion body myositis is presented. Differential diagnosis ofproximal muscle weakness also includes certain non-inflammatory myopathies The statin myopathy, as an example of the drug-induced myotoxicity, is elaborated. The infectious myopathies are described with the emphasis on parasitic myopathy. The endocrine myopathies are overviewed.