Disease characteristics and causes of early and late death in a group of Croatian patients with systemic lupus erythematosus deceased over a 10-year period.

AIM: To assess the causes of early death (ED) and late death (LD) in patients with systemic lupus erythematosus (SLE) and determine the features of deceased SLE patients followed-up in a single Croatian tertiary hospital center, because little if any data on causes of death (CODs) in SLE patients are available for Croatia. METHOD: We identified SLE patients regularly followed-up at the Division of Clinical Immunology and Rheumatology, University Hospital Center Zagreb, who died from 2002 to 2011. Death was ascertained by matching our institutional records with the Croatian National Death Database. Patients were grouped according to their disease duration to ED and LD and compared by demographic characteristics, classification criteria, organ damage, and CODs. RESULTS: We identified 90 patients (68 women), who died at the age of 58±15 years. The most frequent COD category was cardiovascular diseases (40%), followed by infections (33%), active SLE (29%), and malignancies (17%). No significant difference was found between the frequencies of causes of ED and LD, except for stroke, which caused only LD≥10 years after the diagnosis. SLE was reported in death certificates of only 41 of 90 patients. CONCLUSION: Although stroke occurred both in the early and late disease course, it was primarily associated with LD. Given the low proportion of SLE recorded in death certificates of deceased SLE patients, matching of institutional and vital statistics records may be required to assess the true impact of SLE on mortality.

GIANT CELL AORTITIS DIAGNOSED WITH PET/CT - PARANEOPLASTIC SYNDROME?

Vasculitides are heterogenic group of autoimmune connective tissue diseases which often present difficulties in early diagnosing. Giant cell arteritis is vasculitis of large and medium arteries. It predominantly presents with symptoms of affection of the external carotid artery branches. Furthermore, the only symptoms can be constitutional. In clinical practice, vasculitides are sometimes considered as paraneoplastic, but no definite association with malignancies has been established and the mechanisms are still debated. The gold standard for diagnosing giant cell arteritis is a positive temporal artery biopsy, but the results can often be false negative. Additionally, more than half of the patients have aorta and its main branches affected. Considering aforementioned, imaging studies are essential in confirming large-vessel vasculitis, amongst which is highly sensitive PET/CT. We present the case of a 70-year-old female patient with constitutional symptoms and elevated sedimentation rate. After extensive diagnostic tests, she was admitted to our Rheumatology unit. Aortitis of the abdominal aorta has been confirmed by PET/CT and after the introduction of glucocorticoids the disease soon went into clinical and laboratory remission. Shortly after aortitis has been diagnosed, lung carcinoma was revealed of which the patient died. At the time of the comprehensive diagnostics, there was no reasonable doubt for underlying malignoma. To the best of our knowledge, there are no recent publications concerning giant cell arteritis and neoplastic processes in the context of up-to-date non-invasive diagnostic methods (i.e. PET/CT). In the light of previous research results, we underline that the sensitivity of PET/CT is not satisfactory when estimating cancer dissemination in non-enlarged lymph nodes and that its value can at times be overestimated.

[Pregnant patient with rheumatoid arthritis treated with methotrexate and infliximab].

Tumor necrosis factor-alpha inhibitors have become an established therapeutic regimen for patients with rheumatoid arthritis. Regarding their harmful potential they are classified as category B medications. Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women. Disease-modifying antirheumatic drugs (DMARDs) are often used in combination with biological therapy and treatment with methotrexate has shown good results. This antimetabolite is classified as a category X drug and its teratogenic effect is well known. The incidence of inflammatory rheumatic diseases is significantly higher in women. There are many reports on pregnant patients treated with biological therapy, oft en in combination with DMARDs. The effects of such a therapy on reproductive health is a theme of debate, with controversial views on the matter. We present a patient with rheumatoid arthritis whose pregnancy was discovered at 31 weeks of gestation. During that period she had been treated with methotrexate and infliximab, with no adverse effects.

[Classification of vasculitides]. / Klasifikacija vaskulitisa.

Vasculitides are heterogeneous group of inflammatory diseases with one common feature--inflammation in the blood vessel wall. The diagnosis of vasculitides is probably one of the biggest challenges in medicine. Clinical presentation of the disease depends on the extent of affection of single organ or organ systems and the total number of affected organs. A broad spectrum of clinical manifestations and low incidence of the disease makes it difficult to conduct a systematic clinical research of the disease. Everyday practise and a need for systemic clinical research of the disease necessitate the differentiation of individual entities that constitute this heterogeneous group of the inflammatory diseases. In past decades various concepts of the disease classification were proposed--according to the etiology, pathogensis, type of immune response in the blood vessel wall, histological findings in the affected vessels or depending on the involment of particular organs and organ systems. None of the proposed methods of the classification of vasculitides was entirely adequate. This paper briefly presents the historical development of the classification of the vasculitides. The emphasis of this paper was on the novelties from the recent classification and nomenclature of vasculitides that was proposed at the second consensus conference held in Chapel Hill.

Prevalence of the American College of Rheumatology classification criteria in a group of 162 systemic lupus erythematosus patients from Croatia.

AIM: To identify systemic lupus erythematosus (SLE) patients diagnosed and treated at the outpatient clinic of our Division fulfilling at least four American College of Rheumatology (ACR) classification criteria at the time of the study, to determine the prevalence of each of the criteria at three different time points, and to compare the data with similar studies. METHODS: We performed retrospective and descriptive analysis of medical records of 162 patients fulfilling at least 4 ACR criteria. Classification criteria were counted and the frequency of each criterion was identified at three different time points: disease onset, time of diagnosis, and the time when the study was conducted. RESULTS: At diagnosis and at the time when the study was conducted there were 3.8 and 5.4 fulfilled classification criteria, respectively. The most common criterion at the time of the disease onset was arthritis (52.6%); at the time of diagnosis it was positive antinuclear antibody (ANA) titer (88.0%); and at the time when the study was conducted it was positive ANA titer (95.7%), immunologic disorder (89.5%), arthritis (71.0%), hematologic disorder (70.4%), malar rash (61.7%), and photosensitivity (51.9%). CONCLUSION: The prevalence of ACR criteria in our patients is similar to that in other studies, especially those involving Caucasian patients. Our results confirm the value of the ACR criteria in patients with an already established diagnosis. This is the first study on the prevalence of disease manifestations among Croatian patients with SLE.

[Polymyositis/dermatomyositis--clinical picture and treatment]. / Polimiozitis/dermatomiozitis--klinicka slika i terapija.

The clinical presentation ofmyositis ranges from a painless muscle weakness to significant myalgia with muscle weakness and constitutional symptoms. Along with muscle and skin affection and constitutional symptoms, the disease can affect lungs, joints, heart and gastrointestinal system. It is important to note that the clinical presentation ofmyositis syndrome may overlap with symptoms of other connective tissue disease in overlap syndromes (SLE, SSCL, RA, SSjö). Common manifestations of the disease are weakness and muscle fatigue, which is the result of skeletal muscles inflammation (usually the proximal group of muscles, bilaterally and symmetrical). Severe forms of the disease with affection of the throat and respiratory muscles can vitally endan- ger patients. Among constitutional (general) symptoms, fever, malaise and weight loss are usually expressed. Skin affection in dermatomyositis can be localized or generalized like vesiculobullous erythroderma. Pathognomonic cutaneous manifestations of dermatomyositis are Gottron's papules and heliotrope erythema. Lungs are most commonly affected organs (with exception of muscles and skin) in polymyositis and dermatomyositis. The affection of lung can sometimes result in fatal outcome (interstitial lung disease, secondary pulmonary hypertension). Cardiac affection is usually subclinical, but can also be expressed as heart failure, acute coronary syndrome or conduction disturbances. Infrequent manifestations of the disease are gastroesophageal reflux, malabsorption, gastrointestinal mucosal ulceration, soft tissue calcification, Raynaud's syndrome, arthralgia/arthritis and some other less common clinical manifestations of the disease. Treatment of polymyositis/dermatomyositis includes immunosuppressive/immunomodulatory therapy and supportive, symptomatic treatment. The basis for myositis treatment are glucocorticoids, which are applied orally in a daily dosage regimen of 0.75 to 1 mg/kg/day, and in severe forms of the disease in the i.v. pulse doses of 1 g/day. Immunosuppressants/immunomodulators are added in the therapy along with glucocorticoids for better control of the disease and to reduce the required dose of glucocorticoids (side effects of longterm high doses glucocorticoide use). The most commonly used immunosuppressive drug is methotrexate at a dose of up to 25 mg/week. Hydroxychloroquine has a good effect on the cutaneous manifestations of the disease. Among other immunosuppressants which are used in the treatment of myositis are azathioprine, cyclosporine (in patients with pulmonary affection), mycophenolate mofetil and tacrolimus. Intravenous immunoglobulins applied parenterally in a dose of 2 g/kg divided into multiple doses showed an excellent clinical effect in patients with affection of the esophagus and throat muscles, in patients with pulmonary affection and in patients with resistant disease. The experience with the biologics is limited to a small number of patients. Physiotherapy is a necessary form of treatment for the recovery of muscle strength in the remission phase of the disease. A prompt treatment of infections and heart failure is sometimes life-saving in patients with myositis. Symptomatic treatment of pain with analgesics and NSAIDs reduces pain, speeds up recovery and improves the quality of life in patients with myositis.

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.

[Etiology of erythema nodosum in rheumatology outpatient clinic]. / Etiologija nodoznog eritema u bolesnika u reumatoloskoj ambulanti.

Erythema nodosum (EN) is a skin lesion presenting with the acute appearance of red nodular eflorescences caused by a reactive immunological process. In most cases EN regresses spontaneously within 3 to 6 weeks and often recurs. This paper is based on a sample of 98 patients from Croatia which were treated in a rheumatologic outpatient clinic by the same internal medicine and rheumatology specialist. Presentation and differences between secondary and idiopathic forms of EN in the Croatian population were analyzed. The results show the final proportion of EN associated with secondary etiology as 47/98. Secondary etiology of EN included mostly infectious diseases (23/98), sarcoidosis (18/98) and IBD (4/98). Comparison of various clinical and laboratory parameters of both idiopathic and secondary EN resulted in a small number of statistically significant differences found (sore throat, recent respiratory infections, ASO titer changes, antibiotics use). The conclusion is that the approach to patients with EN starts by a careful taking of patient history, with an emphasis on recent upper respiratory tract infections and occurrence of diarrhea. A thorough physical examination, basic hematological and biochemical tests, basic inflammatory markers (ESR, CRP), chest X-ray and PPD test are required to determine which patients need further evaluation. A throat swab and/or determination of the titer ofASO on two occasions at intervals of 2-4 weeks should be done. It is important to perform regular patient follow-up. Considering literature substantiated regional differences in the etiology of EN it is recommended that for each population the prevalence of individual causes of EN is determined and the clinical approach accordingly standardized.

[Etiology and pathogenesis of spondyloarthritides]. / Etiologija i patogeneza spondiloartropatija.

Seronegative spondyloarthritides are inflammatory rheumatic diseases which are classified together because of numerous common and similar clinical, epidemiologic and genetic characteristics. Pathogenesis of seronegative spondyloarthritides is usually described as development of clinical characteristics of the disease in genetically susceptible person in the presence of favorable environmental factors. Development of seronegative spondyloarthritides, notably ankylosing spondylitis, is strongly connected with presence of the HLA-B27 gene. There are clear evidence that HLA-B27 positive individuals have significantly higher risk for disease development. The role of infection in occurence of seronegative spondyloarthritides is not completely understood--its role is better clarified in the case of reactive arthritis than in ankylosing spondylitis. The relation between HLA-B27 gene and infection is not clarified. Molecular mimicry theory is based on similarities between HLA-B27 molecule and microbial particle.

Corrigendum to "The Association of TNF-Alpha Inhibitors and Development of IgA Nephropathy in Patients with Rheumatoid Arthritis and Diabetes".

[This corrects the article DOI: 10.1155/2020/9480860.].

The Association of TNF-Alpha Inhibitors and Development of IgA Nephropathy in Patients with Rheumatoid Arthritis and Diabetes.

IgA nephropathy (IgAN) is a rather uncommon complication of TNF-alpha inhibition with a range of findings such as asymptomatic microscopic/macroscopic hematuria or different degrees of proteinuria and could progress to end-stage renal disease. We are reporting three patients with longstanding rheumatoid arthritis (RA), which developed IgAN while receiving TNF-alpha inhibitors. All off our three patients had RA, which lasted 2-4 years, and none of them had a prior history of chronic kidney disease. Two patients were treated with adalimumab while one patient was treated with golimumab. Discontinuation of anti-TNF-alpha therapy and initiation of immunosuppressive therapy led to improvement in serologic abnormalities and renal function in two patients, while the third patient's 24-hour proteinuria was only partially reduced, which supports previous reports on TNF-alpha inhibitor induced autoimmunity. Two of our patients had previously been diagnosed with type 2 diabetes mellitus while the third patient developed diabetes years after the onset of IgAN. This is in line with the previously described association of IgAN and diabetes mellitus. To our best knowledge, this is the first report to analyze the development of IgAN as a potential consequence of anti-TNF-alpha therapy and its possible association with pretreatment or posttreatment diabetes.

[Cryptococcal meningitis as a diagnostic problem in a patient with SLE--case report]. / Kriptokokni meningitis kao dijagnosticki problem u bolesnika sa sustavnim eritemskim lupusom- prikaz bolesnika.

Systemic erythematosus lupus (SLE) is a disease with wide range of clinical manifestations, signs and symptoms. Disease outcome depends mostly on the affection of kidneys and central nervous system by the disease. Very important cause of death in patients with SLE is infection. Infections are very common among these patients due to aggressive immunosuppressive treatment that is needed for the disease inflammatory activity control. In this case report we have presented a patient with SLE who initially had severe renal affection, but also complications of immunosuppressive therapy that was administered. Even though the disease was accidentally diagnosed, it had a severe clinical progress. Because of lupus nephropathy, in the early phase of the disease we administered aggressive immunosuppressive therapy (combined parenteral therapy of glucocorticoides and cyclophosphamide). As an outcome of the combined effect of disease and immunosuppressive agents used in the treatment of the disease, the patient had increased infective diathesis (repeated infections caused by S. enteritidis--urinary infections and sepsis). During one of the disease flares the patient was hospitalized an opportunistic infection developed. It was meningitis caused by C. neoformans. This opportunistic mycosis infection presented with clinically totally nonspecific signs and symptoms of CNS affection. Therefore, we suspected affection of CNS with SLE. Even though all diagnostic procedures were made on time and that adequate antifungal and supportive agents were applied very early after the infection onset, the outcome was fatal. Because of infective diathesis in patients with SLE, which present with common and opportunistic infections, and due to high mortality rates caused by these infections, we have tried to emphasise the importance of taking adequate specimens early after infection outcome for these rare infective agents like C. neophormans. In recent medical literature are dominant cases reported in Asia. Reports from Europe are very rare, and this case is the one of that kind in Croatia.

[Polymyalgia rheumatica]. / Reumatska polimialgija.

The etiology, pathogenesis, epidemiology, clinical picture, diagnosis, differential diagnosis and treatment of polymyalgia reumatica are presented.

[Kidney in inflammatory rheumatic diseases]. / Zahvacanje bubrega u upalnim reumatskim bolestima.

Renal lesions in inflammatory rheumatic diseases are presented.

Clinical features of the SAPHO syndrome and their role in choosing the therapeutic approach: report of four patients and review of the literature.

Although the SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome was defined as a distinct entity more than 20 years ago, its classification within the spectrum of inflammatory rheumatic diseases and the proper therapeutic approach are still a matter of debate. We present four patients diagnosed with the SAPHO syndrome treated and followed-up in our Department, demonstrating the diversity of their clinical courses and their responses to different therapeutic approaches. We also review the clinical, laboratory, and imaging features of the SAPHO syndrome described in the relevant literature. Despite the growing quantity of published data on the clinical features of the syndrome and the recognition of two disease patterns (inflammatory and bone remodeling disease), it is still not clear whether these possible disease subsets require different therapeutic strategies. Tumor necrosis factor-alpha (TNF-α) inhibitors have been suggested to be effective in patients with the inflammatory pattern, whereas bisphosphonates seem to be effective in patients with bone remodeling disease; however, this is still a hypothesis not yet confirmed by adequately designed clinical studies. Further research is needed to assess disease features predicting favorable response to the two therapeutic modalities beyond the first line of therapy - TNF-α inhibitors and bisphosphonates.

Antiphospholipid syndrome and central nervous system.

Classification criteria, etiology, pathogenesis, major central nervous system (CNS) manifestations of the antiphospholipid syndrome (APS), as well as diagnostic and therapeutic approach are discussed in the article, supported by several MRI findings to illustrate differential complexity of selected topics. Close interplay of inflammation, autoimmunity, coagulation cascade, vasculature bed, neuron physiology and demyelinization in APS is elaborated. Cerebrovascular disease, multiple sclerosis-like syndrome, seizures, cognitive disfunction, headache and migraine, chorea and catastrophic antiphospholipid syndrome (CAPS) are discussed as the most prominent CNS manifestations of the APS.

Propylthiouracil-induced anti-neutrophil cytoplasmic antibodies (ANCA) skin vasculitis: the first case reported in Croatia.

Drug-induced vasculitis is a known side effect of prolonged treatment with several drugs. It is characterized by inflammation and cellular infiltration of small vessels and presence of anti-neutrophil cytoplasmic antibodies (ANCA). Propylthiouracil and hydralazine (anti-thyroid and antihypertensive drugs) are the drugs most commonly associated with drug-induced vasculitis. Small vessels of the skin are most frequently affected, while affection of the vessels of the kidneys, central nervous system and lungs make the diagnosis life-threatening. When drug-induced vasculitis is suspected, quick and punctual diagnostic procedure should be carried out to exclude systemic manifestations. Treatment comprises of elimination of the causative drug, which is sufficient in most cases, but sometimes oral or parenteral glucocorticoids and even immunosuppressants are indicated. A case is presented of an 18-year-old male with a history of Graves disease treated with standard dose of propylthiouracil. Approximately 2.5 years after starting therapy he noticed formation of shallow skin ulcerations on both of his ear lobes and elbows. Detailed hospital work-up found high titers of perinuclear-staining anti-neutrophil cytoplasmic antibodies/myeloperoxidase (pANCA/MPO, 1:1024). Biopsy of the affected skin revealed leukocytoclastic vasculitis. Additional tests excluded systemic vasculitis. The patient was diagnosed with propylthiouracil-induced vasculitis, a form of drug-induced vasculitis. Propylthiouracil was discontinued and the skin lesions disappeared over time without the need of any specific therapy (such as glucocorticoids).

Rare zoonosis (hemotrophic mycoplasma infection) in a newly diagnosed systemic lupus erythematosus patient followed by a Nocardia asteroides pneumonia.

Systemic lupus erythematosus (SLE) is per se a disease characterized by suppressed immune response and thus susceptibility to various opportunistic infections. We describe the case of a 21-year old woman who developed a rare zoonosis - hemotrophic mycoplasma infection in the initial stage of SLE, complicated with Nocardia asteroides pneumonia afterwards. Nocardia infection coincided with initiation of glucocorticoids and cyclophosphamide therapy for SLE. After the treatment she recovered completely. To our knowledge the only case of human hemoplasmosis (then referred to as eperythrozoonosis) in medical literature was the one described by a group of Croatian authors 22 years ago. No cases of a hemotrophic mycoplasma infection in a SLE patient have been published up to now.