Branimir Anić

Mapping and predicting mortality from systemic sclerosis

Objectives To determine the causes of death and risk factors in systemic sclerosis (SSc). Methods Between 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation. Results We identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile. Conclusion Combining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients’ survival.

Vitamin D Serum Level, Disease Activity and Functional Ability in Different Rheumatic Patients

Background:The aim of the study was to determine the serum vitamin D levels in patients with psoriatic arthritis (PsA) and compare it with patients with rheumatoid arthritis (RA) and with osteoarthritis (OA), as well as to explore the relationship of the vitamin D level with indices of disease activity and functional ability in a real-life setting in a South-European country. Methods:In a cross-sectional study, 120 adult patients with established diagnosis of PsA, RA and OA were consecutively enrolled. Serum 25-hydroxyvitamin D and intact parathyroid hormone were determined. Parameters of disease activity and functional ability were obtained using standard instruments. Results:Serum vitamin D insufficiency (⩽75 nmol/L) was found in 74% of patients with PsA, 94% patients with RA and 97% of patients with OA, whereas vitamin D deficiency (⩽25 nmol/L) was found in 13% of patients with PsA, 39% of patients with RA and in 38% of patients with OA. Compared with RA, patients with PsA had significantly higher serum vitamin D (P = 0.002), and when controlling for age and gender, their serum vitamin D level was significantly associated with disease activity and functional activity. Conclusions:In the group of rheumatic patients, a high prevalence of serum vitamin D insufficiency/deficiency was found regardless of the type of arthritis. Patients with PsA might have higher levels of vitamin D than patients with RA, and this was associated with disease activity and functional ability. The results of this study indicate that prophylactic supplementation with vitamin D might be recommended for all rheumatic patients.

Effect of cyclosporine in a murine model of experimental colitis.

The use of immunosuppressive therapy may be associated with significant toxicity. The aim of this study was to investigate the effect of cyclosporine A (CsA) in murine model of experimental colitis. Experimental colitis was induced in NMRI mice using an enema of 0.2% solution of dinitrofluorobenzene, combined with skin sensitization. After inducing colitis, experimental groups of animals were treated with CsA (1, 3, 5, 10, 25, 50 mg/kg/day) intraperitoneally (i.p.) or intracolonically (i.c.), and control groups were treated with phosphate-buffered saline intraperitoneally or intracolonically, respectively. Colonic inflammatory changes were assessed using a histopathologic score of 0–30, and pooled whole blood samples were processed with monoclonal antibodies for cyclosporine concentration. In addition, two groups of animals with experimental colitis were treated intraperitoneally or intracolonically with 3 mg/kg/day of CsA, and the colons were also taken for immunohistochemistry for CD25. CsA diminished the extent of colitis in groups treated with 3, 5, 10, or 25 mg/kg intraperitoneally or intracolonically, and in groups treated with 1 and 50 mg/kg intracolonically (P < 0.05). The effect of intracolonic application of CsA was not related to whole blood cyclosporine concentrations. In addition, the effect of CsA at 3 mg/kg, applied intraperitoneally or intracolonically was, in part, expressed in decreasing the numbers of CD25+ cells within colonic mucosa/submucosa (P < 0.05). In conclusions, the results of this study indicate the possibility of intracolonic application of cyclosporine in order to widen the therapeutic window for effective, but possibly toxic drug, such as cyclosporine.

Decrease in circulating DNA, IL-10 and BAFF levels in newly-diagnosed SLE patients after corticosteroid and chloroquine treatment

Arsenal of pattern-recognition receptors alongside antibody production machinery make B cells vulnerable to autoimmune response if an autoantigen elicits both pathways in a self-sustained fashion. Systemic lupus erythematosus is an autoimmune disease characterized by autoantibodies to DNA, RNA and related structures. Murine studies demonstrated autoreactive B cell activation upon TLR9 stimulation with DNA-containing immune complexes. This activation could be abolished with chloroquine, a drug used in SLE treatment that also blocks TLR9 signaling. We investigated whether chloroquine modulates TLR9 expression, circulating DNA levels and B cell-related cytokines in newly discovered, untreated SLE patients. TLR9 was measured in peripheral blood B cells by flow cytometry, serum DNA by real-time PCR, and IL-10 and BAFF by ELISA before treatment, after 3weeks on corticosteroids, and 3months after introduction of chloroquine. We found that circulating DNA is higher in SLE patients than in controls in every time-point and decreases significantly after chloroquine treatment. Untreated patients had higher serum IL-10 than controls or patients on corticosteroids. Also, corticosteroids decreased and chloroquine completely abolished CpG-mediated CD86 upregulation on B cells and IL-10 secretion in PBMC culture. Providing the TLR9 pathway activation demonstrates its importance in pathogenesis of human SLE, this data supports continuation of chloroquine in SLE treatment protocol. In addition, observed modulation of cytokine and DNA levels after immunomodulatory treatment prompts for inclusion of untreated patients in studies of human immune disorders.

The lobster sign in SAPHO syndrome: unusually extensive osteitis of the anterior chest wall partially responsive to infliximab

The synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome is an uncommon entity comprising several osteoarticular and cutaneous features [1]. Osteitis and hyperostosis remain key diagnostic features, since the proposed clinical criteria [2] have never been validated, especially regarding the distinction between the SAPHO syndrome and psoriatic arthritis [3]. Tumor necrosis factoralpha (TNF-a) antagonists are starting to play an important role in the treatment of patients inadequately responsive to conventional treatment [4]. We present a 48-year-old female patient diagnosed with SAPHO syndrome 5 years ago. She has been treated with nonsteroidal anti-rheumatics, sulfasalazine and methylprednisolone, with partial and unsatisfactory response in terms of clinical and laboratory features, as well as radiological and bone scan findings [5, 6]. Four years after initiating conventional treatment, she underwent a reevaluation to assess disease extent and activity. Physical examination revealed palmoplantar pustulosis and multiple joint tenderness, including sternoclavicular, costochondral, sacroiliac and peripheral joints. Laboratory investigation revealed elevated inflammatory markers, also suggesting disease activity. A technetium 99-m bone scan was subsequently performed [5]. Increased tracer uptake was observed in both sternoclavicular joints, the sternum, first ribs bilaterally, fifth and sixth ribs near the costosternal junctions and the anterior portion of the eighth left rib, resembling a lobster. It was also revealed in the right hip and pubic bone, as well as in the pubic symphysis (Fig. 1). Less pronounced accumulation was noticed in the L4 and L5 vertebrae. Infliximab was added to the treatment, leading to an almost complete regression of osteoarticular complaints and normalization of laboratory findings. However, a follow-up bone scan performed after the fourth application of infliximab revealed a pattern of tracer accumulation almost identical to the one described previously. Moreover, psoriasiform skin lesions developed on the palms and trunk following the introduction of the biological agent: although similar lesions were observed before, they were now more pronounced. The skin lesions disappeared within several weeks following the fifth application of infliximab. TNF-a antagonists are included in standard treatment strategies for seronegative spondyloarthropathies; however, their use in the SAPHO syndrome is still considered as off-label [4]. This might change in the future due to new insights into their role on the molecular level [7] and an increasing number of individual reports suggesting a positive impact on disease activity [4]. Nevertheless, some questions still remain to be answered. Our patient experienced a temporary aggravation of cutaneous lesions, which is in accordance with other authors’ findings [8]. The aggravation is probably a side effect of infliximab and not a result of worsening of the disease course. Furthermore, the impact of infliximab on bone tracer uptake should also be addressed. Although an alleviation of osteoarticular complaints was observed soon after the beginning of the biological treatment, no regression was observed on the control B. Anić I. Padjen (&) M. Barešić Division of Clinical Immunology and Rheumatology, Department of Internal Medicine, University of Zagreb School of Medicine, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia e-mail: ivan_padjen@yahoo.ca

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.

FRI0284 Altered patterns of histone acetylation point to mechanisms of transcriptional dysregulation in patients with systemic lupus erythematosus

Background Systemic lupus erythematosus (SLE) is a chronic autoimmune disease designated by a heterogeneous course and systemic nature. It arises as a result of complex pathways, as well as the interaction of genetic and environmental factors, leading to the altered reactivity of the immune system that culminates in autoantibody formation. Epidemiological studies have shown an important role of the genetic component in the emergence of SLE and genome-wide association studies have identified more than 50 SLE-associated risk loci, pointing to a complex genetic background. Objectives The aim of the study was to further elucidate the genetic mechanisms influencing the development of SLE. Methods We performed chromatin immunoprecipitation experiments to ascertain the levels of histone acetylation in peripheral blood mononuclear cells collected from 5 recent onset and treatment naive SLE patients compared to 5 age and gender matched controls. Results The analysis revealed 16 379 significantly enriched genomic regions in control patients compared to 39 204 significantly enriched genomic regions in SLE patients. Among the SLE specific regions several pathways were significantly enriched including the adaptive immune system pathway, cytokine signalling in immune system, disease of immune system and inflammation mediated by chemokine and cytokine pathway. Conclusions The collective data point to a significant alteration of histone acetylation patterns in SLE patients possibly mediated by the DNA specific autoantibodies. The results of the study offer additional insight into the genetics of SLE pointing to putative mechanisms of transcriptional dysregulation. Disclosure of Interest None declared

Echoes of the Sarajevo Declaration on integrity and visibility of scholarly publications

To the Editor: We read with great interest the Sarajevo Declaration on Integrity and Visibility of Scholarly Publications published as the editorial in the Croatian Medical Journal (1). We appreciate the efforts made by the authors, Journal Editors Group comprised of the selected lecturers at the First Mediterranean Seminar on Science Writing, Editing & Publishing (SWEP 2016). We agree with the statements of the Declaration, which highlights the main problems with editing scholarly journals in non-mainstream science countries and provides incentive for improving their standards, integrity, and visibility. The point we wish to bring forth is that the Declaration omitted to refer to journals published in languages other than English. We understand that these journals are less visible and out of focus of general scientific community, but given the main scope of the Declaration, we feel that it would have been valuable mentioning that the Declaration applies not only to journals published in English but also to journals published in other languages. The reason is that the problem of poor management, lack of understanding of how indexing services operate, and corruptive and predatory practice are even more manifest in these journals, which are vastly not covered by any kind of surveillance, such as Jeffrey Beall’s List of Predatory Publishers (2). Therefore, our efforts should be directed at all scientific journals, including those published in national languages. We believe that this should also be clearly stated in the Declaration. We thank the authors for the Declaration and feel that, with our suggestion taken into account, we can enforce the ultimate goal of the Declaration, which is to improve scientific and publishing practice.

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

Schnitzlers 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 Schnitzlers 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 patients 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.

AB0460 Causes of Early and Late Death of Patients with Systemic Lupus Erythematosus over A 10-Year Period

Background Causes of death (CODs) of patients with systemic lupus erythematosus (SLE) comprise active SLE and comorbidities that develop as a result of SLE and immunosuppressive therapy: infections, cardiovascular disease and malignant tumors. Active disease and infections are typical causes of early death, while cardiovascular disease typically causes late death. However, COD frequencies depend on the source population and data ascertainment method. Objectives To identify and compare causes of early and late death of SLE patients deceased during a ten-year period. Methods We retrospectively identified SLE patients followed-up by our Department, deceased between 2002 and 2011, and included patients with ≥4 classification criteria of the American College of Rheumatology (ACR), ≥18 years of age and Croatian residency at the time of death. Death and causes of death were retrospectively identified using patient medical records, as well as death certificates and autopsy reports, when available. We also matched data on all SLE patients that visited our Department from 2002 to 2011 with the National Mortality Database. We classified CODs into five categories: active SLE, cardiovascular disease, infection, malignant tumor and other. More than one COD category was possible in a single patient. We compared the frequencies of each COD category between patients deceased within and after 5 years following diagnosis (early vs. late death). Frequencies were compared using the χ2 and Fishers exact test, and continuous variables using the t-test and Mann-Whitney U test. The study was approved by the local ethics committee. Results We identified 90 deceased patients (68 females, 22 males; 21 in the early death group (EDG), 69 in the late death group (LDG)). EDG patients were older than LDG patients at diagnosis (mean age±SD: 56±15 vs. 46±17 years; p=0.005), but there was no difference between the age at death (mean age±SD: 58±15 years for all patients). Patients were followed-up for a median of 10 years (IQR: 5–15 years). LDG patients fulfilled a higher number of ACR criteria compared to EDG patients (median, IQR: 6, 5–7 vs. 5, 4–6; p=0.018). No difference between COD category frequencies was detected between EDG and LDG. Nevertheless, infections and active SLE were leading causes of early death (9/21 and 8/21, respectively), while cardiovascular disease was the most frequent cause of late death (30/69), followed by infection and active SLE (21/69 and 18/69, respectively)(Table). SLE was mentioned in the death-related medical records of only 41/90 patients. Cause of death Patients deceased % Early death Late death (N=90) (N=21) (N=69) Active disease (SLE) 26 29 8 18 Infection 30 33 9 21  a) Sepsis 20 22 6 14  b) Pneumonia 18 20 5 13  c) Urinary tract infection 8 9 3 5 Cardiovascular disease 36 40 6 30  a) Myocardial infarction + ischemic heart disease 12 (7+5) 13 1 11  b) Myocardial infarction 5 6 1 4  c) Stroke 8 9 0 8  d) Pulmonary embolism 3 3 1 2 Malignant tumor 15 17 1 14 Other 10 11 4 6 Unknown 8 9 1 7 Conclusions Infections and active SLE are leading causes of early death, while cardiovascular disease is the most frequent cause of late death in SLE. Lack of recording of SLE in death-related medical records requires matching of clinical data with a complementary source, such as a population-based mortality database, to identify deceased SLE patients. References Nossent J et al. Lupus 2007;16:309–17. Disclosure of Interest None declared