Four Janus kinases (JAKs) (JAK1, JAK2, JAK3, TYK2) and seven signal transducers and activators of transcription (STATs) (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6) mediate the signal ...transduction of more than 50 cytokines and growth factors in many different cell types. Located intracellularly and downstream of cytokine receptors, JAKs integrate and balance the actions of various signaling pathways. With distinct panels of STAT-sensitive genes in different tissues, this highly heterogeneous system has broad in vivo functions playing a crucial role in the immune system. Thus, the JAK/STAT pathway is critical for resisting infection, maintaining immune tolerance, and enforcing barrier functions and immune surveillance against cancer. Breakdowns of this system and/or increased signal transduction may lead to autoimmunity and other diseases. Accordingly, the recent development and approval of the first small synthetic molecules targeting JAK molecules have opened new therapeutic avenues of potentially broad therapeutic relevance. Extensive data are now available regarding the JAK/STAT pathway in rheumatoid arthritis. Dysregulation of the cytokines is also a hallmark of systemic lupus erythematosus (SLE), and targeting the JAK/STAT proteins allows simultaneous suppression of multiple cytokines. Evidence from in vitro studies and animal models supports a pivotal role also in the pathogenesis of cutaneous lupus and SLE. This has important therapeutic implications, given the current paucity of targeted therapies especially in the latter. Herein, we summarize the currently available literature in experimental SLE, which has led to the recent promising Phase II clinical trial of a JAK inhibitor.
ObjectiveOur aim was to present our first experience with the use of caplacizumab, an anti-von Willebrand factor monoclonal antibody, in an SLE patient who developed TTP. Data on the use of ...caplacizumab in SLE-associated TTP are scarce.MethodsWe present a single SLE patient with TTP, successfully treated with plasma exchange, caplacizumab, and rituximab.ResultsA 64-year-old patient was admitted to our department in 2023 due to severe thrombocytopenia (15x109/L), multiple hematomas of the extremities, and a history of transient dysarthria lasting 30 minutes the evening prior to admission. Her previous history was remarkable for inactive SLE and splenectomy due to B-non-Hodgkin’s splenic lymphoma of the marginal zone in 2016. Her blood count was compatible with hemolytic anemia (hemoglobin 95 g/L, LDH 984 U/L, bilirubin 17 umol/L, haptoglobin undetectably low). Her anti-dsDNA levels were not increased, antiphospholipid antibodies and complement levels were normal, despite an elevated erythrocyte sedimentation rate (120 mm/h). Her brain CT and CT angiography were unremarkable. Given the negative Coombs test, an urgent peripheral blood smear was ordered, revealing the presence of 12 shistocytes per high power field, compatible with microangiopathic hemolytic anemia. Given that the patient was stable, she was started on pulse-dose iv methylprednisolone the same evening, and a blood ADAMTS13 test was ordered early in the next morning (0,05 kIU/L, reference range: 0.60–1.21). The patient was diagnosed with TTP and was treated with plasma exchange for three consecutive days, as well as caplacizumab 10 mg sc daily for the duration of plasma exchange and 30 days subsequently. She was also treated with rituximab iv 375mg/m2 body surface area (four consecutive weekly doses). Neither the chest-abdomen CT scan nor the bone marrow biopsy revealed signs of lymphoma relapse. Thrombocytopenia was resolved within a week following treatment initiation, and no relapse of TTP or SLE was observed within four months of follow-up.ConclusionsEven a history of transient neurological symptoms should warrant a diagnosis of TTP in the context of SLE with Coombs-negative hemolytic anemia. The role of caplacizumab in the therapeutic algorithm of TTP in SLE patients still needs to be established.
Objective
We explored damage occurrence in patients with childhood-onset SLE (cSLE) and aimed to predict the risk of organ damage occurrence in time.
Methods
The retrospective study included patients ...treated for cSLE at the Centre of Reference for Pediatric and Adolescent Rheumatology of the Republic Croatia over a 29-year period.
Results
The disease development of 97 patients (77 females) with cSLE was examined. The median (Q1, Q3) follow-up time was 6.5 (2.3, 12.0) years. SDI was determined at 5 time points (6, 12, 24, 36 months, and last follow-up). Thirty-eight patients (48%) had organ damage at the last follow-up. Prepubertal group of patients showed higher SLEDAI scores at the disease onset, while post-pubertal group had significantly lower proportion of patients with relapses. We estimated the time from the first symptom to the moment of damage and our findings suggest that it is unlikely that organ damage will occur in 50% of patients in the first 6 years since the diagnosis. The number of 2019 ACR/EULAR classification criteria at the time of diagnosis associated with SDI determined after 1 year of the follow-up period. The patients who received higher doses of glucocorticoids accumulated damage faster and mycophenolate mofetil was found to be a more frequent therapy in patients with SDI ≥3.
Conclusion
Knowing that damage will most likely happen after the first 6 years after diagnosis in 50% of patients enables physicians to better predict damage occurrence. High number of 2019 ACR/EULAR criteria and treatment with glucocorticoids in childhood-onset SLE are associated with damage accrual and these findings could enable us to detect patients which should be closely monitored for higher risk of damage development.
Ischemic heart disease (IHD) morbidity and mortality indices, along with medical intervention rates, were analyzed among Mediterranean countries, Croatia, Slovenia, Spain, Italy, and France, in the ...pre-COVID period. Standardized IHD incidence and prevalence rates from 1990 and mortality rates from 1985 were obtained from the Global Burden of Disease Study 2017 and Health for All databases. Coronary artery bypass graft (CABG) and transluminal coronary angioplasty (TCA) rates in the 2011–2019 period were obtained from Eurostat. Trends were estimated with Joinpoint regression analysis. IHD mortality rates range from 13.6 to 74.3 for females and from 37.8 to 126.03 for males. IHD mortality rates in Croatia were 5.6-fold higher among females and 3.3-fold higher among males compared to France. All countries decreased standardized IHD prevalence and incidence rates, although the magnitude varied. The high-to-low ratio, Croatia vs. Spain, was 3.5-fold for CABG and 3.2-fold for TCA. Slovenia, as opposed to Croatia, reduced the gap for all medical indicators except for relatively high prevalence rates. Despite a significant rise in medical interventions in Croatia, ineffective clinical and public health initiatives have led to only modest declines in IHD mortality rates over the past decade.
The article discusses the contribution of Croatian political science to the development of democracy in Croatia. The focus of the analysis is the concept of culture which author talks about in five ...steps. In the first step it is understood in the modern key, in the second step as different for nature and in the third as different from society. In the fourth step author differentiates political culture from political economy and political institutions, but in the fifth part there is an attempt to show culture as a fundamental part of politics, policy and polity. On the basis of these insights author shows that the matrix of Croatian political science is more and more devoted to scientific investigation of politics as culture as both study of political culture and as a source of development as politics as culture.
ObjectiveLight chain deposition has been shown to be an important histologic hallmark with differences in isotype, characteristics and ratio of kappa and lambda light chains having a significant role ...in pathobiology, pathogenesis and prognosis of several glomerular diseases. However, there is, to the best of our knowledge, no study dedicated to evaluating light chain deposits in patients with lupus nephritis (LN).MethodsWe have conducted a retrospective cohort study to evaluate the characteristics and prognostic significance of light chain deposition profile in the kidney of subjects with LN. We have collected data on demographics, clinical and laboratory parameters and histopathology (light, immunofluorescent and electron microscopy). Lambda domination (LD) was defined as lambda intensity – kappa intensity ≥ +1. SLE was diagnosed using the ACR criteria and renal outcomes per KDIGO.ResultsA total of 56 patients with LN were followed up for at least one year after kidney biopsy (79% women, mean age at biopsy 38±13 years). Mean number of glomeruli per biopsy sample was 26±12. A total of 42 (75%) patients had light chain deposition in the glomerulus with 4 (7%) having restricted lambda chain deposition and none had restricted kappa chain deposition. Mean immunofluorescent intensity was 1.6±1.0 for lambda and 1.8±1.0 for kappa light chain. A total of 12 (21%) patients had LD in the glomerulus. When examining renal outcomes at one year post-biopsy, 55% of patients achieved complete response (CR), 30% achieved partial response (PR) and 15% had no response. There were no differences in achievement of remission (CR or PR) between patients with vs. without light chain deposition (88% vs. 71%, p=0.60) as well as between those with vs. without LD (90% vs. 83%, p>0.99).ConclusionLight chain deposition is prevalent in LN, but LD is much lower than in IgA nephropathy. While their deposition did not affect renal outcomes in our patients, light chains are an important factor to consider in LN patients, especially where restriction is present and further work-up, primarily for hematologic disease, is needed. Further investigation of the potential effect of pathobiologic characteristics of light chains in LN is warranted.
Despite the development of targeted therapies, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) remain the cornerstone of treatment of rheumatoid arthritis (RA). A literature ...search was conducted on treatment recommendations and relevant papers regarding new insights on therapeutics in rheumatoid arthritis. Methotrexate is considered the "anchor drug" due to its high efficacy as monotherapy and in combination with other conventional and targeted agents. Leflunomide and sulfasalazine are sound alternatives, whereas (hydroxy)chloroquine is primarily used in combination with other csDMARDs. Their use is encouraged in all treatment phases - in combination with targeted agents, and with other csDMARDs. Combining different csDMARDs is especially attractive in lower income settings given the evidence proving (almost) equal efficacy and safety of the csDMARD combination approach compared to the combination of targeted agents with a csDMARD. The aim of this review is to provide a clinically oriented insight into the pharmacology of each csDMARD and their place in treatment algorithms.
Cilj rada: Cilj istraživanja jest utvrditi opću i dobno-specifičnu stopu smrtnosti za akutni i ponavljajući infarkt miokarda (IM) po hrvatskim županijama za razdoblje od 2015. do 2019. godine, ...koristeći revidiranu europsku populaciju iz 2013. godine (RESP). Dodatni je cilj usporediti utvrđene stope s prosječnim stopama za Hrvatsku i EU, kao i istražiti povezanost između stopa i makroekonomskih pokazatelja. Materijal i metode: Izračunate su opće i dobno standardizirane stope mortaliteta za akutni i ponovljeni IM koristeći RESP kao i njegovu stariju verziju, europsku standardnu populaciju iz 1976. godine (ESP). Dobno standardizirane stope uspoređene su s prosječnom stopom u Hrvatskoj (2017. godine) i EU (2019. godine). Prosječna stopa smrtnosti u EU temeljena je na RESP-u i dobivena je iz baze Eurostat. Broj umrlih dobiven je od Hrvatskog zavoda za javno zdravstvo, a popis
stanovnika iz Državnog zavoda za statistiku. Analizirana je povezanost stopa mortaliteta i dvaju indikatora: bruto domaćeg proizvoda (BDP) i indeksa gospodarske snage Hrvatske gospodarske komore. Rezultati: Opće stope mortaliteta za akutni i ponovljeni IM iznosi od 72 do 91 (na 100.000 stanovnika), s velikim rasponom između županija od 35 do 120. Dobno standardizirane stope temeljene na RESP-u za većinu županija brojčano su više spram stopa temeljenih na ESP-u. U svim županijama dobno standardizirane stope nadilaze prosjek EU-a (do tri puta), a smrtnost u kontinentalnim županijama viša je od smrtnosti u obalnim županijama. Dok indeks HGK-a ne korelira značajno sa smrtnošću, BDP negativno korelira u muškaraca (r = -0.492, p = 0,023). Zaključci: Primjena RESP-a umjesto ESP-a preduvjet je za usporedbu dobno standardiziranih stopa smrtnosti s članicama EU-a. Usprkos međužupanijskim razlikama, stope smrtnosti u Hrvatskoj i dalje uvelike nadilaze prosjek EU-a.
Lupus nephritis (LN) is one of the most severe features of systemic lupus erythematosus (SLE). Data on LN is scarce in the Croatian population. We analysed the characteristics of LN patients ...diagnosed at our tertiary referral centre. In this retrospective study, we analysed the following features of patients with biopsy-proven LN diagnosed between 2011 and 2020: demographics, renal laboratory parameters, renal histopathology, and treatment. A total of 38 patients were included (30 females; mean age 39+ or -15 years).The most common indication for kidney biopsy was proteinuria (89%). The proportion of LN classes was: class I (2.6%), II (5.3%), III (18.4%), IV (42.1%), V (13.2%), III+V (10.5%), IV+V (5.3%).The median time from SLE diagnosis to histologic confirmation of LN was 1.0 year. All patients were treated with methylprednisolone (MP), 68% received MP pulses. Induction treatment included intravenous (IV) cyclophosphamide (CYC) (71%) (15 patients treated per Euro-Lupus and 9 per the National Institutes of Health regimen), oral CYC (3%), or mycophenolate mofetil (11%). 79% of patients received antimalarials. While there is heterogeneity between different populations, our patient profile was similar to that from other European studies. Further follow-up of this group is necessary to assess outcomes in our population. Key words: systemic lupus erythematosus, lupus nephritis, treatment, population characteristics
ObjectiveThis international task force aimed to provide healthcare professionals and persons living with systemic lupus erythematosus (SLE) with consensus-based recommendations for physical activity ...and exercise in SLE.MethodsBased on evidence from a systematic literature review and expert opinion, 3 overarching principles and 15 recommendations were agreed on by Delphi consensus.ResultsThe overarching principles highlight the importance of shared decision-making and the need to explain the benefits of physical activity to persons living with SLE and other healthcare providers. The 15 specific recommendations state that physical activity is generally recommended for all people with SLE, but in some instances, a medical evaluation may be needed to rule out contraindications. Pertaining to outdoor activity, photoprotection is necessary. Both aerobic and resistance training programmes are recommended, with a gradual increase in frequency and intensity, which should be adapted for each individual, and ideally supervised by qualified professionals.ConclusionIn summary, the consensus reached by the international task force provides a valuable framework for the integration of physical activity and exercise into the management of SLE, offering a tailored evidence-based and eminence-based approach to enhance the well-being of individuals living with this challenging autoimmune condition.
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