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Objectives To re-evaluate cut-offs for disease activity states according to the Axial Spondyloarthritis Disease Activity Score (ASDAS), and study the impact of sex, age, calendar time, disease and symptom duration on ASDAS and ASDAS cut-offs in a large contemporary cohort.Methods Data from 2939 patients with axial spondyloarthritis (axSpA) starting their first tumour necrosis factor inhibitor in nine European registries were pooled and analysed. Receiver operating characteristic analyses were performed to identify cut-offs against external criteria. Six-month data including patient and physician global assessments, both ≤1 (0–10 integer scale), and Assessment of SpondyloArthritis International Society partial remission were used for separation of inactive disease (ID) from low disease activity (LDA), while patient and physician global ≤3 were applied as external criteria to separate LDA from high disease activity (HDA). Patient and physician global ≥6 were applied to separate HDA from very high disease activity in baseline data.Results The three ASDAS cut-offs identified to separate the four disease activity states in the overall patient population were 3.5. Cut-offs for ID and LDA in women were higher (

Objectives To compare the treatment effectiveness of secukinumab in radiographic (r) versus non-radiographic (nr) axial spondyloarthritis (axSpA) patients treated in routine care across Europe.Methods Prospectively collected data on secukinumab-treated axSpA patients with known radiographic status were pooled from nine countries.Remission rates based on patient-reported outcomes (PROs; Numeric Rating Scale (0–10), for example, pain ≤2/Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≤2 and Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease (ID)

Abstract Background In European axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) clinical registries, we aimed to investigate commonalities and differences in (1) set-up, clinical data collection; (2) data availability and completeness; and (3) wording, recall period, and scale used for selected patient-reported outcome measures (PROMs). Methods Data was obtained as part of the EuroSpA Research Collaboration Network and consisted of (1) an online survey and follow-up interview, (2) upload of real-world data, and (3) selected PROMs included in the online survey. Results Fifteen registries participated, contributing 33,948 patients (axSpA: 21,330 (63%), PsA: 12,618 (37%)). The reported coverage of eligible patients ranged from 0.5 to 100%. Information on age, sex, biological/targeted synthetic disease-modifying anti-rheumatic drug treatment, disease duration, and C-reactive protein was available in all registries with data completeness between 85% and 100%. All PROMs (Bath Ankylosing Spondylitis Disease Activity and Functional Indices, Health Assessment Questionnaire, and patient global, pain and fatigue assessments) were more complete after 2015 (68–86%) compared to prior (50–79%). Patient global, pain and fatigue assessments showed heterogeneity between registries in terms of wording, recall periods, and scale. Conclusion Important heterogeneity in registry design and data collection across fifteen European axSpA and PsA registries was observed. Several core measures were widely available, and an increase in data completeness of PROMs in recent years was identified. This study might serve as a basis for examining how differences in data collection across registries may impact the results of collaborative research in the future.

Objective Evidence indicates reduced treatment effectiveness of TNFi in women with axial spondyloarthritis (axSpA) compared with men. We aimed to investigate sex differences in treatment response and retention rates over 24 months of follow-up in axSpA patients initiating their first TNFi.Methods Data from axSpA patients initiating a TNFi in 1 of 15 registries within EuroSpA collaboration were pooled. We investigated the association of sex with treatment response using logistic regression. The primary outcome was clinically important improvement (CII) at 6 months according to Ankylosing Spondylitis Disease Activity Score with C-reactive protein (CRP) (≥1.1 decrease). We adjusted for age, country and TNFi start year. A secondary outcome was retention rates over 24 months of follow-up assessed by Kaplan-Meier estimator.Results In total, 6451 axSpA patients with data on CII were assessed for treatment response; 2538 (39%) were women and 3913 (61%) were men. Women presented at baseline with lower CRP levels but had higher scores on patient-reported outcome measures. At 6 months, 53% of the women and 66% of the men had CII. Women had a lower relative risk of CII compared with men (0.81; 95% CI 0.77 to 0.84). This sex difference was similar in adjusted analysis (0.85; 95% CI 0.82 to 0.88). Retention rates were evaluated in 27 702 patients. The TNFi 6/12/24 months retention rates were significantly lower among women (79%/66%/53%) than men (88%/79%/69%).Conclusion Treatment response and retention rates are lower among women with axSpA initiating their first TNFi. Sex differences in treatment effectiveness were present regardless of the outcome measure used for treatment response, and differences in retention rates transpired early and increased as time progressed.

Summary: This is the first report comparing EULAR and national treatment recommendations for PsA patients across Europe, and the first this decade to compare ASAS-EULAR and national treatment recommendations in axSpA patients. An electronic survey was completed from October 2021–April 2022 by rheumatologists in 15 European countries. One and four countries followed all EULAR and ASAS-EULAR recommendations, respectively. Five countries had no national treatment recommendations for PsA and/or axSpA, but followed other regulations. In several countries, national treatment recommendations predated the most recent EULAR/ASAS-EULAR recommendations. Entry criteria for starting biologic/targeted synthetic disease-modifying anti-rheumatic drugs varied considerably. In several countries, for PsA patients with significant skin involvement, interleukin-17 inhibitors were not given preference. The positioning of Janus Kinase inhibitors differed and Phosphodiesterase-4 inhibitors were not in use/reimbursed in most countries. This study may motivate European countries to update their national treatment recommendations, to align them better with the latest international recommendations.

ObjectivesThis study aimed to assess the risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) treated with any of the commercially available tumour necrosis factor inhibitors (TNFis) in Slovenia.DesignThis is a cohort, registry (biorx.si) cross-linked with the Slovenian National TB Registry.SettingNational, involving all Slovenian rheumatology centres (six secondary and two secondary/tertiary).Participants2429 patients with RA, AS or PsA exposed to at least one TNFi participated in the study.Primary and secondary outcome measuresThe primary outcome measures were age-adjusted and sex-adjusted TB incidence rates (IRs) and the standardised incidence ratios (SIRs) compared with the general population exploring different TNFi exposure windows. The secondary outcome measures were a detailed characterisation of the national latent tuberculosis infection (LTBI) screening and TB chemoprophylaxis protocol implementation.ResultsAmong the 2429 patients exposed to at least one TNFi for a total of 10 445 (49% RA, 33% AS and 18% PsA) person-years (PY), 99% completed LTBI screening and 6% required TB chemoprophylaxis. Six RA (three adalimumab, three certolizumab), two PsA (two golimumab) and zero AS patients developed TB. Five out of eight had miliary TB, three out of eight had pulmonary TB and two patients died. The age-standardised and sex-standardised TB IR (95% CI) per 100 000 PYs/SIRs (95% CI) compared with the general Slovenian population for the current TNFi exposure were 52 (0 to 110)/6.7 (0.6 to 80), 47 (0 to 110)/6.1 (0.3 to 105), 45 (0 to 109)/5.8 (0.3 to 112) overall, in RA and PsA, respectively.ConclusionsThe TB IR in the Slovenian patients with RA, AS and PsA treated with TNFi was comparable with TB IRs in TB non-endemic countries with less than a tenth of the patients requiring TB chemoprophylaxis.

Summary: In this study, we optimized the dissociation of synovial tissue biopsies for single-cell omics studies and created a single-cell atlas of human synovium in inflammatory arthritis. The optimized protocol allowed consistent isolation of highly viable cells from tiny fresh synovial biopsies, minimizing the synovial biopsy drop-out rate. The synovium scRNA-seq atlas contained over 100,000 unsorted synovial cells from 25 synovial tissues affected by inflammatory arthritis, including 16 structural, 11 lymphoid, and 15 myeloid cell clusters. This synovial cell map expanded the diversity of synovial cell types/states, detected synovial neutrophils, and broadened synovial endothelial cell classification. We revealed tissue-resident macrophage subsets with proposed matrix-sensing (FOLR2+COLEC12high) and iron-recycling (LYVE1+SLC40A1+) activities and identified fibroblast subsets with proposed functions in cartilage breakdown (SOD2highSAA1+SAA2+SDC4+) and extracellular matrix remodeling (SERPINE1+COL5A3+LOXL2+). Our study offers an efficient synovium dissociation method and a reference scRNA-seq resource, that advances the current understanding of synovial cell heterogeneity in inflammatory arthritis.

Vnetne revmatične bolezni so heterogena skupina bolezni, ki lahko prizadenejo tudi pljučni intersticij. Tako kot je pogostnost intersticijske pljučne bolezni (IPB) v okviru vnetnih revmatičnih bolezni variabilna, je tudi klinična slika zelo raznolika: od omejene nenapredujoče prizadetosti pljučnega intersticija do fulminantno potekajoče življenje ogrožajoče bolezni. Podatki za diagnosticiranje in zdravljenje IPB v sklopu vnetnih revmatičnih bolezni so razmeroma skopi. Temeljno zdravljenje praviloma predstavljajo imunomodulacijska zdravila. Nedavno so se jim pri progresivni pljučni fibrozi pridružili še protifibrotiki. Odločitev pri kom, kdaj in kako intenzivno zdraviti IPB pogosto predstavlja izziv. V prispevku podajamo sklepe multidisciplinarnega posvetovalnega sestanka slovenskih revmatologov in pulmologov, ki po mnenju avtorjev glede na dostopne podatke pomenijo dobro prakso pri obravnavi tovrstnih bolnikov. Osredinjamo se na bolnike s sistemskimi vezivnotkivnimi boleznimi in revmatoidnim artritisom.

V Sloveniji kljub pomanjkanju revmatologov in s tem daljšimi čakalnimi dobami revmatološkim bolnikom zagotavljamo sodobno obravnavo, ki je primerljiva z delom v najbolj priznanih svetovnih ustanovah. Da visoko raven obravnave tudi vprihodnosti ohranimo, je bistvenega pomena, da so poslane napotnice primerno izpolnjene in opremljene z vsemi podatki, ki jih potrebujemo za ustrezno razvrščanje v čakalno knjigo glede na resnost in vrsto bolezni (triažiranje). V prispevku podajamo osnovna navodila glede napotitev v revmatološko ambulanto s strokovno ustreznimi stopnjami nujnosti.

BackgroundFollow-up data on IgA vasculitis (IgAV) in adults are scarce. We aimed to investigate the outcome of adult IgAV in a well-defined cohort.MethodsData from histologically proven patients diagnosed between January 2010 and July 2022 with at least a 3-month follow-up were analyzed. The frequency and type of relapses and information on kidney function were extracted. Risk factors for IgAV relapse and decline in renal function were studied using the Cox hazards regression analysis. Mortality in IgAV was assessed using the Kaplan–Meier analysis and the standardized mortality ratio (SMR).ResultsIn total, 265 patients were followed for a median of 24 months. At baseline, 38.9, 29.8, and 44.5% had articular, gastrointestinal, and renal involvement, respectively. Initially, 189 (71.3%) patients received systemic glucocorticoids, and 32 (12.1%) patients received an additional immunomodulator. During follow-up, 42 (15.8%) patients relapsed. Relapses were more common in younger patients (HR 1.03 [95%CI 1.01–1.05]) and those without baseline glucocorticoid treatment (HR 3.70 [95%CI 2.0–6.67]). Furthermore, 74 (27.9%) patients had persistent abnormal urinalysis and a substantial (≥20%) decline in glomerular filtration rate (eGFR) was recorded in 41 (15.5%) patients. The factors associated with persistent abnormal urinalysis were an absence of IgAV joint involvement and baseline immunomodulatory treatment. Pre-existent chronic kidney disease and heart failure were associated with eGFR decline. The overall SMR was 1.4 (95%CI 1.14–1.71) compared to the Slovenian general population.ConclusionIgAV relapses occurred in 15% of patients, with younger patients with symptomatically managed IgAV experiencing it more frequently. Heart failure emerged as a predictor of persistent abnormal urinalysis and a decline in eGFR. Adults with IgAV had increased mortality compared to the general population.

BackgroundThe management of giant cell arteritis (GCA) remains challenging and many patients require prolonged glucocorticoid treatment due to high disease relapse rates. We aimed to evaluate the role of leflunomide as a steroid-sparing agent in GCA.MethodsThis prospective open-label study included patients diagnosed with GCA between July 2014 and August 2020 and followed them for 96 weeks. At the time of diagnosis all patients received treatment following a predefined glucocorticoid regimen. At week 12 of follow-up, 10 mg of leflunomide per day was recommended as an adjunctive therapy. The decision to start with leflunomide treatment was patient-dependent. Follow-up visits were performed adhering to a predetermined protocol. The number of relapses, the cumulative glucocorticoid dose and treatment-related adverse events were recorded and compared between glucocorticoid-only and leflunomide groups.ResultsOf the 215 GCA patients [67.6% female, median (IQR) age 74 (66–79) years], 151 (70.2%) received leflunomide at week 12 (leflunomide group); the others continued with glucocorticoids (glucocorticoid-only group). During the study 64/215 (29.8%) patients relapsed. Of the 51 patients who relapsed after 12 weeks, 22/151 patients (14.6%) and 29/64 patients (45.3%) were in the leflunomide and glucocorticoid-only group, respectively (p = 0.001; NNT 3.3 for leflunomide). Furthermore, 80/151 patients in the leflunomide group managed to stop glucocorticoids at week 48 [with relapses in 6/80 patients (7.5%)]. The cumulative glucocorticoid dose was lower in the leflunomide group (p = 0.009).ConclusionIn our cohort, leflunomide safely and effectively reduced the GCA relapse rate and demonstrated a steroid-sparing effect in over three quarters of patients.

The correct balance between reactive oxygen species and antioxidant defense in an organism is disturbed in oxidative stress. To assess oxidative balance in 36 SSc patients and 26 healthy controls (HCs), we measured reactive oxidative metabolites (ROMs), total antioxidant capacity (TAC), lipid peroxidation (measuring 4-HNE), and DNA oxidative damage (measuring 8-OHdG) in serum. Furthermore, DNA breaks in leukocytes of 35 SSc patients and 32 HCs were evaluated using COMET. While we report high ROMs for both SSc patients and age/sex matched HC samples, there was a significant increase in TAC in SSc patients as compared to HCs, and thus also a significantly higher oxidative stress index in SSc patients. TAC was significantly higher in SSc patients with ILD and gastrointestinal involvement, as well as in patients with anti-topoisomerase antibodies. We observe no difference in serum lipid peroxidation status or oxidative DNA damage. However, SSc patients had significantly more leukocyte DNA breaks than HCs; the most damage was observed in patients treated with immunosuppressives. Thus, our study confirms presence of oxidative stress and increased DNA damage in leukocytes of SSc patients; however, it points toward increased antioxidant capacity, which needs to be further studied.

BackgroundSafe and effective vaccines against COVID-19 are critical for preventing the spread of SARS-CoV-2, but little is known about the humoral immune response more than 9 months after vaccination. We aimed to assess the humoral immune response after the first, second, and third (booster) doses of BNT162b2 vaccine in SARS-CoV-2 naïve and previously infected healthcare professionals (HCP) and the humoral immune response after infection in vaccinated HCP.MethodsWe measured anti-spike (anti-S) and anti-nucleocapsid antibodies at different time points up to 12 months in the sera of 300 HCP who had received two or three doses of BNT162b2 vaccine. Mixed-model analyses were used to assess anti-S antibody dynamics and to determine their predictors (age, sex, BMI, and previous infection).ResultsNaïve individuals had statistically lower anti-S antibody concentrations after the first dose (median 253 BAU/ml) than previously infected individuals (median 3648 BAU/ml). After the second dose, anti-S antibody concentrations increased in naïve individuals (median 3216 BAU/ml), whereas the second dose did not significantly increase concentrations in previously infected individuals (median 4503 BAU/ml). The third dose resulted in an additional increase in concentrations (median 4844 BAU/ml in naïve and median 5845 BAU/ml in previously infected individuals). Anti-S antibody concentrations steadily decreased after the second dose and after the third dose in naïve and previously infected individuals. In addition, we found that age had an effect on the humoral immune response. Younger individuals had higher anti-S antibody concentrations after the first and second doses. After infection with the new variant Omicron, a further increase in anti-S antibody concentrations to a median value of 4794 BAU/ml was observed in three times vaccinated HCP whose anti-S antibody concentrations were relatively high before infection (median 2141 BAU/ml). Our study also showed that individuals with systemic adverse events achieved higher anti-S antibody concentrations.ConclusionIn this study, significant differences in humoral immune responses to BNT162b2 vaccine were observed between naïve and previously infected individuals, with age playing an important role, suggesting that a modified vaccination schedule should be practiced in previously infected individuals. In addition, we showed that the high anti-S antibodies were not protective against new variants of SARS-CoV-2.

We present an optimized dissociation protocol for preparing high-quality skin cell suspensions for in-depth single-cell RNA-sequencing (scRNA-seq) analysis of fresh and cultured human skin. Our protocol enabled the isolation of a consistently high number of highly viable skin cells from small freshly dissociated punch skin biopsies, which we use for scRNA-seq studies. We recapitulated not only the main cell populations of existing single-cell skin atlases, but also identified rare cell populations, such as mast cells. Furthermore, we effectively isolated highly viable single cells from ex vivo cultured skin biopsy fragments and generated a global single-cell map of the explanted human skin. The quality metrics of the generated scRNA-seq datasets were comparable between freshly dissociated and cultured skin. Overall, by enabling efficient cell isolation and comprehensive cell mapping, our skin dissociation-scRNA-seq workflow can greatly facilitate scRNA-seq discoveries across diverse human skin pathologies and ex vivo skin explant experimentations.

Background: Idiopathic inflammatory myopathies (IIMs) are rare systemic diseases associated with significant morbidity and mortality. The aim of our study was to estimate for the first time the survival of IIM patients in Slovenia.Methods: We included IIM patients diagnosed between January 2005 and December 2020 and followed at two secondary/tertiary rheumatology centers in the country. To study survival/mortality the censor date of April 14 2021 was set. Kaplan–Meier analysis and standardized mortality ratio (SMR) were plotted using data of age and sex matched Slovenian population as a reference. Cox proportional hazards regression analysis was used to study prognostic factors for IIM mortality.Results: During the 16-year observation period, we identified 217 new IIM patients. During follow up 65 (30.0%) patients died. In the first year following IIM diagnosis the SMR was nearly 7-fold higher compared to the matched general population [SMR 6.88 (95%CI 4.41–10.24)] and remained higher also during the following 4 years. However, when excluding IIM patients with cancer, the survival outcome was, except in the first year after IIM diagnosis [SMR 5.55 (95%CI 3.10–9.15)], comparable to matched general population. In addition to cancer [HR 3.71 (95% CI 2.18–6.04)], cardiac involvement [HR 2.18 (95% CI 1.07–4.45)], fever [HR 2.13 (95% CI 1.13–4.03)], and older age [HR 1.07 (95% CI 1.04–1.09)] were extracted as prognostic factors associated with death.Conclusion: The survival of patients with IIM patients was substantially worse compared to matched general population. Cancer was the leading cause of death in our cohort.

Abstract Background Immunoglobulin A vasculitis (IgAV) is still poorly defined in the adult population. We aimed to determine the predictors of gastrointestinal (GI) or renal involvement in adult IgAV. Methods The prospective study included histologically proven adult IgAV cases diagnosed between January 2013 and July 2019 at our secondary/tertiary rheumatology center. We evaluated the role of clinical and the laboratory parameters as markers predicting the GI or renal involvement in IgAV, using the multiple logistic regression analysis. Results During the 79-month observation period, we identified 214 new adult IgAV cases (59.3% males, median (interquartile range) age 64.6 (57.2–76.7) years). The GI tract and renal involvement developed in 58 (27.1%) and 83 (38.8%) cases, respectively (concurrently in 26 (12.1%) cases). In the multivariate logistic regression analysis, generalized purpura (OR 6.74 (95%CI 3.18–14.31)), the pre-treatment neutrophil to lymphocyte ratio (NLR) > 3.5 (OR 2.78 (95%CI 1.34–5.75)), and elevated serum IgA levels (OR 0.40 (95%CI 0.20–0.79)) were extracted as factors associated with GI complications, whereas current smoking (OR 3.23 (95%CI 1.50–6.98)), generalized purpura (OR 1.98 (95%CI 1.08–3.61)), elevated serum IgA (OR 2.25 (95%CI 1.21–4.18)), NLR > 3.5 (OR 1.96 (95%CI 1.02–3.77)), and marginally age (1.02 (95%CI 1.01–1.04)) emerged as factors associated with renal complications. Conclusion Generalized purpura and pre-treatment NLR predicted both GI and renal involvement, whereas active smoking was associated with renal involvement, and the serum IgA level had a divergent effect on renal and GI involvement in adult IgAV.

Autoimmune diseases and infections are often closely intertwined. Patients with autoimmune diseases are more susceptible to infections due to either active autoimmune disease or the medications used to treat them. Based on infections as environmental triggers of autoimmunity, an autoimmune response would also be expected in COVID-19. Although some studies have shown the occurance of autoantibodies and the possible development of autoimmune diseases after SARS-CoV-2 infection, current data suggest that the levels of autoantibodies following SARS-CoV-2 infection is comparable to that of some other known infections and that the autoantibodies might only be transient. The risk of SARS-CoV-2 infection in patients with a systemic autoimmune rheumatic disease (SARD) appears slightly higher compared to the general population and the course of COVID-19 disease does not seem to be very different, however, specific therapies such as glucocorticoids and anti-TNF might modulate the risk of hospitalization/death. Cytokine release syndrome is a severe complication in COVID-19. Many drugs used for the treatment of SARD are directly or indirectly targeting cytokines involved in the cytokine release syndrome, therefore it has been suggested that they could also be effective in COVID-19, but more evidence on the use of these medications for the treatment of COVID-19 is currently being collected.

Antiphospholipid syndrome (APS) is an important cause of deep vein thrombosis (DVT). According to current APS classification criteria, APS cannot be confirmed until 24 weeks after DVT. This time frame results in frequent discontinuation of anticoagulant treatment before APS is diagnosed. Therefore, the aim of our study was to evaluate the potential predictive value of anticardiolipin (aCL) and anti-β2glycoprotein I (anti-β2GPI) before discontinuation of anticoagulation therapy. Patients with newly diagnosed DVT were included into a 24-month prospective study. All patients received anticoagulant therapy. aCL and anti-β2GPI were determined at inclusion and every four weeks for the first 24 weeks and then one and two years after inclusion. APS was confirmed in 24/221 (10.9%) patients. At the time of acute DVT 20/24 (83.3%), APS patients had positive aCL and/or anti-β2GPI. Two patients had low aCL levels and two were negative at the time of acute DVT but later met APS criteria due to lupus anticoagulant (LA). Our data indicate that negative aCL and/or anti-β2GPI at the time of acute DVT make further aPL testing unnecessary; however, LA should be determined after discontinuation of anticoagulant therapy. Positive aCL and/or anti-β2GPI at the time of acute DVT have a strong positive predictive value for APS and may support therapeutic decisions.

Gigantocelični arteritis (GCA) je najpogostejši primarni sistemski vaskulitis pri odraslih po 50. letu starosti v Evropi. Prizadene velike in srednje velike arterije in vnetni proces, ki zožuje ali popolnoma zapre svetlino žile, lahko dovede do hudih/trajnih ishemičnih zapletov kot so oslepitev, možganska kap ali miokardni infarkt. V zadnjem desetletju se je z vključitvijo slikovnih preiskav v diagnostični postopek pomembno skrajšal čas do prepoznave bolezni (t.i. zgodnji GCA). Pospešena obravnava bolnikov (ang. “fast track clinic”) je vodila v zmanjšanje pojavnosti najresnejših ishemičnih zapletov bolezni in znižanje stroškov zdravljenja. Vendar pa bolezen praviloma poteka kronično, s poslabšanji, kar skupaj s kroničnim glukokortikoidnem zdravljenjem vodi v kopičenje okvar organov in tkiv. Prav zato se intenzivno preučuje patogeneza bolezni, z možnostjo implementacije izsledkov kot so sodobne molekularno in celično usmerjene tarčne terapije. Glavni cilji našega preglednega članka so bili: a) analiza raziskav z navedenim časom trajanja od začetka simptomov do postavitve diagnoze, b) raziskava obetavnih molekularnih tarč za zdravljenje GCA in c) prepoznava klinično pomembnih celičnih podtipov. Najbolj obetavne tarčne molekule za tarčno zdravljenje so IL-6, IL-12/IL-23 in citototoksični z limfociti T povezan protein 4, medtem ko terapija z zaviralci TNF-α ni bila uspešna. Kliničnih raziskav z učinkovinami, usmerjenimi proti IL-17, še ni. V prispevku pa smo se dotaknili tudi drugih potencialnih terapevtskih tarč, vključno z molekulami, ki sodelujejujo v signalnih poteh.