COLOUR DOPPLER SONOGRAPHY OF FACIAL AND OCCIPITAL ARTERIES IN PATIENTS WITH GIANT CELL ARTERITIS

Background: Giant cell arteritis (GCA) is the most common systemic large and medium size artery vasculitis in Western countries. Colour Doppler Sonography (CDS) allows the study of involvement of cranial arteries other than the temporal arteries, which are inconvenient to biopsy, such as the facial (FaA), and occipital (OcA) arteries. Objectives: We aimed to estimate the frequency of the FaA, and OcA involvement in GCA; and to explore the clinical characteristics of these subgroups of patients. Methods: From 1 January 2014 to 31 December 2016, we prospectively performed a CDS of the FaA, and OcA in addition to the temporal (TA), and the extracranial supra-aortic arteries in all newly diagnosed patients suspected of having GCA. We used a Philips IU22 with a 5–17.5 MHz multi-frequency linear probe from January 2014 to August 2016 and a Philips Epiq 7 with a 5–18 MHz multi-frequency linear probe from September 2016 to December 2016. All the arteries were evaluated in two planes for the highly specific halo-sign. Results: During the 36-month observation period we performed a CDS of the cranial and extra-cranial arteries in 93 GCA (66.7% female) patients. The patients’ median (IQR) age was 73.7 (66.1–79.1) years, and they had a median (IQR) symptom duration of 30 (21–90) days. We observed the halo-sign on the FaA, and OcA in 38 (40.9%), and 29 (31.2%) cases, respectively. The FaA, and OcA were simultaneously affected in 18/93 (19.4%) cases. Either FaA, or OcA were affected in 4/22 (18.2%) patients with a negative TA CDS. FaA involvement significantly correlated with jaw claudication and with severe visual manifestations, including permanent visual loss. Patients with OcA involvement least commonly had extracranial large vessel disease. Conclusions: A fifth of patients with a negative CDS of the TAs had signs of vasculitis on the CDS of the FaA, or OcA. Th e addition of FaA and OcA CDS to the routine CDS of the TAs could identify 4.3% more patients and thus further improve the sensitivity of the CDS in the suspected GCA. References: 1. Ješe R, Rotar Ž, Tomšič M, Hočevar A. Th e role of colour doppler ultrasonography of facial and occipital arteries in patients with giant cell arteritis: A prospective study. European Journal of Radiology. 2017;95:9–12

Short-term outcome of patients with adult IgA vasculitis: a single-center experience

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

Koga, kdaj in kako napotiti k revmatologu

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

Dysregulated Expression of Arterial MicroRNAs and Their Target Gene Networks in Temporal Arteries of Treatment-Naïve Patients with Giant Cell Arteritis

In this study, we explored expression of microRNA (miR), miR-target genes and matrix remodelling molecules in temporal artery biopsies (TABs) from treatment-naïve patients with giant cell arteritis (GCA, n = 41) and integrated these analyses with clinical, laboratory, ultrasound and histological manifestations of GCA. NonGCA patients (n = 4) served as controls. GCA TABs exhibited deregulated expression of several miRs (miR-21-5p, -145-5p, -146a-5p, -146b-5p, -155-5p, 424-3p, -424-5p, -503-5p), putative miR-target genes (YAP1, PELI1, FGF2, VEGFA, KLF4) and matrix remodelling factors (MMP2, MMP9, TIMP1, TIPM2) with key roles in Toll-like receptor signaling, mechanotransduction and extracellular matrix biology. MiR-424-3p, -503-5p, KLF4, PELI1 and YAP1 were identified as new deregulated molecular factors in GCA TABs. Quantities of miR-146a-5p, YAP1, PELI1, FGF2, TIMP2 and MMP9 were particularly high in histologically positive GCA TABs with occluded temporal artery lumen. MiR-424-5p expression in TABs and the presence of facial or carotid arteritis on ultrasound were associated with vision disturbances in GCA patients. Correlative analysis of miR-mRNA quantities demonstrated a highly interrelated expression network of deregulated miRs and mRNAs in temporal arteries and identified KLF4 as a candidate target gene of deregulated miR-21-5p, -146a-5p and -155-5p network in GCA TABs. Meanwhile, arterial miR and mRNA expression did not correlate with constitutive symptoms and signs of GCA, elevated markers of systemic inflammation nor sonographic characteristics of GCA. Our study provides new insights into GCA pathophysiology and uncovers new candidate biomarkers of vision impairment in GCA

Mnenje posvetovalnega sestanka revmatologov in pulmologov glede obravnave bolnika s prizadetostjo pljučnega intersticija v sklopu vnetnih revmatičnih bolezni

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

Zgodnji gigantocelični arteritis

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

The EULAR Study Group for Registers and Observational Drug Studies: comparability of the patient case mix in the European biologic disease modifying anti-rheumatic drug registers

Objective. Under the auspices of the European League Against Rheumatism (EULAR), a study group of investigators representing European biologic DMARD (bDMARD) registers was convened. The purpose of this initial assessment was to collect and compare a cross section of patient characteristics and collate information on the availability of potential confounders within these registers. Methods. Baseline characteristics of patients starting their first bDMARD in an arbitrary year (2008) for the treatment of RA, including demographic and disease characteristics, bDMARD drug details and co-morbidities, were collected and compared across 14 European bDMARD registers. Results. A total of 5320 patients were included. Half the registers had restricted recruitment to certain bDMARDs during the study year. All registers's collected data on age, gender, disease duration, seropositivity for IgM-RF and 28-joint DAS (DAS28). The mean DAS28 ranged from 4.2 to 6.6 and the mean HAQ from 0.8 to 1.9. Current smoking ranged from 9% to 34%. Nine registers reported co-morbidities with varying prevalence. Conclusion. In addition to demonstrating European-wide collaboration across rheumatology bDMARD registers, this assessment identified differences in prescribing patterns, recruitment strategies and data items collected. These differences need to be considered when applying strategies for combined analysis. The lack of a common data model across Europe calls for further work to harmonize data collection across register

Second and third TNF inhibitors in European patients with axial spondyloarthritis: Effectiveness and impact of the reason for switching

OBJECTIVE: To investigate real-world effectiveness of tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA) and the association with 1) treatment line (second and third TNFi-series) and 2) reason for withdrawal from the preceding TNFi (lack of efficacy (LOE) versus adverse events (AE)). METHODS: Prospectively collected routine care data from 12 European registries were pooled. Rates for 12-month drug retention and 6-month remission (Ankylosing Spondylitis Disease Activity Score C-reactive protein inactive disease (ASDAS-ID)) were assessed in second and third TNFi-series and stratified by withdrawal reason. RESULTS: We included 8254 s and 2939 third TNFi-series; 12-month drug retention rates were similar (71%). Six-month ASDAS-ID rates were higher for the second (23%) than third TNFi (16%). Twelve-month drug retention rates for patients withdrawing from the preceding TNFi due to AE versus LOE were similar for the second (68% and 67%) and third TNFi (both 68%), while for the second TNFi, rates were lower in primary than secondary non-responders (LOE < 26 versus ≥26 weeks) (58% versus 71%, p< 0.001). Six-month ASDAS-ID rates for the second TNFi were higher if the withdrawal reason was AE (27%) versus LOE (17%), p< 0.001, while similar for the third TNFi (19% versus 13%, p= 0.20). CONCLUSION: A similar proportion of axSpA patients remained on a second and third TNFi after one year, but with low remission rates for the third TNFi. Remission rates on the second TNFi (but not the third) were higher if the withdrawal reason from the preceding TNFi was AE versus LOE

Differences and similarities between the EULAR/ASAS-EULAR and national recommendations for treatment of patients with psoriatic arthritis and axial spondyloarthritis across Europe

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

Prospective Longitudinal Monitoring of Effectiveness and Safety of Biological Drugs in Patients with Chronic Rheumatic Diseases using BioRx.si

Cilj Prikaz uporabnosti podatkov iz registra BioRx.si za spremljanje učinkovitosti (hipotezi 1A in 1B) in varnosti (hipoteza 2) bioloških zdravil (bDMARD), ki jih uporabljamo za zdravljenje revmatskih bolezni. Hipoteze 1A. Pri bolnikih z revmatoidnim artritisom (RA), pri katerih je prvi zaviralec dejavnika tumorske nekroze (TNFi) odpovedal zaradi neučinkovitosti ali ne prenašanja, je preživetje naslednjega bDMARD odvisno od mehanizma njegovega delovanja. 1B. Pri bolnikih z RA, ankilozirajočim spondilitisom (AS) in psoriatičnim artritisom (PsA) ni razlik v preživetju med različnimi TNFi, npr. golimumaba v primerjavi z ostalimi TNFi (oTNFi). 2. Presejanje latentne okužbe z M. tuberculosis (LTBI) pri bolnikih z RA, AS in PsA pred začetkom zdravljenja s TNFi slovenski revmatologi izvajamo v dveh korakih. Prvi korak vključuje anamnezo, tuberkulinski kožni test in pregledno rentgensko sliko prsnih organov. V primeru odklonov v prvem koraku, opravi drugi korak pulmolog, ki po svoji presoji naroči dodatne preiskave in predpiše kemoprofilakso TB. Ta pristop zagotavlja primerljivo nizko pojavnost tuberkuloze pri bolnikih, izpostavljenih TNFi, kot je opisano v dostopni literaturi. Zasnova raziskave, metode in preiskovanci Vsi slovenski revmatologi preko spletnega vmesnika prispevajo podatke v nacionalni register BioRx.si. Podatke o učinkovitosti in varnosti bDMARD zbiramo od leta 2008 za RA, od leta 2010 pa tudi za AS in PsA. V raziskovalne namene lahko podatke iz registra analiziramo na različne načine. Pri vseh analizah smo za opredelitev trenutno preučevane skupine bolnikov uporabili ustrezne opisne statistične metode. Za preučevanje hipotez 1A in 1B smo ocenjevali preživetje bDMARD, ki je sestavljeni kazalec učinkovitosti in varnosti zdravila, z metodami po Kaplan Meierju in Coxu. Za preverbo hipoteze 2 smo pojavnostno stopnjo TB (TB IR) izračunali upoštevaje Poissonovo razporeditev. Za določitev po starosti in spolu standardizirane TB IR smo uporabili neposredno metodo standardizacije. Standardno populacijo je predstavljala slovenska populacija, razdeljena po spolu v 5 letna starostna obdobja. Izračunali smo tudi standardizirano pojavnostno stopnjo (SIR) v primerjavi s splošno slovensko populacijo. Rezultati 1A. 238/688 bolnikov, ki so kot prvi bDMARD prejeli TNFi, smo po prekinitvi zdravljenja z njim zdravili z drugim bDMARD: 130 drug TNFi in 108 rituksimab (31.5%) ali tocilizumab (68.5%) (ne-TNFi). Aktivnost bolezni pred začetkom zdravljenja z drugim bDMARD in prekinitev zdravljenja s prvim TNFi zaradi izostanka ali izgube učinkovitosti sta bila prepoznana kot možna dejavnika pristranosti. Zdravljenje z ne-TNFi je bilo imelo statistično pomembno prednost pred zdravljenjem z drugim TNFi (test log rank, p=0.000). Prednost se je ohranila tudi po analizi, ki je upoštevala učinke možnih dejavnikov pristranosti v z inverznimi verjetnostmi obteženemu Coxovemu modelu (HR 4.3995% CI 2.62–8.01, p <0.001). 1B. Med 7 letnim opazovanjem je 24 slovenskih revmatologov iz 8 centrov prispevalo podatke za 368 bolnikov izpostavljenih golimumabu 849 bolnik let (BL), in 1.654 bolnikov, izpostavljenih ostalim TNFi (oTNFi) 3,321 BL. Dve leti od začetka zdravljenja se deleži bolnikov, ki so še prejemali golimumab ali oTNFi niso bistveno razlikovali: pri RA 53% proti 47%, pri AS 67% proti 65%, in pri PsA 59% proti 59%. Surova in prilagojena razmerja tveganj za prekinitev zdravljenja z golimumabom se niso pomembno razlikovala med za bDMARD-naivnimi in -izkušenimi bolniki ne glede na indikacijo. Nasprotno so bila surova in prilagojena razmerja tveganj za prekinitev zdravljenja v skupini bDMARD-izkušenih bolnikov z AS in PsA, zdravljenih z oTNFi, pomembno zvečana. 2. Med 2.429 bolniki, izpostavljenimi vsaj enemu TNFi, skupno 10.445 (49% RA, 33% AS, and 18% PsA) bolnik let (BL), jih je 99% zaključilo presejanje za latentno okužbo z M. tuberculosis, 6% jih je prejelo kemoprofilakso TB. Šest bolnikov z RA (3 adalimumab, 3 certolizumab), 2 s PsA (2 golimumab) in 0 z AS je zbolelo s TB. 5/8 je imelo miliarno TB, 3/8 pljučno TB, 2 bolnika sta umrla. Po starosti in spolu standardizirane TB IR (95% CI) na 100.000 BL/SIR (95% CI), v primerjavi s splošno slovensko populacijo za trenutno izpostavljenost TNFi, so bile za celotno kohorto 52 (0–110)/6,7 (0,6–80), za RA 47 (0–110)/6,1 (0,3–105) in za PsA 45 (0–109)/5,8 (0,3–112). Zaključki 1A. Ne glede na razlog za odpoved prvega TNFi, je drugi TNFi odpovedal prej kot ne-TNFi. 1B. Preživetje golimumaba pri bolnikih z RA, AS in PsA v Sloveniji je bilo primerljivo z njegovim preživetjem v bogatejših zahodno evropskih državah. Opazili smo tudi, da je imel v primerjavi z oTNFi, golimumab boljše preživetje pri za bDMARD-izkušenih bolnikih z AS in PsA. 2. TB IR pri slovenskih bolnikih z RA, AS in PsA, zdravljenih s TNFi, je bila primerljiva s TB IR v za TB ne-endemskih državah, čeprav je kemoprofilakso TB prejela manj kot desetina bolnikov.Purpose To demonstrate the usefulness of the BioRx.si registry for monitoring effectiveness (hypotheses 1A and 1B) and safety (hypothesis 2) of biological disease modifying anti-rheumatic drugs (bDMARDs) used for treating rheumatic diseases. Hypotheses 1A. In patients with rheumatoid arthritis (RA) who failed treatment with first tumor necrosis factor inhibitor (TNFi) due to ineffectiveness or intolerance, the survival of the subsequent bDMARD depends on its mechanism of action. 1B. In patients RA, ankylosing spondylitis (AS) and psoriatic arthritis (PsA) there is no difference in the persistence of one TNFi, i.e., golimumab, when compared to other TNFis (oTNFi). 2. Two-step national screening for latent tuberculosis (TB) infection (LTBI) in patients with RA, AS and PsA treated with TNFis, which in the first step includes medical history, tuberculin skin test (TST), chest X-ray and, in the event of pathological findings in the first step, of the examination at a pulmonologist, who, if necessary, orders additional tests and prescribes TB chemoprophylaxis, ensures a comparably small incidence of infection with mycobacteria tuberculosis in this group of patients, as is described in the available literature. Study concept, methodology, subjects All Slovenian rheumatologists contribute data to the Slovenian national registry BioRx.si on-line. Effectiveness and safety data have been collected for RA since 2008, and for AS and PsA since 2010. For research purposes, data from the registry can be accessed using various parameters and can then be statistically analyzed. In all analyses we used appropriate descriptive statistical methods to characterize the currently studied groups of patients. In the analyses pertaining to hypotheses 1A and 1B we assessed the persistence of bDMARDs, a composite marker of effectiveness, and safety, using the Kaplan-Meier and Cox methods. To test hypothesis 2, we assumed Poisson distribution to determine the TB IR. We determined the age and sex standardized TB IR using the direct method of standardization, with the Slovenian general population divided by sex into 5-year brackets as the standard population. Additionally, we estimated the standardized TB IR (SIR) in comparison with the general Slovenian population. Results 1A. Two hundred thirty-eight out of 688 patients who received a TNFi as the first bDMARD were switched to another bDMARD by December 2012: 130 to a second TNFi and 108 to either rituximab (31.5%) or tocilizumab (68.5%) (non-TNFi). Disease activity at starting the second bDMARD and stopping the first TNFi due to either lack or loss of effectiveness were identified as potential confounders. There appeared to be a statistically significant retention advantage of the non-TNFi over the second TNFi (log rank test, p=0.000). This advantage was retained even after adjusting for measured confounders using the inverse probability-weighted Cox model (hazard ratio (HR) 4.3995% CI 2.62–8.01, p<0.001). 1B. During the 8-year observation period, from 1 January 2010 to 31 July 2018, 24 Slovenian rheumatologists from eight centers contributed data on 368, and 1654 patients treated for 849, and 3321 person-years with golimumab and oTNFis, respectively. The overall proportions of RA, AS and PsA patients being persistent on golimumab vs. oTNFis at 2 years after starting the therapy did not differ significantly and were 53%, 67% and 59% vs. 47%, 65% and 59%, respectively. The crude and adjusted hazard ratios for golimumab discontinuation did not differ significantly between bDMARD-naïve and bDMARD-experienced patients for any of the indications. In contrast, bDMARD-experienced AS and PsA patients treated with oTNFis were significantly more likely to discontinue treatment. 2. Among 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-standardized and sex-standardized TB IR (95% CI) per 100,000 PYs/SIRs (95% CI) compared with the general Slovenian population for the current TNFi exposure were 52 (0–110)/6.7 (0.6–80), 47 (0–110)/6.1 (0.3–105), 45 (0–109)/5.8 (0.3–112) overall, in RA and PsA, respectively.   Conclusions 1A. In RA patients that discontinued treatment with the first TNFi due to ineffectiveness or side effects, the persistence of the second bDMARD was better if a non-TNFi agent, rather than a second TNFi was used. 1B. The persistence of golimumab in patients with RA, AS, and PsA in Slovenia was comparable with its persistence in more affluent Western European countries. We observed a better persistence of golimumab compared to other TNFis in bDMARD-experienced AS and PsA patients. 2. The TB IR in the Slovenian RA, AS, and PsA patients treated with TNFi was comparable to TB IRs in TB non-endemic countries with less than a tenth of the patients requiring TB chemoprophylaxis