OBJECTIVES: To systematically review the impact of tapering targeted therapies (bDMARDs or JAKis) on the risk of serious infections and severe adverse events (SAEs) in patients with rheumatoid arthritis (RA) or axial spondyloarthritis (axSpA) in remission or low disease activity (LDA) state. MATERIALS AND METHODS: A meta-analysis based on a systematic review of PubMed, Embase, Cochrane, until August 2019, as well as relevant databases of international conferences, was used to evaluate the risk difference (RD) at 95% confidence interval (95% CI) of incidence density of serious infections, SAEs, malignancies, cardiovascular adverse events (CV AEs), or deaths after tapering (dose reduction or spacing) compared to continuation of targeted therapies. RESULTS: Of the 1957 studies initially identified, 13 controlled trials (9 RA and 4 SpA trials) were included in the meta-analysis. 1174 patient-years were studied in the tapering group (TG) versus 1086 in the usual care group (UC). There were 1.7/100 patient-year (p-y) serious infections in TG versus 2.6/100 p-y in UC (RD (95% CI) 0.01 (0.00 to 0.02), p = 0.13) and 7.4/100 p-y SAEs in TG versus 6.7/100 p-y in UC (RD 0.00 (- 0.02 to 0.02), p = 0.82). The risk of malignancies, CV AEs, or deaths did not differ between the tapering and the usual care groups. Subgroup analysis (RA and SpA) detected no significant differences between the two groups. CONCLUSION: We could not show significant impact of tapering bDMARD or JAKi over continuation concerning the risk of serious infections, SAEs, malignancies, CV AEs, or deaths in RA and SpA patients in remission or LDA state.
- Klíčová slova
- Biological therapies, DMARDs, Infection bacteria, Rheumatoid arthritis, Spondyloarthritis, Systematic review, Viruses infection,
- MeSH
- antirevmatika aplikace a dávkování škodlivé účinky MeSH
- biologické přípravky aplikace a dávkování MeSH
- inhibitory TNF aplikace a dávkování MeSH
- Janus kinasy antagonisté a inhibitory MeSH
- klinické zkoušky kontrolované jako téma MeSH
- lidé MeSH
- revmatoidní artritida * farmakoterapie MeSH
- spondylartritida * farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- systematický přehled MeSH
- Názvy látek
- antirevmatika MeSH
- biologické přípravky MeSH
- inhibitory TNF MeSH
- Janus kinasy MeSH
PURPOSE: Signal transducer and activator of transcription 1 gain-of-function (STAT1 GOF) mutations are the most common cause of chronic mucocutaneous candidiasis (CMC). We aim to report the effect of oral ruxolitinib, the Janus kinase (JAK) family tyrosine kinase inhibitor, on clinical and immune status of a 12-year-old boy with severe CMC due to a novel STAT1 GOF mutation. METHODS: Clinical features and laboratory data were analyzed, particularly lymphocyte subsets, ex vivo IFNγ- and IFNα-induced STAT1, 3, 5 phosphorylation dynamics during the course of JAK1/2 inhibition therapy, and Th17-related, STAT1- and STAT3-inducible gene expression before and during the treatment. Sanger sequencing was used to detect the STAT1 mutation. Literature review of ruxolitinib in treatment of CMC is appended. RESULTS: A novel STAT1 GOF mutation (c.617T > C; p.L206P), detected in a child with recalcitrant CMC, was shown to be reversible in vitro with ruxolitinib. Major clinical improvement was achieved after 8 weeks of ruxolitinib treatment, while sustained suppression of IFNγ- and IFNα-induced phosphorylation of STAT1, STAT3, and STAT5, as well as increased STAT3-inducible and Th17-related gene expression, was demonstrated ex vivo. Clinical relapse and spike of all monitored phosphorylated STAT activity was registered shortly after unplanned withdrawal, decreasing again after ruxolitinib reintroduction. No increase of peripheral CD4+ IL17+ T cells was detected after 4 months of therapy. No adverse effects were noted. CONCLUSION: JAK1/2 inhibition with ruxolitinib represents a viable option for treatment of refractory CMC, if HSCT is not considered. However, long-term administration is necessary, as the effect is not sustained after treatment discontinuation.
- Klíčová slova
- Chronic mucocutaneous candidiasis, Janus kinase inhibitor, candida, ruxolitinib, signal transducer and activator of transcription 1,
- MeSH
- aktivační mutace * MeSH
- biologické markery MeSH
- CD4-pozitivní T-lymfocyty imunologie metabolismus MeSH
- cytokiny metabolismus MeSH
- dítě MeSH
- fosforylace MeSH
- genetická predispozice k nemoci MeSH
- imunofenotypizace MeSH
- inhibitory proteinkinas aplikace a dávkování terapeutické užití MeSH
- Janus kinasy antagonisté a inhibitory MeSH
- kandidóza chronická mukokutánní diagnóza farmakoterapie genetika metabolismus MeSH
- lidé MeSH
- mutace * MeSH
- mutační analýza DNA MeSH
- nitrily MeSH
- pyrazoly aplikace a dávkování terapeutické užití MeSH
- pyrimidiny MeSH
- T-lymfocyty - podskupiny imunologie metabolismus MeSH
- transkripční faktor STAT1 genetika metabolismus MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Názvy látek
- biologické markery MeSH
- cytokiny MeSH
- inhibitory proteinkinas MeSH
- Janus kinasy MeSH
- nitrily MeSH
- pyrazoly MeSH
- pyrimidiny MeSH
- ruxolitinib MeSH Prohlížeč
- STAT1 protein, human MeSH Prohlížeč
- transkripční faktor STAT1 MeSH
Recent insights in rheumatoid arthritis (RA) necessitated updating the European League Against Rheumatism (EULAR) RA management recommendations. A large international Task Force based decisions on evidence from 3 systematic literature reviews, developing 4 overarching principles and 12 recommendations (vs 3 and 14, respectively, in 2013). The recommendations address conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GC); biological (b) DMARDs (tumour necrosis factor (TNF)-inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, clazakizumab, sarilumab and sirukumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (Janus kinase (Jak) inhibitors tofacitinib, baricitinib). Monotherapy, combination therapy, treatment strategies (treat-to-target) and the targets of sustained clinical remission (as defined by the American College of Rheumatology-(ACR)-EULAR Boolean or index criteria) or low disease activity are discussed. Cost aspects were taken into consideration. As first strategy, the Task Force recommends MTX (rapid escalation to 25 mg/week) plus short-term GC, aiming at >50% improvement within 3 and target attainment within 6 months. If this fails stratification is recommended. Without unfavourable prognostic markers, switching to-or adding-another csDMARDs (plus short-term GC) is suggested. In the presence of unfavourable prognostic markers (autoantibodies, high disease activity, early erosions, failure of 2 csDMARDs), any bDMARD (current practice) or Jak-inhibitor should be added to the csDMARD. If this fails, any other bDMARD or tsDMARD is recommended. If a patient is in sustained remission, bDMARDs can be tapered. For each recommendation, levels of evidence and Task Force agreement are provided, both mostly very high. These recommendations intend informing rheumatologists, patients, national rheumatology societies, hospital officials, social security agencies and regulators about EULAR's most recent consensus on the management of RA, aimed at attaining best outcomes with current therapies.
- Klíčová slova
- DMARDs (biologic), DMARDs (synthetic), Disease Activity, Rheumatoid Arthritis, Treatment,
- MeSH
- antirevmatika terapeutické užití MeSH
- časové faktory MeSH
- glukokortikoidy terapeutické užití MeSH
- inhibitory proteinkinas terapeutické užití MeSH
- Janus kinasy antagonisté a inhibitory MeSH
- kombinovaná farmakoterapie MeSH
- lidé MeSH
- methotrexát terapeutické užití MeSH
- monoklonální protilátky terapeutické užití MeSH
- náhrada léků MeSH
- revmatoidní artritida farmakoterapie MeSH
- TNF-alfa antagonisté a inhibitory MeSH
- zapojení pacienta MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- antirevmatika MeSH
- glukokortikoidy MeSH
- inhibitory proteinkinas MeSH
- Janus kinasy MeSH
- methotrexát MeSH
- monoklonální protilátky MeSH
- TNF-alfa MeSH
Primary myelofibrosis (PMF) belongs to Ph- myeloproliferative diseases. The only curative treatment is hematopoietic stem cell transplantation (HSCT). Conservative treatment options comprise supportive care, especially administration of red blood cell and platelet transfusions, and medication. Hydroxyurea, interferon α, anagrelide, corticosteroids, androgens, or inhibitors of angiogenesis (thalidomide, lenalidomide, pomalidomide) may be used for treatment of PMF, depending on the clinical stage and disease symptoms present. Also splenectomy or radiotherapy of enlarged spleen have palliative potential. JAK2 kinase inhibitors represent a novel class of drugs with a very dynamic development. Ruxolitinib, an oral selective inhibitor of JAK1 and JAK2 kinases, has shown high efficacy in patients with high-risk PMF (or with myelofibrosis following polycythemia vera or essential thrombocythemia) to ameliorate disease symptoms and to reduce splenomegaly in randomized trials COMFORT-I and COMFORT-II. Long-term monitoring of the enrolled patients demonstated prolongation of overall survival. The drug is well-tolerated, the most common side effects of treatment with ruxolitinib being deepening of thrombocytopenia and temporary worsening of anemia. The current review deals with the place of JAK2 inhibitors (and the only drug already approved for clinical use - ruxolitinib) in the management of PMF, as an addendum to the Summary of recommendations for the diagnosis and therapy of BCR/ABL-negative myeloproliferations of the Czech Hematological Societys CZEMP.
- MeSH
- Janus kinasy antagonisté a inhibitory MeSH
- lidé MeSH
- nitrily MeSH
- primární myelofibróza farmakoterapie MeSH
- pyrazoly terapeutické užití MeSH
- pyrimidiny MeSH
- randomizované kontrolované studie jako téma MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- Janus kinasy MeSH
- nitrily MeSH
- pyrazoly MeSH
- pyrimidiny MeSH
- ruxolitinib MeSH Prohlížeč