JAK Inhibitors Baricitinib Research Articles

TYK2 as a novel therapeutic target in Alzheimer's Disease with TDP-43 inclusions.

Neuroinflammation is a pathological feature of many neurodegenerative diseases, including Alzheimer's disease (AD)1,2 and amyotrophic lateral sclerosis (ALS)3, raising the possibility of common therapeutic targets. We previously established that cytoplasmic double-stranded RNA (cdsRNA) is spatially coincident with cytoplasmic pTDP-43 inclusions in neurons of patients with C9ORF72-mediated ALS4. CdsRNA triggers a type-I interferon (IFN-I)-based innate immune response in human neural cells, resulting in their death4. Here, we report that cdsRNA is also spatially coincident with pTDP-43 cytoplasmic inclusions in brain cells of patients with AD pathology and that type-I interferon response genes are significantly upregulated in brain regions affected by AD. We updated our machine-learning pipeline DRIAD-SP (Drug Repurposing In Alzheimer's Disease with Systems Pharmacology) to incorporate cryptic exon (CE) detection as a proxy of pTDP-43 inclusions and demonstrated that the FDA-approved JAK inhibitors baricitinib and ruxolitinib that block interferon signaling show a protective signal only in cortical brain regions expressing multiple CEs. Furthermore, the JAK family member TYK2 was a top hit in a CRISPR screen of cdsRNA-mediated death in differentiated human neural cells. The selective TYK2 inhibitor deucravacitinib, an FDA-approved drug for psoriasis, rescued toxicity elicited by cdsRNA. Finally, we identified CCL2, CXCL10, and IL-6 as candidate predictive biomarkers for cdsRNA-related neurodegenerative diseases. Together, we find parallel neuroinflammatory mechanisms between TDP-43 associated-AD and ALS and nominate TYK2 as a possible disease-modifying target of these incurable neurodegenerative diseases.

JAK inhibition during the early phase of SARS-CoV-2 infection worsens kidney injury by suppressing endogenous antiviral activity in mice.

Coronavirus disease 2019 (COVID-19) induces respiratory dysfunction as well as kidney injury. Although the kidney is considered a target organ of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and affected by the COVID-19-induced cytokine storm, the mechanisms of renal reaction in SARS-CoV-2 infection are unknown. In this study, a murine COVID-19 model was induced by nasal infection with mouse-adapted SARS-CoV-2 (MA10). MA10 infection induced body weight loss along with lung inflammation in mice 4 days after infection. Serum creatinine levels and the urinary albumin/creatinine ratio increased on day 4 after MA10 infection. Measurement of the urinary neutrophil gelatinase-associated lipocalin/creatinine ratio and hematoxylin and eosin staining revealed tubular damage in MA10-infected murine kidneys, indicating kidney injury in the murine COVID-19 model. Interferon (IFN)-γ and interleukin-6 upregulation in the sera of MA10-infected mice, along with the absence of MA10 in the kidneys, implied that the kidneys were affected by the MA10 infection-induced cytokine storm rather than by direct MA10 infection of the kidneys. RNA-sequencing analysis revealed that antiviral genes, such as the IFN/Janus kinase (JAK) pathway, were upregulated in MA10-infected kidneys. Upon administration of the JAK inhibitor baricitinib on days 1-3 after MA10 infection, an antiviral pathway was suppressed, and MA10 was detected more frequently in the kidneys. Notably, JAK inhibition upregulated the hypoxia response and exaggerated kidney injury. These results suggest that endogenous antiviral activity protects against SARS-CoV-2-induced kidney injury in the early phase of infection, providing valuable insights into the pathogenesis of COVID-19-associated nephropathy.NEW & NOTEWORTHY Patients frequently present with acute kidney injury or abnormal urinary findings after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we investigated how the kidneys respond during SARS-CoV-2 infection using a murine coronavirus disease 2019 (COVID-19) model and showed that Janus kinase-mediated endogenous antiviral activity protects against kidney injury in the early phase of SARS-CoV-2 infection. These findings provide valuable insights into the renal pathophysiology of COVID-19.

B cell-targeted polylactic acidnanoparticles as platform for encapsulating jakinibs: potential therapeutic strategy for systemic lupus erythematosus.

Background: B cells are pivotal in systemic lupus erythematosus and autoimmune disease pathogenesis. Materials & methods: To address this, Nile Red-labeled polylactic acid nanoparticles (NR-PLA NPs) loaded with the JAK inhibitor baricitinib (BARI), specifically targeting JAK1 and JAK2 in B cells, were developed. Results: Physicochemical characterization confirmed NP stability over 30days. NR-PLA NPs were selectively bound and internalized by CD19+ B cells, sparing other leukocytes. In contrast to NR-PLA NPs, BARI-NR-PLA NPs significantly dampened B-cell activation, proliferationand plasma cell differentiation in healthy controls. They also inhibited key cytokine production. These effects often surpassed those of equimolar-free BARI. Conclusion: This study underscores thepotential ofPLA NPsto regulate autoreactive B cells, offering a novel therapeutic avenue for autoimmune diseases.

Oral JAK inhibitor baricitinib effective in JIA.

Oral JAK inhibitor baricitinib effective in JIA.

STING-associated vasculopathy with onset in infancy: the first case in Bulgaria and review of the literature

We report a clinical case of a 4-year-and-10-month-old boy whose first symptoms (fever and tachypnoea) were noticed at the age of 6 months. In the upcoming months, skin acral violaceous plaques developed. Failure to thrive and growth impairment were detected. In the journey to find the correct diagnosis, a lot of diseases were suspected. The final diagnosis was suggested after more than 2 years since the first symptoms had appeared. A multi-detector computed tomography of the chest with low radiation dose protocol showed signs of interstitial lung disease (ILD). Next-Generation Sequencing was done, and it revealed a pathogenic heterozygous N154S mutation (NM_198282.4 (Stimulator of IFN genes STING1):c.461A > G (p.Asn154Ser)) in STING1 gene. Treatment with JAK-inhibitor baricitinib was started at the age of 3 years and 10 months. The presence of cutaneous vasculopathy, lung involvement, laboratory signs of inflammation, recurrent fevers and failure to thrive should indicate STING1 gene analysis. STING-associated vasculopathy of infantile-onset (SAVI) is one of the newly identified type I interferonopathies. SAVI is characterized by systemic inflammation via the overproduction of type I IFN due to heterozygous gain-of-function mutations in STING1. The onset of the symptoms of SAVI is usually early in infancy with recurrent fevers accompanied by increased acute phase reactants and ulcerating skin lesions.

The Triumph of JAK Inhibitors for the Treatment of Alopecia Areata

Alopecia areata (AA), with a disease incidence of 2% in the USA, is the most common immune-mediated cause of hair loss in the world. There were no FDA approved treatments for AA in the past. All treatment modalities used alone or in combination with each other, were prescribed off label. The JAK inhibitor baricitinib was approved by the FDA in June 2022. While it’s a significant leap forward, we are still missing the safety profile data in multiple areas. Topical JAK inhibitors are being tested along with sublingual options including tofacitinib, ruxolitinib, and ritlecitinib. In this review, we discuss the JAK inhibitor baricitinib in detail, along with its dosing regimen, challenges presented in the clinic, missing data, and what the future may hold.

Identification of novel off targets of baricitinib and tofacitinib by machine learning with a focus on thrombosis and viral infection

As there are no clear on-target mechanisms that explain the increased risk for thrombosis and viral infection or reactivation associated with JAK inhibitors, the observed elevated risk may be a result of an off-target effect. Computational approaches combined with in vitro studies can be used to predict and validate the potential for an approved drug to interact with additional (often unwanted) targets and identify potential safety-related concerns. Potential off-targets of the JAK inhibitors baricitinib and tofacitinib were identified using two established machine learning approaches based on ligand similarity. The identified targets related to thrombosis or viral infection/reactivation were subsequently validated using in vitro assays. Inhibitory activity was identified for four drug-target pairs (PDE10A [baricitinib], TRPM6 [tofacitinib], PKN2 [baricitinib, tofacitinib]). Previously unknown off-target interactions of the two JAK inhibitors were identified. As the proposed pharmacological effects of these interactions include attenuation of pulmonary vascular remodeling, modulation of HCV response, and hypomagnesemia, the newly identified off-target interactions cannot explain an increased risk of thrombosis or viral infection/reactivation. While further evidence is required to explain both the elevated thrombosis and viral infection/reactivation risk, our results add to the evidence that these JAK inhibitors are promiscuous binders and highlight the potential for repurposing.

Current views on the pathogenesis and treatment of atopic dermatitis in adults. Experience with the JAK inhibitor baricitinib in patients with moderate to severe atopic dermatitis

Atopic dermatitis is a common, chronic, immunoinflammatory disease, the study of the pathogenesis of which has recently stepped forward and served as the impetus for the development of new drugs. For the last 10–15 years, in clinical practice, the choice of therapy for patients with moderate and severe atopic dermatitis, which would provide a stable positive effect and possess a favorable safety profile for patients, including those with comorbidities, has become a rather pressing problem. The main links in the pathogenesis of atopic dermatitis and an approach to the management of adult patients with moderate to severe atopic dermatitis are considered. The role of JAK and the JAK-STAT signaling pathway in the mechanisms of inflammation in atopic dermatitis is discussed. The article presents two clinical cases of successful treatment of patients with moderate to severe atopic dermatitis with the JAK inhibitor baricitinib, who had an insufficient response to standard baseline anti-inflammatory therapy. The first case involved the treatment of a 32-year-old patient, who had been ill since early childhood, followed by a long remission and exacerbation in 2016 when the disease began to have a frequent relapsing character. In the second case, a 45-year-old patient had had frequent relapses since the age of 16. Fast and stable results in both cases were achieved with treatment with baricitinib. The drug showed a favorable safety profile and satisfactory tolerability.

Elimination of Aicardi–Goutières syndrome protein SAMHD1 activates cellular innate immunity and suppresses SARS-CoV-2 replication

The lack of antiviral innate immune responses during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is characterized by limited production of interferons (IFNs). One protein associated with Aicardi–Goutières syndrome, SAMHD1, has been shown to negatively regulate the IFN-1 signaling pathway. However, it is unclear whether elevated IFN signaling associated with genetic loss of SAMHD1 would affect SARS-CoV-2 replication. In this study, we established in vitro tissue culture model systems for SARS-CoV-2 and human coronavirus OC43 infections in which SAMHD1 protein expression was absent as a result of CRISPR–Cas9 gene KO or lentiviral viral protein X–mediated proteosomal degradation. We show that both SARS-CoV-2 and human coronavirus OC43 replications were suppressed in SAMHD1 KO 293T and differentiated THP-1 macrophage cell lines. Similarly, when SAMHD1 was degraded by virus-like particles in primary monocyte-derived macrophages, we observed lower levels of SARS-CoV-2 RNA. The loss of SAMHD1 in 293T and differentiated THP-1 cells resulted in upregulated gene expression of IFNs and innate immunity signaling proteins from several pathways, with STAT1 mRNA being the most prominently elevated ones. Furthermore, SARS-CoV-2 replication was significantly increased in both SAMHD1 WT and KO cells when expression and phosphorylation of STAT1 were downregulated by JAK inhibitor baricitinib, which over-rode the activated antiviral innate immunity in the KO cells. This further validates baricitinib as a treatment of SARS-CoV-2–infected patients primarily at the postviral clearance stage. Overall, our tissue culture model systems demonstrated that the elevated innate immune response and IFN activation upon genetic loss of SAMHD1 effectively suppresses SARS-CoV-2 replication.

Efficacy of Combination Therapy with the JAK Inhibitor Baricitinib in the Treatment of COVID-19

Coronavirus disease-19 (COVID-19), resulting from infection with SARS-CoV-2, spans a wide spectrum of illness. In severely ill patients, highly elevated serum levels of certain cytokines and considerable cytolytic T cell infiltrates in the lungs have been observed. These same patients may bear low to negligible viral burdens suggesting that an overactive immune response, often termed cytokine storm, contributes to the severity of COVID-19. We report the safety and efficacy of baricitinib combined with remdesivir and dexamethasone in a retrospective review of 45 hospitalized patients with COVID-19 pneumonia at a tertiary academic medical center. Patients received 7-day course of baricitinib, 5-day course of remdesivir, and 10-day course of dexamethasone. Clinical status and biomarkers were obtained daily. Outcomes assessed include mortality, duration of hospitalization, presence of shock, need for supplemental oxygen, need for non-invasive ventilation, need for mechanical ventilation, and development of thrombosis. Obesity and multiple medical comorbidities were associated with hospitalization in the setting of COVID-19. Treated patients demonstrated rapid declines of C-reactive protein (CRP), ferritin and D-dimer with gradual improvement in hemoglobin, platelet counts, and clinical status. Only 2 of 45 (4.4%) treated patients required mechanical ventilation after initiating treatment, and there were six deaths (13.3%). Only 2 of 45 (4.4%) treated patients required mechanical ventilation after initiating treatment. There were six deaths (13.3%) and these were associated with lower BMI. These findings support the utility of immunosuppression via JAK inhibition in moderate to severe COVID-19 pneumonia.

JAK-inhibitors in dermatology - small molecules, big impact? Overview of the mechanism of action, previous study results and potential adverse effects.

Numerous chronic inflammatory skin diseases are associated with the release of proinflammatory cytokines, which act via the intracellular JAK-STAT pathway. JAK inhibitors represent a promising, targeted therapeutic approach for cutaneous diseases. Impressive effects have been achieved with these agents in recent years. With the approval of the JAK-inhibitors Baricitinib, Upadacitinib and Abrocitinib, new systemic therapeutic agents are now available for moderate to severe atopic dermatitis. Other diseases in which the effectiveness of these small molecules could be shown are psoriasis, chilblain lupus, dermatomyositis, vitiligo and alopecia areata. As dermatologists, we are facing a whole series of new drug approvals. In this minireview we explain the active principles of JAK inhibitors and review study results in selected inflammatory skin diseases. Finally, possible side effects and initial as well as follow-up laboratory examinations for these drugs are discussed.

AB0379 BARICITINIB IN POLYMYALGIA RHEUMATICA AND GIANT CELL ARTERITIS: REPORT OF SIX CASES

Background:Glucocorticoids (GC) are the cornerstone of the treatment of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA), but they are associated with several adverse events (AEs). Moreover, a considerable proportion of patients relapse during GC tapering.Objectives:To describe the efficacy and safety of the JAK-inhibitor baricitinib (BARI) in a group of patients with PMR and/or GCA.Methods:Case series of patients with PMR and/or GCA with a refractory disease course, despite several lines of therapy, including methotrexate (MTX) and tocilizumab (TCZ), started treatment with BARI. All patients underwent periodic, standardised clinical and laboratory examinations, and also FDG-PET/CT. PMR-activity score (AS) was calculated at each visit except in patients with isolated large vessel vasculitis (LVV) or GCA.Results:A total of six patients (five females and one male, median age 64 years, range 50-83) were treated with BARI. Two of them had isolated PMR (patients #1 and #6), two had PMR with associated LVV (patients #2 and #5), and one (patient #3) had cranial-GCA. Demographic and clinical characteristics are provided in Table 1. At the time of starting BARI, patients were taking a median prednisone dose of 8.75 mg/day (range 0-25), and the 4 patients with PMR±LVV had a median PMR-activity score (PMR-AS) of 23.3 (indicating high disease activity), which decreased to 1.58 after 6 months of treatment with BARI. Two of them could stop GC and continued BARI monotherapy (in one case, BARI was tapered down to 2 mg/day after 12 months).After starting BARI, patient #3 (GCA) could gradually taper prednisone from 25 mg/day to 10 mg/day in six months, without reporting fever or headache. After one year of treatment, she feels well while taking prednisone 7.5 mg/day.Patient #4 (LVV) remained clinically stable during the treatment with BARI, but a follow-up FDG-PET/CT showed LVV, and we decided to stop BARI and restart TCZ. After 4 months of treatment with BARI, patient #5 suffered from pneumonia, while she was also taking prednisone 15 mg/day. BARI was therefore stopped. No other AEs attributable to BARI were detected.Conclusion:BARI appears as an appealing option for treating patients with PMR and/or GCA. Although these preliminary results should be confirmed by a RCT, BARI lowered rapidly disease activity and exerted a significant steroid-sparing effect, allowing GC withdrawal in 2 out of 6 patients.Table 1.Demographic and clinical characteristics of patients.Patient #SexAgeDiagnosisPrevious treatmentDisease duration (months)PMR-AS1F66PMRMTX, HCQ, SSZ25.540.52F78PMR+LVVTCZ, MTX41.828.83F61GCACYC, MMF, TCZ119.8N/A4F60LVVTCZ16.4N/A5F83PMR+LVVMTX, TCZ24.415.26M50PMRMTX24.617.8CYC: cyclophosphamide, GCA: giant cell arteritis, HCQ: hydroxychloroquine, LVV: large vessel vasculitis, MMF: mycophenolate mofetil, MTX: methotrexate, N/A: not applicable, PMR: polymyalgia rheumatica, PMR-AS: PMR-activity score, SSZ: sulfasalazine, TCZ: tocilizumab.Disclosure of Interests:Dario Camellino Speakers bureau: Medac, Eli Lilly, Paid instructor for: Mylan, Consultant of: Accord, Celgene, Novartis, Sanofi, Christian Dejaco Speakers bureau: Eli Lilly (<10.000€), Andrea Giusti Speakers bureau: UCB, Amgen, Kyowa Kirin, Abiogen Pharma, and Eli Lilly, Consultant of: EffRx, Abiogen Pharma, FRANCO MARTINI: None declared, Renzo Cosso: None declared, Giuseppe Girasole: None declared, Gerolamo Bianchi Speakers bureau: Amgen, MSD, Novartis, Pfizer, Roche, Sanofi, Genzyme, and Servier, Consultant of: Abbvie, Abiogen Pharma, BMS, Celgene, Eli Lilly, GSK, Janssen-Cilag, Medac

The JAK inhibitor baricitinib inhibits oncostatin M induction of proinflammatory mediators in ex-vivo synovial derived cells.

To investigate the ex vivo effect of the JAK1/2 inhibitor baricitinib on expression of pro-inflammatory mediators in rheumatoid arthritis (RA) fibroblast like synoviocytes (FLS) stimulated with TNFα, IL-1β and oncostatin M (OSM), and in RA synovial membrane cells (SMCs). RA and osteoarthritis (OA) SMCs, were isolated from arthroplasty specimens of RA (n=8) and OA (n=8) patients, respectively, using enzymatic digestion followed by cell propagation to obtain RA (n=5) and OA (n=3) FLS. Normal FLS and normal human foreskin fibroblasts (HSF) were purchased from commercial sources. Fibroblasts were stimulated with cytokines with or without baricitinib. RA SMCs were cultured in the presence of baricitinib without stimulation. JAK/STAT activation and levels of mRNA and proteins of the various inflammatory cytokines (IL-6, IL-8, MCP-1, RANTES and IP-10) were determined by qPCR, ELISA and MSD. Baricitinib inhibited OSM-induced JAK signalling in RA synovial fibroblasts and effectively suppressed subsequent expression of the proinflammatory mediators IL-6, MCP-1 and IP-10. However, baricitinib was not effective in altering levels of spontaneously released TNFα, IL-6 and IL-8 in RA SMC. Although both TNFα and IL-1β signal independently of the JAK/STAT pathway, in HSF, but not in RA FLS, baricitinib significantly inhibited TNFα- and IL-1β-induced MCP-1 and IP-10 protein levels in a dose dependent manner. Furthermore, baricitinib did not inhibit TNFα- and IL-1β-induced expression of IL-6, IL-8 and MCP-1 in RA FLS. These findings are consistent with known signalling pathways employed by OSM, TNFα and IL-1β, but our data suggest that in HSF, baricitinib may have anti-inflammatory effects via downstream modulation of cytokines and chemokines produced in response to TNFα or IL-1β.

Caring for patients in a new pandemic: the necessity and challenges of observational research.

Individuals with coronavirus disease 2019 (COVID-19) can develop pneumonia and a severe inflammatory response with excessive cytokine release known as the cytokine storm. The JAK inhibitor baricitinib, used to treat rheumatoid arthritis, reduces inflammation by modifying the cytokine pathway. In this issue of the JCI, Bronte, Ugel, and colleagues performed an observational longitudinal study to evaluate the use of baricitinib in 20 patients with COVID-19. The treated patients showed reduced levels of plasma IL-6, TNF, IL-1β, and phosphorylated STAT3 as well as swift lymphocyte restoration. Notably, these patients had a dramatically favorable clinical outcome. While bias can plague uncontrolled research, this study has biological credibility and warrants randomized, controlled studies.

Vasculopathy in patients with severe COVID-19 infection

Presented review elucidates one of the manifestations of severe corona virus disease-19, (COVID-19) associated with pathological changes in the microvasculature which can be considered in the context of systemic vasculitis (SV) or vasculopathy. Since there is currently no universal treatment strategy for COVID-19, better understanding of pathomorphology and pathogenesis will provide the foundation for potentially eff ective therapeutic interventions. Along with severe progressive lung damage, patients with COVID-19 often have multiple organ symptoms resembling SV. Evidence of complement-mediated injury in severe COVID-19 comes with C5b-9 and C4d deposition in the microvasculature of lungs and other organs, which is consistent with generalized activation of both alternative and lectin-based pathways, accompanied by damage to endothelial cells, the infl ammatory cascade, and hypercoagulation. Thus, there are arguments in favor of a number of therapeutic strategies for COVID-19. Since inhibitors of the C5 component of the complement (eculizumab, ravulizumab) is eff ective in various thrombotic microangiopathies, and the selective C5aR1 receptor inhibitor аvacopan has proven eff ective for ANCA-SV, strategy targeted at the complement system look as promising in severe COVID-19. The COVID-19 infection has been observed to induce proinfl ammatory cytokine and chemokines generation, which is associated with an unfavorable prognosis. Since interleukin-6 inhibitors are eff ective for the treatment of cytokine release syndrome in various conditions, tocilizumab and sarilumab are used in patients with severe/ catastrophic COVID-19. The relevance and potential eff ectiveness of JAK inhibitor baricitinib in COVID-19 originates from its anti-infl ammatory activity and ability to suppress the early stage of coronavirus replication. Severe COVID-19 infection can be accompanied by generalized vascular pathology, mainly the microvascular, and thrombophilia, which should be considered when planning new treatment strategies.

FRI0134 EFFECT OF JAK INHIBITORS ON PAIN AND QUALITY OF LIFE IN RHEUMATOID ARTHRITIS PATIENTS

Background:Pain control is considered a treatment priority from most patients with Rheumatoid Arthritis (RA). Despite the treat to target approach, residual pain is commonly reported by patients with RA. Treatment with JAK inhibitors (JAKi) has been associated to a rapid control of pain.Objectives:To investigate the effect of JAKi on pain and quality of life in a mono-centric real-life clinical setting.Methods:Patients candidate to baricitinib or tofacitinib were evaluated at baseline and after 12 and 24 weeks of treatment. Disease activity was assessed by Disease Activity Score (DAS)28 with C reactive protein (CRP). A reduction of ≥ 50% of pain visual-analogue scale (VAS) 0-100 mm was recorded as “very much improved, substantially improved” (1). Pain VAS score ≤ 10 mm was considered “no/limited pain” (2). Patients’ satisfaction was assessed by the Patient Acceptable Symptom State question (3). Data were expressed as mean (SD) or median (interquartile range) according to the variables’ distribution. Mann Witney test was use and p values <0.05 were considered statistically significant.Results:Overall 108 patients started a JAK inhibitor (baricitinib n=67, tofacitinib n=41). Eighty-four patients (baricitinib n=51; tofacitinib n=33) were followed-up for at least 3 months and were included in the analysis. Table 1 summarizes demographic and clinical characteristic of the cohort. After 12 and 24 weeks of treatment we detected a significant reduction of DAS28 compared with baseline [from 4.7 (1.5) to 3.2 (1.7) 2.9 (1.5) and 2.7 (1.1), respectively; p<0.001; p<0.00001 and p<0.00001). At week 4, 27% and 51.8% of patients achieved remission and low disease activity, respectively; the percentages increase to 32.1% and 60.7% at week 12 and 42.2% and 70.3% at week 24. When evaluating the extent of reduction of the single items included in the DAS28 composite index we found that number of tender (TJ) and swollen joints (SJ) decreased from 9 (7.8) to 5 (3.5) to 4 (5) and 1 (3) at week 4, 2 (4) and 1 (3) at week 12, and 2 (4) and 1 (3) at week 24, respectively (p<0.00001 for all); the median reduction of TJC and SJC at week 4, 12 and 24 was 60%, 77% and 88%, and 81%, 86% and 100%, respectively. GH decreased from 70(30) to 40(40) at week 4, 40(30) at week 12 and 37(40) at week 24 (p<0.00001) with a median reduction of 37.5%, 44% and 46%. C reactive protein decreased by 54.5% at week 4, 47% at week 12 and 55% at week 24. VAS pain was significantly reduced at week 4, 12 and 24 [from 70(25) to 40(40,)30(40) at the three timepoints, p<0.00001] decreasing by 37.5%, 50% and 54%, respectively. A substantial reduction (≥50%) in VAS pain was reported by 41.3%, 54.4% and 53.9% of patients after 4, 12 and 24 weeks, respectively. Limited/no pain was reported by 21.3%, 24.7% and 36.5% at weeks 4, 12 and 24, respectively. Overall, 81.8% of patients achieved the PASS after a median time of 10 (7-15) days.Conclusion:JAK inhibitors baricitinib and tofacitinib induce a rapid improvement of disease activity driven both by pain and inflammation control. Even if no/limited pain was described only by one third of the patients, most of them reported a rapid and sustained reduction of pain accounting for the achievement of a satisfactory health condition.

Disease course and treatment effects of a JAK inhibitor in a patient with CANDLE syndrome

BackgroundCANDLE syndrome (an acronym for Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature) is a recently described rare autosomal recessive disorder charaterized by systemic autoinflammation. Clinical manifestations include presentation in the first year of life, episodes of fever accompanied by erythematous skin lesions, progressive lipodystrophy, violaceous periorbital swelling and failure to thrive. This syndrome is caused by loss of function mutations and malfunction of the immunoproteasome complex. Most patients have biallelic mutations in the PSMB8 gene that encodes the β5i catalytic subunit of the immunoproteasome. Examples of digenic inheritance have been also described in CANDLE. CANDLE patients have strong type I interferon gene expression signature and they are responsive to treatment with JAK inhibitors. However, possible serious side-effects remain a concern. Here, we report another patient with CANDLE whose disease activity was well controlled by the treatment with baricitinib.Case presentationWe report a Bulgarian patient of the Turkish ancestry who carries biallelic mutations in the PSMB8 gene: p.Ala92Val and p.Lys105Gln. The pathogenic variant p.Ala92Val has not been previously described in patients with CANDLE. We also comment on the unusual feature in this patient, nephrolithiasis, that has not been described in other patients, however it might be related to the positive family history for kidney stones. We have treated the patient with the JAK inhibitor baricitinib for the past year and we observed a significant amelioration of his inflammatory episodes, skin and joint manifestations, and improvements in physical activities and growth. The treatment with glucocorticoids (GC) was completely discontinued. No side effects have been observed, however they remain in consideration for a life-long therapy of this disease.ConclusionsCANDLE should be suspected in patients with early-onset systemic inflammatory disease and prominent skin manifestations. Molecular testing can confirm the clinical diagnosis and is very important in guiding therapies. Treatment with JAK inhibitors is highly efficacious and appears to be safe in children with CANDLE and other intereforonopathies.

JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies.

BACKGROUND. Monogenic IFN–mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease.METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes–associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed.RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5–4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93–1.78) to 0.25 (IQR, 0.1–0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31–1.09) to 0.11 mg/kg/day (IQR, 0.02–0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients’ quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia.CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment.TRIAL REGISTRATION. ClinicalTrials.gov NCT01724580 and NCT02974595.FUNDING. This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.

CANDLE Syndrome As a Paradigm of Proteasome-Related Autoinflammation.

CANDLE syndrome (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature) is a rare, genetic autoinflammatory disease due to abnormal functioning of the multicatalytic system proteasome–immunoproteasome. Several recessive mutations in different protein subunits of this system, located in one single subunit (monogenic, homozygous, or compound heterozygous) or in two different ones (digenic and compound heterozygous), cause variable defects in catalytic activity of the proteasome–immunoproteasome. The final result is a sustained production of type 1 interferons (IFNs) that can be very much increased by banal triggers such as cold, stress, or viral infections. Patients start very early in infancy with recurrent or even daily fevers, characteristic skin lesions, wasting, and a typical fat loss, all conferring the patients a unique and unmistakable phenotype. So far, no treatment has been effective for the treatment of CANDLE syndrome; the JAK inhibitor baricitinib seems to be partially helpful. In this article, a review in depth all the pathophysiological, clinical, and laboratory features of CANDLE syndrome is provided.