A novel treatment for psoriatic arthritis:Janus kinase inhibitors

Psoriatic arthritis(PsA)is a type of chronic inflammatory arthritis which is associated with psoriasis.The early recognition and treatment for PsA are of critical importance.Janus kinase(JAK)inhibitors,as a kind of orally small molecules,have emerged as an encouraging class of drug in PsA treatment.This review provides a discussion of the role and current status of JAK inhibitors in the control of PsA.There are three JAK inhibitors approved for use in autoimmune diseases,for example,tofacitinib,baricitinib,and upadacitinib,and only tofacitinib has been approved in PsA treatment.The clinical trials of upadacitinib and filgotinib in PsA patients are undergoing.The efficacy and safety of these agents were briefly discussed.Although there are still issues in terms of their efficacy and safety currently,JAK inhibitors are expected to benefit more PsA patients in future.

Rapid remission of refractory synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome in response to the Janus kinase inhibitor tofacitinib: A case report

BACKGROUND Synovitis,acne,pustulosis,hyperostosis,and osteitis(SAPHO)syndrome is a rare autoinflammatory disease for which clinical treatment has not been standardized.Janus kinase(JAK)inhibitors represent a novel therapeutic option for rheumatoid arthritis,psoriatic arthritis,and some other autoinflammatory diseases.However,the clinical utility of JAK inhibitors in treating SAPHO syndrome has not been thoroughly investigated.In this study,we describe a patient with SAPHO syndrome who failed to respond to conventional treatment but demonstrated a remarkable and rapid response to the JAK inhibitor tofacitinib.CASE SUMMARY A 62-year-old female patient presented with swelling and pain at the sternoclavicular joints,back pain that limited her activities,arthralgia in the right knee,and cutaneous lesions.Her symptoms were unresponsive to nonsteroidal anti-inflammatory drugs,disease-modifying antirheumatic drugs,Tripterygium wilfordii hook f,and bisphosphonates.SAPHO syndrome was diagnosed in accordance with dermatological and osteoarticular manifestations and abnormal inflammatory factors.Multiple image studies have illustrated bone lesions and pathological fractures of vertebral bodies.Oral treatment with tofacitinib at 5 mg twice daily with methotrexate and bisphosphonates was initiated.The patient reported that her pain symptoms were relieved after 3 d and her cutaneous lesions were reduced after 4 wk of treatment.Vertebral lesions were improved after 6 mo on tofacitinib.No serious adverse effects were noted.CONCLUSION JAK inhibitor therapy may be a promising strategy to treat SAPHO syndrome.

Approach to loss of response to advanced therapies in inflammatory bowel disease

BACKGROUND Remarkable progress over the last decade has equipped clinicians with many options in the treatment of inflammatory bowel disease.Clinicians now have the unique opportunity to provide individualized treatment that can achieve and sustain remission in many patients.However,issues of primary non-response(PNR)and secondary loss of response(SLOR)to non-tumour necrosis factor inhibitor(TNFi)therapies remains a common problem.Specific issues include the choice of optimization of therapy,identifying when dose optimization will recapture response,establishing optimal dose for escalation and when to switch therapy.AIM To explores the issues of PNR and SLOR to non-TNFi therapies.METHODS This review explores the current evidence and literature to elucidate management options in cases of PNR/SLOR.It will also explore potential predictors for response following SLOR/PNR to therapies including the role of therapeutic drug monitoring(TDM).RESULTS In the setting of PNR and loss of response to alpha-beta7-integrin inhibitors and interleukin(IL)-12 and IL-23 inhibitors dose optimization is a reasonable option to capture response.For Janus kinase inhibitors dose optimization can be utilized to recapture response with loss of response.CONCLUSION The role of TDM in the setting of advanced non-TNFi therapies to identify patients who require dose optimization and as a predictor for clinical remission is not yet established and this remains an area that should be addressed in the future.

Real-world efficacy and safety of tofacitinib treatment in Asian patients with ulcerative colitis

BACKGROUND Real-world data on tofacitinib(TOF)covering a period of more than 1 year for a sufficient number of Asian patients with ulcerative colitis(UC)are scarce.AIM To investigate the long-term efficacy and safety of TOF treatment for UC,including clinical issues.METHODS We performed a retrospective single-center observational analysis of 111 UC patients administered TOF at Hyogo Medical University as a tertiary inflammatory bowel disease center.All consecutive UC patients who received TOF between May 2018 and February 2020 were enrolled.Patients were followed up until August 2020.The primary outcome was the clinical response rate at week 8.Secondary outcomes included clinical remission at week 8,cumulative persistence rate of TOF administration,colectomy-free survival,relapse after tapering of TOF and predictors of clinical response at week 8 and week 48.RESULTS The clinical response and remission rates were 66.3%and 50.5%at week 8,and 47.1%and 43.5%at week 48,respectively.The overall cumulative clinical remission rate was 61.7%at week 48 and history of anti-tumor necrosis factor-alpha(TNF-α)agents use had no influence(P=0.25).The cumulative TOF persistence rate at week 48 was significantly lower in patients without clinical remission than in those with remission at week 8(30.9%vs 88.1%;P<0.001).Baseline partial Mayo Score was significantly lower in responders vs non-responders at week 8(odds ratio:0.61,95%confidence interval:0.45-0.82,P=0.001).Relapse occurred in 45.7%of patients after TOF tapering,and 85.7%of patients responded within 4 wk after re-increase.All 6 patients with herpes zoster(HZ)developed the infection after achieving remission by TOF.CONCLUSION TOF was more effective in UC patients with mild activity at baseline and its efficacy was not affected by previous treatment with anti-TNF-αagents.Most relapsed patients responded again after re-increase of TOF and nearly half relapsed after tapering off TOF.Special attention is needed for tapering and HZ.

Role of baricitinib in COVID-19 patients:A systematic review and meta-analysis

BACKGROUND Recent studies have indicated the use of baricitinib in coronavirus disease 2019(COVID-19)patients.However,the use of baricitinib in COVID-19 patients is unclear so far.AIM To determine the precise role of baricitinib in the mortality of COVID-19 patients.METHODS The relevant studies were searched in PubMed,Google scholar,and Clinical trials registries till July 13,2021 and sorted out based on inclusion and exclusion criteria.The quality of studies was assessed using Newcastle-Ottawa Scale.A random-effect model was used,and the pooled estimate was calculated as the odds ratio with a 95%confidence interval using Rev Man 5.RESULTS A total of 11 studies(4 observational and 7 clinical trials)were found relevant for analysis.The overall estimate measure in terms of odds ratio for observational studies was 0.42[0.11,1.67],whereas for clinical trials it was 0.37[0.09,1.46],indicating a non-significant reduction in COVID-19 patient deaths in the baricitinib group versus the non-baricitinib group.CONCLUSION More studies are required to confirm the role of baricitinib in the deaths of COVID-19 patients.

Seronegative spondyloarthropathy-associated inflammatory bowel disease

Seronegative spondyloarthropathy(SpA)usually starts in the third decade of life with negative rheumatoid factor,human leukocyte antigen-B27 genetic marker and clinical features of spinal and peripheral arthritis,dactylitis,enthesitis and extra-articular manifestations(EAMs).Cases can be classified as ankylosing spondylitis,psoriatic arthritis,reactive arthritis,enteropathic arthritis,or juvenileonset spondyloarthritis.Joint and gut inflammation is intricately linked in SpA and inflammatory bowel disease(IBD),with shared genetic and immunopathogenic mechanisms.IBD is a common EAM in SpA patients,while extraintestinal manifestations in IBD patients mostly affect the joints.Although individual protocols are available for the management of each disease,the standard therapeutic guidelines of SpA-associated IBD patients remain to be established.Nonsteroidal anti-inflammatory drugs are recommended as initial therapy of peripheral and axial SpA,whereas their use is controversial in IBD due to associated disease flares.Conventional disease-modifying anti-rheumatic drugs are beneficial for peripheral arthritis but ineffective for axial SpA or IBD therapy.Anti-tumor necrosis factor monoclonal antibodies are effective medications with indicated use in SpA and IBD,and a drug of choice for treating SpA-associated IBD.Janus kinase inhibitors,approved for treating SpA and ulcerative colitis,are promising therapeutics in SpA coexistent with ulcerative colitis.A tight collaboration between gastroenterologists and rheumatologists with mutual referral from early accurate diagnosis to appropriately prompt therapy is required in this complex clinical scenario.

Immediate-release tofacitinib reduces insulin resistance in nondiabetic active rheumatoid arthritis patients:A single-center retrospective study

BACKGROUND An increased risk of insulin resistance(IR)has been identified in rheumatoid arthritis(RA),a chronic inflammatory disorder with elevated levels of pathogenic cytokines.Biologics targeting proinflammatory cytokines can control the disease and improve insulin sensitivity in RA.Although Janus kinase(JAK)signaling can regulate cytokine receptors and participate in RA pathogenesis,it remains to be elucidated whether there is a reduction of IR in such patients under JAK inhibitor(JAKi)therapy.AIM To study the effect of JAKi treatment on the reduction of IR in RA patients with active disease.METHODS A retrospective study was carried out from April 1,2017 to March 31,2021 in a population of non-diabetic patients with active RA who were undergoing tofacitinib(TOF)therapy with 5 mg twice-daily immediate-release formulation.RESULTS Fifty-six RA patients,aged 30 years to 75 years(mean±SD:52.3±11.1)with disease activity score 28 values ranging from 4.54 to 7.37(5.82±0.74),were classified into high-IR(>2.0)and low-IR(≤2.0)groups based on their baseline homeostatic model assessment(HOMA)-IR levels.They had no previous exposure to JAKi,and received TOF therapy for no less than 6 mo.In 30 patients who were naïve to biologics,after a 24-week therapeutic period,the high-IR group showed reduced HOMA-IR levels (3.331 ± 1.036 vs 2.292 ± 0.707, P < 0.001). In another 26patients who were exposed to tumor necrosis factor-α or interleukin-6 blockers, the high-IR group,despite having achieved a decrease but with lower magnitude than in naïve patients, showedreduced HOMA-IR levels (2.924 ± 0.790 vs 2.545 ± 1.080, P = 0.018).CONCLUSIONIn this retrospective study, reduced IR was achieved in non-diabetic active RA patients following24 wk of TOF therapy.

Role of JAK-STAT signaling pathway in pathogenesis and treatment of primary Sjögren’s syndrome

Primary Sjögren’s syndrome(pSS)is a systemic autoimmune disease with high prevalence and possible poor prognosis.Though the pathogenesis of pSS has not been fully elucidated,B cell hyperactivity is considered as one of the fundamental abnormalities in pSS patients.It has long been identified that Janus kinases-signal transducer and activator of transcription(JAK-STAT)signaling pathway contributes to rheumatoid arthritis and systemic lupus erythematosus.Recently,increasing numbers of studies have provided evidence that JAK-STAT pathway also has an important role in the pathogenesis of pSS via direct or indirect activation of B cells.Signal transducer and activator of transcription 1(STAT1),STAT3,and STAT5 activated by various cytokines and ribonucleic acid contribute to pSS development,respectively or synergically.These results reveal the potential application of Janus kinase inhibitors for treatment of pSS,which may fundamentally improve the quality of life and prognosis of patients with pSS.

Toward a better understanding of typeⅠinterferonopathies:a brief summary,update and beyond

Backgrounds TypeⅠinterferonopathy is a group of autoinflammatory disorders associated with prominent enhanced typeⅠinterferon signaling.The mechanisms are complex,and the clinical phenotypes are diverse.This review briefly summarized the recent progresses of typeⅠinterferonopathy focusing on the clinical and molecular features,pathogeneses,diagnoses and potential therapies.Data sources Original research articles and literature reviews published in PubMed-indexed journals.Results TypeⅠinterferonopathies include Aicardi-Goutières syndrome,spondyloenchondro-dysplasia with immune dysregulation,stimulator of interferon genes-associated vasculopathy with onset in infancy,X-linked reticulate pigmentary disorder,ubiquitin-specific peptidase 18 deficiency,chronic atypical neutrophilic dermatitis with lipodystrophy,and Singleton-Merten syndrome originally.Other disorders including interferon-stimulated gene 15 deficiency and DNAseⅡdeficiency are believed to be interferonopathies as well.Intracranial calcification,skin vasculopathy,interstitial lung disease,failure to thrive,skeletal development problems and autoimmune features are common.Abnormal responses to nucleic acid stimuli and defective regulation of protein degradation are main mechanisms in disease pathogenesis.First generation Janus kinase inhibitors including baricitinib,tofacitinib and ruxolitinib are useful for disease control.Reverse transcriptase inhibitors seem to be another option for Aicardi-Goutières syndrome.Conclusions Tremendous progress has been made for the discovery of typeⅠinterferonopathies and responsible genes.Janus kinase inhibitors and other agents have potential therapeutic roles.Future basic,translational and clinical studies towards disease monitoring and powerful therapies are warranted.

Treatment with a JAK1/2 inhibitor ameliorates murine autoimmune cholangitis induced by IFN overexpression

The interferon(IFN)signaling pathways are major immunological checkpoints with clinical significance in the pathogenesis of autoimmunity.We have generated a unique murine model named ARE-Del,with chronic overexpression of IFNγ,by altering IFNγmetabolism.Importantly,these mice develop an immunologic and clinical profile similar to patients with primary biliary cholangitis,including high titers of autoantibodies and portal inflammation.We hypothesized that the downregulation of IFN signaling pathways with a JAK1/2 inhibitor would inhibit the development and progression of cholangitis.To study this hypothesis,ARE-Del^(+/−)mice were treated with the JAK1/2 inhibitor ruxolitinib and serially studied.JAK inhibition resulted in a significant reduction in portal inflammation and bile duct damage,associated with a significant reduction in splenic and hepatic CD4^(+)T cells and CD8^(+)T cells.Functionally,ruxolitinib inhibited the secretion of the proinflammatory cytokines IFNγand TNF from splenic CD4^(+)T cells.Additionally,ruxolitinib treatment also decreased the frequencies of germinal center B(GC B)cells and T follicular helper(Tfh)cells and led to lower serological AMA levels.Of note,liver and peritoneal macrophages were sharply decreased and polarized from M1 to M2 with a higher level of IRF4 expression after ruxolitinib treatment.Mechanistically,ruxolitinib inhibited the secretion of IL-6,TNF and MCP1 and the expression of STAT1 but promoted the expression of STAT6 in macrophages in vitro,indicating that M1 macrophage polarization to M2 occurred through activation of the STAT6-IRF4 pathway.Our data highlight the significance,both immunologically and clinically,of the JAK/STAT signaling pathway in autoimmune cholangitis.