TNF-α Inhibitor Therapy Research Articles

Association between the systemic treatment of psoriasis and cardiovascular risk.

Association between the systemic treatment of psoriasis and cardiovascular risk.

Presence of anti-nuclear antibodies is a risk factor for the appearance of anti-drug antibodies during infliximab or adalimumab therapy in patients with rheumatoid arthritis

This study aimed to directly analyze the potential relationship of anti-nuclear antibodies (ANA) before and after the administration of TNF-α inhibitors (TNFi) with the appearance of anti-drug antibodies (ADrA) in patients with rheumatoid arthritis (RA). A total of 121 cases, viz., 38, 53, and 30 cases treated with infliximab (IFX), adalimumab (ADA), and etanercept (ETN), respectively, were enrolled. The ANA titers were measured using indirect immunefluorescence assay (IF-ANA) and multiplex flow immunoassay (ANA Screen) before and serially during the therapy. The anti-IFX antibodies (HACA) and anti-ADA antibodies (AAA) were measured with a radioimmunoassay. ADrA turned positive in 14 (36.8%) among 38 patients treated with IFX, and 16 (30.2%) among 53 treated with ADA. All of them were positive for IF-ANA before TNFi administration, while ADrA never appeared in any of the 15 patients negative for IF-ANA (< 40). IF-ANA of high titers (≥ 320 and ≥ 640) before IFX treatment showed a significant association with the appearance of HACA 52 weeks after IFX (P = 0.040 and 0.017, respectively), whereas AAA appearance was not related to IF-ANA titers before treatment. Moreover, IF-ANA of high titers before IFX treatment was significantly associated with inefficacy and discontinuation of the treatment. The positivity of anti-SS-A antibodies before therapy might be a risk factor for ADrA appearance in patients treated with IFX or ADA. The percentage of patients whose IF-ANA titers increased was significantly higher with IFX than with ADA or ETN treatments (P = 0.026 and 0.022, respectively). High ANA titers and positive ANA Screen after IFX therapy showed a significant association with HACA appearance and possibly led to treatment failure. Among the three TNFi, only IFX showed a close relationship with IF-ANA and ADrA appearance, suggesting the interaction of immunogenicity with autoimmunity as well as the advantage of ANA measurement before TNFi therapy.

IL6 genetic variants haplotype is associated with susceptibility and disease activity but not with therapy response in patients with inflammatory bowel disease.

The aim of the present study was to evaluate the IL6 -174 G>C (rs1800795) and -572 G>C (rs1800796) genetic variants and their association with inflammatory bowel diseases (IBDs), disease activity, and response to TNF-α inhibitors. The study included 178 patients with IBD and 224 healthy controls. Among the IBD patients, 66 of them were in use of TNF-α inhibitors therapy and were followed during 48weeks and categorized as responders and non-responders. In total, 89 (50.0%) had ulcerative colitis (UC) and 89 (50.0%) had Crohn's disease (CD). The IL6 -572 CC genotype presented a protective effect in CD patients in codominant and recessive models, while the IL6 -174 CC genotype was associated with susceptibility to UC and CD. The presence of G/C haplotype in the recessive model (GCGC) was associated with UC. The Crohn's disease endoscopic index of severity was low in those patients carrying the GCGC haplotype. It was observed that there was no association between the IL6 genetic variants and TNF-α inhibitor therapy response. The G/C haplotype (recessive model) was associated with susceptibility to UC but not to CD. However, the G/C haplotype (dominant model) was associated with the endoscopic activity of CD. Moreover, these IL6 variants did not predict the TNF-α inhibitor therapy response.

TNF-α inhibitors and psychiatric adverse drug reactions in the spectrum of bipolar (manic) or psychotic disorders: Analysis from the French pharmacovigilance database

This study aimed to describe reports of psychiatric adverse drug reaction (ADR) in the spectrum of bipolar (manic features) or psychotic disorders that occurred under tumor necrosis factor alpha (TNF-α) inhibitors therapy. We searched the French pharmocovigilance database for reports of psychiatric ADR in the spectrum of bipolar (manic features) or psychotic disorders during treatment with TNF-α inhibitors. Psychiatric symptoms were divided in 2 categories: (i) confirmed diagnosis of manic episode or acute psychosis and (ii) psychiatric symptoms with psychotic or manic features but not meeting sufficient criteria for diagnosis of psychosis or manic disorder. Overall, 9942 reports of ADR were registered in the French pharmacovigilance database with TNF-α inhibitors, including 243 reports of psychiatric ADR. Among them, we identified 41 reports of psychotic or manic disorders as define above: 9 characterised manic episodes and 32 psychiatric disorders with psychotic or manic features. TNF-α inhibitors were the only medication suspected in 23 reports (56%). The delay between starting TNF-α inhibitors treatment and onset of symptoms varied from hours to years with a median time of 40 days. Psychiatric symptoms improved in 22/23 patients in whom the TNF-α inhibitor was withdrawn. Depressive disorders are well-known ADR of TNF-α inhibitors, but we report, here, 41 reports of psychiatric ADR diagnosed as manic or psychotic disorders or in the spectrum of bipolar or psychotic disorders with these treatments. Epidemiological studies are needed to confirm this signal.

A study into two doses of the drug secukinumab for the treatment of psoriasis in people for whom ANTI TNF biologics have not been successful

British Journal of DermatologyVolume 183, Issue 1 p. e6-e6 Plain Language SummaryFree Access A study into two doses of the drug secukinumab for the treatment of psoriasis in people for whom ANTI TNF biologics have not been successful First published: 01 July 2020 https://doi.org/10.1111/bjd.19176AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Psoriasis is a common skin condition affecting approximately 2% of the population, with up to 1.8 million people affected in the U.K. alone. This article reports the work from a group of U.K. and Republic of Ireland based researchers who set out to determine if secukinumab, a medicine known as an IL-17A inhibitor, was safe and effective in patients with moderate/severe chronic plaque psoriasis for whom previous treatment with a medicine called a TNFα inhibitor had not remained effective. 53 dermatology centres in the U.K. and Republic of Ireland took part. Patients were randomly assigned to to receive secukinumab at a dose of either 300mg or 150 mg subcutaneously (by injection) every week for 4 weeks, then 4-weekly thereafter. The Psoriasis Area Severity Index (PASI) is used to record the redness, thickness and scaling of a patient's psoriasis and to measure how well a treatment works, as a reduction in the PASI score means a reduction in these symptoms. If a patient achieves PASI 75, it means they had a 75% or more reduction in their PASI score from the start. In total, 233 patients were analysed. 77 of 118 patients (65·3%) in the 300mg dose group and 51 of 115 patients (44·3%) in the 150mg dose group had achieved PASI 75 at week 16. After 72 weeks of treatment, 77.1% of patients in the 300 mg group who remained on that treatment throughout the study achieved PASI 75. Improvements in patients’ quality of life were also seen at week 16 and were maintained to week 72. The safety profile of secukinumab was generally consistent with previous secukinumab studies, although a higher incidence of some adverse events, meaning unwanted side effects, were observed (e.g. candida infections, a type of fungal infection). This study has shown evidence of the efficacy and safety of secukinumab for treatment of psoriasis patients for whom prior TNFα-inhibitor therapy has not been effective. Linked Article: Warren et al. Br J Dermatol 2020; 183:60–70. Volume183, Issue1July 2020Pages e6-e6 RelatedInformation

The predictive value of serum soluble ICAM-1 and CXCL13 in the therapeutic response to TNF inhibitor in rheumatoid arthritis patients who are refractory to csDMARDs

Tumor necrosis factor-α (TNFα) inhibitors (TNFi) have greatly improved the prognosis of RA and become the first therapeutic option for patients who failed the conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) therapy, but not all these patients respond well to TNFi. So far, there has been no definite biomarker to predict the response to TNFi yet. Sixty rheumatoid arthritis (RA) patients with disease duration more than 6months and at least low disease activity defined by DAS28-CRP > 3.2 although after csDMARDs (including MTX and/or leflunomide) treatment for more than 3months were included. They were further treated with TNFα receptor Fc fusion protein and MTX 10mg per week for 12weeks. Soluble ICAM-1 (sICAM-1) and CXCL13 concentrations in sera from 60 RA patients and 20 healthy controls were tested by ELISA right before and at the end of 12weeks of TNFi therapy. The correlation between sICAM-1 and CXCL13 with disease activity and their predictive values for TNFi response were analyzed. The mean age of the 60 patients was 54.8 ± 11.6years. Serum sICAM-1 and CXCL13 concentrations were higher in RA patients than heathy controls, higher in seropositive RA patients than in seronegative ones, and higher in RA patients with higher disease activity. Serum sICAM-1 and CXCL13 levels were decreased after TNFi therapy, especially in good responders. Baseline sICAM-1 concentration was independently associated with the EULAR response (p = 0.033, OR = 1.014, 95% CI = 1.003-1.026). The sICAM-1high/CXCL13high patients had the highest response rate, which was significantly higher than the sICAM-1low/CXCL13low group (OR = 8.143, 95% CI = 1.040-75.482, p = 0.045). sICAM-1 and CXCL13 are elevated in RA patients and correlated with disease activity. sICAM-1 is an independent predictor of TNFi response in csDMARDs refractory RA patients. Key Points • This study confirmed the predictive value of soluble ICAM-1 (sICAM-1) and CXCL13 on the response to TNFi in RA patient. • Baseline sICAM-1 concentration was independently associated with the EULAR response. • The sICAM-1high/CXCL13high patients had significantly higher response rate than the sICAM-1low/CXCL13low group.

Histoplasmosis in Inflammatory Bowel Disease with Tumor Necrosis Factor-Alpha Inhibitors: Safe to Continue Biologics?

The advent of tumor necrosis factor-α (TNF-α) inhibitor therapy has transformed inflammatory bowel disease management; however, these medications carry a boxed warning for risk of serious infections, including invasive fungal infections. We aimed to study the clinical features, severity, and outcomes of histoplasmosis in patients on TNF-α inhibitors for IBD. We performed a retrospective review of IBD patients receiving TNF-α inhibitors who developed histoplasmosis from January 1, 2001, to May 31, 2018. Patients with drug indications other than ulcerative colitis or Crohn's disease were excluded. IBD was diagnosed histologically, radiographically, or endoscopically. We identified 49 patients (median age 44years; range 19-76) with histoplasmosis on TNF-α inhibitors. Patients with disseminated disease had a median urine antigen of 10.76ng/mL compared with pulmonary disease alone 0.375ng/mL (p < 0.001). Charlson Comorbidity Index and urine antigen levels showed a trend toward predicting disease severity (p > 0.05). Median length of stay was 9.5days. Itraconazole was used for maintenance in all patients. Median follow-up was 4.7years. Total treatment duration ranged from 3 to 15months. TNF-α inhibitor therapy was continued in nine and resumed in ten patients after completing antifungals. Three deaths occurred (6%). Histoplasmosis outcomes were mostly favorable. Many patients were young with few comorbidities; however, those with more comorbidities experienced more severe histoplasmosis. Compared to prior studies, many of these patients resumed or continued biologic therapy. There were no histoplasmosis recurrences after resuming TNF-α inhibitor therapy. Vigilance for disseminated fungal infections in this patient population is essential.

Screening for acquired latent tuberculosis in rheumatoid arthritis patients on tumor necrosis factor inhibition therapy in Southern California.

There are no studies assessing the development of latent tuberculosis infection (LTBI) in patients on tumor necrosis factor inhibitors (TNFα-I) in high TB prevalence areas of the USA. Our objective was to assess the rate of LTBI development in rheumatoid arthritis (RA) patients on TNFα-I therapies in San Bernardino and Riverside Counties of California, high TB prevalence areas in the US. Data were extracted from the electronic health record for 217 adult RA patients across three health centers from January 2010 to January 2017 who have had at least 1year of TNFα-I use and negative initial QuantiFERON Gold status. Demographics, TNFα-I type, duration of use, TB risk factors, QuantiFERON results, rates of re-screening, TB test seroconversion, and its association with drug use and other factors were assessed. Of the 217 patients, 115 (53%) received baseline and annual screening for LTBI. LTBI was diagnosed in 9.4% (10) of patients. Four patients were on infliximab, three on golimumab, two on adalimumab, and one on etanercept. Hispanic patients tended to have a greater than 200% increase in odds of seroconversion compared to non-Hispanic patients. Infliximab and golimumab were associated with a 92% and 400% increase in odds of seroconversion, respectively. The LTBI developed in 9.4% of the patients. This is higher than what is reported for previous US studies. Screening for LTBI in the US should take into consideration TB prevalence, ethnicity, drug type, and duration of use. For our local population and similar populations, annual screening should be practiced. Key Points • Although patients on TNFα inhibitor (TNFα-I) therapy are at high risk of latent tuberculosis infection (LTBI), few studies report the rate of LTBI in patients living in high prevalence areas of the US. • The rate of LTBI was 9.4% in patients on TNFα-I therapy in Southern California. The risk of seroconversion was higher in patients of Hispanic ethnicity and also higher for those on infliximab and golimumab compared to those on other TNFα-I therapies. • Screening guidelines for LTBI screening on TNFα-I should consider local TB prevalence, drugs used, duration of use and ethnicity for cost efficient, and optimal healthcare.

DOP07 Long-term results of 4.5 years of faecal microbiota transplantation for treatment of refractory ulcerative colitis

Abstract Background Faecal microbiota transplantation (FMT) provides replacement of pathogenic bacteria with more favourable microbiomes in recipients with dysbiosis. The aim of the present study was to prospectively investigate the efficacy of FMT by assessing the clinical and endoscopic response in patients with ulcerative colitis (UC) who had failed anti-inflammatory, immunosuppressive and TNF-α inhibitors (Infliximab, Adalimumab, Vedolizumab) therapy. Methods In this prospective and uncontrolled study, 116 patients with UC were enrolled. All medications except mesalazine were discontinued 1 week before FMT. Colonoscopy was performed both before and after FMT. To assess the efficacy of FMT, Mayo scores were calculated at weeks 0, 24 and 48. A total of 400–600 ml of extracted fresh faecal suspension was administered into the 20 to 30 cm of terminal ileum of recipients. Results After 4.5 years of FMT experience with 116 patients, who have completed their 6 months after 236 procedures of FMT for treatment of UC, 42 of the 116 patients showed full clinical response (100% clinical + laboratory + endoscopically full response) (per-protocol analysis 37.1%), (intention-to-treat analysis 36.2%) at Week 48 and 33 of the 116 patients achieved clinical and endoscopic remission (laboratory 70%, clinically and endoscopically 50–75% improvement) (per-protocol analysis 29.2%), (intention-to-treat analysis 28.4%) at Week 48. Thirty-eight of the 116 patients were accepted as nonresponders at the end of Week 48 (per-protocol analysis 29.2%), (intention-to-treat analysis 32.7%) and 3 patients (2.5%) were lost to follow-up. There was no significant difference among donors concerning both the rate of clinical remission and clinical response. At 4.5 years, serious side effects were observed on 2 patients, 1 colon perforation and 1 toxic megacolon; both were directed to surgery. In 48 weeks’ follow-up, 31 patients (26.7%) experienced mild adverse events after FMT, such as elevated white blood cell counts and ESR, nausea, abdominal pain and high fever, all were managed conservatively. Conclusion FMT could be considered as a promising rescue treatment modality before surgery in patients with refractory UC. Our research is the first in the world for the treatment of UC resistant to medical treatment before surgery. Also, it is the first research to show the long-term results of FMT. FMT appears to be significantly safer and more tolerable than the immunosuppressive and TNF-α inhibitors therapy in patients with UC.

Tuberculosis in patient with psoriasis receiving biologic therapy – case report

Introduction: The introduction of biological therapy has revolutionized the treatment of psoriasis. Due to its immunosuppressive effect, the following side effects might occur: injection-site reactions, exacerbation of autoimmune diseases, increased risk of malignant tumors and infections, including tuberculosis (TB). Aim: The aim of this report is to present a case of a patient who developed TB during tumornecrosis factor α (TNF-α) inhibitor therapy. Case study: A 52-year-old man was admitted to the Dermatology Clinic for re-qualification for biological treatment with adalimumab. The patient was treated with cyclosporin A and lefludomide combined with methotrexate with no effect and the adalimumab therapy was initiated with complete remission of psoriatic lesions. The patient was suspended in the drug program because of TB. TNF-α inhibitor therapy was resumed after antimycobacterial treatment, during which lymphadenopathy was observed and serous TB was confirmed. Three months after the treatment, the patient was rehospitalized because of suspicion of TB relapse. It was decided to requalify the patient for biological therapy after completion of antimycobacterial treatment. Due to the high risk of TB recurrence, switch to the interleukin-17 inhibitor was decided. Results and discussion: The proper qualification and thorough testing before biological treatment ensures patients’ safety and satisfactory therapeutic effect. It should be remembered that during longterm therapy with TNF antagonists, both reactivation of latent TB as well as new infection are serious problems. Therefore, regular tests should be performed, especially in countries with high prevalence of this disease. Conclusions: In patients who develop TB, particularly recurrent, switching to a drug with a different mechanism should be considered.

Management of Primary Nonresponders and Partial Responders to Tumor Necrosis Factor-α Inhibitor Induction Therapy among Patients with Crohn’s Disease

Induction therapy with tumor necrosis factor-α (TNF-α) inhibitors is highly effective for the treatment of Crohn’s disease. However, there are primary nonresponders (PNR) of TNF-α inhibitors without clinical response during the induction period. In addition, there are partial responders (PR), who show some efficacy, but clinical remission is not achieved by induction therapy. To date, the definition and clinical management of PNR and PR have not been established. This report summarizes the opinions of 36 Japanese experts attending the Japan Round Table Discussion on IBD Meeting regarding how to determine PNR and PR of TNF-α inhibitors and how to manage these patients in clinical practice. PNR, who do not show any initial improvement of clinical symptoms and serum C-reactive protein (CRP) levels, require re-assessment of intestinal complications. PR can be determined either by clinical symptoms, serum CRP levels, or imaging results. PR need intensification of the treatment with TNF-α inhibitors either with or without optimization of immunomodulators. Optimization of initial TNF-α inhibitor therapy may improve long-term outcomes, but more evidence is required to improve the use of TNF-α inhibitors for the prevention and management of PNR and PR.

PBI13 TNF-ALPHA INHIBITORS IN THE CZECH REPUBLIC: HOW BIOSIMILARS AFFECT OVERALL CONSUMPTION AND COSTS?

In the Czech Republic, a system of reference groups (RGs) is in place. A RG is a group of medicines with comparable effectiveness, safety profile and clinical use. All medicines within the same RG have the same reimbursement price per usual daily dose. When the first biosimilar product is launched, its maximum and reimbursement price are lowered by 30%. For this reason, the reimbursement price of all medicines in the RG is lowered, too. In this study, we analyzed the change in the consumption and costs of TNF-α inhibitors (TNFis) after the launch of the first biosimilar product (infliximab) in 2013. Firstly, we extracted publicly available data about medicine consumption in the Czech Republic and analyzed all annual reports from 2010 to 2018. Data for relevant medicines were sorted by active substance, type of authorization process, unit and total costs. Identified price decrements were cross-checked with data from national list of reimbursed medicines. The consumption of all TNFis has almost doubled with an 87% increase over the last 5 years. Infliximab and adalimumab are the most used substances of this RG. In 2018, biosimilars market share reached 33% of the total TNFis market. The consumption of certolizumab and golimumab has grown up more than three- and two-times respectively. Since 2017, biosimilar infliximab has been much more used than original infliximab. Between 2013 and 2018, cost per daily dose has, on average, decreased by 24%. The decrease in daily costs significantly differed among substances. The consumption of TNFi is still growing and patient access to biological treatment has been improving over time. The first launched biosimilar improved access to TNFi therapy. The lowering of unit costs over the years has been primarily caused by reassessments of this RG, price contracts between the insurance funds and the companies and market competition.

The effect of tumour necrosis factor inhibitors on radiographic progression in axial spondyloarthritis: a systematic literature review.

The effect of TNF-α inhibitors (TNFi), with or without concomitant NSAIDs, on radiographic progression in axial SpA remains unclear. Therefore, we performed a systematic literature review up to January 2019 to determine whether longer use of standard dose TNFi is superior vs lower duration or lower dose TNFi therapy, conventional synthetic DMARDs alone, or no therapy in inhibiting radiographic progression in patients with axial SpA. Our search yielded 373 titles of which 14 full text articles and five abstracts were eligible for quantitative analysis. Studies had an overall moderate to critical risk of bias. Data could not be pooled due to clinical and methodological heterogeneity. Individual studies showed conflicting results with mainly no significant difference in radiographic progression when comparing effect of TNFi therapy to no TNFi therapy or when comparing to less TNFi therapy until 2 years of follow-up. Results that are more significant are shown after 2 years' follow-up, mainly in subgroups with baseline syndesmophytes. Data on the additional or synergistic effect of concomitant NSAID use were inconclusive.

Pregnancy outcomes in Icelandic female patients with inflammatory arthritides. Nationwide results from the ICEBIO and the Icelandic Medical Birth Register

We used multivariate analysis to evaluate the risk of preterm birth, Caesarean section, low Apgar score at 5-minutes and low birth weight among females with inflammatory arthritis (rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS)) in comparison with healthy controls matched on age and parity. We also investigated pregnancies before and after the diagnosis of respective rheumatic disease and especially in respect to treatment with TNFα inhibitors (TNFi). In the end of 2016, 723 female patients were registered in ICEBIO as they had received treatment with TNFi due to inflammatory arthritis. Of those, 412 women had given birth to 801 children, whereof 597 were delivered before confirmed diagnosis of the mother and 53 were delivered after the start of the TNFi treatment. Relative risk of Caesarean section among these female with various arthritis conditions were 1.47 (95% CI: 1.19-1.82; p < 0,001) compared to controls and was highest in the group with PsA or 2.06 (1.41-3.02; p<0,001). We did not find increased risk of preterm delivery or low Apgar score. Patients with inflammatory arthritis had lower risk of children with low birth weight or 0.37 compared to healthy controls (95% CI: 0.36-0.37; p < 0.05). Due to low numbers of deliveries after the initiation of TNFi therapy (n=53) we were not able to perform any analysis for that group. Icelandic female patients with inflammatory arthritis are at an increased risk of Caesarean section in comparison to healthy controls. However, their newborns are in good condition and healthy at birth. Analysis of the impact of treatment with TNFi on pregnancy is not yet possible due to limited data.

The efficacy of maintenance therapy after remission induction with tacrolimus in ulcerative colitis with and without previous tumor necrosis factor-α inhibitor.

Background and AimTacrolimus (TAC) is an important therapeutic option for remission induction in patients with refractory ulcerative colitis (UC). However, there is little evidence available on long‐term outcomes and maintenance treatments after TAC therapy, especially in cases with previous tumor necrosis factor‐α (TNF‐α) inhibitor therapy.MethodsLong‐term outcomes and remission induction after TAC treatment were retrospectively examined in refractory UC patients with and without previous TNF‐α inhibitor therapy.ResultsThe mean disease activity index and the endoscopic activity index scores decreased significantly during the 12‐week treatment after TAC therapy in both groups, showing a significantly greater decrease in the group without TNF‐α inhibitor therapy than in the group with previous TNF‐α inhibitor therapy. One year or more after TAC therapy, TNF‐α inhibitor and/or azathioprine was used as maintenance therapy in most cases in the group without previous TNF‐α inhibitor treatment, while azathioprine was primarily used in the group with previous TNF‐α inhibitor treatment. Colectomy was performed in 45.5% (5/11) and 15.6% (7/45) of the groups with and without previous TNF‐α inhibitor therapy, respectively, and the group without previous TNF‐α inhibitor treatment had a better colectomy‐free rate than the group with previous TNF‐α inhibitor treatment after TAC therapy on Kaplan–Meier analysis.ConclusionsTAC is effective for remission induction in refractory UC patients with and without previous TNF‐α inhibitor treatment. Maintenance medication after TAC therapy is an issue for the future, especially in UC cases with previous TNF‐α inhibitor treatment failure.

A Review on the Effect of Tumor Necrosis Factor Inhibitors on Structural Progression in Early Axial Spondyloarthritis Using Magnetic Resonance Imaging.

IntroductionConsidering the progressive nature of axial spondyloarthritis (axSpA), it is important to determine whether tumor necrosis factor alpha (TNFα) inhibitors have an effect on early inflammatory and structural lesions detected using magnetic resonance imaging (MRI).MethodsA search of MEDLINE/PubMed for full-text, English-language articles on randomized controlled trials (RCTs) of adalimumab, certolizumab, etanercept, golimumab, or infliximab published since January 2007 was conducted in February 2018 and again in December 2018. The collected articles reported on inflammatory or fatty lesion progression in the spine or sacroiliac joint (SIJ), determined using MRI, in a population that included at least 40% of patients with early axSpA, defined as non-radiographic axSpA.ResultsOf the 105 articles retrieved, 19 were included in this review, of which the majority were on etanercept (n = 11). A majority of selected articles included information on inflammatory lesions (SIJ 15/19; spine 12/19). All five TNFα inhibitors showed benefits on inflammation, assessed by MRI, in patients with early axSpA for up to 204 weeks of treatment. Structural progression in SIJ and the spine was assessed in 6/19 and 3/19 articles, respectively, with mixed evidence on benefits of TNF-inhibitor treatment.ConclusionsIn conclusion, treatment with TNFα inhibitors reduces MRI-evident inflammatory lesions in the SIJ and spine of patients with early axSpA for up to 4 years. There is less evidence of benefits on structural lesions. Additional studies are required to determine whether TNFα-inhibitor therapy can limit or delay radiological progression in patients with early axSpA.FundingPfizer.

Counter-regulation of regulatory T cells by autoreactive CD8+ T cells in rheumatoid arthritis

The mechanisms whereby autoreactive T cells escape peripheral tolerance establishing thus autoimmune diseases in humans remain an unresolved question. Here, we demonstrate that autoreactive polyfunctional CD8+ T cells recognizing self-antigens (i.e., vimentin, actin cytoplasmic 1, or non-muscle myosin heavy chain 9 epitopes) with high avidity, counter-regulate Tregs by killing them, in a consistent percentage of rheumatoid arthritis (RA) patients. Indeed, these CD8+ T cells express a phenotype and gene profile of effector (eff) cells and, upon antigen-specific activation, kill Tregs indirectly in an NKG2D-dependent bystander fashion in vitro. This data provides a mechanistic basis for the finding showing that AE-specific (CD107a+) CD8+ T killer cells correlate, directly with the disease activity score, and inversely with the percentage of activated Tregs, in both steady state and follow-up studies in vivo. In addition, multiplex immunofluorescence imaging analyses of inflamed synovial tissues in vivo show that a remarkable number of CD8+ T cells express granzyme-B and selectively contact FOXP3+ Tregs, some of which are in an apoptotic state, validating hence the possibility that CD8+ Teff cells can counteract neighboring Tregs within inflamed tissues, by killing them. Alternatively, the disease activity score of a different subset of patients is correlated with the expansion of a peculiar subpopulation of autoreactive low avidity, partially-activated (pa)CD8+ T cells that, despite they conserve the conventional naïve (N) phenotype, produce high levels of tumor necrosis factor (TNF)-α and exhibit a gene expression signature of a progressive activation state. Tregs directly correlate with the expansion of this autoreactive (low avidity) paCD8+ TN cell subset in vivo, and efficiently control their differentiation rather their proliferation in vitro. Interestingly, autoreactive high avidity CD8+ Teff cells or low avidity paCD8+ TN cells are significantly expanded in RA patients who would become non-responders or patients who would become responders to TNF-α inhibitor therapy, respectively. These data provide evidence of a previously undescribed role of such mechanisms in the progression and therapy of RA.

The role of biologics in the treatment of chronic granuloma annulare.

Granuloma annulare (GA), a benign inflammatory skin disease, is considered a Th1-type delayed hypersensitivity reaction. Localized GA is likely to resolve spontaneously, whereas disseminated GA (DGA) may persist for decades and can be resistant to treatment. Biologics including TNF-α inhibitors have been proposed and utilized as salvage therapy for GA and other related diseases, interstitial granulomatous dermatitis (IGD), and actinic granuloma (AG). A systematic review was conducted using the combination of search terms "granuloma annulare," "interstitial granulomatous dermatitis," or "actinic granuloma" and either "biologics," "etanercept," "adalimumab," "infliximab," "ustekinumab," "ixekizumab," "secukinumab," "guselkumab," "golimumab," "brodalumab," "tildrakizumab," or "certolizumab" from the years 1970-2017. Review of the literature revealed that 79.3% of the patients with GA, IGD, or AG who had been treated with demonstrated TNF-α inhibitor therapy a clinical response. TNF-α inhibitor therapy has been used to treat chronic GA, IGD, and AG that involved extensive body surface areas. However, the literature is limited to case series lacking control groups. Randomized, controlled trials are required to establish evidence-based treatment of GA and related cutaneous, granulomatous conditions.

The Effect of Tumor Necrosis Factor-Alpha Inhibitors on Uveitis in Patients with Ankylosing Spondylitis.

BackgroundTumor necrosis factor-alpha (TNF-α) inhibitors (TNFis), which are the main treatment for ankylosing spondylitis (AS), have been reported not only to reduce the incidence of anterior uveitis (AU) but also to induce it, and these effects differ among the various types of TNFis in clinical use. The present study investigated the effect of TNFis on uveitis by analyzing the long-term clinical course of AU in AS patients treated with TNFi therapy.MethodsPatients treated with at least one TNFi between January 2007 and July 2017 were reviewed, and 54 patients with at least one episode of AU were included in this study. The TNFis included anti-TNF-α antibodies (adalimumab, infliximab, and golimumab), and a soluble TNF receptor molecule (etanercept). The effect of prevention of AU, the likelihood of new-onset uveitis after the initiation of TNFi therapy, and the effects of drug switching and dose escalation were assessed.ResultsThe first uveitis flare was observed before TNFi therapy in 39 patients and after TNFi therapy in 15 patients. Anti-TNF-α antibodies were more efficacious in decreasing the recurrence of AU than etanercept. Among patients in which uveitis first occurred after beginning TNFi therapy, patients on etanercept tended to first develop AU less than 1 year after starting the drug, and their AS tended to be well-controlled at the time of uveitis flares. Patients with a uveitis flare before their medication was switched did not recur afterwards, and five of eight patients showed no relapse after dose escalation.ConclusionTNFis have various effects on AU. TNFis, particularly anti-TNF-α antibodies, should be considered in patients with AS and frequent AU relapse. Additionally, clinicians should consider whether AU is due to an absence of a therapeutic response of AS to TNFi treatment or to TNFi treatment itself, and appropriate treatment changes should be made accordingly.

Rituximab Therapy in Renal Amyloidosis Secondary to Rheumatoid Arthritis.

Secondary amyloid A (AA) amyloidosis is a late and serious complication of poorly controlled, chronic inflammatory diseases. Rheumatoid arthritis (RA) patients with poorly controlled, longstanding disease and those with extra-articular manifestations are under risk for the development of AA amyloidosis. Although new drugs have proven to be significantly effective in the treatment of secondary AA amyloidosis, no treatment modality has proven to be ideal. To date, only in small case series preliminary clinical improvement have been shown with rituximab therapy for AA amyloidosis secondary to RA that is refractory to TNF-α inhibitors (TNF-i) therapy. In these case series, we assessed the efficacy and safety of rituximab therapy for patients with RA and secondary amyloidosis. Hacettepe University Biologic Registry was developed at 2005. The data of the RA patients who were prescribed a biological drug were recorded regularly. Patients with biopsy proven AA amyloidosis patients were screened. Of 1022 RA patients under biologic therapy, 0.7% patients had clinically apparent histologically confirmed amyloidosis. Four of seven patients who were prescribed rituximab at least one infusion enrolled to those case series. Two of four patients showed significant clinical improvement and one of them also had decrease in proteinuria and the other one had stable renal function and proteinuria. The main goal for the treatment of AA amyloidosis is to control the activity of the underlying disorder. In this study, we showed that rituximab may be an effective treatment in RA patients with amyloidosis who were unresponsive to conventional disease modifying anti-rheumatic drugs (DMARDs) and/or TNFi.