TNF-α Antagonist Therapy Research Articles

Tumor necrosis factor inhibitors and methotrexate are associated with decreased COVID-19-related hospitalization: Follow up of “Clinical outcomes of COVID-19 in patients taking tumor necrosis factor inhibitors and methotrexate”

Tumor necrosis factor inhibitors and methotrexate are associated with decreased COVID-19-related hospitalization: Follow up of “Clinical outcomes of COVID-19 in patients taking tumor necrosis factor inhibitors and methotrexate”

499. Rapid and Sustained Decline in CXCL-10 (IP-10) Annotates Clinical Outcomes Following TNF-α Antagonist Therapy in Hospitalized Patients with Severe and Critical COVID-19 Respiratory Failure

BackgroundTNFα and IFN-γ may synergize to induce cytokine-driven lethal hyperinflammation and immune exhaustion in COVID-19 illness.MethodsTo assess TNFα-antagonist therapy, 18 hospitalized adults with hypoxic respiratory failure and COVID-19 pneumonia received single-dose infliximab-abda therapy 5mg/kg intravenously between April and December 2020. The primary endpoint was time to increase in oxygen saturation to fraction of inspired oxygen ratio (SpO2/FiO2) by ≥ 50 compared to baseline and sustained for 48 hours. Secondary endpoints included 28-day mortality, dynamic cytokine profiles (Human Cytokine 48-Plex Discovery Assay), secondary infections, duration of supplemental oxygen support and hospitalization.Consort diagram Hospitalized patients with SARS-COV2 infection and pneumonia that were referred to the infliximab-abda study team for evaluation.ResultsPatients were predominantly in critical respiratory failure (15/18, 83%), male (14/18, 78%), above 60 years (median 63 yrs, range 31-80), race-ethnic minorities (13/18, 72%), lymphopenic (13/18, 72%), steroid-treated (17/18, 94%), with a median ferritin of 1953ng/ml. Sixteen patients (89%) met the primary endpoint within a median of 4 days, 15/18 (83%) recovered from respiratory failure, and 14/18 (78%) were discharged in a median of 8 days and were alive at 28-day follow-up. Deaths among three patients ≥ 65 years age with pre-existing lung disease or multiple comorbidities were attributed to secondary lung infections. Mean plasma IP-10 levels declined sharply from 9183 pg/ml to 483 pg/ml at Day 3 and 146 pg/ml at Day 14/discharge. Significant declines in IFN-γ, TNFα, IL-27, IL-6 (baseline above 10pg/ml), CRP and ferritin were specifically observed at Day 3 whereas other cytokines were unaffected. Among 13 lymphopenic patients, six (46%) had resolution of lymphopenia by day 3, and 11 by day 14. CXCR3-ligand (IP-10 and CXCL-9) declines were strongly correlated among patients with lymphopenia reversal (Day 3, Pearson r: 0.98, p-value: 0.0006).Demographics and clinical characteristics Demographics, comorbidities, clinical features, inflammatory markers, and outcomes of 18 patients with COVID-19 respiratory failure treated with infliximab-abda between April and December 2020.Changes in oxygen support status following infliximab-abda treatment Colored bars indicate the maximal level of oxygen support for each individual following treatment with infliximab-abda. The status of the patient at last follow-up (discharged, alive or dead) is indicated. ECMO: extracorporeal membrane oxygenationControl of inflammatory markers and cytokines following infliximab therapy Values from individuals are connected with solid lines, with deceased individuals indicated in red. Statistics: n=18, paired ratio t-test compared to baseline; *: P<0.05, **: P<0.01, ***: P<0.001, ****: P<0.0001, n.s.: not significant.ConclusionConsistent with a central role of TNFα, the clinical and cytokine data indicate that infliximab-abda may rapidly abrogate pathological inflammatory signaling to facilitate clinical recovery in severe and critical COVID-19. Randomized studies are formally evaluating infliximab therapy in this context. Funding: National Center for Advancing Translational SciencesDisclosures All Authors: No reported disclosures

Rapid and sustained decline in CXCL-10 (IP-10) annotates clinical outcomes following TNFα-antagonist therapy in hospitalized patients with severe and critical COVID-19 respiratory failure.

A feedforward pathological signaling loop generated by TNFα and IFN-γ synergy in the inflamed lung, driving CXCL-10 (IP-10) and CXCL-9 chemokine-mediated activated T-cell and monocyte/macrophage tissue recruitment, may define the inflammatory biology of lethal COVID-19 respiratory failure. To assess TNFα-antagonist therapy, 18 hospitalized adults with hypoxic respiratory failure and COVID-19 pneumonia received single-dose infliximab-abda therapy 5mg/kg intravenously between April and December 2020. The primary endpoint was time to increase in oxygen saturation to fraction of inspired oxygen ratio (SpO2/FiO2) by ≥50 compared to baseline and sustained for 48h. Secondary endpoints included 28-day mortality, dynamic cytokine profiles, secondary infections, duration of supplemental oxygen support, and hospitalization. Patients were predominantly in critical respiratory failure (15/18, 83%), male (14/18, 78%), above 60 years (median 63 years, range 31-80), race-ethnic minorities (13/18, 72%), lymphopenic (13/18, 72%), steroid-treated (17/18, 94%), with a median ferritin of 1953ng/ml. Sixteen patients (89%) met the primary endpoint within a median of 4 days; 14/18 (78%) were discharged in a median of 8 days and were alive at 28-day follow-up. Three deaths were attributed to secondary lung infection. Mean plasma IP-10 levels declined sharply from 9183 to 483pg/ml at Day 3 and 146pg/ml at Day 14/discharge. Significant Day 3 declines in IFN-, TNFα, IL-27, CRP, and ferritin occurred. IP-10 and CXCL-9 declines were strongly correlated among patients with lymphopenia reversal (Day 3, Pearson r: 0.98, P-value 0.0006). Infliximab-abda may rapidly abrogate pathological inflammatory signaling to facilitate clinical recovery in severe and critical COVID-19.

Clinical characteristics of pediatric synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome: the first Chinese case series from a single center.

Pediatric SAPHO syndrome is regarded as the equivalent of chronic recurrent multifocal osteomyelitis or chronic non-bacterial osteomyelitis. This study aimed to evaluate the clinical features and treatment options for Chinese pediatric patients with SAPHO syndrome. We conducted a single-center, retrospective study on a sample of 24 pediatric patients with SAPHO syndrome who were diagnosed at Peking Union Medical College Hospital from April 2014 to August 2018. The demographic, clinical, laboratory, imaging, histological, and therapeutic data were collected and analyzed. A total of 15 boys and 9 girls were included. The mean age of onset of bone and skin symptoms was 11.7 ± 3.8 and 14.4 ± 2.7years, respectively. The mean follow-up period was 39.2months. Seventeen patients had skin manifestations (46% had severe acne, 100% were boys; 21% had palmoplantar pustulosis, 100% were girls). Bone lesions were localized in four of the following major regions: anterior chest wall (42%), mandible (29%), peripheral bones (50%), and spine and sacroiliac joints (21%). Six patients had been treated with non-steroidal anti-inflammatory drugs, 10 with bisphosphonate, 10 with a tumor necrosis factor-α antagonist, and 1 with glucocorticoids, with variable responses. A total of 70% of the patients had complete remission after bisphosphonate or TNF-α antagonist therapy. Pediatric patients with SAPHO syndrome have different characteristics from other cohorts in the sex ratio, frequency of mandibular involvement, and sex distribution of skin lesions. Bisphosphonate and TNF-α antagonists show a favorable response in pediatric SAPHO syndrome treatment. Key points •Being the first study that describes an Asian pediatric SAPHO case series. •Chinese pediatric patients with SAPHO syndrome have different characteristics from Chinese adult patients and Caucasian pediatric patients.

Adalimumab for maintenance of remission in Crohn's disease

Conventional medications for Crohn's disease (CD) include anti-inflammatory drugs, immunosuppressants and corticosteroids. If an individual does not respond, or loses response to first-line treatments, then biologic therapies such as tumour necrosis factor-alpha (TNF-α) antagonists such as adalimumab are considered for treating CD. Maintenance of remission of CD is a clinically important goal, as disease relapse can negatively affect quality of life. To assess the efficacy and safety of adalimumab for maintenance of remission in people with quiescent CD. We searched the Cochrane IBD Group Specialized Register, CENTRAL, MEDLINE, Embase, and clinicaltrials.gov from inception to April 2019. We considered for inclusion randomized controlled trials (RCTs) comparing adalimumab to placebo or to an active comparator. We analyzed data on an intention-to-treat basis. We calculated risk ratios (RRs) and corresponding 95% confidence intervals (95% CI) for dichotomous outcomes. The primary outcome was failure to maintain clinical remission. We define clinical remission as a Crohn's Disease Activity Index (CDAI) score of < 150. Secondary outcomes were failure to maintain clinical response, endoscopic remission, endoscopic response, histological remission and adverse events (AEs). We assessed biases using the Cochrane 'Risk of bias' tool. We used GRADE to assess the overall certainty of evidence supporting the primary outcome. We included six RCTs (1158 participants). We rated four trials at low risk of bias and two trials at unclear risk of bias. All participants had moderate-to-severe CD that was in clinical remission. Four studies were placebo-controlled (1012 participants). Two studies (70 participants) compared adalimumab to active medication (azathioprine, mesalamine or 6-mercaptopurine) in participants who had an ileocolic resection prior to study enrolment. Adalimumab versus placebo Fifty-nine per cent (252/430) of participants treated with adalimumab failed to maintain clinical remission at 52 to 56 weeks, compared with 86% (217/253) of participants receiving placebo (RR 0.70, 95% CI 0.64 to 0.77; 3 studies, 683 participants; high-certainty evidence). Among those who received prior TNF-α antagonist therapy, 69% (129/186) of adalimumab participants failed to maintain clinical or endoscopic response at 52 to 56 weeks, compared with 93% (108/116) of participants who received placebo (RR 0.76, 95% CI 0.68 to 0.85; 2 studies, 302 participants; moderate-certainty evidence). Fifty-one per cent (192/374) of participants who received adalimumab failed to maintain clinical remission at 24 to 26 weeks, compared with 79% (149/188) of those who received placebo (RR 0.66, 95% CI 0.52 to 0.83; 2 studies, 554 participants; moderate-certainty evidence). Eighty-seven per cent (561/643) of participants who received adalimumab reported an AE compared with 85% (315/369) of participants who received placebo (RR 1.01, 95% CI 0.94 to 1.09; 4 studies, 1012 participants; high-certainty evidence). Serious adverse events were seen in 8% (52/643) of participants who received adalimumab and 14% (53/369) of participants who received placebo (RR 0.56, 95% CI 0.39 to 0.80; 4 studies, 1012 participants; moderate-certainty evidence) and withdrawal due to AEs was reported in 7% (45/643) of adalimumab participants compared to 13% (48/369) of placebo participants (RR 0.59, 95% CI 0.38 to 0.91; 4 studies, 1012 participants; moderate-certainty evidence). Commonly-reported AEs included CD aggravation, arthralgia, nasopharyngitis, urinary tract infections, headache, nausea, fatigue and abdominal pain. Adalimumab versus active comparators No studies reported failure to maintain clinical remission. One study reported on failure to maintain clinical response and endoscopic remission at 104 weeks in ileocolic resection participants who received either adalimumab, azathioprine or mesalamine as post-surgical maintenance therapy. Thirteen per cent (2/16) of adalimumab participants failed to maintain clinical response compared with 54% (19/35) of azathioprine or mesalamine participants (RR 0.23, 95% CI 0.06 to 0.87; 51 participants). Six per cent (1/16) of participants who received adalimumab failed to maintain endoscopic remission, compared with 57% (20/35) of participants who received azathioprine or mesalamine (RR 0.11, 95% CI 0.02 to 0.75; 51 participants; very low-certainty evidence). One study reported on failure to maintain endoscopic response at 24 weeks in ileocolic resection participants who received either adalimumab or 6-mercaptopurine (6-MP) as post-surgical maintenance therapy. Nine per cent (1/11) of adalimumab participants failed to maintain endoscopic remission compared with 50% (4/8) of 6-MP participants (RR 0.18, 95% CI 0.02 to 1.33; 19 participants). Adalimumab is an effective therapy for maintenance of clinical remission in people with quiescent CD. Adalimumab is also effective in those who have previously been treated with TNF-α antagonists. The effect of adalimumab in the post-surgical setting is uncertain. More research is needed in people with recent bowel surgery for CD to better determine treatment plans following surgery. Future research should continue to explore factors that influence initial and subsequent biologic selection for people with moderate-to-severe CD. Studies comparing adalimumab to other active medications are needed, to help determine the optimal maintenance therapy for CD.

A231 UNDERSTANDING THE IMPACT OF TNF-ALPHA ANTAGONISTS ON THE SEVERITY OF NON-MELANOMA SKIN CANCER IN INFLAMMATORY BOWEL DISEASE AND THE CONSEQUENCES FOR THERAPY

Abstract Background Non-melanoma skin cancer (NMSC) accounts for at least 40% of all new cancer diagnoses in Canada annually and presents a significant cost to the health care system due to the volume of cases. The incidence of NMSC in patients with Inflammatory Bowel Disease (IBD) is higher when compared to the general population. Generally, in a non-IBD population, the risk of further NMSC progression is low, however, little data exists that highlights differences in clinical course of patients diagnosed with NMSC who have IBD and are TNF-α antagonist exposed. It is unclear if TNF-α antagonist therapy should be discontinued in this patient population. Aims Our goal is to determine whether TNF-α antagonist exposure in IBD is associated with a high risk NMSC presentation at diagnosis, as defined by the National Comprehensive Cancer Network (NCCN) stratification. Our secondary objectives include presence of positive margins following resection, presence of metastatic disease on initial presentation, requirement of additional therapy to treat NMSC, number of patients who had TNF-α antagonist therapy discontinued following diagnosis of NMSC and number of individuals with recurrent NMSC. Methods Four hundred and twenty-four IBD patients seen at London Health Sciences Centre were reviewed. We have identified 22 patients who were diagnosed with NMSC. Twelve patients had a pre-NMSC TNF-α antagonist exposure while 10 patients who developed an NMSC and had no TNF-α antagonist exposure prior to NMSC diagnosis. Results Preliminary results of the primary outcome demonstrate that fifty-percent (6/12) of patients who have been exposed to TNF antagonist therapy presented with a high risk NMSC lesion at diagnosis compared to 40% (4/10) who were not exposed (OR 5.16, 95%CI 0.47–57.00; p = 0.181). Preliminary results of the secondary outcomes suggest that 25% (3/12) of patients exposed to TNF-α antagonist had positive margins compared with 0% (0/10) of patients who were not exposed. No patients in either group presented with metastatic disease. Twenty-five percent (3/12) of patients in the exposed group received more advanced treatment compared with 0% (0/10) in the non-exposed group. Eight percent (1/12) of patients in the TNF-α antagonist group had their IBD therapy changed from a TNF-α antagonist to an alternative biologic class, and 17% of patients (2/12) in the TNF-α antagonist group had recurrent NMSC lesions. Conclusions In conclusion, preliminary results suggest that TNF-α antagonist exposure may be associated with higher risk NMSC lesion at presentation. Further expansion of the sample size is required to explore these hypotheses further. Funding Agencies None

TNF-Alpha Inhibitors and Rhinosinusitis-A Systematic Review and Meta-Analysis.

Background Tumor necrosis factor alpha (TNFα) plays key role in immunologic process. Patients receiving anti-TNFα therapy may likely be more predisposed to infections including sinus disorders. Objectives Our aims were to review literature and evaluate data regarding TNFα antagonist therapy and its association with reference to various sinus disorders in the form of a systematic review and meta-analysis. Methods Different keyword combinations were used in the screening of the literature including leading scientific databases (PubMed, Embase, and Web of Science). Papers reporting sinus disorders as supposed adverse events of the treatment were included into the meta-analysis. Results A thorough review of literature searches extracted 1154 records and 8 articles were found through other sources. Seventeen papers fulfilled our criteria for inclusion into the meta-analysis. Among 16 174 observed patients, 3018 suffered from a sinus infection. An event rate (ER) of 0.058 was calculated for all the cases. Analysis with regard to the confirmed diseases showed an 0.038 ER. Calculations were performed in accordance to the diagnostic categories used for sinus disorder. Six groups were found including the following: “Bacterial Sinusitis” (ER: 0.046), “Chronic Rhinosinusitis” (ER: 0.027), “Sinusitis Requiring Prescription Medication” (ER: 0.295), “Recurrent Sinusitis” (ER: 0.070), “Sinusitis” (ER: 0.076), “Acute Rhinosinusitis” (ER: 0.002) and, lastly, “Maxillary Sinusitis” (ER: 0.028). Conclusions Our results exhibited a similar prevalence to the healthy population; therefore, infective sinus disorders cannot directly be considered as complications of TNFα antagonist therapy.

P400 Understanding the impact of TNF-α antagonists on the severity of non-melanoma skin cancer in inflammatory bowel disease and the consequences for therapy

Abstract Background Non-melanoma skin cancer (NMSC) accounts for at least 40% of all new cancer diagnoses in Canada annually and presents a significant cost to the health care system due to the volume of cases. The incidence of NMSC in patients with inflammatory bowel disease (IBD) is higher when compared with the general population. Generally, in a non-IBD population, the risk of further NMSC progression is low; however, little data exists that highlights differences in the clinical course of patients diagnosed with NMSC who have IBD and are TNF-α antagonist exposed. It is unclear if TNF-α antagonist therapy should be discontinued in this patient population. Our goal is to determine whether TNF-α antagonist exposure in IBD is associated with a high-risk NMSC presentation at diagnosis, as defined by the National Comprehensive Cancer Network (NCCN) stratification. Our secondary objectives include the presence of positive margins following resection, presence of metastatic disease on initial presentation, the requirement of additional therapy to treat NMSC, number of patients who had TNF-α antagonist therapy discontinued following the diagnosis of NMSC and number of individuals with recurrent NMSC. Methods Four hundred and twenty-four IBD patients seen at London Health Sciences Centre were reviewed. We have identified 22 patients who were diagnosed with NMSC. Twelve patients had a pre-NMSC TNF-α antagonist exposure while 10 patients who developed an NMSC and had no TNF-α antagonist exposure prior to NMSC diagnosis. Results Preliminary results of the primary outcome demonstrate that 50% (6/12) of patients who have been exposed to TNF antagonist therapy presented with a high-risk NMSC lesion at diagnosis compared with 40% (4/10) who were not exposed (OR 5.16, 95% CI 0.47–57.00; p = 0.181). Preliminary results of the secondary outcomes suggest that 25% (3/12) of patients exposed to TNF-α antagonist had positive margins compared with 0% (0/10) of patients who were not exposed. No patients in either group presented with metastatic disease. Twenty-five per cent (3/12) of patients in the exposed group received more advanced treatment compared with 0% (0/10) in the non-exposed group. Eight per cent (1/12) of patients in the TNF-α antagonist group had their IBD therapy changed from a TNF-α antagonist to an alternative biologic class, and 17% of patients (2/12) in the TNF-α antagonist group had recurrent NMSC lesions. Conclusion In conclusion, preliminary results suggest that TNF-α antagonist exposure may be associated with higher risk NMSC lesion at presentation. Further expansion of the sample size is required to explore these hypotheses further.

1728. A Retrospective Analysis of 49 Cases of Histoplasmosis in Inflammatory Bowel Disease Patients on Tumor Necrosis Factor-α Antagonists

BackgroundTumor necrosis factor (TNF)-α antagonist therapy has revolutionized the practice of management of inflammatory bowel disease (IBD); however, these medications carry a boxed warning from the Food and Drug Administration for risk of serious infection. We aimed to study the invasive fungal infection, histoplasmosis, in the setting of TNF-α antagonist therapy.MethodsWe performed a retrospective review of patients with IBD receiving TNF-α antagonist therapy who developed histoplasmosis during the time period January 2001–May 2018 at the Mayo Clinic, Rochester, MN. The medical records of patients were reviewed for demographics, medications, symptoms, diagnosis, treatment, and outcomes including mortality. IBD was diagnosed by biopsy, radiographic, or endoscopic evidence of disease.ResultsWe identified 49 patients (age range 19–74; median 44 years) with a confirmed diagnosis of histoplasmosis while receiving a TNF-α antagonist. 73.5% of cases were classified as disseminated. Median time from starting TNF-α antagonist to histoplasmosis diagnosis was 2.1 years. Liposomal amphotericin B was given in 17 cases as the initial treatment. Itraconazole was given to all 49 patients. Initial treatment was split evenly between inpatient (49%) and outpatient (51%) locations with 6 patients (12%) requiring ICU-level care. Median length of stay was 9.5 days. The total length of treatment for all antifungals was 38.4 weeks, with 20.4% of patients developing documented antifungal side effects. TNF-α antagonist was continued in 9 patients (18.4%) and another 10 patients resumed TNF-α antagonist. Half of those who resumed TNF-α antagonists were on antifungal therapy. There was one histoplasmosis recurrence while off TNF-α antagonist, and three deaths (6%).ConclusionHistoplasmosis outcomes in IBD patients on TNF-α antagonists were mostly favorable; however, approximately half required hospitalization. Many patients were young with few co-morbidities, and over one-third were able to continue or resume TNF-α antagonists without documented recurrence of histoplasmosis. Practitioners should be vigilant for histoplasmosis infections in this patient population who reside in histoplasma-endemic regions. Disclosures All authors: No reported disclosures.

Open: Vedolizumab for Ulcerative Colitis: Treatment Outcomes from the VICTORY Consortium

We aimed to quantify the safety and effectiveness of vedolizumab (VDZ) when used for UC, and to identify predictors of response to treatment. Retrospective review (May 2014-December 2016) of VICTORY Consortium data. Adults with follow-up after starting VDZ for clinically active UC were included. Primary effectiveness outcomes were cumulative rates of clinical remission (resolution of all UC-related symptoms) and endoscopic remission (Mayo endoscopic sub-score 0). Key secondary effectiveness outcomes included cumulative rates of corticosteroid-free remission and deep remission (clinical remission and endoscopic remission). Cox proportional hazard analyses were used to identify independent predictors of treatment effectiveness. Non-response imputation (NRI) sensitivity analyses were performed for effectiveness outcomes. Key safety outcomes were rates of serious infection, serious adverse events, and colectomy. We included 321 UC patients (71% prior TNFα antagonist exposure, median follow-up 10 months). The 12-month cumulative rates of clinical remission and endoscopic remission were 51% and 41%, respectively. Corresponding rates for corticosteroid-free remission and deep remission were 37% and 30%, respectively. Using NRI, 12-month rates were 20% (n = 64/321) for clinical remission, 17% (n = 35/203) for endoscopic remission, 15% (n = 30/195) for corticosteroid-free remission, and 14% (n = 28/203) for deep remission. A majority of the patients without adequate follow-up at 12 months who were deemed non-responders using NRI had already achieved clinical remission (n = 70) or a significant clinical response (n = 36) prior to 12 months. VDZ discontinuation prior to 12 months was observed in 91 patients, for lack of response (n = 56), need for surgery (n = 29), or adverse event (n = 6). On multivariable analyses, prior exposure to a TNFα antagonist was associated with a reduced probability of achieving clinical remission (HR 0.53, 95% CI 0.38-0.75) and endoscopic remission (HR 0.51, 95% CI 0.29-0.88). Serious adverse events and serious infections were reported in 6% and 4% of patients, respectively. Overall cumulative rates of colectomy over 12 months were 13%, with lower rates observed in patients naive to TNFα antagonist therapy (2%) than those who had been exposed to TNFα antagonists (19%). In this large real-world cohort we observed that VDZ was well tolerated and effective in achieving key clinical outcomes.

Evidence‐based consensus on opportunistic infections in inflammatory bowel disease

Evidence‐based consensus on opportunistic infections in inflammatory bowel disease

Loss of Response to Anti-Tumor Necrosis Factor Alpha Therapy in Crohn's Disease Is Not Associated with Emergence of Novel Inflammatory Pathways.

While monoclonal antibodies against tumor necrosis factor-α (TNFα) are effective in treating Crohn's disease (CD), approximately one-third of patients lose response. The mechanisms underlying this loss of response remain elusive. We sought to determine if novel biological pathways, including TNFα-independent inflammatory pathways, emerge in those with loss of response to anti-TNFα. Using RNA microarray technology in 28 patients with CD, we examined the colonic gene expression differences between those with active inflammation in the setting of loss of response to TNFα-antagonist therapy ("loss of responders") compared to anti-TNFα naïve patients with active inflammation and those on anti-TNF therapy in disease remission. Pathway enrichment analyses were performed. We found that colonic expression of chemokines known to drive inflammation (CXCL20, CXCL9, and CXCL10) was elevated in those with loss of response compared to those in remission. Expression of genes critical to modulating oxidative stress burden (DUOX2, DUOXA2, and NOS2) was also elevated. Additionally, MMP3, MMP1, and MMP12 were elevated in those with continued inflammation. Gene enrichment analysis revealed that loss of responders exhibited dysregulation in the cysteine and methionine metabolism pathway, suggesting alteration in oxidative stress burden. There were no differences in genes or pathways between loss of responders and those who were TNFα-naïve. However, loss of response occurred despite the ability of anti-TNFα therapy to normalize APO gene expression. Our analyses suggest that loss of response to anti-TNFα is not driven by the emergence of pathways that bypass the action or induce resistance to anti-TNFα therapy.

Sodium 18F-sodium fluoride PET failed to predict responses to TNFα antagonist therapy in 31 patients with possible spondyloarthritis not meeting ASAS criteria

ObjectivesTo determine whether 18F-NaF positron-emission tomography (PET) contributes to the diagnosis of spondyloarthritis and whether observed uptakes predict the response to TNFα antagonist therapy. MethodsWe studied patients who had suspected spondyloarthritis but did not meet ASAS criteria and who were referred for an assessment of eligibility for TNFα antagonist therapy. 18F-NaF PET was offered instead of bone scintigraphy. TNFα antagonist therapy was given if the clinician's level of confidence in the diagnosis of spondyloarthritis based on 18F-NaF PET findings was≥50/100. ResultsThirty-one patients accepted to undergo 18F-NaF PET. Their mean age was 39.9±11.7years; 22% were HLA-B27-positive and none had evidence of sacroiliitis by magnetic resonance imaging. Of the 31 patients, 30 had abnormal 18F-NaF PET findings. However, of the 312 high-uptake foci, only 123 (39.4%) matched sites of pain. TNFα antagonist therapy was given to 16 patients. The treated group and untreated group (n=15) were not significantly different for the mean number of high-uptake foci per patient (11.7±8.1 vs. 8.3±5.1, respectively) or for the proportion of patients with high uptake by the sacroiliac joints (13/16 [81%] vs. 8/15 [53%], respectively). In the treated group, 5 patients met ASAS response criteria after 3months. These 5 patients were among the 9 treated patients who met Amor's modified criteria (arthritis instead of asymmetrical oligoarthritis). In the 5 responders, the 18F-NaF uptake scores were nonsignificantly lower than in the 11 nonresponders (9.0±8.5 vs. 13.0±6.4, respectively). In the patients for whom the 18F-NaF PET findings increased the level of confidence in the diagnosis of spondyloarthritis, this effect was short-lived. DiscussionThe positive predictive value of 18F-NaF PET for diagnosing spondyloarthritis or predicting a response to TNFα antagonist therapy seems very low. This finding is probably ascribable to poor specificity.

Predictors of response to TNF-α antagonist therapy in Chinese rheumatoid arthritis.

This study aimed to investigate the clinical, immunological, and radiologic predictors of response to tumor necrosis factor (TNF)-α antagonist therapy in Chinese rheumatoid arthritis (RA). Ninety RA patients were divided into two groups according to their responsiveness to TNF-α antagonist therapy at 1 month: group A (responders) and group B (non-responders). After 3 months of therapy, all the 90 patients were re-assessed and re-divided into another two groups: group C (responders) and group D (non-responders). Serum samples and clinical characteristics as well as radiographic features were collected at baseline, first month, and third month post-initial administration of TNF-α antagonist. Serum TNF-α, interleukin (IL)-6, IL-8, IL-34, and matrix metalloproteinase (MMP)-3 were measured by enzyme-linked immunosorbent assay (ELISA). Disease activity and Sharp score were evaluated. (1) Comparisons between groups A and B: subjects in group A showed a lower level of erythrocyte sedimentation rate (ESR) and a higher level of albumin (ALB) at baseline than that of group B (p < 0.05). The cutoff value of ALB for prediction was ≥34.9 g/l and that of ESR was ≤55.5 mm/h. (2) Comparisons between groups C and D: group C showed lower levels of ESR, health assessment questionnaire (HAQ), and IL-34 at baseline (p < 0.05). The threshold for prediction were as follows: ESR ≤60 mm/h, HAQ ≤1.3125, and IL-34 ≤194.12 pg/ml. (3) The serum cytokines were positively correlated with C-reactive protein (CRP) and disease activity index, while ALB was negatively correlated with CRP and disease activity. Baseline ALB ≥34.9 g/l or ESR ≤55.5 mm/h might predict a good response at 1-month treatment of TNF-α antagonist, while baseline ESR ≤60 mm/h, HAQ ≤1.3125, and IL-34 ≤194.12 pg/ml might predict a good response at 3-month treatment.

Serial QuantiFERON-TB Gold In-Tube testing for psoriatic patients receiving antitumor necrosis factor-alpha therapy

Tumor necrosis factor-α (TNF-α) antagonists have become increasingly popular in the treatment of psoriasis. However, the increased risk of latent tuberculosis infection (LTBI) reactivation has also become an important issue in clinical practice. The aim of this study was to evaluate serial QuantiFERON-TB Gold In-Tube (QFT-GIT) testing for detecting LTBI among a cohort of psoriatic patients vaccinated with bacille Calmette-Guérin in a country with an intermediate burden of TB during long-term treatment with TNF-α antagonists. We enrolled psoriatic patients treated with TNF-α antagonists who also accepted yearly serial QFT-GIT testing and regular chest X-ray examinations before and during the anti-TNF-α treatment from January 2010 to August 2014. Patients diagnosed with LTBI received chemoprophylaxis, and QFT-GIT testing was performed in these patients after completion of chemoprophylaxis. In this retrospective study, 101 patients had completed baseline and at least 1 year of follow-up. Among these patients, 60 had continued TNF-α antagonists therapy and received examinations in the 2 nd year, whereas 18 had continued the therapy until the 3 rd year. The conversion rate among these patients was 14.29% (13/91). In this study, 23 patients were diagnosed with LTBI according to the positive results obtained in the QFT-GIT test, with 19 of them having completed chemoprophylactic therapy. Follow-up QFT-GIT testing revealed reversion in 11 patients (57.89%) and decreased interferon-γ (IFN-γ) levels (68.42%) in 13 patients. Patients over 45 years of age tended to have a persistent positive result. This study demonstrated that 14.29% of psoriatic patients undergoing long-term TNF-α antagonist therapy had a QFT-GIT conversion. Although a decreased IFN-γ level and QFT-GIT reversion were observed in most cases following prophylactic therapy, the value of QFT-GIT for evaluating the effect of LTBI prophylaxis remains controversial.

Occurrence of pulmonary rheumatoid nodules following biological therapies

In rheumatoid arthritis (RA), disease activity is generally determined by the joint involvement, but the treatment outcome is often influenced by extra-articular manifestations. Authors present a 74-year-old female patient's case history, who was treated with seropositive RA. Marked disease activity was observed even following combined traditional disease-modifying antirheumatic drug (DMARD) treatment (disease activity score in 28 joints (DAS28) = 6.6). Therefore, the patient received TNF-α antagonist therapy. Golimumab was administered subcutaneous (SC) once monthly which resulted in significant improvement in both clinical and laboratory signs (DAS28 = 3:43). However, the follow-up chest x-ray indicated multiple intrapulmonary foci and enlarged lymph nodes. Biopsies and histology excluded malignancy; rheumatoid nodules were confirmed. Anti-TNF therapy was discontinued and tocilizumab treatment was initiated. The IL-6 receptor inhibitor suppressed arthritic activity, and 2 months later, the follow-up chest x-ray showed a regression of chest nodules. Our cases, as well as reports from other centers, suggest that TNF blockade may induce rheumatoid nodulosis and the use of alternative biologics may be feasible as further treatment of RA.

Early Tumor Necrosis Factor α Antagonist Therapy in Everyday Practice for Inflammatory Back Pain Suggesting Axial Spondyloarthritis: Results From a Prospective Multicenter French Cohort

To determine the frequency of and factors associated with early tumor necrosis factor α (TNFα) antagonist therapy in everyday clinical practice in patients with suspected axial spondyloarthropathy (SpA). We used data from the prospective observational study in the French Devenir des Spondylarthropathies Indifférenciées Récentes (DESIR; Outcome of Recent Undifferentiated Spondylarthropathies) cohort of 708 patients with recent-onset (<3 years) inflammatory back pain (IBP) suggesting axial SpA. TNFα antagonist use was recorded at months 6 and 12 and factors independently associated with TNFα antagonist therapy were identified by multivariate logistic regression. Among the 708 patients (mean age 33.8 years, 46.2% men), 166 (23.4%) patients received TNFα antagonist therapy by month 12, including 120 (73.6%) patients who fulfilled Assessment of SpondyloArthritis international Society (ASAS) axial criteria and 157 (94.6%) who fulfilled at least 1 SpA criteria set; 109 (65.6%) had no sacroiliitis. Factors independently associated with early TNFα antagonist therapy were high Ankylosing Spondylitis Disease Activity Score using the C-reactive protein level (odds ratio [OR]1-point increase 1.60, 95% confidence interval [95% CI] 1.25-2.03, P < 0.001), high physician's global disease activity score (OR 1.37, 95% CI 1.21-1.54, P < 0.001), ASAS nonsteroidal antiinflammatory drug score >50 (OR 1.88, 95% CI 1.24-2.87, P = 0.003), current or past disease-modifying antirheumatic drug use (OR 2.09, 95% CI 1.22-3.59, P = 0.008), systemic corticosteroid use (OR 2.48, 95% CI 1.43-4.34, P = 0.002), and mild to severe radiographic hip abnormalities (OR 9.43, 95% CI 2.11-42.09, P = 0.003). After adjustment on these factors, Achilles enthesis hypervascularization by power Doppler and number of work days missed were associated with TNFα antagonist therapy. In the DESIR cohort, approximately one-fourth of patients with recent IBP suggestive of axial SpA were under anti-TNFα therapy after 1 year of followup. All factors associated with this early initiation reflected higher disease activity, refractoriness, or severity, which suggests compliance of French rheumatologists with current treatment guidelines.

FRI0016 Elevated Serum Igg4 Defines A Specific Clinical Phenotype of Rheumatoid Arthritis

BackgroundRheumatoid arthritis (RA) is a heterogeneous autoimmune disease and subtyping of RA may help optimal therapeutic strategies and outcome prediction. There is no available satisfying classification method until now. Recently,...

FRI0029 The Impact of Very Early Treatment on Patient Reported Outcomes in Rheumatoid Arthritis

BackgroundDespite substantial advances in the treatment of rheumatoid arthritis (RA), patients continue to report long term limitations. The combination of TNFα antagonists and methotrexate (MTX) in early RA (ERA), defined...

Tnfa signaling through tnfr2 protects skin against oxidative stress-induced inflammation.

Author SummaryPsoriasis and lichen planus are chronic, debilitating skin diseases that affect millions of people worldwide. TNFα is a multifunctional cytokine that mediates acute and chronic inflammation. While TNFα antagonist therapy is used for autoimmune or chronic inflammatory diseases, such as inflammatory bowel disease (IBD), numerous studies have reported new-onset psoriasis and lichen planus following such therapy. We have used the unique advantages of the zebrafish embryo to identify a novel phenotype that mirrors this unexplained and paradoxical onset of psoriasis and lichen planus. We found that depletion of Tnfa or its receptor Tnfr2 caused skin inflammation and hyperproliferation of keratinocytes through the activation of a Duox1/H2O2/NF-κB positive feedback inflammatory loop. Strikingly, DUOX1 was drastically induced in the skin lesions of psoriasis and lichen planus patients, and pharmacological inhibition of Duox1 abrogated skin inflammation, placing Duox1-derived H2O2 upstream of this inflammatory loop. Our results suggest that therapies targeting DUOX1 and H2O2 could provide innovative approaches to the management of skin inflammatory disorders.