Infliximab Therapy For Rheumatoid Arthritis Research Articles

P33 Spontaneous regression of confirmed diffuse large B-cell lymphoma after withdrawal of long-term methotrexate and infliximab therapy for rheumatoid arthritis, with concurrent discovery of rare high-grade urothelial carcinoma

Abstract Background A 73 year old man was diagnosed with diffuse large B-cell lymphoma germinal centre phenotype, after presenting with a 86x70x45mm right anterior chest wall lesion. CT CAP showed no further lymphadenopathy but identified an additional solid mass in the right ureter. The patient had been on methotrexate for 15 years and infliximab for 13 years for well controlled rheumatoid arthritis, and these were both discontinued on diagnosis of lymphoma. Within three weeks of discontinuation, the lymphomatous mass had clinically noticeably shrunk, confirmed radiologically, and on PET evaluation showed just low-grade avidity. However, the ureteric tumour was avid on PET, suggestive of second pathology. Biopsy proved high grade urothelial carcinoma with neuroendocrine differentiation. Chemotherapy to treat the urothelial carcinoma was identified as a priority, and carboplatin and etoposide chemotherapy was commenced which also has activity in lymphoma. Radiotherapy will be considered in the future, if indicated following further imaging. Methods A literature search was conducted on occurrence of lymphoma and urothelial carcinoma with anti-TNFα biologics. Results The link between methotrexate and increased risk of lymphoma is well covered in literature. Anti-TNFα biologic drugs have also been linked to lymphoma, but definitive causality is difficult to establish due to low numbers of cases and confounding factors. No cases were found in literature to associate anti-TNFα drugs with urothelial, transitional cell or neuroendocrine carcinomas. Eight case studies were found which show a temporal link between discontinuation of anti-TNFα and regression of lymphoma. Of these, six cases reported regression following withdrawal of infliximab. One case involved infliximab monotherapy, three had combination therapy with methotrexate, and two with azathioprine. One case reported discontinuation of adalimumab, with continuation of methotrexate. Histology showed two cases of low grade lymphoma, two case of Hodgkin’s lymphoma, and four cases of diffuse large B Cell non-Hodgkin’s lymphoma, similar to our patient case. Conclusion This patient presented with two synchronous tumours: diffuse large B cell NHL and high grade neuroendocrine carcinoma of urothelial tract. Whereas lymphoma regressed on withdrawal of methotrexate and infliximab, there was no change in the urothelial malignancy. Lymphoma regression allowed the urothelial malignancy to take priority for oncological therapy. It can be concluded that withdrawal of anti-TNF agents can allow spontaneous regression of lymphoma, and this can modify patient treatment plans. Disclosures B.A. Jones None. A. O'Callaghan None. E.V. Ross None. A. Razack None. E. Wong None.

Risk of tuberculosis during infliximab therapy for inflammatory bowel disease, rheumatoid arthritis, and spondyloarthropathy: A meta-analysis.

Infliximab is a promising drug with good outcomes demonstrated for diseases such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA) and spondyloarthropathy (SpA). However, treatment with this drug may increase the risk of tuberculosis infection. The aim of the present study was to investigate infliximab-associated tuberculosis infection. Literature searches in PubMed, MEDLINE and EMBASE databases were performed. Randomized controlled trials with >95% of the patients >18 years-old were included. Meta-analysis was performed to investigate the incidence of tuberculosis infection after infliximab infusion. A total of 24 RCTs were included in the present meta-analysis. In total, 21 (0.51%) tuberculosis infections were detected among 4,111 patients administered infliximab therapy, compared with 0 (0%) among 2,229 patients assigned to the placebo group. Pooled odds ratio (OR) of developing tuberculosis infection was significantly higher with infliximab therapy than with placebo [2.86; 95% confidence interval (CI), 1.09–7.52]. The OR of tuberculosis infection was 3.93 (95% CI, 0.91–16.91) in RA, 2.46 (95% CI, 0.38–15.92) in SpA and 1.66 (95% CI, 0.26–10.57) in IBD. Rates of tuberculosis infection with infliximab therapy in RA, SpA and IBD were 0.70, 0.22 and 0.52%, respectively. Compared with placebo, infliximab therapy may increase the risk of developing tuberculosis. However, the ORs for the risk of infliximab-associated tuberculosis were not demonstrated to be significant in IBD, RA and SpA; therefore, these findings should be interpreted with caution. The risk of developing tuberculosis demonstrates the importance of the prevention and management of tuberculosis infection with infliximab therapy.

Prediction of clinical response after 1 year of infliximab therapy in rheumatoid arthritis based on disease activity at 3 months: posthoc analysis of the RISING study.

To investigate the probability of clinical remission (REM) or low disease activity (LDA) after 1 year of infliximab (IFX) therapy based on disease activity at 3 months in patients with rheumatoid arthritis (RA). Methotrexate-refractory patients with RA received 3 mg/kg of IFX at weeks 0, 2, and 6, followed by 3 mg/kg, 6 mg/kg, or 10 mg/kg every 8 weeks from Week 14 (W14) to Week 46. Correlation of disease activity at W14 with disease activity at W54 and probability of REM/LDA at W54 were analyzed in each dosing group. Disease activities at W14 were significantly correlated with both disease activity at W54 and probability of REM/LDA at W54 in patients continuing 3 mg/kg as well as in those receiving 6 mg/kg or 10 mg/kg therapy from W14. Results showed that, if approximate REM or LDA had not been achieved by W14, > 50% of patients continuing 3 mg/kg therapy would not be able to achieve REM or LDA at W54. However, even in patients with high or moderate disease activity at W14, dose escalation to 6 mg/kg or 10 mg/kg enabled many to achieve REM/LDA. Disease activity at W14 in standard-dose IFX therapy enabled the prediction of longterm clinical response at continued standard dose, as well as subsequent escalated-dose regimens. Disease activity at W14 was hypothesized to be an important index for IFX treatment strategy.

AB0457 Longitudinal study of serum TNF alpha levels, infliximab, and antibodies to infliximab in rheumatoid arthritis

BackgroundThe infliximab (IFX) is a monoclonal chimeric antibody targeting the Tumor Necrosis Factor alpha (TNFα), indicated in the rheumatoid arthritis (RA) treatment. Only two-third of RA patients respond to anti-TNFα...

Changes in disease activity, lung function and quality of life in patients with refractory sarcoidosis after anti-TNF treatment

Objectives: The effect of infliximab therapy in rheumatoid arthritis and Crohn's disease has been well documented. However, literature on infliximab therapy in the rare disease sarcoidosis is scarce. The aim of our study is to evaluate change in disease activity and quality of life upon infliximab treatment in patients with refractory sarcoidosis.Research design and methods: Retrospective cohort study of 48 patients who received infliximab treatment at a national referral center for sarcoidosis. The clinical effect of infliximab treatment was analyzed in terms of change in disease activity (18F-FDG PET, serum angiotensin-converting-enzyme [ACE], serum-soluble interleukin-2 receptor [sIL-2R]), lung function (predicted VC, FEV1 and DLCOc), fatigue severity (CIS) and physical functioning (SF-36). Study parameters were assessed before the first dose (week 0) and after the last dose (week 18).Results: We found significant decreases in the serum markers ACE and sIL-2R and in SUVmax on 18F-FDG PET. Furthermore, a significant improvement in fatigue severity and physical functioning scores was observed. In patients with a pulmonary treatment indication, we found significant improvements in percentages of predicted VC (7.6%), FEV1 (7.9%) and DLCOc (3.5%).Conclusions: Infliximab improves PET-scan, serum markers, lung function and quality of life in patients with refractory sarcoidosis.

Additional use of tacrolimus after switching to tocilizumab therapy in patients with primary lack of efficacy of infliximab therapy for rheumatoid arthritis

To the Editor, Recently, I reported, in Modern Rheumatology [1], on the characterization of the primary lack of efficacy of infliximab therapy and the efficacy of switching to tocilizumab in patients with rheumatoid arthritis (RA). In that study, nine of the 24 patients (38%) who had started induction therapy with infliximab were found to be primary nonresponders. Based on their trough concentrations of infliximab, the primary nonresponders could be classified into two groups: rapid-clearance type (six cases) and residual type (three cases). Both types of nonresponders benefited from a switch to tocilizumab therapy; eight of the nine patients (89%) were successfully treated with tocilizumab. One patient in the rapid-clearance group (Table 1, case 1), however, failed to achieve a 20% improvement according to the American College of Rheumatology criteria (ACR20) at the end of 24 weeks of tocilizumab therapy. To date, no patients who responded well to tocilizumab therapy have relapsed. Since the publication of this earlier study, it has been pointed out by several rheumatologists that our reported success rate of tocilizumab therapy seemed to be higher than that based on their experience in daily practice. To address this concern, I present the clinical characteristics and therapeutic responses to tocilizumab of primary infliximab-nonresponders who have been newly identified since the last study. I also show the efficacy of the additional use of tacrolimus with tocilizumab therapy. Following the protocol of the previous study, I conducted induction therapy with infliximab (intravenous infusions of 3 mg/kg) in 12 patients. During the infliximab therapy, methotrexate (MTX) (4–8 mg/week) and folic acid (5 mg/week) were given concomitantly. One patient, case 5, was receiving low-dose prednisolone (5 mg/day) at the start of the infliximab therapy and continued to receive this medication concomitantly throughout the period of infliximab therapy. Four of the 12 patients (33%) were characterized by a primary lack of efficacy of infliximab through the induction therapy (Table 1, cases 2–5). In one of these patients (case 2), the trough serum concentration of infliximab at week 14 was below the therapeutic level (1 lg/ml) (rapid-clearance type). The other three patients (cases 3–5) maintained high enough serum infliximab levels to produce therapeutic effects (residual type). Case 2 received a dose escalation (addition of one vial), but he nevertheless showed undetectably low trough concentrations (less than 0.1 lg/ml). All primary nonresponders were switched from infliximab to tocilizumab therapy (intravenous infusion of 8 mg/kg every 4 weeks for 24 weeks). During this therapy, all patients except for case 3 continued to receive MTX (8 mg/week) and folic acid (5 mg/week) concomitantly. MTX was discontinued in case 3 because of hepatic toxicity. Case 5 continued to receive low-dose prednisolone. As shown in Table 2, two patients (cases 3 and 4) in the residual-type group achieved an ACR70 improvement and a good response as defined by the European League Against Rheumatism (EULAR) 24 weeks after making this switch. However, the other two patients (case 2, rapid-clearance type; case 5, residual type) were refractory to tocilizumab therapy; these patients S. Mori (&) Department of Rheumatology, Clinical Research Center for Rheumatic Disease, NHO Kumamoto Saishunsou National Hospital, 2659 Suya, Kohshi, Kumamoto 861-1196, Japan e-mail: moris@saisyunsou1.hosp.go.jp

Fungal arthritis of the wrist caused by Candida parapsilosis during infliximab therapy for rheumatoid arthritis

A 60-year-old woman with rheumatoid arthritis, who had been treated with infliximab, presented with uncontrollable wrist arthritis. Fungal arthritis caused by Candida parapsilosis was confirmed by examining her aspirated joint fluid. Her infliximab therapy was interrupted, and antifungal therapy with fluconazole was started. After the fungal infection had been ameliorated, surgical debridement and arthrodesis of the wrist joint were conducted, and her symptoms completely resolved. Although fungal arthritis is rare, it should be considered as a differential diagnosis of exacerbated monoarthritis in patients treated with biological agents.

Primary lack of efficacy of infliximab therapy for rheumatoid arthritis: pharmacokinetic characterization and assessment of switching to tocilizumab

To characterize primary failure to infliximab and determine the efficacy of switching to tocilizumab in patients with rheumatoid arthritis (RA), we examined 24 RA patients who had started on infliximab therapy (3 mg/kg) as their first biological agent. Nine of the 24 patients were found to be primary nonresponders, defined as patients who had never achieved a 20% clinical improvement according to the American College of Rheumatology criteria (ACR20) during induction therapy. The remaining 15 patients had achieved an ACR20 response to infliximab, without any relapses, for at least the first 14 weeks. A higher baseline health assessment questionnaire score was markedly associated with primary unresponsiveness to infliximab (p = 0.0005). Six of the 9 primary nonresponders showed rapid clearance of infliximab: their trough concentrations of infliximab were under 1 μg/ml. The other 3 were classified as exhibiting the residual type of unresponsiveness, which was defined as unresponsiveness in patients who maintained serum infliximab levels above 1 μg/ml. Human antichimeric antibody was not detected in the rapid-clearance nonresponders. Dose escalation (5 mg/kg) was insufficiently effective. Primary nonresponders to infliximab were started on tocilizumab therapy (8 mg/kg, every 4 weeks), and their responses were assessed after 24 weeks of this second attempt at therapy. All the nonresponders, except for a single rapid-clearance patient, had achieved an ACR20 clinical improvement at the time of assessment. In conclusion, primary nonresponders to infliximab can be classified into rapid-clearance and residual types, based on their trough concentrations of infliximab, but both types of nonresponders seem to benefit from an early decision to discontinue infliximab therapy and switch to tocilizumab.

Primary lack of efficacy of infliximab therapy for rheumatoid arthritis: pharmacokinetic characterization and assessment of switching to tocilizumab

To characterize primary failure to infliximab and determine the efficacy of switching to tocilizumab in patients with rheumatoid arthritis (RA), we examined 24 RA patients who had started on infliximab therapy (3 mg/kg) as their first biological agent. Nine of the 24 patients were found to be primary nonresponders, defined as patients who had never achieved a 20% clinical improvement according to the American College of Rheumatology criteria (ACR20) during induction therapy. The remaining 15 patients had achieved an ACR20 response to infliximab, without any relapses, for at least the first 14 weeks. A higher baseline health assessment questionnaire score was markedly associated with primary unresponsiveness to infliximab (p = 0.0005). Six of the 9 primary nonresponders showed rapid clearance of infliximab: their trough concentrations of infliximab were under 1 μg/ml. The other 3 were classified as exhibiting the residual type of unresponsiveness, which was defined as unresponsiveness in patients who maintained serum infliximab levels above 1 μg/ml. Human antichimeric antibody was not detected in the rapid-clearance nonresponders. Dose escalation (5 mg/kg) was insufficiently effective. Primary nonresponders to infliximab were started on tocilizumab therapy (8 mg/kg, every 4 weeks), and their responses were assessed after 24 weeks of this second attempt at therapy. All the nonresponders, except for a single rapid-clearance patient, had achieved an ACR20 clinical improvement at the time of assessment. In conclusion, primary nonresponders to infliximab can be classified into rapid-clearance and residual types, based on their trough concentrations of infliximab, but both types of nonresponders seem to benefit from an early decision to discontinue infliximab therapy and switch to tocilizumab.

Precore mutant hepatitis B virus-associated fulminant hepatitis during infliximab therapy for rheumatoid arthritis

A 73-year-old female, who suffered from rheumatoid arthritis for 10 years, developed precore mutant hepatitis B virus-associated fulminant hepatitis after 1 year of infliximab therapy and subsequent methotrexate withdrawal. We emphasize the importance of preemptive antiviral therapy before starting infliximab administration and withdrawing immunosuppressive drugs.

The Tumor Necrosis Factor-α-blocking Agent Infliximab Inhibits Interleukin 1ß (IL-1ß) and IL-6 Gene Expression in Human Osteoblastic Cells

Objective.Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine involved in the pathogenesis of several rheumatic diseases, including rheumatoid arthritis (RA), associated with systemic bone loss and subchondral bone erosions. TNF-α-blocking agents such as infliximab have been successful in treatment of disease-modifying antirheumatic drug-resistant rheumatic diseases. Infliximab therapy in RA also had beneficial effects on local bone destruction and bone mineral density. We assessed effects of infliximab treatment on the bone tissue compartment and cytokine profile expression in vitro.Methods.Osteoblast-like cells were exposed for 24 h to sera of RA patients collected at baseline and after 1 month (T1) and 3 years (T2) of infliximab treatment. Total RNA was extracted, and expression of interleukin 1ß (IL-1ß), IL-6, and osteoprotegerin (OPG) was measured by RT-PCR.Results.IL-1ß gene expression was significantly reduced by the T1 serum, and the same decrease was elicited by the T2 serum. IL-6 downregulation was evident with the T2 serum. OPG was unaffected.Conclusion.The finding of downregulation of inflammatory cytokines was interesting, particularly IL-6, which plays a crucial role in arthritis-related bone loss due to its involvement in osteoclast recruitment and activation. These results may represent a biological explanation and a link for the clinical observation of the beneficial effects of anti-TNF-α agents on the progression of rheumatic diseases at the bone level.

Late infection of total knee arthroplasty inflamed by anti-TNFα, Infliximab therapy in rheumatoid arthritis

We report a case of sudden onset of late infection after TKA inflamed by anti-TNFalpha therapy, Infliximab, in a 54-year-old woman with RA. Infliximab therapy was started 3 years and 8 months after TKAs as a result of multiple arthritides showing high inflammation of RA. One week after the third administration of Infliximab, the patient suffered sudden knee pain and infectious clinical symptoms, and bacteria (MSSA) were detected by joint effusion culture. She was successfully treated by open debridement with antibiotics-loaded calcium phosphate bone paste and cement and the prostheses were retained. Early diagnosis and operative treatment might be the key to controlling infected TKA without removing the implant. This present case might indicate a serious risk of immunosuppressive effects caused by Infliximab.

75. Lewis-sumner syndrome associated with infliximab therapy in rheumatoid arthritis

75. Lewis-sumner syndrome associated with infliximab therapy in rheumatoid arthritis

The effects of infliximab therapy on the serum proteome of rheumatoid arthritis patients

IntroductionAlthough the clinical effects of infliximab therapy in rheumatoid arthritis have been documented extensively, the biological effects of this intervention continue to be defined. We sought to examine the impact of infliximab therapy on the serum proteome of rheumatoid arthritis patients by means of a mass spectrometry-based approach.MethodsSera from 10 patients with rheumatoid arthritis were obtained prior to and following 12 weeks of infliximab therapy using a standard clinical protocol. The sera were immunodepleted of the 12 highest abundance proteins, labeled by the iTRAQ (isobaric tagging for relative and absolute protein quantification) technique, and analyzed by mass spectrometry to identify proteomic changes associated with treatment.ResultsAn average of 373 distinct proteins were identified per patient with greater than 95% confidence. In the 3 patients demonstrating the most robust clinical responses, changes of greater than 20% in the serum levels were observed in 39 proteins following treatment. The majority of these proteins were regulated directly or indirectly by tumour necrosis factor-alpha (TNF-α) and nuclear factor-kappa-B, with acute-phase proteins being uniformly down-regulated. A number of proteins, including members of the SERPIN family and S100A8, were down-regulated irrespective of clinical response.ConclusionsThe present study demonstrates that a robust clinical response to infliximab is associated with the down-regulation of a spectrum of serum proteins regulated by TNF-α, and provides a possible basis for defining the broader biological effects of the treatment in vivo.

Lewis–Sumner syndrome associated with infliximab therapy in rheumatoid arthritis

We report 2 cases of Lewis-Sumner syndrome (LSS) diagnosed in patients suffering from rheumatoid arthritis undergoing treatment with the antitumor necrosis factor alpha (TNF-alpha) monoclonal antibody infliximab. While experiencing clinical improvement in their arthritic symptoms, both patients experienced sensory deficits and weakness in multiple nerve distributions. They had electrodiagnostic evidence of motor conduction block and subsequent improvement with intravenous immunoglobulin (IVIg). We describe the details of the cases and review the literature on immune-mediated neuropathies associated with anti-TNF-alpha therapy.

Histological analysis of synovium in cases of effect attenuation associated with infliximab therapy in rheumatoid arthritis

To investigate the histological changes of synovium in cases of effect attenuation occurring after the use of infliximab in the treatment of rheumatoid arthritis (RA), we histologically assessed synovial tissue from ten methotrexate-treated RA patients and 12 infliximab-treated RA patients after arthroscopic synovectomy. The synovium was observed using hematoxylin and eosin (H&E) stain and analyzed immunohistochemically for expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), B-cell transmembrane protein, cluster of differentiation 20 (CD20), nuclear factor kappa B (NFkB), bromodeoxyuridine (BrdU), and vascular endothelial growth factor (VEGF). H&E staining showed significant vascular proliferation in the synovium of the RA patients in the infliximab group (p < 0.05). Immunohistochemical examinations showed that TNF-alpha was completely blocked in patients with effect attenuation who received infliximab (p < 0.05). IL-6 was more strongly expressed in the interstitial cells of synovium of patients who received infliximab than in the cells of patients in the control group (p < 0.05). MMP-3 was expressed on the surface of synovium, and CD20 and BrdU were strongly expressed in the infliximab group compared with the control group (p < 0.05). NFkB was expressed in both groups. VEGF was decreased in the infliximab group compared with control. These findings indicate that the expression pattern of immunohistochemical findings in synovium was changed in effect attenuation cases among RA patients treated with infliximab.

Peripheral Neuropathy during Infliximab Therapy for Rheumatoid Arthritis

Peripheral Neuropathy during Infliximab Therapy for Rheumatoid Arthritis

Fatal miliary Coccidioidomycosis in a patient receiving infliximab therapy: a case report

A 78-year-old white male from Iowa in the United States of America receiving the anti- tumor necrois factor (TNF) agent infliximab therapy for rheumatoid arthritis developed a cheek ulcer which failed to respond to empiric antibiotic therapy. He subsequently presented with progressive respiratory failure from miliary coccidioidomycosis which proved fatal. The patient vacationed in Arizona 6 months previously and likely contracted the organism there as Iowa is not an endemic area for coccidioidomycosis. Respiratory failure from miliary infiltration is an uncommon presentation of coccidioidomycosis. Physicians should be aware of the importance of travel history and potential for life-threatening coccidioidomycosis in patients receiving tumor necrosis factor inhibitors.

Overwhelming Parasitemia with Plasmodium falciparum Infection in a Patient Receiving Infliximab Therapy for Rheumatoid Arthritis

We describe a 45-year-old woman receiving infliximab therapy for rheumatoid arthritis who developed an overwhelming Plasmodium falciparum infection with cerebral malaria. Physicians should be aware that patients receiving tumor necrosis factor inhibitors, such as infliximab, may be at increased risk of life-threatening malarial infections.

FatalSalmonella enteritidissepticaemia in a rheumatoid arthritis patient treated with a TNF-α antagonist

We report a patient with a rare presentation of extra-intestinal salmonellosis after infliximab therapy for rheumatoid arthritis. We discuss the increasing incidence of primary infections and reactivation of intracellular microorganisms after treatment with TNF-alpha blockage, with emphasis on salmonellosis.