Louis R. Ricca

A Safety Assessment of Tumor Necrosis Factor Antagonists During Pregnancy : A Review of the Food and Drug Administration Database

Objective. To present any congenital anomalies with respect to tumor necrosis factor (TNF) antagonists reported to the US Food and Drug Administration (FDA) to determine if there are common findings. Methods. A review of the FDA database of reported adverse events with etanercept, infliximab, and adalimumab from 1999 through December of 2005 was performed. Key words for congenital anomalies were employed as search tools. Duplicate reports were eliminated. Any concomitant medicines were recorded. Results. Our review of > 120,000 adverse events revealed a total of 61 congenital anomalies in 41 children born to mothers taking a TNF antagonist. Of these mothers, 22 took etanercept and 19 took infliximab. There were no reports in women taking adalimumab. The most common reported congenital anomaly was some form of heart defect. Twenty-four of the 41 (59%) children had one or more congenital anomalies that are part of vertebral abnormalities, anal atresia, cardiac defect, tracheoesophageal, renal, and limp abnormalities (VACTERL) association. There were 34 specific types of congenital anomalies in total, and 19 (56%) of those are part of the VACTERL spectrum. Nine of these 19 (47%) types of VACTERL anomalies were observed statistically significantly more than historical controls (p < 0.01); in 4 of these 9 the p value was ≤ 0.0001. Thirteen (32%) of the children had more than one congenital anomaly; 7 of these 13 children had 2 defects that are part of the VACTERL spectrum. However, only 1 child was diagnosed with VACTERL. In 24/41 cases (59%) the mother was taking no other concomitant medications. Conclusion. A seemingly high number of congenital anomalies that are part of the VACTERL spectrum have been reported. These congenital anomalies are occurring at a rate higher than historical controls. This commonality raises concerns of a possible causative effect of the TNF antagonists.

Combination Antibiotics as a Treatment for Chronic Chlamydia-Induced Reactive Arthritis A Double-Blind, Placebo-Controlled, Prospective Trial

OBJECTIVE Chlamydia trachomatis and Chlamydophila (Chlamydia) pneumoniae are known triggers of reactive arthritis (ReA) and exist in a persistent metabolically active infection state in the synovium, suggesting that they may be susceptible to antimicrobial agents. The goal of this study was to investigate whether a 6-month course of combination antibiotics is an effective treatment for patients with chronic Chlamydia-induced ReA. METHODS This study was a 9-month, prospective, double-blind, triple-placebo trial assessing a 6-month course of combination antibiotics as a treatment for Chlamydia-induced ReA. Eligible patients had to be positive for C trachomatis or C pneumoniae by polymerase chain reaction (PCR). Groups received 1) doxycycline and rifampin plus placebo instead of azithromycin; 2) azithromycin and rifampin plus placebo instead of doxycycline; or 3) placebos instead of azithromycin, doxycycline, and rifampin. The primary end point was the number of patients who improved by 20% or more in at least 4 of 6 variables without worsening in any 1 variable in both combination antibiotic groups combined and in the placebo group at month 6 compared with baseline. RESULTS The primary end point was achieved in 17 of 27 patients (63%) receiving combination antibiotics and in 3 of 15 patients (20%) receiving placebo. Secondary efficacy end points showed similar results. Six of 27 patients (22%) randomized to combination antibiotics believed that their disease went into complete remission during the trial, whereas no patient in the placebo arm achieved remission. Significantly more patients in the active treatment group became negative for C trachomatis or C pneumoniae by PCR at month 6. Adverse events were mild, with no significant differences between the groups. CONCLUSION These data suggest that a 6-month course of combination antibiotics is an effective treatment for chronic Chlamydia-induced ReA.

Chlamydiae as etiologic agents in chronic undifferentiated spondylarthritis.

OBJECTIVE The majority of patients with Chlamydia-induced reactive arthritis do not present with the classic triad of arthritis, conjunctivitis/iritis, and urethritis. Moreover, acute chlamydial infections are often asymptomatic. The aim of the present study was to assess the prevalence of synovial Chlamydia trachomatis and Chlamydia pneumoniae infections in patients with chronic undifferentiated spondylarthritis (uSpA). METHODS Study patients met the European Spondylarthropathy Study Group criteria for SpA, without evidence of ankylosing spondylitis, psoriasis, inflammatory bowel disease, or preceding dysentery. Symptoms were present for >or=6 months. Each patient underwent a synovial biopsy; tissue and concomitantly obtained peripheral blood mononuclear cells (PBMCs) were analyzed by polymerase chain reaction (PCR) for C trachomatis and C pneumoniae DNA. Other data collected on the day of the biopsy included standard demographic information and medical history, including any known history of C trachomatis or C pneumoniae. Physical examination (including joint count, evaluation for dactylitis and/or enthesitis, and skin examination) and HLA-B27 typing were performed. Synovial tissue (ST) samples from 167 patients with osteoarthritis (OA) were used as controls. RESULTS Twenty-six patients met the entry criteria and underwent synovial biopsy (25 knee, 1 wrist). Sixteen of them (62%) were positive for C trachomatis and/or C pneumoniae DNA (10 for C trachomatis, 4 for C pneumoniae, and 2 for both). PCR analysis of ST revealed the presence of Chlamydia significantly more frequently in patients with uSpA than in OA controls (P<0.0001). No specific clinical characteristics differentiated Chlamydia-positive from Chlamydia-negative patients. PBMCs from 4 of the 26 uSpA patients (15%) were positive for Chlamydia, and Chlamydia was found in ST from 2 of these 4 patients. No significant correlation between PCR positivity and HLA-B27 positivity was found. CONCLUSION The frequency of Chlamydia-positive ST samples, as determined by PCR, was found to be significantly higher in patients with uSpA than in patients with OA. Our results suggest that in many patients with uSpA, chlamydial infection, which is often occult, may be the cause.

Virtual rheumatology: using simulators and a formal workshop to teach medical students, internal medicine residents, and rheumatology subspecialty residents arthrocentesis.

Background:Arthrocentesis is an important skill for medical practitioners at all levels of training. Previous studies have indicated a low comfort level and performance of arthrocentesis among primary care physicians that could be improved with hands-on training. Objectives:The objective of this study was to improve comfort with knee and shoulder arthrocentesis at all levels of medical training, including medical students, internal medicine residents, and rheumatology subspecialty residents, and in arthrocentesis of the elbow, wrist, and ankle for advanced subspecialty residents in rheumatology through the use of a formal workshop using simulators. Methods:Fourth-year medical students and internal medicine residents were recruited from the University of South Florida. The rheumatology advanced subspecialty residents were participants from University of South Florida and from the American College of Rheumatology national meetings in 2008 and 2009. A 1-hour PowerPoint lecture followed by a hands-on practice session using Sawbones models (shoulder and knee for all groups, and elbow, wrist, and ankle additionally for the advanced subspecialty residents). A preworkshop self-assessment survey allowed the participant to rate his/her comfort level with arthrocentesis on a scale of 1 to 5. A survey with identical questions was completed immediately after the workshop. A follow-up survey was distributed by e-mail 3 to 6 months after the workshop. Results:One hundred forty-one medical students, 75 internal medicine residents, and 39 rheumatology subspecialty residents participated from January 2008 until January 2010. Mean comfort level in knee and shoulder arthrocentesis improved from preworkshop comfort level for all joints and among all participants. In addition, rheumatology subspecialty resident mean comfort level improved for ankle from 2.37 to 3.65, elbow from 2.56 to 3.80, and wrist from 2.31 to 3.77 (P < 0.0001). Conclusions:Our study involved a very large number of participants encompassing different levels of training and is the largest number of advanced subspecialty rheumatology residents studied with regard to joint injection training. We have confirmed that a formal joint injection workshop using simulators is an effective method of improving comfort level in arthrocentesis among participants from all levels of medical training. Future studies should evaluate the effect of such training on actual clinical use and competence.

A MRI Assessment of the Response of Chronic, Occult, Synovial-Based Inflammation of Gout to Serum Urate Lowering Therapy

Objective: We have previously demonstrated the severity of synovitis in patients with inter-critical gout did not correlate with serum urate levels (sUA). The aim of this sub-study was to determine if serum urate lowering therapy can improve this chronic synovitis. Methods: All participants had inter-critical gout and received a 3T MRI with and without gadolinium of their index joint (i.e. the joint most often involved with acute attacks). If the subject had a sUA of ≥ 7.0 mg/dL and evidence of synovial pannus on their MRI, they were eligible for enrollment. All were treated with febuxostat with a target sUA of ≤ 6.0 mg/dL. At month 9, the MRI of the index joint was repeated and compared to baseline. The MRI’s were read by two musculoskeletal radiologists in a blinded fashion. The primary endpoint was to determine if there was significant improvement in the severity of synovial pannus from baseline to month 9. Results: 25/32 subjects completed the protocol. The average sUA and synovial pannus score at screening was 9.3 mg/dL (+/- 1.3 SD) and 3.66 (+/- 1.2 SD), respectively. At month 9, the average sUA decreased to 5.36 mg/dL (+/- 1.4 SD; p < 0.0001), but there was no significant change in the severity of synovial pannus with the average score being 3.42 (+/- 1.3 SD; p = 0.34). The inter-reader agreement between the two radiologists was good (kappa = 0.63). However, a post-hoc analysis using a more quantitative synovial pannus scoring scale suggested a significant decrease. Conclusions: Nine months of serum urate lowering therapy significantly decreases serum urate levels but the effect on the chronic, occult, synovial-based inflammation of gout remains unclear.

SAT0352 An Assessment of Chronic Synovial-Based Inflammation and its Role with Serum Urate Levels.

Background Untreated gout transitions from an acute intermittent arthritis to a chronic inflammatory arthritis indicating at some point the inflammation associated with gout does not abate; it is unclear when this inflammatory process starts. Objectives The aim of this study was to determine the percentage of patients with inter-critical gout who have chronic synovial-based inflammation as evidenced by synovial pannus on a contrast-enhanced MRI of their most involved joint and determine if the presence and/or severity correlates with their serum urate levels. Methods All patients in this prospective trial had inter-critical gout and received a 3T MRI with and without gadolinium of their index joint (i.e. the joint most often involved with acute attacks of gout). Each subject also had a plain radiograph of the index joint as well as a serum urate, highly sensitive (hs)-CRP, and creatinine obtained on the same day. The MRI and radiograph were read by two musculoskeletal radiologists in an independent and blinded fashion. The primary endpoint was to determine the correlation of serum urate levels with the presence and/or severity (previously utilized monoarthritis MRI grading scale of 1-6) of the synovial pannus on the index joint. The MRI and radiographs were also assessed for erosions, intraosseous tophi, soft-tissue tophi, soft tissue swelling, joint effusions, and bone marrow reactive changes (MRI only). Secondary endpoints included the correlation with the presence and/or severity of synovial pannus with hs-CRP and estimated glomerular filtration rate (eGFR). The other MRI and plain radiograph findings were also assessed for correlation with their serum urate level. Results 74 subjects were screened; 72 completed the protocol. 65/72 (90%) participants were males (50 Caucasian, 10 African-American, 9 Hispanic, 3 other) with an average age and disease duration of 56.4 years (range 28-78) and 10.1 years (range 0.5-37), respectively. 53/72 (74%) index joints were the first metatarsalphalangeal joint; the average number of attacks in the index joint was 11.4 (+/- 13.6 SD) and 21.8 (+/- 25.8 SD) total attacks in any joint. 39 (54.2%) of the patients were on urate lowering therapy; 15 (20.8%) and 7 (9.7%) were taking colchicine or a NSAID daily, respectively. 63/72 (87.5%; 95% CI of 5.9%) of the subjects had synovial pannus on their MRI with good inter-reader agreement between the two radiologists (kappa 0.74). The mean serum urate level was 7.93 (+/- 2.13 SD). There was no correlation with the presence (p=0.33 [t-test]) or severity (Spearman correlation coefficient 0.12 [p=0.34]) of synovial pannus and serum urate levels. There was also no correlation with the presence (p=0.32) or severity (p=0.30) of synovial pannus and hs-CRP or the presence of pannus and eGFR (p=0.62), but there was a correlation with the severity of pannus and eGFR (p=0.02). Finally, the serum urate levels did not correlate with the presence of any of the other findings on MRI or plain radiograph of the index joint. Conclusions The overwhelming majority of patients with inter-critical gout have evidence of occult and chronic synovial-based inflammation. However, the presence and severity of this chronic synovial-based inflammation does not appear to correlate with serum urate levels. Acknowledgements Support provided by Takeda Pharmaceuticals USA, Inc. Disclosure of Interest J. Carter Grant/research support from: Takeda Pharmaceuticals, USA, Inc, Speakers bureau: Takeda Pharmaceuticals, USA, Inc, M. Patelli: None Declared, S. Anderson: None Declared, N. Prakash: None Declared, R. Aydelott: None Declared, E. Rodriguez: None Declared, H. Bateman: None Declared, A. Sterrett: None Declared, J. Valeriano: None Declared, L. Ricca: None Declared

Dr. Carter, et al reply

To the Editor: We thank Winger and Reed for their comments regarding our article1. As with any study, ours had limitations. Winger and Reed point out that the data collected are provided voluntarily and, therefore, may not represent the true number of congenital anomalies within the population. We agree. These data represent a “best-case scenario.” It is impossible for there to be fewer congenital anomalies than those actually reported. As we know from any postmarketing data, significant under-reporting is the norm. They also suggest that the data reviewed did not support the calculation of a denominator necessary for the calculation of incidence. It is true that the total number of pregnant women treated with a tumor necrosis factor (TNF) antagonist during pregnancy is an unknown; this was acknowledged in the original article. However, we did not attempt to calculate an incidence of the reported birth defects in the article. The “incidences” listed in Table 2 are historical controls. Winger and Reed also raise the issue of … Address correspondence to Dr. Carter; E-mail: jocarter{at}health.usf.edu