Joanne Valeriano

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.

V2 regions of 16S ribosomal RNA used as a molecular marker for the species identification of streptococci in peripheral blood and synovial fluid from patients with psoriatic arthritis

OBJECTIVE To detect the 16S ribosomal RNA (rRNA) of 3 streptococcal species in the peripheral blood and synovial fluid of patients with psoriatic arthritis (PsA). METHODS Reverse transcription-polymerase chain reaction (RT-PCR) detection targets bacterial 16S rRNA, which is present in bacteria at high copy numbers. The 3 species-specific primers for group A streptococci (GAS; Streptococcus pyogenes), group B streptococci (GBS; Streptococcus agalactiae), and Streptococcus pneumoniae were designed from the fragments of highly variable V2 regions of 16S rRNA. Total RNA was prepared from whole peripheral blood and joint fluid obtained from patients with PsA and rheumatoid arthritis (RA). All positive PCR reactions were then sequenced with a Pharmacia ALF DNA sequencing system. RESULTS Our data in 19 PsA patients showed that 7 peripheral blood samples were positive for GAS (P = 0.006 versus GAS-positive RA patients [n = 0], by Fishers exact test), and 2 were also positive for GBS. One synovial fluid sample from a PsA patient was positive for GAS. S pneumoniae was absent from all specimens. Seventeen patients with RA were PCR negative for the 3 streptococcal species. Peripheral blood from a patient with inflammatory bowel disease was positive for GAS. CONCLUSION The presence of GAS 16S rRNA in the peripheral blood and synovial fluid of patients with PsA supports the concept that PsA is a reactive arthritis to certain streptococci.

Pyoderma gangrenosum in a patient with cryoglobulinemia and hepatitis C successfully treated with interferon alfa

We describe a patient with long-standing pyoderma gangrenosum unresponsive to therapy. The patient had concomitant cryoglobulinemia and hepatitis C. When the hepatitis C was treated with interferon alfa-2a his pyoderma gangrenosum resolved. Whether this was from the interferon alfa or spontaneous resolution is not known.

Prevalence of evaluation and treatment of glucocorticoid-induced osteoporosis in men.

Background:Screening and treatment of glucocorticoid- induced osteoporosis in male patients is less than recommended despite available screening and therapies. Objectives:We determined if men treated with long-term oral glucocorticoid therapy for any reason receive assessment and therapy for the prevention and treatment of glucocorticoid-induced osteoporosis. Methods:A retrospective computer-generated chart review was performed involving all men given prednisone from January 2002 through July 2002. There were 370 patients evaluated from the James A. Haley Veterans Affairs Hospital, Tampa, Florida, a large teaching hospital for the University of South Florida College of Medicine. Charts were reviewed for bone mineral density testing; dose, duration, and indication of glucocorticoid therapy; age of the patients as of January 2002;continuous or intermittent dosing; history of fracture; bone loss prevention medication use, including bisphosphonate, calcitonin, testosterone replacement therapy, calcium, and vitamin D; and the steroid-prescribing and screening practitioners specialty and sex. Results:Of the 370 men, 258 used 7.5 mg prednisone or more daily and 295 used glucocorticoids for more than 3 months. Of the 370 men, 163 had a bone mineral density test; 87 were treated with a bisphosphonate. Calcium and vitamin D were given to half of the patients. Of the patients with a normal T-score, 13 of 55 were treated with a bisphosphonate (24%) compared with 24 of 40 (60%) with an osteopenic score and 14 of 21 (67%) with osteoporosis. Of the 46 patients with no score available but indication that it had been ordered or otherwise addressed, 23 patients were treated empirically with a bisphosphonate. Rheumatology screened 75% of their patients, whereas primary care screened 30% of their patients. Conclusions:Bone mineral density testing was performed or ordered for less than half of the glucocorticoid-treated patients and less than one third were taking bisphosphonate therapy. Further intervention is needed to increase prevention of glucocorticoid-induced osteoporosis and subsequent risk of fracture.

Hydroxychloroquine as a treatment for atrophoderma of Pasini and Pierini

prepared in embryonated eggs. The most frequent side-effect of the influenza vaccination is pain at the site of vaccination in 10–64% of patients. Immediate allergic reactions, including urticaria, angiedema and systemic anaphylaxis, rarely occur. Influenza vaccination has been rarely associated with serious noncutaneous adverse effects, including Guillain–Barre syndrome and systemic lupus erythematosus. A recent report of SS occurring after influenza vaccination describes a woman who developed tender plaques and pseudovesicular papules at the site of vaccination, trunk and limbs 12 h after vaccination. Sweet’s syndrome has been reported following other forms of vaccination, including Bacille Calmette-Guerin and pneumococcal vaccinations. A review of six previously reported cases of vaccine-associated SS revealed that nearly all had fever and an elevated ESR, and the average time from vaccination to the onset of skin lesions was 7.4 days (range 0.5–15 days). In contrast to classic SS, neutrophilia is a less frequent finding than fever and has an elevated ESR in both vaccine-associated SS and drug-induced SS. Sweet’s syndrome has been reported in association with HIV infection. It has been suggested that HIV-induced immune disturbances may be a favorable background for the occurrence of SS. Findings in immunocompetent patients with SS have suggested that SS is mediated through type 1 (IL-2 and IFN-γ) rather than type 2 T-helper-cell cytokines (IL-4). Sweet’s syndrome has rarely been reported in other immunodeficiency disorders, including primary immunodeficiency. The patient we described in this report had been clinically well with a stable CD4 count, not requiring highly active antiretroviral therapy. The patient had no apparent triggers for SS other than the influenza vaccination. This unusual reaction of bullous SS following an influenza vaccination has not previously been reported in the setting of HIV disease. The pathomechanism underlying the reaction is uncertain, and it is not known if the reaction will reoccur following subsequent vaccinations. With increasing global emphasis on influenza vaccination, particularly for susceptible elderly and immunodeficient individuals, it remains to be seen if there is a rise in the frequency of its occurrence. Audrey W. Tan, MBBS, MRCP (UK), FAMS Hiok-Hee Tan, MBBS, MRCP (UK), FRCP National Skin Center, Singapore Poh Lian Lim, MD, MPH, FAMS Tan Tock Seng Hospital, Singapore

Neck mass in a rheumatoid arthritis patient taking etanercept.

A 60-year-old Caucasian woman with a history of rheumatoid arthritis and a remote history of a post-traumatic splenectomy developed a serious head and neck infection 11 weeks after beginning therapy with etanercept. The patient required incision and drainage of a neck abscess and 2 weeks of i.v. antibiotics to achieve complete recovery. Her etanercept was also discontinued. The causative organism was Streptococcus constellatus, which is a member of the group of encapsulated organisms known as S. intermedius. A normal functioning spleen as well as tumor necrosis factor are both necessary to ward off encapsulated bacteria. Patients who have had a splenectomy and are then started with etanercept may be especially prone to infections with encapsulated organisms, such as streptococcus.

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