As a class, tumor necrosis factor (TNF)-alpha inhibitors have provided clinicians significant control over chronic inflammatory diseases. With their widespread use has come the emergence of new side effects such as the reactivation of latent infections. One such infection that may reactivate is the hepatitis B virus (HBV). It is currently unknown if HBV reactivation is a class effect or attributable to a particular TNF-alpha inhibitor. To answer this question, a comprehensive literature review to identify trends in related cases was performed. A systemic literature review was performed using the PubMed and Medline databases (1996 to January 2010) searching for the index term "Hepatitis B" combined with the terms "tumor necrosis factor," "TNF-alpha inhibitors," "etanercept," "adalimumab," "certolizumab," and "golimumab." All relevant articles in English were reviewed, and secondary references of interest were also retrieved. Thirty-five cases with hepatitis B surface antigen (HBsAg) positivity known prior to initiation of TNF-alpha inhibitors were identified. Infliximab was used in 17 cases, etanercept in 12 cases, and adalimumab in 6 cases. All six cases of clinically symptomatic hepatitis were associated with infliximab therapy. Infliximab was associated with the most cases of greater than 2-fold increase in alanine aminotransferase (six of nine cases) and greater than 1,000-fold increase in HBV DNA load (three of four). The two deaths reported occurred with infliximab therapy. Potential mechanisms of action for the reported observations include differences in molecular design, route of administration, and potency in clearing TNF-alpha. In patients with a positive HBsAg prior to starting a TNF-alpha inhibitor, infliximab has the most reported cases associated with HBV reactivation. While such reactivation may be due to a variety of reasons, clinicians prescribing TNF-alpha inhibitors to HBsAg-positive patients should consider prophylactic antiviral therapy and close monitoring for any clinical or serological evidence of hepatitis.
Sternocostoclavicular hyperostosis (SCCH) is a chronic inflammatory disorder which presents with erythema, swelling, and pain of the sternoclavicular joint. Approximately one half of patients have acne or pustular lesions with the best described association being with palmoplantar pustulosis (PPP). Extrasternal articular disease occurs in about a quarter of patients. The inflammatory process spans several years and has periods of exacerbation followed by remission. The histologic picture demonstrates a sterile osteomyelitis of the sternum and medial end of the clavicle. The diagnosis of SCCH is confirmed radiographically by hyperostosis and sclerosis of the sternum with involvement of the first rib on computed tomography (CT). The focal uptake of radiopharmaceutical on bone scintigraphy called the 'bullhead' sign is highly sensitive of SCCH. Treatment is aimed at easing pain and modifying the inflammatory process. Evidence over the last two decades suggests a role for intravenous bisphosphonates and tumor necrosis factor alpha inhibitors. A low level of awareness of SCCH often leads to a delay in diagnosis. This translates into significant morbidity and brings a psychological burden. Untreated chronic inflammation of the sternoclavicular joint leads to restricted mobility and secondary degenerative joint changes. In the search for a diagnosis, patients often undergo multiple serologic and imaging studies and in the experience of the author are referred to multiple specialists before a correct diagnosis is made. Greater awareness of SCCH is needed to prevent the irreversible physical and psychological impairments associated with the disease.
It remains unclear why the dose of xanthine oxidase inhibitors (XOI) allopurinol or febuxostat varies among patients though they reach similar serum uric acid (SUA) goal. We pursued genomic sequencing of XOI metabolism and clearance genes to identify single-nucleotide polymorphisms (SNPs) relate to differences in XOI dose. Subjects with a diagnosis of Gout based on the 1977 American College of Rheumatology Classification Criteria for the disorder, who were on stable doses of a XOI, and who were at their goal SUA level, were enrolled. The primary outcome was relationship between SNPs in any of these genes to XOI dose. The secondary outcome was relationship between SNPs and change in pre- and post-treatment SUA. We enrolled 100 subjects. The average patient age was 68.6 ± 10.6 years old. Over 80% were men and 77% were Caucasian. One SNP was associated with a higher XOI dose: rs75995567 (p = 0.031). Two SNPs were associated with 300 mg daily of allopurinol: rs11678615 (p = 0.022) and rs3731722 on Aldehyde Oxidase (AO) (His1297Arg) (p = 0.001). Two SNPs were associated with a lower dose of allopurinol: rs1884725 (p = 0.033) and rs34650714 (p = 0.006). For the secondary outcome, rs13415401 was the only SNP related to a smaller mean SUA change. Ten SNPs were identified with a larger change in SUA. Though multiple SNPs were identified in the primary and secondary outcomes of this study, rs3731722 is known to alter catalytic function for some aldehyde oxidase substrates.
Kikuchi-Fujimoto disease (KFD) or histiocytic necrotizing lymphadenitis was first described in Japan in 1972. It is described as a benign syndrome most commonly involving cervical lymphadenopathy, fever, and night sweats. The etiology of KFD is unknown but it is thought to be triggered by an autoimmune or viral process with an exaggerated T-cell-mediated immune response. KFD can mimic other serious conditions such as lymphoma, systemic lupus erythematosus (SLE), herpes simplex, and Epstein Barr virus. Diagnosis is confirmed histopathologically. Kikuchi's disease is typically reported to have a self-limiting course, resolving within several months and with a low recurrence rate between 3% and 4%. There is no specific treatment for KFD but any treatment is generally directed towards symptomatic relief with antipyretics and anti-inflammatory medications. In severe cases corticosteroids have been used. Here we describe a case of a previously healthy 26-year-old female that presented with fever and cervical lymphadenopathy. Malignancy and infections were ruled, and she was diagnosed with KFD histopathologically by lymph node biopsy. Her case is a severe case of KFD that despite treatment with multiple courses of corticosteroids and an immune modulating agent, relapsed.
Acute myocardial infarction (MI) occurs when blood supply falls below critical levels and normal cellular maintenance mechanisms fail. Interleukin-6 (IL-6) is a proinflammatory cytokine released in MI and associated with poor clinical outcomes. Tocilizumab (TCZ) is a humanized monoclonal antibody against the IL-6 receptor. In a randomized, double-blinded, placebo controlled trial we assigned subjects admitted with MI a single TCZ dose of 162 mg subcutaneously vs. placebo in addition to standard of care medications and interventions. Primary outcome was a change in major adverse cardiac events (MACE) 30 days after enrollment. Secondary outcomes assessed changes in CRP 30 days after enrollment, changes in QT/QTc, and monitoring for trends in adverse events. Futility analysis was performed as subject enrollment slowed and no trends were noted in either the primary or secondary outcomes. Twenty-eight subjects were enrolled; 12 to TCZ and 16 to placebo. No statistically significant differences were noted between study arms regarding demographics, comorbidities, or medical/interventional therapies received. No statistically significant differences in MACE were observed. CRP increased after administration of TCZ but this was not statistically significant. No adverse events or safety signals were observed. Though futility analysis suggested that the primary outcome was not likely achievable as our recruitment slowed, we did not observe any adverse events or safety trends. Building on this information, future studies should be conducted to assess a true benefit from TCZ as adjunct therapy for MI. The work reported herein was performed under United States Air Force Surgeon General approved Clinical Investigation FKE20140029 and has been registered at ClinicalTrials.gov under identifier NCT02419937.
Over the past few decades, HIV has been transformed from a once-uniformly fatal disease to now a manageable but complex multisystem illness. Before highly active antiretroviral therapy (HAART), reports suggested that HIV-infected patients with rheumatoid arthritis (RA) would experience remission of their disease. It has now become clear that RA can develop in HIV-infected patients at any time, independent of HAART. Choosing the right medication to treat symptoms related to RA while avoiding excess weakening of the immune system remains a clinical challenge. Agents such as hydroxychloroquine and sulfasalazine might best balance safety with efficacy, making them reasonable first choices for therapy in HIV-infected patients with RA. More immune suppressing agents such as methotrexate may balance safety with efficacy, but data are limited. Corticosteroids such as prednisone may also be reasonable but could increase the risk of osteonecrosis. Among biologic response modifiers, tumor necrosis factor α inhibitors may balance safety with efficacy, but perhaps when HIV replication is controlled with HAART. Monitoring RA disease activity remains challenging as only one retrospective study has been published in this area. Those with HIV infection and RA can experience comorbidities such as accelerated heart disease and osteoporosis, a consequence of the chronic inflammatory state that each illness generates. Although HIV-infected patients are at risk for developing the immune reconstitution inflammatory syndrome when starting HAART, it appears that immune reconstitution inflammatory syndrome has a minimal effect on triggering the onset or the worsening of RA.
Since the 1980s, a host of autoimmune phenomena and rheumatologic illnesses have been linked to infection with the human immunodeficiency virus (HIV). Given the broad effects of this virus on both the humoral and cell-mediated arms of the immune system, illnesses such as polymyositis and Reiter's syndrome appear to be more prevalent in HIV-infected individuals and occur in the absence of well-described predispositions. The activities of some rheumatologic illnesses exhibit an inverse relationship with the course of HIV infection, such as rheumatoid arthritis, which becomes more quiescent with advancing disease. Dermatomyositis is a rheumatologic illness that very infrequently occurs and during our review of literature only three other cases were reported. We present the case of a Caucasian male in his mid-20s who presented with acquired immunodeficiency syndrome and subsequently developed dermatomyositis. In this review, we highlight the current relationship between HIV infection and autoimmunity, the possible ways HIV infection may foster an environment favorable for the development of dermatomyositis, and review the previously reported cases of individuals with HIV infection who developed dermatomyositis. The complex issues of how to treat individuals with HIV and dermatomyositis is also discussed.
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