Prabha Ranganathan

TNF-α Antagonist Use and Risk of Hospitalization for Infection in a National Cohort of Veterans With Rheumatoid Arthritis

Medications used to treat rheumatoid arthritis (RA) may confer an increased risk of infection. We conducted a retrospective cohort study of veterans with RA followed in the United States Department of Veterans Affairs health care system from October 1998 through September 2005. Risk of hospitalization for infection associated with tumor necrosis factor (TNF)-&agr; antagonists therapy was measured using an extension of Cox proportional hazards regression, adjusting for demographic characteristics, comorbid illnesses, and other medications used to treat RA.A total of 20,814 patients met inclusion criteria, including 3796 patients who received infliximab, etanercept, or adalimumab. Among the study cohort, 1465 patients (7.0%) were hospitalized at least once for infection. There were 1889 hospitalizations for infection. The most common hospitalized infections were pneumonia, bronchitis, and cellulitis. Age and several comorbid medical conditions were associated with hospitalization for infection. Prednisone (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.88-2.43) and TNF-&agr; antagonist use (HR, 1.24; 95% CI, 1.02-1.50) were associated with hospitalization for infection, while the use of disease-modifying antirheumatic drugs (DMARDs) other than TNF-&agr; antagonists was not. Compared to etanercept, infliximab was associated with risk for hospitalization for infection (HR, 1.51; 95% CI, 1.14-2.00), while adalimumab use was not (HR, 0.95; 95% CI, 0.68-1.33). In all treatment groups, rate of hospitalization for infection was highest in the first 8 months of therapy.We conclude that patients with RA who are treated with TNF-&agr; antagonists are at higher risk for hospitalization for infection than those treated with other DMARDs. Prednisone use is also a risk factor for hospitalization for infection.Abbreviations: CI = confidence interval, DMARD = disease-modifying antirheumatic drug, HFI = hospitalization for infection, HR = hazard ratio, ICD-9-CM = International Classification of Diseases, Version 9, Clinical Modification, NHDS = National Hospital Discharge Survey, RA = rheumatoid arthritis, TNF-&agr; = tumor necrosis factor-&agr;, VA = Veterans Affairs.

Pharmacogenomics of tumor necrosis factor antagonists in rheumatoid arthritis.

Tumor necrosis factor (TNF)-alpha plays a central role in the pathogenesis of rheumatoid arthritis (RA) and is instrumental in causing joint destruction, the clinical hallmark of the disease. Recognizing this, in recent years biological therapies have been developed that work by blocking the damaging effects of TNF-alpha on synovium and cartilage. Three such agents are currently approved for treatment in RA - etanercept, infliximab and adalimumab. Although these agents are very effective in slowing the clinical and structural progression in RA, they are expensive, totaling several thousand dollars in yearly costs. Furthermore, only about 60% of patients respond effectively to these agents. As RA is a chronic disease, with most patients expected to remain on these therapies for life, ways to prospectively identify patients most likely to benefit from these agents are being explored. Pharmacogenomic approaches form the basis of most such screening methods. Polymorphisms in genes encoding TNF-alpha, TNF-alpha receptors, other cytokines, and the major histocompatibility complex region, and their ability to predict response to anti-TNF therapies, have been the focus of many recent studies. The results from such studies are mixed, with some suggesting that single nucleotide polymorphisms (SNPs) in these genes are significant, while others conclude that such SNPs are irrelevant in predicting response. Such conflicting results are likely to be due to a variety of factors, as discussed in this article. Whether pharmacogenomics will allow prediction of anti-TNF therapy efficacy in RA remains a question with no clear answers to date. Large, prospective, multicenter studies with the examination of not just individual SNPs, but also multi-SNP haplotypes, are needed to address this question in the future.

Pharmacogenetics: implications for therapy in rheumatic diseases

DMARDs not only improve the joint pain and swelling associated with rheumatoid arthritis (RA), but also slow down the joint damage associated with the disease. The efficacy of biologic therapies, introduced in the past decade for the treatment of RA, has been unequivocally established. Similarly, in addition to traditional drugs such as hydroxychloroquine, new biologic agents such as rituximab have been introduced for systemic lupus erythematosus in recent years. However, considerable variability occurs in the responses of patients to these therapies. Pharmacogenetics, the study of variations in genes encoding drug transporters, drug-metabolizing enzymes and drug targets, and their translation to differential responses to drugs, is a rapidly progressing field in rheumatology. Pharmacogenetic applications, particularly to the old vanguard DMARD, methotrexate, and the newer, more expensive biologic agents, might make personalized therapy in rheumatic diseases possible. The pharmacogenetics of commonly used DMARDs and of biologic therapies are described in this Review.

Single nucleotide polymorphism profiling across the methotrexate pathway in normal subjects and patients with rheumatoid arthritis

Methotrexate (MTX) is a commonly used disease-modifying antirheumatic drug in rheumatoid arthritis (RA). Polymorphisms occur in several genes encoding key enzymes in the folic acid pathway, which is influenced by MTX, but have not been evaluated in patients with RA. The effect of race on allele frequency has also not been evaluated. In this study, the allele frequencies of polymorphisms in six key enzymes in the MTX-folate pathway in patients with RA and healthy controls, including several common racial groups were studied. European- and African-American patients with RA and European and African healthy controls were genotyped for 22 genetic loci in six genes in the MTX cellular pathway. Differences in genotype distributions between the different racial groups were evaluated using chi(2) tests. Allele frequencies were significantly different (p < 0.001) for eight single nucleotide polymorphisms between the European and African controls. The allele frequencies of two polymorphisms showed significant differences (p < 0.001) between the African- and European-American patients with RA. Thus, racial differences exist between the allele frequencies of several polymorphisms in enzymes in the MTX-folate pathway in patients with RA and healthy controls. Whether such differences contribute to a differential response to MTX in patients with RA deserves to be investigated.

Methotrexate pharmacogenetics in rheumatoid arthritis: a status report

Methotrexate (MTX), an antifolate drug, is the first-line disease-modifying agent for the treatment of rheumatoid arthritis (RA) worldwide. MTX has excellent long-term efficacy, tolerability and safety. Early initiation of MTX in patients with RA controls joint destruction and slows progression of disease. However, the clinical response to MTX and frequency of adverse effects from the drug exhibit marked interpatient variability. Over the past decade, there has been a quest to identify genetic markers that reliably predict MTX efficacy and toxicity and help optimize MTX therapy in RA; that is, the field of MTX pharmacogenetics. This review will summarize key pharmacogenetic studies examining SNPs in the genes encoding enzymes in the MTX cellular pathway and their association with MTX response in RA. As evident from this review, MTX pharmacogenetics in RA remains a muddled field, mostly due to inconsistent results from several small underpowered studies.

Vitamin D Deficiency, Interleukin 17, and Vascular Function in Rheumatoid Arthritis

Objective. Vitamin D deficiency is associated with increased cardiovascular (CV) disease risk in the general population. We examined the association between vitamin D deficiency and CV risk in rheumatoid arthritis (RA). Methods. We measured large artery compliance by pulse wave velocity and microvascular function by the reactive hyperemia index in patients with stable RA (n = 87). We quantified CV risk factors, serum 25-hydroxyvitamin D [25(OH)D], and interleukin 17 (IL-17), and RA disease activity by Disease Activity Score of 28 joints. We used linear regression to test associations between serum 25(OH)D and CV risk factors. Results. The mean serum 25(OH)D level in the cohort was 27.1 ± SD 13.6 ng/ml. Fifty-nine patients (68%) were vitamin D-insufficient (25(OH)D < 30 ng/ml; mean 20.2 ± 5.9 ng/ml) and of these, 25 (29%) were vitamin D-deficient (25(OH)D < 20 ng/ml; mean 14.4 ± 3.4 ng/ml). In the whole cohort and the vitamin D-insufficient group, serum 25(OH)D was inversely associated with IL-17 (log IL-17; β = −0.83, p = 0.04; β = −0.63, p = 0.004, respectively) by univariate analysis, which persisted after adjustment for season, and in multivariate analysis after adjustment for confounders (log IL-17; β = −0.74, p = 0.04; β = −0.53, p = 0.02). In vitamin D-deficient patients, serum 25(OH)D was positively associated with microvascular function by univariate and multivariate analysis after adjustment for confounders (β = 2.1, p = 0.04; β = 2.7, p = 0.04). Conclusion. Vitamin D deficiency in RA may affect Th17 responses and microvascular function. Maintaining normal serum vitamin D levels may protect against IL-17-mediated inflammation and vascular dysfunction in RA.

Neoplastic and Paraneoplastic Vasculitis, Vasculopathy, and Hypercoagulability

It is essential to be aware of both neoplastic and paraneoplastic vasculitides, vasculopathy, and hypercoagulability, considering the importance of an accurate diagnosis and timely treatment of the underlying malignancy. Characteristics such as the type of vasculitis, age, gender, atypical presentation, and lack of response to common therapies should prompt investigation for an occult malignancy, whereas vasculitis such as GPA require due malignancy vigilance given a significantly increased risk of malignancy at the time of diagnosis and in the following years. Vasculopathies are rarer than vasculitides, but are associated with specific malignancies and, in the context of such malignancies, should be kept in mind. Hypercoagulability is a well-documented neoplastic phenomenon with an increased risk of thrombosis in the setting of positive aPLs. Most neoplastic and paraneoplastic vascular syndromes require no specific treatment outside of treatment of the underlying malignancy. The two key exceptions are PACNS, because of its poor prognosis, and erythromelalgia, in which aspirin is an effective agent.

Unrecognized fatalities related to colchicine in hospitalized patients.

Background. Colchicine is commonly used for the treatment of gout and occasionally for other inflammatory diseases. It has a narrow therapeutic index and the potential for severe or fatal toxicity. Objectives. We sought to determine (1) the frequency of colchicine toxicity among hospitalized patients taking colchicine who died during an admission, (2) the likelihood that colchicine contributed to death, (3) whether patients were taking interacting medications that could have contributed to toxicity, and (4) whether colchicine dosing among these patients adhered to established guidelines. Methods. We conducted an IRB-approved, retrospective chart review at an urban, tertiary care, 1228-bed, university hospital. Subjects included hospitalized patients who received colchicine and died in hospital between 1 January 2000 and 28 February 2007. We reviewed charts for signs and symptoms of colchicine toxicity. An expert panel reviewed each case and classified the likelihood of colchicine toxicity, the likelihood of a causal role of colchicine in the death using the WHO classification system, and the appropriateness of colchicine dosing. Results. Thirty-seven hospitalized patients who died during the 86-month study period received colchicine. Toxicity was unlikely in 20/37, possible in 8/37, likely in 5/37, and certain in 4/37. A contributing role for colchicine in causing death was unlikely in 24/37, possible in 7/37, likely in 3/37, and certain in 3/37. Colchicine doses (based on creatinine clearance) exceeded the accepted range for 12 patients, including 10 of 17 cases of toxicity and 8 of 13 cases of death classified as possible or higher. Seventeen patients received interacting medications, including 8 of 17 cases of toxicity and 8 of 13 cases of death classified as possible or higher. Conclusion. Colchicine toxicity was frequent in this cohort and may have contributed to about one-third of the deaths. Inappropriate dosing of colchicine occurred frequently and was related to toxicity and death.

Tumor Necrosis Factor Inhibition and Head and Neck Cancer Recurrence and Death in Rheumatoid Arthritis.

The objective of this retrospective cohort study was to determine the effect of tumor necrosis factor inhibitor (TNFi) therapy on the risk of head and neck cancer (HNC) recurrence or HNC-attributable death in patients with rheumatoid arthritis (RA). RA patients with HNC were assembled from the US national Veterans’ Affairs (VA) administrative databases, and diagnoses confirmed and data collected by electronic medical record review. The cohort was divided into those treated with non-biologic disease-modifying anti-rheumatic drugs (nbDMARDs) versus TNF inhibitors (TNFi) after a diagnosis of HNC. Likelihood of a composite endpoint of recurrence or HNC-attributable death was determined by Cox proportional hazards regression. Of 180 patients with RA and HNC, 31 were treated with TNFi and 149 with nbDMARDs after the diagnosis of HNC. Recurrence or HNC-attributable death occurred in 5/31 (16.1%) patients in the TNFi group and 44/149 (29.5%) patients in the nbDMARD group (p = 0.17); it occurred in 2/16 (13%) patients who received TNFi in the year prior to HNC diagnosis but not after. Overall stage at diagnosis (p = 0.03) and stage 4 HNC (HR 2.49 [CI 1.06–5.89]; p = 0.04) were risk factors for recurrence or HNC-attributable death; treatment with radiation or surgery was associated with a lower risk (HR 0.35 [CI 0.17–0.74]; p = 0.01 and HR 0.39 [CI 0.20–0.76]; p = 0.01 respectively). Treatment with TNFi was not a risk factor for recurrence or HNC-attributable death (HR 0.75; CI 0.31–1.85; p = 0.54). We conclude that treatment with TNFi may be safe in patients with RA and HNC, especially as the time interval between HNC treatment and non-recurrence increases. In this study, TNF inhibition was not associated with an increase in recurrence or HNC-attributable death.

Acquired factor VIII inhibitor in Sjögren's syndrome.

Introduction Patients with factor VIII (FVIII) inhibitors, defined by the presence of autoantibodies to the FVIII molecule, present clinically with mucosal, soft tissue, and systemic bleeding episodes. Most cases are idiopathic, but up to 50% may be associated with autoimmune diseases or malignancies or may occur in the postpartum period (1,2). Associated autoimmune diseases include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and, rarely, primary Sjögren’s syndrome (SS) (3,4). We describe here a case of FVIII inhibitor in a patient with primary SS and its successful treatment with rituximab, a chimeric, monoclonal anti-CD20 antibody.