Development and validation of lupus nephritis case definitions using United States veterans affairs electronic health records.

OBJECTIVE: International Classification of Diseases (ICD) codes are commonly used to identify patients with rare diseases in electronic health records (EHRs). However, misclassification is common, impacting the validity of study results. In this study, we compared the accuracies of several ICD-based case definitions of lupus nephritis (LN) in identifying United States veterans with LN. METHODS: Using the Department of Veterans Affairs (VA) EHR, we identified all veterans with ≥1 ICD-9 or 10 diagnostic codes for systemic lupus erythematosus (SLE) between October 1, 1999 and September 30, 2017. A cohort was randomly selected for diagnostic validation and 9 ICD-based LN case definitions were applied to this cohort. The diagnostic accuracy of each definition was assessed against gold standard criterion of biopsy-proven LN. RESULTS: 18,420 veterans had ≥1 ICD-9 or 10 diagnostic codes for SLE; 981 were randomly selected for diagnostic validation. 95 veterans (9.7%) had biopsy-proven LN. The case definitions had high specificity and NPV but variable sensitivity and PPV. The definition containing ≥2 ICD -9 codes for SLE and ≥2 nephritis indicators had the highest combination of sensitivity and specificity (87.4% and 94.6% respectively). ICD-10 code for LN had high specificity (99.8%) and PPV (93.9%). CONCLUSION: ICD-based case definitions of LN in the VA population have high specificity and NPV but variable sensitivity and PPV. Our results may help guide the design of future LN studies in VA cohorts. The choice of specific case definitions depends on the relative importance of different accuracy measures to individual studies.

Staphylococcus aureus sepsis in rheumatoid arthritis.

Patients with rheumatoid arthritis (RA) are at increased risk of infection. In this study, we determined the risk of and risk factors for Staphyococcus aureus (S. aureus) sepsis in RA. We assembled a retrospective nested case-control subset of RA patients with S. aureus sepsis from the Barnes-Jewish Hospital Medical Informatics database, confirmed the diagnoses, and collected data electronically and by chart review. We used multivariate logistic regression to identify independent risk factors for S. aureus sepsis, with risk expressed as odds ratios (ORs). We extracted data on the length of hospitalization and 30-day and 1-year mortality from the Medical Informatics database for all cases and controls. There were 48 confirmed S. aureus sepsis cases and 232 confirmed controls in the RA cohort. In multivariate analysis, indwelling central venous catheter (OR 15.97; 95 % CI 5.09-50.10; p < 0.01) and congestive heart failure (OR 2.89; 95 % CI 1.26-6.63; p = 0.01) were independently associated with risk of S. aureus sepsis, while treatment with disease-modifying anti-rheumatic drugs (DMARDs), both biologic and non-biologic, was not. S. aureus sepsis was associated with increased 30-day and 1-year mortality (OR 7.37; 95 % CI 2.86-19.0; p < 0.01 for 30-day and OR 5.24; 95 % CI 2.51-10.94; p < 0.01 for 1-year mortality) and longer hospitalization (p < 0.01). Treatment with biologic DMARDs was not associated with longer hospitalization (p = 0.89). Indwelling central venous catheters and congestive heart failure increased the risk of S. aureus sepsis in this observational cohort of patients with RA. Treatment with biologic and non-biologic DMARDs did not increase this risk.

Clinical trials in systemic lupus erythematosus: a status report on ongoing trials.

To describe the characteristics of trials in systemic lupus erythematous (SLE) listed in ClinicalTrials.gov such as study design, funding sources and aspects of the disease and drugs under investigation. We conducted a survey of ongoing clinical trials that were registered in the ClinicalTrials.gov website. We used the advanced search option and applied the following inclusion criteria, "SLE," "open studies," "interventional," and "adults 18 years or older." Of 97 eligible studies, 34.0 % were phase 3 or 4, 49.5 % were phase 1, 2 or 2/3 and in 16.5 %, we could not determine the study phase. Most trials were randomized (69.0 %) and 48.4 % were double blinded; 34 % of the trials were placebo controlled, 19.6 % had an active agent comparator and 46.4 % had no comparator. Universities and pharmaceutical industries were the primary sponsors for 45.3 and 39.1 % of the trials, respectively, and government agencies for 10.3 %. Multi-center trials based in the USA (US) accounted for 40.2 % of the trials, 46.4 % were outside of the US and 13.4 % were in the US as well as other countries. The most frequently used endpoint was drug efficacy (30.9 %) followed by disease severity indices (25.7 %), drug safety (14.4 %), remission rates and times to remission (7.2 %), and inflammatory markers and antibody titers (7.2 %). The majority of ongoing clinical trials in SLE are university or industry-funded, randomized phase 1, 2, or 2/3 trials, focused on drug efficacy. Federal funding for trials in SLE within and outside the US remains low.

Meigs' syndrome: a rare cause of recurrent pleural effusion in scleroderma.

Meigs' syndrome represents a triad of pleural effusion, ascites, and an ovarian tumor, usually benign, occurring together. We describe here a case of Meigs' syndrome in a patient with systemic sclerosis, the first such report to our knowledge, in systemic sclerosis. A 53-year-old woman with systemic sclerosis presented with recurrent right-sided pleural effusion, which led to symptoms of shortness of breath, chest tightness, and a non-productive cough. Physical examination revealed a palpable, mobile mass in the right lower quadrant, in addition to typical physical features of scleroderma. Thoracentesis yielded exudative pleural fluid with cytology negative for malignancy. Pleural biopsy was consistent with inflammatory changes, but negative for malignancy. CT scan of the chest, abdomen, and pelvis revealed a soft tissue mass in the pelvis, which appeared to arise from the left ovary. The patient's cancer antigen 125 (CA-125) level was elevated at 222 U/mL (normal range, 0-30 U/mL). The patient underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Histology of the left ovarian mass was consistent with an ovarian fibrothecoma, a benign tumor of the ovary. At her 1-month follow-up appointment, the patient had complete resolution of the right-sided pleural effusion. To date, at 10 months past the initial presentation, she has not had recurrence of pleural effusion. Although rare, Meigs' syndrome should be considered as a possible cause of recurrent serositis in women with rheumatologic diseases. Removal of the ovarian tumor leads to prompt resolution of the serositis.

Clinical trials in rheumatoid arthritis: a status report from the ClinicalTrials.gov website.

The aims of this study are to describe the characteristics of clinical trials in rheumatoid arthritis (RA) listed in ClinicalTrials.gov and examine existing trends in study design, funding sources, outcomes, and drugs under investigation. We conducted a survey of ongoing clinical trials in RA registered in the ClinicalTrials.gov website. We used the advanced search option and applied the following inclusion criteria, "rheumatoid arthritis", "open studies", "interventional", and "adults 18 years or older". Of 127 eligible trials, 53.5% of the studies were either phase 3 or 4, and 40.2% were phase 1, 2, and 2/3. Two-thirds of the trials were randomized (70.9%), and over half were, in addition, double-blinded (53.5%) and placebo-controlled (53.5%). Universities were listed as the primary sponsor for 18.9% of the trials and pharmaceutical industry for 73.2%. Majority of the trials were multi-center studies (93%) conducted outside the United States (54.3%). The most frequently used endpoint was drug efficacy (54.3%) followed by drug safety (25.2%). Most industry-funded trials were open for less than 12 months, whereas most university-funded trials were open for more than 24 months (58% each). Biologic therapies were the focus of most trials in the registry (78.5%). Randomized, double-blinded, placebo-controlled, phase 3 and 4 trials form the majority of ongoing clinical trials in RA. The preponderance of industry funding of RA trials and the short duration of such trials are troubling trends which need to be addressed.

Pharmacogenetics of Drug Therapies in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder that can lead to severe joint damage and is often associated with a high morbidity and disability. Disease-modifying anti-rheumatic drugs (DMARDs) are the mainstay of treatment in RA. DMARDs not only relieve the clinical signs and symptoms of RA but also inhibit the radiographic progression of disease and reduce the effects of chronic systemic inflammation. Since the introduction of biologic DMARDs in the late 1990s, the therapeutic range of options for the management of RA has significantly expanded. However, patients' response to these agents is not uniform with considerable variability in both efficacy and toxicity. There are no reliable means of predicting an individual patient's response to a given DMARD prior to initiation of therapy. In this chapter, the current published literature on the pharmacogenetics of traditional DMARDS and the newer biologic DMARDs in RA is highlighted. Pharmacogenetics may help individualize drug therapy in patients with RA by providing reliable biomarkers to predict medication toxicity and efficacy.

Risk of non-melanoma skin cancer in a national cohort of veterans with rheumatoid arthritis.

OBJECTIVE: To determine the incidence of and risk factors for non-melanoma skin cancer (NMSC) in a national cohort of veterans with RA. METHODS: We examined skin cancer risk in a cohort of 20 648 patients with RA derived from the Department of Veterans' Affairs (VA) national administrative databases. The cohort was divided into two medication groups: patients treated with non-biologic and TNF-α antagonist DMARDs. We defined skin cancer as the first occurrence of an International Classification of Disease, Version 9, Clinical Modification (ICD-9-CM) code for NMSC after initiation of a DMARD. Outcome risk was described using hazard ratios (HRs) with Cox proportional hazards regression for time-to-event analysis and logistic regression. We performed medical record review to validate the diagnosis of NMSC. RESULTS: Incidence of NMSC was 18.9 and 12.7 per 1000 patient-years in patients on TNF-α antagonists and non-biologic DMARDs, respectively. Patients on TNF-α antagonists had a higher risk of developing NMSC (HR 1.42; 95% CI 1.24, 1.63). Risk factors for NMSC included older age, male gender, NSAID and glucocorticoid use and a history of prior malignancies. There was substantial agreement between ICD-9-CM diagnosis of NMSC and medical record validation (κ = 0.61). CONCLUSION: TNF-α antagonist therapy in veterans with RA may be associated with an increased risk of NMSC, compared with therapy with non-biologic DMARDs. Rheumatologists should carefully screen patients receiving TNF-α antagonists for pre-cancerous skin lesions and skin cancer.

Immunologic rheumatic disorders.

We provide the basics for clinicians who might be called on to consider the diagnosis of diseases such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) in their practice. We will emphasize clinical recognition and first-line laboratory testing. Only characteristics of the classic rheumatic inflammatory diseases (ie, RA, seronegative spondyloarthropathy, SLE, antiphospholipid syndrome, Sjögren syndrome, scleroderma, and polymyositis/dermatomyositis) will be covered. In the past decade, treatment for RA and seronegative spondyloarthropathy has substantially improved. Their treatment has been revolutionized by the use of methotrexate and, more recently, TNF inhibitors, T-cell costimulation modulators, and B-cell depletion. The goal of RA treatment today is to induce a complete remission as early as possible in the disease process, with the mantra being "elimination of synovitis equals elimination of joint destruction." The hope is that if the major mediators of Sjögren syndrome, SLE, or scleroderma can be identified and then blocked, as in the example of TNF inhibitors in patients with RA, more specific treatments will become available. Thus RA has become an excellent model of this evolving paradigm. Through the identification of major mediators in its pathogenesis, novel and highly efficacious therapeutic agents have been developed.

Methotrexate pharmacogenetics in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic inflammatory arthritis that can not only result in permanent joint damage, but is associated with high morbidity and mortality. Disease-modifying antirheumatic drugs (DMARDs) are the mainstay of treatment in RA. DMARDs improve the symptoms of joint pain and swelling, but more importantly, prevent the progression of joint damage. Methotrexate (MTX) is the first-line DMARD in RA with over two decades worth of excellent long-term efficacy and safety. However, there is significant variability in patients' response to MTX, both in efficacy and toxicity. Recent advances in genetics, particularly pharmacogenetics, may permit the prediction, a priori, of an individual patient's response to MTX. In this review, we highlight recent published literature on the pharmacogenetics of MTX in RA. Pharmacogenetics may be a useful means of optimising MTX therapy in patients with RA.

A Potential Role for Stress-Induced Microbial Alterations in IgA-Associated Irritable Bowel Syndrome with Diarrhea.

Stress is a known trigger for flares of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS); however, this process is not well understood. Here, we find that restraint stress in mice leads to signs of diarrhea, fecal dysbiosis, and a barrier defect via the opening of goblet-cell associated passages. Notably, stress increases host immunity to gut bacteria as assessed by immunoglobulin A (IgA)-bound gut bacteria. Stress-induced microbial changes are necessary and sufficient to elicit these effects. Moreover, similar to mice, many diarrhea-predominant IBS (IBS-D) patients from two cohorts display increased antibacterial immunity as assessed by IgA-bound fecal bacteria. This antibacterial IgA response in IBS-D correlates with somatic symptom severity and was distinct from healthy controls or IBD patients. These findings suggest that stress may play an important role in patients with IgA-associated IBS-D by disrupting the intestinal microbial community that alters gastrointestinal function and host immunity to commensal bacteria.

Herpes zoster risk factors in a national cohort of veterans with rheumatoid arthritis.

BACKGROUND: Herpes zoster occurs more commonly in patients taking immunosuppressive medications, although the risk associated with different medications is poorly understood. METHODS: We conducted a retrospective cohort study involving 20,357 patients who were followed in the Veterans Affairs healthcare system and treated for rheumatoid arthritis from October 1998 through June 2005. Cox proportional hazards regression was used to determine risk factors for herpes zoster and herpes zoster-free survival. Chart review was performed to validate the diagnosis of herpes zoster. RESULTS: The incidence of herpes zoster was 9.96 episodes per 1000 patient-years. In time-to-event analysis, patients receiving medications used to treat mild rheumatoid arthritis were less likely to have an episode of herpes zoster than patients receiving medications used to treat moderate and severe rheumatoid arthritis (P < .001). Independent risk factors for herpes zoster included older age, prednisone use, medications used to treat moderate and severe rheumatoid arthritis, malignancy, chronic lung disease, renal failure, and liver disease. Among patients receiving tumor necrosis factor-alpha antagonists, etanercept (hazard ratio, 0.62) and adalimumab (hazard ratio, 0.53) were associated with a lower risk of herpes zoster. There was excellent agreement between the International Classification of Diseases, Version 9, Clinical Modification diagnosis of herpes zoster and diagnosis by chart review (kappa = 0.92). CONCLUSIONS: Risk factors for herpes zoster included older age, prednisone use, medications used to treat moderate and severe rheumatoid arthritis, and several comorbid medical conditions. These results demonstrate that the Department of Veterans Affairs' national administrative databases can be used to study rare adverse drug events.

Successful use of rituximab for hydralazine-induced anti-neutrophil cytoplasmic antibodies-associated vasculitis.

Hydralazine is a commonly used anti-hypertensive medication. It can, however, contribute to the development of autoimmunity, in the form of drug-induced lupus and anti-neutrophil cytoplasmic antibodies-associated vasculitis. We report a 45-year-old patient with hypertension managed with hydralazine for four years who presented with rapidly progressive glomerulonephritis (RPGN), requiring hemodialysis, and diffuse alveolar hemorrhage (DAH), requiring mechanical ventilation, and extracorporeal membrane oxygenation. The patient's autoantibody profile was consistent with a drug-induced autoimmune process and renal histology revealed focal necrotizing crescentic GN. She was treated with high-dose steroids, plasma exchange and rituximab. DAH resolved and her renal function improved, allowing discontinuation of hemodialysis. This case reveals that rituximab can be successfully used in the setting of hydralazine-induced vasculitis, including critically ill patients with severe DAH and acute kidney injury from RPGN.

An update on pharmacogenomics in rheumatoid arthritis with a focus on TNF-blocking agents.

TNFalpha is a proinflammatory cytokine, which is crucial in the pathogenesis of rheumatoid arthritis (RA). In recent years, biological therapies which block the damaging effects of TNFalpha on synovium and cartilage have been developed. TNF antagonists, such as etanercept, infliximab and adalimumab, although highly effective in RA, are expensive, totaling several thousand US dollars in yearly costs. In addition, only approximately 60% of patients respond to these agents. This has led to the need to prospectively identify patients most likely to respond to these agents, which can be achieved by pharmacogenomics approaches. Polymorphisms in genes encoding for TNFalpha, the MHC region, and the Fcgamma receptor IIIA, as well as their ability to predict disease progression in RA and response to anti-TNF therapies, have been the focus of a number of studies, which are discussed in this review. There is no consensus at present as to whether pharmacogenomics will allow prediction of anti-TNF therapy efficacy in RA. Large, prospective, multicenter studies are needed to replicate and validate the results of the studies outlined in this review.

Pharmacogenomics in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic inflammatory arthritis that leads to severe joint damage and is associated with high morbidity and mortality. Disease-modifying antirheumatic drugs (DMARDs) are the mainstay of treatment in RA. DMARDs not only relieve the clinical signs and symptoms of RA but also inhibit the radiographic progression of disease. Recently, a new class of disease-modifying medications, the biologic agents, has been added to the existing spectrum of DMARDs in RA. However, patients' response to these agents is not uniform, with considerable variability in both efficacy and toxicity. There are no reliable means of predicting an individual patient's response to a given DMARD prior to initiation of therapy. In this chapter, the current published literature on the pharmacogenomics of traditional DMARDs and the newer biologic DMARDs in RA is highlighted. Pharmacogenomics may help individualize drug therapy in patients with RA in the near future.

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.

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.