New guidelines and therapeutic updates for the management of lupus nephritis.

PURPOSE OF REVIEW: Systemic lupus erythematosus (SLE) can be a devastating condition, striking young patients often in their prime reproductive years. Lupus nephritis is a common and serious complication occurring in roughly 50% of SLE cases, indicating a high likelihood of disease progression, morbidity, and mortality. As the early trials of steroid therapy, and later cyclophosphamide (CYC), therapeutic changes had been stagnant. Then came the introduction of mycophenolate mofetil (MMF) in the 2000s. After the Aspreva Lupus Management Study, there had been a dearth of trials showing positive therapy results. Since 2020, new studies have emerged for lupus nephritis involving the use of anti-BLYS agents, novel calcineurin inhibitors, CD20 blockade, and antiinterferon agents. Nephrology and rheumatology society guidelines in the United States and across the world are still catching up. RECENT FINDINGS: Although therapeutic guidelines are being developed, updates that have come through have focused on improved diagnostic and monitoring guidelines. One theme is the recommendation of increasingly tight proteinuria control and firmer guidelines for the rapid induction of remission. The reality of multitarget therapy and the expectation of rapid induction for a more complete remission are being widely recognized. SUMMARY: The need for more complete and more rapid induction and control of lupus nephritis is undisputed according to the evidence and guidelines, and the medications to achieve this are growing at a rate not seen over the prior two decades. What remains is a stepwise approach to recognize how to best optimize therapy. Based on available evidence, an algorithm for induction and maintenance treatment of lupus nephritis used by the University of California Irvine Lupus Nephritis clinic, is recommended.

Thrombotic microangiopathy - the importance of a multidisciplinary approach.

PURPOSE OF REVIEW: The purpose of this review is to highlight the importance of a multidisciplinary thrombotic microangiopathies (TMA) Team. This goal will be accomplished through review of the complement system, discuss various causes of thrombotic microangiopathies (TMA), and aspects of their diagnosis and management. In so doing, readers will gain an appreciation for the complexity of this family of disorders and realize the benefit of a dedicated multidisciplinary TMA Team. RECENT FINDINGS: TMA causes derive from multiple specialty areas, are difficult to timely recognize, pose complex challenges, and require multidisciplinary management. Hematopoietic stem cell transplant-associated TMA (TA-TMA) and TA-TMA related multiorgan dysfunction syndrome (TA-TMA MODS) are areas of burgeoning research; use of complement testing and eculizumab precision-dosing has been found to better suppress complement activity in TA-TMA than standard eculizumab dosing. Newer tests are available to risk-stratify obstetric patients at risk for severe pre-eclampsia, whose features resemble those of TA-TMA MODS. Numerous disorders may produce TMA-like findings, and a systematic approach aids in their identification. TMA Teams elevate institutional awareness of increasingly recognized TMAs, will help expedite diagnostic and therapeutic interventions, and create pathways to future TMA-related research and facilitate access to clinical trials. SUMMARY: Establishment of a TMA-Team is valuable in developing the necessary institutional expertise needed to promptly recognize and appropriately manage patients with TMA.

The 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria.

OBJECTIVE: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. METHODS: This international multidisciplinary initiative included 4 phases: 1) Phase I, criteria generation by surveys and literature review; 2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; 3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and 4) Phase IV, validation using independent adjudicators' consensus as the gold standard. RESULTS: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into 6 clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and 2 laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-ß2 -glycoprotein I antibodies). Patients accumulating at least 3 points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria versus the 2006 revised Sapporo classification criteria had a specificity of 99% versus 86%, and a sensitivity of 84% versus 99%. CONCLUSION: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.

2023 ACR/EULAR antiphospholipid syndrome classification criteria.

OBJECTIVE: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. METHODS: This international multidisciplinary initiative included four phases: (1) Phase I, criteria generation by surveys and literature review; (2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; (3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and (4) Phase IV, validation using independent adjudicators' consensus as the gold standard. RESULTS: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into six clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and two laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-ß2-glycoprotein I antibodies). Patients accumulating at least three points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria vs the 2006 revised Sapporo classification criteria had a specificity of 99% vs 86%, and a sensitivity of 84% vs 99%. CONCLUSION: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.

Improvement in disease activity among patients with rheumatoid arthritis who switched from intravenous infliximab to intravenous golimumab in the ACR RISE registry.

Infliximab and golimumab are intravenously (IV) administered tumor necrosis factor inhibitors approved to treat moderate-to-severe rheumatoid arthritis (RA) with concomitant methotrexate. Owing to differences in biologic construct, patients with IV-infliximab treatment failure may benefit from switching to IV-golimumab. Utilizing the ACR's Rheumatology Informatics System for Effectiveness (RISE), a large electronic health records registry based in the USA, we assessed RA disease activity in patients switching from IV-infliximab to IV-golimumab. This retrospective, longitudinal, single-arm study included adults (≥ 18 years) with ≥ 1 RA diagnosis code between 2014 and 2018 and ≥ 1 IV-infliximab prescription within 6 months of a new IV-golimumab order (index date). Longitudinal assessments of disease activity using the Clinical Disease Activity Index (CDAI) were calculated in patients continuing IV-golimumab for 6-9- and 9-12-months post-switch. Paired t-tests evaluated significance of mean improvements during the follow-up periods. Most RA patients with disease activity assessments during the 6-month follow-up (N = 100; mean age: 65.3 years; 81% female; 74% white) demonstrated moderate-to-high disease activity (CDAI: 73% [38/52]) at enrollment. On average, patients showed significant improvement in disease activity within 6-9 months of switching; mean CDAI scores improved from 21.3 to 14.1 (p < 0.0001) and were durable through 9-12 months of treatment. Real-world patients with moderate-to-high disease activity who switched from IV-infliximab to IV-golimumab demonstrated significant and sustained improvements post-switch as measured by the CDAI. Key Points • This study used real-world data from the Rheumatology Informatics System for Effectiveness (RISE) registry to evaluate the efficacy of directly switching from intravenous (IV)-infliximab to IV-golimumab to control rheumatoid arthritis (RA) disease activity. • Most IV-infliximab patients had moderate-to-high disease activity at the time of the switch. • On average, IV-golimumab was effective in improving RA disease activity after switching from IV-infliximab as measured by the Clinical Disease Activity Index. • These data suggest that real-world RA patients with persistent symptoms despite treatment with IV-infliximab may realize improved disease control with a switch to IV-golimumab.

Representation of Skin of Color in Rheumatology Educational Resources.

OBJECTIVE: To investigate the availability of images representing Black, Indigenous, and people of color in rheumatology educational resources. METHODS: Color images were collected from 5 major educational resources and cataloged by the resources they came from, underlying rheumatic conditions, and skin type. Fitzpatrick skin type (FST) was used to categorize images into "light," "dark," or "indeterminate." The images were initially scored by a fellow in the Division of Rheumatology and subsequently validated by a faculty member from the Department of Dermatology. RESULTS: Of the thousands of images reviewed, 1604 images met study criteria. FST validation from the Department of Dermatology resulted in the recoding of 111 images. The final scoring revealed 86% of the images to be light skin, 9% of images to be dark skin, and 5% of images to be indeterminate. CONCLUSION: The paucity of dark skin images in rheumatology resources is incongruent with current diversity estimates in the US. Significant efforts should be made to incorporate images of Black, Indigenous, and people of color into educational resources.

Complement-Mediated Thrombotic Microangiopathy Associated with Lupus Nephritis Treated with Eculizumab: A Case Report.

Thrombotic microangiopathies (TMAs) involve multiple organ systems due to the presence of microangiopathic hemolysis. One such condition, atypical hemolytic uremic syndrome (aHUS), is a complement-mediated process that is part of a spectrum of disorders that have underlying complement dysfunction of the alternative pathway due to overactivity or decreased self-nonself discrimination by innate immunity. Complement-amplifying conditions such as pregnancy may unmask a diagnosis of aHUS. We present an important case of a pregnant 23-year-old Hispanic female who presented in mid-gestation (21 weeks) with an initial diagnosis of systemic lupus erythematosus (SLE) complicated by aHUS. She met clinical criteria for aHUS on presentation and was found to have a pathogenic CFHR1-3 homozygous deletion. She has been treated with intravenous and oral steroids, cyclophosphamide, subsequently also with plasma exchange, and finally with eculizumab with partial improvement in renal function. This case adds to the emerging literature showing that SLE and aHUS (or complement-mediated TMA) can be successfully treated with C5 blockade.

Atypical Hemolytic Uremic Syndrome Secondary to Lupus Nephritis, Responsive to Eculizumab.

Among the spectrum of disease manifestations associated with systemic lupus erythematosus, lupus nephritis is particularly concerning due to the potential for renal failure. This autoimmune attack may not, however, be limited to the kidney and is increasingly being recognized as a trigger for atypical Hemolytic Uremic Syndrome (aHUS). Atypical HUS falls under the spectrum of the thrombotic microangiopathies (TMAs) - a group of disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end organ damage. Although plasma exchange is considered first-line therapy for thrombotic thrombocytopenic purpura - a TMA classically associated with autoimmune depletion of ADAMTS-13 - aHUS demonstrates less reliable responsiveness to this modality. Instead, use of the late complement inhibitor Eculizumab has emerged as an effective modality for the management of such patients. Diagnosis of aHUS, however, is largely clinically based, relying heavily upon a multidisciplinary approach. Herein we present the case of a patient with atypical HUS successfully treated with Eculizumab in the setting of Class IV-G (A) lupus nephritis and hypocomplementemia.

Efficacy of Intravenous Immunoglobulin Monotherapy in Patients with Cutaneous Lupus Erythematosus: Results of Proof-of-Concept Study.

Cutaneous lupus erythematosus (CLE) is a chronic inflammatory autoimmune skin disease. Evidence-based therapy for CLE is lacking in the most part. Intravenous immunoglobulin (IVIg) is being increasingly utilized as off-label therapy for a variety of autoimmune and inflammatory conditions, especially in dermatology. The usefulness of IVIg in CLE is not well established. The goal of the present study was to obtain the proof-of-concept evidence that IVIg can control acute CLE and thus replace current systemic immunosuppressive therapy that causes severe side effects and adverse reactions. Sixteen patients who tried and failed various systemic treatments for CLE were screened and consented to use IVIg as a monotherapy. The IVIg was administered at 500 mg/kg/day on 4 consecutive days up to a total of 2 g/kg/month for 3 months, and the subjects were monitored for additional 6 months off any drug for a possible relapse. The cumulative results revealed an overall improvement, as evinced by a decrease of both objective and subjective measures of disease activity. The most sensitive and specific objective and subjective instruments for assessment of the therapeutic effect of IVIg were CLASI-A (Cutaneous Lupus Erythematosus Disease Area and Severity Index) measuring disease activity and Skindex-29 scores, respectively. The CLASI-A score dropped down from the initial value taken as 100%, and remained in the range of approximately 70% until the last visit. Three patients (18.8%) had a temporary flare of CLE symptoms but recovered within a month from the relapse. No serious side effects and adverse reactions occurred. Thus, IVIg monotherapy in CLE allowed to achieve: i) rapid and persistent decreased in disease activity; ii) steady improvement of patients' quality of life assessed by Skindex-29; iii) low relapse rate; and iv) mild nature and short duration of relapses. Since healing was maintained for months after IVIg treatment, it is possible that the IVIgtriggered molecular events mediating the therapeutic action of IVIg that continued to unfold after the end of therapy.

Papulonodular mucinosis in a patient with systemic lupus erythematosus and antiphospholipid syndrome.

The skin is one of the target organs most commonly affected in lupus erythematosus (LE) and a wide range of cutaneous changes have been described in LE patients. Papulonodular mucinosis (PNM) in particular is an uncommon cutaneous manifestation of LE. We discuss the case of a 26-year-old Senegalese woman with systemic LE and antiphospholipid syndrome (APS) who presented with pruritic papules on her back and extremities that appeared when she was on vacation in Africa and non-compliant with medications. Histopathologic examination was consistent with PNM. The patient was treated with mycophenolate mofetil and hydroxychloroquine, with subjective relief in pruritis at 6-week follow-up. To our knowledge, this is the first case of PNM presenting in a patient with both SLE and APS. Whether APS contributes to the pathogenesis of PNM is currently unknown.

Granulomatous dermatitis related to silicone implant.

Silicone in liquid and gel implantation may induce granuloma formation and migration. Although there are many complications associated with solid silicone implantation, there have been no published reports of distant granuloma formation. We present a case of a woman with clinical and serologic findings that are consistent with systemic lupus erythematosus and a histopathologic diagnosis of foreign body granulomatous dermatitis 20 years after solid silicone nasal implantation. We review the literature on silicone granulomas and their treatment and speculate on the potential etiologies of a challenging case presentation.

Front-line therapy for chronic lymphocytic leukemia.

BACKGROUND: Historically, alkylator-based therapy has been used to treat patients with chronic lymphocytic leukemia (CLL). More effective therapies, such as the use of monoclonal antibodies in combination with chemotherapy, have been shown to prolong both progression-free survival and overall survival. Improvements in the identification of prognostic markers for CLL, as well as novel combinations for chemoimmunotherapy regimens, have improved the outcome for patients with CLL. METHODS: We examine the diagnosis of CLL, the role of prognostic factors in determining treatment goals, and current data on front-line management of CLL. RESULTS: The benefits of single-agent and combination therapies are associated with prolonged progression-free and overall survival. While more aggressive management may therefore be warranted, each patient's comorbidities and performance status must be weighed against the benefits, availability, cost, treatment goals, and incidence of adverse effects associated with each therapy. CONCLUSIONS: New single agents and novel treatment combinations have shown promising results in phase I/II studies. The ultimate therapeutic goals of prolonged survival and improved quality of life will be validated only by ongoing clinical and laboratory research and by continuous enrollment of patients in clinical trials.

Auditory-visual speech perception in normal-hearing and cochlear-implant listeners.

The present study evaluated auditory-visual speech perception in cochlear-implant users as well as normal-hearing and simulated-implant controls to delineate relative contributions of sensory experience and cues. Auditory-only, visual-only, or auditory-visual speech perception was examined in the context of categorical perception, in which an animated face mouthing ba, da, or ga was paired with synthesized phonemes from an 11-token auditory continuum. A three-alternative, forced-choice method was used to yield percent identification scores. Normal-hearing listeners showed sharp phoneme boundaries and strong reliance on the auditory cue, whereas actual and simulated implant listeners showed much weaker categorical perception but stronger dependence on the visual cue. The implant users were able to integrate both congruent and incongruent acoustic and optical cues to derive relatively weak but significant auditory-visual integration. This auditory-visual integration was correlated with the duration of the implant experience but not the duration of deafness. Compared with the actual implant performance, acoustic simulations of the cochlear implant could predict the auditory-only performance but not the auditory-visual integration. These results suggest that both altered sensory experience and improvised acoustic cues contribute to the auditory-visual speech perception in cochlear-implant users.

Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis.

BACKGROUND: Although several agents are available to treat osteoporosis, the relative efficacy and toxicity of these agents when used to prevent fractures has not been well described. PURPOSE: To compare the benefits in fracture reduction and the harms from adverse events of various therapies for osteoporosis. DATA SOURCES: MEDLINE (1966 to November 2007) and other selected databases were searched for English-language studies. STUDY SELECTION: For the efficacy analysis, investigators selected studies that reported the rate of or risk for fractures. For the adverse event analysis, they selected studies that reported the relationship between an agent and cardiovascular, thromboembolic, or upper gastrointestinal events; malignant conditions; and osteonecrosis. DATA EXTRACTION: Using a standardized protocol, investigators abstracted data on fractures and adverse events, agents and comparators, study design, and variables of methodological quality. DATA SYNTHESIS: Good evidence suggests that alendronate, etidronate, ibandronate, risedronate, zoledronic acid, estrogen, parathyroid hormone (1-34), and raloxifene prevent vertebral fractures more than placebo; the evidence for calcitonin was fair. Good evidence suggests that alendronate, risedronate, and estrogen prevent hip fractures more than placebo; the evidence for zoledronic acid was fair. The effects of vitamin D varied with dose, analogue, and study population for both vertebral and hip fractures. Raloxifene, estrogen, and estrogen-progestin increased the risk for thromboembolic events, and etidronate increased the risk for esophageal ulcerations and gastrointestinal perforations, ulcerations, and bleeding. LIMITATION: Few studies have directly compared different agents or classes of agents used to treat osteoporosis. CONCLUSION: Although good evidence suggests that many agents are effective in preventing osteoporotic fractures, the data are insufficient to determine the relative efficacy or safety of these agents.

TNFalpha blockade in human diseases: mechanisms and future directions.

Tumor necrosis factor-alpha (TNFalpha) antagonists have shown remarkable efficacy in a variety of immune-mediated inflammatory diseases (IMIDs). Therapeutic scope and limitations of these agents are reviewed in a recently published article in the Journal. In spite of their therapeutic popularity, little is known about their modes of action in vivo and factors that limit their scope of therapeutic use. Intriguingly, while all TNFalpha antagonists including blocking antibodies and soluble receptors are effective in certain IMIDs, only anti-TNFalpha antibodies are effective in other IMIDs. Early efforts at understanding how TNFalpha antagonists act in IMIDs centered on their ability to neutralize soluble TNFalpha or to block TNF receptors from binding to their ligands. Subsequent studies suggested a role of complement-mediated lysis or antibody-dependent cell cytotoxicity in their therapeutic effects. More recent models postulate that TNFalpha blockers may act by affecting intracellular signaling, with the end result being a hastened cell cycle arrest, apoptosis, suppression of cytokine production, or improved Treg cell function. TNFalpha antagonists can also modulate the functions of myofibroblasts and osteoclasts, which might explain how TNFalpha antagonists reduce tissue damage in chronic IMIDs. Focusing on the human therapeutic experience, this analytical review will review the biology of mechanisms of action, the limiting factors contributing to disease restriction in therapeutic efficacy, and the mechanism and frequency of treatment-limiting adverse responses of TNFalpha antagonists. It is hoped that the overview will address the needs of clinicians to decide on optimal use, spur clinical innovation, and incite translational researchers to set priorities for in vivo human investigations.

TNFalpha blockade in human diseases: an overview of efficacy and safety.

Tumor necrosis factor-alpha (TNFalpha) antagonists including antibodies and soluble receptors have shown remarkable efficacy in various immune-mediated inflammatory diseases (IMID). As experience with these agents has matured, there is an emerging need to integrate and critically assess the utility of these agents across disease states and clinical sub-specialties. Their remarkable efficacy in reducing chronic damage in Crohn's disease and rheumatoid arthritis has led many investigators to propose a new, 'top down' paradigm for treating patients initially with aggressive regimens to quickly control disease. Intriguingly, in diseases such as rheumatoid arthritis and asthma, anti-TNFalpha agents appear to more profoundly benefit patients with more chronic stages of disease but have a relatively weaker or little effect in early disease. While the spectrum of therapeutic efficacy of TNFalpha antagonists widens to include diseases such as recalcitrant uveitis and vasculitis, these agents have failed or even exacerbated diseases such as heart failure and multiple sclerosis. Increasing use of these agents has also led to recognition of new toxicities as well as to understanding of their excellent long-term tolerability. Disconcertingly, new cases of active tuberculosis still occur in patients treated with all TNFalpha antagonists due to lack of compliance with recommendations to prevent reactivation of latent tuberculosis infection. These safety issues as well as guidelines to prevent treatment-associated complications are reviewed in detail in this article. New data on mechanisms of action and development of newer TNFalpha antagonists are discussed in a subsequent article in the Journal. It is hoped that these two review articles will stimulate a fresh assessment of the priorities for research and clinical innovation to improve and extend therapeutic use and safety of TNFalpha antagonism.

The influence of larval diet on adult feeding behaviour in the tobacco hornworm moth, Manduca sexta.

Lab-reared sphingid and noctuid moths appear to feed less than wild moths, and often are starved to enhance responsiveness in feeding assays. To measure the impact of larval nutrition on adult feeding, we raised a model sphingid species, Manduca sexta, on control or modified diets (reduced sugar, protein or water, supplemented beta-carotene) or cut tobacco leaves, then conducted feeding assays with artificial flowers. Behaviour was scored and analysed in a double-blind manner. Larval diet affected adult eclosion time, size and fat content, the latter of which was inversely proportional to moth approaches to the floral array in a flight cage. In contrast, behaviours refractory to feeding (sitting, escaping) were associated with sex and barometric pressure, but not with diet or fat content. Frequency of floral approaches and probing was not associated with any variable. However, moths reared on beta-carotene-supplemented diet were 2-3 times more likely to feed, and significantly less likely to sit or show "escape" behaviour than were moths from most other treatments. Our results suggest that decreased visual sensitivity, rather than increased fat content, accounts for reduced adult feeding by lab-reared M. sexta.

Problems encountered during anti-tumour necrosis factor therapy.

Worldwide, over 400,000 patients have been treated with tumour necrosis factor (TNF)-alpha antagonists for indications that include rheumatoid arthritis, juvenile rheumatoid arthritis, inflammatory bowel disease, psoriatic arthritis and ankylosing spondylitis. Since their approval, concerns regarding safety have been raised. There is a risk of re-activation of granulomatous diseases, especially tuberculosis, and measures should be taken for detection and treatment of latent tuberculosis infections. Preliminary data suggest that anti-TNF therapy may be safe in chronic hepatitis C. However, TNF-alpha antagonists have resulted in re-activation of chronic hepatitis B if not given concurrently with antiviral therapy. Solid tumours do not appear to be increased with anti-TNF therapy. Variable rates of increased lymphoma risk have been described with anti-TNF therapy compared with the general population, although no increased risk was found compared with a rheumatoid arthritis population. Large phase II and III trials with TNF-alpha antagonists in advanced heart failure have shown trends towards a worse prognosis, and should therefore be avoided in this population. Both etanercept and infliximab are associated with the formation of autoantibodies, and these autoantibodies are rarely associated with any specific clinical syndrome. Rare cases of aplastic anaemia, pancytopenia, vasculitis and demyelination have been described with anti-TNF therapy. This chapter will discuss the safety profile and adverse events of the three commercially available TNF-alpha antagonists: etanercept, infliximab and adalimumab. The data presented in this review have been collected from published data, individual case reports or series, package inserts, the Food and Drug Administration postmarketing adverse events surveillance system, and abstracts from the American College of Rheumatology and European Congress of Rheumatology meetings for 2005.