In this update, we summarize 9 articles published in

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1 Update Update in Rheumatology: Evidence Published in 2011 Lindsy J. Forbess, MD, and Anne R. Bass, MD In this update, we summarize 9 articles published in 2011, many of which are likely to change clinical practice. These include a study describing a treat-to-target strategy aimed at inducing disease remission in early rheumatoid arthritis (RA) and an article outlining new international definitions of RA remission. We include a phase 2B trial on the use of a Janus kinase (JAK) inhibitor for RA because these agents show great promise and their efficacy expands our understanding of RA pathogenesis. Studies that led to the recent U.S. Food and Drug Administration approval of belimumab for systemic lupus erythematosus and pegloticase for chronic refractory gout are also included, as well as a small study of stem cell transplant for treatment of scleroderma that demonstrated surprisingly robust results. Finally, articles on the use of allopurinol in patients with gout who have renal insufficiency, the risk for cancer with tumor necrosis factor (TNF) inhibitors, and influenza vaccination in patients with rheumatic disease were chosen because of their relevance to practicing internists. Systemic Lupus Erythematosus Belimumab Provides Modest Benefit to Patients With Mild to Moderate Systemic Lupus Erythematosus Navarra SV, Guzmán RM, Gallacher AE, et al; BLISS-52 Study Group. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377: [PMID: ] Furie R, Petri M, Zamani O, et al; BLISS-76 Study Group. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63: [PMID: ] Background: B-lymphocyte stimulator, a cytokine that promotes B-cell development and survival, is overexpressed in patients with systemic lupus erythematosus. Elevated levels of B-lymphocyte stimulator are associated with increased disease activity. Belimumab is a monoclonal antibody that binds to soluble B-lymphocyte stimulator and inhibits its function. A phase 2 study showed that belimumab was well-tolerated but no more effective than placebo (1). A post hoc analysis of the study showed that a subset of patients who were autoantibody-positive had improved with the drug and that they maintained their improvements during 5-year open-label follow-up. On the basis of this experience, 2 phase 3 international multicenter trials (BLISS-52 [Belimumab in Subjects With Systemic Lupus Erythematosus-52 weeks of duration] and BLISS- 76) that included only patients who were unequivocally seropositive were conducted to evaluate the efficacy of belimumab. Efficacy was measured by using the newly developed Systemic Lupus Erythematosus Responder Index (SRI) (2). Findings: In BLISS-52, 867 patients with active disease were randomly assigned to receive monthly intravenous belimumab, 1 mg/kg; belimumab, 10 mg/kg; or placebo in a 1:1:1 ratio. Prednisone use was unrestricted in the first 24 weeks of the trial, but a return close to the baseline dose was required by 24 weeks with no further increases for the remainder of the study. Forty-two percent of patients were receiving immunosuppressive drugs and 67% were on hydroxychloroquine, and change in these medications was restricted after 24 weeks. The primary end point was the SRI response rate at week 52. BLISS-76 investigators enrolled 826 patients and used a similar study design. The primary end point in BLISS-76 was measured at week 52, but treatment continued to week 76, when secondary end points were assessed. In both studies, more patients in the belimumab groups had an SRI response at week 52 than in the placebo group, with greater efficacy with the 10-mg/kg dose of belimumab (BLISS-52: 58% with belimumab, 10 mg/kg, vs. 42% with placebo; BLISS-76: 43% vs. 34%, respectively). The difference in SRI response at week 76 in BLISS-76 was not statistically significant (39% with belimumab, 10 mg/kg, vs. 32% with placebo; P 0.13). The percentage of patients experiencing severe flares was decreased at week 52 in BLISS-52 (14% with belimumab, 10 mg/kg, vs. 23% with placebo), but the reduction in severe flares by week 76 in BLISS-76 was not statistically significant (21% with belimumab, 10 mg/kg, vs. 27% with placebo; P 0.13). Immunoglobulin levels decreased in patients treated with belimumab. Severe adverse events occurred in 12% (BLISS-52) to 19% (BLISS-76) of patients overall and did not vary across treatment groups. Cautions: On the basis of the SRI, a patient who has serologic improvement but is otherwise clinically unchanged from baseline is considered to be responsive. The use of this soft end point, along with the failure of the earlier phase 2 trial, suggests that the benefits of belimumab are modest at best. Because patients with severe lupus nephritis or central nervous system lupus were ex- Ann Intern Med. 2012;157: For author affiliations, see end of text. This article was published at on 19 April Annals of Internal Medicine American College of Physicians

2 Update in Rheumatology Update cluded, the results cannot be extrapolated to patients with more severe disease. Implications: Belimumab has only modest efficacy in patients with mild to moderate disease but is welltolerated. Given its high cost, the drug should be reserved for patients who cannot tolerate more traditional therapies or for when more traditional therapies have been unsuccessful. Rheumatoid Arthritis A New Definition of Remission Caps More Than a Decade of Progress in RA Pharmacotherapy Felson DT, Smolen JS, Wells G, et al; American College of Rheumatology. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum. 2011;63: [PMID: ] Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis. 2011;70: [PMID: ] Background: With advances in therapy for RA, remission has become a realistic end point for clinical trials and is the main goal in clinical practice. The American College of Rheumatology and European League Against Rheumatism, along with the Outcome Measures in Rheumatology Initiative, sponsored a collaborative project to develop a definition of RA remission for use in clinical trials. Findings: A task force composed of physician and patient experts in RA were surveyed to determine cut points in candidate disease activity indices that would constitute remission. Candidate indices included the Disease Activity Score 28 (DAS28), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index. Cut points were also established for core set measures, including tender and swollen joint counts, physician and patient global assessments, erythrocyte sedimentation rate, and C-reactive protein (CRP) levels. All remission definitions were tested for face and predictive validity by examining raw clinical trial data to determine whether patients in remission by these definitions were more likely to have good radiographic and functional outcomes. Except for the DAS28, the candidate index remission definitions did equally well. The SDAI had the highest task force vote count. The task force produced the 2 following definitions of remission 1 based on their analysis of core set measures and 1 based on the SDAI: 1) score for each core set measure of 1 or less (includes tender and swollen joint counts [both using 28 joints], CRP levels [in mg/dl], and patient global assessment [0 to 10 scale]); and 2) score on the SDAI of 3.3 or less (numerical sum of the tender and swollen joint counts [using 28 joints], patient and physician global assessment [0 to 10 scale], and CRP levels [in mg/dl]). Cautions: The goal was to define remission, not to develop a predictive marker of good radiographic outcomes. The definitions need to be validated prospectively. Implications: Remission is now a realistic end point in RA clinical trials, and the use of these new definitions promises consistent reporting across studies. These definitions help distinguish remission from low disease activity, which is important because remission is associated with a lower risk for radiographic and functional progression. A Treat-to-Target Strategy Is Feasible and May Improve Outcomes for Very Early RA Vermeer M, Kuper HH, Hoekstra M, et al. Implementation of a treat-to-target strategy in very early rheumatoid arthritis: results of the Dutch Rheumatoid Arthritis Monitoring remission induction cohort study. Arthritis Rheum. 2011;63: [PMID: ] Background: The key to inducing remission in RA is early diagnosis and prompt, intensive treatment. A treat-totarget strategy involves close monitoring of disease activity and adjustment of medication to achieve a prespecified treatment goal. The goal of this study was to evaluate the feasibility of that strategy in clinical practice. The tested strategy involved evaluation at weeks 0, 8, 12, 20, 24, 36, and 52 and every 3 months thereafter and adjustment of medications to achieve remission, which was defined as a DAS28 score less than 2.6. Findings: This prospective cohort study involved 534 treatment-naive patients with active RA and symptoms for 1 year or less (median symptom duration of 14 weeks). The mean ( SE) baseline DAS28 score was Three hundred eighty-nine patients completed at least 1 year of follow-up. Treatment was initiated with methotrexate, 15 mg weekly, and stepped up to achieve a DAS28 score less than 2.6 as follows: the dose of methotrexate was increased; sulfasalazine was added; sulfasalazine was replaced by the TNF inhibitor adalimumab (week 24); adalimumab frequency was increased; adalimumab was changed to etanercept; etanercept was changed to infliximab; and infliximab frequency was increased. If patients were in remission for at least 6 months, treatment was gradually stepped down. A DAS28 remission was achieved in 47% of patients at 6 months and in 58% of patients at 12 months. Median time to first remission was 25.3 weeks. Of those who achieved remission, 59% were on methotrexate alone and only 5.7% were on anti-tnf therapy. Of 186 patients who had radiography, 48% had erosive disease at baseline. Radiographic progression at 12 months was seen in 27%. Cautions: There was no comparator group. Only 73% of patients had 12 months of follow-up, and missing data were censored, potentially biasing results in favor of the treat-to-target strategy. Patients with very early RA sometimes improve spontaneously, which may explain the high 17 July 2012 Annals of Internal Medicine Volume 157 Number 2 115

3 Update Update in Rheumatology rates of response seen with methotrexate alone. Only 11% of patients received TNF inhibitors during the first year, a much lower rate than would be expected in the United States. Although a DAS28 score less than 2.6 represents low disease activity, it may not represent true remission. Implications: A treat-to-target strategy for RA is feasible in clinical practice and leads to a DAS28 remission in more than one half of patients. Although most patients achieved this outcome with methotrexate alone, radiographic progression was seen in 27%, suggesting that delayed initiation of a TNF inhibitor may not be optimal. Inhibition of JAK Is a Promising New Therapeutic Strategy for RA Fleischmann R, Cutolo M, Genovese MC, et al. Phase 2B doseranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to DMARDs. Arthritis Rheum [PMID: ] Background: Janus kinases play important roles in intracellular signaling pathways, including those triggered by interleukins-2, -4, -6, -7, -9, -15, and -21; interferon- ; and pathways involved in hematopoiesis. This 24-week, double-blind phase 2B study was designed to assess the safety and efficacy of tofacitinib, an oral JAK inhibitor, compared with adalimumab, a TNF inhibitor, and placebo in patients with RA who had an inadequate response to traditional disease-modifying antirheumatic drugs (DMARDs). Patients had to have active disease and had a washout of all DMARDs (except antimalarials, such as hydroxychloroquine) before entering the study. Findings: Three hundred eighty-four patients with active disease were randomly assigned to placebo; tofacitinib, 1 mg, 3 mg, 5 mg, 10 mg, or 15 mg orally twice daily; or adalimumab, 40 mg subcutaneously every 2 weeks for 12 weeks, followed by tofacitinib, 5 mg twice daily for 12 weeks. Patients randomly assigned to tofacitinib, 1 or 3 mg twice daily or placebo who did not improve by week 12 were blindly reassigned to tofacitinib, 5 mg twice daily. The primary end point was the American College of Rheumatology 20 response rate at week 12. The American College of Rheumatology 20 requires at least a 20% improvement in tender and swollen joint counts, plus a 20% improvement in 3 of the following: patient and physician global assessments, pain, disability, erythrocyte sedimentation rate, or CRP levels. The percentages of patients achieving an American College of Rheumatology 20 at week 12 was 32%, 39%, 59%, 71%, and 72%, respectively, for 1 mg, 3 mg, 5 mg, 10 mg, and 15 mg of tofacitinib orally twice daily, compared with 36% with adalimumab and 22% with placebo (tofacitinib, 1 mg, vs. placebo, P 0.26; 3 mg, vs. placebo, P 0.05; 5 mg, vs. placebo, P 0.001; 10 mg, vs. placebo, P 0.001; 15 mg, vs. placebo, P 0.001; and adalimumab vs. placebo, P 0.105). Responses to tofacitinib were seen as early as 2 weeks and persisted at 24 weeks. Tofacitinib was associated with dose-related neutropenia and dose-related increases in total, low-density lipoprotein, and high-density lipoprotein cholesterol. Six patients treated with tofacitinib (2%) had an increase in serum creatinine levels greater than 50%. Cautions: Response rates may have been magnified by the washout of DMARDs. Patients who did not respond to placebo or low-dose tofacitinib therapy at 12 weeks were reassigned to tofacitinib, 5 mg twice daily, biasing outcomes at 24 weeks in favor of tofacitinib treatment. Finally, 6.5% of patients had not responded to 1 or more TNF inhibitors in the past, biasing results against responses to adalimumab. Implications: This short-term study suggests that tofacitinib monotherapy is an effective treatment for patients with RA for whom traditional DMARDs were unsuccessful. Dose-related hyperlipidemia and neutropenia may limit its use. Another phase 2B study of tofacitinib done in patients who were on background methotrexate therapy produced similar results (3). Whether tofacitinib prevents structural damage is unknown. Gout Allopurinol Dosage Can Be Increased in Patients With Renal Insufficiency to Achieve a Serum Urate Level Less Than 6 mg/dl Stamp LK, O Donnell JL, Zhang M, et al. Using allopurinol above the dose based on creatinine clearance is effective and safe in patients with chronic gout, including those with renal impairment. Arthritis Rheum. 2011;63: [PMID: ] Background: Allopurinol is the most commonly used urate-lowering therapy. It is generally well-tolerated but can be associated with a rare and potentially lifethreatening hypersensitivity syndrome. Risk factors for allopurinol hypersensitivity syndrome include renal insufficiency, concomitant diuretic therapy, and recent initiation of allopurinol treatment. In 1984, Hande and colleagues (4) published guidelines for allopurinol dosing based on creatinine clearance, despite the absence of direct evidence that renal dosing lowers the risk for allopurinol hypersensitivity. Rigid adherence to renal dosing guidelines often results in doses of allopurinol that are too low to reduce serum urate to the target of less than 6 mg/dl. This study was designed to determine the safety of increasing the allopurinol dose above that recommended by the Hande renal-dosing guidelines. Findings: Patients with gout who were receiving a stable dose of allopurinol for at least 1 month were recruited. Patients receiving the recommended or higher-thanrecommended dose whose serum urate concentration was 6 mg/dl or greater (45 of 83 patients) had their allopurinol July 2012 Annals of Internal Medicine Volume 157 Number 2

4 Update in Rheumatology Update dose increased by 50 to 100 mg/mo until the serum urate level was less than 6 mg/dl. Patients were seen monthly until their serum urate level was less than 6 mg/dl for 3 consecutive months, and then every 3 months until the 12-month end point. Thirty-five of 45 patients completed the study. Three patients developed a rash and had to discontinue allopurinol or maintain the recommended dose. Thirty-one of 35 patients achieved the target serum urate concentration of less than 6 mg/dl. Two of the 4 patients who did not achieve the target urate level had no detectable drug in their serum. The final allopurinol dose was 100 mg higher than the recommended dose in 42% of patients (range of 50 to 400 mg higher). Cautions: Allopurinol hypersensitivity syndrome is rare. The study was underpowered and could not disprove that increasing allopurinol above the recommend dose increases risk for this syndrome. Because there was no control group, it is difficult to say whether the rate of milder drug reactions, such as rash, was higher than it would have been without dose increases. Implications: With close patient monitoring and gradual dose adjustment (50 to 100 mg per month), most patients with renal insufficiency can tolerate allopurinol doses that are higher than recommended based on creatinine clearance. Most of these patients can achieve a target urate level of less than 6 mg/dl. Pegloticase Lowers Uric Acid Levels in a Subset of Patients With Chronic Refractory Gout Sundy JS, Baraf HS, Yood RA, et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA. 2011;306: [PMID: ] Background: Xanthine oxidase inhibitors, such as allopurinol, are effective at lowering the serum urate level in most cases of chronic gout, but therapy fails in approximately 3% of patients because of refractory disease, drug contraindication, or intolerance. Pegloticase, a pegylated recombinant mammalian uricase, rapidly degrades urate when given intravenously. Findings: Two identical randomized, double-blind, placebo-controlled trials were done in 225 patients with refractory gout. Refractory gout was defined as uric acid level of 8 mg/dl or greater and at least 1 of the following: 3 flares in the past 18 months, tophi, or joint damage. Patients had to have a contraindication to allopurinol or failure to normalize uric acid with 3 months of allopurinol. Patients with glucose-6-phosphate dehydrogenase deficiency, uncontrolled hypertension, cardiac arrhythmia, or congestive heart failure or who were on dialysis were excluded. Participants were given pegloticase, 8 mg biweekly, pegloticase, 8 mg monthly, or placebo for 6 months in a ratio of 2:2:1. Hydrocortisone, 200 mg, was given with each infusion. All patients received colchicine, 0.6 mg daily or twice daily, or a nonsteroidal anti-inflammatory drug to prevent gout flares during the trial. The primary end point was the proportion of patients achieving a plasma urate level of less than 6 mg/dl for 80% of time during both months 3 and 6 ( urate responders ). Outcomes of the 2 trials were similar, and results of the pooled analysis were presented. The proportion of urate responders was greater in both pegloticase groups than in the placebo group (42% biweekly pegloticase, 35% monthly pegloticase, and 0% placebo; P for both treatment groups vs. placebo). More gout flares occurred in patients treated with pegloticase in months 1 to 3, but not in months 4 to 6. More patients treated with biweekly pegloticase had complete resolution of at least 1 tophus (40% biweekly pegloticase, 21% monthly pegloticase, and 7% placebo; P and P 0.20 for biweekly and monthly pegloticase vs. placebo, respectively). Infusion reactions were common, especially with monthly dosing of pegloticase (42% of patients). A lack of response to pegloticase was associated with antipegloticase antibody titers greater than 1:2430 (seen in 2% of patients who responded vs. 63% of patients who did not respond). There were 3 treatment-associated deaths in patients treated with pegloticase (2 due to cardiovascular disease) and no deaths in patients treated with placebo. Cautions: Pegloticase lost its effectiveness in 60% of patients over the 6-month period, possibly due to the development of antipegloticase antibodies. Implications: Pegloticase is an effective urate-lowering therapy for 40% of patients with chronic refractory gout. Given its cost and potential for serious toxicity, pegloticase should be reserved for patients who cannot receive alternative urate-lowering therapies. Repeated infusions should be avoided in patients whose preinfusion uric acid level is 6 mg/dl or greater. It should be used only with great caution in patients with known cardiovascular disease. Systemic Sclerosis Nonmyeloablative Hemopoietic Stem Cell Transplantation Provides Short-Term Efficacy in Carefully Selected Patients With Systemic Sclerosis Burt RK, Shah SJ, Dill K, et al. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an openlabel, randomised phase 2 trial. Lancet. 2011;378: [PMID: ] Background: Previous nonrandomized trials of hemopoietic stem cell transplantation (HSCT) in systemic sclerosis (SSc) have demonstrated improvements in skin score and stabilization of lung disease, but treatment-related mortality has occurred in as many as 17% of patients. With modifications in patient selection and transplant regimens, treatment-related mortality has been reduced to 9%. This 17 July 2012 Annals of Internal Medicine Volume 157 Number 2 117

5 Update Update in Rheumatology open-label phase 2 trial compared nonmyeloablative HSCT with monthly cyclophosphamide in patients with SSc. Findings: Nineteen patients with diffuse SSc (mean disease duration of 15.6 months) were randomly assigned to either HSCT (with methylprednisolone 1 g preceding each dose of rabbit antithymocyte globulin and no total-body irradiation) or 6 monthly doses of cyclophosphamide 1 g/m 2 (control participants). Inclusion criteria included age younger than 60, modified Rodnan skin score (MRSS) of 14 or greater, internal organ involvement (pulmonary, gastrointestinal, or cardiac), or an MRSS less than 14 with pulmonary involvement. Patients were excluded who had predicted total lung capacity less than 45%, left ventricular ejection fraction less than 40%, symptomatic cardiac disease, creatinine levels greater than 177 mol/l ( 2 mg/ dl), systolic pulmonary artery pressure greater than 40 mm Hg, or more than 4 years of disease. The primary outcome was improvement at 1 year, as defined by a 25% or greater decrease in MRSS or a 10% increase in FVC. All 10 patients who were randomly assigned to HSCT improved, but none of the 9 control participants improved. Planned enrollment was 60 patients, but the study was stopped early because of the imbalance in outcomes. Seven of 8 patients in the control group who progressed at 1 year crossed over to the HSCT group, and all 7 then improved. In 11 patients followed for 2 years after HSCT, improvements in MRSS, predicted FVC, and lung involvement measured on chest computed tomography were seen, but total lung capacity and DLCO did not change from baseline. No deaths occurred after a mean follow-up of 2.6 years. Cautions: This was a short-term study of patients with early disease. Individuals with cardiac disease, pulmonary hypertension, or advanced lung disease were excluded. Implications: In carefully selected patients with SSc, nonmyeloablative HSCT can be an effective short-term therapy with acceptable treatment-related morbidity when done in an experienced medical center with conditioning regimens similar to those used in this study. Previous studies suggest that disease can recur in 1 third of patients treated with HSCT after long-term follow-up. Rheumatic Diseases The Risk for Cancer With TNF Inhibitors Mariette X, Matucci-Cerinic M, Pavelka K, et al. Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and metaanalysis. Ann Rheum Dis. 2011;70: [PMID: ] Background: Meta-analyses of randomized trials have reported conflicting results about whether TNF inhibitor use is associated with an increased risk for cancer. Patients enrolled in randomized trials may differ from those in the general population, however, and the follow-up in these trials is usually short. The goal of this study was to do a systematic review of prospective observational studies done in registries of patients with inflammatory arthritis to assess whether TNF inhibitors affect the risk for cancer. Findings: Twenty-nine studies that included more than patients were reviewed. Most patients had RA. Cancer information in the studies was gleaned from structured questionnaires or medical records, or through record linkage to cancer registries. The overall incidence of cancer was 7.40 (95% CI, 5.81 to 8.99) per 1000 patient-years. Based on results from 7 registries, there was no overall increase in the risk for cancer associated with TNF inhibitor use (risk estimate, 0.95 [CI, 0.85 to 1.05]). Longer duration of exposure to TNF inhibitors did not increase the risk for cancer (data from 2 studies) and TNF inhibitors did not increase the risk for cancer in patients with previous cancer (risk estimate, 0.62 [CI, 0.04 to 1.20]) (data from 2 studies). In the 5 registries reporting lymphoma rates, there was no increased risk for lymphoma associated with TNF inhibitor use (risk estimate, 1.11 [CI, 0.70 to 1.51]). In the 4 registries reporting skin cancer rates, TNF inhibitors were associated with an increased risk for nonmelanoma skin cancer (risk estimate, 1.45 [CI, 1.15 to 1.76]). Two studies suggested an increased risk for melanoma, but these results were not statistically significant (risk estimate, 1.79 [CI, 0.92 to 2.67]). Cautions: Pooled estimates for risk were done by using a small subset of the studies. Although there were nearly patient-years of exposure, the analyzed studies had limited duration of follow-up and probably missed cancers with long latency periods. Studies were observational: Selection and surveillance bias and confounding by indication could have affected the results. Implications: Tumor necrosis factor inhibitors increase the risk for nonmelanoma skin cancer but may not increase the risk for other types of cancer, including lymphoma, in patients with inflammatory arthritis. Until there are more definitive data, physicians should remain vigilant for cancer in patients receiving these agents. Influenza Vaccination Responses Are Lower in Patients With Rheumatic Disease Treated With Nonbiological Disease-Modifying Agents Gabay C, Bel M, Combescure C, et al; H1N1 Study Group. Impact of synthetic and biologic disease-modifying antirheumatic drugs on antibody responses to the AS03-adjuvanted pandemic influenza vaccine: a prospective, open-label, parallel-cohort, single-center study. Arthritis Rheum. 2011;63: [PMID: ] Background: Influenza vaccination is important for immunocompromised patients who are at high risk for respiratory complications of influenza infection. There is conflicting evidence about whether immunosuppressive therapy reduces influenza vaccine responses in patients with auto July 2012 Annals of Internal Medicine Volume 157 Number 2

6 Update in Rheumatology Update immune diseases (except evidence about rituximab, which is known to reduce such responses). The outbreak of a novel influenza A (H1N1) virus in the spring of 2009 provided a unique opportunity to assess the effect of vaccines in patients with autoimmune disease, because only a minority had previous exposure to the virus and none were previously vaccinated. This Swiss study compared responses to the H1N1 vaccine in healthy persons with responses in patients with autoimmune disease treated with various DMARDs. Findings: The study enrolled 173 patients with RA, spondyloarthropathy, antineutrophil cytoplasmic antibodyassociated vasculitis, and other connective tissue diseases and 138 control participants. One hundred fifty-four of the patients with autoimmune disease received 2 doses of the H1N1 vaccine 3 to 4 weeks apart, according to Swiss guidelines, whereas all control participants received 1 H1N1 vaccine dose. Vaccine responses were assessed by using the geometric mean titer, proportion of participants with seroprotection (postvaccination titer 1:40), and proportion with a seroresponse (postvaccination titer 1:40 and a 4-fold increase in geometric mean titer). After 1 H1N1 dose, vaccine responses were lower in patients with autoimmune disease than in control participants (geometric mean titer 146 vs. 340, seroprotection rate 75% vs. 97%, and seroresponse rate 70% vs. 82%; P for all). Patients with autoimmune disease achieved vaccine responses similar to those in control participants after receiving a second H1N1 vaccine dose. Advanced age, the use of nonbiological DMARDs (methotrexate, leflunomide, azathioprine, mycophenolate mofetil, and cyclophosphamide), and recent use within 3 months of rituximab were associated with lower immune responses to the H1N1 vaccine. Neither treatment with prednisone, TNF inhibitors, hydroxychloroquine, or sulfasalazine nor type of autoimmune disease affected vaccine responses. No postvaccine disease flares were seen. Cautions: This study measured antibody responses to the H1N1 vaccine, not protection from infection. The study was not powered to assess the effect of 2 vaccine doses on the rate of rare complications, such as the Guillain Barré syndrome. Implications: Vaccine responses are lower in patients treated with most nonbiological DMARDs, but not with hydroxychloroquine, sulfasalazine, or TNF inhibitors. Two H1N1 vaccination doses may be needed to bring antibody responses to the level seen in healthy control participants. Trials assessing protection from influenza infection are needed before double-dose vaccination can be routinely recommended. From Hospital for Special Surgery, New York, New York. Potential Conflicts of Interest: Disclosures can be viewed at M Requests for Single Reprints: Anne R. Bass, MD, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021; , bassa@hss.edu. Current author addresses and author contributions are available at References 1. Wallace DJ, Stohl W, Furie RA, Lisse JR, McKay JD, Merrill JT, et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum. 2009;61: [PMID: ] 2. Furie RA, Petri MA, Wallace DJ, Ginzler EM, Merrill JT, Stohl W, et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum. 2009;61: [PMID: ] 3. Kremer JM, Cohen S, Wilkinson BE, Connell CA, French JL, Gomez-Reino J, et al. A phase 2B dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate alone. Arthritis Rheum [PMID: ] 4. Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med. 1984;76: [PMID: ] 17 July 2012 Annals of Internal Medicine Volume 157 Number 2 119

7 Annals of Internal Medicine Current Author Addresses: Drs. Forbess and Bass: Hospital for Special Surgery, 535 East 70th Street, New York, NY Author Contributions: Conception and design: L.J. Forbess, A.R. Bass. Analysis and interpretation of the data: L.J. Forbess, A.R. Bass. Drafting of the article: L.J. Forbess, A.R. Bass. Critical revision of the article for important intellectual content: L.J. Forbess, A.R. Bass. Final approval of the article: L.J. Forbess, A.R. Bass. Provision of study materials or patients: L.J. Forbess, A.R. Bass. Administrative, technical, or logistic support: L.J. Forbess, A.R. Bass. Collection and assembly of data: L.J. Forbess, A.R. Bass. W July 2012 Annals of Internal Medicine Volume 157 Number 2