Adherence to the 2012 American College of Rheumatology (ACR) Guidelines for Management of Gout: A Survey of Brazilian Rheumatologists.

OBJECTIVE: To describe the current pharmacological approach to gout treatment reported by rheumatologists in Brazil. METHODS: We performed a cross-sectional survey study using an online questionnaire e-mailed to 395 rheumatologists, randomly selected, from among the members of the Brazilian Society of Rheumatology. RESULTS: Three hundred and nine rheumatologists (78.2%) responded to the survey. For acute gout attacks, combination therapy (NSAIDs or steroid + colchicine) was often used, even in monoarticular involvement, and colchicine was commonly started as monotherapy after 36 hours or more from onset of attack. During an acute attack, urate-lowering therapy (ULT) was withdrawn by approximately a third of rheumatologists. Anti-inflammatory prophylaxis (98% colchicine) was initiated when ULT was started in most cases (92.4%), but its duration was varied. Most (70%) respondents considered the target serum uric acid level to be less than 6 mg/dl. Approximately 50% of rheumatologists reported starting allopurinol at doses of 100 mg daily or less and 42% reported the initial dose to be 300 mg daily in patients with normal renal function. ULT was maintained indefinitely in 76% of gout patients with tophi whereas in gout patients without tophi its use was kept indefinitely in 39.6%. CONCLUSION: This is the first study evaluating gout treatment in a representative, random sample of Brazilian rheumatologists describing common treatment practices among these specialists. We identified several gaps in reported gout management, mainly concerning the use of colchicine and ULT and the duration of anti-inflammatory prophylaxis and ULT. Since rheumatologists are considered as opinion leaders in this disease, a program for improving quality of care for gout patients should focus on increasing their knowledge in this common disease.

Study for Updated Gout Classification Criteria: Identification of Features to Classify Gout.

OBJECTIVE: To determine which clinical, laboratory, and imaging features most accurately distinguished gout from non-gout. METHODS: We performed a cross-sectional study of consecutive rheumatology clinic patients with ≥1 swollen joint or subcutaneous tophus. Gout was defined by synovial fluid or tophus aspirate microscopy by certified examiners in all patients. The sample was randomly divided into a model development (two-thirds) and test sample (one-third). Univariate and multivariate association between clinical features and monosodium urate-defined gout was determined using logistic regression modeling. Shrinkage of regression weights was performed to prevent overfitting of the final model. Latent class analysis was conducted to identify patterns of joint involvement. RESULTS: In total, 983 patients were included. Gout was present in 509 (52%). In the development sample (n = 653), the following features were selected for the final model: joint erythema (multivariate odds ratio [OR] 2.13), difficulty walking (multivariate OR 7.34), time to maximal pain <24 hours (multivariate OR 1.32), resolution by 2 weeks (multivariate OR 3.58), tophus (multivariate OR 7.29), first metatarsophalangeal (MTP1) joint ever involved (multivariate OR 2.30), location of currently tender joints in other foot/ankle (multivariate OR 2.28) or MTP1 joint (multivariate OR 2.82), serum urate level >6 mg/dl (0.36 mmoles/liter; multivariate OR 3.35), ultrasound double contour sign (multivariate OR 7.23), and radiograph erosion or cyst (multivariate OR 2.49). The final model performed adequately in the test set, with no evidence of misfit, high discrimination, and predictive ability. MTP1 joint involvement was the most common joint pattern (39.4%) in gout cases. CONCLUSION: Ten key discriminating features have been identified for further evaluation for new gout classification criteria. Ultrasound findings and degree of uricemia add discriminating value, and will significantly contribute to more accurate classification criteria.

An Internet-based technique for the identification of persons with symptoms of inflammatory polyarthritis of less than 12 weeks.

Identifying persons with early rheumatoid arthritis (RA) is a major challenge. The role of the Internet in making decisions about seeking care has not been studied. We developed a method for early diagnosis and referral using the Arthritis Foundation's website. A person with less than 3 months of joint pain symptom who has not yet sought medical attention was screened. Prescreened persons are linked to a self-scoring questionnaire and get a "likelihood" of RA statement. If "likely," the person is offered a free evaluation and biomarker testing performed by Quest Diagnostics. The system available only to Massachusetts's residents yielded a small steady flow of screen-positive individuals. Over 21 months, 43,244 persons took the Arthritis Foundation website prescreening questionnaire; 196 were from Massachusetts and 60 took the self-scoring algorithm. Of the 48 who screened positive, 29 set up an appointment for a free evaluation, but six never came in. Twenty-four subjects were evaluated and diagnosed independently by three rheumatologists. One met the 1987 American College of Rheumatology (ACR) criteria for RA and two met the 2010 ACR/EULAR RA criteria. The 24 examined individuals were contacted at a minimum of 1 year and asked to redo the case-finding questionnaire and asked about their health resource utilization during the interval. Seventeen of the 24 subjects responded, and 10 had seen a health professional. Three of the 17 had a diagnosis of RA; all were on at least methotrexate. Internet case finding was useful in identifying new potential RA cases. The system's performance characteristics are theoretically limited only by the number of study sites available. However, the major barrier may be that seeing a health professional is not a priority for many individuals with early symptoms.

Amyloid arthropathy associated with multiple myeloma: polyarthritis without synovial infiltration of CD20+ or CD38+ cells.

OBJECTIVES: To describe histological, immunohistochemical and ultrastructural features of synovial biopsies of amyloid arthropathy associated with multiple myeloma (MM). METHODS: Synovial biopsies from affected joints of two patients with MM and amyloid arthropathy were examined with light and electron microscopy, and immunohistochemically for expression of CD3, CD8, CD20, CD38, CD68, Ki-67 and vWF. Results were compared to values from osteoarthritis (OA, n = 26), rheumatoid arthritis (RA, n = 24) and normal (n = 15) synovial membranes. RESULTS: There was no or only mild lining hyperplasia. Vascular density was not elevated, and there were few Ki-67+ proliferating cells in the stroma. The Krenn synovitis score classified one specimen as "low-grade" and one as "high-grade" synovitis. CD68+ and CD3+ cells were the predominant mononuclear inflammatory cells, whereas CD20+ and CD38+ cells were absent from both synovial membrane and synovial fluid sediment. Electron microscopy demonstrated amyloid phagocytosis by synovial macrophages. In hierarchical clustering the two amyloid arthropathy specimens were more closely related to OA than to RA or normal synovium. CONCLUSIONS: This first detailed immunohistological analysis of MM-associated amyloid arthropathy suggests that it is a chronic synovitis that evolves despite the loss of humoral immunity seen in advanced MM. Instead, amyloid phagocytosis by synovial macrophages likely triggers and perpetuates local disease.

Amyloid arthropathy associated with multiple myeloma: a systematic analysis of 101 reported cases.

OBJECTIVE: Amyloid deposition in multiple myeloma (MM) may lead to an arthropathy resembling rheumatoid arthritis (RA). Since a systematic description of its natural history is lacking, we have performed a systematic analysis of all published cases. METHODS: Literature review featuring backward and forward database searches and direct inspection of reference lists. Inclusion criteria were as follows: publication between 1931 and 2012, diagnosis of multiple myeloma, and demonstration of light chain amyloid (AL) in any organ or in synovial fluid, arthritis, or synovitis. RESULTS: Overall, 101 cases were identified. Median age was 59 years and the male-to-female ratio was 1:1. A systemic manifestation of MM was reported in 88 cases. In 53 of these, characteristic physical findings (carpal tunnel syndrome, macroglossia, shoulder pad, and soft tissue swelling/masses) were present. Arthritis manifested before the diagnosis of MM in 63 cases, with 33 cases initially misdiagnosed as RA. There were 72 cases of poly-, 17 of oligo-, and three of monoarthritis. The shoulder joint was most commonly affected, followed by knees and small hand joints. Median synovial fluid leukocyte count was 2460 cells/mm(3), and was normal in seven cases. Synovial histopathology often featured mild synovitis without plasma cell infiltration. Imaging revealed articular or periarticular inflammation in many cases and bone lesions near 22% of affected joints. Treatments varied but led to some improvement in the majority of cases. CONCLUSIONS: These results solidify previous experience that MM arthropathy tends to feature a symmetric RF-negative nonerosive polyarthritis. However, the results also highlight the diversity of its presentations and stress the importance of arthropathy as a potentially under-recognized presenting manifestation of MM.

The relative composition of the inflammatory infiltrate as an additional tool for synovial tissue classification.

OBJECTIVES: Traditionally, differences in absolute numbers of cells expressing a certain marker (e.g., positive staining cells per mm²) have been used in immunohistological synovial tissue classification. We have begun to evaluate the relative composition of the inflammatory infiltrates, i.e. percentages of inflammatory cell types in inflammatory infiltrates, as an alternate classification tool that may potentially improve tissue diagnostics, subgrouping in clinical trials, and understanding of pathogenesis of inflammatory and noninflammatory arthropathies. METHODS: Synovial tissue specimens (normal synovium, n=15; orthopedic arthropathies, n=6; osteoarthritis, n=26; early undifferentiated arthritis, n=10; rheumatoid arthritis, n=26; chronic septic arthritis, n=11) were stained for CD15, CD68, CD3, CD20, and CD38. Densities of cells expressing a given marker were determined in the superficial subintima. Binary and multicategory receiver operating characteristic (ROC) analysis and naïve Bayes classifier were used to compare the abilities of (1) the absolute densities of cells expressing a given marker (absolute method) with (2) the percentages of these cells in the inflammatory cell population (relative method) to differentiate among the six tissue classes. RESULTS: The inflammatory infiltrates in normal synovium and the orthopedic arthropathies consisted almost exclusively of CD68+ and CD3+ cells. Notable fractions of CD20+ and CD38+ cells appeared in a subset of osteoarthritis samples, and increased further in early, rheumatoid and chronic septic arthritis. ROC analyses and naïve Bayes classifier ranked the absolute method above the relative method in terms of overall discriminatory ability. The relative method became slightly superior when the samples were also stratified according to the total number of inflammatory cells/mm². CONCLUSIONS: This exploratory investigation featuring a variety of joint disorders revealed that measuring the relative proportions of inflammatory cell types may aid in synovial tissue classification if the samples are also stratified according to the intensity of inflammation.

Questionnaire survey evaluating disease-related knowledge for 149 primary gout patients and 184 doctors in South China.

This study aims to investigate the disease-related knowledge of gout patients and doctors in south China and to identify the important targets of education for patients and doctors. A cross-section survey of 154 primary gout patients and 185 doctors who may see gout patients was conducted with a modified questionnaire with ten items of gout-related knowledge. The participants were considered to have gout-related knowledge if he or she correctly answered seven or more items. One hundred and forty-nine valid questionnaires from patients, 33 from rheumatology physicians, and 151 from non-rheumatology doctors were collected for statistical analysis. The mean correctly answered items of three groups were 6.6 ± 2.2, 9.6 ± 0.53, and 8.0 ± 1.4, with rate of being considered to have knowledge about gout 51.7, 100, and 90.1 %, respectively (P < 0.05). The correct answer rate for each particular item was over 80 % in the rheumatology physician group. Patients or non-rheumatology doctors knew the optimal serum uric acid (sUA) level (48.3 vs 55.6 %), the need to take lifelong urate-lowering drugs (29.5 vs 43.6 %), that allopurinol is a urate-lowering drug (55.7 vs 76.0 %), and how to prevent attacks induced by urate-lowering therapy (ULT) (60.4 vs 74.0 %). Logistic regression showed that higher education predicted which patients had gout-related knowledge. Both the gout patients and non-rheumatology doctors in south China had poor knowledge on ULT. Since many gout patients do not see rheumatologists, our data suggest that further education should focus on patients and non-rheumatologists and emphasize the use of urate-lowering drugs, treatment duration, the target sUA level, and prophylaxis against acute attacks.

Rilonacept for gout flare prevention during initiation of uric acid-lowering therapy: results from the PRESURGE-2 international, phase 3, randomized, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of IL-1 inhibitor rilonacept (IL-1 Trap) for gout flare (GF) prevention during initiation of uric acid-lowering therapy (ULT) with allopurinol in a multiregional phase 3 clinical trial. METHODS: Hyperuricaemic adults (n = 248) from South Africa, Germany and Asia with gout and two or more GFs within the past year were initiated on allopurinol and randomized 1:1:1 to once-weekly s.c. treatment with placebo (PBO), rilonacept 80 mg (R80) or rilonacept 160 mg (R160) for 16 weeks. The primary endpoint was the number of GFs per patient through week 16. RESULTS: The population was predominantly male and racially diverse (white, 53.2%; Asian, 33.1%; black, 13.7%). Across treatments, most patients completed the study (87.8-92.9%). At 16 weeks the mean number of GFs per patient was reduced by 71.3% with R80 (0.35) and by 72.6% with R160 (0.34) relative to PBO (1.23; both P < 0.0001). The proportion of patients without GFs was higher with R80 (74.4%) and R160 (79.5%) than with PBO (43.9%; both P ≤ 0.0001), and the proportions of patients on rilonacept with multiple GFs were significantly lower (P < 0.001). Overall, the incidence of adverse events (AEs) was similar between PBO (61.0%) and rilonacept (65.1%). Injection site reactions, generally mild, were the most frequent AE with rilonacept (1.2% PBO, 12.2% R80 and 17.9% R160); none of these injection site reactions led to withdrawal. There were no study drug-related serious AEs or deaths. CONCLUSION: Rilonacept significantly reduced the occurrence of GFs associated with initiation of ULT, with >70% of patients having no flares, and demonstrated an acceptable safety and tolerability profile. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00958438.

Light and electron microscopic features of synovium in patients with psoriatic arthritis.

INTRODUCTION: Few ultrastructural studies have been reported in psoriatic arthritis (PsA). The authors report a series of synovial biopsies with emphasis on patients with early disease to look for distinctive light (LM) and electron microscopic (EM) features of possible importance. METHODS: The authors examined synovial biopsies obtained primarily by needle biopsy from 13 PsA patients using LM and/or EM. Sections from 12 patients were evaluated by LM for vascularity, synovial lining thickness, fibrin deposition, and inflammation via a semi-quantitative scale. Nine EM specimens were descriptively analyzed. Clinical, synovial fluid (SF), and radiographic characteristics were recorded. RESULTS: Patients were mostly male, with mean disease duration before biopsy of 2.19 ± 2.60 years; 7 patients had arthritis for less than 1 year. All patients had peripheral arthritis, 2 had axial involvement. SFs disclosed predominance of polymorphonuclear leukocytes. LM demonstrated proliferation of synovial lining cells, lymphocyte and plasma cell infiltration, as well as dramatic clusters of small vessels in the superficial synovium. EMs showed more detailed vascular changes, including small, subendothelial, electron-dense deposits and scattered microparticles in vessel lumens and walls. CONCLUSIONS: Prominent vascularity is confirmed as an important feature of some PsA. Vascular changes and other features, including the first EM demonstration of microparticles in PsA (identified as potent factors in other inflammatory joint diseases), are potential targets for therapy.

Rilonacept (interleukin-1 trap) for prevention of gout flares during initiation of uric acid-lowering therapy: results from a phase III randomized, double-blind, placebo-controlled, confirmatory efficacy study.

OBJECTIVE: To evaluate the efficacy and safety of the interleukin-1 inhibitor rilonacept (interleukin-1 Trap) for gout flare prevention during initiation of uric acid-lowering therapy (ULT). METHODS: In total, 241 adult patients with gout, ≥2 gout flares within the past year, and a serum urate level ≥7.5 mg/dl were initiated on allopurinol 300 mg daily and randomly allocated in a 1:1:1 ratio to receive 16 once-weekly subcutaneous injections of placebo, rilonacept 80 mg, or rilonacept 160 mg, with a double (loading) dose on day 1. Allopurinol was titrated to achieve a serum urate level of <6.0 mg/dl. The study was powered for the primary efficacy end point, the number of gout flares per patient through week 16. RESULTS: More patients in the rilonacept groups (80.0% in the rilonacept 80 mg group, 86.4% in the rilonacept 160 mg group) completed the study than in the placebo group (72.5%; P < 0.05 for the rilonacept 160 mg group versus the placebo group). Over 16 weeks, the mean number of gout flares per patient was significantly reduced by rilonacept treatment (placebo: 1.06, rilonacept 80 mg: 0.29 [P < 0.001], rilonacept 160 mg: 0.21 [P < 0.001]). Significantly lower proportions of patients reported ≥1 gout flares with rilonacept 80 mg (18.8%) and rilonacept 160 mg (16.3%) relative to placebo (46.8%; P < 0.001 for both). Except for injection site reactions (1.3% in the placebo group versus 8.8% in the rilonacept 80 mg group [P = 0.0635, post hoc analysis] and 19.8% in the rilonacept 160 mg group [P = 0.0001, post hoc analysis]), the incidence of adverse events was generally balanced among the treatment groups. CONCLUSION: Rilonacept markedly reduced the occurrence of gout flares associated with the initiation of ULT. The efficacy and safety profile suggests that rilonacept may have the potential to improve long-term disease control for some patients by improving adherence to ULT by reducing flares during the first months after ULT initiation.

Synovial xanthomatosis: are there clues to mechanisms for this rare disease?

We report a 64-year-old man with arthritis and nodules to describe that this picture can be caused by normo-lipidemic xanthomas. Light and electron microscopy (EM) plus polymerase chain reaction (PCR) studies were performed for diagnosis and investigation. These showed features typical of xanthomas plus PCR and EM evidence of possible infection with Chlamydia pneumoniae as a pathogenetic mechanism deserving consideration. With such rare diseases, any clues to possible mechanisms seem important to record and thus to encourage future investigations. This uncommon cause of arthritis and nodules had been confused with rheumatoid arthritis by others in this case.

Rilonacept (interleukin-1 trap) in the prevention of acute gout flares during initiation of urate-lowering therapy: results of a phase II randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the interleukin-1 inhibitor rilonacept (Interleukin-1 Trap) for prevention of gout flares occurring in the first few months following initiation of urate-lowering therapy. METHODS: In this double-blind study, adult patients with hyperuricemia and gout were randomized to receive rilonacept administered subcutaneously once per week (loading dose 320 mg followed by 160 mg weekly) or placebo, and started on allopurinol (300 mg/day, titrated to serum urate <6 mg/dl). At study visits, physical and laboratory assessments were performed and information on any adverse events was ascertained. RESULTS: Baseline characteristics were similar between the rilonacept and placebo groups (n = 41 and n = 42, respectively). The mean number of gout flares per patient through week 12 (primary efficacy end point) was markedly lower in the rilonacept group than in the placebo group (0.15 [6 flares] versus 0.79 [33 flares]; P = 0.0011). Fewer flares were observed with rilonacept as early as 4 weeks after initiation of treatment (P = 0.007). The proportion of patients experiencing a flare during the 12 weeks was lower in the rilonacept group than in the placebo group (14.6% versus 45.2%; P = 0.0037). No rebound in the flare rate was observed for 6 weeks after discontinuation of rilonacept or placebo at week 16. Adverse events were similar between groups, and no deaths or serious infectious adverse events were reported; the most common adverse events were infections (14.6% and 26.2% of rilonacept- and placebo-treated patients, respectively) and musculoskeletal disorders (14.6% and 21.4%, respectively). A higher percentage of rilonacept-treated patients (98%) compared with placebo-treated patients (79%) completed the primary 12-week evaluation period (P = 0.015). CONCLUSION: The current findings indicate that rilonacept significantly reduces the frequency of gout flares during the initial period of treatment with urate-lowering therapy, with a favorable safety profile.

Parathyroid disease.

Patients with parathyroid disease can have important musculoskeletal problems.Hypoparathyroidism can cause subcutaneous calcifications, tetany, muscle cramps,and paresthesias, but also myopathies and an ankylosing spondylitis-like back disease. Hypoparathyroidism can occur in SLE caused by antiparathyroid antibodies.Patients with hyperparathyroidism can develop bone disease with cysts, erosions,and deformities. They can also develop pseudogout, gout, myopathies, and tendon ruptures.

The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial.

INTRODUCTION: The purpose of this study was to compare urate-lowering (UL) efficacy and safety of daily febuxostat and allopurinol in subjects with gout and serum urate (sUA) > or = 8.0 mg/dL in a six-month trial. METHODS: Subjects (n = 2,269) were randomized to febuxostat 40 mg or 80 mg, or allopurinol 300 mg (200 mg in moderate renal impairment). Endpoints included the proportion of all subjects with sUA <6.0 mg/dL and the proportion of subjects with mild/moderate renal impairment and sUA <6.0 mg/dL. Safety assessments included blinded adjudication of each cardiovascular (CV) adverse event (AE) and death. RESULTS: Comorbidities included: renal impairment (65%); obesity (64%); hyperlipidemia (42%); and hypertension (53%). In febuxostat 40 mg, febuxostat 80 mg, and allopurinol groups, primary endpoint was achieved in 45%, 67%, and 42%, respectively. Febuxostat 40 mg UL was statistically non-inferior to allopurinol, but febuxostat 80 mg was superior to both (P < 0.001). Achievement of target sUA in subjects with renal impairment was also superior with febuxostat 80 mg (72%; P < 0.001) compared with febuxostat 40 mg (50%) or allopurinol (42%), but febuxostat 40 mg showed greater efficacy than allopurinol (P = 0.021). Rates of AEs did not differ across treatment groups. Adjudicated (APTC) CV event rates were 0.0% for febuxostat 40 mg and 0.4% for both febuxostat 80 mg and allopurinol. One death occurred in each febuxostat group and three in the allopurinol group. CONCLUSIONS: Urate-lowering efficacy of febuxostat 80 mg exceeded that of febuxostat 40 mg and allopurinol (300/200 mg), which were comparable. In subjects with mild/moderate renal impairment, both febuxostat doses were more efficacious than allopurinol and equally safe. At the doses tested, safety of febuxostat and allopurinol was comparable. CLINICAL TRIAL REGISTRATION: NCT00430248.