Faculty Bibliography

Background: Routine Assessment of Patient Index Data 3 (RAPID3) comprises the three patient-reported ACR RA Core Data Set measures: function (HAQDI), pain and patient global estimate of status (10-cm visual analogue scale). These can be scored in <10 seconds, making it suitable for use in routine clinical practice where it provides quantitative data to supplement qualitative assessments. Significant correlations between RAPID3 scores and DAS28 (CRP) and CDAI have been previously reported.1,2 Objectives: To examine whether RAPID3-defined remission performs similarly to definitions of remission by DAS28 (CRP), CDAI, SDAI or Boolean criteria in patients with early RA. Methods: We performed post hoc analyses on data from the AVERT study, described previously.3 RAPID3 scores were calculated at baseline and 3-monthly intervals thereafter, up to 12 months. Definitions of remission were RAPID3 <1 (scale of 1-10); DAS28 (CRP) <2.6; CDAI <2.8; SDAI <3.3; and Boolean: TJC28 <1, SJC28 <1, patient global assessment of disease activity (0-10 cm) <1 and high-sensitivity CRP <1 mg/dL. Proportions of patients in RAPID3, DAS28 (CRP), CDAI, SDAI and ACR/EULAR Boolean remission at each time point were calculated. Proportions at 3, 6, 9 and 12 months were compared using cross-tabulation analysis. Agreement between RAPID3 disease activity states and those of other measures were assessed using kappa and weighted kappa statistics. Results: Among the total AVERT population, the respective percentages of patients in remission according to each measure at Months 3, 6 and 9 were: RAPID3, 12.3%, 17.4%, 21.9%; Boolean, 8.5%, 12.5%, 21.1%; SDAI, 10.8%, 21.4%, 27.4%; CDAI, 10.0%, 20.8%, 27.1%; and DAS28 (CRP), 25.1%, 35.0%, 42.7%. Similar trends held at Month 12: 29.3%, 28.8%, 32.2%, 33.6%, 50.1%, respectively. When weighted kappa correlations were calculated for RAPID3 versus other remission criteria, RAPID3 remission showed good correlation with Boolean remission, and kappa correlations with SDAI and CDAI remission were (Table presented) higher than those with DAS28 (CRP) (Table). These trends were similar for each treatment arm. Conclusions: RAPID3-defined remission may be as stringent as ACR/EULAR Boolean-defined remission and agrees well with SDAI and CDAI remission criteria. RAPID3 may be used in clinical trials in addition to routine clinical care in early RA, and its ease of use may be an advantage over other indices

Background: Diagnosis of Behcet's syndrome (BS) is based on clinical signs and symptoms, without the use laboratory or imaging tests and the most commonly used diagnostic criteria are the International Study Group (ISG) criteria. Patients have also been diagnosed with BS not meeting ISG criteria based on the clinical impression of the treating physicians. Objectives: To determine differences in disease activity among BS patients meeting and not meeting the ISG criteria. Methods: Behcet's patients seen at the NYU Behcet's Center had their demographic, clinical features and outcomes data abstracted. Confirmed BS diagnosis was determined if ISG criteria were met at any time during the course of observation. Multiple linear regression estimated any association between meeting ISG criteria and gender with the patient-reported outcomes Behcet's Syndrome Activity Scale (BSAS), Pain Visual Analog Scale (VAS), Fatigue VAS, Patient Global Assessment VAS, and RAPID3 as well as Physician Global Assessment VAS. Results: First observation data on 832 subjects were abstracted for this analysis. 504 (63%) met ISG criteria for Behcet's, 616 (74%) were female with an average age of 35 years (+/-13.8). Mean scores for BSAS, pain, fatigue, patient global, RAPID3 and physician global were uniformly higher in those meeting criteria vs not meeting criteria. Meeting ISG criteria was significantly associated with increases in all clinical outcomes independently of gender, ranging from 5 points on the Physician Global VAS to 13 points on the Fatigue VAS (Table). Conversely, gender was only associated with significant increases in BSAS, Fatigue and RAPID3 independent of meeting ISG criteria. Conclusions: Behcet's patients who fulfill ISG criteria have more active disease, based on all measures of disease activity, including patient and physician based outcomes. Interestingly, females were also at risk for more active disease as measured by composite patient reported outcome measures, reflecting possibly the different character of Behcet's in non-endemic areas, such as the US. (Table Presented)

OBJECTIVE: The aim of the Patient/Physician Reported Efficacy Determination In Clinical Practice Trial (PREDICT; ClinicalTrials identifier NCT01255761) was to compare the patient-reported Routine Assessment of Patient Index Data 3 (RAPID-3) instrument with the investigator-based Clinical Disease Activity Index (CDAI) for assessing certolizumab pegol (CZP) treatment response in rheumatoid arthritis patients at 12 weeks and to predict the treatment response at week 52 using the data from week 12 (coprimary end points). METHODS: Patients received 400 mg of CZP at weeks 0, 2, and 4 (loading dose), followed by 200 mg every 2 weeks thereafter. Patients were randomized 1:1 to assessment with the RAPID-3 or the CDAI. Responder classification was performed at week 12; treatment response was defined as a score of 22 or RAPID-3 score >12) at 2 consecutive visits were withdrawn from the study. RESULTS: Patients had longstanding disease (mean 8.9 years) and high levels of disease activity (mean scores of 6.3 on the DAS28-ESR, 16.1 on the RAPID-3, and 40.2 on the CDAI). Previous anti-tumor necrosis factor therapy had failed in 55.5% of them. At week 12, a total of 64.7% (by RAPID-3) and 76.4% (by CDAI) of the patients were classified as responders (difference of -11.9% [95% confidence interval -18.4%, -5.3%]). At week 52, a total of 31.5% (by RAPID-3) and 32.3% (by CDAI) of the responders achieved a low level of disease activity on the DAS28-ESR (difference of -1.3% [95% confidence interval -9.3%, 6.6%]). CONCLUSION: The CDAI classified more patients as CZP responders at week 12 than did the RAPID-3. Although these outcome measures were not statistically comparable, the positive predictive value for low disease activity at week 52 was similar. As these tools cover differing domains of therapy response, further evaluation for clinical disease activity assessments and treatment decisions is needed.

Clinical trials are the optimal method to establish efficacy of a drug versus placebo or another drug. Nonetheless, important limitations are seen, particularly in chronic diseases over long periods, although most are ignored. Pragmatic limitations of clinical trials include a relatively short observation period, suboptimal dosage schedules, suboptimal surrogate markers for long-term outcomes, statistically significant results which may not be clinically unimportant and vice versa. Even ideal clinical trials have intrinsic limitations, including the influence of design on results, data reported in groups which ignore individual variation, non-standard observer-dependent interpretation of a balance of efficacy and toxicity, and distortion of a "placebo effect." Limitations are seen in many clinical trials of methotrexate (MTX) in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). The first MTX clinical trial in rheumatology documented excellent efficacy in PsA, but frequent adverse events in 1964, explained by intravenous doses up to 150 kg. MTX was abandoned until the 1980s for RA, while gold salts and penicillamine were termed "remission-inducing," on the basis limitations of clinical trials. In the most recent MTX in PsA (MIPA) trial, all outcomes favoured MTX, but only patient and physician global estimates met the p<0.05 criterion. A conclusion of "no evidence for MTX improving synovitis" appears explained by insufficient statistical power, wide individual variation, no subsets, low doses, and other limitations. MTX appears less efficacious in PsA than RA, but may be underestimated in PsA, similar to historical problems in RA, resulting more from limitations of clinical trials than from limitations of MTX.

OBJECTIVES: To investigate the frequency of Behcet's syndrome (BS) with pulmonary artery aneurysms (PAA) publications, the most lethal complication of BS, as reported from different countries and to provide a review of diagnostic techniques, treatment approaches and prognosis. METHODS: Countries from each continent with a population of 4 million and over were chosen (n=128). A PubMed search for "BS, PAA and the country name" was conducted and 23 countries with BS and PAA were identified. The full texts of articles (n=91) were analysed for data including gender, age, accompanying vascular findings, diagnostic techniques, treatment modalities and mortality rates. RESULTS: A total of 207 (183 males, 24 females) patients with BS and PAA were reported in 91 articles originating from 23 countries. As expected there was a significant correlation (r=0.88, p<0.001) between the total number of articles about BS (n=4431) and those related to PAA and BS. In a simple linear regression analysis the number of BS and PAA articles from Japan was significantly below the identity line while in Turkey there was a propensity to publish more articles related to PAA than expected. One hundred and sixteen patients (56%) were treated with immunosuppressive therapy. Biologics were used only in 5 patients (2%). Of the 207 patients, 62 (30%) died. CONCLUSIONS: PAA is mostly reported as case reports from countries where BS is common. PAA might be uncommon in Japan. The prognosis of PAA could be getting better.

BACKGROUND: Oral ulcers, the hallmark of Behcet's syndrome, can be resistant to conventional treatment; therefore, alternative agents are needed. Apremilast is an oral phosphodiesterase-4 inhibitor that modulates several inflammatory pathways. METHODS: We conducted a phase 2, multicenter, placebo-controlled study in which 111 patients with Behcet's syndrome who had two or more oral ulcers were randomly assigned to receive 30 mg of apremilast twice daily or placebo for 12 weeks. This regimen was followed by a 12-week extension phase in which the placebo group was switched to apremilast and a 28-day post-treatment observational follow-up phase. The patients and clinicians were unaware of the study assignments throughout the trial. The primary end point was the number of oral ulcers at week 12. Secondary outcomes included pain from these ulcers (measured on a 100-mm visual-analogue scale, with higher scores indicating worse pain), the number of genital ulcers, overall disease activity, and quality of life. RESULTS: The mean (+/-SD) number of oral ulcers per patient at week 12 was significantly lower in the apremilast group than in the placebo group (0.5+/-1.0 vs. 2.1+/-2.6) (P<0.001). The mean decline in pain from oral ulcers from baseline to week 12 was greater with apremilast than with placebo (-44.7+/-24.3 mm vs. -16.0+/-32.5 mm) (P<0.001). Nausea, vomiting, and diarrhea were more common in the apremilast group (with 22, 9, and 12 incidents, respectively, among 55 patients) than in the placebo group (with 10, 1, and 2 incidents, respectively, among 56 patients), findings that were similar to those in previous studies of apremilast. There were two serious adverse events in patients receiving apremilast. CONCLUSIONS: Apremilast was effective in treating oral ulcers, which are the cardinal manifestation of Behcet's syndrome. This preliminary study was neither large enough nor long enough to assess long-term efficacy, the effect on other manifestations of Behcet's syndrome, or the risk of uncommon serious adverse events. (Funded by Celgene; ClinicalTrials.gov number, NCT00866359.).

A single questionnaire regarding to disease activity for all rheumatic diseases may present advantages to introduce quantitative measurement into routine care. The aim of this study was to evaluate the correlation of routine assessment of patient index data 3 (RAPID3) with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS). A total of 341 consecutive AS patients who met the modified New York classification criteria were included. All patients completed BASDAI and RAPID3 at each visit, and their physicians completed physician global assessment. ASDASs were calculated using defined formulas. Proposed RAPID3 severity categories were compared to BASDAI and ASDAS categories. Spearman's rho correlation test and kappa statistics were used to analyze statistical significance. The median age of AS patients was 34.0 (21.0-69.0) years and the median disease duration 10.0 (2.0-35.0) years. Median scores for RAPID3, BASDAI, ASDAS-CRP, and ASDAS-ESR were 13.0 (0.0-27.3), 4.7 (0.0-9.7), 3.0 (0.4-5.8), and 2.5 (0.5-6.3), respectively. RAPID3 was strongly correlated with BASDAI and ASDAS-ESR (r = 0.842, r = 0.815; p < 0.001, respectively). Among the 209 patients with high disease activity according to BASDAI, 83.3 % had high or moderate severity according to RAPID3 (kappa 0.693; p < 0.001). Among the 133 patients with moderate, high, and very high disease activity on ASDAS-CRP, 91.7 % had high or moderate severity according to RAPID3 (kappa 0.548; p < 0.001). RAPID3 is as informative as BASDAI and ASDAS in our cohort of AS patients. We therefore suggest that RAPID3 may be used to assess the patient status quantitatively in AS patients, as part of routine care.