Crystal-induced arthropathies: recent investigative advances.

PURPOSE OF REVIEW: To highlight recent investigations that have stimulated renewed interest in crystal-induced arthropathies. RECENT FINDINGS: Specific diet-related and alcohol-related risks for gout have been clarified, and alternative urate-lowering treatments likely to benefit patients with difficult-to-treat gout are in development. Progress toward understanding mechanisms underlying the renal deficits defining most cases of gout includes characterization of a urate-specific renal tubule transporter explaining many aspects of renal uric acid handling and identification of mutations in the UMOD gene, resulting in altered uromodulin protein in the gout-associated disorders familial juvenile hyperuricemic nephropathy and medullary cystic kidney disease type 2. A genetic marker associated with the risk for severe allopurinol toxicity has been reported. Hyperuricemia and gout are increasing in incidence, as is complicated gout, especially among the elderly and patients with cardiovascular and renal comorbidities, organ transplants, or complex concomitant medication regimens. Asymptomatic hyperuricemia is clearly associated with hypertension, chronic kidney disease, cardiovascular disease, and the insulin resistance syndrome, and the pathogenetic significance of these associations is under intensive study. Mutation in the ANKH gene has been found among some patients with sporadic as well as familial calcium pyrophosphate deposition disease. SUMMARY: The results of these clinical, epidemiologic, experimental, and therapeutic investigations presage advances in the management of crystal-induced arthropathies.

Outcome measurements in scleroderma: results from a delphi exercise.

OBJECTIVE: To obtain a consensus on the minimal clinically relevant treatment effect in various scleroderma disease outcome measures to be used in future clinical trials. METHODS: A Delphi consensus building exercise using a survey was sent out to members of the Scleroderma Clinical Trials Consortium (SCTC). The 65 SCTC members were divided into 2 groups. Group 1 was informed, in a cover letter, of the usual American College of Rheumatology 20% response results in randomized trials using effective biologic treatments for rheumatoid arthritis, while Group 2 was not. The first round of the exercise presented the scleroderma experts with a survey composed of 95 questions/clinical scenarios divided into 8 categories. These included situations where the treatment group improved, or worsened, or where some outcome measures improved, while others worsened. From the responses of this first round, a mean, mode, median, and range of responses for each of the 95 questions was obtained. This information was sent out, in the second round of the Delphi exercise, only to those respondents who answered the first round. The respondent's previous answer and the mean and range from the first round were provided for each question. It gave respondents the option to change any of their initial responses. The median of their responses in the second round was used to calculate the values for the minimal clinically relevant treatment effect. RESULTS: Thirty-two of the 65 SCTC members returned the first round of the Delphi exercise. Twenty-eight members returned the second round. Intraclass correlation coefficients between responses to round 1 and 2 were calculated for the questions. These varied from 0.99 (excellent agreement) to 0.02 (poor agreement). The p value was under 0.09 for 9 questions and under 0.19 for 20 questions. Standard deviations (SD) were calculated and were found to be lesser for each of the questions in round 2 when compared to the SD in responses from round 1, thus indicating a movement towards a consensus by the second round. An average of 33% of the responses were changed by the respondents in the second round of the Delphi exercise to a value closer to the median/average of the first round's responses. A range in required values for the minimal clinically relevant treatment effect for Modified Rodnan skin score is 3 to 7.5 units, Health Assessment Questionnaire Disability Index (HAQ-DI) 0.2 to 0.25 units, HAQ pain 0.2 to 0.3 units, MD global (100 mm visual analog scale) 8 to 13, patient global assessment 10 to 12, and diffusing capacity (percentage predicted) 9 to 10. The scenarios were especially weighted towards overall disease modification, thus organ-specific measures, such as 6 minute walk time (which has been used in many pulmonary artery hypertension trials), forced vital capacity, and a dyspnea rating (which may be important in scleroderma lung trials), were not included in the survey. CONCLUSION: Our study begins to address the current deficiency in our knowledge of appropriate values for the minimal clinically relevant treatment effect in various scleroderma disease outcome measures. A consensus could be achieved, or at least a range of minimal clinically relevant treatment effect values could be found for several outcome measurements. Of course, this consensus statement will be modified by evidence as it accrues in each consensus area.

Measuring disease activity and functional status in patients with scleroderma and Raynaud's phenomenon.

OBJECTIVE: To document disease activity and functional status in patients with scleroderma (systemic sclerosis [SSc]) and Raynaud's phenomenon (RP) and to determine the sensitivity to change, reliability, ease of use, and validity of various outcome measures in these patients. METHODS: Patients with SSc and moderate-to-severe RP participating in a multicenter RP treatment trial completed daily diaries documenting the frequency and duration of RP attacks and recorded a daily Raynaud's Condition Score (RCS). Mean scores for the 2-week periods prior to baseline (week 0), end of trial (week 6), and posttrial followup (week 12) were calculated. At weeks 0, 6, and 12, physicians completed 3 global assessment scales and performed clinical assessments of digital ulcers and infarcts; patients completed the Health Assessment Questionnaire (HAQ), the Arthritis Impact Measurement Scales 2 (AIMS2) mood and tension subscales, 5 specific SSc/RP-related visual analog scales (VAS), and 3 other VAS global assessments. We used these measures to document baseline disease activity and to assess their construct validity, sensitivity to change, and reliability in trial data. RESULTS: Two hundred eighty-one patients (248 women, 33 men; mean age 50.4 years [range 18-82 years]) from 14 centers participated. Forty-eight percent had limited cutaneous SSc; 52% had diffuse cutaneous SSc. Fifty-nine patients (21%) had digital ulcers at baseline. Patients had 3.89 +/- 2.33 (mean +/- SD) daily RP attacks (range 0.8-14.6), with a duration of 82.1 +/- 91.6 minutes/attack. RCS for RP activity (possible range 0-10) was 4.30 +/- 1.92. HAQ scores (0-3 scale) indicated substantial disability at baseline (total disability 0.86, pain 1.19), especially among the subscales pertaining to hand function (grip, eating, dressing). AIMS2 mood and tension scores were fairly high, as were many of the VAS scores. Patients with digital ulcers had worse RCS, pain, HAQ disability (overall, grip, eating, and dressing), physician's global assessment, and tension, but no significant difference in the frequency of RP, duration of RP, patient's global assessment, or mood, compared with patients without digital ulcers. VAS scores for digital ulcers as rated by the patients were not consistent with the physician's ratings. Factor analysis of the 18 measures showed strong associations among variables in 4 distinct domains: disease activity, RP measures, digital ulcer measures, and mood/tension. Reliability of the RCS, HAQ pain and disability scales, and AIMS2 mood and tension subscales was high. The RP measures demonstrated good sensitivity to change (effect sizes 0.33-0.76). CONCLUSION: Our findings demonstrate that the significant activity, disability, pain, and psychological impact of RP and digital ulcers in SSc can be measured by a small set of valid and reliable outcome measures. These outcome measures provide information beyond the quantitative metrics of RP attacks. We propose a core set of measures for use in clinical trials of RP in SSc patients that includes the RCS, patient and physician VAS ratings of RP activity, a digital ulcer/infarct measure, measures of disability and pain (HAQ), and measures of psychological function (AIMS2).