Adipose-Derived Regenerative Cell Transplantation for the Treatment of Hand Dysfunction in Systemic Sclerosis: A Randomized Clinical Trial.

OBJECTIVE: Hand dysfunction is common in systemic sclerosis (SSc). We undertook this study to evaluate the capacity of autologous adipose-derived regenerative cells (ADRCs) to improve hand function in SSc patients. METHODS: The Scleroderma Treatment with Celution Processed Adipose Derived Regenerative Cells Trial was a prospective, randomized, double-blind trial of ADRCs, in which ADRCs were obtained from patients with SSc by small-volume adipose tissue harvest, and the fingers of each patient were injected with ADRCs. The primary end point was change in hand function at 24 and 48 weeks, assessed using the Cochin Hand Function Scale (CHFS). One of the secondary end points included the change in Health Assessment Questionnaire disability index (HAQ DI) at 48 weeks. Separate prespecified analyses were performed for patients with diffuse cutaneous SSc (dcSSc) and those with limited cutaneous SSc (lcSSc). RESULTS: Eighty-eight patients were randomized to receive ADRCs (n = 48 [32 patients with dcSSc and 16 with lcSSc]) or placebo (n = 40 [19 patients with dcSSc and 21 with lcSSc]). Change in hand function according to CHFS score was numerically higher for the ADRC group compared to the placebo group but did not achieve statistical significance (mean ± SD improvement in the CHFS score at 48 weeks 11.0 ± 12.5 versus 8.9 ± 10.5; P = 0.299). For patients with dcSSc, the between-group difference in the CHFS at 48 weeks was 6.3 points (nominal P = 0.069). For the secondary end point, the dcSSc group exhibited a between-group difference of 0.17 points in the HAQ DI (nominal P = 0.044) at 48 weeks. Of the ADRC-treated patients with dcSSc, 52% reported improvement greater than the minimum clinically important difference for both CHFS and HAQ DI compared to 16% in the placebo group (nominal P = 0.016). Small-volume adipose tissue harvest and ADRC treatment were well tolerated. CONCLUSION: While the primary end point of this trial was not achieved, efficacy trends were observed in patients with dcSSc. Adipose tissue harvest and ADRC injection were demonstrated to be feasible. Further clinical trials of this intervention in the setting of dcSSc are warranted.

Bacterial Endocarditis Presenting as Leukocytoclastic Vasculitis.

Subacute bacterial endocarditis can have many different presentations; in rare instances, it can present as leukocytoclastic vasculitis owing to the effect of circulating immune complexes and micro-emboli on the vascular endothelium. A high index of suspicion needs to be maintained to differentiate between infectious vs noninfectious autoimmune vasculitides, keeping in mind that missing a diagnosis can have fatal results. In this case report, we introduce a young female patient who initially presented with a picture of idiopathic autoimmune cutaneous vasculitis delaying the diagnosis of an underlying infective endocarditis with aortic valve involvement.

Polysymptomatic distress in patients with rheumatoid arthritis: understanding disproportionate response and its spectrum.

OBJECTIVE: Fibromyalgia (FM) in rheumatoid arthritis (RA) can cause consternation because symptoms are seen to be out of proportion to physician and laboratory assessments, and composite RA activity scores such as the 28 joint Disease Activity Score, Clinical Disease Activity Index, and Routine Assessment of Patient Index Data 3 (RAPID-3) can yield apparently "wrong" results. We explored the effect of polysymptomatic distress (PSD), a measure of fibromyalgianess and a quantity derived from the American College of Rheumatology 2010 FM diagnostic criteria, to explain the relationship of patient to physician variables. METHODS: We obtained PSD scores on 300 RA patients prior to ordinary clinical care, and assessed the associations of PSD with tender and swollen joints, physician global estimate of RA activity, pain, Health Assessment Questionnaire score, and composite RA activity measures during routine clinic assessments. RESULTS: PSD scores greater than the sample mean (8.8) were associated with increased patient symptoms regardless of the presence or absence of FM, while scores below the mean were associated with better patient outcomes. PSD scores predicted all patient outcomes and less strongly predicted physician outcomes. The discrepancy between patient and physician measures was greatest at low levels of physician-estimated disease activity. CONCLUSION: PSD rather than FM diagnosis more usefully identifies and predicts disproportionate responses. Just as there are patients who lean disproportionately toward greater severity, there are also patients who disproportionately report milder symptoms. Composite measures used to assess RA are flawed, as they confound RA inflammation and patient distress, and more consideration should be given to disaggregated assessments. PSD also appears to be influenced weakly by RA disease activity.

Validity and reliability problems with patient global as a component of the ACR/EULAR remission criteria as used in clinical practice.

OBJECTIVE: To investigate what factors influence patient global health assessment (PtGlobal), and how those factors and the reliability of PtGlobal affect the rate, reliability, and validity of recently published American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) rheumatoid arthritis (RA) remission criteria when used in clinical practice. METHODS: We examined consecutive patients with RA in clinical practice and identified 77 who met ACR/EULAR joint criteria for remission (≤ 1 swollen joint and ≤ 1 tender joint). We evaluated factors associated with a PtGlobal > 1, because a PtGlobal ≤ 1 defined ACR/EULAR remission in this group of patients who had already met ACR/EULAR joint criteria. RESULTS: Of the 77 patients examined, only 17 (22.1%) had PtGlobal ≤ 1 and thus fully satisfied ACR/EULAR criteria. A large proportion of patients not in remission by ACR/EULAR criteria had high PtGlobal related to noninflammatory issues, including low back pain, fatigue, and functional limitations, and a number of patients clustered in the range of PtGlobal > 1 and ≤ 2. However, the minimal detectable difference for PtGlobal was 2.3. In addition, compared with a PtGlobal severity score, a PtGlobal activity score was 3.3% less likely to be abnormal (> 1). CONCLUSION: Noninflammatory factors contribute to the level of PtGlobal and result in the exclusion of many patients who would otherwise be in "true" remission according to the ACR/EULAR definition. Reliability problems associated with PtGlobal can also result in misclassification, and may explain the observation of low longterm remission rates in RA. As currently constituted, the use of the ACR/EULAR remission criteria in clinical practice appears to be problematic.

Remission of rheumatoid arthritis in clinical practice: application of the American College of Rheumatology/European League Against Rheumatism 2011 remission criteria.

OBJECTIVE: To describe use of the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) rheumatoid arthritis (RA) remission criteria in clinical practice. METHODS: Remission was examined using data on 1,341 patients with RA (91% men) from the US Department of Veterans Affairs RA (VARA) registry (total of 9,700 visits) and 1,153 patients with RA (25.8% men) in a community rheumatology practice (Arthritis and Rheumatology Clinics of Kansas [ARCK]) (total of 6,362 visits). Cross-sectional and cumulative probabilities were studied, and agreement between the various remission criteria was assessed. Aspects of reliability of the criteria were determined using Boolean-based definitions, as well as the Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI) scoring methods proposed by the ACR/EULAR joint committee. RESULTS: When the 3-variable ACR/EULAR definition of remission recommended for use in community practice (swollen and tender joint counts ≤1, and visual analog scale score for patient's global assessment of disease activity ≤1) was applied, cross-sectional remission was 7.5% (95% confidence interval [95% CI] 6.4, 8.7%) for ARCK and 8.9% (95% CI 7.9, 9.9%) for VARA, and cumulative remission (remission at any observation) was 18.0% (for ARCK) and 24.4% (for VARA), over a mean followup of ∼2.2 years. Addition of the erythrocyte sedimentation rate or C-reactive protein level to the criteria set reduced remission to 5.0-6.2%, and use of the CDAI/SDAI increased the proportions to 6.9-10.1%. Moreover, 1.8-4.6% of the patients met remission criteria at ≥2 visits. Agreement between criteria definitions was good, as assessed by kappa statistics and Jaccard coefficients. Among patients in remission, the probability of a remission lasting 2 years was 6.0-14.1%. Among all patients, the probability of a remission lasting 2 years was <3%. Remission status and examination results for each patient varied substantially among physicians, as determined by multilevel analyses. CONCLUSION: Cross-sectional remission occurred in 5.0-10.1% of the patients in these cohorts, with cumulative remission being 2-3 times greater; however, long-term remission was rare. Problems with reliability and agreement limit the usefulness of these criteria in the individual patient. However, the criteria can be an effective method for measuring clinical status and treatment effect in groups of patients in the community.

Malignancy-associated multicentric reticulohistiocytosis.

Multicentric reticulohistiocytosis (MR) is a rare systemic disorder of unknown etiology. Up to 25% of patients with MR have associated malignancies. We are reporting a case of a patient with MR who initially had an excellent clinical response to oral methotrexate and prednisone. Subsequent attempts of prednisone taper failed because of disease flare-up. Workup for associated malignancy revealed localized squamous cell carcinoma of the lung. The tumor was resected; methotrexate and prednisone were tapered and discontinued with complete remission of MR. A review of literature and the new advances and treatment modalities for MR is provided.

Is fatigue an inflammatory variable in rheumatoid arthritis (RA)? Analyses of fatigue in RA, osteoarthritis, and fibromyalgia.

OBJECTIVE: To investigate whether fatigue is an inflammatory (rheumatoid arthritis; RA) variable, the contributions of RA variables to fatigue, and the levels of fatigue in RA compared with osteoarthritis (OA) and fibromyalgia (FM). METHODS: We studied 2096 RA patients, 1440 with OA, and 1073 with FM in a clinical setting, and 14,607 RA, 3173 OA, and 2487 patients with FM in survey research. We partitioned variables into inflammatory and noninflammatory factors and examined variable contribution to fatigue (0-10 visual analog scale). RESULTS: Factor analysis identified Disease Activity Score-28 (DAS28) and swollen (SJC) and tender joint count (TJC) as a physician-inflammation factor, and patient global assessment, pain, Health Assessment Questionnaire, and fatigue as patient components. Fatigue demonstrated weak correlations with erythrocyte sedimentation rate (ESR; r = 0.071) and SJC (r = 0.112), weak to fair correlations with TJC (r = 0.294), physician global assessment of RA activity (r = 0.384), and DAS28 (r = 0.399), but strong correlation with patient global assessment of severity (r = 0.567). In hierarchical regression analysis, patient global explained 43.1% of DAS28 fatigue variance; when SJC, TJC, and ESR were entered, the explained variance increased to 43.7%. In reverse order, SJC, TJC, and ESR explained 9.2% of the variance, but explained variance increased to 43.7% when patient global was added. The mean clinic fatigue scores were RA 4.9, OA 4.8, FM 7.6; mean survey scores were RA 4.5, OA 4.4, FM 6.3. Adjusted for age and sex, RA and OA fatigue scores were not significantly different. CONCLUSION: Inflammatory components of the DAS28 contribute minimally to fatigue. RA and OA fatigue levels do not differ. Fatigue is not an inflammatory variable and has no unique association with RA or RA therapy.

The problem of rheumatoid arthritis disease activity and remission in clinical practice.

OBJECTIVE: To investigate the results and feasibility of available scales to measure minimal disease activity (MDA) and remission in rheumatoid arthritis (RA) in the clinic. METHODS: We studied 849 consecutive patients with RA seen in a community rheumatology practice for routine RA care by 4 rheumatologists, beginning in March 2007 and ending in August 2007. Patients and physicians completed a simple form at each visit. We calculated the Disease Activity Score 28 (DAS28), Clinical Disease Activity Index (CDAI), physician assessment of global activity, and the Patient Activity Scale (PAS-II). From these we calculated remission and MDA prevalence in this community practice. RESULTS: The DAS28 could not be determined in more than 50% of patients because of referring physician and insurance company restrictions. Remission prevalences differed by assessment method: DAS28 28.5%, CDAI 6.5%-8.1%, physician global 12.5%, PAS 13.7%. MDA was 26.9% using the American College of Rheumatology core set variables, 34.7% using the DAS28, and 26.8% using the PAS-II. The kappa statistic was only fair (0.2 to 0.4) for most comparisons between assessment methods. No significant differences were noted for remission and MDA according to biologic therapy. CONCLUSION: The CDAI and/or physician global and PAS-II are simple acceptable ways to measure RA activity in the clinic, but results differ strikingly according to method. Further standardization appears to be required for full implementation of the CDAI. Caution is urged before using these methods for regulatory purposes.