Suzanne Kafaja

American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis

In the United States, approximately 35% of adults with Systemic Lupus Erythematosus (SLE) have clinical evidence of nephritis at the time of diagnosis; with an estimated total of 50–60% developing nephritis during the first 10 years of disease [1–4]. The prevalence of nephritis is significantly higher in African Americans and Hispanics than in Caucasians, and is higher in men than in women. Renal damage is more likely to develop in non-Caucasian groups [2–4]. Overall survival in patients with SLE is approximately 95% at 5 years after diagnosis and 92% at 10 years [5, 6]. The presence of lupus nephritis significantly reduces survival, to approximately 88% at 10 years, with even lower survival in African Americans [5, 6]. The American College of Rheumatology (ACR) last published guidelines for management of systemic lupus erythematosus (SLE) in 1999 [7]. That publication was designed primarily for education of primary care physicians and recommended therapeutic and management approaches for many manifestations of SLE. Recommendations for management of lupus nephritis (LN) consisted of pulse glucocorticoids followed by high dose daily glucocorticoids in addition to an immunosuppressive medication, with cyclophosphamide viewed as the most effective immunosuppressive medication for diffuse proliferative glomerulonephritis. Mycophenolate mofetil was not yet in use for lupus nephritis and was not mentioned. Since that time, many clinical trials of glucocorticoids-plus-immunosuppressive interventions have been published, some of which are high quality prospective trials, and some not only prospective but also randomized. Thus, the ACR determined that a new set of management recommendations was in order. A combination of extensive literature review and the opinions of highly qualified experts, including rheumatologists, nephrologists and pathologists, has been used to reach the recommendations. The management strategies discussed here apply to lupus nephritis in adults, particularly to those receiving care in the United States of America, and include interventions that were available in the United States as of April 2011. While these recommendations were developed using rigorous methodology, guidelines do have inherent limitations in informing individual patient care; hence the selection of the term “recommendations.” While they should not supplant clinical judgment or limit clinical judgment, they do provide expert advice to the practicing physician managing patients with lupus nephritis.

Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial

Summary BACKGROUND Twelve months of oral cyclophosphamide (CYC) has been shown to alter the progression of scleroderma-related interstitial lung disease (SSc-ILD) when compared to placebo. However, toxicity was a concern and without continued treatment the efficacy disappeared by 24 months. We hypothesized that a two-year course of mycophenolate mofetil (MMF) would be safer, better tolerated and produce longer lasting improvements than CYC. METHODS Patients with SSc-ILD meeting defined dyspnea, pulmonary function and high-resolution computed tomography (HRCT) criteria were randomized in a double-blind, two-arm trial at 14 medical centers. MMF (target dose 1500 mg twice daily) was administered for 24 months in one arm and oral CYC (target dose 2·0 mg/kg/day) administered for 12 months followed by placebo for 12 months in the other arm. The primary endpoint, change in forced vital capacity as a percent of the predicted normal value (FVC %) over the course of 24 months, was assessed in a modified intention-to-treat analysis using an inferential joint model combining a mixed effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data. The study was registered with ClinicalTrials.gov, number NCT00883129, and is closed. RESULTS Between November, 2009, and January, 2013, 142 patients were randomized. 126 patients (63 MMF; 63 CYC) with acceptable baseline HRCT studies and at least one outcome measure were included in the analysis. The adjusted FVC % (primary endpoint) improved from baseline to 24 months by 2.17 in the MMF arm (95% CI, 0.53–3.84) and 2·86 in the CYC arm (95% confidence interval 1·19–4·58) with no significant between-treatment difference (p=0·24), indicating that the trial was negative for the primary endpoint. However, in a post-hoc analysis of the primary endpoint, within-treatment improvements from baseline to 24 months were noted in both the CYC and MMF arms. A greater number of patients on CYC than on MMF prematurely withdrew from study drug (32 vs 20) and failed treatment (2 vs 0), and the time to stopping treatment was significantly shorter in the CYC arm (p=0·019). Sixteen deaths occurred (11 CYC; 5 MMF) with most due to progressive ILD. Leukopenia (30 vs 4 patients) and thrombocytopenia (4 vs 0 patients) occurred more often in patients treated with CYC. In post-hoc analyses, within- (but not between-) treatment improvements were also noted in defined secondary outcomes including skin score, dyspnea and whole-lung HRCT scores. INTERPRETATION Treatment of SSc-ILD with MMF for two years or CYC for one year both resulted in significant improvements in pre-specified measures of lung function, dyspnea, lung imaging, and skin disease over the 2-year course of the study. While MMF was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than CYC was not confirmed. These findings support the potential clinical impact of both CYC and MMF for progressive SSc-ILD, as well as the current preference for MMF due to its better tolerability and toxicity profile. FUNDING National Heart, Lung and Blood Institute/National Institutes of Health with drug supply provided by Hoffmann-La Roche/Genentech.

Lung Transplant Outcomes in Systemic Sclerosis with Significant Esophageal Dysfunction. A Comprehensive Single-Center Experience

RATIONALE Consideration of lung transplantation in patients with systemic sclerosis (SSc) remains guarded, often due to the concern for esophageal dysfunction and the associated potential for allograft injury and suboptimal post-lung transplantation outcomes. OBJECTIVES The purpose of this study was to systematically report our single-center experience regarding lung transplantation in the setting of SSc, with a particular focus on esophageal dysfunction. METHODS We retrospectively reviewed all lung transplants at our center from January 1, 2000 through August 31, 2012 (n = 562), comparing the SSc group (n = 35) to the following lung transplant diagnostic subsets: all non-SSc (n = 527), non-SSc diffuse fibrotic lung disease (n = 264), and a non-SSc matched group (n = 109). We evaluated post-lung transplant outcomes, including survival, primary graft dysfunction, acute rejection, bronchiolitis obliterans syndrome, and microbiology of respiratory isolates. In addition, we defined severe esophageal dysfunction using esophageal manometry and esophageal morphometry criteria on the basis of chest computed tomography images. For patients with SSc referred for lung transplant but subsequently denied (n = 36), we queried the reason(s) for denial with respect to the concern for esophageal dysfunction. MEASUREMENTS AND MAIN RESULTS The 1-, 3-, and 5-year post-lung transplant survival for SSc was 94, 77, and 70%, respectively, and similar to the other groups. The remaining post-lung transplant outcomes evaluated were also similar between SSc and the other groups. Approximately 60% of the SSc group had severe esophageal dysfunction. Pre-lung transplant chest computed tomography imaging demonstrated significantly abnormal esophageal morphometry for SSc when compared with the matched group. Importantly, esophageal dysfunction was the sole reason for lung transplant denial in a single case. CONCLUSIONS Relative to other lung transplant indications, our SSc group experienced comparable survival, primary graft dysfunction, acute rejection, bronchiolitis obliterans syndrome, and microbiology of respiratory isolates, despite the high prevalence of severe esophageal dysfunction. Esophageal dysfunction rarely precluded active listing for lung transplantation.

Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma

BACKGROUND Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem‐cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma. METHODS We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem‐cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event‐free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score. RESULTS In the intention‐to‐treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per‐protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event‐free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan–Meier estimates of event‐free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease‐modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment‐related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group. CONCLUSIONS Myeloablative autologous hematopoietic stem‐cell transplantation achieved long‐term benefits in patients with scleroderma, including improved event‐free and overall survival, at a cost of increased expected toxicity. Rates of treatment‐related death and post‐transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530.)

Defining skin ulcers in systemic sclerosis: systematic literature review and proposed World Scleroderma Foundation (WSF) definition

Purpose There is a lack of a valid definition for skin ulcers in systemic sclerosis (SSc) to be used in clinical trials. Our aim was to develop a consensus definition for SSc skin ulcers based on the results of a systematic literature review (SLR) for skin ulcer definitions and expert opinion; and to evaluate its face validity, reliability and feasibility. Methods SLR for skin ulcer definitions was conducted using PubMed, Web of Science, and Cochrane library for articles published from inception to January 1st, 2016. SSc experts were to discuss the definition categories and vote for the relevant terms. Reliability of the definition was tested in a second expert meeting, seven SSc experts evaluated 7 SSc patients with skin lesions twice. Face validity and feasibility were evaluated by sending out case report forms (CRFs) to four SSc experts, who were each asked to use the definition in five patients. Results A total of 3464 abstracts and titles were screened, and 446 articles were fully evaluated. Of these, 66 met eligibility criteria and skin ulcer definitions were extracted. SSc experts discussed, refined, and voted on the consensus definition using nominal process. Kappa for inter-rater agreement was 0.51 and for intra-rater agreement was 0.90. The mean time to decide if the lesion is an ulcer was 7.4 seconds. All investigators endorsed the face validity of the new definition in the CRFs. Conclusions Using an SLR and a nominal technique, we developed a preliminary consensus-based definition of SSc skin ulcers. Face validity, feasibility and reliability were demonstrated for the developed definition.

Evaluation of the Satisfaction with Appearance Scale and Its Short Form in Systemic Sclerosis: Analysis from the UCLA Scleroderma Quality of Life Study

Objective. Changes in appearance are common in patients with systemic sclerosis (SSc) and can significantly affect well-being. The Satisfaction with Appearance Scale (SWAP) measures body image dissatisfaction in persons with visible disfigurement; the Brief-Satisfaction with Appearance Scale (Brief-SWAP) is its short form. The present study evaluated the reliability and validity of SWAP and Brief-SWAP scores in SSc. Methods. A sample of 207 patients with SSc participating in the University of California, Los Angeles Scleroderma Quality of Life Study completed the SWAP. Brief-SWAP scores were derived from the SWAP. The structural validity of both measures was investigated using confirmatory factor analysis. Internal consistency reliability of total and subscale scores was assessed with Cronbach’s alpha coefficients. Convergent and divergent validity was evaluated using the Center for Epidemiological Studies Depression Scale, the Health Assessment Questionnaire-Disability Index, and the Medical Outcomes Study Short Form-36 questionnaire. Results. SWAP and Brief-SWAP total scores were highly correlated (r = 0.97). The 4-factor structure of the SWAP fit well descriptively; the 2-factor structure of the Brief-SWAP fit well descriptively and statistically. Internal consistencies for total and subscale scores were good, and results supported convergent and divergent validity. Conclusion. Both versions are suitable for use in patients with SSc. The Brief-SWAP is most efficient; the full SWAP yields additional subscales that may be informative in understanding body image issues in patients with SSc.

Improved Cough and Cough-Specific Quality of Life in Patients Treated for Scleroderma-Related Interstitial Lung Disease: Results of Scleroderma Lung Study II

Background Cough is a common symptom of scleroderma‐related interstitial lung disease (SSc‐ILD), but its relationship to other characteristics of SSc‐ILD, impact on cough‐specific quality of life (QoL), and response to therapy for SSc‐ILD have not been well studied. Methods We investigated frequent cough (FC) in patients with SSc‐ILD (N = 142) enrolled in the Scleroderma Lung Study II, a randomized controlled trial comparing mycophenolate mofetil (MMF) and oral cyclophosphamide (CYC) as treatments for interstitial lung disease (ILD). We determined the impact of FC on QoL (Leicester Cough Questionnaire [LCQ]), evaluated the change in FC in response to treatment for SSc‐ILD, and examined the relationship between gastroesophageal reflux disease (GERD) and cough during the trial. Results Study participants who reported FC at baseline (61.3%) reported significantly more dyspnea, exhibited more extensive ILD on high‐resolution CT, had a lower diffusing capacity for carbon monoxide, and reported more GERD symptoms than did those without FC. Cough‐specific QoL was modestly impaired in patients with FC (total LCQ score, 15.4 ± 3.7; normal range, 3‐21 [higher scores indicate worse QoL]). The proportion of patients with FC at baseline declined by 44% and 41% over 2 years in the CYC and MMF treatment arms, respectively, and this decline was significantly related to changes in GERD and ILD severity. Conclusions FC occurs commonly in SSc‐ILD, correlates with both the presence and severity of GERD and ILD at baseline, and declines in parallel with improvements in both ILD and GERD over a 2‐year course of therapy. Frequent cough might serve as a useful surrogate marker of treatment response in SSc‐ILD trials. Trial Registry ClinicalTrials.gov; No.: NCT00883129; URL: www.clinicaltrials.gov.

Efficacy of Mycophenolate Mofetil and Oral Cyclophosphamide on Skin Thickness: Post Hoc Analyses From Two Randomized Placebo‐Controlled Trials

To assess the efficacy of mycophenolate mofetil (MMF) and cyclophosphamide (CYC) on modified Rodnan skin score (MRSS) in participants enrolled in the Scleroderma Lung Study (SLS) I and II.

Reliability, validity and responsiveness to change of the Saint George’s Respiratory Questionnaire in early diffuse cutaneous systemic sclerosis

OBJECTIVE Dyspnoea is a common, multifactorial source of functional impairment among patients with dcSSc. Our objective was to assess the reliability, construct validity and responsiveness to change of the Saint Georges Respiratory Questionnaire (SGRQ) in patients with early dcSSc participating in a multicentre prospective study. METHODS At enrolment and 1 year, patients completed the SGRQ (a multi-item instrument with four scales: symptoms, activity, impact and total), a visual analogue scale (VAS) for breathing and the HAQ Disability Index (HAQ-DI) and underwent 6 min walk distance and pulmonary function tests, physician and patient global health assessments and high-resolution CT (HRCT). We assessed internal consistency reliability using Cronbachs α. For validity we examined the ability of the SGRQ to differentiate the presence vs absence of interstitial lung disease (ILD) on HRCT or restrictive lung disease and evaluated the 1 year responsiveness to change using pulmonary function tests and patient- and physician-reported anchors. Correlation coefficients of 0.24-0.36 were considered moderate and >0.37 was considered large. RESULTS A total of 177 patients were evaluated. Reliability was satisfactory for all SGRQ scales (0.70-0.93). All scales showed large correlations with the VAS for breathing and diffusing capacity of the lung for carbon monoxide in the overall cohort and in the subgroup with ILD. Three of the four scales in the overall cohort and the total scale in the ILD subgroup showed moderate to large correlation with the HAQ-DI and the predicted forced vital capacity (r = 0.33-0.44). Each scale discriminated between the presence and absence of ILD and restrictive lung disease (P ≤ 0.0001-0.03). At follow-up, all scales were responsive to change using different anchors. CONCLUSION The SGRQ has acceptable reliability, construct validity and responsiveness to change for use in a dcSSc population and differentiates between patients with and without ILD.

Using Optimal Test Assembly Methods for Shortening Patient-Reported Outcome Measures: Development and Validation of the Cochin Hand Function Scale-6: A Scleroderma Patient-Centered Intervention Network Cohort Study.

To develop and validate a short form of the Cochin Hand Function Scale (CHFS), which measures hand disability, for use in systemic sclerosis, using objective criteria and reproducible techniques.