Roland Duculan

Enhanced rho-associated protein kinase activation in patients with systemic lupus erythematosus.

OBJECTIVE Rho-associated protein kinases (ROCKs) have been implicated in the pathogenesis of cardiovascular and renal disorders. We recently showed that ROCKs could regulate the differentiation of murine Th17 cells and the production of interleukin-17 (IL-17) and IL-21, two cytokines associated with systemic lupus erythematosus (SLE). The goal of this study was to assess ROCK activation in human Th17 cells and to evaluate ROCK activity in SLE patients. METHODS An enzyme-linked immunosorbent assay (ELISA)-based ROCK activity assay was used to evaluate ROCK activity in human cord blood CD4+ T cells differentiated under Th0 or Th17 conditions. We then performed a cross-sectional analysis of 28 SLE patients and 25 healthy matched controls. ROCK activity in peripheral blood mononuclear cell (PBMC) lysates was determined by ELISA. Cytokine and chemokine profiles were analyzed by ELISA. RESULTS Human cord blood CD4+ T cells differentiated under Th17 conditions expressed higher levels of ROCK activity than did CD4+ T cells stimulated under Th0 conditions. Production of IL-17 and IL-21 was inhibited by the addition of a ROCK inhibitor. SLE PBMCs expressed significantly higher levels of ROCK activity than did healthy control PBMCs (1.25 versus 0.56; P = 0.0015). Sixteen SLE patients (57%) expressed high levels of ROCK (optical density at 450 nm >1). Disease duration, lymphocyte count, and azathioprine use were shown to be significant independent predictors of ROCK activity in multivariable analyses. CONCLUSION Consistent with previous results in the murine system, increased ROCK activation was associated with Th17 cell differentiation. Moreover, enhanced ROCK activity was observed in a subgroup of SLE patients. These data support the concept that the ROCK pathway could represent an important therapeutic target for SLE.

A surge in anti-dsDNA titer predicts a severe lupus flare within six months

Objective Rising anti-double-stranded (ds) DNA titers have been shown by some, but not all, studies to be predictive of disease flares in systemic lupus erythematosus (SLE). We hypothesized that a rapid and substantial rise in anti-dsDNA titer (anti-dsDNA surge) would be a good predictor of a clinically important SLE flare. Methods A matched case-control study was conducted in an academic rheumatology practice setting. Our primary endpoint was the occurrence of a severe SELENA-SLEDAI (SS) flare within six months of an anti-dsDNA surge, and secondary endpoints were mild/moderate SS flares, as well as BILAG A and B renal flares. Cases were identified as those patients whose disease course included a surge of anti-dsDNA, defined as an increase of anti-dsDNA titer by the Crithidia luciliae immunofluorescence (CLIF) assay from 0 to 3+/4+, or from 1+ to 4+, within a period of less than 12 months. The date of the anti-dsDNA surge was defined as Day 0. Two control SLE patients were identified for each case and were matched for age, sex, race, and visit date closest to case Day 0, but without an anti-dsDNA surge. Logistic regression models were used to detect associations between anti-dsDNA surges and severe SS flares. Result A higher proportion of cases, compared to controls, experienced a severe SS flare within six months of Day 0 (OR 6.3 (95% confidence intervals 2.0–19.9), p = 0.02). Associations with all flares and hospitalizations for flares were also observed. However, an anti-dsDNA surge was not predictive of a renal flare. Conclusion An anti-dsDNA surge predicts the subsequent development of a severe SS flare within six months. Physicians should closely monitor such patients and treat promptly at the first sign of clinical activity.

Proportion of Expectations Fulfilled: A New Method to Report Patient-centered Outcomes of Spine Surgery.

Study Design. Prospective lumbar and cervical surgery cohorts. Objective. Compare fulfillment of expectations with traditional global outcomes and provide evidence for its validity. Summary of Background Data. New lumbar and cervical spine surgery Expectations Surveys can be used to measure fulfillment of expectations and their performance should be compared with existing outcomes. Methods. Three hundred thirty-six lumbar and 133 cervical spine surgery patients preoperatively completed valid 20-item Expectations Surveys measuring symptoms, function, and psychological well-being. Approximately 2 years postoperatively patients rated how much improvement they received for each item. The proportion of expectations fulfilled was compared with traditional outcomes, including global satisfaction and change in standard spine questionnaires, with correlation coefficients (r) and areas under receiver operator characteristic curves (AUC). Results. Ninety percent of lumbar patients had some expectations fulfilled (24% had all expectations fulfilled completely or exceeded). The mean proportion of expectations fulfilled was 0.66 and was associated with satisfaction (r = 0.73 (95% CI 0.68–0.78); AUC = 0.92 (95% CI 0.89–0.95) (P < 0.0001)). Based on the association with satisfaction, a clinically important proportion of expectations fulfilled for lumbar surgery is approximately 0.60 (sensitivity 0.90, specificity 0.79). Ninety-one percent of cervical patients had some expectations fulfilled (31% had all expectations fulfilled completely or exceeded). The mean proportion of expectations fulfilled was 0.78 and was associated with satisfaction (r = 0.62 (95% CI 0.50–0.72); AUC = 0.92 (95% CI 0.87–0.97) (P < 0.0001)). Based on the association with satisfaction, a clinically important proportion of expectations fulfilled for cervical surgery is approximately 0.62 (sensitivity 0.91, specificity 0.80). Conclusion. The proportion of expectations fulfilled is a new patient-centered outcome that measures results of spine surgery. Unique features of this novel outcome are that it requires prospectively acquired pre- and postoperative data, provides details about in what ways patients believe surgery did and did not meet goals, and offers surgeons opportunities to address unfilled expectations directly. Level of Evidence: 1

Fulfillment of patients' expectations of lumbar and cervical spine surgery

BACKGROUND CONTEXT Fulfillment of expectations is an important outcome of spine surgery. PURPOSE The study aimed to compare fulfillment of expectations after surgery with preoperatively stated expectations. STUDY DESIGN This is a prospective cohort study. PATIENT SAMPLE The sample included patients who had lumbar and cervical spine surgeries. OUTCOME MEASURES The outcome measures were self-report valid surveys-[blinded] Lumbar Spine Surgery Expectations Survey and [blinded] Cervical Spine Surgery Expectations Survey-Oswestry Disability Index (ODI), and Neck Disability Index (NDI). METHODS Patients preoperatively completed a valid 20-item lumbar or cervical spine surgery Expectations Survey measuring the amount of improvement expected for symptoms, physical function, and mental well-being. Two years postoperatively, patients were asked about fulfillment of each expectation; a proportion was calculated as the amount of improvement received versus the amount of improvement expected. The proportion ranges from 0 (no expectations fulfilled) to 1 (all expectations fulfilled as expected), to >1 (expectations surpassed). Patients also completed the ODI or NDI, as well as questions about 2-year interval events, such as subsequent surgery. RESULTS Among the 366 patients who had lumbar surgery, 90% had at least some of their expectations fulfilled (15% expectations surpassed, 9% expectations fulfilled as expected, and 66% expectations fulfilled somewhat) and 10% had none of their expectations fulfilled; the mean proportion of expectations fulfilled was .66. In multivariable analysis, variables that were associated with a lower proportion of expectations fulfilled were more preoperative expectations, not working full-time, previous spine surgery, surgery for more vertebral levels, subsequent spine surgery, and less improvement in pre- to postoperative ODI and pain scores (p≤.05 for all variables). Among the 133 patients who had cervical surgery, 91% had at least some of their expectations fulfilled (23% expectations surpassed, 8% expectations fulfilled as expected, and 60% expectations fulfilled somewhat) and 9% had none of their expectations fulfilled; the mean proportion of expectations fulfilled was .78. In multivariable analysis, variables that were associated with a lower proportion of expectations fulfilled were more preoperative expectations and less improvement in pre- to postoperative NDI and pain scores (p≤.05 for all variables). CONCLUSIONS Fulfillment of expectations after spine surgery is associated with multiple pre- and postoperative variables, including the amount of improvement expected preoperatively.

Improvement in Pain after Lumbar Spine Surgery: The Role of Preoperative Expectations of Pain Relief.

Objectives: Improvement in pain is a major expectation of patients undergoing lumbar spine surgery. Materials and Methods: Among 422 patients, the goal of this prospective study was to measure 2-year postoperative pain and to determine whether this outcome varied according to patient and clinical characteristics, including amount of pain relief expected preoperatively. Before surgery patients completed valid questionnaires that addressed clinical characteristics and expectations for pain improvement. Two years after surgery patients reported how much pain improvement they actually received. Results: The mean age was 56 years old and 55% were men. Two years after surgery 11% of patients reported no improvement in pain, 28% reported a little to moderate improvement, 44% reported a lot of improvement, and 17% reported complete improvement. In multivariable analysis, patients reported less pain improvement if, before surgery, they expected greater pain improvement (odds ratio [OR] 1.4), had a positive screen for depression (OR 1.7), were having revision surgery (OR 1.6), had surgery at L4 or L5 (OR 2.5), had a degenerative diagnosis (OR 1.6), and if, after surgery, they had another surgery (OR 2.8) and greater back (OR 1.3) and leg (OR 1.1) pain (all variables P⩽0.05). Conclusions: Pain is not uncommon after lumbar surgery and is associated with a network of clinical, surgical, and psychological variables. This study provides evidence that patients’ expectations about pain are an independent variable in this network. Because expectations are potentially modifiable this study supports addressing pain-related expectations with patients before surgery through discussions with surgeons and through formal preoperative patient education.

A 26‐year‐old white man with a systemic lupus erythematosus flare and acute multiorgan ischemia: Vasculitis or thrombosis?

History of the present illness The patient was in his usual state of health until 2 months before admission, when he developed pain and stiffness in his right shoulder, neck, and back after playing softball. His symptoms progressively worsened despite manipulation by a chiropractor, and he developed new pain in his soles. This was diagnosed as plantar fasciitis and he was given a topical steroid injection and a short course of methylprednisolone. This treatment improved his pain, but at its completion, he developed disabling diffuse arthralgias in his shoulders, elbows, knees, and feet, along with fevers, anorexia, and weight loss. Worsening symptoms prompted hospitalization in another institution 3 weeks before admission, where he was febrile up to 103°F and hypertensive (144/100 mm Hg). An extensive evaluation revealed elevated inflammatory markers, including erythrocyte sedimentation rate (ESR; 102 mm/hour), C-reactive protein level (56 mg/liter), positive antinuclear antibodies (ANAs; 1:640), strongly positive anti–doublestranded DNA (anti-dsDNA) titers, low levels of C4 (9 mg/dl, normal range 16–38), prolonged prothrombin time (16.2 seconds, normal range 10–13), prolonged activated partial thromboplastin time (60 seconds, normal range 27– 38), and positive lupus anticoagulant (LAC) by dilute Russell’s viper venom time. His urine analysis showed proteinuria (0.440 gm protein/gm creatinine), hematuria (11–25 red blood cells [RBCs]/high-power field [hpf]), and pyuria (3–10 white blood cells [WBCs]/hpf). Antibodies to Sm/RNP, Ro/SSA, and La/SSB; anticardiolipin antibodies; antineutrophil cytoplasmic antibodies (ANCAs); and anti– cyclic citrullinated peptide antibodies were negative, and creatine phosphokinase was normal. An infectious disease evaluation was performed and was negative for all pathogens, including Lyme disease, human immunodeficiency virus, and viral hepatitis. Renal ultrasound and Doppler were performed and were negative for renal pathology and venous thrombosis. He was placed on prednisone 10 mg orally twice daily, losartan 50 mg daily, and aspirin 81 mg daily, and his fevers resolved with some improvement in joint pains. Two weeks before admission, he was evaluated by a rheumatologist who discontinued aspirin in anticipation of a kidney biopsy to rule out lupus nephritis. Laboratory evaluation again revealed persistent proteinuria (2 ), hematuria (10–20 RBCs/hpf), C4 hypocomplementemia (C3 111 mg/dl, C4 9 mg/dl), and strongly positive anti-dsDNA. The patient could not tolerate tapering of prednisone to 15 mg and he stayed at 17.5 mg daily. He presented to our clinic 3 days before admission and his scheduled kidney biopsy. Over the course of the previous week he had developed a few small tender erythematous skin lesions and some skin excoriation on his fingers and palms. He also experienced numbness of his fingertips and bilateral soles for 2 or 3 days. Weight loss of 30–33 pounds over the course of 3 months with decreased appetite, nausea, and mild diarrhea was noted. On examination, he appeared ill with a blood pressure (BP) of 140/100 mm Hg, and a heart rate of 96 beats per minute. There were a few erythematous lesions on his palate, as well as small tender erythematous nonblanching lesions in his palms, fingertips, and toe tips with rare splinter hemorrhages. He had dysesthesia/hypoesthesia in bilateral palms and finSupported by the Mary Kirkland Center for Lupus Research. Julie Cherian, MD: Stony Brook University Hospital, Stony Brook, New York; Roland Duculan, MD, Mary K. Crow, MD, Kyriakos A. Kirou, MD: Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, New York, New York; Isabelle Amigues, MD: Teaching Hospital Lyon Sud, Pierre Benite, Rhone Alpes, France. Drs. Crow and Kirou have filed a patent application for an interferon assay. Address correspondence to Kyriakos A. Kirou, MD, Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail: kirouk@hss.edu. Submitted for publication October 21, 2010; accepted in revised form January 18, 2011. Arthritis Care & Research Vol. 63, No. 5, May 2011, pp 766–774 DOI 10.1002/acr.20439

Healthy Physical Activity Levels Below Recommended Thresholds Two Years After Lumbar Spine Surgery.

Study Design. Prospective analysis. Objective. To quantify physical activity after lumbar surgery and identify spine-related variables associated with not meeting recommended activity thresholds. Summary of Background Data. National guidelines recommend ≥150 minutes/week of moderate-intensity activity; however, only 52% of the general population meets this threshold. For patients not participating in exercise/sports, ≥1400 kcal/week of energy expenditure, including from walking, is another threshold. Potential spine-related variables associated with not meeting these thresholds after lumbar surgery have not been described. Methods. Clinical data were collected pre- and intraoperatively for 422 patients. Patients were contacted 2.2 years postoperatively to measure several patient-reported outcomes, including physical activity with the Paffenbarger Physical Activity and Exercise Index. The Paffenbarger Physical Activity and Exercise Index encompasses blocks walked, stairs climbed, and exercise/sports. Minutes/week of activity and total kcal/week were calculated and compared to recommended thresholds. Spine-related variables associated with not meeting thresholds were assessed in multivariable analyses. Results. Mean age was 57 years, 55% were men, 80% had degenerative diagnoses, and 63% had multilevel surgery. Only 35% met ≥1400 kcal/week; in multivariable analysis, not meeting this threshold was associated with revision surgery (OR 0.53, CI 0.30–0.95), surgery at ≥3 levels (OR 0.51, CI 0.31–0.84), and more postoperative back pain (OR 0.38, CI 0.24–0.59) (P <0.05 for all variables). Only 26% met ≥150 minutes/week; in multivariable analysis, not meeting this threshold was associated with degenerative diagnoses (OR 0.53, CI 0.31–0.92), subsequent spine surgery (OR 0.17, CI 0.05–0.58), and more postoperative back pain (OR 0.41, CI 0.25–0.67) (P <0.05 for all variables). All multivariable associations persisted after controlling for demographic characteristics. Conclusion. Physical activity is below population norms after lumbar surgery and is associated with spine-related variables. Patients with stable spine conditions should be encouraged to engage in prudent physical activity to decrease their risk of long-term adverse health outcomes due to inactivity. Level of Evidence: 3

Enhanced Rho-Associated Protein Kinase Activation in Patients With Systemic Lupus Erythematosus: Rock Activation in SLE

OBJECTIVE Rho-associated protein kinases (ROCKs) have been implicated in the pathogenesis of cardiovascular and renal disorders. We recently showed that ROCKs could regulate the differentiation of murine Th17 cells and the production of interleukin-17 (IL-17) and IL-21, two cytokines associated with systemic lupus erythematosus (SLE). The goal of this study was to assess ROCK activation in human Th17 cells and to evaluate ROCK activity in SLE patients. METHODS An enzyme-linked immunosorbent assay (ELISA)-based ROCK activity assay was used to evaluate ROCK activity in human cord blood CD4+ T cells differentiated under Th0 or Th17 conditions. We then performed a cross-sectional analysis of 28 SLE patients and 25 healthy matched controls. ROCK activity in peripheral blood mononuclear cell (PBMC) lysates was determined by ELISA. Cytokine and chemokine profiles were analyzed by ELISA. RESULTS Human cord blood CD4+ T cells differentiated under Th17 conditions expressed higher levels of ROCK activity than did CD4+ T cells stimulated under Th0 conditions. Production of IL-17 and IL-21 was inhibited by the addition of a ROCK inhibitor. SLE PBMCs expressed significantly higher levels of ROCK activity than did healthy control PBMCs (1.25 versus 0.56; P = 0.0015). Sixteen SLE patients (57%) expressed high levels of ROCK (optical density at 450 nm >1). Disease duration, lymphocyte count, and azathioprine use were shown to be significant independent predictors of ROCK activity in multivariable analyses. CONCLUSION Consistent with previous results in the murine system, increased ROCK activation was associated with Th17 cell differentiation. Moreover, enhanced ROCK activity was observed in a subgroup of SLE patients. These data support the concept that the ROCK pathway could represent an important therapeutic target for SLE.

Enhanced ROCK Activation in Patients with Systemic Lupus Erythematosus

OBJECTIVE Rho-associated protein kinases (ROCKs) have been implicated in the pathogenesis of cardiovascular and renal disorders. We recently showed that ROCKs could regulate the differentiation of murine Th17 cells and the production of interleukin-17 (IL-17) and IL-21, two cytokines associated with systemic lupus erythematosus (SLE). The goal of this study was to assess ROCK activation in human Th17 cells and to evaluate ROCK activity in SLE patients. METHODS An enzyme-linked immunosorbent assay (ELISA)-based ROCK activity assay was used to evaluate ROCK activity in human cord blood CD4+ T cells differentiated under Th0 or Th17 conditions. We then performed a cross-sectional analysis of 28 SLE patients and 25 healthy matched controls. ROCK activity in peripheral blood mononuclear cell (PBMC) lysates was determined by ELISA. Cytokine and chemokine profiles were analyzed by ELISA. RESULTS Human cord blood CD4+ T cells differentiated under Th17 conditions expressed higher levels of ROCK activity than did CD4+ T cells stimulated under Th0 conditions. Production of IL-17 and IL-21 was inhibited by the addition of a ROCK inhibitor. SLE PBMCs expressed significantly higher levels of ROCK activity than did healthy control PBMCs (1.25 versus 0.56; P = 0.0015). Sixteen SLE patients (57%) expressed high levels of ROCK (optical density at 450 nm >1). Disease duration, lymphocyte count, and azathioprine use were shown to be significant independent predictors of ROCK activity in multivariable analyses. CONCLUSION Consistent with previous results in the murine system, increased ROCK activation was associated with Th17 cell differentiation. Moreover, enhanced ROCK activity was observed in a subgroup of SLE patients. These data support the concept that the ROCK pathway could represent an important therapeutic target for SLE.

Successful lumbar surgery results in improved psychological well-being: a longitudinal assessment of depressive and anxiety symptoms

BACKGROUND CONTEXT Preoperative psychological symptoms predict surgical outcomes. The impact of surgical outcomes on psychological well-being, however, has not been delineated. PURPOSE This study aimed to compare pre- with postoperative depressive and anxiety symptoms based on success of surgery, defined as fulfilled expectations and improvement in disability and pain. STUDY DESIGN/SETTING A prospective 2-year longitudinal study in a tertiary care center was carried out. PATIENT SAMPLE The sample consisted of 276 patients who underwent lumbar surgery. OUTCOME MEASURES The Geriatric Depression Scale (GDS) and the Spielberger State-Trait Anxiety Inventory (STAI) were the outcome measures. METHODS Patients completed the following validated surveys several days before and again 2 years after surgery: the GDS with a set threshold for a positive screen for depression; the STAI with population norms used as threshold values; the Oswestry Disability Index (ODI); a numerical pain rating; and the Expectations Survey measuring amount of improvement expected. Dependent variables were pre- to postoperative within-patient change in GDS and STAI scores. Independent variables were three outcomes of surgery: proportion of expectations fulfilled, and changes in ODI scores and pain ratings. Analyses were conducted with GDS and STAI scores as continuous variables and according to threshold values, and for expectations, ODI and pain according to minimum clinically important differences (MCIDs). RESULTS Mean age was 55, 56% were men, and 78% had degenerative diagnoses. For depressive symptoms, 41% screened positive preoperatively and 16% screened positive postoperatively; 72% had some improvement. In multivariable analysis adjusted for age, gender, comorbidity, diagnosis, and surgical invasiveness, depressive symptoms improved more for more expectations fulfilled (p<.0001), more ODI improvement (p<.0001), and more pain improvement (p=.001). For anxiety symptoms: 59% were worse than population norms preoperatively and 26% were worse postoperatively; 73% had some improvement. In adjusted multivariable analyses, anxiety symptoms improved more for more expectations fulfilled (p=.0002), more ODI improvement (p<.0001), and more pain improvement (p=.03). Similar results were obtained according to threshold values and MCIDs. CONCLUSION Substantial improvements in psychological well-being resulted after surgery among patients with favorable spine-specific outcomes.