Profibrotic Activation of Human Macrophages in Systemic Sclerosis.

OBJECTIVE: Genome-wide gene expression studies implicate macrophages as mediators of fibrosis in systemic sclerosis (SSc), but little is known about how these cells contribute to fibrotic activation in SSc. We undertook this study to characterize the activation profile of SSc monocyte-derived macrophages and assessed their interaction with SSc fibroblasts. METHODS: Plasma and peripheral blood mononuclear cells (PBMCs) were obtained from whole blood from SSc patients (n = 24) and age- and sex-matched healthy controls (n = 12). Monocytes were cultured with autologous or allogeneic plasma to differentiate cells into macrophages. For reciprocal activation studies, macrophages were cocultured with fibroblasts using Transwell plates. RESULTS: The gene expression signature associated with blood-derived human SSc macrophages was enriched in SSc skin in an independent cohort and correlated with skin fibrosis. SSc macrophages expressed surface markers associated with activation and released CCL2, interleukin-6, and transforming growth factor ß under basal conditions (n = 8) (P < 0.05). Differentiation of healthy donor monocytes in plasma from SSc patients conferred the immunophenotype of SSc macrophages (n = 13) (P < 0.05). Transwell experiments demonstrated that coculture of SSc macrophages with SSc fibroblasts induced fibroblast activation (n = 3) (P < 0.05). CONCLUSION: These data demonstrate that the activation profile of SSc macrophages is profibrotic. SSc macrophages are activated under basal conditions and release mediators and express surface markers associated with both alternative and inflammatory macrophage activation. These findings also suggest that activation of SSc macrophages arises from soluble factors in local microenvironments. These studies implicate macrophages as likely drivers of fibrosis in SSc and suggest that therapeutic targeting of these cells may be beneficial in ameliorating disease in SSc patients.

Pain intensity, depressive symptoms, and functional limitations among older adults with serious mental illness.

OBJECTIVE: To examine pain-related activity interference as a mediator for the relationship between pain intensity and depressive symptoms among older adults with serious mental illness (SMI). METHOD: Ordinary least-squares regressions were used to investigate the mediation analysis among older adults with SMI (n = 183) from community mental health centers. Analyses used secondary data from the HOPES intervention study. RESULTS: Higher pain intensity was associated with greater pain-related activity interference. Higher pain intensity and pain-related activity interference were also associated with elevated depressive symptoms. Finally, greater pain-related activity interference significantly mediated the association between higher pain intensity and elevated depressive symptoms. CONCLUSIONS: These findings demonstrate that pain and depressive symptoms may be linked to functional limitations. Clinicians and researchers in the mental health field should better address pain-related activity interference among older adults with SMI, especially among those with higher pain intensity and elevated depressive symptoms.

Prevalence rates of arthritis among US older adults with varying degrees of depression: Findings from the 2011 to 2014 National Health and Nutrition Examination Survey.

OBJECTIVE: Arthritis and depressive symptoms often interact and negatively influence one another to worsen mental and physical health outcomes. Better characterization of arthritis rates among older adults with different levels of depressive symptoms is an important step toward informing mental health professionals of the need to detect and respond to arthritis and related mental health complications. The primary objective is to determine arthritis rates among US older adults with varying degrees of depression. METHODS: Using National Health and Nutrition Examination Survey 2011 to 2014 data (N = 4792), we first identified participants aged ≥50 years. Measures screened for depressive symptoms and self-reported doctor-diagnosed arthritis. Weighted logistic regression models were conducted. RESULTS: Prevalence of arthritis was 55.0%, 62.9%, and 67.8% in participants with minor, moderate, and severe depression, respectively. In both unadjusted and adjusted regression models, a significant association between moderate depression and arthritis persisted. There were also significant associations between minor and severe depression with arthritis. CONCLUSIONS: Arthritis is commonly reported in participants with varying degrees of depression. This study highlights the importance of screening for and treating arthritis-related pain in older adults with depressive symptoms and the need for future geriatric psychiatry research on developing integrated biopsychosocial interventions for these common conditions.

Antisense Long Non-Coding RNAs Are Deregulated in Skin Tissue of Patients with Systemic Sclerosis.

Systemic sclerosis is an autoimmune disease characterized by fibrosis of skin and multiple organs of which the pathogenesis is poorly understood. We studied differentially expressed coding and non-coding genes in relation to systemic sclerosis pathogenesis with a specific focus on antisense non-coding RNAs. Skin biopsy-derived RNAs from 14 early systemic sclerosis patients and six healthy individuals were sequenced with ion-torrent and analyzed using DEseq2. Overall, 4,901 genes with a fold change >1.5 and a false discovery rate <5% were detected in patients versus controls. Upregulated genes clustered in immunologic, cell adhesion, and keratin-related processes. Interestingly, 676 deregulated non-coding genes were detected, 257 of which were classified as antisense genes. Sense genes expressed opposite of these antisense genes were also deregulated in 42% of the observed sense-antisense gene pairs. The majority of the antisense genes had a similar effect sizes in an independent North American dataset with three genes (CTBP1-AS2, OTUD6B-AS1, and AGAP2-AS1) exceeding the study-wide Bonferroni-corrected P-value (PBonf < 0.0023, Pcombined = 1.1 × 10-9, 1.4 × 10-8, 1.7 × 10-6, respectively). In this study, we highlight that together with coding genes, (antisense) long non-coding RNAs are deregulated in skin tissue of systemic sclerosis patients suggesting a novel class of genes involved in pathogenesis of systemic sclerosis.

Coexistent pulmonary granulomatosis with polyangiitis (Wegener granulomatosis) and Crohn disease.

Crohn disease (CD) may be associated with various extraintestinal manifestations, including, rarely, respiratory tract involvement. When necrobiotic pulmonary nodules are present, the differential diagnosis includes granulomatosis with polyangiitis (Wegener granulomatosis) (GPA). The respiratory tract manifestations of CD and GPA may mimic each other, complicating the diagnosis and suggesting the possible coexistence of these 2 conditions. The aim of this study was to describe the clinical, radiographic, and pathologic features of patients in whom CD and GPA coexist. We reviewed the teaching files of the authors and searched the Mayo Clinic medical records for coexistent inflammatory bowel diseases and antineutrophilic cytoplasmic antibodies (ANCA)-associated vasculitides. We reviewed in detail 97 patient charts and excluded cases of ulcerative colitis and those in whom only one of the diagnoses was present. Pulmonary and gastrointestinal biopsies were reviewed when available. We also searched the medical literature for previously published cases. We found 6 cases of coexistent CD and pulmonary GPA and 4 cases with extrapulmonary GPA; 3 cases (all with extrapulmonary GPA) have been published previously. The diagnosis of CD preceded that of GPA in 11 cases. Proteinase 3-ANCA was positive in 6 cases, negative in 2, and not reported in 5 cases. Myeloperoxidase-ANCA was negative in 6 cases and unavailable in the remainder of patients. Pathology revealed features diagnostic of GPA in all cases with necrotizing granulomatous inflammation and segmental vasculitis. Pulmonary findings in patients with CD or the presence of granulomatous colitis in patients with GPA should prompt the inclusion in the differential diagnosis of a possible coexistence of CD and GPA.

Health-related quality of life in children and adolescents with juvenile localized scleroderma.

OBJECTIVES: To examine the health-related quality of life (HRQOL) of children with juvenile localized scleroderma (JLS) and to compare them with patients with atopic dermatitis (AD) and healthy controls. METHODS: The cohorts were identified through a diagnostic index and were seen between January 1996 and December 2006. We identified 81 JLS patients to whom we age- and sex-matched 75 AD patients and 75 healthy controls. All patients were mailed a survey containing the English-language version of the German Revised Children's Quality of Life Questionnaire (KINDL) and the Children's Dermatology Life Quality Index (CDLQI). Linear regression models, adjusted for age and sex, examined differences in the KINDL and CDLQI scores. RESULTS: Survey completion rates in the JLS, AD and healthy control groups were 40, 28 and 44%, respectively. There was no difference in KINDL scores between JLS vs AD (73 vs 74, P = 0.3) and JLS vs healthy controls (73 vs 74, P = 0.8). However, CDLQI scores showed some impairment in HRQOL in JLS patients as compared with a healthy reference population, but not to the degree seen in AD (2 vs 4, P = 0.05). An exploratory analysis showed that HRQOL did not differ among the types of JLS with either measure. CONCLUSION: JLS patients have some impairment in skin disease-specific HRQOL when compared with a healthy reference population, but not as severe as that seen in AD patients. Overall HRQOL in this JLS cohort was as good as healthy controls, a reassuring finding for patients, families and healthcare providers.

Antiphospholipid antibody-associated chorea.

OBJECTIVE: To describe the clinical features, treatment, and outcomes of patients with antiphospholipid antibody (aPL)-associated chorea. METHODS: The study cohort consisted of consecutive patients with chorea evaluated between 1990 and 2005 with documented aPL at time of their neurologic diagnosis. RESULTS: Eighteen patients were identified, 4 with systemic lupus erythematosus (SLE). The 14 non-SLE patients experienced 1.6 vascular thromboses/pregnancy losses per person, while patients with SLE experienced 0.5 events/person. Four non-SLE patients (29%) and no SLE patients met criteria for antiphospholipid antibody syndrome (APS). None of these 4 tested positive for IgM anticardiolipin antibody (aCL). In contrast, 10 (71%) non-APS patients tested positive for IgM aCL. Chorea was most often bilateral, mild to moderate, and occurred once with a median age at onset of 44 and 33 years in non-SLE and SLE patients, respectively. Therapy included immunosuppression in 3 (21%) non-SLE patients and in all SLE patients. Antidopaminergic agents were used in 7 (39%). All patients responded to treatment. Five patients received anticoagulation for thrombosis and 2 died of bleeding complications, both non-SLE patients. CONCLUSION: aPL-associated chorea occurs most often in women and severity is mild to moderate. Clinical expression of chorea does not differ between those with and without SLE. Anticoagulation should be reserved for thrombosis treatment and not simply for chorea in the presence of aPL, as 2 patients died of bleeding. The absence of IgM aCL in patients with APS supports prior evidence that IgG aCL and lupus anticoagulant may be the more clinically relevant antibodies for thrombosis. However, IgM aCL may be important in patients with chorea.