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Scleroderma is an autoimmune disease with a characteristic vascular pathology. The vasculopathy associated with scleroderma is one of the major contributors to the clinical manifestations of the disease. We used immunohistochemical and mRNA in situ hybridization techniques to characterize this vasculopathy and showed with morphometry that scleroderma has true capillary rarefaction. We compared skin biopsies from 23 scleroderma patients and 24 normal controls and 7 scleroderma patients who had undergone high dose immunosuppressive therapy followed by autologous hematopoietic cell transplant. Along with the loss of capillaries there was a dramatic change in endothelial phenotype in the residual vessels. The molecules defining this phenotype are: vascular endothelial cadherin, a supposedly universal endothelial marker required for tube formation (lost in the scleroderma tissue), antiangiogenic interferon alpha (overexpressed in the scleroderma dermis) and RGS5, a signaling molecule whose expression coincides with the end of branching morphogenesis during development and tumor angiogenesis (also overexpressed in scleroderma skin. Following high dose immunosuppressive therapy, patients experienced clinical improvement and 5 of the 7 patients with scleroderma had increased capillary counts. It was also observed in the same 5 patients, that the interferon alpha and vascular endothelial cadherin had returned to normal as other clinical signs in the skin regressed, and in all 7 patients, RGS5 had returned to normal. These data provide the first objective evidence for loss of vessels in scleroderma and show that this phenomenon is reversible. Coordinate changes in expression of three molecules already implicated in angiogenesis or anti-angiogenesis suggest that control of expression of these three molecules may be the underlying mechanism for at least the vascular component of this disease. Since rarefaction has been little studied, these data may have implications for other diseases characterized by loss of capillaries including hypertension, congestive heart failure and scar formation.

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease, characterized by autoantibody production and immune complex formation, that has the potential to affect virtually any organ. Pleuropulmonary involvement occurs in 50–70% and commonly manifests as pleuritis and pleural effusion. Diffuse alveolar hemorrhage (DAH) is a rare manifestation of SLE. Most cases of DAH occur in young adults with an underlying autoimmune disease such as systemic vasculitis or Goodpasture syndrome. SLE is typically lower on the list of initial differential diagnoses of DAH due to its rarity compared to other etiologies. We present a case of a patient with dyspnea on exertion, dry coughs, lower extremity edema, and intermittent periorbital edema who ultimately succumbed to respiratory failure secondary to DAH in the setting of SLE. The diagnosis of SLE was suspected clinically and confirmed at autopsy due to her rapid clinical deterioration. DAH requires prompt intervention, and management is guided by the underlying disease process. SLE is a potentially treatable disease; therefore, timely diagnosis is important in order to exclude other noninfectious causes of DAH (reviewed in this report) and to initiate appropriate therapy.

Objective To better understand the symptoms and impacts of Raynaud phenomenon (RP) in patients with systemic sclerosis (SSc) and to evaluate the content validity and usability of a new electronic patient‐reported outcome (PRO) measure for RP: the Raynaud Diary. Methods The Raynaud Diary was developed as a daily eDiary for assessing the number and duration of symptomatic Raynaud attacks; worst pain, numbness, tingling, and discomfort in the fingers; and overall disease severity, captured using the Raynaud's Condition Score. The Raynaud Diary was debriefed in two waves of qualitative interviews with adults with self‐reported RP secondary to SSc. All interviews included open‐ended questions about participants' experiences of RP. Results Participants (N = 39) had a mean age of 55.1 years, and 87% were female. Frequently reported RP symptoms were color change (reported by all participants), numbness (90%), tingling (82%), pain (77%), and discomfort (72%). Common attack triggers included temperature‐related factors and stress. Participants reported being unable to be outside or do outdoor activities and had problems gripping objects. All participants demonstrated understanding of the Raynaud Diary instructions. Most participants indicated that they would be able to use the Raynaud Diary to record the worst severity of individual RP symptoms in the previous 24 hours. Conclusion Patients with RP secondary to SSc bear a heavy symptom burden. The Raynaud Diary is a content valid PRO measure that captures the most frequent symptoms of RP in patients with SSc.

Raynaud’s phenomenon (RP) is a condition that causes decreased blood flow to areas perfused by small blood vessels (e.g., fingers, toes). In severe cases, ulceration, gangrene, and loss of fingers may occur. Most treatments focus on inducing vasorelaxation in affected areas by the way of pharmaceuticals. Recently, animal studies have shown that vasorelaxation can be induced by non-coherent blue light (wavelength ~ 430–460 nm) through the actions of melanopsin, a photoreceptive opsin protein encoded by the OPN4 gene. To study this effect in humans, a reliable phototherapy device (PTD) is needed. We outline the construction of a PTD to be used in studying blue light effects on Raynaud’s patients. Our design addresses user safety, calibration, electromagnetic compatibility/interference (EMC/EMI), and techniques for measuring physiological responses (temperature sensors, laser Doppler flow sensors, infrared thermal imaging of the hands). We tested our device to ensure (1) safe operating conditions, (2) predictable, user-controlled irradiance output levels, (3) an ability for measuring physiological responses, and (4) features necessary to enable a double-blinded crossover study for a clinical trial. We also include in the Methods an approved research protocol utilizing our device that may serve as a starting point for clinical study. We introduced a reliable PTD for studying the effects of blue light therapy for patients suffering from Raynaud’s phenomenon and showed that our device is safe and reliable and includes the required measurement vectors for tracking treatment effects throughout the duration of a clinical study.

T cell receptors (TCRs) on T lymphocytes in an individual bind foreign peptides bound to major histocompatibility complex (MHC) molecules expressed in that individual (designated MHCA). Results from radiation bone marrow chimeras and TCR transgenic mice indicate that this complex form of antigen recognition is the result of positive selection of clones with low affinity for self peptide:MHCA complexes during development. Here we used a sensitive peptide:MHC tetramer enrichment method to quantify the role of positive selection in the generation of the preimmune polyclonal T cell repertoire in normal individuals. We made the surprising observation that mouse and human naive T cells capable of binding to foreign peptide:MHCA were present at the same frequency in hosts that expressed MHCA or a different MHC isoform (MHCB). However, most of the clones in MHCB hosts also recognized self peptide:MHCA complexes. When these \"alloreactive\" T cells were removed from the MHCB repertoire via negative selection in an MHCA host, the number of foreign peptide:MHCA-binding T cells was reduced to one fifth and many of the remaining cells did not respond to the peptide. Therefore, although positive selection on MHCA was not required to produce foreign peptide:MHCA-binding clones, it had a large effect on selecting responsive clones.

Gene-level analysis of ImmunoChip or genome-wide association studies (GWAS) data has not been previously reported for systemic sclerosis (SSc, scleroderma). The objective of this study was to analyze genetic susceptibility loci in SSc at the gene level and to determine if the detected associations were shared in African-American and White populations, using data from ImmunoChip and GWAS genotyping studies. The White sample included 1833 cases and 3466 controls (956 cases and 2741 controls from the US and 877 cases and 725 controls from Spain) and the African American sample, 291 cases and 260 controls. In both Whites and African Americans, we performed a gene-level analysis that integrates association statistics in a gene possibly harboring multiple SNPs with weak effect on disease risk, using Versatile Gene-based Association Study (VEGAS) software. The SNP-level analysis was performed using PLINK v.1.07. We identified 4 novel candidate genes (STAT1, FCGR2C, NIPSNAP3B, and SCT) significantly associated and 4 genes (SERBP1, PINX1, TMEM175 and EXOC2) suggestively associated with SSc in the gene level analysis in White patients. As an exploratory analysis we compared the results on Whites with those from African Americans. Of previously established susceptibility genes identified in Whites, only TNFAIP3 was significant at the nominal level (p = 6.13x10-3) in African Americans in the gene-level analysis of the ImmunoChip data. Among the top suggestive novel genes identified in Whites based on the ImmunoChip data, FCGR2C and PINX1 were only nominally significant in African Americans (p = 0.016 and p = 0.028, respectively), while among the top novel genes identified in the gene-level analysis in African Americans, UNC5C (p = 5.57x10-4) and CLEC16A (p = 0.0463) were also nominally significant in Whites. We also present the gene-level analysis of SSc clinical and autoantibody phenotypes among Whites. Our findings need to be validated by independent studies, particularly due to the limited sample size of African Americans.

Background Systemic sclerosis (SSc)-related interstitial lung disease (ILD) has phenotypic similarities to lung involvement in idiopathic interstitial pneumonia (IIP). We aimed to assess whether genetic susceptibility loci recently identified in the large IIP genome-wide association studies (GWASs) were also risk loci for SSc overall or severity of ILD in SSc. Methods A total of 2571 SSc patients and 4500 healthy controls were investigated from the US discovery GWAS and additional US replication cohorts. Thirteen IIP-related selected single nucleotide polymorphisms (SNPs) were genotyped and analyzed for their association with SSc. Results We found an association of SSc with the SNP rs6793295 in the LRRC34 gene (OR = 1.14, CI 95 % 1.03 to 1.25, p value = 0.009) and rs11191865 in the OBFC1 gene (OR = 1.09, CI 95 % 1.00 to 1.19, p value = 0.043) in the discovery cohort. Additionally, rs7934606 in MUC2 (OR = 1.24, CI 95 % 1.01 to 1.52, p value = 0.037) was associated with SSc-ILD defined by imaging. However, these associations failed to replicate in the validation cohort. Furthermore, SNPs rs2076295 in DSP (β = -2.29, CI 95 % -3.85 to -0.74, p value = 0.004) rs17690703 in SPPL2C (β = 2.04, CI 95 % 0.21 to 3.88, p value = 0.029) and rs1981997 in MAPT (β = 2.26, CI 95 % 0.35 to 4.17, p value = 0.02) were associated with percent predicted forced vital capacity (FVC%) even after adjusting for the anti-topoisomerase (ATA)-positive subset. However, these associations also did not replicate in the validation cohort. Conclusions Our results add new evidence that SSc and SSc-related ILD are genetically distinct from IIP, although they share phenotypic similarities.

In this 24-week trial, glucosamine and chondroitin sulfate were not more effective, alone or in combination, than placebo in controlling pain in patients with osteoarthritis of the knee. In secondary analyses, however, in the subgroup of patients with moderate-to-severe osteoarthritis, those given both glucosamine and chondroitin sulfate were more likely than those given placebo to have a decrease in pain (79 percent vs. 54 percent). In this trial, glucosamine and chondroitin sulfate were not more effective, alone or in combination, than placebo in controlling pain in patients with osteoarthritis of the knee. Osteoarthritis is the most common of the arthritides, affecting at least 20 million Americans, a number that is expected to double over the next two decades. 1 , 2 Currently available medical therapies primarily address the treatment of joint pain in patients with osteoarthritis. 3 Analgesics as well as traditional and cyclooxygenase-2–selective nonsteroidal antiinflammatory drugs (NSAIDs) have suboptimal effectiveness, 4 , 5 and there is some question about their safety, especially in the light of recent reports of increased cardiovascular risk. 6 – 8 The dietary supplements glucosamine and chondroitin sulfate have been advocated, especially in the lay media, as safe and effective options for the management . . .

T cell receptors (TCRs) on T lymphocytes in an individual bind foreign peptides bound to major histocompatibility complex (MHC) molecules expressed in that individual (designated MHC super(A)). Results from radiation bone marrow chimeras and TCR transgenic mice indicate that this complex form of antigen recognition is the result of positive selection of clones with low affinity for self peptide:MHC super(A) complexes during development. Here we used a sensitive peptide:MHC tetramer enrichment method to quantify the role of positive selection in the generation of the preimmune polyclonal T cell repertoire in normal individuals. We made the surprising observation that mouse and human naive T cells capable of binding to foreign peptide:MHC super(A) were present at the same frequency in hosts that expressed MHC super(A) or a different MHC isoform (MHC super(B)). However, most of the clones in MHC super(B) hosts also recognized self peptide:MHC super(A) complexes. When these 'alloreactive- T cells were removed from the MHC super(B) repertoire via negative selection in an MHC super(A) host, the number of foreign peptide:MHC super(A)-binding T cells was reduced to one fifth and many of the remaining cells did not respond to the peptide. Therefore, although positive selection on MHC super(A) was not required to produce foreign peptide:MHC super(A)-binding clones, it had a large effect on selecting responsive clones.