Proteinase-activated receptors are a recently described, novel family of seven-transmembrane G-protein-coupled receptors. Rather then being stimulated through ligand receptor occupancy, activation is initiated by cleavage of the N terminus of the receptor by a serine protease resulting in the generation of a new tethered ligand that interacts with the receptor within extracellular loop-2. To date, four proteinase-activated receptors (PARs) have been identified, with distinct N-terminal cleavage sites and tethered ligand pharmacology. In addition to the progress in the generation of PAR-1 antagonists, we describe the role of thrombin in such processes as wound healing and the evidence implicating PAR-1 in vascular disorders and cancer. We also identify advances in the understanding of PAR-1-mediated intracellular signaling and receptor desensitization. The cellular functions, signaling events, and desensitization processes involved in PAR-2 activation are also assessed. However, other major aspects of PAR-2 are highlighted, in particular the ability of several serine protease enzymes, in addition to trypsin, to function as activators of PAR-2. The likely physiological and pathophysiological roles for PAR-2 in skin, intestine, blood vessels, and the peripheral nervous system are considered in the context of PAR-2 activation by multiple serine proteases. The recent discovery of PAR-3 and PAR-4 as additional thrombin-sensitive PARs further highlights the complexity in assessing the effects of thrombin in several different systems, an issue that remains to be fully addressed. These discoveries have also highlighted possible PAR–PAR interactions at both functional and molecular levels. The future identification of other PARs and their modes of activation are an important future direction for this expanding field of study.

Proteinase-Activated Receptors

Proteinase-activated receptors

/pdf/american-thoracic-society-european-respiratory-society-2y7344o0v1.pdf

American Thoracic Society/European Respiratory Society: Standards in Diagnostik und Therapie bei Patienten mit Alpha-1-Antitrypsin-Mangel

Heel pain, whether plantar or posterior, is predominantly a mechanical pathology although an array of diverse pathologies including neurologic, arthritic, traumatic, neoplastic, infectious, or vascular etiologies must be considered. This clinical practice guideline (CPG) is a revision of the original 2001 document developed by the American College of Foot and Ankle Surgeons (ACFAS) heel pain committee.

The Diagnosis and Treatment of Heel Pain: A Clinical Practice Guideline–Revision 2010

The past decade has seen an explosion of data on the new group of autoantibodies known collectively as ANCA (anti-neutrophil cytoplasmic antibodies). ANCA are specific for granule proteins of granulocytes and monocytes and induce distinct fluorescence patterns, e.g. the cytoplasmic (classic) cANCA and the perinuclear pANCA. cANCA is induced by antibodies directed against Proteinase 3 (PR3; PR3-ANCA) in about 90% of all ANCA-positive sera, and pANCA is induced by antibodies against myeloperoxidase (MPO; MPO-ANCA) in about 40%. A further staining pattern, which does not have a clear cut association with a distinct granule protein, is sometimes seen in chronic inflammatory bowel diseases. PR3-ANCA are serological markers for Wegener's granulomatosis (WG) and MPO-ANCA are associated with certain subtypes of primary vasculitides. Evidence exists that both the autoantigen and ANCA participate in the pathogenesis of at least the group of 'ANCA-associated vasculitides'.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2249.1993.tb03345.x

ANCA and associated diseases: immunodiagnostic and pathogenetic aspects.

A controlled study of diffuse idiopathic skeletal hyperostosis. Clinical features and functional status.

Objective. Inflammatory bowel disease (IBD) is generally reported to be associated with spondylarthropathies (SpA) in 5%–15% of cases. Systematic colonoscopic assessment by protocol demonstrated mucosal inflammation characteristic of Crohn disease (CD) in up to one-third of patients with SpA. Video capsule endoscopy (CE) is a superior diagnostic tool to detect small bowel mucosal disease. Our study compared the accuracy of CE to standard colonoscopy for detection of inflammatory bowel lesions in patients with SpA, and to describe predictors of small bowel inflammation (SBI) in this cohort. Methods. Prospective cross-sectional study of adult patients followed for SpA. Patients were evaluated by CE and standard colonoscopy with biopsies. SBI was quantified using the Lewis Score. Additional screening tests included fecal calprotectin (FCP), C-reactive protein (CRP), and a diagnostic panel of serologic, inflammatory and genetic tests (SGI). Results. There were 64 patients recruited (53% female, mean age 42 ± 13 yrs). Chronic gastrointestinal (GI) symptoms were present in 57%. CE revealed significant SBI in 27/64 (42.2%), compared to 7/64 (10.9%) by standard colonoscopy (p = 0.035). Elevated FCP was associated with small bowel CD (OR 4.5, 95% CI 1.01–19.9; p = 0.042). No correlation was observed with presence of GI symptoms, CRP, or SGI results. Finding CD led to a change in management in 65.2% of cases. Conclusion. CE uncovered SBI consistent with CD in 42.2% of patients with SpA, with a significant incremental yield over colonoscopy of 31%. FCP levels were significantly correlated with CE results, while GI symptoms and SGI results were poor predictors of SBI.

https://www.jrheum.org/content/jrheum/early/2018/02/08/jrheum.161216.full.pdf

Detection of Crohn Disease in Patients with Spondyloarthropathy: The SpACE Capsule Study.

Four patients with rheumatoid arthritis received a combination of methotrexate and sulfasalazine for a mean of 24 months (range 20-28 months). All 4 patients experienced clinical improvement, with a reduction in the number of involved joints and in morning stiffness. In all 3 patients who had previously taken methotrexate, we were able to reduce the dosage, and the prednisone dosage was reduced in 2 of 3 patients who had previously taken that drug. No serious toxicity was observed in any patient.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/anr.1780320916

Combination methotrexate and sulfasalazine in the management of rheumatoid arthritis: case observations

OBJECTIVE: To evaluate the sensitivity, specificity, predictive value, interrater reliability and intrarater reliability of using chest radiographs as a screening tool for the diagnosis of diffuse idiopathic skeletal hyperostosis (DISH). METHODS: After review of thoracic spine radiographs by 2 "gold standard" physicians, 45 patients with DISH meeting the criteria of Resnick and Niwayama were contrasted with 106 control patients consisting of 45 with thoracic spondylosis, 45 who lacked spondylosis and whose thoracic spine radiographs were otherwise normal for the age of the patient, and 16 with ankylosing spondylitis. The chest radiographs on the 151 subjects were placed in random order and read independently using an ordinal diagnostic certainty scale by 2 "test" radiologists, experienced in reading bone radiographs. Two months later the order of chest radiographs was rerandomized and the films reassessed by the same test radiologists. RESULTS: The averages for the diagnostic and population test characteristics were sensitivity = 77%; specificity = 97%; positive predictive value = 91%; and, negative predictive value = 91%. The area under the receiver operating characteristic curves was 0.975 and 0.976 for the radiologists, and kappa was 0.93, demonstrating that interrater reliability was high. On rereading the chest radiographs, intrarater reliability was exceptional (weighted kappa of 0.90 and 0.96 for the two test radiologists). DISH patients whose chest radiographs were read as not demonstrating DISH had significantly less extensive disease. CONCLUSIONS: We conclude that chest radiographs are a reliable and valid screening tool for the diagnosis of DISH.

Chest radiographs as a screening test for diffuse idiopathic skeletal hyperostosis.

We describe a 42-year-old woman with polyarteritis nodosa characterized by polyarthritis, purpuric rash, mononeuritis multiplex, focal segmental glomerulonephritis and necrotizing arteritis. alpha-1 antitrypsin deficiency was diagnosed incidentally on a liver biopsy. This is the third reported case of systemic necrotizing vasculitis in association with alpha-1 antitrypsin deficiency of the PI ZZ type, and the first to show significant response to cyclophosphamide and steroids.

Craig S. Watts

Papers

A controlled study of diffuse idiopathic skeletal hyperostosis. Clinical features and functional status.

Detection of Crohn Disease in Patients with Spondyloarthropathy: The SpACE Capsule Study.

Combination methotrexate and sulfasalazine in the management of rheumatoid arthritis: case observations

Chest radiographs as a screening test for diffuse idiopathic skeletal hyperostosis.

Alpha-1 antitrypsin deficiency and systemic necrotizing vasculitis.