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Following the Molecular Pathways toward an Understanding of the Pathogenesis of Systemic Sclerosis

Sergio A. Jimenez, MD; and Chris T. Derk, MD
[+] Article and Author Information

From Thomas Jefferson University, Philadelphia, Pennsylvania.


For definition of terms used, see Glossary.

Acknowledgments: The authors thank Kate Salmon for expert assistance in the preparation of the manuscript and M. Sonsoles Piera-Velazquez, PhD, for assistance in the preparation of some of the illustrations.

Grant Support: By National Institutes of Health Grant AR19616. Dr. Derk was supported by National Institutes of Health Training Grant AR07583.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Sergio A. Jimenez, MD, Division of Rheumatology, Thomas Jefferson University, 233 South 10th Street, Room 509 BLSB, Philadelphia, PA 19107-5541.

Current Author Addresses: Dr. Jimenez: Division of Rheumatology, Thomas Jefferson University, 233 South 10th Street, Room 509 BLSB, Philadelphia, PA 19107-5541.

Dr. Derk: Division of Rheumatology, Thomas Jefferson University, 1025 Walnut Street, Room 613 Curtis, Philadelphia, PA 19107-5541.


Ann Intern Med. 2004;140(1):37-50. doi:10.7326/0003-4819-140-2-200401200-00013
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Background: The Ottawa knee rule is a clinical decision aid that helps rule out fractures and avoid unnecessary radiography.

Purpose: To summarize evidence about the accuracy of the Ottawa knee rule.

Data Sources: Relevant English- and non–English-language articles were identified from PreMEDLINE and MEDLINE (1966–2003), EMBASE (1980–2003), CINAHL (1982–2003), BIOSIS (1990–2003), the Cochrane Library (2002, Issue 3), the Science Citation Index database, reference lists of included studies, and experts.

Study Selection: Articles were included if they reported enough information to determine the sensitivity and specificity of the Ottawa knee rule for detecting fractures confirmed either radiologically or in combination with follow-up.

Data Extraction: Two reviewers independently extracted data on study samples, the ways that the Ottawa knee rule was used, and methodologic characteristics of studies.

Data Synthesis: Of 11 identified studies, 6 involving 4249 adult patients were considered appropriate for pooled analysis. The pooled negative likelihood ratio was 0.05 (95% CI, 0.02 to 0.23), the pooled sensitivity was 98.5% (CI, 93.2% to 100%), and the pooled specificity was 48.6% (CI, 43.4% to 51.0%).

Conclusion: A negative result on an Ottawa knee rule test accurately excluded knee fractures after acute knee injury. However, because the rule is calibrated toward 100% sensitivity and actual fracture prevalences are usually low, large-scale, multicentered studies are still needed to establish the cost-effectiveness of routinely implementing the rule.

Figures

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Figure 1.
General overview of the pathogenesis of systemic sclerosis.

The illustrations on the bottom row show examples of, from left to right, the fibrotic process (biopsy of skin), microvascular alterations in pulmonary arterioles, autoantibodies detected by immunofluorescence, and mononuclear inflammatory cell infiltrates in affected skin.

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Figure 2.
Schematic diagram of the transforming growth factor-β (TGF-β) and Smad pathways involved in stimulation of collagen gene expression.

R = receptor.

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Figure 3.
Diagram of the pathogenesis of systemic sclerosis according to the hypothesis of microchimerism.

CTGF = connective tissue growth factor; IL = interleukin; NO = nitric oxide; PDGF = platelet-derived growth factor; TGF-β = transforming growth factor-β; TNF-α = tumor necrosis factor-α.

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Figure 4.
Diagram of the pathogenesis of systemic sclerosis according to the hypothesis of an environmental agent causing initial tissue inflammation.

CTGF = connective tissue growth factor; HCMV = human cytomegalovirus; NO = nitric oxide; PDGF = platelet-derived growth factor; TGF-β = transforming growth factor-β.

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Figure 5.
Diagram of the pathogenesis of systemic sclerosis according to the hypothesis of phenotypic change in target cells.

CTGF = connective tissue growth factor; HCMV = human cytomegalovirus; IFN = interferon-γ; IL = interleukin; NO = nitric oxide; PDGF = platelet-derived growth factor; TGF-β = transforming growth factor-β; TNF-α = tumor necrosis factor-α.

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