Reliability of the Eight Guiding Principles and Syndrome Diagnosis in Chinese Medicine Diagnosis of Patients with Knee Osteoarthritis.

Abstract Background: A Chinese medicine (CM) "Syndrome" or "pattern of disharmony" is a diagnostic subcategory of a disease/disorder or symptom, characterized by particular symptoms and signs, and indicative of the etiology and the state of pathogenesis at that point in time. In CM, treatment is aimed at addressing the disease/disorder and the underlying CM Syndrome. A few studies have assessed reliability of CM Syndrome diagnosis according to one of the major CM theories, Zang-Fu theory, but only 1 study has investigated the reliability of diagnosis according to a fundamental theory, that of the Eight Guiding Principles. Given that treatment follows diagnosis, if diagnosis is not reliable there will be lower confidence that optimal treatment is received. There have not yet been any reliability studies in osteoarthritis (OA). Little is known about the characteristics or Syndromes of OA with respect to the Eight Guiding Principles and Zang-Fu theory. Objectives: The objectives of this study were to characterize diagnostic subcategories of OA according to the Eight Guiding Principles and Zang-Fu theory and to investigate the inter-rater reliability of CM diagnosis according to these two theories. Methods: An inter-rater reliability study was conducted as a substudy of a clinical trial investigating the treatment of knee OA with Chinese herbal medicine. Two (2) experienced CM practitioners conducted a CM examination separately, within 2 hours of each other, of 40 participants. A CM assessment form was utilized to record the diagnostic data. Cohen's κ coefficient was used as a measure of reliability. Results: Results support the concept that knee OA is more likely a disease with characteristics of Interior, Deficiency, and Yin according to the Eight Guiding Principles. There was no clear agreement on CM Syndromes of knee OA according to Zang-Fu theory. The main Zang Organs involved were broadly agreed on; they were Kidney, Liver, and Spleen. Conclusions: Results lend some empirical evidence to support to the argument that OA of the knee is an Internal disease with the manifestations of Deficient symptoms according to CM theories. To establish if Syndrome diagnosis is reliable, more studies should be conducted for different clinical conditions.

Incidence of melanoma and other malignancies among rheumatoid arthritis patients treated with methotrexate.

OBJECTIVE: To determine cancer risk in a cohort of 459 rheumatoid arthritis (RA) patients treated with methotrexate in community practice. METHODS: All RA patients who started methotrexate prior to June 1986 and were attending 1 of 6 rheumatologists were studied. Demographic data were matched to the State Cancer Registry to identify all malignancies (except nonmelanoma skin cancer) for 1983-1998, and to the National Death Index to identify all deaths to the end of 1999. Followup started on the date when methotrexate was started and ended either on the last confirmed date on which the patient was seen by the rheumatologist or at death. Standardized incidence ratios (SIRs) were calculated using state population cancer rates stratified by sex, age (in 5-year groups), and calendar year. RESULTS: There were 4,145 person-years of followup (average 9.3 years). Eighty-seven malignancies were identified (14 before, 64 during, and 9 after the followup period). There was an estimated 50% excess risk of malignancy among methotrexate-exposed RA patients relative to the general population (SIR 1.5, 95% confidence interval [95% CI] 1.2-1.9), with a 3-fold increase in melanoma (SIR 3.0, 95% CI 1.2-6.2), a 5-fold increase in non-Hodgkin's lymphoma (SIR 5.1, 95% CI 2.2-10.0), and an almost 3-fold increase in lung cancer (SIR 2.9, 95% CI 1.6-4.8). CONCLUSION: Compared with the general population, methotrexate-treated RA patients have an increased incidence of melanoma, non-Hodgkin's lymphoma, and lung cancer. There may be a role for regular skin cancer screening for all RA patients, particularly those receiving immunosuppressive therapy.

Osteoprotegerin reduces osteoclast numbers and prevents bone erosion in collagen-induced arthritis.

Rheumatoid arthritis is characterized by progressive synovial inflammation and joint destruction. While matrix metalloproteinases (MMPs) are implicated in the erosion of unmineralized cartilage, bone destruction involves osteoclasts, the specialized cells that resorb calcified bone matrix. RANK ligand (RANKL) expressed by stromal cells and T cells, and its cognate receptor, RANK, were identified as a critical ligand-receptor pair for osteoclast differentiation and survival. A decoy receptor for RANKL, osteoprotegerin, (OPG) impinges on this system and regulates osteoclast numbers and activity. RANKL is also expressed in collagen-induced arthritis (CIA) in which focal collections of osteoclasts are prominent at sites of bone destruction. To determine the role of RANK signaling events in the effector phase of CIA, we investigated effects of Fc-osteoprotegerin fusion protein (Fc-OPG) in CIA. After induction of CIA in Dark Agouti rats, test animals were treated with or without Fc-OPG (3 mg/kg/day) subcutaneously for 5 days, beginning at the onset of disease. Paraffin-embedded joints were then analyzed histologically and the adjacent bone assessed by histomorphometry. Osteoclasts were identified using TRAP staining and expression of the mRNA for OPG and RANKL was identified by in situ hybridization. The results indicated that short-term Fc-OPG effectively prevented joint destruction, even though it had no impact on the inflammatory aspects of CIA. In arthritic joints, Fc-OPG depleted osteoclast numbers by over 75% and diminished bone erosion scores by over 60%. Although cartilage loss was also reduced by Fc-OPG, the effects on cartilage were less striking than those on bone. In arthritic joints OPG mRNA was highly expressed and co-localized with RANK ligand, and treatment with Fc-OPG did not affect the expression of endogenous RANKL or OPG mRNA. These data demonstrate that short term Fc-OPG treatment has powerful anti-erosive effects, principally on bone, even though synovitis is not affected. These findings indicate the potential utility of disrupting RANK signaling to preserve skeletal integrity in inflammatory arthritis.