In synovial fluid of patients with RA, IgG and IgA levels against some of these bacteria found raised Æ antibodies against periodontopathic bacteria could be important for RA ? 2

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口腔病理科 On-Line KMU Student Bulletin

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原文題目(出處)： Rheumatoid arthritis and periodontitis: Biological links and the emergence of dual purpose therapies Indian J Dent Res 2009;20:86-90

原文作者姓名： Modi DK, Chopra VS, Bhau U

通訊作者學校： Department of pharmacology, Government medical College, Sarwal Hospital Jammu, J & K Health Service, Jammu, India

報告者姓名(組別)： R2黃炯霖

報告日期： 98.08.11

內文：

Introduction

◎ Rheumatoid arthritis (RA)

¾ A systemic autoimmune disease ( about 1% of adult)

¾ Chronic inflammation Æ progressive joint destruction and other systemic manifestations from

¾ Inflammation of synovial membrane Æ invasion into adjacent cartilage matrix Æ degradation of articular cartilage / bone mechanism unclear

¾ MMP, cathepsins, and osteoclast activation / cytokines like TNF-α, IL-1, MCSF involved

◎ Periodontal disease

¾ Gingivitis and periodontitis (10-60% in adults)

¾ Bacterial invaders Æ defensive cells activated and releasing cytokines like IL-1β, TNF-α, and IL-6 Æ production of collagenolytic enzymes like MMPs Æ tissue destruction

¾ Increased risk of atherosclerosis, DM, adverse pregnancy outcome, and RA Clinical Interelation

¾ Individuals with RA are more likely to experience moderate to severe periodontal disease (prospective clinical trials)

¾ A high incidence of RA in patients with periodontitis

¾ A common underlying pathobiology ? Biological Links

1. Periodontopathic bacteria like A.a., P.g., B.f., P.i., prevotella melaninogenica, and eubacterium nodatum. In synovial fluid of patients with RA, IgG and IgA levels against some of these bacteria found raised Æ antibodies against periodontopathic bacteria could be important for RA ?

2. Porphyromonas gingivalis (P.g.) ~ possess peptidyl arginine deaminase (PAD) implicated as a susceptibility factor for RA. Individuals with periodontal infection of P.g. are exposed to antigens generated by PAD, leading to production of rheumatoid factor and local inflammation of both gingiva and synovium

3. Hsp 70 Ab of P.m. and P.i. found raised in periodontal tissue as well as synovial tissue of patients with RA. Hsp 70 expression induced with certain stress-stimulating factors Æ pro-inflammatory cytokines induced in synovium

4. Genes on HLA region remain the most powerful disease risk genes in the patients of both RA and periodontitis. HLA-DR4 antigens (and subtypes) directly associated with both diseases

5. Similar patterns of blood cytokine profile ~ raised titters of IL-10, IL-1α,

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TNF-α, LT-α, and low titters of auto antibodies to IL-1α and IL-6 Æshare common underlying disregulation of the inflammatory and immune response

6. Increased levels of IL-1β found in the synovial tissue macrophages of Patient with RA and in the GCF of patients with periodontitis. Recent study demonstrated that the polymorphism of the IL-1 gene affected the cytokine profile in patients of both periodontitis and chronic arthritis like RA

7. Experimentally induced inflammatory arthritis in rats Æ elevated levels of tissue matrix metalloproteinases (MMPs), TNF -α, and IL-1β in both synovial tissue and gingival tissue. ( share common dysfunction of fundamental inflammatory mechanisms)

Biological base for linking aspects Æ therapies that concordantly target the two diseases will be effective in the pathogenesis of both diseases

Dual Purpose Therapies Based on Biological Links

1. Tetracyclines (and its analogues) ~ broad-spectrum antimicrobial agents for G (+) and G (-) bacteria. (1980s studies)

z Tetracyclines inhibited collagenase (include MMPs). [Enhanced activity of MMP in synovial fluid and fibroblasts of patients with RA.]

Tetracyclines are useful for RA. Minocycline for patients with RA Æ significant reduction in disease activity

z Tissue destruction in periodontitis ~ partly due to MMPs.Tetracyclines and their analogues ~ useful in Tx. of patients with rapidly progressive / refractory periodontitis by suppressing the growth of putative microorganisms & destruction of collagen in gingival, PDL and alveolar bone through inhibiting MMPs

2. NSAIDs ~ inhibition of cycloxygenase ( for biosynthesis of prostaglandins) z Periodontally diseased tissues have higher prostaglandin levels ( esp. E 2 ) Æ

bone resorption. NSAIDs ~ preventing inflammation-induced bone loss.

Animal and human studies ~ NSAIDs show unequivocal therapeutic efficacy in periodontitis

z Tx. of RA by NSAIDs Æ to reduce pain and inflammation by inhibiting neutrophils and TNF-α Æ contribute to the efficacy of Tx. for RA

3. Bisphosphonates: Agents that affect osteoclast function

z A class of drugs are incorporated into the bone and incapacitate osteoclasts Æ inhibiting lysosomal enzyme transport and secretion by osteoclasts.New-generation like zoledronic acid reduced development of new bony erosions in patients with RA

z Bisphosphonate therapy ~ inhibit bone resorption and increase bone mass, Æ improves clinical outcome in patients with periodontitis Æ as adjunctive Tx

Emerging Therapies

1. Ornidazole: A synthetic, nitroimidazole with potent antiprotozoal and antibacterial activity.

Good activity against most of periodontopathic bacteria Æ drug for Tx of periodontitis

 The usefulness with RA Æ (mechanism not known) reduction in pain and overall reduction in disease activity

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9 Well tolerated at a dosage of 500-1000 mg/day with adverse effects, such as headache, dry mouth, and nausea

2. Chemically modified tetracyclines (CMTs):

 To eliminate the antimicrobial properties of tetracyclines

Inhibit synthesis of MMPs.Non antibiotic analogues of doxycyclin (CMT-3) and minocyclin (CMT-8) shown to be potent inhibitors of osteoclastogenesis in vitro

 CMT-8 also shown to exert anti-inflammatory effects and modify cell viability by strong apoptosis

9 CMTs may reduce tissue breakdown and bone resorption in RA and periodontitis

3. Osteoprotegrin (OPG):

 OPG inhibits RANKL^* interaction with RANK

 Interaction between RANKL and RANK has an essential role in the activation of osteoclast and bone resorption

 OPG expression is deficient in synovial lining cells on patients with RA and active synovitis and GCF in patients with periodontitis

9 OPG may have a therapeutic role in RA and periodontitis 4. Conjugated linoleic acid (CLA):

9 Found as an important inhibitor of osteoclastogenesis by modulating RANKL signaling pathway

9 Shows positively influence Ca & bone metabolism Conclusion

Increase in research evidence suggesting an association between periodontitis and an increased risk of RA. Probably the inflammatory mediators and microbial products (endotoxins) are the likely conduits. Inhibition of common mediators and effector molecules such as MMPs can reduce the severity of both diseases Further methodologically rigorous observational studies and therapeutic trials in this area needed

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題號題目

1 針對rheumatoid arthritis之治療選擇,下列何種為非?

(A) Erythomycine之給予

(B) Systemic corticosteroid之給予

(C) Nonsteroidal anti-inflammatory drugs (NSAIDs) 之給予 (D) Severely damaged joint replaced

答案(A) 出處：Oral & Maxillary Pathology 2^nd edition P.758

題號題目

2 針對chronic periodontitis,可使用抗生素或藥物作為治療時之輔助,下

列何者種藥物最少使用?

(A) Tetracycline (B) Metronidazole (C) Cepharosporine

(D) Nonsteroidal anti-inflammatory drugs (NSAIDs) 答案(C) 出處：Oral & Maxillary Pathology 2^nd edition P.154