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The prevalence of gingival overgrowth in rheumatoid arthritis patients treated with cyclosporin McCloy, Deborah F. 2003

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The Prevalence of Gingival Overgrowth in Rheumatoid Arthritis Patients Treated With Cyclosporin by Deborah F. M Cloy, DipDH, BDSc c  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER  OF SCIENCE in  THE FACULTY OF GRADUATE STUDIES D E P A R T M E N T OF O R A L B I O L O G I C A L A N D M E D I C A L SCIENCES  We accept this thesis as conforming to the required standard  THE UNIVERSITY OF BRITISH C O L U M B I A September 2003 © Deborah F. M Cloy 2003 c  In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department  or by his  or her representatives.  It is  understood  that  copying or  publication of this thesis for financial gain shall not be allowed without my written permission.  D e p a r t , o,  QtaJL  The University of British Columbia Vancouver, Canada Date  DE-6 (2/88)  ABSTRACT Cyclosporin has been recognized since the m i d 1980's as a potent disease-modifying agent for inflammatory auto-immune diseases that are unresponsive to standard therapeutic regimens. From the organ transplant literature, cyclosporin is known to induce gingival overgrowth i n the first ninety days o f treatment. In Rheumatoid Arthritis ( R A ) , gingival overgrowth, coupled with the common feature o f compromised manual dexterity, may make dental plaque control difficult for immunosupressed patients, resulting in increased susceptibility to oral complications. Determination o f oral health status has not been included previously i n patient evaluations. The goal o f this study was to determine the prevalence o f gingival overgrowth, predisposing factors and types o f oral complications occurring in this population group. The objectives o f the study were to determine the prevalence and severity o f gingival overgrowth and to determine at what point i n the treatment regime the patients were most at risk. Twenty-eight volunteer R A patients took participated i n the study. Twenty-two were placed on a cyclosporin treatment regime while six were used as a control group and placed on Methotrexate. Methotrexate is an immunosupressive medication frequently used i n the treatment o f advanced R A . It does not induce gingival overgrowth but it does produce a high incidence o f oral ulceration. A t D a y Zero, patients were examined by a calibrated examiner to determine probing depths, periodontal attachment loss, maximum opening and gingival inflammation using standard indices. Plaque scores and the presence and severity o f gingival overgrowth were recorded. Patients completed a Quality o f Life ( Q O L ) Visual Analogue Scale at Day One. Patients were re-examined every four to six weeks for a minimum o f six months. A t each appointment they were interviewed about  their oral health experiences. Upon leaving the study, participants again completed the Q O L visual analogue scale. There was no significant correlation between plaque accumulation and oral complications. Gingival overgrowth was not detected i n any o f the patients. There was no significant correlation between plaque accumulation and gingival inflammation. M a x i m u m opening scores did not correlate with plaque accumulation scores but did correlate with Q O L scores. There was a decrease i n gingival inflammation scores through the course o f the study.  iii  TABLE OF CONTENTS Abstract  ii  Table o f Contents  iii  List o f Tables  vi  List o f Figures  vii  Acknowledgements  viii  Dedication  x  CHAPTER 1: Rheumatoid Arthritis  1  1.1  Oral Manifestations o f Rheumatoid Arthritis  4  1.2  Treatment Standards  6  CHAPTER 2: Disease Modifying Anti-Rheumatic Drugs 2.1  2.2  10  Methotrexate  10  2.1.1  Mechanism o f A c t i o n  10  2.1.2  Oral Side Effects  11  Cyclo sporine  12  2.2.1  Mechanism o f Action  14  2.2.2  Oral Side Effects  16  2.3  Summary  26  2.4  Research Question  28  CHAPTER 3: Methods And Materials  29  3.1  Study Participants  29  3.2  Patient Examination  30  3.3  Plaque Indices  31  iv  3.4  Gingival Inflammation Index  34  3.5  Gingival Overgrowth Index  35  3.6  Quality o f Life Visual Analogue Scale  42  3.7  Statistical Analysis  38  3.8  Ethical Approval  38  CHAPTER 4: Results  39  4.1  Study Population  39  4.2  Gingival Overgrowth  40  4.3  Gingival Inflammation  40  4.3.1  41  4.4  Gingival Bleeding and Colour  Quality o f Life  CHAPTER 5: Discussion  42  46  5.1  Gingival Overgrowth  46  5.2  Gingival Inflammation and Bleeding  51  5.3  Quality o f Life  51  5.4  Future Considerations  51  CHAPTER 6: Conclusion  53  REFERENCES  55  APPENDIX 1: R aw Data  67  V  TABLES Table 1  Pvheumatoid Arthritis Diagnostic Criteria  4  Table 2  Population Size i n C Y A Studies  18  Table 3  O ' L e a r y Plaque Index  32  Table 4  Silness and Loe Plaque Index  33  Table 5  Phenytoin Gingival Inflammation Index  35  Table 6  Hyperplastic Index  36  Table 7  Horizontal Dimension Score; Modification to Hyperplastic Index  36  Table 8  Gingival Overgrowth Index by Angeloloupos and Goaz  37  Table 9  Patient Gender Profile  40  Table 10  Silness and Loe Plaque Index and Tone i n C Y A Patients  40  Table 11  O ' L e a r y Plaque Index and Tone i n C Y A Patients  41  Table 12  C Y A Group; Change i n Tone, Bleeding and Colour  41  Table 13  M T X Group: Change in Tone, Bleeding and Colour  41  Table 14  Silness & Loe and O ' L e a r y  42  Table 15  Quality o f Life Scores  44  vi  LIST OF FIGURES Figure 1  Methotrexate Ulcerative Stomatitis  12  Figure 2  Initial Quality o f Life Score versus M a x i m u m Opening  43  Figure 3  End Quality of Life Score versus M a x i m u m Opening  44  Figure 4  Change i n Quality o f Life Score versus M a x i m u m Opening  45  Figure 5  C Y A Patient Gingival Condition Day Zero  47  Figure 6  Tissue Changes in a Patient on Cyclosporin Day Zero  49  Figure 7  Tissue Changes i n a Patient on Cyclosporin D a y Sixty  50  Figure 8  Tissue Changes in a Patient on Cyclosporin Day Ninety  50  vii  ACKNOWLEDGEMENTS  I would like to express my sincere appreciation to all those people who enabled me to complete this project. A special gratitude is extended to the following people. To all o f the kind and patient individuals at the M a r y Pack Arthritis Centre, who were willing to give o f their time and share their experiences as participants in the study. Y o u made the study possible. To Mrs. Bonnie J. Craig, Associate Professor and Director, Bachelor o f Dental Science Program i n Dental Hygiene, Faculty o f Dentistry, The University o f British Columbia. Y o u r ongoing input throughout this project and a career o f twenty years has had a profound effect on m y development as a person and a dental hygienist. To Dr. Hannu Larjava, Professor and Chair, Division o f Periodontics and Dental Hygiene, Faculty o f Dentistry, The University o f British Columbia. I thank Dr. Larjava for inspiration i n the area o f research while sharing his expertise in research excellence through course work and i n the preparation for this study. Thank you for making me think. To Dr. Jeff C o i l , Assistant Professor and Chair, Division o f Endodontics, Faculty of Dentistry, The University o f British Columbia. Y o u r kind support was most appreciated, as was your input into the final document. To Dr. Doug Waterfield, Associate Professor and Graduate Advisor, Faculty o f Dentistry, The University o f British Columbia. I thank Dr. Waterfield for his positive outlook and motivation through a lengthy project. Y o u r input was invaluable as was your support.  To M r s . V i c k i Koulouris, Coordinator o f Graduate Studies, Faculty o f Dentistry, The University o f British Columbia. Thank you for all your time in basing with graduate studies. To M r s . Ingrid Ellis, Research and Administrative Secretary, Faculty o f Dentistry, The University o f British Columbia. Thank you for your professional input and expertise i n the preparation o f presentations, proposals and posters. To m y family and friends who showed me their love through support and encouragement. Thank you for making it happen. To m y M u m , who by example, has instilled i n me the value o f lifelong learning and whose unwavering belief in m y capabilities has always motivated me to move on to the next step.  ix  Dedicated to Isabel Emily M Cloy, c  a researcher of life and my Mother.  Chapter 1: Rheumatoid Arthritis  The word "Rheumatism" is derived from the ancient Greek word "rheumatismos" which denoted mucus as "evil secretions" that flowed from the brain to the joints producing pain. Rheumatoid Arthritis ( R A ) is a systemic auto-immune disorder characterized by persistent joint inflammation. Arthritis and diseases o f the joints are among the most common causes o f chronic illness i n the United States (Wilkins, 1999). Approximately 1% o f the population suffers from Rheumatoid Arthritis ( R A ) and there is no known cure (Machold et al., 1998). If "probable" cases o f R A are included (see Table 1), R A sufferers make up 3% or more o f the noninstitutionalized population o f North America. In the United States alone, two million people suffer with R A ( A R A , 2003; C D C , 2002). Each year 41 m i l l i o n work-days are lost to the Canadian economy due to lost wages and medical expenses, lost production, and social assistance reaches five billion dollars. R A is responsible for nine million office visits annually i n the United States ( A C R , 2002). Treatment o f R A also has a significant morbidity. In 1992, 1300 Canadians died from gastric ulcers and associated bleeding related to the extensive use o f nonsteroidal anti-inflammatory drugs ( N S A I D ) , routinely recommended for R A pain, compared to 982 Canadians who died from A I D S . Once thought to be a disease o f the aged, R A and Juvenile R A strike children and adults throughout their lifespan. Under the age o f 60 years, women are more likely to be diagnosed with R A but after 60 years o f age the ratio is equal, males to females (Newsome, 2002; NfCarty, 1993). The onset o f R A is usually between 20 and 40 years o f age but may occur at  1  any age. R A is not race or continent specific and affects people o f all ages, ethnic and social classes (Farley & Hendry, 2002). R A is classified as a rheumatic disease which also includes Systemic Lupus Erythematosus and Scleroderma. R A is an acquired chronic disease whose etiology is believed to be multifactorial. Factors include host immune response, the environment and possibly infecting agents. The complex interactions o f the factors obscures the recognition o f a primary causative factor ( A R A , 2003). A s mentioned above, R A is a systemic inflammatory disease displaying both articular and, in severe cases, extra-articular manifestations. R A patients may have heart, liver or kidneys complications, particularly when associated with polyarthritis conditions and scleroderma. Articular destruction is the consequence o f a chronic cellular immune response in the sublining tissue o f the rheumatoid synovial membrane (Tak et al., 1997) The cytology o f R A inflamed joint fluid shows a higher-than-normal leukocyte count. In healthy individuals the leukocyte count averages 150/cmm. Leukocytes in inflamed joints are 3-50,000/cmm and i n very inflamed joint fluid 50-300,000/cmm or as much as 2000 times the normal number (M°Carty, 1993). Polymorphonuclear leukocytes make up less than 25% o f the cells in healthy synovial fluids whereas inflamed joints account for 70%. T cells, macrophages and plasma cells act synergistically with local cells creating a destructive process. It has been hypothesized that some unknown transient exogenous trigger at some time prior to the appearance o f the auto-immune disease may activate a sub-set o f auto-reactive/auto-immune T or B lymphocytes which are then continually stimulated by auto-antigens with which they cross-react, leading to  2  persistent auto-immunity. However, studies do not show higher titres for viral antibodies i n R A population groups compared to n o n - R A groups. More research is required in the area o f acute R A putatively o f a viral origin (Machold et al., 1998; Cassinotti et al., 1995). Activated T cells (the most abundant cell extracted from the synovial membrane o f patients) play a central role in the pathogenic process. Once activated, these cells, together with mononuclear cells and activated synovial A and B cells, locally elaborate a "cascade" o f cytokines which are specifically involved as mediators o f inflammation and joint destruction. In early R A , the production o f Interleukin-1 (IL1) is increased. Patients with established R A have an increased expression o f macrophages and fibroblast-derived factors such as tumour necrosis factor alpha (TNFa) (Feldmann et al., 1996; Arend & Dayer, 1995; Kanik et a l , 1996). The presence o f plasma cells is also characteristic o f the infiltrate seen following the initial acute inflammatory response and is responsible for the extra-vascular immune complex deposition affecting synovial tissue (Muller-Ladner 1997). Several autoantibodies including Rheumatoid Factor (RF) and anti-collagen antibody are produced by synovial plasma cells, suggesting that local antigens may be involved in both the immune complex formation and lymphocyte activation in the involved tissues (NIH, 1984). R F is an auto-antibody and is a feature o f R A which distinguishes it from other arthritises such as osteoarthritis. B l o o d tests may confirm the presence o f R F but a negative result does not preclude a diagnosis o f R A (Williams, 1996).  3  Table 1. Rheumatoid Arthritis Diagnostic Criteria 1. Morning Stiffness 2. Pain on motion or tenderness in at least one joint 3. Swelling (soft tissue thickening or fluid, not bony overgrowth alone) in at least one joint 4. Swelling of at least one other joint 5. Symmetrical joint swelling with simultaneous involvement of the same joint on both sides of the body 6. Subcutaneous nodules over bony prominences, on extensor surfaces, or i n juxtaarticular regions 7. Roentgenographic changes typical o f rheumatoid arthritis which must include at least bony decalcification localized to or greater around the involved joints (and not just degenerative changes) 8. Positive agglutination (anti-gammaglobulin) test 9. Poor mucin precipitate from synovial fluid (with shreds and cloudy solution) 10. Characteristic histological changes to synovial membrane (fibroblasts advance into bone) 11. Characteristic histological changes i n nodules Classic Definite Probable  1.1  7 o f 11 5 o f 11 3 o f 11  Oral Manifestations of Rheumatoid Arthritis  Rheumatoid diseases have numerous oral manifestations. Individuals with Sjogren's Syndrome, a rheumatic disease, have significantly reduced saliva production. Studies o f elder populations classified with reduced saliva flow may attribute the decrease to aging or award a diagnosis o f early/mild Sjogren's Syndrome or R A related diseases rather than to R A directly (Hochberg et al., 1998; Grisius, 2001; H a y et al., 1998). Reduced saliva flow decreases the self-cleansing ability o f the mouth increasing food retention i n the oral cavity. The retention o f cariogenic food particles and decreased buffering capacity associated with reduced saliva flow increases caries risk. Saliva lubricates the oral cavity and facilitates mastication, which may be  4  difficult i n a dry mouth (Garg & Kirsh, 1995). Saliva has anti-fungal and antibacterial properties which, when reduced, increases the risk o f Candidiasis i n rheumatoid patients (Kindelan et al., 1998). The effects o f R A in the mouth are not well documented. Degenerative joint disorders are common in R A populations. Temporomandibular joint ( T M J ) dysfunctions such as crepitus with pain, joint tenderness and pain on opening have been verbally reported by 67% o f a R A study group as compared to 32% i n a nonR A group (Yamakawa et al., 2002). Clinical examination o f another R A group which self-reported 33% T M J dysfunction revealed 40% involvement o f the T M J . Researchers using high resolution computerized tomography ( H R C T ) determined frequency o f involvement was actually 86%. Findings included decreased joint space (33.3%o), subchondral cysts (46.6%), and condylar head resorption and/or demineralization (26.6%). H R C T examinations may be beneficial for R A patients prior to the manifestation o f clinical symptoms (Bayar et al., 2002). Lichen planus is a frequent oral sign associated with rheumatoid diseases. Lichen planus is typically linked with Lupus Erythamatosis, a rheumatoid disease, and not linked with R A directly by researchers. The mucosa o f R A patients may be thin and have lichenoid lesions which are easily traumatized, or appear normal as compared to the general population (Gonzales-Mole et al., 2003). Lichenoid lesions vary i n size, may be painless or sensitive and are prone to causing a burning sensation i n the mouths o f R A patients (Lozada-Nur et al., 1994; Silverman et al., 1985). Potentially fragile tissues, decreased saliva, and compromised hand and elbow function may contribute to higher plaque levels due to compromised self care further  5  increasing risk o f oral disease ( M c M a h o m , 2002). Most tasks can be performed with 100 degrees o f flexion, extension, pronation and supination. A smaller range o f motion results negatively i n function and creates significant disability, further compromising oral self care (Murphy, 2002). R A populations have significantly higher numbers o f decayed, missing and filled teeth as well as edentulous subjects and subjects with partial fixed or removable dentures. Therapies and procedures directed toward pain reduction and improved motion are the cornerstone o f treatment (Heasman & Seymour, 1990; Murphy, 2002).  1.2  Treatment Standards  Rheumatoid Arthritis is a debilitating auto-immune disease. Current treatment modalities attempt to relieve symptoms and suppress the destructive process o f the disease. Traditional therapies are directed at pain management and a reduction o f pain with the goal o f increased mobility and comfort (Murphy, 2002). N e w generation drug therapies attempt to halt the progression o f the disease and associated tissue destruction. Side effects o f medications range from m i l d to severe and vary from diarrhea, increased frequency o f cancers, hypertension, liver degradation and osteoporosis. Oral mucosal ulceration and gingival enlargement also occur. Non-steroidal anti-inflammatory drugs ( N S A I D S ) are used to control the symptoms o f R A but are not effective i n slowing or eliminating the destructive disease processes. N S A I D S also cause significant gastrointestinal toxicity including gastro-  6  duodenal perforations, ulcers and bleeding ulcers (Gaston, 1999). Cyclooxygenase-2 ( C O X - 2 ) inhibitors celecoxib (Celebrex and Rofecoxib) are new generation N S A I D S . The anti-inflammatory activity o f C O X - 2 is attributed to the inhibition o f the production o f prostaglandins by host C O X - 2 . C O X - 1 produced prostaglandins are gastro-protective and are not affected by C O X - 2 inhibitors, which accounts for C O X - 2 having fewer gastrointestinal side effects, specifically gastro-duodenal ulcers, than traditional N S A I D s . Rofecoxib has proven to be as effective as Naproxen with less gastrointestinal bleeding and ulcers. However, myocardial infarction and other cardiovascular events occur more frequently with Refecoxib than Naproxen. The effects o f long-term use o f C O X - 2 inhibitors have not been established. Abdominal pain is the most common cause o f discontinuation o f treatment. Other side effects include myocardial infarction, hypertension and nephrotoxicity. C O X - 2 causes a decrease in renal function caused b y a decrease i n renal blood flow. C O X - 2 not associated with any disease-modifying action and this symptomatic relief may delay more definitive therapy. Biological response modifiers have recently been developed which attempt to neutralize the important pro-inflammatory cytokine T N F a that is responsible for the production/induction o f IL-1 and IL-6 (Bondeson & M a i n i , 2001). The drugs act as free receptor sites for T N F , thereby preventing/halting the sequence o f immune response events which occurs during normal binding. Infliximab (Remicade) is nonantigenic and non-immunogenic. Side effects include upper respiratory infections causing hypertension and death. Patients also experienced fever and chills upon  7  administration o f the injectable drug as well as injection site infections ( K i e l y & Johnson, 2002; Ferraccioli et al., 2002). Another biological response modifier used i n the treatment o f R A is Enbrel (Etanercept), which is a competitive inhibitor o f T N F . Enbrel, a diametric form o f a T N F receptor, acts as a T N F receptor, binding to T N F receptor sites and leaving the naturally occurring T N F inactive (Bondeson J & M i a n i R N 2001). Etanercept is as effective as Methotrexate ( M T X ) in reducing the symptoms, swelling and associated pain o f R A and may be used alone or with M T X . Enbrel does, however, stimulate auto-antibody production and should be reserved for patients unresponsive to M T X or other disease-modifying anti-rheumatic drugs ( D M A R D ) (Strand & Cohen, 2001; Bathon et al., 2000). These drugs are recommended to be used i n conjunction with methotrexate i n order to reduce pain and halt the progession o f the disease. Etanercept is effective alone or with M T X but should be reserved for patients unresponsive to M T X alone or other disease-modifying anti-rheumatic drugs (Strand & Cohen, 2001). Systemic corticosteroids have been one o f the mainstays o f drug therapy i n R A . The glucocorticosteriod Prednisone is used extensively as an anti-inflammatory in the treatment o f R A . The precise mechanism o f action i n R A is not understood. Prednisone inhibits the accumulation o f macrophages i n inflamed areas and decreases the concentration o f immunoglobulin and complement i n an area o f immune response. The side effects from Prednisone are many and range from weight gain to respiratory failure. The use o f Prednisone increases the risk o f infections and osteoporosis. R A patients who are long-term users o f Prednisone have a shortened  8  life span. Corticosteroids such as Prednisone have been shown to be effective i n halting the progression o f the disease process. However, the side effects can be life threatening. There are numerous medications on the market for the treatment o f R A . A n ideal medication for the treatment o f R A should be effective with low toxicity. Such a medication should reduce symptoms o f pain and also halt the progressive destruction of tissues. D M A R D impact the progression o f R A and reduce pain. Once used only as a last stage drug, use o f D M A R D is now recommended early on i n the disease to prevent progressive and irreversible tissue destruction. The benefits o f D M A R D must outweigh the toxicities i n order to be widely accepted as an effective treatment against R A (Fries, 1999).  9  Chapter 2: Disease-modifying Anti-rheumatic Drugs  2.1  Methotrexate  Methotrexate ( M T X ) is a folate antagonist used to treat neoplastic diseases. It is routinely used i n chemotherapeutic management o f bladder, leukemia, breast, head and neck cancers. M T X is also used as a disease-modifying anti-rheumatic drug to treat psoriasis, scleroderma, systemic lupus ( S L S ) and rheumatoid arthritis. M T X is considered the treatment standard for aggressive or severe R A patients who do not respond to N S A I D S . M T X is among the most commonly used drugs for the treatment o f R A . Pharmacologically M T X is classed as an antimetabolite due to its antagonist effect on folic acid metabolism. Hirsutism and oral ulcers as well as poor wound healing and increased risk o f infection are some o f the side effects. M T X has been proven to be effective, however, discontinuation o f M T X treatment regimens is frequently due to adverse side effects including death (Choi et al., 2002).  2.1.1  M e c h a n i s m of A c t i o n  Methotrexate has two primary mechanisms o f action. The first is the competitive inhibition o f the enzyme dihydrofolate reductase ( D H F R ) , the enzyme that reduces folic acid to tetrahydrofolic acid. Tetrahydrofolate must be regenerated by v i a the DHFR-catalyzed reaction i n order to maintain the intracellular pool o f tetrahydrofolate one carbon derivatives for purine and thymidylate nucleotide biosynthesis. The inhibition o f D H F R by M T X results i n a decrease o f nucleic acid synthesis. Thus, D N A synthesis, repair and cellular reproduction are inhibited. M T X  10  is most effective against rapidly reproducing cells, which means it is highly effective against rapidly reproducing malignant tissues. The rapidly reproducing cells o f bone marrow, buccal, intestinal mucosa and fetal tissue may also be adversely affected (Cronstein et al., 1993). The second primary mechanism o f action o f M T X is as an immunosuppressive agent. The exact mechanisms in R A patients are unknown but are thought to relate to immunosuppressive activity. It has been proposed that M T X inhibits the enzyme 5aminomidazole-4-carboxamide ribonucleotide transformylase which precipitates a complex sequence that results i n the release o f adenosine and the stimulation o f an anti-inflammatory signal. Increased intracellular levels o f 5-aminomidazole-4carboxamide ribonucleotide i n R A patients supports this theory. The side effects o f M T X can be severe. They include elevated liver enzymes and cirrhosis o f the liver (29%), leukopenia, thrombocytopenia and renal dysfunction. Despite its life threatening side effects, M T X is the first line drug choice o f rheumatologists for the treatment o f aggressive R A i n the United States (78%) and Canada (68 %) (Maetzel etal., 1998).  2.1.2  Oral  Side Effects  Ulcerative stomatitis is one o f the most commonly reported side effects o f methotrexate. The rapidly reproducing cells o f the oral mucosa are sensitive to methotrexate which targets such cells. The occurrence o f ulcerative stomatitis ranges from 36-83%) in R A patients taking M T X . Lesions are slow to heal and painful (Figure 1). Stomatitis can result in the discontinuation o f treatment, resulting i n  11  disease progression. Patients with a previous history o f stomatitis have an increased risk for the incidence and severity o f stomatitis while on M T X (Carpenter et al., 1997). Cancer patients on M T X have demonstrated an increase i n herpes simplex infection. Studies with R A patients have not supported the use o f prophylactic antivirals due to a low incidence o f herpes infections.  Figure 1: Methotrexate Ulcerative Stomatitis at 34 Days Methotrexate associated ulcerative stomatitis is severe and slow to heal  2.2  Cyclosporin  Cyclosporin ( C Y A ) is potent disease-modifying agent. It is derived from fungi and was originally developed as an antibiotic. C Y A is a cyclic polypeptide produced b y the metabolism o f two fungi, Trichoderma polysporum and Cylindrocarpum lucidum. It is an effective immunosuppressive agent used widely i n organ transplant  12  patients. It differs from other immunosuppressive agents because it does not cause a generalized inhibition o f cell proliferation. ( K a y & Benzie, 1983). C Y A is known to be an effective disease-modifying anti-rheumatic agent. It is also used i n the treatment o f severe or rapidly progressive rheumatoid arthritis cases that are unresponsive to other treatment regimes. C Y A has proven to be effective in reducing joint inflammation at doses up to 5 mg/km/day. Nephrotoxicity is also a problem in R A patients, resulting in discontinuation o f treatment (Feutren & Mihatsch, 1992). Lower dosages o f 3.8-5 mg/kg/day with serum levels o f 150 ng/ml are still effective and have decreased adverse renal dysfunction (Tugwell et al., 1990). Side effects i n transplant patients include nephro and hepatotoxicity, onogenicity, hypertension, hirsutism, gastrointestinal upset and gingival hyperplasia. Gingival overgrowth as a side effect o f C Y A was reported in 1979 i n renal transplant patients (Borel, 1979). The most common reasons for cessation o f C Y A therapy is increased renal dysfunction and elevated blood pressure (Kvien et al, 2002). Side effects also occur when C Y A is used to treat auto-immune diseases such as systemic lupus erythematosus, psoriasis and sclerederma (Britton & Palacios, 1982). In addition to nephrotoxicity, early studies indicate gastrointestinal intolerance is stated as a significant side effect i n R A patients on C Y A . It is speculated that the higher incidence o f gastrointestinal side effects in R A patients compared to n o n - R A is likely due to the past concomitant use o f N S A I D s (Van Rijhoven et al., 1986). Gingival overgrowth as a side effect o f C Y A was first observed i n renal transplant patients (Borel & Gunn, 1986).  13  2.2.1  Mechanism of Action  The mechanisms involved in the action of CYA are not clearly understood. It has a narrow therapeutic range. CYA is bio-transformed to approximately 15 metabolites and then the response in humans is not well understood. There is not one singular metabolic pathway and patients show variations in responses to CYA. In early mouse studies, CYA demonstrated inhibition of early stages of T lymphocyte activation. Mouse splenic lymphocytes were more sensitive to inhibition by CYA than the activation by the B lymphocyte mitogen lipopolysaccharide (LPS), which gave evidence that the effects of CYA on humoral immunity were secondary to inhibition of T-helper cells (Wiesinger & Borel, 1979). Later in vitro studies showed that the sensitivity depended on the specific mitogen used. Subsequent in vivo studies supported the theory that CYA selectively suppresses sub-populations of Tlymphoctyes with only certain subpopulations of T and B lymphocytes showing sensitivity to CYA, with both cellular and humoral immunological responses inhibited (Britton & Palacios, 1982). T suppressor cells are relatively resistant to CYA. The activation by antigen of both T helper and T cytotoxic cells is inhibited by CYA which is not cytotoxic to lymphocytes, and its effects on lymphocyte activity is reversible upon cessation of the drug. However, CYA has been shown to cause inhibition of the rate of protein synthesis in unstimulated lymphocytes (Kay & Benzie, 1983). In pigs, CYA inhibits an early step in lymphocyte proliferation prior to the initiation of DNA synthesis. The main therapeutic effect of CYA is on the cellular immune system suppressing the function of the T-helper cells. CYA interrupts the synthesis of most  14  lymphokines, including IL-2 and gamma interferon by T lymphocytes. Ongoing synthesis o f IL-2 is also affected. Studies o f asthmatic patients on 5 mg/kg/day have shown a marked reduction in T lymphocytes with IL-2 receptors, a marker for T cell activation (Fukuda et al., 1995). T-suppresser cells seem immune to the influence o f C Y A . In an immune response, lymphokines mediate the activation o f macrophages and cytotoxic T lymphocytes, which have a direct lytic effect on the foreign cell (Kjeldsen et al., 1993). IL-1 releasing cytokines are involved i n the inflammatory process which stimulates T cells and fibroblast production. Lymphokines also activate B lymphocytes that produce specific antibodies against the antigen exposed by foreign cells such as a transplanted organ. C Y A has little effect on B-cell mediated antibody production (Borel & Gunn, 1986; Herold et al., 1986). The major effect o f the drug is to suppress the production and function o f lymphocytes, primarily the T helper cells. This affects the T cell activity and the synthesis o f IL-1 and the T cell becomes unresponsive to IL-1 and interferes with the formation o f I L 2 (Herold et al., 1986; Borel & Gunn, 1986). In vitro, C Y A inhibits lymphokine synthesis, transcription o f IL-2 and gamma interferon by preventing the recognition o f the antigen as "non-self. In vivo, C Y A facilitates a complex series o f activities including its ability to bind to macrophages and inhibiting the secretion o f IL-1. The action o f C Y A is not indiscriminate and does not affect the entire immune system. A t therapeutic doses, C Y A modifies the action o f T lymphocytes on the B lymphocytes and consequently has some effect on humoral immunity without affecting B-memory cells and antibody production. This creates a selective immunity i n patients. Although the exact mechanism for the  15  inhibition is not clear, studies have shown that a C a lymphocyte function which increases C a  2 +  2 +  signal is required i n normal  concentrations by releasing C a  2 +  from  intercellular stores. There is evidence that C Y A binds to calmodulin, the protein that mediates the C a  2 +  signal. C Y A may inhibit T and B lymphocyte proliferation by  antagonizing the C a  2 +  signal. The C a  2 +  signal is essential for the induction o f the  synthesis o f the m R N A for IL-2 and other lymphokines. C Y A blocks lymphocyte activation at one or more C a  2 +  dependent steps (Hess & Colombani, 1987). The  exact mechanism or step is not known. Current research is exploring evidence that IL-10 and IL-6 are higher i n non-medicated R A patients than n o n - R A population groups. IL-10 is a B - c e l l stimulator and levels are reduced i n R A patients on C Y A (Ferraccioli et al., 1998). Numerous studies are investigating possible mechanisms for the action o f C Y A on the suppression o f IL-10. The mechanisms by which C Y A creates immunosuppression are not clearly understood and are under ongoing investigation by researchers.  2.2.2  Oral  Side Effects  Three major drug categories are associated with Gingival Overgrowth ( G O ) : anticonvulsants, calcium channel blockers and cyclosporin. Incidence and prevalence studies demonstrate wide variability in gingival responses to these medications (Steele 1994). Differences within study populations, including differences in age and gender o f patients, dose and duration o f drug use, overall health o f patients, and local factors, create a number o f confounding variables. R A is a confounding variable with an unpredictable response (Dongari et al., 1993). Gingival enlargement  16  can occur as a side effect o f these medications. Originally referred to as gingival hyperplasia, histological examination o f tissues from C Y A patients show that the tissues are not hyperplastic (Barber et al., 1992). The more accurate term "gingival overgrowth" refers to histological examination o f Phenytoin-induced gingival enlargement, which showed that the tissues were an over-accumulation o f normal tissue cells resulting in a fibrosis caused b y an accumulation o f collagen fiber bundles, not an overgrowth o f fibroblasts as originally thought (Hassel et al., 1984). The etiology o f drug-induced tissue enlargement varies. The term gingival overgrowth (GO) was used in this study. Phenytoin, an anti-convulsant, was one o f the first medications recognized to cause G O . Used b y over three million North Americans, phenytoin causes G O i n approximately 50% o f daily users (Jones J E 1988). The impact o f G O on patients has been well documented in the phenytoin literature and has been the standard for the development o f G O indices. Recognition o f G O in patients using calcium channel blockers in addition to recognized GO-inducing medications resulted in modification o f indices and the development o f additional assessment tools (Pernu et al., 1993). G O increases tissue irregularities and subsequently increases accumulation o f food debris and plaque. Secondary inflammation as a result o f increased plaque accumulation may increase patient discomfort. Loss o f function may occur when severe G O interferes with mastication and normal speech. Esthetics may also be impacted negatively (Rostock et al., 1985). G O is usually initiated in the interdental papilla and may spread to marginal and attached gingival tissue. Phenytoin G O is often fibrotic and light pink. Calcium  17  channel blockers such as nifedipine initiate G O that is more vascular i n nature with increased friability. G O occurs on the anterior teeth with the labial surface affected more often than the lingual (Somacarrera et al., 1994a). Gingival attachment levels are usually not affected and an increase i n probing depth occurs from increased tissue mass on the clinical crown. Drug-induced G O is frequently linked to poor plaque control and/or drug dosages (Steinberg & Steinberg, 1982; Philstrom, 1980). Studies on the oral side effects o f C Y A have produced conflicting results. Gingival enlargement was first reported i n 1979 i n renal transplant patients (Borel, 1986). C Y A is used i n treating life threatening illnesses or conditions i n relatively small populations. Consequently study populations are usually small with many variables (Table 2). C Y A - i n d u c e d study results rarely reflect the impact o f age, gender or other systemic factors involved.  Table 2: Population Sizes i n C Y A Studies Investigator  Year  Medical Condition  Number of C Y A Participants  Daly Ferraccioli Hefti King Mariani Niimi O'Valle Pernu  1992 1998 1994 1993 1993 1990 1995 1992  renal RA MS renal renal renal renal renal  1 8 40 18 8 8 21 22 (9 Ca blocker, 13 corticosteriods  transplant transplant transplant transplant transplant transplant  Histological examinations o f C Y A G O have shown there are many fibroblasts in C Y A G O , with a particular abundance o f amorphous substance and a marked plasma cell infiltration with marked development o f rough endoplasmic reticulm, Golgi apparatus and plasmatic granules. There is an increase in cytoplasmic volume o f  18  individual fibroblasts with increased collagen and connective tissue matrix ( M G a w c  & Porter, 1988). Early examinations considered that high numbers o f fibroblasts may indicate a hyperplasia while more recent histological examinations do not support an increase i n the number o f fibroblasts. This may be due to biopsy samples viewing an evolutionary stage o f G O with changes in fibroblasts density occurring as the lesion ages, but nonetheless gives evidence that C Y A G O is not true a hyperplasia (Wysocki et al., 1983; Rostock et al., 1985; Pan et a l , 1992). The G O associated with renal transplant patients on C Y A has plasma cells at the gingival level but this may be due to the individual's, sensitivity to the drug or one o f its metabolites, allowing a reaction which is favored by lymphokine inhibition. In vitro studies showed that C Y A induced a proliferation o f fibroblasts but these fibroblasts were not stimulated to synthesize D N A . W i t h no remarkable increase i n proliferation in culture, the statement that lesions are not hyperplastic i n nature is supported (Barbar et al., 1992). Other i n vitro studies suggest another mechanism for C Y A - i n d u c e d G O . Elevated levels o f keratinocyte growth factor ( K G F ) were found i n i n vitro tissue samples i n C Y A - i n d u c e d G O , which produced the hypothesis that K G F receptors ( K G F R ) may be up-regulated in C Y A - i n d u c e d G O (Das et al., 2002). In healthy tissue, K G F R were not found in basal and cornified cell layers o f the inner and outer layers o f epithelium, respectively. In contrast, K G F R were found i n basal as well as granular cell layers o f C Y A G O tissue samples (Kvien et a l , 2002). K G F stimulates T G F p which is actively involved in connective tissue production. This may indicate a hyperplastic growth i n C Y A G O .  19  The initiation o f the G O in C Y A patients is not clearly understood. The link between phenytoin G O and plaque has been well documented (Hassell et al., 1984; Lundstrom et al., 1982). Early studies identified a significant correlation between plaque and G O . Studies supporting a similar etiology for C Y A G O abound (Seymour & Smith, 1991; M G a w et al., 1987; Somacarrera et al., 1994a). Cases c  studies considered C Y A a co-factor with gingival inflammation and plaque i n the development o f G O (Rateitschak-Pluss et al., 1983). A n i m a l studies which stimulated G O i n ferrets on C Y A strengthened the evidence o f plaque as a causative factor i n C Y A G O (Fischer et al., 1996). However, more current studies, and even an early study, questioned whether plaque was a causative factor or i f increased plaque levels i n patients with G O were a result o f accumulation around plaque retentive tissue irregularities ( M G a w et al., 1987; Seymour, 1991). c  The effects o f oral hygiene and plaque removal on C Y A G O is not definitive. Researchers found plaque control reduced inflammation but did not reduce G O or prevent it (Seymour, 1991; Somacarrera et al., 1994b). Research i n a study with 27 renal patients being treated with C Y A showed that plaque control did not significantly prevent G O but may be o f some benefit i n reducing gingival inflammation. Significant G O occurred i n both C Y A and control groups. This study gave rise to the hypothesis that age may be a factor. Older patients demonstrated more G O than younger patients and therefore may be more susceptible to developing G O . G O was not simply a plaque-related or drug-related manifestation.  20  This hypothesis was not supported by studies o f Type I diabetes patients treated with C Y A who demonstrated greater risk i n childhood and adolescence than adulthood (Daley et al., 1986). The degree o f plaque was not as significant as the presence o f plaque i n the presence o f G O i n Type I diabetes patients or transplant patients (Daley e t a l , 1986; Pan etal., 1992). After it was established that the degree o f plaque and the age o f the patients was not a factor, researchers examined the effects o f dose on the occurrence and severity o f G O . A g a i n animal studies produced good evidence o f a strong relationship between dose and G O (Fu et al., 1995). Rats given 450 mg/day developed G O . However, human studies did not support a significant relationship between dose and G O (Thomason et al., 1993; K i n g & Fullinfaw, 1993). Extensive research on kidney transplant patients receiving standard maintenance doses o f 3.2-4.5 mg/kg/day revealed no correlation between dose, blood level, or plaque (Silness & Loe, 1964) in non-responders and C Y A responders who developed G O ( K i n g & Fullinfaw, 1993; Seymour& Smith, 1991; Thomason et al., 1993). Current transplant treatment regimes initiate C Y A therapy prior to transplantation, which avoids the need for high dosages i n the first weeks after surgery (Romanos et al., 1992; Matas et al., 1988). Mean dosages o f 300 mg/day are comparable to mean dosages o f R A patients (Darbar et al., 1996). Duration o f treatment has not proven to be a predictor o f G O i n studies. Cross-sectional studies examining the anterior twelve teeth o f renal transplant patients on C Y A showed that the only significant variables were gingival inflammation and time. G O was less likely to be present the longer the individual had been on the medication (Montebugnoli et al., 1996).  21  One o f the common side effects o f C Y A therapy is hypertension. Calcium channel blockers, especially nifedipine, were traditionally used to control hypertension associated with compromised renal function or renal dysfunction. Diabetes patients on C Y A and nifedipine who received scaling and root planing with ongoing meticulous plaque control had significant improvement in G O (Hancock & Swan, 1992) . Plaque was also strongly correlated with G O in heart and renal transplant patients treated with nifedipine and C Y A (Nishikawa et al., 1991; Thomason et al., 1993) . These studies also firmly established that calcium channel blockers exacerbated G O i n C Y A patients. C Y A G O in patients also taking nifedipine is more vascular than G O from C Y A alone (Barak et al., 1987). When nifedipine was replaced with an alternative hypertension medication, G O was significantly reduced (Pernu et al., 1993; O ' V a l l e et al., 1995; Thomason et al., 1993). This suggests that C Y A G O is not initiated by plaque but is multifactorial and confirms individual patient variability in gingival response to the drug. In a renal transplant case studies, improvement in oral hygiene reduced inflammation and tenderness but did not reduce G O . However, a reduction in the C Y A dose from 400 mg/day to 200 mg/day did result i n a reduction o f G O (Daly, 1992; Rostock et al., 1985). However, these patients had significant compounding factors specifically a liver transplant, Hepatitis B and/or Hepatitis C . Renal transplant patients had an initial decrease i n G O after periodontal therapy but those patients on a combination o f C Y A and dihydropyridine were at risk for reoccurrence or progression (Pernu et al., 1993). These findings led to the hypothesis that plaque itself was not a significant factor but was a reservoir for the retention o f  22  C Y A . C Y A levels were found to be 12 times higher i n whole saliva than pure submandibular or parotid gland saliva, leading researchers to believe that plaque acts as a reservoir for C Y A . Studies that showed serum levels o f C Y A were low and were never exceeded by salivary levels strengthened the evidence for plaque as a causative factor i n G O ( N i i m i et al., 1990). Subsequent studies confirmed that blood levels o f C Y A were exceeded by the levels o f C Y A i n plaque ( M G a w et a l , 1987; c  K i n g & Fullinfaw, 1993). However, when researchers evaluated effects o f frequent prophylaxis and oral hygiene instruction (OHI) over a six month period plaque was not related to G O . Despite an intensive professional debridement regime resulting i n decreased plaque and inflammation levels, the difference i n G O was small. Overgrowth increased i n both the treated and non-treated study groups (Seymour and Smith, 1991). Cyclosporin gingival overgrowth i n 18 renal transplant patients taking C Y A for a minimum o f three months was not related to plaque as recorded using the Silness & Loe Plaque Index (1964). There was no correlation between G O and age, gender, dose, blood levels or saliva levels between responders and non-responders. Dosages o f 3.2-4.5 mg/kg were used i n the study. It was concluded that the degree o f G O was not related to plaque or dependent on pharmacokinetic variables or amount administered but on individual sensitivity and ability to metabolize the drug ( K i n g & Fullinfaw, 1993). The severity o f G O has been measured using primarily two indices. The Phenytoin Gingival Inflammation Index (PGII) (Hassell et al., 1984) which assesses colour, tone and bleeding and the Hyperplasia Index (Angelopoulos & Goaz, 1972) which  23  scores 0 as normal, 1 as mild with blunting o f interdental papilla, 2 as moderate with G O extending up to one third o f the crown, and 3 as severe extending over 2/3 o f the crown or affecting the attached gingiva (Seymour & Smith, 1991; Pernu et al., 1993; Hefti et al., 1994; Montebugnoli et al., 1996). The modified H I index included thickening o f marginal gingiva or lobular granulation o f the gingival pocket or overgrowth less than one third o f the tooth in a score o f " 1 " ; a score o f " 2 " included moderate gingival overgrowth extending to the middle o f the tooth; and severe gingival overgrowth covering up to two thirds o f the crown or the whole attached gingiva was given a score o f " 3 " (Pernu & Pernu, 1992). Other researchers made alternate modifications to the index to measure the vertical component o f G O . Separate scores o f " 0 " indicating normal width o f free gingival margin; " 1 " thickening up to 2 mm; and " 2 " thickening greater than 2 m m were also assigned ( K i n g & Fullifaw, 1993). In the studies where plaque scores were included, two indices were used: the Silness & Loe Plaque Index (Montebugnoli et al., 1996; K i n g & Fullifaw, 1993; Seymour & Smith, 1991; Thomason et al., 1993) and the O ' L e a r y Plaque Index ( O ' V a l l e et al., 1995; Hefti et al., 1994). Studies with heart transplant patients on C Y A therapy reported 60-65% o f patients demonstrating G O (Somacarrera et al, 1994a; Pan et al., 1992). However, the severity o f C Y A G O is not always clearly stated. Only 20% o f the patients in these studies demonstrated a G O score o f 2 or 3, moderate or severe respectively. Dihydropyridine ( D H P ) i n combination with C Y A produced significant increases i n G O i n a study o f 27 renal transplant patients. C Y A alone produced only scores o f  24  " 1 " or G O which is mild with blunting o f papilla, while the combination group showed 50% o f the patients scoring " 2 " or " 3 " , with " 2 " being moderate extending to the middle one-third o f the tooth and " 3 " indicating severe overgrowth covering two-thirds o f tooth or affecting the whole o f the attached gingiva. The C Y A group o f 14 patients had less overgrowth at re-examination after periodontal therapy while the combination group o f 13 patients had more G O . The researchers concluded that the combined effects o f C Y A and D H P medications may be so strong as to overcome the effect o f reduced gingival inflammation from periodontal therapy/gingivectomy (Pernuetal., 1993). G O decreased over the duration o f C Y A therapy i n heart transplant patients. O f the 39 patients, 11 showed some evidence o f G O . The degree o f oral hygiene did not relate to G O . O n l y one o f the 18 patients on C Y A for more than 36 months showed signs o f G O while 10 o f the 21 patients on C Y A for less than 36 months showed G O . This study could not verify i f gingival inflammation was the cause o f 28% o f patients demonstrating G O or a consequence o f G O . The amount o f oral hygiene was not related to G O (Montibugnoli et al., 1996). Other studies have reported 49% and 59%) prevalence o f significant G O ( K i n g & Fullinfaw, 1993; Hefti, 1994). Additional studies found significant G O i n renal patients treated with C Y A . A study o f 22 renal patients on C Y A or C Y A and nifedipine reported a 77% occurrence o f significant G O . However, 11 out o f 22 patients treated with C Y A were also were treated with nifedipine, with only one patient or 5% having a score o f 2 or 3. They found that C Y A - i n d u c e d G O occurs within the first 3-6 months o f treatment and plateaus in the subsequent 9-12 months (Pernu & Perau, 1992; Seibel et al., 1989).  25  C Y A is an effective D M A R D i n therapeutic doses. The exact mechanism o f action is not clearly understood and the mechanisms b y which it causes gingival overgrowth is not known. The prevalence o f G O varies significantly in study results and is influenced by the combined use o f GO-inducing drugs.  2.3  Summary  N e w therapies attempt to halt the progression o f R A disease, not just treat its symptoms. R A patients suffer from pain, increasing disability, decreasing quality o f life and social isolation despite what physicians consider effective treatment drugs (Machold et al., 1998). Studies o f R A populations report that the work attendance o f 62% o f R A patients is negatively affected, with 55% unable to work at all and an additional 13% working a reduced work schedule.(Doeglas et al., 1995). The impact of R A is a substantial cost to society i n lost productivity and cost o f treatment (Lee & Weinblatt, 2001). Poor functional status is a powerful predictor o f mortality with R A patients. Patients with increased dysfunction have higher mortality rates (Soderlin et al., 1998). Self-reporting tools used by R A patients provide researchers with valuable data on pain levels and loss o f function. Self-assessment scales are effective i n evaluating the efficacy o f therapies and the financial benefits o f expensive drug therapies and future treatment modalities (Lubeck, 2002: Dickerson and Fischer, 1995). The trend is increased use o f D M A R D s and D M A R D s i n conjunction with N S A I D s despite evidence that combination therapy increases toxicity (Ward & Fries, 1998).  26  Cyclosporin is a potent disease-modifying agent that is effective i n modifying disease progression and immunological responses. Unlike N S A I D s , which suppress and relieve symptoms only, C Y A is capable o f halting the progression o f the disease and continued degradation o f tissues. In addition to the severe side effect nephrotoxicity, one o f the debilitating side effects o f C Y A is gingival overgrowth. Used primarily as a transplant anti-rejection drug, the transplant literature shows a high occurrence o f the oral side effect, gingival enlargement, associated with the use o f cyclosporin. Gingival enlargement usually arises i n the anterior interdental regions and may be limited in size and location or may become more generalized and severe i n nature (Dahllof et al., 1992: Jones et al., 1988: Penarrocha-Diago et al., 1990). C Y A - i n d u c e d G O is more pronounced on the labial than lingual surfaces o f affected gingival (Tyldesley & Rotter, 1984). The degree o f G O has been related to dose, duration and plasma levels but the majority o f studies do not support this correlation (Dahloff .& Modeer, 1986; Penarrocha-Diago et al., 1990) C Y A G O generally begins i n the anterior o f the mouth within 1-3 months (Seymour & Jacobs, 1992). The role o f C Y A i n promoting the development o f G O is unclear. Primarily used i n transplantation immunosuppression, C Y A ' s effect on G O i n patients with rheumatoid arthritis is unknown. Previous studies have had conflicting results as to the relationship between plaque and the development o f G O . The incidence o f cyclosporin-induced G O varies between studies (Dongari et al., 1993; Seymour & Jacobs, 1992). The purpose o f this study was to determine the prevalence o f gingival enlargement in individuals with R A being treated with the immuno-suppressive medication  27  cyclosporin. R A patients who had begun participation in an initial trial o f the drug had not received oral assessments prior to initiation o f therapy. Oral manifestations of R A are not well documented in the literature. Physicians and nursing staff involved i n the clinical drug trial felt that, with compromised hand function and associated challenges with plaque control, the R A patients with their unique immune response may be at greater risk for G O and oral side effects than transplant study populations reported in the research literature. R A patients are routinely treated with Methotrexate ( M T X ) , a folic acid antagonist, which causes severe oral ulcerations. R A patients on M T X are slow to heal and at greater risk for infection than R A patients on non-steroidal anti-inflammatory drug ( N S A I D ) regimes. N S A I D s are used to control pain but do not modify the disease or to affect the destructive disease process. It was felt by the investigator that, because o f the unique immune response i n the R A study population, a longitudinal study was required to determine the time frame i n which drug treatment patients were most at risk and the prevalence and severity o f G O as a side effect o f C Y A use.  2.4  Research Question  Does plaque, as measured by the Silness & L o e and the O'Leary Plaque Indices, cause gingival enlargement in rheumatoid arthritis patients on cyclosporin? The relationship between plaque scores and the prevalence and severity o f gingival overgrowth w i l l be investigated.  28  CHAPTER 3: Methods and Materials  3.1  Study Participants  Study participants were recruited from the M a r y Pack Arthritis Centre Cyclosporin Clinic i n Vancouver on a voluntary basis. Study participants were examined for a period o f six months i n order to determine the prevalence o f G O and the time parameters when patients are most vulnerable for developing G O . Participants i n the cyclosporin drug trial were individuals identified as having aggressive and severe R A and being unresponsive to standard treatment regimes. A t the time o f this study cyclosporin was not approved for treatment o f R A . It was identified b y the medical staff at the M a r y Pack Arthritis Center that the disease o f numerous patients was not being successfully managed. Patients with severe and aggressive R A and who were unresponsive to standard treatments did not have a treatment alternative. Patients were permitted to receive C Y A through the Emergency Drug Release Program ( E D R ) o f the Canadian Federal Government's Health Protection Branch. A t the time of the research there was only one Drug Monitoring Clinic i n Canada permitted to use this regime for rheumatic disease patients. Cyclosporin had not been approved i n the United States for treating rheumatic diseases. Patients were monitored for high blood pressure and renal dysfunction throughout the study. Patients with a diastolic pressure greater than 95 m m H g or renal dysfunction evidenced by serum creatinine levels greater than 30% over baseline were withdrawn from the study. Edentulous patients and patients who were taking a  29  combination o f methotrexate and C Y A or calcium channel blockers were excluded from the study.  3.2  Patient Examination  Gingival enlargement usually occurs i n the anterior interdental regions and may be limited i n size and location or become generalized and severe. G O i n the treatment o f R A is not well documented. The literature on drug-induced G O is more comprehensive on patients treated with calcium channel blockers, anti-epileptic drugs and C Y A used in transplant patients. Examination o f the twelve anterior teeth is the standard for G O observation. R A patients have a unique immune system compared to these patients, so to increase reliability, an extended oral examination is appropriate (Rams et al., 1993). G O most frequently occurs i n the anterior region (Dahllof et al., 1992; Jones et al., 1988; Penarrocha-Diago et al, 1990). In a previous prospective study o f R A patients taking C Y A , the buccal surface o f a mandibular molar tooth was the only surface to present with m i l d G O . In this study we chose to include all anterior teeth and the first molar in the examination. If the first molar was not present, the second molar was included. Patients were examined at the M a r y Pack Arthritis Centre in Vancouver i n a patient assessment room. A portable dental chair and a standard floor-based dental light were used for each examination. Intra-oral photographs were taken using Kodak Kodachrome 64, 35 m m colour film. M a x i m u m opening and recession were recorded at baseline and each subsequent examination. Periodontal probing depths were measured to the nearest millimeter using a colour-coded Hu-Friedy probe with demarcations o f 3, 6, 9, and 12 m m . A l l  30  measurements were taken from the crest o f the gingival margin to the sulcus depth at six points around each tooth: buccal-mesial, buccal-mid-point, buccal-distal, lingual-mesial, lingual-mid-point, and lingual-distal. Gingival recession was recorded from the cementoenamel junction (CEJ) to the crest of the G M at the same six points. Surfaces having cervical restorations were noted (Thomason et al., 1993). To clearly establish the clinical crown, the C E J to sulcus depth was also recorded on patients with recession. This assisted the investigator i n determining the presence o f gingival enlargement or increased sulcus depth. Patients were examined at Day Zero prior to or on the first day o f initiation o f the drug treatment regime. A l l data and indices were recorded including the Arthritis Hand Function Test ( A H F T ) and the Oral Health Impact Profile (OHIP) which were not included i n this study. Patients were re-examined every 4-6 weeks for six months. G O most frequently occurs i n the first three months o f C Y A treatment (Dahllof et al., 1992; Jones et al., 1988; Penarrocha-Diago et al., 1990). A l l data was collected by one clinical examiner who was blinded to the drug trial group being examined. In a previous observational study the examiner had been calibrated to a 95% reliability i n assessing G O , plaque and PGII with other examiners i n that study. 3.3  P l a q u e Indices  Plaque plays an important role i n gingival inflammation and enlargement (Shibley et al., 1995). Plaque has been linked to the development o f G O i n patients on C Y A . It was therefore important to assess the relationship between plaque and the incidence and severity o f G O in this R A patient pool. Plaque indices vary i n their intent to assess the presence o f plaque or the quality of plaque present. Some indices such as  31  the N a v y Index o f Hancock and Wirthlin are regarded as weak i n identifying subtle changes in plaque development. It also scores occlusal surfaces that are not o f interest in this study but would be in studies o f oral hygiene effectiveness. Each index is useful in a variety o f applications dependent on the purpose o f the study and the use o f more than one is sometimes beneficial (Ainamo & B a y , 1975). It was decided that the use o f two indices would provide a more comprehensive assessment o f plaque for this study. The selected indices have been used extensively i n C Y A G O research: the Silness & Loe (Seymour, 1991; K i n g & Fullinfaw,1993) and the O'Leary (Hefti et al., 1994; O ' V a l l e et al., 1995; Somacarrera et al., 1994a). The O'Leary Plaque Index is used to establish only the presence o f plaque (O'Leary et al., 1972). Extent o f plaque is not reflected i n this index and there is no qualitative or quantitative measurement to this index (Table 3). The plaque is scored by examining the study teeth for visible plaque. The plaque is recorded as present or absent without qualifiers. The number o f assessment points on the tooth surfaces with plaque present is multiplied by 100 and divided by the number o f assessment points scored i n the examination. The resulting score is expressed as a percentage o f surfaces with plaque. A score o f 10% or less is considered good oral hygiene.  Table 3: O'Leary Plaque Index Total Number o f Surfaces with Plaque Number o f Teeth Present X 6  X  100 = % score  The Silness & Loe Index was recorded after the O ' L e a r y to determine i f the degree o f plaque was a factor in the development o f G O . The Silness & Loe Plaque Index (Table 4) measures the amount o f plaque present (Silness & Loe, 1964). Each tooth  32  is dried and examined for plaque. A probe is used to determine the amount o f plaque present. The probe is moved across the tooth at the gingival margin and examined at each o f the six assessment points. If there is no plaque on the probe, the tooth is considered plaque free with a score o f "0". If the plaque is not visible but is visible on the probe after the probe is moved over the tooth surface, a score o f " 1 " is given. Plaque visible to the naked eye is scored " 2 " and heavy accumulation filling the gingival crevices is scored " 3 " . Scores are added and divided by the number o f surfaces for a score o f 0-3. The nominal scale awards a rating o f "Excellent" oral hygiene for a score o f "0", " G o o d " for a score o f 0.1-0.9, "Fair" for 1.0-1.9, and P o o r " for 2.0-3.0.  Table 4  Silness & Loe Plaque Index  Score 0 = Gingival area o f tooth is free o f plaque; the surface is tested by running a probe across tooth surface. If no material adheres, the surface is considered plaque free. 1 = N o plaque observed i n situ with the unaided eye, but plaque is made visible on the point o f a probe after the probe is moved over the tooth surface at the entrance to the gingival crevice. 2 = Gingival area is covered b y a thin to moderately thick layer o f plaque visible to the naked eye. 3 = Heavy accumulation o f soft matter, the thickness o f which fills the crevice produced by the gingival margin and the tooth surface. Rating Excellent Good Fair Poor  Scores 0 0.1-0.9 1.0-1.9 2.0-3.0  The Silness & L o e Plaque Index measures the thickness o f the plaque but does not evaluate the advancement o f the plaque towards the incisal surfaces. This was appropriate for this study group as we anticipated at least a minimal level o f oral  33  hygiene. Routine tooth brushing may be effective on the flat coronal surfaces o f the teeth with plaque remaining i n the gingival areas. The presence o f plaque i n contact with tissues is o f greater interest than the effectiveness o f tooth brushing on coronal areas. Plaque scores were recorded at each appointment. Participants did not receive oral hygiene instruction. Disclosing agents were not used i n order to facilitate assessment o f gingival inflammation and probing depths. Plaque was recorded at six points on each tooth: buccal-mesial, buccal-mid-point, buccal-distal, lingual-mesial, lingual-mid-point, and lingual-distal. 3.4  G i n g i v a l Inflammation Index  Gingival inflammation (GI) is strongly correlated with G O in the Cyclosporin literature. Bleeding is a parameter b y which the presence o f GI is determined. Bleeding may not be a predictor o f periodontal disease activity but is accepted as a indicator o f gingival inflammation (Chaves et al., 1993). Prior to evidence o f bleeding, gingival changes may be identified such as colour and contour (Bollmer et a l , 1986). Some indices record changes i n colour, tone and bleeding i n a single score (Silness & Loe, 1964). This is a reliable method for determining tissue changes i n a non-GO population. Increased tissue masses due to enlargement may obscure bleeding and tissue responses may not correspond to those anticipated i n a general population. A gingival inflammation index was selected that assessed all three aspects o f gingival inflammation (colour, tone and bleeding) individually. The Phenytoin Gingival Inflammation Index (PGII) (Hassell et al., 1984) is a wellvalidated tool for assessing tissue changes, examining colour, tone and bleeding on  34  separate scales of 0-2 (Table 5). Colour is assessed on a three point scale with "0" being no clinical reddening; "1" areas of reddening of papillary or marginal tissue; "2" generalized or extreme reddening or cyanotic appearance. Tone scores "0" for firm resilient tissue, "1" for slightly edematous, and "2" for moderate to severe edema and/or tissue friability. Bleeding is assessed with paper points: "0" no bleeding, "1" blood on the tip of paper point and "2" clinically evident bleeding from the sulcus marginal gingiva or papilla after insertion.  Table 5  Phenytoin Gingival Inflammation Index  Colour Scores 0 = no clinical reddening 1 = areas of reddening of papillary or marginal tissue 2 = generalized or extreme reddening or cyanotic appearance Tone scores 0 =firmresilient tissue 1 = slightly edematous 2 = moderate to severe edema and/or tissue friability Bleeding 0 = no bleeding 1 = blood on the tip of paper point 2 = clinically evident bleeding from the sulcus marginal gingiva or papilla after insertion Tissues were examined at each appointment every 4-6 weeks. Changes in tissue contour, colour and bleeding were recorded.  3.5  Gingival Overgrowth Index  Two indices have been most frequently used to assess gingival overgrowth: the Hyperplastic Index (Table 6) and the Gingival Overgrowth Index (Table 8). The Hyperplastic Index originally used in phenytoin research (Conrad et al., 1974) assesses GO in the horizontal dimension only. Tissues are examined for the presence  35  o f blunting or enlargement and scored on a four point scale (see Table 6) (Pernu et a l , 1993; Pan et al., 1992; M ° G a w et al., 1987).  Table 6  The Hyperplastic Index  Score 0 = no gingival overgrowth or enlargement 1 = mild hyperplasia defined as blunting o f the papilla 2 = moderate hyperplasia with tissue covering up to 1/2 o f the crown 3 = marked hyperplasia with tissue on more than 1/2 the crown This index was modified to include an assessment o f the vertical component o f G O ( K i n g & Fullinfaw, 1993) (Table 7) The vertical measurement was assessed on a three point scale; 0 = normal width o f free gingival margin; 1 = thickening from normal up to 2 mm; 2 = thickening from normal greater than 2 m m . Alginate impressions were taken when possible. If alginate impressions were not possible, the G O was assessed chairside by the investigator.  Table 7  Horizontal Dimension Score Modification to the Hyperplastic Index  Vertical dimension score 0 = normal width o f free gingival margin 1 = thickening from normal up to 2 m m 2 = thickening from the normal greater than 2 m m It was apparent, after discussions with the medical staff, that i n this study group alginate impressions at each appointment were impractical due to jaw dysfunction, undetermined periodontal status and patient stamina. The Gingival Overgrowth Index, a modification by Angelopoulos and Goaz, assesses the vertical dimension and the gingival changes i n the development o f G O . A score o f " 1 " indicates m i l d G O with a thickening o f the marginal gingiva and/or lobular granulation o f the gingival pocket with enlargement covering up to one-third o f the crown. G O  36  extending to the middle o f the tooth scores " 2 " for moderate G O , and G O extending to two-thirds or more o f the crown or affecting the attached gingiva is scored " 3 " for severe G O .  Table 8  Gingival Overgrowth or Enlargement b y Angelopoulos & Goaz  0 = no G O 1 = mild G O (thickening o f the marginal gingiva and/or lobular granulation o f the gingival pocket with G O covering up to 1/3 o f the crown) 2 = moderate G O (overgrowth extending to the middle o f the crown) 3 = severe G O (overgrowth covering 2/3 o f the crown or affectation o f the attached gingiva) C Y A - i n d u c e d G O is frequently described as raspberry-like in appearance with the inflammation represented by red glazed tissues. It is not fibrotic and pale as described i n the phenytoin literature. The Angelopoulos & Goaz Index is an effective measurement for recording lobular tissue changes that occur i n C Y A G O . Papillae are often irregularly swollen or lobulated near the apex and may extend on to the crown without affecting the marginal tissue. G O was recorded at each appointment.  3.6  Quality of Life Visual Analogue Scale  Patients were asked to complete a Quality o f Life ( Q O L ) Visual Analogue Scale at the initial and final appointments. Transplant patients on C Y A and other immunosupressive agents report a higher Q O L than a control group o f a healthy population (Evans, 1991). Quality o f life is a subjective assessment and is influenced by many factors. Self-assessment o f Q O L is relative to other life events (Locker et al., 2000). For example, after a life threatening situation, day-to-day stressors become less important and Q O L may be assessed higher than the day before the life threatening event. Likewise, oral function may be taken for granted until oral complications  37  from new medications disrupt function and cause pain (Allison et al., 1997). However, self-assessment scales are an effective tool for patients to report pain levels and efficacy o f drug treatments (Lubeck, 2002; Dickerson and Oakley, 1995). The Q O L Visual Analogue Scale was included to assess any correlation between patient perception o f Q O L and the impact o f changes i n oral health.  3.7 Statistical Analysis The Statistical Package for the Social Sciences, SPSS, was used to analyze the data. One-way analysis o f variance ( A N O V A ) was used to analyze plaque scores versus bleeding, colour, tone, attachment loss and gingival enlargement. A N O V A reduces the risk o f type one errors. T w o sets o f data were computed, one with the Silnes & Loe Plaque Index and the other with the O ' L e a r y Plaque Index. Pearson correlation was used to correlate plaque indices to maximum opening and Quality o f Life V i s u a l Analogue scores as well as maximum opening and Q O L scores. Cross-tabulations were constructed using Cohen's Kappa to analyze attachment loss versus tone, bleeding and colour.  3.8 Ethical Approval Ethical approval was obtained from the Ethical Review Board for Research on Human Subjects at The University o f British Columbia.  38  Chapter 4: Results 4.1  Study Population  The total number o f participants who completed the study was 28: 22 were on cyclosporin and six took methotrexate. The subjects were predominately Caucasian (92%), with 4% Native and 4% Asian. Their ages ranged from 28 to 76 years o f age with a mean age o f 49.86 years (SD 9.69 yrs). The study population was 68% women and 32% men (Table 9). Cyclosporin dosages were comparable to current treatment dosages for transplant patients (Table 9). Dosages were based on the patient's weight to a maximum o f 5 mg/kg/day. The mean daily dosage was 270.45 mg/day. Patient dosages were between 150-400 mg/day with a median dose o f 250 mg/day. Patient participation and co-operation was excellent. O f the people who applied to be volunteers for the C Y A study, 97% agreed to be part o f this study. Seven individuals were excluded from the study due to the discontinuation o f the study medication. Reasons reported for withdrawal from the C Y A trial related to side effects that were determined to be unacceptable. The side effects were predominately related to increasingly compromised liver function and secondarily for gastrointestinal upset. One patient was withdrawn due to death from cardiac arrest. Reasons for withdrawal unrelated to this study were not reported to the investigator in any detail.  39  Table 9  Patient Gender Profile Cyclosporin  Methotrexate  Men  8 (36%)  1 (17%)  Women  14(64%)  5 (83%)  4.2  Gingival Overgrowth  There was no gingival overgrowth i n any o f the patients. G O did not correlate to plaque scores or any other variable (see Appendix).  4.3  Gingival Inflammation  The C Y A group had a mean plaque index o f 0.94 (SD+50) using the Silness & L o e Plaque Index (Table 10). The M T X group had a mean plaque score o f 0.86 ( S D + 0.82). The scores are comparable and indicate fair to good oral hygiene. U s i n g the O ' L e a r y Index, the C Y A group had a mean plaque score o f 55.66% ( S D + 25.77%). A score o f 10% is considered good oral hygiene. There was no significant correlation between tone and the O'Leary Plaque index (Table 11). The M T X group had a mean score o f 43.75 ( S D + 20.16), indicating less plaque present. Plaque scores did not significantly correlate with tone using A N O V A .  Table 10:  Decrease N o change Increase F-stat  Silness & Loe Plaque Index and Tone in C Y A Patients Tone 1.38542 0.8745 0.9539 16.59  SD .4708 .5193 .2731 p<.0001.  40  Table 11:  O'Leary Plaque Index and Tone in CYA Patients Tone 68.6036 52.510 69.9696 10.45  Decrease No change Increase F-stat 4.3.1  SD 31.5898 24.2920 20.970 p<.0001  Bleeding and Colour  There was a decrease in mean bleeding scores for 20.8% of the CYA patients and an increase for 11.7% of them. In the MTX group, 7% had a decrease and 10.5% had an increase in mean bleeding scores (Table 12).  Table 12  CYA Group: Change in bleeding, tone, and colour Bleeding  Tone  Colour  Decrease  20.8%  6.1%  14.1%  Increase  11.7%  5.0%  7.8%  14.1% of the CYA group demonstrated a decrease in colour score and 7.8% had an increase. The MTX group had less change with 1.4% having a decrease and 5.6% showing an increase in colour score (Table 13). Table 13:  MTX Group: Change in bleeding, tone and colour Bleeding  Tone  Colour  Decrease  7.0%  0  1.4%  Increase  10.5%  16.1  5.6%  One-way analysis of variance is used to analyze the relationship of plaque versus bleeding and colour. The findings for plaque and bleeding, plaque and tone and plaque and colour using the Silness & Loe Plaque Index were not statistically significant. Plaque and colour, were weakly significant using the O'Leary Index.  41  There was a weak inverse relationship between plaque and colour, with higher plaque scores having a reduced colour score.  T A B L E 14 Silness and Loe Bleeding Decrease 1.0684 N o change 0.8410 Increase 1.0217 F-stat 10.74 P<.0001 O'Leary Plaque Index Bleeding Decrease 58.0792 N o change 51.7765 Increase 62.6148 F-stat 5.72 p=.0035  4.4  SD 1.0684 .8410 1.0217  Colour 1.2428 1 0.8437 0.9658 21.88 p<.0001  SD 0.5549 0.4389 0.3468  SD 27.5437 23.7314 26.3918  Colour 61.9538 52.4703 59.5278 4.82 p=.0085  SD 30.9049 23.9072 22.8954  Quality of Life  Quality o f life was found to correlate to maximum opening. The mean quality o f life at the beginning o f the study was 70.09 (SD+J.7.38) for the C Y A group and 67.67 (SD ± 25.97) for the M T X group. A t the completion o f the study Q O L was 66.5 (SD +21.42) for the C Y A group and 60.67 (SD + 26.67) for the M T X group. The mean difference was -3.59 for the C Y A group and -7.00 for the M T X group. Participants who had improved joint function self-rated a higher quality o f life on the visual analogue scale. Patients with reduced maximum opening reported lower quality o f life scores (Table 15). Patients were not asked to relate maximum opening to quality o f life and nor were they asked to specifically relate oral health to their quality o f life when completing the visual analogue scale. A t the completion o f the  42  last exam patients were asked to complete an Oral Health Impact Profile questionnaire the results o f which are not part o f this study.  Table 15: Quality o f Life Scores CYA Q O L start Q O L end Difference  MEAN 70.09 66.5 -3.59  SD 17.38 21.42 21.90  MIN 33 29 -59  MAX 98 100 +36  MTX Q O L start Q O L end Difference  MEAN 67.67 60.67 -7.0  SD 25.97 26.67 15.32  MIN 34 35 -37  MAX 97 92 6  Pearson correlations were used to compute the relationship between quality o f life and maximum opening. There was an inverse relationship between initial Q O L and maximum opening (Figure 2).  Figure 2  C Y A Initial Q O L vs M a x Opening Quality of Life (Start) v s Change in Max Opening  100 -\  -15  -10  -5  O  1Q  5  Change In Max Opening  43  Figure 3  C Y A End Q O L Score vs M a x i m u m Opening Quality of Life (End) vs Change in Max Opening -428-  CO  o  20  -10  -5  0 Change in Max Opening  Individuals who had an increase i n joint function reported an increased Q O L at the completion o f the study (Figure 3).  44  Figure 4  C Y A Change i n Q O L vs M a x Opening Change in Quality of Life vs Change in Max Opening -69-  40  -80 Change in Max Opening  Changes i n Q O L correlated with maximum opening. Patients with a negative change in maximum opening at the completion o f the study reported a lower Q O L than at the start o f the study (Figure 4).  45  CHAPTER 5: 5.1  DISCUSSION  Gingival Overgrowth  The role o f C Y A on the incidence o f G O is not consistent between studies. None o f the participants i n this study demonstrated any manifestations o f C Y A - i n d u c e d G O . The frequency o f C Y A - i n d u c e d G O has been reported as high as 70% i n Type I diabetes patients. The weak correlation between plaque and G O may be related to the increased challenge o f removing plaque from the irregularities created b y G O . Medication dosage also did not relate to the incidence o f G O i n the diabetic group. M a n y studies have shown that dose is unrelated (Daly, 1992; Daley et al., 1986; W y s o c k i et al., 1983; M G a w et al., 1987; Seymour, 1991). Renal transplant patient c  studies have reported a 48% incidence o f G O . The indices used may reflect a false positive. A Silness & Loe Plaque Index score o f "2", which indicates significant plaque levels, scored only " 1 " on the hyperplastic index defined as blunting o f the interdental papilla. These findings show that individuals with moderate plaque demonstrate the early signs o f inflammation but it is reported as G O (Figure 5). A plaque score o f " 2 " would be expected i n a healthy population, or a n o n - C Y A treatment group—some inflammatory response with blunting and bleeding, the usual early manifestations o f gingivitis (Van der Weijden et al., 1994; Wilkins, 1999). Studies reporting significant incidence o f G O state that the average scores o f patients with G O were "1.2" on the hyperplastic index, indicating relatively low severities o f tissue changes. This may also be attributed to signs o f gingival inflammation (Haffajee et a l , 1991). Other studies combined scores o f " 1 " and " 0 " due to  46  examiner inability to calibrate on these two scores (Hefti et a l , 1994). The incidence o f G O was significantly reduced from earlier studies.  Figure 5: C Y A Patient's Gingival Condition Day Zero: blunting and lobular changes evident prior to initiation o f drug therapy  47  The majority o f C Y A - i n d u c e d studies are cross sectional (Savage et al., 1987; Montebugnoli et al., 1996; K i n g & Fullinfaw, 1993). Longitudinal studies are usually initiated after drug therapy and the presence o f G O is evident. Existing gingival inflammation would be recorded as mild G O and would inflate the prevalence o f G O . Type I diabetics are more at risk for G O as children and adolescents than as adults. Adult renal transplant patients have a greater frequency o f G O than children in the same population group. Studies reporting age as a significant factor state that the first and second decades are the years most likely to have G O . In heart transplant patients, the highest incidence o f G O was in the second and third decades o f life (Somacarrera et al., 1994a). This study group did not have any participants i n the child or adolescent years. The youngest patient in the R A study group was i n her third decade and the eldest in her eighth decade. There were no significant findings associated with aging in this study. A larger study population with children and adolescents is required to determine i f R A patients respond similarly to Type I diabetes patients. The dosages o f C Y A in this study are comparable to renal transplant dosages. The literature indicates that dosage is not a causative factor, therefore the lack o f G O can not be attributed to low dose C Y A , ( W y s o c k i et al., 1983; M c G a w et al., 1987; Seymour, 1991). It is possible that different existing immunological conditions affect the influence o f C Y A on gingival tissues. In heart transplant patients, C Y A - i n d u c e d G O decreased or resolved over time without intervention. Patients i n this study had improvements i n  48  G I evidenced b y reductions i n redness. Heart transplant patients taking C Y A for less than 36 months showed more G O than patients on C Y A for longer than 36 months, demonstrating that G O is not simply a pharmacokinetic phenomenon (Montebugnoli et al., 1996). The unique immune system o f R A patients may response differently to C Y A than other populations. Systemic Lupus Erythematosus, a rhematoid disease, affects kidney function. S L S sufferers develop renal dysfunction as a manifestation o f their primary disease. When renal transplants were undertaken, the long-term survival rate for S L S renal transplants was significant higher than for non-SLS patients (Roth et al., 1987). Further study o f the effects o f C Y A i n R A populations is required. Figure 6: Tissue Changes in a Patient on Cyclosporin D a y Zero; edema, lobular changes and redness are evident prior to drug therapy  49  Figure 7: Tissue Changes in a Patient on Cyclosporin D a y Sixty; a reduction in redness is evident  Figure 8: Tissue Changes in a Patient on Cyclosporin D a y Ninety; decreased redness and edema/lobulation are evident  50  5.2 Gingival Inflammation and Bleeding There were no significant findings for the relationship o f G I and G O i n this study. Bleeding and tone did not significantly relate to plaque scores. The absence o f G O negates any relationship between G I and G O . There was a weak inverse relationship between colour and plaque using the O'Leary Plaque Index. A slight decrease i n colour occurred in patients with marked inflammation scores. This was an unanticipated result. Previous C Y A studies that report a decrease i n G O may have been observing a decrease in G I that was not recorded i n initial observations.  5.3 Quality of Life Quality o f life is a subjective measure and significantly influenced by life events (Evans, 1991). Study participants may have been optimistic about the potential o f a new drug regime for the management o f their disease. Participants i n the drug trial had severe or aggressive R A and were considered non-responsive to routine treatment regimes including M T X . Patients who did not perceive a benefit o f increased function and reduced pain may have viewed their quality o f life as poorer than those who felt their disease was being controlled by the new medication (Allison et al., 1997).  5.4 Future Considerations More longitudinal studies are required to examine pre-existing conditions more effectively prior to the initiation o f C Y A therapy. The oral condition o f individuals with R A needs to be researched and isolated from other rheumatoid conditions. Change i n tissue, and not present condition, needs to be reported more frequently to ensure accurate reporting o f G O and not G I . This w i l l narrow the evidence  51  surrounding the incidence o f G O and may clarify causative factors. G I is considered to be an immunological response and consideration must be given to the effect o f a suppressed immune system on existing G I . The role o f C Y A on the immune response during a phase o f periodontal breakdown may lead to the development o f alternative periodontal treatments using immunosuppressive drugs (Kjeldsen et al., 1993).Topical treatments may be able to affect inflammatory immune responses without the undesirable systemic toxicity.  52  CHAPTER 6: CONCLUSION  The effect o f cyclosporin on human gingival tissues was not evident i n this study. Instead o f the anticipated appearance o f gingival overgrowth, there was a reduction o f the existing inflammation i n the participants' gingivae. Traditional theories o f gingival inflammation and periodontal diseases are linked with the host response to pathogens. For disease to occur, there must be a virulent pathogen i n sufficient numbers, the host must be susceptible, and the environment must be conducive to the pathogen (Socransky et al., 1992; Socransky & Haffajee, 1991). During this study, one o f these areas may have been affected to result i n a decrease i n inflammation. Plaque levels remained constant. Oral hygiene instruction was not given and patients continued with previously-established care routines. Cyclosporin may impact the virulence o f mouth bacteria or its ability to produce endotoxins to stimulate an inflammatory response i n the host. Pathogens may adapt to the environment, altering their own virulence factors, i f C Y A creates an inhospitable environment. C Y A affects the activity o f T cells and the production o f I L - 1 , which plays a role in the process o f periodontal disease and tissue inflammation. IL-1 is increased i n the gingival fluids extracted from inflamed sites i n periodontal patients. Mouse splenic lymphocytes are more sensitive to C Y A than L P S , which may reduce the host inflammatory response to putative pathogens (Wiesinger & Borel, 1979). The synthesis o f IL-1 is inhibited by C Y A , yet studies report histological changes i n fibroblasts. Fibroblasts in C Y A lesions have increased cytoplasmic volume but not number. W i t h IL-1 inhibited, another mechanism i n some individuals may impact  53  fibroblast development, resulting i n G O responders and non-responders in C Y A patient populations. The host's ability to regulate fibroblast integrity may be compromised b y the presence o f C Y A . The impact o f IL-1 on collagen or collagenase may impact gingival overgrowth formation. Fibroblasts may be aging abnormally due to poor growth regulation. Patients demonstrating G O may be having an abnormal inflammatory response. W i t h cellular immunity reduced, alternative mechanisms may be responding to specific mitogens. Healing mechanisms may be altered. The regulation o f tissue remodeling may be compromised i f IL-1 and fibroblast function is compromised. The prevalence o f G O may have been overstated i n early studies. Early studies may not have recognized calcium channel blockers as GO-inducing medications. A common side effect o f C Y A is hypertension, so the influence o f calcium channel blockers on the reported frequency o f G O may be significant. Nifedipine causes G O in 24%-38% o f patients and 4% o f the population demonstrates idiopathic G O (Steele & Schreiber, 1994). These factors are not accounted for i n C Y A studies. 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Frequency T a b l e s  (per t o o t h ) , s p l i t by  Group  CYA  MBLEED Mesial - Bleeding Value L a b e l Value -2 -1 0 1 2 3  Valid  cases  461  Total M i s s i n g cases  FBLEED F a c i a l - Bleeding Value L a b e l Value -2 -1 0 1 2  Valid  cases  461  cases  461  MTONE M e s i a l - Tone Value L a b e l  V a l i d cases  461  67  528  67  Frequency 20 45 370 16 10 67  Total M i s s i n g cases Value -2 -1 0 1  528  Frequency 9 7 430 10 5 67  Total M i s s i n g cases  DBLEED D i s t a l - Bleeding Value Label Value -2 -1 0 1 2  Valid  Frequency 14 42 372 20 12 1 67  528  100  0  Percent 1 7 1 3 81 4 1 9 9 12 7 100  0  Percent 3 8 8 5 70 1 3 0 1 9 12 7 100  0  Valid Percent 3.0 9.1 80.7 4.3 2.6 .2 Missing 100.0 Valid Percent 2.0 1.5 93.3 2.2 1.1 Missing 100.0 Valid Percent 4.3 9.8 80.3 3.5 2.2 Missing 100.0  67  Frequency 10 7 430 14 67  Total M i s s i n g cases  Percent 2 7 8 0 70 5 3 8 2 3 2 12 7  528  67  Percent 1 9 1 3 81 4 2 7 12 7 100  0  Valid Percent 2.2 1.5 93.3 3.0 Missing 100.0  FTONE F a c i a l - Tone Value L a b e l  V a l i d cases  461  Value -2 -1 0 1  Total M i s s i n g cases  DTONE D i s t a l - Tone Value L a b e l  V a l i d cases  461  Value • -2 -1 0 1  461  Value -2 -1 0 1  V a l i d cases  461  DCOLOOR D i s t a l - Colour Value L a b e l  V a l i d cases  461  Value -2 -1 0 1  V a l i d cases  461  67  528  67  528  67  Frequency 12 38 402 9 67  Total M i s s i n g cases  MATTACH M e s i a l - Attachment Value L a b e l Value -4 -3 -2 -1 0 1 2  528  Frequency 13 14 409 25 67  Total M i s s i n g cases Value -2 -1 0 1  67  Frequency 12 40 399 10 67  Total M i s s i n g cases  FCOLOUR F a c i a l - Colour Value L a b e i •  528  Frequency 12 7 429 13 67  Total M i s s i n g cases  MC0L0OR Mesial - Colour Value L a b e l  V a l i d cases  Frequency 2 4 451 4 67  528  67  Frequency 1 2 7 56 327 59 9 67  Total M i s s i n g cases  528 • 67  Percent 4 8 85 4 8 12 7  Valid Percent .4 .9 97.8 .9 Missing  100 0  100.0  Percent 2 3 1 3 81 3 2 5 12 7  Valid Percent 2.6 1.5 93.1 2.8 Missing  100 0  100.0  Percent 2 3 7 6 75 6 1 9 12 7  Valid Percent 2.6 8.7 86.6 2.2 Missing  100 0  100.0  Percent 2 5 2 7 77 5 4 7 12 7  Valid Percent 2.8 3.0 88.7 5.4 Missing  100 0  100.0  Percent 2 3 7 2 76 1 1 7 12 7  Valid Percent 2.6 8.2 87.2 2.0 Missing  100 0  100.0  Percent 2 4 1 3 10 6 61 9 11 2 1 7 12 7  Valid Percent .2 .4 1.5 12.1 70.9 12 . 8 2.0 Missing  100.0  100.0  FATTACH Facial Value L a b e l  V a l i d cases  cases  Attachment Value -3 -2 -1 0 1 2 4  461  461  TTONE T o t a l - Tone Value L a b e l  Value -6 -4 -3 -2 -1 0 1 2 3 4 5  67  528  67  Frequency 5 4 3 30 54 311 24 25 3 1 1 67  Total M i s s i n g cases Value -6 -4 -2 -1 0 1 2 3  528  Frequency 1 3 38 353 57 8 1 67  Total M i s s i n g cases  TBLEED Total - Bleeding Value L a b e l  V a l i d cases  Frequency 5 29 366 59 2 67  Total M i s s i n g cases  461  DATTACH Distal Value L a b e l  Valid  Attachment Value -2 -1 0 1 2  528  67  Frequency 1 9 4 14 410 19 2 2 67  Percent 9 5 5 69 3 11 2 4 12 7  Valid Percent 1.1 6.3 79.4 12.8 .4 Missing  100 0  100.0  Percent 2 6 7 2 66 9 10 8 1 5 2 12 7  Valid Percent .2 .7 8.2 76.6 12.4 1.7 .2 Missing  100 0  100.0  Percent 9 8 6 5 7 10 2 58 9 4 5 4 7 6 2 2 12 7  Valid Percent 1.1 .9 .7 6.5 11.7 67.5 5.2 5.4 .7 .2 .2 Missing  100 0  100.0  Percent 2 1 7 8 2 7 77 7 3 6 4 4 12 7  Valid Percent .2 2.0 .9 3.0 88.9 4.1 .4 .4 Missing  Total 528 100 0 V a l i d cases 461 M i s s i n g cases 67 TCOLOUR Total - Colour Value L a b e l Value Frequency P e r c e n t -6 12 2 3 -3 11 2 1 -2 16 3 0 -1 4 9 26 360 68 2 . 0 1 31 5 9 2 5 9 67 12 7 V a l i d cases  461  Total M i s s i n g cases  528  67  100 0  100.0 Valid Percent 2.6 2.4 3.5 5.6 78.1 6.7 1.1 Missing 100.0  TATTACH T o t a l - Attachment Value Label Value -6 -4 -3 -2 -1 0 1 2 3 4  V a l i d cases  461  MBLEED2 Mesial-Bleeding Value L a b e l Decrease No Change Increase  Valid  cases  461  FBLEED2 F a c i a l-Bleeding Value Label Decrease No Change Increase  V a l i d cases  461  DBLEED2 D i s t a l- B l e e d i n g Value Label Decrease No Change Increase  Valid  cases  461  Total M i s s i n g cases  461  Total M i s s i n g cases  461  67  528  67  (categoric) Value Frequency -1 16 0 430 1 15 67 Total M i s s i n g cases  528  67  (categoric) V a l u e Frequency -1 65 0 370 1 26 67 Total M i s s i n g cases  528  67  Frequency 17 430 14 67  Total M i s s i n g cases  FT0NE2 F a c i a l -Tone ( c a t e g o r i c ) Value L a b e l Value Decrease -1 No Change 0 Increase 1  V a l i d cases  528  (categoric) Value Frequency -1 56 0 372 1 33 67  MT0NE2 M e s i a l -Tone ( c a t e g o r i c ) Value Label Value Decrease -1 No Change 0 Increase 1  V a l i d cases  Frequency 1 3 6 24 58 250 • 66 37 11 5 67  528  67  Frequency 6 451 4 67  Total M i s s i n g cases  528 67  Valid Percent Percent 2 .2 6 .7 1 1 1.3 4 5 5.2 11 0 12.6 47 3 54 .2 12 5 . 14.3 7 0 8.0 2 1 2.4 9 1.1 12 7 Missing 100 0  100.0  Percent 10 6 70 5 6 3 12 7  Valid Percent 12.1 80.7 7.2 Missing  100 0  100 . 0  Valid Percent Percent 3 0 3.5 81 4 ' 93.3 2 8 . 3.3 12 7 Missing 100 0  100.0  Percent 12 3 70 1 4 9 12 7  Valid Percent 14.1 80.3 5.6 Missing  100 0  100.0  Percent 3 2 81 4 2 7 12 7  Valid Percent 3.7 93.3 3.0 Missing  100 0  100.0  Percent 1 1 85 4 8 12 7  Valid Percent 1.3 97.8 .9 Missing  100.0  100.0  DT0NE2 Distal-Tone (categoric) Value L a b e l Value Decrease -1 No Change 0 Increase 1  V a l i d cases  461  Frequency 19 429 13 67  Total M i s s i n g cases  528  67  MC0L0UR2 M e s i a l - C o l o u r ( c a t e g o r i c ) Value L a b e l Value Frequency Decrease -1 52 No Change 0 399 Increase 1 10 67 V a l i d cases  461  Total M i s s i n g cases  528  67  FC0L0UR2 Facial-Colour (categoric) Value L a b e l Value Frequency Decrease -1 27 No Change 0 409 Increase 1 25 67 V a l i d cases  461  Total M i s s i n g cases  528  67  DC0L0UR2 D i s t a l - C o l o u r ( c a t e g o r i c ) Value L a b e l Value Frequency Decrease -1 50 No Change 0 402 Increase 1 9 67 V a l i d cases  461  Total M i s s i n g cases  528  67  MATTACH2 M e s i a l - A t t a c h m e n t ( c a t e g o r i c ) Value L a b e l Value Frequency Decrease -1 66 No Change 0 327 Increase 1 68 67 V a l i d cases  461  Total M i s s i n g cases  528  67  FATTACH2 F a c i a l - A t t a c h m e n t ( c a t e g o r i c ) Value L a b e l Value Frequency Decrease -1 34 No Change 0 366 Increase 1 61 67 V a l i d cases  461  Total M i s s i n g cases  528  67  DATTACH2 D i s t a l - A t t a c h m e n t ( c a t e g o r i c ) Value L a b e l Value Frequency Decrease -1 42 No Change 0 353 Increase 1 66 67 V a l i d cases  461  Total M i s s i n g cases  528  67  Percent 3 6 81 3 2 5 12 7  Valid Percent 4.1 93.1 2.8 Missing  100 0  100.0  Percent 9 8 75 6 1 9 12 7  Valid Percent 11.3 86.6 2.2 Missing  100 0  100.0  Percent 5 1 77 5 4 7 12 7  Valid Percent 5.9 88.7 5.4 Missing  100 0  100.0  Percent 9 5 76 1 1 7 12 7  Valid Percent 10.8 87.2 2.0 Missing  100 0  100.0  Percent 12 5 61 9 12 9 12 7  Valid Percent 14.3 70.9 14.8 Missing  100 0  100.0  Percent 6 4 69 3 11 6 12 7  Valid Percent 7.4 79.4 13.2 Missing  100 0  100.0  Percent 8 0 66 9 12 5 12 7  Valid Percent 9.1 76.6 14.3 Missing  100 0  100.0  TBLEED2 T o t a l -Bleeding Value L a b e l Decrease No Change Increase  V a l i d cases  461  (categoric) Value Frequency -1 96 0 311 1 54 67 Total M i s s i n g cases  TT0NE2 T o t a l -Tone ( c a t e g o r i c ) Value Label Value Decrease -1 No Change 0 Increase 1  V a l i d cases  461  TC0L0UR2 T o t a l -Colour Value Label Decrease No Change Increase  V a l i d cases  461  461  67  Frequency 28 410 23 67  Total M i s s i n g cases  528  67  (categoric) Value Frequency -1 65 0 360 1 36 67 Total M i s s i n g cases  TATTACH2 T o t a l -Attachment Value L a b e l Decrease No Change Increase  V a l i d cases  528  528  67  (categoric) Value Frequency -1 92 0 250 1 119 67  Total M i s s i n g cases  528  Percent 18 2 58 9 10 2 12 7  Valid Percent 20.8 67 . 5 11.7 Missing  100 0  100.0  Percent 5 3 77 7 4 4 12 7  Valid Percent 6.1 88 . 9 5.0 Missing  100 0  100.0  Percent 12 3 68 2 6 8 12 7  Valid Percent 14.1 78 .1 7.8 Missing  100 0  100.0  Valid Percent. .Percent 17 4 20.0 47 3 54 .2 22 5 25.8 12 7 Missing  67  100 0  100.0  Percent 4 9 88 2 5 6 7 7  Valid Percent 4.9 88.8 5.6 .7 Missing  100 0  100.0  Percent 7 97 2 1 4 7  Valid Percent .7 97 . 9 1.4 Missing  100 0  100.0  B . MTX MBLEED Mesial - Bleeding Value Label Value -1 0 1 2  V a l i d cases  143  Total M i s s i n g cases  FBLEED F a c i a l - Bleeding Value Label Value -1 0 2  V a l i d cases  143  Frequency 7 127 8 1 1 144  1  Frequency 1 140 2 1  Total • 144 M i s s i n g cases 1  DBLEED D i s t a l - Bleeding Value L a b e l Value -1 0 1 2  V a l i d cases  Total M i s s i n g cases  143  MTONE M e s i a l - Tone Value L a b e l  V a l i d cases  Value 0 1 2  Value 0 1 2  DTONE D i s t a l - Tone Value L a b e l  V a l i d cases  Value 0 1 2  MCOLOOR Mesial - Colour Value L a b e l  V a l i d cases  Value 0 1  FCOLOOR F a c i a l - Colour Value L a b e l  V a l i d cases  Value -1 0 1 2  DCOLOUR D i s t a l - Colour Value L a b e l  V a l i d cases  143  Value' 0 1  144  1  144  1  144  144  1  Frequency 140 3 1  Total M i s s i n g cases  Percent 4 2 88 2 6 3 7 7  Valid Percent 4.2 88.8 6.3 .7 Missing  100 0  100.0  Percent 96 5 2 1 7 7  Valid Percent 97.2 2.1 .7 Missing  100 0  100.0  Percent 86 1 12 5 7 7  Valid Percent 86.7 12 . 6 .7 Missing  100 0  100.0  Percent 97 9 7 7 7  Valid Percent 98.6 .7 .7 Missing  100 0  100.0  Percent 96 5 2 8 7  Valid Percent 97.2 2.8 Missing  100 0  100.0  Percent 1 4 95 8 1 4 7 7  Valid Percent 1.4 96.5 1.4 .7 Missing  100 0  100.0  Percent 97 2 2 1 7  Valid Percent 97.9 2.1 Missing  100.0  100.0  1  Frequency 2 138 2 1 1  Total M i s s i n g cases  143  1  Frequency 139 4 1  Total M i s s i n g cases  143  144  Frequency 141 1 1 1  Total M i s s i n g cases  143  1  Frequency 124 18 1 1  Total M i s s i n g cases  143  144  Frequency 139 3 1 1  Total M i s s i n g cases  143  FTONE F a c i a l - Tone Value L a b e l  V a l i d cases  Frequency 6 127 9 1 1  144  1  MATTACH Mesial Value L a b e l  V a l i d cases  V a l i d cases  Attachment Value -1 0 1  Attachment Value -1 0 1 2 4  143  V a l i d cases  143  TTONE T o t a l - Tone Value L a b e l  V a l i d cases  143  TCOLOUR Total - Colour Value L a b e l  V a l i d cases  143  Value -2 -1 0 1 2 4  Value 0 1 6  1  144 1  144 1  Frequency 120 22 1 1  Total M i s s i n g cases Value -1 0 1 4  144  Frequency 1 9 118 12 1 2 1  Total M i s s i n g cases  144  1  Frequency 2 133 7 1 1  Total M i s s i n g cases  Percent 6 9 85 4 6 3 7 7  Valid Percent 7.0 86.0 6.3 .7 Missing  100 0  100.0  Percent 11 8 81 9 5 6 7  Valid Percent 11.9 82.5 5.6 Missing  100 0  100.0  Percent 6 3 86 1 5 6 7 7 7  Valid Percent 6.3 86.7 5.6 .7 .7 Missing  100 0  100.0  Percent 7 6 3 81 9 8 3 7 1 4 7  Valid Percent .7 6.3 82.5 8.4 .7 1. 4 Missing  100 0  100.0  Percent 83 3 15 3 7 7  Valid Percent 83.9 15.4 .7 Missing  100 0  100.0  Percent 1 4 92 4 4 9 7 7  Valid Percent 1.4 93.0 4.9 .7 Missing  100.0  100.0  1  Frequency 9 124 8 1 1 1  Total M i s s i n g cases  TBLEED Total - Bleeding Value L a b e l  144  Frequency 17 118 8 1  Total M i s s i n g cases  143  DATTACH Distal Value L a b e l  Frequency 10 123 9 1 1  Total M i s s i n g cases  143  FATTACH Facial Value L a b e l  V a l i d cases  Attachment Value -1 0 1 4  144  1  TATTACH T o t a l - Attachment Value L a b e l Value -3 -2 -1 0 1 2 3  V a l i d cases  143  MBLEED2 Mesial-Bleeding Value Label Decrease No Change Increase  V a l i d cases  143  FBLEED2 Facial-Bleeding Value Label Decrease No Change Increase  V a l i d cases  143  DBLEED2 D i s t a l- B l e e d i n g Value Label Decrease No Change Increase  V a l i d cases  143  Total M i s s i n g cases  143  Total M i s s i n g cases  143  Total M i s s i n g cases  143  144  1  144  1  (categoric) Value Frequency -1 6 127 0 1 10 1 Total M i s s i n g cases  144 1  Frequency 139 4 1  Total M i s s i n g cases  144 1  Frequency 124 19 1  Total M i s s i n g cases  DTONE2 Distal-Tone (categoric) Value Label Value No Change 0 Increase 1  V a l i d cases  1  (categoric) Value Frequency -1 1 0 140 1 2 1  FTONE2 F a c i a l -Tone ( c a t e g o r i c ) Value Label Value No Change 0 Increase 1  V a l i d cases  144  (categoric) V a l u e Frequency -1 7 127 0 1 9 1  MT0NE2 M e s i a l -Tone ( c a t e g o r i c ) Value Label Value No Change 0 Increase 1  V a l i d cases  Frequency 1 4 19 95 21 1 2 1  144  Valid Percent .7 2.8 13.3 66.4 14 .7 .7 1.4 Missing  100 0  100.0  Percent 4 9 88 2 6 3 7  Valid Percent 4.9 88.8 6.3 Missing  100.0  100.0  Percent .7 97 .2 1.4 .7  Valid Percent .7 97 . 9 1.4 Missing  100.0  100.0  Percent 4.2 88.2 6.9 .7  Valid Percent 4.2 88.8 7.0 Missing  100.0  100.0  Percent 96.5 2.8 .7  Valid Percent 97.2 2.8 Missing  100.0  100.0  Percent 86.1 13.2 .7  Valid Percent 86.7 13.3 Missing  100.0  100.0  Percent 97.9 1.4 .7  Valid Percent 98.6 1.4 Missing  1  Frequency 141 2 1  Total M i s s i n g cases  Percent 7 2 8 13 2 66 0 14 6 7 1 4 7  144  1  100.0  100.0  MC0L0UR2 M e s i a l - C o l o u r ( c a t e g o r i c ) Value L a b e l Value Frequency No Change 0 139 Increase 1 4 1 V a l i d cases  143  Total M i s s i n g cases  144 1  FC0L0UR2 F a c i a l - C o l o u r ( c a t e g o r i c ) Value L a b e l Value Frequency Decrease -1 2 No Change 0 138 Increase 1 3 1 Valid  cases  143  Total M i s s i n g cases  144 1  DCOLOUR2 D i s t a l - C o l o u r ( c a t e g o r i c ) Value L a b e l Value Frequency No Change 0 140 Increase 1 3 1 Valid  cases  143  Total M i s s i n g cases  144 1  MATTACH2 M e s i a l -Attachment ( c a t e g o r i c ) Value L a b e l Value Frequency Decrease -1 10 No Change 0 123 Increase 1 10 1 Valid  cases  143  Total M i s s i n g cases  144 1  FATTACH2 F a c i a l -Attachment ( c a t e g o r i c ) Value L a b e l Value Frequency Decrease -1 17 No Change 0 118 Increase 1 8 1 Valid  cases  143  Total M i s s i n g cases  144  cases  143  TBLEED2 T o t a l -B l e e d i n g Value L a b e l Decrease No Change Increase  Valid  cases  143  Total M i s s i n g cases  100.0  100.0  Percent 1.4 95.8 2.1 .7  Valid Percent 1.4 96.5 2.1 Missing  100.0  100.0  Percent 97.2 2.1 .7  Valid Percent 97.9 2.1 Missing  100.0  100.0  Percent 6.9 85.4 6.9 .7  Valid Percent 7.0 86.0 7.0 Missing  100.0  100.0  ' 100.0 1  144  144  1  100.0  Percent 6.3 86.1 6.9 .7  Valid Percent 6.3 86.7 7.0 Missing  100.0  100.0  Percent 6.9 81.9 10.4 .7  Valid Percent 7.0 82.5 10.5 Missing  100.0  100.0  1  (categoric) Value Frequency -1 10 0 118 1 15 1 Total M i s s i n g cases  Valid Percent 97.2 2.8 Missing  Valid Percent Percent 11.8 . 11.9 81.9 82.5 5.6 5.6 .7 Missing  DATTACH2 D i s t a l -Attachment ( c a t e g o r i c ) Value L a b e l Value Frequency Decrease -1 9 No Change 0 124 Increase 1 10 1 Valid  Percent 96.5 2.8 .7  76  TT0NE2 Total-Tone Value L a b e l No Change Increase  V a l i d cases  (categoric) Value 0 1  V a l i d cases  Total M i s s i n g cases  143  TC0L0UR2 T o t a l - C o l o u r Value L a b e l Decrease No Change Increase  Part II  143  Total M i s s i n g cases  143  Descriptive  Total M i s s i n g cases  144 1  144  1  Percent 83 3 16 0 7  Valid Percent 83.9 16.1 Missing  100 0  100.0  Percent 1 4 92 4 5 6 7  Valid Percent 1.4 93.0 5.6 Missing  100 0  100.0  Percent 16 7 66 0 16 7 7  Valid Percent 16.8 66.4 16.8 Missing  100 0  100.0  S t a t i s t i c s (per p a t i e n t ) Frequency 6 22  Total  28  Percent 21 4 78 6  Valid Percent 21.4 78.6  100 0  100.0  CYA  Variable SILNESS OLEARY MAX0PEN1 MAXOPEN2 MAXOPEND QOL1 QOL2 QOLD  B.  1  (categoric) Value Frequency -1 24 0 95 1 24 1  GRP Group: MTX o r CYA Value L a b e l Value MTX 1 CYA 2  A.  144  (categoric) Value Frequency -1 2 0 133 1 8 1  TATTACH2 T o t a l - A t t a c h m e n t Value L a b e l Decrease No Change Increase  V a l i d cases  Frequency 120 23 1  Description S i l n e s s & Loe Plaque Index O l e a r y Plaque Index (%) Max O p e n i n g - s t a r t Max Opening-end Max O p e n i n g - d i f f e r e n c e Quality of L i f e - start Q u a l i t y o f L i f e - end Quality of L i f e - difference  Mean .94 55.66 41.41 36.35 -2.65 70.09 66.50 -3.59  SD .50 25.77 10.90 7.88 5.40 17.38 21. 42 21.90  MTX  Variable SILNESS OLEARY MAXOPEN1 MAXOPEN2 MAXOPEND QOL1 QOL2 QOLD  Min 0 11 21 22 -13 33 29 -59  Max 2 100 66 48 7 98 100 36  N 22 22 17 17 17 22 22 22  Max 2 75 42 42 3 97 92 6  N 6 6 6 6 6 6 6 6  Description S i l n e s s & Loe Plaque Index O l e a r y Plaque Index (%) Max O p e n i n g - s t a r t Max Opening-end Max O p e n i n g - d i f f e r e n c e Quality of L i f e - start Q u a l i t y o f L i f e - end Quality of L i f e - difference  Mean .86 43.72 34 .50 34 .17 -.33 67.67 60.67 -7.00  SD .82 20.16 7.58 7.00 2.58 25.97 26. 67 15.32  Min 0 18 21 24 -5 34 35 -37  77  Part I I I . Comparisons between Variables - CYA Group Only A.  Plaque scores vs. max  opening, q u a l i t y of  life  "Per patient" basis, Pearson c o r r e l a t i o n s are computed.  SILNESS OLEARY  MAX0PEN1 -.006 .329  MAX0PEN2 -.045 .127  MAXOPEND -.246 -.152  Q0L1 .189 -.054  None o f t h e s e c o r r e l a t i o n c o e f f i c i e n t s a r e s t a t i s t i c a l l y d i f f e r e n t from zero. B. Quality  of L i f e vs. max  Q0L2 -.050 -.158  QOLD -.199 -.112  significantly  opening  "Per patient" basis, Pearson c o r r e l a t i o n s are computed. MAXOPEN1 MAX0PEN2 MAXOPEND  Q0L1 -.134 .37 9 -.388  Q0L2 -.535** -.210 .139  QOLD -.421* -.447* .386  Note: * i n d i c a t e s a P-value < .10; ** i n d i c a t e s a P-value < .05 C.  Plaque scores vs. bleeding, tone, colour,  attachment loss  Note: Plaque scores are recorded on a "per patient" basis, while bleeding, tone, colour and attachment l o s s are recorded on a "per tooth" basis. One-way analysis of variance i s used here. There are two sets of r e s u l t s , one f o r Silness & Loe and one f o r Oleary. Summaries o f SILNESS S i l n e s s & Loe Plaque Index By l e v e l s o f MBLEED2 Mesial-Bleeding (categoric) Variable Value L a b e l Mean S t d Dev For E n t i r e P o p u l a t i o n .9095 .4708 MBLEED2 -1 Decrease 1.1718 .6458 MBLEED2 0 No Change .8585 .4211 MBLEED2 1 Increase 1.0388 .4956 F - s t a t = 12.73 ; P = .0001 Summaries o f SILNESS S i l n e s s S Loe Plaque Index By l e v e l s o f FBLEED2 Facial-Bleeding (categoric) Variable Value Label Mean S t d Dev For E n t i r e P o p u l a t i o n .9095 .4708 FBLEED2 -1 Decrease 1.3156 .6510 FBLEED2 0 No Change .8886 .4582 FBLEED2 1 Increase 1.0747 .4042 F - s t a t = 7 . 5 1 ; P = .0006 Summaries o f SILNESS S i l n e s s S Loe Plaque Index By l e v e l s o f DBLEED2 Distal-Bleeding (categoric) Variable Value L a b e l Mean S t d Dev For E n t i r e P o p u l a t i o n .9095 .4708 DBLEED2 -1 Decrease 1.1840 .5968 DBLEED2 0 No Change .8509 .4234 DBLEED2 1 Increase 1.0577 .5006 F - s t a t = 16.21 ; P < .0001  Cases 461 56 372 33  Cases 461 16 430 15  Cases 461 65 370 26  Summaries o f SILNESS S i l n e s s & Loe Plaque Index By l e v e l s o f MT0NE2 M e s i a l - Tone ( c a t e g o r i c ) Variable Value Label Mean For E n t i r e P o p u l a t i o n .9095 MT0NE2 -1 Decrease 1.5265 MT0NE2 0 No Change .8822 MT0NE2 1 Increase 1.0000 F - s t a t = 16.64 ; P < .0001 Summaries o f SILNESS S i l n e s s & Loe Plaque Index By l e v e l s o f FTONE2 F a c i a l - Tone ( c a t e g o r i c ) Variable Value Label Mean For E n t i r e P o p u l a t i o n . 9095 FT0NE2 -1 Decrease 1.3883 FT0NE2 0 No Change .9034 FT0NE2 1 Increase .8775 F - s t a t = 3 . 1 8 ; P =.043 Summaries o f SILNESS S i l n e s s & Loe Plaque Index By l e v e l s o f DTONE2 D i s t a l - Tone ( c a t e g o r i c ) Variable Value Label Mean For E n t i r e P o p u l a t i o n .9095 DT0NE2 -1 Decrease 1.5221 DTONE2 0 No Change .8799 DT0NE2 1 Increase .9900 F - s t a t = 18.42 ; P <.0001 Summaries o f SILNESS S i l n e s s & Loe Plaque Index By l e v e l s o f MCOLOUR2 Mesial- Colour (categoric) Variable Value L a b e l Mean For E n t i r e P o p u l a t i o n . 9095 MC0L0UR2 -1 Decrease 1.3083 MCOL0UR2 0 No Change .8551 MC0L0UR2 1 Increase 1.0050 F - s t a t = 23.64 ; P <.0001 Summaries o f SILNESS S i l n e s s & Loe Plaque Index By l e v e l s o f FCOLOUR2 F a c i a l - Colour (categoric) Variable Value L a b e l Mean For E n t i r e P o p u l a t i o n .9095 FC0L0UR2 -1 Decrease 1.7900 FC0L0UR2 0 No Change .8456 FC0L0UR2 1 Increase 1.0036 F - s t a t = 66.05 ; P <.0001 Summaries o f SILNESS S i l n e s s & Loe Plaque Index By l e v e l s o f DC0L0UR2 D i s t a l - Colour (categoric) Variable Value L a b e l Mean For E n t i r e P o p u l a t i o n .9095 DCOLOUR2 -1 Decrease 1.3200 DCOLOUR2 0 No Change . 8578 DCOLOUR2 1 Increase .9389 F - s t a t = 23.55 ; P <.0001  S t d Dev .4708 .5272 . 4574 .2562  Cases 461 17 430 14  Std Dev .4708 .4565 .4691 .4018  Cases 461 6 451 4  S t d Dev .4708 .5349 . 4551 .2139  Cases 461 19 429 13  Std Dev .4708 .5770 .4322 .3473  Cases 461 52 399 10  S t d Dev . 4708 .4000 . 4240 .2604  Cases 461 27 409 25  S t d Dev .4708 . 5801 . 4300 .4753  Cases 461 50 402 9  Summaries o f SILNESS S i l n e s s & Loe Plaque Index By l e v e l s o f MATTACH2 M e s i a l - Attachment ( c a t e g o r i c ) Variable Value Label Mean Std Dev For E n t i r e P o p u l a t i o n .4708 . 9095 MATTACH2 -1 Decrease 1.0677 .4502 MATTACH2 0 No Change .8874 .4764 MATTACH2 1 Increase .8621 .4373 F - s t a t = 4.50 ; P =.012 Summaries o f SILNESS S i l n e s s & Loe Plaque Index By l e v e l s o f FATTACH2 F a c i a l - Attachment ( c a t e g o r i c ) Variable Value L a b e l Mean S t d Dev For E n t i r e P o p u l a t i o n .9095 . 4708 FATTACH2 -1 Decrease 1.2312 .5321 FATTACH2 0 No Change .8887 . 4517 FATTACH2 1 Increase .8548 .4876 F - s t a t = 9.01 ; P =.0001  s  Cases 461 66 327 68  Cases 461 34 366 61  Summaries o f SILNESS S i l n e s s S Loe Plaque Index By l e v e l s o f DATTACH2 D i s t a l - Attachment ( c a t e g o r i c ) Variable Value Label Mean Std Dev For E n t i r e . P o p u l a t i o n . 9095 .4708 DATTACH2 -1 Decrease 1.0257 .4310 DATTACH2 0 No Change .8975 .4860 DATTACH2 1 Increase .8998 .4030 F - s t a t = 1.41 ; P =.24 Summaries o f SILNESS S i l n e s s & Loe Plaque Index By l e v e l s o f TBLEED2 Total-Bleeding (categoric) Variable Value Label Mean For E n t i r e P o p u l a t i o n . 9095 TBLEED2 -1 Decrease 1.0684 TBLEED2 0 No Change . .8410 TBLEED2 1 Increase 1.0217 F - s t a t = 10.74 ; P < .0001 Summaries o f SILNESS S i l n e s s S Loe Plaque Index By l e v e l s o f TTONE2 Total-Tone (categoric) Variable Value Label Mean For E n t i r e P o p u l a t i o n . 9095 TTONE2 -1 Decrease 1.3854 TTONE2 0 No Change .8745 TTONE2 1 Increase .9539 F - s t a t = 16.59 ; P < .0001 Summaries o f SILNESS S i l n e s s & Loe Plaque Index By l e v e l s o f TCOLOOR2 T o t a l -Colour ( c a t e g o r i c ) Variable Value Label Mean For E n t i r e P o p u l a t i o n . 9095 TCOLOUR2 -1 Decrease 1.2428 TCOLOUR2 0 No Change .8437 TCOLOUR2 1 Increase .9658 F - s t a t = 21.86 ; P < .0001  Std Dev .4708 .5879 . 4046 .5105  Cases 461 96 311 54  Std Dev . 4708 .5193 .4589 .2731  Cases 461 28 410 23  S t d Dev .4708 .5549 .4389  Cases 461 65 360 36  .3468  Summaries o f SILNESS S i l n e s s & Loe Plaque Index By l e v e l s o f TATTACH2 T o t a l -Attachment ( c a t e g o r i c ) Variable Value Label Mean Std Dev For E n t i r e P o p u l a t i o n . 9095 . 4708 TATTACH2 -1 Decrease 1.0604 .4215 TATTACH2 0 No Change .8680 .4993 TATTACH2 1 Increase .8800 .4226 F - s t a t = 6.06; P = .0025  Summaries o f OLEARY OLeary Plaque Index (%) By l e v e l s o f MBLEED2 Mesial-Bleeding (categoric) Variable Value Label Mean For E n t i r e P o p u l a t i o n 54 .3586 MBLEED2 -1 Decrease 62 .5750 MBLEED2 0 No Change 52 .2414 MBLEED2 1 Increase 64 .2818 F - s t a t = 7 . 0 6 ; P = .0010 Summaries o f OLEARY OLeary Plaque Index (%) By l e v e l s o f FBLEED2 F a c i a l - B l e e d i n g (ca t e g o r i c ) Variable Value Label Mean For E n t i r e P o p u l a t i o n 54 .3586 FBLEED2 -1 Decrease 76 .5562 FBLEED2 0 No Change 53 .2212 FBLEED2 1 Increase 63 .2867  Cases 461 42 353 66  Cases 461 92 250 119  Std Dev 25.1369 30.0701 23.8836 25.3725  Cases 461 56 372 33  S t d Dev 25.1369 23.0771 24 . 9740 19.7597  Cases 461 16 430 15  80  Summaries o f OLEARY OLeary Plaque Index (%) By l e v e l s o f DBLEED2 D i s t a l -- B l e e d i n g ( c a t e g o r i c ) Variable Value Label Mean For E n t i r e P o p u l a t i o n 54.3586 DBLEED2 -1 Decrease 62.4369 DBLEED2 0 No Change 52.1208 DBLEED2 1 Increase 66.0077 F - s t a t =7.84 ; P = .0004 Summaries o f OLEARY OLeary Plaque Index (%) By l e v e l s of MTONE2 M e s i a l --Tone ( c a t e g o r i c ) Variable Value Label Mean For E n t i r e P o p u l a t i o n 54.3586 MT0NE2 -1 Decrease 76.4294 MT0NE2 0 No Change 52.8830 MT0NE2 1 Increase 72.8786 F - s t a t = 11.61 ; P < .0001 Summaries of OLEARY OLeary Plaque Index (%) By l e v e l s o f FTONE2 F a c i a l --Tone ( c a t e g o r i c ) Variable Value Label Mean For E n t i r e P o p u l a t i o n 54.3586 FT0NE2 -1 Decrease 62.8333 FTONE2 0 No Change 54.1803 FT0NE2 1 Increase 61.7500 F - s t a t = 0.52 ; P = .59 Summaries o f OLEARY OLeary Plaque Index (%) By l e v e l s o f DTONE2 D i s t a l --Tone ( c a t e g o r i c ) Variable Value Label Mean For E n t i r e P o p u l a t i o n 54.3586 DTONE2 -1 Decrease 79.0316 DTONE2 0 No Change 52.8804 DTONE2 1 Increase 67.0769 F - s t a t = 12.12 ; P < .0001 Summaries o f OLEARY OLeary Plaque Index (%) By l e v e l s o f MCOLOUR2 M e s i a l --Colour ( c a t e g o r i c ) Variable Value Label Mean For E n t i r e P o p u l a t i o n 54.3586 MCOLOOR2 -1 Decrease 65.4442 MC0L0UR2 0 No Change 52.4992 MC0L0UR2 1 Increase 70.9000 F - s t a t = 8.59 ; P = .0002 Summaries o f OLEARY OLeary Plaque Index (%) By l e v e l s o f FCOLOUR2 F a c i a l --Colour ( c a t e g o r i c ) Variable Value Label Mean For E n t i r e P o p u l a t i o n 54.3586 FCOLOUR2 -1 Decrease 87.3333 FC0L0UR2 0 No Change 52.0619 FC0L0UR2 1 Increase 56.3200 F - s t a t = 27.95 ; P < .0001 Summaries o f OLEARY OLeary Plaque Index (%) By l e v e l s of DCOLOUR2 D i s t a l --Colour ( c a t e g o r i c ) Variable Value Label Mean For E n t i r e P o p u l a t i o n 54.3586 DCOLOUR2 -1 Decrease 64.6760 DCOLOUR2 52.7127 0 No Change DCOLOUR2 1 Increase 70.5556 F - s t a t = 7 . 1 3 ; P = .0009  S t d Dev 25.1369 27.9649 23.8911 28.5408  Cases 461 65 370 26  S t d Dev 25.1369 33.6283 24.3044 19.8674  Cases 461 17 430 14  S t d Dev 25.1369 22.7105 25.1736 27.3542  Cases 461 6 451 4  S t d Dev 25.1369 29.9740 24.3388 22.9872  Cases 461 19 429 13  S t d Dev 25.1369 31.9285 23.5361 29.2288  Cases 461 52 399 10  S t d Dev 25.1369 22.2071 24.5114 6.7498  Cases 461 27 409 25  S t d Dev 25.1369 33.0944 23.2279 38.5101  Cases 461 50 402 9  Summaries o f OLEARY OLeary Plaque Index (%) By l e v e l s o f MATTACH2 M e s i a l --Attachment ( c a t e g o r i c ) Variable Value Label Mean S t d Dev For E n t i r e P o p u l a t i o n 54.3586 25.1369 MATTACH2 -1 Decrease 56.5045 25.2085 MATTACH2 0 No Change 54.4128 26.5886 MATTACH2 1 Increase 52.0147 16.4842 F - s t a t = 0 . 5 4 ; P = .59  Cases 461 66 327 68  81  Summaries o f OLEARY OLeary Plaque Index (%) By l e v e l s o f FATTACH2 F a c i a l -Attachment ( c a t e g o r i c ) Variable Value Label Mean S t d Dev For E n t i r e P o p u l a t i o n 54.3586 25.1369 FATTACH2 -1 Decrease 61.6706 26.0075 FATTACH2 0 No Change 54.2156 25.7887 FATTACH2 1 Increase 51.1410 19.6360 F - s t a t = 1 . 9 5 ; P = .14 Summaries o f OLEARY OLeary Plaque Index (%) By l e v e l s o f DATTACH2 D i s t a l -Attachment ( c a t e g o r i c ) Variable Value Label Mean S t d Dev For E n t i r e P o p u l a t i o n 54.3586 25.1369 DATTACH2 -1 Decrease 25.2271 52.7833 DATTACH2 0 No Change 26.3757 54 .1201 DATTACH2 1 Increase 56.6364 17.1951 F - s t a t =0.37 ; P = .69 Summaries o f OLEARY OLeary Plaque Index (%) By l e v e l s o f TBLEED2 T o t a l - Bleeding (categoric) Variable Value Label Mean For E n t i r e P o p u l a t i o n 54 .3586 TBLEED2 -1 Decrease 58.0792 TBLEED2 0 No Change 51.7765 TBLEED2 1 Increase 62.6148 F - s t a t = 5 . 7 2 ; P = .0035 Summaries o f OLEARY OLeary Plaque Index (%) By l e v e l s o f TTONE2 Total-Tone ( c a t e g o r i c ) Variable Value Label Mean For E n t i r e P o p u l a t i o n 54 .3586 TTONE2 -1 Decrease 68.6036 TTONE2 0 No Change 52.5100 TTONE2 1 Increase 69.9696 F - s t a t = 10.45 ; P < .0001 Summaries o f OLEARY OLeary Plaque Index (%) By l e v e l s o f TCOLOUR2 Total-Colour (categoric) Variable Value Label Mean For E n t i r e P o p u l a t i o n 54 .3586 TCOLOUR2 -1 Decrease 61.9538 TCOLOUR2 0 No Change 52.4703 TC0L0UR2 1 Increase 59.5278 F - s t a t = 4 . 8 2 ; P = .0085  Cases 461 34 366 61  Cases 461 42 353 66  S t d Dev 25.1369 27.5437 23.7314 26.3918  Cases 461 96 311 54  S t d Dev 25.1369 31.5898 24 .2920 20.9700  Cases 461 28 410 23  S t d Dev 25.1369 30.9049 23.9072 22.8954  Cases 461 65 360 36  Summaries o f OLEARY OLeary Plaque Index (%) By l e v e l s o f TATTACH2 Total-Attachment (categoric) Variable Value L a b e l Mean S t d Dev For E n t i r e P o p u l a t i o n 54.3586 25.1369 TATTACH2 -1 Decrease 56.2130 24.7941 TATTACH2 0 No Change 28.2234 54.0928 TATTACH2 17.4537 1 Increase 53.4832 F - s t a t =0.34 ; P = .72  Cases 461 92 250 119  82  D. Attachment Loss vs. Max Opening Note: Max Opening i s recorded on a "per patient" basis, while attachment loss i s recorded on a "per tooth" basis. One-way analysis of variance i s used here. Summaries o f MAX0PEN1 Max O p e n i n g - s t a r t By l e v e l s o f MATTACH2 Mesial-Attachment (categoric) Variable Value Label S t d Dev Mean For E n t i r e P o p u l a t i o n 10.5450 41.3949 MATTACH2 -1 Decrease 13.3856 40.1489 MATTACH2 0 No Change 9.9842 41.8517 MATTACH2 1 Increase 10.4213 39.9286 F - s t a t = 0.98 ; P = .38 Summaries o f MAXOPEN1 Max O p e n i n g - s t a r t By l e v e l s o f FATTACH2 Facial-Attachment (categoric) Variable Value Label S t d Dev Mean For E n t i r e P o p u l a t i o n 10.5450 41.3949 FATTACH2 -1 Decrease 12.0720 40.6552 FATTACH2 0 No Change 9.7502 41.1644 FATTACH2 1 Increase 15.2752 44.2581 F - s t a t = 1.29 ; P = .28 Summaries o f MAXOPEN1 Max O p e n i n g - s t a r t By l e v e l s o f DATTACH2 Distal-Attachment (categoric) Variable Value Label Mean S t d Dev For E n t i r e P o p u l a t i o n 41.3949 10.5450 DATTACH2 -1 Decrease 37.1429 10.9940 DATTACH2 0 No Change 41.7250 10.3854 DATTACH2 1 Increase 42.0000 10.9140 F - s t a t = 2 . 5 1 ; P = .083 N  Summaries o f MAXOPEN1 Max O p e n i n g - s t a r t By l e v e l s o f TATTACH2 Total-Attachment (categoric) Variable Value Label Mean S t d Dev For E n t i r e P o p u l a t i o n 41.3949 10.5450 TATTACH2 -1 Decrease 39.8806 12.6999 TATTACH2 0 No Change 41.5924 8.8509 TATTACH2 1 Increase 42.2027 12.6729 F - s t a t = .0.94 ; P = .39  Cases 352 47 263 42  Cases 352 29 292 31  Cases 352 28 280 44  Cases 352 67 211 74  Summaries o f MAX0PEN2 Max Opening-end By l e v e l s o f MATTACH2 Mesial-Attachment Variable Value Label For E n t i r e P o p u l a t i o n MATTACH2 -1 Decrease MATTACH2 0 No Change MATTACH2 1 Increase F - s t a t = 13. 13 P < .0001  (categoric) Mean S t d Dev 36.5909 7.7535 32.6809 8.5213 37 .7757 7.5275 33.5476 5.9231  Cases 352 • 47 263 42  Summaries o f MAXOPEN2 Max Opening-end By l e v e l s o f FATTACH2 Facial-Attachment Variable Value Label For E n t i r e P o p u l a t i o n FATTACH2 -1 Decrease FATTACH2 0 No Change FATTACH2 1 Increase F - s t a t =12.94 ; P < .0001  (categoric) S t d Dev Mean 7.7535 36.5909 7.5291 32.5172 7.4278 37.5103 8.1689 31.7419  Cases 352 29 292 31  Summaries o f MAXOPEN2 Max Opening-end By l e v e l s o f DATTACH2 Distal-Attachment Variable Value Label For E n t i r e P o p u l a t i o n DATTACH2 -1 Decrease DATTACH2 0 No Change DATTACH2 1 Increase F - s t a t = 9.41 ; P = .0001  (categoric) S t d Dev Mean 7.7535 36.5909 7.8951 32.5357 7.7357 37.4714 6.1810 33.5682  Cases 352 28 280 44  83  Summaries o f MAX0PEN2 Max Opening-end By l e v e l s o f TATTACH2 Total-Attachment Variable Value Label For E n t i r e P o p u l a t i o n TATTACH2 -1 Decrease TATTACH2 0 No Change TATTACH2 1 Increase F - s t a t = 30.27 ; P < .0001  (categoric) Mean S t d Dev 36.5909 7.7535 33.0746 8.3581 39.0237 6.8871 32 . 8378 6.8347  Cases 352 67 211 74  E. Attachment Loss vs. Bleeding Note: Both Attachment Loss and Bleeding are recorded a "per tooth" basis. Since they have been recoded to three categories, crosstabulations are constructed here. MATTACH2  M e s i a l - A t t a c h m e n t ( c a t e g o r i c ) by MBLEED2 M e s i a l - B l e e d i n g MBLEED2 I Decrease No Change I n c r e a s e Row Count | 0 I -1 I 1 | Total MATTACH2 +Decrease ' -1.1 46 15 I 66 5 I No Change  0  Increase  1  I +I  Column T o t a l Cohen's Kappa = .0 66 FATTACH2  FATTACH2 Decrease  |  270  24  8  I  56  4  372  33  56  | + I +  327 68 461  Facial-Attachment ( c a t e g o r i c ) by FBLEED2 F a c i a l - B l e e d i n g FBLEED2 I Decrease No Change I n c r e a s e Row Count -1 I 1 I Total  No Change  -1 0  I  4  I  27  |  11  I  346  1  I  57  +—  Increase  33  (categoric)  1  | +—  Column T o t a l Cohen's Kappa = .073  16  430  |  3  34  I +| +-  9  366  3  61  15  461  DATTACH2  (categoric)  Distal-Attachment ( c a t e g o r i c ) by DBLEED2 D i s t a l - B l e e d i n g DBLEED2 I Decrease No Change I n c r e a s e Row 1 | Total Count I -1 | 0 I + DATTACH2 + +Decrease -1 I 8 | 31 I 42 3 I + +_ No Change 0 | 50 | 282 | 21 I 353 + + +Increase 1 I 7 | 57 | 2 I 66 + ++ Column T o t a l 65 370 26 461 Cohen's Kappa = - . 0 0 6 TATTACH2  T o t a l - A t t a c h m e n t ( c a t e g o r i c ) by TBLEED2 T o t a l - B l e e d i n g TBLEED2 I Decrease No Change I n c r e a s e Row Count | -1 I 0 | 1 | Total TATTACH2 + + +8 | 92 + Decrease -1 I 28 | 56 | 32 | 250 + No Change 0 I 47 | 171 | 14 | 119 + Increase 1 I 21 | 84 | 54 461 Column T o t a l 96 311 Cohen's Kappa = .043  (categoric)  (categoric)  84  F. Attachment Loss vs. Tone Note: Both Attachment Loss and Tone are recorded a "per tooth" basis. Since they have been recoded to three categories, crosstabulations are constructed here. MATTACH2  Mesial-Attachment (categoric) by MT0NE2 M e s i a l - T o n e MT0NE2 I Decrease No Change I n c r e a s e Row Count | -1 I 0 | 1 | Total MATTACH2 + + + + Decrease -1 I 5 | 57 | 4 | 66 No Change  0  I  7  |  311  I  9  |  Increase  1  I  5  |  62  |  1  I.  Column T o t a l Cohen's Kappa = .04 9  17  430  14  327 68 461  FATTACH2  Facial-Attachment (categoric) by FTONE2 F a c i a l - T o n e FTONE2 I Decrease No Change I n c r e a s e Row Count I -11 0 | 1 | Total FATTACH2 + + + + Decrease -1 I 2 | 31 | 1 I 34 No Change  0  I  Increase  1  I  Column T o t a l Cohen's Kappa = .019  4  | I  6  359  |  61  |  451  3  I I  4  61 461  Distal-Attachment (categoric) by DTONE2 D i s t a l - T o n e DTONE2 I Decrease No Change I n c r e a s e Row Count | -1 I 0 | 1 I Total DATTACH2 + + + + Decrease -1 I 2 | 38 | 2 | 42 0  |  13  Increase  1  I  4  Column T o t a l Cohen's Kappa = -.008  | |..  19  329  |  62  |  429  11  I  353  I  66  13- -• •  Total-Attachment (categoric) by TTONE2 T o t a l - T o n e TTONE2 I Decrease No Change I n c r e a s e Row •• Count | • -1 | 0 | 1 I Total TATTACH2 + + + + Decrease -1 I 7 | 77 | 8 | 92 No Change  0  |  12  j  228  |  10  |  250  Increase  1  I  9  |  105  |  5  |  119  Column T o t a l Cohen's Kappa = .027  28  23  (categoric)  .461  TATTACH2  410  (categoric)  366  DATTACH2  No Change  (categoric)  461  (categoric)  G. Attachment Loss vs. Colour Note: Both Attachment Loss and Colour are recorded a "per tooth" basis. Since they have been recoded to three categories, crosstabulations are constructed here. MATTACH2  M e s i a l - A t t a c h m e n t ( c a t e g o r i c ) by MC0L0UR2 MC0L0UR2 I Decrease No Change I n c r e a s e Row Count I -1 I 0 1 1 1 Total MATTACH2 + + + + Decrease -1 I 12 | 51 | 3 | 66 No Change  0  Increase  1 1  I  Column T o t a l Cohen's Kappa = .012  40  |  281  |  6  |  327  I  67  |  .1  |  68  52  399  10  Facial-Attachment ( c a t e g o r i c ) by FC0L0UR2 FCOLOUR2 I Decrease No Change I n c r e a s e Row Count I -1 I 0 | 1 I Total FATTACH2 + + + +. Decrease - I I 5 | 25 | 4 | 34 0  Increase  1 1  I  Column T o t a l Cohen's Kappa = .137  22  |  333  |  11  |  366  I  51  |  10  I  61  27  409  25  Facial-Colour  (categoric)  Distal-Colour  (categoric)  461  DATTACH2  Distal-Attachment ( c a t e g o r i c ) by DCOLOUR2 DCOLODR2 I Decrease No Change I n c r e a s e Row Count I -11 0 | I I Total DATTACH2 + + + + Decrease -1 I 8 | 33 I 1 I 42 No Change  0  I  41  |  305  |  7  |  353  Increase  1  I  1  I  64  |  1  I  66  Column T o t a l Cohen's Kappa = .002  50  402  (categoric)  461  FATTACH2  No Change  Mesial-Colour  9  461  TATTACH2  T o t a l - A t t a c h m e n t ( c a t e g o r i c ) by TCOLOUR2 T o t a l - C o l o u r TCOLOUR2 I Decrease No Change I n c r e a s e Row Count I -11 0 1 1 | Total TATTACH2 + + + + Decrease - I I 20 | 62 | 10 | 92 No Change  0  I  43  I  197  |  10  I  250  Increase  1  I  2  |  101  I  16  |  119  Column T o t a l Cohen's Kappa = .064  65  360  36  (categoric)  461  86  H. Quality of L i f e vs. Attachment Loss Note: Quality of L i f e i s recorded on a "per patient" basis, while attachment loss i s recorded'on a "per tooth" basis. One-way analysis of variance i s used here. Summaries o f Q0L1 Quality of L i f e - start By l e v e l s o f MATTACH2 Mesial-Attachment (categoric) Variable Value L a b e l Mean S t d Dev For E n t i r e P o p u l a t i o n 17.3643 69.8850 MATTACH2 -1 Decrease 16.9227 72.1515 MATTACH2 0 No Change 17 .4140 69.3547 MATTACH2 1 Increase 17.6137 70.2353 F - s t a t = 0.73 ; P-value = .48 Summaries o f QOL1 Quality of L i f e - start By l e v e l s o f FATTACH2 Facial-Attachment (categoric) Variable Value L a b e l S t d Dev Mean For E n t i r e P o p u l a t i o n 17.3643 69.8850 FATTACH2 -1 Decrease 16.9576 73.8824 FATTACH2 0 No Change 16.5181 70.5191 FATTACH2 1 Increase 21.0988 63.8525 F - s t a t = 4.91 ; P-value = .0078 Summaries o f Q0L1 Quality of L i f e - s t a r t By l e v e l s o f DATTACH2 Distal-Attachment (categoric) Variable Value L a b e l Mean S t d Dev For E n t i r e P o p u l a t i o n 69.8850 17.3643 DATTACH2 -1 Decrease 74.5952 14.5637 DATTACH2 0 No Change 69.4419 17.0446 DATTACH2 1 Increase , 69.2576 20.2722 F - s t a t = 1.71 ; p-value = .18 Summaries o f QOL1 Quality of L i f e - s t a r t By l e v e l s o f TATTACH2 Total-Attachment (categoric) Variable Value L a b e l Mean S t d Dev For E n t i r e P o p u l a t i o n 69.8850 17.3643 TATTACH2 -1 Decrease 73.3043 17.1936 TATTACH2 0 No Change 69.5800 15.5982 TATTACH2 1 Increase 67.8824 20.5101 F - s t a t = 2.63 ; P-value = .073 Summaries o f Q0L2 Q u a l i t y o f L i f e - end By l e v e l s o f MATTACH2 Mesial-Attachment (categoric) Variable Value L a b e l S t d Dev Mean For E n t i r e P o p u l a t i o n 20.7287 66.0499 MATTACH2 -1 Decrease 17.0564 69.3939 MATTACH2 0 No Change 21.1784 65.3609 MATTACH2 1 Increase 21.7273 66.1176 F - s t a t = 1.04 ; P-value = .35 Summaries o f QOL2 Q u a l i t y o f L i f e - end By l e v e l s o f FATTACH2 Facial-Attachment (categoric) Variable Value L a b e l S t d Dev Mean For E n t i r e P o p u l a t i o n 20.7287 66.0499 FATTACH2 -1 Decrease 18.8161 74.2059 20.9092 FATTACH2 0 No Change 66.1175 19.4222 FATTACH2 1 Increase 61.0984 F - s t a t = 4.44 ; P-value = .012 Summaries o f QOL2 Q u a l i t y o f L i f e - end By l e v e l s o f DATTACH2 Distal-Attachment (categoric) Variable Value L a b e l S t d Dev Mean For E n t i r e P o p u l a t i o n 20.7287 66.0499 DATTACH2 -1 Decrease 15.9210 74.2857 DATTACH2 0 No Change 20.7276 65.4504 22.4564 DATTACH2 1 Increase 64.0152 F - s t a t = 3.84 ; P-value = .023  Cases 461 66 327 68  Cases 461 34 366 61  Cases 461 42 353 66  Cases 461 92 250 119  Cases 461 66 327 68  Cases 461 34 366 61  Cases 461 42 353 66  87  Summaries o f Q0L2 Q u a l i t y o f L i f e - end By l e v e l s o f TATTACH2 Total-Attachment (categoric) Variable Value Label Mean For E n t i r e P o p u l a t i o n 66.0499 TATTACH2 -1 Decrease 70.9130 TATTACH2 0 No Change 65.6720 63.0840 TATTACH2 1 increase F - s t a t = 3.84 ; P-value = .022  Std Dev 20.7287 18.3187 20.7921 21.8258  Summaries o f QOLD Q u a l i t y of L i f e - d i f f e r e n c e By l e v e l s o f MATTACH2 Mesial-Attachment (categoric) Variable Value Label Mean Std Dev For E n t i r e P o p u l a t i o n 20.2491 .8351 MATTACH2 -1 Decrease 15.6815 .7576 MATTACH2 0 No Change 19.7661 . 9939 MATTACH2 1 Increase 25.9647 -4 .1176 F - s t a t = 0.11 ; P-value = .90 Summaries o f QOLD Quality of L i f e - difference By l e v e l s o f FATTACH2 Facial-Attachment (categoric) Variable Value Label Mean Std Dev For E n t i r e P o p u l a t i o n -3.8351 20.2491 FATTACH2 -1 Decrease .3235 13.4631 FATTACH2 0 No Change -4.4016 20.8817 FATTACH2 1 Increase -2.7541 19.4496 F - s t a t = 0.95 ; P-value = .39 Summaries of QOLD Quality of L i f e - difference By l e v e l s of DATTACH2 Distal-Attachment (categoric) Variable Value Label Std Dev Mean For E n t i r e P o p u l a t i o n 20.2491 .8351 DATTACH2 -1 Decrease 11.9133 .3095 DATTACH2 0 No Change 20.1067 .9915 DATTACH2 1 Increase 24.7523 .2424 F - s t a t = 0.81 ; P-value = .45 Summaries o f QOLD Quality of L i f e - difference By l e v e l s o f TATTACH2 Total-Attachment (categoric) Variable Value Label Mean S t d Dev For E n t i r e P o p u l a t i o n -3 . 8351 20.2491 TATTACH2 -1 Decrease -2 .3913 14.7365 TATTACH2 0 No Change -3 .9080 20.3372 TATTACH2 1 Increase -4 .7983 23.5709 F - s t a t = 0.37 ; P-value = .69  Cases 461 92 250 119  Cases 461 66 327 68  Cases 461 34 366 61  Cases 461 42 353 66  Cases 461 92 250 119  88  

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