Full Mouth Disinfection and Antibiotics for Periodontitis in High or Moderate Disease Activity Rheumatoid Arthritis

Rheumatoid Arthritis Clinical Trial

— FMD-ABRA  

Official title:

Single Arm Pilot Study of Antimicrobial Treatment of Active Rheumatoid Arthritis Associated With Manifest Periodontitis (Translated From German: Anti-mikrobielle Behandlung Der Aktiven Rheumatoiden Arthritis Bei Manifester Parodontitis - Eine Unkontrollierte Therapie-Pilotstudie)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02096120
• Other study ID #: 130/13
• Secondary ID: 2439
• Status: Completed
• Start date: February 2014
• Est. completion date: October 25, 2017

Study information

• Verified date: October 2018
• Source: University Hospital Inselspital, Berne
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The purpose of this study is to determine whether full mouth disinfection in combination with one week antibiotic amoxicillin plus metronidazole antibiotic therapy is improving periodontitis and disease activity of rheumatoid arthritis.

Description:

Rheumatoid arthritis (RA) is a currently incurable disease of unknown origin characterized by joint inflammation and the breakdown of immune tolerance to a variety of antigens, including citrullinated peptides generated by peptidyl-arginine-deiminases (PAD's). Porphyromonas gingivalis (P. g.) derived PAD enzyme (PPAD) citrullinates preferentially C-terminal arginine residues, which may be generated by P.g. derived gingipain protein (Rgpb) cleavage, but several of the originated peptide sequences from enolase, collagen, vimentin or fibrinogen may be cross-reactant to citrullinated RA candidate autoantigens.

Antigen-specific autoantibodies in RA may be present years before clinical disease onset of arthritis, and their precise role in the initiation or perpetuation of the characteristic articular immune processes is currently unclear. The situation for autoantibodies was in similar poorly understood for decades until an unanticipated reduction of RA disease activity could be achieved by therapeutic B cell depletion using anti-CD20 therapy. While anti-CD20 therapy may affect the regeneration of autoantibody producing cells, the investigators aim in the present study to reduce potential oral trigger mechanisms or antigens for cross-reactant autoreactive B cell or plasma cell populations. The study follows the concept of improved RA disease activity by minimization of any inflammatory stimuli associated with periodontitis, e.g. by any underlying microbial colonization, the amount of microbial foreign antigens, achieved by standard oral hygienic means, full mouth disinfection plus adjuvant short term antibiotic therapy in established periodontitis.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 8
• Est. completion date: October 25, 2017
• Est. primary completion date: August 1, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Written informed consent

• Age 18 years or older

• Diagnosis of rheumatoid arthritis according to the ACR/EULAR 2010 classification criteria plus both serological, high titer (>3x ULN) rheumatoid factor and CCP antibody titer

• Severe chronic periodontitis (clinical attachment loss >/= 5mm at two separate locations)

• DAS 28 > 4.2 at screening and inclusion (within 28 days after screening) and 1 out of two additional disease activity criteria:

1. Synovial hyperplasia >22/66 points on basis of 22 joints, or at least 1/3 of the maximum score when analyzes in at least selected 5 joints of interest OR

2. Serum CRP > 10 mg/l at screening and at inclusion

• Stable doses for >=3 months, if currently under synthetic or recombinant disease modifying anti-rheumatic drugs. If under anti-CD20 treatment: last rituximab infusion >90 days before inclusion.

• Systemic corticosteroids <= 10 mg and stable for at least 14 days

• Nonsteroidal-antirheumatic drugs and peripheral analgesics at stable doses for at least 14 days

Exclusion Criteria:

• Intolerance to amoxicillin und azithromycin (EBV infection, lymphatic leukemia, exanthema), general hypersensitivity to any beta-lactam antibiotics, intolerance to metronidazole or local anaesthesia

• Current intake of allopurinol or probenicid, oral anticoagulation, disulfiram, phenobarbital phenytoin, lithium or ciclosporin

• Seizures

• Severe cardial electric conduction blockade

• Recent myocardial infraction or instable coronary vessel disease, non-compensated myocardial insufficiency or heart failure

• Non-compensated arterial hypertension

• Genetic cholinesterase deficiency

• General hemorrhagic diathesis or intake of oral anticoagulants

• Intake of monoaminooxidase inhibitors or tricyclic antidepressants

• Liver insufficiency

• Renal failure (eGFR < 30 ml/min)

• Hemoglobin <10 g/dl

• Leukocytes < 3/nl

• Neutrophils < 1/nl

• Platelets < 100/nl

• ALAT oder ASAT > 3x ULN

• Pregnancy or breastfeeding

• Psychiatric or any other condition which could, to the opinion of the investigator, interfere with the compliance of this protocol

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Periodontitis
• Rheumatoid Arthritis

Locations

Country	Name	City	State
Switzerland	Inselspital, Department for Rheumatology, and Dpt. For Periodontology, School for Dentistry, University of Bern	Bern

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital Inselspital, Berne	University of Bern

Country where clinical trial is conducted

Switzerland, 

References & Publications (17)

Aimetti M, Romano F, Guzzi N, Carnevale G. Full-mouth disinfection and systemic antimicrobial therapy in generalized aggressive periodontitis: a randomized, placebo-controlled trial. J Clin Periodontol. 2012 Mar;39(3):284-94. doi: 10.1111/j.1600-051X.2011.01795.x. Epub 2012 Jan 4. — View Citation

Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovsky J, Wolfe F, Hawker G. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010 Sep;69(9):1580-8. doi: 10.1136/ard.2010.138461. Erratum in: Ann Rheum Dis. 2010 Oct;69(10):1892. — View Citation

Aletaha D, Smolen J. The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI): a review of their usefulness and validity in rheumatoid arthritis. Clin Exp Rheumatol. 2005 Sep-Oct;23(5 Suppl 39):S100-8. Review. — View Citation

Armitage GC. Development of a classification system for periodontal diseases and conditions. Ann Periodontol. 1999 Dec;4(1):1-6. Review. — View Citation

Brulhart L, Zufferey P, Tamborrini G, Möller B, Gerber T, Krebs A, et al. Reproducibility and feasibility of a 22 joints ultrasound score in rheumatoid arthritis: A study among rheumatologists with diverse expertise in musculoskeletal ultrasound. . Annals of the rheumatic diseases 2012;71(Suppl ).

de Pablo P, Dietrich T, Chapple IL, Milward M, Chowdhury M, Charles PJ, Buckley CD, Venables PJ. The autoantibody repertoire in periodontitis: a role in the induction of autoimmunity to citrullinated proteins in rheumatoid arthritis? Ann Rheum Dis. 2014 Mar;73(3):580-6. doi: 10.1136/annrheumdis-2012-202701. Epub 2013 Feb 23. — View Citation

Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, Katz LM, Lightfoot R Jr, Paulus H, Strand V, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995 Jun;38(6):727-35. — View Citation

Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J, Aletaha D, Allaart CF, Bathon J, Bombardieri S, Brooks P, Brown A, Matucci-Cerinic M, Choi H, Combe B, de Wit M, Dougados M, Emery P, Furst D, Gomez-Reino J, Hawker G, Keystone E, Khanna D, Kirwan J, Kvien TK, Landewé R, Listing J, Michaud K, Martin-Mola E, Montie P, Pincus T, Richards P, Siegel JN, Simon LS, Sokka T, Strand V, Tugwell P, Tyndall A, van der Heijde D, Verstappen S, White B, Wolfe F, Zink A, Boers M. American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis. 2011 Mar;70(3):404-13. doi: 10.1136/ard.2011.149765. — View Citation

Finckh A, Müller R, Möller B, Dudler J, Kyburz D, Walker UA, et al. Tooth Loss is associated with swollen joints in a cohort of healthy individuals at increased risk of developing RA. European Congress of Rheumatology EULAR 2012. Annals of the rheumatic diseases 2012;71(Suppl).

Fransen J, van Riel PL. The Disease Activity Score and the EULAR response criteria. Clin Exp Rheumatol. 2005 Sep-Oct;23(5 Suppl 39):S93-9. — View Citation

Klareskog L, Stolt P, Lundberg K, Källberg H, Bengtsson C, Grunewald J, Rönnelid J, Harris HE, Ulfgren AK, Rantapää-Dahlqvist S, Eklund A, Padyukov L, Alfredsson L. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006 Jan;54(1):38-46. — View Citation

Lundberg K, Kinloch A, Fisher BA, Wegner N, Wait R, Charles P, Mikuls TR, Venables PJ. Antibodies to citrullinated alpha-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase. Arthritis Rheum. 2008 Oct;58(10):3009-19. doi: 10.1002/art.23936. — View Citation

Mandl P, Naredo E, Wakefield RJ, Conaghan PG, D'Agostino MA; OMERACT Ultrasound Task Force. A systematic literature review analysis of ultrasound joint count and scoring systems to assess synovitis in rheumatoid arthritis according to the OMERACT filter. J Rheumatol. 2011 Sep;38(9):2055-62. doi: 10.3899/jrheum.110424. — View Citation

Naredo E, Wakefield RJ, Iagnocco A, Terslev L, Filippucci E, Gandjbakhch F, Aegerter P, Aydin S, Backhaus M, Balint PV, Bruyn GA, Collado P, Finzel S, Freeston JE, Gutierrez M, Joshua F, Jousse-Joulin S, Kane D, Keen HI, Moller I, Mandl P, Ohrndorf S, Pineda C, Schmidt WA, Szkudlarek M, Conaghan PG, D'Agostino MA. The OMERACT ultrasound task force--status and perspectives. J Rheumatol. 2011 Sep;38(9):2063-7. doi: 10.3899/jrheum.110425. — View Citation

Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995 Jan;38(1):44-8. — View Citation

Sampaio E, Rocha M, Figueiredo LC, Faveri M, Duarte PM, Gomes Lira EA, Feres M. Clinical and microbiological effects of azithromycin in the treatment of generalized chronic periodontitis: a randomized placebo-controlled clinical trial. J Clin Periodontol. 2011 Sep;38(9):838-46. doi: 10.1111/j.1600-051X.2011.01766.x. Epub 2011 Jul 19. — View Citation

Zandbergen D, Slot DE, Cobb CM, Van der Weijden FA. The clinical effect of scaling and root planing and the concomitant administration of systemic amoxicillin and metronidazole: a systematic review. J Periodontol. 2013 Mar;84(3):332-51. doi: 10.1902/jop.2012.120040. Epub 2012 May 21. Review. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Reduction in the number of periodontitis associated microbes on a semi-quantitative level	DNA for Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Fusobacterium nucleatum, Tannerella forsythia, Treponema denticola, Filifactor alocis	After 1, 3 and 6 months
Other	Concentration of TNFa, IL-1ß, MMP-1 and TIMP-1 1		After 1, 3 und 6 months
Primary	Improvement in the rheumatoid arthritis disease activity index (DAS28ESR-3v) by >=1.2 points	The DAS28 will be used using 3 variables with 3rd variable erythrocyte sedimentation rate.	3 months
Secondary	Improvement in the rheumatoid arthritis disease activity score (DAS28ESR-3v) by >=1.2 points		At 6 months
Secondary	Improvement in the rheumatoid arthritis disease activity score when with 3rd variable C reactive protein serum concentration (DAS28CRP-3v) by >=1.2 points		After 3 and 6 months
Secondary	Improvement in the clinical disease activity index cDAI		After 3 and 6 months
Secondary	Improvement in the simplified disease activity index cDAI		After 3 and 6 months
Secondary	Number of patients with 20%, 50% or 70% improvement in the American College of Rheumatology (ACR) response criteria		After 3 and 6 months
Secondary	Number of patients in ACR/EULAR remission		After 3 and 6 months
Secondary	% change of B-mode (= gray-scale) and Power-Doppler signals to baseline		After 3 and 6 months
Secondary	Reduction in the probing pocket depth (PPD) in moderately deep (PPD >/= 4mm) und deep periodontal pockets (PPD > 6mm)		After 3 and 6 months
Secondary	Improvement in clinical attachment level (CAL), as the sum of PPD plus gingival recession (GR)		After 3 and 6 months
Secondary	Reduction in the number of sites with bleeding on probing (BoP)		After 3 and 6 months