Re-evaluation of Some Old Rheumatoid Arthritis Therapy: A Randomized Controlled Trial

Rheumatoid Arthritis Clinical Trial

Official title:

Efficacy of Doxycycline as a Combination Therapy in the Treatment of Rheumatoid Arthritis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03194204
• Other study ID #: 17200080
• Status: Completed
• Phase: N/A
• Start date: October 1, 2019
• Est. completion date: February 20, 2020

Study information

• Verified date: May 2020
• Source: Assiut University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Rheumatoid Arthritis (RA) is a chronic inflammatory disease characterized by joint swelling, joint tenderness and destruction of synovial joints, leading to severe disability and premature mortality.

Description:

The rate of cartilage and joint damage in RA is correlated with plasma elevations in inflammatory acute phase reactants, such as C- reactive protein and erythrocyte sedimentation rate, rheumatoid factor positivity and the synovial concentrations of matrix metalloproteinases(MMP), a matrix digesting enzymes directly responsible for joint destruction.

Matrix metalloproteinases (MMP) are a family of zinc-containing endoproteinases that degrade extracellular matrix (ECM) components.The MMPs are thought to play a critical role in the degradation of many components of the extracellular matrix in the synovial joint.

Matrix metalloproteinase-3 (stromelysin-1) is a proteolytic enzyme which is thought to play a pivotal role in joint destruction in RA through breaking down various extracellular components, including collagens (types III, IV, V, IX, and XI), matrix proteins and proteoglycans and activating other pro-MMPs such as pro-MMP-7, pro-MMP-8 and pro-MMP-9.

In RA, MMP-3 is locally produced in the inflamed joint and released into the blood stream. It has been suggested that serum MMP-3 level correlates with levels produced by the synovium, thus reflect the level of activity of rheumatoid synovitis.

MMP-9 has been associated with chronic inflammatory autoimmune diseases. It has been implicated in the pathogenesis of autoimmune diseases.

MMP-9 displays gelatinolytic, elastolytic and collagenolytic activity, thus playing a key role in extracellular matrix turnover, in addition, MMP-9 may also modulate the activity of various biological factors, including other proteinases (e.g., MMP-13), their inhibitors (e.g., α1-antitrypsin) or cytokines.

Matrix metalloproteinases also play key roles in adverse cardiovascular remodeling, atherosclerotic plaque formation and plaque instability, vascular smooth muscle cell (SMC) migration and restenosis that lead to coronary artery disease (CAD) and progressive heart failure.

Matrix metalloproteinases-9 (MMP-9) is mainly found in the most stenotic areas of carotid plaques in humans and is a marker for plaque vulnerability . It can also predict stroke and fatal cardiovascular events . Elevated circulating levels of MMP-9 have been found in subjects with stable angiographic coronary atherosclerosis and intermittent claudication.

The prevalence of athero sclerosis is increased in RA, even in early disease. The earliest vascular change described microscopically in atherosclerosis is intimal media thickening (IMT) , which consists of layers of smooth muscle cells and extracellular matrix. Intimal thickening is more frequent in atherosclerosis-prone arteries such as coronary, carotid, aorta and iliac arteries .

IMT is the "phenotype" of the early phases of atherosclerotic disease and is related to the main traditional risk factors. Moreover, IMT is a marker of organ damage either in the heart or in other vascular districts. The simultaneous measurement of carotid and femoral IMT may improve risk stratification in patients with coronary heart disease.

Atherosclerosis is recognized as a chronic inflammatory condition with key roles for both the innate and adaptive immune systems in the initiation, progression and stability of lesions.

Inflammation is an important trigger of plaque erosion and stability and one focus of secondary prevention of coronary artery disease (CAD) in the general population is the development of anti-inflammatory agents for plaque stabilization.

Many aspects of the pathophysiology of atherosclerosis are mirrored in the inflamed RA synovium, including pronounced infiltration by macro phages and type 1 T-helper cells, collagen degradation and neovascularization . Cytokines such as tumor necrosis factor-α(TNFα), interleukin-6(IL-6) and matrix metalloproteinases are implicated in both processes.

As plaques become more complex, thinning of the fibrous cap occurs. This thinning eventually causes rupture of the plaque, exposing its thrombogenic content to blood, resulting in acute thrombosis and a clinical event .Fibrous cap erosion is thought to be mediated by inflammatory cells, in particular macrophages and T helper cells, via secretion of matrix metalloproteinases.

Doxycycline, a semi-synthetic tetracycline, is a commonly used broad-spectrum antibiotic. It has been shown that it also inhibits the activity of mammalian collagenases and gelatinases, an activity unrelated to its antimicrobial efficacy. Doxycycline not only inhibits MMP-8 and MMP-9 (gelatinase B) activity, but also the synthesis of MMPs in human endothelial cells .

Tetracyclines exhibit multiple anti-inflammatory properties, including the inhibition of T-cell activation and chemotaxis, the downregulation of proinflammatory cytokines, including TNFα and IL-1b and the inhibition of matrixmetalloproteinases.

A study of patients with early disease showed significant efficacy compared with placebo when used in combination with methotrexate .The benefit of minocycline and doxycycline was confirmed in a recent meta-analysis that found clinically significant improvement in disease activity with no increased risk for adverse events. Rheumatologists have not embraced minocycline or doxycycline as primary treatment options for RA and reserve their use primarily in patients with long-standing, refractory disease. Minocycline and doxycycline are safe and moderately effective disease-modifying anti-rheumatic drugs (DMARDs) in the treatment of early rheumatoid arthritis . These drugs are generally well tolerated, with skin complaints, nausea, and dizziness being the most common patient-reported side effects.

Whether RA is caused, triggered, or perpetuated by an infectious agent or agents is still not delineated, it is possible, that suppression of infections in a nonspecific manner, decreasing the stimuli for TNFα production, may play a role in the treatment of RA.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 160
• Est. completion date: February 20, 2020
• Est. primary completion date: February 20, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• Patients included in this study are patients with RA (either newly or previously diagnosed) with their age between 18-50 years old having the same normal range of body mass index

Exclusion Criteria:

1. - The investigators will exclude patients with risk factors for atherosclerosis other than rheumatoid arthritis such as:

• Smoking.

• Obesity.

• Hypertension.

• Diabetes.

• History of renal or liver diseases.

• Corticosteroid therapy. 2- Intercurrent infections as they may interfere with levels of metalloproteinases.

3- Pregnant or lactating females .

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• Doxycycline Tablets
MMP-3 and MMP-9 will be done with blood samples using ELISA technique CIMT will be done using colored doppler ultrasound

Locations

Country	Name	City	State
Egypt	Assiut University	Assiut

Sponsors (1)

Lead Sponsor	Collaborator
Assiut University

Country where clinical trial is conducted

Egypt, 

References & Publications (10)

Abdelnaseer M, Elfayomi N, Esmail EH, Kamal MM, Hamdy A, Samie RMA, Elsawy E. Relationship between matrix metalloproteinase-9 and common carotid artery intima media thickness. Neurol Sci. 2016 Jan;37(1):117-122. doi: 10.1007/s10072-015-2358-z. Epub 2015 A — 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 — View Citation

Bernetti M, Abbate R, Cerini G, Gensini GF, Poggesi L, Boddi M. [Carotid and femoral intima-media thickness as an early atherosclerotic marker. Advantages and limits]. G Ital Cardiol (Rome). 2011 Jan;12(1):72-81. Italian. — View Citation

del Rincón ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum. 2001 Dec;44(12):2737-45. — View Citation

Everett BM, Pradhan AD, Solomon DH, Paynter N, Macfadyen J, Zaharris E, Gupta M, Clearfield M, Libby P, Hasan AA, Glynn RJ, Ridker PM. Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of athero — View Citation

Grzela K, Litwiniuk M, Zagorska W, Grzela T. Airway Remodeling in Chronic Obstructive Pulmonary Disease and Asthma: the Role of Matrix Metalloproteinase-9. Arch Immunol Ther Exp (Warsz). 2016 Feb;64(1):47-55. doi: 10.1007/s00005-015-0345-y. Epub 2015 Jun — View Citation

Ma JD, Zhou JJ, Zheng DH, Chen LF, Mo YQ, Wei XN, Yang LJ, Dai L. Serum matrix metalloproteinase-3 as a noninvasive biomarker of histological synovitis for diagnosis of rheumatoid arthritis. Mediators Inflamm. 2014;2014:179284. doi: 10.1155/2014/179284. E — View Citation

Mittal B, Mishra A, Srivastava A, Kumar S, Garg N. Matrix metalloproteinases in coronary artery disease. Adv Clin Chem. 2014;64:1-72. Review. — View Citation

Nakashima Y, Chen YX, Kinukawa N, Sueishi K. Distributions of diffuse intimal thickening in human arteries: preferential expression in atherosclerosis-prone arteries from an early age. Virchows Arch. 2002 Sep;441(3):279-88. Epub 2002 Mar 14. — View Citation

Webster G, Del Rosso JQ. Anti-inflammatory activity of tetracyclines. Dermatol Clin. 2007 Apr;25(2):133-5, v. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	efficacy of doxycycline	percentage of patients achieving remission or low disease activity as assessed by DAS28	3 months after therapy
Primary	safety of doxycycline in combination with MTX	side effects	at day one of the study and every months till the end of the study
Secondary	CIMT as a method for detection of subclinical atherosclerosis in RA patients	colored doppler ultrasound	1 day
Secondary	MMP-3 and 9 as predictors of cardiovascular affection, disease activity and treatment response	blood samples using ELISA technique	day 1 and 3 months follow up