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

May 14, 2020 updated by: Eman Mohammed Ibrahem Kamel, Assiut University

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Interventional

Enrollment (Actual)

160

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Egypt
      • Assiut, Egypt, 71000515
        • Assiut University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 60 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 .

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: RA patients treated with methotrexate

Disease activity score(DAS28) matrix metalloproteinase-3(MMP-3) and matrix metalloproteinase-9(MMP-9), Erythrocyte sedimentation rate C- reactive protein Complete blood count Urine analysis Renal and liver function tests Lipid profile, blood glucose level Serum uric acid Rheumatoid factor (RF IgM, U/L) Anti- cyclic citrullinated peptide . Radiological assessment :Plain radiographs of both hands and feet in the postero-anterior views .

Cardiac assessment :By electrocardiogram ( ECG ) and echocardiography , Carotid artery intima-medial thickness (IMT) will be done by colored doppler ultrasound.
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
Other Names:
  • Erythrocyte sedimentation rate (ESR)
  • Complete blood count (CBC).
  • Lipid profile
  • Renal and liver function tests
  • Serum uric acid
  • Rheumatoid factor (RF IgM, U/L)
  • Anti- cyclic citrullinated peptide
  • plain radiographs of both hands and feet
  • electrocardiogram ( ECG ) and echocardiography
  • Carotid artery intima-medial thickness (CIMT)
  • C-reactive protein (CRP)
  • blood glucose level
  • Disease activity score(DAS28)
  • Matrix metalloproteinase 3 and 9 (MMP-3)(MMP-9)
Active Comparator: RA patients treated with methotrexate plus doxycycline

Disease activity score(DAS28) Matrix Metalloproteinase-3 (MMP-3) and Matrix Metalloproteinase-9 (MMP-9) Erythrocyte sedimentation rate C- reactive protein Complete blood count Urine analysis Renal and liver function tests Lipid profile, blood glucose level Serum uric acid , Rheumatoid factor (RF IgM(immunoglobulin M), U/L) Anti- cyclic citrullinated peptide. Radiological assessment :Plain radiographs of both hands and feet in the postero-anterior views.

Cardiac assessment :

By electrocardiogram ( ECG ) and echocardiography Carotid artery intima-medial thickness (IMT) will be done by colored doppler ultrasound.
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
Other Names:
  • Erythrocyte sedimentation rate (ESR)
  • Complete blood count (CBC).
  • Lipid profile
  • Renal and liver function tests
  • Serum uric acid
  • Rheumatoid factor (RF IgM, U/L)
  • Anti- cyclic citrullinated peptide
  • plain radiographs of both hands and feet
  • electrocardiogram ( ECG ) and echocardiography
  • Carotid artery intima-medial thickness (CIMT)
  • C-reactive protein (CRP)
  • blood glucose level
  • Disease activity score(DAS28)
  • Matrix metalloproteinase 3 and 9 (MMP-3)(MMP-9)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
efficacy of doxycycline
Time Frame: 3 months after therapy
percentage of patients achieving remission or low disease activity as assessed by DAS28
3 months after therapy
safety of doxycycline in combination with MTX
Time Frame: at day one of the study and every months till the end of the study
side effects
at day one of the study and every months till the end of the study

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
CIMT as a method for detection of subclinical atherosclerosis in RA patients
Time Frame: 1 day
colored doppler ultrasound
1 day
MMP-3 and 9 as predictors of cardiovascular affection, disease activity and treatment response
Time Frame: day 1 and 3 months follow up
blood samples using ELISA technique
day 1 and 3 months follow up

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assiut University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2019

Primary Completion (Actual)

February 20, 2020

Study Completion (Actual)

February 20, 2020

Study Registration Dates

First Submitted

June 10, 2017

First Submitted That Met QC Criteria

June 20, 2017

First Posted (Actual)

June 21, 2017

Study Record Updates

Last Update Posted (Actual)

May 18, 2020

Last Update Submitted That Met QC Criteria

May 14, 2020

Last Verified

May 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 17200080

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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