Re-evaluation of Some Old Rheumatoid Arthritis Therapy: A Randomized Controlled Trial
Condition: Rheumatoid Arthritis
MeSH terms: Arthritis; Arthritis, Rheumatoid
Study type: Interventional

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.
    

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.
    

Intervention name(s): Doxycycline Tablets
Intervention type(s): Drug
Intervention description(s): MMP-3 and MMP-9 will be done with blood samples using ELISA technique CIMT will be done using colored doppler ultrasound
Other intervention name(s): 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)
Intervention MeSH terms: Doxycycline; Uric Acid; Rheumatoid Factor
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: A group of patients will receive methotrexate only, another group will receive methotrexate plus doxycycline
Masking: None (Open Label)
Primary purpose: Treatment