Rheumatoid Arthritis Is A Progressive Inflammatory Disease

Published Date: 02 Nov 2017

Introduction:

Rheumatoid arthritis (RA) is a progressive inflammatory disease. It is an autoimmune disease and the major symptoms are severe pain and stiffness. RA is characterized by chronic joint inflammation which can progressively lead to erosion of the bone resulting in deformities and joint destruction and thus result in disability [1] [2]. Also, RA patients are more prone to Malignant Lymphoma as compared to healthy population [3]. 0.5-1% of the world population suffers from RA[1].

RA can also be classified as a Type III Hypersensitivity reaction as per Gell and Coombs Classification. Type III hypersensitivity reactions are Immune complex-Mediated i.e there is antigen-antibody (Ag-Ab) complex deposition in several body tissues. This results in excessive infiltration of neutrophils at that site leading to excessive inflammation [4].

The etiology of RA is still unknown however; both genetic and environmental factors play a role in establishment of the disease. Propagation of RA involves both innate as well as adaptive immune system[1]. Pro-inflammatory cytokines like TNFα, IL-6, IL-1, IL-21 play an important role in its pathogenesis [5].

There is no permanent cure for RA in todays modern medicines but early detection can help prevent the rapid inflammation and destruction. Polyarthritis can also be avoided however the main problem lies in early detection of RA. The main purpose of this review is to discuss the symptoms, pathogenesis, new novel detection techniques and treatments.

Classification:

RA is a multi-stage disease [6]. As per the American College Of Rheumatology classification scheme of 1987 and its revised criteria: Phase 1 is the genetic risk of the disease and this is followed by phase 2 in which asymptomatic auto immunity and inflammation is observed. In phase 2, a remarkable number of autoantibodies as well as inflammatory markers are observed however there is complete absence of any signs and symptoms of arthritis. In phase 3, slowly the symptoms of inflammatory arthritis begin to appear and finally the disease progresses to phase 4 i.e. classifiable RA. Phase 5 includes progression to extra articular disease. It also includes response to specific therapies and biomarkers, remission, and exacerbation [6]. The term ‘preclinical RA’ is generally used for the asymptomatic phase and not all subjects who suffer from RA go through all the phases as in some cases the presence of circulating antibodies may not precede the inflammation phase.

The American Rheumatism Association enlisted 7 criteria (Table 1) after carrying out a study on 262 Rheumatic disease subjects in 1987. The presence of any four of these criteria defines RA and these criteria assist in making the diagnosis [7].

CRITERIA

DESCRIPTION

1.

Morning Stiffness

Morning stiffness in and around the joints, lasting at least 1 hour before maximal improvement

2.

Arthritis of 3 or more joint areas

At least 3 joint areas simultaneously have had soft tissue swelling or fluid (not bony overgrowth alone). The 14 possible areas are right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints

3.

Arthritis of hand joints

At least 1 area swollen (as defined above) in a wrist, MCP, or PIP joint

4.

Symmetric arthritis

Simultaneous involvement of the same joint areas (as defined in 2) on both sides of the body (bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry)

5.

Rheumatoid nodules

Subcutaneous nodules, over bony prominences, or extensor surfaces, or in juxtaarticular regions.

6.

Serum rheumatoid factor

Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in <5% of normal control subjects.

7.

Radiographic changes

Radiographic changes typical of rheumatoid arthritis on posteroanterior hand and wrist radiographs, which must include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints (osteoarthritis changes alone do not qualify)

In the last decade there has been extensive and breakthrough studies like the discovery of anti-CCP [8] which have helped in early diagnosis of RA and thus in effective treatment. There was a need to develop new criteria to incorporate the new findings and aid faster diagnosis. A joint working group of American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) was formed to make these new criteria (Table 2). The criteria are divided into four domains and a specific score was conferred to each criteria. Patients with a score of 6 or more are said to have RA [8].

CRITERIA

SCORE

JOINTS

1 Large Joint

0

2-10 Large Joints

1

1-3 Small Joints (Large joints Excluded)

2

4-10 Small Joints (Large joints Excluded)

3

>10 Joints (Atleast 1 small joint)

5

SEROLOGY

Negative RF and Negative anti-CCP

0

Low positive RF or low positive anti-CCP (≤ 3 times the upper limit of normal)

2

High positive RF or High positive anti-CCP (> 3 times the upper limit of normal)

3

SYMPTOM DURATION

< 6 weeks

0

≥ 6 weeks

1

ACUTE PHASE REACTANTS

Normal CRP and ESR

0

Abnormal CRP or ESR

1

Pathogenesis:

RA is an Autoimmune and inflammatory disorder [1-10]. Genetic factors play an important role along with the environmental factors in occurrence of RA. Various genes play a role in susceptibility to RA; a region in 6q23, TRAF1/C5locus, STAT 4, HLA-DRB1 and PTPN22 are the five loci associated with the genetic risk to RA. The HLA locus is accountable for 30-50% of the genetic risk [9].

In RA, both innate and adaptive immune systems play a role. In early phase of RA, there is formation of new blood vessels in the synovial tissues and extravasation of leukocytes to the site. Extravasation is regulated by increase in number of adhesion molecules and chemokines [1]. Pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), Interleukin (IL)-1, IL-6, IL-21and IL-23 also play an important role in pathogenesis [1, 4]. TNF-α enhances T-cell and B-cell proliferation and also promotes angiogenesis. It suppresses the activity of Treg cells and induces other inflammatory cytokines [1].

In RA, autoantibodies against Rheumatoid Factor (RF) and cyclic citrullinated peptide (CCP) are produced [1]. Citrullination is a peptidylarginine deiminase (PAD) catalyzed post-translational modification of Arginine side chains [10]. The HLA-DRB1 locus is associated with the presence of CCP antibodies [9, 10].

Porphyromonas gingivalis is the only bacterium associated with RA [10]. The precise molecular mechanism is still not known but Porphyromonas gingivalis expresses endogenous citrullinated proteins and possesses its own bacterial PAD enzyme [10].

Diagnosis:

Diagnosis is mainly based on the classification scores. A patient is diagnosed to have RA if he/she attains a score of six or more as per the ARC/EULAR 2010 classifications [8]. An earlier diagnosis helps in more aggressive primary therapy thus aiming to arrest the disease in the initial stage. RA is currently monitored through continuous clinical examination of some specific signs and symptoms, and through a series of blood and radiological tests.

In RA, excessive inflammation is observed [1-12]. The cytokines invade the tissue and provoke destruction of the bones and cartilage by triggering a cascade reaction. Magnetic resonance imaging (MRI) technique detects inflammatory changes and can help in diagnosis. An advance technique of MPH-SPECT (Multi-pinhole Single-photon emission computed tomography) helps evaluate bone osteoblastic activity. It is a more sensitive technique and detects the very initial alterations in bone metabolism which occur during early RA and often go undetected in MRI [11].

Another novel technique for early diagnosis is the use of biomarkers. Biomarkers for disease activity can be used for diagnosis as well as for prognosis [12]. In RA, changes in the serum level of several proteins, cytokines as well as intercellular adhesion molecules is observed and they play an important role in diagnosis [12]; however, most frequently the increase in the protein levels is observed in the joint spaces which are generally inaccessible thus prohibiting quantitative measurements of the proteins and cytokines [13]. Levels of pro-inflammatory cytokines like TNFα, IL-6, IL-1, IL-21 show 5 to 6 times an increase as compared to their normal levels [1].

An elevation in the serum levels of Matrix Metalloproteinases (MMPs) especially MMP-3 is observed in all cases of RA [14]. MMPs are zinc and calcium dependent enzymes mainly found in the inactive state as proMMPs and activated by serine and cysteine proteinases. Elevated levels of MMP-3 are observed in early as well as established stages of RA. This is because of a genetic change in the HLA-DRB1 loci which is associated with RA susceptibility [15]. The promoter of MMP-3 shows bi-allelic polymorphism, one allele has 6 Adenosines (6A) and the other allele contains 5 Adenosines (5A). Greater radiographic damage is observed in RA patients with the 6A/6A genotype as compared to patients with 5A/5A or 5A/6A genotype during the early stages (Table 3) [14]. Thus estimating the serum MMPs levels is an important diagnostic technique. Studying the promoter genotype of RA patients by immunofluorescence or alternate techniques is also useful as it allows for determining the severity of the disease and in planning the further course of treatment [14].

In RA, increased expression of 48 inflammatory genes i.e. genes coding for pro-inflammatory and some other cytokines is observed (Table 4) [13]. An accurate measurement of the expression of these genes is possible through quantitative reverse transcriptase PCR (qRT-PCR) [13]. Recently, microarray techniques have also been developed for analyzing the complex expressions patterns of these genes [13].

SNP (Single Nucleotide polymorphism) based analysis is another important technique for diagnosis of the genetic loci that contribute to RA development [16]. Since altered gene expression precedes the immunologically important activities, they can act as the earliest diagnostic signs.

Genotype

Number of Patients

Mean Larsen Score

MMP-3 5A/5A

62

93.9

MMP-3 5A/6A

145

89.8

MMP-3 6A/6A

47

109.8