Rheumatoid Arthritis In The Near Future Biology Essay

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Rheumatoid arthritis is a systemic 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 today's 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.

Occurrence:

RA is one of the oldest known disease along with Tuberculosis. Research suggests that RA has been prevalent in North America for more than 3,000 years [16]. Landre-Beauvais was the first to describe RA symptoms in 1800 however the term 'Rheumatoid Arthritis' was coined in 1859 by Garrod [16].

RA occurs in about 1% of the population [1, 16]; however the prevalence rate is found to be higher in some white populations [17]. Some Native American groups show a prevalence rate of 6-8% and the prevalence rate is found to be lower amongst the Asian populations [18]. Around three million individuals in Europe as well as in US suffer from RA.

Like most Autoimmune disease, RA is more common in women as compared to men [16]. Women are three to five times more prone to RA as compared to men [16]. A study also shows that RA is three times more common in people who smoke as compared to non-smokers [18]. The incidences of developing RA are greater after the age of 40-45 in women and little later in men [19].

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 now known as American College of Rheumatology (ARC) 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].

TABLE 1: Criteria for Diagnosis of RA as per the 1987 classification of ARC. [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 has 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 thus 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].

TABLE 2: 2010 Criteria for diagnosis of RA as per ACR and EULAR. [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]. It is a systemic disease however synovial i.e. flexible joints are mainly affected [2]. 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 like Rheumatoid Factor (RF) and anti-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 confirmed 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, autoantibodies against self-antigens RF and CCP are produced [1]. Diagnoses of these antibodies confirm Rheumatoid Arthritis disease condition [12]. However, sometimes RF presence is also observed in certain other disease condition like infection with Hepatitis C and thus RF is not an absolutely reliable marker. The reliability is greater with diagnosis of anti-CCP antibodies [16]. Whole blood samples are generally tested for the presence of ACPAs (anti-citrullinated protein antibodies) and Anti-MCV (antibodies against mutated citrullinated vimentin). Various diagnostic tests especially ELISA- qualitative and quantitative are performed for estimating the serum levels of autoantibodies [12, 13]. Point-of-care-test or more commonly known as POCT is currently the best known serological test for early diagnosis of RA. POCT has a specificity of 99.7% and sensitivity of 72% [20]. POCT is a combined assay for detection of RF, ACPA and Anti-MCV [20].

In RA, excessive inflammation is observed [1-24]. 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 [12]. 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 [13]. 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 [14]. 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) [13]. 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 [13].

In RA, increased expression of 48 inflammatory genes i.e. genes coding for pro-inflammatory and some other cytokines is observed (Table 4) [12]. An accurate measurement of the expression of these genes is possible through quantitative reverse transcriptase PCR (qRT-PCR) [12]. Recently, microarray techniques have also been developed for analyzing the complex expressions patterns of these genes [12].

TABLE 3: Comparison of the radiological damage observed in RA patients with different genotypes [14].

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

SNP (Single Nucleotide polymorphism) based analysis is another important technique for diagnosis of the genetic loci that contribute to RA development [15]. Since altered gene expression precedes the immunologically important activities, they can act as the earliest diagnostic signs.

TABLE 4: The 48 inflammatory genes whose expression is increased during RA.

No

HUGO designation

Gene name

No

HUGO designation

Gene name

1

B7

CD80

25

IL6

Interleukin-6

2

C1QA

Complement component 1,

q subcomponent, A chain

26

IL8

Interleukin-8

3

CD3Z

CD247molecule

27

IL10

Interleukin-10

4

CD4

CD4 molecule

28

IL12B

Interleukin-12b

5

CD8A

CD8a molecule

29

IL13

Interleukin-13

6

CD14

CD14 molecule

30

IL15

Interleukin-15

7

CD19

CD19 molecule

31

IL18

Interleukin-18

8

CXCL1

Chemokine (C-X-C motif) ligand 1

32

IL18BP

Interleukin-18 binding protein

9

CXCL2

Chemokine (C-X-C motif) ligand 2

33

MMP-3

Matrix metallopeptidase 3

10

CSF2

Colony stimulating factor 2

34

MMP-9

Matrix metallopeptidase 9

11

CSF3

Colony stimulating factor 3

35

PLA 2G7

Phospholipase A2, group VII

12

F3

Coagulation factor 3

36

NOS2A

Nitric oxide synthase 2a, inducible

13

HLA-DRB1

Major histocompatibility complex, class II, DR beta 1

37

PLAUR

Plasminogen activator, urokinase receptor

14

HMOX1

Heme oxygenase (decycling) 1

38

PTGS2

Prostaglandin-endoperoxide synthase 2

15

HSPA1A

Heat shock protein A1A

39

PTPRC

Protein tyrosine phosphatase, receptor type, C

16

ICAM1

Intercellular adhesion molecule 1

40

SERPINE1

Serpin peptidase inhibitor, clade E

17

IFNA2

Interferon, alpha 2

41

TGFB1

Transforming growth factor, beta 1

18

IFNG

Interferon gamma

42

TIMP1

TIMP metallopeptidase inhibitor 1

19

IL1A

Interleukin-1, alpha

43

TNF

Tumor necrosis factor

20

IL1B

Interleukin-1, beta

44

TNFSF5

CD40 ligand

21

IL1RN

Interleukin-1 receptor antagonist

45

TNFSF6

Fas ligand (TNF superfamily, member 6)

22

IL2

Interleukin-2

46

TNFSF13B

Tumor necrosis factor (ligand) superfamily, member 13b

23

IL4

Interleukin-4

47

TNFRSF13B

Tumor necrosis factor receptor superfamily, member 13b

24

IL5

Interleukin-5

48

VEGF

Vascular endothelial growth factor

Treatment:

The main focus of researchers in the field of RA, today, is to develop immunomodulatory agents: chemical & biological, which block the activity of pro-inflammatory cytokines [2]. With the improved understanding of pathogenesis and improved diagnostic techniques for RA, new therapeutic agents with improved treatment outcome are being discovered. Though there is no permanent cure for RA, treatment can aid in suppressing the symptoms or help in modifying the disease outcome [20]. The main goals of the treatment are to reduce the clinical symptoms as well as to prevent further bone deformity thus preventing progression of the disease [18].

Often, Disease-modifying antirheumatic drugs (DMARDs) are offered as primary treatments for RA [4]. DMARDs are broadly classified into two types; conventional or synthetic DMARDs (cDMARDs) and Biological DMARDs (bDMARDs). The most common and successful cDMARD is Methotrexate (MTX) which is administered alone or sometimes in combination with other DMARDs [4]. Sulfasalazine, hydroxychloroquine and leflunomide are examples of other cDMARDs used in combination with MTX [2]. Study has shown that cDMARDs are quite effective but complete remission is achieved in only 30-40% cases. Also several patients show intolerance to MTX and some others produce a suboptimal response to MTX therapy [2, 4]. Biological DMARDs act as a solution for these patients.

Biological DMARDs are blocking agents which suppress the activity of pro-inflammatory cytokines and are currently one of the best known therapies for RA. The four best biologics currently in use are TNF inhibitors, IL-6 inhibitors, B-cell inhibitors and T-cell co-stimulation inhibitors [1]. These biologics are mainly monoclonal antibodies targeted against specific cytokine or immunogenic cell whose expression increases greatly during RA [22]. The most common and successful bDMARDs are adalimumab, etanercept, infliximab, anakinra, rituximab and abatacept. Of these, infliximab, golimumab, adalimumab and etanercept are TNF-α inhibitors- a major breakthrough in RA treatment [2, 22]. TNF-α is also related to cardiac diseases and thus RA patients show an increased risk of heart failure which can be reduced by these TNF-α inhibitors especially Infliximab [22].

Corticosteroids more commonly known as glucocorticoids or steroids are commonly used for anti-inflammatory and immunosuppressive response in RA treatment. They interact with steroid-specific receptors in the cells cytoplasm and inhibit movement of the cell to the site of inflammation. Thus steroids reduce inflammation and joint pain. Methylprednisolone, prednisone, and prednisolone are the commonly used oral corticosteroids [23].

Two strategies used for treatment of RA are sequential monotherapy approach and the step-up combination therapy approach (Figure 1) [24]. Sequential monotherapy is the conventional approach where the primary treatment is with a cDMARD generally MTX. If the patient shows no response or shows a suboptimal response to it, the monotherapy is repeated with an alternate cDMARD and this is continued till all the cDMARDs are tried. If none of the classical DMARDs are effective, as a last resort a biological blocking agent or a corticosteroid therapy is given [1, 24]. Thus at a given time only one drug is used.

Now a days the step-up combination therapy approach is more frequently used. In this approach, a more aggressive primary treatment is given thus arresting the disease in the early stages [24]. More than one drugs are simultaneously use and more toxic DMARDs are added if the patient lacks response. Thus the inflammatory process is rapidly brought under control [1, 23,24]. In some sever cases; initial combination therapy is also used where the higher toxic DMARDs are administered from the start itself [24].

Figure 1: The two approaches for RA treatment [24].

Side Effects:

The main drawback of all the therapies is their immunosuppressive nature. Thus RA patients undergoing the therapy are very prone to various infections including tuberculosis and pneumonia. Various studies have shown that patients treated with biological DMARDs show more side effects as compared to patients treated with traditional DMARDs [1, 2, 22, 24]. Other common side effects include abdominal pain, nausea, headache, diarrhea, upper respiratory tract infections and urinary tract infections. The FDA has issued a black box warning about an increased risk of infections with use of adalimumab and infliximab. Few studies have also shown a risk of Cardiovascular diseases with the use of infliximab however the evidences are not completely satisfying and further study in required [17, 21,22].

Conclusion:

Tremendous breakthrough research has been carried out in the field of Rheumatoid Arthritis in the last decade. Novel diagnostic therapies have helped in earlier diagnosis of RA and improved treatment chances. Though no cure for RA, with the availability of modern therapies it is possible to arrest RA in its very initial stages and prevent it from progressing to other parts of the body. Currently many new DMARDs and other therapeutics are under clinical studies and await FDA approvals [4]. The current focus of researchers in this field is to reduce the toll of autoimmune diseases and find therapies for curing rather than only suppressing or delaying the progression of the disease.

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