1. INTRODUCTION
1.1 Rheumatoid Arthritis (RA)
Rheumatoid Arthritis is a disease in which the body’s immune system fails to identify self-antigens, thereby attacking them in the same fashion as any other foreign antigen. In this case, the immune system attacks the membrane which surrounds the joints in the body- called the synovial membrane. This results in severe aches, distension, tautness and inactivation in the affected joints. It is very similar to other joint problems like osteoarthritis but is often distinguished from them based on a unique property – it is a symmetrical disease, i.e. joints affected by this disease on one side of the body are the same as the joints affected on the other side of the body. It’s a common disease which affects about 1 million people every year in India. This disease is persistent, meaning that if a person is once diagnosed with this disease, he/she suffers from it for the rest of his/her life. In fact, the joint complications only aggravate with time. However, the advancement of this disease can be decelerated with the help of physiotherapy and medications like anti-inflammatory (NSAIDs) and anti-rheumatoid (DMARDS) drugs.
The comprehension of this disease has progressed a great deal during the last 10 years. Scientists have evolved groundbreaking remedial approaches not only towards treating patients affected but also the visualization of the advent of this disease. Recent scientific studies have brought to light, the crucial role of a protease-like protein called Inactive Rhomboid protein-2 (iRhom2) in the advancement of this disease. It has served as a model to increase our understanding of the role of cytokines in the perpetuation and chronicity of this disease.
1.1.1 Types of Disease
Since the root causative behind this disease is not known clearly, complete categorization of this disease is inconvenient. Various patients suffering from this disease display unprecedented symptoms and advancements rates. Even though there is no complete clarity as to what leads to such dissimilarities, it is known that it is greatly dependent on genetics.
Mostly, the types and sub-types of rheumatoid arthritis are classified based on the explicit symptoms that patients experience, in adjunction with alternative factors. Due to the tendency of this disease to advance over a period of time, it is possible that patients are informed that they have numerous types or subtypes of rheumatoid arthritis in their life. Efforts are being made to classify rheumatoid arthritis into sub-types which are each defined by a novel set of symptoms and progressions to aid the provision of better customized medical care and therapies.
1.1.1. 1 Primary method of classification
This involves determining whether given patient is positive for the presence of anti-cyclic citrullinated proteins or not.
(i) Seropositive:
Patients classified under this category are characterized by the existence of anti-cyclic citrullinated peptides (anti-CCPs) – also known as anti-citrullinated protein antibodies (ACPAs) – in their blood. These antibodies attack the patient’s body and result in the characteristic symptoms of this disease.
Around 60 – 80 % of RA patients test positively for these anti-CCPs, thus making it a dependable indicator for diagnosis. These antibodies can be detected 5 – 10 years prior to the appearance of these symptoms.
(ii) Seronegative:
It is likely for patients to develop rheumatoid arthritis without the antibodies in their blood. Such patients are said to have seronegative type of rheumatoid arthritis. Such patients do not test positive for the anti-CCPs or other antibodies like rheumatoid factor.
Though seronegative patients lack antibodies, they can still be diagnosed based on the exhibition of clinical symptoms, along with X-ray results showing patterns of cartilage and bone retrogression.
1.1.1.2 Classification based on presence of Rheumatoid Factor
This is another method for the classification of the disease, albeit a lesser used one. Rheumatoid factor is an antibody which is usually detected in autoimmune disorders which lead to rheumatoid arthritis. This test is conducted in addition to a positive test for the presence of anti-CCPs.
However this factor can also appear in patients suffering from other conditions, including infections. This makes the presence of rheumatoid factor an unreliable indicator of rheumatoid arthritis. Generally, those patients that test positively for anti-CCPs, also test positively for this factor.
1.1.1. 3 Juvenile RA
This affects patients that are under 17 years of age. It is also called juvenile idiopathic arthritis. This type of arthritis is typical for this age group and its symptoms can be lasting. Distension, tautness and joint pain lasting for months at a stretch can occur. Some patients may even suffer from the symptoms for the rest of their lives.
The effects of juvenile RA is different from those observed in adult patients, since children and youth can face impairment of growth because of this disease. Eye and lymph node inflammation can also occur.
Just like adult patients, this type of arthritis can be diagnosed via different blood tests for the presence of rheumatoid factor and anti-CCPs. In some cases, doctors may not detect any abnormality in the blood tests of those children and youth displaying clinical symptom in which case X –rays and scans are performed to assess for other defects like bone fracture, tumors or ailments.
RA is often confused with osteoarthritis, particularly in seronegative patients. However the former is a disease caused due to wear and tear of joints while the latter is an autoimmune disease.
Due to the lack of clarity around the development of symptoms and their severity in different patients, researchers now feel the possibility of existence of several types of rheumatoid arthritis. The increasing difficulty in diagnosis of this disease in patients by physicians, specially in conjunction with further autoimmune symptoms (ex: dryness of eyes, rashes in skin) demands for the classification of his disease into subtypes that can be distinguished all the way down till the molecular level for better comprehension of this disease.
1.1.2 Complications involved
It has been discovered that RA patients may develop alternative persistent disorders alongside their RA symptoms. Some of these problems develop before the RA symptoms while others develop afterwards. Some of these ailments are:
• Lyme disease
It is a disorder that affects the skin, heart, and the nervous system. Arthritis is one of its integral features in the later stages. It typically develops months after the onset of this disease in approximately 60% of untreated Lyme patients. Following the initial tick bite, B.burgdorferi spirochetes disseminate and invade synovial joints, where they induce an inflammatory response in synovial tissue consisting of synovial hypertrophy, vascular proliferation, and infiltration of mononuclear cells.
• Joint destruction
Ongoing swelling from rheumatoid arthritis can damage the bone and cartilage near the infected joints. Major erosion of cartilage can result in deformation and fusion of the bones thereby causing (generally irreversible) immobilization of the joint.
• Psoriasis
It is a persistent disease that is initiated when a patient’s immune system dispatches defective signals directing skin cells to multiply expeditiously. As a result, nascent skin cells are formed within days instead of weeks. To add to this, the excess skin cells aren’t shed by the body resulting in their piling up onto the skin exterior, producing patches of psoriasis.
• Osteoporosis
It refers to decrease in bone density thus increasing the chances of fractures. Rheumatoid arthritis patients are more predisposed to osteoporosis. This could be due to the fact that both these diseases occur more frequently in senile females and smokers. It can also be due to the use of corticosteroids in RA treatment and its inherent potential to directly affect bone density in affected joints.
• Sjogren’s Syndrome
This is an autoimmune disorder which is frequently associated with rheumatoid arthritis. It affects the moisture-supplying cells of the patient’s body (ex: salivary and tear glands). This disease is more common in females. Its symptoms typically include dried mouth, eyes and vagina along with increased dental caries and discomfort in guzzling and speaking.
• Anemia
It refers to the decrease in the red blood cell count of the patient’s body. It is characterized by sluggishness, feebleness and giddiness. Extensive soreness due to rheumatoid arthritis can decrease the red blood cell production thus making anemia more prevalent among people suffering from RA.
• Heart disease
Rheumatoid Arthritis can occasionally prompt inflammation inside or near the heart. This can lead to either myocarditis or pericarditis or both. Pericarditis refers to infection of the pericardium. Myocarditis refers to the inflammation in the heart muscle. Both disorders can result in congestive heart failure (CHF), a grave disease characterized by the failure of heart to pump sufficient blood to remainder of the body and fluid collection in lungs.
• Lupus
Lupus is a disorder that affects the skin, joints, brain, heart, kidneys, blood cells and lungs.
Symptoms include fatigue, joint pain, etc. These can constantly get severe with time and improve suddenly.
• Ankylosing Spondylitis disease
This is a type of arthritis that affects the spine. Its manifestations comprise ache and inflexibility from the neck down. The vertebrae merge together leading to a rigid spine. These changes can range from mild to severe, causing a stooped-over pose. Its prevalent early symptoms include pain and stiffness, bony fusion, pain in ligaments and tendons.
• Rheumatoid lung
It is a group of lung conditions that can be found in RA patients. These include pleural effusions, pulmonary fibrosis, nodules and pulmonary hypertension. Its symptoms include shortness of breath, chest pain and persistent cough.
• Carpal tunnel syndrome
It is a common condition in people with rheumatoid arthritis. It’s the result of compression of the nerve that controls sensation and movement in the hands (median nerve) and can cause symptoms such as aching numbness tingling in your thumb, fingers and part of the hand.
• Sleep
The ache from rheumatoid arthritis wakes patients many times at night, thus averting remedial sleep. Rheumatoid arthritis patients can have fibromyalgia that disturbs sleep.
• Disability
Joint damage and pain can keep a person from executing routine tasks. It becomes tough to accomplish mundane tasks like getting dressed, etc.
• Psychological problems
The stress of RA and the lifestyle changes it causes can lead to loss of self-esteem, clinical depression, anxiety, etc.0
1.1.3 Management of RA
1.1.3.1 Previous Remedies
Earlier, doctors took a conventional methodical process in curing rheumatoid arthritis. They began with NSAIDs like ibuprofen and later advanced to more effective drugs. Nowadays, proper management of rheumatoid arthritis in patients comprises of a cohesive strategy involving both pharmacological and non-pharmacological treatment. Non-pharmacological therapies available for this disorder include diet, counseling, exercising, etc. Diligent involvement of the patients and their families in the therapeutic programs aids in boosting morale, ensuring acquiescence and elucidating the reasons behind the therapies utilized.
Medication-based therapies constitute many agent classes like Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), biotic and abiotic Disease-Modifying Anti-Rheumatic Drugs (DMARDs), immune-suppressants and corticosteroids. Premature treatment with DMARDs has been transformed into the paradigm of health care- it has the potential to delay the advancement of the disorder effectively.
Surgical approaches implemented in the therapy of rheumatoid arthritis including surgical removal of synovium or its tendon sheath, tendon realignment, arthroplasty, etc.
1.1.3.2 Current Strategies
These days, doctors follow an assertive procedure to increase effectivity resulting in lesser symptoms, improved function, less joint damage, and decreased disability. The goal, if possible, is to put the disease into remission.
Sr. No Drug Class Molecular target & Observed Effects Side Effects Available drugs
1) Non-steroidal anti-inflammatory medications (NSAIDs) They work by obstructing enzymes which enhances inflammation. By decreasing inflammation, they aid in reduction of aches and soreness. However they are ineffective in alleviating joint damage. • CVD
• Indigestion Diarrhea
• Skin reactions
• Abdominal cramps
• Dizziness
• Ulcer Celecoxib,
diclofenac sodium,
ibuprofen.
2) Disease-Modifying Anti-Rheumatic Drugs (DMARDs) It decreases proof of causatives underlying the disorder like increased RBC sedimentation rate, low hemoglobin level, high level of rheumatoid factor and even raised C-reactive protein level. It also decreases the rate of deterioration of cartilages and bones. • Blurry vision
• Increased light sensitivity
• Headache
• Loss of appetite
• Dizziness
• Hair loss
• Heartburn
• High blood pressure
• Neuropathy
• Skin rash
• Itching hydroxychloroquine sulfate, leflunomide, methotrexate, tofacitinib.
3) Biologic Response Modifiers They are a kind of DMARD which attack those responses of the immune system which lead to soreness and joint deterioration. They can also ameliorate the condition and help alleviate the symptoms. • Cough
• Dizziness
• Headache
• Redness
• Pain
• Itching
• Rash
• Higher risk for cancers
• Low white blood cell count
• Upper respiratory infection
• Lupus
• Multiple sclerosis Abatacept, adalimumab, adalimumab-atto, anakinra, etanercept, rituximab, golimumab, certolizumab pegol,
tocilizumab
4) Glucocorticoids These are strong anti-inflammatory steroids which obstruct alternative immune responses. They relieve symptoms and may delay or cease joint damage. Can be administered by pills or by injection. • Bruising
• Cataracts
• Increased cholesterol
• Atherosclerosis
• High blood pressure
• Indigestion
• Mood swings
• Muscle atrophy
• Osteoporosis
• Infections Betamethasone injectable, prednisone.
5) Analgesics These drugs affect the labyrinth of brain areas (called the “pain matrix”) and participate in pain cognizance and control. • Constipation
• Diarrhea
• Drowsiness
• Increased sweating
• Loss of appetite
• Nausea
• Dry mouth
• Headache
• Increased sweating
• Itchy skin Acetaminophen, tramadol, oxycodone, hydrocodone.
1.1.4 Emerging Targets
Inspite of great amount of progress in the treatment of rheumatoid arthritis, a specific cure for it has not been found as of yet. Even though manipulation of CD4+ regulatory T-cells was proposed to sustain regulation and restoration of damaged immune system, it was in vain due to theoretical and procedural hindrances. This was followed by targeting of B-cell receptors and most recently, the cytokines which aid in inflammation. Recent progress in the field of molecular biology and the clinical success of procedures targeting the tumor necrosis factor (TNF) has helped in furthermore experimentation and investigation into the pathophysiology of rheumatoid arthritis in human beings. Many unique targets for treatment have been discovered due to these endeavours, including not just TNF- controlling molecules (ex: TNF-α convertase), several adipokines, the complicated network of cytokines (ex: IL- 7, IL- 6, IL-15) but even those targets which are derived from the cellular and subcellular constituents of RA. Policies aiming at the cellular targets comprise of antibodies raised against CD20 protein which impedes B cells and those methodologies that disrupt the functioning of microparticles derived from the membrane. Those sections of subcellular pathways that are typically upstream to the chief regulator of the nuclear factor for transcription (κB) have been considered. Among these, those procedures which target the protein kinases initiated by mitogens have a paramount role in the control of this disease and are now on the edge of clinical implementation. In addition to this, the strategies targeting certain molecules like activators and signal transducers of transcription proteins, suppressor of cytokine signaling proteins and Janus kinases show extreme potential of future clinical implementation.
1.2 About IRHOM2 Protein
IRHOM2 protein is also called Rhomboid family member 2 (RHBDF2). It is a protein encoded by the RHBDF2 gene on chromosome 17 of humans. It is a part of the rhomboid family of transmembrane enzymes that split proteins into peptides, also known as serine proteases. Even though this protein comes from a family of proteases, it is itself catalytically inert in function. Instead it manages the discharge of a number of ligands present in the receptor for epidermal growth factor. It also concomitantly triggers the signaling pathway of the epidermal growth factor receptor and can thus regulate a number of activities such as slumber, cell endurance, multiplication and relocation.