RHEUMATOID ARTHRITIS (RA)

EPIDEMIOLOGY

Worldwide, the annual incidence of Rheumatoid Arthritis (RA) is approximately 3 cases per 10,000 populations, and the prevalence rate is approximately 1%, increasing with age and peaking between the ages of 35 and 50 years. RA affects all populations, though it is much more prevalent in some groups (e.g. 5-6% in some Native American groups) and much less prevalent in others (e.g. black persons from the Caribbean region). Women are affected by RA approximately 3 times more often than men are, but sex differences diminish in older age groups.^(1,2)

In the urban population of southern Pakistan, Karachi, the prevalence of RA is reported to be 0.142%, whereas in northern Pakistan the estimated prevalence is 0.55%.⁽³⁾

PATHOPHYSIOLOGY:

The pathogenesis of RA is not completely understood. An external trigger (e.g. cigarette smoking, infection, or trauma) that triggers an autoimmune reaction, leading to synovial hypertrophy and chronic joint inflammation along with the potential for extra-articular manifestations, is theorized to occur in genetically susceptible individuals.

Synovial cell hyperplasia and endothelial cell activation are early events in the pathologic process that progresses to uncontrolled inflammation and consequent cartilage and bone destruction. Genetic factors and immune system abnormalities contribute to disease propagation.

CD4 T cells, mononuclear phagocytes, fibroblasts, osteoclasts, and neutrophils play major cellular roles in the pathophysiology of RA, whereas B cells produce autoantibodies (i.e. RFs). Abnormal production of numerous cytokines, chemokines, and other inflammatory mediators (e.g. tumor necrosis factor alpha [TNF-a], interleukin [IL]-1, IL-6, IL-8, transforming growth factor beta [TGF-ß], fibroblast growth factor [FGF], and platelet-derived growth factor [PDGF]) has been demonstrated in patients with RA.

Ultimately, inflammation and exuberant proliferation of the synovium (i.e. pannus) leads to destruction of various tissues, including cartilage, bone, tendons, ligaments, and blood vessels. Although the articular structures are the primary sites involved by RA, other tissues are also affected.

NATURAL HISTORY:

The hallmark feature of rheumatoid arthritis (RA) is persistent symmetric polyarthritis (synovitis) that affects the hands and feet, although any joint lined by a synovial membrane may be involved. The severity of RA may fluctuate over time, but chronic RA most commonly results in the progressive development of various degrees of joint destruction, deformity, and a significant decline in functional status. Extra-articular involvement of organs such as the skin, heart, lungs, and eyes can also be significant.

Juvenile idiopathic arthritis (JIA), sometimes referred to as juvenile rheumatoid arthritis (JRA), is the most common form of childhood arthritis. In most patients, the immunogenic associations, clinical pattern, and functional outcome of JIA are different from those of adult-onset RA.

SIGN AND SYMPTOMS:

In most patients with RA, onset is insidious, often beginning with fever, malaise, arthralgias, and weakness before progressing to joint inflammation and swelling.

Signs and symptoms of rheumatoid arthritis may include the following:

• Persistent symmetric polyarthritis (synovitis) of hands and feet (hallmark feature)
• Progressive articular deterioration
• Extra-articular involvement
• Difficulty performing activities of daily living (ADLs)
• Constitutional symptoms

DIAGNOSTIC TESTS:

No test results are pathognomonic for rheumatoid arthritis (RA); instead, the diagnosis is made by using a combination of clinical, laboratory, and imaging features.

Routine viral screening by serologic testing does not significantly facilitate the diagnosis of RA in patients with early RA, nor is it helpful as a potential identifier of disease progression.⁽⁴⁾ Potentially useful laboratory studies in suspected RA fall into 3 categories, markers of inflammation, hematologic parameters, and immunologic parameters and include the following:

• Erythrocyte sedimentation rate (ESR)
• C-reactive protein (CRP) level
• Complete blood count (CBC)
• Rheumatoid factor (RF) assay
• Antinuclear antibody (ANA) assay
• Anti−cyclic citrullinated peptide (anti-CCP) and anti−mutated citrullinated vimentin (anti-MCV) assays (currently used in the 2010 American College of Rheumatology [ACR] /European League Against Rheumatism [EULAR] classification criteria)

THERAPY CONSIDERATIONS:

Our overall approach to the treatment of patients with rheumatoid arthritis (RA) depends upon the timely and judicious use of several types of therapeutic interventions.

These principles include:

• Early recognition and diagnosis
• Care by an expert in the treatment of rheumatic diseases, such as a rheumatologist
• Early use of disease-modifying anti-rheumatic drugs (DMARDs) for all patients diagnosed with RA
• Importance of tight control, utilizing a treat-to-target strategy, with a goal of remission or low disease activity
• Use of anti-inflammatory agents, including nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, only as adjuncts to therapy

TREATMENT OPTIONS:

LIFE STYLE MODIFICATION:

A number of non-pharmacologic measures and other medical interventions are important in the comprehensive management of rheumatoid arthritis (RA) in all stages of disease, in addition to anti-rheumatic drug therapies. Patient education that addresses issues related to the disease and its management is indicated for all patients with RA.

These measures include:

• Patient education
• Psychosocial interventions
• Rest, exercise, and physical and occupational therapy
• Nutritional and dietary counseling
• Interventions to reduce risks of cardiovascular disease, including smoking cessation and lipid control
• Screening for and treatment of osteoporosis
• Immunizations to decrease risk of infectious complications of immunosuppressive therapies.

Muscle atrophy often accompanies RA and is exacerbated by inactivity, bed rest, splints, and medications. Isometric exercises restore and maintain strength in affected patients without producing pain. Resistance exercises may be initiated when the isometric program has been well established and when the patient is free of pain.⁽⁵⁾ Occupational therapy also can be very useful for patients with RA.⁽⁶⁾

PHARMACOLOGICAL OPTIONS:

Optimal care of patients with rheumatoid arthritis (RA) requires an integrated approach that includes both non-pharmacologic therapies and pharmacologic agents such as non-biologic and biologic disease-modifying anti-rheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and corticosteroids.

Medication-based therapies comprise several classes of agents, including non-steroidal anti-inflammatory drugs (NSAIDs), non-biologic and biologic disease-modifying anti-rheumatic drugs (DMARDs), immunosuppressants, and corticosteroids. Early therapy with DMARDs has become the standard of care, in that it is capable not only of retarding disease progression more efficiently than later treatment but also, potentially, of inducing more remissions.^(7,8,9)

LEFLUNOMIDE: Leflunomide is indicated for the treatment of active RA to reduce signs and symptoms, inhibit structural damage and improve physical function. Corticosteroids, aspirin, or other NSAIDs may be continued during leflunomide use. Leflunomide is contraindicated in women who are or may become pregnant.

SULFASALZINE: Sulfasalazine (SSZ) is indicated for the treatment of patients with RA who have had an inadequate response to salicylates or other NSAIDs. It acts locally to decrease inflammatory response and systemically inhibits prostaglandin synthesis.

SSZ delayed-release tablets do not have an immediate response; therefore, concurrent treatment with NSAIDs or other analgesics is recommended at least until the effect of the delayed-release tablets is apparent. The initial dosage is 0.5-1 g / day. The dosage can be adjusted to a dose of 3 g / day after 12 weeks if an adequate clinical response is not seen.

HYDROXYCHLOROQUINE: Hydroxychloroquine (HCQ) is approved for the treatment of acute or chronic RA. The initial dosage is 400-600 mg / day; dosages should be computed on the basis of patient body weight. If a good clinical response is seen over a period of 4 to 12 weeks, the dosage can be reduced by 50% and continued at a level of 200-400 mg / day. The risk of retinopathy is greater when this dosage is exceeded. It should be noted that each 200 mg tablet contains only 155 mg of active drug.

TOCILIZUMAB: Tocilizumab is an IL-6 receptor inhibitor. It is indicated for moderate to severe active RA in adults who have had an inadequate response to 1 or more TNF-antagonist therapies. It has been approved as an IV infusion or SC injection that may be used alone or in combination with MTX or other DMARDs.

TOFACITINIB: Tofacitinib is an oral Janus kinase (JAK) pathways inhibitor. It is indicated as second-line treatment for moderate to severe active RA in patients with an inadequate response to or intolerance of MTX. Tofacitinib may be used as monotherapy or in combination with MTX or other non-biologic DMARDs, but it should not be used in combination with biologic DMARDs or potent immunosuppressive agents (e.g. azathioprine and cyclosporine).

Although cyclosporine is approved for the treatment of patients with severe active RA in which the disease has not adequately responded to MTX, it is not commonly used to treat RA, because of its nephrotoxicity. When cyclosporine is used, patients' renal function must be closely monitored.

METHOTREXATE: MTX is a folic acid antagonist that is approved for the management of severe active RA in patients who have had an insufficient therapeutic response to or are intolerant of an adequate trial of first-line therapy, including full-dose NSAIDs.

ANAKINRA: Anakinra is a recombinant, non-glycosylated form of the human interleukin (IL)-1 receptor antagonist (IL-1Ra) that is indicated for reducing signs and symptoms and slowing the progression of structural damage of moderately to severely active RA that has failed treatment with 1 or more DMARDs. Anakinra can be used alone or in combination with DMARDs other than TNF-blocking agents.

ABATACEPT: Abatacept is a selective co-stimulation modulator that inhibits T-cell activation by binding to CD80 and CD86, thereby blocking their interaction with CD28. CD28 interaction provides a signal needed for the full T-cell activation that is implicated in RA pathogenesis.

INFLIXIMAB: Infliximab a chimeric monoclonal antibody against TNF-α, is approved for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active RA, in combination with MTX. This agent binds to cells that express membrane TNF.

ETANERCEPT: Etanercept a bivalent p75–TNF receptor linked to the Fc portion of human immunoglobulin G (IgG), is approved for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active RA. It can be given alone or in combination with MTX. This agent binds lymphotoxin (formerly termed TNF-β) in addition to soluble TNF-α.

GOLIMUMAB: Golimumab a human monoclonal antibody to TNF-α, inhibits TNF-α bioactivity, thereby modulating immune activity in patients with RA. It is approved for the treatment of adults with moderately to severely active RA, in combination with MTX. It may be administered as either a SC injection every month, or as an IV infusion every 2 months following 2 once monthly doses. Golimumab should be given in combination with MTX.

CERTOLIZUMAB: Certolizumab is a pegylated anti−TNF-α agent, which results in disruption of the inflammatory process in RA. It is indicated for the treatment of adults with moderately to severely active RA.

ADALIMUMAB: is indicated to reduce inflammation and inhibit progression of structural damage in moderate to severe RA, alone or in combination with MTX or other nonbiologic DMARDs. This agent is reserved for those who experience an inadequate response to 1 or more DMARDs. Adalimumab can be used alone or in combination with MTX or other DMARDs.

TETRACYCLINS: The minocycline regimen that is most commonly used in RA is 100 mg twice daily for up to 2 years. The anti-inflammatory effects of minocycline may result from inhibition of inflammatory cell migration and transformation of lymphocytes.

IBUPROFEN: Ibuprofen is indicated for patients with mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

NAPROXEN: Naproxen is used to relieve mild to moderate pain. This agent inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, which is responsible for prostaglandin synthesis.

DICLOFENAC: Diclofenac is one of a series of phenylacetic acids that have demonstrated anti-inflammatory and analgesic properties in pharmacologic studies. It is believed to inhibit COX, which is essential in the biosynthesis of prostaglandins.

DICLOFENAC: topical gel is approved in patients with osteoarthritis at a dosage of 32 g / day applied over all affected joints. It has also been used to provide analgesic effects in patients with RA.

KETOPROFEN: Ketoprofen is used to relieve mild to moderate pain and inflammation. Small dosages are initially indicated in small and elderly patients and in those with renal or liver disease. Doses higher than 75 mg do not yield increased therapeutic effects. Administer high doses with caution, and closely observe the patient for response.

CELECOXIB: Celecoxib is approved for the relief of signs and symptoms of RA. It primarily inhibits COX-2, which is considered an inducible isoenzyme (induced during pain and inflammatory stimuli). Inhibition of COX-1 may contribute to NSAID gastrointestinal (GI) toxicity. At therapeutic concentrations, celecoxib does not inhibit COX-1, thus potentially resulting in decreased GI toxicity. Administer the lowest possible dose for each patient. Use of celecoxib has been associated with an increased risk of cardiovascular toxicity.

TRAMADOL: The immediate-release formulation of tramadol is approved for the management of moderate to moderately severe pain in adults. The extended-release formulation is used for the management of moderate to moderately severe chronic pain in adults who require around-the-clock treatment of pain for an extended period of time.

PREDNISONE: Prednisone is an immunosuppressant for the treatment of autoimmune disorders; it may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity. Prednisone stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

METHYLPREDNISOLONE: Methylprednisolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes (PMNs) and reversing increased capillary permeability.

SURGICAL OPTION:

Surgical intervention in patients with RA can achieve pain relief, deformity correction, and functional improvement.⁽¹⁰⁾ A number of surgical procedures are available to obtain these goals, such as myofascial techniques, excisions, reconstructions, joint fusions, and joint replacements. The timing of surgery is a complex decision; the patient’s age, stage of disease, and level of disability, as well as the location of the involved joints, must be considered. Early surgical intervention may help maintain a patient’s functional level of independence.

Deformities of the hand or wrist lead to loss of the ability to grip, grasp, and pinch, often leaving the patient unable to perform the activities of daily living. The surgical treatments for RA of the hand and wrist include synovectomy, tenosynovectomy, tendon realignment, reconstructive surgery or arthroplasty, and arthrodesis.

Cervical spine instability may be observed in patients with established RA who have degeneration of the ligaments and bone in the C-spine area. Degeneration of the transverse ligament can lead to instability at the C1-C2 level. Minor trauma can lead to neurologic sequelae due to inherent instability.

Exercise caution in evaluating RA patients after minor falls, motor vehicle accidents, or other injuries. Cervical spine injury may occur spontaneously. Patients with long-standing disease may need careful evaluation perioperatively to detect any cervical spine instability before neck manipulation or intubation during surgery. Patients with RA of the cervical spine who have refractory pain, clearly evident neurologic compromise, or intrinsic spinal cord signal changes on magnetic resonance imaging (MRI) are generally candidates for surgical intervention.

GOALS OF THERAPY:

The goals of rheumatoid arthritis (RA) treatment are to:

• Stop inflammation (put disease in remission)
• Relieve symptoms
• Prevent joint and organ damage
• Improve physical function and overall well-being
• Reduce long-term complications.

GUIDELINES:

Treatment for Rheumatoid Arthritis is based on guidelines from the prestigious societies such as American College of Rheumatology (ACR) and National Institute for Health and Care Excellence (NICE).

To review the American College of Rheumatology (ACR) guidelines, click on the link below.

http://www.rheumatology.org/Portals/0/Files/ACR%202015%20RA%20Guideline.pdf

To review the National Institute for Health and Care Excellence (NICE) guidelines, click on the link below

https://www.nice.org.uk/guidance/cg79?unlid=42555739020164125229

LONG TERM MONITORING:

• In people with recent-onset active RA, measure CRP and key components of disease activity (using a composite score such as DAS28) monthly until treatment has controlled the disease to a level previously agreed with the person with RA.
• Offer people with satisfactorily controlled established RA review appointments at a frequency and location suitable to their needs. In addition, make sure they:
• have access to additional visits for disease flares,
• know when and how to get rapid access to specialist care, and
• have ongoing drug monitoring.
• Offer people with RA an annual review to:
• Assess disease activity and damage, and measure functional ability (using, for example, the Health Assessment Questionnaire [HAQ])
• Check for the development of comorbidities, such as hypertension, ischaemic heart disease, osteoporosis and depression
• Assess symptoms that suggest complications, such as vasculitis and disease of the cervical spine, lung or eyes
• Organise appropriate cross referral within the multidisciplinary team
• Assess the need for referral for surgery
• Assess the effect the disease is having on a person's life

CONSULTATION AND COUNSELING:

Patient education and counseling help to reduce pain, disability, and frequency of physician visits. These may represent the most cost-effective intervention for RA.

INFORMING PATIENTS OF DIAGNOSIS:

With a potentially disabling disease such as RA, the act of informing the patient of the diagnosis takes on major importance. The goal is to satisfy the patient’s informational needs regarding the diagnosis, prognosis, and treatment in appropriate detail. To understand the patient’s perspective, requests, and fears, the physician must employ careful questioning and empathic listening.

DISCUSSING PROGNOSIS AND TREATMENT:

Patients and families do best when they know what to expect and can view the illness realistically. Many patients fear crippling consequences and dependency. Accordingly, it is valuable to provide a clear description of the most common disease manifestations. Without encouraging false hopes, the physician can point out that spontaneous remissions can occur and that more than two thirds of patients live independently without major disability. In addition, emphasize that much can be done to minimize discomfort and to preserve function.

DEALING WITH MISCONCEPTIONS:

Several common misconceptions regarding RA deserve attention. Explaining that no known controllable precipitants exist helps to eliminate much unnecessary guilt and self-recrimination. Dealing in an informative, evidence-based fashion with a patient who expresses interest in alternative and complementary forms of therapy can help limit expenditures on ineffective treatments.

Another misconception is that a medication must be expensive to be helpful. Generic NSAIDs, low-dose prednisone,  and the first-line DMARDs are quite inexpensive yet remarkably effective for relieving symptoms, a point that bears emphasizing. The belief that one must be given the latest TNF inhibitor to be treated effectively can be addressed by a careful review of the overall treatment program and the proper role of such agents in the patient’s plan of care.

PRECAUTIONS:

Because RA damages joints, an RA patient could very well have weakened joints that can increase the risk of injury during strenuous exercises. Therefore, lower-impact exercises are best. These include activities like stretching to help maintain flexibility, walking and swimming. If arthritis is centered in the hips or knees, climbing activities like stair-step machines should be limited so that excess strain is not placed on the hip or knee joints.

REFERENCES:

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2. Areskoug-Josefsson K, Oberg U. A literature review of the sexual health of women with rheumatoid arthritis.Musculoskeletal Care. 2009 Dec. 7(4):219-26.
3. Farooqi A, Gibson T, Prevalence of the major rheumatic disorders in the adult population of North Pakistan. Br J Rheumatol 1998; 37: 491-5.
4. Varache S, Narbonne V, Jousse-Joulin S, et al. Is routine viral screening useful in patients with recent-onset polyarthritis of a duration of at least 6 weeks? Results from a nationwide longitudinal prospective cohort study.Arthritis Care Res (Hoboken). 2011 Nov. 63(11):1565-70.
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6. Macedo AM, Oakley SP, Panayi GS, Kirkham BW. Functional and work outcomes improve in patients with rheumatoid arthritis who receive targeted, comprehensive occupational therapy.Arthritis Rheum. 2009 Nov 15. 61(11):1522-30.
7. erstappen SM, Albada-Kuipers GA, Bijlsma JW, et al, for the Utrecht Rheumatoid Arthritis Cohort Study Group (SRU). A good response to early DMARD treatment of patients with rheumatoid arthritis in the first year predicts remission during follow up.Ann Rheum Dis. 2005. 64:38-43.
8. Aletaha D, Funovits J, Keystone EC, Smolen JS. Disease activity early in the course of treatment predicts response to therapy after one year in rheumatoid arthritis patients.Arthritis Rheum. 2007. 56:3226-35.
9. Verschueren P, Esselens G, Westhovens R. Predictors of remission, normalized physical function, and changes in the working situation during follow-up of patients with early rheumatoid arthritis: an observational study.Scand J Rheumatol. 2009. 38:166-72.
10. Luqmani R, Hennell S, Estrach C, et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of rheumatoid arthritis (after the first 2 years).Rheumatology (Oxford). 2009 Apr. 48(4):436-9.