Rheumatoid Arthritis – Diagnosis and Treatment

Rheumatoid arthritis is a chronic systemic inflammatory disease of unknown cause triggered by an autoimmune reaction leading to synovial membrane hypertrophy and chronic joint inflammation often with extra-articular manifestations.

The trigger for the reaction could be external and is thought to occur in genetically susceptible individuals.

Wrist and joints are most commonly involved and the disease is often symmetrical i.e. the same joints typically involved on both sides of the body. The disease may also affect other parts of the body.

While the cause of rheumatoid arthritis is not clear, it is believed to involve a combination of genetic and environmental factors. It is a kind of auto-immune disease which implies that body’s tissues are attacked by its own cells.

The term rheumatoid arthritis is based on the Greek for watery and inflamed joints.

Prevalence of rheumatoid arthritis is about 1%. The incidence increases with increasing age and peaks around middle age.

First-degree relatives of individuals with RA are at 2 to 3-fold higher risk for the disease.

Women are affected by RA approximately 3 times more often than men are, but sex differences diminish in older age groups.

RA primarily affects joints, but it also affects other organs in 15–25% of affected people.

Pathophysiology

The pathogenesis of rheumatoid arthritis is not completely understood. An external trigger like cigarette smoking, infection, or trauma triggers an autoimmune reaction, leading to synovial hypertrophy and chronic joint inflammation and other extraarticular manifestations.

Rheumatoid arthritis is a kind of uncontrolled inflammation and inflammatory mediators like CD4 T cells, mononuclear phagocytes, fibroblasts, osteoclasts, neutrophils, and B cells play a major role in the pathophysiology. Various cytokines, chemokines, and other inflammatory mediators including the following –

• Tumor necrosis factor alpha
• Interleukin-1
• IL-6
• IL-8
• Transforming growth factor beta
• Fibroblast growth factor
• Platelet-derived growth factor

Inflammation and proliferation of the synovium [pannus] lead to the destruction of joint cartilage,  bone, tendons, ligaments, and blood vessels and other tissues.

The various phases of progression of rheumatoid arthritis are

• Initiation phase – non-specific inflammation.
• Amplification phase – T cell activation

• Chronic inflammatory phase and tissue injury –  cytokines IL–1, TNF-alpha and IL–6.

Joint Deformities and Other Changes in Rheumatoid Arthritis

Hands

• Boutonniere deformity
  • Nonreducible flexion at the proximal interphalangeal joint along with hyperextension of the distal interphalangeal joint of the finger.
  • Synovitis leads to stretching or rupturing of the proximal interphalangeal joint through the central extensor tendon, with a concomitant volar displacement of the lateral bands.
  • Lateral bands when beyond the transverse axis of the joint, become flexors of the joint
  • Gradual shortening of tendons leads to hyperextension of the distal interphalangeal joint. A compensatory and reducible hyperextension may occur at the MCP joint.
• Swan-neck deformity of the finger
  • Hyperextension at the PIP joint with flexion of the DIP joint
  • Disruption of the extensor tendon occurs at the distal interphalangeal joint causing secondary shortening of the central extensor tendon and hyperextension of the proximal interphalangeal joint.
  • Another mechanism of this deformity is volar herniation of the proximal interphalangeal joint capsule and subsequent tightening of the lateral bands and central extensor tendon.
• Flexor tenosynovitis
• Trigger finger
  • Thickening or nodule formation of the tendon
• Tendon rupture [especially the flexor pollicis longus]
• Arthritis mutilans
  • Severe and extensive arthritis with the dissolution of bone leading to shortening of phalanges and gross instability of joints.
• Subluxation and ulnar deviation of metacarpophalangeal joints
  • Stretching and attenuation of the volar plate and collateral ligaments,
  • Dislocation of the flexor tendon volarward and ulnarward.
• Z-thumb or Z-deformity
• Hyperextension of the interphalangeal joint,
• Fixed flexion and subluxation of the metacarpophalangeal joint

Wrist

• Disruption of the radioulnar joint with dorsal subluxation of the ulna
• Rotation of the carpus on the distal radius
• Entrapment neuropathy
  • Median nerve
  • Ulnar nerve.

Elbow

• Flexion deformity
• Olecranon bursitis

Shoulders

• Rotator cuff degeneration
  • Due to synovitis
  • Superolateral migration of the humerus  with complete tears
• Acromioclavicular arthritis

Hips

• Flexion deformity

Knees

• Large effusions
• Quadriceps inhibition by spinal reflexes leading to atrophy
• Knee instability may develop after the progressive loss of cartilage and weakening of ligaments

Ankles and Feet

• Posterior tibialis tendon involvement or rupture
• Subtalar subluxation
• Loss of arches leading to flattening of the feet.
• Hallux valgus or bunion
• Hammer toes
  • Subluxation at the metatarsophlangeal joint
  • Compensatory flexion of toes

Cervical spine

• C1-C2 instability
• Neck pain and stiffness
• Radicular pain
• Transient ischemic attacks
  • Vertebral artery impingement
• Myelopathy secondary to rupture of the transverse ligament

Extra-articular

• Rheumatoid nodules
  • Seen in 25% of patients
  • Sites
    • Olecranon process
    • Proximal ulna
    • Back of the heel
    • Occiput
    • Ischial tuberosities
    • Fingers
    • Toes
    • Heel pads
    • Tendons
    • Viscera

Rheumatoid factor is almost invariably present in patients with rheumatoid nodules. If rheumatoid factor is absent, other diagnoses should be considered.

Organ systems

Cutaneous

• Subcutaneous nodules
• Vasculitic lesions of the skin
  • Palpable purpura
  • Skin ulceration
• Palmar erythema
• Pyoderma gangrenosum may be noted.

Cardiac

• Myocardial infarction
• Myocardial dysfunction
• Pericardial effusions
• Pericarditis, Myocarditis, coronary vasculitis
• Valvular disease, and conduction defects

Pulmonary

• Pleural effusions
• Interstitial fibrosis
• Bronchiolitis obliterans

Renal

• Amyloidosis

Vascular

• Vasculitis esp in skin

Hematologic

• Anemia of chronic disease

Neurologic

• Nerve entrapment
• Mononeuritis multiplex
• Cervical myelopathy
• Peripheral myopathy

Ocular

• Keratoconjunctivitis sicca
• Episcleritis
• Uveitis
• Nodular scleritis that may lead to scleromalacia

Etiology of Rheumatoid Arthritis

The cause of rheumatoid arthritis not known is unknown. Following factors are thought to be involved.

Genetics

Genetic factors account for 50% of the risk for developing rheumatoid arthritis.

Following genetic associations are known

• Human leukocyte antigen (HLA)-DR4
• PTPN22 and TRAF5 genes

Infections

Numerous infectious agents have been suggested as potential causes

• Mycoplasma organisms
• Epstein-Barr virus
• Rubella virus
• Porphyromonas gingivalis

Hormones

• Sex hormones may play a role suggested by
  • Female preponderance
  • Amelioration of the disease during pregnancy
  • Postpartum recurrence
  • Reduced incidence in women using oral contraceptives
  • Hyperprolactinemia may be a risk factor

Immunologic Factors

• Synovial macrophages and fibroblasts may become autonomous
• B cells produce numerous autoantibodies

Environmental Factors

Tobacco use is the main environmental risk

Clinical Presentation of Rheumatoid Arthritis

Patient classically presents with persistent symmetric polyarthritis that includes hands and feet though any synovial joint may be involved.

Constitutional symptoms like fatigue, fever, malaise, morning stiffness, loss of appetite and loss of weight may be present.

The symptoms of rheumatoid arthritis wax and wane over time. Over the time progressive destruction of joints occur, eventually leading to deformities and decreased function.

Extra-articular involvement of organs such as the skin, heart, lungs, and eyes can also be significant.

Patients with RA may report difficulty performing activities of daily living like dressing, standing, walking, personal hygiene, or use of hands.

Most of the patients have insidious onset which may begin with systemic symptoms and signs.

The joints are examined for swelling, warmth, deformity, tenderness, limitation of motion. Patients are also examined for extra-articular manifestations and rheumatoid nodules

Joints involved in  decreasing frequency are

• Metacarpophalangeal
• Wrist
• Proximal interphalangeal joint
• Knee
• Metatarsophalangeal joint
• Shoulder joint
• Ankle
• Cervical spine
• Hip
• Elbow
• Temporomandibular joints

Direct palpation can elicit joint tenderness.

Thickening of the synovium is most evident in the small joints of the hands and feet and is felt as a doughy texture on palpation.

Baker cyst may be seen in the knee.

Stages of Rheumatoid Arthritis

Stage I or Early Rheumatoid Arthritis

• No destructive changes on x-ray
• Osteoporosis may be seen

Stage II or Moderate Progression

• Periarticular osteoporosis with or without subchondral bone destruction
• Mild cartilage destruction
• Limited joint mobility
• No joint deformities
• Adjacent muscle atrophy
• Extra-articular lesions

Stage III or Severe Progression

• Radiographic evidence of cartilage and bone destruction
• Periarticular osteoporosis
• Joint deformities without fibrous or bony ankylosis
• Extensive muscle atrophy is extensive
• Extra-articular soft tissue lesions

Stage IV or Terminal Progression

• Stage III + Criteria of stage III

Functional status

Patients with RA are categorized into 4 functional classes:

• Class I – Completely able to perform usual activities of daily living
• Class II – Able to perform usual self-care and vocational activities but limited in avocational activities
• Class III – Able to perform usual self-care activities but limited in vocational and avocational activities
• Class IV – Limited inability to perform usual self-care, vocational, and avocational activities

Differential Diagnoses

• Fibromyalgia
• Lyme Disease
• Myelodysplastic Syndrome
• Osteoarthritis
• Paraneoplastic Syndromes
• Relapsing Polychondritis
• Polymyalgia Rheumatica
• Psoriatic Arthritis
• Sarcoidosis
• Sjogren Syndrome
• Systemic Lupus Erythematosus

Lab Studies

There is no specific test for rheumatoid arthritis which is pathognomic. The diagnosis is established using a combination of clinical, laboratory, and imaging features.

Following tests are helpful in rheumatoid arthritis

Markers of inflammation

• ESR
• CRP [Over a period correlates with radiographic progression]

Hematologic parameters

• CBC
  • Shows chronic anemia
  • Thrombocytosis
  • Leukocytosis
  • Leukopenia [Consequence of therapy or a component of Felty syndrome]

Immunologic parameters

• RF
  • Detects IgM antibody against the Fc fragment of IgG
  • Fluctuate somewhat with disease activity, though titers remain.
  • Also present in connective tissue disorders and 1-5% healthy people
  • Predictive of radiographic progression
• Anti-CCP antibodies
  • Assays for Anti-cyclic citrullinated peptide
  • More specific
  • Detectable early in the disease course

• Anti-nuclear antibodies

Imaging

X-rays

Joints and spine should be assessed with standard views. Varying degree of joint destruction and deformities may be noted.

Magnetic Resonance Imaging

MRI provides a better assessment and is able to detect lesions earlier than x-rays. But the practical use is limited to cervical spine because of the smaller joints and high cost.

Joint Aspiration

• To confirm or rule out differentials
• Specially indicated in single joint involvement
• Synovial fluid analysis
  • Gram staining
  • Cell count
  • Culture
• In rheumatoid arthritis, the picture is that of inflammation
• Leucocyte count >2000/µL
• Neutrophilia
• Lower glucose levels than serum

Treatment of Rheumatoid Arthritis

The main treatment goals are to control disease activity and slow the rate of joint damage, in addition to improving the symptoms.

Successful treatment of rheumatoid arthritis includes drugs, exercise, massage, physical therapy, and surgery. Counseling and stress reduction also form part of the treatment wherever required.

Drugs

Various medications used in the treatment of rheumatoid arthritis are

• Nonbiologic and biologic disease-modifying antirheumatic drugs
• NSAIDs
• Immunosuppressants
• Corticosteroids

An early treatment with DMARDs is the standard of care as it stops the disease and can induce remissions.

American College of Rheumatology recommends vaccination for pneumococcal, hepatitis and influenza before patient are put on nonbiologic or biologic disease-modifying antirheumatic [DMARDS].

Vaccination against human papilloma and herpes zoster virus are also recommended in recent guidelines.

Disease-modifying Antirheumatic Drugs

DMARDs can retard or prevent disease progression and, thus, joint destruction and subsequent loss of function.  These agents can eliminate the need for other anti-inflammatory or analgesic medications.

After DMARDs are started anti-inflammatory or analgesic medications may be required initially as bridging therapy to reduce pain and swelling.

Early treatment of rheumatoid arthritis has the potential to retard progression and may also induce remissions.

Nonbiologic DMARDs

• Hydroxychloroquine
• Sulfasalazine
• Methotrexate
• Leflunomide
• Gold salts
• D-penicillamine
  

Methotrexate and sulphasalazine are the most active compounds and provide the best risk-benefit ratios. Methotrexate either alone or in combination with other agents, has become the standard of care for moderate to severe RA.

Gold salts and penicillamine are rarely used now due to the availability of better drug have largely been supplanted by more effective agents.

Biologic DMARDs

Tumor Necrosis Factor Inhibitors

These drugs bind TNF [tumor necrosis factor] and prevent its interaction with its receptors. The drugs include etanercept, infliximab, adalimumab, certolizumab, and golimumab.

The indications for their use arises when at least one nonbiologic DMARD, usually MTX, has been administered without sufficient success.

These drugs are contraindicated in infections, demyelinating disorders, class III or IV heart failure, and the presence or recent history of malignancy.

Patients should be tested for latent tuberculosis before treatment is commenced as the infection could become active when on treatment.

Patients taking anti-TNF agents must avoid live-virus vaccines. Giving live vaccines to patients receiving immunosuppressive drugs leads to a higher risk for serious infection.

A patient with hepatitis B surface infection/history should receive antiviral prophylaxis.

Adverse Effects are

• Generation of antibodies against these compounds
• Emergence of antinuclear
• Drug-induced lupus like syndromes
• Infections
• Demyelination disorders
• Bone marrow suppression occurs

Non-TNF agents

These agents are indicated in  moderately to severely active rheumatoid arthritis when a response to TNF inhibitors is inadequate

Rituximab

• Most often used in combination with methotrexate.
• Decrease in CD20+ B cells seen as adverse effect

Abatacept

• Inhibits T-cell activation
  • Binds to CD80 and CD86
  • Blocks their interaction with CD28 [required for T-cell activation]
• Monthly intravenous infusion or weekly subcutaneous injection
• Indicated in treatment failure with anti-TNF therapy

Tocilizumab

• IL-6 receptor inhibitor
• IV infusion or subcutaneous injection.
• Used alone or in combination with methotrexate or other DMARDs.

Tofacitinib

• Oral Janus Kinase Inhibitor [A group of intracellular tyrosine kinases that modulate signals to maintain the inflammatory condition in rheumatoid arthritis]
• Monotherapy or in combination with methotrexate
• Should not be used along with biologic DMARDs or potent immunosuppressive agents like azathioprine or cyclosporine.

Anakinra

• Recombinant glycosylated IL-1 receptor antagonist
• Has shown improvement in patients in clinical trials.

Patients may require 2-3 months to achieve a full response to DMARDs

Combination therapy of DMARDs

Most successful combinations are

• Methotrexate + sulphasalazine+Hydroxychloroquine
• Methotrexate plus leflunomide
• Methotrexate plus biologic DMARDs.

Corticosteroids

Corticosteroids are potent anti-inflammatory drugs that are commonly used in patients with RA to bridge the time until treatment with DMARDs is effective.

Immunosuppresants

As rheumatoid arthritis is an auto-immune disease, suppressing the immune system helps reduce the damage to good tissue. Cyclosporine, Azathioprine and cyclophosphamide are commonly used agents.

Nonsteroidal anti-inflammatory drugs

NSAIDs interfere with prostaglandin synthesis through inhibition of the enzyme cyclooxygenase (COX), thus reducing swelling and pain.

These drugs, however,  do not retard joint destruction and thus are not sufficient to treat rheumatoid arthritis when used alone

Rehabilitation

• Goals of rehabilitation for RA patients include relief of pain, improving range of motion, enhancement of strength and endurance and prevention or correction of deformities

Following measures are included in the rehabilitation

• Heat and cold therapies
• Orthotics and splints
• Therapeutic exercise
• Aerobic conditioning
• Isometric exercises restore
• Resistance exercises
• Occupational therapy

Surgery

Surgical intervention in patients with RA can achieve pain relief, deformity correction, and functional improvement. Following surgical procedures are available to obtain these goals –

• Synovectomy
• Tenosynovectomy
• Tendon realignment
• Reconstructive surgery or arthroplasty
• Arthrodesis

Prognosis of Rheumatoid Arthritis

The course of rheumatoid arthritis is generally one of exacerbations and remissions.

Early treatment is associated with better outcomes.

Some patients experience a relatively self-limited disease, whereas others have a chronic progressive illness.

Complications associated with rheumatoid arthritis are

• Anemia
• Infections
• Gastrointestinal problems
• Osteoporosis
• Lung disease
• Heart disease
• Sjogren syndrome – Keratoconjunctivitis sicca
• Felty syndrome
  • Splenomegaly
  • Leukopenia
• Recurrent bacterial infections
• Lymphoma and other malignancies

Following  correlate with an unfavorable prognosis

• HLA-DRB1*04/04 genotype
• High serum titer of autoantibodies (RF, anti-CCP)
• Extra-articular manifestations
• Large number of involved joints
• Age < 30 years
• Female sex
• Systemic disease

References

• Carlens C, Hergens MP, Grunewald J, et al. Smoking, use of moist snuff, and risk of chronic inflammatory diseases. Am J Respir Crit Care Med. 2010 Jun 1. 181(11):1217-22.
• Barton A, Worthington J. Genetic susceptibility to rheumatoid arthritis: an emerging picture. Arthritis Rheum. 2009 Oct 15. 61(10):1441-6.
• Guthrie KA, Dugowson CE, Voigt LF, Koepsell TD, Nelson JL. Does pregnancy provide vaccine-like protection against rheumatoid arthritis?. Arthritis Rheum. 2010 Jul. 62(7):1842-8.
• Thompson A. Practical aspects of therapeutic intervention in rheumatoid arthritis. J Rheumatol Suppl. 2009 Jun. 82:39-41.
• Aletaha D, Alasti F, Smolen JS. Rheumatoid factor determines structural progression of rheumatoid arthritis dependent and independent of disease activity. Ann Rheum Dis. Jul 13 2012.
• Daha NA, Toes RE. Rheumatoid arthritis: Are ACPA-positive and ACPA-negative RA the same disease?. Nat Rev Rheumatol. 2011 Apr. 7(4):202-3.
• Tan YK, Conaghan PG. Imaging in rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2011 Aug. 25(4):569-84.
• Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. New therapies for treatment of rheumatoid arthritis. Lancet. 2007 Dec 1. 370(9602):1861-74.

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