General Overview of Rheumatoid Arthritis for Rehabilitation Professionals

Original Editor - Shala Cunningham Top Contributors - Jess Bell

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Introduction

Rheumatoid arthritis (RA) is a “chronic inflammatory autoimmune systemic disease that usually presents with joint inflammation leading to pain, fatigue, and impaired physical functioning and work productivity, all of which negatively impact health-related quality of life.”

RA commonly affects the hands, wrists, shoulders, elbows, knees, ankles and feet. As it is a systemic condition, it also affects multiple body systems, including the cardiovascular and respiratory systems. Without adequate treatment, RA can cause long-term disability, pain and premature death. While pharmacological management is the mainstay treatment for RA, rehabilitation professionals can play a role in the non-pharmacological management of this condition.

Epidemiology

RA affects around 1% of the global population, and up to 3% of older persons. It is 2-3 times more likely to occur in females. However, with improving medical management, the severity, mortality and associated comorbidities appear to be decreasing.

The peak age of onset of RA tends to be in younger populations (approx 30-60 years), although the exact age ranges given in the literature vary:

• younger-onset RA is distinguished from elderly-onset RA (i.e. after 60 years) in the literature
• Slobodin notes that the peak age of onset of RA has increased - in the 1930s, it was typically in the fourth decade of life, whereas by the 2010s, it was the sixth or seventh decade

Risk Factors

RA is a multifactorial disease that has been linked to various genetic, environmental and other factors, including:

• genetic factors: the HLA-DRB1 alleles are linked with an increased risk of developing RA
• certain environmental factors in genetically predisposed individuals, such as:
  • smoking
  • infections (e.g. periodontal disease, Epstein-Barr virus, baterial superantigens etc.)
  • dietary agents
• hormonal factors:
  • effects of oestrogen on immune function are believed to play a role in female pre-dominance in RA
  • other sex-related factors are probably involved as well

Clinical Characteristics

RA is usually symmetrical, with the wrists, fingers (MCP), knees, ankles, feet and upper cervical spine are commonly affected.

Joint symptoms may include:

• symmetrical joint pain
• morning stiffness that lasts for more than one hour or stiffness after inactivity
• joints may feel warm and tender after more than one hour of inactivity
• loss of / limitations in range of motion
• deformity

Typical Joint Deformities

Cervical spine: prevalence of atlantoaxial instability (AAI) in individuals with RA is 40–85%

• hypermobility between C1 and C2
• transverse ligament laxity
• subluxation risk
• possible neurologic involvement

Hand:

• swan neck deformity
• boutonniere deformity
• ulnar drift
• thumb metacarpophalangeal flexion with interphalangeal hyperextension

Knee:

• genu valgus
• Baker cyst

Ankle / foot:

• pronation
• hallux valgus
• claw toes

Other symptoms and extra-articular manifestations:

• pulmonary issues (e.g. pleuritis, pleural effusions, pulmonary fibrosis, interstitial lung disease and arteritis - can be common but often asymptomatic)
• cardiac issues (e.g. atherosclerosis, arterial stiffness, coronary arteritis, congestive heart failure, valvular disease and fibrinous pericarditis)
• Felty’s syndrome (i.e. low white blood cell count, spleen enlargement and rheumatoid arthritis)
• dry eyes and mouth (Sjögren's syndrome)
• numbness, tingling, or burning sensation in the hands and feet
• sleep difficulties
• rheumatic nodules
  • these occur more in individuals with seropositive RA with erosive disease (see Pathophysiology section for information on seropositive / seronegative RA)
• fatigue
• reduced cognitive function
• sarcopenia
• osteoporosis
• vasculitis (can result in “skin manifestations, gastrointestinal complications, cardiac disease, and pulmonary manifestations”)

Pathophysiology

There are two main subtypes of RA:

• seropositive RA:
  • autoantibodies, such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) are present
  • autoantibodies are present in 50% of individuals with early RA and up to 80% of individuals with established RA
  • ACPAs are present in around 67% of individuals with RA
  • “associated with more severe disease and worse clinical outcomes”

• seronegative RA
  • more transient
  • many individuals with RF-negative or ACPA-negative RA do not develop “a chronic progressive disease”
  • other types of autoantibodies may be present

Basic Overview of Rheumatoid Arthritis Pathophysiology

The pathophysiology of RA is complex and multifactorial. The following points describe the pathophysiology of seropositive RA. Please note that patients can have different pathogenic pathways and cell lineages:

• a genetically predisposed individual is exposed to an environmental trigger (e.g. smoking or infection) - this can cause disordered immunity
• disordered immunity may lead to the citrullination of some proteins - citrullination is when the amino acid arginine converts to citrulline
• antigen-presenting cells recognise these modified proteins as foreign and transport them to lymph nodes and mucosal and lymphoid tissues, where they activate CD4+ T-helper cells
• this stimulates B-cells to proliferate and then differentiate into plasma cells
• these plasma cells produce autoantibodies (i.e. ACPAs and rheumatoid factor)
  • ACPAs can be detected before joint symptoms develop in individuals with RA
  • ACPA production indicates a “break of immunological tolerance”

• autoantibodies can then migrate to the joint synovium

• symmetrical swelling in the small joints is the “external reflection of synovial membrane inflammation following immune activation”

• once in the synovium, autoantibodies start producing proinflammatory cytokines (e.g. interferon-gamma and interleukins)
• this causes macrophages, monocytes and synovial fibroblasts to release cytokines, such as tumor necrosis factor alpha (TNF alpha) Interleukin 6 (IL-6) and IL-1
• synovial fibroblasts then start to proliferate, which increases joint inflammation (i.e. synovial hyperplasia)
• proliferating synovial cells produce a pannus, which is a thickened, synovial membrane made of destructive granulation tissue
• this pannus causes the erosion of cartilage and bone
• activated synovial cells also produce proteases which break down cartilage OSMOSIS
• inflammatory cytokines cause increased activity of osteoclasts (cells that break down bone) - there is also decreased activity of osteoblasts (cells that repair / form new bone)
• this leads to articular bone loss and osteoporosis
• ACPAs and RF form immune complexes that activate the complement system ( an important part of the innate immune system), which leads to chronic inflammation
• angiogenesis (i.e. the formation of new capillaries from existing vasculature), occurs alongside chronic inflammation - this enables more inflammatory cells to travel to the joints
• this produces additional pro-inflammatory factors, which exacerbate existing processes
• as RA progresses, multiple joints on both sides of the body are affected
• inflammatory cytokines also spread to other parts of the body, causing extra-articular symptoms, such as
  • vasculitis
  • rheumatoid nodules
  • protein breakdown in skeletal muscle
• please note that RA can wax/wane, with flares

This complex process is explained in detail in Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies and in the following videos: