**2.1 Nosology in evolution**

Although the appearance of rheumatoid arthritis was noted in radiological examination of skeletal remains of Tennessee Indians from as early as 4500 BC, we do not find documented evidence until much later. It is said that realisation of how "taxing" arthritis can be, made Roman Emperor Diocletian free his citizens with the disorder from paying taxes. The term '*rheumatism*' dates back to 1630, and is derived from the Greek '*rheumatos'* that means 'flowing'. It signified an evil humour or mucus that was thought to flow from the brain to the joints, causing inflammation, pain and deformities. Short (Short, 1974)

Rheumatoid Arthritis: A Historical and Biopsychosocial Perspective 191

These observations suggest that rheumatoid arthritis is not a modern disease and was present several centuries before its description as a separate entity by Augustine-Jacob Landré Beauvais' in 1800 (Dequeker J. 1977; Appelboom T. et al, 1981; Dequeker J, Rico H. 1992). A generation later, in 1859, Sir Alfred Garrod, a physician from Ipswich who later was appointed Professor of Materia Medica and Therapeutics and of Medicine, coined the name 'rheumatoid arthritis'. In his renowned treatise with illustrations (Garrod, 1859), he considered the main differential diagnosis, including rheumatic gout of Fuller, chronic rheumatism of Heberden, scorbutic rheumatism and rheumalgia, and rejected them all in favour of 'rheumatoid arthritis' the name he chose for the disease. He divided it into two types: generalised and localised and identified three forms: acute, chronic and irregular. The

Rheumatoid arthritis belongs to a diverse group of musculoskeletal disorders ("arthritis"): there are more than 200 types of these diseases that also encompass osteoarthritis, Still's disease, ankylosing spondylitis, and Reiter's syndrome. Some sources also name Felty's syndrome and Sjogren's syndrome as related disorders (Wilson et al, 1991). Some of these are very serious diseases that can be difficult to diagnose and treat. For instance, hemochromatosis (build up of iron in the body) was misdiagnosed as rheumatoid arthritis

Skeletal evidence of primary ankle (kaki) **osteoarthritis** has been discovered in dinosaurs! In 1715 William Musgrave published the second edition of his most important medical work '*De arthritide symptomatica*' which concerned arthritis and its effects (Cameron, 2004). A common feature in all osteoarthritis is a loss of cartilage in association with bone features such as osteophytes and subchondral bone sclerosis. Large epidemiologic studies of osteoarthritis performed over a period of 30 years (Peyron, 1986) have confirmed that osteoarthritis is a ubiquitous condition, that it is linked to age, that it is more frequent and more widespread in women older than 45 years of age, and that the mechanical overuse of the joints is probably instrumental in the occurrence and the location of certain cases of osteoarthritis. Epidemiologic evidence points to the existence of an entity of "generalised osteoarthritis" composed of three or more locations with involvement of the interphalangeals. Heredity, in cases associated with distal interphalangeal osteoarthritis, and inflammation, in cases with proximal interphalangeal osteoarthritis, are the factors found to be most closely correlated to generalised osteoarthritis. Surveys of several series of osteoarthritis of the hip have pointed to the existence of several clinicoradiologic subsets that could have different clinical correlates and various pathophysiological mechanisms. Interestingly, according to a Boston University study (Hunter *et al*, 2004), ever since their invention five thousand years ago, chopsticks have been a source of osteoarthritis. This epidemiologic study investigated the relationship of chopsticks use to hand arthropathy. The results suggest that chopsticks use is associated with an increased prevalence of osteoarthritis in the interphalangeal joint of the thumb, and in the second and third

In 1897 Sir George Frederick Still published a paper entitled 'On a form of chronic joint disease in children', that was the subject of his MD thesis, where he described several types of juvenile rheumatoid arthritis (FIG.2) and introduced an previously unrecognizable disease, known, as it is today, as **Still's disease** or systemic-onset juvenile rheumatoid

name has remained ever since.

**2.2 Diagnostically diverse group of disorders** 

in the past (Espinosa-Morales et al, 1998).

interphalangeal and metacarpophalangeal joints.

traced the first adequate description of what was probably rheumatoid arthritis to Thomas Sydenham (1624-1689) and emphasised that medical literature before Sydenham's time may have confused gout and other forms of polyarthritis as manifestations of the same disease.

Analysis of the hands in the Flemish paintings and works attributed to Peter Paul Rubens seems to show hand lesions resembling those of rheumatoid arthritis. To illustrate this, on the reproduction here, swelling of three metacarpophalangeal joints are clearly visible on the right hand of Erasmus of Rotterdam painted by the Flemish Quinten Metsys in 1529, (FIG.1). Disiderius Erasmus (1467-1536), the Dutch renaissance scholar is often quoted for his famous aphorism "prevention is better than cure" and is recognised as the Prince of Humanists for his progressive writings of the time. This painting is testimony to the high cultural climate of the time, and evidence of the links between two great humanist thinkers, Erasmus of Rotterdam and Sir Thomas More, both of whom contributed to the publication of Utopia.

Fig. 1. **Quinten Metsys, Portrait of Erasmus of Rotterdam, 1517.** *Oil on panel, 59 x 46.5 cm.*  Reproduced with permission from National Gallery of Antique Art, Rome.

While none of the deformities or swellings is indisputable examples of rheumatoid arthritis, they do at least suggest that the painters must have been confronted with rheumatoid-like lesions in their models. It is established that Rubens was well qualified to accurately depict arthritic deformities, as he had a personal familiarity with arthritis. Although history is uncertain as to who suffered from the disease, Rubens or his long-term co-author, it is easy to imagine artists' working surroundings at the time: ancient damp art studios, oils, powders and drying canvases everywhere – a portrayal of an "ideal" environment for triggering a rheumatic flare-up and causing inflammation.

traced the first adequate description of what was probably rheumatoid arthritis to Thomas Sydenham (1624-1689) and emphasised that medical literature before Sydenham's time may have confused gout and other forms of polyarthritis as manifestations of the

Analysis of the hands in the Flemish paintings and works attributed to Peter Paul Rubens seems to show hand lesions resembling those of rheumatoid arthritis. To illustrate this, on the reproduction here, swelling of three metacarpophalangeal joints are clearly visible on the right hand of Erasmus of Rotterdam painted by the Flemish Quinten Metsys in 1529, (FIG.1). Disiderius Erasmus (1467-1536), the Dutch renaissance scholar is often quoted for his famous aphorism "prevention is better than cure" and is recognised as the Prince of Humanists for his progressive writings of the time. This painting is testimony to the high cultural climate of the time, and evidence of the links between two great humanist thinkers, Erasmus of Rotterdam and Sir Thomas More, both of whom contributed to the publication

Fig. 1. **Quinten Metsys, Portrait of Erasmus of Rotterdam, 1517.** *Oil on panel, 59 x 46.5 cm.* 

While none of the deformities or swellings is indisputable examples of rheumatoid arthritis, they do at least suggest that the painters must have been confronted with rheumatoid-like lesions in their models. It is established that Rubens was well qualified to accurately depict arthritic deformities, as he had a personal familiarity with arthritis. Although history is uncertain as to who suffered from the disease, Rubens or his long-term co-author, it is easy to imagine artists' working surroundings at the time: ancient damp art studios, oils, powders and drying canvases everywhere – a portrayal of an "ideal" environment for

Reproduced with permission from National Gallery of Antique Art, Rome.

triggering a rheumatic flare-up and causing inflammation.

same disease.

of Utopia.

These observations suggest that rheumatoid arthritis is not a modern disease and was present several centuries before its description as a separate entity by Augustine-Jacob Landré Beauvais' in 1800 (Dequeker J. 1977; Appelboom T. et al, 1981; Dequeker J, Rico H. 1992). A generation later, in 1859, Sir Alfred Garrod, a physician from Ipswich who later was appointed Professor of Materia Medica and Therapeutics and of Medicine, coined the name 'rheumatoid arthritis'. In his renowned treatise with illustrations (Garrod, 1859), he considered the main differential diagnosis, including rheumatic gout of Fuller, chronic rheumatism of Heberden, scorbutic rheumatism and rheumalgia, and rejected them all in favour of 'rheumatoid arthritis' the name he chose for the disease. He divided it into two types: generalised and localised and identified three forms: acute, chronic and irregular. The name has remained ever since.

#### **2.2 Diagnostically diverse group of disorders**

Rheumatoid arthritis belongs to a diverse group of musculoskeletal disorders ("arthritis"): there are more than 200 types of these diseases that also encompass osteoarthritis, Still's disease, ankylosing spondylitis, and Reiter's syndrome. Some sources also name Felty's syndrome and Sjogren's syndrome as related disorders (Wilson et al, 1991). Some of these are very serious diseases that can be difficult to diagnose and treat. For instance, hemochromatosis (build up of iron in the body) was misdiagnosed as rheumatoid arthritis in the past (Espinosa-Morales et al, 1998).

Skeletal evidence of primary ankle (kaki) **osteoarthritis** has been discovered in dinosaurs! In 1715 William Musgrave published the second edition of his most important medical work '*De arthritide symptomatica*' which concerned arthritis and its effects (Cameron, 2004). A common feature in all osteoarthritis is a loss of cartilage in association with bone features such as osteophytes and subchondral bone sclerosis. Large epidemiologic studies of osteoarthritis performed over a period of 30 years (Peyron, 1986) have confirmed that osteoarthritis is a ubiquitous condition, that it is linked to age, that it is more frequent and more widespread in women older than 45 years of age, and that the mechanical overuse of the joints is probably instrumental in the occurrence and the location of certain cases of osteoarthritis. Epidemiologic evidence points to the existence of an entity of "generalised osteoarthritis" composed of three or more locations with involvement of the interphalangeals. Heredity, in cases associated with distal interphalangeal osteoarthritis, and inflammation, in cases with proximal interphalangeal osteoarthritis, are the factors found to be most closely correlated to generalised osteoarthritis. Surveys of several series of osteoarthritis of the hip have pointed to the existence of several clinicoradiologic subsets that could have different clinical correlates and various pathophysiological mechanisms. Interestingly, according to a Boston University study (Hunter *et al*, 2004), ever since their invention five thousand years ago, chopsticks have been a source of osteoarthritis. This epidemiologic study investigated the relationship of chopsticks use to hand arthropathy. The results suggest that chopsticks use is associated with an increased prevalence of osteoarthritis in the interphalangeal joint of the thumb, and in the second and third interphalangeal and metacarpophalangeal joints.

In 1897 Sir George Frederick Still published a paper entitled 'On a form of chronic joint disease in children', that was the subject of his MD thesis, where he described several types of juvenile rheumatoid arthritis (FIG.2) and introduced an previously unrecognizable disease, known, as it is today, as **Still's disease** or systemic-onset juvenile rheumatoid

Rheumatoid Arthritis: A Historical and Biopsychosocial Perspective 193

(Dieppe, 1988), and the anatomist and surgeon Realdo Colombo characterised the condition in 1559 (Benoist, 1995). However, it was not until 1892, when Russian neurologist Vladimir Michailovich Bekhterev published a series of papers, that the syndrome was fully described (Bechterev, 1892). Later, Adolf Strümpel of Germany (1897) and Pierre Marie of France (1898) also gave adequate descriptions which permitted an accurate diagnosis of ankylosing spondylitis prior to severe spinal deformity. For this reason, ankylosing spondylitis is also known as Bekhterev's Disease or Marie–Strümpel Disease. Bekhterev advocated physiotherapy and the benefits of hypnosis for the patients with rheumatic spondylitis, the latter treatment method he studied under the direction of Professor Jean-Martin Charcot in

**Reiter's syndrome** was named after Hans Reiter (Reiter, 1916), who reported a case of a soldier with the triad of urethritis, arthritis and conjunctivitis, following an episode of bloody diarrhea. However, the history of this constellation of signs actually predates his description. Urethritis, arthritis and conjunctivitis have subsequently remained as the essential components of this syndrome, but some feel that the eye involvement is so often minimal or insignificant that it need not necessarily be present to make the diagnosis (Gaston & Lillicrap, 2003). Although Reiter's syndrome and psoriatic arthritis are ordinarily two rather discrete entities, there is a significant zone of diagnostic overlap in patients with cutaneous lesions. Both diseases may coexist in the same patient, or Reiter's syndrome seemingly may evolve into psoriatic arthritis. Reiter's syndrome in recent medical literature is simply referred to as reactive arthritis which may or may not be accompanied by extraintestinal manifestations. Salmonella has been the most frequently studied bacteria associated with reactive arthritis. Overall, studies have found rates of Salmonella-associated reactive arthritis to vary between 6 and 30% (Hill Gaston, & Lillicrap, 2003). The term Reiter's syndrome has fallen into disfavour, owning to its author's reputation as a high-

specificity **Major Criteria** 

Typical rash

Sore throat

**Minor Criteria**

 Lymphadenopathy Increased LFT's RF and ANA negative

Rheumatol 19:424, 1992.

**Presence of 5 or more criteria**, of which at least 2 are Major - yields 96% sensitivity; 92%

 Fever > 39 degrees > 1 week Arthralgia/arthritis > 2 weeks

WBC > 10 K with 80% PMN's

According to: Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still's disease. J

**Diagnostic Criteria I Diagnostic Criteria II** 

**Requires ALL of the following:**  Fever > 39 degrees Arthralgia or arthritis Rheumatoid factor < 1:80

**In addition to ANY TWO of the** 

Hepatomegaly, Splenomegaly, or

According to: Cush JJ, Medsger TA, Jr, Christy WC, et al. Adult-onset Still's disease: Clinical course and outcome.

WBC count > 15,000

Pleuritis or Pericarditis

Lymphadenopathy

Arthritis Rheum 30:186, 1987.

Table 1.1 Diagnostic Criteria

Salpetriere (Kannabikh, 1925).

ANA < 1:100

**following:** 

Stills rash

Fig. 2. Rheumatoid arthritis in an 8 yr old boy. From a slide collection of images from Still's *'On a form of chronic joint disease in children'* reproduced with permission from Professor Patricia Woo.

arthritis. He defined the condition as a 'chronic progressive enlargement of joints, associated with general enlargement of glands and enlargement of spleen' with the onset 'almost always before the second dentition' (Still, 1897). Still concluded that this condition differed from rheumatoid arthritis in adults in the enlargement of glands and spleen and in the absence of bony change.

Since then adult onset Still's disease (AOSD) has been described as an acute febrile illness in young adults. It usually affects multiple organs, but is a diagnosis of exclusion. The aetiology of AOSD is unknown; however, a number of infectious triggers have been suggested, including viruses and bacterial pathogens including Mycoplasma pneumoniae. Clinical features include a high fever, arthralgia and arthritis, phayngitis, typical rash (evanescent salmon-coloured, macular or maculopapular eruption), lymphadenopathy, and serositis. Chronic arthritis and constitutional symptoms are common. The triad of fever, rash, and arthralgia are often absent during the first month of the illness. A quotidian (daily, spiking) or "double-quotidian" fever curve is a hallmark of the disease. The usual joints affected are wrists, knees, and ankles in descending order. Several diagnostic criteria sets for AOSD have been proposed. Two of these sets of criteria are shown in the TABLE 1.1. 1987 and 1992 Criteria for the Classification of Adult Onset of Still's Disease.

It is interesting that a recent case series identified patients with **ankylosing spondylitis** who also meet the criteria of adult onset Still's disease (Akkoc et al, 2008). The ankylosing spondylitis existed since ancient times, as verified by the skeletal remains of a 5000-year–old Egyptian mummy with evidence of 'bamboo spine' (Calin, 1985). It is a chronic, painful, degenerative, inflammatory arthritis primarily affecting the spine and sacroiliac joints; the ossification of joints and entheses primarily of the axial skeleton are known as 'bamboo spine'. It was recognised as distinct from arthritis by Galen as early as the second century


Table 1.1 Diagnostic Criteria

192 Rheumatoid Arthritis – Etiology, Consequences and Co-Morbidities

Fig. 2. Rheumatoid arthritis in an 8 yr old boy. From a slide collection of images from Still's *'On a form of chronic joint disease in children'* reproduced with permission from Professor

arthritis. He defined the condition as a 'chronic progressive enlargement of joints, associated with general enlargement of glands and enlargement of spleen' with the onset 'almost always before the second dentition' (Still, 1897). Still concluded that this condition differed from rheumatoid arthritis in adults in the enlargement of glands and spleen and in the

Since then adult onset Still's disease (AOSD) has been described as an acute febrile illness in young adults. It usually affects multiple organs, but is a diagnosis of exclusion. The aetiology of AOSD is unknown; however, a number of infectious triggers have been suggested, including viruses and bacterial pathogens including Mycoplasma pneumoniae. Clinical features include a high fever, arthralgia and arthritis, phayngitis, typical rash (evanescent salmon-coloured, macular or maculopapular eruption), lymphadenopathy, and serositis. Chronic arthritis and constitutional symptoms are common. The triad of fever, rash, and arthralgia are often absent during the first month of the illness. A quotidian (daily, spiking) or "double-quotidian" fever curve is a hallmark of the disease. The usual joints affected are wrists, knees, and ankles in descending order. Several diagnostic criteria sets for AOSD have been proposed. Two of these sets of criteria are shown in the TABLE 1.1. 1987

It is interesting that a recent case series identified patients with **ankylosing spondylitis** who also meet the criteria of adult onset Still's disease (Akkoc et al, 2008). The ankylosing spondylitis existed since ancient times, as verified by the skeletal remains of a 5000-year–old Egyptian mummy with evidence of 'bamboo spine' (Calin, 1985). It is a chronic, painful, degenerative, inflammatory arthritis primarily affecting the spine and sacroiliac joints; the ossification of joints and entheses primarily of the axial skeleton are known as 'bamboo spine'. It was recognised as distinct from arthritis by Galen as early as the second century

and 1992 Criteria for the Classification of Adult Onset of Still's Disease.

Patricia Woo.

absence of bony change.

(Dieppe, 1988), and the anatomist and surgeon Realdo Colombo characterised the condition in 1559 (Benoist, 1995). However, it was not until 1892, when Russian neurologist Vladimir Michailovich Bekhterev published a series of papers, that the syndrome was fully described (Bechterev, 1892). Later, Adolf Strümpel of Germany (1897) and Pierre Marie of France (1898) also gave adequate descriptions which permitted an accurate diagnosis of ankylosing spondylitis prior to severe spinal deformity. For this reason, ankylosing spondylitis is also known as Bekhterev's Disease or Marie–Strümpel Disease. Bekhterev advocated physiotherapy and the benefits of hypnosis for the patients with rheumatic spondylitis, the latter treatment method he studied under the direction of Professor Jean-Martin Charcot in Salpetriere (Kannabikh, 1925).

**Reiter's syndrome** was named after Hans Reiter (Reiter, 1916), who reported a case of a soldier with the triad of urethritis, arthritis and conjunctivitis, following an episode of bloody diarrhea. However, the history of this constellation of signs actually predates his description. Urethritis, arthritis and conjunctivitis have subsequently remained as the essential components of this syndrome, but some feel that the eye involvement is so often minimal or insignificant that it need not necessarily be present to make the diagnosis (Gaston & Lillicrap, 2003). Although Reiter's syndrome and psoriatic arthritis are ordinarily two rather discrete entities, there is a significant zone of diagnostic overlap in patients with cutaneous lesions. Both diseases may coexist in the same patient, or Reiter's syndrome seemingly may evolve into psoriatic arthritis. Reiter's syndrome in recent medical literature is simply referred to as reactive arthritis which may or may not be accompanied by extraintestinal manifestations. Salmonella has been the most frequently studied bacteria associated with reactive arthritis. Overall, studies have found rates of Salmonella-associated reactive arthritis to vary between 6 and 30% (Hill Gaston, & Lillicrap, 2003). The term Reiter's syndrome has fallen into disfavour, owning to its author's reputation as a high-

Rheumatoid Arthritis: A Historical and Biopsychosocial Perspective 195

are debating whether rheumatoid arthritis is one disease or several different diseases with common features. It appears to be a multi-factorial disease in which there are important genetic and environmental influences. There are no reports of clustering in space or time that would support an infectious cause. Jobanputra (Jobanputra et al, 1995) studied and suspected such infectious agents, as mycobacteria, Epstein-Barr virus and parvovirus as causal agents, but without any conclusive or convincing evidence. Sex hormones are implicated since there is an increased incidence in women and RA mostly improves in pregnancy, and relapses post-partum. Nulliparous women, women in the post-partum period, and women who have an early menarche have a greater risk of developing RA (Silman, 1998).While environmental stressors are likely to be involved, no definite environmental factors that precipitate disease onset have been identified. Current research is focused on elucidating the complex interactions of genetic, environmental, hormonal and auto-immune pathways. It becomes more evident that these factors nourish the immunopathogenesis on the initial stages of this disease and continue to fuel its

One of the oldest of explanation was the stress hormone hypothesis championed by Hans Selye (Selye 1949 & 1950). Roughly, his contention was that hormones released by the body, especially those released by the jacket of the adrenal glands, cause an adverse reaction to the joint tissues when they are released in excessive amounts, or in the wrong ratios under the conditions of environmental or psychological stress. His concept was generalised and only mentioned rheumatoid arthritis as an unlikely possibility. The theory had some plausibility since arthritis can be produced by injecting deoxycorticosterone, which is a potassium excreting hormone, into a patient with Addison's disease or reproduced in similar animal studies (Selye, 1944). The dramatic effect that cortisone has on arthritis was demonstrated first in 1948 by Edward C. Kendall and Philip S. Hench at the Mayo Clinic in Rochester, Minnesota. Their discovery stemmed from the astute clinical observation that a woman with severe RA felt much better during pregnancy. They found what was responsible. It was a hormone from the outer part (the cortex) of the adrenal glands that they called 'cortisone'. On September 21, 1948, Hench gave a synthesised version of cortisone developed by Kendall to a patient with arthritis and it became the first 'miracle drug' due to its powerful anti-inflammatory and other effects. In 1950 they shared the Nobel Prize in physiology for their discoveries relating to the hormones of the adrenal cortex. The question of whether patients with rheumatoid arthritis might have a defective hypothalamo–pituitary–adrenal axis was first raised then. It was initially hypothesised that this was due to an impaired ability of RA patients to synthesise sufficient amounts of endogenous glucocorticoids, but intensive investigations over the next few decades failed to reveal any significant defects in HPA axis activity in RA patients. The literature review provided no compelling evidence for significant differences in either basal or stress-stimulated HPA axis activity in RA patients compared with healthy individuals. However, Jessop and Harbuz (1999) did highlight an inherent defect, which resided in the inability of RA patients to mount an appropriately enhanced glucocorticoid response to increased secretion of proinflammatory cytokines such as interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF) - α. 'In other words', they concluded, 'the HPA axis response in RA is defective precisely because it is normal'. Following an insulin-induced hypoglycaemia, which tests the HPA axis at all levels, there were no observed differences in serum cortisol responses between patients with active RA

maintenance and progression.

**2.3.1 Stress theories** 

ranking Nazi official who was responsible for medical experiments in concentration camps (Panush, et al., 2003; Petersel & Sigal, 2005).

**Felty's syndrome** is an uncommon extra-articular manifestation of rheumatoid arthritis. First described in 1924, Felty syndrome is a potentially serious condition that is associated with seropositive rheumatoid arthritis. Felty syndrome is characterized by the triad of rheumatoid arthritis, splenomegaly, and granulocytopenia. Although many patients are asymptomatic, some develop serious and life-threatening infections secondary to granulocytopenia. It is more prevalent among women around 60 with a long history of severe articular disease, positive rheumatoid factor, and who carry the HLA-DR4 allele (Ghavami *et al*, 2005).

 In 1933, Swedish physician Henrik Sjögren observed a large number of his female patients were experiencing dry eyes and mouths along with their arthritis symptoms. The condition became known as **Sjögren's syndrome**. Primary Sjögren's syndrome is defined when only the ocular (ketratoconjunctivities sicca) and oral (xerostomia) components are present, while the secondary form refers to the association with a connective tissue disorder, especially rheumatoid arthritis, or other illness such as AIDS, hepatitis C infection, or biliary cirrhosis. In recent years, Sjögren's syndrome has also been reported to be associated with chronic graft-versus-host disease after allogeneic bone marrow transplantation. Sjögren's syndrome is a common, but often overlooked disorder. Patients with severe disease run a forty-times risk of developing lymphoma usually of the B cell type (Parke and Buchanan, 1998).

#### **2.2.1 Formation of rheumatology as a speciality**

The important work of the time by Boyle, Richardson and Doll on 'The Scientific Method' (Boyle, 1954; Doll, 1954) illustrate the beginning of a change in the practice of physical medicine in UK. The evolution of rheumatology as a subspecialty of General Medicine in England since the 1960s was happening alongside the progressive developments in clinical science, and in academic provision across the country. This initiative aimed at separating the often overlapping and competing communities of physical medicine, rehabilitation, rheumatology and internal medicine.

TJ (Lord) Horder, a distinguished London physician and (Sir) Stanley Davidson, who served as a member of the Empire Rheumatism Council re-branded clinical rheumatology on a scientific basis alongside the evolving research disciplines in pathology and clinical pharmacology. The Empire Rheumatism Council, later known as the Arthritis and Rheumatism Council, also changed its emphasis from welfare to the promotion of scientific research and medical education, while developing charities focused on the welfare of patients with rheumatic disorders instead.

The link with General Medicine, the dissolution of the link with Physical Medicine and Rehabilitation, the growth of clinical science and the increasing sophistication of therapeutics have all influenced the change in paradigm. For example, it was not until 1953 that 'Rheumatoid Arthritis' was in the title of any article in UK and not until 1958 did a systemic rheumatic disease feature at all. As regards therapeutics, salicylates, corticosteroids and the early NSAIDs featured intermittently in clinical reports. Clinical trials were rare in the 1950s, but large clinical series were commonly reported, such as 1723 cases of meniscectomy (Wynn et al, 1958).

#### **2.3 Aetiological debate**

Despite the notable advances in knowledge regarding progression of rheumatoid arthritis, its cause remains elusive. In fact, there probably is not an exact cause for it. Researchers now are debating whether rheumatoid arthritis is one disease or several different diseases with common features. It appears to be a multi-factorial disease in which there are important genetic and environmental influences. There are no reports of clustering in space or time that would support an infectious cause. Jobanputra (Jobanputra et al, 1995) studied and suspected such infectious agents, as mycobacteria, Epstein-Barr virus and parvovirus as causal agents, but without any conclusive or convincing evidence. Sex hormones are implicated since there is an increased incidence in women and RA mostly improves in pregnancy, and relapses post-partum. Nulliparous women, women in the post-partum period, and women who have an early menarche have a greater risk of developing RA (Silman, 1998).While environmental stressors are likely to be involved, no definite environmental factors that precipitate disease onset have been identified. Current research is focused on elucidating the complex interactions of genetic, environmental, hormonal and auto-immune pathways. It becomes more evident that these factors nourish the immunopathogenesis on the initial stages of this disease and continue to fuel its maintenance and progression.

#### **2.3.1 Stress theories**

194 Rheumatoid Arthritis – Etiology, Consequences and Co-Morbidities

ranking Nazi official who was responsible for medical experiments in concentration camps

**Felty's syndrome** is an uncommon extra-articular manifestation of rheumatoid arthritis. First described in 1924, Felty syndrome is a potentially serious condition that is associated with seropositive rheumatoid arthritis. Felty syndrome is characterized by the triad of rheumatoid arthritis, splenomegaly, and granulocytopenia. Although many patients are asymptomatic, some develop serious and life-threatening infections secondary to granulocytopenia. It is more prevalent among women around 60 with a long history of severe articular disease, positive

 In 1933, Swedish physician Henrik Sjögren observed a large number of his female patients were experiencing dry eyes and mouths along with their arthritis symptoms. The condition became known as **Sjögren's syndrome**. Primary Sjögren's syndrome is defined when only the ocular (ketratoconjunctivities sicca) and oral (xerostomia) components are present, while the secondary form refers to the association with a connective tissue disorder, especially rheumatoid arthritis, or other illness such as AIDS, hepatitis C infection, or biliary cirrhosis. In recent years, Sjögren's syndrome has also been reported to be associated with chronic graft-versus-host disease after allogeneic bone marrow transplantation. Sjögren's syndrome is a common, but often overlooked disorder. Patients with severe disease run a forty-times

risk of developing lymphoma usually of the B cell type (Parke and Buchanan, 1998).

The important work of the time by Boyle, Richardson and Doll on 'The Scientific Method' (Boyle, 1954; Doll, 1954) illustrate the beginning of a change in the practice of physical medicine in UK. The evolution of rheumatology as a subspecialty of General Medicine in England since the 1960s was happening alongside the progressive developments in clinical science, and in academic provision across the country. This initiative aimed at separating the often overlapping and competing communities of physical medicine, rehabilitation,

TJ (Lord) Horder, a distinguished London physician and (Sir) Stanley Davidson, who served as a member of the Empire Rheumatism Council re-branded clinical rheumatology on a scientific basis alongside the evolving research disciplines in pathology and clinical pharmacology. The Empire Rheumatism Council, later known as the Arthritis and Rheumatism Council, also changed its emphasis from welfare to the promotion of scientific research and medical education, while developing charities focused on the welfare of

The link with General Medicine, the dissolution of the link with Physical Medicine and Rehabilitation, the growth of clinical science and the increasing sophistication of therapeutics have all influenced the change in paradigm. For example, it was not until 1953 that 'Rheumatoid Arthritis' was in the title of any article in UK and not until 1958 did a systemic rheumatic disease feature at all. As regards therapeutics, salicylates, corticosteroids and the early NSAIDs featured intermittently in clinical reports. Clinical trials were rare in the 1950s, but large clinical series were commonly reported, such as 1723 cases of

Despite the notable advances in knowledge regarding progression of rheumatoid arthritis, its cause remains elusive. In fact, there probably is not an exact cause for it. Researchers now

rheumatoid factor, and who carry the HLA-DR4 allele (Ghavami *et al*, 2005).

(Panush, et al., 2003; Petersel & Sigal, 2005).

**2.2.1 Formation of rheumatology as a speciality** 

rheumatology and internal medicine.

patients with rheumatic disorders instead.

meniscectomy (Wynn et al, 1958).

**2.3 Aetiological debate** 

One of the oldest of explanation was the stress hormone hypothesis championed by Hans Selye (Selye 1949 & 1950). Roughly, his contention was that hormones released by the body, especially those released by the jacket of the adrenal glands, cause an adverse reaction to the joint tissues when they are released in excessive amounts, or in the wrong ratios under the conditions of environmental or psychological stress. His concept was generalised and only mentioned rheumatoid arthritis as an unlikely possibility. The theory had some plausibility since arthritis can be produced by injecting deoxycorticosterone, which is a potassium excreting hormone, into a patient with Addison's disease or reproduced in similar animal studies (Selye, 1944). The dramatic effect that cortisone has on arthritis was demonstrated first in 1948 by Edward C. Kendall and Philip S. Hench at the Mayo Clinic in Rochester, Minnesota. Their discovery stemmed from the astute clinical observation that a woman with severe RA felt much better during pregnancy. They found what was responsible. It was a hormone from the outer part (the cortex) of the adrenal glands that they called 'cortisone'. On September 21, 1948, Hench gave a synthesised version of cortisone developed by Kendall to a patient with arthritis and it became the first 'miracle drug' due to its powerful anti-inflammatory and other effects. In 1950 they shared the Nobel Prize in physiology for their discoveries relating to the hormones of the adrenal cortex. The question of whether patients with rheumatoid arthritis might have a defective hypothalamo–pituitary–adrenal axis was first raised then. It was initially hypothesised that this was due to an impaired ability of RA patients to synthesise sufficient amounts of endogenous glucocorticoids, but intensive investigations over the next few decades failed to reveal any significant defects in HPA axis activity in RA patients. The literature review provided no compelling evidence for significant differences in either basal or stress-stimulated HPA axis activity in RA patients compared with healthy individuals. However, Jessop and Harbuz (1999) did highlight an inherent defect, which resided in the inability of RA patients to mount an appropriately enhanced glucocorticoid response to increased secretion of proinflammatory cytokines such as interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF) - α. 'In other words', they concluded, 'the HPA axis response in RA is defective precisely because it is normal'. Following an insulin-induced hypoglycaemia, which tests the HPA axis at all levels, there were no observed differences in serum cortisol responses between patients with active RA

Rheumatoid Arthritis: A Historical and Biopsychosocial Perspective 197

arthritis share many common features. However the presence of rheumatoid factor, histologically classic rheumatoid nodules, and the histocompatibility cell wall antigen (HLA-B27) helps distinguish one from the other. A much higher association of antigen HLA-B27, which is a known immune factor with the disorders in the arthritic group, such as Reiter's syndrome and ankylosing spondilitis (López-Larrea et al, 1998), has tended to

The hypothesis that rheumatoid arthritis is an allergy is in the same general category as the autoimmune hypothesis. Such a hypothesis has the advantage, not shared by the autoimmune hypothesis directly, of advancing an environmental factor, which is almost certainly involved. The wide geographical variations virtually ensure this. There is evidence from several well documented case reports (Buchanan et al, 1991) that occasional patients with rheumatoid arthritis may develop an aggravation of their arthritis, as a result of allergy to some ingredient in their diet. A variety of foodstuffs have been implicated including milk and milk products, corn and cereals. Total fasting results in an improvement in rheumatoid arthritis, but appears to be mediated by diminution in production of chemical mediators of inflammation, rather than by elimination of a dietary allergen. According to Buchanan (Buchanan et al, 1991), there is conflicting evidence from the studies that used various intestinal probes, that patients with rheumatoid arthritis may have a 'leaky' intestinal mucosa, allowing the food allergens to be more easily absorbed. Clinical therapeutic trials of exclusion diets have employed the standard strategy of the double-blind randomised method. However, this presupposes that patients entered into such a study are capable of improvement with dietary manipulation. Since this is often not the case, a more appropriate method would be to employ the 'intensive research design', also known as 'single case experiment' and 'N of 1' study. The hypothesis pointing towards 'masked food intolerance'

is an attractive theory, but one that is extremely difficult to prove in practice.

Support for a genetic predisposition for rheumatoid arthritis has come from the studies reporting rheumatoid arthritis clusters in families. Formal genetic studies have confirmed this familial aggregation and genetic influence is estimated at 50 to 60% (Ollier et al, 1999). Studies in monozygotic twins have shown a concordance rate of 15% - 30% and a relative risk of 3.5 for rheumatoid arthritis developing in monozygotic versus dizygotic twins of affected cases. A high prevalence rate of 5% - 6% has been described in some Native American populations, suggesting a higher genetic burden of rheumatoid arthritis risk genes. Differences in the prevalence rates in other ethnic groups are rather small and are

Interactive genetic effects are suspected to modulate the impact of individual disease-risk genes and are likely to contribute to the low penetrance. Genetic risk factors not only determine susceptibility for the disease but also correlate with the disease severity and phenotype, providing the unique opportunity to use genetic markers as prognostic tools in the management of rheumatoid arthritis. A measure used to estimate the genetic component to the disease is the coefficient of familial clustering, λs, defined as the ratio of the prevalence in affected siblings to the population prevalence. For rheumatoid arthritis, λs ranges from 2 to 12 in first-degree relatives of patients, depending on the published data (Dieudé & Cornélis, 2005). Although clearly supporting the influence of the genetic factors, this λs is rather low compared with other autoimmune diseases or common genetic diseases, leaving considerable room for any environmental or stochastic events in the pathogenesis of

reinforce evidence for autoimmune aetiology of RA.

**2.3.3 Genetic basis of Rheumatoid Arthritis** 

partially explained by differences in disease ascertainment.

and patients in remission (Demir et al, 1999). This study did not include non-RA subjects as controls, and there was no ACTH response to hypoglycaemia in either test group, suggesting a possible methodological problem. Although the HPA axis in RA is defective because its activity is not increased in response to inflammatory cytokines, as might be predicted from observations of increased corticosterone in rodent models of inflammation (Harbuz, 2002), the current evidence suggest that the HPA axis is not materially different in RA compared with normal healthy subjects under most experimental conditions (Jessop, Harbuz, 2005). Stress theories did not always emphasize steroid hormones. Histamine was suggested as possibly being involved by two University of Utah scientists, Chemist Henry Eyring and Anatomist Thomas F. Dougherty in 1955 (Eyring and Dougherty, 1955). Their theory stated that stress sets off a destructive chain reaction among the body cells with histamine acting as a destructive agent. Each cell is in a membrane envelope and, as long as the membrane is relatively impermeable, the cell functions normally. Under stress, however, the membrane starts to deteriorate. Histamine, which is normally present inside the cell when the cell is healthy, is violently released and stimulated by the cell breakdown. It attacks the disintegrating cell, which swells and bursts, liberating still more histamine to attack neighbouring cells. Over long periods of stress, the spreading destruction can lead to serious illness and may be present in every fatal illness, including cancer.

Supporting evidence of histamine hyperproduction comes from the study by Permin and colleagues (Permin et al, 1981). They found that basophilocytes from patients with rheumatoid arthritis responded to leukocyte nuclei from normal persons with histamine release and recorded 3.5 times as much histamine production in arthritics after the challenge than normally expected. A role of histamine in RA is also supported by the findings from the same study of clinical improvement during treatment with H1 and H2 antihistamines in six of 12 patients with RA in active phase, whereas four showed definite deterioration.

#### **2.3.2 Autoimmune hypothesis**

The most popular current hypothesis is the autoimmune hypothesis. Many do not even regard this concept as a hypothesis, but as a proven theory, as investigations into the autoimmune hypothesis are well funded. When rheumatoid arthritis presents, the immune system overcompensates and acts, attacking the joints and the body in general. The same thing occurs with other autoimmune diseases; the immunological mechanisms that manifest in these diseases have been identified, but there is still no explanation as to why this occurs.

 Immunopathogensis of RA is multifactorial. Evidence suggests that an interaction between an unknown exogenous or endogenous antigen via antigen presenting cells and CD4 T helper cells are involved in the induction of the immune response in RA. Subsequent recruitment and activation of monocytes and macrophages occurs with the secretion of proinflammatory cytokines, in particular TNF-α and IL-1 into the synovial cavity. The release of these cytokines mediates tissue destruction by activation of chondrocytes and fibroblasts which release collagenases and metalloproteinases with resultant cartilage loss and bone erosion. B lymphocyte dysregulation, resulting in the production of rheumatoid factor and other auto-antibodies, as well as in the formation of immune complexes and the release of destructive mediators, also contribute to this process. Rheumatoid factor, an autoimmune response to IgG is a key feature of RA. High levels are relatively specific for RA but rheumatoid factor may also occur in other chronic diseases and is absent in around 30% of patients with established RA. Other auto-antigens have been proposed but as yet no single antigen has been incriminated (Jobanputra, 1992). Ankylosing spondylitis and rheumatoid

and patients in remission (Demir et al, 1999). This study did not include non-RA subjects as controls, and there was no ACTH response to hypoglycaemia in either test group, suggesting a possible methodological problem. Although the HPA axis in RA is defective because its activity is not increased in response to inflammatory cytokines, as might be predicted from observations of increased corticosterone in rodent models of inflammation (Harbuz, 2002), the current evidence suggest that the HPA axis is not materially different in RA compared with normal healthy subjects under most experimental conditions (Jessop, Harbuz, 2005). Stress theories did not always emphasize steroid hormones. Histamine was suggested as possibly being involved by two University of Utah scientists, Chemist Henry Eyring and Anatomist Thomas F. Dougherty in 1955 (Eyring and Dougherty, 1955). Their theory stated that stress sets off a destructive chain reaction among the body cells with histamine acting as a destructive agent. Each cell is in a membrane envelope and, as long as the membrane is relatively impermeable, the cell functions normally. Under stress, however, the membrane starts to deteriorate. Histamine, which is normally present inside the cell when the cell is healthy, is violently released and stimulated by the cell breakdown. It attacks the disintegrating cell, which swells and bursts, liberating still more histamine to attack neighbouring cells. Over long periods of stress, the spreading destruction can lead to

serious illness and may be present in every fatal illness, including cancer.

**2.3.2 Autoimmune hypothesis** 

Supporting evidence of histamine hyperproduction comes from the study by Permin and colleagues (Permin et al, 1981). They found that basophilocytes from patients with rheumatoid arthritis responded to leukocyte nuclei from normal persons with histamine release and recorded 3.5 times as much histamine production in arthritics after the challenge than normally expected. A role of histamine in RA is also supported by the findings from the same study of clinical improvement during treatment with H1 and H2 antihistamines in six of 12 patients with RA in active phase, whereas four showed definite deterioration.

The most popular current hypothesis is the autoimmune hypothesis. Many do not even regard this concept as a hypothesis, but as a proven theory, as investigations into the autoimmune hypothesis are well funded. When rheumatoid arthritis presents, the immune system overcompensates and acts, attacking the joints and the body in general. The same thing occurs with other autoimmune diseases; the immunological mechanisms that manifest in these diseases have been identified, but there is still no explanation as to why this occurs. Immunopathogensis of RA is multifactorial. Evidence suggests that an interaction between an unknown exogenous or endogenous antigen via antigen presenting cells and CD4 T helper cells are involved in the induction of the immune response in RA. Subsequent recruitment and activation of monocytes and macrophages occurs with the secretion of proinflammatory cytokines, in particular TNF-α and IL-1 into the synovial cavity. The release of these cytokines mediates tissue destruction by activation of chondrocytes and fibroblasts which release collagenases and metalloproteinases with resultant cartilage loss and bone erosion. B lymphocyte dysregulation, resulting in the production of rheumatoid factor and other auto-antibodies, as well as in the formation of immune complexes and the release of destructive mediators, also contribute to this process. Rheumatoid factor, an autoimmune response to IgG is a key feature of RA. High levels are relatively specific for RA but rheumatoid factor may also occur in other chronic diseases and is absent in around 30% of patients with established RA. Other auto-antigens have been proposed but as yet no single antigen has been incriminated (Jobanputra, 1992). Ankylosing spondylitis and rheumatoid arthritis share many common features. However the presence of rheumatoid factor, histologically classic rheumatoid nodules, and the histocompatibility cell wall antigen (HLA-B27) helps distinguish one from the other. A much higher association of antigen HLA-B27, which is a known immune factor with the disorders in the arthritic group, such as Reiter's syndrome and ankylosing spondilitis (López-Larrea et al, 1998), has tended to reinforce evidence for autoimmune aetiology of RA.

The hypothesis that rheumatoid arthritis is an allergy is in the same general category as the autoimmune hypothesis. Such a hypothesis has the advantage, not shared by the autoimmune hypothesis directly, of advancing an environmental factor, which is almost certainly involved. The wide geographical variations virtually ensure this. There is evidence from several well documented case reports (Buchanan et al, 1991) that occasional patients with rheumatoid arthritis may develop an aggravation of their arthritis, as a result of allergy to some ingredient in their diet. A variety of foodstuffs have been implicated including milk and milk products, corn and cereals. Total fasting results in an improvement in rheumatoid arthritis, but appears to be mediated by diminution in production of chemical mediators of inflammation, rather than by elimination of a dietary allergen. According to Buchanan (Buchanan et al, 1991), there is conflicting evidence from the studies that used various intestinal probes, that patients with rheumatoid arthritis may have a 'leaky' intestinal mucosa, allowing the food allergens to be more easily absorbed. Clinical therapeutic trials of exclusion diets have employed the standard strategy of the double-blind randomised method. However, this presupposes that patients entered into such a study are capable of improvement with dietary manipulation. Since this is often not the case, a more appropriate method would be to employ the 'intensive research design', also known as 'single case experiment' and 'N of 1' study. The hypothesis pointing towards 'masked food intolerance' is an attractive theory, but one that is extremely difficult to prove in practice.

#### **2.3.3 Genetic basis of Rheumatoid Arthritis**

Support for a genetic predisposition for rheumatoid arthritis has come from the studies reporting rheumatoid arthritis clusters in families. Formal genetic studies have confirmed this familial aggregation and genetic influence is estimated at 50 to 60% (Ollier et al, 1999). Studies in monozygotic twins have shown a concordance rate of 15% - 30% and a relative risk of 3.5 for rheumatoid arthritis developing in monozygotic versus dizygotic twins of affected cases. A high prevalence rate of 5% - 6% has been described in some Native American populations, suggesting a higher genetic burden of rheumatoid arthritis risk genes. Differences in the prevalence rates in other ethnic groups are rather small and are partially explained by differences in disease ascertainment.

Interactive genetic effects are suspected to modulate the impact of individual disease-risk genes and are likely to contribute to the low penetrance. Genetic risk factors not only determine susceptibility for the disease but also correlate with the disease severity and phenotype, providing the unique opportunity to use genetic markers as prognostic tools in the management of rheumatoid arthritis. A measure used to estimate the genetic component to the disease is the coefficient of familial clustering, λs, defined as the ratio of the prevalence in affected siblings to the population prevalence. For rheumatoid arthritis, λs ranges from 2 to 12 in first-degree relatives of patients, depending on the published data (Dieudé & Cornélis, 2005). Although clearly supporting the influence of the genetic factors, this λs is rather low compared with other autoimmune diseases or common genetic diseases, leaving considerable room for any environmental or stochastic events in the pathogenesis of

Rheumatoid Arthritis: A Historical and Biopsychosocial Perspective 199

sensitivities comparable to that of RF (approximately 80%) but with superior specificity (98%) (Nishimura et al, 2007). Early in disease radiographs may show soft tissue swelling and reduced bone density around affected joints. Later there may be evidence of joint damage such as joint erosions (focal loss of bone and cartilage often near the joint margin) or a reduced joint space (indicating diffuse cartilage loss). With continued joint damage there may be extensive joint destruction, features of joint deformity or instability, and bony ankylosis. With advanced joint damage surgical intervention such as joint replacement arthroplasty, joint fusion or osteotomy may be necessary. At an earlier stage surgical treatment such as removal of synovial tissues (synovectomy) or other soft tissue procedures

1. Morning stiffness Morning stiffness in and around the joints, lasting

2. Arthritis of 3 or more joint areas At least 3 joint areas simultaneously have had soft

3. Arthritis of hand joints At least 1 area swollen (as defined above) in a

4. Symmetric arthritis Simultaneous involvement of the same joint areas

5. Rheumatoid nodules Subcutaneous nodules, over bony prominences,

6. Serum rheumatoid factor Demonstration of abnormal amounts of serum

subjects 7. Radiographic changes Radiographic changes typical of rheumatoid

\* For classification purposes, a patient shall be said to have rheumatoid arthritis if he/she has satisfied at least 4 or these 7 criteria. Criteria 1 through 4 must have been present for at least 6 weeks. Patients with 2 clinical diagnoses are not excluded. Designation as classic, definite, or probable rheumatoid

Table 1.4 1987 Criteria for the Classification of Acute Arthritis of RA

at least 1 hour before maximal improvement

tissue swelling or fluid (not bony overgrowth alone) observed by a physician. The 14 possible areas are right or left PIP, MCP, wrist, elbow,

(as defined in 2) on both sides of the body (bilateral involvement of PIPs, MCPs, or MTPs is

or extensor surfaces, or in juxtaarticular regions,

rheumatoid factor by any method for which the result has been positive in <5% of normal control

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)

acceptable without absolute symmetry)

knee, ankle, and MTP joints

wrist, MCP, or PIP joint

observed by a physician

such as tendon release or repair may also be necessary.

Criterion Definition

arthritis is not to be made.

the disease. In part, λs may be rather low because rheumatoid arthritis is a heterogeneous syndrome that includes several genetically semi-homogeneous subsets.

The genetic system studied most thoroughly is the major histocompatibility complex (MHC). In the initial studies, rheumatoid arthritis was shown to be associated with human leukocyte antigen (HLA)-DR4 (Stastny et al, 1978). The association studies in different ethnic populations support the concept that HLA-DRB1 alleles, expressing a particular sequence motif are over-represented among people with rheumatoid arthritis (Ollier et al, 1999). This sequence polymorphism is characterized by a glutamine or arginine at position 70, a lysine or alanine at position 71, and an alanine at position 74. Alleles with a negatively charged amino acid at any one of these positions are not associated with the disease. MHC genes are not the only germline-encoded genes influencing susceptibility to rheumatoid arthritis. Female sex clearly increases the risk, and female patients develop a different phenotype of the disease than do male patients. However, no sex-linked genes have been identified as disease-risk genes. Several consortiums have started genome-wide searches, using affected sibling pairs (Seldin et al, 1999). Eventually, the candidate gene approach may be more sensitive for identifying risk genes, in particular when considering the heterogeneity of the disease severity and phenotype. The recent definition of single nucleotide polymorphisms throughout the human genome has increased significantly the feasibility of this approach. Studies of T-cell receptor (TCR) and immunoglobulin genes have not been revealing; several cytokine polymorphisms, including tumour necrosis factor (TNF)-α and interferon (IFN)- γ were described to influence disease severity, but studies are needed to confirm this hypothesis.

#### **2.4 Diagnostic considerations**

Reliable measurement is often a prerequisite of effective intervention, or at least of enabling clinical trials. Rheumatoid arthritis is diagnosed from a constellation of clinical and laboratory or radiographic abnormalities. Diagnosis may be obvious in some but in others it may be more difficult and require a period of clinical observation. Classification criteria for RA have been devised. The 1987 revised criteria for the classification of rheumatoid arthritis (Arnett et al, 1988) are shown in TABLE 1.4; it superseded The American Rheumatism Association criteria of1958. These criteria were derived from a group of typical patients who had been diagnosed with RA and had well-established disease. They have limited utility in routine practice and most clinicians diagnose RA without formal reference to such criteria, and many patients do not meet formal criteria at least early in disease (Harrison et al, 1998). Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or list of exclusions are required. In addition, a "classification tree" schema is presented which performs equally as well as the traditional (4 of 7) format. The newer criteria demonstrated 91-94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects. Criteria were also developed as an algorithm and these are more readily met in clinical practice (Emery et al, 1997).

Two diagnostic tests are included in the criteria: rheumatoid factor and X-ray changes. Rheumatoid factor (RF), measured in routine blood samples, is a circulating IgM autoantibody that is directed against IgG molecules. In established disease, IgM- RF can be detected with a sensitivity of 60-70% and a specificity of 80-90% (Van Gaalen et al, 2004). Another antibody against the cyclic citrulline protein (CCP) specific for RA was discovered later. In a meta-analysis published in 2007 it was found that anti-CCP antibody displays

the disease. In part, λs may be rather low because rheumatoid arthritis is a heterogeneous

The genetic system studied most thoroughly is the major histocompatibility complex (MHC). In the initial studies, rheumatoid arthritis was shown to be associated with human leukocyte antigen (HLA)-DR4 (Stastny et al, 1978). The association studies in different ethnic populations support the concept that HLA-DRB1 alleles, expressing a particular sequence motif are over-represented among people with rheumatoid arthritis (Ollier et al, 1999). This sequence polymorphism is characterized by a glutamine or arginine at position 70, a lysine or alanine at position 71, and an alanine at position 74. Alleles with a negatively charged amino acid at any one of these positions are not associated with the disease. MHC genes are not the only germline-encoded genes influencing susceptibility to rheumatoid arthritis. Female sex clearly increases the risk, and female patients develop a different phenotype of the disease than do male patients. However, no sex-linked genes have been identified as disease-risk genes. Several consortiums have started genome-wide searches, using affected sibling pairs (Seldin et al, 1999). Eventually, the candidate gene approach may be more sensitive for identifying risk genes, in particular when considering the heterogeneity of the disease severity and phenotype. The recent definition of single nucleotide polymorphisms throughout the human genome has increased significantly the feasibility of this approach. Studies of T-cell receptor (TCR) and immunoglobulin genes have not been revealing; several cytokine polymorphisms, including tumour necrosis factor (TNF)-α and interferon (IFN)- γ were described to influence disease severity, but studies are needed to confirm this

Reliable measurement is often a prerequisite of effective intervention, or at least of enabling clinical trials. Rheumatoid arthritis is diagnosed from a constellation of clinical and laboratory or radiographic abnormalities. Diagnosis may be obvious in some but in others it may be more difficult and require a period of clinical observation. Classification criteria for RA have been devised. The 1987 revised criteria for the classification of rheumatoid arthritis (Arnett et al, 1988) are shown in TABLE 1.4; it superseded The American Rheumatism Association criteria of1958. These criteria were derived from a group of typical patients who had been diagnosed with RA and had well-established disease. They have limited utility in routine practice and most clinicians diagnose RA without formal reference to such criteria, and many patients do not meet formal criteria at least early in disease (Harrison et al, 1998). Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or list of exclusions are required. In addition, a "classification tree" schema is presented which performs equally as well as the traditional (4 of 7) format. The newer criteria demonstrated 91-94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects. Criteria were also developed as an algorithm

Two diagnostic tests are included in the criteria: rheumatoid factor and X-ray changes. Rheumatoid factor (RF), measured in routine blood samples, is a circulating IgM autoantibody that is directed against IgG molecules. In established disease, IgM- RF can be detected with a sensitivity of 60-70% and a specificity of 80-90% (Van Gaalen et al, 2004). Another antibody against the cyclic citrulline protein (CCP) specific for RA was discovered later. In a meta-analysis published in 2007 it was found that anti-CCP antibody displays

and these are more readily met in clinical practice (Emery et al, 1997).

syndrome that includes several genetically semi-homogeneous subsets.

hypothesis.

**2.4 Diagnostic considerations** 

sensitivities comparable to that of RF (approximately 80%) but with superior specificity (98%) (Nishimura et al, 2007). Early in disease radiographs may show soft tissue swelling and reduced bone density around affected joints. Later there may be evidence of joint damage such as joint erosions (focal loss of bone and cartilage often near the joint margin) or a reduced joint space (indicating diffuse cartilage loss). With continued joint damage there may be extensive joint destruction, features of joint deformity or instability, and bony ankylosis. With advanced joint damage surgical intervention such as joint replacement arthroplasty, joint fusion or osteotomy may be necessary. At an earlier stage surgical treatment such as removal of synovial tissues (synovectomy) or other soft tissue procedures such as tendon release or repair may also be necessary.


\* For classification purposes, a patient shall be said to have rheumatoid arthritis if he/she has satisfied at least 4 or these 7 criteria. Criteria 1 through 4 must have been present for at least 6 weeks. Patients with 2 clinical diagnoses are not excluded. Designation as classic, definite, or probable rheumatoid arthritis is not to be made.

Table 1.4 1987 Criteria for the Classification of Acute Arthritis of RA

Rheumatoid Arthritis: A Historical and Biopsychosocial Perspective 201

prednisolone and are most often used in combination with DMARDs, which significantly

"Biologics" directly modify the immune system by inhibiting cytokines or B and T immune cells, which contribute to inflammation. Two types of agents can be used to eliminate circulating TNF: recombinant soluble receptors and monoclonal antibodies to TNF. There are three agents that were originally approved for patients with RA which inhibit the action of TNF-α; – infliximab, etanercept and adalimumab. Two additional novel TNF antagonists, Certolizumab pegol and Golimumab have recently been indicated for patients with RA for the treatment of moderate to severe, active RA in adult patients when the response to

Etanercept, a soluble TNF receptor, is labeled for use in monotherapy and combination therapy with methotrexate for arthritis (NICE guidelines, 2002). The TNF- α blocking agent infliximab is labelled for use in combination with methotrexate for the treatment of RA (NICE guidelines, 2002). Adalimumab is a recombinant human IgG1 monoclonal antibody that binds TNF-α, thereby precluding binding to its receptor. Enthusiastic support for early intervention with TNF- inhibitors for patients with RA comes with a strong safety message. Although infusion reactions and other AEs are infrequent, they may be very serious in some patients, in particular when complications associated with opportunistic infections occur. Certolizumab pegol, which targets TNF-α with a different mechanism of action than widely used biologics, was initially investigated for Crohn's disease but has now been shown to be effective for rheumatoid arthritis. There have been three significant clinical trials demonstrating the efficacy of certolizumab pegol in active rheumatoid arthritis; two with combination methotrexate and one with monotherapy (Ruiz et al, 2011). Significant improvements were observed at 24 weeks and at 52 weeks with the approved dose of 200 mg certolizumab pegol. The most common adverse events with certolizumab pegol 200 mg were: upper respiratory tract infections, hypertension and nasopharyngitis (Ruiz et al, 2011). Golimumab is a humanized inhibitor of Tumor necrosis factor-alpha, recently approved for the treatment of RA. Recent Cochrane systematic review (Singh et al, 2010), identified four Randomised Control Trials with 1,231 patients treated with golimumab and 483 patients treated with placebo. The authors concIuded that Golimumab-treated patients were significantly more likely to achieve remission, low disease activity and improvement in functional ability compared to placebo (all statistically significant). No significant differences were noted between golimumab and placebo regarding serious adverse events, infections, serious infections, lung infections, tuberculosis, cancer, withdrawals due to

Interleukin 1 is a pro-inflammatory cytokine produced by stimulated monocytes, macrophages and some specialised synovial lining cells. IL-1 receptor antagonist competes with IL-1 for binding to the receptor, subsequently down regulating IL-1 actions. By stimulating the release of matrix metalloproteinases and increasing bone resorption by effects on osteoclasts, IL-1 has been shown to have a significant role in RA pathogenesis, particularly in regards cartilage and bone erosion. Mice deficient of IL-1 receptor antagonist, demonstrate the development of inflammatory arthritis similar to RA (Horai et al, 2000). In

conventional DMARDs including methotrexate, has been inadequate.

enhances the benefits of DMARDs.

**2.5.3 Biologic response modifiers** 

adverse events and inefficacy and deaths.

**2.5.4 Interleukin 1 receptor antagonists** 

Among additional diagnostic tests are acute-phase reactants – the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level that correlate with the degree of synovial inflammation. They are useful for following the course of inflammatory activity in an individual patient. Other abnormalities include hypergannaglobulinemia, thrombocytosis, and eosinophilia. These occur more often in patients with severe disease, high RF titer, rheumatoid modules, and extra-articular manifestations.

#### **2.5 Trends in pharmacological and biological therapy**

In more recent years, a number of new exciting therapeutic options have become available, especially with the development of the biologic drugs, thus causing evolution of rheumatological science to spiral. This trend reflects the application of knowledge obtained from advancements in understanding of disease pathogenesis and underlying molecular mechanisms. This therapeutic philosophy has drawn on the model of oncology, with early diagnosis and aggressive treatment. While this has been in parallel with and to an extent dependent upon, sophisticated new imaging techniques such as MRI, clinicians have thought along these lines for many years (Emery, Gough, 1991).A number of these therapies are outlined below, including the various biological modifiers, in particular, anti-tumour necrosis factor-α agents and interleukin-1 (IL-1) receptor antagonists, which have been developed in recognition of the role of pro-inflammatory cytokines in RA. Also notable, is the current interest centering on the development and trials with B cell depletion therapies, specifically rituximab, in patients with RA. This demonstrates acknowledgment for a more significant role for B cells in the aetiology of RA, in contrast to the long held view that RA was a predominantly T cell mediated disease. The main categories of medications used to treat RA considered below.

#### **2.5.1 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)**

It has been shown that NSAIDs cause quite distinct and severe biochemical damage during drug absorption (uncoupling of mitochondrial oxidative phosphorylation proving to be most important) which results in increased intestinal permeability. All commonly used NSAIDs, apart from aspirin and nabumetone, are associated with increased intestinal permeability in man. Whilst reversible in the short term, it may take months to improve following prolonged NSAID use (Bjarnason et al, 1993). Avoiding NSAIDs is advisable in patients with inflammatory bowel disease (Kane et al, 2001).
