Clinical Review of Spondyloarthropathies arthritis by mikesanye


									A Clinical Review of The Seronegative

                Eileen O’Flynn S.R.N. S.C.M.
                St. Anthony’s Rheumatology Centre
                Herbert Avenue,
                Dublin 4

                20th March 04


For many people the word Arthritis conjures up an image of grandparents with the
minor aches and pains inevitably associated with ageing. While Osteoarthritis - the
most common form of arthritis – does tend to occur in old age, the reality is that
rheumatic diseases can be found at every stage of life and can severely limit
individuals activities and effect their ability to perform the life tasks before them.

In this clinical review a group of four heterogeneous diseases are examined in some
detail. Collectively known as Seronegative Spondyloarthrophy, they are: (1)
Ankylosing Spondylitis, (2) Reactive Arthritis (Reiters Syndrome), (3) Psoriate
Anthropthy and (4) Enteropathic Arthritis (associated with Inflammatory Bowel
Disease). However Seronegative Rheumatoid Arthritis is not part of the group. These
are a group of inflammatory disorders that are linked together by a number of
articular, extra-articular and genetic features – the most important being Sacroiliitis.
The prototype of these Spondylarthropathies is Ankylosing Spondylitis.

1.     Ankylosing Spondylitis

Ankylosing means fusion together; Spondylitis indicates inflammation of the
vertebrae - both are Greek words – so Ankylosing Spondylitis describes the condition
by which some or all of the joints and bones of the spine fuse together. Many people
will only have partial fusion – sometimes limited to the pelvic bones. Ankylosing
Spondylitis is a painful, progressive rheumatic disease. It mainly affects the spine, but
it can affect other joints, tendons and ligaments and other areas such as the eyes,
lungs, bowel and heart can also be involved.

The cause of Ankylosing Spondylitis is unknown but medical research has shown that
96% of people with Ankylosing Spondylitis all share the same genetic markers –
Human Lucocyte Antigen B27 (HLA-B27). Genetic markers are protein molecules
located on the surface of white blood cells that act as a type of nametag. People with
this particular marker are more likely to develop the disease.

Inflammation occurs at the site where certain ligaments or tendons attach to bone
(enthesis) and this is followed by some erosion of bone at the site of the attachment
(enthesopathy). As the inflammation subsides, a healing process takes place and new
bone develops. Repetition of this inflammation process leads to further bone
formation and the individual bones that make up the backbone, the vertebrae, can fuse
together. The pelvis is commonly affected first. The lower back, chest wall and neck
may also become involuted at different times.

Clinical Presentations

Typical symptoms of Ankylosing Spondylitis include slow or gradual onset of back
pain and stiffness over weeks or months, early morning stiffness and pain wearing off
or reducing during the day, feeling better after exercise and worse after rest, weight
loss in the early stages, feeling feverish and experiencing night sweats and a
persistence of these symptoms for more than three months. Fatigue is another

It typically strikes people in their late teens and twenties with the average age being
24, however symptoms can start at other periods in life. Ankylosing Spondylitis
affects approximately 1 in 200 men and 1 in 500 women in Britain and is a variable
disease affecting men, women and children differently:
Men: the pelvis and spine are most commonly affected; other joints that may be
involved are the chest wall, shoulders, hips and feet.
Women: spinal involvement is generally less severe than in men. The hips, pelvis,
knees, ankles and wrists are the most commonly afflicted.
Children: it is unusual for children under the age of 11 years to develop symptoms of
Ankylosing Spondylitis Joints that are affected first are the hips, knees, ankles, feet
and buttocks. In juveniles Ankylosing Spondylitis may lead to persistent hip disease,
ultimately requiring a hip replacement sometime in adult life.



FBC, HB (decreased), platelets (elevated), with active disease ESR (elevated) (but in
active disease it does not always correlate), LFT’s. HLA-B27 is occasionally useful
where diagnosis is uncertain but although finding B27 increases the possibility of
Spondylarthropathy but not make the diagnosis.


Spinal X ray can present a number of features including:
       -      Spinal ligament calcification
       -      Apophyseal joint function.
       -      Sacro-joints.
       -      Bilateral Sacroiliitis.


Active exercise is necessary to prevent stiffness and deformity. The importance of
exercise to preserve spinal movement should be strongly emphasised although
compliance with daily exercise is often poor.

N.S.A.I.D’s are recommended for peripheral joint infection and occasionally
methotrexete is given. Anti – TNF agents are very effective and likely to be
increasingly used even in relatively early disease activity.

2.     Reactive Arthritis

Reiters Syndrome, as described by H. Reiter in 1916, consists of a triad: arthritis,
urthritis and conjunctivitis. Reactive Arthritis refers to a form of peripheral arthritis
often accompanied by one or more extra-articular manifestations that appears shortly
after certain infections of genitourinary or gastrointestinal tracts. The majority of
affected individuals – usually young men, have inherited the human lukocyte antigen
(HLA B27).

Clinical Presentations

Reactive Arthritis typically begins acutely two to four weeks after venereal infections
or bouts of gastroenteritis. Most endemic cases of Reactive Arthritis occur in young
men, the ratio of male to female being 9:1 and these cases are believed to result from
venerally acquired infections; cases following food-borne enteric infections affect
both genders equally.
Men mild dysuria and mucopurulent urethreal discharge are the most typical
Women: may have dysuria, vaginal discharge and purulent cerviatis and /or vaginitis.

Conjunctivitis, when present, usually accompanies urethritis or develops within
several days. Acute Anterior Uveitis (Iritis) typically affecting one eye may occur
simultaneously with, conjunctivitis and is characterised by several occular erythema,
pain and photophobia.

Reactive Arthritis affects an average number of four joints. Lower limb joints
especially knees, ankles, and small joints of the feet are affected more commonly than
joints of the upper extremities. At least one third of patients have exclusively lower
limb arthritis and rarely does a patient have only upper extremity involvement. Hip
disease is uncommon but sternoclavicular; shoulder and tempo-mandibular joints are
occasionally affected.

Joints affected with Reactive Arthritis are swollen, warm, tender, and painful on
active and passive movement. When toes or fingers are affected, the entire digit is
usually diffusely swollen - a phenomenon referred to as sausage-digits or Doctylitis.
Enthesitis most commonly occurs at the insertions of the planter oponeurosis and
Achilles tendon on the calcaneus, leading to one of the most frequent, distinctive and
disabling manifestations of the disease - heel pain. Low back symptoms are probably
caused primarily by Sacroiliac involvement, or other spinal joint involvement.

Raised waxy popular lesions that resemble mollusc shells or pustules usually are the
earliest findings. Later these lesions become hyperkeratotic and scaly, often
coalescing into patches indistinguishable from psoriasis. Toenails and finger nails

may become thickened and opaque and may crumble, resembling nail changes similar
to mycotic infections. Oral ulcers, which are shallow and usually painless, may appear
on the tongue or hard palate. A few patients develop chronic uveitis that ultimately
results in visual impairment or loss.

Aortitis occurs in 1-2% of patients. The majority of patients with Aortic regurgitation
have relentless progression of valvular incompetence, leading to left-sided heart
failure and ultimately to Aortic valve replacement. Those who develop complete heart
block need immediate cardiac pacemaker placement.

Lab features

Normochromic anaemia due to chronic inflammation is not uncommon. Acute phase
reactants, including C. R. P. and E. S. R. are typically abnormal. Serum globulins,
especially IgA are frequently elevated. Tests for Rheumatoid Factor, and antinuclear
antibodies, are negative.

Synovial fluid shows highly inflammatory changes, Gram stains show no
microorganisms, and bacterial cultures are sterile.

Radiographic Features.

Abnormalities on joint x-ray only occur after symptoms have been present for several
months. Similar radiographic findings may occasionally be found in people with
Ankylosing Spondylitis, or Psoriatic Arthritis. The diagnosis of Reactive Arthritis is
made on clinical grounds based on disease manifestations and lab findings.

Course and Prognosis

Reactive Arthritis runs a self –limited course of three to twelve months in the majority
of patients, however some studies suggest that many people continue to have minor
residual musculoskeletal symptoms beyond 12 months. Long-term disability usually
is related to chronic foot pain or deformities from arthritis, heel pain or vision loss.
Mortality from Reactive Arthritis is infrequent and results most often from cardiac
complications or amyloidosis.

3.     Enteropathic Arthritis.

Enteropathic arthritis refers primarily to the articular manifestation of two
inflammatory bowel diseases: Ulcerative Colitis and Chron’s disease.

Peripheral Arthritis occurs in approximately10%-20% of people with Chron’s disease
or Ulcerative Colitis.

Clinical Features.

The typical pattern of joint inflammation is migratory Arthralgias or Arthritis.
The Arthritis affects predominately the lower extremity joints, knees, ankles, and feet
but any peripheral joint may be involved including the hip. Large joint effusions,
especially of the knee, are common. Deformities are rare. Peripheral Arthritis can
reflect active Inflammatory Bowel Disease and can subside with treatment of the
bowel inflammation. In fact surgical colectomy in Ulcerative Colitis may result in
permanent remission of the Arthritis; however this is not the case in Crohn’s disease
in which other bowel areas may be affected.

Spinal arthritis, including Sacroiliitis occurs in approximately 10% of people with
Inflammatory Bowel Disease and frequently is asymptomatic. Males develop this
complication more often than females, with a 3:1 ratio. Unlike Peripheral Arthritis,
Spondylitis does not necessarily reflect active bowel inflammation, and it tends to run
an independent course. Having surgery i.e. a colectomy does not halt its progression.

Laboratory Features.

Anaemia is common in Inflammatory Bowel Disease and reflects chronic
inflammation and chronic gastrointestinal blood loss. Leukocytosis is also common
and an extreme Trombocytosis sometimes occurs. Acute – phase reactants, such as C-
reactive protein and erythrocyte sedimentation rate, are typically elevated. Serum
rheumatoid factor and antinuclear antibodies are not found; however, positive tests for
Antineutrophil (P)-ANCA, have been reported in approximately 60% of people with
ulcerative colitis and, less commonly, in people with Crohn’s disease The frequency
of HLA-B27 is no greater in people with Inflammatory Bowel Disease or with
Inflammatory Bowel Disease -associated Arthritis than in the general population.
Synovial fluid findings have been reported infrequently, but show non-specific
inflammatory changes and are sterile on culture.

Radiographic Features

The clinical symptoms, signs, and radiographic features of Inflammatory Bowel
Disease associated Spondylitis are indistinguishable from those of Idiopathic
Ankylosing Spondylitis. Extra-articular manifestations of Inflammatory Bowel
Disease typically reflect active bowel disease and tend to occur at the same time as the
peripheral arthritis. The most common cutaneous complication of Crohn’s disease is
erythema nodosum, while that of Ulcerative Colitis is pyoderma gangrenosa. Painful,
deep oral ulcers may occur in both disorders, as may attacks of acute anterior uveitis.
Fever and weight loss are also common during active disease periods.

4      Psoriatic Arthritis.

Epidemiological studies have confirmed an increased prevalence of inflammatory
Arthritis in association with Psoriasis.

Clinical Features.

There are 78 major joints in the body, and Psoriatic Arthritis can affect any one of
these, however certain joints are more likely to be affected than others and the pattern
of joint involvement also varies widely. In about 70% of patients, psoriasis is present
many years before the onset of arthritis. Although the arthritis is usually insidious in
onset, approximately one-third of patients have an acute onset. In about 15% of
adults, and more often in children, the arthritis appears before skin or nail changes.
Most patients have a family history of psoriasis. Commonly a combination of spine
and peripheral joint disease is observed. Stiffness in the spine occurring after
inactivity and lasting at least 30 minutes in the morning is an important clue to the
presence of psoriatic spondylitis. Daclitis is caused by inflammation occurring
simultaneously in joints and tendons. Inflammation is not limited to the joints and
spine but occurs at the periosteum, along tendons and at areas of insertion points into
bone (enthesitis). These inflammation sites appear to be factors in the development of
the sausage digits, which are typical of Psoriatic Arthritis.

Although typical arthritis can precede a detectable rash, the definite diagnosis of
Psoriatic Arthritis cannot be made without evidence of skin or nail changes typical of
Psoriasis. Psoriatic skin lesions are macular with characteristic scales and bleeding
often occurs at sites of scale removal. Lesions take numerous shapes but are most
often rounded and located over exterior surfaces. Nail involvement is the only clinical
feature that identifies patients with Psoriasis who are likely to develop Arthritis.

Clinical signs of psoriatic involvement of the nails include pitting, separation of the
nail from the nail bed, ridging and cracking, subungual keratosis, brown- yellow
discoloration, and leukonychia. The typical psoriatic skin lesion is a sharply
demarcated erythematous plaque with a well-marked, silvery scale. The lesions
typically appear on the exterior surfaces of the elbows and knees, in the scalp, and on
ears and pre-sacral areas, but they may be found anywhere on the body, including
palms and soles, flexor sites, low back, hair line, perineum, and genitalia. There size
is variable, ranging from 1mm or less in early acute psoriasis to several centimetres in
well-established disease. Systemic involvement is largely limited to eye inflammation
occurring in 30% of patients. Findings include conjunctivitis, irisitis, and episcleritis.
Aortic insufficiency has also been reported, and an associated myopathy has been

Laboratory Findings.

Abnormal laboratory findings are mild and non-specific, including slightly elevated
E.S.R. and mild normochromic anaemia. Results of studies in synovial fluid are also

Radiographic Features.

Several features are characteristic for the disease. The bony changes in Psoriatic
Arthritis are a unique combination of erosion, which helps in differentiating it from
Ankylosing Spondylitis, and bone production in a specific distribution, which
distinguishes it from Reactive Arthritis. In decreasing order of frequency, the
radiographic abnormalities are distributed in the hands, feet, sacroiliac joints, and
spine. Spondylitis may occur with or without involvement of the sacroiliac joints.

Treatment of the Spondyloarthropathies.

The treatment of Seronegative Spondylarthropathies necessitates a global approach to
the management in which patient education is the cornerstone. With the typical onset
being during young adulthood and with a male predominance, people with these
diagnoses frequently display frustration and depression when it becomes apparent that
they have a chronic rheumatic disease that can significantly impair their functional
capabilities and quality of life. Validated measures of disease activity – the Bath
Ankylosing Spondylitis Functional Index [B.A.S.F.I.], Dougados Functional Index
[D.F.I.] and an Ankylosing Spondylitis specific version of the Health Assessment
Questionnaire [H.A.Q.S.] have proved useful in determining functional status and
response to therapy. An Ankylosing Spondylitis specific Arthritis Impact
Measurement Scale 2 [A.S.-A I M S 2], which includes measurements of spine, pain
and mobility, has correlated a marked deterioration in these patients’ quality of life.
Stiffness pain, fatigue, poor sleep, concerns about appearance and worry about the
future are extremely common in people with Spondyloarthropaties. Clinicians treating
people with these diseases should be aware that these psychosocial aspects of the
disease as part of the burden of illness.

Steroidal and Non-Steroidal Therapy.

In general, people with a Spondyloarthropathy experience significant improvement in
joint inflammation after the administration of N.S.A.I.D’s. Indomethacin or
diclofenac (up to 20mgs daily, in divided doses) is well tolerated in these patients. No
trials have specifically addressed the use of selective cox-2 inhibitors, such as
rofecoxib and celecoxib, in the Spondyloarthropaties but these medicines may form
an important part of the therapeutic regime of patients who do not tolerate
conventional N.S.A.I.D. therapy. In the case of Ankylosing Spondylitis the goal of
anti-inflammatory treatment is to achieve sufficient control of pain and stiffness to
allow an active sustained programme of exercise and physical activity and to improve
quality of life.

Corticosteroid therapy for Spondyloarthropathy usually consists of intra-articular
injections into actively inflamed joints. Topical steroids are usually effective for
treating the manifestations of Reactive Arthritis. Topical corticosteroid eye drops are
an integral component of management for Uveitis and treatment should be monitored
with an ophthalmologist.

Second Line Agents

Methotrexate: concurrent with the widespread use of methotrexete in people with
Rheumatoid Arthritis, there has been increasing use of methotrexete in people with
the Spondyloarthropaties. Generally the responses have been good, particularly for
peripheral joint disease, but there have few trials to substantiate these clinical
impressions. In people with Reactive Arthritis where there is a predominance of
young male patients, the hazards of alcohol intake while on M.T.X. must be

Biological Agents.

There has been a dramatic breakthrough in our understanding of the mechanisms of
persisting joint inflammation in recent years. Cytokines such as TNF alpha and
Interlukin1 have shown to have a crucial role in maintaining inflammation. Several
targeted anti-cytokine therapies have been developed over the past number of years,
namely Infliximab (Remicade), Etanarcept and Humera. Understanding why some
patients do not respond to some therapies remains a challenge and provides
opportunities for a better understanding of the pathogenetic mechanisms operative in
sero negative Arthropaties. Important questions that remain regarding these biological
therapies include the likelihood of opportunistic or unusual infections in the context of
their chronic administration. It also remains to be determined whether they will result
in an increased incidence of tumours. Finally, the cost of biological therapies will
need to be evaluated in terms of their long-term benefit, with particular regard to work
stability, the predicted reduction in joint replacements, and their potential to provide
improved quality of life and lifespan.


The ability of individuals to manage their disease will be, to an extent, a function of
their social context. The demands of family, school and work must be considered in
the development of a treatment plan. The successful treatment plan will ascertain the
individual’s life goals as each person brings particular strengths and weaknesses to the
experience of rheumatic disease. A treatment plan that specifies “no tennis” may be
fine for the marginally athletic patient but would be a serious blow to the professional
tennis coach. To design a plan that respects the needs of the individual and maximises
the likelihood of success, it is essential to manage patient expectations regarding the
management of this illness and its place in his or her life. The plan should develop
treatment goals in conjunction with the patients that are based on the realities of the
disease and the realities of the patients’ life also.

The Chinese symbol for crisis is a combination of the symbols for danger and
opportunity. Development of a rheumatic disease can precipitate a life crisis and
present the danger of losses of identity, competence, or productivity but it can also
provide an opportunity to reintegrate psychological strengths and reprioritise family,
work and leisure activities. This can lead to a new equilibrium, which is even more
satisfying as individuals continue adjusting their lives.

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