Non-inflammatory Arthritis

Question 1

What is the most common type of arthritis

Answer 1

Osteoarthritis

Question 2

What is osteoarthritis

Answer 2

It occurs with a variety of patterns in synovial joints and is characterized by cartilage loss with an accompanying periarticular bone response. It is probably not a single disease entity but a multifactorial process in which mechanical factors have a central role. The whole joint structure including cartilage, subchondral bone, ligaments, menisci, synovium and capsule is involved. Pathologically, there is significant inflammation of articular and periarticular structures and alteration in cartilage structure. Osteoarthritis is the subject of intense investigation but no drugs which halt or reverse this process have yet been developed.

Question 3

What is the cause of osteoarthritis

Answer 3

The gene that encodes collagen type II (COL2A1) is a candidate gene for familial OA but there is no single gene that associates with all patterns of OA.

Question 4

What is the pathogenesis of osteoarthritis

Answer 4

Abnormal stress and loading leading to mechanical cartilage damage play a role in secondary OA.
•Obesity is a risk factor for developing OA of the hand and knee, but not the hip in later life. Increased skeletal mass increases cartilage volume.
• Collagenases (MMP-1 and MMP-13) cleave collagen, and other metalloproteinases such as stromelysin (MMP-3) and gelatinases (MMP-2 and MMP-9) are also present in the extracellular matrix.
MMPs are secreted by chondrocytes in an inactive form. Extracellular activation then leads to the degradation of both collagen and proteoglycans around chondrocytes.
• Tissue inhibitors of metalloproteinases (TIMPs)
regulate the MMPs. Disturbance of this regulation

may lead to an increase in cartilage degradation over synthesis and contribute to the development of OA.
TIMPs have not yet proven to be of therapeutic value.
• Osteoprotegerin (OPG), RANK and RANK ligand (RANKL) control the remodelling of subchondral bone remodelling. Their levels are significantly different in OA chondrocytes. Inhibiting RANKL may prove a new therapeutic approach in OA.
• Aggrecanase production is stimulated by pro-inflammatory cytokines and aggrecan (the major proteoglycan) levels fall.
• Synovial inflammation is present in OA, and CRP in the serum may be raised. Interleukin-1 (IL-1) and tumour necrosis factor (TNF-a) release stimulates metalloproteinase production and IL-1 inhibits type lI collagen production. IL-6 and IL-8 may also be involved.
Anticytokine therapy has not yet been tested in OA.
The production of cytokines by macrophages and of MMPs by chondrocytes in O are dependent on the transcription factor NF-B. Inhibition of NF-kB may have a therapeutic role in OA.
• IL-1 receptor antagonist genes are associated with radiographic severity of knee OA.
• Growth factors, including insulin-like growth factor (IGF-1) and transforming growth factor (TGF-B), are involved in collagen synthesis, and their deficiency may play a role in impairing matrix repair. However, increased TGF-B may cause increased subchondral bone density.
• Cartilage breakdown products lead to macrophage infiltration and vascular hyperplasia and IL1-B and TNF-a may contribute to further cartilage degradation.
• Vascular endothelial growth factor (VEGF) from macrophages is a potent stimulator of angiogenesis and may contribute to inflammation and neovascularization in OA. Innervation can accompany vascularization of the articular cartilage.
• Mutations in the gene for type II collagen (COL2A1)
have been associated with early polyarticular OA.
• A strong hereditary element underlying OA is suggested by twin studies. Further studies may reveal genetic markers for the disease.

In the Caucasian population there is an inverse relationship between the risk of developing O and osteoporosis.
• Gender. In women, weight-bearing sports produce a two- to three-fold increase in risk of O of the hip and knee. In men, there is an association between hip OA and certain occupations: farming and labouring. OA may flare after the female menopause or after stopping hormone replacement therapy.
• Periarticular enthesitis has been proposed as a factor in the pathogenesis of nodal generalized OA (NGOA;p. 515) and is the subject of investigation.
The term primary OA is sometimes used when there is no obvious known predisposing factor.

Question 5

What are the clinical features of OA

Answer 5

Osteoarthritis affects many joints, with diverse clinical pat-terns. Hip and knee O are major causes of disability. Early OA is rarelv symptomatic unless accompanied by a joint effusion, whilst advanced radiological and pathological OA is not always symptomatic.
Some flare-ups are due to inflammation and there may be a slight rise in ESR or CRP. Focal synovitis is caused by fragments of shed bone or cartilage. Radiological OA is usually, but not inevitably, progressive. This progression may be stepwise or continual. Radiological improvement is uncommon but has been observed, suggesting that repair is possible.

Question 6

What are some signs of osteoarthritis

Answer 6

Crepitus
• Restricted movement
• Bony enlargement
• Joint effusion and variable levels of inflammation
• Bony instability and muscle wasting.

Question 7

What are some symptoms of osteoarthritis

Answer 7

Joint pain
• Short-lived morning joint stiffness
• Functional limitation.

Question 8

What are some investigations of osteoarthritis

Answer 8

Blood tests. There is no specific test; the ESR is normal although high sensitivity CRP may be slightly raised.
Rheumatoid factor and antinuclear antibodies are negative.
• X-rays are abnormal only when the damage is advanced. They are useful in preoperative assessments.
For knees, a standing X-ray (stressed) is used to assess cartilage loss and ‘skyline’ views in flexion for patello-femoral OA.
• MRI demonstrates meniscal tears, early cartilage injury and subchondral bone marrow changes (osteochondral lesions).
• Arthroscopy reveals early fissuring and surface erosion of the cartilage.
• Aspiration of synovial fluid (if there is a painful effusion) shows a viscous fluid with few leucocytes

Question 9

What is the management for osteoarthritis

Answer 9

The guiding principle is to treat the symptoms and disability, not the radiological appearances; depression and poor quadriceps strength are better predictors of pain than is radiological severity in O of the knee. Education of the individual about the disease and its effects reduces pain, distress and disability and increases compliance with treatment. Psychological or social factors alter the impact of the disease.

Question 10

What are some physical management measures of osteoarthritis

Answer 10

Weight loss and exercises for strength and stability are useful. Hydrotherapy helps, especially in lower-limb OA.
Local heat, ice packs, massage and rubefacients or local NSAID gels are all used. Insoles for flat feet and a walking stick held on the contralateral side to the affected lower limb joint are useful.
There is increasing evidence that acupuncture helps knee
OA. Other forms of complementary medicine are commonly used and, despite lack of scientific evidence, little is lost in trying it since a number of patients do seem to be helped.

Question 11

What are some medication measures for osteoarthritis

Answer 11

Balance the potential benefit against potential side-effects, especially in the elderly. Paracetamol is effective and should be prescribed before NSAIDs (Box 11.3). NSAIDs or coxibs should be used intermittently when possible. Opioids should be used cautiously in older patients.
Intra-articular corticosteroid injections produce short-term improvement when there is a painful joint effusion. Frequent injections into the same joint should be avoided. The role of intra-articular hyaluronan preparations is unclear.
Glucosamine and chondroitin (sold as food supplements)
have no clinically relevant effect on joint pain or joint space narrowing.
There are no proven agents which halt or reverse OA, although they are greatly needed. The role of bisphospho-nates in reducing bone changes is unclear. The role of drugs which block tissue metalloproteinases or cytokines (see pathogenesis, below) is also unclear.

Question 12

What are some surgical management for osteoarthritis

Answer 12

Arthroscopy for knee OA is not beneficial. However, replacement arthroplasty has transformed the management of severe OA. The safety of hip and knee replacements is now equal, with a complication rate of about 1%; loosening, and late blood-borne infection are the most serious. The slight but definite risks make it essential that the patient is certain that surgery is necessary. Resurfacing hip surgery has become popular but may have higher complication rates in women. Unicompartmental knee replacement is a less major procedure and appropriate for some patients.
For the vast majority, a total hip or knee replacement reduces pain and stiffness, greatly increases function and mobility, and - particularly significant for the elderly
- independence.
Other surgical procedures include realignment osteotomy of the knee or hip, excision arthroplasty of the first MTP and base of the thumb, and fusion of a first MTP joint.

Question 13

What are the two types of crystal arthritis

Answer 13

They are sodium rate and calcium pyrophosphate and are distinguished by their different shapes and refringence properties under polarized light with a red filter.

Question 14

What is gout

Answer 14

Gout is an inflammatory arthritis associated with hyperuricaemia and intra-articular sodium rate crystals.

Question 15

The last two steps of purine metabolism in humans are the conversion of hypoxanthine to xanthine and of xanthine to uric acid, catalysed by the enzyme xanthine oxidase. Primates lost the gene for uricase during their evolution about
10-20 million years ago. Hyperuricaemia possibly offered an evolutionary advantage.
True or false

Answer 15

True

Question 16

What are some clinical features of hyperuricemia

Answer 16

Hyperuricaemia may be asymptomatic. It also causes:
• Acute gout, followed by an asymptomatic intercritical phase; a second acute attack likely within 2 years
Chronic interval gout, with acute attacks superimposed on low grade inflammation and potential joint damage
• Chronic polyarticular gout is rare, except in elderly people on longstanding diuretic treatment, in renal failure, or when allopurinol is started too soon after an acute attack
• Tophaceous gout
• Urate renal stone formation

Question 17

What are the investigations for gout

Answer 17

The clinical picture is often diagnostic, as is the rapid response to NSAIDs or colchicine.
• Joint fluid microscopy is the most specific and diagnostic test but is technical difficult.
• Serum uric acid is usually raised (>600 mol/L). If it is not, recheck it several weeks after the attack, as the level falls immediately after an acute attack. Acute gout rarely occurs with a serum uric acid in the lower half of the normal range below the saturation point of
360 Mmol/L.
• Serum urea, creatinine and eGFR are monitored for signs of renal impairment.

Question 18

How is gout treated

Answer 18

The use of NSAIDs or coxibs in high doses rapidly reduces the pain and swelling. The first dose should be taken at the first indication of an attack:
• Naproxen: 750 mg immediately, then 500 mg every
8-12 hours
•Diclofenac: 75-100 mg immediately, then 50 mg every
6-8 hours
• Indometacin: 75 mg immediately, then 50 mg every 6-8 hours. For some, the frequency of side-effects is unacceptably high with indometacin.

After 24-48 hours, reduced doses are given for a further week. Caution: NSAIDs may cause renal impairment. In individuals with renal impairment or a history of peptic ulceration, alternative treatments include:
• Colchicine: 1000 Mg immediately, then 500 Mg every
6-12 hours, but this causes diarrhea or colicky abdominal pain
• Corticosteroids: oral prednisolone or intramuscular or intra-articular depot methylprednisolone.

Question 19

What dietary advice would you give to a gout patient

Answer 19

The first attacks may be separated by up to 2 years and are managed symptomatically. Individuals should be advised to reduce their alcohol intake, especially beer, which is high in purines and fructose. Non-diet carbonated soft drinks are also high in fructose. A diet which reduces total calorie and cholesterol intake and avoids such foods as offal, some fish and shellfish and spinach, all of which are rich sources of purines, is advised. This can reduce serum urate by 15% and delay the need for drugs that reduce serum urate levels.
Dietary advice is readily available on the internet.

Question 20

What are some treatments with agents that reduce serum uric acid levels

Answer 20

The aim of treatment is to reduce the uric acid level below the 360 umol/L level; some guidelines recommend below 300 umol/L.
Allopurinol should only be used when the attacks are frequent and severe (despite dietary changes), associated with renal impairment or tophi, or when the patient finds NSAIDs or colchicine difficult to tolerate. Allopurinol (300-600 mg) blocks the enzyme xanthine oxidase, which converts xanthine into uric acid (see Fig. 16.20). It reduces serum uric acid levels rapidly and is relatively non-toxic but should be used at low doses (50-100 mg) in renal impairment. It should never be started within a month of an acute attack and always be started under cover of a course of NSAID or colchicine for the first 2-4 weeks before and 4 weeks after starting allopurinol, as it may induce acute gout. The dose can be increased gradually from 100 mg every few weeks until the uric acid level is below the 360 mol/L level. Skin rashes and gastrointestinal intolerance are the most common side-effects. A hypersensitivity reaction is the most serious adverse event. This is rare, as is bone marrow suppression.
Febuxostat (80-120 mg) is a non-purine analogue inhibitor of xanthine oxidase but not other enzymes in the purine and pyrimidine pathway. It is well tolerated and as effective as allopurinol in trials and is safer in renal impairment as it is metabolized in the liver and not renally excreted. It has been approved by the FDA and is helpful in patients who cannot tolerate allopurinol but there are anxieties that it may increase cardiovascular risks. At time of writing, most doctors advise trying allopurinol first unless there are strong contraindications to its use.
Pegloticase, a pegylated recombinant uricase given intra-venously, lowers urate levels dramatically but its place in therapy is unclear.
Uricosuric agents also lower the serum uric acid but their use is restricted throughout Europe by the very rare occurrence of serious hepatotoxicity. Benzbromarone acts on the URAT-1 transporter and is well tolerated. Sulphinpyrazone and probenecid are best avoided in renal impairment.

Losartan is an angiotensin I-receptor antagonist and is uricosuric in hypertensive patients with gout. It may reduce the risk of gout in patients with the metabolic syndrome.
Anakinra blocks IL-1B and canakinumab is a human monoclonal antibody with specific cross-reactivity for IL-1 B but not other members of the IL-1 family. Their role in treatment-resistant gout is still subject to trials to establish when their use is justified in gout which has not responded to the more conventional agents.

Question 21

What is pseudogout (pyrophosphate arthropathy)

Answer 21

Calcium pyrophosphate deposits in hyaline and fibrocartilage produce the radiological appearance of chondrocalcinosis (see p. 515). Shedding of crystals into a joint precipitates acute synovitis which resembles gout, except that it is more common in elderly women and usually affects the knee or wrist. The attacks are often very painful. In young people it may be associated with haemochromatosis, hyperparathy-roidism, Wilson’s disease or alkaptonuria.

Question 22

How is pseudogout diagnosed

Answer 22

The diagnosis is made by detecting rhomboidal, weakly positively birefringent crystals in joint fluid, or deduced from the presence of chondrocalcinosis on X-ray. The joint fluid looks purulent. Septic arthritis must be excluded and joint fluid should be sent for culture. The attacks may be associated with fever and a raised white blood cell count.

Question 23

How is pseudogout treated

Answer 23

Aspiration of the joint reduces the pain dramatically but it is usually necessary to use an NSAID or colchicine, as for gout.
If infection can be excluded, an intra-articular injection of a corticosteroid helps.

Question 24

What is septic arthritis

Answer 24

This is a serious complication with significant morbidity and mortality. In immunosuppressed patients, the affected joints may not be hot and inflamed with accompanying fever. There is usually a neutrophil leucocytosis. Any effusion, particularly of sudden onset, should be aspirated. Staphylococcus aureus is the most common organism. Blood cultures are often positive. Treatment is with systemic antibiotics and drainage.

Question 25

What is ankylosing spondylitis

Answer 25

This is an inflammatory disorder of the spine affecting mainly young adults (late teens to early 30s). It occurs worldwide, with a male to female ratio of 5:1. Women present later and are underdiagnosed. The frequency of AS in different populations is roughly paralleled by the incidence of HLA-B27; Africans and Japanese have a low incidence of both HLA-B27 and ankylosing spondylitis, while the North American Haida Indians have a high incidence of both.

Question 26

What is the pathogenesis of ankylosing spondylitis

Answer 26

Environmental factors may also be involved but although Gram-negative organisms, e.g. Yersinia, Klebsiella, Salmo-nella, Shigella, can cause a reactive arthropathy, there is no conclusive evidence for their involvement in the pathogenesis of AS. There is lymphocyte and plasma cell infiltration and local erosion of bone at the attachments of the intervertebral and other ligaments (enthesitis). This heals with new bone (syn-desmophyte) formation.

Question 27

What are some clinical features of ankylosing spondylitis

Answer 27

Episodic inflammation of the sacroiliac joints in the late teenage years or early 20 is the first manifestation of AS. Pain in one or both buttocks and low back pain and stiffness are typically worse in the morning and relieved by exercise. Initially the diagnosis is often missed because the patient is asymptomatic between episodes and radiological abnormali-ties are absent. Retention of the lumbar lordosis during spinal flexion is an early sign. Later, paraspinal muscle wasting develops. Criteria for classifying inflammatory back pain as ankylosing spondylitis are shown in Box 11.14. Spinal stiffness can be measured by Schober's test: a tape measure is placed in the midline 10 cm above the dimples of Venus. Any movement of a marker at 15 cm during flexion is recorded. A reading of <5 cm implies spinal stiffness. Indi-viduals may be able to touch the floor with a stiff back if they have good hip movements but serial measurement of the finger tip to floor distance highlights any change. •Non-spinal complications (uveitis or costochondritis) suggest the diagnosis of spondyloarthritis Costochondral junction inflammation causes anterior chest pain. Measurable reduction of chest expansion is due to costovertebral joint involvement. Peripheral joint involvement is asymmetrical and affects a few, predominantly large joints. Hip involvement leads to fixed flexion deformities of the hips and further deterioration of the posture. Young teenage boys occasionally present with a lower-limb monoarthritis (see p. 546), which later develops into AS. Acute anterior uveitis is strongly associated with HLA-B27 in AS and related diseases and is occasionally the presenting complaint. Severe eye pain, photophobia and blurred vision are an emergency (see p. 1062). Overall clinical assessment is based on pain, tenderness, stiffness and fatigue using, e.g. the Bath Ankylosing Spondylitis Disease Activity Index.

Question 28

What are some investigations for ankylosing spondylitis

Answer 28

Blood. The ESR and CRP are usually raised. HLA testing is rarely of value because of the high frequency of HLA-B27 in the population, but may give supporting evidence in a difficult case. • X-rays. The medial and lateral cortical margins of both sacroiliac joints lose definition owing to erosions and eventually become sclerotic (Fig. 11.20). The earliest radiological appearances in the spine are blurring of the upper or lower vertebral rims at the thoracolumbar junction (best seen on a lateral X-ray) caused by an enthesitis at the insertion of the intervertebral ligaments. These changes may eventually affect the whole spine. Persistent inflammatory enthesitis causes bony spurs (syndesmophytes). Syndesmophytes are more vertically oriented than the beak-like osteophvtes of spondylosis and the disc is preserved, unlike in spondylosis. Syndesmophytes cause bony ankylosis and permanent stiffening. The sacroiliac joints eventually fuse, as may the costovertebral joints, reducing chest expansion. Calcification of the intervertebral ligaments and fusion of the spinal facet joints and syndesmophytes leads to what is often called a 'bamboo' spine (Fig. 11.21). • MRI with gadolinium demonstrates sacroiliitis before it is seen on X-rays, and persistent enthesitis.

Question 29

What is the treatment of ankylosing spondylitis

Answer 29

• The key to effective management of AS is early diagnosis so that a regimen of preventative exercises is started before syndesmophytes have formed. Morning exercises aim to maintain spinal mobility, posture and chest expansion. Failure to control pain and to encourage regular spinal and chest exercises leads to an irreversible dorsal kyphosis and wasted paraspinal muscles. This, along with stiffening of the cervical spine, makes forward vision difficult. When the inflammation is active and the morning pain and stiffness are too severe to permit effective exercise, an evening dose of a long-acting or slow-release NSAID or an NSAID suppository improves sleep, pain control and exercise compliance. Peripheral arthritis and enthesitis are managed with NSAIDs or local steroid injections. • Methotrexate is effective for peripheral arthritis but not for spinal disease. • The TNF-& blocking drugs adalimumab and etanercept (Table 11.16) have revolutionized the lives of people with AS. They produce a rapid, dramatic and sustained reduction of symptoms and of spinal and peripheral joint inflammation. Around half the patients are able to stop NSAIDs. Relapse occurs on stopping therapy but may be delayed by several months making intermittent treatment feasible. Golimumab is also available for severe active disease unresponsive to conventional therapy. Rituximab does not help spondyloarthritis.

Question 30

What is the prognosis for ankylosing spondylitis

Answer 30

With exercise and pain relief, the prognosis is excellent and over 80% of patients are fully employed. Anti-TNF therapies are likely to reduce the morbidity of severe disease, reducing the risk of permanent spinal stiffness and progressive peripheral joint disease. Patients should be made aware that they risk passing the HLA-B27 gene to 50% of their children. HLA-B27 positive offspring then have a 30% risk of developing AS.

Question 31

What are some clinical features of psoriatic arthritis

Answer 31

• Mono- or oligoarthritis • Polyarthritis virtually indistinguishable from RA • Ankylosing spondylitis: uni- or bilateral sacroilitis and early cervical spine involvement; only 50% are HLA-B27 positive •Distal interphalangeal arthritis, which is the most typical pattern of joint involvement in psoriasis, often with adjacent nail dystrophy (see p. 1209) reflecting enthesitis extending into the nail root • Arthritis mutilans, which affects about 5% of patients who have psoriatic arthritis and causes marked periarticular osteolysis and bone shortening ('telescopic' fingers) (Fig. 11.22). Radiologically, psoriatic arthritis is erosive but the erosions are central in the joint, not juxta-articular, and produce a 'pencil in cup' appearance. The skin and nail disease can be mild and may develop after the arthritis.

Question 32

What is the treatment for ankylosing spondylitis

Answer 32

NSAIDs and/or analgesics help the pain but they can occasionally worsen the skin lesions. Local synovitis responds to intra-articular corticosteroid injections. In milder, polyarticular cases, sulfasalazine or methotrexate slows the development of joint damage. When the disease is severe, methotrexate or ciclosporin is given because they control both the skin lesions and the arthritis. Anti-TNF-o agents, e.g. etanercept and golimumab (see p. 1210) and ustekinumab, are highly effective and safe for severe skin and joint disease. They should be given when methotrexate has failed. Corticosteroids orally may destabilize the skin disease and are best avoided but are valuable when injected into a single inflamed joint. Rituximab has no role in treating psoriatic arthritis. The prognosis for the joint involvement is generally better than in RA.

Question 33

What is reactive arthritis

Answer 33

Reactive arthritis is a sterile synovitis, which occurs following an infection (see also post-streptococcal arthritis, p. 546). Spondyloarthritis develops in 1-2% of patients after an acute attack of dysentery, or a sexually acquired infection - nonspecific urethritis (NSU) in the male, nonspecific cervicitis in the female. In male patients who are HLA-B27 positive, the relative risk is 30-50. Not all patients are HLA-B27 positive. Women are less commonly affected.

Question 34

What is the etiology of reactive arthritis

Answer 34

A variety of organisms can be the trigger, including some strains of Salmonella or Shigella spp. in bacillary dysentery. Yersinia enterocolitica causes diarrhea and a reactive arth-ritis. In NSU, the organisms are Chlamydia trachomatis or Ureaplasma urealyticum. People with reactive arthritis are not more susceptible to infection but appear to respond differently. Bacterial antigens or bacterial DNA have been found in the inflamed synovium of affected joints, suggesting that this persistent antigenic material is driving the inflammatory process. The methods by which HLA-B27 increases susceptibility to reactive arthritis may include: • T cell receptor repertoire selection • Molecular mimicry causing autoimmunity against HLA-B27 and/or other self antigens • Mode of presentation of bacteria-derived peptides to T lymphocytes. These are not mutually exclusive. There are other organisms that also trigger reactive arthritis but have a different genetic basis; see post-streptococcal arthritis (p. 533), gonococcal arthritis (p. 546) and brucellosis (p. 533). In these, the borderline between reactive arthritis and septic arthritis is more indistinct and they can cause both.

Question 35

What are the clinical features of reactive arthritis

Answer 35

The arthritis is typically an acute, asymmetrical, lower-limb arthritis, occurring a few days to a couple of weeks after the infection. The arthritis may be the presenting complaint if the infection is mild or asymptomatic. Enthesitis is common, causing plantar fasciitis or Achilles tendon enthesitis (see p. 509). Seventy per cent recover fully within 6 months but many have a relapse. In susceptible individuals with reactive arthritis, sacroiliitis and spondylitis may also develop. Sterile conjunctivitis occurs in 30%. Acute anterior uveitis complicates more severe or relapsing disease but is not synchronous with the arthritis. The skin lesions resemble psoriasis: • Circinate balanitis in the uncircumcised male causes painless superficial ulceration of the glans penis. In the circumcised male the lesion is raised, red and scaly. Both heal without scarring. • Keratoderma blennorrhagica - the skin of the feet and hands develops painless, red and often confluent raised plaques and pustules histologically similar to pustular psoriasis. • Nail dystrophy occurs.

Question 36

What is the treatment for reactive arthritis

Answer 36

Treating persisting infection with antibiotics alters the course of the arthritis, once it has developed. Cultures should be taken and any infection treated. Sexual partners must be screened. Pain responds well to NSAIDs and locally injected or oral corticosteroids. The majority of individuals with reactive arthritis have a single attack which settles, but a few develop