1Arthritis of the Knee: Diagnosis and Management 1 1

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Summary

In this chapter,an algorithm for the diagnosis of a painful and swollen knee is presented. Arthritis of the knee can be restricted to a monoarticular clinical manifestation,or it may be part of an oligo- or polyarticular disease.A care- ful anamnesis and clinical examination will allow the clinician to classify the clinical presentation of arthritis of the knee into disease groups such as osteoarthritis, rheumatoid arthritis, spondyloarthropathy, or miscellaneous arthritic diseases. These disease entities are briefly discussed and their therapeutic approaches reviewed.

Finally,the case is made for a more routine use of synovial biopsies in daily clinical practice, for diagnosis and to evaluate targeted therapies.

Introduction

Appropriate treatment of arthritis of the knee starts with correct diagnosis of the underlying disease and identification of the causes of the condition.Therefore,in the first part of this chapter we propose a comprehensive and practical algorithm for dealing with “arthritis of the knee”, typically with signs and symptoms of pain, swelling, and loss of motion and function, separately or in combination. Subsequently, we discuss clinically important separate disease entities such as osteoarthritis, knee involvement in the major groups of chronic inflammatory arthritis – rheumatoid arthritis and the spondyloarthropathies –, and some miscellaneous forms of arthritis of the knee, perhaps less frequent but certainly clinically relevant, such as crystal-induced arthritis, septic arthritis, and Lyme disease. In these discussions we highlight the predominant clinical features and recent advances in therapeutic options.Special attention is given to the concept of spondyloarthropathies, since this has still apparently not entered the daily practice of many physi- cians. Finally, we discuss in more detail the synovium of the knee, as this is easily accessible and has received increased attention from rheumatologists. Indeed, through the study of synovial biopsies we have gained increasing insight into the pathophysiology of chronic arthritis.

1 Arthritis of the Knee:

Diagnosis and Management

F. P. Luyten, R. Westhovens, V. Taelman

Major advances in our understanding of the molecular basis of arthritic diseases has led to the development of new targeted therapies with a profound impact on the management of patients with rheumatoid arthritis and the spondyloarthropathies.

Algorithm for Diagnosis of the Arthritic Knee

When one is confronted with a patient who has a painful, swollen knee, a well-structured approach is helpful for forming a working hypothesis and ultimately critical for arriving at the most likely diagnosis.

The most important tool we have in a diagnostic workup is the clinical history, which must be as complete as possible.A patient can say what brings him to your office,but in most cases precise and well-directed questions are needed to obtain critical information. Taking a complete history is a demanding task, but a lot of circumstantial evidence can evolve from a full history of the current problem, past medical conditions, and the family history.

The nature of the pain belongs to “the basics”, whether it be mechanical, inflammatory, neuropathic, or poorly defined. Mechanical pain occurs when the joint is used: walking becomes difficult, and especially climbing stairs causes problems.On resting,there is less pain.Start- ing pain and stiffness are very characteristic of a more advanced mechanical pain pattern.

Inflammatory pain typically presents at night. More specifically, the second part of the night is troublesome, and patients need to get out of bed and move. They experience morning stiffness for at least 1 h, and this stiffness diminishes progressively as the patient begins to move.

When pain is neuropathic in origin, a typical distrib- ution pattern corresponding to the innervation is found.

Psychosomatic pain has no typical presentation or distribution.Complaints are always more impressive than the clinical findings.

Additional questions can help the clinician to identi- fy the problem as acute/subacute or a chronic arthritis.

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How long has the knee problem existed? When pain and swelling have been present for less than 6 weeks,the problem is acute. Beyond 6 weeks' duration, the term chronic is used and implies that spontaneous healing of the arthritis is unlikely. How acutely did the problem occur?

Suddenly, as seen in trauma, within hours, which is more likely in septic and crystal-induced arthritis, or over days or weeks, as in rheumatoid arthritis?

Ask the patient whether this is the first time he has ex- perienced arthritis of the knee or if he has had knee or other joint problems in the past. This may provide hints as to whether it is a problem in a single joint or an oligo/

polyarticular disease.

It is also important to look for circumstantial evidence.Did trauma occur just before the knee swelling be- gan? Did the patient have an episode of fever? Did the patient experience an infection such as angina, gastro- enteritis, or urethritis? Does the patient have other clinical conditions that could be linked to the knee arthritis, such as skin problems (psoriasis, erythema nodosum), chronic diarrhoa as seen in inflammatory bowel disease, eye problems such as uveitis or scleritis? In this setting a complete familial history can also add useful information.

Thereafter, a clinical workup including a complete joint assessment and a full clinical examination, evaluat- ing all the peripheral joints and the axial skeleton, can provide further clues to the diagnosis and help to local- ize the problem to the joint, periarticular structures, or muscle. It is not always trivial to distinguish a synovitis from joint pain by intra-articular swelling, the distinction being crucial for the diagnosis. For instance, a diagnosis of rheumatoid arthritis requires a (poly)synovitis; inflammatory polyarthralgia is not sufficient.

When the knee is swollen and the presence of intra- articular joint fluid is suspected, arthrocentesis should be performed. The results of the white blood cell count and cell differentiation, Gram staining, bacterial culture, and detection of crystals of urate or pyrophosphate are diagnostic in case of infectious arthritis, gout, or pseudo-gout. The white blood cell count in the synovial fluid differentiates between a non-inflammatory problem (<2000 WBC/mm³), an inflammatory picture (2000–20 000 WBC/mm³), a strongly inflammatory picture such as in crystal arthritis (20 000–50 000), and a most prob- able septic arthritis (WBC >50 000 with >75% PMN).

Finally, it is important to establish whether the knee problem is a genuine monoarthritis or rather one where multiple joints are involved. The latter is classified as oligoarthritis when fewer than five joints are involved, or as polyarthritis when five or more joints are inflamed. In addition, assessments of symmetrical or asymmetrical joint involvement are performed.

A few typical clinical entities, most frequent in daily clinical practice, are briefly presented.

Monoarthritis, Mechanical in Origin

Once the knee pain is recognized as mechanical,the most likely diagnosis in the older patient is osteoarthritis with or without a meniscal or ligamentous pathology. Further investigations can be limited to standard weight-bearing X-rays.

In younger people, mechanical pain will more likely be associated with a meniscal or chondral/osteochondral problem or defect. Further investigations include MRI, CT-arthrography, and arthroscopy.

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⊡Fig. 1-1. Algorithm flow chart for the patient presenting with a painful and swollen knee

Painful and swollen knee

Trauma?

Mechanical?

No Yes

Referral to specialist Monoarthritis?

Oligo/Polyarticular Joint aspiration

Infectious RA, SpA ...

Crystal-induced Inﬂammatory

Description of traumatic event

Clinical examination

Joint aspiration

Suspected Diagnosis

Arthroscopy MRI X-rays Additional Anamnesis

+ Clin. Examination

X-rays Joint aspiration

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Acute Inflammatory Monoarthritis of the Knee

With inflammatory knee pain and swelling the differential diagnosis is far more complex.Acute monoarthritis of the knee is infectious until proven otherwise. Previous arthrocentesis, skin wounds, typically on lower leg regions or the feet, should be asked about and looked for.

Fever is not always present, certainly not in the immuno- compromised patient. Arthrocentesis is mandatory for bacterial examination and culture.Gram staining and the white blood cell count can be quickly obtained and are mostly sufficient to begin antibiotic treatment. Arthro- scopic lavage and intravenous antibiotic treatment must be started as soon as possible.

In older patients, a crystal-induced arthritis such as gout or pseudogout is the most likely explanation for acute monoarthritis of the knee. Again, arthrocentesis is the key to the correct diagnosis, demonstrating the presence of urate or pyrophosphate crystals.

Chronic Monoarthritis of the Knee

Monoarthritis of the knee is often a presenting feature of spondyloarthropathy.This group of diseases is marked by inflammatory back pain, asymmetrical synovitis of peripheral joints, and enthesopathy (see “Spondyloarthro- pathies”,below).Again,the importance of a complete history for detecting related conditions of the skin, eyes, or bowels should be stressed.

Less frequently, chronic monoarthritis of the knee is the result of a low-grade infection (Mycobacteria), sar- coidosis, Lyme disease, villonodular synovitis, or algody- strophy.

Chronic Polyarthritis, with Knee Arthritis as First Symptom

On clinical examination, so-called monoarthritis often turns out to be polyarthritis. This can be the onset of spondyloarthropathy. Monoarthritis of the knee as the presenting manifestation of rheumatoid arthritis is less common; more typically, rheumatoid arthritis shows a picture of symmetrical polyarthritis, including smaller joints of the hands and feet. In this setting, a blood examination with biochemical testing for inflammatory parameters and rheumatoid factor is helpful.

Osteoarthritis of the Knee

The clinical history and examination typically reveal a chronic noninflammatory, mono- or oligoarticular pre-

sentation (both knees, hands) in middle-aged and older individuals. The signs and symptoms are usually local and restricted to one or both knees, sometimes associated with hand OA or more generalized OA. Pain is by far the predominant symptom, relieved by rest and without night pain or morning stiffness, but, especially in more advanced disease, there is pronounced pain at the beginning of movement. It is still unclear what causes the pain in OA. Most probably it is caused not by the cartilage, as this tissue has no nerve supply, but rather by the subchondral bone and other intra- and periarticular structures such as synovium, menisci, and ligaments. Acute flares with an inflammatory component and swelling of the joint may occur, frequently caused by crystals, which may indicate the possible association with calcium pyrophosphate crystal arthritis (CPPD).

The clinical examination reveals pain on passive and active motion, together with local tenderness, and crepi- tus in the more advanced stages. Joint swelling can be seen and may be the result of hydrops, synovitis, and osteophytosis or bone remodeling. Muscle atrophy, typically of the quadriceps, is secondary to disuse in the more advanced cases or in patients with more chronic synovitis,and is an additional reason to look for crystal-induced arthritis.Advanced loss of articular cartilage in one compartment, predominantly the medial one, will be associated with secondary axis deviations such as genu vara or valga. Retropatellar OA can be presented as a single com- partmental involvement,particularly in younger patients, evolving in some cases from the so-called chondromala- cia patellae.In these cases,the pain is localized around the patella and is typically aggravated by climbing stairs.

The diagnosis of OA is confirmed by radiographic imaging.For diagnostic purposes,since OA involves three compartments,anteroposterior,mediolateral,and skyline views are recommended. X-ray findings typically show joint space narrowing (JSN), subchondral bone sclerosis, and osteophytosis. The subchondral bone reaction, and especially osteophytosis, appears most often earlier than JSN. However, JSN is more significant and sensitive to change. In some cases of knee OA, JSN is more striking and can be present without any osteophytosis. Most importantly, there is a poor correlation between clinical symptoms, clinical outcome, and X-ray changes. It is impossible to predict the outcome of knee OA in individual patients based on radiographic appearance alone.

Laboratory findings are usually normal, although sometimes a slight elevation of C-reactive protein and some elevation of the erythrocyte sedimentation rate can be seen, especially in patients with more generalized OA, with combined erosive osteoarthritis of the hands or in patients with associated crystal arthropathy. Synovial fluid reveals minimal abnormalities, with a cell count usually below 2000 cells/mm³. Calcium pyrophosphate or apatite crystals are seen quite frequently. Scintigra-

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phy is of little or no use in the diagnosis.Despite the advances that have been made in the development of sensitive assays, serological markers for diagnostic or prognostic purposes remain investigational.

Newer imaging modalities such as computed tomo- graphy (CT) and magnetic resonance imaging (MRI) provide additional insight into the degree or nature of damage to the cartilage, subchondral bone, and soft tissues.

MRI shows great promise for detecting early changes in OA, especially with regard to the articular cartilage soft- tissue involvement and bone narrow abnormalities.

Treatment modalities have recently been presented and discussed, and this has resulted in recommendations and guidelines proposed by both the American College for Rheumatology [1] and the European League Against Rheumatism [2]. The treatment algorithm in- cludes nonmedical approaches, with education, weight loss, and restoring muscle strength as the most critical parameters. The medical approach focuses mainly on treating pain, the major symptom of OA, and on pain- relieving drugs. Paracetamol preparations in doses of up to 4× 1 g/day remain the first-line treatment for mild and moderate gonarthritis. The addition of non- steroidal anti-inflammatory drugs (NSAIDs) is recommended when insufficient pain relief is achieved with proper doses of analgesics alone. Topical anti-inflammatory treatments appear reasonably efficacious and should be tried. The place in the treatment algorithm of nutritional supplements such as glucosamine and chondroitin sulfate is still not clear. The position of intra-articular treatments with corticosteroids and hyaluronic acid remains controversial, and it is clear that we lack convincing predictors of response to iden- tify those patients likely to benefit from these treatments.

Surgical treatments include tissue-repair approaches, arthroscopic lavage and débridement, osteotomy, and unicompartmental and total knee replacement. There is little or no evidence that surgical reconstruction of torn cruciate ligaments or the meniscus prevents the development of knee OA. It remains to be seen whether cartilage repair procedures prevent or slow down knee OA. The combination of tissue repair, such as the repair of cartilage defects, with an osteotomy, performed on the right patient and by a trained surgeon, may delay the need for knee replacement and will most likely benefit the younger patient population (below 50 years). Indeed, OA in the young and active population remains a largely unsolved problem. Developments of new structure-modifying drugs together with tissue-engineering approaches are the hope for the near future.

Knee Involvement in Rheumatoid Arthritis

In rheumatoid arthritis (RA), knee arthritis is frequently just one component of symmetrical polyarthritis. Espe- cially when the symmetrical polyarthritis of small joints of the hands and feet is mild and/or overlooked in the clinical examination, a late diagnosis can lead to considerable damage from this disease.

Signs and Symptoms

The classical presentation of RA is that of a gradually de- veloping symmetrical polyarthritis of the hands and feet, with a peak incidence in women in their fourth and fifth decades of life. Although we know a good deal about the epidemiology and immunologic and genetic aspects of RA, it is still unclear what initiates and perpetuates the process. At present, RA is still best described and depict- ed by the 1987 revised classification criteria of the Amer- ican Rheumatism Association [3] (⊡ Table 1-1).

It must be remembered that RA not only involves joints and tendon sheets, but is also a systemic disease affecting the body as a whole (fatigue, extra-articular features such as nodules, serositis, vasculitis, anemia, interstitial lung disease). It has a major impact on every patient’s physical and psychosocial life.

Involvement of the knee in RA is common and usually obvious. Minor inflammation in the knees should not be overlooked. Examination of the “bulge” sign and loss of the “cool patella” sign can contribute to an adequate diagnosis.When the knee synovitis is important,a Baker’s cyst is a frequent finding. Ruptures of Baker’s cysts can mimic acute thrombophlebitis.

Joint Damage and Destruction

Early disease is not synonymous with mild disease. Al- though it is still unpredictable whether patients with early disease will eventually develop a malignant rheumatoid course,a number of prognostic factors should be looked for:

▬ High persisting disease activity and early joint damage – Persistently elevated levels of CRP and ESR – Uncontrolled persisting polyarthritis

– Early X-ray damage (joint erosion and JSN) and joint deformity

– Functional disability (as measured by the HAQ – health assessment questionnaire)

▬ Extra-articular features as RA nodules, vasculitis

▬ Rheumatoid factor positivity,especially at high levels, CCP positivity (antibodies to cyclic citrullinated pep- tides)

▬ Psychosocial problems, low level of education

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Persisting disease activity is associated with increased mortality.

Joint damage occurring within the first year of disease activity is assessed by standard X-rays.X-rays of the hands and feet show early periarticular osteoporosis; at the later stage joint erosions and JSN can be seen, followed by the presence of joint subluxation or even dislocation. Joint damage in the hands, and even earlier damage detectable in the feet, is correlated with involvement of other joints and with general disease severity and shows continuous progression without appropriate treatment. Standard X- rays of the knee do not contribute to the early diagnosis of RA. Ultrasound techniques can reveal joint effusion, synovial hypertrophy, and vascularity. MRI techniques addi- tionally reveal aspecific bony edema in early disease.These examinations contribute little,however,when an adequate clinical examination is performed.

Eventually, destruction of the knee by RA will lead to functional disability. The loss of cartilage and the presence of ligament laxity at the level of the collateral and cruciate ligaments further contribute to difficulties in walking and climbing stairs.

A classical valgus deformity is the late outcome of RA knee arthritis, marked by posterior subluxation of the tibia,resulting in a fixed flexion contracture of the knee.

Treatment

Comprehensive management of RA involves pharma- cological but also a variety of nonpharmacological in- terventions to improve and maintain function, such as patient education, physical therapy, surgery, and occu- pational therapy. Early disease control is mandatory, as

there seems to be a window of opportunity to prevent joint damage. Therefore, the classical therapeutic pyra- mid is reversed with early use of so-called disease-modifying antirheumatic drugs (DMARDs) such as methotrexate and sulfasalazine. A fast control of inflammation, even using temporary oral steroids, is of benefit.

The study of the etiopathogenesis of the disease has provided insights into the immunological reactions between the antigen-presenting cells and the T and B lymphocytes, as well as into the cytokine imbalance resulting from this disease process. This has led to the development of new targeted treatments such as blocking antibodies or soluble receptors of TNFα. These novel treatments appear to exert a more profound disease control in patients refractory to standard DMARDs, and the data even suggest an arrest in joint tissue damage. The use of these powerful but expensive treatment options in early disease should be carefully weighed, also in view of the still unknown possible long- term side effects.

Involvement of the Knee in Spondyloarthropathy

In spondyloarthropathy, knee arthritis can present as acute inflammatory monoarthritis, as chronic inflammatory monoarthritis, or as a first sign of chronic inflammatory oligo- or polyarthritis.The spondyloarthropathies [4,5] comprise a number of related diseases with common clinical, radiological, biological, genetic, and therapeutic features and include the following entities:

▬ 1. Ankylosing spondylitis (AS)

▬ 2. Reactive arthritis

⊡ Table 1-1.American Rheumatism Association revised criteria for the classification of rheumatoid arthritis

Criteria Definition

1. Morning stiffness Morning stiffness in and around the joints, lasting at least 1 h before maximal improvement

2. Arthritis of three or more joint areas At least three joint areas (out of 14 possible areas; right or left PIP, MCP, wrist, elbow, knee, ankle, MTP joints) simultaneously have had soft-tissue swelling or fluid (not bony overgrowth alone) as observed by a physician

3. Arthritis of hand joints At least one area swollen (as defined above) in a wrist, MCP or PIP joint

4. Symmetrical arthritis Simultaneous involvement of the same joint areas (as defined in 2) on both sides of the body (bilateral involvement of PIPs, MCPs, or MTPs without absolute symmetry is acceptable)

5. Rheumatoid nodules Subcutaneous nodules over bony prominences or extensor surfaces, or in juxta-articular regions as observed by a physician

6. Serum rheumatoid factor Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in less than 5% of normal control subjects

7. Radiographic changes Radiographic changes typical of rheumatoid 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)

a For classification purposes, a patient has RA if at least four of these criteria are satisfied (criteria 1–4 must have been present for at least 6 weeks)

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▬ 3. Psoriatic arthritis

▬ 4. Idiopathic acute anterior uveitis

▬ 5. Inflammatory bowel disease-related arthritis

▬ 6. Undifferentiated spondyloarthropathy

▬ 7. Late-onset pauciarticular juvenile chronic arthritis

The characteristics of spondyloarthropathies (SpA) are listed in ⊡ Table 1-2.

Characteristics of Spondyloarthropathies

According to the respective clinical diagnosis (see above),inflammatory knee involvement in SpA can present in different ways, usually as part of oligoarthritis, less frequently as monoarthritis or as part of an asymmetrical polyarthritis.

Oligoarthritis is seen in undifferentiated spondy- loarthropathy, psoriatic arthritis, inflammatory bowel disease (IBD)-associated arthritis, late-onset pauciarticular juvenile arthritis, and, to a lesser extent, in AS and reactive arthritis. Peripheral arthritis is a key feature in these SpA and is generally asymmetrical, nonerosive,

and self-resolving. It involves the large weight-bearing joints of the lower limbs, most frequently the knees and ankles. Knee monoarthritis may be the presenting feature. Some patients develop a chronic erosive mono- or oligoarthritis. In psoriatic arthritis, the asymmetrical oligoarthritis subtype is the most prevalent and affects predominantly the joints of the lower limbs. This implies that the knee is often affected. In 2%–20% of patients with IBD,peripheral joint involvement is present and can fluctuate with the activity of the bowel inflammation. A monoarticular presentation is found in reactive arthritis and AS. AS has predominantly axial involvement, but 25% of patients with AS also develop peripheral arthritis. The hip and shoulder are frequently involved, and, to a lesser extent,knee involvement is seen in these patients.

Knee arthritis as a first symptom of polyarthritis is seen in psoriatic arthritis and in IBD-related SpA.

Knee pain in patients with SpA must be differentiated from knee arthritis with or without synovitis and enthesitis at the insertions of the patellar ligament on the patellar apex and the tubercle of the tibia. In patients with late-onset pauciarticular juvenile chronic arthritis, enthesitis of the tuberositas tibiae is seen as the presenting sign in about 10% of patients. Although in SpA cal- caneal enthesitis is the most frequent enthesopathy, enthesitis of the patellar ligament and the quadriceps in- sertion can be present as well.

The enthesitis frequently causes pain but can be asymp- tomatic as well. Soft-tissue swelling is sometimes present and can be shown by ultrasound (US), conventional radi- ography, and MRI. Enthesitis of the patellar ligament is often mistaken for osteonecrosis or traction apophysitis (Os- good-Schlatter and Sinding-Larsen disease).Enthesitis can be differentiated by ultrasound from bursitis,which is om- nipresent in the vicinity of enthesis as well.

1 ^⊡^{Table 1-2.}Characteristics of spondyloarthropathies 1. Absence of rheumatoid factor and rheumatoid nodules 2. Inflammatory peripheral arthritis

3. Spinal inflammation: inflammatory back pain, sacroiliitis with or without spondylitis

4. Inflammatory enthesopathy

5. Clinical overlap between the different clinical entities of the group 6. Familial aggregation

7. Association with HLA B27

⊡ Table 1-3. Differences in characteristics of peripheral arthritis in SpA and in RA

Characteristics Peripheral arthritis in SpA Rheumatoid arthritis

Age Younger (av 30 years) Older (av 50 years)

Sex predominance No Female

Onset Abrupt Gradual

Behavior Migratory Nonmigratory

Affected joints Mono- to pauciarticular Polyarticular

Asymmetrical Symmetrical

Lower limbs Hands and feet >hip and knees

Course Non deforming Deforming

Enthesitis Often No

Rheumatoid factor Absent Present

Radiology No erosions Erosive

Prior symptoms Urogenital or enterogenic infection None

Extra-articular manifestations Psoriasis Rheumatoid nodules

Bowel inflammation Vasculitis

Urethritis Uveitis

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Imaging.MRI and US can be of value in diagnosing SpA, especially in cases where peripheral arthritis is the only clinical manifestation. Knee synovitis in SpA differs from that in RA due to the involvement of adjacent enthesopathy [6]. MRI detects both perienthesial fluid or edema and bone marrow edema at the enthesial insertions in the knees of spondyloarthropathy patients, while the latter is absent in the knees of RA patients. US demonstrates the relationship between enthesial abnormalities and bone edema at the cortex–enthesis interface. A recent study suggests that enthesitis of the adjacent entheses is always present in peripheral synovitis of spondyloarthropathy in contrast to its absence in RA, an observation which has important implications for diagnosis.

Differential Diagnosis.Other arthritides such as RA need to be excluded. The main differences between peripheral arthritis in SpA and RA are listed in ⊡ Table 1-3.

Differences in Characteristics Between Peripheral Arthritis in SpA and RA

Young patients with a swollen knee in the absence of trauma must be suspected of having a spondyloarthropathy. The possibility of spondyloarthropathy must be considered if, in addition to the knee arthritis, certain particular symptoms are present. The clinical characteristics of these associated symptoms must be evaluated, e.g., synovitis of other joints, dactylitis (sausage toe or finger), inflammatory axial disease, and extra-articular manifestations such as uveitis or con- junctivitis, urethritis or cervicitis, bowel inflammation, skin lesions such as psoriasis, and endocarditis. The patient must be repeatedly interviewed for family history of SpA and episodes of urogenital and enterogenic infection prior to the arthritis.

Detailed characteristics of the symptoms reported by the patients are in most cases sufficient to strongly suggest the diagnosis. If not, two additional investigations can be helpful: testing for HLA-B27 and pelvic radiographs.

The final diagnosis is made on the basis of concor- dance of the clinical manifestations and the physician’s personal experience in the field. There are no diagnostic criteria available, but the available classification criteria can be used to examine the specific manifestations. If these criteria are fulfilled the diagnosis can be made, but even if a patient does not fulfill the classification criteria, he can still suffer from an incomplete or unusual form of spondyloarthropathy.

Treatment of Knee Arthritis in SpA

Suitable rest is advisable for patients with arthritis of the weight-bearing joints. The further therapeutic approach is decided depending on the clinical presentation such as an nonarthritis, or of the knee arthritis is part of an oligo- or polyarticular disease.

Acute monoarthritis is treated with NSAIDs for 6 weeks. If the first-line treatment fails, other therapeutic options are introduced. The indications for NSAID use are pain and morning stiffness. No controlled data are available regarding the efficacy of NSAID treatment in peripheral arthritis in SpA,but in clinical practice it appears that NSAIDs can be efficacious, especially in reactive arthritis. Patients should be treated for 6 weeks at the optimal dose. The use of NSAIDs is less desirable, and in some cases contraindicated, if concomitant IBD is present.

A single intra-articular injection of corticosteroids in spondyloarthropathy patients with monoarthritis may have a beneficial effect and last for some time.Such an injection can be repeated at a maximum frequency of 3–4 injections in the same joint during a 1-year period.

Physiotherapy is helpful in maintaining the function of the affected joint. Mobilization exercises and strength- ening of the quadriceps without weight-bearing are useful. However, physiotherapy appears to have no effect on the inflammatory process.

If monoarthritis persists, or knee involvement is part of chronic oligo- or polyarticular disease, disease-modi- fying antirheumatic drug (DMARD) therapy is started.

Sulfasalazine and methotrexate are frequently used as DMARDs in SpA.

Sulfasalazine is the only “second-line” drug with proven efficacy in prospective controlled trials for the treatment of peripheral arthritis in SpA. It is considered a safe and well-tolerated treatment for persistent, chronic peripheral synovitis in SpA. The effect is greater when it is started at an early stage of the disease than in patients with already existing joint deformities. Incremental dosages starting at 0.5 g twice daily and increasing to 1.5 g twice daily are used. The clinical effect must be evaluated at 3 months.Although sulfasalazine has a good safety pro- file, biochemical evaluation of liver enzymes and white cell blood counts must be performed on a regular basis.

Sperm count can be reduced in men but is particularly a problem in men with pre-existing fertility problems.

However, sulfasalazine is a safe drug for women contem- plating pregnancy.

In daily practice,methotrexate is used on a regular basis in SpA, in analogy to its use in RA. Methothrexate is started at a weekly dose of 10–15 mg on a fixed day in combination with folic acid 1 mg OD. No placebo-controlled data are available, however, addressing the efficacy of methotrexate in peripheral spondyloarthropathy.

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Pamidronate and thalidomide have shown some efficacy in open studies for AS patients with refractory disease.Although designed for refractory spinal disease, patients with concomitant peripheral arthritis also experience a beneficial effect in the peripheral joints.

Recent advances in biological therapies with cytokine-blocking strategies are promising. TNFα blockade is efficacious in the treatment of axial disease in AS and peripheral synovitis, and in patients with psoriatic arthritis. In open studies TNFα blockade also showed a beneficial effect on the peripheral manifestations of SpA and on the articular manifestations of Crohn’s disease.

Finally, arthroscopic lavage can be of use in chronic monoarthritis for individual patients,but it’s effect is usually only temporary.

Crystal-induced Arthritis

The clinical presentation of crystal-induced arthritis is predominantly acute inflammatory monoarthritis, or re- current episodes of inflammatory mono- or oligoarthritis. Crystal arthritis comprises a group of acute and chronic arthritides caused by the deposition of different types of crystals in the joint tissues. Monosodium urate crystals in gout and calcium pyrophosphate dihydrate (CPPD) crystals in pseudogout are the clinically most frequent crystal deposition diseases. Correct diagnosis is made by the identification of crystals in the synovial fluid.Pain relief during the acute event and prevention of re- current attacks is the goal of the treatment.

Gout occurs as a result of hyperuricemia, although asymptomatic hyperuricemia is common. In early stages of gout, the clinical manifestation is an acute attack of inflammatory monoarthritis in the MTP joint, but the knee is also frequently involved. Subsequent attacks can occur more frequently, and may become oligo- to polyarticular and persist longer. Radiographic features are soft-tissue swelling, the presence of tophi (soft-tissue densities which occasionally are calcified) and bony erosions (punched-out lesions) with sclerotic margins and over- hanging edges. In contrast to other inflammatory arthritides, the joint space is preserved. NSAIDs and colchicine are effective in the treatment of gout. Drugs that alter serum acid levels (allopurinol, probenecid) should be started after more than two or three attacks have oc- curred, not at the time of the acute attack, but once started they should never be stopped.

Pseudogout is an acute inflammatory crystal mono- or oligoarthritis, and frequently seen with chondrocalcinosis, a radiographic diagnosis associated with deposition of CPPD in cartilage. The release of CPPD crystals in the joint space causes the inflammation, and diagnosis is made by polarized light microscopy of the joint fluid, identifying weakly positively birefringent blunt or square

crystals. NSAIDs are preferentially used as treatment. In some cases,differentiating CPPD disease and other forms of polyarthritis, such as RA, can be difficult. Some patients display a pseudo-rheumatoid pattern, with involvement of multiple joints, particularly the knees, wrists,and elbows.Lack of erosions,low RF titers,and the presence of synovial fluid crystals help to establish the correct diagnosis.

Crystals are also commonly found in osteoarthritis of the knee. Distinguishing osteoarthritis from CPPD arthritis is therefore not always easy, but this is usually of little consequence, as there are no “dramatic” therapeutic implications. In primary OA, the medial compartment is more involved, while the pseudo-osteoarthritis caused by CPPD deposition is more in the lateral compartment.

Radiographs typically show chondrocalcinosis in the latter case.

Miscellaneous Forms of Arthritis of the Knee Infectious Arthritis

Infectious arthritis presents typically as an (sub)acute inflammatory monoarthritic disease. Up to 90% of infectious arthritis cases present as monoarthritis. The only exception is gonococcal arthritis, which presents more commonly as a migratory polyarthritis. If the condition is unrecognized, joint destruction will occur rapidly.

In any acute joint disease, infection must be suspected. However, infectious arthritis is an uncommon condition; the incidence in the developed world is estimated to be about six cases per 100 000 per year [7].The knee is indeed the most commonly involved joint. The pathogenic process starts when the synovium or the synovial fluid becomes a culture medium for bacteria. Usually, the mi- croorganisms reach the joint via bacteremia, although spreading from adjacent tissues or direct inoculation through the skin also occurs.Whether a clinically relevant infection develops depends on the virulence of the in- fecting organism, the size of the bacterial inoculum, and the resistance of the host. The most likely causative or- ganism is Staphylococcus aureus, but many other organ- isms have been isolated from septic joints, including streptococci and Enterobacteriaceae.Age-specific organ- isms are Haemophilus influenzae type b in children and Neisseria gonorrhoeae in adults. Rare pathogens such as fungi are more often found in case of immunodeficiency, the presence of penetrating wounds, or intravenous sub- stance abuse. Most patients suffer from an underlying medical condition such as diabetes mellitus, or an underlying joint condition such as RA.

Fever is common but can be absent. The only defini- tive diagnostic test is the demonstration of bacteria in the

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synovial fluid or in the synovium, or recovery of bacteria from a synovial fluid/synovium biopsy culture. When a joint is suspected of being infected,arthrocentesis should be performed prior to the initiation of any antimicrobial therapy. This procedure is not yet sufficiently practiced.

The fluid should be subjected to a cell count, Gram staining, and culture, preferably in blood culture medium. A count of more than 50 000 cells/mm³,of which more than 90% are polymorphonuclear leukocytes,makes infection highly likely.

Treatment requires both adequate drainage of pu- rulent joint fluid and appropriate antimicrobial therapy.

Following aspiration of the joint, and after blood, oral, and genital swabs have been obtained for culture, an- tibiotics should be administered on an “educated/best- guess” basis, considering the patient's age and history and the results of the Gram stain. The choice and the appropriate dosage should be adjusted when an etiologi- cal agent is identified and its antibiotic sensitivity is de- termined. There is no need to inject antimicrobials into the joint. Irrigation of the joint is recommended to evac- uate bacterial products and debris associated with infection. The optimal duration of treatment is controversial, as is the route of administration of the antibiotic drug. An empirical period of 4–6 weeks of intravenous antibiotic treatment is commonly suggested. In case of gonococcal arthritis, treatment for 7 days is believed to be sufficient.

Lyme Arthritis

Arthritis in Lyme disease can present as chronic inflammatory monoarthritis or as migratory polyarthritis.

Lyme arthritis is one of many possible features of Lyme disease (LD), a complex multisystem and infectious disease, resulting from infection with species of the spiro- chete Borrelia burgdorferi sensu latu, which is spread in Europe by the bite of infected Ixodes ricinus ticks [8]

(in North America by Ixodes scapularis). LD occurs in endemic pockets with an incidence of 50–300 cases per 100 000 per year. Lyme manifestations can be grouped in three stages: an early localized stage in which a pathog- nomonic skin feature,erythema migrans,usually occurs;

an early disseminated stage in which spirochetemia causes seeding of many organs, which leads to a wide spectrum of clinical manifestations; and the late disseminated stage when mainly neurological and muscu- loskeletal symptoms are reported. Clinical presentation of LD in the later stages is not uncommon. Of the un- treated patients, 50% develop migratory polyarthritis, while 10% develop chronic, intermittent monoarthritis, usually of the knee, characterized by large inflammato- ry articular effusions.The diagnosis is based on the char- acteristic clinical findings and a history of exposure in an

area where LD is endemic, and it can be confirmed by serological testing (ELISA).A positive result of the ELISA test should be confirmed by Western blot. Borrelia burgdorferi can be detected in joint fluid or synovial tis- sue by polymerase chain reaction. LD is usually cured by antibiotic treatment at any stage of the disease. Treat- ment is easier and more successful the earlier it is given.

In the case of Lyme arthritis, either oral or intravenous regimens are usually effective. If accompanying neu- roborreliosis is suspected, intravenous regimens are in- dicated.

Pigmented Villonodular Synovitis/Synovial Chondromatosis

Pigmented villonodular synovitis (PVNS) and synovial chondromatosis are two types of proliferative disorders affecting the synovial lining of joints. The clinical presentation is typically chronic inflammatory monoarthritis. In PVNS, histology is characterized by hypercellular synovial connective tissue containing hemosiderin-laden macrophages. In synovial chondromatosis the synovial mesenchymal cells mature into chondroblasts that form nodules of cartilage.Both conditions are uncommon.The incidence of PVNS is estimated to be approximately 1.8/1 million. The presentation is usually monoarticular, affecting mainly the knee.All age groups can be affected, although PVNS occurs more frequently in young adults, whereas the average age of synovial chondromatosis is in the fifth decade of life.In both conditions patients present with slowly progressive joint pain and swelling. Plain radiographic investigation often shows only increased soft-tissue density. MRI usually demonstrates key diagnostic features.The diagnosis is confirmed by biopsy,and the treatment of choice is synovectomy [9].

The Knee and the Study of the Synovium: From Research to Clinical Practice

The knee synovium is easily accessible and has provided an excellent tool for diagnosis, but most importantly for studying the pathogenesis of the disease processes. It is anticipated that synovial biopsies will also be routinely used in evaluating treatment response.

The classical clinical indication for taking a synovial biopsy is chronic (>6 weeks) nontraumatic inflammatory (synovial fluid WBC count >2000 cells/mm³) arthritis limited to one or two joints in which the diagnosis remains unclear after an appropriate noninvasive diagnostic workup, including synovial fluid analysis with culture for fungi and mycobacteria.There has never been much discussion about the usefulness of synovial biopsies for the diagnosis of atyp-

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ical chronic infections (e.g., fungi, mycobacteria), plant- thorn and other foreign-body synovitis,all kinds of synovial tumors, chronic sarcoidosis, and some infiltrative and deposition diseases (e.g., amyloidosis, hemochromatosis).

Although the synovium is also an important target tissue of RA and the SpA, the examination of synovial biopsies for clinical reasons has never been popular in these prototypical chronic arthritides, probably because their diagnosis does not depend so much on histology.

Given the fact that it is impossible to obtain access to the target tissue without an invasive procedure, most of our knowledge of synovial histology in chronic arthritis has come from postmortem studies or from studies of synovial biopsies taken during curative orthopedic procedures in end-stage disease. The popularity of synovial biopsies for differential diagnosis in chronic arthritis has suffered greatly from the lack of disease-specific light- microscopic characteristics at this late stage of the disease, and this for a very long time [10].

The introduction of arthroscopy, and particularly of the minimally invasive needle arthroscopy technique under local anesthesia, has made it possible to take synovial biopsy samples at every stage of the disease, and even repetitively, in an office-based setting. This evolution has led to a renewed interest in the synovium. Since the beginning of the 1990s, numerous studies based on the analysis of synovial biopsies obtained by needle arthroscopy have provided better insight into the pathophysiology of the chronic arthritides. Thanks to the use of immunohistological techniques and molecular biolo- gy, the analysis of synovial biopsy material has been car- ried beyond the structural level.A closer identification of the cells infiltrating the synovium by their cell surface molecules and receptors, together with an analysis of their protein products, has given us a better understanding of the driving forces and the dynamics of synovial inflammation. We now know that what we call early arthritis from a clinical point of view reflects an already chronic disease stage at the histological level, and that an asymptomatic phase precedes the onset of clinical signs and symptoms of arthritis [11]. The signs and symptoms of arthritis have been correlated with the production of specific key cytokines such as TNFα and IL1-β in the synovium by macrophages [12]. In chronic arthritis, synovial macrophages are part of a well-organized cellular network together with lymphocytes and synovial fibroblasts.

Communication between these cells takes place via direct cell–cell contact but also via the production of growth factors, cytokines, and chemokines. Thanks to both in vivo and in vitro research based on synovial biopsy material, we are beginning to understand this complex network [13]. The process of bone destruction in RA has been much elucidated, and destructive factors such as RANK Ligand, TNF-α,and IL1-β have been found in the synovium, as well as protective factors such as osteoprotegerin

(OPG) [14]. Matrix metalloproteinases, enzymes pro- duced at the cartilage–pannus interface,have been shown to be responsible for cartilage degradation and are coun- terbalanced by inhibitory proteins [15].It appears that the synovial tissue itself sometimes has, especially at later disease stages, an invasive, tumor-like nature [16].

Much effort has been made to differentiate the chronic arthritides from one another at the synovial level.

Quantitative differences have been found in the different inflammatory cell types infiltrating the synovium and in the balances of several cytokines and growth factors [17].

Moreover, at both the macroscopic and the microscopic level, the synovial vascularity has been postulated to be specifically increased in SpA in comparison to RA [18].

Looking for the origin of the perinuclear factor,an old but very specific blood test for RA,researchers have identified specific serum antibodies against certain citrullinated proteins, which in turn have been traced back to the synovium and are very specific for RA [19]. The more new specific markers are found, the more we can expect synovial biopsies to become an attractive differential diagnostic tool in daily practice.

During the past decade, the benefit of an earlier and more aggressive treatment of chronic arthritis has become clear. Better knowledge of the pathophysiology of chronic arthritis has led to the development of new, more targeted treatment strategies such as blocking of TNFα and IL1-β. Sequential synovial biopsies are increasingly being used for disease monitoring and for the rapid evaluation of new treatment modalities,which are themselves often based on the identification of new candidate targets in the synovium [20]. The high cost and the considerable risk of severe side effects of these new therapies will make it necessary to look for predictive drug-response markers, and most probably these will be found in the synovium too.We are only beginning to realize how informative the study of the synovium will become.

Acknowledgements.We thank our colleagues for their generous assistance in preparing this chapter, especially to K. de Vlam, F. Lensen, P.Verschueren.

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