1 Arthritis of the Knee: Diagnosis and Management F

Home , Crystal arthropathy, Monoarthritis

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1 Arthritis of the Knee: Diagnosis and Management F. P. Luyten, R. Westhovens, V. Taelman

Summary Major advances in our understanding of the molecular basis of arthritic diseases has led to the development of In this chapter,an algorithm for the diagnosis of a painful new targeted therapies with a profound impact on the and swollen knee is presented. Arthritis of the knee can management of patients with rheumatoid arthritis and be restricted to a monoarticular clinical manifestation,or the spondyloarthropathies. 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 Algorithm for Diagnosis of the the knee into disease groups such as osteoarthritis, Arthritic Knee rheumatoid arthritis, spondyloarthropathy, or miscellaneous arthritic diseases.These disease entities are briefly When one is confronted with a patient who has a painful, discussed and their therapeutic approaches reviewed. swollen knee, a well-structured approach is helpful for Finally,the case is made for a more routine use of synovial forming a working hypothesis and ultimately critical for biopsies in daily clinical practice, for diagnosis and to arriving at the most likely diagnosis. evaluate targeted therapies. 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 of- Introduction fice,but in most cases precise and well-directed questions are needed to obtain critical information. Taking a Appropriate treatment of arthritis of the knee starts with complete history is a demanding task,but a lot of circum- correct diagnosis of the underlying disease and identifi- stantial evidence can evolve from a full history of the cation of the causes of the condition.Therefore,in the first current problem, past medical conditions, and the family part of this chapter we propose a comprehensive and history. practical algorithm for dealing with “arthritis of the The nature of the pain belongs to “the basics”, knee”, typically with signs and symptoms of pain, whether it be mechanical, inflammatory, neuropathic, or swelling, and loss of motion and function, separately or poorly defined. Mechanical pain occurs when the joint is in combination. Subsequently, we discuss clinically im- used: walking becomes difficult, and especially climbing portant separate disease entities such as osteoarthritis, stairs causes problems.On resting,there is less pain.Start- knee involvement in the major groups of chronic inflam- ing pain and stiffness are very characteristic of a more ad- matory arthritis – rheumatoid arthritis and the spondy- vanced mechanical pain pattern. loarthropathies –, and some miscellaneous forms of Inflammatory pain typically presents at night. More arthritis of the knee, perhaps less frequent but certainly specifically, the second part of the night is troublesome, clinically relevant, such as crystal-induced arthritis, sep- and patients need to get out of bed and move. They ex- tic arthritis, and Lyme disease. In these discussions we perience morning stiffness for at least 1 h, and this stiff- highlight the predominant clinical features and recent ad- ness diminishes progressively as the patient begins to vances in therapeutic options.Special attention is given to move. the concept of spondyloarthropathies, since this has still When pain is neuropathic in origin,a typical distrib- apparently not entered the daily practice of many physi- ution pattern corresponding to the innervation is found. cians. Finally, we discuss in more detail the synovium of Psychosomatic pain has no typical presentation or the knee, as this is easily accessible and has received in- distribution.Complaints are always more impressive than creased attention from rheumatologists.Indeed,through the clinical findings. the study of synovial biopsies we have gained increasing Additional questions can help the clinician to identi- insight into the pathophysiology of chronic arthritis. fy the problem as acute/subacute or a chronic arthritis. 4 I . Essentials

1 Painful and swollen knee

؁ ؁ ؁ ؁ ؁ ؁ ؁ ؁

ᮣ Yes؁؁؁؁؁؁؁؁ ?Noᮣ Trauma

Mechanical? Description of traumatic event

؁ ؁ ؁

؁ ؁

؁ ᮣ ᮣ ᮣ

؁Yes ؁No ؁ ؁

ᮣ ᮣ Clinical examination ؁ ؁

Monoarthritis? Additional Anamnesis ᮣ

؁ ؁؁ ؁

ᮣ ᮣ + Clin. Examination Joint aspiration ؁ ؁ ؁ ؁ ؁ ؁

No Yes ᮣ ᮣ ؁ ؁ ᮣ ᮣ X-rays Suspected Diagnosis ؁

؁ Oligo/Polyarticular Joint aspiration

Joint aspiration ᮣ

؁ ؁ ؁ ؁ ؁

؁؁ ؁ ᮣ ᮣ ᮣ ؁

Arthroscopy ؁ ؁

MRI ؁ ᮣ ᮣ Infectious Crystal-induced Inﬂammatory X-rays ؁؁ ᮣ ⊡ Fig. 1-1. Algorithm flow chart for ᮣ Referral to specialist the patient presenting with a painful؁؁؁؁؁؁؁؁؁؁؁؁؁؁؁؁؁؁؁؁ ...RA, SpA and swollen knee

How long has the knee problem existed? When pain and When the knee is swollen and the presence of intra- swelling have been present for less than 6 weeks,the prob- articular joint fluid is suspected, arthrocentesis should lem is acute. Beyond 6 weeks' duration, the term chronic be performed. The results of the white blood cell count is used and implies that spontaneous healing of the and cell differentiation,Gram staining,bacterial culture, arthritis is unlikely. How acutely did the problem occur? and detection of crystals of urate or pyrophosphate are Suddenly, as seen in trauma, within hours, which is more diagnostic in case of infectious arthritis, gout, or pseu- likely in septic and crystal-induced arthritis,or over days do-gout. The white blood cell count in the synovial flu- or weeks, as in rheumatoid arthritis? id differentiates between a non-inflammatory problem Ask the patient whether this is the first time he has ex- (<2000 WBC/mm3), an inflammatory picture (2000–20 perienced arthritis of the knee or if he has had knee or 000 WBC/mm3), a strongly inflammatory picture such other joint problems in the past. This may provide hints as in crystal arthritis (20 000–50 000),and a most prob- as to whether it is a problem in a single joint or an oligo/ able septic arthritis (WBC >50 000 with >75% PMN). polyarticular disease. Finally, it is important to establish whether the knee It is also important to look for circumstantial evi- problem is a genuine monoarthritis or rather one where dence.Did trauma occur just before the knee swelling be- multiple joints are involved. The latter is classified as gan? Did the patient have an episode of fever? Did the oligoarthritis when fewer than five joints are involved, or patient experience an infection such as angina, gastro- as polyarthritis when five or more joints are inflamed. In enteritis, or urethritis? Does the patient have other clini- addition, assessments of symmetrical or asymmetrical cal conditions that could be linked to the knee arthritis, joint involvement are performed. such as skin problems (psoriasis, erythema nodosum), A few typical clinical entities, most frequent in daily chronic diarrhoa as seen in inflammatory bowel disease, clinical practice, are briefly presented. eye problems such as uveitis or scleritis? In this setting a complete familial history can also add useful information. Monoarthritis, Mechanical in Origin Thereafter, a clinical workup including a complete joint assessment and a full clinical examination, evaluat- Once the knee pain is recognized as mechanical,the most ing all the peripheral joints and the axial skeleton, can likely diagnosis in the older patient is osteoarthritis with provide further clues to the diagnosis and help to local- or without a meniscal or ligamentous pathology. Further ize the problem to the joint, periarticular structures, or investigations can be limited to standard weight-bearing muscle. It is not always trivial to distinguish a synovitis X-rays. from joint pain by intra-articular swelling, the distinction In younger people, mechanical pain will more likely being crucial for the diagnosis. For instance, a diagnosis be associated with a meniscal or chondral/osteochondral of rheumatoid arthritis requires a (poly)synovitis; in- problem or defect. Further investigations include MRI, flammatory polyarthralgia is not sufficient. CT-arthrography, and arthroscopy. 5 1 Chapter 1 · Arthritis of the Knee: Diagnosis and Management – F.P. Luyten et al.

Acute Inflammatory Monoarthritis sentation (both knees, hands) in middle-aged and older of the Knee individuals. The signs and symptoms are usually local and restricted to one or both knees, sometimes associat- With inflammatory knee pain and swelling the differen- ed with hand OA or more generalized OA. Pain is by far tial diagnosis is far more complex.Acute monoarthritis of the predominant symptom, relieved by rest and without the knee is infectious until proven otherwise. Previous night pain or morning stiffness, but, especially in more arthrocentesis, skin wounds, typically on lower leg re- advanced disease, there is pronounced pain at the begin- gions or the feet, should be asked about and looked for. ning of movement. It is still unclear what causes the pain Fever is not always present, certainly not in the immuno- in OA. Most probably it is caused not by the cartilage, as compromised patient. Arthrocentesis is mandatory for this tissue has no nerve supply, but rather by the sub- bacterial examination and culture.Gram staining and the chondral bone and other intra- and periarticular struc- white blood cell count can be quickly obtained and are tures such as synovium, menisci, and ligaments. Acute mostly sufficient to begin antibiotic treatment. Arthro- flares with an inflammatory component and swelling of scopic lavage and intravenous antibiotic treatment must the joint may occur, frequently caused by crystals, which be started as soon as possible. may indicate the possible association with calcium py- In older patients, a crystal-induced arthritis such as rophosphate crystal arthritis (CPPD). gout or pseudogout is the most likely explanation for The clinical examination reveals pain on passive and acute monoarthritis of the knee.Again, arthrocentesis is active motion, together with local tenderness, and crepi- the key to the correct diagnosis, demonstrating the pres- tus in the more advanced stages. Joint swelling can be ence of urate or pyrophosphate crystals. 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 Chronic Monoarthritis of the Knee advanced cases or in patients with more chronic synovitis,and is an additional reason to look for crystal-induced Monoarthritis of the knee is often a presenting feature of arthritis.Advanced loss of articular cartilage in one com- spondyloarthropathy.This group of diseases is marked by partment, predominantly the medial one, will be associ- inflammatory back pain, asymmetrical synovitis of pe- ated with secondary axis deviations such as genu vara or ripheral joints, and enthesopathy (see “Spondyloarthro- valga.Retropatellar OA can be presented as a single com- pathies”,below).Again,the importance of a complete his- partmental involvement,particularly in younger patients, tory for detecting related conditions of the skin, eyes, or evolving in some cases from the so-called chondromala- bowels should be stressed. cia patellae.In these cases,the pain is localized around the Less frequently, chronic monoarthritis of the knee is patella and is typically aggravated by climbing stairs. the result of a low-grade infection (Mycobacteria), sar- The diagnosis of OA is confirmed by radiographic coidosis,Lyme disease,villonodular synovitis,or algody- imaging.For diagnostic purposes,since OA involves three strophy. compartments,anteroposterior,mediolateral,and skyline views are recommended. X-ray findings typically show joint space narrowing (JSN),subchondral bone sclerosis, Chronic Polyarthritis, with Knee Arthritis and osteophytosis. The subchondral bone reaction, and as First Symptom especially osteophytosis, appears most often earlier than JSN. However, JSN is more significant and sensitive to On clinical examination, so-called monoarthritis often change. In some cases of knee OA, JSN is more striking turns out to be polyarthritis. This can be the onset of and can be present without any osteophytosis. Most im- spondyloarthropathy. Monoarthritis of the knee as the portantly, there is a poor correlation between clinical presenting manifestation of rheumatoid arthritis is less symptoms, clinical outcome, and X-ray changes. It is im- common; more typically, rheumatoid arthritis shows a possible to predict the outcome of knee OA in individual picture of symmetrical polyarthritis, including smaller patients based on radiographic appearance alone. joints of the hands and feet. In this setting, a blood ex- Laboratory findings are usually normal, although amination with biochemical testing for inflammatory pa- sometimes a slight elevation of C-reactive protein and rameters and rheumatoid factor is helpful. 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 Osteoarthritis of the Knee patients with associated crystal arthropathy. Synovial fluid reveals minimal abnormalities, with a cell count The clinical history and examination typically reveal a usually below 2000 cells/mm3. Calcium pyrophosphate chronic noninflammatory, mono- or oligoarticular pre- or apatite crystals are seen quite frequently. Scintigra- 6 I . Essentials

phy is of little or no use in the diagnosis.Despite the advan- Knee Involvement in 1 ces that have been made in the development of sensitive Rheumatoid Arthritis assays, serological markers for diagnostic or prognostic purposes remain investigational. In rheumatoid arthritis (RA), knee arthritis is frequently Newer imaging modalities such as computed tomo- just one component of symmetrical polyarthritis. Espe- graphy (CT) and magnetic resonance imaging (MRI) pro- cially when the symmetrical polyarthritis of small joints vide additional insight into the degree or nature of dam- of the hands and feet is mild and/or overlooked in the age to the cartilage, subchondral bone, and soft tissues. clinical examination, a late diagnosis can lead to consid- MRI shows great promise for detecting early changes in erable damage from this disease. OA, especially with regard to the articular cartilage soft- tissue involvement and bone narrow abnormalities. Treatment modalities have recently been presented Signs and Symptoms and discussed, and this has resulted in recommendations and guidelines proposed by both the American The classical presentation of RA is that of a gradually de- College for Rheumatology [1] and the European League veloping symmetrical polyarthritis of the hands and feet, Against Rheumatism [2]. The treatment algorithm in- with a peak incidence in women in their fourth and fifth cludes nonmedical approaches, with education, weight decades of life. Although we know a good deal about the loss, and restoring muscle strength as the most critical epidemiology and immunologic and genetic aspects of parameters. The medical approach focuses mainly on RA, it is still unclear what initiates and perpetuates the treating pain, the major symptom of OA, and on pain- process.At present, RA is still best described and depict- relieving drugs. Paracetamol preparations in doses of ed by the 1987 revised classification criteria of the Amer- up to 4 × 1 g/day remain the first-line treatment for mild ican Rheumatism Association [3] (⊡ Table 1-1). and moderate gonarthritis. The addition of non- It must be remembered that RA not only involves steroidal anti-inflammatory drugs (NSAIDs) is recom- joints and tendon sheets, but is also a systemic disease mended when insufficient pain relief is achieved with affecting the body as a whole (fatigue, extra-articular proper doses of analgesics alone. Topical anti-inflam- features such as nodules, serositis, vasculitis, anemia, matory treatments appear reasonably efficacious and interstitial lung disease). It has a major impact on every should be tried.The place in the treatment algorithm of patient’s physical and psychosocial life. nutritional supplements such as glucosamine and Involvement of the knee in RA is common and usual- chondroitin sulfate is still not clear. The position of in- ly obvious. Minor inflammation in the knees should not tra-articular treatments with corticosteroids and be overlooked. Examination of the “bulge” sign and loss hyaluronic acid remains controversial, and it is clear of the “cool patella” sign can contribute to an adequate that we lack convincing predictors of response to iden- diagnosis.When the knee synovitis is important,a Baker’s tify those patients likely to benefit from these treat- cyst is a frequent finding. Ruptures of Baker’s cysts can ments. mimic acute thrombophlebitis. Surgical treatments include tissue-repair approaches, arthroscopic lavage and débridement, osteotomy, and unicompartmental and total knee replacement. There is Joint Damage and Destruction little or no evidence that surgical reconstruction of torn cruciate ligaments or the meniscus prevents the develop- Early disease is not synonymous with mild disease. Al- ment of knee OA. It remains to be seen whether cartilage though it is still unpredictable whether patients with early repair procedures prevent or slow down knee OA. The disease will eventually develop a malignant rheumatoid combination of tissue repair, such as the repair of carti- course,a number of prognostic factors should be looked for: lage defects, with an osteotomy, performed on the right ▬ High persisting disease activity and early joint damage patient and by a trained surgeon, may delay the need for – Persistently elevated levels of CRP and ESR knee replacement and will most likely benefit the younger – Uncontrolled persisting polyarthritis patient population (below 50 years). Indeed, OA in the – Early X-ray damage (joint erosion and JSN) and young and active population remains a largely unsolved joint deformity problem. Developments of new structure-modifying – Functional disability (as measured by the HAQ – drugs together with tissue-engineering approaches are health assessment questionnaire) the hope for the near future. ▬ 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 7 1 Chapter 1 · Arthritis of the Knee: Diagnosis and Management – F.P. Luyten et al.

⊡ 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)

there seems to be a window of opportunity to prevent Persisting disease activity is associated with increased joint damage. Therefore, the classical therapeutic pyra- mortality. mid is reversed with early use of so-called disease-mod- Joint damage occurring within the first year of disease ifying antirheumatic drugs (DMARDs) such as activity is assessed by standard X-rays.X-rays of the hands methotrexate and sulfasalazine. A fast control of in- and feet show early periarticular osteoporosis; at the later flammation, even using temporary oral steroids, is of stage joint erosions and JSN can be seen, followed by the benefit. presence of joint subluxation or even dislocation. Joint The study of the etiopathogenesis of the disease has damage in the hands, and even earlier damage detectable provided insights into the immunological reactions in the feet, is correlated with involvement of other joints between the antigen-presenting cells and the T and B and with general disease severity and shows continuous lymphocytes, as well as into the cytokine imbalance progression without appropriate treatment. Standard X- resulting from this disease process. This has led to the rays of the knee do not contribute to the early diagnosis of development of new targeted treatments such as block- RA. Ultrasound techniques can reveal joint effusion, syn- ing antibodies or soluble receptors of TNFα. These ovial hypertrophy, and vascularity. MRI techniques addi- novel treatments appear to exert a more profound tionally reveal aspecific bony edema in early disease.These disease control in patients refractory to standard examinations contribute little,however,when an adequate DMARDs, and the data even suggest an arrest in joint clinical examination is performed. tissue damage. The use of these powerful but expensive Eventually, destruction of the knee by RA will lead to treatment options in early disease should be carefully functional disability. The loss of cartilage and the pres- weighed,also in view of the still unknown possible long- ence of ligament laxity at the level of the collateral and term side effects. cruciate ligaments further contribute to difficulties in walking and climbing stairs. A classical valgus deformity is the late outcome of Involvement of the Knee RA knee arthritis, marked by posterior subluxation of in Spondyloarthropathy the tibia,resulting in a fixed flexion contracture of the knee. In spondyloarthropathy, knee arthritis can present as acute inflammatory monoarthritis, as chronic inflam- Treatment matory monoarthritis,or as a first sign of chronic inflammatory oligo- or polyarthritis.The spondyloarthropathies Comprehensive management of RA involves pharma- [4,5] comprise a number of related diseases with common cological but also a variety of nonpharmacological in- clinical, radiological, biological, genetic, and therapeutic terventions to improve and maintain function, such as features and include the following entities: patient education, physical therapy, surgery, and occu- ▬ 1. Ankylosing spondylitis (AS) pational therapy. Early disease control is mandatory,as ▬ 2. Reactive arthritis 8 I . Essentials

and self-resolving. It involves the large weight-bearing ⊡ Table 1-2. Characteristics of spondyloarthropathies 1 joints of the lower limbs, most frequently the knees and 1. Absence of rheumatoid factor and rheumatoid nodules ankles. Knee monoarthritis may be the presenting fea- 2. Inflammatory peripheral arthritis ture. Some patients develop a chronic erosive mono- or 3. Spinal inflammation: inflammatory back pain, sacroiliitis with or oligoarthritis. In psoriatic arthritis, the asymmetrical without spondylitis oligoarthritis subtype is the most prevalent and affects 4. Inflammatory enthesopathy 5. Clinical overlap between the different clinical entities of the group predominantly the joints of the lower limbs.This implies 6. Familial aggregation that the knee is often affected. In 2%–20% of patients 7. Association with HLA B27 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 ▬ 3. Psoriatic arthritis 25% of patients with AS also develop peripheral arthri- ▬ 4. Idiopathic acute anterior uveitis tis.The hip and shoulder are frequently involved,and,to ▬ 5. Inflammatory bowel disease-related arthritis a lesser extent,knee involvement is seen in these patients. ▬ 6. Undifferentiated spondyloarthropathy Knee arthritis as a first symptom of polyarthritis is seen ▬ 7. Late-onset pauciarticular juvenile in psoriatic arthritis and in IBD-related SpA. chronic arthritis Knee pain in patients with SpA must be differentiated from knee arthritis with or without synovitis and en- The characteristics of spondyloarthropathies (SpA) are thesitis at the insertions of the patellar ligament on the listed in ⊡ Table 1-2. 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 present- Characteristics of Spondyloarthropathies ing sign in about 10% of patients. Although in SpA cal- caneal enthesitis is the most frequent enthesopathy, en- According to the respective clinical diagnosis (see above),in- thesitis of the patellar ligament and the quadriceps inflammatory knee involvement in SpA can present in differ- sertion can be present as well. ent ways, usually as part of oligoarthritis, less frequently as The enthesitis frequently causes pain but can be asymp- monoarthritis or as part of an asymmetrical polyarthritis. tomatic as well. Soft-tissue swelling is sometimes present Oligoarthritis is seen in undifferentiated spondy- and can be shown by ultrasound (US), conventional radi- loarthropathy, psoriatic arthritis, inflammatory bowel ography,and MRI.Enthesitis of the patellar ligament is of- disease (IBD)-associated arthritis,late-onset pauciartic- ten mistaken for osteonecrosis or traction apophysitis (Os- ular juvenile arthritis, and, to a lesser extent, in AS and good-Schlatter and Sinding-Larsen disease).Enthesitis can reactive arthritis. Peripheral arthritis is a key feature in be differentiated by ultrasound from bursitis,which is om- these SpA and is generally asymmetrical, nonerosive, nipresent in the vicinity of enthesis as well.

⊡ 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 9 1 Chapter 1 · Arthritis of the Knee: Diagnosis and Management – F.P. Luyten et al.

Imaging. MRI and US can be of value in diagnosing SpA, Treatment of Knee Arthritis in SpA especially in cases where peripheral arthritis is the only clinical manifestation. Knee synovitis in SpA differs Suitable rest is advisable for patients with arthritis of the from that in RA due to the involvement of adjacent en- weight-bearing joints. The further therapeutic approach thesopathy [6]. MRI detects both perienthesial fluid or is decided depending on the clinical presentation such as edema and bone marrow edema at the enthesial inser- an nonarthritis,or of the knee arthritis is part of an oligo- tions in the knees of spondyloarthropathy patients, or polyarticular disease. while the latter is absent in the knees of RA patients. US Acute monoarthritis is treated with NSAIDs for 6 demonstrates the relationship between enthesial abnor- weeks. If the first-line treatment fails, other therapeutic malities and bone edema at the cortex–enthesis inter- options are introduced. The indications for NSAID use face.A recent study suggests that enthesitis of the adja- are pain and morning stiffness. No controlled data are cent entheses is always present in peripheral synovitis of available regarding the efficacy of NSAID treatment in pe- spondyloarthropathy in contrast to its absence in RA,an ripheral arthritis in SpA,but in clinical practice it appears observation which has important implications for dia- that NSAIDs can be efficacious, especially in reactive gnosis. arthritis. Patients should be treated for 6 weeks at the optimal dose. The use of NSAIDs is less desirable, and Differential Diagnosis. Other arthritides such as RA need to in some cases contraindicated, if concomitant IBD is be excluded. The main differences between peripheral present. arthritis in SpA and RA are listed in ⊡ Table 1-3. A single intra-articular injection of corticosteroids in spondyloarthropathy patients with monoarthritis may have a beneficial effect and last for some time.Such an in- Differences in Characteristics Between jection can be repeated at a maximum frequency of 3–4 Peripheral Arthritis in SpA and RA injections in the same joint during a 1-year period. Physiotherapy is helpful in maintaining the function Young patients with a swollen knee in the absence of of the affected joint.Mobilization exercises and strength- trauma must be suspected of having a spondy- ening of the quadriceps without weight-bearing are use- loarthropathy. The possibility of spondyloarthropathy ful. However, physiotherapy appears to have no effect on must be considered if, in addition to the knee arthritis, the inflammatory process. certain particular symptoms are present. The clinical If monoarthritis persists, or knee involvement is part characteristics of these associated symptoms must be of chronic oligo- or polyarticular disease, disease-modi- evaluated, e.g., synovitis of other joints, dactylitis fying antirheumatic drug (DMARD) therapy is started. (sausage toe or finger), inflammatory axial disease, and Sulfasalazine and methotrexate are frequently used as extra-articular manifestations such as uveitis or con- DMARDs in SpA. junctivitis, urethritis or cervicitis, bowel inflammation, Sulfasalazine is the only “second-line” drug with skin lesions such as psoriasis, and endocarditis. The pa- proven efficacy in prospective controlled trials for the tient must be repeatedly interviewed for family history of treatment of peripheral arthritis in SpA. It is considered SpA and episodes of urogenital and enterogenic infec- a safe and well-tolerated treatment for persistent, chron- tion prior to the arthritis. ic peripheral synovitis in SpA. The effect is greater when Detailed characteristics of the symptoms reported it is started at an early stage of the disease than in patients by the patients are in most cases sufficient to strongly with already existing joint deformities. Incremental suggest the diagnosis. If not, two additional investiga- dosages starting at 0.5 g twice daily and increasing to 1.5 g tions can be helpful: testing for HLA-B27 and pelvic ra- twice daily are used.The clinical effect must be evaluated diographs. at 3 months.Although sulfasalazine has a good safety pro- The final diagnosis is made on the basis of concor- file, biochemical evaluation of liver enzymes and white dance of the clinical manifestations and the physician’s cell blood counts must be performed on a regular basis. personal experience in the field. There are no diagnostic Sperm count can be reduced in men but is particularly a criteria available, but the available classification criteria problem in men with pre-existing fertility problems. can be used to examine the specific manifestations. If However, sulfasalazine is a safe drug for women contem- these criteria are fulfilled the diagnosis can be made, but plating pregnancy. even if a patient does not fulfill the classification criteria, In daily practice,methotrexate is used on a regular ba- he can still suffer from an incomplete or unusual form of sis in SpA, in analogy to its use in RA. Methothrexate is spondyloarthropathy. 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. 10 I . Essentials

Pamidronate and thalidomide have shown some effi- crystals. NSAIDs are preferentially used as treatment. In 1 cacy in open studies for AS patients with refractory dis- some cases,differentiating CPPD disease and other forms ease.Although designed for refractory spinal disease,pa- of polyarthritis, such as RA, can be difficult. Some patients with concomitant peripheral arthritis also experi- tients display a pseudo-rheumatoid pattern, with in- ence a beneficial effect in the peripheral joints. volvement of multiple joints, particularly the knees, Recent advances in biological therapies with cy- wrists,and elbows.Lack of erosions,low RF titers,and the tokine-blocking strategies are promising. TNFα block- presence of synovial fluid crystals help to establish the ade is efficacious in the treatment of axial disease in AS correct diagnosis. and peripheral synovitis, and in patients with psoriatic Crystals are also commonly found in osteoarthritis of arthritis. In open studies TNFα blockade also showed a the knee. Distinguishing osteoarthritis from CPPD beneficial effect on the peripheral manifestations of SpA arthritis is therefore not always easy,but this is usually of and on the articular manifestations of Crohn’s disease. little consequence,as there are no “dramatic”therapeutic Finally, arthroscopic lavage can be of use in chronic implications. In primary OA, the medial compartment is monoarthritis for individual patients,but it’s effect is usu- more involved, while the pseudo-osteoarthritis caused ally only temporary. by CPPD deposition is more in the lateral compartment. Radiographs typically show chondrocalcinosis in the latter case. Crystal-induced Arthritis

The clinical presentation of crystal-induced arthritis is Miscellaneous Forms of predominantly acute inflammatory monoarthritis,or re- Arthritis of the Knee current episodes of inflammatory mono- or oligoarthritis. Crystal arthritis comprises a group of acute and Infectious Arthritis chronic arthritides caused by the deposition of different types of crystals in the joint tissues. Monosodium urate Infectious arthritis presents typically as an (sub)acute in- crystals in gout and calcium pyrophosphate dihydrate flammatory monoarthritic disease. Up to 90% of infec- (CPPD) crystals in pseudogout are the clinically most fre- tious arthritis cases present as monoarthritis. The only quent crystal deposition diseases. Correct diagnosis is exception is gonococcal arthritis, which presents more made by the identification of crystals in the synovial flu- commonly as a migratory polyarthritis. If the condition id.Pain relief during the acute event and prevention of re- is unrecognized, joint destruction will occur rapidly. current attacks is the goal of the treatment. In any acute joint disease, infection must be suspect- Gout occurs as a result of hyperuricemia, although ed. However, infectious arthritis is an uncommon condi- asymptomatic hyperuricemia is common. In early stages tion; the incidence in the developed world is estimated to of gout,the clinical manifestation is an acute attack of in- be about six cases per 100 000 per year [7].The knee is inflammatory monoarthritis in the MTP joint,but the knee deed the most commonly involved joint. The pathogenic is also frequently involved. Subsequent attacks can occur process starts when the synovium or the synovial fluid more frequently,and may become oligo- to polyarticular becomes a culture medium for bacteria. Usually, the mi- and persist longer. Radiographic features are soft-tissue croorganisms reach the joint via bacteremia, although swelling, the presence of tophi (soft-tissue densities spreading from adjacent tissues or direct inoculation which occasionally are calcified) and bony erosions through the skin also occurs.Whether a clinically relevant (punched-out lesions) with sclerotic margins and over- infection develops depends on the virulence of the in- hanging edges. In contrast to other inflammatory arthri- fecting organism, the size of the bacterial inoculum, and tides,the joint space is preserved.NSAIDs and colchicine the resistance of the host. The most likely causative or- are effective in the treatment of gout. Drugs that alter ganism is Staphylococcus aureus, but many other organ- serum acid levels (allopurinol, probenecid) should be isms have been isolated from septic joints, including started after more than two or three attacks have oc- streptococci and Enterobacteriaceae.Age-specific organ- curred, not at the time of the acute attack, but once start- isms are Haemophilus influenzae type b in children and ed they should never be stopped. Neisseria gonorrhoeae in adults. Rare pathogens such as Pseudogout is an acute inflammatory crystal mono- or fungi are more often found in case of immunodeficiency, oligoarthritis, and frequently seen with chondrocalci- the presence of penetrating wounds, or intravenous sub- nosis, a radiographic diagnosis associated with deposi- stance abuse. Most patients suffer from an underlying tion of CPPD in cartilage.The release of CPPD crystals in medical condition such as diabetes mellitus,or an under- the joint space causes the inflammation, and diagnosis is lying joint condition such as RA. made by polarized light microscopy of the joint fluid, Fever is common but can be absent. The only defini- identifying weakly positively birefringent blunt or square tive diagnostic test is the demonstration of bacteria in the 11 1 Chapter 1 · Arthritis of the Knee: Diagnosis and Management – F.P. Luyten et al. synovial fluid or in the synovium,or recovery of bacteria area where LD is endemic, and it can be confirmed by from a synovial fluid/synovium biopsy culture. When a serological testing (ELISA).A positive result of the ELISA joint is suspected of being infected,arthrocentesis should test should be confirmed by Western blot. Borrelia be performed prior to the initiation of any antimicrobial burgdorferi can be detected in joint fluid or synovial tis- therapy. This procedure is not yet sufficiently practiced. sue by polymerase chain reaction.LD is usually cured by The fluid should be subjected to a cell count,Gram stain- antibiotic treatment at any stage of the disease. Treat- ing, and culture, preferably in blood culture medium. A ment is easier and more successful the earlier it is given. count of more than 50 000 cells/mm3,of which more than In the case of Lyme arthritis, either oral or intravenous 90% are polymorphonuclear leukocytes,makes infection regimens are usually effective. If accompanying neu- highly likely. roborreliosis is suspected, intravenous regimens are in- Treatment requires both adequate drainage of pu- dicated. 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- Pigmented Villonodular Synovitis/Synovial tibiotics should be administered on an “educated/best- Chondromatosis guess” basis, considering the patient's age and history and the results of the Gram stain.The choice and the ap- Pigmented villonodular synovitis (PVNS) and synovial propriate dosage should be adjusted when an etiologi- chondromatosis are two types of proliferative disorders cal agent is identified and its antibiotic sensitivity is de- affecting the synovial lining of joints. The clinical pre- termined. There is no need to inject antimicrobials into sentation is typically chronic inflammatory monoarthri- the joint.Irrigation of the joint is recommended to evac- tis. In PVNS, histology is characterized by hypercellular uate bacterial products and debris associated with in- synovial connective tissue containing hemosiderin-laden fection. The optimal duration of treatment is contro- macrophages. In synovial chondromatosis the synovial versial,as is the route of administration of the antibiotic mesenchymal cells mature into chondroblasts that form drug. An empirical period of 4–6 weeks of intravenous nodules of cartilage.Both conditions are uncommon.The antibiotic treatment is commonly suggested. In case of incidence of PVNS is estimated to be approximately gonococcal arthritis, treatment for 7 days is believed to 1.8/1 million. The presentation is usually monoarticular, be sufficient. 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 Lyme Arthritis the fifth decade of life.In both conditions patients present with slowly progressive joint pain and swelling. Plain Arthritis in Lyme disease can present as chronic inflam- radiographic investigation often shows only increased matory monoarthritis or as migratory polyarthritis. soft-tissue density. MRI usually demonstrates key diag- Lyme arthritis is one of many possible features of Lyme nostic features.The diagnosis is confirmed by biopsy,and disease (LD), a complex multisystem and infectious dis- the treatment of choice is synovectomy [9]. ease, 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] The Knee and the Study of the (in North America by Ixodes scapularis). LD occurs in Synovium: From Research to Clinical endemic pockets with an incidence of 50–300 cases per Practice 100 000 per year.Lyme manifestations can be grouped in three stages: an early localized stage in which a pathog- The knee synovium is easily accessible and has provided nomonic skin feature,erythema migrans,usually occurs; an excellent tool for diagnosis, but most importantly for an early disseminated stage in which spirochetemia studying the pathogenesis of the disease processes. It is causes seeding of many organs, which leads to a wide anticipated that synovial biopsies will also be routinely spectrum of clinical manifestations; and the late dis- used in evaluating treatment response. seminated stage when mainly neurological and muscu- The classical clinical indication for taking a synovial loskeletal symptoms are reported. Clinical presentation biopsy is chronic (>6 weeks) nontraumatic inflammatory of LD in the later stages is not uncommon. Of the un- (synovial fluid WBC count >2000 cells/mm3) arthritis lim- treated patients, 50% develop migratory polyarthritis, ited to one or two joints in which the diagnosis remains un- while 10% develop chronic, intermittent monoarthritis, clear after an appropriate noninvasive diagnostic workup, usually of the knee, characterized by large inflammato- including synovial fluid analysis with culture for fungi and ry articular effusions.The diagnosis is based on the char- mycobacteria.There has never been much discussion about acteristic clinical findings and a history of exposure in an the usefulness of synovial biopsies for the diagnosis of atyp- 12 I . Essentials

ical chronic infections (e.g., fungi, mycobacteria), plant- (OPG) [14]. Matrix metalloproteinases, enzymes pro- 1 thorn and other foreign-body synovitis,all kinds of synovial duced at the cartilage–pannus interface,have been shown tumors, chronic sarcoidosis, and some infiltrative and to be responsible for cartilage degradation and are coun- deposition diseases (e.g., amyloidosis, hemochromatosis). terbalanced by inhibitory proteins [15].It appears that the Although the synovium is also an important target synovial tissue itself sometimes has, especially at later tissue of RA and the SpA, the examination of synovial disease stages, an invasive, tumor-like nature [16]. biopsies for clinical reasons has never been popular in Much effort has been made to differentiate the chron- these prototypical chronic arthritides, probably because ic arthritides from one another at the synovial level. their diagnosis does not depend so much on histology. Quantitative differences have been found in the different Given the fact that it is impossible to obtain access to inflammatory cell types infiltrating the synovium and in the target tissue without an invasive procedure, most of the balances of several cytokines and growth factors [17]. our knowledge of synovial histology in chronic arthritis Moreover, at both the macroscopic and the microscopic has come from postmortem studies or from studies of level, the synovial vascularity has been postulated to be synovial biopsies taken during curative orthopedic pro- specifically increased in SpA in comparison to RA [18]. cedures in end-stage disease. The popularity of synovial Looking for the origin of the perinuclear factor,an old but biopsies for differential diagnosis in chronic arthritis has very specific blood test for RA,researchers have identified suffered greatly from the lack of disease-specific light- specific serum antibodies against certain citrullinated microscopic characteristics at this late stage of the dis- proteins, which in turn have been traced back to the syn- ease, and this for a very long time [10]. ovium and are very specific for RA [19]. The more new The introduction of arthroscopy, and particularly of specific markers are found, the more we can expect syn- the minimally invasive needle arthroscopy technique un- ovial biopsies to become an attractive differential diag- der local anesthesia,has made it possible to take synovial nostic tool in daily practice. biopsy samples at every stage of the disease, and even During the past decade, the benefit of an earlier and repetitively,in an office-based setting. This evolution has more aggressive treatment of chronic arthritis has be- led to a renewed interest in the synovium. Since the become clear. Better knowledge of the pathophysiology of ginning of the 1990s, numerous studies based on the chronic arthritis has led to the development of new,more analysis of synovial biopsies obtained by needle targeted treatment strategies such as blocking of TNFα arthroscopy have provided better insight into the patho- and IL1-β. Sequential synovial biopsies are increasingly physiology of the chronic arthritides. Thanks to the use being used for disease monitoring and for the rapid eval- of immunohistological techniques and molecular biolo- uation of new treatment modalities,which are themselves gy, the analysis of synovial biopsy material has been car- often based on the identification of new candidate targets ried beyond the structural level.A closer identification of in the synovium [20].The high cost and the considerable the cells infiltrating the synovium by their cell surface risk of severe side effects of these new therapies will make molecules and receptors, together with an analysis of it necessary to look for predictive drug-response markers, their protein products, has given us a better understand- and most probably these will be found in the synovium ing of the driving forces and the dynamics of synovial in- too.We are only beginning to realize how informative the flammation.We now know that what we call early arthri- study of the synovium will become. tis from a clinical point of view reflects an already chronic disease stage at the histological level, and that an Acknowledgements. We thank our colleagues for their asymptomatic phase precedes the onset of clinical signs generous assistance in preparing this chapter, especially and symptoms of arthritis [11]. The signs and symptoms to K. de Vlam, F.Lensen, P.Verschueren. 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 References macrophages are part of a well-organized cellular network together with lymphocytes and synovial fibroblasts. 1. American College of Rheumatology Subcommittee on Osteoarthritis Communication between these cells takes place via direct Guidelines (2000) Recommendations for the medical management of os- cell–cell contact but also via the production of growth fac- teoarthritis of the hip and knee: 2000 update. Arthritis Rheum 43:1905–1915 tors, cytokines, and chemokines. Thanks to both in vivo 2. Pendleton A et al (2000) EULAR recommendations for the management of knee osteoarthritis: report of a task force of the Standing Committee and in vitro research based on synovial biopsy material, for International Clinical Studies Including Therapeutic Trials (ESCISIT). we are beginning to understand this complex network Ann Rheum Dis 59:936–944 [13]. The process of bone destruction in RA has been 3. Arnett FC et al (1988) The American Rheumatism Association 1987 revised cri- much elucidated, and destructive factors such as RANK teria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324 α β 4. Wright V (1978) Seronegative polyarthritis. A unified concept. Arthritis Ligand, TNF- , and IL1- have been found in the synovi- Rheum 21:619–633 um, as well as protective factors such as osteoprotegerin 13 1 Chapter 1 · Arthritis of the Knee: Diagnosis and Management – F.P. Luyten et al.

5. Miceli-Richard C et al (2003) Spondyloarthropathy for practicing rheuma- 14. Haynes DR et al (2003) Osteoprotegerin expression in synovial tissue from tologist: diagnosis, indication for disease-controlling antirheumatic thera- patients with rheumatoid arthritis, spondyloarthropathies and os- py, and evaluation of response. Rheum Dis Clin N Am 29:449–462 teoarthritis and normal controls. Rheumatology 42:123–134 6. Mc Gonagle D et al (1998) Characteristic magnetic resonance imaging 15. Seemayer CA et al (2003) Cartilage destruction mediated by synovial entheseal changes of knee synovitis in spondylarthropathy. Arthritis fibroblasts does not depend on proliferation in rheumatoid arthritis. Am Rheum 41:694–700 J Pathol 162:1549–1557 7. Nade S (2003) Septic arthritis. Best Practice Res Clin Rheumatol 16. Zvaifler NJ, Firestein GS (1994) Pannus and pannocytes. Alternative models 17:183–200 of joint destruction in rheumatoid arthritis. Arthritis Rheum 37:783–789 8. Franz J, Krause A (2003) Lyme disease (Lyme borreliosis). Best Practice Res 17. Baeten D et al (2000) Comparative study of the synovial histology in Clin Rheumatol 17:241–264 rheumatoid arthritis, spondyloarthropathy, and osteoarthritis: influence 9. Ruddy S, et al (2001) Kelley’s textbook of rheumatology. W.B. Saunders, of disease duration and activity. Ann Rheum Dis 59:945–953 Philadelphia 18. Fearon U et al (2003) Angiopoietins, growth factors, and vascular mor- 10. Schulte E et al (1994) Differential diagnosis of synovitis. Correlation of phology in early arthritis. J Rheumatol 30:260–268 arthroscopic biopsy to clinical findings (in German). Pathologe 15:22–27 19. Baeten D et al (2001) Specific presence of intracellular citrullinated pro- 11. Kraan MC et al (1998) Asymptomatic synovitis precedes clinically mani- teins in rheumatoid arthritis synovium: relevance to antifilaggrin auto- fest arthritis. Arthritis Rheum 41:1481–1488 antibodies. Arthritis Rheum 44:2255–2262 12. Tak PP et al (1997) Analysis of the synovial cell infiltrate in early rheuma- 20. Smeets TJ et al (1999) Analysis of serial synovial biopsies in patients with toid synovial tissue in relation to local disease activity. Arthritis Rheum rheumatoid arthritis: description of a control group without clinical im- 40:217–225 provement after treatment with interleukin 10 or placebo. J Rheumatol 13. Firestein GS (2003) Evolving concepts of rheumatoid arthritis. Nature 26:2089–2093 423:356–361