CHAPTER 5 Rheumatoid arthritis (RA) 250 Table 5.7 Pharmacotherapy of rheumatoid arthritis Drug type Examples Pain relief Simple analgesia NSAIDs Disease-modifying drugs Glucocorticoids (oral, IM, intra-articular) Methotrexate Sulfasalazine Hydroxychloroquine Le \202 unomide Biological therapies Anti-TNF: etanercept, in \202 iximab, adalimumab, golimumab, certolizumab Anti B-cell: rituximab CTLA4 Ig: abatacept IL-6 antibodies: tocilizumab For disease complications Anemia: iron, erythropoietin Osteoporosis: estrogens, bisphosphonates, teriparatide Vasculitis: glucocorticoids, cyclophosphamide Amyloidosis: chlorambucil, anti-TNF therapies There is potential for accumulation of HCQ in the fetus during pregnancy, and for chromosomal damage, although in studies of SLE, no signi \201 cant risk to the fetus has been found among women who have taken HCQ prior to conception and during pregnancy. Sulfasalazine has been used successfully in pregnancy. There have been case reports of cong enital malformations, although the overall risk is considered very small. Sulfasalazine may cause leukopenia, pancytopenia, hemolysis, and aplastic anemia. Serious bone marrow toxicity is, however, uncommon. It can also induce a h epatic transaminitis. Sulfasalazine can rarely cause a hypersensitivity reaction characterized by liver function test abnormalities, lymphadenopathy, and rash. \200 Spermatogenesis can be affected by SSZ, but it is reversible. There does not appear to be an adverse effect on female fertility. Methotrexate \200 Methotrexate (MTX 10 \200\22330 mg) is given weekly by mouth or SQ or I M injection. Toxicity, particularly stomatitis, GI disturbance, and alopecia, may be reduce d by the addition of folic acid daily, without loss of therapeutic effect. All patients taking methotrexate should receive 1 \200\2235 mg of folic acid to reduce toxi city; higher doses of folic acid may be used to manage side effects, if necessary. THE EVALUATION AND TREATMENT OF RHEUMATOID ARTHRITIS 251 Pneumonitis is uncommon and pulmonary \201 brosis (a rare complication of MTX) should not deter the physician from using MTX in aggressive systemic and skeletal disease. Rare, life -threatening, pulmonary toxicity can occur at any time and is not necessarily related to do se or duration of treatment. A chest X-ray should be taken before MTX is started. Mild drug-induced hepatitis is relatively common and is often corrected by the addition of folic acid. Overt liver disease is rare. Routine liver biopsy is not necessary, being restricted to pretreatment assessment of patients with other liver disease and patients with persistent liver function abnormalities in spite of discontinuing treatment. Myelosuppression is rarely severe. Antifolate drugs such as trimethoprim and folate de \201 ciency increase the risk of toxicity. Penicillins lead to decreased clearance of methotrexate, but are often used in combination without ill effect. Renal impairment reduces methotrexate clearance and may lead to toxicity; doses may need to be adjusted in patients with renal insuf \201 ciency. Pregnancy and breastfeeding are con traindications to the use of MTX. Both men and women should wait 3 months after stopping tr eatment before trying to conceive a child. Diminished fertility caused by MTX is reversible . NSAID use is not contraindicated. There is the potential for interaction and hepatotoxicity and close monitoring remains a pre- requisite for commencing therapy. Patients having major operations are often advised to stop treatment for 1 \200\2232 weeks either side of surgery, although there is no evidence to suggest that this reduces the risk of postoperative complications such as wound healing or sepsis, and increases the risk of a disease \202 are, particularly among patients who remain off of methotrexate > 4 weeks. Le \202 unomide \200 Le \202 unomide (LEF 10 \200\22320 mg po qd) is effective for the treatment of moderately active rheumatoid arthritis. A loading dose of le \202 unomide is no longer recommended; most patients may simply start taking 20 mg daily. Gastrointestinal side effects, including diarrhea, nausea, and transaminitis, may all occur. Patients with pre-existing liver disease should not be treated with le \202 unomide, and it should be used with caution in combination with other drugs that a re also associated with hepatotoxicity (such as methotrexate). If liver toxicity is observed, the drug should be stopped, and washout with cholestyramine should be used to help clear the drug. Peripheral neuropathy has been reported, but seems uncommon. Other DMARDs \200 Other DMAR Ds, including oral and IM gold, D-penicillamine, azathioprine, cyclosporine, and cyclophosphamide, have largely fallen out of favor due to t he availability of more effective or less CHAPTER 5 Rheumatoid arthritis (RA) 252 toxic regimens. Combined therapy (such as MTX + HCQ + SSZ) is substantially more effective than monotherapy, particularly for patients with early disease. 1 Decisions should be based on discussion between the doctor and patient taking into account the risks and bene \201 ts. These agents, their side-effects and monitoring are detailed in Table 5.7. Biologic Agents \200 Biologic DMARDs are drugs that are directed against speci \201 c components of the immune system. Broadly speaking, these drugs fall into three major groups \200 Cytokine-directed strateg ies (anti-TNF- A , anti-IL6) \200 T-cell directed strategies (CTLA4-Ig) \200 B-cell dir ected strategies (anti-CD20) Overall, these agents are associated with a roughly equal increased rate of serious infecti on (i.e., infections requiring hospitalization or intravenous antibiotics) Table 5.8 Adverse reactions of NSAIDs Organ/complication Occurrence Comments GI tract Common Gastritis, bleeding, and perforation. High risk in elderly and those with ulcer history Renal Common Fluid retention Papillary necrosis Hypertension Common Interference with drugs such as thiazide diuretics Myocardial infarction Increased risk in those with cardiovascular risk factors Associated with COX-2 inhibition Pulmonary Not uncommon Exacerbation of asthma Pneumonitis (naproxen) Skin Not uncommon Hypersensitivity Erythema multiforme CNS Not uncommon Tinnitus, fatigue, cognitive disturbance Rare Aseptic meningitis Hepatic Uncommon Drug-induced hepatitis Hematological Rare Bone marrow dyscrasias 1 O \200\231Dell JR. Therapeutic strategies for rheumatoid arthritis. N Engl J Med 2004; 35 0: 2591 \200\2232602. Table 5.9 Monitoring guidelines for DMARDs in rheumatoid arthritis T H E Monitoring Other side-effects Main toxicity Drug E V A L U A T O N A N D CBC and LFT every 2 weeks until dose stable and thereafter every 3 months Stains body \202 uid, rash, hepatitis Myelosuppression Sulfasalazine CBC and LFT every 2 weeks until dose stable. Baseline CXR. CBC and LFT every 4 \200\2236 we eks. BMP every 6 months thereafter Hepatitis, pneumonitis, rash Myelosuppression Methotrexate I Ophthalmic review if visual disturbance Visual disturbance Macular damage Hydroxychloroquine CBC and urinalysis before every dose Rash, reversible proteinuria Myelosuppression Intramuscular gold T R E A T M E N T O F CBC and urinalysis every 2 weeks until dose stable then monthly Rashes, proteinuria Myelosuppression, drug-induced myastheic syndrome D-penicillamine CBC every 2 weeks until dose stable then every 8 weeks. LFT every 3 months Hepatitis Myelosuppression Azathioprine R H E U M A T O D CBC every 2 weeks for 6 weeks then every 8 weeks. LFT and blood pressure every 12 weeks Hepatitis, diarrhea, alopecia, skin allergies Myelosuppression Le \202 unomide Serum creatinine and BP every 2 weeksuntil the dose has been stable for 3 months. Thereafte r serum creatinine and BP monthly. CBC, LFTs monthly until dose stable for 3 months and the n 3-monthly. Serum lipids 6-monthly Gum hyperplasia, hyperlipidemia, hyperuricemia Hypertension, renal toxicity Cyclosporine (Neoral ) I A R T H R CBC = complete blood count; CXR = chest radiograph; LFT = liver function tests; U+E = urea and electrolytes. (*) agents are no longer commonly used for RA. I T I S 2 5 3 CHAPTER 5 Rheumatoid arthritis (RA) 254 Patients treated with anti-TNF- A strategies are at increased risk of opportunistic infecti ons, including tuberculosis, coccidiomycosis, cryptococcus, histoplasmosis, and aspergillus . Both anti-TNF- A drugs and rituximab have been associated with reactivation of Hepatitis B. If possible, patients should receive necessary vaccines before initiation of therapy with b iologic agents; all live vaccines are contraindicated in patients actively receiving therap y with biologic DMARDs Anti-TNF- AA therapy \200 TNF- A is a potent proin \202 ammatory cytokine whose levels a re elevated in RA. At present, there are 5 agents available for the treatment of active RA, namely etanercept (Enbrel ), in \202 iximab (Remicade ), adalimumab (Humira ) , golimumab (Simphoni ), and certolizumab pegol (Cimzia ). Etanercept is a recombinant human TNF receptor fusion protein. In \202 iximab is a chimeri c human \200\223murine anti-TNF- A monoclonal antibody, while adalimumab and golimumab are fully humanized anti- TNF monoclonal antibodies. Certolizumab pegol is a PEGylated Fab frag ment of a fully human TNF- A monoclonal antibody. The ef \201 cacy of all TNF inhibitors is enhanced by co-administration with low dose methotrexate (e.g., 15 \200\22325 mg po/SQ/IM weekly). These agents are dosed as follows: \200 In \202 iximab (3 \200\2235 mg/kg) is administered by slow IV infusion at 0, 2, and 6 weeks, and every 4 \200\2238 weeks thereafter depending on response. Etanercept is administered by SQ injection and can be given either once or twice weekly (i.e., 50 mg SQ weekly. Adalimumab (40 mg) is given by SQ injection every 1 \200\2232 weeks. \200 Certolizumab pe gol (400 mg) is administered SQ every two weeks for the \201 rst month, and then monthly afterwards. Golimumab (50 mg) is also given by SQ injection every 4 weeks. \200 These therapies are n ot without their adverse events. Serious bacterial infections have been reported, and patients with active infection should have their treatme nt stopped. Patients at risk of recurrent infection should not use these drugs (e.g., indwe lling urinary catheter, immunode \201 ciency states). Other reported side-effects include demyelination, worsening of heart failure, lupus-like syndromes, and bone marrow dyscrasias . Reactivation of tuberculosis has been reported mainly in in \202 iximab patients, and most commonly within 3 months of beginning of treatment. Patients should be assessed for TB ris k, and guidelines for assessing risk and managing Mycobacterium tuberculosis infection in p atients due to start anti-TNF therapy have been published by the British Thoracic Society ( www.brit-thoracic.org.uk). There remains concern about the long-term safety of these drugs, especially with regard to malignancy. Debate continues about whether reports of lymphoma in RA patients on anti-TNF- A therapy re \202 ect a real drug effect or the known increased incidence of lymphoma in RA patients. It is reassuring that an increased risk of lymphoma h as not THE EVALUATION AND TREATMENT OF RHEUMATOID ARTHRITIS 255 been observed in registry studies. No increased risk has been found with other types of sol id tumor malignancy, but there is an increased risk of skin cancer, and patients should und ergo yearly screening. \200 TNF-inhibitors are category B for pregnancy, and there have b een many reports of successful pregnancies in patients on anti-TNF- A therapy. Interleukin-6 receptor antagonists: tocilizumab (Actemra ) Tocilizumab (4 mg/kg IV q 4 wee ks), is an effective therapy for patients who fail treatment with methotrexate or TNF inhib itors. Tocilizumab may be used as monotherapy, but like the TNF inhibitors, is more ef \201 cacious when used in combination with methotrexate. Patients should be carefully monit ored for liver function test abnormalities, dose-dependent neutro- penia and hypercholester olemia. Some patients may require dose adjust- ments, or addition of a statin for hyperchol esterolemia. Diverticulitis is a relative contraindication, due to a potential risk of bowe l perforation identi \201 ed in clinical trials. CTLA4-Ig: abatacept (Orencia ) Abatacept disrupts the CD80/86 co-stimulatory signal requir ed for T-cell activation by competing with CD28 for binding. Dosing is weight-based (<60 kg : 500 mg; 60 \200\223100 kg: 750 mg; >100 kg: 1000 mg). The drug is administered intravenou sly on weeks 0, 2, and 4, and then monthly after- wards, and is effective in patients who h ave previously failed methotrex- ate or TNF-inhibitors. Following an intravenous loading do se, patients may be transitioned to a subcutaneous formulation (125 mg SQ weekly). Abatacep t should be avoided in patients with COPD, due to a higher risk of infection. B cell therapy: rituximab (Rituxan ) Rituximab is a chimeric monoclonal antibody against h uman CD20 that leads to rapid CD20-positive B cell depletion in the peripheral blood. Treat ment with rituximab (two-1000 mg infusions, given 2 weeks apart) may lead to responses last ing for 6 months or longer. There is con- cern about persistent hypogammaglobulinemia in pa tients who receive repeated courses of this drug, and it is prudent to monitor immunoglobu- lin levels annually in such patients. Patients should be carefully monitored for infusion reactions, especially those with pre-existing cardiopulmonary conditions. Janus Kinase (JAK) inhibitors: tofacitinib (Xejanz ) Tofacitinib is the \201 rst of a ne w class of agents that interfere with the JAK- STAT cell signaling pathway, and the \201 rst oral biologic agent available in the United States. Tofacitinib is an inhibitor of Janu s Kinase 3 (JAK-3), and inhibits the production of multiple cytokines. In clinical trials, tofacitinib appears to be effective for the treatment of moderate to server rheuma- toid ar thritis. Tofacitinib 5 mg po BID has been approved by the FDA for the treatment of patients with an inadequate response to methotrexate, and may be used in combination with methotrex ate, or as monotherapy. Prior to initiating treatment with tofacitinib, patients should be tested for latent tuberculosis. Also, tofacitinib has been associated with an increased CHAPTER 5 Rheumatoid arthritis (RA) 256 risk of zoster; it therefore may be prudent to consider vaccination prior to initiating the rapy. Pharmacotherapy: Take-Home Message The number of treatment options for patients with RA can be overwhelm- ing; although several treatment guidelines exist, one simple approach to the management of the newly diagnosed patients is the following: \200 Methotrexate remains t he cornerstone of therapy \200 Once started, methotrexate should be titrated rapidly to t herapeutic levels (as tolerated) over a few weeks. Combination therapy with conventional DMARDs may be as effective as TNF-antagonists for some patients Patients with risk factors (e.g., RF/ACPA positive, patients with erosive disease, high dis ease burden, high levels of disability, or persistent elevation of acute phase reactants) s hould be early candidates for combination or biologic therapy. All TNF antagonists are approximately equally effective when combined with methotrexate. For patients who fail treatment with TNF-antagonists, one reasonable strategy is to start with a four-month trial of either abatacept or tocilizumab. Patients w ho fail to respond to treatment with these agents may still respond to rituximab Abatacept and tocilizumab may also be reasonable treatments for patients with early rheumatoid arthritis. Pregnancy \200 Hydroxychloroquine, sulfasalazine, TNF-inhibitors, and low dose prednisone may be the best options for women during conception and pregnancy. Hydroxychloroquine is FDA Pregnancy Class C, but there are no clear fetal risks associated with use of this drug. Sulfasalazine is FDA Pregnancy Class B, but should be used with folate (800 mcg po qd), since it inhibits dihydrofolate reductase. Glucocorticoids are FDA Pregnancy Class B. Prednisone is inactivated by the placenta, which decreases the risk to the fetus, but prednisone use is still associated with an increased risk of cleft lip/palate and lower birth weight. TNF inhibitors have been linked to VACTERL (vertebral anomalies, anal atresia, cardiovascular anomalies, tracheoesophageal \201 stula, renal and limb anom alies), but the relationship is controversial. Etanercept and certolizumab appear to cross the placenta at a lower rate than in \202 iximab and adalimumab. Methotrexate and le \202 unomide are both FDA Pregnancy Class X, and cannot be used during any stage of pregnancy. Methotrexate should be stopped at least 3 months prior to conception \200 Women who have been treated with le \202 unomide must be treated with cholestyramine 8g po TID for 11 days, and plasma levels must be <0.02 mg/L on two test s taken 14 days apart before conception may be considered. Tocilizumab has been associated with an increased frequency of spontaneous miscarriage, and should be avoided. THE EVALUATION AND TREATMENT OF RHEUMATOID ARTHRITIS 257 Rituximab is FDA Pregnancy Class C, and has been associated with a 21% \201 rst-trimester pregnancy loss, which is higher than the 10 \200\22315% loss reported in the general popul ation, but it is dif \201 cult to know if this is a statistically signi \201 cant differe nce. Surgery in RA \200 Damage to joints, with associated pain and loss of function remains a familiar feature of chronic RA. Surgical intervention may have a place in such situations b ut certain procedures (e.g., shoulder replacement) may only be effective in reducing pain a nd may not necessarily improve function. Synovectomy is less frequently performed now, although tenosynovectomy is common, and a quick and safe relief of nerve entrapment. Common surgical procedures include: \200 decompression of the carpal tunnel \200 recons tructive arthroplasty of hip and knee; less often the shoulder, elbow, and small joints of the hand corrective arthrotomies of the metatarsals \200 stabilization of the cervical spine \200 tendon release and transfer \200 arthrodesis, particularly of the ankle joint. Patients should ideally be seen by a surgeon with expertise in dealing with patients with RA. Management summary for treating RA \200 Figure 5.2 summarizes the management of RA. \200 There remains a need for the development of early predictors of long-term outcome in RA, allowing better patient selection for early intervention. Early fu nctional impairment remains a crude but reliable indicator of poor prognosis. A high RF titer, high ESR or CRP at diagnosis, male gender, radiographic evidence of erosions, and rheumatoid nodules are features associated with aggr essive disease. Thorough evaluation of early onset disease, combination therapies, and earl y institution of biologic agents (when appropriate) dramatically improve outcomes associate d with aggressive disease. Of all patients with RA, 20% will have mild disease, 75% moderate disease with relapses and remissions, and 5% will have severe destructive disease. Patients are at risk of early cardiovascular disease. It is important to assess cardiovascu lar risk factors such as cholesterol, blood pressure, diabetes, corticosteroid use, smoking , etc. and modify them if possible. A multidisciplinary team is important in patient care and should be involved at an early stage. DMARD monitoring is needed to ensure patients do not suffer serious side effects. Patients should be involved directly in any decisions about their care. CHAPTER 5 Rheumatoid arthritis (RA) 258 Phase I Clinical diagnosis of rheumatoid arthritis Contraindication for methotrexate No contraindication for methotrexate Combine with short-term low or high dose glucorticoids Start leflunomide, intramuscular gold or sulfasalazine Start methotrexate Failure phase I: go to phase II Achieve target* within 3-6 months No Continue Yes phase II prognostically unfavorable factors absent prognostically unfavorable factors present Failure or lack of efficacy and/or toxicity in phase I such as RF/ACPA, esp, at high levels; very high disease activity; early joint damage Start a second synthetic DMARD: Leflunomide, Sulfasalzine, MTX or intramuscular gold as mon otherapy or eventually as combination therapy (with or without addition of glucocorticoids as above) Add a biological drug (especially a TNF-inhibitor) Achieve target* within 3-6 months No Failure phase II: go to phase III Achieve target* within 3-6 months Continue No Yes phase II Failure or lack of efficacy and/or toxicity in phase II Biological agent synthetic DMARD Change the biological treatment: Switch to second TNF-blocking drug (+ DMARD) Achieve target* within 3-6 months or Replace TNF - blocking drug by abatacept (+ DMARD) or rituximab (+ DMARD) or tocilizumab ( DMARD) Yes Continue Yes The treatment target is clinical remission or, if remission is unlikely to be achievable, a t least low disease activity Fig. 5.2 An algorithm for the management of adult rheumatoid arthritis based on European Le ague Against Rheumatism recommendations. RHEUMATOID FACTOR POSITIVE POLYARTHRITIS IN CHILDHOOD 259 Rheumatoid factor positive polyarthritis in childhood \200 This subset of juvenile idiopa thic arthritis (see Chapter 9 for further details of classi \201 cation) is clinically and genetically indistinguishable from adult RA. Approximately 25% of cases have a family hist ory of seropositive RA. The disease usually presents as a polyarthritis ( \201 ve or more joints) of the small joi nts of the hands and feet. In patients who present at 10 years of age or younger, there is often associated early involvement of the wrists, knees, ankles, and hindfeet as well. All other features of adult RA may be seen in children. Fever is rare. \200 The ILAR criteria suggest that three consecutive positive tests for s erum IgM RF should be taken twice over the course of 3 months before the diagnosis is made. That said, in clinical practice, the diagnosis is generally made on the basis of clinical presentation. Children are commonly ACPA-negative, although when present, these antibodies may help con \201 rm the diagnosis. This is because transient positive titers are seen in infection. It is also important to bear in mind that RF is also found in SLE (see Chapter 1 0), vasculitis (see Chapter 15), hypergammaglobulinemia, and sarcoidosis (see Chapter 18). The clinical features may also appear similar to juvenile psoriatic arthropathy (see Chapte r 9). Radiological changes with periostitis and local osteoporosis tend to occur early in the dis ease. One-third of cases progress to severe functional limitation within 10 \200\22315 year s. Differences from adult RA include the problem of growth retardation, a tendency to early fu sion of the carpal bones, and erosions at the distal interphalangeal joints. A few cases of aortic regurgitation and pericarditis have been reported. Pulmonary manifestations of RA are, however, relatively uncommon. In the few cases that have been followed through pregnancy, there appears to be an almost u niversal post-pregnancy relapse of the RA. Treatment of RA in children is much the same as for adults. Early introduction of a DMARD i s encouraged and most centers use as \201 rst-line therapy. MTX is well-tolerated in chil dren. Oral therapy is \201 rst-line, but SQ administration is increasingly used, and has been shown to be effective in those with poor adherence or side-effects to oral treatment. A recent study using le \202 unomide found high rates of clinical improvement, but not as great as with MTX. Cytotoxic agents tend to be spared for use in those with associated amyloidosis, vasculitis, pulmonary \201 brosis, or aortic valve disease in the presence o f active arthritis. Biologic therapy is appropriate for patients with active polyarticular disease who have bee n intolerant of, or not responded to, MTX. This page intentionally left blank 261 Chapter 6 Osteoarthritis (OA) Introduction 262 Clinical features of OA 264 The investigation of OA 266 The management of OA 268 CHAPTER 6 Osteoarthritis (OA) 262 Introduction Epidemiology and pathology \200 Osteoarthritis (OA) is a chronic degenerativ e disorder characterized by cartilage loss; it is the most common condition to affect joint s in humans. It is estimated that 12.1% of the population of the United States >25 years ha ve OA, and the prevalence increases with age. \200 In the elderly in the West, OA is seco nd to cardiovascular disease as a cause of disability. Although there are recognized associations between OA, age, and trauma, advances in cartila ge biochemistry and the recognition of crystal-associated disease have renewed interest in OA as a dynamic condition of cartilage loss (chondropathy) with a periarticular bone reacti on. At present, however, OA is assessed and managed clinically as a structural rather than physiological condition, with an emphasis on late, rather than early, disease. OA is now viewed as a dynamic process with episodic progress. Chondrocyte dysfunction leads to metalloproteinase enzyme release causing collagen and prot eoglycan degradation. Synovial in \202 ammation is present, with production of cytokines s uch as IL-1 and TNF- A that also induce metalloproteinase production. Macroscopic changes in OA include cystic bone degeneration, cartilage loss, and growth of irregular abnormal bone at joint margins (osteophytes). Micro scopic changes include \202 aking and \201 brillation of articular cartilage with varia tions in vascularity and cellularity of subchondral bone, leading to sclerosis and new bone formation. \200 Most surveys of OA rely on radiographic features for de \201 nition and severity. These are problematic because correlation of radiographic change with clinical s tatus, symptoms, and function can be poor; it is best at the hip and knee, but poor in the hand and spine. The correlation between pathology and radiology is shown in Table 6.1. \200 There are various subgroups of OA and these are described below in the section on clinical features. Risk factors \200 Although no gender difference occurs in mild disease, severe disease favors women and patients older than 50 years. There is also a polyarticular form of hand O A \200\224 \200\234nodal generalized OA \200\235 \200\224that has a predilection for perime nopausal women. OA of the hip is more common in Europeans than Asians or African Americans. The Framingham study found that 27% of those aged 63 \200\22370 years had radiographic evid ence of knee OA; this increased to 44% in those over 80 years old. Susceptibility factors include: obesity (close association with knee OA, but not hip) \200 family history (particularly n odal generalized OA) \200 high bone density such as osteopetrosis (there is a negative co rrelation between OA onset and low bone density) trauma INTRODUCTION 263 femoral dysplasia (for hip OA) \200 hypermobility (rigorous studies required, though one recent large study suggests hypermobility is protective against hand OA). \200 There is i ncreased concordance for OA in monozygotic compared to dizygotic twins. Smoking appears to be protective for knee OA. \200 Suggested risk factors for hip OA incl ude previous hip disease (e.g., Perthes \200\231), acetabular dysplasia, avascular necrosis of the femoral head, severe tra uma, generalized OA, and occupation (e.g., farming). \200 There is little evidence to lin k OA with repetitive injury from occupation, except perhaps knee-bending in men. Longshoremen and miners have a higher incidence of knee OA. Table 6.1 Radiographic \200\223pathological correlates in OA Pathological change Radiographic abnormality Cartilage \201 brillation, erosion Localized joint-space narrowing Subchondral new bone Sclerosis Myxoid degeneration Subchondral cysts Trabecular compression Bone collapse/attrition Fragmentation of osteochondral surface Osseous ( \200\234loose \200\235) bodies CHAPTER 6 Osteoarthritis (OA) 264 Clinical features of OA \200 The clinical features of pain and stiffness, functional impa irment, and anatomical change, are interrelated but often discordant. There are several potential mechanisms for pain; none are completely understood. Pain may a rise from in \202 ammatory mediators or intra- articular hypertension, stimulating capsula r, periosteal, and synovial nerve \201 bers. Pain may also arise from enthesopathy or bur sitis that can accompany structural alteration, muscle weakness, and altered joint use. Although stiffness is a common complaint in OA, prolonged early morning stiffness should lead the clinician to consider the presence of an in \202 ammator y arthropathy. Bony enlargement and deformity, crepitus, restricted movement, joint instability, and \200 \234stress \200\235 pain can also occur. Muscle weakness and wasting may be present. There are several subsets of OA that are worth noting. They are not absolute, and one set o f characteristics may dominate the evolving disease at any one time. These subsets are: \200 primary OA: Nodal generalized OA \200 Erosive ( \200\234in \202 ammatory \200\235) OA \200 Large j oint OA (knee and hip) \200 Spinal OA secondary OA (see Table 6.2). Nodal generalized OA \200 This common condition is characterized by: polyarticular \201 nger involvement \200 Heberden \200\231s nodes (distal interphalange al joint) \200 Bouchard \200\231s nodes (proximal interphalangeal joint) \200 predispos ition to OA of knee, hip, and spine \200 good functional outcome in the hands \200 fema le preponderance \200 peak onset around the menopause \200 strong family history. There is a tendency to greater distal joint disease. The \201 rst carpometacarpal (CMC), metacarpophalangeal (MCP), and interphalangeal (IP) joints of the thumb are also often invo lved, as are the index and middle MCP. The more proximal joints of the hand and wrist are otherwise relatively spared. Erosive OA \200 This uncommon condition is characterized by: hand interphalangeal involvement \200 tendency to joint ankylosis \200 \202 orid in \202 ammation (episodic) \200 radiographic subchondral erosive change. CLINICAL FEATURES OF OA 265 Unlike nodal OA, proximal and distal IP joints are equally involved and, less frequently, the MCPs. IP joint instability is common. Given the additional risk of ankylosis, functional impairment is more likely than nodal OA. The principal hallmark of the condition is subchondral erosive change that can lead to remodeling. Large joint OA \200 The knee is commonly affected and most frequently in the patellofemoral and medial tibiofemoral compartments; severe bone and cartilage loss at the latter site causes instability and the classic varus (bow knee) deformity. Subdivision of hip disease is usually made on the basis of local radiographic patterns. There are two principal groups: i. Superior pole: common pattern, of ten unilateral, more common in men, and likely to progress ii. Central (medial): less common, usually bilateral, more common in women, and less likely to progress. Indeterminate \200\234concentric \200\235 radiographic patterns also exist. Secondary OA \200 Secondary OA is seen in association with a wide variety of disorders as illustrated in Table 6.2. Natural history of OA \200 Progression in the knee may take many years. Cohort studies ha ve found that radiographic deterioration occurs in one-third. Progression of hip disease is variable. A Danish study found that 66% of hips worsened radi ologically over 10 years, although symptomatic improvement was common. Hand disease is relapsing and remitting with episodic in \202 ammatory phases associated w ith redness and swelling. Flares then reduce in frequency, and pain also improves. Table 6.2 Secondary causes of OA Trauma In \202 ammatory arthritis Metabolic/endocrine Crystal deposition disease Hemochromatosis Calcium pyrophosphate Acromegaly Uric acid Hyperparathyroidism Hydroxyapatite Ochronosis (alkaptonuria) Neuropathic disorders Anatomical abnormalities Diabetes mellitus Bone dysplasia CHAPTER 6 Osteoarthritis (OA) 266 The investigation of OA \200 OA is a clinical and radiological diagnosis. There are no sp eci \201 c laboratory tests. Joint space narrowing may be dif \201 cult to appreciate in early OA; as the disease progr esses, other \201 ndings may appear, including osteophytes, subchondral bone sclerosis, a nd subchondral cysts. Radiographs correlate poorly with symptoms and clinical function. Many older patients will have radiographic changes consistent with OA, but will be asymptomatic. MRI may be better at identifying early loss of articular cartilage, but this and other imaging modalities have not been well validated for the evaluation of osteoa rthritis. Laboratory tests (including synovial \202 uid analysis) may be useful to exclude other causes of joint pain, such as pseudogout. There are potential markers of tissue destruction and in \202 ammation that may be of use clinically in the future. A pro \201 le of several markers with genetic analysis may in the future provide an individual assessment for disease development and re sponse to therapy. Examples of markers include: \200 cartilage oligomeric matrix protein (COMP) \200 pyridinoline and bone sialoprotein \200 metalloproteinases \200 hylaurona n. This page intentionally left blank CHAPTER 6 Osteoarthritis (OA) 268 The management of OA Successful management Successful management centers on: \200 A good history: symptoms and impact on life \200 functional disability \200 functional requirements \200 patient expectation \200 psychological factors. A good examination: extent of abnormality \200 origin of pain \200 degree of in \202 ammation \200 insta bility of joint \200 muscle condition \200 other medical, soft-tissue, and neurological disease. A multidisciplinary approach. Modalities for management \200 There are several resources that provide speci \201 c gui dance regarding the treatment of osteoarthritis. The Osteoarthritis Research Society International (OARSI) has developed evidence-based expert consensus guidelines regarding the management of osteoa rthritis of the hip and knee (http:// www.oarsi.org). In the United Kingdom, the National I nstitute for Health and Clinical Excellence (NICE) has published evidence-based guidelines for the cost-effective treatment of osteoarthritis (http://www.nice.org.uk/ CG59). Both of these guidelines include a discussion of pharmacologic and non-pharmacologic therapies, and may help with treatment decisions. Exercise is an important intervention, to build muscle strength, encourage weight loss, imp rove endurance and joint proprioception. Advice alone is not as good as a speci \201 c pro gram with follow-up. Evidence-based guidelines for exercise in hip and knee OA have been pu blished. 1 In more marked disease, support splints and walking aids may be necessary. Education has been shown in meta-analyzes to have a signi \201 cant effect on pain and fun ction, but only 20% as effective as NSAID treatment. \200 Topical preparations have minim al systemic absorption, and may help patients avoid cumulative toxicities associated with p olypharmacy. Topical 1% diclofenac gel (2 \200\2234 g every 6 hours) has been FDA approved for the treatment of osteoarthritis, and may be useful for treatment of symptomatic osteoar thritis in the hands and knees. Topical capsaicin (0.025% or 0.075% every 6 \200\2238 hours ) may also provide signi \201 cant pain relief. When topical therapies are not practical or ef \201 cacious, treatment often starts with a cetaminophen. That said, it is only modestly more effective than placebo, and chronic use i s associated with cardiovascular and gastrointestinal toxicity. Unintentional overdose is t he most common cause of liver failure in the United States, and patients must be counseled to avoid other medications that may contain acetaminophen. THE MANAGEMENT OF OA 269 NSAIDs are more effective than acetaminophen. Short-acting NSAIDs, such as ibuprofen (400 m g every 4 \200\2236 hours) are widely available, but patients may \201 nd greater levels of relief with longer acting NSAIDs, such as diclofenac (50 mg every 8 hours), naproxen (50 0 mg every 12 hours), or nabumetone (500 \200\223750 mg every 8 \200\22312 hours); these ma y be of particular use for short periods during disease \202 ares. Long-term use of NSAIDs may be problematic, particularly among the elderly. The selective C OX-2 inhibitors are as ef \201 cacious as standard NSAIDs, but there remains concern over cardiovascular safety; they should be used with caution and avoided in patients with cardio vascular risk factors. Tramadol and duloxetine may also be useful for control of the pain associated with osteoart hritis. Narcotics are associated with a high rate of discontinuation due to side effects. Intra-articular injections of corticosteroids are very useful in treating in \202 ammatory disease \202 ares, and may result in sustained symptom improve ment, although response duration is variable. Many practitioners also add local anesthetic, although there is no clear evidence that this improves the ef \201 cacy of the treatment. Most data are available for knee OA. Infection is rare ( < 1 in 10,000 incidence), but car e should be taken to clean overlying skin, and injection through infected/psoriatic skin sh ould be avoided. Other side effects to warn patients about are skin depigmentation and fat atrophy. It is advised that patients receive no more than 2 or 3 injections per year. The ef \201 cacy of intra-articular injection of hyaluronic acid derivatives (visco-supple mentation) is controversial, although it may provide prolonged relief in some cases. Glucosamine and chondroitin sulfate are found in articular cartilage. Anecdotal evidence su ggests that when given as oral supplements, these agents have an analgesic effect in mild-t o-moderate OA of the knee, but this has been dif \201 cult to demonstrate consistently in controlled trials. There is little evidence for use in OA at other sites. \200 Acupunctur e has been shown in randomized controlled trials to be better than placebo acupuncture in improving symptoms. There is some evidence that avocado/soybean unsaponi \201 able (ASU) supplementation, even ing primrose oil, and omega-3 \201 sh oils improve pain. The clinician should also seek ways to reduce the impact of disability. Options include: 1 \200 occupational therapy: splints, tools, safe environment \200 tre at depression, anxiety, \201 bromyalgia \200 coping strategies \200\224behavioral thera py \200 patient education. For patients with activity-limiting osteoarthritis, joint replacement is effective at reducing pain, although function may not be restored. Arthroscopy and osteo tomy may be helpful in some cases. 1 Roddy E, Zhang W, Dohetry M et al . Evidence-based recommendations for the role of exerci se in the management of osteoarthritis of the hip or knee: the MOVE consensus. Rheumatology 2005; 44: 67 \200\22373. This page intentionally left blank 271