Small cell lung. Can occur up to 2 \200\2233 years after ELMS Autonomic disturbances. EMG + poor response to anticholinesterasedistinguish from MG Oncogenic osteomalacia Generalized. Develops insidiously Small, discrete mesenchymal tumors in bone, soft tissues, and sinuses. Neuro \201 bromatos is Bone pain and bone demineralization. Hypophosphatemia and lowcirculating 1,25 OH vitamin D M A L G N A N C Y I 2 3 1 CHAPTER 4 The spectrum of presentation 232 Nonmyopathic paraneoplastic syndromes The nonmyopathic paraneoplastic syndromes are rare: \200 Hypertrophic pulmonary osteoarthropathy (HPOA) consists of clubbing, periostitis of tubular bones, and an arthropathy (may range from arthralgias to d iffuse polyarthritis). Suspicion of this should prompt a request for an isotope bone scan, which typically shows abnormally increased bone turnover in the long bones. Radiographs oft en show periosteal elevation. HPOA complicates 20% of primary lung tumors, but it is associ ated with other malignancies. Polyarthritis may be the presenting feature of cancer. Most cases occur in those over 60 ye ars old. Unlike RA, the arthritis associated with malignancy tends to be asymmetric, and do es not cause erosions. \200 Eosinophilic fasciitis, severe bilateral palmar fasciitis (of ten mistaken for scleroderma), and fasciitis associated with panniculitis have been associa ted with malignancy. Cases of \200\234shoulder \200\223hand \200\235 syndrome (a form of r e \202 ex sympathetic dystrophy) that have been reported in association with malignancy pr obably re \202 ect similar pathological processes. Rheumatic diseases associated with an increased incidence of malignancy There are a number of rheumatic diseases that are associated with an increased incidence of malignancy compare d with healthy populations. These are dealed with brie \202 y here and in more detail in P art 2 of this book. \200 Non-Hodgkin \200\231s lymphoma is most strongly associated with RA. Myeloma and paraproteinemias are also found in RA patients. The relative risk of colon cancer among RA patients is 0.77; this may be due to the use of chronic NSAIDs in this patient population, which may be protective. Use of cyclophosphamide is associated with an increased risk of lymphoma and bladder cancer. Methotrexate may also be associated with an increased risk of lymphoma. Chronic azathioprine use is associated with an increased risk of skin cancer; patients taki ng azathioprine long term should be counseled about sun protection and monitoring for skin cancer. Non-Hodgkin \200\231s lymphoma develops in a subset of patients with Sj gren \200\231s s yndrome (4%). Its onset may be indicated by rapid enlargement of salivary glands, the appea rance of a paraprotein, or decrease in circulating immunoglobulins or RF titer. Scleroderma has been associated with an increased risk of both lung cancer and non-Hodgkin \200\231s lymphoma. Dermatomyositis is probably associated with malignancy in adults, though convincing evidenc e for an association of polymyositis with malignancy is lacking. Neither is associated with malignancy in children. Part II The clinical features and management of rheumatic diseases 5 Rheumatoid arthritis (RA) 6 Osteoarthritis (OA) 7 The crystal arthropathies 8 The spondyl oarthropathies 9 Juvenile idiopathic arthiritis (JIA) 10 Systemic lupus erythematosus (SLE) 11 The antiphospholipid (antibody) syndrome (APS) 12 Sj gren \200\231s syndrome (SS) 13 S ystemic sclerosis and related disorders 14 Idiopathic in \202 ammatory myopathies \200\224 polymyositis 235 261 271 283 309 329 351 361 373 (PM) and dermatomyositis (DM) 397 417 443 481 499 15 Primary vasculitides 16 Metabolic bone diseases and disorders of collagen 17 Infection a nd rheumatic disease 18 Miscellaneous conditions 19 Common upper limb musculoskeletal lesions 20 Back pain 21 Complementary and alternative medicine in 529 537 rheumatology 553 561 22 Rheumatologic emergencies 235 Chapter 5 Rheumatoid arthritis (RA) Disease criteria and epidemiology 236 Incidence, prevalence, and morbidity 238 The clinical features of rheumatoid arthritis 239 Organ disease in rheumatoid arthritis 240 The evaluat ion and treatment of rheumatoid arthritis 244 Rheumatoid factor positive polyarthritis in c hildhood 259 CHAPTER 5 Rheumatoid arthritis (RA) 236 Disease criteria and epidemiology There is no perfect test for rheumatoid arthritis (RA). T he diagnosis rests on a composite of clinical and laboratory observations. It is a common s ys- temic in \202 ammatory disease characterized by the presence of a destructive polyarth ritis with a predisposition for affecting the small joints of the hands and feet and the wr ists (although it can affect any synovial joint). Disease criteria are often developed for epidemiological work and for classi \201 cation i n the context of clinical trials. Classi \201 cation criteria for RA in particular are dom inated by signs and symptoms from the musculoskeletal system. It is important to remember, however, that there are a number of \200\234extra-articular \200\235 manifestations to the disease, with involvement of, for example, the eyes, lungs, skin, heart, and nervous syste m. The criteria for the diagnosis of RA ranges from the original American Rheumatism Associati on (ARA) scheme of 1958, through the develop- ment of the simpler New York criteria, to the 1987 ARA criteria (see Table 5.1) which replaced the 1958 ARA criteria. These criteria wer e not designed to diagnose patients with RA; in particular, it is often dif \201 cult to a pply these criteria to the diagnosis of \200\234possible, \200\235 \200\234early, \200 \235 or atypical RA. It is most straightforward to apply these criteria in clinical trials aimed at patients with well-established disease. Signi \201 cant evidence, however, indicates that early treatment of rheu- matoid arthriti s greatly improves the long-term outcomes associated with this disease, highlighting the im portance of early diagnosis and therapy. For this reason, in 2010, the American College of Rheumatology (ACR) and the European Leagu e Against Rheumatism (EULAR) developed a revised set of classi \201 cation criteria (see T able 5.2), designed to identify patients with early RA, at the time of initial presentation . Therefore, the new criteria are not interchangeable with the old criteria; using the new criteria, for example, a patient who presents with 6 weeks of bilateral knee swelling or te nderness, in the setting of a high-positive rheumatoid factor and abnormal ESR, would be cl assi \201 ed as having rheumatoid arthritis by the 2010 criteria, but not the 1987 criteri a. DISEASE CRITERIA AND EPIDEMIOLOGY 237 Table 5.1 The 1987 American College of Rheumatology criteria for the diagnosis of rheumatoi d arthritis Criterion Comments 1 Morning stiffness Duration >1 hour lasting >6 weeks 2 Arthritis of at least three joints* Soft tissue swelling/exudation lasting >6 weeks 3 Arthritis of hand joints Wrists, MCPs, or PIPs lasting >6 weeks 4 Symmetrical arthritis At least one area, lasting >6 weeks 5 Rheumatoid nodules 6 Positive rheumatoid factor 7 Radiographic changes Erosions, particularly wrists, hands,and feet At least four criteria must be ful \201 lled and there are no exclusion criteria. * Possib le areas: metacarpophalangeal joints (MCP), proximal interphalangeal joints (PIP), wrist, e lbow, knee, ankle, metatarsophalangeal joints (MTP). Table 5.2 The 2010 American College of Rheumatology/European League Against Rheumatism crit eria for rheumatoid arthritis Criterion Score 2 \200\22310 large joints 1 Joint Involvement* 1 \200\2233 small joints 2 4 \200\22310 small joints 3 >10 joints 5 Serology \200 Low-positive RF or ACPA 2 High-positive RF or ACPA 3 Acute phase reactants Abnormal CRP or ESR 1 Symptom duration (cid:2) 6 weeks 1 For a de \201 nite diagnosis of rheumatoid arthritis, a total score of (cid:3)(cid:4) 6 is required, including at least one point from each of the \201 rst three categories. In pa tients with long-standing or inactive disease, it is adequate if the patient would have ful \201 lled these criteria at some point in the past. * Large joints include the shoulders, elbows, hips, knees, and ankles. Small joints includes the metacarpophalangeal joints, pro ximal interphalangeal joints, second to \201 fth metatarsophalangeal joints, thumb interp halangeal joints, and wrists. The distal interphalangeal joints, \201 rst carpometacarpal joints, and \201 rst metatarsophalangeal joints are excluded from this assessment. \200 RF, rheumatoid factor; ACPA, anti-citrullinated protein antibody, including anti-cyclic c itrullinated peptide antibody (CCP) CHAPTER 5 Rheumatoid arthritis (RA) 238 Incidence, prevalence, and morbidity \200 The disease has a worldwide prevalence, and has been identi \201 ed in all populations that have been examined. Figures for prevalence range from 0.2 to 5.3%, but the age distribution in developing countries may be a confounding factor and perhaps contr ibutes to low \201 gures in, for example, some parts of Africa. Population studies on the incidence of the disease suggest \201 gures of 3.4/10 000 in wo men and 1.4/10 000 in men. The incidence in men declines with age from age 45. In women, it increases until age 45, then plateaus and falls after the age of 75. RA is extremely heterogeneous with regard to severity and progression. Permanent remission can occur but is rare once joint damage has started. A dis tinction is sometimes made between cyclical disease and relentless progression, but in prac tice it is perhaps more useful to consider widespread versus limited chronic joint involvem ent. Without adequate treatment, life expectancy is reduced by approximately 7 years in men and 3 years in women. This is mainly due to cardiovascular dis ease, infections, respiratory disease, and RA itself. THE CLINICAL FEATURES OF RHEUMATOID ARTHRITIS 239 The clinical features of rheumatoid arthritis \200 A typical onset of insidious pain, sti ffness, and symmetrical swelling of small joints is only one of several presenting patterns . Up to one-third of patients may have a subacute onset with symptoms of fatigue, malaise, weight loss, myalgias, morning stiffness, and joint pain without overt signs of swelling or radiological evidence of joint erosions. Traditionally, rheumatoid arthritis is described as a symmetric synovitis of the small join ts of the hands, wrists, and feet (sparing the distal interphalangeal joints. Symmetry, how ever, develops later in the disease course, and one should not wait for symmetry to develop prior to initiating therapy. A mono- or bilateral arthropathy of the shoulder or wrist, fo r example, may account for up to 30 \200\22340% of initial presentations; 5% of initial pre sentations involve the knee. Any synovial joint can become involved in RA. The hands, wrists, elbows, shoulders, and knees are involved most commonly, followed by the hip and temporoman dibular joints. RA also affects the clavicular joints and the cricoarytenoid. Atlantoaxial (C1-C2) subluxation is a known complication of RA, and may present with pain r adiating towards the occiput, spastic quadriparesis, or sensory \201 ndings. Such patient s are at high risk of progression, and patients with evidence of cord compression require i mmediate surgical stabilization. Patients may also present with a tenosynovitis or bursitis. The diagnosis and management of these conditions is covered in Chapter 2 of this book. \200\234Classic \200\235 features of RA, such as \200\234swan neck \200\235 and \200\234 boutonniere \200\235 deformity of the digits appear late in disease and are features of chr onic disease; they are not usually seen at initial presentation where signs of synovitis an d joint damage may be subtle. Though often suspected, there is no absolute evidence that stress, whether physical or psychological, triggers the disease. Pregnancy has a bene \201 cial effect on RA in some women, especially during the last trim ester. Arthritic symptoms usually return within 1 \200\2232 months postpartum and may be mo re severe than prior disease. Lactation has no effect and there is no evidence that RA pati ents have more medical complications during pregnancy per se. Therapeutics and pregnancy ar e discussed later in this chapter. CHAPTER 5 Rheumatoid arthritis (RA) 240 Organ disease in rheumatoid arthritis (see Table 5.2) Lymph nodes Lymph nodes are often enl arged but rarely palpable. In a few cases RA may present with widespread nodes mimicking Ho dgkin \200\231s disease. Pulmonary disease \200 Pleuritis (like pericarditis) is frequent but often mild. Like oth er pulmonary and cardiac manifestations, it is more common in older men. Pleural effusions may also occur. Rheumatoid pulmonary nodules are usually an asymptomatic \201 nding in seropositive RA. R adiographically they are coin-shaped lesions that can be dif \201 cult to distinguish from malignancy. In patients in whom malignancy is clinically suspected, further imaging or tis sue biopsy may be required. Diffuse interstitial \201 brosis and \201 brosing alveolitis are rare associations. Met hotrexate may be associated with the development of \201 brosis, although this is controv ersial. Cardiovascular system There is increasing evidence that patients with RA suffer from increa sed cardiovascular disease, independent of the traditional risk factors. In \202 ammation is thought to play an important part in the development of atherosclerosis and the systemic in \202 ammatory response in RA may explain the link. Epidemiological studies show that c ardiovascular mortal- ity is increased in patients with early and established disease and i s worse in women, a group traditionally at lower risk. Standardized mortality ratios for ca rdiovascular disease in men are approximately 1.3 and 1.9 in women. Skin \200 Rheumatoid nodules occur in up to 30% of patients, and are found principally on the extensor surface of the forearm, Achilles tendon, and over pressure areas throughout t he skin. Nodules are not speci \201 c for RA but are useful in diagnosis and prognosis, co rrelating with seropositivity, disease activity, and progression. The differential diagnosi s includes tophaceous gout. Leukocytoclastic vasculitis also occurs and is seen as palpable purpura; most often this resolves spontaneously. Rheumatoid vasculitis can lead to large ulcerations on the lower extremities, although this is an uncommon manifestation. Ocular involvement \200 Rheumatoid vasculitis gives rise to a severe form of painful scle ritis, leading to scleromalacia. Episcleritis is typically benign and resolves spontaneously. Uveitis and conjunctivitis are not associated with RA. ORGAN DISEASE IN RHEUMATOID ARTHRITIS 241 Table 5.3 Some organ disease in rheumatoid arthritis Organ Manifestation Frequency (%) Lymph nodes Enlargement >50 Spleen Enlargement 25 Felty \200\231s syndrome <1 Lungs Pleuritis >30 Nodules 5 Fibrosis Rare Heart Pericarditis >10 Myocarditis >5 Nodules 5 Cardiovascular disease(RA is an independent risk factor) Standardized mortality ratio: 4 7 1.3 5 7 1.9 Muscle Atrophy Common Myositis Rare Bone Osteoporosis Common Skin Nodules >20 Vasculitis 1 Eyes Sicca syndrome 10 Scleritis 1 Nodules <2 Nervous system Nerve entrapment Common Mononeuritis multiplex <1 Cord compression Rare Neurological involvement \200 Entrapment neuropathy secondary to synovitis is common. Med ian nerve compression can occur early in the disease. Other rarer examples included the uln ar nerve at the elbow, and the posterior tibial nerve at the tarsal tunnel. Mononeuritis multiplex, a peripheral and occasionally bilateral neuropathy causing a \200\234wrist drop \200\235 or \200\234foot drop \200\235, can prese nt acutely. A sudden onset of motor neuropathy can signal the presence of aggressive vascul itis and poor prognosis. Rheumatoid vasculitis classically occurs in patients with with high titer RF and a history of erosive arthritis. Cervical subluxation at the atlantoaxial level is present in one-third of RA patients but i s usually asymptomatic. Subluxation at lower levels is rare, but is more likely to cause pa in and neurological symptoms. CHAPTER 5 Rheumatoid arthritis (RA) 242 Cervical myelopathy due to cervical instability can be fatal. Symptoms include paresthesias , weakness, paralysis, sensory loss, incontinence, and syncope. Patients with gait dysfunction or clumsiness of the hands should be evaluated promptly for cervical myelopathy; most patients will not present with neck pain. Patients at risk for cervical myelopathy should be instructed to avoid prolonged cervical e xtension. Hairdressers should be instructed to allow the patient to face the sink when havi ng hair washed. Anesthesiologists should be informed regarding this concern as well. Fractures \200 Cytokines, generated in in \202 ammation, encourage bone resorption by osteoclast induction leading to periarticular osteoporosis. Inactivity, nutritional de \201 ciency, glucocorticoids, and pre-existing osteoporosis constitute additional risk factors for vertebral fractures. Tendons and ligaments Spontaneous rupture is common, most often at the wrist, hand, and rot a- tor cuff. More often, tenosynovitis and weakening of ligaments leads to joint instabilit y and subluxation. Acute inability to raise the fourth and \201 fth digits may be seen wi th rupture of the extensor tendons due to wrist disease, and may be surgically corrected. Infection There is anecdotal evidence that infections may trigger \202 ares in RA. More i mportantly, RA patients are more susceptible to septic arthritis, often compounded by the u se of immunosuppressive drugs, including steroids (see later in this chapter). In such a si tuation, the usual signs of sepsis may be absent, delaying the diagnosis. Secondary amyloidosis Renal involvement is the most common type of organ failure, though th e skin, liver, and GI tract are often affected. Intensive antirheumatic therapy now gives a more favorable outlook, with 80% 5-year survival rates. Felty \200\231s syndrome This is the association of splenomegaly and neutropenia with serop ositive RA. Systemic disease, hepatomegaly, and lymphadenopathy are also com- mon. In uncom plicated cases, treatment should be conservative, splenec- tomy remaining controversial and often only transient in effect. Large granular lymphocyte (LGL) syndrome Like Felty \200\231s syndrome, LGL syndrome is ass ociated with neutropenia and splenomegaly. LGL syndrome is differentiated from Felty \200 \231s syndrome by the presence large granular lymphocytes and a clonal lymphocytosis. Clona lity can be demonstrated through PCR of the T-cell receptor-gamma gene. The arthritis that accompanies LGL syndrome is typically less destructive than that seen with Felty \200\231s syndrome, although this is not always the case. This page intentionally left blank CHAPTER 5 Rheumatoid arthritis (RA) 244 The evaluation and treatment of rheumatoid arthritis \200 A clearly documented assessment is invaluable for the ongoing monitoring of the disease and treatment (see Table 5.3). The ESR and CRP are useful measures periodically in the assessment of disease activity, and hematological and biochemical parameters will not only expose underlying organ disease but are also important in the regular monitoring of a number of drug treatments. That said, it is important to note that many patients can have active synovitis without elevation in acu te phase reactants. Early erosive changes on plain radiographs of the hands and feet can be of great value in t he assessment of patients with minimal clinical signs. The presence of typical erosions con \201 rms the diagnosis of RA, and merits aggressive treatment with DMARDs. IgM rheumatoid factor (RF) is of value in establishing the diagnosis, however, a low positive result can be misleading and a negative result should not alter a d iagnosis made on clinical grounds. Only 70 \200\22380% of patients with RA will be RF posit ive. RF is also found in association with other diseases, including hepatitis, monoclonal gammopathy, malignancy, tuberculosis, and syphilis. \200 Anti-citrullinated pr otein antibodies (ACPA), including anticyclic citrullinated peptide (anti-CCP) antibodies are important markers for diagnosis and prognos is in RA. In both early and established disease, ACPA are more sensitive and more speci \201 c than RF. ACPA antibodies may be detected in roughly 50 \200\22360% of patients with early RA, and have a speci \201 city for RA >99%. They are also a marker of erosive diseas e and may predict the development of RA in patients with nonspeci \201 c in \202 ammatory symptoms. RF and ACPA measurements are not re-tested routinely, although repeat testing may be useful in patients whose initial test results are negative, but whose examination is strongly sug gestive of RA, since patients with seropositive RA require more aggressive treatment. \200 The ultimate goal is complete remission of disease; the standard of care is to \200\234t reat to target \200\235 of remission (or low disease activity). \200 Patient reported out comes may be more responsive than other measures in detecting disease activity. The management of RA requires a multidisciplinary approach. Working with physical therapist s, occupational therapists, podiatrists, social services, and surgeons is an important part of management (see Table 5.4). Disease activity assessment \200 The current approach to the management of RA advocates f or \200\234treatment to target \200\235. Patients should be evaluated (and medications adjust ed) monthly until remission (i.e., the absence of synovitis) or low disease activity is ach ieved. THE EVALUATION AND TREATMENT OF RHEUMATOID ARTHRITIS 245 Table 5.4 Comparison of clinical composite indices of disease activity for rheumatoid arthr itis. DAS DAS28 SDAI CDAI RAPID3 >3.7 >5.1 >26 >22 >12 High disease activity Moderate disease activity 2.4 \200\2233.7 3.2 \200\2235.1 11.1 \200\22326 10.1 \200\22322 6.1 \200\22312.0 Low disease activity 1.6 \200\2232.4 2.6 \200\2233.2 3.3 \200\22311 2.8 \200\22310 3.1 \200\2236.0 Remission <1.6 <2.6 <3.3 <2.8 0 \200\2233.0 Key to this goal is the routine use of a validated measure of disease activity, which allows the clinician to compare disease activity between visits and assess response to therapy objectively. Disease activity may be quanti \201 ed using clinical composite indices (e.g., DAS, DAS-28 , SDAI, CDAI), patient-reported outcome measures (e.g., Health Assessment Questionnaire (HA Q), Routine Assessment of Patient Index Data (RAPID)), or imaging (e.g., radiographs, ultra sound, MRI). The Disease Activity Score (DAS) is a composite score using the Ritchie Articular Index (0 \200\22378), a swollen joint count (0 \200\22344 joints), ESR, and patient global assessmen t of disease activity using a 100 mm visual analog scale. The DAS has been used in clinical trials to assess response to treatment, but is cumbersome. It provides a score from 1 \200 \22310: DAS = 0.(cid:5) 4 (Ritchie Articular Index) + (cid:6).06 (number of swollen joints) + 0.33 ln(ESR) + 0.007 Global assessment (in mm) The DAS28 is calculated by surveying 28 joints (knees + upper extremities). The DAS28 provi des a score from 0.49 \200\2239.07: DAS28 = 0.(cid:5) 6 (number tender joints) + (cid:6).28 (number of swollen joints) + 0.70 ln(ESR) + 0.014 Global assessment (in mm) \200 The DAS-28 CRP uses the CRP in place of the ESR: DAS28 = 0.(cid:5) 6 (number ten der joints) + (cid:6).28 (number of swollen joints) + 0.36 ln(CRP+1) + 0.014 Global assessment (in m m) + 0.96 The Simpli \201 ed Disease Activity Index (SDAI) is calculated by surveying the same 28 jo ints used in the DAS28. The SDAI provides a score from 0.1 to 86.0: SDAI=(number of tender joints) + (number of swollen joints) + CRP (mg/dL) +(patient global health on 10 cm VAS) + (evaluator global health on 10 cm VAS ) CHAPTER 5 Rheumatoid arthritis (RA) 246 The Clinical Disease Activity Index (CDAI) is calculated by without the use of lab data. The CDAI provides a score from 0 to 76.0: CDAI = (number of tender joints) + (number of swollen joints) + (patient global health on 10 cm VAS) + (evaluator global health on 10 cm VAS) The RAPID3 is an example of a patient-reported outcome measure that correlates with disease activity. It is derived from the MDHAQ, which was designed to facilitate clinic visits. Th e RAPID3 uses only 3 parts of the MDHAQ: patient self-assessed physical function, patient p ain assessment, and patient global assessment. Even in the absence of physician input or la boratory tests, the RAPID3 correlates with the DAS and CD28, and can be completed more quic kly than any of the preceding indices. Fig. 5.1. RAPID3 Questionnaire. Used with permission of Ted Pincus THE EVALUATION AND TREATMENT OF RHEUMATOID ARTHRITIS 247 Table 5.5 Documenting the initial evaluation of RA 1 The duration of morning stiffness The degree of pain Fatigue Function (utilizing a score system such as Health Assessment Questionnaire \200\224HAQ) Patient global assessment of disease activity 2 The distribution and number of painful joints, and the distribution and number of swollen j oints, including periodicity The distribution and nature of mechanical joint disease noting loss of function, instabilit y, and modifying factors The presence or absence of extra-articular disease 3 Radiographs of affected joints looking for erosive disease and mechanical damage 4 Laboratory tests ESR and CRP CBC Renal and liver function tests Urinalysis Rheumatoid factor Anti-citrullinated peptide antibodies (ACPA) Which drugs, when, and what to monitor? (see Table 5.5) Nonsteroidal anti-in \202 ammatory drugs (NSAIDs) \200 Most patients will either periodically or continuously be taking NSAIDs. These agents offer reliable, even if sometimes limited, relief of pain, swelling, a nd stiffness, improving quality of life in the majority of cases. These drugs do not, howev er, alter the natural history of RA. Adverse effects are, however, common and sometimes lif e-threatening; careful monitoring and patient education are essential. Combinations of NSAI Ds should be avoided. Selective COX-2 NSAIDs are of similar ef \201 cacy to diclofenac or naproxen, and may be of value in patients intolerant of NSAIDs. Many agents in this class, however, have been withdrawn from the market due to concerns regarding COX-2 inhibitors and increased risk of myocardial infarction. Of concern is a study showing that even standard NSAIDs such as ibuprofen and diclofenac are also associated with an increased risk of myocardial infarctio n. It is therefore vital that these drugs are used appropriately and avoided for long-term use in patients with adverse cardiovascular or GI risk pro \201 les (see Table 5.6). Furth er research is needed in this area. CHAPTER 5 Rheumatoid arthritis (RA) 248 Table 5.6 The main components in the treatment of RA Modality Examples Education and counseling Specialist registered nurse or nurse practitioner Self-care groups National organizations Physical therapy Exercise Joint protection Occupational therapy Adaptation Aids Splints Podiatry Orthotics Surgical shoes Medication Pain control Disease control Nonmedical pain management Transcutaneous nerve stimulation Acupuncture Psychotherapy Surgery Surgery Joint replacement Arthrodesis Tendon release/repair Glucocorticoids \200 IM and oral steroids are very effective in active RA, reducing activ e disease in an acute crisis or while waiting for a DMARD to take effect. Many patients are o ften on a combination of NSAID and DMARD with intermittent doses of systemic steroid. Local steroid injections are of value in symptom control both early in the disease and in a n acute \202 are. The effect on joint recovery may be dramatic but short lived, with litt le impact on the overall process of RA, and should not be repeated any more than once every 3 months. It is sometimes of value to combine injections with a joint \200\234washout \200\235 in refractory cases. There is no evidence to suggest an increased risk of joint in fection, as long as aseptic technique is used. High-dose systemic administration may reduce overall disease activity in the short-term but adverse effects preclude its uninhibited use and it is best preserved for refractory RA an d severe extra-articular complications. There have been reports linking glucocorticoid therapy to fetal congenital malformations, a nd there is little data on lactation. THE EVALUATION AND TREATMENT OF RHEUMATOID ARTHRITIS 249 Prednisone, dexamethasone, and betamethasone appear to be safe, but should be used only whe n necessary. Long-term use of glucocorticoids may be associated with a wide range of consequences, including cataracts, premature coronary artery disease, accelerated osteop orosis, muscle atrophy, and increased risk of avascular necrosis. Risks of infection associated with use of low dose glucocorticoids may be as great as the risks associated with anti-TNF therapy. Disease-modifying antirheumatic drugs (DMARDs) \200 All patients with active disease shou ld be offered a DMARD early. The rationale is to prevent or reduce joint destruction. Evide nce from systematic reviews suggest that early introduction of DMARDs decrease pain, swelli ng, and joint damage, and improves the likelihood of achieving remission. Guidelines now recommend that the majority of patients with newly diagnosed RA should be st arted on DMARD therapy within 3 months of diagnosis. However, ef \201 cacy is unpredictabl e and variable in duration. Toxicity is an important concern and this should always be discussed with patients. These agents are also slow-acting, sometimes taking up to 6 \200\2239 months to have maxima l effect (although treatment decisions based on ef \201 cacy can generally be made in 3 \200\2234 months). The \201 nal choice of DMARD is in \202 uenced by a number of factors including, patient compliance, convenience of administration, severity of disease, presenc e of other medical conditions, pregnancy, monitoring requirements and frequency, and nature of adverse events. Both the American College of Rheumatology and EULAR have published recommendations regardin g the appropriate use of DMARDs for the treatment of RA. 1 , 2 Sulfasalazine and hydroxychloroquine \200 Sulfasalazine (SSZ 1.0 \200\2231.5 g po bid) an d hydroxychloroquine (HCQ 400 mg po qd) are sometimes used initially in RA, partly because of their relative safety and convenience. Both agents are generally well- tolerated and tak e effect within 1 \200\2233 months. Many clinicians would now, however, choose methotrexate \201 rst if there is evidence of early aggressive disease. Retinal toxicity and maculopathy with HCQ are rare. The risk increases with abnormal liver or kidney function, after a cumulative dose of 800 g, and in patients aged 70 years and over. The eyes should be checked formally by an ophthalmologist yearly and the patient informed to report any visual disturbances. 1 Singh JA et al . 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheuma- toid arthritis. Arthritis Care Res 2012: 64 : 625 \200\223639. 2 Smolen JS, et a l. EULAR recommendations for the management off rheumatoid arthritis with syn- thetic and b iological disease-modifying antirheumatic drugs. Ann Rheum Dis 2010; 69 : 964 \200\223976. 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